Rearrangement of 3,5-dicyano-1,4-dihydropyridines to densely functionalized cyclopentadienes

Article abstract of DOI:10.1016/j.tetlet.2008.07.129

3,5-Dicyano-1,4-dihydropyridines underwent ring contraction to give functionalized cyclopentadienes upon treatment with trifluoroacetic anhydride.

Full text of DOI:10.1016/j.tetlet.2008.07.129

Tetrahedron Letters 49 (2008) 5820–5822
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Rearrangement of 3,5-dicyano-1,4-dihydropyridines to densely
functionalized cyclopentadienes
a
a
b,
Stefania Fusi a, , Fabio Ponticelli , Antonio Ventura , Mauro F. A. Adamo
*
*
a Dipartimento di Chimica, Università di Siena, Via Aldo Moro, Siena 53100, Italy
b Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Dublin, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
3,5-Dicyano-1,4-dihydropyridines underwent ring contraction to give functionalized cyclopentadienes
upon treatment with trifluoroacetic anhydride.
Received 12 June 2008
Revised 15 July 2008
Accepted 24 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dihydropyridine
Rearrangement
Ring contraction
Dihydropyridines (DHPs) have a rich medicinal chemistry.1 In
particular, 4-aryl-substituted 1,4-dihydropyridines are an impor-
tant class of organic calcium-channel modulators used for the
treatment of cardiovascular diseases.2
More recently, DHPs were recognized as inhibitors of the per-
meability-glycoprotein (P-gp).3 This finding revitalized the interest
of the synthetic community in the 1,4-dihydropyridine core.4
As a part of our ongoing studies on the synthesis of bioactive
compounds,5 we became interested in preparing 1,4-dihydropyr-
idines 1 bearing two symmetrical ketone functionalities at C-3
and C-5 (Scheme 1). A retrosynthetic analysis of target 1 identified
3,5-dicyanodihydropyridine 4 as a suitable starting material. In our
plan, protection of 4 as its N-trifluoroacetate 3 and subsequent
treatment with a Grignard reagent would furnish the protected
target 2. Then hydrolysis of the trifluoroacetamide in 2 would give
the desired compound 1. Reaction of 3 with various Grignard
reagents was identified as a simple and effective means to expand
the diversity of scaffold 4, while the trifluoroacetate group in 3
would activate the two nitrile groups towards nucleophiles.
Compound 4 was prepared using a literature procedure,6 and
then was treated with trifluoroacetic anhydride (TFA) and triethyl-
amine (TEA). Surprisingly, this reaction furnished compound 5 in
43% isolated yield as the exclusive product (Scheme 2). The struc-
ture of 5 was determined by X-ray analysis (Fig. 1).7
Intrigued by this result, we have studied the reaction of com-
pound 4 with TFA and TEA by 1H NMR. This study revealed that
reaction of 4 with TFA generated the desired target 3 in quantita-
tive amounts and in a very short reaction time (Table 1). Typically
Grignard
Addition
O
O
O
O
Hydrolysis
Protection
NC
CN
NC
CN
R
R
R
R
N
N
N
N
H
H
COCF
3
COCF
3
1
2
3
4
Scheme 1.
* Corresponding authors. Tel.: +39 0577 234273; fax: +39 0577 234278 (S.F.).
E-mail address: fusiste@unisi.it (S. Fusi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.129

S. Fusi et al. / Tetrahedron Letters 49 (2008) 5820–5822
5821
of TEA gave initially a quantitative yield of 3 that with time became
a 40:60 mixture of compounds 5 and 4 (Table 1, Scheme 3).
Reaction of 4 with smaller amounts of TFA (1.1 equiv) or larger
amounts of TEA gave similar results. The rearrangement of 3 to 5
was operative only when the trifluoroacetamide and the nitrile
functionalities were present. Reaction of 4 with acetic anhydride
or p-toluenesulfonyl chloride did not furnish the rearranged prod-
uct; similarly, 3,5-dibenzoyl-1,4-dihydropyridine reacted with TFA
to give the expected N-trifluoroacetamide. A proposed mechanism
for the formation of 5 is outlined below (Scheme 4).
NC
NC
CN
TFA (1.5 equiv)
TEA( 2 equiv)
CN
N
H
NHCOCF3
4
5
43% yield
Scheme 2.
Initial reaction of 4 with TFA furnished 3. Deprotonation of the
benzylic proton in 3 then resulted in the rearrangement. This pro-
posal is supported by the following observations: (a) rearrange-
ment of 3 to 5 was faster when 3 equiv or more of base were
used; (b) rearrangement of 3 to 5 did not occur when only one
equivalent of base was used; (c) the rearrangement was more effi-
cient with compounds 9–10 (Table 2) bearing electron-withdraw-
ing groups on the phenyl ring. We prepared compounds 8–11 and
submitted them to reaction with TFA and TEA. The yields of 12–15
were calculated relative to starting materials 8–11 in the crude 1H
NMR (Table 2).
N9
N001
F1b
O002
As expected based on the proposed mechanism (Scheme 4),
conversion of 4 to 5 correlated with the acidity of the benzylic pro-
ton. The structure of compound 15 was confirmed by X-ray analy-
sis (Fig. 2).8
N8
In conclusion, we have reported a rearrangement of 3,5-di-
cyano-1,3-dihydropyridines, which furnished highly functionali-
zed cyclopentadienes. The reaction was fast and made use of
cheap and commercially available reagents. Considering the versa-
tility of cyclic dienes it is easy to envisage several applications of
Figure 1. ORTEP drawing of compound 5 with 20% probability thermal ellipsoids.
Table 1
5–10 min was required to observe full conversion of 4 to 3. The
formation of 3 was also confirmed by GC–MS analysis, which
revealed the presence of a molecular ion of mass m/z 331 as the
main component of the reaction mixture. Compound 3, however,
proved to be unstable and with time underwent ring rearrange-
ment to give cyclopentadiene 5.
1H NMR study of the reaction between 4 and TFA in the presence of TEA
Typically, compound 5 was formed in 40% yield after 5.5 h
(Table 1). The yields of 5 were never greater than 40–45%: the
remaining 3 underwent hydrolysis to give starting material 4.
Hence, treatment of compound 4 with 1.5 equiv of TFA and 2 equiv
NC
CN
NC
CN
TFA
TEA
4
5
N
H
N
COCF
3
4
3
Scheme 3.
NC
CN
NC
CN
NC
CN
NC
CN
TFA (1.5 equiv)
TEA( 2 equiv)
5
-H+
N
N
N
N
H
COCF3
COCF3
COCF3
4
3
6
7
Scheme 4.

5822
S. Fusi et al. / Tetrahedron Letters 49 (2008) 5820–5822
Table 2
s, CH3), 6.92 (1H, br s, NH), 7.49–7.79 (5H, m, Ph); dC (100 MHz,
Preparation of compounds 5 and 12–15
CDCl3) 12.9, 21.8, 68.6, 113.2, 113.6, 114.0, 117.5, 127.9, 129.2,
129.3, 131.4, 152.5, 153.9, 170.4; m/z (EI) 331 (M+, 100%); Anal.
Calcd for C17H12F3N3O: C, 61.63; H, 3.65; N, 12.68. Found: C,
61.51; H, 3.91; N, 12.71.
Ar
NC
Ar
CN
NC
CN
TFA (1.5 equiv)
TEA( 2 equiv)
N-(2,4-Dicyano-1,5-dimethyl-3-(40-methoxyphenyl)cyclopenta-
2,4-dienyl)-20,20,20-trifluoroacetamide (12): yellow solid, 72 mg
(26% yield), mp 185–187 °C; dH (400 MHz, CDCl3) 1.60 (3H, s,
CH3), 2.15 (3H, s, CH3), 3.85 (3H, s, OCH3), 6.90 (1H, br s, NH),
7.00 (2H, d, J = 7, Ar), 7.75 (2H, d, J = 7, Ar); dC (100 MHz, CDCl3)
12.9, 21.9, 55.5, 68.5, 111.0, 112.8, 113.5, 114.7, 117.8, 121.8,
129.8, 152.7, 155.2, 162.2, 170.5; m/z (ESI) 360 (MꢀH+ 100%); Anal.
Calcd for C18H14F3N3O2: C, 59.83; H, 3.91; N, 11.63. Found: C, 59.81;
H, 3.92; N, 11.66.
N
H
NHCOCF
3
8-11
12-15
Entry
Substrate
Product
Ar
C6H5
4-CH3O–C6H4
4-NO2–C6H4
2,4-NO2–C6H3
2-Thienyl
Yielda (%)
1
2
3
4
5
4
8
9
10
11
5
12
13
14
15
45
26
63
75
23
N-(2,4-Dicyano-1,5-dimethyl-3-(40-nitrophenyl)cyclopenta-
2,4-dienyl)-20,20,20-trifluoroacetamide (13): 218 mg, yellow so-
lid (63% yield), mp 199–200 °C; dH (400 MHz, CDCl3) 1.65 (3H, s,
CH3), 2.19 (3H, s, CH3), 6.91 (1H, br s, NH), 7.89 (2H, d, J = 7, Ar),
8.37 (2H, d, J = 7, Ar); dC (100 MHz, CDCl3) 13.1, 21.6, 68.9,
112.0, 112.7, 113.1, 116.53, 124.4, 129.1, 130.0, 135.0, 149.8,
150.9, 171.7; m/z (ESI) 375 (MꢀH+, 100%); Anal. Calcd for
a
Calculated by relative integration of the methyl groups in the 1H NMR spectra
(400 MHz, CDCl3).
N011
C
17H11F3N4O3: C, 54.26; H, 2.95; N, 14.89. Found: C, 54.32; H,
2.94; N, 14.93.
N-(2,4-Dicyano-1,5-dimethyl-3-(20,40-dinitrophenyl)cyclopenta-
2,4-dienyl)-20,20,20-trifluoroacetamide (14): 286 mg, pale yellow so-
lid (75% yield), mp 190–192 °C; dH (400 MHz, CDCl3) 1.63 (3H, s,
CH3), 2.15 (3H, s, CH3), 7.49 (1H, br s, NH), 7.82 (1H, d, J = 7, Ar),
8.63 (1H, d, J = 7, Ar), 9.13 (1H, s, Ar); dC (100 MHz, CDCl3) 14.1,
20.3, 69.2, 111.7, 112.3, 113.4, 116.2, 117.8, 121.2, 129.1, 131.2,
133.5, 146.7, 149.4, 150.2, 168.9; m/z (ESI) 420 (MꢀH+, 100%); Anal.
Calcd for C17H10F3N5O5: C, 48.47; H, 2.39; N, 16.62. Found: C, 48.56;
H, 2.38; N, 16.68.
F1b
N002
F3
F2
S1
F2b
F3b
F1
O003
N-(2,4-Dicyano-1,5-dimethyl-3-(thiophen-20-yl)cyclopenta-
2,4-dienyl)-20,20,20-trifluoroacetamide (15): yellow solid, 67 mg
(23% yield), mp 250 °C dec.; dH (400 MHz, CDCl3) 1.54 (3H, s,
CH3), 2.13 (3H, s, CH3), 6.64 (1H, br s, NH), 7.18 (1H, app t,
J = 6, H4(thiophene)), 7.61 (1H, d, J = 6, H3(thiophene)), 8.06 (1H, d,
J = 6, H5(thiophene)); dC (100 MHz, CDCl3) 12.9, 21.6, 68.8, 109.8,
111.1, 112.0, 114.6, 128.3, 130.7, 130.9, 132.0, 144.3, 171.8;
m/z (ESI) 336 (MꢀH+, 100%); Anal. Calcd for C15H10F3N3OS: C,
53.41; H, 2.99; N, 12.46. Found: C, 53.23; H, 3.05; N, 12.43.
N013
Figure 2. ORTEP drawing of compound 15 with 20% probability thermal ellipsoids.
compounds 5 and 12–15 in synthesis. Studies aimed at obtaining
enantiopure samples of 5 by reacting 4 in the presence of chiral
amines are in progress.
Preparation of compound 3: To a solution of 1,4-dihydropyridine
4 (1 mmol) in anhydrous CH2Cl2 (10 mL) kept at 0 °C by means of
an ice bath were sequentially added anhydrous TEA (2 equiv) and
TFA (1.5 equiv). The reaction mixture was then allowed to reach
room temperature, and was stirred for 5 min. After this time, the
solvent was evaporated, and the oil so obtained was purified by
flash chromatography (petroleum ether–ethyl acetate 3:1) to give
compound 3 as a colourless solid, 305 mg (92% yield), mp 55–
57 °C; dH (400 MHz, CDCl3) 2.41 (6H, s, CH3), 4.34 (1H, s, H-4),
7.18–7.40 (5H, m, Ph); dC (100 MHz, CDCl3) 20.2, 43.5, 102.2,
113.3, 115.8, 126.8, 128.9, 129.6, 136.4, 148.3, 161.8; m/z (EI)
331 (M+, 100%); Anal. Calcd for C17H12F3N3O: C, 61.63; H, 3.65;
N, 12.68. Found: C, 61.55; H, 3.85; N, 12.65.
General procedure for the preparation of compounds 5 and 12–15:
To a solution of 1,4-dihydropyridine, 4 or 8–11 (1 mmol) in anhy-
drous CH2Cl2 (10 mL) kept at 0 °C by means of an ice bath, were
sequentially added anhydrous TEA (2 equiv) and TFA (1.5 equiv).
The reaction mixture was then allowed to reach room temperature,
and was stirred for a further 5 h. After this time, the solvent was
evaporated, and the oil obtained was purified by column chroma-
tography (petroleum ether–ethyl acetate 4:1) to give compounds 5
or 12–15 as solids.
Acknowledgements
We acknowledge the PTRLI cycle III for a Grant to MFAA and
CIADS (University of Siena) for recording mass spectra and X-ray
diffractions.
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N-(2,4-Dicyano-1,5-dimethyl-3-phenylcyclopenta-2,4-dienyl)-
20,20,20-trifluoroacetamide (5): yellow solid, 149 mg (45% yield),
mp 205–207 °C; dH (400 MHz, CDCl3) 1.62 (3H, s, CH3), 2.19 (3H,