8184
W. P. Malachowski, M. Banerji / Tetrahedron Letters 45 (2004) 8183–8185
Fleming, I., Eds.; Pergamon: Oxford; Vol. 5, Chapter
O
O
1) K, t-BuOH
Me
Me
7.1; (d) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22,
1.
NH /THF
N
N
3
Br
2)
OMe
OMe
3. One example involves cyclohexadienone rearrangement:
(a) Miller, B. J. Am. Chem. Soc. 1965, 87, 5115; (b) Miller,
B. J. Am. Chem. Soc. 1970, 92, 6246; (c) Miller, B. J. Org.
Chem. 1970, 35, 4262; The second example involves the
rearrangement of methylenecyclooctene: (d) Buchanan, G.
L.; McKillop, A.; Raphael, R. A. J. Chem. Soc. 1965, 833.
4. For reviews of Birch reduction–alkylation chemistry see:
(a) Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42,
1; (b) Mander, L. N. Partial Reduction of Aromatic Rings
by Dissolving Metals and by Other Methods. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 8, Chapter 3.4.
8
(61%)
7
HCl
MeOH
(52%)
O
N
O
O
∆
Me
Me
N
1,2-dichloro-
benzene
(88%)
O
10
9
Scheme 3. Birch reduction–allylation and Cope rearrangement of N-
pyrrolidinyl 2-methoxy-5-methylbenzamide.
5. N-Pyrrolidinyl 2-methoxybenzamide, 3, was synthesized
from o-anisic acid by conversion to the acid chloride and
reaction with pyrrolidine. The product matched the
spectroscopic data previously reported in: Katrizky, A.
R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210.
as used for 3 to afford an excellent yield of the rear-
ranged product 10.11
6. Compound 5: 1H NMR (CDCl3):
d 5.99 (d, 1H,
It is apparent that Birch reduction–allylation can be
combined with Cope rearrangement to create a powerful
tool for the construction of substituted 2-cyclohexe-
nones, a potentially versatile synthetic intermediate.12
Most notably, the Cope rearrangement of 9 afforded a
new quaternary center in 10 in excellent yield. This rep-
resents the first example of quaternary carbon synthesis
on a cycloalkenone ring by a Cope rearrangement proc-
ess. When combined with the reported stereocontrol of
the Birch reduction–alkylation reaction of o-anisic acid
derivatives,13 the Cope rearrangement will also result
in 1,3-chirality transfer and access to enantiomerically
pure products.
J = 10Hz), 5.88–5.76 (m, 1H), 5.64 (d, 1H, J = 10Hz),
5.04 (s, 1H), 4.99 (d, 1H, J = 7Hz), 3.47 (br s, 2H), 3.26 (br
s, 1H), 3.03 (br s, 1H), 2.74–2.59 (m, 2H), 2.58–2.45 (m,
4H), 1.78 (br s, 4H) ppm. 13C NMR (CDCl3): d 207.9,
168.1, 134.1, 128.8, 127.3, 118.0, 61.4, 47.3, 46.0, 41.7,
37.2, 26.4, 25.8, 23.4ppm. IR (CDCl3): 2980, 1710, 1619,
1420cmÀ1. Mp = 50.5–52.5ꢁC. EIMS m/z (relative inten-
sity) 233 (M+, 13), 177 (26), 164 (14), 98 (100). GC
retention time: 15.74min.7
7. All new compounds were pure as determined by a
combination of NMR, GC, and, where applicable, melting
point. GC analyses were performed on an Agilent 6890 gas
chromatograph with an EIMS detector fitted with a
30m · 0.25mm column filled with crosslinked 5% PH ME
siloxane (0.25lm film thickness); gas pressure: 7.63psi He.
The method for analysis of all samples involved heating
from 50 to 150ꢁC (10ꢁC/min), then from 150 to 260ꢁC
(5ꢁC/min) and finally holding at 260ꢁC for 2min.
