A two-step procedure for the preparation of mono-protected bis-N-heterocyclic alkyl ether systems

Article abstract of DOI:10.1016/j.tetlet.2006.11.161

A two-step convenient sequence for the synthesis of previously inaccessible mono-Boc-protected bis-N-heterocyclic alkyl substituted ether derivatives 4 is described. Mitsunobu protocol was applied to the preparation of pyridinyl ether precursor 5. The reduction of the electron rich pyridinyl system 5 has been achieved catalytically using the combination of PtO₂-H₂SO₄ or PtO₂-pTsOH under a hydrogen atmosphere maintained by a gas balloon at ambient temperature.

Full text of DOI:10.1016/j.tetlet.2006.11.161

Tetrahedron Letters 48 (2007) 791–794
A two-step procedure for the preparation of mono-protected
bis-N-heterocyclic alkyl ether systems
Jianhua Chao,a,* Mariam Israiel,b Junying Zhenga and Cynthia Akia
aSchering-Plough Research Institute, Kenilworth, NJ 07033, USA
bNew Jersey City University, Jersey City, NJ 07305, USA
Received 5 November 2006; revised 21 November 2006; accepted 28 November 2006
Available online 19 December 2006
Abstract—A two-step convenient sequence for the synthesis of previously inaccessible mono-Boc-protected bis-N-heterocyclic alkyl
substituted ether derivatives 4 is described. Mitsunobu protocol was applied to the preparation of pyridinyl ether precursor 5. The
reduction of the electron rich pyridinyl system 5 has been achieved catalytically using the combination of PtO2–H2SO4 or PtO2–
pTsOH under a hydrogen atmosphere maintained by a gas balloon at ambient temperature.
ꢀ 2006 Elsevier Ltd. All rights reserved.
As part of our recent medicinal chemistry efforts, we
needed to make bis-N-heterocyclic alkyl substituted
ether systems, illustrated as general formula 1 in Figure
1. A survey of the literature found no precedent for the
construction of such ether systems, in spite of numerous
methods for the preparation of substituted piper-
idines.1,2 The underlining difficulty lies in connecting
two N-heterocycles via an ether linkage without using
harsh conditions. Only two patent applications to date
have reported simple examples containing solely [6,6]
bicyclic ring systems (2 and 3, Fig. 1), prepared through
multi-step synthesis, which are intended for anti-inflam-
matory use (2)3 or for treatment of neurological and
psychiatric disorders (3).4 To serve our purpose, we have
developed a two-step sequence, carried out under mild
conditions, that has been effective in the preparation
of such ether systems (1) in various ring sizes. Herein,
we report our results and findings.
The preparation of compound 1 could be readily
achieved via the mono-protected building block 4. We
envisioned a two-step sequence to access this key inter-
mediate (Scheme 1), by reduction of the pyridinyl–piper-
idyl ether precursor 5, which could be generated from
hydroxy pyridine 6 and hydroxy-N-heterocycle 7 utiliz-
ing the Mitsunobu protocol. With the two N-terminals
properly differentiated, mono-protected bis-N-hetero-
cyclic ethers 4 would allow asymmetric functionaliza-
tion, thus providing uninhibited access to 1.
Pyridinyl ethers 5 were smoothly prepared by taking
advantage of the Mitsunobu reaction,5 which offers an
1R
N
R2
N
x
O
1
y
1R
1R
R2
O
N
N
N
N
O
R2
2
3
Figure 1. Bis-N-heterocyclic alkyl substituted ethers.
Keywords: Bis-N-heterocyclic alkyl ethers; PtO2–H2SO4 mediated reduction; Mitsunobu reaction.
*
Corresponding author. Tel.: +1 908 740 2815; fax: +1 908 740 7152; e-mail: jianhua.chao@spcorp.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.161

