Copper(I) chloride-catalyzed three-component coupling reaction of primary amines with electrophiles and α-halogen-substituted allylsilanes to form unsymmetrical tertiary amines

Article abstract of DOI:10.1002/adsc.200505406

Tertiary amines with three different substituents, in one of which a vinylsilane functionality was included, were straightforwardly formed by the copper(I) chloride-catalyzed tandem reaction of primary amines, α-halogen-substituted allylsilanes, and electrophiles such as electron-deficient olefins, alkyl halides, alkyl tosylates, or epoxides. In the case using electron-deficient olefins as the electrophile, the addition of chloroacetone to the reaction system afforded the three-component coupling reaction more effectively. The addition of trimethyl borate as a co-catalyst improved the yields of the three-component coupling products in the reaction using alkyl halides, alkyl tosylates, or epoxides as the electrophiles, although the reaction times were lengthened.

Full text of DOI:10.1002/adsc.200505406

FULL PAPERS
DOI: 10.1002/adsc.200505406
Copper(I) Chloride-Catalyzed Three-Component Coupling
Reaction of Primary Amines with Electrophiles and
a-Halogen-Substituted Allylsilanes to Form Unsymmetrical
Tertiary Amines
Makoto Kozuka, Akihiko Inoue, Teruko Tsuchida, Michiharu Mitani*
Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato,
Nagano 380-8553, Japan
Fax: (þ81)-26-269-5424, e-mail: mitanim@gipwc.shinshu-u.ac.jp
Received: October 14, 2005; Revised: March 17, 2006; Accepted: March 24, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Tertiary amines with three different sub- the three-component coupling reaction more effec-
stituents, in one of which a vinylsilane functionality tively. The addition of trimethyl borate as a co-cata-
was included, were straightforwardly formed by the lyst improved the yields of the three-component cou-
copper(I) chloride-catalyzed tandem reaction of pri- pling products in the reaction using alkyl halides, alkyl
mary amines, a-halogen-substituted allylsilanes, and tosylates, or epoxides as the electrophiles, although
electrophiles such as electron-deficient olefins, alkyl the reaction times were lengthened.
halides, alkyl tosylates, or epoxides. In the case using
electron-deficient olefins as the electrophile, the addi- Keywords: amines; CÀN coupling; copper catalysis;
tion of chloroacetone to the reaction system afforded silicon; three-component coupling
Introduction
and acids to afford amide derivatives which is known
as the Ugi reaction.
We have recently found that tertiary amines with
[
4]
The preparation of higher amines starting from primary
amines has been widely accomplished by the reactions three different substituents are obtained in a single
of the latter with a range of electrophiles, including alkyl step by the CuCl-catalyzed three-component coupling
halides. However, alkylated amines tend to undergo fur- reaction of primary amines, a-halogen-substituted allyl-
ther alkylation more readily because of their enhanced silanes 1, and electrophiles such as electron-deficient
[
5]
[6]
nucleophilicity compared with that of the parent amines. olefins or halides. We herein present this type of re-
Thus, primary amines usually incline to the formation of action, including other electrophiles (i.e., tosylates and
a complex mixture via polyalkylation by the reaction of epoxides) in detail. The vinylsilane functionality, which
electrophiles. Therefore, tertiary amines bearing three is seemingly derived from the S 2’ bond formation from
N
different substituents have commonly been prepared 1 and the amine, is included in one of three different sub-
by step-wise alkylation on the nitrogen atom with stituents on the nitrogen atom of the tertiary amine ob-
some manipulations to effect the selective formation tained in this reaction. While the S 2’-type of reaction of
N
[
1]
of secondary amines in the first steps. The production 1 with a nucleophile such as lithium amide to give vinyl-
[
7]
of tertiary amines from primary amines by the simulta- silane derivatives has been known, 1 has been also re-
neous formation of different nitrogen-carbon bonds in ported to undergo an attack of electrophiles under acti-
a single step has not yet been reported, to the best of vation by a Lewis acid to form vinyl halides via elimina-
our knowledge, although three-component joining reac- tion of the silyl group accompanied by migration of the
[
8]
tions for the simultaneous formation of two different carbon-carbon double bond, similarly to the allylation
carbon-carbon bonds or the nitrogen-carbon bond to- reaction of electrophiles by allylsilanes.
[
2]
[9]
[
3]
gether with the carbon-carbon bond in one step have
Vinylsilanes are useful synthetic intermediates for ef-
been actively investigated, along with four-component fecting versatile transformations via reactions with a
[
10]
joining reactions of amines, aldehydes, isocyanates, range of electrophiles, e.g., acyl halides to form conju-
Adv. Synth. Catal. 2006, 348, 953 – 966
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953

FULL PAPERS
Makoto Kozuka et al.
[11]
gated enones. Although the preparation of vinylsi- trimethylsilyl-2-propenylamine 3a (23% yield) along
lanes has been accomplished by various methods such with 2a and b (33% yield) (Table 1, run 1). The substitu-
[
12]
as the hydrosilylation of alkynes, the reaction of car- tion of electron-rich olefins such as 1-pentene or styrene
[
13]
bonyl compounds with silylated metal species, the si- instead of acrylonitrile did not afford the type 3 product,
[
14]
lylation of alkenylmetals, or the hydrometalation or but formed 2 as well as the 1:2 S 2’-type product, 4, of 1a
N
[
15]
hydrogenation of alkynylsilanes, it has been rather with ethanolamine (2a and b: 40–42% and 4: 39–41%)
difficult to synthesize vinylsilane derivatives containing without consuming these olefins. The reaction using
functional groups. The reaction developed in this inves- (1-chloro-2-propenyl)trimethylsilane 1b instead of 1a
tigation is able to provide vinylsilane derivatives bearing was also examined under the same conditions to afford
some functional groups along with an amino group. 3a in a 78% yield with no formation of 2 (Table 1, run
Thus, our method presented here is also intriguing 2). Diminishing the amount of ethanolamine decreased
from the viewpoint of usefully complementing previous the yield of 3a (Table 1, runs 2–5). Although reducing
techniques for the preparation of vinylsilanes.
