Phosphonic acid mediated practical dehalogenation and benzylation with benzyl halides

Article abstract of DOI:10.1039/c9ra04770k

For the first time, by using H₃PO₃/I₂ system, various benzyl chlorides, bromides and iodides were dehalogenated successfully. In the presence of H₃PO₃, benzyl halides underwent electrophilic substitution reactions with electron-rich arenes, leading to a broad range of diarylmethanes in good yields. These transformations feature green, cheap reducing reagents and metal-free conditions. A possible mechanism was proposed.

Full text of DOI:10.1039/c9ra04770k

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Phosphonic acid mediated practical
dehalogenation and benzylation with benzyl
Cite this: RSC Adv., 2019, 9, 22343
halides†
a
*
Jing Xiao,
Yonghao Ma,a Xiaofang Wu,a Jing Gao,a Zilong Tanga
b
*
and Li-Biao Han
For the first time, by using H3PO3/I2 system, various benzyl chlorides, bromides and iodides were
dehalogenated successfully. In the presence of H3PO3, benzyl halides underwent electrophilic
substitution reactions with electron-rich arenes, leading to a broad range of diarylmethanes in good
yields. These transformations feature green, cheap reducing reagents and metal-free conditions. A
possible mechanism was proposed.
Received 25th June 2019
Accepted 16th July 2019
DOI: 10.1039/c9ra04770k
rsc.li/rsc-advances
Dehalogenation and reactions of benzylation with benzyl and cheap cost.13 It is estimated that a million tons of phosphonic
halides are important transformations in synthetic organic acid was generated as the side-product from the process of elec-
chemistry. Herein we report a simple and green method for troless nickle plating using H3PO2 and other chemical processes.
dehalogenation and benzylation with benzyl halides under Although most of the H3PO3 was lain idle as waste, we are still
metal-free conditions. Thus, under the H3PO3/I2 system, deha- fascinated by the great potential ability in reduction reactions since
logenation took place readily with benzyl chlorides, bromides H3PO3 has a reactive P(O)H bond that might serve as a green H
and iodides to produce the corresponding benzyl derivatives in source. Thus, for the rst time, the H3PO3/I2 combination was used
high yields. In addition, in the absence of I2, benzyl halides for the reduction of benzyl halides, generating a variety of benzyl
underwent electrophilic substitution reactions with electron- derivatives in good yields. This reducing system has the advantages
rich arenes, generating diarylmethanes efficiently.
of being green, cheap and metal-free.
Over the past few decades, signicant efforts have been
Our investigation began with the reduction of benzyl bromide in
devoted to the reduction of halides.1 Among them, a variety of the presence of H3PO3 and I2. As shown in Table 1, reduction of
reducing reagents were applied to dehalogenation reactions benzyl bromide took place in benzene at 100 ꢀC for 22 h, generating
successfully. Some of the most representative reducing agents the desired product toluene in 48% GC yield (entry 1). Next, the
include metal hydrides such as tri-n-butyltin hydrides,2 orga- temperature of the reaction was examined (entry 2 and 3). The
nosilanes,3 sodium borohydrides4 and lithium aluminium suitable temperature was 120 ꢀC and gave the product in 76% yield.
hydride.5 Besides, catalytic hydrogenation is also an important Further screening of the amount of I2 or H3PO3 failed to improve the
approach to the reduction of halides. For example, dehaloge- reaction efficiency (entry 4–6). Among the solvents examined, polar
nation catalyzed by transition-metals such as nickle,6 palla- solvents such as chlorobenzene, CH3CN and dioxane gave poor
dium,3b,7 ruthenium,8 rhodium,9 indium,2a,10 iron11 and cobalt12 results (entry 7–9). To our delight, a weak polar solvent DCE (1,2-
etc. have gained increased attention. Although great progress dichloroethane) was a relatively good solvent with a yield of 69%
has been achieved in dehalogenation reactions, nontoxic, (entry 10). When prolonging the reaction time to 36 h, DCE gave
green, simple and cheap reducing systems still need to be a better result than benzene with a yield of 92% (entry 11 and 12).
explored (Scheme 1).
