Titanium-catalyzed, one-pot synthesis of 2-amino-3-cyano- pyridines

Article abstract of DOI:10.1002/adsc.201301046

Earth-abundant and inexpensive titanium can catalyze alkyne iminoamination, which generates tautomers of 1,3-diimines. Upon treatment with base (DBU) and malononitrile, the multicomponent coupling product is converted to 2-amino-3-cyanopyridines in a one-

Full text of DOI:10.1002/adsc.201301046

FULL PAPERS
DOI: 10.1002/adsc.201301046
Titanium-Catalyzed, One-Pot Synthesis of 2-Amino-3-cyano-
pyridines
Amila A. Dissanayake,a Richard J. Staples,a and Aaron L. Odoma,*
a
Michigan State University, Department of Chemistry, 578 S. Shaw Ln, East Lansing, MI 48824, USA
E-mail: odom@chemistry.msu.edu
Received: November 22, 2013; Revised: January 10, 2014; Published online: April 15, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301046.
Abstract: Earth-abundant and inexpensive titanium vide significant evidence for a Dimroth rearrange-
can catalyze alkyne iminoamination, which generates ment mechanism for 2-aminopyridine formation, in-
tautomers of 1,3-diimines. Upon treatment with base cluding isolation of a 2-imino-1,2-dihydropyridine in-
(DBU) and malononitrile, the multicomponent cou- termediate that undergoes rearrangement under the
pling product is converted to 2-amino-3-cyanopyri- reaction conditions.
dines in a one-pot procedure in good to modest
yields. There is substantial control of regioselectivity
for the substituents on the pyridine ring and on the Keywords: heterocycles; multicomponent reactions;
2-amino group. Several studies were done that pro- pyridines; titanium
Introduction
amine is on one of the carbons derived from the ma-
lononitrile in the 2-aminopyridine product, a detail
The pyridine[1] core is one of the most important het- that needed to be accounted for in the proposed
erocyclic ring structures found in pharmaceuticals and mechanism (vide infra).
natural products. Among pyridine structures, 2-
amino-3-cyanopyridine derivatives have been found
to be an important subclass. Substituted 2-amino-3-cy-
anopyridine derivatives exhibit biological activities
and are, for example, kinase inhibitors,[2] antimicrobial
agents,[3] antitumour agents,[4] anti-inflammatory
agents,[5] cannabinoid receptor agonists[6] and anticon-
vulsants.[7] In addition, they are also being studied for
their optical properties.[8]
In recent studies we have applied earth-abundant,
non-toxic titanium to the synthesis of important heter-
ocyclic classes.[9] The procedures involve a titanium-
catalyzed multicomponent coupling reaction between
a primary amine, isonitrile, and an alkyne to generate
tautomers of 1,3-diimines; the alkyne undergoes imi-
noamination, addition of imine and amine across the
triple bond (Figure 1).[10]
Here, we report that 2-amino-3-cyanopyridines (1)
are available in a one-pot procedure from the cou-
pling of alkynes, primary amines, isonitriles, and ma-
lononitrile in good to modest yields.[11] The overall
transformation is shown in Scheme 1. Of particular
mechanistic interest is the fact that the primary amine
Figure 1. Proposed catalytic cycle for iminoamination of an
alkyne and structures of the precatalysts Ti(dpma)(NMe2)2
(dpm)(NMe2)2 (B).
is on the same carbon as R2 from the alkyne in the
N
ACHTUNGTRENNUNG
iminoamination intermediate (brackets), but the (A) and Ti
N
ACHTUNGTRENNUNG
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Amila A. Dissanayake et al.
Results and Discussion
The two titanium catalysts employed in this work are
shown in Figure 1. The pyrrole-based ancillary ligands
are available in a single step from commercially avail-
able compounds.[12] Placement of the ligands on titani-
um occurs in high yield with commercially available
TiACTHNUTRGNEUNG
(NMe2)4.[13]
Catalyst A is less active but is also less prone to
side reactions with more reactive terminal alkynes.
Catalyst B is more active and is often used for less re-
active internal alkynes. In the end, each catalyst can
exhibit somewhat different regioselectivities, and
these two catalysts were screened during optimiza-
tion. For most reactions explored here, the dipyrrolyl-
methane-based B was optimal.
Scheme 1. One-pot synthesis of 2-amino-3-cyanopyridines
(1) using a titanium-catalyzed multicomponent coupling.
Our initial screens utilized multicomponent cou-
pling between aniline, 1-phenylpropyne, tert-butyl iso-
nitrile and malononitrile. The 2-amino-3-cyanopyri-
dine (1a) was obtained in 72% yield using catalytic
DBU in dry ethanol (Scheme 2).
First, we examined a single alkyne, 1-phenylpro-
pyne, with a variety of amines and tert-butyl isonitrile;
these reactions gave a host of 2-amino-3-cyano-5-
phenyl-6-methylpyridines with different groups on the
2-amino nitrogen. The results with 1-phenylpropyne
are found in Figure 2. The multicomponent coupling
reaction is regioselective, and the phenyl group de-
rived from 1-phenylpropyne is found in the 5-position
of all the pyridine products.[14]
The reaction was amenable to the use of a variety
of aromatic and heterocyclic amines as well as some
alkylamines. A few similar alkylamines such as 1-ami-
nohexane, benzylamine, and benzhydrylamine provid-
Scheme 2. One-pot synthesis 1a.
Figure 2. Examples of substituted 2-amino-3-cyanopyridine syntheses using 1-phenylpropyne and a variety of primary aryl
and alkylamines.
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Titanium-Catalyzed, One-Pot Synthesis of 2-Amino-3-cyanopyridines
Table 1. Other examples of substituted 2-amino-3-cyanopyri-
dine syntheses.[a]
Scheme 3. Primary amine selectively becomes the 2-amino
substituent in 1 when internal alkynes are employed.
ed the 3-component coupling product; however, the
cyclization with malononitrile to generate the pyri-
dine was not successful with the conditions developed.
Yields ranged from 76–42% with the average being
64% for 11 examples in Figure 2 with this one-pot
procedure.
The primary amine in the reaction is selectively
found as the group in the 2-position of the product
(Scheme 3) when using internal alkynes. This is likely
due to initial malononitrile attack on the more steri-
cally available formimine carbon rather than the keti-
mine carbon of the multicomponent coupling inter-
mediate and is true for all the compounds derived
from internal alkynes examined.
