Isoquinoline-catalyzed reaction of phenacyl bromide and N, N -dialkylcarbodiimides: Novel synthesis of azirines

Article abstract of DOI:10.1055/s-0031-1290487

A practical and efficient procedure for the synthesis of polysubstituted azirines and in some cases benzamides was developed through reaction of phenacyl bromides and N,N-dialkylcarbodiimides, in the presence of catalytic amount of isoquinoline in dry ace

Full text of DOI:10.1055/s-0031-1290487

LETTER
▌859
lIestteor quinoline-Catalyzed Reaction of Phenacyl Bromide and N,N-Dialkyl-
carbodiimides: Novel Synthesis of Azirines
Novel Synthesis of Azirines
Abdolali Alizadeh,* Atieh Rezvanian
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
Received: 26.09.2011; Accepted after revision: 02.02.2012
Aziridines may take part in various chemical transforma-
tions since they can act as dienophiles and dipolarophiles
as well as electrophiles and nucleophiles.8 Numerous
methods have been reported for the synthesis of different-
Abstract: A practical and efficient procedure for the synthesis of
polysubstituted azirines and in some cases benzamides was devel-
oped through reaction of phenacyl bromides and N,N-dialkylcar-
bodiimides, in the presence of catalytic amount of isoquinoline in
dry acetonitrile under mild conditions at ambient temperature. The ly substituted azirines, falling into two main synthetic
salient features of this process include operational simplicity, high
yields, and easily accessible starting materials.
strategies for the construction of the three-membered
azirine ring: (a) intramolecular reactions of N-functional-
Key words: azirine, benzamide, phenacyl bromide, dialkylcarbodi-
imide, isoquinoline
ized imines, vinyl azides, isoxazoles, and oxazaphospho-
les and (b) intermolecular reactions between nitriles and
carbenes or nitrenes and acetylenes.9
The presence of different functionalities at nitrogen and
other positions of the ring has been observed to play a sig-
nificant role in determining the geometry of the azirine
ring and its fate. This has been exploited in the synthesis
of diverse types of organic compounds with biological im-
portance, such as α-lactams, azinomycins, tetrahydropyr-
idines, indolizidine and pyrrolizidine alkaloids, allylic
amines, and amino acids.10,11
Azirines constitute the smallest nitrogen unsaturated het-
erocyclic system, with two carbon atoms and one double
bond in a three-membered ring. The theoretical biological
applications, and the synthetic chemistry of these hetero-
cycles have been extensively explored since the mid-
1960s.1 A number of general reviews on azirines has ap-
peared during this period.2 Interest in these nitrogen-con-
taining heterocycles stems from the general influence of
ring strain upon chemical reactivity and the potential for
their derivatives to act as precursors to more elaborate het-
erocyclic molecules such as alkaloids,3 acyclic functional-
ized amino derivatives,3a–c and heterocycles.3d–h
As part of our current studies into the development of ef-
ficient routes in heterocycle synthesis,12 we wish to report
herein a simple and mild method for the preparation of
highly functionalized azirines. We have found that a mix-
ture of phenacyl bromide (1) and N,N-dialkyl carbodi-
imides 2, in the presence of a catalytic amount of
isoquinoline (10 mol%) underwent a smooth addition re-
action in dry MeCN at ambient temperature to afford
azirines 3 in good yields (Table 1). Different types of
phenacyl bromide with electrophilic substitution in the
para or meta position were used to investigate the scope
and limitation of the reaction. It was found that the pres-
ence of Br in the para position afforded benzamides 4;
whereas with Br in the meta position no desired products
were obtained as shown in Scheme 1. The choice of an ap-
propriate reaction medium and base was of crucial impor-
tance for successful synthesis. It is shown in Table 2 that
the reaction using MeCN as the solvent and K2CO3 as the
base gave the best result at ambient temperature.
Even though highly reactive, the azirine ring has been
found in several natural products (Figure 1). Azirinomy-
cin,4 isolated from Streptomyces aureus and its methyl es-
ter were found to exhibit a broad spectrum of antibiotic
activity, in vitro, against both Gram-positive and Gram-
negative bacteria.5 In addition, the azirine-containing nat-
ural products (R)-(–)-6 and (S)-(+)-dysidazirine7 and (S)-
(+)-antazirine7 were isolated from Dysidea fragilis.
