Copper-catalyzed three-component synthesis of 3-Aminopyrazoles and 4-iminopyrimidines via β-alkynyl-N-sulfonyl ketenimine intermediates

Article abstract of DOI:10.1021/ol502302w

3-Aminopyrazoles and 4-iminopyrimidines were efficiently prepared via copper-catalyzed three-component reactions of butadiynes, sulfonylazides, and hydrazides or imidamides. The reactions were regioselectively approached via the formation of a β-alkynyl-N-sulfonyl ketenimine intermediate which represented a new and effective 1,3-dielectrophilic equivalent in organic synthesis.

Full text of DOI:10.1021/ol502302w

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Three-Component Synthesis of 3‑Aminopyrazoles
and 4‑Iminopyrimidines via β‑Alkynyl‑N‑sulfonyl Ketenimine
Intermediates
Yanpeng Xing, Binyu Cheng, Jing Wang, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: 3-Aminopyrazoles and 4-iminopyrimidines
were efficiently prepared via copper-catalyzed three-compo-
nent reactions of butadiynes, sulfonylazides, and hydrazides or
imidamides. The reactions were regioselectively approached
via the formation of a β-alkynyl-N-sulfonyl ketenimine
intermediate which represented a new and effective 1,3-
dielectrophilic equivalent in organic synthesis.
trapped by various nucleophiles,8,9 electrophiles,10 or readily
opper catalyzed alkyne azide cycloaddition (CuAAC) has
available reagents containing both nucleo- and electrophilic
Cbecome a powerful and reliable tool for the construction
centers.11 Additionally, [2 + 2] and [4 + 2] cycloadditions12 as
of 1,4-disubstituted-1,2,3-triazole since Sharpless and Meldal
well as sigmatropic rearrangement13 of ketenimines generated
through CuAAC have also been explored. Thus, a number of
amidines, amidates, carbocycles, and heterocycles were feasibly
assembled via these copper catalyzed tandem reactions. We
would like to report a new reaction model based on the β-
alkynyl-N-sulfonyl ketenimine intermediate and its trapping by
reagents with two nucleophilic centers.
Initially, p-toluidine (2 equiv) was applied to trap the β-
alkynyl-N-sulfonyl ketenimine intermediate in situ generated
from 1-phenyl-1,3-butadiyne (1a) and tosyl azide (2a) in the
presence of CuI (10 mol %) and triethylamine (1.2 equiv)
(Scheme 2). To our delight, imidamide 3 was obtained in 56%
yield. Stimulated by this result and attracted by the importance
of heterocycles, we tried to use the reagents with two
nucleophilic centers to trap the ketenimine intermediate.
Thus, p-tolylhydrazine hydrochloride was preliminarily consid-
published their pioneer works.1 It represents one of the most
important click reactions and has been widely applied in
bioconjugation,2 drug discovery,3 and material science.4 Mean-
while, the CuAAC mechanism was well demonstrated by
Fokin’s research group.5 Nevertheless, the ring of the 1,2,3-
triazole is fragile when the N1-position of the triazole is
occupied by the electron-withdrawing group such as sulfonyl
and phosphoryl.6 For this reason, the 4-substituted-1-sulfonyl-
1,2,3-triazole ring would open to form ketenimine or ynamine
intermediates with the exclusion of nitrogen gas after the
CuAAC process (Scheme 1).7 In these cases, ketenimine or
ynamine intermediates could be inter-8 or intramolecularly9
Scheme 1. Previous Works and Our Design
Scheme 2. Formation of β-Alkynyl-N-sulfonyl Ketenimine
and Its Trapping with p-Toluidine or Hydrazine
Received: August 3, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
ered. After the mixture of 1a, 2a, p-tolylhydrazine hydro-
chloride, CuI (10 mol %), and Et3N in dichloroethane (DCE)
was stirred at room temperature for 6 h, pyrazole 4 and its
isomer 4′ were isolated in 50% total yield. Pyrazole is a
significant heterocycle in a series of bioactive compounds, and
many conventional approaches for the preparation of pyrazoles
have been disclosed.14 Although the pyrazole ring was ideally
constructed via this three-component strategy, the outcome
lacks the regioselectivity. We have expended much effort to
obtain better regioselectivity, but we failed. Therefore, we
changed the trapping reagent from p-tolylhydrazine to
benzohydrazide (5a). In this case, 5a reacted with 1-
(naphthalene-1-yl)-1,3-butadiyne (1b) and 2a to give 3-
aminopyrazole 6a in 77% yield (Table 1, entry 1).
