Efficient aldol-type reaction of o-protected α-Hydroxy Aldehydes and N-Trimethylsilyl ketene imines: Synthesis of β,γ-Dihydroxy-Nitriles

FULL PAPER

DOI: 10.1002/ejoc.201300430

Efficient Aldol-Type Reaction of O-Protected α-Hydroxy Aldehydes and

N-Trimethylsilyl Ketene Imines: Synthesis of β,γ-Dihydroxy-Nitriles

Sha Long,^[a]Mauro Panunzio,*^[a]Wenling Qin,^[a]Alessandro Bongini,*^[b]and

Magda Monari^[b]

Keywords: Ketene imines / Diastereoselectivity / Density functional calculations / Silicon / Aldol reactions

An uncatalyzed aldol-type reaction of aromatic N-trimethyl-

silyl ketene imines with O-protected α-trialkylsilyloxy or α-

benzyloxy aldehydes is reported. It is shown that N-trimeth-

ylsilyl ketene imines (SKIs) are essential for the success of

this aldol-type reaction, and that almost complete control of

stereochemistry in the formation of the stereocentre vicinal

to the stereogenic centre present in the starting aldehyde is

seen when these compounds are used. A very high syn

stereoselectivity was observed at room temperature, and a

reversal of stereoselectivity to favour the formation of the anti

product may be achieved at low temperature. Preliminary

theoretical calculations support the hypothesis that the aldol-

type reaction is facilitated by the formation of a cyclic transi-

tion state, with concomitant silatropic migration from the ke-

tene imine-nitrogen to the aldehyde oxygen. The catalyst-

free aldol reaction has been applied to aromatic N-trimethyl-

silyl ketene imines bearing two different aromatic groups. In

these reactions, the diastereoselectivity for the stereocentre

arising from aldehyde sp²carbon remained extremely high,

but the stereoselectivity for the formation of the new quater-

nary stereocentre was unsatisfactory.

chemistry,^[2]we report, in this paper, our results on the cata-

lyst-free reaction of silyl ketene imines (SKIs),^[3]a special

type of ketene imines,^[4]with O-protected α-hydroxy alde-

hydes. Recent studies have shown that SKIs can be used

as neutral versatile synthetic intermediates^[5]in aldol-type

reactions, among other applications. Two important advan-

tages result from this approach: some of the issues associ-

ated with α-anion nitriles^[6]will be avoided, and the reaction

of SKIs with aldehydes will generate highly versatile α-hy-

droxy nitriles, which may then be converted into more com-

plex molecules.^[5c,7]The reaction of SKIs with benzalde-

hyde, crotonaldehyde, and ketones has been reported by

Frainnet et al.^[8]More recently, Denmark’s group reported,

in a series of papers, the enantioselective construction of

two chiral centres derived from the sp²carbon in the start-

ing aldehyde and tertiary carbon in the nitrile, by the Lewis-

base-catalysed addition of SKIs to aldehydes.^[5c,9]

Introduction

The aldol-type reaction is a well established method for

C–C bond formation with control of the stereochemistry

during the formation of a new stereocentre derived from an

sp²carbonyl moiety. For many years, it has been a very

powerful tool in the paraphernalia of organic synthesis,

used for the formation of C–C bonds.^[1]Generally speaking,

two main approaches may be identified for achieving high

stereocontrol in this C–C-bond-forming reaction: (i) the use

of a catalyst; or (ii) the use of an appropriate starting mate-

rial containing at least one stereogenic centre that can be

used as a source of high stereochemical induction. In the

second approach, appropriate starting materials usually

come from the natural chiral pool, and are easy accessible

and have a low cost. In the context of our continuing stud-

ies on the synthesis and use of N-silylimines in organic

[a] ISOF-CNR, Department of Chemistry “G. Ciamician”,

University of Bologna,

Via Selmi 2, 40126 Bologna, Italy

Fax: +39-051-2099456

Results and Discussion

E-mail: mauro.panunzio@unibo.it

Homepage: http://ww w .isof.cnr.it/

Previous studies have shown that SKIs are easily pre-

pared in high yields by deprotonation of disubstituted alkyl

or aryl nitriles with LDA (lithium diisopropylamide), fol-

lowed by trapping the resulting anion with a trialkylsilyl

chloride. The choice of alkylsilyl group and the nature of

the substituents on the starting nitrile are crucial in de-

termining the site of silylation of the resulting lithium

[b] Department of Chemistry “G. Ciamician”,

University of Bologna,

Via Selmi 2, 40126 Bologna, Italy

Fax: +39-051-2099456

E-mail: alessandro.bongini@unibo.it

Homepage: www.chimica.unibo.it

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300430.

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anion. On this subject, Frainnet^[10]reported that: (i) the N-

From a stereochemical point of view, as far as the forma-

trimethylsilyl ketene imine alone was formed when di- tion of the new chiral centre is concerned, the highest ste-

phenylacetonitrile was used as the starting nitrile and reocontrol was achieved using (S)-2-(benzyloxy)propanal

TMSCl (TMS = trimethylsilyl) as the silylating agent; (ii) a derivative 3b at room temp. In this case, an adduct with a

mixture of C-silylated and N-silylated products was formed syn relationship between the benzyloxy group and the new

when 2-phenylpropanenitrile and TMSCl were used; (iii) al- TMS-protected hydroxy functionality (Table 1, entry 5) was

most exclusive C-silylation was obtained when 2-phenylbut- obtained. On the other hand, a complete anti selectivity (for

anenitrile or 2-phenylhexanenitrile were used with TMSCl the assignment of the stereochemistry, see below) was

as the silylating agent. On these bases, it has been reported achieved by using an aldehyde bearing an extremely hin-

that to avoid the formation of C-silylated derivatives, a very dered protecting group (i.e., TBDPhS, tert-butyldiphenyl-

bulky silylating agent, such as tert-butyldimethylsilyl silyl, in 3d) and a reaction temperature of –78 °C (Table 1,

(TBDMS) chloride or triisopropylsilyl (TIPS) chloride, entry 7). The value of J_3,4(Table 1) did not give conclusive

must be used.^[5c,5e,5h]Bearing in mind these drawbacks, the information on the stereochemical relationship of the two

aim of this study was to ascertain whether, with stable bi- hydroxy functionalities. Thus, the stereochemistry was as-

phenyl-N-trialkyl silyl ketene imines, an uncatalysed aldol- certained by transformation of the diastereomeric products

type reaction can be achieved via a Zimmerman–Traxler (i.e., 4a and 5a) into their acetonide derivatives 7a and 7b

six-membered-ring transition state^[12]taking advantage of a (Scheme 2) and studying these compounds by NOE experi-

silatropic migration from the imine nucleophile to the alde- ments. The transformation of 4a and 5a into the corre-

hyde electrophile.^[11]With this goal inmind, the first experi- sponding diols (i.e., 6a and 6b) was performed by treatment

ment we performed was to test whether metallated di- with hydrogen chloride (1 n) in acetonitrile. The diols were

phenylacetonitrile 1a, obtained by reaction of 1 with LDA, then converted into acetonides 7a and 7b by reaction with

would form an aldol adduct by reaction with aldehydes 3a 2,2-dimethoxypropane in the presence of pyridinium p-tolu-

and 3b (Scheme 1, path a, and Table 1, entry 1). After 2 d enesulfonate (PPTS). The assignment of the relative stereo-

at room temperature, no product but only starting materials chemistry of the substituents at positions 4 and 5 of the

were detected in the crude reaction mixture. The next step dioxolane rings of 7a and 7b based on the results of NOE

of our study was to attempt a catalyst-free reaction of N- experiments was straightforward (Scheme 2). For com-

TBDMS-ketene imine 2a, prepared according to a literature pound 7a, the NOE’s between CH₃and 5-H and between

procedure, and aldehyde 3a. The reaction was performed CH₃and 4-H were almost of the same magnitude, which is

starting from –78 °C and allowing the reaction mixture to consistent with a trans configuration, according to geomet-

warm spontaneously to room temperature. After 2 d, once ric analysis. For compound 7b, the NOE effect between

again, no reaction had occurred. Substitution of the pro- CH₃and 5-H was about ten times larger than the NOE

tecting group on the hydroxy functionality of the aldehyde effect between CH₃and 4-H, and so the relative configura-

with a less hindered one (i.e., the benzyl group in 3b) gave tion between the two substituents on C-4 and C-5 must be

the same results (Scheme 1, path b, and Table 1, entries 2 assigned as cis. Accordingly the syn configuration was as-

and 3). The simple substitution of TBDMS-ketene imine 2a signed to compound 4a, and the anti configuration was as-

with less hindered TMS-ketene imine 2b allowed the reac- signed to compound 5a.

tion to happen (Scheme 1, path c, and Table 1, entry 4).

Scheme 1. Reaction of SKIs 2 with aldehydes 3. Reagents and conditions: i) THF, LDA, –78 °C; a) THF, 3a, –78 °C to room temp., 2 d;

b) THF, TBDMSCl, –78 °C, room temp., 10 min, then 3a or 3b, room temp. 2 d; c) THF, TMSCl, –78 °C, 10 min, room temp., then see

Table 1 and experimental section.

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Synthesis of β,γ-Dihydroxy-Nitriles

Table 1. Reaction of nucleophiles 1a, 2a, and 2b with aldehydes 3a–3d.

[a] Method A: Aldehyde 3a–3d was adde to imine 2b at room temperature. [b] Method B: Aldehyde 3a–3d was added to imine 2b at

–78 °C, and after 3 h at this temperature, the mixture was left to warm spontaneously to room temp.

whereas the silyl-ether-protected compounds (i.e., 4c and

4d) were transformed into diol 6a by simple treatment with

hydrogen chloride/acetonitrile. Thus, the absolute configu-

rations of isomers 5b, 5c, and 5d were also assigned.

Scheme 3. Preparation of diol 6a from 4b, 4c, and 4d. Reagents and

conditions: i) Pd/C, Pd(OAc)₂, MeOH; ii) HCl (1 n aq.), CH₃CN,

room temp.

It has been reported that the phenylacetonitrile carban-

ion does not add satisfactorily to benzophenone due to its

weakly basic nature.^[6a,14]However, magnesium and alumin-

ium derivatives of the phenylacetonitrile carbanion have

Scheme 2. Preparation of acetonides 7a and 7b from 4a and 5a.

Reagents and conditions: i) HCl (1 n), CH₃CN, 30 min, room temp.;

ii) PPTS (pyridinium p-toluenesulfonate; 2 equiv.), 2,2-dimeth-

been shown to undergo addition to benzophenone. It has

oxypropane, acetone, overnight, room temp. NOE correlations of

the final products are shown.

been presumed that, under the latter conditions, the coordi-

nating capacities of the metallic cations (e.g., magnesium or

aluminium) play an important role. In our case, as men-

tioned above, the lithium anion of diphenylacetonitrile 1a

The configuration of compounds 4b, 4c, and 4d was as- failed to give an adduct with aldehydes 3a and 3b

signed by transforming them into the corresponding diol (Scheme 1, path a, and Table 1, entry 1). However, the cor-

(i.e., 6a). Compound 4b was transformed into the corre- responding TMS-ketene imine (i.e., 2b) adds spontaneously

sponding dihydroxy derivative (i.e., 6a) by hydrogenolysis to (S)-2-(tert-butyldimethylsilyloxy)propanal (3a) to form

[13]

over a mixture of Pd/C and Pd(OAc)₂

(Scheme 3), compounds 4a and 5a (Table 1, entry 4). In the light of

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these results, we can presume that the N-silyl group plays from the SKI’s nitrogen to the aldehyde oxygen results in

an important role in this uncatalyzed reaction, because of the formation of the O–Si bond (1.98 Å, 0.35 bond order;

a silatropic migration from the imine nitrogen to the carb- Scheme 4 and Figure 1). Finally, this transition state evolves

onylic oxygen to generate a stable β-silyloxy derivative. into neutral end product EP (Scheme 4). On the basis of

Based on the above hypothesis, we envision that the real these calculations, we can assume that the low energy of EP

facilitating force of this uncatalyzed reaction is represented is the driving force that allows the reaction to happen. It is

by the transfer of the silyl group from the SKI to the form- important to emphasize that, at the level of our calculations

ing hydroxy group of the aldehyde via a Zimmerman– and with or without the addition of diffuse functions, no

Traxler-type transition state in which a hypervalent sili- dipolar structure with the silicon group singly bonded to

con^[11]functions as a chelating agent (Figure 1). This gives the nitrogen atom was found. It appears to be more difficult

two important advantages: to give an energetically favour- to explain the high diastereoselectivity observed under the

able pathway for the reaction to take place, and to form a reaction conditions. Experimental evidence (Scheme 1 and

final product that is already protected on its hydroxy group Table 1) shows that at room temperature, the syn product

as a TMS-derivative. It must be stressed that as a result of (i.e., 4) is largely predominant when a benzyl moiety is used

this second point, a retro reaction, which is well known to as protecting group (see, for example, Table 1, entry 5). At

occur in the presence of a catalytic amount of base, is avoid- low temperature and when the steric hindrance of the hy-

ed.^[15]The hindered TBDMS group in SKI 2a lowers the droxy aldehyde protecting group is increased, the anti prod-

transferability of the silyl group, and as a result, the product uct (i.e., 5) becomes predominant (see, for example, Table 1,

is not formed (see above, Scheme 1, and Table 1, entries 2 entry 7). These observations show that the syn isomer is

and 3). These observations should be considered to be fur- formed under thermodynamic control and the anti isomer

ther support for our mechanistic hypothesis. To acquire ad- is formed under kinetic control. The stereochemical assign-

ditional evidence, DFT calculations^[16]were performed for ment of the syn and anti isomers has been confirmed, be-

a model reaction between SKI 2b and formaldehyde yond any doubt, by NOE experiments (see above). How-

(Scheme 4).

ever, at the moment, dedicated studies, such as theoretical

calculations or kinetic experiments, have not been per-

formed to explain this behaviour. As a working hypothesis,

we can assume that an important role is played by the steric

interaction between the aldehyde substituent and the phenyl

groups. Work directed towards this aim is in progress, and

the results will be reported in due course.

