A modified U-4CR reaction with 2-nitrobenzylamine as an ammonia equivalent

Article abstract of DOI:10.1055/s-2006-951485

A modified U-4CR reaction has been done by using commercially available 2-nitrobenzylamine as an ammonia equivalent and it involves a multi-component reaction, followed by photochemical cleavage of the 2-nitrobenzyl group, which can be done in one pot with good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951485

LETTER
2667
A Modified U-4CR Reaction with 2-Nitrobenzylamine as an Ammonia
Equivalent
A
M
odifie
d
U
-4CR
u
Reaction angsen Sung,* Fu-Lin Chen, Pei-Chun Huang
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan
Fax +886(6)2740552; E-mail: kssung@mail.ncku.edu.tw
Received 19 July 2006
R3
R3
R3
R1CO2H
Abstract: A modified U-4CR reaction has been done by using
commercially available 2-nitrobenzylamine as an ammonia equiva-
lent and it involves a multi-component reaction, followed by photo-
chemical cleavage of the 2-nitrobenzyl group, which can be done in
one pot with good yields.
NH
R2
NH
R2
NH
R2
+
O
O
O
R2
R2
R2C(O)H
+
+
+
MeOH
N
N
HN
R1
O
NH3
+
O
H2N
O
MeO
R1
R1
R3NC
Key words: multicomponent reaction, photochemistry, peptides,
by-products
U-4CR product
isocyanide, ammonia equivalent
Scheme 1
The U-4CR reaction, invented by Ugi in 1959,1 is one of allows the two-step processes to be carried out in one pot
many useful multi-component reactions.2 It consists of without the isolation of the stable intermediate and adding
four components: amine, carboxylic acid, aldehyde, and any other reagent.
isocyanide. A variety of the four components allows the
According to the U-4CR,2 we mixed commercially avail-
U-4CR reaction to produce various interesting structures2
able 2-nitrobenzylamine hydrochloride with isocyanide,
including biologically active benzodiazepines,3 unnatural
aldehyde, and carboxylic acid components in methanol at
room temperature, but the product we obtained was a P-
peptide fragments,4 cyclopeptides,5 and PNA.6
Incorporation of an unnatural peptide into a bioactive 3CR product.2 Free base of 2-nitrobenzylamine, which
peptide framework often increases bioactivity, bio- was generated by neutralization of 2-nitrobenzylamine
availability, and degradative resistance.7 The U-4CR is
able to prepare the unnatural peptides. To mimic the nat-
ural peptides, the amine component of the U-4CR reaction
has to be ammonia. However, very few examples of the
U-4CR reaction used ammonia as the amine component.8
Recently, Kazmaier characterized the by-products of the
U-4CR reaction with ammonia as the amine component9a
(Scheme 1), and the problem was solved by a less nucleo-
philic solvent of trifluoroethanol or hydrolysis of the by-
products with pyridinium p-toluenesulfonate (PPTS).9b
No wonder several attempts have been undertaken to
solve these problems by using primary amines as the
amine component, whose auxiliaries can be cleaved under
acidic conditions after the U-4CR reaction.10,11 The most
successful primary amine used for this purpose is a carbo-
hydrate with an amino group at the anomeric position, and
the carbohydrate can been removed under acidic condi-
tions after the U-4CR.12 This method has been used to pre-
pare chiral a-amino acids with high stereoselectivity, but
it takes several steps to prepare the chiral 1-amino-
glucopyranoses.12
hydrochloride with sodium carbonate, was treated with
isocyanide, aldehyde, and carboxylic acid components in
methanol at room temperature and the expected U-4CR
product was produced (Scheme 2).
R1CO2H
R3
R3
+
R2C(O)H
+
NH
R2
NH
R2
O
O
hν
MeOH
O2N
N
HN
O
O
R1
NH2
R1
NO2
+
R3NC
1a–1e
1a: R1 = Ph, R2 = i-Pr, R3 = p-MeC6H4
1b: R1 = n-Pr, R2 = m-BrC6H4, R3 = c-Hex
1c: R1 = Ph, R2 = Ph, R3 = c-Hex
1d: R1 = Boc-NHCH2, R2 = i-Pr, R3 = cyclohexenyl
1e: R1 = Me, R2 = n-Pr, R3 = p-MeC6H4
Scheme 2
After the U-4CR product with a 2-nitrobenzylamine moi-
ety was subjected to irradiation at l = 254 nm in methanol
for 6–13 hours, and the 2-nitrobenzyl group was success-
fully cleaved off from the U-4CR product. The reaction
In this communication, we used commercially available
2-nitrobenzylamine as the amine component in the U-
4CR reaction, and cleaved the 2-nitrobenzyl group photo-
chemically after the reaction (Scheme 2). This design
1
progress was monitored by H NMR spectroscopy, and
longer reaction time diminished the yield.
SYNLETT 2006, No. 16, pp 2667–2669
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951485; Art ID: W14806ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
6
To find out if this method can be applied to various U-
4CR reactions, various carboxylic acid, aldehyde, and
isocyanide components with aromatic, alkyl, bulky, or

2668
K. Sung et al.
LETTER
(7) (a) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W.
H. J. Am. Chem. Soc. 1992, 114, 10646. (b) Kerr, J. M.;
Banville, S. C.; Zuckermann, R. N. J. Am. Chem. Soc. 1993,
115, 2529. (c) Karle, I. L.; Rao, R. B.; Prasad, S.; Kaul, R.;
Balaram, P. J. Am. Chem. Soc. 1994, 116, 10355.
(d) Cornish, V. W.; Mendel, D.; Schultz, P. G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 621. (e) Voyer, N.;
Lamothe, J. Tetrahedron 1995, 51, 9241.
Table 1 Syntheses of Dipeptides 1a–e by the U-4CR Reactions,
Followed by Photochemical Cleavage of 2-Nitrobenzyl Group
(Scheme 2)
R1
R2
R3
Product (yield)
1a (93%)
Ph
i-Pr
p-MeC4H6
m-BrC6H4
c-Hex
n-Pr
m-BrC6H4
Ph
1b (84%)
1c (89%)
(8) (a) Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 2797.
(b) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1998,
63, 867.
Ph
(9) (a) Kazmaier, U.; Hebach, C. Synlett 2003, 1591. (b) Pick,
R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005, 757.
(10) (a) Ugi, I.; Offermann, K. Chem. Ber. 1964, 97, 2996.
(b) Costa, S. P. G.; Maia, H. I. S.; Pereira-Lima, S. M. M. A.
Org. Biomol. Chem. 2003, 1, 1475.
Boc-NHCH2
Me
i-Pr
c-Hex
1d (68%)
1e (91%)
n-Pr
p-MeC6H4
(11) (a) Urban, R.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1975, 87,
61. (b) Siglmüller, F.; Herrmann, R.; Ugi, I. Tetrahedron
1986, 42, 5931.
functional substituents were used in the U-4CR reactions.
The U-4CR reactions, followed by photochemical cleav-
age of 2-nitrobenzyl group were done in one pot without
isolation of the stable U-4CR products. As shown in
Table 1, they all worked fine with good yields.13
(12) (a) Lehnhoff, S.; Goebel, M.; Karl, R. M.; Klosel, R.; Ugi, I.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1104. (b) Kunz, H.;
Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651. (c) Kunz,
H.; Pfrengle, W.; Sager, W. Tetrahedron Lett. 1989, 30,
4109. (d) Linderman, R. J.; Sophie, B.; Samantha, R. P. J.
Org. Chem. 1999, 64, 336. (e) Ziegler, T.; Kaiser, H.;
Schlomer, R.; Kunz, C. Tetrahedron 1999, 55, 8397.
(f) Oertel, K.; Zech, G.; Koch, H. Angew. Chem. Int. Ed.
2000, 39, 1431.
In conclusion, we successfully modified the U-4CR with
commercially available 2-nitrobenzylamine as the ammo-
nia equivalent. This method can be done in one pot with
high yields.
(13) The general procedure of this method is shown as follows:
An aldehyde component (1 mmol), 2-nitrobenzylamine (1
mmol), and MeOH (5 mL) were mixed in a 10-mL quartz
flask until the mixture became a clear solution. An
isocyanide component (1 mmol) and a carboxylic acid
component (1 mmol) were added into the solution and the
mixture was stirred at r.t. for 2 d. Then the mixture was
irradiated in a quartz flask inside a Rayonet photochemical
reactor with four 254-nm lamps at r.t. The reaction was
monitored by 1H NMR spectroscopy, and the reaction was
complete in 6–13 h. After the reaction was completed,
MeOH was removed by a rotary evaporator, and the residue
was purified by column chromatography to get the
dipeptides 1a–1e.
Acknowledgment
Financial support from the National Science Council of Taiwan
(NSC 94-2113-M-006-009) is gratefully acknowledged.
References and Notes
(1) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I.; Steinbruckner, C. Angew.
Chem. 1960, 72, 267.
(2) (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Domling, A. Chem. Rev. 2006, 106, 17.
(3) (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc.
1996, 118, 2574. (b) Hulme, C.; Peng, J.; Morton, G.;
Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron
Lett. 1998, 39, 7227. (c) Kennedy, A. L.; Andrew, M. F.;
Josey, J. A. Org. Lett. 2002, 4, 1167. (d) Cuny, G.; Bois-
Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475.
(4) (a) Cheng, F. L.; Waki, M.; Minematsu, Y.; Meienhofer, J.;
Izumiya, N. Chem. Lett. 1979, 823. (b) Lin, Q.; O’Neill, J.
C.; Blackwell, H. E. Org. Lett. 2005, 7, 4455.
1a: Light brown solid; mp 119 °C; yield: 93%. 1H NMR
(CD3OD): d = 0.94 (d, J = 7.6 Hz, CH3, 3 H), 0.96 (d, J = 7.6
Hz, CH3, 3 H), 2.14–2.15 (m, 1 H, CH), 2.20 (s, 3 H, CH3),
4.37 (d, J = 8.4 Hz, CH, 1 H), 7.06 (d, J = 8.2 Hz, PhH, 2 H),
7.44–7.47 (m, 5 H, PhH), 7.84 (d, J = 8.2 Hz, PhH, 2 H). 13
NMR (CDCl3): d = 19.46, 19.74, 20.83, 31.19, 60.81,
120.39, 128.23, 129.00, 129.81, 132.12, 133.55, 134.95,
136.82, 167.98, 171.04. IR (thin film): 1654, 1642 (C=O)
cm–1.
C
(5) (a) Failli, A.; Immer, H.; Gotz, M. Can. J. Chem. 1979, 57,
3257. (b) Bayer, T.; Riemer, C.; Kessler, H. J. Peptide Sci.
2001, 7, 250.
1b: Brown oil; yield: 84%. 1H NMR (CDCl3): d = 0.89 (d,
J = 7.2 Hz, CH3, 3 H), 1.22 (m, 2 H, CH2), 1.27–1.29 (m, 4
H, CH2), 1.55–1.57 (m, 2 H, CH2), 1.67–1.69 (m, 4 H, CH2),
2.18 (t, J = 7.4 Hz, CH2, 2 H), 3.56–3.58 (m, 1 H, CH), 5.37
(s, 1 H, CH), 7.22–7.26 (m, 1 H, PhH), 7.34–7.36 (m, 1 H,
PhH), 7.41–7.43 (m, 1 H, PhH), 7.57 (s, 1 H, PhH). 13C NMR
(CDCl3): d = 16.45, 22.75, 28.51, 28.56, 29.07, 35.95, 36.08,
41.00, 60.39, 125.96, 129.70, 133.84, 134.65, 135.41,
144.43, 173.31, 178.13. IR (thin film): 1649, 1634 (C=O)
cm–1.
(6) (a) Groger, H.; Hatam, M.; Kintscher, J.; Martens, J. Synth.
Commun. 1996, 26, 3383. (b) Domling, A. Nucleosides
Nucleotides 1998, 17, 1667. (c) Domling, A.; Chi, K.-Z.;
Barrere, M. Bioorg. Med. Chem. Lett. 1999, 9, 2871.
(d) Maison, W.; Schlemminger, I.; Westerhoff, O.; Martens,
J. Bioorg. Med. Chem. 2000, 8, 1343. (e) Kvumas Das, B.;
Shibata, N.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1
2002, 197. (f) Baldoli, C.; Maiorana, S.; Licandro, E.;
Zinzalla, G.; Perdicchia, D. Org. Lett. 2002, 4, 4314.
(g) Xu, P.; Zhang, T.; Wang, W.; Zou, X.; Zhang, X.; Fu, Y.
Synthesis 2003, 1171. (h) Baldoli, C.; Gianmimi, C.;
Licandro, E.; Maiorana, S.; Zinzalla, G. Synlett 2004, 1044.
1c: Red brown oil; yield: 89%. 1H NMR (CDCl3): d = 1.22–
1.27 (m, 4 H, CH2), 1.27–1.29 (m, 2 H, CH2), 1.66–1.70 (m,
4 H, CH2), 3.67–3.69 (m, 1 H, CH), 5.63 (s, 1 H, CH), 7.36–
7.39 (m, 3 H, PhH), 7.49 (d, 2 H, PhH), 7.63–7.66 (m, 2 H,
PhH), 7.75–7.79 (m, 1 H, PhH), 8.10–8.14 (m, 2 H, PhH).
13C NMR (CDCl3): d = 26.06, 26.12, 26.63, 33.50, 33.66,
Synlett 2006, No. 16, 2667–2669 © Thieme Stuttgart · New York

LETTER
50.15, 59.25, 125.49, 128.76, 129.32, 129.76, 130.41,
A Modified U-4CR Reaction
2669
57.93, 80.59, 97.23, 124.10, 156.32, 169.91, 173.55. IR (thin
film): 1701, 1672, 1648 (C=O) cm–1.
131.88, 133.69, 135.05, 138.63, 147.81, 168.95, 171.14.
IR (thin film): 1650, 1629 (C=O) cm–1.
1e: Red brown oil; yield: 89%. 1H NMR (CDCl3): d = 0.90
(t, J = 7.3 Hz, CH3, 3 H), 1.39–1.41 (m, 2 H, CH2), 1.68–1.70
(m, 1 H, CH2), 1.88–1.90 (m, 1 H, CH2), 2.02 (s, 3 H, CH3),
2.29 (s, 3 H, CH3), 4.59 (q, J = 6.9 Hz, 1 H, CH), 7.09 (d,
1d: Light yellow oil; yield: 68%. 1H NMR (CD3OD): d =
0.92 (d, J = 6.9 Hz, CH3, 3 H), 0.95 (d, J = 6.9 Hz, CH3, 3
H), 1.44 (s, 9 H, CH3), 1.64–1.66 (m, 2 H, CH2), 1.73–1.75
(m, 2 H, CH2), 1.85–1.87 (m, 1 H, CH), 2.10–2.12 (m, 4 H,
CH2), 3.77–3.79 (m, 2 H, CH2), 4.22 (dd, J = 7.8, 8.1 Hz, 1
H, CH), 5.29 (t, J = 5.4 Hz, 1 H, CH). 13C NMR (CDCl3):
d = 19.24, 25.41, 26.99, 28.25, 29.68, 32.72, 41.96, 44.60,
J = 8.4 Hz, 2 H, PhH), 7.41 (d, J = 8.4 Hz, 2 H, PhH). 13
C
NMR (CDCl3): d = 13.78, 18.89, 20.85, 23.18, 34.30, 53.84,
120.01, 129.41, 134.06, 135.16, 170.01, 170.69. IR (thin
film): 1679, 1651 (C=O) cm–1.
Synlett 2006, No. 16, 2667–2669 © Thieme Stuttgart · New York