Hypervalent iodine(iii)-induced oxidative [4+2] annulation of o-phenylenediamines and electron-deficient alkynes: Direct synthesis of quinoxalines from alkyne substrates under metal-free conditions

Article abstract of DOI:10.1039/c3cc45469j

Hypervalent iodine(iii)-induced oxidative [4+2] annulation of o-phenylenediamines and electron-deficient alkynes under metal-free conditions has been developed. The reaction allows for direct access to quinoxalines bearing two electron-withdrawing groups in an efficient manner.

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ARTICLE TYPE
Hypervalent Iodine(III)-Induced Oxidative [4+2] Annulation of o-
Phenylenediamines and Electron-Deficient Alkynes: Direct Synthesis of
Quinoxalines from Alkyne Substrates under Metal-Free Conditions
Sota Okumura,a Youhei Takeda,*a,b Kensuke Kiyokawaa and Satoshi Minakata*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
40 subsequent nucleophilic attack on the highly electrophilic Nꢀ
center (NI2) by the resulting enamine could form dihydro
quinoxaline skeleton. The following elimination of HI would
produce quinoxalines. At the outset, we attempted the oxidative
annulation of oꢀphenylenediamine (1a) and DMAD (2a) as a
45 model reaction (Table 1). However, contrary to our preliminary
expectation, the results were disappointing: the treatment of an
equimolar mixture of 1a and 2a with tꢀBuOI (4 equiv) at –20 ˚C
gave cis,cisꢀmucononitrile (5) as a major product, which should
be formed through oxidative dearomatization and the following
50 C–C bond cleavage of the benzene core (entries 1 and 2).8 These
results clearly suggested that tꢀBuOI is not appropriate oxidant
for the aimed transformation, probably due to the rapid H–I
exchange and dearomatization processes of 1a prior to Michaelꢀ
addition. After extensive screening of iodineꢀcontaining reagents,
55 we were delighted to find that the employment of phenyliodine
diacetate (PIDA) was highly effective for the progression of the
desired annulation (entries 3–6). It should be noted that protecting
groupꢀfree phenylenediamines, which are usually labile to
oxidation reactions, were applicable to the annulation.
60 Hypervalent iodine(III) compounds have been emerging as
powerful reagents in organic synthesis due to their diverse
reactivity as well as to highꢀavailability and environmentallyꢀ
benign character.9 Specifically, PIDA and its derivatives have
been utilized to develop privileged oxidative C–N bond forming
65 reactions.10,11 Nonetheless, to the best of our knowledge,
hypervalent iodine(III)ꢀmediated oxidative annulation reaction
that leads to quinoxaline, has not been reported to date.12
Intriguingly, a significant solvent effect was observed (entries 3–
6): as the polarity of solvent increased, the yield of 3a was
70 enhanced while byꢀproduct 4a13 decreased.14 Other representative
hypervalent iodine(III) reagents were found ineffective for the
annulation (entries 7–10), and PIDA was indispensable for the
annulation reaction (entry 11).
Hypervalent iodine(III)-induced oxidative [4+2] annulation of
o-phenylenediamines and electron-deficient alkynes under
metal-free conditions has been developed. The reaction allows
10 for direct access to quinoxalines bearing two electron-
withdrawing groups in an efficient manner.
Quinoxaline derivatives not only constitute an important class of
biologically active agents,1 but also find tremendous applications
in materials science such as luminescent materials2 and lowꢀbandꢀ
15 gap polymers.3 Of the reported methods,4 the most widely used
approach involves condensation of oꢀphenylenediamines with
1,2ꢀdicarbonyl compounds bearing electronꢀrich or neutral
substituents, which are generally prepared by oxidation of
upstream alkynes (Scheme 1a). On the other hand, the synthetic
20 methods of the quinoxalines bearing electronꢀwithdrawing groups
(EWGs, e.g., –COR, –CO2R, –SO2R) have been poorly
explored,5 although such compounds can serve as promising
candidates for (opto)electronic materials5a,6 and as versatile
synthetic intermediates. Herein we present
a hypervalent
25 iodine(III) reagentꢀinduced oxidative [4+2] annulation of oꢀ
phenylenediamines and electronꢀdeficient alkynes (Scheme 1b),
which allows for direct access to electronꢀdeficient quinoxalines
from alkynes instead of diketo substrates in an efficient manner.
