Formation of 4,5,6,7-tetrahydroisoindoles by palladium-catalyzed hydride reduction

Article abstract of DOI:10.1021/jo7016845

(Chemical Equation Presented) Substituted 1,3-dihydro-2H-isoindoles (2, isoindolines) were prepared and subjected to palladium-catalyzed formate reduction. Alkyl isoindolines were reduced to 4,5,6,7-tetrahydro-2H-isoindoles (1). Only partial reduction was observed for 5-methoxyisoindoline, and 4-methoxy-, 5-carbomethoxy-, amino-, and amidoisoindolines were inert to the reaction. Halogen-substituted isoindolines were dehalogenated and reduced to 4,5,6,7-tetrahydro-2H-isoindoles. Isoindole 24 was also reduced to a mixture of an isoindoline and a 4,5,6,7-tetrahydro-2H-isoindole. In contrast, 2,3-dihydro-1H-indoles 21 underwent dehydrogenation to give thermodynamically stable indoles. Theoretical calculations show the significant difference in aromaticity between isoindoles and indoles, corresponding to the observed differences in reactivities. Tetrahydro-2H-isoindoles 1 were oxidized to 4,5,6,7-tetrahydroisoindole-1,3-diones in the presence of NBS and air.

Full text of DOI:10.1021/jo7016845

Formation of 4,5,6,7-Tetrahydroisoindoles by Palladium-Catalyzed
Hydride Reduction
Duen-Ren Hou,* Ming-Shiang Wang, Ming-Wen Chung, Yih-Dar Hsieh, and
Hui-Hsu Gavin Tsai*
Department of Chemistry, National Central UniVersity, Jhong-Li City, Taoyuan, Taiwan 320
drhou@cc.ncu.edu.tw; hhtsai@cc.ncu.edu.tw
ReceiVed August 2, 2007
Substituted 1,3-dihydro-2H-isoindoles (2, isoindolines) were prepared and subjected to palladium-catalyzed
formate reduction. Alkyl isoindolines were reduced to 4,5,6,7-tetrahydro-2H-isoindoles (1). Only partial
reduction was observed for 5-methoxyisoindoline, and 4-methoxy-, 5-carbomethoxy-, amino-, and
amidoisoindolines were inert to the reaction. Halogen-substituted isoindolines were dehalogenated and
reduced to 4,5,6,7-tetrahydro-2H-isoindoles. Isoindole 24 was also reduced to a mixture of an isoindoline
and a 4,5,6,7-tetrahydro-2H-isoindole. In contrast, 2,3-dihydro-1H-indoles 21 underwent dehydrogenation
to give thermodynamically stable indoles. Theoretical calculations show the significant difference in
aromaticity between isoindoles and indoles, corresponding to the observed differences in reactivities.
Tetrahydro-2H-isoindoles 1 were oxidized to 4,5,6,7-tetrahydroisoindole-1,3-diones in the presence of
NBS and air.
Introduction
Pyrroles and indoles are important groups of N-heterocyclic
compounds, occur widely in living matter, and have significant
biological roles.1 Isoindoles and their derivatives are less known,
but they have been found as inhibitors of cyclooxygenase
isoenzyme (COX-2) and thrombin.2 These factors and the
versatile chemistry of these heterocycles have attracted the
attention of organic chemists.3 Recently we reported a new
approach for forming 4,5,6,7-tetrahydro-2H-isoindoles, 1, from
1,3-dihydro-2H-isoindoles (isoindolines), 2, under palladium-
catalyzed hydrogenation conditions (eq 1).4 In this transforma-
tion, formation of the pyrrole is accompanied by partial
reduction of the benzene moiety. We also found that this process
is quite general for many functional groups attached to the
nitrogen atom, such as alcohol, ether, ester, and amide. Extensive
C-H/C-D exchange in the products was also observed.
However, the effects of the substituents on the isoindoline ring
and the mechanistic rationale for this process remain unknown.
Here, we report our further studies on this process, including
effects of substituents, comparison with indolines to show their
remarkable differences in reactivity, and application of theoreti-
cal calculations to facilitate understanding of the experimental
observations.
(1) (a) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p
313. (b) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
Publishing: Oxford, U.K., 2000; p 237 and p 324. (c) Cacchi, S.; Fabrizi,
G. Chem. ReV. 2005, 105, 2873.
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G. J. Med. Chem. 2000, 43, 4582. (b) Peterlin-Masˇicˇ, L.; Mlinsˇek, G.;
Sˇolmajer, T.; Trampusˇ-Bakija, A.; Stegnard, M.; Kikelja, D. Bioorg. Med.
Chem. Lett. 2003, 13, 789.
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R. P. Org. Lett. 2005, 7, 775. (b) Clayden, J.; Kenworthy, M. N. Synthesis
2004, 1721. (c) Thomson, D. W.; Commeureuc, A. G. J.; Berlin, S.; Murphy,
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1993, 93, 1991.
Results and Discussion
Studied first were the effects of substituents at the carbon
atoms of 2 on the course of the reaction. Thus, substituted
isoindolines 5 were prepared using two strategies: alkylation
of glycine methyl ester with various R,R′-dibromo-o-xylene
(4) Hou, D.-R.; Hsieh, Y.-D.; Hsieh, Y. W. Tetrahedron Lett. 2005, 46,
5927.
10.1021/jo7016845 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/24/2007
J. Org. Chem. 2007, 72, 9231-9239
9231

Hou et al.
SCHEME 1. Synthesis of Isoindolines 5
SCHEME 2. Synthesis of Isoindolines 8
derivatives 4 (Scheme 1) and the reduction of substituted
phthalimides (Scheme 2). Radical bromination at the two
benzylic positions of arenes 3 gave a series of dibromides 4,5
the precursors to isoindolines 5a-d. The stereochemistry of
compounds 4b and 5b needed further clarification. Although
Utley and Wyatt reported that the bromination reaction produced
1,2-bis-(bromoethyl)benzene (4b) as a mixture of two diaster-
eomers and that one of them dominated after recrystallization
by a factor of 15:1, they did not assign their stereochemistry.5a
Thus, we performed the dialkylation of glycine methyl ester
with the recrystallized, dibromide 4b and harvested the dias-
tereomerically pure isoindoline 5b after flash column chroma-
tography. The stereochemistry of the isoindoline 5b produced
was assigned as anti (d,l) because of two 1H NMR spectroscopic
facts: the two hydrogens of R-methylene are diastereotopic
(2JH-H ) 17.0 Hz) and protonated 5b showed two distinct
methyl and two methine absorptions, both of equal intensity.
The syn (meso) isomer of 5b contains an enantiotopic R-me-
thylene, and its N-protonated form still possesses a plane of
symmetry, leading to single methyl and methine groups.6 The
formation of anti-5b also indicates that the main diastereomer
harvested in recrystallization of dibromide 4b is a d,l-isomer,
since the alkylation process is stereochemically conservative.7
The second route to isoindolines 8 started from condensation
of phthalic anhydrides 6 and 3-phenoxypropanamine8 to form
phthalimide derivatives 7,9 followed by reduction with lithium
aluminum hydride. We found that the nitro- and hydroxy-
substituted phthalimides (7c, 7f, and 7g) gave complicated
mixtures after reduction. To circumvent this, hydroxyphthal-
imide 7c was first converted into its methoxy derivative, 7h,
which was then smoothly reduced to isoindoline 8h; the
reduction of nitrophthalimides (7f and 7g) was achieved by the
sequence of hydrogenation, acetylation, and reduction to provide
the isoindolines bearing secondary amine, tertiary amine, or
amide groups (11f,g, 13f,g, and 12f,g, respectively, Scheme 3).
With these substituted isoindolines in hand, we studied the
effect of substituents on the formation of tetrahydroisoindoles
under palladium-catalyzed hydride reduction. The results are
summarized in Table 1. Previous results using N-substituted
isoindolines 14 and 15 are also included for purposes of
reference (entries 1, 2).4 All methyl-substituted isoindolines
(5a,b and 8a,b, entries 3-6) were successfully transformed into
the corresponding 4,5,6,7-tetrahydroisoindoles. However, isoin-
dolines with a methyl group on the benzene moiety (8a,b), only
gave modest yields (53-71%, entries 5, 6). Isoindoline 18,
which bears a sterically bulky N-tert-butyl group, is also a good
substrate for this reaction (entry 15). Our results indicate that
this reaction is compatible with alkyl groups. However, the
results from other substituted isoindolines are variable. 5-Meth-
oxyisoindole 5c was converted to tetrahydroisoindole 16c in
poor yield with an extended reaction time (43 h) and 20 equiv
of ammonium formate, but its 4-methoxy analogue 8h was inert
to these reaction conditions (entries 7, 8). The 5-methylcar-
boxylateisoindoline 5d also failed to undergo the transformation.
Fluorinated and chlorinated isoindolines 8d,e were first deha-
logenated to isoindoline 15 and then reduced to 1a in good yields
(entries 10-13). The cleavage of the carbon-fluorine bond in
8d shows that this reaction is highly reductive. Unfortunately,
all nitrogen substituents, including secondary and tertiary amines
and amides at the 4- or 5-positions of isoindolines, prohibited
the formation of tetrahydroisoindole 1 (entry 14).
