Pd/C-mediated depropargylation of propargyl ethers/amines in water

Article abstract of DOI:10.1016/j.tetlet.2012.12.093

Propargyl ethers and amines are effectively depropargylated to the parent alcohols or amines via a C-O/C-N bond cleavage catalyzed by 10% Pd/C in water. This simple, facile, and inexpensive methodology could be utilized for the selective removal of propargyl groups from a variety of aryl ethers and amines.

Full text of DOI:10.1016/j.tetlet.2012.12.093

Tetrahedron Letters 54 (2013) 1169–1173
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Tetrahedron Letters
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Pd/C-mediated depropargylation of propargyl ethers/amines in water
D. Rambabu a, S. Bhavani b, Nalivela Kumara Swamy c, M. V. Basaveswara Rao d, , Manojit Pal a,
⇑
⇑
a Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
b Department of Chemistry, K. L. University, Vaddeswaram, Guntur 522 502, Andhra Pradesh, India
c Organic Chemistry Institute, University of Heidelberg, Im Neuenheimer Feld 271, 69120 Heidelberg, Germany
d Department of Chemistry, Krishna University, Machilipatnam 521001, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Propargyl ethers and amines are effectively depropargylated to the parent alcohols or amines via a
CÀO/CÀN bond cleavage catalyzed by 10% Pd/C in water. This simple, facile, and inexpensive methodol-
ogy could be utilized for the selective removal of propargyl groups from a variety of aryl ethers and
amines.
Received 18 November 2012
Revised 19 December 2012
Accepted 22 December 2012
Available online 2 January 2013
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Propargyl ether/amine
Deprotection
Pd/C
Water
Protection/deprotection of organic functional groups is of enor-
mous importance in organic synthesis1 especially in the synthesis
of complex natural products. Thus development of elegant method-
ologies attaining high functional group compatibility and selectiv-
ity is desirable for this purpose. Among the various protecting
groups propargyl group is attractive due to the presence of two
system for the removal of propargyl groups.12 While many of these
methods are useful most of them however required either the use of
multiple reagents or prior preparation of the actual reagent.5,8,9
Moreover, a few of them were found to be incompatible with sev-
eral functional groups especially halogens7 where dehalogenation
was observed frequently. Earlier, we have developed a copper-free
palladium-mediated cleavage of O/N propargyl bonds in aqueous
media affording a mild and convenient method for the deprotection
of phenols and anilines.13 While this reaction was found to be effec-
tive the methodology, however, involved the use of relatively
expensive palladium catalyst, that is, (PPh3)2PdCl2 and an organic
co-solvent, for example, DMF along with water. Recently, the use
of Pd/C has been explored as efficient and effective catalyst for var-
ious C–C bonds forming reaction either in pure water or other or-
ganic solvent.14 The catalyst Pd/C is stable and easy to handle as
well as separable from the product. Moreover, the catalyst can be
recycled. This prompted us to explore the use of Pd/C as an alterna-
tive catalyst in the cleavage of O/N-propargyl bonds. We chose
water as a medium in the present transformation as the water
based reactions are inherently safer and inexpensive. Herein we re-
port our preliminary results on Pd/C-mediated depropargylation of
propargyl ethers/amines (1) in water in the presence of 2-ethanol-
amine (Scheme 1).
orthogonal
p-bonds, which perhaps help in its facile cleavage in
the presence of transition metal complexes.2 A number of reports
are available in the literature for the cleavage of the carbon oxy-
gen3/carbon nitrogen4 bond in a variety of compounds such as allyl,
vinyl, and benzyl ethers/amines. Although the cleavage of C–O
bonds in allylethers/esters has been thoroughly investigated, only
a few examples are known dealing with the cleavage of the C–X
(X = O, N) bond in propargyl ethers/esters or amines. These include
the use of low valent titanium,5 hydrogenolysis of propargyl esters
with formic acid or formates,6 nickel-catalyzed electro reductive
cleavage of propargyl compounds,7 palladium-catalyzed reductive
cleavage of propargyl esters mediated by Bu3SnH or by SmI2,8 cleav-
age of propargyl ethers or propargyl oxycarbonyl protected amines
with tetrathiomolybdate,9 and oxidative cleavage of 1-naphthyl
propargyl ether or allenyl ether generated by the treatment with
KOtBu followed by catalytic OsO4 and N-methyl morpholine N-
oxide.10 Allyl and propargyl ethers were effectively deallylated or
depropargylated to the parent alcohols via a CÀO bond cleavage
catalyzed by a low-valent titanium reagent (LVT).11 The combina-
tion of SmI2–amine–water has also been explored as a catalyst
In our earlier study Et3N was used as a base/ligand in the ab-
sence of which the reaction did not proceed.13 However, being vol-
atile the nitrogen containing agent Et3N is likely to cause
environmental hazard especially in a large scale preparation. We
envisioned that 2-ethanolamine in place of Et3N could facilitate
the depropargylation reaction in water because of its better
⇑
Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.093

