Modified Pictet-Spengler reaction. A highly diastereoselective approach to 1,2,3-trisubstituted-1,2,3,4-tetrahydro-β-carbolines using perhydro-1,3-heterocycles

Article abstract of DOI:10.1016/S0040-4020(01)00763-3

A flexible variant of the Pictet-Spengler reaction employing oxazinanes as synthetic equivalents of several carbonyl compounds has been developed. Using acid catalyzed one pot condensation of perhydro-1,3-heterocycles various 1,3-disubstituted and 1,2,3-trisubstituted-1,2,3,4-tetrahydro-β-carbolines (THBCs) have been synthesized diastereoselectively.

Full text of DOI:10.1016/S0040-4020(01)00763-3

TETRAHEDRON
Pergamon
Tetrahedron 57 ꢀ2001) 7939±7949
Modi®ed Pictet±Spengler reaction. A highly diastereoselective
approach to 1,2,3-trisubstituted-1,2,3,4-tetrahydro-b-carbolines
using perhydro-1,3-heterocycles
Kamaljit Singh,a,p Prasant K. Deba and P. Venugopalanb
aDepartment of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143-005, India
bDepartment of Chemistry, Panjab University, Chandigarh, India
Dedicated to the loving memory of ꢀthe late) Maninder Kaur Chawla
Received 26 March 2001; revised 21 June 2001; accepted 19 July 2001
AbstractÐA ¯exible variant of the Pictet±Spengler reaction employing oxazinanes as synthetic equivalents of several carbonyl compounds
has been developed. Using acid catalyzed one pot condensation of perhydro-1,3-heterocycles various 1,3-disubstituted and 1,2,3-trisubsti-
tuted-1,2,3,4-tetrahydro-b-carbolines ꢀTHBCs) have been synthesized diastereoselectively. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
and asymmetric reductions of corresponding dihydro
b-carbolines24 etc have also been developed.
The interest in the synthesis of indole alkaloids stems from
their intricate cyclic frame-work and diverse medicinal
properties such as anti-tumor1 and cardiovascular effects.2
Many 1,2,3-trisubstituted-1,2,3,4-tetrahydro-b-carbolines
ꢀTHBC) alkaloids2,3 in their skeleton embody l-tryptophan
unit pointing to its use in their synthesis as an enantio-
merically pure starting material for control of the stereo-
chemistry at C-1 and C-3 in the Pictet±Spengler reaction
with aldehydes, which has long been in use for the synthesis
of THBCs and other related systems.4 Out of a variety of
reaction conditions employed, the use of non-acidic aprotic
media becomes more obvious when acid-labile aldehydes
are used,5 and aqueous-acidic conditions6 result in con-
siderably lower yields of the THBCs in comparison to
We have for quite some time been engaged in developing an
alternate synthetic strategy using the `Folate model
approach',25 wherein variously C-2 substituted perhydro
1,3-heterocycles have been convincingly employed26 as
carbonyl equivalents for obtaining a variety of useful
synthetic targets through a single pot, acid catalyzed C-2
unit transfer reaction of these reagents to various nucleo-
philes, thus avoiding the direct use of aldehydes. Owing to
the ease in synthesis, proven carbonyl resource and
ef®cacious elaboration at C-2 of oxazinanes27 and oxazoli-
dines,28 a conspicuous merit of these reactions has been
diversi®cation of the transferred carbon unitÐan attribute
of potential utility in the synthesis of lead compounds for a
variety of pharmacologically interesting26d,e events. Herein
we report on the synthetic usefulness of this modi®ed
Pictet±Spengler reaction,26a wherein stable oxazinanes and
oxazolidines are reacted with l-tryptophan derivatives to
obtain the title compounds diastereoselectively as in the
conventional Pictet±Spengler reaction.4,5a,10,29
non-acidic or acidic±aprotic reaction conditions.7±10
A
few variant approaches involving combinatorial
chemistry,11 solid phase synthesis,12 and alternatives for
aldehydes such as conjugated alkynoates,13 azalactones,14
D1-piperidines,15 acetals,16 active methylene compounds17
etc. have also appeared. Most of these methods exhibit
good to excellent asymmetric control10b,18 and several
elegant routes leading to enantioselective and/or diastereo-
selective preparation of the title compounds using chiral
auxiliaries such as carbohydrates,19 amino acid esters,20
ꢀR) and ꢀS)- glyceraldehydes,21 ꢀ2)-8-phenylmethylcarba-
mates,22 chiral acetylenic sulfoxides23 or chemoselective
2. Results and discussion
2.1. Synthesis of oxazinanes and oxazolidines
Oxazinanes 1a±e and g used in this study are obtained by
condensing g-hydroxypropyl amine with aldehydes and 1f,
h±m were synthesized through borohydride reductions of
correspondingly 2-substituted-4,4,6-trimethyl-5,6-dihydro-
ꢀ4H)-1,3-oxazines 2a±f obtained by condensation of
Keywords: oxazinane; oxazolidine; tetrahydro-b-carboline; Pictet±
Spengler reaction; diastereoselectivity; carbonyl equivalent.
Corresponding author. Tel.: 191-0183-258853; fax: 191-0183-258819/
20; e-mail: kamal_deb@yahoo.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020ꢀ01)00763-3

7940
K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
Scheme 1. Reagents: ꢀi) Acetonitrile ꢀanhyd.), LDA/THF, 2788C. ꢀii) Acetophenone, LDA/THF, 2788C. ꢀiii) Ethyl acetoacetate, ꢀa) NaH/THF/08C,
ꢀb) n-BuLi, 08C.
appropriate nitriles ꢀR2CN) with 2-methyl-2,4-pentanediol
in the presence of concentrated sulphuric acid following the
method of Meyers et al.27 2-Cyanoethyl-4,4,6-trimethyl-
5,6-dihydro-ꢀ4H)-1,3-oxazine 2g was obtained by reacting
carbanion of acetonitrile with corresponding 2-chloro-
methyl oxazine 2h obtained from chloroacetonitrile. For
the synthesis of oxazolidines 3a±c stabilized carbanions
of acetonitrile, acetophenone and ethyl acetoacetate, respec-
tively were reacted with 3,4,4,-trimethyl-D2-oxazolinium
iodide 430 at low temperature following a method
developed31 by us ꢀScheme 1).
ꢀTable 1, entry 1). However, 1a cleanly reacts with 5a under
acid catalyzed conditions to furnish 6a in which sCHAr unit
ꢀC-2) of 1a gets incorporated as a new chiral center as C-1 of
THBC 6a. To monitor the in¯uence of bulkiness of R2
appended as C-2 of 1 ꢀC-1 in THBCs 6) on the distereo-
selectivity of this reaction, differently substituted
oxazinanes 1b±f have been reacted with 5a ꢀScheme 2).
Reactions of oxazinanes 1b±f with l-TrpOMe in anhydrous
acetonitrile/TFA ꢀ10:0.1) solution at re¯ux furnished the
corresponding THBCderivatives 6b±f, respectively in
74±78% yield but with very similar diastereomeric ratios
ꢀTable 1, entries 2±6). However, when the reactions were
performed at ambient temperature or by using ultrasonicator
as energy transfer medium ꢀambient temperature), an
increase in cis selectivity ranging from 71:29 to 91:9
ꢀcis:trans) was observed. This is consistent with the
reported29c,d observation of enhanced cis stereoselectivity
in conventional Pictet±Spengler reaction under kinetically
controlled reaction conditions and considering the bulkiness
of R2 at C-1, there seems to be a marginal increase in cis
selectivity which in fact disappears when the reactions are
conducted at re¯ux.
2.2. Diastereo-control in the synthesis of THBCs
To study the in¯uence of reaction conditions on the stereo-
selection in the alternative Pictet±Spengler reaction
involving perhydro 1,3-heterocycles 1 and 3 and the stereo-
genic amino acid esters viz. Nb-H l-tryptophan methyl ester
ꢀl-TrpOMe) 5a, Nb-H l-tryptophan isopropyl ester
ꢀl-TrpOPri) 5b, Nb-benzyl l-tryptophan methyl ester ꢀNb-
benzyl-l-TrpOMe) 5c and Nb-p-methoxybenzyl l-trypto-
phan isopropyl ester ꢀNb-p-MeObenzyl-l-TrpOPri) 5d
were chosen. Reactions of 1 or 3 with 5a±d were conducted
in anhydrous acetonitrile using tri¯uoroacetic acid ꢀMeCN/
TFA 10:0.1) or acetic acid ꢀMeCN/AcOH 10:1.0) as
catalysts at room temperature using stirring or ultrasonica-
tion ꢀkinetic control) or alternatively at re¯ux temperature
ꢀthermodynamic control). Various C-1 substituted title
THBCs have been obtained in these reactions in varying
diastereomeric ratios. Under the conditions of thermo-
dynamic control 1,2,3-trisubstituted THBCs are formed
mainly/exclusively as trans-isomers.
To monitor the effect of steric bulk of the ester function in 5,
l-TrpOPri 5b was reacted with oxazinanes 1a±f ꢀScheme
2). These reactions point to the incorporation of sCHR2 unit
in between indolyl C-2 and ±NH2 of 5b and formation of cis
and trans 2-methylethyl 1-substituted-1,2,3,4-tetrahydro-
9H-pyrido
[3,4-b]-indole-3-carboxylates
6g±l,
but
switching from 5a to 5b has only a modest effect on the
diastereoselectivity with no clear-cut trend becoming
apparent ꢀTable 1, entries 7±12). However this method
offers a variant route and demonstrates that oxazinanes
can be employed in place of aldehydes in this key reaction.
