(3+2)-Cycloaddition of Donor-Acceptor Cyclopropanes with Thiocyanate: A Facile and Efficient Synthesis of 2-Amino-4,5-dihydrothiophenes

Article abstract of DOI:10.1055/a-1385-2385

An easy and efficient route to obtain 2-amino-4,5-dihydrothiophenes is presented. A formal (3+2)-cycloaddition of donor-acceptor cyclopropanes and ammonium thiocyanate catalyzed by Yb(OTf) ₃delivers the desired products in good to excellent yields. A broad range of functional groups is tolerated during this process.

Full text of DOI:10.1055/a-1385-2385

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 901–904
letter
901
en
A. Jacob et al.
Letter
Synlett
(3+2)-Cycloaddition of Donor–Acceptor Cyclopropanes with Thio-
cyanate: A Facile and Efficient Synthesis of 2-Amino-4,5-dihydro-
thiophenes
Anu Jacoba
CO2R2
Philip Barkawitza
Ivan A. Andreevb,c
Nina K. Ratmanovab
Igor V. Trushkovb,c
Daniel B. Werz*a
CO2R2
CO2R2
Yb(OTf)3
NH4SCN
+
NH2
R1
THF, 75 °C, 20 h
S
R1
21 examples, 22–95% yield
broad substrate scope
R
1 = aryl, vinyl, 2-thienyl, succinimidyl
R2 = Me, Et, Bn, t-Bu
a Technische Universität Braunschweig, Institute of Organic Chemistry,
Hagenring 30, 38106 Braunschweig, Germany
d.werz@tu-braunschweig.de
b Dmitry Rogachev National Medical Research Center of Pediatric
Hematology, Oncology and Immunology, Samory Mashela 1, 117997
Moscow, Russian Federation
c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Leninsky pr. 47, 119991 Moscow, Russian Federation
Corresponding Author
Received: 21.01.2021
Accepted after revision: 07.02.2021
Published online: 07.02.2021
ting up the need for more efficient and simple ways to ac-
cess them. In 2010, Chandrasekaran and co-workers uti-
lized tetrathiomolybdate as the sulfur transfer agent to
doubly activated cyclopropanes to obtain dihydrothio-
phenes.15 Srinivasan et al. introduced a two-step route to
access tetrasubstituted thiophene by a (3+3)-cycloaddition
of DACs with in situ generated mercaptoacetaldehyde.16 In
2017, the synthesis of highly substituted tetrahydrothio-
and tetrahydroselenophenes via a (3+2)-cycloaddition of
DACs with thio- and selenoketones, respectively, was re-
ported by our group.17 Later in 2018, a similar transformation
using thionoester was disclosed by Yazaki and Ohshima.18 An
Yb(OTf)3-catalyzed (3+2)-cycloaddition involving DACs and
thiourea to obtain dihydrothiophenes was disclosed by Guo
and co-workers in 2019.19 Very recently, our group success-
fully prepared dihydroselenophenes via a (3+2)-cycloaddi-
tion of DACs and tetramethylammonium selenocyanate
(Scheme 1a).20
Very recently, Trushkov and co-workers made use of
protic ionic liquids with thiocyanate anion (Scheme 1a).21
With electron-rich DACs, the protic ionic liquid served as a
reagent, catalyst, and solvent and converted the three-
membered ring into pyrrolidine-2-thiones. This result is
noteworthy since the ambident thiocyanate anion attacks
the three-membered ring with the less nucleophilic nitro-
gen atom. Inspired by these investigations and our previous
results with selenocyanate, we were interested in whether
we can find conditions that enable the sulfur terminus of
thiocyanate anion to attack the electrophilic carbon of the
DAC. Such an initial step should lead – analogously to the
selenium congeners – to thiophene derivatives (Scheme
1b).
DOI: 10.1055/a-1385-2385; Art ID: st-2021-b0021-l
Abstract An easy and efficient route to obtain 2-amino-4,5-dihydro-
thiophenes is presented. A formal (3+2)-cycloaddition of donor–accep-
tor cyclopropanes and ammonium thiocyanate catalyzed by Yb(OTf)3
delivers the desired products in good to excellent yields. A broad range
of functional groups is tolerated during this process.
