Synthesis and hetero-Michael addition reactions of 2-alkynyl oxazoles and oxazolines

Article abstract of DOI:10.1039/b413604g

A method for the synthesis of 2-alkynyl oxazoles and oxazolines was discussed. These compounds were synthesized from readily available starting materials and were sufficiently polarized to participate in nucleophillic conjugate addition reactions. The addition of an acetate salt to the reaction mixture was found to be improving the overall yield. The conjugate addition reaction of heteronucleophiles to oxazole and oxazoline alkynes offers a versatile approach to produce heterocyclic building blocks for the synthesis of biologically active products.

Full text of DOI:10.1039/b413604g

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C O M M U N I C A T I O N
Synthesis and hetero-Michael addition reactions of 2-alkynyl
oxazoles and oxazolines†
Peter Wipf* and Thomas H. Graham
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260, USA.
E-mail: pwipf@pitt.edu; Fax: +1-412-624-0787; Tel: +1-412-624-8606
Received 6th September 2004, Accepted 10th November 2004
First published as an Advance Article on the web 25th November 2004
Stereoselective conjugate additions of alcohols, amines,
thiols, and halides to C(2)-alkynyl oxazoles and oxazolines
provide a versatile entry to heterocyclic building blocks.
2,4-Disubstituted oxazoles and oxazolines derive biosyntheti-
cally from processing of readily available serine residues by
a nonribosomal peptide synthetase (NRPS)1 and represent a
common structural motif of many biologically active natural
products.2 More specifically, 4-formyl-2-(2-oxoalkyl)oxazoles 1
originate from the joint action of NRPS and polyketide synthase
(PKS),3 a pathway that results frequently in diverse and very po-
tent secondary metabolites such as phorboxazoles,4 disorazoles,5
and the streptogramin group A antibiotics (virginiamycin,6 mad-
umycin II,7 and griseoviridin)8 (Fig. 1). As part of our program
directed towards the synthesis of natural products containing
oxazole moieties,9 we have investigated the conversion of 2-
alkynyl oxazoles into C2-b-heteroatom-substituted oxazoles. We
now report our results involving the conjugate addition of S-, O-,
and N-nucleophiles to 2-alkynyl oxazoles.10 Similar additions
can be conducted on oxazolines.
Fig. 2
envisioned the target aldehyde to arise from 2-ethynyl oxazole
5 (path C). Alternatively, an internal alkyne could be converted
to C(2)-b-ketone 6 via Michael addition of a heteronucleophile
followed by hydrolysis (path D).17
2-Alkynyl oxazoles 5 can be prepared by (a) the cou-
pling of aminoalcohols with an alkynoic acid followed by
cyclodehydration/oxidation,18,19 (b) the transition metal cat-
alyzed cross-coupling of a 2-halo or 2-trifluoromethylsulfonyl
oxazole with a terminal alkyne,20 or (c) the condensation of an a-
diazoketone with a nitrile.21 We selected a cyclization/oxidation
approach since many amino alcohols are commercially available,
alkynes can be readily carbonylated to give alkynoic acids and
expensive and potentially toxic transition metal catalysts are not
required.
