Carbonylative Negishi-Type Coupling of 2-Iodoglycals with Alkyl and Aryl Halides

Article abstract of DOI:10.1002/ejoc.201901081

C-Glycosides are valuable organic compounds in the field of medicinal chemistry due to their ubiquity inside living systems and pronounced biological activity. Herein, we describe an approach to alkyl-ketones bearing glycal units via the Pd-catalyzed carb

Full text of DOI:10.1002/ejoc.201901081

A Journal of
Accepted Article
Title: Carbonylative Negishi-type Coupling of 2-iodoglycals with Alkyl
and Aryl Halides
Authors: Henrique A. Esteves, Mariana P. Darbem, Daniel C. Pimenta,
and Helio Alexandre Stefani
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901081
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901081
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201901081
COMMUNICATION
Carbonylative Negishi-type Coupling of 2-iodoglycals with
Alkyl and Aryl Halides
[
a]
[a]
[b]
Henrique A. Esteves, * Mariana P. Darbem, Daniel C. Pimenta, Hélio A.
[
a]
Stefani. *
A. Previous work
RO
RO
RO
RO
Abstract. C-glycosides are valuable organic compounds in
the field of medicinal chemistry due to their ubiquity inside
living systems and pronounced biological activity. Herein,
we describe an approach to alkyl-ketones bearing glycal
units via the Pd-catalyzed carbonylative coupling of 2-
iodoglycals and alkyl and aryl halides. Examples bearing a
variety of functional groups are presented as well as a
mechanistic proposal for this transformation.
O
O
RO
RO
“
CO”
RO
R
R
RO
Pd
R
Y
O
O
O
N
O
H
RO
ref. 7a
ref. 7a, 8c
base
Y = OH, NH2,
RO
RO
RO
RO
I
O
O
CCH, B(OH)2,
RO
RO
O
O
Ar
R
ref. 8a, 8b
ref. 7b, 8b
B. This work: Barbieri-Negishi carbonylative coupling
RO
RO
Introduction
RO
RO
Modular synthesis
One-pot procedure
O
O
key features
“
CO”
RO
RO
In the field of carbohydrate chemistry, a C-
glycoside is a class of molecules in which a
carbohydrate unit is connected to an aglycone by a
C–C bond, a modification that directly impacts its
Pd(dba)2/RuPhos
Scope versatility
Mild conditions
I
0
Mg /ZnCl2, THF
O
X
C(sp2) or
C(sp3): primary, secondary,
cyclic or acyclic
[
1 ]
chemical stability in a biological environment.
Scheme 1. Pd-catalyzed carbonylative coupling reactions
These compounds are found in a variety of
biologically active natural products, as well as in
important therapeutic agents, making them desirable
targets.[
Given their importance, many strategies have
been developed for C-glycosylation and, among them, Negishi conditions). Transmetalation with a Pd-aryl
some of the most attractive involve the
of 2-iodoglycals.
One common strategy involves the intermediacy
of an alkyl-metal species, such as an organozinc,
either pre-formed of generated in situ (Barbier-
2]
complex followed by reductive elimination then
forges a new C–C bond.
[
15]
functionalization of unsaturated sugars derivatives,
For this process to be
known as glycals.[
3 ]
Typical approaches rely on
viable, however, some limitations have to be
addressed: a) the dehalogenation of the aryl halide
substrate via the formation of an undesired
organometallic species followed by protonolysis and
b) the formation of isomeric products caused by chain
migration of the alkylpalladium intermediate. A fine
tune in the electronic and steric properties of the
ligand employed, however, can reduce these side
classical cross-coupling procedures, such as
[4]
[5]
[6]
Heck’s, Suzuki-Miyaura’s and Stille’s.
[7]
[8]
Our group and others, on the other hand, have
been focusing on the use of carbonylative cross-
coupling reactions of 2-iodoglycals for glycal
functionalization. In this approach, the carbohydrate
unit is connected to different nucleophiles through a
carbonyl link originated from a carbon monoxide
molecule. This approach permits not only a rapid
connection of two fragments, but also gives rise to a
[16]
reactions and render the process viable.
With these considerations in mind, we wondered
whether a carbonylative Negishi-type coupling of 2-
iodoglycals with alkyl halides would be feasible
[9]
rich variety of functional groups (Scheme 1a).
While carbonylative reactions to obtain
(
Scheme 1b). Unlike previous reports (Scheme 1a),
amides,[ esters, aryl-ketones[12] and alkynones
10]
[11]
[13]
this process would deliver valuable alkyl-ketones
bearing acidic -protons that can give rise to a rich
variety of enolate-based functionalizations, such as
[
14 ]
are widespread, those aiming alkyl-ketones
are
much more limited, due to the challenges associated
2
3
[
17 ]
with making C(sp )–C(sp ) bonds.
electrophile trapping,
de novo synthesis of
[
18]
[19]
[
a]
Departmento de Farmácia, Faculdade de Ciências
Farmacêuticas,. Universidade de São Paulo.
Av. Prof. Lineu Prestes, 580, São Paulo, 05508-000, Brazil.
E-mail: carloshenrique85@gmail.com; hstefani@usp.br
Instituto Butantan
heterocycles,
-arylation,
hydrogen-borrowing
[20]
[21]
alkylation, -fluorination, etc.
Herein we describe our efforts towards the
synthesis of this important class of C2-branched
sugars via the carbonylative coupling of 2-
iodoglycals with alkyl and aryl halides.
[
b]
Av. Vital Brasil 1500, São Paulo, 05503-000, Brazil.
Supporting information for this article is given via a link at the
end of the document.
1
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European Journal of Organic Chemistry
10.1002/ejoc.201901081
COMMUNICATION
Results and Discussion
Tri-O-benzyl-2-iodoglucal (2a) was then
selected for the optimization of the reaction
conditions for the Negishi-type carbonylative
coupling with 1-bromobutane (Table 1). Initial
We began our studies by synthesizing four
different 2-iodoglycals (2a-d) via Ag-catalyzed
electrophilic iodination of glycals 1a-d (Scheme
conditions based on a previous report by Wu and co-
[22]
2).
[14a]
workers
gave 3a in encouraging 56% (Entry 1).
Changing the catalyst to a NHC-based Pd complex,
[
23]
NIS (1.2 equiv.)
PEPPSI,
led to a poor conversion of 2a and the
RO
RO
RO
RO
AgNO3 (20 mol%)
O
O
formation of significant amounts of 1a, resulting
from de dehalogenation of the starting material (Entry
2). Bidentate phosphine ligand dppf, on the other
hand, considerably increased the reaction yield (Entry
RO
RO
MeCN, 70 ºC, 1 h
I
1a (4S, R = Bn)
1b (4R, R = Bn)
1c (4S, R = Ac)
1d (4S, R = Me)
2a (64%)
2b (62%)
2c (72%)
2d (58%)
3) and bulky monophosphine RuPhos was identified
as the best choice for this transformation with no
significant formation of 1a, result in agreement with
previous findings by Buchwald (Entry 4).
Scheme 2. Synthesis of 2-iodoglycals.
[16c]
Table 1. Optimization of the reaction conditions
Entry
Pd (mol%)/ligand (mol%)
Additives
Temperature
Solvent
Yielda
Effect of catalyst/ligand
0
1
Pd(dba)
PdPEPPSI (6)
Pd(dppf)Cl (6)
Pd(dba) (6)/RuPhos (6)
Pd(dba)2
2
(6)/PPh
3
(6)
Mg (2.5 equiv.), ZnCl
2
2
2
2
2
(2.5 equiv.)
(2.5 equiv.)
(2.5 equiv.)
(2.5 equiv.)
(2.5 equiv.)
55 C
55 C
55 C
55 C
55 C
THF
THF
THF
THF
THF
56%
30%
62%
72%
0%
0
2
3
Mg (2.5 equiv.), ZnCl
0
2
Mg (2.5 equiv.), ZnCl
0
4
2
Mg (2.5 equiv.), ZnCl
0
5
Mg (2.5 equiv.), ZnCl
Effect of solvent
0
6
7
8
Pd(dba)
Pd(dba)
Pd(dba)
2
2
2
(6)/RuPhos (6)
(6)/RuPhos (6)
(6)/RuPhos (6)
Mg (2.5 equiv.), ZnCl
2
2
2
(2.5 equiv.)
(2.5 equiv.)
(2.5 equiv.)
55 C
55 C
55 C
Toluene
1,4-Dioxane
MeCN
0%
7%
5%
0
Mg (2.5 equiv.), ZnCl
0
Mg (2.5 equiv.), ZnCl
Effect of temperature
0
9
Pd(dba)
Pd(dba)
Pd(dba)
2
2
2
(6)/RuPhos (6)
(6)/RuPhos (6)
(6)/RuPhos (6)
Mg (2.5 equiv.), ZnCl
2
2
2
(2.5 equiv.)
(2.5 equiv.)
(2.5 equiv.)
40 C
50 C
65 C
THF
THF
THF
50%
74%
16%
0
1
1
0
1
Mg (2.5 equiv.), ZnCl
0
Mg (2.5 equiv.), ZnCl
Effect of the additive concentration
b
0
1
2
Pd(dba)
2
(6)/RuPhos (6)
Mg (5.0 equiv.), ZnCl
2
(6.0 equiv.)
50 C
THF
86%
Effect of the catalyst loading
b
0
1
1
3
4
Pd(dba)
Pd(dba)
2
2
(5)/RuPhos (5)
(3)/RuPhos (3)
Mg (5.0 equiv.), ZnCl
2
2
(6.0 equiv.)
(6.0 equiv.)
50 C
50 C
THF
THF
85%
56%
b
0
Mg (5.0 equiv.), ZnCl
a
b
Reaction scale: 0.1 mmol (2a). Isolated yield. 5.0 equiv. of 1-bromobutane.
2
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European Journal of Organic Chemistry
10.1002/ejoc.201901081
COMMUNICATION
No conversion was observed in the absence of an further functionalization.[ 24 ] Despite the low yield
external ligand (Entry 5). Next, a solvent screening observed for ketone 3h, this example demonstrates a
revealed this to be a key factor in this transformation: valuable selectivity for alkyl bromides over chlorides,
0
replacing THF with toluene, 1,4-dioxane or MeCN regardless the excess Mg required for this
[16]
dramatically decreased the efficiency of the reaction.
Methyl 3-bromopropionate was also
carbonylative coupling and only trace amounts of 3a compatible with this reaction and dicarbonyl
were observed (Entries 6-8). The reaction temperature compound 3i was isolated in moderate yield. Allyl
was then surveyed and the optimum temperature was bromides, on the other hand, were not amenable to
3
established as 50 °C (Entry 10). Increasing the this transformation, possibly due to competitive  -
0
equivalents of Mg and ZnCl
2
added had a positive allyl-Pd formation. Gratifyingly, aryl halides were
impact in the reaction outcome: full conversion of 2a well tolerated and aryl-ketones 3l-m were isolated in
was observed, while 1a was not detected, leading to good yields.
an isolated yield of 86% (Entry 12). Finally, we
Next, we sought to investigate the scope for the
investigated different catalyst loadings and these 2-iodoglycal coupling partner (Table 3).
experiments showed that a reduction to 5 mol% was
tolerated with no significant decrease in the reaction Table 3. Scope for 2-iodoglycals
yield (Entry 13). It is worth mentioning that some
aspects proved fundamental for reproducibility and
high yields of the coupling reaction: a vigorous
stirring to allow an adequate gas transfer between the
reaction medium and the tube headspace and a proper
degasification of the reaction solvent prior to use (see
Supporting Information for details).
With the optimal conditions in hand, we set out
to demonstrate the reaction scope for the alkyl halide
partner using 2a as the 2-iodoglycal (Table 2).
Table 2. Scope for alkyl halides
CO (1 atm)
R-Br (5.0 equiv)
Pd(dba)2 (5 mol%), RuPhos (5 mol%)
OBn
O
OBn
O
BnO
BnO
BnO
BnO
Mg0 (5.0 equiv.), ZnCl2 (6.0 equiv.)
THF, 50 ºC, 16 h
I
O
R
2a
3
a
OBn
OBn
O
OBn
OBn
O
Reaction scale: 0.25 mmol of 2b-d. Catalyst loading: 10
mol%
BnO
BnO
O
BnO
BnO
BnO
BnO
O
BnO
BnO
Me
Me
Me
O
O
O
O
Me
3
5
Tri-O-benzyl-D-galactal 2b was first tested and
cleanly reacted under the standard reaction conditions,
delivering ketones bearing primary (4a-b), secondary
(4c) and cyclic alkyl moieties (4d) in moderate to
good yields. Tri-O-acetyl-D-glucal 2c and tri-O-
methoxy-D-Glucal 2d, on the other hand, required a
higher catalyst loading to achieve full conversion of
the 2-iodoglycal starting materials. Despite the higher
catalyst concentration, only moderate yields were
obtained (4e-g). In the case of some bromoalkanes
3
a
3b
72%
3c
49%
3d
51%
8
5%
OBn
O
OBn
O
OBn
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
O
BnO
BnO
Me
Cl
O
O
O
O
4
Me
3
e
3f
75%
3g
57%
3h
31%
6
2%
OBn
O
OBn
O
OBn
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
O
BnO
BnO
O
O
OMe
O
O
O
2
(
e.g. bromocyclopropane), the reactions yielded
3
i
3j
0%
3k
69%
3l
75%
OMe
Me
4
4%
intractable mixtures containing large amounts of the
corresponding dehalogenated glycal and a complex
mixture of by-products.
Reaction scale: 0.25 mmol of 2a.
Linear primary alkyl groups were successfully
installed, giving products 3a-d in moderate to good
yields. Secondary alkyl bromides also proved to be
well tolerated, with both acyclic (3e) and cyclic (3f-g)
structures forming the desired products in moderate to
good yields. In the case of cyclopropyl-ketone 3g, the
alkyl moiety can also be used as a useful handle for
In order to increase the attractiveness of the
methodology, ketones 3d and 3l were deprotected
under Lewis-acidic conditions, affording deprotected
glycals 5d and 5l in 64% yield.
3
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European Journal of Organic Chemistry
10.1002/ejoc.201901081
COMMUNICATION
catalyzed carbonylative Negishi-type coupling. 16
examples were synthesized from 4 different 2-
iodoglycals in moderate to good yields. Several
substituents were tolerated, demonstrating the
versatility of this methodology.
Scheme 3. Deprotection of ketones 3d and 3l.
Experimental Section
The proposed mechanism for the Carbonylative
coupling of 2a with 1-bromobutane is depicted in
Figure 1. Oxidative addition of Pd to 2-iodoglycal 2a
gives complex ii. CO complexation, followed by
transmetallation with the alkylzinc species formed in
situ from Mg and the corresponding halide (iv), leads
to complex v. Carbonylation generates acylpalladium
complex vi that undergoes reductive elimination to
General procedure B: Pd-catalyzed carbonylative
Neigishi-type coupling of 2-iodoglycals and alkyl halides
To a flame-dried 25-mL reaction tube capped with a rubber
0
septum were added Mg (30 mg, 1.3 mmol, 5.0 equiv.) and
ZnCl
was thoroughly dried under vacuum while heated by a heat
gun and then backfilled with dry N . Pd(dba) (7.0 mg, 12
mol, 5 mol%) and Ruphos (6 mg, 12 mol, 5 mol%) were
then added to the reaction tube under a flow of dry N2, the
2
(205 mg, 1.5 mmol, 6.0 equiv.). The solid mixture
0
2
2

deliver the alkyl-ketone 3a and regenerate the active
0
Pd species. In some cases, as observed during the tube was then evacuated and backfilled with CO. Dry and
screening of the reaction conditions (Table 1) and the degassed THF was added to the system (2.5 mL), followed
by the corresponding 2-iodoglycal (0.25 mmol, 1.0 equiv.).
The mixture was then stirred at 50 °C for 5 min and then
the corresponding alkyl halide (1.25 mmol, 5.0 equiv.) was
added via syringe. A CO-filled balloon was connected to
the reaction tube and the system was stirred at 50 °C for 16
h. The resulting mixture was filtered through a plug of
silica using EtOAc as eluent, concentrated under reduced
pressure and purified by flash column chromatography.
Notes for this procedure:
reaction scope (Table 2 and 3), significant amounts of
dehalogenated glycals were observed. We speculate
that this by-product is formed via -hydride
elimination of complex v followed by reductive
elimination of the complex formed or by the
formation of an organomagnesium species from 2a
followed by its protonolysis.
BnO
BnO
OBn
O
1
) THF was degassed via freeze-thaw technique in 3
BnO
BnO
OBn
O
3a
cycles. Vacuum broken with CO in the last freeze-thaw
cycle;
2) The reaction yield is influenced by the quality of the
glycal and the alkyl halide used. Freshly purified glycals
produce superior results;
3) Vigorous stirring is also important, therefore the size of
the reaction vessel as well as the magnetic bar rotation
should to be taken into account.
Me
O
Pd0L
2a
I
i
reductive
elimination
oxidative
addition
BnO
BnO
OBn
O
vi
Me
BnO
OBn
O
Pd
BnO
Acknowledgements
O
ii
L
L
PdI
The authors gratefully thank the São Paulo Research
Foundation (FAPESP grant 2017/24821-4 to HAS,
CO
2
017/26673-2 to CHAE and 2016/24396-9 to MPD) and
The National Council for Scientific and Technological
Development (CNPq) for fellowship 306119/2014-5 to
HAS.
BnO
BnO
OBn
O
BnO
OBn
v
O
Me
BnO
iii
L
Pd
L
Pd
CO
I
CO
Keywords
transmetalation
BrZn
ZnBrI
iv
2
-iodoglycals, cross-coupling, palladium, carbon monoxide,
carbonylative coupling.
Figure 1. Proposed mechanism for the carbonylative
coupling of 2-iodoglycal 2a with 1-bromobutane.
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European Journal of Organic Chemistry
10.1002/ejoc.201901081
COMMUNICATION
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901081
COMMUNICATION
Graphical abstract
RO
RO
RO
RO
key features
Modular synthesis
One-pot procedure
O
O
“
CO”
RO
RO
Pd(dba)2/RuPhos
Scope versatility
Mild conditions
I
Mg0/ZnCl , THF
2
O
X
C(sp2) or
C(sp3): primary, secondary,
cyclic or acyclic
2
3
A versatile C(sp )-C(sp ) carbonylative Negishi-type
reaction allowing the access to glyco-ketones bearing
alkyl and aryl groups is described in this report. The
tolerance for different functional groups as well as
protecting groups denote the usefulness of the
methodology.
6
This article is protected by copyright. All rights reserved.