This aldol-type reaction has been applied to a range of

O-protected α-hydroxy aldehydes. The results are reported

in Scheme 5 and Table 2. The configurations of compounds

4e and 4g were identified by their transformation into the

corresponding acetonide derivatives (i.e., 10 and 12, respec-

tively; Scheme 6).

Figure 1. Transition state TS in the reaction between SKI 2b and

formaldehyde.

Scheme 4. DFT calculations for the reaction between SKI 2b and

formaldehyde.

Scheme 5. Reaction of diphenyl ketene imine 2b with different O-

protected aldehydes. Reagents and conditions: i) THF, r.t., over-

night.

The calculations showed the preliminary formation of a

stabilized electrostatic complex EC, whose zero energy

(–1117.70047 Hartrees) was taken as the zero point.^[17]

The configuration of 4f was assigned by comparison the

Then, a six-membered transition state TS (Scheme 4 and value of the J_3,4of di-hydroxy derivative 14 with the corre-

Figure 1) is generated by the nucleophilic attack of the β- sponding J value of compound 9 (Scheme 6 and Scheme 7).

carbon of SKI 2b onto the sp²carbonyl functionality of The configurations of 4h and 4i were assigned by simply

formaldehyde. An incipient C–C bond (2.13 Å, bond order comparing the values of their J_3,4values with that of prod-

0.34) begins to form, and concomitant silatropic migration uct 4g (Table 2, entries 3–5). To further investigate the scope

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Synthesis of β,γ-Dihydroxy-Nitriles

Table 2. Reaction of aldehydes 3e–3i with ketene imine 2b.

[a] Method A: Aldehyde 3e–3i was added to imine 2b at room temperature. [b] For the sake of simplicity, only one enantiomer is shown.

Scheme 6. Preparation of acetonides 10 and 12 from products 4e and 4g. Reagents and conditions: i) Pd/C (10%), Pd(OAc)₂, MeOH, H₂;

ii) HCl (1 n aq.), CH₃CN, room temp., 30 min; iii) PPTS, 2,2-dimethoxypropane, acetone, room temp.

of this reaction, nitriles with different aromatic substituents characterized by X-ray single crystal analysis (Figure 2).

were investigated (Scheme 8 and Table 3). The addition of For the other products, the configuration of the C-2

the corresponding N-trimethylsilyl ketene imines, prepared stereocentre was assigned arbitrarily.

as described above, to α-O-protected hydroxy aldehydes 3b

and 3g was examined. Generally speaking, the aldol prod-

ucts were isolated in satisfactory yields, and both electron-

poor and electron-rich ketene imines could be used. The

main drawback in this last series was the lack of selectivity

in the formation of the quaternary stereocentre bearing the

cyano group, even though complete stereoselectivity in the

formation of the C-3 stereocentre was retained. For the sake

Scheme 7. Preparation of dihydroxy derivative 14 from 4f. Reagents

and conditions: i) Pd/C (10%), Pd(OAc)₂, MeOH, H₂; ii) HCl (1 n

of simplicity, only a few examples of the products were fully aq.), CH₃CN, room temp., 30 min.

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Scheme 8. Reaction of unsymmetrical SKIs 2 with different aldehydes 3. Reagents and conditions: i) LDA, TMSCl, –78 °C; ii) THF, room

temp.

tion measurements on the crystal; the enantiomer was assigned by

reference to an unchanging chiral centre in the synthetic procedure.

Conclusions

The molecular graphics were generated using the SCHAKAL99^[24]

program. Colour codes for the molecular graphics: blue (N), red

(O), grey (C), white (H), green (Cl). Crystal data and other experi-

mental details for 15e, 15i, 15k, 16g, 16h-monohydroxy, and 18 are

reported in Table S1 (See Supporting Information).

We have developed a catalyst-free aldol-type reaction be-

tween a N-trimethylsilyl ketene imine and an O-protected

2-hydroxy aldehyde. The aldol products, already protected

on the newly-formed hydroxy functionality as TMS-ethers,

were isolated in high yields and with excellent selectivities

under well-established reaction conditions, at least for the

C-3 stereocentre. The transfer of the TMS-group from the

ketene imine to the aldol product avoids any retro-reaction,

which are well known to constitute a severe drawback in

similar reactions. Even when a lower diastereoselectivity for

the asymmetric C-2 quaternary carbon was observed, the

stereochemical induction for C-3 remained very high.

CCDC-929480 (for 15e), -929481 (for 15i), -929482 (for 15k),

-929483 (for 16g), -929484 (for 16h), and -929485 (for 18) contain

the supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Experimental Details: All starting materials were purchased and

used without purification unless otherwise stated. Solvents were

distilled and dried according to standard procedures. (S)-2-(tert-

Butyldimethylsilyloxy)propanal (3a), (S)-2-(benzyloxy)propanal

(3b), (S)-2-(triisopropylsilyloxy)propanal (3c), (S)-2-(tert-butyldi-

phenylsilyloxy)propanal (3d), (S)-2-(benzyloxy)-3-methylbutanal

(3e), and (S)-2-(tert-butyldimethylsilyloxy)-2-phenylacetaldehyde

(3g) were prepared according to a general procedure reported pre-

viously.^[19]2-(Benzyloxy)-3,3-dimethylbutanal (3f), 2-(tert-butyldi-

methylsilyloxy)-2-(4-chlorophenyl)acetaldehyde (3h), and 2-(tert-

butyldimethylsilyloxy)-2-(4-methoxyphenyl)acetaldehyde (3i) were

prepared according to the general procedure reported by Mild-

land.^[19b]2-Phenyl-2-p-tolylacetonitrile (1c), 2-phenyl-2-m-tolyl-

acetonitrile (1d), 2-phenyl-2-o-tolylacetonitrile (1e), 2-(3-bromo-

phenyl)-2-phenylacetonitrile (1f), 2-(3-methoxyphenyl)-2-phenyl-

acetonitrile (1g), 2-phenyl-2-[3-(trifluoromethyl)phenyl]acetonitrile

(1h), 2-(3-nitrophenyl)-2-phenylacetonitrile (1i), 2-phenyl-2-(pyr-

idin-3-yl)acetonitrile (1j), and 2-(3-chlorophenyl)-2-phenylaceto-

nitrile (1k) were prepared from the corresponding ketones by

TosMic methodology.^[18]Column chromatography was performed

using Merck KGaA silica gel 60 (230–400 Mesh-ASTM). Melting

points were obtained using a Stuart Scientific SMP3 melting point

apparatus. Optical rotations were obtained using a Unipol L1700

Schmidt+Haensch polarimeter and concentrations are given in

units of g100 mL^–1. IR spectra were recorded with a Nicolet 380

FTIR infrared spectrometer. NMR spectroscopy was performed on

a Varian Mercury 400 spectrometer, and the residual signal of the

solvent was used as the internal standard. Chemical shifts are re-

ported in ppm, and coupling constants (J) are reported in Hz. All

signals attributed to OH groups were confirmed by deuterium ex-

change. GC–MS spectra were recorded using Agilent Technologies

6850 and 5975 GC–MS instruments. LC–MS spectra were obtained

using an Agilent Technologies MSD1100 single quadrupole mass

spectrometer. The diastereomeric ratios reported in Table 1,

Table 2, and Table 3 were calculated from HPLC data (Agilent,

Poroshell 120. SB-C18. 2.7 μm, 3.0ϫ100 mm) and data from the

¹H NMR spectra of the crude reaction mixtures, based on unam-

Experimental Section

Computational Methods: DFT calculations were carried out at the

B3LYP 6-31G* level using the Gaussian G03W suite of pro-

grams.^[16]Geometries were fully optimized by standard gradient

techniques, and the final structures were checked by frequency

analysis. The transition state showed only one imaginary frequency,

and the corresponding vibration was associated with the nuclear

motion along the reaction coordinate. Zero-point vibrational en-

ergy corrections were applied without scaling for all the structures

examined. The electron densities of the incipient bonds in the tran-

sition state were determined by calculation of the natural atomic

orbital bond order (NAO) with the natural bond orbital (NBO)

method,^[17]as implemented in G03W.

X-Ray Crystallography: The X-ray intensity data for 15e, 15i, 15k,

16g, 16h-monohydroxy, and 18 were measured with a Bruker Apex

II CCD diffractometer. The cell dimensions and orientation matrix

were initially determined from a least-squares refinement on reflec-

tions measured in three sets of 20 exposures, collected in three dif-

ferent ω regions, and eventually refined against all data. A full

sphere of reciprocal space was scanned using 0.3° steps of ω. The

software SMART^[20]was used for collecting frames of data, in-

dexing reflections, and determining lattice parameters. The col-

lected frames were then processed for integration by the SAINT

program,^[20]and an empirical absorption correction was applied

using SADABS.^[21]The structures were solved by direct methods

(SIR 97)^[22]and subsequent Fourier syntheses, and were refined by

full-matrix least-squares on F²(SHELXTL),^[23]using anisotropic

thermal parameters for all non-hydrogen atoms. All the hydrogen

atoms were located in difference Fourier maps. Those bonded to

aromatic, methyl, or methylene carbons were treated as riding

atoms in geometrically idealized positions. The absolute configura-

tion was not established by anomalous dispersion effects in diffrac-

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Synthesis of β,γ-Dihydroxy-Nitriles

Table 3. Reaction of unsymmetrical SKIs 2 with different aldehydes 3.

[a] The corresponding nitriles [i.e., 1c (67%), 1d (76%), 1e (68%), 1f (44%), 1g (57%), 1h (61%), 1i (78%), 1j (73%), 1k (47%)] were

prepared from the corresponding ketones by TosMic methodology.^[18][b] Because the lack of diastereoselectivity and the difficulty in

isolating the pure diastereoisomers by column chromatography, no effort was taken to assign the right configuration for each compound.

[c] Identified as the corresponding mono-hydroxy derivatives 15a¹and 16a¹. [d] Identified as the corresponding mono-hydroxy derivatives

15b¹and 16b¹.

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Figure 2. Crystal structures of compounds 15e, 15i, 15k, 16g, 16h-monohydroxy, and 18.

biguous peaks due to each diastereomer. Elemental analyses were

obtained using a Flash 2000 series CHNS/O Analyser (Thermo

Scientific).

Method B: A solution of (S)-2-(tert-butyldimethylsilyloxy)propanal

3a (231 mg, 1.23 mmol) in THF (1 mL) was added to ketene imine

2b at –78 °C. The reaction mixture was kept at this temperature for

3 h, then it was allowed to reach room temp. and kept at room

temp. overnight. The solvent was removed under vacuum, and the

residue was purified by flash chromatography (n-hexane/EtOAc,

50:1) to give 4a and 5a (4a: 175 mg, 5a: 215 mg, total yield: 70%,

ratio 4a/5a: 45:55).

N-(2,2-Diphenylvinylidene)-1,1,1-trimethylsilanamine (2b): Trimeth-

ylsilyl ketene imine 2b was prepared according to a literature pro-

cedure.^[3a,10]In detail, BuLi (2.5 m in n-hexane; 0.49 mL,

1.23 mmol) was added to a THF (3 mL) solution of diisopropyl-

amine (0.19 mL, 1.35 mmol) at –78 °C under a nitrogen atmo-

sphere. Diphenylacetonitrile (238 mg, 1.23 mmol), dissolved in

THF (1 mL), was added dropwise into the solution at –78 °C. The

colour of the reaction mixture became yellow. After 5 min, a solu-

tion of TMSCl (0.17 mL, 1.35 mmol) in THF (1 mL) was added to

the reaction mixture. A sample of the resulting ketene imine (i.e.,

Data for 4a: White solid, m.p. 106–107 °C. [α]²_D⁰= –16.80 (c = 1.0,

1

CHCl ). IR (film): ν = 2242 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= –0.16 (s, 9 H), –0.13 (s, 3 H), –0.07 (s, 3 H), 0.85 (s, 9 H), 1.21

(d, J = 6.4 Hz, 3 H), 4.16 (dq, J = 2.8, J = 6.4 Hz, 1 H), 4.43 (d,

J = 2.8 Hz, 1 H), 7.24–7.36 (m, 6 H), 7.50 (d, J = 7.2 Hz, 2 H),

7.70 (d, J = 7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

–4.41, –4.17, 0.12, 18.20, 22.00, 26.12, 57.35, 69.37, 81.88, 121.31,

127.62, 127.86, 128.16, 127.43, 127.50, 138.63, 139.04 ppm. MS

(EI): m/z = 438 [M – CH₃]. C₂₆H₃₉NO₂Si₂(453.77): calcd. C 68.82,

H 8.66, N 3.09, Si 12.38; found C 68.92, H 8.67.

