BuLi-triggered phospha-Brook rearrangement: Efficient synthesis of organophosphates from ketones and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2015.04.073

A variety of organophosphates are synthesized from n-BuLi-triggered, (additional) solvent-free reactions of diethyl phosphite with both activated/unactivated ketones and aldehydes preferably at room temperature via phospha-Brook rearrangement. We could successfully synthesize the naphthylic/allylic phosphates using this approach.

Full text of DOI:10.1016/j.tetlet.2015.04.073

Accepted Manuscript
n-BuLi-Triggered Phospha-Brook Rearrangement: Efficient Synthesis of Or-
ganophosphates from Ketones and Aldehydes
Gangaram Pallikonda, Ranga Santosh, Subhas Ghosal, Manab Chakravarty
PII:
S0040-4039(15)00710-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.073
TETL 46212
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2015
16 April 2015
18 April 2015
Please cite this article as: Pallikonda, G., Santosh, R., Ghosal, S., Chakravarty, M., n-BuLi-Triggered Phospha-
Brook Rearrangement: Efficient Synthesis of Organophosphates from Ketones and Aldehydes, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.073
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Gangaram Pallikonda, Ranga Santosh, Subhas Ghosal, Manab Chakravarty*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
n-BuLi-Triggered Phospha-Brook Rearrangement: Efficient Synthesis of
Organophosphates from Ketones and Aldehydes
Gangaram Pallikonda, Ranga Santosh, Subhas Ghosal and Manab Chakravarty
*
Birla Institute of Technology and Sciences, Pilani -Hyderabad Campus
Jawahar nagar, Shamirpet, Hyderabad-500078, India.
Fax: +91-040 66303998
E-mail: manabchakravarty@gmail.com.
ARTICLE INFO
ABSTRACT
Article history:
Received
A variety of organophosphates are synthesized from n-BuLi-triggered, (additional) solvent–
free reactions of diethyl phosphite with both activated/unactivated ketones and aldehydes
preferably at room temperature via phospha-Brook rearrangement. We could successfully
synthesize the naphthylic/allylic phosphates using this approach.
Received in revised form
Accepted
Available online
Keywords:
Phosphate
2009 Elsevier Ltd. All rights reserved.
Phospha-Brook rearrangement
Solvent-free conditions
Lithium
Phosphorylation
The chemistry of organophosphates has been extensively studied
because they play significant roles in many major physiological
processes such as energy transfer, photosynthesis etc.1 The
phosphates were also successfully used in versatile organic
synthesis2 including Cu/Pd-catalyzed cross-coupling reactions to
access di/triarylmethanes.2b-d Specifically, the benzylic and allylic
phosphates were employed for the conversion of alcohol to azide
via phosphate activation.2e These phosphates were also shown to
exhibit the anomalous behaviour to produce allyl or benzyl
iodides by the treatment of iodotrimethylsilane.2f Therefore, the
synthesis of organophosphates has shown a significant topic of
interest. The main conventional procedure for the synthesis of
phosphates includes the phosphorylation of alcohols with highly
air sensitive and hazardous phosphorus halides in the presence of
a base.3 Recently, an efficient synthesis was reported by iodine
catalyzed phosphorylation of alcohols in the presence of H2O2.4
The organophosphates were also obtained as a minor/major
product from the base mediated synthesis of α-
hydroxyphosphonates5a-b and α-aminophosphonates5c-d starting
from aldehydes or few selective ketones via phosphorylation
rearrangement (phospha-Brook) (path I, Scheme 1). It is also
relevant to mention that α-hydroxyphosphonates can also
undergo base catalyzed retro-hydrophosphonylation reactions as
shown in path-II (Scheme 1).5 These transformations depend
upon the substrates, bases and the reaction conditions employed
for a particular reaction.5-6 This phospha-Brook rearrangement is
subjected to vary with the type of aldehydes or ketones and also
the bases.6 The several bases like NEt3,5a-b NaH,5b n-
butylamine,5c-d K2CO3/KOH (for phosphinate addition to
ketones),5e cinchona alkaloid/Na2CO3 (for asymmetric synthesis
t
of phosphates),5f NaOEt5g and BuOK5h were used for phospha-
Brook rearrangement reactions to afford organophosphates along
with hydroxyphosphonates.
path-I
Ar
O
RO
RO
O
RO
RO
P
base
P
OH
R1
O
R1
O
H
Ar
Ar
RO
RO
P
O
+
path-II
R1
Scheme 1 Transformations of α-hydroxyphosphonates in the
presence of base
Most of these routes suffer from several drawbacks like
the requirement of stoichiometric amount of bases, higher
temperature and the presence of unsafe solvents etc. It has been
observed that the aldehydes or ketones only with electron
withdrawing substrates prone to undergo this rearrangement.5,6
The attempt to get phosphates from the reactions of H-
phosphonates with acetophenone was not satisfactory as
mentioned in most of those reports. Therefore, with our present
research on organophosphorus chemistry,7 we demonstrate here
the n-BuLi- triggered route for the synthesis of organophosphates
from the direct reactions of diethyl phosphite with
activated/unactivated ketones or aldehydes preferably at r.t. (25
oC) under additional solvent-free conditions. A related DBU
catalytic method is known to afford phosphates only from
electron-deficient aldehydes or ketones in the presence of DMF
as solvent at elevated temperature (85 oC).8

2
In very recent studies, catalytic amount of
organolanthanides9a and n-BuLi9b (0.1 mol%) have been used to
synthesize α-hydroxyphosphonates from the reactions of
unactivated ketones with dialkyl phosphite under mild and
solvent-free conditions. By increasing the mol% (5-10) of n-BuLi
the yield of α-hydroxyphosphonates got reduced due to
aforementioned retro-hydrophosphorylation reactions.9b The
same observation was reported in the presence of hexane, used as
additional solvent. Surprisingly, in those reports, the formation of
phosphates was not stated under any circumstances. We could
isolate phosphates effectively when diethyl phosphite was treated
with ketones or aldehydes in the presence of 10 mol% n-BuLi
(1.6 M in hexane) at r.t. To the best of our knowledge, n-BuLi
was not explored as a triggering agent to synthesize phosphate
before in the literature. It is pertinent to note that the unexpected
phosphate formation is one of the major pitfalls for the base
catalyzed synthesis of α-hydroxyphosphonates starting from
phosphites and ketones/ aldehydes and therefore the Lewis acid
catalyzed hydrophosphorylation of ketones is described in the
literature.10
and 1i (3-4 h). The presence of electron withdrawing groups in
case of 1g-h (analogues of 1i) makes the reactions faster as
expected. We could not isolate the corresponding α-
hydroxyphosphonates under the present reaction conditions in the
case of ketones.
As ketones were proved earlier to be less reactive in
phosphate formation,5c-d,8 we initiated our studies with easily
available, cheap benzophenone and diethyl phosphite to optimize
the reaction conditions by varying different bases (see Table 1).
Table 1. Screening of reaction conditions to optimize the
yield for phosphate 1a.a
Scheme 2. Synthesis of phosphates from the reactions of ketones
and diethyl phosphite. ayields refer to chromatographically
Entry
Base (mol %) Time (h)
Temp (oC)
Yield of
1ab
b
purified products. yield is calculated based on 31P/1H NMR of
the reaction mixture (see supporting information for details)
1
NEt3 (100)
8 -14
8 -14
14
25- 65
25-65
25
n.rc
n.r
n.r
40
30
90
5
2
DIPEA (100)
K2CO3 (100)
K2CO3 (100)
tBuOK (100)
NaH (100)
Aldehydes also generated the corresponding phosphates
2a-g (Scheme 3) efficiently as expected. Surprisingly, our
attempt to perform these reactions at r.t. was not promising to
obtain the phosphates. In the case of compounds 4-
3
4
6
65
5
8
65
6
12
25
chlorobenzaldehyde,
2-fluorobenzaldehyde
and
1-
naphthaldehyde, the phosphate formation was observed at r.t.
only after 8-10 h. The reaction times were reduced by heating the
reaction mixture at 60 oC.
7
NaH (10)
8-14
25-65
25
8
Cs2CO3 (100) 12
92
30
n.r.
n.r.
n.r.
9
Cs2CO3 (10)
NMP (100)
piperazine
14
25
10
11
12
8-14
25-60
25-60
0-25
8-14
n-BuLi d(0.1- 10
5)
13
n-BuLi (10)
0.4
0-25
92
aReaction conditions: benzophenone (1 mmol), diethyl phosphite (1.2 mmol)
under additional solvent free conditions (except for entry 4 where THF was
used as solvent) in the presence of N2 balloon. bIsolated yield cn.r.:No
reaction dThe used n-BuLi strength: 1.6M in hexane.
Among different organic and inorganic bases, n-BuLi (10 mol%)
was much more effective to afford the phosphate 1a. Surprisingly
no reaction could be observed even with 0.1-5 mol% of n-BuLi.
Although the bases NaH and Cs2CO3 were equally effective for
this reaction but stoichiometric amount of bases were necessary
to access 1a in higher yield. A range of organophosphates (1a-i),
synthesized herein, are demonstrated in Scheme 2. To our
delight, both benzophenone and acetophenone reacted with
diethyl phosphite smoothly to furnish the phosphates 1a and 1i
respectively in excellent yields under the present conditions
whereas the earlier reported attempt to synthesize these
phosphates was not satisfactory.5b-c,8 Unexpectedly, the presence
of methyl group(s) in one of the benzene rings for benzophenone
also led to the smooth formation of compounds 1b (100%,
verified by 31P/1H NMR). Unfortunately 1b could not be purified
using column chromatography (SiO2) as it got decomposed in the
column and afforded the compound phenyl(p-tolyl)methanol.
Fluorene based phosphate 1f5c was also successfully produced at
room temperature in a manner similar to other phosphates. Most
of these phosphates were formed within 10-20 min excluding 1f
Scheme 3. Synthesis of phosphates from the reactions of
aldehydes and diethyl phosphite. ayields refer to
chromatographically purified products.
The reactions of aldehydes with diethyl phosphite
generated corresponding α-hydroxyphosphonates initially at r.t.
and subsequently formed phosphates upon heating. In
comparison to the earlier report on DBU-catalayzed phosphate
synthesis,8 important phosphates 2d and 2f were synthesized here
in excellent yields using n-BuLi as
a triggering agent.
Replacement of n-BuLi with NaH failed to afford the product 1i
as reported earlier.5b
Furthermore, we could generate very useful allylic
phosphate 2g successfully from the reaction of (E)-α-

3
methylcinnamaldehyde with diethyl phosphite in the absence of
any additional solvent. The room temperature reaction produced
SR/FT/CS-129/2011. GP thanks BITS, Pilani-Hyderabad
Campus Campus and RS thanks CSIR for the fellowship.
We also acknowledge reviewers for helpful suggestions.
compound
2g
along
with
the
corresponding
α-
hydroxyphosphonate as a mixture (1:1), from which compound
2g was isolated in moderate yield (40%). The yield of 2g was
improved to 73% when the reaction was performed at 60 oC.
Notably this compound 2g has been used in asymmetric allylic
silylation11a and formation of enantioselective intermediates that
have applications to natural product synthesis.11b It is interesting
to note that the alkyl lithium mediated reverse phosphate- α-
hydroxyphosphonate rearrangement is reported in the literature12,
however, we could not observe such a fact from our studies.
Based on the earlier reports5,6 and our experimental
General Procedure: n-BuLi (0.17 mL of a 1.6 M solution in
hexanes, 0.274 mmol, 0.1 equiv) was added drop wise to diethyl
phosphite (0.45 mL, 3.29 mmol) at room temperature (rt) under
o
N2 balloon at 0 C. The resulting solution was stirred at rt for 2
min. Then, benzophenone (500 mg, 2.74 mmol) was added and
the resulting solution was stirred at rt for 15 min. After
completion of the reaction as indicated by TLC, the reaction
mixture was quenched with saturated NH4Cl solution. The
aqueous layer was extracted with ethyl acetate (3 x 25 ml). After
filtration and removal of solvent in vacuum, the crude product
was purified by column chromatography using ethylacetate/ pet
ether (20/80) as the eluent to afford 1a. Unless otherwise stated,
all the other compounds 1b-i were prepared analogously using
similar molar quantities of carbonyl compounds, diethyl
phosphite and n-BuLi. In case of aldehydes, reactions were
observations, the mechanistic scheme for synthesis of phosphates
is presented in Scheme 4. In case of aldehydes, the intermediate
II was isolated and the corresponding product α-
hydroxyphosphonates were obtained upon work-up whereas the
intermediate II could not be isolated for ketones as mentioned
earlier. To understand this difference in reactivity, density
functional theory (DFT) studies were performed and that
revealed the carbanion IV is formed via three-membered
transition state III. It was found that the activation energy to
form III is much higher (~10 Kcal/mol, see SI for details) in case
of benzaldehyde compared to benzophenone. Therefore, the
transformation from II to IV is much slower for benzaldehyde.
Presumably, for that reason, we could isolate the corresponding
α-hydroxyphosphonates for aldehydes but not for ketones at r. t.
Thus, we can also explain the favourable phosphate formation for
ketones in comparison to aldehydes.
o
performed in a manner similar to the phosphates 1a-i at 60 C.
All the spectroscopic data is included in the supporting
information.
References and notes
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Scheme 4. Plausible Mechanistic pathway for the formation
of phosphates
From this scheme 4, it is clear that n-BuLi triggers the reaction.
This could explain the fact that the transformation does not work
at lower loadings of this reagent because the concentration of the
carbanion would be too low to maintain a workable concentration
of the phosphite anion, and the catalytic cycle would fade out.
The stability of the intermediate IV in the presence of electron
donating substituent(s) could be explained by the fact of tight
ion-pair formation (not much polar bond) with smaller alkali
metal Li. The extra stability of this intermediate could also arise
due to the coordination of Li ion with the phosphoryl (P=O)
oxygen and that led to the formation of stable five membered
chelate ring.13
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2335 and references cited therein.
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128, 1173.
In conclusion, both ketones and aldehydes are
conveniently used to generate phosphates from the n-BuLi-
triggered reactions with diethyl phosphites under solvent-free and
mild conditions. In this approach, the ketones with electron
donating substituents can also be applied successfully. The
synthetically useful allylphosphate also could be synthesized
using this protocol. Mechanistic studies on this rearrangement for
other substrates and applications of these phosphates towards
organic synthesis are currently ongoing in our laboratory.
Acknowledgments
MC thanks DST-SERB (SB/S1/IC-07A/2013) for financial
support and SG acknowledge support from DST grant no.