Readily prepared resin-bound thioimidates as reagents for the synthesis of amidines

Article abstract of DOI:10.1055/s-2001-11384

The use of commercially available resins to prepare novel and stable polymer supported thioimidates was investigated. Polymer supported thioimidates were found to enable acetamidine formation in a convenient manner, with a significantly easier work-up than solution-phase reactions.

Full text of DOI:10.1055/s-2001-11384

3
88
LETTER
Readily Prepared Resin-Bound Thioimidates as Reagents for the Synthesis of
Amidines
Antonella Ursini*, Monica Delpogetto, Giuseppe Guercio, Alcide Perboni, Tino Rossi
GlaxoWellcome S.p.A. Chemical Development Department, Via A. Fleming 4, 37135 Verona, Italy
E-mail: au4438@GlaxoWellcome.co.uk
Received 28 December 2000
Unfortunately, S-benzyl thioimidate results in the genera-
Abstract: The use of commercially available resins to prepare nov-
tion of benzyl mercaptan as an unwanted reaction by-
el and stable polymer supported thioimidates was investigated.
product. The use of S-(2-naphtylmethyl)thioacetimidate
formation in a convenient manner, with a significantly easier work- bromide represents a great improvement since it affords
Polymer supported thioimidates were found to enable acetamidine
up than solution-phase reactions.
acetamidines and non odorous thiol byproducts. Never-
theless, in our hands some reagent-related impurities were
detected in the final drug substance and proved to be dif-
ficult to be completely removed without any chromato-
graphic procedure during the scale-up phase.
Key words: amine, acetamidine, scale-up, solid-phase synthesis,
polymers
New procedures or alternative work-ups were therefore
A variety of procedures for the synthesis of amidineshave needed.
1
,2
previously been reported. Among them, the use of thio-
imidates such as S-benzylthioacetimidate hydrochloride3
or hydrobromide or S-(2-naphtylmethyl) thioacetimidate
The current interest in solid-phase organic synthesis has
led to a renewed interest in a complementary technique in
which solid supported reagents are used in solution phase
chemistry. In an effort to make the above reaction more
convenient, we linked the methyl thioacetamide moiety to
polymer supports (Scheme 2) and here report on initial
studies for the preparation of such reagents and their reac-
tivity. The new polymer-supported reagent results from
reaction of methyl thioacetamide with different polymer
4
is well established. The exploitation of thioimidates as
general reagents for the synthesis of substituted acet-
amidines capitalises on their ability to react with poor nu-
cleophilic amines. The reaction of thioimidate
hydrochlorides with amines occurs smoothly in methanol
or ethanol at room temperature in an inert atmosphere.
However, the method has significant drawbacks when ap-
plied to large-scale synthesis.
8
types. Wang Bromo resin, Argopore and chloromethyl-
polystyrene (PL-CMS) were selected for a preliminary
During the course of our investigations in process re- screening and gave respectively the new polymer support-
search directed towards the scale up of the synthesis of se- ed thioimidates 4a-c (Scheme 2).9
5
lective NOS inhibitors , we sought alternative PL-CMS afforded from 70% to 90% substitution of the
amidination procedures.
benzylic chlorine atoms by the thio function, whereas
0% was obtained with the Wang Bromo resin. Data ob-
tained from running MAS H NMR spectra with Argopore
resin are not predictable due to the resin properties. Nev-
ertheless, subsequent reaction with amine 2a (entry 5, Ta-
ble) indirectly confirms the expected functionalisation.
5
The key transformation in the above process involved the
use of thioimidates to convert amines to acetamidines.
Thus, the thioimidates 1a,b can be prepared from the cor-
responding benzyl or naphtyl chlorides and treated with
1
5
amine 2a to give the amidine 3a using standard proce-
6
,7
dures (Scheme 1).
Reaction of the polymer-bound thioimidate was initially
carried out by adding suspension of the amine to the resin
and leaving the mixture stirring overnight at room temper-
ature. A variety of experiments were then tried using 2a as
substrate and are reported in the Table (entries 1-6). Al-
though a good conversion was observed (entry 6, Method
A) isolation of 3a by simple filtration was not feasible
since the reaction never went to completion.10 An addi-
tional problem in our hands was the very poor solubility
of amine 2a in the most suitable solvents used with the se-
lected resins. The use of dioxane/water gave the best re-
sult in terms of conversion.
Scheme 1
Synlett 2001, No. 3, 388–390 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Readily Prepared Resin-Bound Thioimidates
389
Scheme 2
Scheme 3
Table Reaction of resin bound thioimidates with amines to give amidines
astoichiometry calculated on the basis of the typical loading of starting commercially
available resins, assuming 100% functionalisation with thiourea.
b
c
3
a/2a ratio ca. 1/1 calculated by HPLC; isolation of 3a not carried out in these cases.
In order to overcome the solubility issue and with the aim Acknowledgement
of getting a complete reaction, amines 2b and 2c were se-
The authors wish to acknowledge Dr Mike Loft for providing useful
data on solution phase experiments, Dr A. Paio for providing advi-
lected as simpler models to optimise the reaction (entries
7
-8, Scheme 3, Method B). By using a larger excess of
ses and comments on solid phase reactions. Dr C. Marchioro and Mr
1
resin 4c (from PL-CMS) a complete conversion of the C. Loda are kindly acknowledged for carrying out some MAS H
starting amine 2 into the acetamidine was thus observed NMR spectroscopy and HPLC analysis.
by HPLC. After aqueous work-up to remove traces of tri-
4
ethylamine, 3b and 3c were isolated in 60% and 70%
References and Notes
1
1
yield, respectively, as pure compounds.
(
1) Roger, R.; Neilson, D. G. The Chemistry of Imidates; Patai, S.,
Ed.; Wiley: New York 1960, p179.
In summary, polymer-bound thioacetamidine reagents
were prepared and their potential use as reagent for acet-
imidation reaction was demonstrated. The polymer-sup-
ported approach affords easy isolation of the products
from thioamidation, provided that the reaction goes to
completion. Even though further studies remain to be
done to establish the scope and limitations of this proce-
dure, this paper marks the first efforts in adapting the re-
action to polymer-supported reagents.
(2) Roger, R.; Neilson, D. G. The Chemistry of Amidines and
Imidates; Patai, S., Ed.; Wiley: New York 1975.
(3) Takido, T.; Itabashi, K. Synthesis 1987, 9, 817-819.
(4) Shearer, B. G.; Oplinger, J. A.; Lee, S. Tetrahedron Lett.
997, 38, 179-182.
1
(
5) a) Hodson, H. F.; Palmer, R. M. J.; Sawyer, D. A.; Knowles,
R. G.; Franzmann, K.W.; Drysdale, M. J.; Smith, S.; Davies,
P. I.; Clark, H. A. R.; Shearer, B. G. WO 9534534 a1 CAN
124:261737 1996 b) Alderton, W. K.; Knowles, R. G.; Ladel,
C.H. WO9959566, CAN 131:346497 1999
Synlett 2001, No. 3, 388–390 ISSN 0936-5214 © Thieme Stuttgart · New York

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A. Ursini et al.
LETTER
(
(
6) Collins, J. L.; Shearer, B. G.; Oplinger, J. A.; Lee, S.; Garvey,
E. P.; Salter M.; Duffy, C.; Burnette, T. C.; Furfine, E. S.
J.Med.Chem. 1998, 41, 2858-2871.
acetonitrile 85/15+0.1% HClO 1 mL/min; r.t. (min) of comp.
4
,
3a: 8.28; r.t. (min) of unreacted compound 2a: 7.18.
5
Spectroscopic and analytical data for compound 3a are in
7) Solution-phase synthesis. See:
agreement with those obtained by solution phase experiments.
(11) Reaction of polymer-bound thioimidate (Method B). A
typical experiment was carried out as follow: (3.5 g; 7 eq
calculated assuming loading = 1.98 mmol/g) of 4c were added
to amine 2b (0.107 g; 1 mmol) or 2c (0.160 g; 1 mmol) in 40
mL of THF in the presence of triethylamine (0.97 mL; 7 eq).
The suspension was left at reflux for 3 h and at r.t. for 20 h.
The reaction was monitored by HPLC until disappearance of
the starting amine. (Luna C18(2), 50 2.0 mm, Mobil Phase
A1 = water with 0.05%TFA, Mobil Phase B1 = Acetonitrile
with 0.05%TFA, from 100% A1 t = 0 to 95/5 B1/A1 t = 8. r.t.
(min) of compound 2b: 0.898; r.t. (min) of compound 3b:
1.894. r.t. (min) of compound 2c: 3.549; r.t. (min) of
compound 3c: 2.246.
Young, R. J.; Beams, R. M.; Carter, K.; Clark, H. A. L.; Coe,
D. M.; Chambers, C. L.; Davies, P. F.; Dawson, J.; Drysdale,
M. J.; Franzman, K. W.; French, C.; Hodgson, S. T.; Hodson,
H. F.; Kleanthous, S.; Rider, P.; Sanders, D.; Sawyer, D. A.;
Scott, K. J.; Shearer, B. G.; Stocker, R.; Smith, S.; Tackley, M.
C.; Knowles, R. G. Biorganic &Medicinal Chemistry Letters
2000, 10, 597-600.
(
8) Argopore-Cl (loading 1.06 mmol/g) was purchased from
ARGONAUT Technologies; PL-CMS (loading 1.98 mmol/g)
from Polymer Laboratories and Bromo-Wang (loading 1.19
mmol/g) from NOVA BIOCHEM.
(
9) General procedure to synthesise Polymer-Bound
thioimidate. The reaction mixtures resulting from the
addition of 0.5 g of each resin to 3 mL of 1M solution of
thioacetamide in the selected solvent (THF for Argopore and
Chloromethylpolystyrene and 1,4-dioxane for Bromo-Wang),
were left at 70 °C for 15 h. After filtration, washing with the
selected solvent and drying, the degree of substitution was
determined quantitatively by NMR analysis. The new resins
The resin was filtered off, washed with methanol and the
resulting solution concentrated under vacuum. After aqueous
work-up to remove traces of triethylamine, 3b was isolated in
60% yield and 3c in 70% yield, respectively. The latter was
converted into the corresponding hydrochloride and
characterised as salt.
1
4 1
were fully characterised by MAS H NMR Spectroscopy. (400
Compound 3b : H NMR (400 MHz, CDCl ): δ 8.50 (bs, 2H);
3
MHz CD Cl ):δ 4.5 (m, 2H, -CH Cl of the commercial
7.2-7.35 (m, 5H); 4.26 (s, 2H); 1.97 (s, 3H). Compound 3c (as
2
2
2
available PL-CMS resin), 2.5 (m, 3H, -CH -)
hydrochloride): calc. C H N O HCl: C: 45.47 H8.45 N17.68
found C: 45.73 H8.44 N17.23; MS (FAB) m/e 202 (MH ); IR
3
9
19
3
2
+
(
10) Reaction of polymer-bound thioimidate (Method A). A
suspension of amine 2a (0.0296 g; 0.1 mmol) in 3 mL of
solvent (dioxane/water 7/3) was added to resin 4c (0.1 g; 2 eq
calculated assuming loading 1.98 mmol/g) and left at room
temperature overnight. The resulting suspensions were stirred
overnight at room temperature, then filtered and the solution
concentrated under vacuum to give almost quantitatively a
crude material containing 3a and unreacted 2a in 84/16 ratio.
HPLC analysis (Hypersil BDS, 25 × 4.6 cm, water/
νmax 3264 and 3112 (NH and NH ), and 1694, 1677, 1645
2
-
1 1
(C=O and C=N) cm ; H NMR (400 MHz, CDCl ): δ 8.50 (bs,
3
2H); 7.2-7.35 (m, 5H); 4.26 (s, 2H); 1.97 (s, 3H).
Article Identifier:
1437-2096,E;2001,0,03,0388,0390,ftx,en;G22200ST.pdf
Synlett 2001, No. 3, 388–390 ISSN 0936-5214 © Thieme Stuttgart · New York