Synthesis and Reactivity Profile of Ylidenemalononitrile Enamines and Their Ester Analogs Towards Electrophiles and Nucleophiles

Article abstract of DOI:10.1021/acs.joc.5b01169

Herein, we describe the synthesis and reactivity of enamines derived from ylidenemalononitriles and ylidenecyanoacetates. The enamine scope was expanded by (1) increasing yields of aldehyde-derived ylidenemalononitriles, (2) incorporating silyl functional

Full text of DOI:10.1021/acs.joc.5b01169

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“
Synthesis and reactivity profile of ylidenemalononitrile enamines and their ester analogs
towards electrophiles and nucleophiles”
†
†
Ashley R. Longstreet , Daniel Rivalti , and D. Tyler McQuade*
Authors contributed equally to this article
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†
Address: Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way,
Tallahassee, FL 32306, United States
Email: D. Tyler McQuade* ꢀ mcquade@chem.fsu.edu
* Corresponding author
Abstract: Herein, we describe the synthesis and reactivity of enamines derived from
ylidenemalononitriles and ylidenecyanoacetates. The enamine scope was expanded by: (1)
increasing yields of aldehydeꢀderived ylidenemalononitriles, (2) incorporating silyl
functionalities, and (3) using other amide acetals to expand the substitution patterns of pyridines
resulting from enamine cyclization. In addition, methods to produce αꢀpyrones and
polysubstituted pyridines from both ylidenemalononitriles and ylidenecyanoacetates is described.
Organozinc
reagents
Organohalides
R1
N
R1
EWG
R
E-X
microwaves
R2
CN
R'
NC
R'-ZnX
3
E
CN
O
R1
N
R2 = H
EWG = CN
O
R2
2
EWG = CO R
H-X, AcOH
EWG = CN, CO R
2
Brønsted-Lowry Acids
R1
R2
R3
EWG
X
N
Introduction
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Enamines are intermediates in classic chemical transformations such as Stork enamine synthesis
and Mannichꢀtype reactions due to their unique nucleophilic and electrophilic properties. The
synthesis and applications of pushꢀpull enamines, unlike classic enamines, has a more modest
history. Early reports described reactions of enol ethers with secondary amines to yield pushꢀpull
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enamines (Scheme 1, eq 1). Entry into this class of enamine was later simplified by producing
them directly from alkylidenemalononitriles and cyanoacetates by reaction with a C source,
1
typically Vilsmeier reagent or N,Nꢀdimethylformamide dimethyl acetal (DMFꢀDMA) (Scheme 1,
2
eq 2). Aside from the Pinner and amineꢀinitiated cyclizations to polysubstituted azaheterocycles
1,3a,2,3bꢀh
as shown in Scheme 1 (eq 2),
the reactivity of pushꢀpull enamines towards electrophiles
and nucleophiles is largely unexplored. The use of these pushꢀpull enamines to produce
4
,3b
substituted pyridines was highlighted in the synthesis of the natural products amphimedine
5
1,3f
3d
and ascididemin, as well as biological probes and analogs to biologically active compounds.
a) Previous work:
R1
R2
3
R O
2
C
CN
N
RO
2
C
CN
H
R1
eq. 1
H
N
R2
H
OMe
R
EWG
X
HX
NH
N
R
EWG
R
CN
EWG
R
CN
N
X
EWG
3
eq. 2
X = OMe, Cl
2
H NAlk
N
R
NH
CN
NH
2
N
EWG = CN
EWG = CO
2
R
EWG = CN
EWG = CO
2
R
N
Alk
c) Our work:
R1
NC
R1
CN
NC
CN
DMF-DMA
O (0.2 equiv)
R2
CN
X
Ac
2
HX
α
β
eq. 3
R1
N
AcOH
R2
R2
N
15 examples
32-97%
Scheme 1. Strategies for the synthesis of enamines and of pyridines
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Despite the advances described above, synthetic routes into enamines containing the
malononitrile fragment remain low yielding and this lack of convenient synthetic access might
explain the paucity of literature despite the number of potential nucleophilic and electrophilic
sites present. Recently, we added another chapter to this area by developing a new method that
enables the formation of ylidenemalononitrile enamines in high yield (Scheme 1, eq 3). The key
aspect of our new method was the observation that substoichiometric addition of acetic
anhydride significantly improved the yield of the desired enamine, in turn enabling access to a
wide range of 4ꢀsubstituted and 4,5ꢀdisubstituted 2ꢀhalonicotinonitrile scaffolds in good to
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excellent yield.
Herein, we report a more thorough study of the synthesis and reactivity of enamines
derived from ylidenemalononitriles and ylidenecyanoacetates. We begin by describing a physical
organic study that provides a more detailed understanding of the role of acetic anhydride in the
formation of these types of pushꢀpull enamines. We then expand the scope of the method to
increase the substitution pattern at the αꢀposition of the enamine and include a new approach to
introduce silylꢀfunctionalities in both the enamines and the pyridine products after cyclization
under Pinner conditions. Lastly, we explore the reactivity of the enamines towards both
electrophiles and nucleophiles by showcasing how these molecules can be used as entry points to
both highly substituted pyridines and αꢀpyrones, via a cyclization with organozinc halides and
organohalides, respectively.
Results and Discussion
Mechanistic Considerations:
Anhydrides as Additives for Enamine Formation. In 2013, we reported an improved
synthesis
of
4ꢀsubstituted
and
4,5ꢀdisubstitutedꢀ2ꢀhalonicotinonitriles
from
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alkylidenemalononitriles by improving the yield of the enamine (Scheme 1, eq 3) through the
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a
addition of substoichiometric quantities of acetic anhydride. The synthesis of 2a (see Table 1)
established by Baldwin, Raab, and Ponticello was originally hindered by competing dimerization
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of the ylidenemalononitriles. Acetic anhydride was originally chosen as a methanol scavenger
because removing methanol would either slow the rate of dimerization or increase the
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a
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concentration of the reactive iminium species. However, monitoring the reaction by H NMR
spectroscopy revealed the reaction between acetic anhydride and methanol to be slow thus
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contradicting the methanol scavenging hypothesis. The H NMR experiment did indicate the
formation of byꢀproducts N,Nꢀdimethylacetamide (DMA), methyl formate, and trimethyl
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a
orthoformate (TMOF) at the very start of the reaction. In addition, acetic anhydride was also
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a
shown to increase the rate of the desired reaction. Combined with the knowledge obtained in
the last communication and new experiments, a more informed model for the role of acetic
anhydride in the reaction is described below.
The formation of byꢀproducts DMA, methyl formate, and TMOF suggest an aminolysis
between DMFꢀDMA and acetic anhydride yielding an oxocarbenium acetate salt (A) and DMA
(Scheme 2). From this model, we propose the following catalytic cycle that uses the acetate
anion generated in the process shown in Scheme 2 to catalyze the reaction (Scheme 3).
Scheme 2. Aminolysis of acetic anhydride with DMFꢀDMA.
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Scheme 3. Proposed catalytic cycle for acetate catalyzed rate enhancement of the enamine formation.
After the formation of the oxocarbenium salt (A, Scheme 3), an anion exchange occurs
between A and iminium salt of DMFꢀDMA (B) to produce the iminium acetate salt (C). The
methoxide anion is paired with the oxonium cation to produce TMOF or methyl formate if
adventitious water is present. The iminium acetate salt C is now in equilibrium with the
covalently bound species D. Because the equilibrium between D and C should favor C due to the
stability of the acetate over methoxide, rate enhancement would occur as we have originally
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observed in the previous communication. Although no acetateꢀmethoxide exchange have been
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reported, formation of iminium salts similar to C from carboxylic acids or equilibria between
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alcohols or amines with their amine acetals, are known. After the formation of hemiaminal F
occurs by iminium salt C reacting with the alkylidenemalononitrile tautomer, E, the free acetate
is regenerated and exchanged with methoxide in another molecule of B. The methoxide in this
previous exchange then facilitates the formation of product 2a from iminium intermediate G.
This catalytic cycle is favorable because the increased rate is achieved by altering the reactivity
of DMFꢀDMA, not the alkylidene malononitrile. Increasing the rate of the alkylidene
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malononitrile tautomerization to D will also increase the rate of both the desired reaction and the
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undesired dimerization. Attempts to identify reactive intermediates C or D by H NMR
spectroscopy by combining DMFꢀDMA and acetic anhydride in DCMꢀd (0.2 M) were not
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successful. Without the alkylidenemalononitrile present, we hypothesized that C decomposes by
hydrolysis to form DMF or a known demethylation between the methoxy and acetate occurs to
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form DMF and methyl acetate (as both are observed).
With the acetate identified as the potential cause for the observed rate enhancement, other
acetate sources were investigated in hopes of further improving the formation of 2a (Table 1).
The addition of acetic acid alone provided the same yield as using no additive (43%, entries 1
and 2) suggesting that acetate is critical, not acetic acid. To test the “acetate not acetic acid”
hypothesis, the enamine yield in the presence of a series of acetate sources was measured. As
shown in Table 1, 1:1 triethylamineꢀacetic acid (TEAꢀAcOH) at varying concentrations provided
an improvement in yield compared to acetic acid (entries 3ꢀ5). The increase in yield was still not
as dramatic as when acetic anhydride was used. A control experiment also indicated the slight
increase in yield was not due to TEA alone (entry 6). The data may indicate that the nature of the
acetate ion is important and that counter ions play a significant role. Tetrabutylammoniumꢀ
acetate (TBAꢀOAc) exhibited even lower yields at 34% (entry 7) further demonstrating the
impact that the counter ion plays. When anion exchange occurs between DMFꢀDMA and TEAꢀ
AcOH or TBAꢀOAc, triethylamine or methoxide are produced, respectively. The base formation
can negatively effect the reaction for two reasons: (1) the formation of base during the exchange
increases the rate of dimer formation because this process is base catalyzed or (2) if the anion
exchange is reversible, the presence of acid or base negatively effects the equilibrium so less of
the iminium acetate salt (C, Scheme 3) is produced. Acetic anhydride is unique because the only
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base present after the anion exchange is the acetate, the critical component of the reaction. While
the data is consistent with our mechanistic model, we recognize that this study is merely the
beginning. One test of a good model is whether or not the model provides new insight. As we
demonstrate below, our improved understanding of the system has enabled us to increase the
yields associated with aldehyde substrates by leveraging our new mechanistic model.
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a
Table 1. Addition of varying acetate sources
a
entry
additive
none
AcOH
TEAꢀAcOH
TEAꢀAcOH
TEAꢀAcOH
TEA
addition (mol %) yield (%)
1
2
3
4
5
6
7
8
9
ꢀ
43
43
54
54
56
45
34
83
80
2.5
2.5
5
10
10
2.5
10
5
TBAꢀOAc
Ac O
2
Ac O
2
a
Calibrated yields determined by gas chromatography using dodecane (10 mol %) as an internal standard.
As we demonstrated in our initial communication, the use of aldehydeꢀbased alkylidene
malononitriles as substrates yielded the desired enamines but with lower yields compared to
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a
ketoneꢀbased alkylidenes. In our mechanistic study described above, we demonstrated that the
sources of the acetate anion was important and we speculated that by changing the acetate ion
source might improve the yield when aldehydeꢀbased substrates were used in the enamine
synthesis. To test this hypothesis, anhydrides with varying steric and electronic factors were
tested with propylidenemalononitrile 3b (Table 2). When compared to acetic anhydride (Table 2,
entry 2), bulkier anhydrides (entries 3 and 4) provided progressively lower yields as the bulk of
the anhydride increased. Modest yield increases began to emerge when benzoic and succinic
anhydrides (entry 5 and 6) were used. Phthalic anhydride (entry 7) demonstrated a further
increase in yield to 64%, and no further improvement was seen with trifluoroacetic anhydride
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(
59%, entry 8). Based on the observed trends, the electronics of the carboxylate play a role in the
outcome of the reaction. While the increase in yield appears modest, we observed an
improvement in the scaleꢀup and purification of the reaction. When phthalic anhydride is used as
an additive to synthesize 2ꢀbromoꢀ5ꢀmethylnicotinonitrile (5a) from 3a, the overall yield of these
two steps is 53% (Scheme 4). This is an improvement over using acetic anhydride, which
0
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a
provided an overall yield of 36% for 5a.
a
Table 2. Anhydride screen for the enamine formation
1
equiv anhydride
NC
H
CN
NC
H
CN
2 equiv DMF-DMA
DCM (0.1 M), rt
20-24 h
3
a
4a
N
a
entry
anhydride
none
acetic
isobutyric
trimethylacetic
benzoic
succinic
phthalic
trifluoroacetic
yield (%)
<10
53
1
2
3
4
5
6
7
8
37
17
57
58
64
59
a
Calibrated yields determined by GC analysis using dodecane (10 mol %) as an internal standard.
Scheme 4. Synthesis of 2ꢀbromoꢀ5ꢀmethylnicotinotrile via acyclic enamine derived from propionaldehyde. Yields
reported are of isolated product.
Increasing the Scope of Push-Pull Enamine Synthesis:
Incorporation of Silicon. In addition to understanding the role of acetic anhydride, we
also wanted to expand the scope of the method to prepare enamines. Examples of enamines (such
1
11
those in Scheme 5) bearing heteroatoms (N or O) at the R position are known and are
produced via (1) reaction of malononitrile with a trialkylorthoacetate or (2) dimethylacetate
1
2
dimethylacetal (DMAꢀDMA) to generate the alkoxyꢀsubstituted or dialkylamineꢀsubstituted
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11c,13
ylidenemalononitriles,
respectively. These heteroatomꢀsubstituted enamines are entry points
1
2e
12c
to heterocyclic scaffolds such as azafluorenones, polysubstituted pyridines and to bioactive
1
2b
molecules such as gimeracil.
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NC
MeO OMe
N
CN
NC
CN
NC
CN
R1 = OMe
R1 = NMe
2
MeO OMe
MeO OMe
R1
MeO OMe
N
H
N
MeO
H
N
1
1
Scheme 5. Formation of Granikꢀtype enamines (R = OMe) and Mittelbachꢀtype enamines (R = NMe )
2
1
We hypothesized that R could also be silicon and that our general approach leading to
1
enamines might enable incorporation of a CꢀSi bond. Enamines where R is an alkylsilyl
substituent could yield pyridines featuring CꢀSi bonds (vide infra) in the 4ꢀposition. We tested
our hypothesis using three ylidenemalononitrile derived from acylsilanes of varying substitution
2
with respect to the silicon functionality as well as the R position (Table 3). Commercially
available acetyltrimethylsilane was converted to the corresponding silylalkylidene malononitrile
14
via a Knoevenagel condensation according to previously reported procedure (entry 1). The
acylsilane 6b was synthesized via a previously reported dithiane route using
1
5
hydrocinnamaldehyde, whereas acylsilane 6c was obtained from its corresponding morpholine
16
amide precursor, via the method developed by Scheidt. The Knoevenagel condensation
products 7b and 7c were obtained without much difficulty (entry 2 and 3). Data shown in Table 4
indicates that the incorporation of a CꢀSi substituent into the enamine backbone using our DMFꢀ
2
DMA and acetic anhydride method is possible but only when the R substituent is small.
