On the scope of radical reactions in aqueous media utilizing quaternary ammonium salts of phosphinic acids as chiral and achiral hydrogen donors

Article abstract of DOI:10.1016/j.tetlet.2008.05.097

A broad range of fundamental free radical reactions such as hydrogen atom transfer, radical deoxygenations, and radical cyclizations utilizing quaternary ammonium salts of phosphinic acids as chiral and achiral hydrogen donors at room temperature are investigated. The reactions proceed in good to excellent yields with some degree of enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2008.05.097

Tetrahedron Letters 49 (2008) 4777–4779
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Tetrahedron Letters
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On the scope of radical reactions in aqueous media utilizing quaternary
ammonium salts of phosphinic acids as chiral and achiral hydrogen donors
a,
a
b
V. T. Perchyonok a,b, , Kellie L. Tuck , Steven J. Langford , Milton W. Hearn
*
*
a Centre for Green Chemistry, Monash University, Clayton 3800, Australia
b School of Chemistry, Monash University, Clayton 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A broad range of fundamental free radical reactions such as hydrogen atom transfer, radical deoxygen-
ations, and radical cyclizations utilizing quaternary ammonium salts of phosphinic acids as chiral and
achiral hydrogen donors at room temperature are investigated. The reactions proceed in good to excellent
yields with some degree of enantioselectivity.
Received 28 March 2008
Revised 10 May 2008
Accepted 20 May 2008
Available online 24 May 2008
Ó 2008 Published by Elsevier Ltd.
Radical hydrogen atom transfer reactions have become a versa-
tile and powerful tool for forming new bonds due to the mild and
neutral nature of this transformation as well as its broad functional
group tolerance.1,2 Considerable effort has been devoted to
developing free radical reactions in aqueous media as well as intro-
ducing a degree of stereochemical outcome into a desired transfor-
mation.3–7
Phosphinic acid has been used as a radical chain carrier and rad-
ical hydrogen donor,8 for processes including hydrogen atom
transfer,9 addition to carbon–carbon,10 and carbon–nitrogen dou-
ble bonds.11 It is proposed that quaternary ammonium hypo-
phosphites can generate radicals readily from alkyl halides as
well as playing the role of efficient surfactants thereby increasing
the solubility of organic molecules.8 Recently, Jang et al. reported
the use of quinine and quinidine-based chiral quaternary ammo-
nium hypophosphates for enantioselective radical additions to
C@N bonds in aqueous media (1:1 CH2Cl2–H2O).12 More recently,
triethylborane (Et3B/O2) has been applied successfully in free
radical reactions in aqueous and organic media as a radical chain
initiator as well as chain propagator.13–17
We chose to investigate the radical hydrogen transfer reaction
of 1-bromoadamantane (1-BrAd) in the presence of tetrabutylam-
monium hypophosphite based ionic liquids at either elevated tem-
peratures (80 °C, 10 wt % AIBN, H2O) or at room temperature
(0.5 equiv of Et3B/air, H2O) (Scheme 1). Reductions were carried
out with 0.1 M substrate partially solubilized in H2O and initiated
with AIBN (10 wt %) at 80 °C or at ambient temperature with Et3B/
air as a suitable radical initiator. The reduced product (adamantane
(Ad)) was obtained in good to excellent yields and characterized by
1H NMR spectroscopy and GC/MS analysis.
Table 1 lists data obtained for the hydrogen atom transfer of 1-
bromoadamantane as a model compound in water in the presence
of radical initiators such as AIBN (entry 1) as well as in the absence
H2PO2
(NBu4)
Br
In this Letter, we report the extension of the use of various hyp-
ophosphites for a diverse range of synthetic transformations with
certain mechanistic aspects being addressed. The advantages of
the quaternary ammonium hypophosphites (QAHPs) lie in their
tolerance, availability, and their ease of preparation. The quater-
nary ammonium hypophosphites are prepared by reaction of the
corresponding tetrabutylammonium salt or tertiary amine with
an equimolar amount of phosphinic acid at room temperature in
water. The chiral and achiral hypophosphites were prepared in
quantitative yields and did not require any additional purification.
Ad
1-BrAd
Scheme 1. Reduction of 1-bromoadamantane (1-BrAd) under various free radical
conditions.
Table 1
Reduction of 1-bromoadamantane under various free radical conditions in the
presence of tetrabutylammonium hypophosphite ðNBu4ÞþH2PO
as an efficient
ꢀ
2
hydrogen donor in water as the solvent
Entry
Additive
Temperature (°C)
Product
Yielda (%)
1
2
3
4
AIBN
Et3B/air
None
80
22
80
80
Ad
Ad
Ad
Ad
90
85
0
* Corresponding authors. Tel.: +61 3 990 55417/54510.
E-mail addresses: tamara.perchyonok@sci.monash.edu.au (V. T. Perchyonok),
kellie.tuck@sci.monash.edu.au (K. L. Tuck).
Phenol
0
Yields are determined via 1H NMR spectroscopy.
a
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.097

