Synthesis of 2-Amino Substituted Oxazoles from α-Amino Ketones and Isothiocyanates via Sequential Addition and I2-Mediated Desulfurative Cyclization

Article abstract of DOI:10.1002/adsc.202000171

Oxazol-2-amines were synthesized by annulation of α-amino ketones and isothiocyanates. This sequential synthetic process involves addition of α-amino ketones to isothiocyanates and I₂-promoted desulfurative cyclization omitting isolation of the less stable thiourea intermediates. It is transition metal-free and operationally simple, providing access to a variety of 2-amino substituted oxazole derivatives under mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000171

Title: Synthesis of 2-Amino Substituted Oxazoles from α-Amino
Ketones and Isothiocyanates via Sequential Addition and I2-
Mediated Desulfurative Cyclization
Authors: Shuangshuang Zhang, Qiongli Zhao, Yifei Zhao, Wenquan
Yu, and Junbiao Chang
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10.1002/adsc.202000171
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of 2-Amino Substituted Oxazoles from α-Amino
Ketones and Isothiocyanates via Sequential Addition and I2-
Mediated Desulfurative Cyclization
Shuangshuang Zhang,a Qiongli Zhao,a Yifei Zhao,a Wenquan Yua,*, Junbiao Chang a,*
a
College of Chemistry, Zhengzhou University, Zhengzhou, Henan Province 450001, China
[Fax: +86-(0)371-6778-1588; Phone: +86-(0)371-6778-1788; e-mail: wenquan_yu@zzu.edu.cn;
changjunbiao@zzu.edu.cn]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
building blocks in the presence of gold, cobalt or
of α-amino ketones and isothiocyanates. This sequential selenium catalysts.[11]
Abstract. Oxazol-2-amines were synthesized by annulation
synthetic process involves addition of α-amino ketones to
isothiocyanates and I2-promoted desulfurative cyclization
omitting isolation of the less stable thiourea intermediates.
It is transition metal-free and operationally simple,
providing access to a variety of 2-amino substituted
oxazole derivatives under mild reaction conditions.
Desulfurative cyclization of readily accessible
thiourea or thiosemicarbazide intermediates has
become a valuable method for the construction of
various amine-substituted heterocyclic skeletons,
such as (fused) 1,2,4-triazole,[12] benzimidazole,[13]
benzothiazole/benzoxazole,[14]
and
1,3,4-
oxadiazole/thiadiazole.[15] However, to the best of our
knowledge, reactions for the synthesis of oxazol-2-
amines via this cyclodesulfurization strategy have not
been investigated to date. Herein, we describe an
annulation reaction of α-amino ketones and
isothiocyanates in the presence of molecular iodine[16]
leading to 2-amino substituted oxazole derivatives.
Initially, we used 2-aminoacetophenone
hydrochloride (1a) as a model substrate for the
optimization of reaction conditions leading to oxazol-
2-amine (4a) (Table 1). The addition of 1a to phenyl
isothiocyanate (2a) under basic conditions formed a
thiourea intermediate (3a). In view of the poor
stability of 3a, the above mixture was promptly
treated with iodine upon the completion of the first
step addition. Solvent screening (entries 1−8)
demonstrated that this transformation proceeds well
in MeCN and afforded the expected product (4a) in
82% yield (entry 5). The structure of oxazol-2-amine
4a was confirmed by X-ray crystallography.[17]
Screening of inorganic and organic bases (entries 5,
9−15) indicated that K2CO3 is optimal (entry 5), and
further optimization of the reaction conditions
suggested that 60 °C is the ideal temperature for this
transformation. The conversion was slow at lower
temperatures (entries 16−17 vs entry 5) and the yield
of the product was decreased at higher temperatures
(entry 18 vs entry 5). Complete consumption of
isothiocyanate 2a requires at least 1.2 equiv. of the
Keywords: oxazol-2-amine; iodine; desulfurative
cyclization; α-amino ketone; isothiocyanate
Oxazol-2-amine is a privileged structure motif found
in
inhibitors
of
inosine
monophosphate
dehydrogenase (IMPDH)[1] and other molecules with
enzyme inhibitory,[2] antiviral,[3] analgesic,[4] and
antitubercular[5] activities. Nevertheless, among
numerous methods for oxazole synthesis, only a few
pathways provide access to oxazole derivatives
bearing an amine substituent.[6] The synthesis of
oxazol-2-amines in drug discovery has relied on the
PPh3-mediated annulations of β-ketoazides and
isothiocyanates.[1-4, 7] In this reaction, two substrates
form
a
carbodiimide which then undergoes
intramolecular cycloaddition to give an oxazol-2-
amine product. In 2015, Rassadin and Kukushkin[8]
described a gold-catalyzed cyclization of terminal
alkynes and cyanamides forming substituted 2-
aminooxazoles and subsequently, Soeta and Ukaji[9]
developed a one-pot reaction for the synthesis of
oxazol-2-amines using isocyanide dichlorides.