NC
1.37 equiv)
AcOH (0.8 equiv)
NH OAc (0.27 equiv)
CN
(
NC
CN
R2
O
4
R2
R
3
Si
R
3
Si
PhH, 95 o
C
6a-c
7a-c
NC
CN
NC
CN
NC
CN
TMS
TMS
2
PhMe Si
Bn
n-Bu
entry 1, 7a, 96% yield
entry 2, 7b, 49%
entry 3, 7c, 52%
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6
Table 3. – Synthesis of silylalkylidene malononitriles
NC
CN
R2
NC
CN
MeO OMe
R
3
Si
H
N
Ac
2
O (20 mol %)
R
3
Si
N
2
R
PhMe, rt
7
a-c
8a-c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NC
CN
H
NC
CN
NC
CN
TMS
N
TMS
N
PhMe2Si
N
Bn
n-Bu
entry 3, 8c, not observed
entry 1, 8a, 57% yield
entry 2, 8b, not observed
Table 4. – Formation of siliconꢀsubstituted enamines
Next, we wanted to demonstrate whether simple silylꢀfunctionalized enamines such as 8a
could be viable substrates for the Pinner cyclization. The cyclization was carried out at room
temperature with TMSꢀsubstituted enamine 8a using an HBr (33% in acetic acid). While we
postulated that the strongly acidic conditions necessary for the cyclization might cleave the CꢀSi
bond, product 9a was isolated in 85% yield (Scheme 6). No cleavage of the CꢀSi bond was
1
observed by crude H NMR, further demonstrating that these pushꢀpull enamines featuring a silyl
group support formation of 4ꢀsilyl substituted pyridines.
TMS
NC
CN
HBr (6.6 equiv)
CN
Br
TMS
N
AcOH/PhMe
rt, 3 h
N
8a
85% yield
9a
Scheme 6. Formation of 2ꢀbromoꢀ4ꢀtrimethylsilyl nicotinonitrile from enamine 8a
Use of DMA-DMA. The enamine formation followed by Pinner cyclization is unique in
enabling access to 4ꢀsubstituted and 4,5ꢀdisubstitutedꢀ2ꢀhalonicotinonitriles. However, the scope
might offer the potential to increase substitution to include the 6ꢀposition. Functionalizing this
position would require amide acetals other than DMFꢀDMA. While more elaborate amide acetals
1
7
are known, we found limited evidence of their application to form enamines of the class shown
in Table 5. We tested our hypothesis by reacting N, Nꢀdimethylacetamideꢀdimethyl acetal
(DMAꢀDMA) with various ylidenemalononitriles (Table 5). The reaction between the
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alkylidenemalononitrile 1a with DMAꢀDMA furnished the desired enamine in 50% yield (entry
1). We determined that the outcome of the reaction of ylidenemalononitriles (1) and DMAꢀDMA
2
2
was dependent on the size of the R substituent. As the R substituent size increases, the yield of
the enamine decreases (entries 2, 7 and 8). Arylꢀ and heteroarylꢀderived ylidenemalononitriles
afforded the expected enamines 10d, 10e and 10f with yields in the 82−85% range (entries 4ꢀ6).
In addition, the TMSꢀderived ylidenemalononitrile 7a could be used to give a high yield of the
10
11
12
13
14
15
16
17
18
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corresponding product 10c (entry 3) further illustrating the use of the silylꢀsubstituted enamines.
Table 5. ꢀ Substrate scope for αꢀmethyl substituted enamines
NC
R1
CN
β
NC
CN
Me
MeO OMe
Me
2
Ac O (20 mol %)
R1
N
α
N
PhMe, rt
R2
R2
1
a-g & 7a
10a-h
NC CN
NC
CN
Me
NC
CN
Me
Me
Me
N
t-Bu
N
TMS
N
entry 1, 10a, 50% yield
NC CN
entry 2, 10b, 15% yield
NC CN
entry 3, 10c, 77% yield
NC
CN
Me
Me
Me
N
N
N
S
OMe
entry 5, 10e, 85% yield
entry 4, 10d, 82% yield
entry 6, 10f, 85% yield
NC
CN
NC
CN
Me
Me
N
N
Me
entry 7, 10g, trace
entry 8, 10h, trace
Cyclization of Substituted Enamines Yielding 6-substituted Nicotinonitriles. As we
previously demonstrated, these pushꢀpull enamines cyclize to form nicotinonitriles under Pinner
6
conditions. We expected that enamines with greater substitution would also cyclize to yield
nicotinonitriles. We tested this premise by treating a range of enamines containing methyl groups
in the αꢀposition (Table 6). As is evident from the uniformly strong yields, methylꢀsubstitution at
the αꢀposition does not impede the cyclization. This method is a convenient strategy to install a
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
wide variety of groups in the 4ꢀ and 6ꢀpositions of nicotinonitriles including a tꢀbutyl 11b (entry
2), trimethylsilane 11c (entry 3), and various aromatic and heteroaromatic substrates 11d, 11e
and 11f (entries 4ꢀ6).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 6. Synthesis of 2ꢀbromonicotinonitriles from various alkylidene malononitriles
R1
NC
CN
Me
CN
Br
HBr (6.6 equiv)
AcOH/PhMe
R1
N
Me
N
1
0a-f
11a-f
Me
t-Bu
TMS
CN
CN
CN
Br
Me
N
Br
Me
N
Br
Me
N
entry 1, 11a, 95% yield
entry 2, 11b, 70% yield
entry 3, 11c, 54% yield
S
MeO
CN
CN
CN
Me
N
Br
Me
N
Br
Me
N
Br
entry 4, 11d, 83% yield
entry 5, 11e, 83% yield
entry 6, 11f, 92% yield
Reactivity of Push-Pull Enamines Towards Electrophiles and Nucleophiles:
Cyclization with Organohalides. Until now, cyclizations between ylidenemalononitrile
enamines and electrophiles only include Pinner cyclizations with hydrogen halides to afford
1
a,3c
polysubstituted nicotinonitriles. While a notional Pinner cyclization mechanism is suggested,
few mechanistic studies provide evidence to support these widely presented arrowꢀpushing
mechanisms. Our hypothesis of the mechanism illustrated in Scheme 7 (eq 1) involves the
addition of a proton at the enamine βꢀcarbon. To test this, the cyclization of enamine 12 was
performed with DCl in AcOD (Scheme 7, eq 2). The cyclization resulted in a high ratio of the
deuteriumꢀlabeled product at 5ꢀposition of the corresponding nicotinonitrile (13a and 13b)
supporting our proposed mechanism. This enamine protonation model suggests that enamine
alkylation, silylation, or electrophilic halogenation should also promote the reaction.
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a)
X
X
X
N
NC
CN
NC
NC
NC
R
N
N
R
N
R
N
H
eq. 1
R
N
H
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
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29
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31
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46
47
48
49
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60
b)
t-Bu
t-Bu
NC
CN
DCl
AcOD
D
CN
Cl
CN
Cl
+
eq. 2
t-Bu
N
N
N
1
2
13a
13b
8
:
1
Scheme 7. a) Proposed mechanism for Pinner cyclization. b) Deuterium incorporation studies.
With evidence of electrophilic addition at the βꢀcarbon, enamine 2a was subjected to a
variety of electrophiles: bromine, acetyl chloride and bromide, and trimethylsilyl chloride,
bromide, and iodide. Despite many changes in the reaction conditions, no evidence for the
cyclization event was observed. Instead, the silylation of the nitrogen, a Pinner cyclization with
HCl/HBr impurities, or no reaction were the observed outcomes. We then speculated that use of
allyl bromide might enable cyclization via an alternative mechanism whereby NꢀAlkylation is
1
8
followed by a [3,3]ꢀsigmatropic shift (azaꢀClaisen) (Scheme 8a). Although attempts using
conventional heating failed, reactions performed under microwave irradiation provided
promising results. Microwaveꢀbased heating at 125 °C for 10 min in acetonitrile enabled the
conversion of 2a to product (14a, Scheme 8b). While the NMR data provided evidence of the
predicted cyclization, only trace quantities were isolated. Longer reaction times only led to
product decomposition. The low reactivity of the enamine is most likely due to the low
nucleophilicity of the nitrogen. By replacing the malononitrile fragment for the less electronꢀ
withdrawing cyanoacetate group, we hypothesized the enamine would be more nucleophilic and
the product stability would increase. Enamine substrates 15a-d were synthesized using our
previously developed procedure for malononitrile substrates. The formation of the enamines with
the ethylcyanoacetate moiety were lower yielding than with the malononitrile fragment
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1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
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5
5
5
5
5
5
6
potentially due to the slower rates of reaction between DMFꢀDMA and the ylidenecyanoacetates
compared to ylidenemalononitriles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8. a) Hypothesized mechanism to produce 5ꢀallyl substituted pyridines from allyl bromide via Nꢀalkylation
followed by an azaꢀClaisen rearrangement. b) Cyclization with ylidenemalononitrile enamine with allyl bromide.
When 15a was treated with allyl bromide at 125 °C for 6 h (Table 7, entry 1), the starting
1
material was consumed and less byꢀproduct formation was observed by H NMR spectroscopy
compared to the reaction shown in Scheme 8b. Interestingly, the product was not the expected
2
a
pyridine. In contrast to the Pinner cyclization affording the 2ꢀhalonicotinoate, the cyclization of
15a with allyl bromide gave exclusively 5ꢀallylꢀ3ꢀcyanoꢀ4ꢀmethylꢀαꢀpyrone (16aa) due to the
involvement of the ester in the cyclization. Despite less byꢀproduct formation, the cyclization
with allyl bromide to the corresponding αꢀpyrone (16aa) yield was low at 38% (Table 7, entry
1
9
1). Baldwin et al. described the cyclization of 15a under Pinner conditions and observed a fair
2a
yield (58%) of the desired 2ꢀhalonicotinoates from the ylidenecyanoacetate. The fair yield was
originally assumed to be due the low yielding enamine formation with DMFꢀDMA. However,
the results described here suggest that pyrone formation may have been a competing factor.
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a
Table 7. Cyclization of 15a with various organohalides to produce αꢀpyrones.
10
11
12
13
14
15
16
17
18
19
20
21
22
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48
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52
53
54
55
56
57
58
59
60
a
b
Isolated yields. Reaction concentration at 2.5 M.
This unexpected result led us to investigate other organohalides (Table 7). The
performance with propargyl bromide (entry 2) and cinnamyl bromide (entry 3), resulted in
significantly slower reaction rates that contributed to lower yields of the desired product. Benzyl
bromide was shown to produce 16ad with the highest yield at 65% (entry 4) under much milder
conditions (80 °C) than allyl bromide. Also, while methyl iodide was efficient in producing 16ae
at 50% yield (entry 5), ethyl iodide was much less reactive providing only a small amount of the
desired product (entry 6). Further optimization of the reaction and purification conditions could
result in significant yield improvements in the future for this novel approach to αꢀpyrones.
Other enamines derived from acetophenones were cyclized with benzyl bromide to
determine how well the reaction tolerates varying electronics of the enamine backbone (Table 8).
The reaction rates for all three substrates were much slower, so an increase in temperature from
8
0 °C (Table 8, entry 4) to 120 °C was required. While the cyclization tolerated electronꢀrich
substrates well (Table 8, entry 1) producing the highest yield at 48%, electronꢀpoor substrates
(entry 3) showed sluggish rates and poor yields. The effects in yield are likely due to the change
in the nucleophilicity of the enamine.
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Table 8. Cyclization of acetophenone derived enamines (15b-d) to 16bd-dd with benzyl bromide.
EtO
2
C
CN
R
BnBr (4 equiv)
ACN (1 M)
N
CN
O
R
Ph
1
20 ºC, 6 h, MW
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
15b-d
16bd-dd
MeO
Ph
Cl
CN
O
CN
CN
Ph
Ph
O
O
O
O
O
entry 1, 16bd, 48% yield
entry 2, 16cd, 26% yield
entry 3, 16dd, 15% yield
a
Isolated yields.
The participation of benzyl bromide and methyl iodide in the cyclization to αꢀpyrones
suggests that Cꢀalkylation occurs which is opposite of what is proposed in Scheme 9a. Alkyl
halides are known to undergo Nꢀalkylation with aldehydeꢀderived enamines leading us to
2
0
speculate both Nꢀ and Cꢀalkylations were reversible at high temperatures. We tested the
validity of this hypothesis by performing the cyclization of 15a with MeIꢀd (Scheme 9a). The
3
product ratio between labeled (16ag) and nonꢀlabeled (16ae) 3ꢀcyanoꢀ4,5ꢀdimethylꢀ2ꢀpyrone was
6
: 1 (Scheme 9a). The small percentage of nonꢀlabeled αꢀpyrone present suggests Nꢀalkylation
is occurring and is reversible by a von Braunꢀlike dealkylation leading to the scrambling of the
methyl groups. Upon Cꢀalkylation, the cyclization occurs followed by an irreversible
nucleophilic dealkylation to drive the reaction forwards. Dimethylamine then eliminates to afford
the desired αꢀpyrone (Scheme 9b).
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58
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60
Scheme 9. a) Deterium labeling studies with MeIꢀd . b) Proposed mechanism of αꢀpyrone formation
3
Reactivity towards Nucleophiles. The chemistry of these pushꢀpull enamines towards
3
a,2b
nucleophiles has been explored, albeit rarely. Hiroshi and Ege
demonstrated that these types
3
a,21a,11c,21bꢀd,3c
of enamines can react with a variety of amineꢀbased nucleophiles such as ammonia,
2
2,3g
3e
23
24
primary amines,
hydrazine, diazonium salts, and hydroxylamine. The addition of
carbonꢀbased nucleophiles to these types of enamines has not been described in the literature
prompting us to ascertain whether the chemoselectivity of the addition would be similar to that
observed with the amineꢀbased nucleophiles. We carried out a reactivity screen across a series of
experiments using enaminomalononitrile 2a and various organometallic nucleophiles. The
reaction of this enamine with allylzinc bromide at room temperature for 16 hours furnished the
2
ꢀallylꢀsubstituted nicotinonitrile 17a in 70% yield (Table 9, entry 1). The reaction between
phenylꢀsubstituted enaminomalononitrile and allylzinc bromide (entry 2) yielded the desired 1,3ꢀ
substituted nicotinonitrile 17b in 47% yield. The addition of allylzinc bromide to other
enaminomalononitriles furnished the desired 2ꢀallylꢀsubstituted pyridine: a thiophene derivative
(
entry 3) is very well tolerated, however, the introduction of substitution at the βꢀposition on the
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2
2
2
2
2
2
2
2
2
2
3
3
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4
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5
5
5
5
6
enamine led to decreased yields for the formation of the diphenylꢀ (entry 4) and acenaphthenylꢀ
derived (entry 5) nicotinonitriles 17d and 17e, respectively. Interestingly, the more reactive zinc
species such as diethylzinc and benzyl zinc chloride did not participate in the reaction,
conversely the Grignard reagents led to the formation of an intractable mixture of products.