The yield of the product could not be increased by elevating the
Recently, our group was interested in the use of H3PO3 in temperature to 130 ꢀC in DCE (entry 13).
synthetic methodologies due to its low-toxicity, ready availability
aKey Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry
of Education, School of Chemistry and Chemical Engineering, Hunan University of
Science and Technology, Xiangtan 411201, China
bNational Institute of Advanced Industrial Science and Technology (AIST), Tsukuba,
Ibaraki 305-8565, Japan. E-mail: libiao-han@aist.go.jp; Fax: +81-29-861-6344; Tel:
+81-298-61-4855
Scheme 1 Phosphonic acid mediated dehalogenation and benzyla-
tion with benzyl halides.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra04770k
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Table 1 Optimization of the reaction conditionsa
(2d–2f). Other electron-decient bromides having CF3, C(O)
OMe and NO2 groups were also tolerated well in this reductive
system (2g–2i). Secondary and tertiary benzyl bromides such as
(1-bromoethyl)benzene and (bromomethanetriyl)tribenzene
also underwent this reduction successfully generating the
product in 95% and 97% yield, respectively (2j and 2k). When 1-
(bromomethyl)naphthalene was subjected into the reaction,
78% yield of the product was obtained (2l). Unfortunately, alkyl
and aryl bromides did not go through this dehalogenation
reaction.
We next extended the scope of benzyl halides under similar
conditions. As shown in Table 3, benzyl chloride also proceeded
smoothly (2a), and various reduction products were obtained.
Chlorides bearing substituents (Me, F, Cl and Br) were suitable
for this reduction reaction, generating the corresponding
product in good yields (2b, 2d–2f). With regard to electron-
withdrawing group under H3PO3/I2 system, we observed that
CF3, CN and NO2 substituents were tolerated in good yields (2g,
2m and 2i). Furthermore, secondary chlorides such as (1-
chloroethyl)benzene and chlorodiphenylmethane were also
worked well in this transformation, providing the product in
high yields (2j and 2n). Gratefully, large steric hindrance
triphenylmethane chloride was reduced readily under the
present condition in 97% yield (2k). Finally, we conducted the
dehalogenation of benzotrichloride and benzyl iodide to
explore possible reduction of polyhalogenated substrates and
iodides. Indeed, 2a was formed in 41% and 88% yield,
respectively.
Entry H3PO3 (equiv.) I2 (equiv.) Solvent
Temp/ꢀC Yield (%)
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
10%
10%
10%
15%
5%
10%
10%
10%
10%
10%
10%
10%
10%
Benzene 100
48%
76%
75%
74%
70%
64%
21%
7%
26%
69%
92%b
61%b
82%
Benzene 120
Benzene 130
Benzene 120
Benzene 120
Benzene 120
PhCI
CH3CN
120
120
9
Dioxane 120
10
11
12
13
DCE
120
DCE
120
Benzene 120
DCE 130
a
Conditions: a mixture of 1a (0.3 mmol), H3PO3, and I2 in solvent (0.6
mL) was stirred at indicated temperature for the 22 h. Yield based on
b
GC yield using dodecane as an internal standard. 36 h.
With the optimized reaction conditions in hand, the scope of
the reaction with respect to benzyl halides was examined (Table
2). Benzyl bromide was reduced to the corresponding product in
84% GC yield, albeit 38% isolated yield was obtained due to its
low boiling point (2a). Bromides bearing methyl or phenyl
groups at the para-position on benzene were reduced smoothly
to afford the product in high yields (2b and 2c). Interestingly,
substrates containing halogens such as F, Cl and Br at the para-
position on benzene stayed intact during the dehalogenation
During the above studies of dehalogenation of benzyl
halides, we found that interestingly, when the reaction was
performed in the absence of I2, electrophilic substituent
a
Table 3 Reduction of the benzyl chloride derivatives with H3PO3/I2
a
Table 2 Reduction of the benzyl bromide derivatives with H3PO3/I2
a
Conditions: a mixture of 3 (0.6 mmol), H3PO3, and I2 in benzene was
stirred at 100 ꢀC for 36 h. Isolated yield based on three parallel reactions.
Conditions: a mixture of 1 (0.6 mmol), H3PO3, and I2 in DCE was Yield in parenthesis are GC yield. b 120 ꢀC. c 4.0 equiv. H3PO3. d 130 ꢀC.
a
e
f
stirred at 120 ꢀC for 36 h. Isolated yield based on three parallel
reactions. Yield in parenthesis are GC yield.
Benzotrichloride and 5.0 equiv. H3PO3 was used. Benzyl iodide was
used.
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reaction took place to affording diarylmethane in excellent It is worth noting that benzyl bromide with electron-drawing
yields. Diarylmethane are widely used in organic synthesis, group such as methyl ester was also applicable in this
pharmaceutical development and material science.14 Among reaction, albeit in moderate yield of the product (4i).
the methods reported, Friedel–Cras (FC) benzylation of Unfortunately, the reaction gave trace product with benzyl
arenes15 and transition-metal catalysed cross coupling halides having strong electron-withdrawing groups such as
reactions16 are the important approaches to preparing these nitro or triuoromethyl group.
compounds. However, those methods are usually need
To highlight the synthetic utility of these transformation,
equivalent expensive Lewis acids, metal and not readily some gram–scale reactions were conducted. As shown in
available materials. Although various strategies for the Scheme 2, 12 mmol (chloromethylene)dibenzene 3n was
metal-free access to diarylmethanes have been explored,17 reduced smoothly in the presence of 2.0 equiv. H3PO3 and
a more simple, practical, and greener method for their 10 mol% I2 in benzene at 130 ꢀC for 36 h, generating 1.956 g
preparation are highly desirable.
product in 97% isolated yield (eqn (1)). Besides, we were
As shown in Table 4, various arenes were subjected into pleased to nd that the gram scale synthesis of diphenyl-
this electrophilic substitution reaction. Thus, in the pres- methane by reaction of benzyl chloride with benzene was
ence of H3PO3, benzyl chlorides and bromides underwent also achieved (eqn (2)). The above results revealed that these
this transformation successfully with benzene or mesitylene reactions were practical and have the potential to scale up.
to afford the corresponding diarylmethanes in good to
Finally, some control experiments were conducted to
excellent yields (2n and 4a). Gratifying, electron-rich arenes evaluate the different halides and electron effect of these
such as toluene, phenol and anisole were also compatible in reactions. 4-Methylbenzyl chloride and 4-methylbenzyl
this reaction conditions with isomer products generated bromide were reduced to the product with 20% and 31%
(4b–4d). In addition, when chlorobenzene was used as the substrate conversion, respectively (eqn (3)). Benzyl
substrate, good yield of the corresponding product was bromides bearing electron-donating group methyl, H and
observed (4e). Subsequently, a serious of benzyl halides with electron-withdrawing group CF3 were also subjected into the
benzene were investigated in the presence of H3PO3. Benzyl reaction in one pot, and the corresponding product were
halides bearing methyl, phenyl, uoride, chloride and obtained in 17%, 9% and trace yield with a large amount of
bromide led to good to high yield of the products (4b, 4f–4h). substrate recovered, respectively (eqn (4)). Similarly, the
benzylation of benzene by the above three bromides
affording the corresponding diarylmethanes in a downward
trend in yields (eqn (5)). The above results revealed that
benzyl bromides were more reactive than benzyl chloride in
Table 4 Benzylation of arenes with benzyl halidesa
dehalogenation reactions. Besides, in the same type of
halides, electron-donating group having more positive
inuence than electron-decient whether in reduction or
benzylation reactions, which may suggest that these reac-
tions were involving a carbon cation mechanism (Scheme 3).
Based on the above results and previous reports,13 a possible
mechanism was proposed in Scheme 4. HI was generated in situ
by reaction of H3PO3 and I2, halogen exchange between benzyl
halides and HI afforded intermediate A, further reduction of A
by HI to give the corresponding product (eqn (a)). For benzyla-
tion of arenes by halides, we deduced that carbon cation
intermediate B was generated via C–X bond cleavage in the
presence of H3PO3, B underwent electrophilic substitution
reaction with arenes to afford the corresponding diaryl-
methanes (eqn (b)).
a
Conditions: a mixture of 1 or 3 (0.6 mmol) and H3PO3 in arenes was
stirred at 130 ꢀC for 24 h. Isolated yield based on three parallel
reactions. Isomer ratio was determined by GC. b 36 h. c 150 ꢀC. d 160 ꢀC.
Scheme 2 Gram-scale reactions.
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In summary, we report a practical method for dehalogenation of
benzyl halides and preparation of diarylmethanes by using
a H3PO3 system. Various benzyl halides could be readily
reduced by the H3PO3/I2 combination for the rst time. In the
absence of I2, electrophilic substitution reactions between
benzyl halides and arenes occurred smoothly, furnishing dia-
rylmethanes in good yields. This method provides a simple,
cheap and green approach for the reduction of benzyl halides
and synthesis of diarylmethanes.
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JX is thankful for a postdoc fellowship from AIST and nancial
support from the National Natural Science Foundation of China
(21703061) and the Natural Science Foundation of Hunan
province (2017JJ3081).
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