Rhodium-Catalyzed Arylation of Cyclopropenes Based on Asymmetric Direct Functionalization of Three-Membered Carbocycles

Article abstract of DOI:10.1002/anie.201713324

A variety of highly diastereo- and enantiomerically enriched arylcyclopropanes is obtained through the asymmetric rhodium-catalyzed arylation reaction of achiral nonfunctionalized cyclopropene derivatives with commercially available aryl boronic acids in the presence of (R,S)-Josiphos.

Full text of DOI:10.1002/anie.201713324

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Accepted Article
Title: Rh-Catalyzed Arylation of Cyclopropenes Based on Asymmetric
Directed Functionalization of Three-Membered Carbocycles
Authors: Ilan Marek and Longyang Dian
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Rh-Catalyzed Arylation of Cyclopropenes Based on Asymmetric
Direct Functionalization of Three-Membered Carbocycles
Longyang Dian, Ilan Marek*
Abstract: A large variety of highly diastereo- and enantiomerically
enriched arylcyclopropanes is obtained through the asymmetric Rh-
catalyzed arylation reaction of achiral non-functionalized
cyclopropene derivatives with commercially available aryl boronic
acids and (R,S)-Josiphos.
high diastereo- and enantioselectivities from symmetrical
cyclopropenes. In this context, we have contributed in the
development of diastereo- and enantioselective 1,2-
bisfunctionalization of achiral cyclopropene derivatives through
the copper-catalyzed asymmetric ethylzincation,[18] the copper-
catalyzed asymmetric carbomagnesiation[19] as well as the
copper-catalyzed vinylmetalation reactions[20] with excellent
diastereo- and enantioselectivities. However, one important class
of nucleophiles that failed to provide high enantioselectivity in all
previously reported strategies is the enantioselective addition of
aryl groups. For instance, all our attempts to perform the
asymmetric copper-catalyzed arylmagnesiation or arylzincation of
cyclopropenes led to very disappointing enantioselectivities.[18,19]
The only asymmetric direct functionalization of three-membered
carbocycles approach leading to arylated cyclopropanes from
achiral cyclopropenes consisted in the two-steps diastereo- and
The most classical methods to prepare chiral cyclopropanes rely
either on the asymmetric addition of carbenes and carbenoids to
alkenes or on the Michael initiated ring closure reactions (Scheme
1a).[1] These powerful strategies have been extensively used in
the literature to access large varieties of functionalized
cyclopropanes
with
excellent
diastereo-
and
enantioselectivities.[2] However, one intrinsic consequence of this
strategy is that for every cyclopropane, a different alkene or
carbene precursor is needed limiting the rapid structural
diversification usually required for biological studies. An
alternative strategy would consist in the preparation of a unique
achiral precursor that would be transformed through a single set
of reactions into a multitude of products with very high diastereo-
and enantiomeric ratios. In this context, the strategy of
Asymmetric Direct Functionalization of Three-Membered
Carbocycles should provide an efficient and straightforward
approach to a wide range of diversely enantiomerically enriched
functionalized polysubstituted cyclopropanes (Scheme 1b). To
realize this goal, two possible scenarios could be envisaged: i) the
direct functionalization of an achiral cyclopropyl ring or ii) the
direct functionalization of an achiral cyclopropenyl ring (Scheme
1b). In the former case, the field has been dominated by diversity
oriented enantioselective C-H functionalization processes and
metalation[3] whereas in the latter case, the Rh-catalyzed
enantioselective Cu-catalyzed hydroboration followed by
a
subsequent Pd-catalyzed Suzuki-Miyaura cross-coupling
reaction reported by Tortosa[9] and others.[5,21] Interested to find
an alternative and step-economical solution to this problem, we
wondered if we could develop a direct highly diastereo- and
enantioselective metal-catalyzed arylation of cyclopropenes.
Herein, we report our results on the diastereo- and
enantioselective Rh-catalyzed asymmetric arylation reactions of
cyclopropene derivatives with commercially available aryl boronic
acids and chiral ligand (Scheme 1c).
a. Cyclopropanation of alkenes
R
1 R2
R1
LG
Carbenes
or
Carbenoids
R3
+ R3M
+
R2
R3
hydrostannation,[4]
hydroboration,[5]
hydroformylation,[6]
b. Direct Functionalization of Three Membered Carbocycles
R1 R2
hydroacylation,[7] the copper-catalyzed hydronitronylation,[8]
hydroboration,[9] the carbocupration,[10] carbozincation,[11]
carbomagnesiation,[12] the iron[13] and palladium[14] - catalyzed
carbozincation, the Ln-catalyzed hydroamination[15] and addition
of 2-methyl azaarenes[16] as well as the NHC-metal free
enantioselective hydroacylation reactions[17] have been reported
for the preparation of variously functionalized cyclopropanes with
1 R2
R
Asymmetric
or
R1 R2
achiral
functionalization
R3
chiral
c. Asymmetric Rh-catalyzed arylation (this work)
R1 R2
R1 R2
ArB(OH)2
Rh (cat), L*
achiral
Ar
diastereoselectivity?
enantioselectivity?
[a]
[b]
Dr. Longyang Dian, Prof. Dr. Ilan Marek
The Mallat Family Laboratory of Organic Chemistry, Schulich
Faculty of Chemistry, Technion-Israel Institute of Technology,
Haifa, 3200009 (Israel)
Scheme 1. Asymmetric Direct Functionalization of Three-Membered
Carbocycles as a new approach to diastereo- and enantiomerically enriched
cyclopropanes
E-mail: chilanm@technion.ac.il
We began
exploring the diastereoselectivity and
This research was supported by a grant from the European
Research Council under the Seventh Framework Program of the
European Community (ERC Grant Agreement 338912). I.M. is
holder of the Sir Michael and Lady Sobell Academic Chair.
enantioselectivity of the rhodium-catalyzed arylation reaction of
cyclopropene 1a by varying the catalyst, chiral ligands, solvents
and additives as summarized in Table 1 (for full details and
optimization see the Supporting Information). After screening
different catalysts, we were pleased to observe that the desired
arylated product 2a could be obtained with moderate diastereo-
and enantioselectivity (dr 82:18, er 71:29) by the use of
[Rh(acac)(cod)] as catalyst in toluene with (R)-BINAP as chiral
ligand (Table 1, entry 1). Based on this primary result, subsequent
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201713324
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COMMUNICATION
screening underlines the crucial role of the solvent in the
selectivity of the reaction (Table 1, entries 2-6).
improved to 98:02 when the temperature was decreased to 45 °C
(Table 1, entry 16). Additional studies showed that the reaction
could be performed similarly with a lower catalyst loading (2 mol%
[Rh(OMe)(cod)]2 with 5 mol% of (R,S)-Josiphos, (Table 1, entry
17). Control experiments confirmed that the combination
described in entry 17 is required to achieve the expected chemical
transformation with high diastereo- and enantioselectivities (Table
1, entries 18-20). Having established a straightforward and
smooth access to arylated cyclopropanes through a highly
diastereo- and enantioselective rhodium-catalyzed arylation
reaction of cyclopropene derivatives, we then extended the scope
of this transformation by performing various asymmetric Rh-
catalyzed addition with commercially available aryl boronic acids
on 1a (Scheme 2). For most of the cases, excellent diastereo- and
enantioselectivities were obtained for the addition of boronic acids.
For instance, aryl boronic acids containing electron-donating-
groups (Scheme 2, formation of 2b-e) have nearly no influence
on the diastereoselectivity and enantioselectivity of the catalytic
reaction. Similarly, boronic acids containing electron-withdrawing-
groups were also tested and we were pleased to observe good
selectivities (Scheme 2) at the exception of 2l where we observed
an erosion of the enantioselectivity.
Table 1 Optimization of the Rh-catalyzed asymmetric arylation of cyclopropene
1a.a
Ph Me
Me Ph Rh cat. (5 mol%), L* (12 mol%)
PhB(OH)2 (3 equiv.)
base (100 mol%), solvent
1a
2a
Entry
1
Rh
L
Solvent
toluene
toluene
THF
dr[b]
82:18
83:17
76:24
64:36
/
er[c]
71:29
78:27
66:34
73:27
/
Rh(acac)(cod)
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
[Rh(OMe)(cod)]2
/
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L7
L7
L7
L7
/
2
3
4
5d
dioxane
H2O
6
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
toluene/dioxane/H2O
89:11
90:10
91:09
68:32
90:10
93:07
93:07
90:10
86:14
93:07
93:07
93:07
/
83:17
88:12
88:12
82:18
88:12
93:07
95:05
95:05
73:27
96:04
98:02
98:02
/
7
8
9
10
11
12
13
14
15e
16f
17f,g
18d
19d
20d
[Rh(OMeCOD)]2 (2 mol%)
(R,S)-Josiphos (5 mol%)
ArB(OH)2 (3.0 equiv.)
K2CO3 (100 mol%)
Ph Me
Ph Me
toluene/dioxane/H2O (2:2:1, 0.1 M)
Ar
45 ºC, 36 h
Ph Me
Ph Me
Ph Me
Ph Me
[Rh(OMe)(cod)]2
/
/
/
OMe
/
/
/
2a
78%
2b
55%
2c
65%
2d
71%
Me
OMe
[a] The reactions were run on a 0.10 mmol scale, and the reaction mixture was
heated at 80 °C for 12 h; full conversion was observed by GC analysis in all
cases. [b] Determined by GC or GC−MS analysis. [c] Determined by chiral GC. [d]
No detection of the desired product, cyclopropene 1a was recovered. [e] The
reaction was performed at 60 oC. [f] The reaction was performed at 45 °C for 36
h. [g] 2 mol% [Rh(OMe)(cod)]2, 5 mol% (R,S)-JOSIPHOS was used.
dr 93:07
er 98:02
dr 92:08
er 96:04
dr 92:08
er 99:01
dr 95:05
er 98:02
Ph Me
Ph Me
Ph Me
Ph Me
OMe
OMe
Cl
NO2
2e
65%
2f
65%
2g
58%
2h
63%
Br
dr 94:06
er 97:03
dr 94:06
er 99:01
dr 88:12
er 92:08
dr 93:07
er 94:06
O
O
Ph
Ph
PAr2
PAr2
P
N
Ph Me
Ph Me
Ph Me
Ph Me
F
L4 (S,R,R)-phosphoramidite
2i
55%
dr 92:08
er 92:08
2j
72%
dr 95:05
er 97:03
2k
50%
dr 93:07
er 91:09
2l
56%
dr 93:07
er 89:11
L1 Ar = Ph; (R)-BINAP
F
CF3
CO2Me
L3 Ar = p-Tol; (R)-p-TolBINAP
L5 Ar = Ph; (R)-SEGPHOS
t-Bu
O
PAr2
PAr2
O
O
Unsuccesful boronic acids
N
PPh2
PPh2
L6 Ar =
OMe
HO
B(OH)2
B(OH)2
S
O
t-Bu
(R)-DTBM-SEGPHOS
B(OH)2
O
B(OH)2
L2 (R)-H8-BINAP
Scheme 2. Rh-catalyzed asymmetric arylation reaction of cyclopropene 1a.
L7 Ar = Ph; (R,S)-JOSIPHOS
L8 Ar = (R,S)-4-methoxy-3,5-dimethyl JOSIPHOS
L9 Ar = (R,S)-3,5-ditrifluoromethyl JOSIPHOS
P(cHex)2
Ar2P
Fe
Even aryl boronic acid containing a NO2 moiety in a meta-position
gave the desired arylated product 2h with rather high selectivities
(2h, Scheme 2, dr 93:07, er 94:06). This approach could also be
implemented to introduce fluorine substituents (2i,j) or the
trifluoromethyl group (2k) on the aromatic ring with unaltered
selectivities. Increasing the scale of the reaction from 0.1 to 5
mmol did not hamper yields and selectivities as 2a was obtained
with exactly the same selectivities. It should be emphazised that
in all cases, the arylation is syn-directed towards the Me group,
and a DFT mechanistic investigation is currently performed to
rationalize these results.[4-14] A few functionalized heteroaromatic
Me
The best selectivity was observed when
a mixture of
toluene/dioxane/H2O in a 2:2:1 ratio was used (Table 1, entry 6,
dr 89:11, er 83:17). After assessment of chiral ligands (Table 1,
entries 7-14; see supporting Information for a full list of chiral
ligands tested), we were pleased to find that (R,S)-Josiphos in
combination with [Rh(OMe)(cod)]2 (Table 1, entry 12) gave the
desired product 2a with excellent diastereo- and enantioselectivity
(dr 93:07, er 95:05). The enantioselectivity could be further
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10.1002/anie.201713324
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boronic acids as well aromatic boronic acid possessing an acidic
hydrogen could not produce the addition product (See Scheme 2).
As we have a rather broad scope for the introduction of aryl
boronic acids possessing either electron donating or withdrawing
substituents with good to excellent diastereo- and
enantioselectivities, we were then interested to extend the scope
of this reaction to various cyclopropene species (Scheme 3).
Cyclopropenes containing a substituent on the aromatic group
(2m-p) undergo the asymmetric arylation reaction with similar
selectivities. The absolute configuration of the cyclopropane
product was determined by X-Ray crystallographic analysis of
compound 2m (see the Supporting Information)[22] and assigned
by analogy for all other products. When the solvent mixture was
changed to toluene/dioxane/D2O, the 1,2,3-polysubstituted
cyclopropane 2n was obtained with a syn-diastereoselectivity
between the aryl group of the boronic acid and the deuterium
confirming the syn-addition of the aryl-rhodium species across the
double bond of the three-membered ring (Scheme 3).[23] When the
two substituents phenyl and alkyl on the cyclopropene are fused
in a cyclic structure, the aryl addition proceeds with similar
diastereo- and enantioselectivity (2q). In contrast, when the
phenyl group of the cyclopropene was changed to a benzyl moiety,
the diastereoselectivity of the reaction decreased (2r, dr 72:28)
but still with an excellent enantioselectivity (er for the major isomer
is 95:05 and 98:02 for the minor isomer). Similarly, when the
methyl group on the cyclopropene ring was changed to a bulkier
substituent such as a secondary alkyl group, the reaction is no
more diastereoselective but still proceeds with an outstanding
enantioselectivity (2s, dr 50:50, er >99:01 for both
diastereoisomers). The diastereoselectivity can be restored when
a very bulky substituent is present but at the expense of the
enantioselectivity of the reaction (2t, dr 98:02, er 82:18). Other
interesting class of cyclopropenyl substrates have been
envisaged such as the one who have identical substituents on the
C2 of the cyclopropenyl ring. For instance, the addition of various
aryl boronic acids to cyclopropene possessing two phenyl
substituents lead invariably in good to excellent enantioselectivity
(Scheme 3, 2u-y). Finally, the volatile dimethylcyclopropene was
also tested in the asymmetric rhodium-catalyzed arylation
reaction and we were pleased to observe that the desired arylated
dimethylcyclopropane 2z-ac could be isolated with high
enantioselectivity in all cases. One potential application of the
current methodology consists in the synthesis of a selective
estrogen receptor modulator 3,[24] that could be easily achieved in
good diastereoselectivity and enantioselectivity by deprotection of
2o into 3. The proposed reaction mechanism probably involves
the generation of an organorhodium species B by transmetalation
between ArB(OH)2 and the chiral rhodium complex A. Then the
large variety of aryl boronic acids in the presence of 5 mol% of
commercially available (R,S)-Josiphos easily transforms
carbocycle with
a
C2-symmetry into numerous chiral
arylcyclopropanes possessing a quaternary carbon stereocenter
with excellent selectivities.
organorhodium species
B stereoselectively adds to the
cyclopropene 1 to afford the species C, which is in-situ hydrolyzed
by H2O (or D2O) to deliver the final arylated cyclopropane 2 and
regenerate the chiral rhodium species A. The stereoinduction of
the asymmetric Rh-catalyzed arylation process is more difficult to
rationalize but one could consider than from the two possible
transition states, less steric interactions are present in TS-1 that
in TS-2.[25]
In conclusion, the asymmetric direct functionalization of three-
membered carbocycles represents a very efficient, step-economy
approach, to chiral cyclopropanes with very high diastereo- and
enantioselectivities. This robust and flexible asymmetric Rh-
catalyzed arylation of non-functionalized achiral substrates with a
Scheme 3. Asymmetric Rh-catalyzed arylation of different substituted
cyclopropenes.
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10.1002/anie.201713324
Angewandte Chemie International Edition
COMMUNICATION
Layout 1:
COMMUNICATION
[Rh(OMeCOD)]2 (2 mol%)
(R,S)-Josiphos (5 mol%)
ArB(OH)2 (3.0 equiv.)
The
asymmetric
Rh-catalyzed
Longyang Dian, Ilan Marek*
Page No. – Page No.
arylation of simple achiral non-
functionalized cyclopropene provides
R1 R2
R
1 R2
K2CO3 (100 mol%)
toluene/dioxane/H2O (2:2:1, 0.1 M)
45 ºC, 36 h
a
large
variety
of
arylated
Ar
cyclopropanes with high diastereo-
and enantioselectivity.
Mild reaction conditions
Rh-Catalyzed
Arylation
Based
of
Good to excellent selectivity (er from 90:10 to 99:01)
Cyclopropenes
on
Asymmetric Direct Functionalization
of Three-Membered Carbocycles
This article is protected by copyright. All rights reserved.