Copper-catalyzed 1,2-double amination of 1-halo-1-alkynes. Concise synthesis of protected tetrahydropyrazines and related heterocyclic compounds

Article abstract of DOI:10.1021/ja078163b

Reaction of N,N′-di(p-toluenesulfonyl)-1,2-diamine, 1-bromo-1-alkyne, K₃PO₄, and a catalytic amount of CuI in hot DMF afforded N,N′-di(p-toluenesulfonyl)-1,2,3,4-tetrahydropyrazines in good yields. The reaction most likely involves (i) monoalkynylation of the diamine derivative with 1-bromo-1-alkyne, and (ii) 6-endo-dig ring closure between the acetylenic bond and another sulfonylamine moiety of the diamine. When the starting 1,2-diamine derivative was replaced with N,N′-di(p-toluenesulfonyl)-1,3-diamine or N-(p-toluenesulfonyl)-2-amino-1-ethanol, the corresponding seven-membered diazacycle or six-membered N,O-heterocycle was produced. In addition, 1,1-dibromo-1-alkene could be used in place of 1-bromo-1-alkyne. Copyright

Full text of DOI:10.1021/ja078163b

Published on Web 01/17/2008
Copper-Catalyzed 1,2-Double Amination of 1-Halo-1-alkynes. Concise
Synthesis of Protected Tetrahydropyrazines and Related Heterocyclic
Compounds
Yasuhiro Fukudome, Hiroyuki Naito, Takeshi Hata, and Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of
Technology, 4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501 Japan
Received October 25, 2007; E-mail: hurabe@bio.titech.ac.jp
Scheme 1. Proposed Reaction Course
Unsaturated heterocyclic compounds are useful synthetic inter-
mediates as well as important structural units found in natural and
artificial products.1 Their synthesis requires proper alignment of
heteroatoms as well as unsaturation at a defined position in the
ring system. This is often a critical issue, especially when the
heterocycle has multiple heteroatoms.1 Here we report a concise
preparation of 1,4-diaza(or partially oxa)-2-cycloalkenes based on
a new copper-catalyzed double amination of haloacetylenes, as
formulated in eq 1 (X ) N; Y ) N or O).2,3
While investigating copper-catalyzed coupling of sulfonamides
and haloacetylenes,4 we attempted N,N′-dialkynylation of diamine
derivative 3 (see eq 2, Ts ) p-MeC6H4SO2-). However, we were
unable to obtain more than a trace amount of the expected
dialkynylated product, and the actual isolated product was a 1,2,3,4-
tetrahydropyrazine derivative 4. Equation 2 shows the representative
reaction conditions for the preparation of 4 and 5 from aliphatic
and aromatic acetylenes 1 and 2, respectively. The structure of 5
was confirmed by comparison with an authentic sample prepared
by an alternative method.5 As unprotected 1,2,3,4-tetrahydropyra-
zines, which are enamines doubly activated by two nitrogen atoms,
are unstable compounds, this simple one-step method is suitable
for the direct preparation of their protected surrogates.6
dig ring closure to give pyrrolidine derivative 12 under the same
conditions as eq 2 except for the reaction period.10
This reaction shows reasonable generality for the preparation of
tetrahydropyrazines.5 Both aliphatic and aromatic acetylenes af-
forded the desired products 4, 5, and 20 as shown in eq 2 and entries
1-3 of Table 1, where an ester group remains unattacked. Although
the silyl group in 14 did not survive the reaction conditions, product
21 having a terminal acetylene was obtained (entry 4). Branched
1,2-diamine 15 afforded a mixture of two isomers 22, where the
methyl group shows little influence on product composition, but
the isomers were separable by flash chromatography on silica gel
(entry 5). Sterically more congested cyclic diamine derivative 16
still afforded the bicyclic heterocycle 23 with no decrease in product
yield. It should be emphasized that the synthetic protocol shown
in eq 1 proved to be applicable for the preparation of broader types
of heterocycles. For example, 1,3-propanediamine derivatives 17
and 18 afforded the corresponding seven-membered heterocycles
24 and 25 (entries 7 and 8), where the hydroxy group in 18 did not
need protection. On the contrary, the hydroxy group in N-
tosylethanolamine 19 took part in the reaction to give a six-
membered N,O-heterocycle 26 in a regioselective manner. These
observations show that a heteroatom functional group at a suitable
position could work as the second nucleophile in eq 2.
The proposed reaction course of eq 2 is shown in Scheme 1.
After the first alkynylation of sulfonamide with haloacetylene
proceeded as described previously,4 the second amination of the
acetylenic bond in 6 (Tol ) p-MeC6H4-) proceeded in a 6-endo-
dig manner under copper catalysis to produce 7 (path a), protonation
of which completed the catalytic cycle to afford the observed
product 8. Note that the formation of isomeric tetrahydroimidazole
10 via the cyclization of 5-exo-dig mode (6 f 9, path b) was not
observed.7-9 The sulfonylamino group bearing the acetylene moiety
of 6 should play an important role in effecting the endo-type ring
closure, most likely due to coordination to the copper salt as
depicted in 6, because the control reaction of eq 3, where the carbon
analogue 11 exclusively and much more slowly underwent 5-exo-
A convenient modification of the above transformation is that
dibromoolefins 27-30, readily prepared from the corresponding
aldehydes,11 work equally well in place of bromoacetylenes to
produce tetrahydropyrazines 31-34 in good yields, as shown in
eq 4. The reaction most likely involves in situ formation of
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J. AM. CHEM. SOC. 2008, 130, 1820-1821
10.1021/ja078163b CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Preparation of Unsaturated Heterocycles According to eq
2
In conclusion, we report a simple procedure for the facile
preparation of unsaturated heterocyclic compounds having two
heteroatoms. The scope and limitations of the reaction itself and
the synthetic applications of the products obtained are now under
investigation.
Acknowledgment. The authors are grateful to Kyowa Hakko
Kogyo Co., Ltd. for financial support. This work was also supported
in part by a Grant-in-Aid for Scientific Research on Priority Areas
16073208 from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Supporting Information Available: Experimental procedures and
physical properties of products. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(5) For details, see the Supporting Information.
(6) The use of sulfonamides is essential for this reaction, as (CH2NHMs)2 in
place of 3 afforded the desired product like 4 in 58% yield, but (CH2-
NHR)2 (R ) Ac or Boc) did not give such products. For deprotection of
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Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed.
2006, 45, 3822-3825.
a Isolated yields, which are not necessarily optimized. b The methyl
positions have not been assigned to major and minor isomers, which were
separable by silica gel chromatography in 41% and 27% yields, respectively.
c N,N′-Di(1-octynyl)-N,N′-di(p-toluenesulfonyl)-1,3-propanediamine was
also formed in 13% yield. d This reaction was performed at 130 °C for
21 h.
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Tetrahedron 2006, 62, 3783-3938.
bromoacetylenes via dehydrobromination of dibromoolefins
under the basic reaction conditions prior to the catalytic cycle in
Scheme 1.12
(10) This outcome is consistent with that of the closely related cyclization of
ref 8b. For reviews on hydroamination of alkynes, see: (a) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-3159. (b) Pohlki,
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(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(12) A normal double coupling of 1,1-dibromoolefin with a diamine derivative
was also reported: Yuen, J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006,
8, 653-656. The different substrate structures and reaction media may
account for the change in the type of products.
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