C-N bond cleavage of benzylic enaminones in the presence of acetyl or aroyl chlorides: A novel one-pot synthesis of N-acetyl or N-aroyl β-benzylidene α-amino acid esters

Article abstract of DOI:10.1055/s-0030-1261237

Benzylic enaminones generated by addition of benzyl-amines to dialkyl acetylenedicarboxylates are trapped in situ by chloroacetyl or aroyl chlorides in refluxing toluene. Good yields of E-isomers of N-acetyl or N-aroyl -amino acid esters were produced exc

Full text of DOI:10.1055/s-0030-1261237

LETTER
2495
C–N Bond Cleavage of Benzylic Enaminones in the Presence of Acetyl or Aroyl
Chlorides: A Novel One-Pot Synthesis of N-Acetyl or N-Aroyl b-Benzylidene
a-Amino Acid Esters
C
–N
B
ond
Cleava
b
ge of Benzyl
d
ic Enaminon
o
es lali Alizadeh,*a Hamideh Sabahnoo,a Nasrin Zohreh,a Zohreh Noaparast,a Long-Guan Zhub
a
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
b
Received 1 July 2011
nes in the literature by introduction of different substitu-
ents on the nitrogen, the a-carbon and the b-carbonylic
carbon atoms for preparation of various heterocyclic sys-
tems including some natural products and analogues.7
Abstract: Benzylic enaminones generated by addition of benzyl-
amines to dialkyl acetylenedicarboxylates are trapped in situ by
chloroacetyl or aroyl chlorides in refluxing toluene. Good yields of
E-isomers of N-acetyl or N-aroyl a-amino acid esters were pro-
duced exclusively via C–N bond cleavage and C–C bond formation
resulting from a 1,3-benzyl shift.
Recently, our research group reported a novel synthesis of
a-alkylidene-g-butyrolacton-2-ones (tetronic acids) from
the reaction of primary amines, methyl acetoacetate and
chloroacetyl chloride or its bromo analogue (Scheme 1).8
Key words: enaminone, benzylic enaminone, aroyl chloride, chlo-
roacetyl chloride, a-amino acid ester, C–N bond cleavage
R
a-Amino acid derivatives are the fundamental building
blocks of peptides, proteins and many natural products
and play essential roles in living organisms.1 Unnatural
amino acids, particularly synthetic a-amino acids have
also played a significant role in the area of peptide re-
search having been used extensively in peptide analogues
to limit conformational flexibility, enhance enzymatic sta-
bility and improve pharmacodynamics and bioavailabili-
ty.2 For example, salicylanilide esters of a-amino acid
ester 1 have shown high antimicrobial activity3 and aspar-
tame (2) is an artificial sweetener, used as a sugar substi-
tute in some foods and beverages (Figure 1). In addition,
such substrates represent a subclass of building blocks
that may be used to make stereochemically complex tar-
gets such as peptides and valuable heterocycles.4
N
Me
H
O
O
RNH2
O
+
O
O
MeCN–MeOH
reflux, 12 h
Me
OMe
+
O
R
N
X
X
Me
H
X = Cl, Br
O
O
O
Scheme 1 Synthesis of a-alkylidene-g-butyrolacton-2-ones (tetro-
nic acids) from chloroacetyl chloride or bromoacetyl bromide8
O
Along the same lines, we have become interested in appli-
cation of dialkyl acetylenedicarboxylates in place of ace-
toacetic esters. To the best of our knowledge, there has
been no investigation into the reaction of benzylic enami-
nones with chloroacetyl chloride. Thus, in continuation of
our previous work on using enaminones,9 in this letter we
report a straightforward approach to N-chloroacetyl or N-
aroyl b-benzylidene a-amino acid esters via a one-pot pro-
cess.
R
Cl
Ph
N
O
H
O
OMe
O
N
H
H
N
O
OH NH2
O
O
R
O
1
2
Figure 1 Examples of valuable compounds with N-protected a-
amino acid ester substructure
As shown in Scheme 2, the one-pot optimized equimolar
reaction of benzylamine, dimethyl acetylenedicarboxylate
and chloroacetyl chloride proceeded smoothly in toluene
under reflux to produce N-chloroacteyl b-benzylidene a-
amino acid ester 5b after eight hours in 76% yield.