Key words D–A cyclopropanes, dihydrothiophenes, Lewis acid cataly-
sis, thiocyanate, cycloaddition
Donor–acceptor cyclopropanes (DACs) have been widely
used as versatile starting materials showing a 1,3-zwitteri-
onic behavior to access carbo- and heterocyclic com-
pounds.1 The pioneering works on these molecules were
unleashed by Wenkert and Reissig in the late 1970s.2 The
field has seen a revival during the past decades when these
scaffolds have been utilized not just for the synthesis of var-
ious carbo- and heterocycles but also for natural product
synthesis.3 The push–pull effect by the vicinally placed do-
nor and acceptor substituents activates the chemically inert
cyclopropane ring to undergo transformations such as ring
opening,4 cycloadditions, and rearrangements.5 Of these,
the most investigated being the cycloadditions with 1,2-,
1,3-, and 1,4-dipoles including dienes,6 carbonyls,7 imines,8
nitrones,9 alkynes,10 heterocumulenes,11 and other dipola-
rophiles.12 Less explored are the routes to access heterocy-
cles containing sulfur and selenium starting from DACs.
2-Aminodihydrothiophenes and -thiophenes were pre-
viously accessed through various routes, but syntheses
starting from DACs are rather scant.13 These moieties are
often found in many biologically relevant molecules,14 set-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 901–904
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

902
A. Jacob et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditionsa
a) Previous work
Chandrasekaran et al. (2010)
CN
CO2Me
EWG
NH2
KSCN
or
NH4SCN
CO2Me
CO2Me
M(OTf)3
[MoS4]2–
+
NH2
R1
+
EWG
Ph
S
Ph
R1
S
S
1a
2
3a
Guo et al. (2019)
CO2R2
CO2R2
NH2
S
Yb(OTf)3
Entry Reagent
Lewis acid
Solvent
Temp (°C)
Yield (%)b
+
CO2R2
Rb2CO3
R1
H2N
NH2
R1
1
2
3
4
5
6
7
8
9
KSCN
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
THF
THF
THF
DME
DME
DME
THF
THF
THF
25
25
75
75
50
50
50
75
75
–
Werz et al. (2020)
CO2R2
CO2R2
NH2
KSCN
–
Yb(OTf)3
NMe4SeCN
KSCN
–
+
R1
CO2R2
R1
R2O2C
Se
KSCN
–
Trushkov et al. (2021)
CO2R2
S
NH4SCN
NH4SCN
NH4SCN
NH4SCN
NH4SCN
20
32
45
60c
89c
CO2R2
+
NCS
H
N
Me
N
R1
CO2R2
R1
N
H
b) This work
CO2R2
CO2R2
CO2R2
NH2
d
Yb(OTf)3
Yb(OTf)3
NH4SCN
+
a Reaction conditions: 1a (100 μmol), 2 (200 mol), Lewis acid (10 mol%),
solvent (1 mL), under Ar, 4 h.
R1
R1
S
b Yields refer to purified and isolated products.
c The reaction was stirred for 12 h.
1
2
3
Scheme 1 a) Previously reported routes to access sulfur- and seleni-
um-containing heterocycles utilizing DACs. b) New route to access dihy-
drothiophenes from DACs.
d The catalyst loading was increased to 30 mol%.
sponding product 3n in a moderate yield of 61%. Enlarging
the electron-donating -system to the naphthyl group had
no beneficial effect and afforded the product 3o in 52%
yield. Changing the ester type from methyl to ethyl and
benzyl had almost no effect on the yield; only with the ster-
ically encumbered tert-butyl residue, the yield was slightly
lower (3r, 64% yield). However, the transformation gave
only poor yields when a vinyl group (3s, 26% yield) or nitro-
gen-derived residue were installed as a donor (3u, 22%
yield). In contrast, excellent conversion was observed with
the DAC containing the thienyl donor delivering product 3t
in 81% yield.
A plausible mechanistic scenario for this transformation
is proposed in Scheme 3. Yb(OTf)3 coordinates to the accep-
tor moieties, thereby weakening the C–C bond in the DAC.
The activated ring undergoes an SN2-like attack by the nuc-
leophilic thiocyanate ion leading to the ring opening. Unfor-
tunately, we were unable to prove the inversion in this case
because we did not get any separation of the two enantio-
meric products by our HPLC methods. The emerging
malonate anion attacks the nitrile carbon of the thiocya-
nate, resulting in a kinetically favored five-membered ring.
Excess thiocyanate ion, which is required, captures the alkyl
moiety from one of the ester groups, leading to decarboxyl-
ation, followed by the formation of product 3.
To begin with, the model DAC 1a and KSCN were reacted
in the presence of 10 mol% of Sc(OTf)3 in THF as solvent un-
der inert conditions (Table 1, entry 1). After various at-
tempts, KSCN was proved to be an unsuitable reagent for
the desired transformation. Further investigations were
carried out using NH4SCN as a thiocyanate source. With 10
mol% of Sc(OTf)3 as Lewis acid catalyst and DME as a sol-
vent, the desired product was obtained in 20% yield (entry
5). Further trials with Yb(OTf)3 as catalyst and DME as sol-
vent yielded 32% of 3a (entry 6). Switching the solvent to
THF increased the product formation up to 45% (entry 7).
Tuning the reaction conditions by increasing the tempera-
ture to 75 °C proved to be successful and delivered the
product in 60% yield (entry 8). An increased catalyst loading
of 30 mol% was found to deliver the product in 89% yield
(entry 9).
With the optimized conditions in hand, the generality
of the synthetic methodology was explored utilizing am-
monium thiocyanate 2 and diversely substituted DACs. The
para-substituted aryl cyclopropanes underwent the desired
transformation in fair to excellent yields to deliver the cor-
responding products 3a–j (Scheme 2). DACs with an elec-
tron-withdrawing nitro group at the meta position of the
aryl donor 1k showed poor performance in the transforma-
tion to the desired product with only 42% yield. The steri-
cally demanding substrate 1l gave the corresponding prod-
uct 3l in 61% yield. The mesityl donor containing DAC 1m
afforded the product 3m in 60% yield. The highly electron-
deficient perfluorophenyl DAC 1n furnished the corre-
In summary, a simple and straightforward method to
synthesize 2-amino-4,5-dihydrothiophenes is reported.22
The formal (3+2)-cycloaddition reaction of DACs and am-
monium thiocyanate was catalyzed by the action of
Yb(OTf)3. Numerous functional groups are tolerated in this
transformation.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 901–904

903
A. Jacob et al.
Letter
Synlett
Supporting Information
CO2R
NH2
Yb(OTf)3
CO2R
CO2R
NH4SCN
R
Supporting information for this article is available online at
https://doi.org/10.1055/a-1385-2385.
THF, 75 °C, 12 h
S
R
1
2
3
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
n
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
n
CO2Me
NH2
CO2Me
NH2
3a (R = H)
89%a
3b (R = Br) 65%
3c (R = Cl) 50%
O2N
88%
References and Notes
3d (R = F)
S
S
3e (R = Me) 68%
3f (R = OMe) 95%
3g (R = CN) 55%
3h (R = CF3) 60%
3i (R = OAc) 45%
3j (R = NO2) 46%
R
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3k 42%
3a–j
CO2Me
NH2
CO2Me
NH2
CO2Me
NH2
Me
Me
F
F
F
S
S
S
Me
Me
F
F
3l 61%
3m 60%
3n 61%
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CO2Me
NH2
Me
CO2Et
NH2
CO2R
NH2
S
S
S
3q (R = Bn) 84%
3p 84%
3o 52%
64%
3r (R = t-Bu)
CO2Me
NH2
CO2Me
NH2
CO2Me
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O
NH2
S
S
S
N
S
O
3s 26%
3t 81%
3u 22%
Scheme 2 Substrate scope with respect to DACs. Reagents and condi-
tions: 1 (100 mol), 2 (200 mol), Yb(OTf)3 (30 mol%), THF (1 mL), at
75 °C under Ar, 12 h; yields refer to purified and isolated products. a
Large scale: 81% yield for 1.5 mmol of starting material.
CO2R2
CO2R2
CO2R2
R2SCN
CO2
NH2
R1
R1
S
Yb(OTf)3
3
1
O
OR2
R2
R2O2C
O
O
SCN
R1
R2O
NH
Yb(OTf)3
O
S
R1
NH4SCN
NH3
2
CO2R2
CO2R2
R1
S
NH3
H
N
Scheme 3 Plausible reaction mechanism
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Funding Information
A DAAD fellowship to A.J. is gratefully acknowledged.
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Chem. Int. Ed. 2021, 60, in press DOI: 10.1002/anie.202016593.
(22) General Procedure for the Preparation of 2-Amino-dihydro-
thiophenes (3)
Cyclopropane diester 1 (100 mol, 1.00 equiv), ammonium
thiocyanate 2 (200 mol, 2.00 equiv), and ytterbium triflate (19
mg, 30.0 mol, 0.30 equiv were dissolved in THF (1 mL). The
solution was stirred at 75 °C for 12 h. The solvent was removed,
and the residue was purified by flash column chromatography.
Methyl 2-Amino-5-(4-chlorophenyl)-4,5-dihydrothiophene-
3-carboxylate (3c)
(11) (a) Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A. II.; Stoltz, B. M.
Org. Lett. 2012, 14, 5314. (b) Sun, Y.; Yang, G.; Chai, Z.; Mu, X.;
Chai, J. Org. Biomol. Chem. 2013, 11, 7859. (c) Gladow, D.;
Reissig, H.-U. J. Org. Chem. 2014, 79, 4492.
(12) (a) Lebold, T. P.; Leduc, A. B.; Kerr, M. A. Org. Lett. 2009, 11,
3770. (b) Xu, H.; Hu, J. L.; Wang, L.; Liao, S.; Tang, Y. J. Am. Chem.
Soc. 2015, 137, 8006. (c) Su, Z.; Qian, S.; Xue, S.; Wang, C. Org.
Biomol. Chem. 2017, 15, 7878. (d) Petzold, M.; Jones, P. G.; Werz,
D. B. Angew. Chem. Int. Ed. 2019, 58, 6225.
Colorless solid; yield 50%; mp 146 °C. 1H NMR (500 MHz,
CDCl3):  = 7.36–7.33 (m, 2 H), 7.31–7.27 (m, 2 H), 6.08 (s, 2 H),
4.79 (dd, J = 8.5, 6.9 Hz, 1 H), 3.69 (s, 3 H), 3.40 (dd, J = 14.3, 8.5
Hz, 1 H), 3.10 (dd, J = 14.2, 6.9 Hz, 1 H). 13C NMR (156 MHz,
CDCl3):  = 166.5, 161.9, 140.2, 133.5, 128.8, 128.4, 90.4, 50.5,
50.4, 41.4. HRMS (ESI): m/z calcd for C12H12ClNO2S [M + Na]:
292.0175; found: 292.0172.
Methyl
2-Amino-5-(p-tolyl)-4,5-dihydrothiophene-3-car-
boxylate (3e)
(13) (a) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94.
(b) Furukuwa, M.; Nagato, K.; Kojima, Y.; Hayashi, S. Chem.
Pharm. Bull. 1972, 20, 2262. (c) Hesse, S.; Perspicace, E.; Kirsch,
G. Tetrahedron Lett. 2007, 48, 5261. (d) Huang, Y.; Dömling, A.
Mol. Diversity 2011, 15, 3. (e) Adib, M.; Soheilizad, M.;
Colorless solid; yield 68%; mp 100 °C. 1H NMR (500 MHz,
CDCl3):  = 7.30 (d, J = 8.2 Hz, 2 H), 7.15–7.10 (m, 2 H), 6.06 (s, 2
H), 4.83 (t, J = 8.0 Hz, 1 H), 3.68 (s, 3 H), 3.37 (dd, J = 14.2, 8.5 Hz,
1 H), 3.14 (dd, J = 14.2, 7.6 Hz, 1 H), 2.33 (s, 3 H). 13C NMR (156
MHz, CDCl3):  = 166.6, 162.3, 138.4, 137.5, 129.3, 127.0, 90.8,
51.3, 50.4, 41.4, 21.0. HRMS (ESI): m/z calcd for C13H15NO2S [M +
Na]: 272.0721; found: 272.0717.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 901–904