Synthesis of Lactams via a Zwitterion Aza Cope Rearrangement
J . Org. Chem., Vol. 61, No. 8, 1996 2875
N-Ben zyl-2(Z)-(1′-p r op en yl)p yr r olid in e (4). n-Butyl-
lithium (6.25 mL, 10 mmol, 1.6 M in hexane) was added to
3.71 g (10.0 mmol) of ethyl triphenylphosphonium bromide in
30 mL of THF at 0 °C, and the mixture was stirred 1 h at 0
°C. This solution was added slowly to a solution of amino
aldehyde (1.80 g, 9.52 mmol) in 15 mL of THF at 0 °C, and
the mixture was stirred 45 min at 0 °C, allowed to warm to
room temperature, stirred 30 min, and then placed in a warm
water bath and stirred 30 min. The reaction mixture was
partitioned between water and EtOAc, the aqueous layer was
extracted three times using EtOAc, and the EtOAc layers were
combined and dried over MgSO4. The solution was filtered,
and the solvent was removed under reduced pressure. The
resulting oil was purified by column chromatography (5:1
hexanes/ethyl acetate), giving 1.21 g (63%) of 4 as a yellow
oil: 1H NMR δ 1.56 (m, 1H), 1.69 (dd, 3H, J ) 1.8, 6.9 Hz)
1.70 (m, 2H), 1.92 (m, 1H), 2.09 (q, 1H, J ) 9 Hz), 2.93 (dt,
1H, J ) 2.7, 8.7 Hz), 3.06 (d, 1H, J ) 12.9 Hz), 3.15 (q, 1H, J
) 8.7 Hz), 4.0 (d, 1H, J ) 12.9 Hz), 5.42 (tq, 1H, J ) 1.8, 9.0
Hz), 5.63 (m, 1H), 7.29 (m, 5H). 13C NMR δ 13.3, 22.0, 31.0,
53.1, 58.3, 61.3, 126.3, 126.6, 128.1, 129.0, 133.2, 139.6. This
material was used without further purification.
dynamic processes) δ 1.3 (m, 1H), 1.55 (s, 3H), 1.68 (m, 2H),
1.98 (m, 2H), 2.39 (br, 3H), 2.95 (m, 1H), 3.15 (s, 3H), 3.79 (d,
1H, J ) 14.6 Hz), 4.95 (br, 1H), 5.65 (br, 3H), 7.29 (m, 5H);
13C NMR δ 22.8, 24.4, 27.5, 33.0, 41.3, 43.9, 46.8, 51.4, 126.1,
126.8, 127.1, 128.2, 128.3, 136.0, 138.0; IR (film) 1621.6 cm-1
.
This compound was cyclized to 12 and elemental analysis was
then carried out.
Bicyclic La cta m 9a . Because a Lewis acid was not
necessary for this photoreaction, the modified general proce-
dure was followed using 160 mg (0.64 mmol) of (methyl)-
(methoxy)chromium carbene complex 1a , 60 mg (0.32 mmol)
of bicyclic allylic amine 8, and ∼5 mL of dry THF. The reaction
mixture was photolyzed 9 h, and 53 mg (60%) 9a was obtained
as a clear oil and a 9:1 mixture of diastereoisomers: 1H NMR
δ 1.39 (s, 3H major diastereomer A), 1.45 (s, 3H minor
diastereomer B), 1.67 (m, 2H A), 1.95 (m, 1H B), 2.49 (d, 2H,
J ) 12.5 Hz), 2.64 (m, 2H), 2.89 (dd, 1H, J ) 1.3, 12.5 Hz),
2.96 (m, 1H B), 3.14 (s, 3H B), 3.16 (s, 3H B), 3.17 (1H B),
3.97 (dd, 1H A, J ) 4.6, 12.5 Hz), 4.47 (d, 1H A, J ) 14.3 Hz),
4.59 (d, 1H, J ) 14.3 Hz), 5.45 (m, 1H A), 5.64 (m, 2H A and
B), 5.77 (m, 1H B), 7.26 (m, 5H A, 5H B); 13C NMR δ 17.6
(major diastereomer A), 18.1 (minor diastereomer B), 33.2 (A),
35.0 (B), 37.4 (B), 39.9 (A), 49.8 (B), 50.2 (A), 50.6 (B), 51.1
(A), 51.2 (A), 51.5 (B), 55.6 (A), 55.9 (B), 80.0, 127.4, 127.5,
128.4, 128.5, 128.7, 128.9, 131.6, 137.4, 170.5; IR (film) 1659.4
cm-1. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16.
Found: C, 75.48; H, 7.66; N, 5.11.