In a second series of reactions, the amine was held
constant as either aniline or cyclohexylamine and the
alkyne was varied. For these studies, we explored
a mix of terminal and internal alkynes with aromatic
and alkyl substituents. The results are shown in
Table 1. In general, if one of the alkyne substituents
binds to the alkyne with an sp2-carbon, that aromatic
or vinyl group is in the 5-position of the isolated pyri-
dine product.[14]
Several possible reaction mechanisms for the for-
mation of 1 can be envisioned. Among these is the
possibility of a Dimroth rearrangement[15] being in-
volved in the formation of the 2-aminopyridines. The
proposed mechanism is shown in Scheme 4 starting
from the 3-component coupling product. A key inter-
mediate in the Dimroth rearrangement, which in-
volves isomerization where exo- and endocyclic nitro-
gen atoms are exchanged, (Scheme 4) for this system
is 2-imino-1,2-dihydropyridine 2. Rearrangement of 2
would lead to the observed product and would be
thermodynamically driven by aromatization of the
pyridine ring.
[a]
Conditions: 1.2–1.5 mmol tert-butyl isonitrile, 1 mmol ani-
line, 1 mmol alkyne, 10 mol% B, 2 mL toluene, 1008C,
48 h. Then, 2 mmol malononitrile, 0.5 mmol DBU,
200 mg of 3 ꢁ sieves, 2 mL absolute ethanol, 2 h, 808C.
Isolated yield.
20 mol% B was used.
1 mmol cyclohexylamine used in place of aniline and
10 mol% A used in place of B.
[b]
We postulated that intermediate 2 might be avail-
able from the same multicomponent coupling product
by use of a less nucleophilic base, e.g., NEt3, which
would be sufficient to reach this intermediate but per-
[c]
[d]
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Amila A. Dissanayake et al.
We found that synthesis of a 2-iminopyridine prod-
uct 2a was possible using the conditions shown in
Scheme 5. Then, 2a was converted to the 2-aminopyri-
dine 1v in the presence of DBU and malononitrile in
ethanol in 86% yield.
Both DBU and malononitrile were required for
conversion of 2a to 1v; leaving either reagent out of
the solution resulted in no reaction. Apparently, ma-
lononitrile has a dual role in 2-aminopyridine synthe-
sis; it acts as both reagent and as catalytic acid for the
rearrangement. Consistent with this, replacing malo-
nonitrile with phenol as the acid also resulted in Dim-
roth rearrangement of 2a in the presence of DBU.
Consequently, we propose that protonation of 2 is re-
quired prior to base-promoted ring opening
(Scheme 4).
Conclusions
Titanium-catalyzed multicomponent coupling pro-
vides an expedient route to the pyridine core struc-
ture with good control of regioselectivity. This new 4-
component, one-pot route provides 2-amino-3-cyano-
pyridines in good to modest yields.
The reaction involves the initial 3-component cou-
pling (3CC) of an amine, isonitrile and alkyne in the
presence of a titanium catalyst. The product is not iso-
lated. Instead, it is treated with malononitrile, etha-
Scheme 4. Proposed mechanism for 2-aminopyridine forma-
tion. B=base, HA=acid.
haps not strong enough for the ring opening step that nol, molecular sieves and catalytic DBU to give the 2-
DBU can accomplish.[16] Once isolated, submitting the amino-3-cyanopyridine products from the one-pot
2-iminopyridine intermediate 2 to the DBU cycliza- procedure.
tion conditions should give the 2-aminopyridine prod-
uct 1 via exo-/endocyclic nitrogen exchange.
In all cases where an internal alkyne was used
(Scheme 1, R2 and R3 ¼H), the amine substituent
found in the 2-position of the product is derived from
the primary amine used in the multicomponent cou-
pling reaction (Figure 2, Table 1 1l–1p). If R2 =H and
the primary amine is an aniline derivative, then the 2-
amino group bears the aromatic group of the aniline
(Table 1 1q–1u). If R2 =H and both the primary
amine and isonitrile bear alkyl groups, the larger of
the two alkyl groups preferentially is found on the 2-
amino group (Table 1, 1v–1u).
If the alkyne has an sp2-hybridized substituent
(vinyl, aromatic, or heteroaromatic), there is usually
a strong preference for this group to be placed as R3
in Scheme 1.[14]
A Dimroth mechanism was proposed for the trans-
formation (Scheme 4). Dimroth rearrangements in-
volve exchange of endo- and exocyclic nitrogen
atoms, often with aromatization of a heterocycle driv-
ing the reaction. In this case, it was found that addi-
tion of malononitrile and triethylamine in methanol/
water provides the 2-imino-1,2-dihydropyridine (2), at
least in the case where the 3-component coupling
compound is derived from cyclohexylamine, phenyla-
cetylene, and tert-butyl isonitrile (Scheme 5). Com-
Scheme 5. Synthesis of 2a and 1v from the same multicom-
ponent coupling product and conversion of 2a to 1v.
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Titanium-Catalyzed, One-Pot Synthesis of 2-Amino-3-cyanopyridines
Extinction coefficients for all compounds were acquired in
CH2Cl2 solutions using a Varian Cary 50 UV-Visible spectro-
photometer.
pound 2 is likely derived from simple replacement of
NR4 (Scheme 1) in the multicomponent coupling
product by the central carbon of malononitrile, cata-
lyzed by triethylamine. After this first step in the pro-
posed mechanism (Scheme 4), the compound can un-
dergo 6-endo dig cyclization to give 2, and if the base
is NEt3 this is where the reaction stops.
6-Methyl-5-phenyl-2-(phenylamino)nicotinonitrile
(1a)[19]
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with aniline
(95 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and
tert-butyl isonitrile (171 mL, 1.5 mmol). The pressure tube
was sealed with a Teflon screw cap, taken out of the dry
box, and heated for 48 h at 1008C in a silicone oil bath. The
pressure tube was cooled to room temperature. Then, the
tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a yellow solid; yield:
If the reaction with malononitrile and the 3CC
product is run in the presence of the more nucleophil-
ic DBU, the reaction proceeds to the 2-amino-3-cya-
nopyridine (1). Consistent with a Dimroth rearrange-
ment, subjecting 2 to the reaction conditions, malono-
nitrile and DBU, also provides 1 in good yield. In the
conversion of 2 to 1 (Scheme 5), both the malononi-
trile and DBU were required for the rearrangement
to take place, otherwise 2 was simply recovered. The
base, DBU, is required for the Dimroth ring opening,
but what is the purpose of the malononitrile in the re-
arrangement? Naturally, malononitrile is acidic, and
we postulated that an acid was also required. Re-
placement of malononitrile with phenol, a compound
with a comparable pKa in water,[17] leads to Dimroth
rearrangement of 2 to 1 in the presence of DBU. Con-
sequently, we propose that malononitrile has a duel
role in the synthesis of 1, reagent and catalytic acid. It
may be that the optimized reaction conditions involve
2 equiv. of malononitrile because of these two roles,
and that reoptimization of the reaction could be done
with 1 equivalent of malononitrile and an external
acid if desired.
1
205 mg (72%); mp 119–1218C. H NMR (CDCl3, 500 MHz):
d=2.53 (3H, s, CH3), 7.14–7.17 (2H, br, CH-Ar, NH-ani-
line), 7.32–7.34 (2H, d, 8 Hz, CH-Ar), 7.40–7.45 (3H, m,
CH-Ar), 7.47–7.51 (2H, m, CH-Ar), 7.66 (1H, s, 4-CH-pyri-
dine), 7.76–7.78 (2H, d, 8.5 Hz, CH-Ar); 13C{1H} NMR
(CDCl3, 125 MHz): d=23.9, 90.3, 116.5, 119.9, 123.2, 127.5,
127.9, 128.4, 128.7, 128.9, 138.0, 138.9, 141.9, 153.9, 159.9;
MS (EI): m/z=285; electronic absorption (CH2Cl2): l (e,
Mꢀ1 cmꢀ1)=294 (24,800), 342 nm (1,100); elemental analysis:
found: C 80.10, H 5.25, N 14.65; calcd.; C 79.98, H 5.30, N
14.73.
2-(Cyclohexylamino)-6-methyl-5-phenylnicotinonitrile
(1b)
Experimental Section
General Considerations:
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with cyclohex-
ylamine (99 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 1 mmol), molecular sieves (200 mg),
and absolute ethanol (2 mL). The mixture was heated for
2 h at 808C in a silicone oil bath. After completion of the re-
action, the crude product was purified by flash column chro-
matography over silica gel with 9:1 hexanes to ethyl acetate
to afford the desired compound as a brown solid; yield:
All manipulations of air-sensitive compounds were carried
out in an MBraun drybox under a purified nitrogen atmos-
phere. Toluene was purified by first sparging with dry nitro-
gen to remove oxygen and then running through activated
alumina to remove water. H and 13C NMR spectra were re-
1
corded on VXR-500 spectrometers. Melting points are un-
corrected and measured on a Mel-Temp II apparatus (Labo-
ratory Devices Inc, USA) with a mercury thermometer in
an open capillary tube. Ti
ACHUTNGTRENUNG(NMe2)2ACHUTNGTREN(NUNG dpma) (A) and Ti-
A
CHTUNGTRENNUNG
cedures.[13] Alkynes were purchased either from Sigma–Al-
drich or Oakwood chemicals and were distilled from CaO
under dry nitrogen. Amines were purchased from Sigma–Al-
drich, dried over KOH, and distilled under dry nitrogen.
tert-Butyl isonitrile was prepared from H2NBu-t, CHCl3, and
aqueous base according to the literature procedure and puri-
fied by distillation under dry nitrogen.[18] Malononitrile, 1,8-
1
195 mg (67%); mp 144–1478C. H NMR (CDCl3, 500 MHz):
d=1.25–1.32 (4H, m, CH2), 1.43–1.48 (2H, m, CH2) 1.79–
1.83 (2H, m, CH2), 2.07–2.12 (2H, m, CH2), 2.42 (3H, s,
CH3), 4.12–4.13 (1H, m, CH), 4.96–4.98 (1H, d, 8 Hz, NH-
cyclohexyl), 7.26–7.27 (2H, d, 7 Hz, CH-Ar), 7.36–7.39 (1H,
m, 7 Hz, CH-Ar), 7.44–7.41 (2H, t, 7 Hz, CH-Ar), 7.50 (1H,
s, 4-CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz): d=
24.1, 24.9, 25.7, 33.2, 49.7, 88.3, 117.2, 125.6, 127.2, 128.4,
129.1, 138.8, 141.8, 156.4, 160.3; MS (EI): m/z=291; elec-
tronic absorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=272 (14,400),
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU), and silica gel were
purchased from Sigma–Aldrich and used as received. Molec-
ular sieves as 3ꢁ, 1/16“ pellets were purchased from Spec-
trum chemicals and were activated by heating under dynam-
ic vacuum. Absolute ethanol was purchased from KOPTEC
and used as received. Hexanes and ethyl acetate were pur-
chased from Mallinckrodt Chemicals and used as received.
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Amila A. Dissanayake et al.
347 nm (4,400); elemental analysis: found: C 78.29, H 7.20,
N 14.51; calcd.: C 78.32, H 7.26, N 14.42.
2-[(3-methoxyphenyl)amino]-6-methyl-5-phenyl-
nicotinonitrile (1e)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 3-me-
thoxyaniline (123 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a brown
solid; yield: 217 mg (69%); mp 129–1308C. 1H NMR
(CDCl3, 500 MHz): d=2.53 (3H, s, CH3), 3.88 (3H, s,
OCH3), 6.69–6.71 (2H, dd, 1 Hz, 6 Hz, CH-Ar), 7.09 (1H,
br, NH-3-methoxyaniline), 7.20–7.28 (1H, m, CH-Ar), 7.29–
7.33 (3H, m, CH-Ar), 7.42–7.44 (2H, d, 7.5 Hz, CH-Ar),
7.46–7.50 (2H, m, CH-Ar). 7.59–7.60 (1H, m, CH-Ar). 7.66
(1H, s, 4-CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz):
d=21.3, 23.9, 90.2, 116.5, 117.8, 125.1, 127.4, 127.7, 128.4,
128.9, 138.1, 138.4, 138.7, 141.9, 154.1, 160.0; MS (EI): m/z=
315; electronic absorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=299
(22,900), 340 nm (4,700); elemental analysis: found: C 76.02,
H 5.37, N 13.39; calcd.: C 76.17, H 5.43, N 13.32.
2-[(3,5-Dimethylphenyl)amino]-6-methyl-5-phenyl-
nicotinonitrile (1c)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 3,5-dime-
thylaniline (121 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a brown
1
solid; yield: 237 mg (76%); mp 98–1008C. H NMR (CDCl3,
500 MHz): d=2.40 (6H, s, CH3), 2.54 (3H, s, CH3), 6.82
(1H, br, NH-3,5-dimethylaniline), 7.01 (1H, s, CH-Ar),
7.32–7.34 (2H, d, 8.5 Hz, CH-Ar), 7.39 (2H, s, CH-Ar),
7.43–7.44 (1H, m, CH-Ar), 7.47–7.51 (2H, m, CH-Ar), 7.65
(1H, s, 4-CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz):
d=21.3, 23.9, 90.2, 116.5, 117.8, 125.1, 127.4, 127.7, 128.4,
128.9, 138.1, 138.4, 138.7, 141.9, 154.1, 160.0; MS (EI): m/z=
313; electronic absorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=297
(20,600), 342 nm (4,900); elemental analysis: found: C 80.53,
H 6.19, N, 13.28; calcd.: C 80.48, H 6.11, N 13.41.
6-Methyl-2-(naphthalen-2-ylamino)-5-phenyl-
nicotinonitrile (1f)
2-[(4-Chlorophenyl)amino]-6-methyl-5-phenyl-
nicotinonitrile (1d)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with naphtha-
len-2-amine (143 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a yellow
solid; yield: 211 mg (63%); mp 144–1468C. 1H NMR
(CDCl3, 500 MHz): d=2.56 (3H, s, CH3), 7.21 (1H, br, NH-
naphthalen-1-amine), 7.32–7.34 (2H, m, CH-Ar), 7.42–7.43
(2H, m, CH-Ar), 7.44–7.51 (3H, m, CH-Ar), 7.69 (1H, s, 4-
CH-pyridine), 7.70–7.73 (1H, d, 8.5 Hz, CH-Ar), 7.83–7.87
(3H, m, CH-Ar). 8.37–8.38 (1H, d, 2 Hz, CH-Ar);
13C{1H} NMR (CDCl3, 125 MHz): d=24.1, 90.6, 120.8, 124.5,
126.4, 127.4, 127.5, 127.6, 128.1, 128.3, 128.5, 128.6, 129.0,
130.2, 131.4, 134.0, 136.5, 138.0, 142.0, 154.0, 160.2; MS (EI):
m/z=335; electronic absorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=
278 (32,900), 311 nm (31,900); elemental analysis: found: C
82.41, H 5.16, N 12.43; calcd.: C 82.36, H 5.11, N 12.53.
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 4-chlor-
oaniline (127 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a brown
solid; yield: 223 mg (70%); mp 167–1698C. 1H NMR
(CDCl3, 500 MHz): d=2.51 (3H, s, CH3), 7.08 (1H, br, NH-
4-chloroaniline), 7.30–7.32 (2H, d, 8.5 Hz, CH-Ar), 7.34–
7.36 (2H, d, 9 Hz, CH-Ar), 7.42–7.44 (1H, m, CH-Ar), 7.46–
7.49 (2H, m, CH-Ar), 7.67 (1H, s, 4-CH-pyridine), 7.69–7.70
(2H, d, 9 Hz, CH-Ar); 13C{1H} NMR (CDCl3, 125 MHz):
d=24.0, 90.5, 103.6, 107.7, 121.2, 127.6, 128.1, 128.2, 128.4,
128.5, 128.8, 128.9, 142.1, 153.7, 160.1; MS (EI): m/z=319;
electronic absorption (CH2Cl2):
l
(e, Mꢀ1 cmꢀ1)=298
(24,400), 347 nm (4,900); elemental analysis: found: C 71.25,
H 4.37, N 13.21; calcd.: C 71.36, H 4.41, N 13.14.
1816
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 1811 – 1822

FULL PAPERS
Titanium-Catalyzed, One-Pot Synthesis of 2-Amino-3-cyanopyridines
2-[(4-Fluorophenyl)amino]-6-methyl-5-phenyl-
nicotinonitrile (1g)
2-[(4-Methoxyphenyl)amino]-6-methyl-5-phenyl-
nicotinonitrile (1i)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 4-fluoroa-
niline (111 mg, 1 mmol), 1-phenylpropyne (116 mg, 1 mmol),
and tert-butyl isonitrile (171 mL, 1.5 mmol). The pressure
tube was sealed with a Teflon screw cap, taken out of the
dry box, and heated for 48 h at 1008C in a silicone oil bath.
The pressure tube was cooled to room temperature. Then,
the tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a light brown solid; yield:
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 4-me-
thoxyaniline (123 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a yellow
solid; yield: 230 mg (73%); mp 108–1108C. 1H NMR
(CDCl3, 500 MHz): d=2.48 (3H, s, CH3), 3.86 (3H, s,
OCH3), 6.95–6.97 (2H, d, 8.5 Hz, CH-Ar), 6.99 (1H, br,
NH-4-methoxyaniline), 7.30–3.32 (2H, d, 8.5 Hz, CH-Ar),
7.41–7.42 (1H, m, CH-Ar), 7.46–7.49 (2H, m, CH-Ar), 7.60–
7.63 (3H, m, CH-Ar, 4-CH-pyridine); 13C{1H} NMR (CDCl3,
125 MHz): d=23.9, 55.3, 89.6, 103.5, 114.0, 116.7, 122.4,
127.4, 128.4, 128.9, 131.9, 138.1, 142.0, 154.4, 155.9, 160.1;
MS (EI): m/z=315; electronic absorption (CH2Cl2): l (e,
Mꢀ1 cmꢀ1)=296 (19,100), 345 nm (3,900); elemental analysis:
found: C 76.26, H 5.51, N 13.22; calcd.: C 76.17, H 5.43, N
13.32.
1
127 mg (42%); mp 126–1288C. H NMR (CDCl3, 500 MHz):
d=2.50 (3H, s, CH3), 7.08–7.11 (1H, t, 9 Hz, CH-Ar), 7.16
(1H, br, NH-4-fluoroaniline), 7.31–7.33 (2H, d, 5.5 Hz, CH-
Ar), 7.43–7.44 (1H, m, CH-Ar), 7.47–7.50 (2H, m, CH-Ar),
7.65 (1H, s, 4-CH-pyridine), 7.68–7.71 (2H, m, CH-Ar);
13C{1H} NMR (CDCl3, 125 MHz): d=23.9, 90.0, 103.5, 107.6,
115.2, 116.5, 121.9, 127.5, 128.4, 134.9, 137.9, 142.0, 154.0,
157.8, 159.7; 19F NMR (CDCl3, 500 MHz): d=ꢀ119.1 (m);
MS (EI): m/z=303; electronic absorption (CH2Cl2); l (e,
Mꢀ1 cmꢀ1)=291 (23,200), 342 nm (4,700); elemental analysis:
found: C 75.31, H 4.69, N 13.79; calcd.: C 75.23, H 4.65, N
13.85.
