Efficient synthesis of selected phthalazine derivatives

Article abstract of DOI:10.1515/hc-2012-0079

Four phthalazine derivatives have been prepared from substituted 2-bromobenzaldehyde acetals by a sequence involving: (1) lithiation and formylation; (2) deprotection; and (3) condensative cyclization with hydrazine. Two additional phthalazines were prepa

Full text of DOI:10.1515/hc-2012-0079

DOI 10.1515/hc-2012-0079ꢀ
ꢀHeterocycl. Commun. 2012; 18(3): 123–126
Richard A. Bunce*, Todd Harrison and Baskar Nammalwar
Efficient synthesis of selected phthalazine
derivatives
Abstract: Four phthalazine derivatives have been work revealed that space was available in the active site for
prepared from substituted 2-bromobenzaldehyde acetals a small substituent at C5, C6 or C7 on this ring. Based upon
by a sequence involving: (1) lithiation and formylation; this finding and with the goal of maximizing the antibac-
(
2) deprotection; and (3) condensative cyclization with terial activity of 1, we directed our efforts toward prepar-
hydrazine. Two additional phthalazines were prepared by ing several phthalazines substituted by small groups that
a similar sequence following direct lithiation of benzalde- could be accommodated in the DHFR active site.
hyde acetals substituted by anion-stabilizing groups at C3.
These syntheses can be conveniently carried out to give
phthalazines in overall yields of 40–70%.
Results and discussion
Our approach to phthalazine derivatives is outlined in
Keywords: formylation; heteroatom-directed ortho lithi- Scheme 1. The starting bromoacetal derivatives 2a–d were
ation; hydrazine condensative ring closure; lithium- either known or readily prepared using standard meth-
bromide exchange; phthalazines.
odology (Remy et al., 1985; Moody and Warrellow, 1990;
Balczewski et al., 2006). Lithium-bromide exchange was
carried out by adding 1.2 equiv. of n-butyllithium to a solu-
tion of each bromide 2 in THF at -78°C and warming to
*
Corresponding author: Richard A. Bunce, Department of
Chemistry, Oklahoma State University, Stillwater, OK 74078-3071,
USA, e-mail: rab@okstate.edu
-
40°C for 30 min. The mixture was then recooled to -78°C,
Todd Harrison: Department of Chemistry, Oklahoma State
University, Stillwater, OK 74078-3071, USA
Baskar Nammalwar: Department of Chemistry, Oklahoma State
University, Stillwater, OK 74078-3071, USA
and 1.2 equiv. of anhydrous N,N-dimethylformamide was
added. Stirring was continued for 30 min, and the reac-
tion was worked up to give aldehydes 3a–d in 56–84%
yields. Deprotection of 3a–d was accomplished by stirring
®
with wet Amberlyst 15 in acetone (Rohm and Haas Co.,
1978; Kalesse, 1995). This cleanly converted the acetals
back to the aldehydes to give phthalaldehydes 4a–d in
73–93% yields. Finally, o-dialdehydes 4a–d were each
reacted with 1.1 equiv. of anhydrous hydrazine in absolute
Introduction
Structural modifications to optimize the activity of antibi- ethanol at 0°C–23°C for 3 h (Hirsch and Orphanos, 1965;
otic 1 are currently under investigation in our laboratory. Bhattacharjee and Popp, 1980) to give phthalazines 5a–d
These drugs act against inhalation anthrax and multid- in 78–98% yields.
rug-resistant staph by inhibiting dihydrofolate reductase
Our route is similar to one reported earlier (Tsoungas
(
DHFR), a key enzyme required for bacterial growth. An and Searcey, 2001) for the preparation of the 6-meth-
important feature of these compounds is that they selec- oxyphthalazine (5a). In the current study, however, addi-
tively target bacterial DHFR, while not harming human tional examples of this transformation are described and
DHFR (Bourne et al., 2009).
more procedural details are given. Finally, the methodol-
ogy has generally been streamlined to minimize extensive
purification of intermediates.
