Catalytic Conjugate Addition of Electron-Rich Heteroarenes to β,β-Disubstituted Enones

Article abstract of DOI:10.1021/acs.orglett.7b01402

Catalytic conjugate additions of heteroarenes to β,β-disubstituted enones are reported. Additions of a range of heteroarene nucleophiles, including furans, indoles, a pyrrole, and a thiophene, to a variety of β,β-disubstituted enones occur to form the corresponding ketone products containing heteroarylated, all-carbon quaternary centers in up to 90% yield. These reactions occur under mild reaction conditions in the presence of low loadings of bismuth triflate.

Full text of DOI:10.1021/acs.orglett.7b01402

Letter
pubs.acs.org/OrgLett
Catalytic Conjugate Addition of Electron-Rich Heteroarenes to β,β-
Disubstituted Enones
Tanner L. Metz, Joshua Evans, and Levi M. Stanley*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: Catalytic conjugate additions of heteroarenes to β,β-
disubstituted enones are reported. Additions of a range of heteroarene
nucleophiles, including furans, indoles, a pyrrole, and a thiophene, to a
variety of β,β-disubstituted enones occur to form the corresponding
ketone products containing heteroarylated, all-carbon quaternary centers
in up to 90% yield. These reactions occur under mild reaction conditions
in the presence of low loadings of bismuth triflate.
Scheme 1. Current Challenges in Conjugate Additions of
onjugate additions of aryl and heteroaryl nucleophiles to
Heteroarenes to β,β-Disubstituted, Cyclic Enones
C
β,β-disubstituted enones enable rapid generation of
arylated and heteroarylated quanternary carbon centers.
Transition-metal-catalyzed conjugate additions of aryl nucleo-
philes to β,β-disubstituted enones are established methods to
generate benzylic and bis-benzylic all-carbon quaternary
centers.1 However, transition-metal-catalyzed conjugate addi-
tions of heteroaryl nucleophiles to β,β-disubstituted enones to
construct related heteroarylated all-carbon quaternary centers
remain challenging. For example, the conjugate addition of 2-
furylboronic acid to 3-methyl-2-cyclohexenone in the presence
of a previously reported palladium(II) catalyst does not occur,2
likely due to protodeboronation of the heteroarylboronic acid.3
The use of Lewis or Bronsted acid catalysts to promote the
direct attack of heteroarenes provides an alternative method to
construct heteroarylated quaternary centers that circumvents
this pathway for deactivation of the heteroaryl nucleophile.
Catalytic additions of indoles and furans to β,β-disubstituted
enones form heteroarylated quaternary carbon centers;
however, these transformations are currently limited in terms
of scope and reaction efficiency. The majority of these reactions
involve additions of indole or 2-methylfuran to 4-methyl-3-
penten-2-one,4 and additions to cyclic β,β-disubstituted enones
remain challenging (Scheme 1). Lewis acid catalyzed conjugate
additions of difuranyl cyanocuprate and 2-methylfuran to 3-
methyl-2-cyclohexenone occur to form the corresponding cyclic
ketone products in modest yields in the presence of a high
loading of catalyst (Scheme 1a).5
transformations require high reaction pressures and high
catalyst loadings, do not encompass a range of heteroaryl
nucleophiles, or are limited to acyclic β,β-disubstituted enones.
Herein, we report studies to identify a catalyst system that
operates at ambient pressure with low catalyst loadings and
encompasses a range of heteroaryl nucleophiles and β,β-
disubstituted enones to enable the formation of ketone
products containing heteroarylated quaternary centers.
We began our studies by evaluating the model conjugate
addition of 3-methyl-2-cylohexenone 1a and 2,3-dimethylfuran
2a to generate 3-(4,5-dimethylfuran)-3-methylcyclohexan-1-
one 3a (Table 1). We initially evaluated RuCl3·xH2O as a
catalyst based on the high activity of this catalyst in conjugate
Conjugate additions of indole to β,β-disubstituted cyclic
enones occur in low-to-modest yields when the reactions are
conducted at high pressures in the presence of a Lewis acid
catalyst or an organocatalyst (Scheme 1b).4e,6 Catalytic
conjugate additions of thiophenes to β,β-disubstituted enones
have not been reported. The most efficient approach to direct
conjugate addition of heteroaryl nucleophiles to β,β-disub-
stituted enones involves diastereoselective addition of indoles
and a pyrrole to progesterone in the presence of a Ru(III)
catalyst.7 Despite these advances, current catalysts of these
Received: May 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01402
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Identification of Reaction Conditions
Scheme 2. Catalytic Conjugate Addition of Heteroarenes to
1a
a
b
entry
catalyst
ratio 1a:2a
yield (%)
1
2
3
4
RuCl3·xH2O
Sc(OTf)3
Bi(OTf)3
TfOH
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2:1
3:1
3:1
3:1
60
74
76
67
0
c
5
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
d
6
e
22
76
89
98
98
98
7
8
9
f
10
eg
,
11
a
Conditions: 1a (0.25 mmol), 2a (0.50 mmol), catalyst (0.013 mmol),
b
MeCN/MeOH (10:1, 0.5 mL), 1 h. Determined by 1H NMR
spectroscopy using dibromomethane as an internal standard. Reaction
run in the presence of 15 mol % 2,6-di-tert-butylpyridine. Reaction
run with MeCN (0.5 mL) as solvent. Reaction run for 2 h. Reaction
a
Conditions: 1a (0.75 mmol), 2 (0.25 mmol), Bi(OTf)3 (0.0063
c
b
mmol), MeCN/MeOH (10:1, 0.5 mL), 1 h. Reaction run with 1a
d
(1.25 mmol) for 3 h.
