A straightforward organocatalytic alkylation of 2-arylacetaldehydes: An approach towards bisabolanes

Article abstract of DOI:10.1002/adsc.201300250

A highly stereoselective organocatalytic aalkylation of 2-arylacetaldehydes with a commercially available carbenium tetrafluoroborate is described. The stereoselective alkylation was carried out in acetonitrile/ water, under air in the presence of a commercially available imidazolidinone (MacMillan's catalyst). Key intermediates for the synthesis of bisabolanes were obtained through a simple chemistry. In particular a direct, enantioselective and facile synthesis of (R)-(-)-curcumene is described.

Full text of DOI:10.1002/adsc.201300250

FULL PAPERS
DOI: 10.1002/adsc.201300250
A Straightforward Organocatalytic Alkylation of
2-Arylacetaldehydes: An Approach towards Bisabolanes
Andrea Gualandi,a,* Pietro Canestrari,a Enrico Emer,a and Pier Giorgio Cozzia,*
a
Alma Mater Studiorum, Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126, Bologna, Italy
E-mail: andrea.gualandi10@unibo.it or piergiorgio.cozzi@unibo.it
Received: March 25, 2013; Revised: November 13, 2013; Published online: January 27, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300250.
Abstract: A highly stereoselective organocatalytic a- bolanes were obtained through a simple chemistry.
alkylation of 2-arylacetaldehydes with a commercially In particular a direct, enantioselective and facile syn-
available carbenium tetrafluoroborate is described. thesis of (R)-(À)-curcumene is described.
The stereoselective alkylation was carried out in ace-
tonitrile/water, under air in the presence of a com-
mercially available imidazolidinone (MacMillanꢀs Keywords: a-alkylation; bisabolanes; curcumene; en-
catalyst). Key intermediates for the synthesis of bisa- amines; Macmillanꢀs catalyst; organocatalysis
Introduction
they are also used as additives in perfumes and cos-
metics.[3] For these reasons, these natural products
Several important classes of natural products, includ- have attracted considerable interest and several syn-
ing bisabolanes, heliannanes, serrulatanes, and pseu- theses of the enantioenriched (R)-(À)-curcumene
dopterosins, have a characteristic benzylic stereocen- have been reported.[4] (R)-(À)-Curcumene has also
ter carrying a methyl group (Figure 1).[1]
been used as a starting material for the preparation of
These compounds exhibit interesting and diverse other bisabolanes and related terpenes.[5] In the past,
biological activities, such as anti-inflammatory, anti- the synthesis of the simple structure of bisabolanes in-
viral, and anti-mycobacterial properties.[2] In addition, volved considerable synthetic effort as it requires the
the natural products belonging to this class of bisabo- configurational control at the benzylic stereogenic
lane sesquiterpenes [e.g., (R)-(À)-curcumene (I), (S)- centre.
(+)-ar-turmerone (II) and bisacumol (III)] are key
Recently, organocatalysis[6] has reached a level of
components of a large number of essential oils and maturity at which it can be employed for the concise
and selective total synthesis of natural products.[7] Or-
ganocatalysis has also been merged with organometal-
lic methodologies by selection of compatible transi-
tion metal catalysts for use in combination with
amino catalysis.[8]
Following on from this concept, Cꢁrdova has de-
scribed a concise and selective approach to bisabo-
lanes based on the enantioselective b-alkylation of
a,b-unsaturated aldehydes by a combination of amino
catalysis and transition metal catalysis. This copper
salt-catalysed asymmetric addition of dialkylzinc re-
agents to enals promoted by an organocatalyst gave
up to 98:2 er and it was used as the key step for the
efficient total synthesis of bisabolane sesquiter-
penes.[9a] Another organocatalytic approach for the
synthesis of benzylic stereogenic centeres uses iminium
activation to enable stereoselective reduction of b-
Figure 1. Different structures of bisabolanes.
substituted a,b-enals.[9b,c]
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A Straightforward Organocatalytic Alkylation of 2-Arylacetaldehydes
sible by the formation of stabilised carbenium ions
and promoted by organocatalysis.[12] We have expand-
ed the scope of the chemistry by using the commer-
cially available 1,3-benzodithiolylium tetrafluorobo-
rate.[13] The products obtained contain the benzodi-
thiol group as a versatile building block[14] that can be
easily transformed into the corresponding methyl
group by treatment with Raney Ni or metallated by
n-BuLi.[15] Herein, we report that stereoselective a-al-
kylation of benzylic aldehydes with benzodithiolylium
tetrafluoroborate can be used to install the benzylic
stereocentre in the synthesis of bisabolanes.
Scheme 1. An organocatalytic approach to bisabolanes.
We have approached the organocatalytic installa-
tion of the benzylic stereogenic centre by considering
an a-alkylation of aldehydes by a masked methyl Results and Discussion
group as proposed in Scheme 1. The analysis shows
that the alkylated product can be transformed into A variety of substituted 2-arylacetaldehydes, precur-
the required intermediate by a simple chemistry.
sor of natural products[16] can be easily prepared by
Recently, our group[10] and other groups[11] have de- ozonolysis of the corresponding allyl derivatives. The
scribed organocatalytic SN1-type reactions in which commercially available allylic compounds 1a–d
the challenging a-alkylation of aldehydes is made pos- (Scheme 2) were subjected to ozonolysis in the stan-
dard reaction conditions and the corresponding alde-
hydes 2a–d were isolated in high yields after purifica-
tion.
Phenylacetaldehyde 2e was commercially available
and it was used without any purification.
Different aryl-substituted substrates were also ob-
tained through other simple methods (Scheme 3). The
oxidation with Dess–Martin periodinane of the com-
mercially available alcohol 3 gave the compound 2f in
good yield. The aldehydes 2g and 2h were obtained
by a reaction of the phosphorus reagent with commer-
Scheme 2. Preparation of the arylacetaldehydes by ozonoly-
sis.
cially available aldehydes 4a and 4b. The substituted
Scheme 3. Preparation of the aldehydes 2f–k.
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Scheme 4. Reaction sequence for the synthesis of the key intermediates 13a–k.
acetaldehydes 2i–k were obtained by transformation the benzodithiolylium 10. The substitution pattern of
of the corresponding acids 6a, 6b and 8 into methyl the aldehydes does not influence the stereochemical
esters 7a, 7b or the Weinreb amide 9[17] followed by outcome of the reaction, and only in the case of the
reduction with DIBAL-H.
aryl acetaldehyde bearing an electron-withdrawing
After purification by distillation or chromatogra- group (COOMe, 2h) was the corresponding adduct
phy, these 2-arylacetaldehydes 2a–k were reacted with 13h isolated with an inferior enantiomeric excess. Es-
the commercially available 1,3-benzodithiolylium tet- pecially noteworthy, the presence of an electron-do-
rafluoroborate 10 in CH3CN/H2O, employing the nating MeO group in different positions is compatible
MacMillan imidazolidinone 11 as
a
catalyst with this alkylation and allows the preparation of
(20 mol%) in the presence or in the absence of inor- useful intermediates for synthesis of bisabolanes.[18] In
ganic bases. This convenient procedure (procedure addition, the absence of electronic effects due to aro-
B), that use the commercially available MacMillan matic electron-rich aldehydes was also observed. The
catalyst 11 as hydrochloride salt, can give high yields enantiomeric excesses of the isolated products were
and high reproducibility in the alkylation of alde- all above the 92% except with the aldehyde 12h. Con-
hydes, if the organic solvent is evaporated under re- sidering the mild reaction conditions and the effec-
duced pressure at room temperature before adding tiveness, this method is overpassing the stereoselec-
MeOH for the reduction with NaBH4. Using both the tive alkylations employing Evansꢀ auxiliary.[19]
procedures excellent yields and high stereocontrol
In order to prepare the bisabolane skeleton, crude
were observed in all cases tested. The enantiomeric products 12a, b, e were reacted with Witting and
excesses of the alkylated products (Scheme 4) were Horner–Wadsworth–Emmons reagents (Scheme 5),
determined after reduction of the crude product with by using different reaction conditions.
NaBH4 (see the Supporting Information for traces of
Unfortunately, in all cases a severe decrease in the
HPLC analysis). The desired products 13a–k were ob- enantiomeric excess of the isolated final products was
tained in high yields and stereoselectivities by using observed (Table 1), compare to the starting material
a slight excess of aldehyde (1 equiv.) with respect to (from 92–96% to 24–82% ee).
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A Straightforward Organocatalytic Alkylation of 2-Arylacetaldehydes
Scheme 5. Elongation of compounds 12a, b, e by Wittig-type reactions.
Table 1. Reaction of 12a, b, e with different Wittig reagents simple and known procedure.[23] However, the succes-
and conditions.
sive elongation of two carbon atoms, in order to
obtain the key intermediates for bisabolanes synthesis
was proven to be rather challenging. Indeed, the logi-
cal SN2-type addition of the enolate derivatives failed.
In particular, the addition of tert-butyl acetate eno-
lates in the presence of DPMU or HMPA, under dif-
ferent conditions, temperature, or solvents, gave no
traces of the desired product. Otherwise, in the exam-
ined reaction conditions we have principally isolated
the eliminated product (b-methylstyrene), formed by
elimination of HI from 16a–e. We reasoned to use
a more nucleophilic and less basic enolate such as
Entry
Conditions
Substrate
ee of 12[a]
ee of 14[a]
1
2
3
4
5
A
A
A
B
C
12a
12b
12e
12a
12a
92
93
96
92
92
80
82
76
81
24
[a]
The ee values were determined by HPLC analysis. See
the Supporting Information for details.
Several slightly different reaction conditions, by a malonate. Following the straightforward methodolo-
varying solvents and temperature were examined, but gy described recently by List,[24] we have obtained
again, the decrease in enantiomeric excess was always elongation by reacting the iodide derivatives with
recorded. This behaviour was probably due to the in- sodium malonate in DMF at room temperature
creased acidity of the a-substituted benzodithiol alde- (Scheme 7).
hydes.[20]
This strategy provides good reproducible yields in
Therefore, we considered another synthetic ap- all the examined cases and it is also quite straightfor-
proach to install the 2-carbon chain. It was found ward to perform it using inexpensive reagents. No ad-
that, to avoid racemisation, it was necessary to trans- ditives, peculiar solvent mixtures or reduced tempera-
form the 1,3-benzodithiol group into a methyl group tures are necessary to obtain the desired products.
before performing the chain elongation. In order to The malonate adducts 17a–e were decarboxylated by
reduce the amount of functional group manipulation the standard Krapcho procedure,[25] affording the
and avoid numerous oxidation or reduction steps, we products 18a–e in high yields. With the final isolated
have replaced the HWE and Wittig reactions with products 18a–e HPLC analysis proved that the entire
a more efficient strategy, illustrated in Scheme 6 and reaction sequence was achieved without any racemi-
Scheme 7.
sation. The methyl ester 18c was previously used as
This strategy considers the simple formation of a key intermediate in the synthesis of (R)-(À)-curcu-
iodo derivatives, and their successive reaction with mene and (R)-(À)-erogorgiaene (Scheme 8).[26]
nucleophiles. The alcohol derivatives 15a–k were iso-
This synthesis was however, not straightforward
lated and treated with Raney nickel to generate the and additional steps were required for the total syn-
corresponding methyl group. The reaction afforded thesis of curcumene. In fact, the isolated 18c needs to
good yields for all derivatives, with no racemisation. be transformed into the corresponding aldehyde
It is worth mentioning that the oxidation of the deriv- through a reduction/oxidation sequence, and finally,
atives 15a–k provides a straightforward access to the after purification,[27] the intermediate aldehyde, is re-
arylpropionic acids, which constitute an important acted with a Wittig reagent. We want to consider
class of anti-inflammatory drugs.[21] Recently, MacMil- a more direct and simple approach towards curcu-
lan published organocatalytic and organometallic ap- mene, taking advantage of the availability and reactiv-
proaches for the a-arylation of acidic derivatives.[22]
ity of the iodide 16c and considerably shorten the
The a-methyl derivatives 15a–k were converted total synthesis. By inspection of the curcumene mole-
into the corresponding iodides 16a–k by a quite cule it is quite easy to design a retrosynthesis proposal
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Scheme 6. Synthesis of the iodides 16a–k.
Scheme 8. Published synthetic routes to bisabolanes starting
from ester 18c.
Scheme 7. Elongation by two carbons via reaction of iodides
16a–e with malonate ion and successive decarboxylation.
conditions, or performing the reaction at different
temperatures, the desired adduct was always obtained
for the addition of prenylic nucleophilic reagents to in a low quantity. A moderate ratio (up to 1.5:1) in
the iodide 16c. favour of the desired a-adduct 19 (Scheme 8) was af-
Therefore, we have investigated the reaction of forded when prenyllithium, obtained by treatment of
iodide derivatives 16c and 16e with different nucleo- prenyl-tributylstannane with n-BuLi or MeLi, was re-
philic prenylic reagents (see the Supporting Informa- acted with racemic 16e. When the same reaction was
tion for details). We found that prenyl copper or high performed with 16c (ee 95%), the desired adduct was
order allyl cyanocuprate[28] were giving low conver- obtained in quantitative yield as a 71:29 mixture of
sions and regioselectivity. By varying the reaction a and g adducts.
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A Straightforward Organocatalytic Alkylation of 2-Arylacetaldehydes
lent Technologies 1200 instrument equipped with a variable
wave-length UV detector, using a Daicel Chiralpak columns
(0.46 cm I.D.ꢃ25 cm) and HPLC grade 2-propanol and n-
hexane were used as the eluting solvents. Optical rotations
were determined in a 1 mL cell with a path length of 10 mm
(NaD line), specific rotation was expressed as deg
cm3 gÀ1 dmÀ1 and concentration as gcmÀ3. Melting points
were determined with Bibby Stuart Scientific Melting Point
Apparatus SMP 3 and are not corrected.
Materials
Organometallic reactions were carried out under inert gas
and under anhydrous conditions. Anhydrous solvents were
supplied by Aldrich in Suresealꢄ bottles and used as re-
ceived avoiding further purification. Organocatalytic reac-
tions were carried out in vials without using inert atmos-
phere or dried solvents.
Scheme 9. A direct and straightforward synthesis of (R)-
(À)-curcumene.
The reaction of prenyllithium with 16c gave a direct
and rapid approach towards (R)-(À)-curcumene
(Scheme 9). The mixture of a and g adducts 21 and
19, obtained in 86% yield, was easily separated by
preparative TLC using hexane as eluent.
Enantioselective a-Alkylation of Aldehydes
General procedure (A): A vial was charged with MacMillan
catalyst 11 (0.04 mmol, 8.7 mg), benzoic acid (0.04 mmol,
4.8 mg), acetonitrile (0.5 mL) and water (0.5 mL). The mix-
ture was cooled at 08C, and 1,3-benzodithiolylium tetra-
fluoroborate (0.2 mmol, 48 mg), NaH2PO4 (0.2 mmol,
24 mg) and the aldehydes 2a–k (0.4 mmol) were added.
General procedure (B): A vial was charged with MacMil-
lan catalyst hydrochloride 11·HCl (0.04 mmol, 10.1 mg), ace-
tonitrile (0.8 mL) and water (0.8 mL). The mixture was
Conclusions
In conclusion, we have developed a robust approach
towards the a-alkylation of 2-arylacetaldehydes vari-
ously substituted, using an organocatalytic procedure
to prepare key chiral intermediates in the synthesis of cooled at 08C, and 1,3-benzodithiolylium tetrafluoroborate
(0.2 mmol, 48 mg) and the aldehydes 2a–k (0.4 mmol) were
added. The mixture was stirred for 24 h at the same temper-
ature, the organic solvent was evaporated and the mixture
was diluted with Et2O (3 mL). The organic layer was sepa-
rated, and the aqueous layer was extracted with Et2O (2ꢃ
3 mL). The collected organic layers were concentrated
under reduce pressure. The residue was diluted in MeOH
(1 mL) and NaBH4 (0.8 mmol, 30 mg) was slowly added at
08C. After 30 min, the reaction was quenched with water
(0.2 mL), the solvent removed under reduced pressure and
the residue was extracted with AcOEt (3ꢃ5 mL). The col-
lected organic layers were dried over Na2SO4 and concen-
trated under reduce pressure.
bisabolanes. The advantages of this approach include
the possibility to use the key intermediates 12a–k
formed for other transformations. The enantioen-
riched iodo derivative 16c, obtained by a direct iodi-
nation of 15c, was used for a short synthesis of (R)-
(À)-curcumene (five total steps). Further studies are
underway in our laboratory into the application of
this methodology in the stereoselective total syntheses
of various other natural products.
13a: yield: 98%; 92% ee. The desired product was isolated
by flash column chromatography (cyclohexane/AcOEt=
from 9/1 to 8/2) as a yellow oil; The ee was determined by
HPLC analysis (Daicel Chiralcel IA column: n-hexane/i-
PrOH 90:10, flow rate 0.50 mLminÀ1, 308C, l=232,
Experimental Section
General Methods
1H NMR spectra were recorded on Varian Gemini 200 and
Varian MR 400 spectrometers. Chemical shifts are reported
in ppm from TMS with the solvent resonance as the internal
standard (deuterochloroform: d=7.27 ppm). Data are re-
ported as follows: chemical shift, multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, bs=broad singlet, m=
multiplet), coupling constants (J Hz). 13C NMR spectra were
recorded on Varian Gemini 200 and Varian MR 400 spec-
trometers. Chemical shifts are reported in ppm from TMS
with the solvent as the internal standard (deuterochloro-
form: d=77.0 ppm). LC-electrospray ionisation mass spec-
tra were obtained with Agilent Technologies MSD1100
single-quadrupole mass spectrometer. Chromatographic pu-
rification was done with 240–400 mesh silica gel. Determina-
tions of enantiomeric excesses were performed on an Agi-
254 nm):
tmajor =33.3 min,
tminor =31.2 min;
1H NMR
(400 MHz, CDCl3, 258C): d=7.36–7.26 (m, 5H), 7.21–7.19
(m,1H), 7.13–7.10 (m, 1H), 7.02–6.97 (m, 2H), 5.34 (d, J=
9.5 Hz, 1H), 4.08–4.00 (m, 2H), 3.77 (s, 3H), 3.33 (ddd, J=
4.9, 6.1, 9.5 Hz, 1H); 13C NMR (100 MHz, CDCl3, 258C):
d=159.1, 137.3, 137.2, 137.1, 130.9, 129.6 (2C), 125.5, 125.4,
122.3, 122.2, 114.1 (2C), 64.4, 56.9, 55.2, 54.0.
Homologation using the Wittig Procedure
Procedure (A): To
a solution of aldehydes 12a, b,
e (0.1 mmol) in THF (1 mL) under nitrogen the Witting re-
agent (0.25 mmol, 334 mg) was added in one portion. After
20 h the solvent was evaporated.
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Procedure (B): To a suspension of NaH (0.15 mmol) in
THF (2 mL) a solution of the HWE reagent (0.15 mmol,
30 mL) was slowly added at 08C under nitrogen atmosphere.
After 1 h a solution of aldehyde 12a (0.1 mmol) in THF
(1 mL) was added. After 20 h the reaction was quenched
with water (0.2 mL), the solvent removed under reduced
pressure and the residue was extracted with AcOEt (3ꢃ
5 mL). The collected organic layers dried over Na2SO4 and
concentrated under reduced pressure.
Procedure (C): As procedure B at À208C using lithium
alkoxide prepared from HFIP (0.15 mmol, 15 mL) and n-
BuLi (0.15 mmol, 2.5M in THF, 60 mL) in THF (2 mL). The
desired product was isolated by flash column chromatogra-
phy (cyclohexane/AcOEt=from 9/1 to 8/2) as yellow oil.
The ee was determined by HPLC analysis (see the Support-
ing Information).
ture was extracted with ether (3ꢃ6 mL) and the combined
organic phases were dried over Na2SO4 and concentrated.
The crude product was purified by flash column chromatog-
raphy on silica gel (cyclohexane/AcOEt=from 100/0 to 90/
10) to afford 17a–e.
1
17a: Yield: 85%; yellow oil; H NMR (400 MHz, CDCl3):
d=7.11–7.03 (m, 2H); 6.87–6.83 (m, 2H), 3.79 (s, 3H), 3.74
(s, 3H), 3.65 (s, 3H), 3.22 (dd, J=5.8, 9.2 Hz, 1H), 2.25–2.18
(m, 1H), 2.15–2.05 (m, 1H), 2.15–2.05 (m, 1H), 1.26 (d, J=
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=169.9, 169.8,
158.1, 137.2 (2C), 127.94 (2C), 113.9 (2C), 55.2, 52.4 (2C),
50.0, 37.2, 37.0, 22.6.
Standard Krapcho Procedure for Compounds 17a–e:
General Procedure
A mixture of compound 17a–e (0.07 mmol), LiCl (6 mg,
0.14 mmol) and H2O (2.5 mL, 0.14 mmol) in dry DMSO was
stirred for 13 h at 1608C. The crude product was purified by
flash column chromatography on silica gel (n-hexane/
AcOEt=90/10).
Reductive Removal of Benzodithiol Group; General
Procedure
To a solution of 13a–k (0.19 mmol) in ethanol (1 mL),
Raney nickel (0.450 g, slurry in water) was added and the
reaction mixture was kept under an H2 atmosphere (1 atm).
After 3 hours the reaction mixture was filtered through
a Celiteꢄ pad and the organic solvent was removed under
reduce pressure. The residue was diluted with AcOEt, the
organic layer was separated, and the aqueous layer was ex-
tracted with AcOEt (2ꢃ5 mL). The collected organic layers
were washed with brine (5 mL), dried over Na2SO4 and con-
centrated under reduce pressure. The products were used in
the following step without any purification. The enantiomer-
ic excesses of products were not changed during the reaction
with Raney nickel.
18a: Yield: 80%; 92% ee; colourless oil. The ee was deter-
mined by HPLC analysis (Daicel Chiralcel IB column: n-
hexane/i-PrOH 99:1, flow rate 0.50 mLminÀ1, 308C, l=214,
254 nm):
tmajor =12.6 min,
tminor =11.5 min;
1H NMR
(400 MHz, CDCl3, 258C): d=7.12–7.08 (m, 2H), 6.87–6.83
(m, 2H), 3.80 (s, 1H), 3.63 (s, 3H), 2.72–2.62 (m, 1H), 1.25
(d, J=6.9 Hz, 3H), 2.28–2.13 (m, 2H), 1.97–1.80 (m, 2H);
13C NMR (100 MHz, CDCl3, 258C): d=174.1, 157.9, 138.3,
127.8 (2C), 113.8 (2C), 55.2, 51.4, 38.5, 33.3, 32.3, 22.3; HR-
MS: m/z=222.12563, calcd. for C13H18O3: 222.12559.
Synthesis of 19 and 21
To
a solution of n-BuLi (2.5M in hexanes, 192 mL,
Preparation of the Iodides 16a–k; General Procedure
0.48 mmol) in THF (200 mL) tributyl(3-methyl-2-butenyl)tin
(161 mL, 172 mg, 0.48 mmol) was added dropwise at À788C
under stirring. The reaction mixture became yellow. After
1 hour iodide 16c (60 mg, 0.24 mmol) was added and the re-
action mixture was stirred at À788C for 30 min. Water
(1 mL) was added and the resulting mixture was extracted
with ether (3ꢃ10 mL) and the combined organic phases
were dried over Na2SO4 and concentrated. The crude prod-
uct was purified by preparative TLC on silica using hexane
as eluent.
To a solution of Ph3P (200 mg, 0.76 mmol) and 1H-imidazole
(52 mg, 0.76 mmol) in Et2O (860 mL) and MeCN (344 mL), I2
(72.4 mg, 0.57 mmol) was added in portions at room temper-
ature. The resulting suspension was stirred for 1 hour, and
15a–k (0.19 mmol) in Et2O (350 mL) was added dropwise.
The mixture was stirred for 4.5 h, after which it was diluted
with n-hexane (5 mL) and the solid was filtered off. The or-
ganic solvent was evaporated and the residue. The crude
product was purified by flash column chromatography on
silica gel using n-hexane as eluent.
19: Yield: 65%; colourless oil; [a]2D0: À38.1 (c 1.6 in
CHCl3), lit:[29] [a]D20: À45.0 (c 0.75 in CHCl3); Spectral data
are in accord with those in the literature.[29]
16a: Yield: 48%; colourless oil; 1H NMR (400 MHz,
CDCl3, 258C): d=7.16–7.12 (m, 2H), 6.90–6.86 (m, 2H),
3.82 (s, 3H), 3.4 (dd, J=6.1, 9.6 Hz, 1H), 3.31 (dd, J=8.0,
9.6 Hz, 1H), 3.06–2.97 (m, 1H), 1.41 (d, J=6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3, 258C): d=158.4, 136.4, 127.7
(2C), 113.9 (2C), 55.2, 41.5, 21.6, 15.6.
21: yield: 21%; colourless oil; [a]2D0: À22.4 (c 0.5 in
1
CHCl3); H NMR (400 MHz, CDCl3, 258C): d=7.05 (s, 4H),
5.72 (dd, J=10.3, 17.8 Hz, 1H), 4.87–4.82 (m, 2H), 2.74–2.67
(m, 1H), 2.29 (s, 3H), 1.74 (dd, J=7.0, 13.8 Hz, 1H), 1.54
(dd, J=5.2, 13.8 Hz, 1H), 1.17 (d, J=7.0 Hz, 3H), 0.92 (s,
3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=
148.7, 146.5, 134.9, 134.9, 128.9 (2C), 126.9 (2C), 110.0, 51.0,
36.3, 29.7, 28.2, 26.5, 25.4, 21.0; HR-MS: m/z=202.175223;
calcd. for C15H22: 202.17215.
Preparation of Compounds 17a–e; General
Procedure
To a suspension of NaH (60% in mineral oil, 14.4 mg,
0.36 mmol) in DMF (380 mL) dimethyl malonate (41 mL,
41.5 mg, 0.36 mmol) was added dropwise at 08C under stir-
ring. After 15 min a solution of iodide 16a–e (0.09 mmol) in
DMF (380 mL) was added and the reaction mixture was al-
lowed to warm to room temperature. After 13 h a saturated
solution of NH4Cl (1 mL) was added and the resulting mix-
534
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A Straightforward Organocatalytic Alkylation of 2-Arylacetaldehydes
Int. Ed. 2005, 44, 108; c) S. G. Ouellet, J. B. Tuttle,
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