An unexpected ring contraction of two nitroaryl pro-drugs: conversion of N-(nitroaryl)-3-chloropiperidine derivatives into N-(nitroaryl)-2-chloromethylpyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2010.05.095

Treatment of the N-nitroaryl-3-hydroxypiperidine derivatives 12 and 13 with thionyl chloride afforded the corresponding N-aryl-2-chloromethylpyrrolidines 5 and 15 via a ring-contraction process involving an intermediate aziridinium ion.

Full text of DOI:10.1016/j.tetlet.2010.05.095

Tetrahedron Letters 51 (2010) 3918–3921
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected ring contraction of two nitroaryl pro-drugs: conversion
of N-(nitroaryl)-3-chloropiperidine derivatives into
N-(nitroaryl)-2-chloromethylpyrrolidines
Philip J. Burke a, Lai Chun Wong b, William Clegg c, Ross W. Harrington c, Terence C. Jenkins a,
Richard J. Knox a, Ian T. Meikle b, Stephen P. Stanforth b,
*
a Morvus Technology Limited, Tyˆ Myddfai, Llanarthne, Carmarthen, SA32 8HZ, UK
b School of Applied Sciences, University of Northumbria, Newcastle-upon-Tyne, NE1 8ST, UK
c School of Chemistry, Bedson Building, Newcastle University, Newcastle-upon-Tyne, NE1 7RU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 March 2010
Revised 6 May 2010
Accepted 21 May 2010
Available online 27 May 2010
Treatment of the N-nitroaryl-3-hydroxypiperidine derivatives 12 and 13 with thionyl chloride afforded
the corresponding N-aryl-2-chloromethylpyrrolidines 5 and 15 via a ring-contraction process involving
an intermediate aziridinium ion.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Nitroaromatic pro-drugs
Aziridinium ions
NAD(P)H: quinone oxidoreductase 1
NQO1
CB1954
SN-23862
Many nitroaromatic pro-drugs have been designed as potential
substrates for the enzyme DT-diaphorase, also known as NAD(P)H:
quinone oxidoreductase 1 (NQO1).1 Elevated levels of NQO1 are of-
ten found in tumour tissue making this enzyme an attractive target
for nitroaromatic pro-drug therapies.2 CB-1954 (1) (Fig. 1) was
shown to be an effective anti-cancer agent against rat Walker
256 carcinomas,3 but unfortunately, human cell lines were
unresponsive; this was attributed to a change in the amino acid
residue 104 (tyrosine in the rat enzyme and glutamine in the
human enzyme). In the presence of either of the cofactors NADH
or NADPH, NQO1 catalyses the bioreduction of 1 to produce the
4-hydroxylamine derivative 2 which, after reaction with acetyl
CoA, generates compound 3, capable of producing lethal
DNA–DNA interstrand crosslinks.4 However, 1 is reduced more
Figure 1. Nitroaryl pro-drug structures.
* Corresponding author.
E-mail addresses: steven.stanforth@northumbria.ac.uk, steven.stanforth@unn.ac.uk (S.P. Stanforth).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.095

P. J. Burke et al. / Tetrahedron Letters 51 (2010) 3918–3921
3919
Scheme 1. Potential mechanism for DNA alkylation by bioreduction of 5 and 6.
Scheme 2. Formation of pyrrolidines 5 and 15 from 11 and piperidines 12 and 13. (i) SOCl2, CH2Cl2, reflux; (ii) cyanuric chloride, DMF, rt.
Figure 3. X-ray structure of compound 15. Ellipsoids are shown at the 50%
probability level.
Figure 2. X-ray structure of compound 5. Ellipsoids are shown at the 50%
probability level.
virus/gene-directed enzyme pro-drug therapy (VDEPT/GDEPT).5
The structurally related dinitrobenzamide mustard, SN-23862 (4),
is also a poor substrate for NQO1, but has been identified as a bet-
ter substrate for NR than 1.6 We have been interested in developing
new NQO1/NR substrates, and hence potential anti-tumour agents
effectively by Escherichia coli nitroreductase (NR) and this observa-
tion has generated interest in activating 1 in tumours by using
either antibody directed enzyme pro-drug therapy (ADEPT) or

