4H-1-benzopyrans by a tandem SN2-SNAr reaction

Article abstract of DOI:10.1002/jhet.5570450238

(Chemical Equation Presented) Treatment of 2-fluoro-5-nitrobenzyl bromide with active methylene compounds in the presence of excess potassium carbonate in acetone leads to the formation of highly functionalized 4H-1-benzopyrans by a tandem S_N2-

Full text of DOI:10.1002/jhet.5570450238

Mar-Apr 2008
547
4H-1-Benzopyrans by a Tandem SN2-SNAr Reaction
Richard A. Bunce,* David Rogers [1], Takahiro Nago [1] and Scott A. Bryant [1]
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
E-mail: rab@okstate.edu
Received August 30, 2007
O2N
CO2-t-C4H9
O2N
CO2-t-C4H9
excess K2CO3
acetone, 25°
Br
+
F
O
CH3
O
CH3
Treatment of 2-fluoro-5-nitrobenzyl bromide with active methylene compounds in the presence of
excess potassium carbonate in acetone leads to the formation of highly functionalized 4H-1-benzopyrans
by a tandem SN2-SNAr reaction sequence. The reaction works well with β-keto esters, β-keto sulfones, β-
keto phosphine oxides, β-keto phosphonates and β-keto nitriles. The reaction is simple to perform and
affords products in 50-92% yields.
J. Heterocyclic Chem., 45, 547 (2008).
Scheme 2
INTRODUCTION
O2N
CHO
F
O2N
A recent project in our laboratory required monoalkylation
of a tert-butyl acetoacetate (2a) with 2-fluoro-5-nitrobenzyl
bromide (1). Other synthetic work with dialkyl malonates
had shown that potassium carbonate in acetone gave good
yields of mpnoalkylation products using a 24:3:1 ratio of
BH3·THF
THF, 0o
PBr3
OH
1
ether, 0o
F
4
5
A survey of potential activated substrates 2 (R = methyl
or aryl; EWG = electron withdrawing group) revealed that
the reaction is favored for systems not prone to O-
alkylation. Thus, the reaction works well with β-keto
esters, β-keto sulfones, β-keto phosphine oxides, β-keto
phosphonates and β-keto nitriles, generally using an 8:1:1
mole ratio of base:substrate:bromide (Table 1). On the
other hand, with the exception of dibenzoylmethane, β-
diketones such as 2,4-pentanedione and dimedone were
found to yield primarily O-alkylation products while
active ketones such as phenylacetone and deoxybenzoin
base:malonate:bromide at room temperature [2].
We,
therefore, sought to effect a similar transformation using the
β-keto ester in place of the β-diester. Attempts to perform
this reaction under our standard conditions, however, led to
the formation of 2-methyl-6-nitro-4H-1-benzopyran (3a) by
an interesting SN2-SNAr process (Scheme 1). In light of the
limited methodology to prepare highly functionalized 4H-1-
benzopyrans [3-6] and recent reports that several derivatives
of this ring system express powerful anticancer activity [6],
we sought to explore a number of active methylene substrates
to determine the scope and generality of this process.
gave exclusively monoalkylation at carbon.
appropriate substrates, the reaction is simple to perform
and affords solid products in 50-92% yields.
