A convenient, high-yielding copper-free synthesis of skipped 1,4-diynes

Article abstract of DOI:10.1055/s-2007-990885

Alkynylalanes were found to react efficiently with propargylic electrophiles, such as propargyl mesylates and propargyl diethylphosphates. The reaction proceeds with high regioselectivity and does not require copper or any other transition metal. Georg Th

Full text of DOI:10.1055/s-2007-990885

PRACTICAL SYNTHETIC PROCEDURES
655
A Convenient, High-Yielding Copper-Free Synthesis of Skipped 1,4-Diynes
A
C
onven
i
ient
S
y
l
nthesis
a
of Skipped
l
1,4-Diynes Kessabi, Renaud Beaudegnies, Pierre M. J. Jung, Benjamin Martin, Florian Montel, Sebastian Wendeborn*
Research Chemistry, SYNGENTA Crop Protection AG, 4002 Basel, Switzerland
Fax +41(61)3238529; E-mail: sebastian.wendeborn@syngenta.com
Received 14 August 2007; revised 29 August 2007
PSP
No114
Abstract: Alkynylalanes were found to react efficiently with propargylic electrophiles, such as propargyl mesylates and propargyl dieth-
ylphosphates. The reaction proceeds with high regioselectivity and does not require copper or any other transition metal.
Key words: alkynes, alanes, aluminum, cross-coupling, regioselectivity
Procedure 1
AlMe2
CH2Cl2
0 °C, 2 h
MsO
+
92%
Procedure 2
CH2Cl2
–35 °C, 2.5 h
AlMe2
MsO
TBDPSO
+
TBDPSO
55%
Procedure 3
CH2Cl2
0–23 °C, 7 h
AlMe2
MsO
n-C5H11
Cl
+
Cl
n-C5H11
73%
Procedure 4
CH2Cl2
0–23 °C, 1 h
TsCl, K2CO3, cat. Me3N⋅HCl,
CH2Cl2
TsO
HO
55%
AlMe2
74%
Scheme 1 Copper-free synthesis of skipped 1,4-diynes
requisite acetylenic copper species is usually generated in
situ using stoichiometric amounts of copper(I) in the pres-
Introduction
Csp–Csp3 cross-coupling reactions typically still rely on the ence of a weak base such as potassium carbonate.Alterna-
generation of a copper acetylide which reacts with an tively, catalytic quantities of copper(I) are sufficient when
electrophilic halide or sulfonate.1 In particular, the prepa- preformed magnesium acetylides are employed as cou-
ration of methylene-bridged 1,4-diynes (commonly re- pling partners.3
ferred to as skipped diynes) involves cross-coupling of
Although widely employed, this copper-mediated cross-
copper acetylides with propargylic electrophiles.2 The
coupling approach to 1,4-diynes can suffer from a number
of limitations (Scheme 2). Firstly, the yield of the desired
coupled product 1 can be reduced due to competitive for-
mation of regioisomeric alkynylallenes 2 which result
from an undesired nucleophilic attack by the acetylenic
SYNTHESIS 2008, No. 4, pp 0655–0659
Advanced online publication: 13.11.2007
DOI: 10.1055/s-2007-990885; Art ID: Z19407SS
x
x
.
x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

656
J. Kessabi et al.
PRACTICAL SYNTHETIC PROCEDURES
R
R
pathway
A
pathway
B
Cu
R
R'
A
SN2'
1
SN2
B
R'
R'
desired 1,4-diyne
2
allene
A/B
LG
base
pathway
C
1,3-diyne and/or
allenes and polymers
homocoupling
R
R
3
1,3-diyne
Scheme 2 Competitive reactions involved in the formation of 1,4-skipped diynes 1
copper species at the triple bond (SN2¢) rather than at the a propargylic electrophile capable of complexing with the
sp3 carbon of the electrophile (pathways A and B, respec- Lewis acid aluminum species, a coupling reaction could
tively). In turn, these allenic products are prone to poly- ensue and lead to the formation of a skipped diyne. The
merization.
successful transfer of the alkynyl residue would rely in
part on weakening the Csp–aluminum s bond, as well as
the propargylic Csp3–leaving group bond, as a conse-
quence of the proposed complexation shown in Scheme 3.