the amount of chloroacetone to 0.2 mmol gave 3a in al-
most the same yield (74%) as 4 mmol had (Table 1, run
6
), omitting chloroacetone from the reaction system
altogether reduced the yield of 3a to 27% (Table 1, run
). The omission of copper(I) chloride under otherwise
identical conditions afforded 3a in only a trace amount
4% yield) (Table 1, run 8). Furthermore, the reaction
Results and Discussion
7
Three-Component Coupling Reaction using Electron-
Deficient Olefins
(
in a system containing neither chloroacetone nor cop-
per(I) chloride resulted in no formation of 3a (Table 1,
We have recently explored the copper(I) halide-cata- run 9). Thus, chloroacetone and copper(I) chloride
lyzed reaction of polyhalides with 1, and found that seem to be essential promoters for the effective forma-
the a-halogen atom of 1 is eliminated in conjunction tion of 3a. The use of phenacyl bromide as a halo ketone
with the migration of the carbon-carbon double bond in place of chloroacetone diminished the yield of 3a
[
16]
to form vinylsilane derivatives, in contrast to the elim- (10%) (Table 1, run 10). Based on the hypothesis that
ination of the silyl group in the Lewis acid-promoted re- copper(II) chloride would be generated from chloroace-
[
8]
action of 1 with electrophiles. Furthermore, the reac- tone and copper(I) chloride to work as the actual pro-
tion of 1 with a-halo esters also proceeded similarly un- moter, the reaction was performed in the presence of
der the same reaction conditions. However, when 1 was copper(II) chloride without copper(I) chloride and
subjected to the reaction with chloroacetone, the deha- chloroacetone. The result, however, was no formation
logenated dimerization products (2a, b) of 1 were of 3a (Table 1, run 11). Next, the catalytic abilities of
formed (Scheme 1).
copper(I) halides other than CuCl, i.e., CuBr and CuI,
Supposing that 2 might be formed via the generation were examined to reveal that the yields of 3a descended
of a radical species by the dehalogenation of 1, the reac- in the order of CuCl, CuBr, and CuI (Table 1, runs 2, 12
tion was examined in the presence of an olefin expected and 13). The reactions in Table 1 were not accompanied
to trap the putative radical intermediate; a solution com- by concomitant formation of the mono- or symmetrical-
posed of (1-bromo-2-propenyl)trimethylsilane 1a ly dialkylated derivative of ethanolamine, and thus the
(
(
2 mmol), acrylonitrile (3 mmol), chloroacetone consumed starting materials may be transferred to
4 mmol), CuCl (0.2 mmol), ethanolamine (10 mmol), non-volatile products, such as quaternary ammonium
and t-BuOH (5 mL) was subjected to a thermal reaction salts or polymerized products, besides 3a.
at 808C for 3 h. Contrary to the initial expectation, the
Reactions of electron-deficient olefins other than
result was the formation of a three-component joining acrylonitrile with ethanolamine and 1b were carried
product, N-(2-hydroxyethyl)-N-(2-cyanoethyl)-(E)-3- out. Methyl acrylate gave a similar type of product, 3b,
in a slightly better yield (96%) than for the formation
of 3a from acrylonitrile (Table 2, run 2), while diethyl
maleate necessitated more time for the consumption
of 1b and produced only a moderate yield of 3c (Table 2,
run 3). The reaction in the presence of a conjugated
enone such as methyl vinyl ketone or acrolein afforded
a complex mixture of unidentified products, although
1
b was consumed in 3 h. a-Chlorine-substituted allylsi-
lanes other than 1b were also used for this type of reac-
tion. (1-Chloro-2-butenyl)trimethylsilane 1c was react-
ed with acrylonitrile, methyl acrylate, and diethyl male-
Scheme 1. Reaction of a-haloallylsilane in the presence of ate to afford the three-component joining products 3d–f
chloroacetone.
in excellent or good yields (92, 84, 76%, respectively, Ta-
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Copper(I) Chloride-Catalyzed Three-Component Coupling
FULL PAPERS
[a]
Table 1. Reaction of 1a, b, acrylonitrile, and ethanolamine.
Run
1
Ethanolamine
mmol]
Additive [mmol]
Time [h]
Consumption
of 1 [%]
Yield of 3a
[%]
[d]
[d, e]
[
[
b]
[c]
Metal species
Halo ketone
1
2
3
4
5
6
7
8
9
0
1
2
3
a
b
b
b
b
b
b
b
b
b
b
b
b
10
10
6
4
2
10
10
10
10
10
10
10
10
A (0.2)
A (0.2)
A (0.2)
A (0.2)
A (0.2)
A (0.2)
A (0.2)
–
E (4)
E (4)
E (4)
E (4)
E (4)
E (0.2)
–
E (4)
–
F (4)
–
2
2
2
2
2
3
3
3
2
3
3
3
3
100
96
97
70
57
96
99
23
9
99
91
93
94
23
82
49
12
2
74
27
4
0
10
0
49
33
–
1
1
1
1
A (0.2)
B (0.2)
C (0.2)
D (0.2)
E (4)
E (4)
[
[
[
[
[
a]
Reaction conditions: 1 (2 mmol), CH ¼CHÀCN (3 mmol).
2
b]
A¼CuCl, B¼CuCl , C¼CuBr, D¼CuI.
2
c]
d]
e]
E¼ClCH COCH , F¼BrCH COPh.
2
3
2
Determined by GC analysis.
Based on the starting 1.
ble 2, runs 4–6). The reaction of (1-chloro-2-methyl-2- main product (70% yield). Because cyclohexylamine
propenyl)trimethylsilane 1d with acrylonitrile gave 3g formed a three-component joining product, albeit in
in a 96% yield (Table 2, run 7), while that with methyl low yield, the failure of aniline to form a product of
acrylate afforded 3h in a lower yield (Table 2, run 8). type 3 might in a large part be due to the electronic ef-
GC analysis of the reactions in Table 2 revealed no con- fect, i.e., the weak basicity of aniline compared with an
comitant formation of the mono- or symmetrically dia- aliphatic amine, as well as to the steric effect. In fact,
lkylated derivatives of ethanolamine.
