The Synthesis of Ketone-Derived Enamides by Elimination of HCN from Cyanoamides

Article abstract of DOI:10.1002/ejoc.201600638

Treatment of easily available ketone-derived cyanoamides with NaOtBu leads to enamides in a simple, scalable, and inexpensive one-step operation in good yield. Enamides not stabilized by conjugation or by inclusion in a ring can also be prepared. An E1cB mechanism consistent with all results and observations, is proposed. The Z geometry of the product enamide is highly favoured, and the regioselectivity can be directed by one′s choice of protecting group.

Full text of DOI:10.1002/ejoc.201600638

DOI: 10.1002/ejoc.201600638
Full Paper
Enamide Synthesis
The Synthesis of Ketone-Derived Enamides by Elimination of
HCN from Cyanoamides
Guilhem Coussanes,[a][‡] Katharina Gaus,[a] and Anthony C. O'Sullivan*[‡‡]
Abstract: Treatment of easily available ketone-derived cyano- be prepared. An E1cB mechanism consistent with all results and
amides with NaOtBu leads to enamides in a simple, scalable, observations, is proposed. The Z geometry of the product en-
and inexpensive one-step operation in good yield. Enamides amide is highly favoured, and the regioselectivity can be di-
not stabilized by conjugation or by inclusion in a ring can also rected by one′s choice of protecting group.
Introduction
amide functionalities, wherein enamide formation is the key
step.[9]
Enamides are reactive and versatile building blocks.[1] Their
electrophilicity at the α-centre (after protonation to generate
acyl iminium ions) and nucleophilicity at the ꢀ-centre have
been exploited recently through the use of chiral reagents and
catalysts in a number of one-step enantioselective syntheses of
highly functionalized compounds.[2] Furthermore, the enantio-
selective hydrogenation of enamides is probably the most
widely used method for the synthesis of chiral amines in both
academic and industrial settings.[3] A high yielding, cheap, and
scalable methodology for the synthesis of enamides would
clearly further their synthetic utility.[4]
The synthesis of aldehyde-derived enamides is straightfor-
ward in view of the ready accessibility of precursor amidoacyl-
ating agents 1, in which X can be Cl, Br, OH, OR, OCOR, SR,
SO2R, NHCOR, or benzotriazole.[5] (Scheme 1) Treatment of
these compounds with base leads to highly reactive acylimines
2, which tautomerise readily to the desired enamides.[6–8] Fur-
ther developments in the field have been achieved during the
synthesis of natural products containing aldehyde-derived en-
An analogous access to enamides derived from ketones is
not feasible because ketone-derived amidoacylating agents
have not been described,[5] in some or all cases, due to their
instability. Consequently, access to ketone-derived enamides
has been achieved using other approaches. In particular, the
reductive acylation of oximes, using Ac2O/pyridine,[10] Cr(OAc)2
and Ti(OAc)3,[11] Fe,[12] Fe(OAc)2,[13] RuCl2/NaHSO3,[14] Et3P, [15]
H2,[16] and CuI/NaHSO3[17] as reducing agents, provides easy ac-
cess. However, in nearly all cases,[13] only enamides stabilized
by conjugation with aromatic moieties and/or ring formation
have been generated. In addition, a synthesis of enamides di-
rectly from ketones via a proposed titanium imine intermediate
has recently been reported by Boehringer Ingelheim; again
though, only stabilized enamides were reported.[18]
Several methods for the preparation of unstabilised ketone-
derived enamides (shown in Scheme 2 with acetone-derived
enamides as examples) have been reported but are inconven-
ient for the following reasons: i) palladium-catalyzed rearrange-
ment of acyl aziridine 4 starts from carcinogenic aziridines;[19]
ii) the pyrolysis of dimethylazlactone 5 is high yielding but re-
quires the use of special equipment, and provides the product
mixed with its tautomeric acyl imine;[20] and iii) gas phase ther-
Scheme 1. Synthesis of aldehyde-derived enamides using amidoacylating
agents.
[a] Process Research Chemistry, Syngenta Crop Protection AG,
Schaffhauserstrasse 101, 4332 Stein, Switzerland
E-mail: anthony.osullivan@syngenta.com
www.syngenta.com
[‡] University of Barcelona (most of this work was performed by G. C. when
he was in a traineeship from Uni Montpelier).
[‡‡] Present address Carbogen-Amcis AG, 5001 Aarau, Switzerland
E-mail: anthony.osullivan@carbogen-amcis.com
Scheme 2. Known methods for the synthesis of isopropenyl amides/carb-
amates. Reagents and conditions: a) Pd2(dba)3/PCy3, toluene, 40 °C, 7 h, R1
=
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600638.
Ph. b) 550 °C, R1 = Ph. c) 500–600 °C, 12 Torr, R1 = Me. d) approx. 100 °C.
e) ROH for R1 = RO. f) RMgBr for R1 = R.[24]
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molysis of readily available amidonitrile 6 also requires pyrolysis from 1-cyano-cyclohexyl-formamide 16 (Scheme 4). Enamide
apparatus.[21] The most commonly used route to enecarb- 17 was not isolated but was transformed further to isocyanide
amates involves Curtius degradation of methacroyl azide 7 to 18 upon in situ treatment with POCl3.[29] Later, Keating and
isopropenyl isocyanate 8.[22] Although the yield is high, there Armstrong modified Ugi's protocol to isolate and characterize
are safety issues as methacroyl azide is volatile, unstable and intermediate enamide 17.[30a] Besidsky et al. demonstrated
explosive. Another limiting consideration is that isopropenyl the elimination of HCN from a cyanoamide embedded in a qui-
isocyanate is volatile, toxic and unstable.[23] Nevertheless it is nuclidine ring system using KH in THF.[30b] Kurtz and Disseln-
possible to prepare and use kilogram amounts of vinyl isocyan- kötter showed that gas phase pyrolysis of cyanoamides is faster
ate using the Curtius degradation, if the proper safety measures with marble as a packing material rather than with non-basic
are in place.[23b,23c] This method is easier to apply safely with packing materials, indicating base catalysis as a viable mecha-
non-volatile substrates.
nism.[21] Herein, we now describe the scope and limitations of
the Ugi method, which turns out to be applicable to ketone-
derived enamides including those not stabilized by being part
of a cyclohexenyl ring. In addition to its wide scope, the reac-
tion shows high and directable regio- and stereo-selectivity, in
the absence of functional groups associated with influencing
selectivity.
Results and Discussion
We required access to a small amount of acetone derived
enamide 15, but considered the methods described above in
Scheme 2 to be sub-optimal. Unfortunately, attempts to apply
methods described for stabilised enamides proved to be un-
fruitful (Scheme 3). Reductive acylation of acetone oxime 10
with iron powder in acetic anhydride gave only traces of 11.[12b]
Copper-catalyzed cross coupling of isopropenyl bromide with
amide 12 gave desired 13 in 5 % yield.[25] The Boehringer Ingel-
heim method[18] led to low yields of gem-bis-amide 14, and
none of the desired enamide 15.
Scheme 4. Ugi's synthesis of cyclohexenyl isonitrile, involving the elimination
of cyanide from 16.
Cyanoamide 19 was selected for initial screening and optimi-
zation of the methodology (Scheme 5). Initial screening of
bases showed promising results. KOtBu (1 equiv.) in THF or
tBuOH at room temperature gave 26 % and 22 % conversion,
respectively, to desired enamide 20, with no by-products ob-
servable in the NMR. On the other hand, the use of iPrMgCl
gave only 8 % conversion, and attempts to use BuLi led only to
recovered starting material.[41] A small solvent screen showed
THF to deliver higher yields than tBuOH, DMF, and MeCN, and
running the reaction with a wider series of bases identified
KOtBu as the best base of those screened.[41]
Scheme 3. Attempts towards the synthesis of isopropenyl amides in the
present work.
Thermolysis of 14 at 200 °C under vacuum[26] led to a mix-
ture of products containing no enamide, but treatment of 14
with base[27] was more rewarding. The use of 1 equiv. of strong
base such as nBuLi, iPrMgBr or KOtBu at room temperature led
to partial conversion to desired enamide 15. The best conver-
sion were achieved with KOtBu, providing enamide 15 in 54 %
yield, accompanied by 26 % of recovered starting material 14.
Despite this promising result, the lack of direct methods to ac-
cess ketone-derived gem-bis-amides render this approach im-
practical as a general method.[28]
Scheme 5. Reaction used as model system to optimize conditions.
On examining the effects of counter ion, it was found that
The successful base-mediated synthesis of isopropenyl the less expensive NaOtBu reacted a little faster than KOtBu
amide 15 from 1,1-diamide 14 suggested that elimination of and much faster and more cleanly than LiOtBu.[41] Led by the
other leaving groups might also be feasible. As mentioned notion that silver cation could assist in the removal of the cyan-
above, ketone-derived amidoacylating agents analogous to 1 ide, a series of silver salts was screened, but to no avail. It was
are unknown, but the use of cyanide as a leaving group would found that the soluble salts AgOTs, AgO2CCF3, AgOTf, and
be highly attractive in view of the stability of cyanoamines and AgSbF6 inhibit the reaction and that only the insoluble AgNO3
their ready accessibility via the Strecker reaction. There is some and Ag2SO4 allow the reaction to take place.[31] An excess of
precedent for this reaction. Ugi and co-workers demonstrated base was found to be necessary, but more than three equiva-
that KOtBu at reflux brought about the elimination of cyanide lents of NaOtBu offered no advantage.