Application of enaminones as ambident 1,3-binucleo-
philic intermediates in synthetic organic chemistry5 and
especially in heterocyclic synthesis is well documented.6
There are many reports on functionalization of enamino-
To investigate the reaction scope and limitations, different
types of amine were used in the reaction under the same
condition. As depicted in Table 1, the reaction of benzyl-
amine 3, dialkyl acetylenedicarboxylate 4 and chloro-
acetyl chloride is general with regards to the benzylamine
SYNLETT 2011, No. 17, pp 2495–2498
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1261237; Art ID: D20711ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2496
A. Alizadeh et al.
LETTER
at about d = 42 ppm. The vinylic carbons for both of com-
pounds 5 and 7 resonate at d = 40–44 ppm. Finally, results
of single crystal X-ray diffraction analysis of 5c indicated
the E orientation of substitution around C=C (E-isomer)
in addition to confirming of the proposed gross structure
(Figure 2).10
Ph
NH2
+
O
Ph
toluene
reflux, 8 h
NH
H
MeO2C
CO2Me
Cl
+
MeO2C
CO2Me
5b
Cl
O
Table 2 Synthesis of N-Aroyl b-Benzylidene a-Amino Acid Ester
Derivatives
H
Cl
Scheme 2 Reaction of benzylamine, dimethyl acetylenedicarboxy-
late and chloroacetyl chloride in toluene
NH2
R1
R2
Table 1 Synthesis of N-Chloroacetyl b-Benzylidene a-Amino Acid
3
Ester Derivatives
Ar
+
toluene
R2O2C
CO2R2
NH
H
NH2
reflux, 8 h
R1
3
R1
O
4
R2O2C
CO2R2
+
O
Ar
Cl
7
toluene
+
NH
H
O
R2O2C
CO2R2
reflux, 8 h
Cl
6
R2O2C
CO2R2
4
Product
R1
H
H
H
R2
Ar
Yield (%)
5
+
Cl
O
7a
7b
7c
7d
7e
7f
Me
Me
Me
Et
p-NO2C6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
p-NO2C6H4
p-ClC6H4
p-BrC6H4
85
82
80
78
78
76
74
H
Cl
Product
5a
R1
R2
Yield (%)
p-Cl
H
Me
Me
Me
Et
80
76
71
75
72
65
Me
5b
p-OMe
p-OMe
p-OMe
Me
Me
Me
5c
p-Me
o-Cl
H
5d
7g
5e
Et
Although no detailed mechanistic and experimental in-
vestigations have been carried out, a plausible reaction se-
quence to the products is outlined in Scheme 3. On the
basis of the established chemistry of enaminones,8,9,11
5f
p-MeO
Et
component. In addition, the product yield increases with
electron-withdrawing groups on the phenyl moiety
(Table 1).
Regarding the efficiency of the reaction, aroyl chlorides
were also employed to study the substrate scope. As ex-
pected, reaction of benzylamines 3, dialkyl acetylenedi-
carboxylate 4 and aroyl chlorides 6 proceeded smoothly at
reflux in toluene to produce N-aroyl b-benzylidene a-ami-
no acid esters 7 (Table 2).
The structures of 5a–f and 7a–g were deduced from their
1
13
IR, mass, H NMR, and C NMR spectra. For example,
in the IR spectrum of 5a, stretching frequencies of NH,
two C=O of esters and amidic C=O appeared at 3430,
1738, 1706 and 1652 cm–1, respectively.
Almost all mass spectra of compounds 5 and 7 displayed
[M+] or [M+ + 1] peaks at the appropriate value. In the 1H
NMR spectra, two doublets at about d = 5.50–6.50 and
7.50–7.80 ppm (the latter exchangeable with D2O on heat-
ing) related to the CHNH moiety, and a sharp singlet at
around d = 8.00 ppm due to C=CH, are characteristic sig-
13
nals for the compounds 5 and 7. C NMR spectra of all
compounds 5 and 7 showed a NHCH signal at around d =
50 ppm while the CH2Cl signal in compound 5 appeared
Figure 2 X-ray crystal structure of compound 5c
Synlett 2011, No. 17, 2495–2498 © Thieme Stuttgart · New York

LETTER
C–N Bond Cleavage of Benzylic Enaminones
2497
NH2
R2O2C
CO2R2
CO2R2
+
3
R1
Y
4
ready for cleavage
O
O
O
CO2R2
CO2R2
CO2R2
CO2R2
Y
H
N
CO2R2
N
Y
Cl
Cl
N
H
path B
path A
R1
R1
Y
H
H
R1
8
O
electron-
withdrawing
10 (N-attack)
9 (C-attack)
N-debenzylation/C-benzylation
via 1,3-benzyl migration
N-debenzylation/C-benzylation
via 1,3-benzyl migration
H
Y
N
CO2R2
R1
R1
R2O2C
O
Y
H
O
NH
tautomerization
O
CO2R2
CO2R2
11
N
H
R2O2C
CO2R2
R1
Y
12
13
tautomerization
5 (Y = CH2Cl)
7 (Y = Ar)
Scheme 3 Plausible mechanism for the formation of N-chloroacetyl or N-aroyl b-benzylidene a-amino acid esters 5 and 7
compounds 8 apparently results from addition of the pri-
mary amines 3 to the dialkyl acetylenedicarboxylate 4. In
the presence of the acid halide, enaminone C- or N-acyla-
tion occurs to afford push-pull enaminone 9 or amido
enaminone 10.12 The key step involves conversion of
compound 9 or 10 to 11 or 12 via C–N bond cleavage fol-
lowed by 1,3-benzyl migration to afford intermediate 11
or 12. The next step involves 1,3-acyl or 1,3-aroyl shift in
11 or tautomerization in 12 to produce intermediate 13.
Finally, intermediate 13 converts to the N-acetyl or N-
aroyl b-benzylidene a-amino acid esters 5 or 7 via a final
tautomerization.
References and Notes
(1) (a) Hughes, A. B. Amino Acids, Peptides and Proteins in
Organic Chemistry: Origins and Synthesis of Amino Acids,
Vol. 1; Wiley-Interscience: New York, 2009. (b) Hughes,
A. B. Amino Acids, Peptides and Proteins in Organic
Chemistry: Origins and Synthesis of Amino Acids, Vol. 4;
Wiley-Interscience: New York, 2009.
(2) (a) Hasuoka, A.; Nishikimi, Y.; Nakayama, Y.; Kamiyama,
K.; Nakao, M. J. Antibiot. 2002, 55, 322. (b) Ryder, T. R.;
Hu, L. Y.; Rafferty, M. F.; Lotarski, S. M.; Rock, D. M.
Drug Des. Discovery 2000, 16, 317. (c) Jeng, A. Y.;
Savage, P.; Beil, M. E.; Bruseo, W.; Hoyer, D. Clin. Sci.
2002, 48, 98. (d) Beck-Sickinger, A. G. Methods Mol. Biol.
(Totowa, N. J.) 1997, 73, 61. (e) Davis, F. A.; Chen, B. C.
Chem. Soc. Rev. 1998, 27, 13. (f) Goodman, M.; Shao, H.
Pure Appl. Chem. 1996, 68, 1303. (g) Lubec, G.; Rosenthal,
G. A. Amino Acids: Chemistry, Biology, and Medicine;
ESCOM Science Publishers B. V.: Leiden (Netherlands),
1990. (h) Seebach, D.; Jeanguenat, A.; Schmidt, J.; Maetzke,
T. Chimia 1989, 43, 314. (i) Wysong, C. L.; Yokum, T. S.;
McLaughlin, M. L.; Hammer, R. P. Chemtech 1997, 27, 26.
(3) Imramovsky, A.; Vinsov, J.; Ferriz, J. M.; Buchta, V.;
Jampilek, J. Bioorg. Med. Chem. Lett. 2009, 19, 348.
