Accounting for Different Reactivities of Sulfinate and Thiosulfate Salts in Regioselective Azetidine Coupling via C-H Sulfenylation of Indoles

Article abstract of DOI:10.1055/s-0036-1591490

The regioselective incorporation of azetidines into heteroaromatic compounds is reported via a formal C-H sulfenylation reaction. While sodium sulfinate salts undergo C3 sulfenylation of electron-rich indoles only, the corresponding thiosulfate salts have proved to be more generally useful. A mechanistic hypothesis for the different reactivities of sulfinate and thiosulfate salts is provided.

Full text of DOI:10.1055/s-0036-1591490

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
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en
M. A. E. Al-Saedy et al.
Letter
Synlett
Accounting for Different Reactivities of Sulfinate and Thiosulfate
Salts in Regioselective Azetidine Coupling via C–H Sulfenylation of
Indoles
Muhannad A. E. Al-Saedy
Anne-Chloé M. A. Nassoy
Joseph P. A. Harrity*
H
NBoc
S
RS
R
R
N
NBoc
N
H
R'
Department of Chemistry, The University of Sheffield,
Brook Hill, Sheffield, S3 7HF, UK
j.harrity@sheffield.ac.uk
SR = SO2Na
R = H, Me, OR
SR = SSO3Na
R = H, Me, OR,
Hal, Bpin, CHO,
NO2, N(H)Boc
>20 examples
48–100% yield
Narrow scope
via Az-S(O)-I
via Az-S-I
Received: 06.09.2017
Accepted after revision: 16.09.2017
Published online: 20.10.2017
driven hypothesis that has led to the discovery of thiosul-
fate (Bunte) salts as generally useful reagents for regioselec-
tive sulfenylation of indoles and pyrroles.
DOI: 10.1055/s-0036-1591490; Art ID: st-2017- d0669-l
C2 Sulfonylation
Abstract The regioselective incorporation of azetidines into heteroar-
omatic compounds is reported via a formal C–H sulfenylation reaction.
While sodium sulfinate salts undergo C3 sulfenylation of electron-rich
indoles only, the corresponding thiosulfate salts have proved to be
more generally useful. A mechanistic hypothesis for the different reac-
tivities of sulfinate and thiosulfate salts is provided.
O
S
SO2Na
I2
R
O
R
R
+
N
MeOH, r.t.
H
N
H
N
1
Boc
NBoc
C3 Sulfenylation
NBoc
SO2Na
S
Key words azetidines, coupling, indoles, C–H functionalization, thio-
ethers
I2, PPh3
+
R
EtOH, 70 °C
1
N
H
N
Boc
N
H
Scheme 1 Regiodivergent coupling for the introduction of azetidines
into indoles
The direct C–H functionalization of aromatic com-
pounds has seen a recent surge in research activity and a
range of C–C and C–heteroatom bond-forming processes
have now become well established.1 One particularly effec-
tive application of this methodology is in its employment in
the direct coupling of fragments that are of value to the fine
chemicals industry, especially those that are rich in sp3-
based centers. In this context, small-ring heterocycles have
been targeted as valuable molecules because of their attrac-
tive chemical and physical properties,2 and this has in-
spired several approaches for the direct coupling of these
fragments.3 Our own interest in this field has led to the dis-
covery of a C–S bond-forming coupling of azetidine and ox-
etanesulfinate salts to indoles as a direct means of generat-
ing indole 2-sulfones.4 More specifically, as shown in
Scheme 1, the iodine-promoted sulfonylation reaction de-
veloped by Deng and Kuhakarn5 offered a convenient
means for incorporating azetidines and oxetanes at C2. Pre-
liminary studies suggested that a regiocomplementary pro-
cess could be developed that delivered C3-substituted sul-
fides from the same starting materials, using the same au-
thors’ reductive coupling variant.6 We report herein the
scope and limitations of this process, and a mechanism-
We began our studies by exploring the generality of C3
sulfenylation of indoles using sodium sulfinate 1 in the
presence of PPh3 and iodine, and the scope is summarized
in Scheme 2.
Coupling of the parent indole proceeded smoothly to
generate 2 in high yield. Moreover, incorporation of a Me
group on the benzene moiety, indole nitrogen, and C2-posi-
tions were well tolerated, providing 3–5 in excellent yield.
