Single operation palladium catalysed C(sp3)-H functionalisation of tertiary aldehydes: Investigations into transient imine directing groups

Article abstract of DOI:10.1039/c7sc01218g

Simple amine and diamine derivatives can promote the palladium catalysed direct β-C-H arylation of aliphatic aldehydes via transient imine formation. Trifluoroacetate was shown to be crucial in promoting the reaction. Sub-stoichiometric quantities of simple N-tosylethylenediamine was shown to form a bidentate directing group with an imine linkage. Isolation of an unsymmetrical palladacycle has shown different potential binding modes of the secondary NTs coordinating group by single crystal X-ray diffraction analysis, suggestive of a hemilabile ligand.

Full text of DOI:10.1039/c7sc01218g

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. St John-
Campbell, A. J. P. White and J. A. Bull, Chem. Sci., 2017, DOI: 10.1039/C7SC01218G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Volume
7 Number 1 January 2016 Pages 1–812
Chemical
Science
Accepted Manuscripts are published online shortly after
www.rsc.org/chemicalscience
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Francesco Ricci et al.
Electronic control of DNA-based nanoswitches and nanodevices
rsc.li/chemical-science

Page 1 of 9
Chemical Science
Single Operation Palladium Catalysed C(sp3)–H Functionalisation of Tertiary Aldehydes:
View Article Online
DOI: 10.1039/C7SC01218G
Investigations into Transient Imine Directing Groups
TOC Abstract
Mono- and bidentate amine directing groups formed transiently though imine linkages
promote C–H arylation of tertiary aldehydes
H2N
Ts
N
H
ArI
O
H
O
Ar
Pd cat. AgTFA
via transient imine
formation
R1 R2
R1 R2

Chemical Science
Page 2 of 9
View Article Online
DOI: 10.1039/C7SC01218G
Journal Name
ARTICLE
Single Operation Palladium Catalysed C(sp3)–H Functionalisation
of Tertiary Aldehydes: Investigations into Transient Imine
Directing Groups†
fReceived 00th January 20xx,
Accepted 00th January 20xx
S. St John-Campbell, A. J. P. White and J. A. Bull*
DOI: 10.1039/x0xx00000x
Simple amine and diamine derivatives can promote the palladium catalysed direct b-C–H arylation of aliphatic aldehydes
via transient imine formation. Trifluoroacetate was shown to be crucial in promoting the reaction. Sub-stoichiometric
quantities of simple N-tosylethylenediamine was shown to form a bidentate directing group with an imine linkage.
Isolation of an unsymmetrical palladacyle has shown different potential binding modes of the secondary NTs coordinating
group by single crystal X-ray diffraction analysis, suggestive of a hemilabile ligand.
www.rsc.org/
by Yu, described a transient imine linkage with a-amino acids
Introduction
to promote
b-arylation of aliphatic ketones and benzylic
arylation of o-tolualdehydes.10 A bidentate coordination was
proposed involving the imine nitrogen and the carboxylate. A
sub-stoichiometric amount of glycine was shown to be an
effective promoter using a palladium catalyst and AgTFA, in a
Catalytic C–H functionalisation promises powerful strategies to
derivatise otherwise inert sites of organic molecules.1 Using
transition metal catalysts, in particular using palladium, this
approach is becoming increasingly viable to streamline
complex molecule synthesis. For C(sp3)–H functionalisation
issues of low reactivity and regioselectivity are paramount.
Several strategies have been described to control these issues,
invoking an adjacent functional group to position a catalyst in
an appropriate spatial arrangement to enable C–H
activation,2,3 commonly through a concerted metalation–
deprotonation mechanism.4
HFIP:AcOH solvent mixture. The use of L-tert-leucine afforded
enantioselective arylation. Hu showed that an acetylhydrazone
could act as a directing group for the arylation of o-
tolualdehyde.11 Very recently Li and Ge reported the arylation
of aliphatic aldehydes, via a 5,6-palladacyclic intermediate,
using a b
-amino acid to form an imine linked directing group.12
Transient imine directing groups for aldehyde arylation
Daugulis,5 Yu,6 and others, made seminal advances in
C(sp3)–H functionalisation through the use of amide linked
bidentate and monodentate directing groups through Pd0/PdII
and PdII/PdIV redox cycles.2 The potential to cleave these
groups from the substrate provided clear synthetic
advantages, which encouraged the development of alternative
directing groups to allow more facile removal.7,8 Nonetheless,
these strategies require additional steps to install and remove
the directing groups, which can be problematic and reduces
the overall efficiency.
Very recently, and during the course of our investigations,
the concept of transient directing groups has emerged,
whereby the directing group is installed, C(sp3)–H
functionalisation occurs, then the directing group is removed,
all in one reaction pot (Scheme 1).9 The first report in this field,
via
H2N
O
H
O
Ar
ArI
N
H
H
( )n
R
R
H
( )n
R
R
Pd cat.
H
( )n
Seminal examples (2016)
O
i)
H
Ar
H2N
O
O
O
OH
Me
ArI
H
H
H
Pd cat.
Yu
O
via
Y
ii)
H
Ar
H2N
O
N
H
O
X
[Pd]
ArI
H
H
H
N
Pd cat.
n
Hu
H
O
iii)
H2N
OH
O
H
H
O
O
Ar
ArI
H
R
R
Pd cat.
Li and Ge
R
R
via
This work
G
H2N
G
N
N
H
O
Ar
[Pd]
1
N
ArI
H
Pd cat.
H
R1 R2
R1 R2
R2
R1
Scheme 1. Transient directing groups for C–H arylation of aldehydes.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Page 3 of 9
Chemical Science
ARTICLE
Dong,13 Ge,14 Murakami,15 and Yu16 also recently
Journal Name
View Article Online
DOI: 10.1039/C7SC01218G
OMe
independently demonstrated the direct arylation of aliphatic
amines, using aromatic or conjugated aldehydes to form
directing groups incorporating the reverse imine. Yu has
X
4-iodoanisole (2.6 equiv)
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv)
3a mono-Ar
3b di-Ar
3c tri-Ar
O
N
AcOH (0.3 M)
120 °C, 24 h
reported
the
ortho-C(sp2)–H
functionalisation
of
Ar
Ar
benzaldehydes using transient directing groups to install
(0.4 mmol)
2a-n
3
various functional groups.17,18
OMe
CF3
X
O
O
O
O
O
Here we report investigations into a new class of transient,
sub-stoichiometric directing group for single step
S
O
S
O
S
O
S
b
-C(sp3)–H
NH
NH
NH
NH
2a
2b
2c
2d
arylation of tertiary aldehydes using palladium catalysis and
aryl iodides. Over 25 different mono- and bidentate directing
groups are investigated either as preformed imines or through
40%a
27%a
18%a
29%a
(3a:b:c 23:15:2)
(3a:b:c 16:10:1)
(3a:b:c 13:5:<1)
(3a:b:c 19:10:<1)
Cl
O
iPr
iPr
in situ reversible imine formation with simple amines (1), with
Cl
Cl
Cl
O
O
C4H9
O
O
many successful in mediating the reaction. Some mechanistic
studies are also described, including isolation of a palladacycle
as an unusual unsymmetrical dimer, characterized by single
crystal X-ray diffraction.
O
S
O
S
O
S
NH
Cl
NH
iPr
NH
NH
NH
2e
2f
2g
2h
2i
30%a
32%a
37%a
47%a
42%a
(3a:b:c 17:11:2)
(3a:b:c 20:12:<1) (3a:b:c 21:15:1) (3a:b:c 22:20:5) (3a:b:c 19:19:4)
F
F
F
F
F
Results and Discussion
O
O
Ph
Boc
NH
At the outset of our investigation we envisaged that a
reversible imine formation could transiently introduce
directing functionality to promote C–H arylation on aldehyde
substrates using simple primary amines. To mimic many of the
successful bidentate amide-linked directing groups with a
PdII/PdIV catalytic cycle, we proposed moving the amide or
related functional groups to a distal position, presenting a
reversal of the N,N’-coordinating functionality (Figure 1).19
Such groups would be easily prepared from ethylenediamine
and we anticipated that simple modification of the exo-amide
group would be suitable to tune the properties of the directing
group.
NH
F
NH
F
Ph
2j
2k
2l
2m
2n
34%a
43%a
7%a
(3a:b:c 5:2:0)
22%a
(3a:b:c 7:9:6)
27%a
(3a:b:c 15:16:3)
(3a:b:c 23:18:2)
(3a:b:c 11:10:5)
Scheme 2. Screen of bidentate and monodentate directing groups for the arylation of
a
pivaldehyde derived imines. Yields quoted as combined yield for 3a-c, with separate
mono-, di- and triarylated yields quoted below. Yields determined by 1H NMR using
1,3,5-trimethoxybenzene as an internal standard.
After preliminary optimisation, various imines were
subjected to the arylation conditions, using Pd(OAc)2 and
AgOAc in acetic acid at 0.3 M concentration, over 24 h
(Scheme 2). The screen revealed that both the amide and the
sulfonamide containing imines could successfully direct the C–
H arylation. After a simple work up, involving a filtration
easily modified group
X
coordinating
amide-like N
through silica, only the hydrolysed aldehyde product
3 was
NH
observed, with no residual imine . A mixture of mono-, di-
and tri-arylated products were obtained (3a-c).
2
targeted
CH bond
N
H
sp2
N
Sulfonamide-containing imine 2a gave the best result, with
a 40% combined yield of aldehydes 3a–c. Various other
sulfonamides, with differing steric and electronic properties,
gave similar yields. Generally, the amide-containing directing
groups showed higher reactivity than the sulfonamides, with
amide containing imine 2h giving the highest yield of
aldehydes 3a–c. However, these gave both poorer selectivity
of the monoarylated product, and also formed more highly
functionalised aldehydes, giving overall a more complex
mixture of products.21 Carbamate derivative 2l showed much
reduced yield though was presumably unstable under the
reaction conditions. Interestingly, amines which formed
monodentate directing groups also promoted arylation, with
benzylamine 2n affording a 27% yield. This highlighted that
secondary binding was not crucial, but did enhance the yield.
Indeed, the similarity across the different amines examined
suggests that the secondary binding site may not be
continuously bound to the metal centre throughout the
catalytic cycle.
coordinating
group
imine
attachment
Figure 1. Proposed directing group structure.
To establish the viability of the C–H arylation and to design
the distal coordinating group, we initially preformed a series of
imines from pivaldehyde and primary amines. These were
designed to offer potential bidentate coordination through
varied sulfonamides (2a-g), amides (2h-k) and a carbamate (2l
)
(Scheme 2). Simple alkyl and benzyl examples (2m,n) which
could form only monodentate directing groups were also
prepared. We initially subjected preformed imines to common
arylation conditions using 4-iodoanisole.5,7,20 A low yield was
obtained in the absence of solvent [e.g. 8% yield for 2a], and
although various other solvents were unsuccessful an effective
arylation was obtained in acetic acid.21
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Chemical Science
Please do not adjust margins
Page 4 of 9
Journal Name
ARTICLE
To realise a one-pot arylation of pivaldehyde, a 1:1 ratio of (entry 9). At this stage, numerous additives wereViinewveArstitcilgeaOtnelinde;
DOI: 10.1039/C7SC01218G
aldehyde and directing group was used in place of imine 2a while many Lewis basic additives were tolerated, the
(Table 1). Unfortunately, under the conditions used above, maximum increase in yield was on addition of DMSO, with
only trace product
investigated the reaction parameters initially using
3
was observed (entry 1). Therefore, we 1 equiv optimal (entry 10).23,21 A 61% overall yield of arylated
a
products was obtained by performing the reaction at 130 °C
stoichiometric quantity of amine 1a and Pd(OAc)2 at 10 mol%. and 0.5 M concentration. Finally, further reduction in the
Importantly, on changing the silver source to AgTFA a 29% loading of amine 1a to 0.25 and 0.1 equiv was well tolerated,
yield was achieved (entry 2). A wide range of solvents were resulting in only a marginal reduction in yield (57% and 47%
investigated, along with solvent mixtures.21 The presence of respectively).
acetic acid was critical, and various solvents were tolerated
To highlight the crucial role of trifluoroacetate to the
when used in combination with AcOH. The yield was improved reaction conditions,24 we directly compared the effect of TFA
when using hexafluoroisopropanol (HFIP) as a co-solvent.22 additives (Table 2).
Similar yields were obtained with different AcOH:HFIP ratios
Table 2: Effect of TFA additives on the arylation of pivaldehyde using 1a.
and we chose to progress with a 1:1 mixture for maximum
OMe
reproducibility (entry 3). HFIP alone as
a solvent was
H
N
ineffective (entry 4). Using TFA as a co-solvent with acetic acid
was also a slight improvement on acetic acid alone. Varying
the palladium pre-catalyst gave a successful reaction with
PdCl2 and an improvement with Pd(OPiv)2 to a 47% yield (entry
7).
H2N
Ts
1a
4-iodoanisole
Pd cat
Ag salt, additive
O
O
3a mono-Ar
3b di-Ar
3c tri-Ar
DMSO
Ar
AcOH:HFIP, 130 °C, 3h
Ar
3
Table 1: Optimisation of aldehyde arylation with a transient directing group.
yield (%)b
yield 3
entrya
Pd cat.
Ag salt
additive
3a:3b:3c
combined (%)
OMe
H
N
H2N
Ts
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
AgOAc
AgTFA
AgOAc
AgOAc
-
2:0:0
2
54
47
9
1a
4-iodoanisole
Pd cat, Ag salt
additive
-
TFAc
-
26:19:9
21:17:9
9:trace:0
O
O
3a mono-Ar
3b di-Ar
3c tri-Ar
solvent, temperature
time
Ar
Ar
a Conditions: pivaldehyde (0.2 mmol), 1a (0.5 equiv), 4-iodoanisole (2.6 equiv), Pd
cat (5 mol%), Ag salt (2 equiv), DMSO (1 equiv), HFIP:AcOH (1:1, 0.5 M), 130 °C,
3h. b Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard. c 2 equiv.
3
yield (%)b
yield 3
entrya
solvent
Pd cat.
Ag salt
combined
(%)
3a:3b:3c
Using the optimised conditions, but with palladium acetate
1
2
3
4
5
AcOH
AcOH
HFIP:AcOH (1:1)
HFIP
TFA:AcOH (1:3)
HFIP:AcOH (1:1)
HFIP:AcOH (1:1)
HFIP:AcOH (1:1)
HFIP:AcOH (1:1)
HFIP:AcOH (1:1)
HFIP:AcOH (1:1) Pd(OPiv)2 AgTFA
HFIP:AcOH (1:1)
HFIP:AcOH (1:1)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(OPiv)2
Pd(OPiv)2
Pd(OPiv)2
Pd(OPiv)2
AgOAc
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
trace
15:11: 3
20:13:3
9:0:0
20:13:1
19:13:4
23:17:7
22:15:8
22:18:8
29:19:8
29:22:10
28:20:9
26:16:5
trace
29
36
9
34
36
47
45
46
56
61
57
47
and AgOAc, only a trace amount of aldehyde
3 was formed
(entry 1). Using AgTFA (2 equiv) in place of AgOAc returned the
yield to 54%. Interestingly, when using AgOAc with
trifluoroacetic acid (2 equiv) as an additive a 47% yield could
still be achieved, despite the large excess of acetate from the
solvent.25 Using Pd(TFA)2 (5 mol%; comparable to 0.1 equiv of
TFA) gave a 9% yield of monoarylated aldehyde 3a. In contrast,
in the arylation of the preformed imines the presence of TFA in
the reaction mixture was not a requirement. Indeed, running
the arylation on imine 2a with AgTFA gave the same yield as
using AgOAc. Given the lower concentration of imine in the
one-pot process,22 a more electrophilic Pd(TFA)X species may
improve coordination to the imine and overall facilitate the
CMD process.
6
7
8c
9c,d
10c,d,e
11c,d,e,f
12d,e,f,g
13d,e,f,h
Pd(OPiv)2
Pd(OPiv)2
AgTFA
AgTFA
a
Reaction conditions: pivaldehyde (0.2 mmol), 1a (1 equiv), 4-iodoanisole (2.6
equiv), Pd catalyst (10 mol%), silver salt (2 equiv), 0.3 M, 120 °C, 24 h, unless
otherwise stated. b Yields determined by 1H NMR using 1,3,5-trimethoxybenzene
c
With the highest yielding conditions (table 1, entry 11),
Pd(OPiv)2. 3 h reaction time. Added DMSO (1 equiv). Reaction performed at various mono- and bidentate directing groups were
as an internal standard. Reaction performed using 0.5 equiv 1a, 5 mol%
d
e
f
130 °C, and 0.5 M concentration. g 0.25 equiv 1a, 5 mol% Pd(OPiv)2. h 0.10 equiv
1a, 5 mol% Pd(OPiv)2.
