Annulation reaction of cyclic pyridinium ylides with: In situ generated azoalkenes for the construction of spirocyclic skeletons

Article abstract of DOI:10.1039/c9ob02733e

Two new types of cyclic pyridinium ylides were designed and further used in reactions with azoalkenes to access structurally diverse spirocyclic compounds. A range of spiropyrazoline oxindoles could be smoothly obtained in up to 99% yield via a [4 + 1] annulation process with oxindole 3-pyridinium ylides as C1 synthons. Similarly, a series of spiropyrazoline indanones could be prepared with indanone 2-pyridinium ylides as C1 synthons. This work represents the first example of cyclic pyridinium ylides as C1 synthons for the efficient construction of spirocyclic compounds.

Full text of DOI:10.1039/c9ob02733e

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DOI: 10.1039/C9OB02733E
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[4+1] Annulation reaction of cyclic pyridinium ylides
with in situ generated azoalkenes for the construction of
spirocyclic skeletons
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Bao-Xue Quan,a,d Jun-Rui Zhuo,a,d Jian-Qiang Zhao,b,* Ming-Liang Zhang,c Ming-Qiang Zhou,a Xiao-
Mei Zhanga and Wei-Cheng Yuana,b,
*
www.rsc.org/
New types of cyclic pyridinium ylides were designed and further
Since the first synthesis of pyridinium ylides was reported
used in the reaction with azoalkenes to access structurally diverse by Kröhnke,4 pyridinium ylides have proved to be a type of
spirocyclic compounds. A range of spiropyrazoline oxindoles could powerful and versatile reagent in the area of organic
be smoothly obtained in up to 99% yield via [4+1] annulation chemistry.5 Pyridinium ylides can undergo various reactions,
process with oxindole 3-pyridinium ylides as C1 synthons. such as Michael additions,6 1,3-dipolar cycloadditions,7
Similarly, a series of spiropyrazoline indanones could be prepared dearomatizations,8 or cyclopropanations9 depending on the
with indanone 2-pyridinium ylides as C1 synthons. This work nature of the employed electrophiles. Consequently, various
represents the first example of cyclic pyridinium ylides as C1 types of pyridinium ylides derived from the corresponding
synthons for the efficient construction of spirocyclic compounds.
pyridinium salts have been designed and used for diverse
reactions over the past few decades.5 A literature search
Substances possessing
a
spirocyclic skeleton have been revealed that almost all of the reports so far have focused on
identified as an attractive target in organic synthesis due to the reaction of non-cyclic pyridinium ylides (Scheme 1, top
their widespread distribution in biologically active natural and left). In sharp contrast, the application of cyclic pyridinium
non-natural products,1 as well as their increasing application in ylides in organic synthesis has remained elusive (Scheme 1, top
drug discovery, organic optoelectronics, and asymmetric right), and it even remains unknown that using them for the
synthesis.2 The most salient feature of the spirocyclic scaffold construction of spirocyclic compounds. In this context, we
is in that two rings connected through a single shared atom, hypothesized that cyclic pyridinium ylides could serve as C1
which is the spirocyclic central atom or spiroatom. Due to the synthons to react with suitable reactants, which contain an
importance and the widespread application of the privileged electrophilic site and a nucleophilic site in one molecular
spirocyclic structures, extensive effort has been devoted to the structure as Cn synthons. As a result, functionalized spirocyclic
development of efficient methods for the preparation of products will be formed with a possible [n+1] annulation
them.3 Although several elegant protocols have been reported, reaction through a cascade intermolecular/intramolecular
the facile construction of a spirocyclic system is still considered process (Scheme 1, bottom).
overview of the study of pyridinium ylides
to be a formidable challenge in organic synthesis because of
O
O
the formation of a conformationally rigid spirocyclic center.3k
In this context, the development of novel strategy for the
construction of spirocyclic skeletons is of great interest and
remains an important goal in organic synthesis.
R
N
N
non-cyclic pyridinium ylides
widely investigated
cyclic pyridinium ylides
scarcely reported
this work
O
O
N
Nu
E
reaction conditions
[n+1] annulation
+
a. National Engineering Research Center of Chiral Drugs, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China.
