Scalable Synthesis of Acridinium Catalysts for Photoredox Deuterations

Article abstract of DOI:10.1055/s-0039-1690694

The continuous development of photocatalytic methods incentivizes the design of organic catalysts to complement the frequently used and precious polypyridyl transition metal systems. Herein, a scalable synthesis of suitable acridinium dyes and their appli

Full text of DOI:10.1055/s-0039-1690694

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
psp
A
en
B. Zilate et al.
PSP
Synthesis
Scalable Synthesis of Acridinium Catalysts for Photoredox
Deuterations
Br–
Bouthayna Zilate
Br Me Br
N
M
Me
N
M
MeO
O
Me
N+
Christian Fischer
Lukas Schneider
Christof Sparr*
0
0
0
0-0
0
0
2-5
0
2
3-
1
0
8
0
R1
R1
R2
Mg
THF, 60 °C
0
0
0
0-0
0
0
2-
4
2
1
3-0
9
4
1
R1
R1
R1
R1
R2
M = Mg
Department of Chemistry, University of Basel,
St. Johanns-Ring 19, 4056 Basel, Switzerland
christof.sparr@unibas.ch
6
5
Br–
Me
N+
Photocatalyst (2.5 mol%)
i-Pr3SiSH (30 mol%)
R1
R1
Cl
Cl
N
N
1'
Li2CO3, D2O, NMP, 24 h
40 W blue LED
H
N+
3'
N
R2
Cl–
Received: 23.08.2019
Accepted after revision: 12.09.2019
Published online: 21.10.2019
properties of the organophotocatalysts. We hence set out to
explore the synthesis of acridinium salts with and without
amino groups, their scale-up, and the performance in a
photoredox deuteration as benchmark reaction.
DOI: 10.1055/s-0039-1690694; Art ID: ss-2019-t0475-psp
Abstract The continuous development of photocatalytic methods in-
centivizes the design of organic catalysts to complement the frequently
used and precious polypyridyl transition metal systems. Herein, a scal-
able synthesis of suitable acridinium dyes and their application in pho-
toredox deuterations are described. The acridinium catalysts, prepared
on multi-gram scale, allowed the deuteration of a pharmaceutically rel-
evant scaffold in high yield and selectivity under mild conditions.
Fukuzumi:1
–
ClO4
Me
N+
Me
N
MesMgBr
then HClO4
NaOH
Me
Me
O
Key words acridinium salts, deuteration, Grignard reactions,
photoredox catalysis, scalability
Me
Nicewicz:4
–
–
BF4
BF4
Ph
N+
t-Bu
O+
t-Bu
t-Bu
t-Bu
Acridinium salts, pioneered by Fukuzumi1 and utilized
for various innovative methodologies by Nicewicz,2 are es-
tablished as particularly valuable catalysts for photoredox
chemistry (Scheme 1). As organocatalysts, efficient and
scalable processes for their synthesis would render them
potentially suitable for industrial applications. To further
expand their accessibility, we thus developed a method for
the preparation of acridinium salts by a two-fold addition
of a 1,5-bifunctional organometallic reagent to an ester3
while Nicewicz and co-workers recently disclosed an alter-
native synthesis of acridinium salts based on late stage nuc-
leophilic substitution of xanthilium dyes.4 Since the photo-
stability of mesityl acridinium catalysts is impacted by the
oxidation of the para-methyl group,5 methods allowing
variation of this moiety are particularly valuable. Owing to
the expedient accessibility of 1,5-bifunctional organomag-
nesium reagents,6 we anticipated that acridinium salts with
different redox properties can be readily prepared on gram
scale. Furthermore, our direct acridinium synthesis from
esters allows the incorporation of electron-donating groups
such as amino functionalities that impactfully modulate the
Ph-NH2
Me
Me
Me
Me
Me
Me
Benniston:5 photostability of mesityl acridinium salts
–
–
ClO4
ClO4
Me
Me
N+
Me
N+
hυ, O2
Me
Me
Me
Me
This work: gram-scale synthesis
CHO
Br–
Br Me Br
N
M
Me
N
M
MeO
O
Me
N+
R1
R1
R2
Mg
THF
60 °C, 12 h
then HBr
THF
R1
60 °C, 3 h
R1
R1
R1
R2
M = Mg
Scheme 1 Syntheses and photostability of acridinium photocatalysts
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

