Free-radical version of the Strecker synthesis of α-aminoamides promoted by aqueous H2O2/TiCl3/HCONH 2 system

Article abstract of DOI:10.1021/ja061092g

A new reaction of general synthetic interest representing the free-radical version of the Strecker synthesis to α-aminoamides is reported. A hydroxy radical, generated by Ti(III) one-electron reduction of H₂O₂, abstracts a H atom fro

Full text of DOI:10.1021/ja061092g

Published on Web 03/31/2006
Free-Radical Version of the Strecker Synthesis of r-Aminoamides Promoted
by Aqueous H2O2/TiCl3/HCONH2 System
Rosalba Cannella,† Angelo Clerici,† Walter Panzeri,‡ Nadia Pastori,† Carlo Punta,† and
Ombretta Porta*,†
Dipartimento di Chimica, Materiali e Ingegneria Chimica “G. Natta”, Politecnico di Milano, Sezione Chimica, and
CNR Istituto di Chimica del Riconoscimento Molecolare, Sezione “A. Quilico”,
Via Mancinelli 7, 20131 Milano, Italy
Received February 23, 2006; E-mail: ombretta.porta@polimi.it
Table 1. Addition of Formamide to an Equilibrium Mixture of
PMP-NH2 and Aldehydes 2a-u
The development of new methods for the synthesis of natural
and unnatural R-amino acid derivatives is an area of current interest
both in synthetic1,2 and medicinal3 chemistry. Although many
valuable multistep routes to R-amino acid precursors are available,1
syntheses of these compounds by one-pot multicomponent reactions
(MCRs)4 are particularly fascinating since they facilitate rapid
construction of very large compound libraries which can, then, be
used for drug discovery.3
R−CHO
entry
R−
3 yield (%)a
Classical examples of such a reaction are the evergreen Strecker
synthesis and the Ugi condensation,4,5 according to which R-amino
acid precursors are efficiently assembled by adding a nucleophilic
carboxylate synthon (cyanide or isocyanides) to an imine generated
in situ.6 In recent years, glyoxylate imine derivatives, either
preformed or generated in situ, have been used as versatile
electrophilic glycine equivalents to provide rapid access to a wide
range of natural and unnatural R-amino acid derivatives through
radical alkylation7 or nucleophilic addition of organometallic
reagents.8
In the course of our studies,9 we have disclosed the manifold
roles simultaneously played by Ti(III) and Ti(IV) ions in promoting
radical Mannich-type MCRs. As a part of our ongoing interest in
this area, we now report that the aqueous acidic Ti(III)/H2O2 system
readily assembles an amine 1, an aldehyde 2, and formamide in a
one-pot reaction leading to a wide range of R-aminoamides 3 in
fair to good yields (Table 1).
The reaction smoothly proceeds at 20 °C by adding dropwise
(20 min) H2O2 (5 mmol of a 35% aqueous solution) to a
homogeneous solution of 1 (4 mmol), 2 (2 mmol), and TiCl3 (8
mmol, ca. 8 mL of a 15% aqueous acidic solution) in formamide
(10 mL). The reaction is like a titration and its end is clearly shown
by a sharp change of the color from blue to orange; furthermore,
after work up, most of the R-aminoamides 3 crystallize out in pure
form from the crude reaction mixtures dissolved in a suitable
solvent.
In planning the synthesis, we started first with p-methoxyaniline
(PMP-NH2) 1a, as a representative amine, since the protective PMP
group can be further removed by CAN oxidation.6,10 As shown in
Table 1, several types of aldehydes can participate in this process:
these include primary (entries 2 and 3), secondary (entries 4-7),
tertiary (entry 8), R,â-unsaturated (entry 9), aromatic (entries 10-
20), and heteroaromatic (entry 21) ones. Only formaldehyde gave
an abnormal result: N-aminomethylation11 of formamide occurred
(entry 1, 60% yield) instead of the expected C-aminomethylation.
We next proved that the reaction may be extended to other
substituted anilines, allowing structural variety.12 For example,
p-toluidine 1b and p-bromoaniline 1c reacted with benzaldehyde
1
2
3
4
5
6
7
8
H-
CH3-
(CH3)2CHCH2-
(CH3)2CH-
(C2H5)(CH3)CH-
Ph(CH3)CH-
cyclohex-
(CH3)3C-
PhCHdCH2-
Ph-
b
3a: 60
3b: 75
3c: 62
3d: 65
3e: 40
3f: 50
3g: 45
3h: 55
3i: 79 (85)
3j: 66 (75)
3k: 70
3l: 30
3m: 60
3n: 59
3p: 66
3q: 64
3r: 60
3s: 37
3t: 60
3u: 85
3v: 78
3z: 60
9
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
p-HO-C6H4-
piperonyl-
o-HO-C6H4-
o-CH3O-C6H4-
m-CH3O-C6H4-
p-CH3O-C6H4-
p-Br-C6H4-
p-F-C6H4-
1-naphthyl-
2-naphthyl-
2-furyl-
Ph-
Ph-
a Isolated yields based on the starting aldehyde RCHO (2 mmol); yields
in parentheses were determined by 1H NMR with an internal standard added
to the crude reaction mixture; yields based on the converted aldehydes are
always >90%. b N-[(p-Methoxyphenylamino)methyl]formamide was ob-
tained. c 1b was used instead of 1a. d 1c was used instead of 1a.
and formamide (entries 22 and 23) affording the corresponding
N-arylphenylglycinamides 3v and 3z in 78 and 60% yields,
respectively.
From the mechanistic point of view (Scheme 1), the initial step
is the Ti(III) one-electron reduction of H2O2 (step i) leading to a
hydroxy radical and Ti(IV) ion, which both participate in the
subsequent steps leading to 3: (a) hydroxy radical abstracts a H
atom from the C-H bond of formamide forming a carbamoyl
radical (step ii); (b) Ti(IV) ion, owing to its oxophilicity, coordinates
the carbonyl oxygen of the aldehyde favoring imine formation and,
as a strong Lewis acid, increases the imine electrophilicity by
N-complexation (step iii);13 (c) addition of the nucleophilic car-
bamoyl radical14 proceeds at the C atom of A to generate an
aminium radical B (step iV), which is readily reduced to the final
product 3 by a second equiv of Ti(III) ion (step V).
† Politecnico di Milano.
‡ CNR Istituto di Chimica del Riconoscimento Molecolare.
9
5358
J. AM. CHEM. SOC. 2006, 128, 5358-5359
10.1021/ja061092g CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Mechanistic Rationale
amides, utilizing cheap and commercially available starting materi-
als. An aqueous cosolvent and the ultimately nontoxic TiO2 metal
residue contribute to render the reaction significant also from an
ecological point of view.
Future efforts will focus on combinatorial application of the
method in the preparation of new structural types of R-aminoamides.
Acknowledgment. Financial support from MURST (Cofin
2004) is gratefully acknowledged.
Supporting Information Available: Experimental procedures and
characterization of products 3a-z (NMR data, 1H and 13C NMR
spectra). This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 2. Radical Version (path a) of the Strecker Synthesis
(path b) of R-Amino Acid Derivatives
References
(1) Selected reviews: (a) Duthaler, R. D. Tetrahedron 1994, 50, 1539-1650.
(b) Cativiela, C.; Diaz de Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517-3599. (c) Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, J. J.
Chem Soc., Perkin Trans. 1 2000, 4197-4212. (d) Groger, H. Chem. ReV.
2003, 103, 2795-2827. (e) Maruoka, K.; Ooi, T. Chem ReV. 2003, 103,
3013-3028. (f) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506-517.
(2) (a) Ghosh, A. K.; Xu, C. X.; Kulkaruy, S. S.; Wink, D. Org. Lett. 2005,
7, 7-10. (b) Gallos, J. K.; Sarli, V. C.; Massen, S. Z.; Varvogli, A. C.;
Papadojanni, C. Z.; Papaspyron, S. D.; Argyropolous, N. G. Tetrahedron
2005, 61, 565-574. (c) Jiang, B.; Huang, Z. G. Synthesis 2005, 2198-
2204 and references quoted therein.
The H atom abstraction from the C-H bond of formamide (BDE
≈ 94 kcal mol-1) by a hydroxy radical is a fast process due to
favorable enthalpy balance (∆H ≈ -24 kcal) and polar effects,14
but the equilibria involved in the formation of A under aqueous
conditions13 lie by far on the left side.
However, the irreversible addition step iV shifts the whole
reaction sequence on the product side, rendering the process
preparatively advantageous. This approach to R-amino acid deriva-
tives, in which a carbamoyl radical is used as a carboxylate synthon,
may be regarded as a radical version of the Strecker synthesis
(Scheme 2).
(3) Molteni, V.; Penzotti, J.; Wilson, D. M.; Termin, A. P.; Mao, L.; Crane,
C. M.; Hassman, F.; Wang, T.; Wong, H.; Miller, K. J.; Grossman, S.;
Grootenhuis, P. D. J. J. Med. Chem. 2004, 47, 2426-2429 and references
quoted therein.
(4) Diker, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 1700-1702. (b)
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
(5) Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini, M.
Org. Lett. 2004, 6, 3281-3284.
(6) (a) For evidence of Shiff base intermediates in the Strecker synthesis,
see: Ishitani, H.; Komiyama, S.; Asegawa, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 762-767.
(7) For recent reviews on alkyl radical addition to CdN bonds, see: (a)
Friestad, G. Tetrahedron 2001, 57, 5461-5496. (b) Miyabe, H.; Ueda,
M.; Naito, T. Synlett 2004, 1140-1157. (c) Friestad, G. Eur J. Org. Chem.
2005, 3157-3172.
After examining the results of Table 1, the characteristic features
of the reaction are as follows: (a) only a very bulky substituent at
the C atom of the intermediate imine depresses the yield of 3 (entries
6-8, 13, and 19); (b) the reaction is relatively insensitive to the
polar nature of the substituents on the aromatic ring of either
benzaldehyde or aniline, indicating that the polarization of the CdN
bond induced by N-Ti(IV) complexation overcomes the substituent
effect and/or that the equilibrium concentration of A does not affect
the yield of 3, since the driving force of the global reaction sequence
is the two last irreversible steps. The low yield of 3l (30%) may
well be ascribed to steric congestion around the imine C atom, due
to the formation of a chelated Ti(IV)-salicylaldimine complex.15
In fact, the parent o-methoxy-substituted amide 3m was obtained
in 60% yield; (c) interestingly, the reaction can be used for the
synthesis of o-, m-, and p-hydroxy- and methoxy-substituted
arylglycine precursors (entries 11-16), which constitute key
components of some of the most widely used antibiotics, such as
Amoxicillin, Nocardicin, Vancomicin, and Chloropeptins;8b,16 (d)
in addition, biocatalytic kinetic resolution of R-aminoamides,
catalyzed by amidase, does not require the previous nitrile hy-
dratase-catalyzed hydration of a nitrile to an amide.17
(8) (a) Petasis, N. A.; Zavialov, A. J. Am. Chem. Soc. 1997, 119, 445-446.
(b) Petasis, N. A.; Goodman, A.; Zavialov, A. Tetrahedron 1997, 53,
16463-16470. (c) Grigg, R.; Sridharan, V.; Thayaparan, A. Tetrahedron
Lett. 2003, 44, 9017-9019. (d) Huang, T.; Li, C. J. Tetrahedron Lett.
2000, 41, 6715-6719.
(9) (a) Clerici, A.; Porta, O. Tetrahedron Lett. 1990, 31, 2069-2072. (b)
Clerici, A.; Porta, O. Gazz. Chim. Ital. 1992, 122, 165-166. (c) Clerici,
A.; Clerici, L.; Porta, O. Tetrahedron Lett. 1995, 36, 5955-5958. (d)
Cannella, R.; Clerici, A.; Pastori, N.; Regolini, E.; Porta, O. Org. Lett.
2005, 7, 645-648. (e) Clerici, A.; Pastori, N.; Porta, O. J. Org. Chem.
2005, 70, 4174-4176. (f) Clerici, A.; Cannella, R.; Panzeri, W.; Pastori,
N.; Regolini, E.; Porta, O. Tetrahedron Lett. 2005, 46, 8351-8354.
(10) Hasegawa, M.; Tanijama, D.; Tomioka, K. Tetrahedron 2000, 56, 10153-
10158.
(11) Bo¨hme, H.; Rande, H. Chem. Ber. 1981, 114, 3421-3429.
(12) N-aryl arylglycines have been recently identified as a new class of human
corticotropin releasing factor (CRF). See ref 3.
(13) A series of equilibria, not reported for simplicity, are involved in the
formation of A. See: Azend, M.; Westermann, B.; Risch, N. Angew.
Chem., Int. Ed. 1998, 37, 1044-1070.
(14) The carbamoyl radical has a clear-cut nucleophilic character, which permits
amidation of protonated heteroaromatic bases. (a) Minisci, F.; Porta. O.
AdV. Heterocycl. Chem. 1974, 16, 123-180. (b) Porta, O.; Minisci, F.
Handbook of CH Transformations; Dicker, G., Ed.; Wiley-VCH Verlag
GMBH: New York, Berlin, 2005; Vol. 1, pp 212-222.
(15) Coates, G.; Mason, A. J. Am. Chem. Soc. 2004, 126, 16326-16327.
(16) (a) Beller, M.; Eckert, M.; Holla, W. J. Org. Chem. 1998, 63, 5658-
5661. (b) Boger, D.; Borzilleri, R.; Nukui, S. J. Org. Chem. 1996, 61,
3561-3565.
(17) (a) Wang, M. X.; Lin, S. J. J. Org. Chem. 2002, 67, 6542-6545. (b)
Boesten, W. H. J. EP 0002297, 1976. (c) Wang, M. X.; Liu, J.; Wang,
De-X.; Zheng, Q. Y. Tetrahedron: Asymmetry 2005, 16, 2409-2416.
In conclusion, we have developed a new general and convenient
one-pot radical multicomponent reaction for the synthesis of
aliphatic, aromatic, heteroaromatic, and â,γ-unsaturated R-amino-
JA061092G
9
J. AM. CHEM. SOC. VOL. 128, NO. 16, 2006 5359