E-mail: yuanwc@cioc.ac.cn
Nu
= nucleophilic site
spirocyclic products
cyclic pyridinium ylides
as C1 synthons
E
= electrophilic site
b. Institute for Advanced Study, Chengdu University, Chengdu, 610106, China
E-mail: zhaojianqiang@cdu.edu.cn
intramolecular reaction
c. Henan Engineering Laboratory of Green Synthesis for Pharmaceuticals, College
of Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu,
476000, China
d. University of Chinese Academy of Sciences, Beijing, 100049, China
† Electronic Supplementary Information (ESI) available: Experimental procedures,
spectral data of new compounds, and crystallographic data. CCDC-1972117 and
1972118. For ESI and crystallographic data in CIF or other electronic format. See
DOI: 10.1039/x0xx00000x
O
O
N
N
Nu
Nu
E
intermolecular reaction
Scheme 1 Overview of the study of pyridinium ylides and the
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design of employing cyclic pyridinium ylides for the
construction of spirocyclic compounds.
reaction was carried out in EtOH, 3a was also obtained in a
decreased yield (Table 1, entry 10). UlDtiOmI:a1t0e.1ly0,39t/hCe9OoBp0t2i7m33aEl
conditions were determined as that used in entry 4.
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In addition, we noticed that azoalkenes in situ generated
from α-halo hydrazone have been utilized for the [4+1],10
[4+2],11 and [4+3]12 annulation to access various nitrogen-
containing heterocycles. Although several elegant works have
been reported in this area, the possible [4+1] annulation
reaction between cyclic pyridinium ylides and azoalkenes has
not been investigated. Therefore, as a continuation of our
long-lasting research program on the development of creative
method for the synthesis of spirocyclic oxindoles,13 we
designed a new type of oxindole 3-pyridinium ylides and used
them in the reaction with azoalkenes via a [4+1] annulation
reaction, thus generating a range of spiropyrazoline oxindoles,
which represent a privileged family of heterocycles featured in
many biologically active compounds (Scheme 2).14 Moreover,
we also demonstrated that the [4+1] annulation concept can
be extended to another cyclic pyridinium ylide in situ
generated from indanone 2-pyridinium salts to access
spiropyrazoline indanones (Scheme 2).
Table 1 Optimization of reaction conditionsa
Ph
N
Ts
Ts
N
N
NH
Br
O
N
base (3.0 equiv.)
solvent, rt
O
+
Br
N
Ph
N
N2, 48 h
Me
Me
1a
2a
3a
entry base
solvent yield (%)b
1
2
3
4
5
Et3N
DIPEA
Na2CO3
K2CO3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
90
88
96
97
n.d.
14
trace
trace
93
Cs2CO3
6
7
8
9
K2CO3 toluene
K2CO3
K2CO3
K2CO3
K2CO3
MTBE
EtOAc
CH2Cl2
EtOH
10
58
a Unless otherwise specified, the reactions were carried out with 1a
(0.2 mmol), 2a (0.22 mmol) and base (0.6 mmol, 3 equiv.) in 6.0 mL
of solvent under nitrogen atmosphere at room temperature for 48
h. b Isolated yield. n.d. = not determined.
N
N
Br
base
O
O
R2
N
N
N
N
R1
N
R3
R3
oxindole 3-pyridinium ylides
26 examples
up to 99% yield
O
With the optimal reaction conditions in hand, various α-halo
hydrazones were used in the reaction with diverse oxindole 3-
pyridinium salts to investigate the substrate scope. As summarized
in Table 2, different sulfonyl substitutents of the N-protecting group
in the α-halo hydrazones, such as Ts-, Ms-, and Bs-, were found to
be suitable for the [4+1] annulation reaction with 2a, affording the
products 3a-c in high to excellent yields (Table 2, entries 1-3).
Furthermore, different N-acyl protected α-halo hydrazones were
also well tolerated in the [4+1] annulation by reacting with 2a and
provided the corresponding products 3d-f in 63-99% yields (Table 2,
entries 4-6). In addition, the [4+1] annulation process proved to be
almost unbiased towards electron-donating substituents at the
different position on the phenyl ring of α-halo hydrazones, the
spirocyclic products 3g-j could be obtained in 86-99% yields (Table 2,
entries 7-10). Moreover, various electron-withdrawing substituents,
such as F-, Cl-, F3C-, NO2- group, were also tolerated well and
afforded the products 3k-n in high yields (Table 2, entries 11-14).
Disubstituted α-halo hydrazone 1o was also examined, and the
cycloadduct 3o could be obtained in 89% yield (Table 2, entry 15).
Substrate 1p bearing 2-naphthyl group was explored, the
corresponding product 3p was obtained in 89% yield (Table 2, entry
16). Additionally, the heteroaromatic substrate could also
participate in the [4+1] annulation reaction to furnish the product
3q in excellent yield (Table 2, entry 17). Gratifyingly, as for alkyl
substituted substrate 1r, it was found that the reaction also
proceeded smoothly and furnished the expected product 3r in good
yield (Table 1, entry 18). On the other hand, a survey of various
oxindole 3-pyridinium ylides, in situ generated from oxindole 3-
pyridinium salts, was also conducted. It was found that different N-
substituents, such as ethyl-, propyl-, isopropyl and allyl- at the N1
position, were compatible well with the conditions in the [4+1]
R1
N
R1
R3
spiropyrazoline oxindoles
NH
N
base
N
X
R1
O
R2
R2
N
N
10 examples
-halogeno hydrazones
azoalkenes
up to 99% yield
()n
R2
O
O
spiropyrazoline indanones
Br
base
N
N
()n
()n
indanone 2-pyridinium ylides
Scheme 2 Strategy for the construction of spiropyrazoline
compounds with cyclic pyridinium ylides via [4+1] annulation
.
We started our investigation with the reaction of α-
bromo-N-Ts hydrazone 1a and oxindole 3-pyridinium salt 2a by
using triethylamine as the base in CHCl3 under nitrogen
atmosphere. The expected [4+1] annulation product
spiropyrazoline oxindole 3a could be obtained in 90% yield
(Table 1, entry 1). With N,N-diisopropylethylamine (DIPEA) as
the base, the reaction gave 3a in 88% yield (Table 1, entry 2).
Next, different inorganic bases such as Na2CO3, K2CO3 and
Cs2CO3 were examined (Table 1, entries 3-5), and it was found
that K2CO3 was the best choice, giving 3a in up to 97% yield
(Table 1, entry 4). Surprisingly, the reaction performed with
Cs2CO3 as the base made the reaction complicated and gave no
product (Table 1, entry 5). And then, the solvent effect was
examined with K2CO3 as the base (Table 1, entries 6-10), and it
was found that the yield was significantly affected by the
solvent in the [4+1] annulation process. For instance, using
toluene resulted in a reduced yield (Table 1, entry 6).
Meanwhile, only a trace amount of 3a was obtained by using
methyl tertiary butyl ether (MTBE) or ethyl acetate as solvent
(Table 1, entries 7 and 8). In CH2Cl2, the reaction gave a similar
yield as that with CHCl3 (Table 1, entry 9 vs 4). When the
2 | J. Name., 2012, 00, 1-3
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annulation reaction with 1a, giving the corresponding products 3s-v halo hydrazone 1a with cyclic pyridinium salt 4a VdieewriAvreticdle fOrnolimne
DOI: 10.1039/C9OB02733E
in good to excellent yields (Table 2, entries 19-22). These reactions indanone proceeded smoothly and afforded the desired
revealed that the size of the N-alkyl group of oxindole 3-pyridinium spiropyrazoline indanone product 5a in quantitative yield,
ylides has no obvious effect on the reactivity. Ultimately, we also respectively (Table 3, entries 1-2). However, when the reaction
found that regardless of the electronic properties and the position of 1a and 4b was performed with K2CO3 as the base, the
of the substituents on the oxindole skeleton, the oxindole 3- reaction system was complicated and no main product could
pyridinium ylides 2f-i were all able to smoothly react with 1a to be observed (Table 3, entry 3). We guess that it is probably due
generate the corresponding products 3w-z in 65% to 99% yields to the instability of substrate 4b in the reaction mixture.