2-p-Methoxyphenyl oxazinane 1a and l-TrpOMe 5a ꢀ1:1)
upon re¯uxing in acidi®ed anhydrous acetonitrile ꢀMeCN/
TFA 10:0.1) furnished trans-methyl 1-p-methoxyphenyl-
1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxylate
6a ꢀRf 0.7, ethyl acetate/hexane 3:7) and the corresponding
cis isomer ꢀRf 0.8), albeit in poor diastereoselectivity ratio
In the conventional enantiosepeci®c Pictet±Spengler reac-
tion, it has been demonstrated5a that the presence of a benzyl
function at the Nb-nitrogen moiety permitted control of the

K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
7941
Table 1. Cis:trans ratios of THBCs [6, R2ˆaryl ꢀentries 1±22); 9, R2ˆalkyl ꢀentries 23±36)]
Sr. no.
THBCs 6/9
Acid
de ꢀ%)
Time ꢀh)
6/9
diastereomeric ratioa
cis:trans
Yield ꢀ%)
R1
R2
R4
1.
2.
3.
4.
5.
6.
7.
8.
Me
Me
Me
Me
Me
Me
Pri
p-MeOC6H4
3,4-ꢀMeO)2C6H3
3,4,5-ꢀMeO)3C6H2
m-NO2C6H4
o-NO2C6H4
Ph
p-MeOC6H4
3,4-ꢀMeO)2C6H3
3,4,5-ꢀMeO)3C6H2
m-NO2C6H4
o-NO2C6H4
Ph
p-MeOC6H4
3,4-ꢀMeO)2C6H3
3,4,5-ꢀMeO)3C6H2
m-NO2C6H4
Ph
H
H
H
H
H
H
H
H
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
TFA
TFA
TFA
AcOH
AcOH
TFA H
TFA
TFA
AcOH
2
10
12
4
6
3.5
2
49ꢀ71):51ꢀ29)
55ꢀ91):45ꢀ9)
56:44
53:48
50:50
55:45
60:40
59:41
55:45
55:45
50:50
60:40
02b:98
01b:99
01b:99
02b:98
01b:99
03b:97
02b:98
03b:97
01b:99
02b:98
±
77
78
74
75
78
75
68
74
80
78
72
84
91
82
90
78
88
86
88
78
92
78
72
68
71
74
61
80
74
68
72
78
61
78
54
56
12
12
12
10
18
18
14
12
12
13
28
28
15
9
0
10
20
18
10
10
0
20
96
98
98
96
98
94
96
94
98
96
±
10
10
20
20
74
76
86
90
84
86
H76
90
92
Pri
9.
Pri
H
H
H
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
p-MeOC6H4CH2
p-MeOC6H4CH2
p-MeOC6H4CH2
p-MeOC6H4CH2
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.c
36.d
Pri
Pri
Pri
Me
Me
Me
Me
Me
Pri
Ph
7
Pri
p-MeOC6H4
3,4-ꢀMeO)2C6H3
3,4,5-ꢀMeO)3C6H2
m-NO2C6H4
H
Me
Et
CH2COOEt
CH2CN
Me
10
14
18
16
10
12
16
10
12
8
24
24
12
24
30
12
36
40
Pri
Pri
Pri
p-MeOC6H4CH2
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
55:45
55:45
60:40
60:40
13:87
12:88
7:93
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
N
N
CH2Ph
CH2Ph
Et
CH2COOEt
CH2CH2SPh
CH2CH2SEt
CH2CH2C
CH2C
5:95
8:92
2Ph
2Ph
C
7:93
12:88
5b:95
C
CH2COPh
CH2COCH2COOEt
4b:96
^ 3% As determined from the integration of the C-3 ester signal in the 1H NMR spectrum.32
The values in the parenthesis show the diastereomeric ratios of the reactions conducted using ultrasonicator ꢀJulabo USR 05).33
Minor cis compounds were only detected in the 1H NMR spectra and could not be isolated.
Obtained from 10a.
a
b
c
d
Obtained from corresponding enaminoketone 10b.
stereochemical outcome in favor of trans selectivity. We
the loss of appropriate aminopropanol, cyclises spon-
taneously by intramolecular electrophilic attack of the
iminium carbon at C-2 or at C-3 of the indole moiety to
form a spiroindolenine 8 which rearranges and subsequently
deprotonates to yield corresponding THBCs 6.
further envisaged, that the reactions of Nb-benzyl tryptophan
esters with oxazinanes might furnish 1,2,3-trisubstituted
THBCs with trans selectivity as was observed with
aldehydes.
Thus Nb-benzyl-l-TrpOMe 5c or Nb-p-MeObenzyl-l-TrpO-
Pri 5d in anhydrous acetonitrile/TFA ꢀ10:0.1) solution reacts
under re¯ux with various oxazinanes 1 to furnish corre-
sponding methyl Nb-benzyl-1-substituted 1,2,3,4-tetra-
hydro-9H-pyrido [3,4-b]-indole-3-carboxylates 6 ꢀScheme
2) mainly as trans isomers in good to excellent yield
ꢀTable 1, entries 13±22). The trans-Nb- substituted dia-
stereomers are thermodynamically more stable than their
cis-congeners. Evidence for this observation has already
been furnished and proved by equilibration studies in acidic
media.4 Also the origin of diastereoselectivity10b,34,36 in the
reactions depicted herein is similar to the corresponding
aldehyde approach.
From these results, as expected, it is evident that on switch-
ing from a methyl to isopropyl ester, no appreciable effect
on the stereoselectivity of the products was observed. In all
the reactions in Scheme 2, in consonance with the aldehyde
approach, high order of trans diastereoselectivity has been
observed. Also there is no effect of variation of the steric
bulk at C-2 of 1, on the diastereoselectivity of the products,
in contrast to the observation in the reactions of aldehydes in
the conventional Pictet±Spengler approach.36
Further it has been realized that if benzaldehyde derivatives
are employed, the desired THBCs are formed in satisfactory
yields,9,38 whereas with aliphatic counterparts, the THBCs
in a majority of cases, are formed in much lower yield or as
minor products. Furthermore the instability of relatively
vulnerable aliphatic aldehydes necessitates their use in
considerable molar excess,5a,36,38 when implemented under
All these reactions of 1 ꢀexisting as ring-chain tautomers),37
can be visualized to proceed through the formation of an
iminium intermediate 7 ꢀScheme 2) formed in situ, through

7942
K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
Scheme 2. Reagents: ꢀi) MeCN, TFA.
acid catalysed reaction conditions, to drive the reaction to
completion. We have recently demonstrated26a that Nb-
benzyl THBCs bearing various C-1 aryl substituents can
be easily accessed through the use of oxazinanes in a
synthetically useful manner and with very high trans dia-
stereoselectivity. In this vein, we have performed some
reactions of perhydro 1,3-heterocycles with 5 to obtain
various THBCs bearing C-1 aliphatic substituents including
a pivotal indole alkaloidal intermediate.
substituent with oxazinanes 1g±j ꢀScheme 3) and oxazoli-
dine 3a, in 1:1 stoichiometric proportion were conducted
ꢀTable 1, entries 23±27), to monitor the cis/trans selectivity
and the progress of formation of the products. However,
although the corresponding C-1 substituted THBCs 9a±e
were obtained as equilibrated mixtures, the chemical yield
was good to excellent, establishing thereby that 1/3 support-
ing C-2 alkyl substituents could be employed with clear-cut
advantage in terms of the yield of 9 and cleanliness of the
reaction as formation of the by-products was not detected, in
comparison to the conventional approach employing
aldehydes. The diastereoselectivity of THBCs is in¯uenced
Using our standard reaction conditions of thermodynamic
control, initially a few reactions of 5a lacking Nb-benzyl
Scheme 3. Reagents: ꢀi) MeCN, TFA; ꢀii) C6H6 or MeOH, dry HCl.

K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
7943
Figure 1. ORTEP presentation of X-ray structure of trans ꢀA) and cis ꢀB) 9l showing the crystallographic numbering of the atoms ꢀsee Section 4 for details).40
only marginally ꢀcompare entries 26 and 27 with 24 and 25)
by increasing the size of the C-1 substituent. Further the
reactions could not be conducted at ambient temperature
ꢀkinetic control) owing to the lower reactivity of 1/3.
furnished an acyclic product Nb-benzyl-Nb-ꢀ2-benzoyl-
ethylene)-l-tryptophanate 10a [trans enamine, d 5.93,
Jˆ12.7 Hz ꢀvinylic signals)], which upon treatment with a
saturated benzene solution of hydrogen chloride at 08C
1
furnished trans THBC 9m. The H NMR monitoring of
To gain access to trans 1,2,3-trisubstituted THBCs and to
extend the usefulness of the methodology to a variety of
substitutional variations at C-1, reactions of 5c with 1h±m
were conducted under similar conditions. The correspond-
ing products 9f±k ꢀTable 1, entries 28±33) were obtained in
high yield and excellent trans selectivity in consonance with
the results reported for aldehydes ꢀScheme 3). Wherever
possible the minor cis isomers were also isolated ꢀvide
Section 4) along with the major trans isomers and their
structures established. The diastereomers were identi®ed
the crude cyclization reaction mixture through the dis-
appearance of the indole-2H at ca. d 6.96 was indicative
of smooth cyclization leading to 9m. Likewise oxazolidine
3c furnished trans THBC 9n through 10b. Thus in all the
reactions of 5c with 1/3 the C-1 elaborated THBCs 9
were formed with high diastereoselectivity and chemical
yield.
