A scalable, efficient gold-catalyzed oxidative phosphonation of sp 3 C-H bonds using air as sustainable oxidant

Article abstract of DOI:10.1002/adsc.201200360

A scalable, efficient gold-catalyzed oxidative phosphonation of sp ³ C-H bonds with various diarylphosphine oxides and dialkyl phosphites has been developed by using air as a sustainable oxidant under mild reaction conditions. It provides an ea

Full text of DOI:10.1002/adsc.201200360

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DOI: 10.1002/adsc.201200360
A Scalable, Efficient Gold-Catalyzed Oxidative Phosphonation of
3
À
sp C H Bonds using Air as Sustainable Oxidant
Jin Xie,a Huamin Li,a Qicai Xue,a Yixiang Cheng,a and Chengjian Zhua,b,*
a
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, Peopleꢀs Republic of China
E-mail: cjzhu@nju.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, Peopleꢀs
b
Republic of China
Received: April 25, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200360.
À
Abstract: A scalable, efficient gold-catalyzed oxida-
tive phosphonation of sp C H bonds with various
the gold-catalyzed oxidative a-amino C H phospho-
nation using air as a sustainable oxidant.[10] It is well-
known that phosphorus-containing organic com-
pounds, especially a-amino phosphonic derivatives,
are valuable precursors of a multitude of biologically
active molecules.[11] Although several methods have
3
À
diarylphosphine oxides and dialkyl phosphites has
been developed by using air as a sustainable oxi-
dant under mild reaction conditions. It provides an
easy access to a-amino phosphonic compounds in
high yields with a broad reaction scope. The safe,
convenient and environmentally benign process
makes this protocol very promising.
À
been developed for oxidative a-C H phosphonation
of amines, either the catalytic efficiency or reaction
conditions were somewhat unsatisfactory, and the re-
action scope of coupling partner was limited to dialkyl
phosphites.[12] Therefore, the development of a more
environmentally benign and efficient system with
a broad reaction scope for oxidative a-amino C H
phosphonation is highly desirable. Herein, we de-
À
Keywords: air; C H activation; cross-coupling;
gold; phosphonation
À
scribe a mild, practical and intriguing catalytic system
3
À
of gold and air for aerobic sp C H activation, and
À
À
The functionalization of C H bonds offers an unpar- subsequent C P bond coupling with various diary-
alleled platform for organic transformation, as C H lphosphine oxides as well as dialkyl phosphites in
À
bonds are ubiquitous in organic molecules and they a sustainable way. Notably, this is the first example to
could be used as operative functional groups under use a secondary phosphine oxide as a coupling part-
the catalysis of transition metals.[1] In this context, the ner in the oxidative C P coupling reaction due to its
À
À
gold-catalyzed C H bond activations have attracted unstable character in harsh oxidative conditions.
considerable attention and a number of notable ad-
To initiate our study, the reaction of N-phenyltetra-
vances have been achieved in recent years.[2] The hydroisoquinoline 5a with diphenylphosphine oxide
methods in these reports commonly involved the use 6a was chosen as a model reaction. To our delight, the
À
of gold as p-acid to activate the unsaturated C H reaction could occur under the catalysis of 1a with
bonds. However, the gold-catalyzed sp C H bond ac- MeCN as solvent at 608C under air, affording the de-
3
À
tivation under aerobic oxidative conditions remains sired coupling product 7a in 68% yield (Table 1,
a great challenge,[3,4] since a sacrificial external oxi- entry 1). Encouraged by this result, the reaction con-
dant such as F+ was usually required for gold-cata- ditions were investigated in detail, and the results are
lyzed oxidative coupling reactions.[5] In the context of summarized in Table 1. When 1b was employed, the
sustainable chemistry, air has been considered as the yield of 7a could be improved to 83% in 10 h
most ideal oxidant,[6] and has attracted significant in- (entry 2). Among the gold-complexes screened
terest in mordern oxidative chemistry.[7] With these (Figure 1), the catalyst 2a showed the best catalytic
considerations in mind, our group has developed efficiency, and it could complete the reaction in short-
a highly efficient gold-catalyzed aerobic oxidative sp3 er reaction time with a higher yield of 85% (entry 3).
À
À
C H activation for the construction of new C C When the aerobic oxidative phosphonation reaction
3
bonds.[8] As part of our ongoing interest in sp C H was carried out in the absence of any gold catalyst,
À
activation,[9] we wish to disclose our further results on only a trace amount of product was observed
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A Scalable, Efficient Gold-Catalyzed Oxidative Phosphonation of sp C H Bonds
Table 1. Optimization of the conditions for the aerobic oxi-
Table 2. (Continued)
Entry 5 Product 7
dative phosphonation reaction.[a]
Time [h] Yield [%][b]
2[c]
3[c]
4[c]
5
5b
7b 12
90
85
94
84
86
88
91
Entry
Catalyst
Solvent
Time [h]
Yield [%][b]
5c
5d
5e
5f
5g
5a
7c 5
1
2
3
4
5
6
7
8
1a
1b
2a
2b
3
4
–
2a
2a
2a
2a
2a
2a
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
MeOH
CHCl3
MeCN
MeCN
MeCN
10
10
5
68
83
85
76
39
54
trace
76
62
70
75
72
trace
5
10
10
5
5
5
5
5
5
5
7d 3
9
7e
7f
7g
7
5
7
10
11[c]
12[d]
13[e]
6
[a]
Reaction conditions: 5a (0.1 mmol), 6a (4.0 equiv.), sol-
vent (2.0 mL), air, 608C.
Isolated yields.
2.0 equiv. of NaOAc was added as an additive.
100 mg of 4ꢂ MS were added as an additive.
The reaction was performed under an argon atmosphere
(1.0 atm).
[b]
[c]
[d]
[e]
7
8
7h 6
9
5a
5a
5a
5a
7i
7j
6
6
80
87
84
68
Figure 1. Gold complexes screened.
10
11
Table 2. The aerobic oxidative coupling reaction of amines
with phosphine oxides.[a]
7k 8
12
7l
8
[a]
Reaction conditions: 5 (0.1 mmol), 6 (4.0 equiv.), MeCN
(2.0 mL), air, 608C.
Isolated yield.
[b]
[c]
Entry 5
Product 7
Time [h] Yield [%][b]
The reaction was carried out at 508C.
1
5a
7a
5
85
(entry 7). Subsequently, different solvents and addi-
tives were screened, all resulting in less satisfactory
results (entries 8–12). A control experiment demon-
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Jin Xie et al.
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strated that a trace of product could be identified (508C) was essential for a good isolated yield (en-
À
when the aerobic oxidative C P coupling reaction tries 2–4). It is important to point out that electron-
was performed in an argon atmosphere instead of air, donating as well as electron-withdrawing groups on
thus suggesting that air may play an important role in the aromatic rings were compatible in the aerobic oxi-
3
[13]
À
À
the gold-catalyzed sp C H activation (entry 13).
Consequently, the optimal reaction should be cata- afford the desired products 7a–g in short reaction
lyzed by 6 mol% of 2a at 608C in MeCN under air. times with excellent yields (84–94%; entries 1–7).
dative C P coupling reaction. They can uniformly
With the optimized reaction conditions in hand, we Then, various diarylphosphine oxides 6a–f were em-
studied the scope of our protocol (Table 2). First, dif- ployed. The reaction could proceed smoothly to fur-
À
ferent N-aryltetrahydroisoquinolines 5a–g were exam- nish the C P coupling products 7h–l in moderate to
ined. When 5b–d were subjected to the oxidative C P good yields (68–91%, entries 8-12). Moreover, when
À
coupling reaction, a slightly decreased temperature the gold-catalyzed reaction was scaled-up to the gram
scale, 7a could also be isolated in a satisfactory yield
of 74%, demonstrating the practicability of the proto-
col (Scheme 1).
To further illustrate the generality of our protocol,
we applied this protocol to a series of dialkyl phos-
phites, and the corresponding results are listed in
Table 3. It was also found that the substituents on aro-
À
matic rings hardly affected the oxidative C P cou-
pling reaction. All the tertiary amines 5a–g could be
coupled with diethyl phosphite 6g readily to afford
the desired product 7m–s in good yields under air
Scheme 1. The gram-scale experiment. Reaction conditions:
5a (5 mmol), 6a (4.0 equiv.) and 2a (6 mol%) in MeCN
(100 mL) at 608C under air for 10 h.
Table 3. The aerobic oxidative coupling reaction of amine with phosphites.[a,b]
7m, 80% (5 h)
7p, 90%[c] (5 h)
7s, 76% (8 h)
7n, 88%[c] (10 h)
7q, 83% (8 h)
7t, 86% (5 h)
7w, 78% (8 h)
7o, 81%[c] (10 h)
7r, 89% (6 h)
7u, 74% (8 h)
7x, 37% (40 h)
7v, 78% (8 h)
[a]
Reaction conditions: 5 (0.1 mmol), 6 (4.0 equiv.), MeCN (2.0 mL), air, 608C.
Isolated yield.
The reaction was carried out at 508C.
[b]
[c]
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Adv. Synth. Catal. 2012, 354, 1646 – 1650

