Four mechanisms in the reactions of 3-aminopyrrole with 1,3,5-triazines: Inverse electron demand diels-alder cycloadditions vs SNAr reactions via uncatalyzed and acid-catalyzed pathways

Article abstract of DOI:10.1021/jo4012915

Reaction of 3-aminopyrrole with seven 1,3,5-triazines was studied in a one-step reaction (in situ formation of 3-aminopyrrole) and a two-step reaction (using the tetraphenylborate salt and an amine base). An inverse-electron demand Diels-Alder reaction (IEDDA) was observed with R₁ = CF₃, CO₂Et, and H with the formation of 5H-pyrrolo[3,2-d]pyrimidine derivatives. S_NAr was observed when 2,4,6-trifluoro- or 2,4,6-trichloro-1,3,5-triazine were used - 1,3,5-triazines that had leaving groups. If excess 1,3,5-triazine was present the initial S_NAr product reacted further, in the presence of acid and water, with another equivalent of 1,3,5-triazine to give compounds containing three linked heterocyclic rings. No reaction was observed with R₁ = C₆H₅ and OCH₃. Four mechanisms are proposed to explain the experimental results: uncatalyzed and acid catalyzed inverse electron demand Diels-Alder cascades leading to cycloaddition, and uncatalyzed and acid-catalyzed S _NAr reactions leading, respectively, to single and double substitution products. Acid catalysis was a factor when there was reduced reactivity in either reactant.

Full text of DOI:10.1021/jo4012915

Article
pubs.acs.org/joc
Four Mechanisms in the Reactions of 3‑Aminopyrrole with 1,3,5-
Triazines: Inverse Electron Demand Diels−Alder Cycloadditions vs
SNAr Reactions via Uncatalyzed and Acid-Catalyzed Pathways
Michael De Rosa,* David Arnold, and Douglas Hartline
Department of Chemistry, Penn State Brandywine, 25 Yearsley Mill Road, Media, Pennsylvania 19063, United States
S
* Supporting Information
ABSTRACT: Reaction of 3-aminopyrrole with seven 1,3,5-
triazines was studied in a one-step reaction (in situ formation
of 3-aminopyrrole) and a two-step reaction (using the
tetraphenylborate salt and an amine base). An inverse-electron
demand Diels−Alder reaction (IEDDA) was observed with R1
= CF3, CO2Et, and H with the formation of 5H-pyrrolo[3,2-d]pyrimidine derivatives. SNAr was observed when 2,4,6-trifluoro- or
2,4,6-trichloro-1,3,5-triazine were used1,3,5-triazines that had leaving groups. If excess 1,3,5-triazine was present the initial
SNAr product reacted further, in the presence of acid and water, with another equivalent of 1,3,5-triazine to give compounds
containing three linked heterocyclic rings. No reaction was observed with R1 = C6H5 and OCH3. Four mechanisms are proposed
to explain the experimental results: uncatalyzed and acid catalyzed inverse electron demand Diels−Alder cascades leading to
cycloaddition, and uncatalyzed and acid-catalyzed SNAr reactions leading, respectively, to single and double substitution products.
Acid catalysis was a factor when there was reduced reactivity in either reactant.
aminopyrrole (1) in situ in two ways: a one-step reaction in
which the reduction of 3-nitropyrrole (2) to 3-aminopyrrole
(1), with Sn/acetic acid11 in CH2Cl2, was carried out in the
presence of the 1,3,5-triazine 4; whereas, in the two-step
procedure the 3-aminopyrrole (1) was generated in the
presence of the 1,3,5-triazine 4 by treating the tetraphenylbo-
rate salt1 of 3-aminopyrrole (3) with an amine base in THF or
the salt in CH2Cl2/AcOH.
It was found that IEDDA cycloaddition reactions took place
between 3-aminopyrrole and 1,3,5-triazines containing poor
leaving groups 4a, 4b, and 4c (R1 = CF3, CO2Et, and H). It
should be noted that the parent 5H-pyrrolo[3,2-d]pyrimidine
(5c) has been previously prepared in a multistep sequence.12
Water formed during reduction of 3-nitropyrrole hydrolyzed
either 4b or 5b (R1 = CO2Et) and 4 Å molecular sieves were
added to the reaction mixture to optimize the product yield of
5b. Interestingly it was found that the best conditions for the
IEDDA cycloaddition of the tetraphenylborate salt of 3-
aminopyrrole (3) with 4a and 4b were under weakly acidic
reaction conditions: direct mixture of salt 3 with the 1,3,5-
triazine in the absence of an amine base. Reaction of salt 3 with
4c (R1 = H) to give 5H-pyrrolo[3,2-d]pyrimidine (5c) only
occurred in the presence of a large excess of AcOH. Based on
this, and as discussed below, it is proposed that 5c was the
product of a separate acid-catalyzed reaction.
INTRODUCTION
■
Recently the first synthesis of 3-aminopyrrole was reported.1
Prior to this, the only simple 3-aminopyrroles reported, without
further substitution on the pyrrole ring, were 3-amino-1-
tritylpyrrole as the imino tautomer,2 and the picrate3 of 1-
phenyl-3-aminopyrrole. With the 3-aminopyrrole in hand,
reactions not possible with the polyfunctional 3-aminopyrroles
in the literature can now be studied.4 We report on the reaction
of 3-aminopyrrole with a series of 1,3,5-triazines. Inverse
electron demand Diels−Alder (IEDDA) cycloaddition5 com-
peted with a SNAr reaction6 when the 1,3,5-triazine had a
leaving group. The IEDDA reaction gave the 5H-pyrrolo[3,2-
d]pyrimidine scaffoldprivileged chemical structures7 of
interest because of their pharmacological properties. To the
best of our knowledge, this is the first report of the synthesis of
the 5H-pyrrolo[3,2-d]pyrimidine ring system using an IEDDA
reaction.8 Previously two general cyclization routes have been
reported for the synthesis of the 5H-pyrrolo[3,2-d]pyrimidine
ring system:8 starting either from a pyrimidine or from a
polyfunctional 3-aminopyrrole. In the case of the reactions of
1,3,5-triazines with leaving groups, the initially formed SNAr
product could react further with a second equivalent of 1,3,5-
triazine. Heteroaryl-heteroaryl compounds were obtained from
the observed SNAr reactions: compounds that are of increasing
interest in biological compounds, liquid crystals, and optoelec-
tronic compounds.9 Four mechanisms were needed to explain
the results detailed below.
