Anomalous intramolecular C-H insertion reactions of rhodium carbenoids: Factors influencing the reaction course and mechanistic implications

Article abstract of DOI:10.1021/jo049900e

The intramolecular insertion of rhodium carbenoids into the α-C-H bonds of allylic ethers to give 3(2H)-furanones has been explored. Cyclopropanation is favored irrespective of the complex used for carbenoid generation or the substitution pattern of the allylic ether, unless a substituent is placed on the tether connecting the ether to the α-diazo ketone. Unusual acetal products resulting from an anomalous C-H insertion process are obtained in addition to the expected 3(2H)-furanones formed by conventional carbenoid C-H insertion. These acetals are the favored C-H insertion products in certain circumstances and particularly in cases where carbenoid generation is effected using an electron-deficient rhodium complex. Experiments with simple deuterium labeled substrates reveal that anomalous C-H insertion products arise by a mechanism that is distinct from that leading to the formation of conventional C-H insertion products. The formation of acetal products and the outcome of reactions performed using deuterium-labeled substrates suggest that a mechanism involving hydride migration to the rhodium center of the carbenoid is operative.

Full text of DOI:10.1021/jo049900e

An om a lou s In tr a m olecu la r C-H In ser tion Rea ction s of Rh od iu m
Ca r ben oid s: F a ctor s In flu en cin g th e Rea ction Cou r se a n d
Mech a n istic Im p lica tion s
J . Stephen Clark,*,† Alexander G. Dossetter,† Yung-Sing Wong,† Robert J . Townsend,†
William G. Whittingham,‡ and C. Adam Russell‡
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K., and
Syngenta, J ealott’s Hill Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
j.s.clark@nottingham.ac.uk
Received J anuary 16, 2004
The intramolecular insertion of rhodium carbenoids into the R-C-H bonds of allylic ethers to give
3(2H)-furanones has been explored. Cyclopropanation is favored irrespective of the complex used
for carbenoid generation or the substitution pattern of the allylic ether, unless a substituent is
placed on the tether connecting the ether to the R-diazo ketone. Unusual acetal products resulting
from an anomalous C-H insertion process are obtained in addition to the expected 3(2H)-furanones
formed by conventional carbenoid C-H insertion. These acetals are the favored C-H insertion
products in certain circumstances and particularly in cases where carbenoid generation is effected
using an electron-deficient rhodium complex. Experiments with simple deuterium labeled substrates
reveal that anomalous C-H insertion products arise by a mechanism that is distinct from that
leading to the formation of conventional C-H insertion products. The formation of acetal products
and the outcome of reactions performed using deuterium-labeled substrates suggest that a
mechanism involving hydride migration to the rhodium center of the carbenoid is operative.
In tr od u ction
shown that the intramolecular insertion of a carbenoid
into a C-H bond adjacent to a trialkylsilyl ether is
especially favorable and that this reaction can be utilized
to prepare medium-ring cyclic ethers.5
Intramolecular C-H insertion reactions of metal car-
benoids, generated from R-diazocarbonyl compounds,
have been widely used for the stereoselective construction
of substituted cyclopentanones, lactones, and lactams,1
and the advent of asymmetric variants of these reactions
has further extended the scope and general utility of the
methodology.2 The intramolecular insertion of a metal
carbenoid into a C-H bond adjacent to an ether oxygen
is a particularly favorable reaction, and Adams and co-
workers have demonstrated that rhodium carbenoids
generated from R-diazo ketones undergo efficient and
stereoselective C-H insertion to give 3(2H)-furanones.3
Taber and co-workers have used the corresponding
reaction of R-diazo esters for the stereoselective synthesis
of highly functionalized tetrahydrofurans,4 and Lee has
In the course of studies directed toward the synthesis
of the sesquiterpene natural product neoliacinic acid,6 we
prepared the vinyl-substituted 3(2H)-furanone 2 from the
R-diazo ketone 1 by generation of a rhodium carbenoid
and subsequent intramolecular insertion of this reactive
intermediate into the C-H bond of an allyl ether (eq 1).
Although the yield for this transformation was reason-
able and the furanone 2 was the major product, cyclo-
propanation of the alkene to give the pyranone 3 was
found to be a significant competing process.7 To gain a
better understanding of the reaction and elucidate those
factors controlling the selectivity of the C-H insertion
process, we embarked on a study of the rhodium-
catalyzed cyclization reactions of some simple R-diazo
ketones related to 1.8
* To whom correspondence should be addressed. Tel: +44 115
9513542. Fax: +44 115 9513564.
† University of Nottingham.
‡ Syngenta.
(1) For reviews concerning the C-H insertion reactions of metal
carbenoids, see: (a) Taber, D. F. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pattenden, G., Vol. Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 3, Chapter 4.2, pp 1045-1062. (b)
Adams, J .; Spero, D. M. Tetrahedron 1991, 47, 1765. (c) Padwa, A.;
Krumpe, K. E. Tetrahedron 1992, 48, 5385. (d) Ye, T.; McKervey, M.
A. Chem. Rev. 1994, 94, 1091. (d) Doyle, M. P. In Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,
G., Eds.; Hegedus, L. S., Vol. Ed.; Pergamon Press: New York, 1995;
Vol. 12, Chapter 5.2, pp 421-468. (e) Doyle, M. P.; McKervey, M.; Ye,
T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley: New York, 1998. (f) Sulikowski, G. A.; Cha, K. L.;
Sulikowski, M. M. Tetrahedron: Asymmetry 1998, 9, 3145. (g) Merlic,
C. A.; Zechman, A. L. Synthesis 2003, 1137.
Resu lts a n d Discu ssion
(2) For an excellent recent review of asymmetric carbenoid C-H
insertion reactions, see: Davies, H. M. L.; Beckwith, R. E. J . Chem.
Rev. 2003, 103, 2861.
Four R-diazo ketones (17-20) bearing variously sub-
stituted allylic ethers were chosen for our preliminary
10.1021/jo049900e CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/30/2004
3886
J . Org. Chem. 2004, 69, 3886-3898

C-H Insertion Reactions of Rh Carbenoids
SCHEME 1
TABLE 1. Rh od iu m -Ca ta lyzed Rea ction s of th e r-Dia zo Keton e 17
product ratios (capillary GC)
isolated yields (%)
entry
ligand (L)
21:22:23
21:(22 + 23)
22:23
21
22
23
1
2
3
4
5
6
7
O2CCH3
74:19:7
83:14:3
70:24:6
84:12:4
94:6:0
74:26
83:17
70:30
84:16
94:6
73:27
81:19
81:19
72:28
67
15
6
O2CC7H15
O2CCPh3
O2CCF3
O2CC3F7
HNCOCH3
HNCOCF3
80:16:4
61:31:8
80:20
61:39
79:21
80:20
studies concerning the scope of the reaction and those
factors favoring C-H insertion over cyclopropanation.
These carbenoid precursors were prepared from the
appropriate allylic alcohols by a short and efficient route
involving intermolecular carbenoid O-H insertion (Scheme
1).1b,e,9 The route commenced with reaction of the ap-
propriate allylic alcohol with a copper carbenoid (alcohol
4) or rhodium carbenoid (alcohols 4-6) generated by
treatment of ethyl diazoacetate (7) or ethyl diazopropi-
onate (8) with Cu(acac)2 or Rh2(O2CCPh3)4, and the
resulting esters 9-12 were then saponified to give the
carboxylic acids 13-16. The cyclization precursors 17-
20 were obtained in good yield by conversion of the
carboxylic acids 13-16 into mixed anhydrides using
isobutyl chloroformate and subsequent treatment with
diazomethane in diethyl ether.
The intramolecular C-H insertion reactions of each
substrate were performed in dichloromethane at room
temperature, and the carbenoids were generated using
seven structurally diverse rhodium complexes: the stan-
dard relatively electron-rich complexes Rh2(O2CCH3)4 and
Rh2(O2CC7H15)4; the electron-deficient complexes Rh2(O2-
CCF3)4 and Rh2(O2CC3F7)4; the bulky complex Rh2(O2-
CCPh3)4; the carboxamide complexes Rh2(NHCOCH3)4
and Rh2(NHCOCF3)4. The crude reaction mixtures were
analyzed by capillary gas chromatography, and in some
cases, the products were isolated and purified for com-
parison purposes.
(3) (a) Adams, J .; Frenette, R. Tetrahedron Lett. 1987, 28, 4773. (b)
Adams, J .; Poupart, M.-A.; Grenier, L.; Schaller, C.; Ouimet, N.;
Frenette, R. Tetrahedron Lett. 1989, 30, 1749. (c) Adams, J .; Poupart,
M.-A.; Grenier, L. Tetrahedron Lett. 1989, 30, 1753. (d) Spero, D. M.;
Adams, J . Tetrahedron Lett. 1992, 33, 1143.
(4) (a) Taber, D. F.; Song, Y. Tetrahedron Lett. 1995, 36, 2587. (b)
Taber, D. F.; Song, Y. J . Org. Chem. 1996, 61, 6706.
(5) Lee, E.; Choi, I.; Song, S. Y. J . Chem. Soc., Chem. Commun. 1995,
321.
(6) (a) Clark, J . S.; Dossetter, A. G.; Whittingham, W. G. Tetrahedron
Lett. 1996, 37, 5605. (b) Clark, J . S.; Dossetter, A. G.; Blake, A. J .; Li,
W.-S.; Whittingham, W. G. Chem. Commun. 1999, 749.
(7) (a) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati, O.
Tetrahedron 1992, 48, 9767. (b) Cox, G. G.; Moody, C. J .; Austin, D.
J .; Padwa, A. Tetrahedron 1993, 49, 5109.
(8) For preliminary accounts of this work, see: (a) Clark, J . S.;
Dossetter, A. G.; Russell, C. A.; Whittingham, W. G. J . Org. Chem.
1997, 62, 4910. (b) Clark, J . S.; Wong, Y.-S.; Townsend R. J .
Tetrahedron Lett. 2001, 42, 6187.
The R-diazo ketone 17 was selected as a test substrate
because the alkene possesses the substitution pattern
found in the substrate required for the synthesis of
neoliacinic acid.6 Treatment of this compound with the
selected rhodium catalysts afforded the expected cyclo-
propane 21 and 3(2H)-furanone 22 in varying amounts
(eq 2, Table 1). In contrast to the result obtained upon
cyclization of the R-diazo ketone 1 (eq 1), the cyclopropane
21 predominated in all cases. In addition, we were
(9) (a) Cox, G. G.; Kulagowski, J . J .; Moody, C. J .; Sie, E.-R. H. B.
Synlett 1992, 975. (b) Cox, G. G.; Miller, D. J .; Moody, C. J .; Sie, E.-R.
H. B.; Kulagowski, J . J . Tetrahedron 1994, 50, 3195.
J . Org. Chem, Vol. 69, No. 11, 2004 3887

Clark et al.
SCHEME 2
propane 25 and the expected C-H insertion product 26
upon generation of a copper carbenoid by treatment of
the R-diazo ketone 24 with copper bronze (eq 3).11
Following our initial report, several other research groups
reported the isolation of anomalous C-H insertion
products from metal carbenoid reactions.12,13
surprised to find that six of the seven reactions also
delivered an unstable byproduct that we had not observed
in previous studies. After complete characterization, it
transpired that the new product was the cyclic acetal 23
arising from an abnormal C-H insertion reaction. The
ratio of the cyclopropane 21 to the combined C-H
insertion products was heavily dependent on the catalyst
used and varied from 61:39 (entry 7, Table 1) up to 94:6
(entry 5, Table 1). In general, the use of rhodium
complexes bearing strongly electron-withdrawing ligands
resulted in high selectivity for cyclopropanation. The ratio
of normal to abnormal C-H insertion product (22:23) was
relatively insensitive to the catalyst used for carbenoid
generation and ranged between 72:28 and 81:19. In
contrast to the original reaction (eq 1), intramolecular
C-H insertion was not the dominant process, even when
Rh2(O2CCPh3) was employed as the catalyst (entry 3,
Table 4).
The isolation of the abnormal C-H insertion product
23 as a minor product during the rhodium catalyzed
reactions of the R-diazo ketone 17 (eq 2) was completely
unexpected but was explicable by a mechanism involving
hydride migration (Scheme 2). In this mechanism, oxygen-
promoted hydride migration from the allylic ether posi-
tion to the highly electrophilic rhodium carbenoid i occurs
to give the intermediate ii which possesses a rhodium
enolate and an oxenium ion. Nucleophilic attack of the
highly reactive oxenium ion through the oxygen atom of
the rhodium enolate then delivers the anomalous C-H
insertion product 23. It should be noted that if such a
mechanism were operative, ring closure of the intermedi-
ate ii via the carbon of the rhodium enolate could deliver
the expected C-H insertion product 22, circumventing
the generally accepted carbenoid C-H insertion mech-
anisms.1
Although both Doyle10 and Lee5 had isolated decom-
position products from carbenoid C-H insertion reactions
consistent with a hydride migration mechanism analo-
gous to that in Scheme 2, at the time we published our
preliminary results we believed that we were the first to
have isolated an acetal such as 23 from a carbenoid C-H
insertion reaction. However, it transpired that Mander
and Owen had already observed the formation of an
analogous product from a copper carbenoid reaction
performed during their studies concerning the synthesis
of the gibberellins11 and had published this work prior
to our preliminary communication.8a In the course of this
work, Mander and Owen had observed the formation of
the acetal 27 as a minor product along with the cyclo-
We were intrigued by the isolation of the acetal 23,
and to explain its formation and probe the factors
influencing the selectivity for C-H insertion versus
cyclopropanation, the rhodium-catalyzed reactions of the
other R-diazo ketones (18-20, Scheme 1) were explored.
The reactions of carbenoids formed upon treatment of the
R-diazo ketone 18 with a variety of rhodium complexes
were investigated first (eq 4, Table 2). Analysis of the
reaction products by capillary GC revealed that the
cyclopropane 28 was the major product in all cases and
that varying amounts of the expected 3(2H)-furanone 29
and the anomalous acetal 30 were also produced during
these reactions (Table 2). The aldehyde 31 arising from
decomposition of the acetal 30 was also detected by
capillary GC. The highest ratio of C-H insertion products
to cyclopropane (28) was obtained when Rh2(O2CCPh3)4
was employed as the catalyst (entry 3, Table 1), and the
use of Rh2(NHCOCF3)4 as the catalyst also furnished
roughly equal amounts of products arising from C-H
insertion and the cyclopropane 28. Although a significant
amount of the unstable acetal 30 was detected in each
case, it was too unstable to fully characterize. The acetal
30 was identified on the basis of NMR analysis of
partially purified material and by the fact that a sub-
stantial amount of the decomposition product 31 was
produced upon attempted purification. When electron-
rich rhodium complexes were used to catalyze the reac-
tion (entries 1-3 and 6, Table 2), the relative amounts
of the 3(2H)-furanone 29 and the anomalous C-H
insertion product 30 produced in each reaction were
similar with the former predominating. However, when
complexes bearing strongly electron-withdrawing ligands
were employed as catalysts (entries 4, 5, and 7, Table 2),
there was a significant increase in the relative amount
of the acetal 30.
The rhodium-catalyzed reactions of two other allylic
ether substrates (19 and 20) were also investigated (eq
5, Table 3, and eq 6). The rhodium-catalyzed reactions
of the R-diazo ketone 19 delivered the cyclopropane 32
(12) White, J . D.; Hrnciar, P. J . Org. Chem. 1999, 64, 7271.
(13) (a) Wardrop, D. J .; Velter, A. I.; Forslund, R. E. Org. Lett. 2001,
3, 2261. (b) Wardrop, D. J .; Forslund, R. E. Tetrahedron Lett. 2002,
43, 737. (c) Zheng, S.-L.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 4, 889.
(d) Wardrop, D. J .; Forslund, R. E.; Landrie, C. L.; Velter, A. I.; Wink,
D.; Surve, B. Tetrahedron: Asymmetry 2003, 14, 929.
(10) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J . Chem. Soc., Perkin
Trans. 1 1995, 619.
(11) Mander, L. N.; Owen, D. J . Tetrahedron Lett. 1996, 37, 723.
3888 J . Org. Chem., Vol. 69, No. 11, 2004

C-H Insertion Reactions of Rh Carbenoids
TABLE 2. Rh od iu m -Ca ta lyzed Rea ction s of th e r-Dia zo Keton e 18
product ratios (capillary GC)
isolated yields (%)
entry
ligand (L)
28:29:30:31
28:(29 + 30 + 31)
29:(30 + 31)
28
29
1
2
3
4
5
6
7
O2CCH3
78:13:5:4
82:13:5:0
46:30:2:22
75:8:7:10
79:7:5:9
78:22
82:18
46:54
75:25
79:21
65:35
55:45
62:38
73:27
55:45
30:70
30:70
59:41
43:57
51
33
72
10
O2CC7H15
O2CCPh3
O2CCF3
O2CC3F7
HNCOCH3
HNCOCF3
23
8
65:20:15:0
55:20:2:23
TABLE 3. Rh od iu m -Ca ta lyzed Rea ction s of th e r-Dia zo Keton e 19
product ratios (capillary GC)
isolated yields (%)
entry
ligand (L)
32:33:34:35
32:(33 + 34 + 35)
33:(34 + 35)
32
33
34
13
1
2
3
4
5
6
7
O2CCH3
75:11:0:14
80:14:0:6
81:13:3:3
84:0:5:11
89:0:6:5
75:25
80:20
81:19
84:16
89:11
90:10
84:16
45:55
70:30
68:32
64
1
O2CC7H15
O2CCPh3
O2CCF3
O2CC3F7
HNCOCH3
HNCOCF3
90:10:0:0
84:4:0:12
36:64
along with the C-H insertion products 33 and 34 and
the aldehyde 35 arising by decomposition of the acetal
34. Once again, cyclopropanation was the predominant
reaction in each case. The ratio of cyclopropane 32 to the
combined C-H insertion products was rather insensitive
to the complex used for carbenoid generation, although
complexes bearing electron-deficient ligands tended to
give higher ratios in favor of cyclopropanation.
propane 36 was obtained as the major product, the
distribution of products was more consistent with that
obtained from our preliminary experiment (eq 1). This
result suggests that the presence of a substituent on the
tether connecting the R-diazo ketone to the allylic ether
is essential if one requires C-H insertion to be selected
over cyclopropanation of the allylic ether. The isolation
of a substantial amount of the acetal 38 arising from
anomalous C-H insertion at the expense of the expected
C-H insertion is also significant.
In addition to the cyclopropane 36 and the insertion
products 37 and 38, a small amount of the unstable
ketone 39 was obtained and identified using mass
spectrometry and NMR spectroscopy. The isolation of the
ketone 39 may provide a mechanistic insight into the
course of the C-H insertion reaction and can be ac-
counted for by the mechanism shown in Scheme 3.
Treatment of the R-diazo ketone 20 with a rhodium
complex affords the electrophilic carbenoid iii. Oxygen-
assisted hydride migration from the allylic ether then
occurs to give the intermediate iv which contains a
rhodium enolate and an oxenium ion. The enolate then
abstracts a proton from the ring to produce a methyl
ketone and the conjugated diene. It is also conceivable
that proton loss from the intermediate iv and transfer
to the rhodium enolate occurs in an intermolecular
fashion. In addition, it is possible the ketone 39 could be
produced from the acetal 38 by Lewis acid mediated
elimination with ring opening.
The presence of a substituent on the tether connecting
the ether to the R-diazo ketone had a profound influence
on the course of the reaction. The Rh2(HNCOCH3)4-
catalyzed reaction of the R-diazo ketone 20 delivered
significantly increased amounts of the C-H insertion
products (37 and 38) as diastereoisomeric mixtures (eq
6). Although a diastereoisomeric mixture of the cyclo-
J . Org. Chem, Vol. 69, No. 11, 2004 3889

Clark et al.
SCHEME 3
the R-diazo ketones 46 and 47 using the same protocol
as before (Scheme 1).
The rhodium-catalyzed cyclization reactions of the
R-diazo ketone 46 provided the expected C-H insertion
product 48 along with the acetal 49, but the outcome of
this reaction was strongly influenced by the complex used
for carbenoid generation (Table 4). When Rh2(O2CCH3)4
was used as the catalyst, the 3(2H)-furanone 48 was
isolated in 55% yield along with only 8% of the acetal 49
(an isolated ratio of 87:13) (entry 1). However, when
Rh2(O2CCF3)4 was employed as the catalyst, analysis of
the crude reaction mixture by capillary gas chromatog-
raphy indicated an approximately 1:2 ratio of products
(48:49), although roughly equivalent amounts of the two
products were isolated (entry 2). The acetal 49 proved to
be relatively stable in comparison to the allylic ether
derived acetals 23, 30, and 34 and could be isolated in
good yield. The presence of the methyl substituent in
substrate 47 was found to increase amount of acetal
product 51 relative to 3(2H)-furanone product 50 ob-
tained from both reactions (entries 3 and 4, Table 4) but
especially from the reaction catalyzed by Rh2(O2CCF3)4
(entry 4).
SCHEME 4
At this stage, the results suggested that the intramo-
lecular insertion of metal carbenoids into C-H bonds
adjacent to ethers may proceed by a more complex
process than previously recognized and were consistent
with the mechanism illustrated in Scheme 2.8,11,12 In this
mechanism, the acetal product arises by oxygen-assisted
hydride transfer to the electrophilic carbon of the rhod-
ium carbenoid to generate an oxenium ion ii (Scheme 2).
The intermediacy of an oxenium ion is supported by the
fact that the highest proportion of the anomalous C-H
insertion product relative to the expected C-H insertion
product is obtained upon cyclization of the R-diazo ketone
19. This is consistent with our postulated reaction
mechanism because the alkene substituents would sta-
bilize development of incipient positive charge in the allyl
system during formation of the oxenium ion. In addition,
electron-deficient catalysts generally favor the formation
of anomalous C-H insertion products, a fact that can be
accounted for by an increased rate of hydride transfer to
the more electrophilic carbenoid generated and stabiliza-
tion of the resulting rhodium enolate (ii, Scheme 2) by
electron withdrawal.
TABLE 4. Rh od iu m -Ca ta lyzed Rea ction s of th e r-Dia zo
Keton es 46 a n d 47
isolated yields (%)
entry
substrate
ligand (L)
48/50
49/51
1
2
3
4
46
46
47
47
O2CCH3
O2CCF3
O2CCH3
O2CCF3
55
35
62
18
8
40
14
40 (92:8)a
a
Ratio of isomers determined by 1H NMR analysis.
Exper im en ts with Deu ter iu m -Labeled Su bstr ates.
The formation of substantial amounts of the anomalous
C-H insertion products obtained from the rhodium-
catalyzed reactions of the R-diazo ketones 46 and 47
suggests that a zwitterionic intermediate is generated
by hydride migration to the electrophilic metal carbenoid
in each case. In principle, the ionic intermediate could
also serve as an intermediate in the conventional C-H
insertion product allowing the reaction to circumvent the
generally postulated transition states for the reaction,14,15
which involve H-migration to the rhodium or carbon
At this juncture, it was important to establish whether
the formation of anomalous acetal products is a general
phenomenon during the intramolecular C-H insertion
reactions of ethers or is restricted to allylic ethers. It was
also desirable to probe the competing C-H insertion
reaction pathways without the complication of competi-
tive cyclopropanation. To do this, the substrates 46 (the
saturated analogue of the R-diazo ketone 18) and 47 were
prepared (Scheme 4), and their rhodium-catalyzed cy-
clization reactions were investigated (eq 7, Table 4). The
synthesis of these substrates was straightforward and
commenced with the reaction of cyclohexylmethanol with
the rhodium carbenoid generated from either ethyl
diazoacetate (7) or ethyl diazopropionate (8). The result-
ing esters (42 and 43) were saponified to give the
carboxylic acids 44 and 45, and these were converted into
(14) (a) Taber, D. F.; Ruckle, R. E., J r. J . Am. Chem. Soc. 1986, 108,
7686. (b) Taber, D. F.; You, K. K.; Rheingold A. L. J . Am. Chem. Soc.
1996, 118, 547. (c) Taber, D. F.; Malcolm, S. C. J . Org. Chem. 1998,
63, 3717.
(15) (a) 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. (b) Pirrung, M. C.; Morehead, A. T., J r. J . Am. Chem. Soc.
1994, 116, 8991. (c) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J . Am.
Chem. Soc. 2002, 124, 7181.
3890 J . Org. Chem., Vol. 69, No. 11, 2004

C-H Insertion Reactions of Rh Carbenoids
TABLE 5. Rh od iu m -Ca ta lyzed Rea ction s of th e r-Dia zo Keton es 52a ,b
substrate
ligand (L)
ratio 53:54
ratio 53/54
ratio 55:56
ratio 55/56
52a
52a
52b
52b
O2CCH3
O2CCF3
O2CCH3
O2CCF3
77:23
71:29
75:25a
68:32b
3.3
2.4
75:25
3.0
3.0a
2.1b
88:12b
7.1b
a
b
The substrate 52b had 96% deuterium incorporation, and the product ratio is corrected to account for this. The substrate 52b had
91% deuterium incorporation, and the product ratio is corrected to account for this.
SCHEME 5
F IGURE 1. 1H NMR peak assignments for the C-H insertion
products 48 and 49.
sufficient amounts of the anomalous products 55 and 56
from the Rh2(O2CCH3)4-mediated reactions. In the case
of the Rh2(O2CCF3)4-mediated reaction of the R-diazo
ketone 52a , the isomeric acetals 55a and 56a were
isolated and the isomer ratio was similar to but not
identical with that of the conventional C-H insertion
products (53a and 54a ) obtained from the same reaction.
In contrast, the ratio of isomeric acetals 55b and 56b
obtained from the Rh2(O2CCF3)4-mediated reaction of the
R-diazo ketone 52b was substantially higher than the
ratio of the ketones 53b and 54b obtained from the same
reaction.
In subsequent studies, cyclization reactions of the
deuterated R-diazo ketone 52c (derived from deuterated
cyclohexane methanol) were studied and the deuterium
isotope effects in both the conventional and anomalous
C-H insertion reactions were calculated (Scheme 6).
Previous work by Wang and Adams had shown that a
kinetic isotope effect (kH/kD) of 1.2-2 was likely for the
conventional intramolecular insertion reaction of a rhod-
ium carbenoid into a deuterated ether,17 and Sulikowski
and Lee had obtained kinetic isotope effects of a similar
magnitude during intramolecular insertion of rhodium
and copper carbenoids into deuterated positions adjacent
to tertiary amines.18
center of the carbenoid v via the transition state A or B
with concomitant C-C bond formation (Scheme 5).
To gain a better mechanistic understanding of the
anomalous C-H insertion, we prepared deuterium-
labeled derivatives of the R-diazo ketone 46 and inves-
tigated the product distribution obtained upon rhodium
carbenoid generation. The simple R-diazo ketone 46 is a
particularly good test substrate because there are no
overlapping signals in the 1H NMR spectrum of the
conventional C-H insertion product 48 or the anomalous
C-H insertion product 49 (Figure 1). This greatly simpli-
fies peak assignment and means that accurate integra-
tion of signals for individual protons can be performed.
In preliminary studies, the reactions of the deuterium-
labeled substrates 52a ,b (deuterated analogues of the
substrate 46) were explored. The substrate 52a was
prepared from dideuterated cyclohexane methanol using
the route shown in Scheme 4, and the substrate 52b was
prepared by the reaction of CD2N2 with the acid chloride
derived from the carboxylic acid 44. Isomeric mixtures
of the deuterated 3(2H)-furanones 53 and 54 and the
deuterated acetals 55 and 56 were obtained upon treat-
ment of either substrate with a substoichiometric amount
of Rh2(O2CCH3)4 or Rh2(O2CCF3)4 in dichloromethane at
room temperature (eq 8, Table 5). The ketone and acetal
products were separated by careful chromatography, and
the ratio of products arising from each reaction pathway
Treatment of the R-diazo ketone 52c with Rh2(O2CCH3)4
in dichloromethane at room temperature and subsequent
1H NMR analysis of the conventional C-H insertion
products indicated a 65:35 ratio of the diastereoisomers
53b and 54b and a kinetic isotope effect (57/[53b + 54b])
(16) The deuterated acetals 55b, 56b, and 58 were unstable to silica
gel, and the deuterated 3(2H)-furanones 53b and 54b underwent
significant deuterium-hydrogen exchange on exposure to alumina. To
circumvent this problem, the crude reaction mixture was split and half
was purified by flash column chromatography on silica gel while the
other half was purified by flash column chromatography on neutral
alumina prior to analysis by 1H NMR spectroscopy.
1
was determined using H NMR spectroscopy.16 Analysis
of the spectra of the mixtures of conventional C-H
insertion products 53 and 54 revealed that the ketone
53 predominated in all cases and that there was a modest
but significant dependence of product ratio on the
catalyst used. Unfortunately, it was not possible to obtain
(17) Wang, P.; Adams, J . J . Am. Chem. Soc. 1994, 116, 3296.
(18) Sulikowski, G. A.; Lee, S. Tetrahedron Lett. 1999, 40, 8035.
J . Org. Chem, Vol. 69, No. 11, 2004 3891

Clark et al.
SCHEME 6
of 1.2. Unfortunately, it was not possible to isolate
sufficient quantities of the products (55b, 56b, and 58)
arising from the anomalous C-H insertion reaction for
a comparison of the kinetic isotope effect with that of the
conventional C-H insertion reaction to be made. How-
ever, both sets of products were isolable from the
Rh2(O2CCF3)4-catalyzed reaction. In this case, the dias-
tereoisomers 53b and 54b were obtained in a 66:34 ratio
and the kinetic isotope effect (57/[53b + 54b]) was 1.0.In
contrast, the isomeric anomalous products 55b and 56b
were obtained as a 9:91 mixture and the kinetic isotope
effect (58/ [55b + 56b]) was 1.3.
demonstrates that the stereochemistry-defining steps
differ in the conventional and anomalous C-H insertion
reactions. It also precludes the intermediacy of an
equilibrating or freely rotating rhodium enolate gener-
ated by hydride transfer prior to C-C bond formation
(as in Scheme 1) because this would produce a 1:1
mixture of the labeled acetals 55 and 56 (Scheme 1).
Finally, the kinetic isotope effects for both the conven-
tional and anomalous C-H insertion reactions are gener-
ally independent of the reaction temperature, a finding
that is indicative of the nonlinear transition state re-
quired for intramolecular H-transfer.21
The temperature and solvent dependence of the reac-
tion were also explored. The ratios of products obtained
from the Rh2(O2CCF3)4-mediated reaction in dichlo-
romethane were virtually identical at 0 °C, room tem-
perature, or reflux.19 To extend the temperature range,
the same reaction was performed in 1,2-dichloroethane
at 0 °C, room temperature, or reflux.20 Although the ratio
of products differed from those obtained in dichlo-
romethane, there was little variation in the relative ratios
of products within each reaction manifold between 0 and
83 °C.
Several important findings emerge from the results
obtained using deuterium-labeled substrates. First, in the
case of the reaction of the R-diazo ketone 52c mediated
by Rh2(O2CCF3)4, there is a modest but significant
difference between the kinetic isotope effect for the
conventional reaction and that for the anomalous reac-
tion. This finding rules out a common rate determining
C-H bond cleavage step for the conventional and anoma-
lous C-H insertion reactions. Second, the high level of
diastereocontrol (55b:56b, 9:91) obtained from the anoma-
lous C-H insertion reaction contrasts with the modest
level of diastereocontrol (53b:54b, 66:34) obtained during
the conventional C-H insertion reaction; a similar
though less pronounced effect was observed during the
cyclization of the R-diazo ketones 52a ,b . This result
The most plausible explanation for the data obtained
from the reactions of deuterium-labeled precursors is
that conventional C-H insertion occurs by the gener-
ally accepted mechanism illustrated in Scheme 5 and
that anomalous C-H insertion occurs by the mechan-
ism shown in Scheme 7. In the case of anomalous
C-H insertion, oxygen-assisted hydride migration to the
rhodium center of the carbenoid results in enolate
formation. Bond rotation then allows C-O bond forma-
tion by trapping of the oxenium ion with the enolate
oxygen. Subsequent reductive elimination then delivers
the acetal product and allows catalyst regeneration. In
the mechanism shown in Scheme 7, the stereochemical
outcome of the reaction (i.e. 55 > 56, eq 8, and 56b >
55b, Scheme 6) is dictated by attack of hydride on the
metal center of the carbenoid in the most favorable
conformation.
The hydride transfer mechanism outlined in Scheme
7 accounts for both the discrepancy in kinetic isotope
effects between the anomalous and conventional C-H
insertion reactions and for the high stereoselectivity
observed in the anomalous C-H insertion reaction. It
should be noted that an analogous hydride transfer step
appears in the mechanism proposed by White and Hrn-
ciar to explain the formation of anomalous (but nonacetal)
products upon intramolecular C-H insertion of a rhod-
ium carbenoid during their synthetic work on (+)-
codeine.12
(19) The product ratios obtained from reactions performed with
Rh2(O2CCF3)4 at various temperatures in dichloromethane were as
follows: 0 °C, 53b:54b:57, 33:16:51, and 55b:56b:58, 5:39:56; room
temperature, see Scheme 6; reflux, 53b :54b :57, 34:15:51, and 55b :
56b:58, 5:39:56.
(20) The product ratios obtained from reactions performed with
Rh2(O2CCF3)4 at various temperatures in 1,2-dichloroethane were as
follows: 0 °C, 53b:54b:57, 31:13:56, and 55b:56b:58, 3:42:55; room
temperature, 53b:54b:57, 30:12:58, and 55b:56b:58, 2:42:56; reflux,
53b:54b:57, 29:14:57, and 55b:56b:58, 5:40:55.
(21) (a) Kwart, H. Acc. Chem. Res. 1982, 15, 401. (b) Anhede, B.;
Bergman, N.-Å. J . Am. Chem. Soc. 1984, 106, 7634. (c) Dakin, L. A.;
Ong, P. C.; Panek, J . S.; Staples, R. J .; Stavropoulos, P. Organome-
tallics 2000, 19, 2896.
3892 J . Org. Chem., Vol. 69, No. 11, 2004

C-H Insertion Reactions of Rh Carbenoids
SCHEME 7
P r epar ation of 4-P h en yl-2-(h ydr oxym eth yl)bu t-1-en e.23
Osmium tetroxide (2 mL of 1% solution in water) was added
to a stirred solution of 4-phenyl-2-((trimethylsilyl)methyl)but-
1-ene (3.00 g, 13.7 mmol), N-methylmorpholine N-oxide (6.00
g, 51.2 mmol), and pyridine (2 drops) in a mixture of acetone
(30 mL), water (5 mL), and tert-butyl alcohol (5 mL). The
mixture was stirred at room temperature for 16 h and then
concentrated and rediluted with water (100 mL). The mixture
was extracted into CH2Cl2 (4 × 100 mL), and the combined
extracts were dried (MgSO4) and concentrated to an oil in
vacuo. Purification by flash column chromatography (EtOAc/
petroleum ether 40-60, 1:4) gave the diol (3.06 g, 88%) as a
colorless oil. The diol was immediately dissolved in methanol
(40 mL), and glacial acetic acid (15 mL) was added. The
mixture was heated at reflux for 2 h and then cooled, and the
acid was quenched with concentrated ammonia solution (10
mL). The mixture was then concentrated (∼20 mL) and diluted
with water (100 mL), and the products were extracted into
diethyl ether (3 × 100 mL). The extracts were dried (Na2SO4
and then CaCl2) and concentrated in vacuo to an oil. Purifica-
tion by flash column chromatography (EtOAc/petroleum ether,
1:4) gave 2-methylene-4-phenyl-1-butanol (1.97 g, 99%) as a
colorless oil: Rf ) 0.32 (petroleum ether 40-60/diethyl ether,
1:1); IR (liquid film) 3363, 3027, 2928, 1703, 1649, 1602, 898
Exp er im en ta l Section
P r ep a r a tion of 4-P h en yl-2-((tr im eth ylsilyl)m eth yl)-
bu t-1-en e.22 Dry cerium(III) chloride (18.5 g, 75.1 mmol) was
heated at 140 °C under vacuum (∼0.5 mmHg) in a 250 mL
round-bottom flask for 2 h and then cooled to room tempera-
ture. The vacuum was released and the flask immediately
flushed with N2. Dry THF (100 mL) was added to the cerium-
(III) chloride at a steady rate with vigorous stirring to produce
an even suspension. The mixture was stirred at room tem-
perature for 3 h during which sonication was also applied for
1 h. The suspension was then cooled to -72 °C, and then
((trimethylsilyl)methyl)magnesium chloride (80 mL of 1.0 M
solution in diethyl ether, 80 mmol) was added over a period of
45 min in 10 mL aliquots. The mixture was stirred for an
additional 30 min, and then methyl 3-phenylpropionate (4.02
g, 2.44 mmol) in dry THF (10 mL) was added over 2 min. The
mixture was kept at -72 °C for 2 h and then gradually allowed
to come to room temperature and left to stir overnight. The
reaction was cooled to 0 °C and quenched by the addition of
saturated aqueous NH4Cl solution (100 mL). The mixture was
diluted with water (100 mL) and the products extracted into
diethyl ether (3 × 200 mL). The combined extracts were
washed with saturated NaHCO3 solution (100 mL) and then
dried (Na2SO4 and then CaCl2) and concentrated in vacuo. The
residue was redissolved in CH2Cl2 (200 mL) and silica gel
added (40 g), and the resultant slurry was stirred for 2 h and
then filtered and concentrated to an oil in vacuo. Purification
by flash column chromatography (petrololeum ether 40-60)
gave 4-phenyl-2-((trimethylsilyl)methyl)but-1-ene (3.9 g, 73%)
as a colorless oil: Rf ) 0.45 (petroleum ether 40-60); IR (liquid
film) 3068, 3028, 2953, 1940, 1742, 1693, 1631, 1603 cm-1; 1H
NMR (270 MHz, CDCl3) δ 7.30-7.13 (m, 5H), 4.65 (d, 1H, J )
0.9 Hz), 4.56 (d, 1H, J ) 0.9 Hz), 2.78-2.72 (m, 2H), 2.28-
2.22 (m, 2H), 1.58 (s, 2H), 0.03 (m, 9H); 13C NMR (68 MHz,
CDCl3) δ 147.4 (C), 142.6 (C), 128.6 (CH), 128.5 (CH), 126.0
(CH), 107.4 (CH2), 40.4 (CH2), 34.7 (CH2), 27.2 (CH2), -1.1
(CH3); HRMS (EI) for C14H22Si [M+] calcd 218.1491, found
218.1490. Anal. Calcd for C14H22Si: C, 76.99; H, 10.15.
Found: C, 76.71; H 9.99.
1
cm-1; H NMR (270 MHz, CDCl3) δ 7.30-7.12 (m, 5H), 5.04
(s, 1H), 4.90 (s, 1H), 4.04 (s, 2H), 2.77 (t, 2H, J ) 7.8 Hz), 2.35
(t, 2H, J ) 7.8 Hz), 2.11 (br, 1H); 13C NMR (68 MHz, CDCl3)
δ 148.6 (C), 142.0 (C), 128.6 (CH), 128.6 (CH), 126.1 (CH),
110.0 (CH2), 66.1 (CH2), 34.8 (CH2), 34.5 (CH2); HRMS (EI)
for C11H14O [M+] calcd 162.1045, found 162.1042.
Gen er a l P r oced u r e for th e O-H In ser tion of Ca r -
b en oid s Gen er a t ed fr om E t h yl Dia zoa cet a t e or E t h yl
Dia zop r op ion a te. A solution of either ethyl diazoacetate or
ethyl diazopropionate in dry CH2Cl2 was added by syringe
pump over 1 h to a stirred solution of the alcohol and the
catalyst in dry CH2Cl2 at the appropriate temperature under
nitrogen. After the addition was complete, the mixture was
left at the given temperature for a further 20 min and then
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (petroleum ether 40-
60/diethyl ether, 10:1).
(22) Fleming, I.; Pearce, A. J . Chem. Soc., Perkin Trans. 1 1981,
251.
(23) Charlton, J . L.; Williams, G. J .; Lypka, G. N. Can. J . Chem.
1980, 58, 1271.
J . Org. Chem, Vol. 69, No. 11, 2004 3893

Clark et al.
P r ep a r a tion of Eth yl (2-Meth ylen e-4-p h en ylbu toxy)-
a ceta te (9). Ethyl diazoacetate (0.970 mL, 9.22 mmol) in
CH2Cl2 (100 mL) was added to 4-phenyl-2-(hydroxymethyl)-
but-1-ene (1.50 g, 9.25 mmol) and Cu(acac)2 (40 mg) in CH2Cl2
(30 mL) at reflux. The ester 9 (1.72 g, 75%) was isolated as a
colorless oil: IR (liquid film) 3028, 2930, 1756, 1644, 1602,
(CI, CH4) for C11H20O3 [M+] calcd 201.1490, found 201.1507.
Anal. Calcd for C11H20O3: C, 65.97; H, 10.07. Found: C, 65.92;
H 10.19.
Eth yl 2-(Cycloh exylm eth oxy)p r op ion a te (43). Ethyl
diazopropionate (1.00 g, 7.81 mmol) in CH2Cl2 (50 mL) was
added to cyclohexylmethanol (892 mg, 7.81 mmol) and Rh2(O2-
CCH3)4 (20 mg) in CH2Cl2 (10 mL). The ester 43 (1.10 g, 66%)
was isolated as a colorless oil: Rf ) 0.88 (petroleum ether 40-
1
1029 cm-1; H NMR (270 MHz, CDCl3) δ 7.30-7.18 (m, 5H),
5.06 (s, 1H), 4.99 (s, 1H), 4.24 (q, 2H, J ) 7.2 Hz), 4.05 (s,
2H), 4.03 (s, 2H), 2.80 (t, 2H, J ) 7.4 Hz), 2.40 (t, 2H, J ) 7.4
Hz), 1.28 (t, 3H, J ) 7.2 Hz); 13C NMR (68 MHz, CDCl3) δ
170.4 (C), 144.5 (C), 141.8 (C), 128.3 (CH), 128.3 (CH), 125.8
(CH), 113.4 (CH2), 74.4 (CH2), 67.0 (CH2), 60.8 (CH2),
34.6 (CH2), 34.0 (CH2), 14.2 (CH3); HRMS (CI, CH4) for
60/diethyl ether, 1:1); IR (liquid film) 2920, 2852, 1738 cm-1
;
1H NMR (250 MHz, CDCl3) δ 4.19 (dq, 2H, J ) 2.7, 7.3 Hz),
3.90 (q, 1H, J ) 6.9 Hz), 3.36 (dd, 1H, J ) 6.5, 8.9 Hz), 3.15
(dd, 1H, J ) 6.7, 8.9 Hz), 1.80-1.52 (m, 6H), 1.38 (d, 3H,
J ) 6.9 Hz), 1.28 (t, 3H, J ) 7.2 Hz), 1.25-1.12 (m, 3H), 0.98-
0.86 (m, 2H); 13C NMR (68 MHz, CDCl3) δ 173.9 (C),
76.4 (CH2), 75.5 (CH2), 61.0 (CH2), 38.3 (CH), 30.3 (CH2), 26.9
(CH2), 26.1 (CH2), 18.9 (CH3), 14.5 (CH3); HRMS (EI) for
C
C
15H20O3 [M+] calcd 247.1334, found 247.1344. Anal. Calcd for
15H20O3: C, 72.55; H, 8.12. Found: C, 72.60; H 8.29.
Eth yl (1-Cycloh exen -1-ylm eth oxy)a ceta te (10). Ethyl
C
12H22O3 [M+] calcd 214.1568, found 214.1575. Anal. Calcd for
diazoacetate (0.380 mL, 3.60 mmol) in CH2Cl2 (20 mL) was
added to 1-cyclohexenylmethanol (336 mg, 3.00 mmol) and
Rh2(O2CCPh3)4 (10 mg) in CH2Cl2 (5 mL). The ester 10 (331
mg, 56%) was isolated as a colorless oil: Rf ) 0.85 (petroleum
ether 40-60/diethyl ether, 1:1); IR (liquid film) 2930, 1754,
C12H22O3: C, 67.26; H, 10.35. Found: C, 67.28; H 10.25.
Gen er a l Tw o Step P r oced u r e for th e Con ver sion of
a n Ester in to a n r-Dia zo Keton e. A 2 M solution of aqueous
lithium hydroxide (2 equiv) was added to a solution of the ethyl
ester in methanol. The mixture was stirred at room temper-
ature overnight and then diluted with 2 M aqueous NaOH (5
mL) and water (50 mL). The aqueous solution was washed
with diethyl ether (2 × 50 mL) and then acidified to pH 2 with
2 M aqueous HCl. The product was then extracted into diethyl
ether (3 × 75 mL), and the combined were extracts dried
(Na2SO4 and then CaCl2) and concentrated in vacuo. The crude
carboxylic acid was used without further purification.
921, 900, 857, 831, 802 cm-1 1H NMR (270 MHz, CDCl3) δ
;
5.71 (br, 1H), 4.22 (q, 2H, J ) 7.2 Hz), 4.01 (s, 2H), 3.94 (s,
2H), 2.08-2.00 (m, 4H), 1.70-1.50 (m, 4H), 1.30 (t, 3H,
J ) 7.2 Hz); 13C NMR (68 MHz, CDCl3) δ 170.8 (C), 134.2 (C),
126.7 (CH), 76.4 (CH2), 66.8 (CH2), 60.9 (CH2), 26.0 (CH2), 25.2
(CH2), 22.6 (CH2), 22.4 (CH2), 14.4 (CH3); HRMS (EI) for
C
C
11H18O3 [M+] calcd 198.1256, found 198.1247. Anal. Calcd for
11H18O3: C, 66.64; H, 9.15. Found: C, 66.39; H 9.35.
Isobutyl chloroformate (1 equiv) was added to a stirred
solution of the crude acid and triethylamine (1 equiv) in dry
diethyl ether at room temperature under nitrogen. The
mixture was left to stir for 3 h and then filtered and added
dropwise over 30 min to a solution of diazomethane (at least
2 equiv in diethyl ether) at room temperature. The R-diazo
ketone was then left to form overnight. Excess diazomethane
was quenched with acetic acid (1-2 mL) and the mixture
diluted with diethyl ether (100 mL) and washed successively
with saturated sodium bicarbonate solution (50 mL) and brine
(50 mL). The yellow solution was dried (Na2SO4 and then
CaCl2) and concentrated in vacuo to an oil. Flash column
chromatography on silica gel gave the required R-diazo ketone.
1-D i a z o -3-(2-m e t h y le n e -4-p h e n y lb u t o x y )-2-p r o -
p a n on e (17). Ethyl (2-methylene-4-phenylbutoxy)acetate (9)
(1.00 g, 4.03 mmol) was hydrolyzed by following the general
procedure using 2 M aqueous lithium hydroxide (5 mL) and
methanol (10 mL). The resulting carboxylic acid 13 was then
converted into the R-diazo ketone by using the general protocol
and by employing the following quantities of reagents and
solvents: isobutyl chloroformate (0.52 mL, 4.0 mmol); triethy-
lamine (0.56 mL 4.0 mmol); diethyl ether (40 mL); diaz-
omethane (8 mmol in diethyl ether). Flash column chroma-
tography on silica gel (hexane/diethyl ether, 5:1) gave the
R-diazo ketone 17 (747 mg, 76% for two steps) as a yellow oil:
Rf ) 0.45 (petroleum ether 40-60/diethyl ether, 1:1); IR (liquid
film) 2924, 2108, 1641, 909 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.31-7.16 (m, 5H), 5.72 (br, 1H), 5.06 (s, 1H), 5.00 (s, 1H),
3.96 (s, 4H), 2.79 (t, 2H, J ) 8.0 Hz), 2.37 (t, 2H, J ) 8.0 Hz);
13C NMR (68 MHz, CDCl3) δ 193.9 (C), 144.6 (C), 141.8 (C),
128.6 (CH), 128.5 (CH), 126.2 (CH), 113.2 (CH2), 74.7 (CH2),
73.8 (CH2), 53.3 (CH), 34.8 (CH2), 34.3 (CH2); HRMS (CI, CH4)
for C14H17O2N2 [(M + H)+] calcd 245.1290, found 245.1328.
Eth yl (2-Cycloh exylid en eeth oxy)a ceta te (11). Ethyl
diazoacetate (0.830 mL, 7.89 mmol) in CH2Cl2 (30 mL) was
added to (2-cyclohexylidene)ethanol (1.00 g, 7.92 mmol) and
Rh2(O2CCPh3)4 (20 mg) in CH2Cl2 (10 mL). The ester 11 (1.49
g, 89%) was isolated as a colorless oil: Rf ) 0.81 (petroleum
ether 40-60/diethyl ether, 1:1); IR (liquid film) 2930, 2854,
1
1754, 1665, 855 cm-1; H NMR (270 MHz, CDCl3) δ 5.30 (t,
1H, J ) 7.3 Hz), 4.22 (q, 2H, J ) 7.3 Hz), 4.10 (d, 2H, J ) 7.3
Hz), 4.10 (s, 2H), 2.23-2.10 (m, 4H), 1.60-1.45 (m, 6H), 1.30
(t, 3H, J ) 7.3 Hz); 13C NMR (68 MHz, CDCl3) δ 170.8 (C),
146.6 (C), 116.8 (CH), 66.9 (CH2), 66.8 (CH2), 60.9 (CH2), 37.2
(CH2), 29.1 (CH2), 28.5 (CH2), 27.9 (CH2), 26.8 (CH2), 14.4
(CH3); HRMS (CI, CH4) for C12H21O3 [(M + H)+] calcd 211.1334,
found 211.1337. Anal. Calcd for C12H20O3: C, 67.89; H, 9.50.
Found: C, 67.55; H 9.66.
Eth yl 2-(2-Cycloh exyliden eeth oxy)pr opion ate (12). Eth-
yl diazopropionate (1.22 g, 9.52 mmol) in CH2Cl2 (30 mL) was
added to (2-cyclohexylidene)ethanol (1.00 g, 7.92 mmol) and
Rh2(O2CCPh3)4 (20 mg) in CH2Cl2 (10 mL). The ester 12 (1.36
g, 76%) was isolated as a colorless oil: Rf ) 0.85 (petroleum
ether 40-60/diethyl ether, 1:1); IR (liquid film) 2930, 1747,
1665, 855 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.29 (t, 1H, J )
6.9 Hz), 4.25-4.08 (m, 3H), 4.03-3.94 (m, 2H), 4.01-3.94 (m,
1H), 2.10-2.07 (m, 4H), 1.58-1.45 (m, 6H), 1.40 (d, 3H, J )
6.9 Hz), 1.29 (t, 3H, J ) 7.1 Hz); 13C NMR (68 MHz, CDCl3) δ
173.7 (C), 145.8 (C), 117.2 (CH), 73.6 (CH), 65.6 (CH2), 60.8
(CH2), 37.2 (CH2), 29.1 (CH2), 29.1 (CH2), 27.8 (CH2), 26.8
(CH2), 18.9 (CH3), 14.4 (CH3); HRMS (CI, CH4) for C13H21O3
[(M - H)+] calcd 225.1491, found 225.1504. Anal. Calcd for
C
13H22O3: C, 68.99; H, 9.80. Found: C, 68.50; H 9.97.
Eth yl (Cycloh exylm eth oxy)a ceta te (42). Ethyl diazoac-
etate (2.30 mL, 21.9 mmol) in CH2Cl2 (60 mL) was added to
cyclohexylmethanol (2.50 g, 21.9 mmol) and Rh2(O2CCH3)4 (20
mg) in CH2Cl2 (20 mL). The ester 42 (3.84 g, 88%) was isolated
as a colorless oil: Rf ) 0.88 (petroleum ether 40-60/diethyl
1-(1-Cycloh exen -1-ylm eth oxy)-3-diazo-2-pr opan on e (18).
Ethyl (1-cyclohexen-1-ylmethoxy)acetate (10) (771 mg, 3.89
mmol) was hydrolyzed by following the general procedure
using 2 M aqueous lithium hydroxide (8 mL) and methanol (8
mL). The resulting carboxylic acid 14 was then converted into
the R-diazo ketone by using the general protocol and by
employing the following quantities of reagents and solvents:
isobutyl chloroformate (0.50 mL, 3.9 mmol); triethylamine
(0.54 mL 3.9 mmol); diethyl ether (15 mL); diazomethane (8
mmol in diethyl ether). Flash column chromatography on silica
ether, 1:1); IR (liquid film) 2923, 1756 cm-1 1H NMR (270
;
MHz, CDCl3) δ 4.18 (q, 2H, J ) 7.2 Hz), 4.02 (s, 2H), 3.29 (d,
2H, J ) 6.5 Hz), 1.81-1.52 (m, 6H), 1.25 (t, 3H, J ) 7.2 Hz),
1.28-1.10 (m, 3H), 0.98-0.85 (m, 2H); 13C NMR (68 MHz,
CDCl3) δ 170.7 (C), 77.7 (CH2), 68.6 (CH2), 60.7 (CH2), 38.0
(CH), 30.0 (CH2), 26.6 (CH2), 25.9 (CH2), 14.3 (CH3); HRMS
3894 J . Org. Chem., Vol. 69, No. 11, 2004

C-H Insertion Reactions of Rh Carbenoids
gel (hexane/diethyl ether, 7:1 and then 5:1) gave the R-diazo
ketone 18 (455 mg, 60% for two steps) as a yellow oil: Rf )
0.50 (petroleum ether 40-60/diethyl ether, 1:1); IR (liquid film)
3-(Cycloh exylm eth oxy)-1-d ia zo-2-bu ta n on e (47). Ethyl
2-(cyclohexylmethoxy)propionate (43) (1.10 g, 5.13 mmol) was
hydrolyzed by following the general procedure using 2 M
aqueous lithium hydroxide (6 mL) and methanol (6 mL). The
resulting carboxylic acid 45 was then converted into the
R-diazo ketone by using the general protocol and by employing
the following quantities of reagents and solvents: isobutyl
chloroformate (0.67 mL, 5.2 mmol); triethylamine (0.72 mL
5.2 mmol); diethyl ether (35 mL); diazomethane (10 mmol in
diethyl ether). Flash column chromatography on silica gel
(hexane/diethyl ether, 7:1) gave the R-diazo ketone 47 (846 mg,
78% for two steps) as a yellow oil: Rf ) 0.74 (petroleum ether
40-60/diethyl ether, 1:1); IR (liquid film) 2978, 2924, 2852,
3128, 2928, 2104, 1641, 832, 802 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 5.78 (br, 1H), 5.71 (m, 1H), 3.94 (s, 2H), 3.88 (s, 2H),
2.10-1.95 (m, 4H), 1.70-1.53 (m, 4H); 13C NMR (68 MHz,
CDCl3) δ 194.3 (C), 133.9 (C), 126.6 (CH), 76.4 (CH2), 73.3
(CH2), 53.2 (CH), 26.0 (CH2), 25.1 (CH2), 22.6 (CH2), 22.4 (CH2);
HRMS (CI, CH4) for C10H15O2N2 [(M + H)+] calcd 195.1134,
found 195.1120.
1-(2-Cycloh exyliden eeth oxy)-3-diazo-2-pr opan on e (19).
Ethyl (2-cyclohexylideneethoxy)acetate (11) (632 mg, 2.98
mmol) was hydrolyzed by following the general procedure
using 2 M aqueous lithium hydroxide (3 mL) and methanol (5
mL). The resulting carboxylic acid 15 was then converted into
the R-diazo ketone by using the general protocol and by
employing the following quantities of reagents and solvents:
isobutyl chloroformate (0.37 mL, 2.9 mmol); triethylamine
(0.42 mL, 3.0 mmol); diethyl ether (15 mL); diazomethane (6
mmol in diethyl ether). Flash column chromatography on silica
gel (hexane/diethyl ether, 7:1 and then 5:1) gave the R-diazo
ketone 19 (434 mg, 70%) as a yellow oil: Rf ) 0.51 (petroleum
ether 40-60/diethyl ether, 1:1); IR (liquid film) 2930, 2854,
2107, 1641 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.77 (br, 1H,),
5.26 (t, 1H, J ) 7.1 Hz), 4.04 (d, 2H, J ) 7.1 Hz), 3.97 (s, 2H),
2.22-2.10 (m, 4H), 1.62-1.46 (m, 6H); 13C NMR (68 MHz,
CDCl3) δ 194.5 (C), 146.7 (C), 116.6 (CH), 73.5 (CH2), 67.2
(CH2), 53.2 (CH), 37.2 (CH2), 29.2 (CH2), 28.6 (CH2), 27.9 (CH2),
26.7 (CH2); LRMS (CI, CH4) 209.1 [(M + H)+]; 181, 151, 137,
125, 109.
1
2105, 1643 cm-1; H NMR (250 MHz, CDCl3) δ 5.73 (br, 1H),
3.89 (q, 1H, J ) 6.8 Hz), 3.26 (d, 2H, J ) 6.3 Hz), 1.52-1.81
(m, 6H), 1.31 (d, 3H, J ) 6.8 Hz), 1.30-1.13 (m, 3H), 1.02-
0.84 (m, 2H); 13C NMR (68 MHz, CDCl3) δ 198.2 (C), 80.5 (CH),
76.0 (CH), 51.7 (CH), 38.1 (CH), 30.1 (CH2), 29.8 (CH2), 26.4
(CH2), 25.7 (CH2), 18.5 (CH3); HRMS (CI, CH4) for C11H19O2N2
[(M + H)+] calcd 211.1447, found 211.1451. Anal. Calcd for
C
11H18O2N2: C, 62.83; H, 8.63; N 13.32. Found: C, 62.75; H
8.89; N 13.23.
Gen er a l P r oced u r e for th e Rh od iu m (II)-Ca ta lyzed
Rea ction s of th e r-Dia zo Keton es. The rhodium(II) catalyst
was added in one portion to a stirred solution of the R-diazo
ketone in dry CH2Cl2 under N2. The reaction was typically left
to stir for 1 h at room temperature and then the solution
concentrated in vacuo to give an oil. The reaction mixture was
then purified by careful flash column chromatography on
neutral alumina (Brockmann grade 3).
Rea ction of 1-Dia zo-3-(2-m eth ylen e-4-p h en ylbu toxy)-
2-pr opan on e (17). According to the general procedure, 1-diazo-
3-(2-methylene-4-phenylbutoxy)-2-propanone (17) (368 mg,
1.51 mmol) was treated with Rh2(O2CCH3)4 (10 mg) in CH2Cl2
(200 mL). Flash column chromatography on neutral alumina
(petroleum ether 40-60 and then 2%-10% diethyl ether in
petroleum ether 40-60) gave three compounds.
3-(2-Cycloh exylid en eeth oxy)-1-d ia zo-2-bu ta n on e (20).
Ethyl 2-(2-cyclohexylideneethoxy)propionate (12) (1.27 g, 5.61
mmol) was hydrolyzed by following the general procedure
using 2 M aqueous lithium hydroxide (6 mL) and methanol
(12 mL). The resulting carboxylic acid 16 was then converted
into the R-diazo ketone by using the general protocol and by
employing the following quantities of reagents and solvents:
isobutyl chloroformate (0.73 mL, 5.6 mmol); triethylamine
(0.78 mL, 5.6 mmol); diethyl ether (25 mL); diazomethane (12
mmol in diethyl ether). Flash column chromatography on silica
gel (hexane/diethyl ether, 7:1) gave the R-diazo ketone 20 (982
mg, 79% for two steps) as a yellow oil: Rf ) 0.61 (petroleum
ether 40-60/diethyl ether, 1:1); IR (liquid film) 3126, 2930,
1-(2-P h en yleth yl)-3-oxa bicyclo[4.1.0]h ep ta n -5-on e (21).
This was isolated as a colorless oil (219.0 mg, 67% yield): Rf
) 0.48 (petroleum ether 40-60/diethyl ether); IR (liquid film)
1
3014, 2923, 2858, 1700, 1602, 697 cm-1; H NMR (270 MHz,
CDCl3) δ 7.32-7.14 (m, 5H), 4.13 (d, 1H, J ) 18.1 Hz), 4.01
(d, 1H, J ) 11.3 Hz), 3.74 (d, 1H, J ) 18.1 Hz), 3.03 (d, 1H, J
) 11.3 Hz), 2.69 (t, 2H, J ) 8.2 Hz), 1.95-1.63 (m, 4H), 1.09
(dd, 1H, J ) 4.5, 9.8 Hz); 13C NMR (68 MHz, CDCl3) δ 205.6
(C), 141.3 (C), 128.8 (CH), 128.4 (CH), 126.4 (CH), 72.7 (CH2),
66.5 (CH2), 35.8 (CH2), 33.1 (CH), 32.9 (CH2), 28.0 (C), 16.8
(CH2); HRMS (CI, CH4) for C14H17O2 [(M + H)+] calcd 217.1229,
found 217.1222. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46.
Found: C, 77.28; H 7.60.
1
2856, 2105, 1642, 910, 854 cm-1; H NMR (270 MHz, CDCl3)
δ 5.78 (br, 1H), 5.31-5.24 (m, 1H), 4.12-3.97 (m, 2H), 3.88
(q, 1H, J ) 6.9 Hz), 2.18-2.06 (m, 4H), 1.58-1.46 (m, 6H),
1.33 (d, 3H, J ) 6.9 Hz); 13C NMR (68 MHz, CDCl3) δ 198.3
(C), 146.0 (C), 116.9 (CH), 79.5 (CH), 65.8 (CH2), 51.9 (CH),
37.2 (CH2), 29.2 (CH2), 28.5 (CH2), 27.9 (CH2), 26.7 (CH2), 19.0
(CH3); HRMS (CI, CH4) for C12H19O2N2 [(M + H)+] calcd
223.1240, found 223.1233. Anal. Calcd for C12H18O2N2: C,
64.84; H, 8.16; N 12.60. Found: C, 64.53; H 8.13; N 12.19.
Dih yd r o-5-(1-m et h ylen e-3-p h en ylp r op yl)-3(2H )-fu r a -
n on e (22). This was isolated as a colorless oil (48.0 mg, 15%
yield): Rf ) 0.64 (petroleum ether 40-60/diethyl ether); IR
(liquid film) 3088, 2991, 2924, 2852, 1766, 1651, 1603, 902
1-(Cycloh exylm eth oxy)-3-d ia zo-2-p r op a n on e (46). Eth-
yl (cyclohexylmethoxy)acetate (42) (2.00 g, 0.999 mmol) was
hydrolyzed by following the general procedure using 2 M
aqueous lithium hydroxide (5 mL) and methanol (10 mL). The
resulting carboxylic acid 44 was then converted into the
R-diazo ketone by using the general protocol and by employing
the following quantities of reagents and solvents: isobutyl
chloroformate (1.30 mL, 10.0 mmol); triethylamine (1.39 mL,
9.97 mmol); diethyl ether (50 mL); diazomethane (20 mmol in
diethyl ether). Flash column chromatography on silica gel
(hexane/diethyl ether, 7:1) gave the R-diazo ketone 46 (1.66 g,
85% for two steps) as a yellow oil: Rf ) 0.68 (petroleum ether
40-60/diethyl ether, 1:1); IR (liquid film) 3129, 2925, 2853,
1
cm-1; H NMR (250 MHz, CDCl3) δ 7.25-7.01 (m, 5H), 5.11
(s, 1H), 4.97 (s, 1H), 4.63 (dd, 1H, J ) 6.5, 9.1 Hz), 4.03 (d,
1H, J ) 17.0 Hz), 3.82 (d, 1H, J ) 17.0 Hz), 2.75 (m, 2H), 2.52
(dd, 1H, J ) 6.5, 17.8 Hz), 2.41-2.24 (m, 3H); 13C NMR (68
MHz, CDCl3) δ 214.2 (C), 146.7 (C), 141.5 (C), 128.4 (CH), 128.3
(CH), 126.0 (CH), 111.5 (CH2), 80.1 (CH), 71.2 (CH2), 41.8
(CH2), 34.2 (CH2), 33.5 (CH2); HRMS (EI) for C14H16O2 [M+]
calcd 216.1150, found 216.1157.
4-Meth ylen e-2-(1-m eth ylen e-3-p h en ylp r op yl)-1,3-d iox-
ola n e (23). This was isolated as a colorless oil (20.4 mg, 6%
yield): Rf ) 0.83 (petroleum ether 40-60/diethyl ether); IR
1
(liquid film) 3088, 2927, 2861, 1688, 1655, 904, 870 cm-1; H
1
2108, 1642 cm-1; H NMR (270 MHz, CDCl3) δ 5.76 (br, 1H),
NMR (250 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 5.57 (s, 1H), 5.34
(s, 1H), 5.14 (s, 1H), 4.55 (ddd, 1H, J ) 1.5, 1.6, 12.2 Hz), 4.42
(ddd, 1H, J ) 1.9, 2.1, 12.2 Hz), 4.38-4.35 (“q”, 1H, J ) 2.1
Hz), 3.94-3.91 (m, 1H, J ) 2.0 Hz), 2.82 (t, 2H, J ) 7.3 Hz),
2.41 (t, 2H, J ) 7.3 Hz); 13C NMR (68 MHz, CDCl3) δ 155.8
(C), 144.0 (C), 141.8 (C), 128.4 (CH), 128.3 (CH), 125.9 (CH),
3.97 (s, 2H), 3.29 (d, 2H, J ) 6.7 Hz), 1.97-1.50 (m, 6H), 1.30-
1.14 (m, 3H), 1.04-0.91 (m, 2H); 13C NMR (68 MHz, CDCl3) δ
194.5 (C), 77.8 (CH2), 75.0 (CH2), 53.1 (CH), 38.1 (CH), 30.1
(CH2), 30.1 (CH2), 26.6 (CH2), 26.0 (CH2); HRMS (CI, CH4) for
C10H17O2N2 [(M + H)+] calcd 197.1290, found 197.1293.
J . Org. Chem, Vol. 69, No. 11, 2004 3895

