Gewald synthesis of aminothiophene carboxylic acids providing new dipeptide analogues

Article abstract of DOI:10.1055/s-0028-1087243

A new multicomponent synthesis of 2-aminothiophene carbocyclic acids 4 by reaction of methyl 2-siloxycyclopropane-carboxylates 1, alkyl cyanoacetates, and elemental sulfur is reported. This version of the Gewald thiophene synthesis rapidly provides a new type of δ-amino acids, which can be considered as dipeptide analogues. Smooth protective-group manipulations allowed regio-and chemoselective couplings with L-phenylalanine derivatives furnishing new tripeptide analogues such as 5 and 8 or products of type 10. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087243

LETTER
3145
Gewald Synthesis of Aminothiophene Carboxylic Acids Providing New
Dipeptide Analogues
Gewald Synthesis
ü
of
A
minothio
l
phene
y
Carboxylic
Acids Özbek, Ivana S. Veljkovic, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 29 August 2008
Dedicated to Professor Karl Gewald, Technische Universität Dresden
nor-acceptor-substituted cyclopropanes such as 17 serving
as equivalents of carbonyl compounds 2. The smooth in
situ ring opening of 1 in protic solvents or in the presence
of mild acids or fluoride reagent generates carbonyl com-
Abstract: A new multicomponent synthesis of 2-aminothiophene
carbocyclic acids 4 by reaction of methyl 2-siloxycyclopropane-
carboxylates 1, alkyl cyanoacetates, and elemental sulfur is report-
ed. This version of the Gewald thiophene synthesis rapidly provides
a new type of d-amino acids, which can be considered as dipeptide pounds 2 (Figure 2). Our group already developed other
analogues. Smooth protective-group manipulations allowed regio-
and chemoselective couplings with L-phenylalanine derivatives fur-
nishing new tripeptide analogues such as 5 and 8 or products of type
10.
multicomponent reactions employing cyclopropanes 1 as
masked carbonyl compounds, which led to various func-
tionalized heterocycles.8
Key words: multicomponent reaction, thiophenes, cyclopropanes,
amino acids, peptide analogues
R1
TMSO
O
CO2Me
R2
R1
R2
CO2Me
1
2
The synthesis of substituted 2-aminothiophenes via con-
densation of carbonyl compounds with methylene active Figure 2 Vicinally donor-acceptor-substituted cyclopropane deri-
vatives 1 as equivalents of carbonyl compounds 2
nitriles and elemental sulfur in the presence of organic
bases was reported in the 1960s by Gewald and co-work-
ers.1 This novel multicomponent reaction turned out to be-
The aminothiophene derivatives 4a–d were synthesized
come the most versatile and important method for the
preparation of 2-aminothiophenes.2 The thiophene scaf-
fold is required for a broad range of products including
dyes,3 pharmaceuticals,4 and agrochemicals.2a In addition,
this heterocyclic core is present in several natural prod-
ucts.5
employing two different protocols. We applied the classi-
cal one-pot/one-stage Gewald procedure and an alterna-
tive one-pot/two-stage procedure. In the first method the
methyl siloxycyclopropanecarboxylate 1a reacts with the
methylene active nitrile 3 in the presence of elemental sul-
fur and methanol to furnish thiophenes 4a–d. In the alter-
native one-pot/two-stage process the siloxycyclo-
propanecarboxylates 1 were cleaved with a fluoride
source to intermediate aldehydes 2 prior to addition of ni-
trile 3 and elemental sulfur (Scheme 1).
We explored the Gewald reaction as key step for the syn-
thesis of unnatural amino acids A containing a thiophene
backbone. Compounds A are d-amino acids6 and can be
considered as isosters to a natural dipeptide B (Figure 1).
We planned to use the conformationally restricted ami-
nothiophene acids A as building blocks in the synthesis of
linear and cyclic peptides and were therefore interested in
their efficient and flexible preparation.
In general, thiophene derivatives 4a–d were obtained in
moderate to good yields (see Scheme 2). Method A pro-
vided aminothiophene 4a (R1 = H, R2 = t-Bu) in 66%
yield9 whereas the alternative method B furnishes 4a in a
yield of only 44%.10 The corresponding methyl ester 4b
(R1 = H, R2 = Me) was isolated in 43% using method A,
whereas the use of the two-stage protocol afforded this
compound in 54%. With benzyl cyanoacetate 3c as pre-
cursor the 3-methoxycarbonyl-substituted thiophene 4b
(R1 = H, R2 = Me) was formed as a result of transesterifi-
cation of the benzyl ester intermediate. However, using
the two-stage protocol with DMF as solvent, the 3-benzyl-
oxycarbonyl group was retained and thiophene derivative
4c (R1 = H, R2 = Bn) was isolated in 44% yield.
R2
O
R2
O
H
N
HO
HO
NH2
NH2
S
R1
O
R1
A
B
Figure 1 2-Aminothiophene carboxylic acids A as isosters of di-
peptides B
In the original Gewald protocol ketones, aldehydes, or
1,3-dicarbonyl compounds were used to synthesize sub-
stituted thiophenes. We planned to employ vicinally do-
Trisubstituted cyclopropane derivative 1b bearing an ad-
ditional benzyl substituent at C-111 was also used as start-
ing material. The multicomponent reaction with 3a
(method A) furnished aminothiophene 4d in moderate
SYNLETT 2008, No. 20, pp 3145–3148
1
6
.1
2
.2
0
0
8
Advanced online publication: 24.11.2008
DOI: 10.1055/s-0028-1087243; Art ID: G29408ST
© Georg Thieme Verlag Stuttgart · New York

3146
H. Özbek et al.
LETTER
one-pot/one-stage
CO2R2 (3a–c), S, base, MeOH
The use of amino-protected thiophene carboxylic acids in
peptide coupling reactions was also examined. Typical
amino protective groups such as Boc, Cbz, and Fmoc13
were effectively introduced transforming 4a into 6a–c
(Scheme 4). Saponification of 6a (PG = Boc) and 6b
(PG = Cbz) with LiOH at room temperature smoothly
gave the corresponding carboxylic acids 7a and 7b in very
good yields (87–97%). Hydrolysis of the Fmoc-protected
derivative 6c using 3 equivalents of LiOH at 0 °C fur-
nished 7c in only 33% yield. Not unexpectedly, the N-
deprotected thiophene derivative was isolated in 29% as
side product.14
NC
CO2R2
NH2
R1
CO2Me
1a,b
TMSO
O
MeO
S
R1
4a–d
O
CO2Me
R1
1) F–, DMF, base
H
2) NCCH2CO2R2
CO2t-Bu
NHPG
CO2t-Bu
NHPG
2a,b
(3a–c), S
O
O
one-pot/two-stage
4a
MeO
HO
S
S
Scheme 1 Synthesis of 2-aminothiophene carboxylic acids 4a–d
via one-pot/one-stage Gewald reaction (method A) and the alternative
one-pot/two-stage procedure (method B; for substituents R1 and R2
see Scheme 2)
PG = Boc:a
PG = Cbz:b
PG = Fmoc:c
6a 78%
6b 84%
6c 78%
7a 87%
7b 97%
7c 33%
Scheme 4 Synthesis of amino-protected thiophene derivatives 6a–c
and amino-protected thiophene carboxylic acids 7a–c. Reagents and
conditions: protection: a) 1) Boc2O (1.6 equiv), DMAP (1.0 equiv),
MeCN, r.t., 10 min. 2) t-BuOH (1.6 equiv), MeCN, reflux, 62 h.15 b)
CbzCl (1.6 equiv), EtOAc, reflux, 1 d.16 3) FmocCl (1.2 equiv), Et2O,
0 °C, 20 min, then r.t., 89 h.17 Hydrolysis: a) LiOH (3.0 equiv), THF–
H2O (3:2), r.t., 24 h; b) LiOH (3.0 equiv), THF–H2O (3:2), r.t., 2 h; c)
0.2 N LiOH (3.0 equiv), THF, 0 °C, 1 h.18
CO2R2
O
method A or B
CO2R2
R1
TMSO
MeO
NH2
S
R1
CO2Me
CN
1a,b
3a–c
4a–d
4a R1 = H, R2 = t-Bu 66% (A), 44% (B)
4b R1 = H, R2 = Me 43% (A), 54% (B)
4c R1 = H, R2 = Bn 44% (B)
The PyBROP-mediated coupling12 of carboxylic acid 7b
with L-phenylalanine methyl ester hydrochloride (H–
Phe–OMe·HCl) in the presence of Hünig base provided
the desired tripeptide analogue 8 in 80% yield
(Scheme 5).
4d R1 = Bn, R2 = t-Bu 37% (A)
Scheme 2 Synthesis of thiophene derivatives 4a–d. Reagents and
conditions: method A: one-pot/one-stage procedure: 1a,b (1.05
equiv), 3a–c (1.0 equiv), S (1.0 equiv), Et2NH (1.0 equiv), MeOH, re-
flux, 7 h, r.t., overnight; method B: one-pot/two-stage procedure: a)
1a (1.05 equiv), DMF, Et3N (2.9 equiv), Et3N·HF (37%, 1.2 equiv),
r.t., 1 h; b) 3a–c (1.0 equiv), S (1.0 equiv.), 60–75 °C, 7 h, r.t., over-
night.
The presence of the methoxycarbonyl and the tert-butyl-
carbonyl groups allows clear differentiation of the two
functional groups of compounds such as 6b. The high
yielding cleavage of the tert-butyl ester of 6b was accom-
plished using trifluoroacetic acid in the presence of trieth-
ylsilane without touching the methyl ester (Scheme 6).19
Components such as 9 may also serve as amino acid iso-
sters, here with the potential to induce a b-turn.20 Peptide
coupling of thiophene carboxylic acid 9 with L-phenylala-
nine methyl ester hydrochloride (H–Phe–OMe·HCl) us-
ing BOP as reagent12 and DMAP in CH2Cl2 yielded 10 in
almost quantitative yield (Scheme 6).
37% yield. This product can be regarded as dipeptide iso-
ster with a phenylalanine substructure. Other substituents
at C-1 of the precursor cyclopropane 1 should allow the
preparation of different aminothiophene carboxylic acids
of type 4 mimicking other dipeptides.
We investigated the applicability of the aminothiophene
carboxylic acids 4a–d in the synthesis of small peptide an-
alogues. Coupling of 4a with N-Cbz-protected L-phenyl-
alanine (Cbz–Phe–OH) using PyBOP as reagent12 and
DMAP in CH2Cl2 gave tripeptide analogue 5 in very good
yield (Scheme 3).
In conclusion, several 2-aminothiophene carboxylic acids
are smoothly available by the multicomponent reaction
employing siloxycyclopropanes in the Gewald reaction.
We could demonstrate that selective protections and
CO2t-Bu
O
CO2t-Bu
O
a
O
MeO
MeO
84%
NH2
S
N
NHCbz
S
H
Bn
5
4a
Scheme 3 Synthesis of tripeptide analogue 5. Reagents and conditions: a) Cbz–Phe–OH (1.2 equiv), PyBOP (1.5 equiv), DMAP (3.0 equiv),
CH2Cl2, r.t., 24 h.
Synlett 2008, No. 20, 3145–3148 © Thieme Stuttgart · New York

LETTER
Gewald Synthesis of Aminothiophene Carboxylic Acids
3147
CO2t-Bu
NHCbz
Bn
CO2t-Bu
NHCbz
O
O
a
MeO2C
HO
N
80%
H
S
S
7b
8
Scheme 5 Synthesis of tripeptide anlogue 8. Reagents and conditions: a) H–Phe–OMe·HCl (1.0 equiv), PyBrOP (1.5 equiv), DIPEA (3.0
equiv), CH2Cl2, r.t., 24 h.
Bn
O
CO2Me
CO2H
NH
O
O
b
MeO
MeO
NHCbz
NHCbz
S
S
96%
10
91%
9
a
6b
Scheme 6 Cleavage of the tert-butyl ester of N- and C-protected thiophene 6b and synthesis of peptide analogue 10. Reagents and conditions:
a) TFA (13 equiv), Et3SiH (2.5 equiv), CH2Cl2 (32 equiv), r.t., 12 h; b) Phe–OMe·HCl (1.0 equiv), BOP (1.5 equiv), DMAP (3.0 equiv), CH2Cl2,
r.t., 24 h.
(7) (a) Kunkel, E.; Reichelt, I.; Reissig, H.-U. Liebigs Ann.
Chem. 1984, 512. Forreviewsofdonor-acceptor-substituted
cyclopropanes, see: (b) Reissig, H.-U. Top. Curr. Chem.
1988, 144, 73. (c) Reissig, H.-U.; Zimmer, R. Chem. Rev.
2003, 103, 1151.
(8) (a) Reichelt, I.; Reissig, H.-U. Synthesis 1984, 786.
(b) Grimm, E. L.; Reissig, H.-U. J. Org. Chem. 1985, 50,
242. (c) Grimm, E. L.; Zschiesche, R.; Reissig, H.-U. J. Org.
Chem. 1985, 50, 5543. (d) Ullmann, A.; Schnaubelt, J.;
Reissig, H.-U. Synthesis 1998, 1052. (e) Zimmer, R.;
Ziemer, A.; Gruner, M.; Brüdgam, I.; Hartl, H.; Reissig,
H.-U. Synthesis 2001, 1649. (f) Patra, P. K.; Reissig, H.-U.
Eur. J. Org. Chem. 2001, 4195. (g) Veljkovic, I.; Zimmer,
R.; Reissig, H.-U.; Brüdgam, I.; Hartl, H. Synthesis 2006,
2677.
deprotections are possible affording precursors for pep-
tide couplings in three different positions leading to new
peptide analogues.21 The synthesis of extended acyclic
and of macrocyclic peptides incorporating the new 2-ami-
nothiophenes will be reported in due course.
Acknowledgment
Support by the Graduiertenkolleg 788 (PhD fellowship for ISV and
HÖ), the Deutsche Forschungsgemeinschaft, the Fonds der Chemi-
schen Industrie, and the Bayer Schering Pharma AG is most grate-
fully acknowledged. We also thank Houda Al-Ajmi and Keith
Bentley for preliminary results and Dr. Reinhold Zimmer for dis-
cussions and help during preparation of this manuscript.
(9) Typical Procedure for the Synthesis of 2-Aminothio-
phene 4a Using the One-Pot/One-Stage Procedure
Siloxycyclopropanecarboxylate 1a (0.209 g, 1.06 mmol),
tert-butyl cyanoacetate (0.143 g, 1.01 mmol) and sulfur
(0.032 g, 1.01 mmol) were suspended in MeOH (2 mL), then
Et2NH (0.11 mL, 1.01 mmol) was added. The mixture was
refluxed for 7 h, and then stirred overnight at r.t. After
addition of water and EtOAc the layers were separated and
the aqueous layer was extracted two times with EtOAc. The
combined organic layers were dried with Na2SO4, filtered,
and concentrated. Column chromatography (SiO2, hexane–
EtOAc = 8:1 to 7:1 to 6:1) provided 0.180 g (66%) 4a as a
brownish oil.
References and Notes
(1) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99,
94.
(2) For a review on the synthesis of 2-aminothiophenes by
Gewald reaction, see: (a) Sabnis, R. W.; Rangnekar, D. W.;
Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333. For a
review on multicomponent reactions of carbonyl compounds
and derivatives of cyanoacetic acid, see: (b) Shestopalov,
A. M.; Shestopalov, A. A.; Rodinovskaya, L. A. Synthesis
2008, 1.
(3) Maradiya, H. R. Turk. J. Chem. 2001, 25, 441.
(4) (a) LaPorte, M. G.; Lessen, T. A.; Leister, L.; Cebzanov, D.;
Amparo, E.; Faust, C.; Ortlip, D.; Bailey, T. R.; Nitz, T. J.;
Chunduru, S. K.; Young, D. C.; Burns, C. J. Bioorg. Med.
Chem. Lett. 2006, 16, 100. (b) Gütschow, M.; Kuerschner,
L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger,
K. J. Med. Chem. 1999, 42, 5437.
Analytical Data for tert-Butyl 2-Amino-5-(2-methoxy-2-
oxoethyl)thiophene-3-carboxylate (4a)
1H NMR (500 MHz, CDCl3): d = 1.50 [s, 9 H, C(CH3)3],
3.56 (s, 2 H, CH2), 3.68 (s, 3 H, OCH3), 5.90 (br s, 2 H, NH2),
6.70 (s, 1 H, CH). 13C NMR (126 MHz, CDCl3): d = 28.3 [q,
C(CH3)3], 35.0 (t, CH2), 52.1 (q, OCH3), 79.9 [s, C(CH3)3],
107.6 (s, C-2), 115.4 (s, C-5), 125.4 (d, C-4), 162.0 (s, C-3),
164.7, 170.9 (2 s, CO). IR (film): 3445–3255 (NH), 3070–
2845 (CH), 1740, 1670 (C=O), 1590, 1500, 1455 (NH,
CSNH) cm–1. MS (EI, 80 eV, 60 °C): m/z (%) = 271 (14)
[M]+, 215 (59) [M – C4H9]+, 197 (33) [M – C5H12]+, 156
(100) [M – C5H12O2]+, 138 (61), 57 (37) [C4H9]+. HRMS (EI,
80 eV, 60 °C): m/z calcd for C12H17NO4S: 271.0878; found:
271.0880. Anal. calcd for C12H17NO4S (271.3): C, 53.12; H,
(5) Koike, K.; Jia, Z.; Nikaido, T.; Liu, Y.; Zhao, Y.; Guo, D.
Org. Lett. 1999, 1, 197.
(6) (a) Bonauer, C.; Zabel, M.; König, B. Org. Lett. 2004, 6,
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(d) Baldauf, C.; Günther, R.; Hofmann, H.-J. J. Org. Chem.
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Magull, J.; de Meijere, A. Chem. Eur. J. 2006, 12, 8336.
Synlett 2008, No. 20, 3145–3148 © Thieme Stuttgart · New York

3148
H. Özbek et al.
LETTER
6.32; N, 5.16; S, 11.82. Found: C, 53.37; H, 6.43; N, 5.16; S,
11.95.
(15) Knölker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1996, 37,
5861.
(10) We also prepared thiophene 4a in 61% yield starting from
commercially available aldehyde 2a using a one-pot/one-
stage Gewald procedure (method A). Although the result is
comparable with the yield we achieved with cyclopropane
1a the very high cost of aldehyde 2a (100 mg, 77 €) is almost
prohibitive for large-scale preparations of 4a.
(11) Reichelt, I.; Reissig, H.-U. Liebigs Ann. Chem. 1984, 531.
(12) (a) For a review on recent development of peptide coupling
reagents in organic synthesis, see: Han, S.-Y.; Kim, Y.-A.
Tetrahedron 2004, 60, 2447. (b) For a review on chemical
synthesis of natural product peptides, see: Humphrey, J. M.;
Chamberlin, A. R. Chem. Rev. 1997, 97, 2243.
(16) Kruse, C. H.; Holden, K. G. J. Org. Chem. 1985, 50, 2792.
(17) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37, 3404.
(18) Burke, T. R.; Ye, B. Jr.; Akamatsu, M.; Ford, H.; Yan, X. Jr.;
Kole, H. K.; Wolf, G.; Shoelson, S. E.; Roller, P. P. J. Med.
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(21) During peptide couplings presented here we did not observe
racemization of the amino acid moiety since subsequent
couplings with a second amino acid provided only one
diastereomer.
(13) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 4th ed.; Wiley: New York, 2006.
(14) Alternatively, 7c was synthesized in 59% overall yield by a
reversed reaction sequence.
Synlett 2008, No. 20, 3145–3148 © Thieme Stuttgart · New York

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