Base induced cyclobutenone rearrangements and its application in the synthesis of aromatic amines

Article abstract of DOI:10.1016/j.tetlet.2019.151304

A series of fully substituted 2-pyridone 2 and functionalized α-pyrones 3 are synthesized starting from cyclobutenones 1 under a base-promoter in toluene at 80 °C. This rearrangement is complimentary to the previously reported ring expansion of cyclobutenones, providing a divergent synthesis of corresponding products from the same precursor 1. In addition, α-pyrones 3 has also been applied to the synthesis of aromatic amines 7 in good yields (64–83%) and in a highly regioselective manner via D-A reaction under mild conditions.

Full text of DOI:10.1016/j.tetlet.2019.151304

Journal Pre-proofs
Base Induced Cyclobutenone Rearrangements and Its Application in the Syn-
thesis of Aromatic Amines
Xiaodan Han, Jianping Fu, Juwu Hu, Wei Xiong, Huibin Wang, Lei Wu
PII:
S0040-4039(19)31087-1
DOI:
https://doi.org/10.1016/j.tetlet.2019.151304
TETL 151304
Reference:
Tetrahedron Letters
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10 October 2019
18 October 2019
Please cite this article as: Han, X., Fu, J., Hu, J., Xiong, W., Wang, H., Wu, L., Base Induced Cyclobutenone
Rearrangements and Its Application in the Synthesis of Aromatic Amines, Tetrahedron Letters (2019), doi: https://
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Base Induced Cyclobutenone Rearrangements and Its Application in the
Synthesis of Aromatic Amines
Xiaodan Han, Jianping Fu, Juwu Hu, * Wei Xiong, * Huibin Wang, Lei Wu
Department of Applied Chemistry, Jiang Xi Academic of Sciences, Nanchang, 330096, People’s Republic of China
E-mail: hjw19771985@163.com
O
O
O
O
1
O
R
R
O
R
N
base
1
+
1
R
R
1
toluene
80 ℃
N
R
R
N
N
2
2
R
2
R
R
1
2
3
63-80% yield
3
R
3
R
1
R
N
R
Cu(OTf) (5 mol%)
toluene
80 ℃
2
2
R
7
D-A reaction
12 examples
up to 83% yield
a divergent synthesis approach
easily available starting materials
·
·
D-A reaction was realized in good yields and in a highly regioselective
·
manner under mild conditions
Abstract: A series of fully substituted 2-pyridone 2 and functionalized α-pyrones 3 are synthesized starting from
cyclobutenones 1 under a base-promoter in toluene at 80 ℃ . This rearrangement is complimentary to the
previously reported ring expansion of cyclobutenones, providing a divergent synthesis of corresponding products
from the same precursor 1. In addition, α-pyrones 3 has also been applied to the synthesis of aromatic amines 7 in
good yields (64–83%) and in a highly regioselective manner via D-A reaction under mild conditions.
Keywords: substituted pyridones; α-pyrones ; D-A reaction; aromatic amines
Cyclobutenones are extremely versatile synthetic intermediates and have seen a rapid development in the
construction of a wide range of organic compounds including several bioactive natural products and drugs[1].
Owing to their inherent high ring strain, the ring-opening/rearrangement reactions of cyclobutenone triggered by
numerous reaction conditions, primarily involving thermolysis[2], photolysis[3], and transition metal-catalyzed[4]
have been recognized as one of the most direct, effective, atom-economical and rapid methods for chemical
transformations. Over the past decades, the ring-opening reactions of cyclobutenone have been well studied[5] and
they have successfully paved the way for the synthesis of ring-expanded products, e.g. aromatics [6], quinones[7],
pyrone[8], indole alkaloids[9], cycloheptadienone[10] . To date, this type reactions of cyclobutenone are still a topical
area of continuing interest. Recently, series of 3-aminocyclobut-2-en-1-ones 1 incorporating acyl and amino
groups have been easily prepared by our group[11] , which were proven very useful, especially in the synthesis of
persubstituted phenols [12]and 4-quinolones[11]. Encouraged by these results and our continued interest in the
synthesis of highly valuable carbo- and heterocycles from cyclobutenone derivatives, we further explored the
reaction behavior of 3-aminocyclobut-2-en-1-ones 1 and found it was sensitive to base conditions. We now wish to
report a simple and efficient access to 2-pyridones 2 and/or α-pyrones 3 relying upon utilization of
3-aminocyclobut-2-en-1-ones 1 in the presence of base-promoter and present a mechanism involved in the

