Cyclopentane construction by Rh-catalyzed intramolecular C-H insertion: Relative reactivity of a range of catalysts

Article abstract of DOI:10.1021/jo0303766

The preparation and Rh-mediated cyclization of the α-diazoester 1 are outlined, and its utility in determining the elements that contribute to the reactivity of the intermediate Rh-carbenoid is presented. The rate of disappearance of diazo ester 1 catalyz

Full text of DOI:10.1021/jo0303766

complex over another having been reported. We thought
that it would be useful to compare the several catalysts
with a single substrate 1.2-4 As we embarked on this
study, it was apparent that there were four potentially
independent aspects of “reactivity”: the rate of bimo-
lecular transfer of the diazo ester to the Rh-complex,2 the
ratio of C-H insertion to â-H elimination [(3 + 4 + 5)/
2],1l the chemoselectivity (3/4 + 5),1w and the diastereo-
selectivity of the insertion (4/5).1r
Cyclop en ta n e Con str u ction by
Rh -Ca ta lyzed In tr a m olecu la r C-H
In ser tion : Rela tive Rea ctivity of a Ra n ge
of Ca ta lysts
Douglass F. Taber* and Pramod V. J oshi
Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716
taberdf@udel.edu
Received December 4, 2003
Abstr a ct: The preparation and Rh-mediated cyclization of
the R-diazoester 1 are outlined, and its utility in determining
the elements that contribute to the reactivity of the inter-
mediate Rh-carbenoid is presented. The rate of disappear-
ance of diazo ester 1 catalyzed by several representative
Rh(II) complexes was determined. The observed relative rate
constants for the reaction of the Rh(II) complexes with 1
varied over a range of >107. The reactivity of the Rh-
carbenoid intermediate was explored using the ratio of the
sum of (3 + 4 + 5) to 2 (cyclization vs elimination), the ratio
of 3 to the sum of (4 + 5) (chemoselectivity), and the ratio
of 4 to 5 (diastereoselectivity). It is striking that these four
measures of reactivity were found to be independent of each
other.
We selected a series of Rh(II) carboxylates, Rh(II)
carboxamidate1p (Doyle catalysts 6h -j), and the bridged
Rh(II) carboxylate5b (Lahuerta catalyst 6g) as represen-
tative of the various Rh(II) catalysts in use today (Figure
1). Most of the carboxylate and Doyle catalysts were
commercially available. They were purified by silica gel
chromatography before use. The Lahuerta catalyst was
prepared according to the literature procedure,5b and its
structure was confirmed by X-ray analysis.
Cyclopentane construction by Rh-mediated C-H inser-
tion reaction (e.g., 1 f 3 + 4 + 5 ) has achieved wide
popularity.1 Several different Rh complexes have been
reported to effect cyclization, with advantages of one
Ob ser ved R ela t ive R a t e Con st a n t s. Following
Pirrung,2c we expected that the Rh catalysts would show
saturation kinetics, so that disappearance of starting
material would be linear with time. We monitored
disappearance of the diazoester, at 27 ( 1 ° C, by
following the UV absorbance at λ ) 265 nm. Each of the
Rh(II) complexes was purified by silica gel chromatog-
raphy to ensure that no axial ligands would be present
that would affect reactivity. The decrease in absorbance
of the starting material was plotted versus time. The
approximately linear portion of this direct plot, from 80%
to 30% of the absorbance, was used to calculate, by
dividing by catalyst concentrations, the relative rate
constants for each of the Rh(II) complexes.
(1) For studies of selective cyclopentane construction by Rh-mediated
intramolecular C-H insertion, see: (a) Wenkert, E.; Davis, L. L.;
Mylari, B. L.; Solomon, M. F.; da Silva, R. R.; Shulman, S.; Warnet,
R. J .; Ceccherelli, P.; Curini, M.; Pellicciari, R. J . Org. Chem. 1982,
47, 3242. (b) Taber D. F.; Petty, E. H. J . Org. Chem. 1982, 47, 4808.
