One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation

Article abstract of DOI:10.1021/acscatal.6b00134

An efficient, in situ sequential 1,2-addition of alkyllithium reagents to benzamides followed by α-arylation of the resulting alkyl ketones is reported. The use of Pd[P(t-Bu)₃]₂, as catalyst for the α-arylation reaction, allows access to a wide variety of functionalized benzyl ketones in a modular way. The decomposition of the tetrahedral intermediate originated from the 1,2-addition liberates in situ a lithium amide, therefore avoiding the need of an external base for the α-arylation. The method affords good overall yields with a variety of alkyl lithium reagents, benzamides, and aryl bromides, bearing a range of functional groups with complete selectivity toward the monoarylated products.

Full text of DOI:10.1021/acscatal.6b00134

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Letter
One-Pot, Modular Approach to Functionalized
Ketones via Nucleophilic Addition of Alkyllithium
Reagents to Benzamides and Pd-Catalyzed #-Arylation.
Alexander Thomas Wolters, Valentín Hornillos, Dorus Heijnen, Massimo Giannerini, and Ben L. Feringa
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00134 • Publication Date (Web): 07 Mar 2016
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One-Pot, Modular Approach to Functionalized Ketones via
Nucleophilic Addition of Alkyllithium Reagents to Benzamides
and Pd-Catalyzed α-Arylation.
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Alexander T. Wolters,a Valentin Hornillos,*a Dorus Heijnen,a Massimo Giannerini,a and Ben L.
Feringa*a.
aStratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
ABSTRACT: An efficient in situ sequential 1,2-addition of alkyllithium reagents to benzamides followed by α-arylation of
the resulting alkyl ketones is reported. The use of Pd[P(t-Bu)3]2, as catalyst for the α-arylation reaction, allows access to a
wide variety of functionalized benzyl ketones in a modular way. The decomposition of the tetrahedral intermediate origi-
nated from the 1,2-addition liberates in situ a lithium amide, therefore avoiding the need of an external base for the α-
arylation. The method affords good overall yields with a variety of alkyl lithium reagents, benzamides and aryl bromides
bearing a range of functional groups with complete selectivity toward the monoarylated products.
KEYWORDS: α-Arylation, palladium, ketones, organolithium, amides, One-pot.
Palladium-catalyzed α-arylation of carbonyl and related
compounds has emerged as an effective Csp2-Csp3 bond
forming methodology that does not generally require pre-
formation of an organometallic reaction partner.1 This is
an important transformation in organic chemistry as the
α-aryl carbonyl moiety is found in a wide variety of bio-
logically active molecules of interest in medicinal chemis-
try.2 Moreover, α-arylated carbonyl compounds are pre-
cursors to functionalized molecules carrying amine, ole-
fin, nitrile, alcohol and other groups located α or β to the
aryl ring.3 The groups of Buchwald, Hartwig, and Miura
independently reported methods based on palladium
catalysts for the intermolecular α-arylation of ketones.4
Improved procedures5 and methods involving α-arylation
of simple acetone,6 esters,7 α-amino acid esters,8 nitroal-
kanes,9 amides,10 imides bearing the Evans auxiliary,11
aldehydes12 and nitriles13 have since been described. A
requirement frequently found in α-arylation reactions is
that an excess of a strong base is employed to reach full
conversion into the final product, and to avoid quenching
of the starting enolate by the more acidic benzylic pro-
tons of the tertiary α-aryl carbonyl product, which can
lead to the formation of diarylated compounds. The use
of an excess of base can also limit the functional group
tolerance, and promote racemization of carbonyl com-
pounds with an α-proton at a stereogenic center under
the reaction conditions.
