Silver-promoted benzannulations of siloxyalkynes with pyridinium and isoquinolinium salts

Article abstract of DOI:10.1002/adsc.201300443

We describe the development of efficient benzannulations of siloxyalkynes with pyridinium and isoquinolinium salts. Such reactions are successfully promoted by a stoichiometric amount of silver(I) benzolate under mild reaction conditions. This process proceeds via a formal inverse-electron demand Diels-Alder reaction, followed by fragmentation of the initially produced bicyclic adducts to deliver a range of synthetically useful phenols and naphthols. Copyright

Full text of DOI:10.1002/adsc.201300443

COMMUNICATIONS
DOI: 10.1002/adsc.201300443
Silver-Promoted Benzannulations of Siloxyalkynes with
Pyridinium and Isoquinolinium Salts
Jaime R. Cabrera-Pardo,a David I. Chai,a and Sergey A. Kozmina,*
a
Chicago Tri-Institutional Center for Chemical Methods and Library Development, Department of Chemistry, University
of Chicago, Chicago, IL 60637, USA
Fax : (+1)-773-702-0805; phone: (+1)-773-702-6886; e-mail: skozmin@uchicago.edu
Received: May 21, 2013; Published online: August 28, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300443.
Abstract: We describe the development of efficient
benzannulations of siloxyalkynes with pyridinium
and isoquinolinium salts. Such reactions are success-
fully promoted by a stoichiometric amount of sil-
ver(I) benzolate under mild reaction conditions.
This process proceeds via a formal inverse-electron
demand Diels–Alder reaction, followed by frag-
mentation of the initially produced bicyclic adducts
to deliver a range of synthetically useful phenols
and naphthols.
We initially examined a reaction between 1-siloxy-
1-hexyne (1) and 1-ethyl-4-(methoxycarbonyl)pyridi-
nium iodide (2). No significant reaction between
1 and 2 occurred either in the absence of additives or
in the presence of catalytic amounts of several Ag(I)
and Au(I) complexes (Table 1, entries 1–3). However,
treatment of a solution of 1 and 2 with stoichiometric
amounts of several silver salts, which gave suspensions
in the employed solvent, was found to promote for-
mation of imine 3. While AgCO2CH3 and AgCO2CF3
were only moderately effective (Table 1, entries 4 and
5), the use of AgCO2Ph resulted essentially in quanti-
tative conversion to 3 within 2 h at 208C (Table 1,
Keywords: alkynes; benzannulation; cycloaddition;
silver
Table 1. Initial reaction optimization.
Benzannulation is a highly modular way of assem-
bling aromatic compounds starting from two or more
components.[1] Structural variation of the reaction
partners enables rapid diversification of the resulting
aromatic products. Alkynes have been employed suc-
cessfully to develop a number of synthetically useful
benzannulations.[2] Indeed, our recent study demon-
strated that siloxyalkynes underwent benzannulations
with pyrones and isoquinoline N-oxides in the pres-
ence of a catalytic amount of Au(I) phosphine com-
plex.[3] However, pyridine N-oxides were found to be
unreactive under such conditions. We now describe
a solution to this limitation and demonstrate that re-
actions between N-alkylpyridinium iodides and silox-
yalkynes efficiently proceed in the presence of stoi-
chiometric amounts of Ag(I) salts to afford a range of
substituted phenols. The process occurs presumably
via a formal inverse-electron demand Diels–Alder re-
action, followed by fragmentation of the initially pro-
duced cycloadducts. The newly developed benzannu-
lation has a broad substrate scope and also works
with a variety of N-alkylisoquinolinium iodides.
Entry Catalyst
Catalyst load- Conversion
ing
[%][b]
[a]
1
LAu
N
9.1
11.5
8.2
55
50
99
48
60
<5
<5
10
2
AuCl3
5 mol%
5 mol%
3
4
5
6
7
8
9
AgNTf2
AgCO2CH3
AgCO2CF3
AgCO2Ph
Ag2CO3
Ag2SO4
AgF
100 mol%
100 mol%
100 mol%
100 mol%
100 mol%
100 mol%
100 mol%
10 mol%
10
11
AgNO2
AgCO2Ph
[a]
[b]
L=Johnphos.
1
Conversion was measured by 500 MHz H NMR analysis
of the crude reaction mixtures.
Adv. Synth. Catal. 2013, 355, 2495 – 2498
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2495