(Table 2, entries 23-26).
However, the reaction could give the desired spirocyclic
product 5b in 99% yield in the presence of DIPEA as the base
(Table 3, entry 4). Likewise, with K2CO3 or DIPEA as the base,
the reaction of 1a with indanone 2-pyridinium salts 4c could
afford the desired spirocyclic product 5c in 37% and 52% yield,
respectively (Table 3, entries 5-6). These results indicated that
DIPEA serving as the base was slightly better than K2CO3 in the
[4+1] annulation between α-halo hydrazones and indanone 2-
pyridinium ylides. Therefore, we selected DIPEA to further
investigate the substrate scope. As to the α-halo hydrazone
substrates, either installing different sulfonyl substituents as
the N-protecting group (R1) or incorporating different groups
on the phenyl ring (R2), it was found that the reactions of
various α-halo hydrazone substrates with 4a could proceed
smoothly to completion under mild conditions, furnishing the
Table 2 Scope of the [4+1] annulation between α-halo hydrazones
and oxindole 3-pyridinium ylides.a
R2
N
R1
R1
N
N
NH
Br
N
K2CO3 (3.0 equiv.)
CHCl3, N2, rt
R4
+ R4
O
O
X
R2
N
N
R3
R3
1
2
3
: R3 = Me, R4 = H
: R3 = iPr, R4 = H
: R3 = Me, R4 = 5-F
: R3 = Me, R4 = 6-Cl
2a
2d
2e
2g
R
3 = Et, R4 = H
: R3 = allyl, R4 = H
2b:
2c:
2h
2i
3
R
=
nPr, R4 = H
: R3 = Me, R4 = 5-Me
: R3 = Me, R4 = 7-Me
2f
time 3/yield
entry
1
2
(h)
(%)b
1
2
3
4
5
6
7
8
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Bs, R2 = Ph, X = Br (1b)
R1 = Ms, R2 = Ph, X = Cl (1c)
R1 = Boc, R2 = Ph, X = Cl (1d)
R1 = Ac, R2 = Ph, X = Cl (1e)
R1 = Bz, R2 = Ph, X = Cl (1f)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
48
48
48
48
48
48
48
36
36
36
36
8
48
48
48
8
48
48
48
48
48
48
48
48
48
48
3a/97
3b/98
3c/81 desired spiropyrazoline indanones 5d-j in moderate to high
3d/99
3e/72
3f/63
3g/98
3h/96
3i/86
3j/99
3k/99
3l/90
3m/96
3n/92
3o/89
3p/89
3q/93
3r/85
3s/99
3t/82
3u/99
3v/99
3w/99
3x/98
3y/75
3z/65
yields (Table 3, entries 7-13).
Table 3 Scope of [4+1] annulation between α-halo hydrazones
and indanone 2-pyridinium ylides.a
R1 = Ts, R2 = 2-MeC6H4, X = Br (1g)
R1 = Ts, R2 = 4-MeC6H4, X = Br (1h)
R1
R1
O
Br
O
9
R1 = Ts, R2 = 3-MeOC6H4, X = Br (1i)
R1 = Ts, R2 = 4-MeOC6H4, X = Br (1j)
R1 = Ts, R2 = 4-FC6H4, X = Br (1k)
R1 = Ts, R2 = 4-ClC6H4, X = Br (1l)
R1 = Ts, R2 = 4-CF3C6H4, X = Br (1m)
R1 = Ts, R2 = 3-NO2C6H4, X = Br (1n)
NH
N
N
DIPEA (3.0 equiv)
CHCl3, N2, rt
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
+
N
X
R2
()n
()n
R2
1
4
5
4a
4b
4c
: n = 1, : n = 2; : n = 3
time
(h)
5/yield
entry
1
4
(%)b
R1 = Ts, R2 = 2,4-Me2C6H3, X = Br (1o) 2a
1c
2
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Ts, R2 = Ph, X = Br (1a)
R1 = Bs R2 = Ph, X = Br (1b)
R1 = Ms, R2 = Ph, X = Cl (1c)
4a
4a
4b
4b
4c
4c
4a
4a
4a
4a
4a
4a
48
14
48
48
48
48
10
10
14
10
4
5a/99
5a/99
5b/n.d.