1

2b) was characterized by its IR and H and ¹³C NMR spectra. IR

(film): ν = 2038 cm^–1. ¹H NMR (400 MHz, C₆D₆): δ = 0.22 (s, 9

˜

H), 7.12–7.24 (complex pattern, 2 H), 7.37 (m, 4 H), 7.62 (m, 4 H)

ppm. ¹³C NMR (100 MHz, C₆D₆): δ = –0.30, 61.27, 124.74, 127.08,

129.24, 136.61, 180.63 ppm.

(3S,4S)-4-(tert-Butyldimethylsilyloxy)-2,2-diphenyl-3-(trimethylsil-

yloxy)pentanenitrile (4a) and (3R,4S)-4-(tert-Butyldimethylsilyl-

oxy)-2,2-diphenyl-3-(trimethylsilyloxy)pentanenitrile (5a)

Data for 5a: Colourless oil. [α]²_D⁰= +8.72 (c = 1.0, CHCl₃). IR

1

(film): ν = 2242 cm^–1. H NMR (400 MHz, CDCl ): δ = –0.08 (s,

˜

3

9 H), –0.02 (s, 6 H), 0.90 (s, 9 H), 1.21 (d, J = 7.0 Hz, 3 H), 3.99

(dq, J = 7.0, J = 0.8 Hz, 1 H), 4.66 (d, J = 0.8 Hz, 1 H), 7.23–

7.41 (complex pattern, 6 H), 7.49–7.57 (m, 4 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = –4.79, –4.20, –0.04, 17.98, 18.00, 25.89,

57.01, 69.90, 82.34, 121.27, 127.55, 127.67, 127.85, 128.04, 128.33,

128.84, 138.08, 138.85 ppm. MS(EI): m/z = 438 [M – CH₃].

C₂₆H₃₉NO₂Si₂(453.77): calcd. C 68.82, H 8.66, N 3.09, Si 12.38;

found C 68.94, H 8.68.

Method A: A solution of (S)-2-(tert-butyldimethylsilyloxy)propanal

3a (231 mg, 1.23 mmol) in THF (1 mL) was added to ketene imine

2b at room temp. The reaction mixture was kept at room temp.

overnight. The solvent was removed under vacuum, and the residue

was purified by flash chromatography (n-hexane/EtOAc, 50:1) to

give 4a and 5a (4a: 285 mg, 5a: 9 mg, total yield: 65%, ratio 4a/5a:

97:3).

5134

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Eur. J. Org. Chem. 2013, 5127–5142

Synthesis of β,γ-Dihydroxy-Nitriles

(3S,4S)-4-(Benzyloxy)-2,2-diphenyl-3-(trimethylsilyloxy)pentaneni-

trile (4b) and (3R,4S)-4-(benzyloxy)-2,2-diphenyl-3-(hydroxy)pent-

anenitrile (5b¹)

= –0.16 (s, 9 H), 0.97–1.01 (complex pattern, 21 H), 1.26 (d, J =

6.4 Hz, 3 H), 4.31 (dq, J = 2.4, J = 6.4 Hz, 1 H), 4.53 (d, J =

2.4 Hz, 1 H), 7.22–7.36 (complex pattern, 6 H), 7.51 (m, 2 H), 7.54

(m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 0.07, 13.09,

18.09, 18.15, 18.23, 21.26, 57.14, 70.32, 81.63, 121.15, 127.58,

127.63, 127.90, 128.10, 128.41, 128.45, 138.60, 139.13 ppm. MS

(ESI): m/z = 495 [M]. C₂₉H₄₅NO₂Si₂(495.85): calcd. C 70.25, H

9.15, N 2.82, O 6.45, Si 11.33; found C 70.38, H 9.17.

Method A: Following Method A above for the preparation of 4a

and 5a, starting from diphenylacetonitrile (193 mg, 1.0 mmol) and

(S)-2-(benzyloxy)propanal (3b; 164 mg, 1.0 mmol), after flash

chromatography (cyclohexane/ether, 7:1), compound 4b (356 mg,

83%) was isolated as single diastereoisomer.

Data for 5c: Colourless oil. [α]²_D⁰= –7.4 (c = 1.0, CHCl₃). IR (film):

Method B: Following Method B above for the preparation of 4a

and 5a, starting from diphenylacetonitrile (193 mg, 1.0 mmol) and

(S)-2-(benzyloxy)propanal (3b; 164 mg, 1.0 mmol), 4b and 5b were

obtained in the crude product mixture. This mixture was purified

by flash chromatography (cyclohexane/ether, 7:1). Compound 4b

was isolated as the siloxyl derivative (219 mg, 51%), whereas 5b was

isolated as the corresponding monohydroxy derivative 5b¹(86 mg,

24 %). Ratio 4b/5b¹: 68:32. Hydrolysis of the trimethylsilyloxy

group occurred during the flash chromatography. It must be

stressed that this was an isolated case.

ν = 2238 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = –0.06 (s, 9 H),

˜

1.01 (complex pattern, 21 H), 1.25 (d, J = 6.4 Hz, 3 H), 4.02 (dq,

J = 0.8, J = 6.4 Hz, 1 H), 4.77 (d, J = 0.8 Hz, 1 H), 7.29–7.38

(complex pattern, 6 H), 7.51 (m, 2 H), 7.56 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 0.13, 12.44, 18.05, 18.15, 18.21,

57.34, 69.85, 82.46, 121.27, 127.44, 127.77, 127.94, 127.80, 128.43,

128.88, 137.98, 138.57 ppm. MS (ESI): m/z = 495 [M].

C₂₉H₄₅NO₂Si₂(495.85): calcd. C 70.25, H 9.15, N 2.82, O 6.45, Si

11.33; found C 70.42, H 9.17.

(3S,4S)-4-(tert-Butyldiphenylsilyloxy)-2,2-diphenyl-3-(trimethylsil-

yloxy)pentanenitrile (4d) and (3R,4S)-4-(tert-Butyldiphenylsilyloxy)-

2,2-diphenyl-3-(trimethylsilyloxy)pentanenitrile (5d)

Data for 4b: White solid, m.p. 93–94 °C. [α]²_D⁰= +10.36 (c = 1.1,

1

CHCl ). IR (film): ν = 2246 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= –0.22 (s, 9 H), 1.11 (d, J = 6.4 Hz, 3 H), 3.68 (m, 1 H), 4.26 (d,

J = 12.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 4.52 (d, J = 4.4 Hz,

1 H), 7.19–7.35 (m, 11 H), 7.44 (d, J = 7.2 Hz, 2 H), 7.70 (d, J =

7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 0.15, 17.31,

57.21, 71.02, 76.07, 81.46, 121.47, 127.23, 127.66, 127.80, 127.88,

128.09, 128.14, 128.59, 128.69, 137.99, 138.39, 138.70 ppm. MS

(EI): m/z = 430 [M + H]⁺. C₂₇H₃₁NO₂Si (429.63): calcd. C 75.48,

H 7.27, N 3.26, Si 6.54; found C 75.78, H 7.29.

Method A: Following Method A above for the preparation of 4a

and 5a, starting from diphenylacetonitrile (386 mg, 2.0 mmol) and

(S)-2-(tert-butyldiphenylsilyloxy)propanal (3d; 624 mg, 2.0 mmol),

flash chromatography (petroleum ether/ether, 20:1) gave (3S,4S)-4-

(tert-butyldiphenylsilyloxy)-2,2-diphenyl-3-(trimethylsilyloxy)pent-

anenitrile (4d) and (3R,4S)-4-(tert-butyldiphenylsilyloxy)-2,2-di-

phenyl-3-(trimethylsilyloxy)pentanenitrile (5d) (4d: 750 mg, 5d:

404 mg, total yield: 62%, ratio 4d/5d: 65:35).

Data for 5b¹: Colourless liquid. [α]²_D⁰= +131.1 (c = 1.0, CHCl₃).

Method B: Following Method B above for the preparation of 4a

and 5a, 4d and 5d were obtained (total yield: 67%, ratio 4d/5d:

1:99).

IR (film): ν = 2238 cm^–1. ¹H NMR (400 MHz CDCl ): δ = 1.18 (d,

˜

3

J = 6.4 Hz, 3 H), 3.49 (d, J = 9.2 Hz, 1 H, OH), 3.55 (dq, J = 2.0,

J = 6.4 Hz, 1 H), 4.39 (dd, J = 2.0, J = 9.2 Hz, 1 H), 4.41 (d, J =

10.8 Hz, 1 H), 4.51 (d, J = 10.8 Hz, 1 H), 7.27–7.39 (m, 13 H), 7.56

(d, J = 8.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 17.96,

56.94, 71.17, 72.58, 77.47, 120.85, 127.27, 127.83, 127.85, 128.00,

128.02, 128.19, 128.35, 128.66, 129.02, 137.39, 138.59, 139.22 ppm.

MS (ESI): m/z = 380 [M + Na]⁺. C₂₄H₂₃NO₂(357.45): calcd. C

80.64, H 6.49, N 3.92; found C 80.88, H 6.51.

Data for 4d: White solid, m.p. 112–114 °C. [α]²_D⁰= –7.10 (c = 1.0,

1

CHCl ). IR (film): ν = 2248 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= –0.23 (s, 9 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.94 (s, 9 H), 4.08 (dq,

J = 1.6, J = 6.8 Hz, 1 H), 4.50 (d, J = 1.6 Hz, 1 H), 7.19–7.37

(complex pattern, 15 H), 7.57–7.71 (m, 5 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 0.04, 19.17, 20.86, 26.78, 57.67, 71.09,

81.47, 121.11, 127.19, 127.53, 127.63, 127.64, 127.75, 127.78,

128.63, 129.29, 129.47, 133.28, 134.90, 135.57, 135.99, 138.22,

139.73 ppm. MS (ESI): m/z = 600 [M + Na]⁺. C₃₆H₄₃NO₂Si₂

(577.91): calcd. C 74.82, H 7.50, N 2.42, Si 9.72; found C 75.11, H

7.53.

(3S,4S)-2,2-diphenyl-4-(triisopropylsilyloxy)-3-(trimethylsilyloxy)-

pentanenitrile (4c) and (3R,4S)-2,2-diphenyl-4-(triisopropylsilyloxy)-

3-(trimethylsilyloxy)pentanenitrile (5c)

Method A: BuLi (2.5 m in n-hexane; 0.44 mL, 1.1 mmol) was added

to a solution of diisopropylamine (0.155 mL, 1.21 mmol) in THF

(3 mL) at –78 °C. Then a solution of diphenylacetonitrile (212 mg,

1.1 mmol) in THF (1 mL) was added dropwise to the solution at

–78 °C. The colour of the reaction mixture became yellow. After

5 min, a solution of TMSCl (0.14 mL, 1.1 mmol) in THF (1 mL)

was added to the reaction mixture. The reaction mixture was al-

lowed to reach room temp. A solution of (S)-2-(triisopropylsilyl-

oxy)propanal (3c; 253 mg, 1.1 mmol) in THF (1 mL) was added

dropwise. The reaction mixture was kept at room temp. overnight.

The solvent was removed under vacuum, and the residue was puri-

fied by flash chromatography (hexane/CH₂Cl₂, 7:1) to give pure

compounds 4c and 5c (4c: 381 mg, 5c: 163 mg, total yield: 75%,

ratio 4c/5c: 70:30).

Data for 5d: White solid, m.p. 142–145 °C. [α]²_D⁰= –2.80 (c = 1.0,

1

CHCl ). IR (film): ν = 2240 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= 0.05 (s, 9 H), 1.08 (d, J = 6.4 Hz, 3 H), 1.10 (s, 9 H), 3.92 (q, J

= 6.4 Hz, 1 H), 4.89 (s, 1 H), 7.11–7.59 (m, 20 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 0.14, 17.89, 19.00, 27.06, 57.51, 71.10,

82.17, 121.02, 127.35, 127.40, 127.49, 127.66, 127.72, 127.82,

128.39, 128.78, 129.63, 133.47, 133.71, 135.71, 135.85, 135.97,

137.34, 138.91 ppm. MS (ESI): m/z = 600 [M + Na]⁺

.

C₃₆H₄₃NO₂Si₂(577.91): calcd. C 74.82, H 7.50, N 2.42, Si 9.72;

found C 75.00, H 7.52.

(3S,4S)-4-(Benzyloxy)-5-methyl-2,2-diphenyl-3-(trimethylsilyloxy)-

hexanenitrile (4e): Following Method A above for the preparation

of 4a and 5a, starting from diphenylacetonitrile (193 mg, 1.0 mmol)

and (S)-2-(benzyloxy)-3-methylbutanal (3e; 211 mg, 1.1 mmol),

flash chromatography (hexane/ether, 8:1) gave (3S,4S)-4-(benz-

yloxy)-5-methyl-2,2-diphenyl-3-(trimethylsilyloxy)hexanenitrile (4e;

311 mg, 68%) as a white solid, m.p. 86–90 °C. [α]²_D⁰= +3.80 (c =

Method B: Following Method B above for the preparation of 4a

and 5a, 4c and 5c were obtained (total yield: 85%, ratio 4c/5c:

5:95).

Data for 4c: White solid; m.p. 67–71 °C. [α]²_D⁰= –12.0 (c = 1.0,

CHCl ). IR (film): ν = 2239 cm^–1. H NMR (400 MHz, CDCl ): δ 1.0, CHCl ). IR (film): ν = 2240 cm^–1

.