1170
D. Rambabu et al. / Tetrahedron Letters 54 (2013) 1169–1173
10% Pd/C
miscibility with water. Moreover, due to its lower volatility (there-
2-Ethanolamine
by avoiding internal pressure development as well as ensuring its
maximum recovery) in comparison to Et3N, 2-ethanolamine ap-
peared to be a better choice in the present reaction. Thus, when
propargyl ethers/amines (1) were treated with 10% Pd/C (205699
Aldrich) in water in the presence of 2-ethanolamine at 80 °C for
5–6 h the corresponding phenols/amines (2) were isolated in good
yields.15 A preliminary and focused optimization study using 1-ni-
tro-4-(prop-2-ynyloxy)benzene (1a) as substrate indicated that
ꢀ4 mol % of 10% Pd/C was necessary for the best result (Table 1, en-
tries 1–3). A decrease in catalyst quantity from 4 to 3 mol % re-
duced the product yield significantly (Table 1, entry 3). Similarly,
the quantity of 2-ethanolamine (i.e., 3 equiv) used was found to
be vital as decrease in its amount lowered the product yield (Table
1, entry 2 vs 4). Perhaps, in addition to its participation in the gen-
eration of active and water soluble catalytic species for C–X bond
cleavage 2-ethanolamine appeared to play a key role in solubilizing
the substrates in pure water. The reaction did not proceed in the
absence of 2-ethanolamine (Table 1, entry 5). The reaction also
did not proceed when performed in the presence of mercury (Hg)
(Table 1, entry 6) perhaps due to the accumulation of Hg on the
XH
Ar
H2O, 80 °C
5-6 h, N2
Ar
X
2
1
Scheme 1. The deprotection of propargyl ethers and amines.
Table 1
Effect of reaction conditions on Pd/C-mediated depropargylation of 1-nitro-4-(prop-
2-ynyloxy)benzene (1a)a
OH
10% Pd/C
O
2-Ethanolamine
O2N
H2O, 80 ºC
5 h, N2
O2N
1a
2a
Entry
Mol % of Pd/C
catalyst used
Equivalent of
2-ethanolamine used
Yieldb (%)
1
2
3
4
5
6
5.0
4.0
3.0
4.0
4.0
4.0
3.0
3.0
3.0
2.0
0
85
87
52
46
0
charcoal surface thereby alloying with Pd through d
p–dp bonding
3.0
0c
(the catalyst poisoning).16
a
All the reactions were carried out using 1a (1.1 mmol), 2-ethanolamine, and
10% Pd/C in water (4 mL) at 80 °C for 5 h under nitrogen.
Having established the optimized reaction conditions we then
examined the generality and scope of this Pd/C-mediated deprop-
argylation reaction. The results of this study are summarized in
b
Isolated yield.
c
The reaction was performed in the presence of Hg.
Table 2
Pd/C-mediated deprotection of aryl propargyl ethers/amines in watera
Entry
Propargyl derivatives (1)
Productsb (2)
Yieldc (%)
OH
O
1
87
O2N
O2N
1a
O
2a
OH
2
3
4
H3CO
78
87
72
H3CO
2b
1b
OH
O
NC
NC
1c
O
2c
OH
Br
Br
1d
O
2d
OH
5
6
74
65
O
O
2e
1e
O
OH
O
O
1f
2f
OH
O
O
O
7
82
2g
1g

D. Rambabu et al. / Tetrahedron Letters 54 (2013) 1169–1173
1171
Table 2 (continued)
Entry
Propargyl derivatives (1)
Productsb (2)
Yieldc (%)
O
OH
O
O
8
52
73
69
1h
2h
OH
O
9
2i
1i
OH
O
10
2j
1j
H
N
H
N
11
12
77
64
HO
O
2k
1k
N
N
O
HO
2l
1l
O
O
N
N
13
62
O
O
HO
2m
1m
CH3
N
CH3
N
14
15
57
82
HO
2n
1n
H
N
NH2
H3CO
H3CO
2o
2p
1o
H
N
Cl
NH2
Cl
H3CO
16
17
18
85
76
H3CO
1p
H
F
NH2
F
N
2q
1q
H
N
NH2
F3CO
61
F3CO
2r
1r
(continued on next page)

