Organic synthesis methodology. Preparation and diastereoselective birch reduction-alkylation of 3-substituted 2-methyl-2,3-dihydroisoindol-1-ones

Full text of DOI:10.1021/jo005693g

2154
J . Org. Chem. 2001, 66, 2154-2157
tion of o-bromoanilines with carbon monoxide at 100 °C
Or ga n ic Syn th esis Meth od ology.
and 1 atm pressure in the presence of catalytic amounts
P r ep a r a tion a n d Dia ster eoselective Bir ch
Red u ction -Alk yla tion of 3-Su bstitu ted
2-Meth yl-2,3-d ih yd r oisoin d ol-1-on es
of Pd(OAc)2, Ph3P, and n-Bu3N.7
N-Methylphthalimidine 1 was readily prepared in
quantitative yield from N-methylphthalimide by reduc-
tion with zinc in refluxing acetic acid.8 The crude product
Zihong Guo* and Arthur G. Schultz†
1
was pure, witnessed by its very clean H NMR spectrum,
Department of Chemistry, Rensselaer Polytechnic Institute,
Troy, New York 12180-3590
and was used directly in the next step without further
purification. 1 was lithiated with t-BuLi (1.2-1.5 equiv)
in THF and quenched with methyl iodide (4 equiv) at -78
°C (Scheme 1).9 Methylated product 2a was then isolated,
in 69% yield, as an oil, which showed a clear one-proton
(benzylic methine) quartet centered at 4.40 ppm and a
three-proton (methyl) doublet at 1.45 ppm in the 1H NMR
spectrum. CIMS indicated a molecular weight of 161
(M + 1 ) 162, 100%). This suggested that methylation
occurred selectively at the benzylic position. In fact, this
lithiation-methylation process was highly regioselective,
and no evidence was suggestive of dimethylation at the
C(3) position, O-methylation at the carbonyl oxygen atom,
or methylation on the benzene ring. The absence of
alkylation on the aromatic ring is noteworthy because
amido groups on aryl rings are usually regarded as
excellent ortho-metalation substituents. In some cases,
a small amount of unreacted 1 could be recovered (<5%),
but no attempt to optimize this procedure was made.
Efforts to extend this metalation-alkylation approach
to other electrophiles such as ethyl iodide, allyl bromide,
benzyl bromide, ethyl bromoacetate, and bromoacetoni-
trile were made, and the corresponding groups were
incorporated into the benzylic C(3) position with moder-
ate to good yields (Scheme 1).
guo@3dp.com
Received October 22, 2000
The Birch reduction-alkylation of substituted benza-
mides derived from L-prolinol has provided a wide range
of enantiomerically pure cyclohexane derivatives for
utilization in organic synthesis.1 Asymmetric total syn-
theses of (-)-longifolene and (+)-apovinamine are two
decent examples of the applications by this methodology.2
We now report a new efficient preparation and Birch
reductive alkylation of 3-substituted 2-methyl-2,3-dihy-
droisoindol-1-ones 2 and 1. To our knowledge, the Birch
reductions of simple aromatic lactams have not been
previously reported, although Birch reductions and re-
ductive alkylations of achiral tetralones and related
aromatic ketones have received some attention from
synthetic chemists.3 It is expected that the methodology
outlined in this note will offer unique opportunities for
the enantioselective synthesis of alkaloids and other
nitrogen-containing heterocyclic systems when a chiral
nonracemic substrate is used.
There is an increasing interest in the development of
new synthetic methodologies for the preparation of
isoindolinone derivatives because of their importance as
key intermediates in organic synthesis and the demon-
strated activity as nonnucleosidic HIV-reverse tran-
scriptase inhibitors and vasodilators.4 Treated with NBS
and methylamine, for example, methyl o-toluate is trans-
formed in two steps into N-methylisoindolinone.5 A more
general one-step conversion of o-acylbenzoic acids to
isoindolinones is achieved by a reductive amination
process.6 Isoindolinones can also be synthesized by reac-
Conversion of 1 to enolate 3 was accomplished by
reduction with lithium in ammonia at -78 °C. Alkylation
with methyl iodide gave 4a in 69% yield; alkylations with
ethyl iodide, benzyl bromide, p-methoxybenzyl bromide,
and ethyl bromoacetate provided 4b-e in 49-93% yields,
respectively (Scheme 2).
