Ireland-Claisen rearrangement of ynamides: Stereocontrolled synthesis of 2-amidodienes

Article abstract of DOI:10.1016/j.tetlet.2012.07.088

The Ireland-Claisen rearrangement of propargyl ynamido ester substrates is reported. The expected allenamide carboxylic acid products from [3,3]-sigmatropic rearrangement are not isolated, with 2-amidodienes alternatively formed in good yield with high le

Full text of DOI:10.1016/j.tetlet.2012.07.088

Tetrahedron Letters 53 (2012) 5180–5182
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ireland–Claisen rearrangement of ynamides: stereocontrolled synthesis
of 2-amidodienes
⇑
Stephen J. Heffernan, David R. Carbery
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The Ireland–Claisen rearrangement of propargyl ynamido ester substrates is reported. The expected
allenamide carboxylic acid products from [3,3]-sigmatropic rearrangement are not isolated, with 2-amid-
odienes alternatively formed in good yield with high levels of stereocontrol after decarboxylation.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 May 2012
Revised 11 July 2012
Accepted 19 July 2012
Available online 27 July 2012
Keywords:
Sigmatropic
Ireland–Claisen
Furanomycin
Amino acid
Rearrangement
Ynamides have developed a mature and varied area of organic
synthesis in recent years.1 These compounds have been used in a
raft of transition metal catalyzed reactions, such as cycloadditions
and couplings.2 While a strongly electron-donating nitrogen is
tempered by a nitrogen electron-withdrawing protecting group,
the reactivity of ynamides is still pronounced. One area of synthetic
chemistry where ynamides are arguably under-developed is in the
sigmatropic rearrangement chemistry. Reactions such as the
Ireland–Claisen [3,3]-sigmatropic rearrangement3 offer synthetic
versatility, allowing for excellent stereocontrol and the formation
of congested stereocenters.
coupled to 2-oxazolidinone (4), promoted by Cu-catalysis.12 Desi-
lylation mediated by TBAF and subsequent carbodiimide-mediated
esterification formed ynamido substrate 6a in 50% yield over three
steps.
Initial attempts to form an allenamide 3 centered upon utilizing
the protocol developed for the rearrangement of enamides (Table
1).4b However, we were presented with a particularly complex
reaction mixture, with attempted diazomethane-mediated carbox-
ylic acid methylation observed to be non-productive, suggesting
the absence of a carboxylic acid group. After careful chromatogra-
phy, oxazolidinone substituted diene 7a, with the major isomer
We have recently reported the use of enamides in the Ireland–
Claisen [3,3]-sigmatropic rearrangement.4 As part of this area of
research within our group,5 we have utilized ynamides as synthetic
intermediates to the requisite enamide substrates. The availability
of ynamido propargyl alcohols has allowed us to ponder the possi-
bility of conducting an Ireland–Claisen rearrangement of these
ynamido propargyl systems.6,7 If successful, this [3,3]-sigmatropic
rearrangement would offer a novel stereocontrolled entry to
allenamide carboxylic acid fragments (Scheme 1). As allenamides
are important synthetic building blocks,8–10 we felt this rearrange-
ment was worthy of investigation.
R2
O
R2
OSiMe3
R2
CO2H
LiHMDS
Me3SiCl
[3,3]
PG
PG
O
PG
O
N
N
N
Ireland-
Claisen
R1
R3
R1
R3
R1
R3
3
1
2
Scheme 1. Proposed Ireland–Claisen rearrangement of ynamides to allenamides.
O
To examine this proposal, ester 6a was synthesized, incorporat-
ing the phenyl acetate unit which had been shown to be important
1. CuSO4.5H2O,
Ph
O
O
4
K3PO4, PhMe, 110 oC (65%)
NH
O
for the smooth rearrangement of the analogous enamide4b system
O
11
O
2. TBAF, THF (87%)
3. PhCH2CO2H, DCC,
DMAP, CH2Cl2 (88%)
(Scheme 2). Accordingly, bromopropargylsilyl ether 5
was
OTBDPS
Me
N
Br
Me
6a
5
⇑
Corresponding author. Tel.: +44 1225 386 144; fax: +44 1225 386 231.
E-mail address: d.carbery@bath.ac.uk (D.R. Carbery).
Scheme 2. Model substrate synthesis.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.088

S. J. Heffernan, D. R. Carbery / Tetrahedron Letters 53 (2012) 5180–5182
5181
Table 1
Rearrangement optimization
O
Ph
N
CO2H
Me
Ph
LiHMDS
Me3SiCl
Ph
N
O
O
N
O
O
THF, time
temp
O
O
O
6a
3a,
Not Observed
7a
Entry
LiHMDS (equiv)
Me3SiCl (equiv)
Temp (°C)
Time (h)
Yield (%)
Z/E
1
2
1.3
1.3
1.3
1.3
1.3b
1.3
1.3
1.3
1.3
1.3
5.2
2.6
2.3
2
1.3
1.3
0
À78 ? rt
À78 ? rt
À78 ? rt
À78 ? rt
À78 ? rt
À95 ? rt
À78 ? rt
À40 ? rt
À20 ? rt
0 ? rt
À95 ? rt
À95 ? rt
À95 ? rt
À95 ? rt
À95 ? rt
À95 ? rt
À95 ? rt
24
48
24
24
24
1.5
1.5
1.5
1.5
1.5
24
24
24
24
24
24
24
40
41
0
>95:5
>95:5
—
>95:5
>95:5
>99:5
>99:5
—
—
—
—
1:1
3:1
5:1
8:1
>95:5
6:1
3
4a
5
1.3
1.3
1.3
1.05
1.3
1.3
1.3
5.2
2.6
2.3
2
13
25
21
10
0c
6
7
8
9
10
11
12
13
14
15
16
17
0c
0c
0
31
40
42
83
61
19
1.8
1.3
1.05
1.8
1.3
1.05
a
b
c
Reaction conducted in PhMe.
NaHMDS used as base.
Full mass recovery of 6a.
characterized as the Z,E-isomer as displayed was obtained. As dis-
cussed by Hsung, there appears to be no general synthesis of amin-
odienes presently available to the synthesis community, and
therefore new methodologies that offer a controlled entry to such
systems can be viewed as valuable.13 Thus, we sought to optimize
the formation of this amidodiene product (Table 1).
The rearrangement was particularly sensitive to the initial con-
ditions employed (Table 1). For example, low loadings of base and
Me3SiCl resulted in excellent stereocontrol (entries 1–4). The reac-
tion requires the presence of silyl chloride and therefore supports a
traditional Ireland–Claisen process occurring (entry 3). The initiat-
ing temperature is crucial to any rearrangement occurring, with
À95 °C offering the best results (entries 6–10). We feel it is note-
worthy that 6a is re-isolated, with full mass balance, when this
reaction is initiated at À40 °C or higher (entries 8–10). Further-
more, the addition of higher loadings of base and silyl chloride is
also deleterious to the final isolated yield (entries 11–17).
Previous work in our group has demonstrated that the stereo-
controlled formation of aryl-substituted silylketene acetals is a
more complex problem than currently is appreciated where the
E/Z ratios are highly dependent on the loadings of base and silyl
chloride, as well temperature.14 Accordingly, we feel the presently
reported rearrangement is also sensitive to the complications of
forming silylketene acetals from aryl acetate esters.
This diene is presumably the result of a post-rearrangement
decarboxylation. Baldwin has reported the decarboxylation of alle-
nyl carboxylic acids, formed from the Ireland–Claisen rearrange-
ment of propargylic esters.6b,15 However, the decarboxylation
step required forcing thermal conditions (140–250 °C) to accom-
plish the loss of CO2. Therefore, the presence of N-substitution
has a profound effect on this decarboxylation event. With an opti-
mized rearrangement developed on phenyl acetate 6a, we sought
to examine the scope of the aryl acetate moiety (Table 2). The con-
ditions chosen, and in particular the loading of base and silyl chlo-
ride, represents striking a balance between optimized yield and Z/E
selectivity, as highlighted in Table 1. Accordingly, the substrate
scope was studied with 1.8 equiv of LHMDS and Me3SiCl.
