Synthesis of (±)-6-oxa-3-azabicyclo[3.1.1]heptan-2-thione: A potential synthon for the preparation of novel heteroaryl-annulated bicyclic morpholines

Article abstract of DOI:10.1016/j.tetlet.2011.07.017

The novel bridged bicyclic morpholinethione (±)-6-oxa-3- azabicyclo[3.1.1]heptan-2-thione (9) has been prepared in six steps. This conformationally restricted morpholinethione was prepared stereoselectively using straightforward chemistry and inexpensive

Full text of DOI:10.1016/j.tetlet.2011.07.017

Tetrahedron Letters 52 (2011) 4713–4715
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Tetrahedron Letters
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Synthesis of ( )-6-oxa-3-azabicyclo[3.1.1]heptan-2-thione: a potential
synthon for the preparation of novel heteroaryl-annulated bicyclic morpholines
⇑
Donn G. Wishka, Daniel P. Walker
Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel bridged bicyclic morpholinethione ( )-6-oxa-3-azabicyclo[3.1.1]heptan-2-thione (9) has been
prepared in six steps. This conformationally restricted morpholinethione was prepared stereoselectively
using straightforward chemistry and inexpensive starting materials. The key oxetane ring was formed via
an intramolecular alkylation reaction.
Received 7 June 2011
Revised 1 July 2011
Accepted 5 July 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Morpholine
Stereoselective synthesis
Heterocycles
Bicyclic compounds
Alkylation
Introduction
erties.9 For instance, thiolactam 10 (Fig. 3) is the precursor to the
imidazo[2,1-c][1,4]oxazine skeleton contained in BLI-489.4a In a
Morpholines are utilized extensively in drug discovery research.
Numerous drugs possessing a directly linked morpholine have
been approved by the FDA and other regulatory agencies, a snap-
shot of recently marketed drugs is shown in Figure 1, including lin-
ezolid (ZyvoxÒ),1 gifitinib (IressaÒ),2 and reboxetine (VestraÒ).3
Analogs incorporating a fused morpholine ring have also shown
potential for treating various human diseases; some recent pre-
clinical and clinical candidates are shown in Figure 2, including
BLI-489,4 finafloxacin,5 and AGN 193080.6
prior study, we detailed the stereoselective synthesis of thiolac-
tams 7 and 8, both of which were derived from an appropriately
substituted furan (Fig. 4).10 Despite the structural similarities be-
tween thiolactams 7 and 9, a new approach to the construction
of thiolactam 9 was necessitated due to the incompatibility of
the previous synthetic strategies with the 6-oxa-3-azabicy-
clo[3.1.1.]heptane framework contained in 9. We detail below a
stereoselective synthesis of the novel bridged bicyclic thiolactam 9.
In addition, a number of reports detailing analogs incorporating
a bridged bicyclic morpholine (e.g., 1, 2, and 3, Fig. 3) have been re-
ported in the medicinal chemistry literature.7 In some instances,
the bicyclic analog showed enhanced biological activity compared
to the corresponding morpholine analog.7c–e
Given the promising biological profiles of analogs possessing a
fused morpholine ring and the emerging potential of bridged bicy-
clic morpholine analogs, we became interested in preparing
bridged bicyclic morpholines that were fused to an additional het-
eroaryl ring (e.g., 4, 5, and 6, Fig. 4). The logical precursors to struc-
tures 4, 5, and 6 would be thiolactams 7, 8, and 9, respectively. In
general, thioamides and thiolactams are useful synthons for the
preparation of a variety of fused heterocycles;8 many of these het-
eroaryl-annulated analogs have shown interesting biological prop-
Results and discussion
Our synthesis of ( )-6-oxa-3-azabicyclo[3.1.1]heptan-2-thione
(9) commenced from ( )-epichlorohydrin, an inexpensive, readily
available starting material (Scheme 1). Using a modification of
the Pharmacia & Upjohn procedure,11 reaction of (2,4-dime-
thoxyphenyl)methanimine, generated in situ from 2,4-dime-
thoxybenzaldehyde and concentrated aqueous ammonia, with
( )-epichlorohydrin generated imine 11. Sodium borohydride
reduction of imine 11 gave rise (90%) to aminoalcohol 12. While
benzaldehyde and simple monosubstituted benzaldehydes have
been used as starting materials in the above reaction, the choice
of using 2,4-dimethoxybenzaldehyde as a starting material was
to help facilitate its removal late in the synthesis (vide infra).
Subjection of aminoalcohol 12 to chloroacetyl chloride under
Schotten-Baumann conditions initially provided an
mide, which upon exposure to concentrated aqueous sodium
hydroxide effected ring closure, furnishing 79% yield of
a-chloroa-
⇑
Corresponding author. Tel.: +1 860 715 6445; fax: +1 860 686 0013.
E-mail addresses: quassinoid@earthlink.net, daniel.p.walker.pfizer@gmail.com
a
(D.P. Walker).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.017

4714
D. G. Wishka, D. P. Walker / Tetrahedron Letters 52 (2011) 4713–4715
F
NHBOC
R
O
N
N
F
Z
Y
NH
S
O
Cl
O
NH
O
O
O
O
N
N
N
N
O
4
7
MeO2C
O
N
NH
linezolid
gifitinib
R
Z
Y
NHBOC
O
NH
N
O
O
O
O
N
S
5
8
MeO2C
O
O
O
R
N
H
N
NH
Z
Y
O
reboxetine
N
S
9
6
Figure 1. Drugs possessing a directly linked morpholine ring.
Figure 4. Retrosynthesis of novel heteroaryl-annulated bicyclic morpholine ana-
logs 4, 5, and 6; Y = CH, CR or N; Z = CH, CR, C(O) or N; R = H, alkyl, acyl, or aryl (see:
Refs. 8,9). Prior synthetic targets 7 and 8, and new synthetic target 9.
O
N
F
CO2H
O
O
N
a
b
OH
H
N
N
H
O
N
HN
Cl
Ar
N
Cl
O
CN
S
CO2Na
H
90%
92%
O
11
finafloxacin
BLI-489
DMB
DMB
N
OH
c
Me
H
N
N
O
H
N
H
N
Cl
DMB
+
N
Cl
O
HN
AGN 193080
O
12
O
Cl
13 (79%)
14 (7%)
DMB
N
Figure 2. Clinical (BLI-489 and finafloxacin) and preclinical (AGN 193080) candi-
dates possessing a fused morpholine ring.
DMB
N
d
O
O
+
13
O
Me
O
R
15
N
(55%)
16
(25%)
N
N
R
R
O
O
O
Ar = 2,4-dimethoxyphenyl
DMB = 2,4-dimethoxybenzyl
1
2
3
Scheme 1. Reagents and conditions: (a) 2,4-dimethoxybenzaldehyde, 28% aq.
ammonia, 0 °C to rt, 48 h; (b) NaBH4, MeOH, 0 °C, 1 h; (c) ClCH2C(O)Cl, CH2Cl2-aq
NaOH, 0 °C, 1 h; 40% aq NaOH, rt, 4 h; (d) KHMDS (2.0 equiv), THF, 0 °C, 1.5 h.
NH
O
S
10
Figure 3. Row 1: Bicyclic morpholine templates utilized in medicinal chemistry
research programs and structure of compound 10.
presumably arises via an initial elimination reaction, followed
by subsequent acid catalyzed migration of the exocyclic olefin
to the thermodynamically more favorable endocyclic position.14
The 1H NMR spectrum (500 MHz) of the crude reaction mixture
indicated that two compounds were present, morpholinone 15
and oxazinone 16. Thus, the acid catalyzed migration likely
occurred during workup where the initially formed exocyclic
olefin was exposed to aqueous ammonium chloride. The forma-
tion of oxazinone 16 could be controlled to some extent based
on the choice of solvent. For instance, a less polar solvent sys-
tem, toluene-THF (1:1), led to a 60% yield of 16.
morpholinone 13. It is interesting to note that under these con-
ditions less than 10% of epoxide 14 was formed. Similar results
have been observed by others on a related system.12 Bridged
bicyclic morpholinone 15 was realized in 55% yield via an intra-
molecular cyclization reaction. Thus, treatment of a cold (0 °C)
solution of morpholinone 13 with potassium bis(trimethylsilyla-
mide) (KHMDS) generated the corresponding lactam enolate that
underwent subsequent intramolecular alkylation by the primary
alkyl chloride. The use of KHMDS to effect the intramolecular
cyclization proved to be crucial as other strong bases, such as
LDA, led to lower yields or no reaction.13 The major side product
formed in this reaction was oxazinone 16. The formation of 16
Completion of the synthesis of thiolactam
9 necessitated
removal of the dimethoxybenzyl (DMB) moiety and conversion of
the lactam into a thiolactam. As it is known that many N-benzyl
amides are inert toward hydrogenolysis, typically requiring
strongly reducing conditions to facilitate their removal,15 we chose

D. G. Wishka, D. P. Walker / Tetrahedron Letters 52 (2011) 4713–4715
4715
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H
N
a
b
O
15
9
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76%
O
68%
17
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Scheme 2. Reagents and conditions: (a) TFA, Et3SiH (3.0 equiv), 65 °C, 2.5 h; (b)
Lawesson’s reagent, tetrahydrofuran, rt, 24 h.
2,4-dimethoxybenzaldehyde as a starting material (vide supra)
with the hope that the corresponding 2,4-dimethoxybenzyl group
in 15 would be removed under mild conditions. Fortunately, treat-
ment of lactam 15 with TFA16 and triethylsilane as a scavenger17
resulted in efficient removal of the DMB group (Scheme 2), giving
rise to the previously unknown bicyclic lactam 17. Subjection of 17
to Lawesson’s reagent afforded the desired thiolactam 9.
Conclusion
8. Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
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2011, 1113.
In summary, we have prepared in racemic form a conformation-
ally restricted morpholinethione (9), which should serve as a use-
ful synthon for the preparation of novel heteroaryl-annulated
bicyclic morpholine analogs. The synthesis utilized inexpensive re-
agents, and the key step involved an oxetane ring formation via an
intramolecular alkylation reaction.
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Supplementary data
Supplementary data (experimental procedures and character-
ization data for all new compounds ( 9, 11–17) and copies of
NMR spectra) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.07.017.
12. Cf: Morie, T.; Kato, S.; Harada, H.; Matsumoto, J. Heterocycles 1994, 38, 1033.
13. The importance of forming
intramolecular cyclization on
a
a
potassium enolate to effect efficient
related carbocyclic system has been
previously observed, see: Nicolaou, K. C.; Magolda, R. L.; Claremon, D. A. J.
Am. Chem. Soc. 1980, 102, 1404.
14. Cf: Yadav, J. S.; Ather, H.; Gayathri, K. U.; Rao, N. V.; Prasad, A. R. Synthesis 2008,
3945.
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