Lewis acid-mediated Michaelis-Arbuzov reaction at room temperature: A facile preparation of arylmethyl/heteroarylmethyl phosphonates

Article abstract of DOI:10.1021/ol1029436

A facile preparation of arylmethyl and heteroarylmethyl phosphonate esters was achieved involving a Lewis acid mediated Michaelis-Arbuzov reaction at room temperature. Interaction of arylmethyl halides/alcohols with triethyl phosphite in the presence of Lewis acid at room temperature afforded phosphonate esters in good yields.

Full text of DOI:10.1021/ol1029436

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1270–1273
Lewis Acid-Mediated Michaelis-Arbuzov
Reaction at Room Temperature: A Facile
Preparation of Arylmethyl/
Heteroarylmethyl Phosphonates
Ganesan Gobi Rajeshwaran, Meganathan Nandakumar, Radhakrishnan Sureshbabu,
and Arasambattu K Mohanakrishnan*
Department of Organic Chemistry, School of Chemistry, University of Madras, Guindy
Campus Chennai 600 025, Tamil Nadu, India
mohanakrishnan@unom.ac.in
Received December 9, 2010
ABSTRACT
A facile preparation of arylmethyl and heteroarylmethyl phosphonate esters was achieved involving a Lewis acid mediated Michaelis-Arbuzov
reaction at room temperature. Interaction of arylmethyl halides/alcohols with triethyl phosphite in the presence of Lewis acid at room temperature
afforded phosphonate esters in good yields.
Organic phosphonates are a key functional group in
biological chemistry as well as synthetic organic chemistry.1
In particular, arylmethyl and heteroarylmethyl phospho-
nate esters have been widely utilized as prominent precursor
for the synthesis of optical materials such as poly(phenyl-
vinylenes),2 thienylvinylenes,3 trialkylamine tethered viny-
lenes,4 as well as stilbene dendrimers5 involving a
Horner-Wadsworth-Emmons reaction6 with aldehydes.
The required organophosphonate esters have been tradi-
tionally obtained through a Michaelis-Arbuzov reaction.7
The Michaelis-Arbuzov reaction is initiated with an
SN2 reaction of nucleophilic trialkylphosphite with aryl-
methyl halides to give a phosphonium intermediate. The
displaced halide anion upon a second SN2 reaction with
phosphonium intermediate led to the phosphonate ester
along with an alkyl halide. Despite its acceptance, the
Michaelis-Arbuzov reaction has two major drawbacks.
First, the elevated temperature required for the activation
of the reaction, limits the scope of the substrate suitable for
the reaction. Second, the reaction generates one equiv of
alkyl halide, which can react with the phosphite under
reaction conditions to reduce yield and reaction efficiency.
The Michaelis-Becker reaction8 utilizing dialkylphos-
phite salt of alkali metals with alkyl halides somewhat
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r
10.1021/ol1029436
Published on Web 02/24/2011
2011 American Chemical Society

