Preparation of heteroaryloxetanes and heteroarylazetidines by use of a Minisci reaction

Article abstract of DOI:10.1021/jo9010624

(Chemical Equation Presented) Introduction of oxetan-3-yl and azetidin-3-yl groups into heteroaromatic bases was achieved by using a radical addition method (Minisci reaction). To demonstrate utility, the process was used to introduce an oxetane or azetid

Full text of DOI:10.1021/jo9010624

pubs.acs.org/joc
academic community has provided many impressive exam-
Preparation of Heteroaryloxetanes and
Heteroarylazetidines by Use of a Minisci Reaction
ples of both intermolecular1,4 and intramolecular1a,5 variants
of Minisci reactions, its adoption by those working in
industry has been somewhat less developed.6 In part, this
may be due to moderate conversion and regiochemical issues
when examining intermolecular examples of the reaction
(Figure 1).1
Matthew A. J. Duncton,* M. Angels Estiarte,
Russell J. Johnson, Matthew Cox, Donogh J. R. O’Mahony,
William T. Edwards, and Michael G. Kelly
Evotec (USA), Two Corporate Drive, South San Francisco,
California 94080
matthew.duncton@evotec.com; mattduncton@yahoo.com
Received May 20, 2009
FIGURE 1. Minisci reaction with heteroaromatic bases.
Recently, we had reason to investigate the introduction of
an oxetan-3-yl group into aryl and heteroaryl starting mate-
rials.7 Our work was inspired by Rogers-Evans, Carreira,
and co-workers, who showed that oxetanes are “promising
modules in drug discovery”, yielding impressive improve-
ments in drug-like qualities when incorporated into a model
substrate.8 More recently, the same researchers have postu-
lated that an oxetane can be a surrogate for a carbonyl
group.9 Unfortunately, there are few synthetic methods for
Introduction of oxetan-3-yl and azetidin-3-yl groups into
heteroaromatic bases was achieved by using a radical
addition method (Minisci reaction). To demonstrate
utility, the process was used to introduce an oxetane or
azetidine into heteroaromatic systems that have found
important uses in the drug discovery industry, such as the
marketed EGFR inhibitor gefitinib, a quinolinecarbo-
nitrile Src tyrosine kinase inhibitor, and the antimalarial
hydroquinine.
(4) For applications of Minisci reactions to the field of medicinal chemistry
from academic laboratories see: (a) Tadashi, M.; Sawada, S.; Nokata, K.
Heterocycles 1981, 16, 1713–1717. (b) Martin, I.; Anvelt, J.; Vares, L.; Kuehn,
I.; Claesson, A. Acta Chem. Scand. 1995, 49, 230–232. (c) Jain, R.; Cohen
L. A.; El-Kadi, N. A.; King, M. M. Tetrahedron 1997, 53, 2365–2370. (d)
Murthy, K. S. K.; Knaus, E. E. Drug Dev. Res. 1999, 46, 155–162. (e)
Narayanan, S.; Vangapandu, S.; Jain, R. Bioorg. Med. Chem. Lett. 2001, 11,
1133–1136. (f) Naider, N. J. Heterocycl. Chem. 2002, 39, 511–521. (g) Du, W.;
Kaskar, B.; Blumbergs, P.; Subramanian, P.-K.; Curran, D. P. Bioorg. Med.
Chem. 2003, 11, 451–458. (h) Jain, R.; Vaitilingam, B.; Nayyar, A.; Palde, P. B.
Bioorg. Med. Chem. Lett. 2003, 13, 1051–1054. (i) Kaur, N.; Lu, X.;
Gershengorn, M. C.; Jain, R. J. Med. Chem. 2005, 48, 6162–6165. (j) Kaur,
N.; Monga, V.; Lu, X.; Gershongorn, M. C.; Jain, R. Bioorg. Med. Chem. Lett.
2007, 15, 433–443. (k) Nayyar, A.; Monga, P.; Malde, A.; Coutinho, E.; Jain,
R. Bioorg. Med. Chem. 2007, 15, 626–640. (l) Palde, P. B.; McNaughton, B. R.;
Ross, N. T.; Gareiss, P. C.; Mace, C. R.; Spitale, R. C.; Miller, B. L. Synthesis
2007, 2287–2290. (m) Monga, V.; Meena, C. L.; Kaur, N.; Kumar, S.; Pawar,
C.; Sharma, S. S.; Jain, R. J. Heterocycl. Chem. 2008, 45, 1603–1608.
(5) Bowman, R. W.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36, 1803–
1822.
(6) For applications of Minisci reactions to the field of medicinal chemi-
stry from industrial laboratories see: (a) Sawada, S.; Okijima, S.; Aiyama,
R.; Nokata, K.; Furuta, T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.;
Miyasaka, T. Chem. Pharm. Bull. 1991, 39, 1446–1454. (b) Sawada, S.;
Nokata, K.; Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka, T. Chem.
Pharm. Bull. 1991, 39, 2574–2580. (c) Sawada, S.; Matsuoka, S.; Nokata, K.;
Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka, T. Chem. Pharm. Bull.
1991, 39, 3183–3188. (d) Giannousis, P.; Carlson, J.; Leimer, M. Process
Chemistry in the Pharmaceutical Industry; Gadamesetti, K. G., Ed.; Dekker:
New York, 1999; pp 173-188. (e) Phillips, O. A.; Murthy, K. S. K.; Fiakpui, C. Y.;
Knaus, E. E. Can. J. Chem. 1999, 77, 216–222. (f) Cowden, C. J. Org. Lett. 2003,
5, 4497–4499. (g) Uraguchi, A.; Yamamoto, K.; Ohtsuka, Y.; Tokuhisa, K.;
Yamakawa, T. Appl. Catal. 2008, 342, 137–143.
The addition of carbon-centered radicals to hetero-
aromatic systems has a rich history dating from the late
nineteenth century.1a However, the utility of these reactions
in preparative organic chemistry has been a relatively recent
development, after studies by Dou and Minisci demon-
strated that yields may be improved by use of protonated
heteroaromatic bases as reacting substrates (Figure 1).1-3 As
such, addition of a radical to a heteroaromatic base is now
commonly referred to as a “Minisci reaction”. Although the
(1) For an excellent review on the addition of radicals to pyridines,
quinolines, and isoquinolines, including an enlightening discussion on the
historical development of these reactions, see: (a) Harrowven, D. C.; Sutton,
B. J. Prog. Heterocycl. Chem. 2004, 16, 27–53. For other excellent reviews see
also: (b) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489–
519. (c) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem. 1990, 27,
79–96.
(2) (a) Dou, H. J. M.; Lynch, B. M. Tetrahedron Lett. 1965, 6, 897–901.
(b) Dou, H. J. M. Bull. Soc. Chim. Fr. 1966, 1678–1679. (c) Dou, H. J. M.;
Lynch, B. M. Bull. Soc. Chim. Fr. 1966, 3815–3820. (d) Dou, H. J. M.; Lynch,
B. M. Bull. Soc. Chim. Fr. 1966, 3820–3823. See also: (e) Lynch, B. M.;
Chang, H. S. Tetrahedron Lett. 1964, 5, 2965–2968, for arylation of a
postulated pyridinium or imidazolium intermediate with phenyl radicals.
(3) Minisci, F.; Galli, R.; Cecere, M.; Malatesta, V.; Caronna, T. Tetra-
hedron Lett. 1968, 8, 5609–5612.
(7) Duncton, M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony, D.
J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly,
M. G. Org. Lett. 2008, 10, 3259–3262.
€
(8) Wuitchik, G.; Rogers-Evans, M.; Muller, K.; Fischer, H.; Wagner, B.;
Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45,
7736–7739.
(9) Wuitchik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Marki,
M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.; Schneider, J.;
€
Alker, A.; Schweizer, W. B.; Muller, K.; Carreira, E. M. Angew. Chem., Int.
Ed. 2008, 47, 4512–4515.
6354 J. Org. Chem. 2009, 74, 6354–6357
Published on Web 07/17/2009
DOI: 10.1021/jo9010624
r
2009 American Chemical Society

Duncton et al.
JOCNote
the preparation of aryl- and heteroaryloxetanes. For exam-
ple, methods of oxetan-3-yl formation have relied on the
cyclization of 1,3-diols,10 or the addition of an organometallic
to oxetan-3-one, followed by reductive deoxygenation.8
Our own research group recently addressed some of these
limitations by showing that the parent oxetan-3-yl group can
be introduced into certain benzenoid substructures, using an
alkyl-aryl Suzuki coupling.7 However, this method proved
to be less useful when trying to introduce an oxetane into a
heteroaromatic ring. We therefore sought an alternative
procedure for such compounds, and were drawn to the
possibility of using a radical-based approach. In this paper,
we show that a Minisci reaction can be used to incorporate
an oxetan-3-yl, or azetidin-3-yl group, into heteroaromatic
bases in moderate yield. The reaction shows particular
promise for functionalization of heterocyclic scaffolds that
have found importance for the development of kinase in-
hibitors and antimalarials within the drug discovery
industry. For example, an oxetane group was introduced
into a lead quinolinecarbonitrile inhibitor of Src tyrosine
kinase, the marketed EGFR inhibitor gefitinib (Iressa;
AstraZeneca), and the antimalarial hydroquinine.
SCHEME 1. Introduction of the Oxetan-3-yl Group into Lepidine
aReagents and conditions: (a) FeSO4 7H2O, H2O2, H2SO4, DMSO, rt
3
(40% desired product and ca. 15% mixture of desired product and
recovered starting material). (b) FeSO4 7H2O, H2O2, TFA, DMSO, rt
3
(5% desired product and 65% recovered starting material).
in low-to-moderate yield after purification. In some in-
stances, hydrolysis products were observed when certain
chloro- or ether-substituted substrates were employed
(entries 10-12).
Next, we examined the ability of the reaction to incorpo-
rate an azetidine group into select heteroaromatic bases
(Table 2). Gratifyingly, the use of the standard conditions
of H2SO4, H2O2, and FeSO4 in DMSO gave rise to the
desired product, with no evidence of Boc protecting group
removal, even when the reactions were assisted with mild
heating (entries 1-6).
Our initial interest focused on the addition of an oxetane
group into the heteroaromatic base lepidine. Since 3-iodo-
oxetane was readily available, from both synthesis and
commercial sources,11 it was decided to use this building
block as a starting material. An examination of the literature
indicated that Minisci’s conditions of H2O2 and catalytic
FeSO4 in DMSO could generate a secondary radical for
addition into the protonated base.12,13 Thus, these condi-
tions were first investigated. As can be seen from Scheme 1,
the use of H2SO4 as the acid component gave the best results
(condition a). The use of trifluoroacetic acid, which has been
utilized in many other Minisci-type transformations,14 gave a
low yield of the desired product (condition b). As expected,
unreacted starting material was also isolated from the mixture.
Having settled on H2SO4 as the acid of choice, we began to
examine the reaction using other heteroaromatic bases. As
can be seen from Table 1, heteroaromatic bases such as
quinoline, isoquinoline, pyridine, pyridazine, benzothiazole,
benzimidazole, quinoxaline, quinazoline, and phthalazine
could all be reacted smoothly to provide the oxetane product
To demonstrate further utility to the field of medicinal
chemistry, we decided to incorporate an oxetane, or azeti-
dine, into some pharmacologically active starting materials
(Table 3). Thus, 6-methoxy-4-methylquinoline and hydro-
quinine were chosen as model substrates of antimalarials
(entries 1-3). The reaction with hydroquinine is of special
note, due to its complex molecular architecture. Also
of significance was the use of quinolinecarbonitrile and
quinazoline starting materials, as these heterocyclic bases
have been critically important for the development of kinase
inhibitors within medicinal chemistry (entries 3-5). For
example, reactions with a quinolinecarbonitrile Src tyrosine
kinase inhibitor15 (entries 4 and 5) provided the desired
oxetane and azetidine products in reasonably good yield
(38% and 43%, respectively). A successful reaction with the
marketed EGFR kinase inhibitor gefitinib16 was also accom-
plished (entry 6).
The results in Tables 1-3 are significant as they demon-
strate that an oxetane, or azetidine, can be incorporated into
a wide variety of substrates, whose heterocyclic backbone is
frequently encountered during medicinal chemistry pro-
grams. Although yields for the above transformations are
modest, the method is powerful, affording unique products
in a single step that could be difficult to obtain by alternative
procedures. As such, the reaction conditions outlined in this
paper should provide a useful starting point for those
wishing to introduce an oxetane or azetidine into a hetero-
aromatic nucleus. Additionally, specific examples have not
been optimized, so an improvement in yield may be possible
with a thorough investigation of individual conditions. It
should also be noted that many functional groups are
compatible with the reaction conditions. Thus, protection
and deprotection strategies are not usually required, and
compounds with complex structures, or sensitive functionality,
(10) (a) Searles, S.; Hummel, D. G.; Nukina, S.; Throckmorten, P. E. J.
Am. Chem. Soc. 1960, 82, 2928–2931. (b) Castro, B.; Selve, C. Tetrahedron
Lett. 1973, 14, 4459–4460. (c) Picard, P.; Leclercq, D.; Bats, J. P.; Moulines, J.
Synthesis 1981, 550–551. (d) Robinson, P. L.; Barry, C. N.; Kelly, J. W.;
Evans, S. A. J. Am. Chem. Soc. 1985, 107, 5210–5219. (e) Katritzky, A. R.;
Fan, W.; Li, Q. Youji Huaxue 1988, 8, 53–57.
(11) For the studies detailed in this paper, 3-iodooxetane from commer-
cial sources and material synthesized according to Clark et al. ( Clark, S. L.;
Polak, R. J.; Wojtowicz, J. A. US Patent 1966-557376, 1966; Chem. Abstr.
1970, 73, 35211) was used (see also ref 7 and the Supporting Information).
For studies with 1-Boc-3-(iodo)azetidine, material from commercial sources
was used.
(12) Minisci, F.; Vismara, E.; Fontana, F. J. Org. Chem. 1989, 54, 5224–
5227.
(13) A reviewer enquired whether oxetane itself could be used as a
reactant, since other cyclic ethers have been used in Minisci reactions.
However, such a reaction would most likely yield the oxetan-2-yl product.
For a comparable reaction with THF see: Minisci, F.; Vismara, E.; Fontana,
F.; Morini, G.; Serravalle, M.; Giordano, C. J. Org. Chem. 1986, 51, 4411–
4416. Nonetheless, the reviewer’s suggestion is interesting, and should be
explored further.
(14) (a) Fontana, F.; Minisci, F.; Vismara, E. Tetrahedron Lett. 1987, 28,
6373–6376. (b) Minisci, F.; Vismara, E.; Fontana, F.; Barbosa, M. C. N.
Tetrahedron Lett. 1989, 30, 4569–4572. (c) Coppa, F.; Fontana, F.; Minisci,
F.; Pianese, G.; Torotreto, P.; Zhao, L. Tetrahedron Lett. 1992, 33, 687–690.
(15) Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.; Dutia, M.;
Powell, D. W.; Wissner, A.; Arndt, K.; Weber, J. M.; Boschelli, F. J. Med.
Chem. 2001, 44, 822–833.
(16) Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.; Barlow, J.
J.; Healy, M. P.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.;
Henthorn, L.; Richards, L. Bioorg. Med. Chem. Lett. 2001, 11, 1911–1914.
J. Org. Chem. Vol. 74, No. 16, 2009 6355

Duncton et al.
JOCNote
TABLE 1. Introduction of an Oxetane Group into Heterocyclic Bases
Asanextension, it ispossiblethatotherdecorated heterocyclic
bases possessing pharmacological activity could be functio-
nalized, in an intermolecular fashion, using the reaction out-
lined in this paper, or related Minisci transformations. For
example, previous studies have shown that many groups
such as aryl,1,2 alkyl1 (including trifluoromethyl6g and
perfluoroalkyl18), cycloakyl,1 acyl,19 aldehyde (including
masked aldehyde),20 carbamoyl,21 R-alkoxymethyl,22 and
hydroxymethyl23 may be incorporated into a multitude of
heterocyclic bases. Related processes employing ketyl radicals
(Emmert reaction)24 and silyl radicals4g have also shown
promising results. Understanding the scope and limitation
of these reactions with functionalized substrates, such as those
encountered in the “drug universe”, would serve to increase
the attractiveness of this important transformation.
In summary, this paper describes the incorporation of an
oxetane and azetidine group into heteroaromatic bases using
a radical-based (Minisci) approach. The reaction proceeds in
low-to-moderate yield with a broad range of substrate. Of
particular significance were successful transformations with
chemotypes from antimalarial and kinase research. Future
studies will focus on the introduction of an oxetane, azeti-
dine, or other small saturated heterocycle into alternative
bioactive molecules. Additionally, the use of different car-
bon-centered radicals should also be explored.
(18) Antonietti, F.; Mele, A.; Minisci, F.; Punta, C.; Recupero, F.;
Fontana, F. J. Flourine Chem. 2004, 125, 205–211.
(19) (a) Caronna, T.; Gardini, G. P.; Minisci, F. J. Chem. Soc. 1969, 201.
(b) Gardini, G. P.; Minisci, F. J. Chem. Soc. 1970, 929. (c) Minsci, F.;
Caronna, T.; Galli, R.; Malatesta, V. J. Chem. Soc. 1971, 1747–1750. (d)
Caronna, T.; Fronza, G.; Minisci, F.; Porta, O.; Gardini, G. P. J. Chem. Soc.,
Perkin Trans. 2 1972, 1477–1481. (e) Caronna, T.; Fronza, G.; Minisci, F.;
Porta, O. J. Chem. Soc., Perkin Trans. 2 1972, 2035–2038. (f) Fontana, F.;
Minisci, F.; Nogueira, B. M. C.; Vismara, E. J. Org. Chem. 1991, 56, 2866–
2868. (g) Minisci, F.; Recupero, F.; Cecchetto, A.; Punta, C.; Gambarotti, C.;
Fontana, F.; Pedulli, G. F. J. Heterocycl. Chem. 2003, 40, 325–328.
(20) (a) Gardini, G. P. Tetrahedron Lett. 1972, 13, 4113–4116. (b)
Giordano, C.; Minisci, F.; Vismara, E.; Levi, S. J. Org. Chem. 1986, 51,
536–537.
(21) (a) Minisci, F.; Gardini, G. P.; Galli, R.; Bertini, F. Tetrahedron Lett.
1970, 11, 15–16. (b) Gardini, G. P.; Minisci, F.; Palla, G.; Arnone, A.; Galli,
R. Tetrahedron Lett. 1971, 12, 59–62. (c) Arnone, A.; Cecere, M.; Galli, R.;
Minisci, F.; Perchinummo, M.; Porta, O.; Gardini, G. Gazz. Chim. Ital. 1973,
103, 13–29. (d) Citterio, A.; Gentile, A.; Minisci, F.; Serravalle, M.; Ventura,
S. J. Org. Chem. 1984, 49, 3364–3367. (e) Coppa, F.; Fontana, F.; Lazzarini,
E.; Minisci, F. Heterocycles 1993, 36, 2687–2696. (f) Minisci, F.; Recupero,
F.; Punta, C.; Gambarotti, C.; Antonietti, F.; Fontana, F.; Pedulli, G. F.
Chem. Commun. 2002, 2496–2497.
(22) (a) Citterio, A.; Gentile, A.; Serravalle, M.; Tinucci, L.; Vismara, E.
J. Chem. Res. Synop. 1982, 272–273. (b) Citterio, A.; Gentile, A.; Minisci, F.;
Serravalle, M.; Ventura, S. J. Chem. Soc., Chem. Commun. 1983, 916–917. (c)
Citterio, A.; Casucci, D.; Gentile, A.; Serravalle, M.; Venturra, S. Gazz.
Chim. Ital. 1985, 115, 319–324. (d) Minisci, F.; Vasmara, E.; Romano, U.
Tetrahedron Lett. 1985, 26, 4803–4806. (e) Minisci, F.; Citterio, A.; Vismara,
E.; Giordano, C. Tetrahedron 1985, 41, 4157–4170. (f) Vismara, E.; Fontana,
F.; Minisci, F. Org. Prep. Proc. Int. 1988, 20, 105–108. (g) Togo, H.; Aoki,
M.; Yokoyama, M. Tetrahedron Lett. 1991, 32, 6559–6562. (h) Togo, H.;
Aoki, M.; Yokoyama, M. Chem. Lett. 1992, 1673–1676. (i) Vismara, E.;
Torri, G.; Pastori, N.; Marchiandi, M. Tetrahedron Lett. 1992, 33, 7575–
7578. (j) Togo, H.; Aoki, M.; Kuramochi, T.; Yokoyama, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 2417–2427. (k) Togo, H.; Ishigami, S.; Fujii, M.;
IkUma, T.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1 1994, 2931–2942.
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aPercentage yield of isolated product from reaction of
heteroaromatic base (1 equiv) with 3-iodooxetane (2 equiv),
FeSO4 7H2O (3 Â 0.3 equiv), H2O2 (2 Â 3 equiv), H2SO4 (2
3
b
equiv) in DMSO at room temperature. Reaction performed
at 40 °C. cReaction performed at 60 °C. dDifficulties with
product isolation encountered. eCompound 2k (14% yield)
and compound 2j (14% yield).
can participate in the reaction. For example, starting materials
containing an alkyl group, alcohol, ether, amine, aniline,
nitrile, ester, carbamate, and arylhalide were all successfully
employed in our studies.
The introduction of oxetane or azetidine groups into
heterocyclic bases with pharmacological activity may be use-
ful for a variety of reasons. For example, inclusion of a
strategically placed oxetane may give rise to molecules with
improved drug-like characteristics and, or, a reduced side-
effect profile.8 In the case of kinase inhibitors, the influence of
an oxetane group can be assessed by kinome-wide screening.17
(23) Minisci, F.; Porta, O.; Recupero, F.; Punta, C.; Gambarotti, C.;
Pruna, B.; Pierini, M.; Fontana, F. Synlett 2004, 874–876.
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Duncton et al.
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TABLE 2. Introduction of an Azetidine Group into Heterocyclic Bases
TABLE 3. Introduction of Oxetane or Azetidine Groups into Pharma-
cologically-Active Heterocyclic Bases
aPercentage yield of isolated product from reaction of
heteroaromatic base (1 equiv) with 1-Boc-3-(iodo)azetidine
(2 equiv), FeSO4 7H2O (3 Â 0.3 equiv), H2O2 (2 Â 3 equiv),
performed at 40 °C. cReaction performed at 60 °C.
3
H2SO4 (2 equiv) in DMSO at room temperature. bReaction
aPercentage yield of isolated product from reaction of
heteroaromatic base (1 equiv) with 3-iodooxetane or 1-Boc-
Experimental Section
3-(iodo)azetidine (2 equiv), FeSO4 7H2O (3 Â 0.3 equiv),
3
H2O2 (2 Â 3 equiv), H2SO4 (2 or 3 equiv) in DMSO at room
temperature. bReaction performed at 50 °C. cDifficulties
with isolating pure product encountered. Reaction performed
4-Methyl-2-(oxetan-3-yl)quinoline, 2a. H2O2 (30% in H2O;
0.31 mL, 3.0 mmol) was added dropwise over 1-2 min to a
stirred solution of lepidine 1a (132 μL, 1.0 mmol), concentrated
H2SO4 (107 μL, 2.0 mmol), 3-iodooxetane (368 mg, 2.0 mmol),
and iron(II) sulfate heptahydrate (80 mg, 0.3 mmol) in DMSO
(10 mL) at room temperature. After 1-2 min a further portion
of iron(II) sulfate heptahydrate (80 mg, 0.3 mmol) was added
and the mixture was stirred at room temperature for 30 min.
Further H2O2 (0.31 mL, 3.0 mmol) and iron(II) sulfate hepta-
hydrate (80 mg, 0.3 mmol) was added, and the mixture was
stirred for 15 min, then poured into a 0.2 M solution of NaOH
(30 mL) and Et2O (50 mL). The aqueous and organic layers
were partitioned and the aqueous layer was extracted with Et2O
(2Â25 mL). The combined organic extracts were washed with
brine (1Â30 mL), dried (MgSO4), and filtered and the solvent
was removed under vacuum to leave a crude oil. The oil was
purified by preparative thin-layer chromatography with EtOAc/
hexanes (3:7) as eluent to give a mixture of lepidine 1a and
desired product 2a (25 mg), and the desired product 2a (82 mg,
40%) as a solid. An analytical portion of product 2a was
recrystallized from EtOAc/hexanes for data purposes. 1H
NMR (400 MHz; CDCl3) δ 8.07 (d, J=8.3 Hz, 1H), 7.97 (d,
J=8.3 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H),
7.38 (s, 1H), 5.19 (dd, J=8.3, 6.0 Hz, 2H), 5.05 (t, J=6.3 Hz,
2H), 4.51 (app. quint., J=7.5 Hz, 1H), 2.73 (s, 3H); 13C NMR
(100 MHz; CDCl3) δ 160.6, 147.7, 145.4, 129.8, 129.5, 127.3,
126.2, 123.8, 120.0, 76.9, 42.6, 19.0. Anal. Calcd for C13H13NO:
C, 78.36; H, 6.58; N, 7.03. Found: C, 78.09; H, 6.53; N, 6.87.
tert-Butyl 3-(4-Methylquinolin-2-yl)azetidine-1-carboxylate,
3b. H2O2 (30% in H2O; 0.86 mL, 9.0 mmol) was added to a
stirred solution of quinaldine 1b (400 mg, 3.0 mmol), concen-
trated H2SO4 (298 μL, 6.0 mmol), 1-Boc-3-(iodo)azetidine
(1.58 g, 3.0 mmol), and iron(II) sulfate heptahydrate (200 mg,
0.8 mmol) in DMSO (30 mL) at room temperature. After 30 min
a further portion of iron(II) sulfate heptahydrate (200 mg,
0.8 mmol) and H2O2 (30% in H2O; 0.86 mL, 9.0 mmol) was
d
at 60 °C.
added and the mixture was stirred at room temperature for
30 min. Further H2O2 (0.86 mL, 9.0 mmol) and iron(II) sulfate
heptahydrate (200 mg, 0.8 mmol) was added, and the mixture
was stirred for 120 min, then poured into an ice-cold solution of
NaOH and adjusted to pH >10. The aqueous was extracted
with Et2O. The aqueous layer was then saturated with solid
NaCl and extracted with CHCl3 until all the product was
removed from the aqueous layer. The combined organic extracts
were dried (MgSO4), and filtered and the solvent was removed
under vacuum to leave a crude residue. The residue was purified
by column chromatography on silica gel with EtOAc/hexanes
(1:1 to 1:0) as eluent to give the desired product 3b (450 mg,
50%) as an oil that crystallized on standing. 1H NMR (400
MHz; CDCl3) δ 8.07 (d, J=8.3 Hz, 1H), 7.70-7.67 (q, J=7.4
Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.28 (s, 1H), 4.49 (t, J=8.2 Hz,
2H), 4.44-4.38 (m, 1H), 4.17 (br s, 2H), 2.77 (s, 3H), 1.46 (s,
9H); 13C NMR (100 MHz; CDCl3) δ 159.0, 156.4, 148.1, 146.8,
129.8, 129.5, 126.1, 125.0, 122.8, 118.9, 80.0, 54.1, 30.1, 28.5,
25.6; m/z 299.0 (M + 1)+. Anal. Calcd for C18H22N2O2: C,
72.46; H, 7.43; N, 9.39. Found: C, 72.19; H, 7.42; N, 9.21.
Acknowledgment. We thank Andrew Calabrese and
Thomas Ryckmans of Pfizer, Sandwich (UK) for insightful
discussions about the oxetane motif. We also thank
Jonathan Bentley and Rachel Ward of Evotec (UK) for
high-resolution mass spectrometry data.
Supporting Information Available: Detailed experimental
conditions and copies of analytical data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6357