Gold-catalyzed cascade cyclizations of 1,6-diynyl carbonates to benzo[b]fluorenes involving arylation of oxocarbenium ion intermediates and decarboxylative etherification

Article abstract of DOI:10.1002/anie.201201799

Rearranged: The described gold-catalyzed cycloisomerizations give access to highly substituted benzo[b]fluorenes under mild reaction conditions (see scheme). Experimental results indicate that the in situ formed oxocarbenium ion intermediates, derived from gold-catalyzed 3,3-rearrangement and 6-endo-dig cyclization, undergo intramolecular arylation and subsequent decarboxylative etherification to furnish the final ether products. Copyright

Full text of DOI:10.1002/anie.201201799

Angewandte
Chemie
DOI: 10.1002/anie.201201799
Synthetic Methods
Gold-Catalyzed Cascade Cyclizations of 1,6-Diynyl Carbonates to
Benzo[b]fluorenes Involving Arylation of Oxocarbenium Ion
Intermediates and Decarboxylative Etherification**
Yifeng Chen, Ming Chen, and Yuanhong Liu*
In recent years, the gold-catalyzed rearrangement reactions of
propargylic esters have received considerable attention owing
to their synthetic utility in a wide variety of fascinating
transformations.[1] Two main competitive processes, namely,
1,2-acyloxy migration[2] and 3,3-rearrangement[3] are usually
involved in most cases of these gold-catalyzed rearrangement
reactions as an initial step, which depends on the substitution
patterns on either end of the propargyl moiety. The gold-
catalyzed 3,3-rearrangement of propargyl esters leads to the
formation of carboxyallenes, which can be further converted
into various acyloxocarbenium ion intermediates by activa-
tion of the allene moiety by the same gold catalyst. The
oxocarbenium ions generated in these reactions show diverse
reactivities for further functionalization reactions.[1c] The
carboxyallene may also act as a nucleophile to attack
carbon–carbon multiple bonds to form similar oxocarbenium
ion intermediates showcased in a limited number of reports.
Scheme 1. Possible transformations of propargylic carboxylates via
For example, propargyl esters tethered with an alkyne moiety
undergo tandem 3,3-rearrangement/endo-cyclization giving
rise to oxocarbenium ion a, which can be hydrolyzed by H2O
to yield aromatic ketones as reported by Toste and co-
workers[4] and Oh and co-workers (Scheme 1).[5] More
recently, Malacria et al. found that the acyl group on the
oxonium ion b produced through exo-cyclization could be
oxocarbenium ion intermediates.
intermediate like c might be more stable, thus a further
reaction with a nucleophile could be achieved. To this end,
propargyl carbonates would be the right substrates of choice.
It should be noted that compared with the intensive develop-
ment of propargyl esters, little attention has been paid to the
gold-catalyzed transformations of propargyl carbonates.[9]
Herein, we report our success in gold-catalyzed cascade
cyclizations of 1,6-diynyl carbonates leading to benzo[b]fluor-
enes by arylation of oxocarbenium ion intermediates and
subsequent decarboxylative etherification (Scheme 1). It is
also noted that although decarboxylative etherification has
been reported to occur with transition metals such as Pd, Rh,
Fe, or Ru etc.,[10] to our knowledge, there is no report with
gold.
To test the feasibility of our hypothesis, we initially
investigated the cyclization reaction of allyl 3-phenyl-1-[2-
(phenylethynyl)phenyl]prop-2-ynyl carbonate (1a; Table 1).
The reaction of 1a in the presence of the catalyst [Johnphos-
(MeCN)Au]SbF6 (A, 3 mol%) afforded 11-(allyloxy)-11-
phenyl-11H-benzo[b]fluorene 2a in 77% yield in dichloro-
methane or in dichloroethane (Table 1, entries 1 and 2).
However, in these cases, the products were easily contami-
nanted with a small amount of impurity, and purification by
column chromatography was difficult. To our delight, switch-
ing the solvent to toluene allowed the clean formation of 2a
with a yield of 78% (Table 1, entry 3). Other aromatic
solvents such as benzene and o-xylene afforded 2a in 74
and 60% yields, respectively (Table 1, entries 4 and 5). A
À
trapped intramolecularly by the nucleophilic C Au bond,
thereby resulting in a 1,5-migration of the acyl group
(Scheme 1).[6] During our ongoing research on gold-catalyzed
cascade reactions[7] of 1,6-diyn-4-en-3-ols,[7a] we envisioned
that it is possible for oxocarbenium ions a or b to further react
with a nucleophile owing to their high electrophilicities. Such
transformations should be highly dependent on the stability of
the oxocarbenium ion.[8] In intermediates a or b, the acyl
group attached to the oxonium ion is highly electron-deficient
and thus greatly destabilizes the positive charge on the
oxocarbenium ions. We postulated that if the acyl group is
replaced by a -COOR1 group, the resulting oxocarbenium ion
[*] Y.-F. Chen, M. Chen, Prof. Y.-H. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P. R. China)
E-mail: yhliu@mail.sioc.ac.cn
[**] We thank the National Natural Science Foundation of China (Grant
Nos. 21121062, 21125210), Chinese Academy of Science, and the
Major State Basic Research Development Program (Grant No.
