An SN2′ displacement approach to allenyl acetates

Article abstract of DOI:10.1016/j.tetlet.2010.10.013

Reaction of cuprates derived from R³MgBr/CuI/LiBr (R³ = n-alkyl) with R¹CCCH(O₂CR²)₂ (R¹ = sp² hybridised substituent, R² = mainly Me, alkyl, Ph) provides access to allenyl esters R¹R ³CCCH(O₂CR²) (51-88%). Such species are not accessible via rearrangement of precursor propargylic R¹R ³C(O₂CR²)CCH.

Full text of DOI:10.1016/j.tetlet.2010.10.013

Tetrahedron Letters 51 (2010) 6454–6456
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An SN20 displacement approach to allenyl acetates
⇑
Martta Asikainen, William Lewis, Alexander J. Blake, Simon Woodward
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Reaction of cuprates derived from R3MgBr/CuI/LiBr (R3 = n-alkyl) with R1C„CCH(O2CR2)2 (R1 = sp2 hybri-
dised substituent, R2 = mainly Me, alkyl, Ph) provides access to allenyl esters R1R3C@C@CH(O2CR2) (51–
88%). Such species are not accessible via rearrangement of precursor propargylic R1R3C(O2CR2)C„CH.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 11 August 2010
Revised 22 September 2010
Accepted 1 October 2010
As part of a mechanistic study we recently needed access to the
specifically substituted allenyl acetates 3 (Scheme 1) that are not
present in the primary literature. Typically, allenylic acetates are
prepared by rearrangement of propargylic precursors 4 or 5. For
example, dialkyl substituted 4 under Cu-1 (or better Rh-2 or Ag-
catalysis3) provides 1 in good yields. Unfortunately, this methodol-
ogy fails if one or both of the alkyl units are replaced by an aryl or
vinyl unit.4 Similarly, Ag-catalysed rearrangement of 5 to give 2
proceeds in high yields.5 However, terminal propargylic systems
(as required for the preparation of 3) cannot be used—they either
result in oligomerisation or cyclisation of 5 under Au-NHC li-
gand/AgBF4 catalysis.5a
In the absence of a viable propargylic rearrangement strategy
we considered an SN20 displacement of one of the acetates within
6 using a suitable organometallic.6 While the propargylic diace-
tates 6 are inordinately rare,7 formation of such derivatives from
more general RCHO units and Ac2O under Lewis acid catalysis is
well precedented.8 However, such procedures often require use
of excess Ac2O which we found co-elutes with 6 on chromatogra-
phy. A short optimisation study4 indicated that catalytic FeCl3 pro-
vided a chemoselective process giving synthetically viable yields of
6 when using only 1 equiv of anhydride (Table 1).9
The optimised conditions were applied to a representative
range of diacetate starting materials 6 (Table 3)10 allowing us to at-
tain the desired substitution pattern in allene 3 on up to gram
scales at least. The following limitations were found: addition of
MeMgBr gave lower yields compared to higher n-alkyl Grignards,
presumably due to the high bond strength of M-Me derivatives.11
In the present system sec- and aromatic Grignard reagents led to
unsatisfactory yields. Attempts to make the process catalytic in
copper were thwarted by the propensity of 3 to undergo further
coupling reactions.12 Allenyl carboxylates are distinctly electron-
rich due to their enol-like structure. This leads to an upfield shift
of their central allene carbons (e.g., those in 1 typically show dC
189–190 compared to the more normal 205–215 ppm range ex-
pected for substituted allenes13). For the compounds 3 isolated
herein the equivalent range was dC 192–193 for the central allene
carbon. To ensure that the desired substitution pattern had been
attained, a crystallographic study of one representative example
3fb was carried out which confirmed the connectivity (Fig. 1).14
OAc
H
OAc
H
H
OAc
Alk
Alk
Ar
Alk
Alk
In the case of a p-methoxy substituent (6d) the reaction was
much slower leading to lower yields, presumably due to electronic
deactivation of the intermediate onium species. Pivalic anhydride
and benzoic anhydrides were also tolerated in the reaction but
they were not as efficient as Ac2O.
Ar
3
1
2
Optimisation of SN20 additions was carried out on substrate 6a.
While cuprate reagents derived from organolithium reagents gave
only traces of 3, those from RMgBr generated significant yields
(24–72%) at 0 °C in the presence of LiBr (Table 2). Lowering the
temperature to ꢀ10 °C and changing the Grignard solvent provided
the highest amount of 3 while EtMgBr proved to be a superior
nucleophile to its methyl analogue.
OAc
OAc
H
Ar
H
Alk
Alk
Alk
H
OAc
OAc
Ar
rearrangment fails
rearrangment fails
6
2
2
if H or sp substituent
if sp substituent
5
4
Scheme 1. Disconnections for the preparation of allenyl acetates (Alk = sp3
⇑
Corresponding author. Tel.: +44 115 9513541; fax: +44 115 9513564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
substituent, Ar = sp2 substituent).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.013

M. Asikainen et al. / Tetrahedron Letters 51 (2010) 6454–6456
6455
Table 1
Table 3
Preparation of diacetates 6 using 1 equiv of anhydrides
Preparation of allenes 3 by SN20 displacement with RMgBr
O
O
O
O
O
CuI (2.5 equiv)
LiBr (2.5 equiv)
R3MgBr (2.4 equiv)
THF 5-20 min
-10 ºC
R2
R2
R2
R2
O
H
R3
R1
R2
R2
O
O
O
O
R2
O
R1
R1
CHO
R1
FeCl3 (10 mol%)
CH2Cl2 r.t.
3
6
O
6
O
Product
R1
R2
R3
Et
Me
n-Bu
Et
Et
Et
Et
Et
Yield 3 (%)a
Product
R1
R2
Time (h)
Yield (%)a (brsm)b
3ab
3aa
3ac
3ad
3ae
3bb
3cb
3db
3eb
3fb
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
t-Bu
Ph
Me
Me
Me
Me
Me
88
30
65
78
74
81
46
67
51
51
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
p-MeC6H4
Me
Me
1
2
3
24
24
5
18
0.5
6
75 (86)
63 (89)
72
26 (54)
49 (70)
62 (79)
51 (77)
46
m-MeC6H4
p-MeOC6H4
1-Cyclohexenyl
(CH2)2Ph
Phenanthrenyl
Ph
Me
Me
Me
Me
Me
t-Bu
Ph
p-Tolyl
m-Tolyl
1-Cyclohexene
(CH2)2Ph
Et
Et
Ph
20
Phenanthrenyl
a
Isolated yield.
Yield based on recycled starting material.
a
b
Isolated yield.
Table 2
In addition to accessing 3 as a general class of reagents we had
Optimisation of RMgBr/CuX/LiBr addition to 6
need of one example which was appreciably enriched in one enan-
tiomer. Fortunately, compound 3ab undergoes enzymatic kinetic
resolution (Scheme 2) using a supported lipase attained from Burk-
holderia cepacia (referred to here as PS Amano SD). Addition of an
excess of this material, in small portions, to ( )-3ab gave a 54% iso-
lated yield of E/Z-7 (an approximate 1:1 mixture) leading to recov-
ery of 45% isolated yield of (+)-3ab in 85% ee as determined by
chiral GC within 1.5 h.15 Extending the reaction time to 2 h led to
a slight increase in selectivity to 88% ee but a significant drop in
the amount of (+)-3ab recovered (31%). Based on literature prece-
dents16 using this lipase, we tentatively suggest that (+)-3ab corre-
sponds to the (S)-enantiomer.16 Attempts to confirm this via
crystalline 3fb were thwarted by an apparent size restriction in
the lipase active site, even a moderate increase in the size of the
aryl group was not tolerated, for example, ( )-3bb gave only a
45% ee at >75% conversion with the equivalent hydrolysis products
70 as an E/Z mixture.
H
OAc
H
R
RMgBr/CuX/LiBr
OAc
OAc
Ph
Ph
6a
3aa R = Me
3ab R = Et
RMgBr (equiv) CuX
(equiv)
LiBr
(equiv)
Solvent Temp (°C) Yield 3 (%)a
MeMgBr (2.4)
MeMgBr (2.4)
EtMgBr (4.8)
EtMgBr (4.9)
EtMgBr (2.4)
EtMgBr (2.4)b
CuI (2.5)
CuCN (2.5)
CuI (5.0)
CuI (5.0)
CuI (2.5)
CuI (2.5)
2.5
5
5
5
2.5
2.5
THF
THF
Et2O
THF
THF
THF
0
0
0
0
0
ꢀ10
30
24
35
52
72
88
a
Isolated yield.
b
Grignard as a 1.0 M solution in MTBE; all other cases 3.0 M in Et2O.
