Diastereo- And Atroposelective Synthesis of Bridged Biaryls Bearing an Eight-Membered Lactone through an Organocatalytic Cascade

Article abstract of DOI:10.1021/jacs.9b08510

We present herein an unprecedented stereoselective synthesis of bridged biaryls with defined axial and central chirality from readily available starting materials. This N-heterocyclic carbene-catalyzed method proceeds through propargylic substitution of azolium enolates followed by two-directional cyclization, as supported by DFT calculation. A range of benzofuran/indole-derived bridged biaryls bearing an eight-membered lactone are accessed with uniformly high stereoselectivity (>98:2 dr, mostly >98% ee).

Full text of DOI:10.1021/jacs.9b08510

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Communication
Diastereo- and Atroposelective Synthesis of Bridged Biaryls Bearing
an Eight-Membered Lactone through an Organocatalytic Cascade
Shenci Lu, Jun-Yang Ong, Hui Yang, Si Bei Poh, Xi Liew,
Chwee San Deborah Seow, Ming Wah Wong, and Yu Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08510 • Publication Date (Web): 11 Oct 2019
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Diastereo- and Atroposelective Synthesis of Bridged Biaryls Bearing
an Eight-Membered Lactone through an Organocatalytic Cascade
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Shenci Lu, †,‡ Jun-Yang Ong,† Hui Yang,† Si Bei Poh,† Xi Liew,† Chwee San Deborah Seow,† Ming
Wah Wong,*,† and Yu Zhao*,†,¶
†Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543
‡ Shaanxi Key Laboratory of Flexible Electronics, Northwestern Polytechnical University, Xi'an 710072, China
¶Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai
New City, Fuzhou 350207, China
Supporting Information Placeholder
ABSTRACT: We present herein an unprecedented
Due to their significant utility, extensive efforts were devoted
to the atropoenantioselective synthesis of axially chiral biaryls.5
The synthesis of bridged biaryls, however, still requires multi-step
procedures. The control of both axial and central chirality in these
compounds also represents a great challenge, which is typically
achieved by sequential reactions utilizing substrate control. As
exemplified in Scheme 1c, the pre-installed axial chirality of a
bis-carbonyl substrate was exploited to control the installation of
stereocenters in the linker or the helical chirality.6 Only recently,
elegant catalytic enantioselective syntheses of helicenes were
reported, through either metal-catalyzed arene formation from
alkynes (Scheme 2a)7 or Brønsted acid-catalyzed Fischer
indolization (Scheme 2b).8 To the best of our knowledge, the
direct catalytic synthesis of bridged biaryls with simultaneous
control of axial and central chirality remains elusive in the
literature.
stereoselective synthesis of bridged biaryls with defined axial and
central chirality from readily available starting materials. This
NHC-catalyzed method proceeds through propargylic substitution
of azolium enolates followed by two-directional cyclization as
supported by DFT calculation. A range of benzofuran/indole-
derived bridged biaryls bearing an eight-membered lactone are
accessed with uniformly high stereoselectivity (>98:2 dr, mostly
>98% ee).
The significance of axially chiral biaryls has been widely
recognized in catalysis and drug delivery, due to their exceptional,
compact architectures and promising pharmacological profiles.1
An important subclass is bridged biaryls, which bear an additional
linkage between the two arenes and often with stereocenters
(Scheme 1a). These structures are of high natural abundance, as
exemplified by the anti-leukemic lignan (-)-steganacin2 and tubin
inhibitor (-)-rhazinilam.3 Notably, these compounds are
structurally related to helicenes (Scheme 1b), a significant class of
helically chiral, ortho-condensed polycyclic compounds.4
Scheme 2. Catalytic Enantioselective Access to Helicenes
and Bridged Biaryls
a)
Transition-metal-catalyzed enantioselective helicene synthesis from diyne/triynes (Tanaka)
R R
R
R
O
O
X
Ni or
Rh
X
X
Scheme 1. Bridged Biaryls and Helicenes
or
or
NBn
NBn
chiral helicenes:
b)
R
chiral bridged biaryls:
a)
X
anti clockwise
clockwise
O
O
R
up
up
N
OAc
Et
b)
Chiral helicene synthesis by Brønsted acid-catalyzed enantioselective Fischer indolization (List)
O
MeO
MeO
O
N
H
R
R
R
O
R
O
down
down
N
O
N
O
O
NH2
HX*
P
+
OMe
(P)-6
(M)-6
OH
(-)-steganacin
(-)-rhazinilam
enatiomers of [6]helicene
HX*
c) classical synthesis of bridged biaryls and helicenes
c) This work:
organocatalytic cascade to bridged biaryls with defined axial and central chirality
benzylic-type
coupling
(R = OH)
pinacol-type
coupling
(R = H)
O
O
R
COR
COR
X
R
O
cascade
cyclization
R
H
OH
NHC
NHC-catalyzed
SmI2
H
+
1) LiAlH4 2) HBr
3) PhLi
XH
C
O
R'
H
OH
propargylic
substitution
XH
OH
OH
O
(+)-(P)
(-)-(S)
(+)-(P)
(M, S)
R'
R'
38 examples
(X = O or NTs)
>98:2 dr, 92-99% ee
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Herein, we present our discovery and development of a direct,
pure regarding the axial chirality, could be easily separated by
column chromatography; both isomers were obtained with high ee
of 97-99%. The use of related substrates bearing a more bulky
substituent on the internal alkyne (e.g., R2 = i-Pr or Ph) led to no
reactivity.