B
B. Zilate et al.
PSP
Synthesis
Br
H
N
Br
5) Mg, THF, 60 °C
Br
then
R2
Br
CO2Me
1) aq HNO3 (68%), MTBE/
THF
NaH, THF,
then
NH2
R2
Me
N
Br
MeI (81%)
then H2SO4 CH2Cl2 (52%)
R1
R1
Br Me Br
N
2) NH4Cl, Fe,
MeOH/H2O (87%)
NMe2
R3
NMe2
3) Pd2(dba)3 (2.5 mol%)
dppf (5 mol%), NaOt-Bu, toluene (70%)
R2
R2
5
3
+
THF, 60 °C
then HBr
4) NaH, THF, then MeI (71%)
R1
R1
Br
R3
Br
a) aq HCHO (37%), H2SO4
THF, NaBH4 (94%)
2a : R1 = H
2b : R1 = NMe2 (35 g)
I
1a : R1 = R2 = H, R3 = F (63%)
1b : R1 = R2 = H, R3 = OMe (78%)
1c : R1 = NMe2, R2 = R3 = Me (82%; 3.9 g)
1d : R1 = NMe2, R2 = Me, R3 = H (84%; 3.9 g)
b) NaI, CuI (cat)
1,4-dioxane (97%)
c) Br2, CH2Cl2 (57%)
NH2
NMe2
6
4
Scheme 2 Synthesis of acridinium salts 1a and 1b and gram scale preparation of 1c and 1d
Our synthesis of the acridinium catalysts 1 started with
the dibromophenyl-N-methylaniline precursor 2a, which
was obtained through a Buchwald–Hartwig amination fol-
lowed by a methylation (Scheme 2).7 The formation of the
1,5-bifunctional organometallic reagent, nucleophilic addi-
tion to ester substrates, and dehydration using HBr,3a led to
acridinium salts 1a and 1b in good yields (63% and 78%,
Scheme 2). Encouraged by these results and the distinctive
catalytic performance of organophotocatalyst 1c,3a we next
tackled the gram-scale synthesis of 1c and 1d. The former
preparation of reagents 3 and 4 for the C–N cross coupling
proved challenging during scale-up and led us to circum-
vent the Sandmeyer iodination from 3 to 4.8 Gratifyingly, an
alternative route consisting of a reductive amination, a Fin-
kelstein reaction, and bromination allowed us to access in-
termediate 4 in good to excellent yields without any column
chromatography.9 A careful optimization of the nitration
and reduction conditions delivered intermediate 3 in good
yield, purified by recrystallization.10 With the two coupling
partners in hand, a C–N cross-coupling, followed by a meth-
ylation were performed.7 After recrystallization, we ob-
tained 35 g of the key intermediate 2b. Similarly, the forma-
tion of the 1,5-bifunctional organometallic reagent was
achieved on a large scale, using elemental magnesium in re-
fluxing THF. Addition of the different carboxylic acid esters
to the reagents and HBr treatment provided 3.9 g of 1c and
1d in 83% and 84% yield, respectively.
Table 1 Photophysical Properties of the Acridinium Photocatalysts
Br–
Br–
Me
N+
Me
N
Me
N+
Me
N
Me
Me
Me
Me
F
Me
1a
1c
Br–
Br–
Me
N+
Me
N
Me
N+
Me
N
Me
Me
Me
Me
OMe
1b
1d
Dye
abs
em
E0.0
E
1/2 (P/P–)
[V]b
E
1/2 (P*/P–)
[V]
[nm]a
[nm]a
[eV]a
1a
1b
1c
1d
426
438
503
504
512
499
530
533
2.83
2.77
2.40
2.40
–0.51
+2.32
–0.56
–1.15
–1.15
+2.21
+1.25
+1.25
a Measured in MeCN (15 molL–1).
b Measured in 0.1 molL–1 n-Bu4N+PF6– in anhyd, degassed MeCN against
SCE.
Interestingly, catalyst 1a exhibited a higher excited state
reduction potential (Table 1, E1/2 [P*/P–] = +2.32 V vs SCE)
compared to the Fukuzumi catalyst (E1/2 [P*/P–] = +2.18 V vs
SCE).1 On the other hand, 1b displayed a similar excited
state reduction potential (E1/2 [P*/P–] = +2.21 V vs SCE), indi-
cating the influence of electron density at the phenyl moi-
ety. The catalyst 1d without the labile para-methyl group
showed almost identical properties as compared to 1c (E1/2
[P*/P–] = +1.25 V vs SCE), which makes it an ideal candidate
for further investigations in photoredox catalysis.
To explore the catalytic performance of the acridinium
catalysts, we studied the deuteration of clomipramine as
benchmarking reaction.11 An average isotopic incorporation
of 7 deuterium atoms per molecule with a distribution be-
tween aliphatic and benzylic positions (C5, C6, C1′, C3′,
NMe2) has been reported by MacMillan and co-workers us-
ing 4CzIPN [2,4,5,6-tetra(9H-carbazol-9-yl)isophthaloni-
trile] as photocatalyst. We thus tested several acridinium
photocatalysts,12 under identical reaction conditions (Table
2). Gratifyingly, a high selectivity for the aliphatic positions
(C1′ = 20%, C3′ = 64%, NMe2 = 39%), with an average of 4
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

C
B. Zilate et al.
PSP
Synthesis
deuterium atoms per molecule was observed when using
1c with 1 mol% catalyst loading. A similar pattern was ob-
served when employing 1d with an even higher selectivity
for the C3′ position (70%) and an identical average incorpo-
ration of 4 deuterium atoms per molecule.
ium catalysts allowed the large-scale synthesis of amino-
functionalized photocatalysts with attenuated photoredox
properties. The utility of the catalysts was demonstrated by
the deuteration of clomipramine, providing high selectivity
for aliphatic positions using low catalyst loadings.
Table 2 Photochemical Deuteration of Clomipramine
All reactions were carried out in dried glassware under an argon at-
mosphere. THF (99.5%, Extra Dry, over Molecular Sieves, Stabilized,
AcroSeal®, Code: 348455000) was purchased from Acros Organics. All
starting materials and reaction solvents were purchased from com-
mercial sources and used without further purification. Unless noted
otherwise, all photoreactions were performed in a sealed Biotage® 2–
5 mL microwave vial equipped with a 10 mm × 5 mm magnetic stir
bar stirring at 1400 rpm. The vial was placed on a stirring plate later-
ally in 3 cm distance to a Kessil LED A160WE Tuna Blue, 40 W, adjust-
ed to maximum intensity and white (max: 464 nm). A sideward fan
was used to keep ambient temperature (30 °C). Solvents for ex-
tractions and chromatography were technical grade and distilled pri-
or to use. Analytical TLC was performed on pre-coated Merck silica
gel 60 F254 plates (0.25 mm) and visualized by UV. Flash column chro-
matography was carried out on Silicycle SiliaFlash P60 (230–400
mesh). Concentration in vacuo was performed by rotary evaporation
to 10 mbar at 40 °C, unless stated otherwise. 1H and 13C NMR spectra
were recorded on a Bruker Avance III 500 MHz spectrometer at 298 K
in CDCl3 or MeOD supplied by Cambridge Isotope Laboratories (DLM-
7TB-100S). Chemical shifts () are reported in ppm relative to TMS
(0.00 ppm). Standard abbreviations are used to report multiplicities.
