New cleavable isocyanides for the combinatorial synthesis of α-amino acid analogue tetrazoles

Article abstract of DOI:10.1016/j.tetlet.2005.08.101

3-Substituted 3-isocyano propionates as new cleavable isocyanides in combinatorial tetrazole synthesis via Ugi-reaction are introduced. The obtained 5-substituted tetrazoles are transformed into carboxylic acid isosteric 5-substituted 1H-tetrazoles under basic cleavage conditions.

Full text of DOI:10.1016/j.tetlet.2005.08.101

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7393–7396
New cleavable isocyanides for the combinatorial synthesis of
a-amino acid analogue tetrazoles
a,b
a,b
Josef Mayer,a,b, Michael Umkehrer, Cedric Kalinski, Gunther Ross,a Jurgen Kolb,a
*
´
¨
¨
Christoph Burdacka and Wolfgang Hillerb
aPriaton GmbH, Bahnhofstr. 9-15, D-82327 Tutzing, Germany
bTechnical University Munich, Lichtenbergstr. 4, D-85747 Garching, Germany
Received 8 July 2005; revised 19 August 2005; accepted 22 August 2005
Available online 9 September 2005
This paper is dedicated to Professor Ivar K. Ugi on his 75th birthday
Abstract—3-Substituted 3-isocyano propionates as new cleavable isocyanides in combinatorial tetrazole synthesis via Ugi-reaction
are introduced. The obtained 5-substituted tetrazoles are transformed into carboxylic acid isosteric 5-substituted 1H-tetrazoles
under basic cleavage conditions.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In 1956, Herbst suggested that in biologically active car-
boxylic acids, the replacement of carboxyl group with a
5-tetrazolyl group may create compounds with interest-
ing properties.1 Therefore, many amino acid analogous
tetrazoles were synthesized.2,3 In these, carboxylic group
is isosterically replaced by a 5-tetrazolyl group4,5 to pro-
duce amino acids analogues.
sity. Therefore, Ugi and Steinbruckner developed the
¨
first multicomponent reaction (MCR) yielding bis-
substituted tetrazoles, which gives a versatile access to
an enormous structural diversity in a simple one-pot
procedure. Mixing an oxo-component, an amine, tri-
methylsilyl azide (as hydrazoic acid equivalent) and isocy-
anide in a ratio of 1/1/1.5/1.5 in methanol leads to the
formation of the tetrazoles in the MCR (Scheme 1). This
reaction is initiated by condensation of an appropriately
substituted aldehyde or ketone with a reactive amine.
Subsequent reaction with isocyanide produces the inter-
mediate nitrilium ion, as a key intermediate. The desired
The earliest published methods for the preparation of 5-
substituted tetrazoles were reactions of nitriles with
azides.6 Until now most methods are based on nitriles,
so these are the limiting compounds for structural diver-
+ CNCH(R4)CH2COOR
-
R1
N
R2
R1
N
H
R2
R3
O
- H2O
+ H2O
+
+
+ N3
R1 NH2
+
+ H
- H
+
2
R
R3
R3
R1
R2
R3
R1
N
R2
R3
N
CH(R4)CH2COOR
H
N
CH(R4)CH2COOR
H
N
N
+
-
N
N
N
N
N
Scheme 1. Mechanism of tetrazole-U-4CR.
Keywords: Cleavable isocyanides; 1H-Tetrazole; 1H-Tetrazole U-4CR; Combinatorial chemistry.
*
Corresponding author. Tel.: +49 8928913207; fax: +49 8928914587; e-mail: Josef.Mayer@lrz.tum.de
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.101

7394
J. Mayer et al. / Tetrahedron Letters 46 (2005) 7393–7396
tetrazole is obtained by reaction with the azide, followed
by sigmatropic rearrangement.7,8
in the same way (with R = Me), starting with commer-
cially available aspartic acid.
In 1964, Ugi and Offermann9 described amines with an
acidic proton in b-position to amino group as cleavable
amine components in MCRs. Abstraction of the acidic
b-H with alkoxides leads to elimination of stable a-b-
unsaturated esters. We decided to apply the same princi-
ple to our new corresponding isocyanides analogously.
