Regioselective synthesis of β-iodo-enamides and β-yn-enamides

Article abstract of DOI:10.1016/j.tet.2011.07.033

Iodo-enamides were synthesised in a single step, in good yield and with complete selectivity from N-formyl imides. The β-iodo-enamides are stable and were converted efficiently into novel geometrically defined β-yn-enamides.

Full text of DOI:10.1016/j.tet.2011.07.033

Tetrahedron 67 (2011) 7611e7617
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Tetrahedron
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Regioselective synthesis of b-iodo-enamides and b-yn-enamides
, ,
y
Adele E. Pasqua a, Lynne H. Thomas b, James J. Crawford c, Rodolfo Marquez a
*
a WestChem, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
b Department of Chemistry, University of Bath, BA2 7AY, UK
c Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2011
Received in revised form 20 June 2011
Accepted 12 July 2011
Available online 27 July 2011
Iodo-enamides were synthesised in a single step, in good yield and with complete selectivity from N-
formyl imides. The -iodo-enamides are stable and were converted efficiently into novel geometrically
defined -yn-enamides.
b
b
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Enamides
yn-Enamides
Halo-enamides
Takai
R3
O
X
O
1. Introduction
MgX2
CH2Cl2, rt
37-99%
R1
R1
N
N
Halo-enamides are extremely versatile and useful enamide de-
rivatives, which could be used in the generation of highly functional
intermediates in materials, synthetic, medicinal and materials
chemistry. However, despite their great potential to play a key role
in the synthesis of more elaborated enamide derivatives, there re-
mains a lack of reliable approaches and methods available for their
efficient and practical synthesis.1
R2 R3
2
R2
1
Fig. 1.
a-Halo-enamide synthesis from ynamides.
iodomethylacrylate 3, which was converted into enamide
4
Bal’on and Moskaleva reported one of the first and most direct
routes for the synthesis of halo-enamides through the addition of
hydrogen halide (HX) across an ynamide unit 1. However, despite
its efficiency, this method generates mixtures of halo-enamides
with very poor regio- and stereo-chemical control. Furthermore,
the separation of the halo-enamide isomers obtained is often
impossible.2,3
through a copper mediated coupling. Ester hydrolysis followed by
iodo-decarboxylation then afforded the
yield over the three step sequence.
b-iodo-enamide 5 in 14%
Daoust, on the other hand, took advantage of copper promoted
conditions to couple trans-1,2-diiodoethene 7 with three cyclic
amides and an acyl protected acyclic amide derivative in good yield.
Unfortunately, Daoust’s method requires the use of 1,2-
diiodoethene 7, for which only the synthesis of the trans-isomer
is known.
Hsung later reported the unexpected halogenation of ynamides
1 with magnesium halide salts to generate the corresponding
halo-enamides 2 in good yield and with excellent E selectivity.4
Interestingly none of the -halo-enamides could be detected
through either Bal’on’s or Hsung’s methods (Fig. 1).
a-
b
2. Results and discussion
Two examples of the synthesis of b-halo-enamides have been
reported recently (Scheme 1).5,6 Smith’s synthesis began with cis-2-
We have previously reported the use of N-formyl imides 9 in
olefination reactions to generate conjugated E enamides 10 and Z,E-
dienamides 11 in a single step, good yield and most significantly
without the need for nitrogen protection in the acyclic cases
(Fig. 2).7
* Corresponding author. Tel.: þ44 0141 330 5953; fax: þ44 0141 330 488; e-mail
In all cases, the N-formyl group effectively behaves as an alde-
hyde surrogate, which opens the possibility of using N-formyl
address: rudi.marquez@glasgow.ac.uk (R. Marquez).
y
Ian Sword Lecturer of Organic Chemistry.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.033

7612
A.E. Pasqua et al. / Tetrahedron 67 (2011) 7611e7617
Treatment of N-formyl imide 14 under standard Takai condi-
tions8 using commercially sourced chromium(II)chloride afforded
the desired -iodo-enamide 15 in variable yields, and as in-
separable mixtures of E and Z isomers. The reaction proved to be
highly dependent on the quality of the commercially sourced
chromium(II)chloride employed. Indeed, in a number of cases,
some batches of chromium(II)chloride failed to yield any of the
Smith's Method
O
O
b
O
I
O HN
n-Pr
n-Pr
H2N
CuI,
MeHN
MeO
MeO
O
NHMe
42%
3
4
desired b-iodo-enamide adduct.
Faced with such an unreliable procedure, a more reproducible
method was sought. Pleasantly, using Auge’s modification of the
Takai reaction, using chromium(III)chloride hydrate, yielded the
1) LiOH, H2O
2) (collidine)2IPF6
32%
n-Pr
HN
I
5
desired b-iodo-enamide 15 in reasonable yield from N-formyl im-
ide 14. Crucially, the product was obtained as a single E double bond
isomer (Scheme 2).9
Daoust's Method
The assignment of the double bond geometry of the newly
formed b
-iodo-enamide 15 was confirmed by both 1H NMR and
I2, Al2O3
33%
I
crystallographic analysis (Fig. 3).10
H
H
I
6
7
O
O
X
NH
R
I
X
N
R
CuI, Cs2CO3
Ligand
8
40-94%
Scheme 1.