a) Classical Approach
R
R
[O]
NH2
NH2
R
N
N
R
R
O
O
+
condensation
R
(R = aryl or alkyl)
b) This Work
hypervalent
iodine(III)
EWG
EWG
NH2
NH2
N
N
EWG
EWG
+
• No Need to Pre-oxidize Alkynes
• Metal-Free and Mild Conditions
30 Scheme 1 Synthetic approaches to quinoxalines
Recently, we have reported an oxidative dimerization of
anilines through the agency of a unique and powerful iodinating
reagent, tertꢀbutyl hypoiodite (tꢀBuOI), leading to aromatic azo
compounds in an efficient and selective manner.7 The key to the
35 success is an efficient twoꢀfold iodination of nitrogenꢀcenter,
forming ArNI2 species which then serves as an electrophile to
form N–N bond. Based on the findings, we envisioned that a
tandem process consisting of i) the Michaelꢀaddition of oꢀ
phenylenediamine to an electronꢀdeficient alkyne and ii) a
Having optimized the reaction conditions, the scope of the
75 annulation was investigated (Table 2). A wide variety of diamines
bearing an electronꢀrich, ꢀneutral, and ꢀdeficient substituent
reacted with DMAD to give corresponding quinoxalines 3b–3j in
high yields. Multipleꢀsubstituted diamines afforded 3k and 3l.
Furthermore, sterically demanding diamine gave the
80 corresponding product 3m in excellent yield. Although the
reaction of naphthaleneꢀ2,3ꢀdiamine with DMAD required
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Table 1 Summary of the screening of the reaction conditionsa
Table 2 Scope of the oxidative [4+2] annulationa
PhI(OAc)2
(2 equiv)
H
N
R
EWG
Iodine-containing
Oxidant
NH2
NH2
NH2
NH2
N
N
R
R
O
N
EWG
EWG
CN
CN
+
+
+
+
R
R
R
DMF
–20 ˚C, 24 h
24 h
N
N
H
4a
R
EWG
2
(1 equiv)
1a
3
1
2a (1 equiv)
(R = CO2Me)
3a
5
N
N
CO2Me
CO2Me
Me
Cl
N
CO2Me
CO2Me
MeO
Br
N
N
CO2Me
CO2Me
CO2Me
Entry
Oxidant
(equiv)
Solvent
T
[˚C]
Yield [%]b
4a
3a
5
N
N
N
3a (92%)
N
3b (85%)
3c (97%)
1
2
3
4
5
6
7
8
tꢀBuOI (4)
tꢀBuOI (4)
THF
DME
CH2Cl2
THF
DME
DMF
DMF
DMF
–20
–20
–20
–20
–20
–20
–20
–20
12
2
5
63
60c
92c
3
0
0
64
33
0
F
CO2Me
CO2Me
CO2Me
N
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OCOCF3)2 (2)
40
18
4c
4c
–
N
CO2Me
N
3f (85%)
N
CO2Me
CO2Me
3d (94%)
3e (87%)
0
0
0
0
O
F3C
N
CO2Me
CO2Me
EtO2C
N
CO2Me
CO2Me
CO2Me
CO2Me
Ph
N
N
CO2Me
N
3h (80%)
N
3g (91%)
3i (95%)
N
PhI=O (2)
0
–
0
NC
N
CO2Me Me
CO2Me Me
Cl
Cl
CO2Me
CO2Me
HO
O
I
N
N
N
3j (89%)
3k (83%)
3l (76%)
O
9
DMF
–20
0
–
0
MeO2C
MeO2C
N
N
Me
N
CO2Me
CO2Me
N
CO2Me
CO2Me
N
N
CO2Me
CO2Me
(2)
N
10
11
PhI(OH)OTs (2)
–
DMF
DMF
–20
–20
0
0
–
21
0
0
N
3m (98%)
3n (56%)[c]
3o (71%)[d]
N
CO2n-Bu
O2N
N
CO2n-Bu
Cl
Cl
N
SO2Ph
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), and iodineꢀ
N
CO2n-Bu
N
CO2n-Bu
N
CO2Me
containing oxidant (0.50–1.0 mmol) were mixed in a solvent (3 mL) at
3p (77%)
3q (44%)[c]
3r (65%)
the temperature in the column and stirred for 24 h. 1H NMR yields.
