Benzo[c]isothiazole 2-Oxides: Three-Dimensional Heterocycles with Cross-Coupling and Functionalization Potential

Article abstract of DOI:10.1002/adsc.201600823

A robust method for the synthesis of benzo[c]isothiazole 2-oxides has been developed providing a range of functionalized derivatives starting from anilines and DMSO. The reaction sequence can be performed on a gram scale and leads to products that can easily be modified by standard cross-coupling reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.201600823

UPDATES
DOI: 10.1002/adsc.201600823
1
2
3
4
5
6
Benzo[c]isothiazole 2-Oxides: Three-Dimensional Heterocycles
with Cross-Coupling and Functionalization Potential
7
8
9
10
11
12
13
14
15
16
Philip Lamers,a Laura Buglioni,a Steffen Koschmieder,b Nicolas Chatain,b and
Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax: (+49)-241-809-2391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH
b
Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany
Received: July 26, 2016; Revised: September 22, 2016; Published online on && &&, 0000
th
¨
17 Dedicated to Prof. Dr. Bernhard Luscher on the occasion of his 60 birthday.
18
19
20
21
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600823.
22
23
24
25
26
27
28
29
30
31
32
33
34
coupling reactions for further derivatizations. The first
results of these studies are presented here.
Abstract: A robust method for the synthesis of
benzo[c]isothiazole 2-oxides has been developed
providing a range of functionalized derivatives
starting from anilines and DMSO. The reaction
sequence can be performed on a gram scale and
leads to products that can easily be modified by
standard cross-coupling reactions.
Initially, we planned to apply Claus’s synthetic
protocol (Scheme 1), which involved the in situ
formation of dimethylsulfilimines 5 by treating mix-
tures of anilines 4 and DMSO with phosphorus
pentoxide.[11] The subsequent addition of NaOH
afforded benzyl methyl sulfides 6.[12] Intramolecular
oxidative sulfur imidations of 6 with NCS led to
benzo[c]isothiazoles 7, which were subsequently oxi-
dized with KMnO4 to give the desired compounds 3.[8]
Keywords: benzo[c]isothiazole 2-oxides; cross-cou-
pling; sulfur; synthetic methods
35 Heterocyclic architectures are key pillars for crop
36 protection and medicinal chemistry.[1] The finding and
37 development of new effective heterocyclic scaffolds
38 has always been a major challenge for organic
39 chemists.[2] In this context, the importance of nitrogen
40 and sulfur has widely been documented.[3] Combining
41 these elements in one functional group leads to
42 sulfoximidoyl moieties, which are three-dimensional
43 with the potential of having a stereogenic center at
Figure 1. Examples of sulfur- and nitrogen-containing hetero-
cycles.
44 sulfur. Such increased complexity can impact on Unfortunately, however, the reported reaction process
45 clinical success.[4] Following these arguments, com- proved difficult to reproduce und unreliable in the
46 pounds such as benzothiazines 1,[5] benzisothiazol-3- attempt to expand the substrate scope. Consequently,
47 one 1-oxides 2[6] and related structures[7] have exten- the approach had to be modified.
48 sively been studied (Figure 1). To our surprise, 2-
Inspired by the work of Jackson,[13] we decided to
49 substituted 3H-2l4-benzo[c]isothiazole 2-oxides 3 have substitute P2O5 in the first step of the reaction
50 received less attention, although a synthetic strategy sequence by trifluoroacetic anhydride (TFAA)
51 was reported by Claus and co-workers as early as (Scheme 1). Furthermore, NaOMe was used instead of
52 1974.[8] Realizing that heterocycles 3 could be consid- NaOH for initiating the rearrangement from 5 to 6. In
53 ered as three-dimensional bioisosteres[9] of oxindoles, this manner, the reproducibility problems were over-
54 which possess
a
high potential in medicinal come, and a wide range of thiomethoxymethylated
55 chemistry,[10] we wondered about advancing the products 6 became accessible (Figure 2). Although the
56 chemistry of such compounds by preparing a wider yields were only moderate to good due to incomplete
57 range of derivatives, including those allowing cross- conversions, the process proved reliable independent
Adv. Synth. Catal. 2016, 358, 1–6
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
known procedure suggested the use of KMnO4 for the
last step,[8] mCPBA proved superior, allowing for the
preparation of a broad range of products with various
functional groups. With the exception of pyridine
derivative 6t, which led to a highly polar product that
could neither be isolated by column chromatography
nor by extraction from the aqueous phase, all
thiomethoxymethylated anilines 6 reacted well, irre-
spective of the substitution pattern on the arene
affording the corresponding benzo[c]isothiazole 2-
oxides 3 in yields ranging from 28% to 81%
(Scheme 2). Starting from the mixtures of 6n/6o,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Scheme 1. Synthetic approaches towards 3 via 5 and 6.
