Synthesis of Z-N-alkenylformamides

Article abstract of DOI:10.1080/00397910701649023

Commercially available difluorinated benzaldehyde was converted to the Z-N-alkenylformamides via Horner-Emmons olefination and Curtius rearrangement, followed by reduction with tri-tert-butoxy-aluminohydride. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701649023

Synthetic Communicationsw, 38: 45–53, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701649023
Synthesis of Z-N-Alkenylformamides
´
Lucina G. Sanchez, Ratnasamy Somanathan,
Lars H. Hellberg, and Gerardo Aguirre
´ ´
Centro de Graduados e Investigacion, Instituto Tecnologico de Tijuana,
´
Tijuana, Mexico
Abstract: Commercially available difluorinated benzaldehyde was converted to the
Z-N-alkenylformamides via Horner–Emmons olefination and Curtius rearrangement,
followed by reduction with tri-tert-butoxy-aluminohydride.
Keywords: Z-N-alkenylformamides (enamides), Curtius rearrangement, Horner–
Emmons olefination, isocyante
INTRODUCTION
N-Alkenylamides include natural products isolated from a variety of sources,
ranging from micro- and marine organisms to higher plants. These compounds
display a wide variety of physiological properties.[1–9] This prompted us to
synthesize a number of naturally occurring N-alkenylformamides and study
their biological and physical properties.[10–13] Using 2D EXSY NMR, we
found the E-N-alkenylformamides had a rotational barrier of 17–19 kcal/
mol. This subsequently led us to study the barriers to rotation in the Z-N-
alkenylformamides isomer, which showed similar energy values[14,15] in
spite of the fact that the double bond is orthogonal to the benzene ring
(Fig. 1). Because the E-N-alkenylformamides have been exhaustively
studied, it was interesting us to investigate the potential biological properties
of the Z-N-alkenylformamide isomers. In particular, the orthogonality of the Z
Received in the USA June 26, 2007
Address correspondence to Gerardo Aguirre, Centro de Graduados e Investigacion,
´ ´
Instituto Tecnologico de Tijuana, Apartado Postal 1166, 22500 Tijuana, B. C., Mexico.
´
E-mail: gaguirre@tectijuana.mx
45

´
L. G. Sanchez et al.
46
Figure 1. X-ray structure of the Z-N-alkenylformamide 12Z.
double bond to the benzene ring, a unique structural feature, may lead to inter-
esting biological properties.
We report here a general synthetic route to Z-N-alkenylformamides (11, 12),
which can be made in adequate amounts to be subjected to biological testing.
RESULTS AND DISCUSSION
Most of the syntheses reported for N-alkenylformamides have shown the Z-N-
alkenylformamide to be a minor component obtained in yields ranging from 5
to 25% (by NMR).[1,16–22] Most of the detailed synthetic studies have been on
erbstatin and tuberine, both isolated from microorganisms and exhibiting
interesting physiological properties. Erbstatin was shown to inhibit tyrosine
specific kinases,[2] and the latter was shown to exhibit mild antibiotic proper-
ties.[3] In most of the reported cases, the Z-isomer was never isolated, charac-
terized, or biologically tested. Recently Furstner, Taylor, and Hartenstein have
independently reported excellent synthetic routes to Z-N-alkenylamides.[22]
As a model for our synthesis on N-alkenylformamides, we selected 2,5- and
2,6-difuorobezaldehydes (1, 2), which were subjected to Horner–Emmons ole-
fination reaction using the ylid derived from bis(trifluoroethyl) phosphonoester
to give the olefins (3, 4) in 78–80% yield, with Z/E ratios of 75:25 for 3 and
78:22 for 4 (by NMR).[23,24] The mixture was then carried through various
steps without separation until the final step (Scheme 1). Hydrolysis of
the olefinic ester to the acid (5, 6) in 90–97% yield followed by mixed
anhydride formation and azide addition gave the acylazides (7, 8) in 80–81%
yield. Subsequent thermal Curtius rearrangement to give the isocyanates
(9, 10), followed by reduction with lithium tri-tert-butoxy-aluminohydride,
gave the mixture of N-alkenylformamides (11, 12) in 77% yield. Purification
by preparative thin-layer chromatography (TLC) coated with AgNO3 10%