N
CO2H
H
N
CO2H
H
Me
R
azirinomycin
(S)-(+)-dysideazirine R = n-C5H11
Br
Unambiguous evidence for the structure of products 3 and
4 was obtained from their elemental analysis, IR, and
high-field 1H NMR and 13C NMR spectra. The mass spec-
trum of 3a displayed the molecular ion peak at the appro-
priate m/z value. The IR spectrum of compound 3a
showed an absorption band due to the NH stretching fre-
quency at 3247 cm–1. Absorption bands at 1698 and 1620
cm–1 are due to the NC=C and C=O groups. The 1H NMR
spectrum of 3a showed two doublets for the CH3 groups
(δ = 0.98 ppm, 3JHH = 6.6 Hz and δ = 1.43 ppm, 3JHH = 6.7
(S)-(+)-antazirine
R =
Br
Figure 1 Azirines found in natural products
SYNLETT 204012, 236, 0859–0862
Advanced online publication: 16.03.2012
DOI: 10.1055/s-0031-1290487; Art ID: ST-2011-D0298-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

860
A. Alizadeh, A. Rezvanian
LETTER
Table 1 Isoquinoline-Catalyzed Synthesis of Azirine and Benzamide Derivatives
R
O
O
N
R
isoquinoline
R
Ar
Br
•
R
+
N
N
or
Ar
N
H
Ar
N
K2CO3, r.t
MeCN, 6 h
R
H
O
1
2
3
4
Entry
Products 3, 4
Ar
R
Yield (%)
1
2
3a
3b
3c
3d
3e
3f
Ph
Ph
i-Pr
82
77
80
73
65
70
–
c-Hex
i-Pr
3
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
3-O2NC6H4
3-BrC6H4
4
c-Hex
c-Hex
c-Hex
c-Hex
i-Pr
5
6
7
3g
3h
4a
4b
8
3-BrC6H4
–
9
4-BrC6H4
i-Pr
78
80
10
4-O2NC6H4
i-Pr
O
O
R
N
Br
R
Ar
N
Ar
N
Ar
1
R
N
H
8
N
3
O
R
O
O
N+
N+
Ar
Ar
R
Br–
7
N
N
5
–
R
R
K2CO3
N
•
O
N+
N
Ar
R
–
2
6
path A
O
R
O
O–
Ar
N
H
N+
N
N+
N+
4
Ar
–
2
H2O
Ar
O
6
+
path B
N
R
R
R
–
N
R
N
N
R
Ar
O
R
N
R
7
9
10
N+
N
–
H
Scheme 1 Proposed mechanism for the formation of products 3 and 4
Synlett 2012, 23, 859–862
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Synthesis of Azirines
861
5; Katritzky, A. R.; Rees, C. W.; Lwowski, W., Eds.;
Pergamon Press: Oxford, 1984, 47–93. (d) Fowler, F. W.
Adv. Heterocycl. Chem. 1971, 13, 45276.
Hz), two multiplets for the two CH groups (δ = 3.80–3.85
and 4.37–4.41 ppm), one singlet for the NH group
(δ = 6.70 ppm), and the phenyl moiety gave rise to char-
acteristic signals in the aromatic region of the spectrum.
(2) (a) Padwa, A.; Murphee, S. S. Prog. Heterocycl. Chem.
2003, 15, 75. (b) Sweeney, J. B. Chem. Soc. Rev. 2002, 31,
247. (c) Zwanenburg, B.; ten Holte, P. Top. Curr. Chem.
2001, 216, 93. (d) Gilchrist, T. L. Aldrichim. Acta 2001, 34.
(e) Rai, K. L. M.; Hassner, A. Advances in Strained and
Interesting Organic Molecules 2000, 8, 187. (f) Ray, C. A.;
Risberg, E.; Somfai, P. Tetrahedron 2002, 58, 5983.
(3) (a) Lehmann, J.; Linden, A.; Heimgartner, H. Tetrahedron
1999, 55, 5359. (b) Ray, C. A.; Risberg, E.; Somfai, P.
Tetrahedron Lett. 2001, 42, 9289. (c) Banert, K.; Höhler, F.
Angew. Chem. Int. Ed. 2001, 40, 174. (d) Drögemüller, M.;
Jautelat, R.; Winterfeldt, E. Angew. Chem., Int. Ed. Engl.
1996, 35, 1572.
(4) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiotics
1971, 24, 48.
(5) Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller, A. J.
J. Antibiotics 1971, 24, 42.
(6) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53,
2103.
(7) Salomon, C. E.; Williams, D. H.; Faulkner, D. J. J. Nat.
Prod. 1995, 58, 1463.
1
The H-decoupled 13C NMR spectrum of 3a showed 11
distinct resonances in agreement with the suggested struc-
ture.