overcomes the above-mentioned problems. However, the
reaction conditions are often not convenient requiring
either the use of strong anhyd base,9 or longer reaction
time10 and in some cases resulted in low yield of the
phosphonates.11 Salvatore and co-workers achieved a mild
and efficient synthesis of phosphonates via interaction of
dialkylphosphonates with alkyl halides in the presence of
Cs2CO3 and TBAI in dry DMF at room temperature.12
Recently, an efficient preparation of benzyl phosphonates
was achieved involving the Pd(OAc)2-mediated cross-cou-
pling reaction of benzyl halides with H-phosphonate diesters
using Xantphos as a supporting ligand.13 Peyrottes et al.
achieved the synthesis of sugar and nucleoside phosphonate
derivatives involving microwave-assisted Michaelis-
Arbuzov reaction.14 Marder and co-workers reported a
convenient method for the synthesis of electron-rich benzyl
phosphonates by treating the corresponding alcohols with
triethyl phosphite in the presence of 1 equiv of I2 at room
temperature.15 This method proved to be useful for highly
electron-rich heteroaryl methyl alcohols. However, in the
case of less electron-rich systems, the method requires high
temperature. Pei and co-workers achieved the synthesis of
alkyl phosphonate esters via interaction of heteroarylmethyl
alcohols with triethyl phosphite and I2 in the presence of
DBU at elevated temperature.16 Very recently, a room-
temperature alternative to the Michaelis-Arbuzov reaction
was realized through reductive dehydrogenation of acyl
phosphonates.17 Using this method, a one-pot sequence
for the synthesis of alkyl phosphonates was developed from
carboxylic acids. An efficient synthesis of R-aminophospho-
nates via interaction of N-benzyloxycarbonylamino sulfones
with triethyl phosphite in the presence of a catalytic amount
of InCl3 in DCM at room temperature was achieved.18 In
continuation of our studies on Lewis acid mediated domino
reactions,19 we report herein the Lewis acid mediated Mi-
chaelis-Arbuzov reaction of benzylic bromides 1 with
triethyl phosphite at room temperature (Scheme 1).
Scheme 1. Michaelis-Arbuzov Reaction
Scheme 2. Lewis Acid-Mediated Michaelis-Arbuzov Reaction
In our ongoing program on the synthesis of carbazole
alkaloids, we required various types of N-phenylsulfonyl-
2/3-indolylmethylphosphonates as starting materials. The
accessibility of these phosphonate esters using the tradi-
tional method at elevated temperature was problematic
due tothe unstable nature of the bromomethylindoles. Our
recent success with the Lewis acid mediated domino reac-
tion of bromomethylindoles prompted us to explore a
Lewis acid mediated Michaelis-Arbuzov reaction of the
same. Accordingly, when the reaction of bromomethylin-
dole 3a was performed with triethyl phosphite in the
presence of 10 mol % of InBr3 at room temperature for 4
h followed by workup led to the isolation of known
phoshponate ester 4a in 80% yield (Scheme 2). Gratify-
ingly, the reaction could also be carried out at room
temperature using less expensive ZnBr2 as a catalyst in
almost comparable yield. This unexpected Lewis acid-
mediated Michaelis-Arbuzov reaction of the bromo-
methylindole 3a at room temperature prompted us to
study the reaction with other benzylic halides.
(9) Reaction and Methods of Organic Compound Investigation; Ka-
bachnik, M., Ed.; Goskhimizdat: Moscow, 1953; Vol. 13, p 427.
(10) Kosolapoff, G. M. Organophosphorous Compounds; Wiley: New
York, 1950; Chapter 7.
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(b) Weizhen, Y.; Xiugao, L. Synthesis 1985, 10, 986–988.
(12) Cohen, R. J.; Fox, D. L.; Eubank, J. F.; Salvatore, R. N.
Tetrahedron Lett. 2003, 44, 8617–8621.
To our delight, the Lewis acid-mediated Michae-
lis-Arbuzov reaction of a wide variety of aryl as well as
heteroarylmethyl bromides could be successfully per-
formed at room temperature to afford the corresponding
phosphonates in good yields (Table 1). The 2-indolyl-
methanols 3b and 3d also underwent a smooth Lewis acid
mediated Michaelis-Arbuzov reaction at room tempera-
ture in the presence of 1.1 equiv of ZnBr2 (entry 1).
Comparatively, 2-chloromethylindole 3a0/3c0 produced
the respective phosphonate ester in diminished yield than
the 2-bromomethylindole 3a/3c (entry 1).
With the exception of 3-chloromethylindole 3l0, in all
other cases the reaction was found to be successful even in
the presence of electron-withdrawing functional groups
(entries 1-3). The reaction of bromomethyl ketone 3o
ꢁ
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G.; Kalek, M.; Jezowska, M.; Stawinski, J. New. J. Chem. 2010, 34, 967–
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Lett. 2006, 47, 7719–7721.
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Lett. 2003, 44, 7989–7992.
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2008, 10, 4271–4274. (b) Wang, J.-L.; Xiao, Q.; Pei, J. Org. Lett. 2010,
12, 4164–4167.
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Balamurugan, R.; Sureshbabu, R.; Senthil Kumar., N. Tetrahedron
Lett. 2008, 49, 5850–5854. (b) Dhayalan, V.; Arul Clement, J.; Jagan,
R.; Mohanakrishnan, A. K. Eur. J. Org. Chem. 2009, 4, 531–546. (c)
Sureshbabu, R.; Saravanan, V.; Dhayalan, V.; Mohanakrishnan, A. K.
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Org. Lett., Vol. 13, No. 6, 2011
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Table 1. ZnBr2-Mediated Michaelis-Arbuzov Reaction of Arylmethyl Halides/Alcohols and Aryl Aldehydes
a The reaction was performed using bromo compound (1 mmol), ZnBr2 (0.2 mmol), and P(OEt)3 (1.2 mmol) in dichloromethane. b The reaction was
performed using bromo compound (1 mmol), ZnBr2 (0.4 mmol), and P(OEt)3 (2.5 mmol) in dichloromethane. c The reaction was performed using
benzylic alcohol/benzyl chloride (1 mmol), ZnBr2 (1.1 mmol), and P(OEt)3 (5 mmol). d The reaction was performed using aldehyde (1 mol), ZnBr2 (1.1
mmol), and P(OEt)3 (1.3 mmol) in DCE.
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Org. Lett., Vol. 13, No. 6, 2011

failed to produce the expected phosphonate ester 4o and
instead led to the isolation of the respective debrominated
methylindole (entry 5). The Michaelis-Arbuzov reaction
was found to be successful with bis(bromomethyl) com-
pounds as well (entries 4 and 6-9). The reaction of
1-bromomethyl-2-nitroarenes 5d-h with triethyl phos-
phite in the presence of 20 mol % of ZnBr2 furnished the
respective phosphonate esters 6d-h in excellent yields
(entry 10). The ZnBr2-mediated Michaelis-Arbuzov reac-
tion of 1-chloromethyl-2-nitroarene 5d0/5e0 as well as
1-hydroxymethyl-2-nitroarene 5d00/5e00 was found to be
unsuccessful (entry 10). Recently, a facile Lewis-acid
mediated arylation of activated benzylic alcohols was
achieved in good yields.20 Hence, we propose to do a Lewis
acid mediated Michaelis-Arbuzov reaction of benzylic
alcohols. Accordingly, the interaction of electron-rich
heteroarylmethyl alcohols with triethyl phosphite in the
presence of 1.1 equiv of anhyd ZnBr2 led to the formation
of corresponding phosphonate esters in 75-93% yields
(entries 11-15). The interaction of indole-3-carboxalde-
hyde 7 with triethyl phosphite in the presence of 1.1 equiv
of ZnBr2 at room temperature furnished diphosphonate
ester 8 in 85% yield (entry 16). Under identical conditions,
the reaction of aryl aldehydes 9a-d led to the isolation of
respective R-hydroxyphosphonate esters 10a-d in
80-91% yields (entry 17). Gratifyingly, the interaction
of benzhydrol 11 with triethyl phosphite in the presence of
1.1 equiv of ZnBr2 at room temperature led to the isolation
of known phosphonate ester 12 in 89% yield (entry 18).
The reaction was found to be successful with secondary
benzylic alcohols as well (entry 19). As expected, the
reaction of ethyl bromoacetate 15a with triethyl phosphite
in the presence of 20 mol % of ZnBr2 at room temperature
led to the isolation of triethyl phosphonoacetate 16 in 93%
yield. However, under identical conditions, the reaction of
ethyl chloroacetate 15b with triethyl phosphite in the
presence of ZnBr2 failed to produce the phosphonate ester
16 (entry 20). Finally, the Lewis acid mediated Michae-
lis-Arbuzov reaction was also found to be unsuccessful
with n-hexyl bromide/n-butyl bromide (entry 21).
Scheme 3. Lewis Acid-Mediated Michaelis-Arbuzov Reaction
of Chiral Benzylic Alcohol/Bromide
triethyl phosphite in the presence of ZnBr2 (Scheme 3).
Usual workup and purification followed by HPLC analy-
sis (see the Supporting Information) indicated the forma-
tion of racemic phosphonate esters 20 and 22. Hence, it
may be concluded that the LA-mediated Michae-
lis-Arbuzov reaction of benzylic bromide/alcohol in-
volves only an SN1-type mechanism.
In summary, for the first time, LA-mediated Michae-
lis-Arbuzov reaction of arylmethyl as well as heteroar-
ylmethyl halides/alcohols was achieved at room tempera-
ture. The reaction has been successfully extended to the
synthesis of R-hydroxyphosphonate esters as well. The
2-nitroaryl phosphonate esters reported herein may find
application in the synthesis of alkaloids.22 The various
types of heteroarylmethyl phosphonates reported herein
may be regarded as crucial intermediates for the synthesis
of conjugated vinylenes.23
Acknowledgment. Financial assistance from the De-
partment of Science and Technology (DST), New Delhi,
is acknowledged. We thank DST-FIST for the high-reso-
lution NMR facility. A.K.M. thanks Dr. V. Kesavan for
HPLC data. G.G.R. thanks CSIR, New Delhi, for a SRF
fellowship.
Supporting Information Available. Experimental pro-
cedure along with characterization data and 1H and 13
C
To verify the mechanism of the Lewis acid mediated
Michaelis-Arbuzov reaction, (S)-(-)-1-phenylethanol
19/(R)-(þ)-1-phenylbromoethane 2121 was reacted with
NMR spectra of representative phosphonate esters. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Chem., Int. Ed. 2005, 44, 3913–3917. (b) Mertins, K.; Iovel, I.; Kischel,
J.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2006, 348, 691–695. (c)
Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal.
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gal, C.; Cava, M. P.; Baldwin, J. W.; Metzger, R. M. J. Org. Chem. 1998,
63, 3105–3112. (b) Amaladass., P.; Arul Clement, J.; Mohanakrishnan.,
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