Radical-mediated intramolecular C-C bond formation and the deoxygenation of alcohols under solvent-free conditions with tributyl methyl ammonium hypophosphite

Article abstract of DOI:10.1016/j.tetlet.2011.10.063

A green, solvent-free protocol was developed for the radical-mediated intramolecular cyclization of haloacetals and the deoxygenation of S-methyl dithiocarbonates and cyclic thionocarbonate. This process uses tributyl methyl ammonium hypophosphite as a H-donor in the presence of triethylborane or t-butyl peroxide. This methodology provides eco-friendly reaction conditions.

Full text of DOI:10.1016/j.tetlet.2011.10.063

Tetrahedron Letters 52 (2011) 6927–6929
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Tetrahedron Letters
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Radical-mediated intramolecular C–C bond formation and the deoxygenation
of alcohols under solvent-free conditions with tributyl methyl ammonium
hypophosphite
⇑
Eun Hwa Lee, Dae Hyan Cho, Apuri Satyender, Doo Ok Jang
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A green, solvent-free protocol was developed for the radical-mediated intramolecular cyclization of halo-
acetals and the deoxygenation of S-methyl dithiocarbonates and cyclic thionocarbonate. This process
uses tributyl methyl ammonium hypophosphite as a H-donor in the presence of triethylborane or t-butyl
peroxide. This methodology provides eco-friendly reaction conditions.
Received 22 September 2011
Revised 8 October 2011
Accepted 11 October 2011
Available online 18 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Radical reaction
Solvent-free
Deoxygenation
C–C bond formation
Free radical reactions1 represent a ubiquitous class of synthetic
reactions that are traditionally performed in organic solvents.
Recently, efforts have been made to avoid highly volatile, environ-
mentally hazardous, and biologically incompatible organic sol-
vents for radical reactions. Research in this area has investigated
the use of ionic liquids, supercritical carbon dioxide, and fluorous
solvents.2 However, because of its cost, availability, and eco-
friendly nature, water remains an obvious choice for replacing
organic solvents.3 In green chemistry, the reduced use of solvents
is of paramount significance.4 In effect, ‘the best solvent is no sol-
vent.5 Solvent-free radical polymerization reactions are well docu-
mented in the literature.6 Except for a few isolated examples,7
however, the use of such methodology in free radical-based organ-
ic synthesis is scarcely investigated. There is a great need to devel-
op protocols for free radical reactions in the absence of solvent.
Phosphorous hydrides offer a viable alternative to organotin
hydrides.8 Tetraalkylammonium hypophosphites (THAPs) have
received much attention because they are economic, mild, and
known to readily generate radicals from alkyl halides.9 In addition,
they act as surfactants, increasing the solubility of organic com-
pounds.10 Previously, we reported the utility of various THAPs for
the radical deoxygenation of alcohols and the formation of car-
bon–hydrogen bonds in aqueous media without additives.11 Of
the THAPs developed, tributyl methyl ammonium hypophosphite
(TBMAP) was found to be an extremely useful hydride because it
exists in crystalline form at room temperature. This property al-
lows easy handling while its slight solubility in water facilitates
effortless synthesis, isolation, and purification. Due to concerns of
environmental pollution from the extensive use of volatile organic
solvents, we aimed to demonstrate radical-based reactions under
neat conditions using TBMAP.
Intramolecular radical cyclizations in solvents and aqueous
media are now well known.1,12 Due to ecological concerns, how-
ever, the development of an efficient synthetic methodology for
accomplishing these reactions under solvent-free conditions is of
considerable importance. We present here the intramolecular rad-
ical cyclization of haloacetals in solvent-free conditions using
TBMAP as a H-donor.
First, we studied the cyclization of various haloacetals, 1a–f, in
the presence of 5 equiv of TBMAP and 0.25 equiv of triethylborane.
At 60 °C and in neat conditions, this resulted in the cyclic products
2a–c (Table 1).13 The inherent reactivity of haloacetals varied and
was controlled by the nature of the substrate. 3-Iodo-2-(3-methyl-
2-propenyloxy)tetrahydropyran (entry 1) and 2-(hex-2-enyoxy)-
3-iodotetrahydro-2H-pyran (entry 3) reacted readily compared to
2-(cinnamyloxy)-3-iodotetrahydro-2H-pyran (entry 5). The phenyl
ring of the latter substance might have hindered radical cyclization
and caused the low yield of 2c. Bromo-derivatives underwent cycli-
zation quite slowly compared to the corresponding iodo-derivatives
(entries 2, 4, and 6), proving that the iodo-group is easily abstracted
by an TBMAP radical.
Mechanistically, this solvent-free radical cyclization proceeds in
the presence of triethylborane/oxygen via the initial generation of
⇑
Corresponding author.
E-mail address: dojang@yonsei.ac.kr (D.O. Jang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.063

