On the mechanism and selectivity of the combined C-H activation/Cope rearrangement

Article abstract of DOI:10.1021/ja111408v

The combined C-H activation/Cope rearrangement (CHCR) is an effective C-H functionalization process that has been used for the asymmetric synthesis of natural products and pharmaceutical building blocks. Up until now, a detailed understanding of this process was lacking. Herein, we describe a combination of theoretical and experimental studies that have resulted in a coherent description of the likely mechanism of the reaction. Density functional studies on the reactions of rhodium vinylcarbenoids at allylic C-H sites demonstrate that the CHCR proceeds through a concerted, but highly asynchronous, hydride-transfer/C-C bond-forming event. Even though most of the previously known examples of this process are highly diastereoselective, the calculations demonstrate that other transition-states and stereochemical outcomes might be possible by appropriate modifications of the reagents, and this was confirmed experimentally. The calculations also indicate that there is a potential energy surface bifurcation between CHCR and the competing direct C-H insertion.

Full text of DOI:10.1021/ja111408v

ARTICLE
pubs.acs.org/JACS
On the Mechanism and Selectivity of the Combined C-H
Activation/Cope Rearrangement
Jørn H. Hansen,† Timothy M. Gregg,‡ Stephanie R. Ovalles,† Yajing Lian,† Jochen Autschbach,§ and
Huw M. L. Davies†,*
†Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
‡Department of Chemistry and Biochemistry, Canisius College, Buffalo, New York 14208, United States
§Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14226, United States
S Supporting Information
b
ABSTRACT: The combined C-H activation/Cope rearrangement (CHCR) is an effective
C-H functionalization process that has been used for the asymmetric synthesis of natural
products and pharmaceutical building blocks. Up until now, a detailed understanding of this
process was lacking. Herein, we describe a combination of theoretical and experimental
studies that have resulted in a coherent description of the likely mechanism of the reaction.
Density functional studies on the reactions of rhodium vinylcarbenoids at allylic C-H sites
demonstrate that the CHCR proceeds through a concerted, but highly asynchronous,
hydride-transfer/C-C bond-forming event. Even though most of the previously known
examples of this process are highly diastereoselective, the calculations demonstrate that
other transition-states and stereochemical outcomes might be possible by appropriate
modifications of the reagents, and this was confirmed experimentally. The calculations also
indicate that there is a potential energy surface bifurcation between CHCR and the competing direct C-H insertion.
’ INTRODUCTION
Scheme 1. Combined C-H Activation/Cope Rearrange-
ment (CHCR)
New C-H functionalization methods offer exciting strategies
for the synthesis of complex organic architectures.1,2 Since our
original communication in 1997,3 we have been actively engaged
in exploring the use of donor/acceptor-substituted rhodium
carbenoids as intermediates for stereoselective intermolecular
C-H functionalization.2e-g,4 One of the most impressive var-
iants of this chemistry is the reaction between vinyldiazoacetates
and allylic C-H bonds, which has been called the “combined
C-H activation/Cope rearrangement” (CHCR) (Scheme 1).2g,4-7
This reaction occurs with remarkable stereoselectivity, and many
examples have been reported in which the products contain two
new stereocenters formed in >50:1 dr and >98% ee.2g,5-11
The CHCR has been demonstrated to be a powerful tool in
organic synthesis.12 It has been applied as a key reaction in the
formation of medicinally interesting molecules7,9,13 as well as
natural products.12,14-16 The most impressive examples of the
synthetic power of the CHCR are in its application to complex
natural product synthesis.12,14-17 A general approach toward
marine natural products isolated from Pseudopterogorgia elisa-
bethae has been reported, using the CHCR to incorporate
traditionally challenging motifs.12,14-17 This was highlighted in
the total syntheses of (-)-colombiasin A,17 (-)-elisapterosin
B,17 and several other related natural products.14-16 The key step
involved in the combined C-H activation/Cope rearrangement
is an enantiodivergent process from a racemic dihydronaphtha-
lene substrate.16 This led to enantiocontrol over three crucial
stereocenters present in these natural products (Scheme 2).12,14-17
Even though the CHCR reaction is a powerful transformation,
with many substrates, a competing reaction is the direct C-H
insertion, as illustrated in Scheme 3.5 The Rh2(S-DOSP)4-
catalyzed reaction of styryldiazoacetate 3 with 1-methylcyclohex-
ene generates a 1.6:1 mixture of the CHCR product 4 and the
direct C-H insertion product 5.5 On first glance, it would be
reasonable to assume that the CHCR occurs by a C-H insertion
followed by a Cope rearrangement, but it has been shown on
several occasions that the C-H insertion products are thermo-
dynamically more stable and thus are not viable intermediates in
the CHCR process.6,7,18,19 A challenge in this chemistry is to
understand what factors control whether a CHCR or a direct
C-H insertion is the favored transformation.
A model has been proposed to rationalize the stereochemical
outcome of this chemistry, in which the reaction is believed to be
initiated by a C-H insertion process, but this is interrupted by a
Cope rearrangement occurring through a chairlike transition
Received: December 18, 2010
Published: March 08, 2011
r
2011 American Chemical Society
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Scheme 2. Application of the Enantiodivergent CHCR in Natural Product Total Synthesis17
Scheme 3. Competing C-H Insertion and CHCR.5
Scheme 4. Mechanistic Proposals for the CHCR
Reaction.2d,5,7
Figure 1. Current “chair” transition-state hypothesis.5,10
state TS-I (Figure 1).5,10 This model successfully predicts the
observed major stereoisomer. Although the model illustrated in
Figure 1 is predictive of the stereochemical outcome of the reac-
tion, to date, it has not been rigorously evaluated.
