2-(Arylsulfinylmethyl)oxazinanes: Chiral carbonyl equivalents. Application to the asymmetric synthesis of 1,2,3,4-tetrahydro-β-carbolines

Article abstract of DOI:10.1016/j.tet.2004.07.062

2-(p-Tolylsulfinylmethyl)oxazinane, a chiral carbonyl equivalent, has been synthesised and used for the diastereoselective synthesis of tetrahydro-β-carbolines including intermediates of yohimbine and herman alkaloids. A fair degree of diastereoselectivit

Full text of DOI:10.1016/j.tet.2004.07.062

Tetrahedron 60 (2004) 9171–9177
2-(Arylsulfinylmethyl)oxazinanes: chiral carbonyl equivalents.
Application to the asymmetric synthesis of
1,2,3,4-tetrahydro-b-carbolines
a
b
Kamaljit Singh,a, Sonia Behal and Prasant K. Deb
*
aDepartment of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143 005, India
bDepartment of Chemistry, Furman University, Greenville, SC 29613, USA
Received 12 May 2004; revised 30 June 2004; accepted 23 July 2004
Available online 25 August 2004
Abstract—2-(p-Tolylsulfinylmethyl)oxazinane, a chiral carbonyl equivalent, has been synthesised and used for the diastereoselective
synthesis of tetrahydro-b-carbolines including intermediates of yohimbine and herman alkaloids. A fair degree of diastereoselectivity,
comparable with other approaches, has been achieved.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
through a tandem Michael addition/acid induced cyclisation
reaction sequence has also been reported.8 Chiral vinyl
sulfoxides have been implemented,9 via an intramolecular
asymmetric conjugate addition of a nitrogen nucleophile to
synthesise alkaloid systems. Since not many sulfoxide
derivatives of the latter type are available, their use in
asymmetric synthesis of THBCs and THIQs has been
limited.
The tetrahydroisoquinoline (THIQ) and tetrahydro-b-carbo-
line (THBC) cores are structural motifs common to a
diverse family of natural products, which display a variety
of biological activities.1 Most THBC and THIQ derivatives
are optically active and have marked physiological
activities2 which are invariably different from those of
their antipodes. The development of methods for enantio-
selective or diastereoselective synthesis of optically active
1-substituted THBCs is an important area in synthetic
organic chemistry. The Pictet–Spengler reaction,3 employ-
ing reaction of the biogenic amines with carbonyl
substrates, is certainly one of the most powerful methods
for the direct synthesis of THBC and THIQ derivatives.4
Many other traditional synthetic methods are based on
procedures that employ a stoichiometric amount of chiral
building blocks, auxiliaries or reagents, catalytic asym-
metric syntheses, catalytic asymmetric hydrogenation etc.5
The chiral formamidine approach developed by Meyers
et al.6 has been extensively employed in the synthesis of
both THBC and THIQ systems with high enantioselectivity.
The use of a stereogenic sulfur centre of a chiral sulfoxide to
achieve stereocontrol in asymmetric syntheses has been
amply demonstrated.7 Use of chiral acetylenic sulfoxides in
the enantioselective synthesis of THBC and THIQ alkaloids
Using an unconventional approach we have been engaged in
designing and mimicking10 the reactivity pattern of a folate
cofactor and investigating its use in the development of
various types of synthetic strategies. Recently we reported11
that simple and C-2 functionalised oxazinanes embodying a
masked carbonyl substrate can be convincingly employed to
synthesise otherwise inaccessible THBCs in a highly
distereoselective manner and have thus been regarded as
carbonyl equivalents. This has successfully addressed the
problems associated with the direct use of carbonyl
substrates (especially aliphatic carbonyls), in the diversifi-
cation at the C-1 of THBCs, an attribute of potential utility
in the total synthesis of indole alkaloids. These findings
gave us additional impetus in developing optically active
oxazinanes (chiral carbonyl equivalents)12 with a possibility
of further C-2 (at the oxidation level of the carbonyl)
elaboration for exploration in asymmetric synthesis of
THBCs and related systems. We now present a full account
of our investigations on the synthesis of a new, stereo-
chemically homogenous chiral oxazinane and its use as a
two carbon synthon for enantio- and diastereoselective
Keywords: 2-(p-Tolylsulfinylmethyl)oxazinane; Carbonyl equivalents;
Oxazinanes; Yohimbine alkaloids; Diastereoselective synthesis.
* Corresponding author. Tel.: C91-183-2258853; fax: C91-183-2258819;
e-mail: kamaljit19in@yahoo.co.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.062

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K. Singh et al. / Tetrahedron 60 (2004) 9171–9177
synthesis of THBCs, which can be converted into
yohimbine and herman alkaloids.
and carbon–carbon bond formations in a one-pot reaction
and creates a new chiral centre at C-1 of the alkaloid system.
Similarly, secondary amine 5b, which was prepared from
tryptamine through reductive amination with p-methoxy
benzaldehyde, reacts with 3 in MeCN/AcOH (10:1) at reflux
temperature, yielding a mixture of two products, isolated by
flash chromatography. The higher Rf component was minor
and the lower one was the major component. These were
assigned as 7b and 8b, respectively in 80% overall isolated
yield and in a 30:70 (1R/1S) diastereomeric ratio. The NMR
spectra and optical rotations were compared with the
corresponding authentic data17 and were thus assigned the
appropriate absolute configuration at C-1. The THBC 7b has
also been converted into the homochiral pentacyclic
intermediate 11, which is a known precursor18 of the
pentacyclic yohimbine alkaloids (yohimbinol and cory-
nantheine). Yohimbine alkaloids have a range of interesting
biological properties and are used clinically in conventional
medicines and folklore treatments. One interesting outcome
of this methodology is reversal of the stereochemical bias in
comparison with the chiral acetylenic approach. Switching
from the chiral acetylenic sulfoxides to the oxazinane 3, the
stereochemical outcome of the reaction alters from 7a/8a
(30:70) and 7b/8b (70:30) in the former method to 7a/8a
(70:30) and 7b/8b (30:70) in the present approach.
