Convenient synthesis of 2-Amino-4H-chromenes from photochemically generated o-quinone methides and malononitrile

Article abstract of DOI:10.1002/jhet.1964

2-Amino-4H-chromenes were synthesized in moderate to good yields by the reaction of o-quinone methides photochemically generated from o-(dimethylaminomethyl)phenols with malononitrile. This method was applicable to the synthesis of fluorinated chromenes that were difficult to obtain by other methods. In addition, o-(hydroxymethyl)phenols could be used for the reaction in the presence of tertiary amine bases.

Full text of DOI:10.1002/jhet.1964

Month 2014
Convenient Synthesis of 2-Amino-4H-chromenes from Photochemically
Generated o-Quinone Methides and Malononitrile
a
a
a
a
a
*
Makoto Fujiwara, Masanori Sakamoto, Kimihiro Komeyama, Hiroto Yoshida , and Ken Takaki
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Kagamiyama,
Higashi-Hiroshima 739-8527, Japan
*
E-mail: ktakaki@hiroshima-u.ac.jp
Received October 19, 2012
DOI 10.1002/jhet.1964
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
2-Amino-4H-chromenes were synthesized in moderate to good yields by the reaction of o-quinone methides
photochemically generated from o-(dimethylaminomethyl)phenols with malononitrile. This method was
applicable to the synthesis of fluorinated chromenes that were difficult to obtain by other methods. In addition,
o-(hydroxymethyl)phenols could be used for the reaction in the presence of tertiary amine bases.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
would like to disclose the reaction of photochemically
generated o-QMs with malononitrile leading to 2-amino-
4H-chromenes (3).
2-Amino-4H-chromene constituents are widely found
in natural products, and their biological activities have
attracted much attention in medicinal chemistry [1–3]. Of
their synthetic methods, the reaction of phenols (naphthols)
with benzylidenemalononitriles or three-component reaction
of the phenols, aldehydes, and malononitrile via intermediate
A has been used most frequently using various catalysts
and promoters (Scheme 1, path A) [1,3–8]. This reaction is,
however, hardly applicable to the phenols having electron-
withdrawing substituents. Chromenes (3) with nitrogen-
functional groups at 4-position (R2 = CH2NO2, NHBoc)
could be synthesized by amine-thiourea organocatalysts
(path B) [2,9]. On the synthesis of nonsubstituted chromenes
(3) (R2 = H) from salicylaldehyde by use of InCl3, expensive
Hantzsch dihydropyridine ester was necessary as a reductant
[10]. For discovery of new biologically active 2-amino-4H-
chromenes (3), exploitation of their simple and convenient
synthetic methods is desired further.
ortho-Quinone methides (o-QMs) have been used as
reactive intermediates for the synthesis of a variety of
heterocyclic compounds through [4 + 2] cycloaddition with
alkenes [11,12] and conjugate addition of various nucleo-
philes [13]. If addition of malononitrile to o-QMs would take
place similarly as diethyl malonate [14] and phenacyl phenyl
sulfone [15], then the intermediate A would be generated as
well as path A to yield the 2-aminochromenes (3) (path C).
Although this process has remained unexplored [16],
electron-withdrawing substituent (R1) could be expected
to facilitate the reaction in contrast to path A. Of the various
procedures to generate o-QMs such as thermal, base, and
acid initiation [13], photochemical method would be prefer-
able in many respects, because it can be cleanly carried out
at ambient temperature without any additives. Herein, we
RESULTS AND DISCUSSION
The reaction of o-(dimethylaminomethyl)phenol (1a) with
malononitrile (2) was carried out under various conditions as
a model reaction (Table 1). When a mixture of 1a and 2 in
MeCN/H2O (1:1) was irradiated by Hg lamp with Pyrex
filter, the expected chromene (3a) was formed in 59% yield
(entry 1). Irradiation without the filter decreased the yield,
and, of course, no reaction took place in the dark (entries 2
and 3). Water is necessary for the reaction (entry 4). The ratio
of 2 to 1a affected the reaction efficiency; that is, the
optimum yield was attained with 1.5 equiv of 2, but higher
ratio decreased the yield (entries 1 and 5–8). Moreover, as
the concentration of 1a increased from 0.01 to 0.1 M, the
product yield decreased drastically (entries 6 and 9–11).
Under the optimal conditions, the reaction of variously
substituted o-(dimethylaminomethyl)phenols (1) was inves-
tigated (Table 2). 2-Aminochromenes (3b–3d) having
methyl group at 6–8 position were obtained in good yields,
wherein the substituent at 6- and 8-position seemed to facil-
itate the reaction better than 7-methyl group (entries 2–4).
Similarly, phenols (1e–1g) with electron-donating substitu-
ents gave the corresponding 2-aminochromenes (3e–3g) in
high yields (entries 5–7). Although the product 3h with
Et2N substituent was formed in 72% yield, the reaction of
1i with NH2 group gave trace amounts of the expected prod-
uct 3i (entries 8 and 9). These results suggested a depressing
effect of NH2 substituent on the reaction, vide infra. The
products 3 with electron-withdrawing groups were formed
in somewhat lower yields than those with electron-donating
© 2014 HeteroCorporation

M. Fujiwara, M. Sakamotom, K. Komeyama, H. Yoshida, and K. Takaki
Vol 000
Scheme 1
tumor cells and human lung cancer cells [1]. Thus, simple
irradiation of the phenol (1u) (R1 = 5-NEt2, R2 = C6H4Cl-p)
gave 3u in 93% yield (entry 21).
