Iron-catalyzed cross-coupling reactions between a bicyclic alkenyl triflate and Grignard reagents

Article abstract of DOI:10.1021/jo801384e

(Chemical Equation Presented) Fe-catalyzed cross-coupling reactions between a bicyclic alkenyl triflate and Grignard reagents were investigated. Under the optimized reaction conditions, various 2-substituted bicyclic alkenes were synthesized in moderate to excellent yields (52-93%). This method provided an efficient route for the synthesis of 2-substituted bicyclic alkenes with 2° alkyl groups which cannot be synthesized using previous methods such as Pd-catalyzed coupling reactions and lithium-halide exchange reactions.

Full text of DOI:10.1021/jo801384e

of these reversible systems.6 This photochemical isomerization
reaction has recently been investigated as an optical waveguide
utilizing photoinduced refractive index changes,7 as a photo-
chromaic system potentially applicable to data storage,8 or as
light-driven, carrier-mediated, active transport across a mem-
brane against a concentration gradient.9
Iron-Catalyzed Cross-Coupling Reactions
between a Bicyclic Alkenyl Triflate and Grignard
Reagents
Paul Le Marquand, Gavin C. Tsui, John C. C. Whitney, and
William Tam*
Traditionally, substituted norbornenes and norbornadienes can
be synthesized by Diels-Alder reactions between cyclopenta-
diene and an alkene or an alkyne. Since unactivated alkenes
and alkynes are poor dienophiles in Diels-Alder cycloaddi-
tions,10 the variety of 2,3-disubstituted bicyclic alkenes that
could be synthesized using the Diels-Alder method is rather
limited (usually contain at least one electronic withdrawing
group such as an ester, an amide, a cyano group, etc.). We have
recently reported the synthesis of a variety of 2,3-disubstituted
bicyclicalkenesbythreedifferentmethods.Doublelithium-halide
exchange of 2,3-dibromo bicyclic alkenes 2 produced a variety
of substituted bicyclic alkenes 3 with E1, E2 ) 1° alkyl groups,
silyl groups, Cl, Br, I, R3Sn, COOR, R1R2C(OH) (Scheme 1).11
Guelph-Waterloo Centre for Graduate Work in Chemistry
and Biochemistry, Department of Chemistry, UniVersity of
Guelph, Guelph, Ontario, Canada N1G 2W1
wtam@uoguelph.ca
ReceiVed June 25, 2008
SCHEME 1. Previous Synthesis of Substituted Bicyclic
Alkenes
Fe-catalyzed cross-coupling reactions between a bicyclic
alkenyl triflate and Grignard reagents were investigated.
Under the optimized reaction conditions, various 2-substi-
tuted bicyclic alkenes were synthesized in moderate to
excellent yields (52-93%). This method provided an efficient
route for the synthesis of 2-substituted bicyclic alkenes with
2° alkyl groups which cannot be synthesized using previous
methods such as Pd-catalyzed coupling reactions and
lithium-halide exchange reactions.
Bicyclo[2.2.1]hept-2-ene and bicyclo[2.2.1]hepta-2,5-diene
(1), commonly known as norbornene and norbornadiene,
respectively, are strained bicyclic structures. Substituted nor-
bornenes and norbornadienes are important compounds. They
have been used as key intermediates for the synthesis of natural
products, such as prostaglandin endoperoxides PGH2 and PGG2,1
cis-Trikentrin B,2 and ꢀ-santalol.3 Chiral 2,5-disubstituted
norbornadienes have recently been used as chiral ligands in
asymmetric catalysis.4 Photochemical valence isomerization
between norbornadiene and quadricyclane is of interest as a solar
energy conversion and storage system.5 Extensive investigation
of substituted norbornadienes/quadricyclanes for solar energy
storage has demonstrated the efficiency and switching potential
Palladium-catalyzed Sonogashira couplings of 2,3-dibromo
bicyclic alkenes 2 with terminal alkynes yielded bicyclic alkene-
2,3-diynes 4,12 and palladium-catalyzed Suzuki couplings of 2,3-
dibromo bicyclic alkenes 2 with aryl boronic acids afforded 2,3-
diaryl bicyclic alkenes 5.13 These studies significantly broadened
(6) (a) Hirao, K.; Ando, A.; Hamada, T.; Yonemitsu, O. J. Chem. Soc., Chem.
