2-Oxo promoted hydrophosphonylation & aerobic intramolecular nucleophilic displacement reaction

Article abstract of DOI:10.1039/c5ob01310k

Highly efficient catalyst free methods for the synthesis of α-hydroxy-β-oxophosphonates and α-oxoesters have been described. The existence of a 2-oxo group in α-oxoaldehydes is a key factor in promoting the reaction of the tervalent phosphite form towards 2-oxoaldehydes in the synthesis of α-hydroxy-β-oxophosphonates. The in situ activated α-C-H atom of α-hydroxy-β-oxophosphonates sustains aerobic intramolecular nucleophilic displacement in a curious way to produce α-oxoester.

Full text of DOI:10.1039/c5ob01310k

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2-Oxo Promoted Hydrophosphonylation & Aerobic Intramolecular
Nucleophilic Displacement Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Satyanarayana Battula,a,b Narsaiah Battini,a,b Deepika Singh,c Qazi Naveed Ahmeda,b
٭
DOI: 10.1039/x0xx00000x
www.rsc.org/
Highly efficient catalyst free methods for the synthesis of α- synthesis of α-hydroxyphosphonates that involves nucleophilic
hydroxy-β-oxophosphonates and α-oxoesters has been described. addition of H-phosphonates to carbonyl compounds. These
The existence of 2-oxo group in α-oxoaldehydes is a key factor in reactions need the aid of catalyst, including inorganic/ organic
promoting the reaction of tervalent phosphite form towards 2- bases, acids and metal salt promoters. However, most of these
oxoaldehydes in the synthesis of α-hydroxy-β-oxophosphonates. reactions experience several limitations in terms of toxicity of
The in situ activated α-C-H atom of α-hydroxy-β-oxophosphonates reagents, corrosiveness due to acid or basic reagents, moisture
sustains aerobic intramolecular nucleophilic displacement in a sensitivity of the catalyst, usage of stoichiometric or even more
curious way to α-oxoester.
amounts and high rates of reaction times.2 Here in, we primarily
report an efficient cayalyst free 2-oxo promoted
The most imperative feature of H-phosphonates in solution is its
existence as an equilibrium mixture of i) a tetra coordinate
hydrophosphonylation reaction resulting in the formation of α-
hydroxy-β-oxophosphonates which is an important structural unit in
bioactive natural products, viz., fosfazinomycins and Me-HPnA.8 The
versatility of these compounds has been further exploited in
development of novel concept based on air oxidative
intramolecular nucleophilic displacement reaction to α-oxoesters,9
which are recognized as structural elements in many biologically
active compounds10 and are also used as synthetic tool11 in
synthesis of several heterocyclic compounds (scheme 1). This
unique ability of α-hydroxy-β-oxophosphonates to generate α-
oxoesters is probably due to α-C-H activation by adjacent directing
groups, viz., carbonyl, hydroxy and phosphoryl group.
phosphonate form and ii)
a tervalent phosphite form. H-
phosphonates are generally considered as week nucleophiles; that
account for their low reactivity which renders their applications and
needs the aid of catalyst to ensue the reaction. It is well established
fact that the tautomeric equilibrium in solutions is mostly shifted
towards the tetra coordinate phosphonate but it can be shifted to
the phosphite (nucleophilic) form by appropriate catalysts, for
example, Lewis bases and acids.1 On the reactivity part, the
distinctive reactivity of H-phosponates against C=O and C=N system
has been well explored for generation of P-C bond (Pudovik,2
Kabachnik-Fields3 reactions). Amongst, hydrophosphonylation of
carbonyl compounds is considered as a powerful and direct method
for construction of α-hydroxy-β-oxophosphonates. These
compounds have played a key role as a structural unit in many
biologically active compounds and occupy a major position in
organophosphorus chemistry.4 Different methods reported for their
synthesis include i) reduction of keto phosphonates,5 ii) α-
hydroxylation of alkyl phosphonates,6 and iii) addition of trialkyl
phosphites to aldehydes.7 Till date, Pudovik reaction is considered
to be an efficient atom economic and simple method to the
Scheme 1. Catalyst free hydrophosphonylation and synthesis
to α- oxoesters.
In our continuing efforts with 2-oxoaldehyde, the present work
began with a reaction between 1a and 2a in toluene at 50 oC.
Surprisingly, we isolated 85 % of α-hydroxy-β-oxophosphonates 3a
in one hour without the aid of any external catalyst (entry 1, Table
1). Further screening was carried out to improve the yield of 3
(entry 2-5). Best yield of desired product 3a was produced when we
treated 1.0 mmol of phenyl glyoxal 1a with 1.1 mmol of diethyl H-
phosphonate 2a under neat conditions (98 %, entry 5). In contrary,
a.Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM),
Jammu, India-180001.
b.Academey of Scientific and Innovative Research (AcSIR Fax: +91-1912569333), 2-
Rafi Marg, New Delhi, India.
c.Quality Control and Quality Assurance (QC & QA), IIIM, Jammu, India-180001.
٭naqazi@iiim.ac.in (IIIM/1787/2015)
Electronic Supplementary Information (ESI) available: Experimental procedures,
analytical data for products, and NMR spectra of products. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the reactiona
hydes 1 and H-phosphonates 2 under the optimized condition as
demonstrated in Table 2. As we observed, irrespective of the
substitution, all the tested reactions were efficiently transformed to
the required product 3 in 10-25 min duration (92-99 %, 3a-3l).
Table 3. Scope the α-oxoester synthesisa
entry
additive
Temp (oC)
Time
Yields (%)b
3a
4a
1.
2.
3.
4.
5.
6.
7.
8.
9.
toluene
toluene
toluene
toluene
neat
50
rt
60 min
60 min
10 min
10 min
10 min
30 min
7 h
85
˂10
98
93
98
90
-
˂5
ꢀ
ꢀ
80
100
80
80
80
100
80
ꢀ
-
toluene
toluene
toluene
ꢀ
8
(4a, 73%)
(4d, 87%)
(4c, 80%)
(4b, 77%)
(4e, 76%)
73
65
˂10
7 h
ꢀ
7 h
ꢀ
a Reaction condition: phenylglyoxal 1a (0.46 mmol), diethyl phosphite 2a
(0.506 mmol), toluene (1 mL), temperature 80 C; for synthesis of 3a, 4a
needs 10 min and 7
chromatography.
o
(4f, 78%)
(4i, 78%)
b
h
respectively.
Isolated yields after column
o
(4h, 71%)
(4k, 72%)
(4g, 80%)
(4j, 69%)
when the same reaction was performed at 80 C in toluene for 30
min, we isolated α-oxoester 4a (along with 3a) in 8 % yield (entry 6).
This surprising result encouraged us, to further optimize the
reaction conditions for the generation of α-oxoester in good yields
(entry 7-9). We observed that reaction between 1a (1.0 mmol) and
(4l, 68%)
(4o, 70%)
2a (1.1 mmol) in toluene at 80 oC for
7 h furnished the
unprecedented product 4a in 73 % isolated yield (entry 7).
To establish the substrate scope of former reaction (hydrophospho-
nylation), several reactions were conducted between en 2-oxoalde-
(4m, 74%)
(4p, 75%)
(4n, 65%)
(4q, 67%)
Table 2. Scope of the α-hydroxy-β-oxophosphonates synthesisa
(4r, 69%)
(4t, 75%)
(4s, 70%)
a
Reaction condition: 2ꢀoxoaldehyde 1 (0.46 mmol), dialkyl phosphite 2
(0.506 mmol), toluene (1 mL), temperature 80 oC, reaction time 7ꢀ9 h.
