Reactions of terminal polyynes with benzyl azide

Article abstract of DOI:10.1021/jo101870y

Terminal di-, tri-, tetra-, and pentaynes substituted with a variety of functional groups react with benzyl azide in the presence of CuSO ₄·5H₂O and ascorbic acid to give derivatives of 4-ethynyl-, 4-butadiynyl-, 4-hexatriynyl-, and

Full text of DOI:10.1021/jo101870y

pubs.acs.org/joc
Reactions of Terminal Polyynes with Benzyl Azide
Thanh Luu,† Boris J. Medos,† Erin R. Graham,† Danielle M. Vallee,† Robert McDonald,‡
Michael J. Ferguson,‡ and Rik R. Tykwinski*,§
†Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada,
‡X-ray Crystallography Laboratory, Department of Chemistry, University of Alberta, Edmonton,
§
Alberta T6G 2G2, Canada, and Institut fu€r Organische Chemie, Friedrich-Alexander-Universitat,
Erlangen-Nu€rnberg, Henkestrasse 42, D-91054 Erlangen, Germany
€
rik.tykwinski@chemie.uni-erlangen.de
Received September 22, 2010
Terminal di-, tri-, tetra-, and pentaynes substituted with a variety of functional groups react with
benzyl azide in the presence of CuSO4 5H2O and ascorbic acid to give derivatives of 4-ethynyl-,
3
4-butadiynyl-, 4-hexatriynyl-, and 4-octatetraynyl-1,2,3-triazoles in moderate to good yields. These
reactions appear to proceed regioselectively, and functionalization occurs exclusively at the terminal
alkyne moiety. As well, no evidence of multiple azide additions to the polyyne framework is observed.
X-ray crystallographic analysis of nine derivatives is used to document the regioselectivity of the
reaction as well as outline structural characteristics of the 1,2,3-triazole products.
Introduction
natural products, however, it is recognized that terminal poly-
ynes are often unstable in their neat form. In some cases, this
potential reactivity can be selectively harnessed, such as demon-
strated by Fowler and Lauher toward the topochemical
polymerization of terminal diyne derivatives.7 Bryce and
co-workers, on the other hand, have shown that under controlled
Molecules constructed of conjugated triple bonds (i.e.,
polyynes)1 are useful building blocks for advanced materials,2
molecular wires,3 and supramolecular assemblies,4 just to name
a few.5 Polyyne natural products are also an important class of
molecules and have been isolated from a variety of species of
fungi, bacteria, plants, and sponges.6 Whether as materials or
(4) (a) Hisaki, I.; Shigemitsu, H.; Sakamoto, Y.; Hasegawa, Y.; Okajima,
Y.; Nakano, K.; Tohnai, N.; Miyata, M. Angew. Chem., Int. Ed. 2009, 48,
5465–5469. (b) Tahara, K.; Lei, S.; Mamdouh, W.; Yamaguchi, Y.; Ichika-
wa, T.; Uji-i, H.; Sonoda, M.; Hirose, K.; De Schryver, F. C.; De Feyter, S.;
Tobe, Y. J. Am. Chem. Soc. 2008, 130, 6666–6667. (c) Campbell, K.; Kuehl,
C. J.; Ferguson, M. J.; Stang, P. J.; Tykwinski, R. R. J. Am. Chem. Soc. 2002,
124, 7266–7267. (d) Nishinaga, T.; Nodera, N.; Miyata, Y.; Komatsu, K.
J. Org. Chem. 2002, 67, 6091–6096.
(5) (a) Carbon-Rich Compounds: Molecules to Materials; Haley, M. M.,
Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, Germany, 2006. (b) Acet-
ylene Chemistry: Chemistry, Biology, and Material Science; Diederich, F.,
Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(c) Szafert, S.; Gladysz, J. A. Chem. Rev. 2006, 106, PR1–PR33. Szafert, S.;
Gladysz, J. A. Chem. Rev. 2003, 103, 4175–4205.
(1) Chalifoux, W. A.; Tykwinski, R. R. C. R. Chim. 2009, 12, 341–358.
(2) (a) Witulski, B.; Schweikert, T.; Schollmeyer, D.; Nemkovich, N. A.
Chem. Commun. 2010, 46, 2953–2955. (b) Kivala, M.; Diederich, F. Acc.
Chem. Res. 2009, 42, 235–248. (c) Samoc, M.; Dalton, G. T.; Gladysz, J. A.;
Zheng, Q.; Velkov, Y.; Agren, H.; Norman, P.; Humphrey, M. G. Inorg.
Chem. 2008, 47, 9946–9957. (d) Spitler, E. L.; Haley, M. M. Org. Biomol.
Chem. 2008, 6, 1569–1576. (e) Zheng, Q.; Bohling, J. C.; Peters, T. B.; Frisch,
A. C.; Hampel, F.; Gladysz, J. A. Chem. Eur. J. 2006, 12, 6486–6505. (f)
;
Eisler, S.; Slepkov, A. D.; Elliott, E.; Luu, T.; McDonald, R.; Hegmann,
F. A.; Tykwinski, R. R. J. Am. Chem. Soc. 2005, 127, 2666–2676. (g) Slepkov,
A. D.; Hegmann, F. A.; Eisler, S.; Elliott, E.; Tykwinski, R. R. J. Chem. Phys.
2004, 120, 6807–6810.
(3) (a) Ballmann, S.; Hieringer, W.; Secker, D.; Zheng, Q.; Gladysz, J. A.;
€
Gorling, A.; Weber, H. B. ChemPhysChem 2010, 11, 2256–2260. (b) Wang,
C.; Batsanov, A. S.; Bryce, M. R.; Martin, S.; Nichols, R. J.; Higgins, S. J.;
(6) (a) Pan, Y.; Lowary, T. L.; Tykwinski, R. R. Can. J. Chem. 2009, 87,
1565–1582. (b) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed.
2006, 45, 1034–1057. (c) Bohlmann, F.; Burkhardt, H.; Zdero, C. Naturally
Occurring Acetylenes; Academic Press: New York, 1973.
ꢀ
Garcia-Suarez, V. M.; Lambert, C. J. J. Am. Chem. Soc. 2009, 131, 15647–
15654. (c) Long, N. J.; Williams, C. K. Angew. Chem., Int. Ed. 2003, 42, 2586–
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(7) (a) Li, Z.; Fowler, F. W.; Lauher, J. W. J. Am. Chem. Soc. 2009, 131,
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8498 J. Org. Chem. 2010, 75, 8498–8507
Published on Web 11/11/2010
DOI: 10.1021/jo101870y
r
2010 American Chemical Society

Luu et al.
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FIGURE 1. Examples of naturally occurring tri- and tetraynes.
circumstances, quite a number of diynes, triynes, and even a
tetrayne can be isolated as stable solids, and numerous substrates
have been characterized by X-ray crystallography.8 Meanwhile,
terminal di-, tri-, and tetraynes have been obtained from different
natural sources, and some of these compounds have exhibited
interesting biological activity. For example, triynes 1a-c have
been found in the culture medium of Coprinus quadrifidus by
Jones and Stephenson,9 while tetraynes 2a-c (caryoynencins A,
B, and C) have been isolated from the liquid cultures of the plant
pathogen Pseudomonas caryophylli and showed remarkable
antibiotic activity (Figure 1).10 In addition to those natural
products already discovered, it seems quite likely that some
terminal polyynes have not been or cannot be obtained and
fully characterized due to kinetic instability that would cause
them to decompose during the isolation process.11 In view of
this premise, a potential solution to this challenge has been
explored, in which terminal polyynes with many different
pendent functional groups can be trapped in solution as a stable
substrate that can be more easily characterized.
An obvious possibility would be to exploit the potential of a
terminal alkyne to undergo a 1,3-dipolar cycloaddition with an
azide12 in the presence of a Cu(I) or Cu(II) catalyst, as has been
reported independently by Meldal13 and Sharpless.14 This type
of reaction has been widely applied to alkynes of nearly every
flavor, and much of this work has been reviewed.15 Even in light
of the widespread application of this reaction, several questions
remained in terms of its application to terminal polyynes:16,17 (a)
Would the general reaction, as reported, be suitable for trapping
of the more reactive di-, tri-, tetra-, and pentaynes? (b) Would
the regioselectivity of the reaction remain consistent and pro-
duce only 1,4-adducts? (c) Would multiple additions occur from
the reaction of terminal polyynes with benzyl azide? Answers to
these questions and others are provided by this report.18
Results and Discussion
(8) (a) Wang, C.; Batsanov, A. S.; West, K.; Bryce, M. R. Org. Lett. 2008,
10, 3069–3072. (b) West, K.; Wang, C.; Batsanov, A. S.; Bryce, M. R. Org.