Table 2. Substrate Scope for the Synthesis of 3-
Aminopyrazoles 6a−l
a
entry
5 (R)
6/yield (%)
1
5a (C6H5)
6a/83
6b/80
6c/68
6d/82
6e/73
6f/76
6g/63
6h/62
6i/77
6j/72
6k/66
6l/60
2
5b (p-MeOC6H4)
5c (o-MeC6H4)
5d (m-MeC6H4)
5e (o-FC6H4)
5f (m-FC6H4)
5g (p-FC6H4)
5h (2-furyl)
3
4
5
Table 1. Screening of Reaction Conditions for the
6
a
Formation of 6a
7
8
9
5i (2-thienyl)
5j (Me)
10
11
12
5k (Me3CO)
5l (C6H5CH2O)
a
Reaction conditions: 1b (0.24 mmol), 2a (0.24 mmol), 5 (0.2
mmol), Et3N (0.24 mmol), CuCl (0.02 mmol), DCE (1 mL), rt, 3 h.
Isolated yield based on 5.
b
b
entry
catalyst
CuI
base
Et3N
solvent
yield (%)
1
DCE
77
2
CuI
Et3N
DCM
CHCl3
CH3CN
THF
74
(5a) gave the best yield. Furan-2-carbohydrazide (5h) and
thiophen-2-carbohydrazide (5i) furnished 6h and 6i in yields of
62% and 77%, respectively. It was noticeable that acetohy-
drazide (5j) worked for the reaction and produced 6j in 72%
yield. Finally, hydrazine carboxylates (5k, 5l) were tested for
the reaction. 6k and 6l, with Boc and CBz protected on
pyrazoles, were obtained in 66% and 60% yields, respectively.
Various substituted benzenesulfonyl azides 2b−g (Table 3)
worked for the reaction and produced corresponding 6m−6r in
yields varying from 60% to 90%. A moderate electron-donating
group on benzenesulfonyl azide, such as 2,4,6-trimethyl-
benzenesulfonyl azide (2g), furnished 6r in the highest yield
3
CuI
Et3N
69
4
CuI
Et3N
70
5
CuI
Et3N
23
6
CuI
Et3N
toluene
DMF
DCE
59
7
CuI
Et3N
53
8
CuBr
CuCl
CuTc
CuBr(SMe2)
CuCl
CuCl
CuCl
CuCl
Et3N
70
9
Et3N
DCE
83
10
11
12
13
14
15
Et3N
DCE
71
Et3N
DCE
75
DABCO
2,6-lutidine
pyridine
K2CO3
DCE
35
DCE
ND
ND
ND
DCE
DCE
Table 3. Substrate Scope for the Synthesis of 3-
a
a
Reaction conditions: 1b (0.24 mmol), 2a (0.24 mmol), 5a (0.2
mmol), base (0.24 mmol), Cu(I) (0.02 mmol), solvent (1 mL), rt, 3 h.
Isolated yield based on 5a.
Aminopyrazoles 6m−v
b
Encouraged by this result, we optimized the reaction
conditions for the formation of 6a (Table 1). The yield of 6a
largely depended on the solvent. DCE was selected to be
optimal among dichloromethane (DCM), chloroform, acetoni-
trile, THF, toluene, and DMF (Table 1, entries 1−7). Among
the various tested copper catalysts, such as CuBr, CuCl, CuTc,
and CuBr(Me2S), CuCl gave the best yield (Table 1, entries 8−
11). DABCO worked for the reaction, but with a lower yield
(Table 1, entry 12). When 2,6-lutidine, pyridine, or potassium
bicarbonate was used as the base additive, 6a was not detected
with the recovery of 5a (Table 1, entries 13−15). Thus, the
optimal reaction conditions were established (Table 1, entry 9).