5b/99
5c/37
5c/52
5d/80
5e/85
5f/90
5g/81
5h/91
5i/82
R1 = Ts, R2 = 2-naphthyl, X = Br (1p)
2a
2a
2a
2b
2c
2d
2e
2f
R1 = Ts, R2 = 2-thiphenyl, X = Br (1q)
3c
4
R1 = Ts, R2 = Me, X = Cl (1r)
1a
1a
1a
1a
1a
1a
1a
1a
5c
6
7
8
9
10
11
12
R1 = Ts, R2 = 3-MeOC6H4, X = Br (1i)
R1 = Ts, R2 = 4-MeOC6H4, X = Br (1j)
R1 = Ts, R2 = 4-ClC6H5, X = Br (1l)
R1 = Ts, R2 = 3-NO2C6H5, X = Br (1n)
R1 = Ts, R2 = 2,4-Me2C6H3, X = Br
(1o)
2g
2h
1i
4
aUnless otherwise specified, the reactions were carried out with 1
(0.2 mmol), 2 (0.22 mmol,) and K2CO3 (0.6 mmol, 3 equiv.) in CHCl3
(6.0 mL) under nitrogen atmosphere at room temperature for the
13
4a
4
5j/52
aUnless otherwise specified, the reactions were carried out with 1
(0.2 mmol), 4 (0.22 mmol,) and DIPEA (0.6 mmol, 3 equiv.) in CHCl3
(6.0 mL) under nitrogen atmosphere at room temperature for the
specified time. bIsolated yield. cK2CO3 (3.0 equiv.) instead of the
DIPEA was used. Ts = Toluenesulfonyl; Bs = Benzenesulfonyl; Ms =
Methanesulfonyl. n.d. = not determined.
specified time. bIsolated yield. Ts
=
Toluenesulfonyl; Bs
=
t
Benzenesulfonyl; Ms = Methanesulfonyl; Boc = Butyloxycarboryl;
Cbz = Carbobenzyloxyl; Ac = Acetyl; Bz = Benzoyl
.
To extend the above methodology, we continued our
attempt to investigate the base-mediated reaction of α-halo
hydrazones with another type of cyclic pyridinium ylide, in situ
generated from indanone 2-pyridinium salts. As summarized in
Table 3, with K2CO3 and DIPEA as the base, the reaction of α-
To demonstrate the synthetic utility of the developed [4+1]
annulation between cyclic pyridinium ylides and azoalkenes in
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the generation of spiropyrazoline oxindoles, the reaction of 1a 432.1365 could be obviously detected and assiVgienwedArticalesOntlhinee
DOI: 10.1039/C9OB02733E
and 2a was scaled up to 2.73 mmol for 1a, which is 13.6 times spirocyclic product 3a (See ESI†).
larger than the scale of the model reaction in Table 1 entry 4.
Ts
N
As shown in Scheme 3, the gram-scale reaction proceeded well
N
under the standard conditions and afforded 3a in 95% yield.
This reaction suggests that the developed protocol has a good
prospect in the large-scale production.
A
azoalkenes intermediate
Ph
N
+
Ts
A
[
+H]
Ts
N
N
NH
Br
O
N
K2CO3 (3.0 equiv.)
CHCl3, N2, rt
48 h
O
+
Br
N
Ph
N
Me
3a
1.12 g, 95% yield
Me
2a
3.00 mmol, 0.92 g
(1) Program 1: 1a + 3.0 equivalents of K2CO3
1a
2.73 mmol, 1.0 g
Scheme 3 Scale-up synthesis of spiropyrazoline oxindole 3a
.
Ts
N
+
All the spiropyrazoline oxindoles 3 and spiropyrazoline
indanones 5 were unambiguously characterized by nuclear
magnetic resonance spectroscopy and high resolution mass
spectroscopy. Nevertheless, the structures of product 3s and
5a were further confirmed by single crystal X-ray analysis
(Figure 1).15
C
[
+H]
N
N
Ph
O
N
Me
intermediate
C
(2) Program 2: 1a + 3.0 equivalents of K2CO3 + 2a
Fig. 2 Species detected by ESI-MS analysis in different experimental
program.
Ph
N
Ts
N
On the basis of our experimental results and previous
related reports,5,10-12,16 a proposed reaction mechanism is
outlined in Scheme 4. In the presence of potassium carbonate,
the elimination reaction of α-halo hydrazones 1 takes place to
give azoalkene intermediate A. Meanwhile, the deprotonation
of oxindole 3-pyridinium salts 2 with K2CO3 occurs to generate
oxindole 3-pyridinium ylides B. And then, the conjugated
addition of intermediate B to intermediate A leads to the
formation of intermediate C. Subsequently, an intramolecular
annulation reaction occurs to generate the spirocyclic products
3 and then releases pyridine to complete the [4+1] annulation
process.
O
N
Et
3s
Ts
N
O
N
Ph
5a
R1
R1
NH
N
K2CO3
N
N
X
R1
N
Fig. 1 X-Ray crystallographic structures of 3s and 5a.
R2
R2
R2
N
N
A
R1
N
N
azoalkenes
N
-pyridine
O
R2
In order to get insight to the mechanism of the [4+1]
annulation reaction of cyclic pyridinium ylides with azoalkenes
we further investigated the reaction of 1a and 2a with the help of
ESI-MS experiments. When a 1:3 mixture of 1a and K2CO3 was
analyzed by ESI-MS, a peak at m/z 287.0853 was detected and it
can be assigned as azoalkenes intermediate A (Fig 2. (1)). This
O
N
N
Br
N
R3
,
R3
3
K2CO3
C
O
spiropyrazoline oxindoles
O
N
R3
B
[4+1] annulation
N
R3
cyclic pyridinium ylides
Scheme 4 Proposed reaction mechanism for the [4+1]
annulation
observation
led
us
to
propose
a
base-mediated
.
dehydrohalogenation process for the generation of azoalkenes
intermediate A from α-halo hydrazones. And then, adding oxindole
3-pyridinium salt 2a into the mixture, a peak at m/z 511.1780 was
clearly observed, and assigned as intermediate C (Fig 2. (2)). It
suggests that the intermolecular conjugate addition of oxindole 3-
pyridinium ylide B to azoalkene intermediate A takes place to form
intermediate C in the reaction system. Meanwhile, a peak at m/z
In summary, we have successfully designed oxindole 3-
pyridinium ylides and indanone 2-pyridinium ylides, and
further applied these cyclic pyridinium ylides in the reaction
with azoalkenes, in situ generated from α-halo hydrazones,
through a [4+1] annulation process to access structurally
diverse spirocyclic compounds. With the developed protocol, a
range of spiropyrazoline oxindoles could be smoothly obtained
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and C.-G. Yan, J. Comb. Chem., 2010, 12, 260; (c) A. Kumar, G.
in up to 99% yield under mild conditions with oxindole 3-
pyridinium ylides as C1 synthons. Likewise, many
spiropyrazoline indanones could be prepared in up to 99%
yield by using indanone 2-pyridinium ylides as C1 synthons.
Notably, this work represents the first example of cyclic
pyridinium ylides serving as C1 synthons for the efficient
construction of spirocyclic compounds. Studies to develop new
cyclic pyridinium ylides and use them in organic synthesis are
underway.
View Article Online
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for financial support from the National NSFC
(21572223, 21871252, and 21901024), the National Key R&D 9. For selected examples, see: (a) S. Kojima, K. Fujitomo, Y.
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DOI: 10.1039/C9OB02733E
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DOI: 10.1039/C9OB02733E
Graphic Abstract
Two new kinds of cyclic pyridinium ylides have been firstly designed and used in the reaction
with in situ generated azoalkenes to access spirocyclic compounds via [4+1] annulation process.