Ti-catalyzed reactions of hindered isocyanates with alcohols

Article abstract of DOI:10.1021/jo050712d

Highly hindered and sensitive isocyanates react with alcohols under mild catalysis by titanium tetra-t-butoxide to give high yields of the corresponding carbamates.

Full text of DOI:10.1021/jo050712d

even with primary alcohols.9 Hydrochloric acid7a and
copper(I) chloride6,9b are two frequently utilized acid
catalysts for that reaction. The latter, however, is unable
to catalyze the reaction between hindered isocyanates
and alcohols while hydrochloric acid is not tolerant of
many functional groups. Alcoholates add to isocyanates
but they often give low yields of carbamate and the
strongly basic conditions may also be a problem with
other functional or protective groups.
Ti-Catalyzed Reactions of Hindered
Isocyanates with Alcohols
Claude Spino,* Marc-Andre´ Joly, Ce´drickx Godbout, and
Me´lissa Arbour
De´partement de Chimie, Universite´ de Sherbrooke,
2500 Boul. Universite´, Sherbrooke,
Que´bec, J1K 2R1, Canada
We have recently developed a synthetic route to R,R-
dialkylated amino acids that utilizes the Curtius rear-
rangement of an acyl azide to construct the pivotal
nitrogen-carbon bond (cf. Scheme 1).10 The nature of the
targeted structures was such that the isocyanate inter-
mediates 2 were highly hindered, acid-sensitive, and did
not react with alcohols in the absence of a catalyst. For
example, 2a and 2b partly decompose upon simple silica
gel column chromatography. Presumably, the tertiary
and allylic nature of the isocyanate leads to the facile
formation of elimination products. Unfortunately, cu-
prous chloride was incapable of catalyzing their reaction
with alcohols, and hydrochloric acid as well as many
other Lewis acids, including zinc chloride, titanium
tetrachloride, and tin tetrachloride, were either ineffec-
tive or led to elimination and other decomposition
products.
We surmised that a catalyst that would be both mildly
Lewis acidic and yet contain ligands capable of acting as
a base would procure an elegant solution to this problem.
In our search for a better catalyst, we initially found that
titanium isopropoxide gave good results. Indeed, it was
able to catalyze the reaction between isocyanates 2a or
2b and 9-fluorenyl methanol (9-Fm) (Scheme 1).11
However, varying quantities of unwanted carbamates
4a and 4b were formed alongside the desired ones. The
source of 2-propanol was obviously the catalyst itself, the
2-propanol being released by fast ligand exchange with
the surrounding alcohol molecules or by the reaction with
the isocyanate.12 The amount of 4 was indeed propor-
tional to the amount of catalyst used in the reaction. In
some cases, it was not possible to totally suppress this
unwanted reaction even when a large excess of 9-Fm was
used. This indicated that the addition of 2-propanol to
the isocyanate was competitive with that of 9-Fm.
A quick comparison of this mildly Lewis acidic catalyst
with other frequently used catalysts seemed to indicate
that it was similar or better than most in terms of the
claude.spino@usherbrooke.ca
Received April 9, 2005
Highly hindered and sensitive isocyanates react with alco-
hols under mild catalysis by titanium tetra-t-butoxide to give
high yields of the corresponding carbamates.
Isocyanates1 are often stable intermediates in rear-
rangement reactions such as the Curtius or Hofmann
rearrangements.2 Such rearrangements are used to cre-
ate a nitrogen-carbon bond with retention of stereo-
chemistry at carbon, and they have been used, for
instance, to make R- and â-amino acids3 and 3-amino
sugars.4
Frequently, the isocyanate is further reacted with an
alcohol or an amine to produce a carbamate or a urea,
respectively, with water to produce a primary amine, or
with organometallics to produce amides. The carbamate
or urea is normally used as a protective group for the
amine. The reactions between many unhindered isocy-
anates and primary alcohols proceed without catalysis
at temperatures ranging from 25 to 100 °C.5 However,
reactions of secondary and tertiary alcohols may require
catalysis by Lewis acids,6 Brønsted acids,7 or conversion
to the corresponding alkoxide.1a,8 In addition, some
hindered and/or sensitive isocyanates do not react readily
(1) (a) Braunstein, P.; Nobel, D. Chem. Rev. 1989, 89, 1927-1945.
(b) Ozaki, S. Chem. Rev. 1972, 72, 457-496.
(2) (a) Shiori, Y. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 795. (b) Smith,
M. B.; March, J. In Advanced Organic Chemistry, 5th ed.; Wiley-
Interscience: New York, 2001.
(3) See, for example: (a) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.;
Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. J. Org. Chem. 1999, 64,
6411-6417. (b) Braibante, M. E. F.; Braibante, H. S.; Costenaro, E.
R. Synthesis 1999, 943-946. (c) Charette, A. B.; Coˆte´, B. J. Am. Chem.
Soc. 1995, 117, 12721-12732.
(4) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62, 5864-
5872.
(8) (a) Bailey, W. J.; Griffith, J. R. J. Org. Chem. 1978, 43, 2690-
2692. (b) Yu, Q.-S.; Brossi, A. Heterocycles 1988, 27, 745-750. (c)
Mehrotra, R. C.; Rai, A. K.; Bohra, R. J. Inorg. Chem. 1974, 36, 1887-
1888. (d) Bloodworth, A. J.; Davies, A. G. J. Chem. Soc. 1965, 5238-
5244.
(9) See, for example: (a) Kinsman, A. C.; Kerr, M. A. J. Am. Chem.
Soc. 2003, 125, 14120-14125. (b) Miller, J. A.; Hennessy, E. J.;
Marshall, W. J.; Scialdone, M. A.; Nguyen, S. T. J. Org. Chem. 2003,
68, 7884-7886.
(5) (a) Raspoet, G.; Nguyen, M. T.; McGarraghy, M.; Hegarty, A. F.
J. Org. Chem. 1998, 63, 6878-6885. (b) Relative rates of uncatalyzed
reaction of primary, secondary, and tertiary alcohols are available in
Davis, T. L.; Farnum, J. M. J. Am. Chem. Soc. 1934, 56, 883-885.
(6) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131-132.
(7) (a) Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M. Synthesis 1991,
787-788. (b) Lammiman, S. A.; Satchell, R. S. J. Chem. Soc., Perkin
Trans. 2 1974, 877-883.
(10) (a) Spino, C.; Godbout, C.; Beaulieu, C.; Harter, M.; Mwene-
Mbega, T. M.; Boisvert, L. J. Am. Chem. Soc. 2004, 126, 13312-13319.
(b) Spino, C.; Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106-12107.
(11) These procedures are described in the Supporting Information
accompanying ref 10b.
(12) The stoichiometric reaction between Ti(OR)4 and isocyanates
to form insertion products was shown to be reversible. Meth-Cohn, O.;
Thorpe, D.; Twitchett, H. J. J. Chem. Soc. C 1970, 132-135.
10.1021/jo050712d CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005
6118
J. Org. Chem. 2005, 70, 6118-6121

TABLE 2. Efficiency of Ti(Ot-Bu)4 as Catalyst in the
SCHEME 1. Ti(Oi-Pr)4 Catalyzed Reaction of 1
and 9-Fm
Reaction of Hindered Isocyanates and Alcohols
entry SM
alcohol
9-Fm
i-PrOH
t-BuOH
t-BuOH
t-BuCH2OH
9-Fm
i-PrOH
i-PrOH
t-BuOH
Me2NH
product
R′
t (h)a yield (%)b
1
5
5
5
7
7
9
9
9
9
9
6a
9-Fm
i-PrO
t-BuO
t-BuO
t-BuCH2O
9-Fm
i-PrO
i-PrO
t-BuO
Me2N
i-PrO
1
24
92
2
6b
79
3
6c
216c
48c
1
63
4
8c
32d
70
5
8d
6
10a
10b
10b
10c
10e
12b
12c
12d
0.6
81e
58e
64e
60e
81e
87
7
4f
1
8
9
48
10
11
12
13
1
24
96c
TABLE 1. Comparison of Ti(Oi-Pr)4 with Other Lewis
11 i-PrOH
Acids
11 t-BuOH
11 t-BuCH2OH
t-BuO
t-BuCH2O 24
56
92
a Reaction conditions: 1.5 equiv of alcohol in benzene (0.2 M in
isocyanate) with 10 mol % of catalyst at 23 °C. b Isolated yield.
c At 120 °C in sealed vial. d Volatile compound, GC yield is 83%.
e For two steps from the carboxylic acid. f 2% catalyst.
catalyst
temp (°C)a
Rx time (h)
conversion (%)b
TABLE 3. Comparison of Ti(Ot-Bu)4 with HCl and CuCl
in the Reaction of Hindered Isocyanates with t-BuOH
MgCl2‚H2O
ZnCl2
CuCl
CaCl2
Yb(OTf)2‚H2O
Yb(OTf)2‚H2O
Ti(i-OPr)4
HCl
TiCl4
SnCl4
110
110
110
110
110
23
6
7
96
18
entry
SM
product
catalysta
conv (%)b
8
94
6
49
1
5
5
6c
Ti(Ot-Bu)4
none
13
0
3
decompc
80
2
6c
47
1.5
3
3
5
6c
HCl
6
23
100
4
5
6c
CuCl
Ti(Ot-Bu)4
none
HCl
CuCl
Ti(Ot-Bu)4
none
HCl
CuCl
Ti(Ot-Bu)4
none
HCl
CuCl
0
23
98
5
7
8c
92
0
23
-
-
decompc
decompc
6
7
8c
23
7
7
8c
0
8
7
8c
11
88
13
26
33
67
13
26
33
a Reaction conditions: 1.5 equiv of 9-Fm in toluene (0.1 M in 5)
with 10 mol % of catalyst. b % product as determined by HPLC,
the rest is SM. c No product detected.
9
9
10c
10c
10c
10c
12c
12c
12c
12c
10
11
12
13
14
15
16
9
9
9
11
11
11
11
a Reaction conditions: 1.5 equiv of t-BuOH in benzene (0.3 M
in isocyanate) with 10 mol % of catalyst at 120 °C in sealed vial
for 24 h. b Conversion determined by GC after 24 h.
FIGURE 1. Isocyanates used in the Ti-catalyzed reactions
with alcohols.
and used in the crude form. We also chose four alcohols:
two hindered primary, a secondary, and a tertiary
alcohol. Preliminary results indicated clearly that Ti(Oi-
Pr)4 performed much better than all of the other catalysts
tried. However, the snag caused by the formation of the
isopropyl carbamate remained. Noting that tert-butyl
alcohol, as the alcohol component of the reaction, added
substantially slower than the other alcohols, we decided
to try Ti(Ot-Bu)4 as catalyst, hoping that the tert-butyl
alcohol released by ligand exchange would not promptly
add to the isocyanate to give a companion carbamate. We
were pleased to discover the absence of any tert-butyl
carbamate in all of the reactions that we have carried
out with this catalyst (cf. Tables 2 and 3), except, of
course, when tert-butyl alcohol was the added partner.
More pleasingly, the efficiency of the catalyst did not
seem altered by the larger t-butoxide groups. Moreover,
that catalyst is more stable to air and moisture and thus
is more easily handled than Ti(Oi-Pr)4.
efficiency and rapidity with which it catalyzed the
reaction between isocyanate 5 and 9-Fm (Table 1). Not
apparent in Table 1 was the fact that the product mixture
obtained in the reactions catalyzed by Ti(Oi-Pr)4 was
much cleaner than all the other ones (vide infra).
Therefore, we deemed it appropriate to evaluate the
usefulness of this catalyst as part of a general method
for the formation of carbamates or ureas from highly
hindered isocyanates and alcohols or amines.
To do so, we purchased or prepared13 a series of
isocyanates that had in common severe steric hindrance
and a relative sensitivity to acid or base (Figure 1). In
fact, isocyanates 5 and 9 had to be kept in frozen benzene
as they decompose upon standing. In addition, compound
9 is too unstable for chromatography and was prepared
(13) Isocyanates unavailable commercially were made from the
Curtius rearrangement of the corresponding carboxylic acid obtained
from commercial sources. See Supporting Information.
J. Org. Chem, Vol. 70, No. 15, 2005 6119

SCHEME 2. Hypothetical Mechanism of Action of
the Ti Catalyst
SCHEME 3. Formation of Urea 10e Using
Ti(NMe2)4 as Catalyst
Ti(Ot-Bu)4 efficiently catalyzed the reaction of alcohols
with all of the isocyanates screened (Table 2). Catalyst
loadings of 10% allowed for a fast reaction at room
temperature in most cases, but catalyst loadings as low
as 2% afforded a complete reaction (entry 8). As expected,
tert-butyl alcohol underwent addition more slowly and
at higher temperatures. We thus chose that alcohol to
compare the efficiency of Ti(Ot-Bu)4 with that of hydro-
chloric acid and cuprous chloride, two commonly used
catalysts (Table 3).
Ti(Ot-Bu)4 cannot be used to hydrolyze isocyanates
because of its rapid reaction with water to form titanium
oxide. The hydrolysis of hindered isocyanates thus re-
mains a challenge.
In conclusion, we have demonstrated the efficiency and
usefulness of Ti(Ot-Bu)4 as catalyst for the formation of
carbamates and a urea from highly hindered and sensi-
tive isocyanates. Given the growing importance of the
latter intermediates in the synthesis of amino acids and
other compounds containing nitrogen, the present pro-
tocol should prove useful to synthetic organic chemists.
Consumption of the starting isocyanate using Ti(Ot-
Bu)4 was much faster than HCl or CuCl in all cases
(entries 5-16) but isocyanate 5 (entries 1-4). However,
in the latter case, many decomposition products were
formed with HCl or CuCl whereas Ti(Ot-Bu)4 gave a very
clean conversion, as judged by GC. Moreover, with Ti-
(Ot-Bu)4, complete conversion of 5 to carbamate 6c was
obtained by stirring the reaction at 120 °C for 216 h, with
a respectable isolated yield of 63% (Table 2, entry 3). The
other two catalysts led only to decomposition products.
Ti(OR)4 is a milder Lewis acid than other Ti(IV) species
(TiCl4 for example). Scheme 2 displays a possible ratio-
nale for the efficiency of this titanium catalyst. We believe
that the titanium complex is activating both the isocy-
anate and the alcohol as shown in structure I. The
isocyanate is activated by coordination to the Lewis acid,
while the alcohol is activated through a hydrogen bond
with a basic tert-butyl alcohol ligand. The alcohol is thus
delivered through a six-membered transition state. The
metalated carbamate then captures a proton from tert-
butyl alcohol or from the added alcohol. According to the
study of Meth-Cohn and co-workers, each step is revers-
ible and the equilibrium is shifted toward product.12 The
active catalysts could consequently be a mixture of
several titanium species including II and similar inter-
mediates.
The reaction with dimethylamine probably follows the
same pathway (Table 2, entry 10).14 One can use Ti-
(NMe2)4 as catalyst for this reaction with similar success
(Scheme 3). However, there is no advantage in doing so
unless the isocyanate molecule is particularly sensitive
to the higher Lewis acidity of Ti(OR)4. Therefore, we have
not investigated the use of Ti(N(t-Bu)2)4 as general
catalyst for the formation of ureas from isocyanates.
Ti(NMe2)4 can also be used as precursor to form Ti-
(OR)4 in situ, which will catalyze the formation of
carbamates (Scheme 3). The requisite alcohol must be
mixed in first with Ti(NMe2)4 and the dimethylamine
formed, evaporated before use. Failure to do so will
produce a N,N-dimethyl urea in large quantity.
Experimental Section
General Procedure for the Formation of Carbamates.
To a solution of the isocyanate (1.0 equiv of 0.2 M in benzene)
was added the alcohol or the amine (1.5 equiv). Titanium tetra-
t-butoxide (0.10 equiv) was then added, and the mixture was
stirred at the required temperature until completion (monitored
by GC). After quenching with saturated aqueous NH4Cl and
separating the two phases, we extracted the aqueous solution 3
times with CH2Cl2, dried the combined organic layers with
anhydrous MgSO4, and concentrated the layers in vacuo.
(9H-Fluoren-9-yl)methyl 1,1-Diphenylethylcarbamate
(6a).
6a was prepared following the general procedure for the forma-
tion of carbamates starting with 0.444 mmol of 5. Reaction
temperature: 25 °C; Reaction time: 1 h. The crude product was
purified by flash chromatography on silica gel (5-20% AcOEt
in toluene) to afford 6a as a white solid (171 mg, 92%). mp: 141-
1
143 °C. H NMR (300 MHz, CDCl3): δ 7.77 (d, 2H, J ) 7.2 Hz),
7.67-7.52 (m, 2H), 7.38-7.25 (m, 14H), 5.52 (s, 1H), 4.41 (d,
2H, J ) 6.6 Hz), 4.28-4.11 (m, 1H), 2.17 (s, 3H); IR (neat/NaCl):
3335, 2921, 1700; LRMS (m/z, (relative intensity)): 420 ((M+
+
H), 5), 181 (100); HRMS Calcd for C29H26O2N: 420.1963, found:
420.1968.
neo-Pentyl tert-Butylcarbamate (8d).
8d was prepared following the general procedure for the forma-
tion of carbamates starting with 0.500 mmol of tert-butylisocy-
anate. Reaction temperature: 25 °C; reaction time: 1 h. The
crude product was purified by flash chromatography on silica
gel (10% AcOEt in hexanes) to afford 8d as a white solid (66
1
mg, 70% isolated). mp: 49-51 °C. H NMR (300 MHz, CDCl3):
(14) Chandra, G.; Jenkins, A. D.; Lappert, M. F.; Srivastava, R. C.
J. Chem. Soc. A 1970, 2550-2558.
δ 4.61 (br s, 1H), 3.71 (s, 2H), 1.32 (s, 9H), 0.92 (s, 9H); IR (neat/
6120 J. Org. Chem., Vol. 70, No. 15, 2005

NaCl): 3347, 2961, 1708, 1525; LRMS (m/z, (relative intensity)):
187 (M+, 1), 172 ((M+ - CH3), 100), 71 (60), 57 (90); HRMS Calcd
for C9H18O2N: 172.1337, found: 172.1334.
1637, 1521; LRMS (m/z, (relative intensity)): 204 (M+, 12), 104
(90), 77 (100); HRMS Calcd for C12H16ON2: 204.1263, found:
204.1270.
t-Butyl 7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-ylcar-
bamate (12c).
i-Propyl 1-Phenylcyclopropylcarbamate (10b).
10b was prepared following the general procedure for the
formation of carbamates starting with 0.211 mmol of 9. Reaction
temperature: 25 °C; reaction time: 1 h. The crude product was
purified by flash chromatography on silica gel (10% AcOEt in
hexanes) to afford 10b as a white solid (30 mg, 64% for two
steps). mp: 56-58 °C. 1H NMR (300 MHz, CDCl3): δ 7.32-7.16
(m, 5H), 5.39-5.18 (m, 1H), 4.91 (sept, 1H, J ) 6.0 Hz), 1.28-
1.21 (m, 10H); IR (neat/NaCl): 3319, 2979, 1701, 1515; LRMS
(m/z, (relative intensity)): 219 ((M+ + H), 9), 176 (100), 132 (80);
HRMS Calcd for C13H17O2N: 219.1259, found: 219.1255.
1,1-Dimethyl-3-(1-phenylcyclopropyl)urea (10e).
12c was prepared following the general procedure for the
formation of carbamates starting with 0.119 mmol of 11.
Reaction temperature: 25 °C; reaction time: 96 h. The crude
product was purified by flash chromatography on silica gel (10%
AcOEt in hexanes) to afford 12c as an off-white solid (17 mg,
1
56%). H NMR (300 MHz, CDCl3): δ 5.04 (br s, 1H), 3.04 (br s,
1H), 2.39 (dm, 1H, J ) 18.7 Hz), 2.17-2.09 (m, 1H), 2.04-1.97
(m, 2H), 1.44 (s, 9H), 1.25-1.20 (m, 5H), 0.84 (s, 3H); IR (neat/
NaCl): 3399, 2968, 2920, 1726, 1502; LRMS (m/z, (relative
intensity)): 254 ((M+ + H), 60), 225 (95), 198 (78), 125 (100);
HRMS Calcd for C14H24O3N (M+ + H): 254.1756, found:
254.1761.
Acknowledgment. We thank the Natural Sciences
and Engineering Research Council of Canada and the
Universite´ de Sherbrooke for financial support.
10e was prepared following the general procedure for the
formation of carbamates starting with 0.421 mmol of 9, except
that the reaction mixture was concentrated in vacuo without
prior workup extraction. Reaction temperature: 25 °C; reaction
time: 1 h. The crude product was purified by flash chromatog-
raphy on silica gel (50% AcOEt in CH2Cl2) to afford 10e as a
white solid (70 mg, 81% from 1). mp: 146-147 °C; 1H NMR (300
MHz, CDCl3): δ 7.30-7.24 (m, 3H), 7.19-7.13 (m, 2H), 5.19 (br
s, 1H), 2.91 (s, 6H), 1.25 (s, 4H); IR (neat/NaCl): 3308, 2917,
Supporting Information Available: Experimental pro-
cedures, characterization data of all new compounds not
included in the Experimental Section of this note, and 1H NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO050712D
J. Org. Chem, Vol. 70, No. 15, 2005 6121