Hydro/deutero deamination of arylazo sulfones under metal and (photo)catalyst-free conditions

Article abstract of DOI:10.3390/molecules24112164

Hydrodeaminated and monodeuterated aromatics were obtained via a visible-light driven reaction of arylazo sulfones. Deuteration occurs efficiently in deuterated media such as isopropanol-d⁸ or in THF-d⁸/water mixtures and exhibits a high tolerance to the nature and the position of the aromatic substituents.

Full text of DOI:10.3390/molecules24112164

molecules
Article
Hydro/Deutero Deamination of Arylazo Sulfones
under Metal- and (Photo)Catalyst-Free Conditions
Hawraz I. M. Amin 1,2, Carlotta Raviola 1 , Ahmed A. Amin 3, Barbara Mannucci 4,
Stefano Protti 1,
*
and Maurizio Fagnoni 1,
*
1
PhotoGreen Lab, Department of Chemistry, University of Pavia. Viale Taramelli 12, 27100 Pavia, Italy;
hawraz_px@yahoo.com (H.I.M.A.); carlotta.raviola01@universitadipavia.it (C.R.)
Chemistry Department, College of Science, Salahaddin University-Erbil, Erbil 44001, Iraq
Chemistry Department, College of Education, Salahaddin University-Erbil, Erbil 44001, Iraq;
ahmed.dezaye@su.edu.krd
2
3
4
Centro Grandi Strumenti (CGS), University of Pavia, V. Bassi 21, 27100 Pavia, Italy;
barbara.mannucci@unipv.it
*
Correspondence: stefano.protti@unipv.it (S.P.); fagnoni@unipv.it (M.F.); Tel.: +39-03-8298-7314
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Alessandro Palmieri
Received: 16 May 2019; Accepted: 5 June 2019; Published: 8 June 2019
Abstract: Hydrodeaminated and monodeuterated aromatics were obtained via a visible-light driven
reaction of arylazo sulfones. Deuteration occurs efficiently in deuterated media such as isopropanol-d8
or in THF-d8/water mixtures and exhibits a high tolerance to the nature and the position of the
aromatic substituents.
Keywords: arylazo sulfones; deuteration; visible-light induced processes; photochemistry
1. Introduction
Deuterium-labeled compounds, which are physicochemically nearly identical to the
non-deuterated analogues, are widely used in mass spectrometry [
well as in mechanistic elucidation [ ] and metabolic studies [ ]. Selectively deuterated compounds
in medicine are of crucial importance since deuteration was proved to enhance, in some cases,
the metabolic stability of drugs [ ]. Deuterated drug analogues (also called “heavy drugs”) such
1] and in NMR spectroscopy [2], as
3
–5
6,7
8
as lisofylline (CTP-499) and dextromethorphan (AVP-786) are currently in clinical trials, whereas
deuterated tetrabenazine (SD-809) has been recently approved by the FDA for the treatment of chorea
associated with Huntington’s disease [9].
In view of these premises, the interest for the development of synthetic protocols for the selective
deuteration of organic compounds has received much attention in the last decade. Concerning the
formation of an Ar–D bond, various processes has been reported based on the activation of an Ar–H [10
or an Ar–X bond. In the former case, the C–H activation of arenes may occur under Pd- [11], Fe- [12],
Rh- [13] (in the presence of deuterated acetic or trifluoroacetic acids as the deuterating agents), Ru- [14
and Ir- [15 16] catalysis (D2 was used as the deuteron source, see Scheme 1a). Acid/base-mediated
labeling strategies making use of D2O as a rather inexpensive deuteron source were also proposed [17 18].
However, these transition metal-based approaches often lack regioselectivity [ 12], and when using
]
]
,
,
8,9,
substituted iodoarenes, a dehalogenation and/or alkyl group shift under acid conditions may take
place [18]. On the other hand, the Ar–X/Ar–D conversion was achieved via deuterodehalogenation
of (hetero)aryl halides (mainly bromides) catalyzed by Pd-complexes [19–21] (Scheme 1b), mediated
by the potassium methoxide/disilane system [22], by Pd-catalyzed deborylation of boronate esters in
THF/D2O 4:1 [23] or via deamination of anilines (via in situ prepared diazonium salts) [24].
