Low-valent titanium mediated reductive cleavage of O/N-trityl bonds via free radical pathway

Article abstract of DOI:10.1081/SCC-120014795

Low-valent titanium mediated cleavage of trityl-O/N bonds in trityl ethers/amines via electron transfer process is reported. Chemoselective deprotection of trityl ethers in preference to benzyl ethers is achieved. The ease of cleavage of protected alcohols and amines is in the order O-allyl > O-trityl > O-benzyl; N-trityl > O-trityl bonds.

Full text of DOI:10.1081/SCC-120014795

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LOW-VALENT TITANIUM MEDIATED REDUCTIVE
CLEAVAGE OF O/N-TRITYL BONDS VIA FREE RADICAL
PATHWAY
Shyam Rele a & Sandip K. Nayak b
a Bio-Organic Division , Bhabha Atomic Research Centre , Mumbai, 400 085, India
b Bio-Organic Division , Bhabha Atomic Research Centre , Mumbai, 400 085, India
Published online: 22 May 2009.
To cite this article: Shyam Rele & Sandip K. Nayak (2002) LOW-VALENT TITANIUM MEDIATED REDUCTIVE CLEAVAGE OF O/N-
TRITYL BONDS VIA FREE RADICAL PATHWAY, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:22, 3533-3540, DOI: 10.1081/SCC-120014795
To link to this article: http://dx.doi.org/10.1081/SCC-120014795
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 22, pp. 3533–3540, 2002
LOW-VALENT TITANIUM MEDIATED
REDUCTIVE CLEAVAGE OF O/N-TRITYL
BONDS VIA FREE RADICAL PATHWAY
*
Shyam Rele and SandipK. Nayak
Bio-Organic Division, Bhabha Atomic Research Centre,
Mumbai 400 085, India
ABSTRACT
Low-valent titanium mediated cleavage of trityl-O/N bonds in
trityl ethers/amines via electron transfer process is reported.
Chemoselective deprotection of trityl ethers in preference to
benzyl ethers is achieved. The ease of cleavage of protected
alcohols and amines is in the order O-allyl>O-trityl>
O-benzyl; N-trityl>O-trityl bonds.
Development of protection/deprotection strategy is an important
exercise in organic synthesis.[1] To this end, attainment of high degree of
selectivity is of paramount importance. Earlier from our laboratory, several
selective deprotection strategies have been formulated[2] using low-valent
titanium (LVT) reagents.[3] The trityl (triphenylmethyl) group is commonly
used for the protection of primary alcohols and amines in carbohydrate[4]
*Corresponding author. E-mail: sknayak@magnum.barc.ernet.in
3533
DOI: 10.1081/SCC-120014795
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3534
RELE AND NAYAK
and peptide chemistry.[5] Deblocking of the trityl group can usually be
achieved by acid hydrolysis,[6] catalytic hydrogenation (H2–Pd),[7] and
Na/NH3 protocols.[8] However, these methods are not applicable to a
wide range of substrates possessing acid-sensitive functionalities, unsatura-
tion, and other reducible groups. For example, acid catalysed detritylation
in the presence of acetate/benzoate function in carbohydrate derivatives are
often accompanied by acyl/benzoyl migration and yields are low.[6f,g] In
order to circumvent these difficulties, there is a need to develop alternate
and better methods for selective removal of the trityl group.
As an extension of our work on LVT-mediated SET reactions to
induce carbon-heteroatom bond cleavages,[2] we wanted to explore their
potential as single electron reductant for detritylation. Herein, we present
for the first time, a strategy for the cleavage of trityl-O/N bonds of trityl
ethers and amines with LVT reagents (Sch. 1).
In a model reaction, (4-chlorophenyl)trityl ether (1a) was refluxed
(16 h) together with the LVT reagent prepared from TiCl3–Mg–THF[9]
when the deprotected product 4-chlorophenol (2a) was obtained in 55%
yield (Table 1, Entry 1). Since the activity of LVT reagents depends upon
their method of preparation viz., nature of reducing metals, solvents,
external ligands etc.,[10] the above reaction was repeated with a relatively
stronger LVT reagent prepared from TiCl3–Li–THF.[10b] To our satisfac-
tion, the O-trityl bond was cleaved at a faster rate (reflux, 10 h) furnishing
(2a) in 70% yield, without knocking off the chloro group (Table 1, Entry 2).
As a result of its higher activity, better yield and reduced reaction time,
TiCl3–Li–THF reagent was chosen for all subsequent transformations.
Chemoselective deprotection and influence of the substituents on the
rate of detritylation was also investigated (Fig. 1). The results are summar-
ized in the Table 1. From the results it is clear that, deprotection of trityl
ethers can be carried out in the presence of various types of substituents in
the aromatic nucleus such as electron withdrawing [Cl, Ph (1a and 1b)],
electron donating [–CH3 (1d and 1f ), OCH3 (1c)], and bulky [C(–CH3)3
(1e)] groups (Table 1, Entries 2–7). Further, the selective cleavage of trityl
groups in the presence of other reducible functionalities like chloro and
methoxy enhanced the utility of the process.
Scheme 1.