¹H NMR (400 MHz,

1

˜

3

Eur. J. Org. Chem. 2013, 5127–5142

www.eurjoc.org 5135

S. Long, M. Panunzio, W. Qin, A. Bongini, M. Monari

FULL PAPER

CDCl₃): δ = –0.20 (s, 9 H), 0.80 (d, J = 6.4 Hz, 3 H), 0.93 (d, J = acetonitrile (193 mg, 1.0 mmol) and 2-[(tert-butyldimethylsilyl)-

6.4 Hz, 3 H), 1.62 (m, 1 H), 3.37 (dd, J = 4.4, J = 5.6 Hz, 1 H), oxy]-2-(4-methoxyphenyl)acetaldehyde (3i; 280 mg, 1.0 mmol),

4.33 (d, J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.69 (d, J = flash chromatography (petroleum ether/ether, 50:1) gave (3S*,4S*)-

4.4 Hz, 1 H), 7.18–7.37 (complex pattern, 11 H), 7.49 (m, 2 H), 4-(tert-butyldimethylsilyloxy)-4-(4-methoxyphenyl)-2,2-diphenyl-3-

7.75 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 0.42, 17.41, (trimethylsilyloxy)butanenitrile (4i; 371 mg, 68%) as a white solid;

20.41, 31.06, 58.57, 73.77, 79.00, 83.39, 121.01, 127.59, 127.86,

127.98, 128.02, 128.54, 128.58, 128.80, 137.79, 138.22, 139.00 ppm.

MS (EI): m/z = 458 [M + 1]. C₂₉H₃₅NO₂Si (457.69): calcd. C 76.10,

H 7.71, N 3.06, Si 6.14; found C 76.37, H 7.74.

m.p.118–121 °C. IR (film): ν = 2245 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = –0.46 (s, 9 H), –0.44 (s, 3 H), –0.28 (s, 3 H), 0.87 (s, 9

H), 3.80 (s, 3 H), 4.72 (d, J = 2.8 Hz, 1 H), 5.01 (d, J = 2.8 Hz, 1

H), 6.81 (d, J = 9.2 Hz, 2 H), 7.18 (d, J = 8.8 Hz, 2 H), 7.24–7.37

(m, 6 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = –4.84, –4.26, –0.23, 18.26, 26.24,

55.22, 57.57, 74.94, 82.80, 113.22, 120.67, 127.69, 127.73, 127.88,

128.22, 128.61, 128.70, 128.81, 129.16, 134.52, 138.68, 139.06,

159.22 ppm. MS (ESI): m/z = 568 [M + Na]⁺. C₃₂H₄₃NO₃Si₂

(545.87): calcd. C 70.41, H 7.94, N 2.57, O 8.79, Si 10.29; found C

70.27, H 7.2.

(3S*,4S*)-4-(Benzyloxy)-5,5-dimethyl-2,2-diphenyl-3-(trimethylsil-

yloxy)hexanenitrile (4f): Following Method A above for the prepa-

ration of 4a and 5a, starting from diphenylacetonitrile (290 mg,

1.5 mmol) and 2-(benzyloxy)-3,3-dimethylbutanal (3f; 309 mg,

1.5 mmol), flash chromatography (hexane/ether, 9:1) gave

(3S*,4S*)-4-(benzyloxy)-5,5-dimethyl-2,2-diphenyl-3-(trimethylsil-

yloxy)hexanenitrile (4f; 459 mg, 65%) as a colourless oil. IR (film):

ν = 2238 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = –0.16 (s, 9 H),

˜

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-phenyl-2-p-tolyl-3-(hydroxy)-

pentanenitrile (15a¹and 16a¹): BuLi (2.5 m in n-hexane; 0.4 mL,

1.0 mmol) was added into a solution of diisopropylamine

(0.155 mL, 1.1 mmol) in THF (3 mL) at –78 °C. Then a solution

of 2-phenyl-2-p-tolylacetonitrile (1c; 207 mg, 1.0 mmol) in THF

(1 mL) was added dropwise to the solution at –78 °C. The colour

of the reaction mixture became yellow. After 5 min, a solution of

TMSCl (0.14 mL, 1.1 mmol) in THF (1 mL) was added to the reac-

tion mixture. The reaction mixture was allowed to reach room

temp. (S)-2-(Benzyloxy)propanal (180 mg, 1.1 mmol) in THF

(1 mL) was added at room temp. After TLC showed that the reac-

tion was complete, the solvent was removed. The crude residue was

dissolved in HCl (1 n aq.; 1 mL) and acetonitrile (5 mL). The re-

sulting homogeneous solution was kept at room temp. for 30 min

and then iced NaHCO₃(saturated aq.) was added to adjust the pH

to 6.0. The solvent was removed under vacuum, and the residue

was dissolved in water (10 mL) and extracted with diethyl ether

(3ϫ 20 mL). The organic phase was dried with anhydrous Na₂SO₄,

and the solvent was removed under vacuum. The residue was puri-

fied by flash chromatography (hexane/ether, 4:1) to give an insepa-

rable mixture of 15a¹and 16a¹(214 mg, 58% total yield) in a ratio

of 50:50, as determined from HPLC and ¹H NMR spectra. The

inseparable diastereomeric mixture was crystallized from MeCN/

H₂O = 99:1. This allowed the separation of a pure isomer, which

was assigned, arbitrarily, as structure 15a¹, while 16a¹remained

mixed with 15a¹in the mother liquor. Because a retro reaction

easily takes place, no further effort were made to isolate pure 16a¹,

and its spectroscopic data were deduced from the mixture.

0.97 (s, 9 H), 3.30 (d, J = 1.2 Hz, 1 H), 3.99 (d, J = 11.2 Hz, 1 H),

4.18 (d, J = 11.2 Hz, 1 H), 5.02 (d, J = 1.2 Hz, 1 H), 7.19–7.38

(complex pattern, 11 H), 7.47 (m, 2 H), 7.83 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 1.10, 27.18, 37.01, 58.96, 73.96,

77.42, 84.06, 122.24, 126.66, 126.75, 127.83, 128.04, 128.28, 128.36,

128.51, 128.74, 129.27, 136.64, 139.02, 139.66 ppm. MS (EI): m/z

= 472 [M + 1]. C₃₀H₃₇NO₂Si (471.71): calcd. C 76.39, H 7.91, N

2.97, Si 5.95; found C 76.52, H 7.92.

(3S,4S)-4-(tert-Butyldimethylsilyloxy)-2,2,4-triphenyl-3-(trimethyl-

silyloxy)butanenitrile (4g): Following Method A above for the prep-

aration of 4a and 5a, starting from diphenylacetonitrile (193 mg,

1.0 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-2-phenylacetalde-

hyde (3g; 250 mg, 1.0 mmol), flash chromatography (hexane/ether,

98:2) gave (3S,4S)-4-(tert-butyldimethylsilyloxy)-2,2,4-triphenyl-3-

(trimethylsilyloxy)butanenitrile (4g; 402 mg, 78%) as a white solid,

m.p. 135–137 °C. [α]²_D⁰= –4.45 (c = 1.1, CHCl ). IR (film): ν =

˜

3

2247 cm^–1. H NMR (400 MHz, CDCl₃): δ = –0.49 (s, 9 H), –0.46

1

(s, 3 H), –0.28 (s, 3 H), 0.91 (s, 9 H), 4.77 (d, J = 2.4 Hz, 1 H),

5.08 (d, J = 2.4 Hz, 1 H), 7.27–7.37 (m, 11 H), 7.56 (d, J = 8.4 Hz,

2 H), 7.75 (d, J = 7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = –4.89, –4.29, 0.35, 18.25, 26.23, 57.72, 75.07, 82.70, 120.63,

127.66, 127.68, 127.79, 127.88, 128.67, 128.80, 138.96, 138.97,

142.57 ppm. MS (EI): m/z = 515 [M]. C₃₁H₄₁NO₂Si₂(515.84):

calcd. C 72.18, H 8.01, N 2.72, Si 10.89; found C 73.00, H 8.03.

(3S*,4S*)-4-(tert-Butyldimethylsilyloxy)-4-(4-chlorophenyl)-2,2-di-

phenyl-3-(trimethylsilyloxy)butanenitrile (4h): Following Method A

above for the preparation of 4a and 5a, starting from diphenylace-

tonitrile (232 mg, 1.2 mmol) and 2-[(tert-butyldimethylsilyl)oxy]-2-

(4-chlorophenyl)acetaldehyde (3h; 341 mg, 1.2 mmol), flash

chromatography (petroleum ether/ether, 97:3) gave (3S*,4S*)-4-

(tert-butyldimethylsilyloxy)-4-(4-chlorophenyl)-2,2-diphenyl-3-(tri-

methylsilyloxy)butanenitrile (4h; 481 mg, 73 %) as a white solid,

Data for 15a¹: White solid; m.p. 95–98 °C. [α]²_D⁰= +99.5 (c = 1.0,

1

CHCl ). IR (film): ν = 2238 cm^–1. H NMR (400 MHz, CD OD):

˜

3

δ = 1.20 (d, J = 6.8 Hz, 3 H), 2.30 (s, 3 H), 3.37 (dq, J = 2.0, J =

6.8 Hz, 1 H), 4.17 (d, J = 11.6 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1

H), 4.48 (d, J = 2.0 Hz, 1 H), 7.13 (d, J = 11.6 Hz, 2 H), 7.24–7.40

(complex pattern, 10 H), 7.56 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CD₃OD): δ = 16.80, 20.95, 57.81, 72.00, 74.77, 78.05, 122.82,

128.23, 128.33, 128.43, 128.62, 128.87, 128.94, 129.09, 129.14,

129.56, 129.87, 130.20, 130.50, 137.20, 138.95, 139.48, 141.97 ppm.

MS (EI): m/z = 357 [M – CH₃+ H]. C₂₅H₂₅NO₂(371.48): calcd.

C 80.83, H 6.78, N 3.77, O 8.61; found C 81.03, H 6.80.

m.p. 156–160 °C. IR (film): ν = 2251 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = –0.55 (s, 9 H), –0.53 (s, 3 H), –0.36 (s, 3 H), 0.79 (s, 9

H), 4.62 (d, J = 2.8 Hz, 1 H), 4.95 (d, J = 2.8 Hz, 1 H), 7.12–7.27

(m, 10 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.61 (d, J = 7.2 Hz, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = –4.91, –4.25, –0.27, 18.21, 26.17,

57.54, 74.94, 82.45, 120.56, 127.68, 127.79, 127.84, 128.01, 128.35,

128.66, 128.79, 129.02, 133.40, 138.42, 138.74, 140.98 ppm. MS

(ESI): m/z = 572 [M + Na]⁺. C₃₁H₄₀ClNO₂Si₂(550.29): calcd. C

67.66, H 7.33, Cl 6.44, N 2.55, O 5.82, Si 10.21; found C 67.84, H

7.35.

Data for 16a¹: IR (film): ν = 2238 cm^{–1 1}H NMR (400 MHz,

.

˜

CDCl₃): δ = 1.19 (d, J = 6.8 Hz, 3 H), 2.26 (s, 3 H), 3.65 (d, J =

9.6 Hz, 1 H, OH), 3.53 (dq, J = 2.0, J = 6.8 Hz, 1 H), 4.38 (dd, J

= 2.0, J = 9.6 Hz, 1 H), 4.41 (d, J = 10.8 Hz, 1 H), 4.52 (d, J =

10.8 Hz, 1 H), 7.16 (d, J = 7.6 Hz, 2 H), 7.29–7.40 (complex

pattern, 10 H), 7.46 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 17.95, 20.98, 56.68, 71.22, 72.67, 77.50, 121.00, 127.25, 127.81,

(3S*,4S*)-4-(tert-Butyldimethylsilyloxy)-4-(4-methoxyphenyl)-2,2-

diphenyl-3-(trimethylsilyloxy)butanenitrile (4i): Following Method

A above for the preparation of 4a and 5a, starting from diphenyl-

5136

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Eur. J. Org. Chem. 2013, 5127–5142

Synthesis of β,γ-Dihydroxy-Nitriles

127.94, 128.09, 128.19, 128.57, 129.00, 129.72, 136.28, 137.48, Information. C₂₈H₃₃NO₂Si (443.66): calcd. C 75.80, H 7.50, N

137.87, 139.45 ppm. MS (EI): m/z = 357 [M – CH₃+ H].

3.16, O 7.21, Si 6.33; found C 76.08, H 7.53.

Data for 16c: Colourless oil [α]²_D⁰= –57.90 (c = 1.0, CHCl₃). IR

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-phenyl-2-m-tolyl-3-(hy-

droxy)pentanenitrile (15b¹and 16b¹): Following the procedure used

for 15a¹and 16a¹, starting from 2-phenyl-2-m-tolylacetonitrile

(207 mg, 1.0 mmol) and (S)-2-(benzyloxy)propanal (180 mg,

1.1 mmol), column chromatography on silica gel (hexane/ether, 6:1)

gave an inseparable mixture of 15b¹and 16b¹(288 mg, total yield:

65%, ratio: 52:48). The spectral data were deduced from the mix-

ture, and the major set of signals was arbitrarily assigned as 16b¹.

1

(film): ν = 2237 cm^–1. H NMR (400 MHz, CDCl ): δ = –0.11 (s,

˜

3

9 H), 1.18 (d, J = 6.0 Hz, 3 H), 2.20 (s, 3 H), 3.85 (dq, J = 4.4, J

= 6.0 Hz, 1 H), 4.35 (d, J = 12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1

H), 4.63 (d, J = 4.4 Hz, 1 H), 7.12–7.32 (complex pattern, 11 H),

7.42 (m, 2 H), 7.52 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 0.32, 18.20, 21.77, 55.48, 71.11, 76.47, 80.45, 120.89, 125.41,

127.21, 127.53, 127.55, 128.03, 128.07, 128.28, 128.59, 133.04,

135.97, 137.65, 138.44, 138.58 ppm. MS (EI): m/z = 443 [M].

C₂₈H₃₃NO₂Si (443.66): calcd. C 75.80, H 7.50, N 3.16, O 7.21, Si

6.33; found C 75.94, H 7.51.

1

Data for 15b¹: Colourless oil. IR (film): ν = 2238 cm^–1. H NMR

˜

[400 MHz, (CD₃)₂SO/D₂O]: δ = 1.13 (d, J = 6.4 Hz, 3 H), 2.17 (s,

3 H), 3.14 (dq, J = 6.4, J = 1.2 Hz, 1 H), 3.85 (d, J = 12.0 Hz, 1

H), 4.36 (d, J = 12.0 Hz, 1 H), 4.58 (d, J = 1.2 Hz, 1 H), 7.11 (m,

1 H), 7.18–7.38 (complex pattern, 13 H) ppm. ¹³C NMR

[100 MHz, (CD₃)₂SO/D₂O]: δ = 16.09, 21.48, 56.56, 70.19, 74.90,

75.67, 122.07, 125.02, 127.38, 128.56, 127.85, 128.20, 128.28,

128.51, 128.85, 129.06, 138.29, 138.76, 139.26, 141.15 ppm. MS

(EI): m/z = 357 [M – CH₃+ H].

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-(4-bromophenyl)-2-phenyl-3-

(trimethylsilyloxy)pentanenitrile (15d and 16d): Following Method

A above for the preparation of 4a and 5a, starting from 2-(4-

bromophenyl)-2-phenylacetonitrile (1f; 271 mg, 1.0 mmol) and (S)-

2-(benzyloxy)propanal (3b; 164 mg, 1.0 mmol), flash chromatog-

raphy (n-hexane/ether, 9:1) gave a mixture of (2S,3S,4S)-4-(benz-

yloxy)-2-(4-bromophenyl)-2-phenyl-3-(trimethylsilyloxy)pentane-

nitrile (15d) and (2R,3S,4S)-4-(benzyloxy)-2-(4-bromophenyl)-2-

phenyl-3-(trimethylsilyloxy)pentanenitrile (16d) (274 mg, total

yield: 54%, ratio: 45:55). No further efforts to isolate pure 15d from

16d were made. The stereochemistry of 15d was assigned arbitrarily,

and its spectroscopic data were deduced as being the major set of

signals from the product mixture.

1

Data for 16b¹: Colourless oil. IR (film): ν = 2238 cm^–1. H NMR

˜

[400 MHz, (CD₃)₂SO/D₂O]: δ = 1.13 (d, J = 6.0 Hz, 3 H), 2.28 (s,

3 H), 3.14 (dq, J = 6.0, J = 1.2 Hz, 1 H), 3.89 (d, J = 12.0 Hz, 1

H), 4.33 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 1.2 Hz, 1 H), 7.08 (m,

2 H), 7.23–7.38 (complex pattern, 10 H), 7.54 (d, J = 7.6 Hz, 2 H)

ppm. ¹³C NMR [100 MHz, (CD₃)₂SO/D₂O]: δ = 16.01, 21.30,

56.59, 70.25, 74.10, 75.67, 121.98, 124.27, 127.03, 127.44, 127.74,

127.90, 128.26, 128.34, 128.76, 128.92, 138.04, 138.70, 139.13,

140.99 ppm. MS (EI): m/z = 357 [M – CH₃+ H].

Data for 15d: Colourless oil. IR (film): ν = 2239 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 0.00 (s, 9 H), 1.3 (d, J = 6.4 Hz, 3 H), 3.90

(dq, J = 4.4, J = 6.4 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.60 (d,

J = 11.6 Hz, 1 H), 4.66 (d, J = 4.4 Hz, 1 H), 7.36–7.62 (complex

pattern, 10 H), 7.67 (m, 2 H), 7.80 (m, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 0.00, 17.10, 58.99, 70.87, 75.94, 81.50,

121.91, 127.14, 127.49, 127.79, 127.93, 128.57, 129.22, 131.52,

136.63, 137.59, 138.02, 144.75 ppm. MS (EI): m/z = 530 [M +

Na]⁺. C₂₇H₃₀BrNO₂Si (508.53): calcd. C 63.77, H 5.95, Br 15.71,

N 2.75, O 6.29, Si 5.52; found C 63.71, H 5.94.

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-phenyl-2-o-tolyl-3-(trimeth-

ylsilyloxy)pentanenitrile (15c and 16c): Following Method A above

for the preparation of 4a and 5a, starting from 2-phenyl-2-o-tolyl-

acetonitrile (2e; 207 mg, 1.0 mmol) and (S)-2-(benzyloxy)propanal

(3b; 180 mg, 1.1 mmol), flash chromatography (n-hexane/ether,

98:2) gave (2S,3S,4S)-4-(benzyloxy)-2-phenyl-2-o-tolyl-3-(trimeth-

ylsilyloxy)pentanenitrile (15c) and (2R,3S,4S)-4-(benzyloxy)-2-

phenyl-2-o-tolyl-3-(trimethylsilyloxy)pentanenitrile (16c) (239 mg,

total yield: 54%, ratio: 70:30). The stereochemical assignment of

the isomers was determined by X-ray analysis of the corresponding

acetonide (i.e., 18; Scheme 9).

Data for 16d: Colourless oil. IR (film): ν = 2239 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 0.01 (s, 9 H), 1.35 (d, J = 6.0 Hz, 3 H),

3.83 (dq, J = 4.4, J = 6.0 Hz, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.65

(d, J = 12.0 Hz, 1 H), 4.68 (d, J = 4.4 Hz, 1 H), 7.36–7.62 (complex

pattern, 12 H), 7.85 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 0.00, 16.79, 58.95, 70.52, 75.35, 81.01, 121.10, 127.12, 127.47,

127.49, 128.79, 127.93, 128.57, 129.22, 131.39, 136.63, 137.59,

138.02, 144.75 ppm. MS (EI): m/z = 530 [M + Na]⁺.

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-(4-methoxyphenyl)-2-

phenyl-3-(trimethylsilyloxy)pentanenitrile (15e and 16e): Following

Method A above for the preparation of 4a and 5a, starting from

2-(4-methoxyphenyl)-2-phenylacetonitrile (1g; 223 mg, 1.0 mmol)

and (S)-2-(benzyloxy)propanal (3b; 164 mg, 1.0 mmol), flash

chromatography (petroleum ether/ether, 9:1) gave (2S,3S,4S)-4-

(benzyloxy)-2-(4-methoxyphenyl)-2-phenyl-3-(trimethylsilyloxy)-

pentanenitrile (15e) and (2R,3S,4S)-4-(benzyloxy)-2-(4-methoxy-

phenyl)-2-phenyl-3-(trimethylsilyloxy)pentanenitrile (16e) (298 mg,

total yield: 65%, ratio: 50:50).

Scheme 9. Preparation of acetonide 18 from 15c. Reagents and con-

ditions: i) Pd/C (10%), MeOH, H₂; ii) PPTS, 2,2-dimethoxyprop-

ane, acetone, room temp.

Data for 15c: White solid; m.p. 61–62 °C. [α]²_D⁰= +96.90 (c = 1.0,

1

CHCl ). IR (film): ν = 2237 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= –0.03 (s, 9 H), 1.20 (d, J = 6.4 Hz, 3 H), 2.13 (s, 3 H), 3.75 (m,

1 H), 4.35 (d, J = 12.0 Hz, 1 H), 4.39 (d, J = 4.0 Hz, 1 H), 4.58 (d,

J = 12.0 Hz, 1 H), 7.14–7.39 (complex pattern, 12 H), 7.95 (m, 2

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 0.69, 18.78, 21.53,

55.68, 70.98, 75.33, 82.58, 121.06, 125.34, 127.18, 127.42, 127.63,

Data for 15e: White solid m.p. 65–68 °C. [α]²_D⁰= +15.89 (c = 8.75,

1

CHCl ). IR (film): ν = 2242 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= –0.01 (s, 9 H), 1.32 (d, J = 6.4 Hz, 3 H), 3.84 (dq, J = 6.4, J =

4.4 Hz, 1 H), 3.98 (s, 3 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.58 (d, J =

128.14, 128.26, 128.41, 128.73, 132.82, 135.68, 138.29, 138.43, 12.0 Hz, 1 H), 4.65 (d, J = 4.4 Hz, 1 H), 7.00 (d, J = 9.6 Hz, 2 H),

138.75 ppm. MS (EI): m/z = 443 [M]. For the preparation of the

corresponding acetonide (i.e., 18) and X-ray data, see Supporting

7.38–7.54 (m, 8 H), 7.60 (m, 2 H), 7.81 (m, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 0.17, 17.27, 55.29, 56.19, 71.00, 76.26,

Eur. J. Org. Chem. 2013, 5127–5142

www.eurjoc.org

5137

S. Long, M. Panunzio, W. Qin, A. Bongini, M. Monari

81.73, 113.79, 121.81, 127.62, 127.68, 128.07, 128.62, 129.55, H), 4.22 (d, J = 12.0 Hz, 1 H), 4.42 (d, J = 12.0 Hz, 1 H), 4.54 (d,

FULL PAPER

138.44, 139.24, 159.12 ppm. MS (EI): m/z = 459 [M]. C₂₈H₃₃NO₃Si

(459.66): calcd. C 73.16, H 7.24, N 3.05, O 10.44, Si 6.11; found C

73.45, H 7.27.

J = 4.0 Hz, 1 H), 7.12 (m, 2 H), 7.24 (m, 3 H), 7.35 (m, 5 H), 7.93

(d, J = 9.2 Hz, 2 H), 8.15 (d, J = 9.2 Hz, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 0.00, 17.06, 56.75, 70.90, 75.81, 81.89,

120.75, 123.13, 127.23, 127.48, 127.55, 127.88, 128.27, 128.84,

129.52, 137.54, 137.64, 144.67, 145.05 ppm. MS (EI): m/z = 475 [M

+ H]. C₂₇H₃₀N₂O₄Si (474.63): calcd. C 68.33, H 6.37, N 5.90, O

13.48, Si 5.92; found C 68.13, H 6.35.

Data for 16e: Colourless oil. [α]²_D⁰= +3.5 (c = 1.0, CHCl₃). IR

1

(film): ν = 2242 cm^–1. H NMR (400 MHz, CDCl ): δ = –0.17 (s,

˜

3

9 H), 1.13 (d, J = 6.4 Hz, 3 H), 3.70 (dq, J = 6.4, J = 4.0 Hz, 1

H), 3.79 (s, 3 H), 4.32 (d, J = 12.4 Hz, 1 H), 4.42 (d, J = 12.4 Hz,

1 H), 4.50 (d, J = 4.0 Hz, 1 H), 6.85 (d, J = 9.2 Hz, 2 H), 7.22–7.41

(complex pattern, 10 H), 7.65 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 0.19, 17.35, 55.30, 56.61, 71.00, 75.90, 81.35, 113.97,

121.60, 127.21, 127.71, 127.75, 128.00, 128.08, 128.54, 128.80,

130.63, 138.42, 138.52, 158.98 ppm. MS (EI): m/z = 459 [M].

C₂₈H₃₃NO₃Si (459.66): calcd. C 73.16, H 7.24, N 3.05, O 10.44, Si

6.11; found C 73.30, H 7.25.

Data for 16g: White solid, m.p. 130–133 °C. [α]²_D⁰= +18.47 (c =

1.1, CHCl ). IR (film): ν = 2242 cm^{–1 1}H NMR (400 MHz,

.

˜

3

CDCl₃): δ = –0.12 (s, 9 H), 1.26 (d, J = 6.4 Hz, 3 H), 3.66 (dq, J

= 6.4, J = 4.0 Hz, 1 H), 4.21 (d, J = 12.0 Hz, 1 H), 4.52 (d, J =

12.0 Hz, 1 H), 4.62 (d, J = 4.0 Hz, 1 H), 7.26 (m, 4 H), 7.42 (m, 4

H), 7.66 (d, J = 8.8 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2 H), 8.13 (d, J

= 8.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 0.15, 16.57,

57.11, 70.49, 75.46, 81.10, 120.68, 123.57, 127.46, 127.65, 127.74,

127.97, 128.13, 128.56, 128.84, 129.00, 136.69, 137.74, 145.64,

146.05 ppm. MS (EI): m/z = 475 [M + H]. C₂₇H₃₀N₂O₄Si (474.63):

calcd. C 68.33, H 6.37, N 5.90, O 13.48, Si 5.92; found C 68.58, H

6.39.

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-phenyl-2-[4-(trifluorometh-

yl)phenyl]-3-(trimethylsilyloxy)pentanenitrile (15f and 16f): Follow-

ing Method A above for the preparation of 4a and 5a, starting

from 2-phenyl-2-[4-(trifluoromethyl)phenyl]acetonitrile (1h;

261 mg, 1.0 mmol) and (S)-2-(benzyloxy)propanal (3b; 164 mg,

1.0 mmol), flash chromatography (petroleum ether/EtOAc, 14:1)

gave a mixture of (2S,3S,4S)-4-(benzyloxy)-2-phenyl-2-[4-(tri-

fluoromethyl)phenyl]-3-(trimethylsilyloxy)pentanenitrile (15f) and

(2R,3S,4S)-4-(benzyloxy)-2-phenyl-2-[4-(trifluoromethyl)phenyl]-3-

(trimethylsilyloxy)pentanenitrile (16f) (303 mg, total yield: 61%, ra-

tio: 40:60). No further efforts to isolate pure 15f from 16f were

made. The stereochemistry of 15f was assigned arbitrarily, and its

spectroscopic data were deduced as being the major set of signals

from the product mixture.

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-phenyl-2-(pyridin-3-yl)-3-

(trimethylsilyloxy)pentanenitrile (15h and 16h): Following Method

A above for the preparation of 4a and 5a, starting from 2-phenyl-

2-(pyridin-3-yl)acetonitrile (1j; 194 mg, 1.0 mmol) and (S)-2-(benz-

yloxy)propanal (3b; 164 mg, 1.0 mmol), flash chromatography (n-

hexane/ether, 3:2) gave (2S,3S,4S)-4-(benzyloxy)-2-phenyl-2-(pyr-

idin-3-yl)-3-(trimethylsilyloxy)pentanenitrile (15h) and (2R,3S,4S)-

4-(benzyloxy)-2-phenyl-2-(pyridin-3-yl)-3-(trimethylsilyloxy)pent-

anenitrile (16h) (288 mg, total yield: 67%, ratio: 65:35).

Data for 15f: IR (film): ν = 2239 cm^{–1 1}H NMR (400 MHz,

.

Data for 15h: Colourless oil. [α]²_D⁰= +18.40 (c = 1.0, CHCl₃). IR

˜

CDCl₃): δ = –0.10 (s, 9 H), 1.25 (d, J = 6.4 Hz, 3 H), 3.87 (dq, J

= 4.4, J = 6.4 Hz, 1 H), 4.36 (d, J = 11.6 Hz, 1 H), 4.52 (d, J =

11.6 Hz, 1 H), 4.63 (d, J = 4.4 Hz, 1 H), 7.25–7.53 (complex

pattern, 9 H), 7.66 (m, 3 H), 7.97 (d, J = 8.0 Hz, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 0.27, 17.44, 57.11, 70.75, 71.22,

76.24, 81.91, 121.26, 125.54, 125.70, 127.55, 127.85, 128.28, 128.37,

129.00, 129.07, 130.46, 137.30, 138.10, 138.23, 141.98 ppm. MS

(EI): m/z = 497 [M]. C₂₈H₃₀F₃NO₂Si (497.63): calcd. C 67.58, H

6.08, F 11.45, N 2.81, O 6.43, Si 5.64; found C 67.66, H 6.09.

1

(film): ν = 2240 cm^–1. H NMR (400 MHz, CDCl ): δ = –0.04 (s,

˜

3

9 H), 1.28 (d, J = 6.4 Hz, 3 H), 3.90 (dq, J = 6.4, J = 4.0 Hz, 1

H), 4.38 (d, J = 11.6 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 4.67 (d,

J = 4.0 Hz, 1 H), 7.31–7.58 (complex pattern, 11 H), 8.19 (m, 1

H), 8.67 (dd, J = 1.2, J = 4.4 Hz, 1 H), 9.13 (m, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 0.17, 17.27, 55.48, 71.04, 75.92,

81.58, 120.62, 1223.15, 127.31, 127.66, 128.11, 128.26, 128.96,

133.89, 136.28, 137.78, 138.08, 148.95, 149.42 ppm. MS (EI): m/z

= 430 [M]. C₂₆H₃₀N₂O₂Si (430.62): calcd. C 72.52, H 7.02, N 6.51,

O 7.43, Si 6.52; found C 72.72, H 7.04.

Data for 16f: IR (film): ν = 2239 cm^{–1 1}H NMR (400 MHz,

.

˜

CDCl₃): δ = –0.08 (s, 9 H), 1.29 (d, J = 6.4 Hz, 3 H), 3.74 (dq, J

= 4.0, J = 6.4 Hz, 1 H), 4.32 (d, J = 12.0 Hz, 1 H), 4.57 (d, J =

12.0 Hz, 1 H), 4.66 (d, J = 4.0 Hz, 1 H), 7.25–7.53 (complex

pattern, 9 H), 7.66 (m, 3 H), 7.79 (m, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 0.27, 16.97, 57.09, 70.75, 71.22, 75.62,

81.45, 121.12, 125.54, 125.70, 127.55, 127.85, 128.28, 128.37,

129.00, 129.07, 130.43, 137.30, 138.10, 138.23, 141.97 ppm. MS

(EI): m/z = 497 [M].

Data for 16h: White solid, m.p. 59–61 °C. [α]²_D⁰= +12.80 (c = 1.1,

1

CHCl ). IR (film): ν = 2242 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= –0.04 (s, 9 H), 1.33 (d, J = 6.0 Hz, 3 H), 3.78 (dq, J = 6.0, J =

4.4 Hz, 1 H), 4.35 (d, J = 11.6 Hz, 1 H), 4.59 (d, J = 11.6 Hz, 1

H), 4.68 (d, J = 4.4 Hz, 1 H), 7.31–7.58 (complex pattern, 11 H),

7.83 (d, J = 7.6 Hz, 2 H), 7.91 (m, 1 H), 8.63 (dd, J = 1.2, J =

4.8 Hz, 1 H), 8.85 (d, J = 2.0 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 0.09, 16.83, 55.41, 70.70, 75.75, 81.28, 120.66, 123.30,

127.36, 127.65, 128.10, 128.13, 128.33, 128.86, 134.76, 135.47,

136.64, 137.99, 148.77, 148.88 ppm. MS (EI): m/z = 430 [M].

C₂₆H₃₀N₂O₂Si (430.62): calcd. C 72.52, H 7.02, N 6.51, O 7.43, Si

6.52; found C 72.69, H 7.04.

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-(4-nitrophenyl)-2-phenyl-3-

(trimethylsilyloxy)pentanenitrile (15g and 16g): Following Method

A above for the preparation of 4a and 5a, starting from 2-(4-

nitrophenyl)-2-phenylacetonitrile (1i; 238 mg, 1.0 mmol) and (S)-2-

(benzyloxy)propanal (3b; 164 mg, 1.0 mmol), flash chromatog-

raphy (petroleum ether/EtOAc, 10:1) gave (2S,3S,4S)-4-(benz-

yloxy)-2-(4-nitrophenyl)-2-phenyl-3-(trimethylsilyloxy)pentane-

nitrile (15g) and (2R,3S,4S)-4-(benzyloxy)-2-(4-nitrophenyl)-2-

phenyl-3-(trimethylsilyloxy)pentanenitrile (16g) (270 mg, total

yield: 57%, ratio: 36:64).

(2S,3S,4S)/(2R,3S,4S)-4-(Benzyloxy)-2-(2-chlorophenyl)-2-phenyl-3-

(trimethylsilyloxy)pentanenitrile (15i and 16i): Following Method A

above for the preparation of 4a and 5a, starting from 2-(2-chloro-

phenyl)-2-phenylacetonitrile (1k; 227 mg, 1.0 mmol) and (S)-2-

(benzyloxy)propanal (3b; 164 mg, 1.0 mmol), flash chromatog-

raphy (n-hexane/toluene, 1:1) gave (2S,3S,4S)-4-(benzyloxy)-2-(2-

chlorophenyl)-2-phenyl-3-(trimethylsilyloxy)pentanenitrile (15i)

and (2R,3S,4S)-4-(benzyloxy)-2-(2-chlorophenyl)-2-phenyl-3-(tri-

methylsilyloxy)pentanenitrile (16i) (203 mg, total yield: 44%, ratio:

Data for 15g: Colourless oil. [α]²_D⁰= +26.08 (c = 1.3, CHCl₃). IR

1

(film): ν = 2243 cm^–1. H NMR (400 MHz, CDCl ): δ = –0.17 (s,

˜

3

9 H), 1.19 (d, J = 6.4 Hz, 3 H), 3.87 (dq, J = 6.4, J = 4.0 Hz, 1

5138

www.eurjoc.org

Eur. J. Org. Chem. 2013, 5127–5142

Synthesis of β,γ-Dihydroxy-Nitriles

80:20). The absolute configuration of isomer 15i was established by

X-ray analysis (see Supporting Information).

3-yl)-3-(trimethylsilyloxy)butanenitrile (16k) (197 mg, total yield:

40%, ratio: 80:20). The absolute configuration of the isomer 15k

was established by X-ray analysis (see Supporting Information).

Data for 15i: White solid m.p. 75–78 °C. [α]²_D⁰= +73.50 (c = 1.0,

Data for 15k: White solid, m.p. 104–107 °C. [α]²_D⁰= +3.1 (c = 1,

1

CHCl ). IR (film): ν = 2240 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

1

CHCl ). IR (film): ν = 2246 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

= –0.11 (s, 9 H), 1.21 (d, J = 6.4 Hz, 3 H), 3.92 (dq, J = 6.4, J =

3.2 Hz, 1 H), 4.33 (d, J = 11.6 Hz, 1 H), 4.40 (d, J = 3.2 Hz, 1 H),

4.55 (d, J = 11.6 Hz, 1 H), 7.20–7.36 (complex pattern, 13 H), 8.16

(m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 0.46, 18.95,

56.32, 71.20, 75.33, 82.67, 120.25, 126.05, 127.23, 127.52, 127.67,

128.11, 128.20, 128.27, 129.27, 131.46, 131.62, 134.89, 137.82,

138.46 ppm. MS (EI): m/z = 463 [M]. C₂₇H₃₀ClNO₂Si (464.08):

calcd. C 69.88, H 6.52, Cl 7.64, N 3.02, O 6.90, Si 6.05; found C

69.74, H 6.51.

3

= –0.47 (s, 9 H), –0.41 (s, 3 H), –0.27 (s, 3 H), 0.86 (s, 9 H), 4.71

(d, J = 2.4 Hz, 1 H), 5.13 (d, J = 2.4 Hz, 1 H), 7.23–7.45 (complex

pattern, 11 H), 8.05 (m, 1 H), 8.51 (dd, J = 1.6, J = 4.8 Hz, 1 H),

9.05 (d, J = 2.1 Hz, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

–4.89, –4.37, –0.32, 18.21, 26.15, 55.49, 75.69, 83.37, 120.14,

123.20, 127.61, 127.84, 127.96, 128.25, 128.98, 136.40, 138.48,

141.74, 148.57, 149.51 ppm. MS (ESI): m/z = 517 [M + H].

C₃₀H₄₀N₂O₂Si₂(516.83): calcd. C 69.72, H 7.80, N 5.42, O 6.19, Si

10.87; found C 69.80, H 7.81.

Data for 16i: Colourless oil. [α]²_D⁰= +46.90 (c = 1.8, CHCl₃). IR

Data for 16k: White solid, m.p. 88–90 °C. [α]²_D⁰= +18.3 (c = 1,

1

(film): ν = 2240 cm^–1. H NMR (400 MHz, CDCl ): δ = –0.04 (s,

˜

3

1

CHCl ). IR (film): ν = 2246 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

9 H), 1.21 (d, J = 6.4 Hz, 3 H), 3.58 (dq, J = 6.4, J = 4.0 Hz, 1

H), 4.14 (d, J = 11.6 Hz, 1 H), 4.42 (d, J = 11.6 Hz, 1 H), 5.10 (d,

J = 4.0 Hz, 1 H), 7.14–7.38 (complex pattern, 11 H), 7.54 (m, 1

H), 7.64 (d, J = 6.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 0.45, 16.99, 56.38, 70.79, 76.53, 78.51, 120.63, 126.64, 127.18,

127.38, 128.00, 128.08, 128.30, 129.07, 129.28, 131.77, 131.93,

133.31, 135.90, 136.79, 138.46 ppm. MS (EI): m/z = 463 [M].

C₂₇H₃₀ClNO₂Si (464.08): calcd. C 69.88, H 6.52, Cl 7.64, N 3.02,

O 6.90, Si 6.05; found C 70.00, H 6.53.

3

= –0.39 (s, 3 H), –0.38 (s, 9 H), –0.27 (s, 3 H), 0.87 (s, 9 H), 4.77

(d, J = 2.8 Hz, 1 H), 5.08 (d, J = 2.8 Hz, 1 H), 7.21–7.41 (m, 11

H), 7.67 (m, 2 H), 7.96 (m, 1 H), 8.52 (m, 1 H), 8.79 (s, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = –4.69, –4.17, –0.18, 18.30, 26.20,

58.02, 76.24, 82.33, 119.80, 124.02, 127.76, 127.81, 128.07, 128.25,

128.45, 128.77, 129.13, 136.20, 137.82, 141.16, 148.72, 149.50 ppm.

MS (ESI): m/z = 517 [M + 1]. C₃₀H₄₀N₂O₂Si₂(516.83): calcd. C

69.72, H 7.80, N 5.42, O 6.19, Si 10.87; found C 69.51, H 7.77.

(3S,4S)-3,4-Dihydroxy-2,2-diphenylpentanenitrile (6a)

(2S,3S,4S)/(2R,3S,4S)-4-(tert-butyldimethylsilyloxy)-2,4-diphenyl-2-

m-tolyl-3-(trimethylsilyloxy)butanenitrile (15j and 16j): Following

Method A above for the preparation of 4a and 5a, starting from 2-

phenyl-2-m-tolylacetonitrile (1d; 207 mg, 1.0 mmol) and (S)-2-(tert-

butyldimethylsilyloxy)-2-phenylacetaldehyde (3g; 250 mg,

1.0 mmol), flash chromatography (cyclohexane/ether, 99:1) gave a

mixture of (2S,3S,4S)-4-(tert-butyldimethylsilyloxy)-2,4-diphenyl-

2-m-tolyl-3-(trimethylsilyloxy)butanenitrile (15j) and (2R,3S,4S)-4-

(tert-butyldimethylsilyloxy)-2,4-diphenyl-2-m-tolyl-3-(trimethyl-

silyloxy)butanenitrile (16j) (429 mg, total yield: 85%, ratio: 50:50).

Method 1, from 4a: HCl (1 m; 1 mL) was added to a solution of

(3S,4S)-4-(tert-butyldimethylsilyloxy)-2,2-diphenyl-3-(trimethyl-

silyloxy)pentanenitrile (4a; 180 mg, 0.4 mmol) in acetonitrile

(6 mL). The reaction mixture was kept at room temperature for

30 min. Then the solvent was removed under vacuum to give pure

6a (110 mg, 95%) as a colourless oil. [α]²_D⁰= +78.45 (c = 1.1,

1

CHCl ). IR (film): ν = 2239 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= 1.22 (d, J = 6.4 Hz, 3 H), 1.92 (br. s, 1 H, OH), 3.37 (br. s, 1 H,

OH), 4.00 (dq, J = 6.4, J = 1.2 Hz, 1 H), 4.39 (d, J = 1.2 Hz, 1

H), 7.31–7.45 (m, 8 H), 7.56 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CD₃OD): δ = 21.65, 58.36, 67.61, 77.68, 122.89, 128.59, 128.91,

129.11, 129.21, 129.84, 130.12, 140.77, 141.77 ppm. MS (ESI): m/z

= 290 [M + Na]⁺. C₁₇H₁₇NO₂(267.33): calcd. C 76.38, H 6.41, N

5.24, O 11.97; found C 76.50, H 6.42.

Data for 15j: IR (film): ν = 2245 cm^{–1 1}H NMR (400 MHz,

.

˜

CD₃OD): δ = –0.59 (s, 9 H), –0.55 (s, 3 H), –0.38 (s, 3 H), 0.06 (s,

9 H), 2.32 (s, 3 H), 4.95 (d, J = 2.0 Hz, 1 H), 5.16 (d, J = 2.0 Hz,

1 H), 7.06 (d, J = 11.6 Hz, 1 H), 7.20–7.45 (complex pattern, 9 H),

7.53 (m, 2 H), 7.74 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = –4.85, –4.28, –0.36, 18.16, 21.44, 26.90, 57.68, 74.85, 82.46,

120.62, 124.44, 127.62, 127.68, 127.74, 128.33, 128.49, 128.61,

128.79, 138.29, 138.85, 138.97, 142.74 ppm. MS (EI): m/z = 529

[M]. C₃₂H₄₃NO₂Si₂(529.87): calcd. C 72.54, H 8.18, N 2.64, O

6.04, Si 10.60; found C 72.74, H 8.20.

Method 2, from 4b: (3S,4S)-4-(Benzyloxy)-2,2-diphenyl-3-(trimeth-

ylsilyloxy)pentanenitrile (4b; 90 mg, 0.21 mmol), Pd/C (10%;

90 mg), and Pd(OAc)₂(40 mg) were mixed in anhydrous MeOH

(20 mL). The reaction mixture was kept under H₂(50 psi) for 1 h.

Then the reaction mixture was filtered, and the solvent was re-

moved. The crude residue was directly mixed with acetonitrile

(2 mL) and HCl (1 n aq.; 1 mL). The reaction mixture was kept at

room temperature for 30 min. Then the solvent was removed under

vacuum to give a colourless oil, which gave spectroscopic data su-

perimposable with those of authentic 6a obtained as described

above.

Data for 16j: IR (film): ν = 2245 cm^{–1 1}H NMR (400 MHz,

.

˜

CD₃OD): δ = –0.59 (s, 9 H), –0.54 (s, 3 H), –0.38 (s, 3 H), 0.06 (s,

9 H), 2.36 (s, 3 H), 4.93 (d, J = 2.0 Hz, 1 H), 5.15 (d, J = 2.0 Hz,

1 H), 7.13 (d, J = 11.6 Hz, 1 H), 7.20–7.45 (complex pattern, 9 H),

7.53 (m, 2 H), 7.74 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = –4.94, –4.27, –0.35, 18.25, 21.53, 26.23, 57.77, 74.95, 82.60,

120.68, 124.56, 127.66, 127.71, 127.86, 128.42, 128.56, 128.67,

138.54, 138.85, 138.97, 142.74 ppm. MS (EI): m/z = 529 [M].

Method 3, from 4c or 4d: HCl (1 m; 1 mL) was added to a solution

of 4c (198 mg, 0.4 mmol) in acetonitrile (6 mL). The reaction mix-

ture was kept at room temperature for 30 min. Then the solvent

was removed under vacuum to give pure 6a (101 mg, 87%) as a

colourless oil. Starting from 4d (230 mg, 0.4 mmol), following the

same procedure, compound 6a (95 mg, 82%) was obtained.

(2S,3S,4S)/(2R,3S,4S)-4-(tert-Butyldimethylsilyloxy)-2,4-diphenyl-

2-(pyridin-3-yl)-3-(trimethylsilyloxy)butanenitrile (15k and 16k):

Following Method A above for the preparation of 4a and 5a, start-

ing from 2-phenyl-2-(pyridin-3-yl)acetonitrile (1j; 194 mg,

1.0 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-2-phenylacetalde-

hyde (3g; 250 mg, 1.0 mmol), flash chromatography (CH₂Cl₂/ether,

99:1) gave (2S,3S,4S)-4-(tert-butyldimethylsilyloxy)-2,4-diphenyl-2-

(3R,4S)-3,4-Dihydroxy-2,2-diphenylpentanenitrile (6b): Starting

from

(3R,4S)-4-(tert-butyldimethylsilyloxy)-2,2-diphenyl-3-(tri-

methylsilyloxy)pentanenitrile (5a; 30 mg, 0.07 mmol), following the

procedure used to prepare 6a (Method 1, above), compound 6b

(pyridin-3-yl)-3-(trimethylsilyloxy)butanenitrile

(15k)

and

(2R,3S,4S)-4-(tert-butyldimethylsilyloxy)-2,4-diphenyl-2-(pyridin- was obtained (16 mg, 89%) as a colourless oil. [α]²_D⁰= –69.60 (c =

Eur. J. Org. Chem. 2013, 5127–5142

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5139

S. Long, M. Panunzio, W. Qin, A. Bongini, M. Monari

1.0, CHCl ). IR (film): ν = 2243 cm^–1. ¹H NMR (400 MHz, (3S,4S)-3,4-Dihydroxy-5-methyl-2,2-diphenylhexanenitrile (9): Fol-

FULL PAPER

˜

3

CDCl₃): δ = 1.35 (d, J = 6.4 Hz, 3 H), 1.69 (br. s, 1 H, OH), 2.50

(br. s, 1 H, OH), 3.77 (dq, J = 4.0, J = 6.4 Hz, 1 H), 4.69 (d, J =

4.0 Hz, 1 H), 7.30–7.46 (complex pattern, 8 H), 7.60 (m, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 17.94, 55.83, 68.32, 77.58,

120.61, 127.07, 127.61, 128.27, 128.31, 129.05, 129.19, 137.36,

138.24 ppm. MS (ESI): m/z = 290 [M + Na]⁺. C₁₇H₁₇NO₂(267.33):

calcd. C 76.38, H 6.41, N 5.24, O 11.97; found C 76.48, H 6.42.

lowing the procedure used to prepare 6a, starting from (3S,4S)-3-

hydroxy-5-methyl-2,2-diphenyl-4-(trimethylsilyloxy)hexanenitrile

(8; 45 mg, mmol), (3S,4S)-3,4-dihydroxy-5-methyl-2,2-diphenylhex-

anenitrile (9) was obtained (28 mg, 72%) as a colourless oil. [α]²_D⁰

1

= +78.3 (c = 1.0, CHCl ). IR (film): ν = 3400 (b), 2240 cm^–1. H

˜

3

NMR (CD₃OD, 400 MHz): δ = 0.80 (d, J = 6.4 Hz, 3 H), 0.85 (d,

J = 6.4 Hz, 3 H), 1.72 (octet, J = 6.4 Hz, 1 H), 3.00 (dd, J = 6.4,

J = 0.2 Hz, 1 H), 4.65 (d, J = 0.2 Hz, 1 H), 7.28 (m, 2 H), 7.35 (m,

4 H), 7.44 (m, 2 H), 7.59 (m, 2 H) ppm. ¹³C NMR (CD₃OD,

100 MHz): δ = 18.78, 19.35, 33.07, 58.55, 74.11, 75.57, 122.67,

128.33, 128.67, 129.03, 129.65, 129.96, 140.12, 140.53 ppm. MS

(ESI): m/z = 318 [M + Na]⁺. C₁₉H₂₁NO₂(295.38): calcd. C 77.26,

H 7.17, N 4.74; found C 77.57, H 7.20.

2,2-Diphenyl-2-[(4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl]aceto-

nitrile (7a): (3S,4S)-3,4-Dihydroxy-2,2-diphenylpentanenitrile (6a;

117 mg, 0.44 mmol), PPTS (220 mg, 0.88 mmol), and 2,2-dimeth-

oxypropane (1.0 mL) were mixed in anhydrous acetone (5 mL). The

reaction mixture was stirred at room temp. overnight, then it was

quenched with NH₄Cl (saturated aq.) and extracted with EtOAc

(3ϫ 15 mL). The organic phase was dried with Na₂SO₄and con-

centrated under vacuum. The residue was purified by flash

chromatography (cyclohexane/ether, 4:1) to give 7a (86 mg, 63%)

2-[(4S,5S)-5-Isopropyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-diphenyl-

acetonitrile (10): Following the procedure used to prepare 7a, start-

ing from (3S,4S)-3,4-dihydroxy-5-methyl-2,2-diphenylhexanenitrile

(9; 10 mg, 0.07 mmol), 2-[(4S,5S)-5-isopropyl-2,2-dimethyl-1,3-di-

oxolan-4-yl]-2,2-diphenylacetonitrile (10) was obtained (10 mg,

90%) as a white solid, m.p. 172–174 °C. [α]²_D⁰= +94.8 (c = 1.0,

as a white solid, m.p. 120–122 °C. [α]²_D⁰= +3.30 (c = 1.0, CHCl₃).

1

IR (KBr): ν = 2247 cm^–1. H NMR (400 MHz, CDCl ): δ = 0.57

˜

3

(d, J = 6.0 Hz, 3 H), 1.49 (s, 3 H), 1.52 (s, 3 H), 4.20 (dq, J = 6.0,

J = 8.4 Hz, 1 H), 4.41 (d, J = 8.4 Hz, 1 H), 7.30–7.41 (complex

pattern, 8 H), 7.53 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 18.47, 26.73, 27.83, 55.56, 74.93, 83.71, 109.18, 120.29, 127.25,

128.13, 128.25, 128.76, 129.00, 137.03, 138.92 ppm. MS: m/z = 330

[M + Na]⁺. C₂₀H₂₁NO₂(307.39): calcd. C 78.15, H 6.89, N 4.56;

found C 78.29, H 6.90.

1

CHCl ). IR (film): ν = 2247 cm^–1. H NMR (400 MHz, CDCl ): δ

˜

3

= 0.37 (m, 1 H), 0.69 (d, J = 6.8 Hz, 3 H), 0.73 (d, J = 6.8 Hz, 3

H), 1.47 (s, 3 H), 1.48 (s, 3 H), 4.02 (dd, J = 2.8, J = 8.0 Hz, 1 H),

4.59 (d, J = 8.0 Hz, 1 H), 7.28–7.41 (m, 8 H), 7.55 (m, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 14.68, 20.58, 27.23, 27.83, 28.45,

56.28, 79.36, 83.07, 109.64, 120.62, 127.18, 128.04, 128.39, 129.48,

128.71, 128.89, 137.24, 139.15 ppm. MS (ESI): m/z = 336 [M + 1].

C₂₂H₂₅NO₂(335.45): calcd. C 78.77, H 7.51, N 4.18, O 9.54; found

C 79.05, H 7.54.

