Regioselective Functionalization of Chlorophthalazine Derivatives

Article abstract of DOI:10.1055/s-0029-1219231

Chlorophthalazines were efficiently metalated using tmpZnClLiCl under microwave irradiation. This provided novel substituted phthalazine derivatives after subsequent trapping of the resulting organometallic reagents with various electrophiles. Moreover, Negishi cross-coupling reactions have been performed affording new polyfunctionalized phthalazine scaffolds in very good yields.

Full text of DOI:10.1055/s-0029-1219231

PAPER
1097
Regioselective Functionalization of Chlorophthalazine Derivatives
R
egioselective
r
Functio
a
nalization
o
n
f
Chlorophth
ç
alazine De
o
rivatives is Crestey, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 18 November 2009; revised 10 December 2009
phthalazine derivatives providing a versatile, regioselec-
tive, and convenient procedure for the synthesis of new
polyfunctionalized phthalazines.
Abstract: Chlorophthalazines were efficiently metalated using
tmpZnCl·LiCl under microwave irradiation. This provided novel
substituted phthalazine derivatives after subsequent trapping of the
resulting organometallic reagents with various electrophiles. More-
over, Negishi cross-coupling reactions have been performed afford-
ing new polyfunctionalized phthalazine scaffolds in very good
yields.
Thus, the required 1,6-dichlorophthalazine (1) was readi-
ly prepared from commercially available 4-chlorobenzoyl
chloride (2) in four steps in 65% overall yield on a multi-
gram scale.9 Hence tert-butylamide reacted with 2 provid-
ing the corresponding benzamide 3 in 97% yield.
Subsequent addition of methyllithium and trapping of the
resulting dianion with N,N-dimethylformamide furnished
isoindolinone 4 in 88% yield. Finally, after reaction with
hydrazine in glacial acetic acid (92 °C, 3 h, 92%), the ring-
expanded phthalazinol 5 was converted into its chloro de-
rivative 1 in 81% yield (Scheme 1).
Key words: chlorophthalazine derivatives, metalation, microwave
irradiation, Negishi cross-coupling, zinc
Phthalazines and their derivatives are known to possess a
wide range of biological activity. For example, Vatanalib
(I) has been recently described as a tyrosine kinase inhib-
itor of angiogenesis.1 Moreover, many triazolophthala-
zines of type II have been shown to bind to the benzo-
diazepane site of GABA-A receptors2 and phthalazinone
Zopolrestat (III) is a potent inhibitor of aldose reductase
(Figure 1).3 Recently, Carreira and co-workers developed
an efficient ligand (PINAP) bearing a phthalazine moiety
for catalytic and enantioselective alkyne addition.4
O
X
O
X
N
N
ii
iii
N
88%
92%
Cl
Cl
Cl
OH
4
5 X = OH
1 X = Cl
2 X = Cl
3 X = NHt-Bu
i
iv
81%
97%
Cl
Scheme 1 Reagents and conditions: (i) t-BuNH2 (2.2 equiv),
CH2Cl2, 0 °C to 25 °C, 1 h; (ii) (a) MeLi (2.05 equiv), anhyd THF,
–45 °C to –10 °C, 3 h; (b) anhyd DMF (2 equiv), –30 °C to –10 °C,
30 min; (c) sat. aq NH4Cl, –10 °C to 25 °C, 45 min; (iii) NH2NH2·H2O
(1.05 equiv), glacial AcOH, 92 °C, 3 h; (iv) DIPEA (1 equiv), POCl3
(10 equiv), 25 °C, 30 min then 100 °C for 4 h.
HO2C
CF3
NH
N
N
R
N
N
N
N
N
N
N
S
I
II
O
III
(Ar)Het
We first studied the metalation of dichlorophthalazine 1
by using the newly developed and mild complex base
2,2,6,6-tetramethylpiperidin-1-ylzinc chloride–lithium
chloride complex (tmpZnCl·LiCl, 6) prepared by treat-
ment of 2,2,6,6-tetramethylpiperidine with butyllithium
followed by the addition of zinc chloride (Scheme 2). In-
deed, this active base allows chemoselective zincation of
sensitive aromatic compounds as well as heterocyclic sub-
strates.
N
Figure 1 Examples of biologically active phthalazines
However, the construction of substituted and functional-
ized phthalazines reveals two major constraints. It re-
quires the cyclization of substituted benzenes that are
obtained after tedious multistep synthesis.5 Moreover, a
complex mixture is generally obtained due to the lack of
regioselectivity and chemoselectivity.6
Thus, 1,6-dichlorophthalazine (1) reacted at 25 °C with
zinc base 6, unfortunately to furnish instantly the ring
fragmentation product 4-chlorophthalonitrile (7) in quan-
titative yield.10 Alternatively, Negishi cross-coupling
reaction11 was performed using 4-MeC6H4ZnI·LiCl, ob-
tained by the treatment of 4-iodotoluene with zinc dust in
the presence of lithium chloride,12 using PEPPSI-iPr as
catalyst13 to afford the single regioisomer C1-substituted
phthalazine 8, albeit in moderate yield (Scheme 2). More-
over, decomposition of the starting material 1 was mainly
observed when benzylic zinc reagents as well as more re-
With this in mind, we have prepared an unsymmetrical di-
halogenophthalazine 1 and have reacted it with recently
developed Zn/Li bases7 furnishing regioselective substi-
tuted phthalazines after subsequent trapping of the result-
ing zincated species with various electrophiles. Herein,
we report an efficient metalation8 protocol of chloro-
SYNTHESIS 2010, No. 7, pp 1097–1106
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219231; Art ID: T22409SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1098
F. Crestey, P. Knochel
PAPER
active zinc reagents of the type RZnCl·MgXCl·LiCl were
used.14
i
Me
6 (tmpZnCl⋅LiCl)
N
N
1,6-Dichlorophthalazine (1) proved to be a highly sensi-
tive heterocycle. A more stable 6-chlorophthalazine was
prepared by introducing a morpholino group in position 1.
Thus, treatment of 1 with morpholine at 85 °C for 12
hours in toluene gave the desired phthalazine 9 in 95%
yield (Scheme 2). Direct zincation using tmpZnCl·LiCl
(6)7 required 48 hours at 25 °C and produced the zincated
species in low yield. However, microwave irradiation15
led to a complete zincation within 45 minutes (60 °C) fur-
nishing the iodo derivative 10a after iodolysis in 74%
yield (Table 1, entry 1). Additionally, quenching of the
metalated intermediate with 3-bromocyclohexene in the
presence of CuCN·2LiCl16 (5 mol%) provided the allylat-
ed phthalazine 10b in 60% yield (entry 2). After palladi-
um-catalyzed cross-coupling reactions, the functionalized
phthalazines 10c–g bearing an ester, a nitrile, a ketone, or
a thiophene group were obtained in 72–86% yields (en-
tries 3–7). Sonogashira reaction17 of in situ generated 4-
iodophthalazine 10a with hex-1-yne afforded 4-alkynyl-
phthalazine 10h in 89% yield (entry 8).
H
ZnCl⋅LiCl
CN
ii
iii
N
N
1
98%
CN
43%
Cl
Cl
7
8
O
O
N
N
E
X
N
N
N
v
N
N
vi
N
77–95%
60–86%
Cl
Cl
iv
Nu
10a–h
11a–f
1 X = Cl
9 X = morpholine
95%
Nu = aryl, benzyl, alkyl
E = I, aryl, heteroaryl, allyl, alkynyl
Scheme 2 Reagents and conditions: (i) (a) n-BuLi (1 equiv), anhyd
THF, –50 °C to 0 °C; (b) ZnCl2 (1 equiv), anhyd THF, 0 °C to 25 °C;
(ii) 6 (1.1 equiv), anhyd THF, 1 min, 25 °C; (iii) 4-MeC6H4ZnI·LiCl
(1.1 equiv), PEPPSI-iPr (1 mol%), 45 °C, 12 h; (iv) morpholine (4
equiv), toluene, 85 °C, 12 h; (v) (a) 6 (1.1 equiv), anhyd THF, 45 min,
60 °C, mw; (b) electrophile; (vi) NuZnCl·MgX2·LiCl (1.4 equiv),
PEPPSI-iPr (0.75 mol%), anhyd THF.
Table 1 Synthesis and Yields of Phthalazine Derivatives 10 with tmpZnCl·LiCl (6) and Quenching with Electrophiles
Entry
1
Electrophile
Product
Yielda (%)
Cl
Cl
Cl
I2
71
O
N
I
N
N
N
N
N
N
10a
Br
2
3
4
5
60b
83c
74c
84c
O
N
10b
I
O
N
CO2Et
EtO2C
10c
Cl
I
O
N
CN
NC
N
N
10d
Cl
F3C
I
CF3
O
N
N
N
10e
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

PAPER
Regioselective Functionalization of Chlorophthalazine Derivatives
1099
Table 1 Synthesis and Yields of Phthalazine Derivatives 10 with tmpZnCl·LiCl (6) and Quenching with Electrophiles (continued)
Entry
6
Electrophile
Product
Yielda (%)
Cl
Cl
Cl
S
86c
S
I
O
N
N
N
N
N
N
N
10f
I
7
8
72c
c-Hex
O
c-Hex
O
O
N
10g
89d
n-Bu
O
N
n-Bu
10h
a Yield (%) of isolated analytically pure product.
b Transmetalation performed with CuCN·2LiCl (5 mol%).
c Obtained by palladium-catalyzed cross-coupling reaction using Pd(dba)2 (2 mol%) and (o-furyl)3P (4 mol%).
d Obtained by Sonogashira reaction of in situ generated compound 10a.
Table 2 Synthesis and Yields of Phthalazine Derivatives 11
Entry
Nucleophilea
Temp, timeb
Product
Yieldc (%)
O
N
ZnCl
1
25 °C, 30 min
95, 87d
N
N
11a
O
N
ZnCl
2
25 °C, 10 min
79
N
N
Me2N
Me2N
11b
O
N
ZnCl
3
25 °C, 10 min
85
N
N
EtO2C
EtO2C
11c
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

1100
F. Crestey, P. Knochel
PAPER
Table 2 Synthesis and Yields of Phthalazine Derivatives 11 (continued)
Entry
4
Nucleophilea
Temp, timeb
50 °C, 4 h
Product
Yieldc (%)
O
N
MeO
OMe
ZnCl
94
N
N
11d
O
N
5
6
60 °C, 8 h
77
77
NC(CH2)3ZnCl
N
NC
N
3
11e
O
N
60 °C, 30 min
EtO2C(CH2)5ZnCl
N
EtO2C
N
5
11f
a MgCl2·LiCl or MgClBr·LiCl salts are omitted for clarity.
b The reaction conditions for the cross coupling with 9.
c Yield (%) of isolated analytically pure product.
d Using PhZnCl·MgCl2 as zinc reagent at 45 °C for 12 h.
Furthermore, Negishi cross-coupling reactions were per- Additionally, two examples for the synthesis of polyfunc-
formed on the chlorophthalazine 9 (Scheme 2). Thus, us- tionalized phthalazines are depicted in Scheme 3. Thus,
ing PEPPSI-iPr as catalyst PhZnCl·MgCl2·LiCl14 reacted phthalazine 10d bearing a nitrile group underwent
with 9 at 25 °C within 30 minutes providing substituted Negishi cross-coupling with a benzylic zinc reagent18 pro-
phthalazine 11a in 95% yield (Table 2, entry 1). More- viding the 1,4,6-trisubstituted heterocycle 12a in 97%
over, the treatment of arylzinc reagents bearing an ester or yield. Remarkably, pyridinylzinc reagent18 reacted with
an amino group at 25 °C for 10 minutes furnished 6- thiophene 10f within five minutes at 50 °C leading to the
arylphthalazides 11b,c in 79–85% yields (entries 2 and 3). desired phthalazine 12b in 92% yield.
Heating at 50–60 °C and extending the reaction time al-
In summary, we have developed an efficient and valuable
lowed the synthesis of the expected benzyl and alkyl prod-
microwave-assisted procedure for the regioselective met-
ucts 11d–f in 77–94% yields (entries 4–6).
alation of the phthalazine scaffold using tmpZnCl·LiCl as
an effective zinc base. This method allows easy access to
new polyfunctionalized phthalazine libraries which
should find wide applications for the synthesis of new
biologically active and relevant molecules. Further stud-
MeO
ZnCl⋅MgCl2⋅LiCl
OMe
ies concerning construction of new substituted derivatives
are currently in progress.
(1.4 equiv)
10d
O
N
CN
PEPPSI-iPr (0.75 mol%)
dry THF, 3 h, 50 °C
N
N
12a
97%
All reactions were carried out under an argon atmosphere in flame-
dried glassware. Syringes which were used to transfer anhydrous
solvents or reagents were purged with argon prior to use. THF was
continuously refluxed and freshly distilled from Na benzophenone
ketyl under N2. 2,2,6,6-Tetramethylpiperidine (tmpH) was distilled
prior to use. Yields refer to isolated compounds estimated to be
N
ZnCl⋅MgClBr⋅LiCl
(1.4 equiv)
N
10f
S
PEPPSI-iPr (0.75 mol%)
dry THF, 5 min, 50 °C
O
N
1
>95% pure as determined by H NMR (25 °C) and capillary GC.
N
N
NMR spectra were recorded on Bruker ARX-200, AC-300 or WH-
400 using CDCl3 or DMSO-d6 as solvents. Gas chromatography
(GC) were performed with machines of type Hewlett-Packard 6890
or 5890 series II using a column of type HP 5. Column chromatog-
raphy was performed using silica gel (0.040–0.063 mm, 230–400
92%
12b
Scheme 3 Synthesis of polyfunctionalized phthalazines 12a,b
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

PAPER
Regioselective Functionalization of Chlorophthalazine Derivatives
1101
mesh ASTM) from Merck. Melting points were measured using a
Büchi B-540 apparatus and are uncorrected. Mass spectra and
HRMS were recorded on Finnigan MAT 95Q or Finnigan MAT 90
instrument using electron impact (EI); where otherwise noted elec-
tronspray ionization (ESI) was used. Microwave-assisted synthesis
was carried out in a Biotage Initiator apparatus operating in single
mode; the microwave cavity producing controlled irradiation at
2.45 GHz (Biotage AB, Uppsala, Sweden). The reactions were run
in sealed vessels (2.0–5.0 mL). These experiments were performed
by employing magnetic stirring and a fixed hold time using variable
power to reach (over 1 min) and then maintain the desired tempera-
ture in the vessel for the programmed time period. The temperature
was monitored by an IR sensor focused on a point on the reactor vial
glass. The IR sensor was calibrated to internal soln reaction temper-
ature by the manufacturer. PEPPSI-iPr catalyst {[1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)
dichloride} was obtained from Aldrich.
HRMS: m/z [M]+ calcd for C12H14ClNO2: 239.0713; found:
239.0678.
6-Chlorophthalazin-1-ol (5)8
Hydrazine hydrate soln (64 wt%, 5.49 g, 110 mmol, 1.05 equiv) was
added dropwise over 1 h to a heated soln of isoindolinone 4 (25 g,
104 mmol, 1 equiv) in glacial AcOH (105 mL) under argon at 90 °C,
keeping the temperature below 93 °C. The mixture was heated to 92
°C for 3 h, deionized H2O (150 mL) preheated to 80 °C was added,
and the mixture was allowed to cool to 25 °C over 3 h. The yellow-
ish precipitated product was collected by filtration, washed with
deionized H2O (60 mL), and oven dried at 80 °C overnight afford-
ing 5 as a pale yellow solid; yield: 17.4 g (92%); Rf = 0.5 (EtOAc–
pentane, 1:1).
1H NMR (DMSO-d6): d = 12.74 (br s, 1 H), 8.30 (s, 1 H), 8.17 (d,
J = 8.6 Hz, 1 H), 8.02 (d, J = 2.0 Hz, 1 H), 7.82 (dd, J = 8.5 Hz,
J = 2.0 Hz, 1 H).
13C NMR (DMSO-d6): d = 159.5, 138.8, 137.6, 132.3, 131.7, 128.3,
N-tert-Butyl-4-chlorobenzamide (3)8
126.6, 126.5.
t-BuNH2 (132 mL, 1.26 mol, 2.2 equiv) was added dropwise over
45 min at 0 °C to a cooled soln of 4-chlorobenzoyl chloride (2, 100
g, 0.57 mol, 1 equiv) in anhyd CH2Cl2 (350 mL) under argon. The
mixture was then allowed to warm to 25 °C over 1 h. Aq 5 M NaOH
(200 mL) was slowly added and then the aqueous layer was re-
moved. The organic layer was partially concentrated and heptane
(200 mL) was added. CH2Cl2 was removed in vacuo and the white
precipitated product was collected by filtration, washed with hep-
tane (200 mL), and oven dried (40 °C overnight) affording 3 as a
white solid; yield: 117.7 g (97%); Rf = 0.7 (EtOAc–pentane, 1:5).
1H NMR (DMSO-d6): d = 7.78–7.83 (m, 3 H), 7.46 (d, J = 8.0 Hz,
2 H), 1.35 (s, 9 H).
13C NMR (DMSO-d6): d = 165.6, 135.9, 135.0, 129.7 (2 C), 128.4
(2 C), 51.3, 29.0 (3 C).
MS (70 eV): m/z (%) = 182 (27), 180 (100) [M]+, 152 (14), 123
(21), 89 (10).
HRMS: m/z [M]+ calcd for C8H5ClN2O: 180.0090; found:
180.0087.
1,6-Dichlorophthalazine (1)19
DIPEA (7.44 mL, 45 mmol, 1 equiv) was added dropwise to a soln
of phthalazinol 5 (8.13 g, 45 mmol, 1 equiv) in POCl3 (42 mL, 450
mmol, 10 equiv) at 25 °C. The mixture was stirred for 30 min, heat-
ed at 100 °C for 4 h, and then cooled to 25 °C. CHCl3 (175 mL) was
added and the mixture was cooled to 0 °C. The yellowish precipitat-
ed product was collected by filtration, washed successively with
cold CHCl3 (40 mL), deionized H2O (3 × 30 mL), and cold CHCl3
(10 mL), and then oven dried at 80 °C overnight affording 1 as a
pale yellow solid; yield: 7.30 g (81%); mp 147–148 °C; Rf = 0.65
(EtOAc–pentane, 1:1).
1H NMR (DMSO-d6): d = 9.65 (d, J = 0.8 Hz, 1 H), 8.42 (d, J = 2.2
Hz, 1 H), 8.27 (d, J = 9.0 Hz, 1 H), 8.16 (dd, J = 9.0 Hz, J = 2.2 Hz,
1 H).
13C NMR (DMSO-d6): d = 154.6, 151.6, 139.0, 135.4, 129.3, 127.4,
126.9, 124.1.
MS (70 eV): m/z (%) = 211 (11) [M]+, 141 (37), 139 (100), 127
(37), 114 (29), 111 (23), 97 (34), 83 (34).
HRMS: m/z [M]+ calcd for C11H14ClNO: 211.0764; found:
211.0759.
2-tert-Butyl-5-chloro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one
(4)8
A 3.0 M soln of MeLi in diethoxymethane (80.7 mL, 242 mmol,
2.05 equiv) was added dropwise over 45 min at –45 °C to a cooled
soln of benzamide 3 (25 g, 118 mmol, 1 equiv) in anhyd THF (200
mL) under argon, keeping the temperature below –30 °C. The mix-
ture was allowed to warm to –10 °C, stirred at this temperature for
3 h, and cooled down to –30 °C. Anhyd DMF (18.3 mL, 236 mmol,
2 equiv) was added dropwise over 15 min, keeping the temperature
below –20 °C. The mixture was allowed to warm to –10 °C over 30
min and sat. aq NH4Cl (100 mL) was slowly added, keeping internal
temperature below –10 °C. The mixture was allowed to warm to 25
°C over 45 min; the aqueous layer was removed and the organic lay-
er was concentrated to give an orange crude solid. Toluene (110
mL) was added and the mixture was heated to 110 °C for 1 h and
cooled slowly to 25 °C over 3 h. The white precipitated product was
collected by filtration, washed with toluene (200 mL), and oven
dried at 60 °C overnight affording 4 as a white solid; yield: 25 g
(88%); Rf = 0.6 (EtOAc–pentane, 1:4). The filtrate was concentrat-
ed and the starting material 3 (2.17 g, 9%) was recovered.
MS (70 eV): m/z (%) = 202 (10), 200 (66), 198 (100) [M]+, 172
(23), 170 (37), 135 (15), 99 (15).
HRMS: m/z [M]+ calcd for C8H4Cl2N2: 197.9752; found: 197.9741.
Preparation of tmpZnCl·LiCl (6)
A dry and argon-flushed 500-mL Schlenk flask, equipped with a
magnetic stirrer and a septum, was charged successively with fresh-
ly distilled tmpH (8.45 mL, 50 mmol, 1 equiv) and anhyd THF (60
mL). The soln was cooled to –50 °C and 2.36 M n-BuLi in hexane
(21.2 mL, 50 mmol, 1 equiv) was slowly added dropwise. The mix-
ture was then allowed to warm to 0 °C over 1 h prior to addition
dropwise of 1.0 M ZnCl2 in THF (50 mL, 50 mmol, 1 equiv). The
mixture was stirred at 25 °C for 1 h and the solvents were removed
under vacuum affording a yellowish solid. Freshly distilled THF
was slowly added under vigorous stirring until the salts were com-
pletely dissolved. The freshly prepared tmpZnCl·LiCl (6) was titrat-
ed prior to use at 25 °C with benzoic acid using 4-(phenyl-
azo)diphenylamine as indicator. A concentration of 0.72 M in THF
was obtained.
1H NMR (DMSO-d6): d = 7.53–7.56 (m, 3 H), 6.40 (d, J = 10.0 Hz,
1 H), 6.00 (d, J = 10.0 Hz, 1 H), 1.50 (s, 9 H).
13C NMR (DMSO-d6): d = 166.3, 147.3, 136.8, 131.7, 129.8, 124.1,
123.8, 81.3, 54.3, 28.4 (3 C).
MS (70 eV): m/z (%) = 239 (4), [M]+, 224 (57), 169 (40), 167 (100),
139 (12).
4-Chlorophthalonitrile (7)20
To a soln of dichlorophthalazine 1 (199 mg, 1.0 mmol, 1 equiv) in
anhyd THF (1 mL) was added dropwise 0.72 M tmpZnCl·LiCl (6)
in THF (1.54 mL, 1.1 mmol, 1.1 equiv) at 25 °C over 1 min. The
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1102
F. Crestey, P. Knochel
PAPER
mixture was stirred for 1 min then quenched with sat. aq NH4Cl (20
mL) and extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The crude material was purified by column chromatography
(pentane–EtOAc, 1:1) to furnish 7 as a white solid; yield: 160 mg
(98%).
sat. aq NH4Cl soln), the mixture was quenched with sat. aq NH4Cl.
The aqueous layer was extracted with EtOAc (2 ×) and the com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude material was purified by column
chromatography.
4-(6-Chloro-4-iodophthalazin-1-yl)morpholine (10a)
1H NMR (CDCl3): d = 7.72–7.65 (m, 3 H).
To a soln of chlorophthalazine 9 (250 mg, 1.0 mmol, 1 equiv) in an-
hyd THF (1 mL) was added dropwise 0.72 M tmpZnCl·LiCl (6) in
THF (1.54 mL, 1.1 mmol, 1.1 equiv) at 25 °C over 1 min. The mix-
ture was heated under microwave irradiation for 45 min at 60 °C ac-
cording to general procedure 1. A soln of I2 (355 mg, 1.4 mmol, 1.4
equiv) in anhyd THF (0.5 mL) was then added dropwise at 55 °C
and the resulting mixture was stirred at this temperature for 30 min.