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Quenching the reaction mixture appropriately proved to be reaction (Table 1, Entries 1–6). The table (Table 1) is ordered
very important. Considering that enamide product 20 will be according to reactivity, with the pKa values of the correspond-
almost completely deprotonated under the reaction conditions ing carboxylic acids also provided to illustrate this point.[34]
(see below), an acid quench is necessary to isolate the neutral
enamide. However, enamides, although stable to base, are very
acid sensitive. A series of quenching conditions with mild
acids[41] revealed that NaHCO3, either as a solid or more conve-
TFA analog 27 (Table 1, Entry 6) did not react at room tem-
perature, and urea 29 (Table 1, Entry 7) decomposed nonspecif-
ically. Benzyl carbamate 31 (Table 1, Entry 8) gave a mixture of
products, presumably because the known base-catalyzed elimi-
nation of carbamate to isocyanate,[35] competes with enamide
formation. It was anticipated that a poorer leaving group such
as tert-butoxide would be less prone to elimination to isocyan-
ate, and indeed substrate 33 (Table 1, Entry 9), provided 34 in
78 % yield under the standard conditions.
niently as a 1
M aqueous solution, gave a cleaner product than
NH4Cl (solid or aqueous solution) or AcOH. NaHCO3 has the
advantage of being acidic enough to protonate the enamide
anion and that the subsequently formed Na2CO3 serves to
maintain a pH basic enough to stabilize the enamide. The
method used for further purification of the crude products
is also very important. Direct crystallization is favoured with
little or no loss due to decomposition.[32] As ketone-derived
enamides are unstable or only partially stable to chromatogra-
phy,[33] a number of chromatographic methods and stationary
phases were screened.[41] The best results were achieved with
chromatography on silica using eluents containing Et3N, but
there were, on occasion, unpredictable losses even using these
conditions.
Having established the scope of the reaction with acetone-
derived cyanoamides, we studied a larger panel of cyano-
amides, to examine the compatibility of functional groups with
the reaction and to ascertain the regio- and stereo-selectivity
of these more substituted compounds (Table 2). Cyanoamides
with a simple series of substituents (Me, Et, iPr, cPr) as well as
several with diverse functionalities were chosen.
Under the standard conditions most of the substrates exam-
ined provided enamides in good to high yields. The products
were obtained in nearly pure form, and in some cases as mix-
tures of regio- and stereo-isomers. An exception was 64
(Table 2, Entry 11), which gave 65 and 66 in low yield as a
mixture of isomers after chromatography.
Using these now optimised reaction conditions (i.e. with
3 equiv. NaOtBu in THF), the reaction of a series of cyanoamides
derived from acetone was studied (Table 1). Most substrates
reacted fully and cleanly over the course of 24 h at ambient
temperature, with electron-donating groups accelerating the
Cyclic compound 35 (Table 2, Entry 1) is symmetric, and
leads to a single compound 36 in high yield. The regioselectiv-
ity of elimination in the formation of 38 (Table 2, Entry 2) is
unsurprising, having taken place away from the cyclopropyl
group, thus avoiding ring strain.
Table 1. Conversion of a series of cyanoamides derived from acetone to the
corresponding enamides.
The reaction of simple open chain cyanoamides shows sur-
prisingly high regio- and stereo-selectivity. The effect of the N-
acyl group was unforeseen and striking. Cyanoamides 39, 43,
46, and 49 (Table 2, Entries 3–6) derived from butanone and
methyl butanone served as models. In each case, the Boc deriv-
ative preferentially afforded the more substituted enamide
(product of Zaitsev elimination) and the acetamide underwent
Hoffmann elimination in the direction of the methyl group. Also
noteworthy was that the butenyl amide 47Z was formed exclu-
sively as its Z-isomer. To demonstrate that these simple unsta-
bilised enamides are the kinetic products, 43 was heated under
the reaction conditions at 60 °C overnight, which provided the
same result as when the reaction was performed at room tem-
perature. Hoffman enamide 45 was formed as the major prod-
uct along with trace amounts of the presumably more stable
Zaitsev product 44.
The reactions of 52 and 55 (Table 2, Entries 7 and 8) invoke
elimination from the cyanoamides derived from benzyl methyl
ketones. The reactions at room temperature were not regio-
selective. In each case, a mixture of Hoffman (54 and 57) and
Zaitsev products (53 E+Z and 56 E+Z) were formed. It was con-
sidered possible that the initially formed Hofmann elimination
product (54 and 57) isomerized partly to more stable isomers
(53 E+Z and 54 E+Z).[36] Indeed, heating 52 overnight at 60 °C
under the reaction conditions resulted in full conversion of ini-
tially formed 54 to the more stable Zaitzev isomer 53 E+Z in
high yield. These isomers (53E and 53Z) were separately con-
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Table 2. Conversion of a series of diverse cyanoamides to the corresponding enamides.
firmed to be stable on heating under the reaction conditions.
This particular behavior of benzyl compounds 52 and 55 is
compatible with the mechanism shown in Scheme 6. Com-
pound 67 can be transiently deprotonated with NaOtBu to form
conjugated dianion 68,[36] which on reprotonation, can lead to
67, 69E or 69Z. The charge in both 69E and 69Z is conjugated
from the phenyl ring through to the carbonyl oxygen; deproto-
nation leading to 68 would interrupt this conjugation, and con-
sequently, is not observed. Phenethyl analog 58 (Table 2, Entry
9) led, as expected, predominantly to Hofmann product 60, and
cyclic compound 61 (Table 2, Entry 10) reacted unselectively to
yield a mixture of regioisomers.
Aldehyde-derived cyanoamides were so slow to react that
imidate formation took precedence (Scheme 7). Despite heating
overnight 70 remained largely unreacted; partial conversion to
Scheme 6. Isomerization of initially formed 67 to the conjugated enamide
anions 69E and 69Z.
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imidate 71, which appeared to be in equilibrium with 70, was and direction of regio- and stereo-selectivity on the amine pro-
observed. Compound 71 reverted slowly to 70 after workup, tecting group is predictive and useful, we offer no model for its
but could be isolated in low yield after chromatography and mechanistic origin. The selectivity may arise in the stereo-
repeated crystallization.[37]
selective formation of E or Z acylimines 74, or by their regio-
selective elimination. Analogy with the deprotonation of ket-
ones to their enolates is pertinent, because the factors influenc-
ing regio- and stereo-selectivity are only partially understood,
despite considerable study.[43]
Scheme 7. Reaction of aldehyde-derived cyanohydrin 70 with NaOtBu: forma-
tion of imidate.
Conclusions
In conclusion, we have shown that acid-sensitive ketone-
derived enamides can be prepared starting from the easily ac-
cessible cyanoamides using a simple, cheap, and scalable pro-
cedure in high yields. The protecting group has a useful direct-
ing effect on the regioselectivity, with Boc protection leading
to Hoffmann elimination and N-acetylation leading to Zaitsev
regioselectivity, with selective formation of Z-enamides in the
latter case.
The method was validated with 45 on a 168 mmol scale
providing identical results to the 3 mmol scale reaction.
All results and observations are compatible with the E1cB
mechanism shown in Scheme 8.[38] The first step, the deproto-
nation of NH, is expected to be fast. Simple amides have a pKa
of approx. 15–16[39] for the NH protons and would be rapidly
and almost completely deprotonated by NaOtBu (pKa 19)[40]
The NH protons of cyanoamide 72 and enamide 76 are even
more acidic. A deuteration study was undertaken to demon-
strate this fact.[41] The third step, conversion of acyl imine 74
to enamide 75, is fast;[7] so much so that ketone-derived acyl
imines have rarely been detected.[8,42] The second step, the
elimination of cyanide from 73 to 74, is thus the rate determin-
ing step, which explains, and is in accord with, the following
results. Firstly the rate of the reaction is increased by electron-
donating substituents, which is evidenced by the series in
Table 1, and the differences in reactivity of ketone- and alde-
hyde-derived substrates. Secondly the effect of the counterion
on rate decreases in the order Na+ ≈ K+ > MgCl+ > Li+ ≈ Ag+.
And finally, the reaction is independent of base concentration.
In all, two equivalents of base are needed, one to deprotonate
starting cyanoamide 72, and one to deprotonate acyl imine
intermediate 74. The use of three equivalents of base gave a
small improvement in rate and yield over two equivalents, but
the use of five or more equivalents brought no further increase
in rate, as expected since the conversion of 73 to 74 does not
involve base.
Experimental Section
Synthesis of Starting Materials – Acylation of Aminonitriles
For known acylaminonitriles the acylations were performed follow-
ing the reported literature conditions. For new compounds one of
these procedures was applied. In some cases, acylation conditions
gave moderate or low yields. Due to the main focus of these stud-
ies, attempts to optimise these low yielding reactions were not
made.
N-(1-Cyano-1-methylethyl)acetamide (6):[44] 2-Amino-2-methyl-
propanenitrile (1 g, 11.88 mmol) and acetic anhydride (1.35 mL,
14.26 mmol, 1.2 equiv.) were stirred at room temperature without
any solvent. After 19 h, the reaction mixture was diluted with Et2O
and washed 3 times with a 1
M solution of NaHCO3, followed by
2
M
HCl and then by saturated brine. The resulting organic layer was
dried with MgSO4, filtered and concentrated to afford cyanoamide
6 (337 mg, 23 % yield, white solid), m.p. 100–104 °C. 1H NMR
(400 MHz, CDCl3): δ = 5.65 (br. s, 1 H), 2.0 (s, 3 H), 1.7 (s, 6 H) . 13C
NMR (100 MHz, CDCl3): δ = 169.4, 120.7, 46.4, 27.2, 23.4 ppm. MS
(ES): m/z = 149 [M + Na]+. HRMS (ESI+): calcd. for C6H11N2O [M +
H]+ 127.0871, found 127.0870.
