Diversity-Orientated Stereoselective Synthesis through Pd-Catalyzed Switchable Decarboxylative C?N/C?S Bond Formation in Allylic Surrogates

Article abstract of DOI:10.1002/chem.201805295

Switchable catalytic transformation of reactants can be a powerful approach towards diversity-orientated synthesis from easily available molecular synthons. Herein, an endogenous ligand-controlled, Pd-catalyzed allylic substitution allowing for either selective C?N or C?S bond formation using vinylethylene carbonates (VECs) and N-sulfonylhydrazones as coupling partners has been developed. This versatile methodology provides a facile, divergent route for the highly chemo- and stereoselective synthesis of functional allylic sulfones or sulfonohydrazides. The newly developed protocol features wide substrate scope (nearly 80 examples), broad functional group tolerance, and potential for the late-stage functionalization of bioactive compounds. The isolation and crystallographic analysis of a catalytically competent π-allyl Pd complex suggests that the pathway leading to the allylic products proceeds through a different manifold as previously proposed for the functionalization of VECs with nucleophiles.

Full text of DOI:10.1002/chem.201805295

A Journal of
Accepted Article
Title: Diversity-Orientated Stereoselective Synthesis through Pd-
Catalyzed Switchable Decarboxylative C‒N/C‒S Bond Formation
in Allylic Surrogates
Authors: Lei Deng, Arjan Willem Kleij, and Weibo Yang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201805295
Link to VoR: http://dx.doi.org/10.1002/chem.201805295
Supported by

10.1002/chem.201805295
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COMMUNICATION
Diversity-Orientated Stereoselective Synthesis through Pd-
Catalyzed Switchable Decarboxylative C‒N/C‒S Bond Formation
in Allylic Surrogates
Lei Deng,[a,b,c] Arjan W. Kleij*[e,f] and Weibo Yang*[a,b,d]
Abstract: Switchable catalytic transformation of reactants can be a
powerful approach towards diversity-orientated synthesis from easily
available molecular synthons. Herein, an endogenous ligand-
controlled, Pd-catalyzed allylic substitution allowing for either
selective C‒N or C‒S bond formation using vinylethylene carbonates
and N-sulfonylhydrazones as coupling partners has been developed.
This versatile methodology provides a facile, diversicating route for
the highly chemo- and stereoselective synthesis of functional allylic
sulfones or sulfonohydrazides. The newly developed protocol
features wide substrate scope (nearly 80 examples), broad
functional group tolerance and potential for the late-stage
functionalization of bioactive compounds. The isolation and
crystallographic analysis of a catalytically competent -allyl Pd
complex suggests that the pathway leading to the allylic products
proceeds through a different manifold as previously proposed for the
functionalization of VECs with nucleophiles.
1a). To the best of our knowledge, the chemo-switchable and
stereoselective Pd-catalyzed allylic substitution of VECs in the
presence of substrates incorporating different pro-nucleophilic
sites remains elusive to date despite its potential to provide
through a single process a much higher degree of molecular
diversity (Scheme 1b).
Diversity-oriented synthesis aims to generate diverse
structural motifs with a broad range of biological activities in a
concise and efficient manner, and has thus received much
attention in synthetic organic and medicinal communities.[1]
Undoubtedly, controllable and switchable strategies have
emerged as a powerful tool to significantly increase the diversity
and complexity of molecular architectures using reactants with
tunable reactivity.[2] Vinylethylene carbonates (VECs)[3] have
become popular substrates in transition metal catalyzed
transformations including allylic substitution reactions.[4] For
example, highly regio-, stereo and enantioselective Pd-catalyzed
allylic substitutions of VECs with water,[3o] amines[3p,3r] or thiols[3q]
to deliver valuable building synthetic blocks have been reported.
In addition, Zhang et al. disclosed an elegant approach for the
Pd-catalyzed asymmetric allylic substitution of VECs with water
or alcohols towards the formation of branched allylic ethers and
alcohols featuring chiral tertiary carbon centers.[3m]
Scheme 1. (a) Reported Pd-catalyzed allylic substitution reactions using VECs,
(b) new conceptual diversity orientated approach, and (c) reaction design
applied in this work.
