A general synthetic route to 1-azabicyclo[m.n.0]alkenes via cyclisation based on α-sulfinyl carbanions

Article abstract of DOI:10.1039/b308383g

A general synthetic route to 1-azabicyclo[m.n.0]alkenes via cyclisation based on α-sulfinyl carbanions was presented. The intramolecular nucleophillic addition of α-sulfinyl carbanions afforded 1-azabicyclo[m.n.0]alkenes in good yields. It is reported that the developed strategy should provide a general solution for the synthesis of various classes of 1-azabicyclic alkaloids.

Full text of DOI:10.1039/b308383g

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A general synthetic route to 1-azabicyclo[m.n.0]alkenes via
cyclisation based on ꢀ-sulfinyl carbanions
Manat Pohmakotr,* Pornthep Numechai, Saisuree Prateeptongkum, Patoomratana Tuchinda
and Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road,
Bangkok 10400, Thailand. E-mail: scmpk@mahidol.ac.th; Fax: ϩ66(0)2644-5126
Received 22nd July 2003, Accepted 9th September 2003
First published as an Advance Article on the web 16th September 2003
The intramolecular nucleophilic addition of ꢀ-sulfinyl carb-
anions derived from the corresponding sulfinyl lactams
afforded 1-azabicyclo[m.n.0]alkenes in good yields.
The 1-azabicyclo[m.n.0]alkane framework is an important
structural assembly in a number of heterocyclic systems,
especially alkaloid natural products possessing biological
activities such as pyrrolidine,1,2 indolizidine and quinolizidine
alkaloids,3,4 and (Ϫ)-tuberostemonine.5,6 Despite the fact that
various synthetic strategies have been developed for these
classes of compounds, an efficient, general construction is still
regarded as an important synthetic challenge.
Our ongoing interest in cyclisation reactions based on
α-sulfinyl carbanion7 prompted us to search for a general entry
to 1-azabicyclo[m.n.0]alkanes 1 starting from simple lactams.
As shown in Fig. 1, it occurred to us that the construction of a
framework such as 1 should be achievable by annulation onto
lactams 2 by consecutive N–C and C–C bond formations
employing 3-bromo-1-phenylsulfinylpropane and 4-bromo-1-
phenylsulfinylbutane as 3- and 4-carbon building blocks for 1,3-
and 1,4-dipole moieties, respectively. In this communication,
we report our preliminary results for the preparation of
1-azabicyclo[m.n.0]alkanes 1 utilizing such a concept. Thus,
N-phenylthioalkylation of lactam 2 with 3-phenylsulfanyl-1-
bromopropane or 4-phenylsulfanyl-1-bromobutane employing
NaH in N,N-dimethylformamide (DMF) at 0 ЊC to rt afforded
Scheme 1 Reagents and conditions: (i) NaH, DMF, BrCH2(CH2)n-
sulfides 3 (Scheme 1).
CH2SPh, 0 ЊC to rt, overnight; (ii) LDA, THF, Ϫ78 ЊC; then CH3I,
Ϫ78 ЊC to rt, overnight; (iii) NaIO4, aq. MeOH, 0 ЊC, overnight; (iv)
LiHMDS, THF, Ϫ78 ЊC to rt, overnight, then quenched with H2O; (v)
ϪH2O; (vi) NaBH4, MeOH, 5–10 ЊC, 2 h.
formed α-sulfinyl carbanion
6 underwent intramolecular
nucleophilic addition to the carbonyl group of the lactam
moiety to provide an intermediate 7 after quenching the
reaction with water. Elimination of a water molecule from 7
gave 1-azabicyclic compound 8.
Fig. 1
As summarized in Table 1 (entries 1–6),9 1-azabicyclic com-
pounds 8a–f could be synthesized in good yields. Cyclisation of
5g and 5h under the standard conditions proceeded cleanly to
Conversion of the sulfides 3a and 3b to the corresponding
sulfides 4a and 4b could be accomplished by lithiation with
lithium diisopropylamide (LDA, 1.1 equiv.) in tetrahydrofuran
(THF) at Ϫ78 ЊC, followed by treatment with methyl iodide
(1.1 equiv., Ϫ78 to 0 ЊC, overnight). The sulfides 3 and 4 were
then oxidized with NaIO4 in aqueous methanol at 0 ЊC to
provide the requisite sulfoxides 5a–f in good yields as listed in
Table 1. The study for the cyclisation of the sulfoxides 5 to
1-azabicyclic compound 8 was carried out with compound 5a
to find the optimum conditions. It was found that cyclisation
of 5a to 8a could be smoothly effected by employing lithium
hexamethyldisilazide (LiHMDS) (1.1 to 2.0 equiv.) in tetra-
hydrofuran (THF) at Ϫ78 ЊC to rt (overnight), the expected
product 8a8 could be obtained in 85–90% yield after column
chromatography on silica gel. The use of lithium diisopropyl-
amide as a base for the cyclisation under the same conditions
afforded less satisfactory results. It was evident that the initially
1
the expected products of type 8 as indicated by TLC and H
NMR analyses of the crude products. However, purification of
these cyclised products was troublesome and low yields were
obtained due to decomposition at rt. Therefore, the crude
products were further subjected to reduction by using NaBH4
in methanol to 9a and 9b in 65 and 68% yields, respectively.
We considered that the presence of the sulfoxide group in
compounds 8 and 9 would lead to synthetic manipulation on
various 1-azabicyclic skeletons.
In summary, we have demonstrated a new general strategy to
1-azabicyclo[m.n.0]-alkenes and -alkanes via the intramolecular
nucleophilic addition of α-sulfinyl carbanion to the carbonyl
group of lactam ring. This method provided not only a
convenient 3-carbon and 4-carbon annulation onto lactams,
but also the facile introduction of an α-substituent onto the
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Preparation of 1-azabicyclic compounds 8 and 9
Entry
1
Lactam 2
Sulfide 3 or 4 (%)a, b
Sulfoxide 5 (%)a, b
5a, R = H (95%)
m, n in 3, 4 and 5
m = 1, n = 2
Products 8 and 9 (%)a, b
3a (85%)
8a (85–90%)
2
3
3b (80%)
3c (85%)
5b, R = H (95%)
5c, R = H (92%)
m = 2, n = 2
m = 3, n = 2
8b (89%)
8c (87%)
4
5
6
3d (80%)
4a (81%)
4b (80%)
5d, R = H (94%)
5e, R = Me (96%)
5f, R = Me (95%)
m = 4, n = 2
m = 1, n = 2
m = 2, n = 2
8d (85%)
8e (85%)c
8f (87%)c
7
8
3e (87%)
3f (74%)
5g, R = H (86%)
5h, R = H (86%)
m = 2, n = 1
m = 3, n = 1
9a (65%)c, d
9b (68%)c, d
a Isolated yields by column chromatography (SiO2, 2% MeOH in EtOAc containing 0.2% NH4OH solution). b All compounds were characterized
by 1H NMR, 13C NMR, IR, MS, and elemental analyses or HMRS. c Obtained as a mixture of diastereomers. d Overall yields based on compounds
5g and 5h.
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5 P. Wipf, Y. Kim and D. M. Goldstein, J. Am. Chem. Soc., 1995, 117,
11106; D. M. Goldstein and P. Wipf, Tetrahedron Lett., 1996, 37, 739.
6 For examples of general synthetic routes to 1-azabicyclo[5.4.0]- and
[5.3.0]-alkanes, see: W. H. Pearson, D. A. Hutta and W. K. Fang,
J. Org. Chem., 2000, 65, 8326; W. H. Pearson and W. K. Fang, J. Org.
Chem., 2000, 65, 7158; A. Kinoshita and M. Mori, J. Org. Chem.,
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Tetrahedron Lett., 2001, 42, 6621; S. L. Lim, S. Ma and P. Beak,
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7 M. Pohmakotr and S. Chancharunee, Tetrahedron Lett., 1984, 25,
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Lett., 1990, 31, 3783; M. Pohmakotr, T. Junpirom, S. Popaung,
P. Tuchinda and V. Reutrakul, Tetrahedron Lett., 2002, 43, 7385.
8 A compound of type 8a was demonstrated by D. H. Hua and
coworkers to be a versatile precursor for the synthesis of elaeokanine
A and elaeokanine B: D. H. Hua, S. N. Bharathi, P. D. Robinson and
A. Tsujimoto, J. Org. Chem., 1990, 55, 2128.
original lactam ring, the structural feature found in many
natural products.
Furthermore, the developed strategy should provide a general
solution for the syntheses of various classes of 1-azabicyclic
alkaloids, such as indolizidines and quinolizidines. Extension
of this methodology is currently under investigation and will be
reported in due course.
Acknowledgements
We thank the Thailand Research Fund for financial support
(BRG/22/2544) to M. P. and the award of a Senior Research
Scholarship to V. R. S. P. is grateful to NSTDA for a local
graduate scholarship. Thanks are also made to the Higher
Education Development Project: Postgraduate Education and
Research Program in Chemistry (PERCH) for support. We are
grateful to the Chulabhorn Research Institute for the HRMS
determination.
Notes and references
1 For an updated review on pyrrolidine alkaloids, see: J. R. Liddel,
Nat. Prod. Rep., 2001, 18, 441 and references cited therein.
2 For some recent syntheses of pyrrolizidines, see: H. Yodo, T. Egawa
and K. Takabe, Tetrahedron Lett., 2003, 44, 1643; H. Hasegawa,
H. Senboku, Y. Kajizuka, K. Orito and M. Tokuda, Tetrahedron,
2003, 59, 827; P. Renaud, C. Ollivier and P. Panchaud, Angew. Chem.,
Int. Ed., 2002, 41, 3460; M. T. Epperson and D. Y. Gin, Angew.
Chem., Int. Ed., 2002, 41, 1778; S.-H. Kim, Y. Park, H. Choo and
J. K. Cha, Tetrahedron Lett., 2002, 43, 6657.
3 For an updated review on indolizidine and quinolizidine alkaloids,
see: J. P. Michael, Nat. Prod. Rep., 2001, 18, 520 and references cited
therein.
4 For some recent syntheses of indolizidines and quinolizidines, see:
D. Basavaiah and A. J. Rao, Chem. Commun., 2003, 604; Z.-X. Feng
9 Typical procedure for preparation of 1-azabicyclic compound 8a:
A solution of 5a (0.7691 g, 3.0 mmol) in THF (5 cm3) was added
dropwise to a cooled (Ϫ78 ЊC) THF (20 cm3) solution of LHMDS
[3.3 mmol, prepared by reacting hexamethyldisilazane (0.75 cm3, 3.6
mmol) with nBuLi (2.2 cm3, 3.3 mmol, 1.49 M in hexane) at Ϫ78 ЊC].
The resulting mixture was stirred and slowly warmed up to rt (14 h).
The resulting pale yellow solution was quenched with water (7 cm3)
and extracted with ethyl acetate (3 × 50 cm3). The combined organic
extracts were washed with water, then brine and dried over anhydrous
Na2SO4. The crude product was purified by column chromatography
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(silica gel, 2% methanol in ethyl acetate containing 0.2% NH4OH
solution) to afford 8a (0.6307 g, 85% yield) as a pale yellow liquid.
HRMS (FABϩ) found: 247.1025, C14H17NOS requires 247.1027; IR
νmax (film)/cmϪ1: 3049, 2925, 2855, 1613, 1579, 1496, 1442, 1352, 1296,
1211, 1198, 1129, 1092, 1079, 1020, 996, 913, 930, 888, 817, 750, 693;
1H NMR δH (300 MHz; CDCl3; Me4Si): 7.48, 7.36 and 7.28 (each m,
2.85 [dt, J 16, 8 Hz, 1H, CHHC(N)᎐C], 2.21 [dt, J 14.9, 6 Hz, 1H,
᎐
CHHC᎐C(N)], 1.92 [quint, J 7.3 Hz, 2H, CH2CH2C(N)᎐C], 1.72
᎐
᎐
[m, 2H, CH2CH2C᎐C(N)], 1.49 [m, 1H, CHHCC᎐C(N)]. 13C NMR
᎐
᎐
δC (75 MHz; CDCl3; Me4Si) 155.30, 144.35, 128.91, 128.37, 124.92,
95.54, 52.62, 44.40, 29.31, 21.52, 21.15, 16.37. MS: m/z (EI) 248
(Mϩ ϩ 1, 3%), 231 (4%), 199 (67%), 170 (51%), 120 (100%), 108 (6%),
92 (8%), 80 (5%), 77 (4%), 65 (5%).
5H, ArH ), 3.24 and 3.03 [each m, 5H, 2 × CH2N and CHHC(N)᎐C],
᎐
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