2. Results and discussion
2.1. Synthesis of chiral carbonyl equivalent
The reaction of C-2 metallated (n-BuLi/THF) 2,4,4,6-
tetramethyl-5,6-dihydro-(4H)-1,3-oxazine 113,14with (K)-
(S)-menthyl p-toluenesulfinate15 at K78 8C (Scheme 1)
afforded 2-arylsulfinylmethyl oxazine 2 as a mixture of its
diastereomers16 in 85% overall yield, after crystallisation
from hot hexane. On the basis of the fact that such Anderson
type reactions proceed with inversion17 of configuration at
the sulfinyl sulfur atom, the absolute configuration (R) can
be assigned at the sulfinyl sulfur of compound 2. The
assignments of all the protons have been made on the basis
of NOE connectivity while the carbons have been
distinguished by the HMQC spectrum. To further widen
the synthetic scope, 2 was metallated and quenched with
MeI to obtain further elaborated oxazine 4 which after
reduction could be used to obtain C-1 elaborated THBCs.
2.2. Synthesis of THBCs
Acid catalysed reactions of 3 were performed with
tryptamine and tryptophan derivatives 5a–d to obtain
THBCs which could be converted into the alkaloidal targets
(Scheme 2). The chemical yields and the extent of
stereoselectivity was comparable with the known
syntheses.8
Desulfurisation of the major component 8b was conducted
using Raney Ni and proceeded quantitatively to yield 10b.
The optical rotation of this enantiomer was found to be
[a]2D1ZC25.0 (c 0.126, CH2Cl2). On the basis of the correct
spectral data and the fact that the starting 8b is the 1S
isomer, it can be assigned 1R configuration at C-1.
Likewise, the minor component, 7b, was also desulfurised
under similar conditions and the product 9b was assigned 1S
configuration at C-1 {[a]2D1ZK24.0 (c 0.126, CH2Cl2)}.
If a stoichiometric mixture of tryptamine 5a and 3 in
anhydrous MeCN/AcOH (10:1) solution is combined at
ambient temperature, the following sequence takes place:
formation of iminium intermediate 6 (tautomeric equili-
brated, hydrogen bonded), spontaneous in situ conversion
into a spiroindolenine19 through acid induced intramolecu-
lar electrophilic attack of the iminium carbon at C-2 or at
C-3 of the indole moiety and subsequent rearrangement-
deprotonation. This furnishes THBCs 7a and 8a in a 70:30
(1R/1S) diastereomeric ratio (1H NMR spectroscopy
correlation),20 out of which 7a could be isolated in 40%
yield. This sequence establishes the crucial carbon–nitrogen
Similar reactions of a stoichiometric mixture of (L)-
tryptophan methyl ester 5c with 3 in anhydrous MeCN/
AcOH (10:1) at ambient temperature furnished a mixture of
THBCs, 7c and 8c (cis/trans: 33:66) in 76% isolated yield.
trans-selectivity was favoured when the reaction was run at
low temperature. The cis and trans isomers were distin-
guished as reported from the 13C chemical shifts of the C-1
(cis: downfield, trans: upfield)21 and also from the benzylic
Scheme 1. (a) n-BuLi, K78 8C, THF. (b) NaBH4, THF/EtOH (1:1), K45 8C. (c) NaH, MeI, THF, 0 8C.

K. Singh et al. / Tetrahedron 60 (2004) 9171–9177
9173
Scheme 2. (a) CH3CN/AcOH (10:1). (b) Raney Ni, MeOH, 0 8C.
carbons (trans: upfield, cis: downfield),19 which are easily
distinguishable from rest of the signals (ca. 70 ppm). Also,
both 7c and 8c were desulfurised using Raney Ni at 0 8C in
methanol to obtain the corresponding known compounds22
9c and 10c, to further correlate the cis and trans
stereochemistry. Likewise, reaction of tryptophan isopropyl
ester 5d with 3 under a similar set of conditions, yielded the
THBCs 7d and 8d cis/trans diastereomers in 78% yield and
similar diastereomeric ratio (Table 1). 7d and 8d were also
desulfurised to obtain 9d and 10d to correlate the
stereochemistry.
diastereoselective synthesis of tetrahydro-b-carbolines
including an intermediate of yohimbine alkaloids. The
transformations depicted in Scheme 2 showed a fair degree
of diastereoselectivity comparable with the reported
methods,8 when the chiral oxazinanes are employed as
inductors. Also, precursors for the synthesis of optically
pure eleagnine, a herman alkaloid have been synthesised. In
addition, this strategy has scope for asymmetric synthesis of
many more C-1 substituted THBCs and related compounds.
4. Experimental
4.1. General
In view of the facile debenzylation22 of 10b and 9b, and
facile removal of the C-3 ester functions in 9d and 10d
following the method of Yamada,23 the above protocol
constitutes a formal synthesis of optically pure eleagnine,20
a herman alkaloid of known absolute configuration.
All melting points are uncorrected. IR sectra were recorded
on Shimadzu DR-8001 FT and Pye Unicam SP 3-300
spectrophotometer. 1H (200 MHz) and 13C (50 MHz) NMR
spectra were run on Bruker AC 200 instrument using TMS
as the internal standard. Mass (70 eV) spectra were
performed on Shimadzu GCMS QP 2000 spectrometer.
Elemental analyses of the samples were performed on and
Perkin–Elmer 2400 CHN elemental analyser, respectively.
