Synthesis of tetrazolopiperazine building blocks by a novel multi-component reaction

Article abstract of DOI:10.1016/j.tetlet.2004.06.133

A novel Ugi-five-centre-four-component reaction (U-5C-4CR) of aldehydes, primary amines, trimethylsilylazide and 2-isocyanoethyltosylate yielding tetrazolopiperazine building blocks is described.

Full text of DOI:10.1016/j.tetlet.2004.06.133

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6421–6424
Synthesis of tetrazolopiperazine building blocks by a novel
multi-component reaction
a,b,
a
J u¨ rgen Kolb, Christoph Burdack, G u¨ nther Ross
a
a
*
Michael Umkehrer,
b
and Wolfgang Hiller
a
Priaton GmbH, Discovery, Bahnhofstr. 9-15, D-82327 Tutzing, Germany
Technical University Munich, Lichtenbergstr. 4, D-85747 Garching, Germany
b
Received 3 June 2004; revised 23 June 2004; accepted 30 June 2004
Available online 19 July 2004
Abstract—A novel Ugi-five-centre-four-component reaction (U-5C-4CR) of aldehydes, primary amines, trimethylsilylazide and
-isocyanoethyltosylate yielding tetrazolopiperazine building blocks is described.
2
Ó 2004 Elsevier Ltd. All rights reserved.
Combinatorial chemistry has recently gained much
attention in pharmaceutical research, especially in the
context of lead finding and lead optimization. Multi-
component reactions (MCRs) allow rapid generation
of compound libraries containing a variety of different
fused tetrazolopiperazines by the use of alkylating isocy-
1
anides. Therefore we mixed in a typical procedure
aldehydes, primary amines, trimethylsilylazide and 2-
isocyanoethyltoluolsulfonate in a ratio 1/1/1.5/1.5, yield-
ing the desired tetrazolopiperazines (Scheme 2).
7
1
–3
4
–10
and highly relevant organic-chemical scaffolds.
1
1
Intending to the ÔidealÕ organic reaction the discovery
and development of novel MCRs is receiving a growing
An analogue reaction mechanism like in Scheme 1 is
proposed, but the generated secondary amine finally
gets alkylated by the toluolsulfonate, leading to the ex-
1
2
interest from industrial chemistry research groups.
1
8
pected fused tetrazoles 5a–i (Table 1).
Therefore we present a novel, facile Ugi-five-centre-
four-component reaction (U-5C-4CR) yielding 6,7-di-
substituted-tetrazolopiperazines, which represents an
extension of fused tetrazole synthesis, developed by Hul-
In this paper we show an efficient synthesis of various
types of 6,7-disubstituted tetrazolopiperazines (Table
1) using 2-isocyanoethyltosylate 8 as alkylating isocya-
nide, which can be synthesized in two steps from 2-ami-
1
3
me and co-workers. The formation of monocyclic
1
4,15
19
tetrazoles was originally reported in 1961
using a
noethanole 6 (Scheme 3).
variation of classical Ugi reaction. Condensation of an
aldehyde or ketone with a primary or secondary amine
and subsequent reaction with an isocyanide produces
the intermediate nitrilium ion 1, as a key intermediate.
Reaction with azide, followed by sigmatropic rearrange-
ment affords the desired tetrazole 3 (Scheme 1).
In this new four-component reaction the primary amines
and the aldehydes can be varied broadly, producing
products with two potential diversity points.
In summary, a novel one-pot solution phase procedure
for the preparation of 6,7-disubstituted tetrazolopipera-
zine building blocks has been reported. With final prod-
ucts containing two points of potential diversity and a
facile and rapid production protocol, access to thou-
sands of diverse analogues with the aforementioned core
structure is now feasible.
Several combinatorial synthesis of fused tetrazole sys-
tems by the use of post-condensation reaction are de-
1
3,16
scribed,
but we are aiming at novel MCR, forming
Keywords: Ugi-reaction; Tetrazolopiperazines; Combinatorial chemis-
try; Isocyanoethyltosylate.
Work is in progress in our laboratory to synthesize 1,2-
disubstituted 2-isocyanoethyl-tosylates, finally creating
tetrazolopiperazines with four points of diversity.