ring-opening/recyclization process.
At the outset of our study, 3-aminocyclobut-2-en-1-one 1a was prepared and tried the thermal cyclization
reaction by heating from 50 ℃ to 110 ℃ in toluene. Regrettably, no reaction occurred in the absence of catalyst.
After many attempts, it was found when 1a was subjected to K2CO3 (1.0 eqv.) in toluene at 80 ℃ for a period of
time, two different products were obtained (Scheme 1). The structure of 2a was unambiguously established by its
spectra, analytical data and X-ray crystallographic analysis. According to our previous work[12], 3a was named
6-ethyl-3-methyl-4-p-tolylamino-pyran-2-one. This result intrigued us to explore the precious reaction conditions
to prepare 2-pyridone 2 and/or α-pyrones derivatives 3 selectively from 3-aminocyclobut-2-en-1-one 1 since those
compounds with 2-pyridone or α-pyrone structure have emerged not only as key units in many natural product and
pharmaceuticals but also as important intermediates for various biologically active molecules[13]
.
O
O
O
O
N
1.0 eqv. K CO
2
O
3
1
2
3
toluene
O
HN
+
80℃
6h
4
N
N
H
H
1a
2a (58%)
3a (31%)
Scheme 1
Then, we examined the ring-opening/rearrangement of 3-aminocyclobut-2-en-1-one 1a to 2a and 3a by
varying reaction conditions and the results were summarized in table 1. Selecting K2CO3 (1.0 eqv.) as a base, the
reaction of 1a afforded 2a in 58% isolated yield within 6 h in toluene at 80 ℃ along with α-pyrones 3a in 31%
yield (Table 1, entry 1). Increasing the amount of K2CO3 from 1.0 to 1.5 equivment made considerable effect on
the yield of product 2a and the reaction time was shortened to 4 h (Table 1, entry 2). A further increase in the
amount of K2CO3 to 2.0 eqv. was not required (Table 1, entry 3). Moreover, the reaction temperature was also
found to be an important factor for this transformation. By lowing the temperature to RT, the reaction did not take
place (Table 1, entry 4). Higher temperature resulted in a sharply decline in the yield of 2a compared to entry 2,
whereas the yield of 3a increased up to 78% (Table 1, entry 5). Addition of other carbonates, such as Cs2CO3 and
Na2CO3 were less effective for improvement of 2a yield (Table 1, entries 6-7). In particular, it should be noted that
when hydroxide (KOH, NaOH, LiOH) was utilized to replace K2CO3 for this reaction, the product 2a was not
observed even if the reaction time was prolonged and in the meantime, α-pyrone 3a was obtained as the major
product in high yields, concominated by a by-product enamine 4a (Table 1, entries 8-10). Subsequently, we moved
on to screen the reaction solvent. Among the solvents tested, CH3CN gave 2a as the main product in 71% yield
(Table 1, entry11); When the reaction was carried out in DMF or 1,4-dioxane or H2O, instead of 2a, α-pyrones 3a
was obtained as the major product in moderate yields (Table 1, entries 12-14 ); In comparison, no 2a and/or 3a
could be detected with anhydrous toluene as the solvent (Table 1, entry15). Thus, the most suitable reaction
conditions for the formation of 2a or 3a was established by simple changing the base promoter in toluene at 80 ℃.
Table 1. Optimization of reaction conditions for the synthesis of 2-pyridone 2aa and α-pyrone 3ab
O
O
O
O
O
HN
O
HN
N
O
base
Solvent
T(¡æ)
+
+
N
N
H
H
1a
2a
3a
4a
2ac
Yield
(%)
3ad
4ae
Yield
(%)
0
Base
(eqv.)
T
(℃)
Entry
1
Solvent
toluene
Yield
(%)
31
K2CO3 (1.0)
80
58

