New formation of 4,5,6,7-tetrahydroisoindoles

Article abstract of DOI:10.1016/j.tetlet.2005.06.118

The high-yield syntheses of 4,5,6,7-tetrahydro-isoindoles from N-substituted isoindolines under palladium catalyzed hydrogenation conditions are reported. Mechanistic study with deuterated and saturated substrates show extensive H/D exchange and the essence of aromaticity in this transformation.

Full text of DOI:10.1016/j.tetlet.2005.06.118

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5927–5929
New formation of 4,5,6,7-tetrahydroisoindoles
Duen-Ren Hou,* Yih-Dar Hsieh and Yi-Wei Hsieh
Department of Chemistry, National Central University, Jung-Li City, Taoyuan 320, Taiwan
Received 4 May 2005; revised 20 June 2005; accepted 22 June 2005
Available online 11 July 2005
Abstract—The high-yield syntheses of 4,5,6,7-tetrahydro-isoindoles from N-substituted isoindolines under palladium catalyzed
hydrogenation conditions are reported. Mechanistic study with deuterated and saturated substrates show extensive H/D exchange
and the essence of aromaticity in this transformation.
Ó 2005 Elsevier Ltd. All rights reserved.
4,5,6,7-Tetrahydroisoindoles (1) are popular constitu-
tive factors of porphyrins; some of their derivatives are
biologically active.1,2 The synthetic routes followed to
prepare these compounds are generally based on the
synthesis of pyrroles and can be placed into the follow-
ing categories: oxidation of pyrrolidine,3 condensation
of 1,4-dicarbonyl compounds and amines (the Paal–
Knorr synthesis),1a,2a,4 cyclization of a-enamino
acids,1c,2b,5 Diels–Alder reactions of 3-sulfolenes and
alkenes,6 cyclization of isocyanoacetates with vinyl
sulfones or nitroalkenes,7,8 ring contraction of phthal-
azine,2c and samarium-catalyzed reactions of a,b-unsat-
urated imines with nitroalkane.9 In this letter, we
report an interesting route to 4,5,6,7-tetrahydroisoin-
doles by hydrogenation of N-substituted isoindoline (2,
Scheme 1).
To circumvent a bothersome reductive hydrogenation of
dibenzyl amines in our recent syntheses of oncinotines,10
we believed that the isoindoline 2 might be a good pre-
cursor to primary amines. Thus, a model compound, 2a,
was prepared and subjected to the typical hydrogenation
conditions—heating under reflux in methanol for 14 h in
the presence of PearlmanÕs catalyst Pd(OH)2/C and
ammonium formate. We did not, however, obtain the
expected primary amine 3. Instead, mass spectrometric
analysis indicated that two hydrogen atoms had added
to 2a and no fragmentation product resembling 3 was
generated from this reaction. In the 1H NMR spectrum,
we observed new absorptions at 1.74 (m, 4H), 2.54 (m,
4H) and 6.37 (s, 2H) ppm in addition to the original sig-
nals of the OPh and three methylene groups between the
1
nitrogen and oxygen atoms. Through H–13C HMQC
spectroscopic analysis, these new proton absorptions
correlate to two new sp3-hybridized carbon atoms
(d = 22.1, 24.3) and one new sp2-hybridized carbon
atom (d = 116.2); in addition, another new quarternary
sp2-hybridized carbon appears at 119.6 ppm. These
spectroscopic data suggest the symmetrical structure of
4,5,6,7-tetrahydroisoindole 1a. The downfielded proton
absorption (d = 6.37) is consistent with the deshielding
effect of aromatic pyrrole. The IR spectrum of 1a also
i
N(CH2)3OPh
H2N(CH2)3OPh
3
2a
i
MeO2C
CO2Me
ii
N(CH2)3OPh
N(CH2)3OPh
displays characteristic pyrrole absorptions at 1458,
1395 and 1325 cmꢀ1
9,11
.
The formation of the pyrrole
1a
CO2Me
4
MeO2C
ring was further confirmed by the reaction of 1a with
dimethyl maleate, which gave the compound 4 derived
from the electrophilic aromatic substitution of
pyrroles.12 These data indicate that isoindoline 2a
undergoes partial reduction and forms aromatic pyrrole
1a under hydrogenation conditions.13
Scheme 1. Reagents and conditions: (i) ammonium formate (10 equiv),
Pd(OH)2 (10 mol %), MeOH, reflux, 14 h, 97%; (ii) Dimethyl maleate,
AlCl3, CH2Cl2, 57%.
Keywords: Pyrrole; Palladium; Hydrogenation; Aromaticity.
*
To examine the scope and limitations of this process, we
synthesized a number of other N-substituted isoindolines
Corresponding author. Tel.: +886 34227151; fax: +886 34227664;
e-mail: drhou@cc.ncu.edu.tw
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.118

5928
D.-R. Hou et al. / Tetrahedron Letters 46 (2005) 5927–5929
and 10 mol % of catalyst were required to complete
O
LiAlH4
the reactions (entries 1 and 2). Palladium on charcoal
was also practical in this reaction, but it gave a slightly
lower yield (entry 3). Reducing the reaction time led to a
lower yield (entry 4). Simple N-methyl and propyl iso-
indolines, 2c and 2d, were good substrates for this reac-
tion (entry 6 and 7). No interference was caused by
various functional groups on the N-substituted chain,
such as phenyl ether (2a and 2b), ester (2e), alcohol
(2f) and amide (2h) units, during the formation of pyr-
roles 1 and we obtained reasonable to excellent yields
(entries 8–11). The presence of a free amino group (2g)
slowed down the reaction and led to the formation of
impurities. In addition to the formation of tetrahydroiso-
indole, the trichlorinated benzoate moiety of 2i was also
reduced to benzoate (entry 12).16 This result implies that
halogen-substituted isoindolines should also be reduced
and form the pyrrole moiety under this condition.
Unfortunately, N-acetyl isoindoline (2j), failed to give
the corresponding product 1j (entry 13). This finding
suggests that delocalization of the nitrogen atomÕs lone
pair of electrons into the acyl group of 2j inhibits the
reaction.17 Attempts to extend this reaction to other het-
erocycles, that is, thiophene and furan derivatives, were
unsuccessful (entries 14 and 15); the starting materials
were recovered intact. Because, the resonance energies
of pyrrole, furan, thiophene and benzene are 21, 16, 29
and 34 kcal/mol, respectively,18 factors other than reso-
nance energies must play a role in this unique pyrrole
formation.
NR1
NR
ether/THF
O
2a, R = R1 = (CH2)3OPh, 80%
2b, R = R1 = (CH2)4OPh, 79%
2c R = R1 = CH3, 96%
2d, R = CH2CH2CH3, R1 = (CH2)3Br, 99%
2g, R = (CH2)4NH2, R1 =(CH2)4NH3Cl, 64%
2h, R = (CH2)4NHBz, 40%
BzCl
Scheme 2.
Br
+ H2X
Br
base
X
2e, X = NCH2CO2CH3, K2CO3, 66%
2f, X = N(CH2)2OH, 94%
LAH
O
2i, X = N(CH2)2O2C(2,4,6-C6H2Cl3), 40%
2j, X = NCOCH3, NaH, 95%
2k, X = O, NaOH, 47%
2l, X = S, Na2S, 85%
(2,4,6-C6H2Cl3)CCl
Scheme 3.
(2b–j) using two efficient methods: the reduction of N-
substituted phthalimides and the alkylation of primary
amines with a,a0-dibromo-o-xylene (Schemes 2 and 3).
Table 1 summarizes the results we obtained after sub-
jecting these isoindolines to the hydrogenation condi-
tions (Eq. 1). Usually, 10 equiv of ammonium formate
The question of whether the benzylic hydrogen atoms of
2 were transferred to the cyclohexyl ring of 1 prompted
us to prepare an isotope-labeled congener, D4-2a. The
reaction of D4-2a under the hydrogenation conditions
gave product 1a that lacks the deuterium atoms. The
loss of all the deuterium atoms indicates that intensive
H/D exchange occurs during the reaction. Indeed, heat-
ing the product 1a with Pd(OH)2/C in NH4O2CD/
CD3OD under reflux provided a deuterated version of
1a (Scheme 4). Sajiki et al. have also reported recently
such an efficient C–H/C–D exchange of substituted
benzenes catalyzed by Pd/C in D2O.19
H4NO2CH (10 eq.)
X
X
ð1Þ
Pd(OH)2 (10 mol%)
MeOH, reflux, 14 h
2
1
Table 1. Formation of 4,5,6,7-tetrahydroisoindoles
Entry
Reactants
X
Products
Yield
(%)a
1
2a
2a
2a
2a
2b
2c
2d
2e
2f
N(CH2)3OPh
N(CH2)3Oph
N(CH2)3OPh
N(CH2)3OPh
N(CH2)4OPh
NCH3
1a
1a
1a
1a
1b
1c
1d
1e
1f
97
35
90
63
98
77
84
80
85
9
2b
3c
4d
5
One possible mechanistic explanation for the transfor-
mation of 2 to 1 is the formation of octahydroisoindole
intermediate 5, and then dehydrogenation to form
6
7
NCH2CH2CH3
NCH2CO2CH3
N(CH2)2OH
N(CH2)4NH2
N(CH2)4NHBz
N(CH2)2O2C(2,4,6-
C6H2Cl3)
8
O
D
D
9
10
11
12
2g
2h
2i
1g
1h
1ie
i
ii
NR
NR
NR
D
88
80
1a
R = (CH2)3OPh
O
D
D4-2a
13
14
15
2j
NCOCH3
O
1j
N.D.f
N.D.f
N.D.f
(45%)
D
2k
2l
1k
1l
(20%)
D
D (95%)
S
N(CH2)3OPh
N(CH2)3OPh
a Isolated yields.
iii
1a
b 3 mol % of Pd(OH)2 was used.
c 10 mol% of Pd/C was used.
d Reaction time = 4 h.
Scheme 4. Reagents and conditions: (i) LiAlD4, 92%; (ii) ammonium
formate (10 equiv), Pd(OH)2 (10 mol %), MeOH, reflux, 14 h; (iii)
Pd(OH)2 (10 mol %), NH4O2CD (5 equiv), CD3OD, reflux, 14 h. The
percentage of deuterium is provided in parentheses.
e X = N(CH2)2O2CPh.
f No product detected; the starting material was recovered.

D.-R. Hou et al. / Tetrahedron Letters 46 (2005) 5927–5929
5929
Clemens, J. A.; Smalstig, E. B. J. Med. Chem. 1980, 23,
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N(CH2)3OPh
N(CH2)3OPh
3. (a) Bonnaud, B.; Bigg, D. H. Synthesis 1994, 465; (b) Yagi,
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2a
1a
iv
O
ˇ ˇ
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N(CH2)3OPh
Kikelj, D. Tetrahedron 2002, 58, 1557; (b) Gabbutt, C. D.;
Hepworth, J. D.; Heron, B. M.; Pugh, S. J. Chem. Soc.,
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5
O
Scheme 5. Reagents and conditions: (i) H2NNH2, EtOH, 59%; (ii) cis-
1,2-cyclohexanedicarboxylic anhydride, 68%; (iii) LiAlH4, 67%; (iv)
Pd(OH)2 (10 mol %), NH4O2CH (5 equiv), CH3OH, reflux, 14 h.
pyrroles (Scheme 5). To test this hypothesis, compound
5 was prepared independently and subjected to the reac-
tion condition. Only the starting material 5 was recov-
ered and no detectable 1a could be observed from the
NMR spectroscopy. Therefore, compound 5 as the reac-
tion intermediate is unlikely. This result and the above
isotope tracking experiments suggest that this reaction
may start from the benzylic C–H activation of isoindo-
line by palladium, and then the formation of pyrrole is
accompanied with partial reduction of the benzene moi-
ety. Through the process, the aromaticity is essential
and intriguingly transferred to pyrrole at the end.
Unlike deprotection of dibenzyl amines,20 the C–N
bonds of isoindolines 2 are not cleaved by palladium
catalyzed hydrogenation.
´
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Gerardin, P.; Loubinoux, B. Synthesis 1997, 1451; (c)
In summary, we report here a simple and efficient method
for preparing 4,5,6,7-tetrahydroisoindoles that utilizes a
novel pathway to form the pyrrole moiety.
Tang, J.; Verkade, J. J. Org. Chem. 1994, 59, 7793.
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13. Two similar transformations have been reported previ-
ously: hydrogenation of 1-carbomethoxyisoindoles gives
4,5,6,7-tetrahydro-1-carbomethoxyisoindoles14 and hydro-
genation of 4H-benzo[def]carbazole gives 8,9-dihydro-4H-
benzo[def]carbazole.15 A refreeÕs suggestion is acknowl-
edged.
Acknowledgements
The authors thank Professor John C. Gilbert at the Uni-
versity of Texas at Austin for helpful comments. This
research was supported by National Central University
and the National Science Council (NSC 93-2113-M-
008-010), Taiwan.
Supplementary data
Experimental details for preparation and characteriza-
tion of all new compounds can be found, in the online
version, at doi:10.1016/j.tetlet.2005.06.118.
14. Cignarella, G.; Cerri, R.; Grella, G.; Sanna, P. Gazz.
Chim. Ital. 1976, 106, 65.
15. Horaguchi, T.; Yamazaki, R.; Abe, T. Bull. Chem. Soc.
Jpn. 1980, 53, 494.
References and notes
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therein.
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