In order to address this challenge (Scheme 2b), we
envisioned the use of well-known and robust N-
sulfonylhydrazones as coupling partners.[5] From this versatile
coupling partner three distinct intermediates can be generated
including ambiphilic metal carbenes, sulfur nucleophiles as well
as nucleophilic nitrogen species in the presence of suitable
metals under basic conditions. Whereas the ambiphilic metal
carbene intermediates have been widely utilized in transition
metal catalyzed C‒C bond formation,[5b] the use of the S- and N-
nucleophilic species in synthetic chemistry is still in its infancy.
Therefore, the exploration of such unmapped chemical space
can create new opportunities for diversity-orientated synthesis.
Based on the previous successful accomplishments with N-
tosylhydrazones[5b,6] and VECs[3i, 3l, 3o-r] in preparative chemistry,
we hypothesized that activated N-sulfonylhydrazones could trap
the allyl-Pd intermediate after decarboxylation of the VEC. By
carefully manipulating the reaction conditions and ligands, either
S-based or N-based nucleophiles may be generated in situ
thereby creating a useful diversicating approach from a single
Notably, all these reported protocols exclusively employ the
use of single nucleophiles in allylic substitution reactions of
which the regio- and stereo-bias is ligand-controlled (Scheme
[a]
[b]
[c]
[d]
[e]
Chinese Academy of Sciences, Key Laboratory of Receptor
Research, Shanghai Institute of Materia Medica, Shanghai, China;
University of Chinese Academy of Sciences, Beijing, China. E-mail:
yweibo@simm.ac.cn
Nano Science and Technology Institute, University of Science and
Technology of China, Suzhou, Jiangsu 215123, China
University of Science and Technology Liaoning, Anshan 114051, P.
R. China.
Institute of Chemical Research of Catalonia (ICIQ), Av. Països
Catalans 16, 43007 – Tarragona (Spain)
E-mail: akleij@iciq.es
[f]
Catalan Institution of Research and Advanced Studies (ICREA), Pg.
Lluis Companys 23, 08010 – Barcelona (Spain)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201805295
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set of substrates (Scheme 1c). Herein, we report the first
4:1, for 3aa, Z/E = 93:7). These combined results highlight the
challenge of simultaneous achieving high chemo- and
stereoselectivity, and encouraged us to investigate the influence
of different bases. The use of both Na2CO3 and Et3N was
unproductive (entries 4 and 5), and the presence of either
Cs2CO3 or CsF did not further improve the results (entries 6 and
7). Gratifyingly, decreasing the amount of K2CO3 (cf., entries 8-
10) to 0.8 equiv provided optimal chemo- and stereoselectivity
towards 3aa (entry 10; yield 71%, Z/E = 94:6). Variation of the
Pd precursor was also examined (entries 11-14), and when a
mixture of 1a and 2a was treated with Pd(PPh3)4 and K2CO3 in
CH3CN (entry 14), exclusively C‒N bond formation could be
achieved giving allylic hydrazone 4aa in 94% yield and in
excellent stereoselectivity (Z/E >99:1). This complete switch in
chemoselectivity may be attributed to stronger  interactions
between the PPh3 ligand and nucleophilic intermediate obtained
from 2a, and notably no exogenous ligand was required to
induce this switch in chemoselectivity.
example
of
a
conceptually
divergent,
Pd-catalyzed
stereoselective allylic substitution of VECs. This chemo-
switchable C‒N and C‒S bond formation is scrutinized by the
presence of simple endogenous ligands. Moreover, this protocol
allows for easy access to multifunctional allylic scaffolds of
importance in organic synthesis[7] and being frequently
encountered in many bioactive natural products.[8]
Table 1. Optimization of the reaction conditions towards selective formation
of allylic sulfone 3aa or allylic hydrazone 4aa.[a]
Entry
1
Catalyst
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
PdCl2
Base (equiv)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
Na2CO3 (2.4)
Et3N (2.4)
Solv.
Diox
3aa[b]
4aa[b]
19%
‒
47% (87:13)
46% (80:20)
68% (93:7)
trace
2
DMF
3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
17%
trace
trace
‒
4
5
trace
6
Cs2CO3 (2.4)
CsF (2.4)
39% (82:18)
64% (93:7)
68% (94:6)
69% (94:6)
71% (94:6)
61% (92:8)
56% 89:11)
60% (92:8)
‒
7
16%
17%
8%
8
K2CO3 (2.0)
K2CO3 (1.0)
K2CO3 (0.8)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 (2.4)
9
10
11
12
13
14
6%
14%
8%
21%
94%[c]
Pd(PPh3)4
[a] Reaction conditions: 1a (0.05 mmol), 2a (0.1 mmol), [Pd] (5 mol %) in
solvent (0.5 mL) at 80 ºC for 2 h; Diox stands for 1,4-dioxane, note that
Pd2(dba)3 here reflects the use of the CHCl3 solvate. [b] The yield of (Z)-3aa
and (Z)-4aa was determined by the 1H NMR using CH2Br2 as an internal
standard; the Z/E ratios were determined from the crude product by 1H NMR
and values are reported in brackets. [c] The Z/E ratio of the product was >99:1.
Scheme 2. The scope of allylic sulfones 3 derived from various VECs and N-
sulfonylhydrazones using the reaction conditions of Table 1, entry 10.
Reported yields are of the isolated product.
Inspired by the challenge presented in Scheme 1b, we set
out to examine the feasibility of this conceptual approach using
the model VEC substrate 1a and N-tosylhydrazone 2a. To our
delight, an initial trial (Table 1, entry 1) revealed that a catalytic
system comprising Pd2(dba)3·CHCl3 and K2CO3 gave rise to both
C‒S and C‒N bond formation products albeit with unsatisfactory
chemo- and stereoselectivity. The (Z)-configuration of 3aa and
4aa were confirmed by NOE analysis. When DMF was utilized
as solvent under similar conditions, only 3aa was produced in
excellent chemoselectivity but with moderate stereocontrol
(entry 2; 46% yield, Z/E = 80:20). Further solvent screening
indicated that the overall conversion and stereoselectivity of 3aa
could be significantly enhanced in CH3CN though some erosion
of the chemoselectivity was noted (Table 1, entry 3; 3aa:4aa =
With the optimized conditions in hand, first the scope of the
Pd-catalyzed allylic sulfone formation was explored varying both
the VEC and N-sulfonylhydrazone substrate (Scheme 2).[9]
A
series of para-, meta- and ortho-monosubstituted aryl groups in
the substituted VECs with either electron-donating or electron-
withdrawing character are well-tolerated by the developed
protocol to afford 3ba‒3ka in moderate to good yields with
excellent chemo- (typically >90%) and stereoselectivity (for 3ba
X-ray analysis confirmed the major isomer, see also the
Supporting Information, SI).[10] Particularly, substrates bearing
chloro or bromo functional groups were also amenable to the
standard conditions (3ga and 3la), thus offering potential for
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further functionalization. The catalytic system also showed
compatibility with sulfur-containing VECs allowing to isolate 3ma
in high yield without any sign of catalyst deactivation. The R1
group of the VEC could be extended to aliphatic substituents
such as methyl (3na), cyclohexyl (3oa) and tetrahydropyranyl
(3pa) and all provided reasonable yields under high
stereoinduction. Cycloalkyl groups with fused aromatic rings
(3qa and 3ra) could also be introduced in the allylic sulfone
product while maintaining high chemo- and stereoselectivity.
The scope of the Pd-catalyzed formation of allylic
sulfonohydrazides was also evaluated (Scheme 3). The
substrate scope of these reactions also proved extensive, and in
the majority of the cases excellent chemo- and stereoselectivity
was observed regardless the electronic and steric properties of
the substrates. Aryl groups in the VECs with different types of
substitution (ortho, meta or para) were endorsed by the catalytic
procedure (cf., compounds 4ba4la), while the presence of
various heterocyclic, vinyl and alkyl groups also allowed to
deliver allylic sulfonohydrazides 4ma4ra in good yield and
under high stereo-control except for 4ta (Z/E = 74:26).
The generality of this CN bond formation protocol could be
further illustrated by successful synthesis of various allylic
sulfonohydrazides (cf., products 4ab4at) that comprise a
variety of heterocyclic groups such as naphthyl, pyridyl,
(substituted) thiophenelyl, furyl, morpholinyl and piperidinyl, and
substituted aromatics with potentially useful nitro (4af) and
halide substituents (4ae, 4ah and 4ak). In all aforementioned
examples, formation of the targeted products was observed with
good yields (typically >70%) with excellent Z/E ratios of up >99:1.
Scheme 3. The scope of allylic sulfonohydrazides 4 derived from various
VECs and N-sulfonylhydrazones using the reaction conditions of Table 1,
entry 14. Reported yields are of the isolated product.
Subsequently, a series of substituted N-tosylhydrazone
substrates was tested (Scheme 2, lower part; compounds 3ab‒
3am) and those having aryl groups with electron-donating
substituents favored higher yields than those with electron-
withdrawing groups. Apart from simple aromatic rings, also
naphthyl (3aj), cyclopropyl (3al) and 3-pyridyl (3am) could be
introduced in the allylic sulfone product being relevant to target-
Scheme 4. Late-stage functionalization of biologically important scaffolds with
allylic sulfone or sulfonohydrazide groups. Reported yields are of the isolated
product.
oriented synthesis. For the latter derivative,
chemoselectivity was observed, though
stereoselectivity could be achieved.
a
lower
excellent
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Fragment-based drug design has emerged as a crucial
strategy to accelerate lead compound identification,[11] and this
encouraged us to use our develop protocol for late-stage
functionalization of important drug scaffolds (Scheme 4; see also
the SI for further details). We first prepared Erlotinib (used in
lung cancer treatment)[12] and Pregnenolone (neuroprotecting
agent)[13] analogues by incorporating VEC fragments. The late-
stage functionalization of these two biologically relevant
scaffolds was successfully accomplished (compounds 3ua, 4ua,
3va and 4va) and allowed the introduction of functionalized
allylic sulfone and sulfonohydrazide groups. Alternatively,
Erlotinib, Pregnenolone, Fenofibrate,[14] and Testosterone[15]
could be easily substituted with N-tosylhydrazones which after
treatment with VEC 1a under the optimal conditions (Table 1,
entry 14) gave smooth access to the products 4ay, 4az, 5aa,
and 5ab in high yields and with excellent stereocontrol.
First, 9 was combined with substrates 1a and 2a, and allylic
sulfone 3aa could be isolated in 83% yield. When the same
substrates were treated in the presence of a catalytic amount of
PPh3, the chemoselectivity was completely reversed towards the
formation of the allylic sulfonohydrazide 4aa (90% yield). Both
yields obtained for 3aa and 4aa in the presence of 9 were
improved compared to those experiments relying on in situ
preparation of the active catalyst, and indeed suggest that a
Pd(allyl) intermediate similar to 9 may be a catalytic intermediate
with the presence of the phosphine ligand exerting a crucial role
in the switching of the chemo-selectivity.[17]
N
Pd
O
Cl
O
Scheme 5. Gram-scale reaction of 3aa and further transformations furnishing
6a8a. All reported yields are from the isolated product. See for details the SI.
We further evaluated the robustness and practicality of allylic
sulfone formation reactions (Scheme 5) using 3aa as
a
representative case, which could be easily prepared on gram
scale. The alcohol fragment in 3aa could be conveniently
oxidized to an aldehyde through a Dess-Martin oxidation,
whereas the double bond in 3aa could be reduced using a Pd/C
catalyst under H2 to give product 7a in 87% yield. Treatment of
3aa under standard Mitsunobu reaction conditions afforded 8a,
whereas the allylic sulfone could also be a viable starting point
for the formation of 1,3-oxazolidines based on [3+2]
cycloaddition reaction recently reported by Terada and
coworkers.[16]
Scheme 6. Mechanistic control experiments (top) and proposed manifolds for
the formation of the allylic sulfones and sulfonohydrazides (bottom).
Several experiments were conducted to gain insight into the
mechanism of this Pd-catalyzed switchable allylic CN/CS
bond formation process (Scheme 6, top). Treatment of a
stoichiometric combination of [Pd2(dba)3]·CHCl3 and VEC 1a in
CH3CN while adding 2-acetylpyridine resulted in decarboxylation
and afforded unexpectedly the -allyl Pd complex 9 in 45%
On the basis of these mechanistic control reactions and
previous reports, we propose that the synthesis of the allylic
products starts off with the decarboxylative oxidative addition of
the VEC (here 1a used as a representative case) to the Pd(0)
precursor generating a -allyl palladium intermediate similar to 9.
From here the reaction proceeds via nucleophilic attack onto this
Pd(allyl) intermediate involving either CS or CN bond
formation providing selectively the allylic sulfone (via Nu2) or
sulfonohydrazide (via Nu1) and regenerating the requisite Pd(0)
catalyst for subsequent turnover. The type of nucleophile that is
generated in situ can be regulated under basic conditions.
1
isolated yield. Complex 9 was fully characterized by H and 13C
NMR, and X-ray crystallography.[10] The structure of 9 reveals
that the Pd center is 3-ligated by the allyl fragment and the
hydromethyl group is orientated syn to the metal center. Such a
-allyl Pd complex is rather distinct from the DFT-computed six-
membered
palladacycle
recently
determined
in
the
functionalization of VECs with various nucleophiles.[3f,i,q,v] To
examine whether this Pd-complex 9 is catalytically competent, it
was subjected to the optimized conditions reported in Table 1.
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In summary, we have developed the first example of a
chemo-switchable allylic CN or CS bond formation reaction
through an endogenous ligand-controlled, Pd-catalyzed
conversion of versatile vinylethylene carbonate and N-
sulfonylhydrazone substrates. This developed protocol exhibits
broad substrate scope and excellent functional group tolerance
important for diversity-orientated synthesis and drug discovery.
The catalytic methodology can also be applied to late-stage
functionalization of bioactive scaffolds by introduction of various
allylic fragments. Further diversity-oriented transition metal
mediated transformations are currently targeted to further
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Acknowledgements
We gratefully acknowledge 100 talent program of Chinese
Academy of Sciences, Chinese NSF (21702217), "1000-Youth
Talents Plan", Shanghai-Youth Talent, Shanghai-Technology
innovation Action Plan (18JC1415300), the CERCA
Program/Generalitat de Catalunya, ICREA, the Spanish
MINECO (CTQ2017-88920-P), and AGAUR (2017-SGR-232) for
support of this research.
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Keywords: allylic substitution • decarboxylation • N-
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For comparison, we also probed the reaction towards the formation of
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[17] 2-Acetylpyridine addition (5 mol%) during the catalytic reaction leads to
product 3aa (68%, Z/E = 91:9). The result is similar compared with the
optimized protocol provided in Table 1, entry 10 (yield of 3aa: 71%, Z/E
=
94:6). This may further indicate the existence of an allyl-Pd
intermediate as suggested in Scheme 6.
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10.1002/chem.201805295
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents:
COMMUNICATION
Nucleophilic
Switch:
A
Lei Deng, Arjan W. Kleij* and
conceptually
attractive
and
Weibo Yang*
switchable Pd-catalyzed allylic
substitution
carbonates
of
with
vinylethylene
sulfonyl-
hydrazones has been developed
in the context of diversity-
orientated synthesis. The chemo-
switchable CS and CN bond
formation reactions are highly
versatile, and allow for broad
scope under high regio- and
stereocontrol. Examples of late-
stage modification of biologically
relevant scaffolds with functional
Page No. – Page No.
Diversity-Orientated
Stereoselective Synthesis
through Pd-Catalyzed
Switchable Decarboxylative C‒
N/C‒S Bond Formation in Allylic
Surrogates
allylic
groups
add
further
synthetic value to the developed
catalytic protocol.
This article is protected by copyright. All rights reserved.