Titanium-mediated spirocyclization reactions of 4-alkylpyridines

Article abstract of DOI:10.1021/ol1012636

(Equation Presented). Pyridines substituted at the 4-position with alkyl tethers containing β-dicarbonyl moieties were converted to spirocyclic 4,4-disubstituted dihydropyridines. Optimal conditions for these transformations involved N-acylation of the pyridine substrate with a chloroformate electrophile in the presence of Ti(OⁱPr)₄. Cyclization products could be easily converted into spiro-piperidine derivatives or elaborated into more complex heterocyclic frameworks via Au-catalyzed cycloisomerization.

Full text of DOI:10.1021/ol1012636

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3434-3437
Titanium-Mediated Spirocyclization
Reactions of 4-Alkylpyridines
Sharavathi G. Parameswarappa and F. Christopher Pigge*
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
chris-pigge@uiowa.edu
Received June 1, 2010
ABSTRACT
Pyridines substituted at the 4-position with alkyl tethers containing ꢀ-dicarbonyl moieties were converted to spirocyclic 4,4-disubstituted
dihydropyridines. Optimal conditions for these transformations involved N-acylation of the pyridine substrate with a chloroformate electrophile
in the presence of Ti(OiPr)4. Cyclization products could be easily converted into spiro-piperidine derivatives or elaborated into more complex
heterocyclic frameworks via Au-catalyzed cycloisomerization.
Elaboration of pyridine ring systems offers convenient access
to a wealth of substituted aza-heterocyclic derivatives. In
particular, intermolecular addition of nucleophiles to acti-
vated N-alkyl- or N-acylpyridinium cations is well-estab-
lished, and the resulting 1,2- or 1,4-dihydropyridine products
can be converted into substituted piperidines, pyridines, and
other heterocyclic ring systems.1 In contrast, construction
of polycyclic heterocyclic frameworks via intramolecular
nucleophilic additions to pyridines or pyridinium salts is
much less common.2 Importantly, such reaction manifolds
provide concise entry to fused-ring and/or spirocyclic dihy-
dropyridine derivatives that are well-suited for further
synthetic manipulation.3 Moreover, spiropiperidine-based
ring systems are encountered in numerous bioactive materials
of potential pharmacological significance.4 Consequently,
further expansion of intramolecular reaction pathways avail-
able to substituted pyridines (particularly those leading to
spiro-dihydropyridine products) is of general interest to the
synthetic and medicinal chemistry communities.
Most spirocyclization reactions involving pyridine sub-
strates are initiated by alkylation or acylation of the pyridyl
nitrogen to afford electrophilic pyridinium cation intermedi-
(1) For recent examples of intermolecular nucleophilic additions to
activated pyridines, see: (a) McCall, W. S.; Grillo, T. A.; Comins, D. L. J.
Org. Chem. 2008, 73, 9744. (b) Gotchev, D. B.; Comins, D. L. J. Org.
Chem. 2006, 71, 9393. (c) Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7,
5227. (d) Lemire, A.; Charette, A. B. J. Org. Chem. 2010, 75, 2077. (e)
Barbe, G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11, 3398. (f)
Larive´e, A.; Charette, A. B. Org. Lett. 2006, 8, 3955. (g) Focken, T.;
Charette, A. B. Org. Lett. 2006, 8, 2985. (h) Andersson, H.; Banchelin,
T. S.-C.; Das, S.; Olsson, R.; Almqvist, F. Chem. Commun. 2010, 46, 3384.
(i) Donohoe, T. J.; Connolly, M. J.; Walton, L. Org. Lett. 2009, 11, 5562.
(j) Ferna´ndez-Iba´n˜ez, M. A.; Macia´, B.; Pizzuti, M. G.; Minnaard, A. J.;
Feringa, B. L. Angew. Chem., Int. Ed. 2009, 48, 9339. (k) Yamada, S.;
Inoue, M. Org. Lett. 2007, 9, 1477.
(3) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141.
(4) (a) Wang, J.; Cady, S. D.; Balannik, V.; Pinto, L. H.; DeGrado,
W. F.; Hong, M. J. Am. Chem. Soc. 2009, 131, 8066. (b) Methot, J. L.;
Hamblett, C. L.; Mamprien, D. M.; Jong, J.; Harsch, A.; Szewczak, A. A.;
Dahlberg, W. K.; Middleton, R. E.; Hughes, B.; Fleming, J. C.; Wang, H.;
Kral, A. M.; Ozerova, N.; Cruz, J. C.; Haines, B.; Chenard, M.; Kenific,
C. M.; Secrist, J. P.; Miller, T. A. Bioorg. Med. Chem. Lett. 2008, 18, 6104.
(c) Xiao, D.; Palani, A.; Aslanian, R.; McKittrick, B. A.; McPhail, A. T.;
Correll, C. C.; Phelps, P. T.; Anthes, J. C.; Rindgen, D. Bioorg. Med. Chem.
Lett. 2009, 19, 783. (d) Oberdorf, C.; Schepmann, D.; Vela, J. M.; Diaz,
J. L.; Holenz, J.; Wu¨nsch, B. J. Med. Chem. 2008, 51, 6531. (e) Bienayme´,
H.; Cheˆne, L.; Grisoni, S.; Grondin, A.; Kaloun, E.-B.; Poigny, S.; Rahali,
H.; Tam, E. Bioorg. Med. Chem. Lett. 2006, 16, 4830. (f) Bondensgaard,
K.; Ankersen, M.; Thøgersen, H.; Hansen, B. S.; Wulff, B. S.; Bywater,
R. P. J. Med. Chem. 2004, 47, 888. (g) Kazmierski, W. M.; Furfine, E.;
Spaltenstein, A.; Wright, L. L. Bioorg. Med. Chem. Lett. 2002, 12, 3431.
(2) For 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. 2008, 10, 3089. (c) Arnott, G.; Clayden, J.; Hamilton, S. D.
Org. Lett. 2006, 8, 5325. (d) Goldmann, S.; Born, L.; Kazda, S.; Pittel, B.;
Schramm, M. J. Med. Chem. 1990, 33, 1413. (e) Weller, D. D.; Stirchak,
E. P.; Weller, D. L. J. Org. Chem. 1983, 48, 4597.
10.1021/ol1012636  2010 American Chemical Society
Published on Web 07/14/2010

