Convenient method for the synthesis of phthalazinones via carbonylation of 2-bromobenzaldehyde using Co2(CO)8 as a CO source

Article abstract of DOI:10.1016/j.tetlet.2014.04.082

A simple one-pot synthesis of phthalazinones by the condensation and intra-molecular carbonylative cyclization of 2-bromobenzaldehydes with hydrazines is reported. This method utilizes solid Co₂(CO) ₈ as carbonyl source making it rea

Full text of DOI:10.1016/j.tetlet.2014.04.082

Accepted Manuscript
Convenient method for the synthesis of phthalazinones via carbonylation of 2-
bromobenzaldehyde using Co2(CO)8 as a CO source
A.S. Suresh, P. Baburajan, Mansur Ahmed
PII:
S0040-4039(14)00707-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.082
TETL 44544
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 March 2014
23 April 2014
23 April 2014
Please cite this article as: Suresh, A.S., Baburajan, P., Ahmed, M., Convenient method for the synthesis of
phthalazinones via carbonylation of 2-bromobenzaldehyde using Co2(CO)8 as a CO source, Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.082
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1
Convenient method for the synthesis of phthalazinones via carbonylation of
2-bromobenzaldehyde using Co2(CO)8 as a CO source
A. S. Suresh,a,b P. Baburajan,b* Mansur Ahmeda
a Research Department of Chemistry, Islamiah College, Vaniyambadi, , India, 635752
b Syngene International Limited, Bangalore, India, 560099.
ABSTRACT
A simple one-pot synthesis of phthalazinones by the condensation and intra-molecular
carbonylative cyclization of 2-bromobenzaldehydes with hydrazines is reported. This method
utilizes solid Co2(CO)8 as carbonyl source making it readily accessible in small-scale
laboratory applications.
Keywords: Phthalazinone, palladium, carbonylation, aryl halides, Co2(CO)8, hydrazines
Phthalazinones are biologically active compounds and have widespread use in the
treatment of asthma, diabetes, hepatitis B, arrhythmia, vascular hypertension and
cardiovascular diseases.1 Some of the phthalazinone derivatives are evaluated for the
inhibitory activities to the five different forms of PDEs isolated from guinea pig cardiac
ventricle (PDE1, 2 and 3) and lung (PDE4 and 5) in vitro.2 Due to their diverse biological
activities, significant effort has been devoted towards the development of mild and general
synthetic methodologies for their preparation. More specifically, methods including
cyclocondensation reaction, cyclo-additions, reduction by ultrathin Pt nanowires and
biotechnological approaches3 have been developed for its synthesis. Recently, Xiao-Feng Wu
et al. has reported a direct methodology for the carbonylative synthesis of phthalazinones by
using commercially available starting materials like 2-bromobenzaldehydes and hydrazines
using CO (g) in autoclave.4 But the reaction involves initial evacuation of the toxic CO(g) and
high pressure of CO gas (10 bar). Although the methodology is useful on an industrial scale,

2
the toxicity and flammability of carbon monoxide make it inconvenient to use in a laboratory
scale synthesis. Mats Larhed et al. have demonstrated that metal carbonyl can be used as the
alternate CO source for the carbonylation reactions.5 Using this strategy, phthalazinones have
also been synthesised from o-bromoarylaldehydes and hydrazines using Mo(CO)6 as an
alternative to the toxic CO (g) in moderate yields. But the reaction needed high temperature
(140°C) and higher equivalence of CO source (2.5 mmol of Mo(CO)6 required for 1 mmol of
aryl halide).6
Based on our previous work on the palladium-catalyzed carbonylation of aryl halides
to esters and amides,7 we became interested in the synthesis of valuable phthalazinone
derivatives by using Co2(CO)8 as an effective alternate metal carbonyl source. Herein, we
report a general carbonylation method using Co2(CO)8 as CO source for the synthesis of
phthalazinones by reacting 2-bromobenzaldehyde and 2-bromobenzophenones with a variety
of hydrazine hydrochlorides in classical heating as well microwave irradiation conditions.
Guided by the literature and our own results, we began our study of the carbonylation
reaction between 2-bromobenzaldehyde 1 and 4-methoxyphenyl hydrazine hydrochloride 2
as the model reaction for optimizing the reaction conditions. In the presence of 5 mol %
Pd(OAc)2, 6 mol % of xantphos, Co2(CO)8 and TEA as base in 1,4-dioxane at 120 °C for 8 h,
phthalazinone 3 was obtained in 10% isolated yield (Entry 1). Among the different bases
studied (Entries 2-6), the isolated yield improved to 42% (Entry 4) when DBU was used as
the base. Increase in the reaction temperature to 130 °C and 140 °C (Entries 8 and 7)
decreased the yield of 3 indicating that temperature plays an important role in the reaction.
The isolated yield of 3 increased at lower reaction temperatures (Entry 9 and 10). Further
reduction of the reaction temperature to 80 °C gave lower yield of 3 (Entry 11). To improve
the yield further, the reactions were performed in different solvents like THF, toluene,

3
DMSO, DMF, NMP (data not shown in the Table 1) and it was found that DMF afforded 3 in
good yield (Entry 12). During the above optimization reactions, we observed the formation of
the corresponding acid derivative (2-[(4-methoxy-phenyl)-hydrazonomethyl]-benzoic acid) in
lower percentages. This may be formed by the attack of the water molecule present in the
reaction mixture (from imine formation).
TABLE-1: Optimization of reaction conditions for the synthesis of 2-(4-methoxy-phenyl)-
2H-phthalazin-1-one.
O
HCl
H2N
O
O
N
H
2
Br
O
N
N
Co2(CO)8, Pd(OAc)2/L
base, Solvent, 90 °C
H
3
1
Entry
Ligand a
Baseb
Solvents
Temp
Additivec
Yieldd
1
2
3
Xantphos
Xantphos
Xantphos
TEA
Dioxane
Dioxane
Dioxane
120
120
120
-
-
-
10
7
DIPEA
DMAP
19
4
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
BINAP
DPPB
DBU
Pyridine
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
120
120
120
140
130
110
90
-
-
-
-
-
42
20
14
21
28
45
57
49
66
55
41
74
26
60
44
81
85e
80f
49g
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
-
80
-
90
-
DMF
90
MgSO4
Na2SO4
M.sieves
M.sieves
M.sieves
M.sieves
M.sieves
M.sieves
M.sieves
M.sieves
DMF
90
DMF
90
DMF
90
DMF
90
TPP
DMF
90
dppf
DMF
90
dppf
DMF
90
dppf
DMF
90
dppf
DMF
90
All the reactions were executed with 1 mmol of 2-bromobenzaldehyde 1, 1.5 mmol of (4-methoxy-
phenyl)-hydrazine hydrochloride 2, 5 mol % of Pd(OAc)2, 6 mol % of ligand, base and 0.3 mmol of Co2(CO)8 in
DMF were heated in a seal tube for 8 h. M.sieves = Molecular sieves, a 6 mol % of ligands were used, b 2.5 eq of
c
d
corresponding bases were used, additives were used by w/w of the aryl halide used in the reaction, the

4
e
isolated yields by column chromatography, the reaction were performed at 90 °C for 3 h, the reaction were
f
performed in M/W condition at 90 °C for 30 min, g The reaction performed using Mo(CO)6 as an CO source.
So, we evaluated the effect of dehydrating agents such as MgSO4, Na2SO4 and molecular
sieves in the reaction (Entry 13-15). To our delight, addition of molecular sieves significantly
increased the desired phthalazinone yield as the unwanted acid derivative was not formed
(Entry 15). Encouraged by the above results, we explored the scope of increasing the yield of
the aminocarbonylation reaction by changing the ligand used. On the basis of our success
using xantphos, we examined a number of other bidentate ligands as well. Advantageously,
excellent yield was isolated when dppf was used as ligand (Entry 19). Moreover, the reaction
was complete even at 3 h at 90 °C with an increase in the isolated yield (Entry 20). Using the
optimized condition we then carried out the reaction under microwave irradiation. The
conversion of reactants was complete after 30 min at 90 °C (entry 21) and 3 was isolated with
80% yield. With an aim to examine the effectiveness of CO source used in this study, the
reaction was also carried out using Mo(CO)6 as an alternate metal carbonyl source using the
optimized reaction conditions and 3 was isolated in lower yield (Entry 22).
To determine the scope of this process, a set of hydrazine derivatives were examined
as substrates by adopting the optimized condition (Table 1, Entry 20), with which this method
demonstrated good generality and the results are summarized in Table 2. Also, some of the
reactions were performed in microwave irradiation conditions and results are included in
Table 2. This was exemplified by the high yielding transformation of both aliphatic and
aromatic hydrazines to give various N-substituted phthalazinone derivatives (3a- 3i).
Table-2 Synthesis of N-substituted phthalazinone derivatives