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CLEAVAGE OF O/N-TRITYL BONDS
3535
Figure 1.
In a subsequent study, the same LVT protocol was used for the
cleavage of N-trityl bond in trityl amines. Thus, deprotection of N-trityl-
4-methoxy aniline (1g) was easily accomplished in 2 h on refluxing with LVT
generated from TiCl3–Li–THF reagent affording 4-methoxyaniline (2g) in
65% yield (Table 1, Entry 8).
Therefore, N-trityl bonds underwent a faster cleavage in comparison
to O-trityl bonds (reflux, 10 h) (cf. Table 1, Entries 4 and 8). In order to
substantiate this observation, an equimolar mixture of 1c and 1g was refluxed
with the LVT (TiCl3–Li–THF) reagent. In this case also, 1g was chemoselec-
tively deprotected to give 2g (55%) along with recovered 1c (62%) and
minor amount of its detritylated product 2c (17%) (Sch. 2). This protocol
may therefore be useful in the chemoselective deprotection in amino phenols,
thereby augmenting its utility. Detritylation of even sterically hindered
substrate N-tritylnaphthyl amine (1h) could be achieved albeit after 26 h,
furnishing 1-naphthylamine (2h) in 57% yield (Table 1, Entry 9).
Mechanistically, the trityl-heteroatom bond cleavage can, in principle,
proceed via two different routes: (i) Lewis acid mediated cleavage to trityl
cation followed by reduction and (ii) cleavage of trityl-heteroatom bond via
radical anion (SET pathway). Both the routes may then led to the formation
of triphenylmethane as was isolated in all the reactions. However, earlier

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3536
RELE AND NAYAK
Scheme 2.
we have noticed that the acid sensitive groups like tetrahydropyranyl
ethers are stable under the LVT reaction conditions. Thus, we feel that
the deprotection probably proceeded via the second (SET) route.
Chemoselective deprotection of trityl ethers in the presence of allyl and
benzyl ethers was also investigated. It was gratifying to find that, O-allyl
bond of 3-allyloxyphenyl trityl ether (1i) underwent chemoselective cleavage
with respect to O-trityl bond (Table, Entry 10). Similarly, the chemo-
selective cleavage between O-trityl bond and O-benzyl bond was also been
studied. Thus, O-trityl bonds of benzyl trityl ether (1j) (Table, Entry 11)
and (3,4-methylenedioxy)benzyl trityl ether (1k) (Table 1, Entry 12) were
chemoselectively cleaved to yield 2j and 2k in 34 and 45%, respectively. The
yield of the benzyl alcohols, however, was much lower compared to that of
triphenylmethane isolated (67 and 61%, respectively). This might be attrib-
uted to the high oxophilicity of Ti which leads to the extrusion of oxygen
from the incipient benzyloxy radical resulting in the formation of the (sub-
stituted) toluene. Thus, the rate of cleavage of protected phenols with LVT
reagents is in the order: O-allyl > O-trityl > O-benzyl. Considering the im-
portance of polyphenolics as intermediates in various organic synthesis, this
aspect might find wide application.
The potential of this deprotection protocol was also explored with
their aliphatic counterparts. For this alicyclic and acyclic trityl ethers
(1l and 1m) and alicyclic trityl amine (1n) were used as substrates. It was
found that, the same methodology is also applicable to the deprotection of
aliphatic trityl ethers/amines, albeit in poorer yields (Table, Entries 13–15).
In conclusion, a new LVT based protocol for the deprotection of trityl
ethers/amines has been demonstrated. This is the first report on detritylation
of ethers and amines by LVT reagent. The compatibility of the reducible
functions (methylenedioxy, methoxy, chloro) during detritylation enhances

