A Deoxygenative [4+1] Annulation Involving N-Acyldiazenes for an Efficient Synthesis of 2,2,5-Trisubstituted 1,3,4-Oxadiazole Derivatives

Article abstract of DOI:10.1002/adsc.201700935

An unprecedented and highly efficient tris(dimethylamino)phosphine [P(NMe₂)₃]-mediated deoxygenative [4 + 1] annulation of N-acyldiazenes with α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones is reported. The annulation reactions proceed smoothly under mild conditions to deliver a broad range of 2,2,5-trisubstituted 1,3,4-oxadiazole derivatives in moderate to excellent yields from readily available starting materials. It represents the first realization of the [4+1] annulation mode involving N-acyldiazenes to construct five-membered heterocycles. (Figure presented.).

Full text of DOI:10.1002/adsc.201700935

Title: A Deoxygenative [4 + 1] Annulation Involving N-Acyldiazenes
for Efficient Synthesis of 2,2,5-Trisubstituted 1,3,4-Oxadiazole
Derivatives
Authors: Rong Zhou, Ling Han, Honghui Zhang, Rongfang Liu, and
Ruifeng Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700935
Link to VoR: http://dx.doi.org/10.1002/adsc.201700935

10.1002/adsc.201700935
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Deoxygenative [4 + 1] Annulation Involving N-Acyldiazenes
for Efficient Synthesis of 2,2,5-Trisubstituted 1,3,4-Oxadiazole
Derivatives
Rong Zhou,*a Ling Han,a Honghui Zhang,a Rongfang Liu,*a and Ruifeng Lia
a
College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan, 030024, P. R. China
Phone: (+ 86)-351-6018564; e-mail: zhourong@tyut.edu.cn; liurongfang0060@link.tyut.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: An unprecedented highly efficient P(NMe2)3 It represents the first realization of [4 + 1] annulation mode
[tris(dimethylamino)phosphine]-mediated deoxygenative [4 involving N-acyldiazenes to construct five-membered
+ 1] annulation of N-acyldiazenes with -dicarbonyl heterocycles.
compounds such as isatins, -keto esters, and -diketones is
reported. The annulation reactions proceed smoothly under
mild conditions to deliver a broad range of 2,2,5-
trisubstituted 1,3,4-oxadiazole derivatives in moderate to
excellent yields from readily available starting materials.
Keywords: [4 + 1] annulation; phosphine; N-acyldiazenes;
-dicarbonyl compounds; 1,3,4-oxadiazoles
development of a practical synthetic strategy with
broad scope under mild conditions for oxadiazoles,
especially 2,2,5-trisubstituted 1,3,4-oxadiazoles, is
therefore highly desirable.
Introduction
Five-membered heterocycles are ubiquitous structural
motifs in natural products, biologically active
compounds, as well as functional molecules.[1] 1,3,4-
Oxadiazole represents one of the most frequently
encountered heterocycles in bioactive molecules and
advanced materials (Figure 1). For example,
marketed antibiotics such as Furamizole,[2] and HIV-
integrase inhibitor Raltegravir[3] contain the
oxadiazole nucleus. In addition, the chitin synthase
inhibitor, compound DOW416 is also based on the
oxadiazole moiety.[4] Other compounds with an
oxadiazole core have also exhibited a variety of
biological
properties
such
as
antitumor,[5]
antimicrobial,[6] antifungal and MAO inhibitory
activities.[7] Furthermore, the 1,3,4-oxadiazoles are
widely used in the construction of electroluminescent
and electron-transport materials.[8] The development
of synthetic methods for 1,3,4-oxadiazoles has
therefore attracted intensive interest from chemists
due to their broad bioactivities and utilities. A
number of synthetic approaches have been
established during the past decade,[1d,9] but the
reported methodologies usually require harsh reaction
conditions or have limited substrates scope.[1d,9a]
Moreover, the majority of the existing synthetic
methods are centered upon 2,5-disubstituted 1,3,4-
Figure 1. Selected bioactive and functional molecules
containing a 1,3,4-oxadiazole core.