Recently, Dubovtsev and Kukushkin[10] synthesized
2-amino-1,3-oxazoles via a three-component [2+2+1]
gold(I)-catalyzed reaction of internal alkynes,
cyanamides, and 2-chloropyridine N-oxide. Moreover,
several synthetic approaches leading to 4-amino or 5-
amino substituted oxazoles have been reported by
annulation reactions of ynamides and corresponding
1
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10.1002/adsc.202000171
Advanced Synthesis & Catalysis
Table 1. Optimization of Reaction Conditions for the Synthesis of Oxazol-2-amine 4a[a]
entry
1
1a (equiv)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.4
1.2
1.2
1.2
I2 (equiv)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.4
1.2
base
solvent
toluene
DCE
temp.
60 °C
60 °C
60 °C
60 °C
60 °C
25 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
25 °C
40 °C
82 °C
60 °C
60 °C
60 °C
60 °C
60 °C
time (h)[b]
yield (%)[c]
13
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
Na2CO3
Na2HPO4
NaOH
NaOAc
Et3N
1
2
1
trace
16
3
4[d]
THF
1
1,4-dioxane
MeCN
DMSO
DMF
2
27
5
1
82
6[d]
7
1
54
0.5
1
48
8
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
31
9
1
0
10
11
12
13
14
15
16
17
18
19
20
21
22
1
30
1
0
1
19
1
trace
55
1
DBU
2
trace
76
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
12
6
77
0.5
1
42
67
1
82
2
79
1
76
23[e]
[a]
1
66
Optimal reaction conditions (entry 5): 1a (0.6 mmol), 2a (0.5 mmol), K2CO3 (1.1 mmol), MeCN (5 mL), 0 ~ 25 °C;
then I2 (0.6 mmol), K2CO3 (0.75 mmol), 60 °C. [b] The reaction time for the second step. [c] Isolated yields. [d] The first step
at room temperature (25 °C). [e] In a one-pot manner with I2 (0.6 mmol) added at the same time as K2CO3 (1.85 mmol).
substrate 1a (entry 5 vs entries 19−20). The optimum
amount of iodine is 1.2 equiv. (entry 5) and the yield
was slightly affected by the addition of different
quantities of iodine (entries 21−22). In addition, when
iodine was added at the same time as K2CO3, this
reaction also worked, but formed the product in
decreased yield (entry 23). Thus, under the optimal
reaction conditions, the iodine and the second portion
of base was added upon the completion of the first
step addition (entry 5).
electron-donating groups (EDGs) and electron-
withdrawing groups (EWGs) on the aromatic ring (R2)
of the substrate 2. The formation of the products was
favored by the presence of EWGs at the para- (4d−4i
vs 4b−4c) and ortho- (4m−4n vs 4l) positions, which
may stabilize the carbodiimide intermediates (cf.
Scheme 2). However, in the reaction of an alkyl
isothiocyanate, no expected oxazol-2-amine product
(4o) was formed, due probably to the poor stability of
the corresponding carbodiimide intermediate.
We further examined the substrate scope of α-
amino ketones. Under the optimal annulation
conditions, the substituted α-amino ketone
hydrochlorides (1) were also successfully converted
to the oxazol-2-amine products (4p−4w) by the
addition to the corresponding isothiocyanates
To investigate the substrate scope, a variety of aryl
isothiocyanates were subjected to the optimized
reaction conditions (Table 1, entry 5). As shown in
Scheme 1, the reaction of these isothiocyanate
substrates
(2)
with
2-aminoacetophenone
hydrochloride (1a) successfully produced the
expected oxazol-2-amines in good to excellent yields.
This synthetic process is compatible with both
2
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10.1002/adsc.202000171
Advanced Synthesis & Catalysis
Scheme 1. Substrate Scope. Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), K2CO3 (1.1 mmol), MeCN (5 mL), 0 ~
25 °C; then I2 (0.6 mmol), K2CO3 (0.75 mmol), 60 °C (isolated yields are given). [a] The first step at 25 °C. [b] Both steps at
25 °C. [c] DMSO as the solvent.
followed by I2-mediated desulfurative cyclization.
