Intermolecular Pummerer Coupling with Carbon Nucleophiles in Non-Electrophilic Media

Article abstract of DOI:10.1002/anie.201709715

A new Pummerer-type C?C coupling protocol is introduced based on turbo-organomagnesium amides, which unlike traditional Pummerer reactions, does not require strong electrophilic activators, engages a broad range of C(sp³)-, C(sp²)-, and C(sp)-nucleophiles, and seamlessly integrates with C?H and C?X magnesiation. Given the central character of sulfur compounds in organic chemistry, this protocol allows access to unrelated carbonyls, olefins, organometallics, halides, and boronic esters through a single strategy.

Full text of DOI:10.1002/anie.201709715

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Intermolecular Pummerer Coupling with Carbon Nucleophiles in
Non-Electrophilic Media
Authors: Kilian Colas, Raúl Martín-Montero, and Abraham Mendoza
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709715
Angew. Chem. 10.1002/ange.201709715
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Angewandte Chemie International Edition
10.1002/anie.201709715
COMMUNICATION
Intermolecular Pummerer Coupling with Carbon Nucleophiles in
Non-Electrophilic Media
[
a,b]
[a]
[a,b]
Kilian Colas,
Raúl Martín-Montero and Abraham Mendoza*
th
We dedicate this manuscript to Prof. F. J. Fañanás on the occasion of his 65 birthday.
Abstract: A new Pummerer-type C–C coupling protocol is introduced
based on turbo-organomagnesium amides that unlike traditional
Pummerer reactions, does not require strong electrophilic activators,
result,
Pummerer
couplings
engaging
electron-poor
(hetero)arenes, alkyls, vinyls or alkynyls are beyond scope.
These shortcomings could be solved if common, powerful and
localized C-nucleophiles, like Grignard reagents, could engage in
this chemistry. However, reports on the reductive coupling of
Grignard reagents with sulfoxides has only been testimonial,
requiring large excess of reagents to compensate the native
3
2
engages a broad range of sp , sp and sp C–nucleophiles and
seamlessly integrates with C–H and C–X magnesiation. Due to the
central character of sulfur compounds in organic chemistry, this
protocol allows access to unrelated carbonyls, olefins,
organometallics, halides and boronic esters through a single strategy.
[
14,15]
reactivity of these coupling partners (Scheme 1c).
–
–
–X
olefins
ketones
BPin
Li
The development of important new products and technologies
has often relied on the unique properties of sulfur. For example,
A
O
C –Nucleophile
S
C
[– SR1]
R1
S
R1
[
1]
Pummerer
direct strategy
R2
sulfur moieties are present in relevant medicines,
R2
[
2]
[3]
[4]
semiconductors, catalysts and biological probes. Moreover,
sulfur and particularly the carbon-sulfur bond are central in
organic chemistry. Thioethers can be selectively activated
1
2
B
OSiR3
EDG
Pummerer in
SiR3
[
5]
strong E+ media
through mild oxidation, participate in cross-coupling reactions,
be seamlessly transformed into dissimilar functions (including
R
unsaturated silanes e–-rich ArH (SEAr only)
(previous work)
soft enolates
[
6]
carbonyls, olefins, organometallics and halides),
and
[
7]
[8]
R’
Pummerer
in Nu– media
with RMgX
immobilized through native ‘click’ methods. Importantly, the
balanced reactivity-stability profile of thioethers has been
extensively battle-tested in the total synthesis of sulfur-containing
R
EWG
EDG
R
R
R
R
1ary, 2ary & 3
alkyls [sp3]
ary
(het)aryl
alkenyl
alkynyl
[sp]
(this work)
2
2
[
9]
[sp ]
[sp ]
and sulfur-free molecules.
through C–S coupling from custom fragments,
alkylation/reduction sequences. Tactically,
Thioethers are often prepared
[
10]
or multistep
the direct
C
iPr2NH (2-4 equiv.)
O
S
or TMPH (2-4 equiv.)
✓ bulky amine additive
✘ low generality
R3
S
+
R3 MgX
R1
intermolecular reductive coupling of sulfoxides and carbon
nucleophiles (Pummerer, Scheme 1a) provides access to
thioethers bearing elaborate carbon frameworks from simple
sulfur compounds in one step.
