Palladium(II)-catalyzed cyclizative cross-coupling of ortho-alkynylanilines with ortho-alkynylbenzamides under aerobic conditions

Article abstract of DOI:10.1002/anie.201307738

Born to couple: The Pd(OAc)₂-catalyzed reaction of o-alkynylanilines (1) with o-alkynylbenzamides (2) affords the cyclizative cross-coupling products 3 in good to excellent yields. Three bonds are created in the formation of two heterocycles tethered by a tetrasubstituted double bond. Mechanistic studies indicate that the reaction is initiated by aminopalladation with subsequent oxypalladation, N-demethylation, and reductive elimination. Copyright

Full text of DOI:10.1002/anie.201307738

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DOI: 10.1002/anie.201307738
Homogeneous Catalysis
Palladium(II)-Catalyzed Cyclizative Cross-Coupling of ortho-
Alkynylanilines with ortho-Alkynylbenzamides under Aerobic
Conditions**
Bo Yao, Qian Wang, and Jieping Zhu*
Dedicated to Professor Yulin Li on the occasion of his 80th birthday
In light of the importance of heterocycles in medicinal
chemistry and from the viewpoint of synthetic efficiency,
cyclizative dimerization is of particular interest as it allows the
preparation of cyclic dimers from linear starting materials and
indeed a few successful examples have recently been reported
wherein heteronucleometallation[1] is used as a key initiation
step (Scheme 1a).[2,3] Concurrently, palladium(0)-catalyzed
Scheme 2. Cyclizative cross-coupling reaction of o-alkynylanilines (1)
and o-alkynylbenzamides (2).
formation of two heterocycles, an indole and an iminoiso-
benzofuranone, which are tethered by a geometrically defined
tetrasubstituted double bond.
Although conceptually appealing, the practical execution
of the cyclizative cross-coupling between 1 and 2 is challeng-
ing. Indeed, both 1 and 2 have a high propensity to undergo
the cyclization leading to cyclic monomers[5] and recently,
their cyclizative dimerizations[2h,6] have also been reported. In
addition, while the o-alkynylanilines 1 are known to undergo
only the 5-endo-dig cyclization,[7] the o-alkynylbenzamides 2
can cyclize by both the 5-exo-dig and the 6-endo-dig modes
using either an oxygen or nitrogen center as an internal
nucleophile.[8–10] Therefore, to realize the projected reaction,
one might address not only the regio- (endo versus exo
cyclization) and chemoselectivity (O versus N cyclization),
but also the homo- versus heterocoupling processes.
We began our studies by investigating the cyclizative
cross-coupling reaction between N,N-dimethyl-2-(p-tolyl-
ethynyl)aniline (1a) and N-benzyl-2-(phenylethynyl)benz-
amide (2a). Some representative results are shown in
Table 1 (for details see Tables S1–S8 in the Supporting
Information). Key observations, pertinent to optimization of
the reaction conditions, which ultimately led to high yield of
3aa are summarized as follows: a) Pd(OAc)2 was essential
(entry 5), while the presence of Cu(OAc)2 increased signifi-
cantly the efficiency of the desired transformation (entry 1
versus entries 2–4); b) the presence of iodide increased the
selectivity of heterodimerization (3aa) versus homodimeri-
zation (4a; entries 3 versus 4) with nBu4NI being the best;
c) HOAc was needed to ensure the PdII turnover; d) the
reaction temperature of 808C with DMSO as the solvent was
deemed to be optimal. Lower temperature increased the yield
of the homodimers; e) although the reaction proceeded with
0.01 equivalents of Pd(OAc)2 (entries 6–9), a higher yield of
3aa was obtained when the loading of Pd(OAc)2 was
increased (entry 10–13). Finally, the optimum reaction con-
Scheme 1. Strategies of cyclizative cross-coupling reaction. [a] For the
sake of clarity, only the product resulting from the endo-n-dig cycliza-
tion mode is shown.
co-cyclization of two internal alkynes, one bearing an electro-
phile and the other a nucleophile, by a sequence of
carbopalladation and reductive elimination has been devel-
oped by the group of Wu.[4] An even more challenging but
synthetically powerful transformation would be cyclizative
cross-coupling reaction of two different nucleophile-bearing
internal alkynes for the one-step construction of heterodimers
(Scheme 1b). To the best of our knowledge, there are only
few examples developed by Ma and Yu wherein allenes are
used as cyclization partners.[3a–c] We report herein that the
cyclizative cross-coupling reaction between o-alkynylanilines
(1) and o-alkynylbenzamides (2) takes place efficiently to
afford the bis(heterocycle)s 3 (Scheme 2). In this reaction,
three chemical bonds are created, thus leading to the
[*] Dr. B. Yao, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Product, Ecole Polytechnique
Fꢀdꢀrale de Lausanne, EPFL-SB-ISIC-LSPN
BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
[**] We thank the EPFL (Switzerland), Swiss National Science Founda-
tion (SNSF), and Swiss National Centers of Competence in
Research NCCR Chemical Biology for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307738.
12992
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Table 1: Optimization of reaction conditions.[a]
alkyl), including the functionalized 1d, were well tolerated
and the reaction of 1b–h with 2a furnished the cross-coupling
products 3ba–ha in good to excellent yields with high product
selectivity (3/4). No intramolecular bis(amination) product
was detected with 1d, which contains an amide unit.[11] It is
worth noting that in the case of aliphatic o-alkynylanilines (1c
and 1d), only a slightly excess (1.2 equiv) of o-alkynylbenz-
amides (2a–c and 2n) was needed to deliver the desired
products (3ca–cc, 3da, 3cn) in good yields. Presumably, the
alkyl substituent disfavored the competitive homodimeriza-
tion process. The reaction conditions were applicable not only
to N,N-dimethyl substrates, but also to N-methyl-N-alkyl
derivatives. In the latter case, the N-methyl group was
removed selectively.[12] For example, reaction of 1i with 2 f
gave the N-pentyl bis(heterocycle) 3if in 68% yield. A series
of o-(arylethynyl)benzamides (2a–n) bearing various sub-
stituents with different electronic properties were tested. The
nature of the alkyl residue of the N-alkyl amides (R5 = Bn, n-
Pr, nBu, iBu) did not impact the reaction outcome, thus
affording the products (3ga, 3gk, 3 fl, and 3 fm) in good yields
and selectivities. A variety of substituents such as methyl,
methoxy, chlorine, and fluorine at different positions of the
two aromatic rings were tolerated. However, the reaction
involving 6-methyl-2-phenylethynylbenzamide (2i) as the
coupling partner delivered the desired product (3ai) in
reduced yields with concurrent increase of the homocoupling
product 4a. Interestingly, the reaction efficiency was restored
with 6-methoxy-2-phenylethynylbenzamide (2j), thus afford-
ing 3aj in excellent yield and selectivity.
Entry
PdII
[equiv]
CuII
[equiv]
nBu4NI
[equiv]
t
[h]
3aa/4a
3aa
Yield [%][b]
1[c,d]
2[c,d]
3[d]
4[d]
5
6
7
8
9
10
11
12
13[e]
0.10
0.10
0.02
0.02
–
0.01
0.01
0.01
0.01
0.05
0.05
0.10
0.10
–
1.0
1.0
1.0
–
1.0
1.0
1.0
1.0
2.0
2.0
4.0
2.0
2.0
2
12
11
11
3
11
11
11
11
2
1.3:1
2.9:1
2.9:1
1.9:1
–
4:1
4:1
4:1
5:1
6:1
6:1
9:1
16:1
32
59
59
50
trace
66
66
66
68
73
68
81
89
0.5
0.2
0.2
0.2
0.4
0.8
1.2
0.8
0.8
1.6
0.8
0.8
2
1.5
1.5
[a] Reaction conditions: 1a (0.05 mmol), 2a (1.5 equiv), Pd(OAc)2
(0.01–0.10 equiv), Cu(OAc)2 (0.2–1.6 equiv), nBu4NI (1.0–4.0 equiv),
HOAc (1.0 equiv) in DMSO (1.0 mL), air atmosphere, 808C. [b] Yield of
isolated product. [c] 508C. [d] 2a (1.0 equiv). [e] 2a (2.0 equiv).