The Birch reduction-alkylations of 2a occurred to give
5a -c in good yields with high diastereoselectivity under
the same reaction conditions (Scheme 3). In these cases,
1H NMR data were obtained before flash chromato-
graphic purification. The 1H NMR spectrum of 5a showed
the presence of two products of C-methylation with a ∼7:1
ratio. No other resonance peaks could be seen. Reductive
* To whom correspondence should be addressed: 3-Dimensional
Pharmaceuticals, Inc., 665 Stockton Drive, Exton, PA 19341.
† Deceased on J anuary 20, 2000.
(1) (a) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207. (b) Schultz, A.
G. J . Chinese Chem. Soc. 1994, 41, 487.
(2) (a) Schultz, A. G. and Puig, S. J . Org. Chem. 1985, 50, 915. (b)
Schultz, A. G.; Malachowski, W. P.; Pan, Y. J . Org. Chem. 1997, 62,
1223.
(3) However, Birch reductions and reductive alkylations of pyr-
rolobenzoazepin-10-ones and pyrrolobenzodiazepine-5,11-diones have
been reported; see: (a) Schultz, A. G.; Macielag, M.; Sundararaman,
P.; Taveras, A. G.; Welch, M. J . Am. Chem. Soc. 1988, 110, 7828. (b)
Schultz, A. G.; McCloskey, P. J .; Court, J . J . J . Am. Chem. Soc. 1987,
109, 6493.
(4) (a) Allin, S. M.; Vaidya, D. D.; Page, M. I.; Slavwin, A. M.; and
Smith, T. Tetrahedron Lett. 2000, 41, 2219. (b) Mamouni, A.; Daich,
A.; and Decroix, B. Synth. Commun. 1997, 27, 2241. (c) Campbell, J .
B.; Dedinas, R. F.; and Trumbower-Walsh, S. A. J . Org. Chem. 1996,
61, 6205. (d) DeClercq, E. J . Med. Chem. 1995, 38, 2491. (e) Kato, Y.;
Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1993, 41, 2003. (f) Cho,
C. S.; Shim, H. S.; Choi, H. J .; Kim, T, J .; Shim, S. C.; Kim, M. C.
Tetrahedron Lett. 2000, 41, 3891.
(5) Danishefsky, S.; Bryson, T. A.; Puthenpurrayil, J . J . Org. Chem.
1975, 40, 796.
(6) Anderson, P. S.; Christy, M. E.; Colton, C. D.; Shepard, K. L. J .
Org. Chem. 1978, 43, 3719.
1
ethylation of 2a afforded 5b in 79% yield. The H NMR
spectroscopic analyses suggested that the ratio of the two
possible diastereoisomers in the reaction mixture might
be 10:1. When bulkier benzyl bromide was used in the
alkylation step, only a single diastereomer was observed.
Stereochemical assignments were temporarily made
according to conformational analyses and a comparison
with the results of a previous study on the Birch
reduction-alkylation of dihydroisoquinolione 6b (Scheme
(7) (a) Mori, M.; Chiba, K.; Ban, Y. J . Org. Chem. 1978, 43, 1684.
(b) Campbell, J . B.; Dedinas, R. F.; Walsh, S. A. T. J . Org. Chem. 1996,
61, 6205. (c) Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1998, 39,
2285. (d) For a similar approach, see: Bird, C. W. J . Organomet. Chem.
1973, 47, 281.
(8) Brewster, J . H.; Fusco, A. M.; Carosino, L. E.; Corman, B. G. J .
Org. Chem. 1963, 28, 498.
(9) A similar method has appeared recently; see: Couture, A.;
Deniau, E.; Ionescu, D.; Grandclaudon, P. Tetrahedron Lett. 1998, 39,
2319.