With
Scheme 1
O2N
CO2-t-C4H9
Br
+
F
O
CH3
Table 1
1
2a
excess
K2CO3 [a]
EWG
O2N
EWG
R
O2N
CO2-t-C4H9
excess K2CO3
acetone, 25o
+
1
acetone, 25o
O
R
O
O
CH3
2
3
3a
R
EWG
Entry
Ratio 1:2
Yield of 3
RESULTS AND DISCUSSION
a
b
c
d
e
f
g
h
i
CH3
CO2-t-C4H9
CO2CH3
CO2CH3
SO2C6H5
SO2C6H5
P(O)(C6H5)2
P(O)(OCH3)2
CN
1:3
1:1
1:3
1:1
1:1
1:1
1:3
1:1
1:3
92 [b]
85
52
68
80
70
50
67
85 [c]
C6H5
2-Cl-C6H4
CH3
C6H5
CH3
CH3
C6H5
C6H5
The 2-fluoro-5-nitrobenzyl bromide (1) used in our
reactions was readily prepared in 78% overall yield from
the known 2-fluoro-5-nitrobenzaldehyde (4) [7] by
chemoselective reduction of the aldehyde with borane-
tetrahydrofuran complex [8] and treatment of the resulting
alcohol 5 with phosphorus tribromide (Scheme 2). With
the exception of 1-(diphenylphosphinoyl)-2-propanone
[9], the active methylene compounds selected for this
study were commercially available.
C(O)C6H5
[a] 8 eq of potassium carbonate (relative to the active methylene substrate)
were used. [b] For this case, an excess of the !-keto ester was required to
minimize double alkylation at carbon. [c] Some O-alkylation product was also
obtained.

548
R. A. Bunce, D. Rogers, T. Nago and S. A. Bryant
Vol 45
The current protocol generates highly functionalized
strategy and is successful for relatively unhindered active
methylene substrates that favor initial C-alkylation of the
monoanion. The reaction furnishes products as solids in
50-92% yields with a minimum of purification. The
current products differ from those prepared by other
methods in having a nitro group at C6. Other activating
groups on the aromatic ring may also be possible and are
being explored.
4H-1-benzopyrans by an interesting tandem SN2-SNAr
sequence. The method represents a novel 3+3 approach
to these ring systems whereby the 1,3-disposed
nucleophilic centers of the active methylene substrate
react with the 1,3-disposed electrophilic centers of the
alkylating agent (Figure 1).
EWG
R
O2N
EXPERIMENTAL
O
Figure 1
All reactions were run under dry nitrogen in oven-dried
glassware. Potassium carbonate was ground to a fine powder,
dried under vacuum at 120° for 24 hours and stored in an oven at
120°; acetone (ACS Grade) was used from a freshly opened
bottle. Reactions were monitored by thin layer chromatography
The mechanism of the reaction involves (1) deprotonation
of the active methylene substrate, (2) SN2 displacement of
bromide from 2-fluoro-5-nitrobenzyl bromide, (3)
removal of the second active proton and (4) intra-
molecular SNAr displacement of fluoride by the ketone
oxygen of the resulting enolate (Scheme 3).
on silica gel GF plates (Analtech 21521).
Preparative
separations were performed by one of the following methods:
(1) flash column chromatography [11] on silica gel (grade 62,
60-200 mesh) containing ultraviolet-active phosphor (Sorbent
Technologies UV-5) packed into quartz columns or (2)
preparative thin layer chromatography on 20-cm x 20-cm silica
gel GF plates (Analtech 02015). Compound elution in all cases
was monitored using a hand-held ultraviolet lamp. Hexanes
used in chromatography had a boiling range of 65-70°;
petroleum ether used in crystallization and trituration procedures
had a boiling range of 35-60°. Melting points were uncorrected.
Infrared spectra were run as thin films on NaCl disks and
Scheme 3
Br
O2N
EWG
R
K2CO3
1
+ 2
F
O
1
referenced to polystyrene. Unless otherwise indicated, H and
H
13C nuclear magnetic resonance spectra were measured in CDCl3
at 400 MHz and 100 MHz, respectively, using tetramethylsilane
as the internal standard; coupling constants (J) are given in
O2N
EWG
O2N
EWG
R
K2CO3
O
R
O
F
F
Hertz.
Mass spectra (electron impact/direct probe) were
obtained at 30 electron volts. β-Keto phosphine oxide 2f used to
prepare 3f was prepared as described by Torr and Warren [9].