Synthesis of Z-N-Alkenylformamides
47
Scheme 1. Synthesis of Z-N-alkenylformamide (11Z, 12Z).
(wt/vol.) in methanol and then activated for 1 h at 100–1108C afforded Z-N-
alkenylformamides (11Z, 12Z) and E-N-alkenylformamide (11E, 12E).
The crystal structure of 11Z (Data collected at 294 K using highly oriented
graphite crystal monochromated MoK a radiation. The stucture was solved by
direct methods and non-hydrogen atoms were refined anisotropically. In the
final least-squares refinement cycle on F, R ¼ 8.885% wR2 ¼ 15.26%. The
˚
˚
˚
crystal data are a ¼ 14.213(4) A, b ¼ 8.325(3) A, c ¼ 7.352(2) A, a ¼ 908
˚
b ¼ 95.058 g ¼ 908, V ¼ 856.5(5) A3, space group Pc, Z ¼ 4. CCDC
number 225592 for compound 11Z) and 12Z (Data collected at 294 K using
highly oriented graphite crystal monochromated MoK a radiation. The
stucture was solved by direct methods and non-hydrogen atoms were refined
anisotropically. In the final least-squares refinement cycle on F, R ¼ 4.7%,
˚
˚
wR2 ¼ 9.95%. The crystal data are a ¼ 8.954(2) A, b ¼ 8.216(2) A,
˚
˚
c ¼ 11.664(3) A, a ¼ 908, b ¼ 94.808, g ¼ 908, V ¼ 855.1(3) A3, space
group P21/c. CCDC number 225593 for compound 12Z) show the p plane
of the CH55CHN group to be turned 498 by steric repulsion from the p plane
of the benzene ring.[15]
EXPERIMENTAL
Infrared spectra were recorded on a Perkin-Elmer FT-IR 1605 spectrometer.
NMR spectra were recorded on a Varian Gemini (200-MHz) spectrometer

´
L. G. Sanchez et al.
48
1
using CDCl3 as solvent. Chemical shifts for H NMR spectra are relative to
internal Me4Si. MS were determined with a GC HP-5971 spectrometer. Elemen-
tary analyses forcarbonand hydrogen were conducted byGalbraith Laboratories,
Inc. (Knoxville, TN). TheproductswereisolatedbyTLC/AgNO3 10%(wt/vol.).
General Preparation of Methyl 3-(difluorophenyl)acrylate
A
solution of bis-(2,2,2-trifluoroethyl)(methoxycarbonyl) phosphonate
(0.320 g, 1.0 mmol) and 18-crown-6 (0.320 g, 5.0 mmol) in anhydrous THF
(5 mL) was cooled to 2788C and treated with KN(TMS)2 (0.19 g,
0.95 mmol) under an N2 atmosphere. The resulting mixture was stirred for
20 min, and 2,5-difluorobenzaldehyde 1 (0.130 g, 0.93 mmol) was then
added. After stirring for 1 h at 2788C, saturated NH4Cl was added, and the
product was extracted with diethyl ether (3 ꢀ 30 mL). The combined
ethereal extracts were washed with saturated aqueous sodium chloride,
dried, and evaporated, and the crude product was purified by flash chromato-
graphy using hexane–ethyl acetate (98:2) to afford a yellow liquid.
(Z/E) Methyl 3-(2,5-Difluorophenyl)acrylate (3)
(Z/E) 75:25 Yield (0.143 g, 78%). IR nmax (neat): 2953, 1731, 1643,
1
1487 cm21; H NMR (200 MHz, CDCl3): d ¼ 7.60 (m, 2H, Ar-H); 7.34
(m, 1H, Ar-H); 7.08 (d, 0.25H, J ¼ 15.0, CH55); 6.85 (d, 0.75H,
J ¼ 11.2 Hz, CH55); 6.50 (d, 0.25H, J ¼ 15.0 Hz, CH55); 5.85 (d, 0.75H,
J ¼ 11.2 Hz, CH55); 3.81 (s, 3H, O-Me). Anal. calcd. for C10H8F2O2: C,
60.61; H, 4.07. Found: C, 60.81; H, 3.97.
(Z/E) Methyl 3-(2,6-Difluorophenyl)acrylate (4)
(Z/E) 78:22 Yield (0.147 g, 80%). IR nmax IR (neat): 2953, 1726, 1621,
1
1465 cm21; H NMR (CDCl3) d: 7.78 (d, 0.22H, J ¼ 16.4 Hz, CH55); 7.30
(m, 1H, Ar-H); 6.89 (t, 2H, J ¼ 8.0 Hz, Ar-H); 6.82 (d, 0.78H, J ¼ 12.6 Hz,
CH55); 6.75 (d, 0.22H, J ¼ 16.0 Hz, CH55); 6.22 (d, 0.78H, J ¼ 12.2 Hz,
CH55); 3.80 (s, 3H, O-Me). Anal. calcd. for C10H8F2O2: C, 60.61; H, 4.07.
Found: C, 60.52; H, 4.05.
General Preparation of 3-(Difluorophenyl)acrylic Acid
(Z/E) Methyl 3-(2,5-difluorophenyl)acrylate 3 (0.060 g, 0.31 mmol) was
dissolved in MeOH (2 mL)/THF (3 mL), and lithium hydroxide (1 N,
1 mL) was added to the resulting solution. The reaction mixture was heated
at 708C for 3 h and cooled to rt, and the solvent was removed in vacuo. The
residue was taken up in ethyl acetate (50 mL), and the organic phase was