b
c
5
Isolated yield.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.25 mmol), and PhI(OAc)2
(0.50 mmol) were mixed in DMF (3 mL) at –20 ˚C and stirred for 24 h. b
35 The values in parentheses indicate the yields of quinoxaline products.
Reaction time: 48 h. [d] [1,1'ꢀbiphenyl]ꢀ3,3',4,4'ꢀtetraamine (1o) (0.25
mmol), 2a (0.50 mmol), PhI(OAc)2 (1.0 mmol) were employed.
prolonged time, Nꢀheteroacene 3n, which constitutes a family of
electronꢀtransporting materials,15 was obtained in 56% yield.
Using the method, biquinoxanline 3o was prepared in good yield.
In respect to alkyne substrates, dibutyl acetylenedicarboxylate
c
Boc
10 was successfully applied to the reaction conditions to afford 3p
and 3q in 77% and 44% yield, respectively. In addition, an
unsymmetrical alkyne having an ester and a sulfonyl groups also
successfully underwent the annulation to give 3r in good yield.
Taking advantage of the ester functionality, 3a was diversely
15 derivatized into functionalized quinoxalines (Scheme 2). For
example, diester of 3a easily underwent hydrolysis to give
dicarboxylic acid 6 in high yield, which was further efficiently
converted to 7 by dehydration. Moreover, anhydride 7 was
successfully transformed into imideꢀfused quinoxaline 8 by the
20 condensation with pꢀtoluidine, which is an Nꢀanalogue of
triboluminescent material.16 It is noted that such compounds are
quite difficult to prepare by traditional condensation method.17
O
N
CO2Me
CO2Me
NHBoc
NH
PhI(OAc)2 (2 equiv)
CF3COOH (1 equiv)
T = –20 ˚C
N
10 (45%)
DMF, T, 24 h
CO2Me
MeO2C
3a (54%)
T = 25 ˚C
9
Scheme 3 Oxidative cyclization of enamine 9
40 of PIDA. In contrast, at room temperature, quinoxaline 3a was
obtained in 54% yield. In conjunction with the fact that DMAD
does not react with PIDA in the absence of oꢀphenylenediamine,
the most likely intermediate of the annulation would be the
deprotected counterpart of the Michaelꢀadduct 9 as preliminary
45 assumed.
On the basis of the experimental results and accumulated
literature knowledge about hypervalent iodine(III)ꢀmediated
oxidative C–N bond forming reactions using enamine
substrates,20–22 conceivable reaction pathways are illustrated in
50 Scheme 4. The reaction would start with Michael addition of oꢀ
phenylenediamine to DMAD, forming enamine intermediate A,
which has three possible reactive points when react with PIDA,
namely, βꢀcarbon of enamine (a),20 enamine nitrogen (b),21 and
nitrogen on the benzene moiety (c).22 Accordingly, three species
55 should be extrapolated as intermediates prior to cyclization: i) αꢀ
iodo(III) imine B (route a); ii), iii) enamines C and D (route b
and c, respectively). Successive cyclizative nucleophilic
substitution on the iodineꢀattached sp3ꢀcarbon (from B), on the
enamine carbon in a pseudoꢀSN2’ manner (from C), or on the
60 electrophilic Nꢀcenter (from D) would provide common
intermediate E. Oxidative aromatization of E with another
equivalent of PIDA should lead to quinoxaline F. Ma and Lei
N
CO2H
N
aq. NaOH (1 M)
3a
O
reflux, 12 h
Ac2O
reflux, 3 h
N
CO2H
N
7
O
6
94%
93%
(COCl)2 (1.2 equiv)
pyridine (3 equiv)
O
N
p-toluidine
(1 equiv)
N
Me
THF
40 °C, 3 h
reflux, 16 h
N
O
8
55%
N-analogue of triboluminescent material
Scheme 2 Derivatization of 3a
25
To investigate the reaction pathways, several experiments were
conducted as follows: enamine 9, which was readily prepared by
the Michaelꢀaddition of NꢀBocꢀprotected o-phenylenediamine to
DMAD,13 was treated with PIDA in the presence of
trifluoroacetic acid (Scheme 3).18 At –20 ˚C, 9 underwent
30 oxidative cyclization to give NꢀBoc dihydro quinoxaline 10 in
45% yield,19 while 9 was quantitatively recovered in the absence
2
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reported an oxidative dimerization of aromatic amines using
PIDA to give azobenezenes.22 No azo compounds were detected
in our system, suggesting that the pathway via intermediacy of D
(route c) might be excluded. On one hand, according to the
reactivity of carbonylꢀconjugated enamines (i.e., enaminones),23
electrophilic reagents, including iodine electrophiles such as
BTMA•ICl2,24a I(Py)2BF4,24b and CF3CH2I(OH)(OTs),24c react
exclusively at the enamine βꢀcarbon. Taken together, we believe
that the most likely reaction pathway is route a, although routes
45
50
55
60
5
5
6
7
10 b, c, and other possible pathways cannot be excluded
completely.25
NH2
c
NH2
NH2
R
8
9
+
NH
b
R
R
a
R
A
(R = CO2Me)
PhI(OAc)2
route c
route a
route b
Ph
OAc
NH2
I
NH2
65 10 For a review, see: M. A. Ciufolini, N. A. Braun, S. Canesi, M.