With the optimized reaction conditions in hand, we tested
the substrate diversity. A series of monosubstituted benzohy-
drazides (5a−g in Table 2) were tested first. The
corresponding products (6a−g) were obtained in yields
between 63% and 83%. No apparent substituent effect could
be concluded. Without any substitution, the benzohydrazide
entry
1 (R1)
2 (R2)
2b (C6H5)
6/yield (%)
1
2
1b (1-naphthalenyl)
6m/71
6n/72
6o/74
6p/70
6q/60
6r/90
6s/72
6t/80
6u/64
6v/55
1b
2c (p-MeOC6H4)
2d (p-ClC6H4)
2e (p-CF3C6H4)
2f (p-NO2C6H4)
2g (2,4,6-Me3C6H2)
2h (Me)
3
1b
4
1b
5
1b
6
1b
7
1b
8
1c (p-ClC6H4)
1d (p-MeOC6H4)
1e (n-C6H13)
2a
9
2a
10
2a
a
Reaction conditions: 1 (0.24 mmol), 2 (0.24 mmol), 5a (0.2 mmol),
Et3N (0.24 mmol), CuCl (0.02 mmol), DCE (1 mL), rt, 3 h. Isolated
yield based on 5a.
b
B
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(Table 3, entry 6). Besides arenesulfonyl azides, methanesul-
fonyl azide (2h) also worked for the reaction and provided 6s
in 72% yield. From investigation of the substituent effect of 1-
aryl-1,3-butadiynes, it is evident that the electron-withdrawing
group (Cl) benefitted the reaction and gave a better yield (6t,
80%) than the electron-donating group (MeO) did (6u, 64%).
Deca-1,3-diyne (1e) reacted smoothly and prepared 6v in 55%
yield.
Scheme 3. Preparation of 4-Iminopyrimidines 8n and 8o
When N-phenylbenzimidamide (7a) was used as the
trapping reagent under the reaction conditions established for
the pyrazole formation, 4-iminopyrimine (8a) was isolated in
74% yield (Table 4, entry 1). Due to the importance of
Table 5. Substrate Scope for the Synthesis of 4-
Iminopyrimidines 8p−u
a
Table 4. Substrate Scope for the Synthesis of 4-
a
Iminopyrimines 8a−m
entry
1 (R1)
2 (R2)
8/yield (%)
1
2
3
4
5
6
1b (1-naphthalenyl)
1b
2d (p-ClC6H4)
2c (p-MeOC6H4)
2h (Me)
2a (Ts)
8p/72
8q/65
8r/95
8s/69
8t/77
8u/55
1b
1c (p-ClC6H4)
1d (p-MeOC6H4)
1e (n-C6H13)
entry
7 (R1, R2)
8/yield (%)
2a
1
7a (C6H5, C6H5)
8a/74
8b/88
8c/70
8d/83
8e/97
8f/98
8g/98
8h/72
8i/71
8j/65
8k/62
8l/91
8m/86
2a
2
7b (p-MeC6H4, C6H5)
7c (p-MeOC6H4, C6H5)
7d (p-BrC6H4, C6H5)
7e (o-BrC6H4, C6H5)
7f (m-BrC6H4, C6H5)
7g (C6H5, o-FC6H4)
7h (C6H5, p-MeC6H4)
7i (C6H5, p-MeOC6H4)
7j (C6H5, n-C4H9)
a
Reaction conditions: 1 (0.24 mmol), 2 (0.24 mmol), 7a (0.2 mmol),
Et3N (0.24 mmol), CuCl (0.02 mmol), DCE (1 mL), room
temperature, 3 h. Isolated yield based on 7a.
3
4
b
5
6
substituent on 1-aryl-1,3-butadiynes, 1c and 1d reacted
smoothly and produced 8s and 8t in 69% and 77% yields,
respectively. Furthermore, deca-1,3-diyne (1e) could furnish 8u
in 55% yield.
