1
364
S. Goto et al.
LETTER
Table 3 n-BuLi-Mediated Coupling of Fenchone (4) with 2-Bro-a
mopyridine (5) under ISQ Conditions Performed in a Microreactor
(9) The crystallographic data (excluding structure factors) for
compounds 10, 14 and 26 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 645156 (for 10), CCDC 679624 (for
Entry
4/5/n-BuLi
1:1:1
Temp.
–25 °C
–25 °C
0 °C
Yieldb
56%
71%
68%
91%
1
4) and CCDC 645157 (for 26). Copies of the data can be
1
2
3
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK [fax: +44 (1223)336033;
e-mail: deposit@ccdc.cam.ac.uk].
2:1:1.5
2:1:1.5
2:1:2
(
(
(
(
10) (a) Fry, J. L.; West, J. W. J. Org. Chem. 1981, 46, 2177.
(
b) Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K. N.
4
–25 °C
J. Org. Chem. 2000, 65, 77. (c) Goldfuss, B.; Loeschmann,
T.; Rominger, F. Chem. Eur. J. 2004, 21, 5422.
a
Reactions were run in a flow-microreactor (see Figure 1) with a flow
rate 5 mL/min; residence time: 3 min.
11) Compound 12 was recently prepared in only 15% yield from
the same starting materials following a stepwise procedure.
See: Lomas, J. S.; Adenier, A.; Cordier, C. J. Phys. Org.
Chem. 2006, 19, 295.
12) In these cases, products arising from direct attack of n-BuLi
at the ketone (13, 17) or from ketone reduction (19) were
isolated as main products, besides starting material(s)and the
debrominated arene.
b
Isolated yield of 6.
Acknowledgment
This work was supported by the European Commission (ligbank),
the Bundesministerium für Bildung und Forschung (Grant
13) (a) Aidhen, I. S.; Ahuja, J. R. Tetrahedron Lett. 1992, 33,
0
3C0347A), the Daito Chemix Corp., and the Fonds der Chemi-
5431. (b) Paleo, M. R.; Castedo, L.; Dominguez, D. J.
schen Industrie. The authors would like to thank the CPC-Systems
GmbH for providing access to a microreactor system and the Che-
metall GmbH for generous gifts of butyllithium.
J. Org. Chem. 1993, 58, 2763.
(
(
14) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int.
Ed. 2006, 45, 497; Angew. Chem. 2006, 118, 511.
15) General Procedure A for the Coupling of Aryl Bromides
with Ketones (in a flask using n-BuLi): A stirred solution
of an aryl bromide (5 mmol) and a ketone (5 mmol) in THF
References and Notes
(
1) For leading monographs, see: (a) Clayden, J.
Organolithiums: Selectivity for Synthesis; Pergamon/
Elsevier: Oxford, 2002. (b) Schlosser, M. In
(10 mL) was cooled to –78 °C and n-BuLi (3.75 mL, 6
mmol, 1.6 M in hexane) was added dropwise via syringe.
After 1 h at –78 °C, the stirred reaction mixture was allowed
to warm to 0 °C. The reaction was quenched by addition of
sat. aq NH Cl (5 mL) and H O (15 mL), extracted with
Organometallics in Synthesis: A Manual; Schlosser, M.,
Ed.; Wiley: New York, 2002, Chap. 1. (c) Wakefield, B. J.
Organolithium Methods; Academic Press: London, 1988.
2) For leading reviews, see: (a) Gschwind, H. W.; Rodriguez,
H. R. Org. React. (N.Y.) 1979, 26, 1. (b) Snieckus, V.
Chem. Rev. 1990, 90, 879.
4
2
MTBE or Et O (20 mL), and the organic layer was washed
2
(
(
with brine and dried over MgSO . After removal of the
4
solvent in vacuo the crude product was purified by flash
chromatography (typically cyclohexane–EtOAc, 30:1).
General Procedure B for the Coupling of Aryl Bromides
with Ketones (in a flask using t-BuLi): A stirred solution
of an aryl bromide (5 mmol) and a ketone (5 mmol) in THF
3) (a) Wittig, G.; Pockels, U.; Droge, H. Chem. Ber. 1938, 71,
1903. (b) Gilman, H.; Langham, W.; Jacoby, A. L. J. Am.
Chem. Soc. 1939, 61, 106. (c) For a review on halogen–
lithium exchange, see: Bailey, W. F.; Patricia, J. J.
J. Organomet. Chem. 1988, 352, 1.
(10 mL) was cooled to –78 °C and t-BuLi (6.5 mL, 10 mmol,
1
4
.54 M in pentane) was added dropwise via syringe. After
h at –78 °C, the cooling bath was removed and the reaction
(
4) For leading reviews, see: (a) Mason, B. P.; Price, K. E.;
Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107, 2300. (b) Ahmed-Omer, B.; Brandt, J. C.;
Wirth, T. Org. Biomol. Chem. 2007, 5, 733. (c) Watts, P.;
Wiles, C. Chem. Commun. 2007, 443. (d) Geyer, K.; Codée,
J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434.
mixture was stirred at r.t. for 2 h. The reaction was quenched
by addition of sat. aq NH Cl (5 mL) and H O (15 mL),
4
2
extracted with MTBE or EtOAc (3 × 30 mL), and the organic
layer was washed with brine and dried over MgSO . After
4
removal of the solvent in vacuo the crude product was
purified by flash chromatography (typically cyclohexane–
EtOAc, 30:1).
(
e) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew.
Chem. Int. Ed. 2004, 43, 407; Angew. Chem. 2004, 116,
410. (f) Schwalbe, T.; Autze, V.; Wille, G. Chimia 2002, 56,
(
1R,2R,4S)-2-(2¢-Pyridinyl)-1,3,3-trimethyl-
636.
bicyclo[2.2.1]heptan-2-ol (6): Prepared according to the
general procedure A. 2-Bromopyridine (5; 0.79 g, 5 mmol)
and fenchone (4; 0.76 g, 5 mmol) were reacted with n-BuLi
(
5) A Cytos Lab System (microreactor) from CPC-Systems
GmbH was used (see: www.cpc-net.com/cytosls.shtml); for
an overview on the various technological developments, see:
Thayer, A. M. Chem. Eng. News 2005, 83 (22), 43.
6) For a review, see: (a) El Sheikh, S.; Schmalz, H.-G. Curr.
Opin. Drug Discovery Dev. 2004, 7, 882. For relevant
examples, see also: (b) Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org.
Chem. 2002, 67, 5394. (c) Therkelsen, F. D.; Rottländer,
M.; Thorup, N.; Pedersen, E. B. Org. Lett. 2004, 6, 1991.
7) Gilman, H.; Moore, F. W. J. Am. Chem. Soc. 1940, 62, 1843.
8) (a) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron:
Asymmetry 1997, 8, 1869. (b) Herrmann, W. A.; Haider, J.
J.; Fridgen, J.; Lobmaier, G. M.; Spiegler, M. J. Organomet.
Chem. 2000, 603, 69.
(
7
4 mL, 6 mmol) to give 6 (1.14 g, 99%) as a white solid; mp
20
1
3 °C; [a]D –39.9 (c = 2.0, CHCl ). H NMR (300 MHz,
3
(
CDCl ): d = 0.42 (s, 3 H), 0.97 (s, 3 H), 1.00 (s, 3 H), 1.13
3
1
2
(m, 1 H), 1.35 (dd, J = 10.8 Hz, J = 1.5 Hz, 1 H), 1.47 (m,
1
H), 1.79 (m, 1 H), 1.84 (m, 1 H), 2.23 (m, 1 H), 2.34 (m, 1
1
2
3
H), 5.79 (br, 1 H), 7.17 (ddd, J = 7.2 Hz, J = 4.2 Hz, J =
1
2
1.0 Hz, 1 H), 7.49 (td, J = 8.2 Hz, J = 1.0 Hz, 1 H), 7.67 (m,
1
2
3
1
H), 8.45 (ddd, J = 4.2 Hz, J = 1.8 Hz, J = 1.0 Hz, 1 H).
(
(
13
C NMR (75 MHz, CDCl ): d = 17.1, 22.2, 24.3, 29.2, 32.5,
3
4
1
2
2.0, 46.1, 48.9, 51.9, 83.8, 121.6, 123.4, 135.7, 146.2,
62.1. HRMS (EI): m/z calcd for C H NO: 231.162; found:
31.162.
1
5
21
(
1R,2R,4S)-2-(Thiazol-2-yl)-1,3,3-trimethyl-
Synlett 2008, No. 9, 1361–1365 © Thieme Stuttgart · New York