Regioselective trapping of terminal di-, tri-, and tetraynes with benzyl azide

Article abstract of DOI:10.1021/ol062522a

(Chemical Equation Presented) The reaction of benzyl azide with terminal di-, tri-, and tetraynes appended with a range of functional groups has been explored. Standard reaction conditions for BnN₃ catalyzed by CuSO₄·5H₂O

Full text of DOI:10.1021/ol062522a

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6035-6038
Regioselective Trapping of Terminal Di-,
Tri-, and Tetraynes with Benzyl Azide
Thanh Luu, Robert McDonald, and Rik R. Tykwinski*
Department of Chemistry, UniVersity of Alberta, Edmonton AB T6G 2G2, Canada
rik.tykwinski@ualberta.ca
Received October 12, 2006
ABSTRACT
The reaction of benzyl azide with terminal di-, tri-, and tetraynes appended with a range of functional groups has been explored. Standard
reaction conditions for BnN3 catalyzed by CuSO4 5H2O gave alkynyl, butadiynyl, and hexatriynyl triazoles in moderate to good yields. The
‚
reaction proceeds regioselectively as determined by the X-ray crystallographic analysis of three derivatives (1c, 1d, and 3c), and no evidence
of multiple azide addition to the polyyne framework is observed.
A small but interesting subset of naturally occurring organic
molecules contains a conjugated polyyne skeleton composed
of a di-, tri-, tetra-, or pentayne structure.1 Many of these
compounds have been isolated in quantities sufficient to
probe their biological activities, and these studies have shown
that polyynes display an array of interesting properties,
including antibacterial, antimicrobial, antifungal, antitumor,
and pesticidal activities. As a result of their unsaturated
framework, polyynes are typically heat and light sensitive
when neat or in concentrated solution, a fact that can hamper
both isolation and characterization.2 This is particularly true
for polyynes that lack functionality at one terminus (terminal
polyynes). Even so, a surprising number of terminal di- and
triynes, and even a tetra- and pentayne, have been identified
from natural sources, such as the C9 triynes isolated from
the Basidiomycete Coprinus quadrifidus,3 the tetrayne cary-
oynencin from plant pathogen Pseudomonas caryophylli,4
and a pentayne isolated from several Peruvian plants of the
species Leuceri (Figure 1).5
We became intrigued by the possibility that additional
terminal polyynes might occur naturally, but their kinetic
instability could preclude identification under normal isola-
tion procedures. One potential solution to this problem would
be to trap the terminal polyyne in solution as a stable
substrate that could then be more easily characterized. The
recent development of procedures for triazole formation
through the reaction of terminal alkynes with azides under
Cu(I) catalysis and mild conditions seemed ideal for such
an application.6 Several questions, however, presented them-
selves with respect to the outcome of these reactions,
including: (a) Would conditions be sufficiently mild to trap
di-, tri-, and tetraynes with an azide for triazole formation?7
(b) Would the regiochemistry remain consistent with that
(1) (a) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed.
2006, 45, 1034-1057. (b) Bohlmann, F.; Burkhardt, H.; Zdero, C. Naturally
Occurring Acetylenes; Academic Press: New York, 1973. (c) Chemistry
Biology of Naturally Occurring Acetylenes and Related Compounds
(NOARC); Lam, J., Breteler, H., Arnason, T., Hansen, L., Eds.; Elsevier:
New York, 1988. (d) Jones, E. R.; Thaller, V. The Chemistry of the Carbon-
Carbon Triple Bond; Patai, S., Ed.; John Wiley & Sons: New York, 1978;
Vol. Part 2, Chapter 14.
(3) Jones, E. R. H.; Stephenson, J. S. J. Chem. Soc. 1959, 2197-2203.
(4) Kusumi, T.; Ohtani, I.; Nishiyama, K.; Kakisawa, H. Tetrahedron
Lett. 1987, 28, 3981-3984.
(5) Bittner, M.; Jakupovic, J.; Bohlmann, F.; Silva, M. Phytochemistry
1989, 28, 271-273.
(2) Some terminal diynes are, however, surprisingly stable. For examples,
see: West, K.; Wang, C.; Batsanov, A. S.; Bryce, M. R. J. Org. Chem.
2006, 71, 8541-8544.
(6) For a recent review, see: Bock, V. D.; Hiemstra, H.; van Maarseveen,
J. H. Eur. J. Org. Chem. 2006, 51-68.
10.1021/ol062522a CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/29/2006