Weinreb amide, the tetrahedral intermediate formed acts
as a masked ketone moiety allowing for an in situ cross-
coupling reaction with the second organolithium com-
pound. The corresponding ketones are then obtained
without the necessity to separately prepare, purify and
protect/deprotect the ketone intermediate. Inspired by
this process, we envisioned the possibility to combine, in
a one pot procedure, the 1,2-addition of an alkyllithium
reagent to a benzamide 1 with a Pd-catalyzed α-arylation
of the resulting alkylketone 2, where the lithium amide
expelled after the collapse of the tetrahedral intermediate
th could act as a base in the arylation process, therefore
avoiding the use of an external base (Scheme 1).
Scheme 1. One-pot, 1,2-addition of alkyllithium rea-
gents to benzamides, Pd-catalyzed α-arylation.
Our group has recently described a highly efficient one-
pot synthesis of functionalised ketones via sequential 1,2-
addition, Pd-catalyzed cross-coupling of Weinreb amides
using two distinct organolithium reagents.14 After 1,2-
addition of the first organolithium reagent to the
The realization of this process would not only eliminate
an extra synthetic step, and eventual purification of ke-
tone intermediate, but also allows the arylation reaction
to occur in the presence of rather low amount of base, as
this is slowly released from th and then consumed in the
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catalytic reaction. The modular combination of organo-
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Pd2(dba)3/XPhos16 as catalyst, and the presence of the
Buchwald-Hartwig17 coupling product between lithium
methoxy(methyl)amide generated and 4-bromotoluene
was detected in the reaction mixture (Table 1, entry 3).
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lithium reagents, benzamides and aryl bromides would
allow easy access to a variety of structurally diverse α-aryl
ketones from simple starting materials. Here we describe
the implementation of this 3-component strategy which
to the best of our knowledge is unprecedented in litera-
ture.
The formation of 4a involves the consumption of
LiNMe(OMe) that consequently cannot further act as a
base for the α-arylation reaction resulting in drastically
reduced yields of 3a. Employing Pd[P(t-Bu)3]218 as catalyst
the conversion toward 3a was increased although large
amounts of 2a and 4a were still observed in the mixture
(Entry 4). With the aim to reduce the stability of the
tetrahedral intermediate th and then increase the conver-
sion toward 3a, we moved to the more polar solvent THF
with heating at 60 °C. A further survey of different palla-
dium catalysts (Table 1, entries 5-11) revealed Pd[P(t-Bu)3]2
(C3) to be optimal although the presence of product 4a
was still observed (Entry 11). To our delight, when the
more inexpensive and simple N,N-dimethyl benzamide
was used as substrate, the α-arylated product 3a was ob-
tained with excellent selectivity (98%), inhibiting the
formation of the Buchwald-Hartwig amination product 4a
(Entry 12). Moreover, the amount of aryl bromide could
be reduced from 2.0 to 1.2 eq, still affording product 3a as
the exclusive product in 86% isolated yield (Table 1, entry
13).19 Importantly, when this reaction was performed on a
larger scale (6 mmol), using a lower catalyst loading (2.5
mol%), product 3a was still obtained with similar yield
(Table 1, entry 14). Decreasing the reaction temperature to
50 °C still gave 3a with high selectivity although the con-
version decreased slightly (Table 1, entry 15).
We selected the reaction between n-Buli and the
Weinreb amide 1a, at 0 °C, as a model for the first step,
and we then screened a variety of palladium catalysts for
the subsequent α-arylation reaction using 2 eq of 4-
bromotoluene (Table 1).
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Table 1. Optimization for the one-pot, nucleophilic
addition, Pd-catalyzed α-arylation
Entrya
Solvent/T °C
Toluene/80
Toluene/80
Toluene/80
Toluene/80
THF/60
Pd cat. (5 mol%)
Pd-PEPPSI-IPr (C1)
Pd-PEPPSI-IPent (C2)
Pd2(dba)3, XPhos (L1)
Pd[P(t-Bu)3]2 (C3)
R
2a/3a/4a (%)b
66:34:0
61:39:0
51:17:32
27:56:17
71:29:0
59:17:24
54:4:42
52:10:38
100:0:0
100:0:0
3:88:9
1
2
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
3
With the optimized reaction conditions in hand, we
next evaluated the efficacy of this catalyst system in the
arylation of a variety of aryl bromides (Table 2).