Figure 1. Structure of 3fb. Key bond distances C1–C2 1.289 Å, C1–O1 1.407 Å, C2–C3 1.311 Å, C3–C4 1.514 Å, C3–C9 1.495 Å, C6–O2 1.201 Å.

6456
M. Asikainen et al. / Tetrahedron Letters 51 (2010) 6454–6456
Brunette, S. R.; Lipton, M. A. J. Org. Chem. 2000, 65, 5114–5119; (b) Waddell,
M. K.; Bekele, T.; Lipton, M. A. J. Org. Chem. 2006, 71, 8372–8377.
7. Only two diacetates, one of which is complexed to cobalt have been prepared:
(a) Wille, F.; Schwab, W. Monatsh. Chem. 1978, 109, 337–355; (b) Kemmerich,
T.; Nelson, J. H.; Takach, N. E.; Boebme, H.; Jablonski, B.; Beck, W. Inorg. Chem.
Et
OAc
H
Et
OAc
H
PS Amano SD
Ph
pH 7.4 buffer
THF
Ph
(+)-3ab
( )-3ab
1982, 21, 1226–1232; Compound 6a has been identified as
a reaction
intermediate: (c) Suchy, P.; Dvorak, D.; Havelkova, M. Collect. Czech. Chem.
Commun. 1999, 64, 119–129.
+
Et
8. For selected recent examples, see: (a) Meshram, G. A.; Patil, V. D. Synth.
Commun. 2010, 40, 442–449; (b) Khalid, Md. S.; Goud, P. S. K.; Kumar, B. S. Asian
J. Chem. 2009, 21, 5465–5468; (c) Niknam, K.; Saberi, D.; Sefat, M. N.
Tetrahedron Lett. 2009, 50, 4058–4062; (d) Adibi, H.; Samimi, H. A.; Iranpoor,
N. Chin. J. Chem. 2008, 26, 2086–2092. and references therein.
Et
OH
H
O
Ph
H
Ph
9. Typical procedure: anhydrous FeCl3 (0.24 g, 1.5 mmol, 10 mol%) was
suspended in CH2Cl2 (150 ml) and left to stir for 15 min before addition of
RC„CCHO (15 mmol) in 10 ml of CH2Cl2 followed by Ac2O (1.4 ml, 15 mmol).
After 3 h the reaction was quenched with saturated aqueous NaHCO3. The
mixture was extracted with CH2Cl2 (100 ml) and washed with NaHCO3 until
neutral. The washings were back extracted with CH2Cl2 (50 ml). The combined
organic fractions were dried (MgSO4), evaporated and purified by flash column
chromatography (30:1–10:1 petroleum ether:EtOAc). Representative data, 6a:
1H NMR (400 MHz, CDCl3) dH 7.51–7.48 (m, 3H), 7.38–7.31 (m, 3H), 2.15 (s,
6H); 13C NMR (67.9 MHz, CDCl3) dC 168.1, 132.1, 129.5, 128.3, 81.4, 80.0, 20.7;
IR mmax 3620, 3478, 3010, 2976, 2895, 2240, 1826, 1767, 1372, 1245, 1126,
1046, 956, 877; MS m/z (ESI) for C13H12O4Na [M+Na] calcd 255.0628, found
255.0624.
10. Typical procedure: Dry CuI (0.62 g, 3.3 mmol, 2.5 equiv) and LiBr (0.28 g,
3.3 mmol, 2.5 equiv) under argon were cooled to ꢀ10 °C and 25 ml of THF was
added. A solution of EtMgBr (1 M in MTBE, 3.2 ml, 3.2 mmol, 2.4 equiv) was
added slowly and after 10 min, diacetate 6 (1.3 mmol) was added in THF
(5 ml). After 30 min, the reaction was quenched with saturated aqueous NH4Cl/
NH3 solution. The mixture was diluted with Et2O (150 ml), the organic phase
was separated and washed with NH4Cl/NH3 solution three, four times or until
the aqueous phase was no longer blue. The organic fraction was washed with
saturated aqueous NaCl solution, dried over MgSO4, evaporated and purified by
flash column chromatography (30:1 n-pentane:Et2O) to give the products as
yellow oils (except 3fb which was a colourless solid). Representative data, 3ab:
1H NMR (400 MHz, CDCl3) dH 7.73 (t, 1H, J = 2.6 Hz), 7.48–7.45 (m, 2H), 7.37–
7.27 (m, 3H), 2.65–2.51 (m, 2H), 2.17 (s, 3H), 1.18 (t, 3H, J = 7.8 Hz); 13C NMR
(67.9 MHz, CDCl3) dC 192.5, 168.7, 128.4, 128.0, 126.6, 121.8, 113.4, 24.3, 20.9,
12.2; IR mmax 3010, 1750, 1372, 1240; MS m/z (ESI) for C13H14O2Na [M+Na]
calcd 225.0886, found 225.0893.
7
Scheme 2. Lipase-promoted kinetic resolution of allenyl acetate ( )-3ab.
In conclusion a new SN20 displacement strategy allows access to
allenyl acetates of the structure ArRC@C@CH(OAc) that are not
attainable from traditional routes employing rearrangement of
propargylic acetates. In some cases the resulting acetates undergo
lipase-promoted kinetic resolution resulting in enantiomerically
enriched species (45–88% ee). The scope and range of materials
are presently under investigation in our laboratory as is their use
as mechanistic probes in transition metal promoted catalysis.
Acknowledgements
The financial support by the European Community (Marie Curie
Early Stage Researcher Training), (MEST-CT-2005-019780) and the
EPSRC (Grant EP/F033478/1) is gratefully acknowledged. M.A. is
grateful to COST Action D40 for additional support and training.
Supplementary data
11. Woodward, S. Tetrahedron 2002, 58, 1017–1050.
12. The synthetic utility of this chemistry is under current investigation.
13. Runge, W.; Firl, J. Chem. Ber. 1975, 79, 913–922.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.013.
14. Compound 3fb crystallises from i-PrOH: C21H18O2, M = 302.35, monoclinic,
a = 8.380(2), b = 7.611(2), c = 24.952(7) Å, b = 94.366(5), U = 1586.8(7) Å3,
T = 150(2) K, space group P21/c (no. 14), Z = 4. Full crystal data for (3fb) have
been deposited with the Cambridge Crystallographic Data Centre (CCDC
reference number 760895). These data can be obtained free of charge from
the CCDC via www.ccdc.cam.ac.uk/data_request/cif.
References and notes
1. Cookson, R. C.; Cramp, M. C.; Parsons, P. J. J. Chem. Soc., Chem. Commun. 1980,
197–198.
15. To ( )-3-phenylpenta-1,2-dienyl acetate 3ab (105 mg, 0.52 mmol) were added
THF (0.2 ml) and phosphate buffer (15 ml, pH 7.4) with vigorous stirring. PS
Amano SD lipase (400 mg) was added with vigorous stirring in small portions.
After 2 h, the reaction mixture was extracted with Et2O (5 ꢁ 5 ml) and the
combined organics were concentrated under reduced pressure. The product
was purified by flash column chromatography (30:1 n-pentane:Et2O). A sample
2. Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68, 8505–8513.
3. These are the most commonly employed procedures: (a) Oelberg, D. G.;
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C.; Davis, H. A. J. Chem. Soc., Perkin Trans. 1 1973, 2634–2637; (c) Schlossarczyk,
H.; Sieber, W.; Hesse, M.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta 1973, 56,
875–944.
of 3ab with 88% ee (confirmed by chiral GC) gave [a] +83.9 (c = 0.65, CHCl3).
D
4. See Supplementary data.
16. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
1991, 56, 2656–2665; Pseudomonas cepacia was renamed as Burkholderia
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Yasuhiro, H.; Takayuki, E.; Michio, A. Microbiol. Immunol. 1992, 36, 1251–1275.
); For an interesting study of the enantiopreference of Burkholderia cepacia, see:
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Soc. 2006, 128, 8414–8415.
6. Related additons of lower order cuprates to TMS-substituted ynones, as a route
to R(TMS)C@C@CR(OAc), are known but we are unaware of any addition
approaches using propargylic diacetates. For ynone chemistry, see: (a)