Iron-catalyzed chemoselective cross-coupling of primary and secondary alkyl halides with arylzinc reagents

Article abstract of DOI:10.1055/s-2005-871541

Functional-group-compatible cross-coupling reaction of alkyl halides with arylzinc reagents takes place under iron catalysis in the presence of TMEDA, producing a variety of aromatic compounds in good to excellent yield. The pronounced effect of a magnesium salt was found to be the key to the promotion of the iron-catalyzed coupling reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871541

1794
CLUSTER
Iron-Catalyzed Chemoselective Cross-Coupling of Primary and Secondary
Alkyl Halides with Arylzinc Reagents
I
ron-Catalyzed Cross-C
a
oupling of
s
Primary a
a
nd Second
h
a
ry
A
lkyl
H
a
a
lides with
r
A
rylzinc
u
Reagents Nakamura,*a,b Shingo Ito,b Keiko Matsuo,b Eiichi Nakamura*b
a
PRESTO, Japan Science and Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b
Department of Chemistry, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)38128099; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Received 28 March 2005
or phenyllithium, and by the direct insertion of Rieke zinc
with bromobenzene were inert under the same coupling
conditions. Diphenylzinc prepared from ZnCl2 and two
equivalents of phenyl lithium did not react at all with bro-
Abstract: Functional-group-compatible cross-coupling reaction of
alkyl halides with arylzinc reagents takes place under iron catalysis
in the presence of TMEDA, producing a variety of aromatic
compounds in good to excellent yield. The pronounced effect of a
magnesium salt was found to be the key to the promotion of the mocycloheptane under the reaction conditions (Table 1,
iron-catalyzed coupling reaction.
entry 5). The results indicate that magnesium halide is
essential for the reaction.
Key words: iron catalyst, zinc reagents, alkyl halides, cross-cou-
pling, substitution
A subtle but practically important consequence of the use
of zinc in place of the magnesium reagents is that the
reagent can be mixed at once with other reactants as op-
posed to the required (to achieve high yield) slow addition
of the Grignard reagent in our previous protocol.3a We
tentatively ascribe this difference to the lower ligand
transferability of the zinc reagent, which can avoid mal-
function of the iron catalyst caused by further reaction
with the nucleophile.
Iron has enormous practical advantages as a catalyst due
to its low cost, ample supply, environmental friendliness,
and lack of toxicity. Iron catalysis therefore is intensively
studied now to achieve controlled organic synthesis,
especially in cross-coupling reactions.1,2 Considerable
progress has been made recently by ourselves3 and others4
in this field. Iron catalysis not only improves known cata-
lytic processes but also brings about new possibilities in
synthesis; for instance, iron catalysis solved the long-
standing synthetic problem5,6 in the coupling of primary
or secondary alkyl halides with organometallic com-
pounds.3 However, a drawback of the iron-catalyzed
cross-coupling reaction of haloalkanes is that the nucleo-
philic partner has been limited largely to organomagne-
sium reagents,7 in which electrophilic substituents can
survive only at low temperatures.8 Here, we report an
iron-catalyzed cross-coupling of primary or secondary
alkyl halides with arylzinc reagents, where the mild reac-
tivity of the zinc reagents much improves the functional
group tolerance and the synthetic practicability of the
cross-coupling reaction.
The requirement for a diarylzinc reagent is a clear draw-
back of the above reaction, as one of the two aryl groups
cannot be utilized for the coupling. This problem can be
resolved by the use of a mixed diorganozinc reagent bear-
ing a Me3SiCH2 non-transferable ligand.9 In this way,
only one equivalent of an aryl nucleophile in the form of
either an aryllithium or an arylzinc reagent is allowed to
couple with one equivalent of bromocycloheptane in high
yield (Table 1, entries 6 and 7).
arylzinc reagent
(1.5 equiv)
FeCl3 (5 mol%)
Ar
Br
TMEDA (1.5 equiv)
+
+
THF, 50 °C, 0.5 h
1
2
3
4
We first examined various organozinc reagents generated
by several methods. The results summarized in Table 1
show that a diorganozinc reagent (carbanion ligand/
zinc, 2:1) is necessary (Table 1, entries 1 and 2) but not
sufficient (Table 1, entry 4); the presence of a magnesium
salt is mandatory for the cross-coupling reaction. Thus,
we found that bromocycloheptane can be coupled with
Ph2Zn·2MgBrCl in the presence of a stoichiometric
amount of TMEDA and 5 mol% of FeCl3 (Table 1, entry
1). Both, PhZnCl or PhZnBr (Table 1, entries 2–4) pre-
pared by transmetalation from a phenyl Grignard reagent
Scheme 1 Iron-catalyzed cross-coupling between bromocyclo-
heptane and arylzinc reagent.
In the absence of the catalyst, no coupling product was
produced (data not shown). Though we used hygroscopic
anhydrous ZnCl2 for our initial studies, we subsequently
found that air- and moisture-stable ZnCl2·TMEDA
complex10 can be used with equal success and hence was
used for the remaining studies.
The results of the cross-coupling of alkyl halides possess-
ing various functional groups with arylzinc reagents
(Scheme 1) are summarized in Table 2.11 Iodo- and
bromocyclohexane reacted smoothly to give cyclohexyl-
benzene in quantitative yield (Table 2, entries 1, 2).
SYNLETT 2005, No. 11, pp 1794–1798
Advanced online publication: 14.06.2005
DOI: 10.1055/s-2005-871541; Art ID: Y00305ST
© Georg Thieme Verlag Stuttgart · New York
0
7
.0
7
.2
0
0
5

CLUSTER
Iron-Catalyzed Cross-Coupling of Primary and Secondary Alkyl Halides with Arylzinc Reagents
1795
Table 1 Effect of Organozinc Reagents on the Iron-Catalyzed Cross-Coupling of Bromocycloheptanea
Entry
Arylzinc reagent
Yield (%)b
2
3
4
1
1
ZnCl2/2PhMgBr
96
0
3
trace
trace
trace
trace
trace
trace
0
0
2
ZnCl2/PhMgBr
trace
trace
trace
trace
4
>95
>95
>95
>95
0
3
PhZnBr (Mg free)
ZnCl2/2PhLi
0
4c
5c
6d
7e
0
ZnCl2/PhLi
0
ZnCl2/PhMgBr/Me3SiCH2MgCl
ZnCl2/PhLi/Me3SiCH2MgCl
95
92
7
0
a Reactions were performed by the addition of a THF solution of FeCl3 (5 mol%) to a mixture of an alkyl halide (1.0 mmol), PhMgBr
(3.0 equiv), ZnCl2 (1.5 equiv), and TMEDA (1.5 equiv) in THF.
b Yield according to GC using a calibrated internal standard (decane).
c The solvent is THF–Bu2O (2:1).
d The solvent is THF–Et2O–Bu2O (2:2:1).
e The solvent is THF–pentane–Bu2O (2:2:1).
Chlorocyclohexane also takes part in the reaction with a good to quantitative yield by the use of the arylzinc re-
slightly diminished yield and reaction rate (Table 1, entry agents, ArZnCH2SiMe3 (ArZnCH2TMS) prepared by the
3). A steroidal chloride (100% a) reacted smoothly to give treatment of ArZnX (X = Br, I) with one equivalent of
the phenylated product in high yield (Table 1, entry 4; Me3SiCH2MgCl. The aryl zinc reagents bearing an elec-
a/b, 14:86).
tron-withdrawing group, such as ethoxycarbonyl and
cyano groups, were found to be slightly less reactive than
the corresponding phenyl reagent, but reactive enough to
react with primary alkyl iodides (Table 3, entries 1, 2) and
secondary alkyl bromides (Table 3, entries 3–5) in good
yields. 2-Pyridylzinc also took part in the cross-coupling
to give the product in 98% yield (Table 3, entry 6). Some
other heteroaromatic organozinc reagents, which are
prepared easily from the corresponding organolithium
compounds gave 2-substituted benzofuran and indole in
good yield (Table 3, entries 7, 8).
The catalyst system tolerates functional groups such as
alkenyl (data not shown), trimethylsilyl, and alkynyl
groups (Table 2, entry 5), as well as esters (Table 2,
entries 6–9) and nitriles (Table 2, entry 10). The rather
unreactive glucose derivative (Table 2, entry 11) was
completely consumed giving the product in 90% yield
with almost no loss of the acetyl groups, when two
equivalents of the diarylzinc reagent was used.
The method can be applied to cross-coupling with func-
tionalized arylzinc reagents or heteroarylzinc reagents
(Scheme 2, Table 3).12 The coupling was achieved in
arylzinc reagent (2.0 equiv)
FeCl3 (5 mol%)
TMEDA (2.0 equiv)
Ar2Zn·TMEDA (1.5 equiv)
FeCl3 (5 mol%)
(FG)Ralkyl Ar(FG)
(FG)Ralkyl–X
THF, 30 °C, 6 h
(FG)Ralkyl Ar
Me
(FG)Ralkyl–X
THF, 50 °C, 0.5 h
CN
TMSCH2Zn
CO2Et
Ph2Zn
Me
Zn
Zn
10
2
2
TMSCH2Zn
TMSCH2Zn
12
N
5
6
7
11
O
MeO
Zn
O
TMSCH2Zn
Zn
TMSCH2Zn
2
2
N
O
Me
8
9
13
14
Figure 1
Scheme 2
Synlett 2005, No. 11, 1794–1798 © Thieme Stuttgart · New York

1796
M. Nakamura et al.
CLUSTER
Table 2 Iron-Catalyzed Cross-Coupling of Functionalized Alkyl Halides with Diarylzinc Reagentsa
Entry
1
(FG)Ralkyl–X
Arylzincb
Product
Yield (%)c
5
98
97
88
89
I
Ph
2
5
5
5
Br
Cl
Ph
Ph
3d
4e
C8H17m
C8H17m
Me
Me
α/β = 14/86
H
Me
H
Me
Cl
Ph
5
5
5
6
93
Me3Si
Me3Si
I
Ph
( )3
( )3
6
7
99
91
O
O
X
Ph
EtO
( )5
Br
EtO
( )5
8
83
AcO
Me
( )5
AcO
( )5
9
7
98
Br
PivO
NC
Me
PivO
NC
trans/cis = 55/45
10
8
9
86
90
I
OMe
( )3
( )3
11f
OMe
OAc
OMe
O
O
I
OAc
AcO
AcO
OAc
O
O
OAc
a Reactions were performed at 50 °C by the addition of a THF solution of FeCl3 (5 mol%) to a THF solution of an alkylhalide, a diarylzinc
reagent, and TMEDA under vigorous stirring.
b The diarylzinc reagent was prepared at ambient temperature, prior to the addition of the alkyl halide, by mixing ArMgBr (3.0 equiv) and
ZnCl2·TMEDA (1.5 equiv) unless otherwise noted.
c Isolated yield.
d The reaction time was 3 h.
e The reaction time was 12 h.
f ZnCl2·TMEDA complex (2 equiv) and ArMgBr (4 equiv).
Cyclative cross-coupling4a,13 could also be achieved in
arylzinc reagent
O
procedure A or B
good yield and with high chemoselectivity (Scheme 3).
When iodoacetal 5 was treated with a diarylzinc reagent,
tandem 5-exo-cyclization/cross-coupling reaction gave
the tetrahydrofuran derivative 6 (Table 4). This result
suggests participation of radical related intermediates in
the iron-catalyzed cross-coupling of organozinc reagent.3
O
n-BuO
I
Ar
n-BuO
16
15
Scheme 3
Synlett 2005, No. 11, 1794–1798 © Thieme Stuttgart · New York

CLUSTER
Iron-Catalyzed Cross-Coupling of Primary and Secondary Alkyl Halides with Arylzinc Reagents
1797
Table 3 Iron-Catalyzed Cross-Coupling with Functionalized Arylzinc Reagentsa
Entry
1
(FG)Ralkyl–X
Arylzincb
Product
Yield (%)c
91
Me3Si
10
Me3Si
I
( )3
( )3
CO2Et
2
3
10
10
72
78
NC
I
( )3
NC
( )3
CO2Et
PivO
Br
PivO
CO2Et
trans/cis = 33/67
trans/cis = 47/53
4
11
11
90
79
Br
CN
5d
Br
CN
N
Cbz
N
Cbz
6
7
12
13
98
89
n-C10H21
I
n-C10H21
N
EtO2C
I
EtO2C
( )5
( )5
O
8 e
14
78
Cl
N
Me
a Reactions were performed by the addition of a THF solution of FeCl3 (5 mol%) to a mixture of an alkyl halide (1.0 mmol), an arylzinc reagent,
and TMEDA under vigorous stirring.
b Arylzinc reagents were prepared by mixing ArZnX (X = Cl, Br, or I; THF solution, 2.0 equiv) and Me3SiCH2MgCl (ethereal solution,
2.0 equiv) at 0 °C for 1 h.
c Isolated yield.
d The reaction time was 24 h.
e The reaction time was 120 h (reflux).
Table 4 Iron-Catalyzed Tandem Cyclization/Coupling11,12
Entry Aryl- Proce- Product
Acknowledgment
We thank the Ministry of Education, Culture, Sports, Science, and
Technology of Japan for financial support, a Grant-in-Aid for
Specially Promoted Research, a Grant-in-aid for Young Scientist
(A) (KAKENHI 14703011), and 21st Century COE Program for
Frontiers in Fundamental Chemistry.
Yield
zinc
dure
(%)a
1
2
5
A
76
(63:37)
O
n-BuO
References
9
A
B
86
(64:36)
O
O
O
O
(1) (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176. (b) Cross-Coupling Reactions. A Practical Guide,
Topics in Current Chemistry, Vol. 219; Miyaura, N., Ed.;
Springer: Berlin, 2002. (c) Metal-Catalyzed Cross-
Coupling Reactions, 2nd Ed.; Meijere, A.; Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004.
n-BuO
n-BuO
3b
11
73
(63:37)
CN
a Isolated yield. Diastereomeric ratios are in parentheses.
b The reaction time was 24 h.
Synlett 2005, No. 11, 1794–1798 © Thieme Stuttgart · New York

1798
M. Nakamura et al.
CLUSTER
1 h. To the resulting suspension was added 5-iodo-1-
(trimethylsilyl)pent-1-yne (266 mg, 1.0 mmol), and then
FeCl3 (0.1 M solution in THF, 0.5 mL, 0.05 mmol) at 0 °C.
The reaction mixture was stirred at 50 °C for 0.5 h. After
quenching with a saturated aqueous solution of NH4Cl, the
mixture was filtered through a pad of Florisil®, and
concentrated in vacuo. Purification by silica gel
chromatography afforded 5-phenyl-1-(trimethylsilyl)pent-
1-yne (201 mg, 93%); FTIR (neat): 2958 (w), 2902 (w),
2175 (w), 1478 (w), 1451 (s), 1395 (w), 1366 (s), 1268 (w),
1167 (w), 997 (s) cm–1; 1H NMR (500 MHz, CDCl3): d =
7.31–7.25 (m, 3 H), 7.21–7.17 (m, 2 H), 2.72 (t, J = 7.6 Hz,
2 H), 2.24 (t, J = 7.1 Hz, 2 H), 1.84 (tt, J = 7.6, 7.1 Hz, 2 H),
0.16 (s, 9 H); 13C NMR (125 MHz, CDCl3): d = 141.3, 128.2
(2 C), 128.0 (2 C), 125.5, 106.8, 87.4, 34.5, 30.0, 19.1, 0.0 (3
C); HRMS (EI, 70 eV): m/z calcd for C14H20Si [M]+,
216.1334; found, 216.1305; Anal. Calcd for C14H20Si: C,
77.71; H, 9.32. Found: C, 77.53; H, 9.13.
(2) (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. Rev.
2004, 104, 6217. (b) Fürstner, A.; Martin, R. Chem. Lett.
2005, 34, 624. (c) Nagano, T.; Hayashi, T. Org. Lett. 2005,
7, 491. (d) Sapountzis, I.; Lin, W.; Kofink, C. C.;
Despotopoulou, C.; Knochel, P. Angew. Chem. Int. Ed.
2005, 44, 1654. (e) Duplais, C.; Bures, F.; Sapountzis, I.;
Korn, T. J.; Cahiez, G.; Knochel, P. Angew. Chem. Int. Ed.
2004, 43, 2968. (f) Scheiper, B.; Bonnekessel, M.; Krause,
H.; Fürstner, A. J. Org. Chem. 2004, 69, 3943.
(g) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004,
2081. (h) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H.
J. Am. Chem. Soc. 2002, 124, 13856. (i) Dohle, W.; Kopp,
F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901; and
references cited therein.
(3) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686. (b) See also: Nakamura, M.;
Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978.
(c) Nakamura, M.; Matsuo, K.; Inoue, T.; Nakamura, E. Org.
Lett. 2003, 5, 1373.
(12) Typical Experimental Procedure B (Table 3); 4-(4-
Cyanophenyl)-N-(benzyloxycarbonyl)piperidine: In a
dry reaction vessel, a mixture of ArZnBr (0.48 M solution in
THF, 4.2 mL, 2.0 mmol) and Me3SiCH2MgCl (1.1 M
solution in Et2O, 1.8 mL, 2.0 mmol) was stirred at 0 °C for 1
h. To the resulting solution was added TMEDA (0.30 mL,
2.0 mmol), 4-bromo-N-(benzyloxycarbonyl)piperidine (298
mg, 1.0 mmol), and then FeCl3 (0.1 M solution in THF, 0.5
mL, 0.05 mmol) at 0 °C. The reaction mixture was stirred at
30 °C for 6 h. After quenching with a saturated aqueous
solution of NH4Cl, the mixture was filtered through a pad of
Florisil®, and concentrated in vacuo. Purification by silica
gel chromatography afforded 4-(4-cyanophenyl)-N-
(benzyloxycarbonyl)piperidine (253 mg, 79%); FTIR (neat):
3014 (w), 2943 (w), 2923 (w), 2856 (w), 2227 (m), 1688 (s),
1466 (m), 1455 (m), 1436 (m), 1273 (w), 1218 (s), 1125 (m),
1057 (m), 1009 (m), 917 (w), 838 (m), 760 (s), 702 (s) cm–1;
1H NMR (500 MHz, CDCl3): d = 7.59 (d, J = 8.6 Hz, 2 H),
7.39–7.26 (m, 7 H), 5.16 (br s, 2 H), 4.35 (br s, 2 H), 2.89 (br
s, 2 H), 1.90–1.78 (m, 2 H), 1.70–1.58 (m, 2 H); 13C NMR
(125 MHz, CDCl3): d = 155.2, 150.8, 136.7, 132.4 (2 C),
128.5 (2 C), 128.0, 127.9 (2 C), 127.6 (2 C), 118.8, 110.3,
67.2, 44.3 (2 C), 42.7, 32.6 (2 C); Anal. Calcd for
(4) (a) Martin, R.; Fürstner, A. Angew. Chem. Int. Ed. 2004, 43,
3955. (b) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(c) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J.
W.; Hird, M. Chem. Commun. 2004, 2822.
(5) (a) Frisch, A. C.; Beller, M. Angew. Chem. Int. Ed. 2005, 44,
674. (b) Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004,
126, 7788. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004,
126, 1340. (d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 14726. (e) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew.
Chem. Int. Ed. 2002, 41, 4137.
(6) For overviews of the difficulty for cross-coupling of alkyl
halides: (a) Cardenas, D. J. Angew. Chem. Int. Ed. 2003, 42,
384. (b) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. Rev.
2000, 100, 3187.
(7) An organomanganate and an organozincate have been used
in the iron-catalyzed cross-coupling of aryl electrophiles;
see ref. 2h.
(8) Boudier, A.; Bromm, L. O.; Lots, M.; Knochel, P. Angew.
Chem. Int. Ed. 2000, 39, 4414.
(9) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.;
Reddy, C. K. Angew. Chem. Int. Ed. Engl. 1997, 36, 1496.
(10) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett.
1977, 679.
(11) Typical Experimental Procedure A (Table 2); 5-Phenyl-
1-(trimethylsilyl)pent-1-yne: In a dry reaction vessel, a
mixture of ZnCl2·TMEDA (379 mg, 1.5 mmol) and PhMgBr
(0.93 M solution in THF, 3.22 mL, 3.0 mmol) was stirred for
C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.80; H,
6.42; N, 8.54.
(13) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2001, 123, 5374.
Synlett 2005, No. 11, 1794–1798 © Thieme Stuttgart · New York