A novel sodium nitrite-catalyzed oxidative coupling for constructing polymethoxyphenanthrene rings

Article abstract of DOI:10.1002/adsc.201100578

An efficient and green oxidative coupling for the direct construction of polymethoxyphenanthrene rings has been developed, which uses environment-friendly sodium nitrite as catalyst and oxygen as terminal oxidant. This methodology also provides an alterna

Full text of DOI:10.1002/adsc.201100578

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DOI: 10.1002/adsc.201100578
A Novel Sodium Nitrite-Catalyzed Oxidative Coupling for
Constructing Polymethoxyphenanthrene Rings
Bo Su,a Ling Li,a Yanna Hu,a Yuxiu Liu,a and Qingmin Wanga,*
a
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, Peopleꢀs Republic of China
E-mail: wang98h@263.net or wangqm@nankai.edu.cn
Received: July 21, 2011; Revised: September 25, 2011; Published online: January 19, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100578.
Abstract: An efficient and green oxidative coupling
for the direct construction of polymethoxyphenan-
threne rings has been developed, which uses envi-
ronment-friendly sodium nitrite as catalyst and
oxygen as terminal oxidant. This methodology also
provides an alternative possibility for forming biaryl
products.
monly used for constructing phenanthrene ring.[3,4]
However, these reactions need prefunctionalized sub-
strates which, to a large extent, limited their applica-
tions. Direct oxidative coupling of two unfunctional-
lized arenes to form biaryls and a phenanthrene ring
would be much more attractive when taking the sim-
plicity of manual work, availability of starting materi-
als, and atom efficiency into consideration. Several
direct oxidative coupling reagents have been devel-
Keywords: biaryl products; oxidative coupling reac-
tion; phenanthroindolizidines; polymethoxyphenan-
threnes; sodium nitrite
oped, which include thallium
ACHTUNGTRENNUNG
(TTFA),[5] lead(IV) tetraacetate [Pb
AHCTUNGTRENNUNG
dium oxytrifluoride (VOF3) or vanadium oxytrichlor-
ide (VOCl3),[7] hypervalent iodine,[8] and 2,3-dichloro-
5,6-dicyanobenzoquinone
excess amounts of oxidative reagents (at least stoi-
(DDQ).[9] However, large
ACHTUNGTRENNUNG
Phenanthrene ring derivatives and biaryl linkages chiometric equivalent), high toxicity, severe condi-
widely exist in natural products, pharmaceuticals, tions, and/or low yields, also largely limit their appli-
agrochemicals, dyes, organic materials, and many cations. Recently, we applied the less toxic iron
ACHTUNGTRENNUNG(III)
other important organic molecules.[1] Among them chloride (3.5 equiv.) and catalytic iron
AHCTUNGTRENNUNG
polymethoxy-substituted phenanthroindolizidine and (together with 1 equiv. of m-CPBA) for the construc-
phenanthroquinolizidine alkaloids (Figure 1) exhibit tion of a phenanthrene ring and biaryls,[10] which
many interesting and potent pharmacological activi- partly solved the problems. Nevertheless, the develop-
ties.[2] In the past decades, radical cyclization and tran- ment of a more greener and efficient method for the
sition metal-catalyzed coupling reactions were com- construction of the phenanthrene ring is still in high
demand.
NO+ is a remarkable and diverse reagent, which is
commonly applied in nitrosation,[11] nitration,[12] oxy-
genation,[13] and addition to alkenes to yield oximes,
isooxazolines and imidazoles[14]. NO+ is also a rather
strong one-electron oxidant (1.5 V vs. SCE) and this
had led to its use in the formation of cation radical in-
termediates.[15] Using NO+ as catalyst, Neumann and
co-workers reported the alkylation of arenes with al-
kenes,[16] and Tanaka and colleagues reported the cou-
pling of naphthalene derivatives[17]. It is well known
that NO+ could be easily produced by treatment of
NaNO2 with a Brønsted acid. Inspired by these re-
ports, we envisioned that NaNO2 could be applied to
Figure 1. Representatives of phenanthroindolizidine and
phenanthroquinolizidine alkaloids.
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383

