Metal-mediated reactions of aryl isocyanates with dimethoxycarbene to form isatin derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.03.032

Hydantoin derivatives have been established as the observed product in the reaction of aryl isocyanates with dimethoxycarbene. A change in the reactivity profile of dimethoxycarbene with aryl isocyanates was observed upon the addition of a metal species.

Full text of DOI:10.1016/j.tetlet.2013.03.032

Tetrahedron Letters 54 (2013) 2542–2545
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Tetrahedron Letters
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Metal-mediated reactions of aryl isocyanates with dimethoxycarbene
to form isatin derivatives
James H. Rigby a, Stephanie A. Brouet b,
⇑
a Department of Chemistry, Wayne State University, 5101 Cass Ave., Detroit, MI 48202, USA
b Department of Chemistry, Saginaw Valley State University, 7400 Bay Road, University Center, MI 48710, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydantoin derivatives have been established as the observed product in the reaction of aryl isocyanates
with dimethoxycarbene. A change in the reactivity profile of dimethoxycarbene with aryl isocyanates
was observed upon the addition of a metal species. Methodology has been developed in which the out-
come of nucleophilic carbene reactions with isocyanates can be controlled with simple changes to reac-
tion conditions.
Received 20 February 2013
Revised 5 March 2013
Accepted 7 March 2013
Available online 16 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Nucleophilic carbene
Isocyanate
Isatin
Electrophilic aromatic substitution
Dimethoxycarbene
Hydantoin
Nucleophilic carbenes are highly attractive species for synthe-
sis. This can be argued based on the ability of these 1,1-dipole spe-
cies to serve as carbonyl equivalents and their interesting
reactivity profile.1 However, nucleophilic carbenes have not been
fully exploited as reagents in synthesis because of sometimes
unpredictable reactivity and perceived difficultly in handling.
Nucleophilic carbenes have historically been accessed in
synthetic applications by thermolysis of norboradienone acetals
or by photolysis/thermolysis of dimethoxydiazirine precursors,
which are difficult to handle.2 Warkinton has developed a milder
method for accessing dimethoxycarbene via thermolysis of dialk-
Aryl isocyanates react with dimethoxycarbene to form
primarily hydantoin products, while bis(propylthio)carbene forms
isatin derivatives.7
This substituent-dependent reactivity has some inherent limi-
tations. The appropriate substitution must be built into the precur-
sor of the nucleophilic carbene.
A useful synthesis of the
bis(propylthio)carbene precursor was achieved in 1998,4 however
this precursor can be difficult to isolate due to its instability
above 0 °C.
During this investigation, it was observed that a metal impurity
resulted in a small yield of [4+1] cycloadduct while using dimeth-
oxycarbene precursor. Previously, this product was only obtained
when using the bis(propylthio)carbene precursor. This observation
suggested the possibility of altering the reaction pathway by addi-
tion of a metal species rather than by changing the substituents on
the nucleophilic carbene.
oxy-D
3-1,3,4-oxadiazolines.3 Later, a method to synthesize the
bis(propylthio)carbene precursor was developed and this carbene
displayed reactivity significantly different from dimethoxycar-
bene.4 With these advances the use of nucleophilic carbenes in
synthesis has become more common in recent years.5
Nucleophilic carbenes, such as dimethoxycarbene, display a
reactivity pattern very different from their electrophilic counter-
An investigation commenced to identify a suitable metal
species to obtain synthetically useful yields of the [4+1] cycload-
duct. Various metals were screened for optimal reactivity
(Table 1) and it was found that the [4+1] adduct was obtained in
small yields. Control experiments demonstrated that in the ab-
sence of the metal, the hydantoin product was obtained in the
reaction of dimethoxycarbene precursor and phenyl isocyanate.
This was consistent with previous reports from the literature.7
Ultimately, the optimal conditions used sub-stoichiometric
amounts of Cu(acac)2/CuSO4 which afforded a 60% yield of the
[4+1] cycloadduct. With this result in hand, the scope of the reac-
tion was examined next.
parts, owing to the presence of p-donating substituents that stabi-
lize the singlet state.6 It is noteworthy that different species of
nucleophilic carbenes can react to form complementary products.
An excellent example of this variable reactivity is observed during
the reaction of aryl isocyanates with either dimethoxycarbene or
bis(propylthio)carbine (Fig. 1).
⇑
Corresponding author. Tel.: +1 989 964 4292; fax: +1 989 964 2796.
E-mail address: sbrouet@svsu.edu (S.A. Brouet).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.032

J. H. Rigby, S. A. Brouet / Tetrahedron Letters 54 (2013) 2542–2545
2543
Table 2
O
MeO OMe
[4+1] cycloaddition with Cu(acac)2/CuSO4 in chlorobenzene
N
N
C
C
O
O
toluene
reflux
N
N
N
O
MeO OMe
Cu(II) acac (15 mol%)
Cu(II) SO4 (8 mol%)
R4
R3
R1
N
OMe
O
N
O
OMe
A + B + C
N
Chlorobenzene
R2
PrS
SPr
PrS SPr
xylene
reflux
R4
R4
N
O
O
R3
R2
O
N
N
R4
R3
OMe
OMe
B =
SPr
R3
R2
N
N
PrS
A =
O
R2
MeO
MeO
N
O
Figure 1. Anticipated products of phenyl isocyanate and two different nucleophilic
carbene species.
OMe
MeO
OMe
MeO
OMe
OMe
R4
N
Table 1
C =
O
Exploration of Lewis acids to form a [4+1] product
R3
MeO
OMe
O
R2
MeO OMe
N
C O
Lewis Acid
Solvent
N
O
Structure
Entry
1
Yield A (%)
Yield B (%)
Yield C (%)
N
N
N
C
O
OMe
MeO
1A
60
0
0
1
O
Lewis acid
mol (%)
Solvent
Yield (%)
N3
O
2
73
0
0
Pb(OAc)4
SnCl4
TiCl4
Cu(OAc)2
Cu(OTf)2
CuCl2
Rh2(OAc)4
RuCl3
10
10
10
10
10
20
10
10
20
20
15
7
15
15/8
20
10
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Chlorobenzene
Chlorobenzene
Toluene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Toluene
Chlorobenzene
Toluene
Chlorobenzene
13
0
4
24
0
15
26
0
OMe
3
4
73
20
0
0
0
N3
N
C
O
ZnBr2
FeCl3
31
0
26
F3C
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2/CuSO4
Cu(trifluoroacac)2
AlCl3
29
35
31
60
15
23
OMe
N
O
C O
5
6
48
84
0
0
0
0
MeO
MeO
None
None
0 (80 hydantoin)
0 (65 hydantoin)
—
N3
Reagents and conditions: Reactions in toluene were performed at reflux for 4 h and
reactions in chlorobenzene were performed at reflux for 1 h at 0.04 M, with 4 equiv
of carbene precursor in all cases. Reagents were added and heated simultanueously.
OMe
O
N3
N
7
49
0
0
In each case the [4+1] cycloadduct was obtained (Table 2). Acti-
vated aromatic rings produced the best yields, up to 84%. Rings
with electron donating groups in non-resonance contributing posi-
tions led to yields in the 50% range. It is important to note that this
class of aromatic compounds fails to provide the [4+1] cycloadduct
in the absence of metal. Not surprisingly, deactivated rings re-
sulted in low yields of [4+1]. The presence of a metal species in-
creased the yield of the [4+1] cycloadduct in virtually every
example except entry 7 (Table 2).
NMe2
C
O
C
8
9
68
54
0
0
0
0
N
O
MeO
All reactions were conducted at reflux, for 1 h at 0.04 M. See Supplementary
materials for a general procedure. Acyl azides rearrange in situ to form isocyanates.
The most dramatic differences are seen for aromatic rings with
electron-donating groups in non-resonance contributing positions
(entries 5, 8, and 9). This type of aromatic ring forms [4+1] product
only upon addition of the metal (Tables 2 and 3). In these cases, the
products were different when no metal was present, depending on
the solvent used (Table 3).
reaction, 78% yield of the hydantoin product in toluene, and 41%
yield of a b-lactam product in chlorobenzene. This result was
striking since three different principle products could be obtained
through simple manipulations of reaction conditions.
In some cases (entries 5, 8, and 9) b-lactams were observed
when chlorobenzene was used as solvent. This product was re-
cently reported by this laboratory.8
A very interesting example is found in example 9 which
provided 54% yield of the [4+1] adduct in the metal mediated
A perplexing case is seen in entry 7 where a better yield of the
[4+1] cycloaddition product was obtained in the absence of the
metal. This can be explained by a potential coordination of copper
to the dimethylamino nitrogen, causing the group to be less acti-
vating, as is often observed in Friedel–Craft alkylations/acylations.

