In situ generation of phosphoryl alkylindiums and their synthetic application to arylalkyl phosphonates via palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/ol502540z

Phosphoryl alkylindium reagents are generated in situ from the direct insertion of indium with bromoalkyl phosphonates in the presence of CuCl, and their synthetic application to arylalkyl phosphonates is reported via a Pd-catalyzed cross-coupling reactio

Full text of DOI:10.1021/ol502540z

Letter
pubs.acs.org/OrgLett
In Situ Generation of Phosphoryl Alkylindiums and Their Synthetic
Application to Arylalkyl Phosphonates via Palladium-Catalyzed
Cross-Coupling Reactions
Sanghyuck Kim, Cheol-Eui Kim, Boram Seo, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Phosphoryl alkylindium reagents are generated
in situ from the direct insertion of indium with bromoalkyl
phosphonates in the presence of CuCl, and their synthetic
application to arylalkyl phosphonates is reported via a Pd-
catalyzed cross-coupling reaction with tolerance of a diversity
of functional groups including ester, ketone, aldehyde, nitrile,
nitro, trifluoromethyl, chloride, methoxy, hydroxy, and amino.
Scheme 1. Previously Reported Synthetic Methods of 2-Aryl
Phosphonates
rganophosphonate is an essential functional group in
synthetic as well as biological chemistry.1 In synthetic
O
chemistry, it is a starting material for the preparation of alkenes
via the Horner−Wadsworth−Emmons reaction.2 In biological
chemistry, their distinctive structure and polarity provide them a
significant function in pharmaceuticals and agrochemicals.3
Therefore, a wide range of synthetic intermediates and
precursors and biologically active compounds require intro-
duction of a phosphonate group to the molecule. To date, the
most conventional approaches for the formation of the P−C
(sp3) bond are the Michaelis−Arbuzov4 and Michaelis−Becker
reactions.5 Despite its prevalence, the trivalent phosphorus
compounds employed in the Michaelis−Arbuzov reaction
have normally low stability and effuse a repulsive odor. The
Michaelis−Becker reaction occasionally needs long reaction
times and a strong base. Thus, we envisioned that if
organometallic reagents having a phosphonate group can be
successfully prepared, it will be an efficient synthetic method of
functionalized organophosphonates via C−C bond-forming
reaction.
Because 2-aryl phosphonate derivatives have been known
to be inhibitors of the human low molecular weight protein
tyrosine phosphatase (HCPTP),6 synthesis of these compounds
from easily accessible precursors has been continuously
investigated (Scheme 1): Cu-catalyzed synthesis of alkylphosph-
onates from H-phosphonates and N-tosylhydrozones (a),7 the
reductive deoxygenation of acyl phosphonates (b),8 reaction of
phosphorus-containing carbenoids with organoboranes (c),9
Cs2CO3-promoted synthesis of phosphonates (d),10 and
reaction of zirconocene−alkene complexes with chlorophos-
phate (e).11 As shown in Scheme 1, all of these reactions were
achieved via the formation of the P−C (sp3) bond. In contrast,
Takagi and co-workers recently reported a Rh-catalyzed cross-
coupling reaction of arylzinc reagent with 2-iodoethyl phos-
phonate, leading to 2-aryl phosphonates via the formation of a
C−C bond (f).12 However, as far as we are aware, there are no
synthetic methods for 2-aryl phosphonates via the cross-coupling
reaction of electrophilic coupling partners with 2-phosphoryl
organometallic compounds, which are the polarity-inversed
method of pathway (f).
This has triggered intensive investigations on the polarity-
inversed synthetic method of 2-aryl phosphonates. Such a
reaction would enable 2-aryl phosphonates to be easily obtained
from 2-halo phosphonates and aryl halides. In continuing efforts
to develop a synthetic method of organophosphorus com-
pounds13 and organoindium reagents,14,15 we describe herein in
situ generation of phosphoryl alkylindium reagents from the
reaction of bromoalkyl phophonates with indium and their
synthetic application to arylalkyl phosphonates via Pd-catalyzed
cross-coupling reactions (Scheme 2).
Initially, diethyl 2-bromoethylphosphonate (1a) obtained
from triethyl phosphite and 1,2-dibromoethane was selected as
the substrate to explore in situ generation of 2-phosphoryl
indium reagent 2a. After many attempts, it was found that the
insertion took place smoothly in the presence of indium (1.4
equiv) and CuCl (1.4 equiv) in refluxing THF for 12 h, providing
quantitatively the β-phosphoryl indium reagent 2a (Figure 1).
