Coupling of vinyl aziridines and phenyl isocyanate

Article abstract of DOI:10.1016/j.tetlet.2008.04.121

Thermal coupling of vinyl aziridines and phenyl isocyanate was evaluated. Although oxazolidinone products were predominant, some reactions afforded a seven-membered ring heterocycle. When Ni/IMes was employed as a catalyst, a wider array of vinyl aziridines underwent coupling reactions. The Ni catalyzed reactions generally afforded vinyl imidazolidinones as major products.

Full text of DOI:10.1016/j.tetlet.2008.04.121

Tetrahedron Letters 49 (2008) 4306–4309
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Coupling of vinyl aziridines and phenyl isocyanate
*
Kainan Zhang, Pramod R. Chopade , Janis Louie
University of Utah, Department of Chemistry, 315 South 1400 East, Salt Lake City, UT 84112, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Thermal coupling of vinyl aziridines and phenyl isocyanate was evaluated. Although oxazolidinone
products were predominant, some reactions afforded a seven-membered ring heterocycle. When Ni/IMes
was employed as a catalyst, a wider array of vinyl aziridines underwent coupling reactions. The Ni
catalyzed reactions generally afforded vinyl imidazolidinones as major products.
Published by Elsevier Ltd.
Received 3 March 2008
Revised 22 April 2008
Accepted 22 April 2008
Available online 24 April 2008
Keywords:
Phenyl isocyanate
Vinyl aziridine
N-Heterocyclic carbene
Nickel
Imidazolidinone
Oxazolidinone
Tetrahydro-[1,3]diazepin-2-one
The coupling of an isocyanate and a vinylaziridine is an effective
way to access heterocyclic ring systems. Although one example of a
thermal coupling has been reported,1 these reactions are typically
catalyzed by Lewis acids such as sodium iodide2 and nickel iodide.3
These couplings generally afford vinyl-substituted five-membered
imidazolidinone products. Palladium catalysts have also been used
to catalyze this coupling reaction and in some cases, these cou-
plings display high enantioselectivity.4–6 In each of these cyclo-
additions, the vinyl group acts to enhance the reactivity of the
aziridine. For example, in non-metal mediated reactions the vinyl
group is an activating group. In Pd catalyzed coupling reactions,
the vinyl group enhances binding of the aziridine substrate. How-
ever, in all of these cases, incorporation of the vinyl group in the
heterocycle is not observed.
Despite the lack of information regarding simple thermal
coupling of isocyanates and vinyl aziridines, we found that N-
benzyl-2-styryl-aziridine (1a) reacted readily with 3 equiv of
phenyl isocyanate at elevated temperatures (Eq. 1). At 100 °C,
the coupling proceeded smoothly and afforded three distinct
heterocyclic products,
a seven-membered product (2a), an
oxazolidinone 3a,7 and a trace amount of imidazolidinone 4a7
(Eq. 1).
A variety of vinyl azirdines were evaluated in the thermal cou-
pling reaction (Table 1, Eq. 2).8 Electronic factors did not have
much of an effect on the reaction as both para methoxy and para
CF3 substituted substrates afforded relatively equal ratios of het-
erocyclic products 2 and 3 (entries 2 and 3). The reaction with 1b
also afforded a vinyl-substituted imidazolidinone (4b) in trace
amounts. Additional substitution on the olefin led to the selective
formation of the oxazolidine product 3 (entries 5 and 6). In entry
6 where the substrate lacks an activating phenyl group (1f), the
reaction was quite sluggish. Only 38% of the 3f was isolated.
When the N-benzyl group was replaced by an N-cyclohexyl
group, the seven-membered ring (2g) was slightly favored over
the oxazolidine ring (3g). Other substitution patterns lead to no
heterocyclic products. Terminal vinyl aziridines possessing no
activating group (i.e., R = Bn, R1, R2 = H, H, 1h and R = Cy, R1,
R2 = H, H, 1i) did not react. In addition, when N was substituted
with a bulky tert-butyl group (i.e., R = t-Bu, R1, R2 = H, Ph, 1j) or
when the phenyl group was replaced with an ester group (i.e.,
R = Bn, R1, R2 = H, CO2Et, 1k), no reaction took place. N-Phenyl-
We present here a study detailing both thermal reactions and
nickel catalyzed reactions of phenyl isocyanate and vinyl aziri-
dines. These reactions afford interesting heterocyclic products in
addition to the expected vinyl-substituted imidazolidinone.
Ph
O
PhNCO +
N
O
Bn
Ph
Ph
Bn
Ph
Bn
100 ºC
Bn
N
N
N
O
+
+
N
N
ð1Þ
N
Ph
Ph
Ph
1a
2a
3a
4a
* Corresponding author. Tel.: +1 801 581 7309; fax: +1 801 581 8433.
E-mail address: louie@chem.utah.edu (J. Louie).
Present Address: Coker College, 300 East College Avenue, Hartsville, SC 29550, USA.
vinylaziridines underwent
a Ni catalyzed [3,3] sigmatropic
rearrangement.9
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.04.121

K. Zhang et al. / Tetrahedron Letters 49 (2008) 4306–4309
4307
Table 1
PhNCO +
Bn
N
Thermal coupling of PhNCO and vinyl aziridinesa
O
5 mol% Ni(COD)2
10 mol% NHC
Bn
Ph
Ph
N
N
N
(5)
O
100 °C
R
Ph
R
R
+
N
O
N
N
R1
R
R1
R2
R = Ph (1a)
R = H (1h)
R = Ph (4a)
R = H (4h)
R
N
R2
2
3
ð2Þ
100 ºC
O
R1
PhNCO
R
Ph
N
N
R2
+
N
N
N
N
N
R1
1
R2
IMes
ItBu
4
Entry
Vinyl aziridine
(% Yield)
N
N
N
1
R
R1, R2
2
3
4
1
2
3
4
5
6
7
1ab
1bb
1cb
1db
1eb
1f
Bn
Bn
Bn
Bn
Bn
Bn
Cy
H, Ph
2a (41)c
2b (42)c
2c (25)d
2d (42)d
3a (39)c
3b (36)c
3c (28)d
3d (40)d
3e (74)c
3f (38)c
3g (20)c
4a (9)c
4b (3)c
H, 4-C6H4–OMe
H, 4-C6H4–CF3
H, –C2H3
Me, Ph
Me, Me
IPr
SIPr
Figure 1. NHC ligands.
1gb
H, Ph
2g (36)c
reactions described above, 4a was formed as the major product
in almost all Ni/NHC catalyzed reactions. The use of IPr or SIPr
afforded 2a, 3a, and 4a in relatively equal amounts. Vinyl imidazo-
lidinone 4a was the major product when either IMes or ItBu was
employed; however, yields and ratios of 4a were higher when IMes
was used as the ligand.
a
Reaction conditions: 0.1 M vinyl aziridine, 0.3 M isocyanate, toluene, 100 °C.
Mixture of cis and trans.
Isolated yields.
b
c
d
GC or NMR yields determined relative to an internal standard.
When an unactivated vinyl aziridine (1h) was used as a model
substrate in lieu of 1a, only the formation of imidazolidinone 4h
was observed (Eq. 5). The products obtained from thermal reac-
tions, such as the seven-membered product (2h) and the oxazolid-
inone (3h), were not observed in appreciable amounts.12 Although
the combination of Ni/IMes did catalyze the coupling of 1h and
PhNCO (43% NMR yield), higher yields of 4h were formed in the
presence of ItBu (83% NMR yield). Similar results were obtained
Ph
N
O
Bn
Ph
Bn
N
O
+
N
N
ArOMe
Bn
N
ArOMe
2b
3btrans
19%
100 °C
ð3Þ
ð4Þ
63%
O
when N-cyclohexyl-vinylaziridine (1i) was used as
a model
Bn
Ph
N
N
OMe
substrate.
+
1btrans
The Ni/IMes catalyzed coupling of vinyl aziridines and phenyl
isocyanate proved to be a more general reaction than thermal reac-
tions (Table 2).13 Activated vinyl aziridines reacted smoothly with
PhNCO (entries 1–5). In most cases, imidazolidinone (4) was
formed preferentially. Only the reaction of 1b and 1e gave slightly
more seven-membered ring 2b or oxazolidinone 3e, respectively
(entries 2 and 5). In contrast to the thermal reactions shown in
Table 1, unactivated vinyl aziridines were also converted to hetero-
cyclic products. For example, the thermal reaction of 1f was slug-
gish (Table 1, 38% 3f), whereas it afforded heterocyclic products
(3f and 4f) in an overall 64–67% yield in the Ni/NHC catalyzed reac-
tion (entries 6a and b). In addition, terminal vinyl aziridines gave
imidazolidinone products exclusively and in generally good yields
(40% and 60%, entries 8a and 9a, respectively); higher yields were
observed with the Ni/ItBu catalysts (70% and 92%, entries 8b and
9b, respectively). Other vinyl aziridines such as 1j and 1k, which
were unreactive under thermal conditions, did undergo Ni/IMes
catalyzed coupling. Interestingly, the steric hinderance of 1j
resulted in the formation of small amounts of a unique heterocycle
(5j). It appears that with this substrate, C–C bond cleavage
competes with the more favorable C–N bond cleavage of the
aziridine (entry 10). N-Phenyl-substituted vinyl aziridines afforded
low amounts of imidazolidinone products in addition to aza-cope
products (entries 12 and 13).
ArOMe
4btrans
2%
Ph
O
OMe
100 °C
N
Bn
N
Bn
N
ArOMe
1bcis
3bcis
83%
In an effort to differentiate the reactivity of cis and trans vinyl
aziridines, the cis and trans isomers of 1b were evaluated individ-
ually in the thermal rearrangement reaction (Eqs. 3 and 4). Inter-
estingly, oxazolidinone products were observed in both reactions.
However, the seven-membered ring product (2b) was only ob-
served in the reaction of the trans vinyl aziridine.
We have recently found that the combination of Ni(COD)2 and
NHC ligands catalyze the reaction of vinyl aziridines and alkynes.10
We surmised that this catalyst combination may facilitate the cou-
pling of a wider range of vinyl aziridines and isocyanates and in a
selective manner. As such, a series of NHCs were evaluated as
potential ligands (Fig. 1) for the Ni(0) catalyzed cycloaddition of
isocyanates and vinylaziridines. Phenyl isocyanate (0.3 M)11 and
N-benzyl-2-styryl-aziridine (1a, 0.1 M) were again chosen as
model substrates in a reaction catalyzed by 5 mol % Ni(COD)2 and
10 mol % NHC in toluene at 100 °C (Eq. 5). Again, three heterocyclic
products were generally observed. However, unlike the thermal
The amount of catalyst had a profound effect on the ratio of
heterocyclic products in these reactions. Specifically, we found
that increasing the catalyst loading resulted in the increase of the
generation of the imidazolidinone derivative 4a. On the other
hand, reducing the catalyst promoted the formation of the seven-

4308
K. Zhang et al. / Tetrahedron Letters 49 (2008) 4306–4309
Table 2
Ph
O
N
Nickel catalyzed coupling of PhNCO and vinyl aziridines
O
PhNCO +
Bn
N
Bn
Ph
Bn
Ph
100 °C
Ph
Ph
O
N
+
N
N
N
O
Ph
R
Ph
R1
R2
R
N
+
+
N
N
Ph
PhNCO +
R
R1
N
R1
R2
1a
2a
2.4
3a
2.6
5 mol% Ni(COD)2
2
3
5 mol% Ni(COD)2
10 mol% IMes
2 equiv of 1b or CyNCO
O
10 mol% IMes
100 °C
O
O
Bn
R2
N
N
R
Ph
Ph
N
N
N
100 °C
1
+
R1
R1
N
Ph
R
R2
4atrans only
R2
4
5
Not Observed:
O
O
ð6Þ
Bn
Ph
N
N
Entry
Vinyl aziridine
(% Yield)
Bn
Cy
N
N
1
R
R1, R2
H, Ph
2
3
4
5
1
2
1ac
1bc
Bn
Bn
2a (5)a,d
4a (55)a,d
4b (24)a,d
H, 4-C6H4– 2b (30)a,d 3b (11)
a,d
Ph
4n
4b
OMe
OMe
3
1cc
Bn
H, 4-C6H4– 2c (6)e
4c (69)e
CF3
H, –C2H3
Me, Ph
Scheme 1. NMR analysis of Ni catalyzed rearrangement of thermal coupling
products.
4
5
6a
6b
7
8a
8b
9a
9b
10
11
12
13
1dc
1ec
1f
Bn
Bn
Bn
2d (13)e
3d (13)e
4d (41)e
3e (60)a,d
3f (27)a,d
3f (30)a
4e (18)a,d
4f (37)a,d
4f (37)b,d
4g (81)a,d
4h (40)a,d
4h (70)b,d
4i (60)a,d
4i (92)b,d
4j (16)a,d
4k (65)a,d
4l (13)a,d
Me, Me
1gc
1h
Cy
Bn
H, Ph
H, H
and IMes were then added to the solution and the reaction was fur-
ther heated to 100 °C. Interestingly, 4atrans was the only observed
product (Scheme 1). No products (i.e., 4b) arising from the reaction
of 1b and PhNCO were observed. Similarly, no products (i.e., 4n)
arising from the reaction of 1a and CyNCO were observed when
CyNCO was added in lieu of 1b (Scheme 1). Thus, formation of
heterocyclic products (2–4) appears to be irreversible in both
thermal and nickel catalyzed reactions.
1i
Cy
H, H
1jc
1kc
1l
t-Bu H, Ph
2j (7)a,d
5j (15)a,d
Bn
Ph
H, CO2Et
H, H
H, Ph
1mc Ph
4m (35)a,d
a
Reaction conditions: 5 mol % Ni(COD)2, 10 mol % IMes, 0.1 M vinyl aziridine,
0.3 M isocyanate, toluene, 100 °C.
Reaction conditions: 5 mol % Ni(COD)2, 10 mol % ItBu, 0.1 M vinyl aziridine,
0.3 M isocyanate, toluene, 100 °C.
In summary, thermal and Ni/IMes-catalyzed reactions of phenyl
isocyanate and various vinyl aziridines were evaluated. Thermal
reactions generally afford oxazolidinone products. In some cases,
b
c
Mixture of cis and trans.
a
seven-membered heterocycle is also formed. Ni catalyzed
d
Isolated yields.
reactions generally afforded the more thermodynamically favored
imidazolidinone product.
e
GC yields determined relative to an internal standard.
Acknowledgments
membered ring product 2a (Table 3). It may be possible that the Ni/
IMes catalyst serves to enhance the formation of the more thermo-
dynamically favored imidazolidinone products (4). A similar phe-
nomenon has been observed in nickel iodide promoted couplings.3
Given the results in Table 3, it was unclear whether 4a was
formed from a rearrangement of 2a and 3a or whether it was
formed directly from 1a and PhNCO. In addition, it may be possible
for 2a and 3a to revert back to PhNCO and vinyl aziridine before
ultimately affording 4a. To address these possibilities, 1a and
PhNCO were heated to 100 °C until a mixture of 2a and 3a was
obtained. Two equivalents of 1b and catalytic amounts of Ni(COD)2
We gratefully acknowledge the University of Utah, Merck, NSF
(Career Award), the Camille-Dreyfus Foundation, and the NIGMS
for support of this research.
References and notes
1. For the thermal reaction of an isocyanate and an aziridine, see: Pfeil, E.;
Milzner, K. Angew. Chem., Int. Ed. 1966, 5, 667.
2. Nadir, U. K.; Basu, N. Tetrahedron Lett. 1992, 33, 7949.
3. Munegumi, T.; Azumaya, I.; Kato, T.; Masu, H.; Saito, S. Org. Lett. 2006, 8, 379.
4. Alper, H. J. Am. Chem. Soc. 1995, 117, 4700.
5. Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836.
6. Dong, C.; Alper, H. Tetrahedron: Asymmetry 2004, 15, 1537.
7. Bulter, C. D.; Inman, A. G.; Alper, H. J. Org. Chem. 2000, 65, 5887.
8. General procedure for the thermal reactions: A toluene solution of PhNCO
(75.9 mg, 0.637 mmol, 0.3 M) and vinylaziridine 1a (50 mg, 0.212 mmol, 0.1 M)
was heated to 100 °C for 8 h. The reaction mixture was cooled and the solvent
was removed in vacuo. The residue was purified by flash chromatography (2:3
diethyl ether: pentane) to afford imidazolidinone 4a (6.8 mg, 9%) and the
seven-membered ring 2a (30.9 mg, 41%), and oxazolidinone 3a (29.4 mg, 39%).
1-Benzyl-3,4-diphenyl-1,3,4,7-tetrahydro-[1,3]diazepin-2-one (2a): Light yellow
Table 3
Ni/IMes catalyzed coupling of PhNCO and 1aa
Entry
% Ni(COD)2
% IMes
Ratio of productsb
2a
3a
4a
1
2
3
4
10
5
1
20
10
2
1
1
1
1.6
0
0
0
0
24
11
1.5
oil. IR (dissolved in methylene chloride) m: 1656, 1464, 1240 cmꢀ1 1H NMR
.
(300 MHz, CDCl3, ppm) d: 7.42–7.13 (m, 13H), 6.96 (q, 2H), 6.11 (m, 1H), 5.86
(m, 1H), 5.40 (d, 5.7 Hz, 1H), 4.632 (d, 15 Hz, 1H), 4.18–4.08 (m, 2H), 3.46 (dd,
1H). 13C NMR (300 MHz, CDCl3, ppm) d: 47.5, 53.6, 65.0, 125.3, 125.3, 125.9,
127.3, 127.4, 127.6, 128.5, 128.7, 128.9, 129.1, 130.1, 138.0, 141.9, 146.4, 163.9.
EIMS m/z: 354 (M+), 220, 206, 144, 115, 91. HRMS(ESI/APCI) for C24H23N2O
0.1
0.2
1
a
Reaction conditions: 0.1 M 1a, 0.3 M PhNCO, toluene.
Determined by GC using naphthalene as an internal standard.
b

K. Zhang et al. / Tetrahedron Letters 49 (2008) 4306–4309
4309
[M+H]+: calcd. 355.1810, found 355.1807. (3-Benzyl-5-styryl-oxazolidin-2-
ylidene)-phenyl-amine (3atrans): Light yellow oil. IR (dissolved in methylene
11. NHC catalyze the cyclotrimerization of isocyanates. (See Duong, H. A.; Cross, M.
J.; Louie, J. Org. Lett. 2004, 6, 4679.) Thus, excess isocyanate provided optimal
reaction conditions.
chloride) m: 1672, 1591 cmꢀ1 1H NMR (300 MHz, CDCl3, ppm) d: 7.42–7.17 (m,
.
