Synthesis of 21-(dimethylamino)methyl N-confused porphyrin derivatives by Mannich reaction

Article abstract of DOI:10.3184/174751913X13846100471836

The 21-(dimethylamino)methyl N-confused porphyrin derivatives were synthesised by the Mannich reaction of dimethylmethyleneimmonium chloride and N-confused porphyrin. The reaction took place regioselectively in the inner carbon of the inverted pyrrole of

Full text of DOI:10.3184/174751913X13846100471836

764 RESEARCH PAPER
DECEMBER, 764–765
JOURNAL OF CHEMICAL RESEARCH 2013
Synthesis of 21-(dimethylamino)methyl N-confused porphyrin derivatives by
Mannich reaction
Bin Liu, Xiaofang Li*, Mengting Wang and Rongjin Zeng
Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan Province College Key Laboratory of QSAR/
QSPR, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, P.R. China
The 21-(dimethylamino)methyl N-confused porphyrin derivatives were synthesised by the Mannich reaction of
dimethylmethyleneimmonium chloride and N-confused porphyrin. The reaction took place regioselectively in the inner carbon
of the inverted pyrrole of N-confused porphyrins.
Keywords: N-confused porphyrin, Mannich reaction, porphyrin, Eschenmoser’s salt
In porphyrin’s isomers, N-confused porphyrin (NCP)1 has
2.0
created interest due to its unique structure and potential
applications.2 As an analogue of porphyrin, NCP has a
1.6
similar structure and characteristics. The synthesis of new
NCP derivatives is a very important research area.3 NCP has
three main reaction sites: N2 (external nitrogen), C3 (external
1.2
carbon) and C21 (internal carbon). The chemical activity of all
three reaction sites is special due to the “inverted” pyrrole ring,
0.8
for example, the reaction of the internal carbon on the inverted
0.4
pyrrole ring including nitration,4 halogenation,5 cyanisation,6
oxygenation,7 internal fusions,8 alkylation,9 hydroxylation.10
The Mannich reaction11 is a very important reaction that
0.0
forms carbon–carbon bonds in organic synthesis for the
preparation of β‑amino carbonyl compounds. It is widely used
to synthesise medicines12 and alkaloids,13 because the Mannich
reaction can create both functional and structural diversity
of some important compounds. We now report the use of the
Mannich base of Eschenmoser’s salt14 to react with NCP to
synthesise and characterise the new derivatives on C21 of NCP
(Scheme 1).
300
400
500
600
700
800
900
Wavelength/ nm
Fig. 1 UV-Vis spectra of 1a (black line) and 3a (red line) in CHCl3.
1
The H NMR spectrum of 3a (298 K, CDCl3) (Fig. 2) is
characterised by six β‑pyrrole proton signals in the region
of 8.28–8.94 ppm, two singlets at 2.65 and 2.68 ppm are
assigned to four methyls of the meso p-tolyl substituents,
the singlet at 0.04 ppm represents two methyl groups of the
dimethylmethyleneimmonium fragment and was observed
at 0.18 ppm at 213 K. Two doublets at –4.16 and –4.05 ppm
were assigned to the protons of methylene which existed in
(dimethylamino)methyl. The signals of the inner NH groups,
which are too broad to be observed at room temperature, appear
at –2.91 ppm as a singlet at 213 K. In 13C NMR spectrum of 3a,
the inner carbon appeared at 104.9 ppm, which was comparable
with the 13C signal of the inner CH of other NCPs (99.2 ppm
for NCTPP,1 106.0 ppm for 2-NCH3CTPP3 and 114.6 ppm for
21-nitro-NCTPP4). In the HMBC spectrum of 3a, it is clear
that the protons of methylene (–4.16 and –4.05 ppm) in the
(dimethylamino)methyl correlate with the inner carbon at
104.9 ppm and the methyl carbon of (dimethylamino)methyl at
Results and discussion
The position of the reaction and the structure of product 3a were
investigated by the UV-Vis, NMR (1H, 13C, COSY, HMQC) and
mass spectra. The mass spectrum of 3a gave the molecular ion
peak at m/z 728, which indicates the addition of one molecule of
(dimethylamino)methyl to 1a.
The electronic adsorption spectrum of 3a and 1a in CHCl3
are shown in Fig. 1. From the spectrum, we can see the Soret
band (453 nm) accompanied by a set of three Q bonds (554, 601,
750 nm). All the bonds of 3a are bathochromically shifted with
respect to the parent NCP 1a. The detected changes may result
from an electronic effect of 21-substitution of NCP, it could
indicate the possibility of the Mannich reaction taking place
on 21C.
Ar
N
Ar
N
22
NH
NH
H
l
C
2C 2
25
24
HN
Ar
Ar
Ar
+
Ar
N
N CH2
Cl
reflux 5 hr
N
HN
N
26
2
Ar
1a-1b
Ar
3a-3b
3a:
3b:
Ar=4-CH3Ph
Ar=Ph
1a:
1b:
Ar=4-CH3Ph
Ar=Ph
Scheme 1 Synthesis of 21-(dimethylamino)methyl NCP derivatives
* Correspondent. E-mail: lixiaofang@iccas.ac.cn
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JOURNAL OF CHEMICAL RESEARCH 2013 765
Fig.2 1H NMR spectrum (500 MHz, 298 K, CDCl3) of 3a. The inset show fragments of the spectrum recorded at 213 K.
1
3b: H NMR (500 MHz, CDCl3, 298 K) δH –4.16 (d, J=15.5 Hz, 1H),
42.48 ppm. The protons of methyl (0.04 ppm) in (dimethylamino)
methyl correlate with the methylene carbon of (dimethylamino)
methyl at 50.48 ppm. The protons of C3 (7.24 ppm) on the
inverted pyrrole correlate with the inner carbon at 104.9 ppm.
These results confirmed that the Mannich reaction takes place
in the inner carbon of the inverted pyrrole of 1a.
–4.03 (d, J=15.5 Hz, 1H), 0.04 (s, 6H, –CH3), 7.27 (s, 1H), 7.68–7.75 (m,
8H), 7.84–7.87 (m, 4H), 8.07 (d, J=6.0 Hz, 1H), 8.12–8.16 (m, 2H), 8.22
(d, J=6.0 Hz, 1H), 8.41–8.46 (m, 7H), 8.51 (d, J=5.0 Hz, 1H, pyrrH),
8.86 (d, J=4.5 Hz, 1H, pyrrH), 8.93 (d, J=4.5 Hz, 1H, pyrrH); 13C NMR
(125 MHz, CDCl3, 298 K) δC =42.5, 50.6, 105.0, 116.7, 118.2, 125.5, 126.1,
126.6, 126.84, 126.88, 126.90, 126.93, 127.2, 127.4, 127.6, 127.7, 127.8,
127.9, 128.4, 128.6, 129.1, 134.6, 134.7, 135.0, 137.0, 137.4, 137.6, 137.8,
138.2, 139.5, 139.7, 139.9, 140.3, 141.7, 141.8. UV-vis (CHCl3) λmax/nm
(log ε): 452 (5.29), 552 (4.10), 597 (4.24), 745 (4.22). ESI‑HRMS calcd for
[C47H38N5]+ (M+H): 672.3122, Found: 672.3127.
Experimental
The starting porphyrins 1a and 1b were synthesised as previously
described.15 All of the reagents were from commercial suppliers and
used without further purification. All of the solvents were freshly
distilled from the appropriate drying agents before use. The analytical
TLCs were performed with silica gel 60 F254 plates. Column
chromatography was carried out by using silica gel 60 (200–300 mesh).
All NMR spectra were recorded on a Bruker AV-II 500 MHz NMR
spectrometer, operating at 500 MHz for 1H, and 125 MHz for 13C.
TMS was used as an internal reference for 1H and 13C chemical shifts
and CDCl3 was a solvent. MS was conducted by a Finnigan LCQ
Advantage MAX mass spectrometer. 2D experiments were performed
using standard pulse sequences.
Conclusion
In summary, we have synthesised 21-(dimethylamino)
methyl NCP derivatives by the Mannich reaction of
dimethylmethyleneimmonium chloride and NCP in reflux
dichloromethane under N2. The reaction takes place
regioselectively in an inner carbon of the inverted pyrrole and
demonstrates the special reactivity of the inner carbon of NCP.
We are grateful to the National Natural Science Foundation of
China (Nos 21371054, 21172065) and the Scientific Research
Fund of Hunan Provincial Education Department (No. 13A026)
for financial support.
21-(Dimethylamino)methyl NCP derivatives (3): In a flame-dried
50 mL two-neck round-bottom flask under nitrogen, 67 mg (0.1 mmol) of
NCP 1a was dissolved in 25 mL anhydrous dichloromethane, and 14 mg
(0.15 mmol) of dimethylmethyleneimmonium chloride was added. The
reaction mixture was stirred and heated to reflux for 5 h. TLC showed
that no NCP reactant remained. The solvent was evaporated under
vacuum. The residue was chromatographed on a silica gel column with
dichloromethane/methanol (v:v=100:3) solvent as eluent. The greenish
yellow coloured product fractions were combined together, followed
by removal of solvent and recrystallisation with hexane to afford NCP
derivative 3a in 79% yield, and get the derivative 3b in 72% yield with
the same reaction conditions.
3a: 1H NMR (500 MHz, CDCl3, 298 K) δH –4.15 (d, J=15 Hz, 1H), –4.01
(d, J=15 Hz, 1H), 0.04 (s, 6H, –CH3), 2.64 (s, 3H, –CH3), 2.65 (s, 6H, –
CH3), 2.68 (s, 3H, –CH3), 7.25 (s, 1H), 7.49–7.53 (m, 4H), 7.65–7.68 (m,
4H), 7.95 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 8.02 (d, J=7.5 Hz,
1H), 8.10 (d, J=7.5 Hz, 1H), 8.28–8.30 (m, 4H), 8.45–8.46 (m, 3H),
8.50 (d, J=5.0 Hz, 1H, pyrrH), 8.85 (d, J=4.5 Hz, 1H, pyrrH), 8.93 (d,
J=4.5 Hz, 1H, pyrrH); 1H NMR (500 MHz, CDCl3, 213 K) δH –4.25 (d,
J=15 Hz, 1H), –4.07 (d, J=15 Hz, 1H), –2.91 (s, 1H), 0.18 (s, 6H, –CH3),
2.70 (s, 3H, –CH3), 2.71 (s, 6H, –CH3), 2.73 (s, 3H, –CH3), 7.23 (s, 1H),
7.57–7.60 (m, 4H), 7.68–7.82 (m, 4H), 8.03–8.05 (m, 2H), 8.11–8.18 (m,
3H), 8.30–8.47 (m, 2H), 8.53–8.63 (m, 4H), 8.64 (d, J=7.0 Hz, 1H), 8.96
(d, J=4.5 Hz, 1H), 9.04 (d, J=4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3,
298 K) δC =21.46, 21.49, 21.53, 42.5, 50.5, 104.9, 116.6, 117.9, 125.3, 125.9,
126.5, 127.0, 127.6, 127.8, 128.67, 128.73, 129.1, 134.53, 134.59, 134.61,
134.7, 134.8, 136.95, 136.97, 137.18, 137.25, 137.30, 137.4, 137.5, 137.8,
138.3, 138.4, 138.7, 139.0, 139.8, 140.3, 141.7, 151.5, 157.0, 157.7. UV-Vis
(CHCl3) λmax/nm (log ε): 453 (5.32), 554 (4.13), 601 (4.36), 700 (4.31). ESI‑
HRMS calcd for [C51H46N5]+ (M+H): 728.3748, Found: 728.3742.
Received 14 September 2013; accepted 20 October 2013
Paper 1302081 doi: 10.3184/174751913X13846100471836
Published online: 6 December 2013
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