Three-Dimensional Heterocycles by Iron-Catalyzed Ring-Closing Sulfoxide Imidation

Article abstract of DOI:10.1002/anie.201804284

A general and atom-economical method for the synthesis of cyclic sulfoximines by intramolecular imidations of azido-containing sulfoxides using a commercially available Fe^II phthalocyanine (Fe^IIPc) as catalyst has been developed. The method conveys a broad functional group tolerance and the resulting three-dimensional heterocycles can be modified by cross-coupling reactions.

Full text of DOI:10.1002/anie.201804284

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Accepted Article
Title: Three-Dimensional Heterocycles by Iron-Catalyzed Ring-Closing
Sulfoxide Imidation
Authors: Hao Yu, Zhen Li, and Carsten Bolm
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804284
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10.1002/anie.201804284
Angewandte Chemie International Edition
COMMUNICATION
Three-Dimensional Heterocycles by Iron-Catalyzed Ring-Closing
Sulfoxide Imidation
Hao Yu, Zhen Li, and Carsten Bolm*
Abstract: A general and atom-economical method for the synthesis
In recent years, iron has been recognized as important metal
for homogeneous catalysis.[8] Its use in catalyzed nitrene
transfer reactions has led to convenient methods for C–H bond
aminations.[9] In many cases, organoazides have been applied
as nitrene precursors, which is attractive because molecular
nitrogen is the only byproduct being released during substrate
activation.[10-13] We[14] and others[12b,15] used combinations of iron
catalysis and organoazides in sulfur imidations.[16] As a result,
sulfilimines and sulfoximines were obtained, which proved
interesting for asymmetric synthesis[17] and applications in crop
protection and medicinal chemistry.[18] We now wondered if such
approach could also be utilized in the synthesis of sulfur-based
of cyclic sulfoximines by intramolecular imidations of azido-
containing sulfoxides using
a
commercially available FeII
phthalocyanine (FeIIPc) as catalyst has been developed. The
method conveys a broad functional group tolerance and the resulting
three-dimensional heterocycles can be modified by cross-coupling
reactions.
Three-dimensional heterocycles are important molecular
scaffolds in medicinal and crop protection chemistry.[1] A high
degree of saturation and the presence of stereogenic centers
are also relevant factors for successful transitions of newly
identified hits through clinical trials to drugs.[2,3] Aiming at
expanding the rather limited chemical space of heterocyles,[4] we
began studying synthetic opportunities leading to rather under-
represented sulfur-based three-dimensional ring systems such
as benzothiazines,[5] benzo[c]isothiazole 2-oxides[6] and related
structures.[7] In most protocols preformed sulfoximines were
used as starting materials. Here, we introduce an alternative
strategy. It starts from azido-substituted sulfoxides (1 and 3) and
applies readily available FeII phthalocyanine (FeIIPc) as catalyst
for ring-closing sulfur imidations providing products 2 and 4,
respectively (Scheme 1).
three-dimensional heterocycles. The results of
concept study are summarized here.
a proof-of-
In our previous work on intermolecular imidations of
sulfoxides with hydroxylamine triflic acid salts, an
FeSO4/phenanthroline combination or FeIIPc was used as
catalyst.[14g] Those systems were applied here, attempting to
cyclize [(3-azidopropyl)sulfinyl]benzene (1a) to 4,5-dihydro-3H-
isothiazole 1-oxide 2a by intramolecular imidation. The first one,
however, did not give any of the desired product (in benzene at
60 °C or 100 °C for 24 h; Table 1, entries 1 and 2). With FeIIPc
as catalyst, only traces of 2a were observed when the reaction
was performed at 60 °C (Table 1, entry 3). To our delight, the
yield of 2a increased to 80% at 100 °C (Table 1, entry 4).
FeIVPc
N
S
R1
O
– N2
Table 1. Evaluation of reaction conditions.[a]
N
O
S
Fe cat. (20 mol %)
ligand (40 mol %)
O
O
S
N
O
S
S
N3
N
N3
R1
R1
N
N
N
N
solvent, T, 24 h, Ar
1
3
2
N
N
Fe
1a
2a
R2
N
N3
O
N
R2
S
R3
Ligand[b]
Solvent
T
[°C]
60
Yield
[%][c]
n.r.
FeIIPc
O
S
R3
Entry
Fe cat.
4
FeIVPc
1
2
FeSO4
FeSO4
1,10-phen
benzene
benzene
benzene
benzene
toluene
toluene
PhCl
N
R2
O
1,10-phen
100
60
n.r.
trace
80
– N2
S
R3
Ⅱ
3
Fe Pc
-
-
-
-
-
-