4778
V. T. Perchyonok et al. / Tetrahedron Letters 49 (2008) 4777–4779
Table 2
H3PO2
O
I
O
Reduction of 2-iodobenzoic acid (I-BA) in the presence of tetrasubstituted ammonium
hypophosphites (QAHPs) using 0.5 equiv of Et3B/air as a radical initiator in water at
22 °C
Additive
OH
OH
Entry
QAHP
Yielda (%)
H2O, Initiator
ðBu4NÞþH2PO
75
78
85
83
85
90
90
ꢀ
1
2
3
4
5
6
7
2
ðMe4NÞþH2PO
ꢀ
ꢀ
2
BA
I-BA
ðEt4NÞþH2PO
2
ðisoPr4NÞþH2PO
ꢀ
2
ꢀ
Scheme 2. Reduction of 2-iodobenzoic acid (I-BA) under free radical conditions in
aqueous media. (To confirm the radical nature of the transformation and to avoid
any ambiguity of the dual role of Et3B/air as a hydrogen donor and radical initiator,
additional control experiments were performed with 2-iodobenzoic acid as a rad-
ical precursor. Control experiments in the presence of Et3B/N2 or Et3B/O2 and in the
absence of H3PO2/additive yielded no reduced product. Repeated control experi-
ments in the presence of Et3B/N2 or Et3B/O2 and in the absence of H3PO2/no additive
yielded a small amount (<10%) of reduced product. The experimental outcomes are
in line with currently reported rates of background hydrogen atom transfer from
triethylborane in comparison to the published rates20 of H3PO2 as a hydrogen
ðOct4NÞþH2PO2
ðHex4NÞþH2PO
ꢀ
ꢀ
2
HDABCOþH2PO2
a
Yields were determined via 1H NMR spectroscopy.
of AIBN (entry 3) and in the presence of a radical inhibitor such as
phenol (entry 4). In parallel, 1-bromoadamantane underwent
hydrogen atom transfer using Et3B/air in water (entry 2) in the
donor.3c
)
Table 3
Various free radical reactions at room temperature in the presence of chiral and achiral tetrasubstituted-ammonium hypophosphites in water using 0.5 equiv of Et3B/air as a
radical initiator
Entry
QAHP
Radical precursor
Product
Yielda (%)
ꢀ
ꢀ
1
ðBu4NÞþH2PO
65
Br
2
2
2
3
ðBu4NÞþH2PO
ðBu4NÞþH2PO
64
73
Br
O
O
O
ꢀ
+
2
Br
ðBu4NÞþH2PO
ðBu4NÞþH2PO
87
47
ꢀ
ꢀ
4
5
2
2
Br
O
O
Br
OH
OH
O
O
O
O
ꢀ
ꢀ
6
7
ðBu4NÞþH2PO
86
77
2
EtO
OEt
EtO
OEt
Cl
ðBu4NÞþH2PO2
H
H
H
H
H
H
O
S
SMe
OEt
O
OEt
ꢀ
ꢀ
8
ðS; SÞ-HMe2NCHMePhþH2PO
Br
82b
2
O
Br
O
OEt
OEt
9
ðS; SÞ-HMe2NCHMePhþH2PO
76c
2
O
O
O
a
Yields reported for materials obtained without need for purification.
b
c
The absolute configuration of the final product was assigned to the (S)-enantiomer with 15% ee based on comparison of the optical rotation with the literature value.18
The absolute configuration of the final product was assigned as the (S)-enantiomer with 22% ee based on comparison of the optical rotation with the literature value.18