O
O
CO2R
Ph3P
R1
N
O
CO2R
R1
N
R2
Fig. 3. Crystal structure of b-iodo-enamide 15.
R2
9
10
O
Using these optimised conditions, different lactams were for-
mylated and the resulting N-formyl imides 14 and 22e24 were
treated under Auge’s modified Takai conditions to generate the
R1
CO2R
Ph3P
N
R2
11
desired b-iodo-enamides 15, 28e30 in good yield (Table 1). In all
cases, only the E-isomer was detected both in the 1H NMR spectra
of the crude reaction mixture, and after purification by column
chromatography.
CO2R
Fig. 2. N-Formyl imides 9 and their conversion into enamides 10 and dienamides 11.
Having shown the ability of cyclic N-formyl imides to undergo
iodoolefination, we were interested in exploring primary amide
derived N-formyl imides as Takai substrates. The successful
iodoolefination of an unprotected primary amide derived N-formyl
imide is very appealing as this obviate the need to subject the
sensitive enamide derivatives to the typically harsh conditions re-
quired for the removal of nitrogen protecting groups.
The acyclic amides 19e21, were N-formylated using N-for-
mylbenzotriazole/n-BuLi.11 The quality and the purity of the N-
formylbenzotriazole are key to obtaining pure N-formyl imides in
reproducible yields.
imides as key building blocks in the generation of substrates not
readily available through any other means.
We now report our efforts towards the development of an ef-
ficient approach to the regioselective synthesis of b-halo-enamides
as well as a demonstration of their practical synthetic potential.
Our initial studies began with valerolactam 12, which was effi-
ciently N-formylated using acetic formic anhydride 13 to generate
the desired N-formyl imide 14 under our previously reported
conditions (Scheme 2).7
Subsequent iodoolefination of acyclic imides 25e27 under
Auge’s conditions however, yielded some very interesting and in-
triguing results (Table 1). N-Formylbenzimide 26 and N-for-
mylpropionimide 27 yielded mixtures of E/Z iodo enamides 32 and
33 in which the E-iodo olefin was the major isomer formed. On the
other hand, in the case of the dioxolane substituted N-formyl imide
25, a nearly equal mixture of E/Z iodoolefins 31 was obtained in
which the Z isomer was slightly predominant by 1H NMR analysis of
the crude reaction mixture. Interestingly, the dioxolane derived E-
iodoenamide 31E could not be isolated under different separation
conditions.
O
O
O
O
O
H
CHO
NH
N
13
75%
12
14
O
H
J = 14.0 Hz
I
CrCl3.6H2O, CHI3
N
H
NaI, Zn, THF
46%
We believe that the marked difference in behaviour during the
iodoolefination between the lactam derived imides and the acylic
cases can be attributed to the geometry of the N-formyl imide. In the
15
Scheme 2.

A.E. Pasqua et al. / Tetrahedron 67 (2011) 7611e7617
7613
Table 1
Synthesis of
Having generated the desired
b
-iodo-enamides, we were in-
b
-iodo-enamides.
terested in using them in combination with other methodologies,
(i.e., metal mediated couplings) to generate novel and diverse
building blocks.
O
O
O
I
CrCl3.6H2O,
Zn, NaI, CHI3
CHO
a or b
NH
N
N
We decided to initially evaluate the utility of
palladium mediated Sonogashira couplings with the aim of gen-
erating novel
-yn-enamide units.12 It was reasoned that structur-
ally constrained -yn-enamides could have applications as reactive
b-iodo-enamides in
E:Z
O
O
O
b
CHO
I
NH
N
N
46%
75%
72%
b
15
1 : 0
12
14
intermediates in both synthetic and medicinal organic chemistry.
Furthermore, their defined molecular shape makes them prime
candidates for the development of molecular tweezers and other
structurally defined useful units in materials and supramolecular
chemistry.13
O
O
O
O
O
I
CHO
51%
40%
NH
16
N
N
N
1 : 0
22
28
O
Initial Sonogashira coupling of
acetylene afforded the desired -yn-enamide 34 in excellent yield
and as a single isomer (Scheme 3). The structural assignment of the
b-iodo-enamide 15 with phenyl
CHO
I
NH
17
N
81%
85%
73%
b
1 : 0
23
29
b
-yn-enamide 34 was confirmed by X-ray crystallography (Fig. 5).9
O
O
O
I
CHO
N
N
NH
18
42%
24
30 1 : 0
O
O
O
O
O
I
N
N
CHO
CHO
I
32%a
NH2
19
N
H
N
(Ph3P)4Pd, CuI, TEA
93%
H
15
34
O
O
O
O
O
O
25
31
1.0 : 1.1
Scheme 3.
O
O
O
I
NH2
20
N
N
H
65%
60%
41%
H
3 : 1
26
32
O
O
O
21%b
CHO
I
N
H
NH2
21
N
H
27
33
5 : 1
aIsolated yield of the Z isomer.
bIsolated yield of the E isomer.
lactam cases, the availability of the nitrogen’s lone pairs severely
restricts the conformational flexibility of the imide unit, which in
turn translates into the generation of a single E iodoolefin isomer.