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Pd-PEPPSI-IPr (C1)
Pd-PEPPSI-IPent (C2)
Pd2(dba)3, XPhos (L1)
Pd2(dba)3, SPhos (L2)
PdCl2(dppf) (C4)
6
THF/60
Table 2. Scope of (hetero)aryl bromidesa,b,c
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THF/60
8
THF/60
9
THF/60
10
11
12
13c
THF/60
Pd2(dba)3, Josiphos (L4)
Pd[P(t-Bu)3]2 (C3)
THF/60
THF/60
Pd[P(t-Bu)3]2 (C3)
2:98:0
THF/60
Pd[P(t-Bu)3]2 (C3)
CH3
1:99:0
86% yieldd
14
THF/60
THF/50
Pd[P(t-Bu)3]2 (C3)
Pd[P(t-Bu)3]2 (C3)
CH3
CH3
86% yieldd,e
15c
8:92:0
aReaction conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of
amide 1 (0.5 mmol) followed by addition of Pd complex and 4-
bromotoluene (2 eq.). bDetermined by GC and 1H NMR. cUsing 1.2 eq.
d
e
of 4-bromotoluene. Isolated yield. 6.0 mmol (0.9 g) scale reaction
using 2.5 mol% of catalyst.
For this step, the reaction mixture was warmed to 80 °C
in toluene to promote the collapse of the tetrahedral
intermediate as it is stable at rt. The use of Pd-PEPPSI-iPr
or Pd-PEPPSI-iPent15 provided a mixture of the desired α-
arylated product 3a and non-arylated ketone 2a in a 34:66
and 39:61 ratio, respectively (Table 1, entries 1 and 2). Low
conversion toward 3a was also obtained using
aReaction conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of
amide 1 (0.5 mmol) followed by addition of Pd[P(t-Bu)3]2 (5 mol %)
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and (hetero)aryl bromide (1.2 eq.). bSelectivity >98% as determined
nucleophile also allowed the formation of product 3r in
the subsequent arylation reaction with 4-bromoanisole,
although the presence of some diarylated and triarylated
products was also observed (3r, Table 3). Nonetheless, a
more sterically hindered aryl bromide afforded exclusively
the monoarylated product in good overall yield (3s). In
addition, this protocol was also found efficient with dif-
ferent benzamides bearing electron-withdrawing (3t, 3u)
and electron donating substituents (3v). As mentioned
before, the Csp2-Cl bond remained untouched after the
reaction (3u).
by GC and 1HNMR. cIsolated yield.
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Both electron rich (3a-3d, 3g-3i, 3l and 3n) and electron
poor aryl bromides (3e, 3f, 3j, 3k and 3m) participate in
this reaction affording high selectivity and good overall
yields. A sterically more congested aryl bromide could
also be converted to the corresponding arylated ketone
without loss of selectivity (3d). The reaction proceeds
successfully in the presence of a variety of functional
groups including CF3 (3e), OMe (3g), SMe (3h), NMe2 (3i),
an ester (3j), a ketone (3k) and an acetal-protected alde-
hyde (3l). Using p-chloro-bromobenzene, the coupling
occurs exclusively at the bromine-substituted carbon,
leaving the chloride untouched, thereby providing an
opportunity for subsequent Pd-catalyzed cross-coupling
reactions (3f).20 Heterocyclic bromides could also be cou-
pled in high selectivity as demonstrated in the prepara-
tion of 3m and 3n. Importantly, no traces of isomerized
products derived from β-hydride elimination-reinsertion
reactions in the alkyl chain were observed in any of these
examples.21
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To further determine if the ketone enolate is formed di-
rectly from the tetrahedral intermediate or in a subse-
quent stage by reaction with the lithium amide released
in the reaction media, we performed a competition exper-
iment. One equivalent of butyrophenone and hexano-
phenone, respectively, were added after the 1,2-addition
reaction of n-BuLi and benzamide 1 together with 4-
bromoanisole and the palladium catalyst. As shown in
Scheme 2, the formation of a mixture of the three possible
α-aryl ketones and the corresponding starting materials
was observed, supporting therefore the pathway involving
lithium amide release prior to arylation.
We next explored the scope of the reaction with respect
to the alkyl lithium and benzamide components. As
shown in Table 3, alkyllithium reagents bearing different
linear or branched aliphatic substituents provided the
desired products in high selectivity and good overall
yields.22
Scheme 2. Study of the one-pot, nucleophilic addi-
tion of 1, Pd-catalyzed α-arylation in the presence of
butyrophenone and hexanophenone.a
Table 3. Scope of organolithium reagents and ben-
zamides.a,b,c
aConditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1
(0.5 mmol) followed by addition of Pd complex, butyrophenone (1.0
eq.), hexylphenone (1.0 eq.) and 4-bromoanisole (1.2 eq.). Relative
product distribution determined by GC.
In conclusion, we have developed a mild, modular and
highly efficient one-pot 1,2-addition of organolithium
reagents to benzamides, followed by
a palladium-
catalyzed α-arylation of the resulting ketones. The meth-
od is based on the use of commercially available Pd[P(t-
Bu)3]2 as catalyst for the α-arylation reaction and does not
need the addition of an external base to proceed. Moreo-
ver, the formation of di- and triarylated side products is
prevented while arylation is observed solely at the α-
position without isomerized products. The substrate
scope encompasses primary and secondary alkyllithium
reagents, benzamides and aryl bromides. It comprises a
range of functional groups or ortho-substitution, allowing
rapid access to functionalized ketones in a three compo-
nent modular approach.
aReaction conditions: R2Li (1 eq.) is added to a solution of amide 1
(0.5 mmol) followed by addition of Pd[P(t-Bu)3]2 (5 mol %) and
(hetero)aryl bromide (1.2 eq.). bSelectivity >98% as determined by
1
GC and H NMR unless otherwise noted. cIsolated yield. dReaction
performed in refluxing toluene. eGC selectivity (monoary-
lated/diarylated/triarylated 60:34:6). fThe corresponding Weinreb
amide was used instead.
The use of the more challenging s-BuLi allows for the
synthesis of a more congested α-quaternary carbon (3q)
without isomerization of the alkyl chain, presumably due
to a fast reductive elimination step.20c The use of MeLi as
ASSOCIATED CONTENT
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Experimental procedures, characterization data, and H, 19F
and 13C NMR spectra for new compounds are included in the
supporting information. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
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AUTHOR INFORMATION
Corresponding Author
* v.hornillos.gomez.recuero@rug.nl, b.l.feringa@rug.nl
9
(14) Giannerini, M.; Vila, C.; Hornillos, V.; Feringa, B. L. Chem.
Commun. 2016, 52, 1206-1209.
(15) a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.;
Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.
Eur. J. 2006, 12, 4743-4748; b) Valente, C.; Çalimsiz, S.; Hoi, K.
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Notes
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The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was supported financially by the European Re-
search Council (Advanced Investigator Grant, No. 227897 to
B.L.F.); The Netherlands Organization for Scientific Research
(NWO-CW); funding from the Ministry of Education, Cul-
ture and Science (Gravitation program 024.001.035); The
Royal Netherlands Academy of Arts and Sciences (KNAW);
and NRSC-Catalysis are gratefully acknowledged.
(16) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461-
1473.
(17) a) Surry, D. S.; Buchwald, S. L. Chem. Sci., 2011, 2, 27-50;
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(18) a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555; b) He, L.-Y.
Synlett 2015, 26, 851-852.
(19) Following the conversion of 1a into 3a in time showed
that 97% conversion was achieved in 6 h (see Supporting Infor-
mation, Figure S1). However, for practicality, the reactions were
conducted overnight.
(20) Negishi, E. Angew. Chem. Int. Ed. 2011, 50, 6738-6764; b)
Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6723-6737; c) de Mei-
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