Representative experimental procedure for the thermal
Cope rearrangement: Diene 9 (105mg) was dissolved in
1,2-dichlorobenzene (3mL) and heated to reflux tempera-
ture overnight. Upon cooling, the solvent was removed
in vacuo and the residue purified by silica gel column
chromatography (eluted with 1:1 hexanes/EtOAc) to
provide the white crystalline product, 1011 (92mg, 88%).
8. Compound 6: 1H NMR (CDCl3): d 7.02 (s, 1H), 5.84–5.73
(m, 1H), 5.15 (s, 1H), 5.11–5.09 (m, 1H), 3.54 (t, 1H,
J = 6Hz), 3.31–3.18 (m, 2H), 2.64–2.53 (m, 2H), 2.49–2.37
(m, 1H), 2.27 (t, 2H, J = 7Hz), 2.18–2.09 (m, 1H), 1.93–
1.86 (m, 4H), 1.84–1.69 (m, 1H)ppm. 13C NMR (CDCl3):
d 195.3, 165.6, 152.6, 138.9, 134.7, 117.8, 47.6, 45.5, 38.5,
37.0, 35.7, 28.2, 25.8, 24.3ppm. IR (CDCl3) 2980, 1682,
1618, 1469, 1382cmÀ1. EIMS m/z (relative intensity) 233
(M+, 15), 191 (10), 123 (12), 98 (17), 70 (100). GC
retention time: 18.57min.7
Acknowledgements
The authors are grateful for the financial support of
Bryn Mawr College. Manuscript review and helpful dis-
cussions with Prof. Douglass F. Taber of the University
of Delaware are also acknowledged.
9. N-Pyrrolidinyl 2-methoxy-5-methylbenzamide, 7, was syn-
thesized from 5-methylsalicylate by dimethylation and
saponification to make 2-methoxy-5-methyl-benzoic acid.
Conversion of the acid to the acid chloride and reaction
with pyrrolidine afforded 5, which matched the previously
reported spectroscopic data in: Hart, D. J.; Havas, F. C.
R. Acad. Sci., Ser. IIc: Chim. 2001, 4, 591.
References and notes
1. For a few recent examples see: (a) Wolckenhauer, S. A.;
Rychnovsky, S. D. Org. Lett. 2004, 6, 2745; (b) Kerr, M.
S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876; For
recent reviews see: (c) Denissova, I.; Barriault, L. Tetra-
hedron 2003, 59, 10105; (d) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591; (e) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388;
(f) Fuji, K. Chem. Rev. 1993, 93, 2037.
2. (a) Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62,
441; For reviews of the Cope rearrangement, see: (b)
Nubbemeyer, U. Synthesis 2003, 7, 961; (c) Hill, R. K.
Cope, Oxy-Cope and Anionic Oxy-Cope Rearrangements
In Comprehensive Organic Synthesis; Trost, B. M.,
10. Compound 9: 1H NMR (CDCl3): d 5.87–5.73 (m, 1H),
5.34 (s, 1H), 5.02 (s, 1H), 4.98 (d, 1H, J = 6Hz), 3.47 (br s,
2H), 3.22 (br s, 1H), 3.03 (br s, 1H), 2.71–2.58 (m, 2H),
2.58–2.48 (m, 2H), 2.46–2.40 (m, 2H), 1.80 (s, 7H)ppm.
13C NMR (CDCl3): d 208.3, 168.6, 135.5, 134.4, 123.2,
117.8, 60.9, 47.3, 45.9, 41.8, 37.0, 30.4, 26.4, 23.3,
22.9ppm. IR (CDCl3) 2979, 1709, 1619, 1417cmÀ1
.
Mp = 33.5–34.5ꢁC. EIMS m/z (relative intensity) 247
(M+, 10), 191 (57), 178 (13), 98 (100). GC retention time:
16.44min.7
1
11. Compound 10: H NMR (CDCl3): d 6.75 (s, 1H), 5.80–
5.68 (m, 1H), 5.12–5.04 (m, 1H), 3.48 (t, 2H, J = 7Hz),
3.17 (t, 2H, J = 5.5Hz), 2.48 (t, 2H, J = 6.5Hz), 2.20 (d,