Other than malononitrile (2), ethyl cyanoacetate (4)
reacted with o-(dimethylaminomethyl)phenol (1b) under
standard conditions to give the 2-aminochromene (5) in
30% yield (Scheme 2, method A). Preliminary investigation
revealed that the yield of 5 was improved to 96% by use of
DMSO/H2O solvent and a large amount of 4 (method B).
Next, we investigated the reaction using o-(hydroxy-
methyl)phenols (6) instead of 1 to compare their efficiency
for the 2-aminochromene synthesis (Table 3) [17]. The
expected product 3a was not formed from 6a in the absence
of base (entry 1). N,N-Diisopropylethylamine (DIPEA)
showed the best results, of the bases tested, which were
comparable with the reaction of o-(dimethylaminomethyl)
phenol (1a), although longer reaction period was necessary
than that of 1a (entry 2). Because the yield of 3a decreased
drastically in the dark reaction even in the presence of
DIPEA (entry 3), the bases should be necessary for deproto-
nation of 2, not for generation of o-QM. Although Me2NH
liberated together with o-QM would act as a base in the
reaction of 1, secondary amines such as dimethylamine and
piperidine gave no or little product 3a in this reaction (entries
7 and 8). Chromenes (3v–3x) having aromatic and aliphatic
substituents at 4-position were obtained in moderate to good
yields starting from 6b–6d (entries 9–11).
ones unexpectedly. Nevertheless, the product 3k having
6-fluoride substituent was obtained in quantitative yield
(entry 11). Halogenated phenols (1l–1p) could be tolerated
under irradiation, although their product yields were moder-
ate (entries 12–16). Both 2- and 1-naphthol derivatives 1s
and 1t could participate in the reaction, wherein the former
showed better reactivity than the latter (entries 19 and 20).
Utility of the present method has been also demonstrated
by the synthesis of 2-aminochoromene (3u), which was
reported to exhibit high potent activity against human breast
Table 1
Optimization of the reaction of 1a with 2.
Entry
Equiv of 2
Conc (M)
Time (h)
Yielda (%)
1
5
5
5
5
1
1.5
2
10
1.5
1.5
1.5
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.03
0.05
0.10
20
20
20
20
0.5
0.5
1
20
0.5
2
59
10
0
2b
3c
4d
5
0
74
88 (70)
59
50
35
22
6
6
7
8
9
10
11
2
aNMR yield (isolated yield).
bWithout Pyrex filter.
cDark reaction.
dAnhydrous MeCN solvent.
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Convenient Synthesis of 2-Amino-4H-chromenes from Photochemically Generated o-
Quinone Methides and Malononitrile
Table 2
Synthesis of 2-amino-4H-chromene derivatives (3) from 1.
Entry
1
Product 3
Time (h)
0.5
Yielda (%)
88
Entry
11
Product 3
Time (h)
0.5
Yielda (%)
Quant
2
3
0.5
0.5
Quant
70
12
13
0.5
0.5
40
43
67b
4
0.5
90
14
2
5
6
7
1
89
15
16
17
5
2
5
51
37
55
0.5
98
70b
5
72b
30b
8
2
18
1
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Fujiwara, M. Sakamotom, K. Komeyama, H. Yoshida, and K. Takaki
Vol 000
Table 2
(Continued)
Entry
9
Product 3
Time (h)
1
Yielda (%)
Tracec
Entry
19
Product 3
Time (h)
1
Yielda (%)
81b
10d
0.5
59
20
21
13
47
0.5
93
aNMR yield.
bIsolated yield.
cDetected by MS.
d2 equiv of 2 were used.
Scheme 2
Although the failure in biscyclization showed a limita-
tion of the present method, compared with the procedure
using methylenemalononitrile [18], it is worthwhile to
comment on this subject. o-QM photochemically generated
from 1a and 6a should essentially exist in an equilibrium
state (Scheme 4). When the irradiation of 1a in the absence
of malononitrile was monitored by 1H-NMR under
standard conditions (CD3CN/D2O solvent), signals of 1a
disappeared after 5 h, but those of 6a were not observed
throughout the reaction, suggesting that hydration of o-QM
to 6a could be ignored. On the other hand, similar treatment
of 6a in the presence of equimolecular amounts of Me2NH
exhibited signals of 6a and 1a (22% and 24% yield
after 30 min, 0% and 20% yield after 1.5 h). Thus, in the
reaction of 1a with malononitrile, the equilibrium would shift
to o-QM, because liberated Me2NH was consumed for depro-
tonation of malononitrile, giving rise to the product 3a effi-
ciently within 30 min. On the irradiation of the substrates
having NH2 group such as 1i and 8, the equilibrium would
exclusively shift to o-aminomethylphenols (1) by facile ami-
nation of o-QM with another molecule of the substrates,
which were present in large excess relatively to o-QM.
When resorcinol derivative (7a) was irradiated for 0.5 h
in the presence of malononitrile (2) (3 equiv), monocycli-
zation product 8a was formed in 87% yield, wherein one
o-(dimethylaminomethyl)phenol moiety was remained
unchanged (Scheme 3). Irradiation was continued for
longer period (5 h) to promote biscyclization, but the yield
of 8a diminished to 71% without a formation of the
expected product. Similar results were observed for the
reaction of catechol (7b) and 1,5-dihydroxynaphthalene
(7c). Thus, monocyclization took place readily to give 8b
and 8c in 75% (2 h) and 86% (0.5 h) yield, respectively,
which were decomposed faster than the second cyclization
by further irradiation. These results may be caused by the
NH2 group of 2-aminochromenes (8) formed in the first cycli-
zation, in analogy with the reaction of 1i (Table 2, entry 9).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Convenient Synthesis of 2-Amino-4H-chromenes from Photochemically Generated o-
Quinone Methides and Malononitrile
Table 3
Synthesis of 2-amino-4H-chromenes (3) from 6.
Phenol
Entry
6
R
Base
None
Time (h)
Product 3
Yielda (%)
1
6a
H
4
3a
No reaction
2
DIPEA
DIPEA
DMAP
DBU
3
3
3
1.5
3
88
13
28
57
3b
4
5
6
NaOH
53
7
8
9
10
11
Me2NH
Piperidine
DIPEA
DIPEA
DIPEA
4
4
1.5
2
4
No reaction
7
Quant
51
6b
6c
6d
Ph
n-Bu
Ph
3v
3w
3x
49c
DIPEA, N,N-diisopropylethylamine; DMAP, 4-(dimethylamino)pyridine; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene.
aNMR yield.
bDark reaction.
cIsolated yield.
Scheme 3
Scheme 4
was very slow or did not take place, and, thus, 3a was formed
in fairly good yields.
Because fluoride substituent often have a profound effect
on the biological properties of the target molecule [19],
the procedure applicable to the synthesis of fluorinated
2-aminochromenes (3) is strongly desired. However, few
examples have been found in the literature via path B in
Scheme 1 [2,9]. The process via path A is less likely to meet
this requirement. In fact, piperidine-mediated reaction of
4-fluorophenol with benzylidenemalononitrile was tested
under various conditions, but the expected product 3k was
not formed at all. In contrast, the o-QM process gave
3k quantitatively as described earlier (Table 2, entry 11).
Moreover, the reaction could be conveniently carried out in
one-pot, starting from the fluorophenol, although the yield
decreased (Scheme 5).
Hence, 2-aminochromene synthesis from 1i and biscycliza-
tion of 7a would be difficult.
Base effect in the reaction of 6a with malononitrile could
be explained similarly. That is, use of secondary amines such
as Me2NH and piperidine gave no or little 3a, because these
amines quickly converted o-QM to o-aminomethylphenols
(1). In contrast, quenching of o-QM with tertiary amines
Journal of Heterocyclic Chemistry
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M. Fujiwara, M. Sakamotom, K. Komeyama, H. Yoshida, and K. Takaki
Vol 000
brine, dried over MgSO4, and concentrated in vacuo. 1H-NMR
spectra of the crude mixture showed 88% yield of 2-amino-3-cyano-
4H-chromene (3a). The product 3a was isolated in 70% yield
(12 mg) by column chromatography on silica gel with a hexane/
AcOEt eluent (10:1–5:1). The reactions of o-(hydroxymethyl)
phenols (6) and dihydroxybenzenes (7) were carried out similarly,
except for addition of N,N-diisopropylethylamine (1 equiv) in the
former and use of 3 equiv of malononitrile (2) in the latter.
Scheme 5
CONCLUSIONS
One-pot synthesis of 3k. 4-Fluorophenol (11mg, 0.1mmol),
N,N-dimethylmethyleneiminium iodide (20mg, 0.11 mmol),
K2CO3 (15 mg, 0.11 mmol), and MeCN (1mL) were charged in a
20mL Pyrex test tube. After purging with nitrogen, the mixture
was stirred at RT for 12 h. Then, malononitrile (10 mg,
0.15 mmol) was added to the test tube, and the mixture was
diluted with MeCN (4 mL) and water (5mL). The resulting
solution was irradiated by high-pressure Hg lamp for 1h. Usual
workup and purification by column chromatography on silica gel
gave 3k (11mg, 58%).
Synthesis of 2-amino-4H-chromens (3) has been achieved
by the reaction of o-QMs photochemically generated from
o-(dimethylaminomethyl)phenols (1) with malononitrile (2).
The reaction of phenols having NH2 substituent was
exceptionally failed, probably because of quenching of
the active species. Ethyl cyanoacetate (4) reacted also with
o-QM to give the chromenes (5) in high yield, depending
on the reaction conditions. o-(Hydroxymethyl)phenols
(6) could be used for the synthesis of 3 in the presence of
tertiary amines. Moreover, some biologically active
compounds and fluorinated chromenes were readily
obtained by the present method.
Monitoring of 1a and 6a under irradiation by 1H-NMR.
A
solution of o-(hydroxymethyl)phenols (6a) (0.6 mg, 4.8mmol),
dimethylamine (40wt.% in H2O, 0.2 mg, 4.4 mmol), and Ph2CH2
(an internal standard) in CD3CN-D2O (0.25 mL each) was charged
in a Pyrex NMR tube. The mixture was irradiated by high-
pressure Hg lamp. Concentrations of 6a and 1a were measured at
1
adequate intervals by H-NMR on the basis of the integration of
EXPERIMENTAL
their methylene units (1a: d 4:09 ; 6a: d 5:04 Ph2CH2: d 4:30 ).
Irradiation of 1a was carried out similarly.
1H and 13C-NMR spectra were recorded with a Varian 500-MR
and a 400-MR spectrometers. Mass spectra were obtained at 70 eV
on a Shimadzu GCMS-QP5050 apparatus. High resolution mass
spectra were recorded by ESI or APCI (Atmospheric Pressure
Chemical Ionization) mode on a Thermo Fisher Scientific LTC
Orbitrap XL. Melting points were uncorrected. All reactions were
carried out under nitrogen. Acetonitrile and distilled water for the
solvent were degassed with nitrogen. Other commercially avail-
able materials were utilized as provided without further purifica-
tion. Irradiation was conducted using high-pressure Hg lamp
(100 W, Riko UVL-100HA) attached with a Pyrex-cooling jacket.
