A highly reactive dicationic iridium(iii) catalyst for the polarized nazarov cyclization reaction

Article abstract of DOI:10.1002/anie.201000100

(Figure Presented) Pushing the Nazarov envelope: An electrophilic complex (1; see scheme; EDC = electron-donating group, EWC = electron-withdrawing group, binap = 2, 2-bis(diphenylphosphanyl)-l, lbinaphthyl) exhibits unusual catalytic activity in the polarized Nazarov cyclization reaction. Aryl vinyl ketones that show poor reactivity with well-known catalysts can be readily cyclized with 1/AgSbF₆ (1:1) under mild reaction conditions with concurrent AgBr precipitation.

Full text of DOI:10.1002/anie.201000100

Angewandte
Chemie
DOI: 10.1002/anie.201000100
Iridium Catalysis
A Highly Reactive Dicationic Iridium(III) Catalyst for the Polarized
Nazarov Cyclization Reaction**
Tulaza Vaidya, Abdurrahman C. Atesin, Ildiko R. Herrick, Alison J. Frontier,* and
Richard Eisenberg*
Since the discovery of the silicon-directed approach by
Denmark and Jones,[1] the Nazarov reaction has been
employed in the syntheses of a substantial number of natural
products and bioactive molecules that contain highly func-
tionalized five-membered carbocycles.[2] Originally, stoichio-
metric or super-stoichiometric amounts of Brønsted or Lewis
acids were required to promote the Nazarov cyclization of
divinyl ketones and aryl vinyl ketones (aryl enones), to
generate cyclopentanones through a stereospecific 4p elec-
trocyclization reaction.[3] The efficacy of the cyclization is
enormously dependent on both the promoter and the
electronic disposition of the substrate. With polarized sub-
strates,[2a,4] catalytic cyclization is possible using Cu(OTf)2,[4b,5]
Sc(OTf)3,[6] [PdCl2(MeCN)2],[7] or Cu(SbF6)2[8] as a promoter.
While moderate levels of asymmetric induction were ach-
ieved using [Sc(pybox)(OTf)3][9] (pybox = pyridine bisoxazo-
line) and [Cu(pybox)(OTf)2],[10] [Ni(bis{(R)-1-[(S)-2-
(diphenylphosphino)ferrocenyl]ethyl}cyclohexylphosphine)-
(thf)](ClO4)2 offered notable enantioselectivity, but slow
cyclization rates.[11]
Cationic complexes of heavier platinum group metals
have been extensively studied for electrophilicly driven
transformations.[12] In this context, Albeitz et al. reported
the electrophilic complex [Ir(dppe)(CH3)(CO)(dib)](BArF)2
(1), (dppe = 1,2-bis(diphenylphosphino)ethane, dib = 1,2-
diiodobenzene, BArF = tetrakis[3,5-bis(trifluoromethyl)phe-
nyl]borate), which promotes olefin polymerization by a
cationic mechanism.[13] Subsequently, 1 was found to catalyze
the Nazarov cyclization[14] and a tandem Nazarov/Michael
addition sequence[15] with significantly higher reaction rates
and at lower temperatures, when compared to other Lewis
acid catalysts.
nitro groups was not successful, and the catalysis of substrates
that contained PO(OEt)2 or para-tolylsulfonyl substituents
was not efficient.[5] To obtain unusually functionalized cyclo-
pentanones that are fused with aromatic or heteroaromatic
residues, these limitations in scope represented a challenge
that needed to be addressed. Such cyclization reactions
represent powerful strategies for the syntheses of complex
molecules and natural products, such as roseophilin[16] and the
tetrapetalone family.[17] To increase the electrophilicity of the
catalyst, a trication that was generated by BrÀ abstraction was
envisioned. This trication would be stabilized against decom-
position by the bulkier diphosphine ligand, binap (2,2’-
bis(diphenylphosphino)-1,1’-binaphthylene).
Herein, we describe the synthesis and reactivity of
[IrBr(CO)(dim){(R)-(+)-binap}](SbF6)2·CH2Cl2 (2), (dim =
diethylisopropylidene malonate), a new catalyst that exhibits
truly notable activity in these cyclization reactions. Extraction
of the BrÀ ligand in 2 in conjunction with the lability of the
dim ligand opens a new route to generate extremely electro-
philic d6 iridium species for the electrocyclization of aryl
enones that cannot be activated otherwise. Using catalyst 2,
the cyclization reaction of these unreactive substrates to
afford the desired cyclopentanones has been achieved, and
for other less active substrates, cyclization occurs at lower
temperatures with significantly shorter reaction times.
The synthesis of 2 (Scheme 1) began with the preparation
of [IrBr(CO){(R)-(+)-binap}] (3) from the addition of
partially dissolved (R)-(+)-binap in toluene to a solution of
[IrBr2(CO)2](Bu4N). Equimolar addition of bromine to a
solution of 3 in dichloromethane at room temperature
resulted in the formation of a 1:1 mixture of facial (4) and
meridional (5) isomers of [IrBr3(CO){(R)-(+)-binap}] in up to
99% yield of the purified product. Consecutive addition of
two equivalents of diethylisopropylidene malonate (dim) and
silver hexafluoroantimonate to a solution of 4 and/or 5 in
dichloromethane under minimal light conditions led to the
formation of two isomers of 2 in up to 96% yield (Scheme 1).
31P{1H} NMR spectroscopy identified the isomers through two
Despite these successes with the highly active complex 1,
the cyclization of aromatic substrates that contained cyano or
[*] T. Vaidya, Dr. A. C. Atesin, Dr. I. R. Herrick, Prof. A. J. Frontier,
Prof. R. Eisenberg
Department of Chemistry, University of Rochester
Rochester, NY 14627 (USA)
Fax: (+1)585-273-3596
E-mail: frontier@chem.rochester.edu
eisenberg@chem.rochester.edu
[**] We thank the National Science Foundation (Grants CHE-0556225
and CHE-0847851) for supporting this work. We also thank Dr. Jing
Zhang and Dr. Kevin Cariou for helpful discussions, Dr. William
Brennessel (University of Rochester) for X-ray crystallography, and
Dr. Alice Bergmann (SUNY Buffalo) for high-resolution mass
spectrometry.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000100.
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Only 64% conversion was obtained with catalyst 1 at 6 hours,
with completion attained in 12 hours. This observation is
consistent with the fact that 1 has a methyl group, and not
BrÀ, as its sole anionic ligand. While AgSbF6 clearly functions
to enhance the catalytic activity of 2, a control reaction that
contained only AgSbF6 yielded no cyclization catalysis. Based
on these observations, complex 2 plus the AgSbF6 additive
was an impressively effective catalyst system, yielding
enhanced rates under mild conditions.
With this highly active catalyst in hand, the electro-
cyclization reactions of several weakly polarized aryl enones
were examined (Table 1). These substrates contain CO2Me,
PO(OEt)2, CN, or NO2 groups as electron-withdrawing
substituents, and activated aromatic or heteroaromatic moi-
eties as electron-rich substituents. Functionalized cyclopenta-
nones were obtained using 2/AgSbF6 under relatively mild
conditions with high conversion (> 99%) and good yields.
Comparison of catalysts in the aryl enone cyclization reaction
confirmed that the use of 2/AgSbF6 allowed substrate
activation at lower temperatures and enhanced the rate of
reaction more than Cu(ClO4)2, Sc(OTf)3/LiClO4, or 1. As
observed above, precipitation of AgBr is characteristic of
cyclization reactions with 2/AgSbF6.
Scheme 1. Synthesis of [IrBr(CO)(dim)((R)-(+)-binap)](SbF6)2 (2).
Reaction conditions: [a] Br2 (1 equiv), RT, 15 min, CH2Cl2 [b] AgSbF6
(2 equiv), dim (2 equiv), CH2Cl2, RT, 3 h, minimal light conditions.
pairs of doublets, the first of which was observed at d = À15.2
and À19.7 ppm (2JPP = 14.1 Hz) and the second at d = À23.5
and À29.8 ppm (2JPP = 19.6 Hz). While facial isomer
4
afforded only one isomer of 2, the meridional isomer 5
yielded a mixture of both. The presence of dim and (R)-(+)-
binap was confirmed by 1H NMR spectroscopy. Furthermore,
the dicationic nature of 2 was made evident from the
reformation of 4 following bromide addition to a 1:1 mixture
of 2a and 2b (tetrabutylammonium bromide in
[D2]dichloromethane), as observed by 31P{1H} NMR spec-
troscopy.
Initial experiments using catalyst 2 focused on the
electrocyclization of phosphonate aryl enone 6, followed by
a comparison of the catalytic activity of 2 to the most effective
catalysts that are known for each substrate type (Table 1).
Previous investigations into the substituent effects on the
reactivity of polarized aryl enones revealed that Cu(ClO4)2
was an effective catalyst for the cyclization reactions of
activated aromatic compounds, such as 6,[5] while Sc(OTf)3/
stoichiometric LiClO4 was an active promoter for the
cyclization of polarized heteroaryl vinyl ketones.[6]
While the cyclization of 6 with Cu(ClO4)2 required heating
for 24 hours at 808C,[5] the formation of 7 catalyzed by 2
proceeded even at room temperature, albeit slowly. Both of
the IrIII complexes, 1 and 2, catalyzed complete conversion
(>99%) of 6 into 7 at 408C in 12 hours. However, a dramatic
shortening of the reaction time of the 2-catalyzed system was
observed when AgSbF6 (10 mol% with respect to 6) was
added to the reaction mixture. The cyclization reaction of 6
was complete in just 6 hours at 408C, with concurrent
precipitation of AgBr. The observation of AgBr formation
indicates removal of the bromide ligand from 2 to form an IrIII
trication in situ. While the isolation of this active metal
species has not been possible to date, the addition of AgSbF6
is a viable approach to utilizing the high electrophilicity of
tricationic complexes with noncoordinating anions. In sharp
contrast to the results obtained with catalyst 2, addition of
AgSbF6 to the reaction of 6 with 1 did not generate any
precipitate or lead to an enhancement of the reaction rate.
Consistent with the electronic properties of the nucleo-
philic component of the polarized Nazarov substrate, 8 is less
reactive than 6 and cyclizes within 10 hours using 2/AgSbF6 at
608C instead of the 408C required for 6 (Table 1, entry 2).
Cyclization of 8 using catalyst 1 at 608C is much slower than
using 2/AgSbF6, and with Cu(ClO4)2, only 50% conversion is
obtained in 18 hours. For the 3-substituted pyrrole substrate
10, cyclization was reported to occur with Sc(OTf)3/LiClO4 at
808C in 75minutes.[6] In contrast, iridium catalysts 2/AgSbF6
and 1 both afforded complete conversion of 10 even at room
temperature within 20 hours (entry 3). While reactions of the
less-reactive pyrrole substrate 12 using Sc(OTf)3, Sc(OTf)3/
LiClO4, and In(OTf)3/LiClO4 stalled even at 808C, full
conversion was obtained in 2 hours using 1 (entry 4). This
same cyclization reaction was completed in only 50 minutes
with 2 alone, and in the presence of the AgSbF6 additive the
reaction time decreased further to only 20 minutes. The
structure of the cyclobutyl product 13 was confirmed by X-ray
crystallography.[19]
In the presence of catalyst 2 or 2/AgSbF6, the cyclization
of the cyanoaryl enone 14 to form 15 was obtained at 408C
after 60 hours (Table 1, entry 5). While aryl enone 16 did not
cyclize using 2 alone, the desired cyclization was accom-
plished using 2/AgSbF6 at 808C (entry 6). It is worth noting
that Cu(ClO4)2,[5] AgSbF6, and 1 were all ineffective for the
cyclization reactions of 14 and 16, as was 2 or 2/AgSbF6 for 16
at temperatures up to 608C. Similarly, nitroaryl enone 18
could not be cyclized with Cu(ClO4)2,[5] yet 19 is obtained in
the presence of 2/AgSbF6 at 608C in 36 hours (entry 7). The
formation of 19 was confirmed by 1H NMR spectroscopy and
high-resolution mass spectrometry although the sample
decomposed under all isolation conditions. Table 1, entries 5,
6, and 7 show the first examples of the Nazarov cyclization
reaction of polarized aryl enones with cyano and nitro groups.
Similarly, furyl cyclopentanone 21 was obtained only with 2/
AgSbF6 at 808C within 2 hours (entry 8). The reaction with 1
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Table 1: Cyclizations of various polarized aryl enones.[a]
Entry
Aryl enone
Product
Catalyst
2/AgSbF6
1
T [8C]
40
t [h]
6
Conversion[b] [%]
Yield[c] [%]
>99
>99
20
76
68
–
40
12
6
1
Cu(ClO4)2
40
2/AgSbF6
1
60
60
60
10
18
18
>99
>99
50
97
80
–
2
3
4
5
6
Cu(ClO4)2
2/AgSbF6
23
23
80
20
>99
>99
nd[d]
80
62
68
1
20
[6]
Sc(OTf)3/LiClO4
1.25
2/AgSbF6
80
80
80
0.33
2
>99
>99
75[e]
71
70
61
1
Sc(OTf)3/LiClO4
2
2/AgSbF6
1
40
40
80
60
60
12
>99
60
–
[f]
–
[f]
Cu(ClO4)2
–
–
2/AgSbF6
1
80
80
80
20.5
48
>99
59
–
[f]
–
[f]
Cu(ClO4)2
24
–
–
99[b]
–
[g]
2/AgSbF6
60
60
80
36
36
72
>99
[f]
1
–
7
8
[5]
[f]
Cu(ClO4)2
–
–
2/AgSbF6
80
80
80
2
>99
<35
71
–
1
>72
[f]
Sc(OTf)3/LiClO4
2
–
–
[a] Reaction conditions: 2 (10 mol%), 2:AgSbF6 =1:1, CD2Cl2 or CD3NO2, minimal light. [b] Reactions were monitored by and conversion percentage
values were determined using 1H NMR spectroscopy. [c] Yield of isolated product. [d] nd=not determined; monitored by thin-layer chromatography.
[e] Conversion calculated based on recovered starting material. [f] No product detected. [g] AgSbF6 (50 mol% with respect to 18). No catalysis was
observed in CD2Cl2 or with AgSbF6 alone. TIPS=triisopropylsilyl.
gave < 35% conversion in 72 hours and Sc(OTf)3/LiClO4 did
not promote this cyclization.
Importantly, catalyst 2 does not decompose upon pro-
longed heating at 808C, in contrast to 1, which is unstable at
temperatures above 458C.[18] In terms of the synthesis of the
catalysts, the synthesis of 2 avoids the triflate exchange step in
the synthesis of 1[13] and is thus a more accessible, as well as a
more reactive, catalyst. Despite the presence of chiral binap in
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Experimental Section
Representative catalytic reaction: A solution of aryl enone 12
(0.0197 g, 0.0845 mmol), 2 (0.0142 g, 0.00845 mmol), and AgSbF6
(0.00290 g, 0.00845 mmol) in CD3NO2 (0.7 mL) was heated at 808C
for 20 minutes to afford 13 (0.0139 g, 0.00596 mmol) in 71% yield
after column chromatography on silica gel. Experimental details and
spectroscopic information for the preparation of all compounds are
included in the Supporting Information.
Received: January 7, 2010
Published online: March 31, 2010
Keywords: cyclization · homogeneous catalysis · iridium ·
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