In the case of the acyclic N-formyl imides, the situation is more
complicated as both E and Z halo enamides are formed in different
ratios. Crystallographic data for the N-formyl imides 25 and 26
suggest that the N-formyl carbonyl adopts a similar conformation
within the two imides (Fig. 4).7
Fig. 5. Crystal structure of b-yn-enamide 34.
The excellent yield observed in the Sonogashira cross-coupling
b-iodo enamide 15 and phenyl acetylene was then extended
of
using a number of phenyl substituted acetylenes, using both cyclic
and acyclic -iodo-enamides to generate the -yn-enamides
35e38. When alkyl substituted alkynes were used in the cross-
coupling, lower yields of the -yn-enamides 39 and 40 obtained
was observed. We believe that this difference in yield between the
b
b
b
alkyl substituted and phenyl substituted alkyne
products is due to the greater stability of the phenyl
b
b
-yn-enamide
-yn-enamide
adducts obtained rather than due to the Sonogashira coupling itself
(Table 2).
Fig. 4. N-Formylbenzimide 26 and dioxolane derived N-formyl imide 25.
Recent preliminary experiments, have shown that it is possible
to selectively reduce the b-yn-enamides 34 to generate E,Z-dien-
amides 41 in excellent yield through catalytic hydrogenation
(Scheme 4).
In conclusion, we have developed a fast and efficient method,
which takes advantage of the pseudo-aldehyde behaviour of N-
This would imply that it is the rotational freedom of the imide
unit along the bond between the internal carbonyl and the acyclic
unit that determines the selectivity of the reaction. This would be
consistent with the results observed in which the alkyl group in
imide 27 exerts a slightly greater steric influence on the imide
conformation than the flat aromatic substituent in imide 26. The
geometry of N-formyl imide 25 on the other hand, is influenced by
the conformation of the dioxolane ring as well as the potential
electronic interaction of the imide unit with the proximal oxygen of
the ketal unit.
formyl imides to access
thetically useful yields and without the need for nitrogen protect-
ing groups. The -iodo-enamides can be easily functionalised into
-yn-enamides and dienamides in excellent yields and with com-
plete selectivity. We believe that this route complements and
b-iodo-enamides in a single step, in syn-
b
b

7614
A.E. Pasqua et al. / Tetrahedron 67 (2011) 7611e7617
Table 2
Scientific Silica Gel 60, 40e63 micron) as the stationary phase. TLC
Synthesis of yn-enamides from iodo-enamides.
was performed on aluminium sheets pre-coated with silica (Merck
Silica Gel 60 F254). The plates were visualised by the quenching of
UV fluorescence (lmax 254 nm) and/or by staining with either
anisaldehyde, potassium permanganate, iodine or cerium ammo-
nium molybdate followed by heating.
R2
O
R2
O
I
R
N
R
N
(PPh3)4Pd, CuI, TEA
R1
R1
OMe
O
O
N
O
N
N
3.2. General procedure for the synthesis of b-iodo-enamides
35 92%
36 94%
38 99%
39 33%
40%
n-Bu
O
O
OTBS
OTBS
Chromium(III)chloride hexahydrate (18.0 mmol) was placed in
a two neck round bottom flask and was heated using a bunsen
burner until the colour of the chromium(III)chloride changed from
dark green to light green and then to purple. The purple chro-
mium(III)chloride was then treated with zinc (9.0 mmol) and NaI
(15.0 mmol), and the resulting mixture was stirred and heated
under vacuum and for 15 min.
The reaction was then allowed to cool down to room tempera-
ture whilst still under vacuum and then placed under argon. The
dry mixture was then suspended in anhydrous THF (30 mL) and the
reaction mixture was stirred at room temperature for 10 min. A
solution of N-formyl imide (1.3 mmol) and iodoform (2.6 mmol) in
THF (15 mL) was then cannulated into the chromium mixture and
the resulting brown suspension was stirred overnight at room
temperature.
The reaction was then quenched with satd aq NaCl (30 mL),
followed by satd aq IDRANAL III (30 mL) and the solution was
allowed to stir at room temperature for 30 min before being
extracted with diethyl ether (3ꢂ20 mL). The combined organic
extracts were dried over Na2SO4 and concentrated under reduced
pressure. The crude oil was then purified by flash column chro-
matography on silica gel eluting with 10% ethyl acetate in petro-
leum ether to afford the desired E-iodo-enamides.
N
O
O
N
N
H
H
40
37
85%
O
O
Pd, BaSO4, H2
Quinoline
99%
N
N
34
41
Scheme 4.
expands the methodologies available currently for the synthesis of
-halo-enamides, -yn-enamides and dienamides, and can be
easily modified for the generation of novel structural motifs with
potential applications in synthetic, biological, medicinal, supra-
molecular and materials chemistry.
b
b
3.2.1. (E)-1-(2-Iodovinyl)piperidin-2-one, 15. Chromium(III)chlo-
ride hexahydrate (2.90 g, 10.8 mmol), zinc (352 mg, 5.4 mmol),
sodium iodide (1.34 g, 8.9 mmol) and iodoform (614 mg, 1. 6 mmol)
reacted with N-formyl imide 14 (100 mg, 0. 8 mmol) to afford 90 mg
(46%) of E-iodo-enamide 15 as a yellow solid. Mp 33 ꢀC; 1H NMR
3. Experimental
3.1. General
(400 MHz, CDCl3)
d
: 8.11 (1H, d, J¼14.0 Hz), 5.44 (1H, d, J¼14.0 Hz),
3.41 (2H, t, J¼6.0 Hz), 2.48 (2H, t, J¼6.4 Hz), 1.88e1.81 (2H, m),
All reactions were performed in oven-dried glassware under an
inert argon atmosphere unless otherwise stated. Tetrahydrofuran
(THF), diethyl ether and dichloromethane (DCM) were purified
through a Pure Solv 400-5MD solvent purification system (In-
novative Technology, Inc). All reagents were used as received, un-
less otherwise stated. Solvents were evaporated under reduced
pressure at 40 ꢀC.