Commun. 1984, 300–302. (b) Bonfantini, E. E.; Officer, D. L. J. Chem. Soc.,
Chem. Commun. 1994, 1445–1446. (c) Maafi, M.; Lion, C.; Aaron, J. J. New
J. Chem. 1996, 20, 559–570. (d) Franceschi, F.; Guardigli, M.; Solari, E.; Floriani,
C.; Chiesi-Villa, A.; Rizzoli, C. Inorg. Chem. 1997, 36, 4099–4107. (e) Ikeda,
A.; Tsubata, A.; Kameyama, A.; Nishikubo, T. J. Polym. Sci., Part A: Polym.
Chem. 1999, 37, 917–926.
(7) (a) Nishikubo, T.; Shimokawa, T.; Sahara, A. Macromolecules 1989, 22,
8–14. (b) Kinoshita, K.; Horie, K.; Morino, S.; Nishikudo, T. Appl. Phys. Lett.
1997, 70, 2940–2942. (c) Takahashi, S.; Samata, K.; Mura, H.; Machida, S.;
Horie, K. Appl. Phys. Lett. 2001, 78, 13–15.
(1) Corey, E. J.; Shibasaki, M.; Nicolaou, K. C.; Malmsten, C. L.;
Samuelsson, B. Tetrahedron Lett. 1976, 737–740.
(2) Lee, M.; Ikeda, I.; Kawabe, T.; Mori, S.; Kanematsu, K. J. Org. Chem.
1996, 61, 3406–3416.
(3) (a) Sato, K.; Miyamoto, O.; Inoue, S.; Honda, K. Chem. Lett. 1981, 1183–
1184. (b) Monti, H.; Corriol, C.; Bertrand, M. Tetrahedron Lett. 1982, 23, 5539–
5540.
(4) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508–11509. (b) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi,
T. Org. Lett. 2004, 6, 3425–3427. (c) Shintani, R.; Okamoto, K.; Otomaru, Y.;
Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54–55.
(5) For reviews, see: (a) Bren, V. A.; Dubonosov, A. D.; Minkin, V. I.;
Chernoivanov, V. A. Russ. Chem. ReV. 1991, 60, 913–948. (b) Dubonosov, A. D.;
Bren, V. A.; Chernoivanov, V. A. Russ. Chem. ReV. 2002, 71, 917–927.
(8) Kato, Y.; Muta, H.; Takahashi, S.; Horie, K.; Nagai, T. Polym. J. 2001,
33, 868–873.
(9) Winkler, T.; Dix, I.; Jones, P. G.; Herges, R. Angew. Chem., Int. Ed.
2003, 42, 3541–4544.
(10) (a) Ciganek, E. Org. React. 1984, 32, 1–374. (b) The Diels-Alder
Reaction; Fringuelli, F., Taticchi, A., Eds.; John Wiley & Sons: West Sussex,
2002.
(11) Tranmer, G. K.; Yip, C.; Handerson, S.; Jordan, R. W.; Tam, W. Can.
J. Chem. 2000, 78, 527–535.
(12) Tranmer, G. K.; Tam, W. Synthesis 2002, 1675–1682.
(13) Yoo, W.-J.; Tsui, G. C.; Tam, W. Eur. J. Org. Chem. 2005, 1044–
1051.
10.1021/jo801384e CCC: $40.75
Published on Web 09/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7829–7832 7829

the variety of substituted bicyclic alkenes that cannot be prepared
by the Diels-Alder methodology.
