Carbohydrate-Based Pyridine-2-carboxamides for Mo-Catalyzed asymmetric allylic alkylations

Article abstract of DOI:10.1002/ejoc.200801240

Bis(pyridine-2-carboxamides) were prepared from 1,2-di-amines obtained from α-D-glucose and α-D-mannose. The 11-gands were assessed in molybdenum-catalyzed asymmetric allylic alkylations (AAA) by using both methyl (E)-3-phenyl-2-propenyl and methyl rac-l-

Full text of DOI:10.1002/ejoc.200801240

FULL PAPER
DOI: 10.1002/ejoc.200801240
Carbohydrate-Based Pyridine-2-carboxamides for Mo-Catalyzed Asymmetric
Allylic Alkylations
Raffaella Del Litto,[a] Vincenzo Benessere,[a] Francesco Ruffo,*[a] and Christina Moberg*[b]
Keywords: Asymmetric catalysis / Molybdenum / Carbohydrates / Allylation / Microwave reactions
Bis(pyridine-2-carboxamides) were prepared from 1,2-di-
amines obtained from α- -glucose and α- -mannose. The li-
gands were assessed in molybdenum-catalyzed asymmetric
allylic alkylations (AAA) by using both methyl (E)-3-phenyl-
2-propenyl and methyl rac-1-phenyl-2-propenyl carbonates
and dimethyl malonate as nucleophile under microwave irra-
served in reactions of the linear achiral substrate in the pres-
ence of 10 mol-% of a catalyst prepared from a ligand de-
rived from glucose. Somewhat lower enantioselectivity (up to
96% ee) was observed in reactions with the branched race-
mic carbonate by using the same ligand.
D
D
diation. High enantioselectivity (99% ee) and high regiose- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
lectivity (49:1 in favour of the branched isomer) were ob-
Germany, 2009)
Introduction
Asymmetric allylic alkylations (AAA) are synthetically
highly versatile reactions, which are catalyzed by a range of
transition-metal complexes.[1] The stereo- and regiochemis-
try of the product are a function of the metal and the ligand
as well as of the nucleophile and the substituents on the
allyl system, and the different types of catalysts are there-
fore highly complimentary. Catalysts containing palladium
have been most extensively employed in synthetic applica-
tions,[2] but may lead to undesired products when unsym-
metrically substituted allyl derivatives are used.[3] Thus,
whereas palladium complexes as a rule afford the achiral
linear products from monosubstituted allylic substrates,[4]
complexes based on Ir and Mo have a preference for forma-
tion of the branched chiral products. With the introduction
of the (R*,R*)-1,2-diaminocyclohexane derivative 1[5] as li-
gand by Trost,[6] highly enantioselctive Mo-catalyzed al-
lylations became possible. Although Ir catalysts have a
wider scope,[7] catalysts containing Mo have become at-
tractive due to the lower cost of molybdenum as compared
to iridium and the robustness of the in-situ formed catalytic
system.[8] These factors together with our simple experi-
mental protocol using microwave irradiation, allowing the
catalytic reactions to be run in air within less than 10 min
in the presence of stable, crystalline, commercially available
Mo(CO)6 as catalyst precursor,[9] have made Mo catalysts
viable alternatives to those based on Pd and Ir for a variety
of applications.
Bis(pyridine-2-carboxamides), which still are the most ef-
ficient ligands for the Mo-catalyzed process, are easily pre-
pared from a picolinic acid derivative and a chiral enantio-
enriched 1,2-diamine.[10] By comparing the results of reac-
tions of ligands with substituted pyridines it was found that
derivatives with π-donor substituents resulted in particu-
larly high enantioselectivities and high branched/linear ra-
tios.[11] C2-Symmetric 1,2-diaminocyclohexanes have com-
monly been used as ligand precursors together with picol-
inic acid derivatives. In the search for more easily available
diamines, Lloyd-Jones, Kocˇovský and co-workers used
asymmetric diamines derived from naturally occurring
amino acids.[12] The ligands obtained provided catalysts,
some of which exhibited high enantio- and regioselectivity
and high reactivity.