R1
R2
✘ excess reagents
Kobayashi (1995)
R2
1
3
2
(4 - 8 equiv.)
D
3
[Mg] R3
R MgX
3)
Despite
a
century of developments in Pummerer
O
O
S
base
(4)
O [Mg]
S
(
R3
S
[
9,11]
R3
R
R1
chemistry
the intermolecular reaction between sulfoxides and
S
H
R1
R1
4-H+
2
–
–“MgO”
R2
R1
C-nucleophiles is still limited. Fundamental incompatibilities
between electrophilic activation and strong C-nucleophiles is the
main reason for the dominance in the literature of soft surrogates
R2
R2
1
A
C
2
strong base
or RMgX
S-Mg exchange
[
12]
[12a-c]
(
Scheme
1b).
12d,e]
Electron-rich
arenes,
enolate
R1S
R1
O
O
S
[
[11,13]
[12j,k]
+
equivalents,
ene-donors
and silanes
have been
4
-H or
S
R1
1 (or 1’)
S
R MgX
1
+
R2
+
3
O
R3
[
9,11]
R -H
successful nucleophiles in electrophilic Pummerer reactions.
Nevertheless, arenes produce regioisomers dictated by
electrophilic aromatic substitution (S Ar), and olefins or alkynes
R2
– “MgO”
R2
5
1’ R2
3’
B
homodimer(s)
competing substrates
E
[
12k,13]
[12h,j]
[12f,g,i]
act as allyl,
propargyl,
or enolate
equivalents. As a
Scheme 1. Synthesis of thioethers via intermolecular Pummerer C–C coupling:
A) significance, (B) available and desired C-nucleophiles, (C) seminal work
(
using Grignard nucleophiles, and (D) fundamental challenges to control their
reactivity.
[
a]
b]
Kilian Colas, Raúl Martín-Montero and Abraham Mendoza
Department of Organic Chemistry
Stockholm University
Arrhenius Laboratory, 106 91 Stockholm (Sweden)
E-mail: abraham.mendoza@su.se
Namely, sulfoxides 1 undergo fast S-Mg exchange when
exposed to Grignard reagents 3 (Scheme 1d) leading (via A) to
Homepage: www.organ.su.se/am/
[14,16]
recombination into sulfoxides 1’ and Grignard reagents 3’.
[
Kilian Colas and Abraham Mendoza
Berzelii EXSELENT Center for Porous Materials
Stockholm University
This fast process consumes 1 and 3 and generates mixtures of
alternative substrates 1’ and 3’, thus eroding the efficiency of the
desired coupling. Inspired by earlier work by Kobayashi (Scheme
Arrhenius Laboratory, 106 91 Stockholm (Sweden)
[
15b-d]
1
c),
we recognized the key role of the base (4) that is required
Supporting information for this article is given via a link at the end of
the document.
to deprotonate the sulfoxide for productive coupling (Scheme 1d).
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Angewandte Chemie International Edition
10.1002/anie.201709715
COMMUNICATION
Too reactive bases produce sulfoxide anions B (1→B) that
compete with the Grignard reagents as nucleophiles in the
reductive coupling, thus leading to the homodimer 5 (or various
crossover dimers if 1’ is formed through S-Mg exchange).
However, if the base is not reactive enough, intermediate A would
get irreversibly deprotonated by the basic magnesium alkyl
The scope was studied with various aliphatic and aromatic
sulfoxides that yielded arylated thioethers 2a-d (Scheme 2b). The
aromatic and heteroaromatic fragments that would be problematic
E
(or impossible) in traditional S Ar-Pummerer engage in this
reaction. Thus, 1- or 2-naphthyl reagents (2e-g) are obtained
selectively, and electron-rich (hetero)aryls bearing sulfur-,
oxygen- and nitrogen-activating groups provide ortho- and meta-
functionalized coupling products 2h-o, as desired. Even electron-
(
A→B). We hypothesized that a suitable base should thus readily
deprotonate complex A - but not the free sulfoxide 1 - to promote
the formation of the sulfonium intermediate C that would collapse
into the desired thioether 2 (A→C→2). Therefore, an engineered
base seemed the key to bypass the competing side-reactions and
E
deficient (hetero)aryls (non S Ar-reactive) readily participate to
furnish products 2p-s, including basic N-heterocycles
(problematic with hard electrophiles), and medicinally-relevant
fluorinated moieties (2p,s). Importantly, these nucleophilic
[
15]
enable efficient Pummerer C-C coupling in nucleophilic media.
