Anti-Markovnikov addition of both primary and secondary amines to terminal alkynes catalyzed by the TpRh(C2H4)2/PPH 3 system

Article abstract of DOI:10.1021/ja075484e

Terminal alkynes react with secondary amines in the presence of TpRh(C₂H₄)₂/PPh₃ (Tp = trispyrazolylborate) to give anti-Markovnikov E-enamines. Both Tp and PPh₃ ligands are essential for the reaction. The reaction tolerates functional groups, such as ester, nitrile, and siloxy groups, on the terminal alkynes. Primary amines also add to terminal alkynes in anti-Markovnikov fashion, yielding the corresponding imines. The formation of a vinylidene-rhodium complex followed by the intermolecular nucleophilic attack by an amine nitrogen at the α-carbon atom of the vinylidene-metal intermediate may be involved in a key step in the catalytic reaction. Copyright

Full text of DOI:10.1021/ja075484e

Published on Web 10/20/2007
Anti-Markovnikov Addition of Both Primary and Secondary Amines to
Terminal Alkynes Catalyzed by the TpRh(C2H4)2/PPh3 System
Yoshiya Fukumoto,* Harumi Asai, Masaki Shimizu, and Naoto Chatani
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita, Osaka 565-0871, Japan
Received July 23, 2007; E-mail: fukumoto@chem.eng.osaka-u.ac.jp
Scheme 1. Catalytic Addition of Amines to Terminal Alkynes
The simple addition of a N-H bond to a C-C double or triple
bond, known as hydroamination, offers an attractive route for
synthesis of highly substituted nitrogen-containing organic mol-
ecules without formation of any side products.1 Hydroamination
of alkynes provides either enamines or imines, which undergo
further synthetic transformations,2 the exact nature of which depends
on the type of amine. In general, a wide variety of metals, including
early- and late-transition metals, lanthanides, and actinides, have
been employed in catalytic intermolecular hydroamination of
terminal alkynes to yield Markovnikov products.3 In contrast,
hydroamination of terminal alkynes in anti-Markovnikov fashion
is rare (Scheme 1). The first anti-Markovnikov hydroamination of
terminal alkynes with primary amines was realized using of the
organouranium complex, Cp*2UMe2, as a catalyst.4 Subsequently,
some titanocene derivatives have been applied to anti-Markovnikov
alkyne hydroamination, although use of bulky primary amines, such
as tert-butylamine and diphenylmethylamine, was required.5 Re-
cently, Schafer revealed the highly regioselective anti-Markovnikov
hydroamination of terminal alkynes with a wide range of primary
amines, catalyzed by bis(amidate)titanium complexes.6 However,
the complexes described above are not applicable to reactions with
secondary amines because of the formation of imido-metal
complexes (RNdM) as a crucial intermediate in the catalytic cycle.7
The only previous report of anti-Markovnikov addition of secondary
amines to terminal alkynes was limited to the Cs(OH)-catalyzed
reaction of phenylacetylene with substituted anilines or N-hetero-
cycles.8,9 To the best of our knowledge, there is no catalytic system
that allows both primary and secondary amines to react with
terminal alkynes to give anti-Markovnikov products. We wish to
disclose herein the anti-Markovnikov hydroamination of terminal
alkynes not only with primary amines but also with secondary
amines in the presence of a rhodium complex as a catalyst.
The initial hydroamination experiments of 1-octyne (0.5 mmol)
with morpholine (1 mmol) at 100 °C for 24 h in a sealed-tube were
performed to screen catalysts. Among the transition metal com-
plexes examined, TpRh(C2H4)2 (Tp ) trispyrazolylborate) in
combination with PPh3 showed catalytic activity to furnish (E)-1-
morpholino-1-octene (2a) in 61% yield, without the formation of
the Z-isomer or the Markovnikov adduct.10 Treatment of RhCl-
(PPh3)3 with commercially available KTp in situ also provided a
catalyst with activity nearly comparable to that observed with the
TpRh(C2H4)2/PPh3 system (56% yield). Both Tp and PPh3 ligands
were essential since the use of TpRh(C2H4)2 or RhCl(PPh3)3 alone
afforded dimerization products of 1-octyne11 instead of the hy-
droamination product. Other rhodium complex systems, such as
[RhCl(cod)]2/PPh3, [Rh(cod)2]BF4/ PPh3,12 CpRh(C2H4)2/PPh3, and
Tp*Rh(C2H4)2/PPh3 (Tp* ) tris(3,5-dimethylpyrazolyl)borate), were
ineffective catalysts for the formation of 2a. To further optimize
the reaction conditions, the use of 1.5 mmol of morpholine at a
higher dilution (2 mL of toluene) improved the yield of 2a to 70%
(Table 1, entry 1); 2a was directly reduced with NaB(OAc)3H to
Table 1. TpRh(C2H4)2/PPh3-Catalyzed Hydroamination of
1-Octyne with Aminesa
a Reaction conditions: 1-octyne (0.5 mmol), amine (1.5 mmol),
TpRh(C2H4)2 (0.05 mmol), PPh3 (0.1 mmol), in toluene (2 mL) at 100 °C
for 24 h. b Yields determined by 1H NMR spectroscopy with 1,3-
dihydroisobenzofuran as an internal standard. c For 6 h.
isolate 4-octylmorpholine (2a′) in 66% yield. Similarly, several
cyclic (entries 2 and 3) and acyclic amines (entries 4 and 5) also
reacted with 1a to give the corresponding E-isomers, 2b-2e, while
reactions of 1a with dibenzylamine and N-methylaniline did not
take place. When primary amines, such as benzylamine and
octylamine were used, aldimines 2f and 2g were obtained,
respectively, in moderate yields (entries 6 and 7). In contrast to
the results of our previous study, which demonstrated that the
TpRuCl(PPh3)3-catalyzed reaction of terminal alkynes with hydra-
zines yields nitriles,13 the TpRh(C2H4)2/PPh3 system converted 1a
to hydrazone 2h in 64% yield.
Table 2 summarizes the results for the reaction of alkynes with
benzylmethylamine (left column) and benzylamine (right column).14
Both amines reacted with alkynes 1b-1d to give the corresponding
E-enamines 3b-3d or imines 4b-4d, respectively (entries 1-3).
The reaction also occurred in the presence of functional groups,
such as siloxy (1e), ester (1f), and nitrile (1g), on the terminal
alkynes (entries 4-6). Alkynes 1h-1j reacted with benzylmethy-
lamine to yield 3h-3j. In contrast, those of benzylamine gave no
or little product with recovery of the starting alkynes, although the
reasons for the lack of reaction remain unknown (entries 7-9).
2-Octyne, as an internal alkyne, did not react both with primary
and secondary amines under the present reaction conditions at all.
Although details of the reaction mechanism are ambiguous, the
formation of a vinylidene-rhodium complex15 I seems likely to
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J. AM. CHEM. SOC. 2007, 129, 13792-13793
10.1021/ja075484e CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Anti-Markovnikov Hydroamination of
Terminal Alkynes with Amines Catalyzed by TpRh(C2H4)2/PPh3
octyne with benzylamine to obtain information about the reaction
mechanism was unsuccessful, as it resulted in rapid H/D scramble.
In summary, we have demonstrated herein the TpRh(C2H4)2/
PPh3-catalyzed anti-Markovnikov hydroamination of terminal alkynes
both with primary and secondary amines. Efforts are currently
underway to investigate the scope and mechanism of the reaction.
a
Acknowledgment. We thank the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for assistance with the
HRMS and elemental analyses. Y.F. is grateful to Otsuka Phar-
maceutical Co., Ltd., for financial support of this work.
Supporting Information Available: Experimental procedures and
characterization of all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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a Reaction conditions: alkyne (0.5 mmol), amine (1.5 mmol), TpRh(C2H4)2
(0.05 mmol), PPh3 (0.1 mmol), in toluene (2 mL) at 100 °C. b Yields
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Scheme 2. Plausible Reaction Mechanism
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sponding amines. See Supporting Information.
be included in the reaction mechanism, as shown in Scheme 2,
explaining that both primary and secondary amines add to the
terminal carbon of alkynes. A terminal alkyne reacts with a rhodium
complex to give I, which undergoes nucleophilic attack of an amine
at the R-carbon atom of I to afford an R-aminovinylrhodium
complex II.9,16 Reductive elimination from II gives the enamine
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