LETTER
Iron(II)-Catalyzed Chlorolactamization of g,d-Unsaturated Carboxylic Acids
1201
(5) (a) Kuehne, M. E.; Horne, D. A. J. Org. Chem. 1975, 40,
1287. (b) Lessard, J.; Cote, R.; Mackiewicz, P.; Furstoss, R.;
Waegell, B. J. Org. Chem. 1978, 43, 3750. (c) Phan, X. T.;
Shannon, P. J. J. Org. Chem. 1983, 48, 5164. (d) Chow, Y.
L.; Perry, R. A. Can. J. Chem. 1985, 63, 2203. (e) Schulte-
Wülwer, I. A.; Helaja, J.; Göttlich, R. Synthesis 2003, 1886.
(6) Review on radical cyclizations of nitrogen-centered radicals:
Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.
(7) (a) Bach, T.; Schlummer, B.; Harms, K. Chem.–Eur. J. 2001,
7, 2581. (b) Bach, T.; Schlummer, B.; Harms, K. Synlett
2000, 1330. (c) Bach, T.; Schlummer, B.; Harms, K. Chem.
Commun. 2000, 287.
R = Chx and R = C5H11 the preference is less pronounced.
The catalytic cycle is completed by an electrophilic sub-
stitution of the iron with TMSCl. FeCl2 is regenerated in
this step.
Cl
R
Fe Cl
H
.
γ
N
OH
N
Cl
O
O
O
R1
11
12
13
(8) Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron:
Asymmetry 1996, 7, 1649.
Figure 4 Structures of the proposed radical intermediate 11, the tri-
substituted alkene substrate 12 and the resulting chlorolactamization
product 13
(9) General Procedure for the One-Pot Chloro-
lactamization: To 141 mg (1.0 mmol) of 2-(cyclohex-2-
enyl)acetic acid (1)8 dissolved in 5 mL CH2Cl2 were added
94 mL (1.1 mmol) of oxalyl chloride and one drop of DMF.
The reaction mixture was stirred at r.t. for 20 min. CH2Cl2
and the excess oxalyl chloride were removed in vacuum. The
remaining acyl chloride was dissolved in 5 mL of acetone
and a solution of 130 mg NaN3 (2.0 mmol) in 300 mL H2O
was added at –15 °C. The reaction mixture was stirred for
1.5 h at –15 °C and the solvent was removed at this
temperature in vacuum. The acyl azide was dissolved in
10 mL i-PrOH. A solution of 25.3 mg (0.2 mmol) FeCl2 and
252 mL (2.0 mmol) TMSCl in 5 mL i-PrOH was added. The
reaction mixture was stirred for 5 h at –15 °C and for 8 h at
r.t.. After evaporation of the solvent in vacuo 40 mL of
EtOAc were added. The organic layer was washed with H2O
(3 × 20 mL) and brine (2 × 20 mL) and dried over MgSO4.
After filtration the solvent was evaporated and the crude
product was purified by flash chromatography. (silica 60,
pentane–CH2Cl2–MeOH–NH3 (aq) = 65:30:5:0.25) to give
130 mg (75%) of lactam 2. 1H NMR (500 MHz, CDCl3):
d = 1.23–1.36 (m, 2 H, CH2CHHCH2CHCl,
The method can also be applied to higher substituted alk-
enes. Alkenoic acid 12 for example yielded 59% of lactam
13 in the one-pot sequence (Figure 4).
Current research is directed towards possible applications
of the presented method. It is also concerned with studies
on further mechanistic details and improvements of the
catalytic cycle.
Acknowledgment
This project has been supported by the Fonds der Chemischen
Industrie.
References
(1) (a) Corey, E. J.; Fleet, G. W. J.; Kato, M. Tetrahedron Lett.
1973, 40, 3963. (b) Clive, D. L. J.; Wong, C. K.; Kiel, V. S.;
Menchen, M. J. Chem. Soc., Chem. Commun. 1978, 379.
(2) Review: Harding, K. E.; Tiner, T. H. In Comprehensive
Organic Synthesis, Vol. 4; Trost, B., Ed.; Pergamon Press:
Oxford, 1991, 353.
