One-pot sequential 1,2-addition, Pd-catalysed cross-coupling of organolithium reagents with Weinreb amides

Article abstract of DOI:10.1039/c5cc08507a

An efficient sequential 1,2-addition/cross-coupling of Weinreb amides with two organolithium reagents is reported. This synthetic approach allows access to a wide variety of functionalized ketones in a modular way. The one-pot procedure presented here takes advantage of a kinetically stable tetrahedral Weinreb intermediate during subsequent Pd-catalyzed cross-coupling with the second organolithium reagent leading, within short reaction times and under mild conditions, to the formation of ketones in excellent overall yields.

Full text of DOI:10.1039/c5cc08507a

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One-Pot, Fast and Modular Approach to Alkyl- and Aryl Ketones
via Sequential 1,2-Addition,Pd-Catalysed Cross-Coupling of
Organolithium Reagents with Weinreb Amides
Received 00th January 20xx,
Accepted 00th January 20xx
M. Giannerini,a C. Vila,a V. Hornillosa and B. L. Feringa*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient sequential 1,2-addition/cross-coupling of Weinreb place.11 Notably, while this flow protocol affords valuable
amides with two organolithium reagents is reported. This transformations of substrates bearing ketone moieties, it does
synthetic approach allows access to
a wide variety of not account for the synthesis of the ketone itself which has to
functionalized ketones in a modular way. The one-pot procedure be planned in an earlier separate synthetic step. Recently our
presented here takes advantage of a kinetically stable tetrahedral group developed a protocol for the direct Pd-catalysed cross-
Weinreb intermediate during subsequent Pd-catalyzed cross- coupling of organolithium reagents at room temperature.12-16
coupling with the second organolithium reagent leading, within We were attracted by the possibility to explore this cross-
short reaction times and under mild conditions, to the formation coupling methodology toward a novel one-pot procedure that,
of ketones in excellent overall yields.
for the first time, would combine the synthesis and further
modification of unprotected ketones with organolithium
compounds. We envisioned that this could be achieved by
performing a 1,2-addition of an organolithium reagent to a
Weinreb amide17 followed by a direct Pd-catalysed cross-
coupling18 with a second organolithium compound. The well-
Organolithium compounds are highly versatile reagents in
organic synthesis1 finding widespread application also in the
preparation of ketones2, a common structural motif present in
a variety of natural products, drugs3 and fragrancies.4 For
instance the use of organolithium reagents in combination
with carboxylic acids5a, nitriles5a,5b, dialkylamides5a,5c and acyl
chlorides6 to afford the corresponding ketones has been
explored for a long time.5,6 Hatton, Jamison and co-workers
provided an elegant solution in their continuous flow synthesis
of ketones from carbon dioxide and organolithium and
Grignard reagents.7 Other advances to unsymmetrical ketones
include the use of dithianes as dianion equivalents by the
groups of Tietze8 and Smith9 and, more recently, a pyrrole
bearing formyl carbonyl dication linchpin reagent introduced
by Sarpong and co-workers.10 While all these methodologies
deal with the preparation of ketones, still the use of
organolithium compounds in the modification of molecules
containing unprotected ketones has major constraints. 1,2-
Addition to the carbonyl rapidly takes place with
organolithium reagents and prior protection of the ketone
seems often inevitable. Yoshida and co-workers reported the
formation in flow of aryllithium reagents containing
unprotected ketones that, due to the short residence time,
immediately react preventing self-condensation to take
established stable tetrahedral intermediate 2, arising from the
1,2-addition of R1Li to a Weinreb amide, would act as a
masked ketone moiety allowing a safe addition of a second
equivalent of an organolithium for the cross-coupling step
(R2Li, Scheme 1).
-Novel substrate class
Interchanging RLi reagents
in Pd cat. CC
leads easily to modular
-No isolation needed
functionalization
OMe
R2Li
R1
R1
N
R1Li
O
Pd cat.
n
n
n
Li
N
O
O
O
R2
Br
Br
2
1
3
Two very fast processes
Rapid access to various ketones
Scheme 1 One-pot 1,2-addition/Pd-Catalyzed cross-coupling with Weinreb
amides.
Despite the fact that cross-coupling of softer organometallic
reagents19 with ketone-containing molecules has been
established, the combination of the processes involving direct
cross-coupling of organometallic reagents with the synthesis of
the ketone moiety is unprecedented. Consequently, the
ketone is generally synthetized separately requiring an extra
synthetic step and an eventual purification. The process we
present here affords, in
a one-pot operation, various
unsymmetric ketones using organolithium reagents without
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the necessity to separately prepare, purify and S1). Cross-coupling was observed when the Pd-catalyst was
n
introduced prior to (entry 3) or after addition of BuLi (entry
protect/deprotect the ketone.
To the best of our knowledge, combined 1,2-addition to a 4), while the selectivity was significantly improved when the
Weinreb amide and Pd-catalysed cross-coupling in the temperature was raised to 40 °C (entry 5). A brief ligand
presence of the tetrahedral intermediate in a one-pot screening allowed us to optimize the conversion (81% isolated
procedure is unprecedented.20,21. The modular combination of yield of
3) and selectivity (>99% cross-coupled product;
two different RLi reagents in the two sequential steps allows dehalogenation completely suppressed), identifying 2.5 mol%
easy access to a range of structurally diverse ketones from Pd2(dba)3 / 10 mol% XPhos18i as the most efficient catalyst
simple starting materials. Despite the clear potential for the (entry 6).
anticipated approach (Scheme 1), we realized that the nature With the optimized catalytic system in hand we set out to
of the intermediate
2 might also provide an unsurmountable explore the scope, synthetic utility and efficiency of the new
obstacle due to the presence of a metal coordinating site (i.e. procedure for unsymmetric ketone formation. In particular
the charged adduct of the amide) that could potentially with the modular choice of different lithium reagents,
interfere with the Pd-catalyst in the cross-coupling step.
structurally diverse ketones can be obtained rapidly from
Initially we compared the performance of a dimethyl amide simple starting materials. Using aryl- and alkyllithium in the
derivative against the Weinreb amide to use sequential C-C first step and aryl- and heteroaryllithium reagents
bond formation combining two different lithium reagents (1 (commercially available or prepared either via halogen/lithium
n
eq. of BuLi followed by 1.5 eq. of PhLi) using 5 mol% of Pd- exchange or direct lithiation23) in combination with Weinreb
PEPPSI-IPent catalyst22 at room temperature (Table 1, Method amide 1a provided alkyl biaryl ketones (Table 2. Entry 1-3) and
A).
Table 1. Optimization for the one-pot 1,2-addition, cross-coupling of
Weinreb amides.
aryl biaryl ketones (Table 2. Entry 4, 5) in excellent yields in
less than 3 h. To further demonstrate the versatility of the
procedure the use of alkylLi/alkylLi (including the cyclopropyl
moiety24) and heteroaryl/heteroaryllithium reagents in both
steps proved to be successful in the one-pot transformation as
well (Entries 6-9). As a variety of ketones was obtained
successfully from the aromatic amide 1a, we continued to
explore the use of alkyl Weinreb amide 1b to enable the
preparation of alkyl-alkyl ketones. To our delight the one-pot
reaction readily took place also in this case giving rise to a
series of alkyl-alkyl ketones featured with heteroaryl (Entry
10), aryl (Entry 11-13), funtionalized alkyl (Entry 14) and
hindered di-ortho-substituted 1,3-dimethoxyphenyl moieties
(Entry 15). A limitation is seen when using a homobenzylic
Weinreb amide as the acidity of the benzylic protons prevent
effective use or RLi reagents (see ESI, Table S1). It was,
however, possible to successfully access (hetero)aryl-alkyl
ketones from amide 1b with the same efficiency noted for the
benzamide 1a (Entries 16-19). Highlighting the short reaction
times featuring this procedure, the coupling of furyllithium in
the second step was performed successfully in 5 min affording,
Entrya
X
Method
Pd cat. Mol%
PEPPSI-IPent 5
PEPPSI-IPent 5
PEPPSI-IPent 5
PEPPSI-IPent 5
PEPPSI-IPent 5
T1/T2
3/4/5 (%)b
-/-/99
1
2
3
4
5
6
Me
A
B
A
B
B
B
r.t/r.t.
Me
r.t/r.t.
50/24/14c
41/4/56
48/6/46
84/5/11
OMe
OMe
OMe
OMe
r.t/r.t.
r.t/r.t.
r.t/40 °C
r.t/40 °C
Pd2(dba)3 2.5
XPhos 10
99/-/-
81% yieldd
aReaction conditions method A: nBuLi (1 equiv. over 1 h) added to a mixture of
Pd2dba3 2.5 mol%, XPhos 10 mol% and 0.3 mmol of substrate in toluene,
followed by the addition of PhLi (1.5 eq. over 1.5 h). Method B: nBuLi (1 equiv.
over 1 h) added to a solution of 0.3 mmol of substrate in toluene followed by
addition of Pd complex and by PhLi (1.5 eq. over 1.5 h) bDetermined by GC and
1H NMR. c12 % of 1,1-diphenyl-1-pentene was observed. dIsolated yield.
in an overall reaction time slightly above
1 h, the
propiophenone 3p in 80% yield (Entry 16). Furthermore, the
protocol was found efficient also with ortho- and importantly
meta-substituted aryl bromides (Entries 20-23).25 Notably the
latter gives access to meta-acylated aromatic compounds
difficult to obtain via e.g. Friedel-Crafts acylation while various
meta-substituted benzophenones are important building
blocks like in the case of a BACE inhibitor.
Under these conditions, using the dimethylamide, the
expected 1,2-addition takes place but the subsequent cross-
coupling of the bromo-ketone
5 to the final product 3 did not
Finally, we implemented the one-pot 1,2-addition, cross–
coupling procedure to prepare cyclopropyl aryl ketones. These
proceed (Table 1, entry 1). It is also evident from this
experiment that the 1,2-addition proceeds prior to any cross-
coupling or dehalogenation process. Reversing the order by
ketones are versatile intermediates for
a
range of
pharmaceuticals, allowing transformation both at the ketone
and the cyclopropyl moiety (Scheme 2. Equation 1). Starting
with Weinreb amide 1d the sequential addition of
cyclopropyllithium and phenyllithium provided 3x (85% yield),
a known precursor for the HIV protease binding agent.
n
first adding the BuLi (Table 1, Method B) followed by the Pd
catalyst and finally phenyllithium up to 50% of cross-coupling
is observed although dehalogenation is a major competing
reaction (entry 2). Similar experiments with the corresponding
Weinreb amide 1a looked more promising (see also ESI, Table
2 | J. Name., 2012, 00, 1-3
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R1
nBu
R2
Product
Table 2. Scope of the reaction.
Entry
Substrate
14
1b
3n 78%
Entrya
Substrate
R1
R2
Productb
15
1b
nBu
1
nBu
Ph
3o 71%
3p 80%
3q 71%
3r 89%
1a
1a
16d
1b
1b
1b
Ph
3a 81%
3b 76%
3c 84%
3d 85%
2
3
4
nHex
nBu
Ph
Ph
17
Ph
1a
1a
18
Ph
Ph
Ph
19
1b
3s 84%
5
6
7
1a
1a
1a
Ph
nBu
nBu
Ph
3e 84%
3f 87%
20
21
nHex
Ph
1c
Me
3t 67%
3u 72%
Me
Ph
Ph
1d
1d
3g 80%
22
23
nBu
Ph
O
8
1a
1a
3v 71%
3w 72%
1d
3h 80%
3i 86%
3j 81%
9c
aReaction performed on 0.3 mmol of substrate dissolved in toluene. R1Li was
diluted to 0.8 ml with toluene and added over 1 h. Then the Pd complex, formed
in 0.5 ml of toluene, was added, followed by slow addition of a diluted solution
of R2Li 1.5 eq. over 1.5 h. bIsolated yields. c1.5 eq. of TMEDA were added when
performing the addition of R2Li. dR2Li was added over 5 min.
10
nBu
1b
1b
In conclusion we developed a modular and highly efficient
one-pot sequential 1,2-addition, cross-coupling from Weinreb
amides using two distinct organolithium reagents. Avoiding the
work-up/purification of the intermediate bromo-ketone and
taking advantage of the extremely fast cross-coupling with
organolithium compounds under mild conditions, the overall
process requires only 1 to 2.5 h reaction time. Structure
diversity in the products is readily achieved starting with a
range of easily accessible organolithium reagents. Advantage is
taken here of the in situ protection of the ketone (after the
first 1,2-addition of the organolithium to the Weinreb amide)
allowing uncompromised addition and cross-coupling of a
11
12
nBu
Ph
Ph
3k 77%
3li74%
1b
1b
nHex
13
nBu
3m 83%
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12 a) M. Giannerini, M. Fañanás-Mastral and B. L. Feringa, Nat.
Chem. 2013, , 667; b) V. Hornillos, M. Giannerini, C. Vila, M.
second organolithium reagent. This methodology significantly
broadens the functional group tolerance of palladium
catalysed cross-couplings with highly reactive organolithium
reagents making it amenable to the synthesis of molecules
bearing sensitive carbonyl moieties.
5
Fañanás-Mastral and B. L. Feringa, Org. Lett. 2013, 15, 5114;
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Scheme 2. Synthetic applicability of the one-pot 1,2 addition, cross-coupling
with Weinreb amides
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,
The Netherlands Organization for Scientific Research (NWO-
CW), the Royal Netherland Academy of Arts and Sciences
(KNAW) and the Ministry of Education Culture and Science
(Gravitation program 024.601035) are acknowledged for
financial support. C.V. was supported by Intra-European Marie
Curie fellowship (FP7-PEOPLE-2011-IEF) (Contract number:
300826).
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4 | J. Name., 2012, 00, 1-3
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