698
T. Kann et al.
LETTER
Soc. 1996, 118, 4291. (f) Miller, S. J.; Kim, S.-H.; Chen, Z.-
R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108.
(3) For a review on Ns-chemistry, see: Kan, T.; Fukuyama, T. J.
Syn. Org. Chem., Jpn. 2001, 59, 779.
nylphosphine in 0.01 M solution of toluene-THF at room
temperature, the desired cyclization reaction proceeded
smoothly to afford 4a–c in good yields.
(4) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
Table 2 Cyclization via Mitsunobu Reaction
(5) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth., in press.
(6) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(7) Hidai, Y.; Kan, T.; Fukuyama, T. Tetrahedron Lett. 1999,
40, 4711.
Ns
Alkylation
NsHN
HO
Cyclization NsN
NH
Boc
5
n
n
6a; n = 1
6b; n = 2
6c; n = 3
4a; n = 1
4b; n = 2
4c; n = 3
(8) Hidai, Y.; Kan, T.; Fukuyama, T. Chem. Pharm. Bull. 2000,
48, 1570.
(9) Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667.
(10) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
(11) For a review of the substituent effect on the cyclization, see:
Jung, M. E. Synlett 1999, 843.
(12) Experimental procedure for the introduction of Ns-amide
and macrocyclization and spectral data for all new
compounds are described below.
Ring size Bromide Alkylationa (yield %) Cyclizationb (yield %)
8
2a
2b
2c
6a
(66)
4a
(59)
9
6b
(85)
4b
(57)
Representative Experimental Procedures. Synthesis of
3a: To a stirred solution of 2-nitrobenzenesulfonamide (3.20
g, 15.8 mmol), 7-bromo-1-heptanol (2a) (1.00 g, 5.13
mmol), and Ph3P (1.80 g, 8.91 mmol) in toluene (9 mL) and
THF (1.2 mL) was added DEAD (4 mL, 8.80 mmol, 40% in
toluene) dropwise at 0 °C under argon atmosphere. The
solution was stirred at 0 °C for 5 min, then at room
temperature for 2.5 h. After removal of the solvent under
reduced pressure, the remaining residue was purified by
flash chromatography, (9:1 hexane–EtOAc) on a silica gel
column, to give 3a (1.36 g, 70%) as white powder. IR (film,
cm–1): 3346, 3096, 2933, 2857, 1539, 1440, 1414, 1360,
1341, 1166, 1125, 1060, 853, 782. 1H NMR (400 MHz,
CDCl3) : 1.29 (4 H, m), 1.33 (2 H, m), 1.52 (2 H, m), 1.81
(2 H, m), 3.10 (2 H, q, J = 6.8 Hz), 3.37 (2 H, t, J = 6.8 Hz),
5.23 (1 H, m), 7.76 (2 H, m), 7.87 (1 H, m), 8.14 (1 H, m).
13C NMR (100 MHz, CDCl3) : 26.2, 27.8, 28.1, 29.4, 32.5,
33.8, 43.7, 125.3, 131.0, 132.8, 133.5, 133.7, 148.0. FAB-
MS: m/z 379 (MH+); Anal. Calcd. for C13H20BrN2O4S: C,
41.17; H, 5.05; N, 7.39. Found: C, 41.24; H, 5.04; N, 7.30.
Spectral data for 3b (white powder): IR (film, cm–1): 3346,
3099, 2930, 2856, 1592, 1539, 1440, 1414, 1360, 1342,
1165, 1125, 1061. 1H NMR (400 MHz, CDCl3) : 1.26 (6 H,
m), 1.39 (2 H, m), 1.53 (2 H, m), 1.83 (2 H, m), 3.10 (2 H, q,
J = 6.8 Hz), 3.39 (2 H, t, J = 6.8 Hz), 5.23 (1 H, m), 7.75 (2
H, m), 7.87 (1 H, m), 8.15 (1 H, m). 13C NMR (100 MHz,
CDCl3) : 26.4, 28.0, 28.6, 28.9, 29.6, 32.7, 34.0, 43.9,
125.4, 131.2, 132.8, 133.6, 133.8, 148.2. FAB-MS: m/z 393
(MH+); HRMS (FAB): Found 393.0411 (MH+), Calcd.
393.0413 (C14H22BrN2O4S, MH+).