Pummerer conditions enable integration with Knochel’s
Aromatic Grignard reagents are fundamental building blocks
with the potential to surpass S Ar-driven Pummerer arylations.
However, due to their relatively low reactivity they are particularly
[18,21]
magnesiations (see methods B and C).
This way, aryl
E
bromides become viable nucleophiles in Pummerer coupling
[21]
through turbo-halogen exchange (see 2e-h,p,r).
Moreover,
[
9,11]
rare in earlier reports on reductive couplings with sulfoxides.
simple heteroarenes can be selectively C–H magnesiated to
We initially targeted the reductive arylation of the aliphatic
sulfoxide 1a with only 1.05 equiv. of PhMgBr (3a; Scheme 2a).
Without base, only a small amount of the desired product 2a is
formed (entry 1). Unlike the TMP-derived Hauser base 4a (entry
[18]
furnish products 2o,q. This feature allows to override the native
E
S Ar reactivity of the fragment introduced (see 2q) in favor of
proximity-induced activation that was unavailable before in the
context of Pummerer chemistry. Regarding the Grignard coupling
partners, we have only found a limitation with electron-poor
reagents that are prone to decomposition upon gentle warming.
At present, organolithiums do not engage in this reaction. On the
[
15b]
2
), the presence of the DIPA-derivative 4b
has a positive effect
under these restrictive conditions, but cannot produce satisfactory
yields of 2a. Inspired by the recent studies on Knochel-Hauser
[
17]
bases (and in stark contrast to 4b) to our surprise we found that
[22]
sulfoxide side, substrates bearing a ferrocene (2j), as well as
[
18]
the rare DIPAMgCl･LiCl (4d) promoted the formation of 2a in
thiomorpholine (2m) and thioflavanone heterocycles (2s,t) further
[
17b,18]
9
1% yield (entry 5).
The synergy between an optimal Li-Mg
[3,23]
expands the potential of this reaction to impact ligand
and
ratio (entry 6,7 and tables S1,S2) and the specific
diisopropylamide base (entries 4,5) are both critical at enabling
[1b,24]
drug design.
Remarkably, β-heteroatoms and even
unprotected ketones are tolerated (2m,s,t), further suggesting the
[
17a]
this reaction. We speculate that aggregation equilibria
between the Grignard reagents and the base (likely involving
unusual organometallic species that enable this reaction (entries
[19a]
4
,5; Scheme 2a).
Despite these features, sterically hindered
[
19]
organomagnesium amide species), may be the origin of these
experimental results. The efficiency of the system is remarkable
considering the competing pathways available (Scheme 1d) and
the limited Grignard reagent used.
thioethers (neopentylic or α,α-disubstituted) are still a limitation,
producing low yield of the thioether products.
base (4) then
S
nPr
O
S
A) Ar MgX (3)
or
B) Ar Br (6) + i-PrMgCl • LiCl
or
A
nBu
nBu
B
O
S
Ph–MgBr (3a, 1.05 eq.)