Figure 2. Products 6 prepared by the optimized protocol
summarized in Scheme 1.
37 of the aniline substitution pattern. All reactions were
38 performed on gram scale employing approx.
39 150 mmol of the aniline derivatives. In the formation
40 of the 1,2,4-trisubstituted products 6a–j electronic
41 effects induced by the substituents R appeared to be
Scheme 2. Conversions of 6 into 3 under the optimized
conditions.
a
42 irrelevant. While single isomers of products 6k–m 6p/6q, and 6r/6s, the resulting isomeric products 3n–s
43 were obtained starting from ortho-halo-substituted could be separated and individually characterized.
44 anilines, the analogous substrates with meta-substitu- The yield of pyridine derivative 3u was low (28%), but
45 tion patterns led to mixtures of inseparable isomeric considering its high density of reactive positions, its
46 products (6n/6o, 6p/6q, and 6r/6s) with compositions formation was pleasing. Again, all of those trans-
47 ranging from 55:45 to 63:37. Finally, pyridine deriva- formations were performed on a gram scale using ca.
48 tives 6t and 6u were obtained in 22% and 38% yield, 150 mmol of starting materials.[14]
49 respectively.
Considering products 3 as structurally diverse
50
Next, we focused on the cyclization/oxidation molecular scaffolds with potential relevance for
51 sequence allowing the direct conversion of 6 into 3. medicinal and crop protection chemistry, we next
52 As in Claus’s protocol,[8] NCS was used as reagent for focused on exemplifying positional variability. Two
53 the first step. Thus, treatment of 6 with 1.0 equiv. of routes were pursued (Scheme 3). First, a metal-
54 NCS produced salts 7, which upon addition of an catalyzed Suzuki-type cross-coupling was demon-
55 aqueous solution of NaOH afforded benzo[c]isothia- strated using 3d as representative starting material.
56 zoles 8. Without further isolation, compounds 8 were Under conditions reported by Dughera, Ghigo and co-
57 directly oxidized to target products 3. While the workers for the preparation of 7-arylsatines,[15] the
Adv. Synth. Catal. 2016, 358, 1–6
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

UPDATES
asc.wiley-vch.de
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Scheme 3. Structural modifications of 3a and 3d.
17 palladium/SPhos-catalyzed reaction of 3d with phenyl-
18 boronic acid (9) in the presence of cesium fluoride
19 afforded arylated benzo[c]isothiazole 2-oxides 10 in
20 56% yield.
21
The second approach made use of the acidity of
22 the protons at position 3 of the heterocycle. Thus,
23 deprotonation of 3a with a combination of n-butyl-
24 lithium (2.0 equiv.) and trimethylsilyl chloride
25 (1.0 equiv.) followed by trapping of the resulting anion
Scheme 4. Sunitinib (13) and its analog 15b.
26 with benzaldehyde (11) led to olefinic product 12 (as probability of finding enzyme-inhibitory activities by
27 an almost 1:1 mixture of diastereomers) in 81% yield. compounds such as 15b.
28
Based on the idea that compounds 3 could mimic
In summary, we have developed an optimized
29 oxindoles we wondered about a bioisosteric replace- procedure for the preparation of 2-methyl-substituted
30 ment of the latter by the benzo[c]isothiazole 2-oxide 3H-2l4-benzo[c]isothiazole 2-oxides,[20] which can be
31 fragment in a clinically relevant molecule. For pursu- regarded as three-dimensional bioisosteres of oxin-
32 ing this approach sunitinib (13),[16] an FDA approved doles. Standard functionalizations of the core scaffold
33 tyrosine kinase inhibitor with potent antiangiogenic can be applied for molecular modifications, which
34 and antitumor activities, was taken as starting point might be of relevance for subsequent applications in
35 (Scheme 4). Replacing the oxindole part of 13 by the medicinal and agricultural chemistry.
36 respective heterocycle to give 15a required the con-
37 densation of 3b with aldehyde 14b.[17] This trans-
38 formation was achieved under the aforementioned
Experimental Section
39 reaction conditions (Scheme 3) with an alteration in General Two-Step Procedure for the Synthesis of
40 base, which was changed from n-BuLi to LiHMDS. In 2-Methyl-3H-2l4-benzo[c]isothiazole 2-Oxides
41 this manner, 15a was obtained with a 59% yield.
Under an atmosphere of argon, DMSO (21.0 g, 19.1 mL,
42 Cleavage of the remaining Boc group by treatment
270 mmol, 1.8 equiv.) was dissolved in
a mixture of
43 with trifluoroacetic acid gave target compound 15b in
44 39% yield (as 2:1 mixture of double bond isomers).
acetonitrile (50 mL) and DCM (50 mL). The reaction
mixture was cooled to À788C and TFAA (37.5 g, 25.2 mL,
180 mmol, 1.2 equiv.) was added dropwise. The aniline
(150 mmol, 1.0 equiv.) was dissolved in acetonitrile (50 mL)
45
With 15b available, we performed the first bio-
46 activity study. The constitutively active tyrosine kinase
47 receptor (RTK) FLT3-ITD is found in 25–30% of and added slowly to the solution. After stirring of the
48 patients with acute myeloid leukemia[18] and is a target
49 of sunitinib (13), reducing FLT3-ITD kinase activity.[19]
50 We treated the murine pro-B-cell line (Ba/F3) stably
51 expressing the oncogene FLT3-ITD, with increasing
52 concentrations of 15b and 13. Cell viability was
53 measured after 48 h of treatment. To our disappoint-
54 ment, 15b proved inactive in this test. However, in the
55 light of sunitinib’s broad spectrum of effects on
56 cellular processes, we continue to assume a high
57
reaction mixture for 5 h at À788C, sodium methoxide (5.4M
in methanol, 19.1 mL, 450 mmol, 3.0 equiv.) was added
dropwise over a period of 30 min at À788C. Then, the
reaction mixture was allowed to warm up to room temper-
ature and stirring was continued for 12 h. After addition of
NaOH (300 mL, 2.8M), the aqueous layer was extracted
with DCM (33350 mL). The combined organic layers were
dried over anhydrous magnesium sulfate, and the solvent
was removed under reduced pressure. The residue was then
dissolved in acetonitrile (500 mL) and triethylamine (50 mL)
Adv. Synth. Catal. 2016, 358, 1–6
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

UPDATES
asc.wiley-vch.de
was added. After stirring for 16 h at 908C the solvent was
removed under reduced pressure to afford product 6, which
was purified by silica gel column chromatography.
Org. Lett. 2005, 7, 143–145; b) M. Harmata, Y. Chen,
C. L. Barnes, Org. Lett. 2007, 9, 5251–5253; c) A.
Garimallaprabhakaran, X. Hong, M. Harmata, ARKI-
VOC 2012, 119–128; d) W. Dong, L. Wang, K. Partha-
sarathy, F. Pan, C. Bolm, Angew. Chem. 2013, 125,
11787–11790; Angew. Chem. Int. Ed. 2013, 52, 11573–
11576; e) D.-G. Yu, F. de Azambuja, F. Glorius, Angew.
Chem. 2014, 126, 2792–2796; Angew. Chem. Int. Ed.
2014, 53, 2754–2758; f) Y. Cheng, C. Bolm, Angew.
