Facile and Selective O-Alkyl Transesterification of Primary Carbamates with Titanium(IV) Alkoxides

Full text of DOI:10.1021/jo971498z

7096
J . Org. Chem. 1997, 62, 7096-7097
transesterification reaction. When the simple model
F a cile a n d Selective O-Alk yl
substrate, (tert-butoxycarbonyl)phenylethylamine (1), was
treated with 10 mol % Ti(OiPr)4 in benzyl alcohol at 120
°C, conversion to the corresponding benzyloxycarbonyl
derivative, PhCH2CH2NHCbz (2), was insignificant.
For an acceptable rate of conversion it was necessary
to increase the amount of Ti(OiPr)4. After reaction of 1
with 1 equiv of Ti(OiPr)4 in benzyl alcohol at 120 °C for
18 h some starting material still remained. However,
using 2 equiv of Ti(OiPr)4, 1 was completely consumed
after 18 h. Reaction workup was performed by concen-
trating the mixture in vacuo, dissolving the residue in
methanol, and adding 5% water.9 Filtering and concen-
tration yielded a product which, aside from containing
benzyl alcohol, was quite pure by 1H NMR. After
chromatography, the O-alkyl carbamate transesterifica-
tion product 2, was isolated in 82% yield (Figure 2).
Having confirmed the initial result, we expanded the
study to a range of t-Boc-amines (see Table 1).
Tr a n sester ifica tion of P r im a r y Ca r ba m a tes
w ith Tita n iu m (IV) Alk oxid es†
Gideon Shapiro* and Martin Marzi
Preclinical Research, Novartis Pharma Ltd,
CH-4002, Basel Switzerland
Received August 13, 1997
Transesterification reactions mediated by titanium(IV)
alkoxides now constitute a powerful method in organic
synthesis. This is largely due to the work of Seebach who
brought the use of titanium(IV) alkoxides as catalysts
for the transesterification of carboxylic acid esters to the
attention of academic organic chemists some 15 years ago
(Figure 1).1 A broad range of alcohols are effective under
mild, essentially neutral, transesterification conditions
compatible with a wide range of functionality in the
substrate.
F igu r e 1.
Since then, asymmetric esterifications have been
achieved with homochiral titanium(IV) alkoxide com-
plexes2 and the scope of titanium(IV) alkoxide-mediated
transesterification reactions has been broadened to in-
clude sultams3 and phosphite esters.4 Herein, we wish
to report a new application for titanium(IV) alkoxides,
namely, the facile O-alkyl transesterification of primary
carbamates.5-7
In the course of a drug derivatization program we
needed to perform the transesterification of a methyl
ester to the corresponding benzyl ester in a substrate
molecule bearing an array of additional sensitive func-
tionality. Heating the substrate with Ti(OiPr)4 in benzyl
alcohol at 120 °C smoothly effected the desired benzyl
carboxylate formation; however, we also observed the
conversion of a substrate primary tert-butoxycarbonyl
amine (R-NHBoc) function to the corresponding benzy-
loxycarbonyl group (R-NHCbz). This was an unexpected
result in light of work from Steglich.8 He had reported
that terminal N-Boc-dipeptide methyl esters were
smoothly transesterified without racemization to the
corresponding isopropyl or benzyl esters with no detect-
able reaction at the carbamate function.
F igu r e 2.
The O-alkyl carbamate transesterification reaction
proceeded in analogous fashion for PhCH2NHBoc (6) to
give 7. Using 4 equiv of Ti(OiPr)4, the more challenging
bifunctional substrate BocNH(CH2)5NHBoc (8) was also
smoothly converted to the corresponding bis-Cbz deriva-
tive 9. Interestingly, Boc-Gly-OBn (10) was also trans-
esterified to Cbz-Gly-OBn in benzyl alcohol at 120 °C.
Treatment of 10 with Ti(OiPr)4 in benzene at reflux
resulted in only exchange of the ester function to give
Boc-Gly-OiPr (12). However, performing the same reac-
tion in refluxing toluene resulted in smooth carbamate
ester exchange along with concomitant carboxylic acid
transesterification, to give (iPrOCO)-Gly-OiPr, (13). Thus,
by controlling the reaction temperature, it is conveniently
possible to selectively transesterify the ester function of
an amino acid or peptide ester in the presence of
N-terminal carbamate groups even when using excess
titanium alkoxide.10 The secondary substrates N-Boc-
pyrrolidine (14) and N-Boc-piperidine (15) were stable
to the standard reaction conditions.11 This had dramatic
implications since: a general selective removal of a
primary amine protecting group would be a novel trans-
formation in organic synthesis. We have demonstrated
that this can now be readily achieved taking bis-Boc
substrate 16 as an example (Figure 3). Treatment of (16)
with 4 equiv of a Ti(OiPr)4 in benzyl alcohol at 120 °C
for 18 h resulted in smooth conversion of the primary
t-Boc function to give 17 with the secondary t-Boc group
unaffected.
Intrigued by this result, we decided to determine the
scope of this titanium(IV) alkoxide mediated carbamate
† Dedicated to Professor Dieter Seebach on the occasion of his 60th
birthday.
(1) (a) Seebach, D.; Hungerbuehler, E.; Naef, R.; Schnurrenberger,
P.; Weidmann, B.; Zueger, M. Synthesis 1982, 138. (b) Seebach, D.;
Weidmann, B.; Widler, L. In Modern Synthetic Methods 1983; Schef-
fold, R., Ed.; Verlag Sauerlaender: Aarau, 1983; p 217.
(2) (a) Ramon, D.; Guillena, G.; Seebach, D. Helv. Chim. Acta 1986,
79, 875. (b) Seebach, D.; J aeschke, G.; Gottwald, K.; Matsuda, K.;
Formisano, R.; Chaplin, D. A.; Breuning, M.; Bringmann, G. Tetrahe-
dron 1997, 53, 7539.
(3) Oppolzer, W.; Lienard, P. Helv. Chim. Acta 1992, 75, 2572.
(4) Froneman, M.; Modro, T. A. Synthesis 1991, 201.
(5) (a) Sakaitani, M.; Ohfune, Y. J . Org. Chem. 1990, 55, 870. (b)
Sakaitani, M.; Kurokawa, N.; Ohfune, Y. Tetrahedron Lett. 1986, 3753.
(c) Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1985, 5543.
(6) Barrett, A. G. M.; Pilipauskas, D. J . Org. Chem. 1990, 55, 5170.
(7) Roos, E. C.; Bernabe, P.; Hiemstra, H.; Speckamp, W. N. J . Org.
Chem. 1995, 60, 1733.
(9) Ti(OMe)4 is a highly insoluble species. When absolute methanol
was used, the titanium salt precipitate formed slowly, but addition of
5% water accelerated the process dramatically.
(10) This is consistent with the selectivity for carboxylic acid esters
observed by Steglich using 0.25-0.5 equiv of titanium alkoxide in
refluxing THF.
(11) At higher temperatures the starting material began to disap-
pear with the desired transesterification remaining undetected.
(8) Steglich, W.; Rehwinkel, H. Synthesis 1982, 826.
S0022-3263(97)01498-9 CCC: $14.00 © 1997 American Chemical Society

Communications
reactant
J . Org. Chem., Vol. 62, No. 21, 1997 7097
Ta ble 1
Ti(OiPr)4,
equiv
temp, °C
solvent
product
yield, %
PhCH2CH2NHBoc (10)
PhCH2NHBoc (6)
BocNH(CH2)5NHBoc (8)
Boc-Gly-OBn (10)
10
10
(CH2)5NBoc (14)
(CH2)6NBoc (15)
16
1
1
1
120
120
120
120
80
120
120
120
120
120
120
120
120
120
120
120
2
2
4
4
4
2
2
2
4
2
2
2
2
2
2
2
PhCH2OH
PhCH2OH
PhCH2OH
PhCH2OH
PhH
PhCH2CH2NHCbz (2)
PhCH2NHCbz (7)
CbzNH(CH2)5NHCbz (9)
Cbz-Gly-OBn (11)
Boc-Gly-OiPr (12)
(iPrOCO)-Gly-OiPr (13)
no reaction
no reaction
82
73
65
60
65
58
PhCH3
PhCH2OH
PhCH2OH
PhCH2OH
17
85
85
82
75
78
83
85
82
PhCH3/CH2dCHCH2OH12
(CH3)3SiCH2CH2OH
PhCH3
PhCH2CH2NHAlloc (3)
PhCH2CH2NHTeoc (4)
PhCH2CH2NHCOOiPr (5)
3
4
5
5
PhCH2CH2NHCO2Et (18)
18
18
PhCH3/CH2dCHCH2OH12
PhCH3/(CH3)3SiCH2CH2OH12
PhCH3
PhCH2CH2NHCbz (2)
PhCH3
(5). These studies demonstrate that the desired trans-
esterification proceeds with a range of alcohols leading
to synthetically useful protecting groups: Cbz, Alloc, and
Teoc. Furthermore, for low boiling alcohols or cases in
which use of the given alcohol as solvent is undesirable,
it has been demonstrated that the reaction proceeds
smoothly in toluene solvent with the corresponding
titanium(IV) alkoxides.13
F igu r e 3.
Finally, it remained to study the reactivity of the
carbamate ester functionality. To this end we investi-
gated the reaction of 2 and the ethoxycarbonyl derivative
18 of the model phenethylamine substrate with 2 equiv
of Ti(iOPr)4 in refluxing toluene. In both cases, 5 was
formed in good yield. Furthermore, 18 was also readily
converted into the Alloc and Teoc derivatives 3 and 4
using the corresponding titanium alkoxides in refluxing
toluene.
At this point we then turned to the investigation of
different alcohols in the reaction, with particular atten-
tion to those leading to synthetically useful carbamate
protecting groups (Table 1). Taking 1 as the model
substrate, reaction with Ti(OCH2CHdCH2)4 in toluene12
at reflux was found to proceed smoothly to give PhCH2-
CH2NHAlloc (3) in 85% yield. The reaction in trimeth-
ylsilyl ethanol was somewhat slower requiring 2 days for
complete conversion to the trimethylsilyloxycarbonyl
(Teoc) derivative PhCH2CH2NHCOOCH2CH2SiMe3 (4).
Simply treating 1 with 2 equiv of Ti(OiPr)4 in toluene at
reflux also resulted in clean formation of the correspond-
ing isopropyl carbamate PhCH2CH2NHCOOCH(CH3)2
The details of the reaction mechanism remain to be
studied experimentally. We speculate that the first step
involves the formation of an imino-carbonate species
which is only accessible to primary carbamates having
an active hydrogen. We propose that this species dis-
sociates reversibly to a formal isocyanate-titanate com-
plex with transfer of the incoming alkoxide ligand from
the titanium coordination-sphere leading to transesteri-
fication product.
(12) Ti(OCH2CHdCH2)4 was preformed by treating Ti(iOPr)4 in
refluxing toluene twice with an excess, 3-4 equiv, of allyl alcohol with
azeotropic removal of 2-propanol. For higher boiling alcohols such as
benzyl alcohol, a slight excess of the alcohol is used with a single
azeotropic removal of 2-propanol.
In summary, few carbamate ester exchange methods
have been reported heretofore.5-7 These methods are
specific for particular carbamate ester functionalities. We
describe an efficient reaction which is specific for primary
carbamates but is general for the O-alkyl group to be
exchanged. This specificity on one hand, but generality
on the other, is of great utility. One may now readily
employ a carbamate function which tolerates a gamut of
synthetic conditions (e.g. ethoxycarbonyl) and then trans-
form it to one which is easily removed as needed. Finally,
preliminary experiments indicate that this reaction can
be extended to the preparation of ureas from primary
carbamates using titanium(IV) amides.
(13) Qualitatively, the reaction with preformed titanium alkoxides
in toluene appears to be faster. Clearly, this is the method of choice
in case the alcohol is a precious material. In addition, reaction workup
is also more facile for alcohols which are tedious to remove (eg. PhCH2-
OH) when used as solvent. Exa m p le P r oced u r e: A mixture of
titanium tetraisopropoxide (1.14 g., 4.0 mmol) in 25 mL of toluene
containing (20 mmol, 2.1 mL) of benzyl alcohol was distilled to a volume
of ca. 15 mL. Compound 16 (314 mg., 1.0 mmol) was added, and the
resulting mixture was heated under reflux for 18 h. The reaction
mixture was concentrated, the residue was dissolved in methanol, and
5% water was added. The resulting suspension was filtered and
concentrated to a residue which was taken up in ether. This solution
was filtered, concentrated, and chromatographed over silica gel (1:1,
ether:hexane) to give 310 mg (89%) of white crystalline 17. This
reaction was readily repeated on a 10 mmol scale. 1H NMR and MS
characterization was performed for all compounds which were also
independently prepared by standard procedures using the correspond-
ing amine and an appropriate carbamoylating agent.
J O971498Z