A new synthetic route to benzophenone derivatives

Article abstract of DOI:10.1515/hc-2017-0005

The rearrangement reaction of 1-alkyl-2-(benzoylmethyl)pyridinium iodides 3a-d, 6 in the presence of various nucleophiles leads to 2-alkylaminobenzophenone derivatives 4a-c. Best results were achieved with alkylammonium sulfites as recyclization reagents.

Full text of DOI:10.1515/hc-2017-0005

Heterocycl. Commun. 2017; aop
Sraa Abu-Melha*
A new synthetic route to benzophenone
derivatives
DOI 10.1515/hc-2017-0005
into a benzene ring takes place. As simple α-picolinium
salts do not undergo enamine rearrangement in aqueous
ethanolic alkali or aqueous alkylamine [17], the formation
of 4a and 5 in the present study indicates that the benzoyl
group activates the α-methylene group to undergo the
rearrangement. However, in the presence of alkylammo-
nium sulphite as a recyclization reagent, the 2-picolinium
iodide 3a undergoes rearrangement to give 2-methylam-
inobenzophenone (4a) in a much-improved yield of 78%
Received January 6, 2017; accepted April 20, 2017
Abstract: The rearrangement reaction of 1-alkyl-2-
(benzoylmethyl)pyridinium iodides 3a–d, 6 in the
presence of various nucleophiles leads to 2-alkylam-
inobenzophenone derivatives 4a–c. Best results were
achieved with alkylammonium sulfites as recyclization
reagents.
Keywords:benzophenone;enaminerearrangement;meth- (Scheme 3). The mechanism of Scheme 3 is consistent
ylammonium sulphite; pyridinium salt; recyclization.
with many reported similar cases [4–13, 18]. The sulphite
ion being a weak nucleophile undergoes addition to the
softest position C-4 in the pyridine ring to generate a
1,4-dihydropyridine of the type A, which then undergoes
ring opening under hydrolytic conditions followed by
recyclization with elimination of the reagent, forming the
product 4a.
The reaction of N-methylpicolinium iodides 3b and 3c
with methylammonium sulphite furnished the expected
rearrangement products 4b and 4c in 71% and 68% yields,
respectively (Scheme 3).
However, the attempted reaction of compound 3d
failed to give 2-methylaminobenzophenone, and instead,
the parent 4,6-dimethyl-2-pyridylacetophenone (2d) was
obtained, apparently, by direct attack of the nucleophile
to the CH3-N bond (SN2 mechanism) (Scheme 3). Alkyl
groups R reduce the electron deficiency of the ring and
give rise to steric difficulties for the sulphite ion addi-
tion. Accordingly, the yield of R-susbstituted recyclization
products decrease, particularly with a 4,6-dimethylpyri-
Introduction
2-Aminobenzophenones are usually obtained from
N-methylaniline derivatives [1–3]. Fadda and coworkers
[4–13] studied the recyclization/isomerization of pyri-
dinium salts to anilines in the presence of aqueous alkali,
alkylamine or alkylammonium sulphite and observed
that the nature and position of substituents in the pyri-
dine ring have a considerable effect on this reaction [7,
8]. The present work was undertaken to study the effect
of substituents of picolinium salts 3 on the course of the
recyclization reaction.
Results and discussion
2-Pyridylacetophenones 2 were obtained according to dine derivative.
the reported method [14]. Compounds 2 were methylated
3-Substituted pyridines are less susceptible to this
(Scheme 1) to compounds 3 (Schemes 2 and 3), which effect. This suggests a predominant addition of the sulfite
served as direct precursors to the desired products 4 and 5 ion to the C-4 atom, so that the initial products are the
with an expected broad spectrum of biological effects [15,
16]. Thus, treatment of compound 3a with methylamine
furnished products 4a and 5 in low yields (Scheme 2). It
COOEt
can be suggested that the initially formed anhydrobase A
n-BuLi
O
R
R
undergoes addition of a hydroxide anion to generate the
anionic σ-complex B. After ring opening, the recyclization
–40 °C
N
Me
N
Ph
1a–d
2a–d
a: R = H; 73%
b: R = 3-NO2; 53%
c: R = 5-NO2; 63%
d: R = 4,6-diMe; 60%
