The efficient synthesis of carbodiimides using a titanium imido complex

Article abstract of DOI:10.1016/j.tet.2010.09.073

An efficient rt synthesis of carbodiimides or ureas from the combination of a titanium imido complex 2 and a range of 12 aryl and aliphatic isocyanates is described. Control experiments suggest that carbodimide formation is via heterocumulene metathesis t

Full text of DOI:10.1016/j.tet.2010.09.073

Tetrahedron 66 (2010) 9182e9186
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The efficient synthesis of carbodiimides using a titanium imido complex
*
James C. Anderson , Rafael Bou-Moreno
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2010
Received in revised form 2 September 2010
Accepted 20 September 2010
Available online 24 September 2010
An efficient rt synthesis of carbodiimides or ureas from the combination of a titanium imido complex 2
and a range of 12 aryl and aliphatic isocyanates is described. Control experiments suggest that carbo-
dimide formation is via heterocumulene metathesis through a transient intermediate
h
2-ureato-N,O
metallacycle 8.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Imido
Titanium
Carbodiimide
Urea
Isocyanate
Heterocumulene metathesis
1. Introduction
have been used to generate carbodiimides via heterocumulene
metathesis. The reaction of stoichiometric zirconium imido com-
plexes with isocynates in sealed NMR tubes gave carbodiimides,
but only under high temperatures and long reaction times
Although carbodiimides are rare subunits in natural products,
they are precursors for many common and biologically active mo-
tifs, making them valuable functional groups for synthetic chem-
istry. The reactive carbodiimide group has been used in polymer
chemistry1 and can be readily converted into ureas,2 imido car-
bonates,3 imido amides,4 guanidines,5 oxazolidinone derivatives6
and aromatic and non aromatic heterocycles.7 Traditional
methods of preparation have involved the removal of H2X from
urea and its derivatives (X¼O, S, Se), but this requires harsh con-
ditions and reagents.8 Stoichiometric metal and metal catalysed
processes include the combination of potentially explosive alkyl
azides and isonitriles using catalytic Fe(CO)5.9 This was improved
by using PdCl2 as the catalyst for the addition of an amine to an
isonitrile, but required an extra oxidation to give a carbodimide.10,11
Other well known methods involve the treatment of isocyanates
with catalytic phosphine oxide.12 This two-step process generates
an imidophosphine with CO2 as a byproduct, followed by metath-
esis with the remaining isocyanate to generate a symmetrical car-
bodiimide and phosphine oxide as byproduct. This method can be
used for the synthesis of unsymmetrical carbodiimides by prior
formation of the imidophosphine, from Staudinger reduction of
azides or similarly high energy intermediates5b and reaction with
a different isocyanate. More recently transition metal complexes
(Scheme 1).13 The intermediate
h
2-ureato-N,O metallacycle 1 has
been characterized by single crystal X-ray crystallography.13b
N R'
R
R'
R
N
C
N
N
C
O
R
80-110 °C
~ 10 days
N
ZrLn
N
O
+
L
Zr
n
1
R'
Scheme 1.
There have been many other studies investigating the hetero-
cumulene metathesis of imido complexes,14 but none to give iso-
cyanates by treatment with carbodiimide. As part of a research
programme investigating the synthetically useful reactivity of
metal oxo and imido complexes with heterocumulenes15 we found
that treatment of Mountford’s easily prepared titanium imido
complex 216 with 4-chlorophenyl isocyanate 3 gave carbodiimide 4
in an unoptimised 39% isolated yield (Scheme 2). In this paper we
t
Bu
t
N C O
N C N
4
Bu
CH Cl
2
2
N
Ti
+
Cl
Py
Cl
3
5 h, rt
39%
Py
2
Cl
Cl
Scheme 2.
* Corresponding author. E-mail address: j.c.anderson@ucl.ac.uk (J.C. Anderson).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.073

J.C. Anderson, R. Bou-Moreno / Tetrahedron 66 (2010) 9182e9186
9183
describe the optimisation of this process for the efficient synthesis
Assuming these ureas were derived from the corresponding car-
bodiimides, their higher reactivity towards hydrolysis may be
explained by the release of steric strain upon protonation and for-
mation of the linear nitrilium ion. Acidic hydrolysis of the carbo-
diimides 6 to ureas 7 was generally a high yielding process, with the
exception of R¼Me2NPh, which was not isolated. During the iso-
lation of the carbodiimides 6 some product was inevitably lost in
the solvent extraction and some hydrolysis to urea could occur
during isolation and purification. To improve the overall yield of
urea formation a one pot reaction between titanium imido complex
2 and isocyanate 5 was quenched after 16 h with the same 2 M HCl
acetone mixture. This led to a much higher isolated yield of urea 7
in most cases. The yields for the 4-substituted phenyl derivatives
suggest that electron deficient aromatic isocyanates reacted with
higher yields than electron rich ones. The aliphatic isocyanates gave
a similar yield and additional steric hindrance gave lower yields,
with tBu isocyanate not giving any product under this one pot
protocol.
of carbodiimides and control experiments, which suggest the in-
termediacy of a h
2-ureato-N,O metallacycle complex.