Mechanism (1) can be eliminated, since, in several cases, the
CHCR reaction has been demonstrated to produce the thermo-
dynamically less stable (kinetic) product.6,7,18,19 The C-H
insertion product can therefore not be an intermediate in this
process. Mechanism (2) is also an unlikely pathway, particularly
since hydride shift/elimination in alkyl-substituted rhodium car-
benoids is well precedented and is known to form the Z-product
preferentially.20 In the CHCR reaction, the E-product is typically
observed. Mechanisms (3) and (4) are both consistent with the
observed chemistry. The latter pathway has served as the basis of
the currently used stereochemical predictive model for this reac-
tion.5 Pathway (5) may also occur, since vinylogous reactivity
leading to C-C bond formation is known.21 However, in 1,3-
diene-like systems, this would imply that an internal position of
Since its discovery in the late 1990s,7 several mechanistic
hypotheses have been put forth for the CHCR process. Five
proposals currently exist (Scheme 4): (1) a direct C-H inser-
tion, followed by a thermal Cope rearrangement,2d (2) an ene-
type reaction, in which the vinylcarbenoid acts as a 2π-enophile,7
followed by hydride shift/elimination, (3) a hydride transfer,
followed by vinylogous C-C bond formation, (4) a concerted,
synchronous transition state5 involving seven atoms or, (5) initial
attack of the vinyl group onto the vinylogous position of the
carbenoid complex, followed by proton transfer. The latter three
lie on a mechanistic continuum, as indicated in Scheme 4.
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Scheme 5. Model Reactions for the Computational Studies
and O). This composite basis set is abbreviated 6-31G*[Rh-RSCþ4f].24
The main discussion is based on single-point energies calculated at the
B3LYP/6-311þG(2d,2p)[Rh-RSCþ4f]//B3LYP/6-31G*[Rh-
RSCþ4f] level of theory, with zero-point energy corrections calculated
at the B3LYP/6-31G*[Rh-RSCþ4f] level and Gibbs free energies calcu-
lated at the B3LYP/6-31G*[Rh-RSCþ4f] level of theory. Stability of the
SCF-solution was confirmed by stability analyses for selected stationary
points at the same level.29a,b This analysis was conducted since it is well-
known that the transition state for the Cope rearrangement itself has a
considerable triplet-character.29c-e Heavy-atom basis set definitions and
corresponding pseudopotential parameters were obtained from the
EMSL basis set exchange library.30 All stationary points were character-
ized by normal coordinate analysis at the B3LYP/6-31G*[Rh-RSCþ4f]
level of theory. Transition states were confirmed to have only one imag-
inary vibrational mode corresponding to movement along the reaction
coordinate. Equilibrium structures were confirmed to have zero imagin-
ary vibrational modes. Transition states were further characterized by either
full intrinsic reaction coordinate (IRC) analysis using maxpoints = 100
or more, or by using default parameters in Gaussian‘09, followed by
geometry optimization to confirm that the stationary points were smoothly
connected. The calculated harmonic zero-point vibrational energies
(ZPVE) are reported unscaled. Calculated structures have been visua-
lized using Mercury.31
the sp2-system must initiate the reaction, which is inconsistent
with the HOMO electron density distribution.22
In this paper we have undertaken a detailed computational
analysis of the CHCR process. In particular, the likely mechanism
of the reaction has been interrogated in order to evaluate whether
a process that seems to combine the C-H insertion and the
Cope rearrangement is feasible. Second, a conformational anal-
ysis of rhodium vinylcarbenoids and its implications for the
stereochemical outcome of the reaction has been investigated.
Third, studies have been conducted to determine what controls
whether a reaction proceeds by a direct C-H insertion or the
CHCR, because in many instances these reactions compete with
each other. Finally, experimental studies have been conducted to
test the predictions that arose from the computational studies.
Solvent effects have not been considered in this work because the
C-H functionalization chemistry in practice often is carried out in
hydrocarbon solvents such as hexanes, pentane, or 2,2-dimethylbutane,
which have very small dielectric constants.
’ RESULTS AND DISCUSSION
Stereochemical Considerations. The CHCR reaction is
usually highly selective for one stereoisomeric outcome. How-
ever, stereochemical issues exist that could have crucial impact on
the reaction outcome for a given vinylcarbenoid/substrate
combination.21a The two main variables in this regard are
associated with: (1) the vinylcarbenoid conformation and (2) the
substrate orientation. The vinylcarbenoid may exist in both s-cis
and s-trans conformations, which can readily interconvert
(Figure 2a).21a When the vinylcarbenoid is substituted at the
terminus, which is the case for most synthetically useful systems,
reactions via the two conformers will result in two stereochemi-
cally distinct pathways. With two possible orientations of the
substrate, this leads to four possible approach combinations as
shown in Figure 2b. The combinations can be considered to be
boatlike or chairlike, in analogy to the corresponding Cope re-
arrangement, and are therefore classified based on this in addi-
tion to the orientation of the vinylcarbenoid (s-cis/chair etc.). In
the following section, we will describe a conformational analysis
of rhodium vinylcarbenoids and show how substituents on the
vinyl group influence the preferred conformation. This would be
a valuable tool for assessing reactions with more complex viny-
lcarbenoid systems. A detailed evaluation of reactions through all
four possible transition-state combinations of substrate orienta-
tion and vinylcarbenoid conformation will then follow.
