Stereoselective intramolecular 1,3 C-H insertion in Rh(II) carbene reactions

Article abstract of DOI:10.1021/ol051130l

(Chemical Equation Presented) 1,3 C-H insertion has been found to be a predominant reaction pathway in the Rh(II)-mediated reaction of β-tosyl α-diazo carbonyl compounds.

Full text of DOI:10.1021/ol051130l

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3103-3106
Stereoselective Intramolecular 1,3 C
Insertion in Rh(II) Carbene Reactions
−H
Weifeng Shi, Bo Zhang, Jian Zhang, Binge Liu, Shiwei Zhang, and Jianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of
Education, College of Chemistry, Peking UniVersity, Beijing 100871, China
wangjb@pku.edu.cn
Received May 16, 2005
ABSTRACT
1,3 C−H insertion has been found to be a predominant reaction pathway in the Rh(II)-mediated reaction of
â-tosyl
r-diazo carbonyl compounds.
Rh(II)-mediated carbenoid intramolecular C-H insertion
reactions have wide application in organic synthesis (Scheme
1).1,2 The factors that govern the site selectivity of the C-H
is overwhelmingly predominant due to the entropically
favorable six-membered transition state.3,4 It has been known
that steric or electronic factors may override this entropic
preference for 1,5 insertions. 1,6 C-H insertions were
sporadically reported for some structurally rigid systems,5
while 1,4 and 1,7 C-H insertions occur when the C-H bond
is activated by a neighboring heteroatom, in most cases
oxygen or nitrogen.6,7 Doyle et al. have reported a rare case
in which a 14-membered ring macrolide is formed in Rh(II)
carbene C-H insertion.8 However, to the best of our knowl-
Scheme 1
(3) For mechanistic investigations on Rh(II) carbene C-H insertions,
see: (a) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108,
7686-7693. (b) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See,
M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc.
1993, 115, 958-964. (c) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994,
116, 3296-3305. (d) Pirrung, M. C.; Morehead, A. T., Jr. J. Am. Chem.
Soc. 1994, 116, 8991-9000. (e) Taber, D. F.; You, K. K.; Rheingold, A.
L. J. Am. Chem. Soc. 1996, 118, 547-556. (f) Wang, J.; Chen, B.; Bao, J.
J. Org. Chem. 1998, 63, 1853-1862. (g) Davies, H. M. L.; Hansen, T.;
Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063-3070. (h) Pirrung,
M. C.; Liu, H.; Morehead, A. T., Jr. J. Am. Chem. Soc. 2002, 124, 1014-
1023. (i) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc.
2002, 124, 7181-7192. (j) Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky,
A. Y. J. Org. Chem. 2002, 67, 4165-4169. (k) Taber, D. F.; Joshi, P. V.
J. Org. Chem. 2004, 69, 4276-4278.
insertion include electronic, steric, and conformational fac-
tors.3 In a freely rotating chain system, 1,5 C-H insertion
(1) For comprehensive reviews, see: (a) Doyle, M. P.; McKervey, M.
A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998. (b) Ye, T.; McKervey,
M. A. Chem. ReV. 1994, 94, 1091-1160. (c) Davies, H. M. L. Chem. ReV.
2003, 103, 2861-2904.
(2) For examples of Rh(II) carbene mediated intramolecular C-H
insertion in organic synthesis, see: (a) Taber, D. F.; You, K. K. J. Am.
Chem. Soc. 1995, 117, 5757-5762. (b) Yakura, T.; Yamada, S.; Kunimune,
Y.; Ueki, A.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1997, 3643-3649.
(c) Brown, R. C.; Hinks, J. D. Chem. Commun. 1998, 1895-1896. (d) Lim,
J.; Choo, D.-J.; Kim, Y. H. Chem. Commun. 2000, 553-554. (e) Wee, A.
G. Tetrahedron Lett. 2000, 41, 9025-9029. (f) Anada, M.; Mita, O.;
Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett 1999, 1775-1777. (g)
Doyle, M. P.; Hu, W.; Valenzuela M. V. J. Org. Chem. 2002, 67, 2954-
2959. (h) Liu, W.-J.; Chen, Z.-L.; Chen, Z.-Y.; Hu, W.-H. Tetrahedron:
Asymmetry 2005, 16, 1693-1698.
(4) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808-4809.
(5) Cane, D. E.; Thomas, P. J. J. Am. Chem. Soc. 1984, 106, 5295-
5303.
(6) For examples, see: (a) Brown, P.; Southgate, R. Tetrahedron Lett.
1986, 27, 247-250. (b) Nanada, M.; Hashimoto, S.-i. Tetrahedron Lett.
1998, 39, 9063-9066. (c) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.;
Jung, K. W. Org. Lett. 2001, 3, 3539-3542. (d) Doyle, M. P.; Kalinin, A.
V.; Ene, D. G. J. Am. Chem. Soc. 1996, 118, 8837-8846.
(7) Lee, E.; Choi, I.; Song, S. Y. Chem. Commun. 1995, 321-322.
10.1021/ol051130l CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/16/2005

