Regioselective molybdenum-catalyzed allylic substitution of tertiary allylic electrophiles: Methodology development and applications

Article abstract of DOI:10.1039/d0sc01763a

The first molybdenum-catalyzed allylic sulfonylation of tertiary allylic electrophiles is described. The method employs a readily accessible catalyst (Mo(CO)₆/2,2′-bipyridine, both are commercially available) and represents the first example of the use of a group 6 transition metal-catalyst for allylic sulfonylation of substituted tertiary allylic electrophiles to form carbon-sulfur bonds. This atom economic and operationally simple methodology is characterized by its relatively mild conditions, wide substrate scope, and excellent regioselectivity profile, thus unlocking a new platform to forge sulfone moieties, even in the context of late-stage functionalization and providing ample opportunities for further derivatization through traditional Suzuki cross-coupling reactions.

Full text of DOI:10.1039/d0sc01763a

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DOI: 10.1039/D0SC01763A
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Regioselective molybdenum-catalysed allylic substitution of
tertiary allylic electrophiles: methodology development and
applications
Received 00th January 20xx,
Accepted 00th January 20xx
Muhammad Salman,† Yaoyao Xu,† Shahid Khan, Junjie Zhang and Ajmal Khan*
DOI: 10.1039/x0xx00000x
The first molybdenum-catalysed allylic sulfonylation of tertiary allylic electrophiles is described. The method utilizes a
readily accesable catalyst (Mo(CO)6/2,2′-bipyridine, both are commercially available) and represent the first example of
the use of a group 6 transition metal-catalyst to substituted tertiary allylic electrophiles to form carbon-sulfur bonds. This
atom economic and operationally simple methodology is charaterized by its relatively mild conditions, wide substrate
scope, and excellent regioselectivity profile, thus unlocking a new platform to synthesize allylic sulfones, even at late
stages and providing ample oppertunaties for further derivatization through traditional Suzuki cross-coupling reactions.
A) Limitations in Molybdenum-Catalyzed Allylic Substitution
[LnMo]
[LnMo]
Introduction
R2
R
Nu
The concept of -allyl metal-complex was first formulated by Tsuji
in 19651a and, later, properly adopted by Trost in 1973.1b Since
then, this technology has enabled organic chemists to create novel
procedures for the synthesis of simple to complex molecules.2
Among these is the development and utilization of heteroatom
nucleophile reagents, such as oxygen, nitrogen, and or sulfur-based
nucleophiles.2,3 Despite the massive development that has been
made in this area, there still remain untapped opportunities in the
potential application of these heteroatom nucleophile reagents in
transition metal-catalysed allylic substitution. For example,
molybdenum-catalysed allylic substitution reactions of heteroatom
nucleophiles are unknown and largely limited only to the carbon-
carbon bond formation procedures (Figure 1A, left).4 Furthermore,
the substrate scope with respect to the allylic electrophile has also
been unchanged and restricted to the ones that provide products
containing a tertiary center at the allylic position.5 Regardless of the
longstanding interest in the formation of carbon-heteroatom bond
with in the synthetic organic community, as well as the
advancement of other transition-metal-catalysed reactions to
provide heteroatom bearing quaternary and or tertiary allylic
centers,6 molybdenum-catalysed allylic substitution reactions that
R1
Nu
Nu
R2
R1
R
Nu = carbon
all reports
Nu = carbon or
heteroatoms
zero reports
B) This Research
O
R3
OBoc
[LnMo]
R2
Mo/Ln
O
S
R3SO2Na
+
R2
R2
R1
R1
R1
R2 = methyl
R1 = alkyl, aryl, carbocyclic
R3 = alkyl, aryl, heteroaryl, carbocyclic
Tertiary Allylic Sulfone
C) Applications of the Current Research
OH
HN
NH2
OH
NH
O
Me
Me
O
S
Me
Me
Me
Me
Me
Me
Me
Me
(±)-sporochnol
(±)-bakuchiol
(±)-agelasidine A
Fig. 1 (A) Limitations in molybdenum-catalysed allylic substitution, (B) our
research, and (C) applications of the current research.
provide products containing such
prominently absent from the literature and yet to be discovered
(Figure 1A, right).7
a
stereocenter remain
Due the high importance of allylic sulfones as pharmaceuticals8 and
synthetic candidates,9 organic chemists have recently been tested
to design catalytic C-S bond cleavage procedures as a new tool for
carbon-carbon bond formation through Suzuki cross-coupling10 and
or allylic substitution reactions.11 Despite the considerable
development realized in this zone, allylic sulfone formation is still a
challenging task and confined to the use of transition metal-
catalysed allylic sulfonylation procedures.12,13 However, using these
procedures for the synthesis of allylic sulfone containing
tetrasubstituted carbon centers are scarce and largely
unexplored.14 Therefore, at the beginning of our study it was
Department of Applied Chemistry, School of Science, and Xi’an Key Laboratory of
Sustainable Energy Materials Chemistry, Xi’an Jiao Tong University, Xi’an 710049,
P. R. China. ajmalkhan@xjtu.edu.cn
† These authors contributed equally.
Electronic Supplementary Information (ESI) available: For detailed experimental
procedures, characterization data of all of the new compounds, copies of 1H, 13C
NMR spectra of the substrates and products see DOI: 10.1039/x0xx00000x
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unclear whether a molybdenum-catalysed allylic substitution could
ever be implemented with heteroatom (sodium sulfinate)
nucleophile or even with ,-disubstituted allylic precursors. If
successful, such unexplored area of allylic substitution chemistry
might not only provide opportunity to realize currently inaccessible
chemical space (carbon-heteroatom bond formation) in
molybdenum-catalysed allylic substitution, but also provide a new
synthetic approach for rapidly generate quaternary all-carbon
centers through Suzuki cross-coupling of the sulfone functionality.
As part of our ongoing program in developing molybdenum-
catalysed allylic substitution technology and our continued interest
in the catalytic asymmetric synthesis of quaternary
stereocenters,14a, 15 we were attracted to this unmet challenge and
report herein the successful implementation of this idea (Figure
1B). The salient features of this methodology are the atom-
economic procedures, high regioselectivity, and excellent functional
group tolerance for both sulfinate salt and tertiary allylic
carbonates, even at late-stages. Furthermore, the high reactivity of
tertiary allylic sulfones as a new class of electrophiles to yield
structurally diverse products containing quaternary all-carbon
centers through Suzuki cross-coupling are the special characteristic
of this catalytic system (Figure 1C).10a
Results and discussion
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DOI: 10.1039/D0SC01763A
Our optimization began by evaluating the allylic substitution of
tertiary allylic carbonate 1a, readily prepared from the
corresponding alcohol on
a
large scale, with sodium
benzenesulfinate 2a (Table 1). Interestingly, a disappointing amount
of either 3aa or 4aa were detected under reaction conditions
previously reported for other molybdenum-catalysed allylic
substitution events.4 After several experimentation,16 we concluded
that a combination of inexpensive commercially available Mo(CO)6
precursor and 2,2’-bipyridyne as a ligand (L1)17 in EtOH at 60 ℃
afforded 3aa in 92% yield upon isolation with excellent branched to
linear selectivity (3aa/4aa = ﹥ 99:1). Amongst all of the ligands
utilized, 2,2′-bipyridine motifs were crucial for achieving the
targeted transformation. While excellent reactivity towards 3aa was
found with 2,2′-bipyridines and 6,6′-dimethyl-2,2′-bipyridine, better
yields were obtained for the first one (entries 1–7). Interestingly,
the bench-stable terpyridine L7 failed to provide product 3aa. These
results indicate that the coordination geometry of the ligand
dictates the reactivity, with 2,2′-bipyridine ligands being particularly
suited for the high yield and selectivity of 3aa. Subtle changes on
the molybdenum precursor, and or solvent, however, had a
negative influence on the reaction to occur, consistently providing
lower yields if any (entries 8-14). As expected, control experiments
revealed that all of the reaction parameters were necessary for
forging the sulfone moiety (entry 15).
Table 1. Optimization of the reaction parametersa
Mo(CO)6 (10 mol%)
L1 (15 mol%)
O
OBoc
Me
Me
O
S
Ph
EtOH, 60 oC, 24 h
Ph
SO2Ph
Me
PhSO2Na (2a)
Ph
1a
4aa
3aa
Table 2. Sodium sulfinate substrate scopea-c
R2
R2
R1 = H, R2 = H, L1
O
Mo(CO)6 (10 mol%)
L1 (15 mol%)
R1 = Me, R2 = H, L2
R1 = CO2H, R2 = H, L3
R2 = CO2Me, R1 = H, L4
N
R
OBoc
Me
O
S
N
N
N
N
Me
N
N
Me
N
N
Ph
EtOH, 60 oC, 24 h
Ph
SO2R
Ph
R1
R1
L5
L6
L7
RSO2Na (2)
1a
3
trace/no
Entry
1
Deviation in conditions
none
3aa/4aab 3aa (%)c
Entry
2
3b
yield (%)c
92
99:1
99:1
99:1
99:1
25:1
--
92
87
35
52
16
0
1
2a (R = Ph)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
2
L2 was used instead of L1
L3 was used instead of L1
L4 was used instead of L1
L5 was used instead of L1
L6 was used instead of L1
L7 was used instead of L1
(C7H8)3Mo(CO)3 was used
THF was used as solvent
2
2b (R = 4-MeC6H4)
2c (R = 4-MeOC6H4)
2d (R = 4-ClC6H4)
93
3
3
90
4
4
87
5
5
2e (R = 4-FC6H4)
85
6
6
2f (R = 4-NO2C6H4)
2g (R = 4-CNC6H4)
2h (R = 2-FC6H4)
75
7
--
>5
82
>5
>5
35
77
25
63
0
7
72
8
99:1
--
8
88
9
9
2i (R = 2-ClC6H4)
87
10
11
12
13
14
Toluene was used as solvent
DCE was used as solvent
iPrOH was used as solvent
THF/EtOH (5:1) as solvent
DCE/EtOH (5:1) as solvent
Without Mo or L1
-
10
11
12
13
14
15
16
17
2j (R = 2-OCF3C6H4)
2k (R = 3-BrC6H4)
2l (R = 3-CNC6H4)
2m (R = 2,4-MeOC6H3)
2n (R = 3,5-CF3C6H3)
2o (R = 2-MeO,5-BrC6H3)
2p (R = 3,4-ClC6H3)
2q (R = 2-naphthyl)
3aj
72
25:1
99:1
25:1
25:1
--
3ak
3al
82
78
3am
3an
3ao
3ap
3aq
94
95
15
84
a
Reaction conditions: Mo-catalyst (10 mol%), ligand (15 mol%), 1a (0.2 mmol),
PhSO2Na 2a (0.3 mmol), solvent (1.0 mL, 0.2 M), 60 ℃, 24 hours. Determined by 1H-
NMR of the crude reaction mixture. c Isolated yields.
b
87
82
2 | J. Name., 2012, 00, 1-3
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benzoyl (1k), thioether (1l), acetal (1m), and carbonate (1n) on
the alkyl chain of the tertiary allylic carbonates were tolerated,
18
19
20
21
22
23
24
25
2r (R = 1-quinoline)
3ar
78
92
82
86
72
78
82
78
72
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DOI: 10.1039/D0SC01763A
2s (R = 2,3-dihydrobenzofuran) 3as
and the sulfonylation branched products (3ia3na) were
isolated in high yields (8294%). In addition, unprotected
hydroxy group on the alkyl chain of the tertiary allylic
carbonates 1o, and 1p do not interfere with productive
tertiary allylic sulfones formation (3oa and 3pa), thus providing
opportunities for further derivatization. Notably, the reaction
can be easily applied within the context of late-stages,
supported by the formation of branched allylic sulfone 3qa,
derived from Pentoxyfylline. As expected, the allylic
sulfonylation of phenyl substituted allylic carbonate occurred
exclusively at the less-hindered position. The present
optimized conditions were unsatisfactory with such substrate,
provided the desired branched product (3ra) with low
branched to linear ratio (b/l = 1:5); indicating some (steric)
limitation of the current protocol. Besides methyl-substituted
tertiary allylic substrates 1a-1r, other alkyl or aryl substituted
substrates return only starting materials when used under the
optimized conditions, indicating some limitation of the present
protocol.
2t (R = 3-pyridine)
2u (R = 2-thiopene)
2v (R = Me)
3at
3au
3av
3az
3ax
3ay
3az
2w (R = Et)
2x (R = iPr)
2y (R = cyclopropyl)
2z (R = CH3OCOCH2CH2)
26
a
Reaction conditions: Mo(CO)6 (10 mol%), L1 (15 mol%), 1a (0.2 mmol), RSO2Na 2 (0.3
mmol), EtOH (1.0 mL, 0.2 M), 60 ℃, 24 hours. Determined by 1H-NMR of the crude
reaction mixture. c Isolated yields.
b
With reliable access to 3aa, we next turned our attention to
examine the generality of our newly developed molybdenum-
catalysed regioselective sulfonylation of tertiary allylic
electrophiles with sodium sulfinate by using Mo/L1 catalyst
system as shown in Table 2. In all cases analysed for sulfinate
salts (2), excellent reactivity and selectivity was observed. Both
the electron-withdrawing and electron-donating substituents
on the aromatic ring of the sulfinate salts react smoothly with
1a, affording the corresponding ,-disubstituted allylic
products in high yields (3aa-3ap). Sodium sulfinates with bulky
naphthyl (3aq), quinoline (3ar), 2,3-dihydrobenzofuran (3as),
and heteroaryl (3at, 3au) moieties were also tolerated in the
current optimized conditions. Likewise, the targeted tertiary
allylic sulfone formation could be extended to sulfinate salts
with alkyl substituents. Both primary and secondary alkyl
substituted sodium sulfinates worked well to provide ,-
disubstituted allylic sulfones in high yields (72-82%).
Furthermore, a more functionalized sodium sulfinate 2z, when
used as the sulfonylation partner, the branched product 3az
was obtained in 72% of isolated yield. The reaction leading to
tertiary allylic sulfone 3aa was easily scaled up to gram-scale
without significance erosion in yield. Of particular note, almost
in all cases, the reactions proceeded with excellent branched
regioselectivity (﹥99:1).
Table 3. Allylic carbonate substrate scopea-c
Mo(CO)6 (10 mol%)
L1 (15 mol%)
O
Me
OBoc
O
S
Me
EtOH, 60 oC, 24 h
Me
R
SO2Ph
R
R
PhSO2Na (2a)
1
3
trace/no
O
O
O
S
O
S
O
O
Me
Me
O
S
O
S
O
O
Me
Me
Me
Me
3ba, 87% yield
3ca, 24% yield
3da, 91% yield
3ea, 96% yield
O
O
O
O
O
S
O
S
Me
O
S
Me
Me
O
S
Me
Me
Me
Me
Cl
Me
Me
3fa, 85% yield
3ga, 92% yield
3ha, 86% yield
3ia, 82% yield
O
O
S
O
O
O
Me
O
S
O
S
O
S
Me
Me
Me
OBn
OBz
SMe
3la, 88% yield
MeO
OMe
3ja, 92% yield
3ka, 94% yield
3ma, 86% yield
We then focused on investigating the scope of the ,-
disubstituted allylic carbonates and the results obtained were
compiled in Table 3. Tertiary allylic carbonate with simple
propyl substituent (1b) reacted efficiently with sodium
benzenesulfinate (2a) to deliver the branched allylic sulfone
3ba in high yield (87%). However, allylic carbonate with
cyclohexyl moiety afforded the desired branched product in
comparatively low yield (24%, 3ca) due to the steric hindrance
problem. While, with tertiary allylic carbonate (1d) having
longer alkyl chain provided the desired product even at high
yield (91%, 3da). Tertiary allylic carbonates 1e, 1f, 1g and 1h
with different groups in the alkyl chain were coupled with
sulfinate salt 2a, high yields of the branched allylic products
were obtained (8596%, 3ea, 3fa, 3ga and 3ha). Notably,
various common functional groups such as Cl (1i), benzyl (1j),
O
O
S
O
N
Me
O
Me
N
O
S
N
O
O
Me
O
S
O
S
N
O
Me
Me
OH
R
Me
3na: R = OBoc, 87% yield
3oa: R = OH, 78% yield
3pa, 78% yield
3qa, 92% yield
3ra, 15% yield
from Pentoxifylline
a Reaction conditions: Mo(CO)6 (10 mol%), L1 (15 mol%), 1 (0.2 mmol), PhSO2Na 2a (0.3
mmol), EtOH (1.0 mL, 0.2 M), 60 ℃, 24 hours. b Regioselectivity was determined by 1H-
NMR of the crude reaction mixture. c Isolated yields of the products.
In order to illustrate the synthetic utility of these elusive
tertiary allylic sulfones, we focused on the reaction of ,-
disubstituted allylic carbonate (1h), and sodium sulfinate 2az,
to achieve the formal synthesis of (±)-agelasidine A.18 The
desired tertiary allylic sulfone 3haz was isolated in 84% yield
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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under the standard conditions (Figure 1a). This compound [Mo0Ln] species (Scheme 2). While [Mo(bpy)(CO)4] complex23
View Article Online
DOI: 10.1039/D0SC01763A
(3haz) can be readily converted to ()-agelasidine A by was prepared on large scale by reacting Mo(CO)6 and 2,2’-
16
following the literature procedure.13f We further demonstrate bipyridine (L1) in THF at 60
℃
.
As show in Scheme 2, the
that the current methodology can be utilize to prepare other structure was conformed and further analyzed.24 Interestingly,
related compounds containing sulfone-bearing quaternary [Mo(bpy)(CO)4] complex was found to be catalytically more
carbon center.19
efficient when used under the standard condition, supported
by the formation of branched allylic sulfone product 3aa in
96% yield. A small decline in yield of 3aa under [Mo(CO)6]/L1
catalyst system, thus providing evidence and implicit that a
[Mo(bpy)(CO)4] complex is likely the active precatalyst species
in this allylic sulfonylation reaction.
a) Formal synthesis of (±)-agelasidine A
O
Me
O
O
O
S
Me
Me
OBoc
Me
Me
a
ref. 13f
(±)-Agelasidine A
Me
Me
Me
Me
SO2Na
AcO
1h
3haz
84% yield
2az
OBoc
Mo(bpy)(CO)4 (10 mol%)
Table 1, entry 1
Me
b) Formal synthesis of (±)-sporochnol and (±)-bakuchiol
Ph
EtOH, 60 oC, 24 h
OMe
1a
PhSO2Na (2a)
OMe
Me
SO2Ph
Me
Me
CO
Me
Me
b
b
Me
N
N
Me
Me
Me
CO
Mo
3a
3b
4ga
4gb
3ga
O
CO
O
62% yield
58% yield
CO
O
S
O
S
B(OH)2
Me
Me
Ph
Ph
MeO
B(OH)2
MeO
ref. 20
ref. 21
3aa
92% yield
3aa
96% yield
Mo(bpy)(CO)4
3a
3b
OMe
OH
OH
MeO
iPr
P(Cy)2
iPr
Fig. 3 Mechanistic experiments.
Me
Me
Me
Me
iPr
Me
Me
BrettPhos
L8
(±)-Sporochnol
(±)-Bakuchiol
Conclusions
Fig. 2 Importance of current research towards the synthesis of agelasidine A,
sporochnol, and bakuchiol. Reaction conditions: (a) Mo(CO)6 (10 mol%), L1 (15
mol%), 1h (0.2 mmol), 2az (0.3 mmol), EtOH (1.0 mL, 0.2 M), 60 ℃, 24 hours. (b)
Ni(cod)2 (10 mol%) ligand L8 (12 mol%), 3ga (0.2 mmol), 3a or 3b (0.7 equiv),
NaOEt (2.2 equiv), PhMe (0.2 M), 24h, 80 ℃.
In conclusions we have developed a method for the allylic
sulfonylation of ,-disubstituted allylic electrophiles, using
commercially available catalyst components (Mo(CO)6/2,2ˊ-
bipyridine). To the best of our knowledge, the presented
methodology is the first example of the use of sodium
sulfinates as the heteroatom nucleophile reagents with
tertiary allylic electrophiles to employ the group 6 catalyst in
allylic substitution of tertiary allylic electrophiles to form C-S
bonds. The process is characterized by its atom economic
procedure, wide substrate scope, and excellent regioselectivity
profile even at late stages, thus providing ample opportunities
for further derivatization through traditional Suzuki cross-
coupling reactions (as presented in Fig. 2b). Investigations of
enantioselective reactions, mechanism and extension to other
heteroatom nucleophiles are currently ongoing and will be
reported in due course.
Due to their ambiphilic nature, allylic sulfones are synthetically
important electrophiles and recently been utilized in Suzuki
cross-coupling10a as well as allylic substitution reactions.11d
However, selective cross-coupling of tertiary allylic sulfones
remain highly challenging in Suzuki-Miyaura cross-coupling
reactions.10 Indeed, we employed our tertiary allylic sulfone
product 3ga along with typical boronic acids as a coupling
partner, in order to achieved the formal synthesis of (±)-
sporochnol,20 and (±)-bakuchiol,21 both of which are natural
products possesses a quaternary all-carbon center. Our
synthesis is illustrated in Figure 1b. The key step involves a
previously reported Suzuki-Miyaura cross-coupling reaction of
tertiary allylic sulfone 3ga to afford 4ga, and 4gb efficiently
with 62% and 58% of isolated yields respectively. Subsequent
deprotection of phenol then could complete the formal
synthesis of (±)-sporochnol and (±)-bakuchiol (Figure 1b).20,21
Starting from 3ga in 2 total steps indicating that our tertiary
allylic sulfones can be used to prepare such natural products
and other related compounds bearing all-carbon quaternary
centers in a modular way.22
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the “Fundamental Research Funds for
Central Universities" (No. 1191329135), Key Laboratory
Construction Program of Xi’an Municipal Bureau of Science and
Technology (No. 201805056ZD7CG40) and the starting fund of Xi’an
Jiao Tong University (No. 7121182002). We thank the Instrumental
Analysis Center of Xi’an Jiao Tong University for HRMS analysis.
To gain mechanistic insight and the initial understanding on
how the reaction works, we decided to study the reactivity of
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Roggen and E. M. Carreira, Angew. Chem. Int. Ed., 2012, 51,
Notes and references
View Article Online
3470; (n) M. Roggen and E. M. CarreiDraO,I:A10n.g10e3w9./DC0hSeCm01.76In3tA.
Ed., 2012, 51, 8652; (o) S. L. Rössler, D. A. Petrone and E. M.
Carreira. Acc. Chem. Res., 2019, 52, 2657, and references
therein.
1
(a) J. Tsuji, H. Takahashi and M. Morikawa, Tetrahedron Let.,
1965, 6, 4387; (b) B. M. Trost and T. J. Fullerton, J. Am.
Chem. Soc., 1973, 95, 292.
7
The range of nucleophiles that has been used in
molybdenum-catalysed allylic alkylations are limited to
stabilized carbon nucleophiles, and is thus narrower than in
the palladium- and iridium-catalysed reactions. However, to
our knowledge there is no report available in literature on
the use of heteroatom nucleophiles that provide access to
tertiary and or secondary allylic products in Mo-catalysed
allylic substitution reactions
For the application of sulfones in drugs and bioactive
compounds, see: (a) H. Liu and X. Jiang, Chem. Asian J., 2013,
8, 2546; (b) M. Feng, B. Tang, S. H. Liang and X. Jiang, Curr.
Top. Med. Chem., 2016, 16, 1200; (c) K. A. Scott and J. T.
Njardarson, Top. Curr. Chem., 2018, 376, 5; (d) N. Wang, P.
Saidhareddy and X. Jiang, Nat. Prod. Rep., 2019,
(10.1039/c8np00093j).
For the application of sulfones in organic synthesis, see: (a)
P. L. Fuchs and T. F. Braish, Chem. Rev., 1986, 86, 903; (b) B.
M. Trost, M. G. Organ and G. A. O’Doherty, J. Am. Chem.
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1988, 61, 107; (d) T. Zhou, B. Peters, M. F. Maldonado, T.
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Singh, W. Rabten, S. Kerdphon and P. W. Andersson, J. Am.
Chem. Soc., 2014, 136, 16557.
2
For selected reviews on the applications of allylic
substitutions, see: (a) B. M. Trost and D. L. Van Vranken,
Chem. Rev., 1996, 96, 395; (b) B. M. Trost and M. L. Crawley,
Chem. Rev., 2003, 103, 2921; (c) Z. Lu and S.-M. Ma, Angew.
Chem. Int. Ed., 2008, 47, 258; (d) J. D. Weaver, A. Recio, A. J.
Grenning and J. A. Tunge, Chem. Rev., 2011, 111, 1846; (e) L.
Milhau and P. J. Guiry, Top. Organomet. Chem., 2011, 38, 95;
(f) B. Sundararaju, M. Achard and C. Bruneau, Chem. Soc.
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Qu, G. Helmchen and S.-L. You, Chem. Rev., 2019, 119, 1855.
For selected reviews on heteroatom nucleophiles, see: (a) M.
Johannsen and K. A. Jørgensen, Chem. Rev., 1998, 98, 1689;
(b) B. M. Trost, T. Zhang and J. D. Sieber, Chem. Sci., 2010, 1,
427; (c) L. Huang, M. Arndt, K. Gooßen, H. Heydt and L. J.
Gooßen, Chem. Rev., 2015, 115, 2596-2697; (d) R. L. Grange,
E. A. Clizbe and P. A. Evans, Synthesis, 2016, 48, 2911; (e) R.
Takeuchi and S. Kezuka, Synthesis, 2006, 20, 3349; (e) J. F.
Hartwig and L. M. Stanley, Acc. Chem. Res., 2010, 43, 1461.
For selected reviews on Mo-catalysed allylic alkylation
reactions, see: (a) O. Belda and C. Moberg, Acc. Chem.
Res., 2004, 37, 159; (b) C. Moberg, Top. Organomet. Chem.,
2011, 38, 209; (c) B. M. Trost, Org. Process Res.
8
9
3
4
Dev., 2012, 16, 185;
(d)
C.
Moberg,
Organic
Reactions, 2014, 84, 1. For original examples, see: (e) B. M.
Trost and I. Hachiya, J. Am. Chem. Soc., 1998, 120, 1104; (f)
A. V. Malkov, L. Gouriou, G. C. Lloyd-Jones, I. Stary, V.
Langer, P. Spoor, V. Vinader and P. Kocovsky, Chem. - Eur. J.,
2006, 12, 6910; (g) B. M. Trost and K. Dogra, J. Am. Chem.
Soc., 2002, 124, 7256; (h) S. W. Krska, D. L. Hughes, R. A.
Reamer, D. J. Mathre and Y. Sun, J. Am. Chem. Soc., 2002,
124, 12656; (i) B. M. Trost and Y. Zhang, J. Am. Chem. Soc.,
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J., 2010, 16, 296; (k) B. M. Trost and Y. Zhang, Chem. - Eur. J.,
2011, 17, 2916; (l) B. M. Trost, J. R. Miller and C. M. Hoffman,
J. Am. Chem. Soc., 2011, 133, 8165; (m) E. Ozkal and M. A.
Pericas, Adv. Synth. Catal., 2014, 356, 711; (n) B. M. Trost, M.
Osipov, S. Kruger and Y. Zhang, Chem. Sci., 2015, 6, 349.
An attempted example of Mo-catalyzed allylic alkylation
10 (a) Z. T. Arika, Y. Maekawa, M. Nambo and C. M. Crudden, J.
Am. Chem. Soc., 2018, 140, 78; (b) M. Nambo and C. M.
Crudden, Angew. Chem. Int. Ed., 2014, 53, 742; (c) M.
Nambo and C. M. Crudden, ACS Catal., 2015, 5, 4734; (d) M.
Nambo, Z. T. Ariki, D. Canseco-Gonzalez, D. D. Beattie and C.
M. Crudden, Org. Lett., 2016, 18, 2339; (e) M. Nambo, E. C.
Keske, J. P. G. Rygus, J. C.-H. Yim and C. M. Crudden, ACS
Catal., 2017, 7, 1108; (f) J. C.-H. Yim, M. Nambo and C. M.
Crudden, Org. Lett., 2017, 19, 3715.
11 (a) B. M. Trost, Bull. Chem. Soc. Jpn., 1988, 61, 107; (b) B. M.
Trost and C. A. Merlic, J. Org. Chem., 1990, 55, 1127; (c) B.
M. Trost, N. R. Schmuff and M. J. Miller, J. Am. Chem. Soc.,
1980, 102, 5979; (d) K. Takizawa, T. Sekino, S. Sato, T.
Yoshino, M. Kojima and S. Matsunaga, Angew. Chem. Int.
Ed., 2019, 58, 9199.
12 For the synthesis of allylic sulfones via transition metal-
catalysed allylic substitution, see: (a) K. Hiroi and K. Makino,
Chem. Lett., 1986, 15, 617; (b) H. Eichelmann and H.-J. Gais,
Tetrahedron: Asymmetry, 1995, 6, 643; (c) B. M. Trost, M. J.
Krische, R. Radinov and G. J. Zanoni, J. Am. Chem. Soc., 1996,
118, 6297; (d) B. M. Trost, M. L. Crawley and C. B. Lee, J. Am.
Chem. Soc., 2000, 122, 6120; (e) Y. Uozumi and T. Suzuka,
Synthesis, 2008, 12, 1960; (f) M. Jegelka and B. Plietker, Org.
Lett., 2009, 11, 3462; (g) J. A. Wolfe and S. R. Hitchcock,
Tetrahedron: Asymmetry, 2010, 21, 2690; (h) M. Ueda, J. F.
Hartwig, Org. Lett., 2010, 12, 92; (i) X.-S. Wu, Y. Chen, M.-B.
Li, M.-G. Zhou and S.-K. Tian, J. Am. Chem. Soc., 2012, 134,
14694; (j) T.-T. Wang, F.-X. Wang, F.-L. Yang and S.-K. Tian,
Chem. Commun., 2014, 50, 3802; (k) X.-T. Ma, R.-K. Dai, J.
Zhang, Y. Gu and S.-K. Tian, Adv. Synth. Catal., 2014, 356,
2984; (l) A. Najib, K. Hirano and M. Miura, Chem. Eur. J.,
2018, 24, 6525.
13 For selected examples on hydrothiolation of allenes, see: (a)
A. B. Pritzius and B. Breit, Angew. Chem. Int. Ed., 2015, 54,
3121; (b) A. B. Pritzius and B. Breit, Angew. Chem. Int. Ed.,
2015, 54, 15818. For the direct hydrosulfination of allene
and alkyne, see: (c) K. Xu, V. Khakyzadeh, T. Bury and B.
Breit, J. Am. Chem. Soc., 2014, 136, 16124; (d) V.
Khakyzadeh, Y.-H. Wang and B. Breit, Chem. Commun., 2017,
5
6
reaction utilizing
a tertiary allylic substrate has been
mentioned with unclear results (sluggish reactivity), see: (a)
P. Kočovský, A. V. Malkov, S. Vyskočil and G. C. Lloyd-Jones,
Pure Appl. Chem., 1999, 71, 1425.
For selective examples on the synthesis of quaternary, and
or tertiary allylic compounds with heteroatom nucleophiles,
see: (a) B. M. Trost, R. C. Bunt, R. C. Lemoine and T. L.
Calkins, J. Am. Chem. Soc., 2000, 122, 5968; (b) D. F. Fisher,
Z.-Q. Xin and R. Peters, Angew. Chem., Int. Ed., 2007, 46,
7704; (c) J. S. Arnold and H. M. Nguye, J. Am. Chem. Soc.,
2012, 134, 8380; (d) B. W. H. Turnbull and P. A. Evans, J. Org.
Chem., 2018, 83, 11463; (e) W. Guo, A. Cai, J. Xie and A. W.
Kleij, Angew. Chem. Int. Ed., 2017, 56, 11797; (f) J. Cai, W.
Guo, L. Martínez-Rodríguez and A. W. Kleij, J. Am. Chem.
Soc., 2016, 138, 14194; (g) J. Xie, W. Guo, A. Cai, E. C.
Escudero-Adán and A. W. Kleij, Org. Lett., 2017, 19, 6388; (h)
S. Mizuno, S. Terasaki, T. Shinozawa and M. Kawatsura, Org.
Lett., 2017, 19, 504; (i) J. Long, L. Shi, X. Li, H. Lv and X.
Zhang, Angew. Chem. Int. Ed., 2018, 57, 13248; (j) J. E.
Gómez, A. Cristòfol and A. W. Kleij, Angew. Chem. Int. Ed.,
2019, 58, 3903; (k) S. Ghorai, S. S. Chirke, W.-B. Xu, J.-F. Chen
and C. Li, J. Am. Chem. Soc., 2019, 141, 11430; (l) T.
Sandmeier, F. W. Goetzke, S. Krautwald and E. M. Carreira, J.
Am. Chem. Soc., 2019, 141, 12212; (m) M. Lafrance, M.
This journal is © The Royal Society of Chemistry 20xx
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53, 4966. For selected examples on hydrothiolation of olefins
Journal Name
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and dienes, see: (e) E. Mosaferi, D. Ripsman and D. W.
Stephan, Chem. Commun., 2016, 52, 8291; (f) X.-H. Yang, R.
T. Davison, S.-Z. Nie, F. A. Cruz, T. M. McGinnis and V. M.
Dong, J. Am. Chem. Soc., 2019, 141, 3006.
DOI: 10.1039/D0SC01763A
14 The synthesis of ,-disubstituted allylic sulfones through
transition metal catalyzed procedures are limited to the
recent two examples reported by we and others, see: (a) A.
Khan, M. Zhang and S. Khan, Angew. Chem. Int. Ed., 2020,
59, 1340; (b) A. Cai and A. W. Kleij, Angew. Chem. Int. Ed.,
2019, 58, 14944.
15 (a) A. Khan, S. Khan, I. Khan, C. Zhao, Y. Mao, Y. Chen and Y.
J. Zhang, J. Am. Chem. Soc., 2017, 139, 10733; (b) A. Khan, R.
Zheng, Y. Kan, J. Ye, J. Xing and Y. J. Zhang, Angew. Chem. Int.
Ed., 2014, 53, 6439; (c) A. Khan, L. Yang, J. Xu, L. Y. Jin and Y.
J. Zhang, Angew. Chem. Int. Ed., 2014, 53, 11257; (d) A.
Khan, J. Xing, J. Zhao, Y. Kan, W. Zhang and Y. J. Zhang, Chem.
Eur. J., 2015, 21, 120.
16 For details, see Supporting Information.
17 For reviews on the use of bipyridine type ligands, see; (a) C.
Kaes, A. Katz and M. W. Hosseini, Chem. Rev., 2000, 100,
3553; (b) G. Chelucci and R. P. Thummel, Chem. Rev., 2002,
102, 3129.
18 H. Nakamura, H. Wu, J. Kobayashi, Y. Ohizumi, Y. Hirata, T.
Higashijima and T. Miyazawa, Tetrahedron Lett., 1983, 24,
4105.
19 E. P. Stout, L. C. Yu and T. F. Molinski, Eur. J. Org. Chem.,
2012, 2012, 5131.
20 (a) S. Shan and C. Ha, Synthetic Communications, 2004, 34,
4005; (b) Y. Li, J. Han, H. Luo, Q. An, X.-P. Cao and B. Li, Org.
Lett., 2019, 21, 6050; (c) M. Kacprzynski and A. H. Hoveyda, J.
Am. Chem. Soc., 2004, 126, 10676; (d) R. P. Sonawane, V.
Jheengut, C. Rabalakos, R. Larouche-Gauthier, H. K. Scott and
V. K. Aggarwal, Angew. Chem. Int. Ed., 2011, 50, 3760.
21 (a) R. Majeed, M. V. Reddy, P. K. Chinthakindi, P. L. Sangwan,
A. Hamid, G. Chashoo, A. K. Saxena and S. Koul, Eur. J. Med.
Chem., 2012, 49, 55; (b) Y. Xiong and G. Zhang, Org. Lett.,
2016, 18, 5094; (c) F. Gao, K. P. McGrath, Y. Lee and A. H.
Hoveyda, J. Am. Chem. Soc., 2010, 132, 14315; (d) S.
Chakrabarty and J. M. Takacs, J. Am. Chem. Soc., 2017, 139,
6066.
22 N. F. Fine Nathel, T. K. Shah, S. M. Bronner and N. K. Garg,
Chem. Sci., 2014, 5, 2184.
23 (a) K. R. Birdwhistell, B. E. Schulz and P. M. Dizon, Inorg.
Chem. Commun., 2012, 26, 69; (b) G. Neri, P. M. Donaldson
and A. J. Cowan, J. Am. Chem. Soc., 2017, 139, 13791.
24 Despite considerable efforts, we were unable to prepare a
single crystal of Mo(bpy)(CO)4. At present, we have
conformed the structure from NMR-analysis. All the
spectroscopic data for this compound matches with that
reported in the literature. See Ref. 16 and 23 for more
details.
25 For mechanistic hypothesis, see: (a) B. M. Trost and M.
Lautens, J. Am. Chem. Soc., 1982, 104, 5543; (b) B. M. Trost
and M. H. Hung, J. Am. Chem. Soc., 1983, 105, 7757; (c) D. E.
Ryan, D. J. Cardin and F. Hartl, Coord. Chem. Rev., 2017, 335,
103.
6 | J. Name., 2012, 00, 1-3
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Chemical Science
View Article Online
DOI: 10.1039/D0SC01763A
ARTICLE
Regioselective molybdenum-catalyzed allylic substitution of
tertiary allylic electrophiles: methodology development and
applications
Received 00th January 20xx,
Accepted 00th January 20xx
Muhammad Salman,† Yaoyao Xu,† Shahid Khan, Junjie Zhang and Ajmal Khan*
DOI: 10.1039/x0xx00000x
The first molybdenum-catalysed allylic sulfonylation of tertiary allylic electrophiles is described. The method utilizes a
readily accesable catalyst (Mo(CO)6/2,2′-bipyridine, both are commercially available) and represent the first example of
the use of a group 6 transition metal-catalyst to substituted tertiary allylic electrophiles to form carbon-sulfur bonds. This
atom economic and operationally simple methodology is charaterized by its relatively mild conditions, wide substrate
scope, and excellent regioselectivity profile, thus unlocking a new platform to synthesize allylic sulfones, even at late
stages and providing ample oppertunaties for further derivatization through traditional Suzuki cross-coupling reactions.
A) Limitations in Molybdenum-Catalyzed Allylic Substitution
[LnMo]
[LnMo]
Introduction
R2
R
Nu
The concept of -allyl metal-complex was first formulated by Tsuji
in 19651a and, later, properly adopted by Trost in 1973.1b Since
then, this technology has enabled organic chemists to create novel
procedures for the synthesis of simple to complex molecules.2
Among these is the development and utilization of heteroatom
nucleophile reagents, such as oxygen, nitrogen, and or sulfur-based
nucleophiles.2,3 Despite the massive development that has been
made in this area, there still remain untapped opportunities in the
potential application of these heteroatom nucleophile reagents in
transition metal-catalysed allylic substitution. For example,
molybdenum-catalysed allylic substitution reactions of heteroatom
nucleophiles are unknown and largely limited only to the carbon-
carbon bond formation procedures (Figure 1A, left).4 Furthermore,
the substrate scope with respect to the allylic electrophile has also
been unchanged and restricted to the ones that provide products
containing a tertiary center at the allylic position.5 Regardless of the
longstanding interest in the formation of carbon-heteroatom bond
with in the synthetic organic community, as well as the
advancement of other transition-metal-catalysed reactions to
provide heteroatom bearing quaternary and or tertiary allylic
centers,6 molybdenum-catalysed allylic substitution reactions that
R1
Nu
Nu
R2
R1
R
Nu = carbon
all reports
Nu = carbon or
heteroatoms
zero reports
B) This Research
O
R3
OBoc
[LnMo]
R2
Mo/Ln
O
S
R3SO2Na
+
R2
R2
R1
R1
R1
R2 = methyl
R1 = alkyl, aryl, carbocyclic
R3 = alkyl, aryl, heteroaryl, carbocyclic
Tertiary Allylic Sulfone
C) Applications of the Current Research
OH
HN
NH2
OH
NH
O
Me
Me
O
S
Me
Me
Me
Me
Me
Me
Me
Me
(±)-sporochnol
(±)-bakuchiol
(±)-agelasidine A
Fig. 1 (A) Limitations in molybdenum-catalysed allylic substitution, (B) our
research, and (C) applications of the current research.
provide products containing such
prominently absent from the literature and yet to be discovered
(Figure 1A, right).7
a
stereocenter remain
Due the high importance of allylic sulfones as pharmaceuticals8 and
synthetic candidates,9 organic chemists have recently been tested
to design catalytic C-S bond cleavage procedures as a new tool for
carbon-carbon bond formation through Suzuki cross-coupling10 and
or allylic substitution reactions.11 Despite the considerable
development realized in this zone, allylic sulfone formation is still a
challenging task and confined to the use of transition metal-
catalysed allylic sulfonylation procedures.12,13 However, using these
procedures for the synthesis of allylic sulfone containing
tetrasubstituted carbon centers are scarce and largely
unexplored.14 Therefore, at the beginning of our study it was
Department of Applied Chemistry, School of Science, and Xi’an Key Laboratory of
Sustainable Energy Materials Chemistry, Xi’an Jiao Tong University, Xi’an 710049,
P. R. China. ajmalkhan@xjtu.edu.cn
† These authors contributed equally.
Electronic Supplementary Information (ESI) available: For detailed experimental
procedures, characterization data of all of the new compounds, copies of 1H, 13C
NMR spectra of the substrates and products see DOI: 10.1039/x0xx00000x
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unclear whether a molybdenum-catalysed allylic substitution could
ever be implemented with heteroatom (sodium sulfinate)
nucleophile or even with ,-disubstituted allylic precursors. If
successful, such unexplored area of allylic substitution chemistry
might not only provide opportunity to realize currently inaccessible
chemical space (carbon-heteroatom bond formation) in
molybdenum-catalysed allylic substitution, but also provide a new
synthetic approach for rapidly generate quaternary all-carbon
centers through Suzuki cross-coupling of the sulfone functionality.
As part of our ongoing program in developing molybdenum-
catalysed allylic substitution technology and our continued interest
in the catalytic asymmetric synthesis of quaternary
stereocenters,14a, 15 we were attracted to this unmet challenge and
report herein the successful implementation of this idea (Figure
1B). The salient features of this methodology are the atom-
economic procedures, high regioselectivity, and excellent functional
group tolerance for both sulfinate salt and tertiary allylic
carbonates, even at late-stages. Furthermore, the high reactivity of
tertiary allylic sulfones as a new class of electrophiles to yield
structurally diverse products containing quaternary all-carbon
centers through Suzuki cross-coupling are the special characteristic
of this catalytic system (Figure 1C).10a
Results and discussion
View Article Online
DOI: 10.1039/D0SC01763A
Our optimization began by evaluating the allylic substitution of
tertiary allylic carbonate 1a, readily prepared from the
corresponding alcohol on
a
large scale, with sodium
benzenesulfinate 2a (Table 1). Interestingly, a disappointing amount
of either 3aa or 4aa were detected under reaction conditions
previously reported for other molybdenum-catalysed allylic
substitution events.4 After several experimentation,16 we concluded
that a combination of inexpensive commercially available Mo(CO)6
precursor and 2,2’-bipyridyne as a ligand (L1)17 in EtOH at 60 ℃
afforded 3aa in 92% yield upon isolation with excellent branched to
linear selectivity (3aa/4aa = ﹥ 99:1). Amongst all of the ligands
utilized, 2,2′-bipyridine motifs were crucial for achieving the
targeted transformation. While excellent reactivity towards 3aa was
found with 2,2′-bipyridines and 6,6′-dimethyl-2,2′-bipyridine, better
yields were obtained for the first one (entries 1–7). Interestingly,
the bench-stable terpyridine L7 failed to provide product 3aa. These
results indicate that the coordination geometry of the ligand
dictates the reactivity, with 2,2′-bipyridine ligands being particularly
suited for the high yield and selectivity of 3aa. Subtle changes on
the molybdenum precursor, and or solvent, however, had a
negative influence on the reaction to occur, consistently providing
lower yields if any (entries 8-14). As expected, control experiments
revealed that all of the reaction parameters were necessary for
forging the sulfone moiety (entry 15).
Table 1. Optimization of the reaction parametersa
Mo(CO)6 (10 mol%)
L1 (15 mol%)
O
OBoc
Me
Me
O
S
Ph
EtOH, 60 oC, 24 h
Ph
SO2Ph
Me
PhSO2Na (2a)
Ph
1a
4aa
3aa
Table 2. Sodium sulfinate substrate scopea-c
R2
R2
R1 = H, R2 = H, L1
O
Mo(CO)6 (10 mol%)
L1 (15 mol%)
R1 = Me, R2 = H, L2
R1 = CO2H, R2 = H, L3
R2 = CO2Me, R1 = H, L4
N
R
OBoc
Me
O
S
N
N
N
N
Me
N
N
Me
N
N
Ph
EtOH, 60 oC, 24 h
Ph
SO2R
Ph
R1
R1
L5
L6
L7
RSO2Na (2)
1a
3
trace/no
Entry
1
Deviation in conditions
none
3aa/4aab 3aa (%)c
Entry
2
3b
yield (%)c
92
99:1
99:1
99:1
99:1
25:1
--
92
87
35
52
16
0
1
2a (R = Ph)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
2
L2 was used instead of L1
L3 was used instead of L1
L4 was used instead of L1
L5 was used instead of L1
L6 was used instead of L1
L7 was used instead of L1
(C7H8)3Mo(CO)3 was used
THF was used as solvent
2
2b (R = 4-MeC6H4)
2c (R = 4-MeOC6H4)
2d (R = 4-ClC6H4)
93
3
3
90
4
4
87
5
5
2e (R = 4-FC6H4)
85
6
6
2f (R = 4-NO2C6H4)
2g (R = 4-CNC6H4)
2h (R = 2-FC6H4)
75
7
--
>5
82
>5
>5
35
77
25
63
0
7
72
8
99:1
--
8
88
9
9
2i (R = 2-ClC6H4)
87
10
11
12
13
14
Toluene was used as solvent
DCE was used as solvent
iPrOH was used as solvent
THF/EtOH (5:1) as solvent
DCE/EtOH (5:1) as solvent
Without Mo or L1
-
10
11
12
13
14
15
16
17
2j (R = 2-OCF3C6H4)
2k (R = 3-BrC6H4)
2l (R = 3-CNC6H4)
2m (R = 2,4-MeOC6H3)
2n (R = 3,5-CF3C6H3)
2o (R = 2-MeO,5-BrC6H3)
2p (R = 3,4-ClC6H3)
2q (R = 2-naphthyl)
3aj
72
25:1
99:1
25:1
25:1
--
3ak
3al
82
78
3am
3an
3ao
3ap
3aq
94
95
15
84
a
Reaction conditions: Mo-catalyst (10 mol%), ligand (15 mol%), 1a (0.2 mmol),
PhSO2Na 2a (0.3 mmol), solvent (1.0 mL, 0.2 M), 60 ℃, 24 hours. Determined by 1H-
NMR of the crude reaction mixture. c Isolated yields.
b
87
82
2 | J. Name., 2012, 00, 1-3
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benzoyl (1k), thioether (1l), acetal (1m), and carbonate (1n) on
the alkyl chain of the tertiary allylic carbonates were tolerated,
18
19
20
21
22
23
24
25
2r (R = 1-quinoline)
3ar
78
92
82
86
72
78
82
78
72
View Article Online
DOI: 10.1039/D0SC01763A
2s (R = 2,3-dihydrobenzofuran) 3as
and the sulfonylation branched products (3ia3na) were
isolated in high yields (8294%). In addition, unprotected
hydroxy group on the alkyl chain of the tertiary allylic
carbonates 1o, and 1p do not interfere with productive
tertiary allylic sulfones formation (3oa and 3pa), thus providing
opportunities for further derivatization. Notably, the reaction
can be easily applied within the context of late-stages,
supported by the formation of branched allylic sulfone 3qa,
derived from Pentoxyfylline. As expected, the allylic
sulfonylation of phenyl substituted allylic carbonate occurred
exclusively at the less-hindered position. The present
optimized conditions were unsatisfactory with such substrate,
provided the desired branched product (3ra) with low
branched to linear ratio (b/l = 1:5); indicating some (steric)
limitation of the current protocol. Besides methyl-substituted
tertiary allylic substrates 1a-1r, other alkyl or aryl substituted
substrates return only starting materials when used under the
optimized conditions, indicating some limitation of the present
protocol.
2t (R = 3-pyridine)
2u (R = 2-thiopene)
2v (R = Me)
3at
3au
3av
3az
3ax
3ay
3az
2w (R = Et)
2x (R = iPr)
2y (R = cyclopropyl)
2z (R = CH3OCOCH2CH2)
26
a
Reaction conditions: Mo(CO)6 (10 mol%), L1 (15 mol%), 1a (0.2 mmol), RSO2Na 2 (0.3
mmol), EtOH (1.0 mL, 0.2 M), 60 ℃, 24 hours. Determined by 1H-NMR of the crude
reaction mixture. c Isolated yields.
b
With reliable access to 3aa, we next turned our attention to
examine the generality of our newly developed molybdenum-
catalysed regioselective sulfonylation of tertiary allylic
electrophiles with sodium sulfinate by using Mo/L1 catalyst
system as shown in Table 2. In all cases analysed for sulfinate
salts (2), excellent reactivity and selectivity was observed. Both
the electron-withdrawing and electron-donating substituents
on the aromatic ring of the sulfinate salts react smoothly with
1a, affording the corresponding ,-disubstituted allylic
products in high yields (3aa-3ap). Sodium sulfinates with bulky
naphthyl (3aq), quinoline (3ar), 2,3-dihydrobenzofuran (3as),
and heteroaryl (3at, 3au) moieties were also tolerated in the
current optimized conditions. Likewise, the targeted tertiary
allylic sulfone formation could be extended to sulfinate salts
with alkyl substituents. Both primary and secondary alkyl
substituted sodium sulfinates worked well to provide ,-
disubstituted allylic sulfones in high yields (72-82%).
Furthermore, a more functionalized sodium sulfinate 2z, when
used as the sulfonylation partner, the branched product 3az
was obtained in 72% of isolated yield. The reaction leading to
tertiary allylic sulfone 3aa was easily scaled up to gram-scale
without significance erosion in yield. Of particular note, almost
in all cases, the reactions proceeded with excellent branched
regioselectivity (﹥99:1).
Table 3. Allylic carbonate substrate scopea-c
Mo(CO)6 (10 mol%)
L1 (15 mol%)
O
Me
OBoc
O
S
Me
EtOH, 60 oC, 24 h
Me
R
SO2Ph
R
R
PhSO2Na (2a)
1
3
trace/no
O
O
O
S
O
S
O
O
Me
Me
O
S
O
S
O
O
Me
Me
Me
Me
3ba, 87% yield
3ca, 24% yield
3da, 91% yield
3ea, 96% yield
O
O
O
O
O
S
O
S
Me
O
S
Me
Me
O
S
Me
Me
Me
Me
Cl
Me
Me
3fa, 85% yield
3ga, 92% yield
3ha, 86% yield
3ia, 82% yield
O
O
S
O
O
O
Me
O
S
O
S
O
S
Me
Me
Me
OBn
OBz
SMe
3la, 88% yield
MeO
OMe
3ja, 92% yield
3ka, 94% yield
3ma, 86% yield
We then focused on investigating the scope of the ,-
disubstituted allylic carbonates and the results obtained were
compiled in Table 3. Tertiary allylic carbonate with simple
propyl substituent (1b) reacted efficiently with sodium
benzenesulfinate (2a) to deliver the branched allylic sulfone
3ba in high yield (87%). However, allylic carbonate with
cyclohexyl moiety afforded the desired branched product in
comparatively low yield (24%, 3ca) due to the steric hindrance
problem. While, with tertiary allylic carbonate (1d) having
longer alkyl chain provided the desired product even at high
yield (91%, 3da). Tertiary allylic carbonates 1e, 1f, 1g and 1h
with different groups in the alkyl chain were coupled with
sulfinate salt 2a, high yields of the branched allylic products
were obtained (8596%, 3ea, 3fa, 3ga and 3ha). Notably,
various common functional groups such as Cl (1i), benzyl (1j),
O
O
S
O
N
Me
O
Me
N
O
S
N
O
O
Me
O
S
O
S
N
O
Me
Me
OH
R
Me
3na: R = OBoc, 87% yield
3oa: R = OH, 78% yield
3pa, 78% yield
3qa, 92% yield
3ra, 15% yield
from Pentoxifylline
a Reaction conditions: Mo(CO)6 (10 mol%), L1 (15 mol%), 1 (0.2 mmol), PhSO2Na 2a (0.3
mmol), EtOH (1.0 mL, 0.2 M), 60 ℃, 24 hours. b Regioselectivity was determined by 1H-
NMR of the crude reaction mixture. c Isolated yields of the products.
In order to illustrate the synthetic utility of these elusive
tertiary allylic sulfones, we focused on the reaction of ,-
disubstituted allylic carbonate (1h), and sodium sulfinate 2az,
to achieve the formal synthesis of (±)-agelasidine A.18 The
desired tertiary allylic sulfone 3haz was isolated in 84% yield
This journal is © The Royal Society of Chemistry 20xx
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under the standard conditions (Figure 1a). This compound [Mo0Ln] species (Scheme 2). While [Mo(bpy)(CO)4] complex23
View Article Online
DOI: 10.1039/D0SC01763A
(3haz) can be readily converted to ()-agelasidine A by was prepared on large scale by reacting Mo(CO)6 and 2,2’-
16
following the literature procedure.13f We further demonstrate bipyridine (L1) in THF at 60
℃
.
As show in Scheme 2, the
that the current methodology can be utilize to prepare other structure was conformed and further analyzed.24 Interestingly,
related compounds containing sulfone-bearing quaternary [Mo(bpy)(CO)4] complex was found to be catalytically more
carbon center.19
efficient when used under the standard condition, supported
by the formation of branched allylic sulfone product 3aa in
96% yield. A small decline in yield of 3aa under [Mo(CO)6]/L1
catalyst system, thus providing evidence and implicit that a
[Mo(bpy)(CO)4] complex is likely the active precatalyst species
in this allylic sulfonylation reaction.
a) Formal synthesis of (±)-agelasidine A
O
Me
O
O
O
S
Me
Me
OBoc
Me
Me
a
ref. 13f
(±)-Agelasidine A
Me
Me
Me
Me
SO2Na
AcO
1h
3haz
84% yield
2az
OBoc
Mo(bpy)(CO)4 (10 mol%)
Table 1, entry 1
Me
b) Formal synthesis of (±)-sporochnol and (±)-bakuchiol
Ph
EtOH, 60 oC, 24 h
OMe
1a
PhSO2Na (2a)
OMe
Me
SO2Ph
Me
Me
CO
Me
Me
b
b
Me
N
N
Me
Me
Me
CO
Mo
3a
3b
4ga
4gb
3ga
O
CO
O
62% yield
58% yield
CO
O
S
O
S
B(OH)2
Me
Me
Ph
Ph
MeO
B(OH)2
MeO
ref. 20
ref. 21
3aa
92% yield
3aa
96% yield
Mo(bpy)(CO)4
3a
3b
OMe
OH
OH
MeO
iPr
P(Cy)2
iPr
Fig. 3 Mechanistic experiments.
Me
Me
Me
Me
iPr
Me
Me
BrettPhos
L8
(±)-Sporochnol
(±)-Bakuchiol
Conclusions
Fig. 2 Importance of current research towards the synthesis of agelasidine A,
sporochnol, and bakuchiol. Reaction conditions: (a) Mo(CO)6 (10 mol%), L1 (15
mol%), 1h (0.2 mmol), 2az (0.3 mmol), EtOH (1.0 mL, 0.2 M), 60 ℃, 24 hours. (b)
Ni(cod)2 (10 mol%) ligand L8 (12 mol%), 3ga (0.2 mmol), 3a or 3b (0.7 equiv),
NaOEt (2.2 equiv), PhMe (0.2 M), 24h, 80 ℃.
In conclusions we have developed a method for the allylic
sulfonylation of ,-disubstituted allylic electrophiles, using
commercially available catalyst components (Mo(CO)6/2,2ˊ-
bipyridine). To the best of our knowledge, the presented
methodology is the first example of the use of sodium
sulfinates as the heteroatom nucleophile reagents with
tertiary allylic electrophiles to employ the group 6 catalyst in
allylic substitution of tertiary allylic electrophiles to form C-S
bonds. The process is characterized by its atom economic
procedure, wide substrate scope, and excellent regioselectivity
profile even at late stages, thus providing ample opportunities
for further derivatization through traditional Suzuki cross-
coupling reactions (as presented in Fig. 2b). Investigations of
enantioselective reactions, mechanism and extension to other
heteroatom nucleophiles are currently ongoing and will be
reported in due course.
Due to their ambiphilic nature, allylic sulfones are synthetically
important electrophiles and recently been utilized in Suzuki
cross-coupling10a as well as allylic substitution reactions.11d
However, selective cross-coupling of tertiary allylic sulfones
remain highly challenging in Suzuki-Miyaura cross-coupling
reactions.10 Indeed, we employed our tertiary allylic sulfone
product 3ga along with typical boronic acids as a coupling
partner, in order to achieved the formal synthesis of (±)-
sporochnol,20 and (±)-bakuchiol,21 both of which are natural
products possesses a quaternary all-carbon center. Our
synthesis is illustrated in Figure 1b. The key step involves a
previously reported Suzuki-Miyaura cross-coupling reaction of
tertiary allylic sulfone 3ga to afford 4ga, and 4gb efficiently
with 62% and 58% of isolated yields respectively. Subsequent
deprotection of phenol then could complete the formal
synthesis of (±)-sporochnol and (±)-bakuchiol (Figure 1b).20,21
Starting from 3ga in 2 total steps indicating that our tertiary
allylic sulfones can be used to prepare such natural products
and other related compounds bearing all-carbon quaternary
centers in a modular way.22
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the “Fundamental Research Funds for
Central Universities" (No. 1191329135), Key Laboratory
Construction Program of Xi’an Municipal Bureau of Science and
Technology (No. 201805056ZD7CG40) and the starting fund of Xi’an
Jiao Tong University (No. 7121182002). We thank the Instrumental
Analysis Center of Xi’an Jiao Tong University for HRMS analysis.
To gain mechanistic insight and the initial understanding on
how the reaction works, we decided to study the reactivity of
4 | J. Name., 2012, 00, 1-3
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Roggen and E. M. Carreira, Angew. Chem. Int. Ed., 2012, 51,
Notes and references
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3470; (n) M. Roggen and E. M. CarreiDraO,I:A10n.g10e3w9./DC0hSeCm01.76In3tA.
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7
The range of nucleophiles that has been used in
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the palladium- and iridium-catalysed reactions. However, to
our knowledge there is no report available in literature on
the use of heteroatom nucleophiles that provide access to
tertiary and or secondary allylic products in Mo-catalysed
allylic substitution reactions
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6
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24 Despite considerable efforts, we were unable to prepare a
single crystal of Mo(bpy)(CO)4. At present, we have
conformed the structure from NMR-analysis. All the
spectroscopic data for this compound matches with that
reported in the literature. See Ref. 16 and 23 for more
details.
25 For mechanistic hypothesis, see: (a) B. M. Trost and M.
Lautens, J. Am. Chem. Soc., 1982, 104, 5543; (b) B. M. Trost
and M. H. Hung, J. Am. Chem. Soc., 1983, 105, 7757; (c) D. E.
Ryan, D. J. Cardin and F. Hartl, Coord. Chem. Rev., 2017, 335,
103.
6 | J. Name., 2012, 00, 1-3
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Page 13 of 13
Chemical Science
View Article Online
DOI: 10.1039/D0SC01763A
The first general example of molybdenum-catalyzed allylic sulfonylation of tertiary allylic electrophile
provides an efficient and direct way to form tetrasubstituted carbon-sulfur bonds, thus unlocking a new
platform to synthesize tertiary allylic sulfones, even at late stages and providing ample opportunities for
further derivatization through traditional Suzuki cross-coupling.