Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis

Article abstract of DOI:10.1038/s41557-018-0074-z

Achieving site-selectivity in arene functionalization that is complementary to the site-selectivity from electrophilic aromatic substitution reactions has been a long-standing quest in organic synthesis. Palladium/norbornene cooperative catalysis potentia

Full text of DOI:10.1038/s41557-018-0074-z

Articles
https://doi.org/10.1038/s41557-018-0074-z
Complementary site-selectivity in arene
functionalization enabled by overcoming the
ortho constraint in palladium/norbornene catalysis
Jianchun Wang1, Renhe Li1, Zhe Dongꢀ ꢀ1, Peng Liuꢀ ꢀ2 and Guangbin Dongꢀ ꢀ1*
Achieving site-selectivity in arene functionalization that is complementary to the site-selectivity from electrophilic aromatic
substitution reactions has been a long-standing quest in organic synthesis. Palladium/norbornene cooperative catalysis poten-
tially offers a unique approach to this problem, but its use has been hampered by the ortho constraint, which is the requirement
of an ortho substituent for mono ortho functionalization of haloarenes. Here, we show that such a challenge could be addressed
using a new class of bridgehead-modified norbornenes, thereby enabling a broadly useful strategy for arene functionalization
with complementary site-selectivity. A range of ortho-unsubstituted aryl iodides, previously problematic substrates, can now be
employed to provide mono ortho-functionalized products effectively. This method is applicable for late-stage functionalization
of complex bioactive molecules at positions that are difficult to reach by conventional approaches.
ndoubtedly, practical and site-selective arene functionaliza- The availability of such a technology would greatly enrich our tool-
tion plays a pivotal role in pharmaceutical, agrichemical and box for streamlining the synthesis of poly-substituted aromatic
U
material research. Typically, arene functionalization is real- compounds, which is particularly valuable for late-stage derivatiza-
ized through electrophilic aromatic substitution (EAS) followed by tion of complex molecules at positions difficult to reach by con-
further ipso transformations; thus, the substitution prefers to occur ventional means. However, despite the recent breakthroughs of
at the more electron-rich and more accessible positions (Fig. 1a). directing group (DG) strategies1–3 and steric-sensitive C−H boryla-
A fundamentally intriguing question is whether complementary tion/silylation methods4–8, solutions to such a quest for complemen-
and complete site-selectivity can be achieved at positions disfa- tary site-selectivity remain highly sought after.
voured for EAS reactions, such as para to an electron-withdraw-
Palladium/norbornene (Pd/NBE) cooperative catalysis
ing group (EWG) or meta to an electron-donating group (EDG). (namely Catellani-type reactions) offers a unique opportunity
Favoured
a
c
This work
by EAS
H
FG
H
X
Further ipso
I
Nu
H
H
H
transformation
EAS
H
H
E
Pd/L, base, E, Nu
R
R
R
R
E = amino, acyl, aryl
R2
R
R
Nu = alkenyl, aryl, alknyl, H
Disfavoured
by EAS
?
FG
R1
N*
A quest for 'complementary site-selectivity'
R
R
E
Net para
b
ipso
R
I
selectivity
Nu (H)
EWG
EWG
Nu–
E+
Pd/L, base
R
R
E
ortho
Native
1) Iodination
reactive
2) Pd/N*, ‘H–’, E+
PdII
site for EAS
R ≠H
ANP
R
R
Net meta
Nu
selectivity
By-products
E
E
EDG
EDG
E
When R = H
ortho constraint
or
containing
norbornene
Fig. 1 | A quest for complementary site-selectivity in arene functionalization. a, Site-selective arene C−H functionalization at less reactive positions for
EAS is challenging. b, Catellani-type reactions can potentially address the challenge, but are inhibited by the ortho constraint, which is the requirement
of an ortho substituent on haloarene substrates to obtain mono ortho functionalization. c, This work overcomes the ortho constraint by developing a new
norbornene cofactor, and can be applied towards complementary arene functionalizations.