2544
J. H. Rigby, S. A. Brouet / Tetrahedron Letters 54 (2013) 2542–2545
Table 3
electrophilic aromatic substitution. This mechanism is believed
to operate in the reaction of bis(propylthio)carbene with aryl
isocyanates.7
Control experiments without the catalyst in toluene and in chlorobenzene
MeO OMe
R4
R3
R1
Solvent a or b
The role of copper in the reaction was carefully considered. As
has been established in the literature, Cu(acac)2 is used to catalyze
urethane formation via Lewis acid activation,9 but it is also used
to decompose diazonium species to form carbenoids.10 Other met-
als that also promoted formation of the [4+1] cycloadduct did lit-
tle to clarify the role of copper. Rhodium(II) acetate dimer, which
might be associated with carbenoid type mechanisms, promoted
the reaction.11 However, metals associated with Lewis acid coor-
dination also worked, such as AlCl3, and ZnBr2 (Table 1). Studies
were conducted to determine whether decomposition of the car-
bene precursor occurred at lower temperature in the presence
of the metal, but no reaction took place until the normal decom-
position temperature in toluene (ꢀ110 °C). Attempts to isolate or
trap the putative carbenoid were unsuccessful. These results,
combined with careful examination of the literature led to the
conclusion that, in this case, the role of Cu(acac)2 was most likely
that of a Lewis acid. Dimethoxycarbene is proposed to react with
electrophiles to form Zwitterionic species as intemediates.8,12 It
has also been proposed in the literature that copper preferentially
coordinates to the nitrogen of an isocyanate.9 This coordination
could increase the electrophilic nature of the isocyanate, increas-
ing the rate of attack on the isocyanate by the nucleophilic car-
bene. In addition, the metal may decrease the ability of the
nitrogen to participate in amide bond resonance in the presumed
1,3-dipole intermediates. This could cause the cation adjacent to
the carbonyl to become more electron deficient, facilitating elec-
trophilic aromatic substitution. The change in electronic character
of the isocyanate could disfavor the pathway leading to the
hydantoin product since, presumably, the nitrogen necessary for
attack on the second molecule of isocyanate would be complexed
with the Lewis acid.
N
O
A + B + C
N
R2
Solvent a = toluene
Solvent b = chlorobenzene
R4
R1 = Acyl azide or isocyanate
R4
R3
O
R4
OMe
OMe
R3
R2
B =
R3
R2
N
N
R2
A =
O
MeO
N
MeO
O
OMe
MeO
OMe
MeO
OMe
OMe
R4
R3
N
C =
O
R2
Entry
Structure
Yield A (%)
Solvent
Yield B (%)
Yield C (%)
Solvent
Solvent
a
b
a
b
a
b
N
O
C
O
1
2
0
Trace
80
0
60
0
0
0
0
N3
O
34
32
0
OMe
3
4
28
0
49
0
0
0
0
0
0
0
N3
In conclusion, new methodology has been developed using
straightfoward manipulations of reaction conditions to control
the outcome in the reaction of dimethoxycarbene with aryl
isocyanates, allowing new access to highly substituted isatin
derivatives.
N
C
O
32
48
F3C
OMe
N
O
C O
5
6
0
0
0
0
0
0
43
0
49a
MeO
MeO
Acknowledgment
The authors wish to thank the National Science Foundation for
their generous support of this research.
N3
43
52
0
OMe
O
Supplementary data
N3
N
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.032.
7
42
72
0
0
0
0
NMe2
C
O
C
8
9
0
0
0
0
45
78
47
0
0
15
References and notes
N
O
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a
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