(5) (a) Eru, E.; Hawkes, G. E.; Utley, J. H. P.; Wyatt, P. B. Tetrahedron
1995, 51, 3033. (b) Liu, X.; Barrett, S. A.; Kilner, C. A.; Thornton-Pett,
M.; Halcrow, M. Tetrahedron 2002, 58, 603. (c) Bourdonnec, B. L.; Ajello,
C. W.; Seida, P. R.; Susnow, R. G.; Cassel, J. A.; Belanger, S.; Stabley, G.
J.; DeHaven, R. N.; DeHaven-Hudkins, D. L.; Dolle, R. E. Bioorg. Med.
Chem. Lett. 2005, 15, 2647.
(6) Theoretically, protonation of syn 5b gives two isomers: the methyl
and the R-methylene groups either on the same side of the isoindoline plane
or not. However, the two protonated forms, if they do exist, should be
energetically different and recorded as a mixture of major/minor isomers
in NMR. For a related example in assigning the stereochemistry of
N-substituted-2,5-dimethyl-2,5-dihydropyrrole by protonation, see: Beattie,
D. E.; Dover, G. M.; Ward, T. J. J. Med. Chem. 1985, 28, 1617.
(7) Murai, S.; Sugise, R.; Sonoda, N. Angew. Chem., Int. Ed. 1981, 20,
475.
(8) Lever, O. W., Jr.; Bell, L. N.; McGuire, H. M.; Ferone, R. J. Med.
Chem. 1985, 28, 1870.
(9) Raasch, A.; Scharfenstein, O.; Trankle, C.; Holzgrabe, U.; Mohr, K.
J. Med. Chem. 2002, 45, 3809.
9232 J. Org. Chem., Vol. 72, No. 24, 2007

Formation of 4,5,6,7-Tetrahydroisoindoles
SCHEME 3. Synthesis of Isoindolines 12 and 13
There are few reports describing the chemical reactions of
4,5,6,7-tetrahydroisoindoles.10-12 Our previous studies had
shown that compound 1b is the donor component in a Michael
addition with dimethyl maleate.4 In the present study, however,
when 4,5,6,7-tetrahydroisoindoles 1b-d were treated with
another electrophile, namely, N-bromosuccinimide (NBS), the
pyrrole moiety was oxidized to form 4,5,6,7-tetrahydroisoindole-
1,3-diones 20b-d (eq 2) instead of the expected 2-bromopyr-
23, 24 was reduced to isoindoline 15 and 4,5,6,7-tetrahy-
droisoindole 1b in a ratio of 9:1 (Scheme 5). In spite of their
structural resemblance, indoles and indolines have a reaction
pathway opposite to that of isoindole and isoindoline. For
compounds with the indole skeleton, the reaction leads to
aromatic compounds having 10 π-electrons; however, molecules
with the isoindole skeleton can be further reduced to 4,5,6,7-
tetrahydroisoindoles, an aromatic system with six π-electrons.
Density functional theory calculations at the B3LYP/6-31G-
(d,p) level were employed to define the relative aromaticities
of these compounds and to provide further insights into the
experimental results. For computational convenience, the sub-
stituent at the nitrogen atom was modeled as a methyl group.
The aromaticity of a target molecule was evaluated by the
enthalpy of its hydrogenation. For example, the addition of one
hydrogen molecule to 4,5,6,7-tetrahydroisoindole 1c is ac-
companied by the loss of aromaticity; on the other hand,
hydrogenation of hexahydroisoindole 26 (Scheme 6) involves
no change in aromaticity. The resonance energy of compound
1c, then, is the enthalpy difference between these two quasi-
reactions (15.83 kcal/mol at 25 °C). The resonance energy of
1c is lower than that of pyrrole. The accuracy of this strategy
is confirmed by calculating the aromaticity of benzene and
pyrrole to give 35.9 kcal/mol and 21.7 kcal/mol, respectively.
Both values are in good agreement with the experimental data
(36 kcal/mol and 21 kcal/mol).17
Similar calculations were applied to obtain the resonance
energies of other related indoles and isoindoles (see Supporting
Information). However, the aromaticity of N-methylindole could
not be calculated directly by the above approach because of
the coexistence of the benzene and pyrrole moieties. Therefore,
the aromaticity of this 10 π-electron system is considered to be
the sum of the resonance energy (33.7 kcal/mol) of N-
methylindoline and extra stabilization (10.2 kcal/mol) gained
in conjunction of pyrrole, as shown in Scheme 7. The resulting
resonance energy (43.8 kcal/mol) of N-methylindole is in
agreement with calculated and thermodynamic data reported
previously.17,18 The calculated resonance energies of related
isoindole and indole derivatives obtained by this approach are
summarized in Table 2.
roles. N-Substituted 2-bromo- and 2-chloropyrroles are known
to be unstable,13 and multiple halogenations at 5- or 3-positions
were often observed in their reaction with NBS.13b,14 In this
case, we speculate that the diimides 20 come from oxidation of
labile, brominated intermediates, generated from tetrahydroisoin-
doles 1 and NBS, in the presence of air.
The unique formation of pyrroles from 4,5,6,7-tetrahy-
droisoindoles prompted us to apply this reaction to related
indoles. Therefore, 2,3-dihydroindoles 21a,b were prepared and
subjected to palladium-catalyzed hydride reduction. We were
amazed to find that oxidized products, indoles 22a,b, were
generated rather than reduced, hydrogenated products (Scheme
4). Although the reaction conditions are reductive, the catalytic
palladium promotes the dehydrogenation process to form indoles
with 10 π-electrons. This result was further confirmed when
we found that methyl 3-indolecarboxylates 23a,b15 were stable
under the reduction conditions.
We further explored the reduction of isoindole 24, prepared
from partial reduction of phthalimide 25.16 In contrast to indoles
(10) Diels-Alder reactions: (a) Ando, K.; Kankake, M.; Suzuki, T.;
Takayama, H. Synlett 1994, 9, 741. (b) Stephan, D.; Gorgues, A.; Le Coq,
A. Tetrahedron Lett. 1988, 29, 1025.
(11) Aldol condensation: Fuhrhop, J. H.; Hosseinpour, D. Liebigs Ann.
Chem. 1985, 4, 689.
(12) Electrophilic substitution: Kobayashi, T.; Tsuzuki, T.; Tayama, Y.;
Uchiyama, Y. Tetrahedron 2001, 57, 9073.
(13) (a) Cordell, G. A. J. Org. Chem. 1975, 40, 3161. (b) Gilow, H. M.;
Burton, D. E. J. Org. Chem. 1981, 46, 2221.
(14) Martina, S.; Enkelmann, V.; Wegner, G.; Schluter, A.-D. Synthesis
1991, 613.
(15) Hopkins, C. R.; Czekaj, M.; Kaye, S. S.; Gao, Z.; Pribish, J.; Pauls,
H.; Liang, G.; Sides, K.; Cramer, D.; Cairns, J.; Luo, Y.; Lim, H.-K.; Vaz,
R.; Rebello, S.; Maignan, S.; Dupuy, A.; Mathieu, M.; Levell, J. Bioorg.
Med. Chem. Lett. 2005, 15, 2734.
The resonance energies of the three indole derivatives follow
the order of increasing stabilization of pyrrole < benzene <
indole, and the difference between each two is at least 10 kcal/
mol. On the other hand, this trend disappears among isoindole
derivatives. This is mainly because isoindole has a much lower
(17) Katritzky, A. R.; Jug, K.; Oniciu, D. C. Chem. ReV. 2001, 101, 1421
and references cited therein.
(18) Lloyd, D.; Marshall, D. R. Chem. Ind. 1972, 335.
(16) Carpino, L. A.; Padykula, R. E.; Barr, D. E.; Hall, F. H.; Krause, J.
G.; Dufresne, R. F.; Thoman, C. J. J. Org. Chem. 1988, 53, 2565.
J. Org. Chem, Vol. 72, No. 24, 2007 9233

Hou et al.
TABLE 1. Formation of 4,5,6,7-Tetrahydroisoindoles
SCHEME 4. Synthesis and Dehydrogenation of Indolines 21
SCHEME 5. Synthesis of Isoindole and Its Reduction
SCHEME 6. Calculated Aromaticity of 1c by the B3LYP/
6-31G(d,p) Methoda
a Resonance energy of 1c ) -2.67 - (-18.50) ) 15.83 kcal/mol.
SCHEME 7. Calculated Aromaticity of Indole by the
B3LYP/6-31G(d,p) Methoda
a Ammonium formate: 20 equiv, 43 h. b A total of 32% of 5c recovered.
c Starting material recovered. d Yield of 15: 24%.
a Indole gains extra resonance energy (10.17 kcal/mol).
moiety in N-methylisoindole is 0.031 Å, which is significantly
larger than the corresponding value for 2-methylindole (0.014
Å). A similar result is also observed in the X-ray crystal structure
of isoindoles.20 This is in agreement with previous studies, which
indicated that isoindole has a large decrease in the aromaticity
of the benzene ring based on the n-center delocalization
indices.19a The diene character of isoindoles is also shown by
resonance energy, ∼13 kcal/mol less than its indole counterpart19
and ∼4 kcal/mol less than isoindoline. The lower aromaticity
of N-methylisoindole is also revealed in its structural charac-
teristics of alternating single and double bonds. On the basis of
the optimized structures at the B3LYP/6-31G(d,p) level, the
root-mean-square deviation of these bond lengths of the benzene
(19) Similar computational results: (a) Mandado, M.; Otero, N.;
Mosquera, R. A. Tetrahedron 2006, 62, 12204. (b) Jursic, B. S. J. Mol.
