products. Likewise, the use of Pd(0) or Rh(I) catalysts for
the borylative ring opening of 1a with B2pin2 was not
satisfactory, and complex mixtures were obtained.
To our delight, the use of [Ni(cod)2] (cod ) 1,5-cyclo-
octadiene; 5 mol %) in combination with racemic BINAP
(7.5 mol %) in a 30:1 mixture of toluene and MeOH in the
presence of anhydrous K3PO4 was successful. The ring
opening of the epoxide occurred rapidly at room temperature,
and 1,4-trans-cyclopentenyl boronate 2a was cleanly ob-
tained, as determined by 1H NMR examination of the crude
mixture (Scheme 1).8
highly anti-stereoselective formation of the intermediate
cyclic-allylic boronate and of the subsequent selective
carbonyl allylation.1b The kinetic resolution of aziridine 1b
with B2Pin2 in the presence of Ni(0)-(R)-Binap catalyst,
aimed at the formation of enantioenriched bisallylic amino
alcohol 3b, proved to not be efficient due to the concomitant
methanolysis of the strained ring.10
With these results in our hands, representative vinyl
epoxide and vinyl aziridine/aldehyde combinations were
examined to explore the scope of the sequential borylation-
allylation (Table 1). When cyclohexenyl systems 1c and 1d
were allowed to react with B2Pin2 in the presence of Ni(0)-
Binap catalyst, they were smoothly converted into the
corresponding allylic boronates, which were not isolated but
directly treated with benzaldehyde to give the corresponding
diol 3c and amino alcohol 3d having a trans-threo relative
configuration (entries 1 and 2, Table 1).11 The sequential
borylation-allylation process proved to be less effective for
aliphatic aldehydes. Only for acetaldehyde was it possible
to isolate the corresponding adduct 4b (entry 3), whereas
n-butanal and 2-methylpropionaldehyde afforded a complex
mixture of products (data not shown in Table 1). On the
other hand, excellent yields and selectivities were obtained
by the use of electron-poor aryl aldehydes (entries 4 and 5)
as well as with an electron-rich aldehyde (entry 6).
Scheme 1
.
Preliminary Results of Metal-Catalyzed Borylative
Ring-Opening Allylation
It should be noted that the methods most generally applied
for the synthesis of stereoisomeric 1,3-diols9 and 1,3-amino
alcohols12 involve multistep processes culminating in a
reduction reaction. Furthermore, the preparation of stereo-
homogeneous alicyclic amino alcohols possessing three
stereogenic centers is more difficult to achieve, and the trans-
threo isomer can be obtained in very low amounts by means
of reducing procedures.13
Despite the use of a reduced amount of MeOH in the
optimized reaction protocol,11 a competitive methanolysis
of vinyl aziridine 1d was found in the crude mixture (entries
2 and 5). On the other hand, for aliphatic phenyl-vinyl
aziridine 1e,14 an increased amount of MeOH (13 equiv) was
On the other hand, the metal-catalyzed ring-opening
borylation of vinyl aziridine 1b showed some different
interesting features. First of all, as well as nickel, also some
copper-catalyzed procedures6,7 were quite effective to obtain
with a high yield the allyl boronate 2b, which, unlike 2a,
turned out to be stable during chromatographic purification.
It should be noted that the reaction without MeOH did
not proceed at all. However, with increased amounts of this
solvent, also products deriving from the methanolysis of
compounds 1a and 1b were obtained. The finding of effective
reaction conditions to obtain a fast, clean anti-SN2′ addition
of the boron group to substrates 1a and 1b prompted us to
explore simple sequential reactions of the in situ formed
functionalized allylic boronates. For example, allyl boronates
2a and 2b can be directly treated with benzaldehyde without
any external Lewis acid additives, to give a clean allylation
reaction. It is remarkable that 1,3-diol 3a and 1,3-amino
alcohols 3b, containing three stereogenic centers, were
obtained as single trans-threo diastereoisomers after a simple
chromatographic purification.9 The high stereoselectivity
obtained (>15:1 d.r. in the crude mixture) is a result of the
(10) Performing the reaction at low temperatures, as well using half
equivalent of B2Pin2 at room temperature, the kinetic resolution proved to
be difficult to control, and the methanolysis of 1b occurred to a large extent.
For example, compound 3b was obtained (40% ee, at 63% conversion)
after chromatographic purification as a 1.8:1 mixture with N-(2-methoxy-
cyclopent-3-enyl)-4-methylbenzenesulfonamide.
(11) General procedure as follows: A 10 mL Schlenk tube was charged,
under argon protection, with Ni(cod)2 (4.20 mg, 0.015 mmol) and K3PO4 (154.0
mg, 0.70 mmol). Anhydrous toluene (1.5 mL) and racemic Binap (14.0 mg,
0.0225 mmol) were added, and the resulting suspension was stirred for 10
minutes at 0 °C. The substrate (0.30 mmol) in toluene (1.5 mL) and
bis(pinacolato) diboron (114.0 mg, 0.45 mmol) were then added, followed
by methanol (0.10 mL, 8.2 equiv). The suspension was vigorously stirred
at rt and monitored by TLC (hexanes/AcOEt 7:3) up to complete
consumption of the starting material (1-5 h). At this point, the aldehyde
(freshly distilled, 0.45 mmol) was introduced at 0 °C, and the reaction
mixture was stirred at rt overnight. The reaction was treated with H2O (3.0
mL), extracted with CH2Cl2 (5 mL × 3), and dried (MgSO4). Evaporation
of the organic solvent afforded a crude residue which was subjected to
flash chromatography (see Supporting Information for details).
(8) The 1,4-trans relationship of the substituents was deduced by 1H
NMR from the small chemical shift difference between the two ring
methylene protons and by their characteristic coupling patterns.
(9) The relative configuration of compounds of type 3 was determined
by 1H NMR after reduction to the corresponding known saturated
compounds: Thompson, S. H. J.; Mahon, M. F.; Molloy, K. C.; Hadley,
M. S.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1995, 379. Also, selected
derivation of 1,3-difunctionalized products reported in Table 1 with fosgene
and/or acetalization with 2,2-dimethoxypropane were effected (see Sup-
porting Information for details).
(12) For a recent report, see: Davis, F. A.; Gaspari, P. M.; Nolt, B. D.;
Xu, P. J. Org. Chem. 2008, 73, 9619, and references cited therein.
(13) Csomo´s, P.; Berna´th, G.; Soha´r, P.; Csa´mpai, A.; De Kimpe, N.;
Fu¨lo¨p, F. Tetrahedron 2001, 57, 3175.
(14) This compound is easily accessible as a ca. 68/32 cis/trans mixture
by addition of allyl sulfur ylides to N-tosyl phenyl aldimine: Li, A.-H.;
Dai, L.-X.; Hou, X.-L.; Chen, M.-B. J. Org. Chem. 1996, 61, 4641.
Org. Lett., Vol. 11, No. 16, 2009
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Crotti, Stefano