2-[(4-Bromophenyl)amino]-6-methyl-5-phenyl-
nicotinonitrile (1h)
6-Methyl-2-(naphthalen-1-ylamino)-5-phenyl-
nicotinonitrile (1j)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 4-bro-
moaniline (170 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a brown
solid; yield: 247 mg (68%); 164–1668C. 1H NMR (CDCl3,
500 MHz): d=2.51 (3H, s, CH3), 7.08 (1H, br, NH-4-bro-
moaniline), 7.30–7.32 (2H, d, 8 Hz, CH-Ar), 7.42–7.43 (1H,
m, CH-Ar), 7.46–7.50 (4H, m, CH-Ar), 7.64–7.67 (3H, m,
CH-Ar, 4-CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz):
d=21.3, 90.2, 116.5, 117.8, 125.1, 127.4, 127.7, 128.4, 128.9,
138.1, 138.4, 138.7, 141.9, 154.1, 160.0; MS (EI): m/z=363;
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with naphtha-
len-1-amine (143 mg, 1 mmol), 1-phenylpropyne (116 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
The pressure tube was cooled to room temperature. Then,
the tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a brown solid; yield: 174 mg
(52%); mp 152–1568C. 1H NMR (CDCl3, 500 MHz): d=
2.45 (3H, s, CH3), 7.32 (1H, br, NH-naphthalen-2-amine),
7.33–7.34 (1H, m, CH-Ar), 7.41–7.50 (4H, m, CH-Ar), 7.56–
7.62 (3H, m, CH-Ar), 7.71 (1H, s, 4-CH-pyridine), 7.77–7.79
(1H, d, 8.5 Hz, CH-Ar), 7.94–7.96 (1H, d, 8 Hz, CH-Ar),
8.09–8.11 (1H, d, 8 Hz, CH-Ar), 8.18–8.19 (1H, d, 7.5 Hz,
CH-Ar); 13C{1H} NMR (CDCl3, 125 MHz): d=24.0, 90.2,
116.6, 120.0, 120.9, 125.1, 125.5, 125.9, 126.2, 127.5, 127.7,
128.1, 128.5, 128.6, 128.9, 133.7, 134,2, 138.1, 142.1, 155.1,
160.3; MS (EI): m/z=335; electronic absorption (CH2Cl2):
l (e, Mꢀ1 cmꢀ1)=272 (11,100), 328 nm (12,500); elemental
analysis: found: C 82.14, H 5.21, N 12.65; calcd.: C 82.36, H
5.11, N 12.53.
electronic absorption (CH2Cl2):
l
(e, Mꢀ1 cmꢀ1)=299
(41,600), 342 nm (7,400); elemental analysis: found: C 62.57,
H 3.82, N 11.59; calcd.: C 62.65, H 3.87, N 11.54.
Adv. Synth. Catal. 2014, 356, 1811 – 1822
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1817

FULL PAPERS
Amila A. Dissanayake et al.
2-[(1-Benzyl-1H-indol-5-yl)amino]-6-methyl-5-phenyl- 6-Ethyl-2-(phenylamino)-5-(prop-1-en-2-yl)nicotino-
nicotinonitrile (1k)[19]
nitrile (1m)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with 1-benzyl-
1H-indol-5-amine (222 mg, 1 mmol), 1-phenylpropyne
(116 mg, 1 mmol), and tert-butyl isonitrile (171 mL,
1.5 mmol). The pressure tube was sealed with a Teflon screw
cap, taken out of the dry box, and heated for 48 h at 1008C
in a silicone oil bath. The pressure tube was cooled to room
temperature. Then, the tube was charged with malononitrile
(132 mg, 2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a yellow
solid; yield: 223 mg (54%); mp 143–1468C. 1H NMR
(CDCl3, 500 MHz): d=2.47 (3H, s, CH3), 5.36 (2H, s, CH2),
6.57–6.58 (1H, d, J=4 Hz, 2-pyrrole-CH), 7.03 (1H, br, NH-
1-benzyl-1H-indol-5-amine), 7.11–7.18 (3H, m, CH-Ar),
7.27–7.41 (9H, m, CH-Ar), 7.44–7.46 (2H, t, 1.5 Hz, CH-
Ar), 7.63 (1H, s, 4-CH-pyridine), 8.00 (1H, s, CH-Ar);
13C{1H} NMR (CDCl3, 125 MHz): d=24.1, 50.2, 89.5, 101.7,
109.8, 113.6, 116.9, 117.3, 126.7, 127.3, 127.4, 127.6, 128.5,
128.7, 128.9, 129.0, 129.0, 131.2, 133.7, 137.4, 138.4, 142.1,
155.6, 160.2; MS (EI): m/z=414; electronic absorption
(CH2Cl2): l (e, Mꢀ1 cmꢀ1)=283 (21,000), 353 nm (3,800); ele-
mental analysis: found: C 81.33, H 5.27, N 13.40; calcd.: C
81.13, H 5.35, N 13.52.
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 2-methylhex-1-en-3-yne (94 mg, 1 mmol),
and tert-butyl isonitrile (171 mL, 1.5 mmol). The pressure
tube was sealed with a Teflon screw cap, taken out of the
dry box, and heated for 48 h at 1008C in a silicone oil bath.
The pressure tube was cooled to room temperature. Then,
the tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a brown solid; yield: 157 mg
1
(60%); mp 72–748C. H NMR (CDCl3, 500 MHz): d=1.26–
1.30 (3H, t, 7.5 Hz CH3), 2.00 (3H, m, CH3), 2.75–1.79 (2H,
q, 7.5 Hz, CH2), 4.88–4.89 (1H, m, CH), 5.22–5.23 (1H, m,
CH), 6.94 (1H, br, NH-aniline), 7.05–7.07 (1H, t, 7.5 Hz,
CH-Ar), 7.32–7.35 (2H, m, CH-Ar), 7.48 (1H, s, 4-CH-pyri-
dine), 7.66–7.68 (2H, d, 10 Hz, CH-Ar); 13C{1H} NMR
(CDCl3, 125 MHz): d=13.1, 24.4, 28.9, 89.8, 116.7, 116.9,
119.8, 123.1, 128.8, 129.3, 139.1, 140.7, 142.1, 154.1, 164.0;
MS (EI): m/z 263; electronic absorption (CH2Cl2): l (e,
Mꢀ1 cmꢀ1)=290 (20,700), 344 nm (4,400); elemental analysis:
found: C 77.47, H 6.58, N 15.95; calcd.: C 77.54, H 6.51, N
15.96.
5,6-Diethyl-2-(phenylamino)nicotinonitrile (1l)
6-{3-[(tert-Butyldiphenylsilyl)oxy]propyl}-5-phenyl-2-
(phenylamino)nicotinonitrile (1n)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), hex-3-yne (82 mg, 1 mmol), and tert-butyl
isonitrile (171 mL, 1.5 mmol). The pressure tube was sealed
with a Teflon screw cap, taken out of the dry box, and
heated for 48 h at 1008C in a silicone oil bath. The pressure
tube was cooled to room temperature. Then, the tube was
charged with malononitrile (132 mg, 2 mmol), DBU (76 mg,
0.5 mmol), molecular sieves (200 mg), and absolute ethanol
(2 mL). The mixture was heated for 2 h at 808C in a silicone
oil bath. After completion of the reaction, the crude product
was purified by flash column chromatography over silica gel
with 9:1 hexanes to ethyl acetate to afford the desired com-
pound as a brown solid; yield: 160 mg (64%); mp 100–
1028C. 1H NMR (CDCl3, 500 MHz): d=1.21–1.25 (3H, t,
J=8 Hz, CH3), 1.34–1.37 (3H, t, J=8 Hz, CH3), 2.57–2.62
(2H, t, J=8 Hz, CH2), 2.79–2.84 (2H, t, J=8 Hz, CH2), 6.96
(1H, br, NH-aniline), 7.09–7.11 (1H, t, 2.5 Hz, CH-Ar),
7.36–7.39 (2H, m, CH-Ar), 7.54 (1H, s, 4-CH-pyridine),
7.72–7.74 (2H, d, 8.5 Hz, CH-Ar); 13C{1H} NMR (CDCl3,
125 MHz): d=12.4, 14.2, 23.9, 28.0, 90.0, 117.0, 119.5, 122.6,
127.2, 128.6, 139.4, 140.4, 153.6, 164.8; MS (EI): m/z=251;
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), tert-butyldiphenyl[(5-phenylpent-4-yn-1-
yl)oxy]silane (398 mg, 1 mmol), and tert-butyl isonitrile
(171 mL, 1.5 mmol). The pressure tube was sealed with
a Teflon screw cap, taken out of the dry box, and heated for
48 h at 1008C in a silicone oil bath. The pressure tube was
cooled to room temperature. Then, the tube was charged
with malononitrile (132 mg, 2 mmol), DBU (76 mg,
0.5 mmol), molecular sieves (200 mg), and absolute ethanol
(2 mL). The mixture was heated for 2 h at 808C in a silicone
oil bath. After completion of the reaction, the crude product
was purified by flash column chromatography over silica gel
with 9:1 hexanes to ethyl acetate to afford the desired com-
pound as a yellow solid; yield: 345 mg (61%); mp 90–928C.
1H NMR (CDCl3, 500 MHz): d=1.15 (9H, s, Si-CCH3),
2.16–2.19 (2H, m, CH2CH2CH2OTBDMS), 3.01–3.04 (2H, t,
J=7.5 Hz, CH2CH2CH2OTBDMS), 3.81–3.84 (2H, t, J=
6 Hz, CH2CH2CH2OTBDMS), 7.19–7.22 (1H, t, 7.5 Hz, CH-
Ar), 7.29 (1H, br, NH-aniline), 7.38–7.39 (2H, m, CH-Ar),
7.45–7.55 (12H, m, CH-Ar), 7.72 (1H, s, 4-CH-pyridine),
7.75–7.76 (4H, m, CH-Ar), 7.84–7.86 (2H, d, 8.5 Hz, CH-
Ar); 13C{1H} NMR (CDCl3, 125 MHz): d=19.0, 26.7, 31.2,
32.3, 63.3, 90.0, 116.5, 120.0, 123.0, 127.4, 127.5, 127.9, 128.4,
128.6, 129.0, 129.3, 133.7, 135.3, 135.4, 137.9, 138.9, 142.1,
154.1, 163.1; 29Si NMR (CDCl3, 500 MHz): d=ꢀ4.39; elec-
tronic absorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=294 (15,000),
electronic absorption (CH2Cl2):
l
(e, Mꢀ1 cmꢀ1)=286
(14,500), 342 nm (3,600); elemental analysis: found: C 76.32,
H 6.92, N 16.76; calcd.: C 76.46, H 6.82, N 16.72.
1818
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 1811 – 1822

FULL PAPERS
Titanium-Catalyzed, One-Pot Synthesis of 2-Amino-3-cyanopyridines
344 nm (3,300); elemental analysis: found: C 78.22, H 6.64,
N 7.32; calcd.: C 78.27, H 6.57, N 7.40.
5-Phenyl-2-(phenylamino)nicotinonitrile (1q)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), ethynylbenzene (102 mg, 1 mmol), and
tert-butyl isonitrile (137 mL, 1.2 mmol). The pressure tube
was sealed with a Teflon screw cap, taken out of the dry
box, and heated for 24 h at 1008C in a silicone oil bath. The
pressure tube was cooled to room temperature. Then, the
tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a yellow solid; yield:
5-(Cyclohex-1-en-1-yl)-6-methyl-2-(phenylamino)-
nicotinonitrile (1o)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.10 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 1-(prop-1-yn-1-yl)cyclohex-1-ene (120 mg,
1 mmol), and tert-butyl isonitrile (171 mL, 1.5 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 48 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a brown
solid; yield: 159 mg (55%); mp 127–1298C. 1H NMR
(CDCl3, 500 MHz): d=1.70–1.73 (2H, m, CH2), 1.78–1.81
(2H, m, CH2), 2.19–2.21 (4H, m, CH2), 2.51 (3H, s, CH3),
5.65–5.66 (1H, d, 1.5 Hz, CH), 7.02 (1H, br, NH-aniline),
7.10–7.11 (1H, t, 8 Hz, CH-Ar), 7.36–7.39 (2H, m, CH-Ar),
7.49 (1H, s, 4-CH-pyridine), 7.71–7.72 (2H, d, 8.5 Hz, CH-
Ar); 13C{1H} NMR (CDCl3, 125 MHz): d=21.7, 22.7, 23.3,
25.2, 29.7, 89.8, 116.6, 119.7, 122.8, 128.1, 128.6, 130.4, 135.2,
139.1, 140.8, 153.5, 159.8; MS (EI): m/z=289; electronic ab-
sorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=290 (19,000), 344 nm
(3,900); elemental analysis: found: C 78.94, H 6.56, N 14.50;
calcd.: C 78.86, H 6.62, N 14.52.
1
168 mg (62%); mp 142–1448C. H NMR (CDCl3, 500 MHz):
d=7.04 (1H, br, NH-aniline), 7.13–7.14 (1H, t, 1 Hz, CH-
Ar), 7.36–7.39 (3H, m, CH-Ar), 7.43–7.49 (5H, m, CH-Ar),
7.60–7.62 (2H, d, 8.5 Hz, CH-Ar), 7.97–7.98 (1H, d, 7 Hz, 4-
CH-pyridine), 8.61–8.62 (1H, d, 7 Hz, 1-CH-pyridine);
13C{1H} NMR (CDCl3, 125 MHz): d=93.2, 116.3, 120.9,
124.0, 126.2, 127.7, 127.9, 129.0, 129.2, 136.0, 138.4, 139.6,
150.7, 155.0; MS (EI): m/z=271; electronic absorption
(CH2Cl2): l (e, Mꢀ1 cmꢀ1)=302 (25,500), 350 nm (4,300); ele-
mental analysis: found: C 79.77, H 4.77, N 15.55; calcd.: C
79.68, H 4.83, N 15.49.
5-(1-Benzyl-1H-indol-3-yl)-2-(phenylamino)nicotino-
nitrile (1r)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 1-benzyl-3-ethynyl-1H-indole (231 mg,
1 mmol), and tert-butyl isonitrile (137 mL, 1.2 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 24 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a brown
solid; yield: 196 mg (49%); mp 148–1518C; 1H NMR
(CDCl3, 500 MHz): d=5.32 (2H, s, CH2), 7.04 (1H, br, NH-
aniline), 7.09–7.112 (1H, t, 7 Hz, CH-Ar), 7.15–7.17 (2H, d,
7 Hz, CH-Ar), 7.20–7.38 (9H, m, CH-Ar), 7.60–7.62 (2H, d,
8 Hz, CH-Ar), 7.79–7.80 (1H, d, 7.5 Hz, CH-Ar), 8.01–8.02
(1H, d, 2.5 Hz, 4-CH-pyridine), 8.68–8.69 (1H, d, 2.5 Hz, 6-
CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz): d=50.2,
93.3, 110.3, 112.0, 116.5, 119.2, 120.6, 122.7, 122.7, 123.7,
125.5, 125.9, 126.9, 127.9, 128.9, 129.1, 136.7, 136.9, 138.6,
139.7, 150.6, 153.9; electronic absorption (CH2Cl2): l (e,
Mꢀ1 cmꢀ1)=315 (13,300), 367 nm (1,900); elemental analysis:
found: C 80.86, H 5.10, N 14.04; calcd.: C 80.98, H 5.03, N
13.99.
5,6-Diphenyl-2-(phenylamino)nicotinonitrile (1p)[19]
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (62.6 mg,
0.2 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 1,2-diphenylethyne (178 mg, 1 mmol), and
tert-butyl isonitrile (171 mL, 1.5 mmol). The pressure tube
was sealed with a Teflon screw cap, taken out of the dry
box, and heated for 48 h at 1008C in a silicone oil bath. The
pressure tube was cooled to room temperature. Then, the
tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a yellow solid; yield:
1
149 mg (43%); mp 140–1428C. H NMR (CDCl3, 500 MHz):
d=7.11–7.15 (4H, m, CH-Ar, NH-aniline), 7.25–7.31 (6H,
m, CH-Ar), 7.36–7.39 (2H, t, 8 Hz, CH-Ar), 7.42–7.43 (2H,
d, 7.5 Hz, CH-Ar), 7.75–7.76 (2H, d, 8 Hz, CH-Ar), 7.83 (H,
s, 4-CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz): d=
91.5, 116.5, 120.1, 123.4, 127.1, 127.3, 127.8, 128.5, 128.8,
128.9, 129.3, 130.0, 138.4, 138.8, 138.9, 143.9, 153.9, 159.3;
electronic absorption (CH2Cl2):
l
(e, Mꢀ1 cmꢀ1)=299
(37,900), 366 nm (8,800); elemental analysis: found: C 82.82,
H 5.00, N 12.18; calcd.: C 82.97, H 4.93, N, 12.10
Adv. Synth. Catal. 2014, 356, 1811 – 1822
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1819

FULL PAPERS
Amila A. Dissanayake et al.
5-(Cyclohex-1-en-1-yl)-2-(phenylamino)nicotinonitrile
(1s)
2-(Phenylamino)-5-(para-tolyl)nicotinonitrile (1u)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 1-ethynyl-4-methylbenzene (116 mg,
1 mmol), and tert-butyl isonitrile (137 mL, 1.2 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 24 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a yellow
solid; yield: 165 mg (58%); mp 137–1398C. 1H NMR
(CDCl3, 500 MHz): d=2.38 (3H, s, CH3), 7.01 (1H, br, NH-
aniline), 7.10–7.13 (1H, t, 7.5 Hz, CH-Ar), 7.25–7.26 (2H, d,
7.5 Hz, CH-Ar), 7.35–7.38 (3H, m, CH-Ar), 7.59–7.61 (2H,
dd, 1 Hz and 3 Hz CH-Ar), 7.95–7.96 (1H, d, 3 Hz, 4-CH-
pyridine), 8.59–8.60 (1H, d, 3 Hz, 6-CH-pyridine);
13C{1H} NMR (CDCl3, 125 MHz): d=21.1, 93.2, 116.4, 120.8,
123.9, 126.0, 127.7, 129.0, 129.9, 133.1, 138.5, 139.4, 150.5,
154.8; MS (EI): m/z=285; electronic absorption (CH2Cl2):
l (e, Mꢀ1 cmꢀ1)=305 (25,200), 354 nm (2,400); elemental
analysis: found: C 79.91, H 5.34, N 14.75; calcd.: C 79.98, H
5.30, N 14.73.
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 1-ethynylcyclohex-1-ene (106 mg, 1 mmol),
and tert-butyl isonitrile (137 mL, 1.2 mmol). The pressure
tube was sealed with a Teflon screw cap, taken out of the
dry box, and heated for 24 h at 1008C in a silicone oil bath.
The pressure tube was cooled to room temperature. Then,
the tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a yellow solid; yield:
1
154 mg (56%); mp 110–1128C. H NMR (CDCl3, 500 MHz):
d=1.61–1.66 (2H, m, CH2), 1.74–1.79 (2H, m, CH2), 2.17–
2.20 (2H, m, CH2), 2.28–2.31 (2H, m, CH2), 6.04–6.06 (1H,
d, 1.5 Hz, CH), 6.97 (1H, br, NH-aniline), 7.08–7.11 (1H, t,
8 Hz, CH-Ar), 7.33–7.36 (2H, m, CH-Ar), 7.55–7.57 (2H, m,
CH-Ar), 7.75–7.76 (1H, d, 2 Hz, 4-CH-pyridine), 8.39–8.40
(1H, d, 2 Hz, 6-CH-pyridine); 13C{1H} NMR (CDCl3,
125 MHz): d=21.7, 22.6, 25.7, 26.8, 92.7, 116.5, 120.6, 123.8,
125.4, 129.0, 129.1, 131.9, 137.8, 138.6, 148.8, 154.4; MS (EI):
m/z=275; electronic absorption (CH2Cl2): l (e, Mꢀ1 cmꢀ1)=
302 (13,700), 359 nm (2,100); elemental analysis: found: C
78.37, H 6.29, N 15.34; calcd.: C 78.52, H 6.22, N 15.26.
2-(tert-Butylamino)-5-phenylnicotinonitrile (1v)[19]
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst A (32.4 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with cyclohex-
ylamine (95 mg, 1 mmol), ethynylbenzene (102 mg, 1 mmol),
and tert-butyl isonitrile (137 mL, 1.2 mmol). The pressure
tube was sealed with a Teflon screw cap, taken out of the
dry box, and heated for 24 h at 1008C in a silicone oil bath.
