Synthesis and properties of 1-methylthiopropargylammonium salts and their use as key precursors to sulfur-containing enediynes

Article abstract of DOI:10.1021/ol7024923

(Chemical Equation Presented) 1-Methylthiopropargylammonium salts were synthesized in a highly efficient manner by reaction of alkynyl S,N-acetals with methyl triflate. Reactions of the 1-methylthiopropargylammonium salts with Grignard reagents gave propargyl sulfides or allenyl sulfides, whereas the reaction with organocopper reagents led to exclusive formation of allenyl sulfides regardless of the nature of substituents on the acetylenic carbon. The salts undergo self-dimerization reactions when treated with organolithium and lithium amide bases.

Full text of DOI:10.1021/ol7024923

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5295-5298
Synthesis and Properties of
1-Methylthiopropargylammonium Salts
and Their Use as Key Precursors to
Sulfur-Containing Enediynes
Toshiaki Murai,* Kozue Fukushima, and Yuichiro Mutoh
Department of Chemistry, Faculty of Engineering, Gifu UniVersity,
Yanagido, Gifu 501-1193, Japan
mtoshi@gifu-u.ac.jp
Received October 12, 2007
ABSTRACT
1-Methylthiopropargylammonium salts were synthesized in a highly efficient manner by reaction of alkynyl S,N-acetals with methyl triflate.
Reactions of the 1-methylthiopropargylammonium salts with Grignard reagents gave propargyl sulfides or allenyl sulfides, whereas the reaction
with organocopper reagents led to exclusive formation of allenyl sulfides regardless of the nature of substituents on the acetylenic carbon.
The salts undergo self-dimerization reactions when treated with organolithium and lithium amide bases.
Quaternary ammonium salts are among the most ubiquitous
and important classes of organic compounds.1 Numerous
propargylammonium salts have been prepared and utilized
as key reactants in synthetic chemistry.2 Although the
introduction of heteroatom-containing functional groups at
the propargylic positions of these substances is expected to
provide new and interesting classes of compounds, to the
best of our knowledge, no reports describing these substances
have appeared thus far. During the course of studies of the
synthesis and properties of chalcogenoamides,3 we found that
relatively stable alkynyl S,N-acetals are formed in reactions
of thioiminium salts with lithium acetylides.3a Below, we
describe the results of recent efforts which show that
methylation of alkynyl S,N-acetals results in formation of
1-methylthiopropargylammonium salts. In addition, findings
made in studies of the chemical and physical properties of
these substances and their use as key precursors of sulfur-
containing enediynes are reported.
In initial investigations, electrophilic methylation reactions
of alkynyl S,N-acetals by using a variety of reagents were
examined. We observed that reactions promoted by methyl
trifluoromethanesulfonate (MeOTf) give good yields of
1-methylthiopropargylammonium salts 2 within 5 min (Scheme
1).4 All reactions lead to products in which the nitrogen atom
(1) For a book and recent reviews, see: (a) Jones, R. A. Quaternary
Ammonium Salts: Their Use in Phase-Transfer Catalysed Reactions;
Academic Press: San Diego, 2001. (b) Vachon, J.; Lacour, J. Chimia 2006,
60, 266-275. (c) Xue, H.; Verma, R.; Shreeve, J. M. J. Fluorine Chem.
2006, 127, 159-176. (d) Ishihara, K.; Sakakura, A.; Hatano, M. Synlett
2007, 686-703. (e) Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007,
1487-1495.
(2) For recent examples of propargylammonium salts, see: (a) Honda,
K.; Yasui, H.; Inoue, S. Synlett 2003, 2380-2382. (b) Gevorkyan, A. R.;
Chukhadzhyan, E. O.; Chukhadzhyan, El. O.; Panosyan, G. A. Chem. Heter-
ocycl. Com. 2004, 40, 177-182. (c) Ryu, E.-H.; Zhao, Y. Org. Lett. 2005,
7, 1035-1037. (d) Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.; Frost,
T. M.; Michlich, B.; Frey, W.; Bats, J. W. Chem. Eur. J. 2006, 12, 5806-
5814. (e) Ikeda, M.; Hasegawa, T.; Numata, M.; Sugikawa, K.; Sakurai,
K.; Fujiki, M.; Shinkai, S. J. Am. Chem. Soc. 2007, 129, 3979-3988.
(3) (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem.
Soc. 2004, 126, 5968-5969. (b) Murai, T.; Asai, F. J. Am. Chem. Soc.
2007, 129, 780-781. (c) Shibahara, F.; Suenami, A.; Yoshida, A.; Murai,
T. Chem. Commun. 2007, 2354-2356 and references cited therein.
10.1021/ol7024923 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