During our study, it was found that two cases did not
require the presence of bromine on the aromatic ring for
lithiation to proceed, although the reaction regioselectivity
NH
2
O
Pr
1
8
5
2
N
N
7
6
N
3
NH2
N
OMe
4
OMe
1
In an earlier study (Bourne et al., 2009), X-ray analysis was altered (see Scheme 2). Direct lithiation of piperonal
of the DHFR-(S)-1 complex indicated interactions between and 3-fluorobenzaldehyde acetals 6a (Charlton et al., 1996)
DHFR and the dihydrophthalazine portion of the drug. This and 6b (Dellaria, 2001) yielded preferential metalation of
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1
24ꢀ
ꢀR.A. Bunce et al.: Efficient synthesis of selected phthalazine derivatives
O
O
phthalazines substituted by groups stable to metalation
conditions with n-butyllithium. The lithiation process
is facilitated by the acetal group positioned ortho to the
bromine, but direct C2 metalation is also possible when
anion-stabilizing groups are present at C3. These two pro-
cesses allow access to phthalazines with different substi-
tution patterns in yields ranging from 40% to 70%.
2
5
R1
R1
3
O
a
O
b
R2
4
6
R2
Br
CHO
2
3
5
R1
R2
CHO
CHO
R1
R2
c
N
N
4
a R1 = OMe; R2 = H
c R1 R2 = -OCH O-
2
b R = OMe; R2 = OMe
1
d R = Me; R = H
1
2
Scheme 1ꢁSynthesis of 5a–d; (a) i. n-BuLi, THF, -78°C, ii. warm to
Experimental
All reactions were run in oven-dried glassware. Reactions were moni-
tored by TLC using silica gel GF plates. Flash chromatography was
performed in quartz columns using silica gel (Davisil , grade 62,
®
-
40°C, iii. cool to -78°C, iv. DMF, -78°C–23°C; (b) wet Amberlyst 15,
acetone, 23°C; (c) anhyd NH NH , EtOH, 0°C–23°C.
2
2
®
the aromatic site flanked by two heteroatom groups, that
is, at C2 rather than at C6 (Gschwend and Rodriguez, 1979).
6
0–200 mesh). Band elution for all chromatographic separations
1
13
was monitored using a hand-held UV lamp. H and C NMR spectra
Thus, for these two substrates, the resulting aldehydes 7a were measured in CDCl at 300 MHz and 75 MHz, respectively, and
3
(
89%) and 7b (66%) were substituted at C3 and C4 rather were referenced to internal tetramethylsilane. Low-resolution mass
spectra (EI) were recorded at 30 eV.
than at C4 and C5. Similar precursors having a methyl or a
methoxy group at C3 were insufficiently activated or too hin-
dered to allow direct lithiation at C2 and gave no products
under our conditions. Finally, while 7a smoothly underwent
General procedure for lithium-bromine
deprotection to 8a (98%) and conversion to phthalazine 9a exchange and formylation
(
86%), deprotection of 7b was difficult to monitor by thin
2
-(1,3-Dioxolan-2-yl)-4-methoxybenzaldehyde (3a)ꢀTo a solution
of 5.18 g (20.0 mmol) of 2a (Remy et al., 1985) in 50 mL of dry THF at
78°C was added dropwise over 1 h, 10.9 mL (24.0 mmol, 1.2 equiv.) of
layer chromatography and phthalaldehyde 8b was sensitive
toward purification. To circumvent this problem, crude 8b
-
was reacted directly with hydrazine in anhydrous ethanol to 2.2 ꢁ n-butyllithium in hexanes. The reaction mixture was stirred for
give phthalazine 9b in a two-step yield of 61%.
an additional 15 min at -78°C, and then warmed to -40°C and main-
tained at this temperature for 30 min. The mixture was again cooled
to -78°C, and 1.75 g (1.86 mL, 24.0 mmol, 1.2 equiv.) of anhydrous
DMF was added dropwise over 30 min with stirring at -78°C for an
additional 30 min. The crude reaction mixture was added to aqueous
Conclusion
We have developed a convenient synthesis of a series of
substituted phthalazines from readily available benzal-
NH Cl and extracted with ether (2 × 100 mL). The combined organic
4
layers were washed with aqueous NaCl, dried (MgSO ), and concen-
4
trated under reduced pressure to give a yellow oil. This material was
purified by flash chromatography on a 50-cm × 2-cm column eluting
dehyde acetals. The procedure allows the preparation of with 2–10% ethyl acetate in hexanes to give 3.49 g (84%) of 3a as a
-1 1
light yellow oil. IR: 2845, 1689 cm ; H NMR: δ 10.23 (s, 1H), 7.90 (d,
J ꢂ=ꢂ 8.5 Hz, 1H), 7.26 (d, J ꢂ=ꢂ 2.7 Hz, 1H), 6.98 (dd, J ꢂ=ꢂ 8.5, 2.7 Hz, 1H),
O
O
6
13
1
6
.45 (s, 1H), 4.15 (m, 2H), 4.09 (m, 2H), 3.90 (s, 3H); C NMR: δ 190.2,
5
4
O
O
a
b
+
163.8, 141.6, 133.3, 127.6, 114.2, 112.1, 110.3, 65.3, 55.7; MS: m/z 208 (M ).
2
R2
R2
CHO
3
R1
R1
2-(1,3-Dioxolan-2-yl)-4,5-dimethoxybenzaldehydeꢀ(3b)ꢁScale:
6
7
2
0.0 mmol of 2b (Moody and Warrellow, 1990); yield 68% of 3b as
CHO
CHO
a white solid, mp 96–98°C (lit mp 98–99°C; Moody and Warrellow,
c
N
N
-1 1
1
990); IR: 2835, 1682 cm ; H NMR: δ 10.34 (s, 1H), 7.48 (s, 1H), 7.22 (s,
H), 6.36 (s, 1H), 4.18 (m, 2H), 4.12 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H);
R2
R2
1
R1
R1
13
C NMR: δ 189.6, 153.4, 149.5, 134.0, 127.7, 110.5, 108.9, 100.5, 65.3, 56.2,
8
9
+
5
6.1; MS: m/z 238 (M ).
1
2
a R , R = -OCH O-
2
1
2
b R = F; R = H
2-(1,3-Dioxolan-2-yl)-4,5-(methylenedioxy)benzaldehyde
(
3c)ꢀScale: 20.0 mmol of 2c (Balczewski et al., 2006); yield 56% of
Scheme 2ꢁSynthesis of 9a–b; (a) i. n-BuLi, THF, -78°C, ii. warm to
3c as a colorless oil that solidified at 0°C following flash chromatog-
raphy as above, mp 66–68°C (lit mp 69–71°C; Moody and Warrellow,
®
-
40°C, iii. cool to -78°C, iv. DMF, -78°C–23°C; (b) wet Amberlyst 15,
-1
1
acetone, 23°C; (c) anhyd NH NH , EtOH, 0°C–23°C.
1990); IR: 2896, 2788, 1680, 1610 cm ; H NMR: δ 10.25 (s, 1H), 7.36
2
2
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R.A. Bunce et al.: Efficient synthesis of selected phthalazine derivativesꢀ
ꢀ125
(
s, 1H), 7.16 (s, 1H), 6.32 (s, 1H), 6.05 (s, 2H), 4.14 (m, 2H), 4.06 (m, 2H); 8.8, 2.2 Hz, 1H), 7.20 (d, J ꢂ=ꢂ 2.2 Hz, 1H), 4.01 (s, 3H); 13C NMR: δ 162.4,
1
3
+
C NMR: δ 188.9, 152.0, 148.4, 136.5, 129.3, 107.8, 106.6, 102.1, 100.0, 150.6, 150.0, 128.5, 128.0, 124.9, 122.0, 103.9, 55.8; MS: m/z 160 (M ).
+
6
5.2; MS: m/z 222 (M ).
