One-pot synthesis of 1,3,5-triazine derivatives via controlled cross-cyclotrimerization of nitriles: A mechanism approach

Article abstract of DOI:10.1021/jo501144v

The reaction of equimolecular amounts of a nitrile and triflic anhydride or triflic acid at low temperature produces an intermediate nitrilium salt that subsequently reacts with 2 equiv of a different nitrile at higher temperature to form 2,4-disusbstituted-6-substituted 1,3,5-triazines in moderate to good yields. This synthetic procedure has also been applied to the preparation of a 1,3,5-triazine having three different substituents. The results are explained in terms of a mechanism based on the relative stability of the intermediate nitrilium salts that are formed through a reversible pathway. The formation of a substituted isoquinoline using benzyl cyanide as the second nitrile supports the postulated mechanism as well as the structure of derivatives of the proposed intermediate when the reaction is carried out in the presence of different nucleophiles other than nitriles. Theoretical calculations and the monitoring of the reaction using ¹H and ¹³C NMR spectroscopy are in agreement with the proposed mechanism pathway.

Full text of DOI:10.1021/jo501144v

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Article
One-Pot Synthesis of 1,3,5-Triazine Derivatives via Controlled
Cross-Cyclotrimerization of Nitriles. A Mechanism Approach.
Antonio Herrera, Alberto Riaño, Ramón Moreno, Bárbara Caso, Zulay D. Pardo, Israel
Fernandez, Elena Sáez, Dolores Molero, Angel Sánchez-Vazquez, and Roberto Martinez-Alvarez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501144v • Publication Date (Web): 10 Jul 2014
Downloaded from http://pubs.acs.org on July 11, 2014
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Page 1 of 35
The Journal of Organic Chemistry
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One-Pot Synthesis of 1,3,5-Triazine Derivatives via Controlled Cross-
Cyclotrimerization of Nitriles. A Mechanism Approach.
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Antonio Herrera, † Alberto Riaño, † Ramón Moreno, † Bárbara Caso, † Zulay D. Pardo, † Israel
Fernández, † Elena Sáez,‡ Dolores Molero,‡ Angel SánchezꢀVázquez ‡ and Roberto Martínezꢀ
Alvarez †*
† Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense,
E-28040 Madrid, Spain
‡CAI de RMN y RSE, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid,
Spain
rma@quim.ucm.es
Me
O
2
N
Tf2O/ toluene
2h, 0ºC
O
O
CN
N N
N
110ºC, 24h
N
N
C
CN
Me
Me
39-82%
N-Tf
-
TfO
19examples
Abstract
The reaction of equimolecular amounts of a nitrile and triflic anhydride or triflic acid at low
temperature produces an intermediate nitrilium salt which subsequently reacts with two equivalents
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of a different nitrile at higher temperature to form 2,4ꢀdisusbstitutedꢀ6ꢀsubstituted 1,3,5ꢀtriazines in
moderate to good yields. This synthetic procedure has also been applied to the preparation of a
1,3,5ꢀtriazine having three different substituents. The results are explained in terms of a mechanism
based on the relative stability of the intermediate nitrilium salts which are formed through a
reversible pathway. The formation of a substituted isoquinoline using benzyl cyanide as the second
nitrile supports the postulated mechanism as well as the structure of derivatives of the proposed
intermediate when the reaction is carried out in the presence of different nucleophiles other than
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1
nitriles. Theoretical calculations and the monitoring of the reaction using H and 13C NMR
spectroscopy are in agreement with the proposed mechanism pathway.
Introduction
The derivatives of 1,3,5ꢀtriazine are well known compounds1 of considerable interest
because of their applications in many different fields. Thus, triazine derivatives have found
applications as pharmaceuticals,2 liquid crystals,3 building blocks for supramolecular chemistry,4
reactive dyes,5 organic lightꢀemiting diodes (OLEDs),6 and chemical reagents for selected
transformations.7 Nevertheless, the preparation of polyfunctional 1,3,5ꢀtriazines is still a challenge.
Several synthetic methods for their preparation have been reported, fundamentally based on the
controlled stepwise nucleophilic displacement of the chlorine atoms of cyanuric chloride.8
Additionally, the copperꢀcatalyzed crossꢀcoupling of Grignard reagents with monochloro azacycles
leads to pyridine, pyrimidine and 1,3,5ꢀtriazine derivatives.9 Iodotriazines can undergo a Mg/I
exchange for the preparation of monoꢀ and diꢀmagnesiated triazines.10 Finally, nitriles and
dicyanamides undergo [3+2]cycloaddition reactions affording triazines and tetrazoles under
microwave irradiation.11
The sꢀ1,3,5ꢀtriazines are well known substances but the direct synthesis of its derivatives
with different substituents at each carbon atom presents several problems which have not been
appropriately overcome so far. Because of the symmetry of the target compounds, the cyclization of
three identical or different NꢀC units can provide access to these heterocycles. Nitriles11, imidates12
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The Journal of Organic Chemistry
and amidine derivatives13 are the units used in these procedures The cyclization is a multiꢀstep
process whose intermediates have not always been unambiguously identified and the outcome of
the reaction strongly depends on the reaction conditions.1c For example, the cyclotrimerization of
nitriles is a very common route to symmetrical 1,3,5ꢀtriazine derivatives but yields vary
considerably and pressure and/or catalysts play a fundamental role.14 Catalysts used have been
protic and Lewis acids,15 basic compounds,16 solventꢀfree conditions17 and different lanthanide
salts.18
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On the other hand, different NꢀC units have been used for the preparation of
azaheterocycles. Thus, the nucleophilic addition of nitriles to activated amines leads to the
19
formation of pyrimidine derivatives while the reaction of nitriles and alkynes affords substituted
pyridines and isoquinolines.20 The use of cyanic acid derivatives and aminocarbonitriles instead of
nitriles permits the preparation of pyrimidine derivatives bearing methylthio and amino moieties.21
During our investigations on the synthesis of pyrimidines and other azacycles from ketones
and nitriles using triflic anhydride (Tf2O), minor amounts of symmetrically trisubstituted 1,3,5ꢀ
triazines were detected among the reaction products.22 This led to a report of a synthetic procedure
for the preparation of symmetrically trisubstituted 1,3,5ꢀtriazines from nitriles and triflic anhydride
23 and later from nitriles with large amounts of triflic acid (TfOH).24 However, a mechanism for the
reactions was unclear and the intermediates involved were not identified. Reported herein is the
synthesis of 1,3,5ꢀtriazine derivatives via controlled crossꢀcyclotrimerization of nitriles. The process
is examined to provide a deeper understanding of the corresponding reaction mechanism.
Results and Discussion
The oneꢀpot reaction of a nitrile R1CN (1) with Tf2O or TfOH (depending on the reactivity
of nitriles) at low temperature and subsequent addition of a twoꢀfold amount of a different nitrile
R2CN (2) followed by heating at 100 ºC for 24 h affords 1,3,5ꢀtriazines (3) with two different
substituents in moderate to good yields (Scheme 1 and Table 1).
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R1
1
2
3
4
5
a)Tf2O, 0 ºC
N
N
R1-CN
b) R2-CN
R2
N
R2
1
2
3
6
7
8
9
Scheme 1. Synthesis of 2,4ꢀdisubstitutedꢀ6ꢀsubstituted 1,3,5ꢀtriazines 3 from nitriles and Tf2O
Table 1. Synthetized triazines 3 from nitriles 1 and 2
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1
R
N
N
Nitrile 1 (R1)
Nitrile 2 (R2)
Entry
2
2
R
N
R
3 Yield (%)a
1
2
3
4
5
MeCN
MeCN
3a, R1= Me, R2 = pꢀClꢀC6H4 (67%),
3b, R1= Me, R2 = Me(CH2)7 (42%)
3c, R1= tBu, R2 = pꢀMeꢀC6H4 (75%)
3d, R1= tBu, R2 = SMe (69%)
Me(CH2)7CN
MeSCN
(Me)3CꢀCN
(Me)3CꢀCN
MeSCN
3e, R1= SMe, R2 = pꢀOMeꢀC6H4 (51%)
6
3f, R1=
, R2 = pꢀClꢀC6H4 (82%)
, R2 = tBu (67%)
7
8
(Me)3CꢀCN
3g, R1=
(Me)2NCN
(Me)2NCN
(Me)2NCN
3h, R1= NMe2, R2 = pꢀClꢀC6H4 (76%)
3i, R1= NMe2, R2 = pꢀMeꢀC6H4 (81%)
3j, R1= NMe2, R2 = pꢀOMeꢀC6H4 (77%)
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10
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The Journal of Organic Chemistry
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12
3k, R1=
3l, R1=
, R2 = pꢀMeꢀC6H4 (80%)
, R2 = pꢀOMeꢀC6H4 (77%)
, R2 = cyclohexyl (59%)
13
14
15
9
3m, R1=
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MeCH2CN
PhCN
3n, R1= pꢀMeꢀC6H4 , R2 = MeCH2 (49%)
3o, R1= pꢀBrCH2ꢀC6H4, R2 = Ph (50%)
16b
17b
18b
3p, R1=
, R2 = pꢀBrꢀC6H4 (41%)
, R2 = pꢀClꢀC6H4 (45%)
CN
3q, R1=
S
CN
3r, R1= 1ꢀnaphtyl, R2 = pꢀBrꢀC6H4 (39%)
a Yield of isolated product
b Using TfOH
Nitriles have been shown to react with methyl triflate to initially form nitrilium salts25 which
are then converted into synthetically useful molecules by reaction with a variety of nucleophiles.26
This led us to postulate that the first step of the mechanism pathway involves the initial formation
of triflate nitrilium salt 4 from nitrile R1CN (1) and Tf2O (Scheme 2). The carbon atom of the salt´s
imino moiety undergoes nucleophilic attack by the second nitrile R2CN (2) to form an immonium
salt 5. The excess nitrile 2 acts again as a nucleophile on 5 to form another immonium salt,
intermediate 6. A subsequent cyclization reaction forms the triazine ring 7 which yields the triazine
3 upon basic hydrolysis. It is noteworthy that the s-triazines corresponding to the trimerization of
nitriles 1 and 2 are detected albeit in very low yields. The near absence of trimers from either 1 or
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from 2 suggests than nitrile 1 and Tf2O are completely consumed in the formation of the
intermediate 4. Only trace quantities of 1 remain to take the role of nitrile 2 and consequently the
trimerization of 1 very rarely occurs. When nitrile 2 (R2CN) is added to the reaction mixture, little
or no Tf2O is available to react with 2 to form a trimer.
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1
R
R2-CN
Tf2O
0ºC
2
Tf
1
1
-
-
N
N
R -CN
R C N Tf , TfO
TfO
65-110ºC
2
R
5
1
4
2
R -CN
R1
1
R
R1
Tf
Tf
-
-
-
N
N
N
N
N
N
H O/OH
2
TfO
TfO
2
2
2
2
2
2
R
N
R
R
N
R
R
N
R
3
7
6
Scheme 2. Proposed mechanism for the synthesis of triazines 3 from nitriles 1 and 2
The reaction seems to be controlled by the stability of the intermediate nitrilium salt 4. Thus,
when pivalonitrile (nitrile 1) reacts with Tf2O at low temperature to form nitrilium salt 8 followed
by the addition of a two equivalents of pꢀtolunitrile (nitrile 2), triazine 3c is obtained in 75% yield
(Entry 3 of Table 1, Scheme 3). However, when the nitriles are reversed and nitrilium salt 9 formed
first followed by addition of pivalonitrile, only triazine 3c was obtained and in poor yield instead of
the expected triazine 10 (Scheme 4).
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The Journal of Organic Chemistry
CN
1
2
3
2
N
N
4
Tf2O
0ºC
5
6
7
8
Me
-
N
(Me)3C-CN
(Me)3C-C=N-Tf, TfO
110ºC
Me
Me
3c(75%)
8
9
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Scheme 3. Synthesis of triazine 3c
Me
Tf
N
-
TfO
CN
Me
C
Tf2O
0ºC
2(Me)3C-CN
N
N
Me
N
9
10
2(Me)3C-CN
110ºC
CN
110ºC
-
3c(21%)
+
(Me)3C-C=N-Tf, TfO
8
Me
Scheme 4. Formation of triazine 3c instead of triazine 10
The exclusive formation of triazine 3c in both reactions can be explained by a pathway in
which the corresponding nitrilium salts are formed through a reversible process controlled by the
relative stabilities of these intermediates. Thus, the addition of pivalonitrile to intermediate 9 shifts
the equilibrium to form the more stable nitrilium salt 8 and regenerated pꢀtolunitrile, which in turn
reacts with 8 affording 3c (Scheme 4). Similar results were obtained in the preparation of 3e, where
methylthiocyanate unexpectedly reacts faster with Tf2O than pꢀmethoxybenzonitrile affording 3e
instead of the expected 2ꢀ(4ꢀmethoxyphenyl)ꢀ4,6ꢀbis(methylthio)ꢀ1,3,5ꢀtriazine 11 (Scheme 5 and
experimental section).
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SMe
N
1
2
3
N
4
N
5
6
-
MeO
OMe
Me-SC=N-Tf, TfO
3e(51%)
Me-SCN
CN
7
8
9
or
OMe
Tf2O
Tf
N
-
TfO
C
10
11
12
13
14
15
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17
18
19
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N
N
OMe
MeS
N
11
SMe
OMe
not detected
Scheme 5. Formation of triazine 3e
To shed light on the proposed mechanism, the reversibility of its first step was explored. The
corresponding 2,4,6ꢀtriethylꢀ1,3,5ꢀtriazine (13) was prepared by reaction of Tf2O and a threeꢀfold
amount of 12 (see experimental section). The reaction of 4ꢀethylbenzonitrile (12) with Tf2O was
repeated under various reaction conditions. First, equimolecular amounts of 12 and Tf2O were
mixed at 0 ºC and the reaction was allowed to attain room temperature. An equimolecular amount
of benzyl alcohol was added and subsequent heating afforded a mixture of oꢀ and pꢀbenzyltoluene
(15 and 16) in a molecular ratio of 40:60 respectively and 64% overall yield (Scheme 6). The
formation of these compounds can be explained by an initial equilibrium between 4ꢀ
ethylbenzonitrile (12) and Tf2O to form the nitrilium salt 14. The addition of the benzyl alcohol
shifts the initial equilibrium to the starting stage (nitrile 12 and Tf2O). Because alcohols are more
reactive than nitriles toward Tf2O, benzyl triflate is formed rather than 14.27 The benzyl triflate
formed in situ easily generates a very reactive benzyl cation which reacts with toluene to form 15
and 16 via an electrophilic aromatic substitution. Significant amounts of nitrile 12 were recovered
while triazine 13 was detected in very low yield.
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The Journal of Organic Chemistry
Et
1
2
3
4
5
6
7
Tf
N
-
TfO
C
Toluene
0ºC
CN
N
N
+ Tf2O
N
8
9
Et
Et
Et
Et
14
10
11
12
13
14
15
16
17
18
19
20
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12
13
OH
OTf
Toluene
100ºC
Me
Me
CH Ph
2
CH Ph
2
15
16
(64%)
Scheme 6. Reaction of nitrile 12 and Tf2O with addition of benzyl alcohol and formation of
compounds 15 and 16
In addition, the intermediate nitrilium salt 14 was trapped by quenching the reaction mixture
with nucleophiles other than nitriles or alcohols. The equilibrium reaction of 12, Tf2O and the
nitrilium salt 14 was quenched with 1,3,5ꢀtrimethoxybenzene as nucleophile reagent (Scheme 7).
This time, the intermediate reacts with the aromatic substrate affording the substituted
benzophenone 17. Also formed was sulfone 18, a consequence of the attack of the
trimethoxybenzene at the electrophilic sulfur atom of the triflic anhydride. It is important to note
that only minor amounts of the triazine 13 were obtained in this reaction. This fact clearly points to
an initial equilibrium between nitrile, Tf2O and the nitrilium salt. The nitrilium salt intermediate is
stable at low temperature until the addition of either nitriles or activated arenes acting as
nucleophiles. Thus, the addition of a second nitrile leads to the formation of triazines while the
presence of activated arenes results in electrophilic aromatic substitution reactions. Similar
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processes are reported in the literature. For example, the reaction of aromatic nitriles and arenes in
the presence of triflic anhydride affords diarylketones albeit in low yields.28
1
2
3
4
5
6
7
8
9
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
OMe
Tf
TfO
OMe
N
C
-
CN
MeO
OMe
Toluene
0ºC
MeO
OMe
Et
+
O
MeO
OMe
+ Tf2O
100ºC
SO CF3
2
Et
Et
14
18(43%)
17(31%)
12
Scheme 7. Reaction in the presence of 1,3,5ꢀtrimethoxybenzene and formation of
compounds 17 and 18
Dialkyl cyanamides (Table 1, entries 6ꢀ13) are ideal reagents (nitriles 1) to react with Tf2O
because they easily form nitrilium salts that can react with alkyl or aryl nitriles. To demonstrate the
versatility of the synthetic procedure, an equilibrium mixture of dimethylcyanamide, Tf2O and
nitrilium salt was treated with an equimolecular mixture of 4ꢀchloroꢀ and 4ꢀmethylbenzonitrile. The
main product (58%) was the triazine 19 having three different substituents although small amounts
of the different sꢀtriazines were detected (Scheme 8). This result illustrates the enormous potential
of this reaction for the synthesis of substituted triazines by simply controlling the addition order of
the reactants and utilizing the relative reactivities of the nitriles toward the triflic anhydride.