Table 2 Effect of the Different Solvents and Bases on the Time and
Yield of Reaction
Entry
Solvent
Base
Time (h)
Yield (%)
a
b
c
d
e
f
MeCN
MeCN
MeCN
EtOH
KOH
Et3N
5
7
55
32
82
64
47
54
35
40
K2CO3
KOH
Et3N
5
10
8
EtOH
EtOH
K2CO3
KOH
K2CO3
8
(8) Palacios, F.; Ochoa de Retana, A. M.; Martínez de
Marigorta, E.; de los Santos, J. M. Org. Prep. Proced. Int.
2002, 34, 219.
g
h
CH2Cl2
CH2Cl2
13
16
(9) (a) Morrow, D. F.; Butler, M. E.; Huang, E. C. Y. J. Org.
Chem. 1965, 30, 579. (b) Piskunova, I. P.; Eremeev, A. V.;
Mishnev, A. F.; Vosekalna, I. A. Tetrahedron 1993, 49,
4671. (c) Verstappen, M. M. H.; Ariaans, G. J. A.;
Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491.
(d) Smolinsky, G. J. Org. Chem. 1962, 27, 3557.
(e) Hassner, A.; Fowler, F. W. J. Org. Chem. 1968, 33, 2686.
(f) Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 4483.
(g) Hortmann, A. G.; Robertson, D. A.; Gillard, B. K. J. Org.
Chem. 1972, 37, 322. (h) Hassner, A.; Fowler, F. W. J. Am.
Chem. Soc. 1968, 90, 2869.
To explain the mechanism of this reaction, we propose
that the isoquinolinium salt 5, generated in situ from con-
densation of phenacyl bromide 1 and isoquinoline, is con-
verted into the isoquinoliniumylide 6 under the influence
of K2CO3 and adds to dialkylcarbodiimides to form inter-
mediate 7 (Scheme 1). The generated ylide cyclizes, los-
ing isoquinoline to afford the corresponding aziridine 8,
which tautomerizes to produce azirine 3 (path A). In path
B, due to the result of intramolecular cyclization of inter-
mediate 7, intermediate 9 is formed which, after ring
opening and passing through intermediate 10, leads to
benzamide 4.
(10) Mimura, N.; Miwa, Y.; Ibuka, T. J. Org. Chem. 2002, 67,
5796.
(11) Furmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649.
(12) (a) Alizadeh, A.; Rezvanian, A. Synlett 2011, 1105.
(b) Alizadeh, A.; Zarei, A.; Rezvanian, A. Synthesis 2011,
497. (c) Alizadeh, A.; Mokhtari, J. Tetrahedron 2011, 19,
3567. (d) Alizadeh, A.; Firuzyar, T.; Mikaeili, A. Synthesis
2010, 3913.
(13) In a 25 mL round-bottom flask, the requisite phenacyl
bromide (1 mmol) and N,N-dialkyl carbodiimide (1 mmol)
were taken up in the presence of 10 mol% of isoquinoline in
MeCN (5 mL). Then K2CO3 (1 mmol) was added, and the
mixture was stirred continuously for 6 h at r.t. After
completion of the reaction (monitored by TLC), the solvent
was removed under reduced pressure, and the residue was
purified by column chromatography using n-hexane–EtOAc
(8:1).
In conclusion, a novel and facile reaction catalyzed by iso-
quinoline leading to high yields of polysubstituted
azirines from readily available starting materials involv-
ing phenacyl bromide and N,N-dialkyl carbodiimides has
been developed.13 Various bromides and carbodiimides
are suitable for this reaction. Mild reaction conditions,
easy workup, clean reaction profile, short reaction times,
and wide range of substrate applicability are the key ad-
vantages of this methodology. This protocol not only pro-
vides a novel and effective method for the preparation of
functionalized azirines and benzamides but also opens a
brand new way for employing the isoquinolinium ylide in-
termediate to design new multicomponent reactions.
[1-Isopropyl-3-(isopropylamino)-1H-aziren-2-
yl](phenyl)methanone (3a)
Yellow powder; mp 150–152 °C; yield: 0.20 g (82%). IR
(KBr): νmax = 3274 (NH), 1698 (NC=C), 1620 (C=O), 1248
(CN) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 0.98 (d,
3JHH = 6.6 Hz, 6 H, CH3), 1.43 (d, 3JHH = 6.7 Hz, 6 H, CH3),
3.80–3.85 (m, 1 H, CH), 4.37–4.41 (m, 1 H, CH), 6.70 (s, 1
H, NH), 7.25–7.51 (m, 5 H, 5 CH of Ph). 13C NMR (125.7
MHz, CDCl3): δ = 20.31 (2 CH3), 21.72 (2 CH3), 42.16
(CH), 49.80 (CH), 125.83 (CCO), 125.84 (2 CH of Ph),
128.12 (2 CH of Ph), 136.06 (CH of Ph), 136.67 (Cipso–CO),
153.60 (NCN), 171.87 (CO). MS (EI, 70 eV): m/z (%) = 244
References and Notes
(1) (a) Murphree, S. S.; Padwa, A. Progress in Heterocyclic
Chemistry, In Three-Membered Ring Systems, Vol. 9;
Scriven, E. F. V.; Suschitzky, H., Eds.; Pergamon Press:
Oxford, 1997, 43263. (b) Heimgartner, H. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 238. (c) Padwa, A.; Woolhouse, A.