Jaime R. Cabrera-Pardo et al.
COMMUNICATIONS
Table 2. Ag-promoted benzannulations of siloxyalkynes with
N-alkylpyridinium iodides.
entry 6). Changing the nature of the Ag(I) salt coun-
terion seemed to have substantial effect on the effi-
ciency of this reaction. For example, the use of
Ag2CO3 and Ag2SO4 resulted only in moderate con-
version levels (Table 1, entries 7 and 8). In addition,
AgF and AgNO2 were unsuccessful in promoting this
reaction (Table 1, entries 9 and 10). Substoichiometric
amounts of AgCO2Ph did not catalyze this reaction
effectively, showing that a full equivalent of such
a promoter is required (Table 1, entry 11). The use of
other Brønsted bases including K2CO3, Cs2CO3,
NaCO2CH3 and t-BuOK proved to be inefficient in
catalyzing this transformation.
Having identified AgCO2Ph as the best promoter
for this reaction, we then studied the effect of the
counterion and the N-alkyl group of the pyridinium
salt on the reaction efficiency. Various counteÀrions
werÀe investigated including ClÀ, BrÀ, IÀ, BF4 and
PF6 . Halogen counterions proved to be the most ef-
fective, with IÀ leading to the highest cÀonversion
À
levels. On the contrary, use of BF4 and PF6 counter-
ions was much less effective leading to complex mix-
tures of products or no reactivity. Also, examination
of N-n-butyl-, N-ethyl-, and N-isopropylpyridinium
salts revealed that N-ethyl- and N-isopropylpyridini-
um salts were equally reactive towards siloxyalkynes.
Having identified an optimum set of conditions for
benzannulation of siloxyalkyne 1 with N-ethylpyridi-
nium iodide 2, we next investigated the scope of this
transformation in respect to the pyridinium salt. This
study is summarized in Table 2. Pyridinium salts bear-
ing electron-deficient substituents such as 2 (R2 =
CO2CH3) and 5 (R2 =CF3) successfully reacted with
siloxyhexyne 1. Subsequent desilylation using a poly-
mer-supported fluoride source gave the corresponding
phenols 4 and 6 in 70 and 85% yields, respectively
(Table 2, entries 1 and 2). Since the presence of elec-
tron-withdrawing groups may activate the pyridium
moiety towards the initial cycloaddition with siloxyal-
kyne, we examined a range of other pyridinium salts
that would not have such an activating substituent.
Subjection of aryl-containing pyridinium salt 7 to the
standard reaction conditions delivered the corre-
sponding phenol 8 in 85% yield (Table 2, entry 3).
Furthermore, fully unsubstituted pyridinium iodide 9
successfully reacted with alkyne 1 to give phenol 10
(Table 2, entry 4). Substitution of the pyridinium ring
with either one or two methyl groups was also well
tolerated (Table 2, entries 5 and 6). As expected, fur-
ther increase in the electron-donating ability of pyri-
dinium substituents rendered such substrates substan-
tially less reactive. Indeed, introduction of a methoxy
group at the 4-position of the pyridinium ring resulted
[a]
Isolated yields after standard chromatographic purifica-
tion.
We also examined the propensity of quinolinium
in no reaction. However, 3-substituted pyridinium salt and isoquinolinium salts to participate in the same
15 delivered the corresponding benzannulation prod- transformation. While the use of several quinolinium
uct 16 (Table 2, entry 7).
salts resulted in the formation of complex mixtures of
products, isoquinolinium iodides proved to be highly
2496
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2495 – 2498