The use of Nb-benzyl or related substituents in l-tryptophan
esters not only guarantee trans selectivity of the Pictet±
Spengler products, but are also formed with very high
enantioselectivity, although the product ratios are deter-
mined by thermodynamic control.29b On the other hand,
examples of racemisation of especially the trans 1,3-di-
substituted THBCs are known.9c,29a The THBCs of high
optical purity have been isolated either at or below room
temperature or by using excess of acid during reaction. To
this end, in an attempt to investigate if this is also the case in
the methodology described above, the ees of the trans and
cis 6f, synthesized under the conditions of thermodynamic
1
by H- and 13CNMR spectroscopy and by comparison
with the literature data.34,39
The reaction of 3a with 5c under similar reaction conditions
furnished 2-cyanomethyl substituted THBC 9l as a mixture
of cis and trans isomers ꢀ22:88). The overall transformation
of 5c to 9l depicts a straightforward incorporation of the
±CH2CN moiety at C-1, to furnish an analog of a pivotal
intermediate used in the synthesis of corynantheidol and
dihydrocorynantheol and related seco-alkaloids.41
1
control were determined by H NMR spectroscopy42 using
Although a large number of crystal structures of variously
substituted THBCs have been reported,10b,29c,34 to substanti-
ate the stereochemical assignments to the new THBCs and
to unambiguously correlate the stereochemistries of the
other THBCs synthesized herein, the investigations in the
X-ray structures of both cis and trans isomers of 9l have
been undertaken40 ꢀsee Fig. 1 and Section 4 for details). The
results obtained are very similar to the earlier reported struc-
tures.10b Thus it has been found that in both cis and trans 9l,
the didehydropiperidine ring adopts half-chair conformation
with the substituents at C-1, Nb- and C-3 occupying axial/
pseudoaxial, equatorial/pseudoequatorial and axial posi-
tions, respectively. For the cis 9l the 1,3-diaxial conforma-
tion is adopted, whilst for the trans 9l the 1pseudoaxial, 3axial
arrangement is observed.
chiral shift reagent, tris[3-hepta¯uoropropylhydroxy-
methylene-ꢀ1)-camphorato]europium ꢀIII) as well as
speci®c optical rotation correlation with authentic trans
and cis 6f, prepared using racemisation-free conditions of
Bailey10b et al. The products showed fair degree of
enantioselectivity [86% for trans 6f and .95% for cis
6f].
2.3. Synthesis of congeners to naturally occurring
alkaloids
2,4-Dioxo-1,2,3,4,6,7,12,12b-octahydroindolo
[2,3-a]
quinolizine 13, a ketolactam, is of interest in connection
with the total synthesis of indole alkaloids and their analogs.
The known synthesis43 of 13 proceeds in low yield and
requires the use of sensitive 4-ethoxycarbonyl-3,3-ethylene-
dioxybutanal. The reaction of tryptamine with 3c
Reaction of 3b with 5c under a similar set of conditions

7944
K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
Scheme 4. Reagents: ꢀi) MeCN, AcOH; ꢀii) EtOH, dry HCl.
ꢀanhydrous MeCN/AcOH, 10:1, re¯ux) furnished
enaminone ester 11 [Z con®guration, d 4.93, Jˆ7.2 Hz
ꢀvinylic protons)]. The enaminone ester 11 was cyclized
ꢀScheme 4) to THBC 1244 in the presence of dry hydrogen
chloride. The THBC 12 serves as an important intermediate
for 1345 as well as the dihydroindole derivative 14Ða
vindoline alkaloid.44
reported5a procedures. l-Tryptophan was purchased from
Sigma±Aldrich Co., USA.
Spectral data for compounds 6f,9a,34 9a,47 9b,5a,34 9c,34 9f,48
9g,36 11,44 12,44 and 1345 were identical to those reported.
Spectral data for compounds 6b±f, 6h±l, 6n±q and 6s±v are
available as supporting information.
4.1.1.
2-73,4-Dimethoxy)phenyltetrahydro-72H)-1,3-
oxazine 71b). A solution of 3,4-dimethoxy benzaldehyde
ꢀ0.1 mol), 3-amino-1-propanol ꢀ0.1 mol), and p-toluene-
sulfonic acid ꢀcatalytic) in anhydrous benzene ꢀ30 mL)
was re¯uxed for azeotropic removal of water using Dean±
Stark apparatus till the reaction completed ꢀTLC) ꢀ2±3 h).
The solution was then ®ltered and the organic phase washed
with cold aqueous sodium bicarbonate solution ꢀ5% w/v)
and water, in succession. It was then dried ꢀanhydrous
Na2SO4) and the solvent was removed under reduced
pressure. The thick residue solidi®ed when refrigerated
overnight and was pure enough for further use. Yield:
quantitative, pale yellow solid, mp 66±688C. nmax ꢀKBr):
3450, 1639, 1267 cm21. [Found: C, 64.51; H, 7.68; N 6.21.
C12H17NO3 requires C, 64.57; H, 7.62; N, 6.27%]. dH
ꢀ200 MHz, CDCl3): ꢀoxazinane/imineˆ36.5:63.5%), 1.94
ꢀquintet, Jˆ6.2 Hz, 2H, Cꢀ5)H2), 2.61 ꢀbr, 1H, D2O
exchangeable, NH), 3.78 ꢀt, Jˆ6.2 Hz, 2H, Cꢀ4)H2), 3.90
ꢀm, 8H, 2£OMe and Cꢀ6)H2), 5.13 ꢀs, 1H, Cꢀ2)H), 7.20 ꢀm,
3. Conclusions
These few reactions demonstrate a facile incorporation of
both aromatic and aliphatic substituents at C-1 of the THBC
system in a synthetically useful manner through a single pot
C-2 unit transfer reaction of 1/3 and the methodology is
amenable to a variety of substitutional variations at C-1 of
substituted THBCs. The chemical yield, simplicity of the
methodology and ease in synthesis of a variety of oxa-
zinanes makes this approach quite attractive. Although the
diastereocontrol of the reactions described herein is of an
order similar to the conventional Pictet±Spengler approach
employing aldehydes, the method will be most suited for
those cases where the desired aldehydes are unstable or
dif®cult to handle.
4. Experimental
4.1. General
²
³
3H, ArH), 8.18 ꢀs, 1H, ±NvCH±) . dC ꢀ50.6 MHz,
CDCl3): 27.0, 33.3, 44.4, 55.8, 56.0, 59.5, 62.2, 67.8,
88.5, 108.7, 110.8, 126.6, 130.0, 151.4, 160.7. m/z 223
ꢀM1). Likewise 3,4,5-trimethoxy benzaldehyde furnished
2-/3,4,5-Trimethoxy)phenyltetrahydro-/2H)-1,3-oxazine /1c):
yield: quantative, pale yellow solid, mp 478C. nmax ꢀKBr): n
3390, 1645, 1238 cm21. [Found: C, 61.64; H, 7.56; N, 5.49.
C13H19NO4 requires C, 61.66; H, 7.50; N, 5.53%]. dH
ꢀ200 MHz, CDCl3): ꢀoxazinane/imineˆ30.5:69.5%), 1.93
ꢀquintet, Jˆ6.2 Hz, 2H, Cꢀ5)H2), 2.65 ꢀbr, 1H, D2O exchange-
able, NH), 3.85 ꢀm, 13H, 3£OMe, Cꢀ4)H2 and Cꢀ6)H2), 5.10
All melting points are uncorrected. IR spectra were recorded
on Pye UNICAM SP 3-300 spectrophotometer. 1H- and 13
C
NMR spectra were run on Bruker AC200 instrument using
TMS as the internal standard. Mass ꢀ70 eV) spectra and
elemental analyses were performed on Shimadzu QP
2000A spectrometer and Perkin±Elmer 2400 CHN
elemental analyzer, respectively. TLCwas performed on
microplates coated with silica gel-G and the spots were
developed in iodine chamber. Optical rotations were
measured using a Jasco DIP-360 digital polarimeter.
Column chromatography was performed on silica gel
ꢀ60±120 mesh).
²
ꢀs, 1H, Cꢀ2)H), 6.74 ꢀs, 2H, ArH), 6.94 ꢀs, 2H, ArH) , 8.16 ꢀs,
²
³
1H, ±NvCH±) . dC ꢀ50.6 MHz, CDCl3): 26.8, 33.3, 44.2,
55.9, 58.9, 60.6, 61.4, 67.7, 88.5, 105.0, 131.1, 153.2, 160.8.
m/z 253 ꢀM1).
The reagents 1a,26a 1d and e,26e 1f,27 1g,46 1h±j,27 2a±d27
and l-TrpOMe, l-TrpOPri, Nb-benzyl L-TrpOMe and Nb-p-
MeObenzyl-l-TrpOPri were prepared in analogy with the
²
Signals due to ring chain tautomerism.
