Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents with protecting group-free iodophenylmethanols: Synthesis of biarylmethanols

Article abstract of DOI:10.1016/j.tetlet.2020.151676

An atom-efficient procedure for the synthesis of functionalized biarylmethanols via the Pd-catalyzed cross-coupling reactions of differently functionalized iodophenylmethanols and triarylbismuth reagents is described. This protecting group-free direct couplings of 2-, 3- or 4-iodophenylmethanols with triarylbismuth reagents afforded biarylmethanols in good to high yields.

Full text of DOI:10.1016/j.tetlet.2020.151676

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents
with protecting group-free iodophenylmethanols: Synthesis of
biarylmethanols
⇑
Maddali L.N. Rao , Suresh Meka
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An atom-efficient procedure for the synthesis of functionalized biarylmethanols via the Pd-catalyzed
cross-coupling reactions of differently functionalized iodophenylmethanols and triarylbismuth reagents
is described. This protecting group-free direct couplings of 2-, 3- or 4-iodophenylmethanols with triaryl-
bismuth reagents afforded biarylmethanols in good to high yields.
Received 1 December 2019
Revised 14 January 2020
Accepted 24 January 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Triarylbismuth reagents
Iodophenylmethanols
Biarylmethanols
Pd-catalysis
Functionalized biaryls are significant scaffolds prevalent in sev-
eral pharmaceuticals and natural products leading to the develop-
ment of several new approaches for their synthesis [1,2]. In
particular, the alcohol functionality in these skeletons allows easy
modification to other desired functional groups. It also serves as an
alternative electrophile for CAC bond formations [3]. Importantly,
limited synthetic methods, including cross-coupling approaches,
have been reported for the synthesis of biarylmethanols [4]. The
development of atom-economic cross-coupling methods using tri-
arylbismuth reagents as threefold organometallic coupling part-
ners is an ongoing interest [5–7]. It led to the present study of
utilising protecting group-free cross-couplings of iodophenyl-
methanols with triarylbismuth reagents under Pd-catalyzed condi-
tions for the synthesis of biarylmethanols. This effort is in
continuation of our interest in developing atom-economic cross-
coupling methods using triarylbismuth reagents under Pd-cat-
alyzed conditions [5,6].
Our investigation to develop an efficient method for the synthe-
sis of substituted biarylmethanols was carried out using protecting
group-free 2-iodophenylmethanol 1a in the cross-coupling reac-
tion with Bi(p-tolyl)3 under Pd-catalyzed conditions. These results
are summarized in Table 1. The proposed cross-coupling reaction
was initially screened with different Pd-catalytic systems using
KOAc in NMP (Table 1, entries 1–4). This resulted in the develop-
ment of Pd(OAc)2/P(o-tolyl)3 as a more efficient system to deliver
the desired biarylmethanol 2a in 74% yield (Table 1, entry 4).
Other catalytic systems including Pd(OAc)2/PPh3, PdCl2(PPh3)2,
and Pd(PPh3)4 gave 2a in 64–68% yield (Table 1, entries 1–3). The
desired coupling reaction was further screened in different sol-
vents including DMA, DMF, and DMSO (Table 1, entries 5–7). These
solvents provided product 2a in 60–71% yield. Hence, further
screening was carried out in NMP with different bases (Table 1,
entries 8–10). However, the use of different bases did not provide
higher yields in comparison to the yield obtained with KOAc
(Table 1, entry 4). At this stage, we screened the coupling with 4
equiv. of KOAc which gave 2a in 44% yield (Table 1, entry 11).
The control reaction carried out without catalyst and base resulted
in no cross-coupling product (Table 1, entry 12). The above screen-
ing thus provided the standard protocol with Pd(OAc)2 (0.1 equiv.),
P(o-tolyl)3 (0.4 equiv.), KOAc (6 equiv.), TBAB (3 equiv.), NMP
(3 mL) at 110 °C for 4 h (Table 1, entry 4) to deliver biarylmethanol
2a in high yield.
Under these established conditions, the threefold coupling of
various triarylbismuth reagents was tested with 2-iodophenyl-
methanol 1a and the results are given in Table 2. The cross-cou-
plings with Bi(p-tolyl)3 and Bi(m-tolyl)3 reagents proceeded
efficiently to give the corresponding biarylmethanols 2a and 2d
in 74% and 85% yield, respectively. Similarly, triphenylbismuth also
reacted well to give biphenylmethanol 2b in 84% yield. Further
cross-couplings with Bi(p-anisyl)3 and Bi(m-anisyl)3 gave biaryl-
methanols 2c and 2e in 82% and 84% yield, respectively. Other
⇑
Corresponding author.
E-mail address: maddali@iitk.ac.in (M.L.N. Rao).
https://doi.org/10.1016/j.tetlet.2020.151676
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: M. L. N. Rao and S. Meka, Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents with protecting group-free
iodophenylmethanols: Synthesis of biarylmethanols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151676

2
M.L.N. Rao, S. Meka / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Table 2
Screening with 2-iodophenylmethanol (1a).a,b,c,d
Couplings of 2-iodophenylmethanol (1a) with BiAr3 reagents.a,b,c
Entry
Catalyst/Ligand
Base
Solvent
Yield 2a (%)
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
PdCl2(PPh3)2
Pd(PPh3)4
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K3PO4
K2CO3
Cs2CO3
KOAc
–
NMP
NMP
NMP
NMP
DMA
DMF
DMSO
NMP
NMP
NMP
NMP
NMP
64
66
68
74
60
71
63
61
52
65
44d
–
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
Pd(OAc)2/P(o-tolyl)3
–
9
10
11
12
a
Reagents and conditions: 1a (0.75 mmol, 3 equiv.), Bi(p-tolyl)3 (0.25 mmol, 1
equiv.), Pd catalyst (0.025 mmol, 0.1 equiv.), ligand (0.1 mmol, 0.4 equiv.), base (6
equiv.), TBAB (3 equiv.), 110 °C, 4 h, solvent (3 mL).
b
Isolated yield.
c
Homo-coupled bitolyl from Bi(p-tolyl)3 was obtained in minor amounts.
KOAc (4 equiv.).
d
triarylbismuth reagents with different aryl and alkoxy substituents
gave the corresponding biarylmethanols 2f, 2g, 2j, 2k-2n in 70–
88% yield. Further study of triarylbismuth reagents with 4-fluoro
and 4-chloro functionality afforded the corresponding biaryl-
methanols 2h and 2i in 63% and 59% yield, respectively. Thus,
the threefold cross-coupling of 1 equiv. of triarylbismuth reagents
with 3 equiv. of 1a gave different functionalized biarylmethanols
in good to high yields.
We further explored the protecting group-free cross-coupling of
3-iodophenylmethanol 1b with different triarylbismuth reagents
under the above Pd-catalyzed conditions (Table 3). The initial cou-
pling of 3-iodophenylmethanol 1b with triphenylbismuth gave the
corresponding biarylmethanol 3a in 81% yield. Other cross-cou-
plings performed using electron-rich triarylbismuth reagents with
4-methyl, 4-methoxy, 3-methoxy, and 4-benzyloxy groups
afforded differently functionalized biarylmethanols 3b-3e in 74–
84% yield. The cross-coupling carried out with a 4-fluoro function-
alized triarylbismuth reagent gave biarylmethanol 3f in 77% yield.
Also, the cross-couplings of trinaphthalen-2-ylbismuth and tris
(benzo[d][1,3]dioxol-5-yl)bismuthane furnished biarylmethanols
3g and 3h in 85% and 74% yield, respectively.
Next, we studied the protecting group-free cross-coupling of 4-
iodophenyl-methanol (1c) with different triarylbismuth reagents
under the above Pd-catalyzed conditions (Table 4). The cross-cou-
pling of 4-iodophenylmethanol 1c with triphenylbismuth afforded
biarylmethanol 4a in 85% yield. Subsequent couplings of 4-
iodophenylmethanol with electron-rich triarylbismuth reagents
functionalized with 4-methyl, 4-methoxy, 3-methoxy, 4-ethoxy,
4-isoproxy, and 3,5-dimethoxy groups gave the corresponding
biarylmethanols 4b-4g in 78–91% yield. Similarly, the coupling
reaction of tri(naphthalen-2-yl)bismuth also proved to be efficient
giving the corresponding biarylmethanol 4h in 75% yield.
