Direct domino synthesis of azido-dienoic acids: Potential linker units

Article abstract of DOI:10.1055/s-0033-1338452

We report an atom-economical domino synthesis of functionalized and stereodefined dienes. This method hinges on an allylic alkylation-electrocyclic ring-opening sequence and allows direct access to doubly vinylogous azido-dienoic acids bearing challenging

Full text of DOI:10.1055/s-0033-1338452

1286▌
LETTER
lDettierrect Domino Synthesis of Azido-Dienoic Acids: Potential Linker Units
Domino Synthesis of Azido-Dienoic Acids
Caroline Souris, Frédéric Frébault, Davide Audisio, Christophe Farès, Nuno Maulide*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
E-mail: maulide@kofo.mpg.de
Received: 13.02.2013; Accepted after revision: 05.04.2013
presumably through electrocyclic ring opening of the pu-
Abstract: We report an atom-economical domino synthesis of
tative (expected) cyclobutene adducts.9,10 We thus became
functionalized and stereodefined dienes. This method hinges on an
interested in employing nitrogen-based nucleophiles to
achieve a similar outcome.
allylic alkylation–electrocyclic ring-opening sequence and allows
direct access to doubly vinylogous azido-dienoic acids bearing
challenging substitution patterns. This class of compounds re-
presents useful linkers in chemical biology by virtue of the ortho-
gonality between the azido and carboxylic acid moieties.
O
prior work
O
O
(soft) C-nucleophiles
Pd(0)
OH
a)
Key words: azide, dienes, electrocyclic, allylic alkylation, bio-
conjugation
O
one step
Nu
1a
The azido functional group has experienced a dramatic re-
surgence in the past decade as a useful synthetic handle.1,2
Indeed, its reactivity both in the absence and presence of
transition-metal promoters has been extensively studied.3
Azides are usually regarded as ‘high-energy’ substituents
and are thus prone to undergo various useful transforma-
tions with both electrophiles and nucleophiles, giving rise
to a colorful palette of reactivity. The blossoming of
‘click’ chemistry as a paradigm in medicinal chemistry, of
which the Huisgen azide–alkyne cycloaddition is the most
familiar exponent, has definitely contributed to this
scenario.4
prior work
ArONa
Pd(0)
ArO
HO
b)
O
O
one step
1a
(Z,E)-2
Scheme 1 Prior work using soft C- and O-nucleophiles
After initial unsuccessful experiments with phthalimide
and related aminated nucleophiles, our attention focused
on trimethylsilyl azide. Palladium-catalyzed allylic alkyl-
ation employing azide sources has been reported as a ver-
satile route for the introduction of nitrogen into an allylic
system.11
The introduction of an azide moiety into the structure of
organic compounds is usually accomplished by the use of
N3 nucleophilic species, most commonly NaN3 and
TMSN3. Therefore, it is not surprising to note that alkyl
and aryl azides2 are well-represented classes of com-
pounds in organic chemistry, with several reports high-
lighting the advantages conferred by the presence of the
N3 scaffold in medicinal chemistry.5 Nevertheless, only
rare examples of vinyl and dienyl azides have been report-
ed so far.6,7 In particular, it would be interesting to inves-
tigate the behavior of such compounds in the context of
‘click’ applications. Herein, we report the direct synthesis
of various dienyl azides bearing a carboxylate substituent
as well as their orthogonal functionalization, suggestive of
applications as linker subunits in chemical biology.
In the event, the use of TMSN3 in combination with
Pd(PPh3)4 cleanly afforded the E,E-dienyl azide 4a,12 im-
plying the intermediacy of a cyclobutene adduct with
trans configuration prior to spontaneous electrocyclic
ring opening (Scheme 2).13
We then proceeded to investigate the scope and limita-
tions of this transformation. As depicted in Scheme 3, var-
ious azido dienes can be synthesized by the palladium-
catalyzed azidation of lactones 1b,c in good to excellent
yields.14,15 The mildness of the reaction conditions allows
this transformation to take place at 0 °C.