Carbohydrates are other examples of useful naturally oc-
curring starting materials for ligand synthesis, and they are
particularly attractive as they are available in several stereo-
isomeric forms.[13] α--Glucose[14] and α--mannose[15] de-
rivatives with amino substituents in the 2- and 3-positions
of the carbohydrate have been described and have success-
fully been used for the preparation of ligands which have
been applied in metal-catalyzed enantioselective pro-
cesses.[16] Inspired by the structural analogy between trans-
cyclohexanediamine and the glucose derivative and by the
possibility to obtain a chiral cis-substituted ligand from
mannose, we decided to use the two 1,2-diamines for the
[a] Department of Chemistry “Paolo Corradini”, University of
Napoli, Complesso universitario di Monte S. Angelo,
via Cintia, 80126 Naples, Italy
E-mail: ruffo@unina.it
[b] Department of Chemistry, Organic Chemistry,
KTH, 10044 Stockholm, Sweden
E-mail: kimo@kth.se
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Pyridine-2-carboxamides for Mo-Catalyzed Asymmetric Allylic Alkylations
preparation of bis(pyridine-2-carboxamides). We report tries 1 and 4 vs. 2 and 5, respectively). In contrast to results
here the preparation of the new ligands and their use in obtained with ligands derived from 1,2-diaminocyclohex-
Mo-catalyzed allylic alkylations.
ane,[11b] the p-chloro-substituted derivative (Entry 3) gave
the product with lower enantioselectivity than 1a. The
enantioselection of ligands prepared from the pseudo-C2-
symmetric 2,3-gluco derivatives 1a and 1b turned out to be
far superior to that of pseudo-Cs-symmetric 2,3-manno de-
rivative 1c (38–40% ee, Entries 3 and 4). Compound 1a was
thus the ligand of choice, exhibiting higher reactivity and
providing higher enantioselectivity (99% ee) and higher
branched/linear ratio (49:1 with 10 mol-% of catalyst) than
1b and 1c. Reactions using this ligand were therefore
studied in more detail.
The following catalytic reactions using 1a were per-
formed by employing the same procedure as that used in
the initial reactions, but equimolar amounts of nucleophile
and substrate, and lower ligand/metal ratios (1.1:1) were
used. These conditions allowed isolation of pure products
by bulb-to-bulb distillation; in some reactions the product
was isolated by chromatography, which resulted in lower
yields. Again, lower amounts of catalyst resulted in lower
conversion and lower regioselectivity (Table 2, Entries 1–3),
although the enantioselectivity remained high (99% ee).
With 4 mol-% of catalyst, the conversion was merely 50%
after 6 min (Entry 3). Prolonged reaction times resulted in
further product formation, which, however, ceased after
15 min (Entries 4 and 5), probably due to decomposition of
the catalyst; this decomposition could not be prevented by
higher ligand loading (Entry 6). With 1 mol-% of catalyst
somewhat lower enantioselectivity (94% ee) and very low
regioselectivity were observed (Entry 7). The best result, ob-
tained with 10% catalyst loading, (Entry 1) allowed the
product with a branched/linear ratio of 49:1 to be isolated
in 90% yield (99% conversion).
Results and Discussion
Preparation of Ligands
Ligands 1a, 1b, and 1c were prepared from previously
described diamino derivatives 2a[14] and 2b[15] and the ap-
propriate picolinic acid (3a or 3b) in the presence of 1,1Ј-
carbonyldiimidazole (DCI) (Scheme 1). Ligands 1a and 1c
were isolated after extraction (in 77 and 82% yields, respec-
tively) and could be used without any further purification,
while 1b was obtained in pure form by chromatography (in
32% yield). The ligands were characterized by NMR spec-
troscopy. The 1H NMR patterns typical for glucose and
mannose in chair conformations were observed, and the sig-
nals of the newly formed amido protons were found in the
range δ = 8.3–8.6 ppm.
Mo-Catalyzed Asymmetric Allylic Alkylations
The catalytic reactions were performed by using our pre-
viously developed experimental conditions. Thus, Mo(CO)6,
ligand, allylic carbonate 4, dimethyl malonate, and N,O-bis-
(trimethylsilyl)acetamide (BSA) were mixed in THF and
heated at 160 °C in the microwave cavity under air. After
completed reaction, conversions and branched/linear ratios
were determined by 1H NMR spectroscopy and gas
chromatography, respectively, and enantioselectivities by
chiral HPLC. First, the three types of ligands were assessed
by using 4 and/or 10 mol-% of Mo catalyst, a nucleophile/
substrate ratio of 1.1:1, and a ligand/metal ratio of 1.3:1.
Mo-catalyzed allylic alkylations are known to proceed
The results of these initially performed reactions are shown via (η3-allyl)molybdenum complexes, which are formed by
in Table 1. In reactions with 1a and 1b, (+)-(R)-dimethyl 3- oxidative addition of the allylic carbonate to ligated
phenyl-1-butene-4,4-dicarboxylate was formed as the major Mo0.[17] The reactions proceed stereospecifically by syn dis-
product, whereas the opposite enantiomer was obtained in placement of the carbonate.[18] For this reason dia-
reactions with 1c. Higher catalyst loadings resulted not only stereomeric allyl complexes are formed from the two
in higher reactivity but also in higher regioselectivity (En- enantiomers of branched carbonates such as 5. In order to
Scheme 1. Preparation of bis(pyridine-2-carboxamides).
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R. Del Litto, V. Benessere, F. Ruffo, C. Moberg
FULL PAPER
Table 1. Molybdenum-catalyzed asymmetric substitutions of 4 by using ligands 1a–c.[a]
Entry
Ligand
Cat. [%]
Conversion[a] [%]
Regioselectivity[b] (6/7)
ee[c] [%]
1
2
3
4
5
1a
1a
1b
1c
1c
10
4
4
10
4
96
50
42
76
41
49:1
8:1
12:1
14:1
5:1
99 (R)
99 (R)
87 (R)
38 (S)
40 (S)
[a] Reactions were run at 160 °C for 6 min with ligand/metal = 1.3:1 and Nu/4 = 1.1:1. [b] Determined by GC-MS. [c] Determined by
HPLC using a Daicel OD-H (0.46 cm i.d. ϫ 25 cm) column.
Table 2. Molybdenum-catalyzed asymmetric substitutions of 4 by using ligand 1a.[a]
Entry
Cat. [%]
Mo/ligand
Time [min]
Conversion[b] [%]
Yield [%]
Regioselectivity[c](6/7)
ee[d] [%]
1
2
3
4
5
6
7
10
5
4
4
4
4
1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.5
1:1.1
6
15
6
15
30
15
30
99
78
50
65
65
50
10
90[e]
38[f]
35[f]
33[f]
35[f]
35[f]
7[f]
49:1
9:1
8:1
8:1
8:1
8:1
1.5:1
99
99
99
99
99
99
94
1
[a] Reactions were run at 160 °C with ligand/metal = 1.1:1 and Nu/4 = 1:1. [b] Determined by H NMR spectroscopy. [c] Determined
by GC-MS. [d] Determined by HPLC using a Daicel OD-H (0.46 cm i.d. ϫ 25 cm) column. [e] Isolated by bulb-to-bulb distillation. [f]
Isolated by chromatography on silica gel (eluent: petroleum ether/DCM, 1:1).
achieve high enantioselectivity in reactions with branched after 30 min (Entry 4). No major difference was observed
racemic substrates, equilibration of the diastereomeric allyl between reactions run in THF and in toluene (Entries 2 and
complexes via η3-η1-η3 isomerization therefore needs to be 3).
rapid in relation to nucleophilic attack, which also occurs
In the η3-allyl complex obtained after oxidative addition
by a syn mechanism. Under certain conditions equilibration of the allylic carbonate, the ligand has been shown to coor-
is incomplete, resulting in modest memory effects and, as a dinate to Mo in a tridentate manner through one pyridine
consequence, in lower enantioselectivities than in reactions nitrogen atom, one deprotonated amide nitrogen atom, and
with linear substrates.[19]
one carbonyl oxygen atom.[20] Assuming the same configu-
The results from reactions with rac-5 using the present ration at the metal center as that found for the complex
catalytic system are shown in Table 3. The branched sub- containing 1, two modes of coordination (A and B, Fig-
strate 5 gave the product with lower enantio- and regioselec- ure 1) are possible for asymmetric ligand 1a due to the lack
tivity than the linear substrate, but the conversion remained of twofold rotational axis, and thus two different complexes
high when the catalyst loading was decreased from 10 (En- may lead to the observed major enantiomer. Although a
try 1) to 5 mol-% (Entry 2). With a further decrease of the catalyst containing (R)-1-(2-pyridinecarboxamido)-2-(2-
amount of catalyst, the conversion decreased, and with pyridinecarboxy)-1-phenylethane (1d), an ester–amide, has
1 mol-% of catalyst merely 15% conversion was observed been shown to exhibit some activity in Mo-catalyzed allylic
Table 3. Molybdenum-catalyzed asymmetric substitutions of rac-5 by using ligand 1a.[a]
Entry
Cat. [%]
Mo/ligand
Time [min]
Conversion[b] [%]
Yield [%]
Regioselectivity[c](6/7)
ee[d] [%]
1
2
3
4
10
5
5
1:1.1
1:1.1
1:1.1
1:1.1
6
15
99
99
99
15
82[f]
90[f]
85[f]
12[g]
8:1
8:1
8:1
8:1
96
95
96
80
15[e]
30
1
1
[a] Reactions were run at 160 °C with ligand/metal = 1.1:1 and Nu/5 = 1:1. [b] Determined by H NMR spectroscopy. [c] Determined
by GC-MS. [d] Determined by HPLC using a Daicel OD-H (0.46 cm i.d. ϫ 25 cm) column. [e] Reaction run in toluene. [f] Isolated by
bulb-to-bulb distillation. [g] Isolated by chromatography on silica gel (eluent: petroleum ether/DCM, 1:1).
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Pyridine-2-carboxamides for Mo-Catalyzed Asymmetric Allylic Alkylations
substitutions,[12] no product formation was observed when
monoamide 1e, derived from a 2-amino-4,6-O-benzylidene-
2-deoxyglucoside scaffold, was used as ligand. This suggests
that the NH function in position 3 is essential for the reac-
tion, and hence, diastereomer A should be the actual inter-
mediate.
lected organic phases were dried with sodium sulfate, and the sol-
vent was evaporated to afford ligands 1a (245 mg, 77%) and 1c
(225 mg, 82%). Use of the ligands in the catalytic reactions did
not require any further purification. Recrystallization of 1a from
methanol afforded 136 mg (43%) of the product. Ligand 1a: [α]2D0
1
= +107 (c = 0.1, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.53
(d, J = 4.4 Hz, 1 H, H6-py), 8.52 (d, J = 10.4 Hz, 1 H, NH), 8.38
(d, J = 4.7 Hz, 1 H, H6-py), 8.10 (d, J = 10.4 Hz, 1 H, NH), 7.97
(d, J = 7.8 Hz, 1 H, H3-py), 7.90 (d, J = 7.8 Hz, 1 H, H3-py), 7.66–
7.62 (m, 2 H, H4-py), 7.36–7.30 (m, 4 H, H5-py and Ph H), 7.28–
7.16 (m, 8 H, Ph), 5.50 (s, 1 H, OCHO), 4.97 (d, J = 3.6 Hz, 1 H,
H1), 4.81 (q, J = 10.4 Hz, 1 H, H3), 4.77 (d, J = 12.2 Hz, 1 H,
CHHPh), 4.58 (dt, J = 10.4, 3.6 Hz, 1 H, H2), 4.54 (d, J = 12.2 Hz,
1 H, CHHPh), 4.22 (dd, J = 10.2, 4.9 Hz, 1 H, H6eq), 4.06 (dt, J
= 9.9, 4.9 Hz, 1 H, H5), 3.86 (dd, J = 10.2, 9.9 Hz, 1 H, H6ax),
3.76 (t, J = 10.3 Hz, 1 H, H4) ppm. 13C NMR (100 MHz, CDCl3):
δ = 165.5, 165.1, 149.9, 149.8, 148.7, 148.3, 137.6 (2 C, overlapped),
137.4 (2 C, overlapped), 129.3, 128.8, 128.6, 128.4, 128.3, 126.7,
126.5, 126.4, 122.7, 122.6, 102.2, 97.5, 80.3, 70.2, 69.5, 64.6, 53.4,
50.7 ppm. C32H30N4O6 (566.6): calcd. C 67.83, H 5.34, N 9.89;
found C 67.01, H 5.31, N 9.77. Ligand 1c: [α]2D0 = –121 (c = 0.1,
Figure 1. Diastereomeric complexes differing in the mode of coord-
iantion of 1a to Mo.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 4.8 Hz, 1
H, H6-py), 8.45 (d, J = 10 Hz, 1 H, NH), 8.29 (d, J = 4.7 Hz, 1
H, H6-py), 8.11 (d, J = 7.9 Hz, 1 H, H3-py), 8.09 (d, J = 10 Hz, 1
H, NH), 8.03 (d, J = 7.9 Hz, 1 H, H3-py), 7.76 (t, J = 7.9 Hz, 1
H, H4-py), 7.71 (t, J = 7.9 Hz, 1 H, H4-py), 7.40 (dd, J = 7.9,
4.7 Hz, 1 H, H5-py), 7.41–7.36 (m, 2 H, Ph), 7.26–7.22 (m, 4 H,
H5-py and Ph H), 5.58 (s, 1 H, OCHO), 4.93–4.86 (m, 2 H, H2,
H3), 4.69 (s, 1 H, H1), 4.27 (dd, J = 10.3, 4.8 Hz, 1 H, H6eq), 4.07
(dt, J = 9.9, 4.8 Hz, 1 H, H5), 3.90–3.85 (m, 2 H, H4, H6ax), 3.40
(s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.4 (2
C, overlapped), 149.4, 149.1, 148.0, 147.6, 137.3, 137.0 (2 C over-
lapped), 128.9, 128.0, 126.4, 126.1, 125.9, 122.3 (2 C, overlapped),
102.1, 100.8, 77.1, 68.8, 64.1, 55.0, 51.7, 48.1 ppm.
Conclusions
Bis(pyridine-2-carboxamides) were conveniently pre-
pared from 1,2-diamines obtained from α--glucose and α-
-mannose according to known procedures and shown to
serve as efficient ligands in Mo-catalyzed microwave-medi-
ated asymmetric allylic alkylations. The two types of struc-
tures allowed the comparison of ligands having the amide
arms in trans and cis positions in the six-membered ring.
The former type of ligands proved to be more successful,
providing the product, (+)-(R)-dimethyl 3-phenyl-1-butene-
4,4-dicarboxylate, with 99% enantiomeric excess and with
a branched/linear ratio of 49:1 in 90% isolated yield under
optimized conditions.
Synthesis of Ligand 1b: 4-Chloropyridine-2-carboxylic acid hydro-
chloride (285 mg, 1.14 mmol), 1,1Ј-carbonyldiimidazole (185 mg,
1.14 mmol) and potassium carbonate (158 mg, 1.14 mmol) were
mixed at 50 °C in dry tetrahydrofuran (2 mL) under nitrogen, and
the suspension obtained was stirred for 1 h. Then the glucosediam-
ine (200 mg, 0.56 mmol) was added, and the mixture was stirred at
the same temperature for an additional 1 h. The crude product was
concentrated under rotatory evaporation and purified by column
chromatography on silica gel (eluent: hexane/AcOEt, from 1:1 to
3:7) to yield 113 mg (32%) of the pure product. Additional ligand
was eluted together with an unidentified product. [α]2D0 = +12 (c =
0.1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 5.2 Hz,
1 H, H6-py), 8.40 (d, J = 9.8 Hz, 1 H, NH), 8.26 (d, J = 5.6 Hz, 1
H, H6-py), 8.01 (d, J = 9.3 Hz, 1 H, NH), 7.96 (s, 1 H, H3), 7.91
(s, 1 H, H3), 7.36–7.28 (m, 4 H, H5 and Ph H), 7.27–7.12 (m, 8 H,
Ph), 5.49 (s, 1 H, OCHO), 4.94 (d, J = 3.5 Hz, 1 H, H1), 4.76 (q,
J = 9.8 Hz, 1 H, H3), 4.75 (d, J = 12.2 Hz, 1 H, CHHPh), 4.52 (d,
J = 12.2 Hz, 1 H, CHHPh), 4.53 (dt, J = 9.3, 3.5 Hz, 1 H, H2),
4.22 (dd, J = 10.3, 4.8 Hz, 1 H, H6eq), 4.09–4.02 (m, 1 H, H5), 3.78
(t, J = 9.8 Hz, 1 H, H6ax), 3.73 (t, J = 10.3 Hz, 1 H, H4) ppm. 13C
NMR (100 MHz, CDCl3): δ = 164.4, 164.0, 151.2, 151.1, 149.7,
149.2, 146.0 (2 C overlapped), 137.5, 137.2, 129.4, 128.9, 128.6 (2
C overlapped), 128.5, 128.4, 126.8, 126.7, 123.3 (2 C overlapped),
102.2, 97.3, 80.1, 70.3, 69.4, 64.6, 53.4, 50.9 ppm.
Experimental Section
General: THF and toluene were dried by using a Glass-contour
solvent dispensing system. Dichloromethane was distilled from
CaH2. Microwave heating was performed by using a Smith Cre-
1
ator single-mode cavity from Biotage. H NMR spectra were re-
corded at 400 or 300 MHz, and 13C NMR spectra at 100 or
75.3 MHz. The H and 13C chemical shifts are reported relative to
1
CHCl3.
Synthesis of Ligands 1a and 1c: A suspension of picolinic acid
(138 mg, 1.12 mmol) and 1,1Ј-carbonyldiimidazole (182 mg,
1.12 mmol) in dry tetrahydrofuran (2 mL) was heated in a flame-
dried flask at 50 °C under nitrogen for 1 h. Then the appropriate
diamine (0.56 mmol) was added, and the mixture was stirred at the
same temperature for 2 h. The solvent was removed under vacuum
and the residue extracted with dichloromethane. The organic phase
was extracted with water (3ϫ5 mL) and the aqueous phases were
combined and extracted with dichloromethane (2ϫ5 mL). The col-
Synthesis of Ligand 1e: A solution of picolinic acid (520 mg,
4.2 mmol), 4-(dimethylamino)pyridine (48 mg, 0.43 mmol) and 1,3-
dicyclohexylcarbodiimide (890 mg, 4.3 mmol) in dry dichlorometh-
ane (7 mL) was added to a solution of benzyl 2-amino-2-deoxy-
4,6-O-(4-methoxybenzylidene)-α--glucopyranoside,[21] (2.0 mmol)
Eur. J. Org. Chem. 2009, 1352–1356
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R. Del Litto, V. Benessere, F. Ruffo, C. Moberg
[2] B. M. Trost, J. Org. Chem. 2004, 69, 5813–5837.
FULL PAPER
in the same solvent (7 mL). The resulting mixture was stirred at
room temperature under an inert gas for 12 h to afford a yellow
suspension. The precipitate was removed by filtration. The re-
sulting yellow solution was concentrated under vacuum, and the
residue was chromatographed on silica gel (ethyl acetate/hexane,
1:5) to afford the pure product as a white solid (yield: 777 mg,
65%). [α]2D0 = +107.5 (c = 0.1, CHCl3). 1H NMR (300 MHz,
CDCl3, 298 K): δ = 8.60 (d, J = 4.8 Hz, 1 H, H6-py), 8.55 (d, J =
5.1 Hz, 1 H, H6-py), 8.48 (d, J = 9.9 Hz, 1 H, NH), 8.05 (d, J =
7.5 Hz, 1 H, H3-py), 7.95 (d, J = 7.8 Hz, 1 H, H3-py), 7.71 (t, J =
7.8 Hz, 2 H, H4-py), 7.40–7.10 (m, 9 H, H5-py and Ph H), 6.80 (d,
J = 8.4 Hz, 2 H, Ph), 5.85 (t, J = 9.9 Hz, 1 H, H3), 5.50 (s, 1 H,
OCHO), 5.01 (d, J = 3.6 Hz, 1 H, H1), 4.73 (m, 2 H, H2, CHHPh),
4.58 (d, J = 12 Hz, 1 H, CHHPh), 4.25 (dd, J = 10.2, 4.5 Hz, 1 H,
H6eq), 4.11 (dt, J = 10.2, 4.5 Hz, 1 H, H5), 3.96 (t, J = 9.6 Hz, 1
H, H6ax), 3.82 (t, J = 10.2 Hz, 1 H, H4), 3.70 (s, 3 H, OCH3) ppm.
13C NMR (75.3 MHz, CDCl3): δ = 164.7, 164.6, 160.3, 150.1,
149.4, 148.5, 147.8, 137.3, 137.0, 136.8, 129.7, 128.6, 128.4, 128.3,
127.7, 127.0, 126.5, 125.7, 122.3, 113.8, 101.7, 97.6, 79.6, 71.9, 70.2,
69.1, 63.5, 55.4, 52.6 ppm. C33H31N3O8 (597.6): calcd. C 66.32, H
5.23, N 7.03; found C 66.40, H 5.29, N 7.10.
[3] B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921–2944.
[4] See ref.[1] and references cited therein.
[5] M. Mulqi, F. S. Stephens, R. S. Vagg, Inorg. Chim. Acta 1981,
53, L91–L93.
[6] B. M. Trost, I. Hachiya, J. Am. Chem. Soc. 1998, 120, 1104–
1105.
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Microwave-Assisted Allylic Alkylations. General Procedure: Two
different stock solutions were prepared: solution N, containing the
nucleophile, was prepared by adding dimethyl malonate (880 µL,
7.7 mmol) to a suspension of 60% NaH in mineral oil in tetra-
hydrofuran (10 mL), and solution S, containing the substrate, was
prepared by dissolving the allylic carbonate (4 or 5) (7.1 mmol)
in THF (10 mL). Then the appropriate ligand (0.034 mmol) and
Mo(CO)6 (6.9 mg, 0.026 mmol) were transferred to a flame-dried
SmithProcessVialTM. Solution N (1 mL), solution S, and BSA
(208 µL) were added in this order, and the suspension was heated
in the microwave cavity at 160 °C for the desired time. The brown
solution obtained was diluted with Et2O to a total volume of
10 mL, resulting in a dark precipitate. A sample of the solution
was filtered through silica gel and analysed by 1H NMR spec-
troscopy and GC-MS to determine the conversion and the regiose-
lectivity. The crude product was then purified either by bulb-to-
bulb distillation or by chromatography on silia gel (eluent: petro-
leum ether/DCM, 1:1). The ee was determined by HPLC using a
Daicel OD-H (0.46 cm i.d. ϫ 25 cm) column. The structures of the
products were confirmed by comparison with published spectro-
scopic data[21] and GC-MS analyses.
Acknowledgments
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V. D. Bonnet, K. Jack, Y. Sun, R. A. Reamer, J. Am. Chem.
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[20] S. W. Krska, D. L. Hughes, R. A. Reamer, D. J. Mathre, Y. Sun,
B. M. Trost, J. Am. Chem. Soc. 2002, 124, 12656–12657.
[21] J. Lehmann, G. C. Lloyd-Jones, Tetrahedron 1995, 51, 8863–
8874.
We are grateful to the Ministero dell’Istruzione, dell’Università e
della Ricerca (Progetti di Ricerca di Interesse Nazionale – Bando
2007) for financial support, which allowed R. D. L. and V. B. to
perform work in Stockholm. Dr. Oscar Belda and Ms. Ester Fjel-
lander are acknowledged for sharing their knowledge on Mo-cata-
lyzed asymmetric allylic alkylations with R. D. L. and V. B.
Received: December 15, 2008
Published Online: January 29, 2009
[1] Z. Lu, S. Ma, Angew. Chem. Int. Ed. 2008, 47, 258–297.
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