Connecting remote C–H bond functionalization and decarboxylative coupling using simple amines

Article abstract of DOI:10.1038/s41557-020-0428-1

Transition metal-catalysed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements ‘C–H activation’ strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop general para-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of the reaction conditions. [Figure not available: see fulltext.].

Full text of DOI:10.1038/s41557-020-0428-1

Articles
https://doi.org/10.1038/s41557-020-0428-1
Connecting remote C–H bond functionalization
and decarboxylative coupling using simple amines
Francisco de Azambujaꢀ ꢀ1,3,5, Ming-Hsiu Yang1,4,5, Taisiia Feoktistova2, Manikandan Selvaraju1,
2
2
1
2
ꢀ✉
Alexander C. Brueckner , Markas A. Grove , Suvajit Koley , Paul Ha-Yeon Cheongꢀ ꢀ
and Ryan A. Altmanꢀ ꢀ
1
ꢀ✉
Transition metal-catalysed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strate-
gies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst
system to promote a para-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computa-
tional mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety
followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements ‘C–H activa-
tion’ strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an
inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop
general para-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may
be accessed with careful control of the reaction conditions.
n recent decades, transition-metal-catalysed cross-coupling reac- and catalysts. In contrast, reactions to functionalize C–H bonds at
tions1 and unactivated C–H bond functionalization reactions2 the para position of aromatic rings are frequently restricted Fig. 1)
I
emerged as two of the most powerful strategies for constructing to: (1) electron-rich substrates that bear nucleophilic character
C–C bonds. These strategies enabled the regioselective formation of and that typically provide mixtures of ortho- and para-substituted
reactive organometallic species derived from non-reactive groups, products11–22; (2) template-assisted reactions of benzyl and phenol
which has expanded the possibilities for retrosynthetic analysis and derivatives that require extra steps for the installation and removal
simplified synthetic routes. Additionally, these strategies enabled of the large template, which thus restricts a broad application23–26
;
the construction of hard-to-form bonds under mild conditions that (3) catalyst-controlled reactions that remain limited to the reactions
tolerate a broad spectrum of functional groups. Both strategies were of electron-deficient pyridines and arenes27–30 and (4) reactions that
successfully demonstrated with a variety of transition-metal-cata- proceed through a specialized persistent sulfur-based radical that
lyst systems; however, Pd-based systems remain among the most can engage in subsequent transformations31. Given these challenges,
common for both cross-coupling and C–H functionalization reac- alternative strategies to selectively functionalize the para C–H bond
tions, largely due to the low cost relative to that of other precious of aromatic rings, preferably through distinct mechanisms, are still
metals and to the well-behaved 2e– chemistry. Typically, decarbox- highly desirable and rarely realized.
ylative coupling reactions occur under mild, neutral and reductive
To complement these known transformations, we report an
conditions using a cycle starting with Pd(0), whereas C–H function- unexpected catalytic para-selective C–H alkylation reaction of
alization reactions occur with complimentary oxidative conditions arenes controlled by simple bases (Fig. 1e). In this reaction, the
using a cycle starting with Pd(ii). Despite the countless number of use of amine bases overrides the conventional decarboxylative
catalyst systems designed for these two strategies, simple and cre- benzylation pathway and provides products from a C–H function-
ative ways to connect these two reaction models would provide a alization pathway32. Extensive screening and mechanistic studies
significant advancement for synthetic chemistry. Here we report an (quantum mechanical computations, crossover experiments, kinetic
unprecedented switch of a classical cross-coupling reaction into a isotopic effect measurements and isotopic labelling studies) suggest
para-selective C–H functionalization reaction by a simple additive. a mechanism that involves an uncommon reversible Pd-catalysed
The functionalization of C–H bonds represents an important dearomatization event to access a previously ‘hidden’ dearomatized
and powerful strategy to convert simple arenes and hydrocarbons intermediate. In this process, the base differentiates the decarboxyl-
into functionalized molecules, and thus provide an efficient atom- ative benzylation and C–H functionalization pathways by enabling
and step-economic strategy to increase the structural complexity an irreversible 1,5-proton migration that rearomatizes the system
in simple building blocks, and to modify bioactive molecules at a to provide the final product. Despite scattered reports of analo-
late stage of synthesis3–5. However, the practical value of such C–H gous reactions of electron-rich substrates (for example, furan and
functionalization reactions depends on chemoselective activation naphthalenes) controlled by ligands33,34 or the intrinsic character
of a single C–H bond over others. For aromatic systems, ortho-6–8 of the substrate35–41, the present work exploits a simple additive to
and even meta-selective9,10 C–H bond functionalization reactions convert the reaction pathway from cross-coupling into the C–H
normally exploit directing groups and/or specially designed ligands functionalization of a broad set of substrates. Additionally, the
1Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS, USA. 2Department of Chemistry, Oregon State University, Corvallis, OR,
USA. 3Present address: Department of Chemistry, KU Leuven, Leuven, Belgium. 4Present address: The Scripps Research Institute, La Jolla, CA, USA.
5
✉
These authors contributed equally: Francisco de Azambuja, Ming-Hsiu Yang. e-mail: cheongh@oregonstate.edu; raaltman@ku.edu
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a
electron-rich P-based ligands (for example, P(p-C6H4OMe)3).
Although these catalyst systems improved the ratio of arylation to
benzylation, the yields of the arylated product 2 remained less than
40%, and provided varying yields of protonated enolate 4. However,
the use of basic additives improved both the selectivity and yield
of the reaction (Fig. 2a). Nitriles, inorganic bases and weak bases,
such as pyridine (pyr) and anilines, exclusively provided ben-
zylated product 3 (entries 2–7 in Fig. 2a). In contrast, more-basic
amines, which include N,N-dimethylaminopyridine (DMAP),
tripropylamine (nPr3N), triethylamine (Et3N) and N,N,N′,N′-
tetramethylethylenediamine (TMEDA), favoured arylated product 2
(entries 8–11). Further exploration of aliphatic amines demon-
strated a correlation between rigidity/hindrance and selectivity.
The conformationally constrained base, quinuclidine, provided a
low yield of arylated product 2 (entry 12 in Fig. 2a), whereas the
bulkier N,N-diisopropylethylamine (iPr2NEt) favoured benzylated
product 3 (entry 13). Thus, Et3N, with a compromise between basic-
ity and steric hindrance, afforded arylated product 2 in the highest
yield (entry 10). Additionally, the stoichiometry of Et3N also influ-
enced the yields of arylated product 2, with decreased amounts of
Et3N (<0.25equiv.) decreasing the selectivity of 2 (entries 10 and
14–16 in Fig. 2a). However, more than 1equiv. Et3N did not fur-
ther increase the yield (entries 10 and 17). This trend matched the
initial kinetic rates of the reaction, in which increased equivalents
of Et3N (0.05 to 0.20equiv.) increased the rate of reaction; however,
above this range, increases in the equivalents of Et3N did not further
accelerate the reaction (Supplementary Fig. 1). After further opti-
mization, the final conditions (2.5mol% Pd(PPh3)4, 1.0equiv. Et3N,
1,4-dioxane, 100°C) provided the desired arylated product 2 in 75%
isolated yield (entry 18 in Fig. 2a)).
EDG
EDG
Amines
Phthalimides
Phenols
[Cu], [Pd], [Au]
(Strong) oxidant
Isomers
+
+
Aryl silanes
α-Diazoesters
H
R1
R
1 = N-, O-, C-
based groups
b
iPr
iPr
Y
Si
Pd(OAc)2
N–Ac–Phe–OH
Oxidant
X
X
X
Install
template
X = CH2, Y = O
Remove
template
H
R2
H
NC
R2 = alkene, OAc
c
Ir (catalyst)
X
X
H
X
Bulky P–ligands
Ni/AlR3 (catalyst)
Electronic control
Steric control
R3
Bpin
X = C–alkyl, C–Si(alkyl)3
X = N, C–ketone, C–amide
R
3 = alkenyl, alkyl, Bpin
d
R4
R4
R4
Thianthrene
sulfoxide
Various
conditions
H
F
F
S
S
F
F
X
R4 = alkyl, aryl, halogen,
ether, amine, amide
X = C-, P-, B-, S-based
groups and halogens
Both the steric bulk and the strength of the base affected the
selectivity of the reaction (Fig. 2b). The use of weak bases with
pKa values that ranged from 4.0 to 8.0 (for example, pyr or N,N-
dimethylaniline) and bulky trialkyl amine bases (for example,
iPr2NEt) favoured the benzylation product43. Arylation products
only formed using trialkyl amine bases with pKa 8.0–10.5. Additional
experiments confirmed that the base strength governed the product
distribution. Specifically, reactions conducted with mixtures of pyr
and Et3N (4:1 and 1:4) all afforded the arylation product, which thus
confirms that the Brønsted basicity dictated the reaction outcome
(Fig. 2a, entries 19 and 20).
e
EWG
No base
R6 R7
R5
O
Benzylation
Me
Pd(PPh3)4
EWG
R6 R7
Mechanism?