*
Corresponding author. Tel.: +49-8158-90400; fax: +49-8158-
04022; e-mail: umkehrer@priaton.de
9
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.133

6422
M. Umkehrer et al. / Tetrahedron Letters 45 (2004) 6421–6424
O
+
H
R1
R2
R3
R1 NH2
R 1
R2
R3
+
+ R
R3
N
N
2
H
R2
R3
-
R2
R3
N
N3
R4
NC
R1
+
R1
N
+
N
C
N
H
N
H
N
R4
1
N
R4
R2
R3
2
R1
N
N
H
N
N
N
R4
3
Scheme 1. Mechanism of the tetrazole-U-4CR.
+
H
R1
R2
R1 NH2
+ R2
CHO
R1
R2
+
N
N
H
R2
R2
NC
-
N3
TsO
R1
N
+
R1
N
H
+
N
N
H
N
N
N
OTs
TsO
R2
R1
N
N
R2
N
H
-
TsOH
N
O
R1
N
N
N
N
N
N
4
TsO
5
O
S
TsO R :
R
O
Scheme 2. Proposed reaction mechanism for the novel U-5C-4CR.
Table 1. Synthesized tetrazolopiperazines
R2
R1
N
MeOH
TsOH
N
NC
R1
NH2
+ R
CHO
+
TMSN3
2
+ TsO
N
-
N
N
5
Entry
R
1
R
2
Yield (%)
Product
1
2
3
4
5
6
7
8
9
CH Ph
2
CH(CH
CH(CH
3
)
2
49
73
42
48
49
75
50
56
67
5a
5b
5c
5d
5e
5f
p-MeOOCC
6
6
H
4
4
3
)
2
CH
CH
CH
2
Ph
2
Ph
2
Ph
p-MeOC
6
H
4
p-MeOOCC
6 4
H
p-BocNHC
6
H
4
o-MeOOCC
CH
o-MeOOCC
CH CH(OCH
H
CH(CH
Ph
3
)
2
2
CH(OCH
3
)
2
2
5g
5h
5i
6
H
4
p-MeOC
6
H
4
2
3
)
p-MeOOCC
6
H
4
HCOOEt
NH2
NHCHO
TsCl
eq.
NC
HO
HO
TsO
2
6
7
8
Scheme 3. Two-step synthesis of 2-isocyanoethyltosylate.

M. Umkehrer et al. / Tetrahedron Letters 45 (2004) 6421–6424
6423
References and notes
C
6
H
5
CH
2
), 4.39–4.55 (m, 2H, CH
H, CH H ), 6.93 (d, J=8.53Hz, 2H, C H ), 7.40–7.62
2
CH
2
NRNR), 4.88 (s,
3
6 4 6 4
1
1
m, 2H, C H ), 7.21–7.39 (m, 5H, C H ). C NMR
3
(
(
(
(
1
2
3
. Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233.
. Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P.
A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385.
. D o¨ mling, A. Comb. Chem. High Throughput Screen. 1998,
6
4
6
5
CDCl
CH CH
CHC
3
,
62.90MHz): 45.0 (CH
NRNR), 55.3 (OCH
), 114.4, 127.7, 128.6, 128.7, 129.7, 129.9, 130.3,
2
CH
2
NRNR), 45.9
2
2
4
3 6 5 2
), 57.2 (C H CH ), 62.2
6
H
1
z=322.3 [M+H] , 344.1 [M+Na] .
37.2 (C H , C H ), 154.0 (s, R C@NR). MS (ESI): m/
6
5
6
4
2
+ +
1
, 1.
1
Compound 5d was isolated in 48% yield as a yellow oil. H
NMR (CDCl3, 250.13MHz): 2.85–2.96 (m, 1H,
4
5
6
. D o¨ mling, A.; Ugi, I. Angew. Chem. 2000, 112, 3300.
. D o¨ mling, A.; Ugi, I.; H o¨ rl, W. Endeavour 1994, 18, 115.
. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996,
18, 2574.
. Ugi, I.; Steinbr u¨ ckner, C. Chem. Ber. 1961, 94, 734.
. Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2,
7
. Zhu, J. Eur. J. Org. Chem. 2003, 1133.
0. Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
1. Towards the ideal synthesis: Wender, P. A.; Handy, S. T.;
Wright, D. L. Chem. Ind. 1997, 1, 795.
2. Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 3, 366.
3. Nixey, Th.; Kelly, M.; Hulme, Ch. Tetrahedron Lett. 2000,
CH
2
CH
2
NRNR), 3.33–3.41 (m, 1H, CH
2
CH
), 3.91 (s, 3H, CH
6
NRNR), 5.00 (s, 1H, C H
2
NRNR),
2
3
4
7
8
6
.43 (d, J=13.42Hz, 2H, C
2
.27–4.58 (m, 2H, CH CH
.23–7.36 (m, 5H, C H ), 7.56 (d, J=8.24Hz, 2H, C H ),
6
.07 (d, J=8.24Hz, 2H, C
2.90MHz): 44.7 (CH CH NRNR), 45.7 (CH
), 57.3 (C CH ), 62.0 (CHC
28.5, 128.6, 129.8, 130.3, 130.5, 136.6, 141.9 (C H ,
6
H
5
CH
2
3
),
),
1
7
8
2
4
3
5
6
4
3
13
H
4
). C NMR (CDCl
CH NR
), 127.8,
3
,
09.
6
9
2
2
2
2
NR), 52.1 (CH
1
3
6
H
5
2
6 4
H
1
1
6
5
C
6 4 2
H ), 152.7 (R C@NR), 166.4 (COOMe). MS (ESI): m/
+ +
z=350.5 [M+H] , 372.3 [M+Na] .
1
1
Compound 5e was isolated in 49% yield as a yellow solid.
HNMR (CDCl , 250.13MHz): 1.43 (s, 9H, [C(CH ) ],
1
4
1, 8729.
3
3 3
2
CH
.70–2.81 (m, 1H, CH
2
CH
2
NRNR), 3.24–3.31 (m, 1H,
1
1
1
4. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
5. Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734.
6. Bienayme, H.; Bouzid, K. Tetrahedron Lett. 1998, 39,
2
NRNR), 3.29 (d, J=13.42Hz, 1H, C
2
CH
2
2
6
5 2
H CH ),
3.83 (d, J=13.42Hz, 1H, C H CH ), 4.15–4.45 (m, 2H,
CH
6
5
2
CH
2
NRNR), 4.80 (s, 1H, C
).
], 45.0 (CH
6 4
H ), 6.63 (s, 1H, NH),
2
735.
7. Typical procedure: The aldehyde (3mmol) and the amine
3mmol) are stirred in 10mL methanol at room temper-
ature. The imine is pre-condensated for 3h and than
mmol of isocyanide and 2mmol of TMSN are added.
2
1
3
7
.21–7.38 (m, 9H,
C
H
6 5
C
6
H
4
C
NMR (CDCl
3
,
1
6
2.90MHz): 28.3 [C(CH
3
)
3
2
CH NRNR), 45.8
2
(
(CH CH NRNR), 57.2 (C H CH ), 62.1 (CHC H ), 80.7
2 2 6 5 2 6 4
[
C(CH
3
)
3
], 118.9, 127.7, 128.6, 128.7, 129.2, 130.0, 137.1,
, C ), 152.6 (R
2
3
1
MS (ESI): m/z=407.2 [M+H] , 429.1 [M+Na] .
39.0 (C
6
H
5
6
H
4
2
C@NR), 153.5 (COOR).
The reaction mixture is stirred for 24h at room temper-
ature until the reaction is completed (indication by TLC).
When the reaction is completed the solvent is evaporated
and the resulting residue is dissolved in 20mL dichloro-
methane. The organic layer is washed with satd NaHCO3
+ +
Compound 5f was isolated in 75% yield as a white solid.
1
3
3
HNMR (CDCl , 250.13MHz): 0.94 (d, J =6.72Hz, 3H,
3
CH
3 3
), 1.18 (d, J=6.72Hz, 3H, CH ), 2.36 (m, 1H,
CHMe ), 3.91 (s, 3H, COOCH ), 4.28–4.42 (m, 2H, CH
2
solution and satd NaCl solution, dried over MgSO and
4
3
2
CH
2
NRNR), 4.51–4.70 (m, 2H, CH
J=6.72Hz, 1H, CHCHMe
6 4
), 6.65–6.72 (C ), 7.93–7.97 [m, 1H(C H
2
CH
2
NRNR), 4.80 (t,
concentrated in vacuo. The resulting oil is purified by
column chromatography on silica gel (hexane/ethyl ace-
tate).
3
3
2
), 6.53 (d, J=8.54Hz, 1H,
)], 8.37
C
6
H
4
6
H
4
3
13
(
d, J=5.8Hz, 1H, C H ). C NMR (CDCl , 62.90MHz):
6
1
8. Compound 5a was isolated in 49% yield as a white solid.
4
3
1
3
1
9.3 (CH
CH
NRNR), 66.2 (CHCHMe
35.1, 149.2 (C H ), 155.7 (R C@NR), 169.2 (COOMe).
3
), 19.5 (CH
NRNR), 51.8 (COOCH
3
), 33.0 (CHMe
2
), 46.6
CH
), 111.1, 111.5, 116.7, 131.9,
3
HNMR (CDCl , 360.13MHz): 0.96 (d, J=6.8Hz, 3H,
3
(
CH
2
2
3
), 55.2 (CH
2
2
3 3
CH ), 1.20 (d, J=6.8Hz, 3H, CH ), 2.17 (m, 1H,
CHMe ), 2.96–3.02 (m, 1H, CH CH NRNR), 3.30–3.38
2
2
2
2
2
NRNR), 3.64 (d, J=13.5Hz, 1H,
C H CH ), 3.83 (d, J=13.5Hz, 1H, C H CH ), 3.74 (d,
6 5 2 6 5 2
1
(
m, 1H, CH
2
CH
2
6
4
2
+
+
2
MS (ESI): m/z=302.3 [M+H] , 324.2 [M+Na] .
1
Compound 5g was isolated in 50% yield as a yellow oil. H
3
J=6.8Hz, 1H, CHCHMe2), 4.26–4.32 (m, 1H,
CH CH NRNR), 4.42–4.50 (m, 1H, CH CH NRNR),
NMR (CDCl3, 250.13MHz): 2.62–2.81 [m, 2H,
MeO) CHCH ], 3.05–3.15 (m, 1H, CH CH NRNR),
2 2 2 2
2
2
2
2
1
3
(
7
1
.28–7.35 (m, 5H, C
8.4 (CH ), 19.8 (CH
43.5
), 62.3 (CHCHMe
C@NR). MS (ESI): m/z=258.1 [M+H] ,
6
H
5
). C NMR (CDCl
), 31.1 (CHMe
(CH CH NRNR),
3
, 90.56MHz):
3
3
4
7
.58–3.67 (m, 1H, CH
CH], 4.47–
.59 (m, 2H, CH CH NRNR), 5.07 (s, 1H, C H ), 7.26–
.40 (m, 5H, C
CH
4.0 (s, OCH
2
CH
.36 (s, 3H, OCH ), 4.38–4.43 [m, 1H, (MeO)
2
NRNR), 3.21 (s, 3H, OCH
3
),
3
3
2
), 42.4
57.8
(
(
(
CH CH NRNR),
3
2
2
2
2
2
C
C
H
6 5
CH
2
2
), 127.7, 128.5, 128.7, 137.3
2
2
6
5
1
3
+
H
5
). CNMR (CDCl
CH NRNR), 53.4 (OCH
), 54.6 [(MeO) CHCH ], 62.5 (CHC
3
, 62.90MHz): 44.8
H
6 5
), 152.2 (R
2
6
+
(
CH
2
2
NRNR), 47.2 (CH
2
2
3
),
),
2
80.1 [M+Na] .
5
1
1
3
2
2
6
H
5
Compound 5b was isolated in 73% yield as a white solid.
1
3
04.0 [(MeO) CH], 128.6, 128.8, 128.9, 136.8 (C H ),
2
53.3 (R+
HNMR (CDC3l
CH ), 1.05 (d, J=6.71Hz, 3H, CH
CHMe ), 3.85 (s, 3H, COOCH ), 4.32–4.37 (m, 2H,
3
, 250.13MHz): 0.90 (d, J=6.71Hz, 3H,
6
5
+
C@NR). MS (ESI): m/z=290.3 [M+H] , 312.2
3
3
), 2.29–2.37 (m, 1H,
2
[M+Na] .
Compound 5h was isolated in 56% yield as a yellow oil. H
2
3
1
CH CH NRNR), 4.54–4.61 (m, 2H, CH CH NRNR),
2
2
2
2
3
), 6.57 (d, J=8.7Hz,
NMR (CDCl , 250.13MHz): 3.72 (s, 3H, OCH ), 3.82 (s,
3
4
2
.62–4.69 (m, 1H, CHCHMe
H, C H ), 7.77 (d, J=8.7Hz, 2H, C H ). C NMR
6 4 6 4
2
3
3
3
13
3
H, COOCH
3
), 4.22 (t, J= 5.19Hz, 2H, CH
2
CH
NRNR), 6.09
d, 1H, C H ), 6.83 (d, J=8.54Hz, 2H, C H OMe), 7.46
2
3
NRNR), 4.42 (t, J=5.19Hz, 2H, CH CH
(
2 2
(
(
(
1
(
CDCl3, 62.90MHz): 18.8 (CH3), 19.3 (CH3), 32.9
CHMe ), 46.7 (CH CH NRNR), 51.7 (COOCH ), 54.4
CH CH NRNR), 66.6 (CHCHMe ), 112.3, 120.4, 131.8,
50.0 (C ), 155.8 (R C@NR), 166.9 (s, COOMe). MS
ESI): m/z=302.4 [M+H] , 324.3 [M+Na] .
Compound 5c was isolated in 42% yield as a yellow oil. H
NMR (CDCl 250.13MHz): 3.31–3.40 (m, 2H,
CH CH NRNR), 3.76 (s,3H, OCH
3.12Hz, 1H, C H CH ), 3.94 (d, J=13.12Hz, 1H,
3
6
4
6
4
2
2
2
3
3
(
C
(
d, J=8.54Hz, 2H, C
H
6 4
OMe), 7.19–7.28 (m, 4H,
COOMe). C NMR (CDCl , 62.90MHz): 46.4
CH NRNR), 51.7 (CH CH NRNR), 51.8 (COO
CH ), 55.3 (OCH ), 66.3 (CHC H ), 111.7, 112.0, 114.9,
2
2
2
1
3
H
4
3
6
H
4
2
6
+
+
CH
2
2
2
2
1
3
3
6
4
1
16.9, 130.0, 131.6, 131.8, 134.9, 148.5, 160.0 (C
OMe, C OMe), 156.0 (R C@NR), 169.0 (COOMe).
MS (ESI): m/z=366.5 [M+H] , 388.4 [M+Na] .
6 4
H CO-
3
,
2
H
6 4
2
+
2
2
3
), 3.81 (d, J=
+
2
1
6
5
2

6424
M. Umkehrer et al. / Tetrahedron Letters 45 (2004) 6421–6424
1
Compound 5i was isolated in 67% yield as a yellow oil. H
62.90MHz): 44.7 (CH
2
CH
2
NRNR), 47.2 (C
52.2 (COOCH ), 53.6 [(MeO) CHCH ], 54.1 (OCH
2
CH
2
NRNR),
), 54.6
NMR (CDCl
CH ], 3.09–3.19 (m, 2H, CH CH NRNR), 3.23 (s, 3H,
3
, 250.13MHz): 2.72 [m, 2H, (MeO)
2
CH
3
2
2
3
(OCH ), 61.94 (CHC H ), 103.8 [(MeO) CH], 128.6, 130.1,
6
2
2
2
3
4
2
OCH
3
), 3.36 (s, 3H, OCH
3
), 3.92 (s, 3H, COOCH
3
), 4.38–
CH
4
H ), 7.47 (d, J=8.39Hz, 2H,
130.2, 141.9(C
6
H
4
), 152.6 (R+
2
C@NR), 166.5 (COOMe).
+
4.46 [m, 1H, (MeO)
NRNR), 5.18 (s, 1H, C
2
CH], 4.48–4.60 (m, 2H, CH
2
2
MS (ESI): m/z=348.4 [M+H] , 370.1 [M,+Na] .
19. Matteson, D. S.; Bailey, R. A. J. Am. Chem. Soc. 1968, 90,
3761.
3
6
3
13
C H ), 8.05 (d, J=8.39Hz, 2H, C H ). C NMR (CDCl3,
6
4
6
4