The mixture was quenched with sat. aq NH4Cl (10 mL) and sat. aq
Na2S2O3 (10 mL) and extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude material was purified by column
chromatography (gradient elution, pentane–EtOAc, 1:1 to 1:2) to
furnish 10a as a pale orange solid; yield: 273 mg (71%); mp 183–
184 °C (dec); Rf = 0.55 (pentane–EtOAc, 1:1).
1H NMR (CDCl3): d = 8.02 (d, J = 2.2 Hz, 1 H), 7.91 (d, J = 8.6 Hz,
1 H), 7.78 (dd, J = 8.8 Hz, J = 2.0 Hz, 1 H), 3.90–4.00 (m, 4 H),
3.47–3.55 (m, 4 H).
13C NMR (CDCl3): d = 159.9, 139.3, 133.2, 132.7, 131.5, 126.7,
124.1, 120.2, 66.6 (2 C), 51.6 (2 C).
13C NMR (CDCl3): d = 140.2, 134.6, 133.8, 133.6, 117.4, 114.7,
114.2 (2 C).
6-Chloro-1-(4-methylphenyl)phthalazine (8)
A 0.67 M soln of 4-methylphenylzinc iodide·LiCl in THF (1.79 mL,
1.2 mmol, 1.2 equiv) was added to a soln of dichlorophthalazine 1
(199 mg, 1.0 mmol, 1 equiv) in anhyd THF (0.6 mL) and PEPPSI-
iPr (7 mg, 1 mol%) at 25 °C under argon. The mixture was stirred
at this temperature for 1 h, then heated to 45 °C for 12 h and
quenched with sat. aq NH4Cl (20 mL). The aqueous layer was ex-
tracted with EtOAc (2 × 20 mL) and the combined organic layers
were washed with brine, dried (Na2SO4), and concentrated in vacuo.
The crude material was purified by chromatography (pentane–
EtOAc, 1:1) to furnish 8 as a pale yellow solid; yield: 110 mg
(43%); mp 112–113 °C (dec); Rf = 0.45 (EtOAc–pentane, 2:3).
1H NMR (CDCl3): d = 9.42 (d, J = 0.2 Hz, 1 H), 8.03 (ddd, J = 10.0
Hz, J = 1.0 Hz, J = 0.6 Hz, 1 H), 7.96 (ddd, J = 2.2 Hz, J = 0.6 Hz,
J = 0.2 Hz, 1 H), 7.75 (dd, J = 9.0 Hz, J = 2.2 Hz 1 H), 7.57–7.65
(m, 2 H), 7.32–7.38 (m, 2 H), 2.44 (s, 3 H).
13C NMR (CDCl3): d = 159.5, 149.3, 139.8, 138.2, 133.4, 132.7,
129.9 (2 C), 129.4 (2 C), 128.4, 127.9, 125.5, 123.7, 40.7.
MS (70 eV): m/z (%) = 376 (17), 375 (24) [M]+, 374 (41), 318 (51),
317 (32), 248 (26), 192 (20), 165 (27), 164 (20), 163 (81), 162 (26),
86 (100).
HRMS: m/z [M]+ calcd for C12H11ClIN3O: 374.9635; found: 374.
9614.
MS (70 eV): m/z (%) = 254 (40) [M]+, 253 (53), 241 (29), 240 (25),
239 (100), 207 (33), 189 (20).
HRMS: m/z [M]+ calcd for C15H11ClN2: 254.0611; found: 254.0535.
4-[6-Chloro-4-(cyclohex-2-enyl)phthalazin-1-yl]morpholine
(10b)
4-(6-Chlorophthalazin-1-yl)morpholine (9)8
Morpholine (3.14 g, 36 mmol, 4 equiv) was added to a soln of
dichlorophthalazine 1 (1.79 g, 9 mmol, 1 equiv) in toluene (40 mL)
at 25 °C. The mixture was heated to 85 °C for 12 h then cooled to
25 °C. Toluene was removed in vacuo and the crude material was
taken up in EtOAc (50 mL) and washed successively with H2O (50
mL) and brine (50 mL). The organic layer was dried (Na2SO4), fil-
tered, and concentrated in vacuo. The residue was purified by col-
umn chromatography (EtOAc) to give 9 as a pale yellow solid;
yield: 2.13 g (95%); Rf = 0.25 (EtOAc).
1H NMR (CDCl3): d = 9.08 (d, J = 0.8 Hz, 1 H), 8.01 (d, J = 8.8 Hz,
1 H), 7.93 (dd, J = 2.2 Hz, J = 0.8 Hz, 1 H), 7.80 (dd, J = 8.8 Hz,
J = 2.2 Hz, 1 H), 3.88–4.01 (m, 4 H), 3.45–3.58 (m, 4 H).
13C NMR (CDCl3): d = 159.6, 147.0, 137.8, 132.4, 129.6, 126.1,
125.9, 119.6, 66.8 (2 C), 51.6 (2 C).
To a soln of chlorophthalazine 9 (250 mg, 1.00 mmol, 1 equiv) in
anhyd THF (1.00 mL) was added dropwise 0.72 M tmpZnCl·LiCl
(6) in THF (1.54 mL, 1.1 mmol, 1.1 equiv) at 25 °C over 1 min. The
mixture was heated under microwave irradiation for 45 min at 60 °C
according to general procedure 1. The mixture was cooled to –55 °C
and 1 M CuCN·2 LiCl in THF (5 mol%, 5 drops) was added. The
resulting mixture was stirred at this temperature for 10 min and then
3-bromocyclohexene (225 mg, 1.40 mmol, 1.4 equiv) was added
dropwise. The mixture was allowed to warm to 25 °C over 12 h then
quenched with sat. aq NH4Cl (20 mL) and extracted with EtOAc (2
× 20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The crude material was
purified by column chromatography (pentane–EtOAc, 1:2) to fur-
nish 10b as a yellow oil; yield: 196 mg (60%); Rf = 0.5 (pentane–
EtOAc, 1:2).
MS (70 eV): m/z (%) = 251 (11), 249 (33) [M]+, 194 (28), 192
(100), 191 (47), 164 (24), 137 (48), 86 (47).
HRMS: m/z [M]+ calcd for C12H12ClN3O: 249.0669; found:
249.0649.
1H NMR (CDCl3): d = 8.07 (d, J = 2.0 Hz, 1 H), 7.91 (d, J = 8.8 Hz,
1 H), 7.69 (dd, J = 8.8 Hz, J = 2.0 Hz, 1 H), 5.79–5.97 (m, 2 H),
4.10–4.24 (m, 1 H), 3.86–3.96 (m, 4 H), 3.39–3.46 (m, 4 H), 1.62–
2.21 (m, 6 H).
13C NMR (CDCl3): d = 159.0, 158.1, 137.4, 131.6, 128.7, 128.1,
127.9, 126.8, 124.0, 120.0, 66.8 (2 C), 51.7 (2 C), 39.3, 29.2, 24.9,
21.7.
MS (70 eV): m/z (%) = 330 (25), 329 (92) [M]+, 328 (29), 302 (36),
301 (28), 300 (100), 288 (22), 272 (39), 263 (36), 163 (22), 86 (40).
HRMS: m/z [M]+ calcd for C18H20ClN3O: 329.1295; found: 329.
1280.
Zincation of Phthalazine Derivatives with 6; General Procedure
1
To a dry and argon-flushed 5-mL sealed vessel, equipped with a
magnetic stirring bar and charged with the desired phthalazine (1
equiv), was successively added anhyd THF and the zinc reagent 6
(1.1 equiv) at 25 °C under argon. The mixture was heated at the giv-
en temperature under microwave irradiation. The completion of the
metalation was checked by GC analysis of reaction aliquots
quenched with a soln of I2 in anhyd THF. The electrophile or its soln
was added at the given temperature. When the reaction was com-
plete (checked by GC-analysis of reaction aliquots quenched with
Ethyl 4-(7-Chloro-4-morpholinophthalazin-1-yl)benzoate (10c)
To a soln of chlorophthalazine 9 (250 mg, 1.0 mmol, 1 equiv) in an-
hyd THF (1 mL) was added dropwise 0.72 M tmpZnCl·LiCl (6) in
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

PAPER
Regioselective Functionalization of Chlorophthalazine Derivatives
1103
THF (1.54 mL, 1.1 mmol, 1.1 equiv) at 25 °C over 1 min. The mix-
ture was heated under microwave irradiation for 45 min at 60 °C ac-
cording to general procedure 1. A pre-mixed soln of ethyl 4-
iodobenzoate (331 mg, 1.2 mmol, 1.2 equiv), (o-furyl)3P (9 mg, 4
mol%), and Pd(dba)2 (12 mg, 2 mol%) in anhyd THF (0.5 mL) un-
der argon was then added dropwise at 55 °C and the resulting mix-
ture was stirred at this temperature for 12 h. The mixture was
quenched with sat. aq NH4Cl (20 mL) and extracted with EtOAc (2
× 20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The crude material was
purified by column chromatography (pentane–EtOAc, 1:2) to fur-
nish 10c as a pale green solid; yield: 330 mg (83%); mp 221–223
°C; Rf = 0.5 (pentane–EtOAc, 1:2).
1H NMR (CDCl3): d = 8.24 (d, J = 10.0 Hz, 2 H), 8.07 (d, J = 10.0
Hz, 2 H), 7.92 (d, J = 2.0 Hz, 1 H), 7.75–7.83 (m, 2 H), 4.44 (d,
J = 8.0 Hz, 2 H), 3.95–4.05 (m, 4 H), 3.56–3.65 (m, 4 H), 1.44 (t,
J = 8.0 Hz, 3 H).
13C NMR (CDCl3): d = 166.2, 158.9, 154.6, 139.6, 138.4, 132.4,
131.3, 129.90 (2 C), 129.86 (2 C), 128.5, 126.7, 125.8, 119.9, 66.8
(2 C), 61.3, 51.6 (2 C), 14.4.
tion (pentane–EtOAc, 1:1) gave 10f as a pale greenish solid; yield:
285 mg (86%); mp 157–158 °C; Rf = 0.55 (pentane–EtOAc, 1:1).
1H NMR (CDCl3): d = 8.36 (d, J = 1.8 Hz, 1 H), 8.03 (d, J = 8.8 Hz,
1 H), 7.76 (dd, J = 8.8 Hz, J = 2.0 Hz, 1 H), 7.50–7.59 (m, 2 H),
7.18–7.28 (m, 1 H), 3.95–4.05 (m, 4 H), 3.56–3.65 (m, 4 H).
13C NMR (CDCl3): d = 158.6, 149.6, 138.7, 138.2, 132.0, 128.7,
128.5, 127.8, 127.6, 126.6, 125.4, 119.8, 66.8 (2 C), 51.6 (2 C).
MS (70 eV): m/z (%) = 332 (36), 331 (62) [M]+, 330 (59), 300 (19),
275 (40), 274 (100), 273 (76), 247 (25), 246 (24), 245 (26), 110
(27), 86 (58).
HRMS: m/z [M]+ calcd for C16H14ClN3OS: 331.0546; found:
331.0532.
[4-(7-Chloro-4-morpholinophthalazin-1-yl)phenyl](cyclohex-
yl)methanone (10g)
Following the procedure for 10c using cyclohexyl(4-iodophe-
nyl)methanone (377 mg, 1.2 mmol, 1.2 equiv) as electrophile with
chromatographic purification (pentane–EtOAc, 1:2) gave 10g as a
yellow oil; yield: 310 mg (72%); Rf = 0.5 (pentane–EtOAc, 1:2).
1H NMR (CDCl3): d = 8.07 (d, J = 8.4 Hz, 2 H), 8.03 (dd, J = 8.9
Hz, J = 0.4 Hz, 1 H), 7.88 (dd, J = 2.1 Hz, J = 0.4 Hz, 1 H), 7.76 (d,
J = 8.4 Hz, 2 H), 7.72 (dd, J = 8.9 Hz, J = 2.1 Hz, 1 H), 3.91–3.96
(m, 4 H), 3.53–3.57 (m, 4 H), 3.25–3.32 (m, 1 H), 1.87–1.93 (m, 2
H), 1.78–1.84 (m, 2 H), 1.67–1.73 (m, 1 H), 1.44–1.52 (m, 2 H),
1.33–1.42 (m, 2 H), 1.18–1.27 (m, 1 H).
13C NMR (CDCl3): d = 203.3, 159.0, 154.6, 140.0, 137.9, 136.7,
132.1, 130.0 (2 C), 128.5 (2 C), 128.2, 126.6, 125.5, 119.7, 66.7 (2
C), 51.5 (2 C), 45.8, 29.4 (2 C), 25.9, 25.8 (2 C).
MS (70 eV): m/z (%) = 398 (35), 397 (63) [M]+, 396 (63), 342 (36),
341 (44), 340 (100), 339 (71), 283 (20), 137 (10).
HRMS: m/z [M]+ calcd for C21H20ClN3O3: 397.1193; found:
397.1177.
4-(7-Chloro-4-morpholinophthalazin-1-yl)benzonitrile (10d)
Following the procedure for 10c using 4-iodobenzonitrile (275 mg,
1.2 mmol, 1.2 equiv) as electrophile with chromatographic purifica-
tion (pentane–EtOAc, 1:4) gave 10d as a pale yellow solid; yield:
258 mg (74%); mp 229–230 °C; Rf = 0.55 (pentane–EtOAc, 1:4).
MS (70 eV): m/z (%) = 436 (39), 435 (67) [M]+, 434 (76), 404 (30),
1H NMR (CDCl3): d = 8.08 (d, J = 8.6 Hz, 1 H), 7.76–7.88 (m, 6 H),
3.94–4.03 (m, 4 H), 3.56–3.65 (m, 4 H).
380 (36), 379 (52), 378 (100), 377 (75), 267 (40), 86 (68).
HRMS: m/z [M]+ calcd for C25H26ClN3O2: 435.1714; found:
13C NMR (CDCl3): d = 159.2, 153.6, 140.4, 138.3, 132.5 (2 C),
132.3, 130.5 (2 C), 128.0, 126.8, 125.1, 119.7, 118.4, 113.1, 66.8 (2
C), 51.6 (2 C).
435.1698.
4-[6-Chloro-4-(hex-1-ynyl)phthalazin-1-yl]morpholine (10h)
To a soln of generated in situ iodophthalazine 10a [starting from
phthalazine 9 (250 mg, 1.0 mmol, 1 equiv) and according to general
procedure 1] was successively added anhyd Et3N (5 mL), CuI (4
mol%, 8 mg), (o-furyl)3P (4 mol%, 9 mg), Pd(dba)2 (2 mol%, 12
mg), and hex-1-yne (119 mg, 1.4 mmol, 1.5 equiv) under argon. The
mixture was heated at 60 °C for 1 h, quenched with deionized H2O
(20 mL), and extracted with EtOAc (2 × 20 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The crude material was purified by column
chromatography (pentane–EtOAc, 1:1) to furnish 10h as a pale yel-
low solid; yield: 293 mg (89%); mp 130–132 °C; Rf = 0.4 (pentane–
EtOAc, 1:1).
MS (70 eV): m/z (%) = 351 (27), 350 (44) [M]+, 349 (59), 319 (28),
305 (22), 294 (46), 293 (100), 292 (71), 264 (28), 137 (26), 102
(26), 86 (56).
HRMS: m/z [M]+ calcd for C19H15ClN4O: 350.0934; found:
350.0899.
4-{6-Chloro-4-[3-(trifluoromethyl)phenyl]phthalazin-1-
yl}morpholine (10e)
Following the procedure for 10c using 1-iodo-3-(trifluorometh-
yl)benzene (326 mg, 1.2 mmol, 1.2 equiv) as electrophile with chro-
matographic purification (pentane–EtOAc, 1:1) gave 10e as a pale
greenish solid; yield: 330 mg (84%); mp 142–144 °C; Rf = 0.5 (pen-
tane–EtOAc, 1:1).
1H NMR (CDCl3): d = 8.19 (d, J = 2.2 Hz, 1 H), 7.93 (d, J = 8.2 Hz,
1 H), 7.72 (dd, J = 8.2 Hz, J = 2.2 Hz, 1 H), 3.90–3.97 (m, 4 H),
3.50–3.56 (m, 4 H), 2.59 (t, J = 7.5 Hz, 2 H), 1.71 (quint, J = 7.5 Hz,
2 H), 1.55 (sext, J = 7.5 Hz, 2 H), 0.97 (d, J = 7.5 Hz, 3 H).
1H NMR (CDCl3): d = 8.08 (d, J = 8.8 Hz, 1 H), 8.01–8.05 (br s, 1
H), 7.64–7.93 (m, 5 H), 3.95–4.04 (m, 4 H), 3.56–3.65 (m, 4 H).
13C NMR (CDCl3): d = 159.0, 151.4, 138.3, 136.6, 133.0, 132.3,
131.3 (q, J = 33.2 Hz), 129.1, 128.3, 126.74 (q, J = 3.0 Hz), 126.69,
126.0 (q, J = 3.0 Hz), 125.4, 123.9 (q, J = 271.3 Hz), 119.2, 66.7 (2
C), 51.6 (2 C).
MS (70 eV): m/z (%) = 394 (27), 393 (48) [M]+, 392 (62), 362 (29),
338 (34), 337 (44), 336 (100), 335 (67), 309 (19), 307 (24), 172
(14), 145 (23), 137 (30), 86 (62).
13C NMR (CDCl3): d = 158.0, 142.3, 137.9, 132.2, 130.3, 126.1,
125.7, 118.6, 98.6, 75.5, 66.7 (2 C), 51.6 (2 C), 30.4, 22.1, 19.4,
13.6.
MS (70 eV): m/z (%) = 330 (32), 329 (60) [M]+, 328 (67), 300 (29),
298 (32), 273 (42), 272 (100), 271 (76), 86 (56).
HRMS: m/z [M]+ calcd for C18H20ClN3O: 329.1295; found: 329.
1284.
HRMS: m/z [M]+ calcd for C19H15ClF3N3O: 393.0856; found:
393.0844.
Preparation of Functionalized Aryl, Alkyl, Benzylic, and Het-
eroarylzinc Reagents Using Mg/LiCl/ZnCl2; General Proce-
dure 2
A dry and argon-flushed 10-mL Schlenk flask, equipped with a
magnetic stirrer and a septum, was charged with LiCl (2.5 equiv)
4-[6-Chloro-4-(thiophen-2-yl)phthalazin-1-yl]morpholine (10f)
Following the procedure for 10c using 2-iodothiophene (252 mg,
1.2 mmol, 1.2 equiv) as electrophile with chromatographic purifica-
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

1104
F. Crestey, P. Knochel
PAPER
and heated with a heat gun for 3 min under high vacuum. After cool-
ing to 25 °C, ZnCl2 (1 equiv) in anhyd THF and Mg turnings (2.5
equiv) were successively added and the mixture was stirred for 5
min. The desired halide reagent (1 equiv) was added at the given
temperature and the mixture was stirred at this temperature. The
completion of the insertion was checked by GC analysis of reaction
aliquots quenched with a soln of I2 in anhyd THF. Then the super-
natant soln was cannulated to a new dry Schlenk flask and titrated
prior to use at 25 °C with a soln of I2 in anhyd THF.21
(CH2Cl2–MeOH, 30:1) to furnish 11b as a yellow solid; yield: 158
mg (79%); mp 188–190 °C; Rf = 0.2 (EtOAc).
1H NMR (CDCl3): d = 9.13 (s, 1 H), 7.90–8.00 (m, 3 H), 7.58 (d,
J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 3.92–3.99 (m, 4 H),
3.49–3.56 (m, 4 H), 2.99 (s, 6 H).
13C NMR (CDCl3): d = 159.8, 150.8, 148.5, 144.4, 130.2, 129.4,
128.0 (2 C), 126.2, 124.4, 122.3, 119.3, 112.6 (2 C), 66.9 (2 C), 51.6
(2 C), 40.3 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C20H23N4O: 335.1872; found:
Negishi Cross-Coupling Reactions; General Procedure 3
In a Schlenk flask zinc reagent (1.4 equiv) obtained according to
general procedure 2 was slowly added to a soln of desired phthala-
zine derivative (1 equiv) in anhyd THF at 25 °C under argon. The
mixture was stirred for 5 min prior to addition of PEPPSI-iPr (0.75
mol%) and stirred at the given temperature (Table 2). When the re-
action was complete (GC analysis of reaction aliquots quenched
with sat. aq NH4Cl), the mixture was quenched with sat. aq NH4Cl.
The aqueous layer was extracted with EtOAc (2 ×) and the com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude material was purified by column
chromatography.
335.1865.
Ethyl 4-(1-Morpholinophthalazin-6-yl)benzoate (11c)
Following general procedure 2, LiCl (212 mg, 5 mmol), 1.0 M
ZnCl2 in THF (2 mL, 2 mmol), Mg turnings (122 mg, 5 mmol), and
ethyl 4-bromobenzoate (458 mg, 2 mmol) were successively added
to a Schlenk flask under argon at 0 °C and the mixture was allowed
to warm to 25 °C and stir for 2 h at this temperature. Then following
general procedure 3, the freshly obtained zinc reagent (0.99 M in
THF, 0.85 mL, 0.84 mmol, 1.4 equiv) was added to a soln of chlo-
rophthalazine 9 (150 mg, 0.60 mmol, 1 equiv) in anhyd THF (0.6
mL) at 25 °C under argon. The mixture was stirred for 5 min,
PEPPSI-iPr (4 mg, 0.75 mol%) was added, stirring was continued
at this temperature for 10 min, and the reaction was quenched with
sat. aq NH4Cl (20 mL). The aqueous layer was extracted with
EtOAc (2 × 20 mL) and the combined organic layers were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The crude
material was purified by column chromatography (CH2Cl2–MeOH,
30:1) to furnish 11c as a pale yellow solid; yield: 185 mg (85%); mp
169–171 °C; Rf = 0.2 (EtOAc).
4-(6-Phenylphthalazin-1-yl)morpholine (11a)
A dry and argon-flushed 5-mL Schlenk flask, equipped with a mag-
netic stirrer and a septum, was charged with LiCl (36 mg, 0.84
mmol, 1.4 equiv) and heated with a heat gun for 3 min under high
vacuum. The mixture was cooled to 25 °C, 1.0 M ZnCl2 in THF
(0.84 mL, 0.84 mmol, 1.4 equiv) and 1.73 M PhMgCl in THF (0.49
mL, 0.84 mmol, 1.4 equiv) were successively added, and the mix-
ture was stirred for 10 min and then slowly added to a soln of chlo-
rophthalazine 9 (150 mg, 0.60 mmol, 1 equiv) in anhyd THF (0.6
mL) at 25 °C under argon. The mixture was stirred at 25 °C for 5
min, PEPPSI-iPr (4 mg, 0.75 mol%) was added, stirring was contin-
ued at this temperature for 30 min, and the reaction was quenched
with sat. aq NH4Cl (20 mL) and extracted with EtOAc (2 × 20 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The crude material was puri-
fied by column chromatography (EtOAc) to furnish 11a as a white
solid; yield: 166 mg (95%); mp 165–166 °C; Rf = 0.45 (EtOAc).
1H NMR (CDCl3): d = 9.20 (s, 1 H), 8.05–8.16 (m, 3 H), 7.71 (d,
J = 8.6 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 4.36 (q, J = 7.0 Hz, 2 H),
3.90–3.97 (m, 4 H), 3.49–3.56 (m, 4 H), 1.37 (t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): d = 166.0, 159.7, 148.2, 143.21, 143.17, 130.8,
130.5, 130.3 (2 C), 129.0, 127.3 (2 C), 125.0, 124.9, 120.5, 66.8 (2
C), 61.2, 51.5 (2 C), 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C21H22N3O3: 364.1661; found:
364.1654.