3. Conclusions
2-(p-Tolylsulfinylmethyl)oxazinane, a chiral carbonyl
equivalent, has been synthesised and used for the
Table 1. Diastereocontrol in the reactions of 2 with tryptamine derivatives
Sr. no.
THBCs (7/8)
Reaction temperature
Diastereomeric ratioa
of THBCs (7:8)
Reaction time (h)
Isolable yield (%)
1
2
3
4
R1ZR2ZH
rt
2.33:1 (1R:1S)b
Decomposition
Very slow reaction
1:2.33 (1R:1S)b
1:2 (c/t)a
12
—
—
24
30
10
36
12
40 (1R)
—
—
80
72
78
70
75
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
R1ZH
R2ZCH2C6H5(OCH3)p
R1ZCOOCH3 R2ZH
1:1.2 (c/t)a
R1ZCOOCH(CH3)2
R2ZH
1:2 (c/t)c
1:1.2 (c/t)c
a
1
G3% as determined from the integration of the C-3 ester signals in the H NMR spectrum.
Compared with the reported data.12
Identified from the chemical shift of C-1 H signals.
b
c

9174
K. Singh et al. / Tetrahedron 60 (2004) 9171–9177
TLC was performed on aluminium sheets coated with Silica
gel 60 F254 (Merck). Optical rotations were measured using
a Jasco DIP-360 digital polarimeter. All solvents MeCN
(P2O5), THF (Na-benzophenone ketyl), hexane (sodium)
and ethyl acetate (anhydrous K2CO3) were dried and
distilled before use. Column chromatography was per-
formed on silica gel (60–120 mesh).
(arylsulfinylmethyl)-4,4,6-trimethyltetrahydro-(2H)-1,3-
oxazine (3). A solution of 2-(arylsulfinylmethyl)-4,4,6-
trimethyl-5,6-dihydro-(4H)-1,3-oxazine (5 g, 0.017 mol) in
a mixture of ethyl alcohol (95%) and THF (1:1 v/v, 60 mL)
was taken in a round bottom flask (100 mL) and cooled to
K45 8C. Hydrochloric acid (9 N) was added to this
magnetically stirred solution until pH 7 was obtained.
Sodium borohydride solution was prepared separately by
dissolving sodium borohydride (0.681 g, 0.017 mol) in a
minimum amount of water (1–2 mL) containing a drop of
aqueous sodium hydroxide (40%) solution. The sodium
borohydride solution and the 9 N hydrochloric solution
were introduced to the stirred solution of dihydrooxazine
alternatively, so that pH 7–8 was maintained throughout the
course of reaction. After the addition of the borohydride
solution was complete, the solution was stirred at the same
low temperature (K45 8C) for an additional 1 h. During this
period, pH 7 was maintained by the occasional addition of
9 N hydrochloric acid. The contents were then poured into
water (approx. 50 mL) and made basic by the addition of
aqueous sodium hydroxide solution (40%) (care was taken
not to raise the temperature above 10 8C during this
addition). Oil globules/turbidity appeared upon basification
and the solution was extracted with ethyl acetate (2!
30 mL). The combined organic extracts were washed with
saturated sodium chloride solution (50 mL) and dried over
anhydrous potassium carbonate. The solvent was removed
in vacuo to obtain the crude tetrahydrooxazine, which was
purified using column chromatography employing a mixture
of hexane and ethyl acetate (1:1, v/v) as the eluent.
L-Tryptophan methyl/isopropyl esters and 4-methoxy-ben-
zyl tryptamine were prepared following the reported/
modified procedures.22 p-Toluene sulfinic acid, sodium
salt hydrate (97%) and (1R,2S, 5R)-(K)-menthol were
purchased from Aldrich. (K)-(S)-Menthyl (p-tolunesulfi-
nate) was synthesised following the reported procedure.15
4.1.1. Formation of 2-(arylsulfinylmethyl)-4,4,6-tri-
methyl-5,6-dihydro-(4H)-1,3-oxazine (2). A two necked
round bottom flask (250 mL) equipped with a magnetic
stirring bar, and pressure equalising additional funnel
(75 mL) topped with rubber septum and a nitrogen inlet
tube was evacuated and flushed with nitrogen, at least thrice
in succession. Anhydrous THF (100 mL) and 2,4,4,6-
tetramethyl-5,6-dihydro-(4H)-1,3-oxazine (14.1 g, 0.1 mol)
was added using a hypodermic syringe through the rubber
septum. The stirred solution was cooled (K78 8C) and
n-BuLi in hexane (50 mL, 2.2 N) was injected into the
addition funnel and added dropwise over a period of 1 h into
the flask. After approximately 1 h, and after the addition of
n-BuLi, a yellow precipitate was formed (indicative of the
complete anion formation) and a solution of (K)-(S)-
menthyl p-toluenesulfinate (14.7 g, 0.05 mol) in dry THF
(60 mL) was injected into the addition funnel and slowly
added to the reaction mixture over 1 h. After this addition,
the reaction mixture was stirred at the same low temperature
(K78 8C) for 1.5 h. The reaction was then quenched with
saturated ammonium chloride solution (50 mL) and the
organic phase separated. The aqueous phase was extracted
withethyl acetate (2!50 mL). The combinedorganic extracts
were dried (anhydrous Na2SO4) and evaporated in vacuo. The
oily residue was dissolved in hot hexane and was allowed to
crystallise at K5 8C. After the first crop, the mother liquor was
concentrated and allowed once again to crystallise at K5 8C.
This operation was repeated three times, and finally the
product was crystallised once from hot hexane.
Yield: quantitative; colourless oil at rt; nmax (CHCl3) 3390
(N–H), 1230 (C–O), 1045 (S]O) cmK1. dH (200 MHz
CDCl3)† 1.10 (3H, s, Me), 1.43 (3H, s, Me), 1.20 (1H, m,
C(5)HH), 1.40 (1H, dd, JZ6.0, 2.2 Hz, C(5)HH), 1.47 (1H,
dd, JZ6.0, 2.2 Hz, C(5)HH), 2.40 (3H, s, Me), 2.75 (1H, dd,
JZ8.4, 6.1 Hz, CHHSO), 2.81 (1H, dd, JZ8.4, 6.1 Hz,
CHHSO), 3.09 (1H, t, JZ13.2 Hz, CHHSO), 3.11 (1H, t,
JZ13.2 Hz, CHHSO), 3.85 (1H, m, C(6)H), 4.62 (1H, dd,
JZ6.1, 3.8 Hz, C(2)H), 4.66 (1H, dd, JZ6.1, 3.8 Hz,
C(2)H), 7.42 (4H, d, JZ8.1 Hz, Ph), 7.43 (4H, d, JZ8.1 Hz,
Ph); dC (50 MHz CDCl3)† 21.4, 22.1, 23.3, 23.7, 32.6, 45.0,
45.3, 49.2, 49.5, 62.2, 63.3, 69.2, 69.3, 78.3, 79.4, 124.3,
129.9, 141.0, 141.5. dC (50 MHz CDCl3, DEPT-135) 21.4,
22.1, 23.3, 23.7, 32.6, 45.0 (Kve), 45.3 (Kve), 49.2, 49.5,
62.2 (Kve), 63.3 (Kve), 69.2, 69.3, 78.3, 79.4, 124.3,
129.9. m/z 281 (MC); [Found: C, 63.99; H, 8.20; N, 4.95.
C15H23NO2S requires C, 64.05; H, 8.18; N, 4.98].
Yield: 84%; white amorphous solid, mp 54 8C; nmax (KBr)
1597 (C]N), 1218 (C–O), 1041 (S]O) cmK1. dH
(200 MHz CDCl3)† 1.03 (3H, s, Me), 1.06 (3H, s, Me),
1.10 (3H, s, Me), 1.13 (3H, s, Me), 1.17 (3H, d, JZ6.1 Hz,
Me), 1.23 (3H, d, JZ6.1 Hz, CH2), 1.40 (1H, m, C(5)HH),
1.65 (1H, m, C(5)HH), 2.40 (3H, s, Me), 3.43 (1H, distorted
d, JZ12.7 Hz, –CHHSO), 3.60 (2H, m, CH2SO), 3.83 (1H,
distorted d, JZ12.7 Hz, CHHSO), 4.06 (1H, m, C(6)H),
7.29 (4H, d, JZ8.0 Hz, Ph), 7.57 (4H, d, JZ8.0 Hz, Ph); dC
(50 MHz CDCl3)†: d 21.0, 21.3, 29.2, 29.4, 31.2, 41.3, 41.5,
50.4, 62.4, 62.7, 68.6, 124.7, 129.6, 139.2, 139.3, 141.9,
152.0. m/z 279 (MC); [Found: C, 64.54; H, 7.58; N 4.98.
C15H21NO2S requires C, 64.51; H, 7.52; N, 5.01].
4.1.3. Synthesis of oxazine 4. Dry THF (25 mL) was
distilled directly from Na-benzophenone ketyl into a round
bottom flask (50 mL), containing sodium hydride (0.90 g,
3.75 mmol), thoroughly prewashed with anhydrous hexane
and dried. The flask was stoppered with a septum cap,
flushed with nitrogen and cooled in ice, 2 (1.0 g, 3.5 mmol)
dissolved in anhydrous THF (10 mL) was added dropwise
and the colourless solution was stirred (0.5 h) at 0 8C. To
this solution methyl iodide (1.0 mL, 16 mmol) was added
dropwise and the reaction stirred for an additional 2 h at rt.
The reaction was then quenched with saturated ammonium
chloride solution (50 mL) and the organic phase separated.
The aqueous phase was extracted with ethyl acetate (2!
50 mL). The combined organic extracts were dried
4.1.2. Reduction of 2-(arylsulfinylmethyl)-4,4,6-tri-
methyl-5,6-dihydro-(4H)-1,3-oxazine. Formation of 2-
† Extra signals appear owing to diastereomers.

K. Singh et al. / Tetrahedron 60 (2004) 9171–9177
9175
(anhydrous sodium sulphate) and evaporated in vacuo. The
oily residue was purified by column chromatography using
ethyl acetate, hexane and their mixtures as eluents to obtain
the pure product.
2!d, JZ8.5 Hz, Ph), 7.16 (4H, m, Ph), 7.43 (4H, 2!d, JZ
8.3 Hz, Ph), 8.39 (1H, br, D2O exchangeable, NH); dC
(50 MHz CDCl3) 18.3, 21.3, 45.4, 51.2, 55.1, 56.4, 58.6,
107.8, 111.3, 113.6, 118.0, 119.0, 121.5, 124.2, 129.5,
129.9. 130.7, 132.7, 136.0, 138.5, 141.5 158.7; dC (50 MHz
CDCl3, DEPT-135) 18.3 (Kve), 21.3, 45.4 (Kve), 51.2,
55.2, 56.4 (Kve), 58.6 (Kve), 111.3, 113.6, 118.0, 119.0,
121.5, 124.2, 129.5, 129.9. m/z 444 (MC); [Found: C, 72.98;
H, 6.41; N, 6.28 C27H28N2O2S requires C, 72.97; H, 6.30;
N, 6.30]; [a]DZC211.57 (c 0.272, CH2Cl2).