Melting points were measured on a Büchi M-565 melting point appa-
ratus and are uncorrected. IR spectra were measured on an ATR Vari-
an Scimitar 800 FT-IR spectrophotometer and reported in cm–1. The
intensities of the bands are reported as: w = weak, m = medium, s =
strong. High-resolution mass spectrometry (HR-ESI) was performed
by Dr. Michael Pfeffer of the University of Basel on a Bruker maXis 4G
QTOF ESI mass spectrometer. Cyclic Voltammetry was performed in
dry, degassed 0.1 molL–1 n-Bu4N+PF6– in MeCN. Voltammograms were
recorded with a Versastat3-200 potentiostat from Princeton Applied
Research employing a glassy carbon disk working electrode, SCE refer-
ence electrode and a silver wire counter electrode and a potential
sweep rate of 0.1 Vs–1. The glassy carbon electrode and Ag wire were
polished prior to measurement. UV/Vis spectroscopy was performed
on a Shimadzu UV-1650 PC spectrometer in acetonitrile using Hellma
fluorescence cells (111-QS, light path: 10 mm). Molar absorption co-
efficients () were determined at the wavelength of maximum absor-
bance (labs) of a 10 molL–1 dye solution. Steady-state emission
spectroscopy was carried out with a Fluorolog-3-22 instrument from
Horiba Jobin-Yvon. Excitation occurred at the long-wavelength ab-
sorption band of the respective dye. All emission spectra were record-
ed in argon-saturated acetonitrile, and strongly diluted dye solutions
(c <15 mol L–1) were used to avoid inner filter effects. All spectra so
obtained were corrected for the wavelength dependent sensitivity of
the spectrometer. Additional emission spectra of the pure solvent at
all excitation and detection conditions were measured to ensure the
absence of stray light or impurity signals.
6
5
Photocatalyst (2.5 mol%)
i-Pr3SiSH (30 mol%)
Cl
N
Cl
N
3'
H
1'
Li2CO3, D2O, NMP, 24 h
40 W blue LED
N+
N
Cl–
Photocat.a Yieldb (%) Average 2H/molecule 2H Incorporation (%)c
C5 C6 C1′ C3′ NMe2
4CzIPN
80
7.1
<1.0
1.0
13 13 47
71
11
25
10
64
64
70
15
22
49
19
25
43
70
4
Fukuzumi 95
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1ad
1bd
1c
86
88
92
92
98
98
76
88
96
97
97
–
9
<1.0
4.0
–
–
20
20
15
3
39
39
39
7
1cd
1dd
7a
4.0
4.0
<1.0
1.3
7b
7c
6
13
30
5
3.0
12
3
7d
7e
<1.0
1.0
–
8
7f
2.2
4
21
Ph
N+
Ph
N+
Ph
N+
Br
Br
Br
Br
NMe2
NMe2
OMe Mes
OMe m-xylyl
OMe Mes
7c
7a
7b
Ph
N+
Ph
Br
Ph
N+
Br
N+
MeO
OMe
NMe2
OMe m-xylyl
OMe Mes
OMe Mes OMe
7d
7e
7f
Me
Me
Me
Me
m-xylyl :
Mes :
Me
a Reaction performed with clomipramine HCl (100 mol), Li2CO3 (480 mol),
triisopropylsilanethiol (30 mol%), photocat. (2.5 mol%), unless stated other-
wise, D2O (5.00 mmol) in NMP (1.6 mL) at RT, 24 h irradiation with Kessil
A160WE tuna blue.
b Yield of isolated products.
c Determined by 1H NMR of the free base.
Synthesis of Acridinium Salts 1a and 1b
d Using 1 mol% of photocatalyst.
2-Bromo-N-(2-bromophenyl)-N-methylaniline
[CAS Reg. No.: 87345-09-3]
Prepared according to a modified literature procedure.7,13
In conclusion, we have described an efficient synthesis
to access acridinium salts with suitable photophysical
properties. The direct transformation of esters into acridin-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

D
B. Zilate et al.
PSP
Synthesis
Bis-(2-bromophenyl)amine (4.59 g, 14.0 mmol) in THF (70 mL) was
treated with NaH (60% dispersion in mineral oil, 700 mg, 17.5 mmol)
at RT and refluxed for 30 min. MeI (3.78 g, 1.66 mL, 26.6 mmol) was
added and the mixture was refluxed for another 2 h, cooled to RT, and
treated with H2O (50 mL). The resulting mixture was extracted with
Et2O (3 × 65 mL), the combined organic layers were dried (Na2SO4),
and concentrated in vacuo. The residue was washed with pentane and
dried in vacuo to obtain a white solid; yield: 3.87 g (81%); mp 106–
108 °C.
HRMS (ESI): m/z [M+] calcd for C20H15FN+: 288.1183; found: 288.1185.
Absorption spectroscopy (in MeCN): abs: 426 nm; abs: 8.4·102 Lcm–1mol–1;
em (exc 410): 512 nm; Stokes shift: 86 nm; E0.0: 2.83 eV; Cyclic vol-
tammetry (vs SCE): E1/2 (P*/P–): +2.32 V, E1/2 (P/P–): –0.51 V.
