Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands

Article abstract of DOI:10.1002/anie.202016048

The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.

Full text of DOI:10.1002/anie.202016048

Angewandte
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Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 6778–6783
International Edition:
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doi.org/10.1002/anie.202016048
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Cross-Coupling
Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by
Ylide-Functionalized Phosphine Ligands
Zhiyong Hu, Xiao-Jing Wei, Jens Handelmann, Ann-Katrin Seitz, Ilja Rodstein,
Viktoria H. Gessner,* and Lukas J. Gooßen*
Dedicated to Professor Pierre Dixneuf on the occasion of his 80th birthday
Abstract: The coupling of aryl chlorides with Reformatsky
reagents is a desirable strategy for the construction of a-aryl
esters but has so far been substantially limited in the substrate
scope due to many challenges posed by various possible side
reactions. This limitation has now been overcome by the
tailoring of ylide-functionalized phosphines to fit the require-
ments of Negishi couplings. Record-setting activities were
achieved in palladium-catalyzed arylations of organozinc
reagents with aryl electrophiles using a cyclohexyl-YPhos
Figure 1. Examples of biologically active a-aryl alkylcarboxylates.
ligand bearing an ortho-tolyl-substituent in the backbone. This
highly electron-rich, bulky ligand enables the use of aryl
chlorides in room temperature couplings of Reformatsky
reagents. The reaction scope covers diversely functionalized
arylacetic and arylpropionic acid derivatives. Aryl bromides
and chlorides can be converted selectively over triflate electro-
philes, which permits consecutive coupling strategies.
Introduction
The a-aryl ester unit is a key functionality in biologically
active compounds and pharmaceuticals including the non-
steroidal anti-inflammatory agents flurbiprofen, ibuprofen,
naproxen and pranoprofen, as well as the antihistamine
fexofenadine (Figure 1).[1] In addition, a-aryl esters and
Scheme 1. Synthetic entries to a-aryl alkylcarboxylates.
amides are valuable synthons en route to aryl alcohols,
amines or nitriles.
Several methods are available for the construction of a-
aryl ester, but all of them have their individual limitations
À
(Scheme 1). Uncatalyzed C C bond-forming reactions be-
[*] Z. Hu, X.-J. Wei, A.-K. Seitz, Prof. Dr. L. J. Gooß en
Evonik Chair of Organic Chemistry
tween aryl electrophiles and enolates, for example, photo-
chemical reactions,[2] additions to benzynes,[3] reactions with
arylbismuth or aryllead reagents,[4] and nucleophilic aromatic
substitutions at electron-deficient arenes,[5] suffer from lim-
ited substrate scope, toxic reagents, and/or harsh reaction
conditions.
Ruhr-Universität Bochum
Universitätsstrasse 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
J. Handelmann, I. Rodstein, Prof. Dr. V. H. Gessner
Chair of Inorganic Chemistry II
Friedel–Crafts alkylations of arenes with a-halo carbonyl
compounds give a mixture of regioisomers.[6] Reactions
between arylboroxines with diazo esters are restricted by
multistep-synthesis of starting materials.[7] Catalytic carbon-
ylation reactions are advantageous on large scales but
experimentally difficult on lab scales.[8] Couplings of phenyl-
boronic acids or Grignard reagents[9] are convenient but
limited by the availability of the aryl nucleophile.
In the past decades, transition-metal-catalyzed a-aryla-
tions of carbonyl compounds have emerged as a powerful tool
for the late-stage synthesis of a-arylesters,[1a,5] but they call for
strongly basic conditions.[10] The increased acidity of the
Fakultät für Chemie und Biochemie
Ruhr-Universität Bochum
Universitätsstrasse 150, 44801 Bochum (Germany)
E-mail: viktoria.gessner@rub.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016048.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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arylated product compared to the starting material often
that YPhos catalysts would go well beyond the limits of
established ligand systems in the coupling of zinc enolates.
