Palladium-catalyzed sequential acylation/annulation of indoles with acyl chlorides using primary amine as the directing group

Article abstract of DOI:10.1039/d0nj04406g

An attractive and convenient strategy for the direct acylation/annulation of indoles has been developed using Pd(0) as an efficient catalyst. The main feature of this protocol is the use of acyl chlorides as the acylating agents with the primary amine as the directing group. A variety of indolo[1,2-a]quinoxalines were readily obtained in reasonable efficiency and satisfactory yields with good functional group tolerance. Based on control experiments, a tentative catalytic mechanism was proposed.

Full text of DOI:10.1039/d0nj04406g

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Submitted to New Journal of Chemistry
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Palladium-Catalyzed Sequential Acylation/Annulation of Indoles
with Acyl Chlorides Using Primary Amine as the Directing Group
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Guangbin Jiang,a,* Guang Yang,a Xinqiang Liu,a Shoucai Wang,a and Fanghua
Jia,*
aGuangxi Key Laboratory of Electrochemical and Magnetochemical Function
Materials, College of Chemistry and Bioengineering, Guilin University of Technology,
Guilin 541004, People’s Republic of China.
E-mail: jianggb@glut.edu.cn, fanghuaji@glut.edu.cn; Fax: 86-773-899-1304
* Corresponding authors. Tel: +86-773-899-1304; fax: +86-773-899-1304.
E-mail address: jianggb@glut.edu.cn (G.B. Jiang).
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Abstract An attractive and convenient strategy for the direct acylation/annulation of
indoles has been developed using Pd(0) as an efficient catalyst. The main feature of
this protocol is the use of acyl chlorides as the acylating agents with the primary
amine as the directing group. A variety of indolo[1,2-a]quinoxalines were readily
obtained in reasonable efficiency and satisfactory yields with good functional group
tolerance. Based on control experiments, a tentative catalytic mechanism was
proposed.
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Keywords: palladium-catalyzed; acyl chlorides; acylation/annulation; directing group.
1. Introduction
The reliable and convenient construction of heterocyclic compounds has been a
focus of synthetic chemistry because heterocyclic molecules are very significant and
widely present in functional materials, pharmaceutical agents, and numerous natural
products.1-7 During the past few decades, transition-metal-catalyzed C-H bond
functionalization/annulation under the assistance of the directing group has emerged
as an efficient and succinct tool for the synthesis of various heterocyclic
compounds.8-12 For instance, in 2017, Glorius’s group reported a facile Mn-catalyzed
C(sp2)-H annulation of imines.13 In the same year, a study on ruthenium-catalyzed
[3+3] annulation of anilines with allyl alcohols appeared for accessing quinolone.14
Very recently, Song described the cobalt-catalyzed C(sp2)-H activation/annulations of
aromatics with alkynes using N,O-bidentate group as directing group.15 In addition,
various directing groups have been developed within recent years, such as primary
2

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amine, aminoquinoline, amino acids, carboxyl, and hydroxyl.16-21 Among them,
primary amine-assisted cyclization of substrates are particularly attractive due to their
regioselectivity and practicability.22,23 Despite such great achievements, investigation
on the use of primary amine as directing group to build quinoxalines is very limited.
In addition, as the simple and readily available building blocks, acyl chlorides
have received extensive attention in recent years,24-32 and its participation as an acyl
source is mainly accomplished by classic Friedel-Crafts acylation reactions.33-36
However, the classic Friedel-Crafts acylation reactions generally results in a mixture
of products with poor ortho/para regioselectivity, and usually suffer from narrow
substrate scope and poor functional group tolerance.37,38 The use of stoichiometric
Lewis acids is also a deficiency of this type of reaction. In recent years,
palladium-catalyzed directing groups assisted acylation of acyl chlorides are
particularly attractive due to their remarkable regioselectivity and practicability. In
2019, a Pd-catalyzed acylation of acyl chlorides was elegantly developed by Wu and
co-workers (Scheme 1, a).39 Inspired by this excellent work and as part of our
continuing interests in straightforward transition-metal-catalyzed C-H activation,40,41
herein, we report the first palladium-catalyzed sequential acylation/annulation of
indoles using acyl chlorides as the acylating agents with primary amine as the
directing group (Scheme 1, b).
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Scheme 1. Coupling Reaction of Acyl Chloride by Using a Directing GroupDAOsI:s1i0s.1t0e3d9/D0NJ04406G
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Strategy.
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2
a)
Palladium-catalyzed C(sp )-H acylation using a directing group assisted strategy
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O
O
O
N
N
O
NH
H
NH
Pd
Cl
+
Picolinamide moiety as a bidentate directing group
2
b) This Work:
Palladium-catalyzed C(sp )-H acylation/annulation using a directing
group assisted strategy
O
Pd
Cl
+
N
N
NH2
N
H
Ph
Primary amine as a directing group
2. Experimental section
2-(1H-indol-1-yl)anilines 1 (0.1 mmol), acyl chloride 2 (0.1 mmol), Pd(dba)2 (10
mol%), AgSbF6 (25 mol%), CsOPiv (0.2 mmol) and anhydrous toluene/1,4-dioxane =
1:1 (1 mL) were sealed in a Schlenk tube under Ar atmosphere. The mixture was then
o
stirred at 130 C (oil bath temperature) for 24 h. After the condensation was
completed (monitored by TLC), the resulting mixture was cooled to room temperature
and extracted with ethyl acetate, dried over anhydrous MgSO4, filtered and
evaporated in vacuo. The desired products 3 were obtained in the corresponding
yields after purified by column chromatography on silica gel with mixture of
petroleum ether and ethyl acetate.
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3. Results and discussion
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Table 1. Reaction Developmenta
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Pd(dba)2 (10 mol %)
AgSbF6 (25 mol %)
CsOPiv (2 equiv)
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O
N
+
N
N
Ph
Cl
toluene/1,4-dioxane (1/1, v/v) (1 mL)
NH2
130 oC, 24 h, Ar
"standard conditions"
Ph
1a
3aa
2a
entry
variations from standard conditions
yieldb (%)
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16
none
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48
42
26
47
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15
trace
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Pd(OAc)2 instead of Pd(dba)2
Pd(PPh3)4 instead of Pd(dba)2
Pd(TFA)2 instead of Pd(dba)2
PdCl2 instead of Pd(dba)2
AgOAc instead of AgSbF6
Ag2CO3 instead of AgSbF6
K2S2O8 instead of AgSbF6
Cu(OAc)2 instead of AgSbF6
NaOTf instead of CsOPiv
K3PO4 instead of CsOPiv
NaOH instead of CsOPiv
without Pd(dba)2
37
trace
n.d.
trace
n.d.
trace
without CsOPiv
DMF instead of toluene/1,4-dioxane
CH3CN instead of toluene/1,4-dioxane
aReaction Conditions: 1a (0.1 mmol), 2a (0.2 mmol), catalyst (10 mol %), additive
(25 mol %), base (0.2 mmol) and anhydrous toluene/1,4-dioxane (1/1, v/v) (1.0 mL)
were sealed in a 25 mL Schlenk tube at 130 °C for 24 h under Ar; b) Isolated yields;
n.d. = not detected.
Initially, we chose 2-(1H-indol-1-yl)aniline (1a) as the model substrate and
benzoyl chloride (2a) as the acylating agent to identify the optimal reaction conditions,
and significant results are summarized in Table 1. During the screening of several
reaction conditions, including additive, catalysts, bases, and solvents, the expected
acylation/annulation proceeded smoothly to give the corresponding product 3aa in
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76% isolated yield under the following reaction conditions: 1a (0.1 mmol), 2a (0.2
mmol), Pd(dba)2 (10 mol%), AgSbF6 (25 mol %) and CsOPiv (0.2 mmol) were stirred
in 1 mL of solvent (toluene/1,4-dioxane =1:1) for 24 h at 130 oC under an atmosphere
of argon (Table 1, entry 1). Notably, the isolated yield of the reaction was highly
dependent on the palladium(II) generated in situ, and the optimal result was observed
with Pd(dba)2 (Table 1, entries 2-5). Pd(dba)2 supported by other corresponding
additives were inferior (Table 1, entries 6-9). Bases, such as NaOTf and K3PO4,
showed a moderate reactivity, whereas NaOH was ineffective (Table 1, entries 10-12).
Control experiments suggested that both Pd(dba)2 and CsOPiv were vital for this
acylation/annulation reaction (Table 1, entries 13 and 14). Finally, the efficiency of
this transformation could not be improved by changing the reaction solvent (Table 1,
entries 15 and 16, see Supporting Information for details).
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With the optimal reaction condition in hand, the scope of the transformation with
respect to the acyl chlorides was also observed (Table 2). Generally, this reaction
afforded the corresponding products in modest to excellent yield and with unique
regioselectivity. The acyl chlorides with para-substituted electron-donating groups
gave the desired indolo[1,2‑a]quinoxalines 3ba-3ea in 69-80% yields. In addition,
acyl chlorides with halogen-substituted worked well and obtained expected products
3fa and 3ga in moderate yields, which could be used for further transformation via
cross coupling reactions. Other functional groups, such as meta-F, meta-Br and
meta-OCH3 can also be compatible with the reaction system, providing the
corresponding indolo[1,2‑a]quinoxalines 3ha-3ja in good yields. The reaction of 2k,
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2l, 2m and 2n gave the desired products 3ka, 3la, 3ma and 3na respectively, even
though the reaction site is sterically hindered. When the 1-naphthoyl chloride,
benzo[b]thiophene-2-carbonyl chloride, and furan-2-carbonyl chloride were used as
the substrates, the desired products 3oa, 3pa, 3ra were obtained in yields of 57-71%.
Unfortunately, nitrogen-containing acyl chlorides are not compatible with the reaction
system (3qa, 3sa). Finally, double-substituted acyl chlorides also gave the highly
functional products 3ta-3va in reasonable yield.
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Table 2. Synthesis of Indolo[1,2‑a]quinoxalines Derivatives from a Range of Acyl
Chlorides and 2-(1H-indol-1-yl)anilinea,b
Pd(dba)2 (10 mol %)
AgSbF6 (25 mol %)
O
CsOPiv (2 equiv)
N
+
N
N
Ar
Cl
NH2
toluene/1,4-dioxane (1/1, v/v) (1 mL)
130 oC, 24 h, Ar
H
Ar
3
2
1a
N
N
N
R
N
N
N
N
N
R
R
R
3ka
R = CH3,
R = F,
R = Br,
, 76%
3ba
, 80%
3ca
R = Me,
R = Et,
3ha
R = F,
, 77%
, 70%
3la
, 66%
3fa
, 72%
3ga
, 75%
3da
, 79%
R = Cl,
R = Br,
3ia
R = Br,
3ma
, 62%
R = OCH3,
R = n-Bu,
, 69%
, 67%
3ja
R = OCH3,
, 68%
3na
R = CN,
, 30%
3ea
N
N
N
X
N
N
N
N
N
X
R
3ta
R = 2-F, 4-Br,
, 68%
3ua
3va
3ra
, 63%
3pa
, 57%
3qa
X = O,
X = N,
X = S,
X = N,
R = 2,3-dimethyl,
R = 3,4-dichloro,
, 72%
, 64%
3oa,
71%
3sa
, trace
, trace
aA mixture of 1a (0.1 mmol), 2 (0.2 mmol), Pd(dba)2 (10 mol %), AgSbF6 (25 mol%),
CsOPiv (0.2 mmol), and anhydrous toluene/1,4-dioxane (1/1, v/v) (1.0 mL) were
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sealed in a 25 mL Schlenk tube at 130 °C for 24 h under Ar; bYields refer to isolated
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yield.
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Table 3. Synthesis of Indolo[1,2‑a]quinoxalines Derivatives from a Range of Indoles
and Benzoyl Chloridea,b
R2
R2
Pd(dba)2 (10 mol %)
AgSbF6 (25 mol %)
O
R1
CsOPiv (2 equiv)
R1
N
+
N
N
Ph
Cl
NH2
toluene/1,4-dioxane (1/1, v/v) (1 mL)
130 oC, 24 h, Ar
H
3
2a
1
Entry
1
R1
3-CH3
4-CH3
R2
H
H
H
H
H
H
H
H
H
H
H
H
Product Yieldb (%)
3ab
3ac
3ad
3ae
3af
82%
84%
72%
76%
71%
67%
80%
70%
78%
67%
65%
45%
85%
76%
73%
69%
56%
38%
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3
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5
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18
4-OCH3
4-benzyloxy
5-OCH3
6-OCH3
4,6-di-CH3
3ag
3ah
3ai
4-F
4-Cl
5-F
6-F
5-CN
H
H
H
H
H
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
4-CH3
4-Cl
5-Cl
4-F
4-Cl-6-F
4-CF3
H
aA mixture of 1 (0.1 mmol), 2a (0.2 mmol), Pd(dba)2 (10 mol %), AgSbF6 (25 mol %),
CsOPiv (0.2 mmol), and anhydrous toluene/1,4-dioxane (1/1, v/v) (1.0 mL) were
sealed in a 25 mL Schlenk tube at 130 °C for 24 h under Ar; bYields refer to isolated
yield.
Subsequently, the scope of indoles were investigated under the optimal reaction
conditions. As the data of Table 3 shown, indole rings substituted with 3- Me, 4-Me,
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4-OCH3, 4-benzyloxy, 5-OCH3, and 6-OCH3 groups successfully participated in this
transformation to give the corresponding products in moderate to good yields
(3ab-3ag). Further, 2-(4,6-dimethyl-1H-indol-1-yl)aniline reacted well to afford the
expected product (3ah) with excellent yield. Noticeably, the halogen atoms were
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compatible
with
this
reaction
system
(3ai-3al).
In
addition,
1-(2-aminophenyl)-1H-indole-5-carbonitrile was also investigated, and to our delight,
the target product 3am was synthesized, albeit in relatively lower yield (45%).
Remarkably, 2-(1H-indol-1-yl)-4-methylaniline was a suitable substrate, affording the
corresponding product 3an in 85% yield. The indoles 1o-1q bearing a halogen (F, Cl)
at aniline rings were compatible for the transformation, providing the expected
products 3ao-3aq in 76%, 73%, and 69% yields, respectively. In addition, the
dihalogen-substituted starting materials could be functionalized under standard
reaction condition. It should be noted that 1s containing a CF3 group was suitable,
albeit resulting in obviously decreased reactivity (38%).
Scheme 2 Control experiments
Pd(dba)2 (10 mol %)
H
O
AgSbF6 (25 mol %)
CsOPiv (2 equiv)
N
N
Cl
+
a)
H
O
toluene/1,4-dioxane (1/1, v/v) (1 mL)
130 oC, 24 h, Ar
H
Ph
2a
, 0.2 mmol
5aa
, n.d.
4a
, 0.1 mmol
O
standard conditions
1)
TEMPO (2 equiv), 61%
1,1-Diphenylethylene (2 equiv), 57%
3)
N
N
Cl
+
NH2
N
b)
c)
2)
H
BHT (2 equiv), 65%
Ph
2a
3aa
1a
, 0.2 mmol
, 0.1 mmol
Pd(dba)2 (10 mol %)
AgSbF6 (25 mol %)
CsOPiv(2 equiv)
O
N
N
Cl
+
NH2
H/D
N
toluene/1,4-dioxane (1/1, v/v) (1 mL)
130 oC, Ar
Ph
3aa
1a 1a-d
,
2a
1
KH/KD = 1.1
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In order to elucidate the reaction mechanism, a few preliminaryDOcI:o1n0.t10ro39l/D0NJ04406G
experiments were carried out (Scheme 2). First, the designed substrates 4a was
conducted under the standard reaction conditions, and no corresponding product 5aa
was observed (Scheme 2, a), suggesting that the primary amine as a directing group
should be essential in this reaction. When 2.0 equiv. of TEMPO, 1,1-diphenylethylene,
and BHT were added under the optimal reaction conditions, the target product
6-phenylindolo[1,2-a]quinoxaline (3aa) was obtained in 61%, 57% and 65% yields,
respectively (Scheme 2, b). These results indicate that a radical process is not
involved in this transformation.42-44 Furthermore, by employing deuterium-labeled
compound 1a-d1 and 1a as substrates, the experiment for calculating the KIE (kinetic
isotope effect) value was performed (see the Supporting Information),45,46 and the
result (KIE = 1.1) may suggest that the C(sp2)-H bond cleavage of
2-(1H-indol-1-yl)aniline (1a) should not involved in the rate-limiting step (Scheme 2,
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c).
Based on our control experiments and previous literature reports,47-49 a possible
catalytic cycle is outlined in Fig S2. We proposed that the acylation/annulation
process may proceed a Pd(II)/Pd(IV) catalytic cycle. First, the treatment of Pd(dba)2
with silver salts gives rise to the activated Pd(II) catalyst, which undergoes C(sp2)-H
functionalization with 2-(1H-indol-1-yl)aniline (1a) to obtain a six-membered
palladacyclic intermediate B.50-53 Subsequently, the oxidative addition of benzoyl
chloride (2a) to intermediate B gives the probable Pd(IV) intermediate C, which
undergoes reductive elimination to obtain the acylating product D along with
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regeneration of the activated Pd(II) species. Simultaneously, the final productD3OaI:a10w.10a39s/D0NJ04406G
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obtained by an intramolecular dehydration reaction.
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4. Conclusions
In summary, we have reported a unique, directing group protocol for a one-pot
synthesis of functionalized indolo[1,2-a]quinoxalines from acyl chloride and indoles,
utilizing a palladium-catalyzed C(sp2)-H acylation method as the crucial step. This
protocol exhibits a good functional group tolerance, high regioselectivity, and
convenient operation. Dramatically, simple and readily available acyl chlorides and
high step economy make this strategy particularly attractive. In addition, we believe
that these transformation proceed via a classical Pd(II)/Pd(IV) catalytic cycle. Further
studies on the construction of heterocyclic compounds via C-H activation as well as
acylation/annulation are underway in our laboratory
.
Acknowledgements
This work was supported by Guangxi Natural Science Fundation
(2018GXNSFBA050024, 2017GXNSFBA198224 and 2018GXNSFAA281203),
Guangxi Science and Technology Base and Special Fund for Talents (AD19245008
and AD19110110), Ph. D. Scientific Research Foundation of Guilin University of
Technology, and Key Laboratory of Electrochemical and Magnetochemical Function
Materials.
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R2
R2
Pd(dba)2 (10 mol %)
R1
O
AgSbF6 (25 mol %)
N
R1
N
+
N
Ar
Cl
CsOPiv (2 equiv)
toluene/1,4-dioxane
130 oC, 24 h, Ar
NH2
Ar
Indoles
Acyl Chloride
Indolo[1,2-a]quinoxaline
An efficient, palladium(II)-catalyzed, C(sp2)-H acylation/annulation of indoles with
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acyl chlorides for the synthesis of substituted indolo[1,2‑a]quinazolines is reported.