Reactivity and chemoselectivity of allenes in Rh(I)-catalyzed intermolecular (5 + 2) cycloadditions with vinylcyclopropanes: Allene-mediated rhodacycle formation can poison Rh(I)-catalyzed cycloadditions

Article abstract of DOI:10.1021/ja5098308

Allenes are important 2π building blocks in organic synthesis and engage as 2-carbon components in many metal-catalyzed reactions. Wender and co-workers discovered that methyl substituents on the terminal allene double bond counterintuitively change the reactivities of allenes in [Rh(CO)₂Cl]₂-catalyzed intermolecular (5 + 2) cycloadditions with vinylcyclopropanes (VCPs). More sterically encumbered allenes afford higher cycloadduct yields, and such effects are also observed in other Rh(I)-catalyzed intermolecular cycloadditions. Through density functional theory calculations (B3LYP and M06) and experiment, we explored this enigmatic reactivity and selectivity of allenes in [Rh(CO)₂Cl]₂-catalyzed intermolecular (5 + 2) cycloadditions with VCPs. The apparent low reactivity of terminally unsubstituted allenes is associated with a competing allene dimerization that irreversibly sequesters rhodium. With terminally substituted allenes, steric repulsion between the terminal substituents significantly increases the barrier of allene dimerization while the barrier of the (5 + 2) cycloaddition is not affected, and thus the cycloaddition prevails. Computation has also revealed the origin of chemoselectivity in (5 + 2) cycloadditions with allene-ynes. Although simple allene and acetylene have similar reaction barriers, intermolecular (5 + 2) cycloadditions of allene-ynes occur exclusively at the terminal allene double bond. The terminal double bond is more reactive due to the enhanced d-π backdonation. At the same time, insertion of the internal double bond of an allene-yne has a higher barrier as it would break π conjugation. Substituted alkynes are more difficult to insert compared with acetylene, because of the steric repulsion from the additional substituents. This leads to the greater reactivity of the allene double bond relative to the alkynyl group in allene-ynes.

Full text of DOI:10.1021/ja5098308

Article
pubs.acs.org/JACS
Reactivity and Chemoselectivity of Allenes in Rh(I)-Catalyzed
Intermolecular (5 + 2) Cycloadditions with Vinylcyclopropanes:
Allene-Mediated Rhodacycle Formation Can Poison Rh(I)-Catalyzed
Cycloadditions
†
§
†
,§
,†,‡
Xin Hong, Matthew C. Stevens, Peng Liu, Paul A. Wender,* and K. N. Houk*
†Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States
‡Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California 90095,
United States
§
Department of Chemistry, Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305,
United States
*
S Supporting Information
ABSTRACT: Allenes are important 2π building blocks in
organic synthesis and engage as 2-carbon components in many
metal-catalyzed reactions. Wender and co-workers discovered
that methyl substituents on the terminal allene double
bond counterintuitively change the reactivities of allenes in
[
Rh(CO) Cl] -catalyzed intermolecular (5 + 2) cycloadditions
2 2
with vinylcyclopropanes (VCPs). More sterically encumbered
allenes afford higher cycloadduct yields, and such effects are
also observed in other Rh(I)-catalyzed intermolecular cycloadditions. Through density functional theory calculations (B3LYP
and M06) and experiment, we explored this enigmatic reactivity and selectivity of allenes in [Rh(CO) Cl] -catalyzed
2
2
intermolecular (5 + 2) cycloadditions with VCPs. The apparent low reactivity of terminally unsubstituted allenes is associated
with a competing allene dimerization that irreversibly sequesters rhodium. With terminally substituted allenes, steric repulsion
between the terminal substituents significantly increases the barrier of allene dimerization while the barrier of the (5 + 2)
cycloaddition is not affected, and thus the cycloaddition prevails. Computation has also revealed the origin of chemoselectivity
in (5 + 2) cycloadditions with allene-ynes. Although simple allene and acetylene have similar reaction barriers, intermolecular
(
5 + 2) cycloadditions of allene-ynes occur exclusively at the terminal allene double bond. The terminal double bond is more
reactive due to the enhanced d−π* backdonation. At the same time, insertion of the internal double bond of an allene-yne has a
higher barrier as it would break π conjugation. Substituted alkynes are more difficult to insert compared with acetylene, because
of the steric repulsion from the additional substituents. This leads to the greater reactivity of the allene double bond relative to
the alkynyl group in allene-ynes.