Secondly, undesired isomerization of the 1,4-diyne 1 to
the corresponding allenes and eventually the 1,3-isomer is
possible even under the weakly basic conditions, thus
lowering the yield and complicating the isolation of the
skipped diyne.4 Finally, the acetylenic copper species can
be prone to oxidative homocoupling (pathway C,
Scheme 2).5 In addition, copper waste can pose a signifi-
cant issue for the commercialization of such chemical pro-
cesses.
Scope and Limitations
For the preparation of our base-sensitive diynes (vide su-
pra), it was preferable to avoid the use of strongly basic
transmetalation methods (alkynyl–alkali metal–Al ex-
change) commonly applied for the generation of the
requisite alkynylalane species7 (pathway A in Scheme 4).
We therefore opted for a salt-free method recently report-
ed by Micouin8 which involves treating terminal alkynes
with trimethylaluminum in the presence of only catalytic
amounts of triethylamine (pathway B in Scheme 4).
In the course of our search for an efficient and scalable
process for the preparation of skipped diynes in the ab-
sence of copper, we discovered that alkynylalanes react
smoothly and selectively with propargyl sulfonates and
phosphates to give the corresponding skipped dienes in
high yields.6 The origin of this work rests on the expecta-
tion that if an alkynylalane is generated in the presence of
For our purposes, the alkynylalane of phenylacetylene
was prepared according to Micouin’s conditions8 and was
employed as a model substrate for coupling with numer-
ous propargyl electrophiles. The coupling procedure is
straightforward and simply involves dropwise addition of
the phenylethynylalane to the electrophile in dichlo-
romethane at 0 °C or at room temperature. The outcome of
these reactions is reported in Table 1.
R
R
R
Al
Al
+
LG
1
LG
R'
R'
Initially, coupling of the easily prepared propargyl dieth-
ylphosphate with two equivalents of phenylethynylalane
led to a clean reaction according to GC and 1H NMR anal-
ysis of the crude material. Our desired skipped diyne 1
R'
aluminum complex
LG: leaving group containing residues capable of complexing to the alane
Scheme 3 1,4-Diynes via mutual activation of alkynylalanes and
propargylic electrophiles
pathway A
pathway B
H
H
Al
i. n-BuLi
AlMe3, Et3N (cat.)
PhMe, 60 °C, 6 h
R
R
R
ii. Me2AlCl
– LiCl
– CH4
alkynylalane
R: alkyl, aryl
Scheme 4 Approaches to alkynylalanes
Synthesis 2008, No. 4, 655–659 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Convenient Synthesis of Skipped 1,4-Diynes
657
An added improvement for the preparation of methylene-
bridged diynes such as 1 came from the observation that
inexpensive propargylic methyl- and tolylsulfonates were
even better partners in this novel alkynylalane-mediated
cross-coupling than phosphate and phosphinate – they led
to the highest yields of the skipped diyne (cf. entries 4–7
vs entries 1–3). Advantageously, in selected instances just
stoichiometric amounts of alkynylalane were required
when the sulfonate was used as the coupling partner (entry
5).9 Furthermore, the propargylic sulfonates – whether de-
rived from terminal or internal acetylenes – were found to
be as reactive at lower temperatures (–30 °C for the mes-
ylate and 0 °C for the tosylate) as they were at room tem-
perature.
Table 1 Cross-Coupling Reaction of Phenylethynylalane with Pro-
pargylic Electrophilesa
[a]
Ph
X
+
Ph
R'
heptane
CH2Cl2
R'
AlMe2
1
Entry Equiv
of alane
X
R¢
Et
Temp
(°C)
Time Yield of 1
(h)
(%)b
1
2
3
4
5
6
7
2
OPO(OEt)2
0 to r.t.
8
79
2
2
2
1
2
2
OPO(OPh)2 Et
r.t.
r.t.
0
10
8
85
OPOPh2
OMs
OMs
OTs
Et
Et
H
80
2
92
Particularly noteworthy is the high yield of the regioselec-
tive reaction between the terminal propargylic sulfonates
and the alkynylalane (entries 5,7) since literature prece-
dent,10 as well as our own experiences,11 have shown that
SN2¢ attack predominates on terminal propargylic electro-
philes when the nucleophilic coupling partner is an alky-
nylcopper (presumably resulting in allene formation and
subsequent polymerization). Electrophiles which possess
a chloride, methoxy, or methoxymethyl substituent at the
propargylic position did not cross-couple with the alkyn-
0
0.5
88
Et
H
0
1
2
96
OTs
0
85
a Reaction conditions: PhC≡CAlMe2 in CH2Cl2–heptane (1 M) was
added to the electrophile in CH2Cl2 and the conversion was followed
by GC.
