Preparation of novel polycyclic heterocycles using a tin(II) chloride dihydrate-mediated deacetalisation-bicyclisation sequence

Article abstract of DOI:10.1055/s-0028-1083214

Tin(II) chloride dehydrate-mediated deacetalisation-bicyclisation procedures for the construction of novel polycyclic heterocycles from amides possessing a pendant acetal group are reported. Optimisation and scoping studies are described; using this metho

Full text of DOI:10.1055/s-0028-1083214

3846
PAPER
Preparation of Novel Polycyclic Heterocycles Using a Tin(II) Chloride
Dihydrate-Mediated Deacetalisation–Bicyclisation Sequence
Preparationof
N
ov
l
el Poly
e
cyclic
H
ete
x
rocycles
U
sing
T
in
N
(II) Chloride . Cayley,a Katherine A. Gallagher,a Cécilia Ménard-Moyon,a Jan Peter Schmidt,a Louis J. Diorazio,b
Richard J. K. Taylor*a
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
AstraZeneca, Process Research & Development, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, UK
b
Received 12 August 2008
able in the search for bioactive lead compounds. In this
paper we report the preparation of a range of polycyclic
heterocyclic systems using a tin(II) chloride dihydrate
(SnCl2·2H2O) mediated deprotection–bicyclisation se-
Abstract: Tin(II) chloride dihydrate-mediated deacetalisation–
bicyclisation procedures for the construction of novel polycyclic
heterocycles from amides possessing a pendant acetal group are re-
ported. Optimisation and scoping studies are described; using this
methodology, a range of known, and novel, ring-fused heterocyclic quence in the key step. Tin(II) chloride is widely used as
a reducing agent and as a Lewis acid catalyst2 and, as its
systems have been prepared, some in enantiomerically pure form.
dihydrate, has been employed as a mild reagent for the
Key words: heterocycles, tin(II) chloride dihydrate, deacetalisa-
tion, bicyclisation, tandem processes
deprotection of acetals.3
This research was inspired by recent natural product stud-
ies in our group which featured the use of SnCl2·2H2O-
mediated deprotection–cyclisation processes. As illustrat-
ed in Scheme 1, treatment of acetal 1 with SnCl2·2H2O
gave the racemic [6,6,6,6]-tetracyclic core 2 of the HIV-1
integrase inhibitors integrastatins A and B via a presumed
sequence of acetal deprotection, debenzylation, hemi-ace-
tal formation, and alkene etherification.4 More recently, in
an effort directed towards the total synthesis of the macro-
The formation of novel polycyclic heterocycles is of great
interest to the synthetic organic chemist. This interest is
not purely of an academic nature but also based on the fact
that polycyclic heterocycles are considered to be ‘privi-
leged structures’ in the pharmaceutical and agrochemical
industries.1 Thus, new methods for the construction of
such compounds with low molecular weights are invalu-
O
H
O
Boc
O
N
O
SnCl2•2H2O
SnCl2•2H2O
H
OTIPS
OTIPS
BnO
O
CH2Cl2, r.t., 12 h
76%
N
O
CH2Cl2, r.t., 48 h
H
66%
OBn
Boc
3
1
2
4
OBn
O
2 M aq HCl
CH2Cl2, r.t., 17 h
70%
OBn
O
SnCl2•2H2O
O
O
O
OH
O
O
or
CH2Cl2, r.t., 60 h
91%
N
SnCl2•2H2O
CH2Cl2, r.t., 3 h
100%
O
N
OH
HN
O
HN
O
6
7
5
8
O
OMe
Fe(CO)3
O
OMe
O
Fe(CO)3
SnCl2•2H2O
p-TsOH (10 mol%)
H
O
PhMe, 1 h, reflux
92%
(trans/cis = 10:1)
Cbz
N
CO2Me
N
CH2Cl2, r.t., 24 h
63%
(1.5:1 ratio)
O
Cbz NH HN
O
O
CO2Me
OH
O
N
O
HN
O
9
10
11
12
Scheme 1
SYNTHESIS 2008, No. 23, pp 3846–3856
x
x.
x
x
.
2
0
0
8
Advanced online publication: 30.10.2008
DOI: 10.1055/s-0028-1083214; Art ID: P08508SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of Novel Polycyclic Heterocycles Using Tin(II) Chloride
3847
cyclic marine alkaloid ‘upenamide,5 it was found that coupling dioxolane-acids 15 with w-functionalised ali-
SnCl2·2H2O can be employed in the key step for the con- phatic amines 16. In Variant B, the benzannelated ana-
struction of the core systems 4,6 67 and 88 from the res- logues, tricycles 17, would be prepared via amides 18
pective precursors 3, 5 and 7. The SnCl2·2H2O from dioxolane-acids 15 with w-functionalised aryl
deacetalisation–bicyclisation procedure was subsequently amines 19.
employed by Han and Ong to prepare the iron tricarbon-
Similarly, in Variant C, bicycles 20 would be prepared
from amides 21, which would in turn be obtained by cou-
pling dioxolane-amines 22 with w-functionalised aliphat-
ic acids 23. Variant D would then involve the preparation
of the benzannelated analogues, tricycles 24, from amides
25 derived from dioxolane-amines 22 and w-functiona-
lised aryl acids 26.
yl–cyclohexadiene analogue 10,9 thus establishing still
further its mild nature and synthetic utility. It should be
noted that a number of acid-catalysed deprotection–bicy-
clisation procedures have been reported leading to related
O/N-bicyclic acetals10 as well as to N/N-bicyclic sys-
tems.11,12 For example (Scheme 1), in 2006, Blaauw and
co-workers converted acetal 11 into bicycle 12, which
(i) Heterocycles via Variant A
was subsequently transformed into the natural product
(–)-dysibetaine PP.11
Having identified four variants for the construction of
novel polycyclic heterocycles by tandem deprotection–
The generality and simplicity of the SnCl2·2H2O cyclisa-
bicyclisation procedures, we initially decided to evaluate
tion procedures, coupled with the novelty of the heterocy-
the feasibility of Variant A starting from L-cysteine meth-
cles produced, encouraged us to investigate further
yl ester hydrochloride (16a; Scheme 3). Thus, coupling of
applications of this methodology. Preliminary results
the readily available dioxolane-acid 15a14 with amine 16a
using the mixed anhydride method gave the required
amide 14a in 60% purified yield. We were delighted to
observe that treatment of amide 14a with SnCl2·2H2O in
dichloromethane for 72 hours gave methyl 5-oxohexa-
hydropyrrolo[2,1-b]thiazole-3-carboxylate (13a)15 in 70%
yield. This one-pot tandem deprotection–bicyclisation
were published in a recent communication.13 We have
since carried out additional optimisation and scoping
studies and now present a more detailed discussion of this
one-pot, tandem deprotection–bicyclisation procedure.
Four variants of the tandem deprotection–bicyclisation
procedure were investigated and these are outlined in ret-
rosynthetic form in Scheme 2. It was envisaged that the
most useful, general coupling partners would be the diox-
olane-acids 15 and the dioxolane-amines 22. Thus, vari-
ants A and B would both utilise dioxolane-acids 15 as the
coupling partner. In Variant A, bicycles 13 would be pre-
pared from amides 14 which would in turn be prepared by
23
process produced 13a as a single diastereoisomer {[a]D
–250.7 (c 1.25, CHCl3)}, which was tentatively assigned
the (presumed thermodynamically preferred) 3R,7aS-
configuration shown, on the basis of NMR studies.
