A novel efficient three-component one-pot synthesis of 1,3-diazabicyclo[3. 1.0]hex-3-ene system under microwave irradiation

Article abstract of DOI:10.1055/s-2005-869859

Bridgehead aziridines 3 were synthesized in high yields and excellent diastereocontrol by a three-component reaction of an aldehyde, phenacyl chloride and ammonium acetate in acetic acid using microwave irradiation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869859

LETTER
1633
A Novel Efficient Three-Component One-Pot Synthesis of
1,3-Diazabicyclo[3.1.0]hex-3-ene System under Microwave Irradiation
Synthesis of
1
r
,3-Diaza
a
bicyclo[3.1
n
.0]hex-3-ene
cSystem esco Risitano,* Giovanni Grassi, Francesco Foti, Sonia Moraci
Dipartimento di Chimica Organica e Biologica, Università, Vill. S. Agata, 98166 Messina, Italy
Fax +39(090)393897; E-mail: frisitan@isengard.unime.it
Received 15 April 2005
served to proceed, while with bulkier substrates, such as
pivalaldehyde (entry 7), an analogous bicyclic product
was obtained but with markedly reduced yields.
Abstract: Bridgehead aziridines 3 were synthesized in high yields
and excellent diastereocontrol by a three-component reaction of an
aldehyde, phenacyl chloride and ammonium acetate in acetic acid
using microwave irradiation.
The same reactions, performed according to the classic
Key words: multicomponent, microwave, bicyclic aziridine, dia- method of heating under reflux,7 were observed to pro-
stereocontrol
ceed in a similar manner but took longer and gave less sat-
isfactory yields. The results are summarized in Table 1.
Table 1 Synthesis of Aziridines 3
Functionalized aziridines are an extremely important
class of compounds for a number of reasons: they are po-
tentially the precursors of new biologically active com-
pounds, they constitute the structural motif in many
natural products and they are very useful synthetic inter-
mediates.1
Entry
3
a
b
c
d
e
f
R
Yield (%)a Yield (%)b
1
2
3
4
5
6
7
Ph
92
88
78
75
72
79
35
86
75
65
63
61
67
–
2-MeC6H4
3-MeC6H4
3-MeOC6H4
3-ClC6H4
4-MeC6H4
(CH3)3C
Exploration of new routes to the synthesis of aziridine de-
rivatives has thus attracted considerable attention and the
search for a means of rapid access to these heterocycles
and their diverse biological properties is well documented
in literature.2
Our research in this area has been concerned with the ap-
plication of multicomponent reactions3 to the one-pot
synthesis4 of the 1,3-diazabicyclo[3.1.0]hex-3-ene ring
system.5 Here we describe an efficient approach to the
synthesis of stereodefined bridgehead aziridines 3 from
commercially available low-cost compounds. This was
achieved by the addition of phenacyl chloride 1 to alde-
hyde derivatives 2 in the presence of an excess of a mix-
ture of AcOH/AcONH4 in n-propanol under microwave-
assisted conditions (Scheme 1).6
g
a Isolated yields under microwave irradiation; reaction time 5–10 min.
b Isolated yields under traditional conductive-heating method; reac-
tion time 2–3 h.
The identification of compounds 3 was based on their
spectral and analytical data,8 and confirmed by X-ray
crystallographic analysis carried out on 3a.9 Coupling
constants and NOE measurements (irradiation of HC-2
gives rise only to enhancement of HC-6) provided exhaus-
tive information on the exo-stereochemistry of the pro-
cess.