catalytic synthesis of bridged biaryls from readily available
propargylic alcohols and enals with excellent diastereo- and
atropo-enantioselectivity (Scheme 2c). These products possess a
benzofuran or indole-containing biaryl moieties with an eight-
membered lactone bridge, and are produced under NHC-catalysis9
through an enantioselective propargylic substitution followed by
two-directional cyclization.
In addition to desymmetrization of symmetrical triols, we
were curious whether chemo-selective cascade cyclization could
be achieved for unsymmetrical racemic triols as well. As shown in
Scheme 4b, when triols 1s or 1t possessing electronically
differentiated arenes were examined, the formation of a single
product 4s or 4t was observed. The more electron-
rich/nucleophilic phenol moiety attacked the acyl group
selectively to form the lactone functionality in the products. The
level of diastereo- and enantioselectivity remained at the same
level of >98:2 dr, 98-99% ee. It is also noteworthy that these
9
Scheme 3. Discovery of Bridged Biaryl Synthesis
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2 equiv.
i-Pr
O
O
i-Bu
H
OH
OH
OH
2a
OBz
i-Pr
HO
O
O
OH
azolium
10 mol%
O
O
2 equiv. DIPEA
1a
CH2Cl2, 24 oC, 36 h
3
(M,S) - 4a
45%, 99% ee
one step from
commercial materials
not formed
reactions proceeded in
a stereoconvergent fashion. Both
enantiomers of the racemic substrate were converted to the
desired product in excellent enantiopurity.
Previous investigation in our laboratory has led to the
development of NHC-catalyzed enantioselective acylative kinetic
resolution of alcohols/phenols as well as desymmetrization of
meso-bisphenols.10 We became interested in the asymmetric
acylation of the readily available triol 1a to access
enantioenriched propargylic tertiary alcohol 3 (Scheme 3). When
we carried out the reaction of 1a with aldehyde 2a in the presence
of catalytic azolium and DIPEA, to our great surprise, the
expected acylation product 3 was not observed at all. Instead, a
bridged biaryl with an eight-membered lactone linkage 4a was
obtained in moderate yield with excellent diastereo- and
enantioselectivity (45% yield, >98:2 dr, 99% ee). Intriguingly, the
incorporation of the reactive terminal alkyne completely switched
the chemo-selectivity of this catalytic system. The formation of 4a
is believed to follow a pathway initiated by the attack of the
azolium enolate intermediate to the alkyne moiety11 followed by
cascade cyclization. Attracted by this unprecedented one-pot
catalytic synthesis of bridged biaryls, we turned our attention to
the exploration of this transformation.
Scheme 4. Scope of Benzofuran-Derived Bridged Biarylsa
a) Desymmetrization of symmetrical triols:
O
R2
OH
2 equiv.