(3b, 99%)
(3e, 95%)
(3c, 98%)
(3a, 98%)
(3d, 93%)
Further, several reactions were conducted to the synthesis of α-
oxoester based on its standard reaction protocol (Table 3). It was
clearly observed that electronic environment of phenyl ring in 2-
oxoaldehyde had no appreciable effect on the reaction and their
yields. Based on our observation, the 2-oxoaldehydes bearing
electron withdrawing groups, for example, -F (4b, 4c, 4d), -Cl (4e), -
Br (4f, 4g) and -NO2 (4h, 4i) afforded a little bit higher yields than
those with electron donating groups either at meta or para
position, for example -OCH3 (4j, 4k, 4l, 4m), –CH3 (4n, 4o, 4p)
groups. The disubstituted 2-oxoaldehydes also produced
comparable yields, for example, 4q, 4r, 4s. In the case of
naphylglyoxal, reaction was very smooth and produced desired
product (4t) in good yield. Among different phosphite esters 2 used,
benzyl phosphites comparably gave higher yields.
(3f, 97%)
(3i, 98%)
(3g, 95%)
(3j, 96%)
(3h, 92%)
(3k, 97%)
(3l, 92%)
a
Reaction condition: 2ꢀoxoaldehyde 1 (0.46 mmol), dialkyl phosphite 2
(0.506 mmol), temperature 80 oC, reaction time 10ꢀ25 min.
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O
Looking into the unprecedented behavior of later reaction (α-
oxoester generation), we initiated test reaction where in
OEt
P
O
P
a
neat
80 o
(1)
CHO
OEt
H
OEt
+
OH
6 (0%)
compound 3a [diethyl(1-hydroxy-2-oxo-2-phenylethyl)phosphon-
ate] when heated at 80 oC in toluene generated 4a in 80 % yield. In
this direction, different reactions were conducted using our earlier
generated α-hydroxy-β-oxophosphonates as starting material
(Table 4). In all the reactions, we observed that the conversion of 3
to its corresponding α-oxoesters was very smooth and produced
good yields. The yields of α-oxoesters from α-hydroxy-β-
oxophosphonates were observed a bit higher than the direct
synthesis described Table 3.
OEt
2a
O
C
5
OH
CHO
neat
80 o
OEt
(2)
OEt
P
+
P
H
OEt
OEt
2a
O
C
O
8 (0%)
7
OEt
OEt
OEt
P
toluene
80 o
(3)
O
9 (0%)
C
OH
6
OH
O
OEt
OEt
toluene
80 o
P
OEt
(4)
(5)
C
O
Table 4. Scope of the conversion of 3 to 4a
8
10 (0%)
O
O
OEt
toluene
80 o
O
P
HO
C
O
OEt
EtO
4a (0%)
O
11
O
O
P
anhydrous
toluene
OEt
CHO
(6)
(7)
H
OEt
+
OEt
80 o
Ar
C
O
1a
2a
4a (<10%)
O
O
O
P
(4a, 79%)
(4f, 75%)
(4c, 82%)
(4n, 77%)
OEt
(4d, 89%)
(4p, 76%)
TEMPO
toluene
CHO
+
H
H
H
OEt
OEt
O
80 o
C
1a
2a
4a (73%)
O
O
O
P
OEt
CHO
CHO
(8)
(9)
+
+
OEt
a Reaction condition: αꢀhydroxyꢀβꢀoxophosphonates 3 (0.18 mmol) and
O
4a (52%)
O
OEt
EtOH
80 o
C
1a
2a
toluene (1 mL), temperature 80 oC, reaction time 7ꢀ9 h.
O
O
P
OPh
Ph
To interpret the intrinsic mechanism of 3 and 4, we performed a
series of controlled reactions (Scheme 2). In the series, first two
experiments (1, 2) involve reactions of 2-phenylacetaldehyde 5/
benzaldehyde 7 with 2a under standard conditions as mentioned in
Table 2. Both the reactions failed to produce hydrophosphonylated
products 6 & 8 respectively indicating the importance of 2-oxo
group of 2-oxoaldehyde in promoting hydrophosphonylation
reaction under catalyst free condition. In experiments (3, 4)
hydrophosphonylated product 6/or 8 (generated as per literature
procedure)12 heated at 80 oC in toluene remained stable for 24 h.