6928
E. H. Lee et al. / Tetrahedron Letters 52 (2011) 6927–6929
Table 1
Table 2
Intramolecular radical cyclization of haloacetals 1
Deoxygenation of S-methyl dithiocarbonate 6a under various reaction conditions
O
O
S
O
O
R
TBMAP (5 equiv)
O
O
O
O
R'
O
SMe
O
Et3B (0.25 equiv), air
60 oC, 10 min
TBMAP (5 equiv)
Initiator,1 h
O
O
X
R'
R
O
1
2
O
O
Entry
Substrate
X
R
R0
Product
Yield (%)a
6a
7a
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
I
Br
I
Br
I
Br
Me
Me
n-Pr
n-Pr
Ph
Me
Me
H
H
H
2a
2a
2b
2b
2c
2c
90
58
93
85
31
11
Entry
Initiator (equiv)a
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
Et3B (0.25)
Et3B (1)
Et3B (3)
60
60
80
100
100
100
100
62
44
64
65
81
74
68
Ph
H
Et3B (2)
(tBuO)2 (0.25)
(tBuO)2 (0.5)
(tBuO)2 (0.75)
a
Isolated yield.
a
A needle was inserted through a rubber septum for an air inlet when Et3B was
used as initiator.
b
Isolated yield.
1) Radical Generation
Et3B
O2
Et2BOO
Et
Next, the cyclization of 1-(1-(allyloxy)-2-iodoethyl)-4-
methoxybenzene (3) was performed under the reaction conditions
and the desired product 4 was formed. However, product 4 had a
minor yield with 4-methoxy acetophenone (5) as a major by-prod-
uct (Scheme 2). Due to its hydrophobic nature, most of the starting
material may have not participated in the reaction. Instead it
decomposed, resulting in compound 5.
O
P
H
O
P
H
Et
Bu3NCH
3 O
H
EtH
Bu3NCH3
O
2) Cyclization
To evaluate optimized conditions, the radical deoxygenation of
alcohols using S-methyl dithionocarbonate 6a as a test substrate
was investigated (Table 2). Deoxygenation with triethylborane
gave moderate yields even at elevated temperatures (entries
1–4). However, using 0.25 equiv of t-butyl peroxide at 100 °C gave
7a in high yield (entry 5).14 Efforts to increase the yield of 7a with
excess initiator were futile (entries 6 and 7). The deoxygenation of
various S-methyl dithiocarbonates has been performed using
0.25 equiv of (tBuO)2 at 100 °C (Table 3). Both primary and second-
ary dithiocarbonates reacted smoothly and gave products in
respectable yields (entries 1–3). The rate of deoxygenation was
found to be faster without solvent than it was in water and yields
were comparable.11
O
P
H
Bu3NCH3
O
X
O
R'
O
R
R'
X
R
A
O
P
Bu3NCH3
O
H
The reaction of the cyclic thionocarbonate of (R,R)-tartarate 8
under solvent-free conditions was examined (Table 4). After con-
siderable experimentation, it was found that the optimal condi-
tions used 1 equiv of Et3B at 60 °C for 4 h to give product 9 in
63% yield (entry 6).
In conclusion, we have developed an efficient, eco-friendly, and
neat strategy for the radical-promoted C–C bond formation of halo-
acetals and the deoxygenation of S-methyl dithiocarbonates and
cyclic thionocarbonates. This method uses tributyl methyl ammo-
nium hypophosphite. Reaction temperatures and the type of radi-
cal initiator were critical factors for these radical-mediated
reactions in the absence of solvent. Deoxygenation proceeds faster
in solvent-free conditions. These reactions are clean and simple,
and prove the immense potential of tetrasubstituted hypophosph-
ite in green free radical chemistry.
O
O
R'
B
R
R'
O
P
H
R
Bu3NCH3
O
H
Scheme 1. Mechanistic pathway for the cyclization of haloacetals.
a phosphorous radical. The phosphorous radical then abstracts a
halogen from haloacetal A and the subsequent C–C bond formation
(of acetal radical) results in product B (Scheme 1).
MeO
MeO
MeO
O
TBMAP (5 equiv)
O
Et3B (0.25 equiv), air
O
I
70 oC,10 min
3
4 (27%)
Scheme 2. Cyclization of substrate 3.
5 (57%)

E. H. Lee et al. / Tetrahedron Letters 52 (2011) 6927–6929
6929
Table 3
Radicals in Organic Chemistry; Wiley: New York, 1995; (e) Motherwell, W. B.;
Crich, D. In Free Radical Chain Reactions in Organic Synthesis; Academic: New
York, 1992; Vol. 4,
Deoxygenation of various S-methyl dithiocarbonatesa
Entry
S-methyl dithiocarbonate
Product
Yield (%)b
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A. J.; Haddleton, D. M.; Bon, S. A. F.; Seddon, K. R. Chem. Commun. 2000, 1237;
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7406; (e) Matsubara, H.; Yasuda, S.; Sugiyama, H.; Ryu, I.; Fujii, Y.; Kita, K.
Tetrahedron 2002, 58, 4071.
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31, 2957; (c) Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc.
Jpn. 1997, 70, 2519; (d) Maitra, U.; Sarma, K. D. Tetrahedron Lett. 1994, 35, 7861;
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L. J. Am. Chem. Soc. 2001, 123, 8701; (e) Cave, G. W. V.; Raston, C. L.; Scott, J. L.
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Kaupp, G. J. Phys. Org. Chem. 2008, 21, 630.
S
9
O
SMe
9
7b
1
82
6b
S
O
SMe
2
3
73
77
7c
6c
S
O
O
O
O
O
SMe
O
O
O
O
7d
O
O
6. Odell, P. G.; Listigovers, N. A.; Quinlan, M. H.; Georges, M. K. ACS Symp. Ser.
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6d
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2003, 59, 77.
a
Reaction was performed using 0.25 equiv of (tBuO)2 at 100 °C.
Isolated yield.
b
Table 4
Reaction of the cyclic thionocarbonate of (R,R)-tartarate under various reaction
conditions
S
O
O
O
TBMAP (5 equiv)
initiator
OEt
OEt
EtO
EtO
O
O
OH
O
8
9
Entry
Initiator (equiv)a
Temp (°C)
Time (h)
Yield of 9 (%)b
1
2
3
4
5
6
(tBuO)2 (0.25)
(tBuO)2 (0.5)
Et3B (0.25)
Et3B (1.0)
Et3B (1.0)
Et3B (1.0)
100
100
100
60
60
60
0.5
1
0.5
1
3
4
35
38
42
43
51
63
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779.
13. Typical procedure for intramolecular cyclization of haloacetals with TBMAP: A
mixture of 3-iodo-2-(3-methylbut-2-enyloxy)tetrahydro-2H-pyran (1a)
(236 mg, 0.80 mmol), TBMAP (1.07 g, 4.0 mmol) and Et3B/air (0.20 mL,
0.20 mmol, 1 M solution in hexane) was heated at 60 °C for 10 min. After
completion of reaction, mixture was diluted with CH2Cl2, then washed with
aqueous Na2S2O3 solution, dried over MgSO4, and evaporated the solvent in
vacuo. The residue was purified by flash column chromatography over silica
gel (n-hexane/EtOAc, 9:1) to furnish 3-isopropylhexahydro-2H-furo[2,3-
b]pyran (2a) (122 mg, 90%).
a
A needle was inserted through a rubber septum for an air inlet when Et3B was
used as initiator.
b
Isolated yield.
Acknowledgment
This work was supported by the Center for Bioactive Molecular
Hybrids.
14. Typical procedure for deoxygenation of alcohols with TBMAP: a mixture of
1,2:5,6-di-O-isopropylidene3-O-(methylthio)thiocarbonyl-
a-D-glucofuranose
References and notes
(6a) (547 mg, 1.56 mmol), TBMAP (2.07 g, 7.81 mmol) and (tBuO)2 (71
lL,
0.39 mmol) was heated at 100 °C for 1 h. After completion of reaction, mixture
was diluted with CH2Cl2, then washed with aqueous Na2S2O3 solution, dried
over MgSO4, and evaporated the solvent in vacuo. The residue was purified by
flash column chromatography over silica gel (n-hexane/EtOAc, 7:3) to furnish
1. (a) Togo, H. Advanced Free Radical Reactions for Organic Synthesis; Elsevier, 2004;
(b) Renaud, P.; Sibi, M. P. In Radicals in Organic Synthesis; Wiley-VCH:
Weinheim, 2001; Vol. 1, (c) Parsons, A. F. An Introduction to Free Radical
Chemistry; Wiley-Blackwell, 2000; (d) Fossey, J.; Lefort, D.; Sorba, J. Free
3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (7a) (309 mg, 81%).