Chem. 2015, 127, 12526–12529; Angew. Chem. Int. Ed.
2015, 54, 12349–12352; g) R. K. Chinnagolla, A. Vijeta,
M. Jeganmohan, Chem. Commun. 2015, 51, 12992–
12995; h) Y. Cheng, W. Dong, H. Wang, C. Bolm, Chem.
Eur. J. 2016, 22, 10821–10824.
1
2
3
4
5
6
7
8
9
The resulting 2-[(methylthio)methyl]aniline (6, 15.0 mmol,
1.0 equiv.) was dissolved in DCM (50 mL) and the solution
was cooled to À408C. A solution of NCS (2.03 g, 15.0 mmol,
1.0 equiv.) in DCM (50 mL) was added dropwise over a
period of 60 min. After 15 min, an aqueous solution of
sodium hydroxide (10%, 10 mL) was added and the reaction
mixture was warmed to room temperature. After addition of
water (100 mL), the organic layer was separated and cooled
to À408C. Then, mCPBA (77% with water, 3.36 g,
15.0 mmol, 1.0 equiv.) was added in small portions over a
period of 10 min. After 30 min the reaction mixture was
allowed to warm to room temperature and sequentially
washed with saturated aqueous solutions of Na2SO3 and
NaHCO3. The organic layer was dried over anhydrous
magnesium sulfate, and the solvent was removed under
reduced pressure to afford product 3, which was purified by
silica gel column chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[6] a) P. Stoss, G. Satzinger, Chem. Ber. 1972, 105, 2575–
2583; b) P. Stoss, G. Satzinger, Chem. Ber. 1975, 108,
3855–3863; c) J. R. Beck, J. A. Yahner, J. Org. Chem.
1978, 43, 2052–2055; E. A. Serebryakov, S. G. Zlotin,
Russ. Chem. Bull. 2002, 51, 1549–1555.
[7] For recent contributions from our group, see: a) H.
Wang, M. Frings, C. Bolm, Org. Lett. 2016, 18, 2431–
2434; b) R. A. Bohmann, Y. Unoh, M. Miura, C. Bolm,
Chem. Eur. J. 2016, 22, 6783–6786.
Acknowledgements
We thank our colleagues in the Multi-Scale Bioactive Systems
initiative at RWTH Aachen University for stimulating dis-
cussions.
[8] P. K. Claus, P. Hofbauer, W. Rieder, Tetrahedron Lett.
1974, 37, 3319–3322.
[9] For a review on bioisostere, see: N. A. Meanwell, J.
Med. Chem. 2011, 54, 2529–2591.
[10] For the role of oxindoles in medicinal chemistry, see:
a) A. Millemaggi, R. J. K. Taylor, Eur. J. Org. Chem.
2010, 4527–4547; for preparative oxindole chemistry,
see: b) G. M. Ziarani, P. Gholamzadeh, N. Lashgari, P.
Hajiabbasi, ARKIVOC 2013, (i), 470–535.
[11] a) P. Claus, W. Vycudilik, Monatsh. Chem. 1970, 101,
396–404; b) P. Claus, W. Rieder, P. Hofbauer, E.
Vilsmaier, Tetrahedron 1975, 31, 505–510; c) P. K. Claus,
E. Jꢂger, Monatsh. Chem. 1985, 116, 1153–1164; d) P.
Claus, W. Vycudilik, W. Rieder, Monatsh. Chem. 1971,
102, 1571–1582.
[12] P. Claus, W. Vycudilik, Tetrahedron Lett. 1968, 32, 3607–
3610.
[13] E. T. Jackson, U.S. Patent 4,031,227, 1977.
[14] All products reported here were racemates. Their
resolution allows the preparation of enantiomerically
pure compounds.