Struct. 1999, 468, 171. (c) Mandado, M.; Gonzalez-Moa, M. J.; Mosquera,
R. A. J. Comput. Chem. 2007, 28, 127.
(20) X-ray structures of isoindoles also show the large deviation in the
bond lengths: (a) Bonnett, R.; Hursthouse, M. B.; North, S. A.; Trotter, J.
J. Chem. Soc., Perkin Trans. 2, 1985, 2, 293. (b) Simons, S. S.; Ammon,
H. L.; Doherty, R.; Johnson, D. F. J. Org. Chem. 1981, 46, 4739.
9234 J. Org. Chem., Vol. 72, No. 24, 2007

Formation of 4,5,6,7-Tetrahydroisoindoles
TABLE 2. Resonance Energies of Isoindole, Indole, and Their
Derivatives
rationalized in terms of the difference in resonance energies
between the indole and isoindole systems.
Experimental Section
Computational Methods. All calculations were performed with
gradient-corrected hybrid density functional theory (DFT) using the
Gaussian 03 suite of programs23 on a PC cluster at the National
Center for High-Performance Computing (Taiwan). The B3LYP
density functional (Becke’s three-parameter exchange functional24
and the Lee-Yang-Parr gradient-corrected correlation functional25)
was employed. All calculations used the moderate-sized 6-31G-
(d,p) basis set.26
(1-Methyl-1,3-dihydroisoindol-2-yl)acetic Acid Methyl Ester
(5a). Potassium carbonate (0.93 g, 10.2 mmol) was added to the
solution of 4a (0.373 g, 1.34 mmol) and glycine methyl ester
hydrochloride (0.215 g, 1.61 mmol)in acetonitrile (3 mL). The
reaction mixture was heated at reflux for 16 h, filtered, and
concentrated to give the crude product. Pure 5a (0.15 g, 0.75 mmol,
56%) was isolated after column chromatography (SiO2; hexane/
ethyl acetate, 1:1; Rf 0.60). 1H NMR (CDCl3, 200 MHz) δ 1.37 (d,
J ) 6.3 Hz, 3H), 3.47 (d, J ) 16.8 Hz, 1H), 3.70 (s, 3H), 3.72 (d,
J ) 16.8 Hz, 1H), 3.87 (dd, J ) 12.6 Hz, J ) 2.5 Hz, 1H), 4.02-
4.08 (m, 1H), 4.38 (dd, J ) 12.6 Hz, J ) 1.7 Hz, 1H), 7.02-7.25
(m, 4H); 13C NMR (CDCl3, 50 MHz) δ 171.4, 143.8, 138.8, 126.7,
126.6, 122.0, 121.6, 62.8, 57.9, 53.1, 51.4, 18.6; HRMS (FAB)
calcd for [M + H]+ (C12H16NO2) 206.1181, found 206.1180.
trans-(1,3-Dimethyl-1,3-dihydroisoindol-2-yl)acetic Acid Meth-
yl Ester (5b). The procedure to prepare 5a was followed. Starting
with 4b (39 mg, 0.134 mmol) and glycine methyl ester hydrochlo-
ride (21 mg, 0.167 mmol), 5b (15.8 mg, 0.072 mmol, 54%) was
isolated after column chromatography (SiO2; hexane/ethyl acetate,
their reactivity in Diels-Alder reactions.21 Moreover, other
studies have also demonstrated that indoles are much more stable
than isoindoles based on indices such as the HOMO-LUMO
energy gap and NICS values.22
The aromaticity difference between the two series rationalizes
the observed differences in reactivities. Under palladium-
catalyzed formate reduction, isoindole 24 was first reduced to
isoindoline 15. However, the formation of 4,5,6,7-tetrahy-
droisoindole is a stepwise, endothermic process requiring
multiple hydrides. The unusually low aromaticity of isoindole
prevents a thermodynamic sink, e.g., a stable indole, to dictate
the reaction. On the other hand, the excess of hydride and the
presence of catalyst provide a subtle reaction channel to form
4,5,6,7-tetrahydroisoindole in a stepwise manner as a kinetic
product, produced and trapped in the highly reductive environ-
ment. If so, it is natural that the reduction of an isoindoline to
a tetrahydroisoindole is more sensitive to the substituents on
the benzene moiety, since they have a direct influence on the
resonance energy of the isoindoline.
1
3:1; Rf 0.40). H NMR (CDCl3, 500 MHz) δ 1.26 (d, J ) 6.5 Hz,
3H), 3.60 (d, J ) 17.0 Hz, 1H), 3.65 (d, J ) 17.0 Hz, 1H), 3.74 (s,
3H), 4.40 (q, J ) 6.0 Hz, 2H), 7.12-7.13 (m, 2H), 7.18-7.20 (m,
2H); 1H NMR (CDCl3 + one drop of triflouroacetic acid, 300 MHz)
δ 1.56 (d, J ) 6.9 Hz, 3H), 1.78 (d, J ) 6.6 Hz, 3H), 3.83 (s, 3H),
4.06 (d, J ) 17.0 Hz, 1H), 4.16 (d, J ) 17.0 Hz, 1H), 4.74 (q, J )
6.6 Hz, 1H), 5.54 (q, J ) 6.9 Hz, 1H), 7.20-7.30 (m, 2H), 7.40-
7.50 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 172.2, 143.8, 126.9,
121.8, 60.5, 51.8, 48.8, 17.3; HRMS (FAB) calcd for [M + H]+
(C13H18 NO2) 220.1338, found 220.1339.
Conclusion
The formation of a 4,5,6,7-tetrahydroisoindole by palladium-
catalyzed formate reduction is selective to the substituents on
their isoindole ring. Oxidation rather than bromination occurs
in the reaction of tetrahydroisoindoles with NBS. Isoindole and
its derivatives have a chemical behavior distinct from that of
the corresponding indoles, i.e., hydrogenation vs dehydrogena-
tion, under the reaction conditions. This difference can be
(5-Methoxy-1,3-dihydroisoindol-2-yl)acetic Acid Methyl Ester
(5c). The procedure to prepare 5a was followed. Starting with 4c
(0.6 g, 2.04 mmol) and glycine methyl ester hydrochloride (0.26
g, 2.04 mmol), 5c (0.10 g, 0.47 mmol, 22%) was isolated after
column chromatography (SiO2; hexane/ethyl acetate, 1:1; Rf 0.53).
1H NMR (CDCl3, 200 MHz) δ 3.56 (s, 2H), 3.70 (s, 3H), 3.73 (s,
3H), 4.00 (s, 2H), 4.03 (s, 2H), 6.58-6.75 (m, 2H), 7.03 (d, J )
8.9 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 171.1, 158.9, 141.0,
131.6, 122.7, 112.6, 107.7, 58.8, 58.1, 55.9, 55.3, 51.5; HRMS
(FAB) calcd for [M + H]+ (C12H16O3N) 222.1130, found 222.1127.
2-Methoxycarbonylmethyl-2,3-dihydro-1H-isoindole-5-car-
boxylic Acid Methyl Ester (5d). The procedure to prepare 5a was
followed. Starting with 4d (1.20 g, 3.71 mmol) and glycine methyl
ester hydrochloride (0.512 g, 4.08 mmol), 5d (0.368 g, 1.48 mmol,
40%) was isolated after column chromatography (SiO2; hexanes/
ethyl acetate, 1:1; Rf 0.40). 1H NMR (CDCl3, 500 MHz) δ 3.60 (s,
2H), 3.72 (s, 3H), 3.86 (s, 3H), 4.12 (s, 4H), 7.21 (d, J ) 7.7 Hz,
1H), 7.83 (s, 1H), 7.87 (d, J ) 7.7 Hz, 1H); 13C NMR (CDCl3,
125 MHz) δ 171.0, 167.0, 145.1, 140.1, 129.0, 128.6, 123.5, 122.2,
58.5, 58.2, 55.6, 52.0, 51.8; HRMS (FAB) calcd for [M + H]+
(C13H16O4 N) 250.1079, found 250.1085.
(21) (a) Kreher, R. P.; Seubert, J.; Schmitt, D.; Use, G.; Koh, N.; Muleta,
T. Chem. Ber. 1990, 123, 381. (b) Kreher, R. P.; Sewarte-Ross, G.; Vogt,
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L. E.; Salcedo, R. Tetrahedron 2003, 59, 6415.
(23) Frisch, M. J.; Trucks, G. W..; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
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B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03
(Revision B02); Gaussian, Inc.: Pittsburgh, PA, 2003.