2
3
4
5
6
7
8
9
10
11
12
13
14
K2CO3 (1.5)
K2CO3 (2.0)
K2CO3 (1.5)
K2CO3 (1.5)
Cs2CO3(1.5)
Na2CO3(1.5)
KOH (1.5)
NaOH(1.5)
LiOH(1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
DMF
80
80
rt
79
68
0
19
77
36
0
0
0
71
0
0
15
20
0
0
0
0
0
0
0
90
80
80
80
80
80
80
80
80
80
78
17
33
96
90
87
25
58
61
65
trace
9
11
0
0
0
1,4-dioxane
H2O
trace
0
15
K2CO3 (1.5)
anhydrous toluene
80
0
0
0
a/bReaction conditions: 1a (1.0 mmol), solvent (5.0 mL). c/d/eIsolated yields
To generalized this approach, several kinds of 3-aminocyclobut-2-en-1-ones 1 were studied for the synthesis
of fully substituted 2-pyridone 2 in the presence of 1.5 eqv. K2CO3 at 80 ℃ in toluene. As shown in Table 2,
substituted 1 having aryl group on the nitrogen atom can participate in the ring-opening/recyclization process to
afford the major product 2-pyridone 2a-h in moderate yields (Table 2, entries 1-8). However, the reaction of 1i (R
= OMe) under the same optimized reaction conditions failed to produce even trace of 2i or 3i (Table 2, entry 9).
Using 1j (R1 = n-butyl group) as substrate, the reaction gave α-pyrone 3j in good yield whereas the yield of
2-pyridone 2j dropped to trace amounts (Table 2, entry 10). As for 1k (R1 = piperidyl), the corresponding product
2k was not observed and α-pyrone 3k was obtained in 87% yield (Table 2, entry 11). Notably, no formation of 2l
and/or 3l was detected in case of a pyridine group at R1 (Table 3, entry 12), which is due to the conversion of 1l to
naphthyridine 5 (Scheme 2)[9]. The structure of 5 was confirmed by its spectral data (1HNMR, 13CNMR and
HRMS) and finally by the X-ray crystallographic data.
Table 2. Ring-expanding reaction of 1 with K2CO3 in toluenea
O
O
O
O
1
O
R
R
O
R
N
1.5 eqv. K CO
2
3
1
+
1
R
R
1
toluene
80 ℃
N
R
R
N
N
2
2
R
2
R
R
1
2
3
Entry
1
2
3d
4
5
6
7e
8
1
R
Et
Et
Et
Et
Et
Et
Et
Me
R1
R2
H
H
H
H
H
H
H
H
H
H
-
2 Yieldb (%)
79(2a)
74(2b)
73(2c)
77(2d)
71(2e)
63(2f)
75(2g)
80(2h)
0(2i)
trace(2j)
0(2k)
3 Yieldc (%)
15(3a)
19(3b)
20(3c)
16(3d)
25(3e)
30(3f)
17(3g)
11(3h)
0(3i)
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-MeC6H4
C6H5
4-ClC6H4
4-MeOC6H4
2-MeC6H4
2,4-Me2C6H3
4-CF3C6H4
4-MeC6H4
4-MeC6H4
n-butyl
9
OMe
Et
Et
10
11
12f
1j
1k
1l
82(3j)
87(3k)
0(3l)
(CH2)5
C5H4N
Et
H
0(2l)
aReaction conditions: 1 (1.0 mmol), K2CO3 (1.5 mmol), toluene (5 mL), 80 ℃, 5 h. b/cIsolated yields. Reaction conditions: 1
d/e
(1.0 mmol), K2CO3 (1.5 mmol), toluene (5 mL), 60 ℃, 10 h. fSubstrate 1l was converted to naphthyridine 5 in 96% yield.
O
O
N
O
O
1.5 eqv. K CO
2
3
N
toluene, 80 ℃
N
N
H
x-ray crystal
structure of 5
1l
5 (yield = 96%)