Attempts to combine the two-step amide-formation–
deprotection–bicyclisation sequence into a single one-pot
Variant A
R1
HX
R1
X
HX
R1
O
O
H
n
N
N
OH
H2N
m
m
O
O
m
n
n
O
R2
R2
O
R2
O
13
14
15
16
Variant B
XH
XH
O
m
m
m
X
O
O
R
R
R
OH
n
O
H2N
N
N
H
O
O
n
O
17
18
15
19
n
O
Variant C
X
R
HX
R
HX
O
R
O
H
N
n
NH2
N
HO
m
O
m
m
O
n
n
O
O
23
21
20
22
XH
Variant D
XH
X
O
m
m
m
O
R
R
R
NH2
H
HO
O
N
n
N
n
O
n
O
O
O
25
22
26
24
Scheme 2
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

3848
A. N. Cayley et al.
PAPER
H
N
i
S
O
O
SH
SH
ClCO2 Bu, NMP
SnCl2•2H2O
H
+
N
HCl•H2N
O
O
CO2H
CH2Cl2, r.t., 72 h
70%
CH2Cl2, –10 °C to r.t., 2 h
60%
O
CO2Me
O
CO2Me
13a
CO2Me
14a
15a
16a
i
i) ClCO2 Bu, NMP, CH2Cl2, –10 °C to r.t., 2 h
ii) filtration
iii) acid (see Table 1)
Scheme 3
process failed. However, it was found that minimal puri-
fication (filtration through silica gel and removal of the
volatiles in vacuo) of the intermediate amide 14a prior to
treatment with SnCl2·2H2O in dichloromethane was suffi-
cient to provide the bicycle 13a in 68% isolated yield (as
compared to the 42% overall yield for the two-step pro-
cess involving purification of intermediate 14a).
Table 1 Yields of 13a from 15a Using the Deprotection–Bicyclisa-
tion Process
Entry Reagent
Solvent
Temp Time Yield
(h)
72
2
(%)
39
29
26
35
5
1
2
3
4
5
6
7
8
10% aq HCl
CH2Cl2
PhMe
r.t.
p-TsOH·H2O (cat)
BF3·Et2O (2 equiv)
SnBr2 (2 equiv)
reflux
r.t.
At this stage we screened a range of mineral, organic and
Lewis acids in the deprotection–bicyclisation process
(Table 1). In view of related cyclisation sequences, dilute
hydrochloric acid10 and p-TsOH·H2O11 were studied first
(entries 1 and 2) but mixtures of products were obtained
and the yields of compound 13a were disappointing. The
widely used Lewis acid, BF3·Et2O, gave a similarly low
yield (entry 3), as did SnBr2 and SnCl4 (entries 4 and 5).
Anhydrous SnCl2 gave an improved yield (57%, entry 6)
but the original procedure using SnCl2·2H2O proved to be
the best (68% over two steps from 15a, entry 7). A likely
rationale is that SnCl2·2H2O slowly releases dilute hydro-
chloric acid to aid acetal cleavage in addition to the Lewis
acidic Sn(II) to aid the bicyclisation process; this theory is
supported by the fact that addition of potassium carbonate
to the SnCl2·2H2O reaction resulted in a dramatic loss of
activity. However, it is noteworthy that CuCl2·2H2O, a re-
agent which efficiently hydrolyses acetals when used in
ethanol,16 proved to be totally ineffective in dichloro-
methane (entry 8).
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
72
72
72
72
24
r.t.
SnCl4 (2 equiv)
r.t.
SnCl2 (2 equiv)
r.t.
57
68
0
SnCl2·2H2O (2 equiv)
CuCl2·2H2O (2 equiv)
r.t.
r.t.
amide formation between acid 15a and L-serine derivative
16b followed by treatment with SnCl2·2H2O induced the
desired deacetalisation–bicyclisation reaction to give the
23
novel heterocycle 13b {[a]D –124.3 (c 1.0, CHCl3)} in
moderate yield over the two-step process. In a similar
manner, amide formation between acid 15a and 3-amino-
propanol (16c) followed by deacetalisation–bicyclisation
gave the known heterocyclic system 13c17 {hemi-aminal
proton: dH = 4.94 ppm, 1 H, dd, J = 6.5, 2.8 Hz; IR 1690
cm–1; Lit.17 dH = 4.94 ppm, 1 H, m; IR 1690 cm–1}. The
novel, higher homologue 13d was then prepared from 4-
aminobutanol (16d) in reasonable yield over the two
steps.
It should be noted that the ability of tin(II) chloride to act
as a reductant can also be exploited. Thus, processing of
the disulfide, L-cysteine dimethyl ester dihydrochloride
27, through the same coupling and SnCl2·2H2O conditions
via amide 28 gave the same heterocycle 13a in 59% over-
all yield (Scheme 4). In the second step, the SnCl2·2H2O
is mediating the three-step disulfide reduction–deprotec-
tion–bicyclisation sequence.
(ii) Heterocycles via Variant B
Our attention next turned to the second combination of
coupling partners outlined in Scheme 2, in which the same
dioxolane-acid 15a is coupled with w-functionalised aryl
amines 19 to generate benzannelated tricycles 17, via
amides 18. The initial example explored was unsuccess-
Next, three further examples were explored in order to in-
dicate the generality of the procedure (Scheme 5). Thus,
i
i) ClCO2 Bu, NMP,
H
CH2Cl2, –10 °C to r.t.
2 h
iii) SnCl2•2H2O,
2
2
S
S
O
O
S
CH2Cl2, r.t., 72 h
+
H
ClH•H2N
N
ii) filtration
59% overall
from 15a
N
O
O
CO2H
CO2Me
O
CO2Me
O
CO2Me
27
13a
15a
28
Scheme 4
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

PAPER
Preparation of Novel Polycyclic Heterocycles Using Tin(II) Chloride
3849
i
i) ClCO2 Bu, NMP,
iii) SnCl2•2H2O,
CH2Cl2,
H
N
CH2Cl2, –10 °C to r.t.,
2 h
O
O
O
OH
OH
r.t., 12 h
H
+
N
ClH•H2N
O
CO2H
34%
O
ii) filtration
O
CO2Me
O
CO2Me
CO2Me
13b
14b
15a
16b
i
i) ClCO2 Bu, NMP,
iii) SnCl2•2H2O,
CH2Cl2,
CH2Cl2, –10 °C to r.t.,
2 h
HO
O
HO
O
r.t., 12 h
O
H
+
N
N
H2N
O
CO2H
O
ii) filtration
56%
O
O
15a
16c
14c
13c
i
iii) SnCl2•2H2O,
CH2Cl2,
i) ClCO2 Bu, NMP,
CH2Cl2, –10 °C to r.t.,
2 h
O
r.t., 12 h
O
HO
H
O
HO
H2N
+
N
N
O
57%
O
CO2H
ii) filtration
O
O
15a
14d
16d
13d
Scheme 5
ful: conversion of 2-aminophenol (19a) into amide 18a modest yield, to give the novel bicyclo[3.3.0]octane het-
was straightforward, but all attempts to effect the cyclisa- erocyclic products 20a as a separable mixture of two dia-
tion to give 17a failed (Scheme 6). On the assumption that stereoisomers. In a similar manner, N-Boc-L-alanine
this failure was due to the low nucleophilicity of the phe- (23b) was converted into an inseparable mixture of novel
nolic group and/or to ring strain in the product, w-func- diazabicyclo[3.3.0]octanes 20b (ratio established by
tionalised anilines 19b–d were studied. In the case of the NMR spectroscopy).19 In both 20a and 20b, the major dia-
corresponding thiophenol 19b, coupling again proceeded stereoisomer was tentatively assigned by inspection of
smoothly but in this example, treatment with SnCl2·2H2O molecular models (NMR and NOE studies were uninfor-
promoted the desired deacetalisation–bicyclisation reac- mative). Finally in this section, amine 22a and N-Boc-L-
tion to give the novel heterocycle 17b accompanied by the serine 23c gave the bicyclo[4.3.0]nonane adduct 20c as a
cyclisation precursor 29.
single diastereoisomer in 46% yield {[a]D22 +32.5 (c 0.95,
CHCl3)}.
Encouraged by this partial success, we investigated the
use of 2-aminobenzyl alcohol 19c and the corresponding (iv) Heterocycles via Variant D
thiol 19d (Scheme 6). In both cases, the coupling and
The final variant to be explored utilised dioxolane-amine
deacetalisation–bicyclisation proceeded smoothly, giving
the novel benzannelated heterocycles 17c and 17d in 80
and 86% overall yields, respectively. Finally, in a slight
variation, the N-methylated diamine 30 was subjected to
the coupling–deacetalisation–bicyclisation sequence to
produce the linear tricyclic adduct 32 in 43% overall
yield, further illustrating the potential of this methodolo-
gy.
