Iron-Catalyzed Amination of Sulfides and Sulfoxides with Azides in Photochemical Continuous Flow Synthesis

Article abstract of DOI:10.1021/acscatal.5b02495

A photochemical (UVA) continuous flow process for the amination of thioethers and sulfoxides was performed with trichloroethoxysulfonyl azide in the presence of catalytic iron(III) acetylacetonate. Aromatic and aliphatic sulfilimines and sulfoximines were produced in high yields and short reaction times. The reaction with chiral sulfoxides was stereospecific, producing enantioenriched sulfoximines in excellent yields.

Full text of DOI:10.1021/acscatal.5b02495

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Letter
Iron-Catalyzed Amination of Sulfides and Sulfoxides with
Azides in Photochemical Continuous Flow Synthesis.
Hélène Lebel, Henri Piras, and Marie Borduy
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02495 • Publication Date (Web): 12 Jan 2016
Downloaded from http://pubs.acs.org on January 13, 2016
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ACS Catalysis
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Iron-Catalyzed Amination of Sulfides and Sulfoxides with Az-
ides in Photochemical Continuous Flow Synthesis.
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Hélène Lebel,* Henri Piras and Marie Borduy.
Département de Chimie, Center for Green Chemistry and Catalysis, Université de Montréal, C.P. 6128, Succursale
Centre-ville, Montréal, Québec, Canada H3C 3J7.
KEYWORDS. sulfilimines, sulfoximines, iron(III) acetylacetonate, stereospecific amination, nitrene
ABSTRACT: A photochemical (UVA) continuous flow process for the amination of thioethers and sulfoxides was per-
formed with trichloroethoxysulfonyl azide in presence of catalytic iron(III) acetylacetonate. Aromatic and aliphatic sulfilimines
and sulfoximines were produced in high yields and short reaction times. The reaction with chiral sulfoxides was stereospe-
cific, producing enantioenriched sulfoximines in excellent yields.
Sulfilimines and sulfoximines are highly valuable building
blocks due to their importance in biologically active agents
substrate scope and a short reaction time (<2 h). Although
the photochemical decomposition of azides to produce
nitrenes is known,8 their subsequent exploitation in syn-
thetic methods to produce nitrogen-containing molecules
has not yet been reported. We reasoned that the photo-
chemical decomposition of azide reagents could be as-
sisted by the use of a metal catalyst. Furthermore, contin-
uous flow synthesis could be advantageous to decrease
the reaction time by maximizing the light exposure. Herein,
we disclose the photochemical continuous flow synthesis
of sulfilimines and sulfoximines with trichloroethoxysulfonyl
azide using catalytic iron(III) acetylacetonate that proceeds
in under 90 min.
1
(Figure 1). While azides are the most commonly used
reagents to aminate sulfides and sulfoxides to yield sul-
, ,
2 3 4
filimines and sulfoximines,
their application often raises
safety concerns, as many azide reagents are highly ener-
5
getic and may be explosive. Strong acids and high tem-
perature are typically required to undergo metal-free ami-
,
6 7
nation reactions. Metal-catalyzed processes employing
iron3a,b,f and ruthenium2a,3c,d,e complexes were reported to
proceed under milder reaction conditions, albeit for longer
reaction times (12–24 h). In addition, an excess of sub-
strate was required for iron-catalyzed or mediated reac-
tion. 3a,b,f
Continuous flow synthesis is an emerging technology
that has numerous advantages over conventional batch
CF3
Me
O
H
N
9
transformations. Benefits include enhanced heat and
O
OH
N
H
mass transfer, reduced reaction volumes, as well as im-
proved reagent mixing. The combination of these, in addi-
tion to the fact the build up of hazardous intermediates is
N
N
Me
O
HN
HO
Sulfilimine crosslink
in collagen-IV network
10
mitigated, lead to enhanced reaction safety parameters.
N
Continuous flow synthesis has also been demonstrated to
be efficient in photochemical processes due to improved
S
S
O
NH
O
11
BAY 1000394
Cyclin Dependent Kinase
Inhibitor (antitumor)
light penetration. We hypothesized that a continuous flow
H
N
process could be used to decompose azide reagents to
produce reactive metal nitrene species that would under-
go amination of sulfides and sulfoxides. A variety of inex-
pensive, readily available metal complexes and azide rea-
gents were tested for the amination of thioanisole using a
Luzchem LZC-5 photoreactor11h equipped with 8 x 8W
N
H
O
O
O
O NH
S
O
CH3
O
RU 31156 (sudexanox)
oral, prophylactic antiasthmatic
(OHCH2)3CNH3
,
12 13
black light blue UVA (365 nm) tubes.
