One-pot synthesis of benzothiazolines and napthathiazolines via cascade ortho-lithiation, cyclisation and elimination of N-arylsulfonyl lactams

Article abstract of DOI:10.1039/b708967h

ortho-Lithiation of cyclic aryl sulfonamides in the presence of phosphoryl chloride provides a very simple entry to fused polycyclic sultams (benzothiazolines and naphthathiazolines). The Royal Society of Chemistry.

Full text of DOI:10.1039/b708967h

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One-pot synthesis of benzothiazolines and napthathiazolines via cascade
ortho-lithiation, cyclisation and elimination of N-arylsulfonyl lactams†‡
John. D. Harling,b Patrick. G. Steel,*a Tom. M. Woodsa and Dmitry S. Yufita
Received 14th June 2007, Accepted 21st August 2007
First published as an Advance Article on the web 17th September 2007
DOI: 10.1039/b708967h
ortho-Lithiation of cyclic aryl sulfonamides in the presence of phosphoryl chloride provides a very
simple entry to fused polycyclic sultams (benzothiazolines and naphthathiazolines).
Surprisingly, there have only been a limited number of methods
Introduction
describing the synthesis of fused amido sultams.15 In this paper
Sulfonamides have found many important applications in or-
we report the synthesis of fused benzo- and napthathiazoline-1,1-
dioxide heterocyclic ring systems 5 via a sequence involving ortho-
lithiation–cyclisation–elimination reactions of readily prepared N-
arylsulfonyl lactams 4, Fig. 2
ganic synthesis including as protecting groups,1 chiral auxiliaries2
and directed metallation groups (DMGs).3 In addition, the
sulfonamide functionality is present in many biologically active
compounds where it can function as a stable amide equivalent.4,5
In particular, cyclic sulfonamides (sultams), of which there are
many variations, are well documented in the literature. For exam-
ple 3,5-diamino-1,2,6-thiadiazine-1,1-dioxide derivatives 1 pos-
sess anti-parasitic activity,4 1,2-benzisothiazolinone-1,1-dioxides
2 (saccharin derivatives) exhibit, among other properties, human
leukocyte elastase inhibitory6 and anti-fungal5 activity and 1,2-
benzisothiazine-1,1-dioxides such as the oxicams, e.g. piroxicam 3
are known for their anti-inflammatory properties,7 Fig. 1.
Fig. 2
Results and discussion
As part of a program aimed at exploring new electrophilic
partners for cross coupling reactions,17 we have developed an
efficient protocol for the preparation of phosphonites, e.g. 7,
involving treatment of a THF solution of N-Boc caprolactam 6
and TMEDA with LDA and trapping of the resultant anion with
diphenylphosphonic chloride, Scheme 1.
Fig. 1 Selected examples of cyclic sulfonamides.
Reflecting these diverse roles, there have been many methods
described for the synthesis of sultams. These include Diels–Alder
cycloadditions,8 radical cyclisations,9 intramolecular Heck
Scheme 1
couplings,10 ring closing metathasis,11 aziridination of
However, subjecting the N-tosyl caprolactam 4a to these condi-
iminoiodinanes12 and N-chloramine sulfonamides,13 ortho-lithia-
tions afforded a new non-phosphorus containing product (44%)
tion (DMG) strategies14 and lithiation of o-tolyl sulfonamides.15,16
accompanied by smaller amounts of the desired phosphonite 8a
(15%) and recovered starting material, Scheme 2. Analysis of the
1H NMR spectra indicated only three aromatic protons (d (ppm) =
aDepartment of Chemistry, University of Durham, Science Laboratories,
South Road, Durham, UK DH1 3LE. E-mail: p.g.steel@durham.ac.uk
7.29, d; 7.41, s; 7.64, d) together with a new olefinic signal at d =
5.78 ppm (t, J = 7 Hz). Moreover, this last signal showed NOESY
and HMBC correlations with the proton signal at d = 7.41 ppm
and a quaternary carbon signal at d = 132.4 ppm respectively.