has been successfully applied to synthesize biologically active
natural products such as Muscopyridine,16 Latrunculin,17 im-
munosuppressive agent FTY720,18 Ciguatoxin,19 (-)-R-Cube-
bene, (-)-Cubebol, Sesquicarene, and related terpenes.20
To begin our investigation, bicyclic alkenyl triflate 8 was
synthesized (see Supporting Information) and the study on the
Fe-catalyzed coupling reaction was carried out (Table 1). In
These methods allow the formation of a carbon-carbon bond
between a bicyclic alkene and a sp-hybridized carbon (Scheme
1, 4), a sp2-hybridized carbon (5), and a sp3-hybridized carbon
of a 1° alkyl group (3). However, one limitation to these
syntheses is that substitutents with 2° alkyl groups (e.g., iPr or
cycloalkyl) cannot be prepared using these methods. In fact,
lithium-halide exchange of 2-bromonorbornene 6 followed by
trapping with bromocyclohexane did not afford 2-cyclohexyl-
norbornene 7; only cyclohexene and norbornene were formed
(Scheme 2). Attempts to synthesize 2-cyclohexylnorbornene 7
TABLE 1. Effect of Solvent
SCHEME 2. Attempted Synthesis of 7
yield (%)c
coupling
reduced
entrya
solventb
product 9a product 10 recovered 8
1
2
3
4
5
6
7
8
Et2O
THF
DME
NMP
DMPU
DMF
TEA
TMEDA
THF/NMP (1:3)
THF/NMP (1:1)
THF/NMP (3:1)
THF/DMPU (1:3)
THF/DMPU (1:1)
THF/DMPU (3:1)
26
81
9
82
88
50
5
1
6
3
6
1
5
4
0
6
5
12
7
8
13
22
0
61
0
0
8
70
74
0
0
0
0
9
88
79
78
75
66
69
10
11
12
13
14
using palladium-catalyzed Suzuki couplings of 2-bromonor-
bornene 6 with cyclohexylboronic acid using various conditions
were also unsuccessful. To the best of our knowledge, there is
no general method for the synthesis of 2-substituted bicyclic
alkenes with a 2° alkyl group. In this paper, we report our studies
on Fe-catalyzed cross-coupling reactions between bicyclic
alkenyl triflates and Grignard reagents for the synthesis of
2-substituted bicyclic alkenes with 2° alkyl groups.
0
0
0
a 20 mol% of Fe(acac)3 was used in all cases. b DME ) 1,2-dimethoxy-
ethane; NMP ) 1-methyl-2-pyrrolidinone; DMF ) N,N-dimethylform-
amide; TEA ) triethylamine; TMEDA ) N,N,N′,N′-tetramethylethylenedi-
amine; DMPU ) N,N′-dimethylpropyleneurea. c Isolated yield after column
chromatography.
In 1945, Kharasch and co-workers reported the first Fe-
catalyzed alkenylation of Grignard reagents.14a,b Kochi and co-
workers improved the procedures and studied the mechanism
of the reaction in 1971, but the yields of the reactions were
low and not convenient for preparative applications.14c,d More
recently in 1998, Cahiez reported that the use of NMP or DMPU
as a cosolvent which greatly improved the yields of Fe-catalyzed
alkenylations of Grignard reagents, and alkenyl chlorides,
bromides, and iodides as well as alkenyl phosphates can be used
successfully.15b In 2004, Fu¨rstner extended Cahiez’s conditions
to include alkenyl triflates as successful substrates in Fe-
catalyzed alkenylations of Grignard reagents. This methodology
the presence of 5 equiv of cyclohexylmagnesium chloride
(CyMgCl) and 20 mol % of Fe(acac)3 in Et2O at -25 °C, the
desired coupling product 9a was formed in 26% isolated yield
accompanied with 1% of the reduced product 10 and 22% of
the unreacted starting triflate 8 (Table 1, entry 1). To optimize
the yield of the reaction, an investigation on the effect of solvent,
different Fe catalysts, number of equivalent of Grignard reagent,
and reaction temperature was carried out (Tables 1-3).
Solvent plays an important role in Fe-catalyzed coupling
reactions.15 On the basis of various solvent systems used in the
literature in Fe-catalyzed coupling reactions,15 a wide range of
ether, amide, and amine-based solvents were screened. The use
of THF, NMP, DMPU, as well as THF/NMP (1:3) gave the
desired coupling product 9a in >80% isolated yields (entries
2, 4, 5, and 9), and in all cases, a small amount of the undesired
reduced product 10 was also isolated. Fortunately, these products
(9a and 10) could be separated by column chromatography. The
highest yield of the desired coupling product 9a was obtained
when THF/NMP (1:3) or DMPU was used as solvent (entries
5 and 9).
(14) For early work on Fe-catalyzed alkenylations, see: (a) Kharasch, M. S.;
Fuchs, C. F. J. Org. Chem. 1945, 10, 292. (b) Kharasch, M. S.; Lambert, F. L.;
Urry, W. H. J. Org. Chem. 1945, 10, 298. (c) Tamura, M.; Kochi, J. K. J. Am.
Chem. Soc. 1971, 93, 1487. (d) Neumann, S. M.; Kochi, J. K. J. Org. Chem.
1975, 40, 599.
(15) For selected recent examples of Fe-catalyzed alkenylations, see: (a)
Molander, G. A.; Rahn, B. J.; Shubert, D. C.; Bonde, S. E. Tetrahedron Lett.