The pressure tube was cooled to room temperature. Then,
the tube was charged with malononitrile (132 mg, 2 mmol),
DBU (76 mg, 0.5 mmol), molecular sieves (200 mg), and ab-
solute ethanol (2 mL). The mixture was heated for 2 h at
808C in a silicone oil bath. After completion of the reaction,
the crude product was purified by flash column chromatog-
raphy over silica gel with 9:1 hexanes to ethyl acetate to
afford the desired compound as a yellow oil; yield: 145 mg
(58%). 1H NMR (CDCl3, 500 MHz): d=1.43 (9H, s, C-
5-[4-(Benzyloxy)phenyl]-2-(phenylamino)nicotino-
nitrile (1t)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst B (30.8 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with aniline
(93 mg, 1 mmol), 1-(benzyloxy)-4-ethynylbenzene (208 mg,
1 mmol), and tert-butyl isonitrile (137 mL, 1.2 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 24 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a yellow
solid; yield: 248 mg (66%); mp 132–1358C. 1H NMR
(CDCl3, 500 MHz): d=5.01 (2H, s, CH2), 6.99 (1H, br, NH-
aniline), 7.04–7.06 (2H, dd, 2.5 Hz and 5.5 Hz CH-Ar),
7.10–7.13 (1H, t, 8 Hz, CH-Ar), 7.32–7.45 (8H, m, CH-Ar),
7.58–7.60 (2H, dd, 2.5 Hz and 5.5 Hz CH-Ar), 7.91–7.92
(1H, d, 2.5 Hz, 4-CH-pyridine), 8.56–8.57 (1H, d, 2.5 Hz, 6-
CH-pyridine); 13C{1H} NMR (CDCl3, 125 MHz): d=70.1,
93.2, 115.6, 116.4, 120.7, 123.9, 127.42, 127.44, 127.5, 128.1,
128.6, 128.7, 129.1, 136.6, 138.5, 139.2, 150.3, 154.6, 158.7;
MS (EI): m/z=377; electronic absorption (CH2Cl2): l (e,
Mꢀ1 cmꢀ1)=306 (11,600), 353 nm (1,600); elemental analysis:
found: C 79.47, H 5.13, N 11.08; calcd.: C 79.55, H 5.07, N
11.13.
AHCTUNGTREN(GNUN CH3)3), 5.43 (1H, br, NH-2-methylpropan-2-amine), 7.25–
7.27 (1H, m, CH-Ar), 7.31–7.36 (4H, m, CH-Ar), 7.00–7.01
(1H, d, 2 Hz, 4-CH-pyridine), 8.40–8.41 (1H, d, 2 Hz, 6-CH-
pyridine); 13C{1H} NMR (CDCl3, 125 MHz): d=28.9, 52.5,
91.7, 117.1, 124.6, 125.9, 127.3, 129.0, 136.6, 139.1, 150.4,
157.2; MS (EI): m/z=251; electronic absorption (CH2Cl2):
l (e, Mꢀ1 cmꢀ1): 284 (21,800), 352 nm (4,200); elemental
analysis: found: C 76.48, H 6.76, N 16.76; calcd.: C 76.46, H
6.82, N 16.72.
2-(tert-Butylamino)-5-(cyclohex-1-en-1-yl)nicotino-
nitrile (1w)
In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst A (32.4 mg,
1820
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Adv. Synth. Catal. 2014, 356, 1811 – 1822

FULL PAPERS
Titanium-Catalyzed, One-Pot Synthesis of 2-Amino-3-cyanopyridines
0.1 mmol) in dry toluene (2 mL) was loaded with cyclohex-
ylamine (95 mg, 1 mmol), 1-ethynylcyclohex-1-ene (106 mg,
1 mmol), and tert-butyl isonitrile (137 mL, 1.2 mmol). The
pressure tube was sealed with a Teflon screw cap, taken out
of the dry box, and heated for 24 h at 1008C in a silicone oil
bath. The pressure tube was cooled to room temperature.
Then, the tube was charged with malononitrile (132 mg,
2 mmol), DBU (76 mg, 0.5 mmol), molecular sieves
(200 mg), and absolute ethanol (2 mL). The mixture was
heated for 2 h at 808C in a silicone oil bath. After comple-
tion of the reaction, the crude product was purified by flash
column chromatography over silica gel with 9:1 hexanes to
ethyl acetate to afford the desired compound as a yellow
hexanes to ethyl acetate to afford 1v isolated as a yellow oil;
1
yield: 51 mg (86%). H NMR, 13C{1H} NMR, and MS (EI)
were all identical to 1v prepared using the standard condi-
tions directly from the multicomponent coupling product.
Acknowledgements
The authors wish to thank Bill Wulff for helpful discussions,
Jim McCusker for use of his laboratoryꢀs UV-Vis absorption
instrument, and the National Science Foundation (CHE-
1265738) for financial support.
1
oil; yield: 135 mg (53%). H NMR (CDCl3, 500 MHz): d=
1.46 (9H, s, CACHTUNGTRENNUNG(CH3)3), 1.60–1.63 (2H, m, CH2), 1.71–1.74
(2H, m, CH2), 2.13–2.16 (2H, m, CH2), 2.24–2.26 (2H, m,
CH2), 4.95 (1H, br, NH-2-methylpropan-2-amine), 5.95 (1H,
m, CH), 7.57–7.58 (1H, d, 2.5 Hz, 4-CH-pyridine), 8.28–8.29
(1H, d, 2.5 Hz, 6-CH-pyridine); 13C{1H} NMR (CDCl3,
125 MHz): d=21.8, 22.7, 25.6, 26.8, 29.1, 52.4, 91.2, 117.5,
123.9, 126.1, 132.3, 137.2, 148.8, 157.0; MS (EI): m/z=255;
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l
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In a N2 filled glove box, a 40-mL pressure tube, equipped
with a magnetic stirbar, containing catalyst A (32.4 mg,
0.1 mmol) in dry toluene (2 mL) was loaded with cyclohex-
ylamine (95 mg, 1 mmol), ethynylbenzene (102 mg, 1 mmol),
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by flash column chromatography over silica gel with 9:1
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a yellow brown solid; yield: 130 mg (52%); mp 94–968C.
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Adv. Synth. Catal. 2014, 356, 1811 – 1822
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[19] CCDC 980406 (1a), CCDC 980407 (1v), CCDC 980408
(1k), and CCDC 980409 (1p) contain the supplementa-
ry crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/da-
ta_request/cif.
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Adv. Synth. Catal. 2014, 356, 1811 – 1822