Selective synthesis of eight-membered cyclic ureas by the [6 + 2] cycloaddition reaction of 2-vinylazetidines and electron-deficient isocyanates

Article abstract of DOI:10.1021/ol902299p

"Chemical Equation Presented" The [6 + 2] cycloaddition reaction of 2-vinylazetidines with electron-deficient isocyanates such as tosyl isocyanate proceeded smoothly in the absence of the catalyst at room temperature, and various cyclic ureas were isolate

Full text of DOI:10.1021/ol902299p

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5438-5441
Selective Synthesis of Eight-Membered
Cyclic Ureas by the [6 + 2] Cycloaddition
Reaction of 2-Vinylazetidines and
Electron-Deficient Isocyanates
Shunsuke Koya,† Kenichi Yamanoi,† Ryu Yamasaki,† Isao Azumaya,‡
Hyuma Masu,‡ and Shinichi Saito*,†
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science, Kagurazaka,
Shinjuku, Tokyo, Japan 162-8601, and Faculty of Pharmaceutical Sciences at Kagawa
Campus, Tokushima Bunri UniVersity, Shido, Sanuki, Kagawa, Japan 769-2193
ssaito@rs.kagu.tus.ac.jp
Received October 5, 2009
ABSTRACT
The [6 + 2] cycloaddition reaction of 2-vinylazetidines with electron-deficient isocyanates such as tosyl isocyanate proceeded smoothly in the
absence of the catalyst at room temperature, and various cyclic ureas were isolated in good to high yields. Electron-deficient allenes also
reacted with the 2-vinylazetidine, and the corresponding azocine derivatives were isolated.
Medium-sized N-heterocycles are widespread in nature and
often display interesting biological properties.1 However, the
synthesis of medium-sized N-heterocycles is rather difficult,
and the development of a new synthetic method is highly
desirable.
much fewer studies have been reported for the synthesis of
the medium-sized rings by the ring-expansion reaction of
these substrates.4b,d-f,h,i
2-Vinylazetidines are attractive substrates for the synthesis
of larger nitrogen heterocycles, because unlike other azetidine
derivatives, these compounds may react as a six-atom
component. In the literature, however, 2-vinylazetidine
reacted as a four-atom unit,2b and few [6 + 2] cycloaddition
reactions have been reported.5 We anticipated that 2-viny-
lazetidines would be suitable substrates for the synthesis of
eight-membered cyclic compounds by the [6 + 2] cycload-
dition reaction. In this paper we report the [6 + 2]
cycloaddition reaction between 2-vinylazetidines 1 and
electron-deficient isocyanates 2 (Scheme 1).
The ring-expansion reaction of strained nitrogen hetero-
cycles such as azetidines,2 ꢀ-lactams,3 and aziridines4 is a
powerful strategy for the synthesis of heterocyclic com-
pounds, and a large number of five- or six-membered
N-heterocycles have been synthesized. On the other hand,
† Tokyo University of Science.
‡ Tokushima Bunri University.
(1) (a) Yang, L.; Deng, G.; Wang, D. - X.; Huang, Z. -T.; Zhu, J. -P.;
Wang, M.-X. Org. Lett. 2007, 9, 1387–1390. (b) Baran, P. S.; Guerrero,
C. A.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 5628–5629. (c) Baran,
P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904–7905. (d) Nicolau,
K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem., Int.
Ed. 2000, 39, 44–122. (e) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F.; Meyer, D. T.; Jadhav, P. K.; De Lucca, G. V.; Smyser,
T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med.
Chem. 1996, 39, 2156–2169.
(3) (a) Brabandt, W. V.; Dejaegher, Y.; Landeghem, R. V.; De Kimpe,
N. Org. Lett. 2006, 8, 1101–1104. (b) Brabandt, W. V.; Landeghem, R. V.;
De Kimpe, N. Org. Lett. 2006, 8, 1105–1108. (c) Brabandt, W. V.; De
Kimpe, N. J. Org. Chem. 2005, 70, 3369–3374. (d) Brabandt, W. V.; De
Kimpe, N. J. Org. Chem. 2005, 70, 8717–8722. (e) Klapars, A.; Parris, S.;
Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529–
3533.
(2) (a) Couty, F.; Durrat, F.; Evano, G.; Marrot, J. Eur. J. Org. Chem.
2006, 4214–4223. (b) Inman, G. A.; Bultler, D. D.; Alper, H. Synlett 2001,
914–919.
10.1021/ol902299p CCC: $40.75
Published on Web 11/11/2009
 2009 American Chemical Society

observed result is in sharp contrast to the studies reported
by Alper:2b the formation of a six-membered cyclic urea
(tetrahydropyrimidin-2-one) was observed in the reaction of
2-vinylazetidines and isocyanates in the presence of a Pd
catalyst.
Scheme 1
.
[6 + 2] Cycloaddition of 2-Vinylazetidine (1) and
Isocyanate (2)
We also studied the solvent effect on this reaction (Table
2). Polar solvents turned out to be suitable for this reaction.
Table 2. Solvent Effect on the Cycloaddition Reaction
The results of the reactions of 2-vinylazetidine 1a6 with
various isocyanates 2 are summarized in Table 1. Tosyl
isocyanate (2a) turned out to be a good substrate for this
reaction, and the eight-membered cyclic urea 3aa was
isolated in 44% yield, together with an imine 4aa (entry 1).7
yield (%)
Table 1. Reactions of 1a with Various Isocyanates
entry
solvent
3aa
4aa
1
2
3
4
toluene
THF
CH3CN
CH2Cl2
44
60
56
71
10
12
23
19
Thus, when THF was selected as the solvent, compound
3aa was isolated in 60% yield, together with a small
amount of 4aa (entry 2). Though the yields of the products
did not significantly improve by switching the solvent to
acetonitrile (entry 3), the yield of 3aa reached to 71%
when the reaction was carried out in CH2Cl2 (entry 4). It
is noteworthy that a six-membered cycloadduct 5aa was
isolated in 24% yield when the reaction was carried out
in DMF; no eight-membered heterocycle was isolated
(Scheme 2).10
yield (%)
entry
2
R
time (h) temp (°C)
3
4
1
2
3
4
2a
Ts
1
17
21
15
rt
44
19
10
0
2b Bz
2c Ph
2d 4-AcC6H4
100
100
100
no reaction
no reaction
It is noteworthy that the reaction proceeded at room
temperature, and no catalyst was required. On the other hand,
high temperature (100 °C) was required for the reaction of
1a and benzoyl isocyanate (2b), and the yield of the product
was low (entry 2). Other isocyanates such as phenyl
isocyanate (2c) or 4-acetylphenyl isocyanate (2d) did not
react with 1a (entries 3 and 4). These results indicate that
the activation of the isocyanate group by a strong electron-
withdrawing group is essential for the progress of this
reaction.
Scheme 2. Reaction of 1a with 2a in DMF
The molecular structure of an eight-membered cyclic urea
(3aa) was confirmed by an X-ray analysis (Figure 1).8,9 The
The generality of the cycloaddition was examined by
carrying out the reaction of 2-vinylazetidines with various
(4) (a) Wender, P. A.; Strand, D. J. Am. Chem. Soc. 2009, 131, 7528–
7529. (b) D’hooghe, M.; Aelterman, W.; De Kimpe, N. Org. Biomol. Chem.
2009, 7, 135–141. (c) Brichacek, M.; Lee, D.; Njardarson, J. T. Org. Lett.
2008, 10, 5023–5026. (d) Zhang, K.; Chopade, P. R.; Louie, J. Tetrahedron
Lett. 2008, 49, 4306–4309. (e) Munegumi, T.; Azumaya, I.; Kato, T.; Masu,
H.; Saito, S. Org. Lett. 2006, 8, 379–382. (f) D’hooghe, M.; Vanlangen-
donck, T.; To¨rnroos, K. W.; De Kimpe, N. J. Org. Chem. 2006, 71, 4678–
4681. (g) Kim, M. S.; Kim, Y. -W.; Hahm, H. S.; Jang, J. W.; Lee, W. K.;
Ha, H. -J. Chem. Commun. 2005, 49, 3062–3064. (h) Rowlands, G. J.;
Barnes, W. K. Tetrahedron Lett. 2004, 45, 5347–5350. (i) Lindstro¨m, U. M.;
Somfai, P. Chem.sEur. J. 2001, 7, 94–98.
Figure 1. X-ray structure of 3aa.
Org. Lett., Vol. 11, No. 23, 2009
(5) Hassner, A.; Wiegand, N. J. Org. Chem. 1986, 51, 3652–3656.
5439