Scheme 2
To obtain deeper insight into the reaction mechanism, some supplementary experiments were conducted. First,
we were interested in whether an enamine moiety captured in the reaction of 1 with hydroxides (table 1, entries
8-10), would be able to insert into the four-membered ring. Consequently, we tried the reaction of 1a with 4a1
under the same reaction conditions as in Table 2. As a result, the reaction gave 2a in 77% yield and no 2a1 was
produced (Scheme 3), which can be inferred enamine 4a was not involved in the formation of 2-pyridone 2a.
O
O
O
O
O
O
N
N
O
1.5 eqv. K CO
2
3
HN
HN
HN
+
+
toluene
N
H
80 ℃
1a
4a
2a (yield = 77%)
2a (yield = 0)
1
1
Scheme 3
Further evidence for this mechanism was provided by reactions of 1a with different base-promoters in
anhydrous toluene and H2O.The experiments showed that only a trace or no 2a was detected and 3a was generated
as the main product from 1a in 65% and 88% yields when the reactions were carried out in H2O at 80 ℃ in the
presence of K2CO3 (1.5 eqv.) for 8 h and KOH (1.5 eqv.) for 5 h (Table 1, entry 14; Scheme 4), respectively.
Additionally, no reaction occurred when 1a was treated with K2CO3 or KOH in anhydrous toluene under other
identical conditions (Table 1, entry 15; Scheme 5), while most of 1a remained. These results clearly indicate that a
wetted condition even a trace amount of water (Table 1, entries 1-13) and the basicity of the promoter have a
significant bearing on the outcome of this reaction.
O
O
O
O
HN
O
KOH (1.5 eqv.)
+
H O (5 mL)
2
80 ℃
N
N
H
H
1a
3a (88%)
4a (10%)
Scheme 4
O
O
KOH (1.5 eqv.)
no reaction
anhydrous toluene
N
80 ℃
H
1a
Scheme 5
On the basis of all of the results described and the related reports on the OH/NH2-initiated ring-opening
reaction of cyclobutenones[14-17], we considered OH- as a promoter, which comes from KOH solution or hydrolysis
of potassium carbonate in a wetted condition, to initiate the reaction. Therefore, plausible mechanisms for the
synthesis of 2-pyridones 2 and α-pyrones 3 from 3-aminocyclobut-2-en-1-ones 1 were proposed in Scheme 6 and
Scheme 7. The synthesis of 2-pyridones 2 with K2CO3 as a base [14a,17b]: under a base reagent, cyclobutenones 1
undergoes a tautomerism to form imines I. I acts as a nucleophile and rapidly reacts with another molecule of
cyclobutenones 1 to form [4+2] cycloaddition product III via 1,2-addition(III)/ring-opening(IV) and concomitant
intramolecular cyclization (II). Then 1,2-addition of OH- to the carbonyl moiety in III initiated ring opening of
cyclobutanone (IV), accompanied by elimination of β-carbonyl carboxylic acid to give intermediate V, which
eventually led to product 2-pyridones 2 after double bond inward shift. (Scheme 6).

O
O
R
O
1
O
O
O
R
O
-
1
O
R
O
R
N
O
R
R
R
O
1
R
N
O
base
HN
O
1
HN
N
HN
R
1
1
1
R
R
R
1
I
II
III
O
R
O
O
O
O
1
1
R
1
R
2-
O
R
CO + H O
3
2
N
R
N
R
N
R
-
OH
HN
HN
HN
-
O
O
1
O
1
R
1
R
HO
R
R
OH
IV
V
2
Scheme 6 possible mechanism for the formation of 2-pyridones 2
A proposed mechanism for α-pyrones 3 synthesis with KOH as a base promoter is depicted in Scheme 7[15, 18]
:
firstly, OH- attacks the carbonyl moiety of substrate 1(A), leading to ring opening predominantly at the C1-C2 bond
and the formation of intermediate vinyl anion B[19], which is consistent with the description of Roberts and
co-workers[15a]. Followed by a proton transfer, the intermediate C occurs an intramolecular O-nucleophilic addition
to furnish a cyclic intermediate D. Finally, D removes a molecule of water, giving rise to the product α-pyrones 3
(Scheme 7).
proximal
O
O
O
-
O
O
R
1
-
2
R
R
OH
OH
OH
1
R
1
1
N
H
O
3
4
R
R
N
N
distal
H
H
1
A
B
O
O
HO
R
O
O
-
R
O
-H O
2
1
1
R
R
HN
R
N
H
O
N
O
1
H
R
C
D
2
Scheme 7 possible mechanism for the formation of α-pyrones 3
When hydroxides was used instead of K2CO3 as a promoter in the reaction system under otherwise identical
conditions as those in table 2, α-pyrones 3 can be obtained as the mjor product in excellent yields, which was
introduced by Han’s formerly report [12] and no longer elaborated in this paper. To extend the synthetic value of the
protocol, our interest was focused on the synthetic use of α-pyrones 3, which has often been taken as a potentially
useful scaffold for the synthesis of complex heterocyclic compounds[20]. Eventually, we found that aromatic
amines 7 could be obtained from the prepared α-pyrones 3 as a diene component in Diels–Alder reactions with
terminal alkynes 6 in the presence of 5% Cu(OTf)2 in toluene at 80 ℃ for 7 h, followed by the extrusion of CO2
(Table 3). Despite the traditional methods for aromatic compounds via D-A reaction of pyrone with alkynes/
alkenes have been presented, they often suffer from harsh reaction conditions (e.g. high temperatures ≥150 ℃,
expensive catalyst and ligands), poor yields and low regioselectivities[23]. From the previous observations, it is
anticipated that the above D-A reactions will be further improved and afford the expected product under mild
conditions. We detailed herein, the development of this concept into an efficient approach for generating
functionalised aromatic amines in good yields and in a highly regioselective manner.
As can be seen from Table 3, the reactions of α-pyrones 3a-f bearing aryl moiety at R1, including

electron-rich (Table 3, entry 1 and entries 4-6), phenyl (Table 3, entry2), electron-deficient (Table 3, entry 3)
N-aryl groups reacted well with but-3-yn-2-one 6a (1.0 mmol) to afford aromatic amines 7a–f in moderate yields
(64–73%). The presence of a Me group instead of Et at R also showed good reaction activity in the D-A reaction
and gave 7h in 69% yield (Table 3, entry 7). Compounds 7’s structure was determined by its spectral and
analytical data, and further confirmed by the X-ray diffraction of 7a (Figure 1). Similarly, the present procedure
applied to α-pyrones 3j-k bearing a n-butyl or piperidyl group on the nitrogen atom, providing 7j and 7k in good
yields (Table 3, entries 8-9). Subsequently, we examined the reactivity of other terminal alkynes. To our delight,
the reactions of 3a with 6b, 6c and 6d gave rise to aromatic amines derivatives (7l, 7m and 7n) in 83%, 57% and
51% yields, respectively (Table 3, entries 10-12). However, when 1-pentyne (6d) was applied, no reaction
occurred (Table 3, entry 13). Given the results have suggested that the electronic properties of substituents in
terminal alkynes 6 has an important effect on the reactivity of our reaction.
Table 3. D-A reaction of 2-pyrones 3 with terminal alkynes 6[a]
O
R3
O
5% Cu(OTf)2
R3
+
R1
R1
toluene
80 ℃
N
R
N
R2
R
R2
3
6
7
Entry
1
2
3
4
5
6
7
8
1
R
R1
R2
R3
Product 7
7 Yieldb (%)
3a
3b
3c
3d
3e
3f
3h
3j
3k
3a
3a
3a
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
4-MeC6H4
C6H5
4-ClC6H4
4-MeOC6H4
2-MeC6H4
2,4-Me2C6H3
4-MeC6H4
n-butyl
H
H
H
H
H
H
H
H
-
COCH3(6a)
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
CHO(6b)
C6H5(6c)
7a
7b
7c
7d
7e
7f
7h
7j
7k
7l
73
71
67
76
73
64
69
66
78
83
57
51
9
(CH2)5
10
11
12
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
H
H
H
7m
7n
4-MeC6H5(6
d)
13
3a
Et
4-CH3C6H4
H
C3H7 (6e)
7o
0
aReaction conditions: 1 (1.0 mmol), 6 (1 mmol), Cu(OTf)2 (5 mmol%), toluene (5 mL), 80 ℃, 7 h. bIsolated yields.
Figure 1. ORTEP drawing of 7a
In conclusion, we have developed a divergent synthesis of 2-pyridones 2 and α-pyrones 3 in good yields
starting from the same precursor 3-aminocyclobut-2-en-1-ones 1 upon regulation of base conditions. Also a
catalytic amount of Cu(OTf)2-catalyzed Diels-Alder reaction of α-pyrones 3 with terminal alkynes to furnish
aromatic amines 7 has been detailed. Contrasting with the so far reported Diels-Alder reactions of α-pyrones with
alkynes, this method features low-cost, short reaction time, mild reaction conditions, operational simplicity, as well

as high regioselectivity.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Grants 21562023 and 21862007) and
the Jiangxi Provincial Science & Technology Department (20171BBF60074) for financial support.
Supplementary data
The supporting information of detailed experimental procedures, CIF data for 2a and full characterization
data for 2a-h, 3a-k, 4a, 5 and 7a-n is available free of charge on the line.
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Declaration of interests
The authors declare that they have no known competing financial interests or personal
☒
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:

Highlights:
1. It provides a divergent way to form different products from the same precursor .
2. The reaction was successfully realized upon regulation of base promoters.
3. Also a D-A reaction to furnish aromatic amines 7 has been elaborated.
4. The D-A method features mild reaction condition, high yield and regioselectivity.