Diastereoselective preparation of azetidines and pyrrolidines

Article abstract of DOI:10.1021/ol102215e

Iodine-mediated cyclization of homoallyl amines at room temperature delivered cis-2,4-azetidine through a 4-exo trig cyclization. Isomerization of iodo-azetidines to cis-pyrrolidines could be achieved by heating, with complete stereocontrol. The relative stereochemistry of the iodo-azetidines and pyrrolidines was confirmed by NMR spectroscopy and X-ray crystallography. Further functionalization was achieved through nucleophilic displacement of iodine to deliver substituted azetidines and pyrrolidines. 1,2,3-Triazole- appended azetidines and pyrrolidines were also prepared.

Full text of DOI:10.1021/ol102215e

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5044-5047
Diastereoselective Preparation of
Azetidines and Pyrrolidines
Antonio Feula, Louise Male, and John S. Fossey*
School of Chemistry, UniVersity of Birmingham, Edgbaston, Birmingham,
West Midlands, B15 2TT, United Kingdom
j.s.fossey@bham.ac.uk
Received September 15, 2010
ABSTRACT
Iodine-mediated cyclization of homoallyl amines at room temperature delivered cis-2,4-azetidine through a 4-exo trig cyclization. Isomerization
of iodo-azetidines to cis-pyrrolidines could be achieved by heating, with complete stereocontrol. The relative stereochemistry of the iodo-
azetidines and pyrrolidines was confirmed by NMR spectroscopy and X-ray crystallography. Further functionalization was achieved through
nucleophilic displacement of iodine to deliver substituted azetidines and pyrrolidines. 1,2,3-Triazole-appended azetidines and pyrrolidines
were also prepared.
Amido oxidation level nitrogen containing 4-membered rings
(ꢀ-lactams) are a common pharmaceutical motif, and a range
of versatile methods are available for their synthesis.1 Amine
oxidation level 4-membered rings (azetidines) are important
structures, they have been used as ligands2 and as synthetic
building blocks3 and can be found in a range of natural
products.4 The antibacterial activity,5 binding to acetylcho-
line receptors,6 and the psychotropic potency7 of azetidine
derivatives have been studied and contrasted with those of
their 5-membered pyrrolidine congeners, revealing them to
be an intriguing class of compounds.
Azetidines8 can be prepared by cyclization of 1,3-diols
with amines.9 The OH functionality of 1,3-amino alcohols
can be converted into leaving groups which are then
intramolecularly displaced by amine to furnish azetidines.10
Intramolecular epoxide5 and aziridine ring-opening,11 double
(1) (a) Tidwell, T. T. Angew. Chem., Int. Ed. 2008, 47, 1016. (b) Berlin,
J. M.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47, 7048.
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Mas, J.; Valenti, E. J. Med. Chem. 1993, 36, 801.
(2) (a) Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de Gelder, R.;
Smits, J. M. M.; Zwanenburg, B. Tetrahedron 1998, 54, 4991. (b) Keller,
L.; Sanchez, M. V.; Prim, D.; Couty, F.; Evano, G.; Marrot, J. J. Organomet.
Chem. 2005, 690, 2306. (c) Lee, Y. H.; Harrowfield, J.; Kim, Y.; Lim,
W. T.; Park, Y. C.; Thuery, P. Dalton Trans. 2009, 434. (d) Lee, Y. H.;
Harrowfield, J. M.; Kim, J. S.; Kim, Y.; Lee, M. H.; Lim, W. T.; Park,
Y. C.; Thuery, P. Dalton Trans. 2009, 443. (e) Lee, Y. H.; Kim, H. H.;
Thuery, P.; Harrowfield, J. M.; Lim, W. T.; Kim, B. J.; Kim, Y. J. Inclusion
Phenom. Macrocyclic Chem. 2009, 65, 65. (f) Wilken, J.; Erny, S.;
Wassmann, S.; Martens, J. Tetrahedron: Asymmetry 2000, 11, 2143.
(3) Baeg, J. O.; Bensimon, C.; Alper, H. J. Org. Chem. 1995, 60, 253.
