Tetrabutylammonium iodide-catalyzed phosphorylation of benzyl c-h bonds via a cross-dehydrogenative coupling (cdc) reaction

Article abstract of DOI:10.1002/adsc.201400436

Phosphate esters play important roles as biological active principles and synthons in chemistry. An efficient metal-free approach for the synthesis of phosphate esters through sp³ C-H activation is described. By using tetrabutylammonium iodide (Bu₄NI) as a catalyst and tert-butyl hydroperoxide (TBHP) as an oxidant, various toluene derivatives and phosphorus nucleophiles are tolerated in this transformation, affording the corresponding products in moderate to good yields.

Full text of DOI:10.1002/adsc.201400436

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DOI: 10.1002/adsc.201400436
Tetrabutylammonium Iodide-Catalyzed Phosphorylation of
À
Benzyl C H Bonds via a Cross-Dehydrogenative Coupling
(CDC) Reaction
Jian Xu,a Pengbo Zhang,a Xueqin Li,a Yuzhen Gao,a Ju Wu,a Guo Tang,a,*
and Yufen Zhaoa,b
a
Department of Chemistry, College of Chemistry and Chemical Engineering, and the Key Laboratory for Chemical
Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005, Peopleꢀs Republic of China
Fax : (+86)-592-218-5780; e-mail: t12g21@xmu.edu.cn
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
b
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Received: May 1, 2014; Revised: June 22, 2014; Published online: September 24, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400436.
[9]
Abstract: Phosphate esters play important roles as
H2O2. Despite more than 70 years of effort and the
development of numerous methods, the range of
starting materials is still limited to alcohols. The
above methods suffer from several limitations, e.g.,
activating reagents are expensive and moisture-sensi-
tive, use of toxic reagents, or the large amount by-
product leads to environmental pollution (Scheme 1).
Thus, there is still a great demand to search for more
straightforward and clean ways to make phosphate
esters.
biological active principles and synthons in chemis-
try. An efficient metal-free approach for the synthe-
3
À
sis of phosphate esters through sp C H activation
is described. By using tetrabutylammonium iodide
(Bu4NI) as a catalyst and tert-butyl hydroperoxide
(TBHP) as an oxidant, various toluene derivatives
and phosphorus nucleophiles are tolerated in this
transformation, affording the corresponding prod-
ucts in moderate to good yields.
In recent years, the atom efficient cross dehydro-
genative coupling (CDC) has been widely investigat-
À
Keywords: benzyl C H bonds; tert-butyl hydroper-
oxide; phosphate ester; phosphorylation; tetrabutyl-
ammonium iodide
À
ed for the formation of C X bonds as it eliminates
the preparation of functional groups.[10] The concept
À
has also been explored regarding P X bond forma-
tion.[11] Quite recently, several groups independently
Phosphate esters play an important role as structural
elements of many biologically active natural substan-
ces (e.g., nucleic acids, proteins).[1] They also find ap-
plications in analytical chemistry[2] and industry.[3]
Moreover, these types of compounds are useful re-
agents in organic synthesis,[4] for example, benzyl
phosphates are widely used as coupling partners in
metal-catalyzed cross-coupling reactions.[5] Conse-
quently, the increasing demand for phosphate esters
has generated considerable interest in the develop-
ment of efficient and flexible synthetic methods. The
traditional methods for their preparations include the
reaction of alcohols with phosphoryl halides[6] or
copper-catalyzed phosphorylation of alcohol with N-
phosphoryloxazolidinones or Atherton–Todd reac-
tion[7] or transesterification of phosphate esters.[8] Re-
cently, Prabhu reported a green, direct cross-coupling
of phosphites with alcohols in the presence of I2/ Scheme 1. Synthetic routes to phosphate esters.