Biomol. Chem. 2008, 6, 1934–1937. (c) West, K.; Hayward, L. N.; Batsanov,
A. S.; Bryce, M. R. Eur. J. Org. Chem. 2008, 5093–5098. (d) West, K.; Wang,
C.; Batsanov, A. S.; Bryce, M. R. J. Org. Chem. 2006, 71, 8541–8544.
(9) Jones, E. R. H.; Stephenson, J. S. J. Chem. Soc. 1959, 2197–2203.
(10) For isolation, see: (a) Kusumi, T.; Ohtani, I.; Nishiyama, K.;
Kakisawa, H. Tetrahedron Lett. 1987, 28, 3981–3984. For the synthesis of
2a, see: (b) Yamaguchi, M.; Park, H. J.; Hirama, M.; Torisu, K.; Nakamura,
S.; Minami, T.; Nishihara, H.; Hiraoka, T. Bull. Chem. Soc. Jpn. 1994, 67,
1717–1725.
(11) Luu, T.; Tykwinski, R. R. J. Org. Chem. 2006, 71, 8982–8985.
(12) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; pp 1-176.
(13) (a) Tornøe, C. W.; Meldal, M. Peptides 2001, Proceedings of the
American Peptide Symposium; Lebl, M., Houghten, R. A., Eds.; American
Peptide Society and Kluwer Academic Publishers: San Diego, CA, 2001;
pp 263-264. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057–3064.
Synthesis. Initial efforts targeted formation of 4-ethynyl-
1,2,3-triazole derivatives 3a-r (Table 1) from the terminal
diynes derived from 4a-r. In many cases, the kinetic stability
of the terminal diyne was either insufficient for isolation or
unknown. Thus, a two-step process of desilylation followed
by trapping of the terminal polyyne intermediate with benzyl
azide was employed. The Me3Si- or i-Pr3Si-protecting group
was first removed by subjecting the diyne to either K2CO3/
THF/MeOH or TBAF/THF, respectively, at room tempera-
ture. Following an aqueous workup, DMF (ca. 2 mL) was
added to the resulting organic solution, which was then con-
centrated under vacuum to approximately 2 mL19 and subse-
quently diluted with additional DMF (10 mL). The resulting
diyne was then used for a Cu-catalyzed Huisgen reaction with
benzyl azide (ca. 0.66-1.0 equiv20 based on 4), in the presence
(14) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
of CuSO4 5H2O, ascorbic acid, and water. Reactions were
(15) For selected reviews, see: (a) Hein, J. E.; Fokin, V. V. Chem. Soc.
Rev. 2010, 39, 1302–1315. (b) Amblard, F.; Cho, J. H.; Schinazi, R. F. Chem.
Rev. 2009, 109, 4207–4220. (c) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008,
108, 2952–3015. (d) Meldal, M. Macromol. Rapid Commun. 2008, 29, 1016–
1051. (e) Johnson, J. A.; Finn, M. G.; Koberstein, J. T.; Turro, N. J.
Macromol. Rapid Commun. 2008, 29, 1052–1072. (f) Tron, G. C.; Pirali, T.;
Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res.
Rev. 2008, 28, 278–308. (g) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018–
1025. (h) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249–
1262. (i) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51–68.
3
typically complete within several hours, and the products could
be isolated by either column chromatography or recrystalliza-
tion. This general protocol gave 1,2,3-triazole adducts 3a-r in
46-86% yields (with the exception of 3o).
Several of these reactions deserve specific comment. The
Me3Si-protecting groups of 4a,b were selectively removed with
K2CO3 in THF/MeOH, and the reaction of the resulting
(16) Parts of this work have been communicated, see: Luu, T.; McDonald,
R.; Tykwinski, R. R. Org. Lett. 2006, 8, 6035–6038.
(18) The thermal reaction of azides with di- and triynes has been reported,
see: (a) Domnin, I. N.; Remizova, L. A.; Starova, G. L.; Rominger, F. Russ.
J. Org. Chem. 2009, 45, 1678–1682. (b) Bettison, R. M.; Hitchcock, P. B.;
Walton, D. R. M. J. Organomet. Chem. 1988, 341, 247–254. (c) Tikhonova,
L. G.; Serebryakova, E. S.; Proidakov, A. G.; Sokolov, I. E.; Vereshchagin,
L. I. J. Org. Chem. USSR 1981, 17, 645–648. (d) Sokolyanskaya, L. V.;
Volkov, A. N.; Trofimov, B. A. Khim. Geterotsikl. Soedin. 1979, 849-849;
Chem. Heterocycl. Compd. 1979, 15, 689-689. (e) Dornow, A.; Rombush, R.
Chem. Ber. 1958, 91, 1841–1851.
(19) It is important to note that during the concentration process, heat
should not be applied and the solution should not be reduced to dryness since
this could result in decomposition of the terminal alkyne.
(20) The amount of benzyl azide was roughly based on the apparent
success of the desilylation reaction, and varied from 0.66 to 1.0 equiv.
Isolated yields are reported based on the amount of benzyl azide used; see
the Experimental Section for details.
(17) At the start of our work in this area (see ref 16), the reaction of
terminal tri-, tetra-, or pentaynes with organic azides under Cu(I)/Cu(I)
catalysis had not been explored, whereas one example existed 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. Since this time, several reports have appeared, see:
(a) Aizpurua, J. M.; Azcune, I.; Fratila, R. M.; Balentova, E.; Sagartzazu-
Aizpurua, M.; Miranda, J. I. Org. Lett. 2010, 12, 1584–1587. (b) Fiandanese,
V.; Bottalico, D.; Marchese, G.; Punzi, A.; Quarta, M. R.; Fittipaldi, M.
Synthesis (Stuttgart) 2009, 3853–3859. (c) Gauthier, S.; Weisbach, N.;
Bhuvanesh, N.; Gladysz, J. A. Organometallics 2009, 28, 5597–5599. (d)
Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.; Capuzzolo, F.
Tetrahedron 2009, 65, 10573–10580. (e) Reference 8c. (f) Monkowius, U.;
€
Ritter, S.; Konig, B.; Zabel, M.; Yersin, H. Eur. J. Inorg. Chem. 2007, 4597–
4606.
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TABLE 1. Synthesis of Triazoles 3a-r from Diynes 4a-r
t-BuMe2Si- and Me3Si-protecting groups, ultimately generat-
ing triazole 3m with a benzyl alcohol moiety. Trapping the
terminal diyne derived from dibromoolefinic diyne 4n with a
benzyl azide gave 3n in 65% yield with no evidence of reaction
between the dibromoolefin moiety and the Cu-catalyst (i.e., the
Castro-Stephens reaction21). The formation of ynone 3o,
however, was not particularly successful, seemingly due to
rapid decomposition of the terminal alkyne during desilylation
(observed as the formation of a black precipitate). An attempt was
made to effect formation of 3o through a one-pot desilylation/
trapping reaction with 4o via the addition of K2CO3 and
MeOH to a DMF solution of 4o containing benzyl azide,
CuSO4 5H2O, ascorbic acid, and water. While this procedure
3
did allow for isolation of the desired product, the yield re-
mained abysmal (5%). Finally, the estrone 3-methyl ether end-
capped diyne 4r was also successfully deprotected with TBAF
and the resulting terminal diyne was reacted under the general
conditions to give compound 3r in good yield.
This protocol was also employed to trap two diynes that
have been previously isolated and identified from natural
sources. The terminal ynone derived from desilylation of 4p
has been isolated from the crown daisy (Chrysanthemum
coronarium) by Bohlmann and co-workers,22 and could be
trapped with benzyl azide under the described conditions to
produce 3p in 68% yield. The diyne derived from desilylation
of 4q has been obtained from the Laughing Jim mushroom
(Gymnopilus spectabilis) by Jones and co-workers,23 and the
reaction with benzyl azide produced triazole 3q in 46% yield.