Using isocyanides 1 and 2 several 5-substituted tetra-
zoles 3a–h and 4i–k14—bearing three points of diver-
sity—are synthesized in good yields (Table 1). Upon
treatment with an alkoxide base 5-substituted 1H-tetra-
zoles 5a–k15 (Table 1) are obtained. The proposed b-
elimination mechanism is also promoted by mesomeric
stabilization of the delocalized charge over the whole
tetrazole ring system (Scheme 3). Using potassium
tert-butoxide the cleavage is faster, attaining higher
yields in comparison to sodium ethanolate. With ethano-
late base the reaction conditions are slightly milder
especially for compound 3d and e, where otherwise par-
tial cleavage of the acetal group and consecutive reac-
tions were observed.
The sequence of tetrazole-U-4CR using our new iso-
cyanides followed by basic cleavage of this isocyanide
moiety leads to 1H-tetrazoles in an easy way.
The new cleavable isocyanide 3-isocyano-3-phenyl-eth-
ylpropionate 1 is synthesized starting with b-amino acid
obtained by an a-amino alkylation.10 This compound is
esterified in ethanol with thionyl chloride. After formyl-
ation in ethyl formate, the isocyanide is obtained by
dehydration in a two-step procedure. First, the formam-
ide solved in dry methylene chloride is treated with
phosphoryl chloride in the presence of triethylamine.
When the reaction is finished, an aqueous solution of
sodium carbonate is added. After extraction, the
pure product is obtained by distillation (Scheme 2).11–13
2-Isocyano succinic acid dimethylester 2 is synthesized
O
NH2
NC
ROOC
ROOC
a
b, c, d
4
R
H
R4
R4
Scheme 2. Synthesis of the isocyanides. Reagents: (a) NH4OAc,
malonic acid, MeOH; (b) SOCl2, ROH; (c) Et3N, ROCHO; (d) (1)
POCl3, Et3N, CH2Cl2, (2) Na2CO3, H2O.
R1
N
R2
R3
R1
N
R2
R3
R1
N
R2
R3
R1
N
R2
R3
R1
N
R2
R3
COOR
R4
HCl
H
N
H
N
+
ROOC
H
H
N
H
N
H
N
N
N
THF
THF
N
N
-
N
N
N
N
HN
N
N
N
-
-
H
-
N
N
N
R'O
R4
5
3: R = Et, R4 = C6H5
4: R = Me, R4 = COOMe
Scheme 3. Proposed cleavage mechanism of the isocyanide moiety by b-elimination.
Table 1. Synthesized tetrazoles 5a–k
R1
N
R2
R3
R1
N
R2
R3
NC
O
1. base
2. HCl
ROOC
R1 NH2
H
N
(H3C)3SiN3
+
+
+
MeOH
ROOC
2
R
R3
R4
H
N
N
N
1: R = Et, R4 = C6H5
2: R = Me, R4 = COOMe
HN
N
N
N
R4
3: R = Et, R4 = C6H5
4: R = Me, R4 = COOMe
5
R1
R2
R3
R4
R
Yield (%)
Product
Base
Yield (%)
Product
PhCH2
PhCH2
PhCH2
(MeO)2CHCH2
(MeO)2CHCH2
p-MeOCOC6H4
Ph2CH
PhCH2
PhCH2
PhCH2
PhCH2
(CH3)2CH
p-MeOC6H4
p-BOCNHC6H4
Ph
p-MeOC6H4
(CH3)2CH
(CH3)2CH
Me
H
H
H
H
H
H
H
Me
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Et
Et
Et
Et
Et
Et
Et
Et
89
83
92
65
40
37
42
67
77
88
73
3a
3b
3c
3d
3e
3f
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
KO-t-Bu
NaOEt
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
33
45
56
65
36
47
65
37
42
67
55
5a
5b
5c
5d
5e
5f
3g
3h
4i
5g
5h
5i
(CH3)2CH
Ph
Me
COOMe
COOMe
COOMe
Me
Me
Me
H
Me
4j
4k
5j
5k

J. Mayer et al. / Tetrahedron Letters 46 (2005) 7393–7396
7395
1H, –CH(CH3)2], 2.96 (d, 2J = 13.2 Hz, 1H, –NHCH2Ph),
3.11 (dd, 3J = 5.0 Hz, 2J = 12.02 Hz, 1H, –CH2COOEt),
In summary, combinatorial synthesis of 5-substituted
tetrazoles with new cleavable isocyanides has been
reported. With final products containing three points
of potential diversity, access to huge amount of diverse
analogues is now feasible. Current efforts are now focus-
ing on the diverse combinations of cleavable amines and
the described isocyanide components in Ugi-tetrazole-
MCR widening the domain of 1H-tetrazoles.
