Thiourea participation in [3+2] cycloaddition with donor-acceptor cyclopropanes: A domino process to 2-amino-dihydrothiophenes

Article abstract of DOI:10.1039/c8cc09595g

The Yb(OTf)₃-catalyzed [3+2] cycloaddition of donor-acceptor cyclopropanes with thiourea offers an efficient route to diverse 2-amino-4,5-dihydrothiophenes (up to 92% yield), in which optically active 2-amino-dihydrothiophenes can be produced f

Full text of DOI:10.1039/c8cc09595g

ChemComm
View Article Online
View Journal
COMMUNICATION
Thiourea participation in [3+2] cycloaddition with
donor–acceptor cyclopropanes: a domino process
to 2-amino-dihydrothiophenes†
Cite this:DOI: 10.1039/c8cc09595g
Received 3rd December 2018,
Accepted 7th January 2019
Ming-Sheng Xie,
Hai-Ming Guo
Guo-Feng Zhao, Tao Qin, Yong-Bo Suo, Gui-Rong Qu and
*
DOI: 10.1039/c8cc09595g
rsc.li/chemcomm
The Yb(OTf)3-catalyzed [3+2] cycloaddition of donor–acceptor
cyclopropanes with thiourea offers an efficient route to diverse
2-amino-4,5-dihydrothiophenes (up to 92% yield), in which optically
active 2-amino-dihydrothiophenes can be produced from enantiomeri-
cally pure cyclopropanes. Thiourea, which is an odorless and cheap
Q
reagent, provides a C S double bond, serves as an amino source, and
functions as a decarbalkoxylation reagent in this reaction. Preliminary
mechanistic studies demonstrate that the reaction undergoes a
sequential [3+2] cycloaddition/deamination/decarboxylation process.
Fig. 1 Examples of bioactive agents with 2-aminothiophene fragments.
2-Aminothiophene is a special structural moiety present in
many biologically active molecules.1 Examples of such molecules
Donor–acceptor (D–A) cyclopropanes are exceptionally use-
are shown in Fig. 1. Olanzapine is an atypical antipsychotic drug ful three-carbon building blocks due to their synthetic utility
used for treating schizophrenia and bipolar disorder.2 Tinoridine and ease of preparation.9 In the presence of a Lewis acid, the
is an anti-inflammatory drug that has potent antiperoxidative normal [3+n] cycloaddition reactions of D–A cyclopropanes with
properties.3 T-62 is an allosteric enhancer of the adenosine A1 various dipolarophiles, such as CQC, CQO, CQN, NQO,
receptor, and TPCA-1 is a small-molecule IkB kinase b inhibitor.4 NQN, CRC, CRN, nitrones, heterocumulenes, and other
AX20017 has antituberculosis properties and has been identified dipolarophiles, have proven to be valuable tools for producing
as a specific inhibitor of protein kinase G.5 2-Amino-4,5-dihydro- highly functionalized cyclic ring systems.10–19 However, the
thiophene I exhibits antibacterial and antifungal properties.6 For CQS double bond has less been employed as a 2p component
most of these 2-aminothiophenes, which exhibit biological to react with D–A cyclopropanes.20,21 Very recently, the normal
activities, it is found that an electron-withdrawing group (e.g., [3+2] cycloaddition of thioketones and D–A cyclopropanes has
ester, CQO, or CN) is connected to the C3 position of the been published concurrently with the preparation of the present
thiophenes. The most convenient method for preparing 2-amino- manuscript (Scheme 1a).20a Highly substituted tetrahydrothio-
thiophenes is the Gewald reaction, which involves the condensation phenes with two adjacent quaternary carbon atoms were generated
of a ketone (or aldehyde) with activated nitrile and elemental in high yields using AlCl3 as a catalyst. Soon afterwards, a highly
sulfur.1,7 Although great achievements to construct 2-aminothio- efficient Fe(OTf)3-promoted normal [3+2] cycloaddition of thiono-
phenes have been made through the Gewald reaction, developing esters with D–A cyclopropanes was developed for the synthesis
an alternative method to synthesize 2-aminothiophenes and their of trans-configured tetrahydrothiophenes (Scheme 1b).21 As an
derivatives, which have an electron withdrawing group at the C3 odorless, cheap, and easy-to-handle sulfur source,22 thiourea has
position, is still highly desirable.8
never previously been employed to react with D–A cyclopropanes.