5-Methyl-2-(3-phenoxypropyl)isoindole-1,3-dione (7b). 4-Me-
thylphthalic anhydride (6b) (1.73 g, 10.68 mmol) was dissolved in
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J. Org. Chem, Vol. 72, No. 24, 2007 9235

Hou et al.
toluene (12 mL) at 80 °C, 3-phenoxypropanamine8 (1.78 g, 11.8
mmol) was added dropwise, and the resulting solution was heated
at reflux in an apparatus fitted with a Dean-Stark trap. After about
16 h, the reaction mixture was concentrated to give the crude
phthalimide. This was further purified by column chromatography
(SiO2; ethyl acetate/hexanes, 1:1; Rf 0.63) to give pure 7b as a
colorless solid (2.9 g, 9.8 mmol, 91%). Mp 102-104 °C; 1H NMR
(CDCl3, 500 MHz) δ 2.15 (m, 2H), 2.49 (s, 3H), 3.87 (t, J ) 6.9
Hz, 2H), 4.00 (t, J ) 6.1 Hz, 2H), 6.79-6.95 (m, 3H), 7.19-7.28
(m, 2H), 7.48 (d, J ) 7.6 Hz, 1H), 7.62 (s, 1H), 7.69 (d, J ) 7.6
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 168.6, 168.4, 158.7, 145.1,
134.4, 132.5, 129.5, 129.3, 123.8, 123.1, 120.7, 114.4, 65.5, 35.4,
28.4, 22.0; HRMS (FAB) calcd for [M + H]+ (C18H18NO3)
296.1287, found 296.1291; IR (neat) 2942, 2930, 1695, 1610, 1500,
NMR (CDCl3, 50 MHz) δ 165.8, 162.9, 158.5, 145.0, 135.2, 134.1,
129.3, 128.4, 126.9, 123.8, 120.8, 114.3, 65.4, 36.3, 27.9; HRMS
(FAB) calcd for [M + H]+ (C17H15N2O5) 327.0981, found 327.0984.
5-Nitro-2-(3-phenoxypropyl)isoindole-1,3-dione (7g). The pro-
cedure to prepare 7b was followed. Starting with 6g (0.50 g, 2.6
mmol) and 3-phenoxypropanamine (0.43 g, 2.7 mmol), 7g (0.56
g, 1.7 mmol, 65%) was isolated after column chromatography (SiO2;
1
CH2Cl2; Rf 0.67). H NMR (CDCl3, 200 MHz) δ 2.19 (m, 2H),
3.95 (t, J ) 6.9 Hz, 2H), 4.02 (t, J ) 5.9 Hz, 2H), 6.71-7.00 (m,
3H), 7.05-7.30 (m, 2H), 8.00 (d, J ) 8.0 Hz, 1H), 8.45-8.70 (m,
2H); 13C NMR (CDCl3, 50 MHz) δ 166.2, 165.9, 158.5, 151.7,
136.5, 133.5, 129.4, 129.2, 124.4, 120.9, 118.6, 114.3, 65.4, 36.3,
28.0; HRMS (FAB) calcd for [M + H]+ (C17H15N2O5) 327.0981,
found 327.0972.
1450, 1250, 1050, 840, 750, 700 cm-1
.
4-Methoxy-2-(3-phenoxypropyl)isoindole-1,3-dione (7h). To
a solution of phthalimide 7c (0.20 g, 0.66 mmol) and potassium
carbonate (0.45 g, 3.3 mmol) in acetone (3 mL) was added methyl
iodide (0.19 g, 1.3 mmol). The reaction mixture was refluxed for
16 h, then cooled to rt, filtered, and concentrated to give the crude
product. This was further purified by column chromatography (SiO2;
ethyl acetate/ hexanes, 1:1; Rf 0.67) to give pure 7h as a colorless
4-Methyl-2-(3-phenoxypropyl)isoindole-1,3-dione (7a). The
procedure to prepare 7b was followed. Starting with 6a (0.05 g,
0.34 mmol) and 3-phenoxypropanamine (0.06 g, 0.37 mmol), 7a
(0.07 g, 0.24 mmol, 71%) was isolated after column chromatog-
raphy (SiO2; hexanes/ethyl acetate, 3:1; Rf 0.50). 1H NMR (CDCl3,
200 MHz) δ 2.16 (m, 2H), 2.65 (s, 3H), 3.87 (t, J ) 7.0 Hz, 2H),
4.01 (t, J ) 6.0 Hz, 2H), 6.72-6.98 (m, 3H), 7.11-7.29 (m, 2H),
7.40-7.73 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ 169.2, 168.5,
158.7, 137.9, 136.3, 133.4, 132.5, 129.4, 128.8, 120.9, 120.7, 114.5,
65.6, 35.3, 28.4, 17.6; HRMS (FAB) calcd for [M + H]+ (C18H18-
NO3) 296.1287, found 296.1292.
4-Hydroxy-2-(3-phenoxypropyl)isoindole-1,3-dione (7c). The
procedure to prepare 7b was followed. Starting with 6c (0.11 g,
0.70 mmol) and 3-phenoxypropanamine (0.12 g, 0.77 mmol), 7c
(0.20 g, 0.66 mmol, 94%) was isolated after column chromatog-
raphy (SiO2; hexanes/ethyl acetate, 3:1; Rf 0.23). 1H NMR (CDCl3,
200 MHz) δ 2.15 (m, 2H), 3.84 (t, J ) 6.8 Hz, 2H), 4.00 (t, J )
6.0 Hz, 2H), 6.77-6.94 (m, 3H), 7.11-7.37 (m, 4H), 7.52-7.70
(m, 1H), 7.60 (br, 1H, OH); 13C NMR (CDCl3, 50 MHz) δ 170.4,
167.9, 158.6, 154.6, 136.3, 132.1, 129.4, 122.6, 120.8, 115.9, 114.6,
114.4, 65.4, 35.3, 28.2; HRMS (FAB) calcd for [M + H]+ (C17H16-
NO4) 298.1079, found 298.1085.
1
solid (0.18 g, 0.59 mmol, 90%). H NMR (CDCl3, 200 MHz) δ
2.13 (m, 2H), 3.83 (t, J ) 6.9 Hz, 2H), 3.90-4.05 (m, 5H), 6.70-
6.95 (m, 3H), 7.05-7.25 (m, 3H), 7.37 (d, J ) 7.3 Hz, 1H), 7.55-
7.65 (m, 1H); 13C NMR (CDCl3, 50 MHz) δ 167.9, 166.9, 158.6,
156.4, 135.9, 134.1, 129.2, 120.6, 117.3, 115.3, 114.4, 65.4, 56.2,
35.1, 28.2; HRMS (FAB) calcd for [M + H]+ (C18H18NO4)
312.1236, found 312.1240.
5-Methyl-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindole (8b).
A solution of phthalimide 7b (1.0 g, 3.4 mmol) in anhydrous ether
(8 mL) was added dropwise to a suspension of lithium aluminum
hydride (0.39 g, 12 mmol) and ether (2 mL) in a flame-dried flask
at 0 °C. After the addition, the reaction mixture was heated at reflux
for 3 h, then quenched with water (1 mL) and sat. K2CO3(aq) (4
mL) to form a gray-white precipitate. The liquid was decanted,
and the solid was further washed with ethyl acetate (9 mL). The
organic solution was combined, concentrated, and purified with
column chromatography (SiO2; ethyl acetate/hexanes, 1:3; Rf 0.23)
to give pure 8b as a light brown solid (0.65 g, 2.4 mmol, 70%).
Mp 46-48 °C; 1H NMR (CDCl3, 500 MHz) δ 2.08 (m, 2H), 2.32
(s, 3H), 2.91 (t, J ) 7.3 Hz, 2H), 3.92 (s, 4H), 4.08 (t, J ) 6.4 Hz,
2H), 6.85-6.94 (m, 3H), 6.95-7.05 (m, 2H), 7.07 (d, J ) 7.5 Hz,
1H), 7.24-7.30 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 159.0,
140.0, 136.8, 136.4, 129.4, 127.5, 122.9, 122.0, 120.5, 114.5, 65.9,
59.1, 58.9, 52.8, 28.7, 21.3; HRMS (FAB) calcd for [M + H]+
(C18H22NO) 268.1701, found 268.1703; IR (neat) 3017, 2947, 2930,
2876, 2791, 1600, 1497, 1468, 1450, 1250, 1050, 860, 750, 700
5-Fluoro-2-(3-phenoxypropyl)isoindole-1,3-dione (7d). The
procedure to prepare 7b was followed. Starting with 6d (0.73 g,
4.4 mmol) and 3-phenoxypropanamine (0.80 g, 5.3 mmol), 7d (1.13
g, 3.78 mmol, 86%) was isolated after column chromatography
1
(SiO2; hexanes/ethyl acetate, 3:1; Rf 0.60). Mp 106-108 °C; H
NMR (CDCl3, 500 MHz) δ 2.15 (m, 2H), 3.89 (t, J ) 6.9 Hz,
2H), 4.00 (t, J ) 6.0 Hz, 2H), 6.70-6.90 (m, 3H), 7.10-7.25 (m,
2H), 7.30-7.40 (m, 1H), 7.49 (dd, J ) 7.0 Hz, J ) 2.2 Hz, 1H),
7.82 (dd, J ) 8.2 Hz, J ) 4.5 Hz, 1H); 13C NMR (CDCl3, 125
MHz) δ 167.4, 167.3, 166.1 (JC-F ) 204 Hz), 158.6, 135.0 (JC-F
) 9.5 Hz), 129.4, 127.9, 125.6 (JC-F ) 9.1 Hz), 121.0, 120.8, 114.4,
111.1 (JC-F ) 24.8 Hz), 65.5, 35.8, 28.2; HRMS (FAB) calcd for
[M + H]+ (C17H15FNO3) 300.1036, found 300.1031; IR (neat) 2930,
1700, 1610, 1500, 1450, 1250, 1050, 850, 750, 700 cm-1
cm-1
.
