Metal-free, n-Bu4NI-catalyzed regioselective difunctionalization of unactivated alkenes

Article abstract of DOI:10.1021/cs400250m

A new synthetic approach toward difunctionalization of alkenes has been developed under metal-free conditions. Various carboxylic acids and amines could react smoothly with alkenes to give dioxygenation and oxyamidation products, respectively. This organocatalytic process delivers 2-hydroxy alcohols directly from simple alkenes with high levels of region control.

Full text of DOI:10.1021/cs400250m

Letter
pubs.acs.org/acscatalysis
Metal-Free, n‑Bu4NI-Catalyzed Regioselective Difunctionalization of
Unactivated Alkenes
Qicai Xue,† Jin Xie,† Pan Xu,† Kaidong Hu,† Yixiang Cheng,† and Chengjian Zhu*,†,‡
†State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, People’s Republic of China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, People’s Republic of
China
S
* Supporting Information
ABSTRACT: A new synthetic approach toward difunctionalization of alkenes
has been developed under metal-free conditions. Various carboxylic acids and
amines could react smoothly with alkenes to give dioxygenation and
oxyamidation products, respectively. This organocatalytic process delivers 2-
hydroxy alcohols directly from simple alkenes with high levels of region control.
KEYWORDS: alkene, dioxygenation, oxyamidation, metal-free, regioselective
Scheme 1. Difunctionalization of Alkenes
INTRODUCTION
■
Direct difunctionalization of alkenes has attracted considerable
attention, providing the most attractive strategy for the
assembly of functionalized organic compounds. In recent
years, a number of transition-metal-catalyzed difunctionaliza-
tions of alkenes have been reported, such as dioxygenation,1
oxyamidation,2 oxyphosphorylation,3 and diamination.4 How-
ever, the cost, toxicity and environmental impact of these
catalysts have hindered its further application. In this context,
the development of a metal-free difunctionalization procedure
provides a challenging and highly attractive target. Despite
some remarkable progress that has been made, this area is
considerably less established than their metal-based counter-
parts,5−7 and regioselective difunctionalization of alkenes is still
a challenge. Recently, the catalytic system “n-Bu4NI−TBHP”
has been a focus of interest because of high efficiency, lower
toxicity, and environmental friendliness,8 and some excellent
results about C−O9 and C−N10 bond formations have been
achieved. Herein, we report a protocol for an n-Bu4NI-catalyzed
regioselective difunctionalization of alkenes using TBHP as an
oxidant (Scheme 1).
was rapidly consumed when K2S2O4 was used as an oxidant;
only a trace amount of product 3a was detected (Table 1, entry
5). Other oxidants such as O2, H2O2, and DTBP gave
unsatisfactory results (Table 1, entries 6−8). To maximize
the yields, different solvents were also tested. The results
showed that n-hexane is a highly effective solvent, affording the
product 3a with the highest isolated yield (Table 1, entry 12).
In addition, control experiments demonstrated that no 3a could
be identified when either n-Bu4NI or TBHP was absent (Table
1, entries 13 and 14).
With the optimized reaction conditions established (Table 1,
entry 12), the scope of our protocol was investigated (Table 2).
First, a variety of alkenes were tested. Under the optimized
conditions, α-methylstyrene and 1,1-diphenylethylene were
converted to dioxygenation products in good isolated yields
(Table 2, 3a and 3b). Styrene substrates bearing electron-
withdrawing groups were converted into the corresponding
products with higher yields than electron-donating groups
RESULTS AND DISCUSSION
■
Initially, the reaction of α-methylstyrene 1a with 4-
chlorobenzoic acid 2a was selected as a model reaction. The
dioxygenation product 3a could be formed under the catalysis
of n-Bu4NI (Table 1, entry 1). Encouraged by this result, we
investigated the reaction conditions in detail, and the results are
summarized in Table 1. Among the catalysts screened, n-Bu4NI
showed the best catalytic efficiency (Table 1, entry 1). The use
of n-Bu4NBr, KI, or I2 instead of n-Bu4NI decreased the yields
dramatically (Table 1, entries 2−4). Subsequently, various
oxidants were evaluated in this process. The starting material 1a
Received: April 1, 2013
Revised: May 16, 2013
© XXXX American Chemical Society
1365
dx.doi.org/10.1021/cs400250m | ACS Catal. 2013, 3, 1365−1368