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CLEAVAGE OF O/N-TRITYL BONDS
3537
Table 1. LVT-Mediated Cleavage of O-Trityl/N-Trityl Bondsa
Conditionsb
(h)
Productc
(% of yield)
Entry
Substrate
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1b
1c
1d
1e
1f
16
10
4
10
12
28
14
2
26
3
4
16
40
60
40
2a (55)
2a (70)
2b (80)
2c (68)
2d (72)
2e (55)d
2f (92)
2g (65)
2h (57)e
2i (85)
1g
1h
1i
1j
2j (34)
1k
1l
1m
1n
2k (45)
2l (20)f
2m (15)g
2n (38)h
aReactions were carried out using TiCl3–Li–THF reagent except in
b
Entry 1 where TiCl3–Mg–THF system was used; All reactions were
c
performed under refluxing conditions; Yields refer to pure, isolated
products, unless otherwise stated. Products were characterized by
1H NMR and IR spectral data; d4% of starting compound was
e
recovered; 7% of starting compound was recovered; 70% starting
f
g
compound was recovered; 77% starting compound was recovered;
h43% starting compound was recovered.
the scope of the methodology. Chemoselective deprotection of trityl ethers
in the presence of benzyl ether was also achieved. The rate of
cleavage of protected phenols and amines was found to be in the order:
O-allyl > O-trityl > O-benzyl; N-trityl > O-trityl. The present investigation
thus holds considerable promise in protecting group chemistry and will
encourage the use of LVT reagents to effect SET induced selective organic
transformations.
EXPERIMENTAL
FT-IR spectra were run on a Nicolet spectrophotometer (model 410).
1H NMR were recorded on a Bruker AC 300 (300 MHz) or Varian EM

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RELE AND NAYAK
360 (60 MHz) spectrometer with TMS as internal standard. All reactions
were carried out under argon atmosphere. TiCl3 was obtained from
Aldrich Chemical Co., U.S.A. THF was distilled freshly from sodium–
benzophenone ketyl prior to use.
General procedure for the preparation of trityl ethers and trityl amines:
A solution of alcohol/phenol/amine (10 mmol) in dichloromethane (30 mL)
was cooled in an ice bath and dry triethylamine (12 mmol) was added to it
followed by the addition of tritylchloride (11 mmol) in small portion. The
reaction mixture was stirred at ice temperature. The progress of the reaction
was monitored by TLC and on completion, the reaction mixture was washed
with water, brine, and dried (Na2SO4). The solvent was removed and the
crude product was purified by column chromatography (neutral Al2O3,
eluant Pet. ether–EtOAc ¼ 19 : 1) to furnish the desired trityl ethers and
trityl amines which were characterized by physical (melting point) and
1
spectral data (IR, H NMR).
Spectral data of selected trityl ethers and amines:
(3-Allyloxyphenyl) trityl ether (1i): ꢀ 4.4 (m, 2H); 5.1–5.5 (m, 2H);
5.76–6.2 (m, 1H); 6.4–6.5 (m, 3H); 6.95–7.5 (m, 16H). IR (KBr): ꢁ ¼ 3056,
3021, 2978, 1588, 1510, 1448, 1282 cmꢀ1
.
(3,4-Methylenedioxybenzyl) trityl ether (1k): ꢀ 3.83 (s, 2H); 5.73 (s, 2H);
6.66 (d, 2H, J ¼ 8 Hz); 7.03–7.43 (m, 16H). IR (KBr): ꢁ ¼ 3018, 2902, 1598,
1498, 1490, 1445, 1392, 1258, 1041 cmꢀ1
.
General procedure for the deprotection of trityl ethers and trityl amines:
A mixture of TiCl3 (1.54 g, 10 mmol) and Li (0.23 g, 33 mmol) in freshly
dried THF (30 mL) was refluxed for 3 h in an inert atmosphere. To the
LVT reagent thus prepared, an appropriate trityl ether/amine (2.5 mmol)
in THF (10 mL) was added and the mixture was refluxed for the different
time periods as indicated in the Table. After completion (cf. TLC), the
reaction mixture was diluted with petroleum ether–ethyl acetate (3 : 2)
mixture and passed through Celite. The organic layer was washed with
water, brine, and dried (Na2SO4). Removal of solvent afforded the crude
product which was purified by preparative thin layer chromatography
(SiO2) using a pet. ether–EtOAc (9 : 1, v/v) as eluant to furnish the respective
alcohol/amine and triphenylmethane.
Spectral data of a few selected detritylated products:
1
3-Triphenylmethyloxyphenol (2i): H NMR (CDCl3): ꢀ 5.12 (brs, 1H,
D2O exchangeable); 6.24–6.31 (m, 2H); 6.98–7.46 (m, 16H). IR (KBr):
ꢁ ¼ 3380, 3056, 3021, 1596, 1490, 1448, 1148 cmꢀ1
.
(3,4-Methylenedioxy)benzyl alcohol (2k): 1H NMR (CDCl3): ꢀ 1.83
(brs, 1H, D2O exchangeable); 4.3 (s, 2H); 5.76 (s, 2H); 6.66 (d, 2H,
J ¼ 8 Hz), 7.19 (s, 1H). IR (KBr): ꢁ ¼ 3358, 3073, 3018, 2885, 1605, 1498,
1490, 1443, 1379, 1250, 1095 cmꢀ1
.

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CLEAVAGE OF O/N-TRITYL BONDS
ACKNOWLEDGMENT
3539
One of the authors (S.R) is grateful to the Department of Atomic
Energy (DAE), Government of India, for the award of a Senior Research
Fellowship.
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Received in the UK August 6, 2001