V. T. Perchyonok et al. / Tetrahedron Letters 49 (2008) 4777–4779
4779
presence of tetrabutylammonium hypophosphite, as an aqueous
ionic liquid. As expected, reaction of 1-bromoadamantane in the
absence of ‘aqueous ionic liquid’ yielded only unreacted starting
material (entry 3). Reaction in the presence of phenol, a well-
known free radical inhibitor, gave no formation of the reduced
product (entry 4), thereby confirming the free radical nature of
the transformation in question.
2-Iodobenzoic acid (I-BA) as a test case alkyl halide was reduced
under radical reduction conditions at room temperature in the
presence of Et3B/air (0.5 equiv) as a radical initiator (Scheme 2)
in the presence of a range of hypophosphite hydrogen donors, a
series of which were prepared from the corresponding achiral tet-
rasubstituted ammonium salts and H3PO2 (Table 2, entries 1–7).
The reduced product was obtained in good to excellent yields. This
transformation highlights the immense potential of the tetrasub-
stituted hypoposphites in green free radical chemistry.
To test the scope and limitations of this novel method, ‘aqueous
ionic liquids/hydrogen donors’ were subjected to a broad range of
typical radical precursors (1°, 2°) halides (Table 3, entries 1, 5, and
6), benzyl bromide (Table 3, entry 4) as well as the xanthate of
cholesterol (entry 7). Free radical cyclization of 1-(allyloxy)-2-bro-
mobenzene (Table 3, entry 3)19 proceeded smoothly under the
specified conditions at room temperature and the results are sum-
marized in Table 3. The same reactions were repeated at 80 °C
under predetermined reaction conditions using either AIBN
(10 wt %) (organic soluble radical initiator) or V-501 (10 wt %)
(a water soluble radical initiator) and comparable results were
obtained.
The results exceeded expectations as not only did the reactions
proceed with good to excellent yields but they also showed a
degree of stereoselectivity and enantioselectivity (Table 3, entry
8, 15% enantiomeric excess obtained. Table 3, entry 9, 22% enantio-
meric excess obtained). The results represent the first examples of
enantioselectivity being observed in free radical hydrogen transfer
reactions in aqueous media and work is currently in progress to
explore this novel aspect of enantioselectivity in an aqueous
environment.
General experimental procedure at ambient temperature: To a
solution of H3PO2 (20% solution in water, 5 equiv) and Bu4N+Clꢀ
(5 equiv) in water (5 ml) was added radical precursor (0.1 mmol)
followed by Et3B/air (0.5 equiv, 1 M solution in hexane). The solu-
tion was stirred at room temperature for 3 h. The reaction mixture
was then extracted with EtOAc (2 ꢁ 10 ml) and the organic phase
dried with MgSO4. The crude mixture did not require further puri-
fication and was analyzed by 1H, gCOSY NMR spectroscopy, and
GC–MS to confirm formation of the reduced product.
References and notes
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In conclusion, we have expanded the utility of novel and green
aqueous chiral and achiral hypophosphites and have applied them
to a broad range of organic halides as radical precursors in hydro-
gen transfer reactions, radical deoxygenation reactions as well as
in cyclizations. The performance of novel aqueous ionic liquids
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Acknowledgments
We wish to thank the Australian Research Council and Mon-
ash’s Centre of Green Chemistry for their support. Funding support
of the CSIRO Food Futures Flagship is also gratefully acknowledged.