A versatile combined N-heterocyclic carbene and base-catalyzed multiple cascade approach for the synthesis of functionalized benzofuran-3-(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2011.10.078

Functionalized 2,2-disubstituted benzofuran-3-(2H)-ones have been synthesized from simple aldehyde building blocks in a combined NHC- and base-catalyzed one-pot cascade reaction in moderate to excellent yields. This modular approach comprises a NHC-catalyzed hydroacylation/Stetter reaction sequence followed by a retro-Michael, 1,3-H shift and oxa-Michael cascade rearrangement promoted by strong bases.

Full text of DOI:10.1016/j.tetlet.2011.10.078

Tetrahedron Letters 52 (2011) 6952–6956
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A versatile combined N-heterocyclic carbene and base-catalyzed multiple
cascade approach for the synthesis of functionalized benzofuran-3-(2H)-ones
⇑
Johannes F. Franz, Patrick J.W. Fuchs, Kirsten Zeitler
Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized 2,2-disubstituted benzofuran-3-(2H)-ones have been synthesized from simple aldehyde
building blocks in a combined NHC- and base-catalyzed one-pot cascade reaction in moderate to excel-
lent yields. This modular approach comprises a NHC-catalyzed hydroacylation/Stetter reaction sequence
followed by a retro-Michael, 1,3-H shift and oxa-Michael cascade rearrangement promoted by strong
bases.
Received 20 September 2011
Revised 11 October 2011
Accepted 14 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzofuranones
N-Heterocyclic carbene catalysis
Cascade catalysis
Retro-Michael reaction
Rearrangements
Hydroacylation
Catalytic, multistep one-pot reactions, in addition to tandem,
domino, and cascade transformations, i.e., multicatalytic se-
quences,1 have attracted considerably increased levels of interest
during the last few years.2 This is not just due to the obvious advan-
tages with respect to the avoidance of typical cost-increasing inter-
mittent isolation and purification steps as well as the omitting of
waste-producing and time-consuming manual operations. Com-
pared to the traditional ‘one-step, one-pot’ approach, multicatalytic
single-flask strategies can circumvent serious detrimental
drawbacks associated with iterative synthesis. Hence, they
represent an attractive more step- and atom-economical synthetic
strategy.3
Admittedly, here critical issues, such as reliability and compat-
ibility (e.g., unwanted interaction of different catalysts) can bedevil
such processes. But the growing number of organocatalytic trans-
formations4 coupled with their increased tolerance to air and mois-
ture (relative to many transition-metal ion-based systems) has
recently started to offer new perspectives for the development of
simple and efficient single-flask sequences.5 While organocatalysts
are commonly remarkably robust, substrate selective and condi-
tion tolerant, the highly versatile ‘dual’ character of NHCs6 has lim-
ited their frequent use in cascade and domino reactions. In recent
years a few notable such applications have been reported. These
include both multiple step sequences promoted by NHCs7 and
reactions involving carbenes employed in concert with other
catalysts.8,9 Some of these transformations have been proven to
operate via concurrent activation of the reaction partners; others
benefit from improved yield and selectivity only if simultaneous
addition of both catalysts is attempted. Only recently, Scheidt
could demonstrate that the combination of early transition metal
Lewis acids with NHC organocatalysis results in a complete change
of the reaction course to provide access to hitherto inaccessible
products.10 Rovis and co-workers proved the beneficial effects of
co-operative Brønsted acid H-bonding catalysis in certain NHC-
catalyzed transformations.11 However, whereas most NHC pro-
cesses rely on the presence of a base to generate the catalytically
active free carbene from their corresponding heterazolium precat-
alysts,12 examples of cascade catalysis involving NHCs in combina-
tion with alternative base-catalyzed steps are very rare.9f,h,i
Following on from our ongoing interest in the application of al-
kyne building blocks in NHC catalysis,13 the recently disclosed
work on carbene-catalyzed alkene hydroacylation14 inspired us
to investigate the possible extension of this chemistry to propar-
gylic substrates.
Our initial goal was to use the expected
a-methylene ketone
product 5 (Scheme 1) as an active intermediate in further organo-
catalytic one-pot transformations for the cascade assembly of
interesting heterocyclic target structures. While this work was in
progress Glorius and co-workers reported the selective generation
of chromanones via a hydroacylation–Stetter reaction cascade se-
quence.15 However, under our (more basic) conditions the reaction
always yielded a mixture of products (i.e., 3 and 4, Scheme 1).
⇑
Corresponding author. Fax: +49 941 943 4121.
E-mail address: kirsten.zeitler@chemie.uni-regensburg.de (K. Zeitler).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.078

