An investigation of the bromination of 1,4-dihydropyridine rings

Article abstract of DOI:10.1016/j.tetlet.2010.11.146

Conditions for bromination at the C3 and C5 positions of a 1,4-dihydropyridine (DHP) were investigated. The effect of base concentration, base type, reaction temperature, and solvent were examined. DHP derivatives with ester and amide moieties were synthe

Full text of DOI:10.1016/j.tetlet.2010.11.146

Tetrahedron Letters 52 (2011) 757–760
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An investigation of the bromination of 1,4-dihydropyridine rings
Ori Rorlik a, Zeev Tashma a, Claudia M. Barzilay a,b, Morris Srebnik a,
⇑
a Institute of Drug Research, School of Pharmacy, Hebrew University in Jerusalem, Jerusalem 99120, Israel
b Bargal Analytical Instruments, Air Port City 70100, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Conditions for bromination at the C3 and C5 positions of a 1,4-dihydropyridine (DHP) were investigated.
The effect of base concentration, base type, reaction temperature, and solvent were examined. DHP deriv-
atives with ester and amide moieties were synthesized and brominated. The bromine atoms can be
replaced by other substituents, utilizing Suzuki cross coupling.
Received 2 August 2010
Revised 2 November 2010
Accepted 29 November 2010
Available online 4 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1,4-Dihydropyridine (DHP) derivatives have several important
uses in medicine and as precursors for the preparation of
multisubstituted pyridines.1–4 To this day, only one general and
widely used synthetic pathway exists for the preparation of DHP
derivatives: the Hantzsch synthesis,5,6 first reported in 1882. There
are several minor synthetic pathways for DHP preparation, but
their use is relatively limited. As with any chemical reaction, the
Hantzsch synthesis is limited by its scope, that is, the reaction
works better with specific side groups. Hantzsch DHPs usually con-
tain strong electron-withdrawing groups at the C3 and C5 posi-
tions (esters, ketones, and nitriles). Therefore, DHP derivatives
with weak electron-withdrawing and electron-donating groups at
those positions are relatively rare.
Surprisingly, and considering their potential to be further
substituted, thus increasing the range of DHP derivatives available,
there have been few attempts to prepare DHPs with halogens at
the C3 and C5 positions.7 Bromination of the DHP ring demon-
strated a possible general approach to the synthesis of halogenated
DHPs. Herein we report the synthesis of several new halogenated
DHPs and investigate different conditions for bromination of the
DHP ring, resulting in both mono and disubstituted derivatives,
and demonstrate the use of the products in the versatile Suzuki
coupling reaction.
route8 was used to prepare two known derivatives and several
new ones (Scheme 1). The synthesis was conducted according to
the known procedure and the resulting bis(dioxolanemethyl) dies-
ter 1 was obtained in 61% yield. The second step proceeded exactly
as described in the literature and afforded the required DHP 2a in
47% yield. The structure of the final product was established by
comparing its 1H NMR spectrum with the literature. By using dif-
ferent primary amines in the last step, a set of DHP derivatives
was synthesized (Scheme 1). Several attempts were made to syn-
thesize DHPs with methyl cyanoacetate and methyl acetoacetate,
but these were unsuccessful. Since this synthetic approach seems
to only work with esters, a different synthetic route was estab-
lished, based on converting the ester groups into different moie-
ties, after the construction of the DHP ring. To this end we chose
O
O
O
Br
O
O
O
MeO
O
OMe
O
KOtBu
DMSO
+
MeO
OMe
O
O
1
For successful bromination, DHPs with two structural proper-
ties are desired: (1) the DHP should not posses, a substituent on
the double bonds, and (2) the DHP derivative should not contain
a hydrogen atom at C4. DHP derivatives with a C4 hydrogen might
be oxidized to the corresponding pyridine in the presence of a
strong oxidizing agent such as bromine. The first requirement
proved to be a major obstacle since most known 1,4-DHPs have
substituents on the C3 and C5 positions, or at C2 and C6 which help
stabilize the ring by reducing its electron density. Only one group
has synthesized suitable DHP derivatives and their published
O
O
O
O
H2O
HCl
amine
MeO
OMe
MeO
OMe
N
R
O
O
2
2a R= n-hexyl
2b R= cyclopentyl
2c R= n-butyl
(47%)
(42%)
(42%)
2d R= 2-methoxy ethyl (33%)
2e R= CH2CH2OH
(0%)
⇑
Corresponding author. Tel.: +972 79722675301; fax: +972 797226758201.
E-mail addresses: morris.srebnik@ekmd.huji.ac.il, msrebni@md.huji.ac.il (M.
Scheme 1. Preparation of DHP derivatives with different substituents on the
Srebnik).
nitrogen atom.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.146

758
O. Rorlik et al. / Tetrahedron Letters 52 (2011) 757–760
Table 1
DHP derivatives with amide groups at C4
O
O
O
O
MeO
OMe
R'
R''
amine, solvent
N
R
N
R
3
2
Product
R
R0
R00
Solvent
Time (d)
Recoverya (%)
Yieldb (%)
3a
3b
3e
Cyclopentyl
2-Methoxyethyl
Cyclopentyl
–NH2
–NH2
–NH2
–OMe
–OMe
–NH2
Methanol
Methanol
Water
2
2
2
52
58
—
23
25
<20
OH
OH
3c
Cyclopentyl
Cyclopentyl
–OMe
THF
THF
1
3
66
—
21
80
NH
NH
OH
3d
NH
a
Percent of reactant 2 recovered after column separation.
Percent of product separated from the column.
b
two DHPs (2b and 2d) and attempted to transform one of the
ester groups, or both, to amides with ammonia and ethanolamine
(Table 1).
and 4f) and in other cases, product isolation was impossible be-
cause of complete degradation on the column (substances 4g and
4h). The limited yields in several brominations (substances 4c,
4e–4h) might be a result of the acid formed during the bromina-
tion process. It would appear that this lack of stability is brought
about by DHP ring hydrolysis which is, apparently, accelerated
by the presence of amide side groups. Despite these problems, sev-
eral dibrominated DHP derivatives were obtained in reasonable to
high yields and of required purity levels.
During the process of investigating different bromination condi-
tions9 we observed the formation of a monobrominated DHP
(Scheme 2) even though most conditions showed a preference
for the dibrominated product. To gain a better understanding of
the mechanism of the reaction and to comprehend the observed
trend, we examined this reaction with only 1 equiv of bromine.
Thus 2a was dissolved in distilled CH2Cl2, cooled to 0 °C, and a
solution containing 1.1 equiv of Br2 was added over 30 min. The
reaction was attempted several times in the presence of an internal
standard, and the product type and yield were examined by 1H
NMR spectroscopy. Scheme 2 shows the resulting yield when the
reaction was performed with 1 equiv of triethylamine.
In an attempt to further improve the yield of 5 and gain insight
into the reaction mechanism, the effect of Et3N concentration on
reaction yield was examined. A series of brominations was under-
taken, utilizing different concentrations of Et3N (Fig. 1), starting
from 0 equiv and gradually increasing up to 5 equiv. Increasing
the amount of Et3N improved the yield of both monobrominated
and dibrominated products up to 4% and 40%, respectively, at
1.2 equiv of Et3N. At higher Et3N concentrations the yield of the
monobrominated product continued to increase while the yield
of the dibrominated product decreased until, at 2 equiv of Et3N,
the major product was 5 (36% yield) accompanied by a 9% yield
of 4a.
We obtained eight DHP derivatives in acceptable yields and
purity and proceeded to examine their bromination under stan-
dard conditions: 2 equiv of bromine, 2 equiv of pyridine, CH2Cl2,
0 °C.9 Each derivative was first brominated in the presence of trib-
romobenzene,10 as an internal standard, and then brominated in
larger quantities without the internal standard.11 The products
were isolated by chromatography (followed by recrystallization
where possible). A comparison between the 1H NMR estimated
yields and the obtained yields is shown in Table 2.
In all cases the appropriate dibromo product was observed and/
or obtained. One fact became obvious during this work and is
worth mentioning. DHP molecules of the general structure that
we chose are unstable under acidic conditions, to a varying degree.
As a rule, derivatives with an amide group were far less stable than
their diester counterparts. The amides were so unstable that they
could not even be washed with dilute aqueous HCl. Adding bro-
mine atoms to these already sensitive DHPs increased their vulner-
ability to such an extent that they could not be recrystallized. In
several cases, purity problems were observed because of partial
product degradation on the silica column (substances 3c, 3d, 4e,
Table 2
Bromination of various DHP derivatives
O
O
O
O
R1
Br
R2
Br
R1
R2
Pyridine, 0 ºC
dry CH2Cl2
+
Br2
N
R
2 eq.
N
R
4
Higher Et3N concentrations (3 equiv and 5 equiv) did not im-
prove the overall yields and did not change the observed trend.
An attempt to separate the mono and dibrominated products using
normal phase column chromatography failed.
Starting material
Product
Solvent
Estimated
yield (%)
Obtained
yield (%)
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
74
82
57
89
80
—
51
91
46
86
60
42
—
One possible explanation for these results is that the bromina-
tion of the DHP ring proceeds via two different reaction pathways
(Scheme 3) with each favoring a different product, and the ratio be-
tween them being dependent upon the amount of base present
during the reaction.
4g
4h
28
39
The first possible mechanism (Scheme 3A) proceeds via addi-
tion/elimination on one of the double bonds, resulting in the
—

O. Rorlik et al. / Tetrahedron Letters 52 (2011) 757–760
759
O
O
O
O
O
O
MeO
Br
OMe
Br
MeO
Br
OMe
MeO
OMe
1.0 eq. Et3N
1.1 eq. Br2
+
+
N
N
N
C6H13
C6H13
C6H13
yield: 29%
2a
yield=2%
4a
5
Scheme 2. Bromination of 2a.
45
40
35
30
25
20
15
10
5
formed at all. It is possible that at low base concentrations
(1 equiv) the elimination of HBr is slow, thus supporting the sec-
ond mechanism and the dibrominated DHP as the major product.
Higher base concentrations (2 equiv) accelerate pathway A, and
thus support the monobrominated DHP.
From these results it was expected that stronger bases (piper-
idine and proton-spongeÒ) would favor the monobrominated
DHP (as was demonstrated with 2 equiv of Et3N) but it appeared
that, in most cases, a stronger basic environment accelerated
the formation of side products which limit the bromination
process.
0
0
1
2
3
4
5
6
Number of Et3N equivalents
The utility of our brominated DHP derivatives as reagents for
further modification was verified by Suzuki reaction, chosen be-
cause of its versatility. Toward this goal compound 2b was reacted
with 4 equiv of phenylboronic acid in distilled toluene, with PdCl2
as catalyst, KOH as base at reflux temperature (Scheme 4). The
reaction required two days, during which time both bromine
atoms were replaced by phenyl groups. Product 6 was separated
and characterized by NMR and MS spectroscopy.12
In summary, the bromination of DHP rings was examined and
the reaction conditions were optimized. Both monobrominated
and dibrominated products were observed. Possible mechanisms
are suggested. Eight new dibrominated DHP derivatives were char-
acterized and one was utilized to demonstrate the feasibility of the
versatile Suzuki reaction with DHPs.
4a % yield 5 % yield
Figure 1. The effect of concentration of Et3N on yields of 4a and
5 in the
bromination reaction.
monobrominated DHP and then a second addition/elimination pro-
cess occurs. This mechanism is expected to favor the monosubsti-
tuted compound as the major product since the first bromine atom,
attached to the DHP, decreases the electron density of the entire
resonance system, making the second double bond less susceptible
to bromination. In the other possible mechanism (Scheme 3B) the
DHP undergoes two addition reactions and then two elimination
reactions. This mechanism is expected to produce the dibrominat-
ed product exclusively, since the monobrominated DHP is not
A
1
2
R
R
Br
HBr
Br
HBr
Br
1
2
2
1
2
1
2
R
R
1
2
R
R
R
R
N
R
R
R
3
Br
Br
Br
Br
Br
Br
Br
2
+
N
R
N
R
N
N
R
1
2
3
R
R
3
3
3
R
Br
Br
Br
Br
Br
2
N
R
3
HBr
B
Scheme 3. Possible mechanisms for the bromination of DHPs.
O
O
O
O
MeO
Br
OMe
Br
MeO
Ph
OMe
Ph
phenylboronic acid, PdCl2,
toluene, 110 ºC, KOH
N
N
yield: 70%
cyclopentyl
cyclopentyl
2b
6
Scheme 4. Suzuki cross-coupling reaction of 2b and phenylboronic acid.

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O. Rorlik et al. / Tetrahedron Letters 52 (2011) 757–760
10. All the reactions were performed in the presence of a constant concentration of
Acknowledgments
1,3,5-tribromobenzene (internal standard) and the yields of both products
were estimated by comparing the area of the peak of the vinylic hydrogens of
the products (by 1H NMR) to the area of the peak of the internal standard.
11. Representative procedure: Preparation of 3,5-dibromo-1-n-hexyl-1H-pyridine-
4,4-dicarboxylic acid dimethyl ester (4a). Compound 2a (2.0 g, 0.00712 mol)
and pyridine (0.115 mL, 0.0142 mol) were dissolved in distilled CH2Cl2 (50 mL).
This work was partially supported by a grant from the Institute
of Drug Research. O.R. was the recipient of a fellowship from the
School of Pharmacy, Hebrew University.
The mixture was cooled to 0 °C under
a nitrogen atmosphere. Bromine
(0.73 mL, 0.0142 mol) dissolved in distilled CH2Cl2 (10 mL) was added, over
30 min, to the reaction mixture and after 10 min the mixture was diluted with
aqueous HCl (0.1 M) and washed with CH2Cl2 (3 ꢀ 100 ml). The organic phase
was dried aver MgSO4 and the solvent was evaporated. The product was
separated by column chromatography on silica gel (7% EtOAc in petroleum
ether). The resulting white powder was recrystallized from hot CH3CN to give
4a (1.84 g, 59%) as a white crystalline solid: mp 66–67 °C; 1H NMR (300 MHz,
CDCl3) d 6.47 (s, 2H), 3.83 (s, 6H) 3.17 (t, J = 4.5 Hz, 2H), 1.54 (m, 2H), 1.26 (m,
6H), 0.88 (t, J = 3.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 168.24, 132.19, 88.99,
65.57, 54.33, 53.29, 31.49, 30.39, 26.06, 22.67, 14.16; ESI m/z 900.95 (2M+Na)+,
461.97 (M+Na)+, 439.98 (M+H)+; HRMS calcd for C15H21NO4Br2 ([M+H]+)
439.98896, found 439.98962.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.146.
References and notes
1. Romero, M.; Sanchez, I.; Pujol, M. D. Curr. Med. Chem. 2003, 1, 113–141.
2. Schramm, M.; Thomas, G.; Towart, R.; Franckowiak, G. Nature 1983, 303, 535–
537.
3. Loev, B.; Goodman, M. M.; Snader, K. M.; Tedeschi, R.; Macko, E. J. Med. Chem.
1974, 17, 956–965.
4. Yamagishi, S.; Matsui, T.; Nakamura, K. Med. Hypotheses 2007, 68, 1096–1098.
5. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
6. Reddy, G. M.; Shiradkar, M.; Chakravarthy, A. K. Curr. Org. Chem. 2007, 11, 847–
852.
7. Kato, T.; Tejima, M.; Ebiike, H.; Achiwa, K. Chem. Pharm. Bull. 1996, 44, 1132–
1134.
12. Preparation of 1-cyclopentyl-3,5-diphenyl-1H-pyridine-4,4-dicarboxylic acid
dimethyl ester (6). Compound 4a (100 mg, 0.236 mmol), phenylboronic acid
(115.2 mg, 0.944 mmol), KOH (52.8 mg, 0.944 mmol), and PdCl2 were mixed in
distilled toluene. The mixture was stirred at 110 °C, under
a nitrogen
atmosphere, for 2 d. The product was purified by column chromatography on
silica gel (10% EtOAc in petroleum ether) to give 6 (69 mg, 70%) a yellow solid:
mp 145–149 °C; 1H NMR (300 MHz, CDCl3) d 7.46 (d, J = 6 Hz, 4H), 7.16–7.30
(m, 6H) 6.56 (s, 2H), 3.91 (m, 1H), 3.42 (s, 6H), 2.05 (m, 2H), 1.52–1.79 (m, 6H);
13C NMR (75 MHz, CDCl3) d 172.02, 138.64, 128.33, 128.25, 128.22, 128.17,
126.53, 108.67, 64.41, 52.70, 32.30, 24.22; ESI m/z 873.35 (2M+K)+, 456.15
(M+K)+; HRMS calcd for C26H27NO4 ([M+Na]+) 440.18323, found 440.18350.
8. Oba, M.; Tanaka, M.; Takano, Y.; Suemune, H. Tetrahedron 2005, 61, 593–598.
9. These conditions were selected after running the reaction with different bases,
at various temperatures and in different solvents.