Bicyclic La cta m 9b. The modified general procedure was
followed using 209 mg (0.64 mmol) of the (methyl)(benzyloxy)-
chromium carbene complex 1b, 59 mg (0.32 mmol) of the
bicyclic, allylic amine 8, and ∼5 mL of dry THF. The reaction
mixture was photolyzed 15 h, and 56 mg (51%) of 9b was
obtained as a clear oil: 1H NMR δ 1.54 (s, 3H), 1.72 (d, 1H, J
) 17.1 Hz), 2.52 (ddd, 1H, J ) 1.8, 10.2, 17.1 Hz), 2.70 (m,
1H), 2.93 (d, 1H, J ) 12.3 Hz), 3.32 (d, 1H, J ) 9.3 Hz), 4.04
(dd, 1H, J ) 4.5, 12.6 Hz), 4.16 (d, 1H, J ) 11.1 Hz), 4.57 (m,
1H), 5.52 (m, 1H), 5.67 (m, 1H), 7.28 (m, 10H); 13C NMR δ
18.4, 33.2, 39.3, 50.4, 51.5, 55.6, 66.1, 80.1, 127.5, 127.6, 127.7,
128.3, 128.4, 128.8, 128.9, 133.7, 137.4, 138.2, 170.7; IR
(film): 1658 cm-1. Anal. Calcd for C23H25NO2: C, 79.49; H,
7.25; N, 4.03. Found: C, 79.27; H, 7.23; N, 3.89.
8-(Ben zyla m in o)-2,3-d im et h yl-2-m et h oxyoct -4-en oic
Acid La cta m (5a ). The general procedure was followed using
50 mg (0.2 mmol) of (methyl)(methoxy)chromium carbene
complex 1a ,121 mg (0.6 mmol) of the allylic amine 4, ∼5 mL
of dry THF, and 0.2 mL (0.2 mmol) of 1 M ZnCl2 (in Et2O)
under 80 psi CO, and a 12.5 h photolysis gave 12 mg (20%) of
5a as an oil (a 2:1 mixture of diastereoisomers): 1H NMR δ
1.09 (d, 3H, J ) 6.6 Hz), 1.11 (d, 3H, J ) 6.9 Hz), 1.46 (s, 3H),
1.53 (s, 3H), 1.65 (m, 1H), 1.90 (m, 1H), 2.09 (m, 1H), 2.43 (m,
2H), 3.05 (dd, 1H, J ) 5.4, 14.1 Hz), 3.15 (s, 3H), 3.18 (s, 3H),
3.85 (d, 1H, J ) 14.4), 3.90 (d, 1H, J ) 15.0 Hz), 4.48 (dd, 1H,
J ) 10.5, 14.4 Hz), 5.31 (d, 1H, J ) 15.0 Hz), 5.42 (dd, 1H),
5.54 (dd, 1H, J ) 9.9, 15.6 Hz), 6.04 (dd, 1H, J ) 5.7, 16.5
Hz), 7.26 (m, 5H); 13C NMR δ 12.4, 12.9, 22.0, 22.1, 26.9, 27.7,
31.8, 32.5, 41.5, 44.3, 44.4, 45.2, 48.9, 49.2, 51.1, 51.3, 90.7,
91.8, 102.6, 127.0, 127.1, 127.6, 128.4, 129.2, 135.4, 137.2,
138.3, 176.1; IR (film): 1617 cm-1. Anal. Calcd for C18H25
-
NO2: C, 75.23; H, 8.77; N, 4.87. Found: C, 75.11; H, 8.50; N,
4.85.
8-(B e n zyla m in o )-2,3-d im e t h y l-2-(b e n zy lox y )o c t -4-
en oic Acid La cta m (5b). This compound was prepared in
the same manner as 5a . The quantities of reagents used were
as follows: 65 mg (0.2 mmol) of (methyl)(benzyloxy)chromium
carbene complex 1b, 121 mg (0.6 mmol) of allylic amine 4, and
0.2 mL (0.2 mmol) of 1 M ZnCl2 (in Et2O). This mixture was
photolyzed 13 h and gave 28 mg (39%) of 5b as an oil. It was
obtained as a 3:1 mixture of diastereoisomers. By radial
chromotography (6:1 hexanes/ethyl acetate) a single diastere-
oisomer of 5b was obtained, and the spectral data for this
single diastereoisomer is given: 1H NMR δ 1.20 (d, 3H, J )
6.6 Hz), 1.58 (m, 1H), 1.58 (s, 3H), 1.86 (m, 1H), 1.99 (m, 1H),
2.32 (m, 1H), 2.47 (dddd, 1H, J ) 6.6, 6.6, 6.6, 9.9 Hz), 2.92
(dd, 1H, J ) 5.4, 14.4 Hz), 3.82 (d, 1H, J ) 14.7 Hz), 4.16 (d,
1H, J ) 14.4 Hz), 4.41 (dd, 1H, J ) 10.2, 14.1 Hz), 4.55 (d,
1H, J ) 14.4 Hz), 5.35 (d, 1H, J ) 14.7 Hz), 5.45 (dd, 1H, J )
3.6, 10.2 Hz), 5.59 (dd, 1H, J ) 9.9, 15.9 Hz), 7.30 (m, 10H);
13C NMR δ 13.2, 23.0, 27.0, 31.7, 44.6, 44.9, 49.1, 65.2, 90.5,
126.8, 127.2, 128.2, 128.4, 128.5, 129.2, 137.3, 138.3, 138.8,
Bicyclic La cta m 9c. The modified general procedure was
followed using 168 mg (0.64 mmol) of the cyclic alkoxy carbene
1c, 59 mg (0.32 mmol) of 8, and ∼5 mL of dry THF.