10.1021/jo005693g CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/07/2001

Notes
J . Org. Chem., Vol. 66, No. 6, 2001 2155
Sch em e 1
Sch em e 2
Sch em e 3
It is believed that the stereoselectivity of the methyl-
ation of the enolate generated from 2a was kinetically
controlled by the methyl substituent at C(3) by an early
transition-state model resembling the enolate (steric
approach control). Calculations by MM2 indicated that
both cis and trans isomers of 5a have similar minimized
energy (10.3 vs 10.5 kcal/mol). If thermodynamic factors
(product development control) played a role in the alkyl-
ation both isomers should have been obtained in ap-
proximately equal amounts. Shown in Figure 1 is the
lowest energy enolate structure obtained by MM2 calcu-
lations. Because the five-membered ring is planar, the
proton and the methyl substituent associated with C(3)
have equivalent positions with respect to the ring plane.
However, the differences in size and bond length between
a proton and a methyl group differentiate each side of
the ring plane. As a result, the C(3) methyl substituent
provides unusually effective shielding of the bottom face
of the enolate and blocks the approach of an incoming
electrophile very efficiently.
4).10,11 The Birch reductive alkylation of 6b provided 7b
with the trans-diastereomer as a major product. The
diastereomeric ratios were determined by HPLC before
chromatographic separation. The stereochemical struc-
ture of 7b was assigned with a high degree of confidence
by comparison of experimentally determined coupling
constants for protons at C(3) and C(4) with those deter-
mined by utilization of MacroModel, Version 3 (MM2).
Latest studies on the chemistry of the bridged cyclo-
hexene analogues 8a -c, which were obtained from 7
(R2 ) CH2Ar) by Grewe cyclization, have provided more
useful stereochemical information (Scheme 4)12 and can
help further understand the effects of the C(3) methyl
substituent (in both isoqunolinone and isoindolinone
numbering) on the stereoselectivity of the Birch reductive
alkylation of 7 and 2a . For example, allylic oxidation of
bridgehead olefin 8c provided keto lactam (+)-8d (shown
in Scheme 5 is its enantiomer (-)-8d ).12 The product (8e)
with cis ring fusion is obtained by hydrogenation (H2, 5%,
Pd/C, EtOAc, 79 psi) of the enone double bond in (-)-8d ,
while the trans ring junction isomer 8f is available by
Birch reduction (Li, NH3/THF, -78 °C) in the presence
of 1 equiv of t-BuOH (Scheme 5). The axial methyl
substituent is responsible for the observed stereoselec-
tivity, because, in the absence of the axial methyl group
(such as in 8a ), hydrogenation of the corresponding
bridgehead olefin provided the trans ring junction prod-
uct.10,11
The less steric hindrance double bond of the two in 5
can be regioselectively reduced with diimide, which is
formed in situ from heating excess p-toluenesulfonyl
hydrazide (PTSH) and catalytic sodium acetate, to fur-
nish 9. For example, the selective saturation of 5a and
5b by the diimide method provided 9a and 9b in good
yields (Scheme 6). No other products were isolated from
the reactions.
Cyclization of 4c and 4d with trifluoromethanesulfonic
acid in CH2Cl2 at 0 °C gave the bridged olefin 10a ,b in
61-81% isolated yields (Scheme 6). A potential applica-
tion of 10b will be the synthesis of the analogues of
levorphanol 11, the levo isomer of N-methylmorphinan,
which is four times as potent as morphine.13 Racemic 12a
is synthesized as a lead structure from 8a in a three-
step reaction sequence:10 (1) LiAlH4/THF; (2) H2, PtO2;
and (3) DIBAL/PhCH3 and shows modest affinity for the
µ-receptor. Structural modifications have been made to
enhance opiate receptor affinity and selectivity. Among
the modified structures, analogue (-)-12b is found to be
(10) Schultz, A. G.; Kirincich, S. J .; Rahm, R. Tetrahedron Lett. 1995,
36, 4551.
(11) Kirincich, S. J . Ph.D. Thesis, Rensselaer Polytechnic Institute,
Troy, NY, 1996.
(12) Schultz, A. G.; Guzi, T. J .; Larsson, E.; Rahm, R.; Thakkar, K.;
Bidlack, J . M. J . Org. Chem. 1998, 63, 7795.
(13) Benson, W. M.; Stefko, P. L.; Randall, L. O. J . Pharmacol. Exp.
Ther. 1953, 109, 189.

