A reaction for sp3-sp3 C-C bond formation via cooperation of Lewis acid-promoted/Rh-catalyzed C-H bond activation

Article abstract of DOI:10.1021/ja0528331

A new method for intermolecular sp³-sp³ C-C bond formation between primary aliphatic alcohol and olefin by use of a RhCl(PPh₃)₃ (cat.)/BF₃·OEt₂ (2.5 equiv)/BuBr (0.5 equiv)/toluene system was first disclosed, which possessed quite significant utilities for organic synthesis, especially for that of secondary alcohols. The most significant aspect is the discovery that rhodium-catalyzed C-H bond activation of alcohols is feasible under Lewis acid-promoted conditions. Copyright

Full text of DOI:10.1021/ja0528331

Published on Web 07/16/2005
A Reaction for sp3-sp3 C-C Bond Formation via Cooperation of Lewis
Acid-Promoted/Rh-Catalyzed C-H Bond Activation
Lei Shi, Yong-Qiang Tu,* Min Wang, Fu-Min Zhang, Chun-An Fan, Yu-Ming Zhao, and Wu-Jiong Xia
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou UniVersity,
Lanzhou 730000, P. R. China
Received May 1, 2005; E-mail: tuyq@lzu.edu.cn
Table 1. Coupling of Alcohols with Olefinsa
The sp3-sp3 C-C bond formation has been one of the most
significant but challenging basic subjects in organic chemistry. The
effects toward the direct and selective formation of the sp3-sp3
C-C bond via C-H bond activation have long been intriguing
organic chemists. Since the landmark report of the ruthenium-
catalyzed hydroarylation of alkenes by Murai and co-workers,1 some
good pioneering progresses have been achieved in this area.2 As a
continued research in our group on C-C bond formation via C-H
bond activation,3 recently we interestingly found that the combina-
tion of BF3‚OEt2 with Wilkinson catalyst RhCl(PPh3)3 could
promote effectively a new cross-coupling reaction between the
primary aliphatic alcohol and the olefin, which could be developed
to a new method for the synthesis of secondary alcohol. To the
best of our knowledge, this kind of intermolecular reaction of
primary aliphatic alcohols with olefins via Rh-catalyzed/Lewis acid-
assisted C-H bond activation has not been reported.4 The most
significant aspect of our work is the discovery that rhodium-
catalyzed C-H bond activation of alcohols is feasible under Lewis
acid-promoted conditions.
We commenced our studies in the experimental procedure: a
mixture of styrene (1 equiv), ethanol (10 equiv), and RhCl(PPh3)3
(0.02 equiv) in freshly distilled solvent was stirred for 5 h at 55 °C
under argon atmosphere. Subsequently, Lewis acid was added to
the above reaction system, and the resulting mixture was further
stirred for 24 h efficiently. Following this general procedure, various
Lewis acids (TiCl4, Ti(Oi-Pr)4, CuCl2, BF3‚OEt2, BF3‚N(n-Bu)3,
BEt3, and B(Oi-Pr)3) and solvents (benzene, toluene, n-hexane, CH3-
CN, DME, DMF, and DMSO) were examined (Scheme 1). As a
result, the expected 4-phenylbutan-2-ol product could be obtained
by use of styrene, ethanol, Wilkinson catalyst (RhCl(PPh3)3), and
BF3‚OEt2 in the mole ratios of 1:10:0.02:2.5 in toluene, although
the yield was merely 27%. Importantly, it should be noticed that
this reaction did not work in the absence of Lewis acid BF3‚OEt2.
Through further GC-MS analyses, the major byproducts in this
reaction proved to mainly come from the Friedel-Crafts reaction
between styrene and toluene5 and, minorly, from the dimerization
of styrene.6 No ether product7 resulting from the ethanol O-H
addition with the olefin double bond was isolated. To optimize this
reaction, BuBr (0.5 equiv) as an additive was chosen to suppress
the undesired Friedel-Crafts reaction of olefin with toluene, and
pleasingly, the good yield of 70% was afforded.
yield
entry
olefin (R1, R2)
alcohol (R3, R4)
product (%)b
1
2
3
4
5
6
7
8
9
R1 ) Ph, R2 ) H
R3 ) CH3, R4 ) H
R3 ) n-Pr, R4 ) H
R3 ) i-Pr, R4 ) H
R3 ) n-C13H27, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
1a 70
1b 70
1c 68
1d 74
1e 65
78
1g 63
c
1h 57
c
71
73
1k 66
64
d
1m 64
1n 31e
c
R1 ) Ph, R2 ) H
R1 ) Ph, R2 ) H
R1 ) Ph, R2 ) H
R1 ) 2-MeC6H4, R2 ) H
R1 ) 3-MeC6H4, R2 ) H
R1 ) 4-MeC6H4, R2 ) H
R1 ) 2-OMeC6H4, R2 ) H
R1 ) 3-OMeC6H4, R2 ) H
1f
10 R1 ) 4-OMeC6H4, R2 ) H
11 R1 ) 4-(CH2Cl)C6H4, R2 ) H R3 ) CH3, R4 ) H
1i
1j
12 R1 ) 1-naphthyl, R2 ) H
13 R1 ) 2-ClC6H4, R2 ) H
14 R1 ) 2-BrC6H4, R2 ) H
15 R1 ) 2-NO2C6H4, R2 ) H
16 R1 ) Ph, R2 ) Ph
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) CH3, R4 ) H
R3 ) n-C7H15, R4 ) H
R3 ) CH3, R4 ) CH3
1l
17 R1 ) CH3, R2 ) CH3
18 R1 ) Ph, R2 ) H
a For detailed experimental operation, see Supporting Information.
b Isolated yields of expected products. c Complicated products, and no
expected products were isolated. d No reaction. e With 1 equiv of alcohol,
20 equiv of olefin, room temperature.
Scheme 1. Optimization Studies
those with the electron-withdrawing group (entries 13 and 14)
reacted very slowly and usually a longer reaction time (>2 days)
was required. The coupling reaction for 2-nitrostyrene (entry 15)
bearing the strong electron-withdrawing group could not even occur
under the present condition. Furthermore, aromatic olefins bearing
the ortho- or para-substituent reacted more quickly than those
bearing the meta-substituted group (entries 5-10); consequently,
the 2 (or 4)-methoxy styrene reacted too rapidly to isolate the
expected products. It is particularly notable that the disubstituted
aromatic olefin (entry 16) gave the desired products in good isolated
yield (64%). To expand the scope of substrates, we further examined
the disubstituted aliphatic olefin (entry 17) and obtained the
expected product, although the yield was merely 31%. However,
the monosubstituted aliphatic olefin (n-hexene) was ineffective
under this reaction condition, which maybe supported a possible
Following the above optimized condition, some other alcohols
and olefins, as depicted in Table 1, were further investigated, from
which it could be seen that the coupling of a series of the primary
aliphatic alcohols (entries 1-4) and various olefins (entries 5-7,
9, 11-14, 16, and 17) could proceed smoothly to afford the
corresponding secondary alcohol products in good yields. In
addition, the electronic effect of the substituents of aromatic olefins
was also observed. For example, the substrates with an electron-
rich group on the aromatic ring (entries 5-12) reacted rapidly, while
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C O M M U N I C A T I O N S
sch radical reaction10d-h to afford the secondary alcohol product
by releasing the Rh(I) catalysts for the next cycle.
Scheme 2. Deuterium Crossover Experiment
In summary, we have first successfully developed a new Rh-
catalyzed/Lewis acid-promoted C-C bond formation with olefins
via sp3 C-H activation of aliphatic alcohols, which can be simply
performed in good yields without the need to sacrifice any extra
functional groups. The more detailed and widespread investigation
of this new reaction is underway.
Scheme 3. Plausible Reaction Mechanism
Acknowledgment. We are grateful for the financial support of
the NSFC (Nos. 30271488, 20021001, and 203900501) and the
Chang Jiang Scholars Program.
Supporting Information Available: Experimental procedures,
spectroscopic and analytical data, and copies of NMR spectra of the
products. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529-531.
(2) For C-H bond activation reviews, see: (a) Naota, T.; Takaya, H.;
Murahashi, S. I. Chem. ReV. 1998, 98, 2599-2660. (b) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698-1712. (c) Ritleng, V.; Sirlin, C.; Pfeffer,
M. Chem. ReV. 2002, 102, 1731-1770. (d) Labinger, J. A.; Bercaw, J. E.
Nature 2002, 417, 507-514. For representative examples of sp3-sp3 C-C
bond formation via C-H bond activation, see: (e) Jun, C.-H.; Hwang,
D.-C.; Na, S.-J. Chem. Commun. 1998, 1405-1406. (f) Davies, H. M.
L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063-
3070. (g) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.;
Murai, S. J. Am. Chem. Soc. 2001, 123, 10935-10941. (h) Yao, X.-Q.;
Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884-6885.
radical mechanism because the third alkyl radical was more stable
than the secondary alkyl radical.
To propose a possible reaction mechanism, we conducted some
more supporting experiments. For example, RhCl3/BF3‚OEt2/toluene
was tested and could be effective to this coupling reaction, which
showed the formation of Rh(III) intermediates. Addition of PPh3
(0.05 equiv) could prevent the reaction, indicating that the presence
of PPh3 could prohibit the ligand dissociation and exchange. The
crossover experiment was performed using styrene and a 1:1
mixture of deuterated and undeuterated alcohols (Scheme 2). The
resulting mixtures were isolated and analyzed by mass spectrometry
to determine the isotopic distribution. This experiment result
indicated that a possible radical reaction mechanism was involved,
which would lead to a statistical distribution of the labels in the
products.8 Furthermore, formation of the expected adducts could
be inhibited completely by the addition of radical scavenger (1,4-
benzoquinone, TEMPO, and FeCl3) in the system of ethanol with
styrene (in the same experimental procedure as entry 1 in Table
1), which further confirmed the presence of a radical reaction
mechanism. Besides, 4-phenylbutan-2-one could not have been
observed in the cross-coupling of ethanol and styrene (entry 1, Table
1), and when acetaldehyde was used in place of the primary alcohol
substrate, the corresponding coupling reaction with styrene could
not proceed under the same condition. These experimental facts
mentioned above indicated that the reaction could not undergo the
reaction mechanism as reported:9 first hydrogen transfer from
alcohol to form aldehyde, and subsequent radical hydroacylation,
followed by hydrogenation of ketone, to give the corresponding
product.
(3) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A. Org. Lett. 2004,
6, 1001-1003.
(4) For photoinitiated additions and the reactions initiated by di-tert-butyl
peroxide of alcohols to aliphatic olefins, see: (a) Walling, C.; Huyser, E.
S. Org. React. 1963, 13, 91-149. (b) Stacey, F. W.; Harris, J. F. Org.
React. 1963, 13, 150-376. (c) Curran, D. P. Synthesis 1988, 489-513.
(d) Urry, W. H.; Stacey, F. W.; Huyser, E. S.; Juveland, O. O. J. Am.
Chem. Soc. 1954, 76, 450-455. (e) LaZerte, J. D.; Koshar, R. J. J. Am.
Chem. Soc. 1955, 77, 910-914.
(5) Pearson, D. E.; Buthler, C. A. Synthesis 1972, 533-542.
(6) (a) Tsuchimoto, T.; Kamiyama, S.; Negoro, R.; Shirakawa, E.; Kawakami,
Y. Chem. Commun. 2003, 852-853. (b) Peppe, C.; Lang, E. S.; de
Andrade, F. M.; de Castro, L. B. Synlett 2004, 1723-1726.
(7) (a) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620-1621.
(b) Qian, H.; Han, X.-Q.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536-9537. (c) Oe, Y.; Ohta, T.; Ito, Y. Synlett 2005, 179-181.
(8) For the similar crossover experiments’ description, see: (a) Bergman, R.
G. Acc. Chem. Res. 1980, 13, 113-120. (b) Janowicz, A. H.; Bergman,
R. G. J. Am. Chem. Soc. 1983, 105, 3929-3939.
(9) For the reaction mechanism, see: (a) Cho, C. S.; Kim, B. T.; Kim, T.-J.;
Shim, S. C. J. Org. Chem. 2001, 66, 9020-9022. (b) Lee, D.-Y.; Moon,
C. W.; Jun, C.-H. J. Org. Chem. 2002, 67, 3945-3948. (c) Taguchi, K.;
Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. J. Am. Chem.
Soc. 2004, 126, 72-73. (d) Chang, D.-H.; Lee, D.-Y.; Hong, B.-S.; Choi,
J.-H.; Jun, C.-H. J. Am. Chem. Soc. 2004, 126, 424-425.
(10) (a) Halpern, J.; Wong, C. S. J. Chem. Soc., Chem. Commun. 1973, 629-
630. (b) Green, M. L. H.; O’Hare, D. Pure Appl. Chem. 1985, 57, 1897-
1910. (c) Hill, C. L. Synlett 1995, 127-132. For the Kharasch addition
reaction mechanism, see: (d) Kharasch, M. S.; Jensen, E. V.; Urry, W.
H. Science 1945, 102, 128-129. (e) Murai, S.; Sugise, R.; Sonada, N.
Angew. Chem., Int. Ed. Engl. 1981, 20, 475-476. (f) Bland, W. J.; Davis,
R.; Durrant, J. L. A. J. Organomet. Chem. 1985, 280, 397-406. (g) Cable,
C. J.; Adams, H.; Bailey, N. A.; Crosby, J.; White, C. J. Chem. Soc.,
Chem. Commun. 1991, 165-166. (h) Pereira, S.; Srebnik, M. J. Am. Chem.
Soc. 1996, 118, 909-910. For palladium-catalyzed activation/oxidation
of alcohols, see: (i) Mueller, J. A.; Goller, C. P.; Sigman, M. S. J. Am.
Chem. Soc. 2004, 126, 9724-9734. (j) Stoltz, B. M. Chem. Lett. 2004,
33, 362-367. (k) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem.
Soc. 2004, 126, 11268-11278.
On the basis of the above experimental results and the previously
reported literature,10 a tentative mechanism was thus proposed, as
shown in Scheme 3, which involved the Lewis acid-promoted11
direct C-H bond activation of alcohol by a Rh(I) species. The
reaction first proceeded by coordination of Lewis acid with an
oxygen atom, and then the oxidation addition of the C-H bond to
RhCl(PPh3)3, followed by olefin coordination, to give the Rh(III)
complexes A.12 The formed Rh(III) complexes A then generated a
coordinated radical pair B, which underwent the analogical Khara-
(11) For Lewis acid in free radical reactions, see: Renaud, P.; Gerster, M.
Angew. Chem., Int. Ed. 1998, 37, 2562-2579.
(12) (a) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem.sEur. J. 2002, 8, 2422-
2428. (b) Williams, N. A.; Uchimaru, Y.; Tanaka, M. J. Chem. Soc., Chem.
Commun. 1995, 1129-1130.
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