R1
azolium:
R2
Mes
O
R
H
R1
N
2
BF4
OH
R
OH
N
O
azolium
10 mol%
N
H
O
2 equiv. DIPEA
4Å MS, CH2Cl2
24 oC, 36 h
O
R
R
>98:2 dr in
all cases
H
1
4
Scope of aldehydes:
O
(R1 = n-Pr):
60%, 99% ee
85%, 99% ee
4b
1 = n-Bu):
4c (
4d
R
R1
(R1 = n-pentyl): 84%, 99% ee
(R1 = n-hexyl): 50%, 99% eeb
4e
4f (R1 = Bn):
O
O
35%, 99% eeb
4g
56%, 99% ee
2 OTBS
X-ray of 4b
Scope of triols:
O
R
O
R
Bu
Bu
4h
4i
4j
(R = Me): 70%, 99% ee
(R = t-Bu): 75%, 99% ee
(R = OMe): 44%, 99% ee
The representative optimization studies are included in the
supporting information (SI). The use of commercially available
α,β-unsaturated aldehydes instead of 2a provided similar level of
efficiency in most cases and was therefore a more convenient
choice. With the optimal reaction conditions in hand, the
generality of this catalytic desymmetrization was examined.
O
O
O
R
O
4k
4l
4n
4o
4p
(R = F):
(R = Cl):
56%, 97% ee
55%, 97% ee
(R = Me): 71%, 99% ee
(R = t-Bu): 76%, 99% ee
(R = Br): 42%, 98% ee
R
4m
(R = Br): 51%, 97% ee
R2 = Me
Using internal alkyne (
O
):
Me
Bu
O
O
Me
Me
As shown in Scheme 4a, the scope of this system regarding
the aldehydes proved to be general. A range of aldehydes 2
bearing simple alkyl or ether-containing substituents participated
in the reaction equally well to yield 4b-4g in moderate to high
yield with uniformly >98:2 dr and ≥99% ee. The absolute
configuration of 4b was assigned by single crystal X-ray
diffraction analysis.
i-Pr
i-Pr
+
O
O
O
O
O
O
32%, dr = 3:2
major 97% ee
minor 99% ee
c
4r': 8%, 97% eec
4q
4r
: 24%, 99% ee
b) Divergent cyclization of racemic triols:
O
Bu
OH
OH
OH
O
The variation on the triol substrates was explored next. It is
noteworthy that triols 1 bearing various substituents are easily
accessible within two steps from commercial materials. The
variations of either electron-donating or withdrawing character on
1 could be well-tolerated to yield the corresponding products 4h–
4p in good yield and again with >98:2 dr and excellent
enantioselectivity (97-99% ee).
standard conditions
O
O
+
n-Pr
H
OMe
MeO
4s
2c
-1s
: 52%, 99% ee
O
OH
OH
OH
O
standard conditions
O2N
Bu
O
+
n-Pr
H
O
NO2
To further expand the substrate scope, triol containing an
internal alkyne was tested. When hex-2-enal was used as the
aldehyde, the corresponding product 4q was obtained in relatively
low yield and dr (of the two stereocenters). Nonetheless, the
enantioselectivities for both isomers are excellent. Alternatively,
by the use of the bulky aldehyde 2a, two diastereomeric
compounds 4r and 4r´ (3:1 dr), each being diastereomerically
2c
-1t
4t
: 62%, 98% ee
aThe reactions were carried out using 1 (0.15 mmol), 2 (2.0
equiv.), azolium (10 mol%), DIPEA (2.0 equiv.) and 4Å
o
molecular sieves (100 mg) in CH2Cl2 (2.0 mL) at 24 C for 36 h.
b2-chloroaldehyde was used instead of 2. c Aldehyde 2a was used.
