Nickel-catalyzed cross-coupling between functionalized primary or secondary alkylzinc halides and primary alkyl halides

Article abstract of DOI:10.1021/jo0105787

In the presence of Bu₄NI (3 equiv) and 4-fluorostyrene (20 mol %), unreactive primary and secondary alkylzinc iodides undergo nickel-catalyzed cross-couplings with various primary alkyl iodides or bromides. More reactive secondary dialkylzincs and the mixed zinc organometallics RZnTMSM undergo the cross-coupling reaction in the absence of Bu₄NI. The bicyclic secondary diorganozinc 6 prepared via boron-zinc exchange reacts with high retention of configuration. Free NH-groups are tolerated in the cross-coupling allowing the synthesis of aminated products.

Full text of DOI:10.1021/jo0105787

J . Org. Chem. 2002, 67, 79-85
79
Nick el-Ca ta lyzed Cr oss-Cou p lin g betw een F u n ction a lized P r im a r y
or Secon d a r y Alk ylzin c Ha lid es a n d P r im a r y Alk yl Ha lid es
Anne Eeg J ensen and Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universit a¨ t M u¨ nchen,
Butenandtstr. 5-13, 81377 Munich, Germany
knoch@cup.uni-muenchen.de
Received J une 11, 2001
4
In the presence of Bu NI (3 equiv) and 4-fluorostyrene (20 mol %), unreactive primary and secondary
alkylzinc iodides undergo nickel-catalyzed cross-couplings with various primary alkyl iodides or
bromides. More reactive secondary dialkylzincs and the mixed zinc organometallics RZnTMSM
undergo the cross-coupling reaction in the absence of Bu
prepared via boron-zinc exchange reacts with high retention of configuration. Free NH-groups
are tolerated in the cross-coupling allowing the synthesis of aminated products.
4
NI. The bicyclic secondary diorganozinc
6
In tr od u ction
4
the presence of Bu NI allows the cross-coupling between
various functionalized primary alkyl iodides and primary
or secondary alkylzinc iodides. Since a broad range of
polyfunctional alkylzinc iodides are available from the
corresponding alkyl iodides by insertion of zinc foil, this
modification significantly expands the scope of the cross-
coupling reaction. The limitations of the reaction as well
as applications to the preparation of nitrogen-containing
products are reported.
Transition metal catalyzed cross-coupling reactions are
1
important methods for forming new C-C bonds. Espe-
8
2
3
cially, Pd(0) catalysis and Cu(I)-mediated reactions have
occupied a central role. Other transition metals such as
nickel-4 and iron-complexes5 have found less general
applications. Recently, we have reported a new cross-
coupling between functionalized diorganozincs and pri-
mary alkyl iodides in the presence of catalytic amounts
of Ni(acac) (7.5-10 mol %) and a reaction promotor such
2
Resu lts a n d Discu ssion
6
as m- or p-trifluoromethylstyrene. Although various
diorganozincs react well under these conditions with a
range of primary alkyl iodides, the reaction does not
proceed with alkylzinc halides. Recently, we have also
Primary or secondary alkyl iodides readily react with
zinc foil or zinc dust in THF, furnishing alkyzinc iodides
of type 1 in good yields.4
h-i,8
These alkylzinc iodides of
found that the presence of Bu
4
NI (3 equiv) considerably
type 1 react with functionalized primary alkyl iodides of
improves the rate of Ni(0)-catalyzed cross-coupling reac-
type 3 in the presence of Bu NI (3 equiv), p-fluorostyrene
4
tions between functionalized benzylic zinc halides and
primary alkyl iodides. Herein, we wish to report that
(2, 20 mol %), and Ni(acac) (10 mol %) in a 2:1 THF/
NMP (N-methylpyrrolidinone) mixture at -5 °C within
2
7
a few hours, providing the expected cross-coupling prod-
ucts of type 4 in 48-82% yields (Scheme 1 and Table 1).
The role of 4-fluorostyrene is to facilitate the reductive
(
1) (a) Diederich, F., Stang, P. J ., Eds. In Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, Germany, 1998. (b)
Nicolaou, K. C.; Sorensen, E. J .; In Classics in Total Synthesis; VCH:
Weinheim, Germany, 1996; pp 565-631. (c) Tsuji, J . Transition Metal
Reagents and Catalysts: Innovations in Organic Synthesis; Wiley: New
York, 1995. (d) Erdik, E. Tetrahedron 1992, 48, 9577-648.
elimination step by removing electron density from the
6
metal center. The presence of Bu
4
NI is essential for the
reaction. In its absence, no product was formed.
(2) Tsuji, J . Palladium Reagents and Catalysts. Innovations in
Organic Synthesis, Wiley: Chichester, 1995.
Both keto and ester groups (entries 1 and 3-6 of Table
(
(
3) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
4) (a) Kumada, M. Pure Appl. Chem. 1980, 52, 669-79. (b) Luh,
1
) as well as an amido function (entry 2) are well
tolerated in the alkyl iodides. The presence of a functional
group reduces the reactivity of the organozinc reagent
through intramolecular complexation of zinc with the
functional group. However, by increasing the amount of
zinc reagent from 3 to 5 equiv, the cross-coupling product
1b, entry 6 of Table 1) can be obtained in good yield.
The use of a larger excess of the alkylzinc iodide (5 equiv)
allows, in all cases, an improvement of the reaction yield
T.-Y. Acc. Chem. Res. 1991, 24, 257-63. (c) Sengupta, S.; Leite, M.;
Raslan, D. S.; Quesnelle, C.; Snieckus, V. J . Org. Chem. 1992, 57,
4
066-68. (d) Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513-16. (e)
Shirakawa, E.; Yamasaki, K.; Hiyama, T. Synthesis 1998, 1544-49.
f) Sophia, A.; Karlstr o¨ m, E.; Itami, K.; B a¨ ckvall, J .-E. J . Org. Chem.
(
1
2
4
1
999, 64, 1745-49. (g) Tang, X. Q.; Montgomery, J . J . Am. Chem. Soc.
000, 122, 6950-54. (h) Montgomery, J . Acc. Chem. Res. 2000, 33,
67-73. (i) Giovannini, R.; Knochel, P. J . Am. Chem. Soc. 1998, 120,
1186-87. (j) Lipshutz, B. H. Adv. Synth. Catal. 2001, 343, 313-26.
(
(
k) Lipshutz, B. H.; Bulow, G.; Fernandez-Lazaro, F.; Kim, S.-K.; Lowe,
R.; Mollard, P.; Stevens, K. L. J . Am. Chem. Soc. 1999, 121, 11664-
3.
(
2
entries 1, 2, and 6). Diorganozinc reagents (R Zn) are
more reactive than organozinc iodides; however, only one
7
(
5) (a) Cahiez, G.; Marquais, S. Pure Appl. Chem. 1996, 68, 53-60.
b) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199-205.
6) (a) Devasagayaraj, A.; St u¨ demann, T.; Knochel, P. Angew. Chem.
(
alkyl group is transferred, leading to the waste of one
(
alkyl group.4
h-i,8
The use of mixed diorganozincs bearing
1
995, 107, 2952-54; Angew. Chem., Int. Ed. Engl. 1995, 34, 2723-
5. (b) Giovannini, R.; St u¨ demann, T.; Dussin, G.; Knochel, P. Angew.
2
a nontransferable trimethylsilylmethyl group solves this
problem. Thus, when mixed organozinc reagents of the
Chem. 1998, 110, 2512-17; Angew. Chem., Int. Ed. 1998, 37, 2387-
0. (c) Giovannini, R.; St u¨ demann, T.; Devasagayaraj, A.; Dussin, G.;
Knochel, P. J . Org. Chem. 1999, 64, 3544-53.
7) Piber, M.; J ensen, A. E.; Rottl a¨ nder, M.; Knochel. P. Org. Lett.
999, 1, 1323-26.
9
(
(8) Knochel, P., J ones, P., Eds. Organozinc Reagents: A Practical
Approach; Oxford University Press: New York, 1999.
1
1
0.1021/jo0105787 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

8
0
J . Org. Chem., Vol. 67, No. 1, 2002
J ensen and Knochel
Sch em e 1
Ta ble 2. Ni(0)-Ca ta lyzed Cr oss-Cou p lin g of Mixed
Alk yl(TMSM)zin cs 5a -c w ith Alk yl Iod id es in th e
P r esen ce of 2 (20 m ol%) in THF /NMP
Ta ble 1. Ni(0)-Ca ta lyzed Cr oss-Cou p lin g of P r im a r y
Alk yl Iod id es 3a -e w ith Alk ylzin c Iod id es 1a -b in th e
P r esen ce of Bu 4NI (3 equ iv) a n d 2 (20 m ol%) in THF /NMP
a
Isolated analytically pure products. b 4-trimethylsilylbutyl
phenyl ketone is also isolated in 21% yield.
in 50% yield. In this case, the cross-coupling product with
the TMSM group (phenyl trimethylsilyl ketone) is also
isolated in 21% yield (entry 4). The secondary alkyl
reagent cyclohexyl trimethylsilylmethyl zinc (5c) reacts
smoothly with 3a , affording the coupling product 4h in
6
5% yield (entry 5). This result led us to examine in more
detail the reaction of secondary dialkylzincs with alkyl
iodides. With these more reactive zinc reagents, a fast
cross-coupling occurs at -30 °C (16 h), furnishing the
products 4h -m in 56-73% yields. Due to the higher
reactivity of secondary dialkylzincs compared to that of
primary or secondary alkylzinc iodides, the use of
a
Isolated yield of analytically pure product. b Yield obtained by
using 5 equiv of RZnI instead of 3 equiv.
4
Bu NI as an additive is unnecessary. The results of these
cross-couplings are summarized in Table 3. Interestingly,
Sch em e 2
di-exo-2-norbornylzinc 6, obtained by the hydroboration
of norbonene with Et
2
BH and subsequent boron-zinc
exchange10 with i-Pr
Zn, reacts with the iodoketone 3a
2
and provides diastereomerically enriched ketone 7 in 61%
yield (Scheme 3), demonstrating that this nickel-cata-
lyzed cross-coupling proceeds with high retention of
configuration of the secondary zinc reagent.1 Over 95%
retention of configuration was observed, and the product
1
9
type RZnCH
2
SiMe
3
(5) are used, the cross-coupling with
7
was obtained in an exo:endo ratio of >95:5. This
various alkyl iodides proceeds readily at -20 °C and does
not require the use of Bu NI as a reaction promoter. Only
the addition of 4-fluorostyrene (2) is necessary for the
indicates that this Ni-catalyzed cross-coupling proceeds
4
with retention of configuration of the metalated carbon
1c
(
>95% retention).1
reaction to occur (Scheme 2 and Table 2).
The mixed zinc reagents RZnCH
) were prepared by reacting the corresponding alkylzinc
iodide (RZnI) with commercially available Me SiCH Li.
2 3
SiMe (RZnTMSM,
(
9) (a) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.;
5
Reddy, C. K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1496-98. (b)
3
2
J ones, P.; Reddy, K. C.; Knochel, P. Tetrahedron 1998, 54, 1471-90.
(
1
c) J ones, P.; Knochel, P. J . Chem. Soc., Perkins Trans. 1 1997, 3117-
Thus, the reaction of pentyl trimethylsilylmethyl zinc
with various functionalized alkyl iodides furnishes the
expected cross-coupling products in 71-75% yields (en-
tries 1-3 of Table 2). A functionalized zinc reagent like
8.
(
10) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J . Org. Chem. 1996, 61, 8229-43.
11) (a) Boudier, A.; Darcel, C.; Flachsmann, F.; Micouin, L.;
(
Oestreich, M.; Knochel, P. Chem. Eur. J . 2000, 6, 2748-61. (b) Boudier,
A.; Knochel, P. Tetrahedron Lett. 1999, 40, 687-90. (c) Boudier, A.;
Hupe, E.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2294-97.
PivO(CH
2 5
) ZnTMSM (5b) reacts with 3-iodopropyl phenyl
ketone (3a ) and provides the cross-coupling product 4f

Ni-Catalyzed Cross-Coupling
J . Org. Chem., Vol. 67, No. 1, 2002 81
Ta ble 3. Ni(0)-Ca ta lyzed Cr oss-Cou p lin g of Secon d a r y
Alk ylzin c Iod id es 1c-d w ith Alk yl Iod id es in th e
P r esen ce of 2 (20 m ol%) in THF /NMP
Ta ble 4. Ni(0)-Ca ta lyzed Cr oss-Cou p lin g of
F u n ction a lized P r im a r y Alk yl Br om id es w ith Va r iou s
Zin c Or ga n om eta llics in th e P r esen ce of Bu 4NI (3 equ iv)
a n d 2 (20 m ol%) in THF /NMP
a
Isolated yields of analytically pure products. b Reaction tem-
a
Isolated yield of analytically pure product.
perature ) -25 °C; Bu4NI was omitted.
Sch em e 3
Sch em e 4
We have also examined the reactivity of alkyl bromides
of type 8 and found that in the presence of Bu NI (3
4
Sch em e 5
equiv), the cross-coupling reaction takes place to furnish
the desired product. As nucleophiles dialkylzincs such as
Pent Zn (entry 1 of Table 4), alkylzinc iodides such as
2
pentylzinc iodide (1a ; entries 2 and 3), or the function-
alized alkylzinc reagent 4-pivaloyloxybutyl zinc iodide
(1e; entry 4) have been used. Finally, a secondary
alkylzinc iodide such as c-HexZnI (1d ) aslo reacts, leading
to the product 4m in 63% yield (Scheme 4 and Table 4).
The side reactions in these nickel-catalyzed cross-
couplings are mainly an iodine-zinc exchange reaction.
No homocoupling product is observed.
This cross-coupling procedure can be successfully ap-
plied to alkyl iodides bearing an amino function with an
unprotected NH group. Thus, the reaction of Pent
2
Zn
We noticed that an excess of this ammonium salt is
necessary to achieve the optimum rate enhancement. The
with the amino acid derivative 9 and the oxazolidinone
1
2
1
0
provides, under the standard reaction conditions, the
4
Bu NI-saturated reaction mixture has proven to be the
1
4
expected products 11 and 12 in 56 and 60% yields,
best medium for this type of cross-coupling. Concerning
respectively (Scheme 5).
Whereas we have shown that 4-fluorostyrene facili-
6
(13) (a) Wright, S. W.; Hageman, D. L.; McClure, L. D. J . Org. Chem.
994, 59, 6095-97. (b) Nguefack, J .-F.; Bollit, V.; Sinou, D. Tetrahedron
1
tates the reductive elimination of the intermediate
Lett. 1996, 37, 5527-30. (c) Powell, N. A.: Rychnovsky, S. D.
Tetrahedron Lett. 1996, 37, 7901-04. (d) Albanese, D.; Landini, D.
Penso, M.; Petricci, S. Synlett, 1999, 199-200. (e) Nakamura, K.;
Okubo, H.; Yamaguchi, M. Synlett 1999, 549-50. (f) Herrmann, W.
A.; Brossmer, C.; Reisinger, C.-P.; Riermeier, T. H.; O¨ fele, K.; Beller,
M. Chem. Eur. J . 1997, 3, 1357-64.
1
2
Ni(II) complex (R )(R )NiL
n
by removing electron density
1
3
from the metal center, the effect of Bu
4
NI is less clear.
(12) Sibi, P.; Renhowe, P. A. Tetrahedron Lett. 1990, 31, 7407-10.

8
2
J . Org. Chem., Vol. 67, No. 1, 2002
J ensen and Knochel
Sch em e 6
a
With NMP as a cosolvent. b With TBAI, in the absence of NMP.
phenyl sulfide (3f),18 5-iodopentyl pivalate (3h ),19 3-chloro-1-
piperidino-1-propanone,20 3-iodo-1-piperidino-1-propanone.
P r ep a r a tion of Alk ylzin c Iod id es of Typ e 1 (P en tyl-
zin c Iod id e). A 25 mL two-necked flask equipped with a
dropping funnel, a reflux condenser, and a stirring bar was
charged with cut zinc foil (Merck) (1.77 g, 27 mmol), flame-
dried, and flushed with argon. THF (1 mL) and 1,2-dibromo-
ethane (51 mg, 0.27 mmol) were added, and the zinc was
activated by being heated to reflux with a heat gun and then
cooled to room temperature. This procedure was repeated until
foam no longer formed as a result of the heating. The mixture
was heated to 50 °C followed by dropwise addition of pentyl
iodide (1.77 g, 9 mmol) in THF (4 mL). The mixture was kept
at 50 °C until complete conversion was reached (checked by
GC analysis, approximately 4 h).
the mechanism of action of TBAI, the coordination of
iodide to the alkylzinc iodide would possibly lead to a
zincate of type 13 as an intermediate. This species should
have an enhanced reactivity. To test this possibility,
TBAI was used as an additive in the 1,4-addition reaction
of dipentylzinc to cyclohexanone. Earlier experiments
with this system had shown that NMP is needed as a
cosolvent (THF/NMP 1:1) for the addition to take place.15
In pure THF, no reaction occurs. However, when TBAI
21
(1 equiv) was added, the addition reaction did take place
in pure THF, although in lower yield (41%) than in the
THF/NMP mixture, leading to the 1,4-addition product
1
4 (Scheme 6). Other possibilities like a change of the
ionic strength of the medium or stabilization of a highly
reactive low-valent nickel species may also be considered.
In summary, reaction conditions have been found
allowing the cross-coupling of readily available function-
alized alkylzinc halides with functionalized (and unfunc-
tionalized) alkyl iodides. Further investigations are
currently underway.
Typ ica l P r oced u r e A: Nick el-Ca ta lyzed Cr oss-Cou p -
lin g b et w een P r im a r y Alk yl Iod id es a n d Alk ylzin c
Iod id es. P r ep a r a tion of 1-P h en yl-1-octa n on e (4e). A dry
and argon-flushed 10 mL two-necked flask was charged with
Ni(acac)
-iodo-1-phenyl-1-propanone (3e, 780 mg, 3 mmol), 4-fluo-
rostyrene (74 mg, 0.6 mmol), and Bu NI (3.3 g, 9 mmol) were
2
(77 mg, 0.3 mmol). Dry THF (2 mL), NMP (1 mL),
3
4
successively added at room temperature. The reaction mixture
was cooled to -35 °C before the slow addition of a solution of
pentylzinc iodide (4.5 mL, 2 M, 9 mmol). The reaction mixture
was then allowed to warm to -5 °C. The conversion was
complete in 16 h, after which time the reaction was quenched
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under an
argon atmosphere in flame-dried glassware. THF was distilled
under argon from sodium/benzophenone. NMP was distilled
under argon from calcium hydride. Commercially available
materials were used without further purification. Reactions
were monitored by gas chromatography (GC) analysis of
worked up reaction aliquots. Analytical thin-layer chromatog-
raphy (TLC) was performed using Merck silica gel (60 F-254)
plates (0.25 mm) precoated with a fluorescent indicator.
Column chromatography was performed with 40-63 µm silica
gel (Merck). GC analysis was performed on a bonded 5%
phenylmethylpolysiloxane DB 5 capillary column (Megabore,
with saturated aqueous NH
extracted with ether (4 × 50-75 mL). The combined organic
phases were dried (MgSO ) and the solvents removed in vacuo.
4
Cl solution (2 mL) and the mixture
4
Flash chromatography on silica gel (pentane/ether 20:1)
furnished the cross-coupling product 4e as a colorless oil (349
mg, 57%). IR (KBr): 2956 (s), 2856 (m), 1687 (s), 1449 (s), 1266
-1
1
(
2
(
2
2
7
m) cm . H NMR (300 MHz, CDCl
3
): δ 7.97 (d, J ) 7.2 Hz,
H), 7.56-7.42 (m, 3H), 2.95 (t, J ) 7.5 Hz, 2H), 1.76-1.20
13
m, 10H), 0.89 (t, J ) 6.6, 3H). C NMR (75 MHz, CDCl
3
): δ
00.8, 137.5, 133.2, 128.9, 128.4, 39.0, 31.9, 29.7, 29.5, 24.7,
3.6, 14.4. MS (EI, 70 eV): 204 (5), 133 (9), 120 (90), 105 (100),
7 (35). Anal. Calcd for C14 20O: C, 82.30; H, 9.87. Found:
1
5 m, 0.53 mm i.d., 2.65 µm df). NMR spectra were recorded
H
on a 200 or 300 MHz NMR spectrometer. Infrared spectroscopy
was performed with a Spectrum 1000 Perkin-Elmer FT-IR
spectrometer. The ionization method used for mass spectrom-
etry was electron impact (EI, 70 eV). Elemental analyses were
performed by the Microanalytical Service Laboratory of Uni-
versit a¨ t M u¨ nchen.
C, 82.52; H, 9.53. The products 4a -f as well as 4m ,n were
prepared according to this method.
1
-P h en yl-1-n on a n on e (4a ): From 4-iodo-1-phenyl-1-bu-
tanone (3a , 820 mg, 3 mmol) and pentylzinc iodide (6.0 mL,
1
.5 M, 9 mmol). Reaction time: 16 h at -5 °C. Purification by
flash chromatography (pentane/ether 20:1) yielded 4a as a
Sta r tin g Ma ter ia ls. The following starting materials were
prepared according to literature procedures: 1-iodo-4-octanone
colorless oil (509 mg, 78%). IR (KBr): 2926 (s), 2855 (m), 1688
6
c
16
(
(
3c), 4-iodo-1-phenyl-1-butanone (3a ), 5-iodopentanenitrile
1
7
6c
(17) Booth, B. L.; J ibodu, K. O.; Procenca, M. F. J . Chem. Soc.,
Perkin Trans. 1 1983, 1067-73.
3g), 3-iodo-1-piperidino-1-propanone (3b), 3-iodopropyl
(18) Rao, S. A.; Chou, T.-S.; Schipor, I.; Knochel, P. Tetrahedron,
(
14) The positive influence of highly ionic media for the performance
1992, 48, 2015-43.
of transition metal reactions has already been noticed: Calo, V.; Nacci,
(19) Ostwald, R.; Chavant, P.-Y.; Stadtm u¨ ller, H.; Knochel, P. J . Org.
Chem. 1994, 59, 4143-53.
A.; Lopez, L.; Mannarim, N. Tetrahedron Lett. 2000, 41, 8973-76.
(15) Reddy, C. K.; Devasagayaraj, A.; Knochel, P. Tetrahedron Lett.
(20) Willy, W. E.; McKean, D. R.; Garcia, B. A. Bull. Chem. Soc.
J pn. 1976, 49, 1989-95.
(21) Kuivila, H. G.; Maxfield, P. L. J . Organomet. Chem. 1967, 10,
41-51.
1
996, 37, 4495-98.
16) Kimura, N.; Takamuku, S. Bull. Chem. Soc. J pn. 1991, 64,
433-37.
(
2

Ni-Catalyzed Cross-Coupling
J . Org. Chem., Vol. 67, No. 1, 2002 83
(
(
1
s), 1445 (m) cm-1. 1H NMR (300 MHz, CDCl
m, 2H), 7.59-7.44 (m, 3H), 2.96 (t, J ) 7.4 Hz, 2H), 1.79-
.68 (m, 6H), 1.31-1.17 (m, 4H), 0.92 (t, J ) 7.4 Hz, 3H). 13
): δ 201.0, 137.5, 133.2, 128.9, 128.4,
9.3, 38.0, 37.5, 33.7, 27.1, 26.8, 22.1. MS (EI, 70 eV): 218
6), 133 (8), 120 (73), 105 (100), 77 (18). Anal. Calcd for
22O: C, 82.52; H, 10.16. Found: C, 82.90; H, 10.38.
Alternatively, 4a was prepared from 4-bromo-1-phenyl-1-
butanone (8c, 681 mg, 3 mmol). Reaction time: 24 h at -5 °C
457 mg, 70%) (entry 3, Table 4).
-P ip er id in o-1-octa n on e (4b): Prepared from 3-iodo-1-
3
): δ 8.00-7.96
1.67-1.58 (m, 2H), 0.68 (t, J ) 7.2 Hz, 2H), 0.00 (s, 9H). 13C
NMR (75 MHz, CDCl ): δ 198.9, 136.7, 133.2, 128.6, 127.8,
3
C
42.4, 18.7, 16.5, -2.0. MS (EI, 70 eV): 234 (3), 219 (44), 215
NMR (75 MHz, CDCl
3
(
3
(72), 144 (35), 120 (100), 105 (43), 73 (87).20
1-(3-Cycloh exylp r op a n oyl)-p ip er id in e (4m ): Prepared
from 3-bromo-1-piperidino-1-propanone (8b, 801 mg, 3 mmol)
and cyclohexylzinc iodide (4.5 mL, 2 M in THF, 9 mmol).
Reaction time: 16 h at -5 °C. Purification by flash chroma-
tography (pentane/EtOAc 8:2) yielded 4m as a colorless oil (421
15
C H
-1
(
mg, 63%). IR (KBr): 2922 (s), 2851 (m), 1644 (s) 1445 (m) cm .
1
1
H NMR (300 MHz, CDCl
(m, 2H), 1.76-1.63 (m, 13H), 1.57-1.50 (m, 4H), 1.23-1.20
(m, 2H). 13C NMR (75 MHz, CDCl
): δ 172.2, 47.1, 43.0, 37.9,
3
): δ 3.52-3.42 (m, 4H), 2.35-2.29
piperidino-1-propanone (3b, 798 mg, 3 mmol) and pentylzinc
iodide (6.0 mL, 1.5 M in THF, 9 mmol). Reaction time: 16 h
at -5 °C. Purification by flash chromatography (pentane/
EtOAc 8:2) yielded 4b as a colorless oil (392 mg, 62%). IR
3
33.5, 33.5, 33.3, 31.4, 27.0, 27.0, 26.6, 26.6, 26.0, 25.0. MS (EI,
70 eV): 223 (3), 140 (25), 127 (100), 84 (18), 55 (10). Anal. Calcd
for C14H25ON: C, 75.29; H, 11.28; N, 6.27. Found: C, 75.31;
-
1
1
(
(
(
KBr): 2930 (s), 2855 (m), 1644 (s), 1434 (m) cm . H NMR
300 MHz, CDCl ): δ 3.47 (bs, 2H), 3.32 (bs, 2H), 2.27-2.21
m, 2H), 1.60-1.48 (m, 8H), 1.25-1.21 (m, 8H), 0.81 (t, J )
3
H, 11.16; N, 6.11.
7-Oxo-7-p h en ylh ep t yl p iva la t e (4n ): Prepared from
4-bromo-1-phenyl-1-butanone (8c, 227 mg, 1 mmol) and {4-
[(2,2-dimethylpropanoyl)oxy]-butyl}zinc iodide (2.5 mL, 2 M
in THF, 5 mmol). Reaction time: 20 h at -5 °C. Purification
by flash chromatography (pentane/EtOAc 95:5) yielded 4n as
a colorless oil (222 mg, 73%). IR (KBr): 2934 (s), 2859 (m),
1
3
6
4
7
3
.6 Hz, 3H). C NMR (75 MHz, CDCl ): δ 171.9, 47.1, 43.0,
2.7, 33.9, 32.1, 29.9, 29.5, 27.0, 25.9, 25.0, 23.0, 14.4. MS (EI,
0 eV): 211 (7), 140 (41), 127 (100), 84 (41). Anal. Calcd for
13
C H25ON: C, 73.88; H, 11.92; N, 6.63. Found: C, 73.94; H,
1
1.86; N, 6.40.
-
1 1
Alternatively, 4b was prepared from 3-bromo-1-piperidino-
-propanone (8b, 220 mg, 1 mmol). Reaction time: 16 h at 0
1727 (s), 1688 (s), 1285 (s), 1157 (s) cm . H NMR (300 MHz,
CDCl ): δ 7.89 (d, J ) 6.9 Hz, 2H), 7.53-7.38 (m, 3H), 3.97 (t,
J ) 6.6 Hz, 2H), 2.89 (t, J ) 7.5 Hz, 2H), 1.80-1.25 (m, 10H),
1.12 (s, 9H). 13C NMR (75 MHz, CDCl
): δ 200.8, 179.0, 137.5,
1
°
3
C (145 mg, 69%) (entry 2, Table 4).
-Tr id eca n on e (4c): Prepared from 1-iodo-4-octanone (3c,
4
3
2
2
.29 g, 9 mmol) and pentylzinc iodide (13.5 mL, 2 M in THF,
7 mmol). Reaction time: 16 h at -5 °C. Purification by flash
133.3, 128.9, 128.4, 64.7, 39.1, 38.9, 29.6, 29.5, 29.0, 27.6, 26.2,
24.6. MS (EI, 70 eV): 304 (2), 120 (94), 105 (100), 57 (23). Anal.
chromatography (pentane/ether 20:1) yielded 4c as a colorless
Calcd for C19
9.40.
28 3
H O : C, 74.96; H, 9.27. Found: C, 74.99; H,
-
1
oil (925 mg, 52%). IR (KBr): 2873 (s), 1716 (s), 1467 (m) cm
.
1
H NMR (300 MHz, CDCl
.52 (m, 4H), 1.33-1.26 (m, 12H), 0.92-0.84 (m, 6H). 13C NMR
75 MHz, CDCl ): δ 212.0, 43.2, 42.9, 32.2, 29.7, 29.6, 29.5,
6.3, 24.2, 23.0, 22.7, 14.4, 14.2. MS (EI, 70 eV): 198 (6), 156
26O: C,
3
): δ 2.39 (t, J ) 7.4 Hz, 4H), 1.57-
P r ep a r a t ion of Mixed Alk yl(TMSM)zin cs of Typ e 5
(P en tyl(TMSM)zin c). A 25 mL two-necked flask equipped
with a stirring bar was flame-dried and flushed with argon.
Pentylzinc iodide (4.5 mL, 2 M in THF, 9 mmol) was added
and cooled to -40 °C before adding trimethylsilylmethyl-
lithium (9 mL, 1 M, 9 mmol) dropwise over 5 min. The reaction
was left for 1 h at -40 °C before being warmed to room
temperature and then concentrated in vacuo until an ap-
proximately 2 M solution was obtained, which was used
directly in the cross-coupling reaction.
1
(
2
3
(10), 141 (72), 85 (85), 57 (100). Anal. Calcd for C13
H
7
8.72; H, 13.21. Found: C, 78.65; H, 13.31.
Eth yl Non a n oa te (4d ): Prepared from ethyl 4-iodobu-
tanoate (3d , 726 mg, 3 mmol) and pentylzinc iodide (4.5 mL,
2
M in THF, 9 mmol). Reaction time: 16 h at -5 °C.
Purification by flash chromatography (pentane/ether 20:1)
yielded 4d as a colorless oil (266 mg, 48%). IR (KBr): 2957
Typ ica l P r oced u r e B: Nick el-Ca ta lyzed Cr oss-Cou -
p lin g betw een P r im a r y Alk yl Iod id es a n d Mixed Alk yl-
(TMSM)zin cs. P r ep a r a tion of 1-P h en yl-1-n on a n on e (4a ).
A dried and argon-flushed 10 mL two-necked flask was
-
1
1
(m), 2928 (s), 2856 (m) 1739 (s) cm
.
H NMR (300 MHz,
CDCl
3
): δ 4.10 (q, J ) 7.2 Hz, 2H), 2.27 (t, J ) 7.5 Hz, 2H),
1
.60 (q, J ) 7.2 Hz, 2H), 1.26-1.21 (m, 13H), 0.86 (t, J ) 6.6
13
Hz, 3H). C NMR (75 MHz, CDCl
7.9, 27.8, 27.8, 21.3, 16.3, 12.9, 12.7. MS (EI, 70 eV): 186
4), 141 (39), 101 (60), 88 (100). Anal. Calcd for C11 : C,
8.72; H, 13.21. Found: C, 78.65; H, 13.31.
Alternatively, 4d was prepared from ethyl 4-bromobu-
tanoate (8a , 585 mg, 3 mmol) and dipentylzinc (1.2 mL, 5 M,
3
): δ 172.5, 58.8, 33.0, 30.5,
2
charged with Ni(acac) (77 mg, 0.3 mmol). Dry THF (2 mL),
2
(
7
NMP (1 mL), 4-iodo-1-phenyl-1-butanone (3a , 820 mg, 3
mmol), and 4-fluorostyrene (74 mg, 0.6 mmol) were added
successively at room temperature. The reaction mixture was
cooled to -60 °C before the slow addition of a solution of
pentyl(TMSM)zinc (4.5 mL, 2 M in THF, 9 mmol). The reaction
mixture was then allowed to warm to -20 °C. The conversion
was complete in 1 h, after which time the reaction was
22 2
H O
6
1
mmol) omitting Bu
6 h at -25 °C (102 mg, 55%) (entry 1, Table 4).
-Oxo-8-p h en yloctyl P iva la te (4f): Prepared from 4-iodo-
-phenyl-1-butanone (3a , 274 mg, 1 mmol) and {5-[(2,2-
4
NI (typical procedure C). Reaction time:
8
quenched with saturated aqueous NH
the mixture extracted with ether (4 × 50-75 mL). The
combined organic phases were dried (MgSO ) and the solvents
4
Cl solution (2 mL) and
1
dimethylpropanoyl)oxy]-pentyl}zinc iodide (2.5 mL, 2 M in
THF, 5 mmol). Reaction time: 16 h at -5 °C. Purification by
flash chromatography (pentane/EtOAc 95:5) yielded 4f as a
colorless oil (250 mg, 78%). IR (KBr): 2933 (s), 2857 (m), 1728
4
removed in vacuo. Flash chromatography on silica gel (pen-
tane/ether 20:1) furnished the cross-coupling product 4e as a
colorless oil (481 mg, 74%). The products 4a ,b,f-h were
prepared according to this method.
-
1
1
(
(
s) 1688 (s) cm
3
. H NMR (300 MHz, CDCl ): δ 7.98-7.95
m, 2H), 7.56-7.44 (m, 3H), 4.05 (t, J ) 6.6 Hz, 2H), 2.97 (t,
Octyl P h en yl Su lfid e (4 g): Prepared from 3-iodopropyl
phenyl sulfide (3f, 556 mg, 2 mmol) and pentyl(TMSM)zinc
iodide (2 mL, 2 M in THF, 4 mmol). Reaction time: 16 h at
-20 °C. Purification by flash chromatography (pentane/ether
20:1) yielded 4g as a colorless oil (300 mg, 71%). IR (KBr):
J ) 7.4 Hz, 2H), 1.77-1.72 (m, 2H), 1.63-1.60 (m, 2H), 1.36
m, 6H), 1.20 (s, 9H). 13C NMR (75 MHz, CDCl
): δ 200.9,
79.6, 137.5, 133.2, 128.9, 128.4, 64.8, 39.1, 38.9, 29.7, 29.6,
9.5, 29.0, 27.6, 26.2, 24.7. MS (EI, 70 eV): 318 (3), 120 (88),
05 (100), 57 (28). Anal. Calcd for C20 : C, 75.43; H, 9.49.
(
3
1
2
1
-
1
1
H
30
O
3
2957 (m), 2927 (s), 2855 (m), 1480 (w) cm
MHz, CDCl ): δ 7.25-7.03 (m, 5H), 2.82 (t, J ) 7.5 Hz, 2H),
1.59-1.51 (m, 2H), 1.35-1.31 (m, 2H), 1.21-1.10 (m, 6H), 0.80
(t, J ) 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl
): δ 137.5, 129.2,
129.2, 126.0, 34.0, 32.2, 29.6, 29.3, 23.1, 14.5. MS (EI, 70 eV):
222 (55), 126 (26), 110 (100), 77 (9). Anal. Calcd for C14
. H NMR (300
Found: C, 75.47; H, 9.32.
3
Alternatively, 4f was prepared from 4-iodo-1-phenyl-1-
butanone (3a , 820 mg, 3 mmol) and {5-[(2,2-dimethylpro-
panoyl)oxy]-pentyl}(TMSM)zinc (4.5 mL, 2 M in THF, 9 mmol)
3
omitting Bu
20 °C (474 mg, 50%) (entry 4, Table 2). By this reaction,
additional 1-phenyl-4-(trimethylsilyl)-1-butanone was formed
4
NI (typical procedure B). Reaction time: 6 h at
H22S:
-
C, 75.61; H, 9.97; S, 14.42. Found: C, 75.82; H, 10.28; S, 14.41.
4-Cycloh exyl-1-p h en yl-1-bu ta n on e (4h ): Prepared from
4-iodo-1-phenyl-1-butanone (3a , 544 mg, 2 mmol) and pentyl-
(TMSM)zinc iodide (2 mL, 2 M in THF, 4 mmol). Reaction
1
as a byproduct (147 mg, 21%). H NMR (300 MHz, CDCl
7
3
): δ
.95-7.90 (m, 2H), 7.60-7.46 (m, 3H), 2.97 (t, J ) 7.2 Hz, 2H),

8
4
J . Org. Chem., Vol. 67, No. 1, 2002
J ensen and Knochel
time: 5 h at -20 °C. Purification by flash chromatography
pentane/ether 20:1) yielded 4h as a colorless oil (303 mg, 65%).
1.53 (m, 6H), 1.21-1.10 (m, 8H), 0.87 (t, J ) 7.1 Hz, 3H), 0.81-
(
0.79 (m, 1H). 13C NMR (75 MHz, CDCl
3
): δ 174.3, 60.5, 37.7,
-
1 1
IR (KBr): 2925 (s), 2849 (s), 1687 (s), 1448 (m) cm . H NMR
300 MHz, CDCl ): δ 7.87-7.84 (m, 2H), 7.46-7.32 (m, 3H),
.83 (t, J ) 7.5 Hz, 2H), 1.70-1.53 (m, 4H), 1.18-1.02 (m, 2H),
37.3, 35.6, 33.6, 27.0, 26.7, 22.7, 18.8, 14.6, 14.0. MS (EI, 70
eV): 198 (3), 155 (94), 135 (37), 101 (27), 88 (100). Anal. Calcd
for C12H O : C, 72.68; H, 11.18. Found: C, 72.80; H, 10.96.
22 2
(
3
2
0
1
1
3
.81-0.77 (m, 2H). C NMR (75 MHz, CDCl
3
): δ 200.8, 137.5,
5-Cycloh exylp en tyl P iva la te (4k ): Prepared from 5-io-
dopentyl pivalate (3h , 894 mg, 3 mmol) and dicyclohexylzinc
(7.5 mL, 0.8 M in THF, 6 mmol). Reaction time: 16 h at -20
°C. Purification by flash chromatography (pentane/ether 20:
1) yielded 4k as a colorless oil (425 mg, 56%). IR (KBr): 2924
28.9, 128.0, 39.3, 38.0, 37.5, 33.7, 33.7, 27.1, 26.8, 26.8, 22.7.
MS (EI, 70 eV): 230 (8), 120 (100), 105 (71), 77 (28). Anal.
Calcd for C16 22O: C, 83.43; H, 9.63. Found: C, 83.44; H, 9.85.
H
P r ep a r a tion of Din or bor n ylzin c (6). A 25 mL two-
necked flask equipped with a stirring bar was flame-dried and
flushed with argon. 2-Norbornene (376 mg, 4 mmol) was added
and the flask degassed 3 times before the dropwise addition
of diethylborane (1.6 mL, 7 M, 12 mmol) at room temperature.
The reaction mixture was then left for 16 h at 50 °C. Excess
-
1
1
(s), 2852 (m), 1731 (s), 1156 (s) cm
CDCl ): δ 3.97 (t, J ) 6.6 Hz, 2H), 1.63-1.54 (m, 6H), 1.50-
1.42 (m, 5H), 1.20-1.09 (m, 6H), 1.125 (s, 9H), 0.83-0.72 (m,
2H). 13C NMR (75 MHz, CDCl
): δ 179.0, 64.8, 39.1, 38.7, 29.0,
27.6, 27.1, 26.8, 26.6. MS (EI, 70 eV): 254 (0), 152 (26), 124
. H NMR (300 MHz,
3
3
diethylborane was distilled off (25 °C, 1 mmHg, 3 h). i-Pr
2.4 mL, 5 M, 12 mmol) was added via syringe at room
temperature and the resulting mixture stirred at room tem-
perature for 5 h before excess i-Pr Zn was distilled off (25 °C,
mmHg, 2 h). The zinc reagent was taken up in THF (7 mL)
and transferred to a dried and argon-flushed Schlenk flask;
after centrifugation, the supernatant was concentrated in
vacuo and used directly in the cross-coupling reaction.
Typ ica l P r oced u r e C: Nick el-Ca ta lyzed Cr oss-Cou -
p lin g betw een P r im a r y Alk yl Iod id es a n d Secon d a r y
Dia lk ylzin cs. P r ep a r a tion of 4-Bicyclo[2.2.1]h ep t-2-yl-1-
p h en yl-1-bu ta n on e (7). A dried and argon-flushed 10 mL
2
Zn
(13), 103 (100), 96 (62), 57 (86). Anal. Calcd for C16
75.54; H, 11.89. Found: C, 75.77; H, 11.93.
30 2
H O : C,
(
5-Cycloh exylp en ta n en itr ile (4l): Prepared from 5-iodo-
pentanenitrile (3f, 624 mg, 3 mmol) and dicyclohexylzinc (7.5
mL, 0.8 M in THF, 6 mmol). Reaction time: 16 h at -20 °C.
Purification by flash chromatography (pentane/ether 20:1)
yielded 4l as a colorless oil (330 mg, 67%). IR (KBr): 2924 (s),
2
1
-
1
1
2851 (s), 2246 (w), 1448 (m) cm
CDCl ): δ 2.26 (t, J ) 7.1 Hz, 2H), 1.64-1.52 (m, 7H), 1.43-
1.33 (m, 2H), 1.15-1.09 (m, 6H), 0.85-0.79 (m, 2H). C NMR
(75 MHz, CDCl ): δ 120.2, 37.8, 36.9, 33.2, 33.2, 27.0, 26.7,
26.7, 26.3, 26.0, 17.5. MS (EI, 70 eV): 164 (12), 136 (67), 110
(100), 83 (63), 55 (79). Anal. Calcd for C11 19N: C, 79.94; H,
.
H NMR (300 MHz,
3
1
3
3
two-necked flask was charged with Ni(acac)
2
(26 mg, 0.1
H
mmol). Dry THF (0.7 mL), NMP (0.3 mL), 4-iodo-1-phenyl-1-
11.59; N, 8.47. Found: C, 79.91; H, 11.08; N, 8.38.
butanone (3a , 274 mg, 1 mmol), and 4-fluorostyrene (25 mg,
4-Hexyl-1,3-oxa zolid in -2-on e (12): Prepared from 4-(io-
domethyl)-1,3-oxazolidin-2-one (10, 340 mg, 1.5 mmol) and
dipentylzinc (0.6 mL, 5 M in THF, 3 mmol). Reaction time: 3
h at -30 °C. Purification by flash chromatography (pentane/
EtOAc 1:1) yielded 12 as a colorless oil (143 mg, 60%). IR
0
.2 mmol) were added successively at room temperature. The
reaction mixture was cooled to -60 °C before slow addition of
a solution of dinorbornylzinc (6) (2 mL, 2 M in THF, 4 mmol).
The reaction mixture was then allowed to warm to -15 °C.
The conversion was complete in 16 h, after which time the
-
1
1
(KBr): 3272 (m), 2956 (s), 2857 (s), 1754 (s) cm . H NMR
(300 MHz, CDCl ): δ 6.96 (bs, 1H), 4.43-4.37 (dt, J ) 8.4 and
0.9 Hz, 1H), 3.95-3.90 (m, 1H), 3.81-3.76 (m, 1H), 1.51-1.47
reaction was quenched with saturated aqueous NH
2 mL) and the mixture extracted with ether (4 × 50-75 mL).
The combined organic phase was dried (MgSO ) and the
solvents removed in vacuo. Flash chromatography on silica gel
pentane/ether 20:1) furnished the cross-coupling product 7 as
4
Cl solution
3
(
1
3
4
(m, 2H), 0.83-0.79 (t, J ) 8.0 Hz, 3H). C NMR (75 MHz,
CDCl ): δ 160.9, 70.7, 53.1, 37.7, 31.9, 29.3, 25.2, 23.1, 14.3.
MS (EI, 70 eV): 154 (0), 86 (100), 58 (6). Anal. Calcd for
9 16 2
C H O N: C, 63.13; H, 10.06; N, 8.18. Found: C, 63.20; H,
3
(
a colorless oil (146 mg, 61%, diastereomeric ratio > 95:5). IR
-
1
1
(
(
2
1
KBr): 2947 (s), 2868 (m), 1687 (s), 1449 (m) cm . H NMR
300 MHz, CDCl ): δ 7.88-7.84 (m, 2H), 7.47-7.32 (m, 3H),
.85 (t, J ) 7.5 Hz, 2H), 2.10 (bs, 1H), 1.88 (bs, 1H), 1.64-
.59 (m, 2H), 1.39-0.94 (m, 11H). 13C NMR (75 MHz, CDCl
):
10.00; N, 8.12.
3
Eth yl 2-[t-Bu toxyca r bon yl)a m in o]u n d eca n oa te (11):
Prepared from ethyl 2-[t-butoxycarbonyl)-amino]-6-iodohex-
anoate (9, 385 mg, 1 mmol) and dipentylzinc (0.4 mL, 5 M, 2
mmol). Reaction time: 4 h at -30 °C. Purification by flash
chromatography (pentane/EtOAc 8:1) yielded 11 as a colorless
oil (184 mg, 56%). IR (KBr): 3306 (m), 1745 (s), 1440 (m), 1403
3
δ 199.4, 136.1, 131.8, 127.0, 41.1, 40.9, 37.8, 37.6, 36.2, 35.5,
4.3, 29.1, 27.8, 22.6. MS (EI, 70 eV): 242 (9), 133 (13), 120
100), 105 (53). Anal. Calcd for C17 22O: C, 84.25; H, 9.15.
Found: C, 83.98; H, 9.24. The stereochemistry of the product
3
(
H
-
1
1
(m), 1226 (s) cm . H NMR (300 MHz, CDCl
3
): δ 4.95 (bd,
1
was determined by NOESY, HMBC, HMQC, COSY, and
H
1H), 4.23-4.08 (m, 3H), 1.70-1.62 (m, 1H), 1.59-1.48 (m, 1H),
1
3
13
and C NMR experiments. The observation of a NOE between
one of the protons (1.5 ppm) of the one carbon bridge with the
protons of the methylene group attached to the ring (1.2 ppm)
clearly indicated that the exo product had been formed.
The products 4h -m were prepared according to this method.
-Meth yl-1-ph en yl-1-h exan on e (4i): Prepared from 4-iodo-
-phenyl-1-butanone (3a , 274 mg, 1 mmol) and diisopropylzinc
0.55 mL, 3.7 M in THF, 2 mmol). Reaction time: 3 h at -30
C. Purification by flash chromatography (pentane/ether 20:
) yielded 4i as a colorless oil (121 mg, 63%). IR (KBr): 2955
1.39 (s, 9H), 1.25-1.16 (m, 17H), 0.81 (t, J ) 7.2 Hz, 3H).
C
NMR (75 MHz, CDCl ): δ 173.4, 155.8, 80.1, 61.5, 53.9, 42.7,
3
33.2, 32.2, 29.8, 29.7, 29.6, 29.6, 28.7, 23.0, 14.6, 14.4. MS (EI,
70 eV): 329 (2), 256 (42), 212 (76), 57 (100). Anal. Calcd for
C H O N: C, 63.13; H, 10.06; N, 8.18. Found: C, 63.20; H,
18 35 4
5
10.00; N, 8.12.
1
(
°
2-[t-Bu toxycar bon yl)am in o]-6-iodoh exan oate (9). A 250
mL flame-dried and argon-flushed flask containing LDA (60
mmol, 0.5 M in THF/hexane) was cooled to -78 °C before slow
addition of ethyl 2-[t-butoxycarbonyl)amino]acetate (4.0 g, 20
mmol) in THF (70 mL). The mixture was allowed to warm to
-60 °C, left for 1 h, and then cooled again to -78 °C before
the slow addition of 4-chloro-1-iodobutane (17.4 g, 80 mmol).
After complete addition, the reaction mixture was allowed to
warm to room temperature overnight. The reaction was
1
-
1
1
(
s), 2870 (m), 1687 (s), 1449 (m) cm
.
H NMR (300 MHz,
CDCl
3
): δ 7.99-7.96 (m, 2H), 7.57-7.45 (m, 3H), 2.96 (t, J )
7
.4 Hz, 2H), 1.79-1.74 (m, 2H), 1.65-1.50 (m, 1H), 1.33-1.27
13
3
(m, 2H), 0.92 (d, J ) 3.3 Hz, 6H). C NMR (75 MHz, CDCl ):
δ 201.0, 137.5, 133.2, 128.9, 128.4, 39.2, 39.0, 28.3, 22.9, 22.6.
MS (EI, 70 eV): 190 (8), 133 (8), 120 (78), 105 (100), 77 (37).
4
quenched with saturated NH Cl solution and the mixture
Anal. Calcd for C13
H, 9.26.
H
18O: C, 82.06; H, 9.53. Found: C, 81.92;
extracted several times with EtOAc. Purification by flash
chromatography (pentane/EtOAc 8:2) gave 2-[t-butoxycarbo-
nyl)amino]-6-chlorohexanoate as a pale yellow oil (3.16 g, 54%).
Eth yl 4-Cycloh exylbu ta n oa te (4j): Prepared from ethyl
-iodobutanoate (3d , 726 mg, 3 mmol) and dicyclohexylzinc
-1
4
IR (KBr): 3306 (m), 1745 (s), 1440 (m), 1403 (m), 1226 (s) cm .
1
(
°
1
7.5 mL, 0.8 M in THF, 6 mmol). Reaction time: 16 h at -30
C. Purification by flash chromatography (pentane/ether 20:
) yielded 4j as a colorless oil (351 mg, 61%). IR (KBr): 2955
H NMR (300 MHz, CDCl
3H), 3.46 (t, J ) 7.2 Hz, 2H), 1.82-1.38 (m, 6H), 1.37 (s, 9H),
): δ 173.0,
3
): δ 4.95 (bd, 1H), 4.28-4.08 (m,
1.22 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl
155.7, 80.2, 61.7, 53.6, 44.9, 32.4, 32.2, 28.7, 22.9, 14.5. MS
(EI, 70 eV): 293 (2), 258 (42), 212 (76), 57 (100). The alkyl
3
-
1
1
(
s), 2870 (m), 1687 (s), 1449 (m) cm
.
H NMR (300 MHz,
CDCl
3
): δ 4.06 (q, J ) 7.1 Hz, 2H), 2.23-2.17 (m, 2H), 1.65-

Ni-Catalyzed Cross-Coupling
J . Org. Chem., Vol. 67, No. 1, 2002 85
chloride (2.5 g, 8.5 mmol) was taken up in acetone (30 mL),
and NaI (12.6 g, 85 mmol) was added; then, the reaction was
refluxed for 16 h. The solvent was distilled off in vacuo and
the crude product taken up in EtOAc and washed with aqueous
min. The reaction mixture was then extracted with ether, dried
over MgSO
4
, and concentrated in vacuo. Purification by flash
chromatography (pentane/diethyl ether 95:5) yielded 14 as a
1
colorless oil (98 mg, 41%). H NMR (300 MHz, CDCl
1.80 (m, 9H), 1.13-1.20 (m, 8H), 0.81 (t, J ) 7.1 Hz, 3H).
NMR (75 MHz, CDCl ): δ 211.0, 47.2, 40.5, 38.1, 35.6, 31.3,
3
): δ 2.37-
13
Na
2
S
2
0
3
, dried over MgSO
4
, and concentrated. Purification by
C
flash chromatography (pentane/EtOAc 8:2) gave the product
as a pale yellow oil (2.87 g, 89%). IR (KBr): 3306 (m), 1745
3
30.6, 25.1, 24.3, 21.6, 13.0. MS (EI, 70 eV): 168 (11), 88 (100),
72 (22).
-
1
1
(
s), 1440 (m), 1403 (m), 1226 (s) cm
.
H NMR (300 MHz,
CDCl
3
): δ 4.95 (bd, 1H), 4.28-4.08 (m, 3H), 3.46 (t, J ) 7.2
Hz, 2H), 1.82-1.38 (m, 6H), 1.38 (s, 9H), 1.22 (t, J ) 7.2 Hz,
Ack n ow led gm en t. We thank the Deutsche Fors-
chungsgemeinschaft (Leibniz program) for financial
support and L′Or e´ al (France) for a fellowship to A.E.J .
We thank also BASF AG, Chemetall (Frankfurt), and
Degussa (Hanau) for the generous gift of chemicals.
1
3
3
5
2
4
H). C NMR (75 MHz, CDCl
3.6, 33.2, 32.1, 28.7, 26.5, 14.5, 6.6. MS (EI, 70 eV): 293 (2),
58 (42), 212 (76), 57 (100). Anal. Calcd for C13 NI: C,
0.53; H, 6.28; N, 3.64. Found: C, 40.33; H, 6.49; N, 3.65.
3
): δ 173.0, 155.7, 80.3, 61.8,
24 4
H O
1
5
Syn th esis of 3-P en tyl-cycloh exa n on e (14). A 23 mL
Schlenk flask charged with TBAI (738 mg, 2 mmol) and THF
2 mL) was cooled to -30 °C; then, cyclohexenone (192 mg, 2
(
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
mmol) and TMSCl (200 mg, 2 mmol) were added, followed by
dipentylzinc (3a ) (0.4 mL, 5.0 M, 2 mmol). The resulting
mixture was stirred for 1 h at -30 °C, poured into aqueous
1
0% HCl solution (20 mL) in THF (20 mL), and stirred for 15
J O0105787