4-ethylaniline gave a coupling product with 1b and acryl-
The reactions of a range of amines with a-chloroallyl- onitrile, albeit in a trace amount (7% yield) (Table 3, run
silanes (1b–d) and acrylonitrile are summarized in Ta- 9).
ble 3. The amines substituted with primary alkyl groups,
i.e., benzylamine and heptylamine, produced the three-
component joining products in excellent to good yields, Three-Component Coupling Reaction using Alkyl
similarly to the reactions using ethanolamine (Table 3, Halides as Electrophiles
runs 1–3 and 10–15). GC analysis of these reaction mix-
tures revealed no concomitant formation of the secon- The binary promoter consisting of CuCl and chloroace-
dary or symmetrical tertiary amines. In contrast, the tone, which proved to be the best conditions for the
stereo-congested amines bearing branched alkyl groups three-component coupling reaction including the elec-
gave similar products in low yields under the standard
reaction conditions, while the same products were ob-
tained in good to moderate yields in the reaction system
by reducing chloroacetone to a catalytic amount
(
0.1 equiv.), as exemplified by the reactions of 1b with
tert-butylamine to form 3k and with cyclohexylamine
to form 3 l (Table 3, runs 4–7). Aniline afforded no
three-component joining products by the reaction with
1
b (Table 3, run 8), but formed the S 2’-type product, Scheme 2. S 2’-type products of amines with a-haloallylsi-
N
N
(
E)-3-phenylamino-1-trimethylsilyl-1-propene 5, as the lanes.
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FULL PAPERS
Makoto Kozuka et al.
[a]
Table 2. Reaction of 1b–d, olefins, and ethanolamine promoted by copper(I) chloride and chloroacetone.
[
b]
Run
1
Olefin
Time [h]
Product
3
4
[c]
R
R
3
Yield [%]
1
2
3
4
5
6
7
8
b
b
b
c
c
c
H
H
CN
2
2
6
1
a
b
c
d
e
f
82
96
45 (37)
92
84
76 (68)
96
COOMe
COOEt
CN
COOMe
COOEt
CN
[
[
d]
d]
COOEt
H
H
COOEt
H
H
1
2.5
3.5
1
[e]
d
d
g
[e]
COOMe
h
34
[
[
[
[
[
a]
b]
c]
d]
e]
Reaction conditions: 1 (2 mmol), olefin (3 mmol), NH (CH ) OH (10 mmol), CuCl (0.2 mmol), ClCH COCH (4 mmol).
Time at which 1 was almost consumed.
Determined by GC analysis.
Determined by TLC isolation.
2
2
2
2
3
A 50/50 mixture of (E)- and (Z)-stereoisomers.
tron-deficient olefin, was applied to the reaction of 1- no concomitant formation of the ethanolamine deriva-
bromopropane (3 mmol), 1d (2 mmol), and ethanol- tive via single or double alkylation with 1-bromopro-
amine (10 mmol) in t-BuOH (5 mL), resulting in the for- pane.
mation of a trace amount of the expected three-compo-
Although solvents other than t-BuOH (i.e., MeOH,
nent coupling product 6a (Table 4, run 1). Next, the re- THF, CH Cl and cyclohexane) were examined, t-
2
2
action using CuCl alone as a promoter was examined. BuOH proved to be best.
As a result, the initial 1a was entirely consumed after Next, halides other than 1-bromopropane were sub-
h under reflux, and 6a was formed in 69% yield (Ta- jected to the reaction with ethanolamine and 1d. Allyl
ble 1, run 2). The use of Al(O-i-Pr) or B(OMe) as a bromide, benzyl bromide, and 2,3-dibromopropene
4
4
3
Lewis acid afforded 6a in excellent yields, although a formed the three-component joining products, 6b–d,
long period of time was necessary to complete the con- in excellent to good yields (Table 5, runs 1–5). A stereo
sumption of 1d (96 and 72 h in runs 3 and 4, respective- bulky halide, i.e., tert-butyl bromide, produced the
ly). Increasing the amount of B(OMe) did not shorten three-component coupling product, 6e, in a low yield
3
the time for consumption of 1d (Table 4, run 5). Thus, (Table 5, run 6), and, in this case, the major products
the reaction using CuCl in combination with B(OMe)3 were the 1:1 and 1:2 S 2’ products of ethanolamine
N
as the promoter was explored with the expectation with 1d. Furthermore, reactions using 1b and 1c instead
that it would produce 6a in an excellent yield under of 1d were explored. The B(OMe) -promoted reaction
3
the accelerated consumption of 1d. Under these condi- of 1b with 1-bromopropane, allyl bromide, or benzyl
tions, 6a was produced in a 93% yield and 1d was con- bromide produced the three-component coupling prod-
sumed in 18 h (Table 4, run 6). However, the use of ucts, 6f–h, in an excellent yield (Table 5, runs 7, 9 and
CuCl together with Al(O-i-Pr) gave 6a in a 49% yield 11), while the binary promoter of CuCl/B(OMe)3
3
under the same time for consumption of 1a (Table 4, formed 6f in 70% yield (Table 5, run 8). The B(OMe)3-
run 7). The reaction without a promoter furnished promoted reaction of 1c with allyl bromide, benzyl bro-
only 23% yield of 6a after consuming 1a in 36 h (Table 4, mide, or 2,3-dibromopropene produced the correspond-
run 8). The effect of the amount of ethanolamine upon ing three-component coupling products, 6i–k in excel-
the formation of 6a was explored to reveal that the yield lent yields (Table 5, runs 12–14). GC analysis of the re-
of 6a was diminished as this was reduced (Table 4, runs 6, actions in Table 5 revealed no concomitant formation of
9
–11). GC analysis of the reactions in Table 4 revealed the ethanolamine derivative via single or double alkyla-
956
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Adv. Synth. Catal. 2006, 348, 953 – 966

Copper(I) Chloride-Catalyzed Three-Component Coupling
FULL PAPERS
[a]
Table 3. Reaction of 1, acrylonitrile, and amines promoted by copper(I) chloride and chloroacetone.
[
b]
Run
1
Amine
Time [h]
Product
3
[c]
R
3
Yield [%]
82
72(55)
89
1
2
3
4
b
b
b
b
b
b
b
b
b
c
c
c
d
d
d
HO(CH2)2
PhCH2
CH (CH )
2
3
3
a
i
j
[d]
3
2
6
(CH ) C
24
24
5
5
7
7
1
2
3
k
k
l
20
70
15
42
0
7
92
85(82)
76
96
81(73)
83(74)
3
3
[
[
e]
e]
5
6
7
8
9
0
1
2
3
4
5
(CH ) C
3
3
cyclohexyl
cyclohexyl
Ph
l
m
n
d
o
p
4-EtC H
6
4
1
1
1
1
1
1
HO(CH2)2
PhCH2
[
d]
CH (CH )
3
2 6
[
f]
HO(CH2)2
PhCH2
3.5
2
4
g
[
f]
[d]
[d]
q
[
f]
CH (CH )
r
3
2 6
[
[
[
[
[
[
a]
Reaction conditions: 1 (2 mmol), CH ¼CHÀCN (3 mmol), amine (10 mmol), CuCl (0.2 mmol), ClCH COCH (4 mmol).
2
2
3
b]
Time at which the initial 1 was almost consumed.
c]
d]
e]
f]
Determined by GC analysis.
Determined by TLC isolation.
Amount of chloroacetone¼0.2 mmol.
A 50/50 mixture of (E)- and (Z)-stereoisomers.
tion with the halide or, if any, in only trace amount ex- giving the 1:1 and 1:2 S 2’-products of the amine with
N
cept for the case using benzyl bromide where N,N-di- 1d as the primary by-products. GC analysis of the reac-
benzylethanolamine was obtained in 17–23% yields tions in Table 6 revealed no concomitant formation of
(
Table 5, runs 3, 4, 11, and 13).
the amine derivative via single or double alkylation
Amines other than ethanolamine, such as benzyl- with the halide.
amine, heptylamine, cyclohexylamine and tert-butyl-
amine, were also subjected to reaction with 1d and alkyl
halides. In contrast to the results using ethanolamine Three-Component Coupling Reaction using Alkyl
shown in Table 4, the yield of the three component cou- Tosylates as Electrophiles
pling product was almost same in the cases using 5 equiv-
alents and 2 equivalents of the amine (Table 6, runs 1, 2 Propyl tosylate (3 mmol) was subjected to the reaction
and 7, 8). Thus, the reactions were performed in the sys- with 1d (2 mmol) and ethanolamine (10 mmol) under
tem containing 2 equivalents of the amine. The primary reflux for 3 h in a t-BuOH solution containing the binary
alkyl amines, such as benzylamine and heptylamine, promoter of CuCl/B(OMe) . As a result, the three-com-
3
gave the corresponding three-component coupling ponent coupling product 6a was formed in 78% yield
products 6 l–n in good yields (Table 6, runs 2, 4–6, 8, (Table 7, run 1). On the other hand, the use of
1
0). On the other hand, secondary or tertiary alkyl B(OMe) alone diminished the yield of 6a to 42% (Ta-
3
amines, such as cyclohexylamine and tert-butylamine, ble 7, run 2), in contrast to the reaction using 1-bromo-
formed the corresponding three-component coupling propane as an electrophile (cf. Table 4, runs 4 and 6).
products 6o and p in low yields (Table 6, runs 11–14), Some combinations of 1 and alkyl tosylates were similar-
Adv. Synth. Catal. 2006, 348, 953 – 966
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FULL PAPERS
Makoto Kozuka et al.
[a]
Table 4. Effects of metal species on three-component coupling reaction of 1d, ethanolamine, and 1-bromopropane.
[
b]
[c]
[d]
Run
Promoter
Ethanolamine [mmol]
Time [h]
Yield 6a [%]
1
2
3
4
5
6
7
8
9
CuCl/ClCH COCH
CuCl
10
10
10
10
10
10
10
10
6
3
4
Trace
69
92
93
93
93 (87)
49
23
78
58
2
3
Al(O-i-Pr)3
B(OMe)3[
96
72
72
18
18
36
10
2
e]
B(OMe)3
[
f]
CuCl/B(OMe)3
CuCl/Al(O-i-Pr)3
None
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
1
1
0
1
4
2
3
18
[
[
[
[
[
[
a]
Reaction conditions: 1d (2 mmol), 1-bromopropane (3 mmol), metal species (0.2 mmol).
Time at which the initial 1d was almost consumed.
A 50/50 mixture of (E)- and (Z)-stereoisomers.
b]
c]
d]
e]
f]
Determined by GC analysis.
B(OMe) ¼1 mmol.
3
Determined by column chromatographic isolation.
ly subjected to the reaction with ethanolamine and, fur- sumption of 1d (Table 8, run 5). Next, it was revealed
thermore, the reactions with amines (4 mmol) other that increasing the amount of butylamine did not pro-
than ethanolamine were also performed. These results mote the formation of 7a (Table 8, runs 3, 6–10), in con-
are collected in Table 7. Compared with the cases using trast to a proportional relationship of the yields of the
alkyl bromides, the three-component coupling reactions three-component coupling products to the amounts of
proceeded quickly, although in comparable or slightly ethanolamine in the cases using electron-deficient ole-
lower yields. In these reactions using alkyl tosylates, fins or alkyl halides. Thus, 7a was obtained in a good
the 1:1 or 1:2 products of amines with tosylates were yield even in the reaction using the same equivalents
not concomitantly formed.
of glycidyl methyl ether, 1d, and butylamine (Table 8,
run 6). These results are collected in Table 8, and GC
analysis of the reaction mixture revealed no concomi-
Three-Component Coupling Reaction using Epoxides tant formation of the 1:1 or 1:2 adduct of butylamine
as Electrophiles
with glycidyl methyl ether, except for the reaction in
run 1 where the 1:1 adduct (60% yield) was formed as
The reaction of glycidyl methyl ether (3 mmol), 1d a by-product.
(
2 mmol), and butylamine (10 mmol) was performed The reactions in the solvents other than t-BuOH were
for 3 h under reflux in a t-BuOH solution containing performed, and it was revealed that t-BuOH was the
the binary promoter of CuCl and chloroacetone which best of the alcoholic and aprotic dipolar solvents exam-
was the best system for the three-component coupling ined, as shown in Table 9.
reaction using the electron-deficient olefin. As a result,
Various combinations of 1 (1 equiv.), an epoxide
the expected three-component coupling product 7a was (1.5 equivs.), and an amine (2 equivs.) were subjected
afforded in a modest yield (55%, Table 8, run 1). The use to a thermal reaction under reflux in a t-BuOH solution
of CuCl alone improved the yield of 7a to 67% (Table 8, containing the binary promoter of CuCl and B(OMe)3,
run 2). Using CuCl in combination with B(OMe) still and the results are shown in Table 10. The reaction of
3
promoted the formation of 7a (Table 8, run 3), although ethanolamine with 1d and glycidyl methyl ether afford-
B(OMe) alone gave 7a in only a low yield (Table 8, run ed the three-component coupling product 7d in only a
3
4
3
). The reaction without any promoter furnished only a trace amount (Table 10, run 3), which is in contrast to
0% yield of 7a along with lengthened time for the con- the reaction of 1 with ethanolamine and an electrophile
958
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Copper(I) Chloride-Catalyzed Three-Component Coupling
FULL PAPERS
[a]
Table 5. Reaction of 1b–d, alkyl bromides, and ethanolamine promoted by CuCl/B(OMe) or B(OMe) .
3
3
3
[b]
Run
1
Alkyl bromide R
Metal species
Time [h]
Product
[c]
6
Yield [%]
[
[
d]
d]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
d
d
d
d
d
d
b
b
b
b
b
c
CH ¼CHCH
CuCl/B(OMe)3
B(OMe)3
B(OMe)3
CuCl/B(OMe)3
B(OMe)3
CuCl/B(OMe)3
B(OMe)3
CuCl/B(OMe)3
B(OMe)3
CuCl/B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
18
48
60
14
72
18
72
18
55
18
55
36
36
36
b
b
c
c
d
e
f
f
g
g
h
i
j
k
98
98
95
72
94 (80)
26 (18)
99
70
96
95 (85)
94
90
93 (83)
97
2
2
2
CH ¼CHCH
2
[d]
PhCH
2
[
d]
PhCH2
[
d]
[e]
CH ¼CBrCH
2
2
[d]
[e]
t-Bu
Pr
Pr
CH ¼CHCH
2
2
[
[
e]
e]
1
1
1
1
1
CH ¼CHCH
2
2
PhCH
2
CH ¼CHCH
2
2
c
c
PhCH
2
CH ¼CBrCH
B(OMe)3
2
2
[
[
[
[
[
a]
Reaction conditions: 1 (2 mmol), alkyl bromide (3 mmol), ethanolamine (10 mmol), metal species (0.2 mmol).
Time at which the initial 1 was almost consumed.
Determined by GC analysis.
A 50/50 mixture of (E)- and (Z)-stereoisomers.
Determined by column chromatographic isolation.
b]
c]
d]
e]
other (e.g., halide) than an epoxide to afford the three- nent coupling product 7m in a low yield (Table 10, run
component coupling products in good yields. This may 12). GC analysis of the reactions in Table 10 revealed
likely result from the low nucleophilicity of ethanol- no concomitant formation of the amine derivatives via
amine compared with an alkylamine such as butylamine, single or double alkylation with epoxides, except for
as exemplified by the findings that allyl glycidyl ether run 3 in which the major product was the 1:1 adduct of
(
3 mmol) was entirely consumed after 35 min by reac- ethanolamine with glycidyl methylamine (85% yield).
tion with butylamine (4 mmol), while only after
10 min by reaction with ethanolamine (4 mmol). Fur-
1
thermore, it may also be related to the rather low sus- Three-Component Coupling Reaction using
ceptibility of an epoxide to an amine compared with Analogues of 1
that of other electrophiles used in the present investiga-
tion; e.g., the consumption time of benzyl bromide The three-component coupling reaction using chlorotri-
(
3 mmol) or propyl tosylate (3 mmol) in the reaction methylsilane, 1-chlorobutane, allyl chloride, and meth-
with ethanolamine (4 mmol) was shorter (30 min or allyl chloride as analogues of 1 was examined. The
0 min, respectively) compared with that of the epoxide CuCl/chloroacetone-promoted reaction of acrylonitrile
vide supra). The primary, secondary, and tertiary alkyl- and ethanolamine with chlorotrimethylsilane or allyl
5
(
amines, except for ethanolamine, gave the three-compo- chloride did not afford the corresponding three-compo-
nent coupling products with 1b–d and monosubstituted nent coupling product. In the CuCl/B(OMe) -promoted
3
epoxides. In the reaction with 1b and butylamine, a 1,1- reaction of 1-bromopropane or propyl tosylate with
disubstituted epoxide (i.e., 1,2-epoxy-2-methylpropane) ethanolamine or that of glycidyl methylether with butyl-
formed the three-component coupling product 7k in a amine, while chlorotrimethylsilane or 1-chlorobutane
good yield (Table 10, run 10), while the 1,2-disubstituted did not afford the three-component coupling product,
epoxide (i.e., cyclohexene oxide) gave the three-compo- methallyl chloride gave the corresponding three-com-
Adv. Synth. Catal. 2006, 348, 953 – 966
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FULL PAPERS
Makoto Kozuka et al.
[a]
Table 6. Reaction of 1d, alkyl bromides, and amines promoted by CuCl/B(OMe) or B(OMe) .
3
3
[
b]
[c]
Run
Alkyl bromide
Amine
Time [h]
Metal species
Product
1
2
[d]
R
R
Amount [mmol]
6
Yield [%]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
CH ¼CHCH
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
CH (CH )
10
4
2
4
4
4
10
4
2
4
2
2
2
36
2
24
2
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
B(OMe)3
l
l
l
l
m
m
n
n
n
n
o
o
p
p
62
62
18
72 (55)
67
85
61
61
36
50
37
30
24
2
2
2
2
2
CH ¼CHCH
2
[e]
CH ¼CHCH
2
[
f]
CH ¼CHCH
2
Pr
Pr
Pr
Pr[
3
2
6
6
6
6
CH (CH )
2
2
3
2
e]
Pr
CH (CH )
3
2
1
1
1
1
1
Pr
Pr
Pr
Pr
Pr
CH (CH )
32
10
36
24
96
3
2
cyclohexyl
cyclohexyl
t-Bu
4
4
4
4
CuCl/B(OMe)3
B(OMe)3
CuCl/B(OMe)3
B(OMe)3
t-Bu
26
[
[
[
[
[
[
a]
Reaction conditions: 1d (2 mmol), alkyl bromide (3 mmol), metal species (0.2 mmol).
Time at which the initial 1d was almost consumed.
A 50/50 mixture of (E)- and (Z)-stereoisomers.
b]
c]
d]
e]
f]
Determined by GC analysis.
2
mmol.
Determined by column chromatographic isolation.
ponent coupling product, albeit in a lower yield (60%, Insights into the Mechanistic Aspects of the Reaction
4%, or 37%, respectively) compared with the reaction
1
using 1d. In the CuCl/B(Me) -promoted reaction of Concerning the reaction mechanism, a step-wise path-
3
methallyl chloride and 1-bromopropane with ethanola- way by way of the intermediate formationof asecondary
mine, GC analysis along the time course revealed that amine was envisaged for the production of tertiary
the yield of the three-component coupling product at- amines with three different substituents from the pri-
tained the maximum value (60%), although methallyl mary amines in our reaction system. Actually, the other-
chloride still remained, after 3 h and then gradually di- wise similar reaction of ethanolamine with 1b, except
minished (30% after 5 h) with the disappearance of without the electrophile, gave the 1:1 S 2’-type product
N
methallyl chloride, probably owing to conversion to a 8. Furthermore, when the secondary amine, i.e., 8 or di-
quaternary ammonium salt. This reaction course is in ethylamine, was reacted in a t-BuOH solution with
contrast to that of 1d and 1-bromopropane with ethanol- acrylonitrile in the presence of CuCl or with 1d in the
amine catalyzed by CuCl/B(OMe) in which the three- presence of CuCl/B(OMe) , respectively, the expected
3
3
component coupling product, 6a, was accumulated pro- tertiary amine, i.e., 3a or diethyl(2-methyl-3-trimethyl-
portionally to the disappearance of 1d (Table 4, run 6). silyl-2-propenyl)amine, was formed. GC analysis of
Thus, it may be likely that the trimethylsilyl substituent our reaction using any electrophile along the time
at the allyl position is operative to impede transforma- course, however, did not reveal an intermediate produc-
tion of a three-component coupling product to a quater- tion of a secondary amine, such as 8 or the 1:1 adduct of
nary ammonium salt via the further reaction with the a- an amine with an electrophile, but resulted in the direct
chloroallylsilane.
appearance of the three-component coupling product,
along with the 1:2 S 2 product of an electrophile with
N
an amine in some cases. On the other hand, the time
course for the consumption of 1 and the electrophile var-
ied depending on the type of electrophile; i.e., while an
electron-deficient olefin was consumed according to al-
960
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Copper(I) Chloride-Catalyzed Three-Component Coupling
FULL PAPERS
[a]
Table 7. Reaction of 1b–d, alkyl tosylates, and amines promoted by CuCl/B(OMe) or B(OMe)
3
3.
3
4
[b]
Run
1
Alkyl tosylate R
Amine R
Metal species
Time [h]
Product
[c]
6
Yield [%]
[
[
d]
d]
1
2
3
4
5
6
7
8
9
d
d
d
d
b
b
c
d
d
d
d
Pr
Pr
HO(CH2)2
HO(CH2)2
HO(CH2)2
HO(CH2)2
HO(CH2)2
HO(CH2)2
HO(CH2)2
PhCH2
CuCl/B(OMe)3
B(OMe)3
3
72
2
2
1
2
0.5
2
2
3
a
a
b
c
f
78
42
82
72
75
92
50
44
46
73
37
[
d]
CH ¼CHCH
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
2
2
[d]
PhCH
2
Pr
CH ¼CHCH
g
i
2
2
2
CH ¼CHCH
2
[
d]
Pr
l
[d]
CH ¼CHCH
PhCH2
m
2
2
[
[
d]
d]
1
1
0
1
Pr
Pr
CH (CH )
n
o
3
2 6
cyclohexyl
3
[
[
[
[
a]
Reaction conditions: 1 (2 mmol), alkyl tosylate (3 mmol), amine (10 mmol), metal species (0.2 mmol).
Time at which the initial 1 was almost consumed.
Determined by GC analysis.
b]
c]
d]
A 50/50 mixture of (E)- and (Z)-stereoisomers.
most the same time course with 1, other electrophiles the efficient formation of 3. Furthermore, in order to
such as halides, tosylates, or epoxides were consumed get some mechanistic information about the reaction us-
prior to 1. The addition of chloroacetone as aco-promot- ing the electron-deficient olefins, the reaction of run 2 of
er in addition to CuCl substantially increased the yield Table 2 were compared with that between each compo-
of the three-component coupling product in the reaction nent, i.e., ethanolamine with 1b or methyl acrylate, the
using an electron-deficient olefin (Table 1, runs 2 and 7), ethanolamine-methyl acrylate 1:1 adduct with 1b, or
but rather inhibited the three-component coupling reac- the ethanolamine-1b S 2’ product with methyl acrylate,
N
tion using other electrophiles such as halides or epoxides in the presence or absence of CuCl/ClCH COCH . The
2
3
(
Table 4, runs 1 and 2; Table 7, runs 1 and 2). From these results are revealed in Table 11. GC analysis of the reac-
findings, it could be speculated that some different tion along the time course revealed that methyl acrylate
mechanisms would operate between the three-compo- and 1b were consumed almost at the same time in the
nent coupling reactions using electron-deficient olefins three-component mixing reaction in the presence of
and other electrophiles. The reaction of 1a and chloro- the binary promoter of CuCl and chloroacetone to result
acetone in the presence of CuCl and ethanolamine with- in the direct appearance of 3b without the detection of
out an electrophile furnished the dimerization product the secondary amine via the reaction of ethanolamine
of 1a, i.e., 2, in which the pathway via the radical inter- with 1b or methyl acrylate (Table 11, runs 1 and 2). Sub-
mediate based on the dehalogenation of 1a by CuCl un- jecting the 1:1 adduct 9 of ethanolamine and methyl
der the intervention of chloroacetone might be assumed acrylate to the reaction with 1b in the presence of the bi-
(
vide supra). Thus, the chloroacetone-promoted reac- nary promoter brought about the disappearance of 9
tion including an electron-deficient olefin to furnish 3 along with 1b remaining intact after 1 h (Table 11, run
might also proceed via the radical pathway. Therefore, 11). Thus, the pathway via the intermediate formation
the addition of a radical quencher (i.e., galvinoxyl, 0.1 of 9 may be less possible. When the 1:1 S 2’ product
N
equiv.) to the standard reaction system for 1b, acryloni- 10 of ethanolamine and 1b was subjected to the reaction
trile, and ethanolamine was examined to result in a di- with methyl acrylate in the presence of the binary pro-
minution of the yield of 3a from 82% to 46%. Thus, moter, 3b was formed along with a slightly faster con-
some radical species generated via the reaction of sumption of methyl acrylate compared with that of 1b
CuCl and chloroacetone might play a critical role in in the reaction of 1b and ethanolamine (Table 11, runs
Adv. Synth. Catal. 2006, 348, 953 – 966
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FULL PAPERS
Makoto Kozuka et al.
Scheme 3. Postulated pathways for the reactions using electron-deficient olefins as electrophiles.
Scheme 4. Postulated pathway for the reactions using halides, tosylates, or epoxides as electrophiles.
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Copper(I) Chloride-Catalyzed Three-Component Coupling
FULL PAPERS
Table 8. Effect of promoters and amounts of reagents on the three-component coupling reaction of 1d, butylamine, and gly-
[a]
cidyl methyl ether.
[
b]
[c]
Run
Amount [mmol]
Epoxide
Promoter
Yield 7a [%]
Amine
1
2
3
4
5
6
7
8
9
0
3
3
3
3
3
2
3
3
3
3
10
10
10
10
10
2
3
4
6
8
CuCl/ClCH COCH
CuCl
CuCl/B(OMe)3
B(OMe)3
none
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
CuCl/B(OMe)3
55
67
78
30
12
80
78
83
78
78
2
3
[
[
d]
d]
1
[
[
[
[
a]
Reaction conditions: 1d (2 mmol), promoter (0.2 mmol), reaction time¼3 h except for runs 4 and 5.
A 50/50 mixture of (E)- and (Z)-stereoisomers.
Determined by GC analysis.
Reaction time¼72 h.
b]
c]
d]
8, 9 and 13, 14). Both steps of formation of 10 and its con- with the electrophile to hinder detection by GC analysis,
version to 3b were accelerated by the binary promoter in turn reacts with 1 immediately after gradual deproto-
(
Table 11, runs 9, 10 and 14, 15). The results of these con- nation (Scheme 4). The reason why the three-compo-
trol experiments may suggest that the step-wise pathway nent coupling reaction using the tosylate proceeded fast-
in which 10 was temporarily formed to be converted to er than that using the halide (e.g., Table 5, run 1 and Ta-
3
b immediately after its formation without detection ble 6, run 3) might be due to the fact that HBr is a stron-
[17]
by GC analysis may likely be operative [Scheme 3 (a)], ger acid than TsOH, and thus the ammonium salt of
although the pathway via the simultaneous formation the latter undergoes deprotonation more readily com-
of two different CÀN bonds cannot be entirely excluded pared to that of the former. A promoter such as CuCl
[
Scheme 3 (b)], considering the somewhat faster con- alone or in combination with B(OMe) might function
3
sumption of 1b in the three-component mixing system to accelerate, not the step to form the secondary amine
compared with that in the two-component system con- intermediate, but rather the reaction step of 1 with this
sisting of 1b and ethanolamine (Table 11, runs 1 and 8). putative intermediates in the above-mentioned hypo-
In the cases using electrophiles (i.e., halides, tosylates, thetical pathway, since the absence of the promoter re-
and epoxides) other than electron-deficient olefins, sulted in the sluggish consumption of 1 and the low yield
those electrophiles were perfectly consumed prior to 1, of the three-component coupling product (e.g., Table 4,
and the three-component coupling products were then runs 2, 6, and 8) while the consumption time of the elec-
formed progressively along with the disappearance of trophile was almost not influenced by the presence of
1
. Therefore, a step-wise pathway via the intermediary the promoter.
formation of the 1:1 product of the primary amine and
electrophile could be considered a possible candidate.
GC analysis of the reaction mixture along the time Conclusion
course, however, did not disclose the generation of
such an intermediate. Thus, although the precise mech- We have demonstrated the preparation of a tertiary
anism for the selective formation of the three-compo- amine bearing three different substituents by way of
nent coupling product has not been unambiguously as- the tandem assembly reaction of a primary amine, an
certained, it might be reasonable to assume the pathway electrophile, and an a-halogenated allylsilane. While
where the secondary amine, which is at first generated in the binary promoter of CuCl/ClCH COCH was advan-
2
3
a protonated form via the reaction of the primary amine tageous for the reaction using an electron-deficient ole-
Adv. Synth. Catal. 2006, 348, 953 – 966
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FULL PAPERS
Makoto Kozuka et al.