Base
O
R5
H
EWG
R5 = H, alkyl, OR, SR, CF3, CO2Me
R6, R7 = alkyl, F
R5
R6 R7
EWG = CN, C(O)R
Arylation
Substrate scope. A variety of substrates that bear distinct elec-
tronic properties and substitution patterns on the benzylic moieties
underwent the decarboxylative arylation to incorporate an α,α-
difluoroketone group at the para position of the arenes relative to
the original benzyl position (Table 1). Generally, ortho-substituted
electron-rich (5a and 5b) and -deficient (5c and 5d) substrates pro-
vided the arylated products (6a–6d) in good yields and selectivi-
ties (>10:1). Particularly in the case of substrate 5d, no benzylated
product was observed by 19F NMR spectroscopy. The reaction of
substrate 5e, which bears a bulky phenyl group on the ortho position
Fig. 1 | C–H functionalization versus decarboxylative cross-coupling.
a–d, Current strategies for para-selective C–H functionalization of arenes
involve intrinsic substrate-derived selectivity (a), template-assisted
selectivity (b), catalyst-controlled selectivity (c) and reagent-controlled
selectivity (d). e, This work: base additives override the conventional
decarboxylative coupling (benzylation) and enable para-selective C–H
functionalization of arenes (arylation). Bpin, boronic acid pinacol ester;
EWG, electron withdrawing group.
experimental and computational studies provide new insights to of the aromatic ring, gave product 6e in modest yield. This reac-
support a previously speculative mechanism and demonstrate tion generated 35% of 9H-fluorene as the major side product, which
the specific role of the base in rendering the aforementioned might derive from an intramolecular cyclization reaction. Moreover,
selectivity. Finally, this mechanism provides an alternative pathway substrates that bear an ortho coordinating group (5f and 5g)
relative to classical Cα–C(sp2)-bond-forming reductive elimination and two ortho groups (5h) tolerated the present transformation and
at a metal centre42.
produced the arylated products (6f–6h) in good yields, although
they required a higher catalyst loading and increased reaction
temperatures. Even a non-substituted benzylic substrate (5i) was
Results and discussion
Brønsted basicity controls selectivity. Several factors, which transformed into the arylated product (6i) in good yield and selec-
include solvents, ligands and basic additives, affect the known tivity. This example demonstrated that the selectivity arose from
decarboxylative coupling process and enable the unusual C–H func- Et3N rather than from a substituent effect. The regioselectivity of
tionalization reaction. In early probing experiments, the use of vari- the arylation products was confirmed by extensive 2D NMR char-
ous Pd-based precatalysts afforded the α-aryl-α,α-difluoroketone acterization of adducts 2, 6b, 6d and 6f (Supplementary Fig. 2 and
product 2 in polar-coordinating solvents, as well as when exploiting Supplementary Tables 1–4).
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Steric hindrance on the benzyl moiety influenced the yields and
selectivity of the reaction (Table 1). Specifically, meta-substituted
substrates provided lower yields of the arylated products relative to
their ortho-substituted counterparts (6j versus 2, 6k versus 6a and
6l versus 6d). This trend probably arose from the steric hindrance
induced by the meta substituent that disfavoured the attack of α,α-
difluoroketone enolates at the para position, which thus reduced
the yields and selectivity of the arylated products. Accordingly,
substitution of both meta positions only provided the benzylation
product 7m. Further, substitution of the para position exclusively
afforded the benzylation products (7n–7o), with no evidence of
dearomatized species.
a
Me
Me
O
Ph
F
F
2
O
O
Me
O
5% Pd(PPh3)4
Base
O
Ph
Ph
Toluene, 110 °C
F
F
F
F
3
H
Me
O
1
H
Ph
F
F
4
The decarboxylative arylation reaction also selectively con-
verted substrates bearing a variety of aryl, heteroaryl and alkyl
α,α-difluoroketones into the products of C–H functionalization
(Table 1). Substrates bearing electron-rich (8a), -neutral (8b) and
-deficient (8c) aryl α,α-difluoroketone moieties provided the ary-
lated products (9a–9c) in high yields and selectivities (>20:1). Even
heteroaryl-containing α,α-difluoroketone substrates (5d–5e) worked
well under the standard reaction conditions. The tolerance to S- and
N-containing heterocycles suggests that the current reaction can be
applied towards accessing fluorinated analogues of biologically active
molecules. Additionally, the reaction of an aliphatic α,α-difluoroketone
substrate (8f) afforded a good yield of the arylated product (9f) with-
out further optimization. In general, products derived from C–C bond
formation at the meta and ortho positions were not detected.
The reaction demonstrated a broader utility, and was not
restricted to α-aryl-α,α-difluoroketones (Table 1). The reactions
of α,α-dialkyl and α-fluoro-α-alkyl nitrile-derived substrates were
successful (11a–11f). However, these substrates required reoptimi-
zation of the reaction conditions to achieve appropriate reactivities.