Attempts to couple propiolic acid directly to serine methyl
ester resulted in decomposition. TMS and TES protective groups
at the terminal alkyne, while allowing access to the hydrox-
yamide, were too labile to survive the reaction conditions of
the subsequent oxazole formation. The triisopropylsilyl (TIPS)
group proved to be more suitable. Anionic carboxylation of the
commercially available acetylene 7 followed by coupling to serine
methyl ester hydrochloride with PyBOP22 in the presence of
diisopropylethylamine gave hydroxyamide 8 in quantitative yield
(Scheme 1). For large scale preparations, a more cost-effective
strategy involved converting the triisopropylsilylpropynoic acid
to the acid chloride using oxalyl chloride and catalytic DMF. The
crude acid chloride was then coupled to serine methyl ester
hydrochloride in the presence of diisopropylethylamine to afford
8 in 82% overall yield. Cyclization using diethylaminosulfur tri-
fluoride (DAST) occurred rapidly and afforded crude oxazoline
which was oxidized with BrCCl3 and DBU to furnish the desired
Fig. 1
The most common route toward scaffolds 1 and 2 involves
the condensation of an aldehyde with a 2-methyloxazole anion
3 (Fig. 2, path A). Numerous metal counter-ions including
lithium,11 zinc,12 chromium,13 samarium,14 and sodium15 have
been employed in this transformation. A much less frequently
explored disconnection is at the Cb/Cc bond, which requires the
coupling of the C(2)-b-aldehyde 4 with a suitable nucleophile
(path B).16 Consistent with the strategy outlined above, we
18a
oxazole in 74% yield. Removal of the triisopropylsilyl group
with buffered TBAF at ambient temperature gave 9 in low yield.
Conducting the reaction at −78 ◦C increased the yield to 99%.
The 2-ethynyl oxazole 9 is a crystalline solid that can be stored for
months at ambient temperature with no special precautions.23,24
† Electronic supplementary information (ESI) available: experimental
procedures, 1H and 13C NMR spectra for all new compounds. See
http://www.rsc.org/suppdata/ob/b4/b413604g/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 – 3 5
3 1
©

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Scheme 2
Scheme 1
Oxidation of 11 under Trost’s conditions31 gave the 1,3-
dithiolane dioxide 12 in 97% yield. The hydrophilic properties of
12 required an anhydrous workup that involved concentrating
the reaction mixture onto a mixture of Florisil and Celite. The
crude mixture was then directly subjected to chromatography on
silica gel. Using a variation of a method developed by Aggarwal
and co-workers,32 rearrangement of the 1,3-dithiolanedioxide
12 under Pummerer conditions and quenching with ethanethiol
No examples of Michael additions to 2-alkynyl oxazoles have
been reported. However, based on the ease with which the
TBAF deprotection of the TIPS-protected alkyne occurred,
we expected that this substrate would readily participate in
conjugate addition reactions. Indeed, a variety of nucleophiles
including ethanethiol and thiophenol added in moderate to good
yields and with good (Z)-selectivity (Table 1, entries 1–3).25 2-
Mercaptoethanol afforded only the thioenolether and did not
cyclize to the thioxolane even after an extended reaction time
(entry 4). Benzyl alcohol also furnished an adduct with good
kinetic selectivity for the (Z)-isomer, thus allowing access to
enol ethers (entry 5).26 Interestingly, secondary amines produced
(E)-configured adducts in excellent yields (entries 6 and 7).27
Steric hindrance and a basic reaction medium readily explains
the thermodynamic control for the preferred (E)-double bond
geometry in the latter case. In agreement with our results
for conjugate additions of thiols and alcohols, other studies
have determined that the (Z)-selectivity with thiol nucleophiles
strongly depends on the nature of the activating group on the
alkyne, increasing when the substituent is capable of delocalizing
the incipient negative charge.28
To gain access to aldehyde 4, hydrolysis of 10a–f was
attempted under a variety of conditions but only decomposition
products were observed. In order to eliminate the conjugation
of the donor heteroatom with the electron-deficient oxazole
ring and thus facilitate solvolysis, alkyne 9 was exposed to
1,2-ethanedithiol to give the 1,3-dithiolane 11 in 97% yield
(Scheme 2).25 In contrast, 1,3-propanedithiol resulted in an
inseparable mixture of mono- and bis-addition adducts in low
yield. Unfortunately, all attempts to deprotect 11 resulted in
decomposition. We reasoned that the apparently highly labile29
aldehyde 4 could be obtained by a mild Fukuyama reduction30
of the corresponding thioester.
33
gave thioester 13 in 80% yield. Reduction with Pd(OH)2
in dichloromethane gave a new compound by TLC analysis;
however, preparative isolation failed. When the experiment was
conducted in CD2Cl2 and monitored by 1H NMR, no aldehyde
signal was observed. Instead, a pair of doublets with J =
6.4 Hz was observed, at 6.76 and 5.47 ppm. These data suggest
that compound 4 exists predominantly in the tautomeric form
14, which is possibly stabilized by hydrogen bonding to the
oxazole nitrogen.34 However, 14 decomposes in CD2Cl2 at room
temperature with a half-life of several hours, and we were unable
to obtain preparative samples of this compound.
The transient nature of 4 and the shift of the equilibrium to
enol 14 discouraged any further attempts to use this compound
as a synthetic intermediate. However, based on the ease of
preparation of 13, we expected the corresponding ketones to
have greater chemical stability. The 2-alkynyl oxazole 16 was
readily obtained from 15 (Scheme 3). Deprotonation with methyl
lithium followed by the addition of CO2 gave the alkynoic acid.
Coupling with serine methyl ester hydrochloride in the presence
of PyBOP22 and diisopropylethylamine led to the hydroxyamide
in 90% yield over 2 steps. Cyclodehydration with DAST and
oxidation of the crude oxazoline with BrCCl3 and DBU18a gave
16 in 76% yield. 2-Alkynyl oxazole 16 was found to readily accept
ethanedithiol at the b-position to give the 1,3-dithiolane 17 in
94% yield. Further conversion with N-bromosuccinimide in 10%
aqueous acetone35 provided ketone 18 in 77% yield. In contrast,
deprotection with a combination of N-chlorosuccinimide and
silver nitrate35 gave the corresponding dichloroketone 19 in low
Table 1 Conjugate additions of heteronucleophiles to alkynyl oxazole 9 resulting in alkenyl oxazoles 10
Entry
R–H
Additive
Time/ha
Product
(Z/E) ratio
Yield (%)b
1
2
3
4
5
6
7
EtSH
EtSH
PhSH
HO(CH2)2SH
PhCH2OH
Et2NH
n-Bu3P
K2CO3/18-C-6
NMM
n-Bu3P
n-Bu3P
—
36
10a
10a
10b
10c
10d
10e
10f
10.5 : 1.0
16.4 : 1.0
1 : 0
6.4 : 1.0
6.4 : 1.0
0 : 1
70
89
1.5
48
97c
68e
76
25d
0.5
20f
72
100
100
i-Pr2NH
—
0 : 1
a All reactions were conducted at ambient temperature unless noted otherwise. b Yields were determined after purification on SiO2 and refer to the
major isomer, unless stated otherwise. c Purification by recrystallization. d Reaction mixture was heated to 66 ◦C. e Yield is for the (Z/E) mixture.
f Reaction mixture was heated to 60 ◦C.
3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 – 3 5

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Scheme 4
Scheme 3
yield, suggesting that the a-methylene group readily enolizes
under the reaction conditions. Both ketones are markedly more
stable than aldehyde 4.
acid.41–43 Indeed, heating 9 in acetic acid in the presence of so-
dium or lithium halides afforded moderate to good yields of the
corresponding vinyl halides (Table 2). For the preparation of
vinyl bromide 10h, NaBr gave a slightly better (Z/E)-ratio than
LiBr (entry 2 vs. entry 6). For the formation of vinyl iodide 10i,
the (Z/E)-ratio was found to decrease with increasing quantities
of NaI (entries 8, 10, 12) or increasing temperature (entry 10 vs.
entry 13). The presence of lithium or sodium acetate provided
remarkably increased (Z)-selectivities.
Some of the results shown in Table 2 can be explained by an
alkene isomerization, and therefore the pure (Z)-isomers were re-
subjected to the reaction conditions. In the absence of NaOAc,
1.5 to 3.0 equiv. of NaBr and NaI led to a thermodynamic ratio
of 1 : 6–8 for 10h and 10i, in preference for (E)-isomers.44 If
NaOAc was added to the reaction mixture, the rate of (Z)- to
(E)-isomerization decreased dramatically. In addition, NaOAc
also inhibited the isomerization of (E)-10i to (Z)-10i.
