An intramolecular sulfoxide alkylation-elimination approach to the [1,2,3]triazolo[1,5-a]pyrimidine ring system

Article abstract of DOI:10.1055/s-2001-13354

A novel approach to the [1,2,3]triazolo[1,5-a]pyrimidine ring system has been developed. The key reaction step involves an unusual one-pot intramolecular sulfoxide alkylation-elimination reaction.

Full text of DOI:10.1055/s-2001-13354

712
LETTER
An Intramolecular Sulfoxide Alkylation-Elimination Approach to the
[1,2,3]Triazolo[1,5-a]pyrimidine Ring System
Karl R. Gibson,* Steven R. Thomas, Michael Rowley
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK
Fax +44 1279 440390; E-mail: karl_gibson@merck.com
Received 1 January 2001
from nucleophilic attack and prevent enolisation of the
Abstract: A novel approach to the [1,2,3]triazolo[1,5-a]pyrimidine
amide. To the best of our knowledge this cyclisation strat-
ring system has been developed. The key reaction step involves an
egy is completely unprecedented. Gratifyingly, treatment
unusual one-pot intramolecular sulfoxide alkylation-elimination re-
of sulfoxide 5 with KHMDS in THF not only effected the
intramolecular alkylation but also, in one pot, the elimina-
tion of the phenyl sulfoxide moiety to afford the [1,2,3]tri-
azolo[1,5-a]pyrimidin-6-one 6 in good yield, although
analysis of the product by NMR showed a 10:1 mixture
with isomer 7 (Scheme 1).
action.
Key words: sulfoxides, alkylations, cyclisations, eliminations, re-
arrangements
In the course of work towards the discovery of subtype se-
lective benzodiazepine site GABA-A ligands,1 such as
[1,2,4]triazolo[4,3-b]pyridazine 1, the [1,2,3]triazolo[1,5-
a]pyrimidine ring system as typified by 2 was identified
as an attractive target.2 This heterocycle has received little
attention from synthetic chemists and at the outset of the
work no known methodology existed to access such a
highly substituted ring system.3
F
F
N
N
N
i
PhS
NC
PhS
NH2
nOe
N3
3
ii
F
F
F
F
N
N
N
N
N
N
N
N
iii
N
N
F
N
N
N
NH
N
NH
O
Cl
Cl
O
O
S
PhS
O
O
Ph
R
R
N
N
5 R = Ph
N
N
78%
31%
77%
22%
4 R = Ph
R = c-Bu
N
N
iv
F
R = c-pentyl
R = tBu
1
2
N
N
Our chosen strategy was to construct the 5-membered tri-
azole ring first. Condensation of the commercially avail-
N
NH
F
azide4
with
2-fluoro-
H
N
able
phenylacetonitrile under basic conditions provided the N-
phenylthiomethyl-aminotriazole 3.5 Acylation with
phenylthiomethyl
R
O
N
N
-
64%
62%
59%
0%
N
6 R = Ph
chlorophenylacetyl chloride afforded amide 4. The sulfide
was cleanly oxidised to a mixture of the corresponding di-
astereomeric sulfoxides 5 by treatment with ozone at low
temperature.6 From this intermediate it was envisaged that
the closure of the 6-membered ring could be achieved by
an intramolecular alkylation of the sulfoxide moiety. It
was surmised that treatment of the sulfoxides with a
strong base would generate an anion at the carbon doubly
activated by both the sulfoxide and the triazole and that
this anion could be alkylated by the halogen bearing car-
bon. Furthermore, it was hoped that deprotonation of the
NH group of the amide would protect the carbonyl carbon
8 R = c-Bu
O
9 R = c-pentyl
R = tBu
7
Scheme 1 Reagents: i) K2CO3, DMSO, rt, 29% ii) PhCHClCOCl or
RCHBrCOCl, pyridine, DMF, 0 °C iii) O3, CH2Cl2, -78 °C iv)
KHMDS, THF, -78 -20 °C
The synthetic sequence could be employed with compara-
ble levels of success to introduce both phenyl and alkyl
groups (e.g. cyclobutyl, cyclopentyl) with the exception
of the sterically demanding tert-butyl substituent.7 The
Synlett 2001, No. 5, 712–714 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Intramolecular Sulfoxide Alkylation-Elimination Approach
713
resulting [1,2,3]triazolo[1,5-a]pyrimidinones 8 and 9
could be isolated by crystallisation after work-up, howev-
er, attempted recrystallisation led to formation of isomers
of type 7.
F
F
N
N
N
N
i
N
N
N
The formation of isomer 7 can be explained by the Dim-
roth rearrangement3,8 of 6. Thus triazole ring opening of 6,
followed by re-closure on the other pyrimidinone nitro-
gen, slowly affords 7 (Scheme 2). This rearrangement was
found to occur in d6-DMSO even at room temperature,
leading to a product ratio of roughly 1:3 6:7 over time.9
NH
O
R
O
nOe
R
nOe
N
N
N
6 R = Ph
8 R = c-Bu
9 R = c-pentyl
2 R = Ph
11 R = c-Bu
12 R = c-pentyl
74%
70%
30%
F
F
N
N
N
Scheme 3 Reagents: i) RCH2OH, PPh3, DEAD, THF, rt
N
N
N
NH
N
H
Acknowledgement
O
O
The authors would like to thank Luis Castro for helpful discussions.
10
6
rotn about
C-C
References and Notes
(1) McKernan, R. M.; Rosahl, T. W.; Reynolds, D. S.; Sur, C.;
Wafford, K. A.; Atack, J. R.; Farrar, S.; Myers, J.; Cook, G.;
Ferris, P.; Garrett, L.; Bristow, L.; Marshall, G.; Macaulay,
A.; Brown, N.; Howell, O.; Moore, K. W.; Carling, R. W.;
Street, L. J.; Castro, J. L.; Ragan, C. I.; Dawson, G. R.;
Whiting, P. J. Nat. Neurosci. 2000, 3, 587.
(2) Broughton, H. B.; Castro Pineiro, J. L.; Collins, I. J.; Gibson,
K. R.; Rowley, M.; Street, L. J. WO 99/65907 (Merck Sharp
and Dohme Ltd, UK)
(3) For previous work on less substituted [1,2,3]triazolo[1,5-
a]pyrimidines see Sutherland, D. R.; Tennant, G.; Vevers, R.
J. S. J. Chem. Soc. Perkin Trans. 1 1973, 943 and Sutherland,
D. R.; Tennant, G. J. Chem. Soc. Chem. Commun. 1969, 1070.
(4) Trost, B. M.; Pearson, W. H. J. Am. Chem. Soc. 1981, 103,
2483. This azide is commercially available from Aldrich.
(5) Cottrell, I. F.; Hands, D.; Houghton, P. G.; Humphrey, G. R.;
Wright, S. H. B. J. Heterocycl. Chem. 1991, 28, 301. The
regiochemistry of the cyloaddition was confirmed by the
observation of a nOe between the methylene protons adjacent
to sulphur and the protons of the amino group.
(6) Bordwell, F. G.; Pitt, B. M. J. Am. Chem. Soc. 1955, 77, 572.
(7) -Bromo-cyclopentylacetyl chloride and -bromo-cyclobutyl
chloride prepared according to standard literature procedure:
Harpp, D. N.; Bao, L. Q.; Coyle, C.; Gleason, J. G.; Horovitch,
S. Org. Synth. 1988, VI, 190. In the course of acylation the
bromine was displaced by chloride ion, leading to isolation of
the chlorinated products.
F
F
H
H+
N
N
N
N
N
transfer
N
N
NH
O
O
7
Scheme 2
Mechanistic studies10 of the Dimroth rearrangement have
proposed an intermediate such as 10 (Scheme 2). It was
reasoned that after alkylating the ring system on oxygen,
as in 2, the lone pair of the nitrogen exocyclic to the tria-
zole would be orthogonal to the system and therefore
unable to participate in the initial ring opening of the tria-
zole.
O-selective alkylation of 6, 8 and 9 with the desired
[1,2,4]triazole fragment could be achieved under Mit-
sunobu conditions11 to afford compounds 2, 11 and 12 in
good yield. In each case the product structures were con-
firmed by the nOe’s shown (Scheme 3). The alkylation
was not limited to this [1,2,4]triazole alcohol but also pro-
ceeded with other heterocyclic alcohols.2 As anticipated
these products showed no propensity to undergo the Dim-
roth rearrangement even during prolonged heating at
50 °C in DMSO.
(8) For 2 recent reveiws see a) L’Abbé, G. J. Heterocyclic Chem.
1984, 21, 627. b) Fan, W-Q; Katritzky, A. R. in
Comprehensive Heterocyclic Chemistry II, Vol 4; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V. Eds; Pergamon: London,
1996, p 30.
(9) The final isomer ratio is solvent dependent, heating in either
acetonitrile or methanol affords a 1:10 ratio of 6:7. The
product structures were assigned by analysis of a NOESY
spectrum of the mixture of isomers. In 6 the pyrimidinone C-
H shows an nOe only to the unsubstituted phenyl ring. In 7 the
pyrimidinone C-H shows this nOe and an additional nOe to
the exchangeable NH signal.
In summary, a concise route, requiring just 5 steps from
commercially available starting materials, has been de-
vised to access highly functionalised [1,2,3]triazolo[1,5-
a]pyrimidines for the first time.12 The key step is com-
prised of an unprecedented sulfoxide alkylation/elimina-
tion reaction. The biological properties of these
compounds will be disclosed at a later date.
(10) Lieber, E.; Rao, N. R.; Chao, T. S. J. Am. Chem. Soc. 1957,
79, 5962.
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714
K. R. Gibson et al.
LETTER
(11) a) Comins, D. L.; Jianhua, G. Tetrahedron Lett. 1994, 35,
2819. b) Kim, T. H.; Rappoport, H. J. Org. Chem. 1990, 55,
3699.
diastereomers. 1H NMR (400 MHz, CDCl3) H 5.21 5.51
(3H, m), 6.98 7.04 (1H, m), 7.19 (1H, t, J = 8 Hz), 7.29
7.60 (11H, m), 7.74 (1H, t, J = 8 Hz), 9.80 and 9.84 (1H, s);
m/z (ES+) 469 (M+H+).
(12) Representative experimental procedures: 5-(2-Fluorophenyl)-
3-phenylsulfanylmethyl-3H-[1,2,3]triazol-4-ylamine 3:
2-Fluorophenylacetonitrile (5.9 mL, 46 mmol) was added to a
suspension of K2CO3 (19.5 g, 141 mmol) in dry DMSO (100
mL) under nitrogen. The reaction was stirred for 5 min then
azidomethylphenylsulfide (5 mL, 35.3 mmol) was added. The
reaction was stirred at room temperature for 16 h before
addition to water (2 L). The mixture was extracted with
EtOAc (4 0.5 L) and the organic extracts were washed with
brine (0.5 L), dried (Na2SO4) and the solvent removed in
vacuo. The resultant oil was purified by flash chromatography
(25% EtOAc / isohexane) and the product crystallised from
Et2O (3.04 g, 29%). Mpt 79-80 °C; Anal. Calcd for
3-(2-Fluorophenyl)-6-phenyl-4H-[1,2,3]triazolo[1,5-a]-
pyrimidin-5-one 6: Potassium bis-trimethylsilylamide (8.44
mL, 0.752 M in toluene, 6.34 mmol) was added to a solution
of 5 (850 mg, 1.81 mmol) in dry THF (50 mL) at 78 °C and
the reaction stirred for 90 min. The reaction was then warmed
to 20 °C and stirred for 15 min before pouring into water
(200 mL) and stirring for 10 min. The aqueous mixture was
acidified with citric acid (10% aq.) and extracted with EtOAc
(2 200 mL). The combined organic extracts were washed
with water (100 mL), brine (100 mL), dried (Na2SO4) and
concentrated in vacuo to about 10 mL total volume. The title
compound (355 mg, 64%) preciptated out and was collected
by filtration and washed with Et2O. The product was used in
subsequent reactions without further purification. 1H NMR
(400 MHz, d6-DMSO) H 7.32 7.39 (6H, m), 7.70 7.74
(3H, m), 9.17 (1H, s), 12.70 (1H, br s); m/z (ES+) 307
(M+H+). Rearranged isomer 7: 1H NMR (400 MHz, d6-
DMSO) H 7.31-7.59 (6H, m), 7.72 (2H, d, J = 7 Hz), 7.82
(1H, t, J = 7 Hz), 8.23 (1H, s), 13.0 (1H, br s) m/z (ES+) 307
(M+H+).