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D. Rambabu et al. / Tetrahedron Letters 54 (2013) 1169–1173
Table 2 (continued)
Entry
Propargyl derivatives (1)
Productsb (2)
NH2
Yieldc (%)
H
N
19
F
55
F
2s
1s
a
All the reactions were carried out using the compound 1 (1.1 mmol), 2-ethanolamine (3.3 mmol), and 10% Pd/C (0.045 mmol) in water (4 mL) at 80 °C for 5–6 h under
nitrogen.
b
c
Identified by 1HNMR, IR, mass.
Isolated yield.
NH2
Pd(0)
NH2
OH
Ar
X
Pd
O
H
H
[Pd] ArX
H
1
H
leaching
Pd in
C
C
C
C
complex in
solution
Pd/C
solution
E-1
Generation of actual
catalytic species
The catalytic
cycle
H2O
Precipitation of
ArX
H
C
H
[Pd]
H
Pd on C at the end
of catalytic cycle
C
OH
Pd(0)
OH
H
ArX
[Pd]
C H
H
H
H
H2O
C
C
O
ArXH
+
H
O
2
E-2
Scheme 2. Proposed mechanism for the Pd/C catalyzed depropargylation reaction.
Table 2. A wide variety of arylpropargyl ethers and amines were
cleaved to the corresponding phenols and amines. Various substit-
uents on the phenyl ring of the starting ether or amine (1) were
well tolerated under the condition of the reaction employed. Ethers
afforded good yields of products irrespective of the presence of an
electron withdrawing group such as nitro and cyano (Table 2, en-
tries 1 and 3), or electron donating group, for example, methoxy
and bromo (Table 2, entries 2 and 4) on the phenyl ring. A remark-
able selectivity toward O-depropargylation was observed when the
O-allyl (Table 2, entries 5 and 6) or O-benzyl moiety (Table 2,
entries 7 and 8) was present in the substrate in addition to the
O-propargyl group. Ethers containing poly nuclear aromatic ring
such as naphthyl (Table 2, entries 9 and 10) or heteroaryl group
such as indole (Table 2, entries 11–14) were depropargylated un-
der the conditions employed. A number of arylpropargyl amines
containing substituents like OMe, Cl, F, or OCF3 were depropargy-
lated (Table 2, entries 16–19) using the present method. Overall,
the chloro group was found to be well tolerated in this Pd/C-med-
iated reaction, as no dechlorinated products were detected in these
cases (Table 2, entries 4 and 16). Also, reducible functional groups,
for example, nitro present in the substrate remained unaffected
(Table 2, entry 1). While the methodology worked for a range of
substrates it has shown some limitations. For example, an attempt
to deprotect 1,4-bis(prop-2-ynyloxy)benzene afforded a complex
mixture of unidentified products. Similarly, the N-deprotection of
1-(prop-2-ynyl)-1H-indole using the present methodology re-
mained unsuccessful. Also yields of the depropargylated products
were not particularly high in certain cases (Table 2, entries 8, 14,
19 etc.).
depropargylation is shown in Scheme 2. The C–X bond cleavage
proceeds via generation of an active Pd(0) species in situ which
reacts with propargylether or amine leading to the formation of
an allenylpalladium intermediate E-1. The active Pd(0) species is
generated from the minor portion of the bound palladium (Pd/
C) via a Pd leaching process into the solution.14 The leaching of
Pd in a Pd/C-mediated coupling reaction has been investigated
and confirmed earlier.17 The leached Pd then becomes an active
species by interacting with water miscible 2-ethanolamine li-
gands. Thus, a dissolved Pd(0)/2-ethanolamine complex (which
expected to have enhanced solubility in water) is the active spe-
cies that actually catalyzes the depropargylation reaction in solu-
tion. The catalytic cycle therefore works in solution rather than on
the surface and at the end of the reaction re-precipitation of Pd
occurs on the surface of the charcoal. Once generated, the allenyl-
palladium species E-1 then undergoes nucleophilic attack on the
central sp carbon by a water molecule followed by tautomeriza-
tion to afford the
a-Pd carbonyl intermediate E-2. Subsequent
hydrolysis of E-2 released the desired phenol or aniline (2) with
the regeneration of Pd(0) to complete the catalytic cycle. The pro-
posed mechanism was further supported by the detection of
hydroxyacetone (1-hydroxy-2-propanone) as a side product in
the reaction mixture.
In conclusion, we have described a facile and inexpensive Pd/C-
mediated regioselective deprotection of aryl propargyl amines and
ethers in water. To the best of our knowledge this is the only exam-
ple of cleavage of O/N-propargyl bonds catalyzed by Pd/C in water.
The limitations and advantages of the methodology are discussed.
Due to its operational simplicity, and functional group tolerability
the present methodology certainly has advantages and could be-
come a useful alternative to the existing methods. The methodol-
ogy therefore would find a wide usage in the protecting group
chemistry as well as organic synthesis.
We have shown that a variety of aryl propargyl ethers and
amines (1) can be deprotected in a regio-selective manner using
10% Pd/C as a catalyst in water without affecting the other func-
tional groups. A plausible mechanism for this Pd/C-mediated

D. Rambabu et al. / Tetrahedron Letters 54 (2013) 1169–1173
1173
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The authors thank the management of Dr. Reddy’s Institute of
Life Sciences for continuous support and encouragement.
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propargyl ether/amine
1 (1.1 mmol) in water (4 mL) was added 2-
ethanolamine (3.3 mmol) and 10% Pd/C (0.045 mmol). The mixture was then
stirred at 80 °C for 5–6 h under nitrogen. After completion of the reaction, the
mixture was diluted with water (10 mL), acidified with cold 2N HCl, and
extracted with ethyl acetate (2 Â 40 mL). The organic layers were collected,
combined, washed with cold water (2 Â 50 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under low vacuum. The residue was purified by
column chromatography using hexane/EtOAc as eluant to afford the desired
compound 2.
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(PPh3)2PdCl2 in the presence of 2-ethanolamine in water at 80 °C for 5 h. We
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