Silver(I)- or copper(II)-mediated dearomatization of aromatic ynones: Direct access to spirocyclic scaffolds

Article abstract of DOI:10.1002/anie.201501812

A high-yielding silver(I)- or copper(II)-catalyzed dearomatizing spirocyclization strategy allows the conversion of simple aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, into functionalized spirocyclic scaffolds. A high-yielding asymmetric variant furnishes spirocyclic indolenines in up to 89:11 e.r. Dearomatization: Simple achiral aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, can be converted into complex chiral spirocyclic scaffolds. The silver(I)-catalyzed dearomatizing spirocyclization typically provides the products in more than 95 % yield and up to 89:11 e.r.

Full text of DOI:10.1002/anie.201501812

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501812
German Edition: DOI: 10.1002/ange.201501812
Spirocycles
Silver(I)- or Copper(II)-Mediated Dearomatization of Aromatic
Ynones: Direct Access to Spirocyclic Scaffolds**
Michael J. James, James D. Cuthbertson, Peter OꢀBrien, Richard J. K. Taylor,* and
William P. Unsworth*
Abstract: A high-yielding silver(I)- or copper(II)-catalyzed
dearomatizing spirocyclization strategy allows the conversion
of simple aromatic compounds that contain ynone substituents,
including indole, anisole, pyrrole, and benzofuran derivatives,
into functionalized spirocyclic scaffolds. A high-yielding
asymmetric variant furnishes spirocyclic indolenines in up to
89:11 e.r.
D
earomatizing spirocyclization reactions[1] are an effective
means to generate functionalized three-dimensional scaffolds
from simple aromatic precursors, which is important in
research programs driven by the formation of molecular
complexity and the exploration of chemical space.[2] The
dearomatization strategy described herein is based on the
conversion of aromatic ynone derivatives into spirocycles
through alkyne activation with a simple Lewis or p-acidic
catalyst, illustrated by the conversion of indole derivative
1 into 3,3-substituted spirocyclic indolenine 2 (Figure 1a).[3,4]
A significant problem with this type of transformation is the
proclivity of the spirocyclic products to undergo a facile 1,2
migration under acidic conditions, which is driven by the
restoration of aromaticity. This issue is particularly prevalent
with indolenines. An illustrative example was recently
reported by Van der Eycken (Figure 1b):[5] spirocyclic indo-
lenine 4a was formed in low yield when alkyne 3 was treated
with AuPPh3Cl/AgOTf, the other major product being the
rearomatized indole 4b. Indeed, while processes involving the
electrophilic activation of alkynes have been well studied in
recent years,[6] Van der Eyckenꢀs example is, to the best of our
knowledge, the highest-yielding acid-catalyzed spirocycliza-
tion of its type reported in the literature;[7] in related
processes, rearomatized products such as compound 4b are
reported far more often (not only with indoles, but across
a range of heteroaromatics).[7,8]
Figure 1. Dearomatizing spirocyclization through electrophilic alkyne
activation.
Figure 2. Dearomatizing spirocyclization.
enones (right in Figure 2) using low loadings of simple
silver(I) or copper(II) salts. The ynone subunit was chosen
on the basis of its synthetic accessibility and the utility of the
enone products, but is also a key design feature, as the
carbonyl group reduces the migratory aptitude of the adjacent
alkene, thus stabilizing the spirocyclic products with respect
to 1,2 migration. Studies demonstrating that asymmetric
dearomatizing spirocyclization reactions can be achieved in
high yield and good e.r. are also reported.
The new methods described herein provide a general,
high-yielding strategy for the conversion of a range of achiral
heteroaromatics (left in Figure 2) into complex, spirocyclic
To begin our study, we examined the conversion of indole
5a into spirocycle 6a using a range of Brønsted, Lewis, and
p acids to activate the alkyne. Full details of this screen can be
found in the Supporting Information, with the key results
given in Table 1.
