Gold-catalyzed intramolecular cyclization of alkynones with pyridine anhydrobases

Article abstract of DOI:10.1016/j.tetlet.2013.08.110

4-Alkylpyridines functionalized with alkynyl amide substituents can be converted to pyridyl-substituted lactams via Au-catalyzed cyclization at the pyridine benzylic carbon. These transformations proceed through alkylidene dihydropyridine (anhydrobase) in

Full text of DOI:10.1016/j.tetlet.2013.08.110

Tetrahedron Letters 54 (2013) 6067–6070
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed intramolecular cyclization of alkynones with pyridine
anhydrobases
⇑
Lokesh Pawar, 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:
4-Alkylpyridines functionalized with alkynyl amide substituents can be converted to pyridyl-substituted
lactams via Au-catalyzed cyclization at the pyridine benzylic carbon. These transformations proceed
through alkylidene dihydropyridine (anhydrobase) intermediates and demonstrate the ability to utilize
these species in metal-catalyzed C–C bond forming reactions.
Received 12 August 2013
Accepted 26 August 2013
Available online 3 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Anhydrobase
Gold catalysis
Alkyne
Introduction
have appeared.8 More recently, several groups have examined the
ability of relatively simple methyl pyridines (picolines) and related
Substituted pyridines and their reduced analogues (e.g.,
dihydropyridines and piperidines) are common structural motifs
encountered in numerous natural products, pharmaceuticals, and
other pharmacologically active compounds.1 Consequently, meth-
ods for the synthesis of functionalized pyridine derivatives, along
with methods that facilitate elaboration of readily available pyri-
dines are valuable preparative tools.2
Intermolecular addition of nucleophiles to pyridines activated
by prior N-alkylation or N-acylation is widely used to introduce
substituents to the C2 and/or C4 position.3 Application of this strat-
egy for intramolecular nucleophilic addition, however, is less com-
mon.4 In this context, we recently reported a high-yielding and
operationally simple procedure for converting easily prepared 4-
alkyl pyridines to stable azaspiro-dihydropyridines via intramolec-
ular nucleophilic addition (Scheme 1).5
heterocycles to participate in intermolecular condensation reac-
tions via enamine (anhydrobase) intermediates generated in the
presence of both Brønsted and Lewis acids,9,10 Pd complexes,11
and by thermal activation.12 Notably, the range of electrophiles
employed in these transformations is almost exclusively confined
to C@O/C@N groups and highly activated alkenes. Intrigued by
the straightforward means that substituted pyridines might be ob-
tained through the intervention of anhydrobase intermediates, we
have sought to expand the scope of intramolecular annulation
reactions (Scheme 1) to include alternative electrophiles. Accord-
ingly, we have examined the reactivity of tethered alkynones with
anhydrobase nucleophiles in the presence of various transition
metal catalysts, and our preliminary results are reported below.
Results and discussion
Interestingly, a different reaction manifold was observed with
structurally similar substrates under basic conditions. In these in-
stances an aldol-like condensation occurred involving the C4 alkyl
carbon resulting in net cyclization at the pyridine benzylic position
(Scheme 1).6 This latter reaction type is believed to proceed
through initial formation of anhydrobase intermediates (1) gener-
ated by deprotonation of acylated pyridine species.
While pyridine anhydrobases are well-established entities,
their use as readily accessible nucleophilic intermediates has not
been extensively investigated.7 A few examples of acid-promoted
intramolecular condensations with attached carbonyl electrophiles
Tertiary amide 3 was initially used as a substrate as this mate-
rial is easily prepared from commercially available N-ethyl amino-
methylpyridine. We envisioned that exposure of 3 to conditions
outlined in Scheme 1 would lead to the corresponding anhydro-
base intermediate, that is, poised to undergo 5-endo-dig cyclization
with the attached alkynone. All attempts to carry out this transfor-
mation in the presence of iPr2NEt (DIPEA) and ClCO2Et along with a
variety of Lewis acids (Ti(OiPr)4, TMSOTf, Cu(OTf)2, Mg(OTf)2, and
InCl3) in several different solvents (THF, dioxane, and toluene)
followed by workup under acidic conditions resulted only in recov-
ery of unreacted starting material or substrate decomposition.
Consequently, we examined the effect of added transition metal
complexes capable of further activating the alkynone moiety.
⇑
Corresponding author. Tel.: +1 319 335 3805; fax: +1 319 335 1270.
E-mail address: chris-pigge@uiowa.edu (F.C. Pigge).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.110

6068
L. Pawar, F. C. Pigge / Tetrahedron Letters 54 (2013) 6067–6070
R2
O
Table 2
Catalyst screening
ClCO2Et, iPr2NEt
R1
N
Ti(OiPr)4 (50 mol %)
ref. 5
R1 = H
O
O
R
THF, reflux
(ref. 6)
ClCO2Et (1.5 equiv)
Pr2NEt (1.5 equiv)
i
MeO2C
n
R2
R1
O
3
4
catalyst (5 mol%)
CH2Cl2, rt, 48 h; then
TFA, H2O
N
NR
n
O
n = 1, 2
R = alkyl
EtO2CN
68-93%
NR
n
EtO2CN
n = 1, 2
% Yielda
4
1
Entry
Catalyst
n = 0, 1
1
2
3
4
5
6
7
8
9
AuCl(PPh3)
AgOTf
AuCl3
0
0
0
0
R1
R1
R2
O
AuCl(P(OPh)3) + AgOTf
(JohnPhos)AuCl + AgOTf
(JohnPhos)Au(MeCN)SbF6
AuCl(P(C6F5)3) + AgOTf
(Bt)AuClb + AgOTf
AuCl(PPh3) + AgBF4
AuCl(PPh3) + AgPF6
AuCl(PPh3) + AgSbF6
R2
O
TFA, H2O
10
0
0
10
32
18
Trace
NR
n
NR
n
N
EtO2CN
n = 0, 1
36-94%
2
n = 0, 1
10
11
Scheme 1. Reactivity of 4-alkylpyridines.
a
Isolated yield.
Bt = benzotriazole.
b
Nucleophilic addition to alkynes in the presence of transition
metal catalysts (especially gold and platinum complexes) has re-
ceived considerable attention.13 Typically, stabilized or ‘soft’ nucle-
ophiles exhibit good reactivity toward electrophilic (alkynyl)gold
or platinum complexes.14 Given the resonance stabilization avail-
able to anhydrobase nucleophiles, we postulated that these species
may also serve as viable participants in metal-catalyzed alkyne
functionalization. Our initial efforts to effect this transformation
are summarized in Table 1.
addition of the catalyst mixture in the indicated solvent to a solu-
tion of 3, ClCO2Et, and DIPEA. Reactions were monitored by TLC
and in cases where 4 was ultimately obtained a relatively non-po-
lar intermediate assigned a structure analogous to 2 (Scheme 1)
was observed. In each case TFA and H2O were added after 48 h
and product was isolated by flash column chromatography
(SiO2). While the expected cyclized product 4 was formed in most
reactions, isolated yields were disappointing. Reactions performed
at elevated temperatures (Table 1, entries 1–5) were uniformly low
yielding. Reactions conducted at room temperature were slightly
higher yielding, and the best result was obtained in CH2Cl2 (Table 1,
entry 11).
The effect of catalysts generated from Au(I) or Pt(II) chlorides
and AgOTf was examined in several solvents under elevated as well
as ambient temperatures. These reactions were performed by
Encouraged by the successful benzylic cyclization of 3, we
briefly examined the efficacy of different catalysts and catalyst pre-
cursors as shown in Table 2. Entries 1 and 2 reveal the importance
of both AuCl(PPh3) and AgOTf in order to observe conversion to 4.
Other gold catalysts possessing a phosphite supporting ligand
(entry 4), a bulky biphenylphosphine ligand (entries 5 and 6), an
electron-withdrawing tris(pentafluorophenyl)phosphine ligand
(entry 7), or a triazole ligand (entry 8)15 were largely ineffective.
Table 1
Initial conditions for metal-catalyzed cyclization
O
NEt
O
NEt
ClCO2Et (1.5 equiv)
Pr2NEt (1.5 equiv)
i
catalyst (5 mol%)
solvent, 48 h; then
TFA, H2O
N
3
N
4
R1
O
NR
O
Entry
Catalysta
Solvent
Temp. (°C)
% Yieldb
4
ClCO2Et, DIPEA
NR
R1
1
2
3
4
5
6
7
8
9
A
A
A
A
B
A
A
A
A
A
A
B
PhMe
THF
90
20
20
0
0
9
20
30
15
0
12
48
9
AuCl(PPh3) (5 mol%)
AgOTf (5 mol%)
CH2Cl2, rt, 48 h; then
TFA/H2O
Reflux
Reflux
Reflux
Reflux
rtc
rt
rt
rt
rt
MeCN
Dioxane
PhMe
PhMe
THF
N
N
7 R = Et, R1 = Ph, 42%
8 R = Bn, R1 = Me, 43%
5 R = Et, R1 = Ph
6 R = Bn, R1 = Me
O
DCEd
Bn
N
MeCN
Dioxane
CH2Cl2
CH2Cl2
10
11
12
Bn
N
rt
rt
N
a
Catalyst A: 5 mol % AuCl(PPh3) + 5 mol % AgOTf; Catalyst B: 5 mol % PtCl2 + 5 -
mol % AgOTf.
O
N
10
b
Isolated yield.
Room temperature.
1,2-Dichloroethane.
9
c
d
Scheme 2.

L. Pawar, F. C. Pigge / Tetrahedron Letters 54 (2013) 6067–6070
6069
Several other Ag(I) additives were examined (entries 9–11), but
none were as effective as AgOTf.
shows no evidence of distinct rotamers, indicating that the pres-
ence of the Boc group has resulted in the formation of a single
rotamer or rotamer interconversion has become rapid on the
NMR time scale. Gratifyingly, exposure of 11 to Au-catalyzed
cyclization conditions afforded 12 in a much improved 74% iso-
lated yield (Eq. 1).
The catalyst prepared from the combination of AuCl(PPh3) and
AgOTf was also used to promote cyclization of other 4-alkylpyri-
dine substrates (5–6, Scheme 2). As was the case with 3, however,
isolated yields of cyclized products 7–8 were modest. Moreover,
several other substrates, such as the aminoethylpyridine 9 and
the 2-alkylpyridine 10 failed to react under these conditions. Thus,
attention was directed toward modifying the substrate structure in
order to possibly increase both the scope and efficiency of
cyclization.
One notable feature of cyclization substrates 3 and 5–6 is the
presence of two distinct rotamers of ꢀ1:1 ratio in the alkynone
side chain in the room temperature NMR spectra. Distinct rot-
amer populations were also evident in the NMR spectrum of
the crude anhydrobase formed from 3 (see Supplementary data).
Consequently, we speculated that stereoelectronic factors in the
alkynone side chain may play a critical role in the cyclization
event. To investigate this issue we prepared a substrate in which
the N-alkyl group was replaced with a bulky t-butoxy carbonyl
(Boc) group. The room temperature 1H NMR spectrum of 11
O
O
O
ClCO2Et, DIPEA
N
N
O
(1)
O
AuCl(PPh3) (5 mol%)
AgOTf (5 mol%)
CH2Cl2, rt, 48 h; then
TFA/H2O
ð1Þ
O
N
N
12 (74%)
11
The beneficial effect of carbamate protecting groups in these
Au-catalyzed transformations extends to other substrates as
well (Table 3). Phenyl-substituted alkynone amides bearing
phenoxycarbonyl and CBZ groups were each converted to the
corresponding cyclized products in much higher yield than their
N-ethyl analogue shown in Scheme 2 (Table 3, entries 1 and 2).
In addition, 6-endo-dig cyclization also was observed under
these conditions with carbamate protected aminoethylpyridine
substrates (entries 3 and 4). The Boc group in 17 is lost during
this transformation, presumably during the acidic hydrolysis
phase of the reaction that takes place after cyclization. Finally,
an N-acetyl group was found to be compatible with the reac-
tion, but in this case the yield of cyclization was comparable
to those encountered with N-alkyl groups (entry 5). This may
indicate that both electronic and steric effects exerted by the
carbamate groups are important in facilitating anhydrobase
cyclization.
Table 3
Cyclization of carbamate protected alkynonesa
Entry
Substrate
Product
% Yieldb
Ph
O
O
O
N
Ph
N
O
OPh
1
58
OPh
N
14
N
13
A plausible mechanism to account for these benzylic cycliza-
tions is illustrated in Scheme 3. Acylation of the pyridine with ethyl
chloroformate followed by benzylic deprotonation generates anhy-
drobase intermediate 23. Activation of the alkynone unit by coor-
Ph
O
O
NCBZ
Ph
N
O
2
62
dination of Au(PPh3) and endo-dig cyclization affords 24.
A
OBn
second benzylic deprotonation and proto-demetalation then gives
rise to anhydrobase 25. Quenching the reaction with TFA/H2O re-
protonates 25 and promotes hydrolysis of the acyl pyridinium
group to give the observed product.
N
16
N
15
O
N
O
O
O
NH
Ph
Ph
Ph
3
4
58
R1
Au(PPh3)+
O
R1
17
O
N
O
N
O
18
ClCO2Et
iPrNEt
[Au(PPh3)]
NCO2R
O
NCO2R
n
n
N
N
O
OBn
NCBZ
EtO2CN
n = 0, 1
64c
23
Ph
19
N
O
N
N
20
R3NH+
[Au]
O
R1
O
R1
H
O
R3N
O
N
NCO2R
NCO2R
n
n
5
48
EtO2CN
EtO2CN
25
H3O+
24
N
22
N
21
a
Reaction conditions: ClCO2Et (1.5 equiv), DIPEA (1.5 equiv), AuCl(PPh3)
Product
(5 mol %), AgOTf (5 mol %), CH2Cl2, rt, 48 h; then TFA, H2O, rt.
b
Isolated yield.
Scheme 3. Mechanistic rationale for intramolecular Au-catalyzed pyridine anhy-
drobase cyclization.
c
Yield calculated based on 10% recovered starting material.

6070
L. Pawar, F. C. Pigge / Tetrahedron Letters 54 (2013) 6067–6070
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We thank the Roy J. Carver Charitable Trust (09-3279) and the
Department of Chemistry, University of Iowa for financial support.
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