Regioselective intramolecular dipolar cycloaddition of azides and unsymmetrical alkynes

Article abstract of DOI:10.1021/ol902681t

(Figure presented) Enantioenriched allenylsilanes are used in three-component propargylatlon reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally Induced intram

Full text of DOI:10.1021/ol902681t

ORGANIC
LETTERS
2010
Vol. 12, No. 2
336-339
Regioselective Intramolecular Dipolar
Cycloaddition of Azides and
Unsymmetrical Alkynes
Ryan A. Brawn, Morgan Welzel, Jason T. Lowe, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth
AVenue, Boston UniVersity, Boston, Massachusetts 02215
panek@bu.edu
Received November 20, 2009
ABSTRACT
Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic
ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions,
resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient
access to compounds containing significant structural and stereochemical variation.
Recent advancements in the Huisgen 1,3-dipolar cycload-
dition reaction have led to a renewed interest in its application
in the synthesis of 1,2,3-triazoles.1 Small molecules contain-
ing a triazole functionality have been shown to exibit a range
of biological functions, including antitumor, antibacterial,
antiparasitic, and antiviral activity (Figure 1).2
Historically terminal and symmetrically substituted
alkynes have been used predominantly in these reactions
(1) (a) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004–2021. (c) Rostovtsev, V. V.; Green,
L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596–2599. (d) Kelly, A. R.; Wei, J.; Kesavan, S.; Marie´, J.-C.; Windmon,
N.; Young, D. W.; Marcaurelle, L. A. Org. Lett. 2009, 11, 2257–2260. (e)
Spiteric, C.; Moses, J. E. Angew. Chem., Int. Ed. 2009, 48 (early view DOI,
Figure 1. Representative examples of biologically active molecules
containing 1,2,3-triazoles.
10.1002/anie.200905322).
(2) (a) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radiæ, Z.; Carlier,
P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 1053–1057. (b) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico,
P. L.; Sorba, G.; Genazzani, A. A. Med. Res. ReV. 2008, 28, 278–308. (c)
Lee, T.; Cho, M.; Ko, S.-Y.; Youn, H.-J.; Baek, D. J.; Cho, W.-J.; Kang,
C.-Y.; Kim, S. J. Med. Chem. 2007, 50, 585–589. (d) Maurya, S. K.;
Gollapalli, D. R.; Kirubakaran, S.; Zhang, M.; Johnson, C. R.; Benjamin,
N. N.; Hedstrom, L.; Cuny, G. D. J. Med. Chem. 2009, 52, 4623–4630. (e)
Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128–1137.
(f) Puig-Basagoiti, F.; Qing, M.; Dong, H.; Zhang, B.; Zou, G.; Yuan, Z.;
Shi, P.-Y. AntiViral Res. 2009, 83, 71–79.
since unsymmetrical alkynes often result in diminished
reaction rates and poor regioselectivity.3 One solution to
this problem is a tandem dipolar cycloaddition/cross
coupling reaction, which can access fully substituted
triazoles.4 Another approach is an intramolecular cycload-
dition, where the regioselectivity is determined by the
10.1021/ol902681t  2010 American Chemical Society
Published on Web 12/17/2009

initial positions of the azide and alkyne in the starting
material.5 While both of these strategies have proven to
be useful, methods for the formation of fully functional-
ized triazoles remain underdeveloped.
of the aldehyde. The propargylation reaction provided
homopropargylic ether 7, and heating this product in toluene
gave desired triazole 8 in 90% isolated yield. This reaction
sequence demonstrates that the methodology can be ex-
panded to aliphatic systems using acetals with imbedded
azides.
We have recently reported a three-component reaction of
enantioenriched allenylsilanes with aldehydes and silyl ethers,
resulting in highly functionalized syn-homopropargylic
ethers.6 In our continued interest in developing these allenes
as chiral carbon nucleophiles,7 we sought to further expand
the use of the resulting homopropargylic ethers by incorpo-
rating a pendant azide moiety which will further react to
provide heterocycles containing fused 1,2,3-triazoles. In this
paper, we describe the development of a three-component
propargylation/cycloaddition strategy to give access to
densely functionalized fused triazole ring systems.
The propargylation of enantioenriched allenylsilane (Ra)-
4a with 2-azidobenzaldehyde8 and methoxytrimethylsilane
(TMSOMe), promoted by TMSOTf, resulted in the formation
of alkyne 5 in 71% yield as a single observed diastereomer
(Scheme 1). Heating alkyne 5 in toluene at 110 °C promoted
When this strategy was applied to more substituted
azidobenzaldehydes, we observed that some of the triazole
product was formed in the crude propargylation reaction
mixture.8 Attempts to purify these propargylation products
proved difficult, as the triazole product would be observed
in postchromatographic NMR spectra. This observation led
to the development of a two-step sequence where the
propargylation reaction was quenched, and the crude product
was heated to 70 °C in toluene, to directly produce the
desired triazole product.
This modified procedure gave the desired tricyclic system
with an imbedded triazole 6 in good yield and high
diastereoselectivity (Scheme 2). The reactions were tolerant
Scheme 2.
One-Pot Propargylation/Cycloadditiona,b
Scheme 1.
Two-Step Triazole Formationa,b
a Isolated yields after purification over silica gel. b Diastereomeric ratios
1
determined by H NMR analysis on crude material.
the desired dipolar cyclization reaction, resulting in the
formation of triazole 6a in 90% yield. As anticipated, a single
regioisomer of the desired triazole was observed.
A similar experiment was conducted with 2-azidoacetal-
dehyde dimethylacetal (Scheme 1). Due to concerns with
volatility and stability, the preformed acetal was used instead
(3) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998–
15999. (b) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680–
8683.
a Isolated yields after purification over silica gel. b Diastereomeric ratios
determined by H NMR analysis on crude material. c Reaction run using
1
(4) (a) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
Org. Lett. 2008, 10, 3081–3084. (b) Chowdhury, C.; Mukherjee, S.; Das,
B.; Achari, B. J. Org. Chem. 2009, 74, 3612–3615.
achiral allenylsilane 4b.
(5) (a) Pearson, W. H.; Bergmeier, S. C.; Chytra, J. A. Synthesis 1990,
156–159. (b) Oliva, A. I.; Christmann, U.; Font, D.; Cuevas, F.; Ballester,
P.; Buschmann, H.; Torrens, A.; Yenes, S.; Perica´s, M. A. Org. Lett. 2008,
10, 1617–1619. (c) Balducci, E.; Bellucci, L.; Petricci, E.; Taddei, M.; Tafi,
A. J. Org. Chem. 2008, 74, 1314–1321.
to a range of functionality on the aromatic ring, including
electron-donating and -withdrawing groups. When achiral
allenylsilane 4b was subjected to the same reaction condi-
tions, products 6f and 6g were formed in moderate yield.
Further structural variation was achieved by using silyl
ether reaction partners containing an azide functionality
(Table 1). The silyl-protected 2-azidoethanol could be
prepared from 2-bromoethanol in two steps using a known
(6) Brawn, R. A.; Panek, J. S. Org. Lett. 2007, 9, 2689–2692.
(7) For a recent review on chiral organosilanes in diversity oriented
synthesis, see: Shaw, J. Nat. Prod. Rep. 2009, 26, 11–26.
(8) For the synthesis of functionalized 2-azidobenzaldehydes, see: (a)
Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603–5606. (b)
Main, C. A.; Petersson, H. A.; Rahman, S. S.; Hartley, R. C. Tetrahedron
2008, 64, 901–914. (c) Cuevas, J. C.; De Mendoza, J.; Prados, P. J. Org.
Chem. 1988, 53, 2055–2066.
Org. Lett., Vol. 12, No. 2, 2010
337