Yield: 74%; viscous oil; nmax (KBr) 1590 (C]N), 1220 (C–
O), 1035 (S]O) cmK1; dH (200 MHz CDCl3) 0.95 (3H, d,
JZ8.0 Hz, Me), 1.20 (9H, m, 3!Me), 1.63 (2H, m, CH2),
2.40 (3H, s, PhMe), 3.25 (0.6H, q, JZ8.0 Hz, CHMe), 3.58
(0.4H, q, JZ8.0 Hz, CHMe), 4.02 (1H, m, CH), 7.27 (2H,
m, Ph), 7.53 (2H, m, Ph); dC (50 MHz CDCl3) 21.0, 21.3,
29.1, 29.3, 29.5, 31.1, 31.3, 41.5, 41.7, 41.9, 41.9, 50.1,
50.2, 50.3, 63.9, 64.3, 66.7, 66.9, 68.2, 96.0, 125.3, 125.6,
130.5, 130.7, 138.8, 141.5. m/z 293 (MC); [Found: C, 65.50;
H, 7.81; N, 4.82 C16H23NO2S requires C, 65.52; H, 7.84; N,
4.77].
4.2.3. (1S,SR)-N-(p-Methoxybenzyl)-1-(p-tolylsulfinyl-
methyl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]indole
(8b). Yield: 56%; white solid, mp 82 8C; nmax (KBr) 3265
(N–H), 1032 (S]O) cmK1; dH (200 MHz CDCl3) 2.40 (3H,
s, Me), 2.55 (1H, m, NCH2CHH), 3.00 (3H, m, NCH2CHH),
3.19 (2H, m, CH2SO), 3.81 (3H, s, OMe), 3.86 (2H, m,
CH2Ph), 4.48 (1H, br t, JZ6.0 Hz, C(1)H), 7.00 (4H, 2!d,
JZ8.5 Hz, Ph), 7.14 (4H, m, Ph), 7.42 (4H, 2!d, JZ
8.6 Hz, Ph), 9.28 (1H, br, D2O exchangeable, NH); dC
(50 MHz CDCl3) 17.2, 21.3, 43.5, 53.2, 55.1, 56.8, 63.2,
107.8, 111.3, 113.7, 117.9, 119.0, 121.5, 124.0, 126.9,
129.6, 130.0, 132.4, 136.2, 140.7, 141.5, 158.8. m/z 427
(MCKOH), 291 (MCKCH2SOC6H4Me); [Found C, 72.85;
H, 6.29; N, 6.42 C27H28N2O2S requires C, 72.97; H, 6.30;
N, 6.30]; [a]2D1ZC138.57 (c 0.221, CH2Cl2).
4.2. General procedure for the reaction of 2-(arylsulfinyl
methyl)-4,4,6-trimethyltetrahydro-(2H)-1,3-oxazine 2
with L-tryptophan methyl/ isopropyl ester or Nb-4-
methoxy benzyl tryptamine or tryptamine
2-(Arylsulfinylmethyl)-4,4,6-trimethyltetrahydro-(2H)-1,3-
oxazine 2 (2.29 mmol), the appropriate tryptophan ester/
tryptamine derivative (2.29 mmol) and acetic acid (cata-
lytic) in anhydrous acetonitrile (30 mL) were stirred at rt/
refluxed at 80 8C till the reaction completed (TLC). The
reaction was basified with cold aqueous sodium carbonate
(5%) solution and extracted with ethyl acetate (3!50 mL).
The extract was washed once with cold water (50 mL) and
dried (anhydrous Na2SO4). The solvent was removed in
vacuo and the residue was chromatographed on silica gel
(60–120 mesh) using hexanes, ethyl acetate or their
mixtures as eluents.
Following the above procedure the reaction of L-tryptophan
methyl ester with oxazinanes provided the following
products.
4.2.4. (cis, SR)-Methyl-1-(p-tolylsulfinylmethyl)-1,2,3,4-
tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxylate (7c).
Yield: 35%; yellow viscous oil; nmax (CHCl3) 3430 (N–H),
1720 (C–O), 1030 (S]O) cmK1; dH (200 MHz CDCl3) 1.91
(1H, br, D2O exchangeable, NH), 2.41 (3H, s, C6H4Me),
3.07 (3H, m, C(4)H2 and HB of ABX of CH2SO), 3.72 (3H,
m, C(3)H and HA of ABX CH2SO), 3.76 (3H, s, OMe), 4.26
(1H, dd, JZ9.0, 2 Hz, C(1)H), 7.23 (4H, m, Ph), 7.42 (4H,
2!d, JZ8.1 Hz, Ph), 10.38 (1H, br, D2O exchangeable,
NH); dC (50 MHz CDCl3) 21.4, 25.5, 48.2, 52.2, 56.6, 57.8,
107.3, 111.6, 117.9, 119.2, 121.8, 124.3, 126.7, 130.3,
132.4, 136.0, 136.7, 142.0, 173.2; dC (50 MHz CDCl3,
DEPT-135) 21.4, 25.5 (Kve), 48.2, 52.2, 56.6, 57.8 (Kve),
111.6, 117.9, 119.2, 121.8, 124.3, 130.3. m/z 382 (MC);
[Found: C, 65.78; H, 5.84; N, 7.29 C21H22O3N2S requires C,
65.96; H, 5.75; N, 7.32]; [a]DZC253.97 (c 0.175, CHCl3).
The reaction of L-tryptamine with oxazinanes provided the
following product.
