Synthesis of Tertiary Propargylamines by Sequential Reactions of in Situ Generated Thioiminium Salts with Organolithium and -magnesium Reagents

Article abstract of DOI:10.1021/ja048627v

Sequential reactions of thioiminium salts generated from thioamides and methyl triflate with organolithium and -magnesium reagents proceed smoothly to give tertiary propargylamines in moderate to high yields. In all cases, two different organometallic rea

Full text of DOI:10.1021/ja048627v

Published on Web 04/28/2004
Synthesis of Tertiary Propargylamines by Sequential Reactions of in Situ
Generated Thioiminium Salts with Organolithium and -magnesium Reagents
Toshiaki Murai,*,† Yuichiro Mutoh,† Yukiyasu Ohta,† and Masahiro Murakami‡
Department of Chemistry, Faculty of Engineering, Gifu UniVersity, Yanagido, Gifu 501-1193, Japan, and
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
Received March 10, 2004; E-mail: mtoshi@cc.gifu-u.ac.jp
Scheme 1
It would become a useful synthetic reaction if two kinds of
organometallic reagents1 are incorporated into an electrophilic
organic molecule in one pot. It is important to choose appropriate
organometallic reagents of suitable nucleophilicity to achieve such
a stepwise transformation. During the course of our studies on thio-
and selenoamides,2 we have found that thioiminium salts generated
in situ from thioamides and methyl triflate (MeOTf) are highly
electrophilic acyl equivalents.2f We report here a new carbon-
carbon bond forming reaction in which organolithium and -mag-
Scheme 2
nesium reagents are sequentially incorporated into thioiminium salts.
A variety of tertiary propargylamines are conveniently synthesized
by this protocol.
Initially, the reaction of in situ generated thioiminium salt 1a
with various organometallic reagents was tested (Scheme 1). As a
result, a substantial difference in reactivity was observed between
alkynyllithium and -magnesium reagents, both among the most
common organometallics. Whereas the reaction of the salt 1a with
(phenylethynyl)lithium (3a) selectively gave S,N-acetal 5 at a purity
higher than 95%,3,4 the use of (phenylethynyl)magnesium bromide
(4a) afforded, after aqueous workup, unreacted phenylacetylene
mainly with decomposition products of 1a.
Scheme 3
Next, the second reaction of S,N-acetal 5 thus obtained from 1a
and 3a was examined also with the alkynyllithium and -magnesium
reagents (Scheme 2). Notably, the reactivity order was reversed.
(Phenylethynyl)lithium (3a) failed to react with the S,N-acetal 5.5
In contrast, S,N-acetal 5 was selectively converted to 3-amino-1,4-
diyne 6 by the reaction with (phenylethynyl)magnesium bromide
(4a).6 We assume that thioiminium salt 1a reacts with more ionic
alkynyllithium rather than with alkynylmagnesium bromide. On the
other hand, the neutral S,N-acetal 5 prefers more Lewis acidic
alkynylmagnesium bromide as the reacting partner.
Scheme 4
On the basis of these results, we envisioned sequential additions
of two different alkynylmetals to thioiminium salt 1 would present
a reaction forming two carbon-carbon bonds with a high efficiency.
In fact, the salt 1a was sequentially reacted with (phenylethynyl)-
lithium (3a, 1.5 equiv) and ethynylmagnesium bromide (4b, 1.5
equiv) to give 3-amino-1,4-diyne7 7 in 91% yield (Scheme 3). A
product that incorporated two molecules of 3a was not formed at
all even with the use of excess 3a.
We examined the generality of the present sequential protocol
and found a wide applicability (Table 1). Unsymmetrically substi-
tuted 3-amino-1,4-diyne 8 was efficiently obtained by reacting
different alkynylmetals (entry 1). Not only alkynylmagnesium
bromides, but a wide range of organomagnesium reagents success-
fully reacted with the intermediate S,N-acetals. A variety of
alkynyllithiums 3a-3d gave propargylamines in good yields (entries
2-4, 6, 8, 11, and 12).8 Ene-ynes are useful compounds for making
various cyclic frameworks. These classes of compounds were
conveniently synthesized by the present reaction (entries 5, 7, 9,
10, 13, and 14), although they are otherwise hardly accessible.9,10
Thioacetamide 2c and aromatic thioamides 2d-2f worked well as
the starting thioamide to give tertiary amines bearing a tertiary
carbon atom adjacent to a nitrogen atom (entries 11-14).
A wide variety of elegant methods for synthesizing propargyl-
amines via the addition of alkynylmetals to imines, iminium salts,
and enamines11 have been developed, but they use single organo-
metallic reagents. In contrast, in the present reaction, two different
organometallic reagents are nucleophilically introduced to the
carbon atom of the thiocarbonyl group of thioamides 2 in one
operation.
Finally, propargylamines obtained in the present reaction were
subjected to silylcarbocyclization.12 N,N-Diallyl propargylamines
22 were reacted with PhMe2SiH in the presence of a catalytic
amount of Rh4(CO)12 to give 2,3,4-trisubstituted pyrrolidines 23
with high regio- and stereoselectivity (Scheme 4).
† Gifu University.
‡ Kyoto University.
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J. AM. CHEM. SOC. 2004, 126, 5968-5969
10.1021/ja048627v CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Sequential Reactions of in Situ Generated Thioiminium
Salts 1 from 2 and MeOTf with 3 and 4a
generated thioiminium salts leading to tertiary propargylamines.
The substantial differences in the reactivity of these two reagents
toward thioiminium salts and S,N-acetals have played important
roles in achieving the transformations. The versatility of these
starting materials allows for the construction of diverse sets of
tertiary propargylamines. Further mechanistic studies on the present
reactions and synthetic applications of thioiminium salts and S,N-
acetals are in progress.
Acknowledgment. This research was supported by a Grant-in-
Aid for Scientific Research on Priority Areas (A) (No. 14044035)
“Exploitation of Multi-Element Cyclic Molecules” from the Min-
istry of Education, Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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In summary, we have demonstrated highly efficient sequential
reactions of organolithium and -magnesium reagents with in situ
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