The reaction of 3-aminopyrrole with electron deficient 1,3,5-
triazines, containing leaving groups 4d (R1 = Cl) and 4e (R1 =
F), proceeded via a SNAr reaction generating heteroaryl-
heteroaryl compounds 6d and 6e. Optimal conditions for these
RESULTS
■
The reaction of 3-aminopyrrole (1) with seven symmetrical
1,3,5-triazines10 4 was carried out by generating the 3-
Received: June 20, 2013
Published: July 30, 2013
© 2013 American Chemical Society
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Scheme 1. Optimized Reactions of 3-Aminopyrrole with 1,3,5-Triazines
Table 1. Yields of 5H-Pyrrolo[2,3-d]pyrimidines
a,
b
d
entry
R1
method
equiv (4)
solvent
additive
temp
time (h)
5
1
CF3
CF3
CF3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
Two-Step
One-Step
One-Step
Two-Step
Two-Step
One-Step
One-Step
One-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
One-Step
One-Step
One-Step
One-Step
Two-Step
One-Step
One-Step
Two-Step
One-Step
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
2
2
1
1
1
2
1
1
1
1
1
THF
X
X
X
X
room temp
reflux
2
85%
75%
90%
52%
49%
trace
54%
72%
0%
2
3:2 DCM:AcOH
3:2 DCM:AcOH
THF
1
3
room temp
room temp
room temp
reflux
1
4
2.5
2.5
1
5
THF
50% Et3N
6
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
THF
X
7
4 Å MS
room temp
room temp
room temp
reflux
2
c
8
4 Å MS
2
9
X
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
THF
X
0.5
0.25
1
0%
H
THF
100% Et3N
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
reflux
trace
0%
H
THF
X
H
THF
NaHCO3
18
23
4
0%
H
THF
500% AcOH
trace
44%
50%
38%
45%
44%
41%
68%
NR
H
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
THF
X
H
X
4
c
H
4 Å MS
22
1.5
0.5
2.5
2
H
X
H
X
H
4 Å MS
room temp
room temp
reflux
H
X
X
X
X
X
X
Ph
2
Ph
3:2 DCM:AcOH
3:2 ACN:AcOH
THF
reflux
5
NR
Ph
reflux
20
72
2
NR
OMe
OMe
room temp
reflux
NR
3:2 DCM:AcOH
NR
a
b
c
d
Two-Step Method/3. One-Step Method/2/Sn (5 equiv). Solvent mixture dried over 4 Å MS prior to reaction. Isolated yield of purified
products.
reactions were found to be the more basic two-step procedure
conditions with the reaction of salt 3 with 4d in the presence of
2 equiv DIPEA13 and reaction of salt 3 with 4e in the presence
of 0.5 equiv Et3N. Surprisingly the reaction of 3-aminopyrrole
with 5 equiv of 4d or 4e (in an attempt to increase the yield of
6) produced the double substitution products 7d and 7e as the
major reaction products, but only under acidic conditions;
results that suggested that formation of 7 was acid catalyzed.14
The reaction of 3-aminopyrrole with electron rich 1,3,5-
triazines 4f (R1 = C6H5) and 4g (R1 = OCH3) failed under all
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Scheme 2. Cascade Mechanism for the Reaction of 3-Aminopyrrole with a 1,3,5-Triazine
the conditions explored. X-ray crystallography was used to
confirm the structures of 5a (R1 = CF3) and 7e (R1 = F).15
During the course of the reaction of 2,4,6-tris-
(trifluoromethyl)-1,3,5-triazine (4a) with 3-aminopyrrole
(two-step) an unstable intermediate 11 was isolated. Based
on its H-1 (three different NH protons), F-19 (four CF3 groups
in a ratio of 2:1:1) NMR spectra and HRMS, structure 11 was
proposed (Scheme 2). When this reaction was carried out with
the one-step method this intermediate was not observed by
TLC. Its formation and subsequent reaction will be discussed
below.
Based on the results summarized in Scheme 1 and Table 1 it
is proposed that there are four possible mechanisms: they are
determined by the nature of the substituent present on the
1,3,5-triazine or the 3-aminopyrrole, and if an acid is added or
generated in situ. The four possible mechanisms are an inverse
electron demand Diels−Alder cascade leading to cycloaddition
products 5a (R1 = CF3) and 5b (R1 = CO2Et), acid catalyzed
cycloaddition that gives product 5c (R1 = H), a neutral SNAr
reaction that gives products 6d (R1 = Cl) and 6e (R1 = F), and
an acid catalyzed SNAr reaction that gives the double
substitution products 7d and 7e. Each of these mechanisms
will be discussed in a separate section below.
aminopyrroles,16d SNAr reactions of 1-alkyl-substituted-2-
aminopyrroles with 2,4,5,6-tetrachloropyrimidine,24 and in
other systems16f,17b,25−27 that, in retrospect, are Wheland-
Meisenheimer complexes. It is also possible that the initially
formed zwitterion ion (Wheland-Meisenheimer complex 8)
was present as, or in equilibrium with, its ammonium tautomer
as has been observed for the conjugate acids of 3-aminopyrrole
(1).1 Once formed, 8 (or a tautomer) can then cyclize to
tricyclic adduct 9, that in turn could undergo a retro-Diels−
Alder reaction, followed by loss of ammonia to give 5a. It is also
possible that loss of ammonia occurred first,6d followed by the
retro-Diels−Alder reaction.28
When the reaction was carried out by the two-step method
with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine (5a), unstable 11
was isolated. It is the product of the reaction of intermediate 10
with trifluoroacetonitrile (formed in the cascade leading to 5a).
Reactions of amines with trifluoroacetonitrile under mild
conditions have been reported.29 A similar derivative was
reported in a previous study of the reaction of 1-tert-butyl-2-
aminopyrrole with 5a.16d Intermediate 10 is a tautomer of
Wheland-Meisenheimer 8; its isolation, as 11, is additional
evidence for the formation of 8.30 Over a period of 2-weeks
isolated intermediate 11 converted to the cycloadduct 5a.
Intermediate 11 was not detected in the one-step process
possibly because its conversion to product was acid catalyzed or
it was not formed in the presence of acid.
2. Cycloaddition via an Acid Catalyzed Inverse
Electron Demand Diels−Alder (IEDDA) Cascade. As
noted above and in Table 1, the reaction of 1,3,5-triazine
(4c) and 3-aminopyrrole (1) only occurred under acidic
conditions (acetic acid). Boger has reported acid-catalyzed
IEDDA reactions of 1,3,5-triazines and enamines.31,32 It has
been reported that the IEDDA reaction of 1,3,5-triazine (2c)
with enaminones was acid-catalyzed.33 Protonation of 4c
lowered the LUMO−HOMO interaction and made cyclo-
addition easier.33 This calculation was carried out using AM1.33
The reaction of 1,3,5-triazine (2c) with naphthalene and 2-
napthyl ethers was facilitated by polyphosphoric acid
(PPA).34,35 The IEDDA reaction of 1-substituted-5-amino-
1H-imidazoles with 1,3,5-triazines17b,25 has been reported to be
catalyzed by TMSO-triflate, a strong Lewis acid.36 Lewis acid
catalysis of other IEDDA reactions have been reported.37
Interestingly the IEDDA reactions of 2-amino-4-cyanopyrroles
with 1,3,5-triazines were carried out using the HCl salts of the
2-aminopyrroles studied.16a,38 Literature precedent, and the
results in Table 1, suggested that the reaction leading to 5c was
DISCUSSION
■
1. Cycloaddition via an Inverse Electron Demand
Diels−Alder (IEDDA) Cascade. The inverse electron demand
Diels−Alder reactions of 2-aminopyrroles,16 1-substituted-5-
amino-1H-imidazoles,17 5-amino-1H-pyrazoles,18 and amino-
thiophenes19 with azadienes have been reported. These studies
have proposed that the IEDDA reactions of electron-rich
aminoheterocycles with azadienes were stepwise in nature and
the first step was the formation of a zwitterion. Reaction of 1-
tert-butyl-2-aminopyrrole16d with 2,4,6-tris(trifluoromethyl)-
1,3,5-triazine has been shown, by multinuclear NMR, to
involve at least five intermediates, one of them a zwitterion
analogous to 8. Scheme 2 (with R1 = CF3) illustrates the
proposed cascade mechanism.
Reaction at C2 of 3-aminopyrrole (1) gave zwitterion 8. This
type of zwitterion, formed when the nucleophile/electrophile
pair are aromatic and/or heteroaromatic, has been termed a
Wheland-Meisenheimer complex;20−22 recently, the X-ray
structure of such a complex was reported.23 Formation of
Wheland-Meisenheimer complexes has also been reported to
be reversible.23 Other examples of zwitterions have been
proposed as intermediates in IEDDA reactions with 2-
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acid-catalyzed as shown below in Scheme 3. Yields of 5a and 5b
were slightly higher under acidic conditions (Table 1). It is
unexpected. It might have been expected that in 6, an
electron-withdrawing difluoro- or dichloro-1,3,5-triazine group
bonded to the 3-amino group would have reduced its
nucleophilic character such that it would not have been very
reactive toward electrophiles. As noted above 7 was obtained
when, in order to increase its yield, excess 1,3,5-triazine (5
equiv) was used, but only under specific conditions did 6 react
further to give 7. Studies, with 2,4,6-trifluoro-1,3,5-triazine (4e)
and its derivatives, are summarized in Scheme 5.
Scheme 3. Suggested Mechanism for Reaction of 1,3,5-
Triazine and 3-Aminopyrrole
Both acid and water (from the reduction of the nitro group)
were needed for the formation of disubstituted 7e. This can be
seen from the following (Scheme 5 and Table 2): (1) reaction
of 6e with 2,4,6-trifluoro-1,3,5-triazine (4e) to give 7e, under
neutral conditions, was slow and the yield was very low (3%);
and (2) no 7e was formed in the presence of molecular sieve,
even when excess 2,4,6-trifluoro-1,3,5-triazine (4e) was present.
Analogous aminations of chloropyrimidines41 and halopuri-
nes41e,42 have been reported to be acid-catalyzed;43 in some
cases they were carried out in aqueous acid, or needed
water.41a,b,g,h Given the role that water played in this reaction,
specific-acid catalysis is proposed in which the catalytic species
was the hydronium ion: formation of 16 occurred in a rapid
pre-equilibrium followed by a subsequent rate-determining step
(Scheme 6). This appears to the first time that specific-acid
catalysis has been identified as the catalytic mechanism in these
types of aminations.
HF was formed as a byproduct of the second SNAr reaction
(Scheme 6), and possibly by the hydrolysis 2,4,6-trifluoro-1,3,5-
triazine (4e); as an acid, stronger than acetic acid, it would
increase the stoichiometric concentration of hydronium ion
present in the reaction mixture. Since HF was formed as the
reactions progressed, its effect was likely autocatalytic;
autocatalysis of aminations of halopyrimidines and halopurines
have also been reported.41d,e,42b Studies with 2,4,6-trichloro-
1,3,5-triazine (4d) were not as clear; this was most likely a
consequence of the much greater reactivity44,45 of this 1,3,5-
triazine with the resulting formation of HCl and the likely
autocatalytic nature of the reaction. Scheme 6 illustrates the
proposed acid-catalyzed SNAr mechanism.
possible that both the neutral and acid catalyzed cycloadditions
were occurring under these conditions.
3. Nucleophilic Aromatic Substitution (SNAr). For-
mation of 6 took place via a conventional SNAr mechanism.6
Reaction of 3-aminopyrrole (1) with a 1,3,5-triazine 4 at the 3-
amino group would give zwitterion 15. When a leaving group
(F or Cl) was present, a SNAr reaction took place and 6 was
formed (Scheme 4 with R1 = F). Reaction at the 3-amino group
would also be expected when the 1,3,5-triazine had a poor
leaving group. Zwitterions 8 (Scheme 2) and 15 were likely in
equilibrium, with the formation of 5 (IEDDA) or 6 (SNAr)
determined by the nature of the leaving group present in the
1,3,5-triazine.
An analogous SNAr reaction was observed in the reaction of
1-substituted-2-aminopyrroles with 2,4,5,6-tetrachloropyrimi-
dine; reactions took place at the 3-amino group or at C2 or
C5 of the pyrrole ring depending on the size of the 1-
substituent.24 In the reaction of pyrrole and 1-methylpyrrole
with 4,5-dicyanopyridiazine a SNAr reaction competed with
cycloadditionhere the leaving group was cyanide ion.39
Reactions of 1 equiv of 2,4,6-trifluoro- or 2,4,6-trichloro-1,3,5-
triazine with 3-aminopyrrole (1) to give 6, took about the same
time (60−90 min) using either method (Table 1). There did
not appear to be an element effect. This implied that the
formation of zwitterion 15 was the rate-determining step in the
formation of 6, and not the breaking of the C-X bond.6 These
results are typical for conventional SNAr reactions. It is
proposed that the formation of the zwitterion 15 was reversible
as is generally found in SNAr reactions.6 No evidence was found
for a SNAr reaction at C2 or C5 of the pyrrole ring of 3-
aminopyrrole (1), as was found in the reaction 1-alkyl-2-
aminopyrroles with 2,4,5,6-tetrachloropyrimidine.24 There was
also no evidence of the tautomerism of 6 as was observed in the
analogous chloropyrimidyl derivatives.40 Table 2 summarizes
the data for the SNAr reactions.
CONCLUSIONS
■
Aminopyrroles are highly electron-rich and unstable com-
pounds. Only when one or more electron-withdrawing groups
are present2b can aminopyrroles be isolatedbut the same
groups that stabilize the aminopyrroles also diminish the scope
of their possible reactions. This can be seen in the synthetic and
mechanistic results presented in this work on 3-aminopyrrole
without further substitution on the ring.
Synthetically the first example of the inverse electron demand
Diels−Alder reaction of 3-aminopyrrole, or of any 3-amino-
pyrrole, has been reported. Starting with 3-nitropyrrole the 5H-
pyrrolo[3,2-d]pyrimidine ring system can be obtained in one
4. Acid Catalyzed Nucleophilic Aromatic Substitution
(SNAr). Formation of the disubstituted product 7 was
Scheme 4. Nucleophilic Aromatic Substitution (SNAr) Mechanism
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Table 2. SNAr Reactions of 3-Aminopyrrole with 2,4,6-Trifluoro- or 2,4,6-Trichloro-1,3,5-triazine
a,
b
h
h
entry
R1
method
equiv (4)
solvent
additive
temp
time (h)
6
7
1
F
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
1
1
1
1
1
1
5
5
1
2
5
5
5
5
1
1
1
1.5
5
1
1
5
THF
THF
THF
THF
THF
THF
THF
THF
X
room temp
room temp
room temp
0 °C to rt
room temp
room temp
room temp
room temp
room temp
reflux
1
46%
64%
54%
29%
34%
33%
X
X
c
2
F
50% Et3N
1
X
3
F
200% Et3N
200% Et3N
200% DIPEA
1
X
4
F
1.5
1
X
5
F
X
f
6
F
200% base
1.5
23
20
1.5
2
X
7
F
X
37%
20%
X
8
F
100% Et3N
4 Å MS
X
X
d
e
9
F
One-Step
One-Step
One-Step
One-Step
One-Step
One-Step
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
3:2 DCM:AcOH
THF
49%
26%
X
10
11
12
13
14
15
16
17
18
19
20
21
22
F
X
F
X
reflux
1.5
72
20
1.5
1
45%
trace
dec
trace
X
d
d
e
e
e
F
4 Å MS
4 Å MS
4 Å MS
50% Et3N
room temp
reflux
50%
dec
11%
38%
37%
59%
33%
X
F
F
reflux
c
g
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Two-Step
Two-Step
Two-Step
Two-Step
Two-Step
One-Step
room temp
room temp
room temp
room temp
room temp
room temp
room temp
reflux
f
THF
200% base
1
X
THF
200% DIPEA
1
X
e
DCM
4 Å MS
20
26
1.5
1.5
X
f
THF
100% base
37%
g
g
3:2 DCM:AcOH
3:2 DCM:AcOH
4 Å MS
4 Å MS
X
7%
45%
d
One-Step
42%
X
trace
30%
One-Step
3:2 DCM:AcOH
2.5
a
b
c
d
Two-Step Method/3. One-Step Method/2/Sn (5 equiv). Triazine and salt premixed before the addition of base. 3-Aminopyrrole formed prior
e
f
g
to addition of the triazine. Solvent mixture dried over 4 Å MS prior to reaction. Base = 2,6-di-tert-butylpyridine. 80−90% pure after
chromatography. Isolated yield of purified products.
h
Scheme 5. Reactions of 2,4,6-Trifluoro-1,3,5-triazine
Scheme 6. Suggested Mechanism for the Acid-Catalyzed SNAr Reaction
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step or two. When a leaving group was present (F or Cl) SNAr
reaction took place leading to the reaction of 3-aminopyrrole
with 1 or 2 equiv of the 1,3,5-triazine; the latter resulted in
novel compounds with three-linked heterocyclic rings.
Mechanistically evidence that 3-aminopyrrole could react
with 1,3,5-triazines via four reaction pathways was uncovered.
Aminopyrroles are ambident nucleophiles that can react at
either the 3-amino group or at a pyrrole-ring carbon; the
attacking electrophile can be either the 1,3,5-triazine or its
conjugate acid. These possibilities are illustrated in Scheme 7.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were per-
formed under an atmosphere of either argon or nitrogen gas.
Reactions were monitored by TLC analysis and visualization was
accomplished with a 254 nm UV light. Melting points are uncorrected.
1H and 13C NMR spectra were obtained in CDCl3, acetone-d6, or
THF-d8 unless otherwise specified. Chemical shifts were reported in
parts per million with the residual solvent peak or TMS used as an
internal standard. 1H NMR spectra were recorded at either 300 or 400
MHz and are tabulated as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad),
number of protons, and coupling constants. 13C NMR were recorded
at either 75 or 100 MHz using a proton-decoupled pulse sequence
with a d1 of 5 s, and are tabulated by observed peak. All of the triazines
used in this work were commercially available except for 2,4,6-
tricarbethoxy-1,3,5-triazine which was synthesized according to a
literature procedure.10 The 3-nitropyrrole (2) used in this work was
commercially available and the 1H-pyrrol-3(2H)-iminium tetraphe-
nylborate (3) was synthesized according to a newly published
procedure.1
Scheme 7. Ambident Reactivity of 3-Aminopyrrole
Two-Step IEDDA Cascade Reaction Procedures: 2,4-Bis-
(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine (5a, Table 1:
Entry 1). To a black solution of 3 (78.4 mg, 0.195 mmol) in THF
(1.0 mL) was added 4a (52.7 μL, 0.186 mmol). The reaction mixture
was stirred at room temperature for 2 h and was then concentrated
under reduced pressure (50 °C) in the presence of SiO2 (1.0 g). The
dry SiO2 was then added to the top of a preconditioned column for
chromatography (SiO2; 2:1 petroleum ether/EtOAc). The product
fractions were concentrated under reduced pressure (30−50 °C),
transferred to a preweighed vial with DCM (2.5 mL), and
reconcentrated by a stream of N2 (g). The resulting solids were
then redissolved in DCM (1.0 mL) and reconcentrated by a stream of
N2 (g) 3× to remove traces of EtOAc. The product was dried in vacuo
over P2O5 to afford 5a as a pale yellow crystalline solid (40.1 mg,
Interestingly, it can be seen that if equilbria exist between
intermediates 8, 13, 15, and 19, respectively, with starting
compounds, then the equilibria between 8 and 15, and 13 and
19, are tautomeric, in which the mobile group is a 1,3,5-triazine
moiety.46,47
1
85%): Rf = 0.50 (SiO2; 1:1 hexane/EtOAc); Mp 110−112 °C; H
NMR (400 MHz, CDCl3) δ 10.07 (br-s, 1H), 8.05 (app. t, 1H, J = 3.0
Hz), 7.03 (dd, 1H, J = 3.6, 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ
154.2 (d, JC−F = 1.0 Hz), 148.4 (q, JC−F = 37 Hz), 137.7 (q, JC−F = 38
Hz), 137.0, 122.5, 121.1 (q, JC−F = 273 Hz), 120.1 (q, JC−F = 273 Hz),
104.7; 19F NMR (282 MHz, CDCl3) δ −66.23 (3F), −68.87 (3F);
HRMS (TOF MS ES+) m/z calcd for C8H4N3F6 256.0309, found
256.0302.
Formation of the initial intermediates is reversible. If the
initial reactions were not reversible it might be expected that
some cycloaddition would be observed under all reaction
conditions. Only one type of reaction is observed under a given
set of conditions: determined by the substituent present on the
1,3,5-triazine and the reactivity of the reactants. Acid-catalyzed
pathways became important when the 1,3,5-triazine did not
contain an electron-withdrawing activating group or the 3-
amino group had an electron-withdrawing group attached to it.
Protonation increased the electrophilicty of the resulting
conjugate acid of the 1,3,5-triazine and made reaction possible.
No direct evidence for intermediate 19 was obtained. Evidence
for the analogous intermediate 17, leading to the double
substitution product, was presented above (Scheme 6). Scheme
7 indicates that stoichiometric concentrations of all four
intermediates might be expected when acid is present. If the
same product is formed under both acidic and neutral
conditions (one-step and two-step reactions respectively in
this study) the possibility that both the catalyzed and
uncatalyzed reactions were taking place, under acidic
conditions, cannot be explicitly ruled out, e.g., the formation
of 5 and 6. As noted above the yields of 5a (R1 = CF3) and 5b
(R1 = CO2Et) were slightly higher under acidic conditions
(Table 1) suggesting that both the neutral and acid catalyzed
cycloadditions were occurring under these conditions. It can be
seen that when studying reactions of aminoazoles with
azadienes it is necessary to rule out the possibility that the
reaction under study is not acid catalyzed, even when acid has
not been added, given that acid could be formed as a by-
product or be adventitious.
Diethyl 5H-pyrrolo[3,2-d]pyrimidine-2,4-dicarboxylate (5b,
Table 1: Entry 4). To a mixture of 3 (210 mg, 0.523 mmol) and 4b
(148 mg, 0.498 mmol) was added THF (2.0 mL). The resulting black
reaction mixture was stirred at room temperature for 2.5 h and was
concentrated under reduced pressure (55−60 °C) in the presence of
SiO2 (1.0 g). The dry light green SiO2 was added to the top of a
preconditioned column for chromatography (SiO2; EtOAc). The
mixture was chromatographed 2× under identical conditions. The
product fractions were concentrated under reduced pressure (55−60
°C). The resulting light brown solids were found to be contaminated
1
with a mixture of unknown tetraphenylborate salts by TLC and H
NMR (60 MHz, CDCl3). The solids were dissolved in EtOAc (1.0
mL) and hexane (2.0 mL) was added at room temperature. A dark
brown oil precipitated which was removed from the mother liquor by
decantation and was triturated 5× with a 2:1 hexane/EtOAc mixture
(3.0 mL). The EtOAc/hexane washings were combined, brought to a
boil, diluted with hexane (5.0 mL), and concentrated to 10 mL. The
resulting turbid solution was cooled to room temperature for 1 h and a
solid precipitated which was isolated by vacuum filtration, washed with
hexane (10 mL), and dried in vacuo over P2O5 to afford 5b as a light
yellow crystalline solid (57.9 mg, 44%). The mother liquor containing
the hexane wash was concentrated to 10 mL by boiling and was cooled
to −20 °C for 4 d to afford an additional batch of 5b as a yellow
crystalline solid (10.1 mg, 8.0%). Combined yield (68.0 mg, 52%): Rf
1
= 0.42 (SiO2; EtOAc); Mp 141.9−142.8 °C; H NMR (300 MHz,
acetone-d6) δ 11.42 (br-s, 1H), 8.15 (d, 1H, J = 3.0 Hz), 6.87 (d, 1H, J
= 3.2 Hz), 4.52 (q, 2H, J = 7.1 Hz), 4.43 (q, 2H, J = 7.1 Hz), 1.41 (dt,
6H, J = 7.1 Hz); 13C NMR (75 MHz, acetone-d6) δ 165.4, 164.9,
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155.1, 149.9, 137.7, 137.2, 126.5, 103.8, 62.8, 62.0, 14.6, 14.5; HRMS
(TOF MS ES+) m/z calcd for C12H14N3O4 264.0984, found 264.0972.
5H-Pyrrolo[3,2-d]pyrimidine (5c, Table 1: Entry 16). A yellow
suspension of 3 (78.4 mg, 0.195 mmol) and 4c (31.6 mg, 0.390 mmol,
2 equiv) was stirred in a 3:2 DCM/glacial AcOH mixture (2.5 mL) at
room temperature for 4 h. The resulting black reaction mixture was
concentrated under reduced pressure (55−60 °C) in the presence of
SiO2 (1.0 g). The dry light brown SiO2 was then added to the top of a
preconditioned column for chromatography (SiO2; DCM (10%
MeOH)). Two fractions A and B were isolated, combined separately,
concentrated under reduced pressure (50−55 °C), transferred to
preweighed vials with DCM (2.0 mL, fraction A) or EtOAc (2.0 mL,
fraction B), reconcentrated by a stream of N2 (g), and dried in vacuo
over P2O5. Fraction A (TLC: SiO2; DCM (10% MeOH); Rf = 0.88)
was isolated as a pale orange solid and was found to be an unknown
tetraphenylborate salt by 1H NMR (60 MHz, CDCl3, 30.9 mg).
Fraction B was isolated crude as an orange/pink solid which was
dissolved in boiling EtOAc (3.0 mL), filtered through a plug of cotton
(to remove a black solid), and washed through with boiling EtOAc
(1.0 mL). The EtOAc solution was concentrated to 1.0 mL by boiling
and then hexane (2.0 mL) was added slowly to the boiling mixture. A
solid precipitated upon cooling to room temperature and then to −20
°C for 1 h. The resulting solid was isolated by vacuum filtration,
washed with hexanes (10 mL), and dried in vacuo over P2O5 to afford
5c as a pale orange solid (11.7 mg, 50%): Rf = 0.29 (SiO2, DCM (10%
MeOH)); Mp 168.8−170.0 °C; Lit mp12 172−174 °C; 1H NMR (300
MHz, acetone-d6) δ 11.0 (br-s, 1H), 8.92 (s, 1H), 8.85 (s, 1H), 7.87
(s, 1H), 6.63 (d, 1H, J = 3.2 Hz).
One-Step IEDDA Cascade Reaction Procedures: 2,4-Bis-
(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine (5a, Table 1:
Entry 3). To a gray suspension of 2 (50.0 mg, 0.446 mmol) and tin
powder (265 mg, 2.23 mmol, 5 equiv) in a 3:2 DCM/glacial AcOH
(5.0 mL) mixture was added 4a (126 μL, 0.446 mmol). The light
yellow/green heterogeneous reaction mixture was stirred at room
temperature for 1 h and then concentrated under reduced pressure
(50−55 °C, vacuum pump) in the presence of SiO2 (1.0 g). The dry
SiO2 was added to the top of a preconditioned column for
chromatography (SiO2; DCM). The product fractions (TLC: SiO2;
DCM; Rf = 0.20) were concentrated under reduced pressure (50 °C),
transferred to a preweighed vial with DCM (2.0 mL) and
reconcentrated by a stream of N2 (g). The product was dried in
vacuo over P2O5 to afford 5a as a white solid (102 mg, 90%).
Diethyl 5H-Pyrrolo[3,2-d]pyrimidine-2,4-dicarboxylate (5b,
Table 1: Entry 8). A 3:2 DCM/glacial AcOH (5.0 mL) solution was
dried over powdered 4 Å molecular sieves (500 mg) for 3.5 h prior to
reaction. To this suspension was added 2 (50.0 mg, 0.446 mmol) and
tin powder (265 mg, 2.23 mmol, 5 equiv) followed by 4b (133 mg,
0.446 mmol). The dark brown heterogeneous reaction mixture was
stirred at room temperature for 2 h and then concentrated under
reduced pressure (65−70 °C, vacuum pump) in the presence of SiO2
(1.0 g). The dry light brown SiO2 was added to the top of a
preconditioned column for chromatography (SiO2; EtOAc). The
product fractions were concentrated under reduced pressure (50 °C),
transferred to a preweighed vial with DCM (2.0 mL), and
reconcentrated by a stream of N2 (g). The product was dried in
vacuo over P2O5 to afford 5b as a pale yellow solid (84.5 mg, 72%).
5H-Pyrrolo[3,2-d]pyrimidine (5c, Table 1: Entry 21). A gray
suspension of 2 (50.0 mg, 0.446 mmol), tin powder (265 mg, 2.23
mmol, 5 equiv), and 4c (72.4 mg, 0.892 mmol, 2 equiv) in a 3:2
DCM/glacial AcOH (5.0 mL) mixture was stirred at room
temperature for 2 h. The resulting brown reaction mixture was
concentrated under reduced pressure (50−60 °C, vacuum pump) in
the presence of SiO2 (1.0 g). The dry light brown SiO2 was added to
the top of a preconditioned column for chromatography (SiO2; DCM
(10% MeOH)). The product fractions were concentrated under
reduced pressure (45−50 °C). The isolated product was dissolved in
boiling EtOAc (4.0 mL), filtered through a plug of cotton, and washed
through with boiling EtOAc (1.0 mL). The EtOAc solution was
concentrated to 1.0 mL by boiling and then hexane (5.0 mL) was
added slowly to the boiling mixture. A solid precipitated upon cooling
to room temperature and was isolated by vacuum filtration, washed
with hexanes (5.0 mL), and dried in vacuo over P2O5 to afford 5c as a
pale yellow solid (36.0 mg, 68%).
Two-Step SNAr Reaction Procedures (Mono-Addition Prod-
uct): 4,6-Dichloro-N-(1H-pyrrol-3-yl)-1,3,5-triazin-2-amine (6d,
Table 2: Entry 17). To a brown solution of 3 (78.4 mg, 0.195 mmol)
in THF (1.0 mL) was added DIPEA (66.4 μL, 0.381 mmol, 2 equiv) at
room temperature. After 5 min, the reaction mixture turned dark green
and 4d (34.3 mg, 0.186 mmol) was added. After 1 h, the reaction
mixture was concentrated under reduced pressure (55−60 °C) and the
resulting black oil was added in EtOAc (2.0 mL) to the top of a
preconditioned column chromatography (SiO2, 3:1 hexane/EtOAc).
The product fractions were concentrated under reduced pressure (55−
1
60 °C). The resulting product was found to be ∼90% pure by H
NMR (60 MHz, acetone-d6) and was recrystallized from boiling DCM
(2.5 mL) followed by cooling to room temperature and then to −20
°C for 1 h. The resulting precipitate was isolated by vacuum filtration,
washed with hexane (15 mL), and dried in vacuo over P2O5 to afford
6d as a light green solid (22.4 mg, 52%). An additional 2.7 mg of 6d
precipitated from the mother liquor upon the addition of hexane (15
mL) and was isolated to afford additional 6d (25.1 mg total, 59%): Rf
= 0.18 (SiO2; 3:1 hexane/EtOAc); Mp >260 °C; 1H NMR (400 MHz,
acetone-d6) δ 10.10 (br-s, 1H), 9.89 (br-s, 1H), 7.27−7.26 (m, 1H),
6.77−6.75 (m, 1H), 6.33−6.31 (m, 1H); 13C NMR (100 MHz,
acetone-d6, mixture of 2 rotamers) δ 171.4, 169.7, 163.7, 163.6, 122.3,
122.2, 117.6, 117.4, 110.5, 110.3, 102.6, 102.5; HRMS (TOF MS ES+)
m/z calcd for C7H6N5Cl2 230.0000, found 229.9994.
4,6-Difluoro-N-(1H-pyrrol-3-yl)-1,3,5-triazin-2-amine (6e,
Table 2: Entry 2). To a solution of 3 (75.0 mg, 0.186 mmol) in
THF (1.0 mL) was added 4e (15.2 μL, 0.186 mmol) followed by Et3N
(13.0 μL, 0.093 mmol, 0.50 equiv) at room temperature. The resulting
black reaction mixture was stirred at room temperature for 1 h and
then concentrated under reduced pressure (35 °C) in the presence of
SiO2 (1.0 g). The dry SiO2 was added to the top of a preconditioned
column for chromatography (SiO2; 3:1 hexane/EtOAc). Two fractions
A and B were isolated, concentrated under reduced pressure (50 °C),
transferred to preweighed vials with EtOAc (3.0 mL), reconcentrated
by a stream of N2 (g), and dried in vacuo over P2O5. Fraction A (TLC:
SiO2; 3:1 hexanes/EtOAc; Rf = 0.47) was isolated as a clear crystalline
1
solid and was found to be an unknown tetraphenylborate salt by H
NMR (60 MHz, CDCl3, 13.9 mg). Fraction B was isolated as an off
white solid affording 6e (23.4 mg, 64%): Rf = 0.19 (SiO2; 3:1 hexane/
1
EtOAc); Mp 230.9 to >260 °C (dec.); H NMR (400 MHz, acetone-
d6) δ 10.07 (br-s, 1H), 9.97 (br-s, 1H), 7.25−7.24 (m, 1H), 6.77−6.75
(m, 1H), 6.32−6.30 (m, 1H); 13C NMR (100 MHz, acetone-d6,
mixture of 2 rotamers) δ 173.2 (d, JC−F = 123 Hz), 173.0 (d, JC−F
=
123 Hz), 171.0 (d, JC−F = 123 Hz), 170.8 (d, JC−F = 123 Hz), 167.4 (t,
JC−F = 17.5 Hz), 122.4, 122.3, 117.5, 117.4, 110.6, 110.4, 102.7, 102.6;
19F NMR (282 MHz, DMSO-d6) δ −39.5 (d, 1F, J = 14.79 Hz), −42.5
(d, 1F, J = 14.9 Hz); HRMS (TOF MS ES+) m/z calcd for C7H6N5F2
198.0591, found 198.0580.
One-Step SNAr Reaction Procedures (Mono-Addition Prod-
uct): 4,6-Dichloro-N-(1H-pyrrol-3-yl)-1,3,5-triazin-2-amine (6d,
Table 2: Entry 21). A gray suspension of powdered 4 Å molecular
sieves (500 mg), 2 (50.0 mg, 0.446 mmol), and tin powder (265 mg,
2.23 mmol) in a 3:2 DCM/AcOH (5.0 mL) mixture was stirred at
room temperature for 2 h when 2 was found to be consumed by TLC
(1:1 hexane/EtOAc). At this time, 4d (82.2 mg, 0.446 mmol) was
added and the resulting heterogeneous yellow reaction mixture was
stirred at room temperature for 1.5 h. The reaction mixture was
concentrated under reduced pressure (50−60 °C) and dried in vacuo
over P2O5. The dry solids were suspended in acetone (25 mL) and
vacuum filtered through a plug of Celite which was flushed with
additional acetone (40 mL). The filtrate was concentrated under
reduced pressure (45−50 °C) and the residue was dissolved in EtOAc
(2.0 mL). The EtOAc solution was added to the top of a
preconditioned column for chromatography (SiO2; 3:1 hexane/
EtOAc). The product fractions were concentrated under reduced
pressure (50−55 °C), transferred to a preweighed vial with EtOAc
(2.0 mL), reconcentrated by a stream of N2 (g), and dried in vacuo
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Article
over P2O5 to afford 6d as a yellow solid (61.6 mg, 60%, ∼90−95%
pure). The product was then dissolved in boiling EtOAc (7.0 mL) and
hexane (14 mL) was slowly added when the solution became turbid.