N-Acyldiazenes are an important class of diazenes
with distinct reactivity. Recent reports unveiled that
N-acyldiazenes could serve as good synthons for [2 +
3] and [4 + 2] annulations.[10-13] In 2008, Scheidt and
oxadiazoles,[1d,9]
methodologies
and
efficient
synthetic
1,3,4-
to
2,2,5-trisubstituted
co-workers reported
(NHC)-catalyzed [2
a
N-heterocyclic carbenes
3] cyclization of N-
oxadiazoles thus far have been underdeveloped
although they have comparable bioactivities as that of
+
acyldiazenes with ,-unsaturated aldehydes,
2,5-disubstituted
1,3,4-oxadiazoles.[5-7]
The
affording pyrazolidinones (Scheme 1, eq a).[10] The
1
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10.1002/adsc.201700935
Advanced Synthesis & Catalysis
Table 1. Survey of reaction conditions.[a]
NHC-catalyzed [4 + 2] annulations of N-acyldiazenes
with ketenes or -chloroaldehydes leading to 1,3,4-
oxadiazin-6-ones were subsequently demonstrated by
Ye[11] and Zhong,[12] respectively (Scheme 1, eq b and
c). Recently, Wang and co-workers developed a
DMAP-catalyzed [4 + 2] cycloaddition between N-
acyldiazenes and allenoates, providing direct access
to 1,3,4-oxadiazines (Scheme 1, eq d).[13] These
reactions exhibit distinct annulation reactivity
patterns of N-acyldiazenes in preparation of
heterocycles. However, a [4 + 1] annulation mode
involving N-acyldiazenes for constructing five-
membered heterocycles has by far never been
realized, particularly under the influence of
phosphines.[14] Considering the broad bioactivities
and utilities of 1,3,4-oxadiazoles,[2-7] and also as part
of our continuous research efforts in exploring the
reactivity patterns of Kukhtin-Ramirez adducts
obtained from trivalent phosphorus reagents and -
dicarbonyl compounds,[15] we envisioned that a
deoxygenative [4 + 1] annulation between N-
acyldiazenes and Kukhtin-Ramirez adducts would be
feasible to deliver the 1,3,4-oxadiazoles (Scheme 1,
eq e). Herein, we report an unprecedented P(NMe2)3-
mediated deoxygenative [4 + 1] annulation of N-
acyldiazenes with -dicarbonyl compounds such as
isatins, -keto esters, and -diketones, leading to a
practical synthesis of a board range of 2,2,5-
trisubstituted 1,3,4-oxadiazoles in moderate to
excellent yields under mild conditions. It also
represents the first realization of [4 + 1] annulation
mode involving N-acyldiazenes to construct five-
membered heterocycles.
Entry Isatin Solvent
PR'3
Yield
(%)[b]
2
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CHCl3
Toluene
CH3CN
P(NMe2)3 3aa, 54
P(OMe)3 3aa, 0
PPh3
PBu3
P(NMe2)3 3aa, 33
P(NMe2)3 3aa, 37
P(NMe2)3 3aa, 24
P(NMe2)3 3aa, 60
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
3aa, 29
3aa, 13
9
10
11
CH2Cl2/ CH3CN P(NMe2)3 3aa, 66[c]
CH2Cl2/ CH3CN P(NMe2)3 3ab, 45[c]
CH2Cl2/ CH3CN P(NMe2)3 3ac, 43[c]
CH2Cl2/ CH3CN P(NMe2)3 3aa, 47[d]
12
[a]
Reaction conditions: N-benzoyldiazene 1a (0.4 mmol),
isatin 2 (0.2 mmol), PR'3 (0.22 mmol), and 4Å molecular
sieves in solvent (2.0 mL), -78 oC to r.t., 12 h.
[b] Isolated yield based on 2.
[c] V(CH2Cl2):V(CH3CN) = 1:1.
[d] The reaction was conducted from 0 oC to r.t.
We initially attempted the annulation reaction by
treating N-benzoyldiazene 1a with isatin 2a in the
presence of P(NMe2)3 under the predetermined
conditions listed in Table 1. To our delight, a
deoxygenative [4 + 1] annulation reaction between 1a
and 2a occurred as expected, affording the
spirooxindole-1,3,4-oxadiazole 3aa in 54% isolated
yield (entry 1). The structure of compound 3aa was
unambiguous confirmed by X-ray crystallographic
analysis (CCDC 1562365).[16] This result therefore
demonstrates the first [4 + 1] annulation involving N-
acyldiazenes and also provides a novel approach to
1,3,4-oxadiazoles. Optimization of the reaction
conditions was subsequently conducted to improve
the reaction efficiency. Screening of several trivalent
phosphorus reagents indicated that P(NMe2)3 was the
optimal phosphorus reagent for the reaction.