References
[1] a) R. Dua, S. Shrivastava, K. S. Sonwane, S. K. Srivasta-
va, Adv. Biol. Res. 2011, 5, 120–144; b) A. Gomtsyan,
Chem. Heterocycl Compd. 2012, 48, 7–10; c) M. Bau-
mann, R. I. Baxendale, Beilstein J. Org. Chem. 2013, 9,
2265–2319; d) Heterocyclic Chemistry in Drug Discov-
ery, (Ed.: J. J. Li), Wiley, Weinheim, 2013; e) Modern
Crop Protection Compounds, (Eds.: W. Kraemer, U.
Schirmer, P. Jeschke, M. Witschel), Wiley-VCH: Wein-
heim, 2012.
[2] a) P. Ertl, S. Jelfs, J. Mꢁhlbacher, A. Schuffenhauer, P.
Selzer, J. Med. Chem. 2006, 49, 4568–4573; b) W. R. Pitt,
D. M. Parry, B. G. Perry, C. R. Groom, J. Med. Chem.
2009, 52, 2952–2963.
[3] a) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med.
Chem. 2014, 57, 2832–2842; b) B. R. Smith, C. M. East-
man, J. T. Njardarson, J. Med. Chem. 2014, 57, 9764–
9773; c) E. Vidaku, D. T. Smith, J. T. Njardarson, J.
Med. Chem. 2014, 57, 10257–10274; d) B. R. Beno, K.-S.
Yeung, M. D. Bartberger, L. D. Pennington, N. A.
Meanwell, J. Med. Chem. 2015, 58, 4383–4438; e) see
also: U. Lꢁcking, Angew. Chem. 2013, 125, 9670–9580;
Angew. Chem. Int. Ed. 2013, 52, 9399–9408.
[4] a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem.
2009, 52, 6752–6756; b) F. Lovering, Med. Chem.
Commun. 2013, 4, 515–519; c) J. T. Bagdanoff, Y. Xu, G.
Dollinger, E. Martin, J. Med. Chem. 2015, 58, 5781–
5788.
[15] M. Barbero, S. Bazzi, S. Cadamuro, L. Di Bari, S.
Dughera, G. Ghigo, D. Padula, S. Tabasso, Tetrahedron
2011, 67, 5789–5797.
[16] S. Faivre, G. Demetri, W. Sargent, E. Raymond, Nat.
Rev. Drug Discov. 2007, 6, 734–7445.
[17] For the synthesis of N-Boc-protected aldehyde 14b
commercially available 14a was used as starting materi-
al.
[18] S. Kayser, R. F. Schlenk, M. C. Londono, F. Breiten-
buecher, K. Wittke, J. Du, S. Groner, S. Spꢂth, S.
Krauter, A. Ganser, H. Dçhner, T. Fischer, K. Dçhner,
Blood 2009, 114, 2386–2392.
[19] A.-M. OꢃFarrell, T. J. Abrams, H. A. Yuen, T. J. Ngai,
S. G. Louie, K. W. H. Yee, L. M. Wong, W. Hong, L. B.
Lee, A. Town, B. D. Smolich, W. C. Manning, L. J.
Murray, M. C. Heinrich, J. M. Cherrington, Blood 2003,
101, 3597–3605.
[5] For selected examples, see: a) M. Harmata, K. Rayanil,
M. G. Gomes, P. Zheng, N. L. Calkins, S.-Y. Kim, Y.
Fan, V. Bumbu, D. R. Lee, S. Wacharasindhu, X. Hong,
Adv. Synth. Catal. 2016, 358, 1–6
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

UPDATES
asc.wiley-vch.de
[20] With the vision of potential applications in medicinal
and crop protection chemistry, the current approach
only focused on the preparation of 2-methyl-substituted
3H-2l4-benzo[c]isothiazole-2-oxides. The development
of preparative protocols towards products with other
substituents will be part of future studies.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Adv. Synth. Catal. 2016, 358, 1–6
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1
2
UPDATES
Benzo[c]isothiazole 2-Oxides: Three-Dimensional Het-
erocycles with Cross-Coupling and Functionalization
Potential
3
4
5
6
7
8
Adv. Synth. Catal. 2016, 358, 1–6
9
P. Lamers, L. Buglioni, S. Koschmieder, N. Chatain, C.
Bolm*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57