Molecules 2019, 24, 2164; doi:10.3390/molecules24112164
www.mdpi.com/journal/molecules

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Scheme 1. Synthesis of deuterated arenes via (
of aryl halides, ( ) photocatalyzed reductive dediazoniation of arenediazonium salts, (
induced deuteron deamination of arylazo sulfones.
a
) Ir-catalytic C-H activation, (
b
) Pd-catalyzed deuteration
c
d) visible-light
The use of photochemical and photocatalyzed processes received impressive attention due to
the potentiality of visible or solar light as an economic, traceless reagent, and to the mild conditions
adopted [25–28]. In this field, the versatile conversion of aryl halides to the corresponding deuteroarenes,
in the presence of porous CdSe nanosheets as the photocatalyst, has been recently described [29],
despite the use of Na2SO3 as the sacrificial electron donor.
However, photochemistry also offers the chance to carry out chemical processes in the absence of
rather expensive and toxic transition metal catalysts/reactants, the presence of which is strictly limited
in the preparation of heavy drugs [30]. An interesting example has been reported (for a rather limited
range of substrates) and involved the photocatalytic reductive dediazoniation of arenediazonium salts
in DMF-d7 in the presence of Eosin B as the photoorganocatalyst ((POC) [31], Scheme 1c). On the
other hand, the adoption of visible-light induced, photocatalyst-free procedures received increasing
attention in organic synthesis [32–36].
We recently focused on a class of photoactivable aromatic substrates namely arylazo sulfones.
Such derivatives (smoothly obtained in a two-step procedure from the corresponding anilines) bear a
dyedauxiliary group (-N2SO2CH3) that, when incorporated in a compound, make it both colored and
photoreactive [37]. Indeed, the irradiation with visible light of an arylazo sulfone in polar solvents
resulted in the homolytic cleavage of the S–N bond, with the subsequent formation of the corresponding
aryl radical. Such behavior has been exploited in the preparation of aromatic amides [38], allylarenes [39],
triarylethylenes [40], as well as in the photocatalyst-free, gold catalyzed Suzuki coupling to biaryls [41].
We reasoned that such substrates could be employed in the development of a photocatalyst-free,
visible-light driven hydro/deutero deamination process exploiting the well-known hydrogen atom
abstraction capability of aryl radicals (Ar•, Scheme 1d), as detailed below.

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2. Results and Discussion
Initial experiments were carried out under deuteron-free conditions on the photoinduced reductive
dediazoniation of 1-(methylsulfonyl)-2-(4-acetylphenyl)diazene 1a to give acetophenone . The reaction
2
was tested in different media, at different concentrations of 1a and by using different photochemical
set-ups. These preliminary results have been summarized in Table S1 (see Electronic Supplementary
Information, ESI). The best performance was obtained in the iPrOH/H2O 9:1 mixture upon irradiation
◦
at 456 nm by means of a Kessil lamp (32 W) under temperature control (25 C), where
2
was
formed in 76% yield. We thus decided to extend such conditions to arylazo sulfones 1b
–
r
(Table 1).
The reduction took place for a wide range of substrates and the process exhibited a satisfactory
functional group tolerance, since aromatics bearing either electron-withdrawing (e.g., CH3CO-, -CN, or
-COOMe) or electron-donating (-Me, -tBu, or -OMe) substituents can be efficiently employed. Notably,
reduction yield was almost quantitative for halogenated derivatives 1e
of 2-nitrophenylazo sulfone 1j the corresponding nitrobenzene was obtained in a discrete yield (41%).
The process is still efficient even with polysubstituted aromatics (e.g., 1l and 1q). In the case of 1a
–f and 1k, whereas in the case
4
,
reduction took place efficiently also when increasing the amount of water. A THF/H2O 4:1 mixture
was used in selected cases as alternative reducing medium, giving comparable results (see the case of
1a and 1b in Table 1).
Table 1. Reductive dediazoniation of arylazo sulfones. Substrate scope a.
Ar-N2SO2Me
Product, % Yield
2, 76, 71 b, 61 c
3, 68, 54 c
4, 55
1a, Ar = 4-CH3CO-C6H4
1b, Ar = 4-CN-C6H4
1c, Ar = 4-NO2-C6H4
1d, Ar = 4-Cl-C6H4
5, 82
1e, Ar = 4-Br-C6H4
6, 97
1f, Ar = 4-I-C6H4
7, 97
1g, Ar = 4-COOMe-C6H4
1h, Ar = 3-CH3CO-C6H4
1i, Ar = 3-CN-C6H4
1j, Ar = 2-NO2-C6H4
1k, Ar = 2-Br-C6H4
8, 79
2, 77
3, 54
4, 41
6, 97
1l, Ar = 2-Cl, 4-F-C6H3
1m, Ar = 4-Me-C6H4
1n, Ar = 4-tBu-C6H4
1o, Ar = 4-CH3O-C6H4
1p, Ar = 2-CH3O-C6H4
1q, Ar = 3,4,5-CH3O-C6H2
1r, Ar = α-Naphthyl
9, 57
10, 75
11, 78, 55 c
12, 55
12, 80
13, 89
14, 57
a
Reaction conditions. A solution of the chosen arylazo sulfone 1a–r (0.025 M) in an iPrOH/H2O 9:1 mixture
irradiated for 14 h at 456 nm (32 W Kessil lamp). b Irradiation carried out in an iPrOH/H2O 4:1 mixture. c Irradiation
carried out in a THF/H2O 4:1 mixture.
With these results in our hand we investigated the feasibility of the preparation of deuterated
analogues of compounds 2–
14 (compounds 2-d1/14-d1) making use of an isopropanol-d8/H2O 9:1
mixture as the deuteron source. In selected cases, the same reaction was also performed in a THF-d8/H2O
4:1 mixture (Table 2).

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Table 2. Preparation of deuterated arenes (2-d1-14-d1) a.
a
Reaction conditions: 1a–r
(0.025 M) in an isopropanol-d7/H2O 9:1 mixture irradiated at 456 nm (Kessil lamp, 32W)
for 14 h. Reaction carried out in an isopropanol-d7/H2O 4:1 mixture. Reaction carried out in a THF-d8/H2O 4:1
b
c
mixture. Reaction carried out in an isopropanol-d7/H2O 9:1 mixture on a 0.1 mmol scale (0.1 M, 1 mL), isolated
d
e
yield. 2-Nitrophenyl methylsulfone (<10%) detected by GC-MS.
Gratifyingly, moving to deuterated solvents did not affect the efficiency of the process and a
satisfactory yield of products 2-d1/14-d1 was always obtained. In particular, high deuteration yields
were found in the case of 4-nitro- and bromo-derivatives 1c
1q. Contrary to what observed in non-deuterated media, good results were also obtained when using
2-nitrophenylazo sulfone 1j since compound 40-d1 was formed in 71% yield.
-Deuteronaphthalene
,e,k, and (poly)methoxyphenylazo sulfone
α
14-d1 was likewise formed in discrete amounts (64% yield). Noteworthy, the amount of non-deuterated
2–14 is always negligible, even in the presence of H2O as the co-solvent. This allowed us, in a couple
of reactions (the synthesis of 2-d1 and 6-d1), to reduce the amount of deuterated isopropanol from 9:1
to 4:1 maintaining comparable yields. The use of a THF-d8/H2O 4:1 mixture as the medium often led to
a lower efficiency of the process (compare for instance the yields obtained for 7-d1 and 12-d1). The
deuteration reaction is essentially clean (see Table 2 and ESI).

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We carried out preparative reactions (on a 0.1 mmol scale) only in selected cases due to the volatility
of the other aromatics. Thus, deuterated arenes 4-d1 13-d1 and 14-d1 were isolated in satisfactory
,
yields (54–89%, see Table 2), pointing out the synthetic potentiality of our approach.
Based on the observed results, we suggested the mechanism described in Scheme 2. Arylazo
sulfones (1a–r) show a wavelength-selective behavior [37,42] where the homolytic cleavage of the N–S
bond and the subsequent formation of an aryl radical (Ar•, path b) takes place from the singlet excited
state (1nπ*) upon visible light irradiation (path a).
Scheme 2. Plausible mechanism for the visible light induced dediazoniation of arylazo sulfones 1a
–r to
form hydrogenated/deuterated derivatives 2–14/2-d1–14-d1.
Hydrogen atom transfer (HAT) between Ar• and the surrounding environment (path c) is efficient
and widely investigated in the literature [43 48]. Our results confirmed that such highly reactive
(but yet selective) Ar• selectively abstracts a hydrogen (or a deuteron) from a C–H bond (or a C–D
bond) in both isopropanol (C–H BDE = 91 1.6 kcal
1.0 kcal mol−1) and THF (C–H BDE = 92.1
mol−1
35]; the C–H/C–D bond cleaved is the weakest one as indicated in red in Scheme 2) to form
the corresponding Ar–H or Ar–D product (Ar–H BDE in benzene: 112.9 49]). The
0.5 kcal mol−1
–
±
±
[
±
[
presence of a significant amount of non-deuterated water (up to ca. 11 M in the case of a deuterated
isopropanol/H2O 4:1 mixture) did not appreciably affect the deuteration yield.
3. Conclusions
Summing up, with the “proof of concept” presented herein we highlighted the potentialities of
bench stable, colored arylazo sulfones in the preparation of deuterated aromatics via visible light
irradiation at room temperature under both metal- and photocatalyst-free conditions.
4. Materials and Methods
4.1. General
1H- and 13C-NMR spectra were recorded on a 300 MHz spectrometer (Bruker, Milan, Italy),
chemical shifts were reported in ppm downfield from TMS, and the attributions were made based on
1H and 13C signals; chemical shifts were reported in ppm downfield from TMS.
The reaction course was followed by means of GC-MS. GC-MS analyses were carried out using a
Thermo Scientific DSQII single quadrupole GC/MS system (Thermo Scientific®, San Jose, CA, USA).
A Restek Rtx-5MS (30 m
×
0.25 mm
×
0.25 µm) capillary column (Restek Corporation, Bellefonte,
USA) was used for analyte separation with helium as carrier gas at 1 mL min−1. The injection in
the GC system was performed in split mode and the injector temperature was 250 ◦C. The GC oven
temperature was held at 80 ◦C for 2 min, increased to 220 ◦C by a temperature ramp of 10 ◦C min−1
and held for 10 min. The transfer line temperature was 250 ◦C and the ion source temperature 250 ◦C.
Mass spectral analyses were carried out in full scan mode. Deuterated solvents were commercially

Molecules 2019, 24, 2164
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available and were used as received. Arylazo sulfones (1a
–1e
,
1g
,
1i
,
1j
,
1n–
p, and 1r,
[
38]; 1f
[
50]; and
1m [40]) were previously synthesized and fully characterized in our lab.
4.2. General Procedure for the Synthesis of Arylazo Sulfones (1h, 1k, 1l, 1q)
Arylazo sulfones (1h, 1k, 1l, and 1q) were synthesized according to the literature procedure [37].
Diazonium salts were freshly prepared prior to use from the corresponding anilines and purified by
dissolving in acetonitrile and precipitation by adding cold diethyl ether. To a cooled (0 ◦C) suspension
of the chosen diazonium salt (1 equiv, 0.3 M) in CH2Cl2 was added sodium methanesulfinate (1.2
equiv) in one portion. The temperature was allowed to rise to room temperature, and the solution
stirred overnight. The resulting mixture was then filtered, and the obtained solution was evaporated.
The crude product was finally dissolved in CH2Cl2 and precipitated by adding cold N-hexane.
1-(Methylsulfonyl)-2-(3-acetylphenyl)diazene (1h). From 3-acetylphenydiazonium tetrafluoroborate [51
]
(1.50 g, 6.4 mmol) and 790 mg (1.2 equiv) of sodium methanesulfinate in CH2Cl2 (21 mL).
