Copper-catalyzed regio- and stereoselective intermolecular three-component oxyarylation of allenes

Article abstract of DOI:10.1021/ol501022d

A copper(II)-catalyzed intermolecular three-component oxyarylation of allenes using arylboronic acids as a carbon source and TEMPO as an oxygen source is described. The reaction proceeded under mild conditions with high regio- and stereoselectivity and functional group tolerance. A plausible reaction mechanism is proposed, involving carbocupration of allenes, homolysis of the intervening allylcopper(II), and a radical TEMPO trap.

Full text of DOI:10.1021/ol501022d

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Regio- and Stereoselective Intermolecular Three-
Component Oxyarylation of Allenes
Taisuke Itoh,† Yohei Shimizu,*,† and Motomu Kanai*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡ERATO, Japan Science and Technology Agency, Kanai Life Science Catalysis Project, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: A copper(II)-catalyzed intermolecular three-com-
ponent oxyarylation of allenes using arylboronic acids as a carbon
source and TEMPO as an oxygen source is described. The reaction
proceeded under mild conditions with high regio- and stereo-
selectivity and functional group tolerance. A plausible reaction
mechanism is proposed, involving carbocupration of allenes,
homolysis of the intervening allylcopper(II), and a radical
TEMPO trap.
arbooxygenation of carbon−carbon (C−C) multiple
control is not satisfactory.5 We report herein the first copper-
catalyzed intermolecular, three-component oxyarylation of
allenes using arylboronic acids as a carbon source and
TEMPO as an oxygen source (Scheme 1b). The reaction
proceeded with excellent regio- and stereoselectivity under mild
conditions.
We recently reported copper-catalyzed intramolecular oxy-
and amidocupration of allenes to generate allylcopper species
and its direct use in asymmetric allylation of carbonyl
compounds to give enantiomerically enriched 1H-isocromenes
and indoles, respectively.6 In these reactions, regioselectivity
was extremely high. The results encouraged us to examine
intermolecular oxyarylation of allenes via in situ generated
allylcopper species.7
C
bonds is a powerful tool in organic synthesis. Simulta-
neous formation of C−C and C−O bonds in a single operation
rapidly increases the molecular complexity starting from
unsaturated C−C bonds. Although carbooxygenation of alkenes
and alkynes has been extensively studied,1,2 that of allenes is
less well-studied. The literature contains only a few examples of
intramolecular oxyarylation of allenes using palladium catalysis
(Scheme 1a).3 In most of these examples, however, π-
Scheme 1. Oxyarylation of Allenes
We first investigated the reaction between phenylboronic
acid (2a) and phenylallene (1a) using copper salts as a catalyst
in the presence of various oxidants (Table 1). Preliminary
studies revealed that oxyarylation of 1a was promoted by a CuI
catalyst with molecular oxygen as an oxygen source in DMF at
room temperature (entry 1). The obtained product, however,
was an enone rather than the desired allylic alcohol. The
regioselectivity was low in favor of 4, where oxygenation
occurred at the benzylic position. To suppress overoxidation
into enones, other oxygen sources were investigated (entries
2−5). The combination of TEMPO and MnO2 provided the
best yield and regioselectivity (entry 5). In contrast to the
reaction using molecular oxygen, the major regioisomer was 3.
Furthermore, the geometry of the C−C double bond was
exclusively (E). Screening of various copper sources revealed
that Cu(OAc)2 was the most reactive catalyst (entry 9). The
yield, however, decreased to 70% when performed in a larger
scale (entry 10). A complex of Cu(OTf)2 and the t-BuBox
ligand proved to be the most effective, even in a larger scale,
allylpalladium intermediates are generated via migratory
insertion of allenes to arylpalladium species, and subsequent
trapping of the intermediates by an intramolecular oxygen atom
affords α-alkenyl cyclic ether products. In contrast, intermo-
lecular carbooxygenation of allenes can be more versatile for
the synthesis of multisubstituted allylic alcohol derivatives that
are otherwise difficult to access.4 Despite its potential utility,
intermolecular, three-component oxyarylation of allenes is
rarely exploited. In the few reported cases, regioselective
Received: April 8, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
could be an electrophile in the presence of an organocopper
reagent, was tolerated under the reaction conditions (entry 6).
