Experimental and Computational Studies on Rh(I)-Catalyzed Reaction of Siloxyvinylcyclopropanes and Diazoesters

Sheng Feng, Kang Wang, Yifan Ping, and Jianbo Wang*

Article

Experimental and Computational Studies on Rh(I)-Catalyzed

Reaction of Siloxyvinylcyclopropanes and Diazoesters

Cite This: https://dx.doi.org/10.1021/jacs.0c08089

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: The Rh(I)-catalyzed reaction of siloxyvinylcyclo-

propanes and diazoesters leads to the formation of siloxyvinylcy-

clobutane and 1,4-diene derivatives. With [Rh(cod)Cl] as the

catalyst, the formation of 1,4-diene was favored over the formation

of siloxyvinylcyclobutane. By changing the catalyst to [Rh-

(

cod) OTf], siloxyvinylcyclobutane derivatives are formed with

excellent chemoselectivities and in moderate to good yields. The

alkene products are also obtained as single E conﬁgured isomers. A

detailed mechanism for this transformation is proposed on the

basis of mechanistic experiments and DFT calculations. The eﬀect

of catalysts on the chemoselectivity of these reactions is also

examined computationally.

INTRODUCTION

Scheme 1. Rh(I)-Catalyzed Reaction of Vinylcyclopropanes

■

Transition-metal-catalyzed cycloaddition reactions of vinyl-

cyclopropanes (VCPs) and π-components have emerged as

one of the eﬃcient approaches for the synthesis of medium and

large ring systems. Since the ﬁrst report of a Rh(I)-catalyzed

intramolecular [5 + 2] reaction of β-yne-VCPs by Wender in

995, Rh(I)-catalyzed [5 + 2] cycloaddition reactions of VCPs

with 2π-components such as alkynes, alkenes, and allenes have

been actively studied for constructing various seven-membered

rings. On the other hand, Yu and co-workers have developed

versatile methodology for constructing ﬁve-membered rings by

using Rh(I)-catalyzed reactions of 1-ene/yne-VCPs as well as 2-

and α-ene-VCPs through a [3 + 2] pathway. In addition, they

also introduced CO as a one-carbon coupling partner to achieve

[

5 + 2 + 1], [5 + 1], and [3 + 2 + 1] cycloaddition reactions of

VCPs (Scheme 1).

As part of our continuous interest in utilizing diazo

compounds as a one-carbon synthon in transition-metal-

catalyzed cross-coupling reactions, and also inspired by the [5

calculations were performed to study the mechanism of the

reactions between VCPs and diazoesters catalyzed by [Rh-

1] reaction of VCPs with CO developed by Yu and co-

workers, we envisioned that VCPs could potentially react with

diazo compounds under Rh(I) catalysis to provide [5 + 1]

products. In 2016, we reported the reaction between VCPs and

(

cod) OTf] and [Rh(cod)Cl] , respectively, and shed light on

the origin of the interesting catalyst-dependent chemoselectiv-

ity.

diazoesters catalyzed by [Rh(cod)Cl] . Instead of the proposed

[

5 + 1] products, 1,4-dienes were formed in good yields. During

Received: July 28, 2020

our further investigation, we discovered that when employing a

cationic Rh(I) catalyst, [Rh(cod) OTf], the reaction selectively

aﬀorded the vinylcyclobutane as the major product, along with

the minor products of 1,4-dienes. Herein, we report method-

ology for the eﬃcient synthesis of a variety of vinyl-

cyclobutanes. Furthermore, density functional theory (DFT)

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Article

RESULTS AND DISCUSSION

Reaction Condition Optimization. To begin with, we

Scheme 2. Substrate Scope of the Rh(I)-Catalyzed Reaction

■

carefully re-examined the [Rh(cod)Cl] -catalyzed reaction of

VCP 1 and diazo ester 2 that we have reported previously. We

observed that in addition to the 1,4-diene product 4, trace

amounts of cyclobutane product 3 were also formed (Table 1,

Table 1. Optimization of the Reaction Conditions

entry

Rh(I)

3:4

yield (%)

SiMe Bu

[Rh(cod)Cl]₂

1:20

1:3

2:1

Si Pr

SiMe Bu

Rh(cod) OTf

Si Pr

Rh(cod) OTf

>20:1

Si Pr

Rh(cod) OTf

>20:1

10:1

Si Pr

Rh(cod) OTf

Si Pr

CH CF

Rh(cod) OTf

Si Pr

Rh(cod) OTf

SiPh Bu

Rh(cod) OTf

The reaction was carried out with 1 (0.1 mmol) and 2 (0.15 mmol).

Ratio was determined by H NMR of the crude products. Isolated

yield. These reactions were carried out in dioxane at 80 °C for 4 h,

with slow addition of a solution of diazo substrate in dioxane. These

reactions were carried out in THF at 50 °C for 4 h, with slow addition

The reactions were carried out on 0.1 mmol scale. Yields refer to the

of a solution of diazo substrate in THF over 1.5 h. The addition of a

isolated product of a mixture of 3 and 4. TBDPS = SiPh Bu, TIPS =

Si Pr .

solution of diazo substrate in THF was completed over 1.5 h with

initial fast addition for 5 min. See Supporting Information for details.

with moderate yield and excellent chemoselectivity. When

switching to a triisopropylsilyl substituted VCP 1b, the reaction

of 2a with 1b to form 3r could achieve >20:1 chemoselectivity,

but the yield was slightly lower than when 1a was used. If a

methyl-substituted VCP 1c was used for the reaction, 3q was

selectively formed. This result showed that the CC bond in

VCP was cleaved during the course of the reaction, and that the

entry 1). Further study indicated that 3:4 ratio was aﬀected by

the structure of the siloxy group. Switching the Si group from

SiMe Bu to Si Pr changed the ratio of 3:4 from 1:20 to 1:3

(

Table 1, entry 2). A more dramatic change of product ratio was

observed when the Rh(I) catalyst was switched from [Rh(cod)-

Cl] to Rh(cod) OTf (Table 1, entries 3 and 4). With the

cationic Rh(cod) OTf as the catalyst, cyclobutane 3 become the

terminal CH in the vinyl group in VCP became part of the

major product. The four-membered ring and the E conﬁguration

of the double bond of product 3 in the reaction shown in entry 4

was con ﬁ rmed by X-ray crystallography of its derivative (see

Supporting Information for details). The ester group of the

diazo substrate had a marginal eﬀect on the yields (Table 1,

entries 4−6). Because the Et group gave relatively high yield, we

further modiﬁed the ester moiety with a 2,2,2-triﬂuoroethyl

group and found that the yield was slightly improved (Table 1,

entry 7). In addition, we found that adjusting the addition time

of diazo substrate could slightly improve the yield (Table 1,

cyclobutane ring in the product.

To further conﬁrm the structure of the vinylcyclobutane

products, we converted 3r to 3r′ through deprotection and then

acylation. X-ray crystallography of 3r′ was then performed to

determine it to be an E conﬁgured vinylcyclobutane derivative

(Scheme 3). Because only one cis/trans isomer was observed in

the vinylcyclobutane products, the conﬁguration of all the other

products were assigned as E.

To determine which position the terminal CH in the vinyl

group in VCP ended up in the cyclobutane ring in the product,

we subjected 1d and 1e to the reaction. However, both reactions

gave the 1,4-diene product 4′ instead of the vinylcylcobutane

products (Scheme 4). Similar type of product was observed

entry 8). Finally, the reaction of VCP 1 bearing a siloxy group of

SiPh Bu aﬀorded the highest yield, whereas the 3:4 ratio was

decreased to 10:1 (Table 1, entry 9).

Next, we proceeded to investigate the substrate scope of this

reaction (Scheme 2). The reactions of 1a with para- (2a−i),

ortho- (2j), meta- (2k−n), and multisubstituted aryl diazoesters

when a 1-butyl substituted VCP 1f was used with [Rh(cod)Cl]

,10

as the catalyst.

To unambiguously track the terminal vinyl

carbon, we then performed a deuterium labeling experiment

(

2o) were all able to aﬀord the corresponding vinylcyclobutane

using deuterated VCP 1g, in which both hydrogens on the

products 3a−o in moderate to good yields. The ratio of 3:4 in

these reactions ranged from 9:1 to >20:1. Reactions using aryl

diazoesters bearing electron-withdrawing substituents generally

gave higher yields. On the other hand, reactions with aryl

diazoesters that were substituted by electron-donating groups

had very high chemoselectivities but gave slightly lower yields.

Naphthyl diazoester 2p could also undergo this transformation

terminal vinyl carbon were 79% deuterium incorporated. H

NMR analysis of the product (3t) suggested that the terminal

vinyl carbon in 1g ended up at the C2-position of cyclobutane in

the product.

The mechanism for the rhodium(I)-catalyzed cycloaddition

reactions involving VCPs has been well studied. Theoretical

studies suggest that these reactions proceed through a common

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Article

Scheme 3. Structural Determination of the Product

Scheme 5. Mechanistic Experiments of Rh(I)-Catalyzed

Reaction of VCP

Scheme 6. Proposed Mechanism

Scheme 4. Rh(I)-Catalyzed Reactions of 1-Substituted or

Deuterated VCPs with Diazoester

undergo reductive elimination to form vinylcyclobutane 3 if

[

Rh(cod) OTf] was used as the catalyst, but would reductive

eliminate and then β-H eliminate to form 1,4-diene 4 if

[

Rh(cod)Cl] was used instead. However, if the terminal

alkene position in VCP bears a substituent that has an α-H, then

β-H elimination of C using the hydrogen from the substituent in

VCP would be much more favorable as compared to β-H

elimination using the hydrogen from the rhodacyclopentane

ring or reductive elimination of C. Therefore, 1,4-diene 4′ would

be selectively formed in this case regardless of the choice of

catalyst. Although these proposed pathways align well with the

experimental observations, several questions remain to be

addressed: (i) Only E-vinylcyclobutane products were observed

in the reactions. And because the diastereoselectivity in the [2 +

2] cycloaddition step would be completely transferred into the

E/Z ratio in the product, we wanted to examine the

diastereoselectivity of this step computationally. (ii) The

detailed mechanism from intermediate B to C is currently

unclear. (iii) The eﬀect of the rhodium catalysts on the

competition between the reductive elimination and the β-H

elimination steps of C needs to be determined. Additionally, we

need to conﬁrm through calculations that our proposed pathway

is indeed favored over oxidative cleavage of the C1−C2 or C2−

C3 bond in the cyclopropane of VCP.

intermediate, which is a σ,η -allyl rhodium species generated

from the oxidative addition of the Rh(I) catalyst with VCPs.

Recently, we successfully isolated such a σ,η -allyl rhodium

complex 6 from the reaction of Rh(PPh ) Cl with VCP 5,

reacted it with alkyne, and formed the [5 + 2] products 7 and 8,

showing that such a species is very likely to be the key

intermediate of the Rh(I)-catalyzed [5 + 2] reactions of VCPs

Scheme 5a). However, treating the isolated σ,η -allyl rhodium

complex 6 with diazo compound did not give the 1,4-diene

product 9 (Scheme 5b), suggesting that the σ,η -allyl rhodium 6

is unlikely to be the key intermediate in our reactions.

(

On the basis of the mechanistic observations that we have so

far, we propose several possible pathways for the reactions of

VCPs with diazoesters catalyzed by either cationic or neutral

Rh(I) catalysts (Scheme 6). First, the Rh(I) catalyst reacts with

diazo compound 2 to form Rh(I) carbene A, which then

undergoes a [2 + 2] cycloaddition with the CC bond in VCP

COMPUTATIONAL STUDIES

To gain insights into the mechanistic details, we carried out

density functional theory calculations. First, we computed the

■

. Next, the resulting rhodacyclobutane B rearranges into

rhodacyclopentane C. For VCPs in which R = H, C would

energy proﬁle of the carbene formation and the [2 + 2]

Journal of the American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Article

Figure 1. Energy proﬁle of the carbene formation and the [2 + 2] cycloaddition steps for the cationic rhodium catalyzed reaction between VCP and

diazoester.

cycloaddition steps in the reaction between VCP and diazoester

with cationic Rh(I) as the catalyst (Figure 1). The formation of

the Rh(I) carbene Int2 involves the coordination of the

diazoester 2q to the rhodium center in Int0 and subsequent

pathway (Figure 2a), the cationic rhodium in Int3 ﬁrst serves as

an electrophile to induce a reversible ring-opening of

siloxycyclopropane to provide Int4. The reverse process of

this step is a methylene shift from the rhodium center to the

oxocarbenium ion in Int4 to regenerate the siloxycyclopropane

ring. Because the rhodium center in Int4 has another methylene

group attached to it, this methylene group can also undergo a

similar and yet more facile methylene shift to generate Int5. Int5

then undergoes a nearly barrierless β-C elimination to give the

rhodacyclopentane intermediate Int6. The optimized structures

of each intermediate and transition state are shown in Figure 2b.

We then looked into the competition between the reductive

elimination and β-H elimination of Int6 (Figure 3a). Both of

these steps are very facile and irreversible, with the reductive

elimination being favored over the β-H elimination step by 1.0

kcal/mol. This energy diﬀerence corresponds to a 5:1 ratio of

the cyclobutane product Int7 versus 1,4-diene Int9, which is in

line with the chemoselectivity observed in the experiments. The

overall catalytic cycle for the cationic Rh(I)-catalyzed reaction of

VCP with diazoester has a reasonable Gibbs free energy span of

23.0 kcal/mol. The [2 + 2] cycloaddition of rhodium carbene

with VCP constitutes the rate-determining step of this reaction.

The theoretically predicted E/Z selectivity as well as the

chemoselectivity of the reaction are both in good accordance

with the experimentally observed selectivities. Additionally, we

compared pathway I−III in Scheme 6 using 1-methyl

release of N via TS1. This step is highly exothermic and has a

relatively low energy barrier. To explain why the reaction did not

give our originally proposed [5 + 1] product, we also examined

the scenario in which the Rh(I) catalyst undergoes oxidative

addition with VCP prior to engaging with the diazoester via

TS1a. It turns out that the oxidative addition step is fast and

reversible, whereas the subsequent irreversible carbene for-

mation step strongly favors TS1 over TS1a by 5.6 kcal/mol.

Therefore, Curtin−Hammett kinetics determines that the

reaction should go through TS1 to give Rh(I) carbene Int2,

which then undergoes a [2 + 2] cycloaddition with VCP via TS2

to form rhodacyclobutane Int3. The energy barrier of this step is

3.0 kcal/mol. Alternatively, the [2 + 2] cycloaddition step can

go through TS2a to form the diastereomer of Int3, which will

ultimately lead to the Z-isomer of the vinylcyclobutane product.

Because the energy of TS2a is 9.7 kcal/mol higher than that of

TS2, the [2 + 2] cycloaddition of Int2 should completely

proceed through TS2 and eventually gives the E-alkene product

exclusively. This computational prediction does match the

experimental results. Moreover, the irreversible (based on

results in Figure 1 and 2a) [2 + 2] pathway is energetically more

favorable compared to the oxidative addition of Int2 with either

C1−C2 (TS2b) or C2−C3 (TS2c) bond in the cyclopropane of

VCP.

substituted VCPs as the substrates. The computed results

show that pathway III is indeed the most favorable pathway for

both 1d and 1e, which further support our proposed mechanism.

Finally, we wanted to investigate the origin of the opposite

chemoselectivity obtained with the cationic and the neutral

rhodium catalysts. Because the reactions of diazoesters with

Next, we investigated the detailed mechanism of the

rearrangement from intermediate B to C in Scheme 6. After

several attempts, we came up with a pathway which has a

reasonable activation barrier for each step. In our computed

Journal of the American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Article

Figure 2. (a) Energy proﬁle for the rearrangement of rhodacyclobutane Int3 into rhodacyclopentane Int6. (b) Optimized structures of intermediates

and transition states in the rearrangement steps.

VCPs having diﬀerent substitution patterns all give the same

rhodium catalyst, the CC bond remains uncoordinated to the

rhodium center throughout the subsequent steps. But with the

cationic rhodium catalyst, it is a diﬀerent situation. In order for

β-H elimination to occur, the C−H bond has to have an agostic

interaction with the rhodium center in the transition state.

Therefore, in the β-H elimination transition state TS6a of the

cationic rhodium intermediate Int6, the previously coordinated

CC bond has to dissociate to give way to this C−H agostic

interaction and this will require an additional energy. And yet

reductive elimination of Int6 is able to occur with the CC

bond still coordinated to the rhodium center. Therefore, β-H

elimination becomes more diﬃcult in the case of the cationic

rhodium catalyst.

types of products regardless of whether [Rh(cod) OTf] or

[

Rh(cod)Cl] was used as the catalyst, we expect the reaction to

have the same mechanism in both cases. Therefore, we initiated

our computation for the [Rh(cod)Cl] catalyzed reaction from

the rhodacyclopentane intermediate Int10 (Figure 3b). The β-

H elimination and the reductive elimination of Int10 are both

facile, but this time the β-H elimination step is reversible because

the transition state (TS9) for the reductive elimination that

follows the β-H elimination is slightly higher in energy compared

to TS8. Because the energy of TS8a is 1.2 kcal/mol higher than

that of TS9, the reductive elimination to form the cyclobutane

product Int13 is still disfavored compared to the formation of

the 1,4-diene product Int12. Again, this result matches the

experimental observations.

CONCLUSIONS

■

After comparing the structures resulting from the two types of

catalysts (Figure 3c), we found that a key diﬀerence between the

rhodacyclopentane intermediate coming from the cationic and

the neutral rhodium catalyst was that the cationic rhodium

center was coordinated to the CC bond in Int6, whereas the

neutral rhodium center in Int10 was not. With the neutral

We have developed a cationic Rh(I) catalyzed reaction of VCPs

with diazoesters to selectively form E-vinylcyclobutane deriva-

tives in moderate to good yields. The 1,4-diene products, which

was the major isomer observed in our previously reported

reaction catalyzed by neutral Rh(I) catalysts, now becomes the

minor isomer in this reaction. The origin of this change of the

Journal of the American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

https://pubs.acs.org/doi/10.1021/jacs.0c08089.

Article

Figure 3. (a) Energy proﬁle for the conversion of rhodacyclopentane Int6 to vinylcyclobutane Int7 and 1,4-diene Int9 with [Rh(cod) OTf] catalyst.

(

b) Energy proﬁle for the conversion of rhodacyclopentane Int10 to 1,4-diene Int12 and vinylcyclobutane Int13 with [Rh(cod)Cl] catalyst. (c)

Optimized structures of intermediates and transition states for the reductive elimination and β-H elimination of rhodacyclopentane with

Rh(cod) OTf] and [Rh(cod)Cl] catalyst.

[

chemoselectivity was examined computationally. Reactions

performed with substituted and deuterated VCPs showed that

the CC bond in VCP was cleaved during the reaction. We

proposed a mechanism in which each step is energetically

plausible based on our computations. This mechanism, along

with our computational results, can also help rationalize the

excellent E/Z selectivity as well as the formation of the

unexpected products in the reactions carried out with

substituted VCPs. Through the combination of the metal

carbene chemistry, we have discovered a new reaction mode of

VCPs which is completely diﬀerent from and is energetically

favored over the traditional C−C bond activation of VCPs under

transition metal catalysis. These new ﬁndings and the

mechanistic insights may inspire further development of VCP

chemistry.

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge at

■

sı

Experimental procedures and spectral data for all new

compounds (PDF)

X-ray crystallographic data for the derivative of the

cyclobutane product 3r (CIF)

X-ray crystallographic data for the derivative of the

cyclobutane product 3 (Table 1, entry 4) (CIF)

AUTHOR INFORMATION

Corresponding Author

■

Jianbo Wang − Beijing National Laboratory of Molecular

Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Chemistry, Peking University, Beijing, China; orcid.org/

Article

and Molecular Engineering of Ministry of Education, College of

(d) Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.;

Love, J. A.; Rieck, H. Transition Metal-Catalyzed [5 + 2] Cyclo-

additions with Substituted Cyclopropanes: First Studies of Regio- and

Stereoselectivity. J. Am. Chem. Soc. 1999, 121, 10442 −10443.

000-0002-0092-0937 ; Email: wangjb@pku.edu.cn

e) Wender, P. A.; Barzilay, C. M.; Dyckman, A. J. The First

Authors

Intermolecular Transition Metal-Catalyzed [5 + 2] Cycloadditions with

Simple, Unactivated, Vinylcyclopropanes. J. Am. Chem. Soc. 2001 , 123 ,

Sheng Feng − Beijing National Laboratory of Molecular

Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry

and Molecular Engineering of Ministry of Education, College

of Chemistry, Peking University, Beijing, China; orcid.org/

79 −180. (f) Wegner, H. A.; de Meijere, A.; Wender, P. A. Transition

Metal-Catalyzed Intermolecular [5 + 2] and [5 + 2+1] Cycloadditions

of Allenes and Vinylcyclopropanes. J. Am. Chem. Soc. 2005, 127, 6530−

000-0001-8781-9681

6531. (g) Wender, P. A.; Haustedt, L. O.; Lim, J.; Love, J. A.; Williams,

Kang Wang − Beijing National Laboratory of Molecular

Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry

and Molecular Engineering of Ministry of Education, College

of Chemistry, Peking University, Beijing, China

T. J.; Yoon, J. Asymmetric Catalysis of the [5 + 2] Cycloaddition

Reaction of Vinylcyclopropanes and π -Systems. J. Am. Chem. Soc. 2006,

128, 6302−6303. (h) Wender, P. A.; Fournogerakis, D. N.; Jeffreys, M.

S.; Quiroz, R. V.; Inagaki, F.; Pfaffenbach, M. Structural Complexity

Through Multicomponent Cycloaddition Cascades Enabled by Dual-

Purpose, Reactivity Regenerating 1,2,3-Triene Equivalents. Nat. Chem.

Yifan Ping − Beijing National Laboratory of Molecular Sciences

(

BNLMS), Key Laboratory of Bioorganic Chemistry and

014, 6, 448−452.

Molecular Engineering of Ministry of Education, College of

Chemistry, Peking University, Beijing, China

4) For [3 + 2] cycloaddition, see: (a) Jiao, L.; Ye, S.; Yu, Z. Rh(I)-

Catalyzed Intramolecular [3 + 2] Cycloaddition of trans -Vinyl-

cyclopropane-enes. J. Am. Chem. Soc. 2008 , 130 , 7178 −7179.

(b) Jiao, L.; Lin, M.; Yu, Z. Rh(I)-Catalyzed Intramolecular [3 + 2]

Cycloaddition Reactions of 1-Ene-, 1-Yne- and 1-Allene-Vinyl-

cyclopropanes. Chem. Commun. 2010 , 46 , 1059 −1061. (c) Li, Q.;

Jiang, G.; Jiao, L.; Yu, Z. Reaction of α -Ene-Vinylcyclopropanes: Type

II Intramolecular [5 + 2] Cycloaddition or [3 + 2] Cycloaddition? Org.

Lett. 2010 , 12 , 1332 −1335. (d) Lin, M.; Kang, G. Y.; Guo, Y. A.; Yu, Z.

Asymmetric Rh(I)-Catalyzed Intramolecular [3 + 2] Cycloaddition of

1-Yne-vinylcyclopropanes for Bicyclo[3.3.0] Compounds with a Chiral

Quaternary Carbon Stereocenter and Density Functional Theory Study

of the Origins of Enantioselectivity. J. Am. Chem. Soc. 2012, 134, 398−

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.0c08089

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The project is supported by NSFC (Grant 91956104) and

Beijing Outstanding Young Scientist Program

(

BJJWZYJH01201910001001). We acknowledge Prof. Peng

405.

Liu (University of Pittsburgh) and Dr. Ying Xia (Sichuan

University) for helpful discussions. We appreciate Prof.

Wenxiong Zhang and Dr. Nengdong Wang (Peking University)

for the assistance in obtaining X-ray crystallographic structures.

(5) For [5 + 2+1]/[3 + 2+1]/[5 + 1]/[5 + 1+2 + 1] cycloaddition,

see: (a) Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L.

Three-Component Cycloadditions: The First Transition Metal-

Catalyzed [5 + 2+1] Cycloaddition Reactions. J. Am. Chem. Soc.

002, 124, 2876−2877. (b) Wang, Y.; Wang, J.; Su, J.; Huang, F.; Jiao,

REFERENCES

L.; Liang, Y.; Yang, D.; Zhang, S.; Wender, P. A.; Yu, Z. A

Computationally Designed Rh(I)-Catalyzed Two-Component [5 +

■

1) For reviews, see: (a) Rubin, M.; Rubina, M.; Gevorgyan, V.

Transition Metal Chemistry of Cyclopropenes and Cyclopropanes.

+1] Cycloaddition of Ene-vinylcyclopropanes and CO for the

Synthesis of Cyclooctenones. J. Am. Chem. Soc. 2007 , 129 , 10060 −

Chem. Rev. 2007 , 107 , 3117 −3179. (b) Ylijoki, K. E. O.; Stryker, J. M. [5

0061. (c) Jiao, L.; Lin, M.; Zhuo, L.; Yu, Z. Rh(I)-Catalyzed [(3 +

)+1] Cycloaddition of 1-Yne/Ene-vinylcyclopropanes and CO:

2] Cycloaddition Reactions in Organic and Natural Product

Synthesis. Chem. Rev. 2013, 113, 2244−2266. (c) Wender, P. A.;

Croatt, M. P.; Deschamps, N. M. In Comprehensive Organometallic

Chemistry III; Ojima, I., Ed.; Elsevier: Amsterdam, 2007; Vol. 10 , pp

03 −648. (d) Jiao, L.; Yu, Z. Vinylcyclopropane Derivatives in

Transition-Metal-Catalyzed Cycloadditions for the Synthesis of

Carbocyclic Compounds. J. Org. Chem. 2013 , 78 , 6842 −6848.

e) Wang, Y.; Yu, Z.-X. Rhodium-Catalyzed [5 + 2+1] Cycloaddition

Homologous Pauson-Khand Reaction and Total Synthesis of (±)-α -

Agarofuran. Org. Lett. 2010 , 12 , 2528 −2531. (d) Lin, M.; Li, F.; Jiao, L.;

Yu, Z. Rh(I)-Catalyzed Formal [5 + 1]/[2 + 2+1] Cycloaddition of 1-

Ynevinylcyclopropanes and Two CO Units: One-Step Construction of

Multifunctional Angular Tricyclic 5/5/6 Compounds. J. Am. Chem. Soc.

011 , 133 , 1690 −1693. (e) Jiang, G.; Fu, X.; Li, Q.; Yu, Z. Rh(I)-

Catalyzed [5 + 1] Cycloaddition of Vinylcyclopropanes and CO for the

Synthesis of α ,β - and β ,γ -Cyclohexenones. Org. Lett. 2012, 14, 692−

695. (f) Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.;

Zhang, L. Multicomponent Cycloadditions: The Four-Component [5

+ 1+2 + 1] Cycloaddition of Vinylcyclopropanes, Alkynes, and CO. J.

Am. Chem. Soc. 2005, 127, 2836−2837.

of Ene −Vinylcyclopropanes and CO: Reaction Design, Development,

Application in Natural Product Synthesis, and Inspiration for

Developing New Reactions for Synthesis of Eight-Membered Carbo-

cycles. Acc. Chem. Res. 2015, 48, 2288−2296.

2) Wender, P. A.; Takahashi, H.; Witulski, B. Transition Metal

Catalyzed [5 + 2] Cycloadditions of Vinylcyclopropanes and Alkynes:

A Homolog of the Diels-Alder Reaction for the Synthesis of Seven-

Membered Rings. J. Am. Chem. Soc. 1995, 117, 4720−4721.

(6) For reviews, see: (a) Barluenga, J.; Valdes, C. Tosylhydrazones:

New Uses for Classic Reagents in Palladium-Catalyzed Cross-Coupling

and Metal-Free Reactions. Angew. Chem., Int. Ed. 2011 , 50 , 7486 −7500.

(b) Xiao, Q.; Zhang, Y.; Wang, J. Diazo Compounds and N -

Tosylhydrazones: Novel Cross-Coupling Partners in Transition-

Metal-Catalyzed Reactions. Acc. Chem. Res. 2013 , 46 , 236 −247.

Carbene: From C C/C −C Bond Formation to C −H Bond

Functionalization. J. Org. Chem. 2013 , 78 , 10024 −10030. (d) Xia, Y.;

Zhang, Y.; Wang, J. Catalytic Cascade Reactions Involving Metal

Carbene Migratory Insertion. ACS Catal. 2013 , 3 , 2586 −2598. (e) Xia,

Y.; Qiu, D.; Wang, J. Transition-Metal-Catalyzed Cross-Couplings

through Carbene Migratory Insertion. Chem. Rev. 2017, 117, 13810−

13889.

(

3) For representative examples of [5 + 2] cycloaddition, see:

a) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A. First Studies

of the Transition Metal-Catalyzed [5 + 2] Cycloadditions of Alkenes

and Vinylcyclopropanes: Scope and Stereochemistry. J. Am. Chem. Soc.

998 , 120 , 1940 −1941. (b) Wender, P. A.; Rieck, H.; Fuji, M. The

Transition Metal-Catalyzed Intermolecular [5 + 2] Cycloaddition: The

Homologous Diels-Alder Reaction. J. Am. Chem. Soc. 1998, 120,

0976−10977. (c) Wender, P. A.; Glorius, F.; Husfeld, C. O.;

Langkopf, E.; Love, J. A. Transition Metal-Catalyzed [5 + 2]

Cycloadditions of Allenes and Vinylcyclopropanes: First Studies of

Endo-Exo Selectivity, Chemoselectivity, Relative Stereochemistry, and

Chirality Transfer. J. Am. Chem. Soc. 1999, 121, 5348−5349.

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Article

7) Feng, S.; Mo, F.; Xia, Y.; Liu, Z.; Liu, Z.; Zhang, Y.; Wang, J.

Rhodium(I)-Catalyzed C −C Bond Activation of Siloxyvinylcyclopro-

panes with Diazoesters. Angew. Chem., Int. Ed. 2016, 55, 15401−15405.

(

8) For representative examples of applications of cyclobutanols in

pharmaceuticals and natural product synthesis, see: (a) Charrua, A.;

Cruz, C. D.; Narayanan, S.; Gharat, L.; Gullapalli, S.; Cruz, F.; Avelino,

A. GRC-6211, a New Oral Specific TRPV1 Antagonist, Decreases

Bladder Overactivity and Noxious Bladder Input in Cystitis Animal

Models. J. Urol. 2009, 181, 379−386. (b) Mahaney, P. E.; Krim, L. D.;

Jenkins, D. J. 1-2′(1,4′-Biperidin-1′-yl)-1-(Pheny)-Ethyl Cyclohexanol

Derivatives as Monoamine Reuptake Modulators for the Treatment of

Visomotor Symptoms. International Patent WO037279(A1), April 28,

005. (c) Nemoto, H.; Nagamochi, M.; Fukumoto, K. Chiral

Cyclobutanones as Versatile Synthons: the First Enantioselective

Total Synthesis of (+)-Laurene. J. Chem. Soc., Perkin Trans. 1 1993, 1,

329−2332. (d) Yang, J.; Zhang, X.; Zhang, F.; Wang, S.; Tu, Y.; Li, Z.;

Wang, X.; Wang, H. Enantioselective Catalytic Aldehyde α -Alkylation/

Semipinacol Rearrangement: Construction of α -Quaternary-δ -Carbon-

yl Cycloketones and Total Synthesis of (+)-Cerapicol. Angew. Chem.,

Int. Ed. 2020, 59, 8471−8475.

(

9) For details, see the Supporting Information.

10) In our previously published results (ref 7), the structure of 3u was

wrong. This reaction was repeated and the product structure was

assigned as 4″ (Scheme 4) based on H, C, and COSY NMR analysis.

See the Supporting Information for details.

(

11) For representative computational studies, see: (a) Yu, Z.;

Wender, P. A.; Houk, K. N. On the Mechanism of [Rh(CO) Cl] -

Catalyzed Intermolecular [5 + 2] Reactions between Vinylcyclopro-

panes and Alkynes. J. Am. Chem. Soc. 2004, 126, 9154−9155. (b) Yu, Z.;

Cheong, P. H.; Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N.

Origins of Differences in Reactivities of Alkenes, Alkynes, and Allenes in

[

Rh(CO) Cl] -Catalyzed [5 + 2] Cycloaddition Reactions with

2 2

Vinylcyclopropanes. J. Am. Chem. Soc. 2008 , 130 , 2378 −2379.

c) Jiao, L.; Lin, M.; Yu, Z. Density Functional Theory Study of the

Mechanisms and Stereochemistry of the Rh(I)-Catalyzed Intra-

molecular [3 + 2] Cycloadditions of 1-Ene- and 1-Yne-Vinyl-

cyclopropanes. J. Am. Chem. Soc. 2011, 133, 447−461.

(

12) Ishida, N.; Ikemoto, W.; Murakami, M. J. Am. Chem. Soc. 2014,

(

36, 5912−5915.

13) Calculations were performed at the M06/SDD(Rh)-6-

11+G(d,p)/SMD(THF) level of theory with geometries optimized

at the B3LYP/SDD(Rh)-6-31G(d) level. In the calculations, the

TBDPS group in VCP 1a was replaced with a TMS group and the

CH CF group in diazoester 2a was replaced with a methyl group to

save computation time. See the Supporting Information for details.

14) For a recent review, see: Nikolaev, A.; Orellana, A. Transition-

Metal-Catalyzed C −C and C −X Bond-Forming Reactions Using

Cyclopropanols. Synthesis 2016, 48, 1741−1768.

(

15) When comparing the rate of reductive elimination from Int10

with that of β-H elimination, we noticed that although TS8a is higher in

activation free energy compared to both TS8 and TS9, its enthalpy is

.7 kcal/mol lower than that of TS9. Therefore, to ensure that our

conclusion is not aﬀected by the choice of the computational method,

we performed test calculations using diﬀerent DFT methods and

solvation models for the three key transition states TS8, TS8a, and TS9

(

Table S4). The results suggested that reductive elimination from Int10

via TS8a is the less favorable pathway regardless of the choice of

computational methods. For details, see the Supporting Information.