22a and w-functionalised aryl acids 26 (m = 0) to produce
benzannelated products 24 (Scheme 8). Once again, the
coupling procedure to produce the intermediate amides 25
proved problematic. Using 2-hydroxy-3-methylbenzoic
acid (26a) to ultimately produce heterocycle 24a, the
i
mixed anhydride procedure (ClCO2 Bu) gave no product
and HATU gave the required product 24a in only 45%
yield. Turning to other activated acid derivatives, the acid
chloride and methyl ester derived from 26a gave only
trace amounts of product 24a after attempted coupling and
treatment with SnCl2·2H2O. However, we were delighted
to find that the phenyl ester derivative 33 underwent effi-
cient coupling to amine 22a under microwave irradiation
(iii) Heterocycles Via Variant C
Having established the viability of procedures utilising di-
oxolane-acid 15a for heterocycle formation, we moved on
to explore the potential of dioxolane-amines 22, initially
looking at their coupling with w-functionalised aliphatic
acids 23 (Scheme 7). In the initial example, amine 22a18
was coupled to (R)-mandelic acid 23a; it was established
that 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-
(MW)
and
deacetalisation–bicyclisation
using
SnCl2·2H2O gave the expected product 24a in almost
quantitative yield.
uronium hexafluorophosphate (HATU)-mediated peptide Attempts to develop a tandem process were unsuccessful;
coupling was preferable to the mixed anhydride method heating the mixture of 22a, 33 and SnCl2·2H2O under mi-
for the formation of amide 21a. The SnCl2·2H2O-mediat- crowave conditions resulted in complete degradation of
ed deacetalisation–bicyclisation proceeded cleanly, if in the starting materials. However, a telescoped procedure
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

3850
A. N. Cayley et al.
PAPER
i
i) ClCO2 Bu, NMP,
iii) SnCl2•2H2O, CH2Cl2,
r.t., 48 h (18a recovered)
CH2Cl2, –10 °C to r.t.,
2 h
HO
+
HO
O
O
O
X
N
O
ii) filtration
O
H2N
CO2H
N
H
O
O
17a
15a
18a
19a
i
i) ClCO2 Bu, NMP,
CH2Cl2, –10 °C to r.t.,
2 h
iii) SnCl2•2H2O,
CH2Cl2,
r.t., 48 h
OH
SH
HS
HS
O
S
O
O
+
O
ii) filtration
N
N
O
H2N
N
H
CO2H
O
O
O
15a
19b
18b
17b
29
31%
14%
i
i) ClCO2 Bu, NMP,
CH2Cl2, –10 °C to r.t.,
2 h
OH
OH
iii) SnCl2•2H2O, CH2Cl2,
r.t., 24 h
O
O
O
+
O
ii) filtration
O
80%
CO2H
N
H2N
N
H
O
15a
19c
18c
17c
O
i
SH
SH
i) ClCO2 Bu, NMP,
CH2Cl2, –10 °C to r.t.,
2 h
iii) SnCl2•2H2O, CH2Cl2,
O
S
O
r.t., 18 h
+
O
O
CO2H
N
O
N
H
H2N
ii) filtration
86%
O
15a
19d
18d
17d
i
i) ClCO2 Bu, NMP,
NH2
O
O
CH2Cl2, –10 °C to r.t.,
2 h
iii) SnCl2•2H2O, CH2Cl2,
r.t., 18 h
O
O
NH
N
+
O
O
CO2H
ii) filtration
MeHN
N
43%
Me
MeHN
32
15a
31
30
Scheme 6
H
N
O
Ph
Ph
i) HATU, DIPEA
CH2Cl2, 0 °C to r.t.,
2 h
iii) SnCl2•2H2O,
CH2Cl2, r.t.,
12 h
O
O
HO
Ph
O
O
OH
O
20a (major)
H
N
+
NH2
+
H
ii) filtration
O
43% (α/β = 2:1)
Ph
HO
O
O
N
22a
21a
23a
20a (minor)
O
iii) SnCl2•2H2O,
CH2Cl2, r.t.,
12 h
i) HATU, DIPEA
CH2Cl2, 0 °C to r.t.,
2 h
Boc
H
N
BocHN
Me
O
O
O
N
O
NHBoc
Me
H
N
+
Me
NH2
ii) filtration
O
HO
55% (α/β = 1:3 )
O
O
22a
23b
21b
20b (inseparable)
i) HATU, DIPEA
iii) SnCl2•2H2O,
CH2Cl2, r.t.,
12 h
H
O
HO
O
CH2Cl2, 0 °C to r.t.,
NHBoc
O
O
O
2 h
HO
+
H
NH2
N
N
O
ii) filtration
NHBoc
46%
NHBoc
HO
O
O
22a
23c
21c
20c
Scheme 7
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

PAPER
Preparation of Novel Polycyclic Heterocycles Using Tin(II) Chloride
3851
i) coupling
ii) filtration
iii) SnCl2•2H2O,
CH2Cl2, r.t.
HX
O
HX
O
X
O
O
O
R
H
R
R
NH2
+
HO
N
N
O
O
22a
26
25
24
Me
Me
Me
ii) SnCl2•2H2O,
HO
HO
O
O
i) MW
CH2Cl2, r.t., 18 h
O
O
H
NH2
+
PhO
N
98%
N
O
O
O
O
25a
22a
33
24a
O
F
O
O
O
O
O
O
N
N
N
N
N
N
Cl
24d (87%)
O
O
O
O
O
24c (98%)
24b (77%)
24f (65%)
24e (84%)
24g (56%)
Scheme 8
zu and co-workers;18 all data were in accordance with the assigned
structure, and 1H NMR data was in accordance with the literature.18
was developed that proved to be extremely straightfor-
ward; after heating the amine and ester together neat in a
microwave system, the resulting amide was then dis- Flash column chromatography was performed using Fluka silica gel
60 at a low positive pressure. Analytical TLC was performed on alu-
solved directly in dichloromethane and SnCl2·2H2O was
minium sheets precoated with Merck silica gel 60 F254, and visual-
added in a single portion. After stirring at room tempera-
ised with ultraviolet light (254 nm), aq KMnO4 or alcoholic vanillin
ture, the desired heterocycles could then be isolated by
solutions, as appropriate. Preparative TLC was performed on What-
flash chromatography. These conditions were then ap-
man Partasil K6F precoated 60 Silica Gel Glass plates, and visual-
plied to a range of phenyl esters,20 producing novel poly-
ised under UV light (254 nm). SCX refers to prepacked Varian
cyclic heterocycles 24b–g (Scheme 8). These hetero-
BondElut SCX columns (1 g). All melting points were taken on a
Gallenkamp apparatus. 1H NMR spectra were recorded at 400 MHz
on a JEOL ECX 400 spectrometer or at 270 MHz on a JEOL ECX
270 spectrometer and are reported as follows: chemical shift (d,
ppm), multiplicity, coupling constant J (to the nearest 0.5 Hz), num-
ber of protons, assignment. Residual protic solvent CHCl3
1
cycles all show characteristic H and 13C NMR signals
(hemi-aminal protons between d = 5.33 and 5.65 ppm;
hemi-aminal carbons at d = 87.7–89.0 ppm; e.g. 24a, dH =
5.46 ppm; dC = 88.4 ppm).
In summary, we have developed a mild, cheap and simple (dH = 7.26 ppm) or DMSO (dH = 2.50 ppm) was used as an internal
reference. 13C NMR spectra were recorded at 100 MHz on a JEOL
method of producing a diverse range of polycyclic hetero-
ECX 400 spectrometer or at 125 MHz on a Bruker AV500 spec-
cycles from commercially available or easily accessible
trometer. The central peak of CDCl3 (dC = 77.0 ppm) or DMSO
starting materials using amide coupling followed by a
(dC = 39.4 ppm) was used as an internal reference. 19F NMR spectra
tin(II) chloride mediated deacetalisation–bicyclisation se-
were recorded at 376 MHz on a JEOL ECX 400 spectrometer.
quence. The products, several of which have been ob-
tained in diastereoselective processes, should be of
interest both in their own right and as building blocks for
the production of more complex target molecules. We are
currently investigating the application of this methodolo-
gy to complex natural product targets.
