High yield protection of alcohols, including tertiary and base sensitive alcohols, as benzhydryl ethers by heating with diphenyldiazomethane in the absence of any other reagent

Article abstract of DOI:10.1016/j.tetlet.2008.02.042

A protecting group that can be introduced efficiently without the need for any acid or base catalysis and which is not prone to acid or base catalysed migration is a significant advantage for many syntheses. Benzhydryl [diphenylmethyl] ethers of sugar lac

Full text of DOI:10.1016/j.tetlet.2008.02.042

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2196–2199
High yield protection of alcohols, including tertiary and base
sensitive alcohols, as benzhydryl ethers by heating with
diphenyldiazomethane in the absence of any other reagent
Daniel Best a, Sarah F. Jenkinson a, Sebastian D. Rule a, Rosemary Higham a,
Thomas B. Mercer a, Richard J. Newell a, Alexander C. Weymouth-Wilson c,
a,
b,
*
*
George W. J. Fleet , Sigthor Petursson
a Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Faculty of Business and Science, University of Akureyri, IS-600 Akureyri, Iceland
c Dextra Laboratories Limited, The Science and Technology Centre, Whiteknights Road, Reading RG6 6BZ, UK
Received 19 December 2007; revised 20 January 2008; accepted 7 February 2008
Available online 13 February 2008
This Letter marks the 80th birthday of Professor E. J. Corey
Abstract
A protecting group that can be introduced efficiently without the need for any acid or base catalysis and which is not prone to acid or
base catalysed migration is a significant advantage for many syntheses. Benzhydryl [diphenylmethyl] ethers of sugar lactones are formed
in high yield under neutral conditions when the corresponding alcohol is heated with diphenyldiazomethane in an inert solvent such as
acetonitrile or toluene; this allows the easy protection of base sensitive and highly hindered tertiary alcohols in the absence of any other
reagents.
Ó 2008 Elsevier Ltd. All rights reserved.
For a long time, benzyl and silyl1 ethers have been the
most common and versatile protecting groups for alco-
hols.2 There are, however, limitations in their protection
of hydroxyl groups in base sensitive compounds; the intro-
duction of benzyl ethers is almost always under base cata-
lysis3 or via trichloroacetimidates in the presence of triflic
acid.4 A major disadvantage of silyl ethers is the potential
migration and base catalysed epimerisation during their
introduction;5 migration in subsequent reaction products
from the reduction of lactones, as in the preparation of
imino sugars,6 also causes substantial practical problems.
Benzhydryl [diphenylmethyl] protecting groups have
been used to protect a wide variety of functional groups
such as sulfonamides,7 amines, amides and peptides8 and
even uracils.9 Benzhydryl esters are commonly prepared
by reaction with diphenyldiazomethane,10 diphenylmetha-
nol11 or tribenzhydryl phosphate12 under acidic conditions.
The benzhydryl group has been relatively rarely used for
the protection of alcohols; diphenylmethyl ethers are
usually prepared by treatment of an alcohol with diphenyl-
methanol under acid conditions,13,14 including acid ion
exchange resins15 and silica gel-supported acid.16 The effect
on anomeric stereocontrol of O-alkylation of mannopyr-
anose with diphenylmethyl trichloroacetimidate has been
studied.17
The use of the uncatalysed decomposition of diaryldi-
azomethanes in carbohydrate protection has been mini-
mal;18 the major investigations hitherto have been on the
regioselective monoalkylations of diols in the presence of
catalytic amounts of tin(II) chloride.19,20 Mechanistic
studies21 of the formation of the benzhydryl ether 5 from
*
Corresponding authors.
E-mail address: george.fleet@chem.ox.ac.uk (G. W. J. Fleet).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.042