Synthesis of Z-N-Alkenylformamides
49
washed with 2 N HCl (50 mL), filtered, and dried (MgSO4). The solvent was
removed in vacuo. The product was chromatographed on silica gel, eluting
with CH2Cl2–MeOH (90:10) to afford a yellow solid.
(Z/E) 3-(2,5-Difluorophenyl)acrylic Acid (5)
(Z/E) 75:25 Yield (0.051 g, 90%). IR nmax IR (neat): 3300, 3061, 2976,
;
1711 cm21 1H NMR (CDCl3) d: 7.97 (br. s, 1H, OH); 7.69 (d, 0.25H,
J ¼ 16.0 Hz, CH55); 7.60 (m, 2H, Ar-H); 7.36 (m, 1H, Ar-H); 6.96
(d, 0.75H, J ¼ 12.7 Hz, CH55); 6.50 (d, 0.25H, J ¼ 16.0 Hz, CH55); 6.00
(d, 0.75H, J ¼ 12.7 Hz, CH55). Anal. calcd. for C9H6F2O2: C, 58.70; H,
3.28. Found: C, 58.60; H, 3.23.
(Z/E) 3-(2,6-Difluorophenyl)acrylic Acid (6)
(Z/E) 78:22 Yield (0.055 g, 97%). IR nmax IR (neat): 3330, 3057, 2915,
1
1720 cm21; H NMR (CDCl3) d: 8.25 (br. s, 1H, OH); 7.86 (d, 0.22H, J ¼
16.6 Hz, CH55); 7.3 (m, 1H, Ar-H); 6.92 (m, 2H, Ar-H); 6.91 (d, 0.78H,
J ¼ 12.6 Hz, CH55); 6.74 (d, 0.22H, J ¼ 16.4 Hz, CH55); 6.23 (d, 0.78H,
J ¼ 12.0 Hz, CH55). Anal. calcd. for C9H6F2NO2: C, 58.70; H, 3.28.
Found: C, 58.98; H, 3.26.
General Preparation of 3-(Difluorophenyl)acryloyl Azide
To a stirred mixture of (Z/E) 3-(2,5-difluorophenyl)acrylic acid (0.410 g,
2.19 mmol), 5, and triethylamine (0.25 g, 2.47 mmol) in acetone (10 mL),
ethyl chloroformate (0.26 g, 2.42 mmol) in acetone (1 mL) was added
at 25 to 08C over 5 min. After the mixture was stirred for 15 min, sodium
azide (0.28 g, 4.37 mmol) in water (5 mL) was added at 25 to 08C over
1 min. This mixture was stirred for 45 min at rt, poured into ice water
(50 mL), and extracted with diethyl ether (3 ꢀ 30 mL). The combined
ethereal extracts were washed with saturated aqueous sodium chloride,
dried, and concentrated, leaving yellow liquid.
(Z/E) 3-(2,5-Difluorophenyl)acryloyl Azide (7)
(Z/E) 60:40 Yield (0.366 g, 80%). IR nmax IR (neat): 3070, 2149, 1679,
1
1629 cm21; H NMR (CDCl3) d: 7.78 (d, 0.40H, J ¼ 16.0 Hz, CH55); 7.70
(m, 1H, Ar-H); 7.41 (m, 2H, Ar-H); 7.21 (d, 0.60H, J ¼ 12.7 Hz, CH55);
6.46 (d, 0.40H, J ¼ 16.0 Hz, CH55); 6.11 (d, 0.60H, J ¼ 12.7 Hz, CH55);
MS (EI, 70 eV): m/z (%) ¼ 167 (100), 209 (32) [Mþ]. Anal. calcd. for
C9H5F2N3O: C, 51.68; H, 2.41. Found: C, 51.78, H; 2.33.

