Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes

Article abstract of DOI:10.1021/jacs.0c06244

This report details a decarboxylative cross-coupling of (hetero)aryl carboxylates with iodoarenes in the presence of a gold catalyst (>25 examples, up to 96% yield). This reaction is site specific, which overcomes prior limitations associated with gold catalyzed oxidative coupling reactions. The reactivity of the (hetero)aryl carboxylate correlates qualitatively to the field effect parameter (Fortho). Reactions with isolated gold complexes and DFT calculations support a mechanism proceeding through oxidative addition at a gold(I) cation with decarboxylation being viable at either a gold(I) or a silver(I) species.

Full text of DOI:10.1021/jacs.0c06244

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Article
Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes
Ryan A. Daley, Aaron S. Morrenzin, Sharon R. Neufeldt, and Joseph J Topczewski
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06244 • Publication Date (Web): 07 Jul 2020
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Journal of the American Chemical Society
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Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes
Ryan A. Daley1, Aaron S. Morrenzin2, Sharon R. Neufeldt2*, and Joseph J. Topczewski1*
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1Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States
2Department of Chemistry, Montana State University, Bozeman, Montana 59717, United States
ABSTRACT: This report details a decarboxylative cross-coupling of (hetero)aryl carboxylates with iodoarenes in the presence of a
gold catalyst (>25 examples, up to 96% yield). This reaction is site specific, which overcomes prior limitations associated with gold
catalyzed oxidative coupling reactions. The reactivity of the (hetero)aryl carboxylate correlates qualitatively to the field effect
parameter (Fortho). Reactions with isolated gold complexes and DFT calculations support a mechanism proceeding through oxidative
addition at a gold(I) cation with decarboxylation being viable at either gold(I) or silver(I) species.
Russell, and co-workers demonstrated that all three elementary
∎
INTRODUCTION
steps in a putative gold(I/III) cross-coupling are viable.13,46
However, this reactivity was not incorporated into a catalytic
method. Additionally, aryl boron reagents were found to be sub-
optimal coupling partners, which may be due to a challenging
and potentially endothermic transmetalation.56,57 An alternative
approach is metal catalyzed aryl decarboxylation.
Gold was once thought to have few uses in fine chemical
synthesis.1 Advances in homogeneous gold catalysis
demonstrated that gold(I) complexes can promote a wide
variety of synthetically relevant transformations.2–12 Most
employ a gold(I) catalyst as a Lewis acid or π–activator, where
gold is thought to formally remain at the +1 oxidation state. The
apparent redox stability of gold(I) complexes13–15 contrasts with
prominent two electron redox events known for palladium,
rhodium, platinum, and iridium complexes. The redox stability
of gold(I) complexes has limited development of
complementary methods utilizing redox gold catalysts.16–18 This
work describes a gold catalyzed decarboxylative cross-coupling
reaction, where the redox events are proposed to occur from a
gold(I) complex. Pioneering studies demonstrated that gold(I)
complexes can participate in oxidative addition with methyl
iodide,19,20 trifluoromethyl iodide,21,22 aryl diazonium salts,23–29
iodine(III) reagents, 30–41and other strong oxidants.16,42,43
Initially Lloyd-Jones and co-workers demonstrated a catalytic
oxidative coupling of aryl-silanes in the presence of a strong
acid and a stoichiometric iodine(III) oxidant (Scheme 1a).31,34
A limiting feature of this and subsequent work35–40,44,45 is that
the site selectivity of C-H bond activation is governed by an
apparent electrophilic aromatic substitution (EAS) mechanism.
Patil and co-workers demonstrated a dual gold/photoredox
catalyzed cross-coupling with aryl silanes27 or aryl stannanes,
which is thought to occur via a radical mechanism (Scheme
1b).28
Scheme 1. Gold Catalyzed Biaryl Formations
Previous Work:
a) oxidative coupling
[Au] cat.
I(III) reagent
, CSA
[M]
H
+ Ar'-
Ar-
Ar-Ar'
[M] = SiMe3 or GeEt3


site selectivity determined by EAS non-standard nucleophile
b) coupling of aryl diazonium salts
[Au] cat.
SET Promoter
[M]
N BF
+ Ar'-
2
Ar-Ar'
Ar-
4
[M] = SiMe3 or SnBu3
 hazardous reagents
c) C-H arylation with aryl halides
[Au] cat., AgSbF6
H
Ar-
+ Ar'-I
Ar-Ar'


site selectivity determined by EAS
Ar-H scope limited to trimethoxybenzene and electron rich indoles
d) progress towards traditional cross-coupling
stoichiometric [Au]
[M]
Ar-
+ Ar'-I
Ar-Ar'
[M] = ZnCl or SnMe3

no product with ArB(OH)2 or ArBpin

not catalytic
This Work:
e) decarboxylative cross-coupling with aryl-iodides
[Au] cat.
The direct oxidative addition with more typical and less
hazardous aryl halide electrophiles (e.g. Ar-I), which are
standard for palladium(0) complexes, are relatively rare with
gold(I) complexes.13,14,44–52 The barrier for the oxidative
addition of gold(I) complexes into aryl halides can be decreased
through the use of bidentate ligands with a hemilabile site.13,47,51
Amgoune, Bourissou, and co-workers recently disclosed a gold
catalyzed arylation of electron rich indoles and
trimethoxybenzene with aryl halides (Scheme 1c).44,45 This was
recently expanded to other transformations.52–55 Attempts at
expanding this reactivity to more common organometallic
reagents have been problematic. In an elegant study, Bower,
CO Ag
Ar-Ar'
Ar-
+ Ar'-I
2
CO2
inexpensive carboxylic acids
benign CO2 byproduct standard aryl electrophile




site specific
Our lab has focused on developing decarboxylative cross-
coupling reacitons.58,59 Decarboxylative functionalization
reactions are recognized as promising alternatives to traditional
cross-couplings because expensive or unstable organometallic
reagents can be replaced by readily available benzoic acids.60–64
Inspired by two reports describing stoichiometric gold(I)
mediated decarboxylation,65,66 we surmised that this elementary
step could offer an alternate pathway to gold-aryl
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Journal of the American Chemical Society
Page 2 of 10
complexes.13,56,57 Alternatively, a dual catalytic cycle using a
iodoarene was decreased from 10 equiv to 5 equiv (entries 12-
t
t
1
2
3
4
5
6
7
8
second metal, also capable of decarboxylation, could enable
access to less frequently used transmetalation partners.
Presented herein is a gold catalyzed decarboxylative cross-
coupling reaction between iodoarenes and (hetero)aryl
carboxylates (Scheme 1e). This work represents the first site-
specific gold catalyzed cross-coupling with standard coupling
partners.
13). The BuXPhos ligand outperformed the BuJohnphos
ligand under these conditions. Next, the counterion on the
precatalyst was evaluated (entries 14-16). With LAuCl or LAuI
complexes, in the absence of silver trifluoromethanesulfonate,
significant homocoupling of benzoate 1a was observed. The
optimal precatalyst was LAuNTf2 (entry 17). A further
reduction in iodoarene to 3 equiv was tolerated but decreased
the selectivity (entry 18). The reaction was conducted in a new
vial with a new stir bar to avoid possible contamination,69 which
did not significantly affect the yield (entry 19). In the absence
of gold, small amounts of product were observed along with
significant protodecarboxylation (entry 20, see SI for additional
trials and control experiments).70
∎
RESULTS AND DISCUSSION
9
Reaction Optimization. Initial trials were inspired by
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Amgoune and Bourissou, who recommended MeDalphos as a
ligand.44,45 The use of sodium carboxylate 1a (M = Na) with
NaOTf did not produce any detectible biaryl (Table 1, entry 1).
Excitingly, using AgOTf afforded cross-coupled product 3a
along with protodecarboxylation product 4 (entry 2).67
Switching from a sodium carboxylate to a silver carboxylate
(entry 3) and decreasing the loading of AgOTf dramatically
improved the yield (entry 4). Changing the limiting reagent to
iodoarene 2a significantly diminished the yield (entry 5).