Table 9. Effect of solvent on the three-component coupling to be essential for the effective progression of the three-
reaction of 1d, butylamine, and glycidyl methyl ether promo-
ted by CuCl/B(OMe)3.
component coupling reaction presented herein.
[a]
[
b]
Run
Solvent
Yield 7a [%]
Experimental Section
1
2
3
4
5
6
7
8
t-BuOH
EtOH
n-BuOH
sec-BuOH
THF
83
79
79
81
34
59
49
19
General Remarks
Infrared spectra were recorded on a Horiba FT-210 spectrom-
eter. NMR spectra were recorded on a JNM GX400 spectrom-
CH CN
3
1
13
CH COCH
eter ( H: 400 MHz, C: 100 MHz) for CDCl solutions using
3
3
3
DMF
TMSas internal standard ( d¼0) unless otherwise noted. MS
and HR-MSwere obtained at 70 eV using a Hitachi M-80b
GC-MSinstrument equipped with a 10 m megabore DB-1 col-
umn. GC analysis was performed in 10% silicon SE-30 on chro-
mosorb using a Shimazu GC-14B. Preparative GC was carried
out using a Shimazu GC-12A. Preparative TLC was performed
on Merck silica gel 60F254 (0.5 mm, 20 cmꢀ20 cm). Column
[
a]
Reaction conditions: 1d (2 mmol), glycidyl methyl ether
3 mmol), butylamine (4 mmol), CuCl (0.2 mmol),
(
B(OMe) (0.2 mmol), reaction time¼3 h.
3
[
b]
Determined by GC analysis.
chromatography was performed on Merck silica gel 60F2
54
fin as an electrophile, the reaction using an alkyl halide,
alkyl tosylate, or an epoxide as an electrophile was effec-
tively accomplished by the binary promoter of CuCl/
(
45–75 mm). a-Halogenated allylsilanes 1a – d were prepared
[8] [18]
according to methods of Hosomi and Julia.
were synthesized according to literature procedures. Char-
Toslylates
[19]
B(OMe) . From a comparison with the reactions of ana- acterization data of the products are reported in the Support-
3
logues of 1, the use of a-chlorinated allylsilanes proved ing Information.
[a]
Table 10. Reaction of 1b–d, epoxides, and amines promoted by CuCl/B(OMe)3.
6
[b]
Run
1
Epoxide
Amine R
Time [h]
Product
3
4
5
[c]
R
R
R
7
Yield [%]
[
d]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
d
d
d
d
d
d
b
b
b
b
b
b
c
H
H
H
H
H
H
H
H
H
H
H
CH OCH
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
PhCH2
t-Bu
3
24
3
5
3
3
2.5
3
3
3
b
c
65
70
trace
70 (67)
72
74
65
78
78 (72)
73
2
3
3
3
3
[d]
CH OCH
2
[
d]
CH OCH
HO(CH2)2
cyclohexyl
CH (CH )
d
2
[d]
[e]
CH OCH
e
2
[
d]
CH CH
f
2
3
3
2
3
3
3
3
3
3
3
3
3
3
[d]
CH OCH CH¼CH
CH (CH )
g
h
i
2
2
2
2
3
2
CH CH
CH (CH )
2
3
3
2
CH OCH
CH (CH )
2
3
2 2
[
[
e]
e]
CH OCH CH¼CH
CH (CH )
j
2
2
2
2
1
1
1
1
1
CH
Ph
CH (CH )
k
l
m
n
3
2
2
CH (CH )
3
8
2
1.5
65 (58)
2
2
[
e]
À(CH ) À
CH (CH )
7 (7)
74
70
2
4
2
2
H
H
CH OCH
CH (CH )
2
3
2
2
c
CH CH
CH (CH )
o
2
3
2
2
[
[
[
[
[
a]
Reaction conditions: 1 (2 mmol), epoxide (3 mmol), amine (4 mmol), CuCl (0.2 mmol), B(OMe) (0.2 mmol).
Time at which the initial compound 1 was almost consumed.
Determined by GC analysis.
A 50: 50 mixture of (E)- and (Z)-stereoisomers.
Determined by column chromatographic isolation.
3
b]
c]
d]
e]
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Copper(I) Chloride-Catalyzed Three-Component Coupling
FULL PAPERS
Table 11. Comparison of the reaction in the system consisting of 1b, methyl acrylate, and ethanolamine with that in the two-
[a]
component system.
[
b]
Run
System
Catalyst
Time [min]
Consumption [%]
Yield 3b [%]
1
b
Methyl acrylate
[
[
c]
c]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1b/methyl acrylate/ethanolamine
1b/methyl acrylate/ethanolamine
presence
60
120
120
60
240
10
30
60
120
90
60
60
30
60
60
180
90
100
9
92
100
100
32
100
39
81
96
4
absence
presence
[d]
methyl acrylate/ethanolamine
[d]
methyl acrylate/ethanolamine
absence
100
[
[
e]
e]
1b/ethanolamine
presence
65
100
0
0
0
1
1
1
1
1
1
1
1b/ethanolamine
absence
presence
absence
presence
[
f]
f]
[g]
1b/9[
0
0
45
82
27
82
1b/9
[
[
h]
h]
methyl acrylate/10
methyl acrylate/10
48
100
29
absence
100
[
[
[
[
[
[
[
[
a]
Reaction conditions: reflux in a t-BuOH solution.
CuCl/B(OMe)3.
b]
c]
d]
e]
f]
1
b (2 mmol), methyl acrylate (3 mmol), ethanolamine (10 mmol).
Methyl acrylate (3 mmol), ethanolamine (10 mmol).
1
9
9
1
b (2 mmol), ethanolamine (10 mmol).
¼HO(CH ) NH(CH ) COOMe; 1b (2 mmol), 9 (3 mmol).
2
2
2 2
g]
h]
was completely consumed at this time.
0¼HO(CH ) NHCH CH¼CHSiMe ; methyl acrylate (3 mmol), 10 (2 mmol).
2
2
2
3
General Procedure for the Three-Component
Coupling Reaction of Electron-Deficient Olefins with
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Adv. Synth. Catal. 2006, 348, 953 – 966