Excellent selectivity was retained, even when sterically
congested boronic acids were used (entries 7 and 8). A free
NH group of 6-indolylboronic acid 2i was also compatible with
the oxyarylation (entry 9).
Table 1. Optimization of Copper-Catalyzed Intermolecular
Oxyarylation of 1a
a
We then evaluated the scope of allenes (Table 3). Both
electron-donating and -withdrawing groups on arylallenes
b
Table 3. Scope of Copper-Catalyzed Oxyarylation Regarding
Arylallenes
entry
Cu cat.
oxidant
yields and ratio (3:4)
a
c
1
2
3
4
5
6
7
8
9
CuI
air
54% + 14% (>20:1)
c
CuI
(t-BuO)2
11% + trace
CuI
oxaziridine
0%
c
CuI
TEMPO/air
36% + 44% (16:1)
e
e
e
e
e
e
e
CuI
TEMPO/MnO2
TEMPO/MnO2
TEMPO/MnO2
TEMPO/MnO2
TEMPO/MnO2
TEMPO/MnO2
TEMPO/MnO2
76% (12:1)
58% (14:1)
79% (16:1)
65% (16:1)
quant (17:1)
70% (16:1)
quant (15:1)
CuCl
CuTc
r.r.
(3:4)
E/Z of
b
b
entry
allene 1
product yield
3
Cu(OTf)2
1b R2 = 4-Br, R3 = Me
1c R2 = 4-CF3, R3 = Me
1d R2 = 4-OMe, R3 = Me
1e R2 = 2-Me, R3 = Me
1f R2 = 3,5-Me2, R3 = Me
1g R2 = H, R3 = C5H11
3ba
3ca
3da
3ea
3fa
96%
94%
93%
94%
94%
87%
12:1
12:1
>20:1
>20:1
>20:1
13:1
Cu(OAc)2
1
2
3
4
5
6
d
10
Cu(OAc)2
d
f
11
Cu(OTf)2/t-BuBox
15:1
a
>20:1
15:1
General reaction conditions: 1a (0.10 mmol, 1 equiv), 2a (1.5 equiv),
17:1
Cu catalyst (10 mol %), oxidant (2 equiv), DMF (0.5 mL), rt, 5 h.
b
Yield of alcohol/ether oxidation-state products determined by 1H
3ga
4.1:1
>20:1
a
NMR using t-BuOMe as an internal standard. Regioisomeric ratio (r.r.
= 3:4) was shown in parentheses. Combined yield of enones 8 + 9.
Regioisomeric ratio (8:9) was 1:1.1−1:1.4. 0.30 mmol scale.
TEMPO (1.2 equiv) and MnO2 (1 equiv) were used as oxidants.
Reaction conditions: 1 (0.30 mmol, 1 equiv), 2a (1.5 equiv),
Cu(OTf)2 (10 mol %), t-BuBox (10 mol %), TEMPO (1.2 equiv),
c
d
b
1
MnO2 (1 equiv), DMF (1.5 mL), rt. Determined by H NMR using
e
t-BuOMe as an internal standard.
f
t-BuBox: 2,2′-Isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline].
provided the corresponding products in excellent yield and
selectivity (entries 1−3). Sterically hindered allenes, bearing o-
methyl or 3,5-dimethyl substituents on the aromatic ring, were
also good substrates, and high regioselectivity was maintained
(entries 4 and 5). On the other hand, moderate regioselectivity
was observed when a longer linear alkyl substituent was
attached to the phenylallene (entry 6), likely due to the
increased steric hindrance between TEMPO and the alkyl
chain.
affording the product in quantitative yield with high regio- and
stereoselectivity (entry 11).8
Under these optimized conditions, we next examined the
substrate scope (Table 2). Arylboronic acids containing both
electron-donating and -withdrawing groups were tolerated
(entries 2−5). The regio- and stereoselectivity were excellent in
every entry. The coordinating functionalities did not interfere
with the reaction (entries 3−5). Notably, a formyl group, which
Encouraged by the high reactivity and regio- and stereo-
selectivity with arylallenes, we further investigated other types
of allenes (Scheme 2). Pyridylallene 1h, which has strong
coordinating tendencies toward the copper catalyst, was also
applicable, albeit with low regioselectivity. The reaction with
benzyloxyallene 1i provided an enol ether containing product
3ia and a hemiacetal containing product 4ia in a 1.1:1 ratio.
Allylic ether 3ja with a tetrasubstituted carbon−carbon double
bond was also obtained with excellent regioselectivity from 1,1-
disubstituted alkynylallene 1j, despite low E/Z selectivity.
Interestingly, when a cyclohexenylallene 1k was subjected to
the reaction conditions, oxygenation occurred preferentially at
the cyclohexane ring, affording 5ka with high regio- and
stereoselectivity. These results indicate that the initial C−C
bond formation step proceeded exclusively at the allene moiety
despite the presence of an alkyne or an alkene moiety. Finally,
we examined aliphatic allenes as substrates. The reaction with
strained nine-membered ring allene 1l proceeded smoothly to
give product 3la in 50% yield. The reactivity of a linear aliphatic
allene 1m was significantly lower, however, and product 3ma
was obtained in only 14% yield.9
Table 2. Scope of Copper-Catalyzed Oxyarylation Regarding
Boronic Acids
a
r.r.
E/Z
b
b
entry
boronic acid 2
2a R1 = H
product
yield
(3:4)
of 3
1
2
3
4
5
6
7
8
3aa
3ab
3ac
3ad
3ae
3af
98%
81%
90%
90%
79%
76%
92%
84%
15:1
13:1
12:1
15:1
12:1
13:1
>20:1
12:1
>20:1
17:1
2b R1 = 4-CF3
2c R1 = 4-OMe
2d R1 = 4-SMe
2e R1 = 4-NPh2
2f R1 = 3-CHO
2g R1 = 2-Me
>20:1
>20:1
14:1
17:1
3ag
3ah
>20:1
>20:1
2h 2-naphthylboronic
acid
b
9
2i 6-indolylboronic acid
3ai
83%
15:1
14:1
a
The TEMPO adducts can be converted to allylic alcohols
and enones in high yield (Scheme 3). When a 15:1 mixture of
3aa and 4aa was treated with zinc,10 the corresponding allylic
alcohols 6 and 7 were obtained in 95% combined yield. On the
Reaction conditions: 1a (0.30 mmol, 1 equiv), 2 (1.5 equiv),
Cu(OTf)2 (10 mol %), t-BuBox (10 mol %), TEMPO (1.2 equiv),
b
1
MnO2 (1 equiv), DMF (1.5 mL), rt. Determined by H NMR using
t-BuOMe as an internal standard.
B
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Scheme 2. Scope of Copper-Catalyzed Oxyarylation for
Miscellaneous Allenes
Scheme 4. Radical Clock Experiments (a, b) and TEMPO
Trap Experiment (c)
a
Based on the experimental observations and the general
lability of C(sp3)−Cu(II) bonds,14 we propose the catalytic
cycle shown in Figure 1. First, transmetalation of arylboronic
a
Reaction conditions: 1 (0.30 mmol, 1 equiv), 2a (1.5 equiv),
Cu(OTf)2 (10 mol %), t-BuBox (10 mol %), TEMPO (1.2 equiv),
MnO2 (1 equiv), DMF (1.5 mL), rt. bDetermined by 1H NMR using t-
c
BuOMe as an internal standard. Regioisomeric ratio of 5ka to 4ka.
Scheme 3. Representative Transformations of 3aa
other hand, enones 8 and 9 were obtained in 96% combined
yield by oxidation with mCPBA.11
A series of experiments was performed to gain insight into
the reaction mechanism (Scheme 4). First, a radical clock
experiment using substrate 1n containing a cyclopropane ring
resulted in the exclusive formation of 10 in high yield through a
ring-opening and TEMPO trap at the benzylic position. This
result indicates involvement of allyl radical species in the
oxygenation step.12 Next, boronic acid 2j was used as a
substrate to assess whether aryl radical species were generated
during the reaction.13 As a result, oxyarylation product 3aj was
obtained in 68% yield without producing any cyclized 11. This
result strongly supports that aryl radical species were not
involved in the arylation step. In addition, arylboronic acid 2j
did not react with TEMPO in the absence of an allene under
the reaction conditions, which further supports that the aryl
radical is not generated during the reaction.
Figure 1. Proposed catalytic cycle for the copper-catalyzed oxy-
arylation of allenes.
acid 2 to the copper(II) catalyst generates arylcopper(II)
species 12, which undergoes carbocupration of allenes 1 to give
allylcopper(II) 13. Homolysis of the thus-generated
allylcopper(II) 13 results in the formation of allyl radical
intermediates 14/14′, and a subsequent radical trap by
TEMPO furnishes product 3. Allyl radical species 14 and 14′
should exist in equilibrium, and the regioselectivity of
oxygenation (i.e., TEMPO trap) would be determined by
both steric factors and the relative stability between 14 and 14′.
C
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Organic Letters
Letter
(3) For selected reviews on intramolecular oxyarylation of allenes,
see: (a) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12−21.
(b) Ma, S. Acc. Chem. Res. 2003, 36, 701−712.
(4) For a recent review on preparation of allylic alcohols, see:
Lumbroso, A.; Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52,
1890−1932.
In summary, we developed a copper-catalyzed intermolecu-
lar, three-component oxyarylation of allenes to afford allylic
alcohol derivatives. The reaction proceeded with high regio-,
stereo-, and chemoselectivity under mild conditions (rt). The
substrate scope is broad, and various arylboronic acids and
allenes can be used as substrates with TEMPO as an oxygen
source. The reaction proceeded via (1) transmetalation
between the copper catalyst and arylboronic acid to generate
arylcopper(II) species, (2) carbocupration of allenes to
generate allylcopper(II), (3) homolysis of the C−Cu(II)
bond to give allyl radical species, and (4) a TEMPO trap of
the allyl radical. The in situ generated allyl radical species should
be applicable to other transformations, such as C−C and C−N
bond formation. Further investigation in this direction is
ongoing in our laboratory.
(5) Catalytic intermolecular three-component oxyarylation of allenes
is limited to palladium-mediated reactions: (a) Husinec, S.; Petkovic,
M.; Savic, V.; Simic, M. Synthesis 2012, 399−408. (b) Husinec, S.;
Jadranin, M.; Markovic, R.; Petkovic, M.; Savic, V.; Todorovic, N.
Tetrahedron Lett. 2010, 51, 4066−4068. Highly regio- and
stereoselective oxyarylation of ferrocenylallenes was reported.
(c) Chen, S.; Gao, Z.; Zhao, H.; Li, B. J. Org. Chem. 2014, 79,
1481−1486.
(6) (a) Kawai, J.; Chikkade, P. K.; Shimizu, Y.; Kanai, M. Angew.
Chem., Int. Ed. 2013, 52, 7177−7180. (b) Chikkade, P. K.; Shimizu, Y.;
Kanai, M. Chem. Sci. 2014, 5, 1585−1590.
(7) For selected reports on in situ catalytic generation of nucleophilic
allylmetal species from allenes, see: (a) Han, S. B.; Kim, I. S.; Han, H.;
Krische, M. J. J. Am. Chem. Soc. 2009, 131, 6916−6917. (b) Hopkins,
C. D.; Malinakova, H. C. Org. Lett. 2004, 6, 2221−2224. (c) Meng, F.;
Jang, H.; Jung, B.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2013, 52,
5046−5051. (d) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2010,
49, 8181−8184.
(8) Although the chiral ligand was used for the oxyarylation of
allenes, no enantio-induction was observed (6 derived from 3aa).
(9) When 5-phenyl-1,2-pentadiene was used as a substrate, the yield
was less than 6% and regioselectivity was 1.4:1.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: y-shimizu@mol.f.u-tokyo.ac.jp.
*E-mail: kanai@mol.f.u-ac.tokyo.ac.jp.
(10) Boger, D. L.; Garbaccio, R. M.; Jin, Q. J. Org. Chem. 1997, 62,
Notes
8875−8891.
(11) Inokuchi, T.; Kawafuchi, H. Tetrahedron Lett. 2004, 60, 11969−
11975.
The authors declare no competing financial interest.
(12) Two-electron mechanism for the cyclopropane ring-opening
step cannot be completely excluded.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research (B) (M.K.) and Grant-in-Aid for Young Scientists
(B) from JSPS (Y.S.).
(13) If aryl radical species were involved, cyclization to
dihydrobenzofuran 9 should have been faster than intermolecular
addition to allenes. See: Lockner, J. W.; Dixon, D. D.; Risgaard, R.;
Baran, P. S. Org. Lett. 2011, 13, 5628−5631.
(14) Paderes, M. C.; Belding, L.; Fanovic, B.; Dudding, T.; Keister, J.
B.; Chemler, S. R. Chem.Eur. J. 2012, 18, 1711−1726.
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