Substituent controlled reactivity switch: Selective synthesis of α-diazoalkylphosphonates or vinylphosphonates via nucleophilic substitution of alkyl bromides with Bestmann-Ohira reagent

Article abstract of DOI:10.1039/c4cc05684a

We report a substituent controlled nucleophilic displacement of alkyl bromides with Bestmann-Ohira reagent yielding either dimethyl diazoalkylphosphonates or (E)-vinylphosphonates. The dimethyl diazoalkylphosphonates could be readily converted into corresponding (E)-vinylphosphonates in the presence of Cu following nitrogen elimination in quantitative yields. This journal is

Full text of DOI:10.1039/c4cc05684a

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Substituent controlled reactivity switch: selective
synthesis of a-diazoalkylphosphonates or
vinylphosphonates via nucleophilic substitution of
Cite this: Chem. Commun., 2014,
50, 12896
Received 22nd July 2014,
Accepted 3rd September 2014
alkyl bromides with Bestmann–Ohira reagent†
Mukund M. D. Pramanik,ab Atul Kumar Chaturvediab and Namrata Rastogi*ab
DOI: 10.1039/c4cc05684a
www.rsc.org/chemcomm
We report a substituent controlled nucleophilic displacement of alkyl knowledge BOR has never been utilized in nucleophilic sub-
bromides with Bestmann–Ohira reagent yielding either dimethyl stitution reactions. Herein, we report our observations on the
diazoalkylphosphonates or (E)-vinylphosphonates. The dimethyl reaction of alkyl/benzyl bromides with BOR affording a-diazo-
diazoalkylphosphonates could be readily converted into corre- ethylphosphonates or vinylphosphonates depending on the
sponding (E)-vinylphosphonates in the presence of Cu following substituent on the bromide.
nitrogen elimination in quantitative yields.
We started our investigation with commercially available
benzyl bromide 1a and the DAMP anion was generated in situ
The chemistry of organophosphorus compounds has witnessed by treating BOR 2 with various bases in methanol (Table 1).
enormous advancement in recent times.1 Vinylphosphonates While the desired product 3a was obtained with all the bases
are small molecules known for their interesting properties screened, 1 equivalent of KOH in MeOH appeared to be the best
spanning across chemistry as well as biology.2 They are suitable condition in terms of yield and reaction time (entry 4).
substrates for various name reactions3 and are regularly used in
Furthermore, other substrates 1b and 1c, under optimized
polymer industry4 and medicinal chemistry.5 Despite plenty of conditions, afforded styrylphosphonates 4b and 4c, respectively, as a
methods available for the synthesis of vinylphosphonates,6,7 result of nitrogen expulsion from initial diazo-arylethylphosphonates
their synthesis from readily available precursors remains a (Table 2, entries 2 and 3).13 However, such nitrogen elimination
highly desirable and ever appealing prospect.
did not take place in the case of m-nitro benzyl bromide 1d
On the other hand, a-diazoethylphosphonates are rare com- providing the diazo product 3d exclusively (entry 4). At this stage,
pounds8 and to the best of our knowledge there are very few we carefully selected benzyl bromides bearing substituents with
literature reports mentioning a-diazo-arylethylphosphonates.8d,e,g, j,k diverse electronic character at various positions for a systematic
The rare occurrence combined with the expectation that under examination of substituent effects on the reactivity of benzyl
suitable conditions a-diazo-arylethylphosphonates could be con- bromide towards BOR.
verted into cis- and trans-b-aryl vinylphosphonates selectively8a,g,9
The results summarized in Table 2 revealed that the b-aryl
prompted us to delineate a suitable method for their synthesis. vinylphosphonates 4 were obtained exclusively when the benzyl
We envisaged that the nucleophilic substitution of benzyl halides bromide carried electron withdrawing substituents at ortho- or
with dimethyl (diazomethyl) phosphonate (DAMP) anion could
afford the desired a-diazo-arylethylphosphonates in a single step.