4
INTRODUCTION
π-systems. Subsequent contributions from this and other groups
have advanced the (5 + 2) cycloaddition to a versatile, practical,
and efficient route to various functionalized seven-membered
■
A preeminent goal of organic synthesis is to achieve structural
complexity with functional value in a safe, simple, environ-
mentally acceptable and step-, atom-, and time-economical
5
−7
rings. Among the current transition metal catalysts, rhodium
complexes are found to exhibit high catalytic activity and provide
often exceptional chemo-, regio- and enantioselectivity.
Rhodium catalysts are thus far the only systems to effect inter-
molecular (5 + 2) cycloadditions.
Allenes, one of the most common 2π components in
cycloadditions, have been widely employed in Rh(I)-catalyzed
intramolecular (m + n) and (m + n + o) cycloadditions. For
example, Wender and co-workers reported the Rh(I)-catalyzed
intramolecular (4 + 2) cycloadditions of 1, 3-dienes and allenes,
affording the 6,5-, 6,6-, and 6,7-fused ring systems in an efficient
1
fashion. As exemplified by the Diels−Alder reaction, cyclo-
additions are uniquely powerful processes to achieve this goal.
They proceed in one operation with the convergent assembly of
often commercially or readily available simple molecular
components and produce a new ring system with generally up
to four new stereocenters, enabling a rapid buildup of target
relevant complexity. Prompted by the exceptional and growing
importance of natural and designed targets based on seven-
8
,9
2
membered rings, such as tumor promoting phorbol esters and
latency activating prostratin analogues, the latter uniquely
important leads for HIV/AIDS eradication, Wender et al.
3
reported in 1995 the first examples of transition-metal-catalyzed
Received: September 23, 2014
(
5 + 2) cycloadditions of vinylcyclopropanes (VCPs) and
©
XXXX American Chemical Society
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Scheme 1. Selected Examples of Rh(I)-Catalyzed
Intramolecular (m + n) and (m + n + o) Cycloadditions with
Allenes
More importantly, this “terminal methyl effect” is not only ob-
served in the Rh(I)-catalyzed intermolecular (5 + 2) cyclo-
additions. It also is encountered in Rh(I)-catalyzed intermo-
lecular (4 + 2) cycloadditions of allene-enes and alkenes
17
(
Scheme 2b). The methyl substituents on the terminal allene
double bond are again necessary for efficient (4 + 2)
cycloadditions, while terminally mono- and unsubstituted
allene-enes reacted with much lower efficiencies. Murakami
and co-workers have also observed a similar trend in Rh(I)-
catalyzed (4 + 1) cycloadditions between allene-enes and carbon
monoxide, where terminally mono- and disubstituted allene-enes
underwent the desired cycloaddition, and terminally unsub-
stituted allene-enes formed an unreactive rhodium complex with
18
the catalyst. Similarly, in cases of Rh(I)-catalyzed carbonylative
19
rearrangements of allenyl ethers, (6 + 1) cycloadditions of
20
allenylcyclobutanes, and even iridium-catalyzed (5 + 1)
21
cycloadditions of allenylcyclopropanes, terminally unsubsti-
tuted or monosubstituted allene substrates gave lower yields than
their disubstituted counterparts or were altogether unreactive.
This enigmatic methyl effect limits the intermolecular use of
allenes. Interestingly, this effect is not encountered in many
Rh(I)-catalyzed intramolecular (m + n) and (m + n + o)
cycloadditions, perhaps due to reduced reaction concentrations
that suppress intermolecular side reactions and/or the higher
formal concentration that favors an intramolecular process.
However, in some cases even intramolecular rhodium-catalyzed
cycloadditions have a discernible reactivity preference for
terminally disubstituted allenes over their unsubstituted counter-
parts. Our DFT calculations also indicate that allenes with or
without terminal methyl substituents have similar activation
barriers for (5 + 2) cycloaddition (see discussions below).