substituents. The results are summarized in Table 3. Cy-
cloaddition of 1b (R1 ) CH3) with 2a proceeded smoothly,
Scheme 4. Reaction of 1a with Trichloroacetyl Isocyanate (2e)
Table 3. Reactions of Various 2-Vinylazetidines with Tosyl
Isocyanate (2a)
yield (%)
entry
1
R
3
4
Finally, we found that the [6 + 2] cycloaddition reaction
proceeded with other electron-deficient cumulenes. Thus, the
reaction of 1a with acetylallene (7a) as well as benzoylallene
(7b) proceeded smoothly, and the corresponding azocine
derivatives were isolated in moderate yields (Scheme 5).
1
2
3
4
5
1a
1b
1c
1d
1e
H
CH3
Ph
4-MeOC6H4
4-CF3C6H4
71
65
77
67
89
19
18
trace
6
3
and 3ba, together with a small amount of 4ba, was isolated
in good yield (entry 2). The reaction proceeded selectively
when the phenyl group was introduced, and the reaction
of 1c with 2a gave the corresponding cyclic urea 3ca in
77% yield (entry 3). The electronic effect on the reaction
was examined by introducing substituted phenyl groups
to the olefin moiety. The yield of the product decreased
when a 4-methoxyphenyl group was introduced as a
substituent (entry 4). On the other hand, the yield of 3ea
increased to 89% when a 2-vinylazetidine substituted with
a 4-(trifluoromethyl)phenyl group was used as the substrate
(entry 5). The formation of the eight-membered cyclic urea
3fa was observed even when the 2-vinylazetidine (1f)
reacted with 2a (Scheme 3). In this reaction, however,
the formation of a significant amount of the six-membered
cyclic urea 6fa was observed.
Scheme 5. Reaction of 1a with Allenes 7a,b
A plausible mechanism for the formation of the eight-
membered compound is shown in Scheme 6. The reaction would
Scheme 6. Proposed Mechanism for the Formation of
Eight-Membered Cyclic Compounds
Scheme 3. Reaction of 1f and 2a
When the reaction of 1a with trichloroacetyl isocyanate
(2e) was examined, the eight-membered cyclic imine (4ae)
was isolated as the major product, along with the N-
deacylated cyclic urea (3ae). A small amount of a six-
membered cyclic urea (6ae) was also isolated (Scheme 4).
be initiated by the nucleophilic attack of the nitrogen atom of the
2-vinylazetidine to the carbon atom of the isocyanate group. The
electron-withdrawing group bound to the isocyanate moiety would
facilitate this process. The initially formed zwitterionic intermediate
(9) would be converted to the eight-membered ring by the
intramolecular SN2′ reaction. The formation of 3aa would proceed
when the nitrogen atom attacked the electrophilic allylic moiety,
(6) (a) Evans, G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.;
Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948–956. (b) Gaoni,
Y.; Tomazic, A.; Potgieter, E. J. Org. Chem. 1985, 50, 2943–2947. (c)
Fray, M. J.; Jones, R. H.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1985, 2753–2761. (d) Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.;
Wu, J. S. J. Org. Chem. 1981, 46, 2991–2999.
5440
Org. Lett., Vol. 11, No. 23, 2009

and the imine 4aa would be generated by the attack of the oxygen
atom. The selective formation of eight-membered cyclic urea (not
the imine) in many reactions could be reasonably explained in terms
of the higher nucleophilicity of the nitrogen atom compared to the
oxygen atom.
Scheme 8
.
Proposed Mechanism for the Formation of Cyclic
Urea 6fa
The formation of a six-membered cyclic imine in DMF
would also proceed via an acyclic zwitterionic intermediate.
Thus, DMF is a strong nucleophile compared to other
solvents, and it may induce the ring-opening reaction to give
10.11 This intermediate would cyclize to give a six-membered
cyclic imine (Scheme 7).12
with electron-deficient isocyanates. The reaction proceeded
by mixing the substrates in CH2Cl2 at room temperature,
and no catalyst was required. Further extension of this
reaction to the synthesis of other medium-sized hetero-
cycles is ongoing.
Scheme 7
.
Proposed Mechanism for the Formation of Cyclic
Imine 5aa
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902299P
(8) Crystallographic data were collected on a CCD detector with graphite
monocromated Mo KR (λ ) 0.71073 Å), φ and ω scans. The crystal
structure was solved by direct methods SHELXS-97 and refined by full-
matrix least-squares SHELXL-97.8 All non-hydrogen atoms were refined
anisotropically. All hydrogen atoms were included as their calculated
positions. Crystallographic data for 3aa: C20H22N2O3S, Mr ) 370.46, 0.50
× 0.40 × 0.30 mm, orthorhombic, P212121, a ) 10.0224(6), b ) 10.6131(6),
c ) 17.094(1) Å, V ) 1818.3(2) Å3, Z ) 4, Fcalcd ) 1.353 Mg m-3, 2θmax
The formation of six-membered urea in the reaction of
1f with 2a would not proceed via SN2′ pathway, and the
SN1 reaction would proceed instead. In this reaction, the
ring opening of the zwitterionic intermediate would give
a linear intermediate (11), which would undergo cycliza-
tion (Scheme 8).
In summary, we developed a new, simple, and practical
method for the synthesis of eight-membered cyclic ureas
by the [6 + 2] cycloaddition reaction of 2-vinylazetidines
) 54.44°, T ) 150 K, 8937 reflections measured, 3696 unique (Rint
)
0.0171). µ ) 0.201 mm-1, The final R1 and wR(F2) was 0.03043 and 0.0658
(all data) The residual electron densities (peak and hole) were 0.229 and
-0.263 e Å-3. Flack parameter is 0.02(6). CCDC-739891 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(9) A short history of SHELX: Sheldrick, G. M. Acta Crystallogr. 2008,
A64, 112–122.
(10) The reason for the observed low yield of 5aa is not clear at present.
Products derived from tosyl isocyanate were also recovered.
(11) Alternatively, the solvent (DMF) may stabilize the allyl cation and
the SN1 reaction might proceed.
(7) The structual determination of 4 was based on the analysis of the
1H NMR spectra: the 1H NMR data of structurally similar iminooxazolidines
(five-membered cyclic ureas) and imidazolidinones (five-membered cyclic
imines) were utilized to confirm the formation of 4. See ref 4e.
(12) It is noteworthy that the imine, not the urea, was formed in this
reaction. We assume that the nucleophilicity of the nitrogen atom was
reduced by solvation.
Org. Lett., Vol. 11, No. 23, 2009
5441