We were also able to include a MeO group at all positions
on the arene ring, as well as a free phenol, giving azetidine
sulfides 6–10. Incorporation of a substituent at the indole
C3-position resulted in a turnover of regioselectivity, pro-
viding 11 in modest yield. We next opted to explore indoles
bearing electron-withdrawing groups and were surprised
to find that we were unable to observe any of the expected
sulfides, and starting indole was recovered in each case
(representative examples shown in Scheme 2).
The proposed mechanism of the indole C3 sulfenylation
involves the stepwise reduction of the sodium sulfinate salt
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
M. A. E. Al-Saedy et al.
Letter
Synlett
wondered whether these intermediates were in fact in-
volved in the C–S bond-forming step. In order to investigate
the veracity of this hypothesis, we prepared the corre-
sponding sulfoxide of azetidine sulfide 8 and subjected it to
iodine/PPh3. As shown in Scheme 4 (eq. 1), the sulfoxide
underwent reduction under these conditions to return 8 in
modest yield. Moreover, subjecting an equal mixture of the
same sulfoxide and indole to the reaction conditions gener-
ated both 2 and 8 (Scheme 4, eq. 2). Moreover, during the
preparation of this manuscript, Lu et al. showed that the
PPh3/NaI-promoted trifluoromethylthiolation of indoles
(via a putative sulfenium chloride) generated a sulfoxide
byproduct.8 We believe therefore that a mechanism involv-
ing indole sulfoxide formation followed by reduction should
be considered alongside the currently accepted sulfenyl io-
dide SEAr pathway.
NBoc
NBoc
SO2Na
S
I2, PPh3
R
+
R
EtOH, 70 °C, 24 h
N
N
1
H
N
Boc
H
NBoc
NBoc
S
S
S
H3C
N
N
N
H
C
H
H3
2; 84%
3; 97%
4; 98%
NBoc
NBoc
NBoc
S
S
S
CH3
N
H
N
N
H3CO
H
H
OCH3
5; 100%
6; 66%
7; 86%
NBoc
NBoc
HO
OCH3
S
NBoc
S
S
O
NBoc
NBoc
S
S
H3CO
I2 (1 equiv)
H3CO
H3CO
PPh3 (2 equiv)
N
N
8; 53% (1)
H
N
H
H
EtOH, 70 °C
N
N
H
H
8; 100%
9; 93%
10; 90%
CH3
O
NBoc
NBoc
(2)
I2 (1 equiv)
X
S
S
PPh3 (2 equiv)
S
H3CO
R
X = Cl, Br, CN
R = H, Boc
No reaction
N
N
EtOH, 70 °C
H
R
N
N
NBoc
H
H
SO2Na
(2 equiv)
BocN
(0.5 equiv)
11; 48%
R = H; 2 : R = MeO; 8 = 1:2
+
Scheme 2 C3 sulfenylation of indoles
N
(0.5 equiv)
H
Scheme 4 Evidence for sulfoxide intermediates
to sulfenyl iodide B via the sulfoxinium iodide A (Scheme
3).6 The reaction of sulfenium iodides and indoles is well es-
tablished, and has been found to proceed efficiently with
indole substrates bearing a range of electron-rich/deficient
groups.7 The narrow scope depicted in our results shown in
Scheme 2 did not therefore appear to be consistent with
this mechanism.
As the mechanistic studies suggested that the method-
ology depicted in Scheme 2 may not proceed through a
sulfenium iodide intermediate, we decided to explore alter-
native means by which this electrophilic intermediate
could be accessed. In this regard, Bunte salts represent a
convenient source of sulfenium cations as they are readily
prepared stable crystalline solids.9 Moreover, Luo and Wang
reported the elegant and pioneering use of these salts for
the formation of indole 3-sulfides.10 In order to investigate
the potential of these salts as a vehicle for incorporating
small-ring heterocycles, we explored the preparation of the
required azetidine thiosulfate salt (azetidine Bunte salt),
our results are shown in Scheme 5. In the event, the addi-
tion of sodium thiosulfate to commercially available iodide
12 delivered the corresponding salt 13 in quantitative yield.
We speculated that the intermediate sulfinyl iodide A, if
generated, would be an extremely reactive electrophile and
O
S
I2
Ph3P
PPh3
I
RSO2Na
R
O
– NaI
– Ph3P(O)
NaI
O
S
S
A
R
I
– NaOI
B
R
I
SEAr
?
N
H
I
SSO3Na
SR
S(O)R
Na2S2O3
(1.5 equiv)
N
N
MeOH/H2O
80 °C, 24 h
Boc
Boc
N
N
H
12
13; 100%
H
Scheme 3 Potential mechanisms of indole sulfenylation
Scheme 5 Synthesis of azetidine Bunte salt 13
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
M. A. E. Al-Saedy et al.
Letter
Synlett
With the azetidine thiosulfate salt 13 in hand, we set
about exploring the scope of the sulfenylation reaction us-
ing this compound, and our results are summarized in
Scheme 6. We initially targeted the synthesis of a selection
of indole azetidine sulfides prepared by the earlier sulfinate
salt method (Scheme 2) and were pleased to find that this
chemistry worked well providing compounds 2, 3, 7–10 and
2-Ph-substituted indole 14 in high yield. Given the simple
synthesis of precursor 13 in comparison to the correspond-
ing sulfinate salt 1, this represents a very convenient meth-
od to access these compounds. We next turned our atten-
tion to substrate bearing a halide on the aryl ring that had
proved to be unsuccessful in our earlier studies. The use of
Bunte’s salt 13 in this case delivered a series of halide-sub-
stituted products 15–19 in excellent yield. In addition, the
chemistry could be extended to previously unreactive elec-
tron-deficient indoles, generating carbonyl derivatives 20
and 21. Moreover, nitrogen-containing substrates at the ni-
tro- and amine-oxidation levels could be prepared with
similar efficiencies (22, 23). Finally, arylboronic esters were
found to be compatible as were azaindoles, delivering func-
tionalized scaffolds 24 in high yield. Overall therefore, we
have found azetidine thiosulfate salt 13 to offer several ad-
vantages over the corresponding sulfinate salt 1, including
ease of synthesis and improved scope of reactivity.
Finally, we have been able to extend this method for the
introduction of azetidines to other aromatic systems. As
shown in Scheme 7, azaindole provided 25 in high yield,
and pyrroles could undergo mono- and disulfenylation de-
pending on reaction time and stoichiometry to give 26–28
with excellent regiocontrol. Moreover, we were able to cou-
ple azetidines to imidazo[1,2-a]pyridine to furnish 29 in
excellent yield and regiocontrol. Reaction regiochemistry
was confirmed in this case by X-ray crystallography.11 Final-
ly, we were also able to couple azetidines to less nucleophil-
ic aromatic systems via the corresponding organometallic
intermediates12 as illustrated by the synthesis of benzene
and thiophene bases azetidine thioethers 30 and 31. This
reaction was facilitated by the use of Et4NI which we believe
improves the solubility of the thiosulfate salt.
SSO3Na
NBoc
NBoc
SSO3Na
S
20 mol% I2
20 mol% I2
R
+
R
+
R
S
DMSO, 80 °C, 24 h
N
R
N
DMSO, 80 °C, 24 h
N
N
R
Boc
13
N
H
N
Boc
R
H
13 (1.5 equiv)
NBoc
NBoc
NBoc
H3C
NBoc
S
S
S
S
NBoc
NBoc
HO
S
N
S
Et
N
N
N
N
N
N
H
H
H
H
H
H
2; 89%
3; 94%
10; 86%
26; 46%a
27; 87%
25; 80%
NBoc
H3CO
NBoc
N
N
NBoc
S
S
BocN
OCH3
NBoc
S
S
S
N
H
S
N
N
H3CO
NBoc
N
H
H
28; 67%b
29; 75%
H
9; 90%
7; 92%
8; 89%
SSO3Na
S-Ar
S
Ar-MgBr, Et4NI
NBoc
NBoc
S
S
S
S
X
X = F, 15; 73%
X = Cl,16; 78%
X = Br,17; 92%
X = I, 18; 94%
THF, 0 °C to r.t.
20 min
13
N
N
Boc
Boc
Ph
N
30; 76%
31; 72%
N
H
N
H
N
Boc
Boc
14; 97%
Scheme 7 Synthesis of azetidine thioethers of other aromatic systems.
a Reaction stirred for 8 h. b 3 equiv of 13 used.
NBoc
R
NBoc
R2N
NBoc
O
S
S
S
N
H
N
N
H
Br
H
In conclusion, we report a simple method for the cou-
pling of azetidines to indoles via sulfinate and thiosulfate
salts,13,14 the latter appearing to show significantly broader
scope. Although both salts have been proposed to function
as reactive electrophiles through the intermediacy of a
sulfenyl iodide, the significant differences in reactivities ob-
served in their reaction with indoles has led us to propose
that the sulfinate salts react via an SEAr reaction of an in
situ generated sulfoxonium iodide.
19; 87%
R = H, 20; 88%
R = OH, 21; 84%
NR2 = NO2, 22; 79%
NR2 = N(H)Boc, 23; 81%
NBoc
CH3
S
N
H
S
pinB
N
H
NBoc
24; 86%
11; 57%
Scheme 6 C3 sulfenylation of indoles using Bunte salt 13
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
M. A. E. Al-Saedy et al.
Letter
Synlett
(11) The supplementary crystallographic data for compounds 14, 22,
and 29 have been deposited with the Cambridge Crystallo-
graphic data Center as supplementary publication numbers
CCDC 1534462, 1534463, and 1534461, respectively. This data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/getstructures.
(12) Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca, C. A.;
Senanayake, C. H. Org. Lett. 2014, 16, 1196.
Funding Information
We are grateful to The Iraqi Ministry of Higher Education and Scien-
tific Research and Al-Mustansiriyah University for financial support.
Supporting Information
(13) General Procedure A: Coupling of Azetidine Sulfinate Salt 1
to Indoles
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591490.
Iodine (1.0 equiv) was added to indole (1.0 equiv), PPh3 (2.0
equiv), and sodium 1-(tert-butoxycarbonyl) azetidine-3-sulfi-
nate (1, 2.0 equiv) in EtOH (0.5 mL) at r.t. The resulting solution
was stirred at 70 °C for 1 d. All volatiles were removed in vacuo.
Purification by recrystallization or by flash chromatography
over silica gel, eluting with PE/EtOAc (0–30%) afforded the
desired thioindoles.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) For representative reviews on C–H activation, see: (a) Shin, K.;
Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040. (b) Daugulis,
O.; Roane, J.; Tran, L. D. Acc. Chem. Res. 2015, 48, 1053. (c) Song,
G.; Li, X. Acc. Chem. Res. 2015, 48, 1007. (d) Girard, S. A.;
Knauber, T.; Li, C.-J. Angew. Chem. Int. Ed. 2014, 53, 74.
(e) Sarkar, S. D.; Liu, W.; Kozhushkov, I.; Ackermann, L. Adv.
Synth. Catal. 2014, 356, 1461. (f) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651. (g) Lyons, T. W.; Sanford, M. Chem. Rev.
2010, 110, 1147.
Synthesis of tert-butyl 3-[(1H-Indol-3-yl)thio]azetidine-1-
carboxylate (2)
Following general procedure A, 1H-indole (12 mg, 0.103 mmol),
azetidine sulfinate salt (50 mg, 0.206 mmol), PPh3 (54 mg, 0.206
mmol), and iodine (26 mg, 0.103 mmol) afforded the desired
product as a brown gum (26 mg, 84%). 1H NMR (400 MHz,
CDCl3): δ = 8.64 (br, 1 H), 7.79–7.75 (m, 1 H), 7.45–7.38 (m, 2 H),
7.31–7.21 (m, 2 H), 4.19–4.12 (m, 2 H), 3.92–3.84 (m, 2 H), 3.77
(tt, J = 8.0, 5.5 Hz, 1 H), 1.38 (s, 9 H). 13C NMR (101 MHz, CDCl3):
δ = 156.2, 136.3, 130.5, 129.7, 122.9, 120.8, 119.1, 111.6, 102.5,
79.6, 56.0 (br), 35.6, 28.3. FTIR (neat): νmax = 3278 , (s), 305, (w),
2975, (m), 2882 , (m), 1675 (s) cm–1. HRMS: m/z [M + H]+ calcd
for C16H21N2O2S: 305.1324; found: 305.1319.
(2) (a) Carreira, E. M.; Fessard, T. C. Chem. Rev. 2014, 114, 8257.
(b) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.;
Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49, 9052.
(3) (a) Duncton, M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.;
O’Mahony, D. J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan,
M.; Kincaid, J.; Kelly, M. G. Org. Lett. 2008, 10, 3259.
(b) Duncton, M. A. J.; Estiarte, M. A.; Johnson, R. J.; Cox, M.;
O’Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. J. Org. Chem.
2009, 74, 6354. (c) Presset, M.; Fleury-Brégeot, N.; Oehlrich, D.;
Rombouts, F.; Molander, G. A. J. Org. Chem. 2013, 78, 4615.
(d) Molander, G. A.; Traister, K. M.; O’Neill, B. T. J. Org. Chem.
2014, 79, 5771. (e) Gianatassio, R.; Kawamura, S.; Eprile, C. L.;
Foo, K.; Ge, J.; Burns, A. C.; Collins, M. R.; Baran, P. S. Angew.
Chem. Int. Ed. 2014, 53, 9851. (f) Barré, B.; Gonnard, L.;
Campagne, R.; Reymond, S.; Marin, J.; Ciapetti, P.; Brellier, M.;
Guérinot, A.; Cossy, J. Org. Lett. 2014, 16, 6160. (g) Parmar, D.;
Henkel, L.; Dib, J.; Rueping, M. Chem. Commun. 2015, 51, 2111.
(4) Nassoy, A.-C. M. A.; Raubo, P.; Harrity, J. P. A. Chem. Commun.
2015, 51, 5914.
Synthesis of tert-Butyl 3-[(5-Methyl-1H-indol-3-yl)thio]azeti-
dine-1-carboxylate (3)
Following the general procedure A, using 5-methyl-1H-indole
(14 mg, 0.103 mmol), azetidine sulfinate salt 1 (50 mg, 0.206
mmol), PPh3 (54 mg, 0.206 mmol), and iodine (26 mg, 0.103
mmol) afforded the desired product as a pale brown solid (32
1
mg, 97%); mp 119–120 °C. H NMR (400 MHz, CDCl3): δ = 8.57
(br, 1 H), 7.52 (s, 1 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz,
1 H), 7.08 (dd, J = 8.5, 1.5 Hz, 1 H), 4.16–4.10 (m, 2 H), 3.91–3.82
(m, 2 H), 3.74 (tt, J = 8.0, 5.5 Hz, 1 H), 2.48 (s, 3 H), 1.37 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 156.4, 134.7, 130.8, 130.0, 129.9,
124.4, 118.5, 111.4, 101.4, 79.7, 56.0, 35.4, 28.3, 21.5. FTIR
(neat): νmax = 3282 (br), 3060 (w), 2974 (m), 2930 (m), 2877
(m), 1675 (s) cm–1. HRMS: m/z [M + Na]+ calcd for C17H22N2O2S:
319.1480; found: 319.1473.
(5) (a) Xiao, F.; Chen, H.; Xie, H.; Chen, S.; Yang, L.; Deng, G.-J. Org.
Lett. 2014, 16, 50. (b) Katrun, P.; Mueangkaew, C.; Pohmakotr,
M.; Reutrakul, V.; Jaipetch, T.; Soorukram, D.; Kuhakarn, C.
J. Org. Chem. 2014, 79, 1778.
General Procedure B: Coupling of Azetidine Bunte Salt 13 to
Indoles
To a flame-dried Schlenk tube with a magnetic stirring bar was
added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv),
and iodine (20 mol%). The tube was closed with a rubber
septum, and placed under an atmosphere of argon, followed by
the addition of DMSO via syringe (2 mL). The septum was
replaced by a TeflonTM screw cap under argon flow. The reaction
mixture was stirred at 80 °C for 12 h. After cooling to r.t., a satu-
rated solution of Na2S2O3 was added and the product extracted
with EtOAc. The combined organic layers was washed with H2O
and brine, dried over MgSO4, filtered, and then concentrated in
vacuo. Purification by recrystallization or by flash chromatogra-
phy over silica gel, eluting with PE/EtOAc (0–30%) afforded the
desired thioindoles.
(6) (a) Xiao, F.; Xie, H.; Liu, S.; Deng, G.-J. Adv. Synth. Cat. 2014, 356,
364. (b) Katrun, P.; Hongthong, S.; Hlekhlai, S.; Pohmakotr, M.;
Reutrakul, V.; Soorukram, D.; Jaipetch, T.; Kuhakarn, C. RSC Adv.
2014, 4, 18933.
(7) (a) Raban, M.; Chern, L.-J. J. Org. Chem. 1980, 45, 1688. (b) Yi, S.;
Li, M.; Mo, W.; Hu, X.; Hu, B.; Sun, N.; Jin, L.; Shen, Z. Tetrahe-
dron Lett. 2016, 57, 1912.
(8) Lu, K.; Deng, Z.; Li, M.; Li, T.; Zhao, X. Org. Biomol. Chem. 2017,
15, 1254.
(9) Distler, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 544.
(10) (a) Qi, H.; Zhang, T.; Wan, K.; Luo, M. J. Org. Chem. 2016, 81,
4262. (b) Li, J.; Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Org. Biomol. Chem.
2016, 14, 9384.
(14) General Procedure B: Coupling of Azetidine Bunte Salt 13 to
Indoles
To a flame-dried Schlenk tube with a magnetic stirring bar was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
M. A. E. Al-Saedy et al.
Letter
Synlett
added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv),
and iodine (20 mol%). The tube was closed with a rubber
septum, and placed under an atmosphere of argon, followed by
the addition of DMSO via syringe (2 mL). The septum was
replaced by a TeflonTM screw cap under argon flow. The reaction
mixture was stirred at 80 °C for 12 h. After cooling to r.t., a satu-
rated solution of Na2S2O3 was added and the product extracted
with EtOAc. The combined organic layers was washed with H2O
and brine, dried over MgSO4, filtered, and then concentrated in
vacuo. Purification by recrystallization or by flash chromatogra-
phy over silica gel, eluting with PE/EtOAc (0–30%) afforded the
desired thioindoles.
with EtOAc. The combined organic layers was washed with H2O
and brine, dried over MgSO4, filtered, and then concentrated in
vacuo. Purification by recrystallization or by flash chromatogra-
phy over silica gel, eluting with PE/EtOAc (0–30%) afforded the
desired thioindoles.
Synthesis of tert-Butyl 3-[(5-Fluoro-1H-indol-3-yl)thio]azeti-
dine-1-carboxylate (15)
Following the general procedure B, using 5-fluoro-1H-indole
(47 mg, 0.344 mmol), azetidine Bunte salt 13 (151 mg, 0.517
mmol), and iodine (17 mg, 0.069 mmol) the desired product
was afforded as a white solid (81 mg, 73%); mp 161–162 °C. 1H
NMR (400 MHz, CDCl3): δ = 9.21 (br, 1 H), 7.40–7.35 (m, 2 H),
7.30 (dd, J = 9.0, 4.5 Hz, 1 H), 6.98 (td, J = 9.0, 2.5 Hz, 1 H), 4.19–
4.09 (m, 2 H), 3.86–3.79 (m, 2 H), 3.71 (tt, J = 8.0, 5.5 Hz, 1 H),
1.37 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 158.6 (d, J = 236.5
Hz), 156.3, 132.8, 132.4, 130.5 (d, J = 10.0 Hz), 112.5 (d, J = 9.5
Hz), 111.3 (d, J = 26.5 Hz), 104.0 (d, J = 24.0 Hz), 102.1 (d, J = 3.5
Hz), 79.9, 55.9, 35.4, 28.3. 19F NMR (377 MHz, CDCl3): δ = 110.3.
FTIR (neat): νmax = 3267 (br), 3040 (w), 2979 (m). 2881 (m),
1675 (s) cm–1. HRMS: m/z [M + Na]+ calcd for C16H19FN2O2S:
345.1043; found: 345.1042.
Synthesis of tert-Butyl 3-[(2-Phenyl-1H-indol-3-yl) thio]azeti-
dine-1-carboxylate (14)
To a flame-dried Schlenk tube with a magnetic stirring bar was
added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv),
and iodine (20 mol%). The tube was closed with a rubber
septum, and placed under an atmosphere of argon, followed by
the addition of DMSO via syringe (2 mL). The septum was
replaced by a TeflonTM screw cap under argon flow. The reaction
mixture was stirred at 80 °C for 12 h. After cooling to r.t., a satu-
rated solution of Na2S2O3 was added and the product extracted
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E