The i-Pr3Si-protected diyne acid 5 was reacted with TBAF in
THF, and the resulting product was subjected to benzyl azide
under typical reaction conditions toward the formation of
compound 6 (eq 1). This sequence did not give the expected
triazole, but rather the bis-triazole 7 in 82% yield.24,25 While the
mechanism of this reaction has not been explored, presumably
decarboxylation occurred under the reaction conditions to
liberate the second terminal alkyne moiety, which then under-
went a reaction with benzyl azide. The solubility of compound 7
was quite low under conditions of the reaction, and it thus
precipitated out of solution and was easily isolated by filtration;
no trace of the expected alkynyl triazole 6 was observed.
aThe t-BuMe2Si group is not removed during desilylation of the
alkyne. bStarting material is 4l, product is 3m. cThe t-BuMe2Si group is
removed during desilylation of the alkyne. dDesilylation in situ, see text.
Finally, this methodology was extended to the formation
of bis-triazole 8 from precursor 9,26 which proceeded in good
yield. Purification of the product was problematic due to its
terminal diyne with benzyl azide afforded 3a,b in good yield,
with a t-BuMe2Si- or i-Pr3Si-group in place for further elabora-
tion. Aryl and vinyl terminated diynes 4c-n gave triazoles
3c-n with no particular trend observed in yield with respect to
the electronic nature of the substituents. For diyne 4l, desilyla-
tion with K2CO3 in THF/MeOH and trapping with benzyl
azide produced 3l in 71% yield with t-BuMe2Si-protected
benzyl alcohol still intact. Conversely, subjecting 4l to TBAF
in the alkyne deprotection step resulted in removal of both the
(21) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315.
(22) Bohlmann, F.; Arndt, C.; Bornowski, H.; Kleine, K.-M.; Herbst, P.
Chem. Ber. 1964, 97, 1179–1192. Bohlmann, F.; Herbst., P.; Dohrmann, I.
Chem. Ber. 1963, 96, 226–236.
(23) 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.
(24) Compound7has been previously prepared by another method, see ref 17f.
(25) The successful thermal reaction of azides with propriolic acid has
been reported: Alonso, G.; Garcia-Lopez, M. T.; Garcia-Munoz, G.;
Madronero, R.; Rico, M. J. Heterocycl. Chem. 1970, 7, 1269–1272.
(26) Shi Shun, A. L. K.; Chernick, E. T.; Eisler, S.; Tykwinski, R. R.
J. Org. Chem. 2003, 68, 1339–1347.
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product marasin, isolated in 1959 by Bendz from Marasmius
ramealis28 and more recently by Jones and co-workers from
Aleurodiscus roseus29 and Cortinellus berkeleyanus.30 Trap-
ping of the terminal triyne with benzyl azide gave triazole 10c
in a reasonable yield of 47%.
The prospect of forming triazoles via the trapping of terminal
tetraynes was then explored toward producing 12a and 12b
(eq 3). Great care must be taken during the desilylation of both
13a and 13b to guarantee that they remain solvated at all times
in order to prevent decomposition of these highly unstable
terminal alkyne products prior to reaction with benzyl azide.
Following desilylation, conversion of the resulting alkyne to the
desired triazole proceeded reasonably well under normal con-
ditions to give 12a and 12b in 40% and 25% yield, respectively.
An attempt to circumvent the isolation/concentration step
following desilylation was also made. The one-pot reac-
tion was attempted with 13a toward the in situ formation
and trapping of the terminal tetrayne. As described above
for the formationof3o, to the precursor 13a were added DMF,
TABLE 2. Synthesis of Butadiynyl Triazoles 10a-h from Triynes
11a-h
K2CO3, MeOH, CuSO4 5H2O, ascorbic acid, and benzyl
3
azide, and the reaction was stirred at room temperature.
Standard aqueous workup and column chromatography gave
12b in a similar yield (21%) to the two-step route.
The formation of terminal pentaynes can be plagued by their
instability, but formation and trapping of one example (as well as
an analogous hexayne) with benzyl azide has been recently
reported by Gladysz and co-workers.17c In this case, the penta-
and hexaynes were end-capped with a platinum acetylide moiety.
Using the conditions described above, one purely organic penta-
yne31 has been successfully trapped, giving the triazole product
14 in 24% yield over two steps from pentayne 15 (eq 4).
aThe t-BuMe2Si group also removed during desilylation of alkyne.
minimal solubility in common solvents, but the pure yellow
product could be isolated by recrystallization and character-
ized by 1H NMR spectroscopy and mass spectrometry.
With a successful protocol in hand, attention was then turned
to the trapping of terminal triynes with benzyl azide. In general,
the same procedure used for the formation of 3a-r was followed
for 10a-h (Table 2). It should be noted here that extreme care
must be taken to ensure that, following removal of the Me3Si- or
i-Pr3Si-group of 11a-h, the solution containing the terminal
triyne was neither heated nor concentrated to dryness due to
the known and potentially dangerous instability of these com-
pounds.27 These reactions produced alkyl-, aryl-, and silyl-
terminated butadiynyl-1,2,3-triazole derivatives 10a-h in yields
ranging from 47% to 82% starting with triynes 11a-h (Table 2).
Isolated yields were, more or less, independent of both the nature
of the terminal group of the triyne precursor and whether an
i-Pr3Si- or Me3Si-group was removed prior to trapping.
Noteworthy is the terminal triynol resulting from the
exhaustive desilylation of 11c, which has been proposed as
a product from the hydrolysis of the antibiotic fungal natural
Purification and Characterization. In general, the triazole
products described above could be obtained through a
(27) Caution: It should be noted that Armitage has reported that the
terminal triyne derived from 11d “exploded at 0 °C in the absence of air”, see:
Armitage, J. B.; Entwistle, N.; Jones, E. R. H.; Whiting, M. C. J. Chem. Soc.
1954, 147–154. One should, therefore, not attempt to isolate this terminal
triyne neat. Although we have not experienced any problems, the terminal
polyynes reported herein should all be treated as potentially explosive and
handled with care.
(28) Bendz, G. Ark. Kemi 1959, 14, 305–321.
(29) Cambie, R. C.; Hirschberg, A.; Jones, E. R. H.; Lowe, G. J. Chem.
Soc. 1963, 4120–4130.
(30) Bew, R. E.; Chapman, J. R.; Jones, E. R. H.; Lowe, B. E.; Lowe, G.
J. Chem. Soc. C 1966, 129–135.
(31) Chalifoux, W. A.; Tykwinski, R. R. Nat. Chem. 2010, 2, 967-971.
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FIGURE 2. ORTEP drawings (20% probability level) for (a) 3c, (b) 3e, (c) 3g, (d) 3j, (e) 3l, (f) 3p, (g) 10d, (h) 10f, and (i) 12b.
simple process of aqueous workup and concentration of the
resulting solution to give a solid (except for compounds 3a,o,
10a,h, and 12a which are oils). The solid was then washed
with a minimal amount of hexanes (ca. 10-20 mL) at 0 °C to
remove any remaining DMF as well as soluble byproducts.
The compounds at this point were often sufficiently pure
for spectroscopic characterization. Alternatively, column
chromatography or crystallization was used in cases where
additional purification was required.
EI mass spectral analysis of the 1,2,3-triazole derivatives
shows a common fragmentation pattern. Most derivatives
readily lose the N2 fragment to generate [M - 28]þ, while
the base peak typically arises from the benzyl group to give
tropylium at m/z 91.
products show evidence of multiple azide additions to the
polyyne skeleton, although the occurrence of multiple addi-
tions cannot be rigorously excluded given that these produc-
1
tions would likely show only limited solubility. H NMR
spectroscopy could also, in principle, be used to distinguish
between regioisomers resulting from 1,4- or 1,5-addition,
based on the studies of Tikhonova and co-workers, who
report that the proton of the triazole ring for 1,4-isomers
typically resonates between 8.06 and 7.42 ppm versus those
of the 1,5-isomers that are found slightly upfield at 7.59-
7.42 ppm.18c Unfortunately, there is no clear-cut point from
this trend to rule out 1,5-addition. The triazole protons of
ethynyl compounds 3a-r have chemical shifts ranging from
7.81-7.41 ppm, with the most downfield shifts observed for
compounds 3o and 3p (7.77 and 7.81 ppm, respectively)
resulting from the electronic withdrawing carbonyl group.
Symmetrical disubstituted triazole 7 shows the proton at
7.98 ppm. This may result from the effect of the adjacent
triazole ring, which is also electron deficient. Thus, the
All products, with the exception of bis(triazoles) 7 and 8,
are sufficiently soluble for NMR spectroscopic analysis.32
1
In no case did the H or 13C NMR spectra of the isolated
(32) See the Supporting Information for spectra of new compounds.
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TABLE 3. Selected Bond Lengths of Compounds 3c,e,g,j,l,p, 10d,f, and 12b
˚
selected bond lengths (A)
compd
C1-C4
C4-C5
C5-C6
C6-C7
C7-C8
C8-C9
C5-C21
C6-C21
C7-C21
C9-C21
3c
3e
3g
3ja
1.4301(18)
1.432(3)
1.1948(18)
1.193(3)
1.200(2)
1.192(2)d
1.192(2)d
1.202(6) f
1.180(6)g
1.194(3)
1.196(2)
1.199(2)
1.203(3)
1.4378(18)
1.419(3)
1.4284(19)
1.409(17)b
1.443(16)c
1.421(6) f
1.418(6)g
1.419(3)
1.426(2)
1.4262(18)
1.425(3)
1.4395(19)
1.435(2)d
1.435(2)d
1.453(6) f
1.442(6)g
3le
3p
1.452(3)
1.372(2)
1.376(2)
1.368(3)
1.476(3)
10d
10f
12b
1.200(2)
1.201(2)
1.205(3)
1.435(2)
1.4347(19)
1.371(3)
1.199(3)
1.430(3)
aTwo equally-abundant orientations (A and B) of the disordered benzyltriazine unit. bOrientation A. cOrientation B. dCommon to both orientations.
eTwo crystallographically independent molecules found in the unit cell, molecules A and B. fMolecule A. gMolecule B.
TABLE 4. Selected Bond Angles of Compounds 3c,e,g,j,l,p, 10d,f, and 12b
selected bond angles (deg)
compd C1-C4-C5 C4-C5-C6 C5-C6-C7 C6-C7-C8 C7-C8-C9 C4-C5-C21 C5-C6-C21 C6-C7-C21 C8-C9-C21
3c
3e
3g
3ja
174.45(14)
176.3(2)
176.95(14)
178.8(2)
179.25(17)
173.9(8)b
173.3(9)c
179.5(6) f
178.7(5)g
177.7(2)
177.01(16)
178.9(3)d
178.9(3)d
175.3(5) f
174.4(5)g
3le
3p
173.9(2)
117.18(16)
10d
10f
12b
176.85(18)
177.69(16)
178.4(2)
178.12(18)
179.06(16)
179.5(3)
177.64(19)
178.27(17)
178.9(3)
178.33(18)
177.14(17)
177.8(3)
177.5(3)
176.2(3)
aTwo equally-abundant orientations (A and B) of the disordered benzyltriazine unit. bOrientation A. cOrientation B. dCommon to both orientations.
eTwo crystallographically independent molecules found in the unit cell, molecules A and B. fMolecule A. gMolecule B.
observed chemical shifts for the triazole proton are more con-
sistent with the expected 1,4-addition, but not definitive. It is
interesting to note that within the homologous series of phenyl-
terminated derivatives, there is essentially no variance in the
chemical shift of the triazole proton at δ7.61 (3c), 7.60(10d), and
7.62 (12b). Likewise, there is little change in the chemical shift of
the benzylic protons within the same series, found at δ 5.55 (3c),
5.52 (10d), and 5.52 (12b). Overall, the resonances observed for
the benzylic protons span from 5.44 (3g) to 5.60 ppm (3d), and
the relative values reflect, more or less, the electronic rich/poor
nature of the polyyne substituent pendent to the triazole.
Structures are shown in Figure 2, while selected bond lengths
and angles are tabulated in Tables 3 and 4, respectively.
These data show that the C1-C4 bond that links the alkyne
chain to the triazole moiety is consistently shorter than that
to the pendent aryl- or keto-group (i.e., C5-C21, C7-C21,
or C9-C21). The only exception to this trend is thienyl
˚
derivative 3e, where C5-C21 at 1.419(3) A is shortened
˚
versus C1-C4 at 1.432(3) A, likely due to the mesomeric
effect from the thienyl to the electron-poor ethynyl triazole
moiety. As is typical for alkynes and polyynes,5c bending of
the CtC C bonds is also observed for several of the triazole
;
X-ray crystallography has been used to confirm the regio-
selectivity of the products isolated from the trapping reac-
tions and to explore the structure of ethynyl-, butadiynyl-,
and hexatriynyl-1,2,3-triazole derivatives.33 Crystals of 3c,
3e, 3g, 3j, 3l, 3p, 10d, 10f, and 12b have been analyzed.34
derivatives examined in this study, including C1-C4-C5 for
3c (174.45(14)°) and 3j (173.3(8)° and 173.9(8)°), as well as
C4-C5-C6 for 3p (173.9(2)°).
Conclusions
It has been successfully demonstrated that the terminal di-,
tri-, tetra-, and pentaynes can be trapped with benzyl azide
using the Huisgen reaction in the presence of CuSO4 and
ascorbic acid. In general, the procedure generates useful yields
(33) For the crystallographic characterization of other ethynyl-1,2,3-
triazole derivatives, see refs 17c 18a 18b, and the following: Adamson,
G. A.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1996, 1535–1543.
(34) The structures of 3c, 3g, and 10d have been communicated, see ref 16.
J. Org. Chem. Vol. 75, No. 24, 2010 8503

Luu et al.
JOCArticle
˚
˚
˚
of 4-ethynyl-, 4-butadiynyl-, 4-hexatriynyl-, and 4-octatetra-
ynyl-substituted 1,2,3-triazole derivatives. This approach has
also been used to trap three natural products or their analogues,
suggesting that it should be useful toward the identification of
naturally occurring terminal polyynes that might not otherwise
be found due to instability. Finally, the reactions described
above appear to be quite selective: only 1,4-adducts are isolated
from these transformations, as demonstrated by X-ray crystal-
lography of nine derivatives, and no evidence of multiple
addition(s) to the polyyne skeleton is observed.
Cc (No. 9); a=45.300(8) A, b=10.1710(17) A, c=13.213(2) A;
β=99.865(5); V=5998.0(17); Z=8; Fcalc=1.169 g cm-3; μ=
0.108 mm-1; λ=0.71073 A; T=-80 °C; 2θmax=50.00°; total
˚
data collected=8809; R1(F)=0.0436 (5665 observations [Fo2 g
2σ(Fo2)]); wR2(F2)=0.0956 for 704 variables and all 8809 unique
data; residual electron density=0.309 and -0.152 e A-3. CCDC
˚
deposition no. 771000.
Crystal data for 3p: C18H13N3O, MW = 287.31; crystal
dimensions 0.38 ꢀ 0.16 ꢀ 0.10 mm3; triclinic space group P1
˚
˚
˚
(No. 2); a=7.8486(8) A, b=8.8827(9) A, c=12.1321(13) A; R=
70.6508(19)°, β=79.5467(19)°, γ=68.0695(19)°; V=738.68(13)
A ; Z=2; Fcalc=1.292 g cm-3; μ=0.083 mm-1; λ=0.71073 A;
3
˚
˚
T=-80 °C; 2θmax=50.00°; total data collected=5108; R1(F)=
Experimental Section
0.0428 (1724 observations [Fo2 g 2σ(Fo )]); wR2(F2)=0.1208 for
199 variables and all 2608 unique data; residual electron density=
2
X-ray Crystallographic Details. Single crystals for X-ray
crystallography were obtained by (a) diffusion of hexanes into
a solution of in CH2Cl2 at rt (3c, 3g, 10d), (b) diffusion of
hexanes into a solution of in hexanes/CH2Cl2 at rt (3p), (c) slow
evaporation of a solution of CHCl3 (3j, 3l) or CDCl3 (10f) at
4 °C, or (d) slow evaporation of a CH2Cl2 solution at rt (3e) or
0 °C (12b). The crystallographic coordinates have been depos-
ited with the Cambridge Crystallographic Data Centre. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Rd., Cambridge CB2
1EZ, UK or via www.ccdc.cam.ac.uk/conts/retrieving.html.
Crystal data for 3c: C17H13N3, MW = 259.30; crystal dimen-
sions 0.68 ꢀ 0.29 ꢀ 0.28 mm3; monoclinic space group P21/n
0.130 and -0.181 e A-3. CCDC deposition no. 771001.
˚
Crystal data for 10d: C19H13N3, MW=283.32; crystal dimen-
sions 0.60 ꢀ 0.19 ꢀ 0.16 mm3; triclinic space group P1 (No. 2);
˚
˚
˚
a = 6.3632(8) A, b = 7.9519(9) A, c = 15.1874(18) A; R =
102.3564(18)°, β = 95.3363(18)°, γ = 91.0645(18)°; V =
746.84(15) A ; Z=2; Fcalc =1.260 g cm-3; μ=0.076 mm-1
;
3
˚
˚
λ = 0.71073 A; T = -80 °C; 2θmax = 52.78°; total data
2
collected =5468; R1(F) = 0.0436 (2130 observations [Fo g 2σ-
(Fo )]); wR2(F2) = 0.1274 for 199 variables and all 3013 unique
2
data; residual electron density=0.178 and -0.179 e A-3. CCDC
˚
deposition no. 623597.
Crystal data for 10f: C20H15N3O, MW = 313.35; crystal
dimensions 0.56 ꢀ 0.31 ꢀ 0.12 mm3; monoclinic space group
˚
(an alternate setting of P21/c [No. 14]); a = 5.7277(8) A, b =
˚
˚
˚
˚
P21 (No. 4); a=10.7789(10) A, b=5.6104(5) A, c=14.1828(13)
14.2042(18) A, c=16.811(2) A; β=93.6141(18)°; V=1365.0(3)
A; β=108.6532(13)°; V=812.64(13); Z=2; Fcalc=1.281 g cm-3
;
A ; Z=4; Fcalc=1.262 g cm-3; μ=0.077 mm-1; λ=0.71073 A;
T = -80 °C; 2θmax = 52.80°, total data collected = 7513;
R1(F)=0.0409 (2030 observations [Fo2g2σ(Fo2)]); wR2(F2)=
0.1147 for 181 variables and all 2800 unique data; residual
3
˚
˚
˚
μ=0.081 mm-1; λ=0.71073 A; T=-80 °C; 2θmax=52.78°; total
data collected=6447; R1(F)=0.0306 (3069 observations [Fo2 g
2σ(Fo2)]); wR2(F2)=0.0817 for 218 variables and all 3302 unique
˚
data; residual electron density=0.143 and -0.167 e A-3. CCDC
electron density = 0.134 and -0.184 e A-3. CCDC deposition
˚
˚
deposition no. 771002.
Crystal data for 12b: C21H13N3, MW=307.34; crystal dimen-
no. 623595.
Crystal data for 3e: C15H11N3S, MW=265.33; crystal dimen-
sions 0.55 ꢀ 0.25 ꢀ 0.07 mm3; orthorhombic space group Pca21
sions 0.78 ꢀ 0.65 ꢀ 0.20 mm3; monoclinic space group P21/n
˚
˚
˚
˚
(an alternate setting of P21/c [No. 14]); a = 9.9330(10) A,
(No. 29); a=10.8926(10) A, b=20.0670(19) A, c=7.3933(7) A;
;
V=1616.0(3) A , Z=4; Fcalc=1.263 g cm-3; μ=0.076 mm-1
3
˚
˚
˚
b = 5.7873(6) A, c = 23.287(2) A; β = 101.4178(14)°; V =
1312.2(2) A ; Z=4; Fcalc=1.343 g cm-3; μ=0.235 mm-1; λ=
3
˚
˚
λ=0.71073 A; T=-80 °C; 2θmax=52.76°; total data collected =
2
2
˚
11984; R1(F) = 0.0332 (1621 observations [Fo g 2σ(Fo )]);
wR2(F2)=0.1070 for 217 variables and all 1796 unique data; resid-
0.71073 A; T=-80 °C; 2θmax=52.74°; total data collected=
6037; R1(F)=0.0456 (2254 observations [Fo2 g 2σ(Fo2)]); wR2-
ual electron density=0.169 and -0.148 e A-3. CCDC deposition
(F2)=0.1209 for 179 variables, 4 restraints, and all 2672 unique
˚
data; residual electron density=0.341 and -0.652 e A-3. The
˚
no. 771003.
General Procedure: The Reaction of Di-, Tri-, and Tetraynes
with Benzyl Azide Unless otherwise stated, a mixture of the
appropriate trimethylsilyl- or triisopropylsilyl-protected poly-
yne (0.3-0.9 mmol) and K2CO3 (ca. 0.05 g) or TBAF (2.0 equiv)
in wet THF/MeOH (1:1 v/v, 5 mL) or THF (10 mL), respec-
tively, were combined and stirred at rt until TLC analysis
showed complete conversion to the terminal alkyne. Et2O and
saturated aq NH4Cl were added, then the organic phase was
separated, washed with saturated aq NH4Cl (2ꢀ10 mL) and
saturated aq NaCl (10 mL), dried over MgSO4, and filtered.
DMF (2 mL) was then added and the solution concentrated to
1-2 mL via rotary evaporation to remove Et2O, THF, or
MeOH. To the resulting mixture was added DMF (10 mL),
followed by benzyl azide (0.66-1.0 equiv based on the starting
following restraints were applied to distances involving the
minority-conformer (10%) atoms of the disordered thienyl
˚
˚
group: d(S1B-C21) = 1.70(1) A; d(S1B-C23) = 1.68(1) A;
˚
˚
d(C21-C22B)=1.41(1) A; d(C22B-C24)=1.44(1) A. CCDC
deposition no. 770998.
Crystal data for 3g: C18H15N3O, MW=289.33; crystal dimen-
sions 0.72 ꢀ 0.21 ꢀ 0.19 mm3; monoclinic space group P21
˚
˚
˚
(No. 4); a=9.1938(9) A, b=5.6198(6) A, c=14.7114(14) A;
β=102.6687(14)°, V=741.59(13) A ; Z=2; Fcalc=1.296 g cm-3
;
3
˚
μ=0.083 mm-1; λ=0.71073 A; T=-80 °C; 2θmax=52.82°; total
data collected=5655; R1(F)=0.0303 (2779 observations [Fo2 g
2σ(Fo2)]); wR2(F2)=0.0792 for 199 variables and all 3025 unique
˚
data; residual electron density=0.105 and -0.141 e A-3. CCDC
˚
deposition no. 623596.
Crystal data for 3j: C21H21N3, MW=315.41; crystal dimensions
silylated polyyne),20 CuSO4 5H2O (0.1 g), ascorbic acid (0.1 g),
3
0.38 ꢀ 0.35 ꢀ 0.23 mm3; monoclinic space group P21 (No. 4); a=
and H2O (2 mL). This mixture was then stirred at rt until TLC
analysis showed that either the terminal polyyne or benzyl azide
had been consumed. Saturated aq NH4Cl (10 mL) and Et2O
(10 mL) were added, then the organic phase was separated,
washed with saturated aq NaCl (2 ꢀ 10 mL), dried over MgSO4,
and filtered. Concentration of the resulting solution gave a solid
(except for compounds 3a,o, 10a,h, and 12a which are oils) that
was washed with a minimal amount of hexanes (ca. 10-20 mL)
at 0 °C to remove any remaining DMF as well as soluble
3
˚
˚
˚
˚
5.7566(11) A, b=7.9092(15) A, c=18.846(4) A; β=90.312(3) A ;
V=858.1(3) A ; Z=2; Fcalc=1.221 g cm-3; μ=0.073 mm-1; λ=
3
˚
˚
0.71073 A; T=-80 °C; 2θmax=52.68°; total data collected=6808;
2
2
R1(F) = 0.0532 (2805 observations [Fo g 2σ(Fo )]); wR2(F2) =
0.1431 for 325 variables and all 3498 unique data; residual electron
density=0.198 and -0.218 e A-3. CCDC deposition no. 770999.
˚
Crystal data for 3l: C34H33N3OSi, MW = 527.72; crystal
dimensions 0.58 ꢀ 0.57 ꢀ 0.08 mm3; monoclinic space group
8504 J. Org. Chem. Vol. 75, No. 24, 2010

Luu et al.
JOCArticle
byproducts. When necessary, additional purification via column
chromatography (silica gel) or recrystallization gave analytically
pure material. The synthesis and spectral characterization of the
following compounds and their precursors are described in ref 16:
3a-c,g,i,j,l,p,q, 10a,c-g, and 12a,b.
13C NMR (125 MHz, CDCl3) δ 144.0, 134.1, 131.7, 131.5, 129.2,
129.0, 128.5, 128.2, 125.6, 119.4, 92.9, 77.8, 54.4, 35.9, 31.7,
31.1, 28.9, 22.6, 14.1. ESI HRMS m/z calcd for C23H26N3
([M þ H]þ) 344.2121, found 344.2122. Anal. Calcd for C23H25N3:
C, 80.43; H, 7.34; N, 12.23. Found: C, 80.23; H, 7.39; N, 12.07.
Compound 3m: Diyne 4l16 (129 mg, 0.276 mmol) and benzyl
azide (36.2 mg, 0.272 mmol) were used as per the general
procedure using TBAF desilylation, and yielded 3m (69 mg,
86%) as a white crystalline solid. Mp 125-127 °C. Rf = 0.4
(CH2Cl2). IR (CHCl3, cast) 3191 (br), 3121, 3087, 2203 (w), 1452
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.48 (d, J=8.2
Hz, 2H), 7.40-7.25 (m, 7H), 5.53 (s, 2H), 4.69 (s, 2H), 1.80 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 141.5, 134.0, 131.7, 129.1,
128.9, 128.1, 126.7, 125.7, 121.4, 92.3, 78.4, 64.8, 54.3. ESI
HRMS m/z calcd for C18H16ON3 ([M þ H]þ) 290.1288, found
290.1288.
Compound 3d: Diyne 4d26 (159 mg, 0.490 mmol) and benzyl
azide (58.6 mg, 0.440 mmol) were used as per the general
procedure and yielded 3d (105 mg, 62%) as a yellow powder.
Mp 168-171 °C. Rf=0.2 (CH2Cl2). IR (CH2Cl2, cast) 3139 (w),
1
3041 (w), 2216 (w), 1456 cm-1; H NMR (500 MHz, CDCl3)
δ 8.61 (d, J=9.1 Hz, 1H), 8.20-8.12 (m, 4H), 8.10-8.07 (m,
2H), 8.02 (d, J=9.0 Hz, 1H), 8.01 (t, J=7.6 Hz, 1H), 7.73 (s, 1H),
7.43-7.38 (m, 3H), 7.33-7.31 (m, 2H), 5.60 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 134.2, 132.0, 131.8, 131.6, 131.2, 131.0,
129.6, 129.3, 129.0, 128.5, 128.4, 128.2, 127.2, 126.3, 125.9,
125.8, 125.7, 125.5, 124.5, 124.4, 124.2, 116.7, 91.9, 83.9, 54.5.
EIMS m/z 383.1 (Mþ, 53); HRMS m/z calcd for C27H17N3 (Mþ)
383.1422, found 383.1417. Anal. Calcd for C27H17N3: C, 84.57; H,
4.47; N, 10.96. Found: C, 84.18; H, 4.56; N, 10.81.
Compound 3n: Diyne 4n (257 mg, 0.504 mmol) and benzyl
azide (59.7 mg, 0.448 mmol) were used as per the general
procedure and yielded 3n (167 mg, 65%) as a yellow solid. Mp
42-44 °C. Rf=0.4 (CH2Cl2). IR (CHCl3, cast) 3035, 2927, 2855,
Compound 3e: Diyne 4e26 (182 mg, 0.893 mmol) and benzyl
azide (107 mg, 0.800 mmol) were used as per the general
procedure and yielded 3e (150 mg, 71%) as a white crystalline
solid. Mp 86-88 °C. Rf=0.35 (CH2Cl2). IR (CH2Cl2, cast) 3129,
1
2219 (w), 1246 cm-1; H NMR (400 MHz, CDCl3) δ 7.56 (s,
1H), 7.39-7.33 (m, 5H), 7.25-7.22 (m, 2H), 6.85 (d, J=8.8 Hz,
2H), 5.49 (s, 2H), 3.93 (t, J=6.6 Hz, 2H), 1.76 (quint, J=7.0 Hz,
2H), 1.46-1.43 (m, 2H), 1.32-1.27 (m, 8H), 0.87 (t, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 133.9, 130.8, 129.92,
129.89, 129.3, 129.1, 128.9, 128.1, 126.1, 114.2, 99.1, 91.8, 86.1,
68.0, 54.3, 31.7, 29.2, 29.13, 29.10, 25.9, 22.6, 14.0. EIMS m/z
571.1 (Mþ, 15), 57.0 ([C4H7]þ, 100); HRMS m/z calcd for
C27H29ON379Br81Br (Mþ) 571.0657, found 571.0660. Anal.
Calcd for C27H29ON3Br2: C, 56.76; H, 5.12; N, 7.35. Found:
C, 56.83; H, 5.38; N, 7.08.
3105, 3090, 3066, 3053, 2953, 2220 (vw), 1457 (w) cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.39-7.36 (m, 3H),
7.31-7.26 (m, 4H), 6.99 (dd, J=3.7, 5.1 Hz, 1H), 5.54 (s, 2H);
13C NMR (125 MHz, APT, CDCl3) δ 134.0, 132.7, 131.2, 129.2,
129.0, 128.2, 128.0, 127.1, 125.9, 122.2, 86.0, 82.1, 54.4. EIMS
m/z 265.1 (Mþ, 14), 237.1 ([M - N2]þ, 14), 91 ([C7H7]þ, 100);
HRMS m/z calcd for C15H11N3S (Mþ) 265.0674, found
265.0675. Anal. Calcd for C15H11N3S: C, 67.90; H, 4.18; N,
15.84. Found: C, 67.64; H, 4.25; N, 15.37.
Compound 3o: Diyne 4o26 (120 mg, 0.464 mmol) was dissolved
in DMF (10 mL) and benzyl azide (53.3 mg, 0.400 mmol),
CuSO4 5H2O (0.1 g), ascorbic acid (0.1 g), and H2O (2 mL)
Compound 3f: Diyne 4f26 (107 mg, 0.476 mmol) and benzyl
azide (56.5 mg, 0.424 mmol) were used as per the general
procedure and yielded 3f (83 mg, 69%) as a yellow solid. Mp
113-115 °C. Rf=0.3 (CH2Cl2). IR (CH2Cl2, cast) 3126, 3054,
3028, 3006, 1454 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53 (s,
1H), 7.40-7.25 (m, 10H), 7.03 (d, J=16.3 Hz, 1H), 6.30 (d, J=
16.3 Hz, 1H), 5.52 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 142.3,
136.0, 134.1, 131.6, 129.2, 129.0, 128.9, 128.7, 128.1, 126.4,
125.6, 107.1, 92.1, 80.5, 54.4. EIMS m/z 285.1 (Mþ, 15), 257.1
([M - N2]þ, 28), 91 ([C7H7]þ, 100); HRMS m/z calcd for
C19H15N3 (Mþ) 285.1266, found 285.1266. Anal. Calcd for
C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found: C, 79.55; H,
5.32; N, 14.52.
3
were added. To this mixture was then added K2CO3 (0.05 g) and
MeOH (0.25 mL), and the resulting solution was stirred at rt.
Saturated aq NH4Cl (10 mL) and Et2O (10 mL) were added,
then the organic phase was separated, washed with saturated aq
NaCl (2 ꢀ 10 mL), dried over MgSO4, and filtered. Solvent
removal and purification via column chromatography (silica
gel, CH2Cl2/EtOAc 9:1) gave 3o (6.6 mg, 5%) as a brown oil.
Rf=0.6 (CH2Cl2/EtOAc 9:1). IR (CHCl3, cast) 3136 (w), 2916
(w), 2219, 1613 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=
15.8 Hz, 1H), 7.77 (s, 1H), 7.47 (d, J=5.1 Hz, 1H), 7.41-7.36
(m, 3H), 7.29-7.26 (m, 3H), 7.09 (dd, J=5.0, 3.7 Hz, 1H), 6.63
(d, J=15.8 Hz, 1H), 5.56 (s, 2H); 13C NMR (125 MHz, CDCl3)
δ 176.8, 141.2, 139.3, 133.6, 132.9, 130.5, 129.4, 129.2, 129.0,
128.8, 128.6, 128.2, 126.9, 89.9, 80.3, 54.6. ESI HRMS
m/z calcd for C18H13OSN3Na ([M þ Na]þ) 342.0672, found
342.0674.
Compound 3h: Diyne 4h26 (69 mg, 0.27 mmol) and benzyl
azide (30 mg, 0.224 mmol) were used as per the general proce-
dure and yielded 3h (61 mg, 82%) as a white crystalline solid. Mp
117-119 °C. Rf=0.3 (CH2Cl2). IR (CHCl3, cast) 3099, 3067,
3037, 2958, 2229 (w), 1608 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.55 (s, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.39-7.34 (m, 3H),
7.27-7.25 (m, 2H), 6.82 (d, J=8.9 Hz, 2H), 5.52 (s, 2H), 3.94
(t, J=6.6 Hz, 2H), 1.74 (quint, J=7.0 Hz, 2H), 1.47 (sex, J=7.4
Hz, 2H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
159.6, 134.2, 133.1, 131.8, 129.2, 128.9, 128.1, 125.4, 114.6,
114.1, 92.7, 67.8, 54.3, 31.2, 19.2, 13.8 (one signal coincident
or not observed). EIMS m/z 331.2 (Mþ, 41), 246.1 ([M - N2 -
C4H9]þ, 94); HRMS m/z calcd for C21H21ON3 (Mþ) 331.1685,
found 331.1686. Anal. Calcd for C21H21ON3: C, 76.11; H, 6.39;
N, 12.68. Found: C, 75.89; H, 6.44; N, 12.55.
Compound 3r: Diyne 4r (127 mg, 0.258 mmol) and benzyl
azide (30.9 mg, 0.232 mmol) were used as per the general
procedure and yielded 3r (81.6 mg, 75%) as a white solid. Mp
173-175 °C. Rf=0.6 (CH2Cl2/EtOAc 3:1). IR (CHCl3, μscope)
1
3378 (br), 3138, 2933, 1609, 1498 cm-1; H NMR (400 MHz,
CDCl3) δ 7.53 (s, 1H), 7.36-7.33 (m, 3H), 7.26-7.33 (m, 2H),
7.17 (d, J=8.6 Hz, 1H), 6.69 (dd, J=2.7, 8.6 Hz, 1H), 6.61 (d, 2.7
Hz, 1H), 2.88-2.78 (m, 2H), 2.48 (br s, 1H), 2.42-2.37 (m, 1H),
2.35-2.30 (m, 1H), 2.20 (dt, J=4.0, 11.5 Hz, 1H), 2.10-2.04 (m,
1H), 1.92 (dt, J = 4.1, 12.9 Hz, 1H), 1.88-1.82 (m, 1H),
1.79-1.75 (m, 2H), 1.74-1.70 (m, 1H), 1.53-1.29 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 157.3, 137.9, 134.0, 132.5, 131.0,
129.1, 128.9, 128.1, 126.3, 125.8, 113.7, 111.4, 96.4, 80.3, 75.3,
55.1, 54.2, 49.6, 47.5, 43.3, 39.4, 38.8, 33.0, 29.8, 27.1, 26.4, 22.9,
12.8. EIMS m/z 467.3 (Mþ, 10), 284.2 ([M - C11H9N2]þ, 100);
HRMS m/z calcd for C30H33O2N3 (Mþ) 467.2573, found
467.2578. Anal. Calcd for C30H33O2N3: C, 77.06; H, 7.11; N,
8.99. Found: C, 76.90; H, 7.19; N, 8.78.
Compound 3k: Diyne 4k26 (126 mg, 0.445 mmol) and benzyl
azide (53.3 mg, 0.400 mmol) were used as per the general
procedure and yielded 3k (99.7 mg, 73%) as a white solid.
Mp 84-86 °C. Rf = 0.4 (CH2Cl2). IR (CHCl3, cast) 3099,
3075, 3040, 2923, 1453 cm-1 1H NMR (500 MHz, CDCl3)
;
δ 7.56 (s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.36 (m, 3H), 7.28-7.26
(m, 2H), 7.12 (d, J=8.1 Hz, 2H), 5.53 (s, 2H), 2.58 (t, J=7.7 Hz,
2H), 1.60-1.58 (m, 2H), 1.28 (m, 6H), 0.86 (t, J=6.6 Hz, 3H);
J. Org. Chem. Vol. 75, No. 24, 2010 8505

Luu et al.
JOCArticle
Compound 4n: To 4-n-octyloxybenzoic acid35 (2.70 g, 10.8
mmol) in a flame-dried flask fitted with a drying tube was added
SOCl2 (2.58 g, 21.6 mmol). The mixture was allowed to stir at rt for
24 h. Excess SOCl2 was removed in vacuo with a water aspirator
and the resulting acid chloride was diluted with dry CH2Cl2
(20 mL). Bis(trimethylsilyl)butadiyne (2.51 g, 12.9 mmol) was
added and the mixture cooled to -20 °C. AlCl3 (2.16 g, 16.2 mmol)
was added and the mixture allowed to warm to rt. The reaction was
poured into HCl and ice (10% v:v) and the organic layer was
washed with NH4Cl (2 ꢀ 20 mL) and NaCl (2 ꢀ 20 mL), dried
over MgSO4, and filtered. Solvent was removed in vacuo and the
crude ketone was carried to the next reaction without further
characterization.
To this ketone were added PPh3 (8.36 g, 31.9 mmol) and CBr4
(5.00 g, 15.6 mmol) in CH2Cl2 (40 mL) at 0 °C. The reaction was
slowly warmed to rt until the ketone was no longer observed by
TLC analysis (about 3 h). The reaction was diluted with hexanes
(40 mL) and filtered through a short plug of silica with hexanes
to give pure 4n (1.12 g, 20%) as a white crystalline solid. Mp
50-52 °C. Rf = 0.6 (hexanes/CH2Cl2 3:1). IR (CHCl3, cast)
2926, 2093 (w), 1506 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31
(d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.94 (t, J=6.6 Hz,
2H), 1.76 (quint, J=7.0 Hz, 2H), 1.45-1.39 (m, 2H), 1.38-1.27
(m, 8H), 0.87 (t, J=6.4 Hz, 3H), 0.20 (s, 9); 13C NMR (125 MHz,
CDCl3) δ 159.5, 129.9, 129.6, 129.1, 114.3, 101.6, 95.1, 87.4,
81.8, 75.2, 68.1, 31.8, 29.3, 29.23, 29.19, 26.0, 22.7, 14.1, -0.53.
EI HRMS m/z calcd for C23H30OSi79Br81Br 510.0412, found
510.0410. Anal. Calcd for C23H30OSiBrBr: C, 54.13; H, 5.92.
Found: C, 54.08; H, 5.62.
Compound 4r: Dibromoolefin 1,1-dibromo-4-triisopropyl-
silylbut-3-ene-4-yne2f (523 mg, 1.43 mmol) in Et2O (10 mL) was
cooled to -78 °C. LDA [reaction between BuLi (2.5 M in
hexanes, 1.70 mL, 4.25 mmol) and i-Pr2NH (0.60 mL, 0.466 g,
4.28 mmol) in Et2O (10 mL) at -78 °C; stirred for 30 min] was
added over a period of ca. 1 min and the resulting solution
stirred for 1 h. Estrone 3-methyl ether (0.365 g, 1.28 mmol) was
then added by syringe and the reaction allowed to warm to rt
and stirred overnight. The reaction was quenched through the
addition of saturated aq NH4Cl (10 mL) and Et2O (10 mL). The
organic layer was separated, washed with saturated aq NaCl
(10 mL), dried over MgSO4, and filtered, and the solvent was
removed. Column chromatography (silica gel, hexanes) provided
4r (584 mg, 93%) as a white crystalline solid. Mp 155-158 °C.
Rf=0.5 (CH2Cl2). IR (μscope) 3402, 2943, 2866, 2216 (w), 2096,
1257 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.20 (d, J=8.3 Hz,
1H), 6.70 (dd, J=2.8, 8.5 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 3.76
(s, 3H), 2.84 (m, 2H), 2.36 (m, 2H), 2.25 (dt, J=4.0, 11.0 Hz, 1H,
ddd, J = 13.8, 12.0, 3.9 Hz, 1H), 1.94 (t, J = 3.0 Hz, 1H),
1.89-1.65 (m, 5H), 1.55-1.34 (m, 4H), 1.08 (s, 21H), 0.86 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 157.5, 137.9, 132.5, 126.4,
113.8, 111.5, 89.1, 85.0, 80.6, 79.8, 71.5, 55.2, 49.8, 48.0, 43.4,
39.5, 39.0, 33.1, 29.8, 27.2, 26.4, 23.0, 18.6, 12.8, 11.3. EIMS m/z
490.3 (Mþ, 10), 447.3 ([M - i-Pr]þ, 41); HRMS m/z calcd for
C32H46O2Si (Mþ) 490.3267, found 490.3260.
Compound 5: A solution of compound 1,1-dibromo-4-triiso-
propylsilylbut-3-ene-4-yne2f (369 mg, 1.01 mmol) in hexanes
(5 mL) was cooled to -78 °C and BuLi (2.5 M in hexanes,
0.85 mL, 2.13 mmol) was added; the mixture was stirred for 1 h.
Carbon dioxide generated from dry ice and passed through a
drying tube (Drierite) was bubbled into the reaction overnight.
The reaction was then quenched via the addition of water
(10 mL) and Et2O (10 mL). The aqueous phase was separated
and neutralized with HCl (10%) and Et2O (10 mL) was added.
The organic layer was separated, washed with saturated aq
NaCl (10 mL), dried over MgSO4, and filtered. Solvent removal
afforded 5 (170 mg, 67%) as a light yellow oil. IR (film) 3400-
2500 (br), 2946, 2868, 2246 (w), 2204, 2105, 1687 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.08 (s), COOH signal not observed; 13
C
NMR (100 MHz, CDCl3) δ 155.2, 94.1, 87.1, 73.6, 64.8, 18.4,
11.1. EIMS m/z 250.1 (Mþ, 7), 207.1 ([M - i-Pr]þ, 100); HRMS
1
m/z calcd for C14H22O2Si (Mþ) 250.1389, found 250.1393. H
and 13C NMR, IR, and mass spectral data are consistent with
that previously reported for the synthesis of 5 by an alternative
method, see ref 36.
Compound 7: Diyne 5 (169 mg, 0.675 mmol) and benzyl azide
(89.5 mg, 0.672 mmol) were used as per the general procedure
and yielded 7 (86 mg, 82%) as a white powder. Mp 224-227 °C
(lit.17f mp 228 °C). IR (CHCl3, cast) 3131, 3075, 1458 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.98 (s, 2H), 7.38-7.33 (m, 6H),
7.29-7.26 (m, 4H), 5.54 (s, 4H); 13C NMR (100 MHz, CDCl3)
δ 134.3, 129.2, 128.9, 128.2, 54.5 (two quaternary carbons not
observed because of limited solubility). ESI HRMS m/z calcd
for C18H17N6 ([M þ H]þ) 317.1509, found 317.1509.
Compound 8: Compound 937 (188 mg, 0.591 mmol) and
benzyl azide (170 mg, 1.13 mmol) were used as per the general
procedure and yielded 8 (206 mg, 79%) as an orange powder.
Mp >200 °C. IR (CHCl3, cast) 3119, 3072, 3036, 2924, 2853,
1479 cm-1; 1H NMR (500 MHz, CD2Cl2) δ 7.69 (s, 2H), 7.51
(s, 4H), 7.41-7.37 (m, 6H), 7.30 (d, J=7.5 Hz, 4H), 5.55 (s,
4H); a useful 13C NMR spectrum could not be obtained due to
its low solubility. EIMS m/z 440.2 (Mþ, 7), 384.2 ([M - N4]þ,
7); HRMS m/z calcd for C28H20N6 (Mþ) 440.1750, found
440.1743.
Compound 10b: Triyne 11b37 (0.116 g, 0.502 mmol) and benzyl
azide (0.061 g, 0.46 mmol) were used as per the general proce-
dure and yielded 3h (0.062 g, 47%) as a white crystalline solid.
Mp 58-60 °C. Rf=0.27 (hexanes/ethyl acetate 9:1). IR (micro-
scope) 3096 (s), 3054 (s), 2952 (s), 2935 (s), 2850 (s), 2250 (w),
2162 (w), 1604 (s), 1496 (s) cm-1. 1H NMR (400 MHz, CDCl3) δ
7.55 (s, 1H), 7.40-7.36 (m, 3H), 7.29-7.26 (m, 2H), 5.52 (s, 2H),
2.34 (t, J=7.0 Hz, 2H), 1.56 (quint, J=7.6 Hz, 2H), 1.44-1.36
(m, 2H), 1.34-1.26 (m, 4H), 0.89 (t, J=7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 134.0, 130.7, 129.2, 129.0, 128.1, 127.0,
86.0, 78.0, 64.6, 63.5, 54.4, 31.2, 28.5, 28.0, 22.5, 19.5, 14.0.
EIMS m/z 291.2 (Mþ, 1), 234.1 ([M - N2 - C2H5]þ, 18), 91.1
([C7H7]þ, 100). HRMS calcd m/z for C19H21N3(Mþ) 291.1735,
found 291.1730.
Compound 10h: Compound 11h37 (40 mg, 0.132 mmol) and
benzyl azide (17 mg, 0.128 mmol) were used as per the general
procedure to yield 10h (26 mg, 56%) as a yellow oil. Rf =0.8
(hexanes/EtOAc, 1:1). IR (cast film, CH2Cl2) 3138 (w), 3091 (w),
3067 (w), 3034 (w), 2945 (s), 2891 (s), 2866 (s), 2219 (m), 2105
(m), 1461 (s); 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H),
7.42-7.36 (m, 3H), 7.2 -7.24 (m, 2H), 5.53 (s, 2H), 1.09 (s, 21H);
13C NMR (100 MHz, CDCl3) δ 134.0, 130.4, 129.4, 129.2, 128.3,
127.6, 89.8, 88.9, 78.3, 64.6, 54.6, 18.7, 11.4. EIMS m/z 363.2
(Mþ, 1), 335.2 ([M - N2]þ, 100). EI HRMS calcd for C22H29N3-
Si 363.2131, found 363.2132.
Compound 15: To a solution of 1531 (20 mg, 0.023 mmol) in
THF (8 mL) at rt was added CsF (4 mg, 0.03 mmol) and the
mixture was stirred at rt until TLC analysis showed complete
desilylation, ca. 20 min. CH2Cl2 (15 mL) and saturated aq
NH4Cl (10 mL) were added, the organic layer was separated,
washed with saturated aq NH4Cl (10 mL), dried over (MgSO4),
and filtered, and the solvent was reduced in vacuo. The resulting
product was plugged through silica (hexanes/CH2Cl2 10:1), and
the solvent was removed. To this crude product was added THF
(1 mL), H2O (3 drops), benzyl azide (3 mg, 0.02 mmol),
(36) Kendall, J.; McDonald, R.; Ferguson, M. J.; Tykwinski, R. R. Org.
Lett. 2008, 10, 2163–2166.
(35) Liesbet Jongen, L.; Goderis, B.; Dolbnya, I.; Binnemans, K. Chem.
Mater. 2003, 15, 212–217.
(37) Eisler, S.; Chahal, N.; McDonald, R.; Tykwinski, R. R. Chem. Eur.
;
J. 2003, 9, 2542–2550.
8506 J. Org. Chem. Vol. 75, No. 24, 2010

Luu et al.
JOCArticle
CuSO4 5H2O (10 mg, 0.040 mmol), ascorbic acid (10 mg,
HRMS calcd m/z for C60H72N3 ([M þ H]þ) 834.5726, found
3
0.057 mmol), and NEt3 (1 drop); the reaction was stirred at rt
until TLC analysis confirmed the absence of starting materi-
al. CH2Cl2 (15 mL) and H2O (15 mL) were added, the organic
layer was separated, washed with H2O (10 mL), dried over
MgSO4, and filtered, and the solvent was reduced in vacuo.
The crude product was purified by column chromatog-
raphy (silica gel, hexanes/CH2Cl2 1:2) to afford 14 (4 mg,
24%) as a yellow solid. Rf =0.50 (1:2 hexanes/CH2Cl2). IR
(microscope) 3067 (w), 2963 (s), 2905 (w), 2868 (w), 2214 (w),
834.5708.
Acknowledgment. This work has been generously supported
by the University of Alberta and the Natural Sciences and
Engineering Research Council of Canada (NSERC) through
the Discovery and Nano Innovation Platform (NanoIP) grant
programs. T.L. thanks the University of Alberta for a Disserta-
tion Fellowship and Edward Ha for help in the reaction to form
compound 10c.
2146 (w), 1591 (w) cm-1 1H NMR (500 MHz, CD2Cl2) δ
;
7.73 (s, 1H), 7.41-7.38 (m, 3H), 7.32 (t, J = 1.8 Hz, 3H),
7.29-7.27 (m, 2H), 6.95 (d, J=1.8 Hz, 6H), 5.53 (s, 2H), 1.21
(s, 54H); 13C NMR (125 MHz, CD2Cl2) δ 150.4, 143.3, 134.4,
129.2, 129.05, 128.95, 128.9, 128.2, 123.5, 121.6, 87.0, 77.4,
68.8, 68.4, 65.7, 65.0, 62.0, 60.4, 57.3, 54.4, 34.7, 31.0. ESI
Supporting Information Available: General experimental
1
details and copies of H and 13C NMR spectra for new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8507