(4) (a) Beholz, L. G.; Benovsky, P.; Ward, D. L.; Barta, N. S.;
Stille, J. R. J. Org. Chem. 1997, 62, 1033. (b) Honda, Y.;
Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett.
2002, 4, 447. (c) Park, O. J.; Jeon, G. J.; Yang, J. W. Enzyme
Microb. Technol. 1999, 25, 455. (d) Diederichsen, U.;
Lindhorst, T. K.; Westermann, B.; Wessjohann, L. A.
Bioorganic Chemistry: Highlights and New Aspects; Wiley-
Interscience: New York, 1999. (e) Domling, A. Chem. Rev.
2006, 106, 17. (f) You, S. L.; Kelly, J. W. Org. Lett. 2004, 6,
1681.
In conclusion, a novel, convenient and efficient one-pot
synthesis of N-acetyl or N-aroyl b-benzylidene a-amino
acid esters is reported from readily available and inexpen-
sive starting materials. It is proposed that the reaction pro-
ceeds via C–N bond cleavage resulting from benzyl
migration; a novel behavior for N-benzyl enaminones. All
of the reactions are stereoselective for the E-alkene. The
reaction also allows the introduction of three diversity
points into the final amino acid. From a structural view-
point, all of the products are similar to aspartic acid
Figure 3). Other notable features of this reaction include
easy reaction performance, purification and good yield.
Further investigations on the reaction mechanism, scope
and limitations are underway.
R1
YOCHN
R2O
H2N
HO
(5) Rappoport, Z. The Chemistry of Enamines, Part 1; John
Wiley: New York, 1994.
OR2
OH
(6) (a) Kucklander, U. In The Chemistry of Enamines;
Rappoport, Z., Ed.; Wiley: Chichester, 1994, Chap. 10, 523.
(b) Stille, J. R.; Barta, N. S. Stud. Nat. Prod. Chem. 1996, 18,
315. (c) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem.
1997, 67, 207. (d) Granik, V. G.; Makarov, V. A.; Parkanyi,
C. Adv. Heterocycl. Chem. 1999, 72, 283. (e) Katritzky, A.
O
O
O O
aspartic acid
5, 7
Figure 3
Synlett 2011, No. 17, 2495–2498 © Thieme Stuttgart · New York

2498
A. Alizadeh et al.
LETTER
7.69 (d, 3JH,H = 9.1 Hz, 1 H, NH), 7.95 (s, 1 H, C=CH). 13
R.; Fang, Y.; Donkor, A.; Xu, J. Synthesis 2000, 2029.
C
(7) (a) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem. 1997,
67, 207. (b) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G.
P.; Simoni, D. Synthesis 1987, 857. (c) Vales, M.; Lokshin,
V.; Pepe, G.; Samat, A.; Guglielmetti, R. Synthesis 2001,
2419. (d) Michael, J. P.; De Koning, C. B.; Gravestock, D.;
Hosken, G. D.; Howard, A. S.; Jungmann, C. M.; Krause, R.
W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure
Appl. Chem. 1999, 71, 979. (e) Seki, H.; Georg, G. I. J. Am.
Chem. Soc. 2010, 132, 15512. (f) Stanovnik, B.; Svete, J.
Chem. Rev. 2004, 104, 2433.
NMR (125.7 MHz, CDCl3): d = 21.39 (Me), 42.41 (CH2Cl),
49.87 (CHN), 52.36 (OMe), 53.06 (OMe), 126.33 (C=CH),
129.17 (2 × CH of Ar), 129.63 (2 × CH of Ar), 130.95 (Cipso
C=C), 139.98 (Cipso-Me), 144.55 (C=CH), 165.41 (CON),
167.13 (CO2Me), 170.05 (CO2Me). MS (EI, 70 eV): m/z
(%) = 340 (64) [M+ + 1], 280 (80), 248 (100), 172 (57), 157
(53), 144 (52), 129 (44), 105 (6), 91 (24), 77 (27), 59 (22).
Anal. Calcd for C16H18ClNO5: C, 56.56; H, 5.34; N, 4.12.
Found: C, 56.53; H, 5.32; N, 4.90. Crystal data for 5c
(CCDC 695674): C16H18ClNO5, MW = 339.76, triclinic,
space group P21/n, a = 13.5932 (12) Å, b = 7.9447 (7) Å, c
= 16.5222 (15) Å, a = 90°, b = 106.461 (1)°, g = 90°, V =
1711.2 (3) Å3, Z = 4, Dc = 1.319 mg/m3, F(000) = 712,
crystal dimension: 0.31 × 0.26 × 0.23 mm, radiation, Mo Ka
(l = 0.71073 Å), 1.72£2q£25.18, intensity data were
collected at 295 (2) K with a Bruker APEX area-detector
diffractometer, and employing w/2q scanning technique, in
the range of –16£h£15, –9£k£9, –19£l£19; the structure was
solved by a direct method, all non-hydrogen atoms were
positioned and anisotropic thermal parameters refined from
2546 observed reflections with R(into) = 0.0734 by a full-
matrix least-squares technique converged to R = 0.0614 and
Raw = 0.1475 [I >2s(I)]. Compound 7a: cream powder
(0.34 g, yield: 85%); mp 118–120 °C. IR (KBr): 3333 (NH),
1752 (CO2Me), 1694 (CO2Me), 1668 (NC=O), 1603 (C=C),
1484, 1342 (NO2) cm–1. 1H NMR (500.13 MHz, CDCl3): d =
3.80 (s, 3 H, OMe), 3.87 (s, 3 H, OMe), 6.19 (d, 3JH,H = 8.6
Hz, 1 H, CHN), 7.43 (d, 3JH,H = 7.2 Hz, 1 H, NH), 7.47 (t,
3JH,H = 7.5 Hz, 2 H, 2 × CHmeta of Ph), 7.49 (t, 3JH,H = 7.5 Hz,
1 H, CHpara of Ph),7.57 (d, 3JH,H = 7.3 Hz, 2 H, 2 × CH of Ph),
7.94 (d, 3JH,H = 8.7 Hz, 2 H, 2 × CH of Ar), 8.02 (s, 1 H,
C=CH), 8.26 (d, 3JH,H = 8.6 Hz, 2 H, 2 × CH of Ar). 13C NMR
(125.7 MHz, CDCl3): d = 50.32 (CHN), 52.50 (OMe), 53.25
(OMe), 123.78 (2 × CH of Ar), 127.17 (C=CH), 128.44 (2 ×
CH of Ar), 128.94 (2 × CH of Ar), 129.13 (2 × CH of Ar),
129.74 (CH of Ar), 133.82 (Cipso-C=C), 139.42 (Cipso-CON),
144.56 (C=CH), 149.80 (Cipso-NO2), 164.58 (CON), 167.36
(CO2Me), 170.30 (CO2Me). MS (EI, 70 eV): m/z (%) = 399
(8) [M+ + 1], 366 (16), 339 (79), 307 (100), 279 (5), 248 (16),
173 (17), 150 (75), 120 (12), 104 (33), 92 (16), 76 (18), 59
(7). Anal. Calcd for C20H18N2O7 (398.37): C, 60.30; H, 4.55;
N, 7.03. Found: C, 60.28; H, 4.52; N, 7.01.
-
(8) Alizadeh, A.; Sabahnoo, H.; Noaparast, Z.; Zohreh, N.;
Mikaeili, A. Synlett 2010, 1854.
(9) (a) Alizadeh, A.; Movahedi, F.; Esmaili, A. A. Tetrahedron
Lett. 2006, 47, 4469. (b) Alizadeh, A.; Movahedi, F.;
Masrour, H.; Zhu, L. G. Synthesis 2006, 3431. (c)Alizadeh,
A.; Babaki, M.; Zohreh, N.; Rezvanian, A. Synthesis 2008,
3793. (d) Alizadeh, A.; Babaki, M.; Zohreh, N. Tetrahedron
2009, 65, 1704. (e) Alizadeh, A.; Babaki, M.; Zohreh, N.
Synthesis 2008, 3295.
(10) Typical Procedure: To a magnetically stirred 5-mL flat-
bottom flask containing benzylamine (0.22 g, 2 mmol)
and toluene as solvent was added dimethyl
acetylenedicarboxylate (0.28 g, 2 mmol). After 30 min, a
solution of chloroacetyl chloride (0.37 g, 2 mmol) for 5a or
p-nitrobenzoyl chloride (0.44 g, 2 mmol) for 7a was added
to the reaction mixture and stirring was allowed to continue
at 100–120 °C for 8 h. After the completion of the reaction,
the solvent was removed under reduced pressure. The
residue was purified by column chromatography on silica
gel (n-hexane–EtOAc, 9:1) to obtain 5a and crystallized
from Et2O to obtain 7a. Compound 5a was obtained as a
yellow oil (0.28 g, yield: 80%). IR (KBr): 3430 (NH), 1738
(CO2Me), 1706 (CO2Me), 1652 (NC=O) cm–1. 1H NMR
(500.13 MHz, CDCl3): d = 3.77 (s, 3 H, OMe), 3.87 (s, 3 H,
OMe), 4.04 (AB system, 3JH,H = 15.2 Hz, 2 H, CH2Cl), 5.75
(d, 3JH,H = 8.8 Hz, 1 H, CHN), 7.33–7.35 (m, 2 H, 2 × CH of
Ar), 7.44–7.46 (m, 1 H, CH of Ar), 7.55–7.57 (m, 1 H, CH
of Ar), 7.68 (d, 3JH,H = 9.2 Hz, 1 H, NH), 8.01 (s, 1 H, s,
C=CH). 13C NMR (125.7 MHz, CDCl3): d = 42.37 (CH2Cl),
49.97 (CHN), 52.59 (OMe), 53.19 (OMe), 127.09 (CH of
Ar), 128.84 (C=CH), 129.75 (CH of Ar), 130.07 (CH of Ar),
130.71 (CH of Ar), 132.61 (Cipso-Cl), 134.20 (Cipso-C=C),
141.62 (C=CH), 165.36 (CON), 166.50 (CO2Me), 169.71
(CO2Me). MS (EI, 70 eV): m/z (%) = 324 (15), 296 (69), 268
(71), 236 (73), 207 (63), 125 (100), 111 (74). Anal. Calcd for
C15H15Cl2NO5: C, 50.02; H, 4.20; N, 3.89. Found: C, 50.00;
H, 4.17; N, 3.87. Compound 5c: white powder (0.24 g, yield:
71%); mp 82–85 °C. IR (KBr): 3425 (NH), 1761 (CO2Me),
1697 (CO2Me), 1670 (NC=O) cm–1. 1H NMR (500.13 MHz,
CDCl3): d = 2.37 (s, 3 H, Me), 3.76 (s, 3 H, OMe), 3.85 (s, 3
H, OMe), 4.05 (AB system, 3JH,H = 15.2 Hz, 2 H, CH2Cl),
6.01 (d, 3JH,H = 9.0 Hz, 1 H, CHN), 7.24 (d, 3JH,H = 7.9 Hz, 2
H, 2 × CH of Ar), 7.40 (d, 3JH,H = 8.0 Hz, 2 H, 2 × CH of Ar),
(11) (a) Yavari, I.; Souri, S. Synlett 2007, 2969. (b) Yavari, I.;
Souri, S. Synlett 2008, 1209.
(12) (a) Venkov, A. P.; Angelov, P. A. Synthesis 2003, 2221.
(b) Rosa, F. A.; Machado, P.; Rossatto, M.; Vargas, P. S.;
Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synlett
2007, 3165. (c) Vales, M.; Lokshin, V.; Pepe, G.;
Guglielmetti, R.; Samat, A. Tetrahedron 2002, 58, 8543.
(d) Vales, M.; Lokshin, V.; Pepe, G.; Samat, A.;
Guglielmetti, R. Synthesis 2001, 2419. (e) Al-Mousawi, S.
M.; El-Apasery, M. A.; Elnagdi, M. H. Molecules 2010, 15,
58.
Synlett 2011, No. 17, 2495–2498 © Thieme Stuttgart · New York