Table 1 Screening of bases for the reaction of benzyl bromide 1a with
BOR 2a
The DAMP anion can conveniently be generated in situ from
Bestmann–Ohira reagent (BOR) 2.10 The BOR is commonly
used for the aldehyde to alkyne homologation11 or as a dipole
in the 1,3-dipolar cycloaddition reactions for the synthesis
of phosphonylated heterocycles.12 However, to the best of our
Entry
Base
Time (min)
Yield of 3ab (%)
a Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute,
Sector 10, Jankipuram extension, Sitapur Road, P.O. Box 173, Lucknow 226031,
India. E-mail: namrataiit@gmail.com, namrata.rastogi@cdri.res.in
b Academy of Scientific and Innovative Research, New Delhi 110001, India
† Electronic supplementary information (ESI) available: Complete analytical data
and copies of 1H, 13C and 31P NMR spectra of all new compounds. See DOI:
10.1039/c4cc05684a
1
2
3
4
K2CO3
KOt-Bu
NaOMe
KOH
30
30
20
15
60
55
85
87
a
All reactions were performed with 1 mmol of 1a, 1.2 mmol of 2 and
b
1.2 mmol of base in 5 mL of MeOH. Isolated yields.
12896 | Chem. Commun., 2014, 50, 12896--12898
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Table 2 Reaction of benzyl bromides 1 with BOR 2 under optimized
Table 3 Reaction of alkyl bromides 1 with BOR 2 under optimized conditions
conditions
Yield of
Entry
1
R
Product
3/4a (%)
1
2
3
4
5
6
a
b
c
d
e
f
H
4-NO2
2-NO2
3-NO2
4-Me
3-OMe
3a
4b
4c
3d
3e
3f
87 (85)b
85 (80)b
88
80
78
Yield of
Entry
1
R
Product 3/4a (%)
79
7
8
9
10
11
12
13
14
g
h
i
j
k
l
2-Br
3-Br
4-F
2-CN
3g
3h
3i
4j
4k
4l
76
75
78
86
83
78
80
79
1
2
3
4
5
6
7
8
o
p
q
r
s
t
Vinyl
3-Thienyl
2-CH2Br-Ph
4-CH2Br-Ph
Cinnamyl
2-Naphthyl
9-H-Fluorene
(E)-1-(2-Nitroethene)-4-methoxybenzene
3o
3p
3q
3r
3s
3t
4u
5
76
78
86
88
79
87
85
65
4-CN
2-NO2-3,4-(–OCH2O–)
2-NO2-5-Cl
2-NO2-3-OMe
m
n
4m
4n
u
v
a
b
Isolated yields. Yield for reaction at 1 gram scale.
a
Isolated yields.
para-positions (entries 2, 3, 10–14). The presence of an electron
withdrawing substituent at the meta-position did not cause
nitrogen elimination and afforded the a-diazo arylethylphos-
phonate 3 as the only product (entry 4). With benzyl bromides
bearing either no substituent (entry 1) or electron releasing
substituent (entries 5–9) at any position of the aryl ring, the diazo
arylethylphosphonates remained the preferred product. In the case
of benzyl bromides bearing two substituents with different electronic
properties, the effect of electron withdrawing substituent dominated
over the electron releasing one (entries 13 and 14). Here it is
noteworthy that the transformation of 1 to 3/4 could be carried
out in small as well as on gram scale with comparable yields (entries
1 and 2). The plausible mechanism compatible with these observa-
tions is depicted in Scheme 1. The benzyl bromide undergoes
SN2 substitution with the DAMP anion A generated in situ by basic
methanol promoted deacylation of the BOR 2. The resultant reso-
nance stabilized diazomethyl arylethylphosphonate 3 can be isolated
in the case of unsubstituted benzyl bromides or benzyl bromides
bearing substituents other than ortho- and para-electron withdraw-
ing ones. However, when benzyl bromide bears electron withdrawing
substituents at ortho- or para-positions, the benzylic proton, which is
sufficiently acidic due to the –M mesomeric effect of the
o-/p-substituent, undergoes 1,2-migration furnishing zwitterion B.
Zwitterion B following nitrogen elimination leads to the b-aryl
vinylphosphonate product 4.
Furthermore, in order to explore the potentialities of the
protocol, diverse substrates such as allyl bromide 1o, heteroaryl
bromide 1p, bis-bromomethyl benzenes 1q–1r, alkyl bromides
with extended conjugation 1s–1t and secondary bromide 1u were
studied (Table 3). We also used the allylic bromide 1v derived
from the Morita–Baylis–Hillman (MBH) alcohol of (E)-4-methoxy
nitrostyrene14 since this substrate can react with BOR in different
capacities i.e. substitution and/or cycloaddition.
The reaction proceeded well with allyl bromide 1o as well as
with 3-(bromomethyl)thiophene 1p, furnishing the diazo products
3o and 3p, respectively, in high yields (entries 1 and 2). In the case
of 1,2- and 1,4-bis-bromomethyl benzenes 1q and 1r only one
bromide underwent substitution with the diazomethylphosphonate
group while the other bromide was replaced by the methoxide
anion from the solvent (entries 3 and 4). In both these cases, the
excess BOR suffered decomposition within 15 min. The extended
conjugation in 1s and 1t appears to exert a negligible effect on the
acidity of b-hydrogen, leading to the isolation of diazo products in
both the cases (entries 5 and 6). However, 1u possessing secondary
bromide afforded the vinylphosphonate product 4u as expected,
due to the enhanced stability of the secondary carbanion generated
during the reaction leading to nitrogen expulsion (entry 7). It was
interesting to note that the MBH product derived allyl bromide 1v
preferred dipolar cycloaddition over nucleophilic substitution
of bromide with the DAMP anion. However, the bromide group
was replaced with the methoxide anion from the solvent yielding
product 5 (entry 8).
Finally, in order to convert the dimethyl diazoethylphosphonate
products 3 into corresponding vinylphosphonates 4 stereo-
selectively, we analyzed the possibility of nitrogen elimination
Scheme 1 Plausible mechanism for the formation of 3 and 4.
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Table 4 Conversion of dimethyl diazoethylphosphonates 3 into vinyl-
phosphonates 4a
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Entry
3
R
Product
Yield of 4b (%)
1
2
3
4
5
6
7
8
a
d
e
f
g
h
i
o
p
q
r
Ph
4a
4d
4e
4f
4g
4h
4i
4o
4p
4q
4r
98
88
98
96
95
91
98
85
95
96
96
96
3-NO2-Ph
4-Me-Ph
3-OMe-Ph
2-Br-Ph
3-Br-Ph
4-F-Ph
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Vinyl
9
3-Thienyl
2-CH2OMe-Ph
4-CH2OMe-Ph
2-Naphthyl
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t
4t
a
All reactions were performed with 1 mmol of 3 and 10 mol% of Cu
b
powder in 5 mL of toluene. Isolated yields.
´
´
´
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under base catalyzed,9 acid catalyzed9 as well as metal catalyzed8a,9
conditions (see ESI,† Table S1). The copper catalyzed decomposi-
tion of 3a which is likely to proceed via a carbenoid intermediate
and therefore expected to provide a cis–trans mixture of the
corresponding vinylphosphonate8a,9,15 provided the trans isomer
4a in excellent yield in toluene (see ESI,† Table S1). Thus other
dimethyl diazoethylphosphonates 3d–i, 3o–r and 3t were converted
into corresponding vinylphosphonates under the optimized reac-
tion conditions (Table 4). However, dimethyl-a-diazo-4-phenylbut-
3-enylphosphonate 3s under these conditions led to a complex
mixture of products.
In summary, we devised an efficient method for the selective
synthesis of substituted dimethyl diazoethylphosphonates and
(E)-vinylphosphonates via a nucleophilic substitution reaction of
commercially available and inexpensive bromides with Bestmann–
Ohira reagent. The diazoethylphosphonates obtained were smoothly
transformed into corresponding (E)-vinylphosphonates by copper
mediated nitrogen expulsion.
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MMDP and AKC thank CSIR, New Delhi, and UGC, New Delhi,
respectively, for the PhD fellowships. We thank SAIF division of
CSIR-CDRI for the analytical support and CSIR-Network project
‘BSC0102’ (CSIR-CDRI-THUNDER) for the financial support. We
also thank Dr B. Kundu, Chief Scientist & Head, Medicinal &
Process Chemistry Division, CSIR-CDRI, for helpful discussions.
CDRI Communication No: 8784.
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13 Configuration assigned on the basis of chemical shifts and JP–H
coupling constants.
Notes and references
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12898 | Chem. Commun., 2014, 50, 12896--12898
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