Recrystallization afforded 999 mg of 1-(methylsulfonyl)-2-(4-acetylphenyl)diazene (1h, yellow solid,
1
69% yield, mp: 74–76 ◦C dec). H-NMR (300 MHz, CD3COCD3,
δ
): 2.73 (s, 3H), 3.35 (s, 3H), 7.84-7.89
(t, 1H, J = 7.5 Hz), 8.19–8.22 (dd, 1H, J = 7 and 2 Hz), 8.35–8.39 (dd, 1H, J = 7 and 2 Hz), 8.52–8.54 (d,
1H, J = 2.5 Hz). 13C-NMR (75 MHz, CD3COCD3,
δ): 27.3 (CH3), 35.4 (CH3), 125.25 (CH), 128.4 (CH),
131.7 (CH), 135.3 (CH), 140.2, 150.7, 197.3. IR (neat, ν/cm−1): 3056, 2992, 1690, 1340, 1146.
1-(Methylsulfonyl)-2-(2-bromophenyl)diazene (1k). From 2-bromophenydiazonium tetrafluoroborate [52
]
(1.50 g, 5.5 mmol) and 680 mg (1.2 equiv) of sodium methanesulfinate in CH2Cl2 (21 mL).
Recrystallization afforded 706 mg of 1-(methylsulfonyl)-2-(2-bromophenyl)diazene (1k, yellow solid,
1
49% yield, mp: 97.6–99.3 ◦C dec). H-NMR (300 MHz, CD3COCD3, δ): 3.35 (s, 3H), 7.64–7.78 (m, 3H)
7.98–8.01 (dd, 1H, J = 8 and 1.5 Hz). 13C-NMR (75 MHz, CD3COCD3,
δ
): 35.6 (CH3), 119.3 (CH), 128.8,
130.3 (CH), 136.0 (CH), 137.7 (CH), 147.7. IR (neat,
ν
/cm−1): 3056, 2992, 1690, 1340, 1146. IR (neat,
ν/cm−1): 3060, 2990, 1342, 1156.
1-(Methylsulfonyl)-2-(2-chloro-4-fluorophenyl)diazene (1l). From 2-chloro-4-fluorophenydiazonium
tetrafluoroborate [53] (1.50 g, 6.1 mmol) and 753 mg (1.2 equiv) of sodium methanesulfinate in CH2Cl2
(21 mL). Recrystallization afforded 910 mg of 1-(methylsulfonyl)-2-(2-chloro-4-fluorophenyl)diazene (1l
,
1
yellow solid, 63% yield, mp: 73–75 ◦C dec). H-NMR (300 MHz, CD3COCD3,
δ): 3.35 (s, 3H), 7.39–7.46
(m, 1H), 7.68–7.71 (dd, 1H, J = 8 and 2.5 Hz), 7.91–8.00 (m, 1H). 13C-NMR (75 MHz, CD3COCD3,
δ):
35.6 (CH3), 117.4 (d, CH, J = 23 Hz), 119.9 (d, CH, J = 26 Hz), 121.4 (d, CH, J = 10.5 Hz), 140.7 (d, J = 11
Hz), 143.5 (d, J = 3 Hz), 167.7 (d, J = 258 Hz). IR (neat, ν/cm−1): 3099, 3037, 2937, 1587, 1345, 1161.
1-(Methylsulfonyl)-2-(3,4,5-trimethoxyphenyl)diazene (1q). From 3,4,5-trimethoxybenzenediazonium
tetrafluoroborate [54] (1.50 g, 5.3 mmol) and 654 mg (1.2 equiv) of sodium methanesulfinate in CH2Cl2
(21 mL). Recrystallization afforded 654 mg of 1-(methylsulfonyl)-2-(3,4,5-trimethoxyphenyl)diazene
1
(
1i, yellow solid, 45% yield, mp: 114–116 ◦C dec). H-NMR (300 MHz, CD3COCD3,
δ
): 2.29 (s, 3H),
3.91 (s, 3H), 3.97 (s, 6H), 7.35 (s, 2H). 13C-NMR (75 MHz, CD3COCD3,
(CH3), 103.5 (CH), 105.9, 146.0, 155.3. IR (neat, ν/cm−1): 3055, 2941, 1471, 1343, 1129.
