Synthesis of Alkyl-Substituted Pyridines by Directed Pd(II)-Catalyzed C-H Activation of Alkanoic Amides

Article abstract of DOI:10.1055/s-0035-1560810

A general alkylation protocol for substituted iodopyridines was developed (32 examples, 44-97% yield). The reaction is based on the Pd(II)-catalyzed C-H activation of 8-aminoquinoline-derived alkanoic amides and it employs a catalyst cocktail of Pd(OAc)₂ (10 mol%), NaI (30 mol%), and (BuO)₂POOH (20 mol%), with Ag₂CO₃ as base.

Full text of DOI:10.1055/s-0035-1560810

SYNLETT
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1
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-
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0
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6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2853–2857
letter
2853
P. Hu, T. Bach
Letter
Synlett
Synthesis of Alkyl-Substituted Pyridines by Directed Pd(II)-Cata-
lyzed C–H Activation of Alkanoic Amides
Peng Hu
Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 equiv), NaI (30 mol%)
Thorsten Bach*
N
N
(BuO)2POOH (20 mol%)
(PhMe–DMA = 20:1)
120–130 °C, 24 h
Department Chemie and Catalysis Research Center (CRC),
Technische Universität München, 85747 Garching, Germany
thorsten.bach@ch.tum.de
HN
O
HN
O
+
R
R
3
I
32 examples, 44–97%
4
2
N
substitution of iodide
N
in position 2, 3, or 4 possible
X
X
Received: 07.09.2015
Accepted after revision: 09.10.2015
Published online: 16.11.2015
kanoic 8-AQ amides based on directed C–H activation.7–9
Applications of this valuable functionalization approach to
the construction of pyridines are rare, however, and in no
instance has a yield been reported that significantly ex-
ceeds 50%.7j,10 Indeed, the use of pyridines in this reaction
seems somewhat problematic due to the fact that they
might compete with the directing group for binding to pal-
ladium. Catalyst inhibition could result from coordination
of the Lewis basic pyridine nitrogen atom to the active met-
al center.11 Nevertheless, given the importance of alkylated
pyridines, a study that would establish a general protocol
for the alkylation of pyridines with alkanoic amides, ideally
with high functional group tolerance, appeared warranted.
Herein, we report our preliminary results towards this goal.
Initial experiments confirmed the superiority of 8-AQ
as a directing group compared with related amines (see the
Supporting Information for further details). Nevertheless,
the reaction of 2-iodopyridine with alkanoic amide 1a gave,
under typical reaction conditions for this type of transfor-
mation [AgOAc, 10 mol% Pd(OAc)2 in tert-amyl alcohol], a
low yield of product (12%). Extensive optimization was re-
quired to establish appropriate conditions for a higher turn-
over. A key improvement was achieved by using a solvent
mixture of toluene and a polar component, preferably N,N-
dimethylacetamide (DMA); empirically, a ratio of 20:1 (v/v)
was found to be optimal. A further increase of yield was ac-
complished by the use of Ag2CO3 instead of AgOAc, by sub-
stoichiometric addition of additives [NaI, (BuO)2POOH], and
by employing the alkylating agent 1a in excess (see the Sup-
porting Information for further details). The beneficial role
of a phosphoric acid12 and of NaI12a in related reactions has
been reported. Complete conversion was achieved after 24
hours at 130 °C.
DOI: 10.1055/s-0035-1560810; Art ID: st-2015-b0706-l
Abstract A general alkylation protocol for substituted iodopyridines
was developed (32 examples, 44–97% yield). The reaction is based on
the Pd(II)-catalyzed C–H activation of 8-aminoquinoline-derived al-
kanoic amides and it employs a catalyst cocktail of Pd(OAc)2 (10 mol%),
NaI (30 mol%), and (BuO)2POOH (20 mol%), with Ag2CO3 as base.
Key words alkylation, 8-aminoquinoline, C–H activation, palladium,
pyridine
Synthetic access to substituted pyridines can be
achieved either by constructing the heterocyclic skeleton de
novo1 or by attaching substituents to the preformed hetero-
cycle.2 The latter approach offers the benefit of a wider se-
lection of groups to be introduced at a later stage of the syn-
thesis. We became interested in the synthesis of alkylated
pyridines in the context of their biological activity3 and we
searched for ways to attach functional side chains to the
pyridine nucleus. Indeed, many naturally occurring pyri-
dines contain an alkyl group with further functionalization
at the terminal position of the chain. The β-carboline alka-
loids represent a typical compound class, many members of
which contain a pyridine core that is attached to the 3-posi-
tion of an alkanoate unit.4
Recent work on the functionalization of alkanoic acid
derivatives has revealed that a directing group that is cova-
lently attached to the acyl carbon atom can serve as a han-
dle to regioselectively activate the alkanoyl group in the 3-
position.5 In pioneering work by Daugulis and co-workers,
it was established that an 8-aminoquinoline (8-AQ) amide
is particularly suited for this purpose and enables a pallada-
tion at position C3 by C–H activation.6 Several Pd-catalyzed
transformations have subsequently been developed that al-
low regioselective C–C bond formation at substituted al-
After the optimized conditions for the transformation to
2a were established,13 a first set of experiments was per-
formed with 2-iodopyridine as the heterocyclic substrate
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2853–2857

2854
P. Hu, T. Bach
Letter
Synlett
Table 1 (continued)
(Table 1). Various alkanoic amides 1 were used for the de-
sired alkylation. The substrates could be readily prepared
from the respective alkanoic acids via the anhydride or the
acyl chloride, or by direct coupling with the amine in the
presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbo-
diimide hydrochloride (EDC) and 1-hydroxybenzotriazole
(HOBt) (see the Supporting Information). For an aliphatic
chain (entries 1–7) it was shown that the reaction is com-
patible with a protected (Phth = phthaloyl) amino group
(entry 4), an olefinic double bond (entry 5), and an ester
group (entries 6 and 7). When derivatives of 3-arylpropa-
noic acids were employed (entries 9–14), the reaction tem-
perature could be reduced to 120 °C. Functional group com-
patibility with fluoro (entry 9), chloro (entry 10), bromo
(entries 11–13), and alkoxy groups (entry 14) was estab-
lished. With the exception of the last example, yields for the
alkylation exceeded 50% in all cases and ranged from 55 to
94%. For several examples, the reactions were not only per-
formed on a small scale (0.1 mmol) but also on 0.5 mmol
scale. The transformation of 2-iodopyridine into product 1j
(entry 10) was also performed on a gram scale in a yield of
82%.
Entry
Substrate
R
Product
Yield (%)a
Br
Br
11
1kd
2k
82
81
62
45
12
13
14
1ld
2l
Br
1md
1nb,d
2m
2n
O
O
a Yield of isolated product after chromatographic purification. Reactions
were performed on 0.1 mmol scale. Some reactions were run on 0.5 mmol
scale to ensure reproducibility upon scale-up (see the Supporting Informa-
tion).
b Two equivalents of the alkanoic amide 1 were used.
c (BnO)2POOH was used instead of (BuO)2POOH.
d The reaction temperature was 120 °C.
e Reaction was also performed on 4 mmol (gram) scale.
Table 1 Pd(II)-Catalyzed Alkylation of 2-Iodopyridine with Alkanoic
Amides Derived from 8-Aminoquinoline (8-AQ)
Mechanistically, the previously suggested reaction
course for related alkylations of aryl halides is assumed to
operate.6,7 The initial C–H activation event is mediated by
the directing group, which leads to the formation of a 3-
palladated alkanoic amide 3 (Scheme 1). This Pd(II) inter-
mediate undergoes oxidative addition to 2-iodopyridine
with concomitant formation of a Pd(IV) intermediate 4. Re-
ductive elimination establishes the desired C–C bond and
delivers products 2 after ligand exchange.
8-AQ
8-AQ
O
Pd(OAc)2 (10 mol%)
R
N
Ag2CO3 (1.5 equiv), NaI (30 mol%)
(BuO)2POOH (20 mol%)
(PhMe–DMA = 20:1)
I
N
N
+
HN
O
130 °C, 24 h
R
1 (1.5 equiv)
2
N
I
Entry
Substrate
R
Product
Yield (%)a
N
N
reductive
elimination
1
2
3
1a
Me
H
2a
2b
2c
80
66
74
IV
oxidative
addition
II
Pd
I
N
N
O
O
1bb,c
1c
Pd
N
2
L
Bu
R
R
4
3
4
5
6
1d
1e
1f
2d
2e
2f
62
55
90
NPhth
Scheme 1 The oxidative addition of 2-iodopyridine to intermediate 3
en route to the formation of alkylation products 2
COOMe
Given the high electrophilicity at C2, 2-iodopyridine is
expected to undergo the oxidative addition step readily.2e,f
In a second set of experiments, we examined whether the
reaction conditions could be applied to other pyridines
(Scheme 2). To this end, butanoic amide 1a was employed
as the alkylating agent and the pyridyl donor was varied.
Other 2-iodopyridines reacted smoothly and produced the
respective alkylation products 5a–g in yields of 76–90%.
COOMe
7
8
1g
1h
2g
2h
76
84
Ph
F
9
1id
1jd
2i
2j
80
Cl
10
82e
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P. Hu, T. Bach
Letter
Synlett
eral of the reactions were not only run on a small scale (0.1
mmol) but also on 0.5 mmol scale to demonstrate the pos-
sibility of scale-up.
8-AQ
O
X
Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 eq), NaI (30 mol%)
(BuO)2POOH (20 mol%)
(PhMe–DMA = 20:1)
I
8-AQ
+
O
Although the results summarized in Table 1 and Scheme
2 illustrate the broad applicability of the pyridine alkylation
protocol, it seemed desirable to probe whether the method
would also be suitable for the conversion of more complex
pyridines. In this context, the β-carboline alkaloids infrac-
tin (9)14,15 and dihydrocanthinone (10)16,17 appeared to be
ideal target compounds (Scheme 3) because their synthesis
requires the use of a relatively complex 1-iodo-9H-β-carbo-
line (7). Iodide 7 has previously been prepared from the re-
spective bromide.18 Our reaction sequence started from tri-
flate 6,17a,19 which could be readily obtained from β-trypt-
amine in three steps (50% overall yield) by following
reported procedures.17a The displacement of the triflate
group by iodide was achieved in 76% yield. Without any fur-
ther changes to the previously established reaction condi-
tions, the alkylation of iodide 7 was performed with an ex-
cess of propanoic amide 1b. Remarkably, the carboline ni-
trogen atom could be left unprotected in the reaction and
most of the unreacted amide 1b was recovered. Conversion
of product 8 into infractin (9) was achieved in 89% yield
with methanol under acidic conditions. The previously re-
ported conversion of the latter compound into 4,5-dihydro-
canthin-6-one (10) was accomplished by employing report-
ed conditions.15c
N
130 °C, 24 h
N
X
5
1a (1.5 equiv)
:
N
N
N
N
N
N
X
CN
COOMe
Cl
Br
CF3
5a 88% 5ba 87% 5c 76%
5d 81%
5e 79%
OMe
N
N
N
N
N
N
NHAc
5ha 73% 5ia 90% 5ja 97% 5k 77%
Cl
F
5fa 90%
5g 88%
N
N
N
N
N
Cl
N
Br
NPr2
5l 58%
NHPr
OPr
5m 55% 5n 67% 5oa 66%
5pa 74%
5qb 52%
Scheme 2 Pd-catalyzed alkylation of iodopyridines with alkanoic acid
amide 1a. Yield of isolated product after chromatographic purification.
Reactions were performed on 0.1 mmol scale. Some reactions were run
on 0.5 mmol scale to ensure reproducibility upon scale-up (see the
Supporting Information). a (BnO)2POOH was used instead of
1b, Ag2CO3
[Pd(OAc)2]
NaI, (BuO)2POOH
(PhMe–DMA = 4:1)
NaI, HOTf
(BuO)2POOH. b Two equivalents of the alkanoic derivative 1a were used.
N
N
(MeCN)
76%
N
N
H
44%
H
I
OTf
Most notably, chloro (product 5a) or bromo (product
5b) substitution at the pyridine ring was compatible with
the desired transformation. A limited functional group tol-
erance was noted for a nitro group and for protic substitu-
ents (OH, NH2) in the 4-position of the 2-iodopyridine. In
the former case, the product yield remained low (27%),
whereas in the latter cases there was no product formation.
Gratifyingly, the less electrophilic 3-iodopyridines were
also found to be competent substrates for the alkylation re-
action. The respective products 5h–n were isolated in yields
of 55–97%. It appeared as if an acceptor-substituted amino
group (product 5k) was better tolerated than a dialkyl-
(product 5l) or monoalkylamino group (product 5m). Even
in the latter cases, the yield exceeded 50%. Finally, 4-io-
dopyridines were shown to be successfully converted under
the standard reaction conditions (products 5o–q). In gener-
al, the yields for the synthesis of alkylated pyridines varied
between 52 and 97%, which demonstrates the broad utility
of the method. For the examples presented in Table 1, sev-
7
6
N
H2SO4
(MeOH)
N
N
ref.15c
57%
N
N
N
H
H
89%
O
COOMe
CO(8-AQ)
10
9
8
Scheme 3 Synthesis of the natural products infractin (9) and 4,5-dihy-
drocanthin-6-one (10) by alkylation of 1-iodo-9H-β-carboline (7)
In summary, a general method for the alkylation of vari-
ous iodopyridines was established. The method is compati-
ble with several functional groups (F, Cl, Br, CF3, COOMe,
CN, NHAc, NPhth, NHPr, NPr2, and OMe) and delivers the
desired alkylation products in yields of 44–97%. It has been
demonstrated by the synthesis of the natural products in-
fractin (9) and 4,5-dihydrocanthin-6-one (10) that more
complex iodopyridines also undergo the desired alkylation
reaction.
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Acknowledgment
(8) For selected work on sp3 C–H functionalization using other
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This project was supported by the Deutsche Forschungsgemeinschaft
(Ba 1372-19/1) and by the Alexander von Humboldt foundation (post-
doctoral fellowship to P.H.).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560810.
S
u
p
p
ortioInfgrmoaitn
S
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p
p
ortiInfogrmoaitn
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1H NMR (300 MHz, CDCl3): δ = 9.87 (br s, 1 H), 8.78 (dd, J = 4.2,
1.7 Hz, 1 H), 8.69 (dd, J = 6.6, 2.5 Hz, 1 H), 8.64 (dd, J = 2.4,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2853–2857