Reactions of oxetan-3-tert-butylsulfinimine for the preparation of substituted 3-aminooxetanes

Article abstract of DOI:10.1021/ol100119e

(Figure Presented) The oxetane ring Is useful In drug discovery as a bioisostere for both the geminal dimethyl group and the carbonyl group. A convenient, straightforward approach to access structurally diverse 3-aminooxetanes through the reactivity of oxetan-3-tert-butylsulfinimine and the corresponding sulfinylaziridine Is described.

Full text of DOI:10.1021/ol100119e

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1116-1119
Reactions of Oxetan-3-tert-butylsulfinimine
for the Preparation of Substituted
3-Aminooxetanes
Philip J. Hamzik and Jason D. Brubaker*
Department of Chemistry, Merck and Co., Inc., 33 AVenue Louis Pasteur,
Boston, Massachusetts 02115
jason_brubaker@merck.com
Received January 17, 2010
ABSTRACT
The oxetane ring is useful in drug discovery as a bioisostere for both the geminal dimethyl group and the carbonyl group. A convenient,
straightforward approach to access structurally diverse 3-aminooxetanes through the reactivity of oxetan-3-tert-butylsulfinimine and the
corresponding sulfinylaziridine is described.
The replacement of a geminal dimethyl group with an
oxetane ring is a potentially useful exercise in drug discov-
ery.1 Although presenting a similar van der Waals volume
to a geminal dimethyl group, an oxetane ring can be more
stable to oxidative metabolism and exhibit decreased lipo-
philicity, two properties that can confer an enhanced phar-
macokinetic profile.1a The decreased lipophilicity can also
mitigate undesirable off-target effects, such as hERG channel
binding2 and hPXR activation.3 Additionally, studies suggest
that an oxetane ring can also act as a stable surrogate for
the carbonyl group; both groups have similar hydrogen-bond
basicity,4 but oxetanes do not have the same electrophilic
reactivity or susceptibility toward R-epimerization of
stereocenters.1b
During the course of a medicinal chemistry program, we
became interested in preparing a 3-aryl-3-aminooxetane
(Figure 1) in order to examine the possibility of replacing
(1) (a) Wuitschik, G.; Rogers-Evans, M.; Mu¨ller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2006, 45, 7736–7739. (b) Wuitschik, G.; Rogers-Evans, M.; Buckl,
A.; Bernasconi, M. M.; Godel, T.; Holger, F.; Wagner, B.; Parilla, I.;
Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Mu¨ller, K.; Carreira,
E. M. Angew. Chem., Int. Ed. 2008, 47, 4512–4515.
Figure 1. Oxetanes as potential bioisosteres for the geminal
dimethyl or carbonyl group.
the dimethyl group in a key pharmacophore for the reasons
outlined above. At the time, we found no reports of this
structural motif, which was surprising given the apparent low
degree of structural complexity.5
(2) (a) Fermini, B.; Fossa, A. Nat. ReV. Drug DiscoVery 2003, 2, 439–
447. (b) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. J. Med. Chem.
2006, 49, 5030–5046.
(3) (a) Ngan, C.; Beglov, D.; Rudnitskaya, A. N.; Kozakov, D.; Waxman,
D. J.; Vajda, S. Biochemistry 2009, 48, 11572–11581. (b) Gao, Y.-D.; Olson,
S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Yabut, J.; Evers, R.; Tan, E. Y.;
Tang, W.; Hartley, D. P.; Mosley, R. T. Xenobiotica 2007, 37, 124–138.
(4) (a) Berthelot, M.; Besseau, F.; Laurence, C. Eur. J. Org. Chem. 1998,
925–931. (b) Besseau, F.; Lucon, M.; Laurence, C.; Berthelot, M. J. Chem.
Soc., Perkin Trans. 2 1998, 101–107.
(5) During the preparation of this manuscript, a related report was
published in the patent literature: Rainer, A.; Cooke, N. G.; Zecri, F.; Lewis,
I. International Patent Application WO 2009/068682 A2, June 4, 2009.
10.1021/ol100119e  2010 American Chemical Society
Published on Web 02/08/2010

One attractive approach to the synthesis of 3-aryl-3-
aminooxetanes involved the 1,2-addition of an arylmetal
nucleophile into an activated oxetan-3-imine, as it could
potentially allow for the modular, late-stage introduction of
the oxetane ring onto an appropriate aryl building block
(Figure 2). We chose to utilize Ellman’s tert-butylsulfinimine
Table 1. Aryllithium Additions into 1 To Access Protected
3-Aryl-3-aminooxetanes
Figure 2. Retrosynthesis of 3-aryl-3-aminooxetanes, and preparation
of sulfinimine 1.
chemistry because of the availabilty of 2-methyl-2-propane-
sulfinamide, the well-studied reactivity of tert-butylsulfin-
imines, and the ease of removal of the tert-butylsulfinyl group
to provide the deprotected amines.6
Condensation of commercially available oxetan-3-one with
racemic 2-methyl-2-propane-sulfinamide at 60 °C, utilizing
titanium(IV) ethoxide as a dehydrating reagent,6a provided
oxetan-3-tert-butylsulfinimine (1) as a slightly volatile oil.7
With access to sulfinimine 1, we began to explore its
reactivity toward organometallic reagents. Phenyllithium
underwent 1,2-addition to 1 at -78 °C in tetrahydrofuran to
give the tert-butylsulfinyl protected 3-phenyl-3-aminooxetane
in 91% yield (Table 1, entry 1). It is noteworthy that the
addition proceeds in high yield without the use of trimethyl-
aluminum as a Lewis acid, as is typically required to enhance
the yield in the addition of organolithium reagents to
N-sulfinyl ketimines.6c We next examined several other
phenyllithium reagents, including electron-deficient (Table
1, entries 2-5) and electron-rich (Table 1, entries 6-8)
aromatic rings. The required aryllithium reagents were each
generated by lithium-halogen exchange8 of the correspond-
ing bromides and underwent clean 1,2-addition to give
products 2b-2h in good to excellent yield.
dioxane, 1.5 equiv) to give the pure hydrochloride salt of
3-phenyl-3-aminooxetane (3) in 91% yield after trituration
with diethyl ether. Prolonged exposure to hydrochloric acid
should be avoided, as the ring-opened chlorohydrin 4 begins
to form (Scheme 1) under the deprotection conditions.9
Selective removal of the tert-butylsulfinyl group6b was
accomplished in the presence of the potentially acid-labile
oxetane ring by brief (1-5 min) treatment of a solution of
2a in methanol at 0 °C with hydrochloric acid (4 N in
Scheme 1. Removal of the tert-Butylsulfinyl Group To Give 3
(6) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. J.
Org. Chem. 1999, 64, 1278–1284. (b) Cogan, D. A.; Liu, G.; Ellman, J.
Tetrahedron 1999, 55, 8883–8904. (c) Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268–269.
(7) Sulfinimine 1 was stable to chromatography on silica gel and bench-
stable at 22 °C for several weeks.
(8) (a) Wittig, G.; Pockels, U.; Droge, H. Chem. Ber. 1938, 71, 1903–
12. (b) Gilman, H.; Langham, W.; Jacoby, A. L. J. Am. Chem. Soc. 1939,
61, 106–109. For general reference, see: (c) Leroux, F.; Schlosser, M.; Zohar,
E.; Marek, I. The preparation of organolithium reagents and intermediates.
In Organolithium Compounds; Strasbourg, F., Ed.; John Wiley & Sons Ltd.:
Chichester, U.K., 2004; Vol. 1, pp 435-493. (d) Wakefield, B. J.
Organolithium Methods; Pergamon Press: New York, 1988. (e) Bailey,
W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1–46.
Although our initial goal was to prepare 3-aryl-3-ami-
nooxetanes, we next decided to explore further the reactivity
of sulfinimine 1 toward diverse nucleophiles for the prepara-
tion of a variety of 3-substituted-3-aminooxetanes. Several
Org. Lett., Vol. 12, No. 5, 2010
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representative heterocycles bearing an acidic hydrogen were
metalated with n-butyllithium, and the corresponding anions
underwent 1,2-addition to 1 to generate 5f-5i in excellent
yield (Table 2, entries 6-9).
MeOH, 0 °C, 1-5 min, 95%)6b or the free alkyne (K2CO3,
MeOH-CH2Cl2, 5 min, 22 °C, 94%),11 allowing selective
elaboration of either the terminal alkyne12 or amine func-
tionality. Vinyllithium reagents13 (Table 2, entry 4) also
added to 1 efficiently, giving access to allylic aminooxetanes
in good yield. Finally, lithium enolates14 underwent addition
to 1 in excellent yield to give ꢀ-(3-aminooxetane)-esters
(Table 2, entry 5).
Table 2. Addition of Diverse Nucleophiles to 1 To Access
Substituted 3-Aminooxetanesa
Primary alkyllithium reagents such as n-butyllithium and
(2-phenylethyl)lithium15 added to 1 in poor yield (17% and
18%, respectively). Attempts at optimizing the reaction
conditions suggested that competitive deprotonation of the
oxetane ring within 1 was a source of low conversion and
side-products; conversion was not improved by the addition
of excess n-butyllithium (4 equiv), and deuterium quench
experiments indicated that 1 recovered from the reaction
mixture was enriched in deuterium.16
Having explored the reactivity of 1 toward several classes
of nucleophiles, we next examined the possibility of generat-
ing a sulfinylaziridine from sulfinimine 1. Ring-opening
reactions of a spiro-aziridine would expand the product scope
to homologated 3-aminooxetanes. Treatment of sulfinimine
1 with dimethyloxosulfonium methylide17 (DMSO, 22 °C,
2 h) generated the novel, highly strained aziridine 6 in 83%
yield (Scheme 2).
Scheme 2. Synthesis and Ring-Opening Reactions of 6
a Entries 1-3 and 5-9 performed in THF, entry 4 performed in 3:2
hexanes/diethyl ether.
Branching out from aryllithium substrates, we examined
several classes of carbanions across a range of nucleophil-
icity. Ethyl propiolate, phenylacetylene, and trimethylsilyl-
acetylene were deprotonated with n-butyllithium, and each
of the corresponding anions added to 1 in good yield to give
3-alkynyl-3-aminooxetanes 5a-5c in protected form10 (Table
2, entries 1-3). The trimethylsilylacetylene adduct (5a) could
be selectively deprotected to give either the free amine (HCl,
Aziridine 6 could be opened with phenylmagnesium
bromide (promoted by CuI)18 to give a benzyl substituted
(11) Cai, C.; Vasella, A. HelV. Chim. Acta 1995, 78, 732–757.
(12) For example, the terminal alkyne could undergo cycloaddition with
azides to give access to a triazole functionalized with a 3-aminooxetane;
see Supporting Information for details.
(13) Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847–853.
(14) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819–7832.
(15) Bailey, W. F.; Punzlan, E. R. J. Org. Chem. 1990, 55, 5404–5406.
(9) After 5 min at 22 °C, only the desired deprotected product was
observed. However, after 30 min at 22 °C, the ratio of 3 to 4 was 85:15 by
1H NMR, and after 6 h at 22 °C with 2.5 equiv of HCl, the ratio of 3 to 4
was 8:92.
(10) Representative deprotection of select examples can be found in
Supporting Information.
1118
Org. Lett., Vol. 12, No. 5, 2010

3-aminooxetane (7) in excellent yield (98%). In addition to
carbon-based nucleophiles, aziridine 6 could also be opened
efficiently with sulfur-based18 (thiophenol, triethylamine, 60
°C) and nitrogen-based19 (benzylamine, 130 °C) nucleo-
philes, further expanding the product scope of this methodol-
ogy for generating substituted 3-aminooxetanes.
interest to medicinal chemists for use as bioisosteres for the
geminal dimethyl group. We have also described the conver-
sion of 1 to the novel sulfinylaziridine 6, enabling access to
an expanded product scope by ring-opening reactions of 6
with both carbon- and heteroatom-based nucleophiles.
In conclusion, we have described here the synthesis of
oxetan-3-tert-butylsulfinimine (1) and demonstrated the util-
ity of 1 in reactions with a variety of organolithium reagents
for the straightforward synthesis of 3-aminooxetanes. As
outlined above, the product 3-aminooxetanes are of general
Acknowledgment. Part of this work was completed as
part of the Cooperative Education Program with Northeastern
University, Boston, MA (P.J.H.). We thank our Merck
colleagues Bridget Becker and Bruce Adams for assistance
with NMR analysis, Charles W. Ross III for providing
accurate mass measurement analysis, and Roy Helmy for
determination of deuterium enrichment.
(16) Recovered 1 was 50% mono-deuterated by MS analysis when 1
was treated with n-BuLi (1 equiv, -78 °C, 1 h), followed by addition of
deuterated acetic acid at -78 °C.
Supporting Information Available: Detailed experimen-
tal procedures, tabulated spectroscopic data, and copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) TMSOI: (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965,
87, 1353–1364. TMSOI in aziridinations: (b) Davis, F. A.; Zhou, P.; Liang,
C.; Reddy, R. E. Tetrahedron: Asymmetry 1995, 6, 1511–1514.
(18) Hodgson, D. M.; Hughes, S. P.; Thompson, A. L.; Heightman, T. D.
Org. Lett. 2008, 10, 3453–3456.
(19) Burgaud, B. G. M.; Horwell, D. C.; Padova, A.; Pritchard, M. C.
Tetrahedron 1996, 52, 13035–13050.
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