(c) Cane, D. E.; Thomas, P. J . J . Am. Chem. Soc. 1984, 106, 5295. (d)
Rao, V. B.; George, C. F.; Wolff, S.; Agosta, W. C. J . Am. Chem. Soc.
1985, 107, 5732. (e) Taber, D. F.; Ruckle, R. E., J r. J . Am. Chem. Soc.
1986, 108, 7686. (f) Corbel, B.; Hernot, D.; Haelters, J .-P.; Sturtz, G.
Tetrahedron Lett. 1987, 28, 6605. (g) Hashimoto, S.-i.; Shinoda, T.;
Shimada, Y.; Honda, T.; Ikegami, S. Tetrahedron Lett. 1987, 28, 637.
(h) Corey, E J .; Kamiyama, K. Tetrahedron Lett. 1990, 31, 3995. (i)
Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990,
31, 5173. (j) Doyle, M. P.; Pieters, R. J .; Taunton, J .; Pho, H. Q.; Padwa,
A.; Hertzog, D. L. J . Org. Chem. 1991, 56, 820. (k) Ceccherelli, P.;
Curini, M.; Marcotullio, M. C.; Rosati, O.; Wenkert, E. J . Org. Chem.
1991, 56, 7065. (l) Taber, D. F.; Hennessy, M. J .; Louey, J . P. J . Org.
Chem. 1992, 57, 436. (m) Padwa, A.; Austin, D. J .; Hornbuckle, S. F.;
Semones, M. A.; Doyle, M. P.; Protopopova, M. N. J . Am. Chem. Soc.
1992, 114, 1874. (n) Hashimoto, S.-i.; Watanabe, N.; Ikegami, S.
Tetrahedron Lett. 1992, 33, 2709. (o) Doyle, M. P.; Wetsrum, L. J .;
Wolthius, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson,
M. M. J . Am. Chem. Soc. 1993, 115, 958. (p) Wang, P.; Adams, J . J .
Am. Chem. Soc. 1994, 116, 3296. (q) Doyle, M. P.; Dyatkin, A. B.; Roos,
G. H. P.; Canas, F.; Pierson, D. A.; van Basten, A.; Muller, P.; Polleux,
P. J . Am. Chem. Soc. 1994, 116, 4507. (r) Taber, D. F.; You, K. K. J .
Am. Chem. Soc. 1995, 117, 5757. (s) Miah, S.; Slawin, A. M. Z.; Moody,
C. J .; Sheehan, S. M.; Marino, J . P.; Semones, M.; Pawda, A.; Richards,
I. C. Tetrahedron 1996, 52, 2489. (t) Doyle, M. P. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclo-
propanes to Ylides; Wiley: New York, 1998. (u) Wang, J .; Chen, B.;
Bao, J . J . Org. Chem. 1998, 63, 1853. (v) Taber, D. F.; Green, J . H.;
Zhang, W.; Song, R. J . Org. Chem. 2000, 65, 5436. (w) Taber, D. F.;
Malcolm, S. C. J . Org. Chem. 2001, 66, 944. (x) Davies, H. M. L.;
Grazini, M. V. A.; Aouad, E. Org. Lett. 2001, 3, 1475. (y) Yoon, C. H.;
Zaworotko, M. J .; Moulton, B.; J ung, K. W. Org. Lett. 2001, 3, 3539.
(z) Doyle, M. P.; Davies, S. B.; May, E. J . J . Org. Chem. 2001, 66, 8112.
The rate constants (Table 1) varied over a range of
>107. The pivalate catalyst (entry 3) stands out, being
(2) (a) Alonso, M. E.; Carmen Garcia, M.-d. Tetrahedron 1989, 45,
69. (b) Chipperfield, J . R. J . Organomet. Chem. 1989, 363, 253. (c)
Pirrung, M. C.; Morehead, A. T. J . Am. Chem. Soc. 1994, 116, 8991.
(d) Pirrung, M. C.; Morehead, A. T. J . Am. Chem. Soc. 1996, 118, 8162.
(e) Pirrung, M. C.; Liu, H.; Morehead, A. T. J . Am. Chem. Soc. 2002,
124, 1014.
(3) For the development of this model, see: (a) Taber, D. F.; You,
K.; Rheingold, A. L. J . Am. Chem. Soc. 1996, 118, 547. (b) Taber, D.
F.; Malcolm, S. C. J . Org. Chem. 1998, 63, 3717.
(4) For a detailed theoretical treatment of Rh(II)-mediated C-H
insertion, see: Nakamura, E.; Yoshikai, N.; Yamanaka, M. J . Am.
Chem. Soc. 2002, 124, 7181.
(5) (a) Taber, D. F.; Malcolm, S. C.; Bieger, K.; Lahuerta, P.; Sanau,
M.; Stiriba, S.-E.; Perez-Prieto, J .; Monge, M. A. J . Am. Chem. Soc.
1999, 121, 860. (b) Lahuerta, P.; Periera, I.; Perez-Prieto, J .; Sarau,
M.; Stiriba, S.-E.; Taber, D. F. J . Organomet. Chem. 2000, 612, 36.
10.1021/jo0303766 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/15/2004
4276
J . Org. Chem. 2004, 69, 4276-4278

F IGURE 2. Newman projection of Rh-carbenoid.
SCHEME 1a
a
Conditions: (a) Rh2Oct4, CH2Cl2, rt, I/A ) 2.8/1; Rh2(MPPIM)4,
CH2Cl2, rt, I/A ) 0.
MEPY catalyst (entry 8) and MPPIM catalyst (entry 10).
The amide analogue, MPPIM, showed the least â-elim-
ination product. We were concerned that the application
of an enantiomerically pure catalyst to a racemic sub-
strate might bias the results, so we repeated one of the
cyclizations using “racemic” (1:1 R/S) catalyst. The
resulting product ratios (entry 11) were the same as those
observed for the enantiomerically pure catalyst.
We believe that two factors govern the ratio of insertion
to elimination: the “earliness” vs “lateness” of the transi-
tion state and the steric bulk of the ligand on the Rh-
carbenoid. A“hot” carbenoid would have an early tran-
sition state, favoring â-H elimination over 1,5 insertion.
We expect that the increased proportion of elimination
observed with Rh trifluoroacetate (entry 5), for instance,
is due to the electron-withdrawing nature of the ligand.
This makes the carbene carbon more strongly positive
and thus more reactive.
The steric effects become clear on inspecting the
Newman projections of the transition states as shown in
Figure 2. The conformation 7a can lead to cyclopentane
formation, while the conformation 7b can give only â-H
elimination. As the Rh carbenoid becomes larger, con-
formation 7b is increasingly favored. Thus, as the steric
bulk of the ligands on the Rh carbenoid increases going
from acetate (entry 1) to the TPA catalyst (entry 4), there
is a significant increase in the proportion of â-hydride
elimination.
The R-diazo ester 1 with its γ-branching was designed
to minimize â-H elimination. The reaction of R-diazo
methyl undecylenate 8 with Rh2Oct4 (6b) gave an I/A
ratio of 2.8, while reaction with Rh2(MPPIM)4 (6j) gave
only the â-H elimination product 10 (Scheme 1).
Meth in e to Meth ylen e Selectivity. In the carbox-
ylate series, the TPA catalyst (Table 3, entry 4) was the
most selective for methine over methylene insertion.
Should this prove to be general, 6d may add a possibility
for high chemoselectivity not previously observed with
Rh(II) catalysts. The other carboxylate catalysts show
less preference for CH over CH2 insertion. Our design of
the R-diazo ester 1 included the p-methoxy group on the
benzene ring, so the methylene benzylic C-H would
approach the methine in reactivity. We expect that the
CH/CH2 ratios would be more pronounced with a less
carefully balanced substrate.
F IGURE 1. Structures of Rh(II) catalysts used in this study.
TABLE 1. Rela tive Ra te Con sta n ts for th e Rh (II)
Ca ta lysts
catalyst
Rh2Ac4, 6a
Rh2Oct4, 6b
Rh2Piv4, 6c
Rh2TPA4, 6d
Rh2TFA4, 6e
Rh2(R-PTPA)4, 6f
Rh2Ac2(Ph2P(C6H4))2, 6g
Rh2(5R-MEPY)4, 6h
Rh2(4S-MeOX)4, 6i
Rh2(4S-MPPIM)4, 6j
relative kob
1
2
3
4
5
6
7
8
9
2.56 × 104
4.28 × 104
2.34 × 107
1.06 × 105
1.03 × 105
2.24 × 105
5.82 × 104
1.0
3.53 × 101
10
1.97 × 101
TABLE 2. Ra tio of In ser tion (3 + 4 + 5) to Alk en e (2)
(I/A) for th e Rh (II) Ca ta lysts
isolated
catalysts
Rh2Ac4, 6a
Rh2Oct4, 6b
Rh2Piv4, 6c
Rh2TPA4, 6d
Rh2TFA4, 6e
Rh2(R-PTPA)4, 6f
Rh2Ac2(Ph2P(C6H4))2, 6g
Rh2(5R-MEPY)4, 6h
Rh2(4S-MeOX)4 6i
yields (%) I/A (HPLC) I/A (NMR)
1
2
3
4
5
6
7
8
9
99
87
91
94
96
96
94
92
95
96
94
15.4
31.3
16.9
4.02
2.87
43.5
32.1
1.65
0.83
10.3
16.4
27.8
20.8
4.05
3.13
52.6
26.2
1.75
1.05
10.3
1.1
10 Rh2(4S-MPPIM)4 6j
11 rac- Rh2(4S-MeOX)4
almost 2 orders of magnitude faster than any of the other
catalysts studied. The Rh2(MEPY)4 catalyst (entry 8) was
slower than any of the carboxylates, while the bridged
phosphine catalyst (entry 7) behaved like most of the
other carboxylates.
In ser tion to Elim in a tion Ra tios. The ratio of the
insertion (Table 2) to the â-hydride elimination product
(I/A) was determined for each of the catalysts. In the
carboxamidate class of complexes the MeOX catalyst
(entry 9) showed the most â-elimination compared to the
J . Org. Chem, Vol. 69, No. 12, 2004 4277

TABLE 3. Ra tio of CH/CH2 (3/4 + 5) for th e Rh (II)
Ca ta lysts
catalyst
Rh2Ac4, 6a
Rh2Oct4, 6b
Rh2Piv4, 6c
Rh2TPA4, 6d
Rh2TFA4, 6e
Rh2(R-PTPA)4, 6f
Rh2Ac2(Ph2P(C6H4))2, 6g
Rh2(5R-MEPY)4, 6h
Rh2(4S-MeOX)4, 6i
CH/CH2 (HPLC) CH/CH2 (NMR)
1
2
3
4
5
6
7
8
9
1.09
1.57
1.77
1.03
1.46
1.67
CH-only
2.11
2.66
0.93
1.18
2.18
2.84
2.11
10.9
2.23
2.73
0.94
1.15
2.01
2.67
10 Rh2(4S-MPPIM)4, 6j
11 rac- Rh2(4S-MeOX))4
TABLE 4. Ra tio of CH2 In ser tion P r od u cts
catalyst
4/5a /5b
F IGURE 3. Transition states for the CH2 insertion.
1
2
3
4
5
6
7
8
9
Rh2Ac4, 6a
Rh2Oct4, 6b
Rh2Piv4, 6c
Rh2TPA4, 6d
831/1/-
9.1/1/-
short at the point of commitment (tight transition state),
there will be a substantial steric interaction between the
arene and the ester, and 11b will be disfavored. If the
C-C distance is longer, this interaction will not be as
severe and more of 5 will be formed. Thus, it is our
interpretation that the ratio of 4 to 5 is a measure of the
C-C bond distance at the point of commitment of the
Rh carbenoid.
5.0/1/0.4
20.7/1/-
2.1/1/0.06
1.7/1/0.09
1438/1/4.2
15.8/1/0.9
208/1/-
Rh2TFA4, 6e
Rh2(R-PTPA)4, 6f
Rh2Ac2(Ph2P(C6H4))2, 6g
Rh2(5R-MEPY)4, 6h
Rh2(4S-MeOX)4, 6i
Rh2(4S-MPPIM) 4, 6j
rac-Rh2(4S-MeOX)4
10
11
1.6/1/0.07
4 only
Con clu sion
In the carboxamidate class, MPPIM catalyst (entry 10)
was more selective than the corresponding MeOX catalyst
(entry 9), with the MEPY catalyst (entry 8) being the
least discriminating for CH over CH2 insertion.
The R-diazo ester 1 was developed to study the several
reaction parameters for Rh(II)-mediated intramolecular
C-H insertion. This design incorporated an electronically
biased methylene (CH2) to compete with the methine
(CH) in the insertion process. Another advantage of using
diazo ester 1 was the diminution of the â-H elimination
product. The reactivity of the Rh-carbenoid intermediate
was explored using the ratio of the sum of (3 + 4 + 5) to
2 (insertion vs elimination), the ratio of 3 to (4 + 5)
(chemoselectivity), and the ratio of 4/5 (diastereoselec-
tivity). A fourth reactivity parameter was the observed
relative rate constants for the reaction of the Rh(II)
complexes with the diazo ester 1. We had expected that
we might see some correlations among these four pa-
rameters of reactivity, but in fact plots of one vs the other
showed no such correlation.
It is clear that there is still much to be learned about
the factors that govern selectivity in these cyclizations.
Why, for instance, should there be such a difference in
the turnover rate for amide vs carboxylate-derived cata-
lysts? We hope that the results outlined here will help
to establish, in time, a more detailed understanding of
the mechanism of Rh-mediated intramolecular C-H
insertion.
We believe that the selectivity of methine (CH) inser-
tion over methylene (CH2) insertion (Table 3) is a
reflection of the polarizability of the Rh-carbenoid. As the
carbenoid approaches the target C-H, the methine C-H
is more electron rich than the methylene C-H. A more
easily polarized carbenoid would respond more fully to
this and give proportionally more of the methine insertion
product. Statistically, for geometric reasons, only one of
the two benzylic methylene C-H’s is available for inser-
tion, for cyclization leading to 4.
Ra tio of th e Meth ylen e In ser tion Dia ster eom er s.
The major methylene insertion diastereomer seen with
each of the Rh(II) catalysts surveyed was 4 (Table 4). For
the TFA catalyst (entry 5), we observed a significant
proportion of the cis diastereomers 5a and 5b. Among
the other carboxylate catalysts, the acetate catalyst
(entry 1) and the bridged catalyst (entry 7) generated Rh
carbenoids that showed remarkable selectivity for the
trans diastereomer 4. In the carboxamidate (Doyle)
series, the MeOX catalyst (entry 9) showed excellent
selectivity for the diastereomer 4. The MPPIM catalyst
(entry 10) was the least selective.
For the cyclization of diazo ester 1 there are four3a
competing diastereomeric chair transition states leading
to CH2 insertion products. In our model of the transition
state, the Rh-C bond is aligned with the target C-H
bond leading to C-C bond formation. The two most stable
of these chairlike transition states, the two having the
pendant alkyl group equatorial, are depicted in Figure
3. The actual product from cyclization is determined as
the intermediate carbenoid commits to a particular
diastereomeric transition state. If the C-C distance is
Ack n ow led gm en t. We thank the NIH (GM 60287)
for financial support of this work. We express our
appreciation to Profs. Charles G. Riordan, Michael P.
Doyle, and Huw M. L. Davies for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures including the preparation of 1, the analysis of the
product mixtures from cyclization of 1, and 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0303766
4278 J . Org. Chem., Vol. 69, No. 12, 2004