Use of achiral additives to increase the stereoselectivity in Rh(ii)-catalyzed cyclopropanations

Article abstract of DOI:10.1039/b920587j

We describe our studies on the effect of various Lewis bases and Bronsted acids as achiral additives on the stereoselectivity of some Rh(ii)-catalyzed cyclopropanations. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b920587j

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Use of achiral additives to increase the stereoselectivity
in Rh(II)-catalyzed cyclopropanationswz
David Marcoux, Vincent N. G. Lindsay and Andre B. Charette*
Received (in Cambridge, UK) 5th October 2009, Accepted 11th December 2009
First published as an Advance Article on the web 7th January 2010
DOI: 10.1039/b920587j
We describe our studies on the effect of various Lewis bases and
Brønsted acids as achiral additives on the stereoselectivity of
some Rh(II)-catalyzed cyclopropanations.
Over the past two decades, stereoselective Rh(II)-catalyzed cyclo-
propanation reactions have received much attention.1 These
methods have been demonstrated to be among the most reliable
means of accessing chiral 1,1-disubstituted cyclopropanes.
Donor–acceptor Rh(II)-carbenes are well established to provide
high levels of diastereocontrol.1a As such, many reports of highly
enantio- and diastereoselective cyclopropanations using diazo
reagents bearing an acceptor and a donor group have been
described.2 However, little is known about the stereoselective
cyclopropanation using diazo reagents bearing two acceptor
groups.3 Indeed, low levels of enantio- and diastereocontrol are
associated with such reagents. As part of our research program
Fig. 1 Structures of different Rh(II) catalysts.
aimed at addressing these issues, we recently reported several
highly enantio- and diastereoselective reactions using diazo
reagents bearing two acceptor groups.4–6 During the course of
these studies, we observed the important effect of various achiral
additives on the corresponding selectivity. The purpose of this
communication is to describe our results on the study of the effect
of achiral Lewis bases and Brønsted acids as additives on
stereoselective Rh(II)-catalyzed cyclopropanation reactions.7,8
During our work towards developing a highly stereoselective
method for the synthesis of cyclopropane 3a, we observed that
diazo 1a was quite stable to Rh(II)-catalyzed decomposition
(Fig. 1). In some reactions that did not go to completion, the
residual diazo starting material was recovered. To fully consume
the unreacted diazo 1a and to facilitate purification of the
corresponding cyclopropane 3a, we considered adding different
Brønsted acids to decompose this residual diazo compound.
Surprisingly, 1a was found to be quite stable to acidic media as
well, but performing the reactions in the presence of these acidic
additives, in catalytic amounts, affected the enantioselectivity
(Table 1).4b Indeed, sulfonic amide additives displayed a non-
negligible effect (entries 8–10). TfNH2 was found to be optimal,
increasing the enantioselectivity from 49 : 1 er to 57 : 1 er
(entry 8). Interestingly, none of the Lewis bases examined led
to an increase of the selectivity (entries 2–6). Instead, the catalyst
Table 1 Study of the effect of achiral additives on the stereoselective
formation of 3a
Entry
Additive (x)
Yield (%)a
erc
1
2
3
4
5
6
7
8
9
10
None
79
—
10
14
67
62
73
78
75
75
49 : 1
—
ND
DMAP (10)
DMAP (1)
Pyridine (1)
MeCN (10)
DMF (10)
AcOH (10)
TfNH2 (10)
MsNH2 (10)
TsNH2 (10)
ND
49 : 1
49 : 1
49 : 1
57 : 1
39 : 1
28 : 1
a
Determined by 1H NMR spectroscopy of the crude mixture using an
internal standard. Determined by 1H NMR spectroscopy of the crude
c
mixture. Determined by SFC analysis on a chiral stationary phase.
b
was deactivated by these bases, leading to a low consumption of
diazo 1a, consequently affording a low yield of the desired
cyclopropane 3a. In all cases (Table 1), the investigated additives
had no effect on the diastereoselectivity of this reaction.
´
Departement de chimie, Universite de Montreal, 2900, boul. Edouard-
´
Montpetit, Montreal, Canada. E-mail: andre.charette@umontreal.ca;
´
´
´
Fax: +1 (514) 343-5900; Tel: +1 (514) 343-6283
Interested by the stereoselective formation of cyclopropane 3b,
we developed conditions to obtain 3b in 10 : 1 dr and 13 : 1 er
(Table 2, entry 1). Cognizant of the effect of different additives on
the formation of 3a, we considered their application in the synthesis
of 3b.4a,f Performing the reaction with 10 mol% of different Lewis
bases led to a negative effect on the selectivity (entries 2–6).