Clark et al.
116.4 (CH2), 107.8 (CH), 78.3 (CH2), 67.3 (CH2), 34.1 (CH2),
30.8 (CH2); HRMS (EI) for C14H16O2 [M+] calcd 216.1150, found
216.1145.
2-(Cycloh e xylid e n e m e t h yl)-4-m e t h yle n e -1,3-d ioxo-
la n e (34). This was isolated as a colorless oil (55.6 mg, 13%
yield): Rf ) 0.90 (petroleum ether 40-60/diethyl ether, 1:1);
IR (liquid film) 3017, 2936, 2858, 1673, 919, 869 cm-1; 1H NMR
(270 MHz, CDCl3) δ 5.90 (d, 1H, J ) 7.4 Hz), 5.23 (ddd, 1H, J
) 1.1, 1.1, 7.4 Hz), 4.56 (ddd, 1H, J ) 1.5, 1.6, 12.2 Hz), 4.38
(ddd, 1H, J ) 2.0, 2.2, 12.2 Hz), 4.33 (ddd, 1H, J ) 1.5, 1.8,
2.0 Hz), 3.90 (ddd, 1H, J ) 1.6, 1.8, 2.2 Hz), 2.28-2.22 (m,
2H), 2.18-2.14 (m, 2H), 1.65-1.54 (m, 6H); 13C NMR (68 MHz,
CDCl3) δ 156.2 (C), 151.0 (C), 117.0 (CH), 102.1 (CH), 78.2
(CH2), 67.5 (CH2), 37.1 (CH2), 29.7 (CH2), 28.3 (CH2), 27.9
(CH2), 26.6 (CH2); HRMS (EI) for C11H16O2 [M+] calcd 180.1150,
found 180.1142.
Rea ction of 3-(2-Cycloh exylid en eeth oxy)-1-d ia zo-2-bu -
ta n on e (20). According to the general procedure, 3-(2-cyclo-
hexylideneethoxy)-1-diazo-2-butanone (20) (401 mg, 1.80 mmol)
was treated with Rh2(HNCOCH3)4 (10 mg) in CH2Cl2 (200 mL).
Flash column chromatography on neutral alumina (petroleum
ether 40-60 and then 2%-10% diethyl ether in petroleum
ether 40-60) gave four fractions.
Rea ction of 1-(1-Cycloh exen -1-ylm eth oxy)-3-d ia zo-2-
p r op a n on e (18). According to the general procedure, 1-
(1-cyclohexen-1-ylmethoxy)-3-diazo-2-propanone (18) (44.8 mg,
0.231 mmol) was treated with Rh2(O2CCF3) (2 mg) in CH2Cl2
(30 mL). Flash column chromatography on neutral alumina
(petroleum ether 40-60 and then 10% diethyl ether in
petroleum ether 40-60) gave three compounds.
Hexah ydr o-1H-ben zo[1,3]cyclopr opa[1,2-c]pyr an -4(3H)-
on e (28). This was isolated as a colorless oil (27.0 mg, 72%
yield): Rf ) 0.64 (petroleum ether 40-60/diethyl ether); IR
(liquid film) 3015, 2939, 1684 cm-1; 1H NMR (270 MHz, CDCl3)
δ 4.10 (d, 1H, J ) 18.2 Hz), 3.85 (d, 1H, J ) 11.3 Hz), 3.72
(dd, 1H, J ) 0.8, 18.2 Hz), 3.56 (d, 1H, J ) 11.3 Hz), 2.43-
2.37 (m, 1H), 2.03-1.90 (m, 1H), 1.80-1.59 (m, 4H), 1.44-
1.24 (m, 4H); 13C NMR (68 MHz, CDCl3) δ 205.6 (C), 72.3
(CH2), 68.0 (CH2), 38.8 (CH), 28.3 (C), 24.2 (CH2), 23.4 (CH),
22.9 (CH2), 21.0 (CH2), 20.3 (CH2); HRMS (EI) for C10H14O2
[M+] calcd 166.0994, found 166.0990.
4′-Met h ylsp ir o[cycloh exa n e-1,7′-[3]oxa b icyclo[4.1.0]-
h ep ta n ]-5′-on e (36). This was isolated as a colorless oil (160.0
mg, 46% yield, 75:25 mixture of diastereoisomers). Data for
major isomer: Rf ) 0.49 (petroleum ether 40-60/diethyl ether,
1:1); IR (liquid film) 2928, 2854, 1694 cm-1; 1H NMR (270 MHz,
CDCl3) δ 4.23 (dd, 1H, J ) 4.7, 12.2 Hz), 3.85 (dd, 1H, J )
2.5, 12.2 Hz), 3.75 (q, 1H, J ) 7.0 Hz), 1.70-1.85 (m, 2H),
1.60-1.51 (m, 7H), 1.37-1.25 (m, 3H), 1.31 (d, 3H, J ) 7.0
Hz); 13C NMR (68 MHz, CDCl3) δ 208.1 (C), 76.3 (CH), 58.8
(CH2), 39.1 (CH2), 35.5 (C), 32.2 (CH), 28.1 (CH), 27.4 (CH2),
26.1 (CH2), 25.6 (CH2), 25.4 (CH2), 16.3 (CH3); HRMS (EI) for
5-(1-Cycloh exen -1-yl)d ih yd r o-3(2H)-fu r a n on e (29). This
was isolated as a colorless oil (3.2 mg, 8% yield): Rf ) 0.70
(petroleum ether 40-60/diethyl ether); IR (liquid film) 3017,
1
2932, 1758 cm-1; H NMR (250 MHz, CDCl3) δ 5.79 (br, 1H),
4.59 (dd, 1H, J ) 6.7, 9.0 Hz), 4.08 (d, 1H, J ) 17.0 Hz), 3.87
(d, 1H, J ) 17.0 Hz), 2.52 (dd, 1H, J ) 6.7, 18.0 Hz), 2.41 (dd,
1H, J ) 9.1, 18.0 Hz), 2.00-2.06 (m, 4H), 1.54-1.72 (m, 4H);
13C NMR (68 MHz, CDCl3) δ 215.4 (C), 135.7 (C), 125.5 (CH),
81.7 (CH), 71.5 (CH2), 41.2 (CH2), 25.1 (CH2), 23.9 (CH2), 22.6
(CH2), 22.5 (CH2); HRMS (EI) for C10H14O2 [M+] calcd 166.0994,
found 166.0989.
C
12H18O2 [M+] calcd 194.1307, found 194.1291.
5-(Cycloh exylid en em eth yl)d ih yd r o-2-m eth yl-(2H)-fu -
2-(1-Cycloh exen -1-yl)-4-m eth ylen e-1,3-d ioxola n e (30).
Rf ) 0.92 (petroleum ether 40-60/diethyl ether). Partial
data: 1H NMR (270 MHz, CDCl3) δ 4.33 (“q”, 1H, J ) 2.0 Hz),
4.39 (“dt”, 1H, J ) 2.0, 12.2 Hz), 4.54 (“dt”, 1H, J ) 1.5, 12.2
Hz), 5.44 (s, 1H), 5.81-5.99 (m, 1H); GC-MS peak at Rt ) 2.88
min; LRMS (EI) calcd for C10H14O2 166, mass found 166, 137,
108, and 93.
r a n -3-on e (37). This was isolated as a colorless oil (18.0 mg,
5% yield, 81:19 mixture of diastereoisomers). Data for the
major isomer: Rf ) 0.60 (petroleum ether 40-60/diethyl ether,
1:1); IR (liquid film) 2938, 2858, 1762, 1671 cm-1 1H NMR
;
(250 MHz, CDCl3) δ 5.23 (d, 1H, J ) 8.4 Hz), 4.87 (ddd, 1H, J
) 5.5, 8.4, 10.6 Hz), 3.83 (q, 1H, J ) 6.8 Hz), 2.57 (dd, 1H, J
) 5.5, 18.1 Hz), 2.28-2.10 (m, 4H), 2.24 (dd, 1H, J ) 10.6,
18.1 Hz), 1.64-1.42 (m, 6H), 1.33 (d, 3H, J ) 6.8 Hz); 13C NMR
(68 MHz, CDCl3) δ 216.7 (C), 146.9 (C), 120.5 (CH), 77.5 (CH),
71.4 (CH), 43.4 (CH2), 37.0 (CH2), 29.5 (CH2), 28.1 (CH2), 27.7
(CH2), 26.5 (CH2), 15.9 (CH3); HRMS (EI) for C12H17O2
[(M - H)+] calcd 193.1487, found 193.1488.
R ea ct ion of 1-(2-Cycloh exylid en eet h oxy)-3-d ia zo-2-
p r op a n on e (19). According to the general procedure, 1-(2-
cyclohexylideneethoxy)-3-diazo-2-propanone (19) (500 mg, 2.40
mmol) was treated with Rh2(O2CCH3)4 (20 mg) in CH2Cl2 (120
mL). Flash column chromatography on neutral alumina
(petroleum ether 40-60 and then 10% diethyl ether in
petroleum ether 40-60) gave three compounds.
2-(Cycloh exylid en em eth yl)-5-m eth yl-4-m eth ylen e-1,3-
d ioxola n e (38). This was isolated as a colorless oil (112 mg,
32% yield, 82:18 mixture of diastereoisomers). Data for major
isomer: Rf ) 0.87 (petroleum ether 40-60/diethyl ether, 1:1);
IR (liquid film) 2931, 2856, 1674, 970, 800 cm-1; 1H NMR (270
MHz, CDCl3) δ 6.02 (d, 1H, J ) 7.8 Hz), 5.24-5.20 (m, 1H),
4.78 (ddq, 1H, J ) 1.4, 1.6, 6.5 Hz), 4.30 (dd, 1H, J ) 1.6, 2.2
Hz), 3.84 (dd, 1H, J ) 1.4, 2.2 Hz), 2.32-2.22 (m, 2H), 2.19-
Sp ir o[cycloh exa n e-1,7′-[3]oxa bicyclo[4.1.0]h ep ta n ]-5′-
on e (32). This was isolated as a colorless oil (278 mg, 64%
yield): Rf ) 0.63 (petroleum ether 40-60/diethyl ether, 1:1);
IR (liquid film) 3013, 2932, 2855, 1681 cm-1 1H NMR (270
;
MHz, CDCl3) δ 4.21 (dd, 1H, J ) 1.6, 12.2 Hz), 4.03 (dd, 1H,
J ) 3.3, 12.2 Hz), 3.89 (d, 1H, J ) 17.8 Hz), 3.76 (d, 1H, J )
17.8 Hz), 1.95-1.89 (m, 2H), 1.76-1.69 (m, 1H), 1.62-1.49 (m,
6H), 1.43 (ddd, 1H, J ) 1.6, 3.5, 7.8 Hz), 1.36-1.31 (m, 2H);
13C NMR (68 MHz, CDCl3) δ 205.5 (C), 71.9 (CH2), 62.9 (CH2),
39.3 (CH2), 35.9 (C), 34.8 (CH), 27.6 (CH2), 27.3 (CH), 26.2
(CH2), 25.8 (CH2), 25.7 (CH2); HRMS (EI) for C11H16O2 [M+]
calcd 180.1150, found 180.1140. Anal. Calcd for C11H16O2: C,
73.29; H, 8.95. Found: C, 72.75; H 9.03.
2.12 (m, 2H), 1.64-1.54 (m, 6H), 1.37 (d, 3H, J ) 6.5 Hz); 13
C
NMR (68 MHz, CDCl3) δ 161.2 (C), 149.9 (C), 117.5 (CH), 100.0
(CH), 78.0 (CH2), 73.8 (CH), 37.1 (CH2), 29.5 (CH2), 28.2 (CH2),
27.9 (CH2), 26.6 (CH2), 19.7 (CH3); HRMS (EI) for C12H19O2
[(M + H)+] calcd 195.1385, found 195.1385.
(E)-[2-(1-Cycloh exen -1-yl)eth en yloxy]p r op a n on e (39).
This was isolated as a colorless oil (9.4 mg, 3% yield). Partial
data: 1H NMR (270 MHz, CDCl3) δ 6.32 (d, 1H, J ) 12.8 Hz),
5.60 (d, 1H, J ) 12.8 Hz), 5.54 (t, 1H, J ) 4.1 Hz), 4.18 (q, 1H,
J ) 7.0 Hz), 2.19 (s, 3H), 2.18-1.99 (m, 4H), 1.70-1.53 (m,
4H), 1.38 (d, 3H, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ
210.4 (C), 143.0 (CH), 132.2 (C), 125.4 (CH), 112.7 (CH), 81.1
(CH), 25.7 (CH2), 24.9 (CH3), 24.7 (CH2), 22.5 (CH2), 22.4 (CH2),
17.4 (CH3); LRMS (CI, CH4) 196 [(M + H)+] 195 [M+].
Rea ction of 1-(Cycloh exylm eth oxy)-3-d ia zo-2-p r op a n -
on e (46). According to the general procedure, 1-(cyclohexyl-
methoxy)-3-diazo-2-propanone (46) (500 mg, 2.55 mmol) was
treated with Rh2(O2CCF3)4 (10 mg) in CH2Cl2 (140 mL). Flash
column chromatography on neutral alumina (petroleum ether
5-(Cycloh exyliden em eth yl)dih ydr o-3(2H)-fu r an on e (33).
This was isolated as a colorless oil (5.1 mg, 1% yield): Rf )
0.74 (petroleum ether 40-60/diethyl ether, 1:1); IR (liquid film)
2937, 2856, 1759, 1669, 858 cm-1; 1H NMR (250 MHz, CDCl3)
δ 5.26 (ddd, 1H, J ) 0.9, 1.1, 9.4 Hz), 4.98 (ddd, 1H, J ) 6.0,
6.8, 9.4 Hz), 4.13 (d, 1H, J ) 17.0 Hz), 3.84 (d, 1H, J ) 17.0
Hz), 2.55 (dd, 1H, J ) 6.0, 18.0 Hz), 2.25 (dd, 1H, J ) 6.8,
18.0 Hz), 2.28-2.14 (m, 4H), 1.65-1.56 (m, 6H); 13C NMR (68
MHz, CDCl3) δ 215.6 (C), 147.3 (C), 120.3 (CH), 73.9 (CH),
71.3 (CH2), 43.8 (CH2), 37.0 (CH2), 29.5 (CH2), 28.3 (CH2), 27.8
(CH2), 26.5 (CH2); HRMS (EI) for C11H16O2 [M+] calcd 180.1150,
found 180.1149.
3896 J . Org. Chem., Vol. 69, No. 11, 2004

C-H Insertion Reactions of Rh Carbenoids
40-60 and then 2%-10% diethyl ether in petroleum ether
40-60) gave two fractions.
1.59 (m, 6H), 1.31-1.11 (m, 3H), 1.02-0.88 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 175.0 (C), 76.6 (quintet, J ) 21.4 Hz, CD2),
71.7 (CH2), 67.6 (CH2), 37.3 (CH), 29.5 (CH2), 26.3 (CH2), 25.5
(CH2); HRMS (CI, CH4) for C9H15D2O3 [(M + H)+] calcd
175.1303, found 175.1288.
(Cycloh exyl[2H]m eth oxy)a cetic Acid . Following the gen-
eral procedure, ethyl (cyclohexyl[2H]methoxy)acetate (289 mg,
1.34 mmol) was dissolved in THF (3 mL) and 2 M aqueous
lithium hydroxide (2 mL) was added at room temperature. The
carboxylic acid (227 mg, 90%) was obtained as a white solid:
mp 29-30 °C; 1H NMR (400 MHz, CDCl3) δ 4.11 (s, 2H), 3.34
(d, 1H, J ) 6.4 Hz), 1.86-1.59 (m, 6H), 1.34-1.10 (m, 3H),
1.03-0.88 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.5 (C),
77.2 (t, J ) 21.8 Hz, CHD), 67.8 (CH2), 37.6 (CH), 29.7 (CH2),
26.4 (CH2), 25.7 (CH2); LRMS (CI, CH4) 174 [(M + H)+, 57],
98 (100); HRMS (CI, CH4) for C9H16DO3 [(M + H)+] calcd
174.1240, found 174.1229.
Gen er a l Meth od for P r ep a r in g th e Deu ter a ted r-Di-
a zo Keton es 52a -c fr om th e Cor r esp on d in g Ca r boxylic
Acid s. The carboxylic acid was dissolved in a mixture (1:1) of
dried CH2Cl2 and diethyl ether under nitrogen. Oxalyl chloride
and DMF (one drop) were added at room temperature, and
the mixture was stirred for 2 h. The solvent and excess of
oxalyl chloride were removed in vacuo, and the resulting yellow
oil was diluted with dried CH2Cl2. The solution was cooled to
4 °C (ice bath), and an excess of cold CH2N2 or CH2D2 in diethyl
ether was added in one portion with vigorous stirring. After 2
h at 4 °C, the excess CH2N2 or CH2D2 was destroyed by the
careful addition of acetic acid. The solvent and acetic acid were
evaporated in vacuo, and the residue was purified by flash
chromatography on silica gel (hexanes-ethyl acetate, 9:1) to
give the R-diazo ketone as a yellow oil.
5-Cycloh exyld ih yd r o-3(2H)-fu r a n on e (48). This was
isolated as a colorless oil (149 mg, 35% yield): Rf ) 0.66
(petroleum ether 40-60/diethyl ether, 1:1); IR (liquid film)
1
2926, 2853, 1762 cm-1; H NMR (250 MHz, CDCl3) δ 4.01 (d,
1H, J ) 17.1 Hz), 3.94 (ddd, 1H, J ) 6.0, 7.3, 9.8 Hz), 3.82 (d,
1H, J ) 17.1 Hz), 2.46 (dd, 1H, J ) 6.0, 17.8 Hz), 2.23 (dd,
1H, J ) 9.8, 17.8 Hz), 2.05-1.95 (m, 1H), 1.83-1.50 (m, 6H),
1.38-0.92 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 215.4 (C),
82.6 (CH), 71.5 (CH2), 42.8 (CH), 41.0 (CH2), 28.9 (CH2), 28.7
(CH2), 26.3 (CH2), 25.8 (CH2), 25.6 (CH2); HRMS (EI) for
C10H16O2 [M+] calcd 168.1150, found 168.1153.
2-Cycloh exyl-4-m eth ylen e-1,3-d ioxola n e (49). This was
isolated as a colorless oil (172 mg, 40% yield): Rf ) 0.88
(petroleum ether 40-60/diethyl ether, 1:1); IR (liquid film)
2928, 2855, 1685, 886 cm-1; 1H NMR (270 MHz, CDCl3) δ 4.96
(d, 1H, J ) 5.1 Hz), 4.50 (ddd, 1H, J ) 1.6, 1.6, 12.2 Hz), 4.34
(ddd, 1H, J ) 2.0, 2.0, 12.2 Hz), 4.29 (ddd, 1H, J ) 1.6, 1.9,
2.0 Hz), 3.86 (ddd, 1H, J ) 1.6, 1.9, 2.0 Hz), 1.87-1.56 (m,
6H), 1.58-1.02 (m, 5H); 13C NMR (68 MHz, CDCl3) δ 156.4
(C), 110.1 (CH), 77.7 (CH2), 67.4 (CH2), 41.6 (CH), 26.9 (CH2),
27.0 (CH2), 26.4 (CH2), 25.7 (CH2); HRMS (EI) for C10H17O2
[(M+H)+] calcd 169.1228, found 169.1236.
Reaction of 3-(Cycloh exylm eth oxy)-1-diazo-2-bu tan on e
(47). According to the general procedure, 3-(cyclohexylmethoxy)-
1-diazo-2-butanone (47) (311 mg, 1.48 mmol) was treated with
Rh2(O2CCF3)4 (5 mg) in CH2Cl2 (120 mL). Flash column
chromatography on neutral alumina (petroleum ether 40-60
and then 2%-10% diethyl ether in petroleum ether 40-60)
gave two compounds.
5-Cycloh exyldih ydr o-2-m eth yl-3(2H)-fu r an on e (50). This
was isolated as a colorless oil (47.5 mg, 18% yield): Rf ) 0.63
(petroleum ether 40-60/diethyl ether, 1:1); IR (liquid film)
1-(Cycloh exyl[2H,2H]m eth oxy)-3-diazopr opan on e (52a).
Following the general procedure, (cyclohexyl[2H,2H]methoxy)-
acetic acid (780 mg, 4.46 mmol) was dissolved in a mixture
(1:1) of dried CH2Cl2 and diethyl ether (15 mL) and reacted
with oxalyl chloride (1.4 g, 11 mmol). The resulting acid
chloride was diluted with dried CH2Cl2 (10 mL) and added to
an excess of CH2N2 in diethyl ether. Purification gave the
R-diazo ketone 52a (658 mg, 74%) as a yellow oil: 1H NMR
(400 MHz, CDCl3) δ 5.76 (br, 1H), 3.97 (s, 2H), 1.97-1.50 (m,
6H), 1.35-0.91 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 193.9
(C), 74.5 (quintet, J ) 21 Hz, CD2), 52.6 (CH), 37.5 (CH), 29.6
(CH2), 26.2 (CH2), 25.5 (CH2); LRMS (CI, CH4) 199 [(M + H)+,
100], 99 (32), 97(9); HRMS (CI, CH4) for C10H15D2O2N2 [(M +
H)+] calcd 199.1416, found 199.1407.
2979, 2925, 2852, 1760 cm-1 1H NMR (250 MHz, CDCl3) δ
;
3.88-3.74 (m, 2H), 2.45 (dd, 1H, J ) 5.5, 18.0 Hz), 2.18 (dd,
1H, J ) 10.7, 18.0 Hz), 2.04-1.92 (m, 1H), 1.83-1.48 (m, 6H),
1.30 (d, 3H, J ) 6.8 Hz), 1.31-0.91 (m, 4H); 13C NMR (68 MHz,
CDCl3) δ 216.7 (CH), 80.2 (CH), 77.7 (CH2), 42.8 (CH), 40.6
(CH2), 29.1 (CH2), 28.6 (CH2), 26.4 (CH2), 25.8 (CH2), 25.6
(CH2), 15.8 (CH3); HRMS (EI) for C11H18O2 [M+] calcd 182.1307,
found 182.1312.
2-Cycloh exyl-4-m eth yl-5-m eth ylen e-1,3-d ioxola n e (51).
This was isolated as a colorless oil (109 mg, 40% yield, 92:8
mixture of diastereoisomers of a colorless oil). Data for major
isomer: Rf ) 0.83 (petroleum ether 40-60/diethyl ether, 1:1);
IR (liquid film) 2977, 2927, 2854, 1684, 998, 886 cm-1; 1H NMR
(250 MHz, CDCl3) δ 5.07 (d, 1H, J ) 5.2 Hz), 4.69 (ddq, 1H, J
) 1.5, 1.5, 6.5 Hz), 4.26 (dd, 1H, J ) 1.5, 2.2 Hz), 3.79 (dd,
1H, J ) 1.5, 2.2 Hz), 1.80-1.50 (m, 6H), 1.33 (d, 3H, J ) 6.5
Hz), 1.30-1.00 (m, 5H); 13C NMR (68 MHz, CDCl3) δ 161.3
(C), 108.0 (CH), 77.2 (CH), 73.7 (CH2), 41.9 (CH), 26.8 (CH2),
26.7 (CH2), 26.2 (CH2), 25.5 (CH2), 25.5 (CH2), 19.8 (CH3);
HRMS (EI) for C11H18O2 [M+] calcd 182.1307, found 182.1304.
Gen er a l Meth od for th e P r ep a r a tion of Mon o- a n d
Did eu ter a ted An a logu es of th e Ca r boxylic Acid 44. The
deuterated ester was dissolved in THF, and 2 M aqueous
lithium hydroxide was added at room temperature. The
mixture was then heated at reflux for a period of 1.5 h.
Aqueous 2 M HCl was added, and the solvents (THF and
water) were evaporated in vacuo. (Final traces of water were
removed azeotropically with toluene.) The resulting viscous
white precipitate was triturated with ethyl acetate, and the
organic solutions were combined and filtrated through a pad
of silica gel using ethyl acetate. After evaporation, the product
was obtained as a white solid.
3-[2H]-1-(Cycloh exylm eth oxy)-3-d ia zop r op a n on e (52b).
Following the general procedure, (cyclohexylmethoxy)acetic
acid (44) (2.03 g, 11.8 mmol) was dissolved in a mixture (1:1)
of dried CH2Cl2 and diethyl ether (30 mL) and reacted with
oxalyl chloride (2.9 g, 23 mmol). The resulting acid chloride
was diluted with dried CH2Cl2 (20 mL) and added to an excess
of CD2N2 in diethyl ether. Purification gave the R-diazo ketone
52b as a yellow oil. Dideuteriodiazomethane (CD2N2) was
prepared according to the procedure of Gassman.24
IR (CHCl3): 2913, 2847, 2226, 2116, 1644, 974, 890 cm-1
,
1H NMR (500 MHz, CDCl3): δ 3.88 (s, 2H), 3.28 (d, J ) 6.4
Hz, 2H), 1.79-1.55 (m, 6H), 1.31-1.13 (m, 3H), 1.02-0.92 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 194.1 (C), 77.5 (CH2), 74.6
(CH2), 52.5 (t, J ) 30 Hz, CDN2), 37.8 (CH), 29.7 (CH2), 26.3
(CH2), 25.6 (CH2). LRMS (CI, CH4): 198 ([M + H]+, 12), 197
(73), 97 (95), 84 (89). HRMS (CI, CH4) for C10H15DO2N2 [M+]:
calcd, 197.1275; found, 197.1280.
1-(Cycloh exyl[2H ]m et h oxy)-3-d ia zop r op a n on e (52c).
Following the general procedure, (cyclohexyl[2H]methoxy)-
acetic acid (225 mg, 1.29 mmol) was dissolved in a mixture
(1:1) of dried CH2Cl2 and diethyl ether (5 mL) and reacted with
oxalyl chloride (0.7 g, 6 mmol). The resulting acid chloride was
diluted with dried CH2Cl2 (5 mL) and added to an excess of
CH2N2 in diethyl ether. Purification gave the R-diazo ketone
(Cycloh exyl[2H,2H]m eth oxy)a cetic Acid . Following the
general procedure, ethyl (cyclohexyl[2H,2H]methoxy)acetate
(1.13 g, 5.22 mmol) was dissolved in THF (6 mL) and 2 M
aqueous lithium hydroxide (5 mL) was added at room tem-
perature. The carboxylic acid (784 mg, 80%) was obtained as
a white solid: 1H NMR (400 MHz, CDCl3) δ 4.11 (s, 2H), 1.88-
(24) Gassman, P. G.; Greenlee W. J . Org. Synth. 1973, 53, 38.
J . Org. Chem, Vol. 69, No. 11, 2004 3897

Clark et al.
52c (186 mg, 72%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
δ 5.76 (br, 1H), 3.96 (s, 2H), 3.27 (d, 1H, J ) 6.3 Hz), 1.84-
1.55 (m, 6H), 1.33-1.11 (m, 3H), 1.05-0.90 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 194.2 (C), 77.5 (t, J ) 21 Hz, CHD), 74.7
(CH2), 52.8 (CHN2), 37.8 (CH), 29.8 (CH2), 26.4 (CH2), 25.7
(CH2); LRMS (CI, CH4) 198 [(M + H)+, 100], 98 (58); HRMS
(CI, CH4) for C10H16DO2N2 [(M + H)+] calcd 198.1353, found
198.1343.
thank Professor H. M. L. Davies (State University of
New York at Buffalo) and Dr. D. M. Hodgson (Univer-
sity of Oxford) for helpful discussions regarding this
work.
Su p p or tin g In for m a tion Ava ila ble: General experiment
methods, preparation of starting materials, and 1H and 13C
NMR spectra for compounds 17-23, 28, 29, 32-34, 36-38,
and 46-51. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by
Engineering and Physical Sciences Research Council
(U.K.) (Grant No. GR/L62856). The authors wish to
J O049900E
3898 J . Org. Chem., Vol. 69, No. 11, 2004