*Corresponding author: Sraa Abu-Melha, Faculty of Science for
Girls, King Khalid University, Abha, Saudi Arabia,
e-mail: sraa201313@yahoo.com
Scheme 1ꢀ
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ꢀꢀꢀꢁ
2ꢀ
ꢀS. Abu-Melha: Synthesis of benzophenone derivatives
O
aq. MeNH2
or NaOH
OH
O
O
O
O
Ph
O
OH
HO
H
I
–H2O
N
Ph
Ph
N
Ph
O
O
Ph
Ph
NHMe
4a (15%)
N
Ph
H
NHMe
Me
Me
Me
B
A
3a
O
OH
5 (10%)
O
H
Scheme 2ꢀ
O
H
SO3NH3R
H
SO3NH3R
O
(MeNH3)2SO3
O
aq. MeNH2
O
Ph
NHMe
4a–c
R
R
–(MeNH3)2SO3
–OH
N
I
Ph
OH
O
Ph
N
Ph
H
NHMe
Me
Me
3a–d
A
(EtNH3)2SO3
3a: R = H
3b: R = 3-NO2
3c: R = 5-NO2
4a: R = H; 78%
4b: R = 3-NO2; 71%
4c: R = 5-NO2; 68%
4a (45%) + 5 (12%) + 2a (10%)
4a (10%) + 5 (15%) + 2a (55%)
3a
3d: R = 4,6-diMe
((Me)2NH2)2SO3
Scheme 3ꢀ
H
SO3NH3Me
O
O
O
MeNH2
Me(NH3)2SO3
ZnCl2
4a (51%)
N
Ph
N
Ph
N
Ph
ZnCl2
ZnCl2
2a
(MeNH3)2SO3
(NH4)2SO3
O
H
SO3NH3Me
O
H
H
SO3NH3Me
COPh
NH2
O
Ph
NHMe
4a (35%)
N
Ph
O
O
H
H
Ph
NHCH3
H
MeNH2
H2O
H
O
SO3NH3Me
SO3NH3Me
O
Ph
CHCOPh
NH2
O
H
Ph
OH
O
5 (15%)
Scheme 4ꢀ
1,4-dihydropyridines A, which recyclize into aromatic open chain intermediate and the product of the recycliza-
compounds by elimination of the reagent. tion reaction was 4a obtained in a 35% yield (Scheme 4).
The recyclization of unquaternized 2-pyridylaceto- However, the bulk of the compound 2a was recovered
phenone 2a was also studied [9]. Upon treatment of 2a unchanged. There is no evidence for the formation of
with aqueous methylammonium sulphite, the amine frag- 2-aminobenzophenone as a product of the recyclization
ment was exchanged for a methylamine fragment in the reaction by spectroscopic data. All attempts to obtain
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S. Abu-Melha: Synthesis of benzophenone derivativesꢂ
ꢂ3
+
+
(m, 5H, Ar-H), 7.63 (s, 2H, Ar-H); MS: m/z 378 (M ꢁ+ꢁ1, 40), 367 (M ,
100%). Anal. Calcd for C16H18INO (367.23): C, 52.33; H, 4.49; N, 3.81.
Found: C, 52.23; H, 4.36; N, 3.70.
the latter compound by treatment of compound 2a with
aqueous ammonium sulphite failed.
When zinc chloride was used as a catalyst [8] in the
reaction of 2a, the yield of product 4a increased to 51%
(Scheme 4). It can be noted that the yield of 4a was invari-
ably less in the presence of aqueous alkylamine than in
the presence of methylammonium sulphite as a recycliz-
ing agent. It was also demonstrated that the treatment of
N-ethyl-2-picolinium iodide (6, analog of 2a, not shown)
with methylammonium sulphite led to the formation of
a mixture of 2-methylaminobenzophenone (4a) (60%),
2-hydroxybenzophenone (5) (12%) and 2-pyridylacetophe-
none (2a) (10%).
Synthesis of 2-methylaminobenzophenone (4a)
Aqueous methylamine (25 mL, 35%) was added to 3a (0.15 mol) and
the mixture was heated in a pressure tube at 150°C for 15 h. The prod-
ucts were extracted with ether and the extract was dried (MgSO4),
concentrated and subjected to silica gel chromatography, eluting
with benzene to give 4a (15%), 5 (10%) and 2a (50%).
Reaction of 3a–d with methylammonium sulphite
Aqueous methylammonium sulphite (33%, 35 mL) was added to the
pyridinium salts 3a–d (0.02 mol) and the mixture was heated in a
pressure tube at 150°C for 20–30 h. The product was extracted with
ether, the extract was dried (MgSO4), concentrated and chromato-
graphed over silica gel using benzene as eluent. Concentration under
reduced pressure furnished 4a–c. Product 4a was obtained in a 78%
yield.
Experimental
Melting points are uncorrected. The infrared (IR) spectra were
recorded in KBr disks on a Mattson 5000 FTIR spectrometer. The 1H-
NMR spectra were determined on a Bruker WPSY 200 MHz spectrome-
ter in DMSO-d6 with tetramethylsilane (TMS) as an internal standard.
The electron ionization (EI) mass spectra were recorded at 70 eV with
Varian MAT 311. Elemental analyses (C, H and N) were carried out at
the Faculty of Science, Cairo University, Egypt. Compounds 2a [14],
2b [14, 19], 2c [18, 20], 2d [21, 22], 4a [23], 4c [24], 5 [25] and 6 [19]
were synthesized as previously reported.