D. Comprehensive Heterocyclic Chemistry I, Vol. 7, Chap.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 859–862

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A. Alizadeh, A. Rezvanian
LETTER
(6) [M+], 227 (100), 214 (20), 201 (52), 170 (31), 145 (26),
115 (92), 97 (45), 77 (80), 57 (88), 43 (87). Anal. Calcd for
C15H20N2O (244.335): C, 73.74; H, 8.25; N, 11.47. Found:
C, 73.72; H, 8.26; N, 11.46.
2 CH of Ph). 13C NMR (125.7 MHz, CDCl3): δ = 24.49 (2
CH2), 25.29 (CH2), 25.38 (CH2), 26.28 (2 CH2), 30.85 (2
CH2), 32.41 (2 CH2), 55.43 (CH), 57.63 (CH), 113.77 (2 CH
of Ph), 128.56 (CCO), 129.05 (2 CH of Ph), 130.10 (Cipso
–
[1-Cyclohexyl-3-(cyclohexylamino)-1H-aziren-2-
yl](phenyl)methanone (3b)
CO), 154.74 (NCN), 161.83 (Cipso–OMe), 171.18 (CO). MS
(EI, 70 eV): m/z (%) = 354 (1) [M+], 233 (19), 185 (8), 151
(33), 135 (100), 98 (16), 56 (19). Anal. Calcd for
C22H30N2O2 (354.49): C, 74.54; H, 8.53; N, 7.90. Found: C,
74.53; H, 8.55; N, 7.92.
Yellow powder; mp 170–172 °C; yield: 0.310 g (77%). IR
(KBr): νmax = 3429 (NH), 1699 (NC=C), 1599 (C=O), 1211
(CN) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 0.86 (m, 20
H, CH2), 3.45–3.50 (m, 1 H, CH), 3.94–4.10 (m, 1 H, CH),
6.04 (s, 1 H, NH), 7.38–7.75 (m, 5 H, 5 CH of Ph). 13C NMR
(125.7 MHz, CDCl3): δ = 24.84 (2 CH2), 25.53 (CH2), 26.23
(2 CH2), 30.71 (2 CH2), 32.29 (CH2), 33.23 (2 CH2), 48.64
(CH), 57.58 (CH), 126.59 (CCO), 126.79 (2 CH of Ph),
128.53 (2 CH of Ph), 131.18 (CH of Ph), 135.16 (Cipso–CO),
154.29 (NCN), 171.46 (CO). MS (EI, 70 eV): m/z (%) = 395
(1), 347 (100), 318 (36), 241 (47), 171 (92), 98 (83), 55 (61).
Anal. Calcd for C21H28N2O (403.37): C, 77.74; H, 8.70; N,
8.83. Found: C, 77.48; H, 8.71; N, 8.82.
[1-Cyclohexyl-3-(cyclohexylamino)-1H-aziren-2-yl](4-
nitrophenyl)methanone (3e)
Yellow powder; mp 152–154 °C; yield: 0.240 g (65%). IR
(KBr): νmax = 3298 (NH), 1710 (NC=C), 1650 (C=O), 1248
(CN) cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 0.69–1.82
(m, 20 H, CH2), 3.11–3.13 (m, 1 H, CH), 4.01–4.03 (m, 1 H,
CH), 8.29 (s, 1 H, NH), 7.67 (d, 3JHH = 8.6 Hz, 2 H, 2 CH of
Ph), 8.25 (d, 3JHH = 8.6 Hz, 2 H, 2 CH of Ph). 13C NMR
(125.7 MHz, CDCl3): δ = 23.99 (2 CH2), 24.89 (CH2), 25.50
(2 CH2), 30.30 (2 CH2), 31.10 (2 CH2), 32.29 (CH2), 49.08
(CH), 53.77 (CH), 123.28 (2 CH of Ph), 128.34 (2 CH of
Ph), 128.82 (CCO),143.16 (Cipso–CO), 148.89 (Cipso–NO2),
153.18 (NCN), 166.26 (CO). MS (EI, 70 eV): m/z (%) = 369
[M+], 292 (13), 248 (23), 167 (100), 104 (33), 69 (27). Anal.