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The Journal of Organic Chemistry
CN
1
2
3
N(Me)2
4
5
6
7
8
9
N
N
N
Tf2O
0ºC
Me
Me
Cl
-
(Me)2N-C=N-Tf, TfO
N CN
CN
Cl
Me
19(58%)
10
11
12
13
14
15
16
17
18
19
20
21
22
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44
45
46
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58
59
60
Me
Scheme 8. Synthesis of trisubstituted triazine 19
Alkyl cyanides other than acetonitrile and pivalonitrile are unreactive toward Tf2O and are
recovered unaltered even after prolonged reaction times and harsh conditions. However, this lack of
reactivity permits the use of these compounds as nitriles 2 (entries 13 and 14). On the other hand,
aromatic nitriles of reduced reactivity toward Tf2O can be used as nitriles 1 if the reaction is carried
out with triflic acid (TfOH) instead of Tf2O (entries 16ꢀ18).
Unsubstituted benzyl cyanide shows a particularly interesting reactivity. Thus, when the
nitrilium salt formed from pivalonitrile and Tf2O, is treated with benzyl cyanide, the expected
dibenzyl substituted triazine 20 is not found. Instead, the substituted isoquinoline 21 was obtained
in 41% reaction yield (Scheme 9). In this case, the cyclization step of the general proposed
mechanism (Scheme 2) takes place at the activated ortho position of the phenyl ring of the benzyl
cyanide. Moreover, the absence of triazine ring also precludes the elimination of the
trifluoromethylsulfenyl group (Tf) in the last step of the process. The presence of the NꢀTf moiety
in the final product 21 supports the proposed mechanism outlined in Scheme 9.
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N
1
2
3
4
5
6
7
8
N
N
Tf2O
-
(Me)3C-C=N-Tf, TfO
(Me)3C CN
N
N
20
9
10
11
12
13
14
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(Me)3C N-Tf
(Me)3C N-Tf
N
(Me)3C N-Tf
N
N
N
+
- H
N
N
(Me)3C N-Tf
NH
N
21(41%)
Scheme 9. Proposed mechanism for the formation of isoquinoline 21
Nuclear Magnetic Resonance experiments
To test the proposed mechanism outlined in Scheme 2, we monitored the process using
NMR techniques. In this regard, the reaction of 4ꢀethylbenzonitrile (12) with Tf2O was selected. In
1
its H NMR spectrum this compound exhibits the typical signals of a deceptively simple AA´XX´
spin system corresponding to the protons of the pꢀsubstituted benzene ring. The same spin system is
found in the triazine 13, and the chemical shifts are sufficiently distinct to distinguish the species
during the monitoring (Scheme 10). We used 1,1,2,2ꢀtetrachloroethaneꢀd2 as solvent (undeuterated
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The Journal of Organic Chemistry
portion δ 6.00 ppm) to avoid signal overlap in the aromatic region and to facilitate the recording of
1
2
3
4
the spectra at variable temperature.
5
6
7
8
9
Et
10
11
12
13
14
15
16
17
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19
20
21
22
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Tf
TfO
N
-
CN
C
N
N
HA(8.69)
HX(7.44)
HA´
HX´
HA(7.57)
HX(7.30)
HA(8.18)
calculated
HX(7.91)
N
Et
HA´
13
Et
Et
Et
HX´
14
12
Scheme 10. Observed 1H chemical shifts for the AA´XX´spin systems for 4ꢀ
ethylbenzonitrile 12 and triazine 13 in 1,1,2,2ꢀtetrachloroethaneꢀd2 and calculated chemical shifts
for nitrilium salt 14 in CDCl3
1
Thus, the reaction of 12 with Tf2O at 50 ºC was monitored in a sample tube with H NMR
spectra at different times and temperatures. Figure 1 collects selected spectra of the aromatic region.
The starting nitrile 12 (spectrum A, Figure 1) displays aromatic signals at 7.30 and 7.57 ppm (black
arrows). The addition of an equimolecular amount of Tf2O and heating at 50 ºC during 2 h produces
a new AA´XX´ spin system (spectrum B, Figure 1, red arrows). The chemical shifts for compounds
12 and 13 in the reaction mixture are quite different than those of the pure compounds (Scheme 10)
due to the presence of triflic anhydride and the possible formation of traces of TfOH that modify the
pH of the reaction mixture. The new AA´ portion resonates at 8.56 ppm while the corresponding
XX´ portion appears at 7.55 ppm, practically overlapped with a signal of the starting nitrile. This
new spin system can reasonably be assigned to the postulated nitrilium salt 14. Theoretical
calculations of the 1H chemical shits for intermediate 14 are in agreement with the observed values,
despite the difference of the solvent. Continuous monitoring of the reaction reveals a new aromatic
system (7.44 and 7.98 ppm) corresponding to the protonated final product 13 (spectrum C, Figure 1,
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green arrows). Since the product triazine 13 (Scheme 2) is protonated in the crude mixture, its
spectrum (spectrum C, Figure 1) is different from that of pure triazine 13 (spectrum D, Figure 1). It
is noteworthy that the chemical shift differences for the aromatic protons between pure triazine and
protonated triazine (reaction mixture) are higher for the protons of the AA´portion than for the
XX´portion because the deshielded protons are closer to the protonated nitrogen atom. The increase
of the signal intensities for the triazine 13 is commensurate with the decrease of those for the
starting nitrile and the corresponding intermediate.
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13
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58
59
60
Figure 1. 1H NMR monitoring (aromatic region) of the reaction of 4ꢀethylbenzonitrile 12
and Tf2O in 1,1,2,2ꢀtetrachloroethaneꢀd2
The same results were obtained when the reaction was monitored by 13C NMR. Chemical
shifts of compounds 12, 13 and intermediate 14 are shown in Scheme 11. Figure 2 collects selected
spectra recorded from the region between 110 and 170 ppm. The starting nitrile 12 (spectrum A,
Figure 2) shows the signal assigned to C4 at 150.0 ppm (black arrow). Addition of an
equimolecular amount of Tf2O and heating at 50 ºC during 2 h produces new signals, some of them
overlapped, making assignments of these peaks more complicated. Among these, two important
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signals at 168 and 156 ppm (spectrum B, Figure 2) are indicated by red arrows. The broad signal of
low intensity at 168 ppm can be more easily assigned with an HMBC spectrum (Figure 3). The
observed correlations over three bonds with the aromatic protons of the AA´portion (8.55 ppm)
point to an unambiguously assignment of the peak at 168 ppm to the imino carbon atom of
intermediate 14. The new signal at 156 ppm corresponds to the C4 of the intermediate 14. The
peaks for the protonated triazine 13 are observed after 10 h of reaction (spectrum C, Figure 2). The
carbon atom of the protonated triazine ring resonates at 174 ppm while the C4 of this compound
appears at 155 ppm (green arrows). The spectrum of the pure triazine 13 is displayed as spectrum D
in Figure 2. As was the case in the 1H NMR spectra, there are differences in the 13C chemical shifts
between protonated triazine (reaction mixture) and pure triazine 13. Figure 4 shows the two
overlapped quadruplets (1JC,F = 323 Hz) assigned to the two CF3 groups of nitrilium salt 14
underpinning the structure of the proposed intermediate.