(4) (a) Singh, S.; Crossley, G.; Ghosal, S.; Lefievre, Y.; Pennington,
M. W. Tetrahedron Lett. 2005, 46, 1419. (b) Yoda, H.; Uemura, T.; Takabe,
K. Tetrahedron Lett. 2003, 44, 977.
(6) Schmitt, J. D.; Sharples, C. G.; Caldwell, W. S. J. Med. Chem. 1999,
42, 3066.
(7) Wang, D. X.; Booth, H.; Lerner-Marmarosh, N.; Osdene, T. S.;
Abood, L. G. Drug DeV. Res. 1998, 45, 10.
(8) (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. ReV. 2008, 108,
3988. (b) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 2002, 3099.
(9) (a) Hillier, M. C.; Chen, C. Y. J. Org. Chem. 2006, 71, 7885. (b)
Burkhard, J.; Carreira, E. M. Org. Lett. 2008, 10, 3525. (c) Sato, M.; Gunji,
Y.; Ikeno, T.; Yamada, T. Synthesis 2004, 1434.
(10) (a) Secor, H. V.; Edwards, W. B. J. Org. Chem. 1979, 44, 3136.
(b) de Figueiredo, R. M.; Frohlich, R.; Christmann, M. J. Org. Chem. 2006,
71, 4147.
(11) Albrecht, Ł.; Jiang, H.; Dickmeiss, G.; Gschwend, B.; Hansen,
S. G.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 9188.
10.1021/ol102215e  2010 American Chemical Society
Published on Web 09/29/2010

halide displacement from 1,3-dihalides by amines,2a,f sulfuric
acid treatment of homoallyl amines,12 and selenium mediated
reactions of homoallyl amines have delivered both 4-exo and
5-endo azetidines and pyrrolidines, respectively.13 Upon
treatment of homoallyl amines with NBS Corey was also
able to produce a bicyclic 4-exo azetidine.14 Bromonium-
mediated 4-endo cyclizations have also been achieved.15-17
perhaps offer high stereodefinition, it was selected as the
cyclization promoter.
Compound 1a was treated with molecular iodine under a
variety of conditions, and while consumption of starting
material could be monitored by TLC, in most cases only
very small amounts of mixtures of cis-2a and cis-3a, where
3 was the major product, were obtained following column
chromatography (silica). However, when a 3-fold excess of
iodine was used at room temperature in acetonitrile ac-
companied by a 5-fold excess of NaHCO3 azetidine cis-2a
could be obtained, albeit in 45% isolated yield, but most of
the starting amine (1a) had been consumed (Table 1).
The homoallyl amine motif is readily accessible through
allylation of imines, yet their cyclization protocols are
plagued with problems. Mixtures of 2,4-azetidines (overall
4-exo) and 2,4-pyrrolidines (overall 5-endo, Baldwin disfa-
vored) are commonplace, decomposition can be problematic,
and stereochemical integrity is not always high. These issues
can be addressed when the homoallylic carbon is a quaternary
center, but even then robust protocols for the diastereose-
lective 4-exo trig cyclization of homoallylic amines to furnish
3-unsubstituted azetidines has remained somewhat elusive.18
Park and co-workers cyclized homoallyl amines (with a bulky
amine substituent) to deliver pyrrolidines.19 Outurqin and
co-workers have shown that treatment of homoallylic amines
with PhSeX (X ) Br, Cl, or I) results in ring closure to give
SePh-appended 4-membered azetidines and 5-membered
pyrrolidines.13b,c When X ) I low yields of an azetidine
product could be obtained.13c
Table 1. 2,4-cis-Azetidine Formation by Iodocyclization of
Homoallylamines
(2 + 3)
2
R1
R2
Conv,a
%
2:3b yield,c % yield,d
%
45e
41e
45e
42f
51f
46f
42f
41e
Herein a highly diastereoselective, 4-exo trig, iodo-cy-
clization of homoallyl amines to furnish 2,4-cis-azetidines,
in up to quantitative conversion is reported. Functionalization
of the obtained azetidines is exemplified and thermal
isomerization to the apparent 5-endo product akin to the ring
expansion protocol of Couty et al.20 is also demonstrated,
a
b
c
d
e
f
Ph
Bn
>99
>99
>99
>99
>99
>99
>99
>99
>99:1
>99:1
>99:1
5:1
96
85
93
91
95
90
83
87
Ph
PMBg
PTBh
Bn
Ph
3-Py
4-Py
Bn
6:1
4-NO2-phenyl Bn
2-Br-phenyl
t-Bu
a Conversion to 2 + 3 based on consumption of 1 by 1H NMR
3:1
3:1
>99:1
g
h
Bn
Bn
Homoallyl amines, 1a-h, were prepared as racemates by
a standard literature protocol.21 To probe the potential for
direct funtionalized azetidine synthesis compound 1a was
initially investigated. We envisaged 4-exo halide-mediated
cyclization ought to deliver azetidines. Since iodine has
already been shown to deliver pyrrolidines in a 5-exo
fashion,22 and this sterically encumbered halide could
spectroscopy. b cis-(2:3) ratio obtained by inspection of the 1H NMR
spectrum post aqueous workup. c Yield (2 + 3) post aqueous workup. d Yield
obtained after flash chromatography. e The 2:3 ratio was eroded after column
chromatography to ∼20:1 due to isomerization of 2 to 3. f The 2:3 ratio
was ∼20:1 after column chromatography. g PMB ) p-methoxybenzyl. h PTB
) p-tolylbenzyl.
To address the apparent mass loss we examined the crude
reaction mixture in more detail, and to our delight discovered,
after workup, the corresponding azetidine cis-2a was the
major constituent. A number of trials confirmed that chro-
matography (on silica) results in a dramatic loss of material.
(12) (a) Varlamov, A. V.; Sidorenko, N. V.; Zubkov, F. I.; Chernishev,
A. I.; Turchin, K. F. Khim. Geterotsikl. Soedin. 2004, 1261. (b) Varlamov,
A. V.; Sidorenko, N. V.; Zubkov, F. I.; Chernyshev, A. I.; Turchin, K. F.
Chem. Heterocycl. Compd. (N.Y., NY, U.S.) 2004, 40, 1097.
(13) (a) Berthe, B.; Outurquin, F.; Paulmier, C. Tetrahedron Lett. 1997,
38, 1393. (b) Outurquin, F.; Pannecoucke, X.; Berthe, B.; Paulmier, C. Eur.
J. Org. Chem. 2002, 1007. (c) Pannecoucke, X.; Outurquin, F.; Paulmier,
C. Eur. J. Org. Chem. 2002, 995.
With satisfactory reaction conditions in hand the homoallyl
amines 1b to 1h were also cyclized, with iodine, to the
corresponding azetidines cis-2b to cis-2h. Purification by
column chromatography, in our hands, gave only around 45%
isolated yield in all cases. Analysis of the crude materials’
proton NMR spectra revealed some pyrrolidine had formed
in the case of d to g but azetidines cis-2 were always the
major product.23 The cyclization of the 2-pyridyl analogue
was also attempted but failed to give the desired product(s).24
The X-ray crystal structure of 2b (Figure 1a) along with
(14) Corey, E. J.; Loh, T. P.; Achyutharao, S.; Daley, D. C.; Sarshar, S.
J. Org. Chem. 1993, 58, 5600.
(15) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2000, 3007
(16) For a review of 5-endo electrophile assisted ring closures see ref
17.
.
(17) Knight, D. W. In Progress in Heterocyclic Chemistry; Gordon,
W. G., Thomas, L. G., Eds.; Elsevier: Amsterdam, The Netherlands, 2002;
Vol. 14, p 19
.
(18) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. Tetrahedron Lett.
1998, 39, 8909. (b) Ichikawa, J.; Lapointe, G.; Iwai, Y. Chem. Commun.
2007, 2698.
(19) Lee, W. S.; Jang, K. C.; Kim, J. H.; Park, K. H. Chem. Commun.
1999, 251.
(20) (a) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2003, 44, 5209.
(b) Drouillat, B.; Couty, F.; David, O.; Evano, G.; Marrot, J. Synlett 2008,
2008, 1345. (c) Durrat, F.; Sanchez, M. V.; Couty, F.; Evano, G.; Marrot,
J. Eur. J. Org. Chem. 2008, 3286. (d) Couty, F.; Kletskii, M. THEOCHEM
2009, 908, 26.
(22) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell,
A. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry
2009, 20, 758.
(23) For proton NMR spectra comparing post work-up and post column
chromatography on obtained 2d see the Supporting Information.
(21) Keck, G. E.; Enholm, E. J. J. Org. Chem. 1985, 50, 146.
Org. Lett., Vol. 12, No. 21, 2010
5045

of 2 and 3 are initially obtained. To test this hypothesis the
iodo-cyclization of 1a was repeated; after aqueous workup
the obtained material was dissolved in neat p-methoxyben-
zylamine, and stirring at room temperature for 48 h gave
the corresponding amino azetidine in 78% yield (Scheme
2). Thus, demonstrating derivatization of material obtained
Scheme 2. Two-Step Protocol for the Conversion of Homo
Allylamines 1a into Substituted Azetidine 4
Figure 1. X-ray crystal structures with ellipsoids drawn at the 50%
probability level of (a) cis-2b25 and (b) cis-3c. Most of the hydrogen
atoms have been omitted for clarity and cis-stereochemistry is
confirmed in both cases.
inspection of NOE data and comparison among the NMR
spectra obtained confirmed cis stereochemistry for the
azetidines.
It was rapidly discovered that storage of iodo-azetidines
cis-2 (even at 4 °C) resulted in the formation of some of the
corresponding pyrrolidines cis-3. Thermal ring-expansion,
in accordance with the findings of Couty et al.,20 was
confirmed: heating cis-2c-e in acetonitrile at reflux for 4 h
gave cis-3c-e in 97%, 95%, and 98% overall yield,
respectively (Scheme 1). The relative stereochemistry of cis-
from the cyclization reactions may be performed without
purification, to give higher yields than would be possible
otherwise.
Next 1d was exposed to an analogous two-step cycliza-
tion-derivatization sequence. Derivatives of 2d (and 3d) are
especially attractive owing to the 3-pyridyl motif, allowing
access to a potentially useful class of azetidine (and pyrro-
lildine), nicotine analogues, and derivatives. The pharma-
cological activity of such analogues is an area of persistent
interest.7,10a,26 In the case of the cyclization of 1d it had
already been shown a 5:1 mixture of 2d:3d in high
conversion was obtained, yet only 42% of 2d could be
isolated by column chromatography (Table 1). Pleasingly,
purification post-derivatization gave the corresponding amino
azetidine 5 as a single diastereoisomer in 72% overall isolated
yield (Scheme 3, upper).
Scheme 1
.
Thermal Isomerization of Azetidines 2c-e to
Pyrrolidines 3c-e
Scheme 3
.
Conversion of Amine 1d to the Corresponding
Amino-Azetidine 5 and Pyrrolidine 6
3c was corroborated by NOE studies and confirmed by X-ray
crystal structure analysis (Figure 1b).
This isomerization can account for not only our initial
trouble of product distribution between azetidine and pyr-
rolidine but also the apparent mixtures of products obtained
by others discussed earlier.
Since azetidines 2 were not robustly stable and initially
obtained reaction products, post-workup, contained mostly
the desired cis-azetidines (Table 1), it was speculated that
replacement of iodide might arrest decomposition or isomer-
ization and post-derivatization purification might provide
higher overall yield, especially in the cases where mixtures
To demonstrate the versatility of iodoazetidines 2 a second
reaction sequence starting from homoallyl amine 1d was
conceived. A 4 h preheating step was performed, as such
isomerization to the corresponding pyrrolidine (3d) and
(24) (a) Pyridinium iodide formation was postulated. Cf.: (b) Chen, W.;
Elfeky, S. A.; Nonne, Y.; Male, L.; Ahmed, K.; Amiable, C.; Axe, P.;
Yamada, S.; James, T. D.; Bull, S. D.; Fossey, J. S. Chem. Commun. DOI:
10.1039/c0cc01420f. Published Online: July 5, 2010. (c) Richter, I.; Minari,
J.; Axe, P.; Lowe, J. P.; James, T. D.; Sakurai, K.; Bull, S. D.; Fossey,
J. S. Chem. Commun. 2008, 1082.
(25) The X-ray crystal structure of 2b consists of two crystallographically
independent molecules, the geometry of which are very similar to one
another and of which only one has been shown.
(26) (a) Vagg, R.; Chapman, S. Addiction 2005, 100, 701. (b) Denton,
T. T.; Zhang, X. D.; Cashman, J. R. J. Med. Chem. 2005, 48, 224. (c)
Barlow, R. B.; Hamilton, J. T. Br. J. Pharmacol. Chemother. 1962, 18,
510. (d) Pogocki, D.; Ruman, T.; Danilczuk, M.; Danilczuk, M.; Celuch,
M.; Walajtys-Rode, E. Eur. J. Pharmacol. 2007, 563, 18
.
5046
Org. Lett., Vol. 12, No. 21, 2010

subsequent iodide displacement was anticipated (Scheme 3,
lower). Following solvent removal in vacuo exposure to neat
benzylamine afforded a 3:2 mixture of diastereomeric
pyrrolidines 6 in 75% isolated yield.27
A similar protocol employing 1d with more nucleophilic
azide was next performed. A room temperature reaction was
compared with a reaction that included a preheating step. In
one pot, the obtained azides were transformed into the
corresponding 1,2,3-triazoles utilizing conditions similar to
those employed elsewhere (Scheme 4).28
reaction performed with a 4 h preheating step gave the
corresponding pyrrolidine triazole. The anionic nucleophile
N3 had displaced iodide with inversion delivering only
trans-pyrrolidine 8 in 57% isolated yield, via cis-2d (Scheme
4); the relative stereochemistry was confirmed by NOE
experiments (see the Supporting Information).
-
To confirm the thermal stability of azetidines samples of
cis-5 and cis-7 were each heated in refluxing DMSO for 4 h.
Solvent removal in vacuo gave materials with unchanged
proton NMR spectra, confirming the robustness of the
azetidine motif in the absence of iodide.
Electrophile-mediated 4-exo trig azetidine formation fur-
nishes azetidines with a reactive leaving group-appended
methylene functionality in the 4-position, resulting in a
tendency for isomerization to the more stable pyrrolidine
congener. However, performing iodo-cyclization reactions
at room temperature delivered cis-2,4-azetidines. If desired,
full conversion to trans-pyrrolidines could be achieved with
complete stereocontrol by heating. Displacement of iodide
with nitrogen nucleophiles gave thermally stable azetidines;
the analogous pyrrolidines were also prepared demonstrating
the versatility of this iodo-cyclization protocol. We are
currently perusing single enantiomer azetidines and pyrro-
lidines for the generation of libraries with applications in
synthesis and catalysis.
Scheme 4. Conversion of Azetidine 2d to the Corresponding
Triazole-Appended azetidine 7 and Pyrrolidine 8
Acknowledgment. The University of Birmingham is
thanked for funding and studentship (A.F.). ERDF AWM II
is thanked for support. Dr Neil Spencer (UoB NMR Facility)
is thanked for invaluable help with NMR spectroscopy. The
EPSRC National Crystallography Service is thanked for
collection of X-ray diffraction data.
Addition of sodium azide to the pseudo in situ generated
2d at room temperature in DMF, followed by addition of
copper(I) iodide and phenyl acetylene gave azetidine triazole
derivative cis-6 in 46% isolated yield, whereas the same
Supporting Information Available: Experimental pro-
cedures, analysis, and X-ray crystallographic data including
CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) The trans:cis ratio for 6 was 1:1 when the benzylamine addition
step was carried out in DMF (71% yield).
(28) Scrafton, D. K.; Taylor, J. E.; Mahon, M. F.; Fossey, J. S.; James,
T. D. J. Org. Chem. 2008, 73, 2871.
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