Combined with a molecular ion at MH+ of m/z = 250.0896, this
suggested the unusual fused sultam 5a. Ultimate confirmation of
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, UK SG1 2NY
† Electronic supplementary information (ESI) available: Characterisation
data for compounds 4b–4h, 5d, 5e, 5g, 8d, 8e and 8g. See DOI:
10.1039/b708967h
‡ CCDC reference number 650785. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b708967h
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Fig. 3 X-Ray molecular structure of 5f (50% displacement ellipsoids).
The scope and limitations of this process were then examined
varying both the lactam ring and sulfonyl group, Scheme 3
and Table 1. Each substrate 4 was prepared in variable but
unoptimised yields (33–80%) by metallation of the parent lactam
with n-BuLi and subsequent reaction with the appropriate sulfonyl
chloride. Cyclisation of both N-tosyl pyrrolidinone 4b and N-
tosyl piperidinone 4c were unsuccessful, entries 2 and 3. With
the exception of 3-nitrophenylsulfonamide 4h, entry 12, which
failed to provide any products, all the other sulfonamide analogues
Scheme 2
this structure was subsequently realised when the bromo derivative
5f, which showed similar NMR correlations, provided crystals
suitable for an X-ray structure determination, Fig. 3.‡
Surprisingly, the Cambridge Crystallographic Database (Ver.
5.28, Nov. 2006) does not contain any structures of fused sultams.
However, the geometrical parameters of 5f are close to the expected
values. The 7-membered ring is disordered over two positions.
Within the crystal, 5f stacks to form slightly bent columns with
antiparallel arrangement of the molecules. Aromatic rings of
adjacent molecules are partially overlapped with the shortest
ꢀ
˚
interatomic distance C7 · · · C7 (1 − x, y, 0.5 − z) being 3.192 A.
The molecules are also linked together by a 3-D network of
Scheme 3 Reagents and conditions: (a) i. n-BuLi, THF; ii. ArSO2Cl; (b) i.
LDA, TMEDA, THF, −78 ◦C, 30 min; ii. Ph2P(O)Cl, 2 h.
CH · · · O and CH · · · Br interactions.
Table 1 Formation of cyclic sultams 5 by sequential ortho-lithiation, cyclisation and elimination
Entry
n
Ar
Yield 5 (%)
Yield 8 (%)
Recovered 4 (%)
1
2
3
3
1
2
4
3
3
3
3
3
3
3
3
4-Me–C6H4 4a
4-Me-C6H4 4b
4-Me-C6H4 4c
4-Me-C6H4 4d
4-Me-C6H4 4a
4-Me-C6H4 4a
4-Me-C6H4 4a
4-Me-C6H4 4a
1-Napthyl 4e
41
0
Trace
18
44
11
0
15
0
30
24
14
0
0–50
43
32
0–16
0
15
100
0
41
0
0
4
5a
6b
7c
8d
9
0
0
73
17
0
23
0
26
46
32e
0
10
11
12
4-Br-C6H4 4f
3-MeO-C6H4 4g
4-NO2–C6H4 4h
50–100
a No TMEDA present. b Ph2P(O)Cl replaced with TMSCl. c No Ph2P(O)Cl present. d LDA–TMEDA replaced with NaHMDS. e Mixture of two
regioisomeric sultams (4 : 1).
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examined followed a similar profile, providing mainly the fused
sultam accompanied by smaller quantities of the phosphonite and
recovered starting materials, with the exception of the 8-membered
ring which gave a higher proportion of the phosphonite, entry 4.
Attempts to enhance the yields through the use of alternative bases
(BuLi, LHMDS) and other additives (DMPU, HMPA) and higher
reaction temperatures provided no significant benefit.
The formation of the sultam can be explained when the powerful
directing metallating properties of the sulfonamide group are
taken into account.3 We speculate that the reaction proceeds
via initial ortho-lithiation of the aryl sulfonamide. The resulting
carbanion then attacks the lactam carbonyl group activated by
co-ordination to the phosphorus centre. The presence of the
phosphorus reagent is essential, as experiments undertaken in
the absence of phosphoryl chloride and simply quenched with
water, entry 7, afforded only recovered starting sulfonamide 4a.
Replacement of phosphoryl chloride by trimethylsilyl chloride
also afforded the desired sultam 5a although in greatly reduced
yield of 11%, entry 6.
The competing formation of the phosphinite can arise either
from direct metallation or from the initial aryl carbanion func-
tioning as a base to generate the enolate through either lateral
or intermolecular proton abstraction.18 The latter is favoured as
increasing the concentration of the reaction leads to higher levels
of phosphinite formation (4a 0.08 M, 5a : 8a 3 : 1; 0.16 M,
1 : 1; 0.32 M, 1 : 1.6). The alternative possibility of initial
enolate formation cannot be ruled out although metallation with
NaHMDS, which does not lead to ortho-metallation, affords
only phosphinite and no sultam, entry 8. Moreover, isolating
a pure sample of the phosphinite and re-subjecting this to the
deprotonation conditions, either in the presence or absence of
diphenylphosphoryl chloride, failed to provide any evidence for
sultam formation and led to efficient recovery of the phosphinite.
The failure of smaller lactam rings to undergo sultam formation
is attributed to the increased level of ring strain in the transition
state leading to preferential lateral metallation and phosphinite
formation.19
Scheme 4
1H and 13C NMR spectroscopy or elemental analysis (Durham
University Microanalytical Laboratory).
Melting points were determined using Gallenkamp melting
point apparatus and are uncorrected. Infrared spectra were
recorded as thin films between KBr plates (liquids) or using an
ATR attachment (golden gate apparatus) on a Perkin-Elmer FT-
1
IR 1600 spectrometer. Unless otherwise stated H NMR spectra
were recorded in CDCl3 on either a Varian Mercury 200, Varian
Unity-300, Mercury-400 or Varian Inova-500 and are reported as
follows: chemical shift d (ppm) (number of protons, multiplicity,
coupling constant J (Hz), assignment). Residual protic solvent
CHCl3 (dH = 7.26 ppm) was used as the internal reference. 13C
NMR spectra were recorded at 101 MHz or 126 MHz on a
Mercury-400 or Varian Inova-500 respectively, using the central
resonance of CDCl3 (dC = 77.0 ppm) as the internal reference.
All chemical shifts are quoted in parts per million relative to
tetramethylsilane (dH = 0.00 ppm) and coupling constants are
given in Hertz to the nearest Hz. All 13C spectra were proton
decoupled. Assignment of spectra was carried out using DEPT,
COSY, HSQC, HMBC and NOESY experiments. Low-resolution
electrospray mass spectra (ES) were obtained on a Micromass LCT
mass spectrometer or a Thermo-Finnigan LTQ. High-resolution
mass spectra (ES) were obtained on a Thermo-Finnigan LTQFT
mass spectrometer in Durham. Characterisation data for com-
pounds 4b–4h, 5d, 5e, 5g, 8d, 8e and 8g can be found in the ESI.†
Conclusion
In conclusion, ortho-lithiation of cyclic aryl sulfonamides in the
presence of phosphoryl chloride provides a very simple entry to
fused polycyclic sultams that are not easy to prepare by more stan-
dard methods. Moreover, further functionalisation of these prod-
ucts is straightforward. For example, Suzuki–Miyaura reaction
of bromosultam 5f affords biphenyl derivative 9 in excellent yield
(86%) whilst conversion of the methyl analogue 5a to the saturated
sultam 10 is easily achieved by simple hydrogenation, Scheme 4.
General method for N-alkylsulfonyl protection of lactams
To a cold (0 ◦C) solution of lactam (0.34 M, 1.0 eq.) in dry THF was
added a solution of n-BuLi (1.6 M, 1.1 eq.) via a syringe and the
reaction mixture was stirred at 0 ◦C for 1 h (white precipitate (salt)
◦
forms). To this was added a cold (0 C) solution of arylsulfonyl
chloride (1.0 M, 1.3 eq.) in dry THF via cannula. The reaction
mixture was stirred at 0 ◦C and followed by TLC or LCMS until
all the starting material was consumed. The reaction was warmed
to room temperature and concentrated in vacuo, the crude material
was taken into DCM, washed with water (3×), dried over MgSO4
and concentrated under reduced pressure.
Experimental
All reactions were carried out under an argon atmosphere unless
otherwise stated. Solvents were purified following established
protocols. Petrol refers to petroleum spirit boiling in the 40–
60 ◦C range. Ether refers to diethyl ether. Commercially available
reagents were used as received unless otherwise stated. Flash
column chromatography was performed according to the method
of Still et al. using 200–400 mesh silica gel.20 Yields refer to isolated
yields of products of greater than 95% purity as determined by
N-[(4ꢀ-Methylphenyl)sulfonyl]-2-oxoazepane 4a
Purification by flash chromatography (1: 15%, 2: 25%, 3: 35%
ethyl acetate–pet. ether) afforded the desired product as a white
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solid (1.10 g, 4.12 mmol, 46%). Mp 117–120 ◦C. Found; C, 58.11;
H, 6.28; N, 4.92%; calc. for C13H17NO3S; C, 58.40; H, 6.41; N,
Crystal data for 5f. C12H12BrNO2S, M = 314.20, orthorhom-
bic, space group Pbcn, a = 16.5525(3), b = 10.1393(2), c =
3
˚
˚
=
5.24%. mmax (KBr) 2941, 2861, 1697 (NC O), 1597, 1353 (SO2),
14.0826(3) A, U = 2363.5(1) A , F(000) = 1264, Z = 8, Dc =
1168 (SO2), 1123, 1088, 813, 549, 535 cm−1. dH (500 MHz, CDCl3)
1.64–1.76 (4H, m, 4-H2, 5-H2), 1.81 (2H, m, 6-H2), 2.41 (3H, s,
4ꢀ-CH3), 2.53 (2H, t, J = 6 Hz, 3-H2), 4.01 (2H, t, J = 5 Hz, 7-H2),
7.29 (2H, d, J = 9 Hz, 3ꢀ-H, 5ꢀ-H), 7.87 (2H, d, J = 9 Hz, 2ꢀ-H,
6ꢀ-H). dC (125 MHz, CDCl3) 21.9 (4ꢀ-CH3), 23.2 (C-4), 29.4 (C5),
29.6 (C-6), 39.0 (C-3), 46.7 (C-7), 128.8 (C-2ꢀ), 129.5 (C-3ꢀ), 136.8
(C-4ꢀ), 144.7 (C-1ꢀ), 175.1 (C-2). m/z (ES+) 268.0 (MH+).
1.766 Mg m−3, l = 3.643 mm−1 (Mo-Ka, k = 0.71073 A), T =
˚
120(1)K. 30330 reflections were collected on a Bruker SMART
CCD 6000 diffractometer (x-scan, 0.3◦ per frame) yielding 3450
unique data (Rint = 0.0259). The SADABS absorption correction
has been applied. The structure was solved by direct methods
and refined by full-matrix least squares on F2 for all data
using SHELXTL software.21 All non-hydrogen atoms (except the
disordered ones) were refined with anisotropic displacement pa-
rameters, H-atoms were located on the difference map and refined
isotropically. Final wR2 (F2) = 0.0724 for all data (190 refined
parameters), conventional R (F) = 0.0285 for 3450 reflections with
I ≥ 2r(I), GOF = 1.145. Crystallographic data for the structure
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication CCDC 650785.
General method for cyclisation of N-alkylsulfonyl protected
lactams
To a cold solution (0.08 M, −78 ◦C) of N-sulfonyl lactam (1 eq.)
and N,N,Nꢀ,Nꢀ-tetramethyl-1,2-ethylenediamine (TMEDA,
1.3 eq.) in dry THF was added a cold solution of lithium diiso-
propylamide (LDA, 1.3 eq.) via cannula. The resulting reaction
mixture was stirred at −78 ◦C for 2 h after which time a cold
solution (0.2 M, −78 ◦C) of diphenylphosphonic chloride (1.2 eq.)
in dry THF was added via cannula. The reaction mixture was
stirred at −78 ◦C for 1 h then warmed to room temperature and
quenched with NH4Cl (aq.). The mixture was concentrated in
vacuo and the aqueous layer was extracted with ethyl acetate. The
organic phase was washed with NaHCO3 (aq.) then brine, dried
over MgSO4 and concentrated in vacuo affording crude material.
1-Tosyl-4,5,6,7-tetrahydro-1H-azepin-2-yl diphenylphosphinate 8a
To a cold solution (−78 ◦C) of N-tosyl caprolactam (0.63 g,
2.36 mmol, 1 eq.) in dry THF (30 ml) was added sodium
hexamethyldisilazane (NaHMDS, 2 M, 1.25 ml, 2.51 mmol,
1.2 eq.)◦ via syringe. The resulting reaction mixture was stirred
at −78 C for 1 h after which time diphenylphosphonic chloride
(0.48 ml, 2.51 mmol, 1.2 eq.) was added via syringe. The reaction
mixture was stirred at −78 ◦C for 2 h before being warmed to
room temperature and quenched with H2O. The mixture was
concentrated in vacuo and the aqueous layer was extracted with
ethyl acetate. The organic phase was washed with brine then
dried over MgSO4 and concentrated in vacuo affording the crude
1,2,3,4-Tetrahydro-7-methylazepino[1,2-b][1,2]benzothiazole-
10,10-dioxide 5a
Purification by flash chromatography (15% ethyl acetate–
dichloromethane) afforded the title compound as a white solid
(0.19 g, 0.76 mmol,◦41%) and phosphonite (0.13 g, 0.28 mmol,
15%). Mp 112–114 C. mmax (KBr) 2936, 1666, 1610, 1464, 1305,
1178, 1146, 1061, 941 cm−1. dH (500 MHz, CDCl3) 1.79 (2H, m,
3-H2), 1.98 (2H, m, 2-H2), 2.42 (5H, m, 4-H2, 7-CH3), 3.57 (2H,
t, J = 6 Hz, 1-H2), 5.78 (1H, t, J = 7 Hz, 5-H), 7.29 (1H, d, J =
8 Hz, 8-H), 7.41 (1H, s, 6-H), 7.64 (1H, d, J = 8 Hz, 9-H). dC
(125 MHz, CDCl3) 22.2 (7-CH3), 27.0 (C-3), 27.3 (C-4), 28.9 (C-
2), 45.3 (C-1), 106.3 (C-5), 120.8 (C-6), 121.1 (C-9), 128.9 (C-9a),
130.6 (C-8), 132.4 (C-5b), 135.9 (C-5a), 144.1 (C-7). m/z (ES+)
249.6 (MH+), HRMS (ES) found MH+ 250.0896, C13H16NO2S
requires M+ 250.0896.
R
material as a yellow soild. Purification on a Horizonꢀ column
chromatography system (1: 5% ethyl acetate–pet. ether, 2: 10%
ethyl acetate–pet. ether) afforded the desired product as a white
solid (0.80 g, 1.71 mmol, 73%). mmax (KBr) 3056, 2947, 2914, 2848,
1672, 1595, 1440, 1343, 1230, 1160, 1031, 993, 953, 869 cm−1.
dH (400 MHz, CDCl3) 1.34 (2H, quint., J = 6 Hz, 5-H2), 1.65
(2H, quint., J = 6 Hz, 6-H2), 1.85 (2H, q, J = 6 Hz, 4-H2), 2.35
(3H, s, 4ꢀꢀ-CH3), 3.19 (2H, m, 7-H2), 5.52 (1H, dt, JP = 2 Hz,
JH = 8 Hz, 3-H), 7.07 (2H, d, J = 8 Hz, 3ꢀꢀ-H, 5ꢀꢀ-H), 7.41–7.47
(4H, m, Ar-H), 7.52–7.57 (2H, m, 4ꢀ-H), 7.67 (2H, d, J = 8 Hz,
2ꢀꢀ-H, 6ꢀꢀ-H), 7.78–7.86 (4H, m, Ar-H). dC (100 MHz, CDCl3) 21.9
(4ꢀꢀ-CH3), 24.1 (C-5), 24.4 (C-4), 30.1 (C-6), 49.6 (C-7), 113.6 (C-
3), 127.7 (C-2ꢀꢀ), 128.8 (ArCH), 129.9 (C-3ꢀꢀ), 130.3 (ArC), 131.6
(ArC), 132.4 (ArCH), 132.8 (C-4ꢀ), 138.4 (ArC), 143.9 (C-2). dP
(162 MHz, CDCl3) 33.0. m/z (ES+) 468.2 (MH+), 490.3 (MNa+),
956.8 (2MNa+). HRMS (ES) found MH+ 468.1398, C25H27NO4PS
requires M+ 468.1393; found MNa+ 490.1214, C25H26NNaO4PS
requires M+ 490.1212.
1,2,3,4-Tetrahydro-7-bromoazepino[1,2-b][1,2]benzothiazole-
10,10-dioxide 5f
Purification by flash chromatography (1: 15% ethyl acetate–
cyclohexane, 2: 30% ethyl acetate–cyclohexane) afforded the title
compound as a white solid (0.219 g, 0.70 mmol, 46%). Mp
199–200 ◦C. Found; C, 46.25; H, 3.96; N, 4.38%; calc. for
C12H12NO2SBr; C, 45.87; H, 3.85; N, 4.38%. mmax (KBr) 2939,
2866, 1661, 1589, 1572, 1455, 1418, 1309, 1229, 1177, 1143, 1073,
1055 cm−1. dH (400 MHz, CDCl3) 1.79 (2H, quint., J = 6 Hz, 3-
H2), 1.98 (2H, m, 2-H2), 2.44 (2H, q, J = 6 Hz, 4-H2), 3.58 (2H, m,
1-H2), 5.79 (1H, t, J = 6 Hz, 5-H), 7.58–7.68 (2H, m, 8-H, 9-H),
7.76 (1H, s, 6-H). dC (100 MHz, CDCl3) 26.9 (C-4), 27.4 (C-3),
28.8 (C-2), 45.4 (C-1), 108.2 (C-5), 122.8 (C-9), 123.9 (C-6), 128.0
(ArC), 130.3 (ArC), 132.6 (C-8), 134.0 (C-5b), 134.7 (C-5a). m/z
(ES+) 314.2 [MH+ (Br79)], 316.2 [MH+ (Br81)].
1,2,3,4-Tetrahydro-7-tolylazepino[1,2-b][1,2]benzothiazole-10,10-
dioxide 9
A mixture of p-tolylboronic acid (0.05 g, 0.37 mmol, 1 eq.),
NaHCO3 (0.09 g, 1.10 mmol, 3 eq.) and 5f in a DME (7 ml)–
H2O (3 ml) mixture was degassed by 3 freeze–pump–thaw cycles.
Pd(PPh3)4 (0.02 g, 0.017 mmol, 0.05 eq) was then added and the
reaction mixture was heated at 80 ◦C for 45 min. The mixture was
allowed to cool to room temperature and concentrated in vacuo
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and the aqueous layer was extracted with ethyl acetate. The organic
phase was washed with H2O then brine, dried over MgSO4 and
concentrated in vacuo affording crude material. Purification by
flash chromatography (10% ethyl acetate–pet. ether) afforded the
title compound as an off-white solid (0.102 g, 0.31 mmol, 86%).
Mp >130 ◦C (sinters and decomposes). mmax (KBr) 2940, 2920,
1622, 1393, 1291, 1173, 1142, 1067, 1005, 973, 829, 805, 701 cm−1.
dH (500 MHz, CDCl3) 1.83 (2H, quint., J = 6 Hz, 3-H2), 2.01
(2H, m, 2-H2), 2.43 (3H, s, 4ꢀ-CH3), 2.48 (2H, s, J = 6 Hz, 4-H2),
3.63 (2H, m, 1-H2), 5.90 (1H, t, J = 6 Hz, 5-H), 7.30 (2H, d, J =
Acknowledgements
We thank GlaxoSmithKline for financial support of this work
(CASE award to TMW) Dr A. M. Kenwright for assistance with
NMR experiments and Dr M. Jones for mass spectra.
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=
9 Hz, J2 = 1 Hz, 8-H), 7.77 (1H, d, J = 1 Hz, 6-H), 7.82 (1H, d,
J = 9 Hz, 9-H). dC (125 MHz, CDCl3) 21.4 (4ꢀ-CH3), 27.0 (C-3),
27.3 (C-4), 28.9 (C-2), 45.3 (C-1), 106.7 (C-5), 118.9 (C-6), 121.7
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(C-5b), 136.0 (C-5a), 136.8 (C-1ꢀ), 138.9 (C-4ꢀ), 146.6 (C-9a). m/z
(ES+) 326.1 (MNa+), 389.1 (MNaMeCN+). HRMS (ES) found
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18 Attempts to probe this through time dependent deuteration experi-
ments proved inconclusive.
1,2,3,4,5-Quintahydro-7-methylazepino[1,2-b][1,2]benzothiazole-
10,10-dioxide 10
A solution of 5a (0.05 g, 0.20 mmol, 1 eq.) in EtOH (1 ml,
0.2 M) was added via cannula to a flask containing 10% Pd/C
(7.5 mg, 15% w/w). The flask was placed under an atmosphere
of H2 and the reaction mixture was stirred at room temperature
overnight. The flask was flushed with argon and the suspension
was filtered through a pad of Celite and washed through with
EtOAc; the organics were concentrated in vacuo affording crude
material. Purification by flash chromatography (20% ethyl acetate–
pet. ether) afforded the title compound as a white solid (0.022 g,
0.088 mmol, 44%). Mp 113–115 ◦C. mmax (KBr) 2934, 2856, 1610,
1464, 1305, 1178, 1146, 1061, 941 cm−1. dH (500 MHz, CDCl3)
1.57–1.90 (6H, m), 2.08 (1H, m, 2-HH), 2.28 (1H, m, 5-HH), 2.45
(3H, s, 7-CH3), 3.29 (1H, ddd, J1 = 12 Hz, J2 = 8 Hz, J3 = 4 Hz,
1-HH), 3.68 (1H, ddd, J1 = 12 Hz, J2 = 8 Hz, J3 = 4 Hz, 1-HH),
4.47 (1H, dd, J1 = 10 Hz, J2 = 3 Hz, 5a-H), 7.16 (1H, s, 6-H),
7.31 (1H, d, J = 8 Hz, 8-H), 7.66 (1H, d, J = 8 Hz, 9-H). dC
(125 MHz, CDCl3) 22.1 (7-CH3), 27.1, 27.6 (2 × CH2), 27.7 (C-2),
36.3 (C-5), 42.5 (C-1), 62.3 (C-5a), 121.1 (C-9), 124.3 (C-6), 130.3
(C-8), 132.0 (C-9a), 139.2 (C-5b), 143.9 (C-7). m/z (ES+) 252.0
(MH+), 503.1 (2MH+), 525.1 (2MNa+). HRMS (ES) found MH+
252.1060, C13H17NO2S requires M+ 252.1858.
19 Phosphonites 8a and 8b, particularly 8a, are not stable to chromatogra-
phy undergoing rapid hydrolysis to regenerate the starting lactam which
may account for the apparent low conversions in these experiments.
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21 SHELXTL (ver. 6.14), Bruker-AXS Inc., Madison, WI, USA, 2003.
3476 | Org. Biomol. Chem., 2007, 5, 3472–3476
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