2156 J . Org. Chem., Vol. 66, No. 6, 2001
Notes
Sch em e 4
3-Ben zyl-2-m eth yl-2,3-d ih yd r o-isoin d ol-1-on e (2d ). Iso-
lated in 58% yield: 1H NMR (CDCl3) δ 2.90 (dd, 1 H), 3.12 (s, 2
H), 3.35 (dd, 1 H), 4.63 (dd, 1 H), 6.95 (m, 1 H), 7.05 (m, 2 H),
7.23 (m, 3 H), 7.37 (m, 2 H), 7.74 (m, 1 H); IR (film) 3000, 2995,
1655, 1405, 1375 cm-1; CIMS m/z (rel intensity) 238 (M+ + 1,
100).
(2-Meth yl-3-oxo-2,3-d ih yd r o-1H-isoin d ol-1-yl)a cetic Acid
Eth yl Ester (2e). Isolated in 57% yield: 1H NMR (CDCl3) δ
1.20 (t, 3 H), 2.75 (dq, 2 H), 3.08 (s, 3 H), 4.13 (q, 2 H), 4.81 (t,
1 H), 7.38-7.53 (m, 3 H), 7.78 (d, 1 H); IR (film) 1650, 1375 cm-1
;
F igu r e 1. Most stable conformation of the enolate generated
from 2a .
CIMS m/z (rel intensity) 234 (M+ + 1, 100).
(2-Met h yl-3-oxo-2,3-d ih yd r o-1H -isoin d ol-1-yl)a cet on i-
tr ile (2f). Isolated in 42% yield: 1H NMR (CDCl3) δ 2.90 (dq, 2
H), 3.16 (s, 3 H), 4.62 (dd, 1 H), 7.47-7.60 (m, 3 H), 7.84 (d, 1
H); IR (CDCl3) 1660, 1455, 1410, 1375 cm-1; CIMS m/z (rel
intensity) 187 (M+ + 1, 100).
Sch em e 5
Gen er a l P r oced u r e for th e Bir ch Red u ctive Alk yla tion .
A solution of 1 (2a or 6)(1.82 g, 12.4 mmol) and tert-butyl alcohol
(1.16 mL, 1.0 equiv) in THF (50 mL) was cooled to -78 °C, and
ammonia (∼700 mL) was added. Lithium (0.38 g, 3 equiv) was
added in small pieces, and after 15 min, excess metal was
consumed by the addition of 1,3-pentadiene (0.8 mL). Methyl
iodide (0.38 mL, 4 equiv) in THF (3 mL) was added, and the
reaction mixture was stirred at -78 °C for 1 h. Ammonia was
allowed to evaporate, water was added, and the mixture was
extracted with methylene chloride (3 × 150 mL). The combined
organic layers were washed with 10% sodium thiosulfate, dried
over MgSO4, filtered, evaporated, and purified by flash chroma-
tography on silica gel (hexane/ethyl acetate 2:1) to afford pure
samples.
10-fold greater potent than that of determined for the
lead structure 12a (Scheme 7).12
Exp er im en ta l Section
IR spectra were recorded on a Perkin-Packard model spec-
trometer in CHCl3 solution or in liquid film. 1H NMR and 13C
NMR were measured with a 500 HMz spectrometer and in
CDCl3 solution using TMS as an internal standard. Extracts
were dried over anhydrous MgSO4 before evaporation of solvents
on a rotary evaporator under reduced pressure. Dry THF and
diethyl ether were freshly distilled from sodium benzophenone
ketyl prior to use. Dry dichloromethane was distilled from CaH2
prior to use.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Su bstitu ted
2-Meth yl-2,3-d ih yd r oisoin d ol-1-on es. 2,3-Dim eth yl-2,3-d i-
h yd r o-isoin d ol-1-on e (2a ). To a solution of 1 (1.12 g, 7.6 mmol)
in THF (90 mL) at -78 °C was added t-BuLi (5.4 mL, 1.2 equiv,
1.7 M in pentane). After the resulting solution was stirred at
-78 °C for 1 h, MeI (1.9 mL, 4.0 equiv) was added to the solution.
Stirring was continued for 1 h, and the reaction mixture was
allowed to warm to room temperature and quenched with water.
Removal of solvent in vacuo and chromatography of the resulting
residue on silica gel (hexane/ethyl acetate 1:1) gave 2a (0.85 g,
69%): 1H NMR (CDCl3) δ 1.44 (d, 3 H), 3.09 (s, 3 H), 4.40 (q, 1
H), 7.35-7.60 (m, 3 H), 7.80 (d, 1 H); IR (film) 1660, 1460, 1380
cm-1; CIMS m/z (rel intensity) 162 (M+ + 1, 100). Analytical
data are consistent with literature values.5
(+)-(3S,8a R)-3,4,6,8a -Tetr a h yd r o-2,3,8a -tr im eth yl-1(2H)-
isoqu in olin on e [7b (R2 ) Me)]: 72% isolated yield; IR (CHCl3)
1610 cm -1; 1H NMR δ (500 MHz, CDCl3) 6.17 (dt, J ) 10.0, 1.5
Hz, 1 H), 5.76-5.72 (m, 1 H), 5.55-5.53 (m, 1 H), 3.48 (m, J )
6.0, 1.6, 6.6 Hz, 1 H), 2.98-2.94 (m, 1 H), 2.90 (s, 3 H), 2.68-
2.66 (m, 2 H), 2.06 (dd, J ) 13.2, 1.6 Hz, 1 H), 1.38 (s, 3 H), 1.13
(d, J ) 6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 173.1, 133.2,
130.7, 123.0, 120.9, 53.7, 43.5, 35.1, 34.0, 28.4, 26.1, 18.1; [R]21
D
+170 (c 0.80, CHCl3); CIMS m/z (rel intensity) 192 (M + 1, 100).
Anal. Calcd for C12H17NO: C, 75.36; H, 8.96; N, 7.32. Found:
C, 74.24; H, 8.99; N, 7.23.12
2,7a -Dim eth yl-2,3,5,7a -tetr a h yd r oisoin d ol-1-on e (4a ). Iso-
lated as a light yellow oil in 69% isolated yield (1.26 g): 1H NMR
(CDCl3) δ 1.12 (s, 3 H), 2.62 (q, 2 H), 2.81 (s, 3 H), 3.69 (d, J )
12.2 Hz, 1 H), 4.02 (d, J ) 12.5 Hz, 1 H), 5.67 (br, 1 H), 5.78 (m,
1 H), 6.04 (dd, J ) 9.3, 1.2 Hz, 1 H); IR (film) 2900, 1650, 1415,
1385 cm-1; CIMS m/z (rel intensity) 164 (M+ + 1, 100).
7a-Eth yl-2-m eth yl-2,3,5,7a-tetr ah ydr oisoin dol-1-on e (4b).
Isolated as an oil (74%): 1H NMR (CDCl3) δ 0.82 (t, 3 H), 1.60
(m, 2 H), 2.65 (m, 2 H), 2.87 (s, 3 H), 3.73 (d, 1 H), 4.05 (d, 1 H),
5.82 (m, 1 H), 5.95 (m, 1 H), 5.99 (d, 1 H); CIMS m/z (rel
intensity) 178 (M+ + 1, 100).
3-Eth yl-2-m eth yl-2,3-d ih yd r oisoin d ol-1-on e (2b). Isolated
as an oil in 56% yield: 1H NMR (CDCl3) δ 1.45 (t, 3 H), 1.95 (m,
2 H), 3.00 (s, 3 H), 4.40 (t, 1 H), 7.32 (d, 1 H), 7.41 (q, 2 H), 7.72
(+)-(3S,8a R)-3,4,6,8a -Tet r a h yd r o-2,3-d im et h yl-8a -(p h e-
n ylm eth yl)-1(2H)-isoqu in olin on e [7b (R2 ) CH2P h )]. Iso-
1
lated in 68% isolated yield: IR (CHCl3) 1620 cm -1; H NMR δ
(d, 1 H); IR (film) 2960, 2920, 2870, 1655, 1450, 1415, 1385 cm-1
;
(500 MHz, CDCl3) 7.18-7.14 (m, 3 H), 7.09-7.06 (m, 2 H), 6.13
(dd, J ) 9.8, 2.5 Hz, 1H), 5.74-5.70 (m, 1 H), 5.49 (dt, J ) 3.1,
1.6 Hz, 1 H), 3.46 (dd, J ) 6.0, 1.6 Hz, 1 H), 3.10 (d, J ) 12.5
Hz, 1 H), 2.95 (s, 3 H), 2.94 (d, J ) 12.5 Hz, 1 H), 2.86-2.81 (m,
1 H), 2.28 (dt, J ) 22.2, 4.8 Hz, 1 H), 2.04 (dd, J ) 13.1, 1.3 Hz,
1 H), 1.66 (m, 1 H), 1.12 (d, J ) 6.4 Hz, 3 H); 13C NMR δ (125.7
MHz, CDCl3) 172.4, 137.0, 130.8, 130.2, 128.5, 127.0, 126.3,
CIMS m/z (rel intensity) 176 (M+ + 1, 100). Analytical data are
consistent with literature values.5
3-Allyl-2-m eth yl-2,3-d ih yd r o-isoin d ol-1-on e (2c). Isolated
as an oil in 47% yield: 1H NMR (CDCl3) δ 2.70 (m, 2 H), 3.08 (s,
3 H), 4.45 (t, 1 H), 4.98 (t, 3 H), 5.30 (m, 1 H), 7.35-7.50 (m, 3
H), 7.77 (d, 1 H); IR (film) 2890, 1655, 1455, 1405, 1377 cm-1
;
CIMS m/z (rel intensity) 188 (M+ + 1, 100).