Extra signals appear due to ring-chain tautomerism.
³

K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
7945
Following dihydrooxazines were synthesized from corre-
sponding nitriles ꢀR2CN) following Meyer's27 method.
1255 cm21
. [Found: C, 66.62; H, 8.92; N, 15.49.
C10H16N2O requires C, 66.66; H, 8.88; N, 15.55%]. dH
ꢀ200 MHz, CDCl3): 1.16 ꢀs, 3H, Me), 1.19 ꢀs, 3H, Me),
1.25 ꢀd, Jˆ6.5 Hz, 3H, Me), 1.38 ꢀm, 1H, Cꢀ5)HH), 1.75
ꢀdd, Jˆ13.5, 2.7 Hz, 1H, Cꢀ5)HH), 2.43 ꢀdistorted t, 2H,
±CH2CH2CN), 2.60 ꢀdistorted t, 2H, ±CH2CH2CN), 4.16
ꢀm, 1H, CH). dC ꢀ50.6 MHz, CDCl3): 14.1, 21.1, 29.3,
30.2, 31.5, 41.8, 49.8, 68.2, 119.0, 154.5. m/z 180 ꢀM1).
4.1.2. 2-72-Thiophenyl)ethyl-4,4,6-trimethyl-5,6-dihydro-
74H)-1,3-oxazine 72e). Yield: 84%. Colorless free ¯owing
oil. nmax ꢀCHCl3): 2950, 1640, 1250 cm21. [Found: C,
68.39; H, 8.02; N, 5.28. C15H21NOS requires C, 68.44; H,
7.98; N, 5.32%]. dH ꢀ200 MHz, CDCl3): 1.09 ꢀs, 3H, Me),
1.13 ꢀs, 3H, Me), 1.20 ꢀd, Jˆ6.2 Hz, 3H, Me), 1.26 ꢀm,
overlapped by d of Me, 1H, Cꢀ5)HH), 1.70 ꢀdd, Jˆ13.5,
2.6 Hz, 1H, Cꢀ5)HH), 2.45 ꢀt, Jˆ7.5 Hz, 2H, ±CH2CH2S±
), 3.13 ꢀt, Jˆ7.5 Hz, 2H, ±CH2CH2S), 4.10 ꢀm, 1H, CH),
7.26 ꢀm, 5H, ArH). dC ꢀ50.6 MHz, CDCl3): 21.3, 29.5, 30.9,
31.7, 35.4, 41.8, 49.7, 67.7, 125.9, 128.7, 129.6, 136.1,
156.3. m/z 263 ꢀM1).
Following tetrahydrooxazines were synthesized by the
reduction27 of their corresponding dihydrooxazines 2e, 2f
and 2g.
4.1.6. 2-72-Thiophenyl) ethyl-4,4,6-trimethyl tetrahydro-
72H)-1,3-oxazine 71k). Yield: quantitative. Colorless
viscous oil. nmax ꢀCHCl3): 3350, 1245 cm21. [Found: C,
67.98; H, 8.71; N, 5.25. C15H23NOS requires C, 67.92; H,
8.67; N, 5.28%]. dH ꢀ200 MHz, CDCl3): 1.14 ꢀm, 10H,
3£Me, Cꢀ5)HH), 1.44 ꢀm, 1H, Cꢀ5)HH), 1.53 ꢀbr, 1H,
D2O exchangeable, NH), 1.85 ꢀm, 2H, ±CHCH2CH2Ph),
3.07 ꢀt, Jˆ7.3 Hz, 2H, ±CHCH2CH2Ph), 3.65 ꢀm, 1H,
CH), 4.35 ꢀt, Jˆ6.0 Hz, 1H, ±CHCH2CH2Ph), 7.36 ꢀm,
5H, ArH). dC ꢀ50.6 MHz, CDCl3): 22.1, 23.7, 29.3, 32.6,
35.8, 45.4, 48.9, 68.4, 81.6, 125.6, 128.6, 129.0, 136.0. m/z
265 ꢀM1).
4.1.3. 2-72-Thioethyl)ethyl-4,4,6-trimethyl-5,6-dihydro-
74H)-1,3-oxazine 72f). Yield: 62%. Colorless free ¯owing
oil. nmax ꢀCHCl3): 2950, 1640, 1250 cm21. [Found: C,
61.35; H, 9.69; N, 6.49. C11H21NOS requires C, 61.39; H,
9.76; N, 6.51%]. dH ꢀ200 MHz, CDCl3): 1.15 ꢀs, 3H, Me),
1.17 ꢀs, 3H, Me), 1.20 ꢀt, Jˆ7.5 Hz, 3H, ±SCH2Me), 1.22 ꢀd,
Jˆ6.0 Hz, 3H, Me), 1.25 ꢀm, overlapped by d of Me, 1H
Cꢀ5)HH), 1.76 ꢀdd, Jˆ13.4, 2.3 Hz, 1H, Cꢀ5)HH), 2.38 ꢀt,
Jˆ7.6 Hz, 2H, ±CH2CH2SEt), 2.53 ꢀq, Jˆ7.5 Hz, 2H,
±SCH2Me), 2.75 ꢀt, Jˆ7.6 Hz, 2H, ±CH2CH2SEt), 4.12
ꢀm, 1H, CH). dC ꢀ50.6 MHz, CDCl3): 14.6, 21.3, 25.5,
28.2, 29.5, 30.8, 35.8, 41.8, 49.9, 67.7, 156.4. m/z 215 ꢀM1).
4.1.7. 2-72-Thioethyl) ethyl-4,4,6-trimethyl tetrahydro-
72H)-1,3-oxazine 71l). Yield: quantitative. Colorless
viscous oil. nmax ꢀCHCl3): 3380, 1260 cm21. [Found: C,
60.84; H, 10.64; N, 6.51. C11H23NOS requires C, 60.82;
H, 10.59; N, 6.45%]. dH ꢀ200 MHz, CDCl3): 1.15 ꢀm,
10H, 3£Me, Cꢀ5)HH), 1.24 ꢀt, Jˆ7.2 Hz, 3H, SCH2Me),
1.44 ꢀm, 1H, Cꢀ5)HH), 1.64 ꢀbr, 1H, D2O exchangeable,
NH), 1.80 ꢀq, Jˆ6.2 Hz, 2H, ±CHCH2CH2SEt), 2.53 ꢀq,
Jˆ7.2 Hz, 2H, ±SCH2Me), 2.64 ꢀt, Jˆ6.2 Hz, 2H, ±
CHCH2CH2SEt), 3.73 ꢀm, 1H, CH), 4.34 ꢀt, Jˆ6.2 Hz,
1H, ±CHCH2CH2SEt). dC ꢀ50.6 MHz, CDCl3): 14.7, 22.3,
23.9, 25.8, 27.2, 32.8, 36.3, 45.7, 48.9, 63.6, 82.0. m/z 217
ꢀM1).
4.1.4. 2-Chloromethyl-4,4,6-trimethyl-5,6-dihydro-74H)-
1,3-oxazine 72h). Yield: 74%. Colorless free ¯owing oil.
nmax ꢀCHCl3): 2925, 1660, 1255 cm21. [Found: C, 54.72;
H, 7.85; N, 7.95. C8H14NOCl requires C, 54.70; H, 7.97;
N, 7.97%]. dH ꢀ200 MHz, CDCl3): 1.18 ꢀs, 3H, Me), 1.21 ꢀs,
3H, Me), 1.32 ꢀd, Jˆ6.2 Hz, 3H, Me), 1.34 ꢀm, overlapped
by d of Me, 1H, Cꢀ5)HH), 1.72 ꢀdd, Jˆ13.7, 2.6 Hz, 1H,
Cꢀ5)HH), 3.91 ꢀs, 2H, ±CH2Cl), 4.20 ꢀm, 1H, CH). dC
ꢀ50.6 MHz, CDCl3): 20.3, 28.4, 30.6, 40.8, 42.8, 49.4,
67.8, 152.7. m/z 175 ꢀM1).
4.1.8. 2-7b-Cyanoethyl)-4,4,6-trimethyl tetrahydro-72H)-
1,3-oxazine 71m). Yield: quantative. Colorless viscous oil.
n
4.1.5. 2-7b-Cyanoethyl)-4,4,6-trimethyl-5,6-dihydro-74H)-
1,3-oxazine 72g). To a solution of diisopropylamine
ꢀ1.34 mL, 0.986 g, 9.5 mmol) in anhydrous THF ꢀ2 mL),
n-BuLi ꢀ6.13 mL, 1.5N solution in hexanes) was added
dropwise at 2788Cunder nitrogen atmosphere. The solution
was allowed to warm to 08Cand stirred for additional
10 min. It was then cooled to 2788Cand addition of pre-
cooled THF ꢀ25 mL) was made whilst stirring under nitro-
gen. Anhydrous MeCN ꢀdried over P2O5) ꢀ0.5 mL, 0.393 g,
9.5 mmol) was introduced, dropwise, with the help of a
hypodermic syringe through septum cap ꢀAldrich). The
solution was stirred for additional 10 min, and a solution
of 2h ꢀ1.67 g, 9.5 mmol) in THF ꢀ10 mL) was added over
a period of 15 min. The reaction mixture was stirred for an
additional hour at the same low temperature ꢀ2788C),
treated with saturated aqueous solution of ammonium
chloride ꢀ25 mL), and extracted with ethyl acetate
ꢀ2£25 mL). The combined extract was dried ꢀanhydrous
Na2SO4). Solvent was removed under reduced pressure
and the residue was chromatographed using ethyl acetate/
hexane mixtures ꢀ3:7 v/v).
max ꢀCHCl3): 3385, 2255, 1265 cm21. [Found: C, 66.02; H,
9.94; N, 15.35. C10H18N2O requires C, 65.93; H, 9.89; N,
15.38%]. dH ꢀ200 MHz, CDCl3): 1.12 ꢀm, 9H, 3£Me), 1.22
ꢀm, 1H, Cꢀ5)HH), 1.31 ꢀm, 1H, Cꢀ5)HH), 1.65 ꢀbr, 1H, D2O
exchangeable, NH), 1.80 ꢀm, 2H, CHCH2CH2CN), 2.48 ꢀt,
Jˆ7.4 Hz, 2H, CHCH2CH2CN), 3.71 ꢀm, 1H, CH), 4.31ꢀt,
Jˆ5.7 Hz, 1H, CHCH2CH2CN). dC ꢀ50.6 MHz, CDCl3):
12.8, 21.7, 23.3, 30.9, 32.2, 44.9, 48.5, 68.3, 80.7, 119.1.
m/z 182 ꢀM1).
4.2. General procedure for the reaction of oxazinanes 1
or oxazolidines 3 with l-tryptophan esters
Oxazinanes 1 or oxazolidines 3 ꢀ1.0 mmol), appropriate
tryptophan ester 5a±d ꢀ1.0 mmol) and acetic acid ꢀ3 mL)/
TFA ꢀ0.3 mL) in anhydrous acetonitrile ꢀ30 mL) were stir-
red/sonicated at rt or re¯uxed at 808Ctill the reaction
completed ꢀTLC). The reaction was basi®ed with cold
aqueous sodium carbonate ꢀ5% w/v) solution and extracted
with ethyl acetate ꢀ3£50 mL). The extract was washed once
with cold water ꢀ2£50 mL) and dried ꢀanhydrous Na2SO4).
Yield: 54%. Pale yellow oil. nmax ꢀCHCl3): 2260,

7946
K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
Solvent was removed in vacuo and the residue was chroma-
tographed on silica gel ꢀ60±120 mesh) using hexanes, ethyl
acetate or their mixtures as eluents.
4.2.3. trans-Methyl Nb-benzyl-1-74-methoxyphenyl)-
1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxy-
late 76m). Yield: 91%. White solid. Mp 1928C. nmax
ꢀKBr): 3337, 1722cm21. [Found: C, 76.01; H, 6.15; N,
6.62. C27H26N2O3 requires C, 76.05; H, 6.10; N, 6.57%].
dH ꢀ200 MHz, CDCl3): 3.20 ꢀm, 2H, Cꢀ4)H2), 3.61 ꢀs, 3H,
OMe), 3.77 ꢀs, 3H, OMe), 3.85 ꢀs, 2H, CH2Ph), 3.90 ꢀm, 1H,
Cꢀ3)H), 5.40 ꢀs, 1H, Cꢀ1)H), 6.85 ꢀm, 2H, ArH), 7.28 ꢀm,
12H, ArH and D2O exchangeable NH). dC ꢀ50.6 MHz,
CDCl3): 24.3, 51.2, 54.1, 55.1, 56.0, 60.0, 106.3, 110.7,
114.0, 118.1, 119.2, 121.4, 127.0, 128.2, 128.5, 129.9,
134.0, 135.1, 136.4, 139.5, 159.9, 173.5. dC ꢀCDCl3,
DEPT-135): 24.3ꢀ2ve), 51.2, 54.1 ꢀ2ve), 55.1, 56.0, 60.0,
110.7, 114.0, 118.1, 119.2, 121.4, 127.0, 128.2, 128.5,
129.9. m/z 426 ꢀM1).
Using the above procedure the following products were
synthesized.
4.2.1. cis-Methyl 1-7p-methoxyphenyl)-1,2,3,4-tetra-
hydro-9H-pyrido [3,4-b]-indole-3-carboxylate 76a).
Yield: 38%. White solid, mp 2158C. nmax ꢀKBr): 3464,
1736 cm21
. [Found: C, 71.38; H, 5.89; N, 8.42.
C20H20N2O3 requires C, 71.42; H, 5.95; N, 8.33%]. dH
ꢀ200 MHz, CDCl3): 2.01 ꢀbr, 1H, D2O exchangeable, NH),
2.95 ꢀm, 2H, Cꢀ4)H2), 3.79 ꢀs, 6H, 2£OMe), 3.94 ꢀdd,
Jˆ11.0, 4.3 Hz, 1H, Cꢀ3)H), 5.15 ꢀs, 1H, Cꢀ1)H), 7.10
ꢀAA0BB0 system, Jˆ8.5, 8.5 Hz, 4H, ArH), 7.15 ꢀm, 4H,
ArH), 7.76 ꢀbr, 1H, D2O exchangeable, NH). dC ꢀ50.6 MHz,
CDCl3): 25.6, 52.1, 55.3, 56.8, 57.8, 108.6, 110.8, 114.2,
114., 118.1, 119.5, 121.8, 129.7, 132.6, 134.8, 135.9, 159.7,
173.2. m/z 336 ꢀM1). trans-Methyl 1-/p-methoxyphenyl)-
1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxylate
ꢀ6a): Yield: 39%. White solid. Mp 2058C. nmax ꢀKBr):
3380, 1741. [Found: C, 71.42; H, 5.95; N, 8.29.
C20H20N2O3 requires C, 71.42; H, 5.95; N, 8.33%]. dH
ꢀ200 MHz, CDCl3): 1.89 ꢀbr, 1H, D2O exchangeable, NH),
3.14 ꢀABX system, Jˆ15.2, 5.6, 6.8 Hz, 2H, Cꢀ4)H2), 3.71
ꢀs, 3H, OMe), 3.78 ꢀs, 3H, OMe), 3.97 ꢀdd, Jˆ6.8, 5.5 Hz,
1H, Cꢀ3)H), 5.37 ꢀs, 1H, Cꢀ1)H), 6.84 ꢀAA0BB0 system,
Jˆ8.5, 8.5 Hz, 4H, ArH), 7.16 ꢀm, 3H, ArH), 7.52 ꢀm,
1H, ArH), 7.59 ꢀbr, 1H, D2O exchangeable, NH). dC
ꢀ50.6 MHz, CDCl3): 24.5, 52.0, 52.4, 54.2, 55.3, 109.1,
110.8, 114.6, 118.2, 119.4, 121.8, 129.5, 132.1, 151.4,
174.1. m/z 336 ꢀM1).
4.2.4. trans-2-Methylethyl Nb-74-methoxybenzyl)-1-74-
methoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-
indole-3-carboxylate 76r). Yield: 88%. Yellow viscous
oil. nmax ꢀCHCl3): 3400, 1730 cm21. [Found: C, 74.42; H,
6.70; N, 5.73. C30H32N2O4 requires C, 74.38; H, 6.61; N,
5.78%]. dH ꢀ200 MHz, CDCl3): 1.10 ꢀd, Jˆ6.2 Hz, 3H, Me),
1.20 ꢀd, Jˆ6.2 Hz, 3H, Me), 3.13 ꢀm, 2H, Cꢀ4)H2), 3.78 ꢀs,
8H, 2£OMe and CH2Ph), 3.85 ꢀt, Jˆ6.0 Hz, 1H, Cꢀ3)H),
4.98 ꢀheptet, Jˆ6.2 Hz, 1H, CHꢀMe)2), 5.37 ꢀs, 1H, Cꢀ1)H),
6.84 ꢀm, 4H, ArH), 7.12 ꢀm, 6H, ArH), 7.42 ꢀm, 3H, ArH
and D2O exchangeable NH). dC ꢀ50.6 MHz, CDCl3): 21.8,
21.9, 24.3, 53.5, 55.2, 55.9, 60.2, 67.6, 106.4, 110.7, 112.0,
113.7, 114.0, 118.1, 119.2, 121.4, 127.2, 129.7, 129.9,
131.6, 134.3, 135.2, 136.5, 158.7, 159.3, 172.7. m/z 484
ꢀM1).
4.2.5. cis- and trans-Methyl 1-carbethoxymethyl-1,2,3,4-
tetrahydro-9H-pyrido [3,4-b]indole-3-carboxylate 79d).
Yield: 74%. Yellow viscous oil, nmax ꢀCHCl3): 3684,
1740 cm21. [Found: C, 64.58; H, 6.28; N, 8. 87.