1.79e1.70 (2H, m); 13C NMR (100 MHz, CDCl3)
d: 167.8, 137.7, 55.0,
45.0, 32.8, 22.4, 20.6; nmax (neat)/cmꢁ1; 2924, 2854, 1651, 1599,
1458, 1404, 1296, 1257; HRMS (CI/ISO) found (MþH)þ 251.9885,
C7H11INO requires 251.9886.
3.2.2. (E)-1-(2-Iodovinyl)pirrolidin-2-one, 28. Chromium(III)chlo-
ride hexahydrate (4.80 g, 18.0 mmol), zinc (588 mg, 9.0 mmol),
sodium iodide (2.25 g, 15.0 mmol) and iodoform (1.02 g, 2.6 mmol)
reacted with N-formyl imide 22 (147 mg, 1.3 mmol) to afford
156 mg (51%) of E-iodo-enamide 28 as a yellow solid. Mp 28 ꢀC; 1H
IR spectra were recorded using a JASCO FT/IR410 Fourier
Transform spectrometer using a diamond gate. Only significant
absorptions (nmax) are reported in wavenumbers (cmꢁ1). Melting
points were recorded using a Bibby Stuart Scientific Melting Point
SMP1 and are uncorrected.
NMR (400 MHz, CDCl3)
d
: 7.60 (1H, d, J¼13.9 Hz), 5.37 (1H, d,
J¼13.9 Hz), 3.52 (2H, t, J¼7.3 Hz), 2.48 (2H, t, J¼7.9 Hz), 2.13 (2H, app
Proton magnetic resonance spectra (1H NMR) and carbon
magnetic resonance spectra (13C NMR) were, respectively, recorded
at 400 MHz and 100 MHz using a Bruker DPX Avance400 in-
qn, J¼7.7 Hz); 13C NMR (100 MHz, CDCl3)
d: 172.3, 134.6, 54.9, 44.5,
30.5, 17.3; nmax (neat)/cmꢁ1; 3057, 2957, 2917, 2889, 1685, 1607,
1480, 1457, 1263, 1174; HRMS (EI) found (M)þ 236.9651, C6H8INO
requires 236.9655.
strument. Chemical shifts (d) are reported in parts per million
(ppm) and are referenced to the residual solvent peak. The order of
citation in parentheses is (1) number of equivalent nuclei (by in-
tegration), (2) multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, b¼broad, dm¼double multiplet), and (3)
coupling constant (J) quoted in Hertz to the nearest 0.5 Hz. High
resolution mass spectra were recorded on a JEOL JMS-700 spec-
trometer by electrospray and chemical ionisation mass spectrom-
eter operating at a resolution of 15,000 full widths at half height.
Flash chromatography was performed using silica gel (Flourochem
3.2.3. (E)-1-(2-Iodovinyl)azepan-2-one, 29. Chromium(III)chloride
hexahydrate (4.80 g, 18.0 mmol), zinc (588 mg, 9.0 mmol), sodium
iodide (2.25 g, 15.0 mmol) and iodoform (1.02 g, 2.6 mmol) reacted
with N-formyl imide 23 (183.5 mg, 1.3 mmol) to afford 137 mg
(40%) of E-iodo-enamide 29 as a yellow solid. Mp 36 ꢀC; 1H NMR
(400 MHz, CDCl3)
3.59e3.49 (2H, m), 2.64e2.57 (2H, m), 1.79e1.64 (6H, m); 13C NMR
(100 MHz, CDCl3) : 173.5, 137.4, 54.9, 45.2, 36.9, 29.5, 27.5, 23.5;
d: 7.85 (1H, d, J¼14.0 Hz), 5.51 (1H, d, J¼14.0 Hz),
d

A.E. Pasqua et al. / Tetrahedron 67 (2011) 7611e7617
7615
nmax (neat)/cmꢁ1; 2930, 1658, 1602, 1476, 1389, 1325, 1191; HRMS
3.3. General procedure for the Sonogashira coupling of b-
iodo-enamides
(CI/ISO) found (MþH)þ 266.0042, C8H13INO requires 266.0041.