Chemical shifts are reported in parts per million (ppm) to the nearest
1
0.01 ppm for H and the nearest 0.1 ppm for 13C and 19F. Infrared
spectra were carried out on a ThermoNicolet IR100 spectrometer
and are recorded as a liquid film or a Nujol® mull between NaCl
disks. Absorption maxima are reported in wavenumbers (cm–1) and
only selected absorbencies are reported. Mass spectra and accurate
mass measurements were recorded on a Micromass Autospec spec-
trometer.
Et2O was dried using an MBraun MPS solvent purification system.
Anhydrous THF was obtained by distillation over sodium ben-
zophenone. Petroleum ether (PE) refers to light petroleum ether, bp
40–60 °C. All reagents were used as supplied by the manufacturers,
unless otherwise stated. SnCl2·2H2O was purchased from Aldrich
and used without further purification. 3-[1,3]-Dioxolan-2-ylpropi-
onic acid (15a) was prepared by the method of Shea and co-work-
ers;14 all data were in accordance with the assigned structure, and 1H
NMR data was in accordance with the literature.14 3-[1,3]-Diox-
olan-2-ylpropylamine (22a) was prepared by the method of Shimi-
Microwave irradiation refers to the use of a CEM ‘Discovery’ reac-
tor, with reactions contained in 10 mL CEM tubes with Intellivent®
caps.
Methyl 2-(3-[1,3]Dioxolan-2-ylpropionylamino)-3-mercapto-
propanoate (14a)
Isobutyl chloroformate (44 mL, 0.34 mmol) was added dropwise to
a solution of acid 15a14 (50 mg, 0.34 mmol) and N-methylpiperidine
(41 mL, 0.34 mmol) in CH2Cl2 (4 mL) at –10 °C (acetone–ice bath).
After exactly 2 min, an ice-cold solution of L-cysteine methyl ester
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

3852
A. N. Cayley et al.
PAPER
hydrochloride (16a; 62 mg, 0.36 mmol) and N-methylpiperidine (44
mL, 0.36 mmol) in CH2Cl2 (1 mL) was added dropwise and stirring
was continued at –10 °C for 1 h and then the reaction mixture was
slowly allowed to warm to r.t. and stirred for a further 1 h. The so-
lution was then filtered through a short pad of silica gel, washing
through with EtOAc (3 × 5 mL) and the volatiles removed from the
filtrate in vacuo to give the crude amide 14a, which was used imme-
diately in the subsequent cyclisation reaction without further purifi-
cation. If so desired, the crude amide 14a could be purified by flash
column chromatography (SiO2, EtOAc), to give the title compound
14a.
Yield: 46 mg (68% over two steps from 15a); clear colourless oil.
Method C: From Disulfide 27
L-Cysteine dimethyl ester dihydrochloride (27; 128 mg, 0.37 mmol)
and 3-[1,3]dioxolan-2-ylpropionic acid (15a; 100 mg, 0.68 mmol)
were converted into amide 28 according to the procedure used for
amide 14a (see above). The unpurified amide 28 was then treated
with SnCl2·2H2O (306 mg, 1.36 mmol) for 72 h following the pro-
cedure used in methods A and B above. The crude product was pu-
rified by flash column chromatography (SiO2, Et2O), to give the title
compound 13a.
23
Yield: 82 mg (59% over two steps); clear colourless oil.
Yield: 54 mg (60%); clear colourless oil; [a]D +41.9 (c 1.00,
CHCl3); Rf = 0.40 (EtOAc).
Methyl (3S,8S)-5-Oxohexahydropyrrolo[2,1-b]oxazole-3-car-
boxylate (13b)
IR (neat): 3300 (br), 2955, 2886, 1740, 1659, 1531, 1439, 1242,
1215, 1140, 1042 cm–1.
Prepared from L-serine methyl ester hydrochloride (16b; 56 mg,
0.36 mmol) and 3-[1,3]dioxolan-2-ylpropionic acid (15a; 50 mg,
0.34 mmol) according to the procedures described for the prepara-
tion of compound 13a. The unpurified amide was stirred with
SnCl2·2H2O (153 mg, 0.68 mmol) for 12 h and the crude product
was purified by flash column chromatography (SiO2, Et2O), to yield
the title compound 13b.
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 9.0 Hz, 1 H, SH),
1.98–2.03 (m, 2 H, CH2), 2.37 (t, J = 7.5 Hz, 2 H, CH2C=O), 2.96
(dd, J = 9.0, 4.0 Hz, 2 H, CH2SH), 3.76 (s, 3 H, CO2CH3), 3.82–
3.87 (m, 2 H, OCH2), 3.92–3.99 (m, 2 H, OCH2), 4.86 (dt, J = 7.5,
4.0 Hz, 1 H, CHCO2CH3), 4.92 [t, J = 4.0 Hz, 1 H, CH(OCH2)2],
6.71 (br d, J = 7.5 Hz, 1 H, NHCO).
23
13C NMR (100 MHz, CDCl3): d = 26.7, 28.9, 30.1, 52.7, 53.5, 64.9,
103.1, 170.6, 172.2.
Yield: 21 mg (34% over two steps); clear colourless oil; [a]D
–124.3 (c 1.0, CHCl3); Rf = 0.24 (Et2O).
MS (ESI): m/z (%) = 286 (20) [M + Na]+, 264 (100) [M + H]+.
IR (neat): 2956, 2921, 1719, 1403, 1279, 1212, 1173, 1007 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C10H18NO5S: 264.0900;
found: 264.0907 (3.3 ppm error).
1H NMR (400 MHz, CDCl3): d = 2.06–2.17 (m, 1 H, CHH), 2.38–
2.56 (m, 2 H, CHHC=O, CHH), 2.65–2.75 (m, 1 H, CHHC=O),
3.78 (s, 3 H, CO2CH3), 3.91 (dd, J = 8.5, 6.5 Hz, 1 H, CHHO), 4.36
(t, J = 8.5 Hz, 1 H, CHHO), 4.68 (dd, J = 8.5, 6.5 Hz, 1 H,
CHCO2CH3), 5.20 (dd, J = 6.0, 2.0 Hz, 1 H, NCHO).
Methyl (3R,8S)-5-Oxohexahydropyrrolo[2,1-b]thiazole-3-car-
boxylate (13a)
Method A: From Purified 14a
13C NMR (100 MHz, CDCl3): d = 23.8, 30.9, 52.7, 56.0, 69.5, 93.0,
Amide 14a (100 mg, 0.38 mmol) was dissolved in CH2Cl2 (5 mL)
and SnCl2·2H2O (0.17 g, 0.76 mmol) added. The reaction mixture
was stirred for 72 h at r.t. then diluted with CHCl3 (5 mL) and treat-
ed with K2CO3 (0.25 g, 1.8 mmol). Stirring was continued for a fur-
ther 30 min then the mixture was filtered through a short pad of
Celite®, washing through with CHCl3 (3 × 10 mL). The filtrate was
concentrated in vacuo and the crude product was purified by flash
column chromatography (SiO2, PE–EtOAc, 1:1), to give the title
compound 13a.
170.6, 179.5.
MS (ESI): m/z (%) = 186 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C8H12NO4: 186.0761; found:
186.0761 (0.1 ppm error).
Tetrahydropyrrolo[2,1-b][1,3]oxazin-6-one (13c)
Prepared from 3-amino-1-propanol (16c; 55 mL, 0.71 mmol) and 3-
[1,3]dioxolan-2-ylpropionic acid (15a; 100 mg, 0.68 mmol) accord-
ing to the procedures described for the preparation of compound
13a. The unpurified amide was stirred with SnCl2·2H2O (306 mg,
1.36 mmol) for 12 h, then the crude product was purified by flash
column chromatography (SiO2, MeOH–CH2Cl2, 5:95), to give the
title compound 13c.
23
Yield: 53 mg (70%); clear colourless oil; [a]D –250.7 (c 1.25,
CHCl3); Rf = 0.33 (PE–EtOAc, 1:1).