4-Methyl-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindole (8a).
The procedure to prepare 8b was followed. Starting with 7a (0.07
g, 0.24 mmol) and LAH (0.03 g, 0.73 mmol), 8a (0.05 g, 0.17
mmol, 70%) was isolated after column chromatography (SiO2;
4,5,6,7-Tetrachloro-2-(3-phenoxypropyl)isoindole-1,3-dione (7e).
The procedure to prepare 7b was followed. Starting with 6e (1.04
g, 3.65 mmol) and 3-phenoxypropanamine (0.66 g, 4.4 mmol), 7e
(1.36 g, 3.24 mmol, 89%) was isolated after solvent evaporation.
1
hexanes/ethyl acetate, 1:1; Rf 0.42). H NMR (CDCl3, 200 MHz)
δ 2.09 (m, 2H), 2.25 (s, 3H), 2.93 (t, J ) 7.0 Hz, 2H), 3.93 (s,
2H), 3.98 (s, 2H), 4.10 (t, J ) 6.4 Hz, 2H), 6.80-7.18 (m, 6H),
7.20-7.35 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 159.0, 140.0,
138.9, 132.0, 129.4, 127.6, 126.9, 120.5, 119.5, 114.5, 65.9, 59.4,
58.1, 52.8, 28.8, 18.7; HRMS (FAB) calcd for [M + H]+ (C18H22-
NO) 268.1701, found 268.1705.
1
Mp 182-187 °C; H NMR (CDCl3, 500 MHz) δ 2.17 (m, 2H),
3.91 (t, J ) 6.9 Hz, 2H), 4.02 (t, J ) 5.9 Hz, 2H), 6.77 (d, J ) 7.9
Hz, 2H), 6.90 (t, J ) 7.3 Hz, 1H), 7.17-7.26 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 163.6, 158.5, 140.0, 129.6, 129.4, 127.7,
120.9, 114.4, 65.4, 36.5, 27.9; HRMS (FAB) calcd for [M]+
(C17H11Cl4NO3) 416.9493, found 416.9502; IR (neat) 1717, 1250,
5-Fluoro-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindole (8d).
The procedure to prepare 8b was followed. Starting with 7d (0.68
g, 2.3 mmol) and LAH (0.30 g, 8.0 mmol), 8d (0.37 g, 1.36 mmol,
60%) was isolated after column chromatography (SiO2; hexanes/
1110, 1060, 1050, 750, 700 cm-1
.
4-Nitro-2-(3-phenoxypropyl)isoindole-1,3-dione (7f). The pro-
cedure to prepare 7b was followed. Starting with 6f (0.77 g, 4.0
mmol) and 3-phenoxypropanamine (0.67 g, 4.4 mmol), 7f (0.87 g,
2.7 mmol, 66%) was isolated after column chromatography (SiO2;
1
ethyl acetate, 3:1; Rf 0.23). H NMR (CDCl3, 200 MHz) δ 2.06
(m, 2H), 2.91 (t, J ) 7.0 Hz, 2H), 3.85-3.98 (br, 4H), 4.08 (t, J
) 6.3 Hz, 2H), 6.80-7.00 (m, 5H), 7.05-7.18 (m, 1H), 7.20-
7.35 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 162.2 (JC-F ) 241.6
Hz), 159.0, 142.2 (JC-F ) 8.5 Hz), 135.5 (JC-F ) 2.5 Hz), 129.5,
123.3 (JC-F ) 8.7 Hz), 120.6, 114.5, 113.6 (JC-F ) 22.5 Hz), 109.6
1
hexanes/ethyl acetate, 1:1; Rf 0.57). H NMR (CDCl3, 200 MHz)
δ 2.18 (m, 2H), 3.92 (t, J ) 6.9 Hz, 2H), 4.01 (t, J ) 5.9 Hz, 2H),
6.72-6.92 (m, 3H), 7.15-7.24 (m, 2H), 7.83-8.10 (m, 3H); 13C
9236 J. Org. Chem., Vol. 72, No. 24, 2007

Formation of 4,5,6,7-Tetrahydroisoindoles
(JC-F ) 23.0 Hz), 65.9, 59.1 (JC-F ) 2.4 Hz), 58.5, 52.7, 28.8;
HRMS (FAB) calcd for [M + H]+ (C17H19FNO) 272.1451, found
272.1452.
(br, 1H), 7.76 (d, J ) 8.6 Hz, 1H), 7.90-8.00 (m, 2H); 13C NMR
(CDCl3, 50 MHz) δ 168.8, 168.2, 167.9, 158.6, 143.6, 133.6, 129.4,
126.7, 124.5, 123.7, 120.8, 114.4, 113.9, 65.5, 35.6, 28.3, 24.7;
HRMS (FAB) calcd for [M + H]+ (C19H19N2O4) 339.1345, found
339.1343.
4,5,6,7-Tetrachloro-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoin-
dole (8e). The procedure to prepare 8b was followed. Starting with
7e (0.50 g, 1.2 mmol) and LAH (0.14 g, 3.6 mmol), 8e (0.15 g,
0.39 mmol, 33%) was isolated after column chromatography (SiO2;
Ethyl-[2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-4-yl]-
amine (11f). The procedure to prepare 8b was followed. Starting
with 10f (0.43 g, 1.26 mmol) and LAH (0.14 g, 3.79 mmol), 11f
(0.29 g, 0.99 mmol, 78%) was produced after column chromatog-
1
hexanes/ethyl acetate, 3:1; Rf 0.67). H NMR (CDCl3, 200 MHz)
δ 2.04 (m, 2H), 2.91 (t, J ) 7.1 Hz, 2H), 3.95-4.15 (m, 6H), 6.80-
7.00 (m, 3H), 7.20-7.35 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ
158.9, 139.2, 130.9, 129.4, 126.6, 120.7, 114.5, 65.4, 59.7, 52.2,
28.6; HRMS (FAB) calcd for [M + H]+ (C17H16Cl4NO) 389.9986,
found 389.9978.
1
raphy (SiO2; ethyl acetate; Rf 0.47). H NMR (CDCl3, 200 MHz)
δ 1.21 (t, J ) 6.9 Hz, 3H), 2.02 (m, 2H), 2.86 (t, J ) 7.0 Hz, 2H),
3.13 (q, J ) 7.1 Hz, 2H), 3.15 (br, 1H, NH), 3.75 (s, 2H), 3.91 (s,
2H), 4.04 (t, J ) 6.4 Hz, 2H), 6.43 (d, J ) 8.0 Hz, 1H), 6.56 (d,
J ) 7.3 Hz, 1H), 6.80-6.97 (m, 3H), 7.00-7.13 (m, 1H), 7.18-
7.33 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 159.0, 143.1, 140.6,
129.4, 128.3, 124.2, 120.5, 114.5, 111.2, 108.5, 65.9, 59.8, 56.6,
52.8, 38.4, 28.8, 15.0; HRMS (FAB) calcd for [M + H]+
(C19H25N2O) 297.1967, found 297.1968.
4-Methoxy-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindole (8h).
The procedure to prepare 8b was followed. Starting with 7h (0.18
g, 0.59 mmol) and LAH (0.07 g, 1.8 mmol), 8h (0.11 g, 0.40 mmol,
67%) was isolated after column chromatography (SiO2; hexanes/
1
ethyl acetate, 3:1; Rf 0.50). H NMR (CDCl3, 500 MHz) δ 2.05
(m, 2H), 2.90 (t, J ) 7.0 Hz, 2H), 3.80 (s, 3H), 3.94 (s, 2H), 3.96
(s, 2H), 4.08 (t, J ) 6.4 Hz, 2H), 6.69 (d, J ) 8.2 Hz, 1H), 6.80
(d, J ) 3.8 Hz, 1H), 6.88-6.95 (m, 3H), 7.14-7.20 (m, 1H), 7.22-
7.30 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 159.1, 154.6, 142.0,
129.4, 128.3, 127.7, 120.6, 114.7, 114.6, 108.6, 66.0, 59.6, 56.4,
55.3, 52.8, 28.8; HRMS (FAB) calcd for [M + H]+ (C18H22NO2)
284.1651, found 284.1649.
N-Ethyl,N-[2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-5-
yl]amine (11g). The procedure to prepare 8b was followed. Starting
with 10g (0.05 g, 0.13 mmol) and LAH (0.02 g, 0.40 mmol), 11g
(0.04 g, 0.12 mmol, 94%) was isolated after column chromatog-
raphy (SiO2; hexanes/ethyl acetate, 1:1; Rf 0.27). 1H NMR (CDCl3,
200 MHz) δ 1.23 (t, J ) 7.0 Hz, 3H), 2.04 (m, 2H), 2.89 (t, J )
7.2 Hz, 2H), 3.13 (q, J ) 7.2 Hz, 2H), 3.14 (br, NH), 3.86 (s, 2H),
3.88 (s, 2H), 4.08 (t, J ) 6.4 Hz, 2H), 6.46 (m, 2H), 6.85-7.03
(m, 4H), 7.20-7.35 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 159.0,
147.8, 141.2, 129.4, 128.7, 122.7, 120.5, 114.5, 111.8, 106.7, 66.0,
59.4, 58.7, 52.9, 38.8, 28.8, 14.9; HRMS (FAB) calcd for [M +
H]+ (C19H25N2O) 297.1967, found 297.1967.