Materials. o-(Dimethylaminomethyl)phenols and naphthols
(1) were prepared by the conventional method as follows.
Formalin (35 wt.% in H2O, 1.3 equiv) was added slowly to a
solution of the corresponding phenol and dimethylamine (40 wt.
% in H2O, 1.3 equiv) at RT, and stirring was continued for 12 h.
The reaction mixture was extracted with CHCl3, dried
over MgSO4, and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel using
2-Amino-3-cyano-4H-chromene (3a) [10]. Isolated yield 70%;
white solid, mp 120–121ꢀC (lit. mp 125ꢀC); Rf (Hexane/
1
AcOEt = 5:1) 0.12; H-NMR (CDCl3, 399.82MHz) d 3.54 (2H, s),
4.54 (2H, br s), 6.93 (1H, d, J=8.0Hz), 7.06–7.11 (2H, m),
7.19 (1H, td, J= 8.0, 2.4 Hz); 13C-NMR (CDCl3, 125.68 MHz)
d 23.8, 53.8, 116.3, 118.9, 120.3, 124.8, 127.9, 128.7, 149.3, 159.9;
MS m/z (%) 172 (M+, 62), 171 (100), 146 (11), 128 (10), 116 (9).
2-Amino-3-cyano-6-methyl-4H-chromene (3b) [10]. Isolated
yield 90%; yellow solid, mp 186–187ꢀC; Rf (Hexane/AcOEt = 3:1)
1
0.32; H-NMR (CDCl3, 499.82MHz) d 2.29 (3H, s), 3.48 (2H, s),
4.54 (2H, br s), 6.81 (1H, d, J= 8.0 Hz), 6.90 (1H, s), 6.97
(1H, d, J = 8.0Hz); 13C-NMR (CDCl3, 125.68MHz) d 20.6, 23.8,
53.6, 116.0, 118.5, 120.6, 128.5, 128.9, 134.3, 147.2, 160.2;
MS m/z (%) 186 (M+, 52), 185 (100), 160 (9), 140 (6).
2-Amino-3-cyano-7-methyl-4H-chromene (3c). Isolated yield
59%; white solid, mp 163–165ꢀC; Rf (Hexane/AcOEt = 3:1)
1
0.35; H-NMR (CDCl3, 499.82MHz) d 2.31 (3H, s), 3.48 (2H, s),
4.53 (2H, br s), 6.74 (1H, s), 6.89 (1H, d, J= 7.5 Hz), 6.97
(1H, d, J=7.5Hz); 13C-NMR (CDCl3, 125.68 MHz) d 21.0,
23.5, 53.8, 115.7, 116.7, 120.5, 125.6, 128.4, 138.1, 149.1, 160.1;
MS m/z (%) 186 (M+, 52), 185 (100), 160 (9), 140 (7), 115 (8);
HRMS Calcd for C11H10N2NaO [(M + Na)+] 209.0685, found
hexane/AcOEt eluent. The substrates
7 were prepared
similarly from the corresponding dihydroxybenzenes and
naphthalenes, dimethylamine (2.6 equiv), and formalin
(2.6 equiv). o-(Hydroxymethyl)phenols (6) were prepared
from salicylaldehyde and the corresponding Grignard or
lithium reagents (2.2 equiv).
209.0686.
2-Amino-3-cyano-8-methyl-4H-chromene (3d). Isolated yield
77%; white solid, mp 94–95ꢀC; Rf (Hexane/AcOEt = 5:1) 0.21;
1H-NMR (CDCl3, 499.82 MHz) d 2.24 (3H, s), 3.52 (2H, s),
4.58 (2H, br s), 6.92 (1H, d, J= 7.5 Hz), 6.97 (1H, t, J=7.5Hz),
7.02 (1H, d, J=7.5Hz); 13C-NMR (CDCl3, 125.68 MHz) d 15.7,
24.0, 53.8, 118.6, 120.5, 124.2, 125.6, 126.2, 129.4, 147.7, 160.0;
MS m/z (%) 186 (M+, 50), 185 (100), 160 (12), 140 (10), 115 (15);
HRMS Calcd for C11H10N2NaO [(M + Na)+] 209.0685, found
209.0685.
General procedure for synthesis of 2-amino-4H-chromenes
3, 5, and 8.
o-(Dimethylaminomethyl)phenol (1a) (15 mg,
0.10mmol) and malononitrile (2) (10 mg, 0.15 mmol) were
charged in a 20mL Pyrex test tube. The tube was purged with N2,
closed with a rubber septum, and attached with N2 balloon. The
solution was diluted with MeCN (5 mL) and H2O (5 mL). Then,
the mixture was irradiated at RT by high-pressure Hg lamp with
monitoring by GC. The phenol (1a) was consumed within 30min.
After addition of diphenylmethane as an internal standard and
water, the reaction mixture was extracted with Et2O, washed with
2-Amino-3-cyano-6,8-dimethyl-4H-chromene (3e).
Isolated
yield 78%; white solid, mp 201–202ꢀC; Rf (Hexane/
AcOEt = 3:1) 0.24; 1H-NMR (CDCl3, 499.82 MHz) d 2.20
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Convenient Synthesis of 2-Amino-4H-chromenes from Photochemically Generated o-
Quinone Methides and Malononitrile
(3H, s), 2.24 (3H, s), 3.47 (2H, s), 4.54 (2H, br s), 6.73 (1H, s),
6.83 (1H, s); 13C-NMR (CDCl3, 125.68 MHz) d 15.6, 20.5,
24.0, 53.7, 118.2, 120.6, 125.2, 126.4, 130.0, 133.7, 145.6,
160.1; MS m/z (%) 200 (M+, 52), 199 (100), 185 (9), 156 (12),
135 (11); HRMS Calcd for C12H12N2NaO [(M + Na)+]
223.0842, found 223.0841.
2-Amino-3-cyano-6-methoxy-4H-chromene (3f) [16].
Isolated yield 83%; yellow solid, mp 195–196ꢀC (lit. mp 193–
194ꢀC); Rf (Hexane/AcOEt = 3:1) 0.23; 1H-NMR (CDCl3,
499.82 MHz) d 3.51 (2H, s), 3.77 (3H, s), 4.51 (2H, br s),
6.59 (1H, d, J = 3.0 Hz), 6.72 (1H, dd, J = 9.0, 3.0 Hz), 6.86
(1H, d, J = 9.0 Hz); 13C-NMR (CDCl3, 125.68 MHz) d 24.2,
53.2, 55.6, 112.7, 113.8, 117.2, 119.7, 120.5, 143.3, 156.3,
160.2; MS m/z (%) 202 (M+, 58), 201 (100), 186 (14), 158
(122), 137 (15).
(CDCl3, 100.53MHz) d 23.7, 53.9, 114.8 (d, J = 17.2 Hz), 121.5,
123.5 (d, J = 3.7Hz), 124.5 (d, J =7.5 Hz), 137.7 (d, J = 11.1Hz),
150.4 (d, J = 249.3Hz), 159.4 (one carbon was obscured); HRMS
Calcd for C10H7FN2NaO [(M + Na)+] 213.0435, found 213.0435.
2-Amino-6-chrolo-3-cyano-4H-chromene (3n) [16]. Isolated
yield 67%; white solid, mp 210–212ꢀC (lit. mp 213–215ꢀC); Rf
(Hexane/AcOEt= 3:1) 0.28; 1H-NMR (CDCl3, 499.82 MHz)
d 3.51 (2H, s), 4.55 (2H, br s), 6.87 (1H, d, J = 8.5Hz), 7.10
(1H, d, J = 2.0 Hz), 7.16 (1H, dd, J = 8.5, 2.0Hz); 13C-NMR
(CDCl3, 100.53MHz) d 23.7, 53.5, 117.7, 119.9, 120.6, 128.0,
128.4, 129.7, 147.8, 159.7; HRMS Calcd for C10H8ClN2O
[(M + H)+] 207.0312, found 207.0312.
2-Amino-3-cyano-6,8-dichloro-4H-chromene (3o). Isolated
yield 40%; white solid, mp 243–244ꢀC; Rf (Hexane/AcOEt = 3:1)
0.18; 1H-NMR (CDCl3, 499.82 MHz) d 3.54 (2H, s), 4.68 (2H, br
s), 7.02 (1H, d, J = 2.5 Hz), 7.27 (1H, d, J = 2.5 Hz); 13C-NMR
(CDCl3, 125.68 MHz) d 24.2, 53.8, 119.3, 122.1, 122.6, 126.9,
128.6, 129.6, 144.1, 159.4; MS m/z (%) 241 (M+, 26), 207 (100),
191 (23), 177 (34), 114 (25); HRMS Calcd for C10H7Cl2N2O
[(M + H)+] 240.9930, found 240.9930.
2-Amino-6-bromo-3-cyano-4H-chromene (3p) [10]. Isolated
yield 32%; white solid, mp 192–193ꢀC; Rf (Hexane/AcOEt = 3:1)
0.24; 1H-NMR (CDCl3, 499.82 MHz) d 3.51 (2H, s), 4.57 (2H, br
s), 6.82 (1H, d, J = 9.0 Hz), 7.25 (1H, d, J = 2.0Hz), 7.29 (1H, dd,
J = 9.0, 2.0 Hz); 13C-NMR (CDCl3, 125.68 MHz) d 23.7, 53.5,
117.2, 118.1, 119.9, 121.1, 131.0, 131.4, 148.4, 159.7; MS m/z
(%) 251 (M+, 95), 250 (80), 249 (100), 143 (41), 114 (64).
2-Amino-3-cyano-6-methoxycarbonyl-4H-chromene (3q).
Isolated yield 41%; white solid, mp 203–205ꢀC; Rf (Hexane/
AcOEt = 3:1) 0.11; 1H-NMR (CDCl3, 499.82 MHz) d 3.58
(2H, s), 3.91 (3H, s), 4.58 (2H, br s), 6.98 (1H, d, J = 8.5Hz), 7.83
(1H, s), 7.88 (1H, d, J = 8.5Hz); 13C-NMR (CDCl3, 125.68 MHz)
d 23.7, 52.3, 54.0, 116.5, 119.1, 119.8, 126.7, 129.7, 130.7,
152.5, 159.5, 166.0; HRMS Calcd for C12H10N2NaO3 [(M + Na)+]
253.0584, found 253.0584.
2-Amino-3-cyano-5,7-dimethoxy-4H-chromene (3g). Isolated
yield 70%; yellow solid, mp 223–224ꢀC; Rf (Hexane/AcOEt = 1:1)
1
0.44; H-NMR (CDCl3, 499.82 MHz) d 3.29 (2H, s), 3.77 (3H, s),
3.78 (3H, s), 4.45 (2H, br s), 6.08 (1H, d, J= 2.0 Hz), 6.19
(1H, d, J=2.0Hz); 13C-NMR (CDCl3, 125.68 MHz) d 19.1, 54.5,
55.5, 55.7, 92.9, 94.5, 100.7, 120.6, 150.2, 157.8, 159.6,
159.8; MS m/z (%) 232 (M+, 29), 231 (48), 230 (88), 207
(100), 203 (60); HRMS Calcd for C12H12N2NaO3 [(M + Na)+]
255.0740, found 255.0741.
2-Amino-3-cyano-7-diethylamino-4H-chromene (3h). Isolated
yield 72%; white solid, mp 218–220ꢀC; Rf (Hexane/AcOEt = 5:1)
0.25; 1H-NMR (CDCl3, 499.82 MHz) d 1.14 (6H, t, J=6.0Hz),
3.30 (4H, q, J= 6.0 Hz), 3.40 (2H, s), 4.45 (2H, br s), 6.19 (1H, s),
6.42 (1H, d, J= 7.5 Hz), 6.90 (1H, d, J=7.5Hz); 13C-NMR
(CDCl3, 100.53MHz) d 12.4, 23.0, 44.4, 54.4, 98.9, 104.9,
108.8, 120.8, 129.1, 147.7, 150.2, 160.0; HRMS Calcd for
C14H17N3NaO [(M + Na)+] 266.1265, found 266.1264.
2-Amino-3-cyano-6-phenyl-4H-chromene (3j). Isolated yield
48%; white solid, mp 211–212ꢀC; Rf (Hexane/AcOEt= 5:1) 0.13;
1H-NMR (CDCl3, 499.82 MHz) d 3.60 (2H, s), 4.59 (2H, br s),
7.00 (1H, d, J = 8.0Hz), 7.32 (1H, d, J = 2.0Hz), 7.35
(1H, dd, J = 7.5, 1.5 Hz), 7.40–7.45 (3H, m), 7.53 (2H, dd, J = 8.0,
1.5 Hz); 13C-NMR (CDCl3, 125.68MHz) d 24.0, 53.7, 116.7,
119.2, 120.4, 126.7, 126.8, 127.3, 127.4, 128.8, 138.0, 139.9,
148.7, 160.0; HRMS Calcd for C16H12N2NaO [(M + Na)+]
271.0844, found 271.0842.
2-Amino-3-cyano-6-fluoro-4H-chromene (3k). Isolated yield
86%; white solid, mp166–167ꢀC; Rf (Hexane/AcOEt=3:1) 0.32;
1H-NMR (CDCl3, 499.82 MHz) d 3.52 (2H, s), 4.54 (2H, br s),
6.81 (1H, d, J = 8.0 Hz), 6.89–6.90 (2H, m); 13C-NMR
(CDCl3, 100.53 MHz) d 24.1, 53.1, 114.8 (d, J = 3.8Hz), 115.0
(d, J = 3.6 Hz), 117.7 (d, J = 8.4Hz), 120.1, 120.6 (d, J = 8.3 Hz),
145.3 (d, J = 2.4 Hz), 159.2 (d, J = 243.8 Hz), 160.0; HRMS Calcd
for C10H7FN2NaO [(M + Na)+] 213.0435, found 213.0436.
2-Amino-3-cyano-7-fluoro-4H-chromene (3l). Isolated yield
31%; white solid, mp 200–202ꢀC; Rf (Hexane/AcOEt= 3:1) 0.24;
1H-NMR (CDCl3, 99.82 MHz) d 3.49 (2H, s), 4.54 (2H, br s),
6.67 (1H, dd, J = 8.5, 2.5Hz), 6.81 (1H, td, J = 8.5, 2.5 Hz),
7.06 (1H, dd, J = 8.5, 6.0 Hz); 13C-NMR (CDCl3, 100.53 MHz)
d 23.3, 54.1, 104.1(d, J = 26.0Hz), 112.1 (d, J =21.3Hz), 114.7,
120.0, 129.7 (d, J = 9.3 Hz), 149.7, 159.5, 161.7 (d, J = 246.6Hz);
HRMS Calcd for C10H8FN2O [(M + H)+] 191.0615, found
191.0615.
2-Amino-3,6-dicyano-4H-chromene (3r).
Isolated yield
30%; white solid, mp 253–254ꢀC; Rf (Hexane/AcOEt = 1:1)
1
0.12; H-NMR (CDCl3, 499.82 MHz) d 3.58 (2H, s), 4.63 (2H,
br s), 7.03 (1H, d, J = 8.5 Hz), 7.45 (1H, s), 7.50 (1H, d,
J = 8.5 Hz); 13C-NMR (DMSO-d6, 125.68 MHz) d 23.7, 49.4,
107.4, 117.8, 118.8, 120.9, 122.0, 132.8, 133.8, 152.9, 160.9;
HRMS Calcd for C11H7N3NaO [(M + Na)+] 220.0481, found
220.0482.
2-Amino-3-cyano-4H-benzo[f]chromene (3s) [16]. Isolated
yield 81%; Yellow solid, mp 205–207ꢀC (lit. mp 209–211ꢀC); Rf
(Hexane/AcOEt= 3:1) 0.30; 1H-NMR (CDCl3, 399.82 MHz)
d 3.85 (2H, s), 4.59 (2H, br s), 7.12 (1H, d, J = 8.0Hz), 7.49
(1H, td, J = 8.0, 1.2 Hz), 7.59 (1H, td, J = 8.0, 1.2Hz), 7.74 (2H, d,
J = 8.0 Hz), 7.83 (1H, d, J =8.0 Hz); 13C-NMR (CDCl3,
125.68 MHz) d 21.9, 54.3, 115.1, 116.7, 120.5, 122.7, 125.2,
127.3, 128.4, 128.8, 130.7, 131.2, 146.4, 159.5.
2-Amino-3-cyano-4H-benzo[h]chromene (3t) [20]. Isolated
yield 40%; orange solid, mp 200–201ꢀC; Rf (Hexane/
AcOEt = 3:1) 0.28; 1H-NMR (CDCl3, 399.82 MHz) d 3.69
(2H, s), 4.69 (2H, br s), 7.17 (1H, d, J = 8.0 Hz), 7.52 (2H, td,
J = 7.6, 1.6Hz), 7.58 (1H, d, J = 8.0Hz), 7.80 (1H, dd, J = 7.6,
1.6 Hz), 8.08 (1H, dd, J = 8.0, 1.6 Hz); 13C-NMR (CDCl3,
125.68 MHz) d 24.4, 54.3, 113.6, 120.4, 124.4, 125.7, 126.4,
126.5, 127.3, 127.7, 133.3, 143.9, 153.6, 159.9.
2-Amino-3-cyano-8-fluoro-4H-chromene (3m). Isolated yield
36%; white solid, mp 164–165ꢀC; Rf (Hexane/AcOEt = 3:1) 0.33;
1H-NMR (CDCl3, 499.82 MHz) d 3.55 (2H, s), 4.67 (2H, br s),
6.88 (1H, d, J = 7.0 Hz), 6.96–7.04 (2H, m); 13C-NMR
2-Amino-4-(4-chlorophenyl)-3-cyano-7-diethylamino-4H-
chromene (3u) [1].
Isolated yield 85%; yellow solid, mp
155–156ꢀC (lit. mp 152–153ꢀC); Rf (Hexane/AcOEt = 3:1)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Fujiwara, M. Sakamotom, K. Komeyama, H. Yoshida, and K. Takaki
Vol 000
0.38; 1H-NMR (CDCl3, 399.82 MHz) d 1.15 (6H, t, J = 6.8 Hz),
3.31 (4H, q, J = 6.8 Hz), 4.54 (2H, br s), 4.61 (1H, s), 6.23 (1H, s),
6.36 (1H, d, J = 7.2Hz), 6.70 (1H, d, J = 7.2Hz), 7.14 (2H, d,
J = 8.0Hz), 7.27 (2H, d, J = 8.0 Hz); 13C-NMR (CDCl3,
125.68 MHz) d 12.4, 30.9, 39.7, 44.4, 98.1, 109.1, 120.0, 128.8,
129.3, 129.9, 132.7, 143.8, 147.9, 149.5, 159.3, 165.7.
2-Amino-3-cyano-4-phenyl-4H-chromene (3v) [21]. Isolated
yield 87%; white solid, mp 210–211ꢀC (lit. mp 210ꢀC); Rf (Hexane/
AcOEt = 3:1) 0.24; 1H-NMR (CDCl3, 499.82 MHz) d 4.59 (2H, br
s), 4.75 (1H, s), 6.98–7.05 (3H, m), 7.20 (3H, d, J = 7.5 Hz), 7.24
(1H, t, J = 7.5Hz), 7.32 (2H, t, J = 7.5 Hz); 13C-NMR (CDCl3,
125.68 MHz) d 40.9, 60.9, 116.3, 119.7, 122.8, 125.1, 127.3,
127.9, 128.2, 128.8, 129.7, 144.5, 148.5, 159.1; MS m/z (%) 248
(M+, 23), 201 (10), 172 (17), 171 (100).
13C-NMR (CDCl3, 100.53 MHz) d 25.4, 46.6, 59.2, 119.8,
120.5, 122.0, 124.3, 130.6, 131.1, 143.5, 148.0, 178.2;
HRMS Calcd for C13H16N3O2 [(M + H)+] 246.1238, found
246.1237.
2-Amino-3-cyano-8-dimethylaminomethyl-7-hydroxy-4H-
benzo[h]chromene (8c). Isolated yield 75%; yellow solid,
mp183–184ꢀC; Rf (DCM/MeOH = 10:1) 0.65; 1H-NMR
(CDCl3, 499.82 MHz) d 2.39 (6H, s), 3.49 (1H, br s), 3.66
(2H, s), 3.81 (2H, s), 4.65 (2H, s), 7.11 (2H, dd, J = 8.6,
2.0 Hz), 7.48 (1H, d, J = 8.6 Hz), 7.97 (1H, d, J = 8.6 Hz);
13C-NMR (CDCl3, 100.53 MHz) d 24.4, 44.4, 54.5, 62.7,
90.2, 110.5, 113.8, 115.0, 118.7, 120.4, 121.9, 124.5, 127.0,
169.4 (two carbons were obscured); HRMS Calcd for
C17H18N3O2 [(M + H)+] 296.1399, found 296.1394.
2-Amino-4-butyl-3-cyano-4H-chromene (3w). Isolated yield
44%; yellow solid, mp 79–80ꢀC; Rf (Hexane/AcOEt= 3:1) 0.38;
1H-NMR (CDCl3, 499.82 MHz) d 0.85 (3H, t, J = 7.5 Hz),
1.06–1.33 (4H, m), 1.70–1.75 (2H, m), 3.64 (1H, t, J = 5.0 Hz),
4.55 (2H, br s), 6.94 (1H, dd, J = 8.0, 1.0 Hz), 7.10–7.16
(2H, m), 7.19 (1H, td, J = 8.0, 1.0 Hz); 13C-NMR (CDCl3,
125.68 MHz) d 14.0, 22.6, 26.8, 34.5, 37.8, 58.9, 116.1, 120.3,
123.7, 124.8, 127.7, 128.1, 149.5, 160.4; MS m/z (%) 228
(M+, 2), 207 (1), 171 (100), 142 (3), 128 (6); HRMS Calcd for
C14H16N2NaO [(M + Na)+] 251.1156, found 251.1155.
REFERENCES AND NOTES
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A.; Righi, P.; Sartori, G. Tetrahedron 2001, 57, 1395.
[9] Du, Z.; Siau, W.-Y.; Wang, J. Tetrahedron Lett 2011, 52, 6137.
[10] Shanthi, G.; Perumal, P. T. Tetrahedron Lett 2007, 48, 6785.
[11] Radomkit, S.; Sarnpitak, P.; Tummatorn, J.; Batsomboon, P.;
Ruchirawat, S.; Ploypradith, P. Tetrahedron 2011, 67, 3904.
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[13] For a review, see: Van De Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367.
2-Amino-3-cyano-4-phenylethynyl-4H-chromene (3x). Isolated
yield 49%; orange solid, mp 235–236ꢀC; Rf (Hexane/AcOEt = 5:1)
0.12; 1H-NMR (CDCl3, 499.82 MHz) d 4.67 (2H, br s), 4.90
(1H, s), 6.98 (1H, dd, J= 8.0, 1.0 Hz), 7.19 (1H, td, J =8.0,
1.0 Hz), 7.27–7.29 (4H, m), 7.43–7.45 (2H, m), 7.50
(1H, d, J = 7.5 Hz); 13C-NMR (CDCl3, 125.68 MHz) d 27.6,
57.4, 82.4, 88.8, 116.5, 119.3, 119.5, 122.7, 125.3, 128.2,
128.3, 128.9, 129.2, 131.8, 148.0, 159.5; MS m/z (%) 272
(M+, 100), 243 (7), 214 (15), 195 (31); HRMS Calcd for
C18H12N2NaO [(M + Na)+] 295.0842, found 295.0843.
2-Amino-3-ethoxycarbonyl-6-methyl-4H-chromene (5). Isolated
yield 80%; colorless viscous oil; Rf (Hexane/AcOEt = 10:1)
1
0.35; H-NMR (CDCl3, 499.82 MHz) d 1.31 (3H, t, J =7.5Hz),
2.28 (3H, s), 3.53 (2H, s), 4.20 (2H, q, J= 7.5 Hz), 6.19 (2H, br s),
6.79 (1H, d, J = 8.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 6.94 (1H, s);
13C-NMR (CDCl3, 125.68 MHz) d 14.7, 20.7, 23.2, 59.4,
115.5, 121.5, 128.3, 129.1, 129.4, 133.5, 147.6, 160.2, 169.9;
MS m/z (%) 233 (M+, 36), 204 (98), 160 (100), 121 (30);
HRMS Calcd for C13H16NO3 [(M + H)+] 234.1127, found
234.1125.
[14] Gardner, P. D.; Rafsanjani, H. S.; Rand, L. J Am Chem Soc
1959, 81, 3364.
[15] Balasubramanian, K. K.; Selvaraj, S. Synthesis 1980, 138.
[16] During the course of our study, it has been reported that base
mediated reaction of o-hydroxybenzylammonium salts with malononitrile
under reflux gave 2-aminochromenes: Osyanin, V. A.; Osipov, D. V.;
Klimochkin, Y. N. Tetrahedron 2012, 68, 5612.
[17] It has been reported that 1 was superior to 6 in the reaction of
o-QM with ethyl vinyl ether, see: Nakatani, K.; Higashida, N.; Saito, I.
Tetrahedron Lett 1997, 38, 5005.
[18] Elagamey, A. G. A.; El-Taweel, F. M. A.-A.; Khodeir, M. N.
M.; Elnagdi, M. H. Bull Chem Soc Jpn 1993, 66, 464.
[19] For a review, see: Hagmann, W. K. J Med Chem 2008,
51, 4359.
[20] Mekheimer, R. A.; Sadek, K. U. Chin Chem Lett 2009,
20, 271.
2-Amino-3-cyano-6-dimethylaminomethyl-7-hydroxy-8-methyl-
4H-chromene (8a).
Isolated yield 72%; yellow solid, mp
1
246–247ꢀC; Rf (AcOEt/MeOH = 10:1) 0.64; H-NMR (CDCl3,
399.82 MHz) d 2.11 (3H, s,), 2.31 (6H, s), 3.41 (2H, s), 3.56
(2H, s), 4.54 (2H, br s), 6.53 (1H, s); 13C-NMR (CDCl3,
125.68 MHz) d 8.06, 23.5, 44.3, 54.0, 62.3, 108.4, 118.0,
120.8, 124.6, 128.0, 147.6, 155.5, 160.0; HRMS Calcd for
C14H18N3O2 [(M + H)+] 260.1394, found 260.1397.
2-Amino-3-cyano-7-dimethylaminomethyl-8-hydroxy-4H-
chromene (8b). Isolated yield 65%; yellow solid, mp 154–155ꢀC;
Rf (DCM/MeOH = 10:1) 0.25; 1H-NMR (CDCl3, 499.82 MHz) d
2.37 (6H, s), 3.49 (2H, s), 3.69 (2H, s), 4.50 (1H, br s), 4.67
(2H, s), 6.51(1H, d, J = 6.8 Hz), 6.69 (1H, d, J = 6.8 Hz);
[21] Kamdar, N. R.; Heveliwala, D. D.; Mistry, P. T.; Patel, S. K.
Med Chem Res 2011, 20, 854.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet