Four-Component Synthesis of Phosphonium Salts: Application Toward an Alternative Approach to Cross-Coupling for the Synthesis of Bis-Heteroarenes

Article abstract of DOI:10.1002/anie.201700945

A series of stable phosphonium salts have been synthesized via a novel four-component reaction of an arene nucleophile, 2-heteroatom substituted aryl aldehyde, and phosphine in presence of an acid. The phosphonium salts thus obtained were utilized for the synthesis of a variety of bis-heteroarenes, providing an efficient alternative method to the classical cross-coupling strategies.

Full text of DOI:10.1002/anie.201700945

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700945
German Edition: DOI: 10.1002/ange.201700945
Multicomponent Reactions
Four-Component Synthesis of Phosphonium Salts: Application Toward
an Alternative Approach to Cross-Coupling for the Synthesis of Bis-
Heteroarenes
+
+
Yi-Ru Chen , Ganapuram Madhusudhan Reddy , Shao-Hao Hong, Ying-Zheng Wang, Jhen-
Kuei Yu, and Wenwei Lin*
Abstract: A series of stable phosphonium salts have been
synthesized via a novel four-component reaction of an arene
nucleophile, 2-heteroatom substituted aryl aldehyde, and
phosphine in presence of an acid. The phosphonium salts
thus obtained were utilized for the synthesis of a variety of bis-
heteroarenes, providing an efficient alternative method to the
classical cross-coupling strategies.
S
ince almost a century, organophosphorus compounds have
been extensively used industrially as well as in synthetic
organic laboratories owing to their easy accessibility, high
reliability, and the ability to offer interesting reactivity
Scheme 1. Methods for generation of phosphonium salts for Wittig
[
1]
profiles.
In particular, organophosphonium salts have
reaction.
a wide range of applications as phase transfer catalysts,
Lewis acids, countercations in complex salts, and as ionic
[
2]
liquids.
The requisite phosphonium ylides for the Wittig reaction
nium salts (Scheme 1d) that could further be employed in
Wittig-type reactions for the synthesis of heteroarenes.
In such an instance, we realized that it would also be
[3]
are commonly generated from the corresponding phosphoni-
um salts, which are in turn obtained by the treatment of an
alkyl halide with phosphine (Scheme 1a). Besides this, our
group has been working towards the in situ generation of
phosphonium salts either by Michael addition of a phosphine
on to a,b-unsaturated carbonyl compounds (Scheme 1b) or
[
6]
possible to synthesize bis-heteroarenes following our strat-
egy, which could prove to be a powerful method further to the
existing traditional cross-coupling methods. Most of the
reported cross-coupling strategies suffer from limitations
such as 1) use of highly sensitive, expensive, and toxic
transition-metal catalyst; 2) the need for the prefunctionali-
zation of substrates; 3) limited functional group tolerance;
4) difficulty in the presence of an ortho substitution, and
1
,2-addition to aldehydes or N-acyl imines for their subse-
[4]
quent Wittig reaction (Scheme 1c). Isolable organophos-
phonium salts offer certain advantages over the in situ
generated ones, as they enable us to tune their reactivities
by varying the reaction conditions at different stages of
a reaction. More importantly, they allow us to synthesize
phosphonium salts with a variety of counterions that could
dictate their physical properties and reactivity towards
[7]
5) poor regioselectivity in the absence of a directing group.
In particular, heteroarene–heteroarene cross-coupling is
[
8]
considered to be much more challenging. Most of the
above constraints could be overcome by our proposed
strategy (Scheme 2). We envisioned that bis-heteroarenes
could be synthesized via intramolecular Wittig reaction of
acylated phosphonium salts, which in turn could be derived
[
5]
various substrates. During the development of phosphine-
mediated methods for the synthesis of different heterocycles
and multifunctional olefins via a chemoselective intramolec-
[
4]
ular Wittig reaction, we attempted to explore alternative
methods for the generation of stable and isolable phospho-
[
+]
[+]
[
*] Y.-R. Chen, Dr. G. M. Reddy, S.-H. Hong, Y.-Z. Wang, J.-K. Yu,
Prof. Dr. W. Lin
Department of Chemistry, National Taiwan Normal University
88, Sec. 4, Tingchow Road, Taipei 11677 (Taiwan, R.O.C.)