2011CB808700) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201799.
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Table 1: Optimization studies for the formation of benzo[b]fluorene 2a.
second alkyne terminus. Substrate 1 f with an electron-
donating (p-Me) group on the aromatic ring worked effi-
ciently and furnished the corresponding product 2 f in 74%
yield, whereas substrate 1g with an electron-withdrawing
substituent (p-Br) gave the cyclization product 2g in only
34% yield along with 37% of naphthyl ketone 3g. The low
yield observed for 2g is attributed to the reduced nucleophi-
licity of the aromatic ring. The ortho-bromo-substituted
substrate 1h did not give the expected product, presumably
owing to steric effects. Interestingly, this method could be
used for the synthesis of the thienyl-fused polycycle 2i by
using the substrate 1i with a thienyl sustituent (R3). The
reactions proved to be quite general with respect to sub-
stitution of R2 on the first alkyne terminus, since aryl and alkyl
groups were all suitable for this substituent, thereby showing
a wide diversity of the products. Functional groups such as
-Me, 3,4,5-trimethoxy, 1-naphthyl, -Br, -CF3, and cyclopropyl
groups were well tolerated (2j–2n, 2p). The reactions with
bulky tBu-substituted diynes were also satisfactory and lead
to 2q and 2r in good yields. Furthermore, substrate 1s,
carrying a fluoro substituent on the parent phenyl ring, was
also compatible for this transformation, and 66% yield for
product 2s was realized. It should be noted that in some cases
as indicated in Table 2, the addition of molecular sieves was
necessary. In the absence of molecular sieves, these reactions
were either not clean or resulted in lower yields of the desired
products. The structure of benzo[b]fluorene was further
confirmed by X-ray crystallographic analysis of 2s.[11]
Entry Catalyst (mol%)
Solvent
t
Yield of 2a[a]
[h]
[%]
1
2
3
4
A (3)
A (3)
A (5)
A (5)
CH2Cl2
ClCH2CH2Cl
toluene
benzene
o-xylene
toluene
1
1
2
1
2
77[b]
77[b]
78
74
60
5
A (5)
6[c]
7[d]
8
[JohnphosAuCl]/AgPF6 (5)
[CyJohnphosAuCl]/AgSbF6 (5) toluene
[PPh3 AuCl]/AgSbF6 (5)
[tBu3PAuCl]/AgSbF6 (5)
AgSbF6 (5)
2.5 59
4
1
1
12
[e]
[e]
[e]
–
–
–
toluene
toluene
toluene
9
10
NR[f]
[a] Yields of isolated product. [b] Contaminanted with a small amount of
impurity. [c] Johnphos=(2-biphenyl)di-tBu-phosphine. [d] CyJohn-
phos=(2-biphenyl)di-cyclohexyl-phosphine. [e] Several products were
formed. [f] NR=No reaction.
combination of [JohnphosAuCl] with AgPF6 gave a lower
yield of 59% (Table 1, entry 6). We also examined the
influence of various phosphine ligands in this transformation.
CyJohnphos, PPh3, and P(tBu)3 all failed to give clean
reactions (Table 1, entries 7–9). The results indicate that the
nature of the phosphine ligand plays an important role in
controlling the chemoselectivity of this reaction. AgSbF6
alone did not promote any transformation (Table 1,
entry 10). For comparison, we also prepared the OAc-
protected substrate 3-phenyl-1-[2-(phenylethynyl)phenyl]-
prop-2-ynyl acetate. It was found that several products were
formed catalyzed by catalyst A (5 mol%) in toluene by using
this substrate; among these products was naphthyl ketone
phenyl(3-phenylnaphthalen-2-yl)methanone 3a, which was
derived by hydration of the oxocarbenium ion intermediate
and was isolated in 31% yield. The results imply that the
protecting group on the alcohol can strongly affect the
reaction pathway.
To understand the reaction mechanism, we tried to
determine and isolate the possible reaction intermediates.