After cooling to room temperature, a solid crystallized which was
isolated by vacuum filtration, washed with hexane (15 mL), and dried
in vacuo over P2O5 affording 6d as yellow/orange crystals (43.5 mg,
42%).
One-Step SNAr Reaction Procedures (Double-Addition
Product): 4,6-Dichloro-N-(2-(4,6-dichloro-1,3,5-triazin-2-yl)-
1H-pyrrol-3-yl)-1,3,5-triazin-2-amine (7d, Table 2: Entry 22).
To a gray suspension of 2 (100 mg, 0.829 mmol) and tin powder (529
mg, 4.46 mmol, 5 equiv) in a 3:2 DCM/AcOH (10 mL) mixture was
added 4d (822 mg, 4.46 mmol, 5 equiv) at room temperature. The
reaction mixture was heated to reflux for 2.5 h, cooled to room
temperature, and the resulting suspension was vacuum filtered through
a plug of Celite which was then flushed with EtOAc (50 mL). The
yellow filtrate was concentrated under reduced pressure (55−60 °C)
in the presence of SiO2 (0.50 g). The yellow/orange SiO2 mixture was
added to the top of a preconditioned column for chromatography
(SiO2; gradient elution: 4:1 to 2:1 hexane/EtOAc). The product
fractions were concentrated under reduced pressure (55 °C). The
resulting yellow solids were recrystallized from a boiling 5:1 hexane/
EtOAc mixture (25 mL) and after slowly cooling to room temperature,
the precipitate was isolated by vacuum filtration, washed with hexane
(20 mL), and dried in vacuo to afford 7d as a light yellow solid (70.3
mg, 21%). The mother liquor was recrystallized a second time by the
above method to afford an additional 30.8 mg of 7d (101 mg total,
30%).
N-(2-(4,6-Difluoro-1,3,5-triazin-2-yl)-1H-pyrrol-3-yl)-4,6-di-
fluoro-1,3,5-triazin-2-amine (7e, Table 2, Entry 11). To a gray
suspension of 2 (100 mg, 0.829 mmol) and tin powder (529 mg, 4.46
mmol) in a 3:2 DCM/AcOH (10 mL) mixture was added 4e (383 μL,
4.46 mmol, 5 equiv) at room temperature. The reaction mixture was
heated to reflux over 15 min and at reflux for 1.5 h. At this time, the
reaction mixture was concentrated under reduced pressure (55−60 °C,
vacuum pump) in the presence of SiO2 (0.50 g). The dry solids were
added to the top of a preconditioned column for chromatography
(SiO2; gradient elution: 3:1 → 1:1 hexane/EtOAc). The product
(TLC: SiO2; 1:1 hexane/EtOAc; Rf = 0.65) fractions were
concentrated under reduced pressure (55 °C). The resulting pale
yellow solid was recrystallized from a boiling 1:1 DCM/hexane (40
mL) mixture which was slowly cooled to room temperature and then
to −20 °C for 15 h. The resulting precipitate was isolated by vacuum
filtration, washed with hexane (10 mL), and dried in vacuo over P2O5
to afford 7e as a pale yellow/green solid (124 mg, 45%).
4,6-Difluoro-N-(1H-pyrrol-3-yl)-1,3,5-triazin-2-amine (6e,
Table 2: Entry 9). To a predried 3:2 mixture of DCM/AcOH (5.0
mL) containing powdered 4 Å molecular sieves (500 mg) was added 2
(50.0 mg, 0.446 mmol) and tin powder (265 mg, 2.23 mmol) at room
temperature. After 2 h, 2 was consumed by TLC (SiO2; 1:1 hexane/
EtOAc; Rf = 0.49) and 4e (38.3 μL, 0.446 mmol) was added to the
greenish/brown 3-aminopyrrole solution. After 1.5 h, the reaction
mixture was concentrated under reduced pressure (55−60 °C, vacuum
pump) in the presence of SiO2 (1.0 g). The resulting light brown SiO2
was added to the top of a preconditioned column for chromatography
(SiO2; 3:1 hexane/EtOAc). The product fractions were concentrated
under reduced pressure (55−60 °C), transferred to a preweighed vial
with EtOAc (2.0 mL), reconcentrated by a stream of N2 (g), and dried
in vacuo over P2O5 to afford 6e as a white solid (42.8 mg, 49%).
Two-Step SNAr Reaction Procedures (Double-Addition
Product): 4,6-Dichloro-N-(2-(4,6-dichloro-1,3,5-triazin-2-yl)-
1H-pyrrol-3-yl)-1,3,5-triazin-2-amine (7d, Table 2: Entry 19).
To a black solution of 3 (100 mg, 0.249 mmol) in THF (1.0 mL) was
added 2,6-di-tert-butylpyridine (55.0 μL, 0.249 mmol, 1 equiv) at
room temperature. After 5 min, 4d (230 mg, 1.25 mmol, 5 equiv) was
added and the resulting light brown suspension was stirred at room
temperature for 26 h. The reaction mixture was then added directly to
the top of a preconditioned column for chromatography (SiO2; 3:1
hexane/EtOAc). The resulting impure product fractions were
concentrated under reduced pressure (50 °C) in the presence of
SiO2 (1.0 g). The resulting solids were added to the top of a
preconditioned column for a second chromatography (SiO2; 4:1
hexane/EtOAc). The product fractions were concentrated under
reduced pressure (50 °C), transferred to a preweighed vial with DCM
(2.0 mL), reconcentrated by a stream of N2 (g), and dried in vacuo
over P2O5 to afford 7d as a light yellow solid (35.1 mg, 37%): Rf = 0.43
(SiO2; 3:1 hexane/EtOAc); Mp >260 °C; 1H NMR (400 MHz, THF-
d8) δ 11.83 (br-s, 1H), 10.42 (br-s, 1H), 7.28 (app. t, 1H, J = 3.2 Hz),
7.18 (app. t, 1H, J = 2.6 Hz); 13C NMR (100 MHz, THF-d8, mixture
of 2 rotamers) δ 171.9, 171.1, 166.2, 164.6, 134.2, 134.0, 129.3, 129.2,
114.7, 105.6 (2C); HRMS (TOF MS ES+) m/z calcd for C10H5N8Cl4
376.9391, found 376.9406. An unidentified tetraphenylborate salt was
also isolated (31.5 mg; yellow oil; TLC; SiO2; 3:1 hexane/EtOAc; Rf =
0.62).