3-(2-Fluorophenyl)-5-(2-methyl-2H-[1,2,4]triazol-3-
ylmethoxy)-6-phenyl-[1,2,3]triazolo[1,5-a]pyrimidine 2:
Compound 6 (60 mg, 0.196 mmol), PPh3 (128 mg, 0.49 mmol)
and 2-methyl-2H-[1,2,4]triazol-3-yl)-methanol (62 mg, 0.49
mmol), were suspended at room temperature in dry THF (1.5
mL). Diethylazodicarboxylate (78 µL, 0.49 mmol) was added
and the resulting yellow solution was stirred at room
temperature for 64 h before purification by preparative thin
layer chromatography (EtOAc) to afford the title compound
(60 mg, 74%) as a white solid. Mpt 166-167 °C; Anal. Calcd
for C21H16FN7O: C, 62.84; H, 4.02; N, 24.43. Found: C, 62.79;
H, 3.78; N, 24.25; 1H NMR (400 MHz, CDCl3) H 3.79 (3H,
s,), 5.69 (2H, s,), 7.24 (1H, td, J = 9 and 1 Hz), 7.31 (1H, td,
J = 8 and 1 Hz), 7.39 7.43 (1H, m), 7.48 7.51 (3H, m),
7.54 7.58 (2H, m), 7.86 (1H, s), 8.00 (1H, td, J = 8 and 2
Hz), 8.80 (1H, s); 13C NMR (100.6 MHz, CDCl3) C 35.8,
59.4, 116.1 (d, JC-F = 21 Hz), 118.2, 118.3 (d, JC-F = 10 Hz),
124.4 (d, JC-F = 4 Hz), 128.9, 129.3, 129.5, 129.9, 130.0, 130.3
(d, JC-F = 4 Hz), 130.8, 132.2, 138.0, 149.8, 150.9, 159.3,
159.8 (d, JC-F = 241 Hz); m/z (ES+) 402 (M+H+).
C15H13FN4S: C, 59.98; H, 4.36; N, 18.65. Found: C, 59.73; H,
4.36; N, 18.97; 1H NMR (400 MHz, CDCl3) H 4.10 (2H, br
s), 5.55 (2H, s), 7.11 (1H, ddd, J = 12, 8 and 1 Hz), 7.22-7.32
(5H, m) 7.39-7.41 (2H, m), 7.89 (1H, td, J = 8 and 2 Hz); 13
C
NMR (100.6 MHz, CDCl3) C 50.9, 115.7 (d, JC-F = 23 Hz),
119.0 (d, JC-F = 14 Hz), 124.9 (d, JC-F = 4 Hz), 126.6, 128.9,
129.1 (d, JC-F = 8 Hz), 129.5, 130.0 (d, JC-F = 5 Hz), 131.2,
132.9, 138.6, 158.6 (d, JC-F = 241 Hz); m/z (ES+) 301 (M+H+).
2-Chloro-N-[5-(2-fluorophenyl)-3-phenylsulfanylmethyl-3H-
[1,2,3]triazol-4-yl]-2-phenyl-acetamide 4: Pyridine (0.46 mL,
5.62 mmol) was added to a solution of 3 (1.30 g, 4.32 mmol)
in DMF (30 mL) under nitrogen at 0 °C followed by rac- -
chlorophenylacetyl chloride (0.79 mL, 4.97 mmol). After 1 h
the reaction was poured into water (200 mL). The aqueous
solution was extracted with EtOAc (2 100 mL) and the
organic extracts were washed with citric acid (100 mL, 10%
aq.), NaHCO3 (100 mL, sat. aq.), water (100 mL), brine (100
mL) and dried (Na2SO4). The solvent was removed in vacuo
and the product crystallised from Et2O (1.514 g, 78%). Mpt
121-122 °C 1H NMR (400 MHz, CDCl3) H 5.37 (1H, s),
5.49 (1H, d, J = 14 Hz), 5.61 (1H, d, J = 14 Hz), 7.11 (1H, dd,
J = 11 and 9 Hz), 7.24 7.44 (12H, m), 7.82 (1H, td, J = 8 and
1 Hz), 8.21 8.19 (1H, m); 13C NMR (100.6 MHz, CDCl3)
C
53.3, 61.1, 115.6 (d, JC-F = 22 Hz), 117.4 (d, JC-F = 14 Hz),
125.0 (d, JC-F = 3 Hz), 127.7, 128.4, 129.0, 129.2, 129.5,
129.6, 130.6, 130.7 (d, JC-F = 7 Hz), 131.6, 133.2, 135.5, 159.1
(d, JC-F = 245 Hz), 166.5; m/z (ES+) 453 (M+H+).
N-[3-Benzenesulfinylmethyl-5-(2-fluorophenyl)-3H-[1,2,3]-
triazol-4-yl]-2-chloro-2-phenyl-acetamide 5: Ozone gas was
bubbled into a cold ( 78 °C) solution of 4 (1.48 g, 3.27 mmol)
in CH2Cl2 (100 mL). After 4 h the stream of ozone was ceased
and the apparatus flushed with nitrogen. The solvent was
removed to afford the title compound as a mixture of
Article Identifier:
1437-2096,E;2001,0,05,0712,0714,ftx,en;D01401ST.pdf
Synlett 2001, No. 5, 712–714 ISSN 0936-5214 © Thieme Stuttgart · New York