Palladium-Catalyzed Directed C(sp3)-H Arylation of Saturated Heterocycles at C-3 Using a Concise Optimization Approach

Article abstract of DOI:10.1002/ejoc.201501300

Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C-H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium-catalyzed stereoselective C(sp³)-H arylation at unactivated 3-positions of 5- and 6-membered N- and O-heterocycles with aminoquinoline directing groups. Subtle differences in substrate structures altered their reactivity significantly; and different conditions were required to achieve high yields in each case. Successful conditions were developed using a short empirical optimization approach to cover reaction space with a limited set of variables. Excellent cis-selectivity was achieved in all cases, except for the THP substrate where minor trans-products were formed through a different palladacyclic intermediate. Here, differences in reactivity and selectivity with other directing groups were examined.

Full text of DOI:10.1002/ejoc.201501300

DOI: 10.1002/ejoc.201501300
Full Paper
C–H Functionalization
Palladium-Catalyzed Directed C(sp3)–H Arylation of Saturated
Heterocycles at C-3 Using a Concise Optimization Approach
Dominic P. Affron[a] and James A. Bull*[a]
Abstract: Saturated heterocycles, such as THFs, pyrrolidines, nificantly; and different conditions were required to achieve
piperidines and THPs, are essential components of many bio-
logically active compounds. Examples of C–H functionalization
on these important ring systems remain scarce, especially at
unactivated positions. Here we report the development of con-
ditions for the palladium-catalyzed stereoselective C(sp3)–H
arylation at unactivated 3-positions of 5- and 6-membered N-
and O-heterocycles with aminoquinoline directing groups. Sub-
tle differences in substrate structures altered their reactivity sig-
high yields in each case. Successful conditions were developed
using a short empirical optimization approach to cover reaction
space with a limited set of variables. Excellent cis-selectivity was
achieved in all cases, except for the THP substrate where minor
trans-products were formed through a different palladacyclic
intermediate. Here, differences in reactivity and selectivity with
other directing groups were examined.
Introduction
be resolved. Recently, selective arylation of C(sp3)–H bonds has
been achieved using directing groups to locate transition metal
species and stabilize intermediates.[8–22] Amide-linked directing
groups have permitted arylation processes for a variety of sub-
strates, while also making subsequent removal of the directing
group possible.[9] In a seminal report in 2005, Daugulis reported
the use of 8-aminoquinoline (AQ) amides for C–H arylation at
sp3 centers with aryl iodides, employing catalytic Pd(OAc)2 and
stoichiometric AgOAc (Scheme 1, a).[10] Later, Daugulis intro-
duced the 2-(methylthio)aniline group as an effective auxiliary
for the arylation of primary C–H bonds, while avoiding bis-aryl-
ation, which was a characteristic of the AQ group.[10b] At a simi-
lar time, Yu reported the palladium-catalyzed β-C–H arylation
of carboxamides employing monodentate directing groups to
facilitate functionalization with aryl iodide coupling partners.
This weaker coordination mode used finely-tuned, designed li-
gands.[11] This approach has subsequently been extended to
enantioselective variants using enantioenriched ligands.[12]
Saturated heterocycles, particularly 5- and 6-membered rings
containing N or O, are crucial components across a wide range
of biologically active compounds, featuring prominently in nat-
ural products and pharmaceuticals.[1,2] Extensive synthetic stud-
ies have continued across many decades to provide efficient
access to substituted heterocyclic derivatives.[3] For medicinal
chemistry this has become increasingly relevant, with recent
calls for increased saturation and more 3-dimensional charac-
teristics in drug-like and lead-like compounds.[4,5] The concepts
of lead-oriented synthesis[4a] and “escape from flatland”[4d] have
provided renewed vigor in the study of polar saturated hetero-
cycles.[6] Compounds with reduced aromaticity, low lipophilicity
and an increased fraction of sp3 centers (Fsp3) have been pro-
posed to afford drug candidates more likely to successfully pro-
ceed through all stages of development.[4,5] Reliable synthetic
methods that can divergently access saturated heterocyclic
frameworks with control over the 3D arrangement of substitu-
ents are therefore highly valuable.
The last few years has seen the development of alternative
strongly coordinating bidentate directing groups for use with
palladium catalysts.[13–16] These approaches have extended pal-
ladium-catalyzed arylation to a variety of methyl and methylene
centers.[9–17] A number of cyclic systems have been investi-
gated, including cyclopropanes[18] and cyclobutanes.[12,19] Fur-
thermore, C–H arylation of amino acid derivatives using both
acid[20] and amine,[21,22] linked directing groups have been de-
veloped.[23] These reactions with bidentate directing groups are
likely to operate through a PdII/PdIV catalytic cycle.[10] A con-
certed metalation-deprotonation is often proposed, invoking an
acetate ligand on Pd to assist in breaking the C–H bond and
forming a PdII metallacycle.[24] This intermediate undergoes
oxidative addition with an aryl iodide, giving a PdIV intermedi-
ate, followed by reductive elimination to form the new C–C
bond.[25] There remain limited examples of successful arylation
Transition metal catalyzed functionalization of unactivated
C–H bonds promises to revolutionize the synthesis of complex
molecules.[7] For C–C bond formation at sp3 centers, issues of
stereochemistry, the stability of metalated intermediates, and
selectivity across often poorly differentiated C–H bonds must
[a] Department of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, United Kingdom
E-mail: j.bull@imperial.ac.uk
http://www3.imperial.ac.uk/people/j.bull
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501300.
© 2015 The Autors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This
is an open access article under the terms of the Creative Commons Attribu-
tion License, which permits use, distribution and reproduction in any me-
dium, provided the original work is properly cited.
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directing group (Figure 1). Different arylation conditions are de-
veloped for each of the THF, pyrrolidine, piperidine and THP
substrates to achieve high yields. We present a comparison of
substrate success in these transformations, and provide a con-
densed optimization approach using only a limited set of reac-
tion conditions. A comparison of directing groups was under-
taken on the THP substrate in terms of reactivity and stereose-
lectivity. Finally, our optimization approach was demonstrated
on a carbocyclic and an acyclic aminoquinoline amide to dem-
onstrate the flexibility and applicability of this process, provid-
ing comparisons with literature results (Figure 1).
Figure 1. Substrate classes in this study optimized through a concise
optimization protocol, posing questions of stereoselectivity or mono vs. bis-
arylation (DG = CONHQ, X = Boc, Cbz).
Results and Discussion
Scope of Study and Optimization Protocol
For our study we selected to use Daugulis' bidentate
aminoquinoline directing group, which has been shown to be
compatible with several substrate classes and varying condi-
tions. Our preliminary investigations indicated that one set of
conditions was unlikely to be applicable across the range of
substrates of interest; indeed, in our previous study, there was
a remarkable variation in reaction outcome even between N-
Boc- and N-Cbz-prolinecarboxamides.[35] In many cases in the
literature, extensive optimization is reported for C–H arylation
Scheme 1. Directed C(sp3)–H arylation: acyclic, cyclic and heterocyclic sub-
strates.
using aryl bromides,[13a,26] and of using alkyl halides for C–H
alkylation.[10b,27] Examples of the use of Ni[28] and Fe[29] catalysts
in C(sp3)–H arylation have recently been developed.
Notably absent through these extensive works are studies of different AQ-amide substrates, and there are no general con-
on the catalytic C–H functionalization of saturated heterocycles ditions. However, it was striking that these final optimized con-
at unactivated positions (Scheme 1, b).[30–33] Yu has shown a ditions frequently fell within a limited set. We considered that
single example of arylation[17a] and alkynylation[34] of a 4- a logical, programmed route to optimization of different sub-
amido-tetrahydropyran derivative, with C–H functionalization strates would be valuable in expanding access to new hetero-
occurring at the 3-positions, beta to the directing groups. Chen cyclic derivatives. Consequently, based on examination of the
demonstrated a single example of β-C–H alkylation on a 2- literature and our prior experience we selected a much-reduced
piperidinecarboxamide with ethyl iodoacetate, employing the set of reaction variables that we considered would cover the
AQ directing group.[27a] We recently published the stereospe- relevant reaction space and offer the best chance of success.
cific palladium-catalyzed C–H arylation at the 3-position of The resulting optimization process we designed is illustrated in
proline derivatives, starting from N-Cbz-protected proline with Figure 2.
the AQ directing group.[35,36] During the course of this work
A number of parameters were maintained constant through-
Babu reported the arylation of THF derivatives.[37] This limited
out the optimization process: catalyst loading (5 mol-%), equiv-
set of examples is surprising given the importance of saturated
heterocycles in biologically active compounds, and the poten-
tial for C–H functionalization to provide efficient divergent and
iterative synthesis of derivatives, which is essential in the opti-
mization of compounds in drug discovery.
alents of base (2 equiv.), iodobenzene (3 equiv.), temperature
(110 °C), time (18 h) and scale (0.20 mmol). For efficiency, we
limited the optimization to three rounds and 4 new sets of
conditions per round, along with selected repeat reactions as
control experiments. Initial experiments (round 1) were to es-
Here, we report the development of C–H arylation protocols tablish the viability of the reaction, the preferred Pd source and
for various heterocyclic derivatives using the aminoquinoline solvent.[38] One significant decision was to run the reaction un-
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Crucial to our hypothesis was that this result was likely to
be a maximum yield for this substrate subject to the imposed
constraints (i.e. the AQ directing group with these loadings of
base and iodide). To demonstrate this, we progressed a full
standard optimization at the same time.[39] By this alternative
route we also converged on the same solvent-free conditions,
and did not obtain an improved yield.
Encouraged, we ran a small scope with the successful condi-
tions, using a representative range of electron rich, electron
poor and heterocyclic aryl iodides (Scheme 2). This was per-
formed using AgOAc as a base with no solvent, but the reaction
time was increased to 24 h in an attempt to further conversion.
High yields were obtained across the substrates types; the
phenyl example 2a proceeded in 78 % yield, electron rich 4-
iodoanisole gave 83 % of the arylated compound 2b and the
p-chlorophenyl example 2c was isolated in a 78 % yield. Addi-
tionally, a chloropyridyl substituent could be installed in an ex-
cellent yield of 81 %. When using enantiopure (R)-1, an 88 %
ee of the phenylated product (–)-2a was obtained, suggesting
a small degree of racemization of the starting material occurred
under these conditions. Notably, only the cis-diastereoisomer of
the product was observed in all cases.
Figure 2. Process and parameters used for optimization of the C–H arylation
for each substrate. [a] Reactions were performed at 0.3 concentration with
respect to amide. [b] Using preferred solvent and Pd source from round 1;
1 equiv. Ag2CO3, 30 mol-% PivOH. [c] Using preferred solvent, Pd source and
base from rounds 1 and 2.
M
der solvent-free conditions early on. Examples in the litera-
ture,[10] as well as our own work,[35] indicated this could be
advantageous for challenging substrates, particularly when us-
ing AgOAc, but may then offer little scope for further optimiza-
tion. Next, round 2 would examine halophilic bases, with K, Cs
and AgI salts featuring prevalently in the literature. Acidic addi-
tives (PivOH) were used with Ag2CO3 or K2CO3, where they ap-
peared most advantageous. For conditions that used a solvent,
the concentration of the reaction would then be varied (round
3). Finally, we considered it prudent to allow some flexibility in
reaction time or catalyst loading, to generate isolated yields.
We anticipated that this study could provide valuable insight
into the reactivity of differing substrates, as well as an opportu-
nity for comparison of conditions and directing groups across
related substrates.
THF Substrate
Tetrahydrofuran AQ-amide 1 was investigated first through this
process (Table 1). Applying round 1 of the optimization process,
the solvent-free conditions gave the best result, with a 79 %
1
yield of the desired 3-phenyl-THF 2a by H NMR spectroscopy
(Entry 4). No further improvement was obtained when examin-
ing bases (Entries 5–8).
Scheme 2. Selected scope of aryl iodides compatible with the C–H arylation
reaction of THF carboxamide 1.
Table 1. Optimization of the C–H arylation of THF carboxamide 1.
Entry
Round
Varied conditions
Yield 2a [%][a]
RSM 1 [%][a]
1
2
3
4
1
1
1
1
2
2
2
2
AgOAc, Pd(OAc)2, toluene
AgOAc, Pd(TFA)2, toluene
46[b]
13
54[b]
87
AgOAc, Pd(OAc)2, tert-amyl-OH
AgOAc, Pd(OAc)2, no solvent
Ag2CO3, Pd(OAc)2, no solvent
Ag2CO3, PivOH, Pd(OAc)2, no solvent
K2CO3, PivOH, Pd(OAc)2, no solvent
CsOAc, Pd(OAc)2, no solvent
57
43
79[b]
19
21[b]
81
5[c]
6[c,d]
7[d]
8
56
6
17
44
94
83
[a] Yield of product 2a or recovered starting material 1 determined by 1H NMR spectroscopy with respect to an internal standard (1,3,5-trimethoxybenzene).
[b] Average yield of 2 reactions. [c] 1 equiv. Ag2CO3. [d] 30 mol-% PivOH.
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During the course of this work Babu reported a related set the starting material returned unreacted in each case. As the
of conditions for the arylation of THF carboxamide 1,[37] obtain- solvent-free conditions were only marginally better than the
ing a 73 % yield for 2a, a 62 % yield for 2c and 56 % yield reaction using Pd(OAc)2 in toluene, we chose to examine condi-
for 2d.[40] The optimization process we describe here afforded tions using toluene as solvent to provide greater scope for opti-
improved yields with lower catalyst and reagent loadings, mization. On examining bases, the Ag2CO3 and pivalic acid ad-
based on the examination of reaction concentration as a varia- ditive combination was found to be best, providing a 40 % yield
ble (solvent-free vs. 0.08
M
).
by NMR spectroscopy. Varying the concentration of the reaction
with these sets of conditions did not improve the yield
(Table 2).
The AQ directing group was then removed under two sets
of conditions to provide either the cis or trans isomer selectively
(Scheme 3).[41]
For this challenging substrate, additional variables were con-
sidered to improve the yield to an acceptable value. Increasing
the reaction time to 72 h gave a similar conversion. Increasing
the Pd(OAc)2 loading to 10 mol-% at this longer reaction time
gave a conversion of 70 %. These conditions were then used to
examine the reactivity of the representative scope of aryl
iodides (Scheme 4). Pleasingly, all four aryl iodides were com-
patible in modest to good yields. The phenyl example 6a was
isolated in 53 %, as a single enantiomer, yields ranged from
38 % for the pyridyl example 6d to 59 % for the p-methoxy-
Scheme 3. Selective removal of the 8-aminoquinoline directing group to af-
ford either the trans-acid 3 or cis-acid 4.
Hydrolysis and epimerization to the trans-THF acid 3 was ob-
served in 88 % yield, upon treating the THF carboxamide 1 with
sodium hydroxide in ethanol at 70 °C for 24 h, with 8-amino-
quinoline recovered in 99 %. Alternatively, the cis-acid 4 could
be isolated in the same yield, when using conditions reported
by Babu.[37]
N-Boc Pyrrolidine Substrate
In our previous work on the arylation of N-Cbz-proline deriva-
tives we observed significantly reduced reactivity for N-Boc-
proline AQ-amide 5.[35] Applying the first round conditions to
the N-Cbz substrate gave quantitative conversion to the aryl-
ated product under the solvent-free conditions, similar to the
final conditions developed previously. With the N-Boc-pyrrol-
idine derivative 5 the best yield achieved through round 1 was
also under solvent-free conditions, giving a 21 % yield by 1H
NMR spectroscopy (Table 2, Entries 1–4), with the majority of
Scheme 4. Selected scope of aryl iodides compatible with the C–H arylation
reaction of N-Boc-pyrrolidinecarboxamide 5.
Table 2. Optimization of C–H arylation of N-Boc-pyrrolidinecarboxamide 5.
Entry
Round
Varied conditions
Yield 6a [%][a]
RSM 5 [%][a]
1
2
3
4
1
1
1
1
2
2
2
2
3
3
3
3
AgOAc, Pd(OAc)2, toluene (0.3
AgOAc, Pd(TFA)2, toluene (0.3 M)
AgOAc, Pd(OAc)2, tert-amyl-OH (0.3
AgOAc, Pd(OAc)2, no solvent
Ag2CO3, Pd(OAc)2, toluene (0.3
Ag2CO3, PivOH, Pd(OAc)2, toluene (0.3
K2CO3, PivOH, Pd(OAc)2, toluene (0.3
CsOAc, Pd(OAc)2, toluene (0.3
Ag2CO3, PivOH, Pd(OAc)2, toluene (0.2
Ag2CO3, PivOH, Pd(OAc)2, toluene (0.5
Ag2CO3, PivOH, Pd(OAc)2, toluene (1.0
Ag2CO3, PivOH, Pd(OAc)2, no solvent
M
)
18[b]
0
10
21
24
40[e]
3
12
33
33
36
34
82[b]
100
90
M
)
79
5[c]
6[c,d]
7[d]
8
M
)
76
M
)
60[e]
97
M
)
M)
88
67
67
64
9[c,d]
10[c,d]
11[c,d]
12[c,d]
M)
M)
M
)
66
[a] Yield of product 6a or recovered starting material 5 determined by 1H NMR spectroscopy with respect to an internal standard (1,3,5-trimethoxybenzene).
[b] Average yield of 3 reactions. [c] 1 equiv. Ag2CO3. [d] 30 mol-% PivOH. [e] Average yield of 2 reactions.
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phenyl example 6b. In all cases, single cis-diastereoisomers by using AgOAc as a base in neat conditions, the desired 3-
were observed.[42]
phenylpiperidine 8a was formed in 99 % conversion, which cor-
responded to a 95 % isolated yield, comparable to using the
aryl iodide. However, despite the increased reactivity of this
substrate, attempts to use 2-iodotoluene as a coupling partner
were unsuccessful, demonstrating the difficulties of using
ortho-substituted aryl iodides in directed C–H arylation proc-
esses.[45]
N-Cbz-Piperidine: A Highly Reactive Substrate
For N-Cbz-piperidinecarboxamide 7 all conditions attempted in
the first round of optimization provided quantitative conversion
to the 3-phenyl-piperidine 8a (Table 3, Entries 1–4). This is a
remarkable increase in reactivity vs. the five-membered ring de-
rivatives. The conditions using Pd(OAc)2 and toluene (Entry 1)
were selected to examine reaction scope due to the increased
ease of processing of the crude reaction compared to the reac-
tions without solvent. This gave excellent yields with all exam-
ples, ranging from 90 % for the p-chlorophenyl example 8c to
98 % for the p-methoxyphenyl 8b and pyridyl 8d examples
(Scheme 5). In all cases, only the cis-configured isomer was ob-
served.[43,44]
N-Boc Piperidine Substrate
Given the reduced propensity of N-Boc-pyrrolidine amide 5 to
undergo C–H arylation compared to the N-Cbz derivative, we
were interested to compare this trend in the piperidine series.
Indeed, on subjecting the N-Boc-piperidine derivative 9 to
round 1 of the optimization, reduced yields were obtained com-
pared with N-Cbz-piperidine substrate 7 (Table 4). Only 14 % of
3-phenyl-Boc-piperidine 10a was obtained with Pd(TFA)2 (Entry
2), but 90 % was obtained with Pd(OAc)2 under solvent-free
conditions (Entry 4). For the N-Cbz derivative these reaction
conditions both gave quantitative conversion to the desired
arylated compound, indicating that the Boc group again caused
a reduction in reactivity. With the solvent-free conditions signifi-
cantly better than the others investigated, we took these for-
ward to the base screen. The silver carbonate and pivalic acid
additive combination gave the best yield of arylated compound
1
10a (Entry 6, 96 % by H NMR spectroscopy). This combination
of Ag2CO3 and pivalic acid has not been previously reported
under solvent-free conditions.
These conditions were then used to examine the reaction
scope with the same selection of aryl iodides. Good to excellent
yields were achieved, ranging from 52 % for the pyridyl exam-
ple 10d to 89 % for the p-chlorophenyl example 10c
(Scheme 6).
Scheme 5. Selected scope of aryl iodides compatible with the C–H arylation
reaction of N-Cbz-piperidinecarboxamide 7.
Given the much increased reactivity of this substrate, the
Using 4-iodoanisole in a one gram scale reaction gave an
first round of optimization was repeated using bromobenzene identical yield after 36 h. With this more challenging N-Boc-
(Table 3, Entries 5–8). Aryl bromides are generally considerably piperidine substrate, a wider selection of aryl iodides was em-
less expensive than aryl iodides, but have been mostly ineffect- ployed to demonstrate functional group tolerance under these
ive in this mode of C–H arylation. On this substrate, the yields relatively forcing conditions. The reaction was successful with
were lower than those reactions employing the aryl iodide, but 3-iodobenzonitrile as well as para-ester and methyl ketone sub-
Table 3. Optimization of the C–H arylation of N-Cbz-piperidinecarboxamide 7.
Entry
Round
Varied conditions
Yield 8a [%][a]
RSM 7 [%][a]
1
2
3
4
1
1
1
1
PhI, Pd(OAc)2, toluene
PhI, Pd(TFA)2, toluene
PhI, Pd(OAc)2, tert-amyl-OH
PhI, Pd(OAc)2, no solvent
100[b]
100
100
0[b]
0
0
100
0
5
6
7
8
1
1
1
1
PhBr, Pd(OAc)2, toluene
PhBr, Pd(TFA)2, toluene
PhBr, Pd(OAc)2, tert-amyl-OH
PhBr, Pd(OAc)2, no solvent
92[b]
7
83
99
8[b]
93
17
1
[a] Yield of product 8a or recovered starting material 7 determined by 1H NMR spectroscopy with respect to an internal standard (1,3,5-trimethoxybenzene).
[b] Average yield of 2 reactions.
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Table 4. Optimization of the C–H arylation of N-Boc-piperidinecarboxamide 9.
Entry
Round
Varied conditions
Yield 10a [%][a]
RSM 9 [%][a]
1
2
3
4
1
1
1
1
2
2
2
2
AgOAc, Pd(OAc)2, toluene
AgOAc, Pd(TFA)2, toluene
47[b]
14
50[b]
85
AgOAc, Pd(OAc)2, tert-amyl-OH
AgOAc, Pd(OAc)2, no solvent
Ag2CO3, Pd(OAc)2, no solvent
Ag2CO3, PivOH, Pd(OAc)2, no solvent
K2CO3, PivOH, Pd(OAc)2, no solvent
CsOAc, Pd(OAc)2, no solvent
53
47
90[b]
88
10[b]
12
5[c]
6[c,d]
7[d]
8
96
29
48
4
71
52
[a] Yield of product 10a or recovered starting material 9 determined by 1H NMR spectroscopy with respect to an internal standard (1,3,5-trimethoxybenzene).
[b] Average yield of 2 reactions. [c] 1 equiv. Ag2CO3. [d] 30 mol-% PivOH.
acid afforded pipecolinic acid derivative 12 which constituted
an interesting scaffold for further elaboration in multiple direc-
tions.
THP Substrate: cis/trans Selectivity
When tetrahydropyran AQ-carboxamide 13 was subjected to
round 1 of optimization, a mixture of 3-phenyl-THP products
was observed (14a-cis and 14a-trans, Table 5). Unlike in the
previous cases, the trans-configured arylated product was now
observed as a minor component under all conditions.[46] The
solvent-free conditions showed the most reactivity, but pro-
vided low cis-trans selectivity (Entry 4). The best balance of yield
and diastereomeric ratio (dr) was observed using tert-amyl-OH
and Pd(OAc)2 (Entry 3), therefore these conditions were pro-
gressed to the next round. On varying the bases, both Ag2CO3
(Entry 5) and Ag2CO3/PivOH (Entry 6) gave similar results, with
66 % cis-14a and approximately 11 % trans-14a under both
conditions. The set of conditions without PivOH were taken for-
ward to the concentration screen for reasons of experimental
simplicity. In this case, the concentration of the reaction was
found to have little effect on yield and dr (Entries 9–12).
Scheme 6. Selected scope of aryl iodides compatible with the C–H arylation
reaction of N-Boc-piperidinecarboxamide 9. [a] 36 h reaction time.
This substrate provided an interesting opportunity to com-
pare reactivity and selectivity with different directing groups.
Therefore, Shi's PIP-amine directing group and the 2-(methyl-
thio)aniline auxiliary were examined and taken through the op-
timization procedure. However, these gave reduced reactivity
and reduced selectivity vs. the aminoquinoline auxiliary (Fig-
ure 3; see the Supporting Information for full details). For the
PIP-amine tetrahydropyran carboxamide, round 1 of optimiza-
tion gave the desired arylation with just 14 % cis and 4 % trans
products 15a as the best conditions [tert-amyl-OH, Pd(OAc)2].
These conditions were carried forward to the second round of
optimization, where the Ag2CO3/PivOH additive combination
was found to be the best base/additive mixture, giving 48 % cis
and 11 % trans-configured arylated THP 15a. The concentration
of the reaction was found to have little effect on yield or dr.
These optimised conditions gave a 34 % isolated yield of 15a
as the cis-isomer. Interestingly, the optimized conditions were
very similar for 14a and 15a. The 2-(methylthio)aniline directing
stituents to give piperidines 10e–10g respectively. In addition,
2-iodothiophene afforded piperidine 10h in good yield. Again,
in all cases, only a single diastereoisomer was observed.[43]
From 3-(4-methoxyphenyl)piperidine derivative 10b the Boc
group could be removed with TFA to give the free amine 11
(Scheme 7). Alternatively, heating in concentrated aqueous HCl
gave full deprotection, removing the Boc group, the amino-
quinoline directing group, and also converted the anisole to
the phenol. Subsequent Boc protection of the resulting amino
Scheme 7. Deprotection of 10b to form amine 11 or 3-arylpipecolinic acid
derivative 12.
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Table 5. Optimization of the C–H arylation of THP carboxamide 13.
Entry
Round
Varied conditions
cis [%][a]
trans [%][a]
1
2
3
4
1
1
1
1
2
2
2
2
3
3
3
3
AgOAc, Pd(OAc)2, toluene (0.3
AgOAc, Pd(TFA)2, toluene (0.3 M)
AgOAc, Pd(OAc)2, tert-amyl-OH (0.3
AgOAc, Pd(OAc)2, no solvent
Ag2CO3, Pd(OAc)2, tert-amyl-OH (0.3
Ag2CO3, PivOH, Pd(OAc)2, tert-amyl-OH (0.3
K2CO3, PivOH, Pd(OAc)2, tert-amyl-OH (0.3
CsOAc, Pd(OAc)2, tert-amyl-OH (0.3
Ag2CO3, PivOH, Pd(OAc)2, tert-amyl-OH (0.2
Ag2CO3, PivOH, Pd(OAc)2, tert-amyl-OH (0.5
Ag2CO3, PivOH, Pd(OAc)2, tert-amyl-OH (1.0
Ag2CO3, PivOH, Pd(OAc)2, no solvent
M
)
38[b]
22
13[b]
3
M
)
47[b]
49
11[b]
23
13
11
10
6
5[c]
6[c,d]
7[d]
8
M
)
66
66
24
32
65
62
62
61
M
)
M)
M)
9[c,d]
10[c,d]
11[c,d]
12[c,d]
M)
M)
M
)
13
17
11
16
[a] Yield determined by 1H NMR spectroscopy with respect to an internal standard (1,3,5-trimethoxybenzene). In all cases, the remainder of the mass balance
corresponded to unreacted starting material 13. [b] Average yield of 2 reactions. [c] 1 equiv. Ag2CO3. [d] 30 mol-% PivOH.
group was also examined, but less than 5 % yield of the corre- time of 24 h. Good to excellent yields were achieved in all cases.
sponding product 16a was observed in all cases. This unbiased Diastereomeric ratios of between 83:17 and 80:20 were ob-
comparison, indicated the AQ amide 13 to be most successful tained on isolation of phenyl derivatives 14a–14c, with the pyr-
in this case, and therefore this derivative was used to exemplify idyl example 14d giving a 72:28 dr.
the C–H arylation on the THP ring (Scheme 8).
Stereochemical Outcomes
To provide insight into the origin of the diastereomeric mixture
formed from THP 13, the purified product 14a (as an 81:19
cis/trans mixture of diastereoisomers by 1H NMR) was resub-
jected to the reaction conditions for 18 h. Identical dr (81:19
cis/trans) was observed on workup. In addition, the reaction of
THP 13 with PhI, under the optimized conditions, was stopped
after a series of time points, and at each time point the same
dr was observed.[47] These results indicate that epimerization of
the product does not occur under the reaction conditions. We
propose that this is a result of both cis and trans-palladacycles
being formed, leading to the two diastereoisomers. These
would correspond to three feasible intermediates leading to the
syn and anti-substituted products (Scheme 9).
Figure 3. Comparison of optimal yields and product ratios of different direct-
ing groups on THP carboxamides, following the standard optimization proce-
dure, yields and diastereomeric ratio (dr) quoted as observed in the crude
reaction mixture against an internal standard after 18 h reaction time.
This is consistent with the outcome observed by Yu on
C(sp3)–H arylation of a 4-amido tetrahydropyran, which af-
forded a 6:1 cis/trans mixture, albeit with a different substitution
pattern on the heterocycle (Scheme 1, b). Also, Daugulis re-
ported the di-arylation of a cyclohexane AQ-carboxamide,
which afforded a 69 % all-cis to 13 % cis-trans mixture of iso-
mers, using 4-iodoanisole and AgOAc as base under solvent-
free conditions.[10b]
By contrast, for the THF and pyrrolidine substrates, the trans-
5,5-palladacycle would likely be significantly higher in energy,
hence the observation that only cis diastereoisomers are
formed in these cases. Interestingly, both N-carbamate piper-
idine examples (7 and 9) gave only the cis-diastereoisomers,
which is likely due to the strong preference for the ring to
Scheme 8. Selected scope of aryl iodides compatible with the C–H arylation
reaction of THP carboxamide 11, yield and dr of products on isolation after
a 24 h reaction time.
Under the conditions optimized for THP AQ-amide 13 the adopt conformations with the directing group in an axial posi-
reaction scope was investigated, with an increased reaction tion, to minimize A(1,3) strain with the N-carbamate group.[48]
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sponding to 63 % isolated yield), with a 24 % yield of di-aryl-
ated 19 also observed (Scheme 10).
During the first optimization round, di-arylation of cyclo-
pentanecarboxamide 17 was achieved in 71 % yield under the
solvent-free conditions (25 % mono-arylation). Varying the
bases did not afford an improved yield. The di-arylated product
19 was isolated in a 75 % yield under these conditions using
AgOAc as base with a 24 h reaction time (Scheme 10). This
short optimization process enabled selective mono-arylation of
the cyclopentane derivative in 63 % yield, or di-arylation in
75 % yield, which provides similar or improved outcomes in
comparison to the literature results.
A similar process was performed with propionamide 20
where sequential C–H arylations may occur on the same carbon
atom, the second at a more acidic benzylic position. This short
optimization process provided conditions for selective mono or
bis-arylation, using Pd(OAc)2 and an excess of aryl iodide in
both cases.[50] Using Ag2CO3 in tert-amyl-OH gave mono-select-
ive arylation product 21 in 58 % yield (Scheme 11). On the
other hand, using a K2CO3/PivOH combination and tert-amyl-
OH as solvent provided quantitative conversion to bis-arylated
product 22 (91 % isolated yield), giving a similar set of condi-
tions to those reported by Zeng. These results compare favora-
bly with those previously reported for this substrate.[51]
Scheme 9. Viable conformations of the palladacyclic intermediate formed
from THP carboxamide 13.
Cyclopentane and Propionamide Substrates: Selectivity in
Mono/Di-Arylation
To further study the applicability of this optimization process,
we examined two non-heterocyclic substrates to provide a
comparison with previously reported conditions, particularly
with substrates that can undergo multiple arylation reactions
to probe for selectivity.
Cyclopentanecarboxamide 17 can undergo mono or di-aryl-
ation, to provide trifunctionalized cyclopentanes. The best
yields of mono β-C–H arylation of cyclopentane carboxylic acid
derivatives have been achieved by Daugulis (52 % yield)[10b]
and Yu (71 % yield as a 7:1 mono/di mixture).[17a,49] Shi demon-
strated di-arylation of cyclopentanecarboxamide 17, installing
two phenyl groups in 51 % yield, as the all-cis diastereoisomer,
using diarylhyperiodonium salts as coupling partners.[17b]
Cyclopentanecarboxamide 17 was subjected to the round 1
of optimization. All reaction conditions gave over 90 % conver-
sion to mixtures of mono and di-arylated products,[50] display-
ing considerably increased reactivity compared to the five-
membered heterocyclic derivatives. The highest mono-selectiv-
ity was obtained using toluene with Pd(OAc)2 as catalyst (64 %
yield of mono-arylated cyclopentane 18). These conditions
were taken on to the base screen, where CsOAc gave an im-
provement to 71 % yield. The concentration of the reaction had
Scheme 11. Isolated yields for the mono and bis-selective β-C–H arylations
of propionamide 20.
Conclusions
In conclusion, C–H functionalization can rapidly afford 2,3-sub-
stituted heterocycles with stereocontrol. We have developed
successful conditions for C–H arylation at the 3-position of THF
and pyrrolidine derivatives, and the first examples on piperidine
and THP substrates, using AQ carboxamide directing groups at
C-2. High yields were achieved with each heterocyclic substrate
across a representative collection of aryl iodides. Complete cis-
selectivity was achieved for the THFs, pyrrolidines, and piper-
idines. The THP substrate was also cis-selective, but the trans-
configured product was also formed as a minor component.
Removal of the aminoquinoline group was demonstrated on
the THF substrate, to selectively access either trans or cis-config-
ured THF carboxylic acids.
little effect on the yield, but with a 1.0
M concentration the
yield of mono-arylated compound 18 increased to 72 % (corre-
The same concise optimization process was adopted across
all substrates, using a limited number of variables designed to
cover appropriate reaction space. This process afforded success-
ful conditions for each heterocyclic substrate. We have also
demonstrated that this short optimization procedure could af-
ford conditions that were selective for either mono-arylation or
Scheme 10. Isolated yields for the mono and di-selective β-C–H arylations of
cyclopentanecarboxamide 17.
Eur. J. Org. Chem. 2016, 139–149
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di-arylation of cyclopentane and propionamide substrates. We
consider this may provide a useful process for developing C–H
arylation reactions.
This programmed approach allowed facile comparison of the
reactivity of the different substrates. The six-membered rings
(piperidine and THP) were considerably more reactive than the
corresponding five-membered ring derivatives (pyrrolidine and
THF). Interestingly, the N-Boc-protected N-heterocycles were
much less reactive than the analogous N-Cbz derivatives for
both 5- and 6-membered rings. The reasons for the differences
in substrate reactivity are not yet well-explained by current
models and require further investigation, which will be re-
ported in due course.
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[7]
Experimental Section
Supporting Information (see footnote on the first page of this
article): All experimental details can be found in the supporting
information. This includes experimental procedures, characteriza-
1
tion data, copies of H and 13C NMR spectra and further details of
[8]
[9]
reaction optimization.
Acknowledgments
For financial support we gratefully acknowledge the Engineer-
ing and Physical Sciences Research Council (EPSRC) (Career Ac-
celeration Fellowship to J. A. B.; EP/J001538/1), The Royal Soci-
ety for a research grant (RG2014/R1, RG130648), and Imperial
College London. We thank Mr. Peter Haycock (Imperial College
London) for NMR services.
[10]
[11]
Keywords: Homogeneous catalysis · Palladium · C–H
arylation · N Heterocycles · O Heterocycles
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See supporting information for further details of optimization on THF
carboxamide 1 (extended optimization process). There was no advan-
tage of using alternative concentrations, additives or bases, with toluene
or tert-amyl-OH as solvent, providing confidence in this approach.
Babu and co-workers reported the following conditions: 4 equiv. ArI,
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For selected examples, see: a) S.-Y. Zhang, Q. Li, G. He, W. A. Nack, G.
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[40]
[41]
10 mol-% Pd(OAc)2, 2.2 equiv. AgOAc, toluene (0.08
the amide), 36 h, 110 °C; see ref. 37.
M with respect to
The stereochemical outcome was assigned on the basis of 1H NMR cou-
pling constants. For the (i) cis-configured THF acid 4: δ = 4.65 (d, J =
7.6 Hz, 1 H, HCC=O); and (ii) trans-configured THF acid 3: δ = 4.56 (d,
J = 6.0 Hz, 1 H, HCC=O). See reference 37 for crystal structures and J
values for compounds 2a and 4 indicating stereochemistry.
[28]
a) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2014, 136, 898–901; b) M. Li,
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11933–11939.
The stereochemical outcome was assigned on the basis of 1H NMR cou-
pling constants. For example, the cis-configured N-Boc-3-phenylpyrrol-
idinecarboxamide 6a gave the following signal for the C(2)-H: δ = 4.77
(d, J = 8.5 Hz, 1 H, HCC=O). For representative values for cis (J = 8.1–
8.5 Hz) and trans (J = 4.0–6.3 Hz) coupling constants of related cis and
trans-configured N-acetyl-3-phenylproline and derivatives, see: J. Y. L.
Chung, J. T. Wasicak, W. A. Arnold, C. S. May, A. M. Nadzen, M. W. Holla-
day, J. Org. Chem. 1990, 55, 270.
The stereochemical outcome was assigned on the basis of 1H NMR cou-
pling constants and NOE studies. For the piperidine substrates, the best
comparison was achieved on deprotection to the N-H derivative 11. The
observed signal for 11 C(2)-H: δ = 3.98 (d, J = 4.2 Hz, 1 H, HCC=O). This
contrasts with known trans-3-phenylpipecolinic acid derivatives which
display coupling constants of 10.2–10.5 Hz. Related, 2,3-disubstituted N-
PMP and N–H derivatives displayed characteristic cis (3.7–5.0 Hz) and
trans (9.5 Hz) coupling constants. See the supporting information of: R.
He, X. Jin, H. Chen, Z.-T. Huang, Q.-Y. Zheng, C. Wang, J. Am. Chem. Soc.
2013, 136, 6558–6561. Additionally, NOE experiments were performed
on compound 10b that indicated cis-stereochemistry. See the Support-
ing Information for further details.
[42]
[43]
[29]
[30]
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mann, Angew. Chem. Int. Ed. 2014, 53, 3868–3871; Angew. Chem. 2014,
126, 3949.
For selected approaches to the catalytic α-C–H arylation of saturated
heterocycles, see: a) Z. Zuo, D. W. C. MacMillan, J. Am. Chem. Soc. 2014,
136, 5257–5260; b) Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G.
Doyle, D. W. C. MacMillan, Science 2014, 345, 437–440; c) J. Jin, D. W. C.
MacMillan, Angew. Chem. Int. Ed. 2015, 54, 1565–1569; Angew. Chem.
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A. Matsumoto, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2010, 132, 5568–
5569; g) A. McNally, C. K. Prier, D. W. C. MacMillan, Science 2011, 334,
1114–1117; h) A. Peschiulli, V. Smout, T. E. Storr, E. A. Mitchell, Z. Eliáš,
W. Herrebout, D. Berthelot, L. Meerpoel, B. U. W. Maes, Chem. Eur. J. 2013,
19, 10378–10387; i) D. Liu, C. Liu, H. Li, A. Lei, Angew. Chem. Int. Ed. 2013,
52, 4453–4456; Angew. Chem. 2013, 125, 4549. Also see: j) C. J. Cordier,
R. J. Lundgren, G. C. Fu, J. Am. Chem. Soc. 2013, 135, 10946–10949; k)
K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer, C. Chen, J. Am.
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Zhang, H. Zipse, B. F. Straub, P. Mayer, P. Knochel, J. Am. Chem. Soc. 2011,
133, 4774–4777.
[44]
For trans-3-phenylpipecolinic acid derivatives, related biological activity,
as well as the corresponding relevant coupling constants for stereo-
chemical assignment, see: a) D. G. Liu, Y. Gao, X. Wang, J. A. Kelley, T. R.
Burke, J. Org. Chem. 2002, 67, 1448–1452; b) D. G. Liu, X. Z. Wang, Y.
Gao, B. Li, D. Yang, T. R. Burke, Tetrahedron 2002, 58, 10423–10428; c)
S. R. Stauffer, Piperidine and Pyrrolidine Beta-Secretase Inhibitors for the
Treatment of Alzheimer's Disease, 2008, WO2008036316 A2.
[31]
For Ru-catalyzed arylation at the beta position of cyclic amines, see: B.
Sundararaju, M. Achard, G. V. M. Sharma, C. Bruneau, J. Am. Chem. Soc.
2011, 133, 10340–10343. For Pd-catalyzed beta coupling of lithiated
Eur. J. Org. Chem. 2016, 139–149
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Full Paper
[45] For a rare example of C–H arylation with sterically hindered ortho-substi-
tuted aryl iodides, see: G. He, S.-Y. Zhang, W. A. Nack, R. Pearson, J. Rabb-
Lynch, G. Chen, Org. Lett. 2014, 16, 6488–6491.
yield). Yu used a ligand-enabled arylation to install a p-tolyl group in
71 % yield (as a 7:1 mono/di mixture) where the mono-arylated com-
pound was obtained as a single diastereoisomer.
[46] The stereochemical outcome was assigned on the basis of 1H NMR cou-
pling constants. For example, for the (i) cis-configured pyridyl THP
carboxamide 14d-cis: δ = 4.46 (d, J = 3.2 Hz, 1 H, HCC=O); and (ii) trans-
configured pyridyl THP carboxamide 14d-trans: δ = 4.25 (d, J = 9.8 Hz,
1 H, HCC=O). For coupling constants and NOE studies of related cis (J =
3.4 Hz) and trans (J = 10.1 Hz) configured THPs, see supporting informa-
tion of: A. McNally, B. Evans, M. J. Gaunt, Angew. Chem. Int. Ed. 2006, 45,
2116–2119; Angew. Chem. 2006, 118, 2170.
[50] See supporting information for further details.
[51] The best yields of mono β-C–H arylation of propionamide derivatives
have been achieved by Yu (58 % yield) using a monodentate fluoro-aryl
amide directing group in a ligand-enabled process.[11a] Chen reported
the mono-arylation of N-Phth alanine derivatives, using the AQ directing
group (91 % yield by 1H NMR spectroscopy).[20e] Zeng demonstrated the
bis-arylation of propionamide 20 (91 % yield), using 4-bromoanisole
(4 equiv.),
5
mol-% Pd(TFA)2, and
a
potassium carbonate/
[47] The following diastereomeric ratios were observed at given time points:
82:18 cis/trans (90 min), 83:17 cis/trans (5 h), 83:17 cis/trans (8 h), 83:17
cis/trans (12 h), 83:17 cis/trans (18 h), 83:17 cis/trans (24 h).
pivalic acid combination (3.5 equiv. and 0.5 equiv., respectively) in tert-
amyl-OH as solvent.[26]
[48] Y. L. Chow, C. J. Colón, J. N. S. Tam, Can. J. Chem. 1968, 46, 2821–2825.
[49] Daugulis employed the AQ directing group with this substrate in a reac-
tion with 3-methoxyiodobenzene, using Cs3PO4 in tert-amyl-OH (52 %
Received: October 9, 2015
Published Online: November 27, 2015
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© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim