Three-component Pd/Cu-catalyzed cascade reactions of cyclic iodoniums, alkynes, and boronic acids: An approach to methylidenefluorenes

Article abstract of DOI:10.1021/ol5006714

Linear diaryliodonium salts are widely used as arylating reagents for C-C and C-X bond formation. Meanwhile, synthetic applications of cyclic iodoniums are relatively rare although they offer the opportunity to set up reaction cascades. We demonstrate an atom and step economical three-component reaction involving cyclic diphenyleneiodoniums, alkynes, and boronic acids, resulting in the construction of methylidenefluorenes in a single operation. Our route enables facile access to both symmetrical and unsymmetrical methylidenefluorene derivatives, compounds that have attracted interest due to their optical properties.

Full text of DOI:10.1021/ol5006714

Letter
pubs.acs.org/OrgLett
Three-Component Pd/Cu-Catalyzed Cascade Reactions of Cyclic
Iodoniums, Alkynes, and Boronic Acids: An Approach to
Methylidenefluorenes
Daqian Zhu,†,‡ Yongcheng Wu,§ Baojian Wu,∥ Bingling Luo,†,‡ A. Ganesan,⊥ Fu-Hai Wu,§ Rongbiao Pi,‡
Peng Huang,*,† and Shijun Wen*,†,‡
†Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for
Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510060, China
‡School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, China
§Guangdong Pharmaceutical University, 280 Waihuan East Road, Guangzhou 510006, China
∥College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
⊥School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kindgom
S
* Supporting Information
ABSTRACT: Linear diaryliodonium salts are widely used as
arylating reagents for C−C and C−X bond formation. Meanwhile,
synthetic applications of cyclic iodoniums are relatively rare
although they offer the opportunity to set up reaction cascades.
We demonstrate an atom and step economical three-component
reaction involving cyclic diphenyleneiodoniums, alkynes, and boronic acids, resulting in the construction of methylidenefluorenes
in a single operation. Our route enables facile access to both symmetrical and unsymmetrical methylidenefluorene derivatives,
compounds that have attracted interest due to their optical properties.
inear diaryliodonium salts have been broadly studied as
Nachtsheim reported the synthesis of carbazole derivatives from
cyclic diphenyleneiodoniums with anilines using Pd catalysts.4
We have also discovered that a variety of carbazoles could be
obtained easily from cyclic diphenyleneiodoniums with anilines,
amines, and sulphonamides, mediated by Cu(OAc)2.5 In the
construction of carbazoles with cyclic iodoniums, the amino
group reacts twice as a bis-nucleophile. We envisioned that other
scaffolds could be accessed from cyclic iodoniums by reaction
with compounds that contain two different intercepting
functional groups XH and Y.
L
arylating agents to construct C−C1 and C−X bonds.2 In the
arylation reactions with linear diaryliodoniums, the formation of
an iodoarene Ar2−I (Type 1 reaction, Scheme 1) is usually
Scheme 1. Arylation Reactions with Linear and Cyclic
Iodonium Salts
Fluorene-based derivatives are present in a number of
biologically active compounds6 and advanced materials.7 The
subfamily of methylidenefluorenes have attracted attention due
to their unique structure and interesting optical properties.8 A
series of de novo synthetic methods have been developed to
construct these fused aromatic rings. The Larock group
synthesized 9-alkylidene-9H-fluorenes by a Pd-catalyzed cou-
pling of aryl iodides and 1-aryl-1-alkynes.9 Later, they reported an
alternative method to access 9-fluorenylidenes through Pd-
catalyzed annulation of ortho-halogen substituted styrenes with
in situ generated arynes.10 Gevorgyan et al. took advantage of a
C−H activation strategy to construct the methylidenefluorene
frame.11 In addition to these representative synthetic strategies,
miscellaneous methods have also contributed to the develop-
ment of methylidenefluorene synthetic chemistry.12
ignored and accepted as an unwanted byproduct. With cyclic
iodoniums, the iodoarene remains as a part of the arylated
product B. Thus, the reaction is more atom economical
compared to linear iodoniums. Moreover, if the reaction partner
A contains a second functional group that is able to react with
iodoarenes, B will undergo further transformation to provide
more structurally complicated molecules C (Type 2 reaction).
However, there are few reports that focus on the cyclic
iodoniums although they are potentially valuable synthons.
One major reason could be that cyclic iodoniums have a rigid
geometry in regards to the tricoordinate iodine complex and a
concomitant tendency to homolytical decomposition compared
to linear iodoniums.3 Recently, the groups of Detert and
Received: March 4, 2014
Published: April 17, 2014
© 2014 American Chemical Society
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Letter
Multicomponent reactions represent an important approach
to aromatic skeletons, as they construct a complex product by
formation of multiple bonds between several substrates in one
single operation.13 Chen et al. have achieved a multicomponent
reaction involving linear iodoniums to prepare quinolines14 and
quinazolines15 with linear iodoniums. However, one problem
remains, as byproduct iodoarenes were ignored. Based on
literature precedents that alkynes can be arylated by linear
diaryliodoniums,16 we envisaged that 3a resulting from the
arylation of alkyne 2a with cyclic iodoniums 1a could undergo an
intramolecular cyclization catalyzed by Pd species. A subsequen-
tial incorporation of a nucleophile such as a boronic acid 4a will
lead to a rapid formation of fluorene derivatives (Scheme 2).
system for this transformation was Pd(OAc)2/CuI/PPh3 in
DMF.
Since 2-iodo-1,1′-biphenyl 3a was obtained, we envisaged that
the same catalyst system should be suitable for further cyclization
followed by the interception of nucleophiles by the vinyl-
palladium intermediate. Indeed, methylidenefluorene 5a was
obtained when p-tolylboronic acid 4a was added as a nucleophile
when the reaction was performed at a higher temperature (Table
S1, Supporting Information (SI)), with the highest yield (91%)
achieved at 100 °C.
Next, we investigated whether these two stepwise reactions
could be coupled as a cascade whereby 1a, 2a, and 4a react in an
atom and step economical fashion to form the methylidene-
fluorene in a single operation. To our delight, 5a was obtained in
an excellent yield (93%) by stirring the three components at 100
°C (Figure 1). To explore the general utility of our method, a
Scheme 2. A Proposed Multicomponent Route to
methylidenefluorenes
Here, we report this novel multicomponent cascade reaction to
construct methylidenefluorenes by Pd/Cu-catalyzed alkynyla-
tion/annulation of cyclic diphenyleneiodoniums, alkynes, and
boronic acids.
To test our hypothesis, we initially investigated the arylation of
p-tolylacetylene 2a with cyclic iodonium 1a using CuI as a
catalyst and Na2CO3 as the base in DMF under an argon
atmosphere at rt (Table 1). The reaction gave the desired
Table 1. Optimization of Reaction Conditions for 3a from 1a
a
and 2a
entry
catalysts
base
solvent
yield
1
CuI
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
dioxane
DCE
17
23
1
2
Pd(PPh)2Cl2, CuI
3
PdCl2, CuI, PPh3
4
Pd(OAc)2, PPh3
43
51
89
38
20
33
10
59
21
29
5
Pd(PPh3)4, CuI
6
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
Pd(OAc)2, CuI, PPh3
7
8
K3PO4
Figure 1. Scope of boronic acids. Conditions: 1a (0.23 mmol), 2a (1.1
equiv), 4 (1.2 equiv), Pd(OAc)2 (10 mol %), CuI (20 mol %), PPh3 (30
mol %), Na2CO3 (3.0 equiv), DMF (2.0 mL), 100 °C, 12 h, Ar.
9
Et3N
10
11
12
13
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
variety of boronic acids were investigated for this transformation.
Phenylboronic acids with substituents regardless of electron-
withdrawing or -donating properties were suitable substrates. It
appears that the strong electron deficiency of the substituted
groups on phenylboronic acids resulted in lower yields (5e, 5i). It
is noteworthy that the heterocyclic furan boronic acid also gave
the expected methylidenefluorene in a good yield (5k).
To further explore the synthetic versatility of the multi-
component reactions, we examined the scope of alkynes in this
process (Figure 2). Not only terminal aryl but also alkyl alkynes
(for 6i, 6j) were found to perform well in the reactions. Among
the aryl alkynes, those with electron-deficient groups gave
methylidenefluorenes in lower yields (6e−6h vs 6a−d). It is
notable that halogens including fluorine and chlorine were well
tolerated in the reactions, providing an opportunity for further
functionalization of the products.
a
Conditions: 1a (0.23 mmol), 2a (1.2 equiv), Pd catalyst (10 mol %),
CuI (20 mol %), PPh3 (30 mol %) when used, base (3.0 equiv),
solvent (2 mL), rt, 3 h, Ar. DCE: 1,2-dichloroethane.
compound 3a albeit in 17% yield (entry 1). To further optimize
the reaction conditions, various Pd catalyst systems were
examined (entries 2−6), and Pd(OAc)2/CuI in the presence of
the PPh3 ligand was discovered to be optimal (entry 6). Next,
different bases including K2CO3, K3PO4, Et3N, and Cs2CO3 were
screened, and Na2CO3 was found to be the best in promoting the
reaction (entries 7−10). Finally, solvents were found to play an
important role in the efficiency of the reaction, with DMF giving
the highest yields (entries 11−13). Thus, the optimal catalytic
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Letter
Figure 2. Scope of alkynes. Conditions: 1a (0.23 mmol), 2 (1.1 equiv),
4f (1.2 equiv), Pd(OAc)2 (10 mol %), CuI (20 mol %), PPh3 (30 mol
%), Na2CO3 (3.0 equiv), DMF (2.0 mL), 100 °C, 12 h, Ar.
Finally, a variety of unsymmetrical cyclic diphenyleneiodo-
niums were tried to generate more diverse methylidenefluorenes
(Figure 3). In the first trials with p-tolylacetylene 2a and p-
tolylboronic acid 4a, the iodoniums with different substitutions
regardless of their electron property provided the expected
methylidenefluorenes (7a−f), demonstrating the generality of
this three-component cascade reaction. To our knowledge,
chemoselective arylation with unsymmetrical linear iodoniums
are not well solved except for cases influenced by large differences
in steric and electronic effects.17 In this work, it was also of
interest to investigate the chemoselectivity of our multi-
component reactions with unsymmetrical cyclic diphenylene-
iodoniums to give isomeric methylidenefluorenes (7g−7j).
Under our conditions, it seemed that the electronic effect had
an influence on chemoselectivity in the reactions. Electronically
poor substituted unsymmetrical cyclic diphenyliodoniums gave
7h (−CN) in high chemoselectivity (1/4) while electronically
rich diphenyliodoniums gave 7g (−OMe) in a mixture of 65/35.
Meanwhile, the steric effect of the 3-tert-butyl substituent was not
significant, and the chemoselectivity was 61/39 (7i). Based on
our observations, we envisaged that the chemoselectivity should
be synergistically enhanced if one side of cyclic diphenylene-
iodoniums was electron-rich and the other side electron-poor.
Thus, compound 7j, as predicted by our hypothesis, was indeed
obtained in higher chemoselectivity (1/9). Further investigations
to enhance the chemoselectivity of unsymmetrical iodoniums are
underway.
Figure 3. Scope of cyclic iodoniums. Conditions: 1 (0.23 mmol), 2 (1.1
equiv), 4 (1.2 equiv), Pd(OAc)2 (10 mol %), CuI (20 mol %), PPh3 (30
mol %), Na2CO3 (3.0 equiv), DMF (2.0 mL),100 °C, 12 h, Ar. a The
ratio was determined by HPLC; for details, see SI.
of 3a and the unexpected 9-(4-methylbenzylidene)-9H-fluorene
8 was obtained when the iodonium 1a was treated with alkyne 2a.
In the other two control experiments involving boronic acid 4a,
they unexpectedly provided dimethyl [1,1′-biphenyl]-4,4′-dicar-
boxylate 9 exclusively, likely resulting from self-coupling of p-
tolylboronic acid.20 The findings further confirmed that the
reactivity of cyclic iodoniums is different from that of linear
iodoniums.3 Also, the coupling reaction of boronic acid and the
alkyne was surprisingly suppressed under our conditions. Based
on these observations, a mechanism was thus proposed (Scheme
3). Initially, Pd(0) resulting from the reduction of Pd(II)
undergoes oxidative addition with the iodonium to form
organopalladium(II) D. Then, a transmetalation between D
Scheme 3. Proposed Mechanism for the Multicomponent
Synthesis of Fluorenes
Since all possible pairwise combinations of iodonium,
acetylene, and boronic acid are able to react together,18,19 it
was of importance to investigate the mechanism by which the
three components underwent cascade reactions under our
conditions. Three control reactions were then performed, in
which two of the three components, cyclic diphenyleneiodonium
1a, p-tolylacetylene 2a, and (4-(methoxycarbonyl)phenyl)boro-
nic acid 4a, were mixed together under the same conditions for
the synthesis of methylidenefluorenes (Figure S1, SI). A mixture
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Letter
(4) (a) Lettessier, J.; Schollmeyer, D.; Detert, H. Acta Crystallogr. 2011,
and Cu(I) activated alkyne species E generates intermediate F,
followed by a reductive elimination to form 3. Our results
implied that the electron-deficient ring side of cyclic iodoniums is
favorable in this alkynylation step (7g−7j). A further oxidative
addition of 3 produces Pd species G, which undergoes an
intramolecular insertion into the neighboring alkyne, leading to
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methylidenefluorene is obtained from I after a second reductive
elimination. It is noteworthy that in situ formation of a similar Cu
species substituting for Pd species D is possible since the
formation of 3 was obtained with CuI albeit only in a low yield
(entry 1, Table 1).
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compatible, providing an opportunity to further functionalize the
product methylidenefluorenes by subsequent transformations.
We have demonstrated that the method can be applied to the
synthesis of unsymmetrical fluorenes in cases where the cyclic
diphenyleneiodoniums are markedly different in the electronic
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S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: wenshj@sysucc.org.cn.
*E-mail: huangpeng@sysucc.org.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Doctoral Program of Higher
Education of China (Grant 20110171120098) and National
Basic Research Program of China (973 Program Grant
2012CB967004).
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