IR (neat): 2954, 1743, 1709, 1437, 1388, 1285, 1218, 1177 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.09–2.19 (m, 1 H, CHH), 2.48–
2.59 (m, 2 H, CHHC=O, CHH), 2.60–2.73 (m, 1 H, CHHC=O),
3.33 (dd, J = 11.5, 4.5 Hz, 1 H CHHS), 3.38 (dd, J = 11.5, 7.5 Hz,
1 H, CHHS), 3.73 (s, 3 H, CO2CH3), 5.08 (dd, J = 7.5, 4.5 Hz, 1 H,
CHCO2CH3), 5.19 (dd, J = 7.0, 4.0 Hz, 1 H, NCHS).
13C NMR (100 MHz, CDCl3): d = 24.6, 31.0, 36.1, 52.7, 57.6, 66.3,
170.2, 176.3.
Yield: 54 mg (56% over two steps); clear colourless oil; Rf = 0.46
(MeOH–CH2Cl2, 5:95).
IR (neat): 2960, 2864, 1690, 1451, 1277, 1076, 1053 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.44–1.50 (m, 1 H, CHHCNO),
1.74–1.93 (m, 2 H, CH2), 2.22–2.39 (m, 2 H, CHHC=O, CHH),
2.45–2.54 (m, 1 H, CHHC=O), 3.08 (td, J = 13.0, 4.0 Hz, 1 H,
CHHN), 3.71 (td, J = 12.0, 2.0 Hz, 1 H, CHHO), 4.06–4.12 (m, 1 H,
CHHO), 4.15–4.21 (m, 1 H, CHHN), 4.94 (dd, J = 6.5, 2.5 Hz, 1 H,
NCHO). Consistent with published data.16
MS (ESI): m/z (%) = 202 (100) [M + H]+, 142 (10) [M – CO2Me]+.
HRMS (ESI): m/z [M + H]+ calcd for C8H12NO3S: 202.0532; found:
202.0539 (3.3 ppm error).
13C NMR (100 MHz, CDCl3): d = 24.6, 24.7, 28.8, 38.6, 67.0, 88.0,
173.5.
Method B: Telescoped Procedure
Unpurified amide 14a (see above) was redissolved in CH2Cl2 (5
mL). SnCl2·2H2O (0.17 g, 0.75 mmol) was added to this solution
and the reaction mixture was stirred at r.t. for 72 h, whereupon it
was diluted with CHCl3 (5 mL) and then treated with K2CO3 (0.25
g, 1.8 mmol). Stirring was continued for a further 30 min then the
mixture was filtered through a short pad of Celite®, washing
through with CHCl3 (3 × 10 mL). The filtrate was concentrated in
vacuo and the crude product was purified by flash column chroma-
tography (SiO2, PE–EtOAc, 1:1), to give the title compound 13a.
MS (CI, NH3): m/z (%) = 159 (80) [M + NH4]+, 142 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C7H11NO2Na: 164.0682;
found: 164.0680 (1.3 ppm error).
Hexahydropyrrolo[2,1-b][1,3]oxazepin-7-one (13d)
Prepared from 4-amino-1-butanol (16d; 33 mL, 0.36 mmol) and 3-
[1,3]dioxolan-2-ylpropionic acid (15a; 50 mg, 0.34 mmol) accord-
ing to the procedure described for the preparation of compound 13a.
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

PAPER
Preparation of Novel Polycyclic Heterocycles Using Tin(II) Chloride
3853
The unpurified amide was stirred with SnCl2·2H2O (153 mg, 0.68
mmol) for 12 h and the crude product was purified by flash column
chromatography (SiO2, MeOH–CH2Cl2, 5:95), to yield the title
compound 13d.
13C NMR (100 MHz, CDCl3): d = 23.9, 30.5, 31.0, 60.9, 122.7,
123.5, 124.4, 127.6, 128.7, 135.9, 173.2.
MS (ESI): m/z (%) = 228 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H11NOSNa: 228.0454;
Yield: 30 mg (57% over two steps); clear colourless oil; Rf = 0.30
(MeOH–CH2Cl2, 5:95).
found: 228.0459 (2.1 ppm error).
IR (neat): 2931, 1689, 1419, 1374, 1279, 1186, 1099 cm–1.
4-Methyl-3,3a,4,9-tetrahydro-2H-pyrrolo[2,1-b]quinazoin-1-
one (32)
1H NMR (400 MHz, CDCl3): d = 1.65–1.95 (m, 5 H, CH2), 2.21–
2.35 (m, 2 H, CHHC=O, CHH), 2.47–2.58 (m, 1 H, CHHC=O),
3.20 (ddd, J = 13.5, 6.5, 3.0 Hz, 1 H, CHHN), 3.46–3.53 (m, 1 H,
CHHO), 3.57–3.66 (m, 1 H, CHHN), 3.82–3.89 (m, 1 H, CHHO),
5.06 (dd, J = 6.5, 2.5 Hz, 1 H, NCHO).
13C NMR (100 MHz, CDCl3): d = 25.6, 26.4, 29.4, 30.9, 42.5, 68.8,
90.3, 174.8.
Prepared from 2-methylaminobenzylamine (30; 60 mg, 0.43
mmol)22 and 3-[1,3]dioxolan-2-ylpropionic acid (15a; 58 mg, 0.39
mmol) according to the procedure described for the preparation of
compound 13a. The crude amide was stirred with SnCl2·2H2O (175
mg, 0.78 mmol) for 18 h and the crude product was purified by pre-
parative TLC (EtOAc–PE, 1:1) to yield the title compound 32.
Yield: 35 mg (43%); colourless oil; Rf = 0.31 (EtOAc–PE, 1:1).
IR (neat): 1685, 1498, 1447, 1369, 1307, 1273, 1212 cm–1.
MS (ESI): m/z (%) = 156 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C8H14NO2: 156.1019; found:
1H NMR (400 MHz, CDCl3):
d = 2.02–2.09 (m, 1 H,
156.1018 (0.5 ppm error).
CHHCH2C=O), 2.36–2.57 (m, 3 H, CHHCH2C=O, CH2C=O), 2.81
(s, 3 H, NCH3), 4.25 (d, J = 17.0 Hz, 1 H, ArCHH), 4.56 (t, J = 6.0
Hz, 1 H, NCHN), 4.85 (d, J = 17.0 Hz, 1 H, ArCHH), 6.79–6.81 (m,
2 H, Ar-H), 7.03 (d, J = 7.5 Hz, 1 H Ar-H), 7.16 (t, J = 7.5 Hz, 1 H,
Ar-H).
2,3,3a,5-Tetrahydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-1-
one (17c)
Prepared from 2-aminobenzyl alcohol (19c; 89 mg, 0.72 mmol) and
acid 15a (100 mg, 0.72 mmol) according to the procedure described
for the preparation of compound 13a. The crude amide was stirred
with SnCl2·2H2O (324 mg, 1.44 mmol) for 24 h and the crude prod-
uct was purified by flash column chromatography (SiO2, Et2O), to
yield the title compound 17c.
13C NMR (100 MHz, CDCl3): d = 28.8, 29.5, 33.8, 41.1, 71.9, 113.7,
119.2, 119.6, 126.8, 128.0, 145.7, 173.5.
MS (ESI): m/z (%) = 225 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14N2ONa: 225.0998;
Yield: 104 mg (80%); colourless solid; mp 89–90 °C; Rf = 0.38
(Et2O).
found: 225.1006 (3.5 ppm error).
IR (neat): 1695, 1494, 1490, 1215, 1080 cm–1.