Herein, we report the Yb(OTf)3-catalyzed [3+2] cycloaddition of
thiourea with D–A cyclopropanes to generate 2-amino-4,5-
dihydrothiophene derivatives with only one ester group at the
C3 position of thiophene (Scheme 1c).
Initially, D–A cyclopropane 1a and thiourea 2a were selected
as the model reactants (Table 1). When Cu(OTf)2 or Ni(OTf)2
was employed as a Lewis acid catalyst, the reaction did not
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China. E-mail: ghm@htu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 1849437 (3na),
1852130 ((R)-1a), 1852128 ((S)-3aa), 1852129 (7aa) and 1852131 (8aa). For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c8cc09595g
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun.

View Article Online
Communication
ChemComm
Scheme 1 Different CQS 2p components react with D–A cyclopropanes.
Table 1 Optimization of the reaction conditionsa
a
Scheme 2 Substrate scope of D–A cyclopropanes. Unless otherwise
noted, the reaction conditions are: 1a–1s (0.2 mmol), 2a (0.4 mmol),
Yb(OTf)3 (20 mol%), Rb2CO3 (20 mol%), and DCE (3.0 mL) at 90 1C for 8 h.
Isolated yields were reported. bReaction time: 24 h.
Yieldb (%)
Entry
LA
Solvent
T (1C)
Base
3aa
4aa
could also be obtained. For the cyclopropanes with electron-
withdrawing groups at the aryl moieties, the adducts 3ia–3oa
were given in 62–86% yields. The structure of adduct 3na was
determined by X-ray diffraction analysis. With respect to cyclo-
propanes with an alkyl group as the donor-substituent, the
adducts 3pa and 3qa were afforded in 80–82% yields. In
addition, D–A cyclopropanes with different ester groups were
good reactants. It should be noted that the geminal diesters 4
were not observed in all of the cases.
When ethyl 1-cyano-2-phenylcyclopropane-1-carboxylate 1t
was reacted with thiourea 2a, the ester group was removed
and the cyano group remained, giving the 2-amino-3-cyano-4,
5-dihydrothiophene 3ta in 56% yield (Scheme 3a). Then, several
2-amino-4,5-dihydrothiophenes (3aa, 3la, 3ra, and 3sa) were
selected as the representative substrates to react with DDQ, and
the oxidation products, 2-aminothiophene derivatives (5aa, 5la,
5ra, and 5sa), were obtained in 43–78% yields (Scheme 3b). As
for 2-aminothiophene 5aa, the corresponding ring-fused thieno-
pyrimidinedione could be afforded in 2 steps.24 With 2-amino-
thiophene 5la as the reactant, the desired small-molecule IkB
kinase b inhibitor TPCA-1 could be generated in 3 steps
(Scheme 3b).23
1
2
3
4
5
6
7
8
Cu(OTf)2
Ni(OTf)2
MgI2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
DCE
DCE
DCE
DCE
rt
rt
rt
rt
rt
rt
rt
90
90
90
90
90
90
90
—
—
—
—
—
—
—
—
Cs2CO3
Na2CO3
Rb2CO3
Et3N
Rb2CO3
Rb2CO3
NR
NR
9
15
—
Trace
29
41
53
61
—
—
7
—
—
—
—
—
—
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
9
10
11
12
13c
14d
65
NR
84
DCE
DCE
DCE
43
a
Unless otherwise noted, the reaction conditions were: 1a (0.2 mmol),
2a (0.4 mmol), LA (10 mol%), solvent (3.0 mL), and base (20 mol%) at rt
b
c
d
for 8 h. Isolated yield. Yb(OTf)3 (20 mol%). 2a (0.2 mmol) was
used. NR = no reaction.