The regioselectivity of this reaction was determined by the
NOE technique. The NOE between Ha and Hb in the molecule
of 8v clearly indicated that the reaction was highly
regioselective (Scheme 4).
7
8
9
10
11
12
13
7k (C6H5, o-ClC6H4)
7l (C6H5, p-ClC6H4)
7m (C6H5, m-ClC6H4)
a
Reaction conditions: 1b (0.24 mmol), 2a (0.24 mmol), 7 (0.2
mmol), Et3N (0.24 mmol), CuCl (0.02 mmol), DCE (1 mL), rt, 3 h.
Isolated yield based on 7.
b
Scheme 4. Determination of Regioselectivity of Reaction
pyrimidine base pairs in genomics and other utilities of
pyrimidine in pharmaceutics,15 we investigated the substrate
scope for the formation of 4-iminopyrimidines. The reaction
tolerated a variety of substituents on imidamides (7a−m) and
afforded corresponding 4-iminopyrimidines (8a-m) in yields
varied from 62% to 98% without the apparent substitution
effect. It was noticeable that pentanimidamide (7j) afforded 8j
in 65% yield.
Imidamide hydrochlorides 7n and 7o could be directly used
as the starting materials without pretreatment. They could work
well and afforded 8n and 8o in 52% and 61% yields,
respectively. In these cases, 3 equiv of triethylamine should
be applied to consume hydrochloride (Scheme 3).
The substituent effect on benzenesulfonyl azides was also
investigated. 4-Chlorobenzenesulfonyl azide (2d) and 4-
methoxybenzenesulfonyl azide (2c) provided the correspond-
ing 4-iminopyrimidines 8p and 8q in 72% and 65% yields,
respectively (Table 5). To our surprise, methanesulfonyl azide
(2h) gave the best yield in comparison with other arenesulfonyl
azides. This is different from the result obtained for the
aforementioned synthesis of 3-aminopyrazoles. By changing the
We postulated a working mechanism for the formation of 3-
aminopyrazoles 6 and 4-iminopyrimidines 8 (Scheme 5). First,
butadiyne 1 reacts with sulfonyl azide 2 in the presence of CuI
and Et3N to form ketenimine intermediate A through a cascade
CuAAC/intramolecular rearrangement. Second, A is trapped by
5 and 7 to form B and B′, respectively. Finally, B and B′
undergo a propargyl-allenyl isomerization,16 followed by
cyclization to afford 6 and 8, respectively. It is noteworthy
that β-alkynyl-N-sulfonyl ketenimine A functions as a 1,3-
dielectrophilic equivalent in this process.
In conclusion, we have developed a facile and efficient
synthesis of 3-aminopyrazoles and 4-iminopyrimidines via a
copper-catalyzed three-component reaction of butadiynes,
sulfonylazides, and hydrazides or imidamides. The reaction
C
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Organic Letters
Letter
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Scheme 5. Proposed Mechanism
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
E.; Muller, T. J. J. Beilstein J. Org. Chem. 2011, 7, 1173. (e) Boersch, C.;
̈
Merkul, E.; Muller, T. J. J. Angew. Chem., Int. Ed. 2011, 50, 10448.
̈
AUTHOR INFORMATION
Corresponding Authors
■
(f) Willy, B.; Muller, T. J. J. Eur. J. Org. Chem. 2008, 4157.
(15) Ono, A.; Torigoe, H.; Tanaka, Y.; Okamoto, I. Chem. Soc. Rev.
̈
*E-mail: pinglu@zju.edu.cn.
*E-mail: orgwyg@zju.edu.cn.
2011, 40, 5855.
(16) (a) Xing, Y.; Wei, Y. X.; Zhou, H. Curr. Org. Chem. 2012, 16,
1594. (b) Muller, T. J. J. Synthesis 2012, 44, 159.
̈
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the financial support from the National
Natural Science Foundation of China (Nos. 21032005,
21272204, and J1210042).
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