b Isolated yields.
had been generated for the first time not only in high iso- ylalane under these conditions.
lated yield (79%, entry 1) but also free from the regioiso-
The preparation of dialkyl substituted methylene-bridged
meric alkynylallene. Attempts to carry out the reaction of
propargyl phosphates with just one equivalent of the alky-
nylalane resulted in absolutely no consumption of the
electrophile even in the presence of different Lewis acids
[ZnCl2, ZnI2, Al(Oi-Pr)3, Al(Oi-Bu)3]. In addition, the
cross-coupling reactions of the corresponding readily
available, diphenylphosphate and diphenylphosphinate
with phenylethynylalane were similarly regioselective
and equally effective (entries 2,3, respectively).
diynes was also shown to be possible using this alkynyl-
alane-mediated cross-coupling as shown in Scheme 1 and
Table 2. Firstly, the use of a propargyl diethylphosphate
as the electrophilic coupling partner provided dodeca-3,6-
diyne regioselectively, albeit in low yield (entry 1, 23%).
In contrast, the coupling of the corresponding mesylate
was significantly higher yielding (entry 2, 77%) and ad-
vantageously could be carried out at temperatures much
lower than that required for the phosphate (0 °C vs 90 °C).
Table 2 Cross-Coupling Reaction of Alkyl-Substituted and Functionalized Alkynylalanes with Propargylic Electrophiles
heptane
CH2Cl2
R
X
+
R
AlMe2
R'
R'
1
R' = Et, n-C5H11, EtC CCH2
Entry
1b
R
Alane (equiv)
X
Temp (°C)
0–90
Time (h)
Yield of 1 (%)a
n-C5H11
n-C5H11
EtO
2
1
2
OPO(OEt)2
OMs
73
1
23
77
49
2b
0–23
3b
OMs
–35 to r.t.
4
O
4b,c
2
OMs
–35 to r.t.
4
55
TBDPSO
5d
6e
Cl(CH2)6
Ph
1
1
OMs
OTs
0–23
7
1
73
74
0 to r.t.
a Isolated yields.
b R¢ = Et.
c The alane was added to the mesylate in toluene.
d R¢ = n-C5H11.
e R¢ = EtC≡CCH2.
Synthesis 2008, No. 4, 655–659 © Thieme Stuttgart · New York

658
J. Kessabi et al.
PRACTICAL SYNTHETIC PROCEDURES
acid pent-2-ynyl ester diphenyl ester, diphenylphosphinic acid pent-
2-ynyl ester,12 methanesulfonic acid pent-2-ynyl ester,13 methane-
sulfonic acid prop-2-ynyl ester,14 toluene-4-sulfonic acid pent-2-
ynyl ester,15 and toluene-4-sulfonic acid prop-2-ynyl ester.14
Moreover, the mesylate necessitated a significantly short-
er reaction time compared to the phosphate (1 h vs 73 h),
and only required the use of stoichiometric amounts of the
alane which is consistent with what was previously ob-
served (cf. Table 1, entry 5).
The phenylethynyltrimethylaluminum was prepared according to
the procedure described by Micouin et al.8 This alane solution was
diluted in CH2Cl2 to a final concentration of 1 M in order to avoid
crystallization. This solution could be stored under argon in the dark
for several days.
A useful extension of this methodology would be its ap-
plication for the preparation of functionalized diynes
which are amenable to further transformations. To this
end, the propargyl alcohol-derived ethoxyethyl ether and
tert-butyldiphenylsilyl ether were selected as precursors
to representative functionalized alkynylalanes (entries 3
and 4, respectively). While Micouin’s conditions for alky-
nylalane preparation failed to provide the requisite nu-
Procedure 1
Hepta-1,4-diynylbenzene
Phenylethynyltrimethylaluminum (1 M in CH2Cl2–heptane, 2 mL,
2.0 mmol, 1 equiv) was added dropwise to a stirred solution of pent-
2-ynyl methanesulfonate (325 mg, 2.0 mmol, 1 equiv) in CH2Cl2 (3
cleophilic coupling partners in these instances, they were mL) at 0 °C. The reaction progress was followed by GC. After stir-
ring for 2 h at this temperature, the reaction was quenched carefully
at 0 °C by dropwise addition of an aq Rochelle’s salt solution (2 M,
attainable on treatment with n-BuLi and transmetalation
with AlMe2Cl at –35 °C. Their subsequent cross-cou-
~15 mL) and the resulting mixture was diluted with Et2O (20 mL).