occur (entries 1 and 2). When MgI2 was used, 2-amino-4,5-
dihydrothiophene 3aa, which has only one ester group at the C3
position of dihydrothiophene, was obtained in 9% yield (entry
3). When the Lewis acid was changed to Yb(OTf)3, the yield of
3aa increased to 15% (entry 4). In the presence of Sc(OTf)3, only
the cyclic imine 4aa, which has two ester groups at the C3
position of dihydrothiophene, was generated (entry 5). The
solvents were then explored, and DCE is the optimal solvent
(entries 4, 6 and 7). Increasing the temperature from rt to 90 1C
resulted in an enhanced yield (entries 7 and 8). Several bases
were then added, and the inorganic base Rb2CO3 delivered
monoester 3aa in a better yield (entries 9–12). The cycloadduct
3aa can be afforded in 84% yield when 20 mol% of Yb(OTf)3
was employed (entry 13). When 1 equiv. of thiourea 2a was
employed, the yield decreased (entry 14).
Stereospecificity of the cycloaddition was explored using the
enantiopure cyclopropane (R)-1a (499% ee), and (S)-3aa was
obtained in 92% yield and 499% ee (Scheme 4). The absolute
Under the optimized reaction conditions (Table 1, entry 13),
the scope of D–A cyclopropanes was explored (Scheme 2). For
cyclopropanes bearing electron-rich substituents at the aryl
moieties, the adducts 3ba–3fa were produced in 65–83% yields.
In the case of naphthalene-2-yl cyclopropane 1g and tetrahydro-
naphthalene-derived cyclopropane 1h, the adducts 3ga and 3ha
Scheme 3 (a) Synthesis of 2-amino-3-cyano-4,5-dihydrothiophene;
(b) transformation of 2-amino-4,5-dihydrothiophenes.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2019

View Article Online
ChemComm
Communication
Scheme 4 Stereospecificity experiments.
configurations of (R)-1a and (S)-3aa were determined by X-ray
analysis, and these configurations confirmed that an inversion
at the stereogenic center was observed.
To understand the cycloaddition process, several control
experiments were performed (Fig. 2). When Sc(OTf)3 was used
as the catalyst, the reaction between cyclopropane 1a and
thiourea 2a generated cycloadduct 4aa and released NH3 gas
(Fig. 2a(i)). The released NH3 gas was detected by wet red litmus
paper with blue color. When 1-methylthiourea 2b was used to
react with cyclopropane 1a, NH3 or CH3NH2 could also be
released (see ESI† for details). After that, geminal diester 4aa
was then reacted with thiourea 2a in the presence of Yb(OTf)3,
and the final product 3aa was formed in 87% yield within 0.5 h,
indicating that the geminal diester 4aa might be an intermediate
in the model reaction (Fig. 2b(ii)). Meanwhile, in the formation of
monoester 3aa from geminal diester 4aa, an esterified thiourea
7aa was obtained (52% yield) and confirmed by X-ray diffraction
analysis, which showed that thiourea 2a might function as a
decarboxylation reagent (Fig. 2b(ii)). In the absence of thiourea
2a, geminal diester 4aa could also be converted into monoester
3aa with the release of CO2 gas, which was captured by
2-phenyloxirane (Fig. 2b(iii)). By comparing different reaction
times (0.5 h vs. 1 h), the decarboxylation step proceeded faster
in the presence of thiourea 2a (Fig. 2b(ii) and (iii)). Finally, the
cycloaddition of D–A cyclopropane 1a with thiourea 2a produced
the monoester 3aa (78% yield), esterified thiourea 7aa (45%
yield), NH3 gas, CO2 gas, and a ring-opened triester 8aa (see ESI†
for details) under the standard conditions (Fig. 2c(iv)). Formation
of the esterified thiourea 7aa in a large proportion indicates that
thiourea 2a participated in the decarboxylation reaction and was
the main pathway during the decarboxylation step.
Scheme 5 Proposed reaction pathways for the domino process.
A plausible sequential mechanism of [3+2] cycloaddition/
deamination/decarboxylation was proposed for this reaction on
the basis of the stereospecificity experiments (Scheme 4) and
preliminary mechanistic studies (Fig. 2), and this mechanism is
depicted in Scheme 5. First, D–A cyclopropane (R)-1a is acti-
vated by Yb(OTf)3 via coordination with the geminal diester
moiety (A). The sulfur atom in thiourea 2a attacks the activated
cyclopropane (R)-1a in an SN2 manner to produce the zwitter-
ionic intermediate (B),11a–c which generates the cycloadduct
4,5-dihydrothiophene (C) through a ring-closure step. Because
two amino groups are both connected at the C2 position in the
dihydrothiophene (C), the dihydrothiophene (C) is unstable
and produces the cyclic imine (S)-4aa along with a release of
NH3 gas. The cyclic imine (S)-4aa is activated by Yb(OTf)3 via
coordination with the geminal diester moiety to enhance the
positive charge at the carbonyl group (D). The nitrogen atom in
another thiourea 2a attacks the carbonyl group and generates
the tetrahedral intermediate (E).25 The crowded tetrahedral
intermediate eliminates the protonated methyl carbamothioyl-
carbamate and generates the dihydrothiophene anion with a
single ester group (F). Finally, the dihydrothiophene anion
deprotonates the protonated methyl carbamothioylcarbamate,
generating 2-amino-4,5-dihydrothiophene (S)-3aa and the esterified
thiourea 7aa and releasing Yb(OTf)3.
In summary, thiourea, which is an odorless, cheap, and
easy-to-handle sulfur source, was developed to react with D–A
cyclopropanes to construct 2-amino-dihydrothiophenes. In this
reaction, thiourea exhibited three functions: (1) providing
a CQS double bond, (2) serving as an amino source for the
2-amino thiophenes, and (3) acting as a decarboxylation reagent.
Through a Yb(OTf)3-catalyzed [3+2] cycloaddition/deamination/
decarboxylation domino process, a range of D–A cyclopropanes
could produce 2-amino-4,5-dihydrothiophenes in moderate to
good yields (up to 92% yield).
We are grateful for the financial support from the NSFC (No.
21472037 and 21672055), China Postdoctoral Science Foundation
Fig. 2 Preliminary mechanistic studies.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun.

View Article Online
Communication
ChemComm
12 Selected examples with CQN: (a) C. A. Carson and M. A. Kerr, J. Org.
Chem., 2005, 70, 8242; (b) S. K. Jackson, A. Karadeolian, A. B. Driega
and M. A. Kerr, J. Am. Chem. Soc., 2008, 130, 4196; (c) A. T. Parsons,
A. G. Smith, A. J. Neel and J. S. Johnson, J. Am. Chem. Soc., 2010, 132, 9688;
(d) D.-C. Wang, M.-S. Xie, H.-M. Guo, G.-R. Qu, M.-C. Zhang and S.-L. You,
Angew. Chem., Int. Ed., 2016, 55, 14111; (e) J. Preindl, S. Chakrabarty and
J. Waser, Chem. Sci., 2017, 8, 7112; ( f ) M.-C. Zhang, D.-C. Wang, M.-S. Xie,
G.-R. Qu, H.-M. Guo and S.-L. You, Chem, 2019, 5, 156.
13 With NQO: (a) S. Chakrabarty, I. Chatterjee, B. Wibbeling, C. G. Daniliuc
and A. Studer, Angew. Chem., Int. Ed., 2014, 53, 5964With NQN:
(b) V. S. Korotkov, O. V. Larionov, A. Hofmeister, J. Magull and A. de
Meijere, J. Org. Chem., 2007, 72, 7504.
funded project (2016M592293 and 2018T110726), and the 111
Project (No. D17007).
Conflicts of interest
There are no conflicts to declare.
Notes and references
¨
1 Y. Huang and A. Domling, Mol. Diversity, 2011, 15, 3.
14 Selected examples with CRC: (a) V. K. Yadav and V. Sriramurthy,
Angew. Chem., Int. Ed., 2004, 43, 2669; (b) S. Racine, B. Hegedu¨s,
R. Scopelliti and J. Waser, Chem. – Eur. J., 2016, 22, 11997.
2 H. Y. Meltzer and H. C. Fibiger, Neuropsychopharmacology, 1996,
14, 83.
3 P. D. Kalariya, P. N. Patel, P. Kavya, M. Sharma, P. Garg, R. Srinivas 15 Selected examples with CRN: (a) M. Yu and B. L. Pagenkopf, Org.
and M. V. N. K. Talluri, J. Mass Spectrom., 2015, 50, 1222.
4 (a) X. Li, D. Conklin, H.-L. Pan and J. C. Eisenach, J. Pharmacol. Exp.
Lett., 2003, 5, 5099; (b) M. Yu and B. L. Pagenkopf, J. Am. Chem. Soc.,
2003, 125, 8122.
Ther., 2003, 305, 950; (b) P. L. Podolin, J. F. Callahan, B. J. Bolognese, 16 Selected examples with nitrones: (a) I. S. Young and M. A. Kerr,
Y. H. Li, K. Carlson, T. G. Davis, G. W. Mellor, C. Evans and A. K.
Roshak, J. Pharmacol. Exp. Ther., 2005, 312, 373.
5 A. Walburger, A. Koul, G. Ferrari, L. Nguyen, C. Prescianotto-Baschong,
K. Huygen, B. Klebl, C. Thompson, G. Bacher and J. Pieters, Science, 2004,
304, 1800.
Angew. Chem., Int. Ed., 2003, 42, 3023; (b) M. P. Sibi, Z. Ma and
C. P. Jasperse, J. Am. Chem. Soc., 2005, 127, 5764; (c) Y.-B. Kang,
X.-L. Sun and Y. Tang, Angew. Chem., Int. Ed., 2007, 46, 3918;
(d) P.-W. Xu, J.-K. Liu, L. Shen, Z.-Y. Cao, X.-L. Zhao, J. Yan and
J. Zhou, Nat. Commun., 2017, 8, 1619.
6 E. S. Darwish, Molecules, 2008, 13, 1066.
17 Selected examples with heterocumulenes: (a) C. Bru¨ckner and H.-U.
Reissig, Angew. Chem., Int. Ed. Engl., 1985, 24, 588; (b) A. F. G. Goldberg,
N. R. O’Connor, R. A. Craig II and B. M. Stoltz, Org. Lett., 2012, 14, 5314;
(c) Y. Sun, G. Yang, Z. Chai, X. Mu and J. Chai, Org. Biomol. Chem., 2013,
11, 7859; (d) D. Gladow and H.-U. Reissig, J. Org. Chem., 2014, 79, 4492.
18 Selected examples with other dipolarophiles: (a) T. P. Lebold,
A. B. Leduc and M. A. Kerr, Org. Lett., 2009, 11, 3770; (b) S.-W.
Wang, W.-S. Guo, L.-R. Wen and M. Li, RSC Adv., 2015, 5, 47418;
(c) H. Xu, J.-L. Hu, L. Wang, S. Liao and Y. Tang, J. Am. Chem. Soc.,
2015, 137, 8006; (d) Z. Su, S. Qian, S. Xue and C. Wang, Org. Biomol.
Chem., 2017, 15, 7878.
¨
7 (a) K. Gewald, E. Schinke and H. Bottcher, Chem. Ber., 1966, 99, 94;
(b) R. W. Sabnis, D. W. Rangnekar and N. D. Sonawane, J. Heterocycl.
¨
Chem., 1999, 36, 333; (c) H. Ozbek, I. S. Veljkovic and H.-U. Reissig,
Synlett, 2008, 3145.
8 P. Gopinath and S. Chandrasekaran, J. Org. Chem., 2011, 76, 700.
9 (a) H.-U. Reissig and R. Zimmer, Chem. Rev., 2003, 103, 1151;
(b) M. Yu and B. L. Pagenkopf, Tetrahedron, 2005, 61, 321;
(c) C. A. Carson and M. A. Kerr, Chem. Soc. Rev., 2009, 38, 3051;
(d) F. de Nanteuil, F. De Simone, R. Frei, F. Benfatti, E. Serrano and
J. Waser, Chem. Commun., 2014, 50, 10912; (e) T. F. Schneider,
J. Kaschel and D. B. Werz, Angew. Chem., Int. Ed., 2014, 53, 5504; 19 Selected examples with nucleophiles: (a) Y. Xia, X. H. Liu, H. F. Zheng,
( f ) M. A. Cavitt, L. H. Phun and S. France, Chem. Soc. Rev., 2014,
43, 804; (g) H. K. Grover, M. R. Emmett and M. A. Kerr, Org. Biomol.
Chem., 2015, 13, 655.
L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2015, 54, 227; (b) Y. Xia,
L. L. Lin, F. Z. Chang, X. Fu, X. H. Liu and X. M. Feng, Angew. Chem., Int.
Ed., 2015, 54, 13748; (c) Y. Xia, L. L. Lin, F. Z. Chang, Y. T. Liao, X. H. Liu
and X. M. Feng, Angew. Chem., Int. Ed., 2016, 55, 12228.
10 Selected examples with CQC: (a) D. B. England, T. D. O. Kuss,
R. G. Keddy and M. A. Kerr, J. Org. Chem., 2001, 66, 4704; (b) F. de 20 (a) A. U. Augustin, M. Sensse, P. G. Jones and D. B. Werz, Angew.
Nanteuil and J. Waser, Angew. Chem., Int. Ed., 2011, 50, 12075;
(c) B. M. Trost and P. J. Morris, Angew. Chem., Int. Ed., 2011, 50, 6167;
(d) H. Xiong, H. Xu, S. Liao, Z. Xie and Y. Tang, J. Am. Chem. Soc., 2013,
Chem., Int. Ed., 2017, 56, 14293; (b) A. U. Augustin, M. Busse,
P. G. Jones and D. B. Werz, Org. Lett., 2018, 20, 820; (c) A. Kreft,
P. G. Jones and D. B. Werz, Org. Lett., 2018, 20, 2059.
135, 7851; (e) F. de Nanteuil, E. Serrano, D. Perrotta and J. Waser, J. Am. 21 Y. Matsumoto, D. Nakatake, R. Yazaki and T. Ohshima, Chem. – Eur.
Chem. Soc., 2014, 136, 6239; ( f ) S. Racine, F. de Nanteuil, E. Serrano and
J. Waser, Angew. Chem., Int. Ed., 2014, 53, 8484.
11 Selected examples with CQO: (a) P. D. Pohlhaus and J. S. Johnson,
J. Am. Chem. Soc., 2005, 127, 16014; (b) P. D. Pohlhaus and
J., 2018, 24, 6062.
22 (a) G.-p. Lu, F. Chen and C. Cai, J. Chem. Educ., 2017, 94, 244;
(b) J. Wang, Q.-Y. Zhang, M.-S. Xie, D.-C. Wang, G.-R. Qu and
H.-M. Guo, Org. Lett., 2018, 20, 6578.
J. S. Johnson, J. Org. Chem., 2005, 70, 1057; (c) P. D. Pohlhaus, 23 D. C. Cole, U.S. Pat. Appl., US20050038088 A1, 2005.
S. D. Sanders, A. T. Parsons, W. Li and J. S. Johnson, J. Am. Chem. 24 J. M. Salamoun, K. E. McQueeney, K. Patil, S. J. Geib, E. R. Sharlow,
Soc., 2008, 130, 8642; (d) A. T. Parsons and J. S. Johnson, J. Am.
Chem. Soc., 2009, 131, 3122.
J. S. Lazo and P. Wipf, Org. Biomol. Chem., 2016, 14, 6398.
25 D. H. Miles and B.-S. Huang, J. Org. Chem., 1976, 41, 208.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2019