The decreased yield of product 4r (vs 4p−q) could be
due to the lower reactivity of the enol oxygen (cf.
Scheme 2) caused by the presence of the electron-
withdrawing chloro group. Annulations of α-amino
ketones bearing EDGs and aryl isothiocyanates with
EWGs porduced oxazol-2-amines in excellent yields
(4v−w). The reactions of phenyl isothiocyanate with
substrates in which R1 is an alkyl group proceeded
better in DMSO at room temperature (25 °C),
affording the desired products (4x−4y) in moderate
yields.
On the basis of the above results and the previous
work,[7a] a tentative reaction mechanism is proposed
and is shown in Scheme 2. Taking the formation of
Scheme 2. Proposed Mechanism
the product 4a as an example, addition of 2-
aminoacetophenone (1a) to the phenyl isothiocyanate
(2a) in the presence of a base gives the thiourea
In summary, we have established a novel method
for the synthesis of 2-amino substituted oxazoles
from readily accessible substrates. Under mild
reaction conditions, base-promoted addition of α-
amino ketones to isothiocyanates generates thiourea
intermediates, which then undergo desulfurative
cyclization in the presence of iodine to afford the
oxazol-2-amine products. This transition metal-free
intermediate (3a). Then, the base-promoted
desulfurization[18] of compound 3a by molecular
iodine generates a carbodiimide intermediate[19] (B),
which may revert to the tautomeric enol form (C).
Subsequently, nucleophilic addition of the enol
oxygen to the carbodiimide group and proton transfer
leads to the oxazol-2-amine framework (4a).
3
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10.1002/adsc.202000171
Advanced Synthesis & Catalysis
protocol is operationally simple and broadly
applicable to a range of α-amino ketone and
isothiocyanate substrates.
Scullino, M. R. Pitman, A. Sexton, V. Oliver, L.
Davies, R. J. Rebello, L. Furic, D. J. Creek, S. M.
Pitson, B. L. Flynn, J. Med. Chem. 2016, 59, 965-
984; e) X. X. Chai, Z. P. Cai, M. T. Yang, Y. Zhou, Y.
J. Fu, Y. Z. Xiong, Arch. Pharm. 2016, 349, 523-531;
f) M. Murar, J. Dobias, P. Sramel, G. Addova, G.
Hanquet, A. Bohac, Eur. J. Med. Chem. 2017, 126,
754-761.
Experimental Section
General Procedure for the Synthesis of the Products 4.
To a mixture of 2-aminoacetophenone hydrochloride (1,
0.6 mmol) and the corresponding isothiocyanate (2, 0.5
mmol) in MeCN (5 mL) was added K2CO3 (152 mg, 1.1
mmol). After stirred at 0 °C for 1 h, the reaction was
allowed to warm up to room temperature (25 °C) until
TLC indicated the complete consumption of 2. Then the
reaction mixture was treated with K2CO3 (104 mg, 0.75
mmol) and iodine (152 mg, 0.6 mmol) in sequence, and
maintained at 60 °C until TLC indicated the disappearance
of the addition intermediate. Upon the completion of the
reaction, it was quenched with 5% Na2S2O3 (5 mL), diluted
with brine (10 mL) and then extracted with EtOAc (15 mL
× 3). The combined organic layer was dried over
anhydrous Na2SO4, concentrated, and then purified
through silica gel column chromatography to afford the
oxazol-2-amine product 4.
[3] S.-H. Kim, B. Markovitz, R. Trovato, B. R. Murphy,
H. Austin, A. J. Willardsen, V. Baichwal, S. Morham,
A. Bajji, Bioorg. Med. Chem. Lett. 2013, 23, 2888-
2892.
[4] R. J. Perner, J. R. Koenig, S. Didomenico, A.
Gomtsyan, R. G. Schmidt, C. H. Lee, M. C. Hsu, H.
A. McDonald, D. M. Gauvin, S. Joshi, T. M. Turner,
R. M. Reilly, P. R. Kym, M. E. Kort, Bioorg. Med.
Chem. 2010, 18, 4821-4829.
[5] D. Sriram, P. Yogeeswari, R. Thirumurugan, R. K.
Pavana, J. Med. Chem. 2006, 49, 3448-3450.
[6] a) A. M. van Leusen, H. J. Jeuring, J. Wildeman, P. J.
M. S. van Nispen, J. Org. Chem. 1981, 46, 2069-
2072; b) P. Frøyen, Phosphorus Sulfur 1991, 60, 81-
84; c) P. Molina, P. M. Fresneda, P. Almendros,
Synthesis 1993, 54-56; d) K. Fukushima, T. Ibata,
Heterocycles 1995, 40, 149-154.
Acknowledgements
We thank the National Natural Science Foundation of China (Nos.
81773570 and U1804283), the Young Backbone Teachers Fund
of Zhengzhou University (No. 2017ZDGGJS020), and the College
Students’ Innovation and Entrepreneurship Training Program of
Zhengzhou University (No. 2019cxcy490) for financial support.
[7] a) T. G. M. Dhar, J. Guo, Z. Shen, W. J. Pitts, H. H.
Gu, B.-C. Chen, R. Zhao, M. S. Bednarz, E. J.
Iwanowicz, Org. Lett. 2002, 4, 2091-2093; b) R.
Zhao, B.-C. Chen, M. S. Bednarz, B. Wang, A. P.
Skoumbourdis, J. E. Sundeen, T. G. M. Dhar, E. J.
Iwanowicz, B. Balasubramanian, J. C. Barrish,
ARKIVOC 2007, 2007, 36-42.
References
[1] a) T. G. M. Dhar, Z. Shen, J. Guo, C. Liu, S. H.
Watterson, H. H. Gu, W. J. Pitts, C. A. Fleener, K.
Rouleau, N. Z. Sherbina, K. W. Mcintyre, M. Witmer,
J. A. Tredup, B. C. Chen, R. Zhao, M. S. Bednarz, D.
L. Cheney, J. F. MacMaster, L. F. Miller, K. K. Berry,
T. W. Harper, J. C. Barrish, D. L. Hollenbaugh, E. J.
Iwanowicz, J. Med. Chem. 2002, 45, 2127-2130; b) T.
G. M. Dhar, Z. Shen, C. A. Fleener, K. A. Rouleau, J.
C. Barrish, D. L. Hollenbaugh, E. J. Iwanowicz,
Bioorg. Med. Chem. Lett. 2002, 12, 3305-3308; c) T.
G. M. Dhar, Z. Shen, H. H. Gu, P. Chen, D. Norris, S.
H. Watterson, S. K. Ballentine, C. A. Fleener, K. A.
Rouleau, J. C. Barrish, R. Townsend, D. L.
Hollenbaugh, E. J. Iwanowicz, Bioorg. Med. Chem.
Lett. 2003, 13, 3557-3560; d) P. Chen, D. Norris, K.
D. Haslow, T. G. M. Dhar, W. J. Pitts, S. H.
Watterson, D. L. Cheney, D. A. Bassolino, C. A.
Fleener, K. A. Rouleau, D. L. Hollenbaugh, R. M.
Townsend, J. C. Barrisha, E. J. Iwanowicza, Bioorg.
Med. Chem. Lett. 2003, 13, 1345-1348.
[8] V. A. Rassadin, V. P. Boyarskiy, V. Y. Kukushkin,
Org. Lett. 2015, 17, 3502-3505.
[9] T. Soeta, A. Matsumoto, Y. Sakata, Y. Ukaji, J. Org.
Chem. 2017, 82, 4930-4935.
[10] A. Y. Dubovtsev, D. V. Dar'in, V. Y. Kukushkin, Adv.
Synth. Catal. 2019, 361, 2926-2935.
[11] a) M. Chen, N. Sun, H. Chen, Y. Liu, Chem.
Commun. 2016, 52, 6324-6327; b) A. D. Gillie, R.
Jannapu Reddy, P. W. Davies, Adv. Synth. Catal.
2016, 358, 226-239; c) X.-L. Han, C.-J. Zhou, X.-G.
Liu, S.-S. Zhang, H. Wang, Q. Li, Org. Lett. 2017, 19,
6108-6111; d) L. Liao, H. Zhang, X. Zhao, ACS
Catal. 2018, 8, 6745-6750; e) X. Tian, L. Song, C.
Han, C. Zhang, Y. Wu, M. Rudolph, F. Rominger, A.
S. K. Hashmi, Org. Lett. 2019, 21, 2937-2940.
[12] a) H. Comas, G. Bernardinelli, D. Swinnen, J. Org.
Chem. 2009, 74, 5553-5558; b) S. Guin, S. K. Rout,
A. Gogoi, S. Nandi, K. K. Ghara, B. K. Patela, Adv.
Synth. Catal. 2012, 354, 2757-2770; c) K.
Pandurangan, A. B. Aletti, D. Montroni, J. A. Kitchen,
M. Martinez-Calvo, S. Blasco, T. Gunnlaugsson, E.
M. Scanlan, Org. Lett. 2017, 19, 1068-1071; d) S.
Jiao, Z. Wang, Q. Zhao, W. Yu, J. Chang,
Tetrahedron 2018, 74 3069-3073; e) N. Jatangi, N.
[2] a) P. A. Harris, M. Cheung, R. N. Hunter, M. L.
Brown, J. M. Veal, R. T. Nolte, L. Wang, W. Liu, R.
M. Crosby, J. H. Johnson, A. H. Epperly, R. Kumar,
D. K. Luttrell, J. A. Stafford, J. Med. Chem. 2005, 48,
1610-1619; b) M. G. Bursavich, D. P. Parker, J. A.
Willardsen, Z. H. Gao, T. Davis, K. Ostanin, R.
Robinson, A. Peterson, D. M. Cimbora, J. F. Zhu, B.
Richards, Bioorg. Med. Chem. Lett. 2010, 20, 1677-
1679; c) J. H. Suh, E. K. Yum, Y. S. Cho, Chem.
Pharm. Bull. 2015, 63, 573-578; d) L. Aurelio, C. V.
4
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Advanced Synthesis & Catalysis
Tumula, R. K. Palakodety, M. Nakka, J. Org. Chem.
2018, 83, 5715-5723.
[17] CCDC 1977758 (4a) contains the supplementary
crystallographic data for this paper. These data are
provided free of charge by The Cambridge
Crystallographic Data Centre.
[13] a) Z. Wang, Q. Zhao, J. Hou, W. Yu, J. Chang,
Tetrahedron 2018, 74, 2324-2329; b) H.-J. Ryu, S.-J.
Yang, G.-H. Lee, Y.-D. Gong, ACS Comb. Sci. 2018,
20, 282-291.
[18] When the reaction was quenched with brine instead
of 5% Na2S2O3 and extracted with EtOAc, the
resulting S8 could be detected in the organic layer by
TLC (Rf = 0.83, eluent: 100% petroleum ether).
[14] X. Zhang, X. Jia, J. Wang, X. Fan, Green Chem.
2011, 13, 413-418.
[19] Carbodiimide intermediate B (or C) can be observed
by TLC, but cannot be isolated due to the poor
stability. For the synthesis and isolation of stable
diaryl carbodiimides via similar desulfurization, see:
a) A. R. Ali, H. Ghosh, B. K. Patel, Tetrahedron Lett.
2010, 51, 1019-1021; b) C. Duangkamol, M.
Pattarawarapan, W. Phakhodee, Monatsh. Chem.
2016, 147, 1945-1949; c) D. A. Siriwardane, O.
Kulikov, J. F. Reuther, B. M. Novak,
Macromolecules 2017, 50, 832-840; d) C. Zhu, D. Xu,
Y. Wei, Synthesis 2011, 711-714.
[15] a) S.-J. Yang, S.-H. Lee, H.-J. Kwak, Y.-D. Gong, J.
Org. Chem. 2013, 78, 438-444; b) Q. Zhao, L. Ren, J.
Hou, W. Yu, J. Chang, Org. Lett. 2019, 21, 210-213.
[16]
For representative reviews on molecular iodine
promoted synthesis, see: a) P. T. Parvatkar, P. S.
Parameswaran, S. G. Tilve, Chem. Eur. J. 2012,
18, 5460-5489; b) Y.-M. Ren, C. Cai, R.-C.
Yang, RSC Adv. 2013, 3, 7182-7204; c) J. Zhao,
W. Gao, H. Chang, X. Li, Q. Liu, W. Wei,
Chinese J. Org. Chem. 2014, 34, 1941-1957 (in
Chinese); d) T. B. Nguyen, Asian J. Org. Chem.
2017, 6, 477-491; e) A. Monga, S. Bagchi, A.
Sharma, New J. Chem. 2018, 42, 1551-1576; f)
P. T. Parvatkar, R. Manetsch, B. K. Banik,
Chem. Asian J. 2019, 14, 6-30.
5
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10.1002/adsc.202000171
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of 2-Amino Substituted Oxazoles from
α-Amino Ketones and Isothiocyanates via
Sequential Addition and I2-Mediated
Desulfurative Cyclization
Adv. Synth. Catal. Year, Volume, Page – Page
Shuangshuang Zhang, Qiongli Zhao, Yifei Zhao,
Wenquan Yu*, Junbiao Chang*
6
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