126.0, 124.5, 54.0, 50.0, 45.0, 35.7, 34.4, 26.2, 18.5; [R]24 -150
D

Notes
J . Org. Chem., Vol. 66, No. 6, 2001 2157
Sch em e 6
MgSO4, and concentrated in vacuo. Flash chromatography on
silica gel (hexane/ethyl acetate 2:1) afforded 9a as a yellowish
oil (90 mg, 50%): 1H NMR (CDCl3) δ 1.16 (s, 3 H), 1.26 (d, J )
6.4 Hz, 3 H), 1.72 (m, 2 H), 1.83 (dt, J ) 12.7, 4.4 Hz, 1 H), 2.11
(m, 1 H), 2.79 (s, 3 H), 4.07 (m, 1 H), 5.50 (t, J ) 3.4, 2.2 Hz, 1
H); IR (film) 2400, 2830, 1645, 1405, 1375 cm-1; CIMS m/z (rel
intensity) 180 (M+ + 1, 100).
Sch em e 7
7a-Eth yl-2,3-dim eth yl-2,3,5,6,7,7a-h exah ydr o-1H-isoin dol-
1-on e (9b). Isolated in 75% yield as an oil: 1H NMR (CDCl3) δ
0.85 (t, J ) 7.6 Hz, 3 H), 1.24 (d, J ) 6.0 Hz, 3 H), 1.63 (m, 3 H),
1.95 (dt, J ) 13.5, 3.5 Hz, 1 H), 2.04-2.13 (m, 2 H), 2.80 (s, 3
H), 4.04 (q, J ) 6.0 Hz, 1 H), 5.55 (q, J ) 2.6 Hz, 1 H); IR (film)
2910, 2850, 1650, 1405, 1375 cm-1; CIMS m/z (rel intensity) 194
(M+ + 1, 100).
(c 1.0, CHCl3); CIMS m/z (rel intensity) 268 (M + 1, 100); HRMS
calcd for C18H21NO (M + H) 268.1701, found 268.1704.12
7a-Ben zyl-2-m eth yl-2,3,5,7a-tetr ah ydr oisoin dol-1-on e (4c).
Isolated in 93% yield. Benzyl bromide (1.5 equiv) was used in
the alkylation step: 1H NMR (CDCl3) δ 2.17 (d, 1 H), 2.59 (d, 1
H), 2.65 (s, 3 H), 2.94 (d, 1 H), 3.13 (m, 1 H), 3.45 (d, 1 H), 5.74
(d, 1 H), 5.84 (m, 1 H), 6.13 (dd, 1 H), 7.09 (m, 2 H), 7.18 (m, 3
H).