plings with the mesylate derived from pent-2-yn-1-ol
The aqueous layer was extracted with Et2O (2 × 20 mL). The com-
were regioselective and afforded the desired acetal and si-
lyloxy functionalized diynes in moderate yields [49% and
55%, respectively, Table 2 (R¢ = Et)].
bined Et2O extracts were dried (Na2SO4) and concentrated in vacuo
to give a clear oil, which was purified by flash chromatography
(hexane, Rf = 0.8) to give the product as a clear oil (308 mg, 92%).
3
1H NMR (300 MHz, CDCl3): d = 1.07 (t, J = 6.0 Hz, 3 H, CH3),
In addition, the chloroalkyl-substituted diyne was suc-
cessfully prepared as shown in entry 5 via the intermedia-
cy of 1-chlorooct-7-ynylalane, highlighting the
chemoselective nature of the substitution at the mesylate
centre rather than at the chloride during the cross-cou-
pling. Further steps towards extending the utility of this
method was the successful preparation of a skipped triyne,
deca-1,4,7-triynylbenzene from 1,3-diyne tosylate and
phenylethynylalane (entry 6).
2.08–2.16 (m, 2 H, CH2), 3.30 (t, 3J = 3.0 Hz, 2 H, CH2), 7.17–7.23
(m, 3 H, C6H5), 7.34–7.37 (m, 2 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 10.4, 12.4, 13.8, 72.9, 80.3, 82.3,
80.3, 123.4, 128.0, 128.2, 131.7.
Procedure 2
tert-Butylocta-2,5-diynyloxydiphenylsilane
A solution of tert-butylprop-2-ynyloxysilane (1.178 g, 4 mmol) in
anhyd toluene (10 mL) under argon was metalated with n-BuLi (1.6
M in hexane, 2.8 mL, 4.4 mmol, 1.1 equiv) at –35 °C for 30 min.
The resulting solution was treated with Me2AlCl (1 M, 4.4 mL, 4.4
mmol, 1.1 equiv) at the same temperature and stirred at –35 °C for
an additional 30 min. This solution was transferred via a cannula at
this temperature to a solution of the pentyne mesylate (324 mg, 2
mmol). The stirring was continued at –35 °C for 2.5 h. The cooling
bath was removed and on reaching r.t., the mixture was quenched
with MeOH (1 mL), poured into H2O (20 mL), and extracted with
Et2O (3 × 15 mL). The organic layers were dried (Na2SO4) and con-
centrated in vacuo to give a clear oil which was purified by flash
chromatography (Et2O–hexane: 0.5:10, Rf = 0.45) to give the pro-
tected diyne as an oil (397 mg, 55%); GC: tR = 8.51 min.
In summary, a novel copper-free and regioselective syn-
thesis of methylene-bridged skipped diynes has been de-
veloped, which relies on cross-coupling alkynylalanes
with phosphinate-, phosphate- or sulfonate-based propar-
gylic electrophiles capable of complexation with the nu-
cleophile. The method is efficient, mild and
advantageously does not lead to detrimental isomerization
of the base-sensitive skipped diyne since only catalytic
amounts of triethylamine are required for initial prepara-
tion of the alkynylalane.
1H NMR (300 MHz, CDCl3): d = 0.99 (s, 9 H, CH3), 1.04 (t, 3J = 6
Hz, 3 H, CH3), 2.06–2.13 (m, 2 H, CH2), 3.03–3.05 (m, 2 H, CH2),
4.23 (t, 3J = 3 Hz, 2 H, CH2), 7.28–7.37 (m, 3 H, C6H5), 7.63–7.65
(m, 2 H, C6H5).
13C NMR (100 MHz, CDCl3): d = 9.9, 12.4, 13.8, 19.2, 26.8, 52.9,
72.9, 78.5, 80.0, 82.2, 127.8, 129.9, 133.2, 135.7.
All experiments sensitive to air and/or to moisture were carried out
under argon in dried glassware assembled under a stream of argon.