14H), 6.97 (t, 1H), 6.65 (d, 15.9 Hz, 1H), 6.18 (q, 1H), 4.68 (d, 15 Hz, 1H), 4.55 (d,
15 Hz, 1H), 3.56 (t, 1H), 3.19 (dd, 1H). 13C NMR (300 MHz, CDCl3, ppm) d: 49.5,
50.9, 77.4, 122.3, 123.8, 125.4, 127.0, 127.9, 128.6, 128.7, 128.8, 128.9, 134.8,
135.8, 137.0, 147.8, 152.8. EIMS m/z: 354 (M+), 250, 206, 91, 28. HRMS(ESI/
APCI) for C24H23N2O [M+H]+: calcd. 355.1810, found 355.1802. (3-Benzyl-5-
styryl-oxazolidin-2-ylidene)-phenyl-amine (3acis) Light yellow oil. IR (dissolved
12. No reaction occurred when couplings were run in the presence of Ni(COD)2 and
NHC alone.
13. General procedure for Ni(COD)2/NHC catalyzed reaction: In glovebox,
a
scintillation vial equipped with a magnetic stir bar was charged with PhNCO
(75.9 mg, 0.637 mmol, 0.3 M) and vinylaziridine 1a (50 mg, 0.212 mmol, 0.1 M)
in toluene. A solution of Ni(COD)2 (2.9 mg, 0.0106 mmol, 0.005 M) and IMes
(6.5 mg, 0.0212 mmol, 0.01 M) in toluene was added. The reaction was stirred
at 100 °C for 6 h. The reaction was cooled and the solvent was removed in
vacuo. The residue was purified by flash chromatography (2:3 diethyl ether/
pentane) to afford imidazolidinone 4a (41.4 mg, 55%) and the seven-membered
ring 2a (3.77 mg, 5%). 1-Benzyl-3-phenyl-4-styryl-imidazolidin-2-one (4atrans):
in methylene chloride) m: 1675, 1591, 1493 cmꢀ1 1H NMR (300 MHz, CDCl3,
.
ppm) d: 7.40–7.14 (m, 13H), 6.96 (t, 1H), 6.75 (d, 11.4 Hz, 1H), 5.76 (dd, 1H),
5.31 (q, 1H), 4.66 (d, 15 Hz, 1H), 4.54 (d, 15 Hz, 1H), 3.54 (t, 1H), 3.17 (t, 1H). 13
C
NMR (400 MHz, CDCl3, ppm) d: 49.5, 51.3, 72.7, 122.1, 123.8, 127.9, 128.2,
128.6, 128.7, 128.9, 135.5, 135.7, 137.0, 147.8, 152.8. EIMS m/z: 354 (M+), 250,
206, 91, 28. HRMS(ESI/APCI) for C24H23N2O [M+H]+: calcd. 355.1810, found
355.1811.
Light yellow oil. IR (dissolved in methylene chloride) m: 1701, 1499, 1423 cmꢀ1
.
1H NMR (300 MHz, CDCl3, ppm) d: 7.56–7.02 (m, 16H), 6.59 (d, 15.9 Hz, 1H),
6.13 (q, 1H), 4.80 (q, 1H), 4.58 (d, 15 Hz, 1H), 4.44 (d, 15 Hz, 1H), 3.60 (t, 1H),
3.13 (dd, 1H). 13C NMR (300 MHz, CDCl3, ppm) d: 48.3, 48.8, 56.5, 120.8, 123.5,
126.8, 127.8, 128.0, 128.4, 128.5, 128.8, 128.9, 133.5, 136.1, 137.0, 139.5, 158.2.
EIMS m/z: 354 (M+), 263, 250, 223, 206, 91. HRMS(ESI/APCI) for C24H23N2O
[M+H]+: calcd. 355.1810, found 355.1806.
9. (a) Scheiner, P. J. Org. Chem. 1967, 32, 2628; (b) Figeys, H. P. Tetrahedron Lett.
1981, 22, 637.
10. (a) Zuo, G.; Louie, J. Unpublished results. For Pd-catalyzed conversion of
aziridines to imines, see: (b) Wolfe, J. P.; Ney, J. E. Org. Lett. 2003, 5,
4607.