6
,7-Dimethoxyphthalazine (5b)ꢀScale: 1.20 mmol of 4b; yield 82%
2
-(1,3-Dioxolan-2-yl)-4-methylbenzaldehyde (3d)ꢀScale: 20.0 mmol of 5b as a tan solid, mp 196–198°C (lit mp 198–200°C; Bhattacharjee
-1 1
of 2d; yield 70% of 3d as a colorless oil following flash chromatogra- and Popp, 1980); IR: 2840, 1612 cm ; H NMR: δ 9.38 (s, 2H), 7.18 (s, 2H),
-1
1
13
+
phy as above; IR: 1692, 1389 cm ; H NMR: δ 10.33 (s, 1H), 7.83 (d, J ꢂ=ꢂ 4.09 (s, 6H); C NMR: δ 154.1, 149.4, 123.2, 104.2, 56.4; MS: m/z 190 (M ).
7
.9 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J ꢂ=ꢂ 7.9 Hz, 1H), 6.40 (s, 1H), 4.16 (m, 2H),
.09 (m, 2H), 2.44 (s, 3H); 1 C NMR: δ 191.4, 144.7, 138.8, 132.0, 130.7, 6,7-(Methylenedioxy)phthalazine (5c)ꢀScale: 1.20 mmol of 4c;
3
4
+
1
30.0, 127.5, 100.8, 65.3, 21.8; MS: m/z 192 (M ).
yield 98% of 5c as a tan solid, mp 255–257°C (lit mp 255°C; Dallacker
-1 1
et al., 1961); IR: 1606 cm ; H NMR: δ 9.33 (s, 2H), 7.19 (s, 2H), 6.21 (s,
1
3
+
2
H); C NMR: δ 152.0, 149.8, 124.9, 102.43, 102.37; MS: m/z 174 (M ).
General procedure for aldehyde
deprotection
6-Methylphthalazine (5d)ꢀScale: 10.0 mmol of 4d; yield 78% of
d as a tan solid, mp 69–71°C (lit mp 72°C; Robev, 1981); IR: 1620,
5
-1 1
1
374 cm ; H NMR: δ 9.47 (s, 2H), 7.87 (d, J ꢂ=ꢂ 8.5 Hz, 1H), 7.76 (d, J ꢂ=ꢂ
1
3
4
-Methoxyphthalaldehyde (4a)ꢀA solution of 3.22 g (15.5 mmol) of 8.5 Hz, 1H), 7.73 (s, 1H), 2.63 (s, 3H); C NMR: δ 150.7, 150.6, 143.5,
a in 50 mL of acetone was treated with 0.50 g of wet Amberlyst 15 134.6, 126.6, 125.9, 125.1, 124.7, 22.1; MS: m/z 144 (M ).
®
+
3
and stirred vigorously for 1 h, during which time a white solid formed.
At this point, 30 mL of dichloromethane was added to dissolve the
product, the mixture was filtered through Celite , and the solution
®
General procedure for direct metalation
and formylation
was concentrated under reduced pressure. The resulting oil was
purified by flash chromatography using increasing concentrations
(
5–20%) of ether in hexane to give 1.86 g (73%) of 4a as a white solid,
mp 39–41°C (lit mp 41–42°C; Pappas et al., 1968). IR: 2751, 2848, 1692 6-(1,3-Dioxolan-2-yl)-2,3-(methylenedioxy)benzaldehyde
-1 1
cm ; H NMR: δ 10.66 (s, 1H), 10.33 (s, 1H), 7.94 (d, J ꢂ=ꢂ 8.2 Hz, 1H), 7.46 (7a)ꢀUsing the lithium-bromide exchange conditions above, 2.50 g
13
(
d, J ꢂ=ꢂ 2.7 Hz, 1H), 7.23 (dd, J ꢂ=ꢂ 8.2, 2.7 Hz, 1H), 3.96 (s, 3H); C NMR: δ (12.9 mmol) of 6a (Charlton et al., 1996) was directly metalated and
+
1
91.9, 191.0, 163.8, 138.6, 134.6, 129.4, 118.7, 114.7, 55.9; MS: m/z 164 (M ). treated with anhydrous DMF to give a yellow solid. Trituration of this
product in ether gave 2.55 g (89%) of 7a as a white solid; mp 70–72°C;
-1
1
4
,5-Dimethoxyphthalaldehyde (4b)ꢀScale: 2.20 mmol of 3b; yield IR: 1690 cm ; H NMR: δ 10.41 (s, 1H), 7.18 (d, J ꢂ=ꢂ 8.0 Hz, 1H), 6.96
9
3% of 4b as a white solid, mp 165–167°C (lit mp 168–169°C; Bhat- (d, J ꢂ=ꢂ 8.0 Hz, 1H), 6.23 (s, 1H), 6.15 (s, 2H), 4.11 (m, 2H), 4.07 (m, 2H);
-1 1
13
tacharjee and Popp, 1980); IR: 2849, 2772, 1677 cm ; H NMR: δ 10.59
C NMR: δ 188.5, 149.9, 149.5, 130.9, 129.2, 120.7, 117.5, 111.7, 102.8, 101.5,
13
+
(
5
s, 2H), 7.48 (s, 2H), 4.04 (s, 6H); C NMR: δ 190.0, 153.1, 130.9, 111.5, 65.0; MS: m/z 222 (M ).
+
6.4; MS: m/z 194 (M ).
2
-(1,3-Dioxolan-2-yl)-6-fluorobenzaldehyde (7b)ꢀScale: 10.0
4
,5-(Methylenedioxy)phthalaldehyde (4c)ꢀScale: 2.20 mmol of mmol of 6b (Dellaria, 2001); yield 66% of 7b as a colorless oil follow-
-1 1
3
c; yield 91% of 4c, mp 143–145°C (lit mp 143.5°C; Kessar et al., 1991); ing flash chromatography as above; IR: 1700 cm ; H NMR: δ 10.51 (s,
-1 1
IR: 2862, 2754, 1691, 1675 cm ; H NMR: δ 10.50 (s, 2H), 7.42 (s, 2H), 6.19 1H), 7.61–7.55 (complex m, 2H), 7.19 (ddd, J ꢂ=ꢂ 10.4, 9.9, 3.8 Hz, 1H), 6.50
1
3
+
13
(
s, 2H); C NMR: δ 189.7, 152.1, 133.4, 109.5, 103.0; MS: m/z 178 (M ).
(s, 1H), 4.11–4.05 (complex m, 4H); C NMR: δ 188.4 (d, J ꢂ=ꢂ 9.1 Hz),
1
64.8 (d, J ꢂ=ꢂ 258.5 Hz), 140.7, 135.1 (d, J ꢂ=ꢂ 10.0 Hz), 122.9 (d, J ꢂ=ꢂ 6.8 Hz),
4
-Methylphthalaldehyde (4d)ꢀScale: 15.5 mmol of 3d; yield 85% of 122.4 (d, J ꢂ=ꢂ 3.4 Hz), 117.1 (d, J ꢂ=ꢂ 21.8 Hz), 99.7 (d, J ꢂ=ꢂ 2.9 Hz), 65.3; MS:
+
4
d as a colorless oil (lit mp 37–38°C; Pappas et al., 1968), which was m/z 196 (M ).
-1 1
used without further purification; IR: 2861, 2745, 1695 cm ; H NMR:
δ 10.55 (s, 1H), 10.46 (s, 1H), 7.88 (d, J ꢂ=ꢂ 7.7 Hz, 1H), 7.77 (s, 1H), 7.57 (d, 3,4-(Methylenedioxy)phthalaldehyde (8a)ꢀUsing wet Amber-
J ꢂ=ꢂ 7.7 Hz, 1H), 2.51 (s, 3H); 1 C NMR: δ 192.4, 191.9, 144.8, 136.1, 134.0, lyst 15 as described above, 0.22 g (1.00 mmol) of 7a was reacted
3
®
+
1
33.7, 131.4, 131.2, 21.3; MS: m/z 132 (M ).
to give 0.18 g (98%) of 8a as a white solid; mp 145–148°C. IR: 1682
cm ; H NMR: δ 10.65 (s, 1H), 10.21 (s, 1H), 7.54 (d, J ꢂ=ꢂ 8.0 Hz, 1H), 7.10
-1 1
1
3
(
1
d, J ꢂ=ꢂ 8.0 Hz, 1H), 6.26 (s, 2H); C NMR: δ 190.9, 189.1, 153.5, 150.0,
+
30.3, 129.3, 118.4, 111.4, 103.7; MS: m/z 178 (M ).
General procedure for condensative
cyclization using hydrazine
5
,6-(Methylenedioxy)phthalazine (9a)ꢀScale: 4.70 mmol of 8a and
5
.17 mmol of anhydrous hydrazine; yield: 0.71 g (86%) of 9a as a tan
-1 1
6
-Methoxyphthalazine (5a)ꢀTo a stirred solution of 1.64 g (10.0 solid; mp 167–169°C; IR: 1639 cm ; H NMR: δ 9.52 (s, 1H), 9.35 (s, 1H),
13
mmol) of 4a in 30 mL of absolute ethanol at 0°C was added dropwise 7.55 (d, J ꢂ=ꢂ 8.0 Hz, 1H), 7.51 (d, J ꢂ=ꢂ 8.0 Hz, 1H), 6.34 (s, 2H); C NMR: δ
+
0
.35 g (0.34 mL, 11.0 mmol, 1.1 equiv.) of anhydrous hydrazine. Stirring 150.5, 149.5, 144.6, 141.0, 121.5, 121.2, 115.8, 112.0, 103.4; MS: m/z 174 (M ).
was continued with gradual warming to 23°C until TLC indicated the Anal. Calcd for C H N O : C, 62.07; H, 3.45; N, 16.09. Found: C, 62.21; H,
9
6
2
2
reaction was complete (3 h). The solvent was removed under vacuum, 3.49; N, 15.97.
and the resulting product was crystallized from benzene-pentane to
-1
give 1.31 g (82%) of 5a as a tan solid; mp 117–119°C; IR: 2854, 1616 cm ; 5-Fluorophthalazine (9b)ꢀTo a solution of 1.08 g (5.50 mmol) of 7b
1
®
H NMR: δ 9.47 (s, 1H), 9.40 (s, 1H), 7.87 (d, J ꢂ=ꢂ 8.8 Hz, 1H), 7.51 (dd, J ꢂ=ꢂ dissolved in 30 mL of acetone was added 50 mg of wet Amberlyst 15,
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1
26ꢀ
ꢀR.A. Bunce et al.: Efficient synthesis of selected phthalazine derivatives
and the mixture was stirred vigorously for 2.5 h. The crude reaction Acknowledgments: T.H. gratefully acknowledges the
®
mixture was filtered through Celite and concentrated under reduced
Department of Chemistry at Oklahoma State University
pressure. The resulting oil (1.01 g of crude 8b) was dissolved in 20 mL
(
OSU) for a teaching assistantship. Funding for the
00-MHz NMR spectrometers of the Oklahoma Statewide
Shared NMR Facility was provided by NSF (BIR-9512269),
of absolute ethanol, cooled to 0°C, and treated with 0.20 g (0.20 mL,
3
6
.25 mmol) of anhydrous hydrazine. The reaction mixture was stirred
for 2.5 h with gradual warming to 23°C and then was concentrated to
give a product that was triturated in ether to yield 0.51 g (62% for two the Oklahoma State Regents for Higher Education, the W.M.
steps) of 9b as a tan solid; mp 110–112°C (lit mp 109–110°C; Omata et
Keck Foundation, and Conoco, Inc. The authors also wish
to thank the OSU College of Arts and Sciences for funds to
upgrade our departmental FT-IR and GC-MS instruments.
-1 1
al., 1989); IR: 1619 cm ; H NMR: δ 9.80 (s, 1H), 9.59 (s, 1H), 7.92 (td, J ꢂ=ꢂ
1
3
8
.2, 5.5 Hz, 1H), 7.79 (d, J ꢂ=ꢂ 8.2 Hz, 1H), 7.60 (t, J ꢂ=ꢂ 8.2 Hz, 1H); C NMR:
δ 157.4 (d, J ꢂ=ꢂ 258.8 Hz), 150.1 (d, J ꢂ=ꢂ 2.6 Hz), 144.5 (d, J ꢂ=ꢂ 2.9 Hz), 133.4
d, J ꢂ=ꢂ 7.7 Hz), 127.1 (d, J ꢂ=ꢂ 3.4 Hz), 122.1 (d, J ꢂ=ꢂ 4.9 Hz), 116.9 (d, J ꢂ=ꢂ 18.6
(
+
Hz), 116.8 (d, J ꢂ=ꢂ 15.8 Hz); MS: m/z 148 (M ).