5
O
R-NHNH2.HCl (2a - 2i),
Br
O
R
Co2(CO)8, Pd(OAc)2/dppf
N
N
DMF, 90 °C, 3 h
1
(3a - 3i)
Product
(3a-i)
R-NHNH2.HCL
(2a - 2i)
Yield ( % )a
Entry
O
NH2
NH
O
85/80b
N
N
1
3a
O
NH2
HN
O
N
64.6
O
3b
2
3
N
O
NH2
NH
74.2/ 70b
O
N
3c
N
Cl
Cl
O
67.6
NH2
N
H
N
N
4
3d
O
O
85.5/ 77b
O
NH2
NH
N
5
6
7
3e
N
NH2
NH
O
O
84.7
N
N
3f
Cl
NH2
NH
66.4/71b
N
N
3g
Cl
O
O
NH2
NH
62.5
76.2
8
N
N
3h
3i
F
F
NH2
NH
N
N
9
All the reactions were executed with 0.5 mmol of 2-bromobenzaldehyde, 0.6 mmol of hydrazine derivatives, 5
mol % of Pd(OAc)2, 6 mol % of dppf, 1.25 mmol of DBU, 0.15 mmol of Co2(CO)8 were heated at 90 °C in a
seal tube for 3 h. a the isolated yields by column chromatography. b The isolated yields from M/W reaction
condition.
Next, to further explore the application of this method, we sought to apply the
conditions to synthesize of 4-substituted phthalazinones by the carbonylation of the

6
corresponding 2-bromobenzophenones with different hydrazines and the results are outlined
in the Table 3. Also, some of the reactions were performed in microwave irradiation
Table 3 Synthesis of 4-substituted phthalazinone derivatives
O
Br
R1
R1-NHNH2.HCl, Co2(CO)8,
Pd(OAc)2/dppf
N
N
O
DMF, 90 °C, 3 h,
Sealed tube
R2
R2
R2 = H (1a), t-bu (1b)
(3j - 3u)
Yield(%)a
Product (3j-u)
Yield(%)a
Entry
Reactant
Br
Reactant
Product (3j-u)
Entry
O
O
N
O
N
Br
O
72/ 64b
3j
O
N
N
80.3/66b
7
3p
1
O
O
N
Br
Br
N
N
O
8
2
O
F
3q
3k
N
86.5
63.2
O
O
Br
Br
NH
N
N
N
O
O
O
3r
9
3l
3
72
82.9
O
Br
O
O
Br
N
N
O
10
4
83.3
N
N
66.2/ 60b
O
Cl
3m
3s
O
Br
O
Br
N
N
O
N
N
3n
O
87.2
11
64.5
5
F
3t
O
O
Br
Br
NH
N
O
N
N
12
84.2/ 74b
6
76.5
O
3o
3u

7
a the isolated yields by column chromatography. b The isolated yields from M/W reaction condition.
conditions and results are included in Table 3. Both aliphatic and aromatic hydrazines were
found to be suitable substrates and produced the corresponding 4-substituted phthalazinones
(3j-3u) in good to excellent yields. Despite the wide scope indicated by the results described
in Table 3, the yield was slightly reduced in the case of ortho substituted phenyl hydrazines
(3m, 3q and 3t).
Having demonstrated a wide scope for the direct preparation of phthalazinones, we
further validated our methodology by synthesizing 4-(3,4-dimethoxy-phenyl)-2-phenyl-2H-
phthalazin-1-one 3v, a selective PDE4 inhibitor,2a starting from (2-bromo-phenyl)-(3,4-
dimethoxy-phenyl)-methanone 1c, in good yield (78.2%) as shown in Scheme 1. To get more
information on the synthesis of ketones 1a, 1b in Table 1 and 1c in Scheme 1, refer
supplementary data.
Scheme 1 Synthesis of 4-(3,4-dimethoxy-phenyl)-2-phenyl-2H-phthalazin-1-one (PDE4
inhibitor)
O
Br
N
Ph-NHNH2.HCl, Co2(CO)8,
Pd(OAc)2/dppf
O
N
DMF, 90 °C, 3 h,
OMe
OMe
OMe
1c
OMe
3v
(78.2%)
In conclusion, a general and efficient procedure8 for the production of phthalazinone
derivatives has been established. By starting from easily available o-halobenzaldehydes and
benzophenones with various hydrazines in one pot using Co2(CO)8 as effective carbonyl
source, the corresponding phthalazinones have been produced in moderate to good yields.
The reaction is simple, efficient, tolerates a range of different functional groups and the
desired products were obtained in good yields with short reaction times. More importantly,
these methods utilise nearly stoichiometric amount of solid CO source (0.3 eq for 1 eq of aryl

8
halide) to get high yield at low temperature. It is especially suitable in medicinal chemistry to
rapidly enlarge compound library for biological evaluation.
Supplementary data
Supplementary data (synthesis procedures, characterization of compounds) associated with
this article can be found, in the online version, at http:
References and notes
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Y. L.; Yu, H.J.; Don, M. J.; Wu, T. S.; Nakamura, S.; Lee, K. H. J Med Chem., 2004,
47, 5816-5819. (c) Menear, K. A.; Adcock, C.; Alonso, F. C. Bioorg. Med. Chem,
Lett., 2008, 18, 3942-3945. (d) Miller-Moslin, K.; Peukert, S.; Jain, R. K. J Med
Chem., 2009, 52, 3954-3968.
2. (a) Van Der Mey, M.; Hatzelmann, A.; Van der Laan, I. J.; Sterk, G. J.; Thibaut, U.;
Timmerman. H. J Med Chem., 2001, 44, 2511-2522. (b) Torphy, T. J.; Undem, B. J.;
Cieslinski, L. B.; Luttmann, M. A.; Reeves, M. L.; Hay, D. W. P. Identification,
characterization and functional role of phosphodiesterase isozymes in human airway
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14, 1876-1879. (b) Baghernejad,; Bita.; Heravi.; Majid Oskooje, M.; Hossein
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Kuznetsov, Viktor.; Mikhail, Petrove.; Schipalkin, Andrej.; Kirill, Shubin.
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5. Odell, Luke R.; Francesco Russo.; Mats Larhed. Synlett 2012, 23, 685-698.

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6. Penta Rao, K.; Basak, K.; Deb, K.; Sharma, S.; Krishnakanth Reddy, L. Tetrahedron
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8. General procedure for the synthesis of phthalazinones: To a stirred mixture of 2-
bromobenzaldehyde (0.5 mmol) and the corresponding hydrazine hydrochloride (0.6
mmol) in DMF taken in a 25 mL sealed tube, was added Pd(OAc)2 (5 mol %), dppf (6
mol %), molecular sieves (W/W), DBU (1.25 mmol), and Co2(CO)8 (0.15 mmol). The
reaction vessel was closed immediately and heated at 90 °C for 3h. The reaction mixture
was cooled to room temperature, filtered through celite bed. The filtrate was diluted
with water and extracted with ethyl acetate. The ethyl acetate layer was washed with
water, brine solution, dried over MgSO4, evaporated in vacuum and purified using
column chromatography on silica gel (60-120 mesh) to afford the pure products.

10
R1NHNH2.HCl,
Co2(CO)8,
O
R
R1
Br
O
Pd(OAc)2/dppf
N
N
R = H, Ar
R1 = H, CH3, Ar
R
DMF, 90 °C, 3 h
Sealed tube