ditions were determined to be: 1a (0.05 mmol, 1.0 equiv), 2a
(2.0 equiv), Pd(OAc)2 (0.1 equiv), Cu(OAc)2 (0.8 equiv),
nBu4NI (2.0 equiv), HOAc (1.0 equiv), DMSO (1.0 mL),
808C, air. Under these reaction conditions, the cyclizative
cross-coupling product 3aa was isolated in 89% yield with an
excellent product selectivity (3aa/4a = 16:1; entry 13).
With the optimum reaction conditions in hand, the scope
of the reaction was examined. The substrates used are listed in
Figure 1 and the structures of the products are shown in
Table 2. With respect to the scope of the o-alkynylanilines 1,
both the aromatic and aliphatic substituents (R1 = Ar or
The structure of 3ae was determined by X-ray structural
analysis.[13] The stereochemistry of the C N and C C bonds
was assigned to be Z and E, respectively. Two enantiomers
with axial chirality were seen in the crystal structure because
=
=
ꢀ
of the restricted rotation of the C C s bond. Indeed, the
reaction of a chiral benzamide 2n with 1c delivered a mixture
of two diastereomers (3cn) in 62% yield (d.r. = 1:1).
Mechanistically, the present cyclizative cross-coupling
reaction could be initiated by either aminopalladation of
1 or oxypalladation of 2 to form the intermediates A or A’,
respectively (Scheme 3). To gain insight into the mechanism,
a series of control experiments were performed. Firstly,
addition of Pd(OAc)2 (0.8 equiv) to the mixture of 1a
(1.0 equiv) and 2a (1.0 equiv) in [D6]DMSO at room temper-
ature gave, after 5 minutes, the intermediate A as the only
product in about 56% yield [Eq. (1), Scheme 3].[6,11,14] In a set
of two parallel experiments, we found that reaction of
Pd(OAc)2 with 1a at room temperature afforded A cleanly,
while reaction of Pd(OAc)2 with 2a directly afforded the
cyclic dimer.[15] These results clearly showed that Pd(OAc)2
can catalyze the cyclization of both 1 and 2. Nevertheless, it is
capable of selectively activating the 1 in the presence of 2.
Secondly, mixing the freshly prepared solution of A in
[D6]DMSO with 1a (1.0 equiv) and 2a (1.0 equiv) under
argon at RT for 12 hours delivered 3aa and 4a in a ratio of 7:1
at 30% conversion [Eq. (2), Scheme 3]. Therefore, A reacted
with 2a much faster than with 1a. Overall, the results of these
control experiments indicated that Pd(OAc)2 mediated pref-
erentially the cyclization of 1, while the resulting vinyl-
palladium selectively catalyzed the ring closure of 2.
Figure 1. Substrates for the cyclizative cross-coupling reaction.
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Table 2: Scope of cyclizative cross-coupling between o-alkynylanilines (1) and o-alkynylbenzamides (2).
[a] Reaction conditions: 1 (0.05 mmol), 2 (0.10 mmol), Pd(OAc)2 (0.10 equiv), Cu(OAc)2 (0.8 equiv), nBu4NI (2.0 equiv), HOAc (1.0 equiv), and
DMSO (1.0 mL) was heated in a 5 mL reaction tube at 808C under an air atmosphere for 1.5 h. [b] Yield of isolated product. [c] Ratio of 3 to 4,
calculated according to the 1H NMR spectra of the crude reaction mixture. [d] Used 1.2 equiv of 2, and no 3,3’-bisindole 4 was detected.
Although reasons behind these selectivities are at present
unclear, the different reactivity of Pd(OAc)2 and A towards
two arylalkynes ensured the occurrence of the desired
reaction at the expense of the homodimerization processes.
A tentative reaction pathway is depicted in Scheme 4.
Selective coordination of Pd(OAc)2 to the triple bond of 1 and
subsequent anti aminopalladation (5-endo-dig) affords A,
which would then act as Lewis acid to selectively activate
the 2.[16] The subsequent chemo- and regioselective anti-5-
exo-dig oxypalladation provides the intermediate B which,
upon N-demethylation by nucleophilic attack of Iꢀ or OAcꢀ,
provided C. Reductive elimination from C furnishes 3 and
Scheme 3. Control experiments.
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Scheme 4. A plausible reaction pathway. Ligands on Pd were omitted
for clarity.
Pd0. The oxidation of Pd0 to PdII by Cu(OAc)2 completes the
catalytic cycle.
In conclusion, an efficient palladium(II)-catalyzed cycli-
zative cross-coupling of two internal alkynes has been
developed. In this operationally simple reaction, three
chemical bonds are formed, thus leading to the formation of
two different heterocycles which are tethered by a tetrasub-
stituted double bond. Further work is in progress to exploit
the power of this reaction for the synthesis of other
bis(heterocyclic) compounds.
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[13] CCDC 958685 (3ae) contains the supplementary crystallo-
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www.ccdc.cam.ac.uk/data_request/cif.
Experimental Section
General procedure: A 5 mL-vial was charged with 1a (0.05 mmol), 2a
(0.1 mmol), Pd(OAc)2 (0.1 equiv), Cu(OAc)2 (0.8 equiv), nBu4NI
(2.0 equiv), HOAc (1.0 equiv), and DMSO (1.0 mL). After being
heated under air (1 atm) at 808C for 1.5 h, the reaction was quenched
with water and the aqueous phase was extracted with EtOAc. The
combined organic extracts were washed with brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The residue was dissolved
in CDCl3 (0.6 mL) for 1H NMR analysis to calculate the ratio of 3aa
to 4a. Then the sample was purified by silica gel chromatography
(petroleum ether/ethyl acetate 20:1) to give the cross-coupling
product 3aa (23.6 mg, 89% yield, foam). 1H NMR (400 MHz,
CDCl3): d = 7.94–7.79 (m, 1H), 7.61–7.54 (m, 2H), 7.49 (d, J =
8.2 Hz, 1H), 7.47–7.43 (m, 2H), 7.40–7.22 (m, 9H), 7.22–7.16 (m,
1H), 7.16–7.10 (m, 1H), 7.10–7.03 (m, 3H), 7.00 (d, J = 7.9 Hz, 2H),
6.39 (d, J = 8.0 Hz, 1H), 4.86 (s, 2H), 3.79 (s, 3H), 2.27 ppm (s, 3H);
13C NMR (101 MHz, CDCl3): d = 156.3, 147.4, 140.6, 140.1, 139.2,
138.0, 137.8, 137.2, 131.6, 130.2, 129.8, 129.6, 129.0, 128.9, 128.5, 128.3,
128.1, 128.0, 127.9, 127.0, 126.8, 123.4, 122.8, 122.4, 120.5, 120.1, 112.2,
~
110.5, 109.8, 52.1, 31.6, 21.4 ppm; ATR-IR (neat): n ¼3052 (w), 3051
(w), 3028 (w), 2920 (w), 1695 (m), 1465 (m), 1061 (m), 1033 (m), 1021
(s), 987 (m), 764 (m), 740 (s), 739 (s), 696 (s); HRMS (ESI) calcd for
C38H31N2O+ [M+H]+ 531.2431; found 531.2432.
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Received: September 3, 2013
Published online: November 4, 2013
Keywords: cross-coupling · cyclization · heterocycles ·
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palladium · synthetic methods
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[15] A minor compound that matches the structure of A’ was
detected in the NMR spectrum of the crude reaction mixture of
this control experiment. However, we did not have convincing
evidence to support this structural assignment.
[16] Reviews on palladium(II)-catalyzed oxidative transformation of
alkenes and alkynes: a) see Ref. [1]; b) W. Wu, H. Jiang, Acc.
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