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Jian Xu et al.
reported metal- or non-metal-catalyzed oxidative cou- oxidant (entries 7–11). To our delight, an 89% prod-
À
À
pling of P H bonds with N H bonds to afford a phos- uct yield was obtained when the amount of TBHP
phoramidate.[12] On the other hand, the green catalyt- was increased to 8 equiv. (entry 12), while more
ic system ꢂBu4NI/TBHPꢀ exhibited excellent catalytic TBHP (10 equiv.) did not increase the product yield
3
À
activity in sp C H activation, especially for benzyl significantly. The amount of toluene could be reduced
À
C H bonds that are not adjacent to a nitrogen or to 10 equiv. without decreasing the yield of 3a. The
oxygen atom.[13] Some significant progress about use of some other solvents such as EtOAc, dioxane,
À
esterification and amination of the benzyl C H bond THF, decreased the yields dramatically (entries 13
has been achieved.[14] However, phosphorylation of and 14). Decreasing the load of Bu4NI to 10 mol% re-
À
benzyl C H bonds is not yet reported. As part of our sulted in a poorer yield. Finally, the temperature eval-
continued interest in organophosphorus transforma- uation demonstrated that 908C was the best choice.
tions,[15] herein, we describe a Bu4NI-catalyzed phos- The reaction did not occur at all in the absence of
À
phorylation of benzyl C H bonds leading to phos- either Bu4NI or TBHP (entries 17 and 18).
phate esters through a CDC approach.
Having the optimal conditions in hand (Table 1,
Initially, we began our study by using Ph2P(O)H entry 12), we next examined the reactions of substi-
(1a) and toluene (2a) as the starting substrates to op- tuted toluene with H-phosphonates and phosphites to
timize the reaction conditions (Table 1). When Bu4NI probe the scope of the reaction (Table 2). It was
(20 mol%) was used as the catalyst and tert-butyl hy- found that a wide range of various substituted tol-
droperoxide (TBHP, 4 equiv.) as the oxidant at 908C uenes reacted efficiently. Both xylenes and mesitylene
for 12 h, the desired product 3a was obtained in 60% gave the corresponding phosphate esters in satisfacto-
yield (Table 1, entry 1). A brief survey of different ry yields (Table 2, 3b–d). Noteworthy, although xy-
catalysts, such as Bu4NBr, Bu4NCl, KI, I2, indicated lenes or mesitylene have more reactive positions, only
that Bu4NI is the best one (entries 2–6). However, no mono-ester products were observed (see the Support-
target product was observed using H2O2, di-tert-butyl ing Information). Halide groups at different positions
peroxide (DTBP), PhIACHTNUGRTENUNG(OAc)2, oxone, or DDQ as the were well tolerated in this system and the correspond-
ing products were obtained in good yields (3e–j).
Products 3i and 3j are important reagents for the pro-
duction of biaryls through intramolecular radical
transfer.[16] Toluene derivatives bearing electron-with-
drawing COOMe, NO2, CN and COCH3 groups react-
ed smoothly to give the corresponding products in
a slightly lower yield (3k–n). More bulky substrates
like 2-methylnaphthalene (2p), and 2-methylquinoline
(2q) also efficiently reacted with 1a and afforded the
corresponding phosphate esters 3p and 3q in 62% and
85% yields, respectively. Ethylbenzene derivatives
were also successfully converted to the corresponding
products in moderate to good yields (3r–3u). The
phosphorylation of propylbenzene also resulted in the
formation of benzyl phosphate derivative (3v) in
a slightly lower yield due to a potential steric hin-
drance. However, when the more sterically hindered
cumene and diphenylmethane were used as sub-
strates, only a trace of products was detected by
NMR. The substrate scope was further investigated
by reacting toluene (1a) with different phosphine
oxides and H-phosphonates. When bis(para-methox-
y)phenylphosphine oxide was used, 3w was obtained
in 89% yield. In regard to the H-phosphonates, dieth-
yl and dibutyl H-phosphonates all could be used as
the substrates, generating the corresponding phospho-
nates 3x–3z, respectively, in 84%, 86% and 82%
yields. When ethyl phenylphosphinate was used, 3aa
was obtained in good yield. Moreover, 9,10-dihydro-
9-oxa-10-phosphaphenanthrene 10-oxide (DOPO)
also could react with toluene, giving the excepted
product 3ab in 45% yield.
Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
(mol%)
Oxidant
ACHTUNGTRENN(UNG equiv.)
Solvent
Yield
[%]
U
1
2
3
4
5
6
7
8
Bu4NI (20)
Bu4NBr (20)
Bu4NCl (20)
KI (20)
Bu4NOH (20)
I2 (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
Bu4NI (20)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
H2O2
2a
2a
2a
2a
2a
2a
2a
2a
60
0
0
23
0
0
0
0
DTBP
9
PhI
N
trace
0
trace
89
23
10
11
12
13
14
Oxone (8)
DDQ
TBHP (8)
TBHP (8)
TBHP (8)
2a
2a
2a
EtOAc
1,4-diox- 10
ane
15
16
17
18
Bu4NI (20)
Bu4NI (20)+I2 (20) TBHP (8)
–
TBHP (8)
THF
2a
2a
2a
12
40
0
TBHP (8)
–
Bu4NI (20)
0
[a]
Reaction conditions: catalyst (0.06 mmol), 1a (0.3 mmol),
2a (3 mmol), 908C, 12 h. Isolated yield; TBHP=tert-
butyl hydroperoxide 70% in water; H2O2 30% in water;
DTBP=di-tert-butyl peroxide.
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Tetrabutylammonium Iodide-Catalyzed Phosphorylation
À
Table 2. Bu4NI-catalyzed phosphorylation of benzyl C H
Further experiments were conducted to gain insight
into the mechanism of the reaction (Scheme 2). At
the beginning of this study, benzyl alcohol or benzyl
aldehyde was assumed to be a potential intermediate
in the reaction. Replacement of toluene with benzyl
alcohol or benzyl aldehyde also did not yield the de-
sired product. When the radical scavenger 2,2,6,6-tet-
ramethylpiperidine N-oxyl (TEMPO) or 2,6-di-tert-
butyl-4-methylphenol (BHT) was added in the reac-
tion of 1a with toluene under the optimal conditions,
only a trace amount of 3a was observed. 1-(Benzyl-
bonds.[a]
AHCTUNGTREGoNNNU xy)-2,2,6,6-tetramethylpiperidine was successfully
separated from the above reactions (Scheme 2, b).
This result indicated that the radical may be inter-
cepted by TEMPO or BHT. Meanwhile, Ph2P(O)OH
was obtained in almost quantitative yield in the ab-
sence of toluene, and replacing Ph2P(O)H with
Ph2P(O)OH also gave 3a in 87% yield. So we specu-
lated that Ph2P(O)OH should be the key intermediate
in this transformation. No 3a was detected when
Ph2P(O)OH reacted with benzyl alcohol or benzyl al-
dehyde. It was found that the reaction was completely
suppressed when I2 was used instead of Bu4NI
(Table 1, entry 6). However, the combined using of I2
and Bu4NI led to 3a in 40% yield (Table 1, entry 16).
The results suggested that either ammonium hypo-
A
+A[IO2]À) 5
CHTUNGTRENNUNG
Based on the above experiments and previous re-
search,[14] a plausible catalytic cycle is presented in
Scheme 3. Initially, the reaction between Bu4NI and
TBHP would give the active intermediate ammonium
hypoiodite 4 or iodite 5.[13a] Then 4 or 5 promoted the
[14a,e]
À
benzyl C H bond to form the benzyl radical
which would be further oxidized to afford the benzyl
[a]
Reaction conditions: Bu4NI (0.06 mmol), 1 (0.3 mmol), 2
Scheme 2. Experiments for the mechanistic study.
(3 mmol), TBHP (2.4 mmol), 908C, 12 h. Isolated yield.
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Jian Xu et al.
(2012CB821600), and the Program for Changjiang Scholars
and Innovative Research Team in University.
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À
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Experimental Section
Typical Procedure for Bu4NI-Catalyzed
Phosphorylation of Benzyl C H Bonds
À
Ph2P(O)H (1a) (0.3 mmol), Bu4NI (0.06 mmol), TBHP
(2.4 mmol) and toluene (2a) (3 mmol) were sequentially
added to a Schlenk tube with a magnetic stir bar at room
temperature. The resulting mixture was stirred at 908C for
12 h. The reaction solution was allowed to cool to ambient
temperature, and then transferred to a round-bottom flask.
Silica gel (3.0 g) was added, and the solvent was removed
under reduced pressure to afford a free-flowing powder.
This powder was then dry-loaded onto a silica gel column
and purified by flash chromatography using petroleum
ether-AcOEt (3:1–1:1, v/v) as the eluent to give benzyl di-
phenylphosphinate (3a). Other phosphate esters were pre-
pared similarly.
Acknowledgements
We acknowledge financial support from the Chinese National
Natural Science Foundation (21173178, 21232005, 21375113),
the National Basic Research Program of China
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