Copper(I)-Catalyzed Synthesis of Chlorinated Tetrahydropyridazin-3-ones and 1,2-Diazepan-3-ones from N-Allyl-N′-trichloroacetylhydrazines

Article abstract of DOI:10.1002/adsc.201500876

The synthesis of chlorinated tetrahydropyridazin-3-ones and 1,2-diazepan-3-ones has been developed. The present paper describes the application of Cu(I)-catalyzed ATRC for the synthesis of heterocyclic molecules containing two heteroatoms (i.e., nitrogen)

Full text of DOI:10.1002/adsc.201500876

FULL PAPERS
DOI: 10.1002/adsc.201500876
Copper(I)-Catalyzed Synthesis of Chlorinated Tetrahydropyrida-
zin-3-ones and 1,2-Diazepan-3-ones from N-Allyl-N’-trichloroace-
tylhydrazines
Ram N. Rama and Vineet Kumar Sonia,b,*
a
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi – 110016, India
Department of Chemistry, Indian Institute of Technology Jodhpur, Rajasthan – 342011, India
b
Fax: (+91)-291-251-6823; phone: (+91)-291-244-9052; e-mail: soni.1@iitj.ac.in
Received: September 21, 2015; Revised: November 6, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500876.
Abstract: The synthesis of chlorinated tetrahydropyr- mixture could be achieved by considering their solu-
idazin-3-ones and 1,2-diazepan-3-ones has been de- bility/insolubility in n-hexane. The presence of three
veloped. The present paper describes the application chlorine atoms provides possibilities for further deri-
of Cu(I)-catalyzed ATRC for the synthesis of hetero- vatization.
cyclic molecules containing two heteroatoms (i.e., ni-
trogen) in the ring for the first time. An easy separa- Keywords: copper(I) catalysis; high yields; hydra-
tion of the individual compounds from the product zines; nitrogen heterocycles; radical reactions
Introduction
in which two heteroatoms are present in the ring.
Therefore, it seemed worthwhile to investigate the
Over the years, the copper(I)-catalyzed halogen atom Cu(I)-catalyzed ATRC of suitably substituted hydra-
transfer radical cyclization (ATRC) of unsaturated zines for the synthesis of such chlorinated heterocy-
polyhalomethyl compounds has emerged as an impor- cles.
tant tool for the synthesis of various heterocyclic com-
Compounds containing a tetrahydropyridazin-3-one
pounds.[1] Several advantageous features of this or diazepan-3-one rings are known to possess several
method include its catalytic nature, cost effectiveness, biological activities. For example, the macrocycle
preservation of all the halogen atoms, and high yields. 1 (Figure 1) is an OT antagonist,[5] and 2 is a highly
The reaction can be performed at high substrate con- potent and selective FXa inhibitor.[6] The bicyclic tet-
centrations with almost no reductive dehalogenation rahydropyridazin-3-ones[7] 3 and the extended b-
and telomerization of the starting materials. Several strand mimetics[8] 4 and 5 show selectivity and poten-
sensitive groups like Ts, Boc and Cbz etc. are also tol- cy towards various serine proteases such as thrombin,
erated in such transformations.[1b,2] Due to the pres- trypsin, factor VIIa and tryptasein in in vitro assays.
ence of halogen atoms, further transformations of the Diazepan-3-ones 6 have been utilized in treating hy-
products are also possible. Furthermore, the use of pertension.[9] Cilazapril 7 is a drug for treating hyper-
copper(I) halides with various nitrogenous ligand- tension and congestive heart failure.[10]
based Cu(I) complexes have been explored to en-
Tetrahydropyridazin-3-ones and 1,2-diazepan-3-
hance the catalytic efficiency and selectivity. Recently, ones could be prepared by the reaction of hydrazines
an electrochemically mediated atom transfer radical with either 4- or 5-oxo-carboxylic acids/esters[11] or
cyclization (eATRC) has been reported, where Cu(I) suitably substituted halocarboxylic acid derivatives[12]
was in situ genarated from Cu(II) species by reduc- in a few steps. However, the preparation of these acid
tion at a platinum electrode.[3] However, Cu(I)-cata- derivatives having suitable substituents on the carbon
lyzed ATRC is dominated by 5-exo-trig cyclization. framework results in an increase in the number of
Only a few examples of Cu(I)-catalyzed 6-exo-trig synthetic steps.[13] In some cases, the starting materials
cyclization are known,[4] where 7-endo-trig cyclization themselves are prepared in several steps. Moreover,
as the other alternative was not observed. This meth- sauch molecules containing chlorine atom(s) have not
odology has not been applied to synthesize pyridazin- been prepared. The advantage of chlorine atom(s) in
3-ones and diazepan-3-ones or any other heterocycles a molecule is that other substituents can be intro-
276
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Copper(I)-Catalyzed Synthesis of Chlorinated Tetrahydropyridazin-3-ones
Result and Discussion
Initially, a Cu(I)-catalyzed ATRC of hydrazine 8a was
performed in the presence of commercially available
ligands such as 2,2’-bipyridine (bpy), tetramethylethy-
lenediamine (TMEDA) and pentamethyldiethylene-
triamine (PMDETA) in DCE at reflux under a nitro-
gen atmosphere (Table 1). Attempts to cyclize 8a
Table 1. Optimization of the reaction conditions.[a]
Entry Ligand
Solvent T
Conversion Yield [%] of
[h] [%][b]
9a/10a
1
2
3
4
bpy
DCE
16 nil
16 nil
0/0
0/0
59/30
57/29
TMEDA DCE
PMDETA DCE
PMDETA MeCN
2
2
100
100
[a]
Reactions were performed with 8a (1 mmol), CuCl
(0.3 mmol) at reflux temperature under a N2 atmosphere.
60 mol% each of bpy and TMEDA, and 30 mol% of
PMDETA were used.
[b]
1
Based on H NMR analysis.
were unsuccessful with bpy and TMEDA even after
heating the reaction mixture at reflux for 16 h, and
the starting material 8a was recovered. A slow deacti-
vation of copper(I) species could be observed after
several hours, as the colour of reaction mixture start-
ed changing to green, indicating the presence of
Figure 1. Some biologically active compounds containing
a tetrahydropyridazin-3-one or diazepan-3-one rings.
duced by replacement of chlorine atom(s)[14] or dehy- Cu(II). This might be attributed to DCE, a chlorinated
drochlorination[15] and thus, a library of such mole- solvent and/or disproportionation of Cu(I). However,
cules can be prepared for biological investigations. the reaction was completed in 2 h with PMDETA.
Additionally, the halogen substitutent is known to en- The mixtures of the products 9a and 10a thus ob-
hance the bioactivity of lead molecules by way of tained were filtered through a short pad silica gel
changing the volumetric and conformational proper- column to remove the coloured impurities and then
ties of the molecules and increasing the membrane stirred in warm n-hexane.
permeability for improved absorption.[16] Chlorine
During this process, the pyridazin-3-ones 9a got dis-
plays an important role in drug design as it acts as solved in n-hexane, while 1,2- diazepan-3-one 10a sep-
a moderate halogen bond acceptor and forms a stable arated out as a solid. The products 9a and 10a were
chlorine-carbon bond.[17] With the consideration to obtained in 59% and 30% yields, respectively
further explore the application of Cu(I)-catalyzed (Table 1). The structure of 10a was confirmed by
ATRC and the biological significance of such mole- single crystal X-ray diffraction data (see the Support-
cules, herein, we report a facile synthesis of chlorinat- ing Information).[18] The ORTEP diagram of 10a is
ed tetrahydropyridazin-3-ones and 1,2-diazepan-3- shown in Figure 2. The reactivity difference of Cu(I)
ones.