3.2.4. (E)-1-(2-Iodovinyl)azocan-2-one, 30. Chromium(III)chloride
hexahydrate (4.80 g, 18.0 mmol), zinc (588, 9.0 mmol), sodium io-
dide (2.25 g, 15.0 mmol) and iodoform (1.02 g, 2.6 mmol) reacted
with N-formyl imide 24 (201.5 mg,1.3 mmol) to afford 150 mg (42%)
of E-iodo-enamide 30 as a yellow solid. Mp 54 ꢀC; 1H NMR
A 0.3 M solution of b-iodo-enamide (1.0 equiv) in DMF was
treated with Pd(PPh3)4 (0.1 equiv) and the suspension was stirred at
room temperature for 10 min. Then the alkyne (5.0 equiv), CuI
(0.2 equiv) and TEA (2.0 equiv) were sequentially added, and the
resulting mixture was stirred at room temperature for 72 h.
The reaction mixture was quenched with distilled water (20 mL)
and extracted with diethyl ether (3ꢂ20 mL). The combined organic
extracts werethenwashed with water (10ꢂ20mL), dried overNa2SO4
and concentrated under vacuum to afford a brown residue. The crude
product was purified by flash column chromatography on silica gel
eluting with 50/50 petroleum ether/dichloromethaneþ5% diethyl
(400 MHz, CDCl3)
d
: 7.95 (1H, d, J¼14.1 Hz), 5.51 (1H, d, J¼14.1 Hz),
3.72 (2H, dd, J¼5.9, 5.8 Hz), 2.63e2,56 (2H, m), 1.88e1.78 (2H, m),
1.73e1.68 (2H, m), 1.62e1.58 (2H, m), 1.50e1.42 (2H, m); 13C NMR
(100 MHz, CDCl3) d: 173.1, 136.2, 55.5, 43.6, 34.3, 29.1, 27.9, 26.4,
24.2; nmax (neat)/cmꢁ1; 3083, 2938, 2929, 2915, 1647, 1603, 1484,
1453,1388,1312; HRMS (CI/ISO) found (MþH)þ 280.0198, C9H15INO
requires 280.0203.
ether to afford the pure b-yn-enamide products.
3.2.5. (Z)-N-(2-Iodovinyl)-2,2,5,5-tetramethyl-1,3-dioxane-4-
carboxamide, 31Z. Chromium(III)chloride hexahydrate (4.80 g,
18.0 mmol), zinc (588 mg, 9.0 mmol), sodium iodide (2.25 g,
15.0 mmol) and iodoform (1.02 g, 2.6 mmol) reacted with N-
formyl imide 25 (280 mg, 1.3 mmol) to afford a crude 1.0/1.1
mixture of E/Z isomers. After column purification, 140 mg (32%)
of Z-iodo-enamide 31Z was obtained as a light yellow solid. Mp
3.3.1. (E)-1-(4-Phenylbut-1-en-3-ynyl)piperidin-2-one, 34.
enamide 15 (60 mg, 0.24 mmol) was coupled with phenyl acetylene
(132 L, 1.2 mmol) in the presence of Pd(PPh3)4 (28 mg, 24 mol),
L, 0.48 mmol) to afford
-yn-enamide 34 as a yellow-brown solid. Mp 92 ꢀC;
b-Iodo-
m
m
CuI (10 mg, 48
50 mg (93%) of
mmol) and triethylamine (72 m
b
1H NMR (500 MHz, CDCl3)
d
: 8.02 (1H, d, J¼14.8 Hz), 7.37e7.32 (2H,
m), 7.26e7.17 (3H, m), 5.21 (1H, d, J¼14.8 Hz), 3.43 (2H, t, J¼6.0 Hz),
110 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 8.63e8.42 (1H, m), 7.28
2.54 (2H, t, J¼6.5 Hz), 1.90e1.82 (2H, m), 1.79e1.73 (2H, m); 13C
(1H, dd, J¼11.2, 6.4 Hz), 5.42 (1H, d, J¼6.4 Hz), 4.17 (1H, s), 3.72
NMR (125 MHz, CDCl3) d: 168.2,137.3, 131.3, 128.4, 127.7, 123.7, 89.8,
(1H, d, J¼11.8 Hz), 3.32 (1H, d, J¼11.8 Hz), 1.54 (3H, s), 1.47 (3H,
88.9, 87.4, 45.0, 32.9, 22.4, 20.3; nmax (neat)/cmꢁ1; 3086, 2939, 2877,
2198, 1728, 1658, 1612, 1458; HRMS (CI/ISO) found (MþH)þ
226.1232, C15H16NO requires 226.1233.
s), 1.05 (3H, s), 1.04 (3H, s); 13C NMR (100 MHz, CDCl3)
d: 167.6,
129.4, 99.4, 77.2, 71.4, 61.4, 33.3, 29.5, 21.9, 19.1, 18.8; nmax
(neat)/cmꢁ1; 2988, 2956, 2872, 1699, 1626, 1464, 1375, 1285,
1235; HRMS (EI) found (M)þ 339.0332, C11H18INO3 requires
339.0331.
3.3.2. (E)-1-(4-(4-Methoxyphenyl)but-1-en-3-ynyl)piperidin-2-one,
35.
ethynylanisole (132 mg, 995
(23 mg, 19 mol), CuI (7 mg, 38
39.8 mol) to afford 47 mg (92%) of
brown solid. Mp 132 ꢀC; 1H NMR (500 MHz, CDCl3)
b
-Iodo-enamide 15 (50 mg,199
mol) in the presence of Pd(PPh3)4
mol) and triethylamine (60 L,
-yn-enamide 35 as a yellow-
: 7.99 (1H, d,
mmol) was coupled with 4-
m
3.2.6. (E)-N-(2-Iodovinyl)benzamide, 32E and (Z)-N-(2-Iodovinyl)
benzamide, 32Z. Chromium(III)chloride hexahydrate (3.70 g,
13.8 mmol), zinc (452.3 mg, 6.9 mmol), sodium iodide (1.73 g,
11.5 mmol) and iodoform (0.78 g, 2.0 mmol) reacted with N-formyl
imide 26 (149 mg, 1.0 mmol) to afford 113 mg (41%) of a 3.0/1.0
mixture of E/Z isomers from which an analytical clean fraction of
the E isomer could be obtained. Mp 115e130 ꢀC.
m
m
m
m
b
d
J¼14.8 Hz), 7.35 (2H, dm, J¼8.7 Hz), 6.83 (2H, dm, J¼8.8 Hz), 5.20
(1H, d, J¼14.8 Hz), 3.81 (3H, s), 3.43 (2H, t, J¼6.0 Hz), 2.54 (2H, t,
J¼6.5 Hz),1.96e1.88 (2H, m),1.84e1.77 (2H, m); 13C NMR (125 MHz,
CDCl3) d: 168.1, 159.2, 136.7, 132.7, 115.9, 114.0, 90.2, 88.8, 85.9, 55.3,
45.0, 33.0, 22.5, 20.4; nmax (neat)/cmꢁ1; 3080, 2949, 2837, 2191,
1660, 1616, 1565, 1506, 1473; HRMS (EI) found (M)þ 255.1259,
C16H17NO2 requires 255.1260.
3.2.6.1. (E)-N-(2-Iodovinyl)benzamide, 32E. 1H NMR (400 MHz,
CDCl3)
d
: 8.01e7.92 (1H, m), 7.79 (2H, app dd, J¼7.3, 1.4 Hz), 7.65
(1H, dd, J¼13.7, 10.1 Hz), 7.55 (1H, appt, J¼7.3 Hz), 7.46 (1H, appt,
J¼8.1 Hz), 5.84 (1H, d, J¼13.8 Hz); 13C NMR (100 MHz, CDCl3)
d:
3.3.3. (E)-1-(4-(4-Pentanoylphenyl)but-1-en-3-ynyl)piperidin-2-
164.3, 132.8, 132.7, 130.7, 129.1, 127.4, 61.2; nmax (neat)/cmꢁ1; 3299,
2929, 1687, 1652, 1620, 1508, 1464, 1283; HRMS (EI) found (M)þ
272.9654, C9H8INO requires 272.9651.
one, 36.
(4-ethynylphenyl)pentan-1-one (130 mg, 0.7 mmol) in the pres-
ence of Pd(PPh3)4 (16 mg, 14 mol), CuI (5 mg, 28 mol) and trie-
thylamine (40 L, 0.3 mmol) to afford 40 mg (94%) of enynamide 36
as a yellow-brown solid. Mp 170 ꢀC; 1H NMR (400 MHz, CDCl3)
b-Iodo-enamide 15 (35 mg, 139 mmol) was coupled with 1-
m
m
m
3.2.6.2. (E)-N-(2-Iodovinyl)benzamide, 32Z. 1H NMR (400 MHz,
d:
CDCl3)
(1H, d, J¼6.70 Hz).
d
: 8.06 (1H, br s), 7.89e7.84 (2H, m), 7.62e7.48 (3H, m), 5.49
8.07 (1H, d, J¼14.9 Hz), 7.89 (2H, d, J¼8.7 Hz), 7.47 (2H, t, J¼8.7 Hz),
5.22 (1H, d, J¼14.8 Hz), 3.45 (2H, t, J¼6.0 Hz), 2.95 (2H, t, J¼7.4 Hz),
2.57 (2H, t, J¼6.4 Hz),1.99e1.91 (2H, m),1.89e1.82 (2H, m),1.71 (2H,
app qn, J¼7.1 Hz), 1.41 (2H, appsextet, J¼7.5 Hz), 0.88 (3H, t,
3.2.7. (E)-N-(2-Iodovinyl)butyramide, 33E. Chromium(III)chloride
hexahydrate (4.80 g, 18.0 mmol), zinc (588 mg, 9.0 mmol), sodium
iodide (2.2.5g, 15.0 mmol) and iodoform (1.02 g, 2.6 mmol) reacted
with N-formyl imide 27 (149 mg, 1.3 mmol) to afford a crude 5.0/1.0
mixture of E/Z isomers. After column purification, 65 mg (21%) of E-
iodo-enamide 33E was obtained as a yellow solid. Mp 85e90 ꢀC; 1H
J¼7.3 Hz); 13C NMR (100 MHz, CDCl3)
d: 197.5, 168.5, 138.3, 134.7,
131.2, 128.6, 128.0, 100.0, 95.4, 89.3, 45.1, 38.4, 33.0, 26.5, 22.5, 22.4,
20.4, 14.0; nmax (neat)/cmꢁ1; 3078, 3045, 2955, 2193, 1680, 1664,
1616, 1593, 1552, 1500; HRMS (EI) found (M)þ 309.1729, C20H23NO2
requires 309.1727.