S
nPr
DIPAMgCl•LiCl (4d)
(1.05 equiv)
THF, 65 °C
S
AA r
nBu
R1
R1
nBu
+
nPr
then
S
THF, 65 °C
Ph
R2
0 °C, 1h
R2
nPr
1
a
O
C) Ar
H
(7) + TMPMgCl • LiCl
#
base (4)
2aa (%)
10
5aa (%)
1
2a-t
1
2
3
4
5
6
7
none
0
35
16
28
7
= commercial ArMgX (method A)
= via turbo-halogen exchange (meth. B)
= via C–H magnesiation (meth. C)
TMPMgCl (4a)
DIPAMgCl (4b)
TMPMgClżLiCl (4c)
DIPAMgClżLiCl (4d)
4d + 1eq. LiCl
LDA
6
S
Ph
R1
Me
41
Me
S
S
R1
R2
14
S
R2
2a - R = Bu;R = Pr 91%A
1
n
2
n
Ph
S
91
Me
1
2
71%A
- R ,R =(CH ) 63%B
1
2
2
2
b - R =Ph;R =H
2f
2g - R =Ph;R =H 71%B
1
2 3
61
15
0
c - R =Ph;R =Ph 61%A
1
2
2d - 53%A
2e - 59%B
1
2
22
S
NH2
MeS
S
S
MeS
S
Fe
p-tol
S
SMe
Ph
OMe
SMe
H
N
nPr
2k - 59%A
h - 62%B
2i - 54%A
2j - 63%A
2l - 52%A
2m - 55%A,‡
2
ketone
compatible!
O
O
CF3
N
S
Bn
S
O
S
S
S
OCF3
SMe
Ph
N
S
S
H
H
NH2
2
n - 89%A
2o - 60%C
2p - 70%B
2q - 77%C
2r - 62%B
2s - 67%
A,§
2t - 76%
A
Scheme 3. Discovery and scope of the intermolecular (hetero)arylation including its Integration with in situ magnesation methods. [A] Conditions: 1a (0.1 mmol),
a
1
4
d (0.11 mmol), THF (1 mL), 0 °C, 1 h; then 3 (0.105 mmol), 0 °C then 65 °C, 12 h. Determined by H NMR using 1,1,2,2-tetrachloroethane as internal standard.
TMP, 2,2,6,6-tetramethylpiperid-1-yl; DIPA, diisopropylamide. [B] Conditions: Method A: 1 (0.3 mmol), 4d (0.33 mmol), THF (2.5 mL), 0 °C, 1 h, then Grignard
[
20]
‡
§
[20]
reagent 3 (0.315 mmol), 0 °C, then 65 °C, 14 h. Methods B and C.
N-Boc thiomorpholine substrate. Isolated as thioflavone due to auto-oxidation.
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Angewandte Chemie International Edition
10.1002/anie.201709715
COMMUNICATION
A
O
S
scale). Even tertiary alkyls, which would not be accessible to
sulfoxide alkylation–reduction strategies, do provide neopentyl
sulfides 2ai-al in a single operation. These reactions also allow
the late-stage functionalization of relevant heterocycles and
spx MgX
DIPAMgCl•LiCl
S
spx
R2
R1
R1
then
R2
THF, T
0 °C, 1h
1
2u-al
[
1b]
organometallics (2ac,ak). Moreover, the compound 2e that is
obtained through our reductive arylation (Scheme 2b) can be
oxidized to the sulfoxide 1t (Scheme 3b) and coupled with a
second Grignard reagent to obtain product 2am, which
underscore the utility of the reaction in the late-stage edition of
thioethers and its complete regioselectivity for the least hindered
secondary position. Sulfur compounds are also central synthetic
intermediates that can be used to mask both electrophilic and
nucleophilic functions (Scheme 4c). For example, the oxidative
hydrolysis of 2af leads to the ketone 9, while nickel boride gives
2
vinyls (sp ) - T= 65 °C
alkynyls (sp) - T= 65 °C
Me
Me
SPh
Me
PhS
(p-tol)S
n-Pr
Me
(
p-tol)S
Me
Me
PhS
2x - 76%
n-Pr
2y - 68%
2
u - 67%
2v - 87%
2w - 64%
alkyls (sp ) - T= rt (1 & 2ary
3
ary
)
1
2
3
S
R3
2za - R =Bn;R =Ph;R =Me
85%
62%
H
S
R1
1
2
3
N
2aa - R =Ph;R =Ph;R =Me
1
n
2
n
3 n
2ac - 80%‡
R2
2ab - R = Bu;R = Pr;R = Bu 81%
Me
Cy 2ae - R =H
2
68%
62% (54%)¶
(p-tol)S
1
access to the isotopically-labelled alkane 10-d (or unlabeled 10,
PhS
2
[6e]
[6d]
PhS
2af - R =Ph
see SI).