Whereas no reac-
tion was observed with copper(II) and cobalt(II) acety-
lacetonate, the desired product was obtained with corre-
sponding iron catalysts. Iron(III) proved superior to iron(II)
Figure 1. Selected Examples of Biologically Rele-
vant Sulfilimines and Sulfoximines
14
acetylacetonate. Analysis by UV spectroscopy revealed
To the best of our knowledge, there are no accounts
that combine the application of a commercially available
catalyst with a stable azide reagent to enable a broad
that among the tested metal complexes, only Fe(acac)3
wascapable of absorbing UVA light. Using trichloroethoxy-
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ACS Catalysis
Table 1. Iron-Catalyzed Amination of Sulfides
sulfilimine 1 derived from thioan-
Page 2 of 6
,
15 16
sulfonyl azide (TcesN3)
1
2
3
4
5
6
7
8
with TcesN3.
isole was produced in 90% yield with a residence time (tR)
of 150 min. In sharp contrast, no photodecomposition of
aryl and alkyl azides (p-tolN3 and BnN3) was observed
under the same catalytic conditions and starting material
was recovered. Conversely, acyl azides (CBzN3 or TrocN3)
were decomposed, but only the Troc-protected sulfilimine
was produced albeit in low yield. Only trace amounts of
the desired product were obtained using TsN3. In the
absence of catalyst, only traces of sulfilimine 1 were pro-
duced and TcesN3 was not decomposed in the absence
of UV light.
UVA (365 nm)
NTces
S
S
R1 R2
BPR
2.8 bar
R1 R2 / DCM
TcesN3 (1.5 equiv)
Fe(acac)3 (10 mol %)
tR : 50-90 min
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Entrya
10
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Product
Yield
(%)b
tR (min)
50c
90d
90d
1
94
70
84
R = Me (1)
NTces
To accelerate the rate of the reaction (thus decrease the
residence time), a novel photoreactor was designed to
maximize the exposure of the tubing to the light (Figure 2).
The PFA tubing was wrapped around four small metal
tubes to create a big cylinder around the light bulb. Three
cylinders were connected in a row to a Syrris pump, and
the system could be safely operated in laboratory fume
S
R = n-C14H29 (2)
R = i-Pr (3)
2
3e
R
90d
90d
90d
R = F (4)
4
5e
6e
97
98
86
NTces
R = OMe (5)
R = BPin (6)
S
Me
17
hood using an aluminum foil-lined photobox.
R
NTces
S
7e
8
90d
98
Me
7
Br
NTces
90d
90d
S
75
71
Me
8
N
NTces
9e
S
Me
9
Figure 2. Capillary Cylinder Photoreactor
S
NTces
The residence time and the catalyst loading were opti-
mized using the described photoreactor for the amination
of thioanisole with TcesN3. The use of 5 mol % of
Fe(acac)3 in a 90 min residence time afforded the desired
product in 94% yield. The optimal result was obtained
using 10 mol % of the iron catalyst and 50 min residence
time (Table 1, entry 1). Given the concentration and the
flow rate, the productivity of the process was calculated to
produce 1.34 g/h of sulfilimine 1. The reaction time could
be even shorter if 20 mol% of Fe(acac)3 was used, afford-
ing 89% of sulfilimine 1 with a residence time of 15 min.
Cl
N
S
10f
90d
56
10
N
Cl
NTces
S
50c
50c
11
12
>98
86
11
NTces
S
12
The substrate scope was then investigated (Table 1).
Phenyl thioethers containing larger alkyl groups were re-
acted in good yields (entries 2, 3). Electron withdrawing
and donating aryl substituents were compatible with the
reaction conditions (entries 4, 5). Sulfilimine 6 was pro-
duced in 86% yield, with no side-reaction on the boronate
substituent (entry 6). Ortho-substituted thioethers are also
compatible (entry 7) Sulfides containing pyridine and thio-
phene moiety produced desired sulfilimines 8 and 9, in
75% and 71% yield respectively (entries 8, 9). With less
reactive thioethers, it is possible to perform two cycles.
This strategy was used to synthesize pyrimidine-
substituted sulfilimine 10 (entry 10).
O
NTces
S
13
50c
13
83
MeO
NHBoc
NTces
S
50c
90d
14
15
>98
73
14
NTces
15
S
a
All experiments were conducted with 0.17 mmol of thi-
oether in 2 mL of solvent (C = 0.085 mmol/min) using 37.5
2
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ACS Catalysis
b
c
Table 2. Iron-Catalyzed Amination of Sulfoxides
with TcesN3.
mL PFA tubing (ID 1 mm). Isolated yields. Flow : 0.75
mL/min. Flow : 0.42 mL/min. 20 mol % of Fe(acac)3.f 2
d
e
1
2
3
4
5
cycles of 90 min using 2 x 20 mol % of Fe(acac)3.
UVA (365 nm)
O NTces
S
R1 R2
The reaction conditions were particularly suitable to
O
S
produce often difficult to access alkyl substituted sul-
BPR
2.8 bar
18
R1 R2 / DCM
filimines.
The reaction of tetrahydrothiophene with
6
TcesN3 (1.5 equiv)
TcesN3 afforded sulfilimine 11 in a quantitative yield with a
residence time of 50 min (entry 11). Long alkyl chains were
also tolerated, as well as functional groups such as an
ester and a Boc-protected amine (entries 12, 13). More
sterically hindered cyclohexylmethyl sulfilimine 14 was
also produced in a quantitative yield (entry 14). The reac-
tion of an alkylthioether containing a terminal double bond
produced the desired sulfilimine 15 in 73% yield, with no
side-reaction on the double bond (entry 15).
7
8
9
Fe(acac)3 (10 mol %)
tR : 90 min
Entrya
1
Yield (%)b
87
10
11
12
13
14
15
16
17
18
19
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Product
O NTces
S
Me
18
Ph
O NTces
S
Me
2
85
95
It is also possible to use a chiral azide reagent, 2-
3 c
19
,
19
phenyltrichloroethoxyacyl azide 16 (PhTrocN3) to pro-
duce a 1:1 mixture of diastereomers of sulfilimines 17 that
can be separated (Scheme 1). This method is a straight-
forward facile process to access both enantiomers of the
desired chiral molecule and should find many applications
in pharmaceutical industries.
F
O NTces
S
4
5
97
96
20
O NTces
S
21
Scheme 1. Iron-Catalyzed Amination of Thioan-
isole with 2-Phenyltrichloroethoxyacyl azide.
O NTces
S
6
87
22
O
Ph
a
N
S
O
CCl3
All experiments were conducted with 0.17 mmol of thi-
oether in 2 mL of solvent (C = 0.085 mmol/min) using 37.5
(S*,R*)-17
UVA (365 nm)
Ph
Me
+
PhSMe/ DCM
b
mL PFA tubing (ID 1 mm) and a flow rate of 0.42 mL/min.
O
Ph
Isolated yields. c 20 mol % of Fe(acac)3.
(+)-16
O
Ph
BPR
2.8 bar
N3
O CCl3
(1.5 equiv)
N
S
O
CCl3
(R*,R*)-17
Fe(acac)3
(20 mol %)
Scheme 2. Stereospecific Iron-Catalyzed Amina-
tion of Thioanisole Sulfoxide and Synthesis of the
Free Sulfoxime.
tR : 90 min
Ph
Me
86%
The amination of sulfoxides was next studied. Using the
Luzchem UV reactor with TcesN3 and 10 mol %
Fe(acac)3, the amination of phenyl methyl sulfoxide pro-
ceeded in only 6% yield with a residence time of 150 min.
Gratifyingly, using the capillary cylinder photoreactor
shown in Figure 2, the desired sulfoximine 18 was ob-
tained in 87% yield while decreasing the residence time to
90 min (Table 2, entry 1). The scale-up of the reaction was
very easy, and 1 gram (91% yield) of sulfoximine 18 could
UVA (365 nm)
O NTces
S
O
95:5 er
S
Ph
Me
BPR
2.8 bar
Ph
Me/ DCM
18
TcesN3 (1.5 equiv)
87%
95:5 er
Fe(acac)3 (10 mol %)
tR : 90 min
20
be synthetized in 90 min. Under the same reaction con-
1. Zn (10 equiv)
AcOH, 25 °C, 12 h
O NH
S
O NTces
S
Me
ditions, the p-fluoro-substituted phenyl methyl sulfoximine
19 was isolated in 85% yield, while the use of 20 mol %
of Fe(acac)3, afforded 95% of the desired product (entries
2, 3). Alkyl sulfoxides were highly reactive affording the
desired sulfoximines in 87–97% yield (entries 4-6).
2. AcCl, MeOH
25 °C, 1 h
Ph
Me
Ph
21
97%
The amination of sulfoxides was found to be stereospe-
cific. Starting with a 95:5 er of phenylmethyl sulfoxide,
sulfoximine R-18 was isolated in 87% yield with the same
enantiomeric ratio (Scheme 2). The Tces protecting group
could be easily cleaved from sulfoximine 18 using zinc in
acetic acid to afford free sulfoximine 23 in high yield.
The reaction optimization had revealed that both UVA
light and Fe(acac)3 were required for a productive process.
In addition, the structure of the azide reagent strongly
influenced the reaction outcome. While absorption of UVA
light by Fe(acac)3 was observed, none of the azide rea-
gents explored demonstrated absorption at λ > 320 nm.
3
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