Ring expansion of 2-alkenyl azetidines into unsaturated azocanes

Article abstract of DOI:10.1055/s-0029-1218351

Enantiomerically pure 2-alkenyl azetidines undergo a ring expansion into N-alkyl-1,2,3,6-azocines upon reaction with activated alkynes (ethyl propiolate or ethynyl p-tolyl sulfone). The scope of this ring enlargement, which provides a new entry to functio

Full text of DOI:10.1055/s-0029-1218351

3182
LETTER
Ring Expansion of 2-Alkenyl Azetidines into Unsaturated Azocanes
Ring Expansion
o
r
f
2-Alke
u
nyl Azetidin
n
es into Unsa
o
turated Azocane
s
Drouillat, François Couty,* Vanessa Razafimahaléo
Institut Lavoisier de Versailles, UMR CNRS 8180, Universud Paris, Université de Versailles Saint Quentin en Yvelines,
45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: couty@chimie.uvsq.fr
Received 30 June 2009
Abstract: Enantiomerically pure 2-alkenyl azetidines undergo a
ring expansion into N-alkyl-1,2,3,6-azocines upon reaction with ac-
tivated alkynes (ethyl propiolate or ethynyl p-tolyl sulfone). The
scope of this ring enlargement, which provides a new entry to func-
tionalized eight-membered ring nitrogen heterocycle, is discussed.
EWG
N
N
R
EWG
R
N
1
2
3
EWG
R
Scheme 1 [3,3]-Sigmatropic rearrangement of 2-alkenyl azetidines
reacting with activated alkynes would produce unsaturated azocanes
Key words: azetidines, ring expansion, azocanes
Azetidines are rather underused heterocycles1 due to their
somewhat restricted availability, particularly when an
enantiomerically pure starting material is required.1f
Nonetheless, the strain in these heterocycles makes them
particularly interesting candidates for ring opening or ring
expansion reactions, which can, in the latter case, give ac-
cess to larger nitrogen heterocycles. Thus, expansions of
azetidines can produce up to seven-membered rings
through various reactions such as photolysis2 (production
of pyrroles), cobalt-catalysed carbonylation3 (production
of pyrrolidinones), intramolecular rearrangement4 (pro-
duction of pyrrolidines or piperidines), [4+2]
cycloadditions5 (production of piperidines), [2,3]-sigmat-
ropic shifts6 (production of azepanes), and other process-
es.7 However, to the best of our knowledge, the ring
expansion of azetidines into azocanes (eight-membered
nitrogen heterocycles) has not yet been described. We
wish to report in this letter the first example of such a ring
expansion based on a [3,3]-sigmatropic rearrangement of
2-alkenyl azetidines reacting with activated alkynes
(Scheme 1). The prototype of such a rearrangement was
described recently by Back et al,8 and its feasibility has
been evaluated for 3-, 5-, 6- or larger 2-vinyl nitrogen het-
erocycles,9 but not with 2-alkenyl azetidines. In addition,
this rearrangement did not take place with strained 2-vinyl
aziridines, due to competitive ring opening of the interme-
diate zwitterion 2 by the solvent,9 a result that casts doubt
on the possible use of a strained four-membered ring as a
substrate. When starting from azetidines, this ring expan-
sion would give access to unsaturated azocanes, a class of
nitrogen heterocycles that has been little studied, probably
due to the well-known inherent difficulty in forming such
medium-sized heterocycles.10 Despite their restricted
methods of preparation,11 functionalized azocanes have
been used as useful intermediates for the preparation of
pyrrolizidinic alkaloids, through ring contraction,12 or as
flexible scaffolds for the preparation of new iminocycli-
tols.13
In order to test this reaction, a set of 2-alkenyl azetidines
was selected (see Table 2 below). These compounds were
prepared by previously described procedures6 involving
either (i) Swern oxidation of the corresponding 2-hy-
droxymethyl azetidine, followed by Wittig olefination of
the resulting aldehyde (compounds 5, 6 and 9–12) or (ii)
formation of a ketone moiety at C-2, resulting from the
reaction of the corresponding 2-cyano azetidine with a
Grignard reagent,14 followed by Wittig olefination (com-
pounds 13 and 14). All these syntheses occurred with fair
yields for unreported compounds 5, 6, 9, 13 and 14. As an
illustration, Scheme 2 highlights the synthesis of stereo-
isomers 5 and 6, which were produced with low selectiv-
ity, but could be conveniently separated by flash
chromatography.