NMR (500 MHz, CDCl3)
d
: 7.45 (1H, dd, J¼13.9, 10.6 Hz), 7.38e7.18
(1H, br s), 5.64 (1H, d, J¼13.9 Hz), 2.20 (2H, t, J¼7.3 Hz), 1.68 (2H,
3.3.4. N-((E)-4-Phenyl-but-1-en-3-ynyl)-benzamide, 37E and N-((Z)-
sext, J¼7.5 Hz), 0.96 (3H, t, J¼7.4 Hz); 13C NMR (125 MHz, CDCl3)
d:
4-phenyl-but-1-en-3-ynyl)-benzamide, 37Z. A 2/1 mixture of E/Z
iodo-enamides 32 (55 mg, 201 mol) was coupled with phenyl
acetylene (120 L, 1.00 mmol) in the presence of Pd(PPh3)4 (23 mg,
21 mol), CuI (8 mg, 40.2 mol) and triethylamine (60 L,
b-
169.8, 133.7, 56.6, 38.3, 18.9, 13.8; nmax (neat)/cmꢁ1; 3265, 2960,
1664, 1624, 1492, 1462, 1222; HRMS (CI) found (MþH)þ 239.9880,
C6H11INO requires 239.9885.
m
m
m
m
m

7616
A.E. Pasqua et al. / Tetrahedron 67 (2011) 7611e7617
0.40 mmol) to afford 42 mg (85%) of enynamides 37E/37Z as a 2/1
mixture of double bond isomers.
organic layers were dried over Na2SO4. The solution was filtered
and concentrated under vacuum to afford 10 mg (99%) of the de-
sired E,Z-dienamide as a yellow oil, which required no further pu-
3.3.4.1. N-((E)-4-Phenyl-but-1-en-3-ynyl)-benzamide,
37E. 1H
rification. 1H NMR (400 MHz, CDCl3)
d
: 7.78 (1H, d, J¼13.6 Hz),
NMR (400 MHz, CDCl3)
d
: 7.98 (1H, br d, J¼9.8 Hz), 7.86e7.80 (1H,
7.37e7.30 (5H, m), 6.36e6.22 (3H, m), 3.44 (2H, t, J¼6.1 Hz), 2.53
m), 7.65e7.28 (10H, m), 5.56 (1H, d, J¼14.5 Hz); 13C NMR (100 MHz,
(2H, t, J¼6.6 Hz), 1.93e1.87 (2H, m), 1.85e1.78 (2H, m); 13C NMR
CDCl3)
d: 163.8, 133.1, 132.5, 132.2, 131.3, 128.8, 128.5, 128.3, 127.2,
(100 MHz, CDCl3) d: 168.7, 132.2, 128.7, 128.6, 128.5, 128.3, 127.4,
122.9, 97.5, 89.9, 83.5; nmax (neat)/cmꢁ1; 3302, 2930, 2854, 2360,
1699, 1657, 1626, 1597, 1518, 1491; HRMS (CI/ISO) found (MþH)þ
248.1074, C17H14NO requires 248.1075.
126.6, 107.8, 45.5, 33.1, 22.9, 20.7; nmax (neat)/cmꢁ1; 2950, 2929,
1726, 1665, 1629, 1595, 1402; HRMS (EI) found (M)þ observed
227.1306, C15H17NO requires 227.1310.
3.3.4.2. N-((Z)-4-Phenyl-but-1-en-3-ynyl)-benzamide, 37Z. 1H
3.4. Crystallographic data collection and refinement details
NMR (400 MHz, CDCl3)
7.65e7.28 (10H, m), 5.11 (1H, d, J¼8.8 Hz).
d
: 7.97 (1H, br d, J¼9.8 Hz), 7.82 (1H, m),
X-ray data for 15 were collected at 100 K on a Bruker Nonius
Kappa CCD diffractometer equipped with an Oxford Cryosystems
Cryostream low-temperature device and using graphite mono-
3.3.5. (E)-1-(4-p-Tolylbut-1-en-3-ynyl)piperidin-2-one, 38.
b-Iodo-
ꢀ
enamide 15 (50 mg, 0.2 mmol) was coupled with p-tolyl acetylene
(116 mg, 1.0 mmol) in the presence of Pd(PPh3)4 (23 mg, 20 mol),
CuI (8 mg, 40 mol) and triethylamine (60 L, 0.4 mmol) to afford
48 mg (99%) of -yn-enamide 38 as a yellow-brown solid. Mp
148 ꢀC; 1H NMR (500 MHz, CDCl3)
chromated Mo K
a
radiation (
l
¼0.71073 A) radiation. Data reduction
was carried out using DENZO14 and a semi-empirical absorption
correction applied using SADABS (BrukerAXS Inc, Madison,
Wisconsin, USA). X-ray data for 34 were collected at 100 K on
a Rigaku R-Axis RAPID Image Plate diffractometer equipped with an
m
m
m
b
d
: 8.00 (1H, d, J¼14.8 Hz), 7.30
(2H, d, J¼8.0 Hz), 7.10 (2H, d, J¼7.6 Hz), 5.20 (1H, d, J¼14.8 Hz),
3.43 (2H, t, J¼6.2 Hz), 2.54 (2H, t, J¼6.6 Hz), 2.34 (3H, s), 1.97e1.91
Oxford Cryosystems Cryostream low-temperature device and using
ꢀ
graphite monochromated Mo K
a
radiation (
l
¼0.71075 A) radiation.
(2H, m), 1.86e1.81 (2H, m); 13C NMR (125 MHz, CDCl3)
d: 168.2,
Data reduction and an empirical absorption correction was carried
out using CrystalClear15. The structures were both solved by direct
methods using the program SHELXS9716 and refined using full-
matrix least-squares refinement on F2 using SHELXL9716 within
the WinGX program suite17. All non-hydrogen atoms were refined
anisotropically. The H atom positions were located on a difference
Fourier map and their positions and isotropic thermal parameters
were allowed to freely refine.
137.8, 137.0, 131.1, 129.1, 120.7, 90.1, 89.1, 86.7, 45.0, 33.0, 22.4, 21.5,
20.4; nmax (neat)/cmꢁ1; 3086, 2955, 2924, 2877, 2191, 1666, 1620,
1504, 1458; HRMS (EI) found (M)þ 239.1310, C16H17NO requires
239.1311.
3.3.6. (E)-1-(6-(tert-Butyldimethylsilyloxy)hex-1-en-3-ynyl)piper-
idin-2-one, 39.
with 1-(tert-butyldimethylsilyloxy)-3-butyne (92 mg, 0.5 mmol) in
the presence Pd(PPh3)4 (12 mg, 10 mol), CuI (4.0 mg, 20 mol) and
triethylamine (30 L, 0.2 mmol) to afford 10.2 mg (33%) of enyna-
mide 39 as a yellow oil. 1H NMR (500 MHz, CDCl3)
: 7.78 (1H, d,
b-Iodo-enamide 15 (25 mg, 100 mmol) was coupled
m
m
3.4.1. Crystal data for 15. C7H10INO, Mr¼251.06, monoclinic, C2/c,
ꢀ
m
a¼10.2578(9), b¼15.9675(16), c¼9.9684(10) A,
b
¼93.715(3)ꢀ,
d
T¼100(2) K, Z¼8, R¼0.0277 for 1635 data with F0>2
s(F),
J¼14.8 Hz), 4.88 (1H, dm, J¼14.8Hz), 3.64 (2H, t, J¼7.3 Hz), 3.28 (2H,
wR2¼0.058 for 1873 unique data (all data 8841), GOF¼1.231.
t, J¼6.3 Hz), 2.43 (4H, m), 1.85e1.78 (2H, m), 1.77e1.69 (2H, m), 1.46
(6H, s), 0.81 (9H, s); 13C NMR (125 MHz, CDCl3)
d: 168.5,136.7, 90.21,
3.4.2. Crystal data for 34. C15H15NO, Mr¼225.28, monoclinic, P21/c,
ꢀ
77.6, 62.1, 44.9, 32.9, 25.9, 23.9, 22.5, 20.4, 18.4, ꢁ5.2 (one un-
resolved carbon); nmax (neat)/cmꢁ1; 2931, 2854, 2337, 1736, 1666,
1620; HRMS (CI/ISO) found (MþH)þ 308.2051, C17H30NO2Si re-
quires 308.2046.
a¼11.5713(3), b¼8.1426(2), c¼12.6750(3) A,
T¼100 K, Z¼4, R¼0.0416 for 1590 data with F0>2
for 2735 unique data (all data 9810), GOF¼0.917.
b
¼92.5340(10)ꢀ,
s
(F), wR2¼0.0809
CCDC 804820e804821 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
3.3.7. N-[(E)-6-(tert-Butyl-dimethyl-silanyloxy)-hex-1-en-3-ynyl]-
benzamide, 40. A 3/1 mixture of E/Z
201 mol) was coupled with 1-(tert-butyldimethylsilyloxy)-3-
butyne (153 mg, 0.33 mmol) in the presence of Pd(PPh3)4 (20 mg,
17 mol), CuI (7 mg, 33 mol) and triethylamine (50 L, 0.33 mmol)
to afford 153 mg (40%) of enynamide 40E as a single isomer. 1H NMR
(400 MHz, CDCl3)
b-iodo-enamides 32 (55 mg,
m
Acknowledgements
m
m
m
We would like to thank Dr. Ian Sword and the University of
Glasgow for postgraduate support (A.E.P.). We would also like to
thank Dr. Ian Sword and the EPSRC for funding.
d
: 7.95e7.85 (1H, m), 7.79 (2H, d, J¼6.8 Hz),
7.58e7.39 (3H, m), 5.33 (1H, app dt, J¼14.4, 2.2 Hz), 3.75 (2H, t,
J¼6.9 Hz), 2.54 (2H, app td, J¼7.1, 2.2 Hz), 0.91 (9H, s), 0.09 (6H, s);
13C NMR (100 MHz, CDCl3)
d: 164.9, 133.4, 132.4, 131.2, 128.9, 127.3,
References and notes
93.2, 88.2, 78.1, 62.6, 26.8, 24.2, 18.4, ꢁ4.8; nmax (neat)/cmꢁ1; 3292,
2929, 2855, 2359, 1707, 1627, 1519, 1488, 1252, 1090. HRMS (CI/ISO)
found (MþH)þ 330.1893, C19H28NO2Si requires 330.1889.
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