To our delight, when tBu-substituted compound 1r was used
as a substrate, the carbonate product 4r was obtained in 43%
yield in the presence of catalyst A (1 mol%), together with
33% of decarboxylated product 2r [Scheme 2, Eq. (1)].
With the optimized reaction conditions in hand, the scope
of this cascade cyclization reaction was investigated. As
shown in Table 2, the method is applicable to a wide range of
suitably substituted 1,6-diynyl carbonates. We first examined
the substituent effect (R1) on the carbonate groups. The allyl,
alkyl, and benzyl groups are all compatible under the
cyclization conditions, leading to products 2a–2c and 2e in
66–85% yields. When R1 is a sterically more demanding alkyl
group, the efficiency of this reaction decreased. For example,
the methyl-substituted substrate 1b afforded 2b in 85% yield.
When the methyl group in the carbonate moiety was replaced
by an iPr group, the yield of the cyclization product 2c
decreased to 66%. Substrate 1d with a tert-butyl substituent
could not deliver the desired benzofluorene product, but only
the product 2-naphthyl ketone 3a in 77% yield. Clearly the
bulkiness of the substituent on the carbonate moieties had
a detrimental effect on the reactivity. Next, we investigated
the electronic effects of the arene substitution (R3) on the
Scheme 2. Determination of the reaction intermediates.
Control experiments with 4r catalyzed by catalyst
A
(5 mol%) in the presence of 5 ꢀ MS indicated that only
a trace amount of 2r was formed at room temperature;
however, upon heating a toluene solution of 4r at 708C, the
decarboxylation indeed occurred to give 2r in 70% yield
[Scheme 2, Eq. (2)]. Without the gold catalyst, no reaction
occurred. The results disclosed that gold could catalyze the
decarboxylative etherification of benzylic carbonates. The
reason why a higher reaction temperature than in the one-pot
procedure was required is not clear yet.
A crossover experiment was also performed. Treatment of
a 1:1 mixture of two diynes, 1a and 1r, bearing different
protecting groups under the catalytic conditions shown in
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Table 2: Gold-catalyzed cyclizations of 1,6-diynyl carbonates to benzo[b]fluorenes.
Scheme 3 delivered ethers 2a and
2r, as well as the crossover products
2b and 2q. The results indicated
that the decarboxylative etherifica-
tion might proceed through the
formation of an ion pair of a cationic
species and an alkoxide. Dissocia-
tion of ion pairs led to rapid
exchange of the nucleophilic alkox-
ides during the process.[12]
A possible reaction mechanism
for this cascade cyclization reaction
is shown in Scheme 4. p Complex-
ation of the cationic gold complex
to the alkyne moiety followed by
3,3-rearrangement results in the
formation of allenyl carbonate 6.
Subsequent nucleophilic attack of
the allenic moiety to the gold-coor-
dinated triple bond affords oxocar-
benium ion intermediate 7. Inter-
mediate
7 is stable enough to
undergo the subsequent intramo-
lecular arylation/deauration to yield
carbonate 9. Decarboxylative ether-
ification of 9, possibly via benzylic
cation intermediate 10 generated by
+
À
a Au -assisted C O bond cleavage
reaction,[13] would finally furnish
ether 2. Alternatively, intermediate
8 may undergo the subsequent reac-
tions directly before protonation.
In summary, we have developed
a new cascade reaction of 1,6-diynyl
carbonates that involves rare reac-
tion patterns of arylation of oxocar-
benium ion intermediates and
decarboxylative etherification. Our
results suggest that when propargyl
carbonates are employed instead of
carboxylates, it is possible to form
more-stable oxocarbenium ion
intermediates, which can be further
attacked by nucleophiles. The
results also indicate that the sub-
stituents on the migrating groups
may play an important role for
defining the reaction pathway in
gold-catalyzed rearrangement reac-
[a] Yields of isolated products. Unless noted, all the reactions were carried out on 0.2 mmol scale. [b] 5 ꢀ tions of propargyl esters. We are
molecular sieves (MS, 50 mg) were added. [c] The hydration product phenyl(3-phenylnaphthalen-2-
yl)methanone 3a was obtained in 77% yield. [d] The hydration product [3-(4-bromophenyl)naphthalen-
2-yl](phenyl)methanone 3g was also formed in 37% yield. [e] The hydration product [3-(2-bromophe-
nyl)naphthalen-2-yl](phenyl)methanone 3h was obtained in 94% yield. [f] 4 ꢀ MS (25 mg) were added
now exploiting the new synthetic
possibilities by examining the gold-
catalyzed reactions of simply sub-
stituted propargylic carbonates.
(0.1 mmol scale). [g] 4 ꢀ MS (50 mg) were added.
Experimental Section
Typical procedure for the synthesis of
benzo[b]fluorene 2a. Catalyst
A
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119, 2806; Angew. Chem. Int. Ed. 2007, 46, 2750; c) S. Wang, G.
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J. Am. Chem. Soc. 2010, 132, 4720; k) T. M. Teng, R. S. Liu, J.
Am. Chem. Soc. 2010, 132, 9298; l) G. Zhang, V. J. Catalano, L.
Zhang, J. Am. Chem. Soc. 2007, 129, 11358; m) G. Li, G. Zhang,
L. Zhang, J. Am. Chem. Soc. 2008, 130, 3740; n) S. Wang, L.
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Org. Lett. 2007, 9, 2147; L. Ye, L. Zhang, Org. Lett. 2009, 11,
3646.
Scheme 3. Crossover experiment.
[4] J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc. 2006, 128,
7436.
Scheme 4. Possible reaction mechanism.
[5] a) C. H. Oh, A. Kim, W. Park, D. I. Park, N. Kim, Synlett 2006,
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related papers, see: b) Y. Chen, Y. Liu, J. Org. Chem. 2011, 76,
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Li, Y. Liu, J. Org. Chem. 2010, 75, 2903; f) Y. Chen, Y. Lu, G. Li,
Y. Liu, Org. Lett. 2009, 11, 3838; g) Y. Lu, X. Du, X. Jia, Y. Liu,
Adv. Synth. Catal. 2009, 351, 1517; h) Y. Lu, X. Fu, H. Chen, X.
Du, X. Jia, Y. Liu, Adv. Synth. Catal. 2009, 351, 129.
(7.7 mg, 0.010 mmol) was added to a solution of allyl 3-phenyl-1-[2-
(phenylethynyl)phenyl]prop-2-ynyl
carbonate
(1a;
78.5 mg,
0.2 mmol) in toluene (2 mL). After stirring at room temperature for
two hours, the solvent was evaporated under reduced pressure, and
the residue was purified by chromatography on silica gel (petroleum/
dichloromethane = 3:1) to afford 2a (54.4 mg, 78%) as a white solid.
m.p. 129–1308C. 1H NMR (300 MHz, CDCl3, Me4Si): d = 3.52–3.62
(m, 2H), 5.06 (dd, J = 10.2, 1.5 Hz, 1H), 5.27 (dd, J = 17.4, 1.8 Hz,
1H), 5.78–5.90 (m, 1H), 7.18–7.47 (m, 10H), 7.73 (s, 1H), 7.74 (d, J =
6.9 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),
8.09 ppm (s, 1H); 13C NMR (75.5 MHz, CDCl3, Me4Si): d = 64.52,
88.21, 115.58, 118.23, 120.47, 124.65, 126.63, 125.70, 125.86, 126.39,
127.07, 128.07, 128.18, 128.62, 128.86, 129.28, 133.64, 134.29, 135.22,
138.84, 140.22, 144.22, 145.30, 147.53 ppm. HRMS (EI): m/z calcd for
C26H20O: 348.1514, found 348.1515.
[8] There are only two reports involving the nucleophilic attack to
oxocarbenium ion intermediates in gold-catalyzed reactions of
propargyl carboxylates, to our knowledge. See: a) L. Zhang, J.
Am. Chem. Soc. 2005, 127, 16804; b) W. Rao, D. Susanti, P. W. H.
Chan, J. Am. Chem. Soc. 2011, 133, 15248.
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F. M. Istrate, F. Gagosz, Tetrahedron 2009, 65, 1889; c) Y. X.
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Received: March 6, 2012
Revised: April 13, 2012
Published online: May 16, 2012
Keywords: gold · homogeneous catalysis ·
.
propargyl carbonates · rearrangement · synthetic methods
[1] For reviews, see: a) J. Marco-Contelles, E. Soriano, Chem. Eur. J.
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J. A. Tunge, Org. Lett. 2009, 11, 5650.
[11] CCDC 855980 (2s) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[12] To understand the possible reaction pathway, we also tried the
gold-catalyzed decarboxylative etherification reaction of the
simple substrate benzhydryl tert-butyl carbonate with methanol.
It was found that the desired product of (methoxymethylene)-
dibenzene was obtained in 99% yield.
[13] a) S. Guo, F. Song, Y. Liu, Synlett 2007, 964; b) M. Georgy, V.
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Synth. Catal. 2006, 348, 2063.
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