e
f
g
run in the presence of 2.5 mol % Bi(OTf)3. Reaction run in the
methylfuran to 1a occurs to form product 3b in 90% yield.
Additions were not limited to furan derivatives, and the
reactions of 2-methoxythiophene 2c and 2-methylpyrrole 2d to
1a formed ketone products 3c and 3d in 70% yield. The
conjugate addition of indole 2e to 3-methyl-2-cyclohexenone
1a generated the corresponding ketone product 3e in 63%
yield. The modest yield of 3e led us to further investigate
reaction conditions, and we found that the reaction of 2e with 5
equiv of 1a formed 3e in 84% yield when the reaction was run
for 3 h. Additions of benzofuran and benzothiophene to 1a did
not occur, while additions of unsubstituted pyrrole and furan
formed the products of double addition exclusively.
The lower yields observed for conjugate additions of more
nucleophilic 2-methylpyrrole 2d and indole 2e compared to
additions of less nucleophilic 2,3-dimethylfuran 2a and 2-
methylfuran 2b were unexpected.9 We conducted a series of
competition experiments between 2-methylfuran, indole, and 2-
methylpyrrole to gain insight into these results (Scheme 3).
The competition between 2-methylfuran and indole formed
ketone 3e, the product of indole addition, exclusively. The
observed relative rates of addition of 2-methylfuran and indole
are consistent with nucleophilicity parameters determined for
these heterocycles.9 In addition, the competition between 2-
methylfuran and 2-methylpyrrole formed ketone 3d, the
product of 2-methylpyrrole addition, exclusively. Competition
reactions between indole (3.0 equiv) and 2-methylpyrrole (3.0
equiv) did not occur to form products of conjugate addition.
This result suggests that pyrrole and/or indole nucleophiles can
inhibit the acid catalyst (see Supporting Information for
additional information) and offers a plausible explanation for
the lower reaction efficiency observed for the conjugate
addition reactions of pyrrole and indole nucleophiles. However,
a competition between indole (1.5 equiv) and 2-methylpyrrole
(1.5 equiv) formed ketone 3d exclusively, again consistent with
nucleophilicity parameters for these heterocycles.
presence of 1 mol % Bi(OTf)3.
additions of indoles to progesterone. However, the model
reaction catalyzed by RuCl3·xH2O formed 3a in modest yield
(60%, entry 1). Increased yields of 3a (74−76%) were observed
when the model reaction was run in the presence of Sc(OTf)3
and Bi(OTf)3 (entries 2−3). Based on a previously reported
work, we hypothesized that Bi(OTf)3 could be a source of triflic
acid, and ketone 3a is formed in 67% yield when the reaction is
conducted in the presence of triflic acid (entry 4).8 Next, we
sought to determine whether this transformation is catalyzed by
the Lewis acidic Bi(OTf)3or triflic acid generated in situ. When
the model reaction was run in the presence of catalytic amounts
of Bi(OTf)3 and 2,6-di-tert-butylpyridine, ketone 3a was not
formed (entry 5). These results suggest that triflic acid catalyzes
the model reaction, but we chose to proceed with further
studies using Bi(OTf)3 as a convenient source of triflic acid.
When the model reaction was run in the absence of methanol, a
decrease in reaction efficiency was observed (entries 6). We
hypothesize methanol serves as a proton shuttle that enhances
the efficiency of the model conjugate addition reaction. Longer
reaction times did not lead to an increase in the yield of 3a
(entry 7), likely to due to product inhibition of the acid catalyst
when higher concentrations of 3a relative to 1a are present in
solution. When the model reaction is run in the presence of
excess enone 1a, increased yields of 3a (89−98%) were
observed (entries 8−9). The loading of the Bi(OTf)3 can be
lowered to 2.5 mol % without impacting the yield of 3a when
the model reaction is conducted with a 3:1 ratio of 1a:2a, but a
decrease in reaction efficiency is observed at a 1 mol % catalyst
loading (entries 10−11).
We chose to proceed with studies to evaluate the conjugate
additions of various heteroarenes nucleophiles to 3-methyl-2-
cyclohexenone 1a under the reaction conditions shown in entry
10 of Table 1. These results are summarized in Scheme 2. As
noted above, the addition of 2,3-dimethylfuran 2a to 1a
generated 3a in high yield (88%). The addition of 2-
With practical reaction conditions identified for addition of
indole to 1a, we next evaluated conjugate additions of a variety
of substituted indoles. These results are summarized in Table 2.
B
DOI: 10.1021/acs.orglett.7b01402
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phene 2c, and indole 2e to a variety of 3-substituted enones
(Scheme 4). The reactions of 3-ethyl-2-cyclohexenone 1b, 3-
Scheme 3. Competition Experiments between 2-
Methylfuran, Indole, and 2-Methylpyrrole
a
a
Scheme 4. Scope of β,β-Disubstituted Enones
a
1
Yields determined by H NMR spectroscopy using dibromomethane
as an internal standard.
a
Table 2. Scope of Indole Nucleophiles
a
Conditions: 1a (0.75 mmol), 2 (0.25 mmol), Bi(OTf)3 (0.0063
b
mmol), MeCN/MeOH (0.5 mL), 1 h. Reaction run at 1.0 mmol (2a)
scale. Reaction run with 1a, 1e, or 1f (1.25 mmol) for 3 h.
c
b
entry
2
R1
R2
3
yield (%)
1
2
2e
2f
H
H
H
H
Me
H
H
H
H
H
H
3e
3f
84
58
54
46
70
0
benzyl-2-cyclohexenone 1c, and 3,5,5-trimethyl-2-cyclohexe-
none 1d with 2,3-dimethylfuran 2a occurred to form the ketone
products 3o−3q in 53−69% yield. Additions of 2a to 3-
substituted cyclo-2-hexenones with larger substituents at the 3-
position did not occur.
Additions of 2,3-dimethylfuran 2a, 2-methoxythiophene 2c,
and indole 2e to 3-methyl-2-cyclopentenone 1e and 3-methyl-
2-cycloheptenone 1f occurred to form ketone products 3r−3w
in 37−79% yield. Additions of heteroarenes 2a, 2c, and 2e are
not limited to β,β-disubstituted cyclic enones, and reactions of
these heteroarenes with 4-methyl3−3penten-2-one 1g occurred
to form the conjugate addition products 3x−3z in 66−79%
yield.
5-MeO
5-Br
3
2g
2h
2i
3g
3h
3i
4
5-CN
H
5
6
2j
2-Me
4-Me
5-Me
6-Me
7-Me
3j
7
2k
2l
3k
3l
0
8
58
76
76
9
2m
2n
3m
3n
10
a
Conditions: 1a (1.25 mmol), 2a (0.25 mmol), Bi(OTf)3 (0.0063
mmol), MeCN/MeOH (10:1, 0.5 mL), 3 h. Isolated yields after
purification by flash column chromatography.
b
In conclusion, we have developed a series of conjugate
additions of heteroarenes to β,β-disubstituted enones that form
ketones containing heteroarylated, all-carbon quaternary
centers. These addition reactions occur in the presence of
catalytic Bi(OTf)3 and improve the efficiency and expand the
scope of heteroarene additions to β,β-disubstituted enones.
Additions of furan, thiophene, pyrrole, and indole nucleophiles
to a variety of cyclic and acyclic β,β-disubstituted enones occur
to form the ketone products bearing the heteroarylated, all-
carbon quaternary centers in up to 90% yield. Studies are
ongoing in our laboratory to develop an enantioselective variant
of this method and to expand these conjugate addition
reactions to encompass additional classes of heteroarene
nucleophiles.
As noted above, the addition of indole 2e to 3-methyl-2-
cyclohexenone 1a occurred to form 3e in 84% yield (entry 1).
Reactions of indoles containing electron-donating and -with-
drawing substituents at the 5-position with 1a occurred to form
ketone products 3f−3h,l in moderate yields (46−58%). The
addition of N-methylindole 2i to enone 1a formed product 3i
in 67% yield (entry 5). Reactions of 2-methyl and 4-
methylindole did not occur likely due to the increased steric
bulk adjacent to the C3 position of indole (entries 6−7).
However, additions of 5-methyl-, 6-methyl-, and 7-methyl-
indole to 1a formed 3l−n in 58−77% yield (entries 8−10).