Scheme 1. Methylation of Alkynyl S,N-Acetals 1 with MeOTf
Table 1. Reaction of 1-Methylthiopropargylammonium Salts 2
with Grignard or Organocopper Reagentsa
of the starting S,N-acetals 1 is methylated. Substituents at
the alkynyl carbon of 1, such as alkyl, aryl, alkenyl, and
silyl, do not affect the yields or stabilities of the salts.
Purification of 2 is achieved simply by washing with
solvents. Elemental analyses of 2a,b,d,g-i, obtained in this
manner, indicate high levels of purity.
a The details of the reaction conditions are included in the Supporting
Information. b NMR yields. The isolated yields are shown in parentheses.
c M ) MgBr. d M ) MgCl. e M ) CuLi‚LiI.
PhMgBr gives predominantly propargyl sulfide 3a along with
allenylsulfide 4a as a minor product (entry 1). In contrast,
reactions of 2g with Grignard reagents proceed selectively
by addition to the alkynyl carbon atom to yield allenyl
sulfides 4 (entries 2 and 3). More interestingly, reactions of
organocopper reagents with 2 take place exclusively at the
alkynyl carbon atom regardless of the substituents present
at the alkynyl position (entries 4-6).
X-ray structural analyses of the 1-methylthiopropargy-
lammonium salts (Figure 1) confirm their structures and show
The reaction of the salts 2 with lithium reagents was also
probed (Table 2).
Table 2. Reaction of 1-Methylthiopropargylammonium Salts 2
with Lithium Reagentsa
Figure 1. Molecular structure of 2g. Selected intraatomic distances
(Å) and angles (deg): S1-C1, 1.805(3); N1-C1, 1.561(3); C1-
C6, 1.459(3); C6-C7, 1.190(3); S1-C1-N1, 112.7; C1-S1-C2,
105.6(1), C2-S1-C1-C6, -25.3(2).
that the methyl group in the methylthio moiety and trim-
ethylamino group adopt an almost anti conformation with
respect to the C-S single bond. In addition, no apparent
interaction exists between ammonium cation and triflate
anion groups. Finally, the length of the N1-C1 bond in 2g
was found to be 1.56 Å, which is longer than the length of
ordinary N-C single bonds (1.47 Å).
The reactivity of the salts 2 toward carbon nucleophiles
was examined. The results of reactions with Grignard and
organocopper reagents are shown in Table 1. In all cases,
substitution reactions with these carbon nucleophiles proceed
with elimination of trimethylamine to give propargyl sulfides
3 and/or allenyl sulfides 4.6 For example, reaction of 2a with
a The details of the reaction conditions are included in the Supporting
Information. b Isolated yield. c Major and minor products correspond to E
and Z isomers of 5, but it has not determined which are major products.
d n-BuLi (1 equiv) was used.
(4) Methylation of propargylamines with MeI is known to give propar-
gylammonium salts,5 but alkynyl S,N-acetals 1 were inert toward MeI at
room temperature and the reaction in refluxing THF results in the formation
of complex product mixtures.
(5) (a) Nussbaumer, P.; Leitner, I.; Mraz, K.; Stu¨tz, A. J. Med. Chem.
1995, 38, 1831-1836. (b) Turgunov, E.; Sadikov, M. K.; Nurnakhmedova,
T.; Sirlibaev, T. S. Russ. J. Org. Chem. 1999, 35, 1131-1134. (c) Quash,
G.; Fournet, G.; Chantepie, J.; Gore, J.; Ardiet, C.; Ardail, D.; Michal, Y.;
Reichert, U. Biochem. Pharm. 2002, 64, 1279-1292.
At first, we believed that lithium reagents would depro-
tonate 2 and promote Stevens rearrangements.7 However,
reaction of 2a with BuLi gives the enediyne 5a8 (entry 1),
in which the starting salt has formally undergone self-
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Org. Lett., Vol. 9, No. 25, 2007

dimerization accompanied by elimination of the proton and
trimethylamine from the propargylic carbon. This process
can also be performed by using LDA as the base (entry 2).
By choosing appropriate bases, it is possible to carry out
dimerization reactions of a variety of ammonium salts, having
aliphatic, alkenyl, and aromatic groups at the alkynyl carbon
(entries 4-8). The stability of the enediyne products is
pronouncedly impacted by the nature of substituents at the
alkynyl carbon. Those with aromatic groups at this position
(e.g., 5g and 5i) are labile and gradually decompose even at
low temperature.
to give 5. However, the present reaction in the presence of
styrene did not give cyclopropanes. Therefore, the reaction
via carbene intermediates 8 is less plausible.
Finally, an intramolecular counterpart of the dimerization
reaction of the methylthiopropargylammonium salts was
explored (Scheme 3). The S,N-acetal 9 was methylated with
Scheme 3. Reaction of 6 with MeOTf and LDA
Reaction of the Ph3Si-containing salt 2b under these
conditions gives enediyne 5b as a crystalline solid (entry
3). The molecular structure of 5b, successfully determined
by using X-ray crystallographic analysis (Figure 2), contains
MeOTf to generate the ammonium salt 10. Addition of LDA
to a solution of 10 results in formation 11, which to our
knowledge is the first example of a sulfur-containing cyclic
enediyne13 and can be a candidate for photochemical
Bergman cyclization.14
In summary, the studies described above have led to the
first synthesis of novel 1-methylthiopropargylammonium
salts. Preparation of these salts is achieved by selective
MeOTf-promoted electrophilic N-methylation reactions of
alkynyl S,N-acetals. Reactions of the salts with a variety of
carbon nucleophiles take place to form propargyl and allenyl
sulfides. Importantly, lithium amides react in an unprec-
edented manner with these salts to generate enediynes.
Further studies are underway probing the scope and applica-
Figure 2. Molecular structure of 5b. Selected intraatomic distances
(Å) and angles (deg): C1-C1*, 1.353(3); C1-C3, 1.421(2); C3-
C4, 1.205(2); C1-S1, 1.762(2); S1-C1-C1*, 119.9(1); S1-C1-
C3, 118.8(1), C1-S1-C2, 102.9(9), C2-S1-C1-C3, 26.1(2),
Si1-C4-C3-C1, -116; S1-C1-C1*-S1*, 180.8.
(6) For recent examples of alkyl propargylsulfides and alkyl allenyl
sulfides, see: (a) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J.
Am. Chem. Soc. 2002, 124, 15172-15173. (b) Huang, X.; Xiong, Z.-C.
Tetrahedron Lett. 2003, 44, 5913-5915. (c) Tsutsumi, K.; Fujimoto, K.;
Yabukami, T.; Kawase, T.; Morimoto, T.; Kakiuchi, K. Eur. J. Org.
Chem. 2004, 504-510. (d) Shavrin, K. N.; Gvozdev, V. D.; Pinus, I. Y.;
Dotsenko, I. P.; Nefedov, O. M. Russ. Chem. Bull. Int. Ed. 2004, 53, 2546-
2553.
two silylethynyl groups oriented in the same plane and two
methylthio groups with a trans disposition.
In this dimerization reaction, deprotonation from 2 may
initially take place to generate zwitterionic intermediates 6
(Scheme 2). Then, 6 reacts with another molecule of 2,
(7) (a) Babakhanyan, A. V.; Manukyan, M. O.; Baltayan, A. O.;
Kocharyan, S. T. Russ. J. Gen. Chem. 2005, 75, 1648-1650.
(8) Fuller, L. S.; Iddon, B.; Smith, K. A. J. Chem. Soc., Perkin Trans.
1 1999, 1273-1278.
Scheme 2. Possible Reaction Pathway to 5
(9) Additionally, carbon-centered radicals stabilized by alkynyl, thio and
amino groups may be generated from 6 and undergo coupling reaction to
give 5.10 For the reaction of cyclic oxonium ylides, the formation of
homodimers is reported, and the radical coupling process has been
proposed.11
(10) Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62, 1043-
1062.
(11) Eberlein, T. H.; West, F. G.; Tester, R. W. J. Org. Chem. 1992, 57,
3479-3482.
(12) Shavrin, K. N.; Gvozdev, V. D.; Pinus, I. Y.; Dotsenko, J. P.;
Nefedov, O. M. Russ. Chem. Bull. 2004, 53, 2546-2553.
(13) For examples of oxygen-containing 1,2-bis(ethynyl)cycloheptenes,
see: (a) Anthony, J.; Knobler, C. B.; Diederich, F. Angew. Chem., Int. Ed.
Engl. 1993, 32, 406-409. (b) Anthony, J.; Boldi, A. M.; Rubin, Y.; Hobi,
M.; Gramlich, V.; Knobler, C. B.; Seiler, P.; Diederich, F. HelV. Chim.
Acta 1995, 78, 13-45. (c) Casey, C. P.; Dzxwiniel, T. L.; Kraft, S.; Guzei,
I. A. Organometallics 2003, 22, 3915-3920. (d) Casey, C. P.; Dzwiniel,
T. L. Organometallics 2003, 22, 5285-5290.
followed by the elimination of trimethylammonium, to give
5.9 Alternatively, the carbene intermediates 8, which have
been known to be trapped with styrene to give cyclopro-
panes,12 are generated from 6 and may undergo dimerization
(14) Fouad, F. S.; Wright, J. M.; Plourde, G., II; Purohit, A. D.; Wyatt,
J. K.; El-Shafey, A.; Hynd, G.; Crasto, C. F.; Lin, Y.; Jones, G. B. J. Org.
Chem. 2005, 70, 9789-9797.
Org. Lett., Vol. 9, No. 25, 2007
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tions of reactions of heteroatom-containing cationic species
and cyclic enediynes.15
‘‘Advanced Molecular Transformations of Carbon Re-
sources’’) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Area (No. 19020020,
Supporting Information Available: Experimental proce-
dures and characterization of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) For reviews of cyclic enediynes, see: (a) Galm, U.; Hager, M. H.;
Lanen, S. G. V.; Ju, J.; Thorson, J. S.; Shen, B. Chem. ReV. 2005, 105,
739-758. (b) Maretina, I. A.; Trofimov, B. A. Russ. Chem. ReV. 2006, 75,
825-845.
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