The copper-catalyzed decarboxylative coupling of the sp3- hybridized carbon atoms of α-amino acids

Article abstract of DOI:10.1002/anie.200805122

(Chemical Equation Presented) Joined at the Cs: A novel intermolecular decarboxylative C_sp3-C_sp3, C_sp3-C _sp2, and C_sp3-Csp coupling catalyzed by CuBr and using a-amino acids as starting materials has

Full text of DOI:10.1002/anie.200805122

Communications
DOI: 10.1002/anie.200805122
ꢀ
C C Coupling
The Copper-Catalyzed Decarboxylative Coupling of the sp3-Hybridized
Carbon Atoms of a-Amino Acids**
Hai-Peng Bi, Liang Zhao, Yong-Min Liang,* and Chao-Jun Li*
Carbon–carbon bond formation by transition-metal-catalyzed
decarboxylative couplings has proven to be an important
synthetic method because of its efficiency, selectivity, as well
as convenience.[1,2] For example, Gooßen and co-workers and
Myers and co-workers have reported palladium-catalyzed
decarboxylative coupling of sp2-hybridized carbon centers. A
large number of useful building blocks, such as biaryls, aryl
ketones, and vinyl arenes were obtained.[3,4] Tunge and co-
workers reported the intramolecular decarboxylative cou-
pling reaction of sp3- and sp-hybridized carbon atoms, a
bond formations, and various products having the functional
groups adjacent to the nitrogen center were obtained
(Scheme 1).
Scheme 1. Copper-catalyzed decarboxylative coupling of a-amino
acids.
ꢀ
powerful strategy for the formation of a C C bond through
decarboxylation of ester derivatives.[5] In contrast to the
above-mentioned decarboxylative coupling reactions, inter-
molecular decarboxylative coupling of sp3-hybridized carbon
atoms with other nucleophiles remains a significant challenge.
Compounds containing heteroatoms such as nitrogen
atoms exist widely in nature.[6] The synthesis of these
compounds has attracted much attention in both industrial
and academic research because of their biological and
pharmaceutical properties.[7] a-Amino acids are often more
readily available than other compounds in nature and are
among the most attractive nitrogen-containing motifs. There-
fore, site-specific functionalization of a-amino acid skeletons
using various nucleophiles would provide a useful and
Our study began with the reaction of N-benzyl-proline 1a,
1.5 equivalents of phenylacetylene (2a), 1.4 equivalents of
tert-butyl hydroperoxide (TBHP), and 15 mol% of CuBr as
the catalyst stirred in toluene under an argon atmosphere at
1108C overnight. The desired product 3a was obtained in
42% yield (Table 1, entry 1). To improve the yields, various
oxidants were examined (Table 1, entries 2–5). We later found
Table 1: Optimization of reaction conditions.[a]
economically efficient synthetic approach to active molecules.
3
ꢀ
Furthermore, the functionalization of sp -hybridized C H
Entry Catalyst Oxidant
Ligand
NMR
Dimer
bonds adjacent to nitrogen atoms is of great interest in the
synthesis of heterocycles.[8] The carboxylic group adjacent to
the nitrogen atom in a-amino acids provides the possibility for
selective functionalization by using decarboxylative coupling
reactions. Herein we report a novel intermolecular decarbox-
ylative coupling of a-amino acids catalyzed by CuBr. This
yield [%][b]
yield [%][c]
1
2
3
CuBr
CuBr
CuBr
–
–
–
42
31
45
8
trace
trace
ꢀ
ꢀ
ꢀ
methodology was applied to Csp3 Csp, Csp3 Csp2, and Csp3 Csp3
4
5
CuBr
–
–
trace
81
6
7
[*] H.-P. Bi, Prof. Dr. Y.-M. Liang
CuBr
CuI
CuOTf 4a
CuCl
CuBr
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (PR China)
Fax: (+86)931-891-2582
6
7
8
9
4a
–
–
–
65
36
54
82
11
trace
trace
trace
4a
4a
E-mail: liangym@lzu.edu.cn
NEt3
H.-P. Bi, L. Zhao, Prof. Dr. C.-J. Li
Department of Chemistry, McGill University
Montreal, QC, H3A 2K6 (Canada)
Fax: (+1)514-398-3797
10
CuBr
4a
90
trace
E-mail: cj.li@mcgill.ca
11
CuBr
4a
73
trace
[**] This work was initiated and completed at McGill University. We are
grateful to the Canada Research Chair (Tier I) Foundation (C.J.L.),
the CFI, and the NSERC for support of our research. H.-P. Bi thanks
the National Graduate Students Program of Building World-Class
Universities grant (Grant No. [2007]3020) for financial support.
[a] Reactions were carried out on a 0.3 mmol scale in toluene (1.5 mL)
under argon at 1108C, overnight with 1a (1.0 equiv), 2a (1.5 equiv),
oxidant (1.4 equiv), catalyst (0.15 equiv), and ligand (0.30 equiv).
[b] Reported yields were based on 1a and determined by NMR methods
using an internal standard. [c] Yield of isolated product.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805122.
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Chemie
that tert-butyl peroxide (4a) was the oxidant of choice for this
reaction, giving higher yields than other oxidants. Among the
copper catalysts examined, CuBr was the most effective
catalyst for this reaction compared to CuI, CuOTf, and CuCl
(Table 1, entries 6–8). In addition, different nitrogens were
examined (Table 1, entries 9–11). After additional screening,
2-Methylindole (6a) and 5-bromoindole (6b) each reacted
smoothly with N-benzyl-proline 1a to give the desired
products (Table 3, entries 1 and 2). Various
a-amino acid derivatives were subjected to the decarboxyla-
tive coupling reaction and moderate to good yields of the
products were obtained (Table 3, entries 3–5). Notably, the
reactions occurred selectively at the C3-position of the
indoles when this position was not substituted. When the
30 mol%
of
N,N,N’,N’-tetramethylethylenediamine
(TMEDA) gave the best results, leading to the product in
90% yield. Notably, only a small
amount of phenylacetylene dimer-
ized under all the oxidative reaction
conditions examined (Table 1). The
Table 2: Decarboxylative Csp3 Csp coupling of a-amino acids with alkynes.[a]
ꢀ
optimized
reaction
conditions
employ 1.0 equivalents of a-amino
acid 1, 1.5 equivalents of alkyne 2,
1.4 equivalents of tert-butyl proxide
(4a), 15 mol% of CuBr, and
30 mol% ligand 5a, in toluene at
1108C under argon.
Entry
1
1
R3
Product
Yield [%][b]
Ph
2a
1a
1a
1a
1a
3a
3b
3c
3d
90(80)
86(70)
89(73)
95(80)
To examine the scope of this
decarboxylative coupling reaction,
various alkynes were reacted under
the optimized reaction conditions,
and the results are summarized in
Table 2. In most cases, aromatic
alkynes afforded the corresponding
products in good yields (Table 2,
entries 1–5), and alkynes containing
an aliphatic group or a 1-cyclohex-
enyl group were also applicable
(Table 2, entries 6 and 7). Mean-
while, the use of N-benzyl-proline
bearing different substituents at the
meta- and para-positions of the
phenyl ring gave the corresponding
products in moderate to good yields
(Table 2, entries 8 and 9). When
N-benzyl-pipecolic acid (1d) was
used in this reaction, N-benzyl-
piperidine derivative 3j was
obtained in 81% yield (Table 2,
entry 10). For catenarian amino
acid 1e, which is noncyclic and
does not have an a-substituent, the
corresponding product 3k was also
formed albeit in lower yield
(Table 2, entry 11).
2
3
4
4-MeOC6H4
2b
4-MeC6H4
2c
4-PhC6H4
2d
5
6-methoxynaphthalenyl
1a
1a
1a
1b
1c
2e
3e
3 f
3g
3h
3i
74(56)
83(65)
76(56)
86(77)
58(41)
6
7
8
9
C8H17
2 f
1-cyclohexenyl
2g
2a
2a
Encouraged by these results of
ꢀ
this decarboxylative Csp3 Csp cou-
pling, we envisaged the trapping of
the cationic intermediate by other
nucleophiles (pronucleophiles). We
tested this method on the decarbox-
10
11
1d
1e
2a
2a
3j
81(74)
39(20)
ꢀ
ylative Csp3 Csp2 coupling of
a-amino acids with indoles. To our
delight, the reaction proceeded
under the same conditions to
afford the indole coupling products
3k
[a] a-Amino acid (1.0 equiv), alkyne (1.5 equiv), 4a (1.4 equiv), 5a (30 mol%), and CuBr (15 mol%) in
toluene (1.5 mL). [b] NMR yields are based on a-amino acid and determined by NMR methods using an
having an unprotected NH group. internal standard; yield of isolated product is given in parentheses.
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Communications
ꢀ
ꢀ
Table 3: Decarboxylative Csp3 Csp2 and Csp3 Csp coupling of a-amino
important structural motifs in biologically active natural
products and are used as core units for chiral auxiliaries and
chiral ligands in asymmetric catalysis.[9]
acids.[a]
The effect of copper in the decarboxylation process was
also examined. Not surprisingly, the direct coupling product
3a was not observed in the reaction of 1a and 2a without the
CuBr catalyst. On the contrary, the decarboxylative coupling
reaction between 1a and 6a afforded the desired coupling
product in a diminished yield and conversion (Scheme 2).
These results confirmed that CuBr facilitates the decarbox-
Entry
1
1
6
Product
Yield [%][b]
87(74)
1a
ꢀ
ylation process and catalyzes the C C bond formation.
6a
6b
7a
7b
2
3
1a
1d
87(74)
78(63)
6c
6c
7c
7d
7e
4
5
6
1c
1b
1a
57(50)
82(69)
0
Scheme 2. Decarboxylative coupling reaction without CuBr.
6c
A proposed mechanism based on the experimental data is
shown in Scheme 3. The oxidative decarboxylation of
a-amino acid 1 is catalyzed by CuBr to gave imine-type
intermediate 8.[10–12] The organocopper intermediate 8 then
tautomerizes to give intermediate 9. Finally, the coupling of 9
with 2a results in the desired products 3,[13] and regenerates
the copper catalyst for additional reaction.
6d
CH3NO2
6e
7 f
7
8
9
1a
1c
1b
89(86)[c]
73(58)[c]
77(67)[c]
In summary, we have developed a novel CuBr-catalyzed
ꢀ
ꢀ
7g
intermolecular decarboxylative Csp3 Csp3
,
Csp3 Csp2
,
and
ꢀ
Csp3 Csp coupling reaction using a-amino acids as starting
materials under neutral conditions. In this process, propargyl-
amines, indolyl pyrrolidines and piperidines, and b-nitro-
amines were obtained, all of which are important structural
6e
7h
6e
7i
[a] a-Amino acid (1.0 equiv), nucleophile (1.5 equiv), 4a (1.4 equiv), 5a
(30 mol%), and CuBr (15 mol%) in toluene (1.5 mL). [b] NMR yields are
based on a-amino acid and determined by NMR methods using an
internal standard; yield of isolated product is given in parentheses.
[c] Used 3 equivalents of the nucleophile.
C3-position of the indole was substituted, the C2-products are
not obtained (compare entries 1 and 6 in Table 3). This
methodology provides the simplest way to construct indolyl
pyrrolidines and piperidines, and also opens a new avenue to
constructing and studying more complex alkaloids. Excitingly,
this method was also applied to the decarboxylative coupling
ꢀ
of Csp3 Csp3 centers and the reaction proceeded readily for
various a-amino acids and nitromethane (Table 3, entries 7–
Scheme 3. Proposed mechanism for the copper-catalyzed decarboxyla-
tive coupling between an a-amino acid and phenylacetylene.
9). The further reaction products, vicinal diamines, are
794
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General procedure (Table 2, entry 1): CuBr (0.045 mmol, 15 mol%)
was added to a solution of N,N,N’,N’-tetramethylethylenediamine
(5a; 0.09 mmol, 30 mol%) in toluene (1.5 mL). The mixture was
stirred for 10 min under argon. N-Benzyl-proline 1a (0.30 mmol),
alkyne 2a (0.45 mmol), and tert-butyl peroxide (4a; 0.42 mmol) were
then added to the reaction mixture. The reaction was heated to 1108C
as soon as possible, stirred overnight, and then cooled to room
temperature. The resulting suspension was diluted with ethyl acetate
and filtered through a short column of Fluorisil using ethyl acetate.
The solvent was evaporated and the residue was purified on silica gel
(hexanes/diethyl ether 15:1!10:1) to afford propargylamine deriv-
atives 3a in 80% yield upon isolation as a yellowish oil. 1H NMR
(300 MHz, CDCl3) d = 7.48–7.23 (m, 10H), 4.07 (d, J = 12.9 Hz, 1H),
3.64–3.58 (m, 2H), 2.83–2.76 (m, 1H), 2.59–2.52 (m, 1H), 2.22–
1.76 ppm (m, 4H); 13C NMR (75 MHz, CDCl3) d = 138.7, 131.7, 129.2,
128.2, 128.2, 127.9, 126.9, 123.4, 88.7, 84.9, 57.2, 54.4, 51.5, 31.6,
22.0 ppm; HRMS calcd for C19H19N: 261.1518; found: 261.1505.
Received: October 20, 2008
Keywords: amino acids · copper · cross-coupling ·
.
decarboxylation · peroxides
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