2-Fluoro-5-nitrobenzyl Alcohol (5). A solution of 5.00 g
(29.6 mmoles) of 4 [7] in 75 mL of anhydrous tetrahydrofuran
was prepared and cooled to 0°. This solution was stirred and
12.0 mL of 1 M borane tetrahydrofuran complex (12.0 mmoles)
in tetrahydrofuran [8] was added by syringe over 35 minutes.
The reaction was stirred at 0° for 1 hour and at 22° for 1 hour.
The reaction was quenched at 0° by slow addition of 10 mL of
water, then transferred to a separatory funnel with ether and
washed with saturated aqueous sodium chloride (three times).
The combined ether layers were dried (magnesium sulfate) and
concentrated under vacuum to give a yellow oil that solidified
on standing. The product was crystallized from 50% ether in
petroleum ether to give 4.89 g (97%) of 5 as light yellow
O2N
EWG
R
3
- F
O
F
Finally, attempts to expand the scope of this process by
varying the R group revealed a further limitation. For
example, when methyl isobutyrylacetate (R = i-C3H7,
EWG = CO2Me) was reacted, the simple SN2 alkylation
product was isolated, but the subsequent cyclization did
not occur. Based on earlier results in a related system
[10], we believe that the failure to cyclize in this case
results from an unfavorable steric interaction that
develops as the large R group is forced into coplanarity
with the ester moiety during the final ring closure.
Though this finding limits the procedure from a synthetic
perspective, it does provide some insight into the reaction
chronology by suggesting that the SN2 is the first step of
the tandem sequence.
1
crystals, mp 69-71°. ir: 3533, 1524, 1352, 1244 cm-1; H nmr: δ
8.42 (dd, 1H, J = 6.2, 3.0), 8.19 (ddd, 1H, J = 9.0, 4.6, 3.0), 7.19
(t, 1H, J = 9.0), 4.86 (s, 2H), 2.23 (br s, 1H); 13C nmr: δ 163.5 (d,
J = 257.0), 144.1, 129.7 (d, J = 17.1), 125.0 (d, J = 10.3), 124.7
(d, J = 6.9), 116.1 (d, J = 24.0), 58.3 (d, J = 4.3); ms: m/z 171
(M+). Anal. Calcd. for C7H6FNO3: C, 49.12; H, 3.51; N, 8.19.
Found: C, 49.07; H, 3.48; N, 8.13.
2-Fluoro-5-nitrobenzyl Bromide (1). A solution of 4.75 g
(27.8 mmoles) of 5 in 75 mL of anhydrous ether was prepared
and cooled to 0°. This solution was stirred and 3.77 g (1.31 mL,
13.9 mmoles) of phosphorus tribromide was added dropwise
during 1 hour. The reaction was stirred for 3 hours with gradual
warming to room temperature and then poured onto crushed ice
CONCLUSION
We have developed a new approach to the synthesis of
4H-1-benzopyrans based on a novel tandem SN2-SNAr
reaction sequence. The method represents a formal 3+3

Mar-Apr 2008
4H-1-Benzopyrans by a Tandem SN2-SNAr Reaction
549
and extracted with ether (three times). The combined ether
layers were washed with saturated aqueous sodium chloride,
dried (magnesium sulfate) and concentrated under vacuum to
give a light yellow solid. Recrystallization from 2% ether in
petroleum ether gave 5.21 g (80%) of 1 as light yellow powder,
mp 73-74°. ir: 1524, 1352, 1244 cm-1; 1H nmr: δ 8.36 (dd, 1H, J
= 6.4, 3.0), 8.22 (ddd, 1H, J = 9.0, 4.3, 3.0), 7.25 (t, 1H, J = 9.0),
4.53 (d, 2H, J = 0.8); 13C nmr: δ 163.9 (d, J = 260.8), 144.2,
127.1 (d, J = 5.2, obscures a second C signal), 126.1 (d, J =
10.3), 116.9 (d, J = 24.0), 23.6 (d, J = 4.3); ms: m/z 233, 235
(M+, M++2). Anal. Calcd. for C7H5BrFNO2: C, 35.90; H, 2.14;
N, 5.98. Found: C, 35.96; H, 2.17; N, 5.93.