Other alkyl zinc reagents such as ethyl zinc iodide did not react, suggesting that the electronic
properties of the nucleophile play a greater role than steric factors. We also suggest that
aggregation and clustering effects may preclude certain organozinc halides from being viable
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
25
nucleophiles towards enaminomalononitriles.
Table 9. Substrate scope for allylation of enamines
R1
NC
R1
CN
R2
CN
allylZnBr
N
THF, rt
R2
N
2
a-e
17a-e
S
Me
N
Ph
CN
CN
CN
N
N
entry 1, 17a, 70% yield
entry 2, 17b, 47% yield
entry 3, 17c, 99% yield
CN
CN
N
N
entry 4, 17d, 30% yield
entry 5, 17e, 24% yield
2
2b
On the basis of the above results and previous reports,
a possible mechanism is
proposed and shown in Scheme 10. First, the nucleophilic attack of the organozinc halide at the
nitrile of A generates intermediate B. Subsequently, a Baldwinꢀfavored 6ꢀendoꢀtrig cyclization
furnishes cyclized intermediate C. The elimination of the dimethylamine then generates the
desired nicotinonitrile D.
Scheme 10. Proposed mechanism cyclization with organozinc halides
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ZnBr
R'
R'
NC
N
NC
R1
ZnBr
N
N
R1
N
A
B
6
-endo-trig
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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42
43
44
45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
R'
R'
NC
NC
R1
N
N
R1
N
D
C
In conclusion, we have extended the methodology to produce a class of pushꢀpull
enamines to better suit aldehydeꢀderived ylidenemalononitriles, include silyl group
functionalities, and extend the sites for substitution by utilizing the N,Nꢀdimethylacetamide
acetal. Based on the existing mechanistic data, we propose that acetic anhydride provides acetate
anions without introducing other base species that might catalyze the alkylidene dimerization.
We have also demonstrated how cyanoacetateꢀderived enamine species can be used as an
intermediate to αꢀpyrones, which differs from original pathways involving transitionꢀmetal
catalysis or a series of condensation reactions. Lastly, we show the cyclization to nicotinonitriles
can also be performed under basic conditions using certain organozinc compounds.
Experimental Section
General Information. Deuterated solvents were used as received, with the exception of
deuterated chloroform which was stored over activated 4Å molecular sieves. Alkyl halides were
passed through basic alumina prior to use. Tetrahydrofuran, dichloromethane, acetonitrile,
toluene, and benzene were obtained from a solvent system passing HPLC or reagent grade
solvents through activated alumina or activated 5Å molecular sieves. All other reagents were
commercially available and used without further purification unless otherwise noted. All nonꢀ
aqueous reactions were carried out in flameꢀ or ovenꢀdried (120 ºC) glassware fitted with rubber
septa under a positive pressure of argon with magnetic stirring, unless otherwise noted.
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5
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6
Analytical thin layer chromatography (TLC) was performed using glassꢀbacked silica gel 60F254
(250 ꢁm thickness. Flash column chromatography was carried out using 60Å Silica Gel (230ꢀ400
1
13
mesh). Microwave reactions were performed using a Biotage Initiator instrument. H and C
were obtained on 400 or 600 MHz spectrometers. NMR chemical shifts are reported as δ values
0
1
2
3
4
5
6
7
8
9
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3
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7
8
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6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
13
in ppm relative to TMS in CDCl for all H spectra and relative to CDCl for all C spectra. Data
3
3
are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, quin = quintuplet, sext = sextet, m = multiplet), coupling constants in Hertz
(Hz), integration. The mass analyzer type TOF was used for HRMS measurements.
1
Isopropylidenemalononitrile (1a). Prepared according to the previously reported procedure.
1
13
H NMR (600 MHz, CDCl ) δ 2.32 (s, 6H); C NMR (151 MHz, CDCl ) δ 178.8, 111.8, 86.1,
3
3
1
24.5. Spectra were in accordance with those described in the literature.
(E)-2-(4-(dimethylamino)but-3-en-2-ylidene)malononitrile (2a). Prepared according to the
1
1
previously reported procedure. Yellow solid, mp 150ꢀ152 °C; H NMR (600 MHz, CDCl ) δ
3
1
3
7
.25 (d, J = 12.7 Hz, 1H), 5.63 (d, J = 12.6 Hz, 1H), 3.23 (s, 3H), 2.99 (s, 3H), 2.23 (s, 3H); C
NMR (151 MHz, CDCl ) δ 168.3, 152.4, 116.9, 116.1, 97.2, 65.8, 45.9, 37.6, 17.3. Spectra were
3
1
in accordance with those described in the literature.
6
a
Propylidenemalononitrile (3a). Prepared according to the previously reported procedure. To a
stirring solution of malononitrile (11.45 g, 173 mmol, 1 equiv) and propionaldehyde (12.5 mL,
1
73 mmol, 1 equiv) in CHCl (100 mL) was added aluminum oxide (Brockmann I, activated
3
basic) (24.6 g, 241 mmol, 1.4 equiv) slowly (reaction is very exothermic). After the addition of
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aluminum oxide was complete, the reaction stirred for 1 h at room temperature. The aluminum
oxide was then filtered off by vacuum filtration using CH Cl to rinse. The filtrate was
2
2
concentrated in vacuo to yield a yellow oil. The oil was purified by short path distillation (70 °C,
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1
000 mTorr) to yield 3a (12.65 g, 69% yield) as a clear, colorless oil. H NMR (600 MHz,
13
CDCl ) δ 7.34 (t, J = 7.9 Hz, 1H), 2.62 (m, J = 7.6 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H); C NMR
3
(
151 MHz, CDCl ) δ 170.9, 112.2, 110.5, 89.6, 26.4, 12.0. Spectra in accordance with those
3
6
a
described in the literature.
(
E)-2-(3-(dimethylamino)-2-methylallylidene)malononitrile (4a). Prepared according to the
6
a
previously reported procedure with some modifications. To a stirring solution of 3a (1.06 g, 10
mmol, 1 equiv) and phthalic anhydride (1.48 g, 10 mmol, 1 equiv) in anhydrous CH Cl (100
2
2
mL) was added DMFꢀDMA (2.7 mL, 20 mmol, 2 equiv). The reaction stirred at 20.5 h at room
temperature. As the reaction proceeded, some product precipitated out. The reaction was
concentrate in vacuo and the resulting orange solid was recrystallized in CH Cl /hexanes to yield
2
2
1
4a (0.99 g, 61%) as an orange solid, mp 185ꢀ190 °C; H NMR (600 MHz, CDCl ) δ 6.86 (s, 1H),
3
13
6
.75 (s, 1H), 3.23 (s, 6H), 2.25 (s, 3H); C NMR (151 MHz, CDCl ) δ 162.9, 159.1, 119.0,
3
+
117.1, 106.7, 60.6, 44.2, 13.0; HRMS (ESI+) m/z: [M + Na] calcd for C H N Na, 184.08507;
9
11
3
Found, 184.08647.
2-bromo-5-methylnicotinonitrile (5a). To a stirring slurry of 4a (0.806 g, 5 mmol, 1 equiv) in
AcOH (3 mL) was added an HBr in AcOH solution (5.5 mL, 31.4 mmol, 6.3 equiv). The
reaction was stirred at 55 °C for 45 min. Once complete, the reaction was poured over a mixture
of ice and Na CO (20 g). Once the ice melted, the product was extracted using 3 x 50 mL
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CH Cl . The organic layers were combined, dried with MgSO , and then concentrated under
2
2
4
vacuum to yield 5a (0.85 g, 87%) as a tan solid, mp 110ꢀ113 °C; No additional purification was
1
needed. H NMR (600 MHz, CDCl ) δ 8.40 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 2.39 (s,
3
0
1
2
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3
3
H). C NMR (151 MHz, CDCl ) δ 153.6, 142.7, 140.6, 133.1, 115.9, 113.7, 17.7. Spectra in
3
6
a
accordance with those described in the literature.
2-(1-(trimethylsilyl)ethylidene)malononitrile (7a). Prepared according to the previously
1
4
reported procedure. Acetyltrimethylsilane (2.00 g, 17.20 mmol), malononitrile (1.56 g, 23.57
mmol, 1.37 equiv) and ammonium acetate (358.0 mg, 4.644 mmol) were dissolved in acetic acid
(0.83 mL, 13.76 mmol) and benzene (40 mL) in a 100 mL round bottom flask attached to a
Dean–Stark trap and filled with benzene and 4Å molecular sieves. The reaction mixture was
stirred and heated to 95 °C for 36 h. The resulting orange solution was cooled and diluted with
ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water,
brine and dried over MgSO . The product was purified by column chromatography (ethyl
4
1
acetate/hexanes) to give 7a (2.712 g, 96% yield) as a pale yellow oil. H NMR (600 MHz,
1
3
CDCl ) δ 2.33 (s, 3H), 0.35 (s, 9H); C NMR (151 MHz, CDCl ) δ 188.1, 113.4, 111.4, 94.6,
3
3
1
4
24.0, ꢀ2.1. Spectra in accordance with those described in the literature.
2-(3-phenyl-1-(trimethylsilyl)propylidene)malononitrile
(7b).
3ꢀphenylꢀ1ꢀ
(
trimethylsilyl)propanꢀ1ꢀone (590 mg, 2.84 mmol), malononitrile (260 mg, 3.90 mmol, 1.37
equiv) and ammonium acetate (60 mg, 0.770 mmol) were dissolved in acetic acid (0.14 mL,
.280 mmol) and benzene (8 mL) in a 25 mL round bottom flask attached to a Dean–Stark trap
and filled with benzene and 4Å molecular sieves. The reaction mixture was stirred and heated to
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5 °C for 36 h. The resulting orange solution was cooled and diluted with ethyl acetate. The
organic layer was washed with saturated sodium bicarbonate solution, water, brine and dried
over MgSO . The product was purified by column chromatography (ethyl acetate/hexanes) to
4
10
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60
1
give 7b (354 mg, 49% yield) as a pale yellow solid, mp 58ꢀ61 °C; H NMR (600 MHz, CDCl ) δ
3
7.33 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.21ꢀ7.19 (m, 2H), 2.94ꢀ2.91 (m, 2H), 2.74ꢀ2.71
13
(
m, 2H), 0.40 (s, 9H); C NMR (151 MHz, CDCl ) δ 192.4, 140.7, 130.6, 130.2, 128.7, 114.9,
3
+
113.1, 97.4, 41.7, 36.8, 0.0. HRMS (ESI+) m/z: [M + Na] calcd for C H N SiNa, 277.11369;
1
5
18
2
Found, 277.11368.
2-(1-(dimethyl(phenyl)silyl)hexylidene)malononitrile (7c). 1ꢀ(dimethyl(phenyl)silyl)hexanꢀ1ꢀ
one (0.83 g, 3.54 mmol), malononitrile (0.32 g, 4.85 mmol, 1.37 equiv) and ammonium acetate
(
74 mg, 0.956 mmol, 0.27 equiv) were dissolved in acetic acid (0.16 mL, 2.83 mmol) and
benzene (9 mL) in a 50 mL round bottom flask attached to a Dean–Stark trap and filled with
benzene and 4Å molecular sieves. The reaction mixture was stirred and heated to 95 °C for 36 h.
The resulting orange solution was cooled and diluted with ethyl acetate. The organic layer was
washed with saturated sodium bicarbonate solution, water, brine and dried over MgSO . The
4
product was purified by column chromatography (ethyl acetate/hexanes) to give 7c (524 mg,
1
52% yield) as a pale yellow oil. H NMR (600 MHz, CDCl ) δ 7.51ꢀ7.33 (m, 5H), 2.55 (t, J = 7.9
3
13
Hz, 2H), 1.31ꢀ1.28 (m, 2H), 1.21ꢀ1.18 (m, 4H), 0.82ꢀ0.81 (m, 3H), 0.66 (s, 6H); C NMR (151
MHz, CDCl ) δ 190.5, 134.2, 133.2, 130.6, 128.4, 113.3, 111.6, 95.3, 38.2, 31.7, 28.5, 22.1, 13.8,
3
+
ꢀ
3.2; HRMS (ESI+) m/z: [M + Na] calcd for C H N SiNa, 305.14499; Found, 305.14486.
1
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(
E)-2-(3-(dimethylamino)-1-(trimethylsilyl)allylidene)malononitrile (8a). Prepared according
6
a
to the previously reported procedure. To a stirring solution of 7a (500 mg, 3.04 mmol, 1 equiv)
and acetic anhydride (58 ꢁL, 0.609 mmol, 0.2 equiv) in toluene (8 mL) was added DMFꢀDMA
0
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(485 ꢁL, 3.65 mmol, 1.2 equiv). The reaction stirred at overnight at room temperature. As the
reaction proceeded, some product precipitated out. The reaction was concentrate in vacuo and
the product was purified by column chromatography (ethyl acetate/hexanes) to give 8a (380 mg,
1
5
7% yield) as a yellow solid, mp 139ꢀ143 °C; H NMR (600 MHz, CDCl ) δ 7.60 (d, J = 12.7 Hz,
3
1
3
1H), 5.66 (d, J = 12.7 Hz, 1H), 3.19 (s, 3H), 2.98 (s, 3H), 0.42 (s, 9H); C NMR (151 MHz,
+
CDCl ) δ 174.2, 152.3, 117.6, 116.5, 101.5, 69.1, 45.2, 36.2, 0.0; HRMS (ESI+) m/z: [M + H]
3
calcd for C H18N Si, 220.12520; Found, 220.12574.
11
3
2
-bromo-4-(trimethylsilyl)nicotinonitrile (9a). Prepared according to the previously reported
6
a
procedure with some modifications. To a stirred slurry of 8a (80mg, 0.365 mmol, 1.0 equiv) in
toluene (1.0 mL) was added a 33 wt% solution of HBr in AcOH (370 ꢁL, 2.298 mmol, 6.3
equiv) dropwise, and the reaction was allowed to stir at room temperature for 3 hours. The
reaction mixture was poured into a solution of sodium hydroxide (1M) and extracted with ethyl
acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate and
the combined organic layers were washed with water, brine, dried with anhydrous magnesium
sulfate and the solvent was removed under reduced pressure. The crude material was purified by
flash column chromatography on silica gel (ethyl acetate/hexanes) to yield the 9a (79 mg, 85%)
1
as a white solid, mp 120ꢀ124 °C; H NMR (600 MHz, CDCl ) δ 8.46 (d, J = 4.7 Hz, 1H), 7.45 (d,
3
1
3
J = 4.7 Hz, 1H), 0.47 (s, 9H); C NMR (151 MHz, CDCl ) δ 161.3, 153.3, 147.4, 129.2, 120.2,
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19.0, 0.00. Anal. Calcd. for C H BrN Si: C: 42.46; H: 4.34; Br: 31.31; N: 10.98; Si: 11.01.
9
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2
Found: C: 42.21; H: 4.28; Br: 31.05; N: 10.86.
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(
E)-2-(4-(dimethylamino)pent-3-en-2-ylidene)malononitrile (10a). To a stirring solution of
the alkylidene malononitrile 1a (1.00 g, 9.42 mmol, 1.0 equiv) in toluene (19 mL) was added
acetic anhydride (180 ꢁL, 1.89 mmol, 0.2 equiv) followed by N,Nꢀdimethylacetamide
dimethylacetal (1.65 mL, 11.31 mmol, 1.2 equiv) dropwise. The reaction mixture was stirred
overnight. The solvent was removed under reduced pressure and the crude material was purified
by flash column chromatography on silica gel (ethyl acetate/hexanes as eluent) to yield the
1
enamine 10a (820 mg, 50%) as a greenishꢀyellow solid, mp 154ꢀ158 °C; H NMR (600 MHz,
1
3
CDCl ) δ 5.61 (s, 1H), 3.16 (s, 6H), 2.35 (s, 3H), 2.29 (s, 3H); C NMR (151 MHz, CDCl ) δ
3
3
+
1
68.3, 161.8, 117.5, 117.1, 99.7, 41.5, 22.0, 19.1. HRMS (ESI+) m/z: [M + Na] calcd for
C H N Na, 198.10072; Found, 198.10126.
10 13
3
(E)-2-(5-(dimethylamino)-2,2-dimethylhex-4-en-3-ylidene)malononitrile (10b). To a stirring
solution of 2ꢀ(3,3ꢀdimethylbutanꢀ2ꢀylidene)malononitrile (505 mg, 3.41 mmol, 1.0 equiv) in
toluene (13 mL) was added acetic anhydride (65 ꢁL, 0.681 mmol, 0.2 equiv) followed by N,Nꢀ
dimethylacetamide dimethylacetal (600 ꢁL, 4.09 mmol, 1.2 equiv) dropwise. The reaction
mixture was stirred overnight. The solvent was removed under reduced pressure and the crude
material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes as
1
eluent) to yield the enamine 10b (111 mg, 15%) as a yellow solid , mp 74ꢀ78 °C; H NMR (600
13
MHz, CDCl ) δ 4.95 (s, 1H), 3.13 (s, 6H), 2.23 (s, 3H), 1.34 (s, 9H); C NMR (151 MHz,
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6
CDCl ) δ 182.4, 163.6, 119.8, 118.3, 97.7, 63.8, 60.4, 41.2, 38.4, 29.4, 19.9. HRMS (ESI+) m/z:
3
+
[
M + H] calcd for C H N , 218.16572; Found, 218.16588.
13 20
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(E)-2-(3-(dimethylamino)-1-(trimethylsilyl)but-2-en-1-ylidene)malononitrile (10c). To a
stirring solution of the alkylidene malononitrile 7a (200 mg, 1.217 mmol, 1.0 equiv) in toluene
5 mL) was added acetic anhydride (23 ꢁL, 0.243 mmol, 0.2 equiv) followed by N,Nꢀ
(
dimethylacetamide dimethylacetal (195 mg, 1.461 mmol, 1.2 equiv) dropwise. The reaction
mixture was stirred overnight. The solvent was removed under reduced pressure and the crude
material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes as
1
eluent) to yield the enamine 10c (219 mg, 77%) as a yellow solid , mp 109ꢀ112 °C; H NMR
1
3
(600 MHz, CDCl ) δ 5.06 (s, 1H), 3.13 (s, 6H), 2.18 (s, 1H), 0.32 (s, 9H); C NMR (151 MHz,
3
+
CDCl ) δ 177.4, 163.9, 120.0, 119.9, 104.3, 70.1, 42.6, 21.8, 0.0. HRMS (ESI+) m/z: [M + H]
3
calcd for C H N Si, 234.14265; Found, 234.14330.
12 20
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(E)-2-(3-(dimethylamino)-1-phenylbut-2-en-1-ylidene)malononitrile (10d) To a stirring
solution of 2ꢀ(1ꢀphenylethylidene)malononitrile (960 mg, 5.70 mmol, 1.0 equiv) in toluene (11.4
mL) was added acetic anhydride (109 ꢁL, 1.14 mmol, 0.2 equiv) followed by N,Nꢀ
dimethylacetamide dimethylacetal (1.00 mL, 6.84 mmol, 1.2 equiv) dropwise. The reaction
mixture was stirred overnight. The solvent was removed under reduced pressure and the crude
material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes as
1
eluent) to yield the enamine 10d (1.11 g, 82%) as a dark yellow solid, mp 171ꢀ174 °C; H NMR
(
600 MHz, CDCl ) δ 7.42ꢀ7.46 (m, 3H), 7.31ꢀ7.33 (m, 2H), 5.78 (s, 1H), 3.15 (s, 6H), 1.50 (s,
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3
H); C NMR (151 MHz, CDCl ) δ170.8, 163.6, 137.6, 130.3, 128.9, 128.7, 117.4, 117.3, 99.2,
3
+
6
4.8, 41.4, 18.9; HRMS (ESI+) m/z: [M + H] calcd for C H N , 238.13442; Found, 238.13579.
15 16
3
10
11
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(
E)-2-(3-(dimethylamino)-1-(2-methoxyphenyl)but-2-en-1-ylidene)malononitrile (10e). To a
stirring solution of 2ꢀ(1ꢀ(2ꢀmethoxyphenyl)ethylidene)malononitrile (200 mg, 1.009 mmol, 1.0
equiv) in toluene (4 mL) was added acetic anhydride (19 ꢁL, 0.202 mmol, 0.2 equiv) followed
by N,Nꢀdimethylacetamide dimethylacetal (161 mg, 1.211 mmol, 1.2 equiv) dropwise. The
reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the
crude material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes
1
as eluent) to yield the enamine 10e (229 mg, 85%) as a dark orange solid, mp 130ꢀ134°C; H
NMR (600 MHz, CDCl ) δ 7.39 (m, 1H), 7.04ꢀ6.97 (m, 3H), 5.89 (s, 1H), 3.86 (s, 3H), 3.14 (s,
3
13
6H), 1.55 (s, 3H); C NMR (151 MHz, CDCl ) δ 167.7, 162.9, 156.0, 131.3, 129.5, 121, 2,
3
+
117.5, 117.2, 111.8, 99.0, 65.5, 55.9, 41.4, 17.3; HRMS (ESI+) m/z: [M + H] calcd for
C H N O, 268.14499; Found, 268.14579.
16
18
3
(E)-2-(3-(dimethylamino)-1-(thiophen-2-yl)but-2-en-1-ylidene)malononitrile (10f). To a
stirring solution of 2ꢀ(1ꢀ(thiophenꢀ2ꢀyl)ethylidene)malononitrile (204 mg, 1.171 mmol, 1.0
equiv) in toluene (5 mL) was added acetic anhydride (22 ꢁL, 0.234 mmol, 0.2 equiv) followed
by N,Nꢀdimethylacetamide dimethylacetal (206 ꢁL, 1.405 mmol, 1.2 equiv) dropwise. The
reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the
crude material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes
1
as eluent) to yield the enamine 10f (242 mg, 85%) as a dark yellow solid, mp 146ꢀ148 °C; H
NMR (600 MHz, CDCl ) δ 7.55 (m, 1H), 7.47 (m, 1H), 7.13 (m, 1H), 5.58 (s, 1H), 3.17 (s, 6H),
3
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4
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5
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5
5
5
5
5
6
13
1
.82 (s, 3H); C NMR (151 MHz, CDCl ) δ 164.1, 161.3, 139. 2, 130.8, 130.7, 128.3, 117.8,
3
+
1
17.7, 99.4, 62.9, 41.4, 19.4. HRMS (ESI+) m/z: [M + H] calcd for C H N S, 244.09084;
13 14
3
Found, 244.09039.
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2-bromo-4,6-dimethylnicotinonitrile (11a). Prepared according to the previously reported
6
a
procedure with some modifications. To a stirred slurry of the enamine 10a (117 mg, 0.668
mmol, 1.0 equiv) in toluene (700 ꢁL) was added a 33 wt% solution of HBr in AcOH (740 ꢁL,
4.21 mmol, 6.3 equiv) dropwise, and the reaction was allowed to stir at room temperature for 3
hours. The reaction mixture was poured into a solution of sodium hydroxide (1M) and extracted
with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl
acetate and the combined organic layers were washed with water, brine, dried with anhydrous
magnesium sulfate and the solvent was removed under reduced pressure. The crude material was
purified by flash column chromatography on silica gel (ethyl acetate/hexanes) to yield pyridine
1
1
1a (133 mg, 94%) as a white solid, mp 106ꢀ109 °C; H NMR (600 MHz, CDCl ) δ 7.10 (s, 1H),
3
13
2
.56 (s, 3H), 2.54 (s, 3H); C NMR (151 MHz, CDCl ) δ 162.9, 154.1, 143.4, 123.5, 115.4,
3
+
111.7, 24.5, 20.7. HRMS (ESI+) m/z: [M + H] calcd for C H BrN , 210.98709; Found,
8
8
2
2
6
2
10.98707. Spectra in accordance with those described in the literature.
2-bromo-4-(tert-butyl)-6-methylnicotinonitrile (11b). Prepared according to the previously
6a
reported procedure with some modifications. To a stirred slurry of the enamine 10b (66 mg,
0
.304 mmol, 1.0 equiv) in toluene (700 ꢁL) was added a 33 wt% solution of HBr in AcOH (740
ꢁ
3
L, 4.21 mmol, 6.3 equiv) dropwise, and the reaction was allowed to stir at room temperature for
hours. The reaction mixture was poured into a solution of sodium hydroxide (1M) and
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extracted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with
ethyl acetate and the combined organic layers were washed with water, brine, dried with
anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The crude
10
11
12
13
14
15
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17
18
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44
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material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes) to
1
yield pyridine 11b (133 mg, 94%) as a white solid, mp 137ꢀ140 °C; H NMR (600 MHz, CDCl )
3
1
3
δ 7.20 (s, 1H), 2.60 (s, 3H), 1.50 (s, 9H); C NMR (151 MHz, CDCl ) δ 166.0, 163.2, 146.5,
3
+
1
19.7, 117.5, 109.3, 36.2, 29.2, 24.9. HRMS (ESI+) m/z: [M + H] calcd for C H BrN ,
1
1
14
2
253.03404; Found, 253.03427.
2-bromo-6-methyl-4-(trimethylsilyl)nicotinonitrile (11c). Prepared according to the previously
6
a
reported procedure with some modifications. To a stirred slurry of the enamine 10c (219 mg,
0.938 mmol, 1.0 equiv) in toluene (3.7 mL) was added a 33 wt% solution of HBr in AcOH (973
ꢁ
3
L, 5.91 mmol, 6.3 equiv) dropwise, and the reaction was allowed to stir at room temperature for
hours. The reaction mixture was poured into a solution of sodium hydroxide (1M) and
extracted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with
ethyl acetate and the combined organic layers were washed with water, brine, dried with
anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The crude
material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes) to
1
yield pyridine 11c (135 mg, 54%) as a white solid, mp 130ꢀ133 °C; H NMR (600 MHz, CDCl )
3
13
δ 7.26 (s, 1H), 2.60 (s, 3H), 0.45 (s, 9H); C NMR (151 MHz, CDCl ) δ 164.1, 160.7, 146.6,
3
129.0, 119.4, 116.9, 26.4, 0.00. Anal. Calcd. for C H BrN Si: C: 44.61; H: 4.87; Br: 29.68; N:
10 13 2
10.41; Si: 10.43. Found: C: 44.49; H: 4.73; Br: 29.52; N: 10.34.
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2
-bromo-6-methyl-4-phenylnicotinonitrile (11d). Prepared according to the previously
6
a
reported procedure with some modifications. To a stirred slurry of the enamine 10d (174 mg,
.733 mmol, 1.0 equiv) in toluene (3.0 mL) was added a 33 wt% solution of HBr in AcOH (760
L, 4.62 mmol, 6.3 equiv) dropwise, and the reaction was allowed to stir at room temperature for
0
0
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0
1
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0
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0
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9
0
1
2
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4
5
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7
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9
0
ꢁ
3 hours. The reaction mixture was poured into a solution of sodium hydroxide (1M) and
extracted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with
ethyl acetate and the combined organic layers were washed with water, brine, dried with
anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The crude
material was purified by flash column chromatography on silica gel (ethyl acetate/hexanes) to
1
yield pyridine 11d (167 mg, 83%) as a white solid, mp 152ꢀ155 °C; H NMR (600 MHz, CDCl )
3
1
3
δ 7.45ꢀ7.48 (m, 1H), 7.21ꢀ7.23 (m, 1H), 7.03ꢀ7.08 (m, 2H), 3.86 (s, 3H), 2.64 (s, 3H); C NMR
(151 MHz, CDCl ) δ 163.1, 155.6, 144.8, 135.3, 130.5, 129.1, 128.4, 122.7, 116.1, 109.6, 24.7.
3
+
HRMS (ESI+) m/z: [M + H] calcd for C H BrN , 273.00274; Found, 273.00257.
13 10
2
2-bromo-4-(2-methoxyphenyl)-6-methylnicotinonitrile (11e). Prepared according to the
6
a
previously reported procedure with some modifications. To a stirred slurry of the enamine 10e
(222 mg, 0.830 mmol, 1.0 equiv) in toluene (3.3 mL) was added a 33 wt% solution of HBr in
AcOH (861 ꢁL, 5.23 mmol, 6.3 equiv) dropwise, and the reaction was allowed to stir at room
temperature for 3 hours. The reaction mixture was poured into a solution of sodium hydroxide
(1M) and extracted with ethyl acetate. The layers were separated, and the aqueous layer was
extracted with ethyl acetate and the combined organic layers were washed with water, brine,
dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure.
The crude material was purified by flash column chromatography on silica gel (ethyl
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