complexes is due to decreased standard potential of
the Cu(II)/Cu(I) couple with a tridentate ligand, i.e.,
PMDETA over bidentate ligands.[19] Acetonitrile as
the solvent was observed to be as effective as DCE in
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Ram N. Ram and Vineet Kumar Soni
provided a mixture of the pyridazin-3-one 9 and 1,2-
diazepan-3-one 10 in a 2:1 ratio via 6-exo and 7-endo
cyclizations, respectively, as in the case of 8a. Howev-
er, in the other cases where the allyl group was mono-
or disubstituted at the terminal position (Table 2, en-
tries 5–12), pyridazin-3-ones 9 were obtained as the
sole product. N-Crotyl derivatives (Table 2, entries 5,
8) gave diastereomeric mixtures (7:3 ratio) of tetrahy-
dropyridazin-3-ones, which was in agreement with the
earlier observations.[1l,20] Separation of 9b–d from
10b–d was performed in a similar manner as discussed
for 9a and 10a.
The structures of 9 and 10 were supported by
1H NMR, 13C NMR, DEPT and IR spectroscopy, and
high resolution mass spectrometry (HR-MS). The dia-
stereotopic protons were located using COSY and
HSQC data. The structures of these cyclized products
were further supported by single crystal X-ray diffrac-
tion data of 9j, 10a, and 10c (see the Supporting Infor-
mation).
Figure 2. X-ray structure of 10a.
terms of the conversion and reaction time with slight-
ly lower product yields.
The synthesis of trichloroacetylhydrazines as ATRC
precursors 8 was realized in four steps starting from
On the basis of these observations, the Cu(I)-cata- arylhydrazines (Scheme 1). Arylhydrazines were pro-
lyzed ATRC of 8 (Table 2) was performed with other tected by treatment with (Boc)2O in THF at room
substrates 8b–l under the optimized reaction condi- temperature (23–258C).[21] The Boc-protected arylhy-
tions in the presence of 30 mol% each of CuCl and drazines 11 were successively and selectively allylated
PMDETA in DCE under a nitrogen atmosphere at and alkylated by first lithiation with excess n-BuLi in
reflux for 2 h. In the cases where the allyl group was THF at À788C for 10 min, followed by allylation with
not substituted (Table 2, entries 1–4), the reaction allyl halide at À608C and then alkylation with methyl
Table 2. Cu(I)/PMDETA-catalyzed ATRC of trichloroacetylhydrazines 8.[a]
Entry
8
Ar
R1
R2
R3
9:10[b]
Yield [%]
9
10
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
phenyl
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2CO2Et
2:1
2:1
2:1
2:1
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
59
57
56
58
30
29
28
29
0
0
0
0
0
p-chlorophenyl
m-fluorophenyl
m-tolyl
phenyl
phenyl
m-fluorophenyl
phenyl
phenyl
p-chlorophenyl
m-fluorophenyl
m-tolyl
H
88[c]
91
Me
Me
H
Me
Me
Me
Me
89
87[c]
92
9
10
11
12
j
k
l
90
89
92
0
0
0
[a]
All the reactions were performed with 8 (1 mmol), CuCl (0.3 mmol) and PMDETA (0.3 mmol) in DCM (20 mL) at
reflux for 2 h under a nitrogen atmosphere.
Calculated from peak areas of N-Me protons in the H NMR spectra of the crude products.
Diastereomeric mixtures (7:3 ratio).
[b]
[c]
1
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Copper(I)-Catalyzed Synthesis of Chlorinated Tetrahydropyridazin-3-ones
À
amide C N bond. For example, the signals of the
three N-methyl protons of 8a were split into two sin-
glets at d=3.55 and 3.08 ppm, integrating for 0.7H
and 2.3H, respectively, indicating the presence of the
two rotamers in a 7:23 ratio. And the carbon of the
N-methyl group appeared at d=43.4 and 34.2 ppm.
Similarly, the signals of the nine protons of the N-Boc
group of 12a were split into two singlets at d=1.48
and 1.31 ppm. The ratio of the areas of the two sin-
glets indicated the presence of two rotamers in a 1:2
ratio. In the 13C NMR spectrum of 12a, the three
methyl carbons of the tert-butyl group showed up at
d=35.2 and 28.0 ppm (see the Supporting Informa-
tion).
With a view to further explore the applicability of
this method, N-benzoyl-N-prenyl-N’-ethoxycarbonyl-
N’-trichloroacetylhydrazine 18 (Scheme 2) was pre-
pared from N-benzoylhydrazine 14 in 4 steps. The
condensation of 14 with ethyl glyoxalate (50% solu-
tion in toluene) was realized by reacting them in etha-
nol at 808C for 15 min.[24] N-Prenylation of the result-
ing hydrazone 15 was performed in acetone under
reflux in the presence of potassium carbonate. N-Pre-
Scheme 1. Preparation of trichloroacetylarylhydrazines 8.
iodide/ethyl bromoacetate at 23–258C.[22] The allylat- nylhydrazone 16 was reduced with NaBH3CN in etha-
ed-alkylated products 12, thus obtained were treated nol at 5–258C to give trisubstituted hydrazine 17,
with trifluoroacetic acid in DCM at room temperature which was unstable. Therefore, 17 was immediately
(23–258C) for 1 h to furnish the deprotected trisubsti- reacted with trichloroacetyl chloride in the presence
tuted hydrazines 13. Trichloroacetylation[23] of 13 with of triethylamine in diethyl ether to yield trichloro-
trichloroacetyl chloride in diethyl ether in the pres- acetylhydrazine 18. ATRC of 18 was performed with
ence of triethylamine at 23–258C afforded the cycliza- CuCl/PMDETA (30 mol%) under the similar condi-
tion precursors 8 in high yields.
tions to obtain N-benzoyltetrahydropyridazin-3-one
The structures of 8, 12 and 13 were supported by 19 in 86% isolated yield. The presence of two rotam-
1H NMR, 13C NMR, DEPT and IR spectroscopy, and ers (1:4 ratio) of the product 19 could be observed in
high resolution mass spectrometry (HR-MS). Some of the NMR spectra, which was probably due to the N-
the signals of the protons and carbons in the NMR benzoyl group. The ratio was calculated from the rela-
spectra of 8 and 12 were split into twin sets of signals tive intensities of the methyl protons at the exocyclic
1
of unequal intensities. This might be due to the two quaternary carbon in the H NMR spectrum (see the
rotamers resulting from restricted rotation about the Supporting Information). The advantage of having an
Scheme 2. Synthesis of N-benzoyltetrahydropyridazin-3-one 19.
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Ram N. Ram and Vineet Kumar Soni
Scheme 3. Mechanistic overview of Cu(I)-catalyzed ATRC.
N-benzoyl group in 19 is that it can be selectively de- for the first time. The separation of the two products
protected[25] and further N-substitution is possible.