J. F. Franz et al. / Tetrahedron Letters 52 (2011) 6952–6956
6953
O
O
N
S
ClO4
O
O
O
O
O
O
O
O
2
(20 mol%)
H
+
1,4-dioxane or THF
120°C or 80°C
O
O
O
1
3
4
O
O
O
ratio of products3:4
2:1 (dioxane, 120°C)
1:1 (THF, 70°C)
intermolecular
Stetter Reaction
O
O
5
Scheme 1. Initial results of the hydroacylation attempts of propargylated salicylaldehydes.
Careful analysis revealed that in addition to the presence of the
known 1,4-diketo chromanone 3,15a as a second major product (of
very similar polarity and identical mass) 2,2-disubstituted benzo-
furan-3(2H)-one 4 was formed—especially upon prolonged reac-
tion times. These structures were unambiguously confirmed by
X-ray structure analysis16 (see Fig. 1).
(which provides 2-alkylcarboxylate substituted benzofuranones)
can be considered a rare exception.
Hence, we were encouraged to attempt to exploit the serendip-
itous formation of the benzofuran-3(2H)-one unit in the reactions
outlined in Scheme 1 toward the development of a general, novel
protocol for the preparation of these highly attractive synthetic
The broad range of biological activities17 of the benzofuranone
motif containing a quaternary stereocenter at C2, which forms a
key subunit of several natural products such as griseofulvin or
photinides,18 has led to the development of a number of methods
to access these structures (also including NHC-catalyzed intramo-
lecular approaches pioneered by Rovis and She, Scheme 2).19 De-
spite, most of the existing methodologies require quite advanced
synthetic precursors of considerable synthetic complexity. The ele-
gant multi-catalytic Michael–Stetter approach devised by Rovis9f
targets. A
very recent similar report by Biju and Glorius20
prompted us now to disclose our own results in this area.21
The predominance of 4 after extended reaction times led us to
speculate that 3 was being converted into 4 via an initial retro-
Michael reaction, followed by a base-catalyzed 1,3-H shift,22 and
a subsequent 5-exo-trig oxa-Michael ring closure (Scheme 3).
If this hypothesis is correct, it potentially allows developing a
process of expanded scope and utility through the use of distinct
coupling partners, such as easily accessible propargylated salicy-
laldehydes, in conjunction with either aromatic or aliphatic alde-
hyde partners, in an atom-economic one-pot, five-step sequence
involving NHC-catalyzed hydroacylation, a subsequent intermolecu-
lar Stetter reaction, followed by a base-promoted retro-Michael reac-
tion and a 1,3-H shift, completed by a 5-exo-trig oxa-Michael ring
closure (for a detailed mechanistic proposal vide infra—Scheme 5).
As we anticipated a base-catalyzed isomerization/rearrange-
ment of the NHC catalysis-derived 1,4-diketo intermediate15a we
first examined the use of several bases of variable strength (see
Table 1) with the aim to gain further insight into the pKaH23 depen-
dency of this process.
O
O
O
O
O
O
4
O
O
Weak to medium bases (entries 1–5) only produce traces of the
desired benzofuranone. In contrast, stronger bases such as DBU
(entries 6–8) and guanidines (entries 9 and 10) proved to be suit-
able to trigger the initial retro-Michael24 ring-opening (phenoxide
elimination) by deprotonation. Potassium tert-butoxide resulted in
decomposition of the substrate. Relatively low loadings of either
O
11
Cl
Figure 1. X-ray structure of symmetrical and ‘crossed’ benzofuranones 4 and 11.
O
O
COR
R2
R3
O
O
O
COR5
R1
R1
Rovis 2004
+
O
OH
CO2R6
R1
Ar
O
O
Rovis 2010
OTos
O
O
R1
+
She & Pan 2006
R4
R1
this work
Scheme 2. Overview on NHC-catalyzed approaches toward disubstituted benzofuran-3(2H)ones.

6954
J. F. Franz et al. / Tetrahedron Letters 52 (2011) 6952–6956
O
O
O
2
1. cat. (5 mol %)
O
O
R
K2CO3 (10 mol %)
THF, 80°C, 3 h
base
R
H
O
H
R2
R2
O
+
O
O
2. DBU (0.9 equiv.)
THF, 80°C, 2 h
O
O
O
O
R1
8
H
R1
O
10
9
R
'one-pot' conditions
retro Michael
oxa-Michael
O
Cl
O
O
Cl
1,3-H shift
Scheme 3. Proposed pathway for formation of benzofuranones.
O
O
O
O
O
11, 81 %
12, 72 %
OCH3
Cl
O
Table 1
O
The influence of the base on the retro-Michael–1,3-H shift–oxa-Michael rearrange-
ment cascadea
O
O
R
13
14
7
, 20 %; R = H
, 30 %; R = Br
O
, 98 %
O
O
O
R´
base
OCH3
O
O
THF, 80°C
2 h
O
O
O
7
6
O
O
O
15
O
, 95 %
O
16
, 94 %; R = H
17, 32 %; R = Br
pKaH (CH3CN)b
Yields 6/7c
OCH3
Entry
Base
Equiv
O
O
O
1
2
3
4
5
6
7
8
9
K2CO3
NEt3
DIPEA
DMAP
DABCO
DBU
DBU
0.9
0.9
0.9
0.9
0.9
0.9
0.5
0.1
0.9
0.9
100/0
100/0
100/0
100/0
100/0
0/100
13/87
84/16
25/75
0/100
O
18.82
18.81
17.95
18.29
24.34
O
O
4a, 51 %
O
18, 46 %
OCH3
O
O
DBU
Tetramethyl-guanidine
TBD
23.30
25.98
10
O
O
O
O
19
20
, 74 %
, 72 %
a
b
c
Reaction conditions: x equiv base, THF; 80 °C, 2 h.
Literature values of the corresponding conjugate acids according to Leito et al.23
Ratio determined by 1H NMR spectroscopic analysis of crude reaction mixtures
Scheme 4. The cascade transformation substrate scope. (a) Only a single aldehyde
substrate 8 (here: 1) was reacted to generate dimer 4.
using CH2Br2 as internal standard.
Having developed efficient, high yielding conditions to mediate
the five-step cascade for the rapid formation of ‘crossed’ benzof-
uranones 10 in a single-flask procedure with excellent selectivity,
we next investigated the scope of the reaction with respect to
the salicylaldehyde 8 (Scheme 4). While electron-neutral and elec-
tron-rich substrates performed well under our standard conditions
(11 and 12) electron-deficient aldehydes proved to be problematic.
Propargylated 3-nitro salicylaldehyde underwent decomposition
and the bromo substituted aldehyde provided the product 14 in
only moderate yield. Gratifyingly, further examination of the reac-
tion scope revealed a high flexibility with respect to the aldehyde 9
reacting as the ‘nucleophilic’ component in the Stetter reaction.
Apart from electron-neutral, both electron-rich (7 and 15) and
electron-poor aldehydes (11) allow for the formation of benzofura-
nones 10 in excellent yields. In addition, the process is not re-
stricted to aromatic aldehydes; branched aliphatic aldehydes25
are equally well tolerated as substrates and provide the desired
products (19 and 20) in good yields. Only steric bulk results in
diminished product yields (4 and 18).
The proposed mechanism of the quintuple cascade commences
with the NHC-catalyzed intramolecular hydroacylation of the non-
activated triple bond of the propargylated salicylaldehyde 22.15a
The in situ generated highly active exo-methylene chromanone
25 is then able to serve as the acceptor in a subsequent intermole-
cular Stetter reaction with the Breslow-intermediate 24 of the
second aldehyde (acting as nucleophile). In the presence of strong
enough bases a ring-opening retro-Michael-type carbonyl-assisted
elimination of aryloxide 28 occurs, followed by a base-promoted
DBU (entries 7 and 8) or TBD (1,5,7-triazabicylco[4.4.0]dec-5-en)
are capable of promoting the three-step rearrangement, however
in the interest of maintaining convenient reaction times (ca. 2 h),
we decided to continue our studies with the use of 0.9 equiv of
DBU.
We next looked at the viability of combining the two cascades.
As we had observed less clean transformations when DBU was
used both to initially generate the free carbene catalyst (required
to promote the hydroacylation/Stetter sequence from the corre-
sponding heterazolium precursor, see Scheme 1; 1:1 mixture of
chromane 3: benzofuranone 4, THF, 80 °C, overnight), and to medi-
ate the rearrangement, we examined whether our rearrangement
cascade could also be performed in a one-pot, stepwise fashion
where optimal bases specific for either the NHC domino cascade
or the subsequent retro-Michael-isomerization-oxa-Michael rear-
rangement would be applied. Here the combination of K2CO3 and
DBU (or TBD) proved to be most suitable as we could isolate the
desired benzofuranone in our test system in excellent yield and,
importantly, without any traces of the difficult to remove benzopy-
rone products.
A brief solvent screen identified ethereal solvents (THF) as opti-
mal. Lowering the reaction temperature resulted in increased reac-
tion times and incomplete conversion. In our hands this optimized
two-step, one-pot procedure comprising three C-C-bond forming
events clearly outperforms variants involving the use of a single base
to both form the carbene and mediate the rearrangement as well as a
step-wise approach with an intermediate product isolation.