D. Best et al. / Tetrahedron Letters 49 (2008) 2196–2199
2197
H
O
O
O
O
R
Ph
R
O
O
OCHPh2
-
R
R OH
R O
+
OCHPh2
CH3
Ph
1
OCHPh2
RO
RO
RO
OCHPh2
4
5
RO
Ph2CN2
:CPh2
6
7
8
2
3
Scheme 1. Benzhydryl protection of alcohols.
an alcohol 1 with diphenyldiazomethane 222 are compatible
with diphenylcarbene 3 undergoing a nucleophilic addition
reaction with the alcohol to form an ylide structure 4
(Scheme 1).23
This Letter describes the protection with the benzhydryl
group under neutral conditions of hydroxyl groups in sugar
lactones [such as c- and d-lactones 6 and 7] which are sensi-
tive to base catalysed epimerisation and elimination reac-
tions; the efficient protection of hindered tertiary alcohols
[such as 8] can also be achieved. Although this procedure
is likely to be particularly useful in the protection of base
sensitive and highly hindered alcohols, the ease of introduc-
tion of benzhydryl ethers by this method may have attrac-
tions in the protection of a wide cohort of hydroxyl
functionalities. Diphenyldiazomethane 2 can be obtained
on any scale by the oxidation of benzophenone hydrazone
with mercuric oxide;24 under more environmentally friendly
conditions, an alternative oxidising agent is MagtrieveTM.25
The protection of hydroxyl groups in some 15 carbo-
hydrate lactones by heating with diphenyldiazomethane 2
in either toluene or acetonitrile in average yields of over
85% is shown below (Scheme 2).26
O
O
O
O
O
O
O
CH3
O
RO
RO
O
O
RO
OR
O
O
RO
OR
9 R = H
10 R = CHPh2, 77%
11 R = H
12 R = CHPh2, 97%
13 R = H
14 R = CHPh2, 97%
15 R = H
16 R = CHPh2, 92%
(i)
(i)
(ii)
(i)
glass
glass
glass
oil
[α]D18 +2.7 (
c, 1.27)
[α]D24 +18.0 (
c, 1.49)
[α]D23 -27.9 (
c, 0.82)
[α]D21 -1.0 (
c, 0.86)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OR
OR
OR
OR
Ph
Ph
Ph
17 R = H
19D R = H
19L R = H
21 R = H
(ii)
(ii)
(ii)
(i)
18 R = CHPh2, 96%
20D R = CHPh2, 85%
20L R = CHPh2, 88%
22 R = CHPh2, 77%
m.p. 122-124 oC,
m.p. 188-190 oC,
m.p. 187-188 oC,
m.p. 156-158 oC,
23
20
20
[α]D
+129.1 (
c
, 1.02)
[α]D
+76.5 (
c
, 0.87)
[α]D
-81.3 (
c
, 0.86)
[α]D18 +28.8 (
c, 1.41)
O
O
O
O
O
O
t-BuMe2SiO
RO
RO
OR
CH3
OR
RO
O
O
O
O
23 R = H
25 R = H
26 R = CHPh2, 91%
27 R = H
28 R = CHPh2, 82%
(i)
(i)
(i)
24 R = CHPh2, 86%
m.p. 87-89 oC,
glass
glass
[α]D23 +26.9 (
c
, 1.20)
[α]D23 -9.1 (
c
, 1.27)
[α]D23 +59.7 (
c, 1.03)
O
O
O
O
O
O
O
O
RO
OR
CH3
CH3
OR
OR
OR
O
O
O
O
O
O
O
O
Ph
29 R = H
31 R = H
33 R = H
35 R = H
36 R = CHPh2, 80%
(ii)
(i)
(i)
(i)
30 R = CHPh2, 79%
32 R = CHPh2, 90%
34 R = CHPh2, 95%
m.p. 118-120 oC,
m.p. 161-163 oC,
m.p. 131-133 oC,
glass
[α]D19 +124.8 (
c
, 0.67)
[α]D19 -141.2 (
c
, 1.01)
[α]D23 -2.5 (
c
, 1.02)
[α]D23 +1.5 (
c, 1.14)
Scheme 2. Reagents and conditions: (i) Ph2CN2, toluene, reflux; (ii) Ph2CN2, MeCN, reflux.