However, In/LiCl, In/CuI/LiCl, In/CuI, In/InCl3, and InCl3
Received: August 28, 2014
Published: October 22, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol502540z | Org. Lett. 2014, 16, 5552−5555

Organic Letters
Letter
(4-CF3C6H4)3P in the presence of LiCl were used as catalyst,
DMSO provided 2-(4-butylphenyl)phosphonate (4am) in 34%
yield (entry 4, see the Supporting Information). DMA, NMP,
and DMF are less effective (entries 1, 2, and 3). Among the
copper salts examined, CuCl is superior to CuBr and CuI (entries
4−6). Next, a myriad of ligands such as (4-MeOC6H4)3P, DPPP,
DPPE, DPPF, DPEphos, Xantphos, (C6F5)3P, and (2-furyl)3P
were screened, and thus, sterically bulky CyJohnphos gave the
best result (76% yield) in DMSO at 70 °C for 6 h (entry 15).
Next, 2-phosphoryl indium reagents derived from diethyl 2-
haloethylphosphonates were employed in the coupling reaction
with ethyl 4-iodobenzoate (3e) under the optimum reaction
conditions (eq 1). Although diethyl 2-chloroethylphosphonate
Scheme 2. In Situ Preparation of Phosphoryl Alkylindiums
and Their Synthetic Application to Arylalkyl Phosphonates
(1c) was totally ineffective, the corresponding bromide and
iodide gave the desired coupling product 4ae in 88% and 58%
yields, respectively.
Inspired by these results, a wide range of aryl iodides 3 were
examined to demonstrate the scope and limitation of the
coupling reaction using the 2-phosphoryl ethylindium reagents
2a (Scheme 3). When iodobenzene and 1-iodonaphthalene were
treated with 2-phosphoryl indium, the desired 2-aryl phospho-
nates 4aa and 4ab were obtained in good yields. Electronic
variation of substituents at the arene moiety of aryl iodides had
little effect on the reaction efficiency. It is noteworthy that
electron-withdrawing groups such as ethoxycarbonyl, acetyl,
formyl, nitrile, nitro, trifluoromethyl, and chloride are tolerable in
the cross-coupling reaction, which makes the present method
useful. Aryl iodides having electron-withdrawing ethoxycarbonyl
groups at the meta and para position underwent the cross-
coupling reaction in high yield. However, an o-ethoxycarbonyl
substituent lowered the reactivity, probably due to steric reasons
(4ac). Also, the cross-coupling reactions of 2-phosphoryl indium
reagent 2a with aryl iodides bearing an electron-donating methyl,
butyl, and methoxy group proceeded smoothly to deliver the
desired compounds in good yields ranging from 78% and 82%.
An unmasked hydroxyl group was compatible with the present
reaction conditions, affording the desired product 4ao in 76%
yield. 3-Iodoaniline was also converted to 2-(3-aminophenyl)
phosphonate 4ap without protection albeit in slightly low yield.
1,4-Diiodobenzene was effectively coupled with 2-phosphoryl
indium reagent 2a (3 equiv), producing diphosphate 4aq in 66%
yield.
Figure 1. In situ generation of 2-phosphoryl indium reagents.
were not effective for the insertion (see the Supporting
Information).15
Encouraged by this promising result, we investigated a Pd-
catalyzed cross-coupling reaction of 2-phosphoryl indium 2a
with 4-iodobutylbenzene (3m) (Table 1). When Pd2(dba)3 and
Table 1. Pd-Catalyzed Cross-Couplings Using 2-Phosphoryl
a
Indiums
b
entry
ligand
solvent
temp (°C) time (h) yield (%)
1
2
3
4
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-CF3C6H4)3P
(4-MeOC6H4)3P
DPPP
DMA
80
80
80
80
70
70
70
70
70
70
70
70
70
70
70
2
5
5
5
3
5
5
5
5
5
1
6
4
2
6
12 (48)
21 (60)
13 (41)
34 (38)
15 (41)
N.R.
NMP
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
5
d
6
7
1 (76)
2 (84)
N.R.
8
9
DPPE
Upon increasing the chain length between the bromide
and the phosphoryl group, yields of the corresponding
(4-(ethoxycarbonyl)phenyl)alkyl phosphonates 4de and 4ee
were remarkably diminished (eqs 2 and 3). These results indicate
10
11
12
13
14
15
DPPF
7 (64)
14 (52)
6 (37)
28 (42)
14 (54)
76 (70)
DPEphos
Xantphos
(C6F5)3P
(2-furyl)3P
e
CyJohnphos
a
Indium reagent was prepared in situ from 1a (0.5 mmol), In
(1.0 mmol), and CuCl (1.0 mmol) in THF (1.5 mL) at 65 °C for 12 h.
After removal of THF, indium reagent was treated with Pd2(dba)3
(5 mol %), CyJohnphos (20 mol %), LiCl (0.5 mmol), and 3m
that the directing effect is induced by the phosphoryl group and
are in contrast to the reactivity of homologues of ester-containing
indium homoenolates.15d
Next, a variety of electrophilic coupling partners, including aryl
and vinyl bromides and aryl triflate, were investigated (Table 2).
b
(0.35 mmol, 1 equiv) in DMSO (1 mL). NMR yield using mesitylene
as an internal standard. Numbers in parentheses indicate yield of
c
d
4,4′-n-butyl-1,1′-biphenyl. CuBr was used instead of CuCl. CuI was
e
used instead of CuCl. Isolated yield.
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Organic Letters
Letter
Scheme 3. Pd-Catalyzed Cross-Couplings of 2-Phosphoryl
Ethylindiums with Aryl Iodides
Table 2. Pd-Catalyzed Cross-Couplings of 2-Phosphoryl
a
Indiums with Aryl Bromide and Triflate and Alkenyl
a
Bromide
a
Indium reagent was prepared in situ from 1a (0.5 mmol), In
b
(1.0 mmol), and CuCl (1.0 mmol) in THF (1.5 mL). Indium reagent
was prepared in situ from 1a (0.7 mmol), In (1.4 mmol), and CuCl
c
(1.4 mmol) in THF (3.0 mL). 50 °C.
with bromoalkyl phosphonates in the presence of CuCl. The Pd-
catalyzed cross-coupling reaction of the phosphoryl alkylindium
reagents with a number of aryl iodides, bromides, and triflates and
vinyl bromide proceeded smoothly to provide the functionalized
arylalkyl phosphonates in good to excellent yields. A wide range of
functional groups, including ester, ketone, aldehyde, nitrile, nitro,
trifluoromethyl, chloride, methoxy, hydroxy, and amino, are
tolerable in the cross-coupling reactions. Upon increasing the
chain length between the bromide and the phosphoryl group, the
directing effect by the phosphoryl group is observed.
a
Indium reagent was prepared in situ from 1a (0.5 mmol), In (1.0
b
mmol), and CuCl (1.0 mmol), in THF (1.5 mL). Indium reagent was
prepared in situ from 1a (0.7 mmol), In (1.4 mmol), and CuCl (1.4
mmol) in THF (3.0 mL). 1a (1.05 mmol), In (1.47 mmol), CuCl
(1.47 mmol), and 3q (0.35 mmol) were used.
c
ASSOCIATED CONTENT
■
The coupling reaction of 2-phosphoryl indium with ethyl
4-bromobenzoate (3r) proceeded smoothly at 70 °C to produce
4ae in 94% yield after 5 h. 4-Ethoxycarbonylphenyl trifluor-
omethanesulfonate (3s) was compatible with these reaction
conditions (entry 3). α-Bromostyrene (3t) was readily converted
to γ-phenyl phosphonate 4ar in good yield (entry 4).
Because direct preparation of organoindium reagent from
secondary alkyl bromide is generally difficult,15b the insertion
reaction followed by coupling reaction is a current challenge.
Reaction of ethyl 4-iodobenzoate (3e) with 2-phosphorylindium
reagent derived from diethyl 2-bromopropyl phosphonate (1f)
gave the desired product 4fe in acceptable yield (eq 4). However,
diethyl 2-bromo-2-methylethyl phosphonate (1g) is totally
ineffective (eq 5).
S
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
C
NMR spectra for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP)
(No. 2014001403).
REFERENCES
■
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In summary, we have developed in situ preparation of
phosphoryl alkylindiums from the direct insertion of indium
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