C17H20N2O4 requires C, 64.55; H, 6.32; N, 8.86%]. dH
ꢀ200 MHz, CDCl3): 1.28 ꢀm, 6H, CH2Me-cis and trans),
2.09 ꢀbr, 2H, D2O exchangeable, NH-cis and trans), 2.81
ꢀm, 8H, CH2COOEt and Cꢀ4)H2-cis and trans), 3.75 ꢀs, 3H,
OMe-trans), 3.82 ꢀs, 3H, OMe-cis), 3.86 ꢀm, 2H, Cꢀ3)H-cis
and trans), 4.20 ꢀm, 4H, CH2-cis and trans), 4.50 ꢀm, 1H,
Cꢀ1)H-cis), 4.55 ꢀm, 1H, Cꢀ1)H-trans), 7.12 ꢀm, 4H, ArH-
cis and trans), 7.31 ꢀm, 2H, ArH-cis and trans), 7.48 ꢀd,
Jˆ7.2 Hz, 2H, ArH-cis and trans), 8.50 ꢀbr, 1H, D2O
exchangeable, NH-trans), 8.82 ꢀbr, 1H, D2O exchangeable,
NH-cis). dC ꢀ50.6 MHz, CDCl3): 14.0 ꢀcis), 14.2 ꢀtrans),
25.0 ꢀtrans), 25.6 ꢀcis), 40.3 ꢀcis), 40.9 ꢀtrans), 46.7, 49.3,
52.1 ꢀtrans), 52.5, 56.2, 60.9 ꢀtrans), 61.1 ꢀcis), 106.8,
107.9, 110.9, 111.0, 117.9, 119.2, 119.3, 119.5, 121.8,
122.1, 126.6, 126.7, 134.1, 135.6, 135.6, 135.8, 172.7
ꢀcis), 172.9 ꢀtrans), 173.2 ꢀcis), 173.8 ꢀtrans). dC
ꢀ50.6 MHz, CDCl3, DEPT-135): 14.0 ꢀcis), 14.2 ꢀtrans),
25.0 ꢀ2ve) ꢀtrans), 25.6 ꢀ2ve) ꢀcis), 40.3 ꢀ2ve) ꢀcis),
40.9 ꢀ2ve) ꢀtrans), 46.7, 49.3, 52.1 ꢀtrans), 52.5, 56.2,
60.9 ꢀ2ve) ꢀtrans), 61.1 ꢀ2ve) ꢀcis), 110.9, 111.0, 117.9,
119.2, 119.3, 119.5, 121.8, 122.1. m/z 316 ꢀM1).
4.2.2. cis-2-Methylethyl 1-7p-methoxyphenyl)-1,2,3,4-
tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxylate 76g).
Yield: 41%. Yellow viscous oil. nmax ꢀCHCl3): 3310,
1734 cm21
. [Found: C, 72.48; H, 6.59; N, 7.75.
C22H24N2O3 requires C, 72.52; H, 6.59; N, 7.69%]. dH
ꢀ200 MHz, CDCl3): 1.27 ꢀd, Jˆ6.0 Hz, 3H, Me), 1.29 ꢀd,
Jˆ6.0 Hz, 3H, Me), 2.34 ꢀbr, 1H, D2O exchangeable, NH),
2.96 ꢀm, 1H, Cꢀ4)HH), 3.18 ꢀm, 1H, Cꢀ4)HH), 3.75 ꢀs, 3H,
OMe), 3.84 ꢀdd, Jˆ10.9, 4.1 Hz, 1H, Cꢀ3)H), 5.10 ꢀm, 2H,
CHꢀMe)2 and Cꢀ1)H), 7.05 ꢀAA0BB0 system, Jˆ8.4, 8.4 Hz,
4H, ArH), 7.17 ꢀm, 3H, ArH), 7.54 ꢀm, 2H, ArH and D2O
exchangeable NH). dC ꢀ50.6 MHz, CDCl3): 21.8, 25.7, 55.2,
57.1, 57.9, 68.7, 108.8, 110.9, 116.1, 119.4, 121.7, 127.2,
129.8, 132.9, 135.1, 136.2, 159.7, 172.4. m/z 364 ꢀM1).
trans-2-Methylethyl
hydro-9H-pyrido [3,4-b]-indole-3-carboxylate ꢀ6g): Yield:
27%. White Solid. Mp 1858C. nmax ꢀKBr): 3365, 1730 cm21
1-/p-methoxyphenyl)-1,2,3,4-tetra-
.
[Found: C, 72.45; H, 6.65; N, 7.70. C22H24N2O3 requires C,
72.52; H, 6.59; N, 7.69%]. dH ꢀ200 MHz, CDCl3): 1.21 ꢀd,
Jˆ6.2 Hz, 3H, Me), 1.25 ꢀd, Jˆ6.2 Hz, 3H, Me), 1.89 ꢀbr,
1H, D2O exchangeable, NH), 3.18 ꢀABX system, Jˆ15.3,
5.2, 7.2 Hz, 2H, Cꢀ4)H2), 3.78 ꢀs, 3H, OMe), 3.86 ꢀdd,
Jˆ12.3, 5.6 Hz, 1H, Cꢀ3)H), 5.03 ꢀheptet, Jˆ6.2 Hz, 1H,
CHꢀMe)2), 5.35 ꢀs, 1H, Cꢀ1)H), 7.12 ꢀAA0BB0 system,
Jˆ8.5, 8.5 Hz, 4H, ArH), 7.13 ꢀm, 3H, ArH), 7.57 ꢀm,
2H, ArH and D2O exchangeable NH). dC ꢀ50.6 MHz,
CDCl3): 21.7, 24.7, 52.3, 54.3, 55.2, 66.4, 108.4, 110.8,
114.0, 116.1, 119.3, 121.7, 127.7, 129.5, 133.5, 134.5,
136.2, 159.4, 173.1. m/z 364 ꢀM1).
4.2.6. cis- and trans-Methyl 1-cyanomethyl-1,2,3,4-tetra-
hydro-9H-pyrido [3,4-b]indole-3-carboxylate 79e). Yield:
61%. Yellow viscous oil. nmax ꢀCHCl3): 3395, 2170,
1720 cm21
. [Found: C, 66.95; H, 5.58; N, 15.64.
C15H15N3O2 requires C, 66.91; H, 5.57; N, 15.61%]. dH

K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
7947
ꢀ200 MHz, CDCl3): 2.05 ꢀbr, 2H, D2O exchangeable, NH-
cis and trans), 2.76 ꢀm, 8H, CH2CN and Cꢀ4)H2-cis and
trans), 3.75 ꢀs, 3H, OMe-trans), 3.82 ꢀm, 1H, Cꢀ3)H-cis),
3.84 ꢀs, 3H, OMe-cis), 3.97 ꢀdd, Jˆ7.2, 5.2 Hz, 1H, Cꢀ3)H-
trans), 4.61 ꢀbr t, Jˆ6.7 Hz, 1H, Cꢀ1)H-cis), 4.70 ꢀt,
Jˆ6.7 Hz, 1H, Cꢀ1)H-trans), 7.15 ꢀm, 4H, ArH-cis and
trans), 7.36 ꢀd, Jˆ7.5 Hz, 2H, ArH-cis and trans), 7.50 ꢀd,
Jˆ7.5 Hz, 2H, ArH-cis and trans), 8.15 ꢀbr, 1H, D2O
exchangeable, NH-trans), 8.25 ꢀbr, 1H, D2O exchangeable,
NH-cis). dC ꢀ50.6 MHz, CDCl3): 22.8 ꢀcis), 23.8 ꢀtrans),
23.9 ꢀtrans), 24.5 ꢀcis), 46.4, 48.9, 51.1 ꢀcis), 51.2 ꢀtrans),
51.7, 55.2, 106.5 ꢀtrans), 107.6 ꢀcis), 110.4, 117.0, 117.1,
117.6, 118.1, 118.2, 120.8, 125.7, 125.8, 131.3 ꢀtrans),
131.6 ꢀcis), 135.5 ꢀtrans), 135.7 ꢀcis), 172.0 ꢀcis), 173.0
ꢀtrans). m/z 269 ꢀM1).
SCH2CH3), 2.57 ꢀm, 2H, CHCH2CH2S), 3.13 ꢀABX system,
Jˆ15.8, 8.9, 5.3 Hz, 2H, Cꢀ4)H2), 3.70 ꢀABq, Jˆ13.7 Hz,
2H, CH2Ph), 3.77 ꢀs, 3H, OMe), 4.03 ꢀm, 2H, Cꢀ3)H and
Cꢀ1)H), 7.14 ꢀm, 2H, ArH), 7.32 ꢀm, 6H, ArH), 7.55 ꢀm, 1H,
ArH), 7.91 ꢀbr, 1H, D2O exchangeable, NH). dC ꢀ50.6 MHz,
CDCl3): 14.6, 21.1, 25.7, 27.9, 34.2, 51.9, 53.4, 54.7, 56.9,
107.5, 110.8, 118.1, 119.5, 121.7, 121.7, 127.1, 128.2,
128.9, 134.1, 136.1, 139.3. 173.3. m/z 408 ꢀM1).
4.2.10. trans-Methyl 1-7b-cyanoethyl)-Nb-benzyl-1,2,3,4-
tetrahydro-9H-pyrido [3,4-b]indole-3-carboxylate 79k).
Yield: 61%. Yellow viscous oil. nmax ꢀCHCl3): 3360,
2260, 1735 cm21. [Found: C, 74.05; H, 6.21; N, 11.25.
C23H23N3O2 requires C, 73.99; H, 6.16; N, 11.26%]. dH
ꢀ100 MHz, CDCl3): 2.10 ꢀm, 2H, CH2CH2CN), 2.33 ꢀt,
Jˆ7.4 Hz, 2H, CHCH2CH2CN), 3.12 ꢀABX system,
Jˆ16.0, 8.3, 5.8 Hz, 2H, Cꢀ4)H2), 3.63 ꢀm, 2H, CH2Ph),
3.77 ꢀs, 3H, OMe), 3.94 ꢀm, 1H, Cꢀ3)H), 4.05 ꢀdd, Jˆ8.1,
3.7 Hz, 1H, Cꢀ1)H), 7.20 ꢀm, 2H, ArH), 7.31 ꢀm, 6H, ArH),
7.54 ꢀd, Jˆ7.0 Hz, 1H, ArH), 7.86 ꢀbr, 1H, D2O exchange-
able, NH). dH ꢀ50.6 MHz, CDCl3): 13.0, 21.4, 28.6, 51,9,
53.2, 53.6, 56.8, 107.9, 111.0, 118.1, 119.2, 122.0, 127.1,
127.5, 128.4, 132.5, 136.4, 138.6, 173.0. m/z 373 ꢀM1).
4.2.7. cis- and trans-Methyl 1-carbethoxymethyl-Nb-ben-
zyl-1,2,3,4-tetrahydro-9H-pyrido
[3,4-b]indole-3-car-
boxylate 79h). Yield: 86%. Yellow viscous oil. nmax
ꢀCHCl3): 3420, 1715 cm21. [Found: C, 71.01; H, 6.45; N,
6.95. C24H26N2O4 requires C, 70.93; C, 6.40; N, 6.89%]. dH
ꢀ200 MHz, CDCl3): 1.20 ꢀt, Jˆ6.9 Hz, 3H, Me-trans), 1.24
ꢀt, Jˆ6.9 Hz, 3H, Me-cis), 2.98 ꢀm, 8H, CH2COOEt and
Cꢀ4)H2-cis and trans), 3.65 ꢀm, 4H, CH2Ph-cis and trans),
3.74 ꢀs, 3H, OMe-trans), 3.85 ꢀs, 3H, OMe-cis), 3.98 ꢀm,
2H, Cꢀ3)H-cis and trans), 4.08 ꢀq, Jˆ6.9 Hz, 4H, CH2-cis
and trans), 4.34 ꢀdd, Jˆ10.0, 3.8 Hz, 1H, Cꢀ1)H-trans), 4.49
ꢀm, 1H, Cꢀ1)H-cis), 7.15 ꢀm, 4H, ArH-cis and trans), 7.34
ꢀm, 12H, ArH-cis and trans), 7.54 ꢀm, 2H, ArH-cis and
trans), 8.63 ꢀbr, 1H, D2O exchangeable, NH-trans), 8.81
ꢀbr, 1H, D2O exchangeable, NH-cis). dC ꢀ50.6 MHz,
CDCl3): 13.8 ꢀtrans), 13.9 ꢀcis), 21.0 ꢀtrans), 21.3 ꢀcis),
38.1 ꢀcis), 40.6 ꢀtrans), 51.5 ꢀtrans), 51.7 ꢀtrans), 52.3
ꢀtrans), 52.7 ꢀcis), 53.6 ꢀtrans), 54.2 ꢀcis), 56.9 ꢀtrans),
57.2 ꢀtrans), 57.2 ꢀtrans), 57.4 ꢀtrans), 60.7 ꢀtrans), 105.6
ꢀcis), 106.6 ꢀtrans), 110.9 ꢀtrans), 117.9 ꢀtrans), 119.0 ꢀcis),
119.1 ꢀtrans), 121.5 ꢀcis), 121.6 ꢀtrans), 126.5 ꢀtrans), 126.9
ꢀtrans), 127.1 ꢀcis), 128.1 ꢀtrans), 128.4 ꢀtrans), 133.7
ꢀtrans), 135.7 ꢀtrans), 135.8 ꢀcis), 138.7 ꢀcis), 139.1
ꢀtrans), 172.8 ꢀtrans), 172.9 ꢀtrans), 174.1 ꢀcis), 174.2
ꢀcis). m/z 406 ꢀM1).
4.2.11. trans-Methyl 1-cyanomethyl-Nb-benzyl-1,2,3,4-
tetrahydro-9H-pyrido [3,4-b]indole-3-carboxylate 79l).
Yield: 61%. Colorless needles, mp 2058C. nmax ꢀKBr):
3325, 2270, 1740 cm21. [Found: C, 73.55; H, 5.90; N,
11.73. C22H21N3O2 requires C, 73.53; H, 5.84; N,
11.69%]. dH ꢀ200 MHz, CDCl3): 2.87 ꢀABX system,
Jˆ16.6, 4.9, 7.8 Hz, 2H, CH2CN), 3.14 ꢀABX system,
Jˆ15.9, 6.4, 5.6 Hz, 2H, Cꢀ4)H2), 3.69 ꢀs, 3H, OMe), 3.85
ꢀABq, Jˆ14.4 Hz, 2H, CH2Ph), 3.95 ꢀm, 1H, Cꢀ3)H), 4.44
ꢀdd, Jˆ7.5, 5.1 Hz, 1H, Cꢀ1)H), 7.19 ꢀm, 2H, ArH), 7.38 ꢀm,
6H, ArH), 7.53 ꢀd, Jˆ7.7 Hz, 1H, ArH), 8.05 ꢀbr, 1H, D2O
exchangeable, NH). dC ꢀ50.6 MHz, CDCl3): 22.3, 24.2,
51.9, 53.2, 54.4, 57.4, 108.5, 111.2, 118.0, 118.4, 119.8,
122.6, 126.4, 127.5, 128.3, 128.6, 131.2, 136.5, 138.4,
172.7. m/z 360 ꢀM111), 319 ꢀM12CH2CN). cis-Methyl
1-cyanomethyl-N-benzyl-1,2,3,4-tetrahydro-9H-pyrido [3,4-
b]indole-3-carboxylate ꢀ9l): Yield: 9%. Colorless ¯akes,
mp 157±588C. nmax ꢀKBr): 3312, 2270, 1738 cm21
.
4.2.8. trans-Methyl 1-7b-mercaptophenyl)ethyl-Nb-ben-
[3,4-b]indole-3-car-
[Found: C, 73.55; H, 5.85; N, 11.72. C22H21N3O2 requires
C, 73.53; H, 5.84; N, 11.69%]. dH ꢀ200 MHz, CDCl3): 3.00
ꢀABX system, Jˆ16.7, 9.8, 4.1 Hz, 2H, CH2CN), 3.15
ꢀABX system, Jˆ17.7, 2.0, 2.0 Hz, 2H, Cꢀ4)H2), 3.65 ꢀs,
3H, OMe), 3.95 ꢀdd, Jˆ6.8, 2.0 Hz, 1H, Cꢀ3)H), 4.17 ꢀs, 2H,
CH2Ph), 4.50 ꢀm, 1H, Cꢀ1)H), 7.15 ꢀm, 2H, ArH), 7.38 ꢀm,
6H, ArH), 7.54 ꢀd, Jˆ7.3 Hz, 1H ArH), 8.28 ꢀbr, 1H, D2O
exchangeable, NH). dC ꢀ50.6 MHz, CDCl3): 21.8, 22.4,
51.9, 53.4, 57.2, 58.1, 107.2, 111.2, 118.4, 119.8, 120.0,
122.6, 126.2, 127.7, 128.4, 128.7, 131.6, 136.3, 137.8,
173.3. m/z 359 ꢀM1).
zyl-1,2,3,4-tetrahydro-9H-pyrido
boxylate 79i). Yield: 72%. White solid, mp 988C. nmax
ꢀKBr): 3405, 1720 cm21. [Found: C, 73.72; H, 6.15; N,
6.20. C28H28N2O2S requires C, 73.68; N, 6.14; N, 6.14%].
dH ꢀ200 MHz, CDCl3): 1.98 ꢀm, 2H, CHCH2CH2S), 2.94
ꢀm, 4H, CHCH2CH2S and Cꢀ4)H2), 3.64 ꢀm, 2H, CH2Ph),
3.74 ꢀs, 3H, OMe), 4.00 ꢀm, 2H, Cꢀ3)H and Cꢀ1)H), 7.36 ꢀm,
13H, ArH), 7.54 ꢀm, 1H, ArH), 7.68 ꢀbr, 1H, D2O exchange-
able, NH). dC ꢀ50.6 MHz, CDCl3): 21.1, 29.3, 33.6, 51.8,
53.4, 54.6, 56.8, 110.8, 118.1, 119.5, 121.8, 125.7, 126.9,
127.2, 128.3, 128.8, 128.9, 129.0, 133.7, 136.1, 139.1,
173.3. m/z 456 ꢀM1).
Crystal data for trans and cis 9l: Single crystal diffraction
measurement of crystals of trans and cis 9l were carried out
in a Siemens P4 single crystal diffractometer equipped with
4.2.9. trans-Methyl 1-7b-mercaptoethyl)ethyl-Nb-benzyl-
1,2,3,4-tetrahydro-9H-pyrido
Ê
[3,4-b]indole-3-car-
molybdenum sealed tube ꢀlˆ0.71073 A) and highly
boxylate 79j). Yield: 78%. White solid, mp 858C. nmax
ꢀKBr): 3365, 1742 cm21. [Found: C, 70.63; H, 6.90; N,
6.85. C24H28N2O2S requires C, 70.58; H, 6.86; N 6.86%].
dH ꢀ200 MHz, CDCl3): 1.16 ꢀt, Jˆ7.3 Hz, 3H, SCH2Me),
1.98 ꢀm, 2H, CHCH2CH2S±), 2.40 ꢀq, Jˆ7.3 Hz, 2H,
oriented graphite monochromator.