Bo Su et al.
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the oxidative coupling reaction for constructing the tions much milder and to decrease the by-products,
phenanthrene ring. different solvents were screened (Table 1, entries 6–
Herein, we wish to report the first NaNO2-cata- 13). Among these solvents, only CH2Cl2 and CH3CN
lyzed oxidative coupling reaction for construction of could give the coupled product 2a. Extensive investi-
the phenanthrene ring using O2 as terminal oxidant.
gation (entries 12–21) showed that a 99% yield of the
Due to the importance of polymethoxyphenan- desired product 2a was obtained when the reaction
threne derivatives in the natural product field, espe- was performed in TFA/CH3CN (1:4), at 08C and 20%
cially in the synthesis phenanthroindolizidine and NaNO2 (entry 17). It is worth noting that when the re-
phenanthroquinolizidine alkaloids, methyl-(E)-2,3- action was carried at room temperature, no significant
bis(3,4-dimethoxyphenyl)acrylate 1a was selected to increase of the by-products was observed (entries 19
investigate suitable reaction conditions for the intra- and 20). Entries 22–24 show that O2 is the terminal
molecular oxidative coupling reaction. The results are oxidant in the reaction, and NaNO2 is indispensable.
summarized in Table 1.
The concentration effect on the coupling reaction is
The desired product 2a was obtained in 85% yield not very significant, and the corresponding data are
when 0.05 equivalents of NaNO2 in TFA was used in summarized in the Supporting Information (Table 1).
the presence of air (Table 1, entry 5). With increasing
With the optimal reaction conditions in hand, we
amounts of NaNO2, complex by-products increased started to study the substrate scope. Firstly, we inves-
drastically (entries 1–5). To make the reaction condi- tigated the effects of the substitutes at the double
Table 1. Optimization study of the NaNO2-catalyzed intramolecular coupling reaction.[a]
Entry
NaNO2 (equiv.)
Solvent (10 mL)
Temperature [8C]
Time [min]
Conversion[b] [%]
Yield[b] [%]
1
2
3
4
5
6
7
8
1
TFA
TFA
TFA
TFA
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
15
15
15
15
15
30
30
30
30
30
30
30
15
15
15
15
30
60
15
15
15
15
15
15
98
100
100
100
99
12
8
0
0
0
0
100
100
100
93
84
100
12
100
100
63
100
0
24
34
31
69
85
0
0
0
0
0
0.5
0.2
0.1
0.05
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.2
0.2
0.2
0.2
0.1
0.05
0.2
0
TFA
TFA/THF (1:1)
TFA/AcOEt (1:1)
TFA/dioxane (1:1)
TFA/acetone (1:1)
TFA/EtOH (1:1)
TFA/DMSO (1:1)
TFA/CH2Cl2 (1:1)
TFA/CH3CN (1:1)
TFA/CH2Cl2 (1:4)
TFA/CH2Cl2 (1:9)
TFA/CH3CN (1:4)
TFA/CH3CN (1:4)
TFA/CH3CN (1:9)
TFA/CH3CN (1:4)
TFA/CH3CN (1:4)
TFA/CH3CN (1:4)
TFA/CH3CN (1:4)
TFA/CH3CN (1:4)
TFA/CH3CN (1:4)
9
10
11
12
13
14
15
16
17
18
19
20
21
22[c]
23[c]
24[d]
0
66
68
87
93
82
99
12
96
94
58
99
0
0
0
r.t.
r.t.
r.t.
0
0
0
0.2
39
39
[a]
General reaction conditions: 1a (180 mg, 0.5 mmol); under an atmosphere of air unless noted.
Conversion and yield were determined by HPLC.
Reaction was carried out under an atmosphere of O2.
[b]
[c]
[d]
Reaction was carried out under an atmosphere of Ar.
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A Novel Sodium Nitrite-Catalyzed Oxidative Coupling for Constructing Polymethoxyphenanthrene
Table 2. Effects of substituents at the double bond on the re-
agents (such as FeCl3, MnO2, m-CPBA and so on)
could not give the coupled product. When R is a poor
electron-donating group (entry 8), only 29% of the
coupled product was obtained and the other part of
the substrate converted to unindentifiable com-
pounds, which is believed to be due to the small dif-
ference in reactivity and low selectivity between the
two aryls.
action.[a]
Different polyoxy-substituted substrates were
tested due to the common presence and importance
of oxy substituents in alkaloids (Table 3). Entries 1–5
illustrate that electron-donating substituents on both
aryls are extremely important. Substrate 1k (entry 4)
with only two methoxy groups on the phenyl did not
react due to the drastically decreased reactivity. It is
interesting that when substrate 1l (entry 5) was tested
for the coupling reaction, besides 51% of coupled
product, 29% of further intermolecular coupled prod-
uct 2ll[18] was also obtained, which was because of the
increased reactivity. And it should be noted that sub-
strates which contain other electron-rich groups such
as thiols and amines on the phenyls were not suitable
for the coupling reaction. Because thiol groups are
easily oxidized and amine groups would be protonat-
ed under the acidic coupling reaction conditions, this
would make the aryls become electron-deficient.
Encouraged by this exciting result, we applied this
Entry
Substrate
Product
Time
Yield[b]
1
2
3
4
1a: R=COOMe
1b: R=COOH
1c: R=COCH3
1d: R=CO-n-Bu
(Z)-1b: R=COOH
(Z)-1e: R=CN
1f: R=CH2OCH3
1g: R=CH3
2a
2b
2c
2d
2b
2e
2f
2g
15 min
30 min
20 min
20 min
30 min
60 min
10 min
30 min
99%
91%
95%
92%
99%
73%
84%
29%
5
6
7[c]
8[c]