[*] M. J. James, Dr. J. D. Cuthbertson, Prof. P. O’Brien,
Prof. R. J. K. Taylor, Dr. W. P. Unsworth
University of York
York (UK)
The most effective catalysts that were screened were
Cu(OTf)2, AgNO3, and AgOTf (Table 1), while surprisingly,
standard gold p -acids[9] were ineffective,[10] as was triflic acid
(Table 1, entry 2).[11] The dearomatizing spirocyclization reac-
tion of indole 5a can be performed efficiently under a range
of conditions (Table 1, entries 3–7),[12] with the use of
0.01 equivalents of AgOTf in dichloromethane at room
E-mail: richard.taylor@york.ac.uk
william.unsworth@york.ac.uk
[**] The authors wish to thank the University of York (M.J.J., J.D.C., and
W.P.U.) for funding and Dr. A. C. Whitwood (University of York) for
X-ray crystallography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501812.
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Table 1: Optimization of acid-catalyzed indole/alkyne spirocyclization.
Table 2: Substrate scope of indole/ynone spirocyclization.[a]
Entry
Starting material
t
[h]
Isolated product
Yield
[%]
1
2
3
4
5a Ar=4-MeO-C6H4
5b Ar=Ph
5c Ar=4-Me2N-C6H4
5d Ar=4-Br-C6H4
0.5
6a Ar=4-MeO-C6H4
6b Ar=Ph
6c Ar=4-Me2N-C6H4
6d Ar=4-Br-C6H4
100[b]
100[b]
97[b]
0.5
0.3
1.5
100
Entry
Starting
material
Acid (equiv)
t [h]
Product
Yield [%][a]
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5a
5a
7
–
20
1
20
8.5
2.5
1
–
TfOH (0.01)
Cu(OTf)2 (1)
Cu(OTf)2 (0.01)
AgNO3 (0.01)
AgOTf (0.1)
AgOTf (0.01)
AgOTf (0.1)
6a
6a
6a
6a
6a
6a
8
trace
80
89
97
95
5
6
5e R=Me
5 f R=nBu
2
3.5
6e R=Me
6 f R=nBu
95[b]
100[b]
0.5
1
100
80
7
5g Ar=4-MeO-C6H4
5h Ar=4-MeO-C6H4
5i Ar=4-MeO-C6H4
5j Ar=4-MeO-C6H4
0.5
6g Ar=4-MeO-C6H4
6h Ar=4-MeO-C6H4
6i Ar=4-MeO-C6H4
6j Ar=4-MeO-C6H4
95[c]
100
100
84
[a] All reactions performed in CH2Cl2 (0.1m) at RT.
temperature being optimal, furnishing spirocyclic indolenine
6a in quantitative yield (entry 7, for X-ray crystallographic
data see the Supporting Information).[13] The importance of
the ynone carbonyl group is noteworthy, as demonstrated by
the contrasting reactivity of propargyl alcohol 7 (Table 1,
compare entries 6 and 8); treatment of compound 7 with
0.1 equivalents of AgOTf for 1 h at room temperature
resulted in its complete conversion into known carbazole
8,[14] presumably through an initial spirocyclization, followed
by 1,2 migration (compare 4a to 4b, Figure 1b) and dehy-
dration.[8] The relative ease of the migration in the conversion
of 7 into 8 is presumably driven by the higher migratory
aptitude of the more electron-rich alkene.
8
1
9
0.2
0.1
10
In addition to ynone 5a, three electronically diverse aryl
substrates 5b–5d were treated with 0.01 equivalents of
AgOTf in dichloromethane and furnished indolenines 6a–
6d in very good yields with short reaction times at room
temperature (Table 2, entries 1–4). Alkyl-substituted ynones
5e and 5 f were similarly good substrates, furnishing indole-
nines 6e and 6 f, respectively, in excellent yields under the
same conditions (Table 2, entries 5 and 6).[15] Additional
substitution around the indole system is also well tolerated:
for example, benzyl- and bromo-substituted spirocycles 6g
and 6h were each formed in high yields (Table 2, entries 7 and
8). Indolenines 6i and 6j were also formed rapidly in excellent
yields under the standard conditions (Table 2, entries 9 and
10). These results are particularly pleasing as the proximity of
the substituents on the 2 -position of the indole to the reaction
site could have impeded the reaction. The six-membered-ring
product 6k was also formed using ynone homologue 5k. In
this case, the reaction was slower and required moderate
heating (358C) in order to reach completion within 16 h, but
nonetheless, the desired product was still obtained in good
yield (Table 2, entry 11). Indolenine 10[15] was also synthe-
sized, through a desilylation/spirocyclization sequence, by
11[d]
5k Ar=4-MeO-C6H4
16
6k Ar=4-MeO-C6H4
75
93
12[e]
9
16
10
[a] All reactions performed using 0.01 equiv AgOTf as catalyst in CH2Cl2
(0.1m) at RT, unless otherwise stated. [b] Compounds 6a–c and 6e–f can
also be formed using 0.01 equiv Cu(OTf)2 (see the Supporting
Information). [c] d.r. =55:45. [d] Reaction performed using 0.1 equiv
AgOTf as catalyst at 358C. [e] Reaction performed in acetone using
AgNO3 (0.2 equiv) as catalyst.
[16]
stirring ynone 9 with 0.2 equivalents of AgNO3 in acetone
at room temperature for 16 h, affording spirocyclic cyclo-
pentenone 10, which is unsubstituted at C3 (Table 2,
entry 12). This high-yielding one-pot process is important,
given that the terminally unsubstituted alkyne (i.e. 9 with
2
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TMS = H) required to access spirocycle 10 in the standard
way is unstable and could not be isolated.
Promising preliminary studies have also been performed
using AgI salts of chiral phosphoric acids (CPAs) as catalysts
for the indole/ynone spirocyclization (Figure 3). Six catalysts
Figure 4. Asymmetric spirocyclization reactions. All reactions were
performed using 0.09–0.30 mmol of ynone in chloroform (0.1m) and
0.01 equiv of catalyst F. The reaction mixtures were stirred at À108C
for 16 h. Enantiomeric ratios were measured by HPLC using a Chiralpak
IB column, eluting with 10% IPA in hexane.
Figure 3. Asymmetric spirocyclization of 5a. All reactions were per-
formed using 0.09–0.30 mmol of 5a in chloroform (0.1m) and
0.01 equiv of the specified CPA catalyst. The reaction mixtures were
stirred at either RT or À108C for 16 h, unless otherwise stated.
Enantiomeric ratios were measured by HPLC using a Chiralpak IB
column, eluting with 10% IPA in hexane, and the major enantiomer
formed using the (R)-CPA catalysts A, B, D, and F is shown.
[a] Reaction was performed in CH2Cl2 using 0.1 equiv of catalyst A for
5 min. IPA=isopropanol.
zation, expanding the potential scope of the method
(Table 3). Anisole-substituted ynone 11 furnished spirocyclic
dienone 12[20,21] upon treatment with 0.1 equivalents of Cu-
(OTf)2, while ynone 13 reacted very efficiently when treated
with 0.1 equivalents of AgNO3, affording spirocycle 14, with
both reactions proceeding in excellent yields (Table 3,
entries 1 and 2). Benzofuran 15 also reacted well, in this
case furnishing the unusual spirocyclic enol ether 16 in good
yield (Table 3, entry 3).
In summary, a range of high-yielding dearomatizing
spirocyclization reactions are described, including an asym-
metric variant, for the generation of synthetically useful
spirocyclic building blocks from simple heteroaromatic pre-
cursors containing ynone side chains. The reactions are easy
to perform, proceed at room temperature or À108C and are
insensitive to both air and moisture.
were screened, all of which are simple AgI salts of commer-
cially available BINOL-based CPAs.[17] First, ynone 5a was
treated with 0.1 equivalents of catalyst A in dichloromethane
at room temperature, which led to the rapid formation of
spirocycle 6a, with a small amount of asymmetric induction
(54:46 e.r.). Bulkier CPA catalysts (B–F) were next examined
and additional modifications were also made; chloroform
replaced dichloromethane as the solvent, the catalyst loading
was reduced to 0.01 equivalents, the temperature was lowered
to À108C, and the reaction time was increased to 16 h. These
modifications significantly improved the enantioselectivity,
with the highest e.r. observed using 9-phenanthryl derivative
F, which furnished spirocycle 6a in quantitative yield, in 89:11
e.r.
Table 3: Alternative spirocyclization reaction systems.[a]
Entry
Starting material
t
[h]
Isolated product
Yield
[%]
These conditions were then applied to other ynone
substrates. Pleasingly, in all cases the spirocyclic products
were isolated in high yields (6b, 6d,e, 6h,i, 62–100%) and
with consistently good enantioselectivity (e.r. 70:30–89:11),
thus indicating that the reaction is likely to be applicable to
a broad range of substrates (Figure 4). Notably, the e.r. of
compounds 6a and 6d could be easily increased (98:2 e.r.)
following recrystallization from ethyl acetate/hexane. The
fact that good enantiomeric ratios were achieved by testing
a relatively small number of commercially available CPAs
augurs well that further optimization will lead to greater
improvements.[18] The major enantiomer formed in reactions
using (R)-CPA catalysts is the (S)-spirocycle (as shown in
Figures 3 and 4) based on X-ray crystallographic data of
spirocycle 6d.[13,19] A tentative mechanism consistent with this
outcome is included in the Supporting Information.
1[b]
11 Ar=4-Me2N-C6H4
1
12 Ar=4-Me2N-C6H4
95
2[c]
13 Ar=4-MeO-C6H4
15 Ar=4-MeO-C6H4
0.5
18
14 Ar=4-MeO-C6H4
16 Ar=4-MeO-C6H4
99
68
3[d]
[a] Reactions performed in CH2Cl2 (0.1m) at RT. [b] 0.1 equiv Cu(OTf)2
used as catalyst. [c] 0.1 equiv AgNO3 used as catalyst. [d] 0.01 equiv
AgOTf used as catalyst.
Finally, preliminary studies demonstrate that a wider
range of aromatic ynones undergo dearomatizing spirocycli-
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[10] A complex mixture of products was formed when the mixed
AuPPh3Cl/AgOTf catalyst system used in the work of Van der
Eycken (see Figure 1b and reference [5]) was tested.
Keywords: asymmetric catalysis · dearomatization ·
indolenines · silver · spirocycles
[11] The unpurified reaction mixture (Table 1, entry 2) contained
approximately 90% unreacted 5a, along with other unidentified
impurities and only trace amounts of spirocycle 6a. This appears
to rule out the possibility that the successful reactions using
AgOTf or Cu(OTf)2 are catalyzed by adventitious triflic acid
through “hidden Brønsted acid catalysis”. See: T. T. Dang, F.
Boeck, L. Hintermann, J. Org. Chem. 2011, 76, 9353.
[12] Dichloromethane was retained as the optimal solvent for further
development, although the reaction can also be performed with
comparable efficiency in chloroform, THF, toluene, or dichloro-
ethane (see Supporting Information).
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Received: February 25, 2015
Published online: && &&, &&&&
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Spirocycles
M. J. James, J. D. Cuthbertson,
P. O’Brien, R. J. K. Taylor,*
W. P. Unsworth*
&&&& — &&&&
Silver(I)- or Copper(II)-Mediated
Dearomatization of Aromatic Ynones:
Direct Access to Spirocyclic Scaffolds
Dearomatization: Simple achiral aro-
matic compounds that contain ynone
substituents, including indole, anisole,
pyrrole, and benzofuran derivatives, can
be converted into complex chiral spiro-
cyclic scaffolds. The silver(I)-catalyzed
dearomatizing spirocyclization typically
provides the products in more than 95%
yield and up to 89:11 e.r.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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These are not the final page numbers!