Therefore, it was thought that methyl substituents on allenes
might favor the (5 + 2) and other cycloadditions by suppressing
side reactions or catalyst inhibition.
1
0
fashion (Scheme 1a). The same group also reported the Rh(I)-
catalyzed intramolecular (5 + 2) cycloadditions of VCPs and
1
1
allenes (Scheme 1b). The reaction works with mono-, di-, tri-
and tetra-substituted allenes, producing the seven-membered
ring products with an exocyclic double bond that cannot other-
wise be accessed through the corresponding cycloaddition of
alkenes or alkynes. The intermolecular (5 + 2) cycloaddition re-
action with allenes is however limited, prompting the develop-
ment of a general allene equivalent exploiting the reactivity of
15
22
1
2
13
14
alkynes. More generally, Brummond, Mukai, and Wender
have independently studied the Rh(I)-catalyzed intramolecular
Pauson−Khand type (2 + 2 + 1) cycloadditions with allenes,
providing effective routes to functionalized cyclopentanones and
cyclopentenones (Scheme 1c).
In 2005, Wegner, de Meijere and Wender reported the first
Rh(CO) Cl] -catalyzed intermolecular (5 + 2) cycloadditions
of VCPs with allenes containing alkynyl, alkenyl, cyano, and
cyanoalkyl substituents. In that work, the sterically encumber-
ing methyl substituents on the terminal allene double bond were
found necessary to achieve the intermolecular (5 + 2)
cycloaddition, while terminally mono- and unsubstituted allenes
produced the cycloadduct much less efficiently (Scheme 2a).
16
Allene dimerization is well-known. For example, 1,1-
dimethylallene itself slowly dimerizes under mild conditions to
[
2
2
23
5j
form cyclobutane derivatives. Johnson’s calculations show that
the dimerization of allene (uncatalyzed) occurs via a stepwise
mechanism with a significant activation barrier of 34.5 kcal/mol
24
(
Scheme 3). Pertinent to our study, rhodium complexes have
Scheme 3. Experimental and Theoretical Studies of
Scheme 2. Examples of Terminal Methyl Effects on Allene
Uncatalyzed Thermal Dimerization of Allenes (Gibbs Free
Energies in kcal/mol)
2
3,24
Reactivities in Rh(I)-Catalyzed Intermolecular
5j,17
Cycloadditions
been found to catalyze several processes related to allene
dimerization. In 1973, Ingrosso discovered that addition of a
pyridine ligand induces the allene dimerization in the [(acac)-
Rh(C H ) ] complex to form [(acac)Rh(C H )(pyridine) ],
3
4 3
6
8
2
2
5
which has been characterized by X-ray crystallography (Scheme 4a).
Murakami recently reported a Rh(I)-catalyzed 1:2 coupling between
aldehydes and allenes (Scheme 4b), and Himo’s computational
study confirms that this reaction occurs via an initial dimerization
26
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Scheme 4. Selected Examples of Rh(I)-Catalyzed
Dimerization of Allenes and Related Methodologies
(2), formed via dissociation of the dimeric rhodium catalyst and
30
elimination of a CO ligand. Initial cyclopropane cleavage gives
a metallacyclohexene intermediate 3, and subsequent allene
insertion produces a metallacyclooctene intermediate 5. From 5,
C−C reductive elimination gives the seven-membered ring
product. Alternatively, the [Rh(CO) Cl] (x = 1, 2) active catalyst
x
6
could catalyze the allene dimerization, leading to rhodium
complex 8, which could be stable enough to inhibit the catalytic
activity for the (5 + 2) cycloaddition.
Besides the unique reactivity observed for the (5 + 2)
cycloaddition of VCPs with variously substituted allene-ynes, the
chemoselectivity is also intriguing. Although alkynes are typically
more reactive than allenes in (5 + 2) cycloadditions, as
documented in all prior work, reactions with conjugated
allene-ynes occur exclusively at the terminal double bond of
5j
the allene (Scheme 6). To understand the origins of the unique
Scheme 6. Chemoselectivity of [Rh(CO) Cl] -Catalyzed
2
2
Intermolecular (5 + 2) Cycloaddition of VCP 9 and
Allene-yne 10
27
of allene with the rhodium catalyst. Alexanian reported a
Rh(I)-catalyzed ene-allene−allene (2 + 2 + 2) cycloaddition that
proceeds through an allene dimerization and alkene insertion,
giving direct access to stereochemically rich six-membered
28
carbocycles (Scheme 4c). Additionally, Ma reported that
Rh(CO) Cl] , the same catalyst used in the (5 + 2)
cycloaddition, catalyzes the intramolecular dimerization of
[
2
2
reactivity and selectivity of these allene-based reactions, a subject
pertinent to many other metal catalyzed reactions of allenes,
we initiated DFT calculations and experimental studies on the
contrasting behavior of allenes in intermolecular Rh(I)-catalyzed
allene, followed by β-hydride elimination to yield a seven-
29
membered ring product (Scheme 4d). On the basis of these
previous studies of Rh(I)-catalyzed cycloadditions and allene
dimerizations, we propose that the allene dimerization could be a
hidden catalyst-poisoning pathway in Rh(I)-catalyzed intermo-
lecular (5 + 2) and possibly many other (m + n) and (m + n + o)
cycloadditions involving allenes.
(
5 + 2) cycloadditions with VCPs.
COMPUTATIONAL METHODS
■
Geometry optimizations, vibrational frequencies, and thermal energy
corrections were performed with the B3LYP functional, 6-31G(d)
basis set for all main group elements and SDD basis set for rhodium
The competing (5 + 2) cycloaddition and allene dimerization
pathways with allene-ynes are described in Scheme 5. Starting
from the precatalyst [Rh(CO) Cl] (1), the (5 + 2) cyclo-
3
1
implemented in Gaussian 09. Energies were evaluated with the M06
3
2
2
2
method, the 6-311+G(d,p) basis set for all main group elements, and
SDD basis set for rhodium. All reported free energies involve zero-point
addition pathway proceeds with the active catalyst [Rh(CO)Cl]
Scheme 5. Proposed Mechanisms for Competing Rh(I)-Catalyzed (5 + 2) Cycloaddition and Allene Dimerization with Allene-ynes
C
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3
4,35
vibrational energy corrections and thermal corrections to Gibbs free
energy at 298 K. The solvation free energy corrections were computed
with the CPCM model on gas-phase optimized geometries, and
dichloroethane was chosen as the solvent for consistency with the
experiment. Extensive conformational searches for intermediates and
transition states have been conducted, and only the most stable
conformers and isomers are discussed.
On the basis of previous computational studies,
the active
catalyst for the (5 + 2) cycloaddition is [Rh(CO)Cl], which is
formed via dissociation of the dimeric [Rh(CO) Cl] precatalyst
and elimination of CO. From the [Rh(CO)Cl]-VCP complex
33
2
2
1
5, cyclopropane cleavage occurs to give a metallacyclohexene
36
intermediate 16, and subsequent exergonic coordination of
the allene-yne produces π complex 17. Insertion of the terminal
double bond of the allene-yne via TS18 requires an activation
barrier of 15.0 kcal/mol with respect to 17 and produces a
metallacyclooctene intermediate 19. Insertion of the internal
allene double bond or the alkyne requires a higher barrier (see
later for discussions on chemo- and regioselectivity). Subsequent
reductive elimination via TS20 gives the product-coordinated
complex 21. Therefore, the 2π insertion of allene-yne via TS18 is
the rate-determining step of the (5 + 2) cycloaddition pathway.
Because the exact mechanism of allene dimerization is still
RESULTS AND DISCUSSION
. Origins of Reactivity. Reactions with Terminally
Unsubstituted Allenes. We first studied the (5 + 2) cyclo-
addition and allene dimerization pathways with allene-yne 12,
which lacks the terminal allene substituents and experimentally
yields no (5 + 2) cycloaddition product (Scheme 7). The
■
1
37
Scheme 7. Computational Model of [Rh(CO) Cl] -Catalyzed
2
2
(
5 + 2) Cycloaddition and Dimerization of the Terminally
unclear, we computed both mechanisms involving [Rh(CO) Cl]
2
Unsubstituted Allene-yne 12
and [Rh(CO)Cl] as the active catalyst (shown in solid and
dashed black lines, respectively, in Figure 1). If the [Rh(CO)Cl]
complex is the active catalyst, substitution of the coordinated
VCP by two allene-ynes converts 15 to intermediate 22. From
2
2, the oxidative cyclization of allene-ynes via TS23 requires an
1
8.5 kcal/mol barrier and the formed intermediate 24 is very
stable. Alternatively, oxidative cyclization of allene-ynes with
Rh(CO) Cl] occurs from intermediate 25. Although 25 is less
[
2
stable than 22, TS26 is more favorable than TS23. This indicates
that allene dimerization occurs more rapidly with [Rh(CO) Cl].
2
The resultant intermediate 27 is very stable as compared to
the Rh-allene complex 25, making the allene dimerization
38
irreversible. Comparing the two reaction pathways, the overall
barrier of allene dimerization (TS26) is only 1.3 kcal/mol higher
than the (5 + 2) cycloaddition (TS18). These calculations sug-
gest that the (5 + 2) cycloaddition and allene dimerization path-
ways are competitive with terminally unsubstituted allene-ynes.
Therefore, the competitive and irreversible allene dimerization
pathway “poisons” the rhodium catalyst by preventing its
participation in the desired (5 + 2) cycloaddition.
2
-methoxyethoxy group on the VCP was replaced with a
methoxy group in the calculations. With the [Rh(CO)Cl]
active catalyst, the (5 + 2) cycloaddition of 1-methoxy-1-
vinylcyclopropane and 12 gives the seven-membered ring
product 13. Alternatively, the [Rh(CO) Cl] (x = 1, 2) complex
x
can catalyze the dimerization of 12 and form the rhodacyclo-
pentane complex 14. The calculated free energy changes for
both pathways is shown in Figure 1 and optimized structures
of selected intermediates and transition states are shown in
Figure 2.
Reactions with Dimethyl-Substituted Allene. We also
studied the (5 + 2) cycloaddition and allene dimerization path-
ways with terminally dimethyl-substituted allene-yne 10. The
Figure 1. Free energy profile of [Rh(CO) Cl] -catalyzed (5 + 2) cycloaddition and allene dimerization pathways with terminally unsubstituted
2
2
allene-yne 12. Gibbs free energies (298 K) with respect to 15 are shown in kcal/mol.
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Figure 2. Structures of selected intermediates and transition states of the [Rh(CO) Cl] -catalyzed (5 + 2) cycloaddition and allene dimerization
2
2
pathways with terminally unsubstituted allene-yne 12 (only the α-carbon of phenyl group is shown).
Figure 3. Free energy changes of [Rh(CO) Cl] -catalyzed (5 + 2) cycloaddition and allene dimerization pathways with dimethyl-substituted allene-yne
2
2
1
0. Gibbs free energies (298 K) with respect to 15 are shown in kcal/mol.
computed free energy surface is shown in Figure 3. From
Rh(CO)Cl]-VCP complex 15, cyclopropane cleavage gives
metallacyclohexene intermediate 16 and subsequent endergonic
allene-yne coordination produces intermediate 29. The 2π
insertion of the terminal double bond of the allene-yne occurs
via TS30, and the formed metallacyclooctene intermediate 31
[
E
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Figure 4. Optimized structures and relative free energies (with respect to 15) of transition states of [Rh(CO) Cl]-mediated dimerization of allene-ynes
2
1
2 and 10 (only the α-carbon of phenyl group is shown for simplicity).
undergoes a facile C−C reductive elimination to generate the
product-coordinated complex 33. Similar to the unsubstituted
allene-yne 12, the rate-determining step of the (5 + 2)
cycloaddition pathway with methyl-substituted allene-yne 10 is
internal double bonds via TS38. Computation indicates that
TS26 is the most favorable transition state. Dimerization with the
internal double bond (TS37 and TS38) will break the con-
jugation with the alkynyl group and raise the activation barrier.
Therefore, the dimerization of allene-yne 12 occurs with the two
terminal double bonds and requires an activation barrier of 13.3
kcal/mol compared to the [Rh(CO)Cl]-VCP complex 15.
For dimethyl-substituted allene-yne 10, the preference
between the three possible dimerization transition states is
altered by steric repulsion of the methyl substituents (Figure 4).
The dimerization with the two terminal double bonds via TS39 is
no longer favored and the barrier is 25.5 kcal/mol. On the other
hand, dimerization of one terminal and one internal double bond
via TS35 is now the most favorable transition state and the
activation barrier is 17.0 kcal/mol. Still, steric repulsion of the
methyl substituents leads to a higher barrier for dimerization
compared to the unsubstituted allene-yne (TS37, 15.1 kcal/mol).
These results indicate that the high barrier of dimerization of
terminally substituted allenes is due to steric repulsions between
the terminal allene substituents and the rhodium catalyst.
2π insertion, and the overall barrier is 15.4 kcal/mol. The overall
barriers of (5 + 2) cycloaddition pathway with allene-ynes are not
affected by the terminal methyl substituents (15.0 kcal/mol with
allene-yne 12 and 15.4 kcal/mol with methyl-substituted allene-
yne 10). Despite their similar reactivities in the (5 + 2) cyclo-
addition, the methyl-substituted allene-yne 10 has a much higher
barrier for the allene dimerization. The dimerization transition
state TS35 is 4.0 kcal/mol higher in free energy than the 2π
insertion transition state TS30. Therefore, the competing allene
dimerization pathway in this case is disfavored relative to the
experimentally observed (5 + 2) cycloaddition.
Terminal Methyl Effects on Allene Dimerization. In order to
understand the terminal methyl effects on the allene dimerization
reactivity, all possible dimerization transition states with allene-
ynes 12 and 10 are located and shown in Figure 4. Allene-ynes
have a terminal double bond and an internal double bond, so
there are three types of dimerization transition states. Allene-yne
Experimental Observations. To experimentally explore our
computational prediction of a catalyst-poisoning allene dimeriza-
tion pathway, a series of reactions were conducted to examine the
1
2 can dimerize with both the terminal double bonds via TS26,
one terminal and one internal double bond via TS37, or both
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Scheme 8. Poisoning of the Cycloaddition between Vinylcyclopropane and Dimethyl Alleneyne
interaction between des-dimethyl allene-yne 12 and the
proposed active catalytic species. We hypothesized that if
allene-yne 12 does not act as a catalyst poison, then a mixture
of it and catalytically competent dimethyl allene-yne 10 in
the presence of vinylcyclopropane 9 and precatalyst
also showed formation of product, albeit in reduced yield (54%).
These experiments indicate not only that the des-dimethyl
allene-yne is unreactive toward Rh-catalyzed cycloaddition, but
also that it can irreversibly capture a functioning catalyst, as
predicted computationally.
(
[Rh(CO) Cl] ) should provide yields of cycloadduct com-
2. Origins of Chemoselectivity. Although allene-ynes have
three possible π-bonds that could engage in a (5 + 2) cyclo-
addition, the reaction occurs exclusively with the terminal double
bond of the allene. The chemoselectivity is determined in the
2π insertion step, which is rate-limiting and irreversible. We
calculated the three possible insertion transition states with
allene-yne 10. The most favorable TS isomers in each pathway
and their activation barriers are shown in Scheme 9. Consistent
with the experiment, insertion of the terminal double bond via
TS30 requires a barrier of 13.0 kcal/mol relative to the
[Rh(CO)Cl]-VCP complex 15. The 2π insertion of the internal
double bond via TS41 requires a 17.5 kcal/mol barrier and insertion
of the triple bond via TS42 requires an 18.0 kcal/mol barrier, both
are much higher than the 2π insertion barrier of terminal double
bond. In line with this analysis, the (5 + 2) cycloadditions occur
exclusively with the terminal double bond of allene-ynes.
In order to understand the origins of chemoselectivity, we
compared the insertion barrier of allene-yne 10 with those of
simple allene and acetylene to explore the steric and electronic
effects of substituents on the insertion barriers with different
π bonds (Scheme 10). Scheme 10a shows the substituent effects
on the reactivity of the terminal double bond of allene-ynes.
Insertion with simple allene requires a 13.8 kcal/mol barrier via
TS43 with respect to the [Rh(CO)Cl]-VCP complex 15. The
terminal double bond in allene-yne 12 is more reactive in
2π insertion than simple allenes. In TS18, the phenylalkynyl
substituent on allene-yne 12 lowers the 2π insertion barrier by
1.8 kcal/mol. This is presumably due to the increased d−π*
back-donation from rhodium to the conjugated π* orbital of the
allene-yne. Interestingly, the terminal methyl substituents show
only moderate steric repulsions around the forming C−C bond
in 2π insertion. TS30 is only 1.0 kcal/mol higher in energy than
the unsubstituted TS18. This indicates the terminal allene
2
2
parable to those originally reported (Scheme 6). However, if
allene-yne 12 is indeed acting as a catalytic poison, addition of
even a small (catalytic) amount to the cycloaddition of allene-yne
1
0 and vinylcyclopropane should shut down the reaction and no
cycloadduct product would be observed.
First, 1-(2-methoxyethoxy)-1-vinylcyclopropane, dimethyl
allene-yne 10, and [Rh(CO) Cl] in DCE were mixed for
2
2
5
min at room temperature (Scheme 8, Experiment 1). An
aliquot of one-half of the reaction mixture was removed and
added to a vial containing a substoichiometric quantity (10 mol %)
of the suspected catalyst “poison” precursor 12. Both mixtures
were heated to 80 °C for 55 min. As predicted by theory, the
mixture that had been “poisoned” contained no isolable
quantities of the expected (5 + 2) cycloadduct. The original
poison-free reaction mixture, however, provided the expected
cycloadduct in 72% yield and an (E)/(Z) ratio of 1.0:1.5,
consistent with the reported literature values. This result suggests
that the des-dimethyl allene-yne, when added early on to an
otherwise reactive mixture of allene-yne 10, VCP and catalyst,
kills the rhodium catalyst irreversibly.
The above experiment does not indicate whether the catalyst
poison blocks conversion of precatalyst to active catalyst or
irreversibly captures the active catalyst. To address this point, as
in the first experiment, VCP 9, allene-yne 10, and precatalyst in
DCE were combined, this time for 20 min, before an aliquot was
taken and added to a substoichiometric amount (10 mol %) of
allene-yne 12 (Scheme 8, Experiment 2). Both mixtures were
heated to 80 °C for the remaining 40 min. After workup and
purification, the nonpoisoned sample once again provided the
cycloadduct with a yield (69%) and (E)/(Z) ratio (1.0:1.7)
comparable to those previously reported. However, unlike in our
previous experiment, the initiated but then poisoned reaction
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Scheme 9. Possible 2π Insertion Transition States in the
reactions with the internal allenyl double bond (Scheme 10b).
The 2π insertion with internal double bonds of allene-ynes via
TS44 and TS41 requires about 4 kcal/mol higher barriers than
the insertion of simple allene via TS43. The low reactivity of the
internal double bond of allene-ynes is due to the π conjugation
between the allene and the alkyne. Insertion into the internal
double bonds breaks the conjugation and raises the barrier
dramatically.
(
5 + 2) Cycloaddition Pathway with Allene-yne 10
Although acetylene and simple allene have similar 2π insertion
barriers (15.1 kcal/mol, TS45 versus 13.8 kcal/mol, TS43), in
line with our previous computational studies, substituted alkynes
in general have much higher barriers for 2π insertion. The 2π
insertion with the triple bond of allene-yne 12 requires 18.0 kcal/mol
(
(
TS42, Scheme 10c), which is comparable to that of 2-butyne
18.5 kcal/mol, TS46). The lower reactivity of internal alkynes in
the 2π insertion is because of the steric repulsions from the
additional substituents of the alkynes. These calculations indicate
that the 2π insertion with alkynes is more sensitive to steric
effects than the reaction with substituted allenes.
In summary, the terminal double bond of allene-yne is
selectively activated in the 2π insertion step due to the electronic
effects of the conjugated alkynyl group, while the internal double
bond and the triple bond are deactivated. This leads to exclusive
formation of the (5 + 2) cycloadduct with the terminal double
bond of the allene-ynes.
CONCLUSIONS
■
DFT calculations and experiments have revealed the mechanism
and origins of substituent effects on reactivity and chemo-
selectivity of allene-ynes in Rh(I)-catalyzed intermolecular
(5 + 2) cycloadditions with VCP. The Rh(I)-catalyzed (5 + 2)
cycloaddition and allene dimerization are found to be com-
petitive when allene-ynes lack methyl substituents on the
terminal double bond. The competing allene dimerization is
substituents prevent the substrates from dimerizing but have
only minor effects on the rates of (5 + 2) cycloadditions.
In contrast to the activation of the terminal double bond, a
conjugated alkynyl group leads to higher 2π insertion barriers in
Scheme 10. 2π Insertion Barriers (5 + 2) Cycloaddition Pathway with Different Allenes, Alkynes and Allene-ynes
H
dx.doi.org/10.1021/ja5098308 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
irreversible, generating a stable rhodium complex, thereby
effectively poisoning the rhodium catalyst and shutting down
the desired (5 + 2) cycloaddition. With the terminal methyl
substituents, the barrier for allene dimerization of allene-ynes
increases significantly while that of the (5 + 2) cycloaddition
pathway is not affected, so the allene-ynes with terminal methyl
substituents are able to undergo the (5 + 2) cycloaddition.
Intramolecular (5 + 2) cycloadditions of allenes and VCPs are
not similarly affected due to the expected higher formal con-
centration of the two reactive components relative to dimeriza-
tion. The competing allene dimerization pathway explains the
enigmatic reactivities of allenes in Rh(I)-catalyzed inter- and
intramolecular cycloadditions and provides mechanistic insights
into many other Rh(I)-catalyzed (m + n) and (m + n + o)
cycloadditions.
REFERENCES
■
(
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AUTHOR INFORMATION
■
Corresponding Authors
wenderp@stanford.edu
houk@chem.ucla.edu
Notes
(6) For a ruthenium catalyst, see: (a) Trost, B. M.; Toste, F. D.; Shen,
The authors declare no competing financial interest.
H. J. Am. Chem. Soc. 2000, 122, 2379. (b) Trost, B. M.; Shen, H. C. Org.
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ACKNOWLEDGMENTS
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■
(
We are grateful to the National Science Foundation (CHE- 1361104
KNH), CHE-1265956 (PAW)) and the National Institutes of
Steinmetz, B. G.; Koradin, C. Chem.Eur. J. 2005, 11, 2577. For a
Health (CA031845 (PAW)) for financial support of this
research. Additional funding was provided by the NSF Graduate
Research Fellowship (MCS). Calculations were performed on
the Hoffman2 Cluster at UCLA and the Extreme Science and
Engineering Discovery Environment (XSEDE), which is
supported by the NSF (OCI-1053575).
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(
35) For other related DFT studies on Rh(I)-catalyzed reactions, see:
(
a) Baik, M.-H.; Baum, E. W.; Burland, M. C.; Evans, P. A. J. Am. Chem.
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(
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36) The cyclopropane cleavage is very facile with a 1.3 kcal/mol
barrier relative to intermediate 15.
37) Both the insertion transition states leading to Z- and E-
(
(
cycloadducts were studied computationally, and only TS18 is shown in
Figure 1. Experimentally, a mixture of Z- and E-cycloadducts is found.
(
38) We studied the C−C reductive elimination from 27, the barrier is
24.7 kcal/mol, which is significantly higher than the barrier of the
observed (5 + 2) cycloaddition with allene-yne 10 under the same
conditions (15.0 kcal/mol).
K
dx.doi.org/10.1021/ja5098308 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX