Catalyzed selective direct α- And γ-alkylation of aldehydes with cyclic benzyl ethers by using T+BF4- in the presence of an inexpensive organic acid or anhydride

Article abstract of DOI:10.1002/chem.201101786

The cross dehydrogenative coupling (CDC) of cyclic benzyl ethers with aliphatic and α,β-unsaturated aldehydes has been developed. The mild reaction conditions, in which an N-oxoammonium salt derived from TEMPO (2,2,6,6-tetramethyl-1-piperidinoxyl) is employed as the oxidant in combination with a Cu catalyst, allow the use of relatively redox-unstable aldehydes under oxidative CDC conditions. The addition of a catalytic amount of trifluoroacetic acid (TFA) or Ac₂O facilitates the reaction and increases the efficiency and selectivity. In contrast to the expected α-alkylation obtained with aliphatic aldehydes, α,β-unsaturated aldehydes led preferentially to the more challenging γ-alkylated products. The utility of the developed methodology was demonstrated by the synthesis of isochromane-derived bioactive compounds, such as the dopamine antagonist sonepiprazole.

Full text of DOI:10.1002/chem.201101786

DOI: 10.1002/chem.201101786
Catalyzed Selective Direct a- Àand g-Alkylation of Aldehydes with Cyclic
Benzyl Ethers by Using T+BF4 in the Presence of an Inexpensive Organic
Acid or Anhydride**
Heinrich Richter, Renate Rohlmann, and Olga Garcꢀa MancheÇo*[a]
Abstract: The cross dehydrogenative
coupling (CDC) of cyclic benzyl ethers
with aliphatic and a,b-unsaturated al-
dehydes has been developed. The mild
reaction conditions, in which an N-ox-
dehydes under oxidative CDC condi-
tions. The addition of catalytic
amount of trifluoroacetic acid (TFA)
or Ac2O facilitates the reaction and in-
creases the efficiency and selectivity. In
contrast to the expected a-alkylation
obtained with aliphatic aldehydes, a,b-
unsaturated aldehydes led preferential-
ly to the more challenging g-alkylated
products. The utility of the developed
methodology was demonstrated by the
synthesis of isochromane-derived bio-
active compounds, such as the dopa-
mine antagonist sonepiprazole.
a
oammonium
salt
derived
from
TEMPO (2,2,6,6-tetramethyl-1-piperi-
dinoxyl) is employed as the oxidant in
combination with a Cu catalyst, allow
the use of relatively redox-unstable al-
À
Keywords: alkylation · C H activa-
tion
·
copper
·
cross-coupling
·
oxoammonium salt
Introduction
simple carbonyl-based nucleophilic reagents. Considering
that TEMPO oxoammonium salts are generally used for the
selective oxidation of primary alcohols to the corresponding
The development of new environmentally friendly methods
À
for the synthesis of C C bonds is of great significance to
aldehydes,[4] we envisioned the use of T+BF4 in the CDC
À
À
chemists. Direct C H functionalizations present an atom-
of aldehydes.
À
economic approach towards the formation of new C C
In previous work reported by Li and co-workers, the de-
hydrogenative coupling of the related less problematic ke-
tones with benzylic ethers was achieved by employing per-
oxides as oxidants.[5] More recently, Klussmann and co-
workers have reported the a-alkylation of ketones with
amines and diaryl methane derivatives by using tBuOOH or
MeSO3H/O2, respectively.[6] N-substituted glycine esters and
N,N-dialkyl anilines were also coupled with ketones by co-
operative copper and an achiral pyrrolidine catalyst.[7] In ad-
dition, Cozzi and co-workers[8] have shown that the combi-
nation of MacMillan type organocatalysts with DDQ is
indeed able to efficiently promote the asymmetric CDC re-
action of aldehydes with suitable electrophiles[9] through en-
amine activation (Scheme 1). However, the substrate scope
was restricted to activated 1,3,5-cycloheptatriene and diaryl
methane derivatives such as xanthene, which led to very
specific compounds. Moreover, the structurally interesting
and pharmaceutically valuable cyclic benzylic ethers, such as
isochromanes or 6H-benzochromenes, moieties present in a
number of bioactive compounds, were not compatible with
bonds without prior installation of functional groups and
are, therefore, especially attractive.[1] In this research area,
cross dehydrogenative coupling is becoming firmly estab-
lished[2] and allows diverse functionalizations of relatively
3
À
unreactive C
À
(sp ) H bonds. Typically, the oxidation of such
C H bonds by peroxides, 2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone (DDQ), or, more recently, dioxygen generates an
electrophilic species such as an organic radical, a carbocat-
ion, and an oxonium or iminium ion, which can undergo a
coupling reaction with a variety of nucleophiles.
Recently, we have presented a TEMPO oxoammonium
salt (2,2,6,6-tetramethylpiperidine-1-oxoammonium tetra-
À
fluoroborate, T+BF4 ) as a nontoxic and mild hydrogen ac-
ceptor for the Fe
(OTf)2-catalyzed oxidative alkylation of
(sp ) H bonds next to a heteroatom by using acti-
vated enolizable C nucleophiles such as malonates, b-ke-
toesters, or b-nitroketones.[3] We thought that these mild re-
action conditions might be compatible with other types of
3
À
benzylic C
A
these reaction conditions. Therefore, we focused our atten-
[a] H. Richter, R. Rohlmann, Dr. O. Garcꢀa MancheÇo
Organisch-Chemisches Institut
[10]
À
tion upon the C H functionalization of isochromanes by
Universitꢁt Mꢂnster
Corrensstrasse 40, 48149 Mꢂnster (Germany)
Fax : (+49)251-83-33202
selective direct alkylation of aldehydes (Scheme 1), because
it would allow a modular and straightforward synthesis of
interesting biologically active compounds.[11] Several illustra-
tive examples of natural and synthetic bioactive a-function-
alized isochromanes are shown in Scheme 2.
E-mail: olga.garcia@uni-muenster.de
À
[**] T+BF4
: 2,2,6,6-Tetramethylpiperidine-1-oxoammonium tetrafluoro-
borate.
Herein, we report the selective a-alkylation of aliphatic
aldehydes and ketones, as well as a novel g-alkylation of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101786.
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Chem. Eur. J. 2011, 17, 11622 – 11627

FULL PAPER
Table 1. Optimization of the CDC of isochromane (1a) with propanal
(2a).[a]
Entry
Additive (mol%)
–
pKa of
organic
acid
[m]
d.r.[b]
n.d.[e]
Yield of
3a
[%][c,d]
1
2
–
0.2
18
MacMillan I[f] (30)
l-proline (30)
AcOH (40)
TFA (40)
TFA (20)
–
0.2
0.2
0.2
0.2
0.2
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
1:1.1
1:3.3
n.d.[e]
n.d.[e]
n.d.[e]
1:2.1
n.d.[e]
1:2.8
1:2
42
52
45
54
56
58
53
54
61
57
42
–
3
4
5
6
7
8
9
10
11
12
13
14
2.0
4.8
0.2
0.2
0.2
0.2
2.9
2.0
2.2
3.4
À0.6
–
Scheme 1. Cross dehydrogenative couplings with aldehydes.
TFA (20)
TFA (20)
malonic acid (20)
l-aspartic acid (20)
l-glutamic acid (20)
l-tartaric acid (20)
MeSO3H (20)
Ac2O (20)
1:1.9
1:1.8
–
1:4.6
61[g]
[a] Reaction conditions: 1a (0.2 mmol), Cu
(OTf)2 (10 mol%), 2a
À
(5 equiv), T+BF4 (1.2 equiv), and the corresponding additive in dry
CH2Cl2 at room temperature. [b] Diastereomeric ratio determined by
1H NMR spectroscopy. [c] Yield after column chromatography. [d] 1-Iso-
chromanone (4) was also obtained in 10–20% yield. [e] n.d.: not deter-
mined. [f] Bn: benzyl. [g] Three equivalents of 2a were used (same yield
was obtained with five equivalents of aldehyde).
Scheme 2. Selected biologically active simple a-functionalized isochro-
manes.
the over-oxidized compound 1-isochromanone (4). The com-
À
bination of Cu
N
a,b-unsaturated aldehydes, with isochromane derivatives by
using a CDC approach.
achieving this transformation. Other transition-metal cata-
lysts,[14] as well as other oxidants like DDQ, tBuOOH,
(tBuO)2, and H2O2, were less efficient or gave no product at
all. However, 3a was obtained as a racemic mixture under
these initial reaction conditions. In fact, without the Mac-
Millan catalyst, the product 3a was formed in 18% yield
(Table 1, entry 1), which indicated that the aldehyde proba-
bly reacts through the enol/enolate form rather than the en-
amine.
In our previous studies, the use of a catalytic amount of
TFA had a beneficial effect on the reaction rate. Therefore,
several organic acids were next screened as additives. Each
of the acids used were competitive; however, methanesul-
fonic acid[6b] gave no product (Table 1, entry 13). TFA, as-
partic acid, and, more interestingly, the nonacidic and inex-
pensive acetic anhydride (Ac2O) gave the best results. Thus,
the coupling compound 3a was obtained in comparable
good yields of 58–61% (Table 1, entries 7, 10, and 14). Addi-
tionally, the use of Ac2O (20 mol%) allowed us to reduce
the amount of aldehyde to three equivalents with the same
good efficiency being maintained. Additionally, no forma-
tion of the oxidized byproduct 4 was observed if Ac2O was
used as the additive.
Results and Discussion
To the best of our knowledge, no literature precedence for
the direct oxidative coupling of aldehydes with isochromane
derivatives has been set to date. To explore the feasibility of
this transformation, the coupling of isochromane (1a) with
propanal (2a) was initially investigated as a model reaction
(Table 1). We assumed that a MacMillan type catalyst could
play a crucial role by allowing the activation of the aldehyde
through enamine chemistry.[8,12] Thus, a test reaction in the
presence of a transition-metal catalyst, a first-generation
MacMillan catalyst (substituents: Bn/diMe; Macmillan I in
Table 1), the TEMPO-derived oxoammonium salt (T+
À
BF4 ),[13] and an excess of the aldehyde (5 equiv) was per-
formed first. In contrast to our previous results with 1,3-di-
carbonyl nucleophiles,[3] iron catalysis gave only traces of
the coupling product. By switching from Fe
(OTf)2, the desired product 3a was obtained in a promising
42% yield after 18 h (Table 1, entry 2), along with 20% of
ACHTUNGRTENN(UNG OTf)2 to Cu-
ACHTUNGTRENNUNG
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11623

O. Garcꢀa MancheÇo et al.
With the optimized conditions in hand (10 mol% Cu-
plored. Consequently, five equivalents of a-disubstituted al-
dehydes 2h (R1, R2 =Me) and 2i (R1, R2 =cyclohexyl) were
employed to furnish the desired products in 65 and 53%
yields, respectively (Table 2, entries 8 and 9). Finally, substi-
tuted isochromanes 1b and 1c, and 6H-benzo[c]chromene
1d were allowed to react with 2a, to provide the corre-
sponding a-functionalized aldehydes in similar yields (46–
55%; Table 2, entries 10–12). Although the use of Ac2O as
an additive suppressed or minimized the oxidation to 1-oxo
compounds, byproduct 5 was obtained in around 10% yield
in a few cases (Table 2, entries 2 and 11). The formation of 5
can be explained by a further oxidation of 3 under the em-
ployed oxidative reaction conditions to form a conjugated
system.
À
ACHTUNGTRENNUNG
To generalize the procedure for the reaction with carbon-
yl compounds, ketones were next tested (Scheme 3). In this
case, the use of TFA (20 mol%) and a catalytic amount of
water (10 mol%) were crucial to achieve the desired trans-
formation efficiently, although the exact role of water in this
reaction is still unclear. Alkyl–alkyl and alkyl–aryl ketones
underwent the CDC reaction to furnish the products in 43–
54% yield.[15] When unsymmetrical 2-butanone was treated
Table 2. Scope of the CDC reaction with aliphatic aldehydes.[a]
Entry
1
R1/R2
Me/H
Et/H
Product 3
d.r.[b]
1:4.6
1:1.6
1:1.6
Yield of 3
Entry
1
R1/R2
iPr/H
Me/Me
Cy[h]
Product 3
d.r.[b]
1:4.3
–
Yield of 3
[%][c]
[%][c]
1
2
3
1a
1a
1a
3a
3b
3c
3d
61 (75)[d]
7
8
9
1a
1a
1a
3g
3h
3i
52
55[e]
65[g]
53[g,i]
55
nPr/H
64 (73)[d]
–
4
5
1a
1a
nOctyl/H
1:1.4
1:1.9
51
10
11
1b
1c
Me/H
Me/H
3j
1:3.6
Bn/H
3e
3 f
53
3k
3l
1:2:3:5.3
52[j]
6
1a
H/H
–
45[f] (59)[d]
12
1d
Me/H
1:1
46[k]
À
[a] Reaction conditions: 1 (0.2 mmol), CuACTHUNGTERNUNNG
(OTf)2 (10 mol%), Ac2O (20 mol%), 2 (3 equiv), and T+BF4 (1.2 equiv) in dry CH2Cl2 at room temperature.
1
[b] Diastereomeric ratio determined by H NMR spectroscopy. [c] Yield after column chromatography. [d] Yield from the 1 mmol scale reaction in brack-
ets. [e] 12% of 5c was isolated. [f] Ten equivalents of 2b were used. [g] Five equivalents of 2h were used. [h] Cy: cyclohexyl. [i] TFA (20 mol%) was
used instead of Ac2O. [j] 12% of 5k was isolated. [k] Significant amounts of the corresponding 1-oxo compound were detected by GC-MS.
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Chem. Eur. J. 2011, 17, 11622 – 11627

Selective a- and g-Alkylation of Aldehydes with Cyclic Benzyl Ethers
FULL PAPER
Table 3. CDC reaction with a,b-unsaturated aldehydes.[a]
Entry
1
1
R2/R3
Product 9
d.r. 9[b] 9/9’[b] Yield
[%][c]
1a a-Me/Me
1a a-Bn/Bn
9a 1:1.1
9b 1:1.2
–
–
47[d,e]
2
3
44[f]
Scheme 3. T+BF4À-mediated CDC reaction with ketones.
[g]
1a b-Me/H
9c 1:1.4
–
39[d]
with isochromane, a 1:1.5 mixture of regioisomers was ob-
tained, in which the major isomer was the coupling product
at the more substituted carbon atom. On the other hand, 2-
pentanone gave a 1.1:1 mixture of regioisomers.
4
5
1a H/H
1a H/Et
9d
–
(6.7:1) 35[f,h]
ACHTUNGTRENNUNG
The more appealing reaction with a,b-unsaturated alde-
9e 1:1.1
9 f 1:1.2
(12:1) 36[f]
ACHTUNGTRENNUNG
hydes was next explored. Although enals, which are in equi-
librium with their dienol forms, can be alkylated by the in
situ formed oxonium ion of isochromanes at both the a and
g positions, we explored an unprecedented CDC g alkyla-
tion under the given reaction conditions for the aliphatic al-
dehydes.[16] Therefore, 2-methyl-2-pentenal (8a) was initially
submitted to the reaction with isochromane. To our delight,
under slightly modified conditions, the desired g-alkylation
product was selectively formed. Thus, 9a was obtained in a
satisfying 47% yield by increasing the amount of oxidant T+
6
1a a-Me/Me
–
40[d]
[a] Reaction conditions: 1 (0.2 mmol), Cu
(OTf)2 (10 mol%), additive
À
(20 mol%), 8 (5 equiv), and T+BF4 (1.4 equiv) in dry CH2Cl2 at 458C.
1
[b] Diasteriomeric ratios and 9/9’ ratios determined by H NMR spectros-
copy. [c] Yield after column chromatography. [d] Ac2O was used as the
additive. [e] The reaction on the 1 mmol scale gave the same yield.
[f] TFA was used as the additive. [g] The formation of the a-alkylation
product was not observed. [h] Ten equivalents of aldehyde were used.
À
BF4 to 1.4 equivalents and carrying out the reaction at
458C in the presence of 20 mol% of Ac2O (Table 3,
entry 1). Selected a,b-unsaturated aldehydes were then
tested and gave the corresponding alkylated compounds in
moderate yields. In some cases, the use of TFA as an addi-
tive instead of Ac2O gave slightly better results. Remarka-
bly, a-branched (R2 =Me, Bn) and b-substituted (R2 =Me)
enals gave exclusively the g-alkylation products 9 (Table 3,
entries 1–3 and 6). Good to excellent selectivities in favor of
g- rather than a-alkylation were obtained for enals lacking a
substituent at the double bond (Table 3, entries 4 and 5).
Additionally, in the case of the a-alkylated products, the
conjugated compounds 9’ were obtained as the only detecta-
ble isomers.
prepared from simple and commercially available isochro-
mane and alkyl or a,b-unsaturated aldehydes and ketones
such as acetone.
Finally, the racemic synthesis of the dopamine antagonist
sonepiprazole was carried out (Scheme 5). The CDC prod-
uct of acetaldehyde with isochromane, 3 f, was subjected to
the reductive amination reaction with the appropriate sub-
stituted piperazine 13.[18] In this case, we were able to
reduce the amount of amine to 1.5 equivalents and obtain
sonepiprazole (14) in a good 66% yield.
The application of the methodology to the synthesis of
potential bioactive compounds was next accomplished
(Scheme 4). A two-step approach consisting of a CDC reac-
tion and a reductive amination sequence was utilized. The
second step was carried out by using NaBH3CN (2 equiv) as
a reducing agent with an excess of cyclic amines such as
morpholine or piperidine.[17] This methodology allows the
easy structural variation of this class of compounds. Conse-
quently, a small family of aminoisochromanes (10–12) was
Conclusion
In summary, we have developed a general procedure that
allows the CDC reaction of cyclic benzyl ethers with a varie-
ty of simple carbonyl compounds like aliphatic aldehydes,
enals, and ketones. The use of an oxoammonium salt as the
formal hydrogen acceptor in combination with CuACTHUNRGTNEUNG(OTf)2 as
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11625

O. Garcꢀa MancheÇo et al.
Bruker ARX-300 and Varian AV-300 or AV-400 MHz spectrometers.
Chemical shifts (d) are given in ppm and spin–spin coupling constants (J)
are given in Hz. Analytical thin-layer chromatography was performed by
using silica gel 60 F254, and a solution of KMnO4 served as staining agent.
Column chromatography was performed on silica gel 60 (0.040–
0.063 mm) or ALOX N (neutral). Exact masses (HRMS) were recorded
on a Bruker Daltonics MicroTof spectrometer (CH3OH as the sample
solvent). Reactions were conducted under an argon atmosphere, and al-
dehydes were freshly distilled before use. Analytical grade solvents and
other commercially available reagents were used without further purifica-
À
[13]
tion. TEMPO+BF4
,
isochromanes 1b and 1c,[19] 6H-benzochromene
1d,[20] a,b-unsaturated aldehyde 9b,[21] and piperazine 13[18] were pre-
pared following literature procedures.
À
General procedure for the alkylation of aldehydes: T+BF4 (0.24–
0.28 mmol) was added to a mixture of 1 (0.2 mmol), aldehyde 2 or 8
(0.6–2.0 mmol), CuACHTNUGTRNEG(UN OTf)2 (7.2 mg, 0.02 mmol), and TFA or Ac2O
(0.04 mmol) in dry CH2Cl2 (2.0 mL). The reaction mixture was stirred for
16–32 h at room temperature (aliphatic aldehydes) or 458C (a,b-unsatu-
rated aldehydes). After the starting material had been consumed (moni-
tored by GC-MS or TLC), the solvent was concentrated under reduced
pressure and the residue was purified by column chromatography on
silica gel.
Alkylation of ketones 6: A slightly modification of the above-described
procedure was used for the alkylation of ketones 6. The reaction mixture
Scheme 4. Modular synthesis of aminoisochromane derivatives.
comprised
1
(0.20 mmol), ketone
6
(0.6–1.0 mmol), CuACHTUNGTRENNUNG(OTf)2
À
(0.02 mmol), TFA (0.04 mmol), H2O (0.02 mmol), and T+BF4
(0.24 mmol) in dry CH2Cl2 (2.0 mL) at room temperature.
2-(Isochroman-1-yl)propanal (3a): Following the general procedure, the
reaction of 1a (25 mL, 0.2 mmol) with 2a (44 mL, 0.6 mmol) in the pres-
ence of CuACHTNUGTRNEUNG(OTf)2 and Ac2O gave 3a as a colorless oil with a 1:4.6 mix-
ture of diastereoisomers (23 mg, 61%). The reaction on the 1 mmol scale
gave 3a in 75% yield: Chromatography eluent: pentane/ethyl acetate
(30:1); 1H NMR (300 MHz, CDCl3): d=9.90 (d, J=0.4 Hz, 1H major),
9.53 (d, J=1.1 Hz, 1H minor), 7.25–7.10 (m, 3H major and 3H minor),
7.07–7.02 (m, 1H major and 1H minor), 5.43 (d, J=1.1 Hz, 1H major),
5.01 (d, J=1.1 Hz, 1H minor), 4.18 (ddd, J=11.2, 5.7, 1.9 Hz, 1H minor),
4.15 (ddd, J=11.1, 5.7, 1.4 Hz, 1H major), 3.76–3.69 (m, 1H minor), 3.73
(td, J=11.5, 2.9 Hz, 1H major), 3.11–2.97 (m, 1H major and 1H minor),
2.88 (qd, J=6.9, 2.7 Hz, 1H major), 2.65 (d, J=16.3 Hz, 1H minor), 2.59
(d, J=16.3 Hz, 1H major), 1.30 (d, J=7.0 Hz, 3H minor), 0.95 ppm (d,
J=6.9 Hz, 3H major); 13C NMR (75 MHz, CDCl3): d=204.2, 204.0,
135.8, 135.3, 135.2, 134.8, 129.4, 129.3, 127.0, 126.8, 126.7, 126.6, 124.9,
124.3, 75.6, 64.6, 51.7, 51.6, 29.3, 29.1, 11.5, 7.0 ppm; HRMS (ESI): calcd
for C12H14O2·Na+: 213.0886 [M+Na]+; found: 213.0883.
Scheme 5. Synthesis of (+/À)-sonepiprazole by a CDC/reductive-amina-
tion sequence.
General procedure for the reductive amination:[17] The appropriate sec-
ondary amine (1.5–10 equiv) and NaBH3CN (2 equiv) were added to a
solution of the corresponding aldehyde 3, 7, or 9 (0.2 mmol, 1 equiv) in
ethanol (1.0 mL) at room temperature. The pH value was maintained at
6 with dropwise addition of acetic acid while the mixture was stirred. The
reaction was monitored by TLC until completion (typically after 2 h).
NaOMe (0.1 equiv) was added, and the reaction mixture was stirred at
room temperature overnight. The mixture was concentrated and was ba-
sified with a 2m NaOH solution. The aqueous layer was extracted with
CH2Cl2, and the organic phase was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by column chromatog-
raphy on ALOX N (neutral).
the catalyst is key for the success of this transformation.
Moreover, additives, such as organic acids like TFA or anhy-
drides such Ac2O, facilitate the reaction in terms of efficien-
cy and selectivity. Remarkably, in the case of a,b-unsaturat-
ed aldehydes, good to excellent selectivities were obtained
in the challenging g-alkylation reaction. Lastly, we applied
this methodology for the modular and straightforward prep-
aration of a family of aminoisochromane derivatives, includ-
ing the known bioactive compound sonepiprazole, by a
CDC/reductive-amination sequence.
rac-Sonepiprazole (4-(4-(2-(Isochroman-1-yl)ethyl)piperazin-1-yl)benze-
nesulfonamide; 14):[11e] Following the general procedure, the reaction of
3 f (20 mg, 0.11 mmol) with 13 (1.5 equiv, 41.1 mg, 1.7 mmol) gave 14 as a
white solid (29.1 mg, 66%); Chromatography on silica gel with ethyl ace-
tate as the eluent; 1H NMR (300 MHz, [D6]DMSO): d=7.61 (d, J=
9.0 Hz, 2H), 7.24–7.07 (m, 4H), 7.05 (s, 2H), 7.01 (d, J=9.1 Hz, 2H),
4.76 (dd, J=8.3, 2.0 Hz, 1H), 4.04 (ddd, J=11.2, 5.2, 4.0 Hz, 1H), 3.66
(ddd, J=11.3, 9.2, 4.0 Hz, 1H), 3.26 (t, J=4.6 Hz, 4H), 2.86 (ddd, J=
14.9, 9.1, 5.4 Hz, 1H), 2.65 (dt, J=16.4, 3.8 Hz, 1H), 2.60–2.45 (m, 5H),
2.44–2.32 (m, 1H), 2.18–2.03 (m, 1H), 1.96–1.79 ppm (m, 1H); 13C NMR
(75 MHz, [D6]DMSO): d=152.8, 138.1, 133.6, 132.8, 128.7, 127.1, 126.1,
Experimental Section
General methods and materials: All reactions were carried out in heat-
gun-dried glassware under an argon atmosphere. Dichloromethane was
distilled over CaH2. 1H, 13C, and 19F NMR spectra were recorded in
CDCl3 (reference signals: d(1H)=7.26 ppm,
dACTHNGUTERNNUG
(13C)=77.16 ppm) on
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Chem. Eur. J. 2011, 17, 11622 – 11627

Selective a- and g-Alkylation of Aldehydes with Cyclic Benzyl Ethers
FULL PAPER
126.0, 124.8, 113.6, 73.6, 62.3, 54.2, 52.6, 47.1, 32.6, 28.5 ppm; HRMS
(ESI+): calcd for C21H27N3O3S·H+: 402.1846; found: 402.1856.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. We are also thankful to Prof. Frank
Glorius for generous support. R.R. thanks Mꢂnster University within the
Bonusprogram for a predoctoral contract.
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Received: June 10, 2011
Published online: August 31, 2011
Chem. Eur. J. 2011, 17, 11622 – 11627
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www.chemeurj.org
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