Facile one-pot synthesis of carbamoylbenzotriazoles directly from CO Synthesis of tolbutamide

Article abstract of DOI:10.1055/s-0030-1261222

COgas trapped with a primary or secondary amine as a carbamate salt in the presence of DBU reacts with triphenylphosphine and 1-chlorobenzotriazole (BtCl) to form a carbamoylbenzotriazole urea, which reacts with para-toluenesulfonamide under solvent-free conditions to produce N-sulfonyl ureas such as tolbutamide. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261222

LETTER
2335
Facile One-Pot Synthesis of Carbamoylbenzotriazoles Directly from CO2:
Synthesis of Tolbutamide
Synthesis of
T
olb
o
utamide ger Hunter,*a Ath’enkosi Msutu,a Cathy L. Dwyer,b Neville D. Emslie,b Raymond C. Hunt,b
Barend C. B. Bezuidenhoudtc
a
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax +27(21)6505195; E-mail: Roger.Hunter@uct.ac.za
Sasol Technology R & D (PTY) Ltd., 1, Klasie Havenga Road, Sasolburg 1947, South Africa
Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa
b
c
Received 8 June 2011
tion of metal catalysts, crown ethers, and strong, non-
nucleophilic bases, which serve to stabilize the carbamate
anion with an increase in the nucleophilicity of the oxygen
center.3 In such a way, carbamate salts have been convert-
Abstract: CO2 gas trapped with a primary or secondary amine as a
carbamate salt in the presence of DBU reacts with triphenylphos-
phine and 1-chlorobenzotriazole (BtCl) to form a carbamoylbenzo-
triazole urea, which reacts with para-toluenesulfonamide under
solvent-free conditions to produce N-sulfonyl ureas such as tolbut- ed into urethanes,3,4 substituted ureas,5 isocyanates,6 car-
bamoyl chlorides,7 S-thiocarbamates,8 carbamoyl azides,9
amide.
and carbamoyl cyanides.10 In this communication we re-
Key words: CO2, BtCl, Bt urea, sulfonyl urea, tolbutamide
port on the use of the oxophilic reagent combination of
triphenylphosphine and 1-chlorobenzotriazole (BtCl)11
for transforming a range of carbamate salts into their cor-
CO2 consumption as a chemical feedstock has been high-
responding
carbamoylbenzotriazoles
(Bt
ureas,
lighted as a key initiative in an effort to mitigate its envi-
ronmentally unfriendly greenhouse effect.1 The
advantages of using CO2 directly as a C1 building block
are numerous. It is relatively cheap, nontoxic, and is a de-
sirable replacement for current toxic C1 agents such as
phosgene, CO or isocyanates. It is also a renewable feed-
stock compared to oil or coal, and using CO2 to make
valuable chemical intermediates promotes the invention
of new and superior synthetic methodologies.1
R2NCOBt) in good to excellent yield depending on the
amine used. As shown by Katritzky12,13 and others,14 Bt
ureas are versatile C1 building blocks, which we demon-
strate through the facile synthesis of the antidiabetes type
II sulfonylurea drug, tolbutamide.
Initial model studies involved bubbling CO2 into a solu-
tion of amine (piperidine, benzylamine, dicyclohexy-
lamine) in an organic solvent (THF, CH2Cl2, MeCN) in an
attempt to isolate the carbamate salt. However, even in
cases where precipitation occurred, the salts were found to
be difficult to manipulate. Thus, in keeping with literature
reports, it was decided to develop a one-pot sequence. Us-
ing piperidine as the model amine in CH2Cl2 and bubbling
CO2 through the solution for about 20 minutes followed
by the sequential addition of triphenylphosphine (limiting
reagent) and 1-chlorobenzotriazole (1.2 equiv) resulted in
a rapid reaction at room temperature, as judged by TLC.
Removal of solvent and direct column chromatography
without a workup (a base-mediated workup did not im-
prove yields) gave Bt urea 1a as a mixture of Bt-regioiso-
mers (unsymmetrical: symmetrical = 4.5:1) in a 47%
yield as well as the piperidinyl symmetrical urea 2a (35%)
based on triphenylphosphine (Scheme 1). The regioiso-
mers of 1a could be chromatographically separated and
distinguished by 1H NMR and 13C NMR spectroscopy.
As shown in Figure 1, several C1 building blocks are
available as stable reagents in synthetic organic chemis-
try, but in each case their synthesis involves the use of tox-
ic phosgene or carbon disulfide as starting materials.2
O
O
O
O
S
;
;
;
;
Cl3CO
OCCl3 imid
imid Bt
Bt MeS
SMe MeS
OMe
Figure 1 Common C1 building blocks in organic synthesis
Regarding synthetic methodologies that start directly
from CO2, the most commonly used approach is to trap
CO2 with a primary or secondary amine to form a carbam-
ate salt, which can then be further functionalized. Howev-
er, drawbacks to this approach are that carbamate salts are
thermally unstable and release CO2 upon heating; also, the
nucleophilicity of the carbamate alkoxide oxygen tends to
be lower than that of the carbamate nitrogen resulting in
regioselectivity problems of subsequent heteroatom func-
tionalization. Preferential O-functionalization of the
alkoxide oxygen has been accomplished through the addi-
The mechanism of the substitution reaction can be under-
stood in terms of reaction of triphenylphosphine with BtCl
to form the oxophilic chlorotriphenylphosphonium ion,
which results in carbamate salt activation to an acyloxy-
phosphonium intermediate similar to that recently report-
ed in Mitsunobu-based methodologies using DIAD and
DEAD.6,8 Of note is the regioselective reaction at the
oxygen of the carbamate salt during this activation. Sub-
sequent substitution with BtH forms the product 1a. For-
SYNLETT 2011, No. 16, pp 2335–2338
x
x
.x
x
.2
0
1
1
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261222; Art ID: D17311ST
© Georg Thieme Verlag Stuttgart · New York

2336
R. Hunter et al.
LETTER
O
NH
N
O
H2N
CO2, DCM, r.t.
2
carbamate salt
(2.6 equiv)
O
O
O
Ph3P (1 equiv),
BtCl (1.2 equiv)
N
N
N
N
+
N
N
N
N
N
+
N
symmetrical
2a, 35%
unsymmetrical
1a, 47% (4.5:1)
Scheme 1 Initial pilot study to produce Bt urea 1a
mation of the undesirable symmetrical urea byproduct 2a no symmetrical urea 2a. Full conversion of the piperidine
indicated proton exchange to be occurring between the was observed, presumably via a DBU-carbamate salt. The
carbamate salt piperidinium cation and the BtH (or more large variation in reaction outcome with respect to the
likely its conjugate base), which together with the low choice of solvent was significant, presumably reflecting
atom efficiency regarding wastage of half of the amine, varying degrees of solvent-induced ion-pair disruption. In
encouraged us to develop the reaction further.
view of the ready availability of DBU it was decided to
conduct further work using it rather than TMPG.
In careful consideration of the literature regarding the car-
bamate nucleophilicity aspect it was discovered that As a final part of the Bt urea optimization study, the opti-
McGhee et al.3b had established that strong, hindered, mized conditions were applied to a range of primary and
non-nucleophilic bases (such as amidines and guanidines) secondary aliphatic amines in which the steric bulk of the
can help increase the nucleophilicity of the carbamate an- alkyl group was varied. The results of this study are
ion by increasing the ionic separation of the salt in solu- shown in Table 2.
tion, thus exposing the oxygen as a ‘naked’ anion and a
On a 1 mmol scale yields were generally good with prod-
more reactive nucleophile. To this end, the reaction was
ucts isolated by column chromatography. Furthermore,
repeated in a study comparing the use of tetramethylphe-
the reaction was found to have good scope regarding
amine, except that yields of the Bt urea 1 were generally
higher with secondary amines (Table 2, entries 1–5) com-
nylguanidine (TMPG)3b,9,10 as base vs. DBU, which we
hoped would result in full conversion of the secondary
amine via proton exchange with the cation. Reactions
pared to those for primary amines (Table 2, entries 6–10),
were carried out in various solvents as in Scheme 1 except
and for the latter, yields were sensitive to increasing steric
using the following reaction stoichiometry with amine as
bulk of the alkyl group (Table 2, entries 8–10). Interest-
limiting reagent: piperidine (1 equiv), DBU or TMPG
ingly, while secondary amines gave a mixture of regioiso-
(1.25 equiv), Ph3P (1.3 equiv), and BtCl (1.6 equiv). The
mers, in which the unsymmetrical isomer was always
formed as major (Scheme 1), the primary amines gave ex-
results are shown in Table 1.
clusively, or nearly so, the unsymmetrical isomer. Scaling
the reaction up to 10 mmol (or 5 mmol) gave yields equal
to or higher than the yields obtained on the 1 mmol scale,
Table 1 The Effect of Using DBU or TMPG in Various Solvents on
the Yield of Products 1a and 2a
N
with 1g (Table 2, entry 7, primary) showing the most
marked increase.
N
N
N
N
As a final part of developing the methodology it was de-
cided to apply our findings to the synthesis of sulfonyl-
ureas such as tolbutamide (Figure 2), which have found
application as antidiabetes type II drugs15 as well as
shown to have anticancer activity.16
DBU
TMPG
Yield 1a (%) Yield 2a (%) Yield 1a (%) Yield 2a (%)
Solvent
THF
80
76
35
0
4
64
69
48
10
4
Methods for the synthesis of these compounds normally
involve coupling of a sulfonamide to a suitable carbamoyl
partner or equivalent, examples of the latter being isocy-
anates,17 N-alkyl-1,2,4-dithiazolodone-3,5-dione,18 and
carboxylic acid via an in situ Curtius rearrangement.19 The
only reference to producing a sulfonylurea from a Bt urea
prior to our work was a short communication in 1979,14
which reported that Bt ureas derived from primary amines
undergo the reaction using a sulfonamide sodium salt as
CH2Cl2
MeCN
20
3
In accordance with McGhee’s discoveries, it was found
that trialkylamine bases such as triethylamine or Hünig’s
base (EtNi-Pr)2 gave inferior results. We were gratified
that DBU returned an excellent result in THF, producing
a high yield of the desired product 1a (80%, 4:1) and with
Synlett 2011, No. 16, 2335–2338 © Thieme Stuttgart · New York

LETTER
Synthesis of Tolbutamide
2337
Table 2 Conversion of Amines to Bt Ureas 1 Using the Optimized
nucleophile in DMF or dioxane. In our hands, following a
screening of various base-mediated conditions of substi-
tution (NaH, DMF, temp; K2CO3, solvent, temp), it was
established that a smooth and facile synthesis of tolbut-
amide could be achieved under solvent-free conditions by
reacting Bt urea 1g (entry 7, Table 2) with p-tolylsulfon-
amide and K2CO3 in a melt at 100 °C for 15 minutes. Sub-
sequent treatment of the cake with aqueous HCl, followed Entry Amine
by filtration gave pure tolbutamide 3g in a yield of 75%
(entry 1, Table 3). The reaction was extended to Bt ureas
1f and the secondary amine-derived 1a to afford sulfonyl-
Conditionsa of Table 1 (continued)
i) CO2, THF, DBU
O
ii) Ph3P, BtCl
R1
R1R2NH
N
R2
Bt
1
Product
Yield unsym/ Yield
(%)b sym
(%)c,d
O
7
8
9
n-BuNH2
46
14
33
100:0 71c
n-Bu
N
Bt
ureas 3f (benzyl, 79%) and 3a (piperidinyl, 46%), respec-
tively. Bt urea 1c (dicyclohexyl) failed to react under the
conditions designated indicating that substitution in this
case, as one might expect, is more facile with the primary
Bt ureas on steric grounds (Table 3). It must also be noted
that piperidinyl sulfonylurea 3a could not be isolated via
the HCl treatment described and was thus isolated using
column chromatography.
H
1g
O
t-BuNH2
100:0e 24d
t-Bu
N
Bt
H
1h
1i
O
c-PentNH2
100:0e 54d
N
Bt
O
H
Table 2 Conversion of Amines to Bt Ureas 1 Using the Optimized
Conditionsa of Table 1
i) CO2, THF, DBU
ii) Ph3P, BtCl
O
N
Bt
10
a-MeBnNH2
13
100:0
R1
H
R1R2NH
N
Bt
R2
1
1j
a Piperidine (1 equiv), DBU (1.25 equiv), Ph3P (1.3 equiv), BtCl (1.6
equiv).
Entry Amine
Product
Yield unsym/ Yield
(%)b sym
(%)c,d
b On a 1 mmol scale.
c On a 10 mmol scale.
d On a 5 mmol scale.
O
O
e Trace amounts of the symmetrical regioisomer detected by TLC and
1H NMR and 13C NMR spectroscopy.
1
2
piperidine
80,
69
4:1
2:1
94c
N
Bt
1a
O
O
O
O
O
O
S
S
N
N
N
N
H
H
N
Bt
O
Et2NH
H
H
Cl
chlorpropamide
tolbutamide
1b
O
O
O
N
Bt
S
N
3
(c-Hex)2NH
61
2:1
N
N
H
H
gliclazide
1c
Figure 2 Some sulfonylureas used against diabetes mellitus type II
O
Bn
4
5
BnNHMe
60
53
2:1 60d
N
Bt
In conclusion, our new methodology allows a one-pot ac-
cess to Bt ureas derived from both primary and secondary
amines. The reaction conditions are mild and avoid the
use of toxic chlorinating agents, since BtCl can be pre-
pared by the oxidation of BtH with bleach.20 BtH expelled
in subsequent substitutions can in principle be recycled
using acid/base extraction affording the process a degree
of sustainable character.
1d
O
100:0e
100:0
N
Bt
morpholine
O
1e
O
Bn
6
BnNH2
79
N
H
Bt
1f
Synlett 2011, No. 16, 2335–2338 © Thieme Stuttgart · New York

2338
R. Hunter et al.
LETTER
Table 3 Synthesis of Sulfonylureas 3
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mmol) and DBU (190 mg, 1.25 mmol, 1.25 equiv) in THF. Ph3P
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General Procedure for Sulfonylurea Synthesis
A mixture of Bt urea (1.00 mmol) and p-toluenesulfonamide (171
mg, 1.00 mmol, 1 equiv) was heated to 100 °C for a few minutes un-
til both compounds had melted to form a homogeneous mixture.
K2CO3 (138 mg, 1.00 mmol, 1 equiv) was then added, and the re-
sultant mixture was stirred for a further 15 min, after which the re-
action mixture was cooled to r.t. HCl (5 mL, 5 M) was then added,
and the reaction mixture was left to stand in a 60 °C bath for 30 min.
Following cooling, the product was filtered and washed with H2O
(3 × 10 mL) to afford the sulfonylurea as an off-white solid after
drying.
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Acknowledgement
We would like to thank the University of Cape Town, Sasol Ltd and
the South African National Research Foundation for financial sup-
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