2-Methylamino-3-nitrobenzophenone (4b)ꢀThis compound was
obtained from 3b in a 71% yield; mp 115°C; IR: ν 1705, 1530, 1345 cm−1;
1H-NMR: δ 2.64 (s, 3H, N-CH3), 6.72 (s, 1H, NH), 7.31–7.75 (m, 8H, Ar-H);
+
MS: m/z 256 (M , 100%). Anal. Calcd for C14H12N2O3 (256.22): C, 65.62;
H, 4.72; N, 10.93. Found: C, 65.50; H, 4.60; N, 10.80.
General procedure for synthesis of pyridinium salts 3a–d
2-Methylamino-5-nitrobenzophenone (4c)ꢀThis compound was
obtained from pyridinium salt 3c in a 68% yield; mp 163°C (Lit.
1
[26] mp 165–166°C); IR: ν 1700, 1530, 1345 cm−1 ; H-NMR δ 2.60 (s,
A mixture of 2-pyridylacetophenone 2a–d (0.02 mol) and methyl
iodide (0.03 mol) was heated in a pressure tube at 100°C for 15 h. The
resulting solid material was crystallized from ethanol-ether (3:1) as
yellow crystals.
+
3H, N-CH3), 6.62 (s, 1H, NH), 7.31–7.75 (m, 8H, Ar-H); MS: m/z 256 (M ,
100%).
1-Methyl-2-(2-oxo-2-phenylethyl)pyridin-1-ium iodide (3a)ꢀYield
85%; mp 171–173°C; IR: ν 1710 cm−1; 1H-NMR: δ 3.80 (s, 2H, CH2), 4.10
Ring opening and recyclization of 2a
+
(s, 3H, N-CH3), 7.51–8.63 (m, 9H, Ar-H); MS: m/z 340 (M ꢁ+ꢁ1, 40), 339
+
Method AꢀCompound 2a (1.98 g, 0.01 mol) was treated with methyl-
ammonium sulphite (33%, 25 mL) and the mixture heated in a pres-
sure tube for 60 h at 150°C. After cooling, the mixture was extracted
with ether. The extract was dried (MgSO4) and concentrated and the
residue was chromatographed over silica gel using benzene-ethyl
acetate (4:1) as eluent to give compounds 4a (35%), 5 (15%) and the
unreacted 2a (45%).
(M , 100%). Anal. Calcd for C14H14INO (339.18): C, 49.60; H, 4.20; N,
4.10. Found: C, 49.58; H, 4.20; N, 4.08.
1-Methyl-3-nitro-2-(2-oxo-2-phenylethyl)pyridin-1-ium
iodide
(3b)ꢀYield 90%; mp 165–167°C; IR: ν 1695, 1530, 1345 cm−1; 1H-NMR: δ
3.80 (s, 2H, CH2), 4.38 (s, 3H, N-CH3), 7.55–8.61 (m, 8H, Ar-H); MS: m/z
+
+
385 (M ꢁ+ꢁ1, 15), 384 (M , 100%). Anal. Calcd for C14H13IN2O3 (384.17): C,
43.77; H, 3.41; N, 7.29. Found: C, 43.71; H, 3.39; N, 7.26.
Method BꢀA mixture consisting of 2a (0.01 mol), aqueous methyl-
ammonium sulphite (33%, 25 mL) and ZnCl2 (2g) was heated in a
pressure tube at 150°C for 60 h. Analysis of the products showed that
the presence of 4a (51%), 5 (15%) and 2a (30%).
1-Methyl-5-nitro-2-(2-oxo-2-phenylethyl)pyridin-1-ium
iodide
(3c)ꢀYield 80%; mp 148–150°C; IR: ν 1710, 1530, 1345 cm−1; 1H-NMR: δ
3.83 (s, 2H, CH2), 4.20 (s, 3H, N-CH3), 7.45–8.55 (m, 8H, Ar-H); MS: m/z
+
+
385 (M ꢁ+ꢁ1, 15), 384 (M , 100%). Anal. Calcd for C14H13IN2O3 (384.17): C,
43.77; H, 3.41; N, 7.29. Found: C, 43.71; H, 3.39; N, 7.26.
Acknowledgments: The author thanks Prof. Dr. Ahmed A.
Fadda, Faculty of Science, Mansoura University, Egypt,
for guidance, help and valuable discussion.
1,2,4-Trimethyl-6-(2-oxo-2-phenylethyl)pyridin-1-ium
iodide
(3d)ꢀYield 76%; mp 156–158°C; IR: ν 1710 cm−1; 1H-NMR: δ 2.45 (s, 3H,
CH3), 2.91 (s, 3H, CH3), 3.81 (s, 2H, CH2), 4.39 (s, 3H, N-CH3), 7.55–8.00
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