2,2-Diphenyl-2-[(4R,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl]aceto-

nitrile (7b): (3R,4S)-3,4-dihydroxy-2,2-diphenylpentanenitrile (6b;

41 mg, 0.15 mmol), PPTS (75 mg, 0.30 mmol), and 2,2-dimeth-

oxypropane (0.6 mL) were mixed in anhydrous acetone (5 mL). The

reaction mixture was processed as for 7a. The crude product was

purified by flash chromatography (cyclohexane/ether, 4:1) to give

(3S,4S)-3,4-Dihydroxy-2,2,4-triphenylbutanenitrile (11): Following

the procedure used to prepare 6a, starting from (3S,4S)-4-(tert-but-

yldimethylsilyloxy)-2,2,4-triphenyl-3-(trimethylsilyloxy)butane-

nitrile (4g; 100 mg, 0.35 mmol), (3S,4S)-3,4-dihydroxy-2,2,4-tri-

phenylbutanenitrile (11) was obtained (62 mg, 97%) as a colourless

7b (35 mg, 74%) as a white solid, m.p. 107–110 °C. [α]²_D⁰= +99.4

1

(c = 1.0, CHCl ). IR (KBr): ν = 2247 cm^–1. H NMR (400 MHz,

˜

3

oil. [α]²_D⁰= +66.73 (c = 1.1, CHCl ). IR (film): ν = 3420 (b),

˜

3

CDCl₃): δ = 1.17 (d, J = 6.4 Hz, 3 H), 1.43 (s, 3 H), 1.64 (s, 3 H),

4.38 (quintet, J = 6.4 Hz, 1 H), 5.07 (d, J = 6.4 Hz, 1 H), 7.25–

7.40 (complex pattern, 6 H), 7.56 (m, 4 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 16.75, 25.63, 27.77, 53.37, 74.39, 80.28,

108.75, 120.96, 127.23, 127.51, 127.98, 128.42, 128.81, 129.27,

137.45, 140.35 ppm. MS: m/z = 330 [M + Na]⁺. C₂₀H₂₁NO₂

(307.39): calcd. C 78.15, H 6.89, N 4.56, O 10.41; found C 78.26,

H 6.90.

2239 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.63 (br. s, OH), 3.50

(br. m, OH), 4.55 (d, J = 8.0 Hz, 1 H), 4.65 (br. s, 1 H), 7.04–7.45

(complex pattern, 15 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

57.18, 71.23, 77.60, 121.06, 125.73, 127.36, 127.85, 128.03, 128.30,

128.57, 128.86, 129.20, 138.05, 138.38, 141.65 ppm. MS (ESI): m/z

= 352 [M + Na]⁺. C₂₂H₁₉NO₂(329.40): calcd. C 80.22, H 5.81, N

4.25, O 9.71; found C 80.52, H 5.83.

2-[(4S,5S)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-2,2-diphenyl-

acetonitrile (12): Following the procedure used to prepare 7a, start-

ing from (3S,4S)-3,4-dihydroxy-2,2,4-triphenylbutanenitrile (11;

55 mg, 0.17 mmol), 2-[(4S,5S)-2,2-dimethyl-5-phenyl-1,3-dioxolan-

4-yl]-2,2-diphenylacetonitrile (12) was obtained (54 mg, 86%) as a

white solid, m.p. 218–220 °C. [α]²_D⁰= +52.30 (c = 1.0, CHCl₃). IR

(3S,4S)-3-Hydroxy-5-methyl-2,2-diphenyl-4-(trimethylsilyloxy)hex-

anenitrile (8): (3S,4S)-4-(Benzyloxy)-5-methyl-2,2-diphenyl-3-(tri-

methylsilyloxy)hexanenitrile 4e (130 mg), Pd/C (10%; 130 mg), and

Pd(OAc)₂(75 mg) were mixed in MeOH (15 mL). The reaction

mixture was kept under H₂(50 psi) for 4 h. Then the reaction mix-

ture was filtered and the solvent was removed. The residue was

purified by flash chromatography (n-hexane/ether, 10:1) to give

(3S,4S)-3-hydroxy-5-methyl-2,2-diphenyl-4-(trimethylsilyloxy)hex-

anenitrile (8; 65 mg, 63%). During the reaction a 1,4 OǞO mi-

(film): ν = 2238 cm^–1. ¹H NMR (400 MHz, C₆D₆): δ = 1.51 (s, 3

˜

H), 1.65 (s, 3 H), 4.89 (d, J = 8.0 Hz, 1 H), 5.21 (d, J = 8.0 Hz, 1

H), 6.64–7.12 (complex pattern 13 H), 7.56 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 27.00, 27.95, 55.76, 81.47, 84.44,

110.42, 120.21, 127.10, 127.35, 127.76, 127.86, 128.02, 128.06,

128.19, 128.46, 128.76, 135.94, 136.83, 139.19 ppm. MS (ESI): m/z

= 369 [M]. C₂₅H₂₃NO₂(369.46): calcd. C 81.27, H 6.27, N 3.79, O

8.66; found C 81.41, H 6.28.

gration, involving the TMS group, occurred. Colourless oil. [α]²_D⁰

=

1

+68.2 (c = 1.0, CHCl ). IR (film): ν = 3452, 2239 cm^–1. H NMR

˜

3

(400 MHz, CDCl₃): δ = 0.17 (s, 9 H), 0.63 (d, J = 6.4 Hz, 3 H),

0.90 (d, J = 6.8 Hz, 3 H), 1.57 (m, 1 H), 3.73 (dd, J = 1.2, J =

7.6 Hz, 1 H), 4.09 (d, J = 8.0 Hz, OH), 4.46 (dd, J = 1.2, J =

8.0 Hz, 1 H), 7.27–7.44 (m, 8 H), 7.62 (m, 2 H) ppm. ¹³C NMR (3S*,4S*)-3-Hydroxy-5,5-dimethyl-2,2-diphenyl-4-(trimethylsilyl-

(100 MHz, CDCl₃): δ = 0.46, 16.47, 17.44, 33.90, 57.82, 71.14,

oxy)hexanenitrile (13): (3S*,4S*)-4-(Benzyloxy)-5,5-dimethyl-2,2-

73.41, 120.89, 127.52, 127.57, 127.74, 127.97, 128.29, 128.58, diphenyl-3-(trimethylsilyloxy)hexanenitrile (4f; 120 mg,

128.83, 135.73, 135.88, 138.40, 139.12 ppm. MS (ESI): m/z = 368

[M + 1]. C₂₂H₂₉NO₂Si (367.56): calcd. C 71.89, H 7.95, N 3.81, Si

7.64; found C 72.16, H 7.98.

0.25 mmol), Pd/C (10 %; 120 mg), and Pd(OAc)₂(35 mg) were

mixed in anhydrous MeOH (20 mL). The reaction mixture was kept

under H₂(50 psi) for 1 h. After the reaction was complete, the mix-

5140

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Eur. J. Org. Chem. 2013, 5127–5142

Synthesis of β,γ-Dihydroxy-Nitriles

ture was filtered, and the filtrate was concentrated under vacuum.

Flash chromatography (cyclohexane/ether, 4:1) gave (3S*,4S*)-3-

hydroxy-5,5-dimethyl-2,2-diphenyl-4-(trimethylsilyloxy)hexaneni-

137.95 ppm. MS (EI): m/z = 321 [M]. C₂₁H₂₃NO₂(321.42): calcd.

C 78.47, H 7.21, N 4.36, O 9.96; found C 78.49, H 7.21.

Supporting Information (see footnote on the first page of this arti-

cle): Crystal data, structure refinement for 15e, 15i and 15k, 16g,

16h monohydroxide and 18; energy and Cartesian coordinates of

the transition state (TS) of Figure 1; NMR spectra.

trile (13; 95 mg, 98%) as a colourless oil. IR (film): ν = 3445,

˜

2239 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.27 (s, 9 H), 0.65 (s,

9 H), 3.57 (d, J = 1.2 Hz, 1 H), 4.25 (d, J = 7.6 Hz, 1 H, OH), 4.53

(dd, J = 1.2, J = 7.6 Hz, 1 H), 7.23–7.40 (complex pattern, 8 H),

7.62 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 1.21, 25.84,

35.50, 58.04, 70.79, 77.20, 121.49, 127.77, 128.00, 128.07, 128.56,

128.64, 128.71, 138.26, 138.45 ppm. MS (ESI): m/z = 382 [M + 1].

C₂₃H₃₁NO₂Si (381.59): calcd. C 72.39, H 8.19, N 3.67, O 8.39, Si

7.36; found C 72.63, H 8.22.

Acknowledgments

S. L. and W. L. Q. thank the China Scholarship Council (CSC) for

Scholarships (2009–2012 and 2010–2013, respectively). M. M.

wishes to thank the University of Bologna for financial support.

(3S*,4S*)-3,4-Dihydroxy-5,5-dimethyl-2,2-diphenylhexanenitrile

(14): (3S*,4S*)-3-Hydroxy-5,5-dimethyl-2,2-diphenyl-4-(trimethyl-

silyloxy)hexanenitrile (13; 107 mg, 0.28 mmol) was mixed with

acetone (2 mL) and PPTS (104 mg, 0.56 mmol). The reaction mix-

ture was kept at room temp. for 24 h. Then it was filtered, and the

filtrate was concentrated under vacuum. The residue was purified

by LiChroprep^®RP-18 (40–63 μm) chromatography (MeOH/H₂O,

70:30) to give pure (3S*,4S*)-3,4-dihydroxy-5,5-dimethyl-2,2-di-

phenylhexanenitrile (14; 82 mg, 95%) as a white solid, m.p. 63–

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65 °C. IR (film): ν = 3440 (b), 2242 cm^–1. ¹H NMR (400 MHz,

˜

CDCl₃): δ = 0.82 (s, 9 H), 1.99 (d, J = 5.2 Hz, 1 H, OH), 3.50 (d,

J = 5.2 Hz, 1 H), 3.85 (d, J = 8.4 Hz, 1 H, OH), 4.70 (d, J = 8.4 Hz,

1 H), 7.28–7.48 (complex pattern, 8 H), 7.60 (d, J = 7.6 Hz, 2 H)

1

ppm. H NMR (400 MHz, CDCl₃/D₂O): δ = 0.82 (s, 9 H), 3.50 (s,

1 H), 4.70 (s, 1 H), 7.28–7.48 (complex pattern, 8 H), 7.60 (d, J =

7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 25.84, 35.01,

58.08, 71.28, 75.27, 121.84, 127.86, 128.18, 128.23, 128.91, 129.04,

138.10, 138.17 ppm. MS (ESI): m/z = 310 [M + 1]. C₂₀H₂₃NO₂

(309.41): calcd. C 77.64, H 7.49, N 4.53, O 10.34; found C 77.89,

H 7.49.

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(2S,3S,4S)-3,4-Dihydroxy-2-phenyl-2-o-tolylpentanenitrile

(17):

(2S,3S,4S)-4-(Benzyloxy)-2-phenyl-2-o-tolyl-3-(trimethylsilyloxy)-

pentanenitrile (15c; 120 mg, 0.27 mmol) and Pd/C (10%; 120 mg)

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was kept under H₂(50 psi) overnight. Then the reaction mixture

was filtered and concentrated. The residue was purified by flash

chromatography (cyclohexane/ether, 3:2) to give pure compound 17

(45 mg, 59%) as a colourless oil. [α]²_D⁰= +126.18 (c = 1.1, CHCl₃).

1

IR (film): ν = 3444 (b), 2241 cm^–1. H NMR (400 MHz, CDCl ):

˜

3

δ = 1.10 (d, J = 6.8 Hz, 3 H), 2.07 (s, 3 H), 2.13 (d, J = 4.8 Hz, 1

H, OH), 3.69 (d, J = 8.4 Hz, 1 H, OH), 3.76 (m, 1 H), 4.27 (dd, J

= 1.2, J = 8.4 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.25–7.37 (com-

plex pattern, 7 H), 7.80 (d, J = 8.0 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 21.07, 21.68, 55.53, 65.18, 76.68, 120.25,

126.06, 127.05, 128.06, 128.42, 129.03, 133.09, 136.05, 136.99,

138.36 ppm. MS (ESI): m/z = 281 [M]. C₁₈H₁₉NO₂(281.35): calcd.

C 76.84, H 6.81, N 4.98, O 11.37; found C 76.85, H 6.81.

(S)-2-Phenyl-2-o-tolyl-2-[(4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-

acetonitrile (18): Following the procedure used to prepare 7a, start-

ing from (2S,3S,4S)-3,4-dihydroxy-2-phenyl-2-o-tolylpentanenitrile

(17; 23 mg, 0.08 mmol), PPTS (41 mg, 0.16 mmol), and 2,2-dimeth-

oxypropane (1 mL), compound 18 (24 mg, 92%) was obtained as

a white solid. m.p. 95–97 °C. [α]²_D⁰= +126.94 (c = 1.6, CHCl₃). IR

1

(film): ν = 2239 cm^–1. H NMR (400 MHz, CDCl ): δ = 0.34 (d, J

˜

3

= 5.2 Hz, 3 H), 1.54 (s, 3 H), 1.57 (s, 3 H), 2.07 (s, 3 H), 4.27 (dq,

J = 5.2, J = 8.0 Hz, 1 H), 4.34 (d, J = 8.0 Hz, 1 H), 7.13 (d, J =

7.2 Hz, 1 H), 7.26–7.37 (complex pattern, 7 H), 7.82 (dd, J = 7.6,

J = 0.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.41,

20.89, 26.85, 27.94, 54.46, 74.78, 84.73, 109.24, 119.01, 126.12,

127.13, 127.63, 128.40, 128.52, 129.00, 132.76, 135.78, 136.17,

Eur. J. Org. Chem. 2013, 5127–5142

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5141

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Received: March 22, 2013

Published Online: July 4, 2013

5142

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Eur. J. Org. Chem. 2013, 5127–5142

Article Doi

Efficient aldol-type reaction of o-protected α-Hydroxy Aldehydes and N-Trimethylsilyl ketene imines: Synthesis of β,γ-Dihydroxy-Nitriles

DOI: 10.1002/ejoc.201300430

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Full text of DOI:10.1002/ejoc.201300430

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