Approaches to a photocleavable protecting group for alcohols

Article abstract of DOI:10.1039/b201002j

A new protecting group for the alcohol functionality was devised and shown to be removed photochemically under ultraviolet light in the presence of a radical scavenger in high yields.

Full text of DOI:10.1039/b201002j

Approaches to a photocleavable protecting group for alcohols
Gary A. Epling† and Anthony A. Provatas*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut
06269-3060, USA. E-mail: aap94002@uconnvm.uconn.edu
Received (in Corvallis, OR, USA) 26th January 2002, Accepted 15th March 2002
First published as an Advance Article on the web 11th April 2002
A new protecting group for the alcohol functionality was
devised and shown to be removed photochemically under
ultraviolet light in the presence of a radical scavenger in high
yields.
A protecting group is frequently introduced into a molecule
during a multistep synthesis to prevent a certain functional
group from reacting while a chemical reaction is performed
selectively on another site of the molecule.1 One useful
protecting group for a hydroxy group is the benzyl ether group.
The benzyl ether linkage has high stability, but this stability also
means that deprotection is difficult. Existing cleavage methods2
include chemical,3–7 electrochemical,8,9 and photochemi-
cal10–12 methods. Chemical methods usually involve strong
reducing conditions, while photochemical methods may be
slow and complicated by accompanying photodegradation of
the protected fragment. A strongly absorbing aryl group might
minimize undesired photoreactions, and our observation of
facile photocleavage of the phenyl quinolinyl group suggested it
might be easily reacted photochemically. It has a strong
absorption in the near ultraviolet (e.g. e = 22 400 at lmax = 347
nm for compound 4e). This group was utilized as a photo-
chemically removable protecting group for amines via a
sulfonamide photocleavage, which sets the precedent for its use
with alcohols.13
A practical three-step synthesis of candidate quinoline
compounds (4a–4f) with electron withdrawing or electron
supplying substituents utilized a Doebner condensation to give
the phenyl quinolinyl carboxylic acid, which was reduced and
treated with thionyl chloride. The general synthetic pathway to
this protecting reagent is shown in Scheme 1. Ether formation
with alcohols to be protected proceeded smoothly under the
usual conditions.14 It is noted that previous studies reported
successful synthetic pathways to quinoline methanols (com-
pound 2, Scheme 1).15,16
A family of compounds was prepared to test whether
photocleavage of this group would proceed with ultraviolet light
(350 nm) in good yields. The alcohols examined included one
compound (4e), which would likely be destroyed under strong
oxidizing or reducing conditions. Scheme 2 and Table 1
summarize the results from photocleavage of the quinolinyl
methyl ethers. The only quinoline product detected after the
photocleavage of the protected alcohol was 5a (or 5b), while the
yields of deprotected alcohols were excellent.
Photoreactions of substrates 4a–4f in quantities of 50 mg or
500 mg were studied. All irradiations were performed in a 100
Scheme 1 Reagents and conditions: i, absolute ethanol, reflux, 36 h; ii,
ml pyrex tube, under nitrogen gas, and the required reaction
time was observed to range from 15 minutes (for a 50 mg
photoreaction) to 24 h (for a 500 mg photoreaction). A Rayonet
preparative photoreactor (model # RPR-208) was used as the
light source. The solvent used for all photoreactions was
propan-2-ol. We observed that the reactions were reasonably
fast and 100% conversion was achieved in short irradiation
times, in small-scale reactions. In some cases we observed that
the product might be partially destroyed, particularly in the
LAH, THF, 20 h; iii, SOCl2, 2 h; iv, ROH, NaOH, DMF, 3 h.
Scheme 2 Photocleavage of the protected alcohol under UV light (350
nm).
† Deceased (September 9, 2001). This paper is dedicated to his memory.
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CHEM. COMMUN., 2002, 1036–1037
This journal is © The Royal Society of Chemistry 2002

Table 1 Photocleavage of protected alcohols under UV light (350nm)a
Entry
Substrate
Concentration/mmol
t/minb
Scavengerc
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
4d
4e
4f
0.141
0.141
0.141
0.141
0.141
1.410
0.128
0.128
0.128
0.126
0.127
1.170
0.139
0.139
30
30
60
20
15
600
40
90
None
Dodecanethiol
None
Dodecanethiol
Dodecanethiol
65
100
100
100
98
100
33
100
100
99
60
42
83
85
92
92
25
78
93
85
82
88
57
79
D-Sorbitol
None
None
40
D
D
D
D
-Sorbitol
180
180
1440
50
-Sorbitol
-Sorbitol
-Sorbitol
97
100
65
None
None
4f
90
100
a All reactions were carried out under nitrogen gas, in a 100 ml pyrex tube and propan-2-ol as a solvent. b Irradiation time in minutes. c 0.50% w/v
dodecanethiol, 0.18% w/v -Sorbitol.
D
2 For reviews see: P. J. Kocienski, in Protecting Groups, Thieme,
Stuttgart, 1994, pp. 46–54.
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6812.
latter stages of the photochemical reaction, which suggested the
addition of a radical scavenger might improve the overall yield.
Dodecanethiol and sorbitol were effective in achieving im-
proved yields, as shown by entries 5 and 9 of Table 1. The larger
scale reactions of 4a and 4e gave excellent yields when 0.18%
w/v -sorbitol was present. Chloro-substituted phenyl quinoline
D
4f reacted more slowly than 4a, where an electron-supplying
methoxy group seemed to promote a faster cleavage. This
consideration led to the initial design of a phenyl quinoline
system bearing electron-supplying substituents. Table 1 sum-
marizes the results obtained after irradiation of various
protected alcohols under different reaction conditions.
In conclusion, ultraviolet photochemical cleavage of quinoli-
nyl methyl ethers in the presence of a radical scavenger gave
promising results.
10 G. Pandey and A. Krishna, Synth. Commun., 1988, 18, 2309.
11 R. W. Binkley and D. G. Hehemann, J. Org. Chem., 1990, 55, 378.
12 J. N. BeMiller, R. E. Wing and C. Y. Meyers, J. Org. Chem., 1968, 33,
4292.
13 G. A. Epling and M. E. Walker, Tetrahedron Lett., 1982, 38, 3843.
14 S. M. Weinreb, G. A. Epling, R. Comi and M. Reitano, J. Org. Chem.,
1975, 40, 1356.
15 G. A. Epling and N. K. Ayengar, Tetrahedron Lett., 1976, 35, 3009.
16 J. S. Gillespie, R. J. Rowlett and R. E. Davis, J. Med. Chem., 1968, 11,
425.
Notes and references
1 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley, New York, 1991, pp. 1–9.
CHEM. COMMUN., 2002, 1036–1037
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