N-Ethyl,N-[2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-4-
yl]acetamide (12f). The procedure to prepare 10f was followed.
Starting with 11f (0.23 g, 0.78 mmol) and acetyl chloride (0.12 g,
1.6 mmol), 12f (0.21 g, 0.63 mmol, 81%) was produced. 1H NMR
(CDCl3, 200 MHz) δ 1.10 (t, J ) 7.1 Hz, 3H), 1.80 (s, 3H), 2.05
(m, 2H), 2.92 (m, 2H), 3.29-3.50 (m, 1H), 3.80-4.15 (m, 7H),
6.75-7.00 (m, 4H), 7.08-7.35 (m, 4H); 13C NMR (CDCl3, 50
MHz) δ 169.8, 158.8, 142.5, 138.1, 137.2, 129.3, 128.3, 126.8,
122.1, 120.6, 114.4, 65.6, 59.3, 57.3, 52.6, 42.7, 28.6, 22.4, 13.1;
HRMS (FAB) calcd for [M + H]+ (C21H27N2O2) 339.2073, found
339.2079.
N-Ethyl,N-[2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-5-
yl]acetamide (12g). The procedure to prepare 10f was followed.
Starting with 11g (0.19 g, 0.65 mmol) and acetyl chloride (0.10 g,
1.3 mmol), 12f (0.21 g, 0.61 mmol, 94%) was produced. 1H NMR
(CDCl3, 200 MHz) δ 1.07 (t, J ) 7.1 Hz, 3H), 1.79 (s, 3H), 2.06
(m, 2H), 2.93 (m, 2H), 3.70 (q, J ) 7.1 Hz, 2H), 3.96 (s, 4H), 4.08
(t, J ) 6.3 Hz, 2H), 6.75-7.05 (m, 5H), 7.15-7.36 (m, 3H); 13C
NMR (CDCl3, 50 MHz) δ 170.0, 158.9, 141.8, 141.7, 139.8, 129.4,
126.8, 123.3, 122.1, 120.6, 114.5, 65.8, 58.9, 58.7, 52.6, 43.8, 28.7,
22.8, 13.0; HRMS (FAB) calcd for [M + H]+ (C21H27N2O2)
339.2073, found 339.2079.
4-Amino-2-(3-phenoxypropyl)-isoindole-1,3-dione (9f). Pal-
ladium on carbon (5%, 85 mg) was added to the solution of 7f
(0.13 g, 0.39 mmol) in methanol (4 mL) and DMF (1 mL).
Hydrogen gas was bubbled through the reaction mixture at rt for
14 h. The solution was filtered and concentrated. The crude product
was further purified by column chromatography (SiO2; ethyl acetate/
hexanes, 1:1; Rf 0.75) to give pure 9f as a light yellow solid (0.11
g, 0.37 mmol, 94%). Mp 77-79 °C; 1H NMR (CDCl3, 200 MHz)
δ 2.13 (m, 2H), 3.82 (t, J ) 6.8 Hz, 2H), 3.99 (t, J ) 6.1 Hz, 2H),
5.23 (br, 2H), 6.68-6.98 (m, 4H), 7.05-7.42 (m, 4H); 13C NMR
(CDCl3, 50 MHz) δ 170.1, 168.6, 158.6, 145.2, 135.0, 132.7, 129.3,
120.9, 120.6, 114.4, 112.5, 111.2, 65.4, 34.9, 28.4; HRMS (FAB)
calcd for [M + H]+ (C17H17N2O3) 297.1239, found 297.1240.1
5-Amino-2-(3-phenoxypropyl)isoindole-1,3-dione (9g). The
procedure to prepare 9f was followed. Starting with 7g (0.38 g,
1.2 mmol), 9g (0.34 g, 1.13 mmol, 97%) was isolated after column
chromatography (SiO2; ethyl acetate; Rf 0.77). Mp 107-110 °C;
1H NMR (CDCl3, 200 MHz) δ 2.15 (m, 2H), 3.84 (t, J ) 7.0 Hz,
2H), 4.01 (t, J ) 6.2 Hz, 2H), 4.36 (br, 2H), 6.67-7.07 (m, 5H),
7.12-7.32 (m, 2H), 7.58 (d, J ) 8.0 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 168.6, 168.5, 158.7, 152.2, 134.9, 129.3, 125.0, 120.7,
120.6, 117.8, 114.5, 108.5, 65.5, 35.1, 28.5; HRMS (FAB) calcd
for [M + H]+ (C17H17N2O3) 297.1239, found 297.1242.
N-[1,3-Dioxo-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-
4-yl]acetamide (10f). Acetyl chloride (0.16 g, 2.1 mmol) in
acetonitrile (5 mL) was added to the mixture of 9f (0.51 g, 1.7
mmol) and potassium carbonate (0.60 g, 4.3 mmol) in acetonitrile
(7 mL). The reaction mixture was stirred at rt for 16 h, filtered,
concentrated, and purified by flash column chromatography (SiO2;
hexanes/ethyl acetate, 1:1; Rf 0.50) to give pure 10f (0.43 g, 1.3
N,N-Diethyl,N-[2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-
4-yl]amine (13f). The procedure to prepare 8b was followed.
Starting with 12f (0.15 g, 0.42 mmol) and LAH (0.02 g, 0.42 mmol),
13f (0.68 g, 0.21 mmol, 50%) was isolated after column chroma-
tography (SiO2; hexanes/ethyl acetate, 1:1 and Et3N, 2%; Rf 0.62).
1H NMR (CDCl3, 200 MHz) δ 1.04 (t, J ) 7.0 Hz, 3H), 2.09 (m,
2H), 2.92 (m, 2H), 3.11 (q, J ) 7.0 Hz, 4H), 3.94 (s, 4H), 4.10 (t,
J ) 6.4 Hz, 2H), 6.75-7.00 (m, 5H), 7.09-7.36 (m, 3H); 13C NMR
(CDCl3, 50 MHz) δ 159.0, 145.8, 141.6, 132.7, 129.3, 127.3, 120.5,
117.4, 115.1, 114.5, 66.0, 59.5, 58.8, 52.8, 45.9, 28.8, 12.6; HRMS
(FAB) calcd for [M + H]+ (C21H29N2O) 325.2280, found 325.2274.1
N,N-Diethyl,N-[2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-
5-yl]amine (13g). The procedure to prepare 8b was followed.
Starting with 12g (0.11 g, 0.34 mmol) and LAH (0.01 g, 0.34
mmol), 13g (0.03 g, 0.09 mmol, 26%) was isolated after column
chromatography (SiO2; hexanes/ethyl acetate, 1:1 and Et3N, 2%;
1
mmol, 74%) as a light yellow solid. Mp 115-118 °C; H NMR
(CDCl3, 200 MHz) δ 2.15 (m, 2H), 2.22 (s, 3H), 3.86 (t, J ) 6.8
Hz, 2H), 4.01 (t, J ) 5.8 Hz, 2H), 6.63-6.97 (m, 3H), 7.10-7.30
(m, 2H), 7.40-7.70 (m, 2H), 8.73 (d, J ) 8.4 Hz, 1H), 9.45 (br,
1H); 13C NMR (CDCl3, 50 MHz) δ 170.2, 169.2, 167.8, 158.6,
137.3, 135.8, 131.6, 129.4, 124.6, 120.8, 117.9, 115.7, 114.4, 65.5,
35.6, 28.2, 24.9; HRMS (FAB) calcd for [M + H]+ (C19H19N2O4)
339.1345, found 339.1349.
N-[1,3-Dioxo-2-(3-phenoxypropyl)-2,3-dihydro-1H-isoindol-
5-yl]acetamide (10g). The procedure to prepare 10f was followed.
Starting with 9g (0.19 g, 0.65 mmol), 10g (0.21 g, 0.61 mmol,
93%) was produced as a light yellow solid. 1H NMR (CDCl3, 200
MHz) δ 2.12 (m, 2H), 2.24 (s, 3H), 3.87 (t, J ) 7.0 Hz, 2H), 4.00
(t, J ) 6.0 Hz, 2H), 6.72-6.95 (m, 3H), 7.15-7.30 (m, 2H), 7.63
1
Rf 0.43). H NMR (CDCl3, 200 MHz) δ 1.13 (t, J ) 7.0 Hz, 3H),
J. Org. Chem, Vol. 72, No. 24, 2007 9237

Hou et al.
2.06 (m, 2H), 2.89 (m, 2H), 3.31 (q, J ) 7.0 Hz, 4H), 3.86 (s, 2H),
3.90 (s, 2H), 4.09 (t, J ) 6.4 Hz, 2H), 6.50-6.63 (m, 2H), 6.90-
7.09 (m, 4H), 7.17-7.33 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ
159.0, 147.3, 141.2, 129.4, 127.2, 122.7, 120.5, 114.5, 111.2, 106.4,
66.0, 59.7, 58.6, 52.9, 44.7, 28.8, 12.5; HRMS (FAB) calcd for
[M + H]+ (C21H29N2O) 325.2280, found 325.2272.
NMR (CDCl3, 125 MHz) δ 158.7, 129.4, 120.8, 119.9, 119.2, 116.0,
115.9, 114.5, 64.4, 45.9, 32.6, 31.4, 30.7, 30.4, 22.2, 21.7; HRMS
(FAB) calcd for [M + H]+ (C18H24NO) 270.1858, found 270.1852;
IR (neat) 3038, 2909, 1680, 1244, 1601, 1497, 1394, 1045, 810,
754, 692, cm-1
.
2-tert-Butyl-4,5,6,7-tetrahydro-2H-isoindole (19). The proce-
dure to prepare 16a was followed. Starting with 18 (34 mg, 0.20
mmol), 19 (33 mg, 0.19 mmol, 95%) was isolated. 1H NMR
(CDCl3, 200 MHz) δ 1.49-1.55 (s, 9H), 1.66-1.80 (m, 4H), 2.48-
2.69 (m, 4H), 6.51 (s, 2H); 13C NMR (CDCl3, 50 MHz) δ 118.7,
113.0, 54.2, 30.8, 24.2, 22.0; HRMS (FAB) calcd for [M]+
(C12H19N) 177.1517, found 177.1521.
2-tert-Butyl-2,3-dihydro-1H-isoindole (18). The procedure to
prepare 5a was followed. Starting with R,R′-dibromo-o-xylene (0.51
g, 1.9 mmol) and tert-butylamine (0.17 g, 2.3 mmol), compound
18 (0.31 g, 1.8 mmol, 92%) was isolated after column chromatog-
raphy (SiO2; hexane/ethyl acetate, 1:1; Rf 0.20). 1H NMR (CDCl3,
200 MHz) δ 1.18 (s, 9H), 4.04 (s, 4H), 7.18 (s, 4H); 13C NMR
(CDCl3, 50 MHz) δ 139.9, 126.5, 122.4, 52.6, 52.0, 26.0; HRMS
(FAB) calcd for [M + H]+ (C12H18N) 176.1439, found 176.1440.
(1-Methyl-4,5,6,7-tetrahydro-isoindol-2-yl)acetic Acid Methyl
Ester (16a). A solution of 5a (80 mg, 0.39 mmol), palladium
hydroxide on carbon (20%, 28 mg, 0.04 mmol), and ammonium
formate (0.25 g, 3.90 mmol) in methanol (1 mL) was heated at
reflux for 14 h. After being cooled to rt, the reaction mixture was
diluted with ethyl acetate (5 mL), filtered, and concentrated. The
crude product was further purified by column chromatography
(SiO2; hexane/ethyl acetate, 3:1; Rf 0.50) to give 16a (75 mg, 0.36
2-(3-Phenoxypropyl)-4,5,6,7-tetrahydro-isoindole-1,3-dione
(20b). N-Bromosuccinimide (91 mg, 0.51 mmol) was added to a
solution of 1b (52 mg, 0.20 mmol) in CH2Cl2 (10 mL) at rt. The
reaction mixture was stirred at rt for 2 h, washed with sat. Na2-
SO3(aq) (5 mL), water (10 mL × 2), dried over Na2SO4(s), filtered,
and concentrated. The crude product was further purified by column
chromatography (SiO2; hexanes/ethyl acetate, 3:1; Rf 0.65) to give
1
20b (42 mg, 0.16 mmol, 80%) as a light yellow oil. H NMR
(CDCl3, 200 MHz) δ 1.67-1.76 (br, 4H), 2.01-2.08 (m, 2H),
2.26-2.32 (m, 4H), 3.62-3.70 (m, 2H), 3.88-3.98 (m, 2H), 6.69-
6.73 (d, 1H), 6.81-6.94 (m, 2H), 7.20-7.36 (m, 2H); 13C NMR
(CDCl3, 50 MHz) δ 171.2, 158.7, 141.5, 132.2, 129.4, 120.7, 116.2,
114.5, 65.6, 34.9, 28.5, 21.3, 19.9; HRMS (FAB) calcd for [M +
H]+ (C17H20NO3) 286.1443, found 286.1435.
1
mmol, 93%). H NMR (CDCl3, 200 MHz) δ 1.64-1.75 (m, 5H),
2.01 (s, 3H), 2.40-2.58 (m, 4H), 3.73 (s, 3H), 4.47 (s, 2H), 6.26
(s, 1H); 13C NMR (CDCl3, 50 MHz) δ 169.7, 119.5, 116.7, 115.4,
52.4, 48.0, 24.0, 23.9, 21.9, 21.7, 9.2; HRMS (FAB) calcd for [M
+ H]+ (C12H18NO2) 208.1338, found 208.1335.
2-Methyl-4,5,6,7-tetrahydroisoindole-1,3-dione (20c). The pro-
cedure to prepare 20b was followed. Starting with 1c (46 mg, 0.34
mmol) and NBS (150 mg, 0.84 mmol), compound 20c (42 mg,
0.16 mmol, 85%) was isolated after column chromatography (SiO2;
hexanes/ethyl acetate, 3:1; Rf 0.66) as a light yellow oil. 1H NMR
(CDCl3, 200 MHz) δ 1.71-1.75 (br, 4H), 2.27-2.32 (br, 4H), 2.95
(s, 3H); 13C NMR (CDCl3, 50 MHz) δ 171.3, 141.6, 23.4, 21.3,
19.9 HRMS (FAB) calcd for [M + H]+ (C9H12NO2) 166.0868,
found 166.0870.
(1,3-Dimethyl-4,5,6,7-tetrahydro-isoindol-2-yl)acetic Acid Meth-
yl Ester (16b). The procedure to prepare 16a was followed. Starting
with 5b (51 mg, 0.23 mmol), 16b (46 mg, 0.21 mmol, 90%) was
isolated after column chromatography (SiO2; hexanes/ethyl acetate,
1
9:1; Rf 0.33). H NMR (CDCl3, 200 MHz) δ 1.65-1.74 (m, 4H),
2.03 (s, 3H), 2.37-2.48 (m, 4H), 3.74 (s, 3H), 4.46 (s, 2H); 13C
NMR (CDCl3, 50 MHz) δ 169.8, 121.2, 115.4, 52.3, 44.8, 24.1,
21.6, 9.5; HRMS (FAB) calcd for [M]+ (C12H19NO2) 221.1416,
found 221.1407.
(5-Methoxy-4,5,6,7-tetrahydroisoindol-2-yl)acetic Acid Methyl
Ester (16c). The procedure to prepare 16a was followed. Starting
with 5c (66 mg, 0.30 mmol) and ammonium formate (380 mg, 6.0
mmol), 16c (16 mg, 0.07 mmol, 24%) was isolated after column
chromatography (SiO2; hexanes/ethyl acetate, 3:1; Rf 0.30) and 5c
2-(2-Bromoethyl)-4,5,6,7-tetrahydroisoindole-1,3-dione (20d).
The procedure to prepare 20b was followed. Starting with 1d (79
mg, 0.48 mmol) and NBS (213 mg, 1.20 mmol), 20d (65.3 mg,
0.24 mmol, 50%) was isolated after column chromatography (SiO2;
hexanes/ethyl acetate, 1:1; Rf 0.83) as a light yellow oil. 1H NMR
(CDCl3, 200 MHz) δ 1.72 (br, 4H), 2.29 (br, 4H), 3.44 (t, J ) 6.7
Hz, 2H), 3.83 (t, J ) 6.7 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ
170.4, 141.6, 38.8, 28.5, 21.1, 19.9; HRMS (FAB) calcd for [M +
H]+ (C10H13BrNO2) 258.0130, found 258.0120.
1
(22 mg, 0.09 mmol) was recovered. H NMR (CDCl3, 500 MHz)
δ 1.70-1.80 (m, 1H), 2.00-2.10 (m, 1H), 2.50-2.60 (m, 2H),
2.70-2.79 (m, 1H), 2.90-3.00 (m, 1H), 3.41 (s, 3H), 3.75 (s, 3H),
6.33 (s, 1H), 6.35 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 170.0,
119.8, 118.8, 118.0, 117.4, 77.7, 56.3, 55.6, 52.8, 51.0, 29.0, 28.5,
19.9; HRMS (FAB) calcd for [M]+ (C12H17NO3) 223.1208, found
223.1203.
1-Ethyl-2,3-dihydro-1H-indole (21a). Acetyl chloride (3.95 g,
50.4 mmol) was added to a solution of indoline (1.0 g, 8.4 mmol)
in acetic acid (14 mL), and the reaction mixture was refluxed for
3 h. After removing the solvent, N-acetyl indoline (1.34 g, 8.32
4-Methyl-2-(3-phenoxypropyl)-4,5,6,7-tetrahydro-2H-isoin-
dole (17a). The procedure to prepare 16a was followed. Starting
with 8a (30 mg, 0.11 mmol), 17a (22 mg, 0.08 mmol, 71%) was
isolated after column chromatography (SiO2; hexanes/ethyl acetate,
1
mmol, 99%) was produced. H NMR (CDCl3, 200 MHz) δ 2.22
(s, 3H), 3.18 (t, J ) 8.5 Hz, 2H), 4.03 (t, J ) 8.5 Hz, 2H), 6.97-
7.01 (m, 1H), 7.19-7.27 (m, 2H), 8.16-8.22 (d, J ) 7.8, 1H); 13
C
1
9:1; Rf 0.50). H NMR (CDCl3, 500 MHz) δ 1.15 (d, J ) 6.8 Hz,
NMR (CDCl3, 125 MHz) δ 158.5, 142.8, 131.0, 127.4, 124.4, 123.5,
116.9, 48.7, 27.9, 24.1; HRMS (FAB) calcd for [M + H]+ (C10H12-
NO) 162.0919, found 162.1917. N-Acetylindoline (500 mg, 3.1
mmol) was added to a suspension of LAH (176 mg, 4.65 mmol) in
THF (10 mL) and ether (20 mL) at 0 °C. After the addition, the
reaction mixture was refluxed for 2 h, then quenched with water
(1 mL) and sat. K2CO3(aq) (4 mL). The organic solution was
decanted, and the precipitate was washed with ethyl acetate (15
mL). The combined organic solution was concentrated to give 21a
(402 mg, 2.72 mmol, 88%) as a light purple oil.27 1H NMR (CDCl3,
200 MHz) δ 1.18 (t, J ) 7.2 Hz, 3H)), 2.95 (t, J ) 8.2 Hz, 2H),
3.14 (q, J ) 7.2 Hz, 2H), 3.32 (t, J ) 8.2 Hz, 2H), 6.48 (d, J ) 7.9
Hz, 1H), 6.60-6.68 (m, 1H), 7.02-7.09 (m, 2H), 13C NMR (CDCl3,
3H), 1.20-1.30 (m, 1H), 1.53-1.65 (m, 1H), 1.82-1.90 (m, 2H),
2.18 (m, 2H), 2.43-2.74 (m, 3H), 3.93 (t, J ) 5.95 Hz, 2H), 4.00
(t, J ) 6.8 Hz, 2H), 6.31 (s, 1H), 6.38 (s, 1H), 6.88-6.996 (m,
3H), 7.24-7.30 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 158.5,
129.5, 126.1, 120.8, 119.3, 116.0, 115.8, 114.5, 64.5, 46.0, 33.4,
31.4, 28.5, 23.4, 22.2, 22.0; HRMS (FAB) calcd for [M + H]+
(C18H24NO) 270.1858, found 270.1859.
5-Methyl-2-(3-phenoxypropyl)-4,5,6,7-tetrahydro-2H-isoin-
dole (17b). The procedure to prepare 16a was followed. Starting
with 8b (44 mg, 0.16 mmol), 17b (23 mg, 0.09 mmol, 53%) was
isolated after column chromatography (SiO2; hexanes/ethyl acetate,
9:1; Rf 0.57) along with starting material (8.3 mg, 0.03 mmol, 20%).
1H NMR (CDCl3, 500 MHz) δ 1.03 (d, J ) 6.5 Hz, 3H), 1.29-
1.39 (m, 1H), 1.71-1.85 (m, 2H), 2.07-2.21 (m, 3H), 2.47-2.70
(m, 3H), 3.93 (t, J ) 5.9 Hz, 2H), 3.99 (t, J ) 6.8 Hz, 2H), 6.32
(27) Selvakumar, K.; Rangareddy, K.; Harrod, J. F. Can. J. Chem. 2004,
82, 1244.
(s, 1H), 6.33 (s, 1H), 6.88-7.00 (m, 3H), 7.27-7.33 (m, 2H); 13
9238 J. Org. Chem., Vol. 72, No. 24, 2007
C

Formation of 4,5,6,7-Tetrahydroisoindoles
50 MHz) δ 152.3, 130.3, 127.2, 124.3, 117.4, 107.2, 52.3, 43.1,
28.5, 11.9; HRMS (FAB) calcd for [M]+ (C10H13N) 147.1048, found
147.1039.
acetate, 9:1; Rf 0.50) to give 22b (37.5 mg, 0.18 mmol, 71%) as a
light brown oil. H NMR (CDCl3, 200 MHz) δ 1.17 (t, J ) 7.2
Hz, 3H), 4.13 (q, J ) 7.2 Hz, 2H), 4.76 (s, 2H), 6.48-6.50 (d,
1H), 7.01-7.54 (m, 4H), 7.58 (d, J ) 1.0 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) δ 168.5, 136.4, 128.6, 128.4, 122.0, 121.1, 119.8,
108.9, 102.4, 61.6, 47.8, 14.1; HRMS (FAB) calcd for [M]+
(C12H13NO2) 203.0946, found 203.0942.
1
(2,3-Dihydro-indol-1-yl)acetic Acid Ethyl Ester (21b).28 Ethyl
bromoacetate (0.7 mL, 6.3 mmol) was added to a solution of
indoline (0.50 g, 4.2 mmol) and triethylamine (1.17 mL, 8.38 mmol)
in THF (15 mL). The reaction mixture was refIuxed for 6 h, filtered,
and concentrated to give 21b (0.85 g, 4.2 mmol, 99%) as a light
2-(3-Phenoxypropyl)-2H-isoindole (24). Methanol (2.6 mL) was
added dropwise to a solution of LAH (1.40 g, 37.9 mmol) in THF
(25 mL) at 0 °C. The resulting solution was cooled to -40 °C, and
then 25 (3.0 g, 10.7 mol) in THF (15 mL) was added to the reaction
mixture. After 30 min at -40 °C, the reaction mixture was stirred
at 0 °C for 30 min, quenched with Na2SO4(aq) (1.0 g in 9 mL of
water), and filtered. The undissolved material was washed with
acetone (30 mL), and the combined filtrate was concentrated to
give a dark yellow solid. The crude product was recrystallized in
95% ethanol (40 mL) to give pure 24 (0.92 g, 3.66 mmol, 34.5%).
Mp 89-91 °C; 1H NMR (CDCl3, 500 MHz) δ 2.32 (m, 2H), 3.88
(t, J ) 5.7 Hz, 2H), 4.41 (t, J ) 6.7 Hz, 2H), 6.82-6.97 (m, 5H),
7.08 (s, 2H), 7.24-7.30 (m, 2H), 7.47-7.52 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 158.6, 129.5, 124.4, 121.0, 120.6, 119.5,
114.5, 110.8, 63.9, 47.5, 31.5; HRMS (FAB) calcd for [M]+
(C17H17NO) 251.1310, found 251.1315; IR (neat) 3019, 2850, 1684,
1
purple oil. H NMR (CDCl3, 200 MHz) δ 1.46 (t, J ) 7.1 Hz,
3H), 3.02 (t, J ) 8.3 Hz, 2H), 3.52 (t, J ) 8.4 Hz, 2H), 3.87 (s,
2H), 4.20 (q, J ) 7.1 Hz, 2H), 6.40 (d, J ) 7.8 Hz, 1H), 6.63-
6.71 (m, 1H), 7.00-7.09 (m, 2H), 13C NMR (CDCl3, 50 MHz) δ
170.3, 151.3, 129.6, 127.2, 124.5, 118.1, 106.6, 60.8, 53.8, 50.6,
28.6, 14.2; HRMS (FAB) calcd for [M + H]+ (C16H12NO2)
206.1181, found 206.1180.
N-Ethyl-1H-indole (22a).29 A solution of 21a (53 mg, 0.36
mmol), palladium hydroxide on carbon (20%, 25 mg), and
ammonium formate (225 mg, 3.6 mmol) in methanol (5 mL) was
heated at reflux for 14 h. After cooling to rt, the reaction mixture
was filtered and concentrated. The crude product was further
purified by column chromatography (SiO2; hexane/ethyl acetate,
3:1; Rf 0.70) to give 22b (28 mg, 0.19 mmol, 53%) as a light green
1
oil. H NMR (CDCl3, 200 MHz) δ 1.46 (t, J ) 7.3 Hz, 3H), 4.18
1600, 1497, 1495, 1470, 1398, 1242, 1039, 810, 750, 690, cm-1
.
(q, J ) 7.3 Hz, 2H), 6.48 (d, J ) 0.7 Hz, 1H), 7.09-7.33 (m, 4H),
7.65 (d, J ) 1.2 Hz, 1H), 13C NMR (CDCl3, 50 MHz) δ 135.6,
128.6, 126.9, 121.3, 120.9, 119.1, 109.2, 101.0, 40.9, 15.4; HRMS
(FAB) calcd for [M + H]+ (C10H11N) 145.0891, found 145.0883.
Indol-1-yl-acetic Acid Ethyl Ester (22b).30 A solution of 21b
(53 mg, 0.26 mmol), palladium hydroxide on carbon (20%, 18 mg),
and ammonium formate (164 mg, 2.6 mmol) in methanol (5 mL)
was heated at reflux for 14 h. After cooling to rt, the reaction
mixture was filtered and concentrated. The crude product was
further purified by column chromatography (SiO2; hexane/ethyl
Acknowledgment. This research was supported by the
National Science Council (NSC 95-2113-M-008-007), Taiwan.
The authors thank Prof. John C. Gilbert, Santa Clara University,
for helpful comments. Thanks are also due to Ms. Ping-Yu Lin
at the Institute of Chemistry, Academia Sinica, and the Valuable
Instrument Center in National Central University for obtaining
mass analyses.
Supporting Information Available: Calculations of the aro-
maticity of indoles and isoindoles, and spectroscopic data of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J.
N. J. Am. Chem. Soc. 2003, 125, 163.
(29) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050.
(30) Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1981,
13, 7620.
JO7016845
J. Org. Chem, Vol. 72, No. 24, 2007 9239