(2R)-2-Phenyltetrahydropyrrolo[2,1-b]oxazol-3-one (20a)
A solution of 3-[1,3]dioxolan-2-ylpropylamine (22a; 0.10 g, 0.76
mmol) in CH2Cl2 (1 mL) was added dropwise to a solution of (R)-
(–)-mandelic acid (23a; 0.12 g, 0.80 mmol) and DIPEA (0.16 mL,
0.91 mmol) in CH2Cl2 (5 mL) at 0 °C. This was followed immedi-
ately by the portionwise addition of HATU (0.32 g, 0.84 mmol) to
the reaction. The yellow solution was stirred at 0 °C for 1 h and then
allowed to slowly warm to r.t. and stirred for a further 1 h. The re-
action was filtered through a short pad of silica, washing through
with EtOAc (3 × 10 mL). The volatiles were removed from the fil-
trate under reduced pressure to yield the crude amide (contaminated
with tetramethylurea). The unpurified amide was redissolved in
CH2Cl2 (8 mL), SnCl2·2H2O (0.38 g, 1.67 mmol) was added, and the
reaction mixture was stirred at r.t. for 12 h. The mixture was diluted
with CHCl3 (8 mL) and then treated with K2CO3 (0.5 g, 3.6 mmol)
and stirring was continued for a further 30 min. The mixture was fil-
tered through a short pad of Celite®, washing through with CHCl3
(3 × 10 mL). The filtrate was concentrated in vacuo and the crude
product was purified by flash column chromatography (SiO2,
EtOAc), to give the title compound 20a.
1H NMR (270 MHz, CDCl3):
d = 2.01–2.10 (m, 1 H,
CHHCH2C=O), 2.47–2.61 (m, 3 H, CH2C=O, CHHCH2C=O), 4.90
(d, J = 15.0 Hz, 1 H, Ar-CH2O), 5.05 (d, J = 15.0 Hz, 1 H, Ar-
CH2O), 5.27 (dd, J = 7.0, 5.0 Hz, 1 H, OCHN), 7.02 (br d, J = 7.5
Hz, 1 H, Ar-H), 7.10 (td, J = 7.5, 1.0 Hz, 1 H, Ar-H), 7.26–7.27 (m,
1 H, Ar-H), 8.30 (d, J = 8.5 Hz, 1 H, Ar-H).
13C NMR (125 MHz, CDCl3): d = 24.8, 30.1, 58.1, 87.2, 119.6,
123.8, 124.3, 124.4, 127.7, 134.2, 172.0.
MS (ESI): m/z (%) = 212 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H11NO2Na: 212.0682;
found: 212.0687 (2.2 ppm error).
3,3a-Dihydro-2H,5H-pyrrolo[2,1-a][3,1]benzothiazine-1-one
(17d)
Prepared from (2-aminophenyl)methane thiol21 (19d; 106 mg, 0.75
mmol) and 3-[1,3]dioxolan-2-ylpropionic acid (15a; 100 mg, 0.68
mmol) according to the procedure for compound 13a. The crude
amide was stirred with SnCl2·2H2O (306 mg, 1.36 mmol) for 18 h
and the crude product was partially purified by flash column chro-
matography (MeOH–CH2Cl2, 3:97). The impure product was dis-
solved in MeOH and loaded onto an SCX column. Washing with
MeOH then elution with ~0.5M methanolic ammonia and concen-
tration gave the title compound 17d.
Yield: 54 mg (43% over two steps); mixture of diastereoisomers
[2:1, separable by careful chromatography: Rf = 0.50 (major), 0.55
(minor) (EtOAc)]; clear colourless oil.
IR (neat): 2979, 2945, 2894, 1717, 1413, 1309, 1091, 911 cm–1.
1H NMR (400 MHz, CDCl3): d (mixture of diastereoisomers) =
1.69–2.26 (m, 4 H, CH2), 3.07–3.17 (m, 1 H, CHHN), 3.74–3.84
(m, 1 H, CHHN), 5.38 [s, 1 H, CHC=O (minor)], 5.45 [s, 1 H,
CHC=O (major)], 5.59–5.63 [m, 1 H, NCHO (major)], 5.66–5.70
[m, 1 H, NCHO (minor)], 7.30–7.50 (m, 5 H, Ar-H).
13C NMR (100 MHz, CDCl3): d (minor diastereoisomer given in
brackets) = 24.3, (24.0), 31.50, (31.45), 43.0, (42.4), 83.7, (83.3),
(94.2), 92.7, 126.9, (125.6), 128.5, (128.4), 128.7, (128.6), (136.1),
135.6, (173.6), 173.1.
Yield: 105 mg (86%); pale-yellow oil; Rf = 0.65 (MeOH–CH2Cl2,
1:10).
IR (neat): 3430, 2095, 1643, 1468, 1210, 1104 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.03–2.11 (m, 1 H, CHH), 2.57–
2.68 (m, 3 H, CH2=O, CHH), 3.70 (d, J = 17.0 Hz, 1 H, ArCH2N),
4.30 (d, J = 17.0 Hz, 1 H, ArCH2), 5.02–5.05 (m, 1 H, NCHS), 7.10
(br d, J = 8.0 Hz, 1 H, Ar-H), 7.15–7.17 (m, 1 H, Ar-H), 7.30 (br t,
J = 8.0 Hz, 1 H, Ar-H), 8.25 (dd, J = 8.0, 1.0 Hz, 1 H, Ar-H).
MS (ESI): m/z (%) = 204 (100) [M + H]+.
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

3854
A. N. Cayley et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO2: 204.1019; found:
204.1020 (0.5 ppm error).
mmol) in a sealed tube, was heated under microwave irradiation at
135 °C for 10 min (50 W input power). The resulting gum was al-
lowed to cool to r.t., dissolved in CH2Cl2 (5 mL) and SnCl2·2H2O
(100 mg, 0.44 mmol) was added in a single portion. The reaction
was allowed to stir at r.t. for 18 h whereupon it was diluted with
CHCl3 (5 mL) and then treated with K2CO3 (130 mg, 0.94 mmol)
and stirring was continued for a further 30 min. The mixture was fil-
tered through a short pad of Celite®, washing with CHCl3 (3 × 10
mL). The filtrate was concentrated in vacuo and purified by flash
chromatography (SiO2; Et2O) to give the title compound 24a.
tert-Butyl (2S)-2-Methyl-3-oxohexahydropyrrolo[1,2-a]imida-
zole-1-carboxylate (20b)
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 0.10 g, 0.76
mmol) and N-Boc-L-alanine (23b; 0.15 g, 0.80 mmol) according to
the procedure described for the preparation of compound 20a. The
crude amide was stirred with SnCl2·2H2O (342 mg, 1.52 mmol) for
12 h and the crude product 20b was purified by flash column chro-
matography (SiO2, EtOAc), to yield the title compound 20b as an
inseparable mixture of diastereoisomers (3:1).
Yield: 70 mg (98%); colourless solid; mp 111–113 °C; Rf = 0.25
(Et2O).
Yield: 0.10 g (55% over two steps); clear colourless oil; Rf = 0.45
(EtOAc).
IR (Nujol mull): 2955, 2924, 2855, 1669, 1440, 1073 cm–1.
1H NMR (400 MHz, CDCl3):
d = 1.88–1.99 (m, 1 H,
IR (neat): 2977, 2933, 1705, 1477, 1450, 1418, 1175, 1136, 1043
cm–1.
NCHOCH2CHH), 2.07–2.16 (m, 1 H, NCHOCH2CHH), 2.23 (s,
3 H, CH3), 2.24–2.33 (m, 1 H, NCHOCHH), 2.39–2.49 (m, 1 H,
NCHOCHH), 3.61 (ddd, J = 11.5, 8.0, 5.0 Hz, 1 H, CONCHH),
3.84 (dt, J = 11.5, 7.5 Hz, 1 H, CONCHH), 5.46 (t, J = 6.0 Hz, 1 H,
NCHO), 6.99 (t, J = 7.5 Hz, 1 H, Ar-H), 7.26 (d, J = 7.5 Hz, 1 H,
Ar-H), 7.76 (dd, J = 7.5, 1.0 Hz, 1 H, Ar-H).
1H NMR (400 MHz, DMSO-d6, 80 °C): d (mixture of diastereoiso-
mers) = 1.33 [d, J = 7.0 Hz, 3 H, CH3 (major)], 1.37 [d, J = 6.5 Hz,
3 H, CH3 (minor)], 1.45 [s, 9 H, t-Bu (minor)], 1.45 [s, 9 H, t-Bu
(major)], 1.26–1.50 (occluded m, 1 H, CH2), 1.90–2.07 (m, 2 H,
CH2), 2.14–2.30 (m, 1 H, CH2), 2.98–3.06 (m, 1 H, CHHN), 3.50–
3.60 (m, 1 H, CHHN), 4.02 [q, J = 6.5 Hz, 1 H, CHC=O (minor)],
4.21 [q, J = 7.0 Hz, 1 H, CHC=O (major)], 5.06 [dd, J = 8.5, 5.5 Hz,
1 H, NCHN (major)], 5.08–5.10 [m, 1 H, NCHN (minor overlaying
major diastereoisomer)].
13C NMR (100 MHz, CDCl3): d = 15.4, 21.4, 32.0, 44.3, 88.2, 119.4,
121.9, 125.4, 125.8, 134.9, 155.5, 161.3.
MS (ESI): m/z (%) = 204 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO2: 204.1019; found:
13C NMR (100 MHz, DMSO-d6, 80 °C): d (minor diastereoisomer
given in brackets) = 17.7 (both diastereoisomers), 23.2, (23.3), 27.6,
(27.61), 32.2 (both diastereoisomers), 40.9, (40.5), 56.4 (both dias-
tereoisomers), 74.6, (74.4), 79.5, (79.3), 152.6 (both diastereoiso-
mers), 172.3 (both diastereoisomers).
MS (ESI): m/z (%) = 263 (10) [M + Na]+, 241 (100), [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C12H21N2O3: 241.1547; found:
204.1023 (1.7 ppm error).
1,2,3,3a-Tetrahydropyrrolo[2,1-b][1,3]benzoxanin-9-one (24b)
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 79 mg, 0.61
mmol), phenyl salicylate (26b; 100 mg, 0.47 mmol) and
SnCl2·2H2O (212 mg, 0.94 mmol) according to the procedure de-
scribed for compound 24a. Flash chromatography (SiO2; Et2O),
yielded the title compound 24b.23
241.1554 (2.9 ppm error).
Yield: 68.5 mg (75%); colourless oil; Rf = 0.22 (Et2O).
IR (neat): 2884, 1667, 1611, 1468, 1347 cm–1.
tert-Butyl (3S,8aR)-(4-Oxohexahydropyrrolo[2,1-b][1,3]oxazin-
3-yl)carbamate (20c)
1H NMR (400 MHz, CDCl3):
d = 1.89–1.99 (m, 1 H,
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 0.10 g, 0.76
mmol) and N-Boc-L-serine (23c; 0.16 g, 0.80 mmol) according to
the procedure described for the preparation of compound 20a. The
crude amide was stirred with SnCl2·2H2O (342 mg, 1.52 mmol) for
12 h and the crude product 20c was purified by flash column chro-
matography (SiO2, EtOAc), to yield the title compound 20c.
NCHOCH2CHH), 2.07–2.16 (m, 1 H, NCHOCH2CHH), 2.21–2.30
(m, 1 H, NCHOCHH), 2.40–2.47 (m, 1 H, NCHOCHH), 3.59–3.66
(m, 1 H, CONCHH), 3.81–3.88 (m, 1 H, CONCHH), 5.50 (t,
J = 6.0 Hz, 1 H, NCHO), 6.96 (dd, J = 7.5, 1.0 Hz, 1 H, Ar-H), 7.11
(td, J = 7.5, 1.0 Hz, 1 H, Ar-H), 7.42 (td, J = 7.5, 2.0 Hz, 1 H, Ar-
H), 7.93 (dd, J = 7.5, 1.5 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): d = 21.3, 31.9, 44.3, 88.4, 116.4,
Yield: 90 mg (46% over two steps); colourless solid; single diaste-
reoisomer; mp 104–106 °C; [a]D 32.5 (c 0.95, CHCl3); Rf = 0.30
(EtOAc).
22
119.7, 122.6, 127.9, 133.7, 157.2, 160.9.
MS (ESI): m/z (%) = 190 (100) [M + H]+, 212 (8) [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H12NO2: 190.0863; found:
IR (Nujol mull): 3343, 2922, 2853, 1724, 1666, 1519, 1458, 1252,
1165, 1000 cm–1.
190.0863 (0.2 ppm error).
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 9 H, t-Bu), 1.19–2.02 (m,
3 H, CH2, CHHCHNO), 2.20–2.28 (m, 1 H, CHHCHNO), 3.35
(ddd, J = 11.5, 7.5, 5.5 Hz, 1 H, CHHN), 3.64 (dd, J = 13.5, 10.5
Hz, 1 H, CHHO), 3.82 (dt, J = 11.5, 7.0 Hz, 1 H, CHHN), 4.34–
4.40 (m, 2 H, CHHO, CHC=O), 5.08 (t, J = 5.0 Hz, 1 H, NCHO),
5.53 (br s, 1 H, NH).
6-Fluoro-1,2,3,3a-tetrahydro-pyrrolo[2,1-b][1,3]benzoxanin-9-
one (24c)
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 55 mg, 0.41
mmol), phenyl 4-fluoro-2-hydroxybenzoate (26c; 75 mg, 0.32
mmol) and SnCl2·2H2O (144 mg, 0.64 mmol) according to the pro-
cedure described for compound 24a. Flash chromatography (SiO2;
Et2O), yielded the title compound 24c.
13C NMR (100 MHz, CDCl3): d = 21.5, 28.3, 32.5, 45.0, 49.0, 68.7,
80.1, 87.0, 155.8, 166.4.
MS (ESI): m/z (%) = 257 (40) [M + H]+, 201 (100).
HRMS (ESI): m/z [M + H]+ calcd for C12H21N2O4: 257.1496; found:
Yield: 70 mg (98%); colourless solid; mp 79–81 °C; Rf = 0.44
(Et2O).
IR (neat): 1666, 1618, 1450, 1261 cm–1.
257.1502 (2.4 ppm error).
1H NMR (400 MHz, CDCl3):
d = 1.84–1.94 (m, 1 H,
8-Methyl-1,2,3,9a-tetrahydro-9-oxa-3a-azacyclopenta[b]naph-
thalen-4-one (24a)
A mixture of 3-[1,3]dioxolan-2-yl-propylamine (22a; 37 mg, 0.28
mmol) and phenyl 2-hydroxy-3-methylbenzoate (33; 50 mg, 0.22
NCHOCH2CHH), 2.01–2.09 (m, 1 H, NCHOCH2CHH), 2.14–2.23
(m, 1 H, NCHOCHH), 2.34–2.41 (m, 1 H, NCHOCHH), 3.51–3.57
(m, 1 H, CONCHH), 3.73–3.80 (m, 1 H, CONCHH), 5.45 (t, 1 H,
Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York

PAPER
Preparation of Novel Polycyclic Heterocycles Using Tin(II) Chloride
3855
J = 6.0 Hz, NCHO), 6.60 (dd, J = 10.0, 2.0 Hz, 1 H, Ar-H), 6.74 (td,
J = 10.0, 2.0 Hz, 1 H, Ar-H), 7.86 (dd, J = 7.0, 9.0 Hz, 1 H, Ar-H).
procedure described for compound 24a. Flash chromatography
(SiO2; Et2O) yielded the title compound 24f.
13C NMR (100 MHz, CDCl3): d = 21.3, 31.9, 44.3, 88.9, 104.3 (d,
J = 25.0 Hz), 110.3 (d, J = 22.0 Hz), 116.2, 130.0 (d, J = 11.0 Hz),
158.9, 160.9, 164.6, 165.9 (d, J = 252.0 Hz).
19F NMR (376 MHz, CDCl3): d = –103.8 (ddd, J = 10.3, 10.2, 9.0
Hz).
MS (ESI): m/z (%) = 230 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H10NFO2Na: 230.0588;
Yield: 59 mg (65%); colourless solid; mp 111–114 °C; Rf = 0.21
(Et2O).
IR (neat): 1664, 1633, 1436 cm–1.
1H NMR (400 MHz, CDCl3):
d = 1.91–2.02 (m, 1 H,
NCHOCH2CHH), 2.13–2.20 (m, 1 H, NCHOCH2CHH), 2.24–2.33
(m, 1 H, NCHOCHH), 2.44–2.52 (m, 1 H, NCHOCHH), 3.66–3.72
(m, 1 H, CONCHH), 3.87–3.92 (m, 1 H, CONCHH), 5.54 (t,
J = 11.0 Hz, 1 H, NCHO), 7.33 (m, 1 H, Ar-H), 7.38–7.42 (m, 1 H,
Ar-H), 7.49–7.53 (m, 1 H, Ar-H), 7.73 (d, J = 8.0 Hz, 1 H, Ar-H),
7.90 (d, J = 8.0 Hz, 1 H, Ar-H), 8.51 (s, 1 H, Ar-H).
found: 230.0592 (1.9 ppm error).
7-Chloro-1,2,3,3a-tetrahydropyrrolo[2,1-b][1,3]benzoxanin-9-
one (24d)
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 120 mg, 0.60
mmol), phenyl 5-chloro-2-hydroxybenzoate (26d; 150 mg, 0.91
mmol) and SnCl2·2H2O (410 mg, 1.82 mmol) according to the pro-
cedure described for compound 24a. Flash chromatography (SiO2;
Et2O) yielded the title compound 24d.
13C NMR (100 MHz, CDCl3): d = 21.2, 32.1, 44.5, 88.6, 112.1,
120.1, 125.1, 127.0, 128.5, 129.5 (3 × C), 136.4, 153.6, 161.1.
MS (ESI): m/z (%) = 262 (100) [M + Na]+, 240 (30) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13NO2Na: 262.0838;
found: 262.0843 (0.9 ppm error).
Yield: 125 mg (87%); sticky colourless solid; mp 63–64 °C;
Rf = 0.36 (Et2O).
IR (neat): 1669, 1609, 1451, 1413, 1346 cm–1.
7a,8,9,10-Tetrahydro-7-oxa-10a-azacyclopenta[b]phenan-
threne-11-one (24g)
Prepared from 3-[1,3]dioxolan-2-yl-propylamine (22a; 64 mg, 0.64
mmol) and phenyl 2-hydroxynaphthalene-1-carboxylate (26g; 100
mg, 0.49 mmol) according to the procedure described for compound
24a. Flash chromatography (SiO2; Et2O) yielded the title compound
24g.
1H NMR (400 MHz, CDCl3):
d = 1.86–1.95 (m, 1 H,
NCHOCH2CHH), 2.03–2.10 (m, 1 H, NCHOCH2CHH), 2.16–2.24
(m, 1 H, NCHOCHH), 2.35–2.43 (m, 1 H, NCHOCHH), 3.53–3.59
(m, 1 H, CONCHH), 3.75–3.81 (m, 1 H, CONCHH), 5.43 (t,
J = 5.5 Hz, 1 H, NCHO), 6.87 (d, J = 9.0 Hz, 1 H, Ar-H), 7.31 (dd,
J = 9.0, 3.0 Hz, 1 H, Ar-H), 7.83 (d, J = 2.5 Hz, 1 H, Ar-H).
Yield: 51 mg (56%); colourless solid; mp 104–107 °C; Rf = 0.24
(Et2O).
13C NMR (100 MHz, CDCl3): d = 21.2, 31.7, 44.2, 88.6, 118.0,
IR (neat): 1658, 1443, 763 cm–1.
1H NMR (400 MHz, CDCl3):
NCHOCH2CHH), 2.13–2.22 (m, 1 H, NCHOCH2CHH), 2.40–2.57
(m, 2 H, NCHOCH2), 3.62–3.68 (m, 1 H, CONCHH), 3.87–3.93
(m, 1 H, CONCHH), 5.65 (t, J = 5.5 Hz, 1 H, NCHO), 7.49–7.59
(m, 3 H, Ar-H), 7.81 (d, J = 8.0, 1.0 Hz, 1 H, Ar-H), 7.92 (d, J = 9.0
Hz, 1 H, Ar-H), 8.20 (dd, J = 8.5, 1.0 Hz, 1 H, Ar-H).
13C NMR (100 MHz, CDCl3): d = 21.7, 32.1, 44.6, 89.1, 114.3,
122.1, 122.8, 123.2, 123.8, 126.3, 127.8, 128.5, 136.6, 154.8, 161.5.
MS (ESI): m/z (%) = 362 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13NO2Na: 262.0838;
120.8, 127.5, 127.9, 133.5, 155.7, 159.7.
d = 1.94–2.05 (m, 1 H,
MS (ESI): m/z (%) = 224 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for NaC11H10ClNO2: 246.0292;
found: 246.0293 (0.2 ppm error).
5-Isopropyl-8-methyl-1,2,3,3a-tetrahydropyrrolo[2,1-
b][1,3]benzoxanin-9-one (24e)
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 67 mg, 0.51
mmol), phenyl 2-hydroxy-3-isopropyl-6-methylbenzoate (26e; 100
mg, 0.30 mmol) and SnCl2·2H2O (135 mg, 0.60 mmol) according to
the procedure described for compound 24a. Flash chromatography
(SiO2; Et2O) yielded the title compound 24e.
found: 262.0840 (0.2 ppm error).
Yield: 81 mg (84%); colourless oil; Rf = 0.68 (Et2O).
IR (neat): 2960, 1663, 1491, 1428 cm–1.
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 1.15 (d, J = 7.0 Hz, 3 H, CHCH3),
1.18 (d, J = 7.0 Hz, 3 H, CHCH3), 1.87–1.94 (m, 1 H,
NCHOCH2CHH), 2.03–2.16 (m, 1 H, NCHOCH2CHH), 2.21–2.29
(m, 1 H, NCHOCHH), 2.35–2.43 (m, 1 H, NCHOCHH), 2.61 (s,
3 H, CH3), 3.18 [quint, J = 7.0 Hz, 1 H, CH(CH3)2], 3.49–3.55 (m,
1 H, CONCHH), 3.84–3.91 (m, 1 H, CONCHH), 5.33 (dd, J = 6.0,
5.0 Hz, 1 H, NCHO), 6.82 (d, J = 7.5 Hz, 1 H, Ar-H), 7.15 (d,
J = 7.5 Hz, 1 H, Ar-H).
We are grateful to the University of York for studentship and PDRA
support (J.P.S. and A.N.C., respectively), EPSRC Pharmasynth
program for studentship (K.A.G.), AstraZeneca for further funding
(J.P.S., K.A.G.) and the French Ministère des Affaires Etrangères
for a Lavoisier Postdoctoral Fellowship (C.M.M.). We are also gra-
teful to Dr Trevor Dransfield (University of York) for assistance
with mass spectrometry and to Dr Rhona J. Cox (AstraZeneca) and
Dr Mike Edwards (University of York) for helpful discussions.
13C NMR (100 MHz, CDCl3): d = 20.7, 21.8, 22.5, 22.7, 26.7, 32.2,
44.7, 87.7, 118.4, 125.3, 129.3, 133.9, 138.3, 155.4, 162.0.
MS (ESI): m/z (%) = 246 (100) [M + H]+.
References
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893; and references therein.
(2) Faul, M. M. Encyclopedia of Reagents for Organic
Synthesis, Vol. 7; Paquette, L. A., Ed.; Wiley: Chichester,
1995, 4892.
HRMS (ESI): m/z [M + H]+ calcd for C15H20NO2: 246.1489; found:
246.1493 (2.6 ppm error).
1,2,3,11a-Tetrahydro-11-oxa-3a-azacyclopenta[b]anthracen-4-
one (24f)
Prepared from 3-[1,3]dioxolan-2-ylpropylamine (22a; 64 mg, 0.64
mmol), phenyl 3-hydroxynaphthalene-2-carboxylate (26f; 100 mg,
0.49 mmol) and SnCl2·2H2O (220 mg, 0.98 mmol) according to the
(3) Ford, K. L.; Roskamp, E. J. Tetrahedron Lett. 1992, 33,
1135.
(4) Foot, J. S.; Giblin, G. M. P.; Taylor, R. J. K. Org. Lett. 2003,
5, 4441.
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3856
A. N. Cayley et al.
PAPER
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Synthesis 2008, No. 23, 3846–3856 © Thieme Stuttgart · New York