Table 2
Scope of ester functionality16
O
Ar
LiHMDS (1.8 equiv.)
TMSCl (1.8 equiv.)
Ar
O
O
O
N
O
THF, -95 °C to rt, 24 h
N
O
6b-j
7b-j
Entry
Ar
Diene
Yield (%)
Z/E
1
2
3
4
5
6
7
8
9
4-Me2NC6H4 (6b)
4-MeOC6H4 (6c)
3,4-(OCH2O)C6H3 (6d)
4-FC6H4 (6e)
7b
7c
7d
7e
7f
7g
7h
7i
53
62
69
67
65
54
73
42
43
>95:5
9:1
2:1
3:1
4:1
2:1
3:1
6:1
2:1
4-ClC6H4 (6f)
4-O2NC6H4 (6g)
4-MeC6H4 (6h)
3-MeC6H4 (6i)
2-MeC6H4 (6j)
7j
This decarboxylative rearrangement can accommodate elec-
tron-rich aryl groups (entries 1–3) and electron-poor aryl groups
(entries 4–6), with reasonable yields obtained in each instance.
The aryl moiety can also cope with ortho, meta, and para-substitu-
tion in a range of tolyl acetates (entries 7–9). We would like to
point out that the final Z/E ratio was highly sensitive to the initial
conditions, as gauged by the extensive optimization of 6a. There-
fore, it may be reasonable to judge that each individual substrate
may in turn have its Z/E selectivity improved through a local opti-
mization process.
This decarboxylative rearrangement has been demonstrated on
alkyl ester 6k (Scheme 3). While, the rearrangement in this
instance is non-optimized, we feel that the excellent levels of Z/E
control are noteworthy and suggest good substrate scope in future
studies.

5182
S. J. Heffernan, D. R. Carbery / Tetrahedron Letters 53 (2012) 5180–5182
Goundry, W. R. F.; Lam, H. W. J. Chem. Soc., Chem. Commun. 2012, 48, 1505; (f)
O
Et
Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 113; (g)
Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem., Int. Ed. 2011, 50,
8931; (h) Kramer, S.; Odabachian, Y.; Overgaard, J.; Rottlaender, M.; Gagosz, F.;
Skrydstrup, T. Angew. Chem., Int. Ed. 2011, 50, 5090.
LiHMDS (1.8 equiv)
TMSCl (1.8 equiv)
Et
O
O
N
O
O
THF, -95 °C to rt, 24 h
Me
7k, 38%, >95:5 Z/E
N
3. For recent reviews concerning the Ireland–Claisen rearrangement, see: (a)
Castro, A. M. Chem. Rev. 2004, 104, 2939; (b) Chai, Y. H.; Hong, S. P.; Lindsay, H.
A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905; (c) McFarland, C.
M.; McIntosh, M. C. The Claisen Rearrangement In Hiersemann, M. N.,
O
6k
Nubbemeyer, U., Eds.; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim:
Scheme 3. Incorporation of alkyl functionality.
Germany, 2007; p 117; (d) Wipf, P. Claisen Rearrangements, Comprehensive
Organic Synthesis. In Vol 5; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
Pergamon: Oxford, 1991; p 827; (e) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem.
Soc. Rev. 2009, 38, 3133.
O
O
O
4. (a) Harker, W. R. R.; Carswell, E. L.; Carbery, D. R. Org. Biomol. Chem. 2012, 1406;
(b) Ylioja, P. M.; Mosley, A. D.; Charlot, C. E.; Carbery, D. R. Tetrahedron Lett.
2008, 49, 1111.
5. (a) Fairhurst, N. W. G.; Mahon, M. F.; Munday, R. H.; Carbery, D. R. Org. Lett.
2012, 14, 756; (b) Tellam, J. P.; Carbery, D. R. Tetrahedron Lett. 2011, 52, 6027;
(c) Tellam, J. P.; Kociok-Köhn, G.; Carbery, D. R. Org. Lett. 2008, 10, 5199; (d)
Tellam, J. P.; Carbery, D. R. J. Org. Chem. 2010, 75, 7809.
6. For examples of Ireland–Claisen and related ester enolate rearrangements of
propargyl systems, see: (a) Rogakos, V.; Georgiadis, D.; Dive, V.; Yiotakis, A. Org.
Lett. 2009, 11, 4696; (b) Baldwin, J. E.; Bennett, P. A. R.; Forrest, A. K. J. Chem.
Soc., Chem. Commun. 1987, 250; (c) Takai, K.; Ueda, T.; Kaihara, H.; Sunami, Y.;
Moriwake, T. J. Org. Chem. 1996, 61, 8728; (d) Ishihara, J.; Koyama, N.; Nishino,
Y.; Takahashi, K.; Hatakeyama, S. Synlett 2009, 2351.
Ph
H
O
Ph
O
PhMe, 110 °C
O
H
N
O
24 h
N
Me
O
O
7a
8
O
9
Not Observed
,
Ph
Ph
O
Me
O
N
N
O
7. For the synthesis of
a-allenyl-a-amino acids through the ester enolate Claisen
O
rearrangement of -amino propargyl esters, see: (a) Casara, P.; Jund, K.; Bey, P.
a
Me
s-trans-7a
Tetrahedron Lett. 1891, 1984, 25; (b) Castelhano, A. L.; Horne, S.; Taylor, G. J.;
Billedeau, R.; Krantz, A. Tetrahedron 1988, 44, 5451; (c) Kazmaier, U.; Goerbitz,
C. H. Synthesis 1996, 1489.
s-cis-7a
8. For a recent review of allenamide chemistry, see: Hsung, R. P.; Wei, L.-L.; Xiong,
H. Acc. Chem. Res. 2003, 36, 773.
Scheme 4. Attempted Diels–Alder reaction and diene conformation.
9. For recent syntheses of allenamides, see: (a) Armstrong, A.; Emmerson, D. P. G.
Org. Lett. 2009, 11, 1547; (b) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2005, 70,
8628; (c) Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett.
2005, 7, 3081; (d) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117.
10. For recent synthetic usage, see: (a) Hayashi, R.; Hsung, R. P.; Feltenberger, J. B.;
Lohse, A. G. Org. Lett. 2009, 11, 2125; (b) Lu, T.; Hayashi, R.; Hsung, R. P.;
DeKorver, K. A.; Lohse, A. G.; Song, Z.; Tang, Y. Org. Biomol. Chem. 2009, 7, 3331;
(c) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430; (d) Manzo, A. M.; Perboni,
A. D.; Broggini, G.; Rigamonti, M. Tetrahedron Lett. 2009, 50, 4696; (e) Chen, G.;
Fu, C.; Ma, S. Org. Lett. 2009, 11, 2900; (f) Brummond, K. M.; Yan, B. Synlett
2008, 2303; (g) Beccalli, E. M.; Broggini, G.; Clerici, F.; Galli, S.; Kammerer, C.;
Rigamonti, M.; Sottocornola, S. Org. Lett. 2009, 11, 1563; (h) Song, Z.; Hsung, R.
P.; Lu, T.; Lohse, A. G. J. Org. Chem. 2007, 72, 9722.
11. Barbazanges, M.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2008, 49, 2902.
12. Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6,
1151.
13. Hayashi, R.; Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G. Org. Lett. 2009, 11,
2125.
14. Harker, W. R. R.; Carswell, E. L.; Carbery, D. R. Org. Lett. 2010, 12, 3712.
15. Craig has studied extensively a decarboxylative Claisen rearrangement. For a
discussion and leading references, see: Camp, J. E.; Craig, D.; Funai, K.; White, A.
J. P. Org. Biomol. Chem. 2011, 9, 7904.
Finally, we briefly examined the feasibility of 7a acting as a
diene component in a Diels–Alder reaction (Scheme 4).17 To assess
this point, diene 7a was refluxed in toluene for 24 h with the reac-
tive dienophile, maleic anhydride (8). Surprisingly, even though an
electron-rich diene is present with an electron-deficient dieno-
phile, no reaction was observed, with 7a recovered with full mass
balance. To account for this interesting observation, we suggest
that the requisite s-cis conformation of 7a cannot be accessed, even
under forcing conditions, from s-trans-7a.
In conclusion, the first Ireland–Claisen [3,3]-sigmatropic rear-
rangement of an ynamido ester is reported. A range of trisubsti-
tuted amidodienes has been accessed in good to excellent levels
of E/Z selectivity and good yields. We are currently examining
the synthetic utility of these amidodiene products further and
investigating the observed E/Z stereoselectivity. Details will be re-
ported in due course.
16. Representative example; synthesis of 7b. To a flask was added LiHMDS (1 M in
THF, 0.57 mL, 0.57 mmol, 1.8 equiv) and Me3SiCl (73 lL, 0.57 mmol, 1.8 equiv).
The mixture was stirred at À95 °C for 0.25 h before the dropwise addition of 6b
(100 mg, 0.32 mmol, 1 equiv) in THF (2 mL). After 0.5 h at À95 °C, the reaction
mixture was allowed to warm to room temperature after which time it was
stirred for an additional 24 h. The reaction was then quenched with 1:1 1 M
HCl/brine solution (5 mL) and extracted with EtOAc (3 Â 10 mL), with the
combined organic extracts being dried over Na2SO4, filtered, and concentrated
in vacuo. Purification via flash chromatography, eluting with 2:1 petroleum
Acknowledgements
We acknowledge the support of the University of Bath and
EPSRC for studentship funding (S.J.H.).
ether/EtOAc, gave Z/E-7b (46 mg, 53%). FTIR (film/cm–1
) tmax: 2903, 2798,
References and notes
1741, 1604, 1519. 1H NMR (500 MHz, CDCl3) dH: 7.29 (2H, app. d, J = 8.5 Hz),
6.65 (2H, app. d, J = 8.5 Hz), 6.48 (1H, s), 6.17–6.08 (1H, m), 5.79 (1H, dqd,
J = 11.4, 7.2, 0.8 Hz), 4.39 (1H, d, J = 7.7 Hz), 4.36 (1H, d, J = 6.7 Hz), 3.80 (1H, d,
1. For reviews of ynamide synthetic chemistry, see: (a) De Korver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110,
5064; (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840.
2. For recent synthetic usage of ynamides, see: (a) Saito, N.; Ichimaru, T.; Sato, Y.
Org. Lett. 1914, 2012, 14; (b) DeKorver, K. A.; Wang, X.-N.; Walton, M. C.; Hsung,
R. P. Org. Lett. 2012, 14, 1768; (c) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.;
Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V. Chem. Eur. J. 2012, 18, 4337; (d)
Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756; (e) Smith, D. L.;
J = 6.7 Hz), 3.77 (1H, d, J = 7.7 Hz), 2.96 (6H, s), 1.66 (3H, dd, J = 7.2, 1.8 Hz); 13
C
NMR (75 MHz, CDCl3) dC: 156.1, 149.5, 146.8, 130.3, 130.2, 128.5, 125.2, 123.8,
111.9, 61.6, 46.2, 40.4, 14.7; MS (ESI:+ve) m/z: calcd for
C16H20N2O2Na:
295.1422, found: 295.1417, [M+Na]+.
17. For a recent example of an amidodiene Diels-Alder reaction, see: Hayashi, R.;
Ma, Z.-X.; Hsung, R. P. Org. Lett. 2012, 14, 252.