Rapid Bis-Coupling Reactivity with Triarylbismuth Reagents: Synthesis of Structurally Diverse Scaffolds and Step-economic Convergent Synthesis of Quebecol

Article abstract of DOI:10.1002/ejoc.201901830

The cross-coupling study of gem-dibromoesters with triarylbismuths as threefold arylating reagents was investigated under palladium-catalyzed conditions. This study using triarylbismuth reagents explored the cross-coupling reactivity with various functionalized gem-dibromoesters. It furnished a variety of multi-functional trisubstituted acrylates embedded with aryl, alkene and alkyne scaffolds in high yields. The present study in turn, provided easy access to various triarylated acrylates and functionalized 1,3-dienyl and 1,3-enyne esters. Further, the established method applied in the step-economic and convergent synthesis of quebecol natural product in good yield.

Full text of DOI:10.1002/ejoc.201901830

DOI: 10.1002/ejoc.201901830
Full Paper
Cross-Coupling
Rapid Bis-Coupling Reactivity with Triarylbismuth Reagents:
Synthesis of Structurally Diverse Scaffolds and Step-economic
Convergent Synthesis of Quebecol
Maddali L. N. Rao,*[a] Venneti N. Murty,[a] and Sachchida Nand[a]
Abstract: The cross-coupling study of gem-dibromoesters with alkene and alkyne scaffolds in high yields. The present study in
triarylbismuths as threefold arylating reagents was investigated turn, provided easy access to various triarylated acrylates and
under palladium-catalyzed conditions. This study using triaryl- functionalized 1,3-dienyl and 1,3-enyne esters. Further, the es-
bismuth reagents explored the cross-coupling reactivity with tablished method applied in the step-economic and conver-
various functionalized gem-dibromoesters. It furnished a variety gent synthesis of quebecol natural product in good yield.
of multi-functional trisubstituted acrylates embedded with aryl,
Introduction
(F1–F3, Figure 1) are studied for several photophysical proper-
ties.[1f–1l]
Triarylethylene containing scaffolds are prominent for their
presence in drugs and various optical materials.[1] For instance,
triaryl functionalized tamoxifen and their derivatives panom-
ifene and clomifene are studied in breast cancer and other ther-
apeutic applications (Figure 1).[1a,1b] Importantly, quebecol as
process-derived phenolic compound isolated from Canadian
maple syrup, was known for its structural similarity with
tamoxifen. It was associated with antioxidant, antiproliferative
and anti-inflammatory properties.[1c–1e] In material applications,
triphenylamine containing triarylethylene compounds or func-
tionalized with extended π-conjugation involving alkenes
In this context, functionalized acrylates provide ample and
flexible opportunities for selective synthetic manipulations. A
few approaches are reported in the literature[2,3] to access tri-
arylated acrylates. For example, triarylated acrylates with varied
aryl groups could be availed through Pd-catalyzed addition re-
actions of aryl organometallic reagents either using boron or
tin reagents with alkyl 3-arylpropiolates.[2b,3a,3b] Similarly, Pd-
catalyzed three-component coupling of ethyl 3-phenylpropio-
late, aryl iodide and arylboronic acid reported affording triaryl-
ated acrylates.[3c,3d] These two methods are known to give
Figure 1. Important triarylethylene derived compounds.
cis-addition to alkyne affording cis-α,ꢀ-diarylacrylates. The addi-
tion reaction of bis(pinacolato)diboron reported with ethyl
3-arylpropiolate provides trans-α,ꢀ-diboryl acrylates and these
are cross-coupled with aryl bromides to obtain triarylated acryl-
ates.[3e] On the other hand, bromination of ethyl 3-phenyl-
propiolate followed by Suzuki coupling also provides triarylated
[a] Department of Chemistry, Indian Institute of Technology Kanpur,
Kanpur 208016, India
E-mail: maddali@iitk.ac.in
http://www.iitk.ac.in/new/m-l-n-rao
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901830.
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acrylates.[3f] The Suzuki coupling of ethyl 3,3-dibromo-2-aryl-
acrylates under Pd-catalyzed conditions provides bis-coupled
products in a facile manner.[3g] Also, metallo-esterification of
diphenylacetylene with Cp2ZrEt2/ chloroformate and its cou-
pling with iodobenzene reported giving triarylated acrylates
under Pd-catalyzed conditions.[3h] Recently, α,ꢀ,ꢀ-triarylation of
methyl acrylate was reported under Pd-catalyzed Matsuda–
Heck coupling conditions involving 4-methoxybenzenediazo-
nium tetrafluoroborate.[3i]
As enumerated, most of these reported methods provide
variously arylated acrylates with different substrate combina-
tions under metal-catalyzed conditions. However, a few of them
not bestowed with a broader substrate scope in terms of syn-
thetic applicability. The bis-coupling reactivity of ethyl 3,3-di-
bromo-2-arylacrylates under Pd-catalyzed conditions needs a
special mention as this method provides extensive substrate
scope and flexibility with structural variations. Surprisingly, not
many studies are reported to exploit its synthetic utility. It in-
trigued us to explore this reaction with triarylbismuths as three-
fold organometallic coupling reagents and this bestowed broad
substrate scope towards diversified reactivity (Scheme 1). This
interest originated from our earlier coupling studies carried out
under palladium catalysis with gem-dibromo alkenes.[4] As gem-
dibromoester substrates are easily accessible from keto esters
functionalized with various alkyl, aryl, alkenyl, alkynyl groups,[5]
using CBr4/PPh3 conditions,[6] the developed process demon-
strated high synthetic advantage when applied to structurally
diverse functional molecular skeletons. Again, the threefold
coupling advantage of atom-economic triarylbismuth organo-
metallic reagents has been of particular interest to us.[7] It
paved the way to establish the rapid bis-coupling reactivity of
gem-dibromoesters with triarylbismuth reagents under palla-
dium-catalyzed conditions. Further, the developed method was
applied in the step-economic convergent synthesis of quebecol
natural product as elaborated here.
Scheme 1. BiAr3 based bis-coupling approach.
tries 6–8, Table 1). Different bases investigated for their efficacy
using K2CO3, NaHCO3, K3PO4, and Cs2CO3 provided product 2a
in 65–83 % yields (entries 9–12, Table 1). This base screening
thus proved KOAc as the more efficient one to provide a high
bis-coupling yield (entry 3, Table 1). To find the optimum
amount required, screening was carried out with 3 or 5 equiv.
of KOAc and these two conditions afforded lowered yields (en-
tries 13 and 14, Table 1). Further, different reaction times using
1 and 3 hour conditions gave 77 % and 85 % yields respectively
Table 1. Optimization conditions.[a]
Results and Discussion
Entry
Catalyst [equiv.]
Base [equiv.]
Solvent
Yield [%]
The bis-coupling reactivity of ethyl 3,3-dibromo-2-p-tolylacryl-
ate (1a) was screened with tri(p-anisyl)Bi under palladium-cata-
lyzed conditions (Table 1). This reaction was expected to pro-
vide ethyl 3,3-bis(4-methoxyphenyl)-2-p-tolylacrylate (2a) as
bis-coupled product. As a trail reaction, it was initially screened
with 1.5 equiv. of 3,3-dibromo-2-p-tolylacrylate (1a) and
1 equiv. of tri(p-anisyl)Bi using Pd(PPh3)4 and KOAc in N,N-di-
methylformamide (DMF) at 110 °C for 2 hour conditions. En-
couragingly, this protocol afforded bis-coupled product (2a) in
60 % yield (entry 1, Table 1). Further study with 1.7 equiv. of 1a
furnished bis-coupled product 2a in 65 % yield (entry 2,
Table 1). To our delight, the desired yield greatly improved to
86 % with 0.05 equiv. palladium catalyst conditions (entry 3,
Table 1). Further screening with Pd(dba)2/2 PPh3 afforded bis-
coupled product in 57 % yield (entry 4, Table 1). Moreover, this
reaction with Pd(PPh3)4 (0.09 equiv.) did not improve the yield
(entry 5, Table 1). The screening carried out with DMA (N,N-
dimethylacetamide), NMP (N-methyl-2-pyrrolidone) and DMSO
(dimethyl sulfoxide) afforded product 2a in 70–79 % yields (en-
1
2
3
4
5
6
7
8
Pd(PPh3)4 [0.02]
Pd(PPh3)4 [0.02]
Pd(PPh3)4 [0.05]
KOAc [4]
KOAc [4]
KOAc [4]
DMF
DMF
DMF
DMF
DMF
DMA
NMP
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
60[b]
65
86
57
83
79
79
70
65
65
Pd(dba)2/2 PPh3 [0.05] KOAc [4]
Pd(PPh3)4 [0.09]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
Pd(PPh3)4 [0.05]
–
KOAc [4]
KOAc [4]
KOAc [4]
KOAc [4]
K2CO3 [4]
NaHCO3 [4]
K3PO4 [4]
Cs2CO3 [4]
KOAc [3]
KOAc [5]
KOAc [4]
KOAc [4]
KOAc [4]
–
9
10
11
12
13
14
15
16
17
18
19
75
83
75
82
77[c]
85[d]
70[e]
13
KOAc [4]
–
[a] Conditions: 1a (0.212 mmol, 1.7 equiv.), tri(p-anisyl)bismuth (0.125 mmol,
1 equiv.), KOAc (0.5 mmol, 4 equiv.), Pd(PPh3)4 (0.0062 mmol, 0.05 equiv.),
DMF (3 mL), 110 °C, 2 h. [b] 1a (1.5 equiv.). [c] 1 h. [d] 3 h. [e] At 90 °C.
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(entries 15 and 16, Table 1). The desired cross-coupling further for generalized reactivity of different gem-dibromoesters (1a–
screened at 90 °C gave 70 % yield (entry 17, Table 1). A couple 1n) with triarylbismuth reagents. It is worth mentioning that
of control reactions without base and catalyst conditions gave the cross-couplings carried out with different gem-dibromoes-
either poor and no product respectively (entries 18 and 19, ters and triarylbismuth reagents provided the broad substrate
Table 1). Overall, the above systematic investigation revealed scope with good to excellent yields (Table 2).
an effective protocol comprising Pd(PPh3)4 (0.05 equiv.), KOAc
(4 equiv.) in DMF at 110 °C with 2 hour conditions (entry 3,
Table 1) to derive the desired bis-coupling in high yield.
To elaborate, under the optimized protocol conditions, ethyl
3,3-dibromo-2-p-tolylacrylate (1a) reacted very efficiently with
triarylbismuth reagents affording differently functionalized tri-
The facile bis-coupling reactivity thus obtained above under arylated acrylates (2a–2e) in 67–86 % yields (entries 1–5,
the established conditions prompted us to further investigate Table 2). This reactivity was extended further to different 3,3-
Table 2. Bis-arylation of gem-dibromoester derivatives with triarylbismuth reagents.[a–c]
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Table 2. (continued)
[a] Conditions: gem-Dibromoester (0.212 mmol, 1.7 equiv.), BiAr3 (0.125 mmol, 1 equiv.), KOAc (0.5 mmol, 4 equiv.), Pd(PPh3)4 (0.05 equiv.), DMF, 110 °C, 2 h.
[b] Isolated yields. [c] Biaryl formed in minor amounts. [d] 1k (0.106 mmol, 0.85 equiv.), 4 h.
dibromo-2-(aryl)acrylates (1b–1f) in couplings with triarylbis- substituted gem-dibromoester (1f) participated in a chemo-se-
muth reagents (entries 6–20, Table 2). This study with electroni- lective coupling involving gem-dibromo terminus. It afforded
cally different gem-dibromoesters reacted smoothly to deliver the corresponding 7a and 7b products in good yields (entries
the corresponding bis-arylated products (3a–3d, 4a–4c, 5a–5c, 19 and 20, Table 2). To our delight, the bis-coupling reactivity
6a–6c, 7a, and 7b) in high yields. Gratifyingly, 4-bromophenyl- carried out with other gem-dibromoesters (1g–1i) also showed
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facile reactivity under the established conditions delivering the the corresponding benzyl protected aryl bromide (18) in 76 %
corresponding bis-arylated products (8a–8d, 9a–9e, 10a and yield.[8b] This bromide (18) was further used in the preparation
10b) in good to high yields (entries 21–31, Table 2).
of triarylbismuth reagent (TAB-1) through lithiation and reac-
tion with bismuth trichloride. This afforded triarylbismuth rea-
gent (TAB-1) in 64 % yield (Scheme 3).[4d] Further aryl bromide
(18) was subjected to lithiation followed by reaction with dieth-
yloxalate and this afforded the corresponding keto ester (19)
in 81 % yield. This keto ester was then used to prepare gem-
dibromoester (1h) using CBr4/PPh3 reagent in high yield. This
way, the two crucial fragments namely, gem-dibromoester (1h)
and triarylbimsuth reagent (TAB-1) were obtained in a concise
manner starting from guaiacol (16).
Importantly, triphenylamine derivatives with core extended
conjugated system are well known for their photophysical prop-
erties as some of these compounds were earlier studied in ag-
gregation-induced emission (AIE) and intramolecular charge
transfer (ICT) behavior.[1f–1i] Keeping this in mind, it was of inter-
est to extend the present study to bis-coupling of triphenyl-
amine derived gem-dibromoester (1j) with triarylbismuth rea-
gents (entries 32 and 33, Table 2). Amazingly, this substrate
also demonstrated an excellent reactivity under the established
cross-coupling conditions to deliver the corresponding bis-aryl-
ated products (11a and 11b) in high yields. It was further ex-
tended to triphenylamine derived bis-gem-dibromo compound
1k and it was cross-coupled for tetraarylation with triarylbis-
muth reagents (entries 34 and 35, Table 2). In this attempt, the
corresponding triarylated products (12a and 12b) were ob-
tained in high yields. The literature known methods[1c–1f] to pre-
pare this type of compounds required C-N coupling procedures.
The present method thus proved to be very useful to access
triphenylamine based molecules (Figure 1) in a facile manner
and may serve as a viable alternative.
To take forward the proposed synthetic process, the cross-
coupling reaction of gem-dibromoester (1h) was carried out
with triarylbismuth reagent (TAB-1) under the established pal-
ladium-catalyzed conditions (Scheme 4). This step furnished the
bis-arylated product (20) in 81 % high yield. This product was
then subjected to a few known steps to arrive at quebecol (22).
It involved initially the hydrogenolysis step under Pd/C condi-
tions. However, under these conditions employed, benzyl de-
protection was also witnessed along with the reduction of a
double bond. This cumulatively afforded the formation of satu-
rated ester 21 in 90 % yield. The final step of the reduction of
ester was carried out using lithium aluminum hydride under
reflux conditions. It afforded the quebecol (22) in overall good
yield.
The broad spectrum of reactivity obtained above prompted
our further studies with differently functionalized gem-dibro-
moesters (Table 3). As part of this, the bis-coupling reactivity of
gem-dibromoesters functionalized with alkyl, alkenyl and alkyne
moieties (1l–1n) were investigated. The alkyl functionalized
gem-dibromoester (1l) reacted efficiently (entries 1–4, Table 3)
with triarylbismuth reagents providing the corresponding tris-
ubstituted acrylates (13a–13d) in good yields. Similarly, alkenyl
derived gem-bromoester (1m) also fared well in bis-couplings
(entries 5–7, Table 3) to furnish the corresponding functional-
ized 1,3-dienes (14a–14c) in high yields. This encouraging reac-
tivity was continued with alkynyl derived gem-dibromoester
(1n) in couplings with triarylbismuth reagents (entries 8–13,
Table 3). These reactions afforded the corresponding functional-
ized 1,3-eneynes (15a–15f) in good yields. This attempt dem-
onstrated further scope and utility of the developed methodol-
ogy in the preparation of novel functional scaffolds. Overall, an
excellent and broad spectrum of bis-coupling reactivity of gem-
dibromoesters with triarylbismuth reagents was obtained under
the established palladium-catalyzed conditions.
To note, the bis-arylation of gem-dibromoester under the
Suzuki cross-coupling was applied earlier by Voyer et al. in the
synthesis of quebecol.[9] However, it involved the preparation
of two coupling partners from two different starting materials
(Scheme 5). In comparison, the present convergent method
starting from guaiacol (16) delivered an efficient and step-eco-
nomic protocol (Scheme 3 and Scheme 4) with high synthetic
viability. Additionally, our cross-couplings involving triarylbis-
muth reagent furnished atom-economic couplings with im-
proved cross-coupling reactivity and in shorter reaction time
with sub-stoichiometric loading of organometallic reagent. As
mentioned above, gem-dibromoester (1h) utilized in quebecol
(22) synthesis, was also involved in efficient cross-couplings
with different triarylbismuth reagents (entries 25–29, Table 2).
These couplings afforded the corresponding triarylated acryl-
ates (9a–9e) in good to high yields.
As proposed, the formation of bis-coupling product from
gem-dibromoester was expected to follow the general cross-
coupling steps involving oxidative addition, transmetallation
and reductive elimination under Pd-catalyzed conditions
(Scheme 6).[4a,7] As known, the bromide terminus trans to aryl
group in gem-dibromoester (p) preferentially involves the cross-
coupling process to give the product (s).[3g,10] The second cross-
coupling involving intermediate s was expected to provide the
desired bis-coupling product (v). To note, experimentally both
these couplings were completed very fast in 2 h shorter time
under our simple and routinely used palladium protocol condi-
tions. Importantly, the intermediate (s) could not be isolated,
The applicability of our methodology was then assessed in
the synthesis of quebecol (22) natural product. For this, a con-
cise strategy was envisaged as given in Scheme 2, from guaiacol
(16). A retrosynthetic plan comprising the bis-coupling of
gem-dibromoester (1h) with triarylbismuth reagent (TAB-1)
is a key step involved to achieve the synthesis of quebecol (22)
(Scheme 3). Accordingly, aryl bromide (18) required for the
preparation of TAB-1 could be obtained from guaiacol
(16). In turn, the aryl bromide (18) could also be utilized in
the preparation of gem-dibromoester (1h) through keto ester
(19).
Thus, the proposed synthetic effort was started with the probably be due to the faster bis-coupling reactivity under the
bromination of guaiacol (16) using NBS/PTSA to obtain aryl conditions employed. However, analysis of the crude product
bromide (17) in 88 % yield.[8a] It was then benzylated to prepare mixture by mass spectroscopy revealed the presence of mono-
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Table 3. Bis-arylation of gem-dibromoester derivatives with triarylbismuth reagents.[a–c]
[a] Conditions: gem-Dibromoester (0.212 mmol, 1.7 equiv.), BiAr3 (0.125 mmol, 1 equiv.), KOAc (0.5 mmol, 4 equiv.), Pd(PPh3)4 (0.05 equiv.), DMF, 110 °C, 2 h.
[b] Isolated yields. [c] Biaryl formed in minor amounts. [d] 1n (0.25 mmol, 2 equiv.).
Scheme 2. Retrosynthetic analysis of quebecol (22).
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Scheme 3. Synthesis of triarylbismuth TAB-1 and gem-dibromoester (1h).
Scheme 4. Synthesis of quebecol.
Scheme 5. Synthesis by Voyer et al.[9]
coupled intermediate (s) in trace amount. Further, a reaction bromide quantitatively. Overall, the present methodology
was carried out with 2 equiv. of gem-dibromide 1a and presents more than one advantage with triarylbismuth reagents
0.3 equiv. of Bi(p-anisyl)3 to check the possibility for the isola- such as (a) sub-stoichiometric loadings (b) atom-economic
tion of the mono-coupled intermediate (s). However, under threefold reactivity (c) shorter reaction time for bis-arylations.
these conditions also bis-coupled product 2a was isolated in Moreover, the synthesis of quebecol (22) was achieved in a
66 % yield along with the recovery of the unreacted gem-di- step-economic manner from guaiacol (16).
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Scheme 6. Mechanistic proposal.
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Conclusions
We have successfully developed the bis-coupling reactivity of
gem-dibromoesters with triarylbismuth reagents under palla-
dium coupling conditions. These couplings provided a facile
synthesis of various multi-functional trisubstituted acrylates
embedded with aryl, alkene and alkyne scaffolds in high yields.
This study of bis-couplings opened up a viable approach for
the synthesis of various triarylated acrylates and functionalized
1,3-dienyl and 1,3-enyne esters. The present method was also
applied in the concise and convergent synthesis of quebecol
natural product in good yield starting from guaiacol.
Acknowledgments
We acknowledge the financial support (Project No. EMR/2017/
005221) from the Science and Engineering Research Board
(SERB), New Delhi. V. N. M. and S. N. acknowledges CSIR for
their research fellowship support.
Keywords: Cross-coupling · Palladium catalysis ·
Triarylbismuth reagents · Trisubstituted acrylates · Quebecol
synthesis
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Received: December 12, 2019
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Full Paper
Cross-Coupling
M. L. N. Rao,* V. N. Murty,
S. Nand .................................................. 1–9
Rapid Bis-Coupling Reactivity with
Triarylbismuth Reagents: Synthesis
of Structurally Diverse Scaffolds and
Step-economic Convergent Synthe-
sis of Quebecol
The cross-coupling study of gem-di- in high yields under palladium cataly-
bromoesters with triarylbismuths fur- sis. Further, the established method
nished a variety of multi-functional was applied in the step-economic and
trisubstituted acrylates embedded convergent synthesis of quebecol
with aryl, alkene and alkyne scaffolds natural product in good yield.
DOI: 10.1002/ejoc.201901830
Eur. J. Org. Chem. 0000, 0–0
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