9-(4-Methoxyphenyl)-10-methylacridinium Bromide (1b)
Prepared according to the general procedure A using methyl 4-me-
thoxybenzoate (16.6 mg, 100 mol) and the 1,5-bifunctional organo-
magnesium reagent to afford an orange solid; yield: 29.6 mg (78%);
mp 185 °C (dec.); Rf = 0.16 (CH2Cl2/MeOH 10:1).
IR (ATR, neat): 3434w, 3286w, 2959w, 2872w, 166w, 1544w, 1468m,
1341w, 1232w, 1141m, 1074m, 1017m, 990w, 866m, 755s, 625m cm–1
.
IR (ATR, neat): 3336m, 3092w, 2931w, 1605s, 1547m, 1457m, 1376m,
1250s, 1176s, 1113w, 1022m, 922w, 932m, 761s, 725s, 666m, 617s
1H NMR (500 MHz, CDCl3):  = 7.55 (dd, 3J = 7.9 Hz, 4J = 1.5 Hz, 2 H,
C3H), 7.24 (ddd, 3J = 8.0, 7.3 Hz, 4J = 1.5 Hz, 2 H, C5H), 7.00 (dd, 3J = 8.0
cm–1
.
4
3
4
Hz, J = 1.6 Hz, 2 H, C6H), 6.94 (ddd, J = 7.9, 7.4 Hz, J = 1.6 Hz, 2 H,
1H NMR (500 MHz, CDCl3):  = 8.93 (d, 3J = 8.8 Hz, 2 H, C4H, C5H), 8.34
(t, 3J = 7.5 Hz, 2 H, C3H, C6H), 8.02 (d, 3J = 8.6 Hz, 2 H, C1H, C8H), 7.73
(dd, 3J = 8.9, 6.6 Hz, 2 H, C2H, C7H), 7.33–7.37 (m, 2 H, C2′H, C6′H),
7.16–7.18 (m, 2 H, C3′H, C5′H), 5.23 (s, 3 H, NCH3), 3.93 (3 H, s, OCH3).
13C NMR (125 MHz, CDCl3):  = 161.4 (C4′), 161.4 (C9), 141.6 (C4a,
C10a), 139.0 (C3, C6), 131.7 (C2′, C6′), 130.2 (C1, C8), 127.8 (C2, C7),
126.2 (C8a, C9a), 124.8 (C1′), 119.7 (C4, C5), 114.6 (C3′, C5′), 55.7
(OCH3), 41.0 (NCH3).
C4H), 3.23 (s, 3 H, NCH3 ).
13C NMR (125 MHz, CDCl3):  = 148.7 (C1), 134.4 (C3), 128.1 (C5),
124.8 (C4), 123.8 (C6), 120.3 (C2), 41.3 (CH3).
HRMS (ESI): m/z calcd [M + H+] for C13H11Br2N+: 339.9331; found:
339.9334.
1,5-Bifunctional Organomagnesium Reagent for the Ester to Acri-
dinium Transformation
HRMS (ESI): m/z [M+] calcd for C21H18NO+: 300.1383; found:
To a suspension of Mg turnings (13.6 mg, 560 mol) in anhyd THF
(0.20 mL) at 60 °C was added a solution of 2-bromo-N-(2 bromophe-
nyl)-N-methylaniline (47.7 mg, 140 mol) in anhyd THF (0.60 mL).
The mixture was stirred at 60 °C for 3 h during which the reaction
mixture turned yellow, leading to the 1,5-bifunctional organomagne-
sium reagent, which was used directly in the next step.
300.1384.
Absorption spectroscopy (in MeCN): abs: 438 nm; abs: 3.2·102 Lcm–1mol–1;
em (exc 360): 499 nm; Stokes shift: 61 nm; E0.0: 2.77 eV; Cyclic vol-
tammetry (vs SCE): E1/2 (P*/P–): +2.21 V, E1/2 (P/P–): –0.56 V.
Gram-Scale Synthesis of Acridinium Salt 1c and 1d
General Procedure A
4-Bromo-N,N-dimethyl-3-nitroaniline
Prepared according to a modified literature procedure.3,10a
To a solution of the above reagent in THF (140 mol) at 60 °C was add-
ed a solution of carboxylic acid ester (100 mol) in anhyd THF (1.00
mL) and the reaction mixture was stirred at the same temperature for
12 h. Aq HBr (1.00 mL, 8.8 molL–1) was added and the solvent was re-
moved in vacuo. The residue was dissolved in MeOH and filtered over
a bed of Amberlyst A21 free base. The solvent was removed in vacuo,
the residue was dissolved in CH2Cl2, and 3.0 g of silica gel was added.
The solvent was removed in vacuo and the residue purified by column
chromatography with CH2Cl2 100% to CH2Cl2/MeOH 100:2 to 100:5 to
100:8 to yield acridinium salts 1a and 1b.
To a solution of 4-bromo-N,N-dimethylaniline (5; 50.0 g, 250 mmol)
in TBME/THF (1:1, 340 mL) was added dropwise aq HNO3 (68%, 16.5
mL). The mixture was stirred for 1 h at RT. The formed precipitate was
filtered off and the residue was washed with TBME (2 × 30 mL) and
dried under vacuum overnight.14 The yellow salt (35.0 g, 133 mmol)
was then dissolved in CH2Cl2 (210 mL) and the solution was added to
concd H2SO4 (58.0 mL) while maintaining the temperature below 5 °C.
The mixture was allowed to warm up to RT and stirred for 1 h. The
mixture was then slowly added to cold H2O (210 mL) and aq NH4OH
(28%) was added until the mixture reached pH 10. The aqueous resi-
due was extracted with CH2Cl2 (2 × 500 mL), the combined organic
layers were dried (Na2SO4), and concentrated in vacuo to obtain 4-
bromo-N,N-dimethyl-3-nitroaniline as an orange solid; yield: 32.0 g
(52%); mp 90.4–91.9 °C; Rf = 0.73 (CH2Cl2 100%).
9-(4-Fluorophenyl)-10-methylacridinium Bromide (1a)
Prepared according to the general procedure A using methyl 4-fluoro-
benzoate (15.4 mg, 100 mol) and the 1,5-bifunctional organomag-
nesium reagent to afford a yellow solid; yield: 22.8 mg (63%); mp
212–214 °C; Rf = 0.10 (CH2Cl2/MeOH 10:1).
IR (ATR, neat): 2920w, 1609m, 1530s, 1443w, 1369m, 1234w, 1190w,
IR (ATR, neat): 3377w, 3059w, 2999w, 2923w, 2848w, 1601m,
1574m, 1544, 1504m, 1482w, 1446w, 1373m, 1272w, 1217m,
1156m, 1094m, 1023m, 926w, 866w, 816w, 767s, 722m, 666m, 614m
1129w, 1069w, 881w, 679w cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.46 (d, 3J = 9.0 Hz, 1 H, C5H), 7.07 (d,
4J = 3.1 Hz, 1 H, C2H), 6.69 (dd, 3J = 9.1 Hz, 4J = 3.1 Hz, 1 H, C6H), 3.00
[s, 6 H, N(CH3)2].
13C NMR (125 MHz, CDCl3):  = 150.4 (C3), 149.7 (C1), 134.9 (C5),
116.4 (C6), 108.3 (C2), 98.6 (C4), 40.3 (N(CH3)2).
HRMS (ESI): m/z [M + H+] calcd for C8H10BrN2O2+: 244.9920; found:
244.9921.
The spectral data were in agreement with literature data.3a
cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.05 (d, 3J = 9.2 Hz, 2 H, C4H, C5H),
8.41–8.44 (m, 2 H, C3H, C6H), 7.97 (dd, 3J = 8.8 Hz, 4J = 1.2 Hz, 2 H,
C1H, C8H), 7.82 (dd, 3J = 8.7, 6.7 Hz, 2 H, C2H, C7H), 7.47–7.50 (m, 2 H,
C2′H, C6′H), 7.42–7.45 (m, 2 H, C3′H, C5′H), 5.34 (s, 3 H, NCH3).
1
13C NMR (125 MHz, CDCl3):  = 164.1 (d, JC,F = 253 Hz, C4′), 160.0
(C9), 141.8 (C4a, C10a), 139.4 (C3, C6), 132.0 (d, 3JC,F = 8.3 Hz, C2′, C6′),
129.8 (C1, C8), 128.8 (d, 4JC,F = 3.7 Hz, C1′), 128.3 (C2, C7), 126.3 (C8a,
C9a), 120.0 (C4, C5), 116.7 (d, 2JC,F = 22 Hz, C3′, C5′), 41.5 (NCH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

E
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Synthesis
4-Bromo-N1,N1-dimethylbenzene-1,3-diamine (3)
4-Bromo-N3-[2-bromo-5-(dimethylamino)phenyl]-N,N1-dimethyl-
benzene-1,3-diamine
[CAS Reg. No.: 90555-68-3]
To a degassed mixture of 4-bromo-3-iodo-N,N-dimethylaniline (4;
55.4 g, 170 mmol), 4-bromo-N1,N1-dimethylbenzene-1,3-diamine (3;
36.6 g, 170 mmol), Pd2(dba)3 (3.89 g, 4.25 mmol), 1,1′-bis(diphenyl-
phosphino)ferrocene (4.71 g, 8.50 mmol), and NaOt-Bu (24.5 g, 255.0
mmol) was added toluene (560 mL) at RT. The reaction mixture was
stirred for 14 h at 105 °C. The solution was diluted with H2O (800 mL)
and extracted with CH2Cl2 (3 × 2 L). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The crude was purified by
column chromatography on silica gel (pentane/CH2Cl2 3:1 to 2:1 to
1:1) to give 4-bromo-N3-[2-bromo-5-(dimethylamino)phenyl]-N,N1-
dimethylbenzene-1,3-diamine as a beige solid; yield: 48.9 g (70%);
mp 132.2–134.7 °C; Rf = 0.53 (CH2Cl2 100%).
Prepared according to a modified literature procedure.3c,10b To a solu-
tion of 4-bromo-N,N-dimethyl-3-nitroaniline (36.8 g, 150 mmol) in
MeOH/H2O (1:1, 430 mL) was added NH4Cl (64.2 g, 1.20 mol) and Fe
powder (41.9 g, 750 mmol). The reaction mixture was stirred for 1 h
at 70 °C, filtered over Celite, and concentrated to remove MeOH.15 The
aqueous layer was treated with 10% aq HCl and washed with Et2O (2 ×
500 mL). Aq NH4OH (28%) was added until basic pH was reached. The
aqueous layer was extracted with CH2Cl2 (3 × 1 L). The combined or-
ganic layers were washed with brine, dried (Na2SO4), and concentrat-
ed in vacuo to afford 3 as a black solid; yield: 28.1 g (87%); mp 57.1–
58.7 °C; Rf = 0.29 (CH2Cl2 100%).
