U.S. patent application number 14/932724 was filed with the patent office on 2016-02-25 for process for producing an aminopropyne or enaminone.
The applicant listed for this patent is Agency for Science, Technology and Research. Invention is credited to Zhewang Lin, Dingyi Yu, Yugen Zhang.
Application Number | 20160052863 14/932724 |
Document ID | / |
Family ID | 47437297 |
Filed Date | 2016-02-25 |
United States Patent
Application |
20160052863 |
Kind Code |
A1 |
Zhang; Yugen ; et
al. |
February 25, 2016 |
PROCESS FOR PRODUCING AN AMINOPROPYNE OR ENAMINONE
Abstract
There is provided a process for producing an aminopropyne or an
enaminone comprising the step of reacting a metal acetylide, an
amine and a carbonyl-containing compound in the presence of a
transition metal catalyst. There is also provided a process for
producing an aminopropyne comprising the step of reacting a metal
acetylide, an amine and a halide-containing compound in the
presence of a transition metal catalyst at a reaction temperature
of 50.degree. C. to 150.degree. C. There are also provided
processes to further synthesize the aminopropyne produced to obtain
a butyneamine, another aminopropyne or a triazol.
Inventors: |
Zhang; Yugen; (Singapore,
SG) ; Yu; Dingyi; (Singapore, SG) ; Lin;
Zhewang; (Singapore, SG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Agency for Science, Technology and Research |
Singapore |
|
SG |
|
|
Family ID: |
47437297 |
Appl. No.: |
14/932724 |
Filed: |
November 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14131083 |
Jan 6, 2014 |
9193668 |
|
|
PCT/SG2012/000240 |
Jul 6, 2012 |
|
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14932724 |
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Current U.S.
Class: |
544/178 ;
548/579; 564/384; 564/484 |
Current CPC
Class: |
C07C 209/66 20130101;
C07C 209/66 20130101; C07C 253/30 20130101; C07C 213/08 20130101;
C07C 209/66 20130101; C07D 295/023 20130101; C07C 213/08 20130101;
C07C 217/58 20130101; C07C 211/29 20130101; C07C 255/58 20130101;
C07C 211/27 20130101; C07C 253/30 20130101; C07D 249/04 20130101;
C07C 209/78 20130101; C07D 295/03 20130101; C07C 211/35 20130101;
C07D 249/06 20130101; C07C 209/66 20130101; C07B 37/02 20130101;
C07D 207/04 20130101 |
International
Class: |
C07C 209/66 20060101
C07C209/66; C07D 207/04 20060101 C07D207/04; C07D 295/03 20060101
C07D295/03 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 6, 2011 |
SG |
201104950-9 |
Claims
1. A process for producing an aminopropyne comprising the step of
reacting a metal acetylide, an amine and a halide-containing
compound in the presence of a transition metal catalyst at a
reaction temperature of 50.degree. C. to 150.degree. C.
2. The process as claimed in claim 1, wherein said
halide-containing compound is C.sub.1-5-haloalkane.
Description
PRIORITY CLAIM TO RELATED APPLICATIONS
[0001] This application is a divisional application of and claims
the benefit of priority to U.S. patent application Ser. No.
14/131,083, filed on Jan. 6, 2014, which is a U.S. national stage
application under 35 U.S.C. .sctn.371 of PCT/SG2012/000240, filed
Jul. 6, 2012, and published as WO 2013/006143 A1 on Jan. 10, 2013,
which claims priority to Singapore Application No. 201104950-9,
filed Jul. 6, 2011, which applications and publication are
incorporated by reference as if reproduced herein and made a part
hereof in their entirety, and the benefit of priority of each of
which is claimed herein.
TECHNICAL FIELD
[0002] The present invention generally relates to a three component
coupling reaction to produce aminopropynes. The present invention
also relates to a three component coupling reaction to produce
enaminones.
BACKGROUND
[0003] Proparglyamines are frequent skeletons and
synthetically-versatile key intermediates for the preparation of
many nitrogen-containing biologically active compounds. In recent
years, the most useful methods for synthesis of aminopropynes
include using very sensitive Grignard reagent HCCMgBr and metal
catalyzed propargylic substitution reactions with propargylic
acetates, propargylic alcohols and propargylic halides. However,
the organic alkynes used in aldehyde, alkyne and amine coupling or
alkyne, halide and amine coupling processes are generally limited
to substituted terminal alkynes, and when used, produce
proparglyamines with internal alkynes which tend to limit many
further important applications of functionalized alkynes.
[0004] Enaminones as synthetic chemical-intermediates have received
considerable attention in recent years. This is attributed to their
pronounced versatility in having the ability to participate as both
electrophiles and nucleophiles in chemical reactions. While the
earlier uses of enaminones were limited to serving as synthetic
intermediates in organic synthesis, recent exploration for the
various applications of enaminones in the valuable development of
pharmaceutical products has made impressive progress.
[0005] A wide range of methods have been established to develop
enaminones. Namely, these methods include condensation or addition
reactions, the cleaving of heterocycles and the acylation of
enaminones.
[0006] The most commonly-utilized method for the synthesis of
enaminones involves the reaction between ammonia or a primary or
secondary amine and a 1, 3-diketone or 3-keto-ester. Occasionally
this strategy can fail, for example, in the use of weak bases like
those of o- or p-nitroaniline.
[0007] Generally, the preceding described methods to developing
enaminones or proparglyamines either require highly-specific
starting materials or relatively non-facile reactive conditions to
facilitate the obtainment of either the desired enaminones or
proparglyamines. Furthermore, in many instances, the final product
yield of enaminones or proparglyamines may not be satisfactory.
[0008] There is a need to provide a process for producing an
aminopropyne (or propargylamine) that overcomes, or at least
ameliorates, one or more of the disadvantages described above.
[0009] There is also a need to provide a process for producing an
enaminone.
SUMMARY
[0010] According to a first aspect, there is provided a process for
producing an aminopropyne comprising the step of reacting a metal
acetylide, an amine and a carbonyl-containing compound in the
presence of a transition metal catalyst.
[0011] Advantageously, due to the use of the metal acetylide such
as calcium carbide, the produced aminopropyne may have a terminal
alkyne functional group, as opposed to having the alkyne functional
group within the internal structure of the aminopropyne. The
terminal alkyne functional group can be used as a nucleophilic
carbon source via C--H activation.
[0012] More advantageously, the use of the metal acetylide such as
calcium carbide may avoid the disadvantages of the prior art such
as numerous protection and de-protection steps. Accordingly, the
disclosed process may greatly reduce the number of steps in the
synthesis of aminopropynes. Here, the disclosed process may form
the aminopropyne in a single step.
[0013] According to a second aspect, there is provided a process
for producing an aminopropyne comprising the step of reacting a
metal acetylide, an amine and a halide-containing compound in the
presence of a transition metal catalyst at a reaction temperature
of 50.degree. C. to 150.degree. C.
[0014] According to a third aspect, there is provided a process for
producing a butyneamine comprising the steps of:
[0015] (a) reacting a metal acetylide, an amine and a
carbonyl-containing compound in the presence of a transition metal
catalyst to form an aminopropyne intermediate compound; and
[0016] (b) adding a C.sub.1-5-haloalkane to said aminopropyne
intermediate compound of step (a) to produce said acetylamine.
[0017] According to a fourth aspect, there is provided a process
for producing an aminopropyne comprising the steps of:
[0018] (a) reacting a metal acetylide, an amine and a
carbonyl-containing compound in the presence of a transition metal
catalyst to form an aminopropyne intermediate compound; and
[0019] (b) adding a mixture of halobenzene, palladium acetate and
triphenylphosphine to said aminopropyne intermediate compound of
step (a) to produce said aminopropyne.
