Transition-Metal-Free Cross-Coupling of Benzothiophenes and Styrenes in a Stereoselective Synthesis of Substituted (E,Z)-1,3-Dienes

Article abstract of DOI:10.1002/anie.201902903

A transition metal-free one-pot stereoselective approach to substituted (E,Z)-1,3-dienes was developed by using an interrupted Pummerer reaction/ligand-coupling strategy. Readily available benzothiophene S-oxides, which can be conveniently prepared by oxidation of the parent benzothiophenes, undergo Pummerer coupling with styrenes. Reaction of the resultant sulfonium salts with alkyllithium/magnesium reagents generates underexploited hypervalent sulfurane intermediates that undergo selective ligand coupling, resulting in dismantling of the benzothiophene motif and the formation of decorated (E,Z)-1,3-dienes.

Full text of DOI:10.1002/anie.201902903

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Transition metal-free cross-coupling of benzothiophenes and
styrenes in a stereoselective synthesis of substituted (E,Z)-1,3-
dienes
Authors: Mindaugas Šiaučiulis, Nanna Ahlsten, Alex P Pulis, and David
John Procter
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902903
Angew. Chem. 10.1002/ange.201902903
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10.1002/anie.201902903
Angewandte Chemie International Edition
COMMUNICATION
Transition metal-free cross-coupling of benzothiophenes and
styrenes in a stereoselective synthesis of substituted (E,Z)-1,3-
dienes
Mindaugas Šiaučiulis[a], Nanna Ahlsten[b], Alexander P. Pulis[a], and David J. Procter[a]*
Abstract: A transition metal-free, one-pot, stereoselective approach
sulfuranes. Such a process would mimic reductive elimination
from a transition metal, with sulfur taking the place of palladium,
for example, and deliver 1,3-dienes. We postulated that the key
all-carbon sulfuranes could be conveniently formed in one-pot by
the facile interrupted Pummerer reactions13 of sulfoxides and
alkene coupling partners14 followed by the addition of an
organolithium or organomagnesium reagent to sulfur. In
particular, the use of little explored yet readily accessible
benzothiophene S-oxides15 as the sulfoxide partner was
particularly attractive as the benzothiophene unit in the sulfoxide
to
substituted
(E,Z)-1,3-dienes
strategy.
utilizes
an
interrupted
available
Pummerer/ligand-coupling
Readily
benzothiophene S-oxides, conveniently prepared by oxidation of the
parent benzothiophenes, undergo Pummerer coupling with styrenes.
Reaction of the resultant sulfonium
salts with alkyl
lithium/magnesium reagents generates underexploited hypervalent
sulfurane intermediates that undergo selective ligand coupling,
resulting in the dismantling of the benzothiophene motif and the
formation of decorated (E,Z)-1,3-dienes.
would serve as
a
masked Z-alkene and thus allow
stereocontrolled access to 1,3-dienes. Herein, we report an
efficient, transition metal-free, one pot procedure for the
stereocontrolled synthesis of substituted (E,Z)-1,3-dienes.
Benzothiophene S-oxides 1 are used to engage styrene partners
Conjugated dienes constitute an important molecular motif
found in natural products,1 biologically active compounds,2 and
precursors to organic materials.3 They are also mandatory
components in fundamental chemical transformations, such as
the Diels-Alder cycloaddition.4 As different diene isomers can
exhibit different physical properties and the stereochemistry of
dienes can influence the outcome of further chemical
transformations,5 it is highly desirable that any synthesis of
substituted dienes be stereoselective. Unfortunately, this
remains a challenge and fully stereoselective methods for the
construction of substituted dienes are scarce.6
2
by efficient interrupted Pummerer reaction. Subsequent
addition of an organolithium/magnesium triggers the formation of
hypervalent sulfurane intermediates I and selective dismantling
of the benzothiophene motif through selective ligand-coupling to
give substituted (E,Z)-1,3-dienes 3 (Scheme 1).
R3
R2
R2
R3
Substituted 1,3-dienes are typically prepared by transition-
Tf2O
O
S
+
metal-catalysed
cross-coupling
reactions
between
S
R4
then
R4–Mg/Li
R1
R1
prefunctionalised olefinic cross-coupling partners of predefined
stereochemistry.7 Alternatively, well-known olefination methods
for the stereoselective synthesis of alkenes can be extended to
the synthesis of dienes.8 Although useful for the synthesis of
terminal dienes, application to the synthesis of substituted,
conjugated dienes can be problematic. Additional approaches
start from enynes,9a-b alkynes,9c-f or cyclobutenes,9g-i for example.
