Palladium-catalyzed substitution of allylic alcohols with sulfinate salts: A synthesis of bicalutamide

Article abstract of DOI:10.1016/j.tetlet.2021.153060

A method is presented for the direct substitution of allylic alcohols with sodium arylsulfinates. The process involves a cooperative action of palladium catalysts, phenylboronic acid and titanium tetraisopropoxide. By taking advantage of this protocol, we achieved a concise synthesis of bicalutamide, an anti-androgen compound for treating prostate cancer.

Full text of DOI:10.1016/j.tetlet.2021.153060

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Palladium-catalyzed substitution of allylic alcohols with sulfinate salts:
A synthesis of bicalutamide
Yin-Jia Jhang a, Chieh-Yu Chang a, Yu-Huan Lin a, Chein-Chung Lee a, Yen-Ku Wu a,b,
⇑
a Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan
b Department of Applied Chemistry, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A method is presented for the direct substitution of allylic alcohols with sodium arylsulfinates. The pro-
cess involves a cooperative action of palladium catalysts, phenylboronic acid and titanium tetraiso-
propoxide. By taking advantage of this protocol, we achieved a concise synthesis of bicalutamide, an
anti-androgen compound for treating prostate cancer.
Received 24 February 2021
Revised 27 March 2021
Accepted 2 April 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Allylation
CAS bond
Allyl Sulfone
Palladium Catalysis
Titanium tetraisopropoxide
Sulfones are versatile synthetic intermediates and frequently
encountered structural motifs in pharmaceutical agents, agro-
chemicals and polymer materials [1]. The versatility of a sulfonyl
group stems from its transformative ability to masquerade as elec-
trophiles, nucleophiles, or radicals [2]. Moreover, sulfones play a
major role in several name reactions (e.g. Julia olefination, Ram-
berg–Bäcklund reaction, van Leusen reaction, etc.). Given their
importance, practical and efficient syntheses of sulfones continue
to attract interest from researchers [3] . In particular, extensive
efforts have been devoted to the preparation of allylic sulfones as
a highly useful building block in various synthetic applications [4].
Trends in green and sustainable chemistry have justified the use
of allylic alcohols in allylation chemistry. Despite the fact that the
hydroxyl group is intrinsically a modest leaving group in the sub-
stitution reactions, chemists have elegantly developed in situ acti-
vation of unactivated allyl alcohols thus enabling a series of step-
economical transformations [5]. For instance, Lewis or Brønsted
acid-promoted sulfonylation reactions of allylic alcohols with
appropriate sulfur nucleophiles have been reported [6]. But these
protocols are mainly applicable to aryl-substituted allyl alcohols
that can yield resonance-stabilized carbocationic electrophiles.
On the other hand, metal catalysis-enabled approaches hold great
promise for attaining satisfactory reaction scope [7]. Chan-
drasekhar and co-workers described the first palladium-catalyzed
conversion of allylic alcohols to the corresponding allyl sulfones
by engaging triethylborane as an additive for the hydroxyl group
activation [8]. The Tian group subsequently showed a stereospecfic
substitution of enantioenriched allylic alcohols with sodium sulfi-
nates by cooperative actions of palladium catalysts and boric acid
[9]. More recently, the Loh and Ma groups independently demon-
strated dehydrative cross-coupling reactions of sulfinic acids with
a range of allylic alcohols under palladium catalysis [10], but the
procedures are arguably less straightforward than those employing
readily available, bench-stable sulfinate salts as the sulfonyl donor
[11]. Nevertheless, these leading reports endorse the continued
interest and demand for developing catalytic synthesis of allylic
sulfones from alcohol precursors. We have successfully applied
the [Pd]/[Ti(IV)] systems [12,13] for the direct nucleophilic substi-
tution of allylic alcohols with sterically demanding secondary
nitroalkanes (C-nucleophile) [14], and for a highly N1-selective
allylation of indoles (N-nucleophile) [15]. These studies showcased
unique synthetic potentials of the catalytic system and thereby
prompted us to survey the capacity of other heteroatom-based
nucleophiles within this context. In the event, sulfinate salts
emerged as a competent reaction partner. Here we disclose our
pursuit of the palladium-catalyzed sulfination of unactivated
allylic alcohols exploiting titanium tetraisopropoxide as an inex-
pensive and mild additive.
⇑
Corresponding author at: Department of Applied Chemistry, National Chiao
Tung University, 1001 University Road, Hsinchu 30010, Taiwan.
Initially we screened the combination of palladium diacetate and
different organophosphorus ligands (SPhos, DavePhos, DPEPhos,
E-mail address: yenkuwu@ntcu.edu.tw (Y.-K. Wu).
https://doi.org/10.1016/j.tetlet.2021.153060
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Yin-Jia Jhang, Chieh-Yu Chang, Yu-Huan Lin et al., Palladium-catalyzed substitution of allylic alcohols with sulfinate salts: A syn-
thesis of bicalutamide, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153060