Representative Procedure for the Cyclization of 4H-1-
Benzopyans. tert-Butyl 2-methyl-6-nitro-4H-1-benzopyran-
3-carboxylate (3a). To a solution of 1.19 g (7.5 mmoles) of 2a
in 50 mL of acetone was added 8.28 g (60 mmoles) of
anhydrous potassium carbonate followed by dropwise addition
of a solution of 0.59 g (2.5 mmoles) of 1. The reaction was
vigorously stirred for 48 hours at room temperature, vacuum
filtered through a pad of Celite, and concentrated under
reduced pressure. The excess β-keto ester was removed under
high vacuum at 40° and the resulting solid was triturated with
10% petroleum ether in ether to give 0.67 g (92%) of 3a as a
light yellow powder, mp 114-116°. ir: 1709, 1692, 1656, 1529,
1344 cm-1; 1H nmr: δ 8.03 (m, 2H), 6.99 (d, 1H, J = 9.9), 3.63 (s,
2H), 2.37 (t, 3H, J = 1.5), 1.53 (s, 9H); 13C nmr: δ 166.0, 158.7,
154.9, 143.9, 124.8, 123.6, 122.0, 116.7, 94.4, 81.1, 28.3 (3),
25.1, 18.9; ms: m/z 218 (M+-C4H9O). Anal. Calcd. for
C15H17NO5: C, 61.86; H, 5.84; N, 4.81. Found: C, 61.89; H,
5.87; N, 4.76.
Methyl 6-Nitro-2-phenyl-4H-1-benzopyran-3-carboxylate
(3b). This compound (0.66 g, 85%) was prepared using an 8:1:1
mole ratio of base:2b:1 and isolated as a yellow powder after
trituration with ether, mp 153-154°. ir: 1695, 1520, 1348 cm-1;
1H nmr: δ 8.08 (m, 2H), 7.45 (m, 5H), 7.08 (d, 1H, J = 8.6), 3.88
(s, 2H), 3.59 (s, 3H); 13C nmr: δ 167.0, 158.2, 155.1, 144.1,
134.0, 129.9, 128.5, 128.0, 124.8, 123.9, 121.4, 117.2, 102.8,
51.7, 25.7; ms: m/z 311 (M+). Anal. Calcd. for C17H13NO5: C,
65.59; H, 4.18; N, 4.50. Found: C, 65.69; H, 4.22; N, 4.46.
Methyl 6-Nitro-2-(2-chlorophenyl)-4H-1-benzopyran-3-
carboxylate (3c). This compound (0.45 g, 52%) was prepared
using a 24:3:1 mole ratio of base:2c:1 and isolated as a white
powder after flash chromatography on a 25-cm silica gel column
using 5-20% ether in hexanes, mp 154.5-155.5°. ir: 1727, 1705,
1665, 1529, 1344 cm-1; 1H nmr: δ 8.12 (d, 1H, J = 2.6), 8.08 (dd,
1H, J = 8.8, 2.6), 7.47 (d, 1H, J = 7.9), 7.43-7.32 (complex, 3H),
7.06 (d, 1H, J = 8.8), 3.91 (s, 2H), 3.58 (s, 3H); 13C nmr: δ
165.8, 156.2, 155.1, 144.2, 133.7, 133.0, 130.7, 130.3, 129.5,
126.6, 124.9, 124.0, 121.4, 117.2, 105.2, 51.9, 25.2; ms: m/z
345, 347 (M+, M++2). Anal. Calcd. for C17H12ClNO5: C, 59.04;
H, 3.47; N, 4.05. Found: C, 59.23; H, 3.52; N, 4.06.
6-Nitro-2-phenyl-3-(phenylsulfonyl)-4H-1-benzopyran (3e).
This compound (0.79 g, 80%) was prepared using an 8:1:1 mole
ratio of base:2e:1 and isolated as a light yellow powder after
trituration with 12:3:1 ether:chloroform:methanol, mp 196-197°.
1
ir: 1660, 1525, 1346, 1320, 1152 cm-1; H nmr: δ 8.08 (s, 1H),
8.05 (d, 1H, J = 9.0), 7.58-7.45 (complex, 4H), 7.42-7.35
(complex, 6H), 7.01 (d, 1H, J = 9.0), 4.00 (s, 2H); 13C nmr: δ
157.5, 154.2, 144.2, 140.2, 133.2, 131.5, 130.4, 124.4, 128.8,
127.9, 127.5, 124.8, 124.1, 120.3, 117.3, 114.7, 25.5; ms: m/z
393, 395 (M+, M++2). Anal. Calcd. for C21H15NO5S: C, 64.12;
H, 3.82; N, 3.56. Found: C, 64.15; H, 3.83; N, 3.53.
2-Methyl-6-nitro-3-(diphenylphosphinoyl)-4H-1-benzopy-
ran (3f). This compound (0.68 g, 70%) was prepared using an
8:1:1 mole ratio of base:2f:1 and isolated as an off-white powder
after trituration with ether, mp 239.5-240.5°. ir: 1652, 1516,
1
1340, 1194 cm-1; H nmr: δ 8.05 (dd, 1H, J = 9.0, 2.6), 7.81 (d,
1H, J = 2.6), 7.78-7.70 (complex, 4H), 7.59 (m, 2H), 7.56-7.49
(complex, 4H), 7.02 (d, 1H, J = 9.0), 3.18 (d, 2H, J = 4.8), 2.28
(dt, 3H, J = 1.6. 1.5); 13C nmr: δ 160.1 (d, J = 20.2), 155.0,
143.7, 132.2, 131.6 (d, J = 9.2), 131.3, 128.9 (d, J = 12.2), 124.6,
123.9, 120.2 (d, J = 9.2), 116.9, 98.3 (d, J = 106.8), 27.0 (d, J =
9.9), 19.2; ms: m/z 391 (M+). Anal. Calcd. for C22H18NO4P: C,
67.52; H, 4.60; N, 3.58. Found: C, 67.61; H, 4.63; N, 3.54.
2-Methyl-6-nitro-3-(dimethoxyphosphoryl)-4H-1-benzopy-
ran (3g). This compound (0.38 g, 50%) was prepared using a
24:3:1 mole ratio of base:2g:1 and isolated as a light yellow
powder following preparative thin layer chromatography using
ether as the eluant, mp 102-103°. ir: 1661, 1520, 1337, 1244 cm-1;
1H nmr: δ 8.05 (dd, 1H, J = 9.0, 2.7), 7.99 (m, 1H), 7.01 (d, 1H, J =
9.0), 3.77 (d, 6H, J = 11.2), 3.54 (d, 2H, J = 5.1), 2.36 (dt, 3H, J =
2.6, 1.5); 13C nmr: δ 160.0 (d, J = 28.2), 154.9, 143.8, 124.5, 123.8,
120.5 (d, J = 9.9), 116.9, 94.7 (d, J = 200.0), 52.3 (m), 25.1 (d, J =
6.9), 18.5; ms: m/z 268 (M+-OCH3). Anal. Calcd. for C12H14NO6P:
C, 48.16; H, 4.68; N, 4.68. Found: C, 48.29; H, 4.74; N, 4.60.
3-Cyano-6-nitro-2-phenyl-4H-1-benzopyran (3h). This
compound (0.47 g, 67%) was prepared using an 8:1:1 mole ratio
of base:2h:1 and isolated as a light orange powder after
trituration with ether, mp 163-164°. ir: 2204, 1643, 1524, 1344
1
cm-1; H nmr: δ 8.15 (dd, 1H, J = 9.0, 2.7), 8.10 (m, 1H), 7.86
(dd, 2H, J = 7.9, 1.5), 7.58-7.48 (complex, 3H), 7.20 (d, 1H, J =
9.0), 3.88 (s, 2H); 13C nmr: δ 160.8, 154.3, 144.8, 131.6, 130.8,
128.7, 127.8, 124.6, 124.4, 118.8, 118.2, 117.8, 83.3. 26.6; ms:
m/z 278 (M+). Anal. Calcd. for C16H10N2O3: C, 69.06; H, 3.60;
N, 10.07. Found: C, 69.02; H, 3.59; N, 10.10.
3-Benzoyl-6-nitro-2-phenyl-4H-1-benzopyran (3i). This
compound (0.76 g, 85%) was prepared using a 24:3:1 mole ratio
of base:2i:1 and isolated as a light orange powder after
trituration with ether, mp 186-188°. ir: 1648, 1630, 1525, 1348
1
cm-1; H nmr: δ 8.14 (dd, 1H, J = 8.9, 2.4), 8.13 (s, 1H), 7.64
(dd, 2H, J = 7.9, 1.0), 7.34 (dd, 2H, J = 7.7, 1.3), 7.29 (t, 1H, J =
7.5), 7.22-7.12 (complex, 6H), 3.96 (s, 2H); 13C nmr: δ 196.6,
155.7, 154.9, 144.0, 137.1, 132.8, 132.5, 130.2, 129.2, 129.0,
128.1 (2C), 124.9, 123.9, 121.5, 117.2, 109.9, 27.2; ms: m/z 357
(M+). Anal. Calcd. for C22H15NO4: C, 73.95; H, 4.20; N, 3.92.
Found: C, 74.03; H, 4.25; N, 3.84.
2-Methyl-6-nitro-3-(phenylsulfonyl)-4H-1-benzopyran (3d).
This compound (0.56 g, 68%) was prepared using an 8:1:1 mole
ratio of base:2d:1 and isolated as a light yellow powder after
trituration with 12:3:1 ether:chloroform:methanol, mp 172-174°.
1
ir: 1655, 1525, 1345, 1295, 1150 cm-1; H nmr: δ 8,19 (d, 1H, J
Acknowledgment. D. R. was supported as an NSF-REU
student during the summer of 2007 (CHE-0649162). T. N. thanks
Oklahoma State University for a Niblack Scholarship and the
Department of Chemistry for a Skinner Scholarship. Funding for
the 400 MHz NMR spectrometer of the Oklahoma Statewide
Shared NMR Facility was provided by the NSF (BIR-9512269),
the Oklahoma State Regents for Higher Education, the W. M.
= 2.9), 8.06 (dd, 1H, J = 9.0, 2.9), 7.96 (dd, 2H, J = 7.5, 1.6),
7.76 (m, 1H), 7.68 (t, 2H, J = 7.5), 7.20 (d, 1H, J = 9.0), 3.74 (s,
2H), 2.42 (s, 3H); 13C nmr: δ 157.5, 153.5, 143.7, 140.4, 133.8,
129.7, 126.8, 125.1, 124.0, 120.8, 117.1, 111.6, 24.2, 17.5; ms:
m/z 331, 333 (M+, M++2). Anal. Calcd. for C16H13NO5S: C,
58.00; H, 3.93; N, 4.23. Found: C, 58.12; H, 3.97; N, 4.17.

550
R. A. Bunce, D. Rogers, T. Nago and S. A. Bryant
Vol 45
[5] Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
Keck Foundation, and Conoco, Inc. Finally, the authors wish to
thank the OSU College of Arts and Sciences for funds to upgrade
our departmental FT-IR and GC-MS instruments.
[6a] Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.;
Zhao, J.; Jia, S.; Herich, J.; Labreque, D.; Storer, R.; Meerovitch, K.;
Bouffard, D.; Rej, R.; Denis, R.; Blais, C.; Lamothe, S.; Attardo, G.;
Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med. Chem. 2004,
47, 6299. [b] Doshi, J. M.; Tian, D.; Xing, C. J. Med. Chem. 2006, 49,
7331.
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