Synthesis of Highly Functionalized Cyclopropanes
J . Org. Chem., Vol. 64, No. 13, 1999 4723
6.4 Hz, 3H), 1.87 (m, 1H), 4.27 (p, J ) 6.4, 6.4, 6.4 Hz, 2H),
5.60-5.69 (m, 2H), 7.19-7.65 (m, 10H); 13C NMR (63 MHz,
CDCl3) δ (ppm) 23.23, 37.55, 53.27, 68.22, 119.13, 123.22,
127.37, 128.21, 128.99, 135.09, 139.31, 173.19; IR (CCl4) 3680,
3500, 3420, 2240, 1640, 1600, 1580 cm-1; MS (EI) m/z (relative
intensity) 304 (1), 116 (100), 89 (17), 77 (26); MS (CI, NH3)
m/z (relative intensity) 305 (M + 1, 100); exact mass M+
304.1558 (calcd for C20H20N2O 304.1576).
MS (CI, NH3) m/z (relative intensity) 480 (28), 479 (68), 478
(41), 477 (100).
1-Aza -2-cya n o-7,7-d ip h en yl-6-m eth ylcycloh ep ta -2,4-d i-
en e 8b. The seven-membered ring 8b was obtained in 80%
yield as single product from the Pd-catalyzed cyclization of
(6S)-21b. [R]20 -80.9, c 1.58, CHCl3); 1H NMR (250 MHz,
D
CDCl3) δ (ppm) 1.02 (d, J ) 6.8 Hz, 3H), 3.70 (dq, J ) 7.6, 6.8
Hz, 1H), 5.08 (s, 1H), 5.43 (dd, J ) 8.0, 2.0 Hz, 1H), 5.62 (dd,
J ) 10.9, 7.6 Hz, 1H), 6.20 (dd, J ) 10.9, 8.0 Hz, 1H), 7.15-
7.33 (m, 10H); 13C NMR (50 MHz, CDCl3) δ (ppm) 16.76, 29.68,
44.56, 111.91, 123.08, 126.39, 126.75, 127.13, 128.55, 138.39,
146.47; IR (CDCl3) 3435, 2250, 1635, 1600 cm-1; MS (EI) m/z
(relative intensity) 286 (M, 82), 271 165 (100), 104 (82); exact
mass M+ 286.1470 (calcd for C20H18N2 286.1452).
(E)-(6S)-6-Acet oxy-2-(N-(d ip h en ylm et h ylen e)a m in o)-
h ep t-4-en en itr ile 21b. Following the procedure to obtain
(4S)-20b from (4S)-20a (vide supra), the acetate (6S)-21b was
obtained from (6S)-21a (100%) as a 48:52 diastereomeric
1
mixture; H NMR (250 MHz, CDCl3) δ (ppm) 1.25 (d, J ) 6.3
Hz, 6H), 1.90 (s, 3H), 2.65 (m, 4H), 4.25 (td, J ) 6.8, 2.1 Hz,
2H), 5.30 (p, J ) 6.3, 6.3 Hz, 2H), 5.65 (m, 4H), 7.11-7.75 (m,
20H); 13C NMR (63 MHz, CDCl3) δ (ppm) 20.13, 21.27, 37.71,
52.85, 70.36, 119.04, 125.80, 127.44, 128.20, 129.02, 135.17,
138.38, 170.17, 173.27; IR (hexane) 3050, 2250, 1750, 1645
cm-1; MS (EI) m/z (relative intensity) 346 (M, 2.45), 116 (100),
43 (23); MS (CI, NH3) m/z (relative intensity) 347 (M + 1, 80);
exact mass M+ 346.1672 (calcd for C22H22N2O2 346.1681).
(E)-(6S)-6-(2,4-Dich lor oben zoyloxy)-2-((d ip h en ylm eth -
ylen e)a m in o)h ep t-4-en en itr ile 21d . To a solution of 152 mg
(0.5 mmol) of (6S)-21a in 5 mL of dichloromethane containing
81 µL (1 mmol) of freshly distilled pyridine was added dropwise
at room temperature 84 µL (0.6 mmol) of 2,4-dichlorobenzoyl
chloride, under an argon stream. The reaction was complete
within 18 h, as monitored by TLC, and then dichloromethane
was added, followed by 0.5 N HCl. The organic phase was
washed by 0.5 N HCl until acidity and by water until neu-
trality. The aqueous phase was extracted by dichloromethane
(thrice), and the combined organic phases were dried (Na2SO4)
and evaporated in vacuo to give (6S)-21d (240 mg, 100%) as
(1S,2R)-1-(N-(Dip h en ylm et h ylen e)a m in o)-2-(1-p r op e-
n yl)cyclop r op a n eca r bon itr ile 22. To a solution of 3.65 g
(12 mmol) of (6S)-21a in 24 mL of THF at -25 °C under argon
stream was added 24 mL of a 1 M solution (24 mmol) of
trimethylphosphine in THF. Then 3.75 mL (24 mmol) of
diethyl azodicarboxylate (DEAD) were added dropwise at -25
°C. The reaction was complete within 10 min as monitored by
TLC, and the mixture was added to diethyl ether containing
saturated ammonium chloride aqueous solution and was
allowed to warm to room temperature. The organic phase was
washed with 5 mL of saturated NaCl aqueous solution and
with 5 mL of water, dried (Na2SO4), and evaporated in vacuo.