N-(1-Cyano-1-methyl-ethyl)-2,2-dimethylpropanamide (21):[45]
Pivaloyl chloride (430 mg, 3.57 mmol, 1.0 equiv.) was added to a
mixture of K2CO3 (498 mg, 3.57 mmol, 1.0 equiv.) and 2-amino-2-
methylpropanenitrile (300 mg, 3.57 mmol) in EtOAc (5 mL) and
stirred at room temperature for about 48 h. The reaction was then
quenched with water, and washed with saturated brine. The result-
ing organic layer was concentrated to afford cyanoamide 21
(474 mg, 79 % yield, yellow solid), m.p. 119–122 °C. 1H NMR
(400 MHz, CDCl3): δ = 5.6 (br. s, 1 H), 1.75 (s, 6 H), 1.25 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 177.8, 120.9, 46.3, 38.9, 27.6, 27.4;
27.2 ppm. MS (CI): m/z = 169 [M + H]+. HRMS (ESI+): calcd. for
C9H17N2O [M + H]+ 169.1341, found 169.1336.
Scheme 8. Proposed mechanism for conversion of cyanoamides to enamides.
N-(1-Cyano-1-methyl-ethyl)-4-methoxybenzamide (23):[46] 2-
Amino-2-methylpropanenitrile (1 g, 5.95 mmol) was dissolved in
THF (5 mL) and the solution was then cooled down to 0 °C. TEA
Although the evidence supporting an E1cB mechanism is
conclusive, there are details of the mechanism which remain
obscure. Although the remarkable dependence of the degree (2.45 mL, 17.5 mmol, 3.0 equiv.) was then added, stirred for 15 min,
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followed by 4-methoxybenzoyl chloride (1 g, 5.86 mmol, layer was concentrated to afford cyanoamide 33 (310 mg, 28 %
0.98 equiv.), the reaction mixture was then warmed up to room
temperature and stirred for about 48 h. The reaction was then
yield, colorless liquid). 1H NMR (400 MHz, CDCl3): δ = 4.6 (br. s, 1
H), 1.65 (s, 6 H), 1.5 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
153.6, 121.2, 46.8, 28.3, 27.7 ppm. HRMS (ESI+): calcd. for C9H17N2O2
[M + H]+ 185.1290, found 185.1287.
quenched with 2
M HCl, followed by a solution of NaHCO3, and
then saturated brine. The crude product was purified by silica chro-
matography with a gradient cyclohexane/EtOAc to afford cyanoam-
1
N-(4-Cyano-1-methoxy-2,2,6,6-tetramethyl-4-piperidyl)acet-
amide (35): 4-Amino-1-methoxy-2,2,6,6-tetramethylpiperidine-4-
carbonitrile (1.05 g, 5 mmol) was dissolved in EtOAc (5 mL),
followed by K2CO3 (0.768 mg, 5.5 mmol, 1.1 equiv.) and acetic anhy-
dride (0.52 mL, 5.5 mmol, 1.1 equiv.). The reaction mixture was
quenched with water and washed with a saturated brine. The result-
ing organic layer was dried with MgSO4, filtered and concentrated
to afford cyanoamide 35 (742 mg, 59 % yield, white solid), m.p.
166–169 °C. 1H NMR (400 MHz, CDCl3): δ = 5.43 (br. s, 1 H), 3.6 (s, 3
H), 2.6 (d, J = 15 Hz, 2 H), 1.93 (s, 3 H), 1.65 (d, J = 15 Hz, 2 H), 1.45
(s, 6 H), 1.22 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2,
121.3, 65.7, 58.9, 46.9, 46.0, 44.2, 33.7, 32.8, 23.4, 22.5, 19.9 ppm.
MS (CI): m/z = 254 [M + H]+. HRMS (ESI+): calcd. for C13H24N3O2 [M
+ H]+ 254.1869, found 254.1861.
ide 23 (298 mg, 24 % yield, white solid), m.p. 140–148 °C. H NMR
(400 MHz, CDCl3): δ = 7.75 (d, J = 10 Hz, 2 H), 6.92 (d, J = 10 Hz, 2
H), 6 (br. s, 1 H), 3.88 (s, 3 H), 1.8 (s, 6 H) ppm. MS (ES): m/z = 219
[M + H]+.
N-(1-Cyano-1-methylethyl)-4-(trifluoromethyl)benzamide (25):
This compound was prepared following the procedure described
for 23 using 4-(trifluoromethyl)benzoyl chloride (1 g, 4.79 mmol) to
afford cyanoamide 25 (712 mg, 58 % yield, white solid), m.p. 208–
211 °C. 1H NMR (400 MHz, CDCl3): δ = 7.9 (d, J = 9 Hz, 2 H), 7.72 (d,
J = 10 Hz, 2 H), 6.15 (br. s, 1 H), 1.85 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.4, 127.6, 125.9, 125.8, 120.4, 47.0, 27.3 ppm. HRMS
(ESI+): calcd. for C12H12F3N2O [M + H]+ 257.0902, found 257.0897.
N-(1-Cyano-1-methylethyl)-2,2,2-trifluoroacetamide (27): This
compound was prepared following the procedure described for 6
using trifluoroacetic anhydride (1.99 mL, 14.27 mmol) to afford
cyanoamide 27 (2.04 g, 87 % corrected yield for remnants of sol-
N-(1-Cyano-1-cyclopropylethyl)acetamide (37): This compound
was prepared following the procedure described for 35 using 2-
amino-2-cyclopropylpropanenitrile (0.51 g, 5 mmol) to afford
cyanoamide 37 (0.760 g, 76 % corrected yield for remnants of sol-
1
vent, brown oil). H NMR (400 MHz, CDCl3): δ = 7.19 (br. s, 1 H), 1.8
(s, 6 H) ppm. MS (ES): m/z = 181: [M + H]+.
1
vent, colorless oil). H NMR (400 MHz, CDCl3): δ = 6.45 (br. s, 1 H),
2.25 (s, 1 H), 2.05 (s, 3 H), 0.7 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 173.4, 167.5, 115.7, 51.0, 22.7, 21.2, 18.6, 17.3 ppm. MS
(CI): m/z = 153 [M + H]+. HRMS (ESI+): calcd. for C8H13N2O [M + H]+
153.1027, found 153.1023.
1-(1-Cyano-1-methylethyl)-3-phenylurea (29):[47] 2-Amino-2-
methylpropanenitrile (705 mg, 8.40 mmol) was dissolved in di-
chloromethane (5 mL) and the solution was then cooled down to
0 °C. Phenyl isocyanate (1 g, 8.40 mmol, 1.0 equiv.) was added fol-
lowed by TEA (1.5 mL, 10.91 mmol, 1.3 equiv.), the reaction mixture
was then warmed up to room temperature and stirred for 22 h. The
tert-Butyl N-(1-Cyano-1,2-dimethylpropyl)carbamate (39): 2-
Amino-2,3-dimethylbutanenitrile (1 g, 8.92 mmol) was added to a
round bottom flask with Boc-anhydride (10.7 mmol, 1.2 equiv.). The
solution was then heated up to 80 °C for 17 h. The reaction mixture
reaction mixture was then quenched with 2
M HCl, followed by a
solution of Na2CO3, and then saturated brine. The resulting organic
layer was concentrated, then crystallized with a mixture of dichloro-
methane/cyclohexane/MeOH, 60:40:1. The solid was filtered,
washed with Et2O and then dried. The resulting solid was purified
by silica chromatography with a gradient cyclohexane/EtOAc to af-
ford cyanoamide 29 (83 mg, 5 % yield, white solid), m.p. 120–
was cooled to room temperature and 2
M ammonia/methanol solu-
tion (1 mL, 0.2 equiv.) was added, and stirred for 10 min. The reac-
tion mixture was then concentrated to afford cyanoamide 39
(1.839 g, white solid), m.p. 88–92 °C. 1H NMR (400 MHz, CDCl3): δ =
4.6 (br. s, 1 H), 2.25 (septet, J = 7 Hz, 1 H), 1.6 (s, 3 H), 1.5 (s, 9 H),
1.15 (d, J = 7 Hz, 3 H), 1.05 (d, J = 7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.8, 120.2, 81.2, 55.1, 35.2, 28.2, 21.7, 17.6, 16.5 ppm.
1
129 °C. H NMR (400 MHz, CDCl3): δ = 7.41 (m, 2 H), 7.31 (m, 2 H),
7.00 (m, 1 H), 6.35 (bs, 1 H), 5.71 (bs, 1 H), 1.52 (s, 6 H) ppm. MS
(ES): m/z = 204 [M + H]+.
Benzyl N-(1-Cyano-1-methylethyl)carbamate (31):[48] 2-Amino-2-
methylpropanenitrile (700 mg, 8.32 mmol) was dissolved in tBuOMe
(5 mL) and the solution was then cooled down to 0 °C. Benzyl
chloroformate (1.71 g, 9.99 mmol, 1.2 equiv.) was added followed
by iPr2NEt (1.85 mL, 10.82 mmol, 1.3 equiv.), the reaction mixture
was then warmed up to room temperature and stirred for 20 h. The
reaction mixture was then washed with water (3 × 10 mL), followed
by saturated brine. The crude product was crystallized with a mix-
ture cyclohexane/tBuOMe, 90:10 to afford cyanoamide 31 (1.18 g,
65 % yield, white solid), m.p. 100–102 °C. 1H NMR (400 MHz, CDCl3):
δ = 7.45 (m, 5 H), 5.65 (s, 2 H), 4.9 (br. s, 1 H), 1.7 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 154.2, 133.7, 128.7, 128.5, 128.5, 120.9,
67.4, 47.1, 27.5 ppm. MS (ES): m/z = 241 [M + Na]+. HRMS (ESI+):
calcd. for C12H15N2O2 [M + H]+ 219.1134, found 219.1128.
N-(1-Cyano-1,2-dimethylpropyl)acetamide (43): This compound
was prepared following the procedure described for 6 using 2-
amino-2,3-dimethylbutanenitrile (2 g, 17.8 mmol) to afford cyano-
1
amide 43 (1.72 g, 63 % yield, yellow oil). H NMR (400 MHz, CDCl3):
δ = 6.31 (br. s, 1 H), 2.35 (septet, J = 7 Hz, 1 H), 2.05 (s, 3 H), 1.6 (s,
3 H), 1.15 (d, J = 7 Hz, 3 H), 1.05 (d, J = 7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.1, 119.9, 54.8, 34.4, 23.1, 21.0, 17.7, 16.3
ppm. HRMS (ESI+): calcd. for C8H15N2O [M + H]+ 155.1184, found
155.1180.
tert-Butyl N-(1-Cyano-1-methylpropyl)carbamate (46): This com-
pound was prepared following the procedure described for 39 us-
ing 2-amino-2-methylbutanenitrile (0.5 g, 5.1 mmol) to afford
cyanoamide 46 (982 mg, 100 % yield, yellow solid), m.p. 48–52 °C.
1H NMR (400 MHz, CDCl3): δ = 4.65 (br. s, 1 H), 1.95 (m, 2 H), 1.65
(s, 3 H), 1.5 (s, 9 H), 1.1 (t, J = 7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.7, 120.4, 81.2, 51.3, 32.8, 28.3, 24.8, 8.4 ppm. HRMS
(ESI+): calcd. for C10H19N2O2 [M + H]+ 199.1446, found 199.1442.
tert-Butyl N-(1-Cyano-1-methylethyl)carbamate (33):[49] 2-
Amino-2-methylpropanenitrile (500 mg, 5.95 mmol) was dissolved
in dichloromethane (5 mL) and iPrNEt (2.09 mL, 11.90 mmol,
2.0 equiv.) was then added, followed by Boc-anhydride (1.95 g,
8.90 mmol, 1.5 equiv.) and stirred at room temperature for about
N-(1-Cyano-1-methylpropyl)acetamide (49): This compound was
prepared following the procedure described for 6 using 2-amino-2-
methylbutanenitrile (0.5 g, 5.1 mmol) to afford cyanoamide 49
48 h. The reaction was then quenched with 2
M HCl, followed by a
solution of NaHCO3, and then saturated brine. The resulting organic
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1
(303 mg, 42 % yield, yellow oil). H NMR (400 MHz, CDCl3): δ = 5.5 mixtures there were usually very few, or no, observable by-products.
(br. s, 1 H), 2 (m, 2 H), 2 (s, 3 H), 1.65 (s, 3 H), 1.1 (t, J = 7 Hz, 3 The isomers were separated by chromatography. This resulted in a
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7, 120.1, 51.0, 32.2,
24.9, 23.3, 8.4 ppm. HRMS (ESI+): calcd. for C7H13N2O [M + H]+
141.1028, found 141.1024.
greater or smaller loss of material. The optimization of chromato-
graphic separations is described below, and as discussed, the best
solutions were not perfect.
N-[1-Cyano-2-(4-ethoxyphenyl)-1-methylethyl]acetamide (52):
This compound was prepared following the procedure described
for 35 using 2-amino-3-(4-ethoxyphenyl)-2-methylpropanenitrile
(1.02 g, 5 mmol) to afford cyanoamide 52 (1.178 g, 75 % corrected
yield for remnants of solvent, orange oil). 1H NMR (400 MHz, CDCl3):
δ = 7.15 (d, J = 10 Hz, 2 H), 6.85 (d, J = 10 Hz, 2 H), 5.5 (br. s, 1 H),
4.14 (q, J = 6 Hz, 2 H), 3.30 (d, J = 15 Hz, 1 H), 3.15 (d, J = 15 Hz, 2
H), 2.05 (s, 3 H), 1.95 (s, 3 H), 1.62 (s, 3 H), 1.4 (t, J = 6 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.5, 158.7, 131.5, 125.2, 120.2,
114.7, 63.5, 50.7, 43.0, 24.9, 23.5, 14.8 ppm. MS (EI): m/z = 247 [M +
H]+. HRMS (ESI+): calcd. for C14H19N2O2 [M + H]+ 247.1446, found
247.1445.
WARNING: Cyanide in the aqueous phase can be destroyed by oxid-
ation, for example with hypochlorite.[50] The aqueous phase is basic
and should not be acidified, which would generate HCN, which may
escape the vessel as a gas.
N-Isopropenylacetamide (11): Following the general procedure
with 6 (100 mg, 0.79 mmol) afforded enamide 11 (59 mg, 80 %
yield, white solid), m.p. 72–77 °C. 1H NMR (400 MHz, CDCl3): δ =
6.45 (br. s, 1 H), 5.4 (s, 1 H), 4.45 (s, 1 H), 2.1 (s, 3 H), 1.9 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.6, 137.5, 98.8, 24.5, 22.1 ppm.
MS (CI): 99 [M + H]+. HRMS (ESI+): calcd. for C5H10NO [M + H]+
100.0762; found 100.0767.
2,4-Dichloro-N-isopropenylbenzamide (20): Following the gen-
eral procedure with 19 (256 mg, 1 mmol) yielded a crude mixture,
which was purified by chromatography with a gradient of cyclohex-
ane/EtOAc, each containing 1 % Et3N to afford 20 (138 mg, 60 %
N-[2-(1,3-Benzodioxol-5-yl)-1-cyano-1-methylethyl]acetamide
(55): This compound was prepared following the procedure de-
scribed for 35 using 2-amino-3-(1,3-benzodioxol-5-yl)-2-methyl-
propanenitrile (0.41 g, 2 mmol) to afford cyanoamide 55 (0.380 g,
75 % corrected yield for remnants of solvent, orange oil). 1H NMR
(400 MHz, CDCl3): δ = 6.75 (m, 3 H), 5.95 (s, 2 H), 5.45 (br. s, 1 H),
3.3 (d, J = 15 Hz, 1 H), 3.15 (d, J = 15 Hz, 2 H), 2 (s, 3 H), 1.68 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7, 147.9, 147.4, 127.7,
124.1, 120.2, 110.6, 108.5, 101.2, 53.4, 43.4, 24.8, 23.4 ppm. MS (EI):
m/z = 247 [M + H]+. HRMS (ESI+): calcd. for C13H15N2O3 [M + H]+
247.1083, found 247.1075.
1
yield, white solid), m.p. 112–114 °C. H NMR (400 MHz, CDCl3): δ =
7.68 (s, 1 H), 7.48 (s, 2 H), 7.15 (br. s, 1 H), 5.6 (s, 1 H), 4.62 (s, 1 H),
2.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.1, 137.1, 136.5,
133.4, 131.5, 130.2, 128.7, 100.7, 22.1 ppm. MS (ES): 230 [M + H]+.
HRMS (ESI+): calcd. for C10H10Cl2NO [M + H]+ 230.0139, found
230.0139.
N-Isopropenyl-2,2-dimethylpropanamide (22): Following the
general procedure with 21 (256 mg, 1 mmol), yielded 22 (44 mg,
63 % yield, pale yellow solid), m.p. 66–70 °C. 1H NMR (400 MHz,
CDCl3): δ = 6.6 (br. s, 1 H), 5.42 (s, 1 H), 4.45 (s, 1 H), 1.92 (s, 3 H),
1.22 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.5, 137.5, 98.7,
39.6, 27.6, 22.3 ppm. HRMS (ESI+): calcd. for C8H16NO [M + H]+
142.1232, found 142.1229.
N-[1-Cyano-3-(4-methoxyphenyl)-1-methylpropyl]acetamide
(58): This compound was prepared following the procedure de-
scribed for 35 using 2-amino-4-(4-methoxyphenyl)-2-methylbutane-
nitrile (1.02 g, 5 mmol) to afford cyanoamide 58 (0.936 g, 58 %
corrected yield for remnants of solvent, pale yellow oil). 1H NMR
(400 MHz, CDCl3): δ = 7.15 (d, J = 10 Hz, 2 H), 6.85 (d, J = 10 Hz, 2
H), 5.55 (br. s, 1 H), 3.8 (s, 3 H), 2.8 (m, 2 H), 2.2 (m, 2 H), 1.9 (s, 3
H), 1.7 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.4, 158.3,
131.8, 129.3, 120.0, 114.2, 55.3, 50.6, 40.7, 29.8, 25.2, 23.3 ppm. MS
(EI): m/z = 247 [M + H]+. HRMS (ESI+): calcd. for C14H18N2O2 [M +
H]+ 247.1447, found 247.1445.
