Tf2O-mediated Reaction of Alkenyl Sulfoxides with Unprotected Anilines in Flow Microreactors

Article abstract of DOI:10.1246/cl.190831

Flow microreactors have allowed an efficient extended Pummerer reaction of ketene dithioacetal monoxides with anilines by precise control of unstable sulfonium intermediates and spatial separation of the generation of the intermediates and the nucleophilic attack to the intermediates. A new iodoniummediated cyclization has been devised to convert the products, thioimidates, into indoles.

Full text of DOI:10.1246/cl.190831

Advance Publication Cover Page
Tf2O-mediated Reaction of Alkenyl Sulfoxides with Unprotected Anilines
in Flow Microreactors
Alexandre Baralle, Tomoaki Inukai, Tomoyuki Yanagi, Keisuke Nogi, Atsuhiro Osuka,
Aiichiro Nagaki,* Jun-ichi Yoshida, and Hideki Yorimitsu*
Advance Publication on the web December 3, 2019
doi:10.1246/cl.190831
© 2019 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
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Publication manuscripts.

1
Tf2O-mediated Reaction of Alkenyl Sulfoxides with Unprotected Anilines in Flow
Microreactors
Alexandre Baralle,1 Tomoaki Inukai,1 Tomoyuki Yanagi,1 Keisuke Nogi,1 Atsuhiro Osuka,1 Aiichiro Nagaki,*2 Jun-ichi Yoshida,3 and
Hideki Yorimitsu*1
1 Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
2 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto
615-8510
3 National Institute of Technology, Suzuka College, Shiroko-cho, Suzuka, Mie 510-0294
E-mail: anagaki@sbchem.kyoto-u.ac.jp; yori@kuchem.kyoto-u.ac.jp
1
2
3
4
5
6
7
Flow microreactors have allowed an efficient extended
47 nucleophilic attack of a reactive nucleophile onto an acid
48 anhydride activator.
Pummerer reaction of ketene dithioacetal monoxides with
anilines by precise control of unstable sulfonium
intermediates and spatial separation of the generation of the
intermediates and the nucleophilic attack to the intermediates.
A new iodonium-mediated cyclization has been devised to
convert the products, thioimidates, into indoles.
49
Here we disclose a new Tf2O-mediated extended
50 Pummerer reaction of ketene dithioacetal monoxides
51 (KDMs) with nucleophilic unprotected anilines10,11 taking
52 advantage of flow microreactors. The setup to realize the
53 target reaction is shown in Figure 1, consisting of two T-
54 shape micromixers (M1 and M2) and two microtube reactors
55 (R1 and R2). Phenyl KDM 1a and Tf2O were mixed together
56 in M1 and reacted in R1 to generate reactive sulfonium
57 species from 1a. The species was then trapped with aniline
58 (2a) in the presence of iPr2EtN in M2 and R2 to give a
59 mixture of products.
8 Keywords: Flow microreactor, Pummerer reaction,
9 Indole
10
Organosulfur compounds are ubiquitous in nature and
11 play important roles in organic synthesis as well as
12 biochemistry and material science.1 One notable feature of
13 organosulfur chemistry lies in stable high-oxidation-state
14 species such as sulfoxides, which enhances their usefulness
15 as synthetic intermediates. Stable sulfoxides can be activated
16 by the action of acid to induce sulfur-specific reactions.2 The
17 Pummerer rearrangement of alkyl sulfoxides is such a
18 classical example.3 In the last couple of decades, the
19 Pummerer chemistry has been rapidly extending its frontier
20 to alkenyl and aryl sulfoxides as substrates to lead to the
21 exciting discovery of novel characteristic transformations
22 including metal-free C(sp2)–H functionalizations.4–6
60
O
SMe
temperature
SMe
SMe
residence time
Ph
MeS
3aa
M1
Ph
1a
N
R1
M2
Tf2O
R2
iPr2EtN
+
PhNH2
2a
See Figure 4
Flow conditions:
1a, 0.11 M, 1.1 equiv; Tf2O, 0.10 M, 1.0 equiv;
MeS
23
In the modern Pummerer chemistry,4–6 the choice of
NH
2a, 0.05 M, 1.0 equiv; iPr2EtN, 0.075 M, 1.5 equiv;
CH2Cl2 as solvent.
24 acidic activators is crucial. Strong activators such as triflic
25 anhydride (Tf2O) and trifluoroacetic anhydride are usually
26 used to generate very reactive cationic sulfonium
27 intermediates. However, it is generally difficult to control
28 such short-lived intermediates. Indeed, during the course of
29 our study, the reactions of alkenyl and aryl sulfoxides often
30 resulted in the formations of complex mixtures, especially
31 when Tf2O was used as the activator.4j,4k,5 Taming reactive
32 short-lived sulfonium intermediates is important to extend the
33 Pummerer frontier further.
Ph
4aa
61
62 Figure 1. Setup for reaction of KDMs with anilines in flow
63 microreactors.
64
65
In our first trial, to our surprise, we did not obtain the
66 expected indole 4aa at all but thioimidate 3aa12 as the major
67 product apparently through skeletal rearrangement (vide
68 infra). Because we later found a new transformation that can
69 easily convert 3aa into 4aa (vide infra), we started optimizing
70 reaction conditions to obtain 3aa efficiently.
34
Flow microreactors have emerged as a game-changing
35 technology in organic synthesis, offering many practical
36 advantages.7 Most notably, flow microreactors enable to
37 precisely control very unstable intermediates by virtue of
38 extremely fast mixing of a reagent and a substrate and
39 residence time (the duration between the addition of a reagent
40 and that of the next reagent) as short as a few milliseconds.8
41 We envisioned that flow microreactors would offer an
42 opportunity to tame reactive short-lived sulfonium
43 intermediates in the extended Pummerer chemistry.9 As an
44 additional advantage, flow microreactors allow spatial
45 separation of the activation step and the nucleophilic trapping
46 step: we can eliminate the possibility of unwanted direct
71
Given that careful control of unstable sulfonium
72 intermediates is important, we investigated the effects of the
73 temperature of R1 and the residence time in R1 on the yield
74 of 3aa (Figure 2). In regard to the yield of 3aa and the
75 amounts of by-products, we concluded that the best
76 combination is 0 ˚C and 1.0 s for the temperature and the
77 residence time, respectively, to yield 3aa in 91% GC yield.
78 Probably because of the instability of the sulfonium species,
79 a higher temperature and a longer residence time led to a
80 lower yield of 3aa (45% yield at 30 ˚C and for 24 s, for
81 instance). The reaction at a temperature as low as 0 ˚C for a
82 short residence time (0.24 s) resulted in a small decrease of

2
1
2
3
the yield of 3aa (84%) because the activation of 1aa with
Tf2O would be incomplete.
32
SMe
N
3.0 equiv iPr2EtN
1.0 equiv cC6H11NH2
1.0 equiv Tf2O
Ph
1a
1.1 equiv
(1)
in R2
0 ˚C, 1.0 s, in R1
MeS cC6H11
5, 58%
1.5 equiv iPr2EtN
1.0 equiv PhMeNH
SMe
1.0 equiv Tf2O
MeS
1a
1.1 equiv
(2)
NMe
Ph Ph
in R2
0 ˚C, 1.0 s, in R1
6, 74%
(2.5:1 mixture)
33
34
35
The scope of KDMs was also investigated. Both
36 electron-donating methoxy and electron-withdrawing CF3
37 groups in 1b and 1c diminished the yields of the
38 corresponding products (eq 3). The modest yields would
39 originate from differences in the formation rate and stability
40 of the key reactive sulfonium species generated from these
41 electronically biased KDMs. This would be also the case for
42 the alkyl-substituted KDM 1d, and 3da was obtained in only
43 21% yield. Further optimization study would be necessary
44 for each KDM.
4
5
6
7
8
9
Figure 2. Temperature–residence time mapping for the
reaction of KDM 1a with aniline (2a) in the flow
microreactor system.
With the optimized conditions in hand, we screened the
45
10 reaction scope of anilines. As shown in Figure 3, the scope
11 has proved to be very wide. Electron-rich as well as electron-
12 deficient anilines similarly participated in the reaction to
13 isolate 3aa–aj. The propargyl ether, chloro, ester, and cyano
14 groups in 3ad, 3ae, 3af, and 3ah, respectively, were
15 compatible under the reaction conditions. The ortho-methyl
16 substituent and 1-naphthyl skeleton had no influence on the
17 yields of 3ak and 3al, respectively. It is worth noting that all
18 the reactions invariably provided the products in high yields
19 (84–88%), which underscores the advantage of the flow
O
SMe
SMe
SMe
NPh
R
(3)
+ PhNH2
conditions
in Figure 3
R
MeS
R = 4-MeOC6H4: 1b
R = 4-CF3C6H4: 1c
R = Me: 1d
3ba, 43%
3ca, 53%
3da, 21%
46
47
48
Although the exact reaction mechanism for the
49 formation of thioimidates 3 is unclear at this moment, we
50 suppose a mechanism in Scheme 1. KDM 1a is activated by
51 Tf2O to yield sulfonium cation 7. Cation 7 would undergo
52 rapid rearrangement to yield benzylic triflate 8.13 Aniline
53 injected in M2 would react with 8 to yield 9 bearing an N,S,S-
54 orthoester unit. Intramolecular substitution of the triflate
55 with a nucleophilic methylsulfanyl group results in the
56 formation of thiiranium cation 10. Smooth ring-opening of
57 10 provides thioimidate 3aa.14
20 microreactor technology.
In addition, the aniline-
21 independent behavior strongly suggests that nucleophilic
22 attack of anilines and the subsequent reactions in R2 do not
23 involve a yield-determining step and that control of the
24 reactions in R1 is crucial. Aliphatic cyclohexylamine reacted
25 to furnish the corresponding thioimidate 5 in good isolated
26 yield after careful purification albeit 5 is not so stable on
27 silica gel (eq 1). N-methylaniline, a secondary amine, also
28 reacted to yield the corresponding enamine 6 (eq 2).
29
58
F3C
O
O
F3C
O
O
S
SMe
SMe
S
SMe
SMe
PhNH2
O
Tf2O
SMe
O
1a
O
SMe
0 ˚C, 1.0 s
SMe
1a
Ph
MeS
M1
Ph
TfO
Ph
N
TfO
Ph
R1
7
8
M2
Tf2O
+
R2
H
PhN
Ar
PhNH2
SMe
SMe
SMe
SMe
iPr2EtN
+
ArNH2
2a–l
3aa–al
TfO
3aa
iPr2EtN•HOTf
Ph
TfO
Ph TfO
R = H
Me
OMe
3aa, 85%
3ab, 88%
3ac, 88%
iPr2EtN•HOTf
9
Me
10
59
60 Scheme 1. Supposed mechanism for thioimidate formation.
OCH2C CH 3ad, 87%
R
R = Me
61
Cl
3ae, 88%
3af, 89%
3ag, 88%
3ah, 85%
3ak, 84%
3al, 88%
3ai, 85%
3aj, 88%
R
COOEt
CF3
CN
62
To convert thioimidates 3 into indoles, we needed to
OMe
63 invent a new cyclization reaction. Taking advantage of the
64 high electron density at the benzylic sulfide unit, we found
65 that an oxidant, bis(pyridine)iodonium tetrafluoroborate,
66 promotes cyclization to yield 2-methylsulfanyl-3-arylindoles
30
31 Figure 3. Scope of anilines.