NMR spectra were recorded on Bruker Ultrashield Avance (1H, 300
or 400 MHz; 13C, 75 or 100 MHz) spectrometers. Mass spectra were
obtained with GCMS conducted on a Thermo, MS: DSQ and GC:
TRACE GC ULTRA with Zebron phenomenex column: Phase ZB-
5ms 15 m, diam: 0.25 mm, 0.25 mm, H2 flow 1.7 mL/min, temp in-
jector: 280 °C, temp detector: 280 °C, method: 4 min at 40 °C, then
30 °C/min until 320 °C, then 5 min at 320 °C. All reagents and sol-
vents, unless otherwise noted, were purchased from commercial
vendors and used without further purification. GC analysis was con-
ducted on a Varian CP-3800 + AutoSampler CP-8410 + H2 genera-
tor Schmidlin SL-9100 with detector: FID, column: Chrompak CP-
Sil24CB 15 m, diam: 0.32 mm, 0.25 mm, H2 flow 1.7 mL/min, temp
injector: 250 °C, temp detector: 300 °C, method: 4 min 40 °C, then
30 °C/min until 250 °C, then 5 min at 250 °C.
CIMS: m/z = 237, 207.
Procedure 3
16-Chlorohexadeca-6,9-diyne
Me3Al (3.75 mL, 7.48 mmol, 2 M in heptane) was transferred by a
syringe to a flask, upon which Et3N (94.5 mL, 0.68 mmol) was add-
ed, followed after 5 min by 8-chlorooct-1-yne (986 mg, 6.8 mmol).
The stirred solution was heated to 60 °C for 6 h until methane evo-
lution had ceased at which point an aliquot was taken, quenched
with CD3OD, and filtered before an 1H NMR spectrum confirmed
the total disappearance of the terminal alkyne proton. The prepared
(8-chlorooct-1-ynyl)dimethylaluminum (1.28 mL, 2.0 mmol, 1.56
M in heptane) was then added dropwise to a stirred solution of oct-
2-ynyl methanesulfonate (324 mg, 2.0 mmol) in CH2Cl2 (3 mL) at
The electrophilic partners employed in this study were prepared ac-
cording to literature procedures from commercially available alco-
hols: phosphoric acid diethyl ester pent-2-ynyl ester, phosphoric
Synthesis 2008, No. 4, 655–659 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Convenient Synthesis of Skipped 1,4-Diynes
659
0 °C. The solution was allowed to warm up to r.t. and the reaction
progress followed by GCMS. After 7 h, the mixture was transferred
to a separating funnel, diluted with Et2O (20 mL), and quenched
carefully by dropwise addition of an aq Rochelle’s salt solution (2
M, 4 mL). The layers were separated and the aqueous layer extract-
ed with Et2O (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give the desired product as
a yellow oil, which was purified by flash chromatography (hexane,
Rf = 0.28) to give the product as a yellow liquid (368 mg, 73%); GC:
tR = 6.68 min.
1H NMR (400 MHz, CDCl3): d = 0.7 (t, J = 7 Hz, 3 H, CH3), 1.4–
1.1 (m, 12 H, CH2), 1.6 (m, 2 H, CH2), 2.0 (m, 4 H, CH2), 3.0 (m, 2
H, CH2), 3.4 (t, J = 7 Hz, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 9.7, 14.0, 18.6, 18.7, 22.2, 26.4,
28.1, 28.5, 31.1, 32.5, 45.0, 74.4, 74.8, 80.2, 80.6.
13C NMR (100 MHz, CDCl3): d = 9.8, 10.5, 12.4, 13.8, 73.0, 74.0,
75.4, 80.6, 82.3, 83.6, 123.1, 128.1, 128.2, 128.3, 128.8, 131.7,
132.1.
GCMS: m/z = 206 (M+, 100%).
References
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63. Exceptions include the use of tris(alkynyl)indiums with
benzyl bromide catalyzed by Cl2Pd(dppf) and the use of
alkynylboron dichlorides with benzyl, benzylallyl and
benzypropargyl secondary alcohols. (b) Perez, J.; Perez-
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EIMS: m/z = 252 (M+).