N-Isopropenyl-4-methoxybenzamide (24): Following the general
procedure with 23 (100 mg, 0.45 mmol) yielded 24 (87 mg, 80 %
corrected yield for remnants of solvent, pale yellow solid), m.p. 40–
1
43 °C. H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 10 Hz, 2 H), 7.05
(br. s, 1 H), 6.92 (d, J = 10 Hz, 2 H), 5.5 (s, 1 H), 4.55 (s, 1 H), 3.88 (s,
3 H), 1.6 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.8, 162.6,
162.4, 138.0, 131.4, 129.3, 113.8, 101.5, 55.4, 28.3 ppm. MS (ES): 192
[M + H]+. HRMS (ESI+): calcd. for C11H14NO2 [M + H]+ 192.1025,
found 192.1020.
N-{3-Cyano-1-[4-(trifluoromethyl)phenyl]-3-piperidyl}acetamide
(61): This compound was prepared following the procedure de-
scribed for 35 using 3-amino-1-[4-(trifluoromethyl)phenyl]piper-
idine-3-carbonitrile (1.34 g, 5 mmol) to yield cyanoamide 61
(643 mg, 25 % corrected yield for remnants of solvent, brown oil).
1H NMR (400 MHz, CDCl3): δ = 7.5 (d, J = 10 Hz, 2 H), 6.95 (d, J =
10 Hz, 2 H), 5.7 (br. s, 1 H), 4 (d, J = 15 Hz, 1 H), 3.5 (d, J = 15 Hz, 1
H), 3.3 (m, 2 H), 2.15 (t, J = 10 Hz, 2 H), 2.05 (s, 3 H), 1.9 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7, 152.5, 126.6, 126.5,
118.6, 116.0, 56.0, 49.9, 48.2, 33.2, 23.3, 21.0 ppm. MS (EI): m/z =
312 [M + H]+. HRMS (ESI+): calcd. for C15H17F3N3O [M + H]+
312.1324, found 312.1318.
N-Isopropenyl-4-(trifluoromethyl)benzamide (26): Following the
general procedure with 25 (115 mg, 0.45 mmol) yielded enamide
1
26 (90 mg, 84 % yield, pale yellow solid), m.p. 100–106 °C. H NMR
(400 MHz, CDCl3): δ = 7.88 (d, J = 10 Hz, 2 H), 7.70 (d, J = 10 Hz, 2
H), 7.1 (br. s, 1 H), 5.55 (s, 1 H), 4.62 (s, 1 H), 2.05 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 164.6, 137.4, 133.9, 138.4, 127.8, 127.6,
125.8, 122.2, 100.5, 22.1 ppm. MS (ES): 230 [M + H]+. HRMS (ESI+):
calcd. for C11H11F3NO [M + H]+ 230.0793, found 230.0788.
2,2,2-Trifluoro-N-isopropenylacetamide (28): Following the gen-
eral procedure with 27 (144 mg, 0.80 mmol). Starting material 27
was recovered.
General Procedure – Formation of Enamides
Cyanoamide was dissolved in dry THF (1
M) and NaOtBu (2 M in
THF, 3 equiv.) were added with stirring under argon. The reaction
was followed by TLC and/or HPLC-MS. After stirring and heating for
the time indicated, the mixture was diluted with tBuOMe and
1-Isopropenyl-3-phenylurea (30): Following the general proce-
dure with 29 (65 mg, 0.32 mmol). 1H NMR of the crude product
mixture indicated a complex mixture of products.
poured into a stirred mixture of tBuOMe, NaHCO3 (1 M), and ice. On
a large scale it was not necessary to dilute the reaction mixture
with tBuOMe before quenching. The organic phase was dried with
MgSO4 and evaporated to yield the enamide. Apart from isomeric
Benzyl N-Isopropenylcarbamate (32): Following the general pro-
cedure with 31 (70 mg, 0.32 mmol). NMR of the crude product
showed a complex mixture of products.
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tert-Butyl N-Isopropenylcarbamate (34): Following the general
procedure with 33 (92 mg, 0.5 mmol) yielded 34 (66 mg, 78 % yield,
pale yellow oil). H NMR (400 MHz, CDCl3): δ = 5.8 (br. s, 1 H), 5.08
N-[(E)-1-Methylprop-1-enyl]acetamide (50E): 1H NMR (400 MHz,
CDCl3): δ = 6.4 (br. s, 1 H), 5.7 (q, J = 7 Hz, 1 H), 2.05 (s, 3 H), 1.9 (s,
3 H), 1.65 (s, 3 H) ppm.
1
(s, 1 H), 4.27 (s, 1 H), 1.87 (s, 3 H), 1.48 (s, 9 H) ppm.
N-[(Z)-1-Methylprop-1-enyl]acetamide (50Z): 1H NMR (400 MHz,
CDCl3): δ = 6.4 (br. s, 1 H), 5 (q, J = 7 Hz, 1 H), 2.1 (s, 3 H), 2 (s, 3
H), 1.55 (s, 3 H) ppm.
N-(1-Methylenepropyl)acetamide (51): 1H NMR (400 MHz, CDCl3):
δ = 5.75 (br. s, 1 H), 4.74 (q, J = 6.85 Hz, 1 H), 2 (s, 3 H), 1.55 (d, J =
6.85 Hz, 3 H), 1.45 (s, 9 H) ppm.
N-(1-Methoxy-2,2,6,6-tetramethyl-3H-pyridin-4-yl)acetamide
(36): Following the general procedure with 35 (253 mg, 1 mmol)
yielded 36 (217 mg, 96 % yield, white solid), m.p. 109–112 °C. 1H
NMR (400 MHz, CDCl3): δ = 6.2 (br. s, 1 H), 6.85 (s, 1 H), 3.53 (s, 3
H), 2.45 (d, J = 15 Hz, 1 H), 2 (s, 3 H), 1.95 (d, J = 15 Hz, 1 H), 1.3
(br. s, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.4, 127.2, 119.4,
65.4, 59.7, 58.4, 42.4, 32.6, 30.1, 24.5, 23.1, 21.3 ppm. HRMS (ESI+):
calcd. for C12H23N2O2 [M + H]+ 227.1760, found 227.1759.
53 and 54, a: At room temperature. Following the general proce-
dure with 52 (246 mg, 1 mmol) yielded 188 mg (86 % yield) of a
brown oil (ratio 53E/53Z/54 = 27:20:53). This was chromatographed
with a gradient of EtOAc/cyclohexane, with each component con-
taining 1 % Et3N, to yield 83 mg (38 %) of a mixture of 53Z/54 in a
28:72 ratio, and 36 mg (16 %) of 53E as a yellow solid. A sample of
the mixture of 53Z/54 was separated by RP-HPLC to yield 10 mg of
53Z and 2 mg of 54.
N-(1-Cyclopropylvinyl)acetamide (38): Following the general pro-
cedure with 37 (152 mg, 1 mmol) yielded 38 (97 mg, 77 % yield,
1
orange oil). H NMR (400 MHz, CDCl3): δ = 6.6 (br. s, 1 H), 5.62 (s, 1
H), 4.55 (s, 1 H), 2.05 (s, 3 H), 0.7 (m, 2 H), 0.55 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.5, 142.0, 97.4, 21.2, 10.7, 9.3 ppm.
40 and 41: Following the general procedure with 39 (500 mg,
2.4 mmol) yielded 40 (340 mg, 78 % yield, pale yellow oil). Small
signals were observed in the 1H NMR spectrum, which are tenta-
tively assigned to 41 integrating as a 4 % contaminant.
b: At 60 °C As above but heating the reaction mixture for 16 h at
60 °C before workup yielded 214 mg (98 %) of a 2:1 E/Z mixture
which was chromatographed with a gradient of EtOAc/cyclohexane,
with each component containing 1 % Et3N, to yield 53Z (92 mg,
42 % yield) and 53E (50 mg, 23 % yield).
tert-Butyl N-(1,2-Dimethylprop-1-enyl)carbamate (40): 1H NMR
(400 MHz, CDCl3): δ = 5.5 (br. s, 1 H), 1.9 (s, 3 H), 1.7 (s, 3 H), 1.65
(s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.0,
124.0, 122.6, 79.4, 28.3, 19.6, 19.3, 17.3 ppm. HRMS (ESI+): calcd. for
C10H20NO2 [M + H]+ 186.1494, found 186.1492.
N-[(Z)-2-(4-Ethoxyphenyl)-1-methylvinyl]acetamide (53Z): M.p.
1
111–118 °C. H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 10 Hz, 2 H),
6.95 (br. s, 1 H), 6.88 (d, J = 10 Hz, 2 H) 5.65 (s, 1 H), 4.05 (q, J =
10 Hz, 2 H), 2.28 (s, 3 H), 2 (s, 3 H), 1.4 (t, J = 10 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.5, 157.7, 133.1, 129.6, 128.1, 114.8,
63.5, 24.3, 21.4, 14.8 ppm. MS (EI): 219 [M+ H]+. HRMS (ESI+): calcd.
for C13H18NO2 [M + H]+ 220.1337, found 220.1331.
1
tert-Butyl N-(2-Methyl-1-methylenepropyl)carbamate (41): H
NMR (400 MHz, CDCl3): δ = 5.7 (br. s, 1 H), 5.3 (s, 1 H), 4.4 (s, 1 H),
1.45 (s, 9 H) ppm. Some peaks were presumably occluded by the
much larger ones of 40.
N-[(E)-2-(4-Ethoxyphenyl)-1-methylvinyl]acetamide (53E): M.p.
1
102–106 °C. H NMR (400 MHz, CDCl3): δ = 7.13 (d, J = 11 Hz, 2 H),
44 and 45: Following the general procedure with 43 (515 mg,
3.3 mmol) yielded 44/45 in a ratio of 7:93 (340 mg, 94 % yield).
6.88 (s, 1 H), 6.84 (d, J = 11 Hz, 2 H), 4.02 (q, J = 7 Hz, 2 H), 2.10 (s,
3 H), 2.08 (s, 3 H), 1.41 (t, J = 10 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 129.4, 114.4, 63.5, 14.8 ppm. MS (EI): 219 [M+ H]+. HRMS
(ESI+): calcd. for C13H18NO2 [M + H]+ 220.1337, found 220.1332.
N-{1-[(4-Ethoxyphenyl)methyl]vinyl}acetamide (54): 1H NMR
(400 MHz, CDCl3): δ = 7.15 (d, J = 10 Hz, 2 H), 6.85 (d, J = 10 Hz, 2
H), 6.25 (br. s, 1 H), 5.7 (s, 1 H), 4.65 (s, 1 H), 4.05 (q, J = 10 Hz, 2 H),
3.4 (s, 2 H), 1.95 (s, 3 H), 1.4 (t, J = 10 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 131.6, 130.1, 114.2, 63.4, 14.9 ppm. MS (EI):
219 [M+ H]+. HRMS (ESI+): for C13H18NO2 [M + H]+ calcd. 220.1337,
found 220.1334.
N-(1,2-Dimethylprop-1-enyl)acetamide (44): 1H NMR (400 MHz,
CDCl3): δ = 6.4 (br. s, 1 H), 5.6 (s, 1 H), 2.3 (septet, J = 7 Hz, 1 H),
2.05 (s, 3 H), 1.1 (d, J = 7 Hz, 6 H) ppm.
N-(2-Methyl-1-methylenepropyl)acetamide (45): 1H NMR
(400 MHz, CDCl3): δ = 6.9 (br. s, 1 H), 2.05 (s, 3 H), 1.75 (s, 3 H), 1.7
(s, 3 H), 1.65 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.0,
146.7, 96.8, 33.6, 21.0, 18.1 ppm. HRMS (ESI+): calcd. for C7H14NO
[M + H]+ 128.1075, found 128.1074.
47 and 48: Following the general procedure with 46 (500 mg,
2.5 mmol) yielded 47Z/48 in a ratio of 94:6 (347 mg, 80 % yield,
pale yellow oil).
56 and 57: Following the general procedure with 57 (123 mg,
0.5 mmol) yielded 135 mg of product containing 56E/56Z/57 in a
ratio of 27:20:53, which was chromatographed with a gradient of
EtOAc/cyclohexane, with each component containing 1 % Et3N, to
yield a mixture 56Z/57 in a 20:80 ratio (41 mg, 37 % yield) and 56Z
(15 mg, 14 % yield).
tert-Butyl N-[(Z)-1-Methylprop-1-enyl]carbamate (47Z): 1H NMR
(400 MHz, CDCl3): δ = 5.75 (br. s, 1 H), 4.74 (q, J = 6.85 Hz, 1 H), 2
(s, 3 H), 1.55 (d, J = 6.85 Hz, 3 H), 1.45 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.1, 132.0, 109.0, 79.6, 28.3, 21.0, 11.6 ppm.
N-[(Z)-2-(1,3-Benzodioxol-5-yl)-1-methylvinyl]acetamide (56Z):
1H NMR (400 MHz, CDCl3): δ = 6.95 (br. s, 1 H), 6.75 (m, 3 H), 5.95
(s, 2 H), 5.6 (s, 1 H), 2.28 (s, 3 H), 2 (s, 3 H) ppm. MS (EI): 219 [M +
H]+.
tert-Butyl N-(1-Methylenepropyl)carbamate (48): 1H NMR
(400 MHz, CDCl3): δ = 5.65 (br. s, 1 H), 5.2 (s, 1 H), 4.3 (s, 1 H), 1.45
(s, 9 H) ppm. Some peaks were obscured by the much larger ones
of 47Z.
N-[(E)-2-(1,3-Benzodioxol-5-yl)-1-methylvinyl]acetamide (56E):
1H NMR (400 MHz, CDCl3): δ = 6.90 (s, 1 H), 6.67–6.79 (m, 3 H), 6.56
(br. s, 1 H), 5.93 (s, 2 H), 2.08 (s, 3 H), 2.06 (s, 3 H) ppm. MS (EI): 219
[M + H]+.
50 and 51: This compound was prepared following the procedure
described for 22 using substrate cyanoamide 49 (67 mg,
0.47 mmol) to afford 50E/50Z/51 in a 7:11:82 ratio (38 mg, 70 %
yield, pale yellow oil). Chromatography with a gradient of EtOAc/ N-[1-(1,3-Benzodioxol-5-ylmethyl)vinyl]acetamide (57): 1H NMR
cyclohexane, with each component containing 1 % Et3N, yielded
18 mg of 51 and 1 mg of a mixture of 50E/50Z in ratio of 58:42.
(400 MHz, CDCl3): δ = 6.75 (m, 3 H), 6.3 (br. s, 1 H), 5.95 (s, 2 H), 5.7
(s, 1 H), 4.65 (s, 1 H), 1.95 (s, 3 H) ppm. MS (EI): 219 [M + H]+.
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59 and 60: Following the general procedure with 58 (246 mg,
1 mmol) yielded 59E/59Z/60 in a ratio of 4:5:40 (197 mg, 90 %
yield). Chromatography with a gradient of EtOAc/cyclohexane, with
each component containing 1 % Et3N, afforded 60 (88 mg, 40 %
yield) and a 50:50 mixture of 59E/59Z (10 mg, 5 % yield).
a stirred mixture of NaHCO3 (1
M
, 1 L) and tBuOMe (300 mL) to
which ice had been added to bring the temperature down to ap-
prox. 5–10 °C. There was a weak exotherm and the mixture did not
quite reach room temperature. The ethereal phase was dried with
MgSO4, and evaporated down to yield 45 (18.17 g, 85 % yield), with
a
1H NMR spectrum identical to that obtained from the 3 mmol
N-[(Z)-3-(4-Methoxyphenyl)-1-methylprop-1-enyl]acetamide
reaction. Although it was not crystalline, 45 was stable for several
months at 4 °C in the refrigerator.
1
(59Z): H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 10 Hz, 2 H), 6.85
(d, J = 10 Hz, 2 H), 6.6 (br. s, 1 H), 5.15 (s, 1 H), 3.25 (d, J = 10 Hz, 1
H), 2.00 (s, 3 H) ppm. MS (EI): 219 [M + H]+.
Attempts Using Modified Literature Methods
N-(1-Methyl-1-{[2-(trifluoromethyl)benzoyl]amino}ethyl)-2-(tri-
fluoromethyl)benzamide (14): A solution of acetone (10 g,
172 mmol) in toluene (40 mL) was stirred at 0 °C under argon.
N-[(E)-3-(4-Methoxyphenyl)-1-methylprop-1-enyl]acetamide
(59E): H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 10 Hz, 2 H), 6.85
1
(d, J = 10 Hz, 2 H), 6.6 (br. s, 1 H), 5.9 (s, 1 H), 3.35 (d, J = 10 Hz, 1
H), 2 (s, 3 H) ppm. MS (EI): 219 [M + H]+.
Ammonia (7
M in MeOH, 36.9 mL, 258 mmol, 1.5 equiv.) and then
Ti(OiPr)4 (108 mL, 100.9 g, 344.5 mmol, 2 equiv.) were added, the
mixture warmed to room temperature, stirred for 18 h and cooled
again to 0 °C. Triethylamine (97 mL, 70.4 g, 688 7 mmol, 4 equiv.)
and then 2-(trifluoromethyl)benzoyl chloride (51.23 mL, 72.5 g,
344 mmol, 2 equiv.) were added. During the addition of the acid
chloride a thick suspension was formed, so more toluene was
added to keep the mixture mobile. After stirring for 2 h at room
temperature, N,N,N′,N′-tetrakis(2-hydroxyethyl)ethylenediamine
(75.6 mL, 85.4 g, 361 mmol, 2.1 equiv.) in a little toluene was added,
the mixture was stirred at 60 °C for 15 min, cooled to room temper-
N-[3-(4-Methoxyphenyl)-1-methylenepropyl]acetamide (60): 1H
NMR (400 MHz, CDCl3): δ = 7.1 (d, J = 10 Hz, 2 H), 6.85 (d, J = 10 Hz,
2 H), 6.2 (br. s, 1 H), 5.5 (s, 1 H), 4.5 (s, 1 H), 3.7 (s, 3 H), 2.75 (t, J =
7 Hz, 2 H), 2.43 (t, J = 7 Hz, 2 H), 1.95 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.6, 158.0, 141.0, 133.0, 129.3, 113.9, 99.2,
55.3, 37.8, 33.7, 22.6 ppm. MS (EI): 219 [M + H]+. HRMS (ESI+): calcd.
for C13H18NO2 [M + H]+ 220.1338, found 220.1336.
62 and 63: Following the general procedure with 61 (264 mg,
0.848 mmol) yielded a 55:45 mixture of 62/63 (216 mg, 90 % yield).
This mixture was chromatographed using a gradient of EtOAc/cy-
clohexane, with each component containing 1 % Et3N, to yield 62
(75 mg, 31 %) and a 40:60 mixture of 62/63 (62 mg).
ature, then poured into a mixture of water (500 mL) and 7
M NH3
(aq.). The mixture was extracted with EtOAc, and the organic phase
washed with water and brine, dried with Na2SO4 and evaporated
to give a semi-solid mass. This was stirred with ether and the solid
filtered off. The filtrate was evaporated to yield 41 g of an oil, which
appeared, upon NMR analysis, to be a complex mixture of products
containing little or no 15. The solid was a mixture of 14 and 2-
(trifluoromethyl)benzamide. This mixture was chromatographed
with EtOAc/cyclohexane to yield 2.3 g (3 %) of 14 as white crystals,
N-{1-[4-(Trifluoromethyl)phenyl]-3,6-dihydro-2H-pyridin-5-
yl}acetamide (62): 1H NMR (400 MHz CDCl3): δ = 7.47 (d, J = 10 Hz,
2 H), 6.92 (d, J = 10 Hz, 2 H), 6.63 (br. s, 1 H), 5.42 (s, 1 H), 3.98 (s,
2 H), 3.45 (t, J = 5 Hz, 2 H), 2.82 (br. s, 2 H), 2.06 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.7, 152.2, 131.5, 126.5, 126.1, 120.1,
114.0, 112.1, 48.4, 44.6, 24.2, 23.7 ppm. MS (CI): 285 [M+ H]+. HRMS
(ESI+): calcd. for C14H16F3N2O [M + H]+ 285.1209, found 285.1206.
1
m.p. 214–216 °C. H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 9.0 Hz,
2 H), 7.55 (m, 6 H), 6.59 (br. s, 2 H, NH), 1.90 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 167.7, 135.8, 132.1, 130.0, 128.7, 125.0, 120.0,
66.8, 27.0 ppm. MS (CI): 441 [M + Na]+. HRMS (ESI+): calcd. for
C19H17F6N2O2 [M + H]+ 419.1189, found 419.1186.
N-{1-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-2H-pyridin-5-
yl}acetamide (63): 1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 10 Hz,
2 H), 7.30 (s, 1 H), 6.90 (d, J = 10 Hz, 2 H), 6.28 (br. s, 1 H), 3.51 (t,
J = 7 Hz, 2 H), 2.29 (t, J = 7 Hz, 2 H), 2.08 (s, 3 H), 2.05 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.5, 148.5, 128.8, 127.0, 123.1,
121.8, 120.6, 120.3, 44.4, 25.1, 24.0, 21.8 ppm. MS (CI): 285 [M+
H]+. HRMS (ESI+): calcd. for C14H16F3N2O [M + H]+ 285.1209, found
285.1204.
N-Isopropenyl-2-(trifluoromethyl)benzamide (15): A solution of
KOtBu in THF (1
M, 4.4 mL, 4.39 mmol, 1.2 equiv.) was added to a
solution of 14 (1.53 g, 3.66 mmol) in THF (10 mL). After 16 h at
room temperature the mixture was cooled to 0 °C, acetic acid
(0.5 mL) added, and the mixture shaken between EtOAc and water,
washed with a 1
M solution of NaHCO3, brine, dried with MgSO4
65 and 66: Following the general procedure with 64 (386 mg,
1 mmol) yielded crude 65 and 66 (487 mg), which was chromato-
graphed with a gradient of EtOAc/cyclohexane, with each compo-
nent containing 1 % Et3N, to yield 65/66 in a ratio of 80:20 (64 mg,
18 % yield).
and evaporated to yield 1.48 g of crude product which contained
about 20 % starting material. Chromatography with EtOAc/cyclo-
hexane yielded 451 mg (54 %) N-isopropenyl-2-(trifluoro-
methyl)benzamide, m.p. 95–98 °C. 1H NMR (400 MHz, CDCl3): δ =
7.72 (d, J = 9 Hz, 1 H), 7.60 (m, 3 H), 6.72 (br. s, 1 H, NH), 5.53 (s, 1
H), 4.61 (s, 1 H) 1.99 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
165.8, 137.4, 132.1, 130.1, 128.6, 126.3, 100.5, 82.7, 28.3, 21.9 ppm.
MS (CI): 230 [M + H]+. HRMS (ESI+): calcd. for C11H11F3NO [M + H]+
230.0787, found 230.0788.
N-[(Z)-2-Hydroxy-1-methyl-vinyl]-4-(trifluoromethyl)benzamide
(65): 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 10 Hz, 2 H), 7.85
(br. s, 1 H), 7.72 (d, J = 10 Hz, 2 H), 5.78 (s, 2 H), 2.18 (s, 3 H), 0.96
(s, 9 H), 0.18 (s, 6 H) ppm. MS (CI): 360 [M+ H]+.
N-[1-(Hydroxymethyl)vinyl]-4-(trifluoromethyl)benzamide (66):
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 10 Hz, 2 H), 7.72 (d, J =
10 Hz, 2 H), 7.11 (s, 1 H), 6.86 (br. s, 1 H), 5.94 (s, 1 H), 4.73 (s, 1 H),
4.29 (s, 2 H), 0.96 (s, 9 H), 0.18 (s, 6 H) ppm. MS (CI): 360 [M+ H]+.
Initial Base Screen to Establish Proof of Principle: Cyanoamide
19 (256 mg, 1 mmol) was dissolved in dry THF (1 mL) under argon,
and 1 equiv. of the bases [BuLi (1.6
iPrMgCl (1.3 in THF, 0.769, 1 mmol); KOtBu (1
1 mmol); KOtBu (1 in tBuOH) (1 mL, 1 mmol)] was added. After
M
in hexane, 0.625 mL, 1 mmol);
M
M
in THF, 1 mL,
Synthesis of Enamide 45 on 168 mmol Scale: A solution of
M
NaOtBu (2
M
in THF, 252 mL, 505 mmol, 3 equiv.) was added in one
30 min, TLC showed traces of a less polar product. Silver sulfate
(155 mg, 0.5 mmol) was then added and the reaction mixtures were
left for about 48 h at room temperature. Following reaction, the
portion to a solution of 43 (25 g, 168 mmol) in THF (77mL) with
stirring at room temperature. There was no exotherm. During the
addition a smeary precipitate appeared, but after complete addition
a clear solution was formed. After 60 h the mixture was poured into
mixtures were diluted with EtOAc and shaken with a 1
M solution
of NaHCO3, washed with a saturated solution of brine, dried with
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MgSO4, and concentrated. The crude product mixture containing
20 was analyzed by H NMR spectroscopy (Table 3).
Screening of Bases: Cyanoamide 19 (100 mg, 0.39 mmol) was dis-
solved in dry THF under argon and 3 equiv. of base were added
and stirred at room temperature. The reaction mixtures were left
for about 48 h. Reactions were then washed with a saturated solu-
tion of brine, dried with MgSO4, and concentrated and analyzed by
1H NMR spectroscopy (Table 7).
1
Table 3. Initial screen of four strong bases.
Base
SM remaining [%]
Product yield [%]
nBuLi
iPrMgCl
100
92
0
8
KOtBu in THF
KOtBu in tBuOH
74
78
26
22
Table 7. Effect of base on yield and conversion.
Base
pKa
SM remaining [%] Product yield [%]
nBuLi
51
decomp.
100
decomp.
decomp.
100
0
0
0
0
0
Screening of Silver Salts: Cyanoamide 19 (256 mg, 1 mmol) was
dissolved in dry THF (1 mL) under argon and KOtBu (1 in THF,
Schwesinger's base P4
iPrMgCl
AgHMDS
Schwesinger's base BEMP
KOtBu
DBU
42.7
≈ 40
–
27.6
19
M
2 mL, 2 mmol) was added. Silver salts [Ag2SO4 (232 mg, 0.75 mmol);
AgNO3 (253 mg, 1.5 mmol); AgOTs (416 mg, 1.5 mmol); AgSbF6
(513 mg, 1.5 mmol); AgO2CCF3 (330 mg, 1.5 mmol); AgOTf (384 mg,
1.5 mmol)] were then added and the reaction mixture was stirred
at room temperature overnight. Reactions were then were diluted
13
100
87
0
≈ 12
with EtOAc and agitated with a 1
M solution of NaHCO3. They were
then washed with a saturated solution of brine, dried with MgSO4,
concentrated and analyzed by H NMR spectroscopy (Table 4).
Screening of tert-Butoxide Counterions: Cyanoamide 19 (256 mg,
1 mmol) was dissolved under argon in enough dry THF to ensure
that the concentration of substrate and base would be the same in
all cases. Then, 3 equiv. of base [LiOtBu (solid) (96 mg, 1.17 mmol);
1
Table 4. Effect of silver salts on conversion and yields of reaction.
NaOtBu (2
M in THF, 0.59 mL, 1.17 mmol); KOtBu (1 M in THF,
Silver salt
Equiv.
0.75
SM remaining [%]
Product yield [%]
1.17 mL, 1.17 mmol)] were added and stirred at room temperature
overnight. Reactions were then washed with a saturated solution
of brine, dried with MgSO4, concentrated, and analyzed by 1H NMR
spectroscopy. The extents of reaction were determined by integrat-
ing the peaks identified in HPLC-MS analyses; peaks were not cali-
brated (Table 8, Figure 1).
Ag2SO4
AgNO3
AgOTs
AgSbF6
AgO2CCF3
AgOTf
72
71
100
100
100
100
28
29
0
0
0
1.5
1.5
1.5
1.5
1.5
0
Table 8. Effect of tert-butoxide counterion on yield and conversion.
Screening of Other Lewis Acids: Cyanoamide 19 (100 mg,
0.39 mmol) was dissolved in dry THF (1 mL) in a dried flask under
argon and DBU (0.116 mL, 0.78 mmol) was added. To the reaction
was then added 2 equiv. of the Lewis acids [AgOTf (200 mg,
0.78 mmol); CuCl (77 mg, 0.78 mmol); ZnCl2 (106 mg, 0.78 mmol)]
and the reaction stirred at room temperature overnight. Reaction
contents were then washed with a saturated solution of brine, dried
Base
SM remaining [%]
Product yield [%]
LiOtBu
NaOtBu
KOtBu
80
13
14
20
87
86
1
with MgSO4, concentrated, and analyzed by H NMR spectroscopy
(Table 5).
Table 5. Effect of added Lewis acid on the yield and conversion.
Lewis acid
SM remaining [%]
Product yield [%]
AgOTf
CuCl
ZnCl2
100
100
100
0
0
0
Screening of Solvents: Cyanoamide 19 (256 mg, 1 mmol) was dis-
solved in dry solvent (1 mL) under argon and KOtBu (1 in THF,
M
2 mL, 2 mmol) was added. Silver sulfate (232 mg, 0.75 mmol) was
then added and stirred at room temperature for about 48 h. The
reaction contents were then washed with a saturated solution of
brine, dried with MgSO4, and concentrated and analyzed by 1H NMR
spectroscopy (Table 6).
Figure 1. Effect of tert-butoxide counterion on reaction yield as a function of
reaction time.
Amount of KOtBu: Cyanoamide 19 was treated in parallel reactions
with various amounts of KOtBu solution as described above. The
reactions were followed by HPLC-MS. The peaks were not calibrated,
so the results are given in peak areas, rather than mol. When using
less than 3 equiv. of base, the reaction was slow or did not proceed
at all. The results obtained for reactions using 3, 5 and 7 equiv. of
base show a similar reaction profile (Figure 2).
Table 6. Effect of solvent on yield and conversion.
Solvent
KOtBu 1
M
in
SM remaining [%] Product yield [%]
THF
THF
DMF
Acetonitrile
THF
tBuOH
THF
59
90
100
100
41
10
0
THF
0
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then split into 5 batches. Four batches were dissolved in DCM and
adsorbed onto Isolute®. These were then poured on top of the col-
umn with the respective stationary phase shown in the Table and
eluted with the solvent mixture shown. The remaining batch was
distilled in a kugelrohr apparatus. The fractions in the eluent/distil-
late were examined by 1H NMR spectroscopy, and compared with
the spectrum of the crude product to evaluate the extent of decom-
position during purification. There was, in all cases, some decompo-
sition, and furthermore when the purification was repeated using
the same method, the extent of decomposition varied from column
to column, seemingly due to small changes in procedure we were
unable to control. However, a column on silica deactivated by a
small amount of Et3N in the eluent, in general, gave the best results.
Chromatography of other enamides on silica was more or less suc-
cessful using these conditions (Table 10).
Figure 2. Results of varying equivalents of KOtBu on the reaction as a function
of time.
Screening of Workup Conditions: This screen was done with a
crude mixture from the reaction of a benzylcarbamatonitrile 77,
which led to a mixture of products (see the discussion of 32, Table 1
in the main text of the publication). The NMR of the crude reaction
mixture showed peaks tentatively assigned to isomers of the de-
sired product, so a systematic study was done to find mild workup
conditions and purification conditions. Although the products were
never obtained in pure form, it was possible to examine the spectra
of the various fractions to evaluate decomposition, and the results
are worth reporting here, because ketone-derived enamides are so
sensitive that a guide to those working in the area is valuable
(Scheme 9).
Table 10. Stability of enamide mixtures to various purification methods.
Purification
Solvent
Product purified
decomposition
Silica
cyclohexane/EtOAc
some
Silica
Alumina
Florasil®
Reverse phase water/MeCN
HPLC
cyclohexane/EtOAc/Et3N (0.1 %)
cyclohexane/EtOAc
cyclohexane/EtOAc
some
some
variable results
yes
Kugelrohr
–
some
Deuteration of the NH of Amides 79, 6, and 11: Using any of the
three amides (79, 6, or 11), 0.36 mmol of substrate was dissolved
in CDCl3 (1 mL). CD3OD (20 μL, 17.8 mg, 0.488 mmol, 1.35 equiv.)
was added to each, and then either DBU (22 μL, 0.15 mmol,
0.4 equiv.), or K2CO3 (21 mg, 0.15 mmol, 0.4 equiv.) or no base was
added and a measurement made about 30 min later. The NH peak
was integrated against the other signals and the loss of the NH
signal recorded. The NH signal in 79 did not exchange completely
with either base, the corresponding signal for 6 exchanged with
DBU but not with K2CO3. The NH signal of 11 exchanged com-
pletely with both bases (Table 11).
Scheme 9. Conversion of 77 to an enamide mixture used to evaluate workup
and purification conditions.
78: NaOtBu (2
M in THF, 3.9 mL, 7.8 mmol) was added to a solution
of benzyl N-(1-cyano-1,2-dimethylpropyl)carbamate 77 (640 mg,
2.6 mmol) in dry THF (3 mL) under argon at room temperature and
stirred for 25 h. The mixture was then diluted with tBuOMe (10 mL),
split into five batches and each batch quenched in a different man-
ner. Each quenched mixture was washed with saturated brine, and
the organic layer dried with magnesium sulfate and concentrated.
The quenching reagent had an influence on the stability of the
crude reaction mixture. The NMR of a CDCl3 solution of the crude
product was measured immediately, and again after 3 d. The data
depicting the impact of quenching conditions is summarized below
(Table 9).
Table 11. Relative rates of NH deuteration under basic conditions.
Table 9. Effects of quenching agents on the stability of crude enamide mix-
tures.
Quenching
reagent
Equiv.
After workup
decomposition
3 d in CDCl3
decomposition
NaHCO3 (s)
5
no
no
no
some
no
some
some
yes
yes
yes
1
M
NaHCO3 (aq.)
NH4Cl (s)
NH4Cl (aq.)
Acetic acid
excess
5
excess
5
1
M
Screening of Purification Methods: 78: Benzyl N-(1-cyano-1,2-di-
methylpropyl)carbamate (77) was treated with NaOtBu as described
above and worked up with a 1
Reaction of NaOtBu with Aldehyde-Derived Cyanoamides –
Synthesis of Imidate 71: A solution of NaOtBu in THF (2
3 mmol) was added to a solution of 3,5-dichloro-N-(1-cyanoprop-
spectra were recorded on the crude product mixture, which was yl)benzamide 70 (257 mg, 1 mmol) in THF (0.5 mL). After 2 h at
M, 1.5 mL,
M
solution of NaHCO3. 1H NMR
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Burgos, B. Bertrand, S. Roussiasse, J.-F Pluvie, S. Blanchet, J. Martin, F.
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room temperature, TLC showed very little reaction so the mixture
was heated to 60 °C for 3 h, then cooled and poured into NaHCO3
(1
M)/ice/tBuOMe. The phases were separated, dried with MgSO4,
and evaporated to yield 266 mg of a mixture of products contain-
ing, according to the NMR of starting material, peaks that may be
assigned to E and Z products and imidate 71. This mixture was
chromatographed over silica gel with a gradient of EtOAc/hexane
to yield 58 mg of a fraction containing 71 as deemed by NMR
spectroscopy. The spectral data consistent with 71 also showed
peaks consistent with the Z-enamide. Trituration of this sample six
times with cyclohexane ultimately gave 25 mg of pure 71, m.p.
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1
137–142 °C. H NMR (400 MHz, CDCl3): δ = 7.61 (s, 2 H), 7.48 (s, 1
H), 6.32 (br. s, 1 H) 5.47 (m, 1 H), 1.65 (m, 2 H), 1.21 (s, 9 H), 0.94 (t,
J = 8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.1, 137.5
135.6, 131.5, 125.7, 76.5, 75.0, 30.7, 28.3, 9.3 ppm.
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other than silver salts similarly failed to assist the reaction. Treatment of
19 with excess DBU in the presence of AgOTf, CuCl or ZnCl2 produced
no reaction.
[32] When planning a synthetic route it is helpful to choose protecting
groups associated with product crystallinity.
[33] C. Sun, S. M. Weinreb, Synthesis 2006, 3585.
[34] On the basis of pKa data compiled by R. Williams: http://re-
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[37] Similar results were obtained for the reaction of another aldehyde-de-
rived enamide, see the Exp. Section.
The authors thank Syngenta chemists Helmars Smits and Far-
han Bou Hamdan for discussions and careful review and correc-
tions of the manuscript.
Keywords: Synthetic methods · Regioselectivity ·
Elimination · Protecting groups · Cyanoamides · Enamides
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Published Online: ■
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Enamide Synthesis
G. Coussanes, K. Gaus,
A. C. O'Sullivan* ............................... 1–14
The Synthesis of Ketone-Derived En-
amides by Elimination of HCN from
Cyanoamides
Treatment of ketone-derived cyano- all results and observations, is pro-
amides with NaOtBu leads to en- posed. The Z geometry of the product
amides in a simple, scalable, and inex- enamide is highly favoured, and the
pensive one-step operation in good regioselectivity can be directed by
yields. An E1cB mechanism, which fits choice of the protecting group
DOI: 10.1002/ejoc.201600638
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim