Cyclization of acetylenic amides using a cationic rhodium(I) complex

Article abstract of DOI:10.1071/CH04032

The cationic Rh(I) dicarbonyl complex [{Rh(bim)(CO)₂} ⁺BPh₄^-] 1, containing a bidentate bisimidazolylmethane ligand [bim refers to bis(N-methylimidazol-2-yl)methane] acts as a catalyst for the cyclization of alkynyl amides to produce lactams and N-acyl heterocyclic compounds.

Full text of DOI:10.1071/CH04032

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Aust. J. Chem. 2004, 57, 677–680
Cyclization of AcetylenicAmides Using a Cationic Rhodium(i) Complex∗
Suzanne Burling,A Leslie D. Field,A,C Hsiu L. Li,A Barbara A. Messerle,B,C and Adelle ShashaA
A School of Chemistry, University of Sydney, NSW 2006, Australia.
B School of Chemistry, University of New South Wales, Sydney NSW 2052, Australia.
C Authors to whom correspondence should be addressed (e-mail: L.Field@chem.usyd.edu.au,
B.Messerle@unsw.edu.au).
The cationic Rh(i) dicarbonyl complex [{Rh(bim)(CO)2}+BPh4−] 1, containing a bidentate bisimidazolylmethane
ligand [bim refers to bis(N-methylimidazol-2-yl)methane] acts as a catalyst for the cyclization of alkynyl amides
to produce lactams and N-acyl heterocyclic compounds.
Manuscript received: 10 February 2004.
Final version: 6 April 2004.
ϩ
The formation of C N bonds by the addition of N H to
carbon carbon double and triple bonds (hydroamination) is a
processoffundamentalimportanceinthesynthesisoforganic
compounds.[1] Compounds containing C N bonds are com-
mon in biologically active natural and synthetic products[2]
and new catalysts for alkene and alkyne hydroamination
are improving synthetic routes to a range of amino com-
pounds. More recently, several examples of intermolecular
hydroamination reactions have been reported using Rh and
Ir phosphine complexes[3] and organoactinide[4] complexes
as catalysts.
BPhϪ4
H3C
N
N
CO
CO
Rh
H2C
N
N
H3C
1
Scheme 1.
The scope of catalyzed hydroamination is very catalyst-
dependent, and limited to relatively narrow classes of sub-
strates. Most reports of hydroamination have involved the
addition of primary amines to carbon carbon double or triple
bonds, although hydroamination using N-substituted amines
has also been reported. Successful hydroamination of pri-
mary amides would provide a significant advance in the
scope of hydroamination reactions, as amines are commonly
protected with amide functionality and because of the util-
ity of the N-substituted hydroamination products. The early
transition metal catalysts, as well as the lanthanide catalysts
are highly oxophilic, and generally unsuitable for the addi-
tion of amides to alkynes or alkenes. Palladium-catalyzed
addition of tosylamides to alkenes has been used as a route
to form nitrogen-containing heterocycles where the parent
amine bound too aggressively to the catalyst and inhibited
the cyclization.[5] The palladium-catalyzed cyclization of
alkynylacetanilidestoformN-acylindolederivativeshasalso
been reported.[6]
Complex 1 acts as a catalyst for a range of organic reactions
including the hydrosilation of double and triple bonds, the
alcoholysis of silanes, and the cyclization of alkynols and
alkynoic acids to oxygen-containing heterocycles.[8] Com-
plex 1 also acts as a catalyst for hydroamination reactions,
specifically for the facile intramolecular cyclization of amino
alkyne substrates. In this paper, we report the intramolecu-
lar cyclization of both aromatic and aliphatic alkynamides to
form nitrogen-containing heterocycles.
Complex 1 was prepared by reaction of the bidentate
imidazole ligand bim 2 with [Rh(CO)2Cl]2 as described
previously.[9] N-Acetyl-2-ethynylaniline 3 was cyclized by
1 in acetone solvent at 55◦C with 1.5 mol% catalyst to give
N-acetylindole 4. The reaction was slow compared to that
usingthefreeaminesubstrateand, after3days, 4wasobtained
in a yield of 23% (Scheme 2).
In a similar fashion, 1,5-bis(acetamido)-2,4-diethynyl-
benzene 5 was synthesized in five steps from 1,3-
dibromobenzene and cyclized with 1 at a loading of 30 mol%
to form the bisacetylated pyrrolo[3,2-f]indole 6 (Scheme 3).
Thisapproach, viatheintramolecularcyclizationofsubsti-
tuted alkynylanilines, clearly provides a relatively direct entry
We have recently reported the synthesis of a new reacti−ve
cationicRh(i)dicarbonylcomplex[{Rh(bim)(CO)2}+BPh4 ]
1 (Scheme 1), with a bidentate bisimidazolylmethane lig-
and [bim refers to bis(N-methylimidazol-2-yl)methane].[7]
∗ This paper is dedicated to Professor Lew Mander in recognition of his great contribution to organic chemistry in Australia.
© CSIRO 2004 10.1071/CH04032
0004-9425/04/070677

678
S. Burling et al.
enamine. Li and Marks[10] have previously identified enam-
ine intermediates in the cyclization of primary and secondary
amino alkynes by an organolanthanide complex.
H
C
C
[Rh(bim)(CO)2]ϩ
N
To conclude, the cyclization of alkynamides to N-
acylindoles and to other nitrogen-containing heterocycles
provides a useful preparative route to a range of heterocyclic
systems. The reaction of amides is significantly slower than
their free-amine counterparts. It should be noted that amino
alkynes are cyclized by a range of related cationic Rh(i) and
Ir(i) complexes, and the efficiency of the catalyst changes
remarkably even with small changes to the ligand donor set
as well as with the nature of the counter ion. So far, no attempt
has been made to optimize product yields or assess the best
metal complex for the cyclization of alkynamides.
NH
COCH3
COCH3
3
4
Scheme 2.
(a) HNO3/H2SO4
(b) Fe/AcOH
Br
Br
Br
Br
H2N
NH2
(a) Ac2O
(b) HCCTMS/PdCl2
(c) KF
Experimental
HC
CH
C
All manipulations of metal complexes and air-sensitive reagents were
carried out using standard Schlenk or vacuum techniques, or in a
nitrogen- or argon-filled dry box.
All organic starting materials were obtained from Aldrich and
were distilled before use. [Rh(bim)(CO)2]+[BPh4]− 1 was synthe-
sized according to literature methods.[9]N-Acetyl-2-ethynylaniline 3
was prepared by the method of Rudisill and Stille.[6a] 1,5-Diamino-
2,4-dibromobenzene was synthesized following the method of Dumont
and Slegers.[13] Pent-4-ynoic acid was synthesized according to the
procedure of Holland and Gilman.[14]
C
[Rh(bim)(CO)2]ϩ
N
N
HN
COCH3
NH
H3COC
COCH3
COCH3
6
5
Scheme 3.
Tetrahydrofuran was stored over sodium wire and distilled under
nitrogen immediately before use from sodium benzophenone ketyl.
Deuterated solvents for NMR purposes were obtained from Merck
and Cambridge Isotopes. Deuterated chloroform was used as supplied.
Deuterated acetone was dried over P2O5 and deuterated tetrahydrofu-
ran was stored over Na. Solvents were degassed using three consecutive
freeze–pump–thaw cycles and vacuum distilled immediately before use.
Mass spectra of organic compounds were recorded on a Finnigan
Mat TSQ 4600 mass spectrometer by chemical ionization. Infrared
spectra were recorded on a Perkin–Elmer 1600 FTIR spectrometer.
Melting points were determined using a Gallenkamp apparatus and are
uncorrected.
[Rh(bim)(CO)2]ϩ
C
C
H
O
O
H2N
N
H
7
8
Scheme 4.
to the indoles. Since it is known that non-terminal alkynes
also undergo cyclization with 1, this scheme has the flexibil-
ity to access a range of indoles with substituents on the indole
nitrogen or at the 2-position.
1H and 13C NMR spectra were recorded on a Bruker DRX400 spec-
trometer at 400.13 and 100.62 MHz respectively. 1H and 13C NMR
chemical shifts (δ) were referenced to internal solvent resonances.
Cyclization of N-Acetyl-2-ethynylaniline 3
Complex 1 also successfully cyclized non-aromatic
acetylenic amides. 1-Pentynamide 7 was cyclized to 3,4-
dihydro-2-pyridone 8 (Scheme 4) albeit slowly at a loading
of 10 mol% and in modest yield (11%). In principle, the
intramolecular cyclization could give two possible isomers
resulting from either the 5-exo-dig or 5-endo-dig ring closure.
exo-Cyclization gives a five-membered ring, while endo-
cyclization would give the six-membered ring product. With
1 as catalyst, only the six-membered ring product 8 was
observed.
The mechanism of addition of N H bonds to carbon
carbon double and triple bonds has been investigated for
several of the metal-mediated systems. Classical oxidative
addition/reductive elimination reaction pathways have been
proposed using catalysts containing metal centres such as
lanthanides,[10] actinides,[11] and Rh(i).[12] This mechanism
involves oxidative addition of the N H bond of the amine
to the metal centre followed by a migratory insertion to the
tethered alkene to produce a metal-coordinated heterocyclic
N-Acetyl-2-ethynylaniline 3 (42 mg, 0.26 mmol) was added to a solu-
tion of [Rh(bim)(CO)2]+[BPh4]− 1 (3 mg, 4.6 µmol, 1.5 mol%) in
(CD3)2CO (0.5 mL) in an NMR tube under an atmosphere of nitro-
gen. The mixture was heated at 55◦C in an oil bath. N-Acetylindole 4
was formed with 23% conversion from starting material after 3 days.
The material was spectroscopically identical to an authentic sample pre-
pared by the acetylation of indole with acetic anhydride. δH (400 MHz,
(CD3)2CO) 8.42 (d, 1H, J4,5 8.2, H4), 7.71 (d, 1H, J7,6 3.8, H7),
7.59 (m, 1H, H2), 7.32 (m, 1H, H6), 7.25 (m, 1H, H5), 6.68 (m, 1H,
H3), 2.65 (s, 3H, CH3). δC (100 MHz, (CD3)2CO) 169.7 (C=O), 137.0,
127.2, 125.9 (C2), 125.3 (C6), 122.2 (C4), 121.5 (C5), 116.9 (C7), 109.0
(C3), 23.9 (CH3).
3
3
1,5-Bis(acetamido)-2,4-dibromobenzene
Acetic anhydride (0.3 mL) was added to a solution of 1,5-diamino-
2,4-dibromobenzene (52 mg, 0.20 mmol) in dichloromethane (2 mL),
and the reaction mixture was stirred at room temperature for 2 h.
The solvent was removed under vacuum. The residue was recrystal-
lized from ethanol to give 1,5-bis(acetamido)-2,4-dibromobenzene as
a white powder (41 mg, 61%). (Found: m/z 347.9111; C 34.2, H 2.7,
N 7.9%. C10H10Br2N2O2 requires 347.9109; C 34.3, H 2.9, N 8.0%.)

Cyclization of Acetylenic Amides
679
δH (200 MHz, (CD3)2SO) 9.52 (br s, 2H, NH), 7.94 (s, 1H, H3), 7.88
(s, 1H, H6), 2.07 (s, 6H, CH3). δC (75 MHz, (CD3)2SO) 168.7 (C=O),
136.1 (C1 and C5), 135.0 (C3), 124.3 (C6), 114.2 (C2 and C4), 23.3
(CH3). m/z (EI+) 350 (M+, 3%), 271 (100), 269 (93), 266 (28), 229
(60), 227 (53), 189 (50).
Pent-4-ynamide 7
A solution of pent-4-ynoic acid (94.5 mg, 1.00 mmol) in chloroform
(2 mL, anhydrous) was stirred for 30 min in a stoppered Ace pressure
tube, and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-
toluenesulfonate (morpho-CDI; 0.45 g, 1.0 mmol) was added. After the
addition was complete, the resulting mixture was stirred at room tem-
perature for 18 h. The reaction mixture was cooled to −78◦C and then
treated with condensed ammonia (1 mL, excess). The pressure tube was
immediately stoppered and the mixture stirred at room temperature for
18 h.The tube was cooled to −78◦C, the lid was removed, and the excess
ammonia and solvent were evaporated in a stream of nitrogen at room
temperature. The residue was extracted with ethyl acetate (5 × 20 mL).
The ethyl acetate extracts were combined and the solvent was removed
to give a yellow oily residue. The residue was chromatographed using
flash silica (hexane/ethyl acetate, 1 : 3), RF 0.28 (hexane/ethyl acetate,
1 : 3; KMnO4 indicator), and recrystallized from ethyl acetate to give
pent-4-ynamide 7 as a colourless crystalline solid (44.5 mg, 47%), mp
110–111◦C (lit.[15] 112–113◦C). δH (400 MHz, [D8]THF) 6.76 (br, 1H,
NH), 6.57 (br, 1H, NH), 2.41 (m, 2H, H2), 2.33 (m, 2H, H3), 2.22 (t,
4J3,5 2.6, 1H, H5). δC (100 MHz, [D8]THF) 172.2 (C1), 84.0 (C4), 69.4
(C5), 35.1 (C2), 15.0 (C3). m/z (ES+, methanol) 98 ((M + H)+, 31%),
195 (50), 217 (35), 240 (20), 336 (100).
1,5-Bis(acetamido)-2,4-bis(trimethylsilylethynyl)benzene
Palladium(ii) chloride (111 mg, 0.626 mmol), copper(ii) acetate
(128 mg, 1.04 mmol), triphenylphosphine (482 mg, 1.84 mmol), and
1,5-bis(acetamido)-2,4-dibromobenzene (2.0 g, 5.7 mmol) were mixed
under nitrogen with dry and degassed triethylamine (180 mL). (Tri-
methylsilyl)acetylene (2.6 mL, 18 mmol) was added and the reaction
mixture was stirred and heated at 85◦C under nitrogen for 8 h. The mix-
ture was cooled to room temperature, filtered to remove the insoluble
salts, and the triethylamine was removed under reduced pressure.
The solid residue was dissolved in ethyl acetate, pre-adsorbed onto
flash silica, and then purified by chromatography using flash silica
(hexane/ethyl acetate, 1 : 1), RF 0.46 (hexane/ethyl acetate, 1 : 1), to
give 1,5-bis(acetamido)-2,4-bis(trimethylsilylethynyl)benzene as a light
brownsolid(1.1 g, 50%), mp168–170◦C. (Found:m/z384.1685;C63.0,
H 7.4, N 7.2%. C20H28N2O2Si2 requires 384.1689; C 62.5, H 7.3, N
7.3%.) δH (200 MHz, CDCl3) 9.34 (br, 1H, H6), 7.90 (br s, 2H, NH),
7.46 (s, 1H, H3), 2.17 (s, 6H, COCH3), 0.27 (s, 18H, Si(CH3)3). δC
(75 MHz, CDCl3) 167.9 (C=O), 140.7 (C1 and C5), 134.6 (C3), 109.7
(C6), 106.9 (C2 and C4), 102.1 (CCSiMe3), 99.4 (CCSiMe3), 24.9
(COCH3), 0.4 (Si(CH3)3). m/z (EI+) 384 (M+, 75%), 343 (100), 301
(40), 74 (18). νmax/cm−1 (KBr) 3293w (N–H), 2958w (C–H aromatic),
2155m (C≡C), 1671s (C≡O), 1585s, 1412s, 1250s, 842s.
Cyclization of 7 to 3,4-Dihydro-2-pyridone 8
Complex 1 (136 mg, 207 µmol; 10 mol%) was added to pent-4-ynamide
7 (200 mg, 2.07 mmol) in deuterated tetrahydrofuran (0.5 mL) in an
NMR tube under an atmosphere of nitrogen. The mixture was heated
at 60◦C and 1H NMR spectra were recorded at regular intervals. The
product 8 was formed after 24 h. Once the reaction was complete, the
NMR tube was opened to the atmosphere. The residue was poured into
a mixture of hexane (2.5 mL) and ethyl acetate (7.5 mL) to give a solid
brown precipitate. The supernatant liquid was decanted and the brown
precipitate was washed with hexane/ethyl acetate (1 : 3; 4 × 20 mL).The
supernatant liquid and the washings were combined, reduced in volume,
and chromatographed using flash silica (hexane/ethyl acetate, 1 : 3) to
give 3,4-dihydro-2-pyridone 8 as a yellow oil (16 mg, 11%). (Found: m/z
97.0527. C5H7NO requires 97.0528.) δH (400 MHz, CDCl3) 7.90 (br s,
1H, NH), 6.04 (ddt, 3J6,5 7.6, 3J6,NH 4.5, 4J6,4 1.6, 1H, H6), 5.04 (dtd,
3J5,6 7.6, 3J5,4 4.3, 4J5,NH 1.1, 1H, H5), 2.46 (m, 2H, H3), 2.29 (m, 2H,
H4). δC (100 MHz, CDCl3) 171.9 (C2), 125.1 (C6), 105.1 (C5), 30.5
(C3), 20.1 (C4). m/z (EI+) 97 (M+, 48%). m/z (ES+, MeOH/CDCl3)
485 ((M × 5)+, 46%), 418 (100), 316 (75), 217 (36), 152 (34), 120
(33), 98 (17). νmax/cm−1 (NaCl) 3258m (N–H), 1679s, 1654s (C=O),
1367m, 1089m, 798m.
1,5-Bis(acetamido)-2,4-diethynylbenzene 5
1,5-Bis(acetamido)-2,4-bis(trimethylsilylethynyl)benzene
(0.44 g,
1.2 mmol) was dissolved in methanol (40 mL), potassium fluoride
(0.70 g, 12 mmol) was added, and the reaction mixture was stirred for 1 h
at room temperature. Water (30 mL) was added, and the reaction mixture
was extracted with diethyl ether (5 × 50 mL).The combined organic lay-
ers were washed with water (2 × 25 mL) and brine (25 mL), then dried
over magnesium sulfate and the solvent was removed under vacuum to
give the title compound 5 as a creamy brown solid (106.8 mg, 39%), mp
300◦C (dec.). (Found: m/z 240.0897. C14H12N2O2 requires 240.0899.)
δH (400 MHz, [D8]THF) 9.08 (s, 1H, H6), 8.42 (br s, 2H, NH), 7.44
(s, 1H, H3), 3.92 (s, 2H, C≡C–H), 2.11 (s, 6H, CH3). δC (100 MHz,
[D8]THF) 168.2 (C=O), 142.1 (C1 and C5), 136.6 (C3), 133.9 (C6),
108.1 (C2 and C4), 84.8 (C≡C–H), 79.3 (C≡C–H), 24.2 (CH3). m/z
(EI+) 240 (M+, 30%), 198 (77), 156 (100), 104 (26). νmax/cm−1 (KBr)
3392m (N–H), 3278s, 3206s (C≡C–H), 2097w (C≡C–H), 1699s,
1686s, 1664s (C=O), 1577s, 1529s, 1497s, 1417s.
Acknowledgments
We gratefully acknowledge financial support from the
Australian Research Council (ARC) and the generous loan
of rhodium salts from Johnson Matthey Pty Ltd.
Cyclization of 5 to 1,7-Diacetylpyrrolo[3,2-f]indole 6
Complex 1 (48.0 mg, 73.1 µmol; 30 mol%) was added to compound 5
(60.1 mg, 250 µmol) in deuterated tetrahydrofuran (0.5 mL) in an NMR
tube under an atmosphere of nitrogen. The mixture was heated at 60◦C
and 1H NMR spectra were recorded at regular intervals.The product was
formedafter72 h.Thetubewasopenedtotheatmosphereandtheresidue
was poured into a mixture of hexane (2.5 mL) and ethyl acetate (7.5 mL)
to give a solid precipitate. The supernatant liquid was decanted and the
precipitate was washed with hexane/ethyl acetate (1 : 3; 8 × 20 mL).The
washings and the supernatant liquid were combined, reduced in volume,
and purified by chromatography using flash silica (hexane/ethyl acetate,
1 : 3) to give compound 6 as an orange solid (21.5 mg, 36%), mp 205–
207◦C. (Found: m/z 240.0899. C14H12N2O2 requires 240.0899.) δH
(400 MHz, CDCl3) 9.47 (br s, 1H, H8), 7.65 (d, 4J4,3/5 0.77, 1H, H4),
7.50 (d, 3J2,3 3.8, 2H, H2 and H6), 6.67 (dd, 3J3,2 3.8, 4J3,4 0.77, 2H,
H3 and H5), 2.67 (s, 6H, CH3). δC (100 MHz, CDCl3) 168.4 (C=O),
134.3 (C2ꢀ), 128.0 (C3ꢀ), 126.2 (C2 and C6), 111.9 (C4), 109.1 (C3 and
C5), 104.6 (C8), 24.3 (CH3). m/z (EI+) 240 (M+, 53%), 198 (32), 156
(100). νmax/cm−1 (KBr) 1704s, 1688s (C=O), 1263s, 1213s, 1094m,
1029s (C–N), 1378s, 805s.
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