792
J. Chao et al. / Tetrahedron Letters 48 (2007) 791–794
1R
hydropyranylation results reported by Azzouz et al.8 It
R2
Boc
HN
N
N
N
x
x
is also worthy of mention that most of the phosphine
oxide and hydrazine byproducts generated during this
reaction were efficiently removed by taking advantage
of the weakly basic pyridinyl nitrogen in 5 during an
acidic work-up.9 This procedure simplified the isolation
process, and helped to avoid the usually time consuming
removal of spent reagents from the Mitsunobu reaction.
Table 1 summarizes the results of this transformation.
O
O
y
y
1
4
Reduction
Boc
Mitsunobu
Boc
N
N
x
N
N
protocol
x
+
OH
HO
O
y
y
6
7
5
The conversion of the pyridinyl ethers 5 to the saturated
ethers 4 was undoubtedly the key step of the sequence.
Although reduction of a substituted pyridine to the cor-
responding piperidine is a common transformation,10
often the pyridine ring requires activation with the pres-
ence of electron withdrawing groups or by the formation
of the N-oxide. Without such activation, metal mediated
hydrogenation requires high pressure and or high tem-
perature. Initially, we have applied several common
reductive methods, known to be effective for substituted
pyridines, to the pyridinyl system 5. Treatment of pyrid-
inyl–piperidyl ether 5a with samarium diiodide in THF–
H2O,11 or lithium triethylborohydride in THF,12 pro-
duced no reduction product. In order to activate the
pyridinyl system, 5a was oxidized to the corresponding
N-oxide using m-chloroperoxybenzoic acid (m-CPBA).
Scheme 1. General approach.
efficient approach to the formation of C–O bonds under
nearly neutral conditions. Recent advances in this reac-
tion have been reviewed by Dembinski.6 The coupling of
4-hydroxy pyridine (6a), or 3-hydroxy pyridine (6b),
with various hydroxy substituted N-heterocycles 7a–d
under the conditions of triphenyl phosphine (Ph3P)
and diisopropylazodicarboxylate (DIAD) afforded the
desired pyridinyl ether products 5a–e in good yields.7
Although 4-hydroxy pyridine 6a is predominantly in
the pyridinone tautomer, we have observed that the
Mitsunobu reaction proceeded only at the oxygen atom
via the minor pyridine tautomer, similar to the tetra-
Table 1. Preparation of pyridinyl ether 5a,9
Ph3P, DIAD
THF,
NBoc
x
N
N
NBoc
x
+
55 or 70 oC
HO
OH
O
y
y
over night
6
7
5
Entry
1
Hydroxy pyridine 6
Alcohol 7
Pyridyl ether 5
Yieldc (%)
67
N
NBoc
N
NBoc
NBoc
OH
HO
O
5a
6a
7a
NBoc
NBoc
2b
N
O
69
N
OH
HO
5b
7a
6b
N
N
NBoc
NBoc
s
HO
R
3
4
80
78
O
5c
OH
7b
6a
NBoc
N
N
HO
O
5d
OH
6a
7c
NBoc
NBoc
N
N
5
69
O
5e
OH
HO
6a
7d
a Reaction conditions: 1 mol equiv of hydroxy pyridine 6, 1.25 mol equiv of alcohol 7, 1.25 mol equiv of Ph3P, 1.25 mol equiv of DIAD, and 0.3 M of
THF, 55 ꢁC, 14–16 h (over night).
b Reaction was carried out at 70 ꢁC.
c Yields refer to purified products by column chromatography; purity was determined >95% based on LC-MS analysis.

J. Chao et al. / Tetrahedron Letters 48 (2007) 791–794
793
The subsequent reduction of the N-oxide under the con-
ditions of HCOONH4/10% Pd–C in methanol13 only
generated the parent compound 5a. The use of PtO2 in
MeOH–AcOH under a H2 atmosphere was also proved
to be ineffective even after employing a stoichiometric
amount of PtO2.
with the combination of PtO2 (1 wt equiv) and H2SO4
(1 mol equiv) in ethanol under a H2 atmosphere (main-
tained by a gas balloon) at room temperature afforded
the reduced bicyclic ether product 4a. The reaction
was completed within a 10 h period. Following a facile
work-up and column chromatography, ether product
4a was obtained consistently above 50% on reaction
scales ranging from 0.1 g to 1 g. The utility of this reduc-
tion process was extended to pyridinyl ethers 5b–e, and
the respective saturated ether products 4b–e were ob-
tained in good yields.
The above unsuccessful reduction attempts of 5a
strongly suggested that this electron rich pyridinyl sys-
tem needed a much stronger activation in order to facil-
itate the desired reduction process. Weak acids similar
to acetic acid would not be useful, and addition of elec-
tron withdrawing groups was not an option either. We
decided to approach this in an unconventional way, by
employing concentrated sulfuric acid (H2SO4) as the
activator of the pyridinyl system. Under this strongly
acidic condition, a pyridinium acid salt would most
likely form in situ, thus allowing the ensuing reduction
process to succeed. We were certainly concerned about
the potential risk of association between such a strong
acid with compounds like 5a where acid labile Boc pro-
tecting group and ether linkage were present. However,
we believed that under anhydrous conditions, one equiv-
alent of concentrated sulfuric acid would preferably
complex with the basic pyridinyl nitrogen. We were grat-
ified to see that treatment of pyridinyl–piperidyl ether 5a
In order to investigate the possibility of a catalytic
reduction process, we re-evaluated the amount of PtO2
required for the reduction, even though initially a stoi-
chiometric amount of PtO2 seemed necessary to accom-
plish such a difficult reduction. Reductions of 5a–e
under the condition of 1, 0.5, and 0.25 wt equiv of
PtO2 proceeded similarly well and produced comparable
yields of the desired products 4a–e. However, the
amount of PtO2 used influences the duration of the reac-
tion. Longer period of time was needed to ensure the
complete consumption of the starting material when
lesser amount of PtO2 was employed. Results of the
catalytic reduction of the pyridinyl ethers 5 are
summarized in Table 2.14
Table 2. Catalytic reduction of pyridinyl ether 5 with PtO2 in combination with H2SO4 or pTsOH–H2Oa
PtO2(0.25 wt eg.),
H2SO4 or pTsOH-H2O
H2, EtOH,
rt, 10 - 20 h
Boc
Boc
N
N
HN
N
x
x
O
O
y
y
4
5
b
Entry
Pyridyl ether 5
Bis-N-heterocyclic alkyl ether 2
PtO2 (0.25 equiv)
H2SO4
pTsOH
HN
NBoc
NBoc
N
NBoc
NBoc
1
55% 14 h
29% 14 h
60% 14 h
O
4a
O
5a
2
N
O
28% 14 h
HN
HN
O
4b
5b
N
NBoc
NBoc
NBoc
R
R
3
77% 18 h
61% 10 h
51% 20 h
NAc
O
5c
O
4c
N
HN
HN
NBoc
4
80% 20 h
NAc
O
5d
O
4d
NBoc
NBoc
N
5d
O
O
4e
5e
a Reaction conditions: all reactions were performed on a 1.0 g scale of pyridinyl ether 5, 0.25 wt equiv of PtO2, 1.0 mol equiv of H2SO4 or
1.0 mol equiv of pTsOH–H2O, 200 proof ethanol (20 mL), H2 supplied by a gas balloon.
b Yields refer to purified ether products 2 by column chromatography, purity >95% based on LC-MS analysis.
c NA means reaction was not performed.
d A 0.5 wt equiv of PtO2 was used.

