Synthesis of substituted 3,9-diazaspiro[5.5]undecanes via spirocyclization of pyridine substrates

Article abstract of DOI:10.1016/j.tetlet.2011.06.055

Construction of 3,9-diazaspiro[5.5]undecane derivatives can be easily achieved via intramolecular spirocyclization of 4-substituted pyridines. The reaction entails in situ activation of the pyridine ring with ethyl chloroformate followed by intramolecular

Full text of DOI:10.1016/j.tetlet.2011.06.055

Tetrahedron Letters 52 (2011) 4357–4359
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted 3,9-diazaspiro[5.5]undecanes via spirocyclization
of pyridine substrates
⇑
Sharavathi G. Parameswarappa, F. Christopher Pigge
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Construction of 3,9-diazaspiro[5.5]undecane derivatives can be easily achieved via intramolecular spiro-
cyclization of 4-substituted pyridines. The reaction entails in situ activation of the pyridine ring with
ethyl chloroformate followed by intramolecular addition of an attached b-dicarbonyl nucleophile in
the presence of Ti(OiPr)4.
Received 2 May 2011
Accepted 13 June 2011
Available online 4 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Spirocyclization
Spiropiperidine
Dearomatization
Heterocyclic ring systems, particularly aza-heterocycles, are
well-recognized as important structural motifs in numerous bio-
active compounds. In particular, piperidine and piperazine are of-
ten encountered in medicinally active materials. More elaborate
structural fragments in which the piperidine ring system has been
incorporated into a spirocyclic framework have also emerged as
important pharmacophore structures.1 3,9-Diazaspiro[5.5]unde-
canes represent a subset of this compound type that have proven
to be especially versatile structural platforms for development of
pharmacologically significant bio-active agents.
Recent applications of 3,9-diazaspiro[5.5]undecane (1) in
medicinal chemistry include the use of N-substituted analogues
as antagonists of platelet glycoprotein IIb–IIIa.2 In addition, func-
tionalized diazaspiroundecane 2 was found to serve as a potent
antagonist of chemokine receptor CCR5, a G-protein coupled recep-
tor that has been implicated as a viral binding site for HIV-1.3 The
spiroundecane scaffold 1 has also been utilized as the core struc-
ture in QSAR studies aimed at identifying selective CCR8 antago-
nists that might function as lead compounds for treatment of
asthma and other allergic diseases.4 Compound 3 has been identi-
fied as a potential anti-migraine agent by inhibiting binding of cal-
citonin gene-related peptide (a neuropeptide believed to be
important in the pathology of migraines) to its cognate receptor
at nanomolar concentration.5 Other derivatives of 1 have been ad-
vanced as selective muscarinic M3 antagonists with possible rele-
vance to the treatment of chronic obstructive pulmonary disease
(COPD).6
N
N
1
EtO
N
O
O
O
N
nBu
N
N
N
2
F3C
O
NH
F
NH
O
N
F
N
3
In spite of the favorable therapeutic activity and pharmacoki-
netic profile of 3,9-diazaspiro[5.5.]undecane derivatives in a num-
ber of settings, relatively few routes for the synthesis of these
materials have been investigated.7 In this context, we recently re-
ported the construction of related diazaspiro[4.5]decanes via elab-
oration of 4-substituted pyridines.8 Specifically, we found that
O
NEt
MeO2C
O
EtN
Ti(OiPr)4 (50 mol %)
CH2Cl2, 0 oC, 10 min
CO2Me
ð1Þ
N
N
CO2Et
(93%)
CO2Et
5
4
⇑
Corresponding author.
E-mail address: chris-pigge@uiowa.edu (F.C. Pigge).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.055

4358
S. G. Parameswarappa, F.C. Pigge / Tetrahedron Letters 52 (2011) 4357–4359
attachment of b-dicarbonyl pro-nucleophiles to an activated pyri-
O
dine nucleus results in smooth intramolecular spirocyclization in
the presence of Ti(OiPr)4 (Eq 1). Significantly, these transformations
proved to be completely compatible with the acidic benzylic posi-
tion of 4, and formation of undesired anhydrobases arising from
benzylic deprotonation was not observed.9 Given the demonstrated
importance of the homologous spiro(undecane) ring system, we
have examined extension of this spirocyclization method to include
elaboration of 4-(ethylamino)pyridines as a means for rapid con-
NH2
R
N
Ar
1. ArCHO, NaBH4
2. RCO2R', heat
N
N
6
Ar = Ph, 4-MeOC6H4
R' = Me, Et, Bn
(~50-95%)
Scheme 1.
struction of substituted derivatives of
functionalization.
1 suitable for further
Table 1
A series of substrates suitable to evaluate the efficacy of Ti-pro-
moted spirocyclization leading to diaza(undecane) frameworks
was assembled in straightforward fashion by the two-step route
shown in Scheme 1. Reductive amination of commercially avail-
able 4-(aminoethyl)pyridine with either benzaldehyde or p-
methoxybenzaldehyde afforded the corresponding secondary
amine in high yield. Subsequent amidation of the secondary
amines upon heating with alkyl ester derivatives gave 6 in good
overall yield.
Conversion of substituted pyridines 6 to 3,9-diazaspiro[undecane] derivatives 7
1.5 equiv ClCO2Et
6
7
0.5 equiv Ti(OiPr)4
CH2Cl2, 0 oC, 10 min
Entry
1
Substrate
Producta,b
O
Bn
The results of spirocyclization studies are shown in Table 1. The
pyridine substrates 6 were subjected to reaction conditions previ-
ously developed for the preparation of spirodecane derivatives 5
(Eq 1). Specifically, pyridines 6 were exposed to a slight excess of
ethyl chloroformate in order to generate an activated acyl pyridini-
um salt in situ. In the presence of sub-stoichiometric amounts of
Ti(OiPr)4 intramolecular nucleophilic addition was found to occur
rapidly, and the desired spiro(dihydropyridine) products 7 were
easily isolated and purified by column chromatography.10 Pyridine
derivatives 6 possessing an amide-ester b-dicarbonyl side chain
proved to be the best substrates for cyclization and dihydropyri-
dines 7a–c were obtained in good yield. An acyclic b-keto amide
side chain gave the reaction in significantly lower yield; however,
incorporation of the ketone into a cyclopentanone fragment pro-
vided tricyclic dihydropyridines 7e and 7f reasonably efficiently.
Interestingly, incorporation of an alkyl substituent on the activated
methylene group in an acyclic b-ester amide side chain appeared to
shut down the spirocyclization reaction manifold (Table 1, entry 7).
Attempted spirocyclization of a 2-substituted pyridine reactant
also failed, presumably a consequence of steric interference with
formation of the acyl pyridinium intermediate (Table 1, entry 8).
The results depicted in Table 1 illustrate the facility with which
functionalized diazaspiroundecane ring systems can be assembled
starting from readily available pyridine precursors. The dearoma-
tized dihydropyridine products 7 are also well-suited for additional
synthetic elaboration. For example, hydrogenation of 7a in the
N
O
MeO2C
NBn
CO2Me
6a
7a
(72%)
N
E
N
O
PMB
N
O
MeO2C
NPMB
CO2Me
2
3
4
5
6
7
6b
7b
(70%)
N
E
N
O
PMB
N
O
BnO2C
NPMB
CO2Bn
6c
7c
(69%)
N
E
N
O
O
PMB
N
O
NPMB
O
6d
7d
(18%)
N
E
N
O
O
6e
O
Bn
N
O
NBn
O
(56%)
7e
N
E
N
O
PMB
N
O
NPMB
O
Bn
N
O
H
2 (100 psi)
6f
O
(72%)
7f
7a
CO2Me
N
E
Pd/C, MeOH
N
N
CO2Et
8
(94%)
EtO2C
NaH, THF
NPMB
n.p.c
Br
6g
N
O
Bn
Bn
N
N
O
O
CO2Me
CO2Me
MeO2C
AuCl3 (5 mol %)
NMe
N
8
n.p.c
N
N
6h
AgOTf (5 mol %)
PhMe, reflux
CO2Et
CO2Et
9
10
a
b
c
E@CO2Et.
(64%)
(66%)
Numbers in parentheses refer to isolated yield.
No product.
Scheme 2.

S. G. Parameswarappa, F.C. Pigge / Tetrahedron Letters 52 (2011) 4357–4359
4359
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presence of Pd/C catalyst afforded the N-protected spiro-bis(piper-
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excellent yield (Scheme 2). Additionally, 7a is also amenable to
alkylation with carbon electrophiles, as shown in the reaction with
propargyl bromide to give 9. Subsequent gold-catalyzed cycloiso-
merization of 9 was found to proceed smoothly to provide the no-
vel tricyclic compound 10.8,11
In conclusion, intramolecular spirocyclization of 4-aminoethyl
substituted pyridines offers a viable route for accessing 3,9-diaza-
spiro[5.5]undecane derivatives. Moreover, products of this cycliza-
tion manifold (7) are susceptible to further synthetic manipulation
and so may serve as valuable medicinal chemistry building blocks.
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Acknowledgments
We thank the Roy J. Carver Charitable Trust for generous finan-
cial support (Grant No. 09-3279). FCP thanks the University of Iowa
College of Liberal Arts & Sciences and the Obermann Center for Ad-
vanced Studies for sponsorship of a Career Development Award.
8. Parameswarappa, S. G.; Pigge, F. C. Org. Lett. 2010, 12, 3434.
9. For other examples of intramolecular nucleophilic additions to pyridines
leading to spiro-dihydropyridine products, see: (a) Brice, H.; Clayden, J. Chem.
Commun. 2009, 1964; (b) Arnott, G.; Brice, H.; Clayden, J.; Blaney, E. Org. Lett.
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Supplementary data
Supplementary data (compound characterization data for 6–10)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.06.055.
10. The preparation of 7a is representative. Under Ar, a solution of 6a (0.50 g,
1.6 mmol) in dichloromethane (10 mL) was cooled to 0 °C. Titanium
isopropoxide (0.24 mL, 0.8 mmol) was added and the reaction was stirred for
2 min. Ethyl chloroformate (1.52 mL, 2.4 mmol) was then added and the
reaction stirred an additional 5–7 min. The reaction mixture was then loaded
directly onto a silica gel column and purified using 75% EtOAc in hexanes as the
eluent to afford 7a as a yellow gummy oil (0.44 g, 72%). 1H NMR (300 MHz,
CDCl3, mixture of rotamers) d 7.37–7.26 (m, 5H), 6.94–6.83 (m, 2H), 4.84–4.66
(m, 4H), 4.25 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.44 (s, 1H), 3.37–3.18 (m, 2H),
2.11–2.00 (m, 1H), 1.76–1.67 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3, mixture of rotamers) d 169.2, 164.6, 151.1, 136.7, 128.8, 128.1, 127.7,
123.3, 109.6, 109.1, 107.7, 107.1, 63.0, 60.9, 52.3, 50.3, 41.6, 36.9, 35.1, 14.5. IR
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(cmꢀ1
C