Synthesis of 6-(1,2,3-triazoloalkyl)-α-pyrones by a cascade RCM/CM and click chemistry sequence

Article abstract of DOI:10.1055/s-0030-1258577

A RCM/CM process followed by a further nucleophilic substitution allowed the formation of an azido pyrone which was implicated into a copper-catalyzed [3+2] cycloaddition with various alkynes. Among the different conditions tested, the use of copper(II) salts furnished the expected adducts in a range of 42-99% yield. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258577

LETTER
2621
Synthesis of 6-(1,2,3-Triazoloalkyl)-a-Pyrones by a Cascade RCM/CM and
Click Chemistry Sequence
Synthesisof
6
a
-(1,2,3-Tria
n
zoloalkyl)-
a
n
-Pyrone
s
y Cros, Jérémy Ruiz, Béatrice Pelotier, Olivier Piva*
Université de Lyon, Université Lyon 1, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (ICBMS), UMR 5246 CNRS,
Bat Raulin, 43 Bd du 11 novembre 1918, 69622 Villeurbanne cedex, France
Fax +33(472)448136; E-mail: piva@univ-lyon1.fr
Received 19 July 2010
In order to enhance the scope of this methodology and to
Abstract: A RCM/CM process followed by a further nucleophilic
prepare parent structures, we have investigated a further
substitution allowed the formation of an azido pyrone which was
functionalization of pyrones readily prepared by the pre-
implicated into a copper-catalyzed [3+2] cycloaddition with various
viously described RCM/CM strategy.10 To minimize the
alkynes. Among the different conditions tested, the use of cop-
per(II) salts furnished the expected adducts in a range of 42–99% number of steps, we have considered more particularly
click reactions.11,12 As defined by Sharpless, a click reac-
yield.
tion should be performed under very mild conditions to
produce after simple workup procedures new synthetic
building blocks. Among the various reactions which obey
to these requirements, the Huisgen 1,3-dipolar cycloaddi-
tion catalyzed by copper salts (CuAAC) is the most popu-
lar. Moreover, this process tolerates the presence of
numerous additional functional groups. We have singled
out this method usually performed between an azido de-
rivative and an alkyne leading to 1,2,3-triazolo derivatives
recognized as isosteres of amides.13 Since the tandem
RCM/CM could be affected by the presence of an acety-
lenic group14 and to avoid the stoichiometric use of cobalt
derivatives,15 we have refrained from performing the meta-
thesis process between ester 3 and a nonconjugated enyne.
Moreover, to avoid the use of hazardous reagents, the azi-
do group has to be introduced at a later stage of the syn-
thesis. The well-established nucleophilic substitution of a
bromo derivative16 seemed the method of choice and re-
quired at first the synthesis of bromopyrone 4. In the pres-
ence 4-bromobutene (3 equiv) and catalytic amounts of 2,
ester 3 was easily transformed into the expected lactone 4
in 64% yield with complete E stereoselectivity for the
newly created double bond on the lateral chain.16,17 For-
mation of the azidopyrone 5 was then conveniently
achieved by stirring 4 in the presence of sodium azide in
DMF at room temperature (Scheme 2).
Key words: ring-closing metathesis, click chemistry, [3+2] cy-
cloadditions, triazoles, tandem
a-Pyrones are found in a large number of natural products
exhibiting important biological activities.1 For example,
rugulactone (1) recently isolated from Cryptocaria rugu-
losa possess such a substructure and has been reported as
an inhibitor of the nuclear factor Nk-B.2 Therefore, its
synthesis has attracted the attention of synthetic chemists
and to date has been independently reported by three
groups.3–5 The pyrone was built by using a ring-closing
metathesis (RCM) or alternatively by a sequence involv-
ing a Z-selective Wittig–Horner reaction followed by a
lactonization step. In connection with our interest in py-
rone and lactone synthesis,6,7 we have also synthesized 1
by using a regioselective tandem RCM/CM procedure.8 In
the presence of second generation Grubbs’ catalyst GBII
2,9 ester 3 underwent both a ring-closing metathesis and a
cross-metathesis with an appropriate alkene to directly de-
liver a functionalized b,g-unsaturated pyrone which was
further transformed into rugulactone (1; Scheme 1).
O
O
O
O
O
3
O
O
+
catalyst 2 (2.5 mol%)
4-bromobutene
(3 equiv)
Br
Ph
O
O
O
1
CH2Cl2, Δ
Ph
3
4 (64%)
N
N
Mes
Ph
Mes
Cl
Cl
O
Ru
PCy3
O
N–
GBII (2)
N+
NaN3, DMF
r.t.
N
Scheme 1 Access to rugulactone (1) by a RCM/CM sequence
5 (82%)
Scheme 2 Formation of azidopyrone 5
SYNLETT 2010, No. 17, pp 2621–2624
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258577; Art ID: G21310ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0
Numerous experimental conditions have been reported to
promote the [3+2]-cycloaddition. Copper(I) salts which
catalyzed the process can be directly used18 or can also be

2622
F. Cros et al.
LETTER
Table 2 Synthesis of Pyrones 8a–e from Alkynes 6a–e
generated in situ by reduction of copper(II) salts. By this
way, the reaction can be smoothly performed under mild-
er conditions avoiding the use of inert atmospheres. How-
ever, a reducing reagent, usually sodium ascorbate,19
should be added to the reaction mixture; alternatively, this
reduction could be achieved by the alkyne itself, if termi-
nal only, leading to diynes as by-products.20,21 In order to
find the most suitable conditions for our purpose, we have
investigated the reaction of 5 with phenylacetylene (6a)
chosen as a model substrate for the acetylenic derivatives
(Scheme 3) and the results are summarized in Table 1.
Alkyne 6 (R)
6a (Ph)
Triazole 7 (Yield) Triazole 8 (Yield)
7a (99%)
7b (82%)
7c (73%)
7d (56%)
7e (51%)
8a (75%)
8b (72%)
8c (46%)
8d (82%)
8e (62%)
6b (C4H9)
6c (CH2-O-nC9H19)
6d (CO2Me)
6e (SiMe3)
In conclusion, we have reported the synthesis of 1,2,3-tri-
azoloalkyl-a-pyrones by a sequence involving a cascade
RCM/CM process to produce a bromopyrone precursor of
an azido derivative, which is further implicated into an
azide-alkyne cycloaddition promoted by copper(II) salts.
Biological tests are currently underway.
O
O
O
O
6a
Ph
Ph
N
conditions
A, B or C
N3
N
N
5
7a
Acknowledgment
Scheme 3 [3+2]-Cycloaddition of 5 with phenylacetylene (6a)
Table 1 Optimization for the Click Process
F.C. thanks the ‘Ministère de l’Education Nationale, de la Recher-
che et de la Technologie’ for a doctoral fellowship. Support from
the Université de Lyon and the CNRS are warmly acknowledged.
Method
A
Conditions
7a (Yield)
References and Notes
CuSO4 (10 mol%), CH2Cl2–H2O (1:1),
sodium ascorbate (0.2 equiv)
67%
(1) de Fatima, A.; Modolo, L. V.; Conegero, L. S.; Pilli, R. A.;
Ferreira, C. V.; Kohn, L. K.; de Carvalho, J. E. Curr. Med.
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(2) Meragelman, T. L.; Scuderio, D. A.; Davis, R. E.; Staudt, L.
M.; McCloud, T. G.; Cardellina, J. H. II.; Shoemaker, R. H.
J. Nat. Prod. 2009, 72, 336.
B
C
CuI (30 mol%), DIPEA (1.1 equiv), DMF 91%
Cu(OAc)2 (5 mol%), t-BuOH 99%
(3) Mohapatra, D. K.; Das, P. P.; Reddy, D. S.; Yadav, J. S.
According to these results, the direct reduction of
Cu(OAc)2 in tert-butanol by the terminal alkyne as recent-
ly reported by Zhu et al. seems the more appropriate
method20 avoiding the use of sensitive Cu(I) species. Fi-
nally, b,g-unsaturated pyrone 7a was easily reconjugated
into its isomer 8a under basic conditions by using small
amounts of DBU, as already reported for similar sub-
strates.6,22 The dipolar cycloaddition–reconjugation se-
quence was next performed with several terminal alkynes
6b–e (Scheme 4) and the results are collected in
Table 2.23–25
Tetrahedron Lett. 2009, 50, 5941.
(4) Reddy, D. K.; Shekhar, V.; Reddy, T. S.; Reddy, S. P.;
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O
O
O
O
(10) For other applications of RCM/CM of trienes in synthesis,
see: (a) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett.
2004, 6, 4143. (b) Quinn, K. J.; Isaacs, A. K.;
DeChristopher, B. A.; Szklarz, S. C.; Arvary, R. A. Org.
Lett. 2005, 7, 1243. (c) Quinn, K. J.; Smith, A. G.;
Cammarano, C. M. Tetrahedron 2007, 63, 4881.
(d) Riache, N.; Blond, A.; Nay, B. Tetrahedron 2008, 64,
10853. (e) Enquist, J. A. Jr.; Stoltz, B. M. Nature (London)
2008, 453, 1228. (f) Crimmins, M. T.; Jacobs, D. L. Org.
Lett. 2009, 11, 2695. (g) Quinn, K. J.; Curto, J. M.;
McGrath, K. P.; Biddick, N. A. Tetrahedron Lett. 2009, 50,
7121.
R
6a–f
R
conditions C
N
N3
N
N
5
7a–f
O
O
N
N
DBU (0.25 equiv)
THF, r.t.
R
N
8a–f
Scheme 4 Formation of pyrones 8a–e from alkynes 6a–e
Synlett 2010, No. 17, 2621–2624 © Thieme Stuttgart · New York

LETTER
Synthesis of 6-(1,2,3-Triazoloalkyl)-a-Pyrones
2623
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(24) Compound 7a: 1H NMR (300 MHz, CDCl3): d = 2.37–2.63
(m, 2 H), 2.65–2.93 (m, 2 H), 2.93–2.95 (m, 2 H), 4.40–4.46
(m, 2 H), 4.89–4.92 (m, 1 H), 5.41–5.60 (m, 2 H), 5.67–5.79
(m, 2 H), 7.29–7.35 (m, 1 H), 7.39–7.44 (m, 2 H), 7.76 (s, 1
H), 7.79–7.83 (m, 2 H). 13C NMR (75 MHz, CDCl3): d =
29.7, 33.2, 38.3, 49.7, 78.5, 122.0, 121.8, 125.4, 127.1,
127.9, 128.6, 129.5, 130.5, 145.2, 147.2, 168.8. IR: 732, 911,
1049, 1076, 1226, 1382, 1736, 2925, 3136 cm–1. HRMS:
m/z [M + Na+] calcd for C18H19O2N3: 332.1375; found:
332.1375. Compound 7b: 1H NMR (300 MHz, CDCl3): d =
0.91 (t, J = 7.1 Hz, 3 H), 1.36 (sext, J = 7.1 Hz, 2 H), 1.63
(quint, J = 7.1 Hz, 2 H), 2.38–2.43 (m, 2 H), 2.56–2.62 (m,
2 H), 2.69 (t, J = 7.1 Hz, 2 H), 2.99–3.03 (m, 2 H), 4.33 (td,
J = 6.8, 2.2 Hz, 2 H), 4.91–4.94 (m, 1 H), 5.40–5.56 (m, 2
H), 5.71–5.89 (m, 2 H), 7.28 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 13.8, 22.3, 25.3, 29.9, 31.6, 33.5, 38.6, 49.7,
78.8, 120.8, 122.0, 125.7, 127.1, 128.8, 130.0, 168.8. IR:
1049, 1225, 1379, 1735, 2930, 3042 cm–1. HRMS: m/z [M +
H+] calcd for C16H24O2N3: 290.1869; found: 290.1869.
Compound 7c: 1H NMR (300 MHz, CDCl3): d = 0.57 (td,
J = 7.0, 2.3 Hz, 3 H), 0.95 (br s, 12 H), 1.27 (t, J = 6.9 Hz, 2
H), 2.04–2.17 (m, 2 H), 2.28–2.39 (m, 2 H), 2.70 (d, J = 3.6
Hz, 2 H), 3.20 (t, J = 6.8 Hz, 2 H), 4.05–4.09 (m, 2 H), 4.29
(s, 2 H), 4.62–4.66 (m, 1 H), 5.11–5.28 (m, 2 H), 5.43–5.48
(m, 1 H), 5.52–5.58 (m, 1 H), 7.26 (s, 1 H). 13C NMR (75
MHz, CDCl3): d = 14.0, 22.5, 26.0, 29.1, 29.3, 29.4, 29.5,
29.8, 31.7, 33.3, 38.4, 49.6, 64.1, 70.7, 78.6, 121.9, 122.4,
125.6, 127.2, 129.7, 145.2, 168.7. IR: 703, 816, 973, 1049,
1097, 1223, 1378, 1462, 1739, 2855, 2926 cm–1. HRMS:
m/z [M + Na+] calcd for C22H35O3N3: 412.2571; found:
412.2564. Compound 7d: 1H NMR (300 MHz, CDCl3): d =
2.27–2.47 (m, 2 H), 2.70–2.59 (m, 2 H), 3.00 (m, 2 H), 3.91
(s, 3 H), 4.40–4.46 (m, 2 H), 4.87–4.97 (m, 1 H), 5.37–5.56
(m, 2 H), 5.68–5.73 (m, 1 H), 5.79–5.84 (m, 1 H), 8.08 (s, 1
H). 13C NMR (75 MHz, CDCl3): d = 29.9, 33.2, 38.4, 50.1,
52.1, 78.6, 122.1, 125.6, 127.6, 127.9, 129.1, 139.7, 161.1,
168.8. IR: 2952, 1735, 1543, 1435, 1370, 1228, 1161, 1046,
974, 809, 777, 701 cm–1. HRMS: m/z [M + Na+] calcd for
C14H17O4N3: 314.1111; found: 314.1103. Compound 7e: 1H
NMR (300 MHz, CDCl3): d = 0.29 (s, 9 H), 2.37–2.42 (m, 2
H), 2.57–2.70 (m, 2 H), 2.98–3.01 (m, 2 H), 4.36–4.44 (m, 2
H), 4.88–4.93 (m, 1 H), 5.46–5.56 (m, 2 H), 5.69–5.75 (m, 1
H), 5.79–5.86 (m, 1 H), 7.51 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = –1.0, 29.9, 33.6, 38.6, 49.3, 78.8, 121.9, 125.7,
127.1, 129.1, 129.9, 146.4, 168.8. IR: 701, 760, 843, 973,
1050, 1194, 1249, 1379, 1739, 2956 cm–1. HRMS: m/z [M +
Na+] calcd for C15H23O2N3Si: 328.1452; found: 328.1442.