E-mail: wenweilin@ntnu.edu.tw
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201700945.
Scheme 2. Proposed retrosynthetic approach for the synthesis of bis-
heteroarenes.
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from the stable and isolable phosphonium salts by treatment
with a base and acid chloride. We further anticipated that the
phosphonium salt could be synthesized via a four-component
reaction of either 1) neutral heteroarene nucleophile, a 2-
hydroxy substituted aryl aldehyde, and phosphine or 2) het-
eroarenecarboxaldehyde, hydroxy-activated arene nucleo-
phile, and phosphine, both in presence of appropriate acid.
In this proposed pathway, the most challenging part would
be the generation of phosphonium salt via a four-component
reaction. The challenges that needed to be overcome are
in excellent yields (entries 3 and 6). Carrying out the reaction
in acetonitrile could slightly enhance the rate of reaction
(entry 9). It was then found that lowering the amount of acid
used could result in much better yield of 3aa (entry 11).
Under these conditions, other less nucleophilic phosphines
were tested and all of them furnished corresponding phos-
phonium salts in excellent yields (entries 13–15). However,
during the optimization of second step for the generation of
formal cross-coupling products (discussed in later sections),
phosphonium salts appended to PBu3 gave better results.
Remarkably, the addition sequence of reagents also had
a great impact on the yield of 3aa. When 2a and 1a were
1
) [2+1] adducts could be generated instead of the required
phosphonium salt due to competition between arene nucle-
[
9]
ophile and phosphine towards the aldehyde; 2) nucleophi-
licity of phosphine would be perturbed to a great extent by the
acid used; and 3) acid could be trapped by phosphine and vice
versa, thereby preventing the condensation of arene nucleo-
phile with aldehyde.
sequentially added to a solution of TfOH and PBu in MeCN,
3
reaction rate decreased, resulting in slightly lower yield of 3aa
(entry 16). On the other hand, when TfOH and PBu were
3
sequentially added to a solution of 2a in MeCN, followed by
1a, no formation of 3aa was seen, but generation of aldehyde-
[
12]
[9]
To test our idea, we initially treated N-methylindole (1a)
with salicylaldehyde (2a) in presence of various acids and
phosphines for the generation of corresponding phosphonium
salts (Table 1). X-ray crystallographic analysis of obtained
products revealed the existence of resulting phosphonium
acid-phosphine adduct 4 and [2+1] adduct 5 could be
1
31
observed by H and P NMR analysis (entry 17). Therefore,
the optimized conditions to carry out the reaction were as
found in entry 11.
Under the optimized conditions, a series of phosphonium
salts 3 from different N-protected indoles 1 and substituted
salicylaldehydes 2 were synthesized (Table 2). As expected, it
[
10]
species 3 as an ion pair.
Thus a new four-component
reaction involving 1a, 2a, phosphine, and acid was discov-
[
11]
ered. Upon testing different acids, it was seen that using
triflic acid or HBF in THF furnished the phosphonium salt 3
4
[a]
Table 2: Four-component reaction for the synthesis of 3.
Table 1: Optimization of four-component reaction for the generation of
[
a]
3.
1
2
[b]
Entry
PG
R
R
t [h]
Yield [%] of 3
1
2
3
4
5
6
7
8
9
Me
Bn
Ts
H (1a)
H (1b)
H (1c)
H (1a)
H
H
H
H
H
H (2a)
H
H
3
7
20
3
3
3
3
19
3
5
90 (3aa)
76 (3ba)
Trace (3ca)
83 (3ab)
73 (3ac)
88 (3ad)
83 (3ae)
89 (3af)
75 (3ag)
82 (3ah)
85 (3da)
72 (3ea)
[
b]
Entry
HA
PR3
Solvent
t [h]
Yield [%] of 3
Me
Me
Me
Me
Me
Me
Me
Me
Me
5-Br (2b)
5-Cl (2c)
5-Me (2d)
5-OMe (2e)
4-OMe (2 f)
3-OMe (2g)
2-Np (2h)
H (2a)
H
[
10]
1
2
3
4
5
6
7
8
9
TsOH
MsOH
TfOH
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
18
18
18
18
18
18
18
18
3
3
3
3
1
55, 3aa-OTs
[
10]
47, 3aa-OMs
[
10]
90, 3aa
Tf NH
64, 3aa-Tf N
2
2
[
10]
HClO4
HBF4
HBr
67, 3aa-ClO
4
[
c]
[
10]
10
11
12
H
89, 3aa-BF4
79, 3aa-Br
Ph (1d)
Me (1e)
5
5
[10]
HCl
47, 3aa-Cl
81, 3aa
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
PBu3
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.1 equiv), TfOH (1.3 equiv)
and PBu (1.1 equiv) in dry MeCN (5.0 mL) under Ar atmosphere.
[b] Isolated yields. [c] 2h=2-hydroxy-1-naphthaldehyde.
10
11
12
13
14
15
16
17
18
PBu3
32, 3aa
90, 3aa
3
[
[
[
[
[
[
[
[
c]
PBu3
d]
PBu3
48, 3aa
>95, 3aa’
>95, 3aa’’
>95, 3aa’’’
79, 3aa
c]
[10]
[10]
MePh2P
EtPh2P
PPh3
PBu3
PBu3
c]
1
1
3
3
c]
[10]
was seen that the tosyl protection that reduces nucleophilicity
of indole could not yield the corresponding phosphonium salt
(entry 3). A variety of substitutions on salicylaldehydes were
tested, affording the phosphonium salts 3 in good yields
(entries 4–10). Remarkably, even 2-substituted indoles could
be employed under these reaction conditions to provide the
corresponding phosphonium salts in good yields (entries 11
and 12).
c,e]
c,f]
c,g]
Trace, 3aa
87, 3aa
PBu3
3
[a] Reaction conditions: To a solution of 1a (0.2 mmol) and 2a
(
(
1.1 equiv) in dry solvent (1.0 mL), HA (1.8 equiv) and phosphine PR3
1.1 equiv) were added sequentially. [b] NMR yield of 3 as determined by
the analysis of crude reaction mixture using Ph CH as internal standard.
3
[
[
c] 1.3 equiv of TfOH was used. [d] 1.1 equiv of TfOH was used.
e] Addition sequence: MeCN/TfOH/PBu /2a/1a. [f] Addition
Interestingly, the phosphonium salt 3ah (Table 2,
entry 10) could also be synthesized in an alternative way
utilizing 2-naphthol (6a) and indole-3-carboxaldehyde (7a)
3
sequence: 2a/MeCN/TfOH/ PBu /1a. [g] Addition sequence: 2a/
MeCN/TfOH/1a/PBu3.
3
2
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and 3.3 equivalents of DBU (Table 3). An initial screening
showed that PBu -appended salts performed slightly better
3
than the ones generated using other phosphines (entries 1–4).
It was also seen that in cases other than PBu -appended salts,
3
free phosphine was generated during the course of the
reaction by decomposition of the salt, thereby reducing the
efficiency of acylation/intramolecular Wittig reaction cascade
Scheme 3. Synthesis of phosphonium salt derivative 3ah from 6a and
a.
7
(entries 2–4). The counterion of these salts also showed
under slightly modified reaction conditions (Scheme 3). This
is helpful to ascertain the flexibility of present protocol and to
demonstrate that the same phosphonium salts (such as 3ah)
could be furnished by employing either of the two combina-
tions of substrates (such as 1a and 2h or 6a and 7a). This
feature makes this protocol quite versatile and allows us to
choose the better pair of substrates based on their reactivities
and stabilities under the given reaction conditions.
a reasonable impact on the outcome of the reaction, and those
with triflate or tetrafluoroborate anion displayed better
reactivity as compared to that with tosylate (entries 1, 5,
and 6). A brief screening of solvents showed that acetonitrile
was the best one (entries 1, 7–10). Further optimization of the
amount of base used revealed that 2.5 equivalents of DBU
gave the best result (entry 1, 11, and 12). In some cases, minor
1
amounts of a by-product could be observed in the H NMR of
Phosphonium salts could also be conveniently prepared
on a much larger scale, which was demonstrated using
substrates 1a and 2a. The corresponding salt 3aa was
obtained in 72% yield on a 10 mmol reaction scale
crude reaction mixture, which was later identified to be the
[10]
bis-acylated product 10aaa.
This by-product could most
probably be generated by the acylation of ylide formed from 3
[
4d]
and subsequent dephosphorylation.
(
Scheme 4).
Under the optimized conditions, a series of formal cross-
coupling adducts 9 were provided efficiently in high yields
under mild reaction conditions (Table 4). Along with the
expected adducts, formation of 5–10% of bis-acylated
[
a]
Table 4: Synthesis of formal cross-coupling products 9.
Scheme 4. Gram scale reaction for the synthesis of 3aa.
The synthesized phosphonium salts 3 were further exam-
ined for their efficiency in the generation of formal cross-
coupling products 9 via the proposed acylation/intramolecu-
lar Wittig reaction utilizing 1.1 equivalents of acyl chloride 8
1
2
3
[b]
Entry PG, R
R
R
t [h] Yield [%]
[9]
1
2
3
4
5
6
7
8
9
1
Me, H
Bn, H
Me, Ph H (3da)
Me, Me H (3ea)
H (3aa)
H (3ba)
Ph (8a)
Ph
Ph
Ph
1
3
9
9
3
1
3
1
3
2
4
3
6
5
3
1.5
1
7
3
2
2
4
3
6
2
76 (9aaa)
81 (9baa)
63 (9daa)
62 (9eaa)
99 (9aba)
92 (9abb)
84 (9abc)
99 (9aca)
70 (9ada)
81 (9aea)
81 (9afa)
99 (9aga)
83 (9aha)
99 (9aab)
71 (9aac)
91 (9aad)
75 (9aae)
60 (9aaf)
65 (9aag)
72 (9aai)
[
[
c]
c]
[
a]
Table 3: Optimization of the acylation/intramolecular Wittig reaction.
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
5-Br (3ab)
5-Br
5-Br
5-Cl (3ac)
5-Me (3ad)
5-OMe (3ae) Ph
4-OMe (3af) Ph
3-OMe (3ag) Ph
Ph
p-OMePh (8b)
p-BrPh (8c)
Ph (8a)
Ph
0
À
[b]
11
Entry
A
PR3
Solvent
t [h]
Yield [%]
12
À
À
À
À
1
2
3
4
5
6
7
8
9
TfO
TfO
TfO
TfO
PBu (3aa)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
1
1
1
1
1
1
78
74
75
44
77
50
13
14
15
16
17
18
19
20
21
22
23
24
2-Np (3ah)
H (3aa)
Ph
3
MePh P (3aa’)
p-OMePh (8b)
p-BrPh (8c)
p-ClPh (8d)
m-ClPh (8e)
o-ClPh (8 f)
p-NO Ph (8g)
2-furyl (8i)
2-thienyl (8j)
1-naphthyl (8k)
Pr (8l)
2
EtPh P (3aa’’)
H
H
H
H
H
H
H
H
H
H
H
2
PPh (3aa’’’)
3
À
BF4
PBu (3aa-BF )
3
4
À
TsO
PBu (3aa-OTs)
3
À
[c]
[c]
TfO
TfO
TfO
TfO
TfO
TfO
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
1(18)
trace (73)
2
À
THF
1
1
1
3
3
72
73
69
83
79
À
À
À
À
[d]
CH Cl2
79 (9aaj)
67 (9aak)
58 (9aal)
60 (9aam)
78 (9aan)
2
1
1
1
0
1
2
toluene
MeCN
MeCN
[
[
d]
e]
i
n
Pr (8m)
2-styryl (8n)
25
[a] Reaction conditions: 3aa (0.2 mmol), 8a (1.1 equiv) and DBU
(
3.3 equiv) in dry MeCN (1.0 mL) under Ar atmosphere at 308C. [b] NMR
[a] Reaction conditions: 3 (0.2 mmol), 8 (1.1 equiv), and DBU (2.5 equiv)
in dry MeCN (1.0 mL) under Ar atmosphere at 308C. [b] Isolated yield.
[c] reaction carried out at 708C [d] 14% of 10aaj was isolated along
with 9aaj.
yield of 9aaa as determined by the analysis of crude reaction mixture
using CHPh as internal standard. [c] At 608C. [d] 2.5 equiv of DBU was
used. [e] 2.2 equiv of DBU was used.
[
10]
3
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products 10 were observed in most of cases and could be
easily separated from 9.
In our preliminary studies, other heteroarenes were also
employed as nucleophiles for the synthesis of formal cross-
coupling adducts. Phosphonium salts 12 and 15 were success-
fully generated from electron-rich heteroarenes such as N-
methylpyrrole (11) and 2-methoxy thiophene (14) under
modified reaction conditions and then applied for the syn-
Scheme 7. Synthesis of heteroaryl-substituted olefin 24.
[
13]
thesis of bis-heteroarenes 13 and 16 (Scheme 5). Electron-
thus generated phosphonium salts depend to a great extent on
the phosphine and counterion installed in them, thus offering
us a myriad of possible combinations of salts to be employed
accordingly for further transformations. Application of these
salts has been demonstrated for the synthesis of bis-hetero-
arenes, thus delivering an efficient alternative to the tradi-
tional cross-coupling methods. This strategy also has the
potential to install different functionalities in products during
the course of reaction without requiring prefunctionalized
substrates. Efforts towards the synthesis of axially chiral bis-
heteroarenes, generation of chiral phosphonium salts and
their application in preparation of chiral organocatalysts are
currently underway in our laboratory.
Scheme 5. Extension of the method for the synthesis of other bis-
heteroarenes.
Experimental Section
poor heteroarene nucleophiles such as quinoline and isoqui-
noline were also tested under our reaction conditions. As
expected, they were found to be unreactive and could not be
employed under these conditions.
Typical procedure for the synthesis of 3: A dry and argon-flushed
10 mL Schlenk flask equipped with a magnetic stir bar and septum
was sequentially charged with 1 (1.0 mmol), 2 (1.1 equiv), anhydrous
MeCN (5.0 mL), TfOH (1.3 equiv), and PBu3 (1.1 equiv). The
reaction mixture was stirred for the appropriate time (3–19 h) at
Our protocol could be successfully extended for the
synthesis of indole-benzothiophene and indole-indole bis-
heteroarenes (resulting in both hetero cross-coupling and
homo cross-coupling adducts), thus making it more versatile
and powerful (Scheme 6).
3
08C. After the completion of reaction, solvent was removed in vacuo
and diethyl ether (10 mL) was added to the crude residue so as to
obtain a precipitate, which was then filtered and washed with diethyl
ether (3 ꢀ 10 mL) to afford pure phosphonium salt 3.
Typical procedure for the synthesis of 9: A dry and argon-flushed
1
0 mL Schlenk flask equipped with a magnetic stir bar and septum
was sequentially charged with 3 (0.2 mmol), anhydrous MeCN
1.0 mL), acyl chloride 8 (1.1 equiv), and DBU (2.5 equiv). The
(
1
reaction mixture was stirred at 308C and monitored by H NMR
analysis. After the completion of reaction, solvent was removed in
vacuo and the crude product was purified by flash column chroma-
tography over silica gel (hexanes/ethyl acetate) to provide 9.
Acknowledgements
The authors thank the Ministry of Science and Technology of
the Republic of China (MOST 104–2113-M-003-002-MY3)
for financial support.
Scheme 6. Synthesis of indole–benzothiophene and indole–indole bis-
heteroarenes. [a] Base=DBU (1.5 equiv) in MeCN. [b] Base=DBU
Conflict of interest
(
1.5 equiv)+NaH (1.0 equiv) in THF.
The authors declare no conflict of interest.
The efficiency of synthesized phosphonium salts for the
Keywords: bis-heteroarenes · cross-coupling ·
multicomponent reactions · organophosphonium salts ·
Wittig reactions
intermolecular Wittig reation with carbonyl compounds was
also demonstrated by treating 23, that was derived from 1a
and benzaldehyde, with ninhydrin, which resulted in the
heteroaryl-substituted olefin 24 in good yield (Scheme 7).
In conclusion, a novel four-component reaction has been
developed for the generation of a library of phosphonium
salts from commercially available reagents. The properties of
4
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[10] CCDC 1402560 (3aa-OTs), 1527601 (3aa-OMs), 1527718 (3aa),
1527725 (3aa-ClO ), 1527603 (3aa-BF ), 1527744 (3aa-Cl),
[
4] a) U. Das, Y.-L. Tsai, W. Lin, Org. Biomol. Chem. 2014, 12, 4044;
for selected examples using Michael acceptors, see: b) C.-J. Lee,
C.-C. Tsai, S.-H. Hong, G.-H. Chang, M.-C. Yang, L. Mçhlmann,
W. Lin, Angew. Chem. Int. Ed. 2015, 54, 8502; Angew. Chem.
4
4
1527604 (3aa’), 1403386 (3aa’’), 1403240 (3aa’’’), 1402564
(9aaa), 1527605 (10aaa), 1527606 (10aaj), 1535385 (18),
1535383 (21a) and 1535384 (21d) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
2015, 127, 8622; c) Y.-T. Lee, Y.-J. Jang, S.-e. Syu, S.-C. Chou, C.-
J. Lee, W. Lin, Chem. Commun. 2012, 48, 8135; d) C.-J. Lee, C.-
N. Sheu, C.-C. Tsai, Z.-Z. Wu, W. Lin, Chem. Commun. 2014, 50,
5
304; for selected examples using acyl imines or aldehydes, see:
e) S.-e. Syu, Y.-T. Lee, Y.-J. Jang, W. Lin, Org. Lett. 2011, 13,
970; f) Y.-L. Tsai, Y. S. Fan, C.-J. Lee, C.-H. Huang, U. Das, W.
[11] The synthesis of analogous phosphonium salts in a two-step
sequence has been reported; see: E. Follet, P. Mayer, H. Mayr,
Eur. J. Org. Chem. 2016, 4050.
[12] The formation of aldehyde–acid–phosphine adduct 4 was found
to be irreversible at room temperature, but reversible at higher
temperatures.
[13] During the generation of phosphonium salts in these cases,
addition sequence had to be altered. When the same addition
sequence (as used for indole case) was followed, decomposition
of arenes 11 and 14 was observed.
2
Lin, Chem. Commun. 2013, 49, 10266; for other examples, see:
g) Z.-Z. Wu, Y.-J. Jang, C.-J. Lee, Y.-T. Lee, W. Lin, Org. Biomol.
Chem. 2013, 11, 828; h) C.-J. Lee, Y.-J. Jang, Z.-Z. Wu, W. Lin,
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[
6] For a recent report on one-pot, three-component reaction for the
synthesis of indole-benzofuranyl bis-heteroarenes, see: C.
Cheng, C. Liu, Y. Gu, Tetrahedron 2015, 71, 8009.
Manuscript received: January 26, 2017
Revised: March 1, 2017
Final Article published: && &&, &&&&
[
7] a) C. E. Garrett, K. Prasad, Adv. Synth. Catal. 2004, 346, 889;
b) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Multicomponent Reactions
Y.-R. Chen, G. M. Reddy, S.-H. Hong,
Y.-Z. Wang, J.-K. Yu,
W. Lin*
&&&& — &&&&
Four-Component Synthesis of
Phosphonium Salts: Application Toward
an Alternative Approach to Cross-
Coupling for the Synthesis of Bis-
Heteroarenes
Connect four: A four-component reaction
for the generation of an array of phos-
phonium salts has been demonstrated.
The generated salts were applied for the
synthesis of bis-heteroarenes, thereby
promising an efficient alternative to the
classical cross-coupling strategies.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!