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13
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Et
118.9
171.1
Tf
N
C
171.6
TfO
98,0(C1)
calculated
CN
129.1
149.3
N
N
109.3(C1)
149.6(C4)
131.9
128.5
141.5
134.1
N
134.1
Et
Et
160.5(C4)
Et
Et
128.2
14
12
13
Scheme 11. Observed 13C chemical shifts for 4ꢀethylbenzonitrile 12, triazine 13 in 1,1,2,2ꢀ
tetrachloroethaneꢀd2 and calculated chemical shifts for nitrilium salt 14 in CDCl3
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1
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57
58
59
60
Figure 2. 13C NMR monitoring (aromatic region) of the reaction of 4ꢀethylbenzonitrile 12
and Tf2O in 1,1,2,2ꢀtetrachloroethaneꢀd2
ppm
110
120
130
140
150
160
170
8.6
8.4
8.2
8.0
7.8
7.6
7.4
7.2
ppm
Figure 3. HMBC spectrum of the reaction mixture (10 h at 50 ºC) showing the correlations
over three bonds for the imino carbon atom (168 ppm, 8.55 ppm) and C4 (156 ppm, 8.55 ppm) of
intermediate 14
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The Journal of Organic Chemistry
1
2
3
4
o
o
5
6
7
8
9
x
10
11
12
13
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x
o
o
x
x
124
122
120
118
116
114
ppm
Figure 4. Overlapped quadruplets for the two CF3 groups of intermediate 14 (118.8 and
117.4 ppm respectively, 1JC,F = 323 Hz)
Theoretical calculations
To gain further insight into the cyclization process leading to the formation of triazines, a
computational (DFT) study was carried out. The computed reaction profile (PCMꢀB3LYP/6ꢀ
31+G(d)) is shown in Figure 5, which shows the corresponding free energies (computed at 298 K)
in toluene solution.
As reported previously,25 the reaction starts from the nitrilium cation INT0 formed by
reaction of Tf2O and MeCN. In the presence of a new molecule of nitrile (MeCN as model in the
calculations), a weakly bonded van der Waals complex INT1 is formed in a slightly endergonic
(ꢀGR,298 = 2.0 kcal/mol) reaction. Subsequent nucleophilic attack of the loneꢀpair of the nitrile at the
highly electrophilic carbon atom of the nitrilium cation INT0 produces the new cationic
intermediate INT2 through the transition state TS1. Figure 5 shows that this saddle point is
associated with the formation of the new C···N bond with a computed activation barrier of 8.7
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kcal/mol (from the initial weakly bonded complex INT1). Then, a second nucleophilic addition on
INT2 by a new molecule of nitrile leads to the formation of the cation INT3. This step is clearly
endergonic (ꢀGR,298 = 6.6 kcal/mol) with an associated activation barrier of 8.4 kcal/mol (via the
saddle point TS2). At this point INT3, undergoes a ring closure to form triazine INT4 by an easy
intramolecular nucleophilic addition (computed activation barrier of only 3.8 kcal/mol) of the
nitrogen atom attached to the triflic substituent to the carbocationic center in INT3. The gain in
aromaticity in the readily formed triazine INT4 explains the highly exergonic nature of this
transformation (ꢀGR,298 = ꢀ13.0 kcal/mol) and therefore, this last step is the drivingꢀforce of the
process. Finally, basic hydrolysis of INT4 provides the experimentally obtained neutral triazines 3.
1
2
3
4
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7
8
9
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59
60
Figure 5. Computed reaction profile for the transformation of INT0 into INT4. Bond lengths are
given in angstrom and relative free energies (ꢀG298, in toluene) in kcal/mol. All data have been
computed at the PCMꢀB3LYP/6ꢀ31+G(d) level.
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The Journal of Organic Chemistry
Conclusions
1
2
3
4
5
6
7
8
9
We have developed a synthetic procedure for the preparation of 2,4ꢀdisubstituted 6ꢀsubstituted
1,3,5ꢀtriazines using a oneꢀpot reaction. The process is controlled by the initial formation of a
nitrilium salt intermediate. Further reaction with two equivalents of a different nitrile produces the
corresponding triazines. Reactions carried out in the presence of different nucleophiles and
10
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13
followed with 1H and C NMR reaction monitoring support the reversible formation of a nitrilium
salt in the first step of the proposed mechanism. Theoretical calculations are also in agreement with
the postulated mechanism pathway. In conclusion, a variety of triazines can be prepared from two
different nitriles which cyclotrimerize by the action of triflic anhydride.
Experimental Section
All chemicals and solvents were purchased from commercial suppliers. Triflic anhydride was
1
distilled over P2O5 before use. All the reactions were carried out under argon atmosphere. The H
NMR and 13C NMR spectra were recorded in solution of CDCl3, N,Nꢀdimethylformamideꢀd7,
CD2Cl2 and 1,1,2,2ꢀtetrachloroethaneꢀd2 at 300, 500 and 700 MHz for 1H and 57, 125 and 176 MHz
for 13C respectively. Spectra were referenced to 7.26 and 77.0 ppm for chloroform, 8.01 and 166.5
ppm for DMFꢀd7, 5.32 and 53.5 ppm for CD2Cl2 and 6.00 and 74.2 ppm for C2D2Cl4 respectively.
1H NMR spectra often include a water signal. Assignment of 13C NMR signals was based on DEPT,
HMBC and HMQC spectra. High resolution mass spectra (FTꢀICR) were recorded under
electrospray ionization (ESI) in a 7 T FTꢀICR spectrometer. Melting points were uncorrected.
In order to monitor the reaction by NMR, a solution of 4ꢀethylbenzonitrile 12 (50.0 mg, 0.38 mmol)
in 0.6 ml of C2D2Cl4 was prepared in a standard 5ꢀmm NMR tube. H NMR and 13C NMR spectra
1
of the prepared solution were recorded at 50±1°C as references. To this, triflic anhydride (128.0 mg,
0.45 mmol) was added and the tube was transferred to the NMR spectrometer. Further spectra were
recorded under the same conditions over 20 hours.
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General Procedure A. A solution of 2.82 g (10 mmol) of triflic anhydride in 15 mL of toluene was
added dropwise to a solution containing 10 mmol of nitrile 1 in 15 mL of toluene at 0 ºC. The
resulting solution was stirred 3 h at 0 ºC and then a solution of 20 mmol of nitrile 2 in 15 mL
toluene was added and the reaction mixture heated at reflux for 24 h. The progress of the reaction
was monitored by TLC. The reaction mixture was quenched with aqueous sodium hydrogen
carbonate until the pH was basic, washed with water and dried over magnesium sulfate. The solvent
was removed and the residue fractionated by column chromatography using hexane/ethyl acetate
9:1 as eluent. The triazine obtained was purified by recrystallization or distillation.
1
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General Procedure B. A solution of 1.50 g (10 mmol) of triflic acid in 15 mL of toluene was
added dropwise to a solution containing 10 mmol of nitrile 1 in 15 mL of toluene at 0 ºC. The
resulting solution was stirred 3 h at 0 ºC and then a solution of 20 mmol of nitrile 2 in 15 mL
toluene was added and the reaction mixture heated at reflux for 24 h. The progress of the reaction
was monitored by TLC. The reaction mixture was quenched with aqueous sodium hydrogen
carbonate until the pH was basic, washed with water and dried over magnesium sulfate. The solvent
was removed and the residue fractionated by column chromatography using hexane/ethyl acetate
9:1 as eluent. The triazine obtained was purified by recrystallization or distillation.
2,4ꢀ Bis(4ꢀchlorophenyl)ꢀ6ꢀmethylꢀ1,3,5ꢀtriazine (3a). This compound was synthetized according to
the general procedure A using acetonitrile as nitrile 1 and 4ꢀchlorobenzonitrile as nitrile 2 as a white
solid (2.11 g, 67% yield) ; mp 198ꢀ199 ºC (EtOH), Lit.29 mp 200ꢀ202 ºC; FTIR (KBr) ν 1581 (w),
1
1527 (s), 1367 (w), 1090 (w), 801 (s) cmꢀ1; H NMR (CDCl3) δ 2.78 (s, 3H, CH3), 7,50, 8.60
(AA´XX´system, 8H, ArꢀH) ppm; 13C NMR (CDCl3) δ 26.0 (CH3), 128.9 (C meta), 130.2 (C ortho)
134.2 (C ipso) 138.9 (CꢀCl) 170.3 (Cꢀ2, Cꢀ4), 177.3 (Cꢀ6) ppm; HRMS (ESI) [M+H]+ 316.04028;
calc for C16H12Cl2N3 316.04083.
2,6ꢀDioctylꢀ4ꢀmethylꢀ1,3,5ꢀtriazine (3b). This compound was prepared according to general
procedure A using acetonitrile and nonanenitrile as nitriles 1 and 2 respectively (1.34 g, 42% yield);
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bp 200 ºC (1 mbar); FTIR (film) ν 2926 (m), 2859 (w), 1540 (s), 1119 (m) cmꢀ1; 1H NMR (CDCl3)
δ 0.80 (t, J = 7.5 Hz, 6H, CH3CH2), 1.18 (m, 20 H, CH2), 1.72 (m, 4H, CH2), 2.77 (t, J = 7.5 Hz,
4H, CH2Ar), 2.79 (s, 3H, CH3Ar) ppm; 13C NMR (CDCl3) δ 14.5 (CH3CH2), 23.0 (CH3CH2), 27.0
(CH3Ar), 28.2 (CH2), 29.5 (CH2), 29.6 (CH2), 29.7 (CH2), 32.2 (CH2), 39.2 (CH2Ar), 179.5 (Cꢀ2,
Cꢀ6), 180.5 (Cꢀ4) ppm; HRMS (ESI) [M+H]+ 320.30498; calc. for C20H38N3 320.30602.
1
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2ꢀtert-Butylꢀ4,6ꢀbis(4ꢀmethylphenyl)ꢀ1,3,5ꢀtriazine (3c). This compound was prepared according
general procedure A using pivalonitrile as nitrile 1 and 4ꢀtolunitrile as nitrile 2 as a white solid (2.37
g, 75% yield): mp 127ꢀ128 ºC (MeOH); FTIR (KBr) ν 1519 (s), 1370 (m), 813 (m) cmꢀ1; 1H NMR
(CDCl3) δ 1.52 (s, 9H, CH3), 2.47 (s, 6H, CH3), 7.34, 8.60 (AA´XX´system, 8H, ArꢀH) ppm; 13C
NMR (CDCl3) δ 22.1 (CH3ꢀAr), 30.1 [(CH3)3C], 39.6 [(CH3)3C], 128.8 (C meta), 129.2 (C ortho),
133.9 (C ipso), 142.6 (CꢀCH3), 170.8 (Cꢀ4, Cꢀ6), 185.5 (Cꢀ2) ppm; HRMS (ESI) [M+H]+
318.19596, calc for C21H24N3 318.19647.
Following the general procedure A, a solution of 2.82 g (10 mmol) of triflic anhydride in 15 mL of
toluene was added dropwise to a solution containing 1.17 g (10 mmol) of 4ꢀmethylbenzonitrile in
15 mL of toluene at 0 ºC. The resulting solution was stirred 3 h at 0 ºC and then a solution of 1.66 g
(20 mmol) pivalonrile in 15 mL toluene was added and the reaction mixture heated at reflux for 24
h. After the above reported workup, compound 3c (0.66 g, 21% yield) was obtained.
2ꢀtertꢀButylꢀ4,6ꢀbis(methylthio)ꢀ1,3,5ꢀtriazine (3d). This compound was prepared according to
general procedure A using pivalonitrile and methylthiocyanate as nitriles 1 and 2 respectively (1.58
1
g, 69% yield); bp 150 ºC (10 mbar); FTIR (film) ν 1495 (s), 1267 (s), 820 (m) cmꢀ1; H NMR
(CDCl3) δ 1.33 (s, 9H, CH3), 2.55 (s, 6H, SCH3) ppm; 13C NMR (CDCl3) δ 13.7 (SCH3), 28.1
[(CH3)3C], 29.2 [(CH3)3C], 181.3 (Cꢀ4, Cꢀ6), 182.9 (Cꢀ2) ppm; HRMS (ESI) [M+H]+ 230.07870,
calc for C9H16N3S2 230.07802.
2,4ꢀBis(4ꢀmethoxyphenyl)ꢀ6ꢀ(methylthio)ꢀ1,3,5ꢀtriazine (3e). This compound was prepared
according general procedure A using methylthiocyanate and 4ꢀmethoxybenzonitrile as starting
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materials 1 and 2 respectively as a white solid (1.79 g, 53% yield); mp 134ꢀ135 ºC (EtOH), Lit30 mp
132 ºC ; FTIR (KBr) ν 1605 (w), 1495 (s), 1365 (m), 1251 (s, CꢀOꢀC), 1171 (m), 852 (m), 806 (m)
cmꢀ1; 1H NMR (CDCl3) δ 2.62 (s, 3H, SCH3), 3.83 (s, 6H, OCH3), 6.95, 8.50 (AA´XX´system, 8H,
ArꢀH) ppm; 13C NMR (CDCl3) δ 13.6 (SCH3), 55.5 (OCH3), 114.0 (C meta), 128.3 (C ipso), 131.0
(C ortho), 163.4 (CꢀOCH3), 169.3 (Cꢀ2, Cꢀ4), 181.1 (Cꢀ6) ppm; HRMS (ESI) [M+H]+ 340.11044,
calc for C18H17N3 O2S 340.11142; [2M+Na]+ 701.19205, calc for C36H34N6NaO4S2 701.19752.
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A solution of 2.82 g (10 mmol) of triflic anhydride in 15 mL of toluene was added dropwise to a
solution containing 1.33 g (10 mmol) of 4ꢀmethoxybenzonitrile and 0.73 g (10 mmol) of
methylthiocyanate in 30 mL of toluene at 0 ºC. The resulting solution was stirred 3 h at 0 ºC and
heated 24 h at 100 ºC. After hydrolysis and purification of the crude product, compound 3e (0.25 g,
15%) was obtained.
2,4ꢀBis(4ꢀchlorophenyl)ꢀ6ꢀpiperidinꢀ1ꢀylꢀ1,3,5ꢀtriazine (3f). This compound was prepared
according general procedure A using piperidineꢀ1ꢀcarbonitrile and 4ꢀchlorobenzonitrile as starting
nitriles 1 and 2 respectively as a white solid (3.14 g, 82% yield); mp 196ꢀ197 ºC
(hexane/chloroform); FTIR (KBr) ν 2933 (m), 2854 (w), 1588 (m), 1546 (s), 1511 (s), 806 (m) cmꢀ
1
1; H NMR (CDCl3) δ 1.70 (m, 4H, CH2), 1.78 (m, 2H, CH2), 4.04 (t, J = 5 Hz, 4H, NCH2), 7.48,
8.52 (AA´XX´system, 8H, ArꢀH) ppm; 13C NMR (CDCl3) δ 25.2 (CH2), 26.3 (CH2), 44.8 (NCH2),
128.9 (C meta), 130.3 (C ortho), 136.0 (C ipso), 138.2 (CꢀCl), 165.0 (Cꢀ2, Cꢀ4), 170.4 (Cꢀ6) ppm;
HRMS (ESI) [M+H]+ 385.09890, calc for C20H19Cl2N4 385.09813.
2,6ꢀDiꢀtertꢀbutylꢀ6ꢀpiperidinꢀ1ꢀylꢀ1,3,5ꢀtriazine (3g). This compound was prepared according
general procedure A using piperidineꢀ1ꢀcarbonitrile and pivalonitrile as nitriles 1 and 2 respectively
as an undistillable oil (1.85 g, 67% yield); FTIR (film) ν 2935 (m), 2859 (m), 1550 (s), 1522 (s),
1
1398 (w), 1362 (w) cmꢀ1; H NMR (CDCl3) δ 1.04 (s, 9H, CH3), 1.62 (m, 4H CH2), 1.72 (m, 2H,
CH2), 3.86 (t, J = 5 Hz, 4H, NCH2) ppm; 13C NMR (CDCl3) δ 25.3 (CH2), 26.1 (CH2), 29.2 (CH3),
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39.6 (C), 44.2 (NCH2), 165.1 (Cꢀ6), 184.5 (Cꢀ2, Cꢀ4) ppm; HRMS (ESI) [M+H]+ 277.23785, calc
for C16H29N4 277.23867.
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4,6ꢀBis(4ꢀchlorophenyl)ꢀN,Nꢀdimethylꢀ1,3,5ꢀtriazinꢀ2ꢀamine (3h). This compound was prepared
according general procedure A using dimethylcyanamide and 4ꢀchlorobenzonitrile as starting
materials 1 and 2 as a white solid (2.61 g, 76% yield); mp 216ꢀ217 (chloroform/MeOH); FTIR
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(KBr) ν 1585 (m), 1522 (m), 1378 (m), 1089 (w), 804 (m) cmꢀ1; H NMR (CDCl3) δ 3.43 (s, 6H,
NCH3), 7.50, 8.55 (AA´XX´system, 8H, ArꢀH)ppm; 13C NMR (CDCl3) δ 36.7 (NCH3), 128.2 (C
meta), 130.55 (C ortho), 136.0 (CꢀCl), 138.5 (C ipso), 165.9 (Cꢀ2), 170.3 (Cꢀ4, Cꢀ6) ppm; HRMS
(ESI) [M+H]+ 345.06614, calc for C17H15Cl2N4 345.06683.
4,6ꢀBis(4ꢀmethylphenyl)ꢀN,Nꢀdimethylꢀ1,3,5ꢀtriazinꢀ2ꢀamine (3i). This compound was prepared
according general procedure A using dimethylcyanamide and 4ꢀtolunitrile as starting nitriles 1 and
2 respectively as a white solid (2.46 g, 81% yield); mp 193ꢀ194 ºC (chloroform/EtOH); FTIR (KBr)
ν 2920 (w), 1589 (m), 1510 (s), 1376 (w), 800 (m) cmꢀ1; 1H NMR (CDCl3) δ 2.47 (s, 6H, CH3ꢀAr),
3.40 (s, 6H, NCH3), 7.32, 8.51 (AA´XX´ system, 8H, ArꢀH) ppm; 13C NMR (CDCl3) δ 22.0 (Arꢀ
CH3), 36.7 (NCH3), 128.9 (C ortho), 129.4 (C meta), 134.9 (CꢀCH3), 142.3 (C ipso), 166.1 (Cꢀ2),
171.0 (Cꢀ4, Cꢀ6) ppm; HRMS (ESI) [M+H]+ 305.17525, calc for C19H21N4 305.17662.
4,6ꢀBis(4ꢀmethoxyphenyl)ꢀN,Nꢀdimethylꢀ1,3,5ꢀtriazinꢀ2ꢀamine (3j). This compound was prepared
according general procedure A using dimethylcyanamide and 4ꢀmethoxybenzonitrile as starting
materials 1 and 2 respectively as a white solid (2.58 g, 77% yield); mp 159ꢀ160 ºC (MeOH); FTIR
(KBr) ν 1580 (m), 1505 (s), 1379 (s), 1251 (s, CꢀOꢀC), 1167 (m), 813 cmꢀ1; H NMR (CDCl3) δ
1
3.38 (s, 6H, NCH3), 3.92 (s, 6H, OCH3), 7.03, 8.58 (AA´XX´ system, 8H, ArꢀH) ppm; 13C NMR
(CDCl3) δ 36.6 (NCH3), 55.8 (OCH3), 114.0 (C ortho), 114.4 (C ipso), 130.3 (C meta), 163.0 (Cꢀ
OCH3), 166.0 (Cꢀ2), 170.4 (Cꢀ4, Cꢀ6) ppm; HRMS (ESI) [M+H]+ 337.16590, calc for C19H21N4O2
337.16590.
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2,4ꢀBis(4ꢀmethylphenyl)ꢀ6ꢀmorpholinꢀ4ꢀylꢀ1,3,5ꢀtriazine (3k). This compound was prepared
according general procedure A using morpholineꢀ4ꢀcarbonitrile and 4ꢀtolunitrile as nitriles 1 and 2
respectively as a white solid (2.76g, 80% yield); mp 219ꢀ220 ºC (EtOH); FTIR (KBr) ν 1546 (m),
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1510 (s), 1381 (m), 801 (m) cmꢀ1; H NMR (CDCl3) δ 2.47 (s, 6H, CH3), 3.85 (t, J = 5.0 Hz, 4H,
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NCH2), 4.10 (t, J = 5.0 Hz, 4H, OCH2), 7.32, 8.48 (AA´XX´system, 8H, ArꢀH) ppm; 13C NMR
(CDCl3) δ 22.0 (CH3ꢀAr), 44.0 (NCH2), 67.3 (OCH2), 129.1 (C ortho), 129.5 (C meta), 134.7 (Cꢀ
CH3), 142.6 (C ipso), 165.5 (Cꢀ6), 171.4 (Cꢀ2, Cꢀ4) ppm; HRMS (ESI) [M+H]+ 347.18479, calc for
C21H23N4O 347.18664.
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2,4ꢀBis(4ꢀmethoxyphenyl)ꢀ6ꢀmorpholinꢀ4ꢀylꢀ1,3,5ꢀtriazine (3l). This compound
was prepared
according general procedure A using morpholineꢀ4ꢀcarbonitrile and 4ꢀmethoxybenzonitrile as
nitriles 1 and 2 respectively as a white solid (2.91g, 77% yield); mp 190ꢀ192 ºC (MeOH); FTIR
(KBr) ν 1534 (m), 1510 (s), 1385 (m), 1255 (s, CꢀOꢀC), 814 (m) cmꢀ1; 1H NMR (CDCl3) δ 3.85 (t,
J = 4.9 Hz, 4H, NCH2), 3.93 (s, 6H, OCH3), 4.09 (t, J = 4.9 Hz, 4H, OCH2), 7.02, 8.56
(AA´XX´system, 8H, ArꢀH) ppm; 13C NMR (CDCl3) δ 44.0 (NCH2), 55.8 (OCH3), 67.3 (OCH2),
114.0 (C meta), 129.7 (C ipso), 131.2 (C ortho), 162.9 (CꢀOCH3), 165.3 (Cꢀ6), 171.0 (Cꢀ2, Cꢀ4)
ppm; HRMS (ESI) [M+H]+ 379.17617, calc for C21H23N4O3 379.17647.
2,4ꢀDicyclohexylꢀ6ꢀmorpholinꢀ4ꢀylꢀ1,3,5ꢀtriazine (3m). This compound was prepared according
general procedure A using morpholineꢀ4ꢀcarbonitrile and cyclohexanecarbonitrile as nitriles 1 and 2
respectively as an undistillable oil (1.94 g, 59% yield); FTIR (film) ν 2930 (m), 2856 (w), 1545 (s),
1250 (s), 1028 (m) cmꢀ1; 1H NMR (CDCl3) δ 1.55ꢀ1.92 (m, CH2, 20 H), 2.55 (m, 2H, CH), 3.74 (t, J
13
= 4.9 Hz, 4H, NCH2), 3.89 (t, J = 4.9 Hz, 4H, OCH2) ppm; C NMR (CDCl3) δ 26.3 (CH2), 26.4
(CH2), 31.8 (CH2), 43.9 (NCH2), 47.1 (CH), 67.1 (OCH2), 165.0 (Cꢀ6), 181.8 (Cꢀ2, Cꢀ4) ppm;
HRMS (ESI) [M+H]+ 331.25043, calc for C19H31N4O 331.24924.
2,4ꢀDiethylꢀ6ꢀ(4ꢀmethylphenyl)ꢀ1,3,5ꢀtriazine (3n). This compound was prepared according general
procedure A using 4ꢀtolunitrile and propanenitrile as starting materials 1 and 2 respectively as a
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liquid (1.11 g, 49% yield); bp 100 ºC (1 mbar); FTIR (film) ν 3037 (m), 2977 (w), 1533 (s),
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1385(m), 822 (w) cmꢀ1; H NMR (CDCl3) δ 1.45 (t, J = 7.6 Hz, 6H, CH2CH3), 2.50 (s, 3H, Arꢀ
CH3), 3.05 (q, J = 7.6 Hz, 4H, CH2CH3), 7.30, 8.50 (AA´XX´system, 4H, ArꢀH) ppm; 13C NMR
(CDCl3) δ 11.9 (CH3CH2), 21.8 (ArꢀCH3), 32.7 (CH2CH3), 129.1 (C meta), 129.7 (C ortho), 133.8
(C ipso), 143.3 (CꢀCH3), 171.1 (Cꢀ2, Cꢀ6), 180.5 (Cꢀ4) ppm; HRMS (ESI) [M+H]+ 228.14981, calc
for C14H18N3 228.14952.
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2ꢀ[4ꢀ(Bromomethyl)phenyl]ꢀ4,6ꢀdiphenylꢀ1,3,5ꢀtriazine (3o). This compound was prepared
according general procedure A using 4ꢀ(bromomethyl)benzonitrile and benzonitrile as starting
materials 1 and 2 respectively as a white solid (2.00 g, 50% yield); mp 200ꢀ201 ºC (toluene); Lit.32
mp 201ꢀ203 ºC; FTIR (KBr) ν 1519 (s), 1366 (m), 739 (w), 689 (w) cmꢀ1; 1H NMR (CDCl3) δ 4.61
(s, 2H, CH2Br), 7.60 (m, 8H, ArꢀH), 8.55 (m, 6H, ArꢀH) ppm; 13C NMR (CDCl3) δ 33.2 (CH2Br),
129.1 (CH), 129.4 (CH), 129.8 (CH), 129.9 (CH), 133.0 (CH), 136.5 (C), 136.7 (C), 142.5 (C),
171.4 (Cꢀ2), 172.1 (Cꢀ4, Cꢀ6) ppm; HRMS (ESI) [M+H]+ 402.06137, calc for C22H17BrN3
402.06004.
2ꢀ(3ꢀBromoꢀ4ꢀmethylphenyl)ꢀ4,6ꢀbis(4ꢀbromophenyl)ꢀ1,3,5ꢀtriazine (3p). This compound was
prepared according general procedure
B
using 3ꢀbromoꢀ4ꢀmethylbenzonitrile and 4ꢀ
bromobenzonitrile as starting materials 1 and 2 respectively as a white solid (2.28 g, 41% yield); mp
1
267ꢀ268 ºC (chloroform/MeOH); FTIR (KBr) ν 1516 (s), 1357 (m), 803 (m), 772 (m) cmꢀ1; H
NMR (CDCl3) δ 2.57 (s, 3H, ArꢀCH3), 7.45 (d, J = 7.7 Hz, 1H, ArꢀH), 7.75, 8.63 (AA´XX´system,
8H, ArꢀH), 8.58 (m, 1H, ArꢀH), 8.88 (d, J = 1.4 Hz, 1H, ArꢀH) ppm; 13C NMR (45º C, CDCl3)
δ 23.6 (ArꢀCH3), 125.4 (CꢀBr), 127.8 (CꢀBr), 130.5 (C ortho), 131.1 (CH), 132.1 (C meta), 132.8
(CH), 134.9 (C), 135.5 (C), 142.9 (C), 143.0 (C), 170.8 (Cꢀ2), 171.2 (C4, Cꢀ6) ppm; HRMS (ESI)
[M+H]+ 557.88383, calc for C22H15Br3N3 557.88106.
2,4ꢀBis(4ꢀchlorophenyl)ꢀ6ꢀ(2ꢀthienyl)ꢀ1,3,5ꢀtriazine (3q). This compound was prepared according
general procedure B using thiopheneꢀ2ꢀcarbonitrile and 4ꢀchlorobenzonitrile as starting materials 1
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and 2 respectively as a white solid (1.72 g, 45% yield); mp 288ꢀ289 ºC (chloroform); FTIR (KBR)
ν 1585 (w), 1518 (s), 1404 (m), 806 (w) cmꢀ1; 1H NMR (DMFꢀd7) δ 7.58 (dd, J = 4.9 Hz, J = 3.9
Hz, 1H, Hꢀ4, 2ꢀthienyl ring), 7.92, 8.93 (AA´XX´system, 8H, ArꢀCl), 8.25 (dd, J = 4.9 Hz, J = 1.1
Hz, 1H, Hꢀ3, 2ꢀthienyl ring), 8.66 (dd, J = 3.9 Hz, J = 1.1 Hz, Hꢀ5, 2ꢀthienyl ring) ppm; 13C NMR
(DMFꢀd7) δ 129.6 (Cꢀ4 of 2ꢀthienyl ring), 129.8 (CH, ArꢀCl), 131.2 (CH, ArꢀCl), 133.1 (Cꢀ5 of 2ꢀ
thienyl ring), 134.5 (Cꢀ3 of 2ꢀthienyl ring), 135.1 (C, ArꢀCl), 139.2 (CꢀCl), 141.9 (Cꢀ2 of 2ꢀthienyl
ring), 169.0 (Cꢀ6), 171.4 (Cꢀ2, Cꢀ4) ppm; HRMS (ESI) [M+O]●+ 398.98916, calc for
C19H11Cl2N3OS 398.99997.
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2,4ꢀBis(4ꢀbromophenyl)ꢀ6ꢀ(1ꢀnaphthyl)ꢀ1,3,5ꢀtriazine (3r). This compound was prepared according
general procedure B using naphthaleneꢀ1ꢀcarbonitrile and 4ꢀbromobenzonitrile as starting materials
1 and 2 respectively as a white solid (2.00 g, 39% yield); mp 199ꢀ200 ºC (chloroform/MeOH);
FTIR (KBr) ν 1584 (w), 1517 (s), 1369 (w), 801 (w) cmꢀ1; 1H NMR (CDCl3) δ 7.63 (t, J = 7.2 Hz,
1H), 7.66 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.74, 8.66 (AA´XX´system, 8H, BrꢀArꢀH),
8.01 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 7.2 Hz, 1H), 9.01 (d, J = 8.8 Hz,
1H) ppm; 13C NMR (CDCl3) δ 126.3 (CꢀBr), 126.6, 127.8, 128.3, 129.7, 131.0 , 131.3, 131.7,
132.5, 133.0, 134.0, 134.7, 135.3, 171.3 (Cꢀ4), 175.0 (Cꢀ2, Cꢀ6) ppm; HRMS (ESI) [M+H]+
515.97184, calc for C25H16Br2N3 515.97055.
2,4,6ꢀTris(4ꢀethylphenyl)ꢀ1,3,5ꢀtriazine (13). This compound was prepared according general
procedure A using 4ꢀethylbenzonitrile (12) (3.92 g, 30 mmol) in 50 mL of toluene and 2.82 g (10
mmol) of triflic anhydride in 15 mL of toluene. The reaction mixture was heated at 100 ºC for 24 h.
After usual workꢀup, the compound was isolated (3.49 g, 89% yield); mp 114ꢀ115 ºC (EtOH); FTIR
1
(KBr) ν 1509 (s), 1370 (m), 815 (m) cmꢀ1; H NMR (CDCl3) δ 1.35 (t, J = 7.2 Hz, 9H, CH3), 2.80
(q, J = 7.2 Hz, 6H, CH2), 7.42 (AA´XX´ system, 6H), 8.71 (AA´XX´system, 6H) ppm; 1H NMR
(C2D2Cl4) δ 1.37 (t, J = 7.2 Hz, 9H, CH3), 2.82 (q, J = 7.2 Hz, 6H, CH2), 7.44 (AA´XX´ system,
6H), 8.69 (AA´XX´system, 6H) ppm; 13C NMR (CDCl3) δ 15.8 (CH3), 29.5 (CH2), 128.5 (C meta),
129.4 (C ortho), 134.4 (C ipso), 149.6 (C para), 171.9 (C2, C4, C6) ppm; 13C NMR (C2D2Cl4)
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δ 15.2 (CH3), 29.0 (CH2), 128.2 (C meta), 129.1 (C ortho), 134.1 (C ipso), 149.3 (C para), 171.6
(C2, C4, C6) ppm; HRMS (ESI) [M+H]+ 394.22884, calc for C27H28N3 394.22777; [2M+Na]+
809.42681, calc for C54H54N6Na 809.43020.
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1ꢀBenzylꢀ2ꢀmethylbenzene (15) and 1ꢀbenzylꢀ4ꢀmethylbenzene (16). A solution of triflic anhydride
(10 mmol) in 15 mL toluene was added dropwise to a solution containing 1.31 g (10 mmol) of 4ꢀ
ethylbenzonitrile (12) in 15 mL of toluene at 0 ºC. The resulting solution was stirred 3 h at 0 ºC and
then a solution of 1.08 g (10 mmol) of benzyl alcohol in 15 mL of toluene was added and the
reaction mixture heated at reflux for 24 h. The reaction mixture was quenched with aqueous sodium
hydrogen carbonate until the pH was basic, washed with water and dried over magnesium sulfate.
The solvent was removed and the residue fractionated by column chromatography using
hexane/ethyl acetate 9:1 as eluent. After evaporation of solvent, the residue (1.16 g, 64% overall
yield) was analyzed by GC/MS, 1H and 13C NMR.
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Compound 15 (40% of mixture): H NMR (CDCl3) δ 2.29 (s, 3H, CH3), 4.04 (s, 2H, CH2), 7.10ꢀ
7.35 (m, 5H, ArꢀH) ppm; 13C NMR (CDCl3) δ 20.1 (CH3), 40.0 (CH2), 126.3, 126.9, 128.9, 129.2,
129.6, 130.9, 130.7 (CꢀH), 137.0, 139.4, 140.8 ppm; MS(EI, 70 eV) m/z (%B) 182 (M●+, 90), 165
(MꢀCH3, 100), 165 (45), 152 (15), 104 (22).
1
Compound 16 (60% of mixture): H NMR (CDCl3) δ 2.37 (s, 3H, CH3), 4.00 (s, 2H, CH2), 7.10ꢀ
7.35 (m, 5H, ArꢀH) ppm; 13C NMR (CDCl3) δ 21.5 (CH3), 42.0 (CH2), 126.4, 128.8, 129.1, 129.2,
129.6, (CꢀH), 135.9, 138.5, 141.8 ppm; MS(EI, 70 eV) m/z (%B) 182 (M●+, 90), 165 (MꢀCH3, 100),
165 (33), 152 (20), 104 (21).
(4ꢀEthylphenyl)(2,4,6ꢀtrimethoxyphenyl)methanone
(17)
and
1,3,5ꢀtrimethoxyꢀ2ꢀ
[(trifluoromethyl)sulfonyl]benzene (18). A solution of triflic anhydride (10 mmol) in 15 mL toluene
was added dropwise to a solution containing 1.31 g (10 mmol) of 4ꢀethylbenzonitrile (12) in 15 mL
of toluene at 0 ºC. The resulting solution is stirred 3 h at 0 ºC and then a solution of 1.68 g (10
mmol) of l,3,5ꢀtrimethoxybenzene in 15 mL of toluene was added and the reaction mixture heated
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at reflux for 24 h. The progress of the reaction can be monitored by TLC. The reaction mixture was
quenched with aqueous sodium hydrogen carbonate until the pH was basic, washed with water and
dried over magnesium sulfate. The solvent was removed and the residue fractionated by column
chromatography using hexane/ethyl acetate 9:1 as eluent.
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Compound 17 was obtained (0.93 g, 31% yield); mp 110ꢀ111 ºC (toluene/hexane); FTIR (KBr) ν
1
1666 (m), 1603 (s), 1128 (s) cmꢀ1; H NMR (CD2Cl2) δ 1.17 (t, 3H, J = 9 Hz, CH3), 2.62 (q, 2H, J
= 9 Hz CH2), 3.65 (s, 6H, OCH3), 3.78 (s, 3H, OCH3), 6.10 (s, 2H, ArꢀH), 7.17 (2H, AA´XX´
system), 7.65 (2H, AA´XX´system) ppm; 13C NMR (CD2Cl2) δ 15.8 (CH3), 29.7 (CH2), 56.3
(OCH3), 56.6 (OCH3), 91.5 (CaromꢀH), 111.9, 128.8 (CaromꢀH), 130.2 (CaromꢀH), 136.7, 151.0, 159.2
(CꢀOCH3), 163.1 (CꢀOCH3), 194.9 (CO) ppm; HRMS (ESI) [M+H]+ 301.14349, calc for C18H21O4
301.14344, [M+Na]+ 323.12560, calc for C18H20O4Na 323.12538.
Compound 18 was obtained (1.29 g, 43% yield); mp 92ꢀ93 ºC (toluene/hexane); FTIR (KBr) ν 1594
1
(m), 1572 (s), 1345 (m, SO2), 1116 (s, SO2), 1074 cmꢀ1; H NMR (CD2Cl2) δ 3.92 (s, 6H, OCH3),
3.93 (s, 3H, OCH3), 6,19 (s, 2H, ArꢀH) ppm; 13C NMR (CD2Cl2) δ 55.9 (OCH3), 56.6 (OCH3), 91.5
(Cꢀ4, Cꢀ6), 100.6 (Cꢀ2), 120.3 (q, CF3, J = 334 Hz), 163.8 (Cꢀ1, Cꢀ3), 168.0 (Cꢀ5) ppm; HRMS
(ESI) [M+Na]+ 323.01826, calc for C10H11F3NaO5S 323.01715.
4ꢀ(4ꢀChlorophenyl)ꢀN,Nꢀdimethylꢀ6ꢀ(4ꢀmethylphenyl)ꢀ1,3,5ꢀtriazinꢀ2ꢀamine (19). This compound
was prepared according general procedure A using dimethylcyanamide as nitrile 1 and a mixture of
equimolecular amount of 4ꢀchlorobenzonitrile and 4ꢀtolunitrile as nitrile 2 (1.88g, 58% yield); mp
178ꢀ179 ºC (EtOH); FTIR (KBr) ν 1591 (m), 1511 (s), 1377 (m), 801 (m) cmꢀ1; 1H NMR (CDCl3)
δ 2.47 (s, 3H, CH3ꢀAr), 3.39 (s, 6H, CH3ꢀN), 7.33, 8.49 (AA´XX´system, CH3ꢀArꢀH), 7.48, 8.56
(AA´XX´system, ClꢀArꢀH) ppm; 13C NMR (CDCl3) δ 22.0 (CH3ꢀAr), 36.7 (CH3ꢀN), 128.9, 129.0,
129.5, 130.4 (CꢀH), 134.6, 136.2, 138.1, 144.6, 166.0 (Cꢀ2), 170.0 (Cꢀ4), 171.1 (Cꢀ6) ppm; HRMS
(ESI) [M+H]+ 325.12194, calc for C18H18ClN4 325.12145.
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Page 29 of 35
The Journal of Organic Chemistry
(1Z)ꢀN-(1ꢀBenzylisoquinolinꢀ3ꢀyl)ꢀ2,2ꢀdimethylꢀN´-[(trifluoromethyl)sulfonyl]propanimide
(21).
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This compound was prepared according general procedure A using pivalonitrile and benzylcyanide
as starting materials 1 and 2 respectively (1.84 g, 41% yield); mp 158ꢀ159 ºC (chloroform/hexane);
FTIR (KBr) ν 3413 (NH, w), 1523 (m), 1336 (m), 1210 (SO2, s), 1188 (s), 752 (m), 708 (m), 620
9
(m) cmꢀ1; 1H NMR (CDCl3) δ 1.64 (s, 9H, CH3), 4.63 (s, 2H, CH2), 7.20ꢀ7.30 (m, 5H, ArꢀH), 7.54
(t, J = 8.5 Hz, 1H, Hꢀ7 of isoquinoline ring), 7.70 (t, J = 8.5 Hz, 1H, Hꢀ6 of isoquinoline ring), 7.84
(d, J = 8.5 Hz, 1H, Hꢀ5 of isoquinoline ring), 8.12 (d, J = 8.5 Hz, 1H, Hꢀ8 of isoquinoline ring),
8.28 (s, 1H, Hꢀ4 of isoquinoline ring), 8.60 (bs, NH) ppm; 13C NMR (CDCl3) δ 28.0 (CH3), 41.3
(CH2ꢀC6H5), 41.3 [(CH3)3C], 111.6 (Cꢀ4), 119.7 (q, J = 316 Hz, CF3), 126.2 (Cꢀ8), 126.6 (Cꢀ8a),
126.9 (phenyl ring), 127.9 (Cꢀ7), 128.5 (Cꢀ5), 128.9 (phenyl ring), 129.0 (phenyl ring), 131.3 (Cꢀ6),
138.4 (Cꢀ4a), 139.0 (phenyl ring), 143.4 (Cꢀ3), 160.5 (Cꢀ1), 171.7 (C=N) ppm; to distinguish the
quaternary carbon atom of the tert-butyl group in compound 22 a selective INEPT experiment has
been carried out because this nuclei and the CH2 carbon atom of the benzyl group resonate closely
at 41.35 and 41.37 ppm respectively; NOE experiments show that the irradiation of the methyl
groups of the tertꢀbutyl moiety at 1.64 ppm produces a strong dipolar coupling with the NH proton
and weak interactions with Hꢀ4 and Hꢀ5; HRMS (ESI) [M+H]+ 450.14466, calc for C22H23F3N3O2S
450.14576.
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Computational Details
All the calculations reported in this paper were obtained with the GAUSSIAN 09 suite of
programs.33 Electron correlation was partially taken into account using the hybrid functional usually
denoted as B3LYP34 using the doubleꢀζ quality plus polarization and diffuse functions 6ꢀ31+G(d)
basis set35 for all atoms. Reactants and products were characterized by frequency calculations,36 and
have positive definite Hessian matrices. Transition structures (TS’s) show only one negative
eigenvalue in their diagonalized force constant matrices, and their associated eigenvectors were
confirmed to correspond to the motion along the reaction coordinate under consideration using the
Intrinsic Reaction Coordinate (IRC) method.37 Solvents effects were taken into account using the
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