Reversible C-C bond activation enables stereocontrol in Rh-catalyzed carbonylative cycloadditions of aminocyclopropanes

Article abstract of DOI:10.1021/ja511335v

Upon exposure to neutral or cationic Rh(I)-catalyst systems, amino-substituted cyclopropanes undergo carbonylative cycloaddition with tethered alkenes to provide stereochemically complex N-heterocyclic scaffolds. These processes rely upon the generation and trapping of rhodacyclopentanone intermediates, which arise by regioselective, Cbz-directed insertion of Rh and CO into one of the two proximal aminocyclopropane C-C bonds. For cyclizations using cationic Rh(I)-systems, synthetic and mechanistic studies indicate that rhodacyclopentanone formation is reversible and that the alkene insertion step determines product diastereoselectivity. This regime facilitates high levels of stereocontrol with respect to substituents on the alkene tether. The option of generating rhodacyclopentanones dynamically provides a new facet to a growing area of catalysis and may find use as a (stereo)control strategy in other processes.

Full text of DOI:10.1021/ja511335v

Article
pubs.acs.org/JACS
Reversible C−C Bond Activation Enables Stereocontrol in Rh-
Catalyzed Carbonylative Cycloadditions of Aminocyclopropanes
Megan H. Shaw,†,§ Niall G. McCreanor,†,§ William G. Whittingham,‡ and John F. Bower*,†
†School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
S
* Supporting Information
ABSTRACT: Upon exposure to neutral or cationic Rh(I)-
catalyst systems, amino-substituted cyclopropanes undergo
carbonylative cycloaddition with tethered alkenes to provide
stereochemically complex N-heterocyclic scaffolds. These
processes rely upon the generation and trapping of
rhodacyclopentanone intermediates, which arise by regiose-
lective, Cbz-directed insertion of Rh and CO into one of the
two proximal aminocyclopropane C−C bonds. For cyclizations
using cationic Rh(I)-systems, synthetic and mechanistic
studies indicate that rhodacyclopentanone formation is
reversible and that the alkene insertion step determines product diastereoselectivity. This regime facilitates high levels of
stereocontrol with respect to substituents on the alkene tether. The option of generating rhodacyclopentanones dynamically
provides a new facet to a growing area of catalysis and may find use as a (stereo)control strategy in other processes.
addition.3a To probe the relative properties of ureas vs more
INTRODUCTION
■
versatile carbamates, we prepared complexes 6a and 6b, which
Methodologies that provide stereodefined, “sp3-rich” scaffolds
were characterized by X-ray diffraction (Scheme 2).10 Here,
analysis of the ν(CO) values, confirms that carbamates are
weaker donor ligands than ureas (6a, R = OBn, ν(CO) =
2043.8 cm−1; 6b, R = NMe2, ν(CO) = 2022.5 cm−1). Because,
in general, alkenes coordinate to late transition metals less
strongly than alkynes,11 we anticipated that carbamates would
direct oxidative addition efficiently for the processes outlined in
Scheme 1B. Additionally, because access to π-complex 4b
requires dissociation of the directing group from 4a, the greater
lability of carbamates should facilitate the formation of this
intermediate and, in turn, enhance the rate of the alkene
insertion step. Consequently, we elected to explore the
development of Cbz-directed cycloadditions.
will underpin future advances in small molecule drug design.1
This, in turn, requires the invention of catalysis platforms that
(a) exploit readily available chiral precursors and (b) fulfill
contemporary reaction ideals, such as high atom economy.2
Recently, we outlined (3 + 1 + 2) cycloadditions of
aminocyclopropanes, CO and alkynes to provide cyclo-
hexenone products (Scheme 1A).3a These processes rely
upon the regioselective generation of a new class of “sp3-rich”
organometallic intermediate 2 by urea directed insertion of Rh
and CO into aminocyclopropanes 1 (R3 = NMe2).3−8 C−C
bond activation processes of this type can be viewed as
progenitors to a wide range of cycloaddition reactions that are
triggered by directed metal insertion into readily available
cyclopropane derivatives.9 Further development requires
protocols that use synthetically flexible directing groups and
provide increased “sp3-content” in the product. In this report,
we outline diastereoselective Cbz-directed (3 + 1 + 2)
cycloadditions involving aminocyclopropanes, CO and alkenes
to provide stereochemically complex heterocyclic scaffolds 5
(Scheme 1B). Key to these processes is a unique strategy that
exploits reversible C−C bond activation to achieve stereo-
control. These studies provide important synthetic and
mechanistic insights into the emerging area of catalysis based
upon rhodacyclopentanones and related species.3a−c,7,8
Initial synthetic studies focused upon the carbonylative
cycloaddition of Cbz-protected derivative 3a to generate adduct
5a (Table 1). Using a catalyst system similar to that described
in our earlier work, but with 1,2-dichlorobenzene (1,2-DCB) as
solvent and dimethyl fumarate as an additive, target 5a was
isolated in 71% yield and as a single diastereomer, which was
determined to be the trans-isomer by single crystal X-ray
diffraction (see the Supporting Information). The role of
dimethyl fumarate is unclear but, by analogy with other
processes,12 it may function as a labile electron-deficient ligand
that accelerates alkene insertion and/or reductive elimination.
In the absence of this additive, longer reaction times were
required, and the yield of the process was lower.13 Under
RESULTS AND DISCUSSION
■
In our previous studies, competitive coordination of the Rh(I)-
catalyst to the alkyne component mandated the use of strongly
coordinating urea directing groups to effect efficient oxidative
Received: November 4, 2014
© XXXX American Chemical Society
A
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The trans-stereochemistry associated with the ring junction
of 5a reflects the inherent preference of the migratory insertion
step from 4b. We anticipated that this selectivity would be
maintained for systems that possess substitution at R1 or R2.
However, in these cases, an additional complication is how to
control the stereorelationship between the R1/R2-substituted
stereocenters and the ring junction. Indeed, although
cyclizations of adducts 3b and 3c proceeded smoothly to
afford targets 5b and 5c, diastereocontrol with respect to R1 or
R2 could not be achieved (up to 3:2 d.r.).13 If the carbonyl-
directed C−C oxidative addition step is stereodetermining,
then high diastereocontrol requires the R1 or R2 group to bias
Rh-insertion into one of the two diastereotopic cyclopropane
C−C bonds. For both 3b and 3c there is no obvious
mechanism by which this can be achieved.
Scheme 1. Directing Group Controlled Cycloadditions of
Cyclopropanes
An alternate strategy that addresses this stereocontrol issue is
outlined in Scheme 3. Following oxidative addition, two
Scheme 3. Diastereoselectivity via Reversible Rhodacycle
Formation
Scheme 2. Synthesis of Rhodacyclopentanone Complexes
diastereomeric rhodacyclic π-complexes (7a and 7b) form en
route to the two diastereomers of the target. Here, the bicyclic
nature of these intermediates should amplify the steric effects of
the R1 and R2 substituents. This, in turn, should lead to
different rates of alkene insertion (k1 and k2) from 7a and 7b.
Consequently, if a regime for reversible rhodacyclopentanone
formation can be established then, in accord with the Curtin−
Hammett principle, product selectivity should be dependent
largely upon the relative magnitudes of k1 and k2. Murakami, Ito
and co-workers have demonstrated that rhodacyclopentanones,
derived from nondirected oxidative addition of Rh(I)-catalysts
into the acyl-carbon bond of cyclobutanones, can undergo
decarbonylation and reductive elimination to the corresponding
cyclopropanes using specific catalyst systems.7a,b,14 These
studies indicate that conversion of 7a/b to 3 may be feasible.
However, a single catalyst system that effects reversible (i.e.,
dynamic) rhodacyclopentanone formation has not been
reported. In the current scenario, this is especially challenging
since equilibration (via 3) must (a) occur under carbonylative
conditions, which should disfavor the reverse process, (b) be
fast with respect to k1 and k2, and (c) use a catalyst system that
is also effective for directed oxidative addition, alkene insertion,
and reductive elimination. Additionally, side reactions observed
in Murakami and Ito’s studies, such as decomposition of the
metallacycle to alkene byproducts, must be minimized.7a,b
Based upon the idea that free coordination sites on the Rh-
center should promote retro-carbonylation, and, in turn,
provide reversibility, we opted to investigate the use of cationic
Rh(I)-systems. After extensive investigation we established that
replacement of [Rh(cod)Cl]2 with [Rh(cod)2]OTf was
Table 1. (3 + 1 + 2) Cycloadditions Using a Neutral Rh(I)-
System
a
Diastereoselectivities are quoted in a format that allows comparison
with Table 3. Isolated diastereomer ratios were consistent with those
1
determined by H NMR of crude material.
optimized conditions, a more strongly coordinating dimethy-
lurea directing group was not effective, presumably because
access to the intermediate π-complex (cf. 4b) is attenuated.
B
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Table 2. Selected Optimization Results for the Cyclization of 3b to 5b Using a Cationic Rh(I)-System
a
entry
X
Y
additive
none
Z
solvent
temp., °C
Yield (d.r.)
1
2
15
0
-
-
-
1,2-DCB
PhCN
130
130
130
130
130
130
120
110
120
120
120
13% (n.d.)
15
0
150
0
none
48% (3:1:0.5)
27% (14:1:1)
43% (8:1:1)
55% (8:1:1)
60% (8:1:1)
67% (8:1:1)
52% (6:1:1)
79% (8:1:1)
59% (15:1:1)
48% (>15:1:1)
3
15
none
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
1,2-DCB
4
15
Ph(CO)NH2
Ph(CO)NH2
Ph(CO)NH2
Ph(CO)NH2
Ph(CO)NH2
i-Pr(CO)NH2
Me(CO)NHMe
Me(CO)NMe2
150
150
100
100
100
100
100
100
5
15
150
50
6
22.5
22.5
22.5
22.5
22.5
22.5
7
50
8
50
9
50
50
10
11
50
a
Yields and diastereoselectivities were determined by 1H NMR using 1,4-dinitrobenzene as a standard. Diastereoselectivities are quoted in a format
that allows comparison to Table 3: (A:B:C d.r.) = A (depicted): B (invert C-2 stereocenter): C (invert C-4 stereocenter).
possible, but only in the presence of coordinating solvents or
additives.15 Optimization was conducted on the cyclization of
3b to 5b, and key results are presented in Table 2. In the
absence of additives, the use of 1,2-DCB as solvent resulted in
low conversions, and accordingly, low yields of 5b were
obtained (Entry 1). PhCN, a coordinating solvent that was
effective in our previous work,3a provided an increased yield of
5b, albeit with modest diastereoselectivity (Entry 2). In this
case, the formation of a third diastereomer of the product was
observed for the first time (vide infra). Despite considerable
effort, we were unable to further optimize processes conducted
in PhCN. However, during these studies we had noted
hydration to generate small quantities of Ph(CO)NH2, and
this led to the evaluation of amide additives in conjunction with
1,2-DCB as solvent. Gratifyingly, use of 150 mol%
Ph(CO)NH2 in 1,2-DCB had a beneficial effect on both yield
and diastereoselectivity (Entry 1 vs 4). Parallel studies had
shown that dimethyl fumarate also provided significant
enhancements to yield and diastereoselectivity (Entry 3 vs
Entry 1). When both the amide and fumarate additives were
employed together, 5b was isolated in 55% yield and 8:1:1 d.r.
(Entry 5). Further optimization was achieved by the evaluation
of a range of amides and the refinement of other reaction
parameters (Entries 6−11). This resulted in the conditions
outlined in Table 2, Entry 9, which use i-Pr(CO)NH2 and
deliver 5b in 79% yield and 8:1:1 d.r.. Other amide additives
generated 5b with higher diastereoselectivity but in lower yield
(e.g., Entries 10 and 11). The stereochemistry of the major
diastereomer of 5b was determined by single crystal X-ray
diffraction (see Table 3). NMR studies (see the Supporting
Information) indicated that the two minor diastereomers are
related to the major component by inversion of the C-2 or C-4
stereocenter.
substrate 3f, which possesses a cyclopropane substituent,
cyclized efficiently, thereby highlighting the C−C activation
selectivity imparted by the directing group. The structure of 5i
was confirmed by single crystal X-ray diffraction, and, this, in
conjunction with the X-ray structure of 5b, served as the basis
for the other stereochemical assignments. In all cases, further
support was provided by detailed NMR analysis (see the
Supporting Information). At the present stage of development,
the catalytic protocol is applicable to monosubstituted alkenes
only. For example, attempted cyclization of 3l, which possesses
a trans-disubstituted alkene, did not afford 5l. Here, the issue
appeared to be slow insertion of the alkene and byproducts
derived from decomposition of the rhodacyclopentanone were
observed (e.g., N-propenyl carbamate derivatives). Protocols
that tolerate increased substitution on the alkene will be a focus
of future investigations.
The idea that reversible rhodacycle formation provides
diastereocontrol for the processes in Table 3 is supported by a
series of stoichiometric experiments (Scheme 4A−C). Dimeric
Rh-complexes 8a and 8b were prepared in a manner analogous
to 6a/b (Scheme 2).10 Upon exposure to P(3,5-(CF3)2C6H3)3
(400 mol%) and AgOTf (200 mol%), complexes 9a and 9b
1
were formed quantitatively (as determined by H and 31P
NMR) (Scheme 4A). 31P NMR analysis of CD2Cl2 solutions of
9a/b showed significant broadening of the “free” phosphine
ligand at room temperature which suggests rapid exchange with
the triflate ligand. The solid-state structures of 9a/b were
determined by X-ray diffraction; in the case of 9a, substitution
of the triflate ligand by adventitious water occurred during
crystallization (see the Supporting Information). Exposure of a
PhMe solution of rhodacycle 9a to stoichiometric quantities of
cyclopropane 10b under a CO atmosphere resulted in partial
exchange to generate 9b and cyclopropane 10a in 13% and 9%
yield, respectively, along with 70% recovered rhodacycle 9a
(Scheme 4B). In the inverse experiment, rhodacycle 9a and
cyclopropane 10b were both formed in 5% yield. When 9a was
subjected to 10 equiv of 10b, increased yields of 9b and
cyclopropane 10a were obtained, and rhodacycle 9a was
recovered in 76% yield. In all cases, some losses of
aminocyclopropanes 10a/b can be attributed to their relatively
high volatility.16 Overall, these experiments show that reversible
Application of the “cationic conditions” outlined in Table 2,
Entry 9, to 3a and 3c provided adducts 5a and 5c in 80% and
71% yield and, importantly, with high levels of diastereocontrol
for the ring junction and Me-substituted stereocenter (>15:1
diastereoselectivity in both cases) (Table 3). The conditions are
generally applicable, and a range of systems with substitution at
R1 and/or R2 cyclized smoothly to provide the products with
good to excellent levels of stereocontrol. Notably, even
C
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Table 3. Diastereoselective (3 + 1 + 2) Cycloadditions Using
a Cationic Rh(I)-System
Scheme 4. Preliminary Mechanistic Studies
complexes 9a/b are not exact analogues of the active catalytic
species formed under the conditions outlined in Table 3.
We have explored the scope of the cationic Rh(I)-system
outlined in Table 3 with respect to substitution on the
cyclopropane. A series of trans-1,2-disubstituted systems 11a−c
cyclized to afford adducts 12a−c in moderate to good yield
(Scheme 5A). The structure of 12c was confirmed by X-ray
diffraction (see the Supporting Information). In these cases,
complete transfer of cyclopropane stereochemistry is observed,
which accounts for the high levels of diastereocontrol
associated with the R2-substituted stereocenter of 12a−c. A
further point to note is that the products are derived from
highly selective Rh-insertion into the less hindered proximal
C−C bond of the cyclopropane (bond a). This contrasts our
earlier studies where more strongly directing urea groups gave
significantly lower levels of regiocontrol.3a Extension to
trisubstituted cyclopropane 11d resulted in efficient cyclization
to provide tricycle 12d in 67% yield (Scheme 5B). Here,
desymmetrization of the cyclopropane enables the introduction
of four contiguous stereocenters with complete diastereocon-
trol.
a
(A:B:C d.r.) = A (depicted): B (invert C-2 stereocenter): C (invert
C-4 stereocenter). Isolated diastereomer ratios were consistent with
those determined by H NMR of crude material.
1
rhodacycle formation can occur under carbonylative conditions
using the catalyst components outlined in Table 3. To confirm
catalytic competency, rhodacycle 9a was employed as a
precatalyst for the cyclization of 3b (Scheme 4C). This
generated 5b in 31% yield and with similar diastereoselectivity
to that observed earlier (cf. Table 3). It is notable that in this
experiment the turnover frequency is lower than under the
conditions used in Table 3 (31% vs 79% yield over the same
time period) and that the exchange experiments in Scheme 4B
do not provide an equilibrium composition of products. A
plausible explanation that accounts for both of these
observations is that the cyclopropane (3) does not dissociate
readily from the Rh-center after retro-carbonylation and
reductive elimination, and that interconversion between 7a/b
occurs at the metal center.17 Another possibility is that
We have not previously examined cyclizations involving cis-
1,2-disubstituted systems, and so, in these cases, the
regiochemical outcome was uncertain (Scheme 5C). Upon
exposure to the cationic Rh(I)-system described in Table 3, cis-
cyclopropane 11e generated adduct 12e in 42% yield and as a
4.5:1 mixture of diastereomers at C-6. Here, the product is
derived from Rh-insertion into the more hindered proximal C−
C bond (bond b) (cf. 12a−c). The incomplete stereochemical
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regioselective generation of the requisite rhodacyclopentanone
(i.e., preferential insertion of Rh/CO into bond b of 11e).21
The ability to program product regiochemistry by altering the
stereochemistry of the starting material (cf. 11b to 12b vs 11e
to 12e) may be important in target directed settings.
Nevertheless, studies aimed at providing catalyst systems that
deliver products derived from insertion into the less hindered
proximal C−C bond (i.e., bond a) of cis-1,2-disubstituted
cyclopropanes will be a focus of future investigations, as this
would provide access to the alternate C-7 stereoisomers of
12a−c.
Scheme 5. (3 + 1 + 2) Cycloadditions of Substituted
Aminocyclopropanes
CONCLUSIONS
■
In summary, we demonstrate that directing group controlled
carbonylative insertion of Rh(I)-catalysts provides efficient (3 +
1 + 2) cycloadditions between amino-substituted cyclopropanes
and tethered alkenes. Notable synthetic aspects of the current
process include (a) the high levels of stereocontrol achieved,
(b) the use of synthetically flexible carbamate directing groups,
and (c) the high “sp3-content” of the targets. Overall, this
approach provides direct and versatile access to a family of
complex heterocyclic scaffolds that are primed for further
modification. From a mechanistic viewpoint, it is important to
appreciate that two distinct catalyst systems have been
developed. The neutral Rh(I)-system appears to promote
kinetic diastereoselection, and this may be important for the
eventual development of processes that rely upon ligand
enforced stereocontrol. The cationic Rh(I)-system achieves
high levels of, what is essentially, substrate controlled
diastereoselectivity. Synthetic and mechanistic studies indicate
that this is dependent upon reversible C−C bond activation.
The option of generating rhodacyclopentanones dynamically
provides a new facet to a growing area of catalysis3a−c,7,8 and
may find use as a stereocontrol strategy for other processes.22
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
transfer associated with the butyl moiety is tentatively
attributed to epimerization of the labile C-6 stereocenter of
12e under the reaction conditions.18 The divergence in
regiochemistry observed for 12e vs 12a−c is notable. By
analogy with the stabilities of cis/trans-olefin complexes of
rhodium,19 cis-disubstituted cyclopropane C−C bonds might be
expected to coordinate more strongly than trans-disubstituted
variants, and this may facilitate electronically controlled and
contrasteric Rh/CO insertion into bond b of 11e, which would
lead directly to 12e. However, in light of the studies described
in Scheme 4, an alternate possibility is that reversible Rh/CO
insertion (into bond a or b) enables the relative rates of the two
possible alkene insertion steps to determine the regioselectivity
of the product (cf. Scheme 3).20 Consequently, the
regiochemical preference of rhodacyclopentanone formation
may not be reflected in the structure of 12e. To probe this
issue, we have prepared a model complex derived from a cis-1,2-
disubstituted cyclopropane (Scheme 5D). Sequential exposure
of cis-cyclopropane 13 to [Rh(CO)2Cl]2 and PPh3 afforded
monomeric complex 14 in 63% yield (2 steps). The
regiochemistry of 14 was assigned by detailed NMR analysis
(1H, 13C, HSQC, COSY) and arises from insertion of Rh and
CO into the more hindered bond b. This experiment supports a
scenario where the regiochemistry of 12e arises by
AUTHOR INFORMATION
■
Corresponding Author
john.bower@bris.ac.uk
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr Michael Ralph (University of Bristol) for
contributions during preliminary studies. M.H.S. and N.G.M.
thank the Bristol Chemical Synthesis Centre for Doctoral
Training, funded by the EPSRC (EP/G036764/1), and
Syngenta for the provision of a Ph.D. studentship. We thank
the X-ray crystallography service at the School of Chemistry,
University of Bristol, for analysis of heterocyclic products 5a,
5b, 5i, and 12c and Rh-complexes 6a, 6b, 8b, 9a, and 9b. J.F.B.
is indebted to the Royal Society for a University Research
Fellowship.
E
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(11) For discussions, see: Tatsumi, K.; Hoffmann, R.; Templeton, J.
L. Inorg. Chem. 1982, 21, 466 and references cited therein.
(12) See: Huang, C.-Y.; Doyle, A. G. J. Am. Chem. Soc. 2012, 134,
9541 and references cited therein.
(13) In the absence of dimethyl fumarate, 5a was isolated in 57%
yield after 48 h (vs 71% yield after 48 h under the conditions in Table
1). 5b was generated in 42% yield and 2:3 d.r. after 72 h when
dimethyl fumarate was omitted.
(14) In Murakami and Ito’s studies, both neutral and cationic systems
were effective at generating cyclopropanes from cyclobutanones (see
ref 7b). A major side reaction was competing β-hydride elimination
from the rhodacyclopentanone which resulted in alkene byproducts.
This competing pathway could be minimized by judicious choice of
ligand.
(15) For beneficial effects of Lewis basic additives or solvents in other
metal-catalyzed C−C activation processes, see: (a) Yasui, Y.; Kamisaki,
H.; Takemoto, Y. Org. Lett. 2008, 10, 3303. (b) Rondla, N. R.; Levi, S.
M.; Ryss, J. M.; Vanden Berg, R. A.; Douglas, C. J. Org. Lett. 2011, 13,
1940.
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bond of cyclobutanones. For pioneering studies, see: (a) Murakami,
M.; Amii, H.; Ito, Y. Nature 1994, 370, 540. (b) Murakami, M.; Amii,
H.; Shigeto, K.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 8285.
(c) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124,
13976. (d) Matsuda, T.; Tsuboi, T.; Murakami, M. J. Am. Chem. Soc.