Marek’s methylenation furnishes 11,
which can
Me
R2
2
n-Pr
2ag - R =2-Np 54%
produce epoxides, aziridines and cross-metathesis products.
2
ad - 96%
2ah - 80%
[
6c]
T= 65 °C (3ary
Alkyl halides like the chloride 12, and the fluoride 13 can be
obtained (the latter through a new nickel-promoted reaction that
we are currently studying). The reductive lithiation pioneered by
!
)
Me
Me
Me Et
2-Np
Me
Me
Fe
Me
Ph
Et
Me
Me
ai - 92%
Ph
SPh
S
[
6a,f]
3
Ph
S
Me
Screttas,
produce, for example, aldehydes and boronic esters for
provides access to sp -organolithiums that can
S
Me
2
2aj - 51%
2ak - 59%
2al - 58%
[
25]
downstream manipulations (i.e. 14,15).
O
S
15
66%)
BPin
Ph
B
C
§
(
O
9
Cy
(79%)
1
4
CHO
n-PrMgCl
standard
conditions
§
g
Cy
Ph
A
O
S
(
54%)
a
f
1
t (now available in 2-steps)
Cy
Ph
(p-tol)S
radical
mechanism
unlikely
SPh
p-tol
O
[Mg]
DIPAMgCl•LiCl
c-PrMgCl
THF, 0°C to rt
2
10-d
1
(74%)
H
(
72%)
n-Pr
e
b
†
R3
R2
Cy
Ph
1
3
F
1u
2ah
S
(
75%)
2af
Cy
CH
Ph
R1
d
c
c-PrMgCl
DIPAMgClżLiCl
–20 °C
Cy
Ph
B
S
O
S
proposed
intermediate
2
partial
chirality
transfer
(
p-tol)S
Cl
*
1
2
11
Ph (64%)
p-tol
(
91%)
Cy
n-Pr
2
am - 52% (4:1 dr)
Cy
Ph
n-Pr
+)-1k - 98:2 er
(80%)
(
2ah - 70:30 e.r.§
Scheme 3. (A) Extension to various Grignard reagent classes. (B) Versatility of
the method and (C) its products. [A,B] Method A (Scheme 3) at the temperature
C
O
M
1k : 1k-d1
S
M
[
20]
‡
¶
iPr2N-M
p-tol
iPr2NH
+
Li
< 1 : 99
15 : 85
1
k
+
indicated.
N-Boc thiomorpholine substrate. Yield on gram-scale. [C]
[
20]
n-Pr
MgCl
Conditions: (a) Py･9HF, DBH, rt; (b) NiCl
LDA, then n-BuLi, then Zn(CH I) , –50 °C to rt; (d) PhICl
Py･9HF, DBH, rt; (f) LiNp, –78 °C then DMF; (g) LiNp, –78 °C then (i-PrO)BPin.
2
, NaBD
4
, rt; (c) H
2
O
2
, Ac
2
O, rt, then
D O
1k’-M
2
D O
2
MgClżLiCl > 99 : 1
2
2
2
, rt; (e) NiCl
2
･6H O,
2
1
k
1k-d1
†
2
§
>
95% deuterium ( H) incorporation. Via the organolithium intermediate. 2-Np,
-naphthyl; DBH, 1,3-dibromo-5,5-dimethylhydantoin; LiNp, lithium
naphthalenide; DMF, N,N-dimethylformamide.
2
Scheme 4. Preliminary data on the mechanism.
Although the nature of the activation bestowed by the interplay
between the Grignard reagent and the Knochel-Hauser base
requires a discrete study, we have preliminarily investigated the
mechanism of the reductive coupling with sulfoxides. Control
experiments with the cyclopropylcarbinyl substrate 1u (Scheme
4a), disfavor pathways involving radical intermediates that may be
generated through SET from the Grignard reagent to the sulfoxide.
The intermediacy of a loosely associated sulfonium ion pair is
supported by the partial chirality transfer observed when using the
unbiased enantiopure sulfoxide (+)-1k (Scheme 4b). This result
also showcases the potential of this system to develop
enantiospecific S-to-C chirality-transfer reactions in the future.
The specific activation observed with the Knochel-Hauser bases
can be attributed (in part) to their unexpected low basicity towards
sulfoxides (Scheme 4c). The sulfoxide 1k gets fully deprotonated
when using LDA (as evidenced by deuteration into 1k-d1), while
the optimal DIPAMgCl·LiCl (4d) base is completely unreactive. In
After demonstrating the efficient and regioselective coupling
of aryls, we explored the generality of these conditions with sp-,
2
3
sp - and sp -hybridized Grignard reagents (Scheme 3a). Vinyl
transfer can be undertaken to produce linear or branched allylic
sulfides 2u-w. Both internal and terminal C(sp)-alkynyl Grignard
reagents also produce the corresponding propargyl sulfides 2x,y.
As far as we know, these are the first examples of vinyl- and
3
alkynyl-transfer in Pummerer chemistry. The reactive C(sp )-
Grignard reagents were expected to be more challenging to
control due to their fast S-Mg exchange (Scheme 1d), but they
engage in the reaction at room temperature. DIPAMgCl･LiCl is
again superior to other similar bases (see SI). Different primary
alkyls are transferred to form products 2z-ac in the first examples
[
15]
of efficient Pummerer alkylation.
Acyclic or cyclic secondary
alkyls (including cyclopropyl) yield the derivatives 2ad-ah. The
scalability of this reaction is illustrated by 2af (54% yield in gram-
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Angewandte Chemie International Edition
10.1002/anie.201709715
COMMUNICATION
this light, 4d seems to discern between the acidity of free
sulfoxides 1 and their magnesium complexes A (Scheme 2). The
lower concentration of sulfoxide nucleophiles C can explain the
small amounts of homodimerization products 5 that we have
observed using 4d.
1993, 58, 2407; (f) Foubelo, F.; Yus, M. Chem. Soc. Rev. 2008, 37, 2620
and references therein.
[
[
7]
8]
(a) Merrifield, R. B., Science 1965, 150, 178; (b) Caruthers, M. H.,
Science 1985, 230, 281; (c) Plante, O. J.; Palmacci, E. R.; Seeberger, P.
H., Science 2001, 291, 1523.
Hoyle, C. E.; Lowe, A. B.; Bowman, C. N., Chem. Soc. Rev. 2010, 39,
1
355.
In summary, we report herein a protocol to engage sulfoxides
3
2
[9]
(a) Feldman, K. S., Tetrahedron 2006, 62, 5003; (b) Pulis, A. P.; Procter,
D. J., Angew. Chem. Int. Ed. 2016, 55, 9842; (c) Bur, S. K.; Padwa, A.,
Chem. Rev. 2004, 104, 2401
in intermolecular reductive C–C coupling with sp -, sp -, and sp-
Grignard nucleophiles. This transformation covers a gap in sulfur
chemistry that has remained unsolved for decades, taking
advantage of an unusual and specific turbo-Hauser base. To the
best of our knowledge, this reaction is the first efficient Pummerer-
type coupling occurring in non-electrophilic media. Its nucleophilic
conditions allow integration with C–H and C–X metalation
reactions and is naturally orthogonal to other Pummerer-type
reactions. The new protocol has enabled the construction of
complex thioethers, which are precursors of unrelated scaffolds
such as carbonyls, olefins, halides, organometallics and boronic
esters. This concept has preliminarily demonstrated its potential
enantiospecificity, and will motivate further research in
[
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Kilian Colas, Raúl Martín-Montero,
Abraham Mendoza*
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Intermolecular Pummerer coupling
with carbon nucleophiles in non-
electrophilic media
Sulfur-enabled C–C bond formation has been exploited over decades in the
synthesis of both sulfur-containing and sulfur-free molecules. The Pummerer
coupling allows this process to be performed in a single operation but it is limited by
the need of electrophilic activators. Herein we unveil an efficient and orthogonal
protocol for electrophile-free Pummerer C–C coupling that addresses the scope
limitations of traditional approaches.
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