An efficient metal-catalyzed hydroalkylation

Article abstract of DOI:10.1055/s-2007-980363

An efficient metal-catalyzed hydroalkylation of various styrenes, norbornene, and cyclohexadiene with 1,3-dicarbonyl compounds has been developed. This new bismuth-catalyzed C-H functionalization provides the corresponding alkylated pentanediones in good to excellent isolated yields after short reaction times. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980363

LETTER
1391
An Efficient Metal-Catalyzed Hydroalkylation
E
M
fficient
M
etal-Cataly
a
zed Hydroa
g
lkylation nus Rueping,* Boris J. Nachtsheim, Alexander Kuenkel
Degussa Endowed Professorship, Institute of Organic Chemistry and Chemical Biology, Johann-Wolfgang Goethe University
Frankfurt am Main, Max-von-Laue Straße 7, 60438 Frankfurt, Germany
Fax +49(69)79829248; E-mail: M.Rueping@chemie.uni-frankfurt.de
Received 28 February 2007
prepared by use of stoichiometric amounts of base and
alkylhalides or activated alcohol derivatives leading to
large amounts of salt byproducts. More recently, however,
Abstract: An efficient metal-catalyzed hydroalkylation of various
styrenes, norbornene, and cyclohexadiene with 1,3-dicarbonyl
compounds has been developed. This new bismuth-catalyzed C–H
functionalization provides the corresponding alkylated pentanedi- the first intra- and intermolecular addition of 1,3-dicarbo-
ones in good to excellent isolated yields after short reaction times.
nyl compounds to styrenes have been reported using
5
6
palladium, silver, and gold catalysts or heterogeneous
Key words: hydroalkylation, hydroarylation, benzylation, bis-
muth, C–H activation, catalysis, styrene, alkene
Brønsted acids.7
O
O
Hydroalkylation and hydroarylation reactions are of great
general interest in organic chemistry. These transforma-
tions are highly atom-economic and hence represent valu-
able examples of green and sustainable chemistry. In view
of the demand for efficient, economic and environmental-
ly benign processes, the development of direct catalytic
carbon–carbon bond-forming reactions of prior unmodi-
R1
R2
O
O
Bi(OTf)3
+
R1
R2
R3
R3
Scheme 2 Bismuth(III)-catalyzed hydroalkylation of styrenes
fied substrates is an important task. Consequently, consid- Attracted by the direct hydroalkylation of styrenes and
erable progress has been made in the development of therewith the prevention of electrophile preformation and
promising metal-catalyzed C–H functionalizations, in- knowing that bismuth salts are highly reactive catalysts,
cluding the addition of olefins to acetophenones and aro- we started our investigations with the direct addition of
matic imines or the inter- and intramolecular arylation of 2,4-pentanedione (2a) to styrene (1a), as shown in
1
alkynes and alkenes, benzyl acetates and alcohols. In this Table 1. From these experiments we found that the reac-
context we were recently able to successfully develop tion could best be performed in nitromethane using
highly efficient bismuth-catalyzed reactions, such as the Bi(OTf) as catalyst (entries 4–6). Other bismuth salts as
3
2
addition of benzyl alcohols to arenes, the direct benzyl- well as trifluoromethanesulfonic acid did not result in the
ation and allylic alkylation of 2,4-pentanediones as well corresponding product (entries 1–3, 7). Reactions in
3
4
as the hydroarylation of styrenes (Scheme 1).
nonpolar solvents such as cyclohexane led to product
R2
R2
(Ar)Het
Table 1 Evaluation of Different Bismuth Salts in the Hydro-
alkylation of Styrene with 2,4-Pentanedione
10
0.5 mol% Bi(OTf)3
+
Het(Ar)
R1
R1
O
O
catalyst
O
+
Scheme 1 Bismuth-catalyzed hydroarylation of styrenes
O
1a
2a
3a
Generally, these transformations can conveniently be
performed in short reaction times, under mild reaction
conditions with low catalyst loadings. Thus, 0.5 mol% of
Entry Catalyst
mol (%)
Time (h) Yield (%)a
1
2
3
4
5
6
BiCl
5
5
8
8
8
2
2
2
8
0
0
3
Bi(OTf) is sufficient to catalyze the hydroarylation of
3
BiBr3
4
various styrenes.
Bi(NO ) (H O)
5
0
3
3
2
5
Herein, we report an extension of this procedure to the
inter- and intramolecular hydroalkylation of styrenes
Bi(OTf) (H O)
4
1
67
76
81
0
3
2
(
Scheme 2) using 1,3-dicarbonyl compounds as the
Bi(OTf) (H O)
2
nucleophile. Typically, the products obtained have been
3
2
4
4
Bi(OTf) (H O)
5
3
2
SYNLETT 2007, No. 9, pp 1391–1394
0
1.
0
6.
2
0
0
7
7
TfOH
15
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980363; Art ID: G04507ST
a
Isolated yield after flash chromatography.
©
Georg Thieme Verlag Stuttgart · New York

1
392
M. Rueping et al.
LETTER
8
formation, but with the generation of a byproduct. In styrene derivatives electron-donating, as well as electron-
chlorinated solvents including dichloromethane and withdrawing substituents (entries 4–8) are tolerated and
chloroform, an immediate decomposition of the styrene even indene resulted in the cyclic 3-substituted dihydro-
was observed, even at room temperature. Decreasing the indene 3i, though only in moderate yield (entry 9). Fur-
catalyst loading resulted in lower yields (entries 4–6). thermore, we were able to extend the scope of this
Thus, by employing 5 mol% of Bi(OTf) in nitromethane, transformation to other substrates, including norbornene
3
the corresponding product 3a could be isolated in 81% (1h) and cyclohexadiene (1i). For instance, bismuth-cata-
isolated yield after chromatography.
lyzed hydroalkylation of 1h with the more reactive diben-
zoylmethane 2c gave the corresponding alkylated
norbornene 3j in 90% yield after 90 minutes (entry 10).
Surprisingly, cyclohexadiene was also successfully trans-
formed to the alkylated cyclohexene 3k, although the re-
action was performed at ambient temperature (entry 11).9
Using these optimized conditions, we explored the scope
of the bismuth-catalyzed hydroalkylation by varying the
styrene as well as the 1,3-carbonyl components (Table 2).
Generally different styrene derivatives 1a–f and 2,4-pen-
tanediones 2a–c can be employed and the corresponding
products 3a–h could be isolated in good yields after short
reaction times (Table 2, entries 1–8). With regard to the
Table 2 Scope of the Intermolecular Hydroalkylation of Different Styrene Derivatives with 2,4-Pentanediones10,11
Entry
Electrophile 1
Pentanedione 2
Cat. (mol%)
Temp (°C)
Time (h)
Product 3
Yield (%)a
O
O
O
O
O
1
5
80
2
81
O
2
2
a
1
a
3
3
3
a
Ph
O
2
3
4
1a
1a
5
5
5
100
50
4.5
88b
Ph
O
b
b
Ph
O
O
O
2
89
Ph
Ph
Ph
O
2
c
c
O
2a
100
5
78
Cl
Cl
O
1
b
3
d
O
5
2a
5
100
20
41
O
Cl
Cl
1
c
3
e
O
6
7
2a
2a
5
5
100
100
4
4
89
71
F
F
O
1
d
3
f
F
O
F
O
1
e
3
g
Synlett 2007, No. 9, 1391–1394 © Thieme Stuttgart · New York

LETTER
Efficient Metal-Catalyzed Hydroalkylation
1393
Table 2 Scope of the Intermolecular Hydroalkylation of Different Styrene Derivatives with 2,4-Pentanediones10,11 (continued)
Entry
8
Electrophile 1
Pentanedione 2
Cat. (mol%)
5
Temp (°C)
100
Time (h)
3
Product 3
Yield (%)a
2a
86
O
1
1
f
O
3
h
9
2a
2c
5
5
90
90
5
O
41c
O
g
3
i
1
1
0
1
1.5
Ph
90
45
O
O
1
1
h
Ph
3
3
j
2c
5
r.t.
4
Ph
O
O
i
Ph
k
a
b
c
Isolated yield after flash chromatography.
Diastereomeric ratio = 1:1
2
,4-Pentanedione (1 mL) was used as solvent.
Following a successful bismuth-catalyzed hydroalkyl- esting alternative to previous methods. Additionally, an
ation of various styrenes, norbornene, and cyclohexa- intramolecular hydroalkylation of b-ketoesters has been
diene, we decided to examine an intramolecular variant of developed resulting in the corresponding substituted
this transformation. Thus, starting from cinnamyl bro- cyclohexanone in excellent yield.
mide and ethyl 3-oxobutanoate, we prepared the sub-
stituted b-ketoester 4 and carried out the intramolecular
Acknowledgment
hydroalkylation reaction. Although b-ketoesters did not
show efficient reactivity in the intermolecular reaction We gratefully acknowledge Degussa AG for financial support and
with styrene derivatives, in the intramolecular case, the
the Fonds der Chemischen Industrie for a stipend to B.J.N.
substituted cyclohexanone 5 could be isolated in 72%
yield after three hours (Scheme 3).
References and Notes
(
1) For reviews, see: (a) Dyker, G. Angew. Chem. Int. Ed. 1999,
8, 1699. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev.
2002, 102, 1731.
O
O
3
O
O
5
mol% Bi(OTf)3
MeNO2
EtO
Ph
OEt
(2) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth.
Catal. 2006, 348, 1033.
(3) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett.
Ph
4
100 °C, 3 h
5
72%
2
007, 9, 825.
4) Rueping, M.; Nachtsheim, B. J.; Scheidt, T. Org. Lett. 2006,
, 3717.
5) (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123,
Scheme 3 Intramolecular hydroalkylation of b-ketoester 4
(
(
8
In summary we have developed an efficient bismuth-cat-
alyzed hydroalkylation of various styrenes, norbornene,
and cyclohexadiene derivatives with different 2,4-pen-
tanediones. The short reaction times, simplicity and prac-
ticability as well as the use of small amounts of reactive,
cheap, non-moisture-sensitive, and nontoxic Bi(OTf)3
catalyst renders this hydroalkylation procedure an inter-
11290. (b) Pei, T.; Widenhoefer, R. A. Chem. Commun.
2002, 650. (c) Wang, X.; Pei, T.; Han, X. Q.; Widenhoefer,
R. A. Org. Lett. 2003, 5, 2699. (d) Widenhoefer, R. A. Pure
Appl. Chem. 2004, 76, 671. (e) Qian, H.; Pei, T.;
Widenhoefer, R. A. Organometallics 2005, 24, 287.
(f) Han, X. Q.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem.
Eur. J. 2004, 10, 6333.
Synlett 2007, No. 9, 1391–1394 © Thieme Stuttgart · New York

1
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M. Rueping et al.
LETTER
(
6) (a) Yao, X. Q.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 6884.
b) Nguyen, R. V.; Yao, X. Q.; Bohle, D. S.; Li, C. J. Org.
Lett. 2005, 7, 673. (c) Yao, X. Q.; Li, C. J. J. Org. Chem.
005, 70, 5752.
198 mg (89%) of the product as a pale yellow oil which
1
(
solidified upon standing. H NMR (250 MHz, CDCl ): d =
3
7.19–7.09 (m, 2 H, ArH), 7.03–6.91 (m, 2 H, ArH), 3.97 (d,
J = 11.3 Hz, 1 H, CH), 3.58 (dq, J = 11.3, 6.9 Hz, 1 H, CH),
2.25 (s, 3 H, CH ), 1.84 (s, 3 H, CH ) 1.18 (d, J = 6.9 Hz, 3
2
(7) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Angew. Chem. Int. Ed. 2006, 45, 2605.