These results further emphasize the role of 2-oxo group, in
promoting the aerobic intramolecular nucleophilic displacement
reaction/ α-oxoester generation. In experiment (5), no
transformation of 1112 was observed in the synthesis of α-oxoester
4a which ultimately reveal that α-C-H atom exhibits the central role
in transformation of 3 to 4. In one more experiment (6), a reaction
was conducted at 80 oC between 1a and 2a in dry toluene under
argon atmosphere for 24 h. We observed very low yield of 4a,
which indicates the role of air as a promoter/ oxidant. In another
reaction, when performed between 1a and 2a in presence of
TEMPO (5 mmol) under optimized conditions gave desired 4a
product in comparable yields, thereby, excluding the possibility of
free radical mechanism (experiment 7). As expected in experiment
8, desired product 4a was generated in low yields when reaction
was conducted in EtOH. This clearly emphasized on role of H-
bonding interactions in promoting hydrophosphonylation/ aerobic
intramolecular nucleophilic displacement reaction. In addition, the
failure of experiment 9, performed between diphenyl H-
phosphonate 2f, and 1a under said conditions, undoubtedly pointed
toluene
80 o
O
Ph
C
1a
2f
(0%)
Scheme 2. Controlled experiments
αꢀCꢀH proton
O
O
O
O
P
missing of αꢀCꢀH proton
O
OH
DOP
Figure 1. 1H-NMR spectra of 3a, 4a along with its 1,2,3-
dioxaphosphetan intermediate.
towards the low nucleophilicity and more hindrance of phenoxy
group (-OPh).
In order to add further evidences to elucidate mechanism, we
keenly observed the changes in reaction between 1a and 2a at 80
oC with time. Preliminary, we monitored the reaction using TLC
(thin layer chromatography) technique. It was noticed that within
10 min, total reaction mass was converted to 3a, which later
gradually generated desired oxoester 4a through some
intermediate. Luckily, we could succeed in prediction of the
unstable intermediate as dioxaphosphetane, and that intermediate
was purified using preparative TLC and characterized by using 1H-
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O
O
P
O
OR
OR
O
OR
P
base/ catalyst free
H
P
OR
H
RO
O
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OH
OR
O
3
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O
O
O
O
O
O
O
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OR
OR
OR
OH
O2
OH
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O
O
O
O
O
O
O
O
O
O
O
OR
O
O
P
O
P
OR
OR
O
R
O
P
P
H
OR
OH
+
OR
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3
OH
OH2
O
O
DiOxaphosphetane
4
H2
(Isolated)
OR
Scheme 3. Plausible mechanistic scenario for synthesis of
and
3
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dioxaphosphetane intermediate (Figure 1).
4
On the basis of above results, the feasible pathway for formation of
3 and 4 was presented in Scheme 3. Through the assistance of H-
bonding due to 2-oxo group, the dialkyl H-phosphonate form shifts
towards more nucleophilic phosphite form. The phosphite 2 later
attacks 2-oxoaldehyde 1 generating desired product 3. Compound 3
on heating in toluene loses one proton that generates a resonance
stabilized carbanion. These carbanion later attacks molecular
oxygen that ultimately rearranges to dioxaphosphetane
intermediate and releases alkoxy nucleophile. Under in situ acidic
environment the dioxaphosphetane undergoes nucleophilic
displacement reaction to 4 through elimination of H2O and PO3R
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Conclusions
In summary, we have developed efficient methods for the synthesis
of α-hydroxy-β-oxophosphonate and α-oxoester compounds. The
reaction presents simple and direct method compounds. The
reaction presents simple and direct method that justifies the
important role of 2-oxo group in activation/promoting the reaction
through H-bonding. In view of the broad functional group tolerance,
the ease of conducting such reactions, and the mild reaction
conditions, we envisage this protocol will be widely tailored in
synthetic chemistry. Further application towards aliphatic glyoxal is
in progress and will be disclosed in due course of time.
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