To further expand the scope of these reactions, we evaluated
conjugate additions of 2,3-dimethylfuran 2a, 2-methoxythio-
C
DOI: 10.1021/acs.orglett.7b01402
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Kwie, F. H. A.; Baudoin-Dehoux, C.; Blonski, C.; Lherbet, C.
Synth. Commun. 2010, 40, 1082. (b) Ollevier, T.; Nadeau, E. Org.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01402.
■
S
Biomol. Chem. 2007, 5, 3126. (c) Dumeunier, D.; Marko,
̀
I. E.
Tetrahedron Lett. 2004, 45, 825.
(9) (a) Nigst, A. T.; Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J.
Org. Chem. 2008, 2008, 2369. (b) Lakhdar, S.; Westermaier, M.;
Terrier, F.; Goumont, R.; Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org.
Chem. 2006, 71, 9088. (c) Herrlich, M.; Mayr, H. Org. Lett. 2001, 3,
1633.
Experimental procedures, characterization data, and
copies of NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lstanley@iastate.edu.
ORCID
Levi M. Stanley: 0000-0001-8804-1146
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Research Corporation for Science Advancement,
Iowa State University, and the Iowa State University Center for
Catalysis for supporting this work.
REFERENCES
■
(1) (a) Shockley, S. E.; Holder, J. C.; Stoltz, B. M. Org. Process Res.
Dev. 2015, 19, 974. (b) Liu, Y.; Han, S. J.; Liu, W. B.; Stoltz, B. M. Acc.
Chem. Res. 2015, 48, 740. (c) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295. (d) Gottumukkala, A. L.; Matcha, K.; Lutz, M.; de
Vries, J. G.; Minnaard, A. J. Chem. - Eur. J. 2012, 18, 6907. (e) Hahn,
B. T.; Tewes, F.; Frohlich, R.; Glorius, F. Angew. Chem., Int. Ed. 2010,
49, 1143. (f) Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. J.
Am. Chem. Soc. 2011, 133, 6902. (g) Shintani, R.; Takeda, M.;
Nishimura, T.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3969.
(h) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi,
T. J. Am. Chem. Soc. 2009, 131, 13588. (i) Van Zeeland, R.; Stanley, L.
M. ACS Catal. 2015, 5, 5203. (j) Lee, K.-S.; Brown, M. K.; Hird, A.
W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182. (k) Dabrowski,
J. A.; Villaume, M. T.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2013, 52,
8156. (l) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A. Angew. Chem., Int.
Ed. 2008, 47, 8211. (m) May, T. L.; Brown, M. K.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2008, 47, 7358. (n) Brown, M. K.; May, T. L.;
Baxter, C. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097.
(o) Kehrli, S.; Martin, D.; Rix, D.; Mauduit, M.; Alexakis, A. Chem. -
Eur. J. 2010, 16, 9890. (p) Martin, D.; Kehrli, S.; d’Augustin, M.;
Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128,
8416.
(2) Holder, J. C.; Goodman, E. D.; Kikushima, K.; Gatti, M.;
Marziale, A. N.; Stoltz, B. M. Tetrahedron 2015, 71, 5781.
(3) (a) Thakur, A.; Zhang, K.; Louie, J. Chem. Commun. 2012, 48,
203. (b) Fleckenstein, C. A.; Plenio, H. J. Org. Chem. 2008, 73, 3236.
(c) Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am.
Chem. Soc. 2016, 138, 9145.
(4) (a) Dyker, G.; Muth, E.; Hashmi, A.; King, S.; Ding, L. Adv.
Synth. Catal. 2003, 345, 1247. (b) Dujardin, G. Bulletin de la Societe
chimique de France 1994, 131, 900. (c) Kumar, V.; Kaur, S.; Kumar, S.
Tetrahedron Lett. 2006, 47, 7001. (d) Huang, Z.-H.; Zou, J.-P.; Jiang,
W.-Q. Tetrahedron Lett. 2006, 47, 7965. (e) Harrington, P.; Kerr, M. A.
Can. J. Chem. 1998, 76, 1256. (f) Harrington, P. E.; Kerr, M. A. Synlett
1996, 1996, 1047.
(5) (a) Ng, J. S.; Behling, J. R.; Campbell, A. L. Tetrahedron Lett.
1988, 29, 3045. (b) Constantino, M. G.; Junior, V. L.; da Silva, G. V. J.
́
Molecules 2002, 7, 456.
(6) Łyzwa, D.; Dudzinski, K.; Kwiatkowski, P. Org. Lett. 2012, 14,
1540.
(7) Tabatabaeian, K.; Mamaghani, M.; Mahmoodi, N.; Khorshidi, A.
Synth. Commun. 2010, 40, 1677.
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DOI: 10.1021/acs.orglett.7b01402
Org. Lett. XXXX, XXX, XXX−XXX