’ CHEMICAL MODELS
The CHCR reaction is often highly stereoselective. The most
successful substrates in this chemistry have been cyclic 1,3-diene-
like systems such as 1,3-cyclohexadienes,7 cycloheptatriene,6 and
particularly 1,2-dihydronaphthalenes.8,10,19,23 In this work, we
have studied two model catalytic reactions between vinylcarbe-
noids and allylic C-H sites using dirhodium tetrakis(formate),
Rh2(O2CH)4, as a dirhodium carboxylate model24,25 (Scheme 5)
—the reaction between the unsubstituted vinylcarbenoid com-
plex 624,25 and either (1) 1,3-cyclohexadiene to produce 7 or (2)
1,4-cyclohexadiene, to produce 8. Although the unsubstituted
vinylcarbenoid has not been used for synthetic utility of the
CHCR reaction, it was employed herein for computational sim-
plicity. These model reactions serve to study the fundamental
mechanism and to analyze the stereochemical outcome of the trans-
formation. The vinylcarbenoid model 6 has been described in pre-
vious computational studies on cyclopropanation chemistry.24,25c
This study is focused on an analysis of how the rhodium carbenoid
reacts with the substrates. For detailed discussions on the formation
of the reactive vinylcarbenoid complex, see refs 24 and 25c.
’ COMPUTATIONAL METHODOLOGY
All calculations were performed with the Gaussian ‘09 software
package.26 Density functional theory was employed with the three-
parameter hybrid functional B3LYP27 to locate stationary points on the
potential energy surface (PES). Some of the structures were initially
located at the B3LYP/Lanl2DZ level of theory but were then subjected
to full geometry optimization with a basis set consisting of the 1997
Stuttgart relativistic small-core effective core-potential and basis set
[Stuttgart RSC 1997 ECP]28 for Rh, augmented with a 4f-function
(ζf(Rh) = 1.350).24 The split valence basis set 6-31G* was used in the
optimization and frequency calculations for all other atoms (C, H, N,
Conformational Analysis. Considering the vital importance
the vinylcarbenoid conformation can have on the stereochemical
outcome of the CHCR reaction, we decided to investigate the
equilibrium between the s-trans and s-cis vinylcarbenoid con-
formations using differentially substituted vinyl groups. By con-
sidering gas-phase Gibbs free energies from B3LYP/6-31G*[Rh-
RSCþ4f] calculations (Table 1), the equilibrium constants for
the s-cis to s-trans isomerization process were calculated for sub-
stituted vinylcarbenoids. The unsubstituted vinylcarbenoid 6 has
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Table 1. Influence of Substitution on Conformational
Preference
reaction. However, for carbenoids such as 10 and 11, and
especially for systems with even bigger substituents than methyl,
reactions are more likely to be controlled by the major available
conformer. The free energy barrier for vinyl group rotation in
carbenoid 10 is ΔGq = þ6.5 kcal/mol (s-cis to s-trans 10), while
for the Z-vinylcarbenoid 11 it is ΔGq = þ9.1 kcal/mol (s-trans to
s-cis 11).
Figure 2. (a) Vinylcarbenoid conformations. (b) Combinations of sub-
strate approaches and vinylcarbenoid conformations.
a slight preference for the s-trans conformer (-0.59 kcal/mol).
In comparison, previously described calculations at the B3LYP/
6-31G*[Rh-LA2] level of theory give ΔGrot = -0.47 kcal/mol for
this system.25c By introducing a methyl group at the (E) position,
R2 (9), a commonly used vinylcarbenoid in synthesis, there is still
a small preference for the latter conformer of -0.20 kcal/mol.
When the methyl group is introduced at the internal position
(R3), a stronger preference for the s-cis conformation of 10 is
observed by þ1.78 kcal/mol. This is related to the unfavorable
steric interactions involved between the internal substituent and
the catalyst “wall” in the s-trans conformation. This effect is more
pronounced when introducing a (Z)-substituent (R1 = Me) in
vinylcarbenoid 11, which strongly prefers the s-trans conformer
by -3.63 kcal/mol. The (Z)-substituent (R1) is very close to the
catalyst structure in the s-cis conformer and leads to a somewhat
distorted geometry. Another system, often used in synthesis, is
the (E)-styrylcarbenoid 12. Similar to entries 1 and 2, there is a
slight preference for the s-trans conformer by -0.12 kcal/mol.
The general trends appear to be: (1) for vinylcarbenoids with
only an (E)-substituent (other than hydrogen), there is no
strongly preferred conformer, and hence, both potentially have
to be considered in reactions involving the vinyl group. For most
such systems, however, the s-cis conformer appears to be the
more reactive. (2) For vinylcarbenoids with an internal substi-
tuent, the s-cis conformation is preferred. Most likely, this is the
only conformer present for the commonly used vinylcarbenoids,
as the group is usually much larger than methyl (usually siloxy-,
aryl-, or alkyl group). (3) If the vinylcarbenoid has a (Z)-sub-
stituent, the s-trans conformer is strongly preferred. These results
will serve as a foundation for evaluation of specific carbenoid
systems in this chemistry. However, when considering reactions
with the vinylcarbenoid, a Curtin-Hammett situation is likely to
occur.32 The barrier for rotation of the unsubstituted carbenoid 6
is ΔGq = þ8.8 kcal/mol (s-trans to s-cis 6), much smaller than the
free energy barriers for the CHCR process (ΔGq > 16 kcal/mol),
so that conditions for a Curtin-Hammett system are present.32
The least stable conformer may be predominantly involved in the
Reaction with 1,3-Cyclohexadiene. Transition structures
were next sought for all the combinations of substrate orientation
and carbenoid conformation in the reaction between the vinyl-
carbenoid model 6 and 1,3-cyclohexadiene. None of the located
transition states indicated a concerted, synchronous process
involving all seven atoms, as previously hypothesized.5 The most
stable transition structure, TS-II, was the s-cis/chair combination
of vinylcarbenoid and substrate (Figure 3). All the located
transition states were characterized by an almost perpendicular
approach of the allylic C-H bond of the substrate toward the
carbenoid, with C-H-Ccarbenoid angles of ∼170°. When ani-
mated in their imaginary vibrational modes, the transition states
displayed lengthening of the substrate C-H bond with motion
toward the carbenoid carbon. These observations strongly
indicate a predominant hydride-transfer process—consistent
with what has been observed in direct C-H insertion chem-
istry.24,25a,25b However, the hydride-transfer component appears
to be more pronounced for the allylic C-H bonds. The terminal
0
carbons (C3 and C4) are separated by 3.188 Å and display no
signs of rehybridization (unchanged bond lengths and angles),
which indicates that no C-C bond forming interactions have
developed in the TS.
When moving forward on the reaction coordinate from TS-II
(IRC), the potential energy surface following the hydride-transfer
transition state is relatively flat; however, C-C bond formation
between the terminal positions occurs before a zwitterionic
intermediate can form. These observations indicate that the
CHCR reaction proceeds through a concerted, but highly asyn-
chronous, hydride-transfer/C-C bond-formation event. These
results are consistent with previous DFT studies of direct C-H
insertion.24,25a,25b The more accurate picture of the mechanism is
shown in Figure 4a, with the hydride-transfer component occurring
first. From this, a simple predictive model for the sense of
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Figure 4. (a) Concerted, yet highly asynchronous mechanism for the
CHCR reaction. (b) Predictive model for asymmetric induction by
Rh2(S-DOSP)4.
Figure 3. Most stable TS structure and geometrical characteristics.
absolute asymmetric induction can be introduced when con-
sidering the chiral influence of the commonly used catalyst,
Rh2(S-DOSP)4. This catalyst is proposed to exist in a D2-
symmetric conformation33 in nonpolar media, and the chiral
influence can be represented by steric blocking groups as
indicated in Figure 4b—allowing for reaction to occur at the
carbenoid Re-face.24,33 This model can now successfully predict
the stereochemical outcome for this reaction. For a detailed
discussion of the D2-symmetry model for the dirhodium proli-
nates, see refs 33a and 33c.
reaction.34 Although the most stable transition structure TS-II
corresponds to the experimentally observed outcome of the CHCR
reaction, the variation in relative potential energies (þ4.2-6.2 kcal/
mol) and Gibbs free energies (þ16.4-18.5 kcal/mol) for the four
combinations is relatively small. This leads to the exciting possibility
that, even though the examples of the CHCR reactions reported to
date have proceeded through the s-cis/chair approach, other
stereochemical outcomes may be accessible by using the appropriate
combination of carbenoid precursor and substrate.
We decided to test the hypothesis that other transition-state
combinations may be accessible in the CHCR reaction by
experiments with specific carbenoid precursors. As a test sub-
strate, we decided to use 1-methyldihydronaphthalene 17, as
such 1,3-diene-like compounds are known to be effective in the
CHCR reaction.10,19,23 By performing the reactions with an
established chiral catalyst, Rh2(S-DOSP)4, valuable stereochem-
ical information would also result from the experiments
(Scheme 7). The E-vinylcarbenoid derived from diazo com-
pound 18 would undergo a CHCR reaction predicted by the
established model (s-cis/chair TS) to form 19 with excellent
stereocontrol.10 It has been demonstrated experimentally that
the use of a Z-vinyldiazoacetate results in reactions derived from
an intermediate s-trans vinylcarbenoid21a—consistent with our
above conformational analysis showing that just a methyl group
is required to totally control the Z-vinylcarbenoid conformation
(s-trans only). A CHCR reaction using the Z-vinyldiazoacetate
20 would consequently be forced to go through either the s-
trans/chair or s-trans/boat transition states—totally unprece-
dented pathways. Stereochemical analyses of the products from
these reactions would reveal what transition state is pertinent.
The reaction between 18 and 17, catalyzed by Rh2(S-DOSP)4,
in hexanes at 0 °C led to two isolated products, the predicted
CHCR product 19 and the C-H insertion product 21 in a 6:1
ratio (Scheme 8). The CHCR product was formed in 53% yield
and in excellent 98% ee, and with stereochemistry consistent with
the s-cis/chair predictive model.10 Even though the C-H inser-
tion product 21 can be derived from a CHCR reaction to form
19, followed by a Cope rearrangement,10 in this case, 21 is
considered to be formed from a direct C-H insertion. Typically
more vigorous conditions are required to induce the Cope
A given combination of vinylcarbenoid conformation (s-cis/s-
trans) and substrate orientation (boat/chair) gives rise to a
distinct pathway in the CHCR reaction. Scheme 6 shows all
the transition-state combinations for our model system, their
energies (EþZPE) and Gibbs free energies relative to free
carbenoid and 1,3-cyclohexadiene as well as results of forward
intrinsic reaction coordinate analyses. We have added two
unspecified groups R and R0 (R = R0 = H in the calculations)
to demonstrate the stereochemical implications of each pathway,
as this would be important to synthetically relevant reaction
systems. The s-cis/chair transition state TS-II ((EþZPE)rel
=
þ4.2 kcal/mol) corresponds to the basic model for the CHCR
reaction and gives a predicted product consistent with the
experimentally observed stereoselectivity.5,7 This is also the most
stable transition structure. The s-cis/boat combination TS-III
((EþZPE)rel = þ6.2 kcal/mol) would give CHCR product 14,
which would have one inverted stereocenter compared to 13.
However, this stereoisomer has not been observed for the CHCR
reaction. The s-trans/boat transition structure TS-IV ((Eþ
ZPE)rel = þ5.8 kcal/mol) led to a different product 15. As the
hydride transfer proceeds toward completion, the carbonyl oxygen
of the ester group deprotonates the adjacent position on the
substrate (presumably due to a significant cationic character at this
point), leading to an enol 15 and aromatization of the substrate.
Finally, the s-trans/chair structure TS-V ((EþZPE)rel = þ4.4 kcal/
mol) undergoes the CHCR reaction to form 16, with totally
opposite stereocenters to that of 13. A more interesting feature
here is the formation of a Z-double bond, a feature set by the s-trans
orientation of the initial vinylcarbenoid.21a A Z-CHCR product has
only been observed as a minor product with this substrate when a
very electron-deficient catalyst, Rh2(TFA)4, was used in the
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Scheme 6. Forward Intrinsic Reaction Coordinate Analysis and Stereochemical Implicationsa
a Gibbs free energies and ZPE were calculated at the B3LYP/6-31G*[Rh-RSCþ4f] level of theory. Potential energies were calculated at the B3LYP/6-
311þG(2d,2p)[Rh-RSCþ4f]//B3LYP/6-31G*[Rh-RSCþ4f] level of theory. The energies are reported relative to s-trans carbenoid 6 þ 1,3-
cyclohexadiene.
the CHCR product has a Z-double bond, but has retained the
same stereogenic centers as in the reaction with the E-vinyldia-
Scheme 7. Experimental Probe of Vinylcarbenoid Confor-
mational Control
zoacetate. This would only be consistent with a reaction pro-
ceeding through the s-trans/boat transition state (TS-IV). The s-
trans/chair TS may be disfavored for dihydronaphthalene sub-
strates as the aromatic moiety would be expected to have more
steric interference with the catalyst structure compared to in the
s-trans/boat-approach. Nevertheless, we have demonstrated that,
through appropriate vinylcarbenoid conformational control, a
“non-traditional” transition state for the CHCR reaction can be
favored—consistent with our hypothesis. Furthermore, the results
suggest that a given substrate may have a preference for a specific
approach and, hence, a different diastereomeric outcome of the
CHCR reaction may be possible by subtle changes in substrate.
Another interesting observation is that the reaction through an s-
trans vinylcarbenoid appears to slightly favor direct C-H insertion
chemistry over the CHCR reaction. This will be discussed below.
Direct C-H Insertion versus CHCR. 1,3-Diene-like com-
pounds are excellent substrates for the CHCR reaction. How-
ever, it is not fully understood how the substrate structure
controls whether a system undergoes direct C-H insertion or
the CHCR process. The success of dihydronaphthalenes and 1,3-
dienes in the CHCR chemistry, as well as our enhanced under-
standing of the mechanistic details presented herein and in
previous works,24 prompted us to investigate what intrinsic factors
of the substrate could control this delicate balance. In accordance
with our mechanistic description of the CHCR, as the hydride-
transfer stage of the highly asynchronous process becomes advanced,
there would be a strong carbocationic character developing in the
conjugated system of the substrate, as well as carbanionic character
at the vinylcarbenoid portion. For a 1,3-diene-like substrate, the
rearrangement in this substrate. Furthermore, the difference in
the enantiomeric excess of the two products and the lack of
change in the product ratio on allowing the reaction to stand is
not consistent with the formation of the C-H insertion product
21 from 19. Reaction with the Z-vinyldiazoacetate led to a 1:2.5
ratio of CHCR product 22 (14% yield, 91% ee)35 and direct C-
H insertion product 23 (44% yield, 10:1 dr, 84% ee of major
diastereomer). In this case, the latter product is indeed derived
from a direct C-H insertion process, as the attenuated diastereo-
and enantioselectivity relative to the CHCR product is consistent
with previous findings in C-H insertion chemistry.4c Interestingly,
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Scheme 8. E vs Z-Vinylcarbenoids in the CHCR Reaction
bond and inverted stereogenic centers relative to 25, was pro-
duced in 79% ee.36 This product is quite unusual in this chemistry.
The absolute and relative configuration of 25 is consistent with
the established s-cis/chair model for the CHCR reaction (Figure 4).
Furthermore, the direct C-H insertion to form 26 is in agree-
ment with the predictive model developed for C-H insertion
chemistry.24 Consistent with our previous considerations, the
formation of a Z-product (27) must occur through a vinylcarbe-
noid in the s-trans conformation, and the absolute and relative
configurations suggest that it is formed through an s-trans/chair
TS. The observation of direct C-H insertion does indeed lend
support to our hypothesis on the electronic factors that influence
the CHCR reaction in 1,3-diene-like systems. For 1,3-cyclohex-
adienes, no C-H insertion has been reported.7
Considering our hypothesis on the electronic factors influen-
cing the CHCR reaction, as well as the above experimental results
indicating a higher propensity of direct C-H insertion, we decided
to carry out a detailed computational analysis using the 1,4-cyclo-
hexadiene system as substrate. Transition states were located for
the approach of 1,4-cyclohexadiene toward our vinylcarbenoid
model 6. Because of the symmetry, only one hydride-transfer TS
was found for each vinylcarbenoid conformer (Scheme 10). Both
transition structures had very similar potential energies (relative
to free carbenoid plus 1,4-cyclohexadiene), þ5.06 kcal/mol for
TS-VI and þ5.17 kcal/mol for TS-VII. The IRC analysis showed
that reaction through TS-VI proceeded by a hydride-transfer/
C-C bond-forming reaction, consistent with our previous
findings, and ultimately led to CHCR product 28, derived from
an s-cis/chair TS. This is in agreement with the existing stereo-
chemical model and the experimental results. The IRC analysis
from TS-VII, however, led to the direct C-H insertion product
29 with stereochemistry in agreement with the existing model for
this chemistry.24 These results suggest that reaction via the s-trans
vinylcarbenoid may have a preference for direct C-H insertion
Figure 5. Charge stabilization in dienyl substrates.
majority of positive charge buildup would localize onto the central
carbon of the cyclohexadienyl system (Figure 5), consistent with
charge distribution in pentadienyl cation systems.22 For dihy-
dronaphthalenes, this position would also be benzylic, providing
even better positive charge stabilization. One hypothesis is that
this charge stabilization during the reaction progress in 1,3-diene
systems favors the CHCR reaction to occur as the carbanionic
vinylcarbenoid moiety prefers to form a C-C bond between the
vinyl terminus and the internal position of the substrate. In order
to support this idea we hypothesized that, in closely related
substrates such as 1,4-cyclohexadienes, the same charge-localiza-
tion would occur as the hydride transfer becomes advanced.
However, as the internal position of the cationlike system would
be at the site of hydride transfer in this case, C-C bond forma-
tion would preferably occur at this position and, hence, reduce
the propensity of the CHCR process to occur.
To test the above hypothesis, we decided to carry out exper-
iments with 1,4-cyclohexadiene as a substrate in the reaction with
methyl styryldiazoacetate 24, catalyzed by Rh2(S-DOSP)4 (see
Scheme 9). The reaction afforded the CHCR product 25 as the
major product in 72% relative yield and in 93% ee. The product
derived from a direct C-H insertion (26) was also formed in
26% relative yield in 85% ee. This was shown to be the ther-
modynamically most stable product. A minor amount of another
CHCR product 27 (2% relative yield), containing a Z double
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Scheme 9. Reaction between Styryldiazoacetate 24 and 1,4-
Cyclohexadiene
Scheme 10. IRC Analyses of Both Combinations of
1,4-Cyclohexadiene and Vinylcarbenoid 6a
a Gibbs free energies and ZPEs were calculated at the B3LYP/6-
31G*[Rh-RSCþ4f] level of theory. Potential energies were calculated
at the B3LYP/6-311þG(2d,2p)[Rh-RSCþ4f]//B3LYP/6-31G*[Rh-
RSCþ4f] level of theory. The energies are reported relative to s-trans
carbenoid 6 þ 1,4-cyclohexadiene.
rather than the CHCR reaction. Evidence for this was also noted
in the experimental results in the reaction between a Z-vinylcar-
benoid and 1-methyldihydronaphthalene (Scheme 8), which
favored direct C-H insertion even though the substrate was
considered to be “optimal” for the CHCR reaction. The results
are puzzling, because how does direct C-H insertion occur
through the same transition state that would have to be invoked
to explain the existence of the minor Z-CHCR product 27
observed in experiments?
The issue of competition between direct C-H insertion and
the CHCR process is complex, since we have shown that the
latter reaction proceeds initially through a transition state with
hydride-transfer character— the same transition state that would
be expected to lead to direct C-H insertion, according to our
previous studies.24 The idea that both reactions may occur
through the same initial transition state, without an intervening
intermediate, is consistent with a potential energy surface bifurca-
tion (Figure 6).37 This phenomenon is characterized by two
sequential transition states that are not connected via a mini-
mum. Although the minimum energy pathway (MEP), from the
initial transition state leads to one product (for example the
CHCR product), alternative reaction trajectories over the initial
hydride-transfer transition-state ridge may lead to a second
product (direct C-H insertion).37c In retrospect, it is sensible
that the transition-state valley of the hydride transfer ultimately
must be connected with the Cope rearrangement transition-state
Figure 6. Model potential energy surface bifurcation.
ridge, which again connects the two products. Bifurcations of
potential energy surfaces of organic reactions are well-known and
have received much attention in recent years because of several
examples of this phenomenon in synthetically important reaction
systems.37c,38 Unfortunately, no simple, general predictors of the
selectivity in such systems can be formulated,38d as it will be
governed by the potential energy surface shape and Newtonian
dynamic effects, rather than traditional TST considerations.37c,38d
In order to gather evidence of whether direct C-H insertion
and the CHCR reaction are related through a bifurcated potential
energy surface, it was decided study the reaction coordinate
potential energy profile for the model reaction with 1,4-cyclo-
hexadiene, generated from the above analysis, more closely.
Figure 7 shows the reaction coordinate potential energy surface
when moving forward from the hydride-transfer transition state
TS-VII, following the minimum energy path toward the direct
C-H insertion product 29. As the initial hydride-transfer com-
ponent is almost complete, the potential energy surface becomes
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’ CONCLUSIONS
In conclusion, we have conducted extensive DFT studies in
combination with experiments on the mechanism of the com-
bined C-H activation/Cope rearrangement and have found that
the reaction proceeds through a concerted, but highly asynchro-
nous, hydride-transfer/C-C bond-forming process. A delicate
balance exists, governed by the detailed structures of substrate
and vinylcarbenoid, between different possible diastereomeric
outcomes in this reaction. However, the absolute and relative
stereochemical outcome is predictable from models described
herein. We have demonstrated that direct C-H insertion and the
CHCR process can proceed through the same initial transition
state through a potential energy bifurcation. The studies pre-
sented herein have revealed the crucial importance of vinylcar-
benoid conformation and substrate structure in this chemistry
and have provided the tools for a thorough assessment of stereo-
chemical issues related to rhodium vinylcarbenoid chemistry.
Future studies, guided by these computational results, will explore
the utilization of modified carbenoid precursors and substrates to
achieve different stereochemical outcomes.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete reference 26. Com-
b
putational details, theoretical structures, calculated quantities, and
experimental details.This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 7. Forward IRC for reaction of 1,4-cyclohexadiene with s-trans 6.
Upward red arrows represent transition-state optimizations. Downward
red arrows represent geometry optimizations.
’ AUTHOR INFORMATION
relatively flat (∼0.2-0.85 Å) and then follows a steep path
toward product 29 as the C-C bonding occurs. Such flat
portions of the potential energy surface are characteristically
observed for bifurcating systems.38e Furthermore, by inspecting
geometries from the flat region, they are found to have features
that resemble those of [3,3]-sigmatropic rearrangement transi-
tion states. Indeed, by choosing two random geometries and then
subjecting these to transition-state optimization procedures,
both led to transition state TS-VIII, which is that of a Cope
rearrangement. An even more interesting observation was that,
by subjecting an intermediate geometry from the potential energy
surface to geometry optimization, a different CHCR product 30
was obtained rather than the direct C-H insertion product 29.
30 has a Z-double bond geometry, and would have opposite
stereogenic centers to the normal s-cis/chair product 28—in
excellent agreement with the experimental results described
before. These results show that the hydride-transfer transition
structure TS-VII is connected to CHCR product 30, the direct
C-H insertion product 29, and the Cope rearrangement transi-
tion state TS-VIII on the same potential energy surface. In
conjunction with experimental results, this demonstrates that a
potential energy surface bifurcation can exist in the reaction
between vinylcarbenoids and allylic C-H sites.
Corresponding Author
hmdavie@emory.edu
’ ACKNOWLEDGMENT
This material is based on work supported by the National
Science Foundation under the Center for Chemical Innovation
in Stereoselective C-H Functionalization (CHE-0943980) and
CHE-0447321 (for J.A.) We also acknowledge the University at
Buffalo’s Center for Computational Research for technical sup-
port. We thank Dr. Jamal Musaev and Dr. Dean Tantillo for
helpful discussions, Dr. Ken Hardcastle for the X-ray crystal-
lographic structural determination, and Dr. Ravisekhara P. Reddy
and Dr. Douglas G. Stafford for preliminary experimental studies.
’ REFERENCES
(1) For representative examples, see: (a) Milczek, E.; Boudet, N.;
Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825–6828. (b) Stang, E. M.;
White, M. C. Nature Chem. 2009, 1, 547–551. (c) Shi, B. F.; Zhang,
Y. H.; Lam, J. K.; Wang, D. H.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 460.
(d) Mulcahy, J. V.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 12630. (e)
Olson, D. E.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 11248. (f) Rice,
G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11707–11711. (g) Feng,
Y. Q.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958–961. (h) Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316–6317. (i)
Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 4882–4886. (j) Liang, C.; Collet, F.; Robert-Peillard, F.;
Mueller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc. 2008, 130, 343–350.
(k) Chen, M. S.; White, M. C. Science 2007, 318, 783–787. (l) Parker,
K. A.; Chang, W. Org. Lett. 2005, 7, 1785–1788. (m) Chen, Z.; Chen, Z.;
Jiang, Y.; Hu, W. Tetrahedron 2005, 61, 1579–1586. (n) Hinman, A.; Du
Bois, J. J. Am. Chem. Soc. 2003, 125, 11510–11511. (o) Wehn, P. M.;
DuBois, J. J. Am. Chem. Soc. 2002, 124, 12950–12951. (p) Taber, D. F.;
Although we have demonstrated that a bifurcation exists for
the reaction between s-trans vinylcarbenoid 6 and 1,4-cyclohex-
adiene, this would also extend to the reaction through the s-cis
vinylcarbenoid with similar properties. When considering the
1,3-cyclohexadiene model, all four possible transition-state com-
binations may also have bifurcating potential energy surfaces.
Using the tools presented herein, we can now analyze and
rationalize the outcome of any given vinylcarbenoid/substrate
combination in terms of C-H insertion or CHCR processes.
5084
dx.doi.org/10.1021/ja111408v |J. Am. Chem. Soc. 2011, 133, 5076–5085

Journal of the American Chemical Society
ARTICLE
Tian, W. J. Org. Chem. 2008, 73, 7560–7564. (q) Bequette, J. P.;
Jungong, C. S.; Novikov, A. V. Tetrahedron Lett. 2009, 50, 6963–6964.
(2) Recent reviews: (a) Dauban, P.; Dodd, R. H. In Amino group
chemistry: from synthesis to the life sciences ; Ricci, A., Ed.; John Wiley &
Sons: Weinheim, 2008; pp 5592. (b) Bergman, R. G. Nature 2007,
446, 391–393. (c) Davies, H. M. L. Angew. Chem., Int. Ed. 2006,
45, 6422–6425. (d) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
Chem. Rev. 2010, 110, 704–724. (e) Davies, H. M. L.; Denton, J. R.
Chem. Soc. Rev. 2009, 38, 3061–3071.(f) Davies, H. M. L.; Hansen, J. In
Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.; John Wiley &
Sons: Hoboken, NJ, 2010; pp 163-226. (g) Davies, H. M. L.; Manning,
J. R. Nature 2008, 451, 417–424. (h) Godula, K.; Sames, D. Science 2006,
312, 67–72.
(3) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997,
119, 9075–9076.
(4) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 2861–2903. (b) Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem.
2005, 3, 4176–4187. (c) Davies, H. M. L.; Loe, O. Synthesis
2004, 2595–2608.
(27) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988,
37, 785–789. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(28) (a) Kaupp, M.; v. R. S., P.; Stoll, H.; Preuss, H. J. Chem. Phys.
1991, 94, 1360. (b) Bergner, A.; M. D.; Kuechle, W.; Stoll, H.; Preuss, H.
Mol. Phys. 1993, 80, 1431. (c) Dolg, M.; S., H.; Preuss, H.; Pitzer, R. M.
J. Phys. Chem. 1993, 97.
(29) (a) Seeger, R.; Pople, J. A. J. Chem. Phys. 1977, 66, 3045–3050.
(b) Bauernschmitt, R.; Ahlrichs, R. J. Chem. Phys. 1996, 104, 9047–9052.
(c) Dewar, M. J. S.; Wade, L. E., Jr. J. Am. Chem. Soc. 1977,
99, 4417–4424. (d) Osamura, Y.; Kato, S.; Morokuma, K.; Feller, D.;
Davidson, E. R.; Borden, W. T. J. Am. Chem. Soc. 1984, 106, 3362–3363.
(e) Hrovat, D. A.; Beno, B. R.; Lange, H.; Yoo, H.-Y.; Houk, K. N.;
Borden, W. T. J. Am. Chem. Soc. 1999, 121, 10529–10537.
(30) (a) Feller, D. J. Comput. Chem. 1996, 17, 1571–1586. (b)
Schuchardt, K. L.; Didier, B. T.; Elsethagen, T.; Sun, L.; Gurumoorthi,
V.; Chase, J.; Li, J.; Windus, T. L. J. Chem. Inf. Model 2007,
47, 1045–1052.
(31) (a) Taylor, R.; Macrae, C. F. Acta Crystallogr., Sect. B 2001,
57, 815–827. (b) Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M.;
Macrae, C. F.; McCabe, P.; Pearson, J.; Taylor, R. Acta Crystallogr., Sect. B
2002, 58, 389–397. (c) Macrae, C. F.; Edgington, P. R.; McCabe, P.;
Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J.
J. Appl. Crystallogr. 2006, 39, 453–457. (d) Macrae, C. F.; Bruno, I. J.;
Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-
Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr.
2008, 41, 466–470.
(5) Davies, H. M. L.; Jin, Q. H. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5472–5475.
(6) Davies, H. M. L.; Stafford, D. G.; Hansen, T.; Churchill, M. R.;
Keil, K. M. Tetrahedron Lett. 2000, 41, 2035–2038.
(7) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999,
1, 233–236.
(8) Davies, H. M. L.; Yang, J.; Manning, J. R. Tetrahedron: Asymmetry
2006, 17, 665–673.
(32) Seeman, J. I. Chem. Rev. 1983, 83, 83–134.
(9) Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006,
128, 1060–1061.
(10) Davies, H. M. L.; Jin, Q. H. J. Am. Chem. Soc. 2004,
(33) (a) Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008,
252, 545–555. (b) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459–2469.
(c) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J.
J. Am. Chem. Soc. 1996, 118, 6897–6907.
126, 10862–10863.
(11) Manning, J. R.; Davies, H. M. L. Org. Synth. 2007, 84, 334–346.
(12) Davies, H. M. L.; Dai, X. Strategies and Tactics in Organic
Synthesis; John Wiley & Sons: New York, 2008; Vol. 7, pp 383-407.
(13) (a) Davies, H. M. L.; Ni, A. W. Chem. Commun.
2006, 3110–3112. (b) Manning, J. R.; Sexton, T.; Childers, S. R.; Davies,
H. M. L. Bioorg. Med. Chem. Lett. 2009, 19, 58–61.
(14) Dai, X.; Wan, Z. L.; Kerr, R. G.; Davies, H. M. L. J. Org. Chem.
2007, 72, 1895–1900.
(15) Davies, H. M. L.; Dai, X. Tetrahedron 2006, 62, 10477–10484.
(16) Davies, H. M. L.; Walji, A. M. Angew. Chem., Int. Ed. 2005,
44, 1733–1735.
(17) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006,
128, 2485–2490.
(34) Stafford, D. G. Ph.D. Thesis 2001, University at Buffalo, The
State University of New York.
(35) The crystal structure of 22 has been deposited at the Cam-
bridge Crystallographic Data Centre, and the deposition number CCDC
795283 has been allocated.
(36) Description of the stereochemical determination of 25-27 is
given in the Supporting Information.
(37) (a) Carpenter, B. K. Angew. Chem., Int. Ed. 1998,
37, 3341–3350. (b) Carpenter, B. K. Acc. Chem. Res. 1992,
25, 520–528. (c) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.;
Celebi-Olcum, N.; Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7592–
7601.
(38) (a) Ussing, B. R.; Hang, C.; Singleton, D. A. J. Am. Chem. Soc.
2006, 128, 7594–7607. (b) Celebi-Olcum, N.; Ess, D. H.; Aviyente, V.;
Houk, K. N. J. Am. Chem. Soc. 2007, 129, 4528. (c) Celebi-Olcum, N.;
Ess, D. H.; Aviyente, V.; Houk, K. N. J. Org. Chem. 2008, 73, 7472–7480.
(d) Thomas, J. B.; Waas, J. R.; Harmata, M.; Singleton, D. A. J. Am. Chem.
Soc. 2008, 130, 14544–14555. (e) Hong, Y. J.; Tantillo, D. J. Nature
Chem. 2009, 1, 384–389.
(18) Davies, H. M. L.; Beckwith, R. E. J. J. Org. Chem. 2004,
69, 9241–9247.
(19) Davies, H. M. L.; Jin, Q. H. Org. Lett. 2005, 7, 2293–2296.
(20) (a) Minami, K.; Saito, H.; Tsutsui, H.; Nambu, H.; Anada, M.;
Hashimoto, S. Adv. Synth. Catal. 2005, 347, 1483–1487. (b) Taber,
D. F.; Herr, R. J.; Pack, S. K.; Geremia, J. M. J. Org. Chem. 1996,
61, 2908–2910. (c) Ikota, N.; Takamura, N.; Young, S. D.; Ganem, B.
Tetrahedron Lett. 1981, 22, 4163–4166.
(21) (a) Lian, Y.; Davies, H. M. L. Org. Lett. 2010, 12, 924–927. (b)
Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem. 1994,
59, 4535–41.
(22) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York and London, 1976.
(23) Nadeau, E.; Ventura, D. L.; Brekan, J. A.; Davies, H. M. L. J. Org.
Chem. 2010, 75, 1927–1939.
(24) Hansen, J.; Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009,
74, 6555–6563.
(25) (a) Yoshikai, N.; Nakamura, E. Adv. Synth. Catal. 2003,
345, 1159–1171. (b) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am.
Chem. Soc. 2002, 124, 7181–7192. (c) Nowlan, D. T.; Gregg, T. M.; Davies,
H. M. L.; Singleton, D. A. J. Am. Chem. Soc. 2003, 125, 15902–15911.
(26) Frisch, M. J.; et al. Gaussian 09, Rev. A 0.1; Gaussian Inc.:
Wallingford, CT, 2009. See Supporting Information for complete
reference.
5085
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