Most notably, these reactions required the use of a stronger base,
N-tert-butyl-N′,N′,N″,N″-tetramethylguanidine (tBu-TMG), to
deliver arylated products in good yields and excellent selectivities
(>25:1, except for the bulky naphthyl derivative 11f). Further, the
decarboxylative arylation delivered an α-fluoro-α-methyl ketone
(11g), although this reaction was complicated by protonation of
the in situ generated enolate and homocoupling of the benzyl moi-
eties. Nonetheless, isolation and characterization of product 11g
confirms that the reaction is not limited simply to difluorinated
ketones. Finally, α,α-dialkyl ketone substrate 10h afforded the ben-
zylated product without observation of the arylated product 11h.
Combined, these examples (11a–11g) suggest that this strategy can
be further developed to deliver a broad subset of products, although
the identification of appropriate bases might prove crucial to fur-
ther expand the scope.
Entry
1
Base (mol%)
---
2 (%)
3 (%)
89
88
91
0
4 (%)
0
0
0
2
Butyronitrile (300)
Na2CO3 (300)
PhONa (100)
PhCO2K (100)
Pyr (100)
3
3
0
3
4
0
18
6
5
2
71
85
89
4
6
4
0
7
N,N-dimethylaniline (100)
DMAP (100)
nPr3N (100)
0
2
8
54
58
70
69
12
12
65
63
49
69
82 (75b)
75
75
17
6
9
13
5
10
11
12
13
14
15
16
17
18a
19c
20c
Et3N (100)
6
TMEDA (100)
Quinuclidine (100)
iPr2NEt (100)
Et3N (50)
5
8
1
10
4
68
7
5
Et3N (25)
11
26
5
5
Et3N (10)
4
Et3N (300)
5
Et3N (100)
7
6
Et3N:pyr 4:1 (125)
Et3N:pyr 1:4 (125)
5
5
5
4
Best compromise of
b
basicity and steric hindrance
16
Et3N
Me
Me
TMEDA
N
N
12
8
N
Not basic enough
Too bulky
nPr3N
Me
N
Me
4
Mechanistic investigations. The general mechanism of the C–H
functionalization process to furnish α-aryl-α,α-difluoroketone or
α-benzyl-α,α-difluoroketone products is depicted in Fig. 3 (also
see Supplementary Fig. 3). An initial oxidative addition of the
Pd(0) catalyst to the substrate forms the Pd-benzyl carboxylate ion
pair that reversibly dissociates. On decarboxylation, the Pd-benzyl
carboxylate formed Pd-enolate complexes, of which the O-bound
and C-bound states exist in equilibrium. The C-bound Pd-enolate
irreversibly reductively eliminates to directly form the benzylation
product. In contrast, the O-bound Pd-enolate undergoes reversible
C–C bond formation at the para position to generate the dearo-
matized intermediate. Aromatization would provide the arylation
product. At the beginning of this study, the Et3N-controlled switch
of selectivity was not understood; Et3N could either bind to Pd and
facilitate the arylation process over the benzylation process (Pd
ligand sphere; Fig. 3 inset) or facilitate the rearomatization of the
dearomatized intermediate. To investigate these processes in deeper
detail, we conducted crossover, isotopic labelling, the kinetic iso-
tope effect (KIE) and computational studies.
iPr2NEt
PhCO2K
N
0
0
2
4
6
8
10
12
pKa
Fig. 2 | Brønsted basicity controls selectivity. a, Although the addition of
inorganic and non-basic amines favour the generation of the benzylation
product, the addition of basic amines inverts the selectivity and
produces the arylated product. b, The selectivity for arylation (2) versus
benzylation (3) correlated with the basicity and the steric hindrance
of the amine. Only unhindered basic amines (pKaꢀ>ꢀ8.0) favoured
the arylation product. Reaction conditions: 1 (0.10ꢀmmol), Pd(PPh3)4
(5.0ꢀmol%), base, toluene (0.050ꢀM), 110ꢀ°C, 24ꢀh. 19F NMR spectroscopy
yields (α,α,α-trifluorotoluene as standard). aOptimized conditions:
1 (0.50ꢀmmol), Pd(PPh3)4 (2.5ꢀmol%), Et3N (1.0 equiv.), 1,4-dioxane
(0.050ꢀM), 100ꢀ°C, 12ꢀh. bIsolated yield. cOptimized conditions:
1 (0.10ꢀmmol), Pd(PPh3)4 (2.5ꢀmol%), Et3N:pyr mixture (125ꢀmol%),
1,4-dioxane (0.050ꢀM), 100ꢀ°C.
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Table 1 | Substrate scope of benzyl esters
O
2.5–5.0% Pd(PPh3)4
Base (1.0–1.5 equiv.)
Me
Me
R3
O
O
O
X
R2
or
or
O
X
O
R2
R1
1,4-dioxane or DMA
100–130 °C
R4 R5
R1
F
F
R4 R5
11a–11h
R3
F
F
5a–5l, 8a–8fa
10a–10ha
6a–6l, 9a–f
X = CN, C(O)Ph
Substrates bearing distinct benzyl moieties
Me
Me
Me
Me
Me
Ph
Me
O
O
O
O
O
O
Ph
OMe
Ph
iPr
Ph
CO2Me
Ph
CF3
Ph
Ph
SMe
F
F
F
F
F
F
F
F
F
F
F
F
6a, 72%b
6b, 77%
6c, 65%c
Ar:Bn = 11:1d
6d, 83%
6e, 52%
6f, 60%c
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
Ph
SPh
Ph
Ph
Ph
Ph
Ph
F
F
F
F
F
F
F
F
F
F
F
F
Me
OMe
CF3
6g, 52%e
Ar:Bn = 10:1d
6h, 61%
6i, 57%
6j, 61%
Ar:Bn = 1:1d
6k, 52%
6l, 27%
Ar:Bn = 11:1d
Substrates bearing distinct ketone moieties (Ar1 = 4-Me-3-CF3-Ph)
O
O
O
O
O
O
Ar1
Ar1
CF3
Ar1
F
Ar1
Ar1
Ar1
N
F
F
F
F
F
F
F
F
F
F
F
S
N
MeO
F
Me
Ph
9a, 78%
9b, 79%
9c, 75%
9d, 80%
9e, 75%
9f, 73%
Substrates bearing monofluorinated and non-fluorinated moieties
Steric hindrance inhibited arylation
O
O
O
Me
Me
Me
Me
Me
5% Pd(PPh3)4
Et3N (1.0 equiv.)
Me
Me
O
Ph
Ph
NC
Me
NC
Me Bn
NC
Me Me
11c, 40%
F
F
F
F
1,4-dioxane, 100 °C
Me
Me
Me
7m, 59%
11a, 62%
11b, 56%
5ma
Me
Me
Me
Me
Me
R
O
NC
NC
Me
NC
Me Me
Ph
F
F
F
Me
O
O
5% Pd(PPh3)4
Et3N (1.0 equiv.)
11e, 22%f
7n, R = H, 70%f
7o, R = Me, 61%
11d, 26%
11f, 71%
Ar:Bn = 1.3:1g
O
Ph
1,4-dioxane, 100 °C
F
F
Me
R
Me
iPr
Me
O
O
O
5n, R = H
5o, R = Me
Ph
R
Ph
Ph
R1
Me
F
F
Me
11g, 20%h
Me
F
Me
Not observed
11h, 0%
Reaction conditions: a5a–5o or 8a–8f (0.50ꢀmmol), Pd(PPh3)4 (2.5–5.0ꢀmol%), Et3N (1.0ꢀequiv.), 1,4-dioxane (0.05ꢀM), 100ꢀ°C, 12–24ꢀh. For 10a–10e and 10h (0.50ꢀmmol), Pd(PPh3)4 (5.0ꢀmol%),
2-tbutyltetramethylguanidine (tBu-TMG, 1.5ꢀequiv.), N,N-dimethylacetamide (0.25ꢀM), 110ꢀ°C, 15ꢀh. For 10f (0.50ꢀmmol), Pd(PPh3)4 (5.0ꢀmol%), (4-CF3Ph)3P (10ꢀmol%), tetramethylguanidine (TMG,
2.0ꢀequiv.), toluene (0.25ꢀM), 110ꢀ°C, 15ꢀh. Isolated yields. b110ꢀ°C. c120ꢀ°C. dRatio of isolated product determined by 19F NMR spectroscopy. e1,4-dioxane (0.10ꢀM), 120ꢀ°C. f19F NMR spectroscopy yields
(α,α,α-trifluorotoluene as standard). gRatio of products determined by gas chromatography–flame ionization detector. hFor 10g (0.10ꢀmmol), Pd(PPh3)4 (5.0ꢀmol%), TMG (3.0ꢀequiv.), Cs2CO3 (3.0ꢀequiv.),
o-xylene (0.10ꢀM), 130ꢀ°C, 12ꢀh. DMA, N,N-dimethylacetamide.
Dissociation of the Pd-benzyl carboxylate ion pair. Support for the Pd-benzyl carboxylate ion pair, as previously observed in decar-
the reversible dissociation of the Pd-benzyl carboxylate ion pair boxylative allylation reactions44,45
derives from the crossover experiments (Fig. 4a and Supplementary
.
Table 5). The subjection of equimolar amounts of substrates 1 and Nature of C–H functionalization step. In this reaction, the hydro-
12 to standard reaction conditions provided all four possible prod- gen atom initially at the para position of the substrate migrated to
ucts in equivalent yields. This result implicates a fast scrambling of the benzylic position of the final arylation product. This migration
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Pd ligand sphere
studied by DFT
Pd(0)Ln
PPh3
Amine
O
O
Pd PPh3
Pd PPh3
O
Ph
F
F
PPh3
Pd
Amine
Pd
1
O
O
+
Pd(Ln)
–
O
Ph
PdLn
F
F
Pd-benzyl carboxylate
– CO2
O
H
Amine
additive
F
Ph
F
Dearomatized
intermediate
Ln
Ln
Pd
Pd
O
H
O
O
F
O
Ph
Ph
Ph
F
F
F
F
F
F
Ph
F
3
2
O-bound
Pd-enolate
C-bound
Benzylation product
(cross-coupling)
Arylation product
(C–H functionalization)
Pd-enolate
Fig. 3 | General reaction mechanism. The arylation (2) and benzylation (3) products derive from a common Pd-benzyl enolate intermediate for which the
O-bound and C-bound enolates exist in equilibrium. Although the C-bound Pd-enolate generates the expected benzylation product through a traditional
cross-coupling mechanism, the O-bound Pd-enolate rearranges to form the dearomatized intermediate that bears an acidic methine proton, and an
appropriate base facilitates rearomatization. Inset: Pd ligand sphere studied by density functional theory (DFT).
was unequivocally observed using the para-deuterated substrate does not involve cleavage of the C–H bond, but is still influenced by
13, which provided product 14 with a full transfer of deuterium the C–H versus C–D bond strengths. Combined, both experiments
to the benzylic position (Fig. 4b). This proton transfer occurred suggest that the rate-determining step occurs prior to the C–Hpara
in an intramolecular fashion after the C–C bond-forming event, bond cleavage and C–Hbenzyl bond formation (Fig. 3)36,51
as evidenced by a second cross-over experiment using deuterated
.
substrate 13 and unlabelled substrate 15. In this experiment, the Computations. An extensive computational investigation clarified
yields and distribution of the cross-over products closely matched the mechanism and the role of the Et3N in switching the selectiv-
those observed previously (Fig. 4a); however, the deuterium label ity. These results were validated by crossover experiments, label-
i
did not cross away from the Pr-bearing benzyl moiety (Fig. 4b). ling studies and reactivity trends (Fig. 4). All the conformational
Therefore, the hydrogen atom migration occurred inside the solvent and ligand isomers of species that led from the Pd-enolates were
cage and after the formation of the C–C bond. Computational stud- computed (Fig. 5). The results revealed that, uniformly, amine–Pd
ies suggest that this hydrogen transfer–rearomatization sequence coordination is disfavoured over the phosphine–Pd coordination
is enabled by the base (vide infra)40,46–48, as opposed to a hydride complexes (>2.5kcalmol–1; Supplementary Fig. 7). Thus, the amine
transfer mediated by Pd (ref. 34). Attempts to detect and/or isolate does not regulate selectivity by changing the hapticity of the ben-
the dearomatized intermediate and study its reactivity were unsuc- zyl or enolate ligands, but rather by acting as a base to trap a hid-
cessful, probably because conversion into the arylation product den intermediate. More specifically, the arylation transition state
occurs at a sufficiently fast rate to minimize observation under (TS) is kinetically favoured by 4.1kcalmol–1 over the benzylation
reaction conditions.
TS (23.6kcalmol–1 versus 27.7kcalmol–1, respectively) and, on
Further evidence of the late-stage irreversible C–H bond cleav- dearomatization, the critical dearomatized intermediate along the
age–hydrogen migration sequence was derived from KIE experi- arylation pathway bears an acidic methine proton adjacent to two
ments and reactions with a deuterated additive (Fig. 4c). To probe allyl and one fluoroalkyl groups. The pKa of this proton suggests
the nature of the C–H bond cleavage, the reaction was run in the the need for stronger amine bases than pyr (Fig. 2). In the pres-
presence of CD3OD, a tool widely applied to identify metal hydride ence of a trialkyl amine base, rapid rearomatization favours the
intermediates and reversible C–H abstractions49,50. Unlike many arylation product (26.5kcalmol–1 barrier for Me3N). This distinct
C–H functionalization reactions, this reaction formed no deuterated dearomatization and hydrogen-migration mechanism for reductive
product, which discounted mechanisms that involve reversible C–H elimination complements the recently reported reductive elimina-
bond activation and/or Pd–H and Pd–Ar intermediates (Fig. 4c). tion from a [LnPd(CF2COR)(Ar)] complex, which also generates
Additionally, KIEs were explored at both the benzylic and para posi- a C(α)–C(sp2) bond through a standard cross-coupling model42.
tions to investigate the sequence of C–C bond formation, Cpara–H In the absence of an appropriate base, the slower rearomatization
bond cleavage and Cbenzyl–H bond formation (Supplementary (32.1kcalmol–1 for pyr) favours the formation of the benzylation
Figs. 4–6). In parallel experiments, a KIE value of 1.0 was measured product (27.7kcalmol–1). These results match experimental obser-
at both the benzylic and para positions, which suggests that the rate- vations in which the use of Et3N provides the arylation products, but
determining step does not involve C–H bond cleavage (Fig. 4d)49. the use of pyr or no base provides the benzylation products.
In competitive experiments, 2° KIE values of 1.3–1.4 at the same
Overall,theselectivityofthisprocessisultimatelycontrolledbythe
positions support a reaction for which the rate-determining step relative kinetics between the benzylation TS and the deprotonation
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a
Expected
O
Crossover
Me
Me
Me
O
Me
F
F
F
F
5% Pd(PPh3)4
O
O
O
O
H
MeO
Et3N (1.0 equiv.)
+
15%
O
15%
O
O
1,4-dioxane,100 °C
F
F
F
F
Me
Me
iPr
Me
iPr
O
H
OMe
iPr
1
12
(0.5 equiv.)
(0.5 equiv.)
F
F
F
F
MeO
H
15%
13%
b
c
Me
O
O
Me
O
O
O
2.5% Pd(PPh3)4
Et3N (1.0 equiv.)
As in a
O
O
D
4
O
Ph
+
Ph
CD3OD
F
F
iPr
Ph
Ph
F
F
F
1,4-dioxane,100 °C
(5 equiv.)
Me
iPr
F
F
D
F
1
2, 26%
0% D incorporated
15%
13
14, 72%
>98% incorporation of D
D = 95%
d
H
H
O
O
O
O
O
F
2.5% Pd(PPh3)4
Et3N (1.0 equiv.)
O
D/H
O
Ph
F
F
1,4-dioxane
F
iPr
H
Ph
iPr
D
H/D
iPr
O
100 °C, 70 min
13
F
F
As in a
6b/14
kH/kD
1.0
O
O
O
5b and 13
F
F
Parallel
Competitive
1.4
F
F
Me
H
OMe
D/H D/H
H
15
O
O
F
2.5% Pd(PPh3)4
Et3N (1.0 equiv.)
H/D D/H
O
Expected
Crossover
O
Ph
(0.5 equiv. each)
H
OMe
Me
H
OMe
1,4-dioxane
F
Ph
iPr
iPr
100 °C, 70 min
iPr
Me
0%
iPr
F
F
5b and 16
%D
98%
0%
98%
6b/17
kH/kD
1.0
Parallel
Competitive
1.3
Fig. 4 | Mechanistic experiments. a, The detection of cross-over products supports the dissociation of the Pd-benzyl carboxylate ion pair. b, The para
hydrogen atom migrated to the benzylic position at a late stage of the reaction, as indicated using a D-labelled substrate. Using a double-labelled substrate,
the D does not migrate away from the iPr-containing benzyl ring, which suggests that C–C bond formation occurs prior to hydrogen migration, and that the
hydrogen migration occurs within the solvent sphere of the substrate. c, On the addition of MeOH-d4, the lack of deuteration excludes reaction pathways
that involve discrete Pd–H and/or Pd–Ar intermediates that might be formed by direct C–Hpara palladation. d, The experimental KIE values at the para and
benzyl positions indicate that the rate-determining step occurs prior to the C–Hpara bond cleavage and C–Hbenzyl bond formation.
(deprot) TS, as the trialkyl amine base governs the reaction by position, as well as the unfavourable orientations of the benzyl and
providing a low-energy pathway for rearomatization, which can- enolate moieties that would be required to form C–C bonds at the
not otherwise occur in the absence of an appropriate base. Further, ortho position (Supplementary Fig. 9).
this mechanism explains why sterically bulky bases are ineffective
in rendering arylation products, as these bases are too hindered to Conclusions
deprotonate the methine position. This controlling feature not only In summary, amine additives transformed a benchmark decarboxyl-
applies to α,α-difluoroketone-based substrates, for which the fluo- ative-coupling reaction into a unique non-chelation-controlled para-
rine atoms lower the pKa of the methine proton in the deprot TS and selective C–H functionalization reaction. The two reaction models
enable the use of a weaker base (NEt3), but also to nitrile-derived typically require orthogonal substrates and conditions, but can now
substrates (Table 1), which bear less-acidic protons on the analogous be accessed using complementary reaction conditions, namely by
dearomatized intermediate that require stronger bases (for example, simply adding an inexpensive base to a readily available Pd-based
t
TMG and Bu-TMG) to facilitate proton transfer and rearomatiza- catalyst system. Mechanistically, the reaction involves dearomative
tion. To date, reactions of α,α-dialkyl ketone-derived substrates gen- C–C bond formation to generate a hidden dearomatized intermedi-
erated benzylation products, as supported by computational studies ate. This process simultaneously acidified a typically inert proton
(Supplementary Fig. 8) that predicted that the benzylation (ben- and provided a low-energy pathway for base-mediated rearomati-
zylation TS ∆G‡ =33.7kcalmol–1) is favoured over arylation using zation to para-substituted toluene derivatives from substrates that
tBu-TMG (tBu–TMG–deprot TS ∆G‡ =47.2kcalmol–1) and trialkyl would typically provide benzyl-substituted products. This dearo-
amine (Me3N–deprot TS ∆G‡ =43.1kcalmol–1). Computational matized intermediate might exist in other catalytic processes32, and
studies also suggest that the excellent para selectivity derives from exploitation of this strategy should enable the construction of new
the inability of the benzylic cation to distribute charge to the meta and unique products as yet inaccessible by current means.
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‡
Benzylation
Pd-enolates
Arylation
O
F
‡
‡
PPh3
O
Ph
CH2
O
PPh3
F
Pd
H
Pd
PPh3
Ph
Pd
F
F
Amine
32.1
F
F
CH2
Benzylation TS
27.7
Pyridine–deprot TS
Me3N–deprot TS
Arylation TS
23.6
26.5
PPh3
PPh3
Pd
PPh3
11.6
0.2
F
0.0
PdPPh3
F
PdPPh3
F
PPh3
PPh3
Pd
F
O
PPh3
PPh3
CH2
Pd
F
O
O
H
F
Dearomatized
intermediate
C bound
–5.1
Benzylation
product
F
F
–4.8
O
O bound
Arylation
F
CH3
O
product
F
Fig. 5 | energetics of key steps. The computed reaction coordinate diagram for the formation of arylation and benzylation products from Pd-enolate
complexes suggests a process controlled by Curtin–Hammett kinetics in which the O-bound and C-bound enolates and the previously hidden
dearomatized intermediate exist in equilibrium, and the product distribution is regulated by the energies for C–C reductive elimination versus those
for rearomatization. Specifically, the selectivity for arylation versus benzylation is controlled by the ability of the amine additive to lower the energy for
rearomatization (pyr–deprot TS and Me3N–deprot TS) relative to C–C reductive elimination (benzylation TS).
14. Wu, Z. et al. Palladium-catalyzed para-selective arylation of phenols with aryl
Online content
iodides in water. Chem. Commun. 49, 7653–7655 (2013).
15. Yu, Z. et al. Highly site-selective direct C–H bond functionalization of
phenols with α-aryl-α-diazoacetates and diazooxindoles via gold catalysis.
J. Am. Chem. Soc. 136, 6904–6907 (2014).
Any Nature Research reporting summaries, source data, extended data,
supplementary information, acknowledgements, peer review information; details
of author contributions and competing interests; and statements of data and code
availability are available at https://doi.org/10.1038/s41557-020-0428-1.
16. Berzina, B., Sokolovs, I. & Suna, E. Copper-catalyzed para-selective C–H
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Received: 28 April 2018; Accepted: 23 January 2020;
Published: xx xx xxxx
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optimized the reaction conditions. M.-H.Y., F.d.A., M.S. and S.K. explored the substrate
scope. F.d.A. designed and conducted the mechanistic experiments. R.A.A. supervised
the synthetic and mechanistic portions of the experimental work. T.F. used density
functional theory (DFT) to compute the key transition states and intermediates in the
different proposed mechanisms, which ultimately led to pinpointing the operative
pathway; A.C.B. performed the initial DFT computations; M.A.G. performed energy
refinements at various levels of theory to verify that the DFT results were in line with
experimental results. P.H.-Y.C. supervised the computational aspect of the work and also
contributed to the DFT energy refinements. All the authors contributed to the writing
and editing of the manuscript.
Data availability
All data supporting the findings of this study are available within the paper and its
Supplementary Information files.
Acknowledgements
We thank the donors of the Herman Frasch Foundation for Chemical Research
(701-HF12), the National Science Foundation (NSF, CHE-1455163) and the National
Institute of General Medical Sciences (R35 GM124661) for supporting this work.
NMR instrumentation was provided by NIH (S10OD016360, S10RR024664 and
P20GM103418) and NSF Grants (9977422 and 0320648). P.H.-Y.C. acknowledges
financial support from the Bert and Emelyn Christensen Professorship and the Vicki &
Patrick F. Stone family. P.H.-Y.C., T.F., M.A.G. and A.C.B. acknowledge the NSF
(CHE-1352663) and the computing infrastructure in part provided by the NSF
Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF, CHE-1102637).
T.F. acknowledges the Summer Fellowship Award from the department of Chemistry at
Oregon State University.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-020-0428-1.
Author contributions
Correspondence and requests for materials should be addressed to P.H.-Y.C. or R.A.A.
Reprints and permissions information is available at www.nature.com/reprints.
F.d.A. and M.-H.Y. contributed equally. R.A.A. and M.-H.Y. created the project. R.A.A.,
M.-H.Y., F.d.A., M.S. and S.K. designed the experiments. M.-H.Y., M.S. and S.K.
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