1H NMR (CDCl3): d = 9.24 (s, 1 H), 8.03–8.14 (m, 3 H), 7.66–7.73
4-[6-(3-Methoxybenzyl)phthalazin-1-yl]morpholine (11d)
Following general procedure 2, LiCl (212 mg, 5 mmol), 1.0 M
ZnCl2 in THF (2 mL, 2 mmol), Mg turnings (122 mg, 5 mmol), and
3-methoxybenzyl chloride (313 mg, 2.0 mmol) were successively
added to a Schlenk flask under argon at 25 °C and the mixture was
stirred for 2 h at 25 °C. Then following general procedure 3, the
freshly obtained zinc reagent (0.78 M in THF, 1.08 mL, 0.84 mmol,
1.4 equiv) was added to a soln of chlorophthalazine 9 (150 mg, 0.60
mmol, 1 equiv) in anhyd THF (0.6 mL) at 25 °C under argon. The
mixture was stirred for 5 min, PEPPSI-iPr (4 mg, 0.75 mol%) was
added, stirring was continued at 50 °C for 4 h, and the reaction was
quenched with sat. aq NH4Cl (20 mL). The aqueous layer was ex-
tracted with EtOAc (2 × 20 mL) and the combined organic layers
were washed with brine, dried (Na2SO4), and concentrated in vacuo.
The crude material was purified by column chromatography
(EtOAc) to furnish 11d as a yellow solid; yield: 190 mg (94%); mp
102–103 °C; Rf = 0.45 (EtOAc).
1H NMR (CDCl3): d = 9.11 (d, J = 0.6 Hz, 1 H), 7.95 (dd, J = 9.0
Hz, J = 0.6 Hz, 1 H), 7.62–7.69 (m, 2 H), 7.20–7.29 (m, 1 H), 6.72–
6.82 (m, 3 H), 4.16 (s, 2 H), 3.93–3.99 (m, 4 H), 3.77 (s, 3 H), 3.50–
3.56 (m, 4 H).
13C NMR (CDCl3): d = 160.0, 159.8, 148.1, 145.3, 140.9, 133.0,
129.8, 129.0, 126.0, 124.3, 121.4, 120.0, 115.1, 111.7, 66.9 (2 C),
55.2, 51.6 (2 C), 42.0.
(m, 2 H), 7.41–7.58 (m, 3 H), 3.97–4.03 (m, 4 H), 3.56–3.62 (m, 4
H).
13C NMR (CDCl3): d = 159.8, 148.3, 144.6, 139.2, 131.0, 129.24 (2
C), 129.20, 128.7, 127.4 (2 C), 124.7, 124.5, 120.3, 66.9 (2 C), 51.6
(2 C).
MS (70 eV): m/z (%) = 291 (59) [M]+, 290 (59), 260 (35), 246 (25),
234 (100), 233 (58), 206 (26), 205 (22), 179 (49), 86 (20).
HRMS: m/z [M]+ calcd for C18H17N3O: 291.1372; found: 291.1366.
N,N-Dimethyl-4-(1-morpholinophthalazin-6-yl)aniline (11b)
A dry and argon-flushed 5-mL Schlenk flask, equipped with a mag-
netic stirrer and a septum, was charged successively with 1.0 M
ZnCl2 in THF (0.84 mL, 0.84 mmol, 1.4 equiv) and 0.98 M 4-(di-
methylamino)phenylmagnesium bromide·LiCl in THF (0.86 mL,
0.84 mmol, 1.4 equiv); the mixture was stirred for 10 min then slow-
ly added to a soln of chlorophthalazine 9 (150 mg, 0.60 mmol, 1
equiv) in anhyd THF (0.6 mL) at 25 °C under argon. The mixture
was stirred at 25 °C for 5 min, PEPPSI-iPr (4 mg, 0.75 mol%) was
added, stirring was continued at this temperature for 10 min, and the
reaction was quenched with sat. aq NH4Cl (5 mL). The pH value
was adjusted to pH 10 by addition of aq 1 M NaOH and the aqueous
layer was extracted with EtOAc (2 × 30 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The crude material was purified by column chromatography
MS (70 eV): m/z (%) = 335 (75) [M]+, 334 (61), 304 (32), 290 (20),
279 (21), 278 (100), 277 (57), 250 (13), 249 (25), 86 (33).
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

PAPER
Regioselective Functionalization of Chlorophthalazine Derivatives
1105
HRMS: m/z [M]+ calcd for C20H21N3O2: 335.1634; found:
4-[7-(3-Methoxybenzyl)-4-morpholinophthalazin-1-yl]benzoni-
335.1624.
trile (12a)
Following general procedure 2, LiCl (212 mg, 5 mmol), 1.0 M
ZnCl2 in THF (2 mL, 2.0 mmol), Mg turnings (122 mg, 5 mmol, 2.5
equiv), and 3-methoxybenzyl chloride (313 mg, 2 mmol) were suc-
cessively added to a Schlenk flask under argon at 25 °C and the mix-
ture was stirred for 2 h at 25 °C. Then following general procedure
3, the freshly obtained zinc reagent (0.78 M in THF, 1.08 mL, 0.84
mmol, 1.4 equiv) was added to a soln of chlorophthalazine 10d (210
mg, 0.60 mmol, 1 equiv) in anhyd THF (1.2 mL) at 25 °C under ar-
gon. The mixture was stirred for 5 min, PEPPSI-iPr (4 mg, 0.75
mol%) was added, stirring was continued at 50 °C for 3 h, and the
reaction was quenched with sat. aq NH4Cl (20 mL). The aqueous
layer was extracted with EtOAc (2 × 20 mL) and the combined or-
ganic layers were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The crude material was purified by column
chromatography (EtOAc) to furnish 12a as a white solid; yield: 254
mg (97%); mp 168–170 °C; Rf = 0.55 (EtOAc).
1H NMR (CDCl3): d = 8.04 (d, J = 9.0 Hz, 1 H), 7.77–7.84 (m, 4 H),
7.67–7.70 (m, 2 H), 7.21 (t, J = 8.4 Hz, 1 H), 6.77 (dd, J = 8.4 Hz,
J = 2.3 Hz, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.66–6.68 (m, 1 H), 4.10
(s, 2 H), 3.93–3.98 (m, 4 H), 3.75 (s, 3 H), 3.56–3.62 (m, 4 H).
13C NMR (CDCl3): d = 159.9, 159.4, 154.4, 145.6, 141.1, 140.8,
132.8, 132.2 (2 C), 130.6 (2 C), 129.8, 127.2, 125.13, 125.05, 121.3,
120.0, 118.6, 115.2, 112.6, 111.5, 66.8 (2 C), 55.2, 51.5 (2 C), 42.1.
4-(1-Morpholinophthalazin-6-yl)butanenitrile (11e)
Following general procedure 2, LiCl (424 mg, 10 mmol), 1.0 M
ZnCl2 in THF (4 mL, 4 mmol), Mg turnings (244 mg, 10 mmol), and
4-bromobutyronitrile (592 mg, 4 mmol) were successively added to
a Schlenk flask under argon at 25 °C and the mixture was stirred for
4 h at this temperature. Then following general procedure 3, the
freshly obtained zinc reagent (0.49 M in THF, 1.71 mL, 0.84 mmol,
1.4 equiv) was added to a soln of chlorophthalazine 9 (150 mg, 0.60
mmol, 1 equiv) in anhyd THF (0.6 mL) at 25 °C under argon. The
mixture was stirred for 5 min, PEPPSI-iPr (4 mg, 0.75 mol%) was
added, stirring was continued at 60 °C for 8 h, and the reaction was
quenched with sat. aq NH4Cl (20 mL). The aqueous layer was ex-
tracted with EtOAc (2 × 20 mL) and the combined organic layers
were washed with brine, dried (Na2SO4), and concentrated in vacuo.
The crude material was purified by column chromatography (gradi-
ent elution, CH2Cl2–MeOH, 30:1 to 20:1) to furnish 11e as a pale
yellow solid; yield: 130 mg (77%); mp 124–126 °C; Rf = 0.45
(CH2Cl2–MeOH, 20:1).
1H NMR (CDCl3): d = 9.14 (s, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.70
(d, J = 1.8 Hz, 1 H), 7.67 (dd, J = 8.6 Hz, J = 1.8 Hz, 1 H), 3.93–
3.99 (m, 4 H), 3.50–3.57 (m, 4 H), 3.01 (t, J = 7.8 Hz, 2 H), 2.39 (t,
J = 7.8 Hz, 2 H), 2.08 (quint, J = 7.8 Hz, 2 H).
13C NMR (CDCl3): d = 159.7, 147.8, 144.1, 132.5, 129.0, 125.9,
124.7, 120.2, 119.0, 66.9 (2 C), 51.6 (2 C), 34.5, 26.4, 16.6.
HRMS (ESI): m/z [M + H]+ calcd for C27H25N4O2: 437.1978; found:
437.1969.
MS (70 eV): m/z (%) = 282 (37) [M]+, 281 (48), 251 (34), 225
(100), 224 (49), 169 (24), 116 (26), 86 (68).
HRMS: m/z [M]+ calcd for C16H18N4O: 282.1481; found: 282.1470.
4-[6-(Pyridin-3-yl)-4-(thiophen-2-yl)phthalazin-1-yl]morpho-
line (12b)
Following general procedure 2, LiCl (212 mg, 5 mmol), 1.0 M
ZnCl2 in THF (2 mL, 2 mmol), Mg turnings (122 mg, 5 mmol, 2.5
equiv), and 3-bromopyridine (313 mg, 2 mmol) were successively
added to a Schlenk flask under argon at 25 °C and the mixture was
stirred for 1 h at 0 °C. Then following general procedure 3, the
freshly obtained zinc reagent (0.89 M in THF, 0.95 mL, 0.84 mmol,
1.4 equiv) was added to a soln of chlorophthalazine 10f (199 mg,
0.60 mmol, 1 equiv) in anhyd THF (1.2 mL) at 25 °C under argon.
The mixture was stirred for 5 min, PEPPSI-iPr (4 mg, 0.75 mol%)
was added, stirring was continued at 50 °C for 5 min, and the reac-
tion was quenched with sat. aq NH4Cl (5 mL). The pH value was ad-
justed to pH 2 by the addition of 1 M HCl and the aqueous layer was
extracted with EtOAc (2 × 30 mL). The combined organic layers
were discarded then the pH value was adjusted to pH 10 by the ad-
dition of aq 1 M NaOH and the aqueous layer was extracted with
EtOAc (2 × 40 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The crude mate-
rial was purified by column chromatography (CH2Cl2) to furnish
12b as a pale yellow solid; yield: 254 mg (97%); mp 218–219 °C;
Rf = 0.35 (CH2Cl2).
1H NMR (CDCl3): d = 8.99 (d, J = 1.2 Hz, 1 H), 8.74 (dd, J = 3.2
Hz, J = 1.0 Hz, 1 H), 8.65 (d, J = 1.2 Hz, 1 H), 8.26 (d, J = 7.0 Hz,
1 H), 8.05–8.14 (m, 2 H), 7.68 (dd, J = 2.6 Hz, J = 0.8 Hz, 1 H),
7.52–7.61 (m, 2 H), 7.25–7.29 (m, 1 H), 4.01–4.07 (m, 4 H), 3.64–
3.69 (m, 4 H).
13C NMR (CDCl3): d = 158.7, 150.4, 148.8, 147.6, 141.0, 138.7,
135.7, 135.5, 130.2, 128.9, 128.6, 127.8, 127.4, 126.0, 124.7, 124.3,
121.0, 66.8 (2 C), 51.6 (2 C).
Ethyl 6-(1-Morpholinophthalazin-6-yl)hexanoate (11f)
Following general procedure 2, LiCl (424 mg, 10 mmol), 1.0 M
ZnCl2 in THF (4 mL, 4 mmol), Mg turnings (244 mg, 10 mmol), and
ethyl 6-bromohexanoate (892 mg, 4 mmol) were successively add-
ed to a Schlenk flask under argon at 25 °C and the mixture was
stirred for 4 h at this temperature. Then following general procedure
3, the freshly obtained zinc reagent (0.39 M in THF, 2.15 mL, 0.84
mmol, 1.4 equiv) was added to a soln of chlorophthalazine 9 (150
mg, 0.60 mmol, 1 equiv) in anhyd THF (0.6 mL) at 25 °C under ar-
gon. The mixture was stirred for 5 min, PEPPSI-iPr (4 mg, 0.75
mol%) as added, stirring was continued at 60 °C for 30 min, and the
reaction was quenched with sat. aq NH4Cl (20 mL). The aqueous
layer was extracted with EtOAc (2 × 20 mL) and the combined or-
ganic layers were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The crude material was purified by column
chromatography (gradient elution, CH2Cl2–MeOH, 30:1 to 20:1) to
furnish 11f as a pale yellow oil; yield: 165 mg (77%); Rf = 0.5
(CH2Cl2–MeOH, 20:1).
1H NMR (CDCl3): d = 9.09 (s, 1 H), 7.92 (d, J = 9.0 Hz, 1 H), 7.61–
7.64 (m, 2 H), 4.07 (q, J = 7.2 Hz, 2 H), 3.90–3.96 (m, 4 H), 3.47–
3.53 (m, 4 H), 2.80 (t, J = 7.5 Hz, 2 H), 2.26 (t, J = 7.5 Hz, 2 H),
1.70 (quint, J = 7.5 Hz, 2 H), 1.64 (quint, J = 7.5 Hz, 2 H), 1.37
(quint, J = 7.5 Hz, 2 H), 1.19 (t, J = 7.0 Hz, 3 H).
13C NMR (CDCl3): d = 173.5, 159.8, 148.0, 146.8, 132.8, 128.9,
125.4, 124.0, 119.8, 66.9 (2 C), 60.2, 51.5 (2 C), 35.8, 34.1, 30.6,
28.6, 24.6, 14.2.
MS (70 eV): m/z (%) = 358 (19), 357 (62) [M]+, 356 (76), 326 (44),
312 (58), 300 (100), 299 (64), 272 (15), 171 (20), 157 (36), 86 (48).
HRMS: m/z [M]+ calcd for C20H27N3O3: 357.2052; found:
HRMS (ESI): m/z [M + H]+ calcd for C21H19N4OS: 375.1280;
found: 375.1272.
357.2036.
Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York

1106
F. Crestey, P. Knochel
PAPER
Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, Chap.
15. (c) Casares, J. A.; Espinet, P.; Fuentes, B.; Salas, G.
J. Am. Chem. Soc. 2007, 129, 3508.
Acknowledgment
We thank the European Research Council (ERC) for financial sup-
port. We thank Chemetall GmbH (Frankfurt), Evonik AG (Hanau),
W. C. Heraeus GmbH (Hanau), and BASF AG (Ludwigshafen) for
the generous gift of chemicals.
(12) For a comprehensive report on the preparation of zinc
organometallics, see: (a) Knochel, P.; Millot, N.; Rodriguez,
A.; Tucker, C. E. Org. React. 2001, 58, 417. (b) Knochel,
P.; Dohle, W.; Gommermann, N.; Kneisel, F.; Kopp, F.;
Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed.
2003, 42, 4302. (c) Knochel, P.; Calaza, M. I.; Hupe, E.
Carbon-Carbon Bond-Forming Reactions Mediated by
Organozinc Reagents, In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: New York, 2004. (d) Krasovskiy, A.;
Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(e) Handbook of Functionalized Organometallics; Knochel,
P., Ed.; Wiley-VCH: New York, 2005. (f) Knochel, P.;
Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F.
Functionalized Organozinc Compounds, In Chemistry of
Organozinc Compounds, Part 1; Rappoport, Z.; Marek, I.,
Eds.; Wiley-VCH: Chichester, 2006. (g) Krasovskiy, A.;
Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem.
Int. Ed. 2006, 45, 6040.
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Synthesis 2010, No. 7, 1097–1106 © Thieme Stuttgart · New York