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a) Preparation of bridged biaryls with a congested axis
Recognizing the possibility of using unsymmetrical substrates
to realize convergent reactions, we then turned our attention to the
reaction of compounds bearing different functionalities such as
amino phenols 5 (Scheme 5). To our delight, these racemic
substrates underwent a highly chemo-selective reaction to deliver
indole-based bridged biaryls 6 with the eight-membered lactone
exclusively. Notably, no benzofuran-fused lactam product was
observed at all. This is consistent with the intriguing preference
for ester formation over amide formation under NHC catalysis.12
3
4
5
6
7
8
9
O
OH
R2
OH
OH
standard
conditions
R2
Bu
O
R1
R1
Me
O
Me
4u-4w
1u-1w
>98:2 dr in all cases
4u
X - ray for
O
O
O
Bu
O
Bu
O
Bu
O
Br
Ph
Ph
Me
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Scheme 5. Scope of Indole-Derived Bridged Biarylsa
O
O
O
Me
O
Me
Me
R1
NTs
R1
azolium
10 mol%
OH
TsHN
OH
4u,
35%, 86% ee
4v
4w
, 52%, 81% ee
, 38%, 91% ee
2 equiv. DIPEA
+
2
THF, 24 oC, 36 h
b) Axially chiral biaryls after lactone cleavage
O
O
N
O
Ts
4Å MS
-5
-6
(M,S)
>98:2 dr in all cases
not formed
Bu
O
O
CO2Me
Bu
HCl in MeOH
24 o
Me
Me
OH
NTs
Bu
O
C
O
NTs
NTs
NTs
Bu
R
Pr
O
Bu
O
Me
Me
4w
7w:
98%, 91% ee
(M, S)-
,
91% ee
(R, S)-
O
O
O
O
O
O
R
Me
Me
To probe the independent stability of the axial and central
chirality in these bridged biaryls, we explored the reaction of
triols 1u-1w to access 4 with an ortho-group on the bottom arene
(Scheme 6a). These bulky substrates participated in the reaction
and produced 4u-4w with high stereoselectivity, albeit with lower
efficiency. With these bridged biaryls in hand, the cleavage of the
lactone to release the rigidity of the compounds was carried out
smoothly by the use of HCl in MeOH (Scheme 6b). Biaryl 7w
was obtained in excellent yield and as a single diastereomer.14
6a
6b
6c
(R = H): 40%, 94% ee
(R = Me): 60%, 97% ee
(R = t-Bu): 68%, 97% ee
6e
6f
(R = Me): 62%, 97% ee
(R = Br): 40%, 94% ee
6g
: 56%, 92% ee
6d
: 60%, 95% ee
6h
6i
6j
6k
6l
6m
(R = n-Pr):
(R = n-Bu):
58%, 99% ee
70%, 98% ee
Me
NTs
(R = n-pentyl): 57%, 99% ee
R
O
(R = n-hexyl): 40%, 99% eeb
(R= Bn):
(R= i-Pr):
25%, 98% eeb
40%, 99% eec
45%, 98% ee
O
Me
6g
X-ray of
OTBS
6n
This thus represents
a
new entry to axially chiral
aThe general procedure was followed with THF as the solvent.
bcSee Scheme 4.
benzofuran/indole-derived biaryls.15
Scheme 7. DFT Calculation on Reaction Mechanism
The synthesis of indole-derived bridged biaryls dramatically
expanded the scope of this catalytic system.13 The switch of
solvent from CH2Cl2 to THF proved to be crucial to achieve
higher efficiency of the reaction. A wide range of substituents on
the aryl ring in 5 and the substituents in 2 could be well-tolerated
to produce 6a-6f and 6g-6n in uniformly high diastereo- and
enantioselectivity. The absolute configuration of 6g was
unambiguously assigned by single crystal X-ray diffraction
analysis. The relatively low yields were due to a side reaction
pathway, the details are included in the SI. Fused indoles
represent large families of natural products and biologically active
compounds in general, and our method provides access to new
scaffolds of indole-based bridged biaryls linked by an eight-
membered lactone. The evaluation of these new compounds
against various anti-cancer assays is currently underway.
a) Proposed mechanism
NHC
Me
NHC
O
O
H
O
OH
HO
OH
HO
H
base or NHC
Me
H
H
C
O
OH
O
H-bond assisted
propargylic
substitution
TS-QM
1a
o-QM
NHC
INT-1
1,6-addition
H
O
Me
NHC
Me
O
NHC
Me
Me
O
Me
O
H
O
O
NHC
C
H
NHC as
O
O
OH
O
O
Brønsted
base
O
O
H
INT-4
4
INT-3
INT-2
Scheme 6. Access to New Axially Chiral Biaryls
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b) DFT calculations suggests propargylic substitution
governed by steric factors imparted by the catalyst moiety on the
conformation of the enolate moiety in TS1, resulting in a
preferred addition of the Re face to 1a (see SI for details).
G (kcal/mol)
1.454
1.475
1.754
Scheme 8. DFT Calculation of Conformers of 4.