3
À
A Scalable, Efficient Gold-Catalyzed Oxidative Phosphonation of sp C H Bonds
oxides and dialkyl phosphites by using air as a sustain-
able oxidant under mild reaction conditions. This pro-
tocol provides an easy access to a-amino phosphonic
derivatives in high yields with a broad reaction scope.
Moreover, the safe, convenient and environmentally
benign process makes it very practical. Further studies
À
on gold-catalyzed aerobic oxidative C H activation
mechanisms and exploration of the asymmetric ver-
sion of this protocol are under way in our laboratory.
Experimental Section
General Procedure for the Synthesis of 7a–x
To the mixture of the N-aryl-1,2,3,4-tetrahydroisoquinoline
5 (0.1 mmol) and [(phen)AuCl2]Cl 2a (6 mol%, 2.9 mg) in
MeCN (2.0 mL) was added the phosphine oxide or phos-
phite 6 (4.0 equiv.). Then the reaction mixture was stirred at
608C under air for several hours indicated. After the reac-
tion had finished and removal the solvents under vacuum,
the residue was purified by flash column chromatography to
afford the desired coupling products 7a–x.
Scheme 2. A plausible mechanism (L=1,10-phenanthro-
line).
(76–90%). It was reported that dimethyl phosphite
and sterically hindered phosphites were ineffective in
[12d–e]
À
the oxidative C P coupling reaction.
However, in
our catalytic system, all the dialkyl phosphites 6g–k
examined could undergo the oxidative reaction to
give the products 7t–w in satisfactory yields. Further-
more, when N,N,4-trimethylaniline, a non-benzylic
amine was used, an acceptable yield could also be ob-
tained.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (20832001, 20972065, 21074054,
21172106) and the National Basic Research Program of
China (2010CB923303) for their financial support.
At present, the exact mechanism for the formation
of products is not clear, but we would like to proffer
a catalytic cycle for the gold-catalyzed aerobic oxida-
3
À
tive phosphonation of sp C H bonds. The control ex-
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À
Adv. Synth. Catal. 2012, 354, 1646 – 1650
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À
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