δ): 35.3 (CH3), 57.1 (CH3), 61.4
4.3. General Procedure for Photochemical Irradiations
A 0.025 M solution of 1a–r in the chosen medium (iPrOH-H2O 9:1, THF-H2O 4:1,
isopropanol-d8/H2O 9:1, isopropanol-d8/H2O 4:1, and THF-d8/H2O 4:1, 1 mL) was irradiated at
456 nm (Kessil lamp, 32W) for 14 h. An air-cooling system was used to maintain the temperature
below 30 ◦C. The reaction course and the product distribution were analyzed by GC-MS analyses. The
amounts of compounds 2–14/2-d1-14-d1 have been determined by using calibration curves.
In selected cases, deuteration of arylazo sulfones was scaled-up and carried out on a 0.1 mmol scale.
Synthesis of 4-deutero-1-nitrobenzene (4-d1): A 0.1 M solution of 1d (22.4 mg, 0.1 mmol) in an
isopropanol-d8/H2O 9:1 mixture (1 mL) was irradiated for 24 h at 456 nm, then the solvent evaporated

Molecules 2019, 24, 2164
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in vacuo. Purification of the resulting residue by column chromatography (eluant: Neat pentane)
afforded 8.5 mg of 4-d1 (oil, 68% yield). The spectroscopic data of 4-d1 were in accordance with the
literature [19].
Synthesis of 4-deutero-1,2,3-trimethoxybenzene (13-d1): A 0.1 M solution of 1q (27.4 mg. 0.1
mmol) in isopropanol-d8/H2O 9:1 mixture (1 mL) was irradiated for 24 h at 456 nm, then the solvent
evaporated in vacuo. Purification of the resulting residue by column chromatography (eluant: Neat
cyclohexane) afforded 15 mg of 13-d1 (pale yellow solid, mp = 38–40 ◦C, 89% yield). The spectroscopic
data of 13-d1 were in accordance with the literature [55].
1
13-d1. H-NMR (300 MHz, CDCl3,
δ
): 3.88 (s, 3H), 3.89 (s, 6H), 6.61 (s, 2H). 13C-NMR (75 MHz,
CDCl3, δ): 56.0 (CH3), 66.7 (CH3), 105.0 (CH), 123.2 (t, J = 20 Hz, CD), 138.0, 153.4.
Synthesis of α
-deutero-naphthalene (14-d1): A 0.1 M solution of 1r (23.4 mg, 0.1 mmol) in an
isopropanol-d8/H2O 9:1 mixture (1 mL) was irradiated for 24 h at 456 nm, then the solvent evaporated
under vacuo. Purification of the resulting residue by column◦chromatography (eluant: Neat pentane)
◦
afforded 7 mg of 14-d1 (pale yellow solid, mp = 70.2–71.3 C, lit. 71–73 C [56], 54% yield). The
spectroscopic data of 14-d1 were in accordance with the literature [55].
1
Supplementary Materials: The following are available online, MS spectra of compounds 2-d1-14-d1; H- and
13C-NMR spectra of 1h, 1k, 1l, 1q, 4-d1, 13-d1, and 14-d1 [56–65].
Author Contributions: Conceptualization, S.P. and M.F.; methodology, H.I.M.A.; validation, C.R., formal
analysis, B.M.; investigation, H.I.M.A.; data curation, C.R.; writing—original draft preparation, S.P. and M.F.;
writing—review and editing, M.F., C.R. and A.A.A.; supervision, S.P. and M.F.
Funding: This research was funded by the Chemistry Department, College of Science, Salahaddin University-Erbil
(Iraq).
Acknowledgments: Hawraz I. M. Amin is grateful to the Chemistry Department, College of Science, Salahaddin
University-Erbil (Iraq) for financial support.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1a–r are available from the authors.
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