leads to undesired diarylation. In this respect, the use of
mildly basic zinc enolates (Reformatsky reagents)[11] was
a major advance. These reagents are easily accessible from a-
halo carbonyl compounds and zinc metal or zinc reagents, or Results and Discussion
directly from carbonyl compounds via deprotonation/trans-
metalation strategies.[12] Hartwig et al. established the Pd-
catalyzed Negishi coupling[13] of aryl bromides with Refor-
matsky reagents as one of the most generally applicable
synthetic concepts for the synthesis of functionalized a-aryl
alkyl esters and amides (Scheme 2).[14]
To test the potential of YPhos-Pd complexes as catalysts
in Negishi couplings, we chose the coupling of Reformatsky
reagent 2a with 3-chloroanisole (1a) as a test reaction
(Table 1). The reference in this area, Q-Phos-Pd systems,
were found to be inactive at room temperature. Other high-
performance ligands of the Buchwald or Fu-type, as well as
CataCXium A (Ad2PnBu), gave unsatisfactory yields, and
standard alkyl- or arylphosphines were ineffective (Table 1,
entries 1–3 and Table S1). No significant improvement was
observed when using defined Pd complexes. Also, the simple
YPhos ligand L1 with a methyl group in the backbone was
tested without success. However, the introduction of an aryl
substituent at the ylidic carbon atom (L2) unleashed the
desired reactivity. Fine-tuning of the ligand design revealed
a high sensitivity of the catalyst performance towards the
Scheme 2. Pd-catalyzed Negishi couplings of Reformatsky reagents.
Table 1: Coupling of aryl halides with Reformatsky reagent.[a]
The reaction critically depends on the use of extremely
bulky, electron-rich Q-Phos ligands. However, even with this
highly refined ligand system, the reaction is mostly limited to
aryl bromide substrates. Only a small range of activated aryl
chlorides were successfully converted at elevated temper-
atures, which led the authors to conclude that “studies are
required to address the scope of the coupling (… ) with
[15]
chlororarenes.” This limitation is also found for metal-
laphotoredox-catalyzed cross-coupling of aryl electrophiles
with halocarboxylates.[16]
The coupling of Reformatsky reagents with aryl chlor-
ides[17] still poses a substantial challenge, bringing even the
most sophisticated catalyst systems to their performance
limit.[15] This is due to several additional challenges: (1) C-
and O-metalated zinc enolates exist in equilibrium,[12a] and
Entry
X
Ligand L
Additive
t [h]
3 [%]
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
I
Q-Phos
XPhos
tBu-XPhos
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
L3
L3
L3
–
–
–
–
–
–
–
–
–
–
LiCl
LiBr
Et3N
TMEDA
DMPU
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
12
12
12
12
12
12
12
12
12
16
16
16
16
16
16
16
16
16
16
16
4
16
18
traces
35
55
30
10
16
65
80
84
62
97
82
95
À
competing C O bond formation needs to be avoided. (2) The
arylation product is more acidic than the starting material,
and protonation equilibria might lead to diarylation by-
products. (3) Uncatalyzed self-condensation of ester enolates
proceeds rapidly,[18] so that the oxidative addition of the aryl
electrophile must occur rapidly to compete with this back-
ground reaction.[19]
9
10
11
12
13
14
15
16[b]
17[b,c]
18[b,c]
19[b,c]
20[b,c]
We recently established ylide-functionalized monophos-
phine ligands (YPhos) as steering ligands in catalysis.[20]
Palladium-YPhos complexes are easily generated from phos-
phonium salts, which are accessible in great structural
diversity. The high donor strength induced by the ylide group
in combination with bulky substituents at the phosphorous
enables the synthesis of Pd catalysts with exceptional catalytic
activity in Buchwald–Hartwig aminations,[21] ketone aryla-
tions,[22] and cross-couplings of organolithium and Grignard
compounds.[23] The bulky substituents at the ligand facilitate
the formation of highly reactive monoligated Pd complexes,
which allow oxidative additions of deactivated aryl chlorides
at low temperatures.[21a] These properties gave us confidence
96 (95)[d]
97
90
68
L3
L3
OTf
[a] Conditions: 0.25 mmol 1a, 0.375 mmol 2a, 2 mol% Pd2dba3, 4 mol%
L, 1.5 equiv. additive, 0.3 mL THF, RT, 16 h. [b] 2 equiv. of additive were
used. [c] 1 mol% Pd2dba3. [d] Yield of isolated product based on
0.5 mmol scale. Yields determined by GC analysis using n-tetradecane as
internal standard.
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ligand structure, with the o-tolyl group being the optimal
substituent. Further increasing the steric demand and low-
ering the flexibility of the ligand structure by introduction of
a mesityl group (L4) reduced the catalytic activity. Also, the
more electron-rich PtBu2 ligand (L6) led to lower yields
suggesting that oxidative addition is not the critical step in the
catalytic cycle. Based on this knowledge we also tested the
newly designed ligand L5 with an ortho-anisyl substituent (see
the SI), which we hypothesized would facilitate transmetalla-
tion by pre-coordination of the zinc reagent. However, also
this ligand led to no further improvement, thus emphasizing
the challenges posed by this reaction.
Having identified the best ligand structure, we turned our
attention towards a further improvement of the reaction
conditions. The addition of solvents and additives is well
known to modify the solution structure of zinc reagents and
thereby influences their reactivity and stability.[24] The zinc
enolate has been reported to form stable dimers, which could
be one reason for its low reactivity.[24a,b] We thus employed
TMEDA as an additive, since it has been reported to facilitate
the formation of mononuclear organometallic species.[25] To
our delight, this additive strongly increased the efficiency of
the reaction, which we attribute to a higher concentration of
mononuclear zinc species. For this reason, we tested various
solvents, metal halides, and organic donor molecules (Ta-
ble S2). THF was found to be the most effective solvent,
TMEDA the best additive, also allowing a reduction of the
catalyst loading to 1 mol%. Under optimized conditions, the
reaction gave near-quantitative yields within 16 hours at room
temperature. High yields were also achieved when starting
from the corresponding aryl bromide (97%), iodide (90%),
and triflate (68%). The catalyst also effectively promotes the
coupling of aryl chlorides with standard zinc reagents such as
Scheme 3. Pd-catalyzed Negishi couplings with diethylzinc.
Table 2: Coupling of aryl chlorides with Reformatsky reagent 2.[a]
[a] Conditions: 0.5 mmol 1, 0.75 mmol 2a or 2c, 1 mol% Pd2dba3, 2 mol% L3, 2 equiv. TMEDA, 0.3 mL THF, RT, 16 h, yields of isolated product.
[b] 0.5 mol% Pd2dba3 and 1 mol% L3. [c] 2.2 equiv. 2c. [d] No aryl chloride but aryl bromide. [e] 3 equiv. 2c. [f] 40 h reaction time.
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diethyl zinc producing the desired product 4 in 85% yield
(Scheme 3).
A wide variety of aryl and heteroaryl as well as vinyl
tion.[4,9d,10g,26] For example, derivatives of menthol, cholester-
ol, loratadine or clofibric acid as well as estrone and arbutin
could be converted in good to high yields (Table 2, 39–46).
We next investigated the scope of the transformation with
regard to the zinc reagents (Table 3). Not only linear, but also
branched zinc enolates 2d were successfully coupled, which is
of substantial interest given the importance of the phenyl-
propenyl substructure. At this stage, the coupling of a,a-
disubstituted Reformatsky reagents gave only unsatisfactory
yields (see SI). Starting from commercially available 2-
bromo-6-methoxynaphthalene, the naproxen ester 50 was
obtained in almost quantitative yield. Amide enolates, even
with Weinreb-type reactivity, which are easily prepared from
Zn(TMP)2 or lithium enolates,[14b,27] were also successfully
coupled (Table 3, 51–53). The YPhos-Pd catalyst also allows
the room-temperature Negishi cross-coupling[28] of primary or
secondary alkyl-, benzyl-, and arylzinc reagents. Best results
were obtained when using Pd[COD]Cl2 rather than Pd2dba3
as the Pd source (conditions B). At this stage, we have no
explanation why Pd[COD]Cl2, which is almost ineffective as
the Pd source in the coupling of zinc enolates, is a superior Pd
precursor for other organozinc reagents. To our delight,
almost no rearrangement to linear products was observed.
Secondary alkylzinc reagent 2i was converted with 25:1
selectivity in favor of the branched isomer (56); for the
benzylic reagent 2n, solely branched product was observed
(61).
chlorides was successfully coupled with Reformatsky reagent
2a in good yields (Table 2). Suitable substrates range from
electron-deficient (pyrazinyl) to extremely electron-rich (p-
N,N-dimethylamino-phenyl) aryl- or heteroaryl chlorides, and
the scope covers sterically highly demanding groups (o,o-
dimethylphenyl) as well as coordinating pyridine or thio-
phene heterocycles. A wealth of functional groups is toler-
ated, including trifluoromethyl, fluoro, ester, trimethylsilyl,
nitrile, mesylate, and even pinacol boronate (Table 2, 14–17,
20, 22). The efficiency of the coupling is higher for sterically
demanding tert-butyl than for ethyl ester substrates, so that
they are recommended for particularly challenging aryl
chlorides. The performance limit of the system is reached
for 4-chlorophenol, which is likely to be deprotonated by the
enolate leading to an extremely electron-rich chloropheno-
late reluctant to undergo oxidative addition. Still, 4-chloro-
phenol was coupled to give 23 in a yield of 38%. The coupling
of 4-chloroaniline gave only unsatisfactory results, but 4-
bromoaniline gave compound 24 in near-quantitative yield
despite its free NH group (Table 2). The tolerance of these
functionalities is remarkable, especially when considering
À
that Pd-YPhos systems are powerful catalysts also for C N
bond formations. The established reaction protocol also
allowed successful coupling of more complex structures, thus
demonstrating its potential in late-stage functionaliza-
Since the preliminary studies (Table 1) indicated that the
YPhos-Pd complex also convert bromides and triflates to the
coupling products, we next examined a possible discrimina-
tion between the different electrophiles. To this end, we
performed competition experiments in which two electro-
philes were treated with zinc reagents (Scheme 4, Tables S3–
S12).
Table 3: Coupling of aryl chlorides with zinc reagents.
Enolates, alkyl- and arylzinc reagents all gave excellent
selectivities in favor of aryl bromides over triflates. A similar
selectivity pattern was also observed for Q-Phos, whereas X-
Phos was significantly less selective (see Table S13). Remark-
ably, even aryl chlorides were coupled preferentially over
triflates despite their lower inherent leaving group ability.[29]
Conditions A: 0.5 mmol 1, 0.75 mmol 2, 1 mol% Pd2dba3, 2 mol% L3,
0.3 mL THF, 2 equiv. TMEDA, RT, 16 h, yields of isolated product.
Conditions B: 0.5 mmol 1, 0.75 mmol 2, 3 mol% Pd[COD]Cl2, 3 mol%
L3, 0.3 mL THF, RT, 16 h, yields of isolated product. [a] No aryl chloride
but aryl bromide. [b] Using (Et2NCOCH2)2Zn, 2 mol% Pd2dba3, 4 mol%
L3, and 1.5 equiv. LiBr. [c] Zinc reagent was prepared by lithium enolate
with zinc chloride, 0.5 mmol 1, 0.6 mmol amide 2, 1 mol% Pd2dba3,
2 mol% L3, 1 mL THF.
Scheme 4. Selectivity of Br/Cl, Br/OTf, and Cl/OTf coupling with
different zinc reagents. Conditions: 0.25 mmol (1 equiv.) aryl electro-
philes, 1.1–1.5 equiv. zinc reagent 2, 1 mol% Pd2dba3, 2 mol% L3,
2 equiv. additive, 0.3 mL THF, RT or 08C, 16 h. Yields determined by
GC analysis using n-tetradecane or methyl decanoate as internal
standard. For detailed conditions see SI Table S3–S12.
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For the coupling with alkyl zinc reagents, the 20 mL vial was
charged with Pd[COD]Cl2 (4.33 mg, 3 mol%), and L3 (8.71 mg,
3 mol%) and closed with a septum cap. Under exclusion of air and
water, THF (0.3 mL) was added, and the resulting mixture was stirred
at room temperature for 1 h. Aryl chloride 1a (0.50 mmol), and zinc
reagent 2 (0.75 mmol, 1.5 equiv.) were added via syringe under argon
atmosphere. The resulting mixture was stirred at room temperature
for 16 h.
After the reactions were complete, they were quenched with
water (20 mL) and extracted with Et2O (3 ” 20 mL). The combined
organic phases were washed with brine (20 mL), dried over MgSO4,
filtered, and the volatiles were removed in vacuo. The residue was
purified by column chromatography (SiO2, pentane/Et2O or Cy/
EtOAc).
This points towards a strong preference of YPhos-Pd catalysts
for soft nucleophiles. The 10:1 selectivity of aryl bromides
over chlorides is also on a preparatively useful level.
We used the synthesis of ibuprofen as a showpiece to
demonstrate the synthetic utility of the distinct selectivity
pattern of the YPhos-Pd catalyst. Consecutive treatment of p-
bromochlorobenzene or p-bromophenyl triflate with isobutyl
zinc 2g, then with enolate 2d in the presence of YPhos-Pd
gave the desired product 69 in high selectivity and good yield
(Scheme 5).
Acknowledgements
Funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) under Germanyꢀs Excellence
Strategy— EXC-2033–390677874— RESOLV
and
SFB
TRR88 “3MET” and by the European Research Council
(Starting Grant: YlideLigands 677749). We thank UMI-
CORE for donating chemicals, BMBF and the state of
NRW (Center of Solvation Science “ZEMOS”), as well as the
CSC (fellowship to Z.H.) and the Alexander von Humboldt
Foundation (fellowship to X.-J.W.) for financial support and
M. Wüstefeld for HRMS measurements. Open access funding
enabled and organized by Projekt DEAL.
Scheme 5. Synthesis of ibuprofen. Cond. A: 1.3 equiv. 2g, 1 mol%
Pd2dba3, 2 mol% L3, 2 equiv. ZnBr2, 0.3 mL THF, RT, 16 h. Cond. B:
1.3 equiv. 2d, 1 mol% Pd2dba3, 2 mol% L3, 0.3 mL THF, 2 equiv.
TMEDA, RT, 16 h. Hydrolysis: 5 equiv. TFA, 5.5 mL DCM, RT, 12 h.
Conclusion
A sterically demanding YPhos-Pd catalyst has been
shown to be highly efficient in the Negishi cross-coupling of
aryl chlorides. Already the first catalyst generation goes well
beyond the state of the art in the challenging coupling of
Reformatsky reagents. Screening of a series of different
phosphines revealed that the ligand structure crucially affects
the catalyst efficiency resulting in drastic changes even with
seemingly small variations in the ligand architecture. The
developed reaction protocol showed a high tolerance towards
a variety of functional groups, which also allowed for the
coupling of a large substrate scope including the functional-
ization of complex molecular structures. Furthermore, high
selectivities were achieved with secondary alkyl zinc reagents
as well as for the discrimination between chloro, bromo and
triflate electrophiles, thus enabling the consecutive function-
alization with different nucleophiles. Overall, the reported
protocol substantially increases the breadth of application of
zinc reagents in palladium-catalyzed coupling reactions and
thus opens new possibilities for Negishi couplings also in the
functionalization of complex structures.
Conflict of Interest
The authors have filed patent WO2019030304 in collabora-
tion with UMICORE AG & Co. KG, covering YPhos ligands
and complexes.
Keywords: aryl chlorides ·cross-coupling ·phosphine ligands ·
Reformatsky reagent ·selectivity
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(5.80 mg, 2 mol%), and closed with a septum cap. Under exclusion of
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Manuscript received: December 2, 2020
Accepted manuscript online: January 11, 2021
Version of record online: January 28, 2021
Angew. Chem. Int. Ed. 2021, 60, 6778 –6783
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6783