´
L. G. Sanchez et al.
50
(Z/E) 3-(2,6-Difluorophenyl)acryloyl Azide (8)
(Z/E) 60:40 Yield (0.371 g, 81%). IR nmax IR (neat): 3069, 2143, 1691,
1
1627 cm21; H NMR (CDCl3) d: 7.85 (d, 0.40H, J ¼ 15.6 Hz, CH55); 7.32
(m, 1H, Ar-H); 6.91 (t, 2H, J¼ 8.0 Hz, Ar-H); 6.90 (d, 0.60H, J ¼ 11.6 Hz,
CH55); 6.68 (d, 0.40H, J ¼ 16.2 Hz, CH55); 6.16 (d, 0.60H, J¼ 11.8 Hz,
CH55); MS (EI, 70 eV): m/z (%) ¼ 167 (100), 209 (32) [Mþ]. Anal. calcd.
for C9H5F2N3O: C, 51.68; H, 2.41. Found: C, 51.68; H, 2.44.
General Preparation of Difluoro-2-(2-isocyanatovinyl)benzene
The reaction was carried out under an N2 atmosphere. The thermally induced
rearrangement of (Z/E) 3-(2,5-difluorophenyl)acryloyl azide (0.400 g,
1.91 mmol) and 7 in toluene (10 mL) generated the isocyanate 9, which was
isolated by concentration in vacuo. The reaction was monitored by IR appear-
ance of the isocyanate band at 2341 cm21 and disappearance of the azide band
at 2143 cm21. The azides 8 were similarly transformed to their isocyanates 10.
The yields appeared quantitative; they were used without further purification.
General Preparation of the N-(Difluorostyryl)formamides
A solution of (Z/E) 1,4-difluoro-2-(2-isocyanatovinyl)benzene (0.350 g
crude, 1.91 mmol) and 9 in THF (10 mL) was added dropwise to a stirred
and cooled (ice bath) solution of lithium tri-tert-butoxyaluminohydride
(0.570 g, 2.30 mL) in THF (5 mL) under an atmosphere of N2. After stirring
for a further 15 min, aqueous ammonium chloride solution (10%) was
added, and the resultant precipitate was filtered and washed with ethyl
acetate. The combined extracts was dried over anhydrous MgSO4, filtered,
and concentrated under vacuum. The crude product was passed through a
short pad of silica gel using dichloromethane to afford a yellow liquid. The
yields cited (0.269 g, 77%) are overall from the purified azides, and isomers
were separated by preparative thin-layer chromatography (TLC) coated with
AgNO3 10% (wt/vol.) and elution with dichloromethane–methanol (95:5)
to afford a yellow solid.
1
This H NMR spectrum exhibits a doubling of signals due to restricted
rotation about the amide (N-CO) bond, leading to two rotational conformers
(anti and syn).[14,15] The more abundant rotamer is the syn for both E and
Z-N-alkenylformamides (11, 12).
(Z)-N-(2,5-Difluorostyryl)formamides (11Z)
Mp 108–1098C, yield (0.112 g, 32%). IR nmax IR (neat): 3301, 2926, 1716,
1
1653, 1503 cm21; H NMR (CDCl3) d: 7.80 (d, 0.30H, J ¼ 11.8 Hz, CHO);