IR (ATR, neat): 3460w, 3355w, 2956w, 2843w, 2794w, 1604s, 1568s,
1491m, 1350m, 1291m, 1153m, 1123m, 1057w, 972w, 893w, 817s,
IR (ATR, neat): 3399w, 2895w, 2804w, 1590m, 1562s, 1496s, 1441m,
1354s, 1284s, 1230w, 1161m, 1065w, 989w, 921w, 814m, 770s,
778s, 710w cm–1
.
737w, 682w cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.20 (d, 3J = 8.8 Hz, 1 H, C5H), 6.12 (d,
4J = 2.9 Hz, 1 H, C2H), 6.08 (dd, 3J = 8.8 Hz, 4J = 2.9 Hz, 1 H, C6H), 3.97
(br, 2 H, NH2), 2.88 [s, 6 H, N(CH3)2].
13C NMR (125 MHz, CDCl3):  = 151.0 (C1), 144.3 (C3), 132.5 (C5),
105.2 (C6), 99.7 (C2), 97.0 (C4), 40.6 [N(CH3)2].
HRMS (ESI): m/z [M + H+] calcd for C8H12BrN2+: 215.0178; found:
215.0181.
The spectral data were in agreement with literature data.3a
1H NMR (500 MHz, CDCl3):  = 7.36 (d, 3J = 8.7 Hz, 2 H, C3H), 6.76 (d,
4J = 2.9 Hz, 2 H, C6H), 6.32 (br, 1 H, NH), 6.24 (dd, 3J = 8.7 Hz, 4J = 3.0
Hz, 2 H, C4H) 2.89 [s, 12 H, 2 × N(CH3)2].
13C NMR (125 MHz, CDCl3):  = 150.5 (C5), 140.3 (C1), 133.0 (C3),
107.3 (C4), 102.1 (C6), 100.8 (C2), 40.7 [N(CH3)2].
HRMS (ESI): m/z [M + H+] calcd for C16H20Br2N3+: 412.0018; found:
412.0019.
4-Bromo-N3-[2-bromo-5-(dimethylamino)phenyl]-N1,N1,N3-
trimethylbenzene-1,3-diamine (2b)
Prepared according to a modified literature procedure.7
3-Iodo-N,N-dimethylaniline
Prepared according to a modified literature procedure.9a
To a suspension of NaI (39.0 g, 260 mmol), CuI (1.24 g, 6.50 mmol),
and N,N′-dimethylethylenediamine (1.40 mL, 13.0 mmol) in 1,4-diox-
ane (130 mL) at RT was added 3-bromo-N,N-dimethylaniline (pre-
pared from 6 following the reaction step a; 18.6 mL, 130 mmol). The
reaction mixture was stirred for 22 h at 110 °C16 and then cooled to
RT, treated with aq NH4OH (28%, 650 mL) and H2O (300 mL), and ex-
tracted with CH2Cl2 (3 × 1.5 L). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo to give 3-iodo-N,N-dimeth-
ylaniline as a brownish oil; yield: 31.3 g (97%).
To a solution of 4-bromo-N3-[2-bromo-5-(dimethylamino)phenyl]-
N,N1-dimethylbenzene-1,3-diamine (48.3 g, 117.0 mmol) in THF (334
mL) at RT was added NaH (60% dispersion in mineral oil, 14.0 g, 351.0
mmol). The suspension was heated to 75 °C and stirred for 30 min at
this temperature. MeI (7.28 mL, 117.0 mmol) was added within 5 min
at 75 °C and the mixture was stirred for 2 h at this temperature. The
suspension was treated with H2O (585 mL) and extracted with CH2Cl2
(3 × 1.5 L). The combined organic layers were dried (Na2SO4) and con-
centrated in vacuo. The crude solid was recrystallized from hex-
ane/EtOAc (70 mL; 4:1) to give 2b as a beige solid; yield: 35.6 g (71%);
mp 102.5–104.1 °C; Rf = 0.55 (CH2Cl2 100%).
1H NMR (500 MHz, CDCl3):  = 7.01–7.03 (m, 2 H, C4H, C6H), 6.91–
6.94 (m, 1 H, C5H), 6.65–6.67 (m, 1 H, C2H), 2.92 [s, 6 H, N(CH3)2].
13C NMR (125 MHz, CDCl3):  = 151.6 (C1), 130.4 (C5), 125.2 (C4),
121.1 (C6), 111.6 (C2), 95.5 (C3), 40.3 (N(CH3)2).
The spectral data were in agreement with literature data.3a,9c
IR (ATR, neat): 2883w, 2806w, 1588s, 1554s, 1492s, 1446m, 1358s,
1304m, 1233m, 1170s, 1133m, 1084m, 1022w, 987m, 909w, 801m,
735w cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.33 (d, 3J = 8.8 Hz, 2 H, C3H), 6.35 (d,
4J = 3.0 Hz, 2 H, C6H), 6.31 (dd, 3J = 8.8 Hz, 4J = 3.0 Hz, 2 H, C4H), 3.21
(s, 3 H, NCH3), 2.87 [s, 12 H, 2 × N(CH3)2].
13C NMR (125 MHz, CDCl3):  = 150.7 (C5), 149.1 (C1), 134.0 (C3),
109.1 (C4), 108.3 (C6), 106.7 (C2), 41.3 (NCH3), 40.6 [2 × N(CH3)2].
4-Bromo-3-iodo-N,N-dimethylaniline (4)
[CAS Reg. No.: 1291063-32-5]
To a solution of 3-iodo-N,N-dimethylaniline (31.3 g, 127 mmol) in
CH2Cl2 (200 mL) at 10 °C was added Br2 (6.53 mL, 127 mmol). The re-
action mixture was stirred 1 h at that temperature.16 The suspension
was treated with sat. aq Na2SO3 (76.0 mL) and H2O (170 mL) and ex-
tracted with CH2Cl2 (3 × 350 mL). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The red crude solid was re-
crystallized from hexane/EtOAc (50 mL, 4:1) to give 4 as a beige solid;
yield: 23.7 g (57%).17
HRMS (ESI): m/z [M + H+] calcd for C17H22Br2N3+: 426.0175; found:
426.0177.
General Procedure B
To a suspension of Mg turnings (1.36 g, 56.0 mmol) in anhyd THF
(20.0 mL) at 60 °C was added a solution of 2b (5.98 g, 14.0 mmol) in
anhyd THF (60 mL) followed by 1,2-dibromoethane (0.319 mL, 4.20
mmol). The mixture was stirred at 60 °C for 3 h during which the re-
action mixture turned yellow. To this solution at 60 °C was added a
solution of carboxylic acid ester (10.0 mmol) in anhyd THF (100 mL)
and the mixture was stirred at the same temperature for 12 h. Aq HBr
(100 mL, 8.8 molL–1) was added and the aqueous phase was extracted
The spectral data were in agreement with literature data.3a,9c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

F
B. Zilate et al.
PSP
Synthesis
with CHCl3/i-PrOH (85:15; 3 × 200 mL). The solvent was removed in
vacuo and the residue was recrystallized from H2O (10 mL) to yield
acridinium salts 1c and 1d.
The combined organic layers were concentrated in vacuo and the res-
idue purified by column chromatography with n-hexane/acetone/
Et3N (96:2:2) to afford the clomipramine free base; Rf = 0.34 (n-hexane/
acetone/Et3N 8:1:1).
1H NMR (500 MHz, MeOD):  = 7.12–7.17 (m, 3 H), 7.09–7.10 (m, 1 H),
7.02–7.03 (m, 1 H), 6.95–6.98 (m, 1 H), 6.85–6.87 (m, 1 H), 3.73–3.76
(m, 1.75 H, 12% 2 H, C1′H), 3.07–3.15 (m, 4 H, C5H, C6H), 2.33–2.40
(m, 1.03 H, 49% 2 H, C3′H), 2.11–2.15 [m, 4.16 H, 30% 2 H, N(CH3)2],
1.70–1.74 (m, 2 H, C2′H).
3,6-Bis(dimethylamino)-9-mesityl-10-methylacridinium Bro-
mide (1c)
Prepared according to the general procedure B using methyl 2,4,6-
trimethylbenzoate (1.78 g, 10 mmol) to afford an orange solid; yield:
3.9 g (82%); 192.9 °C (dec.); Rf = 0.13 (CH2Cl2/MeOH 10:1).
The spectral data were in agreement with literature.11
IR (ATR, neat): 3373w, 2918w, 2170w, 1591s, 1497s, 1435m, 1352s,
1210s, 1148s, 985w, 921s, 807m, 711s cm–1
.
To prepare the clomipramine HCl salt, the free base was dissolved in
EtOAc, treated with HCl in 1,4-dioxane (4 molL–1, 250 L), concentrat-
ed in vacuo, triturated with Et2O, and filtered.
1H NMR (500 MHz, CDCl3):  = 7.26 (d, 3J = 9.5 Hz, 2 H, C1H, C8H), 7.06
3
(br, 2 H, C3′H, C5′H), 6.95–6.96 (m, 2 H, C4H, C5H), 6.94 (dd, J = 9.4
Hz, 4J = 2.1 Hz, 2 H, C2H , C7H), 4.56 (s, 3 H, NCH3), 3.36 [s, 12 H, 2 ×
N(CH3)2], 2.43 (s, 3 H, CH3) 1.80 (s, 6 H, 2 × CH3).
13C NMR (125 MHz, CDCl3):  = 155.4 (C3, C6), 154.0 (C9), 143.9 (C4a,
C10a), 139.0 (C4′), 136.0 (C2′, C6′), 130.4 (C1, C8, C1′), 128.6 (C3′, C5′),
116.1 (C8a, C9a), 114.3 (C2, C7), 94.3 (C4, C5), 41.1 [2× N(CH3)2], 38.3
(NCH3), 21.2 (CH3), 19.8 (2 × CH3).
HRMS (ESI): m/z [M + H+] calcd for C27H32N3+: 398.2591; found:
398.2594.
Funding Information
We gratefully acknowledge the Schweizerischer Nationalfonds zur
Förderung der Wissenschaftlichen Forschung (Swiss National Science
Foundation) and the Department of Chemistry of the University of
Basel for financial support.()
The spectral data were in agreement with literature data.3a
Acknowledgment
3,6-Bis(dimethylamino)-9-(2,6-dimethylphenyl)-10-methylacrid-
inium Bromide (1d)
We thank Prof. O. S. Wenger for the use of equipment to acquiring
photophysical data. Compounds 7a–f are part of a filed patent
(C. Fischer, C. Sparr. EP 17/188 288) licensed to Solvias. The catalysts
will be commercially available.
Prepared according to general procedure B using methyl 2,6-dimeth-
ylbenzoate (1.78 g, 10 mmol) to afford an orange solid; yield: 3.9 g
(84%); mp 238.6 °C (dec.); Rf = 0.17 (CH2Cl2/MeOH 10:1).
IR (ATR, neat): 2917w, 2662w, 1595m, 1502m, 1439s, 1354m, 1259s,
1215m, 1147m, 1067s, 981s, 924m, 809m, 712s, 649s cm–1
.
References
1H NMR (500 MHz, MeOD):  = 7.44 (t, 3J = 7.6 Hz, 1 H, C4′H),7.31 (d,
(1) (a) Ohkubo, K.; Mizushima, K.; Iwata, R.; Souma, K.; Suzuki, N.;
Fukuzumi, S. Chem. Commun. 2010, 46, 601. (b) Kotani, H.;
Ohkubo, K.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 15999.
(2) (a) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075.
(b) Brasholz, M. In Science of Synthesis: Photocatalysis in Organic
Synthesis; König, B., Ed.; Thieme: Stuttgart, 2019, 371–389.
(3) (a) Fischer, C.; Sparr, C. Angew. Chem. Int. Ed. 2018, 57, 2436.
(b) Fischer, C.; Sparr, C. Synlett 2018, 29, 2176. (c) Fischer, C.;
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(4) (a) White, A. R.; Wang, L.; Nicewicz, D. A. Synlett 2019, 30, 827.
Other approaches: (b) Gini, A.; Uygur, M.; Rigotti, T.; Alemán, J.;
García Mancheño, O. Chem. Eur. J. 2018, 24, 12509.
(c) Bernthsen, A.; Bender, F. Ber. Dtsch. Chem. Ges. 1883, 16,
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3
3J = 7.6 Hz, 2 H, C3′H, C5′H), 7.28 (d, J = 9.5 Hz, 2 H, C1H, C8H), 7.18
3
4
4
(dd, J = 9.5 Hz, J = 2.2 Hz, 2 H, C2H , C7H), 6.88 (d, J = 2.2 Hz, 2 H,
C4H, C5H), 4.30 (s, 3 H, NCH3), 3.34 [s, 12 H, 2 × N(CH3)2], 1.85 (s, 6 H,
2 × CH3).
13C NMR (125 MHz, MeOD):  = 157.2 (C3, C6), 155.3 (C9), 145.4 (C4a,
C10a), 137.3 (C2′, C6′), 135.0 (C1′), 131.4 (C1, C8), 130.6 (C4′), 129.1
(C3′, C5′), 117.3 (C8a, C9a), 116.1 (C2, C7), 94.5 (C4, C5), 40.8 [2 ×
N(CH3)2], 36.7 (NCH3), 19.8 (2 × CH3).
HRMS (ESI): m/z [M + H+] calcd for C26H30N3+: 384.2434; found:
384.2440.
Absorption spectroscopy (in MeCN): abs: 504 nm; abs: 7.1·104 Lcm–1mol–1;

em (exc 450): 533 nm; Stokes shift: 29 nm; E0.0: 2.4 eV; Cyclic voltam-
metry (vs SCE): E1/2 (P*/P–): +1.25 V, E1/2 (P/P–): –1.15 V.
(5) Benniston, A. C.; Elliott, K. J.; Harrington, R. W.; Clegg, W. Eur. J.
Org. Chem. 2009, 253.
Photoredox Catalyzed Deuteration
(6) (a) Link, A.; Fischer, C.; Sparr, C. Angew. Chem. Int. Ed. 2015, 54,
1263. (b) Link, A.; Fischer, C.; Sparr, C. Synthesis 2017, 49, 397.
(c) Knochel, P.; Krasovskiy, A.; Sapountzis, I. In Handbook of
Functionalized Organometallics: Applications in Synthesis;
Knochel, P., Ed.; Wiley-VCH: Weinheim, 2005.
(7) Uchiyama, M.; Matsumoto, Y.; Nakamura, S.; Ohwada, T.;
Kobayashi, N.; Yamashita, N.; Matsumiya, A.; Sakamoto, T. J. Am.
Chem. Soc. 2004, 126, 8755.
General Procedure C
A modified literature procedure was used.11
To a mixture of triisopropylsilanethiol (5.71 mg, 30 mol), Li2CO3
(35.5 mg, 480 mol), photocatalyst (1 or 2.5 mol%, see Table 2) and
D2O (90.0 L, 5.00 mmol) in N-methylpyrrolidone (1.6 mL) was added
clomipramine hydrochloride (33.7 mg, 100 mol) and the reaction
mixture was degassed by a stream of argon for 20 min. The reaction
was performed under an argon atmosphere for 24 h with the light on.
The mixture was diluted with EtOAc (15 mL), washed with brine (20
mL), and the aqueous phase was extracted with EtOAc (3 × 15 mL).
(8) Rzymski, T.; Zarebski, A.; Dreas, A.; Osowska, K.; Kucwaj, K.;
Fogt, J.; Cholody, M.; Galezowski, M.; Czardybon, W.; Horvath,
R.; Wiklik, K.; Milik, K.; Brózka, K. Patent WO072435, 2014.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
B. Zilate et al.
PSP
Synthesis
(9) (a) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
14844. (b) Jiang, X.; Wang, C.; Wei, Y.; Xue, D.; Liu, Z.; Xiao, J.
Chem. Eur. J. 2014, 20, 58. (c) Kowada, T.; Yamaguchi, S.;
Fujinaga, H.; Ohe, K. Tetrahedron 2011, 67, 3105.
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Colletti, S. L.; Davies, I. W.; MacMillan, D. W. C. Science 2017,
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(14) The precipitate was slowly formed after the addition of nitric
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(15) The Celite was washed with EtOAc.
(16) The reaction mixture turns beige immediately and the color
remains until the end of the reaction.
(17) After heating up to 80 °C, a hot filtration allowed to remove
insoluble red solids, while the precipitated product could be
isolated at RT.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G