(25) Compound 8a: 1H NMR (300 MHz, CDCl3): d = 2.12–2.18
(m, 2 H), 2.31–2.46 (m, 2 H), 2.65–2.71 (m, 2 H), 4.27–4.36
(m, 1 H), 4.46 (t, J = 6.7 Hz, 2 H), 5.43–5.62 (m, 2 H), 5.90
(dt, J = 9.7, 1.8 Hz, 1 H), 6.68 (dt, J = 9.7, 4.3 Hz, 1 H),7.30–
7.35 (m, 1 H), 7.39–7.44 (m, 2 H), 7.77 (s, 1 H), 7.81–7.85
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 28.6, 33.5, 37.7,
50.0, 77.1, 121.2, 125.7, 128.2, 128.3, 128.9, 129.1, 129.2,
130.6, 145.1, 147.1, 164.3. IR: 731, 909, 1047, 1227, 1386,
1731, 2924, 3031 cm–1. HRMS: m/z [M + H+] calcd for
C18H20O2N3: 310.1555; found: 310.1555. Compound 8b: 1H
NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.0 Hz, 3 H), 1.37
(sext., J = 7.8 Hz, 2 H), 1.63 (quint, J = 7.8 Hz, 2 H), 2.19–
2.23 (m, 2 H), 2.32–2.47 (m, 2 H), 2.57–2.63 (m, 2 H), 2.68
(t, J = 7.8 Hz, 2 H), 4.36 (t, J = 6.8 Hz, 2 H), 4.28–4.41 (m,
1 H), 5.46–5.50 (m, 2 H), 6.00 (dt, J = 9.8 Hz, 1.9 Hz, 1 H),
6.86 (dt, J = 9.8, 4.5 Hz, 1 H), 7.27 (s, 1 H). 13C NMR (75
MHz, CDCl3): d = 13.8, 22.2, 25.3, 28.5, 31.6, 33.4, 37.6,
49.6, 77.1, 120.6, 121.1, 127.7, 129.3, 145.2, 148.3, 164.2.
IR: 2955, 2929, 2858, 1719, 1550, 1459, 1433, 1387, 1249,
1148, 1133, 1043, 972, 816, 666 cm–1. HRMS: m/z [M + H+]
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(23) Tandem RCM/CM Process: A solution of ester 3 (250 mg,
1.5 mmol) and 4-bromobutene (0.45 mL, 4.3 mmol) in
CH2Cl2 (150 mL) was deoxygenated by bubbling argon for
10 min. Grubbs’ II catalyst (2; 32 mg, 0.04 mmol) was added
at once and the resulting solution was heated at 40 °C until
complete disappearance of the starting material (TLC
control). The solution was concentrated and purified by flash
chromatography on silica leading to 4 as a colorless oil.
Compound 4: 1H NMR (300 MHz, CDCl3): d = 2.48 (br t,
J = 6.0 Hz, 2 H), 2.58 (br q, J = 6.0 Hz, 2 H), 3.03–3.05 (m,
2 H), 3.38 (t, J = 6.9 Hz, 2 H), 5.00–5.03 (m, 1 H), 5.33–5.60
(m, 2 H), 5.86 (br s, 2 H). 13C NMR (75 MHz, CDCl3): d =
29.9, 32.2, 35.8, 38.5, 78.9, 121.8, 125.7, 126.3, 131.7,
168.8. IR: 701, 734, 972, 1073, 1226, 1267, 1380, 1738,
2923, 3034 cm–1. HRMS: m/z [M] calcd for C10H13O2Br:
245.0177; found: 245.0177. Compound 5: 1H NMR (300
MHz, CDCl3): d = 2.29–2.38 (m, 2 H), 2.46–2.50 (m, 2 H),
3.03–3.05 (m, 2 H), 3.29 (t, J = 6.8 Hz, 2 H), 4.98–5.03 (m,
1 H), 5.55–5.60 (m, 2 H), 5.84–5.87 (m, 2 H). 13C NMR (75
MHz, CDCl3): d = 30.0, 32.2, 38.7, 50.8, 79.0, 122.0, 125.8,
126.4, 131.0, 168.8. IR: 701, 734, 972, 1073, 1226, 1267,
1380, 1738, 2923, 3034 cm–1. HRMS: m/z [M + H+] calcd for
C10H14O2N3: 208.1086; found: 208.1085.
Synlett 2010, No. 17, 2621–2624 © Thieme Stuttgart · New York

2624
F. Cros et al.
LETTER
calcd for C16H24O2N3: 290.1863; found: 290.1862.
(m, 1 H), 8.08 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 28.6,
33.3, 37.6, 50.2, 52.2, 77.0, 121.2, 127.6, 127.7, 128.6,
128.6, 145.2, 161.1, 164. 2. IR: 778, 815, 1044, 1207, 1231,
1248, 1366, 1387, 1435, 1543, 1720, 2917, 2950 cm–1.
HRMS: m/z [M + Na+] calcd for C14H17O4N3: 314.1111;
found: 314.1106. Compound 8e: 1H NMR (300 MHz,
CDCl3): d = 0.28 (s, 9 H), 2.17–2.22 (m, 2 H), 2.25–2.47 (m,
2 H), 2.57–2.69 (m, 2 H), 4.30–4.43 (m, 1 H), 4.40 (t, J = 6.9
Hz, 2 H), 5.45–5.50 (m, 2 H), 5.97 (dt, J = 9.6, 1.7 Hz, 1 H),
6.81–6.87 (m, 1 H), 7.50 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = –1.0, 28.7, 33.6, 37.8, 49.3, 77.2, 121.3, 127.8,
127.9, 129.0, 129.3, 145.2, 146.6, 164.3. IR: 655, 759, 816,
843, 972, 1043, 1116, 1146, 1194, 1249, 1387, 1424, 1490,
1719, 2851, 2917, 2955 cm–1. HRMS: m/z [M + Na+] calcd
for C15H23O2N3Si: 328.1452; found: 328.1440.
Compound 8c: 1H NMR (300 MHz, CDCl3): d = 0.83 (t, J =
7.0 Hz, 3 H), 1.22 (br s, 12 H), 1.50–1.57 (m, 2 H), 2.13–2.29
(m, 2 H), 2.31–2.45 (m, 2 H), 2.56–2.67 (m, 2 H), 3.46 (t,
J = 6.8 Hz, 2 H), 4.30–4.41 (m, 1 H), 4.36 (t, J = 6.9 Hz, 2
H), 4.55 (s, 2 H), 5.39–5.56 (m, 2 H), 5.96 (d, J = 9.6 Hz, 1
H), 6.81–6.87 (m, 1 H), 7.52 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 14.1, 22.7, 26.1, 28.6, 29.3, 29.5, 29.6, 29.7,
31.9, 33.4, 37.7, 49.9, 64.3, 71.0, 77.1, 121.2, 122.5, 128.0,
129.1, 145.2, 145.5, 164.3. IR: 666, 814, 971, 1044, 1097,
1245, 1382, 1429, 1459, 1720, 2851, 2926 cm–1. HRMS:
m/z [M + Na+] calcd for C22H35O3N3: 412.2571; found:
412.2566. Compound 8d: 1H NMR (300 MHz, CDCl3): d =
2.18–2.27 (m, 2 H), 2.29–2.46 (m, 2 H), 2.61–2.75 (m, 2 H),
3.92 (s, 3 H), 4.35 (q, J = 6.2 Hz, 1 H), 4.46 (t, J = 7.0 Hz, 2
H), 5.40–5.64 (m, 2 H), 5.99 (d, J = 9.9 Hz, 1 H), 6.81–6.87
Synlett 2010, No. 17, 2621–2624 © Thieme Stuttgart · New York

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