The residue was purified by chromatography over silica gel
eluting with dichloromethane/pentane (8:2) to give 2.19 g (63%)
of a 94:6 diastereomeric mixture of (1S,2R)-22 and (1R,2R)-
22, with spectroscopic and analytical data identical to those
reported for (E)- and (Z)-22 (vide supra).
(E)-2-((N-Dip h en ylm eth ylen e)a m in o)h ep ta -4,6-d ien e-
n itr ile 23. This diene 23 was obtained as single product, in
76% yield, from the Pd-catalyzed attempted cyclization of the
1
an unseparable diastereomeric mixture; H NMR (200 MHz,
1
CDCl3) δ (ppm) 1.46 (d, J ) 5.9 Hz, 6H), 2.72 (t, J ) 6.9 Hz,
4H), 4.30 (dt, J ) 6.9, 1.6 Hz, 2H), 5.59 (p, J ) 5.9, 5.9 Hz,
2H), 5.66-5.88 (m, 4H); 13C NMR (63 MHz, CDCl3) δ (ppm)
20.12, 20.19, 37.52, 37.60, 52.65, 52.83, 71.93, 72.05, 118.88,
118.93, 126.46, 126.82, 126.83, 126.89, 127.32, 128.40, 128.57,
129.32, 130.80, 133.94, 134.07, 134.79, 135.02, 135.08, 138.16,
138.22, 163.78, 163.84, 173.28; IR (CCl4) 2240, 1745, 1625
cm-1; MS (EI) m/z (relative intensity) 476 (M, 12), 116 (100);
exact mass M+ 476.1061 (calcd for C27H22O2Cl2 476.1058).
(E)-(6S)-6-(Ben zyloxy)-2-((d ip h en ylm eth ylen e)a m in o)-
h ep t-4-en en itr ile 21f. Following the procedure to obtain (4S)-
20d from (4S)-20a , (6S)-21f was prepared by benzoylation of
(6S)-21a . Thus, treatment of 100 mg (0.33 mmol) of (6S)-21a
with 148 mg (0.66 mmol) of benzoic anhydride in the presence
of 12 mg (0.1 mmol) of DMAP in 88 µL (0.63 mmol) of
triethylamine in THF gave after usual workup (see above) 115
mg (85%) of (6S)-21f as a 1:1 diastereomeric mixture; 1H NMR
(200 MHz, CDCl3) δ (ppm) 1.43 (d, J ) 6.4 Hz, 3H), 1.48 (d, J
) 6.5 Hz, 3H), 2.71 (t, J ) 6.8, 6.8 Hz, 4H), 4.29 (dt, J ) 6.8,
1.6 Hz, 2H), 5.62 (p, J ) 6.5, 6.5 Hz, 2H), 5.77 (m, 4H), 7.22-
7.63 (m, 30H); 13C NMR (63 MHz, CDCl3) δ (ppm) 20.22, 20.26,
37.52, 37.58, 52.72, 52.83, 70.75, 70.87, 118.94, 118.99, 125.66,
127.35, 128.18, 128.23, 128.92, 129.97, 130.05, 132.36, 133.53,
171.76, 173.41; IR (CCl4) 2240, 1745, 1625 cm-1; MS (EI) m/z
(relative intensity) 408 (M, 3), 116 (100), 105 (56), 77 (50); MS
(CI, NH3) m/z (relative intensity) 409 (M + 1, 100), 408 (M,
73); exact mass M+ 408.1844 (calcd for C27H24N2O2 408.1838).
(E)-(6S)-6-(2,6-Dich lor oben zyloxy)-2-((d ip h en ylm eth -
ylen e)a m in o)h ep t-4-en en itr ile 21g. Following the proce-
dure used for the preparation of (6S)-20d , reaction of 405 mg
(1.33 mmol) of (6S)-20a with 424 µL (2.93 mmol) of 2,6-
dichlorobenzoyl chloride gave, after stirring for 72 h at room
temperature and usual workup (see above), 203 mg (32%) of
(6S)-21g, besides 280 mg (68%) of (6S)-20a ; 1H NMR (200
MHz, CDCl3) δ (ppm) 1.45 (d, J ) 6.1 Hz, 6H), 2.61-2.82 (m,
4H), 4.28 (t, J ) 6.8 Hz, 2H), 5.68 (p, J ) 6.1, 6.1 Hz, 2H),
5.78 (m, 4H), 7.15-7.73 (m, 26H); 13C NMR (63 MHz, CDCl3)
δ (ppm) 19.92, 37.55, 52.84, 72.55, 118.94, 126.56, 127.09,
127.26, 127.73, 128.92, 130.71, 131.93, 133.47, 134.99, 138.22,
163.74, 173.24; IR (CCl4) 2240, 1745, 1625 cm-1; MS (EI) m/z
(relative intensity) 477 (M, 8), 476 (M, 8), 116 (100), 77 (51);
anions of (6S)-21f (vide supra); H NMR (200 MHz, CDCl3) δ
(ppm) 2.71 (m, 4H), 4.28 (t, J ) 6.6 Hz, 2H), 5.15 (m, 4H),
5.63 (dt, J ) 14.5, 6.6 Hz, 2H), 6.25 (m, 4H), 7.07-7.88 (m,
20H); 13C NMR (50.4 MHz, CDCl3) δ (ppm) 37.99, 53.26,
117.33, 127.16, 127.40, 128.22, 129, 129.38, 131.20, 135.32,
136.23, 173.04; IR (CDCl3) 3080, 3060, 3020, 2240, 1660, 1620,
1600 cm-1; MS (EI) m/z (relative intensity) 286 (M, 4), 233
(17), 219 (30), 166 (4), 165 (14), 117 (10), 116 (100), 89 (16), 77
(25).
(E)-1-(N-(Dip h en ylm eth ylen e)a m in o)-2-eth ylcyclop r o-
p a n eca r bon itr ile 24. To a solution of 300 mg (1.1 mmol) of
(E)-4a in 3 mL of methanol containing 810 µL (10 mmol) of
pyridine was added, at room temperature under an argon
stream, 650 mg (3.32 mmol) of potassium azodicarboxylate
(freshly prepared from potassium hydroxide and azodicarbon-
amide49), followed by 420 µL (7 mmol) of acetic acid. The
mixture was stirred for 18 h, and then water and diethyl ether
were added. The aqueous phase was extracted by of diethyl
ether (twice), and the combined organic phases were washed
with a saturated NaCl aqueous solution, dried (Na2SO4), and
evaporated in vacuo. The residue was purified by column
chromatography over silica gel eluting with dichloromethane/
1
pentane (9:1) to give (E)-24 (231 mg, 77%) as a yellow oil; H
NMR (250 MHz, CDCl3) δ (ppm) 1.06 (t, J ) 6.6 Hz, 3H), 1.22-
1.78 (m, 5H), 7.11-7.62 (m, 10H); 13C NMR (63 MHz, CDCl3)
δ (ppm) 12.76, 23.60, 27.11, 33.36, 37.37, 118.21, 128.08,
128.44, 128.56, 129.66, 130, 130.64, 136.06, 139.32, 171.56; MS
(EI) m/z (relative intensity) 274 (M, 29), 165 (100), 77 (32).
Anal. Calcd for C19H18N2: C, 83.18.10; H, 6.61; Cl, 36.23.
Found: C, 83.45; H, 6.39.
(()-(E)-1-Am in o-2-eth ylcyclop r op a n eca r boxylic Acid
[(()-cor on a m ic a cid ] 27a .12,21 To a solution of 69 mg (0.25
mmol) of (E)-24 in diethyl ether was added dropwise 1.6 mL
of a 2 N HCl solution, and the mixture was stirred at room-
temperature overnight. The aqueous phase was extracted by
diethyl ether (twice) and evaporated in vacuo to give 40 mg
(100%) of 1-amino-2-ethylcyclopropanecarbonitrile hydrochlo-
ride.12 A solution of 37 mg (0.25 mmol) of this hydrochloride
in a 6 N solution of HCl was heated at reflux for 15 h. After
filtration through Celite, the solution was evaporated in vacuo.
The residue was dissolved in distilled water and purified by