Phosphite such as P(OMe)3 was ineffective, and
phosphines such as PPh3 and PBu3 both gave inferior
results (entries 2-4). Among several common solvents
including CH2Cl2, THF, CHCl3, toluene, and CH3CN
surveyed, CH3CN afforded the best result although
o
the reaction mixture solidified at – 78 C due to the
relatively higher melting point of CH3CN (entries 5-
8). The yield of 3aa was further improved by
adopting a mixture of CH2Cl2 and CH3CN (V/V =
1:1) as the reaction medium (entry 9). The influence
of substituent R on the nitrogen atom of isatin 2 was
examined as well. Although changing the substituent
R from an allyl group to a benzyl or a methyl group
was all feasible, the corresponding products were
afforded in relatively lower yields (entries 10 and 11).
Scheme 1. Different annulation modes involving N-
acyldiazenes.
Results and Discussion
2
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10.1002/adsc.201700935
Advanced Synthesis & Catalysis
[a]
The N-allyl isatins were therefore chosen for further
investigations. It was found that the yield of 3aa
decreased when elevating the initial reaction
temperature to 0 oC(entry 12).
Reaction conditions: N-acyldiazene 1 (0.4 mmol), isatin
2 (0.2 mmol), P(NMe2)3 (0.22 mmol), and 4Å molecular
sieves in CH2Cl2/CH3CN (2.0 mL, V/V 1:1), -78 oC to r.t.
[b] Isolated yield based on 2.
Having identified the optimal conditions in hand,
we sought to explore the scope of the annulation
reaction (Table 2). A variety of isatins with different
substituent on the benzene ring of the oxindole
framework were first investigated with representative
diazene 1a. As showed in Table 2, both electron-
donating and electron-withdrawing substituted isatins
proceeded smoothly to give the corresponding [4 + 1]
annulation products in moderate to excellent yields
with diazene 1a (entries 1-9). Experiments to
investigate the scope of diazenes 1 unveiled that aryl
substituted diazenes with either electron-rich,
electron-poor, or heteroaryl group on their
substituents R1 and R2 were well tolerated. In the
examined cases, the [4 + 1] annulation reactions of
diazenes 1b-k with isatin 2i uneventfully afforded the
corresponding spirooxindole-1,3,4-oxadiazoles in
good to excellent yields (entries 10-19).
We further expanded this protocol to other types of
-dicarbonyl compounds such as -keto esters and -
diketones (Table 3). Under the standard conditions,
ethyl aroylformates bearing either electron-rich or
electron-poor aryl groups participated in the [4 + 1]
annulation reactions smoothly with diazenes 1
bearing different electronic properties, delivering the
corresponding 2,2,5-trisubstituted 1,3,4-oxadiazoles 5
in moderate to excellent yields (entries 1-6). -
Diketones including benzil, acenaphthoquinone, and
aceanthrenequinone were all demonstrated to be
reliable substrates for this [4 + 1] annulation to afford
the corresponding products in moderate to good
yields with diazene 1a (entries 7-9).
The structures of compounds 3 and 5 were fully
characterized by 1H, 13C NMR and HRMS-
ESI/MALDI measurements, and further confirmed by
single crystal X-ray diffraction analysis of
representative compound 3aa.[16] This deoxygenative
[4 + 1] annulation proceeds smoothly under mild
conditions using readily available N-acyldiazenes and
-dicarbonyl compounds, and particularly exhibiting
a broad substrates scope, which makes it an efficient
protocol for 2,2,5-trisubstituted 1,3,4-oxadiazoles.