Data for trans 9l. C22H21N3O2, Mˆ359.42, crystal in ortho-
rhombic space group P212121, Zˆ4, aˆ9.386ꢀ1), bˆ9.974ꢀ1),
Ê 3
Ê 3
cˆ20.191ꢀ2) A ,
Vˆ1890.2ꢀ3) A ,
Dcˆ1.263 Mg m23,

7948
K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
mˆ0.083 mm21, Fꢀ000)ˆ760. A total of 1815 re¯ections
were measured and the structure was solved by direct methods
and re®ned on F2 using SHELX9749 software. Final
wR2ˆ0.0910, with a conventional R1ˆ0.0368 [1536 re¯ec-
tions with I . 2sꢀI†] and a goodness of ®tˆ1.041 for 245
re®ned parameters.
ArH), 8.24 ꢀbr, 1H, D2O exchangeable, NH). dC
ꢀ50.6 MHz, CDCl3): 14.0, 24.1, 48.1, 52.3, 60.9, 67.4,
97.5, 109.1, 111.5, 117.8, 119.3, 121.9, 123.7, 126.6,
127.0, 127.2, 127.6, 127.8, 128.5, 134.7, 136.2, 151.5,
168.6, 170.6, 189.5. m/z 389 ꢀM12COOMe), 361
ꢀ±CH2COOEt).
4.2.15. trans-Methyl 1-73-ethoxycarbonyl-2-oxo)propyl-
Nb-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
79n). 9n was synthesized from 10b following a procedure
similar to the cyclization of 9m employing anhydrous
MeOH as solvent. Yield: 54%. Yellow viscous oil. nmax
ꢀCHCl3): 3405, 1740, 1710 cm21. [Found: C, 69.65; H,
6.23; H, 6.25. C26H28N2O5 requires C, 69.64; H, 6.25; N,
6.25%]. dH ꢀ200 MHz, CDCl3): 1.98 ꢀt, Jˆ7.3 Hz, 3H, Me),
3.16 ꢀm, 4H, CH2 and Cꢀ4)H2), 3.39 ꢀs, 2H, COCH2COO),
3.76 ꢀs, 3H, OMe), 3.81 ꢀm, 2H CH2Ph), 3.98 ꢀm, 1H,
Cꢀ3)H), 4.12 ꢀq, Jˆ7.3 Hz, 2H, CH2Me), 4.35 ꢀm, 1H,
Cꢀ1)H), 7.25 ꢀm, 8H, ArH), 7.53 ꢀd, Jˆ7.8 Hz, 1H,
ArH), 8.40 ꢀbr, 1H, D2O exchangeable, NH). dC
ꢀ50.6 MHz, CDCl3): 14.0, 20.9, 49.5, 49.8, 51.7, 52.0,
53.5, 57.8, 61.5, 106.9, 111.1, 118.1, 119.4, 21.9, 127.2,
128.4, 128.6, 133.0, 136.0, 139.0, 166.7, 173.0, 203.4. m/z
448 ꢀM1).
Data for cis 9l. C22H21N3O2, Mˆ359.42, crystal in ortho-
rhombic space group P212121, Zˆ4, aˆ8.250ꢀ1), bˆ
Ê 3
Ê 3
10.658ꢀ1), cˆ21.457ꢀ2) A , Vˆ1886.7ꢀ3) A , Dcˆ
1.265 Mg m23, mˆ0.083 mm21, Fꢀ000)ˆ760. A total of
1730 re¯ections were measured, and the structure was
solved by direct methods and re®ned on F2 using
SHELX9749 software. Final wR2ˆ0.1042, with a conven-
tional R1ˆ0.0399 [1449 re¯ections with I . 2sꢀI†] and a
goodness of ®tˆ1.046 for 245 re®ned parameters.
4.2.12. Methyl Nb-benzyl-Nb-72-benzoylethylene)-l-tryp-
tophanate 710a). Yield: 60%. Viscous oil. nmax ꢀCHCl3):
3450, 1740, 1680 cm21. [Found: C, 76.72; H, 5.95; N, 6.36.
C28H26N2O3 requires C, 76.71; H, 5.93; N, 6.39%]. dH
ꢀ200 MHz, CDCl3): 3.42 ꢀABX system, Jˆ15.0, 8.8,
6.6 Hz, 2H, Cꢀ4)H2), 3.62 ꢀs, 3H, OMe), 4.40 ꢀbr, 3H,
Cꢀ3)H and CH2Ph), 5.93 ꢀd, Jˆ12.6 Hz, 1H,
NCHvCHCO), 6.96 ꢀbr, 1H, indolyl Cꢀ2)H), 7.21 ꢀm,
12H, ArH), 7.77 ꢀd, Jˆ6.9 Hz, 2H, ArH), 8.20 ꢀbr d,
Jˆ12.6 Hz, NCHvCHCO), 8.32 ꢀbr, 1H, D2O exchange-
able, NH). dC ꢀ50.6 MHz, CDCl3): 29.7, 52.4, 54.3, 64.5,
95.1, 109.7, 111.5, 118.1, 119.6, 122.1, 123.6, 126.9, 127.5,
127.6, 128.2, 128.6, 131.6, 131.6, 135.2, 136.3, 140.0,
152.1, 170.8, 189.4. m/z 438 ꢀM1).
References
1. ꢀa) Svoboda, G. H. In Pharmacognosy and Phytochemistry;
Wagner, H., Horhammer, L., Eds.; Springer: New York,
1971; p 166. ꢀb) Farnsworth, N. R. Lloydia 1961, 24, 105.
ꢀc) Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett,
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4.2.13. trans-Methyl 1-benzoylmethyl-Nb-benzyl-1,2,3,4-
tetrahydro-9H-pyrido [3,4-b]indole-3-carboxylate 79m).
10a ꢀ10 mmol) was dissolved in anhydrous benzene
ꢀ10 mL) and saturated with dry hydrogen chloride at 08C.
The reaction was stirred at ambient temperature to comple-
tion ꢀ10 min), basi®ed ꢀaq. NaHCO3) and extracted with
dichloromethane ꢀ2£50 mL). After drying ꢀanhydrous
Na2SO4) and evaporation the residue was chromatographed
to obtain 9m. Yield: 54%; viscous yellow oil. nmax ꢀCHCl3):
3470, 1725, 1690 cm21. [Found: C, 76.75; H, 5.98; N,
6.42. C28H26N2O3 requires C, 76.71; H, 5.93; N, 6.39%].
dH ꢀ200 MHz, CDCl3): 3.16 ꢀm, 2H, Cꢀ4)H2), 3.68 ꢀm,
2H, CH2COC6H5), 3.80 ꢀs, 3H, OMe), 3.89 ꢀm, 2H,
CH2Ph), 4.12 ꢀdd, Jˆ9.6, 5.09 Hz, 1H, Cꢀ3)H), 4.53
ꢀdd, Jˆ9.7, 2.6 Hz, 1H, Cꢀ1)H), 7.30 ꢀm, 13H, ArH),
7.92 ꢀd, Jˆ7.1 Hz, 1H, ArH), 8.72 ꢀbr, 1H, D2O exchange-
able, NH). dC ꢀ50.6 MHz, CDCl3): 22.3, 46.3, 51.7,
52.0, 53.5, 58.2, 111.0, 118.0, 119.2, 121.7, 127.1, 128.0,
128.3, 128.6, 129.2, 133.6, 134.8, 172.7, 196.2. m/z 438
ꢀM1).
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K. M.; Deng, L.; Bennett, D. W.; Cook, J. M.; Watson, W. H.;
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4.2.14. Methyl 72S)-3-73-indolyl)-27[1-74-ethoxycarbonyl-
3-oxo-1-butene)]-2-benzyl)
aminopropanoate
710b).
Yield: 60%. Yellow viscous oil. nmax ꢀCHCl3): 3459,
1720, 1660 cm21. [Found: C, 60.69; H, 6.31; N, 6.21.
C26H28N2O5 requires C, 69.64; H, 6.25; N, 6.25%]. dH
ꢀ200 MHz, CDCl3): 1.18 ꢀt, Jˆ7.0 Hz, 3H, Me), 3.40 ꢀm,
4H, Cꢀ4)H2 and COCH2COO), 3.60 ꢀs, 3H, OMe), 4.00±
4.24 ꢀm, 5H, CH2Me, CH2Ph and Cꢀ3)H), 5.25 ꢀd,
Jˆ12.9 Hz, 1H, NCHvCHCO), 7.13 ꢀm, 10H,
NHCHvCHCO, indolyl Cꢀ2)H and ArH), 7.33 ꢀm, 1H,
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1 1993, 431.

K. Singh et al. / Tetrahedron 57 /2001) 7939±7949
7949
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are consistently up®eld than the corresponding cis isomer.34
This has been explained on the basis of the compression effect
arising out of 1,3-diaxial interactions.35 This concept has
been extensively used for assignment of cis/trans stereo-
chemistry.36
12. Mohan, R.; Chou, Y.; Morrisseg, M. M. Tetrahedron Lett.
1996, 37, 3963.
13. ꢀa) Vercauteren, J.; Lavand, C.; Levy, J.; Massiot, G. J. Org.
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