Ph
N
Ph
1) Swern oxidation
Bn
Ph
2) Ph3BnP+, Br–, BuLi,
5 (55)
+
THF, 0 °C
59% overall
N
OH
Ph
Bn
4
N
Bn
Ph
6 (45)
Scheme 2 Example of the preparation of 2-alkenyl azetidines
We first examined the nature of the electrophilic partner
and the reaction conditions as regards to the feasibility of
this ring expansion. Thus, compound 9 was reacted with
an array of Michael acceptors in dichloromethane or,
when higher refluxing temperature was desired, 1,2-
dichloroethane (Table 1, entries 1–6). This first set of ex-
periments demonstrates the feasibility of this ring expan-
SYNLETT 2009, No. 19, pp 3182–3186
x
x
.x
x
.2
0
0
9
Advanced online publication: 11.11.2009
DOI: 10.1055/s-0029-1218351; Art ID: D17309ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ring Expansion of 2-Alkenyl Azetidines into Unsaturated Azocanes
3183
Table 1 Optimisation of the Reaction Conditions with Azetidine 9
Entry
1
Electrophile
Conditions
Equiv
Product [Yield(%)]c
Solvent
DCEb
Temp
reflux
Time (h)
24
CO2Et
5
No reaction
2
3
4
1
1
5
DCEb
DCEb
neat
reflux
reflux
r.t.
24
24
24
No reaction
No reaction
No reaction
NO2
CO2Et
Ph
Ph
DMADa
Ph
Ts
5
6
1
5
CH2Cl2
CH2Cl2
r.t.
r.t.
24
24
Ts
N
Bn
7 (23)
Ph
CO2Et
CO2Et
N
Bn
8 (28)
8 (28)
7
8
5
CH2Cl2
THF
reflux
reflux
MW
r.t.
72
72
12
72
72
5 d
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
5
8 (26)
8 (25)
8 (54)
8 (57)
8 (82)
9
2
DCE
10
11
12
1.5
1.5
2
neat
MeCN
EtOH
r.t.
r.t.
a DMAD = Dimethyl acetylenedicarboxylate.
b No reaction was observed in CH2Cl2 at r.t.
c Yield refers to isolated pure product.
sion but shows that its scope is restricted to activated discussed in the following paragraphs, these parameters
monosubstituted alkynes (ethyl propiolate or ethynyl p- proved to be crucial for the success of this ring enlarge-
tolyl sulfone, entries 5 and 6). Since no other products ment. Thus, the compounds depicted in Table 2 were test-
could be isolated from the crude reaction mixtures, the ed as substrates, using these optimized conditions (2 equiv
moderate yields obtained for 7 and 8 were attributed to of activated alkyne, EtOH, r.t.).
