Allenyl ester precursors for 1H-inden-1-ol carboxylates: Comparisons with their propargylic equivalents having terminal alkyne functions

Article abstract of DOI:10.1016/j.tet.2012.04.086

The reactivity of allenyl carboxylates, Ar(R¹)CCCH(O ₂CR²) and their isomeric equivalents the terminal propargylic carboxylates, ArC(R¹)(O₂CR²)CCH, in gold-catalyzed carbocyclization to ind

Full text of DOI:10.1016/j.tet.2012.04.086

Tetrahedron 68 (2012) 5492e5497
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Allenyl ester precursors for 1H-inden-1-ol carboxylates: comparisons with their
propargylic equivalents having terminal alkyne functions
*
Martta Asikainen, Simon Woodward
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
The reactivity of allenyl carboxylates, Ar(R1)CCCH(O2CR2) and their isomeric equivalents the terminal
propargylic carboxylates, ArC(R1)(O2CR2)CCH, in gold-catalyzed carbocyclization to indenes provides
information on 1,3 and 1,2-carboxylate shifts associated with their interconversion. Allenyl carboxylates
transform specifically to 1H-inden-1-yl carboxylates in high yields, under AuI-catalysis. Their equivalent
propargylic carboxylates give complex mixtures of indene isomers and elimination products. Mechanistic
tests indicate that interconversion of the terminal propargylic carbonate to its allene is at best slow in
this case.
Article history:
Received 17 February 2012
Received in revised form 9 April 2012
Accepted 23 April 2012
Available online 30 April 2012
Keywords:
Allene
Alkyne
Ó 2012 Elsevier Ltd. All rights reserved.
Gold
Cycloisomerization
Reaction mechanism
1. Introduction
In 2006 Nolan published a synthesis of 1H-indene derivatives2a
starting from either the propargylic acetates 1 with internal alkynes
Aryl propargylic carboxylates, ArC(R1)(O2CR2)C^CR3 are easily
attained, highly versatile, starting materials for gold-catalyzed
transformations.1 They have been used in the synthesis of indene
derivatives,2 Au-catalyzed nucleophilic substitutions,3 isomeriza-
tions to dienes,4 MeyereSchuster rearrangements5 and in the
synthesis of various bicyclic compounds.6 Their isomeric allenyl
carboxylates Ar(R1)CCCR3(O2CR2) are attained by a formal 1,3 shift
of the carboxylate in propargylic precursors and such shifts are
frequently promoted by the coinage metals. The reactivity of such
allenyl and propargylic carboxylates has been compared in DFT
computational studies7 and often the allenyl carboxylate is the true
reactive intermediate in the reactions performed with equivalent
propargylic starting materials.1,2,4b,6b,7 While internal propargylic
carboxylates (R3¼alkyl) can often be treated as ‘allene equivalents’
the situation is more complicated for terminal propargylic systems
(R3¼H). Typically, such systems favour 1,2-carboxylate shifts and in
cases where apparent 1,3-shifts occur it is not always clear if this
arises from two successive 1,2-shifts or by a direct 1,3-process. To
attempt to shed some light on this for the terminal propargylic
analogues of the chemistry of Nolan2 we have investigated these
and their ‘allene equivalents’.
or the corresponding allenyl acetates 2 (Scheme 1). As the two
compounds gave very similar product pattern to indenes 3 and 4, it
was concluded that the allenyl acetate 2 acted as an intermediate
via double gold-catalyzed 1,2 or single 1,3 shift of the propargylic
acetate 1 (Scheme 1).7
* Corresponding author. Fax: þ44 (0) 115 9513541; e-mail address: simon.wood
Scheme 1. Nolan’s route2 to substituted 1H-indenes; see Table 1 for the structure of IPr.
ward@nottingham.ac.uk (S. Woodward).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.086

M. Asikainen, S. Woodward / Tetrahedron 68 (2012) 5492e5497
5493
Table 2
Later Nolan reported that the 1H-indenes 3, if left for 14 h in the
Generalised gold-catalysed cyclisation of 5a
presence of the gold catalyst, can further rearrange to the 1H-
indenes 42b and this causes the selectivity problem in the reaction.
Clearly, it would be desirable to develop a mild gold-catalyzed
synthesis of indenes, that is, selective towards one of these 1H-
indenol carboxylate products rather than a mixture and this may be
tied to mechanistic understanding.
2. Results and discussion
We have published a synthesis of the allenyl acetates 5 via SN20
displacement of propargylic diacetates by organocuprates.8 Such
species 5, the putative ‘1,3 shift products’ of ArCR(OAc)CCH, have
not been isolated or detected in the Au-promoted reactivity of
ArCR(OAc)CCH before but could still be an important (undetected)
intermediate. It is important to confirm allenes 5 are able to carry
out gold-catalysed cyclisation to 1H-indene derivatives in order to
find out if the poor reactivity of ArCR(OAc)CCH is associated with its
initial conversion to 5 or due to intrinsic behaviour of 5 itself. Trial
reactions of 5a with AuCl3 and AuCl(PPh3) (Table 1, entries 1e2)
indicated the formation of complex reaction mixtures, but Nolan’s
goldecarbene complex Au(IPr)Cl, with a AgOTf co-catalyst, imme-
diately gave very high yields of a single 1H-indene isomer 4a (entry
3). In a control experiment AgOTf alone yielded the diene 6, as
a mixture of isomers, as only isolable product (entry 4), while no
conversion was evident with just Au(IPr)Cl.
Run
R1
R2
R3
Yield (4)/%
1
2
3
4
5
6
7
8
9
H
H
H
H
Me
Me
Me
Ph
t-Bu
Me
Me
Me
Me
Et
Me
Bu
Et
Et
Et
Et
Et
Et
>99 (4a)
64 (4b)
92 (4c)
82 (4d)
96 (4e)
97 (4f)
70 (4g)
92 (4h/h0)
0
H
4-t-BuPh
4-Me
Table 1
Optimisation of gold-catalysed cyclisation of 5aa
3-Me
1-Cyclohexeneb
a
Isolated yields. Run 1 performed with a 1 mol % catalyst system.
A 1-cyclohexenyl substituent was used in place of the phenyl group.
b
represents an upper limit at room temperature. The selectivity of
the reaction is likely due to the unhindered C1eH to the acetate
a
group. As the gold catalyst favours this unhindered C1eC2 bond
there is no competition between the two allenyl bonds to be acti-
vated towards in the subsequent carbocyclisation (Scheme 2).
Run
Catalyst
Time/min
Yield (4 or 6)/%
1
2
3
4
5
AuCl3 (2 mol %)
20
20
<5
30
45
12 (4a)
50 (4a)
>99 (4a)
37b (6)
<2c
(PPh3)AuCl/AgOTf (2/2 mol %)
(IPr)AuCl/AgOTf (2/2 mol %)
AgOTf (5 mol %)
(IPr)AuCl (2 mol %)
Scheme 2. Assumed steric factors in the cyclisation of 5.
a
Reactions preformed in CH2Cl2 as 0.1 mmol/mL solution of allene 5; yields by
NMR versus standard.
b
In our earlier report we also described the synthesis of the
enantiomerically enriched allenyl acetate (S)-(þ)-5a by lipase-
catalyzed kinetic resolution.8 Gold-catalyzed cycloisomerization
of 5a is too fast to monitor easily at room temperature, but if the
reaction mixture is cooled down to ꢀ2 ꢁC the conversion slows
enough that aliquots can be taken over 40 min (below this tem-
perature the catalyst starts to precipitate). Following the reaction
by chiral GC reveals that the allene (þ)-5a is racemised (zero order
dependence) during the course of the reaction; after 20 min re-
action only racemic allene 5a is left. This behaviour was fitted to the
kinetic model given in Scheme 3 and values of k1, kꢀ1 and k2 could
be determined by standard methods.9 The data, although re-
producible, has quite a high error bar due to issues of fast
quenching of aliquots from such a reactive mixture. Nevertheless,
we are unaware of any previous kinetic determination. We could
Isolated yield, only tractable product.
Starting material 5 recovered intact.
c
The scope of the reaction proved general providing high to
quantitative yields of indene derivatives 4, as no byproducts arise
with the Au(IPr)Cl/AgOTf catalyst system (Table 2). Pivalate and
benzoate carboxylates are tolerated providing high yields (entries
4e5). When the reactionwas scaled up (>0.5 g scale), only 1 mol % of
the catalyst was needed to provide quantitative isolated yield of 4a.
The cycloisomerisation was tested with one non-aromatic allene
(entry 9), but this gave no desired bicyclic product, suggesting an
SEAr cyclisation mechanism is involved. The reaction of allenyl ac-
etates 5 with Au(IPr)þ catalyst is both rapid and highly selective. The
reaction is complete as soon as we can monitor it by TLC; 5 min

5494
M. Asikainen, S. Woodward / Tetrahedron 68 (2012) 5492e5497
derive the equilibrium constant Keq¼0.16 (ꢂ0.08) for formation of
the unseen planar intermediate A. Aside from unlikely racemisation
of the ultimate product, only this achiral species can explain the
formation of racemic 4a when k2 is greater than kꢀ1. Intermediate A
can thus cyclize via electrophilic aromatic substitution (SEAr)
chemistry or return indene 5a in racemic form. On no occasion was
any trace (>1%) of 7a detected in these reactions by GC.
Scheme 5. Conversion of 7b into 8b.
through a ‘carousel’ of intermediates, that is, characterized by low
energy (typically 3e9 kcal molꢀ1) interconversion barriers.7a For at
least 5a this cannot be the casedit must be isolated from the
‘carousel’ by significant energy barriers as it provides a different
product distribution to its nominal interconversion partner 7a. Pure
5a does not retroisomerise to 7a by either 1,2 or 1,3-acetate shifts in
the presence of (IPr)Auþ cations under our conditions. While for-
ward isomerisation of 7a to 5 is viable this appears to take place by
two successive 1,2 acetate shifts. The lack of clean reactivity for 7a
can be traced to its solvolysis to the implied carbocation
[PhCEt(CCH)]þOAcꢀ (Scheme 6, mechanistic arrow ‘1’), de-
composition of which provides the E1 product 9 (25%) and
uncharacterized polymeric products (25%)das the major reaction
pathways. All evidence (studies on isolated 5a and the absence of
chirality transfer from (S)-7a at low temperature and short reaction
times) indicate that a 1,3 carboxylate shift does not occur (mech-
anistic arrow ‘3’ and its reverse). The expected 1,2 shift (mecha-
Scheme 3. Racemisation of 5 versus cyclisation.
To provide comparative data on the potential involvement of
allenes of type 5 in gold-catalysed rearrangement of propargylic
alcohols with terminal alkyne units the catalytic reaction of 7a was
studied in some detail (Scheme 4).
nistic arrow ‘2’) from 7a is facile affording unseen
B and
subsequently C. However, only a minority of C can ‘leak back’ to 5a
(the ultimate source of 4a) and the reverse 1,2 shift from 5a to C
must be of higher (non viable) energy as no 8a is isolated from 5a
alone in the presence of (IPr)Auþ.
Scheme 4. Mechanistic studies of propargylic alcohol 7a as a potential precursor to 5a.
Several points arise from the reactions of Scheme 4: (i) The re-
action is uncleandcompounds 4a and 8e9 account for only 75% of
the reaction mass, but no other long-lived organic species could be
detected in the reaction mixture. (ii) Deuterium labelled 7a results
in complete retention of the label at the expected positions. (iii)
Monitoring quenched aliquots of the reaction at ꢀ2 ꢁC using
enantiomerically enriched (S)-7a does reveal the formation of small
amounts of racemic 5a within the first 90 s (appreciable amounts of
(S)-7a remain along with generated 9) in the reaction. Subsequent
smooth formation of racemic 4a and 8 follows thereafter. A 1,3-
acetate shift via [3,3]-sigmatropic rearrangement of 7a to 5a is
not consistent with such observations. Such processes are expected
to proceed with high chirality transfer, even when gold-pro-
moted.10 Under the ꢀ2 ꢁC conditions of Scheme 4, racemisation of
5a would be slow enough that if a stereoselective 1,3-acetate shift
had occurred it would have been detected. When the chemistry of
Scheme 4 was repeated with the methyl analogue (ꢂ)-7b only ra-
cemic 8b was isolated in low yield (38%) (Scheme 5). Because of the
low mass balance of the reaction enantiomerically enriched 7b and
subsequent reaction monitoring were not carried out.
Scheme 6. Mechanistic behaviour of 5a and 7a; C can also be drawn in its cationic
carbene resonance form.
3. Conclusions
It can be concluded that an ability to prepare 5 via an alternative
precursor to 7 is useful as this allows access to an otherwise poorly
populated intermediate A.
It has been proposed, on the basis of DFT calculations, that
allenes of type 5 freely interconvert with propargylic acetates 7

M. Asikainen, S. Woodward / Tetrahedron 68 (2012) 5492e5497
5495
4. Experimental
4.1. General
2.14 (s, 3H), 1.69e1.62 (m, 2H), 1.46e1.61 (m, 2H), 0.96 (t, 3H,
J¼7.2 Hz); 13C NMR (100.6 MHz, CDCl3) dC 171.6, 148.3, 144.1, 142.7,
128.7, 126.6, 126.2, 124.1, 119.4, 76.7, 29.5, 27.2, 22.6, 21.2, 13.9; IR
(cmꢀ1
) nmax 3012, 2960, 2361, 1732. 1372, 1243; MS m/z (ESI), for
All reactions involving air sensitive materials were carried out
under argon atmosphere using standard Schlenk techniques. Re-
agents and catalysts were purchased reagent grade and used
without further purification. Dichloromethane was distilled from
CaH2. Flash column chromatography: silica gel 35e70 u, 60 A; pe-
troleum ether used in column chromatography had boiling range
40e60 ꢁC. 1H and 13C NMR spectra were recorded on Bruker
(DPX400 or AV400) spectrometers using CDCl3 as standard
(7.26 ppm for 1H spectra and 77.0 ppm for 13C spectra); J values are
given in Hertz. Infrared spectra were recorded using a Bruker Tensor
27 spectrometer. Mass spectra were obtained on Bruker Daltonics
micro TOF (ESI), Bruker Daltonics APEX 4 ECR FTMS (EI) and VG
Autospec (EI). Gas Chromatography on a Varian 420 machine with
C15H18NaO2 [MþNa]þ calcd 253.1199, found 253.1198, error
0.50 ppm.
4.5. 3-Ethyl-1H-inden-1-yl benzoate (4d)
3-Phenylpenta-1,2-dienyl benzoate 5d (92.0 mg, 0.35 mmol)
gave the title compound as a yellow oil (68.7 mg, 0.26 mmol, 82%);
Rf¼0.68 (9:1 petroleum ether/Et2O); 1H NMR (400 MHz, CDCl3) dH
8.09e8.07 (m, 2H), 7.58e7.50 (m, 2H), 7.45e7.41 (m, 1H), 7.37e3.21
(m, 4H), 6.44e6.42 (m, 1H), 6.19e6.17 (m, 1H), 2.58e2.51 (m, 2H),
1.30 (t, 3H, J¼7.4 Hz); 13C NMR (100.6 MHz, CDCl3) dC 167.1, 149.8,
144.1,142.9,133.0,130.1,129.8,128.7,128.3,126.2,126.1,124.2,119.3,
77.1, 20.7, 11.7; IR (cmꢀ1
) nmax 2973, 1713, 1452, 1268; MS m/z (ESI)
a octakis(2,6-di-O-methyl-3-O-pentyl)-
g-cyclodextrin column was
for C18H16NaO2 [MþNa]þ calcd 287.1043, found 287.1038, error
used. The allenes 58 were prepared as previously described and
used immediately. Racemic 7aeb are available through acylation of
the known alcohols11 only the enantiomerically enriched and la-
belled compounds are described here for brevity. Supported lipase
A from Candida antarctica was purchased from SigmaeAldrich.
1.50 ppm.
4.6. 3-Ethyl-1H-inden-1-yl pivalate (4e)
3-Phenylpenta-1,2-dienyl pivalate 5e (0.150 g, 0.61 mmol) gave
the title compound as a clear oil (0.140 g, 0.59 mmol, 96%); Rf¼0.87
(9:1 petroleum ether/Et2O); 1H NMR (400 MHz, CDCl3) dH 7.38e7.18
(m, 4H), 6.19e6.17 (m, 1H), 6.04e6.03 (m, 1H), 2.54e2.50 (m, 2H),
1.28 (t, 3H, J¼7.2 Hz), 1.24 (s, 9H); 13C NMR (100.6 MHz, CDCl3) dC
179.1, 149.4, 144.0, 143.2, 128.5, 126.3 (2C), 123.8, 119.3, 76.5, 39.0,
4.2. 3-Ethyl-1H-inden-1-yl acetate: general procedure
towards the gold-catalyzed cyclization of allenic acetates (4a)
To a solution of 3-phenylpenta-1,2-dienyl acetate 5a (140 mg,
0.64 mmol) in CH2Cl2 (10 mL) was added Au(IPr)Cl (9.2 mg,
0.013 mmol, 2.0 mol %) and AgOTf (2.8 mg, 0.013 mmol, 2.0 mol %)
at room temperature under air. After 10 min the reaction mixture
was filtrated through a pad of silica gel with a CH2Cl2 wash and the
product, 3-ethyl-1H-inden-1-yl acetate 4a, was obtained as yellow
oil (140 mg, 0.64 mmol, 99%). The product did not need purifying
but it could be subjected to flash column chromatography (30:1
pentane/Et2O); Rf¼0.64 (9:1 petroleum ether/Et2O); 1H NMR
(400 MHz, CDCl3) dH 7.44e7.43 (m, 1H), 7.34e7.30 (m, 1H),
7.25e7.19 (m, 2H), 6.20e6.18 (m, 1H), 6.06e6.05 (m, 1H), 2.54e2.47
(m, 2H), 2.15 (s, 3H), 1.27 (t, 3H, J¼7.6 Hz); 13C NMR (67.9 MHz,
CDCl3) dC 171.6, 149.8, 144.0, 142.7, 128.7, 126.3, 125.8, 124.1, 119.3,
27.2, 20.7, 11.7; IR (cmꢀ1
) nmax 2973, 2934, 2254, 1719, 1159; MS m/z
(ESI), for C16H20NaO2 [MþNa]þ calcd 267.1356, found 267.1344,
error 4.20 ppm.
4.7. 6-tert-Butyl-3-ethyl-1H-inden-1-yl acetate (4f)
3-(4-tert-Butylphenyl)penta-1,2-dienyl acetate 5f (0.180 g,
0.68 mmol) gave the title compound as a clear oil (0.170 g,
0.65 mmol, 97%); Rf¼0.77 (4:1 petroleum ether/Et2O); 1H NMR
(400 MHz, CDCl3) dH 7.48e7.47 (m,1H), 7.37e7.34 (m,1H), 7.18e7.16
(m, 1H), 6.19e6.18 (m, 1H), 6.02e6.00 (m, 1H), 2.52e2.46 (m, 2H),
2.16 (s, 3H), 1.33 (s, 9H), 1.26 (t, 3H, J¼7.6 Hz); 13C NMR (100.6 MHz,
CDCl3) dC 171.6, 149.7, 142.6, 141.4, 125.5 (2C), 125.3, 121.4, 118.8,
77.2, 21.2, 20.7, 11.6; IR (cmꢀ1
) nmax 2973, 1732, 1372, 1241; MS m/z
(ESI) for C13H14NaO2 [MþNa]þ calcd 225.0886, found 225.0884,
76.7, 34.8, 31.5, 21.3, 20.7, 11.7; IR (cmꢀ1
) nmax 3011, 2970,1731,1602,
error 1.10 ppm. Chiral GC analysis with an octakis(2,6-di-O-methyl-
1243; MS m/z (ESI), for C17H22NaO2 [MþNa]þ calcd 281.1512, found
3-O-pentyl)-
g
-cyclodextrin column and a temperature gradient
281.1501, error 4.00 ppm.
program 60e150 ꢁC 2 ꢁC/min gave retention times for the enan-
tiomers of (50.9/51.0 min).
4.8. 3-Ethyl-6-methyl-1H-inden-1-yl acetate (4g)
4.3. 3-Methyl-1H-inden-1-yl acetate (4b)
3-p-Tolylpenta-1,2-dienyl acetate 5g (0.170 g, 0.79 mmol) gave
the title compound as clear oil (0.120 g, 0.55 mmol, 70%); Rf¼0.49
(9:1 petroleum ether/Et2O); 1H NMR (400 MHz, CDCl3) dH
7.26e7.25 (m, 1H), 7.13e7.12 (m, 2H), 6.17e6.16 (m, 1H), 6.00e5.97
(m, 1H), 2.50e2.47 (m, 2H), 2.36 (s, 3H), 2.14 (s, 3H), 1.26 (t, 3H,
J¼7.2 Hz); 13C NMR (100.6 MHz, CDCl3) dC 171.6, 149.8, 143.0, 141.3,
3-Phenylbuta-1,2-dienyl acetate 5b (80 mg, 0.42 mmol) gave the
title compound as a yellow oil (51.0 mg, 0.27 mmol, 64%); Rf¼0.69
(9:1 petroleum ether/Et2O); 1H NMR (400 MHz, CDCl3) dH 7.43e7.41
(m, 1H), 7.33e7.31 (m, 1H), 7.24e7.22 (m, 2H), 6.19e6.18 (m, 1H),
6.07e6.05 (m, 1H), 2.14 (s, 3H), 2.12 (d, 3H, J¼1.6 Hz); 13C NMR
(100.6 MHz, CDCl3) dC 171.5, 133.5, 143.8, 142.5, 128.8, 127.9, 126.2,
136.2, 129.2, 125.2, 124.9, 119.1, 76.7, 21.4, 21.2, 20.7, 11.7; IR (cmꢀ1
)
nmax 3011, 2972, 1732, 1372, 1243; MS m/z (ESI), for C14H16NaO2
124.0, 119.3, 76.7, 21.2, 13.0; IR (cmꢀ1
) nmax 3011, 1732, 1626, 1372,
[MþNa]þ calcd 239.1043, found 239.1042, error 0.30 ppm.
1244; MS m/z (EI) for C12H12NaO2 [MþNa]þ calcd 211.0730, found
211.0723, error 3.10 ppm. The compound had identical properties to
that formed by an alternative route.12
4.9. 3-Ethyl-5-methyl-1H-inden-1-yl acetate and 3-ethyl-7-
methyl-1H-inden-1-yl acetate (4h/h0)
4.4. 3-Butyl-1H-inden-1-yl acetate (4c)
3-m-Tolylpenta-1,2-dienyl acetate 5h (0.240 g, 1.11 mmol) gave
the title compounds as a clear oil and inseparable mixture of iso-
mers (0.220 g, 1.02 mmol, 92%); Rf¼0.50 (9:1 petroleum ether/
Et2O); The individual isomers could not be differentiated in the
mixture so they are named as A and B (A/B 2:1) 1H NMR (400 MHz,
CDCl3) dH 7.31 (d, 1H, J¼7.6 Hz, A), 7.23 (d, 1H, J¼8.0 Hz, B),
3-Phenylhepta-1,2-dienyl acetate 5c (0.36 g, 1.56 mmol) gave
the title compound as a clear oil (0.33 g, 1.43 mmol, 92%). Rf¼0.68
(4:1 petroleum ether/Et2O); 1H NMR (400 MHz, CDCl3) dH 7.44e7.19
(m, 4H), 6.18e6.17 (m, 1H), 6.05e6.04 (m, 1H), 2.50e2.46 (m, 2H),

5496
M. Asikainen, S. Woodward / Tetrahedron 68 (2012) 5492e5497
7.09e7.01 (m, 2þ2H, AþB), 6.25e6.23 (m, 1H, B), 6.16e6.15 (m, 1H,
A), 6.08e6.06 (m, 1H, B), 6.04e6.03 (m, 1H, A), 2.52e2.46 (m, 2þ2H,
AþB), 2.38 (s, 3H, A), 2.31 (s, 3H, B), 2.14 (s, 3H, B), 2.13 (s, 3H, A),
1.27 (t, 3H, J¼7.2 Hz, A), 1.25 (t, 3H, J¼7.6 Hz, B); 13C NMR
(100.6 MHz, CDCl3) dC 171.6 (A), 171.3 (B), 149.8 (2C), 144.2, 144.1,
140.0, 139.8, 138.7, 134.2, 129.0, 128.1, 126.8, 126.1, 125.6, 123.9,
120.3, 117.1, 76.5 (A), 76.3 (B), 21.6, 21.2, 21.0, 20.7, 20.6, 17.9, 11.7
(2C); IR (cmꢀ1
) nmax 3011, 2972, 1732, 1372, 1243; MS m/z (ESI), for
C14H16NaO2 [MþNa]þ calcd 239.1043, found 239.1042, error
0.10 ppm.
4.10. (1E/Z, 3E/Z)-3-Phenylpenta-1,3-dienyl acetate (6)
3-Phenylpenta-1,2-dienyl acetate 5a (0.100 g, 0.49 mmol) was
dissolved in CH2Cl2 (5 mL) and AgOTf (6.3 mg, 0.024 mmol, 5 mol %)
added. The reaction was stirred for 30 min at room temperature,
then filtered through a pad of silica with a CH2Cl2 wash and con-
centrated in vacuo. The crude product was purified with flash
column chromatography (9:1 petroleum ether/Et2O) to give the
product as a mixture of two isomers as a yellow oil. As the two C]C
isomers could not be distinguished from the four possible cases,
they are marked in the NMR data as A and B. Compound 6 (37.0 mg,
0.18 mmol, 37%); Rf¼0.54 (9:1 petroleum ether/Et2O); 1H NMR
(400 MHz, CDCl3) dH 7.38e7.17 (m, 10H, AþB), 7.13 (d, 1H, J¼12.4 Hz,
A), 6.82 (d, 1H, J¼12.8 Hz, B), 6.52 (d, 1H, J¼12.4 Hz, A), 6.25 (d, 1H,
J¼12.8 Hz, B), 5.75 (q, 1H, J¼6.8 Hz, B), 5.58 (q, 1H, J¼6.8 Hz, A), 2.13
(s, 3H, A), 2.08 (s, 3H, B), 1.86 (d, 3H, J¼6.8 Hz, A), 1.56 (d, 3H,
J¼6.8 Hz, B); 13C NMR (100.6 MHz, CDCl3) dC 167.9, 167.8, 141.5,
139.2, 137.7, 137.4, 137.0, 136.3, 129.2, 128.8, 128.5, 128.2, 127.3, 127.1,
Fig. 1. Simulation of [4a]t ( in mol dmꢀ3, RHS y axis) and ee(5a)t ( in %, LHS y axis), x
axis time in s. The simulated fit is shown as a solid line.
once with brine. The organic layer was dried (MgSO4) and con-
centrated in vacuo. The product (0.99 g, 6.16 mmol, 99%) was
obtained as a clear oil, which did not need further purification and
was w99% isotopically pure based on 1H NMR spectroscopy;
Rf¼0.65 (4:1 petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) dH
7.64e7.61 (m, 2H), 7.39e7.28 (m, 3H), 2.69 (s, 0.01H, 99% d1), 2.36
(s, 1H, OH), 2.06e1.83 (m, 2H), 0.97 (t, 3H, J¼7.2 Hz); 13C NMR
(100.6 MHz, CDCl3) dC 143.9, 128.2, 127.8, 125.4, 85.6, 73.8, 38.2, 8.9,
127.0, 126.6, 120.2, 112.6, 30.9, 20.7, 14.8, 14.1; IR (cmꢀ1
) nmax 3156,
2903, 2254, 1794, 1752, 1466, 1373, 1103, 919; MS m/z (ESI), for
C13H14NaO2 [MþNa]þ calcd 225.0886, found 225.0884, error
0.80 ppm.
CD not apparent; IR (cmꢀ1
) nmax 3590, 3011, 2595, 1978, 1492, 1449,
1327; MS m/z (EI), for C11H11DO [M]þ calcd 161.0951, found
161.0955, error 2.50 ppm.
4.11. Kinetic study of the conversion of (D)-(S)-5a to ( )-4a
(b) Acetylation. 1-d-3-Phenylpent-1-yn-3-ol (0.90 g, 5.58 mmol)
was dissolved in CH2Cl2 (45 mL) and dimethylaminopyridine
(345 mg, 2.85 mmol) and triethylamine (1.60 mL, 11.4 mmol) were
To a mixture of (IPr)AuCl (3.7 mg, 5.9 mmol, 2.4 mol %) and AgOTf
(1.7 mg, 6.6
m
mol, 2.6 mol %) in CH2Cl2 (10 mL) at ꢀ2 ꢁC was added
added. Acetic anhydride (108 mL, 11.4 mmol) was added slowly and
(þ)-(S)-5a8 (50.1 mg, 0.25 mmol, 71% ee) in CH2Cl2 (1.8 mL) to afford
the following initial concentrations: [5]0¼21.2 mM, [(IPr)Auþ]¼
0.5 mM. Small aliquots (ca. 0.5 mL) were withdrawn at 1e10 min
intervals and immediately filtered through Celite, which removed the
catalyst and quenched the system. The samples were analysed by
the reaction was left to stir overnight. The mixture was concen-
trated in vacuo to give an oil. Purification of the product with flash
column chromatography (9:1 petroleum ether/Et2O) gave the title
compound as a clear oil with 81% isotopic purity; Rf¼0.72 (4:1
petroleum ether/EtOAc); 1H NMR (400 MHz, CDCl3) dH 7.53e7.51
(m, 2H), 7.37e7.28 (m, 3H), 2.82 (s, 0.19H, 81% d1), 2.21e2.14 (m,
1H), 2.08 (s, 3H), 2.02e1.95 (m, 1H), 0.94 (t, 3H, J¼7.2 Hz); 13C NMR
(100.6 MHz, CDCl3) dC 168.6, 140.9, 128.2, 127.8, 125.2, 79.3, 76.4,
chiral GC on a (octakis(2,6-di-O-methyl-3-O-pentyl)-
g-cyclodextrin)
column with a temperature programme of 40e150 ꢁC at 1 ꢁC minꢀ1
.
Enantiomer retention times: (S)-5a 85.1 min, (R)-5a 85.6 min; en-
antiomers of 4a 80.9/81.4 min. The [4a] product data was fitted to the
model of Scheme 3 assuming: (i) as [4a] >> [(IPr)Auþ] pseudo first
order analysis is valid; (ii) the mass balance of the reaction involves
only 4a and 5a. Using the non-linear regression (solver) approach of
37.4, 21.7, 8.5, CD not apparent; IR (cmꢀ1
) nmax 3306, 3010, 2596,
1984, 1743, 1493, 1369, 1242; MS m/z (ESI), for C13H13DNaO2
[MþNa]þ calcd 226.0949, found 226.0942, error 3.00 ppm.
9
Billo to solving Espenson’s model for Scheme 3 provided the fol-
lowing best fit values: k1¼1.2ꢃ10ꢀ2 sꢀ1
;
k
ꢀ1
¼7.5ꢃ10ꢀ2 sꢀ1
;
4.13. Kinetic resolution of 3-phenyl-1-yn-3-yl acetate to give
(S)-(7a)
k2¼1.2ꢃ10ꢀ2 sꢀ1 withanerrorof ꢂ0.3ꢃ10ꢀ2 sꢀ1 and Keq¼k1/k ¼0.16
ꢀ1
(ꢂ0.08) for the formation of A under these conditions. A plot of [4a]t
and ee(5a)t is shown in Fig. 1. The study was conducted in duplicate,
similar results were attained in acetone as a solvent.
To racemic 3-phenyl-1-yn-3-yl acetate (ꢂ)-7a (0.50 g,
2.50 mmol) in phosphate buffer (pH 7.4, 20 mL) was added Lipase A
from C. antarctica (1.00 g on solid support) with vigorous stirring at
ambient temperature. After 18 h the products were extracted with
Et2O (5ꢃ20 mL) and the combined organics were concentrated in
vacuo. Purification by flash chromatography (9:1 petroleum ether/
4.12. 1-d-3-Phenylpent-1-yn-3-yl acetate (d-7a)
The reagent was prepared in two stages.
(a) Deuteration of 3-phenylpent-1-yn-3-ol The parent alcohol
(1.00 g, 6.24 mmol) was dissolved in dry THF (50 mL) and n-BuLi
(1.6 M in hexanes, 8.0 mL, 12.8 mmol) was added slowly at ꢀ60 ꢁC.
After 30 min the reaction was taken out of the cold bath and D2O
(1 mL) was added while the reaction was kept under an argon at-
mosphere. The reaction mixture was diluted with Et2O and washed
EtOAc) gave (ꢀ)-(S)-7a (0.25 g, 48%) with 57% ee showing [
(c 0.86, CHCl3) followed by (ꢀ)-(R)-3-phenylpent-1-yn-3-ol (0.13 g,
32%) with 90% ee showing [
scopic properties of the two components are given above. Their
enantiomeric purities were determined by chiral GC (octakis(2,6-di-
a
]D ꢀ33.9
a]
D ꢀ33.9 (c 0.86, CHCl3). The spectro-
O-methyl-3-O-pentyl)-g-cyclodextrin) and the temperature

M. Asikainen, S. Woodward / Tetrahedron 68 (2012) 5492e5497
5497
programme 60e150 ꢁC at 2 ꢁC minꢀ1. Enantiomer retention times:
(S)-7a 44.1 min, (R)-7a 44.3 min; (R)-alcohol 45.9, (S)-alcohol
46.5 min. The CIP assignments are tentatively based on comparisons
against literature optical rotations.13
a clear oil (36.0 mg, 0.19 mmol, 38%). Rf¼0.75 (9:1 petroleum ether/
Et2O); 1H NMR (400 MHz, CDCl3) dH 7.31e7.14 (m, 4H), 6.62 (d, 1H,
J¼1.2 Hz), 3.58e3.60 (m, 1H), 2.28 (s, 3H), 1.34 (d, 3H, J¼7.6 Hz); 13C
NMR (67.9 MHz, CDCl3) dC 168.0, 159.9, 141.7, 142.8, 126.8, 124.5,
122.3, 121.0, 113.1, 43.2, 21.3, 14.8; IR (cmꢀ1
) nmax 2971, 1764, 1600,
4.14. Products from gold-catalyzed transformation of (S)-3-
phenylpent-1-yn-3-yl acetate (S)-7a
1463, 1370, 1199; MS m/z (ESI) for C12H12NaO2 [MþNa]þ calcd
211.0730, found 211.0742, error 5.80 ppm.
To 3-phenylpent-1-yn-3-yl acetate 7a (130 mg, 0.65 mmol, ra-
cemic or 57% ee) in CH2Cl2 (15 mL) at room temperature were
added Au(IPr)Cl (9.2 mg, 0.013 mmol, 2.0 mol %) and AgOTf (2.8 mg,
0.013 mmol, 2.0 mol %). After 10 min the reaction mixture was
filtered through a pad of Celite with a CH2Cl2 wash and the solvents
were evaporated on a rotary evaporator. Purification of the residue
by column chromatography (30:1 pentane/Et2O) gave 1-ethyl-1H-
inden-2-yl acetate (8a, 51 mg, 0.25 mmol, 39%), 3-ethyl-1H-inden-
1-yl acetate (4a, 14 mg, 0.07 mmol, 11%) and Z/E-pent-3-en-1-yn-3-
ylbenzene (9, 23 mg, 0.16 mmol, 25%). By running the reaction at
ꢀ2 ꢁC the reaction could be monitored by chiral GC in a manner
analogous to Section 4.10.
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) are gratefully acknowledged.
References and notes
1. For reviews, see: (a) Nevado, C. Chimia 2010, 64, 247e251; (b) Marion, N.;
Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750e2752; (c) Wang, S.; Zhang, G.;
Zhang, L. Synlett 2010, 692e706.
ꢀ
ꢀ
2. (a) Marion, N.; Díez-Gonzalez, S.; de Fremont, P.; Noble, A. R.; Nolan, S. P. An-
gew. Chem., Int. Ed. 2006, 45, 3647e3650; (b) Nun, P.; Gaillard, S.; Poater, A.;
Cavallo, L.; Nolan, S. P. Org. Biomol. Chem. 2011, 9, 101e104.
