Passerini reactions for the efficient synthesis of 3,3-disubstituted oxetanes

Article abstract of DOI:10.1016/j.tetlet.2012.03.065

Three-component reactions of oxetan-3-ones with isocyanides and carboxylic acids produce 3,3-disubstituted oxetanes in good yields. Good levels of diastereocontrol (dr = 4:1) can be achieved in these Passerini reactions when the oxetane nucleus possesses a bulky cyclohexyl substituent at C-2. The (2S,3R)-stereochemistry of the major diastereomer was confirmed by X-ray crystallography after ester hydrolysis, and a possible mechanism to account for the diastereofacial selectivity is presented.

Full text of DOI:10.1016/j.tetlet.2012.03.065

Tetrahedron Letters 53 (2012) 2951–2953
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Passerini reactions for the efficient synthesis of 3,3-disubstituted oxetanes
⇑
Benjamin O. Beasley, Guy J. Clarkson, Michael Shipman
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component reactions of oxetan-3-ones with isocyanides and carboxylic acids produce 3,3-disubsti-
tuted oxetanes in good yields. Good levels of diastereocontrol (dr = 4:1) can be achieved in these Passerini
reactions when the oxetane nucleus possesses a bulky cyclohexyl substituent at C–2. The (2S⁄,3R⁄)-ste-
reochemistry of the major diastereomer was confirmed by X-ray crystallography after ester hydrolysis,
and a possible mechanism to account for the diastereofacial selectivity is presented.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 January 2012
Revised 3 March 2012
Accepted 20 March 2012
Available online 4 April 2012
Keywords:
Isocyanide
Multi-component reaction
Oxetane
Passerini reaction
Multi-component reactions (MCRs) are one-pot processes that
bring together three or more starting materials to form a product
that contains most, if not all, elements of the reactants.1,2 They of-
fer a very attractive and efficient approach to chemical synthesis.
The most important examples are those employing isocyanides
as one of the components, such as the Passerini3 and Ugi4 reac-
tions. These isocyanide based MCRs have been widely used as an
avenue to libraries of small drug-like molecules because of their
ability to produce compounds with several degrees of structural
diversity under mild reaction conditions.5
There is much interest in the synthesis of oxetanes for their
application in medicinal chemistry.6 These four-membered oxygen
heterocycles are increasingly being used as surrogates for common
functional groups such as gem-dimethyl or carbonyl groups in drug
molecules. This isosteric replacement can induce profoundly bene-
ficial effects on the aqueous solubility, lipophilicity, metabolic
stability and conformational preference of such molecules.7
3-Substituted oxetanes are especially useful in this regard as no
additional stereocentres are introduced into the molecular scaffold
of the drug.6,7 Although, multi-step routes to 3-substituted
oxetanes are known,6 no isocyanide based MCRs have been re-
ported.8 We imagined that a Passerini reaction involving oxetan-
3-one 1, an isocyanide 2 and a carboxylic acid 3 could provide a
simple, flexible route to 3,3-disubstituted oxetanes 4 (Scheme 1).
As oxetan-3-ones are readily available,9 this chemistry offers a
practical new method for the synthesis of a wide variety of drug-
like molecules containing this important heterocyclic nucleus. In
this Letter, we demonstrate the feasibility and scope of this isocy-
anide based MCR to oxetanes.
The relatively few examples of Passerini reactions involving
ketones as the carbonyl component,3 and the privileged position
Table 1
Passerini reactions of oxetan-3-one (5)
Entry
R
R1
Product
Yielda (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
CbzNHCH2
Ph
2-Thienyl
tBu
Cy
6a
6b
6c
6d
6e
6f
90
79
51
62
47
92
85
52
nBu
Bn
tBu
tBu
tBu
tBu
6g
6h
Scheme 1. Proposed Passerini MCR to 3,3-disubstituted oxetanes.
2-(3-Bromo-thienyl)
a
⇑
Corresponding author.
E-mail address: m.shipman@warwick.ac.uk (M. Shipman).
Full experimental procedures and characterization data are available in the
Supplementary data.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.065

2952
B. O. Beasley et al. / Tetrahedron Letters 53 (2012) 2951–2953
Table 2
Passerini reactions of substituted oxetan-3-ones 7a–c
Scheme 2. Ester hydrolysis of Passerini product 9a.
Entry
R
R1
R2
Product a/b
Yielda (%)
drb
1
2
3
4
CH2CH2Ph
Cy
CO2Et
Cy
H
H
Me
H
Me
Me
Me
Ph
8
9
10
11
76
97
79
49
1.7:1
4:1
2.8:1
3.4:1
a
Full experimental procedures and characterization data are available in the
Supplementary data.
b
Diastereomeric ratios determined by 1H NMR analysis on the crude product.
of the 3,3-disubstituted oxetane skeleton, led us to begin our stud-
ies using commercially available oxetan-3-one (5). Treatment of
this ketone with acetic acid (1.2 equiv) and tert-butyl isocyanide
(1.2 equiv) in dichloroethane (DCE) for 18 h provided the Passerini
adduct 6a in 90% yield (Table 1, entry 1). Other aprotic solvents
such as dichloromethane (91%) were equally effective for this
transformation, but much lower yields were seen with protic sol-
vents such as MeOH (20%). The structural complexity arising in this
MCR was deduced from NMR spectroscopy, and later confirmed by
X-ray crystallography on a single crystal of 6a grown from CH2Cl2/
pentane (see Supplementary material). 10 The scope of this reaction
was readily determined through simple variation in the nature of
the isocyanide (Table 1, entries 1–4) and the carboxylic acid (Table
1, entries 4–8). Good to excellent yields were observed in most
cases.
Next, this chemistry was applied to more hindered oxetan-3-
ones bearing 2- and 2,4-substituents. Known oxetanes 7a–c were
readily made using the method of Zhang and co-workers.8 Despite
the fact that bulky substituents were introduced close to the react-
ing C@O bond, good yields of the Passerini products were obtained
(Table 2). However, the use of benzoic acid led to a lower yield
(Table 2, entry 4). It was found that good levels of stereoselectivity
were seen in these reactions when the substituent at C–2 was rel-
atively large. For example, 7b with a cyclohexyl group at C–2 gave
much better levels of diastereocontrol than 7a bearing the phenyl-
ethyl substituent (Table 2, entry 1 cf. entry 2). For entry 2, we sep-
arated 9a and 9b by column chromatography, and deduced their
relative stereochemistry in the following ways. For minor diaste-
reomer 9b, crystals were grown from CH2Cl2/pentane, and the
structure solved by X-ray crystallography.10 For 9a, the acetate
group was first removed via simple ester hydrolysis with K2CO3
Figure 1. ORTEP representation of one of the crystallographically independent
molecules in the asymmetric unit of the solid-state structure of 12.
in MeOH (Scheme 2). The resultant a-hydroxyamide 12 was suffi-
ciently crystalline that its structure could also be solved by X-ray
crystallography (Fig. 1). Knowing the relative stereochemistry of
12, that of 9a could be deduced with confidence.
Scheme 3. Possible mechanism to account for observed stereoselectivity.
The formation of 9a as the major stereoisomer from 7b was not
anticipated. One might expect that 9b would predominate as a re-
sult of addition of the isocyanide to the opposite face of the C–2
substituent on the oxetane ring (Scheme 3).11 However, the Passe-
rini reaction is a multi-step process in which the steps are often
considered reversible prior to the final acyl migration, and consid-
erable uncertainty remains about the precise mechanistic de-
tails.3,12 To account for the favoured production of 9a, we
propose that both 13 and 14 are produced under equilibrating con-
ditions through the addition of tBuNC and AcOH to both faces of 7b.
The diastereoselectivity then arises from differences in the relative
rates of acyl migration from 13 to 9a, and from 14 to 9b. The ob-
served preference for 9a is explained by suggesting that increased
steric crowding between the cyclohexyl and imidoyl substituents

B. O. Beasley et al. / Tetrahedron Letters 53 (2012) 2951–2953
2953
in 13 encourages faster acyl transfer than that seen for 14 where
References and notes
these substituents are on opposite faces of the four-membered
ring.
1. For a monograph, see: Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2005.
To conclude, oxetan-3-ones have been shown to be excellent
substrates for Passerini reactions providing a simple, direct route
to the pharmaceutically important 3,3-disubstituted oxetane scaf-
fold. This three-component reaction proceeds in high yields with a
range of isocyanides and carboxylic acids, and useful levels of
diastereocontrol are witnessed with oxetanes bearing bulky ring
substituents at C–2. Ongoing work is focused on the development
of other MCRs of the oxetane nucleus, and their application to drug
discovery.
2. (a) Ruijter, E.; Scheffelaar, R.; Orru, R. A. V. Angew. Chem., Int. Ed. 2011, 50,
6234–6246; (b) Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol.
2010, 14, 371–382.
3. Banfi, L.; Riva, R. Org. React. 2005, 65, 1–140.
4. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210 and references
therein.
5. Dömling, A. Chem. Rev. 2006, 106, 17–89.
6. For a review, see: Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Muller, K.;
Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 9052–9067.
7. (a) Wuitschik, 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; (b)
Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.;
Rogers-Evans, M.; Müller, K. J. Med. Chem. 2010, 53, 3227–3246.
8. We are aware of just one example of an MCR involving an oxetane. Zhang and
co-workers describe a single example of a Strecker reaction using oxetan-3-one
(5) in Ref. 9.
Acknowledgements
This work was supported by the University of Warwick and the
Engineering and Physical Sciences Research Council (EPSRC). The
Oxford Diffraction Gemini XRD system was obtained, through the
Science City Advanced Materials project: Creating and Characteriz-
ing Next Generation Advanced Materials, with support from
Advantage West Midlands.
9. Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550–8551 and references
cited therein.
10. Crystallographic data (excluding structure factors) for 6a (CCDC 863326), 9b
(CCDC 863327) and 12 (CCDC 863328) have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK.
11. Indeed, this stereochemical preference has been reported in the addition of
tBuNC to 2-phenoxycyclopentanone, albeit under somewhat different reaction
conditions, see: Lumma, W. C. J. Org. Chem. 1981, 46, 3668–3671.
Supplementary data
12. For
a detailed discussion of the reaction mechanism, see: Maeda, S.;
Komagawa, S.; Uchiyama, M.; Morokuma, K. Angew. Chem., Int. Ed. 2011, 50,
644–649 and references therein.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.065.