1.626
1.658
1.848
2.156
2.155
1.970
1.829
1.712
1.734
TS-QM
TS2
TS3
TS1
O
TS-QM
32.6
9
S
CH3
O
TS-B to A
G = 10.9
TS-B to C
G = 7.0
TS1
26.7
P
TS2
24.9
10
11
12
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2.099
O
s-cis
1.794
2.017
1.962
O
INT-1
24.2
O
B

:
G = 5.0
S
CH3
O
S
CH3
O
M
NHC
P
O
TS4
TS5
o-QM
8.1
O
O
s-trans
Me
C
H
s-trans
TS5
-9.5
1a + enolate
0.0
TS4
-11.5
HO
OH
HO
TS3
-13.9
A
4

[(M, S)- ]: G = 0.0
C
4

[(P, S)- ]: G = 4.2
O
S
CH3
O
O
NHC
M
TS-D to A
G = 8.4
TS-C to D
G = 11.0
INT-3
-16.8
INT-1
H
O
INT-4
-23.6
s-cis
INT-2
-23.9
Me
enolate
NHC
Me
O
D

OH
:
G = 3.5
OH
H
O
Me
C
Me
O
O
O
NHC
O
4
-67.0
O
H
INT-2
INT-3
INT-4
To unravel the origin of the high diastereoselectivity of the
reaction, we investigated computationally the different
conformers of both (M, S)-4 and (P, S)-4, and the rotational
transition states that interconvert the conformers (Scheme 8). The
structure of the eight-membered lactone was found to be quite
rigid, and the conformation of the bridging axis was highly
correlated with that of the lactone moiety. Notably, the
interconversion between M and P isomers involves a key
intermediate s-cis conformer. The low energies of these transition
states, <15 kcal/mol with respect to the lowest energy s-trans (M,
S)-4, indicates that the interconversion is rather facile and the
selectivity between (M, S)-4 and (P, S)-4 is controlled
thermodynamically by their relative stability. The calculated
energy difference of 4.2 kcal/mol between MS-trans-4 and PS-
trans-4 also agrees well with the high level of diastereoselectivity
observed experimentally.
Regarding the mechanism for this NHC-catalyzed cascade
cyclization, we hypothesized two possible initiation pathways.
Firstly, this reaction could proceed through an alkyne-conjugated
ortho-quinone methide (Scheme 7a in the box),16 which would
then react with azolium enolate in a 1,6-conjugate addition
fashion followed by cascade cyclization. Alternatively, a direct
propargylic substitution of the azolium enolate could generate the
same allene INT-2. Such a transformation under NHC catalysis
was realized by our group very recently.17 INT-2 could then
undergo two-directional cyclization to deliver the desired product
4. To gain more insight on the reaction mechanism, DFT
computations at M06-2X/6-311+G(2d,p)//M06-2X/6-31G* level18
were performed (Scheme 7). Solvent effect (in THF) was taken
into account using the SMD continuum solvent method.19
The postulated formation of o-quinone methide (o-QM)
through a base-catalyzed dehydration of 1a was examined first.
Although o-QM was calculated to be reasonably stable with only
8.1 kcal/mol higher in energy than 1a, the activation barrier for
the formation of such species is too high (32.6 kcal/mol for
transition state TS-QM) for the reaction to take place. In fact, all
the literature precedence involving o-quinone methide is carried
out in acidic instead of basic conditions.20
In summary, we have developed a catalytic, diastereo- and
atropoenantioselective synthesis of bridged biaryls from readily
available starting materials. This NHC-catalyzed transformation
proceeds through propargylic substitution-two directional
cyclization cascade, and delivers the products with uniformly
excellent control of axial and central chirality. The development
of new catalytic procedures to access other challenging structures
bearing different types of chirality is currently under
investigation.
We next investigated the direct propargylic substitution of
azolium enolate.16 Our results showed that the nucleophilic
addition to the unactivated alkyne moiety step (via TS1) has a
lower barrier of 26.7 kcal/mol (5.9 kcal/mol lower than that of o-
QM formation). The intermediate INT-1 formed in this way can
readily undergo a facile dehydration to form allene INT-2. At this
stage, the formation of the eight-membered lactone INT-4
proceeds smoothly by the attack of the phenoxide onto the acyl
azolium moiety via TS3 to INT-3 and then TS4 with an overall
low activation barrier of 12.4 kcal/mol. Finally, the attack of the
remaining phenol to the allene unit is facilitated by NHC as a
Brønsted base catalyst21 to deliver product 4 with an activation
barrier of 14.1 kcal/mol (via TS5).22
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
chmwmw@nus.edu.sg; zhaoyu@nus.edu.sg
Notes
The authors declare no competing financial interest.
Regarding the enantioselectivity at the stereocenter of 4, we
propose that it is determined by TS1 in the slow irreversible
addition of enolate to 1a. Calculations of R-producing transition
states showed that the high enantioselectivity of the reaction is
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X.; Glorius, F. Organocatalytic umpolung: N-heterocyclic carbenes and
ACKNOWLEDGMENT
beyond. Chem. Soc. Rev. 2012, 41, 3511–3522. (f) Ryan, S. J.; Candish, L.;
Lupton, D. W. Acyl anion free N-heterocyclic carbene organocatalysis.
Chem. Soc. Rev. 2013, 42, 4906–4917. (g) Bode, J. W. Carbene catalysis:
An internal affair. Nat. Chem. 2013, 5, 813–815. (h) Hopkinson, M. N.;
Richter, C.; Schedler, M.; Glorius, F. An overview of N-heterocyclic
carbenes. Nature 2014, 510, 485–496. (i) Flanigan, D. M.; Romanov-
Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic Reactions
Enabled by N-Heterocyclic Carbenes. Chem. Rev. 2015, 115, 9307-9387.
(j) Yetra, S. R.; Patra, A.; Biju, A. T. Recent Advances in the N-
Heterocyclic Carbene (NHC)-Organocatalyzed Stetter Reaction and
Related Chemistry. Synthesis 2015, 47, 1357-1378. (k) Wang, M. H.;
Scheidt, K. A. Cooperative Catalysis and Activation with N-Heterocyclic
Carbenes. Angew. Chem. Int. Ed. 2016, 55, 14912-14922. (l) Mondal, S.;
Yetra, S. R.; Mukherjee, S.; Biju, A. T. NHC-Catalyzed Generation of
α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of
Heterocycles and Carbocycles. Acc. Chem. Res. 2019, 52, 425-436.
(10) (a) Lu, S.; Poh, S. B.; Siau, W.-Y.; Zhao, Y. Kinetic Resolution of
Tertiary Alcohols: Highly Enantioselective Access to 3-Hydroxy-3-
Substituted Oxindoles. Angew. Chem., Int. Ed. 2013, 52, 1731-1734. (b)
Lu, S.; Poh, S. B.; Zhao, Y. Kinetic Resolution of 1,1’-Biaryl-2,2’-Diols
and Amino Alcohols through NHC-Catalyzed Atroposelective Acylation.
Angew. Chem., Int. Ed. 2014, 53, 11041-11045. (c) Lu, S.; Song, X.; Poh,
S. B.; Yang, H.; Wong, M. W.; Zhao, Y. Access to Enantiopure
Triarylmethanes and 1,1-Diarylalkanes by NHC-Catalyzed Acylative
Desymmetrization. Chem.- Eur. J. 2017, 23, 2275-2281. (d) Lu, S.; Poh,
S. B.; Rong, Z.-Q.; Zhao, Y. NHC-Catalyzed Atroposelective Acylation of
Phenols: Access to Enantiopure NOBIN Analogs by Desymmetrization.
Org. Lett. 2019, 21, 6169-6172.
(11) For significant examples on NHC-catalyzed intramolecular
hydroacylation of unactivated alkynes, see: (a) Biju, A. T.; Wurz, N. E.;
Glorius, F. N-Heterocyclic Carbene-Catalyzed Cascade Reaction
Involving the Hydroacylation of Unactivated Alkynes. J. Am. Chem. Soc.
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Efficient Synthesis of Benzofuranones: N-Heterocyclic Carbene
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Org. Lett. 2011, 13, 5624-5627. (c) Biju, A. T.; Kuhl, N.; Glorius, F.
Extending NHC-Catalysis: Coupling Aldehydes with Unconventional
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We are grateful for the generous financial support from Ministry
of Education of Singapore (R-143-000-A94-112), National
University of Singapore (R-143-000-A57-114) and the
Fundamental Research Funds for the Central Universities (05150-
19GH020157).
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(22) An alternative conversion of INT-2 to 4 that differs in the
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