4.15. 1-Ethyl-1H-inden-2-yl acetate (8a)
ꢀ
3. Amjis, C. H. M.; Lopez-Carrillo, V.; Echavarren, A. M. Org. Lett. 2007, 9,
The title compound was obtained as a clear oil. Rf¼0.28 (30:1
petroleum ether/Et2O); 1H NMR (400 MHz, CDCl3) dH 7.31e7.22 (m,
3H), 7.16e7.12 (m, 1H), 6.65e6.64 (m, 1H), 3.62e3.59 (m, 1H), 2.27
(s, 3H), 1.96e1.83 (m, 2H), 0.76 (t, 3H, J¼7.2 Hz); 13C NMR
(100.6 MHz, CDCl3) dC 168.1, 158.0, 142.5, 141.0, 126.7, 124.3, 122.6,
4021e4024.
4. (a) Li, G.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 3740e3741; (b) Wang,
S.; Zhang, L. Org. Lett. 2006, 8, 4585e4587.
5. (a) Meyer, K. H.; Schuster, L. Ber. Dtsch. Chem. Ges. 1922, 55, 819e821; (b)
Marion, N.; Carlqvist, P.; Gealageas, R.; de Fremont, P.; Maseras, F.; Nolan, S. P.
Chem.dEur. J. 2007, 13, 6437e6451; (c) Ramon, R. S.; Marion, N.; Nolan, S. P.
ꢀ
ꢀ
121.0, 114.3, 49.0, 22.4, 21.3, 9.3; IR (cmꢀ1
) nmax 2969, 1761, 1601,
Tetrahedron 2009, 65, 1767e1773; (d) Tu, M.; Li, G.; Wang, S.; Zhang, L. Adv.
Synth. Catal. 2007, 349, 871e875.
1463, 1192; MS m/z (ESI), for C13H14NaO2 [MþNa]þ calcd 225.0886,
6. (a) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804e16805; (b) Buzas, A.; Gagosz, F. J.
Am. Chem. Soc. 2006, 128, 12614e12615; (c) Mamane, V.; Gress, T.; Krause, H.;
found 225.0890, error 1.70 ppm.
€
Furstner, A. J. Am. Chem. Soc. 2004, 126, 8654e8655.
7. (a) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L.
4.16. (Z)/(E)-Pent-3-en-1-yn-3-ylbenzene (9)
ꢁ
Angew. Chem., Int. Ed. 2008, 47, 718e721; (b) Marion, N.; Lemiere, G.; Correa, A.;
ꢀ
ꢀ
Costabile, C.; Ramon, R. S.; Moreau, X.; de Fremont, P.; Dahmane, R.; Hours, A.;
Lesage, D.; Tabet, J.-C.; Goddard, J.-P.; Gandon, V.; Cavallo, L.; Fensterbank, L.;
Malacria, M.; Nolan, S. P. Chem.dEur. J. 2009, 15, 3243e3260.
8. Asikainen, M.; Lewis, W.; Blake, A. J.; Woodward, S. Tetrahedron Lett. 2010, 51,
6454e6456.
The title compound comprised a 1:1 mixture of E/Z isomers and
was obtained as a yellow oil; Rf¼0.75 (20:1 petroleum ether/Et2O);
1H NMR (400 MHz, CDCl3) dH 7.61e7.58 (m, 2H), 7.36e7.24 (m, 3H),
6.56 (qd, 1H, J¼6.8, 0.8 Hz), 3.37 (s, 1H, the 0.8 Hz coupling to the
alkene was not resolved), 2.10 (d, 3H, J¼6.8 Hz); 13C NMR
(100.6 MHz, CDCl3) dC 137.8, 134.8, 128.3, 127.5, 125.8, 123.6, 83.3,
9. (a) Espenson, J. H. Chemical Kinetics and Reaction Mechanisms, 2nd ed.;
McGraw-Hill: Singapore, 1995, Chapter 4.4,
p 77; (b) Billo, E. J. Excel for
Chemists, 2nd ed.; Wiley-VCH: New York, NY, 2001, Chapter 23, pp 373e388.
10. Fang, R.; Yanga, L.; Wang, Y. Org. Biomol. Chem. 2011, 9, 2760e2770.
11. (a) Schneekloth, J. S.; Pucheault, M.; Crews, C. M. Eur. J. Org. Chem. 2007, 40e43
(supporting data); (b) Olejnik, M.; Jasiobedzki, W.; Pograniczna-Ramza, M. Bull.
Pol. Acad. Sci., Chem. 1986, 33, 467e473; (c) Nakanishi, Y.; Koji Miki, K.; Ohe, K.
Tetrahedron 2007, 63, 12138e12148.
80.8, 16.9; IR (cmꢀ1
) nmax 3306, 3009, 2914, 1711, 1598, 1495, 1440,
1363; MS m/z (EI), for C11H10 [M]þ calcd 142.0783, found 142.0777,
error 4.20 ppm.
12. Braese, S.; Ruemper, J.; Voigt, K.; Albecq, S.; Thurau, G.; Villard, R.; Waegell, B.;
De Meijere, A. Eur. J. Org. Chem. 1998, 671e678.
13. For (S)-7a this assignment is based on the observation of a negative [a] value
D
4.17. 1-Methyl-1H-inden-2-yl acetate (8b)
for the closely related compound PhC(CF3)(CCH)OAc: (a) O’Hagan, D.; Zaidi, N.
A. Tetrahedron: Asymmetry 1994, 5, 1111e1118; (b) O’Hagan, D.; Zaidi, N. A. J.
Chem. Soc., Perkin Trans. 1 1992, 947e949.
Using the same method as described for the preparation of 8a,
2-phenylbut-3-yn-2-yl acetate 7b (94.0 mg, 0.50 mmol) gave 8b as