(3) (a) Biloski, A. J.; Wood, R. D.; Ganem, B. J. Am. Chem. Soc.
1982, 104, 3233. (b) Rajendra, G.; Miller, M. J. J. Org.
Chem. 1987, 52, 4471. (c) Balko, T. W.; Brinkmeyer, R. S.;
Terando, N. H. Tetrahedron Lett. 1989, 30, 2045.
CHHCH2CH2CHCl), 1.60–1.70 (m, 1 H,
CHHCH2CH2CHCl), 1.73–1.85 (m, 2 H,
CH2CH2CHHCHCl, CH2CHHCH2CHCl), 1.93–2.01 (m, 1
H, CH2CH2CHHCHCl), 2.05 (d, J = 16.3 Hz, 1 H,
CHCHHCO), 2.35–2.45 (m, 1 H, CHCH2CO), 2.45 (dd,
J = 16.3 Hz, J = 6.5 Hz, 2 H, CHCHHCO), 3.98–4.07 (m, 2
H, CH2CH2CH2CHCl, CHClCHNH), 5.91 (br s, 1 H, NH).
13C NMR (90.6 MHz, CDCl3): d = 23.9
(CH2CH2CH2CHCl), 26.6 (CH2CH2CH2CHCl), 30.1
(CH2CH2CH2CHCl), 35.9 (CHCH2CO), 40.3 (CHCH2CO),
58.2 (CH2CH2CH2CHCl), 59.7 (CHClCHNH), 177.2 (CO).
Anal. Calcd for C8H12ClNO (173.64): C, 55.34; H, 6.97; N,
8.07. Found: C, 55.31; H, 6.92; N, 7.98.
(d) Harris, N. V.; Smith, C.; Ashton, M. J.; Bridge, A. W.;
Bush, R. C.; Coffee, E. C. J.; Dron, D. I.; Hapter, M. F.;
Lythgoe, D. J.; Newton, C. G.; Riddell, D. J. Med. Chem.
1992, 35, 4384. (e) Arunachalam, T.; Fan, H.; Pillai, K. M.
R.; Ranganathan, R. S. J. Org. Chem. 1995, 60, 4428.
(f) Boeckman, R. K. Jr.; Connell, B. T. J. Am. Chem. Soc.
1995, 117, 12368. (g) Kitagawa, O.; Fujita, M.; Li, H.;
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(10) Crystal structure analysis of lactam 2: C8H12ClNO,
Mr = 173.64, colorless prism (0.56 × 0.64 × 0.97 mm3),
monoclinic, P21/c (No.: 14), a = 10.1739 (1), b = 6.5823 (1),
c = 12.4662 (2) Å, b = 94.0723 (5)°, V = 832.72 (2) Å3,
Z = 4, dcalc = 1.385 gcm–3, F000 = 368, m = 0.398 mm–1.
Preliminary examination and data collection were carried
out on a kappa-CCD device (NONIUS MACH3) at the
window of a rotating anode (NONIUS FR591) with graphite
monochromated Mo-Ka radiation (l = 0.71073 Å). Data
collection were performed at T = 173 K within the Q range
of 2.01°<Q<25.36°. A total of 19024 reflections were
integrated and corrected for Lorentz and polarization effects.
A correction for absorption effects and/or decay was applied
during the scaling procedure. After merging (Rint = 0.035),
1525 [1462: Io>2s(Io)] independent reflections remained
and all were used to refine 149 parameters. The structure was
solved by a combination of direct methods and difference-
Fourier syntheses. All non-hydrogen atoms were refined
(4) (a) Knapp, S.; Rodrigues, K. E.; Levorse, A. T.; Ornaf, R. M.
Tetrahedron Lett. 1985, 26, 1803. (b) Knapp, S.; Levorse,
A. T. J. Org. Chem. 1988, 53, 4006. (c) Kurth, M. J.;
Bloom, S. H. J. Org. Chem. 1989, 54, 411. (d) Takahata,
H.; Yamazaki, K.; Takamatsu, T.; Yamazaki, T.; Momose,
T. J. Org. Chem. 1990, 55, 3947.
Synlett 2004, No. 7, 1199–1202 © Thieme Stuttgart · New York