3920
P. J. Burke et al. / Tetrahedron Letters 51 (2010) 3918–3921
Scheme 3. Interconversion of compounds 5 and 6 via an aziridinium intermediate.
that are structurally related to 1 and 4. To this end the dinitrobenz-
enes 5 and 6 were chosen as potential substrate candidates. It was
anticipated that NQO1-mediated bioreduction of either the 2- or 4-
nitro-group in these compounds would generate the correspond-
ing hydroxylamine derivatives 7 and 8, and the resulting change
in the electronic character of the aryl group would promote the for-
mation of aziridinium ions 9 and 10, respectively (Scheme 1).
These highly reactive aziridinium species 9 and 10 might then be
capable of cross-linking DNA in a similar fashion to the parent
CB-1954 (1) agent.
(S)-Prolinol was treated with 2,4-dinitrofluorobenzene under
basic conditions yielding the N-arylated product 11 in 79% yield
(Scheme 2).7 Racemic 3-hydroxypiperidine was reacted with 2,4-
dinitrofluorobenzene under basic conditions (K2CO3, DMSO, room
temperature, 6 h) producing compound 12 in 91% yield. Treatment
of alcohol 11 with thionyl chloride in boiling dichloromethane
gave a mixture of products (66:34; 81%) that was initially assumed
to comprise the isomers 5 and 6. As a consequence of the similar
connectivity [NCHCH2Cl vs NCH2CHCl] for the 5/6 isomeric pair,
the assignment of structures to each product by NMR spectroscopy
by either prediction of coupling constants from the 1H spectra or
chemical shift prediction from the 13C spectra was inconclusive.
The 1H NMR spectrum (in CDCl3) of the mixture showed two mul-
tiplets at ca. 4.32 and 4.12 ppm which were attributed to the >CH–
protons of compounds 5/6. However, a single chlorinated product
(61%) showing a multiplet at 4.32 ppm (CDCl3) in its 1H NMR spec-
trum was obtained by treating compound 11 with cyanuric chlo-
ride and DMF.8,9 The structure of this solid product was
elucidated by an X-ray crystallographic study which indicated
Treatment of 13 with thionyl chloride similarly afforded the race-
mic ring-contracted product 15 (42%)12 whose structure was also
confirmed by X-ray crystallography (Fig. 3).10 It is evident that
the chlorinated piperidine derivatives 6 and 14 undergo an intra-
molecular ring-contraction to yield the corresponding pyrrolidines
5 and 15, respectively.
The expansion/contraction process can be explained in terms of
an intermediate aziridinium ion species as depicted in Scheme 3.
To our knowledge, there are relatively few examples of ring expan-
sion/contractions of N-arylated compounds. Mino et al. have de-
scribed the reaction of the prolinol derivative 16 with thionyl
chloride and triethylamine in CHCl3 at room temperature which
yielded a mixture of compound 17 (31%) and the ring-expanded
product 18 (51%).13 Heating compound 17 in CHCl3 afforded piper-
idine 18 in quantitative yield. In contrast, the ring expansion/con-
traction of N-alkylated derivatives has been known for a long time.
Fuson and Zirkle described the ring expansion of 1-ethyl-2-chlo-
romethylpyrrolidine (19) to give 1-ethyl-3-chloropiperidine (20)
upon treatment of the hydrochloride salt with alkali.14 Hammer
et al. found that the hydrochloride salts of compounds 19 and 20
afforded either five- or six-membered ring products when treated
with a base and a nucleophile.15 Cossy et al. have reacted N-benzyl
prolinol (21) with firstly a mixture of trifluoroacetic anhydride and
triethylamine, followed by aqueous NaOH to obtain N-benzyl-3-
hydroxypiperidine (22) (63%).16 Related ring-expansions have been
exploited in natural product synthesis.17
In view of the electron-deficient nature of the N-nitroaryl substit-
uents in 6 and 14 this ring contraction process was unexpected and
the examples reported here are, to our knowledge, unprecedented.
the presence of the pyrrolidine ring (Fig. 2).10 Treatment of alcohol
12 with thionyl chloride in boiling dichloromethane solution also
afforded racemic compound 5 (80%)9 whose 1H NMR spectrum
was identical with that obtained from the reaction of 11 with cyan-
uric chloride. In view of these results, we were also interested in
examining the chlorination of the mono-nitro derivative 13.11
Acknowledgements
We thank the EPSRC for a CASE award (to I.T.M.) and an
equipment grant for the X-ray diffractometer, and also Mor-
vus Technology Limited and the University of Northumbria for a
studentship (to L.C.W.). We also thank the EPSRC National

P. J. Burke et al. / Tetrahedron Letters 51 (2010) 3918–3921
3921
temperature (20 h). H2O (20 mL) was added to quench the reaction and the
organic phase was separated, washed with a saturated solution of Na2CO3
(20 mL), followed by 1 M HCl (10 mL) and finally brine (10 mL). The organic
layer was dried (MgSO4) and the solvent evaporated giving the crude
chlorinated compound 5 as a brown oil (0.21 g, 85%). Purification by column
chromatography (silica gel; EtOAc/hexane; 1:1; Rf 0.82) gave compound 5 as a
yellow oil (0.15 g, 61%) which was crystallised from hexane/CH2Cl2, mp 77–
78 °C. 1H NMR (270 MHz, CDCl3): d 1.78–1.96 (m, 1H, CH2), 2.01–2.18 (m, 2H,
CH2), 2.39–2.52 (m, 1H, CH2), 2.94–3.05 (m, 1H, CH2), 3.49–3.66 (m, 2H, CH2),
3.70 (dd, 1H, CH2, J = 11.63 and 2.97 Hz), 4.32 (ddd, 1H, CH, J = 2.72, 7.17 and
14.10 Hz), 7.04 (d, 1H, J = 9.40 Hz), 8.25 (dd, 1H, J = 9.40 and 2.72 Hz), 8.70 (d,
1H, J = 2.72 Hz); 13C NMR (68 MHz, CDCl3): d 24.7, 30.0, 44.7, 53.3, 60.2, 116.2,
124.1, 127.9, 136.5, 136.8, 145.2; HRMS (EI) m/z: C11H12ClN3O4 [M]+: calcd
285.0511, measured 285.0507. Method B: SOCl2 (1 mL) was added to a solution
of compound 12 (0.36 g, 1.347 mmol) in CH2Cl2 (15 mL). The mixture was
heated at reflux (15 h), allowed to cool to room temperature, and then
evaporated. The residue was purified by column chromatography giving
racemic compound 5 (0.31 g, 80%).
Mass Spectrometry Centre, Swansea, for high-resolution mass
spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.095.
References and notes
1. Chen, S.; Wu, K. B.; Knox, R. J. Free Radical Biol. Med. 2000, 29, 276–284; Helsby,
N. A.; Wheeler, S. J.; Pruijn, F. B.; Palmer, B. D.; Yang, S.; Denny, W. A.; Wilson,
W. R. Chem. Res. Toxicol. 2003, 16, 469–478.
2. Cresteil, T.; Jaiswal, A. K. Biochem. Pharmocol. 1991, 42, 1021–1027; Riley, R. J.;
Workman, P. Biochem. Pharmacol. 1992, 43, 1657–1669.
10. X-ray data are given in the Supplementary data. Crystallographic data have
been deposited with the Cambridge Crystallographic Data Centre CCDC 767027
(compound 5) and CCDC 767028 (compound 15). Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [Fax: (international) +44-1223/336-033; e-mail: deposit@ccdc.cam.
ac.uk].
11. Tong, L. K. J.; Glesmann, M. C.; Bent, R. L. J. Am. Chem. Soc 1960, 82, 1988–1996.
12. This product has been reported in the patent literature and was prepared via
chlorination of N-(4-nitrophenyl)prolinol. See: Ramos, L.; Sabelle, S. US Patent
2004/248961 (CAS Registry Number 764662-20-6P).
13. Mino, T.; Saito, A.; Tanaka, Y.; Hasegawa, S.; Sato, Y.; Sakamoto, M.; Fujita, T. J.
Org. Chem. 2005, 70, 1937–1940.
14. Fuson, R. C.; Zirkle, C. L. J. Am. Chem. Soc. 1948, 70, 2760–2762.
15. Hammer, C. F.; Heller, S. R.; Craig, J. H. Tetrahedron 1972, 28, 239–253;
Hammer, C. F.; Weber, J. D. Tetrahedron 1981, 37, 2173–2180.
3. Cobb, L. M.; Connors, T. A.; Elso, L. A.; Khan, A. H.; Mitchley, B. V. C.; Ross, W. J.
C.; Whisson, M. E. Biochem. Pharmacol. 1969, 18, 1519–1527; Knox, R. J.; Burke,
P. J.; Chen, S.; Kerr, D. J. Curr. Pharm. Des. 2003, 9, 2091–2104.
4. Knox, R. J.; Friedlos, F.; Marchbank, T.; Roberts, J. J. Biochem. Pharmocol. 1991,
42, 1691–1697.
5. Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577–595; Denny, W. A.; Wilson, W. R.
J. Pharm. Pharmacol. 1998, 50, 387–394; Denny, W. A. Curr. Pharm. Des. 2002, 8,
1349–1361.
6. Atwell, G. J.; Yang, S.; Pruijn, F. B.; Pullen, S. M.; Hogg, A.; Patterson, A. V.;
Wilson, W. R.; Denny, W. A. J. Med. Chem. 2007, 50, 1197–1212.
7. Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Khera, M. K.; Srinivas, D.; Kumar, M.
S.; Das, J.; Iqbal, J.; Trehan, S. Bioorg. Med. Chem. Lett. 2006, 16, 4416–4419.
8. Blotny, G. Tetrahedron 2006, 62, 9507–9522.
9. Synthesis of compound 5. Method A: Cyanuric chloride (0.92 g, 5.00 mmol) was
added to DMF (1 mL) at room temperature. After the formation of a pale yellow
solid (3 h), CH2Cl2 (5 mL) was added, followed by compound 11 (0.23 g,
0.86 mmol) in CH2Cl2 (5 mL) and the resulting mixture stirred at room
16. Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem. 1999, 1693–1699.
17. Cossy, J. Chem. Rec. 2005, 5, 70–80.