competitive polymerization. Encouraged by these find-
ings, optimization of the reaction conditions using the
reaction of 9 with ethyl propiolate was next undertaken
Back et al. nicely demonstrated that this reaction goes
through an intermediate zwitterion 2, the formation of
which is the rate-limiting step in the case of 2-vinyl pipe-
(entries 7–12). These data demonstrate that neither using
ridines.9 In our experiments, the low yields obtained with
a large excess of electrophile, nor heating the reaction
disubstituted alkenes 13, 14, 5 and 6 (entries 8–11) are due
to competitive opening of this intermediate zwitterion by
ethanol, in an SN2¢ fashion. With these substrates, the ad-
ditional substituent on the double bond probably causes
mixture, increased the yields. Instead, running the reac-
tion in more polar solvents (or without any solvent) had a
clear effect on the efficiency of the reaction, and ethanol
(entry 12) was finally found to be the optimal solvent for
severe steric congestion during the electrocyclic [3,3]-sig-
this ring enlargement. In this solvent, the reaction oc-
matropic rearrangement as shown in Scheme 3 for sub-
curred smoothly, and the product was isolated in 82%
strate 14 (entry 9). This results in a slower process, thus
promoting competitive opening. Furthermore, it raises the
yield.
Next, the scope of this reaction with various starting 2- question of whether protonation of the zwitterion by etha-
alkenyl azetidines was studied. The choice of substrates nol can become competitive. In this case, the rearrange-
was made with the aim of varying two main parameters in ment would result from
a
cationic 3-aza-Cope
the reacting azetidines: the substitution of the alkene, and rearrangement, whose activation energy, though being
the substitution of the azetidine ring, including the effect lower than for 3-aza-Cope,15 is probably higher than that
of the relative configuration of the substituents. As will be required for the zwitterion (Scheme 3).
Synlett 2009, No. 19, 3182–3186 © Thieme Stuttgart · New York

3184
B. Drouillat et al.
LETTER
Table 2 Scope of the Ring Enlargement with Various Azetidinesa
Table 2 Scope of the Ring Enlargement with Various Azetidinesa
(continued)
Entry Starting azetidine
Time Product
(h)
Yield
(%)d
Entry Starting azetidine
Time Product
(h)
Yield
(%)d
Ph
Ph
No azocane isolatede
–
1
5 d
4
8
82
70
77
11
6 d
N
N
Bn
Bn
Ph
9
9
6
2b
3c
7
a Unless stated, ethyl propiolate was used as the electrophile.
b Ethynyl p-tolyl sulfone was used in this experiment.
c Methyl propiolate was used in this experiment.
d Yields refer to isolated pure product.
Ph
CO2Me
9
24
e Products resulting from the opening of the intermediate zwitterion
were produced and isolated (see text).
N
Bn
15
It should be noted that attempts were made to optimize the
yield of 20 by using non-protic solvents (CH2Cl2, THF,
MeCN), in the hope of suppressing the possible protona-
tion of the zwitterion by the solvent. In these experiments,
the yield could not be improved, and the enyne 25, result-
ing from the deprotonation of ethyl propiolate by the zwit-
terion,16 followed by conjugate addition was isolated in
some cases. This highlights the basic nature of the zwitter-
ion.
CO2Et
N
4
12
98
76
N
N
Ph
Ph
10
16
CO2Me
5c
10
5
Ph
Ph
17
Ph
N
Ph
Ph
Ph
O
CO2Et
EtOH
Ph
O
N
Ph
14
CO2Et
Bn
6
7
24
24
45
22
N
N
OEt
Bn
Bn
18
11
Ph
Ph
N
OEt
EtO
Ph
No azocane isolatede
–
Bn
Ph
N
N
Ph
23
Bn
Ph
CO2Et
12
SN2'
1,3-diaxial
interaction
n-Bu
Ph
Ph
20
Ph
n-Bu
OEt
8
9
24
24
16
CO2Et
N
N
Ph
N
Bn
Bn
Bn
19e
13
24
CO2Et
Ph
Ph
Ph
Ph
38
CO2Et
N
N
CO2Et
23
22
+
CO2Et
CO2Et
22
Bn
Bn
14
20e
CO2Et
Ph
Ph
Ph
+
25
CO2Et
10
6 d
8
N
N
Ph
EtO2C
Bn
Bn
21e
Scheme 3 Identification of the competitive side-reactions in the
5
case of 1,1- or 1,2-disubstituted alkenes
Synlett 2009, No. 19, 3182–3186 © Thieme Stuttgart · New York

LETTER
Ring Expansion of 2-Alkenyl Azetidines into Unsaturated Azocanes
3185
The relative configuration of the stereocenters in the
reacting azetidine is also an important parameter. Thus,
2,3-trans-vinyl azetidine 11 gave the expected ring expan-
sion product 18 (entry 6), while its 2,3-cis-isomer 12 only
gave competitive opening (entry 7). This can be under-
stood by an analysis of the conformational preference of
the reacting azetidines: 11 indeed reacts through its low-
energy 1,2,3-triequatorial conformer to give a zwitterion
in which the reacting centers for the ensuing sigmatropic
rearrangement are well disposed in a cis-relationship. On
the other hand, in azetidine 12, among the four possible
conformers and invertomers, only 1,2- or 1,3-diaxial con-
formers A and B can lead to a suitable disposition of the
substituents for ring enlargement (Scheme 4). If their pop-
ulation is low, and the first step is not reversible, then ring
opening becomes the prominent process.
Acknowledgment
The authors thank the CNRS and the University of Versailles St-
Quentin en Yvelines for financial support.
References and Notes
(1) For general reviews on the synthesis of azetidines prior to
2000, see: (a) Moore, J. A. In Heterocyclic Compounds with
Three and Four-Membered Rings; Weissberger, A., Ed.;
Interscience Publishers: New-York, 1964, Part 2, 885–977.
(b) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331.
(c) Moore, J. A.; Ayers, R. S. In Small Ring Heterocycles-
Part 2-Azetidines, b-Lactams, Diazetidines, and
Diaziridines; Hassner, A., Ed.; John Wiley and Sons, Inc.:
New York, 1983, 1. (d) De Kimpe, N. Azetidines, Azetines
and Azete, In Comprehensive Heterocyclic Chemistry II, a
review of the Literature of 1982-1995, Vol. 1B; Pergamon:
Oxford, 1996. For more recent reviews, see: (e) Dejaegher,
Y.; Kuz’menok, N. M.; Zvonok, A. M.; De Kimpe, N. Chem.
Rev. 2002, 102, 29. (f) Couty, F.; Evano, G.; Prim, D. Mini-
Rev. Org. Chem. 2004, 1, 133. (g) Couty, F.; Evano, G. Org.
Prep. Proced. Int. 2006, 38, 427. (h) Brandi, A.; Cicchi, S.;
Cordero, F. M. Chem. Rev. 2008, 108, 3988. (i) Couty, F.
Synthesis of Azetidines, In Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations, Vol. 40a;
Enders, D., Ed.; Georg Thieme Verlag: New York, 2009,
773–817.
Ph
Bn
Ph
18
N
N
Bn
11
CO2Et
Ph
Bn
Ph
(2) Padwa, A.; Gruber, R. J. Am. Chem. Soc. 1970, 92, 107.
(3) Roberto, D.; Alper, H. J. Am. Chem. Soc. 1989, 111, 7539.
(4) (a) Durrat, F.; Vargas-Sanchez, M.; Couty, F.; Evano, G.;
Marrot, J. Eur. J. Org. Chem. 2008, 3286. (b) Drouillat, B.;
Couty, F.; David, O.; Evano, G.; Marrot, J. Synlett 2008,
1345. (c) Van Bradandt, W.; Van Landeghem, R.; De
Kimpe, N. Org. Lett. 2006, 8, 1105.
N
N
Ph
N
Bn
A
B
Bn
12
Scheme 4 The relative configuration of the stereocenters in the star-
ting azetidine is a crucial parameter
(5) Ungureanu, I.; Klotz, P.; Schoenfelder, A.; Mann, A. Chem.
Commun. 2001, 958.
(6) Couty, F.; Durrat, F.; Evano, G.; Marrot, J. Eur. J. Org.
Chem. 2006, 4214.
(7) For a review on this topic, see: Couty, F.; Durrat, F.; Evano,
G. Targets in Heterocyclic Systems-Chemistry and
Properties, Vol. 9; Attanasi, O. A.; Spinelli, D., Eds.; Italian
Society of Chemistry: Rome, 2005, 186.
(8) Weston, M. H.; Nakajima, K.; Parvez, M.; Back, T. G.
Chem. Commun. 2006, 3903.
The unsaturated azocanes produced in this ring expansion
are particularly suited for further functionalization since
both alkenes could be reduced in a chemoselective and dia-
stereoselective manner. For example, upon treatment with
sodium borohydride in the presence of acetic acid, clean
reduction of the enaminoester moiety in 8 was achieved,
leading to 26 with fair diastereoselectivity. On the other
hand, hydrogenation led selectively to 27 (Scheme 5).
(9) Weston, M. H.; Nakajima, K.; Back, T. G. J. Org. Chem.
2008, 73, 4630.
(10) Winnick, M. A. Chem. Rev. 1981, 81, 491.
NaBH4
Ph
Ph
(11) For examples of macrocyclisation involving N-alkylation,
see (a) Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T.
Tetrahedron 2002, 58, 6267. (b) Dolman, S. J.; Sattely, E.
S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002,
124, 6991. (c) Sattely, E. S.; Cortez, G. A.; Moebius, D. C.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 8526. For examples of RCM, see: (d) Gille, S.; Ferry,
A.; Billard, T.; Langlois, B. R. J. Org. Chem. 2003, 68,
8932. For examples of ring cleavage, see: (e) Vedejs, E.;
Galante, R. J.; Goekjian, P. G. J. Am. Chem. Soc. 1998, 120,
3613. (f) Iradier, F.; Arrayás, R. G.; Carretero, C. Org. Lett.
2001, 3, 2957. (g) For examples of rearrangement, see:
MaGee, D. I.; Beck, E. J. J. Org. Chem. 2000, 65, 8367.
For examples of [2,3]-sigmatropic shifts, see: (h) Vedejs,
E.; Hagen, J. P.; Roach, B. L.; Spear, K. L. J. Org. Chem.
1978, 43, 1185. (i) Voskressensky, L. G.; Listratova, A. V.;
Borisova, T. N.; Kovaleva, S. A.; Borisov, R. S.; Varlamov,
A. V. Tetrahedron 2008, 64, 10443.
EtOH–AcOH
H2, Pd/C
87%
8
75%
CO2Et
CO2Et
N
N
26
dr = 8:2
27
Bn
Bn
Scheme 5 Chemo and diastereoselective reduction of 8
In summary, we have reported the first example of a four-
to eight-membered ring expansion of a nitrogen hetero-
cycle. The scope of this rearrangement is quite narrow and
is restricted to 2-vinyl azetidines in which the conforma-
tional equilibrium favours a conformer able to produce an
intermediate zwitterion in which a cis-relationship is ob-
served between the vinyl moiety and the produced alleno-
late. If these prerequisites are observed, then the ring
expansion occurs uneventfully, leading to unsaturated
azocanes17 that can be further functionalized.
(12) White, J. D. J. Org. Chem. 2000, 65, 9129; See also ref. 11e.
Synlett 2009, No. 19, 3182–3186 © Thieme Stuttgart · New York

3186
B. Drouillat et al.
LETTER
(13) (a) Godin, G.; Garnier, E.; Compain, P.; Martin, O. R.;
Ikeda, K.; Asano, N. Tetrahedron Lett. 2004, 45, 579.
(b) Chang, M.-Y.; Kung, Y.-H.; Ma, C.-C.; Chen, S.-T.
Tetrahedron 2007, 63, 1339.
(14) Couty, F.; Prim, D. Tetrahedron: Asymmetry 2006, 13,
2619.
(15) Walters, M. A. J. Org. Chem. 1996, 61, 978.
(16) Ramachandran, P. V.; Rudd, M. T.; Reddy, M. R.
Tetrahedron Lett. 2005, 46, 2547.
J = 7.1 Hz, 2 H, OCH2), 4.27 (d, J = 15.8 Hz, 1 H, NCHH),
4.43 (d, J = 15.8 Hz, 1 H, NCHH), 4.64 (m, 1 H, H8), 5.39
(dd, J = 11.1, 6.5 Hz, 1 H, H6), 5.56 (m, 1 H, H5), 7.03 (d,
J = 7.9 Hz, 1 H, Ar), 7.11–7.27 (m, 9 H, Ar), 7.57 (s, 1 H,
H2); 13C NMR (75 MHz): d = 14.6 (CH3CH2), 18.7 (CH3),
25.1 (C4), 53.3 (NCH2), 56.0, 57.6 (C7, C8), 59.7 (OCH2),
94.9 (C3), 125.2, 126.8, 127.5, 128.4, 128.5, 128.6, 132.0
(C5, C6, CHAr), 139.1, 141.2 (CqAr), 151.9 (C2), 170.0
(C=O); MS (ESI): m/z (%) = 385.3 (20) [M + Na+], 362.2
(100) [M + H+]. Compound 7: white solid; mp 74 °C;
Rf = 0.25 (Pentane–Et2O, 75:25); [a]D25 –548 (c 3.3,
CH2Cl2); 1H NMR (300 MHz): d = 1.07 (d, J = 6.5 Hz, 3 H,
Me), 2.47 (s, 3 H, Me), 3.02–3.16 (m, 2 H, H4, H7), 3.74
(dd, J = 16.2, 7.5 Hz, 1 H, H4¢), 4.44 (d, J = 15.8 Hz, 1 H,
NCHH), 4.58 (d, J = 15.8 Hz, 1 H, NCHH), 4.64 (m, 1 H,
H8), 5.24 (m, 1 H, H5), 5.50 (m, 1 H, H6), 7.03 (m, 2 H, Ar),
7.19–7.44 (m, 10 H, Ar), 7.64 (s, 1 H, H2), 7.72 (d, J = 6.7
Hz, 2 H, Ar); 13C NMR (75 MHz): d = 18.7 (CH3), 21.5
(CH3), 25.4 (C4), 53.2 (NCH2), 56.3, 57.7 (C7, C8), 102.5
(C3), 123.2, 125.5, 127.0, 127.2, 127.3, 127.6, 127.8, 128.3,
128.5, 128.7, 128.8, 129.4, 133.0 (C2, C5, C6, CHAr),
138.8, 139.9, 140.6, 142.4 (CqAr), 149.9 (C2); MS (ESI):
m/z (%) = 466.3 (100) [M + Na+].
(17) Typical Procedure for the Ring Expansion of 2-Alkenyl
Azetidines into Unsaturated Azocanes: The following
procedure for the preparation of azocane 8 is representative.
To a solution of azetidine 9 (800 mg, 3.03 mmol) in absolute
EtOH (30 mL), was added in one portion, ethyl propiolate
(0.62 mL, 6.06 mmol). The reaction mixture was stirred for
5 days and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (Pentane–
Et2O, 75:25 + 0.1% Et3N) to afford 8 as a colourless oil (911
mg, 82%).
Compound 8: Rf = 0.30 (Pentane–Et2O, 75:25); [a]D25 –957
(c 0.95, CH2Cl2); 1H NMR (300 MHz): d = 0.95 (d, J = 6.7
Hz, 3 H, Me), 1.17 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.95 (dd,
J = 12.0, 6.5 Hz, 1 H, H7), 3.41–3.60 (m, 2 H, H4), 4.08 (q,
Synlett 2009, No. 19, 3182–3186 © Thieme Stuttgart · New York