3
NH
1
2
3
4
5
6
7
8
9
4 (Figure 4). The reaction scope is wide although the
electron-deficient aniline units in 3ag and 3ah retarded the
cyclization. The cyclization of m-methoxyaniline derivative
3aj was exclusively regioselective to yield 4aj albeit the
corresponding m-methyl analogue 3ai was converted to a
regioisomeric mixture of 4ai. By considering these electronic
effects observed above, the cyclization is likely to proceed
via oxidation of the benzylic sulfide by the iodonium reagent
followed by Friedel-Crafts-type cyclization (Scheme 2). A
3 mol% PdCl2
2.1 equiv HSiEt3
Ph
4aa
(4)
11, 86%
1) 1.5 equiv MeOTf
2) 5 mol% Pd2(dba)3
10 mol% SPhos
4-MeOC6H4
Ph
NH
2.0 equiv (4-MeOC6H4)4BNa
(5)
COOEt
4af
12, 73%
10 substoichiometric amount of (py)2IBF4 was sufficient
11 because MeSI generated in situ would also serve as an
28
29
12 oxidant.
13
30
In summary, we have developed an efficient extended
31 Pummerer reaction of ketene dithioacetal monoxides with
32 unprotected anilines, taking advantage of flow microreactors.
33 The flow microreactors allowed us to precisely control
34 unstable sulfonium intermediates and to spatially separate the
35 generation of the intermediate and the nucleophilic attack
36 onto the intermediates. The products are useful thioimidates
37 that undergo iodonium-mediated cyclization into indoles of
38 interest. The 2-methylsulfanyl group in the indole products
39 participate in several transformations including palladium-
40 catalyzed cross-coupling reactions. Further extension of
41 Pummerer-type chemistry using flow microreactors is now in
42 progress.
SMe
MeS
Ar
Ar
NH
0.8 equiv (py)2IBF4
ClCH2CH2Cl, 65 °C
N
MeS
Ar
Ar
3
4
MeS
Ph
MeS
NH
MeS
Ph
NH
R
NH
Ph
4Me
Me6
OMe
4ai, 72%
4aj, 69%
(4-/6-Me = 1:1.2)
R = H
Me
OMe
4aa, 84%
4ab, 87%
4ac, 81%
43
MeS
NH
MeS
Ph
44 This work was supported by JSPS KAKENHI Grant
45 Numbers JP16H04109, JP18H04254, JP18H04409,
46 JP19H00895, JP18K14212, and JP 15H05849. A.B. and T.Y.
47 acknowledge JSPS Post- and Predoctoral Fellowship,
48 respectively. H.Y. thanks The Mitsubishi Foundation for
49 financial support.
NH
OCH2C CH 4ad, 63%
Cl
COOEt
CF3
CN
Me
Ph
4ae, 76%
4af, 66%
4ag, 69%a
4ah, 26%b
4ak, 86%
4al, 84%
a) 1.0 equiv (py)2IBF4, 85 °C
b) 1.6 equiv (py)2IBF4, 85 °C
MeS
NH
50
p-XC6H4
51 Supporting
52 http://dx.doi.org/10.1246/cl.******.
Information
is
available
on
X = MeO
4ba, 68%
4ca, 57%
CF3
14
15 Figure 4. Iodonium-promoted cyclization into indoles.
53 References and Notes
16
17
54
55
56
57
58
59
60
61
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64
65
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SMe
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(py)2IBF4
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3aa
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Me S+
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(or as MeS+ and I–)
18
19 Scheme 2. Supposed mechanism for indole formation.
20
21
N-Unprotected indoles 4 bearing a 2-methylsulfanyl
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Although we conducted Suzuki-Miyaura arylation with neutral
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good results and side reactions such as demethylation by base
proceeded.
17