Synthesis of pyrrolidine-substituted benzamides via iodocyclization of β-enaminoesters

Article abstract of DOI:10.1016/j.tetlet.2007.06.166

Novel 2-, and N-substituted 5-methylene-pyrrolidine benzamides and 2-, 3-, and N-substituted 5-methylene-2-pyrroline benzamides were synthesized for the first time in a straightforward manner and in good yields via iodocyclization of γ- and α-alkenyl-β-enaminoesters, respectively. The key step in the process is the synthesis of the methylene-pyrrolidine iodide and methylene-2-pyrroline iodide intermediates. Functional group inter-conversion of these iodides to their amino analogs, and their subsequent coupling to benzoic acids via EDC, afforded the above pyrrolidine/2-pyrroline-substituted benzamides in yields of around 75%.

Full text of DOI:10.1016/j.tetlet.2007.06.166

Tetrahedron Letters 48 (2007) 6393–6396
Synthesis of pyrrolidine-substituted benzamides via
iodocyclization of b-enaminoesters
c
a
Eliseu O. De Oliveira,a,b, Carlos A. Brandt, Maria A. B. Da Silveira and
*
Richard A. Glennonb
a
ˆ
ˆ
Faculdade de Ciencias Farmaceuticas, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP 05508, Brazil
bDepartment of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA
cInstituto Butantan, Sa˜o Paulo, SP 05503, Brazil
Received 13 March 2007; revised 25 June 2007; accepted 26 June 2007
Available online 7 July 2007
Abstract—Novel 2-, and N-substituted 5-methylene-pyrrolidine benzamides and 2-, 3-, and N-substituted 5-methylene-2-pyrroline
benzamides were synthesized for the first time in a straightforward manner and in good yields via iodocyclization of c- and a-alken-
yl-b-enaminoesters, respectively. The key step in the process is the synthesis of the methylene-pyrrolidine iodide and methylene-2-
pyrroline iodide intermediates. Functional group inter-conversion of these iodides to their amino analogs, and their subsequent
coupling to benzoic acids via EDC, afforded the above pyrrolidine/2-pyrroline-substituted benzamides in yields of around 75%.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Heterocyclic benzamides represent an important class of
therapeutic compounds with several agents showing
activity in the central nervous system as antipsychotics,
and as antiemetics and gastric motility stimulants.1 The
actions of these agents are primarily due to the blockade
of dopamine (D2) and/or serotonin (i.e., 5-HT3) recep-
tors. Structure–affinity relationship studies (SAFIR) of
methylene-pyrrolidine benzamides were considered in
order to address what role the heterocyclic substituents
might play regarding their binding to D2 and 5-HT3
receptors. That is, although these benzamides have been
shown to be therapeutically effective, the role of substit-
uents at the pyrrolidine N-, 2-, and 3-positions (i.e., the
equivalent N-, 4-, and 5-positions relative to the parent
unsubstituted compound) has not been systematically
investigated because an useful synthetic route to such
analogs has not yet been developed. The purpose of this
study was to identify a convenient method that would
allow an entry to compounds bearing such substituents.
To this end, we applied the method of iodocyclization of
a- and c-alkenyl-b-enaminoesters to the synthesis of the
2-pyrrolines and pyrrolidines substituted at positions
C2, C3, and at the nitrogen atom.2 This synthetic meth-
odology was previously explored2 and is presented here
as an application to the synthesis of relevant, potentially
biologically active benzamides currently under pharma-
cologic investigation (Fig. 1).
The synthesis of benzamides 1 and 2 started with the
preparation of b-ketoesters 5 and 6 via appropriate
alkylation of methyl acetoacetate enolates with allyl
bromide. These enolates were generated in situ by treat-
ment of the ester with NaH and/or n-BuLi in solution of
THF (Scheme 1). The detailed procedures used for the
synthesis of 5 and 6 are, respectively, noted by Refs.
4a and 4c. From the variety of methods available to pre-
pare b-enaminoesters 3 and 4,3 we chose the condensa-
tion of ethylamine with b-ketoester 5 in a solution of
toluene with azeotropic removal of water4b and the con-
densation of benzylamine to b-ketoester 6 in the pres-
ence of neutral Al2O3 at room temperature.4d Solvent
removal followed by Kugelrohr distillation afforded
the products 3 and 4 in good yields (Scheme 1). The iodo-
cyclization of these b-enaminoesters is the key step for
the synthesis of the desired benzamides. This reaction
was performed under kinetically controlled conditions
that afforded the substituted-pyrrolidine 7 and 2-pyrro-
line 8 derivatives under mild conditions and in good
yields (Scheme 1). The mechanism proposed for this
reaction is the attack of the nitrogen (internal nucleo-
phile) to an iodonium ion intermediate (e.g., 9) in an
Keywords: Iodocyclization; b-Enaminoesters; Benzamides; Pyrrol-
idines; 2-Pyrrolines.
*
Corresponding author. Tel.: +1 804 828 6454; fax: +1 804 828
7625; e-mail: eodeoliveira@vcu.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.166

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E. O. De Oliveira et al. / Tetrahedron Letters 48 (2007) 6393–6396
O
O
4
Cl
Cl
N
N
3
2
CO2CH3
CH3
H
H
N
N
R1
O
R1
O
R2
R2
CO2CH3
CH3
CH3
R1=H, NH2; R2=Et, Bn
R1=H, NH2; R2=Bn
1(a-d)
2(a-b)
Figure 1. Novel pyrrolidine- and 2-pyrroline-substituted benzamides synthesized via iodocyclization of b-enaminoesters and selected for SAFIR at
D2 and 5-HT3 receptors.
O
O
O
i
ii
CO2Me
CO2Me
CO2Me
5
6
O
O
R
NH
Cl
X
CO2Me
N
iii
iv
CO2Me
vii
H
N
N
R
5
R1
R
CO2Me
CH3
7a,b X=I
v
3a,b
13a,b X=N3
11a,b X=NH2
R1=H, NH2; R=Et, Bn
vi
3a, 7a, 13a, 11a (R=Et)
3b, 7b, 13b, 11b (R=Bn)
1(a-d)
O
N
Bn
CO2Me
NH
Cl
CO2Me
X
CO2Me
iii
iv
vii
H
6
N
N
R1
O
Bn
Bn
CH3
4
8 X=I
v
14 X=N3
12 X=NH2
R1=H, NH2
2(a-b)
vi
Scheme 1. Reagents and conditions: (i) NaH, THF, 0 ꢂC, N2, 10 min, then n-BuLi, 10 min, allylbromide, 15 min, 0 ꢂC to rt, then HCl, 74%;4a (ii)
NaH, THF, 0 ꢂC, N2, then allylbromide, 0 ꢂC to rt, 24 h, 49%;4c (iii) 70% EtNH2, AcOH, toluene, reflux, Dean–Stark, 18 h, 95% or BnNH2, Al2O3
neutral, rt, 12 h, 96–98%;16 (iv) I2, NaHCO3, CH2Cl2, rt, 24 h, 49–53%;15 (v) NaN3, (Et)4NBr, DMF, reflux, 4 h, 52–64%;14 (vi) H2 Parr
hydrogenator, 50 psi, Lindlarꢁ, rt, EtOH abs., 2–4 days, 70–90%;13 (vii) 5-chloro-2-methoxybenzoic acid (15) or 4-amino-5-chloro-2-methoxybenzoic
acid (16), EDC, CH2Cl2, rt, 6 h, 74–76%.12
antiperiplanar orientation5 (Fig. 2). Alternatively, an
alkene-iodine p-complex has also been proposed for this
type of reaction.6 The ring-closure process follows clas-
sical Baldwin’s rule and occurs in a 5-exo-trig manner.7
In order for a-allyl-b-enaminoesters 4 to achieve the
proper geometry for nitrogen attack for ring formation,
the tautomeric imine-enamine equilibrium might be
shifted to a less stable enamine tautomer 4a. This is
not required for the cyclization of c-allyl-b-enamino-
esters 3 due to the high flexibility of the iodine-acceptor
carbon chain bearing the double bond. In situ deproto-
nation of putative intermediate (e.g., 10) by NaHCO3
affords heterocyclic iodides 7 and 8 (Fig. 2).
aromatic pyrrole derivatives, which is observed with
reagents of strong basicity but weak nucleophilicity
(i.e., DBU,17 phenoxide anion).2,9 The isolated azides
were then subjected to hydrogenation in the presence
of Lindlarꢁ catalyst in EtOH as solvent10 to give the
amines in a fairly good yield (Scheme 1).
Finally, representative benzamides 1 and 2 were synthe-
sized in good yields by coupling amines 11 and 12 with
benzoic acids 15 and 16, respectively, in the presence of
EDC17 at room temperature in CH2Cl2 (Scheme 1,
Table 1).
In conclusion, we have provided for the first time, a syn-
thetic application of iodocyclization of b-enaminoesters
to the synthesis of potentially interesting N-, C2-, and/or
C3-substituted 5-methylene-pyrrolidine and 5-methyl-
ene-2-pyrroline benzamides. Though not stereoselective,
the method proved to be robust by affording the key,
highly functionalized iodide intermediates in three syn-
thetic steps. Also, their functional group inter-conver-
sion to amines and subsequent coupling with the
benzoic acids via EDC was achieved in a straight-
forward manner and in good yields. Although the scope
of the reaction remains to be fully explored, it provides
The functional group inter-conversion of intermediate
iodides 7 and 8 to amines 11 and 12, respectively, was
achieved by nucleophilic displacement of the iodine
atom by an azide anion with further selective reduction
of compounds 13 and 14 (Scheme 1). Azide formation
was performed in a solid–liquid phase transfer catalysis
fashion.8 The iodide substrates were mixed with NaN3
and (Et)4NBr in anhydrous DMF17 and allowed to stir
for 4 h at reflux. Under these conditions, no product
of dehydrohalogenation was detected which would have
led to double bond migration and formation of the

E. O. De Oliveira et al. / Tetrahedron Letters 48 (2007) 6393–6396
6395
R
R
H
R
N
N
O
NH
CO2Me
OMe
CO2Me
4a
I2
4
(R=Bn)
I
CO2Me
CO2Me
I-
H
R
NaHCO3
I+
N
I
N+
N
R
R
H
CO2Me
CO2, H2O
NaI
10
8
9
R
N
H
I
CO2Me
O
I2, NaHCO3
N
R
MeO
(R=Et, Bn)
3
7
Figure 2. Proposed mechanism for the iodocyclization of b-enaminoesters.
Table 1. Novel representative pyrrolidine- and 2-pyrroline-substituted benzamides synthesized via iodocyclization of b-enaminoestersa
Compound
R1
R
Yieldb (%)
Mpc (ꢂC)
1a
1b
1c
1d
H
NH2
H
Et
Et
Bn
Bn
74
75
76
75
105–106
159–160
120–121
146–148
O
Cl
N
H
N
R
NH2
R1
O
CO2CH3
CO2CH3
CH3
O
Cl
N
H
2a
2b
H
NH2
—
—
75
74
136–137
145–146
N
R1
O
Bn
CH3
CH3
a See Refs. 11 and 12.
b Isolated yield for the last synthetic step after SiO2 flash chromatography.
c Determined in a Thomas–Hoover apparatus. Uncorrected.
Discovery, 6th ed.; Abraham, D. J., Ed.; John Wiley &
Sons: New Jersey, 2003; Vol. 6, pp 599–672.
2. Ferraz, H. M. C.; De Oliveira, E. O.; Payret-Arrua, M. E.;
Brandt, C. A. J. Org. Chem. 1995, 60, 7357–7359.
3. Brandt, C. A.; Da Silva, A. C. M. P.; Pancote, C. G.;
Brito, C. L.; Da Silveira, M. A. B. Synthesis 2004, 10,
1557–1559, and references cited therein.
4. (a) The b-ketoester 5 was prepared following the same
method as reported previously for their ethyl analogs;2 (b)
Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983,
11, 902–903; For the synthesis of 6 see: (c) Sum, P. E.;
Weiler, L. Can. J. Chem. 1978, 56, 2301–2304; (d) Braib-
ante, M. E. F.; Braibante, H. T. S.; Salvatore, S. J. S. A.
Quim. Nova 1990, 13, 67–68.
5. This mechanism is analogous to the iodolactonization of
c,d-alkenyl acids as proposed by Dowle and Davies:
Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171–
197.
6. Charberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S. D.;
Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672–677.
7. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–
736.
entry to analogs that have not been previously readily
available for pharmacological evaluation.
Acknowledgment
The present work was supported in part by CAPES—
Program PDEE-BEX0866/00-8, Brazil.
Supplementary data
Supplementary data (1H and 13C NMR spectra
(300 MHz and 75 MHz, respectively) for compounds
1a–d and 2a,b in CDCl3) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2007.06.166.
References and notes
8. Koziara, A.; Zawadzki, S.; Zwierzak, A. Synthesis 1979, 7,
527–529.
9. Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M.
R. S.; Payret-Arrua, M. E. Tetrahedron 1999, 55, 10915–
10924.
1. (a) Thomas, C.; Hubner, H.; Gmeiner, P. Biorg. Med.
Chem. Lett. 1999, 9, 841–846, and references cited therein;
(b) Altar, C. A.; Martin, A. R.; Thurkauf, A. Antipsy-
chotic Agents. In Burger’s Medicinal Chemistry and Drug

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E. O. De Oliveira et al. / Tetrahedron Letters 48 (2007) 6393–6396
10. Corey, E. J.; Nicolaou, K. C.; Balanson, R. D.; Machida,
Y. Synthesis 1975, 9, 590–591.
removed by filtration through Celiteꢁ and the product
was purified by flash chromatography (CH2Cl2–MeOH
9:1) to give a light yellow oil. 11a (R = Et): yield 88%; 11b
(R = Bn): yield 90%; 12: yield 70%.
11. Data for compound 1a: Yield 74%. Mp 105–106 ꢂC. 1H
NMR (300 MHz, CDCl3): d 1.20 (t, J = 6.96 Hz, 3H),
1.78–1.86 (m, 1H), 2.11–2.21 (m, 1H), 3.10–3.42 (m, 5H),
3.64 (s, 3H), 3.88–3.97 (m, 2H), 3.91 (s, 3H), 4.64 (s, 1H);
6.92 (d, J = 8.8 Hz, 1H), 7.41 (dd, J1 = 8.8 Hz,
J2 = 2.9 Hz, 1H), 7.91 (br s, 1H), 8.17 (d, J = 2.94 Hz,
1H). 13C NMR (75 MHz, CDCl3): d 11.4, 24.8, 31.2, 39.1,
41.3, 50.1, 56.3, 62.1, 78.1, 112.9, 122.2, 126.8, 131.9,
132.6, 155.9, 164.5, 164.9, 169.6.
14. General procedure for the synthesis of azides 13 and 14: A
mixture of iodide (7 or 8) (6 mmol), NaN3 (24 mmol), and
(Et)4NBr (10% w/w over iodide) in DMF (120 mL) was
stirred at reflux for 4 h. The mixture was poured into H2O
(100 mL), extracted with benzene (3 · 50 mL) and dried
(Na2SO4). The solvent was removed and the product
purified by flash chromatography (hexanes–AcOEt 4:1).
13a (R = Et): yield 52%, brownish oil, Rf 0.25; 13b
(R = Bn): yield 64%, brownish oil, Rf 0.15; 14: yield
61%, brownish oil, Rf 0.30. All Rf’s in hexanes–AcOEt 4:1.
15. General procedure for the synthesis of iodides 7 and 8: See
Ref. 2. Compound 7a (R = Et): yield 49% (rec. EtOH),
beige solid, Rf 0.35; 7b (R = Bn): yield 53% (rec. EtOH),
beige solid, Rf 0.25; 8: yield 53% (rec. EtOH), beige solid,
Rf 0.41. All Rf’s in hexanes–AcOEt 4:1.
16. General procedure for the synthesis of b-enaminoesters: 3
(See Ref. 4b and 4d); 4 (see Ref. 4d). Compound 3a
(R = Et): yield 95%, light yellow oil, Rf 0.60; 3b (R = Bn):
yield 98%, light yellow oil, Rf 0.53; 4: yield 96%, light
yellow oil, Rf 0.74. All Rf’s in hexanes–AcOEt 4:1.
17. EDC: N-(3-Dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene;
DMF: N,N-Dimethylformamide.
12. General procedure for the synthesis of benzamides 1 and 2:
A mixture of benzoic acid (15 or 16) (10 mmol), amine 11
or 12 (10 mmol), and EDC (12 mmol) in CH2Cl2 (80 mL),
was allowed to stir at rt for 24 h. The mixture was
successively washed with H2O (20 mL), 10% NaOH
(10 mL), H2O (20 mL), brine (20 mL), and dried
(Na2SO4). The solvent was removed and the product
purified by flash chromatography (CH2Cl2–MeOH 19:1).
1
See Ref. 11 and Supplementary data for complete H and
13C NMR data. See Table 1 for yields and melting points.
13. General procedure for the synthesis of amines 11 and 12:
The azide (13 or 14) (6 mmol) was added to a proper flask
for hydrogenation containing Lindlarꢁ catalyst (372 mg)
dispersed in absolute EtOH (100 mL). The mixture was
shaken in a Parr hydrogenator for 2–4 days at rt and at
50 psi (reaction followed by TLC). The catalyst was