Table 1. Synthesis of Triazoles 1a-i from Diynes 2a-i
Figure 1. Examples of naturally occurring terminal polyynes.
reported for the reaction of azides with terminal alkynes?8,9
(c) Would multiple additions occur due to the more activated
nature of the di-, tri-, or tetrayne substrates?10 We report
herein our preliminary investigations into the trapping of di-,
tri-, and tetraynes with benzyl azide under mild conditions,
which provide initial answers to the questions above.
Terminal diynes were tested first toward formation of
ethynyl triazoles 1a-i (Table 1). Silylated diynes 2a-i were
available via known procedures, and the trimethyl- or
triisopropylsilyl protecting group could be readily removed
through the reaction with methanolic K2CO3 or tetrabuty-
lammonium fluoride (TBAF) in THF, respectively. Once
desilylation was complete, the reaction was subjected to an
aqueous workup, and ca. 2 mL of DMF was added to the
organic phase. The solution was then concentrated to ca. 1-2
a Isolated yield based on benzyl azide. b The t-BuMe2Si group is not
affected.
(7) To our knowledge, the reaction of terminal tri- or tetraynes with azides
under Cu(I) catalysis has not been explored, whereas one example exists
for the reaction with a terminal diyne. See: Reck, F.; Zhou, F.; Girardot,
M.; Kern, G.; Eyermann, C. J.; Hales, N. J.; Ramsay, R. R.; Gravestock,
M. B. J. Med. Chem. 2005, 48, 499-506. For a recent report that may
involve the reaction of an internal diyne with azides under similar conditions
to give ethynyl triazoles, see: Gerard, B.; Ryan, J.; Beeler, A. B.; Porco,
J. A., Jr. Tetrahedron 2006, 62, 6405-6411.
mL, taking care not to let the sample go to dryness, which
typically resulted in partial or complete decomposition of
the terminal diyne product. The resulting solution was then
diluted with DMF (10 mL) and water (2 mL), and the
reaction with benzyl azide in the presence of CuSO4‚5H2O
and ascorbic acid produced the desired triazoles 1a-i. The
ethynyl triazoles could be purified by either column chro-
matography or in the case of less soluble products 1c, 1d,
and 1f recrystallization from hexanes.11
The reaction of benzyl azide with diynes provides reason-
able to good yields of the 1,4-triazole adducts, regardless of
the terminal substituent. The last two examples in Table 1
represent reactions with known diyne natural products. The
terminal diyne derived from 2h has been isolated from the
crown daisy (Chrysanthemum coronarium) by Bohlmann and
co-workers,12 whereas (S)-hepta-4,6-diyn-3-ol (from desilyl-
ation of 2i) is a natural product isolated from Gymnopilus
spectabilis by Jones and co-workers.13 In no case was any
evidence of a multiple addition product found, which would
result from reaction of the resulting ethynyl triazole with a
second equivalent of benzyl azide.
(8) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(9) (a) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Folkin, V. V.; Sharpless,
K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588-9589. (b) Aucagne,
V.; Leigh, D. A. Org. Lett. 2006, 8, 4505-4507. (c) Pirali, T.; Tron, G. C.;
Zhu, J. Org. Lett. 2006, 8, 4145-4148. (d) Lee, J. W.; Kim, B.-K. Bull.
Korean Chem. Soc. 2005, 26, 658-660.
(10) The thermal reaction of terminal diynes with benzyl azide affords
some bisadduct. See: Tikhonova, L. G.; Serebryakova, E. S.; Proidakov,
A. G.; Sokolova, I. E.; Vereshchagin, L. I. J. Org. Chem. USSR 1981, 17,
645-648.
(11) General procedure for the reaction of di-, tri-, and tetraynes
with benzyl azide. A mixture of the appropriate trimethylsilyl- or
triisopropylsilyl-protected polyyne and K2CO3 (0.05 g) or TBAF (2.0 equiv)
in wet THF/MeOH (1:1 5 mL) or THF (10 mL), respectively, was added
and stirred at room temperature until TLC analysis showed the formation
of the terminal alkyne. Et2O and saturated aqueous NH4Cl were added,
and the organic phase was separated, washed with saturated NH4Cl (2 ×
10 mL) and saturated aqueous NaCl (10 mL), and then dried over MgSO4.
DMF (1-2 mL) was then added, and the solution was concentrated to ca.
1-2 mL via rotary evaporation. To the resulting solution of the terminal
polyyne was added DMF (10 mL), followed by benzyl azide (0.66-1.0
equiv based on the starting silylated polyyne), CuSO4‚5H2O (0.1 g), ascorbic
acid (0.1 g), and H2O (2 mL). This mixture was then stirred at room
temperature until TLC analysis no longer showed the presence of benzyl
azide. Aqueous workup, solvent removal, and purification via column
chromatography (silica gel) or recrystallization from hexanes gave the
desired triazole. For diyne precursors, ca. 0.8-0.9 equiv of BnN3 was used,
whereas for triynes, slightly less was used (ca. 0.7-0.8 equiv) due to
increasing material losses observed during the desilylation process. See
Supporting Information for details.
With the successful formation of triazoles from diynes
established, the trapping of terminal triynes was explored.
Overall, the general procedure used for the reaction of 2a-i
(12) Bohlmann, F.; Arnt, C.; Bornowski, H.; Kleine, K.-M.; Herbst, P.
Chem. Ber. 1964, 97, 1179-1192.
(13) Hearn, M. T. W.; Jones, E. R. H.; Pellatt, M. G.; Thaller, V.; Turner,
J. L. J. Chem. Soc., Perkin Trans. 1 1973, 2785-2788.
6036
Org. Lett., Vol. 8, No. 26, 2006

Table 2. Synthesis of Triazoles from Triynes 4a-f
a Isolated yield based on benzyl azide. b The t-BuMe2Si group was also
removed.
Figure 2. ORTEP drawings (20% probability level) and selected
bond lengths (Å) and angles (deg) for (a) compound 1c, C1-C4
1.4301(18), C4-C5 1.1948(18), C5-C21 1.4378(18); C1-C4-
C5 174.45(14), C4-C5-C21 176.95(14); (b) compound 1d, C1-
C4 1.4284(19), C4-C5 1.200(2), C5-C21 1.4395(19), C1-C4-
C5 179.25(17), C4-C5-C21 177.01(16); (c) compound 3c, C1-
C4 1.426(2), C4-C5 1.196(2), C5-C6 1.372(2), C6-C7 1.200(2),
C7-C21 1.435(2), C1-C4-C5 176.85(18), C4-C5-C6 178.12-
(18), C5-C6-C7 177.64(19), C6-C7-C21 178.33(18).
was equally effective with triynes 4a-f (Table 2), although
care must be taken to ensure that the solution containing the
terminal triyne after desilylation is neither heated nor concen-
trated to less than ca. 1-2 mL.14 The formation of butadiynyl
triazoles 3a-f showed a reasonable level of functional group
tolerance for the precursor polyyne, which included alkyl
(3a,b) and aryl (3c-f) moieties. The triyne alcohol resulting
from exhaustive desilylation of 4b has been predicted to be
a product of hydrolysis of the allenediyne fungal natural prod-
uct marasin, from Aleurodiscus roseus,15 and this compound
was successfully trapped with BnN3 to give triazole 3b.
The butadiynyl triazoles 3b-f were isolated as stable
solids (3a was oil) by column chromatography or crystal-
lization from hexanes. Also, no evidence of multiple addition
of benzyl azide to the diyne core of the products 3a-f was
observed.
The trapping of highly unstable terminal tetraynes was then
explored toward producing triynyl triazoles 5a,b (Scheme
1). Desilylation of 6a,b with methanolic K2CO3 in THF
followed by trapping with BnN3 under the conditions
(14) Caution! Phenylhexatriyne has been reported to explode upon at-
tempted isolation. See: Armitage, J. B.; Entwistle, N.; Jones, E. R. H.;
Whiting, M. C. J. Chem. Soc. 1954, 147-154. Although we have never
had any problems with explosive decomposition of terminal di-, tri-, or tet-
raynes under the reaction conditions described, care should nonetheless be
taken.
(15) Cambie, R. C.; Hirschberg, A.; Jones, E. R. H.; Lowe, G. J. Chem.
Soc. 1963, 4120-4130.
(16) Bettison, R. M.; Hitchcock, P. B.; Walton, D. R. M. J. Organomet.
Chem. 1988, 341, 247-254.
Scheme 1
(17) Crystals suitable for X-ray crystallography were obtained by vapor
diffusion of hexanes into a solution of 1c, 1d, or 3c in CH2Cl2 at room
temperature. Crystal data for 1c: C17H13N3; M ) 259.30; monoclinic space
group P21/n (an alternate setting of P21/c [No. 14]); Fc ) 1.262 g cm-3; a
) 5.7277(8), b ) 14.2042(18), c ) 16.811(2) Å; â ) 93.6141(18)°; V )
1365.0(3) Å3; Z ) 4; µ ) 0.077 mm-1. Final R(F) ) 0.0409 (2030
observations [Fo g 2σ(Fo )]); wR2(F2) ) 0.1147 for 181 variables and
2
2
2
2
2800 data with Fo g -3σ(Fo ); CCDC 623595. Crystal data for 1d:
C18H15N3O; M ) 289.33; monoclinic space group P21 (No. 4); Fc ) 1.296
g cm-3; a ) 9.1938(9), b ) 5.6198(6), c ) 14.7114(14) Å; â ) 102.6687
(14)°; V ) 741.59(13) Å3; Z ) 2; µ ) 0.083 mm-1. Final R(F) ) 0.0303
2
2
(2779 observations [Fo g 2σ(Fo )]); wR2(F2) ) 0.0792 for 199 variables
2
2
and 3025 data with Fo g -3σ(Fo ); CCDC 623596. Crystal data for 3c:
C19H13N3, M ) 283.32; triclinic space group P1h (No. 2); Fc ) 1.260 g
cm-3; a ) 6.3632(8), b ) 7.9519(9), c ) 15.1874(18) Å; R ) 102.3564-
(18)°, â ) 95.3363(18)°, γ ) 91.0645(18)°; V ) 746.84(15) Å3; Z ) 2; µ
2
) 0.076 mm-1. Final R(F) ) 0.0436 (2130 observations [Fo2 g 2σ(Fo )]);
2
2
wR2(F2) ) 0.1274 for 199 variables and 3013 data with Fo g -3σ(Fo );
CCDC 623597. X-ray data have been deposited at the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:
(+44)1223-336-033.
developed for di- and triynes resulted in reasonable yield of
the triazoles 5a,b. Great care must be taken when handling
the terminal tetraynes to ensure that they remain in solution
Org. Lett., Vol. 8, No. 26, 2006
6037

to prevent decomposition of the substrate prior to reaction
with BnN3. In an attempt to circumvent the isolation/
concentration step following desilylation, a one-pot reaction
with 6b was explored in which desilylation was followed
directly by in situ reaction with BnN3. Although successful,
the yield was slightly lower (21%).
part unremarkable. Interesting, however, is the fact that in
each case there is a significant dihedral angle between a plane
generated by the triazole ring and that of the terminal phenyl
or anisyl groups of 1c, 1d, and 3c (1c, 39.30(4)°; 1d, 20.43-
(8)°; and 3c, 62.92(5)°). This fact will significantly disrupt
electronic communication along the π-conjugated framework
of these molecules in the solid state.
In conclusion, we have demonstrated the trapping of
terminal di-, tri-, and tetraynes with benzyl azide under Cu
catalysis to give 4-ethynyl, 4-butadiynyl, and 4-hexatriynyl
triazoles in moderate to good yields. Reaction occurs
exclusively at the terminal alkyne unit, and no evidence of
multiple addition to the polyyne framework has been
observed. X-ray crystallography has been used to confirm
that only one regioisomeric product has been formed.
Reaction of azides with terminal alkynes under thermal
conditions typically affords a mixture of 1,4- and 1,5-triazole
products, whereas reactions with alkynes under Cu catalysis
give selectively 1,4-triazoles.8,9 Under thermal conditions,
terminal diynes also give a mixture of products,10 whereas
the reaction of bis(trimethylsilyl)butadiyne and -hexatriyne
with azides is regioselective.16 The regiochemistry for triazole
1
products 1, 3, and 5 could be inferred from their H NMR
spectra, which showed resonances for the triazole ring proton
in the expected range of δ 7.47-7.65.10 The only exception
to this trend is the ynone-substituted 1h, where this signal
is shifted downfield to δ 7.81, presumably due to conjugation
with the ketone.
In addition to 1H NMR spectroscopic data, X-ray crystal-
lographic analysis was used to confirm the constitution of
the 4-ethynyl and 4-butadiynyl triazoles 1c, 1d, and 3c
formed under Cu catalysis (Figure 2).17,18 The bond angles
and bond lengths for the three structures are for the most
Acknowledgment. This work has been supported by the
University of Alberta and the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) through the
Discovery grant program. T.L. thanks the University of
Alberta for a Dissertation Fellowship and Edward Ha for
help with some of the trapping experiments.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data for new compounds, and CIF
files. This material is available free of charge via the Internet
at http://pubs.acs.org.
(18) Only three structures of ethynyltriazole derivatives were found in
the CCDC (GIRMUP, GIRNAW, TUGVEW), and none were derived from
terminal polyynes. See ref 16 and: Adamson, G. A.; Rees, C. W. J. Chem.
Soc., Perkin Trans. 1 1996, 1535-1543.
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Org. Lett., Vol. 8, No. 26, 2006