Ammonia in Ugi reactions - Four-component versus six-component couplings

Article abstract of DOI:10.1055/s-2005-863722

If ammonia is used as amine component in Ugi reactions, the desired peptide sometimes is obtained only as the minor product or in traces. Side reactions such as six-component couplings are responsible for this observation. These side reactions can be suppressed or favoured depending on the reaction conditions used.

Full text of DOI:10.1055/s-2005-863722

LETTER
757
Ammonia in Ugi Reactions – Four-Component versus Six-Component
Couplings
Ammonia in
Ugi
i
Reactio
g
ns obert Pick, Michael Bauer, Uli Kazmaier,* Christina Hebach
Institut für Organische Chemie, Universität des Saarlandes, Postfach 151150, 66041 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 5 January 2005
ammonium benzoate was treated with isobutyraldehyde
(R = i-Pr) and the isonitrile in a 1:1:1 ratio, peptide 1 was
obtained only in traces (5%) while the major product was
2, which was isolated in 33% yield. Obviously a six-com-
ponent coupling is more favoured under these conditions
than the Ugi four-component reaction. To suppress this
undesired side reaction we decided to use a less nucleo-
philic solvent. Indeed, in trifluoroethanol no such side
product was observed, and the required Ugi product was
obtained in 45% yield.
Abstract: If ammonia is used as amine component in Ugi reactions,
the desired peptide sometimes is obtained only as the minor product
or in traces. Side reactions such as six-component couplings are
responsible for this observation. These side reactions can be sup-
pressed or favoured depending on the reaction conditions used.
Key words: ammonia, peptide, Ugi reactions, six-component cou-
pling
Non-proteinogenic amino acids are found in a wide range
of peptides and cyclopeptides produced by marine organ-
isms and microorganisms.1 Many of these structures, es-
pecially the cyclic peptides, are highly interesting from a
pharmaceutical point of view.2 Unfortunately, the quanti-
ties isolated from natural resources are often very small,
and therefore for therapeutic applications and/or for struc-
ture–activity investigations efficient synthetic concepts
are necessary to provide enough material. Multicompo-
nent reactions such as the Ugi reaction allow a straightfor-
ward approach towards peptide fragments containing
unnatural amino acids.3 In most cases good results are ob-
tained with primary amines, giving rise to a wide range of
N-alkylated peptides. In contrast, only a few examples are
described where ammonia was used as a nitrogen source.4
This is quite surprising, because the ‘more natural’ NH
amide bonds are formed in this case. But in general the
yields obtained with ammonia are significantly lower,
compared to other amines.
Scheme 1 Ugi reactions with ammonium salts
Recently, we reported a straightforward approach towards A similar effect was observed during replacing the iso-
the synthesis of cyclic peptides using the Ugi reaction in butyraldehyde by the sterically more demanding pivalde-
combination with a ring-closing metathesis (RCM).5 As hyde. In this case, the desired Ugi product could be
described by Grubbs and others, RCM is a very powerful obtained in excellent yield. Even in methanol as solvent
tool for the synthesis of cyclic peptide structures.6
the yield was higher than 50%.7 Similar observations were
described previously by Whittaker et al.8
During these investigations we became interested in Ugi
reactions with ammonia, and as a model reaction we in- On the other hand, the six-component coupling provides
vestigated the reaction of isobutyraldehyde with the isoni- fascinating structures of high molecular complexity.
trile obtained from glycine esters and the ammonium salt Therefore we were also interested to find reaction condi-
of various carboxylic acids in methanol.7 No product was tions giving mainly access to these products. The most
obtained with salts of strong acids such as trifluoroacetic obvious parameter for modifications is the relative ratio of
acid, toluenesulfonic acid or pentafluorobenzoic acid, the components used. A six-component product should be
while benzoic acid gave the expected peptide 1, albeit in favoured if an excess of aldehyde is used, relatively to the
moderate yield. Two major side products were formed isonitril. And indeed, continuously increasing the relative
depending on the reaction conditions (Scheme 1). When ratio of aldehyde raised the amount of the higher coupling
product(s). Interestingly, besides 2 another six-compo-
nent coupling product 3 was obtained, resulting from
the incorporation of two molecules aldehyde and carbox-
ylic acid as well. Under optimized conditions (ratio iso-
SYNLETT 2005, No. 5, pp 0757–0760
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863722; Art ID: G00305ST
© Georg Thieme Verlag Stuttgart · New York
2
1.
0
3.
2
0
0
5

758
R. Pick et al.
LETTER
nitrile–ammonium benzoate–aldehyde 1:2:4.4) 3 was the we varied the substituion pattern in the aromatic ring. In-
only six-component product besides the expected Ugi terestingly, with electron-donation groups (Table 1, entry
product 1.9
2) only the Ugi product 1 was obtained, while with elec-
tron-withdrawing groups (entry 3) the six-component
product 3 was formed exclusively in rather good yield. To
prove the generality of the reaction aliphatic acids, such as
acetic acid, also were used. Here the six-component
product was the major product (entry 5). Sterically less
hindered aldehydes such as n-butyraldehyde are also
tolerated (entry 4), but in this case a mixture of 4-fold and
6-fold coupling product was obtained albeit in moderate
yield.
Obviously, the imine A formed in the first step does not
react directly with the isonitrile as proposed for the Ugi
reaction (B) but with another nucleophile, methanol or
benzoate (Scheme 2). The resulting ‘semiaminal’-type
intermediates such as C now can react with a second
equivalent aldehyde giving rise to intermediates D and E.
Addition of the isonitrile and the carboxylate generates
the highly reactive intermediates F and G, which sub-
sequently undergo Mumm rearrangement to the amides 2
and 3.
Table 1 Four-Component vs. Six-Component Couplings
If the carboxylic acid (or the carboxylate, respectively) is
directly involved in a product determining step (A → C)
one might expect an relatively strong influence of the car-
boxylic acid used on the product distribution. Therefore,
Entry R1
R2
Products Yield of 1 Yield of 3
(%)
41
21
0
(%)
28
0
1
2
3
4
5
6
Ph
i-Pr
i-Pr
i-Pr
n-Pr
i-Pr
i-Pr
1a/3a
1b/3b
1c/3c
1d/3d
1e/3e
1f/3f
4-MeO-Ph
4-NO2-Ph
4-NO2-Ph
Me
64
17
29
0
6
0
F3C
42a
a MeCN was used as solvent.
Surprisingly in all reactions investigated so far mainly one
diastereomer of 3 was formed, indicated by a single set of
signals in the NMR spectra, in contrast to the spectra of 2,
which showed a second set of signals in the 13C NMR.10
The NMR spectra of 3 were very characteristic.11 The
newly formed aminoacylal centers showed sole doublets
at d = 5.8–6.1 ppm for R2 = i-Pr and a double doublet at
d = 6.1 ppm for R2 = n-Pr, while having a 13C shift of
d = 87–89 ppm. In addition to that, there is a remarkable
difference in the chemical shifts of the two iso-propyl-
idene and n-propylidene signals, respectively (d = 0.2–0.6
1
ppm in the H spectra, d = 3–7 ppm in the 13C spectra).
Compared to the Ugi four-component products 1 the a-1H
signals of the new generated amino acids are shifted
upfield by 0.5 ppm.12 The signals are cleanly separated
and therefore there can be no doubt on the high stereo-
selectivity of the reaction.
Scheme 2 Postulated mechanism for 6-fold couplings
Synlett 2005, No. 5, 757–760 © Thieme Stuttgart · New York

LETTER
Ammonia in Ugi Reactions
759
(2) Gräfe, U. Biochemie der Antibiotika; Spektrum: Heidelberg,
1992.
(3) (a) Ugi, I. Isonitrile Chemistry; Academic Press: New York,
1971. (b) Ugi, I. Chem.-Ztg. 1997, 74, 9. (c) Dömling, A.;
Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168; Angew. Chem.
2000, 112, 3300 and references cited therein.
All coupling products obtained were solids and we were
able to obtain suitable crystals of 3a to figure out the rel-
ative configuration of the stereogenic centers.13 We found
that the ‘positive induced’ products14 (S/S or R/R, respec-
tively) were formed preferentially.
(4) (a) Ugi, I.; Steinbrückner, C. Chem. Ber. 1961, 94, 2797.
(b) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1998,
63, 867.
With respect to the molecular structure of 3 one might ex-
pect that 3 should easily be convertible into 1 by simple
hydrolysis of the aminoacylal subunit (Scheme 3). And
indeed, stirring of 3a under mild acidic conditions gave
rise to the linear peptide 1a in quantitative yield.15 In a few
cases such a cleavage was also observed during purifica-
tion of some 3 via flash chromatography. Hydrolysis
under basic conditions gave rise to the corresponding car-
boxylic acid 4a,16 which can be used directly for further
peptide couplings.
(5) Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596.
(6) (a) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117,
5855. (b) Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc.
1995, 117, 12364. (c) Miller, S. J.; Blackwell, H. E.;
Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606.
(d) Williams, R. M.; Liu, J. J. Org. Chem. 1998, 63, 2130.
(e) Gao, Y.; Lane-Bell, P.; Vederas, J. C. J. Org. Chem.
1998, 63, 2133. (f) Cabrejas, L. M. M.; Rohrbach, S.;
Wagner, D.; Kallen, J.; Zenke, G.; Wagner, J. Angew. Chem.
Int. Ed. 1999, 38, 2443; Angew. Chem. 1999, 111, 2595.
(7) Kazmaier, U.; Hebach, C. Synlett 2003, 1591.
(8) Floyd, C. D.; Harnett, L. A.; Miller, A.; Patel, S.; Saroglou,
L.; Whittaker, M. Synlett 1998, 637.
(9) 4-Component vs. 6-Component Coupling.
Isobutyraldehyde (0.80 mL, 8.8 mmol) was added to a
solution of ammonium benzoate (280 mg, 2.0 mmol) in
methanol (6 mL) at 0 °C. After stirring for 30 min, ethyl
isocyanoacetate (225 mg, 2.0 mmol) was added via syringe
over a period of 5 min. The mixture was allowed to warm to
15 °C overnight. After stirring at r.t. for further 24 h, the
solution was diluted with CH2Cl2 (30 mL) and washed with
1 N KHSO4 and sat. NaHCO3 solution. The organic layer
was dried (Na2SO4) and the solvent was evaporated in
vacuo. The crude product was purified by flash
Scheme 3 Cleavage of 6-fold coupling products
If the acidic hydrolysis was directly converted in one pot
after the multi-component reactions, the required Ugi
products were the only products formed, and the yields,
e.g. of 1a and 1e, could be increased to 84% and 74%, re-
spectively.17
chromatography giving rise to 1a and 3a.
(10) Spectroscopic data of 2: 1H NMR (300 MHz, CDCl3):
d = 0.72 (d, J = 6.7 Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H), 1.01
(d, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 2.08 (m, 1 H),
2.98 (m, 1 H), 3.31 (s, 3 H), 3.59 (d, J = 11.2 Hz, 1 H), 3.70
(s, 3 H), 3.94 (dd, J = 15.2, 2.5 Hz, 1 H), 4.01–4.16 (m, 2 H),
7.32–7.40 (m, 5 H), 8.95 (br s, 1 H). 13C NMR (300 MHz,
CDCl3): d = 18.2 (q), 18.6 (q), 19.2 (q), 19.8 (q), 27.2 (d),
32.1 (d), 40.6 (t), 51.8 (q), 57.5 (d), 67.4 (q), 97.4 (d), 126.4
(d), 128.4 (d), 129.3 (d), 136.5 (s), 169.9 (s), 172.6 (s), 173.3
(s). Selected signals of the minor diastereomer: 13C NMR
(300 MHz, CDCl3): d = 30.7 (d), 40.7 (t), 52.1 (q), 169.8 (s).
(11) Analytical and spectroscopic data of new 6-fold coupling
products 3.
In conclusion, we have shown that Ugi reactions with am-
monia are less predictable than with other amines, be-
cause side reactions such as six-component couplings can
occur. But under certain reaction conditions these prod-
ucts can be formed nearly exclusively, or the reactions can
be directed towards the exclusive formation of the Ugi
products. Further investigations concerning modifications
at the aminoacylal substructure are currently under inves-
tigation.
Compound 3a: mp 128 °C. 1H NMR (400 MHz, CDCl3):
d = 0.74 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.86
(d, J = 6.6 Hz, 3 H), 1.07 (d, J = 6.6 Hz, 3 H), 1.28 (t, J = 7.1
Hz, 3 H), 2.45 (m, 1 H), 3.06 (m, 1 H), 3.81 (d, J = 11.0 Hz,
1 H), 4.01 (dd, J = 17.9, 5.1 Hz, 1 H), 4.14 (dd, J = 17.9, 6.4
Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 6.15 (d, J = 10.6 Hz, 1
H), 7.42–7.45 (m, 7 H), 7.61 (t, J = 7.6 Hz, 1 H), 8.07 (d,
J = 7.6 Hz, 2 H), 9.04 (br s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 173.9 (s), 172.4 (s), 169.5 (s), 164.1 (s), 135.4
(s), 133.7 (d), 130.4 (d), 129.9 (2 d), 129.1 (s), 128.7 (2 d),
128.4 (2 d), 127.3 (2 d), 88.8 (d), 69.5 (d), 61.2 (t), 41.2 (t),
32.0 (d), 27.1 (d), 20.02 (q), 20.01 (q), 18.23 (q), 18.15 (q),
14.2 (q). Anal. Calcd for C27H34N2O6 (482.58): C, 67.20; H,
7.10; N, 5.81. Found: C, 67.18; H, 7.31; N, 5.74. HRMS
(CI): m/z calcd for C27H35N2O6 [M + H]: 483.2495; found:
483.2490.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft. We also thank Prof. M.
Veith and Dr. V. Huch from the Institute of Inorganic Chemistry for
X-ray-structure analysis.
References
(1) (a) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl.
1983, 22, 816; Angew. Chem. 1983, 95, 827. (b) Annual
reports in: Amino Acids, Peptides and Proteins, Specialist
Periodical Reports, Chem. Soc., London. (c) Faulkner, D.
J. Nat. Prod. Rep. 2002, 19, 1.
Compound 3c: mp 176 °C. 1H NMR (400 MHz, CDCl3):
d = 0.76 (d, J = 6.6 Hz, 3 H), 0.78 (d, J = 6.7 Hz, 3 H), 0.91
(d, J = 6.7 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.28 (t, J = 7.1
Hz, 3 H), 2.54 (m, 1 H), 3.07 (m, 1 H), 3.74 (d, J = 11.3 Hz,
Synlett 2005, No. 5, 757–760 © Thieme Stuttgart · New York

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R. Pick et al.
LETTER
1 H), 3.91 (dd, J = 17.9, 4.5 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2
H), 4.25 (dd, J = 17.9, 7.0 Hz, 1 H), 5.89 (d, J = 10.5 Hz, 1
H), 7.68 (d, J = 8.8 Hz, 2 H), 8.23 (d, J = 8.8 Hz, 2 H), 8.33–
8.35 (m, 4 H), 8.59 (dd, J = 7.0, 4.5 Hz, 1 H). 13C NMR (100
MHz, CDCl3): d = 171.7 (s), 171.4 (s), 169.5 (s), 162.8 (s),
151.1 (s), 148.7 (s), 141.2 (s), 134.0 (s), 131.0 (2 d), 128.4 (2
d), 123.8 (2 d), 123.4 (2 d), 89.4 (d), 69.6 (d), 61.3 (t), 41.1
(t), 31.6 (d), 27.2 (d), 19.96 (q), 19.91 (q), 18.27 (q), 18.23
(q), 14.2 (q). Anal. Calcd for C27H32N4O10 (572.57): C,
56.64; H, 5.63; N, 9.79. Found: C, 56.41; H, 5.89; N, 9.65.
HRMS (CI): m/z calcd for C27H31N4O10 [M – H]: 571.2040;
found: 571.2086.
Compound 3d: mp 123 °C (decomp.). Mixture of rotamers:
1H NMR (400 MHz, CDCl3): d = 0.805 (t, J = 7.4 Hz, 3 H),
0.811 (t, J = 7.3 Hz, 3 H), 1.21–1.33 (sh, 4 H), 1.28 (t,
J = 7.2 Hz, 3 H), 1.98 (m, 1 H), 2.06 (m, 1 H), 2.13 (m, 1 H),
2.25 (m, 1 H), 3.87 (dd, J = 18.2, 4.8 Hz, 1 H), 4.18 (dd,
J = 18.2, 6.8 Hz, 1 H), 4.19 (m, 1 H), 4.20 (q, J = 7.2 Hz, 2
H), 6.13 (dd, J = 7.3, 6.2 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 2 H),
7.85 (br s, 1 H), 8.17 (d, J = 8.9 Hz, 2 H), 8.32 (d, J = 8.9 Hz,
2 H), 8.33 (d, J = 8.7 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 172.4 (s), 171.4 (s), 169.6 (s), 163.2 (s), 151.1 (s), 148.7
(s), 141.6 (s), 134.1 (s), 130.8 (2 d), 128.8 (2 d), 123.9 (2 d),
123.8 (2 d), 84.9 (d), 61.5 (d), 61.3 (t), 41.3 (t), 34.9 (t), 32.3
(t), 20.4 (t), 18.2 (t), 14.1 (q), 13.8 (q), 13.3 (q). Anal. Calcd
for C27H32N4O10 (572.57): C, 56.64; H, 5.63; N, 9.79. Found:
C, 56.64; H, 6.24; N, 9.63. HRMS (CI): m/z calcd for
C27H32N4O10 [M]: 572.2118; found: 572.2120.
J = 7.6 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 2 H), 8.22 (d, J = 8.8
Hz, 2 H).
Compound 1f: (400 MHz, CDCl3): d = 0.95 (d, J = 7.0 Hz, 3
H), 0.97 (d, J = 6.9 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 2.12
(m, 1 H), 3.95 (dd, J = 18.2, 4.9 Hz, 1 H), 4.12 (dd, J = 18.2,
5.7 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.39 (dd, J = 8.5, 7.3
Hz, 1 H), 6.77 (dd, J = 5.7, 4.9 Hz, 1 H), 7.46 (d, J = 8.5 Hz,
1 H).
(13) Crystal data of 3a: C27H34N2O6, Mr = 482.58, triclinic, space
group P–1, a = 9.490 (2) Å, b = 15.015 (3) Å, c = 19.527 (4)
Å, a = 83.69 (3)°, b = 78.94 (3)°, g = 78.15 (3)°, V = 2665.4
(9) Å3, Z = 4, rcalcd = 1.203 Mg/m3, F(000) = 1032,
l = 0.71073 Å, T = 293 K, m(MoKa) = 0.085 mm–1. Of the
16984 measured reflections 7822 were independent
[R(int) = 0.0274]. The final refinement converged at
R1 = 0.0404 for I > 2s(I), wR2 = 0.1122 for all data. The
data for structure 3a were collected on a Stoe IPDS
difractometer, the structure was solved by direct methods
(SHELXS-97) and refined with all data by full matrix least
squares on F2.
(14) (a) Ruch, E.; Ugi, I. Theor. Chim. Acta 1966, 4, 287.
(b) Ruch, E.; Ugi, I. Top. Stereochem. 1969, 4, 99.
(15) A solution of pyridinium p-toluenesulfonate (PPTS, 503 mg,
2.00 mmol) in H2O (2 mL) was added to a suspension of 3a
(483 mg, 1.00 mmol) in MeCN (2 mL) at r.t. After stirring
overnight the suspension was diluted with H2O (20 mL) and
extracted with CH2Cl2 (20 mL). The organic layer was
washed with sat. NaHCO3 (20 mL) solution and dried
(Na2SO4). Evaporation of the solvent leads to analytically
pure 1a (302 mg, 0.99 mmol, 99%) as a snow white powder.
(16) An aq NaOH solution (2 mL, 1 mol/L) was added to a
suspension of 3a (483 mg, 1.00 mmol) in MeCN (2 mL) at
r.t. After stirring for 30 min the clear solution was diluted
with H2O (20 mL) and washed with Et2O (20 mL). The
aqueous layer was acidified by the addition of KHSO4
solution (2.5 mL, 1 mol/L) and extracted with CH2Cl2
repeatedly. The organic layer was dried (Na2SO4) and the
solvent was evaporated in vacuo. 1H NMR analysis of the
crude product indicates the formation of 4a (0.67 mmol,
67%) and benzoic acid. Compound 4a: 1H NMR (500 MHz,
CDCl3 + 10% DMSO-d6): d = 0.72 (d, J = 6.8 Hz, 3 H), 0.73
(d, J = 6.8 Hz, 3 H), 1.95 (m, 1 H), 3.64 (dd, J = 17.9, 5.5 Hz,
1 H), 3.68 (dd, J = 17.9, 5.5 Hz, 1 H), 4.29 (dd, J = 8.8, 7.0
Hz, 1 H), 7.13 (dd, J = 7.5, 7.4 Hz, 2 H), 7.20 (tt, J = 7.4, 1.3
Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 7.55 (sh, 3 H).
(17) Isobutyraldehyde (8.03 mL, 88 mmol) was added to a
solution of ammonium benzoate (5.56 g, 40 mmol) in MeOH
(40 mL) at 0 °C. After stirring for 30 min methyl
Compound 3e: mp 89–90 °C. 1H NMR (400 MHz, CDCl3):
d = 0.69 (d, J = 6.6 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H), 0.88
(d, J = 6.6 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.22 (t, J = 7.1
Hz, 3 H), 2.06 (s, 3 H), 2.31 (m, 1 H), 2.35 (s, 3 H), 2.93 (m,
1 H), 3.35 (d, J = 11.1 Hz, 1 H), 3.93 (d, J = 5.8 Hz, 2 H),
4.14 (q, J = 7.1 Hz, 2 H), 5.27 (d, J = 10.2 Hz, 1 H), 8.62 (br
s, 1 H). 13C NMR (100 MHz, CDCl3): d = 173.1 (d), 172.3
(d), 169.9 (d), 169.5 (d), 87.5 (d), 68.7 (d), 61.1 (t), 41.0 (t),
30.6 (d), 27.0 (d), 23.1 (q), 20.3 (q), 19.7 (q), 19.6 (q), 18.4
(q), 17.8 (q), 14.1 (q). Anal. Calcd for C17H30N2O6 (358.44):
C, 56.97; H, 8.44; N, 7.82. Found: C, 56.85; H, 8.33; N, 7.85.
HRMS (CI): m/z calcd for C17H31N2O6 [M + H]: 359.2182;
found: 359.2183.
(12) 1H NMR spectra of Ugi products 1.
Compound 1a: (400 MHz, DMSO-d6): d = 0.94 (d, J = 7.1
Hz, 3 H), 0.96 (d, J = 7.1 Hz, 3 H), 1.17 (t, J = 7.1 Hz, 3 H),
2.14 (m, 1 H), 3.79 (dd, J = 17.2, 5.8 Hz, 1 H), 3.90 (dd,
J = 17.2, 6.2 Hz, 1 H), 4.07 (q, J = 7.1 Hz, 2 H), 4.34 (dd,
J = 8.8, 7.1 Hz, 1 H), 7.46 (dd, J = 7.3, 7.0 Hz, 2 H), 7.53 (t,
J = 7.3 Hz, 1 H), 7.89 (d, J = 7.0 Hz, 2 H), 8.30 (d, J = 8.8
Hz, 1 H) 8.48 (dd, J = 6.2, 5.8 Hz, 1 H).
Compound 1b: (400 MHz, CDCl3): d = 0.99 (d, J = 6.8 Hz,
3 H), 1.00 (d, J = 6.7 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 2.19
(m, 1 H), 3.81 (s, 3 H), 3.88 (dd, J = 18.2, 5.1 Hz, 1 H), 4.11
(dd, J = 18.2, 5.7 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 4.56
(dd, J = 8.5, 7.2 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.94 (d,
J = 8.5 Hz, 1 H), 7.16 (dd, J = 5.7, 5.1 Hz), 7.76 (d, J = 8.8
Hz, 2 H).
isocyanoacetate (2.26 g, 20 mmol) was added. The mixture
was allowed to warm to r.t. overnight. After evaporation of
the solvent in vacuo the residue was suspended in a mixture
of MeCN and H2O (1:1), acidified to pH 2 by dropwise
addition of concd HCl and stirred overnight. The MeCN was
evaporated in vacuo and the resulting aqueous suspension
was treated with H2O and CH2Cl2 until two clear layers were
formed. The organic layer was separated, washed with sat.
NaHCO3, dried (Na2SO4) and concentrated in vacuo. The
solid residue was washed with Et2O (50 mL) filtrated and
dried, giving rise to analytically pure 1a (5.2 g, 17 mmol) as
a snow white powder.
Compound 1d: (400 MHz, CDCl3): d = 0.88 (t, J = 7.3 Hz, 3
H), 1.24 (t, J = 7.1 Hz, 3 H), 1.39 (m, 2 H), 1.71 (m, 1 H),
1.87 (m, 1 H), 3.97 (dd, J = 18.2, 5.2 Hz, 1 H), 4.06 (dd,
J = 18.2, 5.6 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.73 (ddd,
J = 7.6, 6.6, 6.6 Hz, 1 H), 7.02 (dd, J = 5.6, 5.2 Hz), 7.49 (d,
Synlett 2005, No. 5, 757–760 © Thieme Stuttgart · New York