2. Results and discussion
Optimisation studies determined that a homogeneous reaction,
such as that observed with CH2Cl2, gave the highest yields. The only
other useful solvent found was THF, which gave an identical yield.17
Higher reaction temperatures led to increased byproducts. At lower
temperatures the reaction was slow and longer reaction times
resulted in lower yields. The use of 0.5 and 2 M equiv of isocyanate
did not affect the yield of the reaction. Due to concerns that isolation
of the carbodiimide was complicated by hydrolysis to the urea, 1H
NMR experiments were conducted on a 1:1 mixture of isocyanate
and titanium imido complex in CDCl3 at rt in a sealed tube, in order
to ascertain the optimum reaction time. In less than 5 min all
starting materials were consumed and a major intermediate (85%)
and carbodiimide (15%) were observed. From these experiments it
was determined that the optimum time for reaction was 16 h, by
which time the majority of signals were due to carbodiimide.
Leaving the reaction for 24 h or longer resulted in unknown
byproduct formation at the expense of product formation. From
these experiments and those of others (Table 1) the consumption of
starting material was very fast, presumably to an imido-carbamate
metallocycle (like 7 vide infra). Collapse of the intermediate by
a retro-cycloaddition was much slower and presumably represents
the rate determining step of this transformation.
Observing the reaction with tert-butyl isocyanate (5 R¼tBu) in
a 1H NMR experiment showed only a constant w1:1 mixture of an
intermediate and carbodiimide product over 16 h with no impu-
rities [Scheme 3, intermediate (30%): 2 (43%): bis-N,N0-tert-butyl
carbodiimide (23%): corresponding oxo complex of 2 (3%)]. The 13C
NMR spectrum showed the presence of a quaternary carbon at
d
165.5 ppm, which we have tentatively assigned to the quaternary
imine carbon of the intermediate
h
2-ureato-N,O metallocycle 8. We
were unable to isolate this sensitive intermediate from the NMR
experiment in attempts to obtain single crystals for X-ray analysis.
t
Bu
N
Ti
Table 1
t
N Bu
O
Cl
Py
Cl
t
t
Preparation of carbodiimides and ureas from titanium imido complex and
isocyanates
2
Bu
Cl
Bu
Cl
N C O
5
Py
t
N
N
t
Bu
or
O
Cl
N Bu
Cl
Ti
Ti
Py
Py
O
t
Py
Py
2, CH Cl
Bu
t
2
2
2M HCl
8
9
R
Bu
N
N
N
C
6
C O
5
N
H
N
H
16 h, rt
Me CO
2
16 h, rt
Scheme 3.
R
R
7
Few similar compounds have been detected in the literature, but
some examples of carbamate and urea containing metallocycles
have been reported (Fig. 1). The chemical shift of the quaternary
carbon atoms are similar to that observed in our intermediate. It is
possible that the intermediate we observe for the tert-butyl iso-
cyanate experiment is the urea metallocycle 9 and that carbodii-
mide formation is fast from a transient 8.
R
Yield 6%
Yield 7%
Yield 7%
(two steps)
Yield 7%
(one-pot)
4-ClPh
46
49
64
80
da
76
68
38
85
db
db
db
93
94
98
65
da
89
76
89
98
61c
20c
16
43
46
63
52
d
63
93
85
77
da
82
67
78
87
60
35
da
4-EtO2CPh
4-O2NPh
4-MeOPh
4-Me2NPh
Bn
Ph(CH2)2
4-MePh
Cy
68
52
34
83
61
20
16
t
O
Ar
N Bu
O
t
t
N
O Mo
Bu
Cl
Bu
Cl
N
N
2,6-Me2Ph
2,6-iPr2Ph
tBu
t
or
O
Cl
N Bu
Cl
F C
3
Ti
Ti
F C
O
Py
Py
3
O
Py
+
Py
Ph P Me
3
11
7
CF
a
3
F C
3
Not isolated or detected.
Impure urea was isolated.
Obtained directly.
δ 165.5
b
c
δ 165.518
O
t
X
N
Bu
O
Ti
Tol
N
Tol
N
A series of isocyanates were then surveyed under these opti-
O
O
O
O
Ti
mized conditions to delineate the scope of the reaction (Table 1).
After isolation of the carbodiimides 6 they were hydrolysed to the
corresponding ureas 7 by treatment with 2 M aqueous HCl in an
equal volume of acetone at rt.
The isolated yield of the carbodiimide varied from moderate to
good, with higher yields obtained for aliphatic isocyanates. The
exception was for the most hindered aliphatic substituent R¼tBu
and we believe the low yield is due to isolation problems rather
than any severe steric interaction. For the very sterically hindered
substrates R¼2,6-Me2Ph and 2,6-iPr2Ph, carbodiimide could not be
isolated. Instead the corresponding ureas were obtained directly.
N
N
N
N
δ 169.520
X=O, δ 167.319
X=N-Tol, δ 168.7
Fig. 1. 13C NMR chemical shifts for known carbamate and urea metallocycles.18e20
The higher yields from the one pot experiment supported our
notion that we were losing carbodiimide during the isolation

9184
J.C. Anderson, R. Bou-Moreno / Tetrahedron 66 (2010) 9182e9186
procedure. However hydrolysis of the postulated intermediate like
8 would also provide a higher yield of urea.
4.2.1. N0-tert-Butyl-N-4-chlorophenyl carbodiimide. 4-Chlorophenyl
isocyanate (133 mg, 1.00 mmol) gave crude carbodiimide, which
was purified by flash column chromatography (hexanes, 10% Et2O/
hexanes) to give pure carbodiimide (117 mg, 46%) as a yellow oil. Rf
0.80 (50%, Et2O/hexanes); IR nmax (solution in CHCl3) 2965, 2930,
3. Conclusion
We have shown that the readily available titanium imido com-
plex 2 can form isolable carbodiimides when combined with an
equimolar amount of isocyanate at rt. Most aryl and aliphatic iso-
cyanates react efficiently with 2, except for the most sterically
hindered 2,6-iPr2Ph isocyanate and the basic dimethylaniline iso-
cayanate. Control experiments suggest that carbodiimide forma-
2857, 2130 (N]C]N), 1498, 1264 cmꢁ1
;
1H NMR
d
1.41 (9H, s, C
31.6 (C
(CH3)3), 7.02 (2H, m, m-CH), 7.25 (2H, m, o-CH); 13C NMR
d
(CH3)3), 57.7 (C(CH3)3), 124.3 (m-CH), 129.4 (o-CH),129.7 (C), 135.7
(C), 139.7 (C).
4.2.2. N0-tert-Butyl-N-4-ethoxycarbonylphenyl
carbodiimide. 4-
tion is via heterocumulene metathesis through
a
transient
Ethoxycarbonylphenyl isocyanate (191 mg, 1.00 mmol) gave crude
carbodiimide, which was purified by flash column chromatography
(hexanes, 10% Et2O/hexanes) to give pure carbodiimide (121 mg,
49%) as a white semi-solid. Rf 0.75 (50%, Et2O/hexanes); IR nmax
(solution in CHCl3) 2979, 2932, 2128 (N]C]N), 1709, 1602,
intermediate
h
2-ureato-N,O metallocycle 8. A practical and high
yielding one pot synthesis of ureas from 2 and isocyanates has been
devised. Further work is exploring the synthesis of other imido
complexes to be used in this transformation towards a catalytic
synthesis of carbodiimides from amines and CO2.
1278 cmꢁ1
;
1H NMR
d
1.38 (3H, t, J¼7.2, CH3CH2), 1.43 (9H, s, C
(CH3)3), 4.36 (2H, q, J¼7.2, CH3CH2O), 7.10 (2H, d, J¼8.4, o-CH), 7.97
4. Experimental
4.1. General
(2H, d, J¼8.4, m-CH); 13C NMR
d 14.3 (CH3CH2O), 31.6 (C(CH3)3), 58.0
(C(CH3)3), 60.9 (CH3CH2O), 123.0 (CHAr), 126.5 (CAr), 131.1 (CHAr),
134.5 (C), 146.0 (C), 166.2 (C]O). Anal. calcd for C14H18N2O2: C 68.5,
H 7.5, N 11.1, found C 68.3, H 7.4, N 11.4%.
All experimental procedures unless otherwise stated were car-
ried out under an atmosphere of dry, oxygen free nitrogen. Those
involving metal complexes were performed using standard Schlenk
techniques. All glassware was rigourously flame-dried prior to use
and a nitrogen atmosphere was maintained throughout the pro-
cess. Degassed solutions and solvents were prepared by repeating
a cycle of solidifying with a liquid nitrogen bath, applying vacuum
(30 s) and melting three times. NMR experiments were prepared
using a glove box and pre-dried Young’s Tap NMR tubes. Reactions
at rt imply temperatures in the range 20e25 ꢀC. Reaction solvents
were purchased as HPLC grade and dried by passing them through
activated alumina towers (dichloromethane, hexanes and toluene)
or activated alumina and CaO towers (THF and Et2O). All reagents
were purchased and used without further purification unless oth-
erwise stated. All amines, anilines, pyridines and phenols were
redistilled or recrystallised according to literature procedures.21
Column chromatography was performed using BDH 60 silica gel
in the indicated solvent. Chromatography solvents were used as
supplied without further purification. Column chromatography
was monitored by thin layer chromatography (TLC) performed on
Polgram SIL G/UV254 plastic backed plates in the indicated solvent
and were visualised by combination of ultraviolet light (254 nm)
and a visualising dip of potassium permanganate. Melting points
are uncorrected. 1H NMR and 13C NMR spectra were recorded at
298 K in CDCl3, unless otherwise stated.
4.2.3. N0-tert-Butyl-N-4-nitrophenyl carbodiimide. 4-Nitrophenyl
isocyanate (164 mg, 1.00 mmol) gave crude carbodiimide, which
was purified by flash column chromatography (hexanes, 10% Et2O/
hexanes) to give pure carbodiimide (140 mg, 64%) as a pale brown
semi-solid. Rf 0.81 (50%, Et2O/hexanes); IR nmax (solution in CHCl3)
2964, 2928, 2860, 2132 (N]C]N), 1602, 1516, 1342, 1261 cmꢁ1; 1H
NMR
d
1.46 (9H, s, C(CH3)3), 7.15 (2H, m, o-CH), 8.17 (2H, m, m-CH);
31.6 (C(CH3)3), 58.6 (C(CH3)3), 123.5 (o-CH), 125.3 (m-
13C NMR
d
CH), 148.8 (C), 191.8 (C), missing quaternary carbon.
4.2.4. N0-tert-Butyl-N-4-methoxyphenyl carbodiimide. 4-Methox-
yphenyl isocyanate (149 mg, 1.00 mmol) gave crude carbodiimide,
which was purified by flash column chromatography (hexanes, 10%
Et2O/hexanes) to give pure carbodiimide (163 mg, 80%) as a yellow
semi-solid. Rf 0.73 (50%, Et2O/hexanes). 1H NMR
d 1.40 (9H, s, C
(CH3)3), 3.79 (3H, s, OCH3), 6.83 (2H, d, J¼8.9, o-CH), 7.03 (2H, d,
J¼8.9, m-CH). All other spectroscopic data were in agreement with
that previously reported.22
4 . 2 . 5 . N 0- t e r t - B u t yl - N - 4 - ( N 00- d i m e t h y l a m i n o ) p h e n yl
carbodiimide. 4-(N0-Dimethylamino)phenyl isocyanate (162 mg,
1.00 mmol) gave crude carbodiimide, which was purified by flash
column chromatography (hexanes, 10% Et2O/hexanes) to give pure
carbodiimide (104 mg, 48%) as a yellow semi-solid. Rf 0.51 (66%,
Et2O/hexanes); IR nmax (solution in CHCl3) 2974, 2361, 2113 (N]C]
4.2. General procedure for the synthesis of carbodiimides (6)
from titanium imido complex 2 and isocyanates (5)
N), 1603, 1519, 1367, 1261, 1192, 1098 cmꢁ1; 1H NMR
(CH3)3), 2.93 (6H, s, N(CH3)2), 6.68 (2H, m, m-CH), 7.01(2H, m, o-
CH); 13C NMR
31.6 (C(CH3)3), 41.0 (N(CH3)2), 57.0 (C(CH3)3), 113.6
(m-CH), 123.9 (o-CH), 129.4 (ipso-C), 138.2 (N]C]N), 148.3 (p-C).
d 1.39 (9H, s, C
d
To a clear bright orange solution of dichloro tert-butylimido
bispyridine titanium(IV) (2, 1 mmol) in dry dichloromethane
(15 mL) at rt under a N2 atmosphere, a solution of freshly prepared
isocyanate (5, 1 mmol) in dry dichloromethane (5 mL) was added
dropwise over approximately 30 s. The bright orange solution im-
mediately turned to a black mixture. After stirring for 16 h the
solvent was reduced to approximately 3 mL in vacuo and triturated
with dry toluene (20 mL). The solvent was again reduced to ap-
proximately 3 mL and triturated with dry hexanes (20 mL). All
volatiles were removed in vacuo to leave crude carbodiimide as
a yellow oil. Purification by flash column chromatography pro-
duced pure carbodiimide 6. To minimise degradation of the car-
bodiimide to urea due to the acidity of silica gel, chromatography
was performed quickly using a short column of silica.
4.2.6. N-Benzyl-N0-tert-butyl
carbodiimide. Benzyl
isocyanate
(133 mg, 1.00 mmol) gave crude carbodiimide, which was purified
by flash column chromatography (hexanes, 10% Et2O/hexanes) to
give pure carbodiimide (143 mg, 76%) as a yellow oil. Rf 0.87 (50%,
Et2O/hexanes). 1H NMR
d 1.16 (9H, s, C(CH3)3), 4.35 (2H, s, CH2Ph),
7.28e7.41 (5H, m, CHAr). All other spectroscopic data were in
agreement with that previously reported.2b
4.2.7. N0-tert-Butyl-N-2-phenylethyl carbodiimide. 2-Phenylethyl
isocyanate (147 mg, 1.00 mmol) gave crude carbodiimide, which
was purified by flash column chromatography (hexanes, 10% Et2O/
hexanes) to give pure carbodiimide (138 mg, 68%) as a colourless
oil. Rf 0.83 (50%, Et2O/hexanes); IR nmax (solution in CHCl3) 2927,
NB MS data could not be obtained.

J.C. Anderson, R. Bou-Moreno / Tetrahedron 66 (2010) 9182e9186
9185
2870, 2108 (N]C]N), 1679, 1366, 1185, 1083, 1032 cmꢁ1; 1H NMR
1.21 (9H, s, C(CH3)3), 2.89 (2H, t, J¼7.3, CH2Ph), 3.47 (2H, t, J¼7.3,
CH2N), 7.20e7.34 (5H, m, CHAr); 13C NMR
31.2 (C(CH3)3), 37.8
(CH2Ph), 48.2 (CH2N), 55.1 (C(CH3)3), 126.5 (CHAr), 128.5 (CHAr),
128.8 (CHAr), 138.9 (ipso-CAr), 139.9 (N]C]N). Anal. calcd for
C12H18N2: C 77.2, H 9.0, N 13.8, found C 76.9, H 9.0, N 13.4%.
dm, J¼9.2, m-CH). All other spectroscopic data were in agreement
d
with that previously reported.25
d
4.3.4. N0-tert-Butyl-N-4-methoxyphenyl
urea. 4-methoxyphenyl
carbodiimide (100 mg, 0.49 mmol) gave crude urea, which was
purified by flash column chromatography (Et2O/hexanes, 20e50%)
to give pure urea (70 mg, 65%) as a white solid mp 140e143 ꢀC (lit.22
4.2.8. N0-tert-Butyl-N-4-methylphenyl
carbodiimide. 4-Methyl-
142e145 ꢀC); Rf 0.40 (66%, Et2O/hexanes). 1H NMR
d 1.34 (9H, s, C
phenyl isocyanate (133 mg, 1.00 mmol) gave crude carbodiimide,
which was purified by flash column chromatography (hexanes, 10%
Et2O/hexanes) to give pure carbodiimide (71 mg, 68%) as a yellow
(CH3)3), 3.77 (3H, s, OCH3), 4.88 (1H, br s, NH), 6.53 (1H, br s, NH),
6.83 (2H, dm, J¼6.8, o-CH), 7.17 (2H, dm, J¼6.8, m-CH). All other
spectroscopic data were in agreement with that previously
reported.22
oil. Rf 0.84 (50%, Et2O/hexanes). 1H NMR
d 1.40 (9H, s, C(CH3)3), 2.32
(3H, s, CH3Ph), 6.99 (2H, dm, J¼8.3, o-CH), 7.10 (2H, dm, J¼8.3, m-
CH). All other spectroscopic data were in agreement with that
previously reported.8c
4.3.5. N-Benzyl-N0-tert-butyl urea. 4-Benzyl carbodiimide (74 mg,
0.39 mmol) gave crude urea, which was purified by flash column
chromatography (Et2O/hexanes, 20e50%) to give pure urea (78 mg,
89%) as a white solid mp 109e112 ꢀC (lit.26 110e112 ꢀC); Rf 0.25
4.2.9. N0-tert-Butyl-N-cyclohexyl carbodiimide. Cyclohexyl iso-
cyanate (125 mg, 1.00 mmol) gave crude carbodiimide, which was
purified by flash column chromatography (hexanes, 10% Et2O/
hexanes) to give pure carbodiimide (153 mg, 80%) as a yellow oil. Rf
(66%, Et2O/hexanes). 1H NMR
d 1.33 (9H, s, C(CH3)3), 4.30 (2H, d,
J¼5.6CH2Ph), 4.45 (0.96H, br s, NH), 4.73 (0.94H, m, NH), 7.23e7.36
(5H, m, CHAr). All other spectroscopic data were in agreement with
that previously reported.26
0.83 (50%, Et2O/hexanes). 1H NMR
d 1.19e1.40 (16H, m, CH3, CH2),
1.54e1.62 (2H, m, CH2), 1.70e1.76 (2H, m, CH2), 1.90e1.98 (2H, m,
CH2), 3.15e3.42 (1H, m, CHN). All other spectroscopic data were in
agreement with that previously reported.23
4.3.6. N0-tert-Butyl-N-2-phenylethyl urea. 2-Phenylethyl carbodii-
mide (80 mg, 0.40 mmol) gave crude urea, which was purified by
flash column chromatography (Et2O/hexanes, 20e50%) to give
pure urea (67 mg, 76%) as a white solid mp 73e74 ꢀC (lit.27
4.3. General procedure for the hydrolysis of carbodiimides 6
to ureas 7
70e71 ꢀC); Rf 0.20 (66%, Et2O/hexanes). 1H NMR
d 1.33 (9H, s, C
(CH3)3), 2.82 (2H, t, J¼6.9, CH2Ph), 3.41 (2H, q, J¼6.9, CH2N), 4.30
(0.94H, br s, NH), 4.37 (0.94H, br s, NH), 7.19e7.36 (5H, m, CHAr). All
other spectroscopic data were in agreement with that previously
reported.27
To a colourless solution of carbodiimide 6 (from above) in
dichloromethane (20 mL) and acetone (20 mL), 2 M HCl (aq)
(20 mL) was added. The clear byphasic mixture was stirred vigor-
ously for other 16 h before being neutralised with NaHCO3. The two
phases were separated and the aqueous layer was extracted with
dichloromethane (2ꢂ20 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purification by flash
column chromatography produced pure urea 7.
4.3.7. N0-tert-Butyl-N-4-methylphenyl urea. 4-Methylphenyl car-
bodiimide (55 mg, 0.29 mmol) gave crude urea, which was pu-
rified by flash column chromatography (Et2O/hexanes, 20e50%)
to give pure urea (53 mg, 89%) as a white solid mp 184e186 ꢀC; Rf
0.20 (66%, Et2O/hexanes); IR nmax (solution in CHCl3) 3429, 3011,
4.3.1. N0-tert-Butyl-N-4-chlorophenyl urea. 4-Chlorophenyl carbo-
diimide (76 mg, 0.35 mmol) gave crude urea, which was purified by
flash columnchromatography(Et2O/hexanes,10e20%to 50%) to give
pure urea (76 mg, 93%) as awhite solid mp 190e193 ꢀC (lit.24); Rf 0.28
1669 (C]O), 1514, 1453, 1393, 1311 cmꢁ1
;
1H NMR
d
1.36 (9H, s, C
(CH3)3), 2.31 (3H, s, CH3Ph), 4.74 (1H, br s, NH), 6.25 (1H, br s,
NH), 7.08e7.16 (4H, m, CHAr); 13C NMR
20.8 (PhCH3), 29.4 (C
d
(CH3)3), 50.7 (C(CH3)3), 121.7 (m-CH), 129.9 (o-CH), 133.6 (p-CH),
136.1 (ipso-C), 155.2 (C]O); ESI/MS: m/z 229.1316 (MþNa, 11%);
HRMS: found (calcd for C12H18N2ONa) m/z 229.1316 (229.1311).
Anal. calcd for C12H18N2O: C 69.8, H 8.8, N 13.6, found C 69.4, H
8.8, N 13.4%.
(50%, Et2O/hexanes). 1H NMR
d 1.38 (9H, s, C(CH3)3), 4.60 (0.9H, br s,
NH), 6.22 (0.9H, br s, NH), 7.24 (4H, s, CHAr). All other spectroscopic
data were in agreement with that previously reported.24
4.3.2. N0-tert-Butyl-N-4-ethoxycarbonyphenyl
urea. 4-Ethox-
ycarbonylphenyl carbodiimide (117 mg, 0.48 mmol) gave crude
urea, which was purified by flash column chromatography (Et2O/
hexanes, 20e50%) to give pure urea (121 mg, 94%) as a white solid
mp 134e136 ꢀC; Rf 0.10 (50%, Et2O/hexanes); IR nmax (solution in
4.3.8. N0-tert-Butyl-N-cyclohexyl urea. Cyclohexyl carbodiimide
(50 mg, 0.28 mmol) gave crude urea, which was purified by flash
column chromatography (Et2O/hexanes, 20e50%) to give pure urea
(55 mg, 98%) as a white solid mp 223e224 ꢀC (lit.28 226 ꢀC); Rf 0.33
CHCl3) 3440, 3013, 2970, 1708 (C]O), 1506, 1283, 1176 cmꢁ1
;
1H
(66%, Et2O/hexanes). 1H NMR
d 1.00e1.50 (16H, m), 1.55e1.61 (1H,
NMR
J¼7.1, CH3CH2O), 5.47 (1H, br s, NH), 7.37 (2H, m, o-CH), 7.58 (1H, br
s, NH), 7.90 (2H, m, m-CH); 13C NMR
14.4 (CH3CH2O), 29.3 (C
d
1.35 (9H, s, C(CH3)3), 1.37 (3H, t, J¼7.1, CH3CH2O), 4.34 (2H, q,
m, CH), 1.65e1.72 (2H, m, CH2), 1.87e1.96 (2H, m, CH2), 3.40e3.53
(1H, m, NCH), 4.30 (2H, br s, NH). All other spectroscopic data were
in agreement with that previously reported.28
d
(CH3)3), 50.8 (C(CH3)3), 60.9 (CH3CH2O), 117.8 (o-CH), 123.6 (ipso-C),
130.9 (m-CH), 144.1 (p-C), 154.6 (C]O, urea), 166.9 (C]O, ester);
ESI/MS: m/z 265.1547 (MþH, 4%), 287.1357 (MþNa, 100%); HRMS:
found (calcd for C14H21N2O3) m/z 265.1547 (265.1547). Anal. calcd
for C14H20N2O3: C 63.6, H 7.6, N 10.6, found C 63.2, H 7.7, N 10.2%.
4.3.9. N0-tert-Butyl-N-2,6-dimethylphenyl
urea. 2,6-Dimethyl-
phenyl isocyanate (147 mg, 1.00 mmol) gave crude urea, which was
purified by flash column chromatography (Et2O/hexanes, 20e50%)
to give pure urea (133 mg, 61%) as a white solid mp 169e171 ꢀC; Rf
0.13 (50%, Et2O/hexanes); IR nmax (solution in CHCl3) 3344, 3289,
2963, 2922, 1635 (C]O), 1557, 1450, 1362, 1278, 1215, 767 cmꢁ1; 1H
4.3.3. N-tert-Butyl-N-4-nitrophenyl urea. 4-Nitrophenyl carbodii-
mide (48 mg, 0.22 mmol) gave crude urea, which was purified by
flash column chromatography (Et2O/hexanes, 20e50%) to give pure
urea (51 mg, 98%) as a white solid mp 142e143 ꢀC (lit.24); Rf 0.10
NMR
d
1.29 (9H, s, C(CH3)3), 2.30 (6H, s, CH3Ph), 4.08 (1H, br s, NH),
18.3 (CH3Ph),
5.45 (1H, br s, NH), 7.09e7.14 (3H, m, CHAr); 13C NMR
d
29.3 (C(CH3)3), 50.4 (C(CH3)3), 127.7 (p-CH), 128.8 (m-CH), 134.3
(ipso-C), 137.1 (o-C), 155.8 (C]O); ESI/MS: m/z 221.1667 (MþH, 7%),
243.1480 (MþNa, 50%); HRMS: found (calcd for C13H21N2O) m/z
(50%, Et2O/hexanes). 1H NMR
d
1.41 (9H, s, C(CH3)3), 4.78 (0.98H, br
s, NH), 6.73 (0.97H, br s, NH), 7.50 (2H, dm, J¼9.2, o-CH), 8.16 (2H,

9186
J.C. Anderson, R. Bou-Moreno / Tetrahedron 66 (2010) 9182e9186
221.1667 (221.1648); HRMS: found (calcd for C13H20N2ONa) m/z
References and notes
243.1480 (243.1468).
1. Tang, H.-Z.; Novak, B. M.; He, J.; Polavarapu, P. L. Angew. Chem., Int. Ed. 2005, 49,
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4.3.10. N0-tert-Butyl-N-2,6-diisopropylphenyl
urea. 2,6-Diisopro-
ꢀ
ꢀ
2. (a) Garcõa-Moreno, M. I.; Mellet, C. O.; Fernandez, J. M. C. Eur. J. Org. Chem.
2004, 1803; (b) Volonteiro, A.; Arellano, C. R.; Zanda, M. J. Org. Chem. 2005, 70,
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3. Baimikhametov, F. Z.; Zheltukin, S. N.; Ignat’eva, S. N.; Balueva, A. S.; Nikonov,
G. N.; Sinyashin, O. G. Russ. J. Gen. Chem. 2003, 73, 1691.
4. (a) Heo, J. H.; Seo, H. N.; Choe, Y. J.; Kim, S.; Oh, C. R.; Kim, Y. D.; Rhim, H.; Choo,
D. J.; Kim, J.; Lee, J. Y. Bioorg. Med. Chem. Lett. 2008, 18, 3899; (b) Yu, R. T.; Rovis,
T. J. Am. Chem. Soc. 2008, 130, 3262.
5. (a) Liu, M.-G.; Hu, Y.-G.; Ding, M.-W. Tetrahedron 2008, 64, 9052; (b) Seo, H. N.;
Choi, J. Y.; Choe, Y. J.; Kim, Y.; Rhim, H.; Lee, S. H.; Kim, J.; Joo, D. J.; Lee, J. Y.
Bioorg. Med. Chem. Lett. 2007, 17, 5740; (c) Tassoni, E.; Giannessi, F.; Brunetti, T.;
pylphenyl isocyanate (203 mg, 1.00 mmol) gave crude urea, which
was purified by flash column chromatography (Et2O/hexanes,
20e50%) to give pure urea (55 mg, 35%) as a white solid mp
178e179 ꢀC; Rf 0.39 (50%, Et2O/hexanes). 1H NMR
d 1.15e1.25
(12H, br s, CH(CH3)2), 1.27 (9H, s, C(CH3)3), 3.32 (2H, sept, J¼6.9,
CHMe2), 7.20 (2H, d, J¼7.7, m-CH), 7.33 (1H, t, J¼7.7, o-CH). All
other spectroscopic data were in agreement with that previously
reported.29
€
Pessotto, P.; Renzulli, M.; Travagli, M.; Rajamaki, S.; Prati, S.; Dottori, S.; Corelli,
F.; Cabri, W.; Carminati, P.; Botta, M. J. Med. Chem. 2008, 51, 3073; (d) Aguilar,
M.; Prez, P. D.; Garcõa-Moreno, M. I.; Fernandez, J. M. G. J. Org. Chem. 2008, 73,
4.3.11. Bis-N,N0-tert-butyl urea. tert-Butyl isocyanate (99 mg,
1.00 mmol) gave crude urea, which was purified by flash column
chromatography (Et2O/hexanes, 20e50%) to give pure urea (27 mg,
16%) as a white solid mp 238e240 ꢀC (lit.30 238e239 ꢀC); Rf 0.14
ꢀ
ꢀ
1995; (e) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org. Chem. 2007,
72, 6763; (f) Crimmin, M. R.; Barret, A. M.; Hill, M. S.; Hitchcock, P. B.; Proco-
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Dong, C.; Alper, H. Chem.dEur. J. 2004, 10, 6058.
(50%, Et2O/hexanes). 1H NMR
d 1.32 (9H, s, C(CH3)3),4.05 (1H. br s,
NH). All other spectroscopic data were in agreement with that
7. (a) Gushchin, P. V.; Bokach, N. A.; Luzyanin, K. V.; Nazarov, A. A.; Haukka, M.;
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Hofmann, G. A.; Kirkpatrick, R. B.; Jason, C. A.; Jonhson, R. K.; Ma, C.; Mattern,
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Veber, D. F.; Xiong, W. C.; Yamamoto, Y.; Yamashita, K.; Yang, G.; Thompson, S. C.
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previously reported.30
4.4. General procedure for the synthesis of ureas (7) from
titanium imido complex 1 and isocyanates (6)
ꢀ
ꢀ
Org. Chem. 2007, 72, 6878; (e) Alajarõn, M.; Bonillo, B.; Ortõn, M.-M.; Andrada,
P. S.; Vidal, A. Org. Lett. 2006, 8, 5645; (f) Vorobiov, A. N.; Gaponik, P. N.; Petrov,
P. T.; Ivashkevich, O. A. Synthesis 2006, 8, 1307.
To a clear bright orange solution of dichloro tert-butylimido
bispyridine titanium(IV) (2, 350 mg, 1 mmol) in dry dichloro-
methane (15 mL) at rt under a N2 atmosphere, a solution of freshly
prepared isocyanate (1 mmol) in dry dichloromethane (5 mL) was
added dropwise over approximately 30 s. The bright orange so-
lution turned immediately to a black mixture. After stirring the
black mixture for 16 h, 2 M HCl (aq) (20 mL) and acetone (20 mL)
were added. The clear byphasic mixture was stirred vigorously for
other 16 h before being neutralised with NaHCO3. The two phases
were separated and the aqueous layer was extracted with
dichloromethane (2ꢂ20 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Purification by flash
column chromatography produced pure ureas as previously
described.
8. (a) Lee, T. C. P.; Wragg, R. T. J. Appl. Polym. Sci. 1970, 14, 115; (b) Kim, S.; Yi, K. Y.
Tetrahedron Lett. 1985, 26, 1661; (c) Koketsu, M.; Suzuki, N.; Ishihara, H. J. Org.
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9. Saegusa, T.; Ito, Y.; Shimizu, T. J. Org. Chem. 1970, 35, 3995.
10. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1975, 40, 2981.
11. Pri-Bar, I.; Schwartz, J. Chem. Commun. 1997, 347.
12. Campbell, T. W.; Monagle, J. J.; Foldi, V. S. J. Am. Chem. Soc. 1961, 84, 3673.
13. (a) Walsh, P. J.; Hollander, F. J.; Bergman, R. G. Organometallics 1993, 12, 3705;
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14. (a) For selected examples see Guiducci, A. E.; Cowley, A. R.; Skinner, M. E.;
Mountford, P. J. Chem. Soc., Dalton Trans. 2001, 1392; (b) Hsu, S.-H.; Chang, J.-C.;
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Wang, H.; Chan, H.-S.; Xie, Z. Organometallics 2005, 24, 3772; (e) Kilgore, U. J.;
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1775 and references therein.
15. (a) Anderson, J. C.; Blake, A. J.; Bou Moreno, R.; Raynel, G.; van Slageren, J. J.
Chem. Soc., Dalton Trans. 2009, 9153; (b) Anderson, J. C.; Smith, N. M.; Rob-
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Middleditch, M.; Anderson, J. C.; Blake, A. J.; Wilson, C. S. Inorg. Chem. 2007, 46,
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17. Reactions in Et2O, PhMe and hexane were heterogeneous and gave no reaction.
18. Alexander, J. B.; Schrock, R. R.; Davis, W. M.; Hultzsch, K. C.; Hoveyda, A. H.;
Houser, J. H. Organometallics 2000, 19, 3700.
4.4.1. Reaction of titanium imido complex 2 with tert-butyl iso-
cyanate (5, R¼tBu). To a clear bright orange solution of tert-buty-
limido dichloro bispyridine titanium(IV) (2, 25.0 mg,
0.0072 mmol) in CDCl3 (0.4 mL) in a Young’s Tap NMR tube was
added a solution of tert-butyl isocyanate (5, R¼tBu) (7.00 mg,
0.007 mmol) in CDCl3 (0.35 mL). The clear solution immediately
turned to a black suspension and NMR spectra were recorded. A
mixture of metallocycle 8 or 9 (30%): titanium imido complex 2
(43%): bis-N,N0-tert-butyl carbodiimide (23%): corresponding oxo
19. Dubberley, S. R.; Friedrich, A.; William, D. S.; Mountford, P.; Radius, U. Chem.
complex of 2 (3%). 1H NMR data for metallocycle 8 or 9:
d 1.44
dEur. J. 2003, 9, 3634.
20. Blake, A. J.; McInnes, J. M.; Mountford, P.; Nikonov, G. I.; Swallow, D.; Watkin,
D. J. J. Chem. Soc., Dalton Trans. 1999, 379.
21. Perrin, D.D.; Armarego, W.L.F.; Perrin, D.R. Purification of Laboratory Chemicals,
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J. Am. Chem. Soc. 2001, 123, 6179.
(18H, s, C(CH3)3), 7.40e7.47 (4H, m, 3-CH), 7.80e7.90 (2H, m, 4-
CH), 9.07 (4H, app. dd, J¼6.4, 1.6, 2-CH); 13C NMR
d 31.1 (C(CH3)3),
62.9 (C(CH3)3), 124.4 (3-CH), 139.5 (4-CH), 151.8 (2-CH), 165.5 (C]
N or C]O).
24. Braverman, S.; Chevkinsky, M.; Kedrova, L.; Reisdman, A. Tetrahedron Lett. 1999,
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Acknowledgements
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5951.
We thank the University of Nottingham, University College
London and Flexible Foam Research Ltd for funding, Mr. T. Hol-
lingworth, Mr. D. Hooper, Mr. J. Hill and Dr. L. Harris for providing
mass spectra and Dr. T. Liu and Ms G. Maxwell for microanalytical
data.