In these reactions, three stereocenters are created and only
one of the possible diastereoisomers is produced as a ra-
cemic mixture. Reaction process (i) seems most plausibly
to explain the formation exclusively of exo-isomer 3
(Scheme 2). The alternative (ii), in which a key step is the
in situ formation of derivative 8, is not altogether satisfac-
tory. Indeed, in line with previous research in which trans-
aroylaziridines 8 were used as starting products,10 we
would have expected to see a consistent mixture of exo 3
and endo 4 isomers, with the latter prevalent. Moreover,
the relatively lengthy formation times of 8 are not very
consistent with the observed course of the reaction. Ini-
tially, therefore, (Scheme 2, path i) the amino ketone 6 is
produced by means of a stereoselective intermolecular al-
dolization between phenacyl chloride 1 and the aldimine
Scheme 1
From what appears to be a highly diastereoselective pro-
cess, we only ever isolated the exo-isomer 3 in all cases
studied. When extended to aliphatic aldehydes, the same
procedure failed to produce any significant results. With
aldehydes containing an a-hydrogen no reaction was ob-
SYNLETT 2005, No. 10, pp 1633–1635
Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869859; Art ID: G11805ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
6
.2
0
0
5

1634
F. Risitano et al.
LETTER
(2) (a) Shibuya, M.; Terauchi, H. Tetrahedron Lett. 1987, 28,
2619. (b) Armstrong, R. W.; Moran, E. J. J. Am. Chem. Soc.
1992, 114, 371. (c) Hashimoto, M.; Terashima, S. Chem.
Lett. 1994, 1001. (d) Hodgkinson, T. J.; Kelland, L. R.;
Shipman, M.; Vile, J. Tetrahedron 1998, 54, 6029.
(3) Reviews: (a) Weber, L.; Illgen, K.; Almstetter, M. Synlett
1999, 366. (b) Dax, S. L.; McNally, J. J.; Youngman, M. A.
Curr. Med. Chem. 1999, 6, 255.
(4) (a) Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. Tetrahedron
2000, 56, 9669. (b) Grassi, G.; Risitano, F.; Foti, F.;
Cordaro, M. Synlett 2001, 812. (c) Risitano, F.; Grassi, G.;
Foti, F.; Romeo, R. Synthesis 2002, 116. (d) Risitano, F.;
Grassi, G.; Foti, F.; Nicolò, F.; Condello, M. Tetrahedron
2002, 58, 191.
5, which has formed in the interim from the aldehyde in
the presence of the AcOH/AcONH4 mixture. Instead of
cyclizing to 8, this amine intercepts the aldehyde (or the
aldimine) that is still present in the reaction environment
and evolves, again stereoselectively, to E-imine 7. In this
the NH imine and the Schiff base moiety are appropriately
dislocated in order to give rise to an 6-endo-trig cycliza-
tion,11 which in turn guides the formation of aziridine
functionality within the bicyclic ring system 3 by 3-exo-
tet cyclization11 between the nitrogen atom originally
from the Shiff base and the electrophilic C-Cl fragment.
This proposed ring-closure of the intermediate 7 is consis-
tent with a chair-like transition state with R substituents
disposed in a pseudo-equatorial manner.
(5) (a) Heine, H. W.; Weese, R. H.; Cooper, R. A.; Dubertaki,
A. J. J. Org. Chem. 1967, 32, 2708. (b) Mahmoodi, N. O.;
Kiyani, H. Bull. Korean Chem. Soc. 2004, 25, 1417.
(6) Microwave Irradiation.
A mixture of phenacyl chloride 1 (463.7 mg, 3 mmol),
aldehyde 2 (6 mmol), ammonium acetate (1.55 g, 20 mmol)
and glacial acetic acid (10 mL) in n-PrOH (20 mL) in the
presence of molecular sieves (4 Å) was irradiated for 5–10
min in a self-tunable CEM microwave synthesizer at 90 °C.
After cooling the reaction to r.t., the solvent was removed
under vacuum and the residue was crystallized from EtOH to
give 3 as colorless crystals.
(7) Conventional heating.
As above procedure, but absolute EtOH was used as solvent
and the reaction mixture was refluxed for 2–3 h.
(8) Selected data.
Compound 3a: mp 155–156 °C (lit.5a mp 153–154 °C). IR
(nujol): 1597, 1569, 1046 cm–1. 1H NMR (CDCl3): d = 2.72
(d, J = 2.2 Hz, HC-6), 3.74 (dd, J = 2.2 and 2.9 Hz, HC-5),
6.22 (d, J = 2.9 Hz, HC-2), 7.30–8.01 (m, arom., 15 H). 13
C
NMR (CDCl3): d = 49.0 (C-5), 56.4 (C-6), 97.4 (C-2), 170.4
(C-3). Anal. Calcd for C22H18N2: C, 85.13; H, 5.85; N, 9.03.
Found: C, 85.31; H, 5.94; N, 9.14.
Compound 3b: mp 134–135 °C. IR (nujol): 1601, 1578,
1050 cm–1. 1H NMR (CDCl3): d = 2.43 (s, 3 H), 2.65 (s, 3 H),
2.85 (d, J = 2.1 Hz, HC-6), 3.65 (dd, J = 2.1 and 3.0 Hz, HC-
5), 6.35 (d, J = 3.0 Hz, HC-2), 7.18–8.05 (m, arom., 13 H).
13C NMR (CDCl3): d = 47.8 (C-5), 56.8 (C-6), 94.5 (C-2),
171.2 (C-3). Anal. Calcd. for C24H22N2: C, 85.17; H, 6.55; N,
8.28. Found: C, 85.40; H, 6.73; N, 8.11.
Scheme 2
Compound 3c: mp 152–153 °C. IR (nujol): 1599, 1573,
1048 cm–1. 1H NMR (CDCl3): d = 2.43 (s, 3 H), 2.46 (s, 3 H),
2.72 (d, J = 1.8 Hz, HC-6), 3.78 (dd, J = 1.8 and 2.2 Hz, HC-
5), 6.24 (d, J = 2.2 Hz, HC-2), 7.16–8.08 (m, arom., 13 H).
13C NMR (CDCl3): d = 49.3 (C-5), 56.6 (C-6), 99.1 (C-2),
170.4 (C-3). Anal. Calcd for C24H22N2: C, 85.17; H, 6.55; N,
8.28. Found C, 85.32; H, 6.69; N, 8.38.
Compound 3d: mp 148–149 °C. IR (nujol): 1599, 1580,
1040 cm–1. 1H NMR (CDCl3): d = 2.66 (d, J = 1.9 Hz, HC-
6), 3.70 (dd, J = 1.9 and 2.4 Hz, HC-5), 3.77 (s, 3 H), 3.79
(s, 3 H), 6.17 (d, J = 2.4 Hz, HC-2), 6.82–7.98 (m, arom., 13
H). 13C NMR (CDCl3): d = 49.0 (C-5), 53.8 (C-6), 97.3 (C-
2), 170.4 (C-3). Anal. Calcd for C24H22N2O2: C, 77.81; H,
5.99; N, 7.56. Found: C, 77.98; H, 6.08; N, 7.69.
Compound 3e: mp 118–119 °C. IR (nujol): 1596, 1572,
1048 cm–1. 1H NMR (CDCl3): d = 2.62 (d, J = 1.8 Hz, HC-
6), 3.65 (dd, J = 1.8 and 2.7 Hz, HC-5), 6.12 (d, J = 2.7 Hz,
HC-2), 7.23–7.95 (m, arom., 13 H). 13C NMR (CDCl3): d =
48.2 (C-5), 56.5 (C-6), 96.7 (C-2), 170.5 (C-3). Anal. Calcd
for C22H16Cl2N2: C, 69.67; H, 4.25; N, 7.39. Found: C,
69.80; H, 4.32; N, 7.21.
The advantage of this synthesis in comparison with previ-
ous ones is evident: it rests on a highly efficient reaction
that is effectively diastereoselective, requires mild reac-
tion conditions and for which work up is straightforward.
The tedious preliminary preparation procedures required
for type 8 N-unsubstituted aziridines are avoided.12
In conclusion, this easy route to stereodefined bridgehead
aziridines opens the door to various applications for this
attractive class of compounds.5b,13
References
(1) (a) Wang, S.; Kohn, H. J. Org. Chem. 1996, 61, 9202.
(b) Wang, S.; Kohn, H. J. Org. Chem. 1997, 62, 5404.
(c) Coleman, R. S.; Li, J.; Navarro, A. Angew. Chem. Int. Ed.
2001, 40, 1736. (d) Borzilleri, R. M.; Zheng, X.; Kim, S.-H.;
Johnson, J. A.; Fairchild, C. R.; Lee, F. Y. F.; Long, B. H.;
Vite, G. D. Org. Lett. 2001, 3, 2693. (e) Subramaniam, G.;
Paz, M. M.; Kumar, G. S.; Das, A.; Palom, Y.; Clement, C.
C.; Patel, D. J.; Tomasz, M. Biochemistry 2001, 40, 10473.
Compound 3f: mp 135–136 °C. IR (nujol): 1600, 1581, 1049
cm–1. 1H NMR (CDCl3): d = 2.29 (s, 3 H), 2.42 (s, 3 H), 2.69
Synlett 2005, No. 10, 1633–1635 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3-Diazabicyclo[3.1.0]hex-3-ene System
1635
(d, J = 2.0 Hz, HC-6), 3.65 (dd, J = 2.0 and 2.9 Hz, HC-5),
6.21 (d, J = 2.9 Hz, HC-2), 7.10–8.01 (m, arom., 13 H). 13
NMR (CDCl3): d = 48.5 (C-5), 56.5 (C-6), 97.1 (C-2), 170.9
(C-3). Anal. Calcd for C24H22N2: C, 85.17; H, 6.55; N, 8.28.
Found: C, 85.01; H, 6.42; N, 8.39.
(10) (a) Padwa, A.; Clough, S.; Glazer, E. J. Am. Chem. Soc.
1970, 92, 1778. (b) Padwa, A.; Glazer, E. J. Am. Chem. Soc.
1972, 94, 7788. (c) Orlov, V. D.; Kaluski, Z.; Figas, E.;
Vorob’eva, N. P.; Bakumenko, A. I.; Yaremenko, F. G.
Khim. Geterotsikl. Soedin. 1991, 8, 1060.
C
Compound 3g: mp 68–69 °C. IR (nujol): 1610, 1576, 1041
cm–1. 1H NMR (CDCl3): d = 0.99 (s, 9 H), 1.02 (s, 9 H), 1.18
(d, J = 2.1 Hz, HC-6), 3.22 (dd, J = 2.1 and 3.3 Hz, HC-5),
4.49 (d, J = 3.2 Hz, HC-2), 7.39–7.51 (m, arom., 3 H), 7.85–
7.88 (m, arom., 2 H). 13C NMR (CDCl3): d = 49.8 (C-5), 56.2
(C-6), 104.3 (C-2), 170.2 (C-3). Anal. Calcd. for C18H26N2:
C, 79.95; H, 9.69; N, 10.36. Found: C, 79.78; H, 9.60; N,
10.49.
(11) Baldwin, J. E. Chem. Commun. 1976, 734.
(12) (a) Wieland, H. Ber. 1904, 37, 1150. (b) Cromwell, N. H.;
Mercer, G. D. J. Am. Chem. Soc. 1957, 79, 3819. (c) Li, A.-
H.; Zhou, Y.-G.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Lin, L.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1317. (d) Sugihara,
H.; Daikai, K.; Jin, X. L.; Furuno, H.; Inanaga, J.
Tetrahedron Lett. 2002, 43, 2735. (e) Xu, J.; Jiao, P. J.
Chem. Soc., Perkin Trans. 1 2002, 1491.
(9) X-ray data to be submitted to J. Mol. Struct.
(13) Mahmoodi, N. O.; Zanjanchi, M. A.; Hamzeh, K. J. Chem.
Res. 2004, 6, 438.
Synlett 2005, No. 10, 1633–1635 © Thieme Stuttgart · New York