Platinum-catalyzed formal Markownikoff's hydroamination/hydroarylation cascade of terminal alkynes assisted by tethered hydroxyl groups

Article abstract of DOI:10.1021/jo901200j

(Chemical Equation Presented) An efficient method for Markownikoff's hydroamination-hydroarylation of alkynols using PtBr₂ as catalyst has been developed. The platinum-catalyzed reactions of alkynols with amino group containing aromatics were a

Full text of DOI:10.1021/jo901200j

pubs.acs.org/joc
tions, the addition of N-H bonds, O-H bonds, and Ar-H
Platinum-Catalyzed Formal Markownikoff’s
Hydroamination/Hydroarylation Cascade of
Terminal Alkynes Assisted by Tethered Hydroxyl
Groups
bonds across alkynes generally called as hydroamination,3
hydroalkoxylation,4 and hydroarylation,5 respectively, repre-
sents an efficient process to generate desired compounds
(Figure 1, path A). Generally, this type of reaction relies on
interaction of the metal catalyst with the π-bond of alkynes.6
Nowadays, tandem processes involving more than one above-
mentioned process are gaining much interest because of their
elegancy. For example, hydroalkoxylation-hydroarylation,7
double hydroalkoxylation,8 double hydroamination,9 and dou-
ble hydroarylation10 processes have recently been reported
(Figure 1, path B). To our surprise, hydroamination-hydro-
arylation tandem reactions have remained overlooked so far.
Recently, Dixon and co-workers reported gold-catalyzed cycli-
zation of alkynoic acid with amino aromatics involving N-acyl
iminium ion cascade.11 Yi and Yun reported a cationic ruthe-
nium hydride complex-catalyzed process of terminal alkynes,
without having a hydroxyl group in the proximity.12 Herein, we
Nitin T. Patil,* Rahul D. Kavthe, Vivek S. Raut, and
Vaddu V. N. Reddy
Organic Chemistry Division II, Indian Institute of Chemical
Technology, Hyderabad 500 607, India
nitin@iict.res.in
Received June 6, 2009
€
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An efficient method for Markownikoff’s hydroamina-
tion-hydroarylation of alkynols using PtBr2 as catalyst
has been developed. The platinum-catalyzed reactions of
alkynols with amino group containing aromatics were
achieved in methanol over a reaction time of 6-24 h and
temperature ranging from rt to 80 °C. This method works
well for a variety of alkynols and aromatic amino com-
pounds to give substituted pyrrolo[1,2-a]quinoxalines
and indolo[3,2-c]quinolines in good to excellent yields.
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DOI: 10.1021/jo901200j
r
Published on Web 07/15/2009
J. Org. Chem. 2009, 74, 6315–6318 6315
2009 American Chemical Society

Patil et al.
JOCNote
FIGURE 2. Concept of hydroamination-hydroarylation cascade.
FIGURE 1. Various modes of addition of nucleophiles to alkynes.
report an efficient method for hydroamination-hydroaryla-
tion of alkynes, tethered with a hydroxyl group, by using
PtBr2 as catalyst for the synthesis of pharmacologically
important heterocycles such as pyrrolo[1,2-a]quinoxalines13
and indolo[3,2-c]quinolines.14
TABLE 1. Catalyst Screening for Hydroamination-Hydroarylation of
Alkynes
With the above background and keeping in mind some
recent reports,15 we hypothesized that a metal-catalyzed
intramolecular hydroalkoxylation reaction of alkynol would
form corresponding cyclic enol ether, which would react with
amino aromatics 2 to form 3 (Figure 2). A proposed reaction
might allow us to perform formal hydroamination-hydro-
arylation of alkynes and would give access to a wide range of
heterocycles.
Our study began with commercially available 4-pentyn-1-
ol 1a and 2-aminophenyl pyrrole 2a. On the basis of ample
literature precedent on catalytic carbophilic activation, we
studied the reaction of several transition-metal catalysts with
these substrates. Various temperature, solvent, and catalysts,
and a combination of two different catalysts (transition
metal with either Brønsted acid or Lewis acid catalysts)
resulted in either decomposition or complex mixture of
products. We were pleased to find that PtCl2-catalyzed
reaction in DCE and toluene at room temperature afforded
product 3a in 40 and 60% yield, respectively (Table 1, entries
1 and 2). Interestingly, when polar protic solvent such as
methanol was used, the yield of 3a was substantially in-
creased to 92% (entry 3). As shown in entry 4, the use of
entry
catalyst
solvent
yield
1
2
3
4
5
6
7
8
PtCl2
PtCl2
PtCl2
PtBr2
PtCl4
DCE
toluene
40%
60%
92%
94%
90%
80%
75%
72%
methanol
methanol
methanol
methanol
methanol
methanol
Au(PPh3)Cl + AgSbF6
Au(PPh3)Cl + AgBF4
Au(PPh3)Cl + AgOTf
aReaction conditions: 0.6 mmol 1a, 0.6 mmol 2a, 5 mol %
catalyst, solvent (0.4 M), rt, 6 h. Isolated yields. 5 mol % of
Au(PPh3)Cl and 10 mol % of silver salts were used.
b
c
PtBr2 as a catalyst gave the product 3a in 94% yield. When
PtCl4 was employed as a catalyst, the desired product 3a was
formed in 90% yield (entry 5). Not only platinum salts but
also gold salts are effective. The cationic gold(I) complexes
generated in situ from Au(PPh3)Cl and silver salts such as
AgSbF6, AgBF4, and AgOTf give product in 80, 75, and 72%
yield, respectively (entries 6-8).
After we optimized the reaction conditions (5 mol % of
PtBr2, MeOH), the scope of this process was evaluated for
other alkynes and aromatic amino compounds (Table 2).
Treatment of 4-pentyn-1-ol 1a with 2-aminophenylpyrrole
derivatives 2b and 2c under slightly elevated temperature
gave the desired products 3b and 3c in 82 and 98% yield,
respectively (entries 1 and 2). The reaction of 2-(1H-2-
indolyl)aniline derivatives 2d, 2e, and 2f with 1a gave indolo-
[3,2-c]quinoline derivatives 3d, 3e, and 3f, respectively, in
good yields (entries 3-5). The chloro substituent was also
tolerated under present reaction conditions, and thus sub-
strates 2g and 2h smoothly furnished 3g and 3h in 81 and
89% yield, respectively (entries 6 and 7). The alkynols
bearing sterically demanding substituents in the tether such
as 1b, 1c, and 1d reacted well, giving corresponding products
3i, 3j, and 3k in good yields (entries 8-10). A mixture of
diastereomers 3l + 3l0 and 3m + 3m0 was obtained when 1e
and 1f were employed as substrates (entries 11 and 12). Not
only 4-pentyn-1-ols but also 5-hexyn-1-ols undergo reaction
smoothly. Thus, substrate 1g and 1h underwent hydroami-
nation-hydroarylation cascade to provide 3n and 3o, re-
spectively (entries 13 and 14). It should be noted that this
method is applicable to only terminal alkynes, and therefore,
internal alkynes cannot be employed as substrates.
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JOCNote
TABLE 2. PtBr2-Catalyzed Hydroamination/Hydroarylation of Al-
kynes
FIGURE 3. Plausible mechanism for Markownikoff’s hydroami-
nation/hydroarylation of alkynes.
SCHEME 1. PtBr2-Catalyzed Reaction of 1-Octyne with 2a
through intermediates 4 and 5 (cycle A).16 Then, N-H bond
addition of 2a catalyzed by PtBr2 again leads to the N,
O-ketal 8 (cf. 7). The coordination of the oxygen atom
of N,O-ketal to PtBr2 (cf. 8) would form imine 9, which on
intramolecular nucleophilic addition of pyrrole gives 10.
Protonation of the resulting organoplatinum complex 10
affords final product 3a and regenerates PtBr2 (cycle B). The
mechanism triggered by hydroarylation of 6 with the pyrrole
moiety17 in 2a cannot be ruled out completely.7b It is
noteworthy to emphasize that a single catalyst promotes all
reactions, mentioned in catalytic cycles A and B.18
To confirm the role of the tethered hydroxyl group in
alkynes, we have conducted an experiment presented in
Scheme 1. 2-Aminophenylpyrrole 2a and 1-octyne were
subjected to platinum catalysis under previously established
conditions. However, desired product was not obtained; at
room temperature, starting material 2a was recovered, and at
80 °C, a complex mixture was obtained as judged by TLC
and 1H NMR analysis.
Literature analysis on catalytic carbophilic activation
revealed that most of the processes involve the use of alkyne
as a trigger containing both nucleophile in the same
aReaction conditions: 1 (0.5944 mmol), 2 (0.5944 mmol),
b
5 mol % of PtBr2, MeOH (0.4 M), rt or heat, 12 h. Isolated
c
yields. Reaction mixture was heated for 24 h. dInseperable
(17) In order to determine the existence of intermediate X in the reaction
mixture, we have carefully examined the progress of reaction between 1a and
2a by TLC and 1H NMR. However, the presence of X was not detected. The
presence of starting materials and product 3a was only the detectable species.
mixture of diastereomers in the ratio of 2:1 was obtained.
e1:1 mixture of diastereomers obtained, which was separated
by flash column chromatography.
The plausible mechanism is depicted in Figure 3. First, a
PtBr2-catalyzed intramolecular hydroalkoxylation of alky-
nol 1a likely occurs to give 2-methylenetetrahydrofuran 6
(18) The reaction of exocyclic enol ether 6, prepared independently with
2a in methanol at rt for 12 h, did not afford 3a. However, 5 mol % of PtBr2 3a
was obtained in 90% yield. The possibility of Brønsted acid catalysis for the
formation of 3i from 1b and 2a was ruled out. The reaction between 1b and 2a
in the presence of catalytic amounts of HCl in methanol did not give desired
product 3i.
(16) One of the reviewers suggested that compound 6 may exist as
1-methoxy-1-methyltetrahydrofuran. However, the reaction between 1b
under standard Pt(II) catalysis, in the absence of 2a, did not give anticipated
product; decomposition occurred.
J. Org. Chem. Vol. 74, No. 16, 2009 6317

Patil et al.
JOCNote
molecule. Much more appealing strategies would involve the
use of alkyne and nucleophiles present in two different
substrates. In this regard, we have developed a formal
hydroamination-hydroarylation cascade of terminal al-
kynes tethered with a hydroxyl group. The corresponding
heterocycles were isolated in high yields, and this process
constitutes an easy and efficient access to highly substituted
pyrrolo[1,2-a]quinoxalines and indolo[3,2-c]quinolines;
those, as such or their synthetically manipulated forms,
may prove to be an important pharmacophore. Studies
aimed at exploring the mechanistic aspects of this transfor-
mation and developing further uses of this concept to various
heterocycles are ongoing.
J=7.7 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 3.3 Hz, 1H),
5.90 (br d, J = 3.0 Hz, 1H), 3.50 (t, J = 6.2 Hz, 2H), 1.89-1.81
(m, 1H), 1.79-1.70 (m, 1H), 1.64-1.55 (m, 2H), 1.26 (s, 3H); 13
C
NMR (75 MHz, DMSO-d6) δ 136.2, 133.0, 124.6, 123.8, 116.9,
114.7, 114.2, 113.8, 109.2, 102.7, 61.0, 53.0, 39.5, 28.0, 27.2; IR
(KBr) νmax 3246, 3188, 2974, 2941, 2909, 1608, 1516, 1489, 1336,
1288, 1026, 805, 706 cm-1; HRMS calcd for C15H19ON2 (M++
H) 243.1497, found 243.1507.
3-(4,5-Dihydro-4,8-dimethylpyrrolo[1,2-a]quinoxalin-4-yl)propan-
1-ol (3b):. 82% yield, white solid; mp 152-154 °C; Rf 0.35 (hexane/
EtOAc = 60/40); 1H NMR (400 MHz DMSO-d6 +D2O) δ7.41 (s,
1H), 7.04-7.01 (m, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 7.8
Hz, 1H), 6.17 (d, J = 2.9 Hz, 1H), 5.86 (d, J = 2.9 Hz, 1H), 3.44 (t,
J=6.4 Hz, 2H), 2.28 (s, 3H), 1.79-1.67 (m, 2H), 1.57-1.52 (m,
2H), 1.46 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 133.7, 133.2,
125.7, 124.9, 123.8, 114.8, 114.7, 113.6, 109.4, 102.4, 61.0, 53.0, 38.1,
27.8, 26.9, 20.3; IR (KBr) νmax 3242, 3180, 2968, 2951, 2902, 1615,
1546, 1491, 1334, 1289, 807, 712 cm-1; HRMS calcd for
C16H20N2ONa (M++Na) 279.1473, found 279.1466.
Experimental Section
The preparation of 3a is representative. To a methanol
(1.5 mL, 0.4 M) solution of 1a (50 mg, 0.5944 mmol) and
2a (94 mg, 0.5944 mmol) in a 2.5 mL screw-cap vial was added
PtBr2 (11 mg, 5 mol %) under nitrogen atmosphere. The mixture
was stirred at room temperature with methanol as a solvent for
6 h. Then, the reaction mixture was filtered through a pad of
silica gel with ethyl acetate, and the solvent was removed under
reduced pressure. The residue was purified by flash silica gel
column chromatography using ethyl acetate/hexane (3:7) as
eluent to obtain 3a (135 mg, 94%) as a pure compound.
Acknowledgment. We gratefully acknowledge financial
support by Council of Scientific and Industrial Research,
India. N.T.P. is grateful to Dr. J. S. Yadav, Director, IICT,
and Dr. T. K. Chakraborty, Director, CDRI, for their
support and encouragement.
3-(4,5-Dihydro-4-methylpyrrolo[1,2-a]quinoxalin-4-yl)propan-
1-ol (3a):. 94% yield, solid; mp 142-143 °C; Rf = 0.30 (hexane/
EtOAc = 60/40); 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.0
Hz, 1H), 7.15-7.05 (m,1H), 6.89 (t, J = 7.7 Hz, 1H), 6.75 (t,
Supporting Information Available: All experimental proce-
dures, analytical data, and copies of 1H and 13C NMR spectra of
all newly synthesized products. This material is available free of
charge via the Internet at http://pubs.acs.org.
6318 J. Org. Chem. Vol. 74, No. 16, 2009