N-(2-(4,6-Difluoro-1,3,5-triazin-2-yl)-1H-pyrrol-3-yl)-4,6-di-
fluoro-1,3,5-triazin-2-amine (7e, Table 2: Entry 7). To a black
solution of 3 (78.4 mg, 0.195 mmol) in THF (1.0 mL) was added 4e
(83.6 μL, 0.975 mmol, 5 equiv) at room temperature. After 23 h, the
thick green reaction mixture was concentrated under reduced pressure
(50−55 °C) in the presence of SiO2 (1.0 g). The resulting thick
rubbery green solids were pulverized and added to the top of a
preconditioned column for chromatography (SiO2; 3:1 hexane/
EtOAc). The product fractions were concentrated under reduced
pressure (55 °C), transferred to a preweighed vial with EtOAc (2.0
mL), reconcentrated by a stream of N2 (g), and dried in vacuo over
P2O5 to afford 7e as a white solid (22.7 mg, 37%): Rf = 0.43 (SiO2; 3:1
hexane/EtOAc); Mp 228.0−229.5 °C; 1H NMR (400 MHz, THF-d8)
δ 11.9 (br-s, 1H), 10.4 (br-s, 1H), 7.28 (app. t, 1H, J = 3.0 Hz), 7.17
(app. t, 1H, J = 2.8 Hz); 1H NMR (300 MHz, acetone-d6) δ 11.5 (br-s,
1H), 10.39 (br-s, 1H), 7.41 (app. t, 1H, J = 3.1 Hz), 7.14 (app. t, 1H, J
= 2.6 Hz); 13C NMR (100 MHz, THF-d8, mixture of 2 rotamers) δ
173.7 (d, JC−F = 85 Hz), 173.5 (d, JC−F = 85 Hz), 172.9 (br-m), 171.0
(d, JC−F = 85 Hz), 171.3 (d, JC−F = 85 Hz), 170.7 (br-m), 170.1 (t, JC−F
= 14 Hz), 168.5 (t, JC−F = 18 Hz), 134.1, 134.0, 129.3, 129.2, 115.2,
105.7, 105.6; 19F NMR (282 MHz, acetone-d6) δ −38.75 (br-s, 3F),
−39.03 (d, 3F, J = 13.5 Hz), −39.79 (br-s, 3F), −41.05 (d, 3F, J = 13.5
Hz).
2-(5-(2,2,2-Trifluoro-1-iminoethyl)-2,4,6-tris(trifluoro-
methyl)-2,5-dihydro-1,3,5-triazin-2-yl)-1H-pyrrol-3-amine (11).
To a black solution of 3 (200 mg, 0.498 mmol) and 4a (141 μL, 0.498
mmol) in THF (2.0 mL) was added Et3N (34.7 μL, 0.249 mmol, 0.5
equiv), within one min of mixing, at room temperature. After 1 h, the
reaction mixture was concentrated under reduced pressure (50−60
°C) in the presence of SiO2 (0.50 g). The dry SiO2 was added to the
top of a preconditioned column for chromatography (SiO2; 2:1
petroleum ether/EtOAc). Two products were isolated 5a and 11. The
product fractions were combined separately and concentrated under
reduced pressure (50−60 °C). Product 5a was transferred to a
preweighed vial with DCM (2.0 mL), reconcentrated by a stream of
N2 (g), and dried in vacuo over P2O5 to afford 5a as white crystalline
solid (36.6 mg, 29%). Product 11 was diluted with DCM (10 mL) and
concentrated under reduced pressure (55 °C) in the presence of SiO2
(0.50 g). The white SiO2 was added to the top of a preconditioned
column for a second chromatography (SiO2; DCM). The product
fractions were concentrated under reduced pressure (50 °C),
transferred to a preweighed vial with DCM (2.0 mL), reconcentrated
by a stream of N2 (g), and dried in vacuo over P2O5 to afford 11 as a
light green oil (50.6 mg) which was found to be contaminated with
EtOAc by 1H NMR (400 MHz, CDCl3). The CDCl3 was removed by
a stream of N2 (g) and the resulting light yellow/green oil solidified in
vacuo to form 11 as a pale orange solid (46.3 mg, 20%): Rf = 0.63
1
(SiO2; 2:1 petroleum ether/EtOAc); Mp 93.1−94.6 °C; H NMR
(400 MHz, CDCl3) δ 8.92 (br-s, 1H), 6.95 (appt. t, 1H, J = 3.0 Hz),
6.23 (appt. t, 1H, J = 3.0 Hz), 5.46 (br-s, 2H); 13C NMR (100 MHz,
CDCl3) δ 156.5 (br-m), 143.4 (q, JC−F = 36 Hz), 136.1, 126.9, 122.7
(q, JC−F = 288 Hz), 119.4, 118.2 (q, JC−F = 275 Hz), 101.9, 74.0 (q,
JC−F = 34 Hz); 19F NMR (377 MHz, CDCl3) δ −76.77 (3F), −78.17
(6F), −89.64 (3F); HRMS (TOF MS ES+) m/z calcd for C12H7N6F12
463.0514, found 463.0533.
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Conversion of 11 to 5a. A sample of 11 was dissolved in acetone-
d6 in an NMR tube. After 2 weeks at room temperature it was found
that 11 had completely converted to 5a by a H NMR (60 MHz)
comparison of the intermediate solution after 2 weeks vs a solution of
5a in acetone-d6.
Gahtori, P. Lett. Drug Des. Discovery 2012, 9, 329−335. (d) Sosic, I.;
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1
ASSOCIATED CONTENT
* Supporting Information
NMR spectra (H1, C13 and F19) of the products are
presented. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(8) For a review of methods see: Zhao, L.; Tao, K.; Li, H.; Zhang, J.
Tetrahedron 2011, 67, 2803.
(9) Tsuchimoto, T.; Iwabuchi, M.; Nagase, Y.; Oki, K.; Takahashi, H.
Angew. Chem., Int. Ed. 2011, 50, 1375.
AUTHOR INFORMATION
Corresponding Author
*E-mail: MXD19@psu.edu.
■
(10) Only 2,4,6-tricarbethoxy-1,3,5-triazine (4b) was not commer-
cially available. See: Sugiyama, Y.; Sasaki, T.; Nagato, N. J. Org. Chem.
1978, 43, 4485.
Notes
The authors declare no competing financial interest.
(11) (a) Fu, L.; Gribble, G. W. Synthesis 2008, 788. (b) Fu, L.;
Gribble, G. W. Tetrahedron Lett. 2008, 49, 3545.
(12) Imai, K. Chem. Pharm. Bull. 1964, 12, 1030.
(13) DIPEA was used because 4d reacted with Et3N.
(14) Compounds 6e and 7e were mixtures of rotamers (see
experimental and Supporting Information). This will be the subject of
a separate study.
ACKNOWLEDGMENTS
■
This work was supported by grant number 0910668 from the
National Science Foundation. We thank Dr. Scott Van Bramer
and Mr. Marty Schultz (Widener University) for NMR spectra.
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