Highly enantioselective palladium-catalyzed alkylation of acyclic amides

Article abstract of DOI:10.1002/anie.200704629

(Chemical Equation Presented) Even acyclic amides are suitable nucleophile subtrates for asymmetric allylic alkylations. The allylation products are formed in high yields in the presence of a palladium catalyst with a 1,1′-P,N ferrocene ligand (see scheme; R = (S)-1,1′-bi-2-naphthol). The nature of the substituents on the nitrogen atom of the amide has a critical effect on the efficiency and selectivity of the reaction.

Full text of DOI:10.1002/anie.200704629

Angewandte
Chemie
DOI: 10.1002/anie.200704629
Asymmetric Catalysis
Highly Enantioselective Palladium-Catalyzed Alkylation of Acyclic
Amides**
Kai Zhang, Qian Peng, Xue-Long Hou,* and Yun-Dong Wu
Dedicated to Professor Emanuel Vogel on the occasion of his 80th birthday
[8a,d,9]
Transition-metal-catalyzed asymmetric allylic alkylation
(AAA) has found wide application in organic synthesis as a
powerful tool for the enantioselective formation of carbon–
carbon and carbon–heteroatom bonds.[1] A variety of nucle-
ophiles have been used in this reaction, in which stereogenic
centers can be produced in either the allylic substrate, the
nucleophile, or both. However, for a long time, carbon
nucleophiles were limited to “soft” or stabilized carbanions.
A breakthrough was made in 1999 by Trost and Schroeder,
who reported a highly enantioselective alkylation with
enolates derived from cyclic ketones.[2] Since then, enolates
derived from simple ketones and aldehydes have been
applied successfully in the AAA reaction.[3–5]
esters,
and Zn enolates of glycine and peptides,[8b,c,e]
has been reported (Scheme 1).[10] Transition-metal-catalyzed
AAA with carbon nucleophiles derived from general carbox-
Scheme 1. The structures of some special carboxylic acid derivatives
used in transition-metal-catalyzed AAA reactions.
Carboxylic acid derivatives are an extremely useful class
of compounds in organic synthesis. However, it is more
difficult to use carboxylic acid derivatives in AAA reactions
because of the lower acidity of their a hydrogen atom and the
even less stabilized nature of carbanions derived from such
compounds. To date, no report on the use of carboxylic acid
derivatives in transition-metal-catalyzed AAA reactions has
appeared, although the use of a few special carboxylic acid
ylic acid derivatives remains a great challenge. Previously, we
developed a series of 1,1’-P,N ferrocene ligands and applied
them in Pd-catalyzed regio- and enantioselective allylic
alkylation reactions.[5,11] Recently, we also demonstrated, as
did Trost and Xu, that acyclic ketone enolates are suitable
nucleophiles for Pd-catalyzed AAA reactions.[3h,5d,e] To
extend the scope of “hard” nonstabilized carbanions as
nucleophiles in transition-metal-catalyzed AAA reactions,
we turned our attention to carboxylic acid derivatives. Herein
we report that a-carbanions of acyclic amides are suitable
nucleophiles for Pd-catalyzed AAA: We observed high
enantioselectivity with 1,1’-P,N ferrocene compounds as
ligands.
When we treated phenyl propionate with allyl acetate
(2a) in the presence of the ligand (S,Rphos,R)-L1 (5 mol%)
and [{Pd(C3H5)Cl}2] (2.5 mol%), we observed no product
formation. We next investigated the use of amides 1 as
substrates in the hope that the substituents on the amide
nitrogen atom might affect the reactivity of the substrate.[12]
Indeed, the nature of the substituents on the nitrogen atom of
the amide has a critical effect on the reaction (Table 1).[13]
Whereas none of the desired product was observed when
the N,N-dimethyl, N-phenyl, N-methyl-N-phenyl, and N-Boc-
N-methyl amides 1a–d were used (Table 1, entries 1–4), a
trace amount of the product was observed with the N-pyrrol-
1-yl amide 1e (Table 1, entry 5). When the amide 1 f with
phenyl and Boc groups on the nitrogen atom was used, the
product was obtained in about 20% yield (Table 1, entry 6).
The yield increased to about 40% when 1g, with two phenyl
groups on the nitrogen atom, was used (Table 1, entry 7).
Although two methyl substituents are present on the nitrogen
atom of the amide 1p, the desired allylated product was
obtained in 65% yield upon treatment with 3a, probably
because the phenyl ring stabilizes the carbanion produced
from 1p (Table 1, entry 8).[13] However, only low enantiose-
derivatives with additional carbanion-stabilizing features,
[6]
such as azalactones,
3-substituted oxindoles,[7] glycine
[*] Dr. K. Zhang, Prof. X.-L. Hou
State KeyLaboratoryof Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academyof Sciences
354 Fenglin Road, Shanghai 200032 (China)
Fax: (+86)21-5492-5100
E-mail: xlhou@mail.sioc.ac.cn
Q. Peng, Prof. X.-L. Hou, Prof. Y.-D. Wu
Shanghai–Hong Kong Joint Laboratoryin Chemical Synthesis
Shanghai Institute of Organic Chemistry
Chinese Academyof Sciences
354 Fenglin Road, Shanghai 200032 (China)
Prof. Y.-D. Wu
Department of Chemistry
Hong Kong Universityof Science and Technology
Clear Water Bay, Kowloon, Hong Kong (China)
[**] This research was supported financiallybythe Major Basic Research
Development Program (2006CB806106), the National Natural
Science Foundation of China, the Chinese Academyof Sciences, the
Croucher Foundation of Hong Kong, and the Science and
TechnologyCommission of Shanghai Municipality. K.Z. and Q.P.
gratefullyacknowledge the Croucher Foundation of Hong Kong for a
studentship. We also thank Prof. Li-Xin Dai for inspiring discus-
sions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Optimization of the amide 1 in the Pd-catalyzed AAA reaction.[a]
the catalyst rather than that of the P atom (Table 1, entries 7–
11, 14, and 15 versus entries 12 and 13), in contrast to our
previous results.[5b,c,11]
We investigated the influence of the reaction conditions
on the outcome of the reaction. THF was found to give better
results than several other common solvents tested. The
reaction gave the desired amide only when bases with lithium
as the counterion, such as LiHMDS, lithium diisopropyl-
amide, and sBuLi, were used. No product was observed when
NaHMDS, KHMDS, tBuOK, or NaH were used. The yield
and ee value of the product increased to 82 and 85%,
respectively, if 1equivalent of LiCl was used as an additive
in the reaction with L6 as the ligand and the amide substrate
1g.[14,15] On the other hand, both the yield and the enantio-
selectivity decreased if HMPA (10 mol%; hexamethylphos-
phoramide) was added. These results also demonstrate the
importance of lithium ions in the reaction. The amount of
base used is also important. The presence of excess base led to
a decrease in the ee value of the product because of
racemization of the product.[16] The temperature was found
to influence the reaction time and the yield of the product, but
not the enantioselectivity of the reaction. Furthermore, the
product was formed in higher yield with a higher ee value
when allyl acetate was used instead of allyl carbonate or allyl
phosphonate.
We studied the scope of the reaction with respect to the
amide 1 under the optimized reaction conditions (Table 2).
Quite a broad range of amides were transformed into the
corresponding allylic products 3 in good to excellent yields
and with high enantioselectivity. The R1 group can be a
primary or a secondary alkyl group (Table 2, entries 1–4 and
11), a phenyl group (entries 5, 9, 10, and 12), or a heteroatom
functional group (entries 6–8). The R2 group can be H
(Table 2, entries 1–7 and 10–12) or Me; in the latter case, a
stereogenic quaternary center was installed (Table 2, entries 8
and 9). 2-Methylallyl acetate is also a suitable allylation
reagent, with the corresponding products formed in high
EntryAmide
R1, R2 R3, R4
1
1, 3 Lig. Yield [%][b] ee [%][c]
1
2
Me, H Me, Me
Me, H H, Ph
a
b
c
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
NR
NR
NR
NR
trace
20
–
–
–
3
4
Me, H Me, Ph
Me, H Me, Boc
d
e
f
–
–
–
5
6
7
8
Me, H -CH=CH-CH=CH-
Me, H Ph, Boc
Me, H Ph, Ph
Ph, H Me, Me
Me, H Ph, Ph
Me, H Ph, Ph
Me, H Ph, Ph
Me, H Ph, Ph
Me, H Ph, Ph
Me, H Ph, Ph
Me, H Ph, Ph
Me, H Ph, Ph
g
p
g
g
g
g
g
g
g
g
40
65
60
54
70
60
71
35
47 (+)
45 (+)
28 (+)
46 (+)
50 (+)
29 (À)
60 (À)
31 (+)
55 (+)
0
9
10
11
12
13
14
15
16
65
70
[a] Molar ratio: 1/[{Pd(C3H5)Cl}2]/ligand/LiHMDS/2 100:1:2:100:200.
[b] Yield of 3 after isolation bypreparative TLC. [c] The ee value of 3 was
determined byHPLC on a chiral phase. The sign of optical rotation is
given in brackets. Boc=tert-butoxycarbonyl, HMDS=hexamethyldisila-
zide, NR=no reaction.
lectivity was observed in the reactions of 1g and 1p (Table 1,
entries 7 and 8).
Next, we screened ligands with different substituents on
the oxazoline ring and with different chiral elements
(Scheme 2) in the reaction with the substrate 1g. We observed
Table 2: Scope of the Pd-catalyzed AAA of amides 1.[a]
Scheme 2. Ferrocene-based P,N ligands.
1
EntryR
R2
R3
R4
3
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
Me
Et
Pr
iPr
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Me
Me
g
h
i
j
k
l
m
n
o
p
q
r
82
78
75
80
98
95
78
99
75
75
85
90
85
82
83
73
88
86
91
93
93
88
91
91
the best results with (S,Sphos,S)-L6, which has an isopropyl
substituent on the oxazoline ring: The corresponding product
was formed in 71% yield with 60% ee (Table 1, entry 13). The
use of ligands with Ph, Bn, tBu, and iPr as the substituent led
to the product in slightly lower yield with lower enantiose-
lectivity (Table 1, entries 9–12). The product 3g was also
obtained in 65% yield and with 55% ee when the ligand L8
with no stereogenic center in the oxazoline ring was used
(Table 1, entry 15). However, with L9, the diastereoisomer of
L8, 3g was obtained in 70% yield with 0% ee (Table 1,
entry 16). Clearly the chiral elements in L9 are mismatched in
this reaction. The configuration of the product (see below) is
determined by the configuration of the binol component of
Ph
N-piperidinyl
TBSO
PhO
Ph
Ph
Me
Ph
Me Ph
Me Ph
H
H
H
10
11
12
Me
Ph
Ph
[a] Molar
ratio:
1/[{Pd(C3H5)Cl}2]/(S,Sphos,S)-L6/LiHMDS/2/LiCl
100:1:2:100:200:100. [b] Yield of 3 after isolation bypreparative TLC.
[c] The ee value of 3 was determined byHPLC on a chiral phase.
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[2] B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 1999, 121, 6759.
yields with high enantioselectivity (Table 2, entries 11 and
12).
[3] For examples of the use of ketone and aldehyde enolates as
nucleophiles in Pd-catalyzed AAA reactions, see: a) M. Braun,
F. Laicher, T. Meier, Angew. Chem. 2000, 112, 3637; Angew.
Chem. Int. Ed. 2000, 39, 3494; b) B. M. Trost, G. M. Schroeder, J.
Kristensen, Angew. Chem. 2002, 114, 3642; Angew. Chem. Int.
Ed. 2002, 41, 3492; c) U. Kazmaier, Curr. Org. Chem. 2003, 7,
The absolute configuration of the allylation products 3g
and 3h was determined to be R by comparison of their HPLC
trace (chiral phase) and the sign of their optical rotation with
those of the synthetic samples (R)-2-methyl-N,N-diphenyl-
pent-4-enamide (3g) and (R)-2-ethyl-N,N-diphenylpent-4-
enamide (3h). These samples of known configuration were
prepared by the resolution of 2-methylpent-4-enoic acid and
2-ethylpent-4-enoic acid, respectively, by using a chiral
quinine, followed by successive treatment with oxalyl chloride
and diphenylamine according to literature procedures.[17]
We propose a plausible model, in which the binol subunit
and NuÀ (the a-carbanion of the amide) are on the same side
of (below) the p-allyl moiety, to explain the observed
stereochemical course of the reaction (Scheme 3):[18]
Re attack to provide the R product is favored.
317; d) E. C. Burger, J. A. Tunge, Org. Lett. 2004, 6, 41 1 3;
e) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126,
15044; f) B. M. Trost, G. M. Schroeder, Chem. Eur. J. 2005, 11,
174; g) B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 2846;
h) B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 17180; i) M.
Braun, T. Meier, Synlett 2005, 2968; j) B. M. Trost, J. Xu, M.
Reichle, J. Am. Chem. Soc. 2007, 129, 282; k) É. BØlanger, K.
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2007, 129, 1034; l) D. Liu, F. Xie, W. Zhang, Tetrahedron Lett.
2007, 48, 7591.
[4] For examples of other metal-catalyzed AAA reactions with
ketone enolates and enamines, see: a) T. Graening, J. F. Hartwig,
J. Am. Chem. Soc. 2005, 127, 17192; b) D. J. Weix, J. F. Hartwig,
J. Am. Chem. Soc. 2007, 129, 7720; c) S. Constant, S. Tortoioli, J.
Müller, J. Lacour, Angew. Chem. 2007, 119, 2128; Angew. Chem.
Int. Ed. 2007, 46, 2082; d) H. He, X.-J. Zheng, Y. Li, L.-X. Dai, S.-
L. You, Org. Lett. 2007, 9, 4339.
[5] a) L.-X. Dai, T. Tu, S.-L. You, W.-P. Deng, X.-L. Hou, Acc.
Chem. Res. 2003, 36, 659; b) S.-L. You, X.-L. Hou, L.-X. Dai, X.-
Z. Zhu, Org. Lett. 2001, 3, 149; c) S.-L. You, X.-Z. Zhu, X.-L.
Hou, L.-X. Dai, Acta Chim. Sinica 2001, 59, 1667; d) X. X. Yan,
C. G. Liang, Y. Zhang, W. Hong, B. X. Cao, L. X. Dai, X. L. Hou,
Angew. Chem. 2005, 117, 6702; Angew. Chem. Int. Ed. 2005, 44,
6544; e) W.-H. Zheng, B.-H. Zheng, X.-L. Zhang, Y. Hou, J. Am.
Chem. Soc. 2007, 129, 7718.
[6] a) B. M. Trost, X. Ariza, Angew. Chem. 1997, 109, 2749; Angew.
Chem. Int. Ed. Engl. 1997, 36, 2635; b) B. M. Trost, K. Dogra, J.
Am. Chem. Soc. 2002, 124, 7256.
Scheme 3. Plausible transition state for the Pd-catalyzed AAA of allyl
acetate with an amide.
[7] a) B. M. Trost, M. U. Frederiksen, Angew. Chem. 2005, 117, 31 2;
Angew. Chem. Int. Ed. 2005, 44, 308; b) B. M. Trost, Y. Zhang, J.
Am. Chem. Soc. 2006, 128, 4590.
In summary, high enantioselectivity was observed in the
Pd-catalyzed AAA of acyclic amides in the presence of
1,1’-P,N ferrocene ligands to provide the corresponding
g,d-unsaturated amides, which are useful building blocks in
organic synthesis.[19] The nature of the substituents on the
nitrogen atom of the amides has a great impact on the
efficiency and selectivity of the reaction. Further studies are
in progress towards the extension of the scope of the reaction
and the application of this methodology in organic synthesis.
We are also investigating the unusual stereochemical aspects
of the reaction.
[8] a) J.-P. Genet, S. Juge, S. Achi, S. Mallart, J. Ruiz-Montes, G.
Levif, Tetrahedron 1988, 44, 5263; b) U. Kazmaier, F. L. Zumpe,
Angew. Chem. 1999, 111, 1572; Angew. Chem. Int. Ed. 1999, 38,
1468; c) T. D. Weiß, G. Helmchen, U. Kazmaier, Chem.
Commun. 2002, 1270; d) T. Kanayama, K. Yoshida, H. Miyabe,
Y. Takemoto, Angew. Chem. 2003, 115, 2100; Angew. Chem. Int.
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[9] S.-L. You, X.-L. Hou, L.-X. Dai, B.-X. Cao, J. Sun, Chem.
Commun. 2000, 1933.
[10] For non-asymmetric reactions of a-carbanions derived from
esters with p-allylpalladium complexes, see: a) L. S. Hegedus,
R. E. Williams, M. A. McGuire, T. Hayashi, J. Am. Chem. Soc.
1980, 102, 4973; b) L. S. Hegedus, W. H. Darlington, C. E.
Russell, J. Org. Chem. 1980, 45, 5193; c) H. M. R. Hoffmann,
A. R. Otte, A. Wilde, Angew. Chem. 1992, 104, 224; Angew.
Chem. Int. Ed. Engl. 1992, 31, 234; d) A. R. Otte, A. Wilde,
H. M. R. Hoffmann, Angew. Chem. 1994, 106, 1352; Angew.
Chem. Int. Ed. Engl. 1994, 33, 1280; e) H. M. R. Hoffmann,
A. R. Otte, A. Wilde, S. Menzer, D. J. Williams, Angew. Chem.
1995, 107, 73; Angew. Chem. Int. Ed. Engl. 1995, 34, 100.
[11] a) S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou, L.-X. Dai, J. Am.
Chem. Soc. 2001, 123, 7471; b) X.-L. Hou, S. Na, Org. Lett. 2004,
6, 4399 (correction: X.-L. Hou, S. Na, Org. Lett. 2005, 7, 1435).
[12] Acyclic Organonitrogen Stereodynamics (Eds.: J. B. Lambert, Y.
Takeuchi), VCH, New York, 1992.
Received: October 8, 2007
Revised: November 19, 2007
Published online: January 23, 2008
Keywords: allylic alkylation · amides · enantioselectivity ·
.
ferrocene ligands · palladium
[1] For reviews, see: a) B. M. Trost, D. L. Van Vranken, Chem. Rev.
1996, 96, 395; b) A. Pfaltz, M. Lautens in Comprehensive
Asymmetric Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz,
H. Yamamoto), Springer, New York, 1999, p. 833; c) B. M. Trost,
M. L. Crawley, Chem. Rev. 2003, 103, 2921; d) Z. Lu, S. Ma,
Angew. Chem. 2008, 120, 264; Angew. Chem. Int. Ed. 2008, 47,
258.
[13] Density functional calculations at the B3LYP/6-31 + G* level
revealed that the reactivity of amides 1 depends on the stability
Angew. Chem. Int. Ed. 2008, 47, 1741 –1744
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of the derived carbanion as follows: 1hÀ > 1gÀ ~ 1cÀ > 1dÀ >
[17] a) G. Stallburg, Acta. Chem. Scand. 1957, 11, 1430; b) G. I. Fray,
N. Polgar, J. Chem. Soc., 1956, 2036; c) B. ꢁkermark, Acta.
Chem. Scand. 1962, 3, 1 6.
[18] Density functional calculations at the B3LYP/6-31G level
(Lanl2dz for Pd, Fe, P) showed that the binol moiety of the
ligand and NuÀ are also on the same side of (in this case, above)
the allyl moiety when the ligand with the configuration S,S,R was
used; favorable Si attack gives the S product.
[19] For examples of the transformation of N,N-diphenyl amides, see:
a) O. Meth-Cohn, C. Moore, H. C. Taljaard, J. Chem. Soc. Perkin
Trans. 1 1988, 2663; b) M. E. Scott, M. Lautens, Org. Lett. 2005,
7, 3045; c) S. Arai, K. Tokumaru, T. Aoyama, Tetrahedron Lett.
2004, 45, 1845; for some applications of chiral a-allyl carboxylic
acid derivatives in organic synthesis, see: d) C. Aꢂssa, R.
Riveiros, J. Ragot, A. Fürstner, J. Am. Chem. Soc. 2003, 125,
15512; e) D. Lee, J. K. Sello, S. L. Schreiber, J. Am. Chem. Soc.
1999, 121, 10648.
1aÀ.
[14] For reports on the role of LiCl in Pd-catalyzed AAA, see:
a) M. P. T. Sjꢀgren, S. Hansson, B. ꢁkermark, B. Vitagliano,
Organometallics 1994, 13, 1963; b) U. Burckhardt, M. Baumann,
A. Togni, Tetrahedron: Asymmetry 1997, 8, 155; c) B. M. Trost,
F. D. Toste, J. Am. Chem. Soc. 1999, 121, 4545.
[15] Some other additives were also tested. The addition of Bu4NCl
or Zn(OTf)2 (Tf = trifluoromethanesulfonyl) led to the forma-
tion of the product with better enantioselectivity than in the
reaction with no additive, whereas the product was formed with
lower enantioselectivity in the presence of CuI, CuCl, CuBr,
CuBr2, Cu(OTf)2, AgBr, AgOTf, or LiClO4, and none of the
desired product was formed when LiBr, LiOtBu, Bu4NBr, or
AcONa was added.
[16] The treatment of a sample of the amide 3g with 71% ee with
LiHMDS in THF for 2 h at room temperature gave 3g with
43% ee.
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