Table 1. Propargylations with TBS 2-Azidoethanol
Scheme 3. Silyl Ether Synthesis
would allow access to fused triazole systems with greater
complexity.11 Silyl ether 11a was prepared in four steps
from (S)-ethyl lactate and contains a chiral center on the
carbon with the silyl ether. Silyl ether 11b, derived from
the epoxide opening of (R)-styrene oxide, has a chiral
center on the carbon containing the azide. TBS-protected
3-azidopropanol 11c was prepared from 3-bromopropanol
using the same procedure as TBS-protected 2-azidoeth-
anol. Finally, the 3-carbon silyl ether containing a chiral
center at C2 (11d) was accessed using commercially
available (S)-methyl-3-hydroxy-2-methylpropanpoate in
four steps. These procedures are all general and relatively
straightforward, allowing for the rapid incorporation of
stereochemical variation into the synthesis of the desired
fused triazole systems.
a Isolated yields after purification over silica gel. b Diastereomeric ratios
determined by H NMR analysis on crude material.
1
Propargylation reactions with 11a proceeded in good yield,
but with a significant loss of diastereoselctivity when the
(Ra) enantiomer of allenylsilane 4a was used (Scheme 4,
12a+b). When the (Sa) enantiomer of the allenylsilane was
used, the diasteroselectivity was substantially higher (Scheme
4, 12c+d), exhibiting a “matched pair” of reaction partners
in a double stereodifferentiating reaction. The cycloadditions
proceeded with moderate to high yield, although the products
of matched cases (13c+d) showed higher yields than the
mismatched cases (13a+b).12
When the silyl ether’s chiral center was located on the
carbon bearing the azide, the diastereoselectivity of the
reaction products was not effected by switching the enan-
tiomer of the allene. Propargylations with silyl ether 11b
gave high yields and diastereoselectivities with both enan-
tiomers (Scheme 4, 12e-h). The cycloadditions also pro-
ceeded in similar yields for the different diastereomers
(Scheme 4, 13e-h), with moderate yields obtained in all
cases.
procedure.9 The TBS ether was explored after the TMS
version proved to be difficult to work with due to its inherent
volatility.
The propargylation reaction of allenylsilane (Ra)-4 with
aldehydes and silyl-protected 2-azidoethanol resulted in the
formation of syn-homopropargylic ethers 9a-i. High yields
and selectivities were obtained for a variety of aromatic
aldehydes (entries 1-6). The use of aliphatic aldehydes in
this reaction sequence resulted in lower yields (entries 7-9)
and lower selectivity for the unbranched system (entry 8).
For all of the examples studied, heating the reaction
products to 130 °C in toluene gave the desired triazoles
10a-i in good yield.10 None of the triazole products were
observed after the propargylation reaction, as the alkyne
products were stable at room temperature, and as expected,
the dipolar cyclizations proceeded with complete regiose-
lectivity.
Propargylations with the three-carbon silyl ether 11c
proceeded with good yield and excellent diastereoselec-
tivity (Scheme 4, 12i+j). While the reactions were
To expand the scope of this methodology, we synthe-
sized four additional azidosilyl ethers (Scheme 3) which
(9) Smith, R. H.; Mehl, A. F.; Shantz, D. L.; Chmurny, G. N.; Michejda,
C. J. J. Org. Chem. 1988, 53, 1467–1471.
(11) For the synthesis of these silyl ethers, see the Supporting Informa-
tion.
(12) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. 1985, 24, 1.
(10) All of the dipolar cycloaddition reactions were run in a sealed tube.
No reactivity was observed using the copper(I) catalyst systems which have
been previously reported.
338
Org. Lett., Vol. 12, No. 2, 2010

Scheme 4.
Propargylations and Dipolar Cycloadditions with Substituted Silyl Ethersa,b
a All yields refer to isolated products after purification over silica gel. b All diastereomeric ratios were determined by 1H NMR analysis on crude material.
c The (Sa) enantiomer of the allenylsilane 1 was used for the propargylation reaction. d Cycloaddition reaction run in chlorobenzene at 150 °C.
sluggish in toluene, switching the solvent to chlorobenzene
at 150 °C resulted in significantly higher yields for 13i+j.
Use of silyl ether 11d, which contained a stereocenter at
C2, had no effect on the selectivity, as the products were
formed in good yields as a single observed diasteromer
regardless of which enantiomer of allenylsilane 4a was
used (Scheme 4, 12k+l).
systems, along with preliminary biological evaluation, is
currently in progress.
Acknowledgment. Financial support was obtained from
the NIH CA 53604 and through an AstraZeneca graduate
fellowship to RAB.
Supporting Information Available: Experimental data
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have reported a tandem propargylation/
dipolar cycloaddition sequence to rapidly construct structur-
ally and stereochemically diverse fused ring systems con-
taining 1,2,3-triazoles. Continued exploration of these ring
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