Substrate Scope. The substrate scope of the iodoarene was
investigated (Table 2). Biaryl 3a was isolated in excellent yield
(86%). Iodobenzene (3b), 4-iodoanisole (3c), and 4-
iodobenzotrifluoride (3d) afforded product, covering the
traditional Hammett series (4-OMe, σp = -0.27; 4-CF3, σp =
0.54). Iodoanisole gave an improved yield at 120 °C, while
iodobenzotrifluoride required heating to 160 °C. This matches
prior observations demonstrating that oxidative addition at
gold(I) is faster with electron rich substrates (vide infra).45,47
Iodoarenes with meta substituents gave acceptable yields (3e-
3h). The reaction tolerated ortho groups (3i-3k).
Chemoselectivity was observed for oxidative addition in the
presence of aryl chlorides (3j) and aryl bromides (3h, 3k).
Iodonaphthalene (3l) also worked well.
Table 1. Optimization for Decarboxylation
tBu
O
F
F
5 mol % [Au]
additive
tBu
OM
H
Ar
+
+
+
Ar
Ar
1,2-DCB
140 oC, 24 h
I
F
F
1a
2a
3a
4
5
Ar = 2,6-F2C6H3
Entrya
[Au]
1a:2a
M
Additive,
mol %
3ab 4b
5b
(%) (%)
(%)
trace
Table 2. Substrate Scope of Iodoarene
1
MeDalphosAuCl
1:10
Na
NaOTf, 110 n.d. n.d.
51
61
91
25
66
33
74
27
32
9
trace
n.d.
n.d.
N/A
14
2
MeDalphosAuCl
MeDalphosAuCl
MeDalphosAuCl
MeDalphosAuCl
MeDalphosAuCl
IPrAuCl
1:10
1:10
1:10
5:1
Na
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
AgOTf, 110
AgOTf, 110
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
AgOTf, 5
none
F
O
F
5 mol %
R
OAg
tBuXPhosAuNTf2
140 oC, 24 h
3
+
R
2
4
I
F
F
N/A
11
27
3
5
1a
1 equiv
F
5 equiv
6c
1:10
1:10
1:10
1:10
1:10
1:10
1:5
tBu
OMe
CF3
F
F
F
7c
24
8c
CyJohnphosAuCl
tBuJohnphosAuCl
CyXPhosAuCl
tBuXPhosAuCl
tBuJohnphosAuCl
tBuXPhosAuCl
tBuXPhosAuCl
tBuXPhosAuI
trace
16
F
F
F
75% (74%)
F
9c
>95 trace
n.d.
18
a
b
3a
91% (86%)
3b
3c
3d
86% (84%)
n.d. (70%)
10c
11c
12c,d
13c,d
14c,d
15c,d
16c,d
17c,d
18d
19c,d,f
20c,d,f,g
68
95
73
94
35
61
60
91
82
85
6
14
9
Me
Me
CO2Me
Br
n.d.
19
F
F
F
F
n.d.
n.d.
8
Me
n.d.
44
1:5
F
F
F
F
1:5
c
3e
3f
3j
3g
82% (76%)
82% (71%)
85% (68%)
3h
64% (59%)
7
31
1:5
none
F
F
F
F
tBuXPhosAuSbF6
tBuXPhosAuNTf2
tBuXPhosAuNTf2
tBuXPhosAuNTf2
1:5
none
e
11
7
18
n.d.
8
1:5
none
Me
Cl
Br
F
F
F
F
10
9
1:3
none
b
3k
3l
76% (79%)
75% (78%)
n.d. (84%)
3i
59% (53%)
trace
trace
1:5
none
Yield determined by 19F NMR. Yield in parenthesis is the isolated yield. All values
are the average of duplicate reactions. Reaction conducted at a120 °C, b160 °C, cin
1,2-dichlorobenzene. See SI for details and data.
30
5 mol% L No [Au] 1:5
none
aReactions conducted with benzoate 1a (0.1 mmol), iodoarene 2a (0.3-1.0 mmol), in
1,2-dichlorobenzene (0.5 M, DCB), with 5 mol % [Au]. bYield determined by 19F
NMR analysis. All yields reflect the average of duplicate trials. cReactions conducted
neat in iodoarene 2a. dReactions conducted with 0.15 mmol of benzoate 1a. eCH3CN
An inversion in iodoarene reactivity, relative to oxidative
addition at palladium(0),71 is a potential hallmark of gold
mediated oxidative addition.42,45,47 In a competition experiment
with stoichiometric MeDalphosAuSbF6, the use of 4-
iodoanisole (2c) and 4-iodobenzotrifluoride (2d) afforded
gold(III) complexes favoring oxidative addition with 4-
iodoanisole in a 6.7:1 ratio.45 In this system, a competition
experiment was conducted (Scheme 2). The reaction afforded
biaryl 3c as the major product with a 3c:3d ratio of 3.3:1, which
f
g
t
adduct. Reaction conducted with a new stir bar. Used 5 mol % BuXPhos no [Au].
Trace = less than 5% detected, n.d. = not detected. N/A = not applicable. tBuXPhos =
2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl. See SI.
A variety of precatalysts were screened and it was discovered
that Buchwald style phosphine ligands out performed other
ligands under neat conditions (entries 6-11).68 The quantity of
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Journal of the American Chemical Society
is in line with prior gold mediated oxidative additions. These
protodecarboxylation.70 Here, products 3m – 3v could be
1
2
3
4
5
6
results indicate that the observed cross-coupling reaction can be
attributed to the gold catalyst and not trace palladium
contamination.
isolated in good to excellent yield and these results qualitatively
correlate to the field effect parameter. Less activated substrates
required elevated temperatures and/or increased catalyst
loading (3v – 3y). It is particularly exciting that products 3x and
3y could be isolated in any yield given the scope limitations of
Scheme 2. Competition Experiment of Aryl Iodides
other
decarboxylative
cross-coupling
reactions.59,64,72
OMe
F
OMe
Substrates with an ortho C-H bond did not afford product with
palladium catalyzed reactions,58,59,72 which again disfavors a
mechanism based on trace metal contamination. Additionally, a
single ortho-fluorine (3x) or chlorine (3y) substituent is only
mildly polarizing and was sufficient for decarboxylation. A
substrate with an ortho-methoxy group was not activated
enough to provide an appreciable yield (3z, Fortho = 0.29).
Activated pyridine carboxylates afforded products 3aa and 3bb.
Pyridines are particularly challenging substrates in traditional
cross-coupling reactions.73–75
7
8
9
I
F
O
F
F
OAg
5 mol % [Au]
140 oC, 24 h
2c
3c
66%
3 equiv
CF3
+
CF3
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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59
60
1a
1 equiv
I
F
2d
3d
3 equiv
20%
[Au] = tBuXPhosAuNTf2
Table 3. Substrate Scope of (hetero)aryl carboxylates
Mechanistic Experiments. It is conceivable that the
observed cross-coupling reaction could proceed via
protodecarboxylation67,70 and subsequent C-H bond
activation.76 This concern is valid because product 4 was
observed and because metal carboxylates are known to facilitate
C-H bond activation.76 A reaction with 1,3-difluorobenzene (4)
and silver benzoate afforded a negligible quantity of product 3a
(Scheme 3a). The majority of compound 4 was detected after
the reaction, with the mass loss being attributed to volatility. To
confirm that the reaction was still viable under these conditions,
1,3-difluorobenzene (4) and reactive silver benzoate 1o were
subjected to the reaction conditions. Only trace quantities of
product 3a were observed along with a high yield of product 3o,
indicating that product is formed via decarboxylation under
these reaction conditions. Using benzoate 1a and 1,2,4-
trifluorobenzene provided similar results (see SI). As such, a
protodecarboxylation and C-H bond activation sequence is
unlikely.
tBu
O
5 mol %
tBu
OAg
tBuXPhosAuNTf2
140 oC, 24 h
R
+
R
I
3
1
2a
1 equiv
5 equiv
tBu
tBu
tBu
NO2
F
F
O2N
F
F
F
F
b
3m
3n
80% (81%)
Fortho = 0.9
3o
90% (74%)
Fortho = 0.9
96% (93%)
Fortho = 1.1
tBu
tBu
tBu
tBu
tBu
tBu
tBu
F
F
F
Cl
Br
Me
F
F
F
3p
3q
3r
87% (70%)
Fortho = 0.9
91% (81%)
87% (71%)
Fortho = 0.9
Fortho = 0.9
tBu
F
F
Cl
Scheme 3. Test for C-H activation sequence
F
F
Br
F
F
a) C-H activation test - unreactive benzoate
a
a
3s
3t
3u
70% (63%)
Fortho = 0.87
76% (66%)
66% (67%)
tBu
5 mol %
O
tBuXPhosAuNTf2
Fortho = 0.9
Fortho = 0.9
F
F
5 equiv 4-tBuC6H4I
tBu
H
OAg
CF3
+
140 oC, 24 h
F
F
4
3a,
trace
1.0 equiv
72% remaining
b) C-H activation test - reactive benzoate
1.1 equiv
F
NO2
3w n.d. (71%)
Fortho = 0.65
X
c
d
d
3v
3x
3y
X = F, 36% (41%)
X = Cl, n.d. (50%)
n.d. (56%)
Fortho = 0.83
tBu
5 mol %
F
O
tBuXPhosAuNTf2
F
F
Fortho = 0.45 (F), 0.42 (Cl)
tBu
5 equiv 4-tBuC6H4I
tBu
tBu
H
F
X
OAg
F
+
140 oC, 24 h
F
F
F
F
4
1o
3o
3a
1.1 equiv
68% remaining
1 equiv
X = F, 98%
X = H, trace
N
OMe
F
Cl
N
Cl
F
3aa
d
b
d
3z
3bb
n.d. (14%)
n.d. (66%)
n.d. (48%)
With evidence disfavoring the C-H activation mechanism, an
initial mechanistic proposal was made (Scheme 4). The
mechanism could proceed via salt metathesis yielding gold(I)
carboxylate complex Au1 (step i). Decarboxylation (step ii)
would afford gold(I)-aryl Au2.65,66 Oxidative addition could
proceed from complex Au2 (step iii), followed by silver
facilitated reductive elimination (step iv)19,20,22,42 to complete
the catalytic cycle. A series of stoichiometric reactions were
conducted with isolated gold complexes to investigate this
sequence (Scheme 5). Gold(I)-aryl complex Au2 could be
prepared in two steps (Scheme 5a). Salt metathesis between
sodium carboxylate 1a’ and the precatalyst afforded gold
carboxylate complex Au1. Heating this complex readily
Fortho = 0.29
Fortho = 0.9
Fortho = 0.42
Yield determined by 19F NMR. Yield in parenthesis is the isolated yield. All values are
the average of duplicate reactions. aReaction conducted in 1,2-dichlorobenzene at 0.1
M. bReaction conducted in 1,2-dichlorobenzene at 0.17 M. cReaction conducted at 180
°C. dReaction conducted at 180 °C using 10 mol % [Au]. See SI for details and data.
Fortho = field effect parameter.
The substrate scope with respect to the aryl carboxylate was
investigated (Table 3). It is well recognized in the area of
palladium, copper, and silver decarboxylative cross-coupling
that substrates with polarizing ortho substituents are
particularly reactive.60–64 Hoover and co-workers correlated the
field effect parameter (Fortho) to reactivity for silver mediated
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Journal of the American Chemical Society
afforded the aryl complex Au2, which was fully characterized.
Page 4 of 10
products from the pyrolysis of silver aryl complexes was
anticipated based on prior work.70 Next, an analysis of the
presumptive oxidative addition and decarboxylation steps were
explored computationally.
1
2
3
4
Surprisingly, only a minimal quantity of product 3a was
observed from complex Au2 even in neat iodoarene 2a after
prolonged heating. The same experiment was repeated with
-
NaOTf (in place of NTf2 as an additive), which afforded similar
Scheme 6. Mechanistic Proposal with Transmetalation
results (Scheme 5b). The majority of complex Au2 remained
unreacted after 24 h. This contrasts with the catalytic reaction,
where only 5 mol % gold affords high yields of product. The
observed stability of complex Au2 and difficulty identifying a
transition state computationally (vide infra) for the proposed
oxidative addition (step iii) lead us to disfavor the mechanism
outlined in Scheme 4.
5
6
7
8
A
B
L
AuI NTf2
L
AuI NTf2
Ar Ar'
Ar'
Ar Ar'
Ar'
I
I
iii
i
iii
i
9
Ar
AuIII
NTf2
Ar'
Ar
AuIII
Ar'
Ar'
Ar'
L
L
AuIII
I
L
L
AuIII
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NTf2
NTf2
LAu-I
v
NTf2
ii
vii
Scheme 4. Mechanistic Proposal with Oxidative Addition
from L-Au-Ar complex
Ar
Ar
-Ag
-AuL
Ag-I
Ar Ar'
L
AuI NTf2
AgI +
ArCO
2Ag
iv
vi
ArCO
2-Ag
iv
i
CO2
CO2
AgNTf2
AgNTf2
Ar
AuIII
I
Ag-I
ArCO
ArCO
2-AuL
2-Ag
L
L
AuI
Au1
Ar'
O2CAr
L = tBuXPhos
Scheme 7. Reactions with Metal Aryl Complexes
iii
ii
a) product 3a formation from Au2 in the presence of gold cation
CO2
Ar'
I
Ar
L
AuI
tBu
Au2
F
L = tBuXPhos
F
tBu
AuL
140 oC, 24 h
Scheme 5. Reactions with Isolated Gold Complexes
+
+
LAuNTf2
1.1 equiv
F
I
F
a) formation of gold carboxylate Au1 and gold aryl Au2
3a 63%a
Au2
2a
20 equiv
1 equiv
F
O
F
O
a) product 3a formation from Ag1 in the presence of gold cation
DMF
AuL
110 o
C
ONa
O
tBu
+ LAuSbF6
1 equiv
F
F
tBu
F
F
Ag
CO2
140 oC, 24 h
Au1 >95%a
Au2 94%a
+
+
1a'
1.1 equiv
LAuNTf2
5 mol%
F
I
F
b) minimal product 3a formation from Au2 with added sodium triflate
3a 67%b
Ag1
2a
20 equiv
tBu
F
F
tBu
AuL
Computational Analysis of Oxidative Addition and
Decarboxylation. The direct oxidative addition of gold(I)
complexes into iodoarenes has been questioned numerous times
in the literature.14,15 Recently, the seminal works of Amgoune,
Bourissou, and co-workers directly showed the viability of this
elementary step (Scheme 8a).44,45 Bower, Russell, McGrady,
and co-workers elegantly demonstrated that, in some cases, the
oxidative addition is endergonic and reversible (Scheme
8b).13,46 The reaction studied here differs from previous
examples of oxidative addition which used bidentate ligands
like bipy or a monodentate ligand with a hemilabile amine
substituent (MeDalPhos). In the decarboxylative cross-
140 o
24 h
C
+
NaOTf
+
F
I
F
Au2
1.1 equiv
2a
20 equiv
1 equiv
10% 3a
c
60% Au2
remaining
With these results in hand, an alternate mechanistic proposal
was outlined (Scheme 6). The reaction could be initiated from
an oxidative addition of the LAuNTf2 complex (step i). This
oxidative addition would be more analogous to reported gold(I)
oxidative addition reactions with iodoarenes that proceed from
a cationic gold complex.13,44–46 The gold(III) complex could
then undergo transmetalation with a metal-aryl species (step
ii).77–79 The metal-aryl species could arise from either silver
(mechanism A, step iv)63,80,81 or gold (mechanism B, step vi)65,66
mediated decarboxylation. Reductive elimination (step iii) and
a possible salt metathesis (step v) would complete the cycle.
t
coupling, the optimal ligand is the monodentate BuXPhos
(Table 1), although the pendant aryl ring on the ligand could
conceivably coordinate to gold in a hemilabile manner. This
coordination mode is well-known with palladium(II)
complexes.82–85 Notably, MeDalPhos is an acceptable ligand for
the decarboxylative cross-coupling (Table 1, entry 6, 66%
yield); however, the selectivity is superior with BuXPhos.
Consideration of these issues prompted a computational study
on the viability of oxidative addition with BuXPhos (Scheme
8c).
To support this proposal a number of experiments were
conducted from isolated intermediates (Scheme 7). While
isolated gold aryl complex Au2 did not provide a high yield of
product 3a in neat iodoarene (Scheme 5b), when complex Au2
was heated with cationic gold and iodoarene, a reasonable yield
of product 3a was observed (Scheme 7a), supporting step vii
(Scheme 6b). Likewise, when isolated silver aryl complex Ag1
(see SI for synthesis and characterization) was utilized with
catalytic gold, a good yield of product 3a was observed along
with 25% homocoupling of the difluoroaryl (Scheme 7b),
supporting step ii (Scheme 6a). The formation of homocoupled
t
t
The oxidative addition of iodobenzene with gold(I)
complexes relevant to the current reaction was investigated
computationally. DFT calculations were performed with
Gaussian 16.86 Geometry optimizations were conducted using
the MN15L functional, and energies were further refined with
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Journal of the American Chemical Society
t
MN15L using a larger basis set and o-dichlorobenzene as an
likely that the success of BuXPhos in the catalytic system is
due to its influence on a different step of the reaction
mechanism. The possibility for oxidative addition at LAu-Ar
(Au2, see Scheme 4) was also examined. However, this
pathway can be ruled out on the basis of a prohibitively high
calculated activation barrier using ModPhosAuAr (Ar = 2,6-
difluorophenyl; ∆G‡ = 46.1 kcal/mol; see SI).
implicit solvent (see SI).87 To simplify the calculations, the
1
2
3
4
5
6
t
three iso-propyl groups in BuXPhos were abbreviated as
methyl groups (ligand named here as ModPhos; R = mesityl in
Scheme 9). The data obtained here indicate that formation of a
ModPhosAu+-IPh -complex precedes oxidative addition
(Scheme 9; 6b-9b).
7
8
Scheme 9. Summary of DFT Calculations for Oxidative
Addition with Gold Complexes
Scheme 8. Oxidative Addition with Gold Cations
a) oxidative addition with MeDalphosAu complex
9
-
-
SbF6
SbF6
N(Me)2
Au+ Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N(Me)2
rt
+
Ad
P
Au+
Ad
P
I
Ad
Ad
I
1 equiv
99% G = -8.9 kcal/mola
b) oxidative addition with bipyAu complex
R
-
CDCl3
50 o
NTf2
Au+
R
N
N
N
C
+
Au+
-
NTf2
I
I
N
R = CF3, G = +4.4 kcal/molb
R = F, 65% remaining 20 equiv
c) oxidative addition with tBuXPhosAu complex
-
NTf2
I
tBu
tBu
Ar
Au+
Dioxane
tBu
P
140 o
C
tBuXPhosAuNTf2
+
iPr
iPr
I
iPr
Au3
2a
endergonic?
aValues and result from reference 44. bValues and results from reference 13
.
Consistent with previously reported DFT calculations using
MeDalPhos, the counteranion strongly influences the calculated
Because both silver(I) and gold(I) carboxylates are reported
to undergo decarboxylation, this step was also investigated
computationally. The silver mediated decarboxylation is
thought to occur in a concerted manner and has been
investigated both experimentally70,88,89 and computationally.88,90
Here, three sets of calculations were conducted using the free
silver carboxylate (Scheme 10, 10a), ModPhos-ligated silver
carboxylate (11a), or ModPhos-ligated gold carboxylate (12a,
analogous to complex Au1). In all three cases, the barriers for
decarboxylation were similar. As such, the calculations support
the possibility that decarboxylation could proceed from either a
gold(I) or silver(I) carboxylate (e.g. both mechanisms in
Scheme 6a and 6b appear viable). The calculated barriers are
lower than for the oxidative addition with ModPhosAuNTf2,
indicating that decarboxylation may not be turnover limiting.
However, DFT can give unreliable comparisons between
energies of neutral and ionic species due the challenges
associated with accurately modeling solvent effects and ion
pairing.91,92 In light of the counterion dependence noted above,
it is possible that another process is turnover limiting.
–
energy barrier and the highest barrier is predicted using NTf2
(7c-TS, 27.8 kcal/mol).44 This result is somewhat surprising
t
given the use of BuXPhosAuNTf2 in the optimal catalytic
system. Excluding the counterion from the calculations leads to
more favorable energetics (9c-TS, ∆G‡ = 15.2 kcal/mol).45 As
such, the counterion dependence appears to be directly
correlated with the energy required to displace the counterion
with the iodoarene to form the -complex as well as an
energetic penalty for charge separation. Regardless of
counterion, oxidative addition with ModPhos is predicted to be
much slower than oxidative addition with MeDalPhos (see
SI).44,45 However, the calculated barrier with ModPhosAuNTf2
of 27.8 kcal/mol should be readily surmountable under the
experimental conditions (140 °C). The oxidative addition with
the bistriflimide ion was calculated to be endergonic by 25.5
kcal/mol, which is in line with the results of Bower, Russell,
and McGrady (Scheme 8b).13
t
To examine the role of the pendant aryl of BuXPhos, a
transition structure was calculated in which the pendant aryl
group of ModPhos is rotated away so that it cannot coordinate
to gold (see SI). Reaction through this conformation is
prohibitively high-energy (∆G‡ = 45.0 kcal/mol), indicating that
the pendant aryl does interact with gold during oxidative
addition (7c-TS). However, calculations performed with
PPh(tBu)2, a truncated version of tBuXPhos lacking the pendant
aryl, predict an oxidative addition barrier that is very similar to
that using ModPhos (Scheme 9a, 6c-TS). Overall, the
calculations suggest that the pendant aryl of tBuXPhos does not
significantly stabilize the transition state or the resulting Au(III)
adduct relative to the starting Au(I) complex. As such, it is
∎
CONCLUSION
In conclusion, we report the first gold catalyzed
decarboxylative cross-coupling. This work expands on recent
progress regarding gold(I) oxidative addition with iodoarenes.
Decarboxylation overcomes site selectivity limitations
associated with prior gold catalyzed oxidative arylation
reactions. The substrate scope of the aryl carboxylate correlates
qualitatively with the field effect parameter. Preliminary
mechanistic studies indicate that the gold(I) oxidative addition
is viable and that decarboxylation can proceed from either gold
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Pflästerer, D.; Hashmi, A. S. K. Gold Catalysis in Total Synthesis
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Scheme 10. Summary of DFT Calculations for
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: XX.
(13)
Experimental procedures, computational data, and
spectral data (PDF)
Crystallographic Information (cif)
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Livendahl, M.; Goehry, C.; Maseras, F.; Echavarren, A. M.
Rationale for the Sluggish Oxidative Addition of Aryl Halides to
AUTHOR INFORMATION
Corresponding Authors
Au(I).
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Commun.
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https://doi.org/10.1039/C3CC48914K.
Lauterbach, T.; Livendahl, M.; Rosellón, A.; Espinet, P.;
Echavarren, A. M. Unlikeliness of Pd-Free Gold(I)-Catalyzed
Sonogashira Coupling Reactions. Org. Lett. 2010, 12, 3006–
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Levin, M. D.; Toste, F. D. Gold-Catalyzed Allylation of Aryl
Boronic Acids: Accessing Cross-Coupling Reactivity with Gold.
Angew. Chemie. Int. Ed. 2014, 53, 6211–6215.
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*jtopczew@umn.edu
*sharon.neufeldt@montana.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Wu, C. Y.; Horibe, T.; Jacobsen, C. B.; Toste, F. D. Stable
Gold(III) Catalysts by Oxidative Addition of a Carbon-Carbon
Jenna Humke, Brendon Graziano, and Dr. Victor Young are
gratefully acknowledged for assistance collecting the crystal
structure of complex Ag1. This work was supported by the
University of Minnesota. Financial support was provided by the
National Science Foundation award number CHE1942223 (J.J.T.
and R.A.D.). A.S.M and S.R.N. are grateful to Montana State
University for support. Calculations were performed on Comet at
SDSC and Bridges at the Pittsburgh Supercomputing Center
through XSEDE (CHE190050), which is supported by NSF (ACI-
1548562), as well as on the Hyalite High Performance Computing
System at MSU.
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O
5 mol %
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