Yin-Jia Jhang, Chieh-Yu Chang, Yu-Huan Lin et al.
Tetrahedron Letters xxx (xxxx) xxx
dppe, P(2-furyl)3, and PPh3) to promote the Ti(IV)-assisted substitu-
tion of a model substrate 2a with sodium benzenesulfinate
(Table 1). Triphenylphosphine was proven the most effective
among the surveyed monodentate and bidentate ligands (entry
1). The control experiments convincingly indicated that both Pd
(OAc)2 and Ti(Oi-Pr)4 are indispensable to the success of the trans-
formation, thus supporting the synergistic effects posed by the
combination (entries 2 and 3). The allylation with tetrakis(triph-
enylphosphine)palladium in lieu of Pd(OAc)2 and PPh3 gave a trace
amount of the product. Replacing Pd(OAc)2 with Pd(dba)2 under
otherwise identical conditions furnished 3a in only 10% yield. An
increase on reaction temperature to 100 °C or a change of solvent
to DMF did not provide higher yields of 3a. Altering the loadings
of Ti(Oi-Pr)4 or replacing Ti(Oi-Pr)4 with other titanium(IV) alkox-
ides (Ti(OMe)4, Ti(OEt)4, or Ti(Ot-Bu)4) failed to offer improved
results. After extensive experimentation, we serendipitously found
that the addition of phenylboronic acid is beneficial to the allylation
of 2a. The reaction having 150 mol % of phenylboronic acid as the
additive was particularly productive (entries 4–6). The experiments
conducted in the absence of Ti(Oi-Pr)4 only furnished a trace
amount of 3a (entry 7), so we confirmed that the titanium(IV)
reagent is still primarily responsible for the activation of hydroxyl
group even in the presence of phenylboronic acid. We also exam-
ined the reactions with boric acid and 4-methoxyphenylboronic
acid, and the results showed that these additives are less effective
than phenylboronic acid. Regarding to the role of phenylboronic
acid, it may serve as a weak acid to quench expelled (RO)3TiOꢀ dur-
corresponding products 3c and 3d. Interestingly, the synthesis of
3e from prenyl alcohol (2f) proceeded with much lower efficiency
than that with its congener 2g. Geraniol (2h) and linalool (2i) were
also subjected to the reaction conditions, delivering product 3f in
moderate yields. For these stericallly more demanding substrates
(2h and 2i), the use of 6 equiv of alcohols was critical for achieving
the mentioned results. The reaction of 2j furnished an inseparable
trans/cis mixture of crotyl sulfones (3.5:1), and a similar product
distribution was seen with the reaction of 2k. Since the isomeric
alcohols were converted into the same corresponding products
(see entries 5–10), we presumed common p-allylpalladium inter-
mediates were involved in these sets of cases. Also, we noted a sub-
tle reactivity difference between these isomeric allylic alcohols (cf.
2f/2g, 2h/2i, and 2j/2k); more specifically, the one bearing a more
substituted carbinol group, (i.e. with a less substituted alkenyl
moiety) reacts more favorably in the allylation processes. Other
arylsulfinate salts 1b-d worked equally well under the conditions
(entries 11–14).
There has been a long-standing interest in exploring sulfur(VI)-
containing compounds in medicinal chemistry [17]. Being one of
sulfone-derived chemotherapeutic agents, racemic bicalutamide
(4) is the active pharmaceutical ingredient in Casodex [18]. This
small molecule drug is a nonsteroidal anti-androgen for the treat-
ment of prostate cancer [19]. Accordingly, the development of an
efficient and practical access to 4 is certainly of great significance
[20]. Motivated by this concern, we sought to establish a new syn-
thetic route to bicalutamide (4) by exploiting compound 3k
accessed by our method (Scheme 1). The alkene within 3k provides
a synthetic handle for the installation of key tertiary alcohol
through an oxidation reaction. In the event, compound 5 could
be prepared by Upjohn dihydroxylation in good yield [21]. The
ing the formation of palladium p-allyl complex [16]. The allylation
using different equivalents of 2a gave comparable yields (entries 8
and 9).
Next, we set out to examine the reaction of 2b-k with sulfinate
salts 1a-d. Of special interest is to compare reactivity of allylic
alcohols of different substitution patterns in the reaction system
(Table 2). We found that reactivity of 2b-k is lower than 2a, and
therefore it requires the use of 2 or 6 equivalents of the alcohols
for better performance. In general, the arylsulfone group was
regioselectively installed at the less hindered terminus of the allyl
TEMPO-catalyzed conversion of diol 5 into
a-hydroxy acid 6 was
achieved in 94% yield [22]. Subsequent to the oxidation was an
amide coupling between 6 and 4-amino-2-(trifluoromethyl)ben-
zonitrile, thus completing the synthesis of racemic bicalutamide
(4) in 84% yield [23]. The spectral data (1H and 13C NMR) of syn-
thetic 4 are in good agreement with those reported in the literature
[20b].
moiety. The reactions of cinnamyl alcohol (2b) and a-vinylbenzyl
alcohol (2c) gave product 3b in comparable yields. Other cin-
namyl-type substrates 2d and 2e bearing a para-substituent of dif-
ferent electronic properties were uneventfully converted to the
In summary, we present the catalytic approach to a range of
allyl aryl sulfones. The palladium catalyst and the titanium
reagents act synergistically to generate
p
-allylpalladium species
Table 1
Evaluation of conditions.
entry
equiv of 2a
Ti(IV) additive (mol %)
B(III) additive (mol %)
yield (%)a
1
2
3b
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2
Ti(Oi-Pr)4 (150)
ꢀ
ꢀ
46
ꢀ
N.R.
N.R.
68
62
37
N.R.
64
66
Ti(Oi-Pr)4 (150)
Ti(Oi-Pr)4 (150)
Ti(Oi-Pr)4 (150)
Ti(Oi-Pr)4 (150)
ꢀ
ꢀ
PhB(OH)2 (150)
PhB(OH)2 (100)
PhB(OH)2 (50)
PhB(OH)2 (150)
PhB(OH)2 (150)
PhB(OH)2 (150)
Ti(Oi-Pr)4 (150)
Ti(Oi-Pr)4 (150)
6
a
Isolated yield.
Without Pd(OAc)2 and PPh3. N.R. = no reaction.
b
2

Yin-Jia Jhang, Chieh-Yu Chang, Yu-Huan Lin et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 2
Reaction scope.
entry
1
1
allyl alcohol
product(s)
yield (%)a
75
1a
2
3
1a
1a
67
70
4
1a
54
5
6
1a
1a
21
60
7
8
1a
1a
35
45
9
1a
1a
49b
63b
10
11
1b
65
12
13
1b
1c
72
57
14
1d
73
a
Isolated yield.
b
An inseparable mixture. 3g:3g0 = 3.5:1 (determined by NMR analysis).
3

Yin-Jia Jhang, Chieh-Yu Chang, Yu-Huan Lin et al.
Tetrahedron Letters xxx (xxxx) xxx
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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to influence the work reported in this paper.
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Appendix A. Supplementary data
Kaemmerer, Z. Horvath, J.W. Lee, M. Kaspereit, R. Arnell, M. Hedberg, B.
Herschend, M.J. Jones, K. Larson, H. Lorenz, A. Seidel-Morgensten Org. Process
Res. Dev. 16 (2012) 331–342.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153060.
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