Interestingly, bicyclo[2.2.0]lactones are not the only via-
ble substrates. As shown, lactam 1d (Scheme 3b), readily
available through photoisomerization of N-tosylpyridin-
2-one,16 can be ring-opened under similar conditions to
deliver the dienyl sulfonamide 4d in 62% yield. This is, to
the best of our knowledge, a rare direct and atom-econom-
ical synthesis of vinyl (dienyl) azides (vide infra).6,7
We have recently developed a catalytic allylic alkylation
strategy to convert lactone 1a into disubstituted
cyclobutenes8 (Scheme 1a). This approach has enabled
the preparation of several interesting products in high
yields and stereoselectivities. During the course of these
studies, it was observed that phenoxide nucleophiles sur-
prisingly led to stereodefined diene products (Scheme 1b),
Of note, the ensemble of diene products 4a–d in Schemes
1
2 and 3 offered the opportunity to identify H NMR pa-
rameters which eventually proved to be reliable ‘spectral
fingerprints’ of the azido diene geometry, even in the ab-
sence of the opposite stereoisomer.17 The combined use of
SYNLETT 2013, 24, 1286–1290
Advanced online publication: 08.05.2013
DOI: 10.1055/s-0033-1338452; Art ID: ST-2013-D0143-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Domino Synthesis of Azido-Dienoic Acids
1287
O
TMSN3 (2.0 equiv)
Pd(PPh3)4 (5 mol%)
O
O
O
O
N3
OH
THF, 0 °C
1a
N3
3a
4a 81%
Scheme 2 Domino allylic alkylation–4π electrocyclic ring opening of lactone 1a
the magnitude of the three-bond scalar couplings across These cycloadditions, which can be catalyzed by Cu(II) or
the double bond and the chemical shifts of the proton at take place under metal-free conditions23 in solvent or buf-
position 3 and 4 (Scheme 3) were generally reproducible fer solution,24,25 lead to 1-dienyl-1,2,3-triazoles 5a–e in
for all compounds with the E,E geometry, rendering the good yields (Scheme 4). Interestingly, a propargylated bi-
more tedious measurements of NOE or 13C NMR super- otin derivative21 is a suitable substrate for this transforma-
3
fluous.18 Indeed, JHH couplings of 13.0–13.3 Hz (E) in tion, leading to adduct 5e.
contrast to 7.0–9.0 Hz (Z)19 in the case of reported azide–
olefins, of 15.0–15.4 (E) in contrast to 11.3–11.6 Hz (Z)
COOH
R1
N3
R2
in the case of carbonyl–olefins, were observed for the
4a
conditions
products 4a–d. In addition, 1H chemical shifts at position
N
+
N
4 (γ to azide substituents at position 5) were low-field
shifted to δ = 6.1–6.9 ppm in the E configuration com-
pared to the expected shift δ = 5.0–6.0 ppm for the Z con-
figuration. A similar γ induction is observed for the proton
at position 3, with the chemical shift strongly correlating
with the geometry of the carbonyl group (δ = 6.7 ppm for
the Z vs. δ = 6.1–6.3 ppm for the E) irrespective of the sub-
stitution at position 2.20
N
COOH
R
5a–e
MeO
COOH
N
N
N
N
N
N
5a
COOH
80%a
85%c
5b
79%a
R
O
1
O
TMSN3 (2.0 equiv)
Pd(PPh3)4 (5 mol%)
5
3
a)
N3
OH
2
4
THF, 0 °C
O
N
R
N
N
N
N
COOH
1b R = Me
1c R = n-Bu
4b 98%
4c 47%
N
COOH
5c
5d
73%a
quantitativeb
O
1
O
TMSN3 (2.0 equiv)
Pd(PPh3)4 (5 mol%)
3
5
O
DmTr
H
b)
N3
NHTs
N
THF, 0 °C
4
2
N
Ts
N
H
1d
4d 62%
MeO
COOH
Scheme 3 Scope of the domino synthesis of azido dienes; yields re-
fer to analytically pure, isolated compounds
N
S
N
N
4
OMe
HOOC
5e
63%a
It is important to note that, in the cases of substituted azido
dienes 4b,c, rapid analysis of the crude mixture at room
temperature by 1H NMR revealed the simultaneous pres-
ence of variable amounts of compounds bearing only one
olefinic moiety.21 These proved to be the metastable cy-
clobutenes 3b and 3c, identified by typical δ = 6.3–6.5
ppm alkene chemical shifts and 3JHH couplings of 2.8 Hz.
Compounds 3b,c slowly underwent ring opening upon
standing in solution at room temperature, as the mixtures
converted into a single product in the form of dienes 4b,c.
DmTr =
Scheme 4 Click reactions of azido diene 4a. Reagents and condi-
tions: a conditions A: CuSO4·5H2O, sodium ascorbate, THF–H2O, r.t.;
b conditions B: THF, r.t.; yields refer to isolated compounds; c conditions
C: CuSO4·5H2O, sodium ascorbate, Tris·HCl (0.1 M), t-BuOH–H2O,
r.t.
On the other hand, the presence of the carboxylic acid res-
idue affords opportunities for the conjugation with bio-
molecules under reaction conditions that are entirely
different of those of ‘click’ chemistry (Scheme 5). Amida-
tion with either benzylamine or L-tyrosine (to amides
6a,b) proceeded uneventfully, as did esterification with
digitoxigenin to deliver ester 6c. Digitoxigenin as well as
biotin are haptens,26,27 that is, substances which do not
stimulate antibody formation. A hapten can typically elicit
The azido-dienoic acids 4a–d are interesting compounds
due to the presence of rich, potentially orthogonal func-
tionality. For instance, the direct inclusion of an azide
substituent at one of the termini suggests opportunities for
the conjugation to biomolecules through well-established
catalytic 1,3-dipolar cycloadditions (‘click’ chemistry).22
Indeed, these compounds smoothly undergo regioselec-
tive cycloaddition with internal and terminal alkynes.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1286–1290

1288
C. Souris et al.
LETTER
O
O
conditions A or B
nucleophile
+
N3
OH
N3
Nu
4a
6a–c
O
O
OH
H
O
O
O
H
OH
N3
N
H
N3
O
N3
N
H
COOt-Bu
H
6a 55%
6b 71%
6c 22%
Scheme 5 Coupling reactions of azido-dienoic acids 3; for details about reaction conditions, see the Supporting Information
immune response only when attached to a carrier (such as should render these derivatives attractive linkers for
a protein), and usage of a linker subunit for that purpose chemical biology.
can be of potential interest. While these results are only
preliminary forays into bioconjugation chemistry, the
Acknowledgement
flexibility and ease of access to dienes 628 suggests that
We are grateful to the Max-Planck Society and the Max-Planck-In-
stitut für Kohlenforschung for generous funding of our research
programs. The project ‘Sustainable Chemical Synthesis (SusChem-
Sys)’ is cofinanced by the European Regional Development Fund
(ERDF) and the state of North Rhine-Westphalia, Germany, under
the Operational Programme ‘Regional Competitiveness and Em-
ployment’ 2007–2013. Invaluable assistance from our NMR
Department (B. Gabor, C. Wirtz, D. Bartels) is acknowledged.
fine-tuning of a desired chemical property through intro-
duction of an appropriate substituent might make them
useful tools for chemical biology.
The orthogonality of the conditions required for manipu-
lation of either termini of dienes 4 is showcased in
Scheme 6, where it is shown that amidation and ‘click’ of
the parent compound 4a can be performed in any order.
This azido-dienoic acid can thus be seen as a novel, indi-
rect linker unit between an amine/alcohol and an alkyne.
The possibility to fine-tune the UV absorption of com-
pounds 4 by the inclusion of appropriate substituents fur-
ther raises the potential interest of these azido dienes in
terms of future applications.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) (a) Patai, S. In The Chemistry of the Azido Group; Wiley
Interscience: London, 1971, 1–626. (b) Bertrand, G.;
Majoral, J.-P.; Baceiredo, A. Acc. Chem. Res. 1986, 19, 17.
(c) Yoffe, A. D. In Developments in Inorganic Chemistry;
Colbrun, C. B., Ed.; Elsevier: Amsterdam, 1966, 72.
(d) Banert, K. In Organic Azides: Syntheses and
In conclusion, we have developed a direct, stereoselective
catalytic synthesis of azido-dienoic acids, a hitherto un-
known class of compounds with potentially useful appli-
cations. The orthogonality between the azido and
carboxylic acid moieties has been demonstrated and
Applications; Bräse, S.; Banert, K., Eds.; Wiley: Chichester,
MeO
H
CuSO4⋅5H2O
N3
OH
N3
N
COOt-Bu
6a 55%
Na ascorbate
EDCI, HOBt
N
O
O
N
OH
CH2Cl2
0 °C to r.t.
4a
t-BuOH–H2O
N
r.t.
O
OH
5a 80%
CuSO4⋅5H2O
Na ascorbate
t-BuOH–H2O, r.t.
EDCI, HOBt
CH2Cl2, 0 °C to r.t.
60%
MeO
47%
H
N
N
N
COOt-Bu
N
O
OH
7
Scheme 6 Versatile use of azido-dienoic acid 4a as linker
Synlett 2013, 24, 1286–1290
© Georg Thieme Verlag Stuttgart · New York

LETTER
2010. (e) Hassner, A. In Azides and Nitrenes; Scriven, E. F.
Domino Synthesis of Azido-Dienoic Acids
1289
isomer in a 1:1 ratio and lower yield (65%). For details, see
the Supporting Information.
V., Ed.; Academic Press: Orlando, 1984.
(2) For a recent review on azides, see: Bräse, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem. Int. Ed. 2005,
44, 5188.
(3) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297; see
also ref. 2.
(4) For a review on the use of azides in medicinal chemistry,
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L.; Sorba, G.; Genazzani, A. A. Med. Res. Rev. 2008, 28,
278.
(13) Even if azido nucleophiles generally lead to products of
global retention in palladium-mediated allylic alkylation,
exceptions are well documented in the literature (especially
when a monodentate ligand is used). See, for example:
Murahashi, S. I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J.
Org. Chem. 1989, 54, 3292.
(14) The reaction can be performed in up to 3.0 mmol scale
affording 350 mg of the desired dienoic acid 4a.
(15) General Procedure for the Synthesis of Azidodiene 4
In a Schlenk flask, Pd(PPh3)4 (9.0 mg, 8 μmol, 5 mol%) was
evacuated/backfilled with argon three times and dissolved in
THF (3.1 mL). TMSN3 (36 μL, 0.312 mmol, 2.0 equiv) was
added to the stirred solution of Pd(PPh3)4, and the mixture
was cooled to 0 °C. After 5 min, an Et2O solution of lactone
1 (0.20 M in Et2O, 0.78 mL, 0.156 mmol, 1.0 equiv) was
added dropwise to the mixture, and the mixture was then
stirred at 0 °C for 2 days. The solution was quenched with
H2O, and Et2O was added to the mixture. The organic phase
was extracted three times with sat. NaHCO3. The aqueous
phases were acidified using 1 M HCl, extracted three times
with EtOAc, and the combined extracts were evaporated to
give the azido diene.
(5) (a) For examples of azide-containing compounds in
medicinal chemistry, see: Klumpp, K.; Kalayanov, G.; Ma,
H.; Le Pogam, S.; Leveque, V.; Jiang, W. R.; Inocencio, N.;
De Witte, A.; Rajyaguru, S.; Tai, E.; Chanda, S.; Irwin, M.
R.; Sund, C.; Winqist, A.; Maltseva, T.; Eriksson, S.; Usova,
E.; Smith, M.; Alker, A.; Najera, I.; Cammack, N.; Martin,
J. A.; Johansson, N. G.; Smith, D. B. J. Biol. Chem. 2008,
283, 2167. For a drug containing the azido group, see
(b) Zidovudine and its properties: Imming, P.; Sinning, C.;
Meyer, A. Nat. Rev. Drug. Discovery 2006, 5, 821.
(6) For vinyl azide syntheses, see: (a) Huang, X.; Shen, R. W.;
Zhang, T. X. J. Org. Chem. 2007, 72, 1534. (b) Telvekar, V.
N.; Takale, B. S.; Bachhav, H. M. Tetrahedron Lett. 2009,
50, 5056. (c) L’abbé, G.; Hassner, A. Angew. Chem., Int. Ed.
Engl. 1971, 10, 98. (d) Hassner, A.; Boerwinkle, F. P.; Levy,
A. B. J. Am. Chem. Soc. 1972, 27, 4879.
(7) For examples of dienyl azide synthesis, see: (a) Dong, H.;
Shen, M.; Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.;
Driver, T. G. Org. Lett. 2007, 9, 5191. (b) Banert, K.;
Kohler, F.; Melzer, A.; Scharf, I.; Rheinwald, G.; Ruffer, T.;
Lang, H. Synthesis 2011, 1561. (c) Banert, K.; Grimme, S.;
Herges, R.; Hess, K.; Kohler, F.; Muck-Lichtenfeld, C.;
Wurthwein, E. U. Chem. Eur. J. 2006, 12, 7467. (d) Fotsing,
J. R.; Banert, K. Synthesis 2006, 261.
(2E,4E)-5-Azidopenta-2,4-dienoic Acid (4a)
Compound 4a was obtained as a yellow powder in 81% yield
according to the general procedure. 1H NMR (300 MHz,
CD3COCD3): δ = 7.30 (dd, J = 15.4, 11.4 Hz, 1 H), 7.01 (d,
J = 13.2 Hz, 1 H), 6.18 (dd, J = 13.2, 11.4 Hz, 1 H), 5.90 (d,
J = 15.4 Hz, 1 H). 13C NMR (75 MHz, CD3COCD3): δ =
167.8, 142.6, 138.8, 120.7, 118.2. FTIR (neat): νmax = 2926,
2567, 2283, 2103, 1673, 1619, 989 cm–1. ESI-HRMS: m/z
calcd for C5H5N3O2 [M]+: 139.0380; found: 139.0382.
(16) (a) Dilling, W. L. Org. Photochem. Synth. 1976, 2, 5. (b) For
the synthesis of 2-tosyl-2-azabicyclo[2.2.0]hex-5-en-3-one
(1d), see also ref. 9c.
(8) (a) Frébault, F.; Luparia, M.; Oliveira, M. T.; Goddard, R.;
Maulide, N. Angew. Chem. Int. Ed. 2010, 49, 5672.
(b) Luparia, M.; Audisio, D.; Maulide, N. Synlett 2011, 735.
(c) Luparia, M.; Oliveira, M. T.; Audisio, D.; Frébault, F.;
Goddard, R.; Maulide, N. Angew. Chem. Int. Ed. 2011, 50,
12631. (d) Audisio, D.; Luparia, M.; Oliveira, M. T.; Kluett,
D.; Maulide, N. Angew. Chem. Int. Ed. 2012, 51, 7314.
(9) For spontaneous ring-opening of push–pull cyclobutenes,
see: (a) Gauvry, N.; Huet, F. J. Org. Chem. 2001, 66, 583.
(b) Gourdel-Martin, M. E.; Huet, F. J. Org. Chem. 1997, 62,
2166. (c) Youcef, R. A.; Boucheron, C.; Guillarme, S.;
Legoupy, S.; Dubreuil, D.; Huet, F. Synthesis 2006, 633.
(10) For spontaneous ring-opening of cyclobutenes, see:
(a) Binns, F.; Hayes, R.; Ingham, S.; Saengchantara, S. T.;
Turner, R. W.; Wallace, T. W. Tetrahedron 1992, 48, 515.
(b) Binns, F.; Hayes, R.; Hodgetts, K. J.; Saengchantara, S.
T.; Wallace, T. W.; Wallis, C. J. Tetrahedron 1996, 52,
3631. (c) Sheldrake, H. M.; Wallace, T. W.; Wilson, C. P.
Org. Lett. 2005, 7, 4233. (d) Ingham, S.; Turner, R. W.;
Wallace, T. J. Chem. Soc., Chem. Commun. 1985, 1664.
(11) For examples of allylic alkylation with azides, see:
(a) Murahashi, S. I.; Tanigawa, Y.; Imada, Y.; Taniguchi, Y.
Tetrahedron Lett. 1986, 27, 227. (b) Trost, B. M.; Pulley, S.
R. Tetrahedron Lett. 1995, 36, 8737. (c) Safi, M.; Fahrang,
R.; Sinou, D. Tetrahedron Lett. 1990, 31, 527. (d) Trost, B.
M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
(e) Liao, M. C.; Duan, X. H.; Liang, Y. M. Tetrahedron Lett.
2005, 46, 3469. (f) Chang, C. W.; Norsikian, S.; Guillot, R.;
Beau, J. M. Eur. J. Org. Chem. 2010, 2280. (g) Tenaglia, A.;
Waegell, B. Tetrahedron Lett. 1988, 29, 4851.
(17) See Supporting Information for details.
(18) Dorie, J. P.; Martin, M. L.; Odiot, S.; Tonnard, F. Org.
Magn. Reson. 1973, 5, 265.
(19) Isomura, K.; Okada, M.; Taniguchi, H. Chem. Lett. 1972,
629.
(20) It should be noted, however, that these rules, while
applicable to the series at hand, should not be used
indiscriminately without consideration for possible steric
and electronic effects of additional substitutions. See
Supporting Information for tabular data on coupling
constants and chemical shifts.
(21) For further details, see Supporting Information.
(22) For overviews of ‘click’ chemistry, see: (a) Huisgen, R. In
1,3-Dipolar Cycloadditional Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984, 1–176. (b) Kolb, H. C.; Finn, M.
G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
(c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (d) Tornoe, C.
W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (e) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H.
Eur. J. Org. Chem. 2006, 51.
(23) General Procedure for the Click Reaction According to
Conditions B
To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0
equiv) in THF (0.5 mL) was added the corresponding
acetylene (0.21 mmol, 2.0 equiv) followed by H2O (0.25
mL). The reaction mixture was stirred at r.t. for 12 h. EtOAc
was added to the mixture, and the resulting solution was
washed with three times with 1 M HCl. The organic phase
was dried over MgSO4, filtered, and the solvent was
removed under vacuum to afford the desired triazole 5d.
(12) In the absence of Pd0, a notoriously slow background
reaction leading to the same product takes place. The use of
NaN3 as nucleophile afforded azidodiene 4a and its olefin
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1286–1290

1290
C. Souris et al.
LETTER
(2E,4E)-5-(4,5,6,7,8,9-Hexahydro-1H-
cycloocta[d][1,2,3]triazol-1-yl)penta-2,4-dienoic Acid
(5d)
Petsotas, M.; Livaniou, E. Appl. Biochem. Biotechnol. 2010,
162, 221.
(28) General Procedure for the Coupling of N-Nucleophiles
(Conditions A)
Compound 5d was obtained in quantitative yield. 1H NMR
(500 MHz, CD3COCD3): δ = 7.71 (d, J = 13.6 Hz, 1 H), 7.50
(dd, J = 15.4, 11.9 Hz, 1 H), 7.26 (dd, J = 13.6, 11.9 Hz, 1
H), 6.20 (d, J = 15.4 Hz, 1 H), 2.96 (t, J = 6.7 Hz, 2 H), 2.88
(t, J = 6.7 Hz, 2 H), 1.89–0.86 (m, 8 H). 13C NMR (125 MHz,
CD3COCD3): δ = 167.7, 145.7, 142.4, 134.5, 130.4, 124.2,
To a solution of azido diene 4a (15 mg, 0.11 mmol, 1.0
equiv) and amine 10.12 mmol, 1.1 equiv) in CH2Cl2 (2 mL)
were added HOBt (16 mg, 0.12 mmol, 1.1 equiv) and EDCI
(23 mg, 0.12 mmol, 1.1 equiv) at 0 °C. The resulting mixture
was allowed to warm to r.t. and stirred for 12 h. H2O (5 mL)
and CH2Cl2 (5 mL) were added, and the organic layer was
washed with sat. NaHCO3, brine, and dried over MgSO4.
After filtering, the solvent was removed under vacuum, and
the product was purified by column chromatography on
silica gel (pentane–EtOAc, 95:5) to afford the desired
amides 6.
119.4, 29.5, 26.9, 26.8, 25.4, 25.1, 21.7. FTIR (neat): νmax
=
2922, 2859, 1683, 1619, 1049, 995 cm–1. ESI-HRMS: m/z
calcd for C13H16N3O2 [M – H]–: 246.1259; found: 246.1248.
(24) General Procedure for the Click Reaction According to
Conditions A
To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0
equiv) and the corresponding acetylene (0.21 mmol, 2.0
equiv) in THF (0.5 mL) was added a solution of
(S)-tert-Butyl 2-[(2E,4E)-5-Azidopenta-2,4-dienamido]-
3-(4-hydroxyphenyl)propanoate (6a) Compound 6a was
obtained as a pale yellow oil in 55% yield. 1H NMR (500
MHz, CD3COCD3): δ = 8.23 (s, 1 H), 7.28 (br d, J = 8.5 Hz,
1 H), 7.15 (app t, J = 12.7 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 2 H),
6.87 (d, J = 12.7 Hz, 1 H), 6.74 (d, J = 7.5 Hz, 2 H), 6.11 (d,
J = 14.8 Hz, 1 H), 6.05 (app t, J = 12.7 Hz, 1 H), 4.62 (m, 1
H), 2.98 (dd, J = 13.9, 6.1 Hz, 1 H), 2.91 (d, J = 13.9, 8.1 Hz,
1 H), 1.39 (s, 9 H). 13C NMR (125 MHz, CD3COCD3): δ =
171.7, 165.8, 157.1, 137.8, 136.9, 131.3 (2 C), 128.7, 124.1,
118.6, 115.9 (2 C), 81.6, 55.4, 37.8, 28.1 (3 C). FTIR (neat):
CuSO4·5H2O (5.4 mg, 0.02 mmol, 0.2 equiv) in H2O (0.25
mL) followed by a solution of sodium ascorbate (13 mg,
0.06 mmol, 0.6 equiv) in H2O (0.25 mL). The reaction
mixture was stirred at r.t. for 12 h. EtOAc was added to the
mixture, and the resulting solution was washed three times
with 1 M HCl. The organic phase was dried over MgSO4,
filtered, and the solvent was removed under vacuum to
afford the desired triazole 5.
(25) Procedure for the Click Reaction in Buffer Solution
To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0
equiv) and the corresponding acetylene (0.21 mmol, 2.0
equiv) in t-BuOH (0.5 mL) was added a solution of
CuSO4·5H2O (5.4 mg, 0.02 mmol, 0.2 equiv) in H2O (0.25
mL), followed by a solution of sodium ascorbate (13 mg,
0.06 mmol, 0.6 equiv) in H2O (0.25 mL). Finally, a 0.5 mL
solution of 0.1 M Tris·HCl in H2O was added. The reaction
mixture was stirred at r.t. for 12 h. EtOAc was added to the
mixture, and the resulting solution was washed three times
with 1 M HCl. The organic phase was dried over MgSO4,
filtered, and the solvent was removed under vacuum to
afford the desired triazole 5a.
ν
max = 3303, 2978, 2939, 2106, 1719, 1513, 1147 cm–1. ESI-
HRMS: m/z calcd for C18H22N4O4Na [M + Na+]: 381.1534;
found: 381.1533.
General Procedure for the Coupling of O-Nucleophiles
To a stirred solution of azido diene 4a (0.07 mmol, 1.0
equiv) in CH2Cl2 (1 mL) were added DMF (1 drop) followed
by oxalyl chloride (0.01 mmol, 1.5 equiv) at 0 °C. After 30
min, the solution was added to a mixture of alcohol (0.09
mmol, 1.1 equiv) and NaH (60% in mineral oil, 0.09 mmol,
1.1 equiv) in CH2Cl2 (1 mL). The resulting mixture was
stirred for 12 h at r.t. H2O (5 mL) and CH2Cl2 (5 mL) were
added to the reaction mixture, and the layers were separated.
The organic phase was washed three times with H2O, brine,
and dried over MgSO4. The solvent was removed under
vacuum, and the product was purified by column
chromatography on silica gel (pentane–EtOAc, 6:4) to
afford the desired ester 6.
(2E,4E)-5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-
yl)penta-2,4-dienoic Acid (5a)
Compound 5a was obtained as a yellow paste in 85% yield
according to conditions C. 1H NMR (500 MHz,
CD3COCD3): δ = 8.35 (s, 1 H), 7.94 (d, J = 14.2 Hz, 1 H),
7.50 (dd, J = 15.1, 11.4 Hz, 1 H), 7.21 (dd, J = 14.2, 11.4 Hz,
1 H), 6.17 (d, J = 15.1 Hz, 1 H), 4.55 (s, 2 H), 3.35 (s, 3 H).
13C NMR (125 MHz, CD3COCD3): δ = 167.3, 146.5, 141.8,
(2E,4E)-(3S,10S,13R,14S,17R)-14-Hydroxy-10,13-
dimethyl-17-(5-oxo-2,5-dihydrofuran-3-
yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 5-
Azidopenta-2,4-dienoate (6c)
132.4, 128.8, 122.1, 119.2, 66.0, 58.1. FTIR (neat): νmax
=
3094, 2931, 2887, 1677, 1644, 1619, 1044, 993 cm–1. ESI-
HRMS: m/z calcd for C9H10N3O3 [M – H]–: 208.0726; found:
208.0728.
Compound 6c was obtained as a colorless solid in 22% yield.
1H NMR (500 MHz, CD3COCD3): δ = 7.29 (m, 1 H), 7.01 (t,
J = 11.3 Hz, 1 H), 6.17 (t, J = 11.8 Hz, 1 H), 5.93–5.87 (m,
2 H), 5.01 (d, J = 18.5 Hz, 1 H), 4.85 (d, J = 18.5 Hz, 1 H),
3.28 (s, 1 H), 2.27–2.11 (m, 2 H), 2.09–2.08 (m, 3 H), 1.96–
1.20 (m, 18 H), 0.98 (s, 3 H), 0.91 (s, 3 H). 13C NMR (125
MHz, CD3COCD3): δ = 176.3, 174.6, 160.8, 124.4, 123.9,
117.8, 115.6, 110.5, 85.5, 74.1, 70.7, 51.8, 50.6, 42.5, 40.4,
40.3, 36.2, 36.0, 33.6, 31.4, 31.4, 27.6, 27.4, 25.8, 24.1, 22.1,
22.0, 16.2. FTIR (neat): νmax = 2929, 2101, 1746, 1701,
1602, 1165, 989 cm–1. ESI-HRMS: m/z calcd for
(26) (a) Landsteiner, K. The Specificity of Serological Reactions;
Harvard University Press: Cambridge (USA), 1945, 156.
(b) Shreder, K. Methods 2000, 20, 372.
(27) For hapten applications, see: (a) Fujii, Y.; Ikeda, Y.; Fujii,
M.; Yamazaki, M. Biol. Pharm. Bull. 1994, 17, 467.
(b) Johnson, R. D.; Runzheimer, H. V.; Sommer, R. G.; Kin,
F. Y. US 4,822,747, 1989. (c) Papasarantos, I.; Klimentzou,
P.; Koutrafouri, V.; Anagnostouli, M.; Zikos, C.; Paravatou-
C28H38N3O5 [M + H]+: 496.2806; found: 496.2809.
Synlett 2013, 24, 1286–1290
© Georg Thieme Verlag Stuttgart · New York