Full text of DOI:10.1021/acs.orglett.8b00739

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Formation of Tertiary Alcohols from the Rhodium-Catalyzed
Reactions of Donor/Acceptor Carbenes with Esters
Liangbing Fu, Kevin Hoang, Cecilia Tortoreto, Wenbin Liu, and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: Rhodium(II)-catalyzed reactions between isopropyl
acetate and trichloroethyl aryldiazoacetates result in the formation of
oxirane intermediates that ring open under the reaction conditions to
form tertiary alcohols. When the reaction is catalyzed by the
dirhodium tetrakis(triarylcyclopropanecarboxylate) complex, Rh2(S-
2-Cl,4-BrTPCP)4, the tertiary alcohols are formed with good asymmetric induction (80−88% ee).
Scheme 1. Trapping of Donor/Acceptor Carbenes by Esters
hodium-stabilized donor/acceptor carbenes have found
1,2
Rextensive applications in organic synthesis.
The donor
group attenuates the reactivity of the carbene, enabling a wide
variety of selective intermolecular reactions to be feasible.
These include cyclopropanation,2a tandem cyclopropanation
Cope rearrangement,2a,3 C−H insertion,2b−e and a wide variety
of reactions initiated by formation of ylide intermediates.4 Even
though the reaction scope is broad, it is still possible to achieve
reactions in the presence of a variety of functional groups. It has
been suggested that one reason for this broad scope is the
reactions with some nucleophilic functional groups, such as
esters, are reversible.5 This would explain, for example, why
intermolecular functionalization of unactivated C−H bonds can
be achieved, even when the substrates contain nucleophilic
sites.2b−e Furthermore, many examples known of carbene
reactions were conducted in relatively polar solvents such as
ethyl acetate or diethyl ether,6 and even water.7 This paper
describes an unexpected reaction of rhodium-stabilized donor/
acceptor carbenes with simple ester solvents.
Even though intramolecular reactions between carbenes and
esters and intermolecular reactions with aldehydes and
ketones11 are well established, intermolecular reactions with
esters are rare.12 Therefore, we conducted a survey of the most
common achiral catalysts to determine if the reaction can be
developed into a synthetically useful process. The results are
summarized in Table 1. The initial evaluation of the catalysts
was conducted with isopropyl acetate as solvent at room
temperature (entries 1−6), and under these conditions,
Rh2(OAc)4 and Rh2(OOct)4 were the most effective. The
yield could be improved if a mixture of isopropyl acetate/
dichloromethane with a 1/1 volume ratio was used as the
solvent (entries 7 and 8), and further improvement occurred
when the reaction was conducted under reflux (entries 9 and
10).
Comparison studies were conducted between different diazo
esters (Scheme 2). When the diazo compound was switched
from the trichloroethyl ester to the methyl ester 3, the
corresponding product 4 was only formed in trace amounts.
Ethyl acetate was also an effective trapping agent, generating
the tertiary alcohol 5 in 53% yield, but the yield was much
lower when tert-butyl acetate was used as the trapping agent.
The observation of a very small amount of the tertiary alcohol 4
may explain why intermolecular ester trapping of rhodium
carbenes is rare, because the use of the trichloroethyl esters is a
relatively new phenomenon in rhodium carbene chemistry.
The scope of the reaction was then explored with more
elaborate substrates. A series of trichloroethyl aryldiazoacetates
7 were examined, and the results are summarized in Scheme 3.
For some time, we have been developing enantioselective
C−H functionalization strategies by means of rhodium-
catalyzed intermolecular C−H insertions.2a−e The original
chiral catalyst used in these studies, Rh2(S-DOSP)4, gave high
asymmetric induction only in nonpolar solvents,8 but the newer
chiral catalysts also performed well in more polar solvents such
as dichloromethane.9 A further advance has been the use of the
trichloroethyl ester (Troc) derivatives of the carbene
precursors, because they tend to give much cleaner trans-
formations, especially with challenging C−H functionalization
reactions.10 During exploratory studies using isopropyl acetate
as an industrially more favored solvent, we discovered an
unexpected result in the reaction of the trichloroethyl
aryldiazoacetate 1 with cumene. In addition to the expected
C−H functionalization product, a significant amount (10−
20%) of the tertiary alcohol 2 was formed, whose structure was
confirmed by X-ray crystallography. When the Rh2(S-DOSP)4-
catalyzed reaction was conducted without a trapping agent with
isopropyl acetate as solvent, 2 was generated in 38% yield and
35% ee (Scheme 1).
Received: March 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00739
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization Studies
Scheme 3. Substrate Scope
b
entry
catalyst
solvent
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc/CH2Cl2
iPrOAc/CH2Cl2
iPrOAc/CH2Cl2
iPrOAc/CH2Cl2
temp (°C)
yield (%)
1
Rh2(OAc)4
Rh2(OPiv)4
Rh2(TPA)4
Rh2(TFA)4
Rh2(OOct)4
Rh2(esp)2
rt
48
5
2
rt
3
rt
16
10
36
10
52
51
68
64
4
rt
5
rt
6
rt
7
Rh2(OOct)4
Rh2(OAc)4
Rh2(OOct)4
Rh2(OAc)4
rt
8
rt
9
10
40
40
a
Reaction conditions: diazo compound 1 (0.3 mmol) was added in
one portion to a mixture of the catalyst Rh2L4 (1 mol %) in 2 mL of
the solvent at the indicated temperature. The reaction was further
b
stirred for 30 min. Isolated yield.
Scheme 2. Control Studies
Scheme 4. Enol Ether Hydrolysis
A one-pot, two-step procedure was further developed for this
transformation. Diazoacetate 1 was reacted with either
isopropyl acetate or ethyl acetate under the catalysis of
Rh2(OOct)4, followed by direct hydrolysis of the reaction
mixture (Scheme 5). When isopropyl acetate was used,
Diazo ester substrates with different substitution patterns such
as para-, meta-, 3,5-, and 3,4-substitution were all capable
substrates in this transformation. The yields of the reactions
were found to be greatly influenced by the nature of the
substituent on the aryl ring. The yields of the reactions were
generally much higher for substrates with electron-withdrawing
groups on the aryl ring (51−90%), compared to those with an
electron-donating para substituent (29−31%). When a subsrate
bearing a strong electron-donating p-NMe2 on the pheyl ring
was employed, none of the desired products was observed,
further confirming the influence of electronics on the efficiency
of the transformation.
Scheme 5. One-Pot Rhodium-Catalyzed Reaction and Enol
Ether Hydrolysis
The quaternary hydroxyl-enoate thus obtained can be
hydrolyzed under acidic conditions. When compound 2 was
treated with hydrochloric acid in dichloromethane, product 9
was obtained in quantitative yield (Scheme 4). No column
chromatographic purification was required for this hydrolysis
reaction. The scope of the hydrolysis was explored with the
optimized hydrolysis conditions. Gratifyingly, and unsurpris-
ingly, when the pure products 8 obtained from the last step
were employed, all reactions gave the expected hydrolysis
products in high yields, without the need for column
chromatographic purifications (see Supporting Information
(SI)).
compound 9 was obtained in 56% yield for two steps. When
ethyl acetate was used, compound 9 was obtained in 53% yield.
The reaction was found to be applicable to isopropyl
propionate. When isopropyl propionate was subjected to the
same reactions, tertiary alcohol 10 was obtained, although the
yield was a bit lower (42%).
B
DOI: 10.1021/acs.orglett.8b00739
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Organic Letters
Letter
The likely mechanism of this transformation involves ylide
intermediates. Dirhodium-catalyzed reactions are known to give
variable levels of enantioselectivity when ylides are involved
because the metal may have already dissociated when the ylide
reacts or the reaction proceeds via enol intermediates.13 As
already discussed in the introduction, the Rh2(S-DOSP)4-
catalyzed reaction gave the product in 35% ee (Table 2). The
Scheme 6. Enantioselective Reaction
a
Table 2. Evaluation of Chiral Dirhodium Catalysts
a
b
c
entry
Rh2L*4
yield (%)
ee (%)
the asymmetric reactions were assigned by analogy. These
results open up the possibility of achieving enantioinduction for
the intermolecular reactions between carbenes and esters, even
though further development of chiral dirhodium catalysts is still
required for the reaction to be more broadly applicable.
A possible mechanistic pathway for the formation of tertiary
alcohols is shown Scheme 7. Decomposition of the
1
2
3
4
5
6
7
Rh2(S-DOSP)4
38
57
39
7
35
−5
−19
26
Rh2(S-PTAD)4
Rh2(S-TCPTAD)4
Rh2(S-p-BrTPCP)4
Rh2(S-2-CITPCP)4
Rh2(S-2-CI,5-BrTPCP)4
Rh2(S-2-CI,4-BrTPCP)4
10
32
49
51
24
88
a
Scheme 7. Proposed Mechanistic Pathway
Reaction conditions: a solution of 1 (0.3 mmol) in 3 mL of isopropyl
acetate was added over 30 min to the catalyst (1 mol %) in 2 mL of
isopropyl acetate at room temperature. The reaction was allowed to
b
c
stir for an additional 30 min. Isolated yield. Determined by chiral
HPLC analysis.
trichloroethyl aryldiazoacetate 11 by the dirhodium catalyst
generates a rhodium-bound carbene 12. The carbonyl group of
the isopropyl acetate then attacks the carbene 12 to form a
rhodium-bound carbonyl ylide intermediate 13. The inter-
molecular reaction of esters with donor/acceptor carbenes has
been proposed to be reversible,5 but in this case, the ylide
collapses to form an epoxide 14. The epoxide contains a ketal
functional group and, thus, is prone to ring opening to form a
new ylide intermediate 15, which undergoes proton transfer,
possibly in an intermolecular fashion to generate the final
products 16. The stereogenic center is initially generated during
the formation of the ylide 13, and is then at least mostly
retained during the cyclization to the epoxide 14. This result is
different from what was observed in the reactions of aldehydes
with aryldiazoacetates in the presence of chiral dirhodium
catalysts, which resulted in the formation of racemic epoxides,
presumably because the rhodium is no longer bound when
cyclization to the epoxide occurs.16
In summary, these studies demonstrate that even though
rhodium-bound donor/acceptor carbenes are capable of a wide
range of selective transformations, relatively innocuous solvents
such as isopropyl acetate can interfere with the reactions. The
carbene derived with a trichoroethyl ester appears to be more
reactive than the corresponding carbene with a methyl ester.
The rhodium-catalyzed reaction can be used to synthesize
tertiary alcohols by a cascade reaction involving epoxide
intermediates. Rh2(OOct)4 is the optimum achiral catalyst,
14
phthalimido catalysts Rh2(S-PTAD)4 and Rh2(S-TCPTAD)4
gave reasonable yields, but even lower levels of enantiose-
lectivity. The newly developed Rh2(S-p-BrTPCP)4 and (S-p-
PhTPCP)49 gave low yields and enantioselectivity. A promising
result was seen with Rh2(S-2-ClTPCP)4,15 as it gave reasonable
enantioselectivity, albeit poor yield. Further optimization with
two previously unpublished catalysts, Rh2(S-2-Cl,4-BrTPCP)4
and Rh2(S-2-Cl,5-BrTPCP)4, identified Rh2(S-2-Cl,4-
BrTPCP)4 as the optimum catalyst, generating 2 in 49% yield
and 88% ee.
With the optimized conditions for the enantioselective
reaction in hand, the efficiency of Rh2(S-2-Cl,4-BrTPCP)4 in
promoting an enantioselective synthesis of quaternary hydrox-
yl-enoate was explored (Scheme 6). The yields of these
enantioselective reactions were generally inferior to those of
reactions catalyzed by Rh2(OOct)4, but reasonably high levels
of enantioselectivity were achieved (80−88% ee). The absolute
configuration of product 8h was unambiguously assigned by X-
ray crystallography, and the configurations of other products in
C
DOI: 10.1021/acs.orglett.8b00739
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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tates. The yields are lower when chiral catalysts were used, but
Rh2(S-2-Cl,4-BrTPCP)4 was able to generate the products in
80−88% ee.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00739.
■
S
Complete experimental, NMR, chiral HPLC, and X-ray
crystallographic data (PDF)
Accession Codes
CCDC 1576459−1576460 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hmdavie@emory.edu.
ORCID
Huw M. L. Davies: 0000-0001-6254-9398
Notes
The authors declare the following competing financial
interest(s): HMLD is a named inventor on a patent entitled,
Dirhodium Catalyst Compositions and Synthetic Processes
Related Thereto (US 8,974,428, issued 3/10/2015). The other
authors have no competing financial interests.
(12) Padwa, A.; Boonsombat, J.; Rashatasakhon, P. Tetrahedron Lett.
2007, 48, 5938.
ACKNOWLEDGMENTS
■
(13) Li, Z.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 396.
(14) Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013.
(15) Liao, K.; Liu, W.; Niemeyer, Z. L.; Ren, Z.; Bacsa, J.; Musaev, D.
G.; Sigman, M. S.; Davies, H. M. L. ACS Catal. 2018, 8, 678.
(16) (a) Davies, H. M. L.; DeMeese, J. Tetrahedron Lett. 2001, 42,
6803. (b) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3,
933. (c) Russell, A. E.; Brekan, J.; Gronenberg, L.; Doyle, M. P. J. Org.
Chem. 2004, 69, 5269.
This work was supported by the National Science Foundation
(CHE 1465189). We also thank the Swiss National Science
Foundation for the early postdoc grant awarded to Cecilia
Tortoreto. Instrumentation used in this work was supported by
the National Science Foundation (CHE 1531620 and CHE
1626172). We thank Dr. John Bacsa from Emory X-ray
Crystallography Center for the X-ray structure determination.
We thank Mark A. Matulenko from AbbVie for encouraging us
to examine more benign solvents for carbene transformations.
REFERENCES
■
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D
DOI: 10.1021/acs.orglett.8b00739
Org. Lett. XXXX, XXX, XXX−XXX