10
6c
4c
(62)
(62)
a Alkylation conditions: 1) K2CO3, n-Bu4NI, DMF, 60 °C. 2) TFA,
CH2Cl2. 3) K2CO3, MeOH.12
b Cyclization conditions. PPh3, DEAD, toluene–THF.12
In both protocols for the ring closures, the reactions pro-
ceeded successfully without using the branching effect.11
Thus, Ns-strategy proved to be a powerful protocol for the
construction of medium-sized rings, overriding the inher-
ent entropic disadvantage of the ring closure. Considering
the mildness of the alkylation and the deprotection condi-
tions, Ns-strategy would be compatible with a variety of
functional groups. Furthermore, the fact that both alcohols
and halides served as starting materials would allow prep-
aration of a wide range of nitrogen heterocycles. Further
application of this methodology to the total syntheses of
complex natural products is currently under investigation
in our laboratories.
References
(1) For recent syntheses of medium-sized cyclic amines, see:
Ring-opening of bicyclic precursors: (a) Donohoe, T. J.;
Raoof, A.; Linney, I. D.; Helliwell, M. Org. Lett. 2001, 3,
861. (b) Fatima, I.; Ramon, G. A.; Juan, C. C. Org. Lett.
2001, 3, 2957. (c) Cyclization of aminoalkenes: Bergmann,
D. J.; Campi, E. M.; Jackson, W. R.; Patti, A. F.; Saylik, D.
Tetrahedron Lett. 1999, 40, 5597. Ring-enlargement of six-
membered rings: (d) Moris-Varas, F.; Quian, X.-H.; Wong,
C.-H. J. Am. Chem. Soc. 1996, 118, 7647. Others:
Spectral data for 3c (white powder). IR (film, cm–1): 3346,
3099, 2930, 2856, 1592, 1539, 1440, 1414, 1360, 1342,
1165, 1125, 1061. 1H NMR (400 MHz, CDCl3) : 1.25 (8 H,
m), 1.40 (2 H, m), 1.54 (2 H, m), 1.83 (2 H, t, J = 4.0 Hz),
3.10 (2 H, q, J = 3.4 Hz), 3.40 (2 H, t, J = 3.4 Hz), 5.22 (1 H,
m), 7.75 (2 H, m), 7.87 (1 H, m), 8.15 (1 H, m). 13C NMR
(100 MHz, CDCl3) : 26.4, 28.0, 28.5, 28.8, 29.1, 29.5, 32.7,
34.0, 43.8, 125.3, 131.1, 132.7, 133.5, 133.8, 148.1. FAB-
MS : m/z 407 (MH+); Anal. Calcd. for C15H24BrN2O4S: C,
44.23; H, 5.69; N, 6.88. Found: C, 44.46; H, 5.71; N, 6.64.
Synthesis of 4a: To a stirred solution of Cs2CO3 (2.10 g,
6.45 mmol) and TBAI (980 mg, 2.65 mmol) in CH3CN (3.00
mL) was added N-2-nitrobenzenesulfonyl-7-bromo-1-
aminoheptane (3a) (500 mg, 1.32 mmol) in CH3CN (24.0
mL) via syringe pump for 2 h at 60 °C, and stirred for
additional 2 h at the same temperature. The reaction mixture
was poured into water and extracted with EtOAc three times.
(e) Kitano, T.; Shirai, N.; Motoi, M.; Sato, Y. J. Chem. Soc.,
Perkin Trans. 1 1992, 2851. (f) Shaw, R.; Anderson, M.;
Gallagher, T. Synlett 1990, 584. (g) Shaw, R. W.;
Gallagher, T. J. Chem. Soc. Perkin Trans.1 1994, 3549.
(2) For recent synthesis of medium-sized cyclic amines based
on ring-closing metathesis, see: (a) Meyers, A. I.; Downing,
S. V.; Weiser, M. J. J. Org. Chem. 2001, 66, 1413.
(b) Heinrich, M. R.; Steglich, W. Tetrahedron Lett. 2001, 42,
3287. (c) Fujiwara, T.; Kato, Y.; Takeda, T. Heterocycles
2000, 52, 147. (d) Paquette, L. A.; Leit, S. M. J. Am. Chem.
Soc. 1999, 121, 8126. (e) Visser, M. S.; Heron, N. M.;
Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am. Chem.
Synlett 2002, No. 5, 697–699 ISSN 0936-5214 © Thieme Stuttgart · New York