Pyridine-mediated synthesis of 1,3-diazetidin-2-ones (Aza-β lactams): Novel investigations on isocyanate-carbodiimde reaction

Article abstract of DOI:10.1055/s-0030-1260327

The reported cycloaddition reaction of isocyanates and symmetric carbodiimides is reinvestigated in the presence of pyridine. The Huisgen zwitterion generated by the 1:1 addition of pyridine to arylsulfonyl isocyanate is trapped by dialkyl carbodiimide to

Full text of DOI:10.1055/s-0030-1260327

LETTER
2491
Pyridine-Mediated Synthesis of 1,3-Diazetidin-2-ones (Aza-b-lactams):
Novel Investigations on Isocyanate–Carbodiimde Reaction
S
ynthesis of 1,3-D
b
iazetidin-2-o
d
nes olali Alizadeh,*a Nasrin Zohreh,a Ghasem Oskueyan,a Long-Guan Zhub
a
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
b
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Received 16 May 2011
tion pattern emerges in the reaction of dialkyl carbodiim-
ide with arylsulfonyl isocyanates.
Abstract: The reported cycloaddition reaction of isocyanates and
symmetric carbodiimides is reinvestigated in the presence of pyri-
dine. The Huisgen zwitterion generated by the 1:1 addition of pyri-
dine to arylsulfonyl isocyanate is trapped by dialkyl carbodiimide to
obtain symmetrical 1,3-diazetidin-2-ones via a novel intramolecu-
lar rearrangement.
O
Z'
Ar
N
N
Z
+
Ar NCO
N
•
N
Z
Key words: 1,3-diazetidin-2-one, aza-b-lactam, carbodiimide,
arylsulfonyl isocyanate, pyridine
N
3
2
Z'
Z = Z' or Z ≠ Z'
Z, Z' = Ar, R
1
Scheme 1 The reaction of aryl isocyanate and carbodiimides
1,3-Diazetidin-2-ones exhibit activities including
antibacterial1 and anti-inflammatory2 activity. Recently,
they have been found to be potent serine peptidase,
transpeptidase, and b-lactamase enzyme inhibitors.1,3,4
1,3-Diazetidinone derivatives are also used in polyester
polyurethane resins which offer good abrasion resistance5
and heat resistance.6
Based on the studies of Ulrich, the polar cycloaddition re-
action of arylsulfonyl isocyanates 4 with dialkyl carbo-
diimides 5 gave rise to three six-membered ring
cycloadducts 7, 8, and 10. However, it is important to note
that 1,3-diazetidinone intermediate 6 was not isolated, but
simultaneous occurrence of the exchange reaction to form
7 and especially product 8 and 10 support the intermedia-
cy of 6.19 This evidence was also confirmed by IR analysis
of the reaction mixture at the beginning of the reaction
(Scheme 2).19,20
Despite their applications, to our knowledge there are
only a few methods for the preparation of 1,3-diazetidin-
2-ones; these include carbonylation of diaziridines by Pd
or Co complexes,7 addition of isocyanates to imines pref-
erably activated with an electron-donating group such as
OMe (imino ethers),8 photolytic reaction of chromium
carbene complexes with azobenzenes,9 photolysis of the
pyrimidin-2-one derivatives,1,10 and base transformation
of N-(chlorocarbonyl)guanidine.11
R
O
O
+
N
•
N
S
Ar
NCO
R
4
5
O
NR
O
R
O
C
Ts
C
The [2+2]-cycloaddition reaction of heterocumulenes,
such as carbodiimides, isocyanates, and isothiocyanates,
is well-known for the preparation of 1,3-diazetidinones.12
These studies began in 1957;13 then, in 1962, Neumann
and Fischer investigated the reaction of different types of
aryl isocyanates and symmetrical diaryl or dialkyl carbo-
diimides and obtained unsymmetrical carbodiimides via
1,3-diazetidine-2-one intermediates under thermal condi-
tions.14 Finally, Sayigh15 and Ulrich16 identified 1,3-diaz-
etidine-2-one 1 as the main product of the cycloaddition
reaction of arylisocyanates 2 and carbodiimides 3
(Scheme 1).17 They also investigated the regioselectivity
of the reaction in the case of unsymmetrical carbodiimides
and reported that steric hindrance and electronic effects
could influence the product distribution.18 In later studies
it became evident that a considerably more complex reac-
N
C
N
C
R
N
N
Ts
NR
RN
NR
N
R
6
9
4
O
NR
NR
Ts
R
Ts
O
C
R
O
Ts
O
N
N
N
N
N
C
RN
N
R
Ts
NR
•
N
Ts
7
8
ArO2SN
NR
9
NR
R
Ts
+
5, 9
N
N
O
RN
•
RN
N
NR
Ts
10
SYNLETT 2011, No. 17, pp 2491–2494
Advanced online publication: 22.09.2011
DOI: 10.1055/s-0030-1260327; Art ID: D14711ST
x
x
.x
x
.2
0
1
1
Scheme 2 The reaction of arylsulfonyl isocyanate and dialkyl car-
bodiimde
© Georg Thieme Verlag Stuttgart · New York

2492
A. Alizadeh et al.
LETTER
O
O
N
R
O
O
CH2Cl2, 12 h, r.t.
