Highly diastereo- and enantioselective Pd-catalyzed cyclopropanation of acyclic amides with substituted allyl carbonates

Article abstract of DOI:10.1021/ja902410w

(Chemical Equation Presented) A highly diastereo- and enantioselective cyclopropanation reaction was realized in the reaction of acyclic amides with monosubstituted allyl carbonates via Pd-catalysis using a ferrocene ligand with H as a substituent on an o

Full text of DOI:10.1021/ja902410w

Published on Web 06/08/2009
Highly Diastereo- and Enantioselective Pd-Catalyzed Cyclopropanation of
Acyclic Amides with Substituted Allyl Carbonates
Wei Liu,† Di Chen,† Xia-Zhen Zhu,† Xiao-Long Wan,‡ and Xue-Long Hou*,†
State Key Laboratory of Organometallic Chemistry, Department of Analytic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, 200032, China
Received March 26, 2009; E-mail: xlhou@mail.sioc.ac.cn
As one of the most investigated reactions in transition metal catalysis,
palladium-catalyzed asymmetric allylic alkylation reaction has showed its
great power in the enantioselective formation of C-C bonds.1 In most
cases, the products were formed via attack of nucleophiles to the terminal
carbon of π-allyl-Pd intermediates. Hegedus was the first to demonstrate
the formation of cyclopropane by the reaction of π-allylpalladium chloride
with ester enolates via attack of nucleophiles to the central carbon in 1980
that the presence of LiCl had a great impact on the selectivity of
cyclopropanation/allylic alkylation (c/a selectivity) as well as diaste-
reoselectivity of cyclopropanation.7c,d,9 The reaction provided 5a with
a c/a selectivity of 65/35 and dr ratio of 5:1 in the absence of LiCl,
while both c/a selectivity and dr ratio increased to 80/20 and 12:1,
respectively, when 100 mol % of LiCl was added (entry 2 vs 1). Both
c/a selectivity and dr ratio of 5a were lower if nonchloro additives
were used (entries 3-5), which were improved if Bn4NCl or NaCl
was used (entries 8 and 9). The importance of the lithium ion was
revealed from the reaction using NaHMDS or KHMDS as the base;
in both cases the selectivities were lower (entries 10 and 11). The role
of LiCl is confirmed further by the control experiments. The reaction
provided low yields of cyclopropane products with low c/a-, diastereo-
and enantioselectivities using Pd(dba)2/(Sphos,R)-L1 with no additive,
but they increased greatly if 10 mol % of LiCl was added (entry 6 vs
7). The investigation of the effect of solvents on the reaction revealed
that THF was the best among the solvents screened (entry 2 vs entries
14-17). Little fluctuations of yield and selectivity of the reaction were
found when the reaction proceeded at a temperature between 0 to 40
°C (not shown in table).
(Scheme 1).2,4 Since, some procedures have been developed for the
g
formation of cyclopropanes via Pd-mediated reaction of a carbon
nucleophile.3,4 However, few examples have been realized for the
cyclopropanation reaction by using catalytic amounts of Pd-complexes
to date,4 and only one report succeeded in an asymmetric catalytic version
with moderate ee by Satake.5 Pd-catalyzed asymmetric cyclopropanation
reaction with an allyl reagent is still a far less explored field. Recently,
we have showed the use of a “hard” carbanion in Pd-catalyzed asymmetric
allylic alkylation successfully.6,7 Here, we disclose our preliminary results
on the Pd-catalyzed cyclopropanation of acyclic amides with monosub-
stituted allyl carbonates with high diastereo- and enantioselectivities using
our SiocPhox ligand.8
Scheme 1. Pd-Catalyzed Allylic Substitution and Cyclopropanation
The substituent on the oxazoline ring of the ligand has an important
influence on the reaction.6c,d,8,10 Low yield with low c/a- and
diastereoselectivities was given when SiocPhox (S, Sphos,R)-L2 with
an i-Pr group on the oxazoline ring was used as the ligand (entry 12).
An even worse result was provided when (S, Sphos,R)-L3 with a t-Bu
group on the oxazoline ring was used (entry 13). Lower reactivity and
c/a- and diastereoselectivities were also found when allyl acetate or
branched allyl carbonate was used (not shown in table; see SI).
The investigation was initiated from the reaction of amide 1a with
cinnamyl methyl carbonate 2a by using SiocPhox (Rphos,R)-L1 as the
ligand, obtaining branched and linear allylated products 3a and 4a in a
ratio of 4:1. However, cyclopropanation product 5a was obtained
predominantly if SiocPhox (Sphos,R)-L1 was used (eq 1). Although we
failed to separate the products, 3a and 4a were removed by oxidation
using RuCl3/NaIO4 and 5a was obtained exclusively in 60% yield. The
stereochemistry of the major diastereoisomer of 5a was determined by its
2D-NMR (See Supporting Information (SI)).
Under the optimized reaction conditions different amides and
monosubstituted allyl reagents were examined, and the results are
compiled in Table 2. In general, the reaction proceeded smoothly to
afford the cyclopropane products 5 in good yields after removal of
allylation products by oxidation. Three chiral centers were established
in high diastereo- and enantioselectivities, the dr ratio being 4-30 and
the ee value being 83-98%. The acyclic amides with different lengths
of chain are suitable substrates to provide the cyclopropanes 5 in high
To improve the results of this cyclopropanation reaction, the
influence of the reaction parameters was studied (Table 1). It was found
† State Key Laboratory of Organometallic Chemistry.
‡ Department of Analytic Chemistry.
Figure 1. Ferrocene-based ligands SiocPhox L1-L3.
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8734 J. AM. CHEM. SOC. 2009, 131, 8734–8735
10.1021/ja902410w CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
low (entry 13).11 The use of aliphatic allyl reagents in the reaction is
still a challenge.
Table 1. Effects of Additives and Solvents on the Pd-Catalyzed
Reaction of 1a and 2aa
The absolute configuration of 5j was determined as (S,R,R) via its
X-ray diffraction analysis. This result provides support of the NMR
assignment of stereochemistry of 5a mentioned before.
5a
c e
,
entry
solvent
additiveb
3a:4a:5ac
yield%d
d.r.
ee%f
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
Et2O
dioxane
DME
-
LiCl
6:29:65
6:14:80
11:19:70
20:33:47
8:80:12
8:31:61
7:19:74
5:26:69
7:25:68
23:17:60
-
6:77:17
-
13:28:59
14:35:51
16:25:59
10:14:76
60
73
58
40
-
47
62
50
51
46
trace
24l
trace
24
25
40
46
5:1
93
95
84
32
-
84
93
94
91
89
-
-
-
75
72
80
93
The present report realized the asymmetric cyclopropanation reaction
of acyclic amides with monosubstituted allyl substrates in the presence
of Pd-catalyst. Cyclopropane derivatives with three chiral centers were
provided with high diastereo- and enantioselectivities. The impact of
LiCl on the c/a- and diastereoselectivities was demonstrated. Further
investigations on the role of the ligand and the reaction mechanism in
detail as well as on the extension of the reaction scope and applications
of this methodology in organic synthesis are in progress.
12:1
6:1
3:1
4:1
5:1
9:1
11:1
8:1
3:1
-
5.4:1
-
3:1
3:1
5:1
11:1
LiBrg
LiClO4
LiI
g
g
-
LiClh g
,
Bn4NCl
NaCl
NaCli
KClj
LiCl
LiCl
LiCl
LiCl
LiCl
9
10
11
12k
13m
14
15
16
17
Acknowledgment. Financially supported by the Major Basic
Research Development Program (Grant 2006CB806106), National
Natural Science Foundation of China (20532050, 20672130, 20821002),
Chinese Academy of Sciences, Shanghai Committee of Science and
Technology, and Croucher Foundation of Hong Kong. This paper is
dedicated to Professor Li Xin Dai on the occasion of his 85th birthday.
LiCl
a Molar ratio of 1a/[Pd(C3H5)Cl]2/(Sphos,R)-L1/LiHMDS/2a ) 100/2/
4/100/120. b 100 mol % of additive was used. c Determined by GC.
d Isolated yield of 5a. e D.r. of 5a, the structure of minor diastereisomers
was not determined. f Determined by chiral HPLC. g Pd(dba)2 was used.
h 10 mol % of LiCl was added. i NaHMDS as the base. j KHMDS as the
base. k L2 was used. l Isolated yield of 3a, 4a and 5a. m L3 was the
ligand.
Supporting Information Available: General procedure for the Pd-
catalyzed cyclopropanation, NMR spectra and HPLC data for 5, cif file
of X-ray diffraction analysis of 5j. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96,
395. (b) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999;
Vol. 2, p 833. (c) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103,
2921. (d) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(2) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem. 1980, 45,
5193.
(3) (a) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A. Angew. Chem., Int. Ed.
Engl. 1992, 31, 234. (b) Wilde, A.; Otte, A. R.; Hoffmann, H. M. R. J Chem.
Soc., Chem. Commun. 1993, 615. (c) Otte, A. R.; Wilde, A.; Hoffmann,
H. M. R. Angew. Chem., Int. Ed. Engl. 1994, 33, 1280. (d) Hoffmann,
H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams, D. J. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 100.
Table 2. Pd-Catalyzed Cyclopropanation of Acyclic Amides 1 with
Allyl Carbonates 2a
5
entry
R1
R2
R3
yield%b
d.r.c
ee%d
1
2
3
4
5
6
7
8
Me
Et
Ph
Ph
Ph
Ph
H
a, 73
b, 72
c, 72
d, 83
e, 69
f, 68
g, 67
h, 68
i, 67
12:1
12:1
4:1
95
97
94
96
94
96
84
91
83
92
93
98
89
H
H
H
H
H
H
H
H
H
H
Me
H
nPr
iPr
Me
Me
Me
Me
Me
iPr
Me
Me
Me
6:1
p-MeC6H5
p-MeOC6H5
p-FC6H5
p-ClC6H5
p-BrC6H5
p-BrC6H5
1-Naphthyl
Ph
15:1
23:1
11:1
7:1
8:1
5:1
8:1
30:1
3:1
(4) (a) Carfagna, C.; Mariani, L.; Musco, A.; Sallese, G.; Santi, R. J. Org.
Chem. 1991, 56, 3924. (b) Formica, M.; Musco, A.; Pontellini, R.; Linn,
K.; Mealli, C. J. Organomet. Chem. 1993, 448, C6. (c) Satake, A.; Nakata,
T. J. Am. Chem. Soc. 1998, 120, 10391. (d) Satake, A.; Koshino, H.; Nakata,
T. Chem. Lett. 1999, 49. (e) Grigg, R.; Kordes, M. Eur. J. Org. Chem.
2001, 707. (f) Shintani, R.; Park, S.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 14866.
9
10
11
12
13
j, 74
k, 68
l, 37
(5) (e) Satake, A.; Kadohama, H.; Koshino, H.; Nakata, T. Tetrahedron Lett.
1999, 40, 3597.
Me
m, 18
(6) (a) You, S. L.; Hou, X. L.; Dai, L. X.; Zhu, X. Z. Org. Lett. 2001, 3, 149.
(b) Yan, X. X.; Liang, C. G.; Zhang, Y.; Hong, W.; Cao, B. X.; Dai, L.-
X.; Hou, X.-L. Angew. Chem., Int. Ed. 2005, 44, 6544. (c) Zheng, W. H.;
Zheng, B. H.; Zhang, Y.; Hou, X.-L. J. Am. Chem. Soc. 2007, 129, 7718.
(d) Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y. D. Angew. Chem., Int. Ed.
2008, 47, 1741.
a Molar ratio of 1/[Pd(C3H5)Cl]2/(Sphos,R)-L1/LiHMDS/2/LiCl ) 100/
2/4/100/120/100. b Isolated yield of 5. c D.r. of 5 determined by GC, the
structure of minor diastereoisomers was not determined. d Determined
by chiral HPLC.
(7) Some other examples of “hard” carbanions in Pd-catalyzed AAA reactions: (a)
Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759. (b)
Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000, 39, 3494.
(c) Weiss, T. D.; Helmchen, G.; Kazmaier, U. Chem. Commun. 2002, 1270.
(d) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (e)
Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. (f) Trost, B. M.; Xu,
J. J. Am. Chem. Soc. 2005, 127, 17180. (g) Trost, B. M.; Zhang, Y. J. Am.
Chem. Soc. 2006, 128, 4590. (h) Trost, B. M.; Xu, J.; Reichle, M. J. Am.
ee (entries 1-4 and 10), though the diastereoselectivity decreased when
the R1 group of 1 was n-Pr (entry 3) or i-Pr (entries 4 and 10). However,
the reaction of isobutanamide failed to give the desired product (not
shown in table). The electronic property of the substituent on the phenyl
ring in allyl reagents 2 has some impact on the diastereo- and
enantioselectivities of the reaction. The presence of an electron-donating
group in 2 favored the gain of 5 in higher diastereo- and enantiose-
lectivities (entries 5 and 6 vs 7-10). Cyclopropane product 5k in higher
enantioselectivity was also obtained when naphthyl substituted carbon-
ate 2 was used (entry 11). Note that gem-disubstituted allyl carbonate
could also be used, providing 5l with a chiral quaternary carbon center
on the cyclopropane ring with even higher diastereo- and enantiose-
lectivities, the dr ratio being 30:1 and ee being 98%, albeit the yield
was lower (entry 12).11 When crotyl carbonate was the reagent, high
enantioselectivity was given, but the yield and diastereoselectivity were
´
Chem. Soc. 2007, 129, 282. (i) Be´langer, E.; Cantin, K.; Messe, O.;
Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc. 2007, 129, 1034. (j) Deska,
J.; Kazmaier, U. Angew. Chem., Int. Ed. 2007, 46, 4570.
(8) SiocPhox is named after Shanghai Institute of Organic Chemistry where
they are developed. For its first report: You, S.-L.; Zhu, X.-Z.; Luo, Y.-
M.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471.
(9) Some reports on the role of LiCl in Pd-catalyzed AAA: (a) Sjo¨gren,
M. P. T.; Hansson, S.; Åkermark, B.; Vitagliano, A. Organometallics 1994,
13, 1963. (b) Burckhardt, U.; Baumann, M.; Togni, A. Tetrahedron:
Asymmetry 1997, 8, 155. (c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
1999, 121, 4545. (d) Cantat, T.; Ge´nin, E.; Giroud, C.; Meyer, G.; Jutand,
A. J. Organomet. Chem. 2003, 687, 365.
(10) Hou, X.-L.; Sun, N. Org. Lett. 2004, 6, 4399.
(11) The main products were allylation products.
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