Rh(II)-catalyzed reaction of â-substituted R-diazo carbonyl
compounds, we had expected that 1,2-hydride migration
could occur to give the corresponding R,â-unsaturated
compounds.10,12 However, contrary to this expectation, the
Rh2(OAc)4-catalyzed reaction (CH2Cl2, rt, 12 h) of 2a gave
two products, neither of which was the 1,2-hydride migration
product (Scheme 3). One of the products (isolated in 45%
Scheme 2
Scheme 3
edge, 1,3 C-H insertion has not been observed in Rh(II)-
catalyzed reactions of R-diazo carbonyl compounds.9 We
report here the first examples of 1,3 intramolecular C-H
insertion in freely rotating chain systems.
We have recently studied various reactions of â-hydroxy
R-diazo carbonyl compounds, which are easily available by
the deprotonation of acyldiazomethane and the subsequent
addition of the resulting anion to aldehydes or ketones.10 It
has been observed that these diazo compounds react with
TsNHNdCHCOCl/Et3N to give â-(p-tolylsulfonyl) R-diazo
esters.11 Further investigation revealed that the â-position
of R-diazo carbonyl compounds are susceptible to nucleo-
philic substitution.12 Thus, the â-hydroxyl group is converted
to a â-acetoxy group, and the resulting â-acetoxy R-diazo
carbonyl compounds were treated with p-MeC6H4SO2Na to
give â-tosyl R-diazo compounds in good yields (Scheme 2,
Table 1).
yield) was the R-oxo ester 4a, which was generated through
Rh(II)-catalyzed oxidation in the presence of trace oxygen.
The spectral data of the other product (isolated in 40% yield)
showed it was a cyclopropane derivative. Its structure was
unambiguously confirmed as 3a by single-crystal X-ray
analysis, as shown in Figure 1. The X-ray structure reveals
Table 1. Preparation of Diazo Compounds 2a-f by
Nucleophilic Substitution
entry
diazo substrate 1
product
yield (%)a
1
2
3
4
5
6
a, R ) CH3CH2, R′ ) OEt
b, R ) CH3(CH2)2, R′ ) OEt
c, R ) CH3CH2, R′ ) CH3
d, R ) CH3CH2, R′ ) Ph
e, R ) CH3(CH2)3, R′ ) OEt
f, R ) CH3(CH2)5, R′ ) OEt
2a
2b
2c
2d
2e
2f
65
90
80
88
87
82
a Isolated yields after silica gel column chromatography.
To our knowledge, R-diazo compounds with â-tosyl
substituents have not been reported in the literature. We have
been interested in the Rh(II) complex catalyzed reaction of
these novel diazo compounds. From our knowledge of the
Figure 1. X-ray structure of 3a.
(8) Doyle, M. P.; Protopopova, M. N.; Poulter, C. D.; Rogers, D. H. J.
Am. Chem. Soc. 1995, 117, 7281-7282.
that the tosyl group and the ester group are cis to one another,
while the methyl is trans. The formation of a cyclopropane
(9) 1,3 C-H insertion was reported in the Cu-catalyzed reaction of a
structurally rigid diazo compound: Yates, P.; Danishefsky, S. J. Am. Chem.
Soc. 1962, 84, 879-880.
derivative
is
obviously
due
to
an
intra-
molecular 1,3 C-H insertion, and the insertion proceeded
with high stereoselectivity because only one diastereoisomer
was observed.
When the oxidation product 4a was minimized by applying
strict oxygen-free reaction conditions, the yield of 3a
increased to 73%. The 1,3 C-H insertion was found to be
general, as shown in Table 2. For substrates 2b, 2c, and 2d,
(10) (a) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.; Wang, J. J. Org.
Chem. 2003, 68, 893-900. (b) Shi, W.; Jiang, N.; Zhang, S.; Wu, W.; Du,
D.; Wang, J. Org. Lett. 2003, 5, 2243-2246. (c) Yao, W.; Wang, J. Org.
Lett. 2003, 5, 1527-1530. (d) Liao, M.; Yao, W.; Wang, J. Synthesis 2004,
2633-2636. (e) Shi, W.; Xiao, F.; Wang, J. J. Org. Chem. 2005, 70, 4318-
4322.
(11) Shi, W.; Zhang, B.; Liu, B.; Xu, F.; Xiao, F.; Zhang, J.; Zhang, S.;
Wang, J. Tetrahedron Lett. 2004, 45, 4563-4566.
(12) Xu, F.; Shi, W.; Wang, J. J. Org. Chem. 2005, 70, 4191-4194.
3104
Org. Lett., Vol. 7, No. 14, 2005

Table 2. Rh2(OAc)4-Catalyzed Reaction of 2a-e
Table 3. 1,3 C-H Insertion versus 1,5 C-H Insertion
diazo
yield (%)b
(3e+5)
ratioc
(3e:5)
entry substrate solvent temp (°C) yield (3+4)a ratio (3:4)b
entry
solvent
benzene
benzene
benzene
benzene
benzene
ClCH2CH2Cl
ClCH2CH2Cl
catalysta
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2c
2c
2d
2d
2e
CH2Cl2
benzene
CH2Cl2
benzene
CH2Cl2
benzene
CH2Cl2
benzene
benzene
25
80
25
80
25
80
25
80
80
85
88
85
93
75
72
c
86:14
>95:5
47:53
>95:5
88:12
>95:5
1
2
3
4
5
6
7
Rh2(Oct)4
Rh2(OAc)4
Rh2(cap)4
Rh2(pfb)4
Rh2(tfa)4
Rh2(OAc)4
Rh2(tfa)4
96
95
67 (87)d
97
85
80
75
49:51
50:50
57:43
81:19
86:14
54:46
86:14
90
47d
80:20
>95:5
a Rh2(cap)4 is rhodium(II) caprolactamate; Rh2(pfb)4 is rhodium(II)
perfluorobutyrate; Rh2(tfa)4 is rhodium(II) trifluoracetate. b Isolated yields
for 3e and 5 combined. c Ratio determined by 1H NMR (400 MHz). d The
number in brackets refers to the yield based on recovered 2e.
a Isolated yields for 3 and 4 combined. b Ratio determined by isolated 3
and 4. c No reaction occurred under this condition. d 1,5 C-H insertion
product was formed in 51% yield.
4). The structure of 8b was confirmed by single-crystal X-ray
diffraction (Figure 2). Again, the 1,3 C-H insertion proceeds
the Rh(II)-catalyzed reaction gave the corresponding cyclo-
propane derivatives 3b, 3c, and 3d, respectively, in modest
isolated yields, together with the oxidized products 4b, 4c,
and 4d in various amounts. All of the reactions gave a
cyclopropane derivative as a single diastereoisomer. Since
Scheme 4
1
the H NMR spectra data are all similar to that of 3a
(coupling constants 1-H and 2-H are around 9 Hz), it is
reasonable to assume that these products should have the
same configuration as 3a. When the reaction was carried
out in refluxing benzene, the reaction time was shortened (4
h), and the oxidation reaction could be further minimized
(entries 2, 4, and 6).
Diazo compound 2e provides an interesting situation in
which intramolecular 1,5 C-H insertion can compete with
the 1,3 insertion. The Rh2(OAc)4-catalyzed reaction of 2e
gave 1,3 C-H insertion product 3e as a single stereoisomer,
together with the formation of 1,5 C-H insertion products
in approximately the same amount.13 The ratio of 1,5
insertion versus 1,3 insertion is affected by the ligands of
the Rh(II) catalyst (Table 3). The Rh(II) catalysts with
electron-withdrawing ligands favor 1,3 insertion (entries 4,
5, and 7). The solvent, however, does not affect the product
ratio (compare entries 5 and 7).
with high diastereoselectivity with the tosyl group and the
ester group cis to one another.
Intramolecular 1,3 C-H insertion also occurs efficiently
for diazo compounds 7a and 7b, in which spiro compounds
containing the cyclopropane moiety are obtained (Scheme
(13) The 1,3 C-H insertion product 3e and the 1,5 C-H insertion
products 5 could not be separated by silica gel column chromatography.
The ratio was determined by 1H NMR (400 MHz). For the 1,5 insertion
product, there are two stereoisomers.
Figure 2. X-ray structure of 8b.
Org. Lett., Vol. 7, No. 14, 2005
3105

There are two unusual aspects about the Rh2(OAc)4-
catalyzed reaction of 2a-e. The first is that 1,2-hydride
migration, which is usually a very feasible process, does not
occur. The second is the unprecedented formation of the
three-membered ring through Rh(II) carbene 1,3 C-H bond
insertion.
it is noted that one of the 3-H bonds is in close proximity to
the diazo carbon. If one assumes that this is the stable
conformation of the diazo compounds and the corresponding
Rh(II) carbene intermediates in CH2Cl2 solution, then the
1,3 C-H insertion might be simply explained by steric
proximity. This interpretation is supported by the fact that
Rh2(tfa)4 and Rh2(pfb)4 were found to favor 1,3 C-H
insertion in the competition study of 1,3 versus 1,5 C-H
insertion (Table 3, entries 4 and 5). Rh(II) catalysts with
strongly electron-withdrawing ligands are known to make
the Rh(II) carbene more reactive, and thus, the subsequent
reaction proceeds through a earlier, more starting-material-
like transition state.3b Further study is needed to elucidate
the detailed mechanism of 1,3 C-H insertions.
In conclusion, we report here the first examples of 1,3
C-H insertion in freely rotating chain systems. This unusual
1,3 insertion reaction may find utility in organic synthesis
as a new entry to the substituted cyclopropane derivatives.
This study further demonstrates the dramatic effect of
neighboring groups on Rh(II) carbene reactions.
The unique reactivity of â-tosyl diazo compounds may
be interpreted from both steric and electronic considerations.
The strongly electron-withdrawing tosyl group should be
responsible for the inhibition of 1,2-hydride migration. These
results can be compared with the Rh(II)-catalyzed reaction
of â-trichloroacetylamino substituted R-diazo carbonyl com-
pounds, in which case aryl, vinyl, and 1,2-alkynyl migrations
occur exclusively even in the presence of a â-hydrogen.10e
Re-examination of the X-ray structure of 2b11 reveals some
interesting features. The OdC-CdN2 group is found to
possess the s-Z conformation, while the other â-substituted
R-diazo carbonyl compounds that we have studied all have
s-E conformation.14 The diazo group and the carbonyl group
are almost coplanar with a dihedral angle of -0.93°. The
dihedral angle between the C-H bond and the diazo group
is -169.5°. Thus, the C-H is in nearly antiperiplanar
position. The diazo compounds 2a-f are found to be
exceptionally stable. In EI-MS spectra, they all give a
molecular ion peak. In the absence of Rh2(OAc)4, they are
stable when heated in 1,2-dichloroethane.
Acknowledgment. The project is generously supported
by Natural Science Foundation of China (Grant Nos.
20225205, 20390050).
Supporting Information Available: Experimental details
and characterization data for all new compounds, X-ray
crystallographic data of 2b, 3a, and 8b (CIF files). This
material is available free of charge via the Internet at
http://pubs.acs.org.
The intramolecular 1,3 C-H insertions are likely to be
due to conformational factors. In the X-ray structure of 2b,
(14) For a discussion on the conformation of R-diazo carbonyl com-
pounds, see: Kirmse, W. Eur. J. Org. Chem. 2002, 2193-2256.
OL051130L
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Org. Lett., Vol. 7, No. 14, 2005