A
photolysis time of 18 h gave 9.1 mg (10%) of 9c as a clear oil:
1H NMR δ 1.74 (m, 2H), 1.91 (m, 1H), 2.10 (m, 1H), 2.51 (m,
2 H), 2.68 (m, 1H), 2.89 (dd, 1H, J ) 3.9, 12.6 Hz), 3.26 (m,
1H), 3.90 (m, 3H), 4.51 (d, 1H, J ) 14.4 Hz), 4.59 (d, 1H, J )
14.4 Hz), 5.46 (m, 1H), 5.70 (m, 1H), 7.28 (m, 5H); 13C NMR δ
26.1, 31.6, 33.6, 39.4, 50.1, 50.8, 54.9, 68.5, 85.1, 127.4, 128.2,
128.4, 129.1, 133.6, 137.4, 171.9; IR (film) 1659 cm-1. Anal.
Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C,
76.03; H, 7.61; N, 4.78.
Bicyclic La cta m 9e. The modified procedure was followed
using 244 mg (0.64 mmol) of chromium carbene complex 1e,
59 mg (0.32 mmol) of 8, and ∼5 mL of dry THF. A 16 h
photolysis gave 62 mg (∼50% yield) of 9e as a clear oil and as
a 3:1 mixture of diastereoisomers. Spectral data given is for
the single diastereomer that was cleanly separated from the
mixture: 1H NMR δ 1.35 (s, 3H), 1.44 (br, 2H), 1.47 (s, 3H),
2.36 (dd, 1H, J ) 10.2, 12.0 Hz), 2.59 (m, 1H), 2.90 (d, 1H, J
) 13.5 Hz), 3.26 (m, 1H), 3.44 (dd, 1H, J ) 4.2, 13.5 Hz), 3.67
(d, 1H, J ) 5.1 Hz), 3.77 (d, 1H, J ) 7.8 Hz), 4.39 (d, 1H, J )
14.4 Hz), 4.59 (m, 2H), 4.97 (m, 1H), 5.09 (d, 1H, J ) 3.6 Hz),
5.34 (m, 1H), 7.26 (m, 10H); 13C NMR δ 23.3, 28.6, 35.2, 39.9,
50.2, 50.3, 51.5, 58.3, 60.8, 73.2, 97.1, 126.2, 126.2, 127.5, 128.1,
128.4, 128.4, 130.0, 130.0, 133.2, 137.6, 147.8, 172.7; IR (film)
1634 cm-1. Anal. Calcd for C21H25NO2: C, 77.99; H, 7.91; N,
4.33. Found: C, 78.10; H, 7.70; N, 4.47.
N,N-Diben zyl-2-m eth yl-2-m eth oxypen t-4-en am ide (11a).
The general procedure was followed using 160 mg (0.64 mmol)
of (methyl)(methoxy) chromium carbene complex 1a , 76 mg
(0.32 mmol) of N,N-dibenzyl allyl amine 10, ∼5 mL of dry THF,
and 0.32 mL (0.32 mmol) of 1 M Me2AlCl (in hexanes). Glass
beads were added, and the reaction mixture was photolyzed
10 h. This mixture gave 47 mg (45%) of 11a as a clear oil: 1H
176.2; IR (film) 1614 cm-1
. Anal. Calcd for C24H29NO2: C,
79.30; H, 8.04; N, 3.85. Found: C, 79.55; H, 7.86; N, 3.92.
N-Ben zyl-2-vin ylp ip er d in e (6). This was prepared from
D,L-pipecolinic acid following the same procedure that was used
to make 2. Spectral data was identical to that previously
reported for this compound.30
9-(Ben zyla m in o)-2-m eth yl-2-m eth oxyn on -4-en oic Acid
La cta m (7). The general procedure was followed using 46
mg (0.18 mmol) of the (methyl)(methoxy)chromium carbene
complex 1a , 111 mg (0.55 mmol) of 6, 0.18 mL (0.18 mmol) of
1 M Me2AlCl (in hexanes), and ∼4 mL of freshly distilled THF.
The mixture was photolyzed for 15.3 h giving 17 mg (33%) of
7 as a clear oil: 1H NMR (peaks were broad because of slow
(30) Vedejs, E.; Arco, M. J .; Powell, D. W.; Renga, J . M.; Singer, S.
P. J . Org. Chem. 1978, 43, 4831.