Scheme 1
Table 1. Preliminary Screening of Spirocyclization Reaction
Conditionsa
entry
solvent
additiveb
time (min)
% yield 6c
1
2
3
4
5
6
7
8
DCMd
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
none
30
5
5
tracee
93f
trace
0
trace
trace
trace
0
Ti(OiPr)4
g
Ti(OiPr)4
TiCl4
SnCl4
InCl3
B(OMe)3
Mg(ClO4)2
Pd(OAc)2
MgBr2
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
30
30
30
30
30
30
30
30
30
5
ates (1, Scheme 1). Prior attachment of a nucleophilic group
to C4 of the pyridine ring can then result in cyclization to
afford spiro-dihydropyridines 2.2a-c,e Notably, reported
transformations of this type have all utilized pyridyl deriva-
tives that do not possess benzylic hydrogens (i.e., X ) C(sp2)
as in carbonyl or aryl groups). While this feature removes
concerns over unwanted deprotonation events arising from
the increased acidity exhibited by C4 benzylic hydrogens
upon pyridine N-alkylation or N-acylation, it also narrows
the scope of the spirocyclization process. Thus, we became
interested in exploring the feasibility of converting pyri-
dinium electrophiles 3 (possessing C4 alkyl substituents) to
spiro adducts 4 through cyclization with appropriate tethered
nucleophiles. In turn, functionality inherent to dihydropy-
ridines 4 should render these products versatile synthetic
intermediates useful for construction of more elaborate
heterocyclic frameworks.
At the outset, we reasoned that strongly basic reaction
environments would be incompatible with substrates such
as 3 due to formation of anhydrobases via benzylic depro-
tonation.5 Hence, nucleophilic addition would need to
proceed under near neutral or acidic conditions. Conse-
quently, we opted to attach stabilized pro-nucleophiles (i.e.,
ꢀ-dicarbonyls) to our pyridine substrates, and a particularly
convenient class of cyclization precursor (5) was easily
prepared by treatment of commerically available 4-(ethyl-
aminomethyl)pyridine with dimethyl malonate.
9
0
10
11
12
13
14
trace
trace
0
79
77
DMF
MeCN
PhMe
5
a Reactions performed on ∼0.5 mmol scale. b 0.5 equiv used unless
otherwise indicated. c Isolated yield. d Dichloromethane. e Detected by TLC.
f Optimized yield on ∼10 mmol scale. g 0.15 equiv used.
were not as effective in promoting the cyclization (Table 1,
entry 3), nor were other Lewis acid additives (Table 1, entries
4-10). Besides DCM, several other solvents were screened
as well. Reactions performed in THF or DMF were not
successful, but spirocyclization was found to occur in MeCN
and toluene. Although the mechanistic details of this
transformation have not been determined, we speculate that
Ti(OiPr)4 promotes enolization of the ꢀ-dicarbonyl side chain,
thereby facilitating nucleophilic addition to the activated
pyridinium ring. It is unclear why Ti(OiPr)4 is the only Lewis
acid among those screened that facilitates the reaction.6 The
high-yielding conversion of 5 to 6 shown in entry 2 of Table
1 was used as the basis for a preliminary examination of the
scope and limitations of this reaction.
To examine the effect of pyridine acylating agent, substrate
5 was exposed to the reaction conditions indicated in entry
2 of Table 1 except that different electrophiles were used in
place of EtO2CCl. As shown in Table 2, alkyl and aryl
chloroformates were all reasonably effective in activating
the pyridine ring toward nucleophilic addition (Table 2,
entries 1-3), and 7a-c were isolated in good yields. Acetyl
chloride and phenylsulfonyl chloride also gave the reaction,
albeit with significantly decreased efficiency. Attempted
pyridine activation using triflic anhydride, however, produced
only an intractable reaction mixture. Likewise, spirocycliza-
tion in the presence of methyl iodide also failed.
Pyridine derivative 5 was employed for initial screening
of reaction conditions, and results of this study are given in
Table 1. In each case, 5 was converted to an acylated
pyridinium salt in situ by treatment with EtO2CCl. No
spirocyclization was observed in dichloromethane (DCM)
alone. The presence of a substoichiometric amount of
Ti(OiPr)4 (0.5 equiv), however, almost instantly produced
the desired spirodihydropyridine product 6 in excellent (93%)
isolated yield (Table 1, entry 2). Lower loadings of Ti(OiPr)4
(6) Formation of ꢀ-dicarbonyl-Ti adducts presumably results in con-
trolled release of isopropoxide, and this may be an important feature of the
reaction. Notably, Ti(OiPr)4 is the only Lewis acid examined that possesses
basic counterions. The presence of isopropoxide also resulted in contamina-
tion of 6 with trace amounts of the corresponding isopropyl ester 9a.
(5) (a) Zhou, X.; Kovalev, E. G.; Klug, J. T.; Khodorkovsky, V. Org.
Lett. 2001, 3, 1725. (b) Mart´ın-Cantalejo, Y.; Sa´ez, B.; Soto, J.; Villa, M. J.;
Bran˜a, M. F. Synthesis 2003, 2211. (c) Wagner, R.; Wiedel, B.; Gu¨nther,
W.; Go¨rls, H.; Anders, E. Eur. J. Org. Chem. 1999, 2383.
Org. Lett., Vol. 12, No. 15, 2010
3435

Table 2. Screening of Pyridine Activating Agents
Table 4. Initial Scope of Pyridine Spirocyclizationa
entry
R
product
% yielda
1
2
3
4
5
6
7
iPrO2C
BnO2C
PhO2C
CH3C(O)
PhSO2
7a
7b
7c
7d
7e
80
86
66
20
13
0
b
CF3SO2
Mec
0
a Isolated yield. b Tf2O was used. c MeI was used.
Next, the scope of the cyclization under optimal reaction
conditions was examined using several different 4-(amino-
methyl)pyridine derivatives (Table 3). As seen, the identity
Table 3. Spirocyclization of 4-(Aminomethyl)pyridine
Derivatives
entry
substrate
R1
Et
Et
Et
Et
Bn
allyl
PMB
R2
product
% yielda
a Reactions performed according to the conditions given in Table 3 using
∼0.5 mmol of the indicated substrate. b Isolated yield. c Obtained as ∼2.7:1
mixture of diastereomers. d No product was obtained.
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
8f
iPr
tBu
Bn
allyl
Me
Me
Me
9a
9b
9c
9d
9e
9f
79
68
73
71
69
90
90
but 15 was isolated in only modest yield. In contrast, the
ꢀ-diamide 16 afforded cyclized product in a yield comparable
to those obtained using ester-amide analogues (Table 4, entry
4). Attachment of the ꢀ-dicarbonyl unit to the pyridine ring
through an ester or ketone linkage, however, had a negative
impact upon the reaction, and no cycloadduct could be
isolated from reactions of the conformationally flexible
substrate 20. Attempts to prepare spiro-1,2-dihydropyridines
from 2-substituted pyridine precursors (e.g., 22) also failed,
perhaps due to unfavorable steric interactions between the
pyridine side chain and the carbamate moiety.
8g
9g
a Isolated yield.
of the ester group could be varied without significantly
affecting reaction efficiency (Table 3, entries 1-4). Ad-
ditionally, substrates in which the amide nitrogen was
protected with easily removable substituents (Bn, allyl, PMB)
could also be converted to the corresponding spirodihydro-
pyridines in good yields.
Additional permutations in the nature of the spirocycliza-
tion substrate were next examined. The compatibility of a
benzylic substituent with the cyclization reaction was suc-
cessfully demonstrated through conversion of 10 to dihy-
dropyridine 11 (Table 4, entry 1). No reaction was observed,
however, in a substrate bearing an activated methine group
in place of an activated methylene (Table 4, entry 2).
Acetoacetylated (aminomethyl)pyridine 14 gave the reaction,
The Ti(OiPr)4-mediated cyclizations described above offer
an experimentally simple and mild method for the rapid
construction of structurally varied spiro-1,4-dihydropyridines,
particularly those featuring a diaza [4.5]decane framework.
The ability to further functionalize these heterocyclic building
blocks has been briefly examined using 6 as a representative
substrate (Scheme 2). Not surprisingly, simple heterogeneous
hydrogenation of 6 proceeded efficiently to afford the spiro-
piperidine analogue 24 in excellent yield. Additionally,
3436
Org. Lett., Vol. 12, No. 15, 2010

bromide was achieved as well to afford dihydropyridines 27
and 28. These materials were further elaborated by engaging
the 1,6-enyne moieties in Au(III)-catalyzed cycloisomeriza-
tions, and tricyclic products 29 and 30 were isolated in
excellent yield.7-9 These last transformations demonstrate
the ability to efficiently access structurally complex hetero-
cyclic frameworks from simple pyridine derivatives in only
three synthetic operations and in ∼80% overall yield.
In summary, a new and simple method for the preparation
of spiro-1,4-dihydropyridine derivatives has been developed.
These dihydropyridines can serve as versatile synthetic
building blocks in organic and bio-organic chemistry as
demonstrated by the preparation of spiropiperidines as well
as structurally more complex heterocyclic ring systems.
Current work is focused on gaining a better understanding
of the unique role played by Ti(OiPr)4 in the spirocyclization
event, further expanding the scope of this transformation,
and developing asymmetric variants.
Scheme 2
Acknowledgment. We thank the Roy J. Carver Charitable
Trust for generous financial support (Grant No. 09-3279).
Supporting Information Available: Experimental pro-
cedures, NMR spectra, and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1012636
(7) For a review of Au-catalyzed cycloisomerization, see: Jime´nez-
Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326
.
(8) There are only a few reports describing the participation of enamides
in metal-catalyzed cycloisomerizations: (a) Kozak, J. A.; Dodd, J. M.;
Harrison, T. J.; Jardine, K. J.; Patrick, B. O.; Dake, G. R. J. Org. Chem.
2009, 74, 6929, and references cited therein. (b) Harrison, T. J.; Patrick,
B. O.; Dake, G. R. Org. Lett. 2007, 9, 367. (c) Harrison, T. J.; Dake, G. R.
saponification of the pendant ester substituent present on the
lactam ring proceeded smoothly to give the corresponding
acid 25. Alkylation of the lactam ring can also be easily
accomplished as illustrated in the synthesis of allylated
derivative 26. Notably, this alkylation protocol circumvents
an apparent limitation of the spirocyclization procedure
involving the use of substituted ꢀ-dicarbonyl substrates (see
Table 4, entry 2). Alkylation of 6 with propargyl and butynyl
Org. Lett. 2004, 6, 5023
.
(9) Cycloisomerization likely proceeds via activation of the alkyne by
the Au(III) catalyst followed in sequence by nucleophilic addition of the
enamide, elimination of H+, proto-demetalation, and isomerization of the
initially formed exocyclic olefin. Control experiments established the need
for both AuCl3 and AgOTf for efficient cycloisomerization. No reaction
occurred in the presence of TfOH alone.
Org. Lett., Vol. 12, No. 15, 2010
3437