[a]
Unless otherwise noted, the reaction was carried out
with 1 (0.5 mmol) and the solvent (10 mL).
The yield refers to isolated product.
[b]
[c]
The reaction was performed in TFA/CH3CN (1:19).
bond (Table 2). Substrates 1a–d (entries 1–4), which
have an electron-withdrawing group at the double oxidative coupling reaction to the construction of pol-
bond, were found to react smoothly and form the cor- ymethoxybiaryls (Table 4). The results showed that
responding coupled products 2a–d in excellent yields. aryls with two or more methoxy groups could give the
(Z)-1b and (Z)-1e (entries 5 and 6) also gave the cou- coupled products in moderate to good yields. Less re-
pled products, which suggests that the configuration active substrates could also furnish the coupled prod-
of the double bond has no effect on the reaction. It is ucts (2o and 2p) when a much stronger acid
noteworthy that when R is a strong electron-donating (CF3SO3H) was used. It is worth noting that some
group (entry 7), the desired coupled product could other substrates such as methoxybenzene, toluene,
also be obtained, while other reported oxidative re- benzene and chlorobenzene, which are much less re-
Table 3. Effects of oxy substituents on the phenyls.[a]
Entry
Substrate
Product
Time
Yield[b]
1
2
3
4
5
1h: R1 =R2 =OCH2CH2O; R3 =H; R4 =R5 =OMe
1i: R1, R2 =OCH2O; R3 =H; R4 =R5 =OCH2O
1j: R1, R2 =OCH2CH2O; R3 =H; R4, R5 =OCH2CH2O
1k: R1 =R2 =OMe; R3 =R4 =R5 =H
2h
2i
2j
2k
2l
20 min
30 min
30 min
60 min
60 min
93%
92%
73%
0%
1l: R1 =R2 =R3 =R4 =R5 =OMe
51%
[a]
Unless otherwise noted, the reactions were carried out with 1 (0.5 mmol) and the solvent (10 mL).
The yield refers to isolated product.
[b]
Adv. Synth. Catal. 2012, 354, 383 – 387
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Bo Su et al.
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Table 4. NaNO2-catalyzed intermolecular oxidative coupling
radical with O2 forms the NO2 radical after electron
transfer of the NO+ cation with the aryl, and the NO+
cation can be regenerated through equilibrium as il-
lustrated in Scheme 1.
reaction.[a]
In conclusion, we have developed an NaNO2-cata-
lyzed oxidative coupling for the direct construction of
the the phenanthrene ring using O2 in the air as ter-
minal oxidant at room temperature in good to excel-
lent yields. Compared with previous methods, the
present system has the following significant advantag-
es: (i) the use of much more cheaper and less toxic
NaNO2 as catalyst; (ii) the oxidant (O2 in the air) is
really green and environment-friendly; (iii) the prod-
uct is much easier to be separated from the reaction
mixture and less contaminated by heavy metal and/or
organic oxidant; (iv) this is the first truely catalytic
oxidative coupling for the construction of phenan-
threne. Further applications of the methodology in or-
ganic synthesis are currently being studied in our lab-
oratory.
[a]
Unless otherwise noted, the reactions were carried out
with 1 (1 mmol), 2 equiv. CF3SO3H, CH3CN (10 mL) as
solvent, and the yield refers to isolated product.
The reaction was performed in TFA/CH3CN (1:9).
Experimental Section
[b]
General Procedure for the NaNO2-Catalyzed
Intramolecular Coupling Reaction (1a as an
active, did not give coupled products under the pres- Example)
ent conditions due to their low reactivity.
To the solution of 1a (0.5 mmol, 179 mg) in TFA/CH3CN
On the basis of these preliminary studies, the reac-
tion mechanism for the present oxidative coupling
was proposed as shown in Scheme 1. The reaction
proceeds with a typical radical mechanism[10b] via the
one-electron transfer from substrate 1 to the NO+
cation, giving radical cationic species 3 and NO radi-
cal. The newly formed radical cationic species 3 un-
dergoes electrophilic attack to another phenyl ring
and then deprotonation. The oxidation of the NO
(1:4) (10 mL) was added NaNO2 (0.1 mmol, 6.9 mg) under
an atmosphere of air. The mixture was stirred at room tem-
perature for 15 min, and then aqueous saturated Na2CO3
was added until pH 7 was achieved. Water (10 mL) was
added to the mixture which was then extracted with di-
chloromethane (10 mLꢂ3). The combined organic phase
was washed with water, brine, and then concentrated under
vacuum. The product was further purified by flash chroma-
tography on silica gel to give 2a as a white solid; yield:
1
176 mg (99%); mp 201–2038C. H NMR (CDCl3, 400 MHz):
d=8.65 (s, 1H), 8.43 (s, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.27
(s, 1H), 4.14 (s, 3H), 4.13 (s, 3H), 4.08 (s, 3H), 4.04 (s, 3H),
4.02 (s, 3H).
Acknowledgements
We thank the National Key Project for Basic Research (No.
2010CB126100) and the National Natural Science Founda-
tion of China (No. 21132003, 30890143) and the Tianjin Nat-
ural Science Foundation (No. 11JCZDJC20500) for financial
support.
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Scheme 1. Plausible mechanism for the NaNO2-catalyzed
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