a
Reagents and conditions: 1a (0.75 mmol, 3 equiv.), BiAr3 (0.25 mmol, 1 equiv.),
To further expand the general synthetic scope,
a few
Pd(OAc)2 (0.025 mmol, 0.1 equiv.), P(o-tolyl)3 (0.1 mmol, 0.4 equiv.), KOAc
reactions were carried out with differently functionalized
iodophenylmethanols such as 2-iodo-3,4,5-trimethoxyphenyl-
methanol (1d), 5-iodo-2-methoxyphenyl-methanol (1e) and
(1.5 mmol, 6 equiv.), TBAB (0.75 mmol, 3 equiv.), NMP, 110 °C, 4 h.
b
Isolated yields.
c
Homo-coupled biaryls from BiAr3 were obtained in minor amounts.
Please cite this article as: M. L. N. Rao and S. Meka, Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents with protecting group-free
iodophenylmethanols: Synthesis of biarylmethanols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151676

M.L.N. Rao, S. Meka / Tetrahedron Letters xxx (xxxx) xxx
3
Table 3
Table 4
Couplings of 3-iodophenylmethanol 1b with BiAr3 reagents.a,b,c
Couplings of 4-iodophenylmethanol 1c with BiAr3 reagents.a,b,c
a
Reagents and conditions: 1c (0.75 mmol, 3 equiv.), BiAr3 (0.25 mmol, 1 equiv.),
Pd(OAc)2 (0.025 mmol, 0.1 equiv.), P(o-tolyl)3 (0.1 mmol, 0.4 equiv.), KOAc
(1.5 mmol, 6 equiv.), TBAB (0.75 mmol, 3 equiv.), NMP, 110 °C, 4 h.
b
Isolated yields.
c
Homo-coupled biaryls from BiAr3 were obtained in minor amounts.
a
Reagents and conditions: 1b (0.75 mmol, 3 equiv.), BiAr3 (0.25 mmol, 1 equiv.),
Pd(OAc)2 (0.025 mmol, 0.1 equiv.), P(o-tolyl)3 (0.1 mmol, 0.4 equiv.), KOAc
(1.5 mmol, 6 equiv.), TBAB (0.75 mmol, 3 equiv.), NMP, 110 °C, 4 h.
b
Isolated yields.
threefold couplings from triarylbismuth reagents afforded func-
tionalized biarylmethanols in good to high yields [9]. The direct
cross-couplings carried out with iodophenylmethanols without
invoking alcoholic group protection/deprotection protocols for
the synthesis of biarylmethanols under palladium coupling condi-
tions is noteworthy and is expected to be highly useful in organic
synthesis.
c
Homo-coupled biaryls from BiAr3 were obtained in minor amounts.
3-iodo-4-methoxyphenylmethanol (1f) and different triarylbis-
muth reagents under the above Pd-catalyzed conditions (Table 5).
These studies afforded the corresponding functionalized biaryl-
methanols 5a-5d in good to excellent yields. It is important to note
that product 5b is a well-known precursor for the synthesis of
eupomatilone [8].
Declaration of Competing Interest
This study thus established the general cross-coupling ability of
protecting group-free 2-iodo, 3-iodo and 4-iodophenyl-methanols
in threefold coupling reactions with different triarylbismuth
reagents under Pd-coupling conditions. The established conditions
proved to be very efficient as demonstrated by the generalized
cross-couplings with differently substituted iodophenylmethanols
[4].
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
In summary, a convenient method was established for the
atom-efficient synthesis of differently functionalized biaryl-
methanols via the cross-couplings of different iodophenyl-
methanols and triarylbismuth reagents. These reactions involving
We acknowledge the financial support (Project No.
EMR/2017/005221) received from Science and Engineering
Research Board (SERB), New Delhi. S.M. also acknowledges the
research fellowship from the CSIR, New Delhi.
Please cite this article as: M. L. N. Rao and S. Meka, Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents with protecting group-free
iodophenylmethanols: Synthesis of biarylmethanols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151676

4
M.L.N. Rao, S. Meka / Tetrahedron Letters xxx (xxxx) xxx
Table 5
Couplings of substituted iodophenylmethanols with BiAr3 reagents.a,b,c
a
Reagents and conditions: 1d/1e/1f (0.75 mmol, 3 equiv.), BiAr3 (0.25 mmol, 1 equiv.), Pd(OAc)2 (0.025 mmol, 0.1
equiv.), P(o-tolyl)3 (0.1 mmol, 0.4 equiv.), KOAc (1.5 mmol, 6 equiv.), TBAB (0.75 mmol, 3 equiv.), NMP, 110 °C, 4 h.
b
Isolated yields.
c
Homo-coupled biaryls from BiAr3 were obtained in minor amounts.
(e) F. Zeng, Z. Yu, J. Org. Chem. 71 (2006) 5274–5281;
Appendix A. Supplementary data
(f) A.R. Chaudhary, A.V. Bedekar, Tetrahedron Lett. 53 (2012) 6100–6103;
(g) C.A. Contreras-Celedon, D. Mendoza-Rayo, J.A. Rincon-Medina, L. Chacon-
Garcia, Beilstein J. Org. Chem. 10 (2014) 2821–2826;
(h) M. Maity, U.J. Maitra, Mater. Chem. A 2 (2014) 18952–18958;
(i) R.K. Rai, K. Gupta, S. Behrens, J. Li, Q. Xu, S.K. Singh, ChemCatChem 7 (2015)
1806–1812;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151676.
References
(j) B. Li, Y. Yu, P. Zhao, S. Zhang, Chem. Asian J. 11 (2016) 3550–3556.
[5] (a) J.-P. Finet, M.L.N. Rao, Triphenylbismuthine in Encyclopedia of Reagents for
Organic Synthesis, John & Wiley, 2012;
(b) S. Shimada, M.L.N. Rao, Top. Curr. Chem. 311 (2012) 199–228.
[6] (a) Selected references: M.L.N. Rao, S. Meka New. J. Chem. 42 (2018) 4412–
4418;
[1] (a) F. Kloss, T. Neuwirth, V.G. Haensch, C. Hertweck, Angew. Chem. Int. Ed. 57
(2018) 14476–14481;
(b) F.-X. Felpin, S. Sengupta, Chem. Soc. Rev. 48 (2019) 1150–1193.
[2] (a) J.-A. Garcia-Lopez, M.F. Greaney, Chem. Soc. Rev. 45 (2016) 6766–6798;
(b) J. Wencel-Delord, A. Panossian, F.R. Leroux, F. Colobert, Chem. Soc. Rev. 44
(2015) 3418–3430.
(b) M.L.N. Rao, S. Meka, Tetrahedron Lett. 60 (2019);
(c) M.L.N. Rao, J.B. Talode, J. Asian, Org. Chem. 5 (2016) 98–106;
(d) M.L.N. Rao, J.B. Talode, V.N. Murty, Beilstein J. Org. Chem. 12 (2016) 2065–
2076;
[3] (a) G. Guillena, D.J. Ramon, M. Yus, Angew. Chem. Int. Ed. 46 (2007) 2358–
2364;
(e) M.L.N. Rao, A. Kumar, Tetrahedron 71 (2015) 5137–5147;
(f) M.L.N. Rao, R.J. Dhanorkar, RSC Adv. 4 (2014) 13134–13144;
(g) M.L.N. Rao, R.J. Dhanorkar, RSC Adv. 3 (2013) 6794–6798;
(h) M.L.N. Rao, D.N. Jadhav, P. Dasgupta, Eur. J. Org. Chem. (2013) 781–788;
(i) M.L.N. Rao, D.N. Jadhav, P. Dasgupta, Org. Lett. 12 (2010) 2048–2051;
(j) M.L.N. Rao, D.N. Jadhav, D. Banerjee, Tetrahedron 64 (2008) 5762–5772;
(k) M.L.N. Rao, D. Banerjee, D.N. Jadhav, Tetrahedron Lett. 48 (2007) 6644–
6647;
(b) S.J. Hwang, H.J. Kim, S. Chang, Org. Lett. 11 (2009) 4588–4591;
(c) J.K. Laha, K.P. Jethava, S. Patel, K.V. Patel, J. Org. Chem. 82 (2017) 76–85;
(d) Y. Jiang, B. Sun, W.-Y. Fang, H.-L. Qin, Eur. J. Org. Chem. (2019) 3190–3194;
(e) Y. Kwon, H. Cho, S. Kim, Org. Lett. 15 (2013) 920–923;
(f) A.M. Funston, S.V. Lymar, B. Saunders-Price, G. Czapski, J.R. Miller, J. Phys.
Chem. B 111 (2007) 6895–6902;
(g) Z. Li, X. Xu, G. Li, X. Fu, Y. Liu, Y. Feng, M. Wang, Y. Ouyang, J. Han, Bioorg.
Med. Chem. 25 (2017) 6647–6652;
(h) Y. Shi, P. Wan, Can. J. Chem. 83 (2005) 1306–1323;
(i) M.F. Grunberg, L.J. Gooßen, Chem. Eur. J. 19 (2013) 7334–7337;
(j) R. Singha, A. Ahmed, Y. Nuree, M. Ghosh, J.K. Ray, RSC Adv. 5 (2015) 50174–
50177.
(l) M.L.N. Rao, D. Banerjee, D.N. Jadhav, Tetrahedron Lett. 48 (2007) 2707–
2711;
(m) M.L.N. Rao, R.J. Dhanorkar, RSC Adv. 6 (2016) 1012–1017.
[7] (a) B. Cassirame, S. Condon, C. Pichon, J. Mol. Catal. A: Chem. 425 (2016) 94–
102;
[4] (a) H.-M. Li, A.-Q. Feng, X.-H. Lou, Bull. Korean Chem. Soc. 35 (2014) 2551–
2554;
(b) P. Petiot, A. Gagnon, Eur. J. Org. Chem. (2013) 5282–5289;
(c) J. Yang, Y. Wu, X. Wu, W. Liu, Y. Wang, J. Wang, Green Chem. 21 (2019)
5267–5273;
(b) W. Yingchun, L. Xiuying, L. Yajun, P. Yingming, C. Keguang, W. Hengshan,
Chem. Res. Chin. Univ. 30 (2014) 614–618;
(c) H.-M. Li, C. Xu, X.-Q. Hao, Z. Li, Z.-Q. Wang, W.-J. Fu, M.-P. Song, Inorg. Chim.
Acta 404 (2013) 236–240;
(d) C. Xu, L. Yin, B. Huang, H. Liu, M. Cai, Tetrahedron 72 (2016) 2065–2071.
[8] Y. Hirokawa, M. Kitamura, M. Mizubayashi, R. Nakatsuka, Y. Kobori, C. Kato, Y.
Kurata, N. Maezaki, Eur. J. Org. Chem. (2013) 721–727.
(d) Y. Hatanaka, S. Fukushima, T. Hiyama, Chem. Lett. 18 (1989) 1711–1714;
Please cite this article as: M. L. N. Rao and S. Meka, Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents with protecting group-free
iodophenylmethanols: Synthesis of biarylmethanols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151676

M.L.N. Rao, S. Meka / Tetrahedron Letters xxx (xxxx) xxx
5
[9] Representative cross-coupling procedure: Cross-coupling of 1a with Bi(p-
tolyl)3: An oven-dried Schlenk tube was charged with (2-iodophenyl)
methanol (1a) (0.75 mmol, 3 equiv.), Bi(p-tolyl)3 (0.25 mmol, 1 equiv.), Pd
(OAc)2 (0.025 mmol, 0.1 equiv.), P(o-tolyl)3 (0.1 mmol, 0.4 equiv.), KOAc
(1.5 mmol, 6 equiv.), TBAB (0.75 mmol, 3 equiv.) and NMP (3 mL) under a N2
atmosphere. The mixture was stirred in an oil bath at 110 °C for 4 h. The
contents were quenched with water (10 mL) at rt and extracted with ethyl
acetate (30 mL). The organic extract was washed with brine and dried using
MgSO4. The organic solvent was removed under reduced pressure to obtain the
crude product. It was purified by silica gel chromatography using hexane/ethyl
acetate as eluent. The product 2a was obtained in 74% yield. The spectral
characterization data for all the products is given in the Supporting information.
Please cite this article as: M. L. N. Rao and S. Meka, Pd-catalyzed atom-efficient cross-coupling of triarylbismuth reagents with protecting group-free
iodophenylmethanols: Synthesis of biarylmethanols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151676