Cross-dehydrogenative coupling reactions by transition-metal and aminocatalysis for the synthesis of amino acid derivatives

Article abstract of DOI:10.1002/anie.201004940

The direct approach: The title coupling reactions of N-aryl glycine esters with unmodified ketones occurred smoothly in the presence of tert-butyl hydroperoxide (TBHP) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under mild conditions (see scheme). The oxidant used for C-H activation determined the selectivity of the reactions for a particular type of ketone substrate. Copyright

Full text of DOI:10.1002/anie.201004940

Angewandte
Chemie
DOI: 10.1002/anie.201004940
Cooperative Catalysis
Cross-Dehydrogenative Coupling Reactions by Transition-Metal and
Aminocatalysis for the Synthesis of Amino Acid Derivatives**
Jin Xie and Zhi-Zhen Huang*
after C H activation by transition-metal catalysis.[4i,l] In 2009,
À
À
The direct cross-dehydrogenative coupling (CDC) of C H
À
bonds has become a potent strategy for C C bond formation.
Klussmann and co-workers developed a CDC reaction of
tertiary amines with methyl ketones by dual catalysis by a
vanadium complex and proline.[4i] Almost all tertiary-amine
substrates that underwent the CDC reaction efficiently were
tetrahydroisoquinoline derivatives. To the best of our knowl-
edge, there is no successful and disclosed example of a CDC
reaction of secondary amines with ketones. Herein, we
present our preliminary results on the synthesis of amino
acid derivatives by CDC reactions of N-substituted glycine
esters with unmodified ketones by cooperative transition-
metal and aminocatalysis.
As CDC reactions avoid prefunctionalization of the sub-
strates, they are more atom-economical and environmentally
friendly than other cross-coupling reactions.[1] Several
research groups have reported CDC reactions of various sp3
[2,3]
À
À
À
C H bonds, such as benzylic and allylic C H bonds,
a-C
H bonds of tertiary amines[4] and ethers,[5] and C H bonds of
À
alkanes,[6] with other C H bonds. As far as we know, there are
À
only two successful examples of CDC reactions for the
synthesis of amino acid derivatives, although these com-
pounds are so important in terms of their biological activity.
Li and co-workers developed CDC reactions of N-acetylgly-
cine esters and N-aryl glycine amides with malonates and
alkynes in the presence of Cu(OAc)2 (2.0 equiv) and cata-
lyzed by CuBr, respectively.[7,8] However, they reported that
N-aryl glycine esters, unlike N-aryl glycine amides, could not
undergo a CDC reaction.[7] Owing to the importance of amino
acid derivatives and the lack of successful CDC reactions of
glycine derivatives with ketones, we embarked on a study of
CDC reactions of N-substituted glycine esters with unmodi-
fied ketones for the synthesis of amino acid derivatives.
In recent years, cooperative metal and organocatalysis has
received considerable attention, since it can potentially
enable unprecedented transformations currently impossible
with a metal catalyst or an organocatalyst alone.[9] Owing to
their significance and in continuation of our recent inves-
tigation on cooperative metal and organocatalysis,[10] we
planned to carry out the investigation on CDC reactions by
cooperative catalysis. In the last decade, a lot of interest has
Initially, we screened different N substituents on glycine
esters and various organocatalysts, transition-metal catalysts,
ligands, solvents, oxidants, and additives (see the Supporting
Information). The experiments demonstrated that for optimal
results, the reaction should be performed by the cooperative
catalysis of Cu(OAc)2·H2O (10 mol%) and pyrrolidine
(30 mol%) with tert-butyl hydroperoxide (TBHP; 1.5 equiv)
at ambient temperature under neat conditions in air. Under
the optimized conditions, acetone reacted with the N-4-
methylphenylglycine ester 2a smoothly to give the desired
coupling product 3a in 73% yield (Table 1, entry 1). If either
pyrrolidine or Cu(OAc)2·H2O was present, no coupling
product 3a was obtained. A series of N-aryl glycine esters
2a–f were then examined in the CDC reaction. The reaction
Table 1: Cooperative catalytic CDC reaction mediated by TBHP.[a]
À
been paid to C H activation with metal catalysts and
[1]
À
subsequent C C bond formation with nucleophiles. At the
same time, enamines have become crucial reactive inter-
À
mediates in organocatalysis as elegant nucleophiles for C C
bond formation. However, there have been only a few reports
À
on the application of aminocatalysis to C C bond formation
Entry
Ar
R1
t [h]
Product
Yield [%][b]
[*] J. Xie, Prof. Z.-Z. Huang
Key Laboratory of Mesoscopic Chemistry of MOE
College of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210093 (P. R. China)
E-mail: huangzz@nju.edu.cn
1
2
3
4
5
6
7
8
9
4-MeC6H4
C6H5
Et
Et
Et
Et
Et
Et
Me
iPr
tBu
Bn
10
20
8
20
10
12
16
10
16
12
3a
3b
3c
3d
3e
3 f
3g
3h
3i
73
54
46
63
58
75
77
74
62
71
4-MeOC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Prof. Z.-Z. Huang
State Key Laboratory of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (P. R. China)
[**] Financial support from the National Natural Science Foundation of
China (No. 20872059 and 21072091) and MOST of China (973
program, 2011CB808600) are gratefully acknowledged. We also
thank Prof. Chao-Jun Li, McGill University, for helpful discussions.
10
3j
[a] Reaction conditions:
2
(0.15 mmol), acetone (0.75 mL),
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004940.
Cu(OAc)2·H2O (10 mol%), pyrrolidine (30 mol%), TBHP (1.5 equiv,
5.5m in decane). [b] Yield of the isolated product. Bn=benzyl.
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Table 2: Cooperative catalytic CDC reaction mediated by DDQ.[a]
of acetone with various N-aryl glycine esters 2a–f, but not the
corresponding N-4-nitrophenylglycine ester,[11] resulted in the
desired N-aryl amino acid derivatives in satisfactory yields of
46–75% (Table 1, entries 1–6). N-Aryl amino acids are core
structures in many biologically significant compounds and
medicinally important agents.[12]
When the corresponding methyl or isopropyl ester 2g,h
was employed instead of ethyl ester 2a, coupling products
3g,h were also isolated in satisfactory yield (Table 1, entries 7
and 8). However, the reaction of tert-butyl ester 2i proceeded
in lower yield than the reactions of the ethyl, methyl, and
isopropyl esters 2a,g,h (Table 1, entry 9). The reason for this
lower yield may be the steric hindrance of tert-butyl group, as
the CDC reaction of N-aryl glycine ester 2 with TBHP seems
to be sensitive to steric effects. It was significant that when the
glycine benzyl ester 2j, which contains an readily activated
Entry
1
Product
t [h]
18
d.r.[b]
2:1
1:3
Yield [%][c]
3k
3l
83
51
72
2
48
C H bond in the benzyloxy moiety,[5a,b,13] was used, the CDC
À
reaction showed a good regioselectivity to give the expected
coupling product 3j in 71% yield (Table 1, entry 10).
3[d]
3m
12
1:1
When cyclohexanone (1b) was employed instead of
acetone in this CDC reaction with 2a, none of the desired
coupling product was isolated. However, when TBHP was
replaced with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) as the oxidant, the CDC reaction of cyclohexanone
with the N-4-methoxyphenylglycine ester 2c proceeded read-
ily to give the coupling product 3k in 83% yield (Table 2,
entry 1). Without Cu(OAc)2·H2O, 3k was also obtained, but
in decreased yield (68%) with decreased diastereoselectivity
(d.r. 1.1:1; see the Supporting Information). Thus, we
continued to study the CDC reaction with Cu(OAc)2·H2O
as a transition-metal catalyst. When the N-4-methylphenyl-
glycine ester 2a or N-4-chlorophenylglycine ester 2d was used
as a substrate with cyclohexanone, the coupling product was
not formed or was formed in just 28% yield under the same
reaction conditions (see the Supporting Information for
details). In further experiments, the N-4-methoxyphenylgly-
cine ester 2c underwent smooth CDC reactions with different
cycloketones to furnish the desired coupling products 3l–n in
satisfactory yields (51–72%) under very mild conditions in air
(Table 2, entries 2–4).
As in most CDC reactions, the diastereoselectivities
observed for the novel CDC reaction were not high
(Table 2, entries 1–11). If the substituent on ester 2c was
switched from an ethyl to a methyl group, the yield decreased
significantly to 64% (Table 2, entry 5). When isopropyl, tert-
butyl, and allyl esters 2l–n were used, the reaction proceeded
readily to give coupling products 3p–r in good yield (Table 2,
entries 6–8). We also found that without pyrrolidine, the
yields of coupling products 3k and 3m decreased significantly
from 83 and 72% to 76 and 56%, respectively (Table 2,
entries 10 and 11). The CDC reaction may proceed in the
absence of pyrrolidine because the N-4-methoxyphenylgly-
cine esters 2c, 3k, and 3m are secondary amines and might
perform autocatalysis of the CDC reaction.[14]
4[e]
3n
40
4:1
63
5
6
3o
3p
3q
3r
24
20
24
20
15
18
9:5
2:1
5:1
2:1
9:5
2:1
64
83
75
80
78
76
7
8
9[f]
3k
3k
10[g]
11[d,g]
3m
12
1:1
56
[a] Reaction conditions: 2 (0.15 mmol), 1 (15.0 equiv), Cu(OAc)2·H2O
(10 mol%), pyrrolidine (30 mol%), DDQ (1.0 equiv), CHCl3 (1.0 mL).
[b] Diastereomeric ratio: anti/syn. [c] Yield of the isolated product.
[d] The reaction was performed with 10.0 equivalents of the cycloketone.
[e] The reaction was performed with 5.0 equivalents of the cycloketone.
[f] The reaction was performed at room temperature. [g] The reaction
was performed in the absence of pyrrolidine.
To gain insight into these CDC reactions, we carried out
preliminary studies on the mechanistic pathway. We found
that if 2,6-di-tert-butyl-4-methylphenol (BHT), a radical
inhibitor, was added to the reaction system with TBHP
[Eq. (1)], the yield of the coupling product 3a decreased
dramatically from 73 to less than 5%. The key intermediate in
this transformation, the a-tert-butyldioxyl secondary amine 4,
1
was identified by H NMR spectroscopy and MS, although it
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was unstable (see the Supporting Information for details).[15]
Thus, the reaction may proceed by a radical mechanism via
the peroxide intermediate 4 (Scheme 1). Initially, a tert-
Scheme 2. Asymmetric induction in the cooperative catalytic CDC
reaction mediated by TBHP.
absence of cyclohexanone, the imine intermediate 11 derived
from 2c was formed in 57% yield under the catalytic
conditions described in Equation (2) (see the Supporting
Information for details). These results suggest that the CDC
reaction may proceed by a radical pathway via the imine
intermediate 11 (Scheme 3). First, the transfer of a single
Scheme 1. Plausible mechanism of the cooperative catalytic CDC
reaction mediated by TBHP.
butoxyl radical generated by the copper-catalyzed decom-
position of TBHP[16] may abstract a a hydrogen atom of 2a to
form radical 5. Single-electron transfer (SET) from 5 leads to
carbocation 6, which can tautomerize to iminium ion 7.
Nucleophilic attack of tBuOOH on 7 then forms the peroxide
4 with a bulky tert-butyl group. Subsequent nucleophilic
attack of an enamine derived in situ from acetone and
pyrrolidine on the peroxide intermediate 4 under acid
catalysis generates the iminium ion 8. The failure of the
CDC reaction when cyclohexanone was used instead of
acetone may be due to steric hindrance from the tert-butyl
group in 4. Finally, the hydrolysis of 8 gives the coupling
product 3a and regenerates pyrrolidine.
Scheme 3. Plausible mechanism of the cooperative catalytic CDC
reaction mediated by DDQ.
For the development of an asymmetric CDC reaction
mediated by TBHP under cooperative catalysis for the
synthesis of amino acids, we initially examined various
chiral ligands. No enantioselectivity was observed with any
of the chiral ligands employed (see the Supporting Informa-
tion for details). The formation of racemic products is
consistent with the above mechanism (Scheme 1), in which
the only role of the metal is the generation of carbocation 6
through a radical pathway. We then tested various chiral
organocatalysts in the CDC reaction of the N-4-methylphe-
nylglycine ester 2a with acetone. The coupling product 3a was
obtained with 15% ee when the chiral pyrrolidine ester 9 was
used in the presence of the additive PhCOOH (Scheme 2; see
also the Supporting Information). When the chiral pyrrolidine
amide 10, which has an active hydrogen atom for the
formation of a hydrogen bond, was used as the organo-
catalyst, the reverse enantioselectivity (À12% ee) was
observed (Scheme 2; see also the Supporting Information).
The observed asymmetric induction indicates that the chiral
organocatalysts participate in the formation of enamines in
situ, which also supports the proposed mechanism.
electron from the nitrogen atom of 2c to DDQ gives a radical
cation 12 and a radical anion 13. The weaker electron-
donating conjugation effects of the methyl or chloro group in
N-4-methylphenyl- and N-4-chlorophenylglycine esters 2a,d
relative to the methoxy group in 2c probably make it difficult
for these substrates to transfer a single electron, so that the
corresponding coupling product is not formed or is formed in
only 28% yield, respectively (see the Supporting Information
for details). Second, the anionic and radical oxygen atoms in
the DDQ radical anion 13 abstract the N-bonded hydrogen
atom and a-hydrogen atom of radical cation 12, respectively,
to generate imine 11 and DDQH2. Coordination of the copper
salt to imine 11 may activate this intermediate and improve
diastereoselectivity. The coordinated imine 14 then undergoes
nucleophilic attack by an enamine derived from cyclohex-
anone and pyrrolidine to generate iminium ion 15. Finally,
hydrolysis of 15 leads to the coupling product 3k and
regenerates pyrrolidine. It can be deduced from the two
mechanistic pathways that the different oxidants in these
CDC reactions determine the formation of different key
intermediates (such as 4 and 11); the key intermediates in
turn determine the substrate selectivity.
When BHT was used as a radical inhibitor in the reaction
mediated by DDQ [Eq. (2)], the yield of the coupling product
3k decreased greatly from 83 to 18%. Moreover, in the
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of the cycloketone 1b–e (5–15 equiv) and pyrrolidine (3.2 mg,
0.045 mmol, 30 mol%) in CHCl3 (1.0 mL), and the resulting mixture
was stirred at 08C for 5–10 min. DDQ (34.1 mg, 0.15 mmol) was then
added at 08C in portions. The reaction mixture was stirred at 0–58C in
air for 6 h, and at room temperature for the time indicated in Table 2.
When the reaction was finished, a standard workup afforded the
desired N-aryl glycine ester derivative 3k–r.
To improve our understanding of the substrate selectiv-
ities of the CDC reactions with different oxidants, we added
cyclohexanone to the reaction mixture of acetone with 2a in
the presence of TBHP under the reaction conditions in
Equation (1). The expected product 3a of coupling with
acetone was isolated in 61% yield, and no coupling product of
cyclohexanone was observed (Scheme 4; see the Supporting
Received: August 9, 2010
Revised: September 30, 2010
Published online: November 29, 2010
À
Keywords: amino acids · C H activation · cooperative catalysis ·
cross-coupling · organocatalysis
.
[1] For reviews on CDC reactions, see: a) C.-J. Li, Z. Li, Pure Appl.
Chem. 2006, 78, 935; b) C.-J. Li, Acc. Chem. Res. 2009, 42, 335;
c) C. Scheuermann, Chem. Asian J. 2010, 5, 436.
Scheme 4. Substrate selectivity of the CDC reactions with different
oxidants. Reaction conditions: a) Cu(OAc)2·H2O (10 mol%), pyrroli-
dine (30 mol%), room temperature (with TBHP or DDQ).
À
[2] For CDC reactions of benzylic C H bonds, see: a) Z. Li, L. Cao,
C.-J. Li, Angew. Chem. 2007, 119, 6625; Angew. Chem. Int. Ed.
2007, 46, 6505; b) Y.-Z. Li, B.-J. Li, X.-Y. Lu, S. Lin, Z.-J. Shi,
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shkumar, M. Klussmann, Angew. Chem. 2010, 122, 5124; Angew.
Chem. Int. Ed. 2010, 49, 5004; f) C. A. Correia, C.-J. Li, Adv.
Synth. Catal. 2010, 352, 1446; g) C. Guo, J. Song, S.-W. Luo, L.-Z.
Gong, Angew. Chem. 2010, 122, 5690; Angew. Chem. Int. Ed.
2010, 49, 5558.
Information for details). When a mixture of cyclohexanone
and acetone with 2c was subjected to the catalytic conditions
in the presence of DDQ [Eq. (2)], the expected product 3k of
coupling with cyclohexanone was isolated in a 74% yield, and
no coupling product of acetone was observed. The only small
decrease in the yield relative to that observed in the absence
of acetone (78%; Table 2, entry 9) indicates that the presence
of acetone in the reaction system hardly interferes with the
CDC reaction of cyclohexanone and 2c.
In summary, we have developed a facile approach to N-
aryl amino acid derivatives that involves the coupling of N-
aryl glycine esters with unmodified ketones under the
cooperative catalysis of Cu(OAc)2·H2O and pyrrolidine in
the presence of TBHP or DDQ in air under mild conditions.
We have also proposed possible SET mechanisms for the
CDC reactions of secondary amines on the basis of radical-
inhibition experiments and the identification of key reactive
À
[3] For CDC reactions of allylic C H bonds, see: a) Z. Li, C.-J. Li, J.
Am. Chem. Soc. 2006, 128, 56; b) L. Song, C.-X. Song, G.-X. Cai,
W.-H. Wang, Z.-J. Shi, J. Am. Chem. Soc. 2008, 130, 12901;
c) A. J. Young, M. C. White, J. Am. Chem. Soc. 2008, 130, 14090.
[4] See, for example: a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004, 126,
11810; b) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 3672; c) Z.
Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 6968; d) S.-I.
Murahashi, N. Komiya, H. Terai, Angew. Chem. 2005, 117,
7091; Angew. Chem. Int. Ed. 2005, 44, 6931; e) A. J. Catino, J. M.
Nichols, B. J. Nettles, M. P. Doyle, J. Am. Chem. Soc. 2006, 128,
5648; f) Z. Li, D. Bohle, C.-J. Li, Proc. Natl. Acad. Sci. USA 2006,
103, 8928; g) S.-I. Murahashi, T. Nakae, H. Terai, N. Komiya, J.
Am. Chem. Soc. 2008, 130, 11005; h) A. G. Condie, J. C.
Gonzꢁlez-Gꢂmez, C. R. J. Stephenson, J. Am. Chem. Soc.
2010, 132, 1464; i) A. Sud, D. Sureshkumar, M. Klussmann,
Chem. Commun. 2009, 3169; j) Y. Shen, M. Li, S. Wang, T. Zhan,
Z. Tan, C.-C. Guo, Chem. Commun. 2009, 953; k) M.-Z. Wang,
C.-Y. Zhou, M.-K. Wong, C.-M. Che, Chem. Eur. J. 2010, 16,
5723; l) X.-Z. Shu, Y.-F. Yang, X.-F. Xia, K.-G. Ji, X.-Y. Liu, Y.-
M. Liang, Org. Biomol. Chem. 2010, 8, 4077.
À
intermediates. We conclude that the oxidant used for C H
activation determines the substrate selectivity of the CDC
reaction. Further studies on the CDC reactions of secondary
amines for the synthesis of amino acid derivatives by
cooperative transition-metal and aminocatalysis under ambi-
ent conditions are under way. For example, we aim to extend
the scope of the reaction in terms of possible reactants,
elucidate the reaction mechanisms, and develop asymmetric
versions of the reaction.
[5] See, for example: a) Y. Zhang, C.-J. Li, Angew. Chem. 2006, 118,
1983; Angew. Chem. Int. Ed. 2006, 45, 1949; b) Y. Zhang, C.-J. Li,
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Chem. 2008, 120, 7607; Angew. Chem. Int. Ed. 2008, 47, 7497.
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Experimental Section
CDC of N-aryl glycine esters with acetone: An N-aryl glycine ester
2a–j (0.15 mmol) and Cu(OAc)2·H2O (3.0 mg, 0.015 mmol, 10 mol%)
were added to
30 mol%) in acetone (0.75 mL), and the resulting mixture was stirred
for 5–10 min. 5.5m solution of TBHP (41 mL, 0.225 mmol,
a solution of pyrrolidine (3.2 mg, 0.045 mmol,
A
1.5 equiv) in decane was then added, and the reaction mixture was
stirred at room temperature in air for the time indicated in Table 1.
When the reaction was finished, a standard workup afforded the
desired N-aryl glycine ester derivative 3a–j.
CDC of N-4-methoxyphenylglycine esters with cycloketones: An
N-4-methoxyphenylglycine ester 2c,k–n (0.15 mmol) and Cu-
(OAc)2·H2O (3.0 mg, 0.015 mmol, 10 mol%) were added to a solution
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À
Rev. 2009, 38, 2745; b) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010,
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Angew. Chem. Int. Ed. 2008, 47, 5703.
[13] For the C H activation of benzyl ethers, see: a) B. Yu, T. Jiang, J.
Li, Y. Su, X. Pan, X. She, Org. Lett. 2009, 11, 3442; b) W.-J. Yoo,
C. A. Correia, Y. Zhang, C.-J. Li, Synlett 2009, 138; c) H. Richter,
O. G. Mancheꢃo, Eur. J. Org. Chem. 2010, 4460.
[10] J. Xie, Z.-Z. Huang, Chem. Commun. 2010, 46, 1947.
[11] When ethyl 2-(4-nitrophenylamino)acetate was treated with
acetone under the optimal conditions, only a trace amount of
desired coupling product was obtained.
[12] a) D. Ma, J. Yao, Tetrahedron: Asymmetry 1996, 7, 3075; b) D.
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Angew. Chem. Int. Ed. 2010, 49, 10181 –10185
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