Procedure 4
Octa-1,4-diynyl Tosylate
(3) (a) Brandsma, L. Synthesis of Acetylenes, Allenes and
Cumulenes; Elsevier: Amsterdam, 2003, and references
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To a suspension of octa-1,4-diynyl alcohol (1.01 g, 8.25 mmol, 1.0
equiv), trimethylammonium hydrochloride (98%, 81 mg, 0.83
mmol, 0.1 equiv) and K2CO3 (1.37g, 1.2 equiv, 9.90 mmol) in
CH2Cl2 (15 mL) was added TsCl (1.89 g, 9.90 mmol, 1.2 equiv) at
0 °C and the reaction progress was monitored by GC. After 1.5 h,
the reaction was warmed to r.t., and after 4 h, TsCl (0.79 g, 4.13
mmol, 0.5 equiv) was added. After 21 h, an additional amount of
TsCl (1.89 g, 9.90 mmol, 1.2 equiv) was added, and again at 45 h
(1.89 g, 9.90 mmol, 1.2 equiv). At 68 h, GC confirmed 99% conver-
sion and the reaction was cooled to 0 °C and quenched with H2O (5
mL). CH2Cl2 (20 mL) was added and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (3 × 20 mL), the organic
phases were combined, washed with H2O (3 × 20 mL), dried
(Na2SO4) and the solvent evaporated in vacuo to give an orange oil.
The oil was purified by flash chromatography (10% EtOAc–hex-
ane) to give the product as a light brown oil (1.26 g, 55%). GC:
tR = 9.44 min.
(5) (a) Comprehensive Organic Synthesis, Vol. 5; Trost, B. M.;
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Montel, F.; Wendeborn, S. Org. Lett. 2006, 8, 5629.
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1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7 Hz, 3 H, CH3), 2.10
(m, 2 H, CH2), 2.98 (m, 2 H, CH2), 4.62 (m, 2 H, CH2), 7.28 (d, J =
9 Hz, 2 H, C6H5), 7.72 (d, J = 1 Hz, 2 H, C6H5).
13C NMR (100 MHz, CDCl3): d = 9.82, 12.30, 13.75, 58.23, 71.96,
82.75, 84.64, 128.17, 129.76, 133.26, 144.96.
GCMS: m/z = 206 (M+, 100%).
(8) (a) Feuvrie, C.; Blanchet, J.; Bonin, M.; Micouin, L. Org.
Lett. 2004, 6, 2333. (b) Wang, B.; Bonin, M.; Micouin, L.
Org. Lett. 2004, 6, 3481.
(9) The need for two equivalents of alkynylalane when
employing propargyl phosphates and phosphinates suggests
that the reaction proceeds via an alternative mechanism,
essentially involving Lewis acid activation prior to
coordination and transfer brought on by the second
equivalent of alkynylalane.
(10) Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K.
Synthesis 1993, 65.
(11) Unpublished results from this laboratory.
(12) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron
1994, 50, 6017.
10-Phenyldeca-3,6,9-triyne
Phenylethynylaluminum (1 M in CH2Cl2–heptane, 2 mL, 2.0 mmol,
1.0 equiv) was added dropwise to a stirred solution of oct-3,6-
diyne-8-p-toluenesulfonate (552 mg, 2.0 mmol, 1.0 equiv) in
CH2Cl2 (3 mL) at 0 °C. The mixture was allowed to warm to r.t. and
the progress was monitored by GC. After 1 h, the reaction was
quenched carefully at 0 °C by dropwise addition of an aq Rochelle’s
salt solution (2 M, ~15 mL). The resulting mixture was then diluted
with Et2O (20 mL). The aqueous layer was extracted with Et2O (3 ×
20 mL). The combined Et2O extracts were dried (Na2SO4) and con-
centrated in vacuo to provide a brown oil which was purified by
flash chromatography (hexane, Rf = 0.2) to give the product as a
brown oil (340 mg, 74%); GC: tR = 11.23 min.
1H NMR (300 MHz, CDCl3): d = 1.05 (t, J = 7 Hz, 3 H, CH3), 2.11
(m, 2 H, CH2), 3.10 (m, 2 H, CH2), 3.31 (m, 2 H, CH2), 7.18–7.42
(m, 5 H, C6H5).
(13) White, W. L.; Anzeveno, P. B. J. Org. Chem. 1982, 43,
2379.
(14) Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miyawaki, T.;
Utsumi, N. Bull. Chem. Soc. Jpn. 1995, 68, 297.
(15) Easton, C. J.; Ferrante, A.; Robertson, T. A.; Xia, L. Aust. J.
Chem. 2002, 55, 647.
Synthesis 2008, No. 4, 655–659 © Thieme Stuttgart · New York