794
J. Chao et al. / Tetrahedron Letters 48 (2007) 791–794
7. For O-alkylation of 3-hydroxy pyridine under Ph3P/
DEAD condition, see: (a) Dolle, F.; Dolci, L.; Valette,
H.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Fuseau, C.;
Coulon, C.; Bottlaender, M.; Crouzel, C. J. Med. Chem.
1999, 42, 2251–2259, and references cited therein; (b) We
did not pursue the coupling reaction of 2-hydroxy pyridine
and 7a under the discussed Mitsunobu protocol since the
fully saturated bis-N-heterocyclic alkyl ether was consid-
ered unsuitable for our SAR purpose. However, O-
alkylation of 2-hydroxy pyridine under Mitsunobu condi-
tion might be possible, see Ref. 8 for details.
The bis-N-heterocyclic ethers 4 were obtained in moder-
ate to good yields, as illustrated in Table 2, based on the
current un-optimized conditions. During the reduction
process, we did observe the formation of byproducts
consistent with the cleavage of the ether link and the
removal of the Boc protection, based on TLC and MS
analysis. Byproducts resulting from ether link cleavage
were isolated and confirmed to be hydroxy N-hetero-
cycles 7 based on H NMR. Additionally, the amount
of byproducts formed seems to be substrate dependent.
In an effort to minimize the acid induced side reactions,
p-toluenesulfonic acid was evaluated as a possible alter-
native. It was found that p-toluenesulfonic acid was
equivalent to concentrated sulfuric acid in the catalytic
reduction of 5a, 5b, 5d (Table 2), but unfortunately
byproducts were generated at a similar level as those
of the reactions mediated by concentrated sulfuric acid.
8. Azzouz, R.; Bischoff, L.; Fouquet, M.-H.; Marsais, F.
Synlett 2005, 18, 2808–2810.
9. General procedure for the preparation of pyridyl ethers 5:
To a stirred solution of 4-hydroxy pyridine 6a (2.0 g,
21.03 mmol) in 70 mL of anhydrous THF at room
temperature was added N-Boc-4-hydroxy piperidine 7a
(5.3 g, 26.28 mmol). Triphenyl phosphine (6.9 g,
26.31 mmol) was added followed by dropwise addition
of
diisopropylazodicarboxylate
(DIAD,
5.2 mL,
In summary, we have reported here a two-step sequence
for the synthesis of previously inaccessible mono-Boc-
protected bis-N-heterocyclic alkyl substituted ethers
4a–e. The reduction of electron rich pyridinyl system
was realized with the combination of PtO2–H2SO4 (or
pTsOH). Furthermore, the reduction can be carried
out catalytically. The ethers 4a–e thus prepared have be-
come versatile building blocks in our SAR development
being further elaborated into biologically important
chemical entities.
26.41 mmol). The mixture was heated at 55 ꢁC over night
(14 h). Solvent was evaporated in vacuo. The resulting oil
was treated with a 1.0 M HCl aqueous solution (30 mL).
The acidic mixture was washed with CH2Cl2 (30 mL · 2).
The combined CH2Cl2 washings were re-extracted with a
1.0 M HCl aqueous solution (10 mL) and H2O (20 mL),
then discarded. The aqueous fractions were combined,
basified to pH ꢀ 12 using a 1.0 M NaOH aqueous
solution, and extracted with CH2Cl2 (50 mL · 4). The
combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo to a residue, which
was purified by flash column chromatography, eluting
with EtOAc–hexanes–MeOH (5:1:0.1, v/v/v). Removal of
solvents afforded 3.92 g (67%) of pyridyl ethers 5a as a
colorless solid.
Acknowledgments
10. (a) Rylander, P. N. Hydrogenation Methods; Academic
Press: New York, 1990; (b) Glorius, F.; Spielkamp, N.;
Holle, S.; Goddard, R.; Lehmann, C. W. Angew. Chem.,
Int. Ed. 2004, 43, 2850–2852.
11. Kamochi, Y.; Kudo, T. Heterocycles 1993, 36, 2382–
2396.
We thank Drs. John Piwinski, Robert Aslanian, and
Alan Cooper from SPRI, Dr. Kenneth Yamaguchi
and Mr. Ronald Paige from NJCU for their support
of the special SPRI-NJCU Corporate Scholar program
which made Ms. Israiel’s summer internship possible.
12. Blough, B. E.; Carroll, F. I. Tetrahedron Lett. 1993, 34,
7239–7242.
13. Zacharie, B.; Moreau, N.; Dockendorff, C. J. Org. Chem.
2001, 66, 5264–5265.
Supplementary data
14. General procedure for bis-N-heterocyclic alkyl ethers 4: A
stirred solution of pyridyl ether 5a (1.0 g, 3.6 mmol) in
20 mL of 200 proof ethanol was degassed via house
vacuum, and refilled with nitrogen. PtO2 (0.25 wt equiv)
was added. The mixture was degassed again and refilled
with nitrogen. Concentrated sulfuric acid (0.19 mL,
3.6 mmol, 1 equiv) was added. The resulting mixture was
degassed a third time, and refilled with H2 via a stainless
needle connected to a gas balloon. Reaction was continued
at room temperature under a H2 atmosphere for 14 h. The
mixture was poured into 50 mL of an ice cold 1.0 M
NaOH aqueous solution, rinsing with a small volume of
CH2Cl2, and filtered through a Celiteꢂ pad. The filtrate
was concentrated in vacuo to remove ethanol, and the
remaining aqueous solution was extracted with CH2Cl2
(50 mL · 3). The combined organic extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo
to an oily residue, which was purified by flash column
chromatography, eluting with CH2Cl2–MeOH (10:1, 5:1,
and 1:1, v/v). Removal of solvents afforded 0.61 g (60%) of
ether 4a as a colorless solid.
Experimental procedures, characterization data, and
NMR spectra for all new compounds. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2006.11.161.
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