efficient synthesis of selected phthalazine derivatives
TRANSCRIPT
DOI 10.1515/hc-2012-0079 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
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 prepared by
a similar sequence following direct lithiation of benzalde-
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%.
Keywords: formylation; heteroatom-directed ortho lithi-
ation; hydrazine condensative ring closure; lithium-
bromide exchange; phthalazines.
*Corresponding author: Richard A. Bunce, Department of
Chemistry, Oklahoma State University, Stillwater, OK 74078-3071,
USA , e-mail: [email protected]
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
Introduction Structural modifications to optimize the activity of antibi-
otic 1 are currently under investigation in our laboratory.
These drugs act against inhalation anthrax and multid-
rug-resistant staph by inhibiting dihydrofolate reductase
(DHFR), a key enzyme required for bacterial growth. An
important feature of these compounds is that they selec-
tively target bacterial DHFR, while not harming human
DHFR (Bourne et al., 2009).
N
N
NH2
NH2
NN
PrO
OMeOMe
1
12
34 5
6
78
In an earlier study (Bourne et al., 2009), X-ray analysis
of the DHFR-( S )- 1 complex indicated interactions between
DHFR and the dihydrophthalazine portion of the drug. This
work revealed that space was available in the active site for
a small substituent at C5, C6 or C7 on this ring. Based upon
this finding and with the goal of maximizing the antibac-
terial activity of 1 , we directed our efforts toward prepar-
ing several phthalazines substituted by small groups that
could be accommodated in the DHFR active site.
Results and discussion Our approach to phthalazine derivatives is outlined in
Scheme 1 . The starting bromoacetal derivatives 2a – d were
either known or readily prepared using standard meth-
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
-40 ° C for 30 min. The mixture was then recooled to -78 ° C,
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
ethanol at 0 ° C – 23 ° C for 3 h (Hirsch and Orphanos, 1965;
Bhattacharjee and Popp, 1980) to give phthalazines 5a – d
in 78 – 98% yields.
Our route is similar to one reported earlier (Tsoungas
and Searcey, 2001) for the preparation of the 6-meth-
oxyphthalazine ( 5a ). In the current study, however, addi-
tional examples of this transformation are described and
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 regio selectivity
was altered (see Scheme 2 ). Direct lithiation of piperonal
and 3-fluorobenzaldehyde acetals 6a (Charlton et al., 1996)
and 6b (Dellaria, 2001) yielded preferential metalation of
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124 R.A. Bunce et al.: Efficient synthesis of selected phthalazine derivatives
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%.
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,
60 – 200 mesh). Band elution for all chromatographic separations
was monitored using a hand-held UV lamp. 1 H and 13 C NMR spectra
were measured in CDCl 3 at 300 MHz and 75 MHz, respectively, and
were referenced to internal tetramethylsilane. Low-resolution mass
spectra (EI) were recorded at 30 eV.
General procedure for lithium-bromine exchange and formylation 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
2.2 m n -butyllithium in hexanes. The reaction mixture was stirred for
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
NH 4 Cl and extracted with ether (2 × 100 mL). The combined organic
layers were washed with aqueous NaCl, dried (MgSO 4 ), and concen-
trated under reduced pressure to give a yellow oil. This material was
purified by flash chromatography on a 50-cm × 2-cm column eluting
with 2 – 10% ethyl acetate in hexanes to give 3.49 g (84%) of 3a as a
light yellow oil. IR: 2845, 1689 cm -1 ; 1 H NMR: δ 10.23 (s, 1H), 7.90 (d,
J = 8.5 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 6.98 (dd, J = 8.5, 2.7 Hz, 1H),
6.45 (s, 1H), 4.15 (m, 2H), 4.09 (m, 2H), 3.90 (s, 3H); 13 C NMR: δ 190.2,
163.8, 141.6, 133.3, 127.6, 114.2, 112.1, 110.3, 65.3, 55.7; MS: m/z 208 (M + ).
2-(1,3-Dioxolan-2-yl)-4,5-dimethoxybenzaldehyde (3b) Scale:
20.0 mmol of 2b (Moody and Warrellow, 1990); yield 68% of 3b as
a white solid, mp 96 – 98 ° C (lit mp 98 – 99 ° C; Moody and Warrellow,
1990); IR: 2835, 1682 cm -1 ; 1 H NMR: δ 10.34 (s, 1H), 7.48 (s, 1H), 7.22 (s,
1H), 6.36 (s, 1H), 4.18 (m, 2H), 4.12 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H);
13 C NMR: δ 189.6, 153.4, 149.5, 134.0, 127.7, 110.5, 108.9, 100.5, 65.3, 56.2,
56.1; MS: m/z 238 (M + ).
2-(1,3-Dioxolan-2-yl)-4,5-(methylenedioxy)benzaldehyde (3c) Scale: 20.0 mmol of 2c (Balczewski et al., 2006); yield 56% of
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,
1990); IR: 2896, 2788, 1680, 1610 cm -1 ; 1 H NMR: δ 10.25 (s, 1H), 7.36
NN
R1
R2
R1
R2
R1
R2
R1
R2
CHO
CHO
CHOBr
O
O
O
O
2 3
4 5
a b
c
a R1 = OMe; R2 = Hb R1 = OMe; R2 = OMe
c R1 R2 = -OCH2O-d R1 = Me; R2 = H
123
45
6
Scheme 1 Synthesis of 5a – d ; (a) i. n -BuLi, THF, -78 ° C, ii . warm to
-40 ° C, iii . cool to -78 ° C, iv . DMF, -78 ° C–23 ° C; (b) wet Amberlyst ® 15,
acetone, 23 ° C; (c) anhyd NH 2 NH
2 , EtOH, 0 ° C – 23 ° C.
the aromatic site flanked by two heteroatom groups, that
is, at C2 rather than at C6 (Gschwend and Rodriguez, 1979).
Thus, for these two substrates, the result ing aldehydes 7a
(89%) and 7b (66%) were substituted at C3 and C4 rather
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
deprotection to 8a (98%) and conversion to phthalazine 9a
(86%), deprotection of 7b was difficult to monitor by thin
layer chromatography and phthalaldehyde 8b was sensitive
toward purification. To circumvent this problem, crude 8b
was reacted directly with hydrazine in anhydrous ethanol to
give phthalazine 9b in a two-step yield of 61%.
Conclusion We have developed a convenient synthesis of a series of
substituted phthalazines from readily available benzal-
dehyde acetals. The procedure allows the preparation of
NN
R2
R2 R2
R2
CHO
CHO
CHO
O
O
O
O
6 7
8 9
a b
c
a R1, R2 = -OCH2O-b R1 = F; R2 = H
R1 R1
R1 R1
1
23
45
6
Scheme 2 Synthesis of 9a – b ; (a) i. n -BuLi, THF, -78 ° C, ii . warm to
-40 ° C, iii . cool to -78 ° C, iv . DMF, -78 ° C–23 ° C; (b) wet Amberlyst ® 15,
acetone, 23 ° C; (c) anhyd NH 2 NH
2 , EtOH, 0 ° C – 23 ° C.
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R.A. Bunce et al.: Efficient synthesis of selected phthalazine derivatives 125
8.8, 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.01 (s, 3H); 13 C NMR: δ 162.4,
150.6, 150.0, 128.5, 128.0, 124.9, 122.0, 103.9, 55.8; MS: m/z 160 (M + ).
6,7-Dimethoxyphthalazine (5b) Scale: 1.20 mmol of 4b ; yield 82%
of 5b as a tan solid, mp 196 – 198 ° C (lit mp 198 – 200 ° C; Bhattacharjee
and Popp, 1980); IR: 2840, 1612 cm -1 ; 1 H NMR: δ 9.38 (s, 2H), 7.18 (s, 2H),
4.09 (s, 6H); 13 C NMR: δ 154.1, 149.4, 123.2, 104.2, 56.4; MS: m/z 190 (M + ).
6,7-(Methylenedioxy)phthalazine (5c) Scale: 1.20 mmol of 4c ;
yield 98% of 5c as a tan solid, mp 255 – 257 ° C (lit mp 255 ° C; Dallacker
et al., 1961); IR: 1606 cm -1 ; 1 H NMR: δ 9.33 (s, 2H), 7.19 (s, 2H), 6.21 (s,
2H); 13 C NMR: δ 152.0, 149.8, 124.9, 102.43, 102.37; MS: m/z 174 (M + ).
6-Methylphthalazine (5d) Scale: 10.0 mmol of 4d ; yield 78% of
5d as a tan solid, mp 69 – 71 ° C (lit mp 72 ° C; Robev, 1981); IR: 1620,
1374 cm -1 ; 1 H NMR: δ 9.47 (s, 2H), 7.87 (d, J = 8.5 Hz, 1H), 7.76 (d, J =
8.5 Hz, 1H), 7.73 (s, 1H), 2.63 (s, 3H); 13 C NMR: δ 150.7, 150.6, 143.5,
134.6, 126.6, 125.9, 125.1, 124.7, 22.1; MS: m/z 144 (M + ).
General procedure for direct metalation and formylation 6-(1,3-Dioxolan-2-yl)-2,3-(methylenedioxy)benzaldehyde (7a) Using the lithium-bromide exchange conditions above, 2.50 g
(12.9 mmol) of 6a (Charlton et al., 1996) was directly metalated and
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;
IR: 1690 cm -1 ; 1 H NMR: δ 10.41 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.96
(d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 6.15 (s, 2H), 4.11 (m, 2H), 4.07 (m, 2H);
13 C NMR: δ 188.5, 149.9, 149.5, 130.9, 129.2, 120.7, 117.5, 111.7, 102.8, 101.5,
65.0; MS: m/z 222 (M + ).
2-(1,3-Dioxolan-2-yl)-6-fluorobenzaldehyde (7b) Scale: 10.0
mmol of 6b (Dellaria, 2001); yield 66% of 7b as a colorless oil follow-
ing flash chromatography as above; IR: 1700 cm -1 ; 1 H NMR: δ 10.51 (s,
1H), 7.61 – 7.55 (complex m, 2H), 7.19 (ddd, J = 10.4, 9.9, 3.8 Hz, 1H), 6.50
(s, 1H), 4.11 – 4.05 (complex m, 4H); 13 C NMR: δ 188.4 (d, J = 9.1 Hz),
164.8 (d, J = 258.5 Hz), 140.7, 135.1 (d, J = 10.0 Hz), 122.9 (d, J = 6.8 Hz),
122.4 (d, J = 3.4 Hz), 117.1 (d, J = 21.8 Hz), 99.7 (d, J = 2.9 Hz), 65.3; MS:
m/z 196 (M + ).
3,4-(Methylenedioxy)phthalaldehyde (8a) Using wet Amber-
lyst ® 15 as described above, 0.22 g (1.00 mmol) of 7a was reacted
to give 0.18 g (98%) of 8a as a white solid; mp 145 – 148 ° C. IR: 1682
cm -1 ; 1 H NMR: δ 10.65 (s, 1H), 10.21 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.10
(d, J = 8.0 Hz, 1H), 6.26 (s, 2H); 13 C NMR: δ 190.9, 189.1, 153.5, 150.0,
130.3, 129.3, 118.4, 111.4, 103.7; MS: m/z 178 (M + ).
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
solid; mp 167 – 169 ° C; IR: 1639 cm -1 ; 1 H NMR: δ 9.52 (s, 1H), 9.35 (s, 1H),
7.55 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 6.34 (s, 2H); 13 C NMR: δ
150.5, 149.5, 144.6, 141.0, 121.5, 121.2, 115.8, 112.0, 103.4; MS: m/z 174 (M + ).
Anal. Calcd for C 9 H
6 N
2 O
2 : C, 62.07; H, 3.45; N, 16.09. Found: C, 62.21; H,
3.49; N, 15.97.
5-Fluorophthalazine (9b) To a solution of 1.08 g (5.50 mmol) of 7b
dissolved in 30 mL of acetone was added 50 mg of wet Amberlyst ® 15,
(s, 1H), 7.16 (s, 1H), 6.32 (s, 1H), 6.05 (s, 2H), 4.14 (m, 2H), 4.06 (m, 2H);
13 C NMR: δ 188.9, 152.0, 148.4, 136.5, 129.3, 107.8, 106.6, 102.1, 100.0,
65.2; MS: m/z 222 (M + ).
2-(1,3-Dioxolan-2-yl)-4-methylbenzaldehyde (3d) Scale: 20.0 mmol
of 2d ; yield 70% of 3d as a colorless oil following flash chromatogra-
phy as above; IR: 1692, 1389 cm -1 ; 1 H NMR: δ 10.33 (s, 1H), 7.83 (d, J =
7.9 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.40 (s, 1H), 4.16 (m, 2H),
4.09 (m, 2H), 2.44 (s, 3H); 13 C NMR: δ 191.4, 144.7, 138.8, 132.0, 130.7,
130.0, 127.5, 100.8, 65.3, 21.8; MS: m/z 192 (M + ).
General procedure for aldehyde deprotection 4-Methoxyphthalaldehyde (4a) A solution of 3.22 g (15.5 mmol) of
3a in 50 mL of acetone was treated with 0.50 g of wet Amberlyst ® 15
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
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
cm -1 ; 1 H NMR: δ 10.66 (s, 1H), 10.33 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.46
(d, J = 2.7 Hz, 1H), 7.23 (dd, J = 8.2, 2.7 Hz, 1H), 3.96 (s, 3H); 13 C NMR: δ
191.9, 191.0, 163.8, 138.6, 134.6, 129.4, 118.7, 114.7, 55.9; MS: m/z 164 (M + ).
4,5-Dimethoxyphthalaldehyde (4b) Scale: 2.20 mmol of 3b ; yield
93% of 4b as a white solid, mp 165 – 167 ° C (lit mp 168 – 169 ° C; Bhat-
tacharjee and Popp, 1980); IR: 2849, 2772, 1677 cm -1 ; 1 H NMR: δ 10.59
(s, 2H), 7.48 (s, 2H), 4.04 (s, 6H); 13 C NMR: δ 190.0, 153.1, 130.9, 111.5,
56.4; MS: m/z 194 (M + ).
4,5-(Methylenedioxy)phthalaldehyde (4c) Scale: 2.20 mmol of
3c ; yield 91% of 4c , mp 143 – 145 ° C (lit mp 143.5 ° C; Kessar et al., 1991);
IR: 2862, 2754, 1691, 1675 cm -1 ; 1 H NMR: δ 10.50 (s, 2H), 7.42 (s, 2H), 6.19
(s, 2H); 13 C NMR: δ 189.7, 152.1, 133.4, 109.5, 103.0; MS: m/z 178 (M + ).
4-Methylphthalaldehyde (4d) Scale: 15.5 mmol of 3d ; yield 85% of
4d as a colorless oil (lit mp 37 – 38 ° C; Pappas et al., 1968), which was
used without further purification; IR: 2861, 2745, 1695 cm -1 ; 1 H NMR:
δ 10.55 (s, 1H), 10.46 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.77 (s, 1H), 7.57 (d,
J = 7.7 Hz, 1H), 2.51 (s, 3H); 13 C NMR: δ 192.4, 191.9, 144.8, 136.1, 134.0,
133.7, 131.4, 131.2, 21.3; MS: m/z 132 (M + ).
General procedure for condensative cyclization using hydrazine 6-Methoxyphthalazine (5a) To a stirred solution of 1.64 g (10.0
mmol) of 4a in 30 mL of absolute ethanol at 0 ° C was added dropwise
0.35 g (0.34 mL, 11.0 mmol, 1.1 equiv.) of anhydrous hydrazine. Stirring
was continued with gradual warming to 23 ° C until TLC indicated the
reaction was complete (3 h). The solvent was removed under vacuum,
and the resulting product was crystallized from benzene-pentane to
give 1.31 g (82%) of 5a as a tan solid; mp 117 – 119 ° C; IR: 2854, 1616 cm -1 ;
1 H NMR: δ 9.47 (s, 1H), 9.40 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.51 (dd, J =
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126 R.A. Bunce et al.: Efficient synthesis of selected phthalazine derivatives
and the mixture was stirred vigorously for 2.5 h. The crude reaction
mixture was filtered through Celite ® and concentrated under reduced
pressure. The resulting oil (1.01 g of crude 8b ) was dissolved in 20 mL
of absolute ethanol, cooled to 0 ° C, and treated with 0.20 g (0.20 mL,
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
steps) of 9b as a tan solid; mp 110 – 112 ° C (lit mp 109 – 110 ° C; Omata et
al., 1989); IR: 1619 cm -1 ; 1 H NMR: δ 9.80 (s, 1H), 9.59 (s, 1H), 7.92 (td, J =
8.2, 5.5 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H); 13 C NMR:
δ 157.4 (d, J = 258.8 Hz), 150.1 (d, J = 2.6 Hz), 144.5 (d, J = 2.9 Hz), 133.4
(d, J = 7.7 Hz), 127.1 (d, J = 3.4 Hz), 122.1 (d, J = 4.9 Hz), 116.9 (d, J = 18.6
Hz), 116.8 (d, J = 15.8 Hz); MS: m/z 148 (M + ).
Acknowledgments : T.H. gratefully acknowledges the
Department of Chemistry at Oklahoma State University
(OSU) for a teaching assistantship. Funding for the
300-MHz NMR spectrometers of the Oklahoma Statewide
Shared NMR Facility was provided by NSF (BIR-9512269),
the Oklahoma State Regents for Higher Education, the W.M.
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.
Received May 17, 2012; accepted May 31, 2012
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