Calcd for C21H27N3O3 (369.46): C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.28; H, 7.35; N, 11.36.
[1-Isopropyl-3-(isopropylamino)-1H-aziren-2-yl](4-
methoxyphenyl)methanone (3c)
Yellow powder; mp 162–164 °C (decomp.); yield: 0.219 g
(80%). IR (KBr): νmax = 3436 (NH), 1688 (NC=C), 1630
(C=O), 1261 (CN) cm–1. 1H NMR (500.1 MHz, CDCl3):
δ = 0.99 (d, 3JHH = 6.72 Hz, 6 H, CH3), 1.43 (d, 3JHH = 6.99
Hz, 6 H, CH3), 3.81–3.85 (m, 1 H, CH), 3.84 (s, 3 H, OMe),
4.44–4.50 (m, 1 H, CH), 6.47 (s, 1 H, NH), 6.91 (d,
3JHH = 8.75 Hz, 2 H, 2 CH of Ph), 7.52 (d, 3JHH = 8.75 Hz, 2
H, 2 CH of Ph). 13C NMR (125.7 MHz, CDCl3): δ = 20.95 (2
CH3), 22.33 (2 CH3), 42.70 (CH), 50.24 (CH), 55.42 (OMe),
113.85 (2 CH of Ph), 122.11 (CCO), 128.87 (2 CH of Ph),
133.24 (Cipso–CO), 154.20 (NCN), 161.78 (Cipso–OMe),
172.05 (CO). MS (EI, 70 eV): m/z (%) = 278 (54), 263 (10),
192 (100), 178 (64), 143 (36), 135 (99), 92 (41), 77 (54).
Anal. Calcd for C16H22N2O2 (274.36): C, 70.04; H, 8.08; N,
10.21. Found: C, 70.03; H, 8.10; N, 10.10.
[1-Cyclohexyl-3-(cyclohexylamino)-1H-aziren-2-yl](3-
nitrophenyl)methanone (3f)
Yellow powder; mp 170–172 °C; yield: 0.258 g (70%). IR
(KBr): νmax = 3302 (NH), 1705 (NC=C), 1646 (C=O), 1267
(CN). 1H NMR (500.1 MHz, CDCl3): δ = 0.91–2.17 (m, 20
H, CH2), 3.47–3.53 (m, 1 H, CH), 3.96–4.06 (m, 1 H, CH),
6.13 (s, 1 H, NH), 7.70 (d, 3JHH = 8.6 Hz, 1 H, CH of Ph),
7.94 (d, 3JHH = 8.7 Hz, 1 H, CH of Ph), 8.22–8.33 (t,
3JHH = 8.5 Hz, 1 H, 1 CH of Ph), 8.27 (s, 1 H, CH of Ph). 13
C
NMR (125.7 MHz, CDCl3): δ = 24.45 (2 CH2), 25.24 (CH2),
26.11 (2 CH2), 30.77 (2 CH2), 32.31 (2 CH2), 33.11 (CH2),
49.85 (CH), 57.54 (CH), 122.91 (2 CH of Ph), 123.78 (2 CH
of Ph), 123.92 (CCO), 127.65 (2 CH of Ph), 128.02 (2 CH of
Ph), 142.68 (Cipso–CO), 148.82 (Cipso–NO2), 153.43 (NCN),
168.79 (CO). MS (EI, 70 eV): m/z (%) = 368 (1) [M+ – 1],
292 (8), 248 (23), 167 (100), 150 (98), 104 (53), 76 (37).
Anal. Calcd for C21H27N3O3 (369.46): C, 68.27; H, 7.37; N,
11.37. Found: C, 68.28; H, 7.35; N, 11.36.
[1-Cyclohexyl-3-(cyclohexylamino)-1H-aziren-2-yl](4-
methoxyphenyl)methanone (3d)
Yellow powder; mp 174–176 °C (decomp.); yield: 0.258 g
(73%). IR (KBr): νmax = 3300 (NH), 1690 (NC=C), 1653
(C=O), 1260 (CN) cm–1. 1H NMR (500.1 MHz, CDCl3):
δ = 1.17–2.08 (m, 20 H, CH2), 3.49–3.52 (m, 1 H, CH),
4.10–4.12 (m, 1 H, CH), 6.03 (s, 1 H, NH), 6.89 (d,
3JHH = 8.5 Hz, 2 H, 2 CH of Ph), 7.54 (d, 3JHH = 8.5 Hz, 2 H,
Synlett 2012, 23, 859–862
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