(8) 1,3-Diarylbut-1-enes were observed as the major
byproducts.
(
3
3
1
3
H, CH3). C NMR (63 MHz, CDCl ): d = 203.8, 203.7,
3
162.2 (d, J = 245.4 Hz), 139.4 (d, J = 3.4 Hz), 129.4 (d,
J = 7.9 Hz), 116.24 (d, J = 21.3 Hz), 77.4, 40.2, 30.4, 30.2,
21.5. IR (neat): n = 3441, 3260, 2925, 2845, 1647, 1385,
9) For other metal-catalyzed hydroalkylation procedures of
dienes and 1,3-dicarbonyl compounds, see: (a) Jolly, P. W.;
Kokel, N. Synthesis 1990, 771. (b) Trost, B. M.; Zhi, L.
Tetrahedron Lett. 1992, 33, 1831. (c) Goddard, R.; Hopp,
G.; Jolly, P. W.; Kruger, C.; Mynott, R.; Wirtz, C. J.
Organomet. Chem. 1995, 486, 163. (d) Leitner, A.; Larsen,
J.; Steffens, C.; Hartwig, J. F. J. Org. Chem. 2004, 69, 7552.
–
1
1076, 698, 466 cm . ESI-MS: m/z (%) = 240.0(100) [M +
+
NH ] . Anal. Calcd for C H FO : C, 70.25; H, 6.80. Found:
4
13 15
2
C, 70.53; H, 6.76.
(11) Spectroscopic Data for 3-[1-(2-fluorophenyl)eth-
yl]pentane-2,4-dione (3g)
1
H NMR (250 MHz, CDCl ): d = 7.34–6.95 (m, 4 H, ArH),
3
(
10) Typical Procedure: Preparation of 3-[1-(4-fluoro-
phenyl)ethyl]pentane-2,4-dione (3f)
4.24 (d, J = 11.3 Hz, 1 H, CH), 3.89 (dq, J = 11.3, 6.9 Hz, 1
H, CH), 2.28 (s, 3 H, CH ), 1.94 (s, 3 H, CH ) 1.23 (d, J = 6.9
3
3
1
3
A two-necked round-bottom flask charged with Bi(OTf)3
Hz, 3 H, CH3). C NMR (63 MHz, CDCl ): d = 203.13,
3
(
H O) (0.036 g, 0.05 mmol) and 2,4-pentanedione (400 mg,
202.98, 160.5 (d, J = 245.7 Hz), 129.7 (d, J = 14.0 Hz),
129.2 (d, J = 4.9 Hz), 128.6 (d, J = 8.4 Hz), 124.5 (d, J = 3.5
Hz), 116.0 (d, J = 22.6 Hz), 74.86, 34.6, 30.2, 28.9, 19.48. IR
(neat): n = 3441, 2980, 1699, 1493, 1452, 1360, 1281, 1228,
2
4
4
4
mmol) dissolved in MeNO (3 mL) was heated to 100 °C.
-Fluorostyrene (1 mmol) dissolved in 1 mL of MeNO was
2
2
added dropwise via syringe for 4 h and stirred at this
temperature for 1 h. After cooling the reaction mixture to r.t.
the crude reaction mixture was directly purified by column
chromatography on silica gel (hexane–EtOAc, 10:1) to give
–
1
1246, 761 cm . ESI-MS: m/z (%) = 239.9 (100) [M +
+
+
NH ] , 462.3 (90) [2 M + NH ] . Anal. Calcd for C H FO :
4
4
13 15
2
C, 70.25; H, 6.80. Found: C, 70.51; H, 6.78.
Synlett 2007, No. 9, 1391–1394 © Thieme Stuttgart · New York