J. F. Franz et al. / Tetrahedron Letters 52 (2011) 6952–6956
6955
O
R2
9
H
OH
X
R2
24
N
X
N
21
OH
O
N
X
O
O
Hydroacylation
25
23
O
Stetter Reaction
H
O
X
N
O
22
R2
21
NHC
N
HO
26
O
X
O
O
R2
base
O
27
O
R2
Retro Michael
O
O
O
30
Oxa-Michael
R2
O
R2
O
O
O
O
28
29
1,3-H shift
Scheme 5. Proposed mechanism of the cascade reaction.
1,3-H shift22 to generate the conjugated internal double bond. Oxa-
Michael addition of the oxyanion 29 to this sufficiently activated
olefin finally results in the formation of 2,2-disubstituted benzof-
uranones 30 in a 5-exo-trig ring closing reaction.
Intrigued by the versatility of this process we further briefly
investigated the scope of the rearrangement with respect to classi-
cal Stetter conditions6,24d in order to probe whether the consecu-
tive rearrangement would also be possible using less reactive
ester-substituted substrates (Scheme 6). Using easily accessible
crotonylated salicylaldehydes in the cascade sequence, together
with Rovis’ pentafluorophenyl catalyst 32 and triethylamine as
base in the initial step, followed by subsequent addition of DBU
upon full conversion to the chromanone, provided the ester-func-
tionalized benzofuranones 34 and 35 in excellent yields after only
marginally longer reaction times. This novel reaction variant pro-
vides a valuable alternative for the (racemic) synthesis of benz-
ofuranones—which usually requires the application of sterically
demanding 1-substituted vinylogous carbonates (see Scheme 2)
under direct Stetter conditions.19a
In summary, we have developed an efficient organocatalytic
one-pot cascade access to disubstituted benzofuran-3-(2H)-ones
starting from simple aldehyde precursors. The combination of the
NHC-catalyzed hydroacylation/Stetter reaction cascade with a
3-step Brønsted base-mediated rearrangement provides these
attractive heterocycles in a modular, atom-economical and high-
yielding process. Further investigations on NHC-catalyzed cascade
processes are in progress.
N
N
BF4
C6F5
1.
N
O
O
32
(20 mol%)
O
Acknowledgments
NEt3 (40 mol %)
THF, RT, 24 h
H
OR
Generous support from the DBU (Deutsche Bundesstiftung
Umwelt—fellowship for J.F.F.), the Fonds der Chemischen Industrie
and the DFG is gratefully acknowledged.
2. DBU (3 equiv.)
THF, 80°C, 3 h
O
CO2R
O
R1
31
R1
33
O
O
Supplementary data
O
O
Supplementary data (experimental details, spectroscopic and
analytical data) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.10.078.
O
O
O
34,
91 %
35,
90 %
O
Scheme 6. Intramolecular Stetter/rearrangement cascade.

6956
J. F. Franz et al. / Tetrahedron Letters 52 (2011) 6952–6956
Chem. 2010, 2, 766–771; (c) Cohen, D. T.; Cardinal-David, B.; Scheidt, K. A.
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(March 24th, 2011) and ESOC 17 in Crete/Greece (July 10th, 2011).
22. Under basic conditions the 1,3-H shift could result from
a vinylogous
tautomerization process via -deprotonation and -reprotonation.
a
c
23. For a comprehensive basicity scale in CH3CN, see: Kaljurand, I.; Kütt, A.;
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supposing a related ring-opening as racemization pathway, see Ref. 19a.
25. Branched aliphatic aldehydes are less prone to undergo self-benzoin reaction,
see also: (a) O’Toole, S. E.; Rose, C. A.; Gundala, S.; Zeitler, K.; Connon, S. J. J. Org.
Chem. 2011, 76, 347–357; (b) Rose, C. A.; Gundala, S.; Connon, S. J.; Zeitler, K.
Synthesis 2011, 190–198 and references cited therein.
9. For selected recent examples with other organocatalysts, see: (a) Lathrop, S. P.;
Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628–13630; (b) Zhao, G.-L.; Córdova, A.
Tetrahedron Lett. 2007, 48, 5976–5980; (c) Jacobsen, C. B.; Jensen, K. L.; Udmark,
J.; Jørgensen, K. A. Org. Lett. 2011, 13, 4790–4793; (d) Hong, B.; Dange, N. S.;
Hsu, C.; Liao, J.; Lee, G. Org. Lett. 2011, 13, 1338–1341; (e) Filloux, C. M.;
Lathrop, S. P.; Rovis, T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20666–20671; (f)
Ozboya, K. E.; Rovis, T. Chem. Sci. 2011, 2, 1835–1838; (g) Enders, D.;
Grossmann, A.; Huang, H.; Raabe, G. Eur. J. Org. Chem. 2011, 4298–4301; For
the combination of base and ‘non-Umpolung’ NHC catalysis, see: (h) Campbell,
C. D.; Collett, C. J.; Thomson, J. E.; Slawin, A. M. Z.; Smith, Andrew D. Org. Biomol.
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