Synthesis of Z-N-Alkenylformamides
51
7.40 (dd, 1H, J ¼ 11.2, J ¼ 10.4 Hz, NCH55C); 7.26 (s, 0.70H, CHO); 7.14
(br. s, 1H, NH); 7.04 (m, 2H, Ar-H); 7.01 (d, 0.70H, J ¼ 10.0 Hz, CH55);
6.98 (m, 1H, Ar-H); 6.10 (d, 0.30H, J ¼ 10.8 Hz, CH55); MS (EI, 70 eV):
m/z (%) ¼ 127 (60), 183 (100) [Mþ]. Anal. calcd. for C9H7F2NO: C,
59.02; H, 3.85. Found: C, 58.98; H, 3.82. Single crystals suitable for X-ray
structure analysis were obtained by slow evaporation from a concentrated
solution in chloroform at 238C. [Data collected at 294 K using highly
oriented graphite crystal monochromated MoK a radiation. The structure
was solved by direct methods, and nonhydrogen atoms were refined anisotro-
pically. In the final least-squares refinement cycle on F, R ¼ 8.885%,
˚
˚
wR2 ¼ 15.26%. The crystal data are a ¼ 14.213(4) A, b ¼ 8.325(3) A,
3
˚
˚
c ¼ 7.352(2) A, a ¼ 908 b ¼ 95.058, g ¼ 908, V ¼ 856.5(5) A , space
group Pc, Z ¼ 4. CCDC number 225592 for compound 11Z.]
(E)-N-(2,5-Difluorostyryl)formamides (11E)
Mp 106–1078C, yield (0.157 g, 45%). IR nmax IR (neat): 3188, 1749, 1646,
1
1477 cm21; H NMR (CDCl3) d: 9.50 ( br. d, 1H, J ¼ 11 Hz, NH); 8.44
(d, 0.25H, J ¼ 11 Hz, CHO); 8.22 (s, 0.75H, CHO); 7.60 (dd, 0.75H,
J ¼ 15, J ¼ 11 Hz, NCH55C); 7.20 (dd, 0.25H, J ¼ 15, J ¼ 11 Hz,
NCH55C); 7.08 (m, 3H, Ar-H); 6.33 (d, 0.75H, J ¼ 15 Hz, Ar-CH55);
6.15 (d, 0.25 H, J ¼ 15 Hz, Ar-CH55); m/z (%) ¼ 127 (57), 183 (100)
[Mþ]. Anal. calcd. for C9H7F2NO: C, 59.02; H, 3.85. Found: C, 58.96;
H, 3.94.
(Z)-N-(2,6-Difluorostyryl)formamides (12Z)
Mp 95–968C, yield (0.192 g, 55%). IR nmax IR (neat): 3245, 3187, 1705,
1
1653, 1582 cm21; H NMR (CDCl3) d: 8.37 (d, 0.35H, J ¼ 11.2 Hz, CHO);
8.23 (s, 0.65H, CHO); 7.36 (br. s, 1H, NH); 7.23 (m, 1H, Ar-H); 6.95
(m, 2H, Ar-H); 6.69 (dd, 1H, J ¼ 11.2, J ¼ 9.4 Hz, NCH55C); 5.64
(d, 0.65H, J ¼ 9.8 Hz, Ar-CH55); 5.55 (d, 0.35H, J ¼ 9.8 Hz, Ar-CH55);
m/z (%) ¼ 127 (60), 183 (100) [Mþ]. Anal. calcd. for C9H7F2NO: C,
59.02; H, 3.85. Found: C, 59.08; H, 3.78. Single crystals suitable for X-ray
structure analysis were obtained by slow evaporation from a concentrated
solution in chloroform at 238C. [Data collected at 294 K using highly
oriented graphite crystal monochromated MoK a radiation. The structure
was solved by direct methods, and nonhydrogen atoms were refined anisotro-
pically. In the final least-squares refinement cycle on F, R ¼ 4.7%,
˚
˚
wR2 ¼ 9.95%. The crystal data are a ¼ 8.954(2) A, b ¼ 8.216(2) A,
3
˚
˚
c ¼ 11.664(3) A, a ¼ 908, b ¼ 94.808, g ¼ 908, V ¼ 855.1(3) A , space
group P21/c. CCDC number 225593 for compound 12Z.]

´
L. G. Sanchez et al.
52
(E)-N-(2,6-Difluorostyryl)formamides (12E)
Mp 91–928C, yield (0.077 g, 22%). IR nmax IR (neat): 3206, 3126, 1714,
1
1656, 1582 cm21; H NMR (CDCl3) d: 9.60 (br. d, 1H, J ¼ 11 Hz, NH);
8.40 (d,.33H, J ¼ 11.2 Hz, CHO); 8.23 (s, .67H, CHO); 7.82 (dd, .67H,
J ¼ 15, J ¼ 11.2 Hz, NCH55C); 7.40 (dd, .33H, J ¼ 15, J ¼ 11.2 Hz,
NCH55C); 7.06 (m, 1H, Ar-H); 6.91 (m, 2H, Ar-H); 6.21 (d, .67H,
J ¼ 15 Hz, Ar-CH55); 6.06 (d, .33H, J ¼ 15 Hz, Ar-CH55); m/z (%) ¼ 127
(55), 183 (100) [Mþ]. Anal. calcd. for C9H7F2NO: C, 59.02; H, 3.85.
Found: C, 59.09; H, 3.78.
ACKNOWLEDGMENTS
We gratefully acknowledge support for this project by Consejo del Sistema
´ ´
Nacional de Educacion Tecnologica (COSNET) 491–02-P (2002). L. G. S.
´
thanks Consejo Nacional de Ciencio y Tecnologıa (CONACyT) for the
graduate fellowship.
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