– pyridine
+
S
N
•
N
ArO2S
N
N
R
+
R
N
N
R
Ar
NCO
R
N
5
4
N
Ar = Ph, 4-MeC6H4
R
SO2Ar
11
6
not formed
Scheme 3 Synthesis N1-(1,3-alkyl-4-oxo-1,3-diazetan-2-yliden)arylsulfonamides(4-arylimmino-1,3-diazetidine-2-ones)
Cognizant of the potential synthetic interest and pharma- experiment, the reaction of p-toluenesulfonyl isocyanate
cological activities of 1,3-diazetidinone and also consid- and diisopropyl carbdiiimde after 12 hours was subjected
ering the above history of the cycloaddition reaction of to the equivalent amount of pyridine for 5 hours. Both of
dialkyl carbodiimide and isocyanates, we decided to apply the reaction mixtures were analyzed by 1H NMR spectros-
pyridine as a reagent in this reaction to prevent the further copy. As expected, product 1,3-diazetidine-2-one 11b
cyclization toward heterocyclic compound 7, 8, and 10 was not present, even in trace amounts (Scheme 4).
and permit isolation and characterization of the symmetri-
cal 1,3-diazetidinone 11.
In an attempt to extend the scope of this conversion, we
examined phenyl isocyanate and phenyl isothiocyanate
Thus, in a continuation of our efforts directed toward the instead of arylsulfonyl isocyanate in the above reaction.
synthesis of N-containing heterocycles,21 dialkylcarbodi- Unfortunately, no desired product was obtained, and the
imide 5 was subjected to reaction with arylsulfonyl isocy- products were similar to the reported products for the
anate 4 in the presence of an equimolar amount of pyridine-free reactions.23 We also applied other aromatic
pyridine. The reaction proceeded smoothly in CH2Cl2 at N-heterocycles such as N-methyl imidazole and triazine
room temperature for 12 hours. As outlined in Scheme 3, to evaluate their role compared to the pyridine
surprisingly, despite our expectation of a [2+2] product (Scheme 5). It was found that neither led to production of
from this reaction, symmetrical 1,3-diazetidine-2-one 11 the desired 1,3-diazetidin-2-one 11, and again the prod-
was obtained instead of unsymmetrical 1,3-diazetidine-2- ucts were similar to the reported classic reactions.12–20 All
one 6.22
of our results are summarized in Table 1.
To evaluate the vital rule of pyridine in the formation of The structures of products were elucidated from their ele-
symmetrical 1,3-diazetidine-2-one 11, two different reac- mental analysis, MS, IR, and high-field 1H and 13C NMR
tions were designed and performed under conditions sim- spectra as described for 11a. However, the mass spectrum
ilar to the initial reaction. Firstly, the reaction of p- of 11a did not display a molecular ion peak at m/z = 403
toluenesulfonyl isocyanate and diisopropyl carbdiimide but the ion peak at m/z = 322 showed the loss of the cyclo-
was performed without pyridine for 12 hours. In the other hexyl group in the first fragmentation. In the IR spectrum
O
O
O
i-Pr
analysis by 1H NMR
of the reaction mixture
CH2Cl2
+
S
N
•
i-Pr
N
N
i-Pr
N
Ar
NCO
12 h, r.t.
i-Pr
N
Ar = 4-MeC6H4
O
SO2Ar
11b
i-Pr
O
O
analysis by 1H NMR
of the reaction mixture
CH2Cl2
pyridine
5 h
+
S
reaction mixture
N
•
i-Pr
N
N
i-Pr
N
Ar
NCO
12 h, r.t.
i-Pr
Ar = 4-MeC6H4
N
SO2Ar
11b
Scheme 4 Reactions that confirmed the role of pyridine for synthesis of 1,3-diazetidin-2-ones 11
X
CH2Cl2
PhNCO
or
PhNCS
N
R
•
+
+ reported cycloadducts
N R
+
R
N
R
R
N
12 h, r.t.
N
N
Ph
O
N
O
O
CH2Cl2, 12 h, r.t.
N
R
•
or
N
S
+
+
reported cycloadducts
R
N
N R
+
N
N
N
Ar
NCO
– NMI or triazine
Ar = 4-MeC6H4
Me
N
N
SO2Ar
11
Scheme 5
Synlett 2011, No. 17, 2491–2494 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3-Diazetidin-2-ones
2493
of 11a, two absorption bands at 1866 and 1640 cm–1, re-
lated to C=O and C=N stretching frequencies, clearly in-
dicated the most significant functional groups of the four-
membered ring.
1
In the H NMR spectrum of 11a, 20 hydrogens of two
chemically equivalent cyclohexyl exhibited signals be-
tween d = 1.09–1.97 ppm. This fact is more clear for com-
pound 11b where all four chemically equivalent methyl
groups of the isopropyl substituents appear as a 12-proton
doublet at d = 1.34 ppm (3JHH = 6.6 Hz). A sharp singlet
signal at d = 2.45 ppm arises from the aromatic methyl
group in 11a. The most important signal of compound 11a
is the CH of the two chemically equivalent cyclohexyl
groups which appears as a broad resonance at d = 3.68
ppm. The aromatic hydrogens give characteristic signals
in the aromatic region. The 13C NMR spectrum of 11a
showed 11 distinct signals in agreement with the product
structure. Finally, the structure of 11a was further con-
firmed by a single-crystal X-ray diffraction (Figure 1).
Figure 1 ORTEP diagram of 11a
carbodiimide zwitterion 13. Presumably, since the nitro-
gen of NSO2Ar group could stabilize the negative charge
more easily than NR, resulting from the electron-with-
drawing property of the ArSO2, a four-center intramolec-
ular rearrangement converts intermediate 13 into new
zwitterion 14. Finally, intramolecular ring-closure reac-
tion followed by loss of pyridine affords the 4-imino-1,3-
dizaetidin-2-one 11 derivatives.
Table 1 All results for Reactions of Isocyanates and Dialkyl Carbo-
diimide in the Presence of Aromatic N-Heterocycles
X
R
CH2Cl2, 12 h, r.t.
R
N
N R
Z–NCX
+
N-heterocycle
+
N
•
N
R
N
5
Z
11
O
O
O
Entry N-heterocycle Product Z
X
R
Yield
(%)
O
O
S
S
+
N
N
N
Ar
Ar
NCO
N
1
2
pyridine
pyridine
pyridine
pyridine
NMI
11a
11b
11c
11d
–
4-MeC6H4SO2
O
O
O
O
O
O
S
C6H11 42
i-Pr 40
C6H11 46
i-Pr 45
4
12
4-MeC6H4SO2
R
N
•
3
PhSO2
R
O
O
4
PhSO2
R
R
N
N
N
5
4-MeC6H4SO2
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
–
–
–
–
–
–
–
–
SO2Ar
N
R
N
N
N
N
R
6
1,3,5-triazine
pyridine
pyridine
NMI
–
4-MeC6H4SO2
SO2Ar
13
14
– pyridine
7
–
Ph
Ph
Ph
Ph
Ph
Ph
8
–
O
S
9
–
11
Scheme 6 Proposed mechanism for the mentioned reaction
10
11
12
NMI
–
O
S
1,3,5-triazine
1,3,5-triazine
–
In conclusion, we have presented a novel and unprece-
dented one-pot synthesis of symmetrical 4-imino-1,3-di-
azetidin-2-ones from the reaction of arylsulfonyl
isocyanates and dialkyl carbodiimides in the presence of
pyridine. Pyridine has been found to be a vital reagent as,
without it, the reported cycloadducts are formed. Al-
though the yields are relatively low, readily available and
inexpensive starting materials, simple and mild reaction
conditions, and simple purification as well as potential
synthetic and pharmacological interest of the products
make the present procedure an interesting alternative to
the other approaches.
–
O
Although no detailed mechanistic studies have been car-
ried out at this point, our postulated reaction pathway is
shown in Scheme 6. No doubt, the first step involves nu-
cleophilic addition of pyridine to the highly reactive aryl-
sulfonyl isocyanate 4 to produce Huisgen zwitterion 12.24
Subsequent trapping of dipole 12 by dialkyl carbodiimide
5 furnishes new pyridine-arylsulfonyl isocyanate–dialkyl
Synlett 2011, No. 17, 2491–2494 © Thieme Stuttgart · New York

2494
A. Alizadeh et al.
LETTER
the solvent was removed under reduced pressure, and the
residue was purified by column chromatography over silica
gel (Merck 230–240 mesh) using a hexane–EtOAc (20:1)
mixture as eluent. The product was recrystallized from Et2O
to obtain product 11a as colorless crystals, mp 110–112 °C,
0.17 g, yield 42%. IR (KBr): nmax = 1866 (C=O), 1648
(C=N), 1532 and 1439 (Ar), 1317 and 1151 (SO2) cm–1.
Anal. Calcd (%) for C21H29N3O3S (403.53): C, 62.51; H,
7.24; N, 10.41. Found: C, 62.55; H, 7.25; N, 10.42%. MS
(EI, 70 eV): m/z (%) = 322 (88), 279 (14), 248 (21), 220
(19), 197 (28), 155 (66), 123 (17), 91 (100), 69 (15), 55 (43),
41 (7). 1H NMR (500.13 MHz, CDCl3): d = 1.09–1.96 (20 H,
m, 20 H of 2 Cy), 2.45 (Me), 3.68 (2 H, br, 2 NCH), 7.33 (2
H, d, 3JHH = 7.8 Hz, 2 CH of Ph), 7.85 (2 H, d, 3JHH = 7.8 Hz,
2 CH of Ph). 13C NMR (125 MHz, CDCl3): d = 21.55 (Me),
25.01 (2 CH2), 25.18 (4 CH2), 30.89 (4 CH2), 54.65 (2
NCH), 126.74 (2 CH of Ph), 129.49 (2 CH of Ph), 138.55
(Cipso-SO2), 143.65 (Cipso-Me), 154.88 (C=O), 157.05
(C=N).
References and Notes
(1) Chandrakala, P. S.; Katz, A. K.; Carrell, H. L.; Sailaja, P. R.;
Podile, A. R.; Nangia, A.; Desinaju, G. R. J. Chem. Soc.,
Perkin Trans. 1 1998, 2597.
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Klemann, A.; Bohrisch, J.; Gruendemann, E. DD 221735,
1985; Chem. Abstr. 1986, 104, 88516x. (b) Alpaegiani, M.;
Perrone, E.; Orezi, P.; Carminati, P.; Cassinelli, G.
DE 3820420, 1988; Chem. Abstr. 1989, 111, 39093t.
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11, 1691.
(4) (a) Nangia, A. Proc. Indian Acad. Sci., Chem. Sci. 1993,
105, 131. (b) Nangia, A.; Chandrakala, P. S.;
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P. S. Tetrahedron Lett. 1995, 42, 7771.
(5) Michels, E.; Wecher, D. DE 3939698, 1991; Chem. Abstr.
1991, 115, 2092979.
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JP 245519, 1990; Chem. Abstr. 1990, 113, 191328.
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Organometallics 1990, 9, 762.
(8) Aue, D. H.; Thomas, D. J. Org. Chem. 1975, 40, 2356.
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111, 9194. (b) Hegedus, L. S.; Kramer, A. Organometallics
1984, 3, 1263.
(10) (a) Nishio, T.; Kato, A.; Kashima, C.; Omote, Y. J. Chem.
Soc., Perkin Trans. 1 1980, 607. (b) Nishio, T.; Nakajima,
N.; Kashima, C.; Omote, Y. Heterocycles 1983, 20, 849.
(11) Richter, R.; Ulrich, H. J. Org. Chem. 1981, 46, 3011.
(12) Ulrich, H. Cycloaddition Reactions of Heterocumulenes;
Academic Press: New York, 1967.
(13) Hofmann, R.; Schmidt, E.; Reichle, A.; Moosmuller, F.
DE 1012601, 1957; Chem. Abstr. 1959, 53, 19892g.
(14) Neumann, W.; Fischer, P. Angew. Chem., Int. Ed. Engl.
1962, 1, 621; Angew. Chem. 1962, 74, 801.
(15) Farrissejeyr, W. J.; Ricciardai, R. J.; Sayigh, A. A. R. J. Org.
Chem. 1968, 33, 1933.
(16) Ulrich, H. Acc. Chem. Res. 1969, 2, 186.
(17) (a) Ozaki, S. Chem. Rev. 1972, 72, 457. (b) Williams, A.;
Ibrahim, I. T. Chem. Rev. 1981, 81, 589.
(18) (a) Richer, R.; Tucker, B.; Ulrich, H. J. Org. Chem. 1983,
48, 1694. (b) Ulrich, H.; Richer, R.; Tucker, B.
J. Heterocycl. Chem. 1987, 24, 1121.
(19) Ulrich, H.; Tucker, B.; Stuber, F. A.; Sayigh, A. A. R. J. Org.
Chem. 1969, 34, 2251.
(20) Ulrich, H.; Tucker, B.; Sayigh, A. A. R. J. Am. Chem. Soc.
1968, 90, 528.
(21) (a) Zohreh, N.; Alizadeh, A.; Bijanzadeh, H. R.; Zhu, L. G.
J. Comb. Chem. 2010, 12, 497. (b) Alizadeh, A.; Noaparast,
Z.; Sabahnoo, H.; Zohreh, N. Synlett 2010, 1469.
(c) Alizadeh, A.; Sabahnoo, H.; Noaparast, Z.; Zohreh, N.;
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(22) To a magnetically stirred solution of pyridine (160 mg, 2
mmol) and p-toluenesulfonyl isocyanate (400 mg, 2 mmol)
in CH2Cl2 (5 mL) was added dicyclohexyl carbodiimide
(410 mg, 2 mmol) in CH2Cl2 (2mL). The reaction mixture
was stirred for 12 h in r.t. After completion of the reaction,
Crystal Data for 11a
C21H33N3O3S (CCDC824721):MW = 407.57, orthorhombic,
space group 2ac, a = 21.8645 (18) Å, b = 9.7928 (9) Å,
c = 10.0106 (9) Å, a = 90.00, b = 90.00, g = 90.00,
V = 2143.4 (3) Å3, Z = 4, Dc = 1.263 mg/m3, F(000) = 880,
crystal dimension 0.26 × 0.18 × 0.07 mm, radiation, Mo Ka
(l = 0.71073 Å), 1.86 £ 2q £ 25.00, intensity data were
collected at 298 (2) K with a Bruker APEX area-detector
diffractometer, and employing w/2q scanning technique,
in the range of –21 £ h £ 26, –11 £ k £ 11, –9 £ l £ 11; the
structure was solved by a direct method, all nonhydrogen
atoms were positioned and anisotropic thermal parameters
refined from 2014 observed reflections with R (into) =
0.1497 by a full-matrix least-squares technique converged to
R = 0.1334 and Raw = 0.3306 [I > 2 s(I)].
Compound 11c
Colorless crystals, mp 109–111 °C, 0.18 g, yield 46%.
IR (KBr): nmax = 1874 (C=O), 1659 (C=N), 1532 and 1439
(Ar), 1363 and 1150 (SO2) cm–1. Anal. Calcd (%) for
C20H27N3O3S (389.51): C, 61.67; H, 6.99; N, 10.79. Found:
C, 61.66; H, 6.71; N, 10.82. MS (EI, 70 eV): m/z (%) = 389
(2) [M+], 368 (18), 313 (21), 292 (26), 240 (37), 197 (22),
155 (87), 111 (57), 91 (87), 57 (100), 43 (54). 1H NMR
(500.13 MHz, CDCl3): d = 1.12–1.96 (20 H, m, 20 H of Cy),
3.68 (2 H, br, 2 NCH), 7.54 (2 H, t, 3JHH = 7.4 Hz, 2 CH of
Ph), 7.61 (1 H, t, 3JHH = 7.1 Hz, CH of Ph), 7.97 (2 H, d,
3JHH = 8.6 Hz, 2 CH of Ph). 13C NMR (125 MHz, CDCl3):
d = 25.01 (2 CH2), 25.17 (4 CH2), 30.90 (4 CH2), 54.70 (2
NCH), 126.68 (2 CH of Ph), 128.89 (2 CH of Ph), 132.80
(CH of Ph), 141.42 (Cipso-SO2), 154.77 (C=O), 157.34
(C=N).
(23) (a) Ojima, I.; Akiba, K.; Inamoto, N. Bull. Chem. Soc. Jpn.
1973, 46, 2559. (b) Inamoto, N.; Ojima, I. J. Chem. Soc. D
1970, 1629. (c) Exner, O.; Jehlicka, V.; Dondoni, A. Collect.
Czech. Chem. Commun. 1976, 41, 562. (d) Dondoni, A.;
Battaglia, A. J. Chem. Soc., Perkin Trans. 2 1975, 1475.
(e) Ulrich, H.; Sayigh, A. A. R. Angew. Chem., Int. Ed. Engl.
1965, 4, 520. (f) Sayigh, A. A. R.; Ulrich, H. US 3467651,
1969; Chem. Abstr. 1969, 71, 112907.
(24) (a) Huisgen, R.; Herbig, K. Chem. Ber. 1967, 100, 1107.
(b) Alizadeh, A.; Zohreh, N.; Zhu, L. G. Synthesis 2008,
2073.
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