Silver-Promoted Benzannulations of Siloxyalkynes with Pyridinium and Isoquinolinium Salts
Table 3. Ag-promoted benzannulations of siloxyalkynes with
N-alkylisoquinolinium iodides.
Scheme 1. Proposed reaction mechanism.
Scheme 1. [4+2]Cycloaddition between siloxyalkynes
A and pyridinium salts B leads to the bicyclic inter-
À
mediate C that subsequently undergoes C N bond
cleavage to afford intermediate cation D. Subsequent
loss of a proton produces the final aromatic product
E. Currently, the role of Ag(I) salt in promoting this
reaction is not entirely clear since this additive can fa-
cilitate the reaction by either activating the siloxyal-
kyne or promoting pyridinium anion exchange. There-
fore, the observed regioselectivity of this transforma-
tion is difficult to rationalize at the current stage.
However, further mechanistic studies are currently in
progress.
[a]
Isolated yields after standard chromatographic purifica-
tion.
In closing, we have developed a mild, silver-pro-
moted benzannulation of siloxyalkynes with N-alkyl-
pyridinium iodides. Investigation of the substrate
effective substrates (Table 3). Electron-deficient iso- scope revealed that this transformation tolerated
quinolinium salt 17 (R5 =NO2) afforded the expected a broad range of pyridinium salts and siloxyalkynes.
naphthol 18 in 70% yield (Table 3, entry 1). Subjec- Furthermore, high levels of efficiency were also ob-
tion of the unsubstituted isoquinolinium salt 19 (R5 = served for a variety of N-alkylisoquinolinium. This
H) to the general benzannulation protocol furnished new benzannulation reaction enables a rapid access to
the desired product 20 in 88% yield. Furthermore, the a range of synthetically useful, highly functionalized
use of halogenated isoquinolinium salt 21 (R5 =Br) phenols and naphthols.
successfully gave the corresponding naphthol 22
(Table 3, entry 3). Electron-donating groups were also
well tolerated. Reaction of siloxyalkyne 1 with isoqui-
Experimental Section
nolinium salt 23 (R5 =OBn) successfully furnished the
expected product in 80% yield (Table 3, entry 4). This
study also demonstrated that a broad substitution pat-
tern of siloxyalkynes can be well tolerated (Table 3,
entries 5–10). It is also interesting to note that yna-
mines are known to react with quinolinium and iso-
quinolinium salts to produce structurally different
products under thermal conditions,[4] which points to
a unique role of silver(I) salt in promoting the forma-
tion of the observed aromatic products.
General Procedure
N-Alkylpyridinium
or
N-alkylisoquinolinium
iodide
(0.15 mmol) and AgCO2Ph (0.15 mmol) were suspended in
CH2Cl2 (1.5 mL). The resulting mixture was treated with si-
loxyalkyne (0.165 mmol) and stirred at 208C for 2 h under
a nitrogen atmosphere. The precipitate was removed by fil-
tration and the solvent was evaporated under reduced pres-
sure. The crude reaction mixture was then dissolved in
CH2Cl2 (1 mL) and treated with fluoride on a polymer sup-
port (100 mg). After desilylation was complete, as verified
Formation of benzannulation products can be ra-
tionalized using a mechanistic hypothesis depicted in by TLC, the reaction mixture was filtered. Following remov-
Adv. Synth. Catal. 2013, 355, 2495 – 2498
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2497

Jaime R. Cabrera-Pardo et al.
COMMUNICATIONS
al of solvent under reduced pressure, the product was puri-
fied by flash chromatography on silica gel using hexane con-
taining 1% Et3N (for N-alkylpyridinium substrates) and 3%
Et3N (for N-alkylisoquinolinium substrates) as eluent.
[2] a) N. Asao, T. Nogami, S. Lee, Y. Yamamoto, J. Am.
Chem. Soc. 2003, 125, 10921–10925; b) N. Asao, K. Taka-
hashi, S. Lee, T. Kasahara, Y. Yamamoto, J. Am. Chem.
Soc. 2002, 124, 12650–12651; c) V. Gevorgyan, A.
Takeda, Y. Yamamoto, J. Am. Chem. Soc. 1997, 119,
11313–11314; d) N. Asao, H. Aikawa, Y. Yamamoto, J.
Am. Chem. Soc. 2004, 126, 7458–7459; e) R. L. Danheis-
er, R. G. Brisbois, J. J. Kowalczyk, R. F. Miller, J. Am.
Chem. Soc. 1990, 112, 3093–3100; f) W. F. Austin, Y.
Zhang, R. L. Danheiser, Org. Lett. 2005, 7, 3905–3908;
g) R. L. Danheiser, S. K. Gee, J. Org. Chem. 1984, 49,
1672–1674; h) Y. E. Tꢁrkmen, T. J. Montavon, S. A.
Kozmin, V. H. Rawal, J. Am. Chem. Soc. 2012, 134,
9062–9065; i) M. Shindo, Y. Sato, K. Shishido, J. Org.
Chem. 2001, 66, 7818–7824.
Acknowledgements
Financial support of this project was provided by the Nation-
al Institutes of Health (P50 GM086145) and the Chicago Bio-
medical Consortium, with support from the Searle Funds at
the Chicago Community Trust.
References
[3] J. R. Cabrera-Pardo, D. I. Chai, S. Liu, M. Mrksich, S. A.
Kozmin, Nat Chem. 2013, 5, 423–427.
[1] S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901–
[4] R. Fuks, G. S. D. King, H. G. Viehe, Angew. Chem. 1969,
81, 702; Angew. Chem. Int. Ed. Engl. 1969, 8, 675.
2916.
2498
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2495 – 2498