2007, 129, 12596. For selected recent contributions in this area, see:
(e) Liu, L.; Ishida, N.; Murakami, M. Angew. Chem., Int. Ed. 2012, 51,
2485. (f) Masuda, Y.; Hasegawa, M.; Yamashita, M.; Nozaki, K.; Ishida,
N.; Murakami, M. J. Am. Chem. Soc. 2013, 135, 7142. (g) Parker, E.;
Cramer, N. Organometallics 2014, 33, 780. (h) Souillart, L.; Parker, E.;
Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 3001. (i) Souillart, L.;
Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 9640. (j) Ko, H. M.;
Dong, G. Nat. Chem. 2014, 6, 739. See also citations within reference
3a. In the approach outlined here, carbonylative generation of the
rhodacyclopentanone from a cyclopropane is a more appealing
strategy for reasons discussed in reference 3a.
(17) Another feasible method for obtaining stereocontrol involves
the alkene directing Rh-insertion to access selectively 7a or 7b.
Additional evidence disfavoring this selectivity mode includes: (a) less
strongly donating directing groups, such as trifluoroacetamide, are
completely ineffective under the conditions outlined in Table 3; (b)
the processes appear to be insensitive to the steric demands of the R2
substituent; and (c) for 5f, an alkene directed process would likely
favor Rh-insertion into the R1 group (5-ring chelate) rather than the
aminocyclopropane (6-ring chelate).
(18) When 12e (4.5:1 d.r.) was resubjected to the cyclization
conditions for 16 h, it was recovered in 75% yield and as a 3.5:1
mixture of diastereomers.
(19) Cramer, R. J. Am. Chem. Soc. 1967, 89, 4621.
(20) The neutral Rh(I)-system outlined in Table 1, which does not
appear to provide high reversibility for the processes described here,
also afforded selectively regioisomer 12e (43% yield, >15:1 r.r., 6:1
d.r.).
(21) Whether rhodacyclopentanone formation is under kinetic or
thermodynamic control in this case is unclear. For steric reasons,
insertion into bond a may be kinetically favored, but the resulting
rhodacyclopentanone is likely to be less stable than 14 due to steric
interactions between the butyl moiety and the directing group.
Consequently, reversible Rh/CO insertion may enable equilibration to
the thermodynamically favored regioisomer 14. Alternatively, 14 may
form directly for reasons outlined in the main text. At the present time,
evidence for reversible rhodacyclopentanone formation in cases
involving cis-disubstituted aminocyclopropanes has not been obtained
and products derived from Rh-insertion into the less hindered
proximal C−C bond (i.e., bond a of 11e and 13) have not been
observed.
(22) We note that related C−C bond activation/π-insertion
processes have been described as “cut and sew” methodologies.7j,8
In the present case, this terminology does not encompass the dynamic
nature of the C−C activation process.
(8) For processes that involve the generation of rhodaindanones by
oxidative addition of Rh(I)-catalysts into C(sp2)-acyl bonds, see:
(a) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567. (b) Xu, T.;
Ko, H. M.; Savage, N. A.; Dong, G. J. Am. Chem. Soc. 2012, 134,
20005. (c) Chen, P.-h.; Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014,
53, 1674. (d) Xu, T.; Savage, N. A.; Dong, G. Angew. Chem., Int. Ed.
2014, 53, 1891. (e) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53,
10733.
(9) Representative asymmetric approaches to cyclopropane carbox-
ylic acid derivatives: (a) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc.
1998, 120, 10270. (b) Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am.
Chem. Soc. 2005, 127, 14223. (c) Gao, L.; Hwang, G.-S.; Ryu, D. H. J.
Am. Chem. Soc. 2011, 133, 20708. (d) Miyamura, S.; Araki, M.; Suzuki,
T.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed.; DOI: 10.1002/
anie.201409186.
(10) McQuillin, F. J.; Powell, K. C. Dalton Trans. 1972, 2129.
F
DOI: 10.1021/ja511335v
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX