Methylene C(sp3)-H β,β′-Diarylation of Cyclohexanecarbaldehydes Promoted by a Transient Directing Group and Pyridone Ligand

Article abstract of DOI:10.1021/acs.orglett.0c00124

A hindered β-amino amide transient directing group effects di-trans-arylation of cyclohexanecarbaldehydes. The amide N-substituents are shown to affect yield and can enhance the rate of arylation compared with the α-amino acid. Addition of a pyridone ligand further enhanced reactivity. The reaction is successful for a range of aryl iodides, and various substituted cyclohexane carboxaldehydes, providing functionalized products from simple feedstocks. A mechanism is proposed evoking a transient enamine.

Full text of DOI:10.1021/acs.orglett.0c00124

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Letter
Methylene C(sp3)−H β,β′-Diarylation of Cyclohexanecarbaldehydes
Promoted by a Transient Directing Group and Pyridone Ligand
Sahra St John-Campbell, Andrew J. P. White, and James A. Bull*
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ABSTRACT: A hindered β-amino amide transient directing group
effects di-trans-arylation of cyclohexanecarbaldehydes. The amide N-
substituents are shown to affect yield and can enhance the rate of
arylation compared with the α-amino acid. Addition of a pyridone
ligand further enhanced reactivity. The reaction is successful for a
range of aryl iodides, and various substituted cyclohexane carbox-
aldehydes, providing functionalized products from simple feedstocks.
A mechanism is proposed evoking a transient enamine.
Scheme 1. Methylene C(sp3)−H Functionalization of
Aldehydes with Transient Directing Groups
ransition metal catalyzed C−H functionalization has the
T
potential to improve chemical syntheses and reveal
unprecedented retrosynthetic disconnections to access novel
molecular scaffolds.1 In recent years, transient imine directing
groups have emerged as the next generation of directing groups
for C(sp3)−H functionalization of aldehydes/ketones and
amines.2−8 By this approach, the directing group (DG)
installation and removal steps occur in one pot with the key
C−H functionalization, often through a reversible imine
linkage (Scheme 1a). In contrast to powerful amide bound
directing groups,1c,d a transient strategy removes the require-
ment for additional nonproductive steps and allows directing
groups to be installed catalytically. Furthermore, this directly
reveals valuable functionality, such as aldehydes, for further
diversification.
In 2016, Yu first reported glycine as a transient directing
group (TDG) for the C(sp3)−H arylation of o-tolualdehydes
and aliphatic ketones.4 Subsequently, further examples of
transient directing groups for carbonyl C−H functionalization
have emerged for β-arylation of aliphatic ketones,5 as well as
benzylic6 and ortho-functionalization7 of benzaldehyde deriv-
atives. Aliphatic aldehydes are less explored,8 with examples of
β-arylation from Ge,8a ourselves,8b,d and Wei.8c In these cases,
transient imines have been evoked as the proximal directing
group, with distal secondary anionic or neutral coordinating
groups. However, it is notable that to date there have only
been five individual examples (in two reports)8a,c that
demonstrate the challenging β-methylene functionalization of
aldehydes. Ge showed that using β-alanine as a TDG enabled
β-monoarylation of both cyclohexyl- and cyclopentylcarbox-
aldehydes, with a cis-geometry proposed in both cases (Scheme
1b), and acyclic 2-ethylbutanal and pentanal underwent β-
arylation in lower yields.8a Wei later showed that cyclopropyl-
carboxaldehyde was suitable for β-monoarylation using an
isopropyl amide of β-alanine as the TDG, with the aldehyde in
excess (Scheme 1c).8c
Received: January 9, 2020
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© XXXX American Chemical Society
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Figure 1. (a) Effect of amide transient directing groups on methylene C(sp3)−H arylation of cyclohexanecarboxaldehyde; results are averages of
two runs. (b) Reaction profiles using (i) β-alanine, (ii) tBu-amide TDG10, and (iii) DIPA-amide TDG16. Solvent system: HFIP/AcOH (5:1).
1
Total P = yield of mono 2a + di 3a. Yields determined by H NMR using 1,3,5-trimethoxybenzene as an internal standard.
Here we report the development of a trans,trans-β,β′-
methylene-diarylation of cyclohexanecarbaldehydes (Scheme
1d). The reaction proceeds via a dual catalytic cycle using
catalytic palladium and a catalytic amine transient directing
group bearing a β-amide functionality. The use of a pyridone
additive achieves high yields of the diarylated product.
Palladium coordination via an X,L-type enamine ligand is
proposed.
comparison to acid TDG1. Primary amide TDG2 could also
promote the reaction. Changing the electronics of the aromatic
amide by using p-trifluoromethyl TDG4 and p-methoxy TDG5
groups made little difference to the yield or mono-/
diselectivity. Improved yields were seen with benzyl amide
TDG6 which furnished a 38% yield of a 1:1 mixture of the
mono- and diarylated products. Secondary N-alkyl amides
exhibited improved reactivity, aided by increasing the steric
bulk from n-butyl TDG7 to neopentyl TDG8. The most
sterically demanding tert-butyl TDG10 furnished a 50% total
yield with notable diselectivity. Tertiary amides (TDG11−
TDG17) were also reactive, with the highest yield for the most
hindered diisopropyl amide TDG16.
These results, and the preference for bulky amide
substituents, suggest the distal binding for these components
is through the carbonyl oxygen, not the amide nitrogen, in a 6-
membered chelate.12 Installing a benzyl group on the backbone
of the DIPA amide (TDG17) gave a slight improvement in
yield compared to diisopropylamide TDG16.5a
Our previously reported conditions gave complete chemo-
selectivity for methyl groups, and secondary aldehydes were
not tolerated.8b To overcome this, we initially screened a
library of directing groups for the β-arylation of cyclohexane-
carboxaldehyde with aryl iodides, under lower temperature and
concentration conditions (80 °C, 0.15 M). No reaction was
observed with directing groups that would form a 5-membered
chelate, or with 6-membered chelation where the secondary
binding group was a sulfonamide, methyl ether, or sulfonic
acid.9 Pleasingly, arylation was observed at the β-methylene
when using β-alanine TDG1, as used by Ge, as well as with
amide TDG3. Both mono- and diarylated products were trans-
configured as determined by the coupling constants for the
To aid our understanding of the reaction and as a further
comparison of these TDGs, reaction profiles were investigated
using β-alanine TDG1, tert-butyl amide TDG10, and
diisopropylamide TDG16, using 5:1 HFIP/AcOH as solvent,
which gave improved yields. A peak in the yield of
monoarylated product occurred early in the reaction, which
was then gradually converted to the diarylated species over
11
1
CHCHO and CHPh signals in the H NMR.
To tune reactivity we then examined β-amino-amides with
different amide substituents, using a TDG loading of 25 mol %
and a prolonged reaction time (Figure 1a). Under these
conditions, the efficiency of the amide TDG3 was improved in
B
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time. A faster reaction was observed with the amide directing
groups, along with more rapid conversion of the monoarylated
product 2a to di 3a.
Scheme 2. Scope of Aryl Iodides
Optimization continued with tBu-amide TDG10 to drive
conversion to the diarylated species. We examined the
inclusion of additives to assist in the proposed concerted
metalation deprotonation step. As Yu had described previously
in the C(sp3)−H arylation of amines, pyridones can be
effective ligands to transient C−H activation.3d Here, inclusion
of pyridone ligands was found to enhance the yield and rate of
formation of the diarylated aldehyde product 3a, with the
optimal ligand being 5-(trifluoromethyl)pyridin-2-ol (4).9
The loadings of the Pd(OAc)2, AgTFA, ArI, TDG, and
ligand were optimized using a DOE approach, resulting in a
1
68% yield of diarylated aldehyde 3a (by H NMR; average of
two runs) using 5 equiv of iodobenzene, 30 mol % TDG10, 8
mol % of Pd(OAc)2, 2.1 equiv of AgTFA, and 70 mol % of
pyridone 4.9,10 Under these conditions, a final reaction profile
was obtained (Figure 2), showing rapid formation of the
a
Isolated as a mixture; ratios of product calculated from the relative
integrals of the aldehyde signals.
a small amount of the monoarylated species 2o. 2-Chloro-5-
iodopyridine gave an 18% yield of monoarylated 2p.
We then investigated the effect of substituents on the
cyclohexyl ring (Scheme 3). The trans,trans-configuration was
Scheme 3. Diarylation of Cyclohexanecarbaldehydes
Figure 2. Reaction profile under optimized conditions, with each
point from an individual reaction. Results when omitting the pyridone
1
ligand quoted at 72 h. Yields determined by H NMR using 1,3,5-
trimethoxybenzene as an internal standard.
diarylated product in the early stages of the reaction, which
slowed as the remaining starting material was consumed and
the monoarylated species was slowly converted to the
diarylated product (Figure 2). In the absence of the pyridone
ligand, the yield and selectivity for the diarylated product were
reduced. Importantly, in the absence of the amine TDG, the
arylated products were not formed.9
The scope of the aryl iodide was then investigated, to form
diarylated cyclohexanecarboxaldehydes (Scheme 2, 0.2 mmol
1). A 62% isolated yield of diarylated 3a was achieved with
iodobenzene, and 4-iodoanisole gave diarylated aldehyde 3b in
60% yield, which gave an improved 68% yield on a 1 mmol
scale. The trans,trans-stereochemistry was confirmed by X-ray
crystallography. The 4-benzyl ether derivative resulted in a
slightly lower yield of diarylated product 3c with small
amounts of the monoarylated species 2c. 4-Halophenyl groups
were installed in good yields (3d−g). 4-Iodotoluene formed
diarylated product 3g in 55% yield. Electron-withdrawing
groups in the 4-position led to slightly reduced yields (3h−3j).
4-Iodobenzoate gave 43% of 3h with an additional 12% of the
monoarylated species 2h. ortho-Substituted aryl iodides caused
a significant drop in yield (3k and 3l). meta-Substituents,
including a potentially reactive methyl ketone (3n), were more
well tolerated. Ditosylindole 3o was isolated in 21% yield, with
a
Isolated as a mixture; product ratio calculated from the relative
integrals of the aldehyde signals. PMP = paramethoxyphenyl.
observed exclusively in each case for the arylation. Groups in
the 4-position of the ring generally favored the all-equatorial
product (5−9). The size of the 4-substituent influenced the
selectivity; for example, the tert- butyl derivative gave a 51%
yield of a single diarylated product (5-di). The phenyl group
also gave all-equatorial 6-di, using a cis/trans mixture of the
starting material. The smaller methyl substituent gave small
amounts of a minor isomer of 7-di with the methyl group axial.
An ester was tolerated at the 4-position of the aldehyde, giving
C
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the diarylated product as a 3:1 mixture of 8-di isomers, with
monoarylated all-equatorial 8-mono isolated in 9% yield. An
O-benzyl group was tolerated, giving 40% of the diarylated
product, surprisingly for this substrate the major isomer of 9-di
was that with an axial benzyloxy group (12% of the
monoarylated species 9-mono was also isolated). A difluoro
substituent at the 4-position gave a higher proportion of
monoarylation product 10-mono to 10-di.
A 3-Me group gave the monoarylated product in 24% yield,
with the PMP group installed at the least hindered position,
and 12% of the all-equatorial 1,2,3,4-functionalized aldehyde
11-di. A one-pot tetrarylation was possible on a substrate with
two cyclohexylcarbaldehyde groups connected at the four
position, providing major isomer 12 in 32% yield (75% yield
per arylation). A crystal structure of 12 confirmed the all-
equatorial stereochemistry.
Surprisingly, cyclohexane rings had unique reactivity. Other
ring sizes (3-, 4-, 5-, 7-, and 8-) and acyclic 2-ethylbutanal did
not form significant amounts of the diarylated products.9 The
monoarylated product was isolated in low yield for the
cyclopentane substrate (17% monoarylated using 4-iodoani-
sole). However, under these conditions using the 3- and 4-
membered rings only starting material was returned. In the
larger 7-/8-membered rings, the major products were a mixture
of α−β-unsaturated aldehydes.9
Therefore, we considered the mechanism of the reaction,
aiming to explain these interesting reactivity and stereo-
chemical observations. Conducting the arylation in deuterated
solvents revealed full deuteration of the α-C−H for the mono-
and diarylated products (Scheme 4a). This is consistent with
enamine formation under the reaction conditions. Deuteration
at the benzylic positions was not observed in the products,
suggesting an irreversible C−H activation. The stereochemical
outcome of the tert-butyl derivative provided further insight. In
an imine mechanism, the only possibilities suitable to form the
all-equatorial product would be (i) a trans-equatorial pallada-
cycle giving the observed product directly or (ii) a cis
palladacycle with the imine in the axial position, with the
observed product formed on aldehyde epimerization (Scheme
4b). Other potential palladacycles would result in the wrong
product.9
Notably, the tertiary aldehyde methylcyclohexane carbox-
aldehyde was unreactive, as was pivaldehyde, which present
more reactive methyl C−H bonds (Scheme 4c). Given these
results we propose an alternative role for the transient directing
group, as a X,L enamine ligand, rather than an imine (Scheme
4d). This cannot be achieved with the tertiary aldehydes. The
enamine geometry is well aligned with the C−H bonds for the
trans-arylation on the 6-membered ring. However, such an
intermediate would likely lead to increased ring strain, in
comparison to an imine mechanism for both small and
medium sized rings, or to poorer overlap of the β-C−H bond.
The observed stereochemistry can be rationalized though
enamine coordination of the PdII catalyst with the cyclohexyl
ring in a chair conformation and with large 4-substituents
equatorial. The second arylation would then occur in the same
manner, with the installed Ar group also equatorial. Hydrolysis
of the enamine would give the favored trans-product as
observed. Unfortunately, attempts to characterize potential
intermediates were unsuccessful.
Consequently, we propose a catalytic cycle involving an
enamine-derived Pd cycle (Scheme 5). The aldehyde first
condenses with the amine and forms an X, L enamine ligand
with the PdII catalyst (I). C−H activation occurs at the
proximal C−H promoted by the pyridone, affording cyclo-
metalated intermediate II. Oxidative addition and reductive
elimination steps install the first aryl group giving complex IV.
Scheme 4. Mechanistic Considerations
Scheme 5. Proposed Catalytic Cycle
D
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The palladium and directing group can be turned over by
hydrolysis, or complex IV could ligand exchange to give V to
enter the diarylation cycle directly, explaining the initial rapid
formation of the diarylated species (cf. Figure 2).
\180031] and EPSRC [DTP studentship and Doctoral Prize
Fellowship to S.S.J.C.].
REFERENCES
■
In summary, we have developed a palladium catalyzed trans-
selective diarylation of cyclohexane carboxaldehydes enabled
by a transient directing group and promoted by a pyridone
ligand. Hindered secondary or tertiary β-amino alkyl amides
provide effective transient directing groups. The addition of a
pyridone ligand provides enhanced reactivity and selectivity for
the diaryl product. Varying functionality was tolerated on the
aryl iodides and the cyclohexanecarbaldehyde scaffold, with
most giving good selectivity for the all-equatorial products,
giving highly functionalized 3D structures in one step from
simple starting materials. We propose the role of the added
amine is to form a coordinating enamine as the true transient
directing group for PdII.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00124.
Initial TDG screen, trans-stereochemistry determination,
additional optimization reactions, raw data for reaction
profiles, screen of pyridone ligands, DOE procedure and
results, deuteration experiments, X-ray data for 3b and
12, experimental procedures and characterization data
(PDF)
(3) For C(sp3)−H functionalization of amines with transient
directing groups, see: (a) Liu, Y.; Ge, H. Site-Selective C-H Arylation
of Primary Aliphatic Amines Enabled by a Catalytic Transient
Directing Group. Nat. Chem. 2017, 9, 26−32. (b) Wu, Y.; Chen, Y.-
Q.; Liu, T.; Eastgate, M. D.; Yu, J.-Q. Pd-Catalyzed γ-C(sp3)-H
Arylation of Free Amines Using a Transient Directing Group. J. Am.
Chem. Soc. 2016, 138, 14554−14557. (c) St John-Campbell, S.; Ou,
A. K.; Bull, J. A. Palladium-Catalyzed C(sp3)-H Arylation of Primary
Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing
Group. Chem. - Eur. J. 2018, 24, 17838−17843. (d) Chen, Y.-Q.;
Wang, Z.; Wu, Y.; Wisniewski, S. R.; Qiao, J. X.; Ewing, W. R.;
Eastgate, M. D.; Yu, J.-Q. Overcoming the Limitations of γ- and δ-C-
H Arylation of Amines through Ligand Development. J. Am. Chem.
Soc. 2018, 140, 17884−17894.
Accession Codes
CCDC 1970804−1970805 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
James A. Bull − Department of Chemistry, Molecular Sciences
Research Hub, Imperial College London, White City Campus,
Wood Lane W12 0BZ, U.K.; orcid.org/0000-0003-3993-
5818; Email: j.bull@imperial.ac.uk
(4) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q.
Functionalization of C(sp3)-H Bonds Using a Transient Directing
Group. Science 2016, 351, 252−256.
(5) For C(sp3)−H functionalization of ketones with transient
directing groups, see: (a) Hong, K.; Park, H.; Yu, J.-Q. Methylene
C(sp3)-H Arylation of Aliphatic Ketones Using a Transient Directing
Group. ACS Catal. 2017, 7, 6938−6941. (b) Pan, L.; Yang, K.; Li, G.;
Ge, H. Palladium-Catalyzed Site-Selective Arylation of Aliphatic
Ketones Enabled by a Transient Ligand. Chem. Commun. 2018, 54,
2759−2762. (c) Wang, J.; Dong, C.; Wu, L.; Xu, M.; Lin, J.; Wei, K.
Palladium-Catalyzed β -C-H Arylation of Ketones Using Amino
Amide as a Transient Directing Group: Applications to Synthesis of
Phenanthridinone Alkaloids. Adv. Synth. Catal. 2018, 360, 3709−
3715. Also see refs 4 and 8c.
Authors
Sahra St John-Campbell − Department of Chemistry,
Molecular Sciences Research Hub, Imperial College London,
White City Campus, Wood Lane W12 0BZ, U.K.
Andrew J. P. White − Department of Chemistry, Molecular
Sciences Research Hub, Imperial College London, White City
Campus, Wood Lane W12 0BZ, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00124
(6) For benzylic C(sp3)−H functionalization of o-tolualdehydes with
transient directing groups, see: (a) Ma, F.; Lei, M.; Hu, L.
Acetohydrazone: A Transient Directing Group for Arylation of
Unactivated C(sp3)-H Bonds. Org. Lett. 2016, 18, 2708−2711.
(b) Park, H.; Verma, P.; Hong, K.; Yu, J.-Q. Controlling Pd(IV)
Reductive Elimination Pathways Enables Pd(II)-Catalysed Enantio-
selective C(sp3)-H Fluorination. Nat. Chem. 2018, 10, 755−762.
(c) Tang, M.; Yu, Q.; Wang, Z.; Zhang, C.; Sun, B.; Yi, Y.; Zhang, F.-
L. Synthesis of Polycyclic Aromatic Hydrocarbons (PAHs) via a
Transient Directing Group. Org. Lett. 2018, 20, 7620−7623. (d) Park,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Royal Society [University
Research Fellowship, UF140161 (to J.A.B.), URF Appointed
Grant RG150444 and URF Enhancement Grant RGF\EA
E
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H.; Yoo, K.; Jung, B.; Kim, M. Direct Synthesis of Anthracenes from
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(9) See Supporting Information for details.
(10) The observation from the DOE study was that a relatively large
loading of pyridine (70 mol%) enabled increased ArI loading without
causing adverse side reactions.
(11) This reassigns the stereochemistry of the product reported by
Ge (ref 8a) and is confirmed by X-ray analysis of the diarylated
products 3b and 12.
(12) Yu first demonstrated the use of a β-amino amide TDG for
transient C(sp3)−H functionalization of o-tolualdehydes, binding
through the carbonyl oxygen; see ref 6b.
F
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