4.2.1. (1R,SR)-1-(p-Tolylsulfinylmethyl)-1,2,3,4-tetrahy-
dro-9H-pyrido [3,4-b]indole (7a).20 Yield: 33%; white
solid, mp 158–160 8C; nmax (KBr) 3280 (N–H), 1028
(S]O) cmK1; dH (200 MHz CDCl3) 2.41 (3H, s, Me),
2.76 (2H, m, NCH2), 2.82 (1H, br, D2O exchangeable, NH),
3.02 (1H, dd, JZ13.6, 4.9 Hz, CHHSO), 3.20 (2H, m,
PhCH2), 3.40 (1H, dd, JZ13.6, 4.9 Hz, CHHSO), 4.80 (1H,
dd, JZ4.9, 4.3 Hz, CH), 7.29 (4H, m, Ph), 7.48 (4H, 2!d
JZ8.0 Hz, ArH), 9.60 (1H, br, D2O exchangeable, NH); dC
(50 MHz CDCl3) 21.4, 22.2, 42.5, 50.0, 63.8, 108.9, 111.4,
118.1, 119.2, 121.9, 124.0, 126.9, 130.2, 133.4, 135.5,
140.2; [Found: C, 70.26; H, 6.30; N, 8.48 C19H20N2OS
requires C, 70.34; H, 6.12; N, 8.63].
4.2.5. (trans, SR)-Methyl-1-(p-tolylsulfinylmethyl)-
1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxy-
late (8c). Yield: 43%; white solid, mp 215 8C; nmax (KBr)
3210 (N–H), 1740 (C–O), 1045 (S]O) cmK1; dH
(200 MHz CDCl3) 1.85 (1H, br, D2O exchangeable, NH),
2.41 (3H, s, C6H4Me), 3.05 (3H, m, C(4)H2 and HB of ABX
of CH2SO), 3.28 (1H, dd, JZ13.4, 6.8 Hz, HA of ABX of
CH2SO), 3.76 (3H, s, OMe), 3.85 (1H, dd, JZ7.2, 5.3 Hz,
C(3)H), 5.01 (1H, dd, JZ13.3, 8.5 Hz, C(1)H), 7.26 (4H, m,
Ph), 7.42 (4H, 2!d, JZ8.1 Hz, Ph), 9.55 (1H, br, D2O
exchangeable, NH); dC (50 MHz CDCl3) 21.4, 25.2, 47.2,
52.2, 53.1, 64.2, 107.2, 111.4, 118.0, 119.3, 122.0, 124.0,
126.7, 130.2, 132.8, 136.2, 140.2, 142.0, 173.8. m/z 365
(MCKOHK), 229 (MCKCH2SOC6H4CH3); [Found: C,
The reaction of Nb-4-methoxy benzyl tryptamine with
oxazinanes furnished the following products.
4.2.2. (1R,SR)-N-(p-Methoxybenzyl)-1-(p-tolylsulfinyl-
methyl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]indole
(7b). Yield: 24%; white solid, mp 157 8C; nmax (KBr)
3280 (N–H), 1029 (S]O) cmK1; dH (200 MHz CDCl3)
2.41 (3H, s, Me), 2.53 (1H, m, NCH2CHH), 2.90 (3H, m,
NCH2CHH), 3.19 (1H, dd, JZ8.6, 2.7 Hz, CHHSO), 3.33
(2H, m, CH2Ph), 3.52 (dd, JZ8.6, 2.7 Hz, CHHSO), 3.79
(3H, s, OMe), 4.06 (1H, dd, JZ8.6, 2.7 Hz, CH), 6.90 (4H,

9176
K. Singh et al. / Tetrahedron 60 (2004) 9171–9177
65.86; H, 5.78; N, 7.36 C21H22O3N2S requires C, 65.96; H,
5.75; N, 7.32]; [a]21ZC698.39 (c 0.112, CHCl3).
121.4, 127.3, 130.0, 135.9, 136.1, 158.7; dC (50 MHz
CDCl3, DEPT-135) 19.3, 19.4 (Kve), 45.3 (Kve), 52.0,
55.2, 56.6 (Kve), 110.7, 113.7, 118.1, 119.3, 121.4, 130.0;
m/z 306 (MC); [Found: C, 78.45; H, 7.25; N, 9.19
C20H22N2O requires C, 78.43; H, 7.18; N, 9.15];
[a]DZK24.0 (c 0.154, CH2Cl2).
The reaction of L-trptophan isopropyl ester with oxazinanes
furnished the following products.
4.2.6. (cis, SR)-Isopropyl-1-(p-tolylsulfinylmethyl)-
1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxy-
late (7d). Yield: 34.5%; yellow viscous oil; nmax (CHCl3)
3380 (N–H), 1725 (C–O), 1030 (S–O) cmK1; dH (200 MHz
CDCl3) 1.27 (6H, 2!d, JZ6.2 Hz, CH(Me)2), 2.16 (1H, br,
D2O exchangeable, NH), 2.43 (3H, s, C6H4Me), 2.85 (3H,
m, C(4)H and HB of ABX of CH2SO), 3.60 (2H, m, C(3)H
and HA of ABX of CH2SO), 4.18 (1H, br d, JZ9.0 Hz,
C(1)H), 5.09 (1H,heptet, JZ6.2 Hz, CH(Me)2), 7.26 (4H,
m, Ph), 7.48 (4H, 2!d, JZ8.1 Hz, Ph), 10.33 (1H, br, D2O
exchangeable, NH); dC (50 MHz CDCl3) 21.3, 21.7, 25.5,
48.1, 56.7, 57.8, 68.7, 107.4, 111.6, 112.0, 117.9, 119.1,
121.7, 124.3, 126.7, 130.2, 132.6, 135.8, 136.7, 141.9,
172.4; m/z 410 (MC); [Found: C, 67.42; H, 6.35; N, 6.74
C23H26N2O3S requires C, 67.31; H, 6.34; N, 6.82];
[a]DZC212.19 (c 0.250, CHCl3).
4.3.2. (1R)-N-(p-Methoxybenzyl)-1-methyl-1,2,3,4-tetra-
hydro-9H-pyrido [3,4-b]indole (10b). Yield: quantitative;
viscous oil; nmax (CHCl3) 3280 (N–H) cmK1; dH (200 MHz
CDCl3) 1.44 (3H, d, JZ6.7 Hz, Me), 2.62 (m, 1H, PhCHH),
2.85 (2H, m, PhCHH and NCHH), 3.19 (1H, m, NCHH),
3.70 (2H, ABq, JZ13.3 Hz, CH2Ph), 3.82 (3H, s, OMe),
3.89 (1H, m, C(1)H), 7.10 (4H, 2!d, JZ8.5 Hz, Ph), 7.06
(2H, m, Ph), 7.29 (1H, m, Ph), 7.48 (1H, m, Ph), 7.66 (1H,
br, D2O exchangeable, NH); dC (50 MHz CDCl3) 19.21
19.2, 45.4, 51.9, 55.2, 56.6, 107.7, 110.6, 113.6, 118.0,
119.3, 121.4, 127.3, 129.9, 131.0, 135.9, 136.1, 158.7; dC
(50 MHz CDCl3, DEPT-135) 19.2, 19.2 (Kve), 45.4 (Kve),
51.9, 55.2, 56.6, 110.6, 113.6, 118.0, 119.3, 121.4, 129.9;
[Found: C, 78.40; H, 7.29; N, 9.09 C20H22N2O requires C,
78.43; H, 7.18; N, 9.15]; [a]21ZC25.0 (c 0.126, CH2Cl2).
4.2.7. (trans, SR)-Isopropyl-1-(p-tolylsulfinylmethyl)-
1,2,3,4-tetrahydro-9H-pyrido [3,4-b]-indole-3-carboxy-
late (8d). Yield: 40.5%; white solid, mp 225 8C; nmax
(KBr) 3300 (N–H), 1734 (C–O), 1027 (S]O) cmK1; dH
(200 MHz CDCl3) 1.28 (6H, 2!d, JZ6.9 Hz, CH(Me)2),
1.94 (1H, br, D2O exchangeable, NH), 2.86 (1H, dd, JZ
15.2, 8.2 Hz, HA of ABX of C(4)H2), 3.07 (2H,m, HB of
ABX of C(4)H2 and HA of ABX of CH2SO), 3.28 (1H, dd,
JZ8.2, 4.9 Hz, HB of ABX of CH2SO), 3.77 (1H, dd, JZ
8.2, 4.9 Hz, C(3)H), 5.02 (1H, br t, JZ5.6 Hz, C(1)H), 5.11
(1H, heptet, JZ6.9 Hz, CH(Me)2), 7.25 (4H, m, Ph), 7.45
(4H, 2!d, JZ8.1 Hz, Ph), 9.53 (1H, br, D2O exchangeable,
NH); dC (50 MHz CDCl3) 21.3, 21.7, 25.4, 47.1, 53.1, 64.3,
68.6, 107.2, 111.3, 117.9, 119.1, 121.8, 123.9, 126.7, 130.1,
132.9, 136.2, 140.3, 141.8, 172.8; m/z 393 (MCKOHK),
257 (MCKCH2SOC6H4Me); [Found: C, 67.32; H, 6.42; N,
6.83 C23H26N2O3S requires C, 67.31; H, 6.34; N, 6.82];
[a]DZC646.03 (c 0.166, CHCl3).
4.3.3. (1S,3S) Methyl 1-methyl-1,2,3,4-tetrahydro-9H-
pyrido [3,4-b]-indole-3-carboxylate (9c).22 Yield: 72%;
viscous liquid; nmax 3400 (N–H), 1725 (C]O) cmK1; dH
(200 MHz CDCl3) 1.46 (3H d, JZ6.5 Hz, Me), 1.89 (1H, br,
D2O exchangeable, NH), 3.15 (2H, m, C(4)H2), 3.73 (3H, s,
OMe), 4.02 (1H, m, C(3)H), 4.42 (1H, br, C(1)H), 7.10 (2H,
m, Ph), 7.34 (1H, m, Ph), 7.52 (1H, m, Ph), 7.88 (1H, br,
D2O exchangeable, NH); dC (50 MHz CDCl3) 21.2, 24.8,
45.8, 52.2, 52.3, 106.4, 110.8, 118.1, 119.6, 121.9, 127.0,
136.0, 173.5; m/z 244 (MC); [Found: C, 68.39; H, 6.23; N,
11.34 C14H16N2O2 requires C, 68.85; H, 6.55; N, 11.47].
4.3.4. (1R,3S) Methyl 1-methyl 1,2,3,4-tetrahydro-9H-
pyrido [3,4-b]-indole-3-carboxylate (10c).22 Yield: 75%;
viscous liquid; nmax (CHCl3) 3405 (N–H), 1745 (C]O)
cmK1; dH (200 MHz CDCl3) 1.49 (3H, d, JZ6.7 Hz, Me),
1.92 (1H, br, D2O exchangeable, NH), 2.90 (2H, m,
C(4)H2), 3.82 (3H, s, OMe), 3.90 (1H, m, C(3)H), 4.30
(1H, br, C(1)H), 7.14 (2H, m, Ph), 7.40 (2H, m, Ph), 7.83
(1H, br, D2O exchangeable, NH); dC (50 MHz CDCl3) 20.3,
25.7, 48.2, 52.1, 56.3, 107.3, 110.7, 119.5, 119.6, 121.8, 127.0,
136.0, 173.3; m/z 244 (MC); [Found: C, 68.41; H, 6.24; N,
11.43 C14H16N2O2 requires C, 68.85; H, 6.55; N, 11.47].
4.3. Desulfurisation of 7/8. General procedure
To an ice cooled solution of the appropriate 7 or 8 (1.5 mol)
in methanol (30 mL) was added Raney nickel (excess). This
mixture was stirred at 0 8C under a nitrogen atmosphere till
the reaction completed (TLC), was then filtered through a
bed of celite and the residue evaporated. The crude
product was purified by column chromatography on silica
gel (60–120 mesh) using hexane, ethyl acetate and their
mixtures as eluents.
4.3.5. (1S,3S)-Isopropyl 1-methyl-1,2,3,4-tetrahydro-9H-
pyrido [3,4-b]-indole-3-carboxylate (9d). Yield: 89%;
viscous liquid, nmax (CHCl3) 3405 (N–H), 1735 (C]O)
cmK1; dH (200 MHz CDCl3) 1.22 (6H, 2!d, JZ6.1 Hz,
2!Me), 1.47 (3H, d, JZ6.3 Hz, CH3), 2.64 (1H, br, D2O
exchangeable, NH), 2.99 (2H, m, C(4)H2), 3.99 (1H, dd, JZ
7.6, 5.2 Hz, C(3)H), 4.44 (1H, q, JZ6.3 Hz, C(1)H), 5.15
(1H, heptet, JZ6.1 Hz, CH(Me)2), 7.13 (2H, m, Ph), 7.29
(1H, m, Ph), 7.52 (1H, m, Ph), 7.95 (1H, br, D2O
exchangeable, NH); dC (50 MHz CDCl3) 21.4, 21.7, 25.0,
45.9, 52.3, 68.6, 106.4, 110.8, 118.0, 119.4, 121.6, 127.0,
136.0, 172.9; m/z 272 (MC); [Found: C, 70.62; H, 7.41;
N,19.15 C16H20N2O2 requires C, 70.59; H, 7.35; N, 10.30].
4.3.1. (1S)-N-(p-Methoxybenzyl)-1-methyl-1,2,3,4-tetra-
hydro-9H-pyrido [3,4-b]indole (9b). Yield: quantitative;
viscous oil; nmax (CHCl3) 3285 (N–H) cmK1; dH (200 MHz
CDCl3) 1.44 (3H, d, JZ6.6 Hz, Me), 2.67 (1H, m, PhCHH),
2.86 (2H, m, PhCHH and NCHH) 3.14 (1H, m, NCHH),
3.75 (2H, ABq, JZ13.3 Hz, CH2Ph), 3.80, (3H, s, OMe),
3.86 (1H, m, C(1)H), 7.14 (4H, 2!d, JZ8.5 Hz, Ph), 7.17
(2H, m, Ph), 7.28 (1H, m, Ph), 7.46 (1H, m, Ph), 7.68 (1H,
br, D2O exchangeable, NH); dC (50 MHz CDCl3) 19.3, 19.4,
45.3, 52.0, 55.2, 56.6, 107.6, 110.7, 113.7, 118.1, 119.3,
4.3.6. (1R,3S)-Isopropyl 1-methyl-1,2,3,4-tetrahydro-
9H-pyrido [3,4-b]-indole-3-carboxylate (10d). Yield:

K. Singh et al. / Tetrahedron 60 (2004) 9171–9177
9177
Formamidines-mediated Chiral Carbanions in Advances in
Heterocyclic Natural Products synthesis; JAI: Greenwich,
1991.
94%; viscous liquid, nmax (CHCl3) 3400 (N–H), 1725
(C]O) cmK1; dH (200 MHz CDCl3) 1.22 (6H, m, 2!Me),
1.40 (3H, d, JZ6.3 Hz, Me), 1.67 (1H, br, D2O exchange-
able, NH), 2.68 (1H, m, C(4)HH), 2.98 (1H, m, C(4)HH),
3.65 (1H, dd, JZ11.1, 4.3 Hz, C(3)H), 4.15 (1H, q, JZ
6.4 Hz, C(1)H), 5.03 (1H, heptet, JZ6.3 Hz, CH(Me)2),
7.09 (2H, m, Ph), 7.19 (1H, m, Ph), 7.38 (1H, d, JZ7.1 Hz,
Ph), 7.72 (1H, br, D2O exchangeable, NH); dC (50 MHz
CDCl3) 20.2, 21.7, 25.8, 48.3, 56.6, 68.6, 107.4, 110.8,
118.0, 119.5, 121.7, 127.2, 136.0, 172.5; m/z 272 (MC);
[Found: C, 70.60; H, 7.39; N, 10.20 C16H20N2O2 requires C,
70.59; H, 7.35; N, 10.30].
7. For reviews, see: (a) Mikolajczk, M.; Drabowicz, J.;
Kielbasinski, P. Chiral Sulfur Reagents, CRC Press, Boca
Raton, 1997. (b) Posner, G. H. The Chemistry of Sulfones and
Sulfoxides, Patai, S.; Rappoport, Z.; Stirling, C. J. M.; Eds;
Wiley, New York, 1988.
8. Lee, A. W. M.; Chan, W. H. Topics in Current Chemistry;
Springer: Weinheim, 1997 pp 103–129 and references cited
therein.
9. Pyne, S. G.; Dikic, B. J. Org. Chem. 1990, 55, 1932 and
references cited therein.
10. Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron 1999,
55, 12873 and references cited therein.
Acknowledgements
11. (a) Singh, K.; Deb, P. K. Tetrahedron Lett. 2000, 41, 4977.
(b) Singh, K.; Deb, P. K. Heterocycles 1999, 51, 1509.
(c) Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron 2001,
57, 7939.
The authors thank CSIR, New Delhi, for the grant [(1653)/
00-EMR-II]. KS thanks Prof. A.W.M. Lee for supplying
spectral and physical data of some THBCs for comparison
purpose.
12. Singh, K.; Deb, P. K.; Behal, S. Heterocycles 2001, 55, 1937 a
preliminary communication.
13. Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Politzer, I. R.;
Malone, G. R.; Kovelesky, A. C.; Nolen, R. L.; Portnoy, R. C.
J. Org. Chem. 1973, 38, 36.
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Alkaloids: The a-Alkylation of Nitrogen Heterocycles via