from the reaction mixture is quite easy. It takes ad-
A mechanistic overview of the Cu(I)/PMDETA- vantage of the considerable difference in solubility of
catalyzed ATRC is presented in Scheme 3. The first the two products in n-hexane. A highly selective prep-
step involves the formation of a dichlorocarbo radical aration of tetrahydropyridazin-3-ones by 6-exo cycli-
species after abstraction of a chlorine atom by CuCl/ zation could be realized by substituting the radical ac-
PMDETA. The selectivity in the cyclization step fol- ceptor at the terminal position of the carbon-carbon
lows an order similar to that of recent observations double bond. Selective 7-endo cyclization can also be
by Peisino and Pierini[26] for photo-stimulated cycliza- achieved by changing the substitution at the double
tions of aryl radicals. They demonstrated by experi- bond.[26,27] The method has several advantages over
ment and theoretical calculations that the regiochem- previously known methods, as there is a considerable
istry of the 6-exo/7-endo radical ring closure could be reduction in the number of steps for the preparation
controlled by an interplay of conformational effects of such highly substituted heterocycles. The presence
(Baldwinꢁs rule) and the stability of the radical being of three chlorine atoms provides possibilities for fur-
formed (primary<secondary<tertiary). Accordingly, ther derivatization by substitution[14] or dehydro-
for the substrates with substituent(s) at the terminal chlorination.[15] The method may be useful in the
position of the radical-acceptor double bond (Table 1, preparation of a library of such molecules for biologi-
entries 5–12), the conformational effects, which are cal activity evaluation and lead optimization.
generally more favourable to 6-exo cyclization, and
the radical stability factor (more stable secondary or
tertiary radical) reinforce each other leading to a re- Experimental Section
giospecific 6-exo cyclization. However, for the sub-
The general comments and the details for the preparation of
compounds 3, 5 and non-commercially available symmetric
and asymmetric alkynes can be found in the Supporting In-
formation.
strates with no substitution at the double bond
(Table 1, entries 1–4), the conformational factors com-
pensate for the lower stability of a primary radical
and the reaction is less selective.
Copper(I) Chloride/PMDETA-Catalyzed Chlorine
Atom Transfer Radical Cyclization of N-Allyl-N’-
trichloroacetylhydrazines
Conclusions
In conclusion, a method for the synthesis of chlorinat-
ed tetrahydropyridazin-3-ones and 1,2-diazepan-3-
ones has been developed by Cu(I)/PMDETA-cata-
lyzed chlorine atom transfer radical cyclization of N-
allyl-N’-trichloroacetylhydrazines.
method describes the application of a Cu(I)-catalyzed
ATRC for the synthesis of heterocyclic molecules
Typical Procedure: An atmosphere of nitrogen gas was cre-
ated by the Schlenk technique in a flame-dried 50-mL two-
neck round-bottom flask equipped with
a condenser,
a rubber septum and a magnetic bar. Cuprous chloride
(0.030 g, 0.3 mmol), PMDETA (0.06 mL, 0.3 mmol) and dry
degassed DCE (20 mL) were added to the flask. The flask
was again evacuated and filled with dry nitrogen. The mix-
The
present
containing two heteroatoms (i.e., nitrogen) in the ring ture was stirred with a magnetic stirrer for 15 min. A solu-
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Copper(I)-Catalyzed Synthesis of Chlorinated Tetrahydropyridazin-3-ones
tion of 8a (1 mmol) in DCE (5 mL) was slowly injected into
the flask during a period of 5 min. The resulting mixture
was then heated at reflux with stirring for 2 h. Monitoring
the progress of the reaction by TLC indicated the disappear-
ance of 8a after this time. The reaction mixture was cooled
to room temperature and n-hexane (15 mL) was added to it.
The resulting mixture was stirred for 15 min under an open
atmosphere and filtered. The filtrate was evaporated under
reduced pressure. The coloured impurities of the crude
product thus obtained were removed by flash column chro-
matography on a silica gel (60–120 mesh) column using n-
hexane-EtOAc (9:1 v/v) as the solvent for elution to obtain
a mixture of the tetrahydropyridazin-3-one 9a and 1,2-diaze-
pan-3-one 10a. The mixture was shaken thoroughly with
warm n-hexane (3”20 mL) and the insoluble white solid
was separated by filtration. The solid was recrystallized
from n-hexane-EtOAc to obtain 10a in 30% yield. The fil-
trate was evaporated under reduced pressure to obtain 9a as
colorless liquid in 59% isolated yield.
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Acknowledgements
We are thankful to the University Grant Commission, New
Delhi for a research fellowship to V.K.S.
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