investigated, to further explore potential directing group
design. Remarkably, the vast majority promoted the arylation
to some extent. N-Tosylethylenediamine 1a continued to
Pleasingly, the loadings of both amine 1a and Pd(OPiv)2
provide the best directing group.26 Adding a methyl group
could be lowered to 0.5 equiv and 5 mol% respectively without
adjacent to the primary amine gave a decreased yield,
affecting the reaction yield (entry 8). Notably, an almost
presumably due to reduced imine formation. Sulfonamide 1e
identical reaction profile over time was observed under these
and amide 1h, which gave similar yields in the preformed
conditions (entries 7 and 8; and supporting information).21 The
imines, were less successful than 1a. The monodentate
reaction was rapid, reaching maximum conversion within 3 h
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Page 5 of 9
Chemical Science
ARTICLE
Journal Name
directing groups gave generally lower yields. Several of arylation at the benzylic methylene positionViuewndAretircletOhnelisnee
benzylamine derivatives were investigated (1n-u), including conditions. The reaction was performed DoOnI:a10la.1r0g3e9r/Cs7cSaCl0e12w18itGh
those with secondary coordinating groups (1s-u), for which the a reduced amine loading (5 mmol scale, 0.2 equiv 1a). The
best yield of 27% was with 4-trifluoromethylbenzylamine 1q
No arylation occurred with hindered derivative 1p 2- aldehyde
Picolylamine appeared to directly complex with palladium and iodoanisole examples were viable, albeit with sequentially
was unsuccessful in the reaction. Other simple bidentate lower yields of and respectively due to increased steric
.
reaction efficiency was maintained, providing arylated
.
3
in 52% yield. The meta- and importantly the ortho-
4
5
directing groups were also examined. Under these conditions demands. Using 5-iodo-1,3-benzodioxole gave a low yield of
glycine 1v, as used by Yu,10 formed the arylated product in arylated product 6a. The electron poor 1-iodo-4-nitrobenzene
55% yield with an increased proportion of the tri and gave 45% of
diarylated products. Amino alcohol 1w and 2-methoxyethan-1- the aryl iodide. para-Chloro- and fluoro-iodobenzenes gave
amine 1x gave good yields, also with a greater tendency to good yields of aldehydes and , and the ortho-fluoro
form di- and triarylated aldehydes. A simple NH imine formed example gave 18% yield aldehyde 10. para-Bromoiodobenzene
from ammonium carbamate 1y also gave the arylated product, was run with both 1a and 1x as the directing group to form 11
7, along with small amounts of the homo-dimer of
8
9
.
though in very low yield. Using ethylenediamine itself (1z) also Although the yields for both directing groups were similar
gave no product formation, most likely due to coordination to (within 10%), 1x gave a higher proportion of diarylation. It is
the Pd catalyst. Crucially with no amine added, there was no likely that for pivaldehyde multiple arylations may occur
evidence of product formation.
without exiting the catalytic cycle after the monoarylation, the
extent of which is affected by the structure the directing
groups.27 Pyridyl and thienyl iodides were not well tolerated
under the reaction conditions (<10% yield). However, a 5-
iodoindole derivative was successful to afford 12a in 18% yield.
OMe
H2N
1 (0.5 equiv)
4-iodoanisole (2.6 equiv)
Pd(OPiv)2 (5 mol%)
O
3a mono-Ar
3b di-Ar
O
AgTFA (2 equiv)
DMSO (1 equiv)
AcOH:HFIP (1:1, 0.5 M)
130 °C, 3 h
3c tri-Ar
Ar
H
X
N
Ar
H2N
Ts
(0.2 mmol)
3
1a (0.5 equiv)
Ar-I
Pd(OPiv)2 (5 mol%)
AgTFA (2 equiv)
O
O
3-11
Cl
a mono-Ar
b di-Ar
c tri-Ar
H
N
H
H
N
S
N
H2N
S
H2N
S
H2N
DMSO (1 equiv)
AcOH:HFIP
130 °C, 3 h
Ar
O
O
O
O
O
O
1a
1a-Me
1e
Ar
Cl
61%a
31%a
19%a
(3a:b:c 29:22:10)
(3a:b:c 14:11:6)
(3a:b:c 6:6:7)
3 53%
OMe
MeO
(a:b:c 25:16:12)
H2N
H
N
5 mmol scale; 0.2 equiv 1a:
52%
I
I
OMe
Cl
I
H2N
H2N
1h
1m
1n
(a:b:c 26:16:10)
4a 20%
8 59%
5a 9%a
O
37%a
16%a
17%a
NO2
F
O
O
(3a:b:c 16:13:8)
(3a:b:c 4:4:8)
(3a:b:c 7:5:5)
I
I
I
I
H2N
1o
H2N
1p
H2N
H2N
CF3
7 45%
(a:b 29:16)
9 55%
6a 11%
(a:b:c 31:24b:4b)
(a:b:c 26:24b:5b)
O
1q
1r
25%a
27%a
16%a
0%
Ts
N
11 58%
(3a:b:c 7:6:12)
(3a:b:c 11:8:8)
(3a:b:c 6:4:6)
F
I
Br
(a:b:c 30:23b:5b)
Using 1x:c 49%
(a:b:c 24:21b:4b)
H2N
H2N
H2N
1u
I
I
10 18%a
(a:b:c 12:5b:1b)
12a 18%d
N
O
Cl
1s
1t
16%a
11%a
0%
Scheme 4. Scope of aryl iodides to form aldehydes 3-11. Reaction conditions:
pivaldehyde (0.4 mmol), 1a (0.5 equiv), Ar-I (2.6 equiv), HFIP:AcOH (1:1, 0.5 M). Yields
correspond to sum of yields of isolated products, with individual yields a-c given below.
a Reaction time of 24 h. b Isolated as a mixture of di- and tri-arylated products. c Using 1x
in place of 1a. d Reaction time of 6 h.
(3a:b:c 6:5:5)
(3a:b:c 5:3:3)
O
H2N
H2N
6%a (3a:b 5:1)
H2N
1y NH2CO2NH4
1z H2NCH2CH2NH2 0%
without amine 0%
OH
OMe
56%a
OH
55%a
1v
1w
1x
43%a
(3a:b:c 22:19:14) (3a:b:c 18:17:8) (3a:b:c 17:24:15)
Scheme 3. Screen of bidentate and monodentate directing groups for the direct
The aldehyde component was then investigated (Scheme
5). Higher molecular weight aldehydes bearing an alkyl chain,
gave consistent yields around 55% of arylated products 13-15.
arylation of pivaldehyde. Reaction conditions: pivaldehyde (0.2 mmol), 4-iodoanisole
a
(2.6 equiv), HFIP:AcOH (1:1, 0.5 M). Yields quoted as combined yield for 3a-c, with
separate mono-, di- and triarylated yields quoted below. Yields determined by 1H NMR
using 1,3,5-trimethoxybenzene as an internal standard.
The reaction to form aldehyde 15 was also performed on a
larger scale using a lower loading of amine 1a (0.2 equiv),
which gave a comparable result. Cyclohexyl methyl example
16a was successful with both 1a and 1x directing groups
affording 38% and 27% monoarylation respectively. Benzyl and
2-chlorobenzyl ether examples 17 and 18 were formed in good
yield. Benzyl ether 17 was also formed using 2-methoxy-1-
ethylamine 1x, which gave a comparable yield to 1a, again
Next, the steric and electronic requirements of the aryl
iodide coupling partner were explored using pivaldehyde and
amine 1a (Scheme 4). Under the optimised conditions,
4-iodoanisole afforded a 53% combined isolated yield of the
separated mono-, di- and triarylated aldehydes 3a-c. While
arylation occurred at each CH3 group, there was no evidence
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Chemical Science
Please do not adjust margins
Page 6 of 9
Journal Name
ARTICLE
with an increased proportion of diarylation. Phenethyl modes (Fig. 2).29 The first directing group (C1-based ligand)
View Article Online
DOI: 10.1039/C7SC01218G
example 19 was formed in a 32% total yield, and bis-ether- binds to the palladium centre (Pd1) in a tridentate C,N,N'
containing aldehyde 20 in 40% yield. Reapplying monoarylated fashion utilising C1, the imine nitrogen N4, and the
aldehyde 3a and diarylated 3b to the reaction conditions sulfonamide nitrogen anion (N7), the latter of which also binds
afforded the corresponding further arylated aldehydes to Pd2.30,31 This binding mode is consistent with the imine and
(Scheme 6) with some recovered substrate. Secondary centres, sulfonamide acting as a bidentate directing group. By contrast,
and aldehydes with acidic a-hydrogen atoms were not cleanly the other imine (C21-based ligand), coordinates to Pd2
arylated under these conditions.
through C21 and the imine nitrogen (N24) only. The NH-
sulfonamide was retained, and not coordinated to Pd.32 The
coordination sphere at each metal centre was completed by a
bridging acetate group. Each metal centre has a slightly
distorted square planar coordination geometry, consistent
with the PdII oxidation state.33 The two Pd-coordination planes
are steeply inclined with respect to each other [82.63(7)°] such
that the Pd1···Pd2 separation is 3.1098(3) Å.
OMe
H
N
H2N
Ts
1a
4-iodoanisole
Pd(OPiv)2 (5 mol%)
AgTFA (2 equiv)
13-20
O
O
a mono-Ar
b di-Ar
DMSO (1 equiv)
AcOH:HFIP
R1 R2
R1 R2
130 °C, 3 h
O
Ar
13 R = nHex 53% (a:b 31:22)
14 R = nOct 54% (a:b 30:24)
15 R = nDec 55% (a:b 34:21)
R1
a)
2 mmol scale; 0.2 equiv 1a: 49% (a:b 32:17)
CD3
NHTs
Ts
Ts
N
N
Ts
*
17 54%
(a:b 33:21)
O
Ar
O
Ar
Ts
NH
16a 38%
Pd
Pd
O
ND
O
AcOD
O
O
AcOD-d4
Pd(OAc)2
N
N
Pd
Pd
Using 1x:a
52%
*
*
Using 1x:a
27%a
proposed
equilibrium
N
N
CH3CN, 60 °C
56%
N
*
OBn
(a:b 29:23)
O
Ar
O
Ar
O
Ar
2a-Pd-monomer
2a-Pd-dimer
characterised by NMR,
X-Ray crystallography
2a
characterised
in solution from
isolated dimer
18 54%
(a:b 30:24)
19 32%
(a:b 18:13)
20a 40%
*diastereotopic CH2
O
O
O
Cl
monomer
AcOD-d4
Scheme 5. Reaction scope varying the aldehyde. Ar = C6H4OMe. Reaction conditions:
aldehyde (0.4 mmol), 1a (0.5 equiv), 4-iodoanisole (2.6 equiv), HFIP:AcOH (1:1, 0.5 M).
Yields correspond to sum of yields of isolated products, with individual yields a-c given
below. a Using 1x in place of 1a.
Pd-CH2
Pd-CHH'
dimer
CDCl3
conditions
3a
3b
3b
3c
+ 21% RSM
27%
17%
b)
i)a
ii)b
O
conditions
1a, ArI
2a-Pd-dimer
3c
ArI
+ 33% RSM
3 37%c
3 53%c
25%
AgOAc
(2.5 mol%)
2a-Pd-dimer
(a:b:c 18:18:1)
(a:b:c 26:18:8)
AcOH
AgTFA, DMSO
AcOH:HFIP
Scheme 6. Arylation of 3a and 3b. Conditions: 3a (0.099 mmol) or 3b (0.064 mmol), 1a
(0.5 equiv), 4-iodoanisole (2.6 equiv), Pd(OPiv)2 (5 mol%), AgTFA (2 equiv), DMSO
(1 equiv), HFIP:AcOH (1:1, 0.5 M), 130 °C, 3 h. Yields determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard.
a
Scheme 7. Formation and reactions of 2a-Pd-dimer. Conditions: 2a-Pd-dimer (0.04
mmol), 4-iodoanisole (6.0 equiv), AgOAc (4.0 equiv), AcOH (0.3 M), 120 °C, 24 h.
b Conditions: pivaldehyde (0.2 mmol), 1a (0.5 equiv), 4-iodoanisole (2.6 equiv), 2a-Pd-
dimer (2.5 mol%), AgTFA (2.0 equiv), HFIP:AcOH (1:1, 0.5 M), 130 °C, 3 h. c Yields
determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
To gain some insight into the role of the sulfonamide as a
secondary coordinating group, we formed a palladacycle from
imine 2a by reaction with palladium acetate in MeCN (Scheme
6). The reaction was diluted with toluene and filtered through
Celite to give a 56% yield of the palladacycle, a sample of
which was further purified by recrystallisation. By 1H NMR this
gave complex signals indicative of an unsymmetrical dimeric
structure, containing different imine environments and several
diastereotopic CH2 signals, as well as one NH signal with an
integral of 1 H (Scheme 7a).
When 2a-Pd-dimer was dissolved in AcOD a monomeric
species 2a-Pd-monomer was formed, which was characterised
in solution by H and 13C NMR. Due to the broadening of the
1
directing group CH2 signals (3.38 and 3.20 ppm) we speculated
that there may be an equilibrium between the free and
coordinated sulfonamide group, complemented by changing
acetate coordination (Scheme 7a). Furthermore, monitoring
1
the reaction between 2a and palladium acetate in situ by H
It was clear that the sulfonamide may display different
coordination modes in its role as a secondary coordinating
group.28 Pleasingly we obtained the crystal structure of 2a-Pd-
dimer, proving the palladacycle structure, which indeed
showed the two sulfonamides adopted very different binding
NMR in MeCN-d3 suggested a monomeric palladacycle was
formed in solution.34 This suggests that a monomeric species
would be dominant under the reaction conditions.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Page 7 of 9
Chemical Science
ARTICLE
Journal Name
the success of the transient directing group. The reaction
View Article Online
DOI: 10.1039/C7SC01218G
required small quantities of TFA, up to 2 equivalents, even in
an acetic acid solvent, to promote the arylation of
pivaldehyde. The presence of the second N–Ts coordination
site, resulted in increased yields; a general observation with
the potentially bidentate groups. However, it is likely that the
second site is not coordinated to Pd throughout the catalytic
cycle. The structure of a palladacycle formed from imine 2a
was an unusual unsymmetrical dimer in the solid state, as
confirmed by single crystal X-ray diffraction, where only one of
the two N–Ts groups was coordinated to Pd. It is likely the
monomeric form constitutes an intermediate in the reaction,
presumed to be a PdII/PdIV cycle. The isolated palladacyclic
dimer provided an effective catalyst for the reaction of
pivaldehyde with 4-iodoanisole. The aldehyde arylation using
N-tosylethylenediamine 1a was effective on a variety of
Figure 2. Crystal structure of 2a-Pd-dimer. Selected bond lengths (Å), Pd1–C1 2.009(3), aldehyde substrates and aryl iodide coupling partners with
Pd1–N4 1.952(3), Pd1–N7 2.253(3), Pd1–O41 2.046(2), Pd2–N7 2.085(3), Pd2–C21
2.003(3), Pd2–N24 2.018(3), Pd2–O43 2.244(2). The Pd1···Pd2 separation is
3.1098(3) Å.
various steric and electronic properties. This study offers
insight we expect to be valuable in the future development of
directing groups to be formed transiently to promote
C–H functionalisation. We are now examining the use of imine-
Reacting 2a-Pd-dimer with 4-iodoanisole in AcOH, afforded
linked directing groups for the functionalisation of unactivated
a 37% yield of arylated aldehyde
3 (Scheme 7b,i). Importantly,
C(sp3)–H bonds toward pharmaceutically relevant compounds.
using 2a-Pd-dimer (2.5 mol%, i.e. 5% Pd) as the catalyst for the
arylation of pivaldehyde under the optimised conditions, gave
53% yield of aldehyde
3, in the presence of additional 0.5
Acknowledgements
equiv 1a (Scheme 7b,ii).35 These results support the
palladacycle monomer being an intermediate in the reaction.
On the basis of these observations, and previous reports,
we propose a PdII/PdIV mechanism with coordination of an
electrophilic Pd(TFA)X species to a transiently formed imine,
followed by palladacycle formation, likely through a CMD
mechanism. Oxidative addition of the PdII-palladacycle into the
aryl iodide followed by reductive elimination forms the C-C
bond. The PdII species may decomplex and re-enter the
catalytic cycle, or remain bound to the imine and undergo
arylation again. The imine is then readily hydrolysed to the
aldehyde to regenerate the directing group. The binding
modes of the N–Ts groups in 2a-Pd-dimer, and the reactivity
when using monodentate directing groups, suggests that the
secondary binding site is not likely to be continuously bound to
the catalyst while bound to the imine.
For financial support, we gratefully acknowledge The Royal
Society [University Research Fellowship (to J.A.B.) and URF
appointed grant] the EPSRC [CAF to J.A.B. (EP/J001538/1), and
DTP studentship to SSJC]. We acknowledge the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
Notes and references
1
a) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369–
375. b) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew.
Chem. Int. Ed., 2012, 51, 8960–9009. c) K. Liao, S. Negretti, D.
G. Musaev, J. Bacsa and H. M. L. Davies, Nature, 2016, 533
,
230–234. d) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147–1169. e) K. Godula and D. Sames, Science, 2006,
312, 67–72. f) J. He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Q.
Yu, Chem. Rev., 2017, acs.chemrev.6b00622. g) J. F. Hartwig
and M. A. Larsen, ACS Cent. Sci., 2016, 2, 281–292.
2
3
a) O. Daugulis, J. Roane and L. D. Tran, Acc. Chem. Res., 2015,
48, 1053–1064. b) X. Chen, K. M. Engle, D.-H. Wang and J.-Q.
Yu, Angew. Chem. Int. Ed., 2009, 48, 5094–5115. c) O.
Baudoin, Chem. Soc. Rev., 2011, 40, 4902–4911. d) Z. Huang
and G. Dong, Tetrahedron Lett., 2014, 55, 5869–5889. e) G.
Conclusions
In summary, we have described
a palladium catalysed
β-C(sp3)–H functionalisation on tertiary aldehyde substrates
with aryl iodides, assisted by simple bidentate and
monodentate primary amine derivatives. We have shown a
wide variety of simple amines and diamine derivatives, used in
sub-stoichiometric quantities, form transient imine linkages as
directing groups to promote aldehyde C–H arylation, in a single
synthetic operation. Arylation protocols have been developed
both for preformed imine species as well as through transient
imine formation.
Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013, 52
,
11726–11743.
a) J. A. Garcia-Lopez and V. P. Mehta, Chem. Cat. Chem,
2017. 9, 1149-1156. b) B. J. Knight, J. O. Rothbaum and E. M.
Ferreira, Chem. Sci., 2016, 7, 1982–1987. c) C. He and M. J.
Gaunt, Angew. Chem. Int. Ed., 2015, 54, 15840–15844. d) J. J.
Topczewski, P. J. Cabrera, N. I. Saper and M. S. Sanford,
Nature, 2016, 531, 220–224. e) R. Jazzar, J. Hitce, A.
Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem. Eur. J.,
2010, 16, 2654–2672.
Studies using a new directing group, derived from N-
tosylethylenediamine 1a, have highlighted crucial factors in
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Chemical Science
Please do not adjust margins
Page 8 of 9
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C7SC01218G
4
a) D. Lapointe and K. Fagnou, Chem. Lett., 2010, 39, 1118– 19 For computational studies on the potential of related
1126. b) L. Ackermann, Chem. Rev., 2011, 111, 1315–1345. c)
directing groups, see: H. Tang, X.-R. Huang, J. Yao and H.
Chen, J. Org. Chem., 2015, 80, 4672–4682.
M. Lafrance and K. Fagnou, J. Am. Chem. Soc., 2006, 128
,
16496–16497.
20 D. P. Affron and J. A. Bull, Eur. J. Org. Chem, 2016, 139–149.
5
6
V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. 21 See SI for further details.
Soc., 2005, 127, 13154–13155.
22 To indicate the proportion of the imine present in solution,
a) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B.
Saunders and J.-Q. Yu, J. Am. Chem. Soc., 2007, 129, 3510–
3511. b) D.-H. Wang, M. Wasa, R. Giri and J.-Q. Yu, J. Am.
Chem. Soc., 2008, 130, 7190–7191. c) M. Wasa, K. M. Engle
and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 9886–9887.
the pivaldehyde and N-tosylethylenediamine 1a were
dissolved in AcOD-d4 at rt, which gave 8% formation of imine
2a. Using a 1:1 mixture of AcOD-d4 and HFIP gave 20%
formation of imine 2a. By contrast, dissolving the preformed
imine in AcOD-d4 indicated 56% imine remaining at rt, and
this proportion did not change on heating. See SI for further
details.
7
a) M. Fan and D. Ma, Angew. Chem. Int. Ed., 2013, 52
12152–12155. b) N. Rodríguez, J. A. Romero-Revilla, M. Á.
Fernández-Ibáñez and J. C. Carretero, Chem. Sci., 2013,
175–179. c) Q. Zhang, X.-S. Yin, S. Zhao, S.-L. Fang and B.-F.
,
4
,
23 For Pd-DMSO coordination, see: T. Diao, P. White, I. Guzei
and S. S. Stahl, Inorg. Chem., 2012, 51, 11898–11909.
Shi, Chem. Commun., 2014, 50, 8353–8355. d) G. He, S.-Y. 24 For an example of the importance of TFA in recent works
Zhang, W. A. Nack, Q. Li and G. Chen, Angew. Chem. Int. Ed.,
2013, 52, 11124–11128. e) D. Mu, F. Gao, G. Chen and G. He,
ACS Catal., 2017, 1880–1885. f) D. P. Affron, O. A. Davis and
J. A. Bull, Org. Lett., 2014, 16, 4956–4959. g) For AQ removal,
see: M. Berger, R. Chauhan, C. A. B. Rodrigues and N.
Maulide, Chem. Eur. J., 2016, 22, 16805–16808.
see: a) B. Wang, W. A. Nack, G. He, S.-Y. Zhang and G. Chen,
Chem. Sci., 2014, , 3952. b) See refs 10 and 12 for use of
AgTFA in C–H arylation with transient directing groups. c) Y.
Taniguchi, Y. Yamaoka, K. Nakata, K. Takaki and Y. Fujiwara,
Chem. Lett., 1995, 24, 345–346.
5
25 Varying the amount of TFA added from 0.1 to 3 equivalents
gave a steady to rise in yield until 2 equiv were used, with no
further improvement at 3 equiv (see SI for further details).
8
For prior work using stoichiometrically preformed imines or
oxime derivatives for C(sp3)–H arylation, see: a) using
stoichiometric Pd: B. D. Dangel, K. Godula, S. W. Youn, B. 26 N-Tosylethylenediamine 1a is commercially available or
Sezen and D. Sames, J. Am. Chem. Soc., 2002, 124, 11856– easily synthesised on a large scale.
11857. b) J. E. Baldwin, R. H. Jones, C. Najera and M. Yus, 27 The reaction profile using 1a (see Figure S1 and S2) indicates
Tetrahedron, 1985, 41, 699–711. c) A. G. Constable, W. S.
McDonald, L. C. Sawkins and B. L. Shaw, J. Chem. Soc. Chem.
Commun., 1978, 1061–1062. d) Using catalytic Pd, for
oxidation see: S. R. Neufeldt and M. S. Sanford, Org. Lett.,
that 3a, 3b and 3c form simultaneously and each increase
steadily to a maximum at 3h. However, 3a and 3b are also
viable substrates for the reaction in overall reduced yields
(see Scheme 6).
2010, 12, 532–535. e) For arylation using iodonium salts, see: 28 For example, Carretero and Fernández-Ibáñez previously
J. Peng, C. Chen and C. Xi, Chem. Sci., 2016, , 1383–1387. f) observed dimeric palladacycle involving coordination
For Ir catalysed arylation with iodonium salts, see: P. Gao, W. through the sulfonamide O atoms. See reference 7b.
Guo, J. Xue, Y. Zhao, Y. Yuan, Y. Xia and Z. Shi, J. Am. Chem. 29 CCDC 1534094 contains the supplementary crystallographic
7
a
Soc., 2015, 137, 12231–12240. g) Y. Dong and G. Liu, J. Org.
Chem. 2017, 82, 3864-3872.
data for this paper. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
9
Reversibly bound directing groups had previously been
reported with rhodium catalysts and on sp2 centres. For 30 For the limited examples of palladacycles containing a
aldehydes, see: a) C.-H. Jun, H. Lee and J.-B. Hong, J. Org.
Chem., 1997, 62, 1200–1201; b) for arenes, see: R. B.
Bedford, S. J. Coles, M. B. Hursthouse and M. E. Limmert,
Angew. Chem. Int. Ed., 2003, 42, 112–114. c) for enamines: F.
Mo and G. Dong, Science, 2014, 345, 68–72.
bridging sulfonamide nitrogen, see: a) L. Menabue and M.
Saladini, Inorg. Chem., 1991, 30, 1651–1655. b) J. Sanmartín,
F. Novio, A. M. García-Deibe, M. Fondo, N. Ocampo and M.
R. Bermejo, Eur. J. Inorg. Chem., 2008, 1719–1726. c) J.
Sanmartín-Matalobos, C. Portela-García, M. Fondo, A. M.
10 F.-L. Zhang, K. Hong, T.-J. Li, H. Park and J.-Q. Yu, Science,
2016, 351, 252–256.
García-Deibe and A. L. Llamas-Saiz, J. Coord. Chem., 2016, 69,
1358–1370.
11 F. Ma, M. Lei and L. Hu, Org. Lett., 2016, 18, 2708–2711.
12 K. Yang, Q. Li, Y. Liu, G. Li and H. Ge, J. Am. Chem. Soc., 2016,
138, 12775–12778.
13 Y. Xu, M. C. Young, C. Wang, D. M. Magness and G. Dong,
Angew. Chem. Int. Ed., 2016, 55, 9084–9087.
14 Y. Liu and H. Ge, Nat. Chem., 2016, 9, 26–32.
31 The bridging-nitrogen (N7) is asymmetric, the bond to Pd1
[2.253(3) Å], trans to C1, being ca. 0.17 Å longer than that to
Pd2 [2.085(3) Å], trans to N24. The bridging acetate group is
similarly asymmetric with the Pd–O bond trans to carbon
[Pd2–O43 2.244(2) Å], ca. 0.20 Å longer than that trans to
the imine nitrogen N4 [Pd1–O41 2.046(2) Å].
15 A. Yada, W. Liao, Y. Sato and M. Murakami, Angew. Chem. 32 This N–H hydrogen atom is involved in an intermolecular
Int. Ed., 2017, 56, 1073–1076.
16 Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate and J.-Q. Yu, J. Am.
Chem. Soc., 2016, 138, 14554-14557.
hydrogen bond to the O41 acetate oxygen atom in an
adjacent molecule with N···O and H···O separations of
2.882(3) and 1.988(5) Å, and an N–H···O angle of 172(2)°.
17 X.-H. Liu, H. Park, J.-H. Hu, Y. Hu, Q.-L. Zhang, B.-L. Wang, B. 33 The distortion of the square planar genometry is greater at
Sun, K.-S. Yeung, F.-L. Zhang and J.-Q. Yu, J. Am. Chem. Soc.,
2017, 139, 888–896.
18 Also see: a) J. Xu, Y. Liu, Y. Wang, Y. Li, X. Xu and Z. Jin, Org.
Lett., 2017, 19, 1562–1565. b) X.-Y. Chen, S. Ozturk and E. J.
Sorensen, Org. Lett., 2017, 19, 1140–1143.
Pd2 than at Pd1. For the Pd1 case, N7 lies 0.111(6) Å out of
the {Pd1,C1,N4,O41} plane (the atoms of which are coplanar
to within 0.0154(12) Å), whilst at Pd2 it is the C21 donor
atom that lies 0.305(5) Å out of the {Pd2,N7,N24,O43} plane
(the atoms of which are coplanar to within 0.0568(12) Å).
34 In situ NMR experiments showed fast coordination,
characterised by a shift in the peaks of 2a, then a gradual
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Page 9 of 9
Chemical Science
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C7SC01218G
formation of a monomeric palladacycle species, reaching
maximum conversion after approximately 80 min. See SI for
further details.
35 Without the inclusion of additional amine 1a, a 13% yield
was obtained under the same conditions.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins