Intramolecular palladium(II)/(IV) catalysed C(sp3)-H arylation of tertiary aldehydes using a transient imine directing group

Article abstract of DOI:10.1039/c9cc03644j

Palladium catalysed β-C(sp³)-H activation of tertiary aldehydes using a transient imine directing group enables intramolecular arylation to form substituted indane-aldehydes. A simple amine bearing a methyl ether (2-methoxyethan-1-amine) is the optimal TDG to promote C-H activation and reaction with an unactivated proximal C-Br bond. Substituent effects are studied in the preparation of various derivatives. Preliminary mechanistic studies identify a reversible C-H activation, product inhibition and suggest that oxidative addition is the turnover limiting step.

Full text of DOI:10.1039/c9cc03644j

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DOI: 10.1039/C9CC03644J
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Intramolecular Palladium(II)/(IV) Catalysed C(sp3)–H Arylation of
Tertiary Aldehydes using a Transient Imine Directing Group
Sahra St John-Campbella and James A. Bull*a
uReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Palladium catalysed β-C(sp3)–H activation of tertiary aldehydes
using a transient imine directing group enables intramolecular
arylation to form substituted indane-aldehydes. A simple amine
bearing a methyl ether (2-methoxyethan-1-amine) is the optimal
TDG to promote C–H activation and reaction with an unactivated
proximal C–Br bond. Substituent effects are studied in the
preparation of various derivatives. Preliminary mechanistic studies
identify a reversible C–H activation, product inhibition and suggest
that oxidative addition is the turnover limiting step.
Indanes display important and diverse biological activities, and
occur in numerous marketed drugs (Scheme 1).1,2 Important
developments in their synthesis include the use of transition
metal catalysed intramolecular C–H functionalisation to cyclise
relatively simple substrates bearing a halide, through reaction
at a suitably located proximal C–H bond.3-6 To date this has been
achieved using a Pd0/PdII redox cycle where regioselective C–H
activation occurs following oxidative addition to a C–X bond by
a
Pd0 catalyst. Baudoin developed an enantioselective
annulation using a chiral phosphine ligand and Pd(OAc)2
(Scheme 1a)3 and later developed a more general approach for
the formation of 1-indanols and 1-indanamines (Scheme 1b).4
In the only example with an alkyl halide, Alexanian showed that
oxidative addition to unactivated alkyl iodides could promote
proximal C(sp2)–H activation and cyclisation to form 2,2- or
3,3-disubstituted indanes (Scheme 1c).5 Martin later merged
oxidative addition, C(sp3)–H activation, and carbenoid insertion
for Pd0/PdII catalysed indane formation (Scheme 1d).6
Here we disclose the first PdII/PdIV catalysed C–H arylation
for indane synthesis where the C–H activation precedes the
oxidative addition, using a transient directing group (Scheme
1e). The use of in situ generated and catalytic transient imine
Scheme 1: Indane synthesis using C–H functionalisation strategies
directing groups has recently emerged as an efficient strategy
for directed C(sp3)–H functionalisation of aldehydes/ketones
and amines to avoid the discrete steps for installation and
removal of the directing groups.7–9 This is the first example of
using a transient directing for intramolecular C(sp3)–H arylation
and also the first example using unactivated aryl bromides.10
The model aryl halide containing substrates for
intramolecular arylation (1–3) were readily synthesised in one
a. Department of Chemistry Imperial College London Molecular Sciences Research
Hub, White City Campus, Wood Lane, W12 0BZ (UK).
Electronic Supplementary Information (ESI) available: [Additional optimisation and
control reactions, DOE results, kinetic, competition and deuteration experiments,
experimental procedures and characterisation data]. See DOI: 10.1039/x0xx00000x.
All raw and processed data for this manuscript can be found at the Imperial College
London Research Data Repository (doi: 10.14469/hpc/5614).
step from commercial materials. The iodo, bromo and chloro
substrates were subjected to conditions previously reported for
the intermolecular arylation of tertiary aldehydes using
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N-tosylethylenediamine as a transient directing group (TDG1
Table 1).7c Iodide
cyclised to form indane in 38% yield.
Pleasingly, aryl bromide substrate could also be cyclised under
these conditions with better mass recovery than the iodide. The
aryl chloride substrate was unreactive.
;
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DOI: 10.1039/C9CC03644J
1
4
2
3
Table 1: C(sp3)–H annulation with a transient directing group.
TDG1 (0.5 equiv)
Pd(OAc)2 (5 mol%)
AgTFA (2 equiv)
O
DMSO (1 equiv)
O
X
H
HFIP:AcOH (1:1, 0.5 M)
1-3
4
130 °C
entry
X
t (h)
3
RSM (%)a
yield 4 (%)a
1
2
I (1)
0
38
20
0
Scheme 2: Screen of transient directing groups for C–H annulation, indicating the yield
of indane 4. a25 mol% TDG7. b1 equiv TDG7.
Br (2)
Cl (3)
Br (2)
3
82
86
43
3
4b
3
18
39
reactions. When lower concentrations were used (0.3 or 0.1 M
in 2), a low 2.5 mol% loading of Pd(OAc)2 can achieve yields
aYields determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard. bNo DMSO additive, (2:1 HFIP:AcOH). RSM = returned starting material.
>45%. Notably, when using high loadings of TDG7 (0.75 equiv),
increased silver loadings gave better yields, but with less TDG7
(0.25 equiv), a lower loading of AgTFA gave improved yields.
This is likely to be as a consequence of α-oxidation of the amine
by excess AgI. Although the yield remained modest due to
Further investigation was undertaken with bromide 2, due
to reduced degradation and to be more broadly tolerant of
conditions required for the synthesis of a range of possible
substrates.11 An improved yield of indane
4 was obtained with
unreacted 2, this constitutes the first example of intramolecular
a longer reaction time, in the absence of the DMSO additive and
using a higher ratio of HFIP:AcOH (Table 1, Entry 4). Next,
several amines were screened in substoichiometric amounts to
form the transient imine directing group, with varied second
coordinating groups and backbone length (Scheme 2). Simple α-
or β- amino acids gave poor yields in the cyclisation (TDG2 and
C–H functionalisation using a transient directing group, as well
as the first using unactivated aryl bromides.
The study progressed to investigate the effects of different
substituents on the aryl ring and alkyl group (Table 2). Indane
was isolated in a 42% yield from aryl bromide . On larger (2.0
and 4.0 mmol) scales, was isolated in slightly reduced yields,
with losses related to poor separation from the starting
material. Iodo-substrate was less effective under these
conditions, with other unknown side products being formed.
Interestingly, aldehyde has previously been investigated for its
4
2
4
TDG3).
T
aurine (TDG4) formed the product in good yield.
8d
Aromatic TDG’s, anthranilic acid (TDG5
)
and orthanilic acid
1
8e
(
TDG6
)
were ineffective at promoting the reaction. The
highest yield of 47% was obtained with the simple and
inexpensive methoxy ether TDG7. The comparable phenyl ether
4
odour properties.12 5-Fluoroindane 18 was accessed in the same
isolated yield from either the 4-, or 5-fluoro precursors.
5-Chloroindane 19 was formed in good yield from the
(
TDG8) was inferior to the methoxy group. Reducing the
flexibility of the ether in a THF ring in TDG9 gave a similar yield
to TDG7. Homologating the backbone gave only 11% yield
5-substituted precursor 7, even at a larger 2.0 mmol scale. A
(
TDG10).
A
monodentate
TDG11
imine
or benzylamine
formed
from
TDG12
chloride or fluoride in the 6-position was well tolerated for the
cyclisation, however these substituents led to very little
difference in polarity of between the starting material and
4-phenylbutylamine
(
)
(
)
promoted the reaction in low yield. Importantly, when no amine
was present the cyclised product was not formed, supporting
the transient imine mechanism. These studies continue to
demonstrate the importance of the second coordinating group,
along with the potential of varied structure types to be
successful.7-8 It is clear that the second binding site need not be
an acidic group, and neutral coordination is suitable. Using 0.25
or 1 equiv of TDG7 gave the same product yield.
A design-of-experiment (DOE) approach was employed to
assess the continuous reaction parameters.11 The study did not
ultimately lead to an improved yield of indane 4, but did provide
additional insight. The reaction was successful (>25% yield) with
high or low loadings of the TDG (0.25–0.75 equiv), Pd(OAc)2
(2.5–10 mol%) and AgTFA (1–3 equiv). A high concentration
cyclised product, and so were isolated as
a mixture.
5-Trifluoromethyl indane 22 was isolated from both the
bromide and iodide starting material, with the bromide again
giving an improved yield.
Aryl bromides with electron donating substituents were
more challenging due to the already difficult oxidative addition
of PdII to the C–Br bond. This was clearly noticeable with
5-methoxy substituent (12), where low conversions were
observed, and only a 5% isolated yield of 23 was obtained. On
the other hand, the same product could be accessed in higher
yield when the electron donating group was moved to the meta-
position with respect to the bromide (13), with a reduced
influence on the oxidative addition. Larger alkyl substituents led
(1 M at 0.10 mmol 2) caused much decreased yields and poor
mass recovery, particularly at low Pd loadings due to competing
2 | J. Name., 2012, 00, 1-3
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Table 2: Substituent effects for C(sp3)–H annulation with a transient directing group, 0.4 mmol aldehyde precursor.
View Article Online
DOI: 10.1039/C9CC03644J
entry
1
starting material
product
yield (%)
42
34 (2 mmol)
entry
8
starting material
product
yield (%)
42
2
10
33 (4 mmol)
4
22
23
1
5
6
7
11
12
13
14
2
3
4
5
20
41
42
9
28
5
10
11
12
18
26
26
46
19
20
24
25
47 (2 mmol)
8
9
15
16
6
7
38 (16)a
53 (10)a
13
14
23
0
21
26
a Yield of unreacted starting material isolated as a mixture with the product. Both yields calculated by the ratios of the aldehyde signals in the 1H NMR.
reaction in deuterated solvents gave
methyl groups of both aldehyde and indane-aldehyde
(Scheme 4a), suggesting reversible C–H activation, deuteration
at other positions was not observed. Indane was deuterated
under the reaction conditions in absense of starting material
(Scheme 4b), suggesting unproductive product cyclopalladation
may occur in the reaction. On prolonged heating of the product,
side reactions led to poor mass recovery. Competition
experiments with an external aryl iodide (4-iodoanisole) using
b-deuteration of the
to sequentially lower conversions, to afford indane aldehydes
24 and 25 in 26% and 23% yield respectively. Larger groups in
this position suppressed cyclisation. Similarly, more electron
rich or sterically hindered aromatics were not suitable.
Substrates with only methylene C–H bonds accessible, such as
17, were not successful. Secondary aldehydes underwent
preferential oxidation to the conjugated α,β-unsaturated
aldehyde. Attempted cyclisation to other ring sizes (4-, 6- and 7-
membered rings) gave trace product.11
2
4
4
bromide substrate
preferential intermolecular arylation (Scheme 4c). Indane
2
revealed a mixture of products with
was
Indane-aldehydes were derivatised to demonstrate their
4
synthetic utility (Scheme 3). Indane
4 was readily reduced to
observed in only 7% conversion from the starting material, and
the arylated product of the indane (31) was formed in 10%,13
whereas products of intermolecular arylation (mono+di) were
obtained in 44% conversion indicating slow oxidative addition
of the internal aryl bromide. In contrast, the intramolecular
alcohol 28 in excellent yield, and reductive amination with
morpholine furnished amine 29. The addition of methyl
magnesium chloride to methoxy-indane 23 gave secondary
alcohol 30. Finally, we functionalised the remaining methyl
group of chloride containing aldehyde 19 by an intermolecular
transient C–H functionalisation using our previously reported
cyclisation was favoured with iodo-substrate
1, with 62%
conversion to the intramolecular arylation products (Scheme
4d). The reaction profile obtained by running individual
reactions at different time points indicated rapid, apparent
zero-order reaction kinetics under the standard conditions with
the majority of the product formed in only 2 h, after this the
conversion plateaued suddenly.11,14,15 A ‘same excess’ kinetics
study revealed that inhibition from the product was likely in the
reaction.11,16 The higher observed deuterium incorporation in
the product compared to the starting material could suggest a
potential mechanism of product inhibition, through preferential
unproductive reversible β-cyclopalladation of the imine derived
protocol with 4-iodoanisole, to give arylated indane 31 7c
.
O
a)
b)
4
OH
Me
N
92%
47%
27
28
MeO
Cl
c)
d)
23 19
48%
34%
OH
O
OMe
29
30
Scheme 3: Derivatisation of indane products. a) NaBH4, MeOH, 2 h 0–25 °C, b)
morpholine, NaBH(OAc)3, CH2Cl2, 25 °C, 24 h. c) MeMgCl, Et2O, 0–25 °C, 1.5 h. d) TDG1
(50 mol%), 4-iodoanisole, Pd(OPiv)2 (5 mol%), AgTFA, DMSO (1 equiv), HFIP:AcOH (1:1),
130 °C, 3 h. Product isolated as a 5.7:1 mixture with a 4-acetoxyanisole by-product.
from indane
TDG7 first condense to form imine
PdII catalyst (Scheme 4e)
Concerted metallation deprotonation
occurs (II) to activate the C–H bond and form palladacycle III
4
. Mechanistically we propose that aldehyde
2 and
I
which coordinates to the
.
.
The aryl bromide is suitably located to coordinate to the Pd
Studies were undertaken to provide insight to the mechanism
of the intramolecular C–H arylation (Scheme 4). Performing the
centre and undergo oxidative addition to give PdIV intermediate
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deuteration, competition and same excess VeiexwpAertricilme Oennlintse
suggested reversible C–H activation,DOI: 10.1039/C9CC03644J
turnover-limiting
a
oxidative addition and product inhibition through unproductive
cyclometallation of the product imine.
We gratefully acknowledge The Royal Society (University
Research Fellowship UF140161, to JAB), and EPSRC (Doctoral
Prize Fellowship to SSJC).
Notes and references
1
a) M. Vilums, J. Heuberger, L. H. Heitman and A. P. IJzerman,
Med. Res. Rev., 2015, 35, 1097–1126. b) B. D. Dorsey, R. B.
Levin, S. L. McDaniel, J. P. Vacca, J. P. Guare, P. L. Darke, J. A.
Zugay, E. A. Emini and W. A. Schleif, J. Med. Chem., 1994, 37,
3443–3451. c) G. R. Allen, R. Littell, F. J. McEvoy and A. E.
Sloboda, J. Med. Chem., 1972, 15, 934–937. d) G. Villetti, G.
Bregola, F. Bassani, M. Bergamaschi, I. Rondelli, C. Pietra and
M. Simonato, Neuropharmacology, 2001, 40, 866–878.
B. Gabriele, R. Mancuso and L. Veltri, Chem. Eur. J., 2016, 22,
5056–5094.
2
3
4
5
6
7
N. Martin, C. Pierre, M. Davi, R. Jazzar and O. Baudoin, Chem.
Eur. J., 2012, 18, 4480–4484.
S. Janody, R. Jazzar, A. Comte, P. M. Holstein, J.-P. Vors, M. J.
Ford and O. Baudoin, Chem. Eur. J., 2014, 20, 11084–11090.
A. R. O. Venning, P. T. Bohan and E. J. Alexanian, J. Am. Chem.
Soc., 2015, 137, 3731–3734.
Á. Gutiérrez-Bonet, F. Juliá-Hernández, B. de Luis and R.
Martin, J. Am. Chem. Soc., 2016, 138, 6384–6387.
For aldehydes, see: a) F.-L. Zhang, K. Hong, T.-J. Li, H. Park and
J.-Q. Yu, Science, 2016, 351, 252–256. b) K. Yang, Q. Li, Y. Liu,
G. Li and H. Ge, J. Am. Chem. Soc., 2016, 138, 12775–12778.
c) S. St John-Campbell, A. J. P. White and J. A. Bull, Chem. Sci.,
2017, 8, 4840–4847. d) X.-H. Liu, H. Park, J.-H. Hu, Y. Hu, Q.-L.
Zhang, B.-L. Wang, B. Sun, K.-S. Yeung, F.-L. Zhang and J.-Q.
Yu, J. Am. Chem. Soc., 2017, 139, 888–896. e) X.-Y. Chen and
E. J. Sorensen, J. Am. Chem. Soc., 2018, 140, 2789–2792. For
amines, see: f) Y. Liu and H. Ge, Nat. Chem., 2016, 9, 26–32.
g) Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate and J.-Q. Yu, J. Am.
Chem. Soc., 2016, 138, 14554–14557. h) S. St John-Campbell,
A. K. Ou and J. A. Bull, Chem. Eur. J., 2018, 24, 17838–17843.
For reviews on transient C–H functionalisation, see: a) H. Sun,
N. Guimond and Y. Huang, Org. Biomol. Chem., 2016, 14,
8389–8397; b) Q. Zhao, T. Poisson, X. Pannecoucke and T.
Besset, Synthesis, 2017, 4808–4826; c) P. Gandeepan and L.
Ackermann, Chem, 2018, 4, 199–222; d) S. St John-Campbell
and J. A. Bull, Org. Biomol. Chem., 2018, 16, 4582–4595.
a) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902–4911; b) J. C.
K. Chu and T. Rovis, Angew. Chem., Int. Ed., 2018, 57, 62–101;
c) J. He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Q. Yu, Chem.
Rev., 2017, 117, 8754–8786.
Scheme 4: Mechanistic experiments. a) Deuteration experiment showed small levels of
deuteration in RSM
2
and indane 4, yields determined by 1H NMR using
1,3,5-trimethoxybenzene as an internal standard. b) Deuteration of indane 4, yields
determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
Competition experiments with c) external aryl iodide and internal aryl bromide, and d)
external aryl iodide and internal aryl iodide, values given are conversions. e) Proposed
catalytic cycle.
IV. Due to the pronounced effect of electron-rich aromatic
groups on the yield and observed zero reaction order, the
oxidative addition is likely to be the turnover limiting step.
Reductive elimination furnishes indane imine V. Imine V can be
cyclometallated at the methyl group, shown by competition and
deuteration experiments, removing Pd from the productive
8
9
cycle as VI
In conclusion, indanes can be formed by intramolecular
C(sp3)–H arylation using
transient directing group.
.
a
10 Yu has shown that 2-pyridyl bromides can be suitable coupling
partners with a TDG, see: Y.-Q. Chen, Z. Wang, Y. Wu, S. R.
Wisniewski, J. X. Qiao, W. R. Ewing, M. D. Eastgate and J.-Q.
Yu, J. Am. Chem. Soc., 2018, 140, 17884–17894.
11 See SI for further details.
12 B. Winter and S. Gallo-Flückiger, Helv. Chim. Acta, 2005, 88,
3118–3127.
13 Intermolecular arylation must proceed after cyclisation, as
shown by the unsucessful cyclisation of substrate 16.
2-Methoxyethan-1-amine can form a transient imine directing
group to promote proximal β-C(sp3)–H activation of the
cyclisation precursors and facilitate oxidative addition and
subsequent cyclisation through a PdII/PdIV redox cycle. The
product yields for this reaction remained relatively low, related
to the difficult PdII oxidative addition and potential product
inhibition. However, this presents the first intramolecular
C(sp3)–H functionalisation with a TDG and the first use of 14 Addition of further Pd(OAc)2, TDG7 or AgTFA after 3 h did not
lead to further conversion to product 4.
unactivated aryl bromides using a TDG, and may stimulate
further study. Various substituents on the aromatic ring and
secondary alkyl groups were tolerated to prepare indane
aldehydes, and the aldehyde substituent was also further
derivatised. Preliminary mechanistic studies in the form of
15 Comparison of the reaction profiles at 2.5 mol% and 5 mol%
Pd(OAc)2 suggested the reaction was first order in Pd.
16 a) D. G. Blackmond, Angew. Chem. Int. Ed., 2005, 44, 4302–
4320. b) R. D. Baxter, D. Sale, K. M. Engle, J.-Q. Yu and D. G.
Blackmond, J. Am. Chem. Soc., 2012, 134, 4600–4606.
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Intramolecular Palladium(II)/(IV) Catalysed C(sp3)–H Arylation of Tertiary Aldehydes using
View Article Online
DOI: 10.1039/C9CC03644J
a Transient Directing Group
TOC Abstract
Indane-aldehydes are formed using palladium catalysis and a transient directing group to
promote intramolecular C–H functionalisation with aryl bromides
O
O
H2N
Me
O
R
Pd cat., AgTFA
R’
R’
R
Br
H
via transient imine
formation
Intramolecular C(sp3)-H arylation with a TDG
Oxidative addition to unactivated aryl bromide