2198
D. Best et al. / Tetrahedron Letters 49 (2008) 2196–2199
A series of c-lactones were protected. L-Erythrono- 9
an efficient route to the protection of C-2 of a 1,4-lactone,
a hitherto difficult transformation to achieve.
and L-threono- 11 lactones gave the fully protected ethers
10 and 12 on heating with 2 in toluene and acetonitrile,
respectively; attempted protection of such lactones by
benzylation under basic conditions affords low yields of
dibenzyl ethers, probably due to the acidic hydrogen at
C-2. Similarly, efficient protection of the C-5 hydroxyl
group in the acetonides of D-ribonolactone 13 and of 2-
C-methyl-D-ribonolactone 15 was achieved by heating with
2 in toluene to give 14 and 16 in 97% and 92% yields.
The acidity of the proton at C-2 in carbohydrate lac-
tones creates problems for protection under base catalysed
conditions. Protection of the D-xylono- 17 as well as both
enantiomers of the lyxono- 19D and 19L lactones with 2
gave excellent yields of the corresponding ethers 18, 20D
and 20L; the structure of 20D was firmly established by
X-ray crystallographic analysis, confirming that epimerisa-
tion had not occurred during the protection.27 Addition-
ally, the readily available acetonide of glucuronolactone
21 was protected efficiently as the corresponding benz-
hydryl ether 22. The convenient protection of hindered
neopentyl alcohols can be illustrated by the conversion of
the L-apiono- 23 and D-hamamelono- 25 lactones to the
corresponding mono- 24 and di- 26 benzhydryl ethers. Sim-
ilarly, both the secondary and tertiary alcohols in the sily-
lated 2-C-methyl lactone 27 were protected in excellent
yield as the dibenzhydryl ether 28. Carbohydrate d-lactones
are notoriously vulnerable to base treatment. However,
both the L-arabinono- 29 and D-ribono- 31 1,5-lactones
gave excellent yields of the corresponding benzhydryl
ethers 30 and 32.
In summary, this Letter reports the highly efficient pro-
tection of a series of base sensitive and/or highly hindered
alcohols under neutral conditions. Although all the exam-
ples in this Letter are of sugar lactones, it is likely that
the ease of introduction of the protecting group and its effi-
cient removal by acid or hydrogenolysis will make this pro-
cedure of value in other circumstances. It is noteworthy
that more than half of the ethers prepared were readily
crystallised on their first preparation. The preparation of
novel monosaccharides, sugar amino acids and imino sug-
ars using the intermediates prepared in this Letter will be
reported in due course.
Acknowledgements
Support from the University of Akureyri in Iceland,
Summit plc and St. John’s College, Oxford is gratefully
acknowledged.
References and notes
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Toluene was an excellent solvent for the reaction with
the decomposition of 2 [as indicated by the disappearance
of the purple colour] completed within an hour. When
the substrate lactones were not soluble in toluene, then ace-
tonitrile was an alternative solvent in which the reaction
time for the decomposition took several hours. Representa-
tive procedures for the diphenyldiazomethane 2 protections
in both toluene28 and acetonitrile29 are given.
The protecting group in benzhydryl ethers and amines
can be cleaved by hydrogenolysis,30,31 acid hydrolysis32,33
or oxidation;34 more specialised methods, such as the
ozone cleavage of benzhydryl aziridinyl esters, can be used
where the circumstances warrant.35 Acetonides or benzyli-
dene acetals can be removed selectively without affecting
the benzhydryl ether by acid hydrolysis; for example, the
fully protected lyxonolactone 19L on treatment with 80%
aqueous acetic acid gave the benzhydryl lactone 20L {oil,
20
½aꢀD +24.3 (c, 1.81)} in 87% yield (Scheme 3). This allows
7. Poss, M. A.; Reid, J. A. Tetrahedron Lett. 1992, 33, 7291–7292.
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Collect. Czech. Chem. Commun. 1992, 57, 508–524; (e) Amblad, M.;
Rodriguez, M.; Martinez, J. Tetrahedron 1988, 44, 5101–5108.
O
O
O
O
AcOH, H2O
O
HO
O
HO
OCHPh2
OCHPh2
Ph
20L
19L
Scheme 3. Partial deprotection of lactones.

D. Best et al. / Tetrahedron Letters 49 (2008) 2196–2199
2199
9. Wu, F.; Buhendwa, M. G.; Weaver, D. F. J. Org. Chem. 2004, 69,
9307–9309.
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(Rf 0.23). The reaction mixture was concentrated in vacuo and the
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ethyl acetate) to afford benzhydryl acetonide 30 (862 mg, 79%). Mp
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4545–4547; (b) Curini, M.; Rosati, O.; Pisani, E.; Cabri, W.; Brusco,
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15. (a) Stanescu, M. A.; Varma, R. S. Tetrahedron Lett. 2002, 43, 7307–
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Tetrahedron Lett. 2003, 44, 3733–3735.
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C.; Watkin, D. J.; Fleet, G. W. J.; Best, D. Acta Crystallogr., Sect. E
2007, 63, o4121.
21. Dix, E. J.; Goodman, J. L. J. Phys. Chem. 1994, 98, 12609–12612.
22. Diphenyldiazomethane 2, with only one nitrogen molecule in 13
carbon atoms, has been used safely in moderate to large quantities by
one of us (SP) for over 20 years with no untoward incidents.
23. Bethell, D.; Newall, A. R.; Whittaker, D. J. Chem. Soc. B, Phys. Org.
1971, 23–31.
19
118–120 °C; ½aꢀD +124.8 (c, 0.67, CHCl3); mmax (thin film): 1765 (s,
C@O) cmꢁ1; dH (CDCl3, 400 MHz): 1.35, 1.42 (3H ꢂ 2, s ꢂ 2,
0
CH3 ꢂ 2), 4.16 (1H, d, H2, J2,3 3.0), 4.36 (1H, dd, H5, J5,4 2.3, J5,5
0
12.2), 4.56 (1H, dt, H4, J4;5 2.3, J4,3 7.5), 4.62 (1H, dd, H3, J3,2 3.0,
J3,4 7.5), 4.77 (1H, dd, H50, J5 ;4 2.3, J5 ;5 12.2), 5.66 (s, 1H, Ph2CH),
7.27–7.40 (10H, m, ArCH); dC (CDCl3, 100 MHz): 24.1, 26.0
(2 ꢂ CH3), 67.6 (C5), 71.2 (C4), 73.8 (C2), 75.0 (C3), 82.8 (Ph2CH),
110.5 (Me2C), 126.77, 127.67, 127.85, 128.40, 128.45, 128.50, 128.79
(10 ꢂ ArCH), 139.35, 140.75 (2 ꢂ ArC), 167.82 (C1).
0
0
29. In acetonitrile. Ph2CN2 2 (4.13 g, 21.3 mmol) was added to a solution
of the benzylidene-L-lyxono-1,4-lactone 19L (3.08 g, 14.2 mmol) in
acetonitrile (75 mL) at 70 °C. The reaction mixture was stirred at
reflux for 18 h, after which time the purple colour had changed to
yellow. TLC (3:1, cyclohexane/ethyl acetate) showed the formation of
one major product (Rf 0.40), with remaining unreacted starting
material (Rf 0.06). A further portion of Ph2CN2 2 (3.21 g, 16.5 mmol)
was added and the solution stirred at reflux for 18 h; TLC showed
complete consumption of the starting material. The solvent was
removed in vacuo and the residue was purified by column chromato-
graphy (cyclohexane/ethyl acetate) to give the benzhydryl protected
20
lactone 20L (4.63 g, 88%). Mp 187–188 °C; ½aꢀD ꢁ81.3 (c, 0.86 in
CHCl3); mmax (thin film): 1787 (s, C@O) cmꢁ1; dH (CDCl3, 400 MHz):
0
3.99 (1H, ddd, H4, J4;5 1.3, J4,5 2.0, J4,3 2.3), 4.04 (1H, dd, H5, J5,4
2.0, J5;5 13.6), 4.26 (1H, d, H2, J2,3 4.0), 4.42 (1H, d, H50, J5 ;5 13.6),
4.52 (1H, dd, H3, J3,4 2.3, J3,2 4.0), 5.42 (1H, s, PhCH), 5.79 (1H, s,
Ph2CH), 7.18–7.43 (15H, m, ArCH); dC (CDCl3, 100 MHz): 66.4
(C5), 69.6 (C4), 72.7 (C3), 75.5 (C2), 83.0 (Ph2CH), 98.8 (PhCH),
126.3, 127.4, 127.8, 128.0, 128.1, 128.2, 128.4, 128.5, 129.2
(15 ꢂ ArCH), 136.9 (ArC), 140.2, 140.6 (ArC), 172.9 (C@O).
30. Olah, G. A.; Prakash, K. S.; Narang, S. C. Synthesis 1978, 825–828.
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1993, 115, 2992–2993; (b) Baxter, E. W.; Reitz, A. B. J. Org. Chem.
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0
0
24. Smith, L. I.; Howard, K. L. Org. Synth. 1955, Coll. Vol. 3, 351–352.
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26. Full details of spectroscopic characterisation of the compounds will
be reported in subsequent papers. All specific rotations [a]D were
determined in CHCl3.
27. Jenkinson, S. F.; Rule, S. D.; Booth, K. V.; Fleet, G. W. J.; Watkin,
D. J.; Petursson, S. Acta Crystallogr., Sect. E 2008, 64, o26.
28. In toluene. Ph2CN2 2 (1.012 mg, 5.22 mmol) was added to a solution
of the L-arabinono-1,5-lactone 29 (555 mg, 2.95 mmol) in toluene
(60 mL) at 90 °C. The reaction mixture was stirred at reflux for 1 h
15 min, after which time the purple colour had changed to yellow and
32. Mairanovsky, V. G. Angew. Chem., Int. Ed. Engl. 1976, 15, 281–292.
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