Table 2. [4 + 1] Annulation of N-acyldiazenes 1 and
isatins 2.[a]
Table 3. [4 + 1] Annulation of N-acyldiazenes 1 with -
keto esters and -diketones 4.[a]
Entry R1, R2 in 1
R5 in 2
Time Yield
(h)
(%)[b]
1
2
3
4
5
6
7
8
Ph, Ph (1a)
1a
1a
1a
1a
1a
1a
1a
H (2a)
12
8
4
11
12
8
11
11
21
11
3aa, 66
3ad, 58
3ae, 46
3af, 93
3ag, 35
3ah, 55
3ai, 99
3aj, 49
3ak, 42
3bi, 94
5-Me (2d)
5-OMe (2e)
4-Br (2f)
5-Br (2g)
6-Br (2h)
4-Cl (2i)
5-Cl (2j)
5-NO2 (2k)
2i
Entry R1, R2 in 1
R3, R4 in 4
Time Yield
(h)
(%)[b]
1
2
Ph, Ph (1a)
Ph, 4MeC6H4
(1b)
Ph, OEt (4a)
4a
8
11
5aa, 86
5ba, 78
9
10
1a
Ph, 4-MeC6H4
(1b)
3
4
5
6
Ph, 4-ClC6H4
(1d)
Ph, 2-Thienyl
(1g)
10
11
8
5da, 49
5ga, 81
5ab, 95
5ac, 85
4a
4a
11
12
13
14
15
16
17
18
19
Ph, 4-MeOC6H4
(1c)
Ph, 4-ClC6H4
(1d)
Ph, 4-BrC6H4
(1e)
Ph, 2-Furyl
(1f)
Ph, 2-Thienyl
(1g)
4-MeC6H4, Ph
(1h)
4-BrC6H4, Ph
(1i)
4-ClC6H4, Ph
(1j)
10
11
11
11
11
8
3ci, 97
3di, 77
3ei, 80
3fi, 94
3gi, 93
3hi, 89
3ii, 51
3ji, 51
3ki, 78
2i
2i
2i
2i
2i
2i
2i
2i
2i
4-MeC6H4, OEt
(4b)
4-BrC6H4, OEt
(4c)
Ph, Ph (4d)
Acenaphthoquin
one (4e)
Aceanthrenequi
none (4f)
1a
8
1a
7
8
8
9
5ad, 84
5ae, 53
1a
1a
9
8
5af, 43
1a
11
12
12
[a]
Reaction conditions: N-acyldiazene 1 (0.4 mmol), -
dicarbonyl compounds 4 (0.2 mmol), P(NMe2)3 (0.22
mmol), and 4Å molecular sieves in CH2Cl2/CH3CN (2.0
mL, V/V 1:1), -78 oC to r.t.
4-CF3C6H4, Ph
(1k)
[b] Isolated yield based on 4.
3
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10.1002/adsc.201700935
Advanced Synthesis & Catalysis
Experimental Section
Based on the experimental results above and the
most related reports from our group[15] and others,[17]
a proposed mechanism to account for the formation
of 1,3,4-oxadiazole derivatives was depicted in
Scheme 2. The initial step involves the addition of
P(NMe2)3 to -dicarbonyl compound, forming the
Kukhtin-Ramirez adduct A, which is presumably in
equilibrium with dipole B.[15] Through its dipolar
structure B, the Kukhtin-Ramirez adduct can then
trigger a Michael addition to diazene 1 to generate the
intermediate C. Subsequently, the intermediate C
undergoes an intramolecular substitution through its
less hindered oxygen anion to afford the product
oxadiazole and release the phosphoric triamide
byproduct. The existence of two adjacent carbonyl
groups in the substrate is essential for the initial
Kukhtin-Ramirez addition step to form the five-
membered 1,3,2-dioxaphospholene adduct A, which
then can trigger the annulation via its dipolar format
B. Employing other types of activated carbonyl
compounds with only one carbonyl group such as
2,2,2-trifluoroacetophenone and benzoyl cyanide
failed to give the desired [4 + 1] annulation products
with representative diazene 1a under the standard
reaction conditions.
General Information
Unless otherwise noted, all reactions were carried out in
nitrogen atmosphere under anhydrous conditions. All
solvents were purified according to standard procedures.
1H and 13C NMR spectra were recorded in C6D6 with
tetramethylsilane (TMS) as the internal standard. Column
chromatography was performed on silica gel (200  300
mesh) using a mixture of petroleum ether/ethyl acetate as
eluant. N-Acyldiazenes 1,[18] isatins 2,[19] and ethyl
aroylformates 4[20] were prepared according to the
literature procedures.
Typical Procedure for the [4 + 1] Annulation
between N-Acyldiazenes 1 and -Dicarbonyl
Compounds 2 or 4
Under a N2 atmosphere, to a solution of N-acyldiazene 1
(0.4 mmol), -dicarbonyl compound 2 or 4 (0.2 mmol),
and 4Å molecular (150 mg) in a mixture of CH2Cl2 (1.0
mL) and acetonitrile (0.5 mL) was added P(NMe2)3 (40 L,
0.22 mmol) in acetonitrile (0.5 mL) dropwise by means of
o
syringe at -78 C. The resulting reaction mixture was then
slowly warmed up to room temperature and stirred at r.t.
until the -dicarbonyl compound was completely
consumed, as monitored by TLC. The solvent was
removed on a rotary evaporator under reduced pressure
and the residue was subjected to column chromatographic
isolation on silica gel by gradient elution using petroleum
ether /ethyl acetate (20:1  3:1) to give the annulation
product 3 or 5.
1-Allyl-3',5'-diphenyl-3'H-spiro[indoline-3,2'-
[1,3,4]oxadiazol]-2-one (3aa). Table 1, entry 9; prepared
according
to
the
typical
procedure,
(E)-
phenyl(phenyldiazenyl)methanone 1a (84 mg, 0.4 mmol)
and N-allylic isatin 2a (37.4 mg, 0.2 mmol) were employed
to give 3aa (50 mg, 66%) as a yellow solid; mp: 103-105
oC; 1H NMR (400 MHz, C6D6) δ 8.01 – 7.83 (m, 2H), 7.24
– 7.18 (m, 3H), 7.05 – 6.98 (m, 5H), 6.95 (td, J = 7.8, 1.3
Hz, 1H), 6.80 – 6.62 (m, 2H), 6.40 (d, J = 7.9 Hz, 1H),
5.40 (ddt, J = 17.1, 10.5, 5.4 Hz, 1H), 4.90 (dddd, J = 27.2,
10.3, 2.6, 1.4 Hz, 2H), 3.98 (ddt, J = 16.2, 5.0, 1.7 Hz, 1H),
3.69 (ddt, J = 16.2, 5.7, 1.4 Hz, 1H); 13C NMR (101 MHz,
C6D6) δ 169.7, 152.8, 144.1, 143.4, 132.1, 131.0, 130.5,
129.4, 128.7, 126.8, 126.4, 125.6, 124.5, 123.7, 121.7,
117.9, 115.5, 110.1, 95.7, 42.2; HRMSESI ([M + H]+)
Calcd for C24H20N3O2 382.1550, found 382.1544.
Scheme 2. Proposed mechanism for the formation of 1,3,4-
oxadiazole.
Conclusion
Acknowledgements
In summary, we have demonstrated an unprecedented
P(NMe2)3-mediated deoxygenative [4 + 1] annulation
of N-acyldiazenes with -dicarbonyl compounds,
which provides a highly efficient synthesis of 2,2,5-
Financial support from National Natural Science Foundation of
China (Grant No. 21502135) is gratefully acknowledged.
trisubstituted 1,3,4-oxadiazole
derivatives. It
represents the first realization of [4 + 1] annulation
mode involving N-acyldiazenes to prepare five-
membered heterocycles. Features of this annulation
include mild conditions, readily available starting
materials, as well as broad substrates scope. This
work, together with previous reports from our group
and others,[15,17] demonstrates the versatility of
Kukhtin-Ramirez adduct serving as a new type of
dipolar synthon in organophosphorus chemistry.
Future efforts will be directly toward application of
this methodology for synthesis of pharmaceutically
intriguing compounds.
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10.1002/adsc.201700935
Advanced Synthesis & Catalysis
FULL PAPER
A Deoxygenative [4 + 1] Annulation Involving N-
Acyldiazenes for Efficient Synthesis of 2,2,5-
Trisubstituted 1,3,4-Oxadiazole Derivatives
Adv. Synth. Catal. 2017, Volume, Page – Page
Rong Zhou,* Ling Han, Honghui Zhang, Rongfang
Liu,* Ruifeng Li
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