Ousmer, J. Chang and D. Chai, Synthesis, 2007, 3759.
11 For recent examples, see: (a) J. A. Souto, D. Zian and K. Muñiz, J.
Am. Chem. Soc., 2012, 134, 7242; (b) C. Röben, J. A. Souto, Y.
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R
NH
NH
N
N
R
R
R
I
R
I
Ph
OAc
Ph
OAc
R
B
C
D
70
75
80
85
2011, 50, 9478; (c) A. A. Kantak, S. Potavathri, R. A. Barham, K. M.
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H
N
R PhI(OAc)2
R
N
N
R
R
N
E
F
Scheme 4 Conceivable reaction pathways
12 Twoꢀstep synthesis of quinoxalines through hypervalent iodine(III)ꢀ
mediated oxidation of alkynes and condensation of the resultant
diketones with diamines has been reported: M. Tingoli, M. Mazzella,
B. Panunzi and A. Tuzi, Eur. J. Org. Chem., 2011, 399.
13 G. Choudhary and R. K. Peddinti, Green Chem., 2011, 13, 3290.
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Conclusions
15 In summary, a simple, efficient and metalꢀfree synthesis of
electronꢀdeficient quinoxalines through oxidative annulation of oꢀ
phenylenediamines and alkynes has been developed. Further
investigations into mechanism and application to the construction
of functional materials are currently underway in our laboratory.
17 L. HanainehꢀAbdelnour, S. Bayyuk and R. Theodorie, Tetrahedron,
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20 Notes and references
90 18 Although we have tried preparation of the Michaelꢀadduct starting
from 1a (deprotection form of 9) by a similar method reported in ref
13, it failed only to produce 4a alone. Trifluoroacetic acid was added
for the purpose of detaching the Boc group of resulting intermediates.
19 The deprotected counterpart of 9 was not formed at all.
a Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Yamaoka 2-1, Suita, Osaka 565-0871, Japan. Fax:
+81-6-6879-7402; Tel: +81-6-6879-7400; E-mail:
minakata@chem.eng.osaka-u.ac.jp
25 b Frontier Research Base for Global Young Researchers, Graduate
School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka
565-0871, Japan. E-mail: takeda@chem.eng.osaka-u.ac.jp
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† Electronic Supplementary Information (ESI) availabe: Procedure for
the synthesis and experimental data for quinoxalines, NMR spectra. See
30 DOI: 10.1039/b000000x/
‡ This research was partly supported by a research Grant from the
Ogasawara Foundation for the Promotion of Science & Engineering (to
Y.T.), by a GrantꢀinꢀAid for Scientific Research (B) from the JSPS, Japan
(No. 25288047, to S.M.), and by a research Grant from the Nagase
35 Science and Technology Foundation (to S.M.). Also, Y.T. acknowledges
all support from the Frontier Research Base for Global Young
Researchers, Osaka University, from the Program of MEXT.
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25 DielsꢀAlder reacion of oxidatively generated 1,2ꢀdiimines and
DMAD might be possible, although the matching of the frontier
orbitals of these substrates are less likely to be favorable.
4
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