Gen er a l P r oced u r e for t h e Cycliza t ion : 10-Aza -10-
m eth yl-9-oxo-5,6-ben zotr icyclo-1-d od ecen e (10a ). A mixture
of 4c (460 mg, 1.92 mmol) and CF3SO3H (1.5 mL) in CH2Cl2 (35
mL) was stirred at 0 °C for 15 min, allowed to warm to room
temperature, and stirred overnight. Reaction solution was
poured into aqueous NaHCO3 solution, extracted with CH2Cl2
(3 × 40 mL). The combined organic layers were washed with
brine and dried over MgSO4. Removal of the solvent and
chromatography of the residue on silica gel (hexane/ethyl acetate
4:1) gave 10a (370 mg, 81%): 1H NMR (CDCl3) δ 1.69 (dt, J )
12.0, 2.2 Hz, 1 H), 2.14 (d, J ) 18.1 Hz, 1 H), 2.18 (dd, J ) 12.0,
3.8 Hz, 1 H), 2.60 (dd, J ) 8.1, 2.9 Hz, 1 H), 2.73 (d, J ) 16.6
Hz, 1 H), 2.93 (s, 3 H), 3.13 (d, J ) 16.6 Hz, 1 H), 3.30 (m, 1 H),
3.73 (d, J ) 12.3 Hz, 1 H), 4.06 (d, J ) 12.4 Hz, 1 H), 5.51 (s, 1
7a -(p-Meth oxyben zyl)-2-m eth yl-2,3,5,7a -tetr a h yd r o-1H-
isoin d ol-1-on e (4d ). Isolated in 93% yield. Methoxybenzyl
chloride (1.2 equiv) was used: 1H NMR (CDCl3) δ 2.22 (d, 1 H),
2.53 (d, 2 H), 2.68 (s, 3 H), 2.88 (d, 1 H), 3.18 (d, 1 H), 3.47 (d,
1 H), 3.76 (s, 3 H), 5.76 (d, 1 H), 5.86 (q, 1 H), 6.12 (dd, 1 H),
6.72 (q, 2 H), 6.99 (dd, 2 H); CIMS m/z (rel intensity) 270 (M+
1, 100).
+
7a -Eth oxyca r bon ylm eth yl-2-m eth yl-2,3,5,7a -tetr a h yd r o-
1H-isoin d ol-1-on e (4e). Isolated in 49% yield: 1H NMR (CDCl3)
δ 1.20 (t, 3 H), 2.50 (q, 2 H), 2.65 (br, 2 H), 2.87 (s, 3 H), 3.70 (d,
1 H), 4.01 (t, 2 H), 4.14 (m, 2 H), 5.90 (m, 1 H), 5.97 (m, 1 H),
6.10 (dt, 1 H); CIMS m/z (rel intensity) 236 (M+ + 1, 100).
2,3,7a -Tr im eth yl-2,3,5,7a -tetr a h yd r o-1H-isoin d ol-1-on e
(5a ). Isolated in 70% yield: 1H NMR (CDCl3) δ 1.17 (s, 3 H),
1.32 (d, J ) 6.4 Hz, 3 H), 2.70 (m, 2 H), 2.82 (s, 3 H), 4.15 (m, 1
H), 5.71 (d, J ) 1.7 Hz, 1 H), 5.83 (m, 1 H), 6.13 (d, J ) 8.3 Hz,
1 H); CIMS m/z (rel intensity) 178 (M+ + 1, 100). Ratio of the
two isomers: ∼7:1.
H), 7.03 (m, 2 H), 7.14 (m, 2 H); IR (film) 3000, 2880, 1650 cm-1
;
CIMS m/z (rel intensity) 240 (M+ + 1, 100).
10-Aza -10-m et h yl-5,6-(2′-m et h oxyb en zo)t r icyclo-9-ox-
od ocec-1-en e (10b). Isolated in 61% yield: 1H NMR (CDCl3) δ
1.68 (dt, J ) 12.2, 2.2 Hz, 2 H), 2.18 (m, 2 H), 2.57 (m 1 H), 2.67
(dd, J ) 16.1, 1.7 Hz, 1 H), 2.94 (s, 3 H), 3.04 (d, J ) 16.1 Hz, 1
H), 3.26 (d, J ) 1.7 Hz, 1 H), 3.72-3.80 (m, 4 H), 4.05 (dd, J )
12.4 Hz, 2.2 Hz, 1 H), 5.52 (d, J ) 1.3 Hz, 1 H), 6.71 (m, 2 H),
6.96 (d, J ) 8.3 Hz, 1 H); CIMS m/z (rel intensity) 270 (M+ + 1,
100).
8b. Isolated as a colorless solid in 86% yield: mp 113-115
°C; IR (CHCl3) 1610 cm -1; 1H NMR δ (500 MHz, CDCl3) 7.14-
7.09 (m, 3 H), 7.02 (d, J ) 6.6 Hz, 1 H), 5.38 (m, 1 H), 3.49 (m,
1 H), 3.40 (d, J ) 16.5 Hz, 1 H), 3.25-3.23 (m, 1 H), 2.97 (s, 3
H), 2.84 (dd, J ) 16.5, 2.2 Hz, 1 H), 2.79-2.75 (m, 1 H), 2.60-
2.55 (m, 1 H), 2.43 (ddd, J ) 12.5, 4.0, 1.5 Hz, 1 H), 2.03 (m, 1
H), 2.00 (dd, J ) 13.4 Hz, 1 H), 1.74 (dt, J ) 12.5, 2.2 Hz, 1 H),
1.17 (d, J ) 6.6 Hz, 3 H); 13C NMR δ (125.7 MHz, CDCl3) 173.9,
140.2, 134.5, 132.9, 128.6, 128.5, 126.0, 125.8, 122.4, 53.9, 42.3,
38.9, 35.7, 35.5, 34.2, 33.0, 32.2, 18.6; [R]23D -150 (c 1.0, CHCl3);
CIMS m/z (rel intensity) 268 (M+ + 1, 100). Anal. Calcd for
C18H21NO: C, 80.86; H, 7.92. Found: C, 80.46; H, 8.10.12
2,3-Dim eth yl-7a -eth yl-2,3,5,7a -tetr a h yd r o-1H-isoin d ol-1-
on e (5b). Isolated in 79% yield as an oil: 1H NMR (CDCl3) δ
0.79 (t, J ) 7.4 Hz, 3 H), 1.30 (d, J ) 6.4 Hz, 3 H), 1.57 (m, 2 H),
2.67 (m, 2 H), 2.81 (s, 3 H), 4.10 (m, 1 H), 5.78 (d, J ) 1.9 Hz, 1
H), 5.95 (m, 1 H), 6.00 (d, J ) 1.5 Hz, 1 H); IR (film) 3000, 1660,
1405, 1380 cm-1; CIMS m/z (rel intensity) 192 (M+ + 1, 100).
Ratio of the two isomers: ∼10:1.
2,3-Dim eth yl-7a -ben zyl-2,3,5,7a -tetr a h yd r o-1H-isoin d ol-
1-on e (5c). Isolated in 68% yield: 1H NMR (CDCl3) δ 1.14 (dd,
J ) 6.4, 6.3 Hz, 3 H), 2.20 (d, J ) 10.4 Hz, 1 H), 2.56 (t, J ) 5.8,
5.4 Hz, 1 H), 2.59 (d, J ) 12.7 Hz, 1 H), 2.62 (d, J ) 1.0 Hz, 3
H), 2.96 (d, J ) 12.7 Hz, 1 H), 3.23 (m, 1 H), 5.75 (d, J ) 6.1 Hz,
1 H), 5.86 (m, 1 H), 6.18 (dd, J ) 9.5 and 3.2 Hz, 1 H), 7.09 (m,
2 H), 7.19 (m, 3 H); CIMS m/z (rel intensity) 254 (M+ + 1, 100).
Gen er a l P r oced u r e for th e Selective Red u ction of th e
Dou ble Bon d : 2,3,7a -Tr im eth yl-2,3,5,6,7,7a -h exa h yd r o-1H-
isoin d ol-1-on e (9a ). To a solution of 5a (177 mg, 1.0 mmol)
and PTSH (1.80 g, 9.6 mmol) in DME (30 mL) warmed under
reflux was added a solution of NaOAc (1.60 g, 19 mmol) in water
(30 mL) within 2 h. After being heated overnight, the reaction
mixture was cooled to room temperature, poured into water (50
mL), and extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were washed with water (50 mL), dried over
Ack n ow led gm en t. Financial support of this re-
search from the National Institutes of Health (GM
26568) and an ICSC World Laboratories Scholarship to
Z.G. are gratefully acknowledged. Z.G. thanks Dr. Bruce
Tomczuk and Dr. Tianbo Lu for their helpful discussions.
J O005693G