1983, 24, 5449. (b) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199. (c)
Bogdanovic, B.; Schwickardi, M. Angew. Chem., Int. Ed. 2000, 39, 4610. (d)
Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901. (e) Fu¨rstner,
A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856.
(f) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org. Chem. 2004,
69, 3943. (g) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955.
(h) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624. (i) Ottesen, L. K.; Ek,
F.; Olsson, R. Org. Lett. 2006, 8, 1771. (j) Xu, X.; Cheng, D.; Pei, W. J. Org.
Chem. 2006, 71, 6637. (k) Fu¨rstner, A.; Krause, H.; Lehmann, C. W. Angew.
Chem., Int. Ed. 2006, 45, 440. (l) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux,
A. Angew. Chem., Int. Ed. 2007, 46, 4364. (m) Guerinot, A.; Reymond, S.; Cossy,
J. Angew. Chem., Int. Ed. 2007, 46, 6521. (n) Chowdhury, R. R.; Crane, A. K.;
Fowler, C.; Kwong, P.; Kozak, C. M. Chem. Commun. 2008, 94. (o) Fu¨rstner,
A.; Majima, K.; Martin, R.; Krause, H.; Kattnig, E.; Goddard, R.; Lehmann,
C. W. J. Am. Chem. Soc. 2008, 130, 1992.
To determine the effect of different Fe catalysts on the
coupling reaction, several Fe catalysts which were found to be
(16) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308.
(17) Fu¨rstner, A.; De Souza, D.; Parra-Rapado, L.; Jensen, J. Angew. Chem.,
Int. Ed. 2003, 42, 5358.
(18) Seidel, G.; Laurich, D.; Fu¨rstner, A. J. Org. Chem. 2004, 69, 3950.
(19) Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205.
(20) Fu¨rstner, A.; Hannen, P. Chem.sEur. J. 2006, 12, 3006.
7830 J. Org. Chem. Vol. 73, No. 19, 2008

TABLE 2. Effect of Different Fe Catalysts
-40 °C (little reaction was observed for temperature lower than
-40 °C), -25 °C gave the best results among all the temper-
atures tested (entries 1-5). The use of CyMgBr gave a slightly
lower yield of the desired coupling product 9a than CyMgCl,
and CyMgI afforded the desired coupling product 9a in much
lower yield, and a significant increase in the formation of the
reduced product 10 was observed (entries 2, 6, and 7). The effect
of the number of equivalents of Grignard reagent is shown in
entries 2 and 8-10. The use of a larger excess (10 equiv) of
the Grignard reagent led to a decrease in yield of the desired
coupling product 9a and an increase in the formation of the
reduced product 10 (entry 8). Using 5 or 2.1 equiv of the
Grignard reagent (entries 2 and 9) gave similar yields, and
the highest yield was obtained using 1.1 equiv of the Grignard
reagent (entry 10).
yield (%)
Fe catalyst
coupling
reduced
entry
(20 mol %)
solvent
product 9a
product 10
1
2
Fe(acac)3
THF/NMP (1:3)
DMPU
88
88
79
85
67
55
72
68
63
60
6
1
8
4
6
8
6
7
4
7
3
4
FeCl3
THF/NMP (1:3)
DMPU
5
6
7
8
9
10
Fe(dpm)3
Fe(dbm)3
Fe cat. 11
THF/NMP (1:3)
DMPU
THF/NMP (1:3)
DMPU
THF/NMP (1:3)
DMPU
To explore the scope of the Fe-catalyzed cross-coupling
reactions of bicyclic alkenyl triflate 8, various Grignard reagents
(RMgX) were employed, and the results are shown in Table 4.
TABLE 4. Fe-Catalyzed Cross-Coupling of Triflate 8 and RMgX
yield (%)a
equiv of
entry
R
X
RMgX
solvent
product 9
9
10
active in the literature in Fe-catalyzed coupling reactions were
screened, and the results are shown in Table 2. The catalysts
Fe(dpm)3, Fe(dbm)3, and Fe cat. 11 were prepared by literature
procedures.15e,21 All Fe catalysts tested afforded the desired
coupling product 9a in moderate to good yields. The com-
mercially available, air-stable Fe(acac)3 catalyst seems to be
the best choice with high yields and easy handling.
1
2
3
4
5
6
7
8
9
cyclohexyl
cycloheptyl Br
cyclopentyl Cl
Cl
1.1
1.6
1.6
1.6
1.6
1.6
1.6
5
2.1
1.6
1.6
1.6
THF/NMP (1:3)
DMPU
DMPU
DMPU
DMPU
9a
9b
9c
9d
9e
9f
9g
9h
9i
93
52
71
62
67
87
87
80
72
85
74
73
1
2
7
13
3
3
0
0
0
0
cyclobutyl
Cl
cyclopropyl Br
iPr
Cl
Cl
Br
Cl
Cl
DMPU
DMPU
sBu
Me
Bn
THF/NMP (1:3)
THF/NMP (50:1)
THF/NMP (1:3)
THF/NMP (1:3)
THF/NMP (1:3)
10 Ph
11 m-MeO-C6H4 Br
12 m-CF3-C6H4 Br
9j
9k
9l
TABLE 3. Effects of Reaction Temperature, Different Grignard
Halides, and Equivalency of Grignard Reagent
0
0
a Isolated yield after column chromatography.
The highest yield of 93% of the coupling product 2-cyclohexyl
bicyclic alkene 9a was obtained using 1.1 equiv of CyMgCl in
THF/NMP (1:3) (Table 4, entry 1). In the case of other
cycloalkyl Grignard reagents, the use of DMPU as solvent gave
better results in the coupling reactions than using THF/NMP
as solvents, and the corresponding 2-cycloalkyl bicyclic alkenes
9b-9e were formed in moderate yields (52-71%, entries 2-5).
With cyclobutyl and cyclopentyl magnesium chlorides (entries
3 and 4), significant amounts of the reduced product 10 were
produced. This Fe-catalyzed coupling reaction of bicyclic triflate
8 not only works well with cycloalkyl Grignard reagents, it also
works well with acyclic 2 and 1° alkyl groups (entries 6-9),
giving 2-alkyl-substituted bicyclic alkenes 9f-9i in good yields
(72-87%). The use of aromatic Grignard reagents in the Fe-
catalyzed coupling reaction of bicyclic triflate 8 also afforded
the corresponding 2-aryl-substituted bicyclic alkenes 9j-9l in
good yields (73-85%, entries 10-12).
yield (%)a
entry
X
equiv of CyMgX
temp (°C)
9a
10
1
2
3
4
5
6
7
8
9
10
Cl
Cl
Cl
Cl
Cl
Br
I
Cl
Cl
Cl
5
5
5
5
5
5
5
10
2.1
1.1
-40b
-25
0
25
50
-25
-25
-25
-25
-25
78
88
80
71
55
80
58
61
86
93
6
6
5
5
4
8
15
11
4
1
a Isolated yield after column chromatography. b THF/NMP (1:1) was
used to avoid freezing of the solvent at -40 °C.
The effects of reaction temperature (entries 1-5), different
Grignard halides (entries 2, 6, and 7), and equivalent of Grignard
reagent (entries 2, 8-10) are shown in Table 3. Reaction
temperatures above 0 °C led to decomposition of the starting
triflate, and lower yields of the desired coupling product 9a were
observed. Although the reaction seems to work at as low as
A proposed mechanism for the Fe-catalyzed cross-coupling
reaction22 between bicyclic alkenyl triflate 8 and cyclohexyl-
magnesium chloride, which accounts for the formation of
coupling product 9a and the reduced product 10, is shown in
(22) Fu¨rstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann,
C. W. J. Am. Chem. Soc. 2008, 130, 8773.
(21) Neumann, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40, 599.
J. Org. Chem. Vol. 73, No. 19, 2008 7831

SCHEME 3. Proposed Mechanism
Suzuki coupling reactions or by lithium-halide exchange reac-
tions followed by trapping with bromo- or iodocyclohexane.
In conclusion, we have investigated the Fe-catalyzed cross-
coupling reactions between bicyclic alkenyl triflate 8 and
Grignard reagents. Under the optimized reaction conditions,
Fe(acac)3 (20 mol %), 1.1-5 equiv of RMgBr or RMgCl, in
DMPU or THF/NMP (1:3) at -25 °C, various 2-substituted
bicyclic alkenes were synthesized in moderate to excellent yields
(52-93%). This method provided an efficient route for the
synthesis of 2-substituted bicyclic alkenes with 2° alkyl groups,
which cannot be synthesized using the previous methods of Pd-
catalyzed coupling reactions or lithium-halide exchange reactions.
Experimental Section
General Procedure for the Fe-Catalyzed Cross-Coupling
of Bicyclic Alkenyl Triflate 8 and RMgX. To an oven-dried vial
containing triflate 8 (1.0 equiv) dissolved in a solvent (∼0.15 M)
was added Fe(acac)3 (20 mol %) under nitrogen, and reaction
mixture was cooled to -25 °C. The Grignard reagent (1.1-5 equiv)
was added dropwise, and the reaction mixture was stirred at -25
°C for 30-55 min. The reaction was quenched with HCl (1 M) at
-25 °C and extracted with diethyl ether. The organic layers were
washed with saturated sodium bicarbonate solultion, dried on
magnesium sulfate, and concentrated using rotary evaporation. The
crude product was purified by column chromatography (EtOAc-
hexane mixtures) to give the product.
endo-5,6-Bis(methoxymethyl)-2-cyclohexylbicyclo[2.2.1] hept-
2-ene (9a, Table 4, entry 1). Following the above general
procedure, using triflate 8 (26.2 mg, 0.0793 mmol), THF (0.11 mL)/
NMP (0.33 mL) as solvent, Fe(acac)3 (5.9 mg, 0.017 mmol), and
cyclohexylmagnesium chloride (1.1 equiv, 1.4 M in diethyl ether,
0.06 mL, 0.084 mmol). The reaction was stirred at -25 °C for 45
min. The crude product was purified using column chromatography
(EtOAc:hexanes ) 1:9, Rf ) 0.41) to obtain 9a as a light yellow
oil (19.5 mg, 0.0738 mmol, 93%): 1H NMR (CDCl3, 400 MHz) δ
5.58 (m, 1H), 3.28 (s, 3H), 3.27 (s, 3H), 3.22-3.12 (m, 2H),
3.05-2.99 (m, 1H), 2.91-2.83 (m, 2H), 2.81-2.77 (m, 1H),
2.49-2.38 (m, 2H), 2.05-1.96 (m, 1H), 1.84-1.61 (m, 5H),
1.47-1.41 (m, 1H), 1.34-1.10 (m, 5H), 0.99-0.86 (m, 1H); 13C
NMR (APT, CDCl3, 75 MHz) δ 156.2, 123.3, 73.1, 72.7, 58.7,
58.4, 49.4, 47.2, 45.2, 41.7, 41.2, 39.5, 32.9, 30.5, 26.6, 26.5, 26.3;
IR (neat, NaCl, cm-1) 2975 (w), 2923 (m), 2851 (m), 2806 (w),
1613 (w), 1482 (w), 1449 (m), 1388 (w), 1338 (w), 1295 (w), 1258
(w), 1192 (w), 1168 (w), 1104 (m), 969 (w), 943 (w), 826 (w);
HRMS (CI) calcd for C17H28O2 (M+) 264.2089, found 264.2093.
Scheme 3. Reduction of the Fe(acac)3 precatalyst with the
Grignard reagent produced the active catalyst, the Fe-IGR (12).
Oxidative insertion of the Fe-IGR to the bicyclic alkene triflate
8 gave intermediate 13. Addition of the Grignard reagent
afforded 14. Reductive elimination of 14 would provide the
coupling product 9a and regenerate the Fe-IGR active catalyst
12. With alkyl groups containing a ꢀ-hydrogen, ꢀ-hydride
elimination is possible and Fe-hydride 15 would be formed.
Reductive elimination of 15 would give the reduced product
10.
SCHEME 4. Synthesis of 18 and 19
Acknowledgment. This work was supported by Merck Frosst
Centre for Therapeutic Research, Natural Sciences and Engi-
neering Research Council of Canada (NSERC), and Boehringer
Ingelheim (Canada) Ltd. P.L. thanks NSERC for providing a
postgraduate (PGS M) scholarship.
2-Cyclohexylnorbornene 18 and 2,3-dicyclohexylnorborna-
diene 19 could also be synthesized in good yields using the
Fe-catalyzed cross-coupling reactions of 2-bromonorbornadiene
16 or 2,3-dibromonorbornadiene 17 with cyclohexylmagnesium
chloride (Scheme 4). Note that these 2° alkyl-substituted
norbornadienes were not accessible by palladium-catalyzed
Supporting Information Available: Detailed experimental
1
procedures, compound characterization data, and H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801384E
7832 J. Org. Chem. Vol. 73, No. 19, 2008