New methods for the stereoselective synthesis of substituted
1,3-dienes are needed that complement the above approaches.
Since the seminal work of Trost and Oae on all-carbon
sulfurane formation,10 the elusive hypervalent intermediates
have found little application in synthesis.11 This is largely due to
the challenge of controlling the selectivity of ligand coupling in
sulfuranes.10,11 Inspired by the recent work of Stockman on the
development of an approach to diarylmethanes that proceeds
via ligand coupling in oxy-sulfurane intermediates,12 we
envisioned that selective C(sp2)–C(sp2) coupling could be
achieved by the coupling of two alkene ligands in all-carbon
1
2
3
Selective interrupted Pummerer,
ligand-coupling sequence
via
R3
R2
R4
S
n transition metal-free n one-pot
n exclusively (E,Z)-dienes
n benzothiophenes as masked Z-alkenes
n simple styrene coupling partners
I
R1
10-S-4 sulfurane
Scheme 1. An interrupted Pummerer/ligand-coupling strategy for the
construction of (E,Z)-1,3-dienes.
We began by investigating the interrupted Pummerer
reaction between Tf2O-activated 2-methylbenzothiophene 1a
and 2-fluorostyrene 2a. After optimization (see Supporting
Information for details), a one-pot procedure involving the
addition of methyllithium to the intermediate E-alkenyl sulfonium
salt II gave the desired tri-substituted (E,Z)-1,3-diene 3a in 86%
isolated yield. No other stereoisomers of 3a were detected
(Scheme 2).
O
MeLi
CH2Cl2
Tf2O
CH2Cl2
[a] M. Šiaučiulis, Dr. A. P. Pulis, Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Oxford Rd, Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
[b] Dr. N. Ahlsten
S
TfO
1a
(1.5 eq.)
F
S
Me
S
–78 °C
to RT
–40 °C
to RT
F
Me
Me
Me
F
2a
(1.0 eq.)
II
3a 86%
only E,Z isomer
Lilly Research Laboratories, Eli Lilly and Company Limited
Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH
Scheme 2. One-pot, interrupted Pummerer/ligand-coupling sequence for the
construction of (E,Z)-diene 3a from benzothiophene S-oxide 1a and styrene 2a.
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201902903
Angewandte Chemie International Edition
COMMUNICATION
exclusively. Isolated yields. a Yields determined by 1H NMR analysis.b MeMgBr
(1.5 eq.) used.
Exploring the scope of the reaction with respect to the
styrene partner, we found that various substitution patterns and
functional groups were tolerated in the process and diene
products (3a-3p) were formed as single stereoisomers in all
cases (Scheme 3). Remarkably, functional groups that are
typically incompatible with organometallic reagents, such as aryl
bromide (3d, 3e), ester (3h), boronate ester (3i) and benzylic
chloride (3j) emerged from the sequence unscathed. The
process was successfully applied to the coupling of complex
ketone, vinyl estrone, to give 3k in moderate yield. Convenient
variation of the 2-substituent on the benzothiophene-S-oxide 1
allowed (E,Z)-1,3-dienes bearing a range of substituents on the
internal carbons (3a, 3l-3p) to be assembled, including dienyl
bromide (3o) and sensitive α,β-unsaturated nitrile (3p). The
structure of 3p was confirmed by X-ray crystallographic analysis.
In contrast, the use of benzothiophene S-oxides lacking
substituents at the 2-position (i.e. R1 = H) resulted in a clean
switch to an alternative ligand coupling in the sulfurane
intermediates (vide infra) and the formation of 2-alkenyl sulfide
stilbene products (4a-d) (Scheme 3).
The use of alternative organometallic reagents to trigger
ligand coupling in the one-pot process was investigated using
the pairing of methylbenzothiophene S-oxide 1a and 2-
fluorostyrene 2a (Scheme 4). The addition of LiCl proved to be
beneficial for efficient conversion of sulfonium salts to the dienes
3 when organomagnesium reagents were used. A range of
Grignard reagents were successfully employed, including
cycloalkyl (3q, 3r), benzyl (3s), alkenyl (3t, 3u), and aryl (3v).
Interestingly, when alkenyl and aryl organomagnesium reagents
were used, selective ligand coupling to give the diene products
(3t-u) was observed even though the sulfurane intermediates
bear four sp2-hybridised carbon ligands.
1. Tf2O
CH2Cl2, –40 °C to RT
F
F
O
S
2. RMgX (1.5 eq.)
LiCl (2.0 eq.)
THF, –78 °C to RT
S
R
Me
3q-v
Me
1a
(1.5 eq.)
2a
(1.0 eq.)
R3
1. Tf2O (1.6 eq.)
CH2Cl2, –40 °C to RT
R2
F
F
R2
F
R3
S
S
S
O
Me
Me
Me
S
2. MeLi (1.5 eq.)
S
CH2Cl2, –78 °C to RT
R1
3a-p
2
R1
1
3q 81%
3r 81%
3s 59%
Me
(1.0 eq.)
(1.5 eq.)
R1 ≠ H
3a X = 2-F, 86%
3b X = 4-F, 57%
3c X = 2-Cl, 67%
3d X = 3-Br, 68%
3e X = 4-Br, 53%
F
F
X
F
S
S
S
S
Me
Me Me
3u, 74%
Me
S
Me
Me
Me
Me
3t 66%
3v 60%b
3f 78%
CO2Me
Bpin
Me
Me
Scheme 4. Scope with regard to the organometallic partner in the
stereoselective synthesis of (E,Z)-1,3-dienes. (E,Z)-Isomers are formed
exclusively. Isolated yields. a Yields determined by 1H NMR analysis.
S
S
Me
S
Me
Me
Me
3g 54%
Me
Me
Employing dibenzothiophene S-oxides 5, the reaction also
proved amenable to the synthesis of 2,2’-disubstituted biaryls 6
(Scheme 5).16 A variety of substituted styrenes were tolerated in
the process (6a-h), including those containing sensitive aryl
bromide (6g) and benzylic chloride (6h) functionalities.
Substituted dibenzothiophene S-oxides could also be employed
leading to decorated biaryls (6i-n).
3i 55%a
3h 42%
O
Cl
Me
H
H
S
H
Me
S
Me
Me
Me
3j 93%a
3k 51%
3l R = allyl, 70%
3m R = Ph, 48%
F
3n R = 4-F-Ph, 70%
3o R = Br, 73%b
S
Me
X-ray
of 3p
R
3p R = CN, 41% X-ray
R1 = H
Me
S
Me
S
Me
S
F
F
F
Me
4c X = Cl, 51%
4d X = Br, 68%
X
Cl
Scheme 3. Scope with regard to the styrene and benzothiophene partners in
the stereoselective synthesis of (E,Z)-1,3-dienes. (E,Z)-Isomers are formed
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10.1002/anie.201902903
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COMMUNICATION
R2
A
R2
TfO
OTf
1. Tf2O
O
Tf2O
S
2
CH2Cl2, –40 °C to RT
O
S
S
S
S
R
–TfOH
OTf
4
4
2. RLi
CH2Cl2, –78 °C to RT
R1
R1
R1
5
2
6
III
II
1
R1
(1.5 eq.)
(1.0 eq.)
R1
B
R1
R1
Ph
R1 ≠ H
F
Me
S
S
b
S
Me
S
Me
S
R2
R1
S
R2
path
a
Me
Ph
M
Ia
3
R2
6a 74%
6d 2-F, 83%
6e 4-F, 76%
6b 2-Me, 53%
6c 3-Me, 63%a
path
b
Cl
a
Ph
II
Br
R1 = H
S
S
R2
Cl
S
R2
S
Me
Ib
S
Me
4
Me
C
R1
6g 58%a
6h 77%
Br
6f 78%
R1
R1
Ph
R2
M
Ph
S
S
S
R2
R2
S
Me
S
Me
Br
IV
6
Va
4
pseudorotation
Br
Ψ
6i 70%
X-Ray
X-ray of 6i
6j 72%a,b
R2
Ph
S
S
F
F
X-ray of IV
(R1 = H)
F
R2
S
Me
S
Me
S
Me
R1
R1
Vb
Me
4
Ph
Br
4
4
high energy
not observed
6m 80%c
6l 73%
6k 85%
Scheme 6. A) Mechanism of the interrupted Pummerer reaction of
benzothiophene S-oxides and styrenes. B) Proposed origin of selectivity in the
ligand coupling of sulfuranes derived from benzothiophene. C) Proposed origin
of regioselectivity in the ligand coupling of sulfuranes derived from
dibenzothiophene.
Me
F
F
S
S
Me
Me
4
Based
on
previous
reports
describing
sulfurane
intermediates10-12 and our experimental observations, we
propose the following mechanism for the interrupted
Pummerer/ligand-coupling sequence (Scheme 6). Treatment of
benzothiophene S-oxides 1 with Tf2O generates sulfoxonium
salts III that are capable of engaging styrenes 2 in an interrupted
Pummerer process (Scheme 6A). The resultant (E)-alkenyl
sulfonium salts II can then be activated towards ligand-coupling
by addition of an organometallic reagent and generation of
6n 46%
6o 47%d
Scheme 5. Application of the interrupted Pummerer/ligand coupling sequence
to the synthesis of 2,2'-substituted biaryls. (E)-Isomers are obtained exlusively.
Isolated yields. aYields determined by 1H NMR analysis. b1:1 mixture of
regioisomers. c10:1 mixture of regioisomers. dConditions as in Scheme 4.
In particular, sulfuranes generated from 4-substituted
dibenzothiophene S-oxides underwent selective ligand coupling
at the more hindered position, leading to more sterically-
hypervalent (10-S-4) sulfur intermediates
I (Scheme 6B).
Favourable orbital overlap between sp2-hybridised axial and
equatorial ligands then leads to ligand-coupling and formation of
the desired diene products. It is considered that nucleophilic
additions to sulfonium salts II occur opposite to an existing
ligand to give sulfuranes I, in which the nucleophile occupies an
axial postion.11a,11c The most accessible lines of attack are
opposite to the C–S bonds of the heterocycle and the least
sterically hindered approach is preferred. In the case of 2-
substituted benzothiophenium salts II (R1 ≠ H), attack opposite
to the C2–S bond is favored (Scheme 6B, path a), resulting in
sulfurane Ia which upon stereoretentive ligand-coupling delivers
(E,Z)-dienes 3. With C2-unsubstituted benzothiophenium salts II
(R1 = H), nucleophilic attack occurs opposite to the C7a–S bond
congested-products
(6i,k-m).
Alternative
organometallic
reagents successfully triggered ligand coupling in these
reactions; for example, vinylmagnesium bromide was used in
the preparation of 6o.
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10.1002/anie.201902903
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COMMUNICATION
(Scheme 5B, path b) and via sulfurane Ib to stilbenes 4. The
impact of sterics can also be seen in the reactions of
unsymmetrical 4-substituted dibenzothiophenium salts IV
(Scheme 5C). Nucleophilic attack along the least sterically
hindered line of attack delivers intermediate sulfurane Va – with
the substituted aryl unit in the axial position. Subsequent ligand
coupling with the equatorial styryl group then delivers biaryls 6.
While pseudorotation of intermediate sulfuranes Va is
possible,10g formation of the isomeric product requires access to
a high energy sulfurane Vb in which a lone pair unfavourably
occupies an axial position.
In summary, we have developed a transition-metal-free
stereoselective, one pot synthesis of (E,Z)-1,3-dienes that
exploits a new interrupted Pummerer/ligand-coupling sequence.
Readily accessible yet underexplored benzothiophene S-oxides
couple with styrene partners and addition of an organometallic
reagent triggers controlled dismantling of the benzothiophene
scaffold by selective ligand-coupling in rarely-exploited sulfurane
intermediates.
Acknowledgements
To demonstrate the synthetic utility of the interrupted
Pummerer/ligand-coupling reaction sequence, we successfully
accomplished gram scale synthesis of (E,Z)-1,3-diene 3a.
Crucially, the stoichiometry of starting materials can be reversed
without significantly affecting the efficiency of the reaction.
Finally, the organosulfanyl unit in the (E,Z)-1,3-diene
products of the transition-metal-free cross-coupling render them
useful building blocks for further manipulation. For example,
selective oxidation of diene 3a to the corresponding sulfoximine
7,17 sulfoxide 8, and sulfone 9 can be readily carried out
We thank The University of Manchester (Lectureship to A.P.P.),
EPSRC (PhD studentship to M.S. and Established Career
Fellowship to D.J.P.), and Eli Lilly (PhD CASE studentship to
M.S.).
Keywords: sulfoxides • sulfur • Pummerer • sulfurane • ligand
coupling
(Scheme 7). Employing
8 in subsequent sulfoxide-metal
(1) C. Thirsk and A. Whiting, J. Chem. Soc. Perkin 1, 2002, 2, 999–1023.
(2) (a) H. Inano, K. Suzuki, H. Ishii-Ohba, H. Yamanouchi, M. Takahashi and K.
Wakabayashi, Carcinogenesis, 1993, 14, 2157–2163. (b) I. H. Paik, S. Xie, T. A.
Shapiro, T. Labonte, A. A. Narducci Sarjeant, A. C. Baege and G. H. Posner, J.
Med. Chem., 2006, 49, 2731–2734.
(3) (a) J. S. Fritz and D. T. Gjerde, Electronic Materials: The Oligomer Approach,
Wiley-VCH Verlag GmbH, Weinheim, Germany, 1998. (b) G. Moad, Polym. Int.,
2017, 66, 26–41. (c) Z. Zhang, D. Cui, B. Wang, B. Liu and Y. Yang,
International Journal of Mechanics, 2010, 10, 49–108. (d) L. Porri and A.
Giarrusso, Comprehensive Polymer Science and Supplements, Elsevier, 1989,
vol. 44, 53–108.
exchange processes18 and quenching with various electrophiles
allows access to a range of 1,3-dienes. For example, quenching
of the intermediate arylmetal with water, iodine, and
benzaldehyde delivers 1,3-dienes 10a, 10b and 10c,
respectively. Crucially, products 10 contain no trace of the sulfur
atom of the benzothiophene ring system used to selectively
construct the (E,Z)-1,3-diene systems.
(4) (a) O. Diels and K. Alder, Liebigs Ann. Chem., 1928, 460, 98–122. (b) K. C.
Nicolaou, S. A. Snyder, T. Montagnon and G. Vassilikogiannakis, Angew. Chem.
Int. Ed., 2002, 41, 1668–1698. (c) E. J. Corey, Angew. Chem. Int. Ed., 2002, 41,
1650–1667.
(5) (a) J. Sauer and R. Sustmann, Angew. Chem. Int. Ed., 1980, 19, 779–807.
(b) Y. Xiong, Y. Sun and G. Zhang, Tetrahedron Lett., 2018, 59, 347–355.
(6) M. De Paolis, I. Chataigner and J. Maddaluno, Top. Curr. Chem., 2012, 87–
146.
A
1. Tf2O (1.1-1.6 eq.)
CH2Cl2, –40 °C to RT
O
S
F
2. MeLi (1.5 eq.)
CH2Cl2, –78 °C to RT
S
F
Me
Me
3a
Me
1a
2a
(7) For a general review on cross-coupling reactions, see: (a) K. C. Nicolaou, P.
G. Bulger and D. Sarlah, Angew. Chem. Int. Ed., 2005, 44, 4442–4489. For,
selected examples of cross-coupling reactions applied to the synthesis of
conjugated dienes, see: (b) M. Lemhadri, A. Battace, F. Berthiol, T. Zair, H.
Doucet and M. Santelli, Synthesis, 2008, 1142–1152. (c) A. L. Hansen, J.-P.
Ebran, M. Ahlquist, P.-O. Norrby and T. Skrydstrup, Angew. Chem. Int. Ed.,
2006, 45, 3349–3353. (d) D. Fiorito, S. Folliet, Y. Liu and C. Mazet, ACS Catal.,
2018, 8, 1392–1398. (e) A. M. Olivares and D. J. Weix, J. Am. Chem. Soc.,
2018, 140, 2446–2449. (f) M. Liu, P. Yang, M. K. Karunananda, Y. Wang, P. Liu
and K. M. Engle, J. Am. Chem. Soc., 2018, 140, 5805–5813. (g) V. T. Nguyen,
H. T. Dang, H. H. Pham, V. D. Nguyen, C. Flores-Hansen, H. D. Arman and O.
V Larionov, J. Am. Chem. Soc., 2018, 140, 8434–8438. (h) Z. Huang and E.
Negishi, J. Am. Chem. Soc., 2007, 129, 14788–14792. (i) M. Cai, G. Chen and
W. Hao, Synthesis, 2007, 1197–1203. (j) E. I. Negishi, Z. Huang, G. Wang, S.
Mohan, C. Wang and H. Hattori, Acc. Chem. Res., 2008, 41, 1474–1485.
(8) (a) 1,3-Dienes; Rawal,V. H., Kozmin, S. A., Eds.; Science of Synthesis
Vol.46; Georg Thieme Verlag KG: Stuttgart, 2009. (b) B. E. Maryanoff and A. B.
Reitz, Chem. Rev., 1989, 89, 863–927. (c) D. J. Ager, in Organic Reactions,
John Wiley & Sons, Inc., Hoboken, NJ, USA, 1990, pp. 1–223. (d) P. R.
Blakemore, J. Chem. Soc. Perkin 1, 2002, 2, 2563–2585. (e) Y. Wang and F.
West, Synthesis, 2004, 2002, 99–103. (f) J. D. White and M. S. Jensen,
Tetrahedron, 1995, 51, 5743–5756. (g) G. Sirasani, T. Paul and R. B. Andrade,
Tetrahedron, 2011, 67, 2197–2205. (h) B. Schmidt and O. Kunz, Eur. J. Org.
Chem., 2012, 1008–1018.
(1.5 eq.)
(1.0 eq.)
(1.0 eq.)
(1.5 eq.)
78%, 1.33 g
68%, 0.96 g
B
PhI(OAc)2 (2.5 equiv.)
NH3 (1.5 equiv.)
F
F
O
S
S
MeOH, RT
HN
Me
Me
7 74%
Me
Me
3a
mCPBA
(1–2.2 equiv.)
8 n = 1, 98%, X-ray
9 n = 2, 93%
F
(O)nS
Me
Me
conditionsa
conditionsb
conditionsc
F
F
F
HO
H
I
Ph
Me
Me
Me
10a 81%
(from 8)
10b 62%
(from 8)
10c 72%
(from 8)
(9) For selected examples of diene synthesis from enynes, see: (a) K. M. Miller,
T. Luanphaisarnnont, C. Molinaro and T. F. Jamison, J. Am. Chem. Soc., 2004,
126, 4130–4131. (b) J. R. Kong, C. W. Cho and M. J. Krische, J. Am. Chem.
Soc., 2005, 127, 11269–11276. For selected examples of diene synthesis from
alkynes, see: (c) R. Shintani, W.-L. L. Duan, S. Park and T. Hayashi, Chem.
Commun., 2006, 3646–3647. (d) S. Mannathan and C.-H. H. Cheng, Chem.
Commun., 2010, 46, 1923–1925. (e) L. J. Perez, H. L. Shimp and G. C.
Micalizio, J. Org. Chem., 2009, 74, 7211–7219. (f) S. T. Diver and A. J. Giessert,
Chem. Rev., 2004, 104, 1317–1382. For selected examples of diene synthesis
Scheme 7. A) Larger scale Interrupted Pummerer/ligand-coupling sequence.
B) Representative manipulations of the organosulfanyl unit in the (E,Z)-1,3-
diene products. EtMgBr (1.5 eq.), THF, RT, 30 min, then NH4Cl (aq.).
EtMgBr (1.5 eq.), THF, RT, 30 min, then I2 (1.5 eq.). EtMgBr (1.5 eq.), THF,
RT, 30 min, then PhCHO (1.5 eq.).
a
b
c
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10.1002/anie.201902903
Angewandte Chemie International Edition
COMMUNICATION
from cyclobutenes, see: (g) A. Misale, S. Niyomchon and N. Maulide, Acc.
Chem. Res., 2016, 49, 2444–2458. (h) C. Souris, A. Misale, Y. Chen, M.
Luparia and N. Maulide, Org. Lett., 2015, 17, 4486–4489. (i) M. Berger, Y. Chen,
K. Bampali, M. Ernst and N. Maulide, Chem. Commun., 2018, 54, 2008–2011.
(10) For examples of all-carbon sulfurane formation, see: (a) Khim, Y. H.; Oae,
S. Bull. Chem. Soc. Jpn. 1969, 42, 1968–1971. (b) B. M. Trost, R. Larochelle
and R. C. Atkins, J. Am. Chem. Soc., 1969, 91, 2175–2177. (c) B. M. Trost and
H. C. Arndt, J. Am. Chem. Soc., 1973, 95, 5288–5298. For examples of related
oxy-sulfuranes generated from sulfoxides, see: (d) S. Oae, T. Kawai and N.
Furukawa, Tetrahedron Lett., 1984, 25, 69–72. (e) S. Oae, Phosphorous Sulfur
Relat. Elem., 1986, 27, 13–29. (f) S. Oae, T. Kawai, N. Furukawa and F.
Iwasaki, J. Chem. Soc., Perkin Trans. 2, 1987, 405–411. (g) S. Oae, T. Takeda,
T. Kawai and N. Furukawa, Phosphorous Sulfur Relat. Elem., 1987, 34, 133–
137. (h) S. Wakabayashi, M. Ishida, T. Takeda and S. Oae, Tetrahedron Lett.,
1988, 29, 4441–4444. (i) S. Wakabayashi, T. Tanaka, Y. Kubo, J. Uenishi and S.
Oae, Bull. Chem. Soc. Jpn., 1989, 62, 3848–3850. (j) S. Oae, T. Takeda, S.
Wakabayashi, F. Iwasaki, N. Yamazaki and Y. Katsube, J. Chem. Soc., Perkin
Trans. 2, 1990, 273–276. (k) S. Oae and N. Furukawa, Adv. Heterocycl. Chem.,
1990, 48, 1–63. (l) S. Oae and Y. Uchida, Acc. Chem. Res., 1991, 24, 202–208.
(m) S. Oae, Pure Appl. Chem., 1996, 68, 805–812. (n) S. Oae, T. Takeda, J.
Uenishi and S. Wakabayashi, Phosphorus. Sulfur. Silicon Relat. Elem., 1996,
115, 179–182.
(11) For examples of sulfurane ligand coupling reactions in synthesis, see: (a) R.
W. Baker, D. C. R. Hockless, G. R. Pocock, M. V Sargent, B. W. Skelton, A. N.
Sobolev, E. Twiss (née Stanojevic) and A. H. White, J. Chem. Soc., Perkin
Trans. 1, 1995, 2615–2629. (b) R. W. Baker, J. N. H. Reek and B. J. Wallace,
Tetrahedron Lett., 1998, 39, 6573–6576. (c) R. W. Baker, S. O. Rea, M. V
Sargent, E. M. C. Schenkelaars, T. S. Tjahjandarie and A. Totaro, Tetrahedron,
2005, 61, 3733–3743.
(12) W. M. Dean, M. Šiaučiulis, T. E. Storr, W. Lewis and R. A. Stockman,
Angew. Chem. Int. Ed., 2016, 55, 10013–10016.
(13) For recent reviews on the interrupted Pummerer reaction, see: (a) L. H. S.
Smith, S. C. Coote, H. E. Sneddon and D. J. Procter, Angew. Chem. Int. Ed.,
2010, 49, 5832–5844. (b) A. P. Pulis and D. J. Procter, Angew. Chem. Int. Ed.,
2016, 55, 9842–9860. (c) T. Yanagi, K. Nogi and H. Yorimitsu, Tetrahedron
Lett., 2018, 59, 2951–2959. For recent examples of interrupted Pummerer and
related reactions, see: (d) D. Kaldre, I. Klose and N. Maulide, Science, 2018,
361, 664–667. (e) G. Hu, J. Xu and P. Li, Org. Chem. Front., 2018, 5, 2167–
2170. (f) M. Šiaučiulis, S. Sapmaz, A. P. Pulis and D. J. Procter, Chem. Sci.,
2018, 9, 754–759. (g) T. Yanagi, S. Otsuka, Y. Kasuga, K. Fujimoto, K.
Murakami, K. Nogi, H. Yorimitsu and A. Osuka, J. Am. Chem. Soc., 2016, 138,
14582–14585. (h) J. A. Fernández-Salas, A. J. Eberhart and D. J. Procter, J.
Am. Chem. Soc., 2016, 138, 790–793. (i) A. J. Eberhart, H. Shrives, Y. Zhang,
A. Carrër, A. V. S. Parry, D. J. Tate, M. L. Turner and D. J. Procter, Chem. Sci.,
2016, 7, 1281–1285. (j) J. A. Fernández-Salas, A. P. Pulis and D. J. Procter,
Chem. Commun., 2016, 52, 12364–12367. (k) A. J. Eberhart, H. J. Shrives, E.
Álvarez, A. Carrër, Y. Zhang and D. J. Procter, Chem. - Eur. J., 2015, 21, 7428–
7434. (l) G. Hu, J. Xu and P. Li, Org. Lett., 2014, 16, 6036–6039 (m) B. Peng, X.
Huang, L. G. Xie and N. Maulide, Angew. Chem. Int. Ed., 2014, 53, 8718–8721.
(n) X. Huang, M. Patil, C. Farès, W. Thiel and N. Maulide, J. Am. Chem. Soc.,
2013, 135, 7312–7323. (o) X. Huang and N. Maulide, J. Am. Chem. Soc., 2011,
133, 8510–8513. (p) T. Kobatake, S. Yoshida, H. Yorimitsu and K. Oshima,
Angew. Chem. Int. Ed., 2010, 49, 2340–2343. (q) S. Yoshida, H. Yorimitsu and
K. Oshima, Org. Lett., 2009, 11, 2185–2188. (r) S. Akai, N. Kawashita, H. Satoh,
Y. Wada, K. Kakiguchi, I. Kuriwaki and Y. Kita, Org. Lett., 2004, 6, 3793–3796.
(s) K. Colas, R. Martín-Montero and A. Mendoza, Angew. Chem. Int. Ed., 2017,
56, 16042–16046.
(14) (a) V. G. Nenajdenko, P. V. Vertelezkij, I. D. Gridnev, N. E. Shevchenko
and E. S. Balenkova, Tetrahedron, 1997, 53, 8173–8180. (b) M. H. Aukland, F.
J. T. Talbot, J. A. Fernández-Salas, M. Ball, A. P. Pulis and D. J. Procter,
Angew. Chem. Int. Ed., 2018, 57, 9785–9789.
(15) (a) H. J. Shrives, J. A. Fernández-Salas, C. Hedtke, A. P. Pulis and D. J.
Procter, Nat. Commun., 2017, 8, 14801–14807. (b) Z. He, H. J. Shrives, J. A.
Fernández-Salas, A. Abengózar, J. Neufeld, K. Yang, A. P. Pulis and D. J.
Procter, Angew. Chem. Int. Ed., 2018, 57, 5759–5764. (c) K. Yang, A. P. Pulis,
G. J. P. Perry and D. J. Procter, Org. Lett., 2018, 20, 7498–7503. For other
uses of benzothiophenium salts, see: (d) T. Kitamura, B.-X. Zhang and Y.
Fujiwara, J. Org. Chem., 2003, 68, 731–735. (e) T. Kitamura, M. Miyaji, S. Soda
and H. Taniguchi, J. Chem. Soc. Chem. Commun., 1995, 1375. (f) T. Kitamura,
K. Morizane, H. Taniguchi and Y. Fujiwara, Tetrahedron Lett., 1997, 38, 5157–
5160. (g) B. Waldecker, F. Kraft, C. Golz and M. Alcarazo, Angew. Chem. Int.
Ed., 2018, 57, 12538–12542.
(16) Biaryls bearing 2-organosulfanyl substituents are often difficult to prepare
due to poisoning of the metal catalyst by coordination of sulfur, see: D. Vasu, J.
N. Hausmann, H. Saito, T. Yanagi, H. Yorimitsu and A. Osuka, Asian J. Org.
Chem., 2017, 6, 1390–1393, and references therein.
(17) Y. Xie, B. Zhou, S. Zhou, S. Zhou, W. Wei, J. Liu, Y. Zhan, D. Cheng, M.
Chen, Y. Li, B. Wang, X. Xue and Z. Li,ChemistrySelect, 2017, 2, 1620–1624.
(18) (a) L. Melzig, C. B. Rauhut, N. Naredi-rainer and P. Knochel, Chem. - Eur.
J., 2011, 6, 5362–5372. (b) A. Kina, H. Miki, Y.-H. Cho and T. Hayashi, Adv.
Synth. Catal., 2004, 346, 1728–1732. (c) T. Shimada, Y. H. Cho and T. Hayashi,
J. Am. Chem. Soc., 2002, 124, 13396–13397.
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10.1002/anie.201902903
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
R2
R3 R2
via
Transition metal-free cross-coupling
of benzothiophenes and styrenes in a
stereoselective synthesis of
R2
R4
S
O
Tf2O
S
R3
+
substituted (E,Z)-1,3-dienes
R1
S
then
R1
R3
R4
R1
R4–Mg/Li
Mindaugas Šiaučiulis, Nanna Ahlsten,
Alexander P. Pulis, and David J.
Procter*
A transition metal-free stereoselective, one pot synthesis of (E,Z)-1,3-dienes
exploits an interrupted Pummerer/ligand-coupling sequence. Readily accessible yet
underexplored benzothiophene S-oxides couple with styrene partners and addition
of an organometallic reagent triggers controlled dismantling of the benzothiophene
scaffold by selective ligand-coupling in rarely-exploited sulfurane intermediates.
Page No. – Page No.
R3
This article is protected by copyright. All rights reserved.