[0020] According to a fifth aspect, there is provided a process for
producing a triazole comprising the steps of:
[0021] (a) reacting a metal acetylide, an amine and a
carbonyl-containing compound in the presence of a transition metal
catalyst to form an aminopropyne intermediate compound; and
[0022] (b) adding sodium azide and any one of an aryl substituted
with a halo group or a halo-C.sub.1-5-alkane to said aminopropyne
intermediate compound of step (a) to produce said triazole.
[0023] Advantageously, the disclosed process enables the
butyneamine, aminopropyne and triazole to be made in a single step
(ie "one-pot" manufacturing step), without additional steps such as
a solvent removal step.
[0024] According to a sixth aspect, there is provided a process for
producing an enaminone comprising the step of reacting a metal
acetylide, an amine and an aldehyde in the presence of a transition
metal catalyst.
[0025] Definitions
[0026] The following words and terms used herein shall have the
meaning indicated:
[0027] The term `alkyl` is to be interpreted broadly to refer to an
alkyl radical having 1 to 5 carbon atoms. The alkyl radical may be
linear or branched. The alkyl radical may be unsubstituted or may
be substituted with an aryl or a halide.
[0028] The term `alkyne` is to be interpreted broadly to refer to a
functional group having the structure R--C.dbd.C--H.
[0029] The term `aryl` is to be interpreted broadly to refer to an
aromatic hydrocarbon radical. The aryl may be unsubstituted or
substituted with at least one of halide, nitrile,
C.sub.1-5-alkoxide, nitro and halo-C.sub.1-5-alkyl. The term `aryl`
may include phenyl, monosubstituted phenyl or disubstituted
phenyl.
[0030] The term `halide` and related term `halo` are to be
interpreted broadly to refer to bromide, iodide, chloride and
fluoride.
[0031] The term `nitrile` is to be interpreted broadly to refer
refers to a radical having the structure --C.dbd.N.
[0032] The term `alkoxide` is to be interpreted broadly to refer to
a radical having the structure alkyl-O. The alkoxide may have 1 to
5 carbon atoms.
[0033] The term `cyclic` is to be interpreted broadly to refer to a
group having a non-aromatic ring structure. The cyclic group may
have 3 to 6 ring atoms.
[0034] The term `amine` is to be interpreted broadly to refer to a
radical containing the NH functional group. The amine may be an
aliphatic secondary amine, a cyclic secondary amine or may be a
heterocyclic secondary amine. The heterocyclic secondary amine may
have 5 to 6 ring atoms where the amine group is part of the ring
structure. The heterocyclic secondary amine may have oxygen as one
ring atom while the rest of the ring atoms (excluding the N ring
atom) is carbon or all of the ring atoms (excluding the N ring
atom) is carbon.
[0035] The term `carbonyl-containing compound` is to be interpreted
broadly to refer to a radical having the C.dbd.O group. The
carbonyl-containing compound may be an aldehyde or a ketone.
[0036] The term `nitro` is to be interpreted broadly to refer to a
radical of the structure --NO.sub.2.
[0037] The word `substantially` does not exclude `completely` e.g.
a composition which is `substantially free` from Y may be
completely free from Y. Where necessary, the word `substantially`
may be omitted from the definition of the invention.
[0038] Unless specified otherwise, the terms `comprising` and
`comprise`, and grammatical variants thereof, are intended to
represent `open` or `inclusive` language such that they include
recited elements but also permit inclusion of additional, unrecited
elements.
[0039] As used herein, the term `about`, in the context of
concentrations of components of the formulations, typically means
+/-5% of the stated value, more typically +/-4% of the stated
value, more typically +/-3% of the stated value, more typically,
+/-2% of the stated value, even more typically +/-1% of the stated
value, and even more typically +/-0.5% of the stated value.
[0040] Throughout this disclosure, certain embodiments may be
disclosed in a range format. It should be understood that the
description in range format is merely for convenience and brevity
and should not be construed as an inflexible limitation on the
scope of the disclosed ranges. Accordingly, the description of a
range should be considered to have specifically disclosed all the
possible sub-ranges as well as individual numerical values within
that range. For example, description of a range such as from 1 to 6
should be considered to have specifically disclosed sub-ranges such
as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6,
from 3 to 6 etc., as well as individual numbers within that range,
for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the
breadth of the range.
[0041] Certain embodiments may also be described broadly and
generically herein. Each of the narrower species and subgeneric
groupings falling within the generic disclosure also form part of
the disclosure. This includes the generic description of the
embodiments with a proviso or negative limitation removing any
subject matter from the genus, regardless of whether or not the
excised material is specifically recited herein.
DETAILED DISCLOSURE OF EMBODIMENTS
[0042] Exemplary, non-limiting embodiments of a process for
producing an aminopropyne will now be disclosed.
[0043] The process may comprise the step of reacting a metal
acetylide, an amine and a carbonyl-containing compound in the
presence of a transition metal catalyst.
[0044] The process may comprise the step of reacting a metal
acetylide, an amine and a halide-containing compound in the
presence of a transition metal catalyst. This process may be
undertaken at a reaction temperature of about 70.degree. C. to
about 90.degree. C.
[0045] The process may result in the production of an aminopropyne
with a terminal alkyne group. Hence, the presence of the terminal
alkyne group may allow the aminopropyne to be used as a
nucleophilic carbon source via C--H activation.
[0046] The metal acetylide may have the structure MC.sub.2 (that
is, M--C.dbd.C), where M is a metal selected from the group
consisting of an alkali metal, an alkaline earth metal and a
transition metal. M may be selected from lithium, calcium or
lanthanium and hence the metal carbide salt may be selected from
the group consisting of calcium carbide (CaC.sub.2), lithium
acetylide (Li.sub.2C.sub.2) and lanthanium acetylide
(LaC.sub.2).
[0047] The transition metal catalyst may be a transition metal
salt. The transition metal may be selected from Group IB of the
Periodic Table of Elements and hence, may be selected from the
group consisting of copper, silver and gold.
[0048] The copper may be present as copper (I) or copper (II) and
hence, the copper catalyst may be selected from the group
consisting of copper halide (such as copper chloride (CuCl or
CuCl.sub.2), copper bromide (CuBr or CuBr.sub.2), copper iodide
(CuI or CuI.sub.2) and copper fluoride (CuF or CuF.sub.2)), copper
acetate (Cu(OAc).sub.2) and copper acetylacetonate
(Cu(acac).sub.2).
[0049] The carbonyl-containing compound may be an aldehyde having
the structure R.sub.1CHO, where R.sub.1 is selected from aryl or
C.sub.1-5-alkyl, said aryl being optionally substituted by at least
one of halide, nitrile, C.sub.1-5-alkyl, C.sub.1-5-alkoxide, nitro
and halo-C.sub.1-5-alkyl (such as trihalo-C.sub.1-5-alkyl) and said
C.sub.1-5-alkyl being optionally substituted by phenyl. The
aldehyde may be benzaldehyde optionally substituted with one or two
substituents independently selected from the group consisting of a
halide such as chloride, fluoride, iodide or bromide, nitrile,
methyl, ethyl, propyl, butyl, pentyl, methoxide, ethoxide,
propoxide, butoxide, pentoxide, nitro, trifluoromethyl,
trichloromethyl, triiodomethyl or tribromoalkyl. The aldehyde may
be linear or branched ethanal, propanal, butanal, pentanal and
hexanal, which may in turn be optionally substituted with a phenyl
group. The branched aldehyde may be 2-methylpropanal. The aldehyde
may be benzenepropanal.
[0050] The carbonyl-containing compound may be a ketone having the
structure R.sub.2CO, where R.sub.2 is selected from
cyclic-C.sub.3-6-alkyl. The ketone may be selected from the group
consisting of cyclopropanone, cyclobutanone, cyclopentanone and
cyclohexanone.
[0051] The amine may be a secondary amine. The secondary amine may
have the structure R.sub.3R.sub.4NH, where R.sub.3 and R.sub.4 are
independently selected from C.sub.1-5-alkyl. Hence, the secondary
amine may be dimethylamine, methylethylamine, diethylamine,
methylpropylamine, methylbutylamine, diisopropylamine or
ethylpropylamine. The secondary amine may be a heterocyclic
secondary amine having 5 to 6 ring atoms. The heterocyclic
secondary amine may be pyrrolidine, piperidine and morpholine. The
amine may not be a primary amine.
[0052] The process may be undertaken at a temperature selected from
about 50.degree. C. to about 150.degree. C., about 50.degree. C. to
about 60.degree. C., about 50.degree. C. to about 70.degree. C.,
about 50.degree. C. to about 80.degree. C., about 50.degree. C. to
about 90.degree. C., about 50.degree. C. to about 100.degree. C.,
about 50.degree. C. to about 110.degree. C., about 50.degree. C. to
about 120.degree. C., about 50.degree. C. to about 130.degree. C.,
about 50.degree. C. to about 140.degree. C., about 60.degree. C. to
about 150.degree. C., about 70.degree. C. to about 150.degree. C.,
about 80.degree. C. to about 150.degree. C., about 90.degree. C. to
about 150.degree. C., about 100.degree. C. to about 150.degree. C.,
about 110.degree. C. to about 150.degree. C., about 120.degree. C.
to about 150.degree. C., about 130.degree. C. to about 150.degree.
C., about 140.degree. C. to about 150.degree. C. and about
70.degree. C. to about 90.degree. C. The reaction temperature may
be about 80.degree. C. or about 120.degree. C.
[0053] The process may be undertaken for a period of time that is
sufficient for all of at least one of the reactants (metal
acetylide, amine, carbonyl-containing compound or alternatively
halide-containing compound) to be consumed. The reaction time may
depend in part on the temperature used for the reaction. The
reaction time may be from about 18 hours to about 120 hours, about
18 hours to about 24 hours, about 18 hours to about 48 hours, about
18 hours to about 72 hours, about 18 hours to about 96 hours, about
24 hours to about 120 hours, about 48 hours to about 120 hours,
about 72 hours to about 120 hours and about 96 hours to about 120
hours. The reaction time may be about 18 hours, about 24 hours,
about 72 hours or about 120 hours.
[0054] The amount of the catalyst (relative to the
carbonyl-containing compound) in the reaction may be from about 5
mol % to about 15 mol %, about 5 mol % to about 6 mol %, about 5
mol % to about 7 mol %, about 5 mol % to about 8 mol %, about 5 mol
% to about 9 mol %, about 5 mol % to about 10 mol %, about 5 mol %
to about 11 mol %, about 5 mol % to about 12 mol %, about 5 mol %
to about 13 mol %, about 5 mol % to about 14 mol %, about 6 mol %
to about 15 mol %, about 7 mol % to about 15 mol %, about 8 mol %
to about 15 mol %, about 9 mol % to about 15 mol %, about 10 mol %
to about 15 mol %, about 11 mol % to about 15 mol %, about 12 mol %
to about 15 mol %, about 13 mol % to about 15 mol %, and about 14
mol % to about 15 mol %. The amount of the catalyst relative to the
carbonyl-containing compound may be about 10 mol %.
[0055] The molar ratio of the metal acetylide to the
carbonyl-containing compound may be about 0.5 to about 1.5 (that
is, about 0.5:1 to about 1.5:1). The molar ratio of the metal
acetylide to the carbonyl-containing compound may be about 0.5 to
about 1.5, about 0.5 to about 0.6, about 0.5 to about 0.7, about
0.5 to about 0.8, about 0.5 to about 0.9, about 0.5 to about 1.0,
about 0.5 to about 1.1, about 0.5 to about 1.2, about 0.5 to about
1.3, about 0.5 to about 1.4, about 0.6 to about 1.5, about 0.7 to
about 1.5, about 0.8 to about 1.5, about 0.9 to about 1.5, about
1.0 to about 1.5, about 1.1 to about 1.5, about 1.2 to about 1.5,
about 1.3 to about 1.5, about 1.4 to about 1.5 and about 1.3 to
about 1.4. The molar ratio of the metal acetylide to the
carbonyl-containing compound may be about 1.2:1. Representative
amounts of the metal acetylide and the carbonyl-containing compound
may be 1.2 mmol and 1 mmol respectively.
[0056] The molar ratio of the amine to the carbonyl-containing
compound may be about 1 to about 2 (that is, about 1:1 to about
2:1). The molar ratio of the amine to the carbonyl-containing
compound may be about 1 to about 2, about 1.1 to about 2, about 1.2
to about 2, about 1.3 to about 2, about 1.4 to about 2, about 1.5
to about 2, about 1.6 to about 2, about 1.7 to about 2, about 1.8
to about 2, about 1.9 to about 2, about 1 to about 1.1, about 1 to
about 1.2, about 1 to about 1.3, about 1 to about 1.4, about 1 to
about 1.5, about 1 to about 1.6, about 1 to about 1.7, about 1 to
about 1.8, about 1 to about 1.9 and about 1.4 to about 1.6. The
molar ratio of the amine to the carbonyl-containing compound may be
about 1.5:1. Representative amounts of the amine and the
carbonyl-containing compound may be 1.5 mmol and 1 mmol
respectively.
[0057] The process may comprise the step of adding a solvent to the
reaction mixture. The solvent may be an aprotic solvent. The
solvent may be polar or may be non-polar. The solvent may be inert
to the reaction conditions or one or more of the reactants may be
used as the solvent. The solvent may be selected from the group
consisting of acetonitrile, tetrahydrofuran, toluene, pyridine and
mixtures thereof. The solvent may be a dry solvent, that is, an
anhydrous solvent. The solvent may contain water and may be termed
as an "undried solvent". The amount of water in the solvent may be
from about 0.01 vol % to about 1 vol %, about 0.1 vol % to about 1
vol %, about 0.2 vol % to about 1 vol %, about 0.3 vol % to about 1
vol %, about 0.4 vol % to about 1 vol %, about 0.5 vol % to about 1
vol %, about 0.6 vol % to about 1 vol %, about 0.7 vol % to about 1
vol %, about 0.8 vol % to about 1 vol %, about 0.9 vol % to about 1
vol %, about 0.01 vol % to about 0.1 vol %, about 0.01 vol % to
about 0.2 vol %, about 0.01 vol % to about 0.3 vol %, about 0.01
vol % to about 0.4 vol %, about 0.01 vol % to about 0.5 vol %,
about 0.01 vol % to about 0.6 vol %, about 0.1 vol % to about 0.7
vol %, about 0.1 vol % to about 0.8 vol % and about 0.1 vol % to
about 0.9 vol %. The water content in the solvent may be about 0.02
vol %, which is equivalent to 2 mol % of the carbonyl-containing
compound. Due to the trace amount of water in the solvent, this may
help to break down the polymeric structure of the metal acetylide
such as calcium carbide. Hence, this may aid in speeding up the
reaction so as to shorten the reaction time.
[0058] The process may comprise the step of adding a base to the
reaction mixture. The base may be an inorganic base or an organic
base. The base may be selected from the group consisting of a
carbonate, a bicarbonate, a phosphate and an amine. In some
instances, the amine of the reaction may also function as a base.
An excess of that amine may be used in such cases. Alternatively, a
separate amine which cannot participate in the reaction may be
used. Such amines include anilines, secondary aromatic amines and
tertiary amines Suitable amines which may be used as the base may
be selected from the group consisting of diazabicyclononene,
diazabicycloundecene, triethylamine, pyridine and a-methyl
benzylamine. The base may be soluble in the solvent or it may be
insoluble in the solvent, or it may be sparingly soluble in the
solvent. The base, if used, may be soluble in the solvent or may be
insoluble therein. In some instances, the selection of base can
control the product obtained. For example, in the AHA-coupling
process, use of an inorganic base may result in disubstitution to
produce an aminopropyne with an internal alkyne structure while use
of an organic base (or no added base) may result in
monosubstitution to produce an aminopropyne with a terminal alkyne.
This can be shown in the scheme below when calcium carbide,
dichloromethane and diisopropylamine were mixed with CuCl in
different types of base to form either diisopropylaminopropyne (B1)
or the corresponding symmetric bis-substituted propargylic amine
product with internal alkyne structure (B2).
##STR00001##
[0059] The process may be undertaken in an inert atmosphere.
[0060] The aminopropyne produced from the process using reactants
such as the metal acetylide, amine and carbonyl-containing compound
may be of the formula H--C.dbd.C--C(A)-N(B), where A refers to the
substituent(s) of the carbonyl-containing compound and B refers to
the substituent(s) of the amine.
[0061] The halide-containing compound may be a
C.sub.1-5-haloalkane. The C.sub.1-5-haloalkane may be
C.sub.1-5-dihaloalkane. The halide-containing compound may be
selected from the group consisting of dihalomethane, dihaloethane,
dihalopropane, dihalobutane or dihalopentane, where halo may be
chlorine, fluoride, bromine or iodine. The halide-containing
compound may be benzal halide. The halide-containing compound may
be selected from the group consisting of dichloromethane,
dichloroethane, dichloropropane, dichlorobutane, dichloropentane,
diiodomethane, diiodoethane, diiodopropane, diiodobutane,
diiodopentane, dibromomethane, dibromoethane, dibromopropane,
dibromobutane, dibromopentane, difluoromethane, difluoroethane,
difluoropropane, difluorobutane, difluoropentane, benzal chloride,
benzal iodide, benzal bromide and benzal fluoride.
[0062] The aminopropyne produced from the process using reactants
such as the metal acetylide, amine and carbonyl-containing compound
may be of the formula H--C.dbd.C--C(A)-N(B), where A represents the
substituent(s) of the carbonyl-containing compound and B represents
the substituent(s) of the amine. This process is also termed as
AAA-coupling.
[0063] The aminopropyne produced from the process using reactants
such as the metal acetylide, amine and halide-containing compound
may be of the formula H--C.dbd.C--C(D)-N(B), where D represents the
substituent(s) of the halide-containing compound and B represents
the substituent(s) of the amine. This process is also termed as AHA
coupling.
[0064] An exemplary reaction scheme showing the AAA-coupling and
AHA-coupling is shown below where calcium carbide is used as the
metal acetylide.
##STR00002##
[0065] The yield of the aminopropyne produced from the process may
be at least 30%, 40%, 50%, 60%, 70%, 80% or 90%.
[0066] The produced aminopropyne may be used to synthesize a
butyneamine The butyneamine may be a butynediamine. Following the
above AAA-coupling, a C.sub.1-5-haloalkane may be added to form an
asymmetric bis-substituted butynediamine . The butynediamine may be
produced in a single reaction vessel or "one-pot". The
C.sub.1-5-haloalkane may be as described above. An exemplary
process to form a butynediamine may include reacting calcium
carbide, benzaldehyde, diisopropylamine, CuI and CH.sub.3CN for 18
hours at 80.degree. C. (AAA-coupling), followed by addition of
dichloromethane and stirred for another 24 hours at 80.degree. C.
to obtain an asymmetric bis-substituted product,
N.sup.1,N.sup.1,N.sup.4,N.sup.4-tetraisopropyl-1-phenylbut-2-yne-1,4-diam-
ine with 70% isolated yield. A scheme of this reaction (also termed
as AAA-AHA coupling) is shown below.
##STR00003##
[0067] Hence, the process for producing a butyneamine may comprise
the steps of:
[0068] (a) reacting a metal acetylide, an amine and a
carbonyl-containing compound in the presence of a transition metal
catalyst to form an aminopropyne intermediate compound; and
[0069] (b) adding a C.sub.1-5-haloalkane to said aminopropyne
intermediate compound of step (a) to produce said butyneamine.
[0070] The produced aminopropyne may be used as an intermediate to
synthesize another aminopropyne product. In another embodiment,
after the AAA-coupling, a mixture of halobenzene, palladium acetate
and triphenylphosphine may be added to form an aminopropyne. The
aminopropyne may be produced in a single reaction vessel or
"one-pot". An exemplary process to form an aminopropyne may include
reacting calcium carbide, benzaldehyde, diethylamine, CuI and
CH.sub.3CN for 18 hours at 80.degree. C. (AAA-coupling), followed
by addition of iodobenzene, palladium acetate and
triphenylphosphine and stirred for another 10 hours at 60.degree.
C. to obtain IV,IV,-diethyl-1,3-diphenylprop-2-yn-1-amine with 60%
isolated yield. A scheme of this reaction (also termed as
AAA-Sonogashira coupling) is shown below.
##STR00004##
[0071] Hence, the process for producing an aminopropyne may
comprise the steps of:
[0072] (a) reacting a metal acetylide, an amine and a
carbonyl-containing compound in the presence of a transition metal
catalyst to form an intermediate compound; and
[0073] (b) adding a mixture of halobenzene, palladium acetate and
triphenylphosphine to said aminopropyne intermediate compound to
produce said aminopropyne. The halobenzene may be selected from the
group consisting of fluorobenzene, chlorobenzene, iodobenzene and
bromobenzene.
[0074] The process may comprise the step of selecting a temperature
of from about 50.degree. C. to about 90.degree. C., about
50.degree. C. to about 60.degree. C., about 50.degree. C. to about
70.degree. C., about 50.degree. C. to about 80.degree. C., about
60.degree. C. to about 90.degree. C., about 70.degree. C. to about
90.degree. C. and about 80.degree. C. to about 90.degree. C., in
step (b) of the above process. The temperature in step (b) of the
process may be abut 80.degree. C. or may be about 60.degree. C.
[0075] The produced aminopropyne may be used to synthesize a
triazole product. This process may involve AAA-coupling in the
first step followed by click chemistry with sodium azide with
either an aryl substituted with a halo group or a
halo-C.sub.1-5-alkane. A scheme of this reaction (also termed as
AAA-click chemistry) is shown below.
##STR00005##
[0076] An exemplary process to form a triazole product may include
reacting calcium carbide, benzaldehyde, diethylamine, CuI and
CH.sub.3CN for 18 hours at 80.degree. C. (AAA-coupling), followed
by addition of sodium azide, iodobenzene, CuI and
N,N-dimethylethylenediamine in dimethyl formamide and stirred for
12 hours at 40.degree. C. to obtain N-ethyl-N-(phenyl(1-phenyl-1
H-1,2,3-triazol-4-yl)methyl)ethanamine after extraction and
purification with 84% isolated yield.
[0077] Hence, the process for producing an triazole may comprise
the steps of:
[0078] (a) reacting a metal acetylide, an amine and a
carbonyl-containing compound in the presence of a transition metal
catalyst to form an aminopropyne intermediate compound; and
[0079] (b) adding sodium azide with one of an aryl substituted with
a halo group or a halo-C.sub.1-5-alkane to said aminopropyne
intermediate compound of step (a) to produce said triazol.
[0080] The yield of the triazole product may be at least about 30%,
40%, 50%, 60%, 70%, 80% or 90%.
[0081] Exemplary, non-limiting embodiments of a process for
producing an enaminone will now be disclosed.
[0082] The process comprises the step of reacting a metal
acetylide, an amine and an aldehyde in the presence of a transition
metal catalyst. The process may comprise the step of adding a
solvent to the reacting step. The solvent may be selected to induce
formation of an enaminone from the reactants stated above. The
solvent may be a formamide (such as dimethyl formamide) or a
sulphoxide (such as dimethyl sulphoxide). The solvent may include
water in an amount from about 0.5 to about 1.5%, about 0.5 to about
0.6%, about 0.5 to about 0.7%, about 0.5 to about 0.8%, about 0.5
to about 0.9%, about 0.5 to about 1%, about 0.5 to about 1.1%,
about 0.5 to about 1.2%, about 0.5 to about 1.3%, about 0.5 to
about 1.4%, about 0.6 to about 1.5%, about 0.7 to about 1.5%, about
0.8 to about 1.5%, about 0.9 to about 1.5%, about 1 to about 1.5%,
about 1.1 to about 1.5%, about 1.2 to about 1.5%, about 1.3 to
about 1.5%, about 1.4 to about 1.5%, about 0.9 to about 1.1%. The
amount of water in the solvent may be about 1%.
[0083] The metal acetylide may have the structure MC.sub.2 (that
is, M--C.dbd.C), where M is a metal selected from the group
consisting of an alkali metal, an alkaline earth metal and a
transition metal. M may be selected from lithium, calcium or
lanthanium and hence the metal carbide salt may be selected from
the group consisting of calcium carbide (CaC.sub.2), lithium
acetylide (Li.sub.2C.sub.2) and lanthanium acetylide
(LaC.sub.2).
[0084] The transition metal catalyst may be a transition metal
salt. The transition metal may be selected from Group IB of the
Periodic Table of Elements and hence, may be selected from the
group consisting of copper, silver and gold.
[0085] The copper may be present as copper (I) or copper (II) and
hence, the copper catalyst may be selected from the group
consisting of copper halide (such as copper chloride (CuCl or
CuCl.sub.2), copper bromide (CuBr or CuBr.sub.2), copper iodide
(CuI or CuI.sub.2) and copper fluoride (CuF or CuF.sub.2)), copper
acetate (Cu(OAc).sub.2) and copper acetylacetonate
(Cu(acac).sub.2).
[0086] The aldehyde may have the structure R.sub.1,CHO, where
R.sub.1, is selected from aryl, said aryl being optionally
substituted by at least one of halide, nitrile, C.sub.1-5-alkyl,
C.sub.1-5-alkoxide, nitro and halo-C.sub.1-5-alkyl (such as
trihalo-C.sub.1-5-alkyl). The aldehyde may be benzaldehyde
optionally substituted with one or two substituents independently
selected from the group consisting of a halide such as chloride,
fluoride, iodide or bromide, nitrile, methyl, ethyl, propyl, butyl,
pentyl, methoxide, ethoxide, propoxide, butoxide, pentoxide, nitro,
trifluoromethyl, trichloromethyl, triiodomethyl or
tribromoalkyl.
[0087] The amine may be a secondary amine. The amine may be
selected to induce formation of an enaminone. Hence, the solvent
and amine may be selected to induce formation of an enaminone. In
order to form enaminone, the amine may have at least one
substituent which is bulkier (in terms of steric bulk) than a
methyl group or an ethyl group. The amine may be more bulkier than
diethylamine. The secondary amine may have the structure
R.sub.5R.sub.6NH, where R.sub.5 and R.sub.6 are independently
selected from C.sub.1-5-alkyl and cyclo-C.sub.3-6-alkyl. Hence, the
secondary amine may be dimethylamine, methylethylamine,
diethylamine, diisopropylamine, methylpropylamine,
ethylisopropylamine, methylisopropylamine, methylbutylamine,
ethylpropylamine or dicyclohexylamine. The amine may be a
heterocyclic secondary amine having 5 to 6 ring atoms. The
heterocyclic secondary amine may be pyrrolidine, piperidine and
morpholine.
[0088] The process may be undertaken at a temperature selected from
about 50.degree. C. to about 150.degree. C., about 50.degree. C. to
about 60.degree. C., about 50.degree. C. to about 70.degree. C.,
about 50.degree. C. to about 80.degree. C., about 50.degree. C. to
about 90.degree. C., about 50.degree. C. to about 100.degree. C.,
about 50.degree. C. to about 110.degree. C., about 50.degree. C. to
about 120.degree. C., about 50.degree. C. to about 130.degree. C.,
about 50.degree. C. to about 140.degree. C., about 60.degree. C. to
about 150.degree. C., about 70.degree. C. to about 150.degree. C.,
about 80.degree. C. to about 150.degree. C., about 90.degree. C. to
about 150.degree. C., about 100.degree. C. to about 150.degree. C.,
about 110.degree. C. to about 150.degree. C., about 120.degree. C.
to about 150.degree. C., about 130.degree. C. to about 150.degree.
C., about 140.degree. C. to about 150.degree. C. and about
80.degree. C. to about 90.degree. C. The reaction temperature may
be about 85.degree. C. or about 950.degree. C.
[0089] The process may be undertaken for a period of time that is
sufficient for all of at least one of the reactants (metal
acetylide, amine and aldehyde) to be consumed. The reaction time
may depend in part on the temperature used for the reaction. The
reaction time may be from about 10 hours to about 50 hours, about
10 hours to about 20 hours, about 10 hours to about 30 hours, about
10 hours to about 40 hours, about 40 hours to about 50 hours, about
30 hours to about 50 hours, about 20 hours to about 50 hours, about
15 hours to about 20 hours, about 45 hours to about 50 hours. The
reaction time may be about 16 hours or about 48 hours.
[0090] The amount of the catalyst (relative to the aldehyde) in the
reaction may be from about 5 mol % to about 15 mol %, about 5 mol %
to about 6 mol %, about 5 mol % to about 7 mol %, about 5 mol % to
about 8 mol %, about 5 mol % to about 9 mol %, about 5 mol % to
about 10 mol %, about 5 mol % to about 11 mol %, about 5 mol % to
about 12 mol %, about 5 mol % to about 13 mol %, about 5 mol % to
about 14 mol %, about 6 mol % to about 15 mol %, about 7 mol % to
about 15 mol %, about 8 mol % to about 15 mol %, about 9 mol % to
about 15 mol %, about 10 mol % to about 15 mol %, about 11 mol % to
about 15 mol %, about 12 mol % to about 15 mol %, about 13 mol % to
about 15 mol %, and about 14 mol % to about 15 mol %. The amount of
the catalyst relative to the aldehyde may be about 5 mol %.
[0091] The molar ratio of the metal acetylide to the aldehyde may
be about 0.5 to about 1.5 (that is, about 0.5:1 to about 1.5:1).
The molar ratio of the metal acetylide to the aldehyde may be about
0.5 to about 1.5, about 0.5 to about 0.6, about 0.5 to about 0.7,
about 0.5 to about 0.8, about 0.5 to about 0.9, about 0.5 to about
1.0, about 0.5 to about 1.1, about 0.5 to about 1.2, about 0.5 to
about 1.3, about 0.5 to about 1.4, about 0.6 to about 1.5, about
0.7 to about 1.5, about 0.8 to about 1.5, about 0.9 to about 1.5,
about 1.0 to about 1.5, about 1.1 to about 1.5, about 1.2 to about
1.5, about 1.3 to about 1.5, about 1.4 to about 1.5 and about 1.3
to about 1.4. The molar ratio of the metal acetylide to the
aldehyde may be about 1.2:1. Representative amounts of the metal
acetylide and the aldehyde may be 1.2 mmol and 1 mmol
respectively.
[0092] The molar ratio of the amine to the aldehyde may be about 1
to about 2 (that is, about 1:1 to about 2:1). The molar ratio of
the amine to the aldehyde may be about 1 to about 2, about 1.1 to
about 2, about 1.2 to about 2, about 1.3 to about 2, about 1.4 to
about 2, about 1.5 to about 2, about 1.6 to about 2, about 1.7 to
about 2, about 1.8 to about 2, about 1.9 to about 2, about 1 to
about 1.1, about 1 to about 1.2, about 1 to about 1.3, about 1 to
about 1.4, about 1 to about 1.5, about 1 to about 1.6, about 1 to
about 1.7, about 1 to about 1.8, about 1 to about 1.9 and about 1.4
to about 1.6. The molar ratio of the amine to the aldehyde may be
about 1.5:1. Representative amounts of the amine and the aldehyde
may be 1.5 mmol and 1 mmol respectively.
[0093] The process may be undertaken in an inert atmosphere.
[0094] The enaminone produced from this process may be of the
formula R.sub.1C(.dbd.O)C.dbd.CNR.sub.5R.sub.6, where R.sub.1
represents the substituent of the aldehyde and R.sub.5 and R.sub.6
represent the substituents of the amine
##STR00006##
[0095] The yield of the enaminone produced from the process may be
at least 30%, 40%, 50%, 60%, 70%, 80% or 90%.
BRIEF DESCRIPTION OF DRAWINGS
[0096] The accompanying drawings illustrate a disclosed embodiment
and serves to explain the principles of the disclosed embodiment.
It is to be understood, however, that the drawings are designed for
purposes of illustration only, and not as a definition of the
limits of the invention.
[0097] FIG. 1 is a graph showing the effects of water content in
dimethyl formamide solvent on the yield of the isolated enaminone
product.
[0098] FIG. 2 is a kinetic study on the yield of the isolated
enaminone product as a result of the reaction time under different
solvent conditions.
EXAMPLES
[0099] Non-limiting examples of the invention will be further
described in greater detail by reference to specific Examples,
which should not be construed as in any way limiting the scope of
the invention.
[0100] Materials and Methods
[0101] All solvents were purchased from Aldrich or Fluka. All
starting materials are commercially available and were used as
received, unless otherwise indicated. Reactions were monitored by
thin layer chromatography using 0.25-mm E. Merck silica gel coated
glass plates (60E-254) with UV light to visualize the course of
reaction. Chemical yields referred to the pure isolated substances.
Gas chromatography-mass spectrometry (GC-MS) was performed with
Shimadzu GC-2010 coupled with GCMS-QP2010. .sup.1H and .sup.13C NMR
spectra were obtained using a Brucker AV-400 (400 MHz)
spectrometer. Chemical shifts were reported in ppm from
tetramethylsilane with the solvent resonance as the internal
standard. Data were reported in the following order: chemical shift
in ppm (.quadrature.) (multiplicity were indicated by br
(broadened), s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), m.sub.c (centered multiplet)); coupling constants (J,
Hz); integration; assignment.
Example 1--Production of Aminopropyne by AHA-Coupling
[0102] In general, a mixture of calcium carbide (1.0 mmol),
dichloromethane (1.5 mmol), diisopropylamine (1.5 mmol), and copper
halide catalyst (0.1 mmol) was added in a reaction tube (10 mL)
with 2 mL CH.sub.3CN. Where required, a base (2.4 mmol) was also
added. After stirring at a certain temperature for a certain period
of time, the mixture was diluted with H.sub.2O (10 mL), the aqueous
layers were extracted with diethyl ether (2.times.10 mL), dried
over Na.sub.2SO.sub.4 and concentrated under vacuum to give the
crude product which was further purified by column chromatography
on silica gel (ethyl acetate/hexane=1: 1) to afford the
corresponding pure aminopropyne, which is
N,N-diisopropyl-2-yn-1-amine (B1) and
N.sup.1,N.sup.1,N.sup.4,N.sup.4-tetraisopropylbut-2-yne-1,4-diamine
(B2). The different types of catalyst and base as well as the
different reaction times and temperatures are shown in Table 1
below. Both products gave satisfactory spectroscopic data.
TABLE-US-00001 TABLE 1 ##STR00007## ##STR00008## ##STR00009##
Reaction Catalyst Time Temperature Yield (%) Entry (mol %) Base
(hours) (.degree. C.) B1 B2 1 CuCl (10) -- 72 80 70 0 2 CuBr (10)
-- 72 80 72 -- 3 CuCl (10) -- 72 120 72 0 4 CuCl (10) -- 24 80 20 0
5 CuCl (10) -- 120 80 75 0 6 CuCl (10) TEA 72 80 70 0 7 CuCl (10)
DIEA 72 80 65 0 8.sup.a CuCl (10) K.sub.2CO.sub.3 72 80 0 70
9.sup.a CuCl (10) Cs.sub.2CO.sub.3 72 80 0 75 .sup.acalcium carbide
(1.0 mmol), dichloromethane (3 mmol), diisopropylamine (3
mmol).
[0103] Different types of amine were also tested as shown in Table
2 below. Unless otherwise stated, the reaction conditions are: 10
mol % copper chloride (CuCl) catalyst, dichloromethane (1.5 mmol)
with CH.sub.3CH, reaction time was 72 hours and reaction
temperature was 80.degree. C.
TABLE-US-00002 TABLE 2 En- try Amine Product Yield 1 ##STR00010##
##STR00011## N,N-diiso- propyl-2- yn-1- amine (C1) 70% 2
##STR00012## ##STR00013## 4-(prop- 2-ynyl) morpho- line (C2) 70% 3
##STR00014## ##STR00015## 1-(prop-2- ynyl) pyrro- lidine (C3)
75%
Example 2--Production of Aminopropyne by AAA-Coupling
[0104] A mixture of calcium carbide (1.2 mmol), a benzaldehyde (1.0
mmol), diisopropylamine (1.5 mmol), and copper halide catalyst (0.1
mmol) was added in a reaction tube (10 mL) with 2 mL of anhydrous
solvent. After stirring at a certain temperature for a certain
period of time, the mixture was diluted with H.sub.2O (10 mL), the
aqueous layers were extracted with diethyl ether (2.times.10 mL),
dried over Na.sub.2SO.sub.4 and concentrated under vacuum to give
the crude product which was further purified by column
chromatography on silica gel (ethyl acetate/hexane=4:1) to afford
the corresponding pure aminopropyne. The different types of
catalyst and solvent as well as the different reaction times and
temperatures are shown in Table 3 below. All products gave
satisfactory spectroscopic data.
TABLE-US-00003 TABLE 3 ##STR00016## ##STR00017## Reaction En-
Catalyst Time Temperature Yield try (mol %) Solvent (hours)
(.degree. C.) (%) 1 CuCl (10) CH.sub.3CN 72 80 50 2 CuCl.sub.2 (10)
CH.sub.3CN 72 80 5 3 CuBr (10) CH.sub.3CN 72 80 70 5 CuI (10)
CH.sub.3CN 72 80 72 6.sup.a CuI (10) CH.sub.3CN.sup.a 18 80 69 7
Cu(acac).sub.2 (10) CH.sub.3CN 72 80 5 8 Cu(OAc).sub.2 (10)
CH.sub.3CN 72 80 60 9 CuI (10) THF 72 80 10 10 CuI (10) Toluene 72
80 5 11 CuI (10) Pyridine 72 80 5 12 CuI (10) CH.sub.3CN 24 80 25
13 CuI (10) CH.sub.3CN 120 80 72 14 CuI (10) CH.sub.3CN 72 120 70
.sup.aUndried CH.sub.3CN (2 mol), 80.degree. C., 18 hours.
[0105] Different types of aldehyde/ketone as well as amine were
also tested as shown in Table 4 below. Unless otherwise stated, the
catalyst used was 10 mol % copper iodide (CuI), solvent was undried
CH.sub.3CN (2 mol), reaction time was 18 hours and the reaction
temperature was 80.degree. C.
TABLE-US-00004 TABLE 4 ##STR00018## Yield.sup.a Entry
Aldehyde/Ketone Amine (%) Product 1 ##STR00019## ##STR00020## 86
##STR00021## N,N-diethyl-1-phenylprop- 2-yn-1-amine (D1) 2
##STR00022## ##STR00023## 75 ##STR00024## 1-(4-chlorophenyl)-N,N-
diethylprop-2-yn-1-amine (D2) 3 ##STR00025## ##STR00026## 80
##STR00027## 1-(4-bromophenyl)-N,N- diethylprop-2-yn-1-amine (D3) 4
##STR00028## ##STR00029## 76 ##STR00030##
4-(1-(deithylamino)prop-2- ynyl)benzonitrile (D4) 5 ##STR00031##
##STR00032## 70 ##STR00033## N,N-diethyl-1-(3,5-
dimethoxyphenyl)prop-2- yn-1-amine (D5) 6 ##STR00034## ##STR00035##
71 ##STR00036## N,N-diethyl-4,4- dimethylpent-1-yn-3- amine (D6) 7
##STR00037## ##STR00038## 76 ##STR00039## N,N-diethyl-5-phenylpent-
1-yn-3-amine (D7) 8 ##STR00040## ##STR00041## 68.sup.b ##STR00042##
N,N-diethyl-1- ethynylcyclohexanamine (D8) 9 ##STR00043##
##STR00044## 85 ##STR00045## 4-(1-phenylprop-2- ynyl)morpholine
(D9) 10 ##STR00046## ##STR00047## 80 ##STR00048##
1-(1-phenylprop-2- ynyl)pyrrolidine (D10) 11 ##STR00049##
##STR00050## 79 ##STR00051## 1-(1-phenylprop-2- ynyl)piperidine
(D11) 12 ##STR00052## ##STR00053## 69 ##STR00054##
N,N-diisopropyl-1- phenylprop-2-yn-1-amine (D12) 13 ##STR00055##
##STR00056## 0 14 ##STR00057## ##STR00058## 0 .sup.aIsolated yield.
.sup.bReaction time was extended to 48 hours.
[0106] It is to be noted that no product was obtained when primary
amines (see entries 13 and 14) were used.
Example 3--AAA-AHA-Coupling
[0107] A mixture of calcium carbide (1.2 mmol, 77 mg), benzaldehyde
(1.0 mmol, 106 mg), diisopropylamine (2.5 mmol, 252 mg), and CuI
catalyst (0.2 mmol, 40.0 mg) was added in a reaction tube (10 mL)
with 4 mL CH.sub.3CN. The reaction mixture was stirred for 18 hours
at 80.degree. C. followed by addition of dichloromethane (1 5 mmol,
126 mg)_into the same reaction tube (that is, a "one-pot"
reaction). After stirring at 80.degree. C. for 24 hours the mixture
was diluted with H.sub.2O (10 mL), extracted with diethyl ether
(2.times.10 mL), dried over Na.sub.2SO.sub.4 and concentrated under
vacuum to give the crude product which was further purified by
column chromatography on silica gel (ethyl acetate/hexane=4: 1) to
afford the corresponding pure asymmetric aminopropyne,
N.sub.1,N.sup.1,N.sup.4,N.sup.4-tetraisopropyl-1
-phenylbut-2-yne-1,4-diamine with an overall yield of 70%.
Example 4--AAA-Sonogashira-Coupling
[0108] A mixture of calcium carbide (1.2 mmol, 77 mg), benzaldehyde
(1.0 mmol, 106 mg), diethylamine (1.5 mmol, 109.5 mg), and CuI
catalyst (0.1 mmol, 20.0 mg) were added in the reaction tube (10
mL) with 4 mL CH.sub.3CN. The reaction mixture was stirred for 18
hours at 80.degree. C. and then followed by addition of iodobenzene
(1.0 mmol, 204 mg), Pd(OAc).sub.2 (0.05 mmol, 11.2 mg) and
Ph.sub.3P (0.05 mmol, 13.1 mg) into the same reaction tube (that
is, a "one-pot" reaction). After stirring at 60.degree. C. for
another 10 hours, the mixture was diluted with H.sub.2O (10 mL),
extracted with diethyl ether (2.times.10 mL), dried over
Na.sub.2SO.sub.4 and concentrated under vacuum to give the crude
product which was further purified by column chromatography on
silica gel (ethyl acetate/hexane=4: 1) to afford the corresponding
propargylamine, IV,N-diethyl-1,3-diphenylprop-2-yn-1-amine, with an
overall yield of 66%.
Example 5--AAA-Click Chemistry
[0109] A mixture of calcium carbide (1.2 mmol, 80 mg), benzaldehyde
(1.0 mmol, 106 mg), diethylamine (1.5 mmol, 151.5 mg), and CuI
catalyst (20 mg, 10 mol %) was added into a reaction tube (10 mL)
with 2 mL CH.sub.3CN. After stirring at 80.degree. C. for 72 hours
(18 hours in case of undried CH.sub.3CN), the mixture was diluted
with H.sub.2O (10 mL), the aqueous layers were extracted with
diethyl ether (2.times.10 mL), dried over Na.sub.2SO.sub.4 and
concentrated to give the crude product which was further purified
by column chromatography on silica gel (ethyl acetate/hexane=1:4)
to afford the corresponding pure propargylamine,
N,N-diethyl-1-phenylprop-2-yn-1-amine, in 86% isolated yield.
[0110] Following this, a mixture of
N,N-diethyl-l-phenylprop-2-yn-l-amine (0.5 mmol, 93.5 mg), sodium
azide (0.6 mmol, 39 mg), Iodobenzene (0.5 mmol, 102 mg), CuI
catalyst (10 mg, 10 mol %), and N,N-Dimethylethylenediamine (6.6
mg, 15 mol %) was added into the same reaction tube (10 mL) with 2
mL Dimethylformamide (that is, a "one-pot" reaction). After
stirring at 40.degree. C. for 12 hours, the mixture was diluted
with H.sub.2O (10 mL), the aqueous layers were extracted with
diethyl ether (2.times.10 mL), dried over Na.sub.2SO.sub.4 and
concentrated to give the crude product which was further purified
by column chromatography on silica gel (ethyl acetate/hexane=1:4)
to afford the decorated triazole product, N-ethyl-N-(phenyl(1
-phenyl-1 H-1,2 ,3-triazol-4-yl)methyl)ethanamine, with an isolated
yield of 84%.