-
-
-
-
-
Ⅱ
4
Fe Pc
100
100
80
Ⅱ
5
Fe Pc
95
Scheme 1. Iron-catalyzed intramolecular imidation of sulfoxides.
Ⅱ
6
Fe Pc
58
Ⅱ
7
Fe Pc
100
100
100
100
100
100
100
92
Ⅱ
8
Fe Pc
CH3CN
DCE
42
Ⅱ
9
Fe Pc
66
Ⅱ
10
11[d]
12[e]
13
Fe Pc
dioxane
toluene
toluene
toluene
90
Ⅱ
Fe Pc
95
[*]
H. Yu, Dr. Z. Li, Prof. Dr. C. Bolm
Ⅱ
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
Homepage: http://bolm.oc.rwth-aachen.de/
Fe Pc
93
-
n.r.
[a] Reaction conditions: 1a (0.20 mmol), Fe catalyst (0.04 mmol, 20 mol %),
ligand (0.08 mmol, 40 mol %), solvent (0.2 M), under argon, 24 h. [b] 1,10-
phen = 1,10-phenanthroline. [c] n.r. = no reaction. [d] Fe catalyst (0.02 mmol,
10 mol %). [e] Fe catalyst (0.01 mmol, 5 mol %).
Supporting information for this article is given via a link at the end of
the documen.
To further optimize the reaction conditions, various solvents
were screened (Table 1, entries 5-10). Toluene was identified as
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10.1002/anie.201804284
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COMMUNICATION
optimal medium leading to 2a in 95% yield (Table 1, entry 5).
Decreasing the reaction temperature from 100 °C to 80 °C
lowered the yield of 2a (Table 1, entry 5 versus entry 6).
Noteworthy, the catalyst loading could be reduced from 20
mol % to 5 mol % without significantly affecting the product yield
(Table 1, entry 5 versus entries 11 and 12). In the absence of
the iron catalyst, no cyclization occurred (Table 1, entry 13).
Under the optimized conditions using 5 mol % of FeIIPc as
catalyst, various 3-azidoalkyl sulfoxides (1a-r) were subjected to
the intramolecular imidation conditions next. As a result, the
corresponding cyclized products 2 were obtained in yields up to
98% (Scheme 2).
Starting from aryl sulfoxides with benzylic azido groups 3,
3H-1λ4-arylo[d]isothiazole 1-oxides
4
could be prepared
(Scheme 3).[21] In the series of products with an 1-ethyl
substituent and benzo[d]isothiazole core (4a-h), the
a
unsubstituted aryl derivative 4a gave the highest yield (98%).
Otherwise, neither electronic nor steric effects induced by
substituents appeared to play a major role leading to yields
ranging for 77% (4f) to 93% (4b and 4e) for such compounds. 1-
Ethyl-3H-1λ4-thieno[d]isothiazole 1-oxides 4i was obtained in
80% yield. Also starting from aryl sulfoxides with cyclohexyl,
phenyl and 2-thienyl groups was possible, and the
corresponding products (4j: 92%, 4k: 81%, and 4l: 76%) were
formed in good to high yields.
R3
N
O
FeIIPc (5 mol %)
O
S
n
R3
S
N3
n
R1
FeIIPc (5 mol %)
N3
R1
R1
toluene, 100 °C
24 h, Ar
R1
N
R2
O
R2
S
R2
toluene, 100 °C
24 h, Ar
S
R2
O
2
1
(n = 1 or 2)
3
4
N
N
O
O
N
O
O
N
F
Cl
MeO
S
S
S
S
N
Me
Me
N
S
N
N
R
S
S
S
S
N
O
Et
O
O
O
Et
4b, 93%
Et
4c, 91%
Et
4d, 90%
Br
2l, 98%
2n, 94%[a]
2a,
2b,
2c,
2d,
2e,
2f,
2g,
2h,
2i,
R = H, 93%
2m, 95%
4a, 98%
R = p-Me, 84%
R = p-tBu, 88%
R = p-F, 92%
R = p-Cl, 95%
R = p-Br, 88%
R = m-Me, 90%
R = m-F, 93%
R = o-Me, 49%
R = o-Et, 34%
R = o-MeO, 61%
N
N
O
S
O
N
O
S
Me
S
N
N
Me
2o, 90%[a,b]
N
S
S
S
S
F3C
4f, 77%
Me
2q, 68%
O
2p, 63%
O
O
O
Et
4g, 80%
Et
Et
4e, 93%
Et
4h, 91%
F
N
S
N
O
O
S
2j,
2k,
N
2r, 39%[c]
2s, 14%[c]
S
S
N
N
N
O
S
S
S
S
O
O
O
S
Et
Cy
Ph
4k, 81%
Scheme 2. Iron-catalyzed intramolecular imidations of 3-azidosulfoxides 2 (0.2
mmol scale). [a] Use of 20 mol % of FeIIPc at 140 °C. [b] d.r. = 1 : 1. [c] Use of
20 mol % of FeIIPc.
4j, 92%
4l, 76%
4i, 80%
Scheme 3. Iron-catalyzed intramolecular imidations providing 3H-1λ4-
arylo[d]isothiazole 1-oxides 4 (0.2 mmol scale).
In the series of 1-phenyl 4,5-dihydro-3H-isothiazole 1-
oxides 2a-k a wide range of substituents (including various alkyl
and halo groups) were tolerated, and generally, high yields were
achieved for products having para- and meta-substituted arenes
(2a-h). Ortho-substituents on arenes appeared to hamper the
cyclization leading to products 2i-k in only moderate yields (34-
61%). 2-Naphthyl and 2-thiophenyl 3-azidopropyl sulfoxides (1l
and 1m) were very viable substrates providing the
corresponding 4,5-dihydro-3H-isothiazole 1-oxides 2l and 2m in
98% and 95% yield, respectively. To our surprise, cyclizations of
sulfoxides with methyl-substituted azidoalkyl chains (1n and 1o)
proved difficult and starting materials remained. However,
raising the temperature from the common 100 °C to 140 °C and
applying 20 mol % of the catalyst (instead of the normally used 5
mol %) allowed to isolate products 2n and 2o (with a d.r. of 1:1)
in 94% and 90% yield, respectively.[19] Non-aromatic products 2p
and 2q were obtained in yields of 63% and 68%. Even with a
catalyst loading 20 mol %, the yields of products 2r and 2s
remained moderate. Presumaby due to subsequent reactions at
the rather sensitive benzylic position, product 2r was isolated in
39% yield. Although 3,4,5,6-tetrahydro-1,2-thiazine 1-oxide 2s
was formed in only 14% yield, the reaction was relevant as it
indicated that also 4-azidobutyl sulfoxides could be applied as
substrates.[20]
As demonstrated for the cyclization of (S)-1a, the intra-
molecular sulfur imidation is stereospecific (Scheme 4, top).[22]
O
S
N
O
FeII Pc (5 mol %)
S
N3
toluene, 100 °C
Ar, 24 h
(S)-1a
2a, 93%
(e.r. 76:24)
(e.r. 76:24)
PhB(OH)2 (1.2 equiv)
Pd(OAc)2 (4 mol %)
XPhos (4.8 mol %)
N
O
S
N
O
S
CsOH (1.7 equiv)
n-BuOH/H2O
50 °C, Ar, 16 h
Br
2f
5, 93%
Me Me
Me
Me
O
O
Br
B
B2pin2 (1.1 equiv)
PdCl2(dppf) (10 mol %)
N
S
N
KOAc (3 equiv)
DMSO, 50 °C, 16 h
S
O
O
Et
Et
4h
6, 38%
Scheme 4. Stereospecific imidation (top) and cross couplings with 2f and 4h
(middle and bottom).
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10.1002/anie.201804284
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COMMUNICATION
Lee, Adv. Synth. Catal. 2017, 359, 3362–3370; l) G. Zheng, M. Tian, Y.
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cross coupling conditions. Using 2f in a Suzuki-type arylation
reaction with phenylboronic acid in the presence of cesium
hydroxide under catalysis with palladium/XPhos afforded cross
coupling product 5 in 93% yield (Scheme 4, middle). Next,
treating 4h with bis(pinacolato)diboron (B2Pin2), PdCl2(dppf) and
potassium acetate in DMSO at 50 °C led to pinacol boronic acid
ester 6 in 38% yield (Scheme 4, bottom). We consider product 6
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Acknowledgements
H.Y. thanks the China Scholarship Council for a predoctoral
stipend. Furthermore, we are grateful to Plamena Staleva
(RWTH Aachen University) for HPLC analyses and Dr. José G.
Hernández (RWTH Aachen University) for polishing the
manuscript.
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Keywords: azide • cyclic sulfoximine • intramolecular imidation •
iron • nitrene transfer
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[19] Compound 2n has a gem-dimethyl group, which might be of relevance
for applications in medical chemistry. For a recent Perspective, see: T.
T. Talele, J. Med. Chem. 2018, 61, 2166–2210.
[20] For further examples of 6-membered products, see the Supporting
Information.
[21] Recently, we reported on a very different route towards structurally
analogous, but isomeric benzo[c]isothiazole oxides. For details, see ref.
6.
[22] Both (S)-1a and 2a had an e.r. of 76:24. Based on previous work (refs.
12b, 14a, and 14c) we assume that the imidation occurred with
retention of configuration at sulfur.
[23] a) A. D. Steinkamp, S. Wiezorek, F. Brosge, C. Bolm, Org. Lett. 2016,
18, 5348–5351; b) A. K. Bachon, A.D. Steinkamp, C. Bolm, Adv. Synth.
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[24] To the best of our knowledge, this is the first use of alkyl azides in such
iron-catalyzed sulfoxide imidations. The previous conversions (ref. 14
and 15) involved azides with acyl, tosyl, or related electron-withdrawing
substitutents.
This article is protected by copyright. All rights reserved.

10.1002/anie.201804284
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hao Yu, Zhen Li, and Carsten Bolm*
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Page No. – Page No.
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or
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Fe
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Three-Dimensional Heterocycles by
Iron-Catalyzed Ring-Closing
Sulfoxide Imidation
R2
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An iron-catalyzed intramolecular imidation of azido-substituted sulfoxides was
developed. The reactions furnish cyclic sulfoximines in high yields and exhibit a
broad substrate scope. The products can further be functionalized
This article is protected by copyright. All rights reserved.