Vinyl halides are suitable for a wide range of metal-catalyzed
cross-coupling reactions leading to efficient strategies for C–C
bond formation.45 Iodide (Z)-10i readily participated in the
cross-coupling reaction with trimethylsilylacetylene under typ-
ical Sonogashira conditions to afford (Z)-25 in 89% yield
(Scheme 5). In an analogous fashion, (E)-10i was converted
stereospecifically to (E)-25 in 90% yield.
In conclusion, 2-alkynyl oxazoles and oxazolines are synthe-
sized from readily available starting materials and are sufficiently
polarized to participate in nucleophilic conjugate addition
Oxazolines with additional chelating ligands have found
exceptional use in asymmetric catalysis and are among few “priv-
ileged” metal ligands.36–38 Since a range of heteroatoms could
be introduced in the conjugate addition to 2-ethynyl oxazoles
9, we extended the scope of this process to the corresponding
oxazolines (Scheme 4). Oxazoline 2139 was obtained in 3 steps
from L-phenylalaninol and the TIPS-protected alkynoic acid 20.
As expected, 21 was found to participate readily in the conjugate
addition reaction with thiols. Ethanethiol and even the sterically
hindered t-butyl thiol formed adducts 22 and 23, respectively,
in good to excellent yields and (Z)-selectivity. Interestingly,
similar conditions using thiophenol gave the dithioacetal 24.
These results indicate that the conjugate addition methodology
is equally effective for 2-ethynyl oxazolines as for the correspond-
ing oxazoles. Along with varying the thiol or the C4-substituent
of the oxazoline, the conjugate addition methodology affords
products that offer the potential for further modications. The
mild reaction conditions, good yields and (Z/E)-selectivity offer
significant promise for accessing novel bidentate ligands for
asymmetric catalysis.
Electron-deficient alkynes are known to hydrohalogenate
when exposed to HI or HBr.40 Taniguchi as well as Lu and
co-workers have developed a convenient protocol involving a
lithium halide salt in the presence of acetic or trifluoroacetic
Table 2 Hydrohalogenations of alkynyl oxazole 9 to give alkenyl oxazoles 10 (R = Cl, Br, I).
Entry
H–R
Additive (equiv.)
Time/h
Product
(Z/E) ratioa
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13e
HCl
HBr
HBr
HBr
HBr
HBr
HI
HI
HI
HI
HI
NaCl (1.5)
LiBr (1.5)
LiBr/LiOAc (1.0 : 3.0)
LiBr/LiOAc (1.5 : 4.5)
NaBr (1.0)
NaBr (1.5)
LiI (1.5)
NaI (1.0)
NaI/NaOAc (1.0 : 3.0)
NaI (1.5)
16
16
16
16
20
16
12
12
12
12
12
12
12
10g
10h
10h
10h
10h
10h
10i
10i
10i
10i
10i
10i
10i
1.3 : 1.0
4.0 : 1.0
9.1 : 1.0c
20 : 1.0d
8.0 : 1.0c
9.0 : 1.0c
5.6 : 1.0
10.7 : 1.0
> 50 : 1.0
4.2 : 1.0
9.5 : 1.0
1.1 : 1.0
1.0 : 1.2
62
71 (Z)
70 (Z)
87 (Z)
70 (Z)
68 (Z)
77 (Z)
90 (Z)
92 (Z)
75 (Z)
84 (Z)
70
NaI/NaOAc (1.5 : 1.5)
NaI (3.0)
NaI (1.5)
HI
HI
50
a The (Z/E)-ratio was determined by 1H NMR analysis of the crude reaction mixture after aqueous workup. b Yield refers to material isolated
by chromatography on SiO2. c The crude reaction mixture contained approximately 10% starting material (alkyne). d The crude reaction mixture
contained approximately 3% starting material (alkyne). e The reaction was conducted in a sealed tube at 150 ◦C.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 – 3 5
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16 For an example of a nucleophilic addition to a non-enolizable b-
carbonyl group, see: A. Yanagisawa, Y. Matsuzaki and H. Ya-
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17 A. Nishida, M. Shibasaki and S. Ikegami, S. Chem. Pharm. Bull.,
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Scheme 5
reactions. Although the C2-b-aldehyde 4 proved to be unstable,
alkyne 9 could be converted to 1,3-dithiolane 11 and thioester
13. The 1,3-dithiolane 17, derived from internal alkyne 16, was
readily converted to the C2-b-keto oxazole scaffold found in
numerous biologically active natural products. Internal alkynes
can therefore serve as a masked form of the C2-b-carbonyl
function which can be unveiled under mild conditions. Thioenol
ethers such as 10a and 22–24 represent readily accessible metal-
binding motifs. In addition, hydrohalogenation of 9 affords
predominantly (Z)-configured vinyl bromides and iodides under
kinetic control. The addition of an acetate salt to the reaction
mixture improves the (Z/E)-ratio and the overall yield. The cor-
responding (E)-vinyl halides are obtained under thermodynamic
control. Both (Z)- and (E)-vinyl iodides readily participate in
cross-coupling reactions. Accordingly, the conjugate addition
of heteronucleophiles to oxazole and oxazoline alkynes offers
a unique, mild and flexible approach to C(2)-functionalized
heterocyclic building blocks for the synthesis of biologically
active products.
20 (a) L. A. Dakin, N. F. Langille and J. S. Panek, J. Org. Chem., 2002,
67, 6812; (b) K. J. Hodgetts and M. T. Kershaw, Org. Lett., 2002,
4, 2905; (c) N. F. Langille, L. A. Dakin and J. S. Panek, Org. Lett.,
2002, 4, 2485.
21 (a) Y. Wang, J. Janjic and S. A. Kozmin, J. Am. Chem. Soc., 2002,
˚
124, 13670; (b) R. D. Connell, F. Scavo, P. Helquist and B. Akermark,
Tetrahedron Lett., 1986, 27, 5559.
22 J. Coste, D. Le-Nguyen and B. Castro, Tetrahedron Lett., 1990, 31,
205.
23 While this work was in progress, Hoffmann and co-workers reported
the synthesis of the ethyl ester of 9 by a different route: (a) I. V.
Hartung, U. Eggert, L. O. Haustedt, B. Niess, P. M. Scha¨fer and
H. M. R. Hoffmann, Synthesis, 2003, 1844; (b) L. O. Haustedt, S. B.
Panicker, M. Kleinert, I. V. Hartung, U. Eggert, B. Niess and H. M. R.
Hoffmann, Tetrahedron, 2003, 59, 6967.
24 In contrast, 2-vinyloxazole-4-carboxylic acid ethyl ester is reported
to be unstable to storage: W. A. Donaldson and F. Ahmed, Synth.
Commun., 2003, 33, 2685.
25 H. Kuroda, I. Tomita and T. Endo, Synth. Commun., 1996, 26, 1539.
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27 S. Cossu, O. De Lucchi and R. Durr, Synth. Commun., 1996, 26,
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Acknowledgements
This work has been supported by a grant from the National
Institutes of Health (GM-55433).
28 W. E. Truce and G. J. W. Tichenor, J. Org. Chem., 1972, 37, 2391.
29 Attempts to oxidize 2-(2-hydroxyethyl)oxazole-4-carboxylic acid
methyl ester also resulted in decomposition:
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02), (Z)-10h is 1.8 kcal mol−1 less stable than (E)-10h.
45 See, for example: (a) S.-I. Murahashi, J. Organomet. Chem., 2002,
653, 27; (b) E. Negishi, J. Organomet. Chem., 2002, 653, 34.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 – 3 5
3 5