1Department of Chemistry, University of Chicago, Chicago, IL, USA. 2Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
*e-mail: gbdong@uchicago.edu
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a
R
O
Table 1 | selected optimization of reaction conditions
O
Pd
H
Pd
C7H15
Side
Desired
product
X
products
E
N3
E
Far
C–H
β-carbon
elimination
Close
Favoured
metalation
Disfavoured
tBuO2C
O
CO2tBu
CO2tBu
BzO
3a
N
b
R
O
2a
I
O
[Pd(allyl)Cl]2 (5 mol%)
RuPhos (10 mol%)
N3, Cs2CO3
O
R
H
H
N
R
H
Pd
Pd
Side
products
C–H
metalation
Desired
product
β-carbon
elimination
X
Me
Me
Me
1,4-dioxane/toluene (1:1)
100 °C
E
R
E
R
1a
4a
4a'
'Standard conditions'
67% (66% isolated) yield
24% yield
Disfavoured
Favoured
Yield of 4a'
(%)a
Entry
Variations from the
'standard conditions'
Yield of 4a
(%)a
Fig. 2 | Challenge and proposed strategy. a, C−H metallation is favoured
over β-carbon elimination with regular NBE. In the C−H metallation
TS, the newly installed electrophile is close to the bridgehead position.
b, β-carbon elimination is expected to be favoured over C−H metallation
with a bridgehead-substituted NBE due to the steric repulsion introduced
by the R group.
1
Listed below
Cy
Other NBEs instead of N3
Me
N1
N2
N4
4a, <5%
4a', 19%
4a, 54%
4a', 25%
4a, 54%
4a', 38%
CO2tBu
Side products
OnC4H7
CO2Me
Ph
iPr
I
O
O
N
N1
H
N
tBuO2C
N5
N6
N7
N8
4a, 56%b
4a', 46%
Me
Me
Me
Me
ND
12%
4a, 58%
4a', 24%
4a, <5%
4a', 7%
4a, 6%
4a', 38%
CO2tBu
CO2tBu
I
No Pd
0
6
0
0
2
3
4
BzO
N
O
O
O
O
15
85
26
29
No ligand
Conditions in ref. 29
N
N
H
N
No N3
Pd(OAc)2 as precatalyst
46
5
Me
15
P(p-OMeC6H4)3 as ligand
ND
78%
6
Me
Me
K2CO3 as base
23
62
23
35
20
22
7
8
9
1,4-Dioxane only
Toluene only
Fig. 3 | An example of the ortho constraint. Without ortho substituents,
3-iodotoluene and 4-iodotoluene cannot deliver the mono-functionalized
products with regular NBE N1. 3-Iodotoluene delivered norbornene-
containing side products, while 4-iodotoluene only afforded di-amination
products. ND, not detected.
80 °C
50
21
46
17
58
28
10
11
12
10 mol% N3
100 mol% 1a, 110 mol% 2a and 3a
Reaction conditions: 1a (0.18ꢀmmol), 2a (0.18ꢀmmol), 3a (0.1ꢀmmol), [Pd(allyl)Cl]2
(0.005ꢀmmol), RuPhos (0.01ꢀmmol), N3 (0.1ꢀmmol), Cs2CO3 (0.4ꢀmmol), 100ꢀ°C, 24ꢀh. RuPhos:
2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl. aYield determined by 1H NMR using
1,3,5-trimethoxybenzene as the internal standard. bN8 (0.4ꢀmmol) was used instead.
to address the above challenge9–14. Taking advantage of a key
aryl-NBE palladacycle (ANP) intermediate, an electrophile
and a nucleophile can be coupled simultaneously to give either
ortho,ipso-bis-functionalization
or
ortho-functionalization
when a reductant is used (Fig. 1b)15–22. We envisage that elec-
trophilic halogenation of the arene followed by ortho-func- a two-step sequence, as well as site-selective C−H amination of
tionalization would install functional groups at positions complex bioactive natural products and drugs (Fig. 1c).
that are complementary to the outcomes with EAS reactions.
Studies by Catellani and co-workers have shown that the chal-
Unfortunately, such an approach has been inhibited by a major lenge of employing ortho-unsubstituted aryl iodides arises from a
limitationinPd/NBEcatalysis,theso-called‘orthoconstraint’;when facile second C–H metallation instead of β-carbon elimination, as
an ortho-unsubstituted haloarene is used (for example, meta- or β-carbon elimination becomes feasible when both ortho positions
para-substituted ArXs), mono-ortho-functionalization gener- are substituted9,41. As shown in Fig. 2, in the transition state (TS) for
ally cannot be obtained23,24, and, instead, a complex mixture of the C–H metallation with regular NBE, the newly installed electro-
NBE-containing side products19,25,26 or di-functionalization usu- phile (E) must point towards the bridgehead position; in contrast,
ally dominate (Fig. 1b)15–17,24,26–38. Thus, strategies that can over- in the TS for the β-carbon elimination, the aryl-ring plane has to
come such an intrinsic limitation would significantly boost the adopt a nearly perpendicular orientation to the bridgehead C−H
utility of Pd/NBE catalysis, which in turn would provide a use- bond42,43. Hence, the key to inhibiting the undesired second C−H
ful strategy for arene functionalization at unactivated sites. Here, metallation and/or promote the β-carbon elimination pathway
we report our development of a new class of NBE ‘cofactors’ (or would be to control the orientation of the arene group during the
co-catalysts) that can enable mono ortho-functionalization with TS. We hypothesized that by installing a proper substituent (R) at
ortho unsubstituted aryl iodides. The significance of this method the NBE bridgehead (that is, C1 or C4) position, the steric inter-
is illustrated in the realization of unconventional site-selectiv- action between the R and E groups (or between the R group and
ity35,39,40, such as para to an EWG and meta to an EDG, through the ligand on Pd) would destabilize the TS for the C−H metallation
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Table 2 | Reaction scope for meta-substituted aryl iodides
R
I
R
R3
N
Nu
R2
H
R3
R4
'Standard conditions'
N
+
+
H
H
E
R4
OBz
nC7H15
R1
1
R2
2
3
4
R1
R1
N3
R2
or Nu
or E
Phenyl iodide derivatives
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
R1
=
Me
iPr
tBu
MeO
4d, 58%a 4e, 60%
iPrO
O
O
O
O
4a, 66% 4b, 74% 4c, 78%
H
N
O
H
N
H
N
H
N
H
N
TBSO
Me
Me
Me
TBSO
Me2N
MeO2C
F3C
O2N
R1
Cl
Me
NMe2
4l, 70%
CO2Me
4m, 74%
4f, 70%
4g, 69%
4h, 74%a 4i, 65%
4j, 60%a
4k, 68%
4n, 58%
(X-ray obtained)
Poly or heteroaryl Iodides
Drug derivatization
E: CO2tBu
O
O
Me
E
E
Me
E
H
O
E
H
S
H
H
H
N
H
H
H
H
N
N
N
N
N
I
Ts
N
1ab
O
O
4ab, 73%
O
(from oestrone)
tBuO2C
O
4o, 66%a
4p, 74%
4q, 37%a
4r, 36%a
CO2Et
CO2Et
N
N
Amine and olefin scope
O
F
CO2tBu
NR3R4
=
1ac
N
O
H
N
N
Boc
R3
N
N
O
H
N
N
N
O
I
R4
CO2tBu
H
TBSO
4ac, 65%
(from loratadine)
4s, 58%
4t, 64%
4u, 51%
O
Other ipso functionalizations
O
CO2nBu
NR3R4
=
H
O
OH
Ph
Ph
R3
N
H
N
N
5a
Me
H
I
H
OH
6a, 60%b
N
N
Ph
R4
N
tBu
N
H
iPr
4v, 48%
4w, 56%
CO2nBu
4x, 55%
4y, 35%
O
O
Me
Me
tBu
Ph
Ph
O
Ph
B
CO2Me
5b
H
1c
+
O
O
6b, 54%b
tBu
H
N
H
N
O
4z, 75%
4aa, 82%
OH
Me
iPr
iPr
ortho acylation
N
Ph
O
Me
OBz
5c
H
N
3a
CO2tBu
6c, 52%b
O
O
I
tBu
H
O
R
O
R
7
ortho arylation
H
tBuO2C
CO2tBu
R
Me
I
R
1a
2a
8
Me
9
H
Br
R
O
O
Cl
O
Me
H
O
tBuO2C
2a
=
iPr
R
iPr
NO2
1a
10
8a, 62%c
8b, 54%c
8c, 59%c
OMe
O
OMe
O
O
Me
CO2Me
CO2Me
10b, 47%b
CO2Me
10c, 46%b
NO2
10d, 39%b
Me
8e, 60%c
MeO
8d, 84%c
10a, 60%b
8f, 81%c
Reaction conditions: 1 (0.54ꢀmmol), 2 (0.54ꢀmmol), 3 (0.3ꢀmmol), [Pd(allyl)Cl]2 (0.015ꢀmmol), RuPhos (0.03ꢀmmol), N3 (0.3ꢀmmol), Cs2CO3 (1.2ꢀmmol), 100ꢀ°C, 24ꢀh. 12–35% of direct Heck products were
observed. TBS, tert-butyldimethylsilyl. aN4 (0.45ꢀmmol) was used instead of N3. bdppe (0.03ꢀmmol) was used instead of RuPhos. §P(2-furyl)3 (0.06ꢀmmol) was used instead of RuPhos. For experimental
details and yields of Heck side products, see Supplementary Section V.
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nBuO2C
a
c
CO2nBu
CO2nBu
N
R1
2v
G
R1
I
O
O
O
O
H
Pd
[Pd(allyl)Cl]2 (5 mol%)
SPhos (10 mol%)
E
R
N
Pd
H
H
N
N
N
N
Pd
O
R2
TS1
L
N, 3a, 2v, Cs2CO3
L
L
R2
BzO
BzO
TS2
TS3
1,4-dioxane, 100 °C
11a
12a
12a'
∆∆G‡
nC7H15
Cy
E
60
40
20
0
L = SPhos
E = CO2nBu
N1
N3
N4
BzOH
N
N8
12a, ND
12a', 29%
12a, 2%
12a', 12%
12a, 36%
12a', 6%
N
E
Me
Br
N
O
Ph
N
R1
R1
Me
MeO2C
O
Ph
Pd
O
Pd
O
Pd
L
N8
N9
12a, ND
12a', 30% 12a', 13%
N10
R2
R2
INT1
Me
N1 N3
N4 N8 N9 N10
12a 12a'
L
12a, 55%a
12a', 2%
12a, ND
L
INT3
10a
INT2
(mono:di > 20:1)
Monoproduct
Diproduct
CO2nBu
b
Me
nC7H15
Me
N8
I
O
R = OMe; 12b, 47%
H
H
N
(mono:di > 20:1)
Conditions as above
N1
N3
Me
N8
∆∆G‡
∆∆G‡
5.3 kcal mol–1
1.2 kcal mol–1
–2.7 kcal mol–1
R = CO2Me; 12c, 41%
(mono:di > 20:1)
DFT
>2.8 kcal mol–1
~1.1 kcal mol–1
–2.0 kcal mol–1
R
R
exp
Favour diproduct
Favour monoproduct
11
12
Fig. 4 | use of para-substituted aryl iodides. a, For the more challenging phenyl iodide substrate, examination of different substituted norbornenes
reveals that N8 with alkyl substituents at both bridgehead positions gave the highest yield and mono/diselectivity. Reaction conditions: 11
(0.4ꢀmmol), 2v (0.36ꢀmmol), 3a (0.2ꢀmmol), [Pd(allyl)Cl]2 (0.01ꢀmmol), SPhos (0.02ꢀmmol), N (0.8ꢀmmol), Cs2CO3 (0.8ꢀmmol), 100ꢀ°C, 24ꢀh. SPhos,
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; ND, not detected. aA yield of 7% was obtained with 10ꢀmol% N8. b, Examples of other para-substituted
aryl iodides. c, DFT calculation of the key TSs and comparison of calculated and experimental ΔΔG‡. Energies were computed at the M06/SDD–6-311+
G(d,p)/SMD (1,4-dioxane) level of theory, with geometries optimized at the B3LYP-D3/def2-SVP level (see Supplementary Section IX for more details
and references).
pathway due to repulsion, and meanwhile should promote β-carbon 1,2-bis(diphenylphosphino)ethane (dppe) and N-heterocyclic car-
elimination by fixing the orientation of the aryl ring (Fig. 2b).
benes, can also assist this transformation.
The reaction was further optimized with N3 as the cofactor, and
a series of control experiments were conducted to understand the
Results and discussion
To test this hypothesis, the ortho amination/Heck reaction29 was role of each reactant. As expected, the palladium, phosphine ligand
chosen as a model. 2-Iodotoluene gave 81% yield of the ortho ami- and NBE were all essential for this transformation (entries 2–4).
nation product under previously reported conditions, but 3- and [Pd(allyl)Cl]2 was found to be a better precatalyst than Pd(OAc)2
4-iodotoluene were unable to deliver the mono-functionalized (entry 5). RuPhos is significantly more efficient than the originally
products with regular NBE N129 (Fig. 3). Thus, 3-iodotoluene (1a) reported28 P(p-OMeC6H4)3 (entry 6), probably benefiting from the
was used as the initial substrate, and the ortho amination was exam- bulkiness of the ligand. Consistent with previous studies, the use
ined with benzoyloxyamine 2a as the limiting reagent. A number of of potassium carbonate as a base dramatically decreased the yield
structurally modified NBEs were prepared and examined (Table 1, compared to caesium carbonate (entry 7)28. Moreover, a mixed-sol-
entry 1). We envisaged that the size and position of the substitu- vent system is also superior to either 1,4-dioxane or toluene alone
ent would be critical, because increasing the steric hindrance of (entries 8 and 9), and lowering the reaction temperature decreased
NBE can promote β-carbon elimination, but would also reduce the conversion (entry 10). Unsurprisingly, use of 10mol% of N3
its binding affinity and promote the formation of an undesired diminished the yield due to the competing direct Heck reaction,
direct Heck product (4a′). Indeed, NBEs with an alkyl substitu- although turnover of N3 was observed (entry 11). Moreover, on
ent at the bridgehead position (N2–N5) all effectively provided the using ArI 1a as the limiting reagent, the yield decreased to 46%
desired mono amination product (4a) with n-heptyl-substituted (entry 12).
N3 being optimal for substrate 1a (see Supplementary Section III
With the optimized conditions in hand, the scope of iodoarenes
for more detailed discussions and kinetic studies). In contrast, was studied first (Table 2). Both electron-rich (4a–4g) and electron-
N4 with a bulkier cyclohexyl group or N8 with two bridgehead poor (4h–4j) aryl iodides are competent coupling partners, which
substituents produced more Heck product 4a′. In addition, ester- is also evident in the meta-, para-disubstituted substrates (4k–4m).
or phenyl-substituted N6 or N7 only gave a trace amount of 4a With regard to the steric effect, a more sterically hindered meta-
, probably due to a disruptive coordinative interaction with pal- substituent generally improves the yield (from 4a to 4c), probably
ladium. Note that a survey of ligand effects17 revealed that RuPhos by inhibiting the second C–H metallation. When substrates contain
provided an optimal yield for 1a, although other ligands, such as a small meta-substituent (such as a methoxy group), NBE with a
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a
b
Step 1 C–H iodination
Step 2 ortho amination
Step 1 C–H iodination
Step 2 ortho amination
Native
reactive
O
Native
reactive
site for EAS
O
site for EAS
N
N
15d
[Step 1] 95%
Me
Me
15a
F3C
F3C
OMe
11d
OMe
[Step 2] 42%
[Step 1] 83%
[Step 2] 75%
13a
I
I
O
O
N
N
MeO2C
EWG
Me
MeO2C
15e
[Step 1] 96%
[Step 2] 65%a
R
14d–e
EDG
14a–c
15b
MeO2C
MeO2C
OMe
R
[Step 1] 62%
[Step 2] 77%a
OMe
Me
13b
11e
O
N
O
N
15f
[Step 1] 92%
[Step 2] 49%
N
O
15c
O
N
O
13c
tBu
[Step 1] 66%
[Step 2] 58%a
O
tBu
11f
N
c
d
H2N
ClO2S
Ref. 50
N
N
H
H
H
H
N
H
Prior
approach
N
N
Ref. 49 R = H
ClO2S
Prior
approach
O
O
H
O
O
17
O
O
5 steps
35%
2 steps
51%
2
N
N
N
H
2
44%
21a
6%
21b
N
H
H
1
1
58%
N
R2N
N
5
H
H
H
H
(33%c)
O
O
O
O
ortho
amination
O
O
H
H
N
H
4
I
Vinpocetine
N
N
4
Strychnine
19
NR2 = morpholino
I
20
H
H
88%
16
N
N
90%
R2N
56%(40%b)
5
N
C–H iodination
H
H
ortho
C–H
iodination
O
O
amination
O
O
O
O
H
23
NR2 = morpholino
18
Fig. 5 | site-selectivity complementary to eAs reactions. a, For arenes with an EWG, functionalization at positions para to EWG has been achieved via
a sequence of iodination/ortho amination, while EAS generally functionalizes meta positions. b, For arenes with an EDG, functionalization at positions
meta to EDG has been achieved via a sequence of iodination/ortho amination, while EAS generally functionalizes ortho or para positions. c, Amination of
strychnine at the C5 position has been realized (the conventional approach required seven steps to achieve the desired site-selectivity). d, Amination
of vinpocetine at the C5 position was realized (functionalization at the C4 position is usually more common). Reaction conditions: 13 (0.18ꢀmmol), 5a
(0.18ꢀmmol), 3a (0.1ꢀmmol), [Pd(allyl)Cl]2 (0.005ꢀmmol), dppp (0.01ꢀmmol), N3 (0.15ꢀmmol), Cs2CO3 (0.4ꢀmmol), 90ꢀ°C, 24ꢀh. aN4 (0.2ꢀmmol) was used
instead of N3. bUsing 18 (0.1ꢀmmol), 3a (0.11ꢀmmol) and 5a (0.11ꢀmmol). cUsing 22 (0.1ꢀmmol), 3a (0.11ꢀmmol) and 5a (0.11ꢀmmol).
bulkier cyclohexyl group (N4) was found to be more effective (4d). molecules. To our delight, ortho-unsubstituted aryl iodides derived
In addition, broad functional group compatibility was observed from drugs oestrone and loratadine (Claritin) delivered the desired
with tolerance of tertiary amine (4f), silyl ether (4g), ester (4h), amination products (4ab and 4ac) in good yields, demonstrating
nitro group (4j) and aryl chloride (4n). Heterocycles, such as carba- the potential for rapid bis-functionalization of pharmaceutically
zole, quinoline and thiophene, and naphthalene (4o–4r) were also interesting compounds.
suitable substrates. Other amines and olefins were investigated next
To highlight the generality of this strategy, the reaction scope
as coupling partners. A variety of benzoyloxyamines, such as those with different quenches at the ipso position was investigated.
from protected piperidone, piperidine and Boc-protected pipera- In addition to Heck coupling, preliminary success was obtained
zine (4s–4x), were successfully employed, including a complex with reduction (6a)28, Suzuki (6b)30 or Sonogashira (6c)34,45 quenches
example derived from paroxetine (4u). Benzoyloxyamines based on to install a hydrogen, aryl or alkynyl group, respectively, at the
linear amines also provided the mono amination product albeit in ipso position.
a lower yield (4y). Ketal (4t) and tertiary alcohol (4w) were found
Furthermore, the N3 cofactor is also effective for mono ortho
to be compatible. Note that the protected piperidone moiety (4t) is acylation33,46,47 and ortho arylation48, suggesting broad applicability
known to serve as a surrogate for the corresponding free aniline44. of the proposed strategy. Interestingly, ortho substituents on aryl
Furthermore, methyl and n-butyl acrylates can also be smoothly anhydrides have minimal effects on reactivity (8b–8d). Both elec-
coupled at the ipso position.
tron-rich (8d) and electron-deficient (8c) aryl anhydrides worked
Encouraged by the high chemoselectivity, this mono ortho ami- smoothly, and the alkyl anhydrides also afforded the desired prod-
nation method was then explored in a setting with more complex ucts (8e–8f). Similar to previous observations48, aryl bromides with
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an ortho EWG serve as better electrophiles for the ortho arylation been achieved and demonstrated in late-stage derivatization of
reaction (10a–10d). complex molecules. The sequence of C−H iodination followed by
We next sought to examine the reaction with para-substi- ortho-functionalization allows the installation of functional groups
tuted aryl iodides, which is more challenging due to a more facile at positions disfavoured for EAS reactions, thereby offering a dis-
second C−H metallation41. Hence, N8 with alkyl substituents at both tinct approach to control site-selectivity. The broad substrate scope,
bridgehead positions was synthesized to further inhibit the second excellent functional group tolerance and knowledge obtained in
C−H metallation (vide supra, Fig. 2b). Gratifyingly, using N8 as the designing NBE cofactors should open the door to the future devel-
cofactor, simple phenyl iodide (11a) indeed gave the desired mono- opment of more active/selective catalyst systems with more general
functionalized product (12a) in 55% yield with mono/di selectivity applications.
greater than 20:1 (Fig. 4a). Although the efficiency of this prelimi-
nary discovery remains to be improved, it is exciting that this result Data availability. The data supporting the findings of this study
represents the first example for obtaining the mono-functionalized are available within this paper and its Supplementary Information.
product with ortho- and meta-unsubstituted aryl iodides using Pd/ Crystallographic data for compound 4k have been deposited at the
NBE catalysis. For comparison, regular NBE (N1) or NBEs with Cambridge Crystallographic Data Centre (CCDC) under deposi-
substituents at other positions (N9 or N10) gave no such product. tion no. CCDC 1566682. These data can be obtained free of charge
NBEs with a substituent at one bridgehead position (N3 or N4) also from the CCDC (http://www.ccdc.cam.ac.uk/data_request/cif).
yielded the mono product, albeit with reduced yields and selectivity.
Received: 7 October 2017; Accepted: 24 April 2018;
Published: xx xx xxxx
Finally, para-substituted iodoarenes with either an EDG or EWG
still afforded the desired mono products (12b and 12c), thus show-
ing promise for general reactivity (Fig. 4b).
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Acknowledgements
The authors thank the University of Chicago for research support. G. Lu is thanked for
discussions of the DFT results, and K.-y. Yoon is thanked for checking the experiments
and X-ray crystallography.
Author contributions
J.W. and G.D. conceived and designed the experiments. J.W. performed experiments.
R.L. and Z.D. helped perform the experiments during the revision. J.W. and P.L.
performed calculations. J.W. and G.D. co-wrote the manuscript.
Competing interests
The authors declare no competing interests.
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Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-018-0074-z.
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39. Wang, X.-C. et al. Ligand-enabled meta-C‒H activation using a transient
mediator. Nature 519, 334–338 (2015).
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