3
2
3.17 (dd, J = 4.99 Hz, J = 12.02 Hz, 1H, –CH2COOEt),
3.37 (d, 2J = 13.2 Hz, 1H, –CH2NH–), 3.74 [m, 1H, –CH-
(NHCH2Ph)(CHMe2)], 4.08 (m, 2H, –COOCH2CH3),
5.87 [dd, 3J = 5.0 Hz, 3J = 4.99 Hz, 1H, –CH(Ph)CH2-
COOEt], 6.99–7.34 (m, 10H, –C6H5). 13C NMR (CDCl3,
90.56 MHz): 13.8 (–COOCH2CH3), 18.5 [–CH(CH3)2],
19.2 [–CH(CH3)2], 31.9 [–CH(CH3)2], 40.9 (–CH2COOEt),
50.9 (–CH2C6H5), 57.4 (–CH(Ph)CH2COOEt), 58.8 [–CH-
(NHCH2Ph)(CHMe2)], 61.0 (–COOCH2CH3), 126.5,
126.9, 127.8, 128.0, 128.2, 129.0, 137.3, 139.4 (–C6H5),
156.9 [–CN4CH(Ph)CH2COOEt], 170.8 (–COOEt). MS
(ESI): m/z = 408.3 [M+1]+, 430.2 [M+Na]+.
References and notes
1. Herbst, R. M. In Essays in Biochemistry; Graff, S., Ed.;
John Wiley and Son Inc.: New York, 1956; p 141.
2. McManus, J. M.; Herbst, R. M. J. Org. Chem. 1959, 24,
1643.
3. Morley, J. S. J. Chem. Soc. C 1969, 5, 809.
4. Thornber, C. W. Chem. Soc. Rev. 1979, 8, 563.
5. Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26,
499.
Compound 3b was isolated in 83% yield as a yellow oil. 1H
NMR (CDCl3, 250.13 MHz): 1.15 (m, 3H, –COO-
CH2CH3), 3.01 (m, 1H, –CH2COOEt), 3.09 (m, 1H,
–CH2COOEt), 3.45 (m, 2H, –NHCH2Ph), 3.75 (s, 3H,
3
–OCH3), 3.98 (q, J = 7.02 Hz, 2H, –COOCH2CH3), 5.03
[s, 1H, –CH(NHCH2Ph)C6H4OMe], 5.81 (m, 1H,
–CH(Ph)CH2COOEt), 6.72–7.39 (m, 14H, –C6H5,
–C6H4). 13C NMR (CDCl3, 62.90 MHz): 13.9 (–COO-
CH2CH3), 40.6 (–CH2COOEt), 51.0 (–NHCH2Ph), 55.2
(–OCH3), 55.5 [–CH(Ph)CH2COOEt], 58.4 [–CH(NH-
CH2Ph)C6H4OMe], 61.2 (–COOCH2CH3), 114.2, 126.5,
126.8, 127.2, 128.1, 128.4, 128.5, 128.8, 129.3, 136.4, 138.9,
159.6 (aryl), 156.0 [–CN4CH(Ph)CH2COOEt], 169.2
(–COOEt). MS (ESI): m/z = 472.2 [M+1]+, 494.1
[M+Na]+.
6. Kadaba, P. K. Synthesis 1973, 2, 71.
7. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
8. Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734.
¨
9. Ugi, I.; Offermann, K. Chem. Ber. 1964, 97, 2996.
10. Tan, C. Y. K.; Weaver, D. F. Tetrahedron 2002, 58,
7449.
11. Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Ottermann,
K. Angew. Chem. 1965, 77, 492.
12. Ugi, I.; Meyr, R. Angew. Chem. 1958, 70, 702.
13. Procedure for isocyanides 1 and 2: 0.1 mol POCl3 are
added dropwise to 0.1 mol of the 3-formylamino alkyl
propionate, solved in 100 mL dry CH2Cl2, in the presence
of 0.248 mol triethylamine. After stirring 1 h the reaction
mixture is treated with 20 g Na2CO3 in 80 mL water at 20–
25 ꢁC. After stirring 1 h the deposit is filtered off. The
separated dichloromethane layer is washed three times
with brine and dried over K2CO3. The solvent is reduced
in vacuo.
Compound 3e was isolated in 40% yield as a yellow oil. 1H
NMR (CDCl3, 250.13 MHz): 1.11 (t, 3J = 7.02 Hz, 2J =
14.3 Hz, 3H, –COOCH2CH3), 2.48 (dd, 3J = 5.49 Hz,
2J = 11.9 Hz, 1H, –CH2COOEt), 2.59 (dd, 3J = 5.5 Hz,
2J = 11.9 Hz, 1H, –CH2COOEt), 3.27 [s, 3H, –CH-
(OCH3)2], 3.28 [s, 3H, –CH(OCH3)2], 3.50 [m, 2H,
–NHCH2CH(OMe)2], 4.00 (q, J = 7.02 Hz, 2H, –COO-
CH2CH3), 4.39 [m, 1H, –CH(Ph)CH2COOEt], 5.03 [s, 1H,
–CH(C6H4OMe)NHCH2CH(OMe)2], 7.14–7.39 (m, 9H,
–C6H4, –C6H5). 13C NMR (CDCl3, 62.90 MHz): 13.9
(–COOCH3CH2), 40.9 (–CH2COOEt), 48.6 [–NHCH2-
CH(OMe)2], 53.7, 53.9 [–CH(OCH3)], 55.3 (–OCH3), 56.9
[–CH(Ph)CH2COOEt], 58.6 [–CH(C6H4OMe)NHCH2-
CH(OMe)2], 61.1 (–COOCH2CH3), 103.6 [–CH(OCH3)2],
114.3, 126.7, 128.8, 129.1, 137.0, 159.7 (aryl), 155.9
[–CN4CH(Ph)CH2COOEt], 169.2 (–COOEt). MS (ESI):
m/z = 470.2 [M+1]+, 492.3 [M+Na]+.
Compound 1 was obtained as a transparent, colourless
liquid in a yield of 46% by distillation (bp: 110 ꢁC/
1.8 · 10À2 mbar). 1H NMR (CDCl3, 250.13 MHz): 1.26 (t,
3H, 2J = 14.19 Hz, 3J = 7.02 Hz, –COOCH2CH3), 2.95
(dd, 2H, 2J = 16.02 Hz, 3J = 8.85 Hz, –CH2COOEt),
4.20 (q, 2H, 3J = 7.17 Hz, –COOCH2CH3), 5.18 (t, 1H,
3J = 8.24 Hz, –CHNC), 7.38 (s, 5H, –C6H5). 13C NMR
(CDCl3, 62.89 MHz): 14.0 (–COOCH2CH3), 43.4
(–CH2COOEt), 54.7 (–CHNC), 61.2 (–COOCH2CH3),
125.9, 128.7, 129.0, 136.0 (–C6H5), 158.2 (–NC), 168.7
(–COOEt).
Compound 2 was obtained as a pale yellow oil in a yield of
41% by distillation (bp: 127 ꢁC/1.8 · 10À2 mbar).
1H NMR (CDCl3, 250.13 MHz): 3.02 (dd, 2H, 2J =
12.50 Hz, 3J = 5.80 Hz, –CH2–), 3.77 (s, 3H, –CH2-
COOCH3), 3.87 (s, 3H –COOCH3), 4.69 (t, 1H, 3J =
6.04 Hz, –CHNC).
15. Typical procedure: to 1 mmol of 3a–h or 4i–k in dry
tetrahydrofuran 1.2 equiv of the base are added under
nitrogen atmosphere. After stirring overnight, the mixture
is neutralized with hydrochloric acid. Then solvent is
removed under vacuum and water is added. This residue is
extracted with ethyl acetate three times. The combined
organic layers are dried, concentrated and finally dried
under vacuum.
Compound 5a was isolated in 33% yield as a white solid.
1H NMR (D2O, 360.13 MHz): 0.75 [d, 3J = 6.8 Hz, 3H,
3
14. Typical procedure for synthesis of tetrazoles 3 and 4.
Aldehyde (10 mmol) and amine (10 mmol) are stirred in
10 mL methanol at room temperature for 1 h and then
15 mmol of trimethylsilyl azide and 15 mmol of isocyanide
are added. The reaction mixture is stirred for 48 h at room
temperature until the reaction is completed (indication by
TLC). Then the solvent is removed under vacuum and the
resulting residue is purified by column chromatography on
silica gel with hexane/ethyl acetate (1:1).
–CH(CH3)2], 0.81 [d, J = 6.8 Hz, 3H, –CH(CH3)2], 2.35
[m, 6.4 Hz, 1H, –CH(CH3)2], 4.07 (s, 2H, –NHCH2Ph),
6.54 [d, 3J = 6.4 Hz, 1H, –CH(NHCH2Ph)(CHMe2)],
7.17–7.35 (m, 5H, –C6H5). 13C NMR (D2O/1% D3COD,
90.56 MHz): 17.6 [–CH(CH3)2], 19.8 [–CH(CH3)2], 31.8
[–CH(CH3)2], 51.7 (–CH2Ph), 59.3 [–CH(NHCH2Ph)-
(CHMe2)], 129.9, 130.8, 131.4, 131.7 (–C6H5), 155.9
(–CN4H). MS (ESI): m/z = 231.3 [M+1]+, 253.2
[M+Na]+.
Compound 3a was isolated in 89% yield as a white solid.
Compound 5b was isolated in 30% yield as a white solid.
1H NMR (DMSO, 250.13 MHz): 3.55 (s, 2H, –CH2Ph),
3.69 (s, 3H, –OCH3), 4.87 [s, 1H, –CH(NHCH2-
Ph)C6H4OMe], 6.80 (d, J = 8.54 Hz, 2H, –C6H4),
1H NMR (CDCl3, 360.13 MHz): 0.47 [d, 3J = 6.58, 3H,
3
–CH(CH3)2], 0.76 [d, J = 6.58, 3H, –CH(CH3)2], 1.17 (t,
2
3J = 7.27 Hz, J = 14.5 Hz, 3H, –COOCH2CH3), 1.95 [m,

7396
J. Mayer et al. / Tetrahedron Letters 46 (2005) 7393–7396
7.23–7.31 (m, 7H, –C6H4, –C6H5). 13C NMR (DMSO,
Compound 5k was isolated in 55% yield as a white solid.
1H NMR (DMSO, 250.13 MHz): 1.74 [s, 6H, –C(CH3)2],
3.90 (s, 2H, –CH2Ph), 7.37 (m, 5H, –C6H5). 13C NMR
(DMSO 62.90 MHz): 25.3 [–C(CH3)2], 46.0 (–CH2Ph),
128.4, 129.8, 133.7 (aryl), 161.6 (–CN4H). MS (ESI):
m/z = 232.3 [M+1]+, 254.2 [M+Na]+.
69.90 MHz): 50.5 (–CH2Ph), 55.0 (–OCH3), 57.4
[–CH(NHCH2Ph)C6H4OMe], 113.1, 126.4, 127.9, 128.1,
128.9, 135.9, 140.9, 163.4 (–C6H4, –C6H5), 157.8
(s, –CN4H). MS (ESI): m/z = 296.3 [M+1]+, 317.2
[M+Na]+.