Received May 17, 2012; accepted May 31, 2012
References
Balczewski, P.; Koprowski, M.; Bodzioch, A.; Marciniak, B.; Rozycka-
Sokolowska, E. Unusual transformation of the diarylmethanol
derivative into an unknown 1,2,3,6,7,10-hexahydroxylated
anthracene system. J. Org. Chem. 2006, 71, 2899–2902.
Kessar, S. V.; Vohra, R.; Kaur, N. P. Lewis acid complexed
heteroatom carbanions; a convenient route to α-hydroxybenz-
yltetrahydroisoquinoline alkaloids. Tetrahedron Lett. 1991, 32,
3221–3224.
Moody, C. J.; Warrellow, G. J. Vinyl azides in heterocyclic synthesis.
Part 10. Synthesis of the isoindolobenzazepine alkaloid
lennoxamine. J. Chem. Soc. Perkin Trans. 1990, 1,
2929–2936.
Bhattacharjee, D.; Popp, F. D. New compounds: Reissert compound
studies XXXII: facile synthesis of 3-azapapaverine. J. Pharm. Sci.
1
980, 69, 120–121.
Bourne, C. R.; Bunce, R. A.; Bourne, P. C.; Berlin, K. D.; Barrow,
E. W.; Barrow, W. W. Crystal structure of Bacillus anthracis
dihydrofolate reductase with the dihydrophthalazine-based
trimethoprim derivative RAB1 provides a structural explanation
Omata, K.; Tomita, H.; Nakajima, T.; Natsume, B. Design of new
melanin biosynthesis inhibitors. Pest. Sci. 1989, 26,
271–281.
of potency and selectivity. Antimicrob. Agents Chemother. 2009, Pappas, J. J.; Keaveney, W. P.; Berger, M.; Rush, R. V. Directional
53, 3065–3073.
effects of substituents in the ozonolysis of naphthalenes.
Synthesis of o-phthalaldehydes. J. Org. Chem. 1968, 33,
787–792.
Charlton, J. L.; Oleschuk, C. J.; Chee, G.-L. Hindered rotation in
arylnaphthalene lignans. J. Org. Chem. 1996, 61, 3452–3457.
Dallacker, F.; Glombitza, K.-W.; Lipp, M. Derivate des
methylenedioxybenzols, IV. Reacktionen des 4,5-methyl-
endioxy-phthalaldehyds. Liebigs Ann. Chem. 1961, 643, 82–90.
Dellaria, J. F., Jr. Urokinase inhibitors. U.S. Patent 6,207,701, 2001.
Chem. Abstr. 2001, 134, 252255.
Remy, D. C.; King, S. W.; Cochran, D.; Springer, J. P.; Hirshfield,
J. Facile intramolecular tosylhydrazone-mediated cyclopro-
panation reaction of 4-(2-formylphenyl)-1,4-dihydropyridines.
J. Org. Chem. 1985, 50, 4120–4125.
Robev, S. Phthalazine derivatives from aromatic aldazines.
Tetrahedron Lett. 1981, 22, 345–348.
Gschwend, H. W.; Rodriguez, H. R. Heteroatom-facilitated
lithiations. Organic React. 1979, 26, 1–360.
Rohm and Haas Co. Technical bulletin fluid process chemicals:
®
Hirsch, A.; Orphanos, D. Convenient quantitative preparation of
phthalazine. J. Heterocycl. Chem. 1965, 2, 206.
Amberlyst 15 synthetic resin catalyst, 1978.
Tsoungas, P. G.; Searcey, M. A convenient access to benzo-
substituted phthalazines as potential precursors to DNA
intercalators. Tetrahedron Lett. 2001, 42, 6589–6592.
®
Kalesse, M. Synthesis abstract no. 5. Amberlyst 15 as a catalyst in
synthetic organic chemistry. Acros Organic Acta 1995, 1, 67–68.
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