ACS Catalysis
Letter
a
Table 1. Optimization of Reaction for the Alkene
Dioxygenation
Table 2. The n-Bu4NI-Catalyzed Dioxygenation of Alkenes
a
b
entry
catalyst
oxidant
solvent
yield (%)
c
1
2
n-Bu4NI
n-Bu4NBr
KI
TBHP
75
TBHP
TBHP
TBHP
K2S2O8
trace
12
3
4
I2
23
5
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
n-Bu4NI
trace
d
e
6
O2
N.D.
c
7
H2O2
N.D.
trace
55
c
8
DTBP
9
TBHP
TBHP
TBHP
TBHP
TBHP
benzene
c
10
11
12
13
14
15
DCE
73
c
EA
78
n-hexane
n-hexane
n-hexane
n-hexane
85
trace
trace
85
n-Bu4NI
n-Bu4NI
f
TBHP
a
Reaction conditions: 1a (0.6 mmol), 2a (0.3 mmol), catalyst (10 mol
b
c
%), oxidant (0.9 mmol), 120 °C, 12 h. Isolated yield. TBHP, tert-
butyl hydroperoxide 70% in water; H2O2 30% in water; DTBP, di-tert-
butyl peroxide; DCE, 1,2-dichloroethane; EA, ethyl acetate. Under an
oxygen atmosphere (1.0 atm). Not detected. TBHP 5.5 M in decane.
d
e
f
(Table 2, 3c−f). 1,2-Dihydronaphthalene and 1H-indene were
still very effective in our catalytic system and can give good
results (Table 2, 3g and 3h). When styrene was replaced by
tetraphenylethylene, allylbenzene, or cyclohexene, no difunc-
tionalization product was detected. Subsequently, different
aromatic acids were examined in this n-Bu4NI-catalyzed
reaction. In general, both electron-deficient and electron-rich
aromatic acids were suitable for this protocol, and the
corresponding dioxygenation products were obtained in good
to excellent yields (Table 2, 3i−n). To our delight, it was found
that cinnamic acid derivatives were still very effective in our
catalytic system and can give good results (Table 2, 3p−r).
When crotonic acid or aliphatic acid was employed, the reaction
could proceed smoothly, leading to the desired product with
high yield (Table 2, 3s and 3t).
The success of dioxygenation of alkenes encouraged us to
further explore the scope of this protocol. Interestingly, we
found that the reaction of styrene with benzotriazole 4a at 100
°C for 12 h proceeded smoothly to afford the oxyamidation
product 5a with high efficiency (optimization of reaction
conditions; see the Supporting Information). Encouraged by
this result, the scope of oxyamidation of alkenes was
investigated. As shown in Table 3, a variety of alkenes were
tolerated in this process, affording the desired products in good
yields (Table 3, 5a−f). Notably, electron-withdrawing as well as
electron-donating groups on the aromatic rings were
compatible in the oxyamidation of alkenes. Furthermore,
different benzotriazoles could react with alkenes in the presence
of n-Bu4NI to give the desired products in 89−91% yields
(Table 3, 5f and 5g). Moreover, indazole, benzimidazole and
imidazole were also tolerated in this protocol, furnishing the
desired products in good yields (Table 3, 5h−j).
a
Reaction conditions: 1 (0.6 mmol), 2 (0.3 mmol), n-Bu4NI (10 mol
%), TBHP 70% in water (0.9 mmol), n-hexane (1.0 mL), 120 °C, 12 h.
Yields are for the isolated products.
of α-methylstyrene 1a and sodium p-chlorobenzoate 6 did not
result in the formation of 3a (Scheme 2a). Interestingly, styrene
oxide was rapidly consumed in this process; only a trace
amount of 3a was detected (Scheme 2b). The above results
indicate that the carboxylate anion and epoxy compound were
To probe the mechanism of alkene dioxygenation, several
control experiments were conducted (Scheme 2). The reaction
1366
dx.doi.org/10.1021/cs400250m | ACS Catal. 2013, 3, 1365−1368

ACS Catalysis
Letter
a
Table 3. n-Bu4NI-Catalyzed Oxyamidation of Alkenes
Scheme 3. Proposed Reaction Mechanism for n-Bu4NI-
Catalyzed Dioxygenation of Alkenes
radicals abstract hydrogen atoms from the acid, 2, to afford
radical A,9a,11 then it reacts with 1 to form intermdiate B.
Oxidation of radical B forms the benzyl cation C.12 Finally, the
benzyl cation C reacts with water to form the desired product 3
(for the study of HRMS on the mechanism, see the Supporting
Information). However, to disclose the exact mechanics of this
transformation, further studies are needed.
a
Reaction conditions: 1 (0.6 mmol), 4 (0.3 mmol), n-Bu4NI (10 mol
%), TBHP 70% in water (0.9 mmol), 100 °C, 12 h. Yields are for the
isolated products.
Scheme 2. Investigation into the Reaction Mechanism
CONCLUSIONS
■
In summary, we have successfully developed a novel n-Bu4NI-
catalyzed operationally simple method for difunctionalization of
alkenes. Various dioxygenation and oxyamidation products
were obtained in good to excellent yields using TBHP (70% in
water) as an inexpensive and environmentally friendly oxidant.
This metal-free process makes use of simple, inexpensive
starting materials and demonstrates excellent regioselectivity in
all cases. Further studies concerning the detailed mechanism
are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectroscopic characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: cjzhu@nju.edu.cn.
■
not involved in this dioxygenation process. Furthermore, 3-
chloroperoxybenzoic acid, a known acyloxy radical donor, was
also tolerated in this protocol (Scheme 2c).9a Adding a radical
inhibitor BHT (2,6-di-tert-butyl-4-methylphenol) to the re-
action system, the formation of the dioxygenation product was
completely suppressed (Scheme 2d).
On the basis of the above results, a plausible mechanism for
n-Bu4NI-catalyzed dioxygenation of alkenes is proposed in
Scheme 3. Initially, n-Bu4NI reacts with TBHP to give the tert-
butoxyl and tert-butylperoxy radicals. Subsequently, these
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21172106, 21074054), the National
Basic Research Program of China (2010CB923303), and the
Research Fund for the Doctoral Program of Higher Education
1367
dx.doi.org/10.1021/cs400250m | ACS Catal. 2013, 3, 1365−1368

ACS Catalysis
Letter
of China (20120091110010) for their financial support. J. Xie
thanks the academic scholarship for doctoral candidates of
MOE.
REFERENCES
■
(1) For select reviews, see: (a) Bataille, C. J. R.; Donohoe, T. J. Chem.
Soc. Rev. 2011, 40, 114. (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483. For selected
dioxygenation, see: (c) Wang, W.; Wang, F.; Shi, M. Organometallics
2010, 29, 928. (d) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc.
2009, 131, 3846. (e) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc.
2008, 130, 2962. (f) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007,
129, 3076.
(2) For selected oxyamidation, see: (a) de Haro, T.; Nevado, C.
Angew. Chem., Int. Ed. 2011, 50, 906. (b) Mancheno, D. E.; Thornton,
A. R.; Stoll, A. H.; Kong, A.; Blakey, S. B. Org. Lett. 2010, 12, 4110.
(c) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am. Chem. Soc. 2007,
129, 1866. (d) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem.
Soc. 2005, 127, 7690.
(3) Wei, W.; Ji, J. Angew. Chem., Int. Ed. 2011, 50, 9097.
́
(4) For selected diamination, see: (a) Iglesias, A.; Per
́
ez, E. G.;
Muniz, K. Angew. Chem., Int. Ed. 2010, 49, 8109. (b) Sequeira, F. C.;
̃
Turnpenny, B. W.; Chemler, S. R. Angew. Chem., Int. Ed. 2010, 49,
6365. (c) Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132,
3523. (d) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590.
(5) Hydroxamic acid as reactant: (a) Schmidt, V. A.; Alexanian, E. J.
Chem. Sci. 2012, 3, 1672. (b) Schmidt, V. A.; Alexanian, E. J. J. Am.
Chem. Soc. 2011, 133, 11402. (c) Giglio, B. C.; Schmidt, V. A.;
Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 13320. (c1) Schmidt, V.
A.; Alexanian, E. J. Angew. Chem., Int. Ed. 2010, 49, 4491.
(6) Peroxide-mediated reactions: (a) Jones, K. M.; Tomkinson, N. C.
O. J. Org. Chem. 2012, 77, 921. (b) Kang, Y.; Gade, L. H. J. Org. Chem.
2012, 77, 1610. (c) Picon, S.; Rawling, M.; Campbell, M.; Tomkinson,
N. C. O. Org. Lett. 2012, 14, 6250. (d) Griffith, J. C.; Jones, K. M.;
Picon, S.; Rawling, M. J.; Kariuki, B. M. J. Am. Chem. Soc. 2010, 132,
14409. (e) Rawling, M. J.; Tomkinson, N. C. O. Org. Biomol. Chem.
2013, 11, 1434.
(7) PhI(OAc)2 as reactant: (a) Liu, Q.; Zhao, Q. Y.; Liu, J.; Wu, P.;
Yi, H.; Lei, A. Chem. Commun. 2012, 48, 3239. (b) Fujita, M.; Wakita,
M.; Sugimura, T. Chem. Commun. 2011, 47, 3983. (c) Kang, Y.; Gade,
L. H. J. Am. Chem. Soc. 2011, 133, 3658. (d) Zhong, W.; Yang, J.;
Meng, X.; Li, Z. J. Org. Chem. 2011, 76, 9997. (e) Roben, C.; Souto, J.
̈
A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz, K. Angew. Chem., Int. Ed.
́
̃
2011, 50, 9478. (f) Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org.
Lett. 2005, 7, 5071. (g) Santoro, S.; Santi, C.; Sabatini, M.; Testaferri,
L.; Tiecco, M. Adv. Synth. Catal. 2008, 350, 2881.
(8) Uyanik, M.; Ishihara, K. ChemCatChem 2012, 4, 177.
(9) For selected examples, see: (a) Shi, E.; Chen, S.; Chen, S.; Hu,
H.; Chen, S.; Zhang, J.; Wan, X. Org. Lett. 2012, 14, 3384. (b) Feng, J.;
Liang, S.; Chen, S.; Zhang, J.; Fu, S.; Yu, X. Adv. Synth. Catal. 2012,
354, 1287. (c) Huang, J.; Li, L.; Li, H.; Husan, E.; Wang, P.; Wang, B.
Chem. Commun. 2012, 48, 10204. (d) Uyanik, M.; Suzuki, D.; Yasui,
T.; Ishihara, K. Angew. Chem., Int. Ed. 2011, 50, 5331. (e) Chen, L.;
Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem.Eur.
J. 2011, 17, 4085. (f) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K.
Science 2010, 328, 1376.
(10) For selected examples, see: (a) Xue, Q.; Xie, J.; Li, H.; Cheng,
Y.; Zhu, C. Chem. Commun. 2013, 49, 3700. (b) Liu, Z.; Zhang, J.;
Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem., Int. Ed. 2012, 51,
3231. (c) Mai, W.; Wang, H.; Li, Z.; Yuan, J.; Xiao, Y.; Yang, L.; Mao,
P.; Qu, L. Chem. Commun. 2012, 48, 10117. (d) Xie, J.; Jiang, H.;
Cheng, Y.; Zhu, C. Chem. Commun. 2012, 48, 979. (e) Froehr, T.;
Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. Org.
Lett. 2011, 13, 3754. (f) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem.
Commun. 2011, 47, 11333.
(11) Silbert, L. S. J. Am. Oil Chem. Soc. 1969, 46, 615.
(12) (a) Li, Y.; Li, B.; Lu, X.; Lin, S.; Shi, Z. Angew. Chem., Int. Ed.
2009, 48, 3817. (b) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073.
1368
dx.doi.org/10.1021/cs400250m | ACS Catal. 2013, 3, 1365−1368