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: General
experimental procedures. See DOI: 10.1039/b920587j
ꢀc
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Table 2 Study of the effect of achiral additives on the stereoselective
formation of 3b
Table 3 Study of the effect of achiral additives on the stereoselective
formation of 3c
Yield (%)a
drb
erc
Entry
Additive (x)
Yield (%)a
drb
erc
Entry
Additive (x)
1
None
80
42
78
70
77
85
89
68
70
49 : 1
32 : 1
32 : 1
32 : 1
49 : 1
49 : 1
49 : 1
16 : 1
16 : 1
27 : 1
39 : 1
39 : 1
32 : 1
28 : 1
28 : 1
28 : 1
14 : 1
14 : 1
1
2
3
4
5
6
7
8
9
None
73
14
62
59
81
78
77
77
80
75
—
67
10 : 1
6 : 1
7 : 1
13 : 1
9 : 1
10 : 1
6 : 1
12 : 1
7 : 1
10 : 1
39 : 1
24 : 1
5 : 1
2d
3
DMAP (5)
DMAP (1)
Pyr (1)
AcOH (10)
TfNH2 (10)
MsNH2 (10)
None
DMAP (10)
DMAP (1)
Pyr (1)
4
5
6
8 : 1
MeCN (10)
DMF (10)
AcOH (10)
TfNH2 (10)
MsNH2 (10)
TsNH2 (10)
TfOH (10)
Tf2NH (10)
10 : 1
10 : 1
12 : 1
24 : 1
16 : 1
9 : 1
7
8e
9e
DMAP (1)
a
b
Isolated yields. Determined by 1H NMR spectroscopy of the crude
10
11
12
c
mixture. Determined by SFC analysis on a chiral stationary phase.
d
—
2 : 1
—
2 : 1
e
Reaction time of 48 h. Reaction performed at 0 1C.
Determined by 1H NMR spectroscopy of the crude mixture using an
a
internal standard. Determined by 1H NMR spectroscopy of the crude
b
c
mixture. Determined by SFC analysis on a chiral stationary phase.
However, Brønsted acids improved the selectivity of the
reaction quite remarkably (entries 7–12). We were pleased to
isolate the desired cyclopropane 3b in 24 : 1 dr and 39 : 1 er when
10 mol% of TfNH2 was used in the reaction (entry 8). This
represents a significant increase relative to the selectivity of 10 : 1 dr
and 13 : 1 er obtained without the use of additive (entry 1).
Other sulfonamides also affected the selectivity but TfNH2 was
found to be optimal (entries 8–10). More acidic Tf2NH led to
decreased levels of selectivity while TfOH led to a complex mixture
of products (entries 11–12). This is presumably due to the low
stability of diazo 1b in the presence of highly acidic compounds.
Based on these results, we were intrigued by the effect of
additives in other Rh(II)-catalyzed cyclopropanations. We
recently reported a highly enantio- and diastereoselective
formation of 1-nitro-1-phenylketone cyclopropane 3c using
Rh2(S-TCPTTL)4.4d We studied the use of a variety of Lewis
bases and Brønsted acids in this reaction (Table 3). None of
the Brønsted acids investigated increased the selectivity. To
our delight, we found that the use of 1 mol% of DMAP
improved the enantioselectivity from 27 : 1 er to 39 : 1 er
(entry 3). Increasing the amount of DMAP led to decreased
yields with no further improvement in selectivity (entry 2). The
DMAP effect was only observed at low temperature as the
selectivity was not affected when the reaction was performed
at 0 1C (entries 8–9). A possible explanation is that the
uncomplexed and more reactive Rh2(S-TCPTTL)4 is
present at room temperature giving access to a faster
Rh2(S-TCPTTL)4-catalyzed process (Fig. 2). However, at
low temperature, Rh2(S-TCPTTL)4ꢁDMAP is formed exclusively.
The Rh2(S-TCPTTL)4ꢁDMAP is a less active catalyst that would
favour a later transition state, enhancing the enantioinduction
according to the Hammond postulate.
Fig. 2 Reactive catalyst.
Table 4 Study of the effect of achiral additives on the stereoselective
formation of 3d
Entry
Additive (x)
Yield (%)a
drb
1
2
3
4
5
6
7
8
None
97
17
74
91
93
96
96
97
7 : 1
7 : 1
8 : 1
7 : 1
7 : 1
7 : 1
7 : 1
7 : 1
DMAP (10)
Pyridine (10)
DMF (10)
MeCN (10)
AcOH (10)
TfNH2 (10)
MsNH2 (10)
Determined by 1H NMR spectroscopy of the crude mixture using an
internal standard. Determined by 1H NMR spectroscopy of the
crude mixture.
a
b
that the additives in the previous reactions might display their
effects on the chiral environment induced by the chiral catalyst.
When we studied the formation of 3d, we observed that
diazo reagent 1d and the in situ generated iodonium ylide
reagent derived from 4 afforded different level of diastereo-
selectivity in their respective Rh2(oct)4-catalyzed reactions
(eqn (1)–(2)).5b However, performing the same reaction with
diazo 1d in the presence of PhI(OAc)2 and Na2CO3 as
additives furnished a 86 : 14 dr for the desired compound, that
is the same diastereoselectivity observed with the reaction
involving 4. This negative effect of achiral additives in a
Rh2(oct)4-catalyzed cyclopropanation reaction suggests that
We next investigated the effect of these additives on the
diastereoselective Rh2(oct)4-catalyzed reaction involving diazo
1d (Table 4).5b Interestingly, none of the additives investigated
above significantly increased the diastereoselectivity, suggesting
ꢀc
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Table 5 Study of the effect of achiral additives on the stereoselective
formation of 3e
of different Rh(II)-catalyzed cyclopropanations. TfNH2 and
DMAP have been shown to be optimal with Rh2(S-NTTL)4
and Rh2(S-TCPTTL)4, respectively, suggesting a correlation
between the additive and the corresponding symmetry of the
catalyst with a carbene possessing two acceptors groups.
Unfortunately, donor–acceptor Rh(II)-carbenes have not been
positively influenced by the additives investigated in the current
study. Work taking advantage of these effects of additives is
under investigation and will be reported in due course.
This work was supported by the NSERC (Canada), the
Canada Research Chair Program, and the Universite de
Montreal. D.M. is grateful to the NSERC (PGS D), the
Universite de Montreal, and the Financiere Manuvie for
predoctoral fellowships. V.N.G.L. is grateful to the NSERC
(PGS D) and the Universite de Montreal for a predoctoral
fellowship. Jad Tannous (Universite de Montreal) is acknowl-
edged for SFC analysis.
Entry
Additive (x)
Yield (%)a
erc
1
2
3
4
5
6
7
8
9
None
85
24
72
84
83
86
88
80
77
16 : 1
14 : 1
16 : 1
16 : 1
14 : 1
13 : 1
8 : 1
DMAP (10)
DMAP (1)
AcOH (10)
MeCN (10)
DMF (10)
TfNH2 (10)
TfNH2 (50)
MsNH2 (10)
8 : 1
10 : 1
a
Determined by 1H NMR spectroscopy of the crude mixture using an
internal standard. Determined by 1H NMR spectroscopy of the crude
c
mixture. Determined by SFC analysis on a chiral stationary phase.
b
Notes and references
1 (a) H. Lebel, J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem.
Rev., 2003, 103, 977; (b) M. Doyle, M. McKervey and T. Ye,
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides, John Wiley & Sons
Inc., New York, 1998; (c) H. M. L. Davies and E. G. Antoulinakis,
Org. React., 2001, 57, 1; (d) H. Pellissier, Tetrahedron, 2008, 64,
7041.
both processes might go through the same Rh-carbene
intermediate.
2 (a) H. M. L. Davies, Eur. J. Org. Chem., 1999, 2459; (b) H. M.
L. Davies, Curr. Org. Chem., 1998, 2, 463; (c) J. R. Denton and
H. M. L. Davies, Org. Lett., 2009, 11, 787; (d) J. R. Denton,
K. Cheng and H. M. L. Davies, Chem. Commun., 2008, 1238;
(e) J. R. Denton, D. Sukumaran and H. M. L. Davies, Org. Lett.,
2007, 9, 2625; (f) R. P. Reddy and H. M. L. Davies, Org. Lett., 2006,
8, 5013; (g) H. M. L. Davies and G. H. Lee, Org. Lett., 2004, 6,
2117; (h) R. P. Reddy, G. H. Lee and H. M. L. Davies, Org. Lett.,
2006, 8, 3437.
ð1Þ
3 M. P. Doyle, Angew. Chem., Int. Ed., 2009, 48, 850.
4 (a) D. Marcoux, S. Azzi and A. B. Charette, J. Am. Chem. Soc.,
2009, 131, 6970; (b) D. Marcoux and A. B. Charette, Angew. Chem.,
Int. Ed., 2008, 47, 10155; (c) B. Moreau and A. B. Charette, J. Am.
Chem. Soc., 2005, 127, 18014; (d) V. N. G. Lindsay, W. Lin and
A. B. Charette, J. Am. Chem. Soc., 2009, 131, 16383; (e) W. Lin and
A. B. Charette, Adv. Synth. Catal., 2005, 347, 1547; (f) D. Marcoux,
S. R. Goudreau and A. B. Charette, J. Org. Chem., 2009, 74, 8939.
5 For the formation of racemic cyclopropanes bearing 1,1-diacceptor
groups, see: (a) S. R. Goudreau, D. Marcoux and A. B. Charette,
J. Org. Chem., 2009, 74, 470; (b) R. P. Wurz and A. B. Charette,
Org. Lett., 2005, 7, 2313; (c) R. P. Wurz and A. B. Charette, J. Org.
Chem., 2004, 69, 1262; (d) R. P. Wurz and A. B. Charette,
Org. Lett., 2003, 5, 2327; (e) A. B. Charette and R. Wurz, J. Mol.
Catal. A: Chem., 2003, 196, 83; (f) A. B. Charette, R. P. Wurz and
T. Ollevier, Helv. Chim. Acta, 2002, 85, 4468.
6 For an example of Co(II)-catalyzed cyclopropanation using a diazo
reagent bearing two acceptor groups, see: S. Zhu, J. A. Perman and
X. P. Zhang, Angew. Chem., Int. Ed., 2008, 47, 8460.
7 For the study of additives in Rh(II)-catalyzed transformation, see:
(a) H. M. L. Davies and C. Venkataramani, Org. Lett., 2003, 5,
1403; (b) D. C. Wynne, W. M. Olmstead and P. G. Jessop, J. Am.
Chem. Soc., 2000, 122, 7638; (c) T. D. Nelson, Z. J. Song,
A. S. Thompson, M. Zhao, A. DeMarco, R. A. Reamer,
M. F. Huntington, E. J. J. Grabowski and P. J. Reider, Tetrahedron
Lett., 2000, 41, 1877.
ð2Þ
Finally, we investigated the effect of these additives on the
stereoselective cyclopropanation using donor–acceptor diazo
reagent 1e and Rh2(S-DOSP)4 as catalyst (Table 5).9
Unfortunately, TfNH2 and MsNH2 led to decreased levels of
selectivity, presumably due to the low stability of these diazo
reagents toward these acids (entries 7–9). Though weaker acids
do not decompose these reagents, virtually no effect was
observed on the selectivity (entry 4). Unfortunately, none of
the Lewis bases investigated afforded the desired cyclopropane
with enhanced results (entries 2, 3, 5, 6). Though these
additives are not suitable in the reaction, Davies and
Venkataramani have reported that methylbenzoate can increase
the selectivity of this reaction at low catalyst loading.7a This
demonstrates the differences in electronics between diacceptor
and donor–acceptor carbenes.
8 For the study of additives in Co(II)-catalyzed cyclopropanation, see:
(a) Y. Chen, K. B. Fields and X. P. Zhang, J. Am. Chem. Soc., 2004,
126, 14718; (b) Y. Chen and X. P. Zhang, Synthesis, 2006, 1697;
(c) Y. Chen, J. V. Ruppel and X. P. Zhang, J. Am. Chem. Soc., 2007,
129, 12074.
In conclusion, we have demonstrated that various achiral
additives such as Lewis bases and Brønsted acids can sometimes
display moderate to important effects on the stereoselectivity
9 H. M. L. Davies, P. R. Bruzinski and M. J. Fall, Tetrahedron Lett.,
1996, 37, 4133.
ꢀc
This journal is The Royal Society of Chemistry 2010
912 | Chem. Commun., 2010, 46, 910–912