Example 6--Production of Enaminone
[0111] The reaction was conducted in an appropriate solvent with a
copper halide catalyst (5 mol %) under mild conditions in one pot.
Typical reaction conditions: benzaldehyde (1.0 mmol), calcium
carbide (1.2 mmol), diisopropylamine (1.5 mmol), copper halide
catalyst (0.05 mmol, 5.0 mol %), solvent (5.0 mL) and reaction
temperature of 85.degree. C. The different types of catalyst and
solvent as well as the different reaction time are shown in Table 5
below. As can be seen in Table 5, an enaminone is produced when the
solvent used is either dimethyl formamide (DMF) or dimethyl
sulphoxide (DMSO). Other solvents used would result in the product
of the aminopropyne.
TABLE-US-00005 TABLE 5 ##STR00059## ##STR00060## ##STR00061##
##STR00062## Reaction Catalyst Time Yield (%) Entry Solvent (mol %)
(hours) 2a 2b 1 DMF (AR) CuI (5) 48 60 0 2 DMSO (AR) CuI (5) 48 55
0 3 CH.sub.3CN (AR) CuI (5) 48 0 70 4 THF (AR) CuI (5) 48 0 10 5
Toluene (AR) CuI (5) 48 0 5 6 DMF (5 ml) + H.sub.20 CuI (5) 16 83 0
(50 .mu.L, 1.0%) 7 DMF (5 ml) + H.sub.20 CuCl (5) 16 15 0 (50
.mu.L, 1.0%) 8 DMF (5 ml) + H.sub.20 CuBr (5) 16 78 0 (50 .mu.L,
1.0%) 9 DMF (5 ml) + H.sub.20 CuOAc (5) 16 5 0 (50 .mu.L, 1.0%) AR:
analytical reagent
[0112] Different types of aldehyde (1.0 mmol) as well as amine (1.5
mmol) were also tested as shown in Table 6 below. Unless otherwise
stated, the catalyst used was 5 mol % copper iodide (CuI) (0.05
mmol), solvent was DMF (5.0 mL)+H.sub.2O (50 .mu.L), reaction time
was 16 hours and the reaction temperature was 85.degree. C.
TABLE-US-00006 TABLE 6 ##STR00063## ##STR00064## Enaminone
A.sup.3-Coupling Entry Aldehyde Amine (%).sup.a (%).sup.a 1
##STR00065## ##STR00066## 83 0 2 ##STR00067## ##STR00068## 74 0 3
##STR00069## ##STR00070## 77 0 4 ##STR00071## ##STR00072## 72 0 5
##STR00073## ##STR00074## 70 0 6 ##STR00075## ##STR00076## 51 0 7
##STR00077## ##STR00078## 85 0 8 ##STR00079## ##STR00080## 87 0 9
##STR00081## ##STR00082## 69 0 10 ##STR00083## ##STR00084## 65 0 11
##STR00085## ##STR00086## 88 0 12 ##STR00087## ##STR00088## 0 80 13
##STR00089## ##STR00090## <3 77 14 ##STR00091## ##STR00092##
<5 81 15 ##STR00093## ##STR00094## 49 40 16 ##STR00095##
##STR00096## 90 0 17 ##STR00097## ##STR00098## 69 0 18 ##STR00099##
##STR00100## 92 0 19 ##STR00101## ##STR00102## 78 0 20 ##STR00103##
##STR00104## 75 0 21 ##STR00105## ##STR00106## 85 0 22 ##STR00107##
##STR00108## 86 0 23 ##STR00109## ##STR00110## 82 0 24 ##STR00111##
##STR00112## 78 0 25 ##STR00113## ##STR00114## 70 0 .sup.aisolated
yield.
[0113] As observed, the use of amines that are bulkier than
diethylamine resulted in the formation of enaminone, while the use
of diethylamine (entry 14) resulted in the preferential production
of the corresponding aminopropyne. Hence, in order to form the
enaminone, the type of solvent and/or amine should be chosen
appropriately.
[0114] In addition, when comparing between entries 11 and 12, the
use of an aryl aldehyde (entry 11) resulted in the formation of the
enaminone while the use of an alkyl aldehyde (entry 12) resulted in
the formation of the aminopropyne. Hence, the choice of the
aldehyde may also contribute to the product obtained.
[0115] A study on the effects of water content in the DMF solvent
was also investigated. The reaction conditions are: benzaldehyde
(1.0 mmol), calcium carbide (1.2 mmol), diisopropylamine (1.5
mmol), CuI (0.05 mmol, 5.0 mol %), DMF (5.0 mL)+H.sub.2O (0 to
3.0%), reaction temperature of 85.degree. C. and reaction time of
48 hours. The result of this study is shown in FIG. 1 which shows
that the highest isolated yield was obtained when the solvent
contained 1% of water.
[0116] Another study was carried out which was a kinetic study on
the three-component coupling reactions of aldehydes, calcium
carbide and amines to enaminones. Reaction conditions are:
benzaldehyde (1.0 mmol), calcium carbide (1.2 mmol),
diisopropylamine (1.5 mmol), CuI (0.05 mmol, 5.0 mol %), solvent
used was either DMF (5.0 mL) (-.cndot.-) or DMF (5.0 mL)+H.sub.2O
(50 .mu.L, 1.0%) (-.box-solid.-) and reaction temperature was
85.degree. C. The reaction time was varied from 0 to 24 hours (time
points are 1, 2, 5, 16, 24 hours) for DMF+H.sub.2O while that for
DMF only was from 0 to 60 hours (time points are 2, 5, 16, 36, 48,
60 hours). The reactions were quenched at each time point by adding
water.
[0117] Yields provided are of the isolated product. The result of
this study is shown in FIG. 2 which shows that the highest isolated
yield was obtained with DMF+H.sub.2O.
[0118] Applications
[0119] The disclosed process may form aminopropynes with high
yields and at mild conditions. The disclosed process may allow for
the redevelopment of the application of a metal acetylide (such as
calcium carbide) in organic synthesis. Since the development that
calcium carbide can be synthesized from lignocellulosic biomass,
the low production costs of this method allows calcium carbide to
better serve as a sustainable resource for the chemical industry.
The use of calcium carbide in organic synthesis is more
cost-efficient and safer that the use of traditional acetylene
gas.
[0120] The mono-substituted aminopropyne obtained from the
disclosed process can be used to produce other organic compounds
such as an acetylamine or a triazol derivative. Hence, the reaction
to produce complex alkynyl compounds from calcium carbide may be
efficient, fast and simple.
[0121] Advantageously, due to the direct usage of calcium carbide,
the need for numerous protection and de-protection steps may be
greatly reduced, resulting in a more efficient and
environmentally-friendly organic synthesis. Hence, calcium carbide
can play a major role as a sustainable and cost efficient carbon
source in modern organic synthesis.
[0122] It will be apparent that various other modifications and
adaptations of the invention will be apparent to the person skilled
in the art after reading the foregoing disclosure without departing
from the spirit and scope of the invention and it is intended that
all such modifications and adaptations come within the scope of the
appended claims.
* * * * *