Palladium(II)-catalyzed intramolecular diamination of alkynes under aerobic oxidative conditions: Catalytic turnover of an iodide ion

Article abstract of DOI:10.1002/anie.201201640

"I" did it: A sequential intramolecular amination/N- demethylation/amidation of internal acetylenes in the presence of a catalytic amount of Pd(OAc)₂ and nBu₄NI afforded indolo[3,2-c]isoquinolinones under mild aerobic conditions (see

Full text of DOI:10.1002/anie.201201640

Angewandte
Chemie
DOI: 10.1002/anie.201201640
Synthetic Methods
Palladium(II)-Catalyzed Intramolecular Diamination of Alkynes under
Aerobic Oxidative Conditions: Catalytic Turnover of an Iodide Ion**
Bo Yao, Qian Wang, and Jieping Zhu*
Polyheterocycles with an embedded 3-aminoindole moiety
are found in a number of natural products (1–3)[1] and
bioactive synthetic compounds (4, Scheme 1).[2] They show
diverse biological activities, such as antimalarial, antimuscar-
Scheme 1. Natural and synthetic compounds with an embedded 3-
aminoindole moiety.
inic, antibacterial, antiviral, antiplasmodial, antihypoglyce-
mic, and PARP-inhibiting activities.[2,3] They are generally
Scheme 2. Diamination of alkynes. Ts=4-toluenesulfonyl, DMF=N,N-
dimethylformamide, Boc=tert-butoxycarbonyl.
synthesized from 3-aminoindoles,[4] which are in turn pre-
pared by multi-step processes.[5,6] As part of our ongoing
research, which deals with palladium-catalyzed domino
processes for the synthesis of heterocycles,[7] we became
interested in the development of a one-pot synthesis of
indolo[3,2-c]isoquinolinones (4) through a double intramo-
lecular amination of internal alkynes 5 [Eq. (1), Scheme 2].
While the diamination of alkenes has been a field of intensive
research for the past few years,[8,9] investigations on the
diamination of alkynes remained rare.[10] MuÇiz reported the
only successful example of such a transformation, which
occurred through the conversion of bis-tosylamide 6 to
tetrahydropyrrolo[3,2-b]indole 7 [Eq. (2), Scheme 2].[11] The
cyclization substrate 6 for this study was designed in such
a way that neither regio- nor chemo-selectivity issues could
occur during the cyclization.[12] On the other hand, with the
aim to prepare isotryptophan 10, Rutjes studied the cycliza-
tion of alkyne 8, in which two different nucleophiles are
tethered to the triple bond, and showed the initiation of the
cyclization by the carbamate nitrogen atom rather than the
aniline function, thus affording dihydropyrrole 9 after trans-
acylation [Eq. (3), Scheme 2].[13] We set out to study the
cyclization of 5 with the knowledge that the reactivity of an
amide functionality versus that of an aniline nitrogen atom
can be modulated,[14] although they are distinctly different.
We report herein the efficient conversion of 5 into indolo[3,2-
c]isoquinolinones (4) through a sequential amination/N-
demethylation/amidation process under Pd-catalyzed oxida-
tive conditions. We spectroscopically characterized a key
palladacycle intermediate, furthermore we report conditions
for the in situ generation of nBu4NI, thus allowing the use of
only a catalytic amount of this reagent for the removal of the
N-Me group for the first time.
[*] Dr. B. Yao, Dr. Q. Wang, Prof. Dr. J. Zhu
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), the Swiss National Science
Foundation (SNF), and the Swiss National Centres of Competence
in Research (NCCR) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201640.
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Pd-catalyzed Cacchi cyclizations of o-(1-alkynyl)ani-
lines[15] and of o-(1-alkynyl)benzamides[16,17] are two well-
studied processes. Both reactions were generally performed
under basic and non-oxidative conditions. However, Pd0 is
expected to be produced in the reductive elimination step,
therefore a suitable external oxidant is required in order to
complete the catalytic cycle and to realize the reaction
sequence we envisioned. The potential pitfall of this approach
is the high sensitivity of aniline and especially the resulting
indole to oxidative conditions, and, to the best of our
knowledge, the Cacchi indole synthesis has thus never been
performed under such conditions. Indeed, auto-oxidation of
a 3-aminoindole derivative was a key step exploited in the
total synthesis of (À)-mersicarpine described by Fukuyama
and co-workers.[18] In addition, the order of cyclization can
impact the outcome of the reaction significantly. If the
reaction was to be initiated by amidopalladation of the amide
function, then both 5-exo and 6-endo cyclization could take
place with either the nitrogen or the oxygen atom of the
amide as nucleophilic centers,[16] thus complicating the out-
come of the reaction significantly.
Pd(OAc)2 (0.1 equiv), nBu4NI (1.0 equiv), and an oxidant.
Some conclusions could be drawn from the results: 1) The
reaction worked in MeCN, DMF, and DMSO, with the latter
being the solvent of choice (entries 1–4). 2) Cu(OAc)2 is
a competent oxidant both stoichiometrically (entry 1) and
catalytically in combination with molecular oxygen as termi-
nal oxidant (entries 2–4). 3) The addition of HOAc to the
reaction mixture increased the yield of 4a significantly
(entry 2 vs. entry 3). 4) The reaction proceeded efficiently in
DMSO in the presence of acetic acid (2.0 equiv) both under
oxygen atmosphere (entries 5–7)[20] and simply under air
atmosphere without the need to use Cu(OAc)2 as co-oxidant
(entries 8–12). Overall, 5a was converted to 4a in 84% yield
of isolated product under optimized conditions (entry 8;
Pd(OAc)2 (0.1 equiv), nBu4NI (1.0 equiv), HOAc (2.0 equiv),
air atmosphere (1.0 atm) in DMSO at 508C (conditions A)).
The structure of 4a was determined without ambiguity by X-
ray crystallographic analysis (see the Supporting Informa-
tion).
If MeI were indeed formed, it would be converted to
methyl acetate by reacting with acetate present in the reaction
mixture. The 1H NMR spectrum of the crude reaction mixture
of the reaction performed in [D6]DMSO supported this
assumption (see the Supporting Information). As nBu4NI was
regenerated in this reaction, we wondered if the conversion of
5 to 4 could be realized in the presence of a catalytic amount
of nBu4NI. Gratefully, the reaction of 5a in the presence of 10
mol% of nBu4NI under otherwise identical conditions
The easily accessible diarylacetylene 5a was used as
a substrate to test the feasibility of our projected diamination
process (Table 1). Following the seminal work of Larock and
co-workers on the use of tetrabutylammonium iodide as
a nucleophile for removal of the N-methyl group from the
presumed indolium intermediate,[19] the double cyclization of
5a was performed in different solvents in the presence of
1
afforded 4a in 73% yield, determined by H NMR spectros-
copy, after 86 hours (entry 11, Table 1). Through optimization
of the reaction conditions (see the Supporting Information),
we found that a slightly higher reaction temperature (808C)
was required in order to increase the overall catalytic
efficiency. The optimized conditions included the perfor-
mance of the reaction in DMSO at 808C in the presence of
Pd(OAc)2 (0.05 equiv), nBu4NI (0.1 equiv), and HOAc
(2.0 equiv) under air atmosphere (conditions B). Tetracycle
4a was isolated in 75% yield under these conditions (entry 12,
Table 1).[21] With the optimum conditions in hands, the
substrate scope of the reaction was next examined using
both conditions A and B. Both N-methyl and N-aryl amides
are good substrates for this reaction and a range of
substituents, including a chlorine atom, were tolerated at
different positions (Scheme 3), thus providing a handle for
further functionalization.
Neither the desired tetracyclic product nor the iodinated
intermediate was formed when the cyclization of 5c was
performed in the absence of Pd(OAc)2 under otherwise
identical conditions. The result ruled out the possibility of an
iodine-mediated transformation.[22] In addition, treatment of
a solution of 5g in DMSO with a stoichiometric amount of
Pd(OAc)2, HOAc (2 equiv), and nBu4NI (1.0 equiv) under
argon atmosphere afforded the tetracyclic product 4g in 93%
yield. This control experiment indicated that, under our
conditions, the diamination reaction went through a catalytic
cycle involving PdII/Pd0 species. Based on the above-men-
tioned experimental observations, a possible catalytic cycle
was proposed for the reaction (Scheme 4). A sequence of
events that involve the coordination of both alkyne and amide
Table 1: Optimization of reaction conditions for the double cyclization of
1a.[a]
Entry
Pd(OAc)2
[mol%]
Oxidant
(equiv)
HOAc
[equiv]
Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
5
Cu(OAc)2 (2.0)[c]
–
–
MeCN
DMF
DMF
50
19
59
79
77
78
(84)
(84)
72
Cu(OAc)2 (0.1)[d]
Cu(OAc)2 (0.1)[d]
1.0
1.0
1.0
2.0
3.0
2.0
2.0
2.0[g]
1.0[h]
2.0[h]
Cu(OAc)2 (0.05)[d]
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
O2
O2
O2
air
air
air
air
air
9[e]
10[e]
11[f]
12
5
10
5
72
73
(75)[i]
[a] Reaction conditions: A solution of 5a (0.05 mmol), Pd(OAc)2,
oxidants, nBu4NI (1.0 equiv), and HOAc in solvents (2.0 mL) was heated
at 508C under argon, air or oxygen atmosphere (1 atm) for 12 h.
[b] Yields determined by 1H NMR spectroscopy with CH2Br2 as an
internal standard, yields of isolated products in parenthesis. [c] Under Ar
atmosphere (1 atm). [d] Under O2 atmosphere (1 atm). [e] 24 h. [f] 86 h.
[g] 0.4 equiv of nBu4NI was used. [h] 0.1 equiv of nBu4NI was used.
[i] Reaction was performed at 808C.
2
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Scheme 4. Plausible reaction pathway for the double cyclization of 5 to
4.
hours. This compound was identified as intermediate B from
detailed spectroscopic studies (see the Supporting Informa-
tion). Notably, the HRMS data found (489.0791) matched the
calculated value for [C25H23N2O2Pd]+ (489.0804). Intermedi-
ate B, which was stable at room temperature for a few hours,
was readily converted to 4g upon addition of nBu4NI (2 equiv,
RT, 3.5 h), thus indicating that B could indeed be an
intermediate in the conversion of 5 to 4. We noted that this
intermediate can also be converted to 4g upon prolonged
heating at 508C, thus indicating that AcOÀ can also act as
nucleophile to remove the N-methyl group, although this
reaction was less efficient than that with iodide ions.
The chemoselectivity we observed is different from that
described by Rutjes and co-workers, who reported that
amidopalladation occurred preferentially with the N-carba-
mate than with the aniline function [see Eq. (3), Scheme 2].
Strong coordination of the ArNH2 function to Pd could be
one of the reasons for this selectivity.[24] In our case, the
ligation of DMSO (solvent) to Pd(OAc)2 could hamper the
coordination of the bulky N,N-dimethylamino group to PdII,
thus leading to the observed chemoselectivity.[25] The obser-
vation that aminopalladation, which involves N,N-dimethy-
lamino nitrogen as nucleophile, was favored over amidopal-
ladation in the presence of HOAc, is counterintuitive at first
glance. However, 1H NMR titration of 5g in [D6]DMSO with
two equivalents of HOAc at 508C and 808C, respectively,
indicated that the N,N-dimethylamino group in 5g was not
protonated at all.[26]
Scheme 3. Substrate scope of the reaction. Conditions A: 5 (0.1 mmol)
in DMSO (4.0 mL) was heated at 508C in the presence of Pd(OAc)2
(0.1 equiv), nBu4NI (1.0 equiv), and HOAc (2.0 equiv) under air
atmosphere (1 atm) for 12 h. Conditions B: 5 (0.1 mmol) in DMSO
(4.0 mL) was heated at 808C in the presence of Pd(OAc)2 (0.05 equiv),
nBu4NI (0.1 equiv), and HOAc (2.0 equiv) in DMSO (4.0 mL) under air
atmosphere (1.0 atm) for 12 h.
functionalities to the PdII species followed by deprotonation
of the amide NH would afford s,p-chelated Pd complex A.
An anti addition of the tethered N,N-dimethylaniline to the
triple bond through a formal 5-endo-dig mode would afford
the s-C-PdII-amide intermediate B, which upon SN2 displace-
ment with an iodide ion as nucleophile would provide
intermediate C and MeI. Under the present reaction con-
ditions, the acetate anion (AcOÀ) converted MeI to methyl
acetate with concurrent regeneration of the iodide ion,
therefore allowing the use of only a catalytic amount of
nBu4NI to complete the reaction sequence. Reductive
elimination from C gave product 4 and a Pd0 species. Finally,
oxidation of Pd0 to PdII by molecular oxygen completed the
catalytic cycle.[23]
In conclusion, we reported a novel PdII-catalyzed intra-
molecular diamination of alkynes under aerobic oxidative
conditions for the construction of indolo[3,2-c]isoquinoli-
none. To the best of our knowledge, this study presented the
first examples in which the cyclization of o-(1-alkynyl)benz-
amides and the Cacchi indole synthesis were combined and
realized under oxidative conditions. The domino process
proceeded in a highly ordered fashion, was regio- and chemo-
To gain mechanistic insight, we attempted to isolate the
putative s-vinyl Pd complex B. Much to our delight,
monitoring the reaction of 5g with Pd(OAc)2 (1.0 equiv) in
[D6]DMSO at room temperature indicated clean formation of
a new compound, and the conversion was complete in three
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selective, and provided the first examples of the diamination
of alkynes with two differentially protected amino functions.
A palladacycle (B) was characterized and its intermediacy in
the conversion of 5 to tetracycle 4 was demonstrated. In
addition, we documented that, in the presence of HOAc, only
a catalytic amount of nBu4NI is required for removal of the N-
methyl group, and we believe that the in situ generation of
nBu4NI described herein could be applicable in other related
system.
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Experimental Section
General procedure: A solution of 5a (0.1 mmol), Pd(OAc)2 (con-
ditions A: 0.1 equiv; conditions B: 0.05 equiv), nBu4NI (condi-
tions A: 1.0 equiv; conditions B: 0.1 equiv) and HOAc (0.2 mmol)
in DMSO (4 mL) was heated at 508C or 808C under air atmosphere
(1.0 atm) for 12 h. The reaction mixture was diluted with water
(10 mL) and extracted with EtOAc (3 ꢀ 10 mL). The combined
organic extracts were washed with brine, dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel) to give 4a (conditions A: 84%; con-
ditions B: 75%). m.p.: 288–2908C; 1H NMR (400 MHz, CDCl3): d =
8.71 (ddd, J = 8.1, 1.4, 0.5 Hz, 1H), 8.36 (m, 1H), 7.80 (ddd, J = 8.6,
7.2, 1.5 Hz, 1H), 7.56 (ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 7.46–7.39 (m,
3H), 7.39–7.34 (m, 2H), 7.28 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 6.84 (ddd,
J = 8.2, 7.0, 1.0 Hz, 1H), 6.23–6.12 (m, 1H), 4.27 (s, 3H), 2.54 ppm (s,
3H); 13C NMR (101 MHz, CDCl3): d = 161.5, 139.1, 138.8, 136.6,
132.4, 130.7, 130.7, 129.7, 128.6, 126.1, 125.4, 124.4, 122.0, 120.9, 120.3,
~
120.0, 119.4, 116.8, 109.3, 33.6, 21.6 ppm; ATR-IR: n = 2987, 2973,
2901, 1630, 1609, 1566, 1383, 1234, 1068, 1058, 742, 690 cmÀ1; ESI-MS:
m/z 339 [M + H]+; elemental analysis calcd (%) for C23H18N2O: C,
81.63; H, 5.36; N, 8.28; found: C, 81.37, H, 5.54; N, 8.13.
Received: February 29, 2012
Published online: && &&, &&&&
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[11] This example is given in Table 3 of Ref. [8b].
[12] o-(o-Aminophenyl)trifluoroacetanilides and bis(o-trifluoroace-
tamidophenyl)acetylenes have been used in the presence of an
aryl halide/triflate for the construction of indolo[1,2-c]quinazo-
lines. The diamination product was not observed in these cases,
see: a) S. Cacchi, G. Fabrizi, P. Pace, F. Marinelli, Synlett 1999,
620 – 622; b) A. Arcadi, S. Cacchi, A. Cassetta, G. Fabrizi, L. M.
Keywords: alkynes · diaminations · domino reactions ·
heterocycles · indole
.
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[26] pKaH values of ArNMe2: 5.2 in water, 2.5 in DMSO; pKa values
of AcOH: 4.76 in water, 12.3 in DMSO. Although it was
expected that the basicity of 5 would be higher than ArNMe2, we
can nevertheless estimate that, according to our 1H NMR
titration experiment, only a tiny amount of 5 will be protonated
in DMSO.
[27] CCDC-874091 (4a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
B. Yao, Q. Wang, J. Zhu*
&&&& — &&&&
Palladium(II)-Catalyzed Intramolecular
Diamination of Alkynes under Aerobic
Oxidative Conditions: Catalytic Turnover
of an Iodide Ion
“I” did it: A sequential intramolecular
amination/N-demethylation/amidation
of internal acetylenes in the presence of
a catalytic amount of Pd(OAc)2 and
nBu4NI afforded indolo[3,2-c]isoquinoli-
nones under mild aerobic conditions (see
scheme, DMSO=dimethyl sulfoxide).
The iodide ion was regenerated by reac-
tion of in situ generated MeI with HOAc
present in the reaction mixture.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!