Metalated Nitriles: Internal 1,3-asymmetric induction

Article abstract of DOI:10.1002/ejoc.200801053

Stereoselective alkylations of acyclic, metalated nitrites are intimately controlled by a remote stereocenter. Probing the optimal steric demand through alkylations with a series of substituted pentanenitriles reveal the fundamental requirements for 1,3-a

Full text of DOI:10.1002/ejoc.200801053

FULL PAPER
DOI: 10.1002/ejoc.200801053
Metalated Nitriles: Internal 1,3-Asymmetric Induction
Fraser F. Fleming*[a] and Wang Liu[a]
Keywords: Nitrile / Conformation analysis / Alkylation / Diastereoselectivity
Stereoselective alkylations of acyclic, metalated nitriles are
intimately controlled by a remote stereocenter. Probing the
optimal steric demand through alkylations with a series of
substituted pentanenitriles reveal the fundamental require-
ments for 1,3-asymmetric induction. Relaying these require-
ments into a predictive model suggests that the stereoselecti-
vity arises from a preferential electrophilic attack on the
more stable diamond lattice conformation of the metalated
nitrile. Using this strategy a series of metalated alkanenitriles
selectively intercept a diverse range of electrophiles in alky-
lations that efficiently install new quaternary centers. The
metalated nitrile alkylations provide fundamental insight for
remote stereoinduction and a solid foundation for further ad-
vances in stereoselective alkylations of flexible nucleophiles
having a defined shape.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
1.Introduction
Conformational control is a central prerequisite for stereo-
selective asymmetric synthesis.[1] A time-proven stereocon-
trol strategy, whose origin is often equated with the begin-
ning of stereoselective synthesis,[2] is to employ conforma-
tionally constrained cyclic enolates that bias electrophile
trajectories.[3] Underpinning stereoselective transformations
within carbocycles is the ability to accurately predict the
reactive conformation, a concept whose seminal importance
was recognized in the 1969 Nobel Prize for “The Principles
of Conformational Analysis.”[4]
Figure 1. Conformational analogies between cyclic and acyclic al-
kanes.
Seminal advances in acyclic conformational analysis re-
veal how substituents on flexible hydrocarbon chains can
favor surprisingly few well-defined conformations.[7] For ex-
The conformational bias in six-membered rings usually ample, the syn-2,4-dimethylpentane motif, 3 (Figure 2), has
rests on a preference for avoiding steric compression. 1,3- facile rotation around the two core bonds but exhibits a
Diaxial interactions,[5] the steric compression between two strong substituent-dependent preference for one of two con-
axial substituents on a cyclohexane ring, is essentially the formations 3Ј or 3ЈЈЈ to avoid conformations with syn-pen-
cyclic equivalent of the destabilizing syn-pentane interac- tane interactions (3ЈЈ or 3ЈЈЈЈ).[8] The preference for con-
tion encountered in linear hydrocarbons (Figure 1, compare former 3Ј or 3ЈЈЈ depends on the relative steric demand of
1 and 2). The centrality of the syn-pentane interaction is the substituents R1, R2, and Me. Although a precise mea-
readily appreciated by imposing the carbon backbone of sure of the interactions between these substituents and the
pentane onto a diamond lattice, a carbon scaffold in which syn-axial-like methine proton (see symbols in Figure 2) is
the dihedral angles around carbon–carbon bonds are as- compromised by the facile relaxation of substituents away
sumed to approximate the ideal found in diamond. Overlay- from a perfect diamond lattice conformation, the steric in-
ing conformationally mobile chains onto a diamond lattice teractions approximate the corresponding A values deter-
provides a valuable concept for readily identifying the low- mined for substituted cyclohexanes (Figure 1).[9]
energy conformations of acyclic chains without recourse to
Numerous natural products incorporate the 2,4-dimeth-
ylpentane structural motif leading to one favored solution
conformation.[7b] For example, in solution the nitrile-con-
taining natural product calyculin C (4)[10] adopts conforma-
tion 4Ј in the C29–C32 segment (Figure 3, inset) which min-
imizes the potential syn-pentane interactions.[11]
Internal asymmetric induction in alkylations with acyclic
nucleophiles is a significant challenge. The challenge for
metalated nitrile alkylations lies in taming the flexibility in-
computational methods.[6]
[a] Department of Chemistry and Biochemistry,
Mellon Hall, Duquesne University, Pittsburgh PA 15282-1530,
USA
Fax: +1-412-396-5683
E-mail: flemingf@duq.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Figure 2. Acyclic conformational preferences in substituted 2,4-di-
alkylpentanes.
Figure 4. Conformational minima with (1-naphthyl) substituents.
naphthalene ring in a “methine-eclipsed” conformation,
then any reagent approach to the nitrile should occur oppo-
site the naphthalene ring. If the conformational integrity is
maintained on deprotonation then any electrophilic ap-
proach to the metalated nitrile should experience significant
stereodiscrimination.
2. Results and Discussion
2.1 First Generation
Facile and efficient access to the naphthyl-substituted ni-
trile 5 provided a valuable prototype for probing the asym-
metric 1,3-induction strategy. Successive methylation and
reduction of commercial ethyl 1-naphthylacetate (7) af-
forded alcohol 8 that was efficiently iodinated to provide 9
(Scheme 1). Despite the potential for dehydrohalogenation,
alkylating 9 with lithiated propionitrile occurred smoothly
to provide the requisite nitrile 5 as a mixture of dia-
stereomers.
Figure 3. Structure and conformation of calyculin C.
herent in the intervening single bonds while concurrently
propagating high asymmetry along the carbon chain. Pen-
tanenitrile 5a, bearing 2-methyl and 4-(1-naphthyl) substit-
uents (Figure 4), appeared to fulfill the requirements be-
cause of a projected preference for a single diamond-lattice
conformation.[12] Extensive conformational analyses of ibu-
profen analogs,[13] such as 6, demonstrate that the 1-naph-
thyl substituent prefers a conformation[14] with the methine
proton almost eclipsing the naphthyl ring (Figure 4).[15]
While the precise rotation angle depends intimately on the
nature of the substituents, the eclipsed conformation avoids
inherent allylic strain[16] that would otherwise ensue be-
tween one of the carbon substituents and the aromatic ring.
Planar aromatic substituents, such as the naphthyl ring,
exert a surprisingly small steric demand in conformationally
mobile hydrocarbons.[17] In fact, NMR analyses indicate
that a phenyl ring exerts a smaller steric demand than a
methyl group as a consequence of the planar “edge on”
Scheme 1. Synthesis of a naphthyl-substituted nitrile prototype.
The diastereoselective alkylation of the metalated nitrile
topology.[18] Embedding a naphthyl substituent at carbon 4 derived from 5 was probed with methyl cyanoformate as a
of pentanenitrile 5a was therefore envisaged to create a test electrophile. Deprotonating 5 and acylating with methyl
highly asymmetric environment because of the different ste- cyanoformate at –78 °C provided a 4.2:1 ratio of dia-
ric demand of the three substituents; a “large” methyl stereomers 11a and 11b (Scheme 2). The stereochemical
group, a medium-sized naphthyl group, and a small proton. course of the reaction was determined by selectively reduc-
Assuming that the pentane chain adopts a diamond lattice ing the carbonyl group of 11a and esterifying the resulting
conformation (Figure 4, bonds printed in bold) with the alcohol with p-nitrobenzoyl chloride (PNBCl). X-ray crys-
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Metalated Nitriles: Internal 1,3-Asymmetric Induction
tallographic analysis of the resulting crystalline nitrile ester
12a unequivocally established the relative configuration of
the two chiral centers.[19] Relaying the stereochemistry of
12a to the alkylation event is consistent with preferential
electrophilic attack on the planar[20] N-lithiated nitrile con-
former 10Ј from the face opposite the naphthyl group.
Scheme 3. Non-selective alkylation of an isopropyl-substituted ni-
trile.
2.2 Second Generation
Armed with a rudimentary appreciation for the substitu-
tion requirements, attention was focused on determining if
the nature of the electrophile or the metalated nitrile influ-
ences the stereoselectivity.[23] Employing the nitrile proto-
type 19 with a phenyl for naphthyl substitution appeared
particularly attractive because of a more direct synthesis
(Scheme 4) and the potential availability of both enantio-
mers of 16 through the chiral hydroformylation of sty-
rene.[24] Efficient access to the requisite nitrile 19 was
achieved by cyanomethylenation of aldehyde 16, reduction
of the resulting alkenenitrile 17 to 18 with magnesium in
methanol[25] or by hydrogenation,[26] and subsequent meth-
ylation.
Scheme 2. Stereoselective metalated nitrile acylation.
Conformers 10Ј and 10ЈЈ assume a common diamond-
lattice conformation with the naphthylene ring eclipsing the
methine proton (Scheme 2). The main point of difference
between 10Ј and 10ЈЈ lies in the position of the 2-methyl
substituent and, correspondingly, the preferred orientation
of the lithiated nitrile. The stereoselective alkylation of 5 is
consistent with 10Ј being the preferred conformation with
the small lithiated nitrile[21] eclipsing the naphthalene ring
in the sterically more demanding position. Preferential al-
kylation of 10Ј opposite the naphthyl ring leads to the
major diastereomer whereas a similar attack on rotamer
10ЈЈ having a gauche-type methyl-proton interaction, leads
to the minor diastereomer.
Scrutinizing the crystallographic structure of the nitrile
ester 12a identified a rotation of the aliphatic methine pro-
ton away from planarity with the naphthylene ring. Naively
Scheme 4. Synthesis of phenyl-substituted nitrile prototype.
Alkylating the metalated nitrile derived from 19 pro-
assuming that a larger substituent would correct this distor- ceeded with diastereoselectivities comparable to those of
tion stimulated the synthesis[22] and acylation of the isopro- the naphthyl analogue (Table 1). As a point of comparison,
pyl-substituted nitrile 13 (Scheme 3). Unfortunately, se- deprotonating 19 with LDA and intercepting the lithiated
quential deprotonation and acylation of 13 was completely nitrile with methyl cyanoformate preferentially affords two
non-selective. Although speculative, an eclipsing interaction diastereomers in a 3.2:1 ratio (Table 1, Entry 1) whereas the
in 14Ј may cause a rotation away from the diamond lattice naphthyl analog 5 afforded a 4.2:1 ratio of diastereomers
conformation rendering the faces in 14ЈЈ equally accessible. (Scheme 2). For alkylations of 19, the addition of TMEDA
The practical lesson from the alkylations of 5 and 13 is the exerts a decline in selectivity (Table 1, Entry 2) and in com-
requirement for a terminal methyl group with an adjacent parable alkylations with cyclohexanone, lowering the tem-
aromatic ring.
perature from –78 °C to –96 °C does not improve the stereo-
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selectivity (Table 1, Entries 3 and 4). Alkylations with car- substituted nitrile 5. Collectively, the alkylations of the lithi-
bonyl, allylic bromide and alkyl iodide electrophiles occur ated nitrile derived from 19 are consistent with electrophilic
with comparable levels of selectivity (Table 1).
attack onto the more accessible face of the N-lithiated ni-
trile conformer 24Ј (Scheme 5).
Table 1. Diastereoselective metalated nitrile alkylations.
Scheme 5. Stereoselectivity model for metalated nitrile alkylations.
Having established the diastereoselectivity in alkylations
of the N-lithiated nitrile 24 (Scheme 5), a series of metal
additives were used to screen the selectivity preferences of
a range of N- and C-metalated nitriles.[28] Sequentially de-
protonating 19 with LDA, adding a metal halide, and then
methyl cyanoformate generally led to complex reaction mix-
tures.[29] The cleanest reactions of highest selectivity were
achieved with zinc halides which are known to favor trans-
metallation to C-zincated nitriles (24Ǟ25).[30] Rapid, con-
ducted tour equilibration[31] interconverts these dia-
stereomeric C-metalated nitriles through a sequence of C-
to N-metal migration (25ЈǞ24Ј), rotation (24ЈǞ24ЈЈ), and
migration of the metal back to carbon (24ЈЈǞ25ЈЈ). Acylat-
ing the intermediate zincated nitriles affords predominantly
20a (Table 1, Entries 7 and 8) consistent with retentive alky-
lation from the C-zincated nitrile conformer 25Ј (M =
ZnBr) which assumes that the long zinc–carbon bond
places the steric demand of ZnBr between that of the
methyl and nitrile groups.[9] The similar acylation stereose-
lectivity of the C-zincated nitrile offers no advantage over
the corresponding acylation with an N-lithiated nitrile, par-
ticularly because zincated nitriles are generally considerably
less nucleophilic.[32]
[a] The major diastereomer is that depicted. [b] The stereochemistry
of 20a is based on X-ray crystallography[27] of a derivative. [c] The
configuration is assigned by analogy. [d] The configurations of 22a
and 23a are based on chemical correlations. [e] The alkylation was
performed at –50 °C.
Changing the steric demand of the α-substituent in the
metalated nitrile from methyl to hexyl or isopropyl has only
a small influence on the stereoselectivity. Comparable acyl-
ations of hexyl nitrile 26 and isopropyl nitrile 27, prepared
Chemical correlations establish that the alkylations of ni- by alkylations of 18 (Scheme 6), affords the nitrile dia-
trile 19 all occur with the same relative diastereoselectivity stereomers 28a and 28b in a 3.8:1 ratio and diastereomers
(see Supporting Information). In addition, the sense of 29a and 29b with a 2.7: selectivity preference.[33] The dia-
asymmetric induction for 19 parallels that of the naphthyl- stereomer ratios are only slightly different from that ob-
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Metalated Nitriles: Internal 1,3-Asymmetric Induction
served for the α-methyl-bearing nitrile 19 (Scheme 5) sug- 2.4 Fourth Generation
gesting that the alkylations proceed through similar confor-
mations (cf. 24Ј Scheme 5).
Designing a more efficient transfer of stereochemical in-
formation in metalated alkanenitrile alkylations focused on
maximizing the difference in the steric demand of the ter-
minal substituents. Replacing the γ-aromatic substituent
with a tert-butyl group appeared particularly attractive be-
cause the chiral carbon would bear tBu, Me, and H groups
having disparate A values (4.7, 1.7, 0 kcalmol–1).[9] Substi-
tuting an oxygen atom for the intervening methylene unit
was envisaged to enhance the asymmetric induction
through two complementary effects. The shorter C–O bond
length (1.53 Å and 1.43 Å for C–C and C–O bonds, respec-
tively)[39] should accentuate the internal relay of asymmetry
and the n Ǟ σ*C–H stereoelectronic effect[40] should in-
crease the preference for the diamond lattice conformation.
The requisite nitrile 36 was readily prepared in four-steps
(Supporting Information). Sequentially deprotonating ni-
trile 36 and alkylating with several electrophiles selectively
installs the new quaternary center with improved stereose-
lectivity (Scheme 8).[41] Alkylating with propyl iodide af-
forded 38a with a slightly higher diastereoselectivity than
for any other nitrile. By employing the carbonyl electro-
philes, cyclohexanone and benzophenone and performing
the alkylation at –78 °C, the hydroxynitriles 39a and 40a
were obtained with the highest diastereoselectivity of any
acyclic, metalated nitrile.
Scheme 6. Stereoselectivities of α-substituted metalated nitrile alky-
lations.
2.3 Third Generation
The comparable diastereoselectivity for alkylations of N-
and C-metalated nitriles 24 and 25 (Scheme 5) stimulated
alkylations with another type of metalated nitrile, a nitrile
anion. The strategy was based on the highly selective alky-
lations of cyclic nitrile anions in which the anion geometry
is enforced by internal complexation.[34] Experimentally, se-
quentially deprotonating the hydroxy nitriles 30 and 31[35]
with excess LDA, followed by addition of methyl iodide in-
stalls the quaternary center with a modest preference for
34a and 35a.[36] The diastereoselectivity is consistent with
preferential alkylation from the nitrile anions 32Ј and 33Ј
in which the alkoxy lithium is complexed to the nitrile[37] π-
electrons with an additional lithium-π interaction with the
benzene ring[38] (Scheme 7). Although the alkylations pro-
ceed with a consistent preference for the same diastereomer,
the modest diastereoselectivity stimulated a fourth ap-
proach to impart greater stereocontrol.
Scheme 8. Diastereoselective alkylations of an oxygen-containing
nitrile.
Conclusions
Alkylations of acyclic metalated nitriles containing a re-
mote stereocenter predictably install new quaternary centers
through an internal relay of chiral information. The asym-
metric environment was specifically designed using prin-
ciples of allylic strain and syn-pentane interactions to favor
one diamond lattice conformation with different steric de-
mands for electrophilic attack on the diastereotopic faces
of the metalated nitrile. Screening a series of substituted
alkanenitriles reveals a dependable diastereoselectivity pref-
erence consistent with the diamond-lattice alkylation
model.
Scheme 7. Diastereoselective alkylations with dilithiated nitrile
“anions.”.
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8.1 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7, 36.2,
67.8, 122.9, 123.0, 125.4, 125.4, 125.9, 126.9, 128.8, 131.8, 133.8,
139.5 ppm. MS (CI): m/z = 187 [M + H+]. HRMS (EI): calcd. for
C13H14ONa+ 209.0937; found 209.0935.
The strategy is equally selective for N- or C-metalated
nitriles. Quaternary centers are effectively installed in alky-
lations with carbonyl and alkyl halide electrophiles. Aro-
matic phenyl and naphthyl substituents at C-3 and primary
alkyl substituents at C-1 are equally effective whereas sec-
ondary alkyl and hydroxyalkyl substituents at C-1 diminish
the stereoselectivity. Optimal stereoselectivity is achieved
with an oxygen-containing alkanenitrile in which the chiral
center bears tert-butyl, methyl, and hydrogen substituents.
The value of the alkylations lie partly in the stereoselec-
tive installation of quaternary centers, but more in explor-
ing the conceptual use of conformational control in hydro-
carbon chains during stereoselective bond formation. The
modest, but usable, diastereoselectivity likely reflects the dy-
namic nature of conformationally mobile systems; bond
angles greater than the ideal of 109°, and small distortions
of the carbon backbone that prevent an exact correspon-
dence to one diamond lattice conformation. What is re-
1-(2-Iodo-1-methylethyl)naphthalene (9): Solid PPh3 (124 mg,
0.47 mmol), imidazole (32 mg, 0.47 mmol), and iodine (120 mg,
0.47 mmol) were added to a dichloromethane solution (8 mL) of 8
(87 mg, 0.47 mmol). After 4 h, the solvent was removed and the
crude iodide was purified by radial chromatography (EtOAc/hex-
anes, 1:30) to afford 134 mg (96%) of 9 as an oil. IR (film): ν =
˜
1
2965, 795, 773 cm–1. H NMR (400 MHz, CDCl3): δ = 1.59 (d, J
= 6.8 Hz, 1 H), 3.34–3.38 (m, 1 H), 3.60 (dd, J = 9.8, 4.5 Hz, 1 H),
3.84–3.93 (m, 1 H), 7.40 (d, J = 7.1 Hz, 1 H), 7.44–7.58 (m, 3 H),
7.76 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 8.03 (d, J =
8.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.4, 20.9,
36.7, 122.5, 122.6, 125.4, 125.5, 126.3, 127.4, 129.1, 131.0, 133.9,
140.0 ppm. MS (CI): m/z = 296 [M+].
2-Methyl-4-naphthalen-1-ylpentanenitrile (5): The general alky-
lation procedure was employed with propionitrile (33 mg,
markable is the consistency of the diamond lattice model to 0.6 mmol) and 9 (178 mg, 0.6 mmol) with the modification of al-
lowing the reaction mixture to warm to room temp. over 2 h before
the addition of saturated, aqueous NH4Cl. The crude product was
predict the sense of stereoinduction. Collectively the alky-
lations provide fundamental insight for internal asymmetric
induction with metalated nitriles and provide a solid foun-
dation for stereoselective alkylations with acyclic nucleo-
philes.
purified by radial chromatography (EtOAc/hexanes, 1:30) to afford
1
107 mg (71%) of 5 as an oil. IR (film): ν = 2238 cm–1. H NMR
˜
(400 MHz, CDCl3): δ = 1.21 (d, J = 7.1 Hz, 3 H), 1.24 (d, J =
7.0 Hz, 3 H), 1.38 (d, J = 7.8 Hz, 3 H), 1.40 (d, J = 7.3 Hz, 3 H),
1.71–1.79 (m, 1 H), 1.95–2.06 (m, 2 H), 2.27–2.36 (m, 1 H), 2.62–
2.70 (m, 1 H), 3.81–3.92 (m, 1 H each), 7.30–7.34 (m, 1 H each),
7.40–7.48 (m, 2 H each), 7.51–7.54 (m, 1 H each), 7.71 (d, J =
8.2 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H),
7.83 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.6 Hz, 1 H), 8.22 (d, J =
8.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.0 (18.4),
20.5, 22.8, 23.5 (23.9), 41.8 (42.4), 122.3, (122.5), 122.8, (122.8),
123.1, (125.4), 125.4, (125.5), 125.6, (126.1), 126.1 (126.9), 128.9
(128.9), 131.0 (131.6), 133.9 (133.9), 141.2 (141.4) ppm. MS (CI):
m/z = 224 [M + H+]. HRMS (EI): calcd. for C16H17NNa+
246.1253; found 246.1251.
Experimental Section
General Deprotonation–Alkylation Procedure: A THF solution of
the nitrile (1.0 equiv.) was added to a –78 °C cold THF solution of
LDA, generated from butyllithium (1.05 equiv.) and diisopropyl-
amine (1.15 equiv.). After 50 min at –78 °C, neat electrophile
(1.2 equiv.) was added. After 3 h at –78 °C, saturated, aqueous
NH4Cl was added, the crude product was extracted with EtOAc,
dried (MgSO4), concentrated, and purified by radial chromatog-
raphy to afford analytically pure material.
Methyl (2R*,4R*)-2-Cyano-2-methyl-4-(naphthalen-1-yl)pentanoate
(11a) and Methyl (2S*,4R*)-2-Cyano-2-methyl-4-(naphthalen-1-yl)-
pentanoate (11b): The general procedure was employed with 5
(85 mg, 0.38 mmol) and methyl cyanoformate (40 mg, 0.47 mmol)
to afford, after purification by radial chromatography (EtOAc/hex-
anes, stepped gradient 1:19, 1:9), 78 mg (73%) of 11a and 11b as
Ethyl 2-Naphthalen-1-ylpropionate (i): The general procedure was
employed with ethyl 1-naphthylacetate (1.07 g, 5 mmol) and methyl
iodide (852 mg, 6 mmol) with the exception of allowing the reac-
tion to warm to room temp. over 16 h before addition of saturated,
aqueous NH4Cl. The crude product was purified by radial
chromatography (EtOAc/hexanes, 1:20) to afford 958 mg (84%) of
i as an oil: IR (film): ν = 2980, 1727 cm–1. 1H NMR (400 MHz,
an oily 4.2:1 mixture of diastereomers. IR (film): ν = 2954, 2244,
˜
˜
1
1730 cm–1. H NMR (400 MHz, CDCl3): δ = 1.40 (d, J = 7.0 Hz,
CDCl3): δ = 1.14 (t, J = 7.2 Hz, 3 H), 1.65 (d, J = 7.3 Hz, 3 H),
4.07–4.19 (m, 2 H), 4.49 (q, J = 7.3 Hz, 1 H), 7.43–7.55 (m, 4 H),
7.75–7.78 (m, 1 H), 7.85–7.88 (m, 1 H), 8.09 (d, J = 8.5 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 18.2, 41.4, 60.8,
123.1, 124.4, 125.6, 126.2, 127.6, 128.9, 131.3, 133.9, 174.9 ppm.
3 H), 1.48 (d, J = 7.0 Hz, 3 H), 1.53 (s, 3 H), 1.60 (s, 3 H), 2.18
(dd, J = 14.2, 4.9 Hz, 1 H), 2.30 (dd, J = 5.4, 14.2 Hz, 1 H), 2.41
(dd, J = 14.2, 8.7 Hz, 1 H), 2.65–2.71 (m, 1 H), 2.96 (s, 3 H), 3.77
(m, 3 H), 3.97–4.04 (m, 1 H each), 7.24–7.47 (m, 4 H each), 7.71
(d, J = 8.2 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.83–7.88 (m, 1 H
each), 8.16 (d, J = 8.5 Hz, 1 H), 8.21 (d, J = 8.6 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.1, 24.8, 25.4, 43.3, 45.2,
(52.6), 53.5, 119.7, (120.3), 122.6, (123.1), (125.4), 125.4, (125.5),
125.6, (126.1), 126.3, (127.0), 127.1, (128.8), 129.1, 130.8, (131.1),
(133.9), 133.9, 141.8, (169.3), 170.3 ppm. MS (CI): m/z = 281 [M
+ H].
MS (CI): m/z
= 229 [M +
H+]. HRMS (EI): calcd. for
C15H16O2Na+ 251.1043; found 251.1043.
2-Naphthalen-1-ylpropan-1-ol (8): Solid LiBH4 (367 mg, 16.8 mmol)
was added to a THF solution (20 mL) of i (479 mg, 2.1 mmol).
After 18 h, saturated, aqueous NaHCO3 was added, and after
15 min, the layers were separated, and the aqueous phase was then
extracted with diethyl ether (3ϫ). The combined organic phase was
dried (MgSO4), filtered, and concentrated under reduced pressure
and the residue was purified by radial chromatography (EtOAc/
(2R*,4R*)-2-Cyano-2-methyl-4-(naphthalen-1-yl)pentyl 4-Nitroben-
zoate (12a) and (2S*,4R*)-2-Cyano-2-methyl-4-(naphthalen-1-yl)-
hexanes, 1:5) to afford 378 mg (90%) of 8 as an oil. IR (film): ν = pentyl 4-Nitrobenzoate (12b): Solid LiBH4 (18 mg, 0.8 mmol) was
˜
3408, 1736 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.35 (d, J =
6.3 Hz, 3 H), 2.02 (br. s, 1 H), 3.63–3.83 (m, 3 H), 7.31–7.48 (m, 4
added to a THF solution (8 mL) of 11 (56 mg, 0.20 mmol). After
18 h, saturated, aqueous NaHCO3 (5 mL) was added, the mixture
H), 7.67 (d, J = 8.0 Hz, 1 H), 7.79–7.81 (m, 1 H), 8.07 (d, J = was stirred for 15 min and then the phases were separated. The
704 Eur. J. Org. Chem. 2009, 699–708
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Metalated Nitriles: Internal 1,3-Asymmetric Induction
aqueous phase was extracted with diethyl ether (3ϫ) and then the
combined organic extract was dried (MgSO4), filtered, and concen-
trated under reduced pressure and the residue was purified by ra-
dial chromatography (EtOAc/hexanes, 1:5) to afford 36 mg (72%)
of a mixture of diastereomeric alcohols. A hexanes solution of bu-
tyllithium (0.15 mmol) was added to a –78 °C, THF solution
(5 mL) of this mixture of diastereomers (36 mg, 0.14 mmol), fol-
lowed after 10 min, by neat p-nitrobenzoyl chloride (29.4 mg,
0.16 mmol). The resulting solution was warmed to room temp. and,
after 1 h, water was added. The product was extracted with EtOAc
(3ϫ), dried (MgSO4), concentrated and purified by radial
chromatography (EtOAc/hexanes, 1:8) to provide 43.9 mg (78%) of
a mixture of diastereomers from which a pure sample of the major
diastereomer 12a was obtained. The major diastereomer 12a is a
crystalline solid (m.p. 146–147 °C, CCDC-689493) whose structure
The crude alkanenitrile was filtered through a plug of Celite, the
filtrate was concentrated and the residue was purified by radial
chromatography (EtOAC/hexanes, 1:30) to provide 820 mg (86%)
of 18 as an oil: IR (film): ν = 2246 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 1.31 (d, J = 6.8 Hz, 3 H), 1.87–2.28 (m, 4 H), 2.84–2.88
(m, 1 H), 7.20–7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 15.2, 21.6, 33.3, 38.6, 119.4, 126.5, 126.7, 128.5, 144.4 ppm. MS
(CI): m/z = 160 [M + H+]. HRMS (EI): calcd. for C11H13NNa+
182.0946; found 182.0951.
2-Methyl-4-phenylpentanenitrile (19a and 19b): Performing the ge-
neral deprotonation–alkylation procedure with a THF solution
(10 mL) of 18 (795 mg, 5 mmol) and MeI (852 mg, 6 mmol), pro-
vided, after purification by radial chromatography (EtOAc/hex-
anes, 1:30) 692 mg (80%) of pure 19 as an oily mixture of dia-
stereomers in the ratio of 1:1.3. Careful chromatography provided
was solved by X-ray diffraction: IR (film): ν = 2238, 1730 cm–1. 1H
˜
pure samples of two diastereomers for characterization. For the
NMR (400 MHz, CDCl3): δ = 1.29 (s, 3 H), 1.57 (d, J = 7.0 Hz, 3
H), 2.22–2.30 (m, 2 H), 3.99 (br.s, 1 H), 4.24 (d, J = 11.0 Hz, 1 H),
4.29 (d, J = 11.0 Hz, 1 H), 7.41–7.44 (m, 2 H), 7.48–7.51 (m, 1 H),
7.54–7.57 (m, 1 H), 7.73–7.74 (m, 1 H), 7.87 (d, J = 7.9 Hz, 1 H),
8.17–8.20 (m, 2 H), 8.29–8.31 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.3, 23.8, 37.2, 43.5, 69.7, 122.1, 123.7, 125.5, 125.7,
126.4, 127.2, 129.3, 130.7, 130.9, 134.1, 134.4, 142.2, 150.8, 163.8
ppm. MS (CI): m/z = 403 [M + H+]. HRMS (EI): calcd. for [M
+ Na], C24H22N2O4Na+ 425.1477; found 425.1456. For the minor
diastereomer 12b: 1.50 (s, 3 H), 1.55 (d, J = 6 Hz, 3 H), 2.09 (dd,
J = 14.4 Hz, 5.7 Hz, 1 H), 2.48 (dd, J = 13.3 Hz, 7.9 Hz, 1 H),
3.96–4.02 (m, 1 H), 4.11–4.19 (m, 2 H), 7.39–8.31 (m, 11 H). MS
(CI): m/z = 403 [M + H+].
1
first eluting diastereomer 19a: IR (film): ν = 3026, 2237 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.23 (d, J = 7.4 Hz, 3 H), 1.31 (d,
J = 7.3 Hz, 3 H), 1.67–1.73 (m, 1 H), 1.88–1.94 (m, 1 H), 2.19–
2.27 (m, 1 H), 2.96–3.03 (m, 1 H), 7.21–7.34 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 18.5, 22.7, 24.1, 38.3, 42.9, 122.8,
126.7, 126.9, 128.8, 144.9 ppm. MS (CI): m/z = 174 [M + H+]. For
1
the second eluting diastereomer 19b: IR (film): ν = 2238 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.32 (d, J = 7.3 Hz, 3 H), 1.33 (d,
J = 6.9 Hz, 3 H), 1.75–1.81 (m, 1 H), 2.00–2.06 (m, 1 H), 2.52–
2.57 (m, 1 H), 2.93–2.97 (m, 1 H), 7.21–7.36 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.6, 21.5, 23.3, 37.2, 42.2, 122.9,
126.6, 126.8, 128.7, 145.3 ppm. MS (CI): m/z = 174 [M + H+].
Methyl (2R*,4R*)-2-Cyano-2-methyl-4-phenylpentanoate (20a and
20b): The general deprotonation–alkylation procedure was em-
ployed with 19 (450 mg, 2.6 mmol) and methyl cyanoformate
(232 mg, 2.7 mmol) to afford, after purification by radial
chromatography (EtOAc/hexanes, stepped gradient 1:19, 1:9),
390 mg (65%) of 20a and 20b as an oily, 3.2:1 mixture of dia-
Methyl 2-Cyano-2,5-dimethyl-4-naphthalen-1-ylhexanoate (15): The
general deprotonation–alkylation procedure was employed with 13
(63 mg, 0.25 mmol) and methyl cyanoformate (232 mg, 0.27 mmol)
to afford, after purification by radial chromatography (EtOAc/hex-
anes, stepped gradient 1:19, 1:9), 56 mg (73%) of 15 as an oily, 1:1
mixture of diastereomers. IR (film): ν = 2241, 1745 cm–1. 1H NMR
˜
1
stereomers. For the major diastereomer 20a: H NMR (400 MHz,
(400 MHz, CDCl3): δ = 0.80 (d, J = 7.0 Hz, 3 H), 0.82 (d, J =
7.3 Hz, 3 H), 0.98 (d, J = 4.1 Hz, 3 H), 1.00 (d, J = 3.8 Hz, 3 H),
1.18–1.36 (m, 1 H), 1.29 (s, 3 H), 1.58 (s, 3 H), 1.88–1.99 (m, 1 H),
2.36 (dd, J = 14.1, 1.9 Hz, 1 H), 2.51–2.63 (m, 1 H), 2.56 (s, 3 H),
3.54 (s, 3 H), 3.48–3.62 (m, 1 H), 3.76–3.81 (m, 1 H), 7.29–7.56 (m,
4 H each), 7.71 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.83
(d, J = 8.3 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.5 Hz,
1 H), 8.25 (d, J = 9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 20.0, (20.0), 20.4, (20.5), 23.7, (25.2), 34.9, (35.0), 40.1, (41.3),
(41.9), 42.3, (43.4), 43.7, (52.2), 53.3, 119.9, (120.2), (123.0), 123.7,
(124.3), 124.3, 124.9, (125.0), 125.4, (126.1), 127.0, (127.2), 128.6,
(129.1), 132.6, (132.8), (133.8), 133.9, (137.9), 138.9, 169.3, (169.8)
ppm. MS (CI): m/z = 310 [M + H+]. HRMS (EI): calcd. for
CDCl3): δ = 1.20 (d, J = 7.1 Hz, 3 H), 1.41 (s, 3 H), 2.08 (dd, J =
14.2, 7 Hz, 1 H), 2.19 (dd, J = 14.2, 7 Hz, 1 H), 2.93–3.00 (m, 1
H), 3.68 (s, 3 H), 7.10–7.24 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.5, 25.7, 37.4, 43.5, 45.5, 52.9, 119.6, 126.8, 127.7,
128.6, 145.5, 170.1 ppm. HRMS (EI): calcd. for C14H17NO2Na+
254.1152; found 254.1148; For the minor diastereomer 20b: 1H
NMR (400 MHz, CDCl3): δ = 1.26 (d, J = 7.0 Hz, 3 H), 1.50 (s, 3
H), 1.92 (dd, J = 14, 4 Hz, 1 H), 2.35 (dd, J = 14, 10 Hz, 1 H),
2.93–3.00 (m, 1 H), 3.14 (s, 3 H), 7.10–7.24 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 23.7, 24.2, 38.0, 43.0, 46.0, 53.4,
119.9, 126.7, 127.0, 128.3, 143.7, 169.4 ppm.
(2R*,4R*)-2-(1-Hydroxycyclohexyl)-2-methyl-4-phenylpentanenitri-
le (21a) and (2S*,4R*)-2-(1-Hydroxycyclohexyl)-2-methyl-4-phenyl-
pentanenitrile (21b): The general deprotonation–alkylation pro-
cedure was employed with 19 (104 mg, 0.6 mmol) and cyclohexa-
none (69 mg, 0.70 mmol) to afford, after purification by radial
chromatography (EtOAc/hexanes, 1:5), 111 mg (68%) of 21 as an
oily 3.9:1 mixture of diastereomers. For the major diastereomer
+
C20H24NO2 310.1802; found 310.1791.
4-Phenylpentanenitrile (18): A hexanes solution of BuLi (3.1 mL,
6.8 mmol) was added to a 0 °C, THF solution of diethyl (cya-
nomethyl)phosphonate (0.12 mL, 7.4 mmol). After 20 min, the re-
action mixture was warmed to room temp. After 20 min the mix-
ture was re-cooled to 0 °C and a THF solution (2.0 mL) of alde-
hyde 16 (804 mg, 6 mmol) was added. The solution was warmed to
room temp. and after 2 h, saturated aqueous NaHCO3 was added,
and then the mixture was diluted with EtOAc. The layers were
separated and the aqueous layer was extracted with EtOAc
(3ϫ10 mL). The combined organic extract was washed with brine,
dried (Na2SO4), and concentrated to afford essentially pure alkene-
nitrile 17 as judged by NMR analysis. The alkenenitrile was redis-
solved in MeOH (15 mL), solid Pd/C (10%, 200 mg) was added
and then the suspension was stirred under 30 atm of H2 for 6 h.
21a: IR (film): ν = 3470, 2232 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 1.02 (s, 3 H), 1.39 (d, J = 7.0 Hz, 3 H), 1.42–1.80 (m, 12 H),
2.15 (dd, J = 13.8, 5.5 Hz, 1 H), 3.01–3.09 (m, 1 H), 7.18–7.32 (m,
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.8, 21.5, 21.5, 24.3,
25.3, 31.1, 31.6, 37.8, 40.8, 47.4, 74.6, 123.8, 126.3, 127.1, 128.7,
147.5 ppm. MS (CI): m/z = 272 [M + H+]. HRMS (EI): calcd. for
C18H25NOK 310.1573; found 310.1587. For the minor dia-
stereomer 21b: IR (film): ν = 3472, 2231 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 1.35 (d, J = 7.0 Hz, 3 H), 1.42 (s, 3 H), 1.47–1.77 (m,
Eur. J. Org. Chem. 2009, 699–708
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
705

F. F. Fleming, W. Liu
FULL PAPER
12 H), 2.26 (dd, J = 14.0, 7.2 Hz, 1 H), 3.00–3.05 (m, 1 H), 7.20–
2.96–3.05 (m, 1 H), 7.18–7.34 (m, 5 H) ppm. 13C NMR (100 MHz,
7.34 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3, 21.5, CDCl3): δ = 14.3, 22.6, 22.9, 27.0, 28.9, 29.0, 30.2, 31.6, 32.7, 38.2,
21.5, 24.5, 25.3, 31.4, 31.4, 37.3, 41.1, 46.5, 74.6, 122.9, 126.5,
127.1, 128.5, 146.5 ppm. MS (CI): m/z = 272 [M + H+]. HRMS
(EI): calcd. for C18H25NONa 294.1828; found 294.1811.
40.9, 122.3, 126.7, 126.9, 128.8, 144.9 ppm. MS (CI): m/z = 258
[M + H+]. HRMS (EI): calcd. for C18H27NNa+ 280.2041; found
280.2015.
(R*)-2-Methyl-2-[(R*)-2-phenylpropyl]pent-4-enenitrile (22a) and Methyl (R*)-2-Cyano-2-[(R*)-2-phenylpropyl]nonanoate (28a) and
(S*)-2-Methyl-2-[(R*)-2-phenylpropyl]pent-4-enenitrile (22b): The Methyl (S*)-2-Cyano-2-[(R*)-2-phenylpropyl]nonanoate (28b): The
general deprotonation–alkylation procedure was employed with 19
(450 mg, 2.6 mmol) and allyl bromide (327 mg, 2.7 mmol) to af-
ford, after purification by radial chromatography (EtOAc/hexanes,
1:30), 476 mg (86%) of 22 as an oily, 3.8:1 mixture of dia-
general deprotonation–alkylation procedure was employed with 26
(103 mg, 0.4 mmol) and methyl cyanoformate (41 mg, 0.48 mmol)
to afford, after purification by radial chromatography (EtOAc/hex-
anes, 1:9), 91 mg (72%) of 28 as an oily mixture of diastereomers
stereomers. For the major diastereomer 22a: IR (film): ν = 2232,
in the ratio of 3.8:1: IR (film): ν = 2241, 1744 cm–1. MS (CI): m/z
˜
˜
1642 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.07 (s, 3 H), 1.37 (d,
J = 7.3 Hz, 3 H), 1.82 (dd, J = 14.2, 7.8 Hz, 1 H), 1.95 (dd, J =
14.2, 5.2 Hz, 1 H), 2.24 (dd, J = 13.7, 7.3 Hz), 2.33 (dd, J = 13.7,
7.3 Hz, 1 H), 3.06 (sextet, J = 7.3 Hz, 1 H), 5.16 (d, J = 16.6 Hz,
= 316 [M + H+]. For the major diastereomer 28a: 1H NMR
(500 MHz, CDCl3): δ = 0.87 (t, J = 7.8 Hz, 3 H), 1.24 (d, J =
6.9 Hz, 3 H), 1.48–1.89 (m, 10 H), 2.12 (dd, J = 14.1, 6.3 Hz, 1 H),
2.24 (dd, J = 14.1, 6.3 Hz, 1 H), 3.02–3.04 (m, 1 H), 3.80 (s, 3 H),
1 H), 5.22 (d, J = 10.2 Hz, 1 H), 5.81–5.90 (m, 1 H), 7.20–7.33 (m, 7.22–7.34 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0,
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.9, 24.1, 36.2, 37.3,
21.8, 22.5, 25.2, 28.8, 29.1, 31.6, 37.4, 38.5, 44.9, 48.8, 53.3, 118.8,
45.3, 46.6, 120.0, 123.9, 126.4, 127.0, 128.6, 131.9, 146.9 ppm. MS
126.9, 128.6, 145.8, 170.1 ppm. MS (CI): m/z = 316 [M + H+].
(CI): m/z = 281 [M + H+]. HRMS (EI): calcd. for C15H19NNa+ HRMS (EI): calcd. for C20H29NO2K+ 354.1830; found 354.1808.
236.1410; found 236.1418. For the minor diastereomer 22b: IR
For the minor diastereomer 28b: 1H NMR (500 MHz, CDCl3): δ
= 0.87 (t, J = 7.8 Hz, 3 H), 1.24 (d, J = 6.9 Hz, 3 H), 1.48–1.89
1
(film): ν = 2232 cm–1. H NMR (400 MHz, CDCl ): δ = 1.30 (s, 3
˜
3
H), 1.37 (d, J = 6.8 Hz, 3 H), 2.08–2.21 (m, 4 H), 3.02–3.11 (m, 1 (m, 10 H), 1.98–2.02 (m, 1 H), 2.36–2.41 (m, 1 H), 3.05–3.08 (m,
H), 5.06–5.19 (m, 1 H), 5.71–5.85 (m, 1 H), 7.21–7.35 (m, 5 H) 1 H), 3.16 (s, 3 H), 7.22–7.34 (m, 5 H) ppm. 13C NMR (100 MHz,
ppm. HRMS (EI): calcd. for C15H19NNa+ 236.1410; found CDCl3): δ = 23.8, 25.1, 28.8, 38.0, 39.5, 45.1, 49.3, 52.7, 119.3,
236.1398.
126.7, 127.8, 128.3, 143.8, 169.1 ppm. MS (CI): m/z = 316 [M +
H+].
(2R*,4R*)-2-Ethyl-2-methyl-4-phenylpentanenitrile
(23a)
and
(2S*,4R*)-2-Ethyl-2-methyl-4-phenylpentanenitrile (23b): The gene-
ral procedure was employed with 19 (87 mg, 0.5 mmol) and ethyl
2-Isopropyl-4-phenylpentanenitrile (27): The general procedure was
employed with 18 (239 mg, 1.5 mmol) and isopropyl iodide
iodide (94 mg, 0.6 mmol) to afford, after purification by radial (153 mg, 1.8 mmol) to afford, after purification by radial
chromatography (EtOAc/hexanes, 1:30), 56 mg (56%) of 23 as a
chromatography (EtOAc/hexanes, 1:30), 271 mg (90%) of 27 as an
4.2:1 mixture of diastereomers as an oil. For the major dia-
oily mixture of diastereomers. For the first eluting diastereomer
1
stereomer 23a IR (film): ν = 2232 cm–1. 1H NMR (400 MHz,
27a: IR (film): ν = 2235 cm–1. H NMR (500 MHz, CDCl ): δ =
˜
˜
3
CDCl3): δ = 1.03 (t, J = 7.4 Hz, 3 H), 1.06 (s, 3 H), 1.36 (d, J =
7.1 Hz, 3 H), 1.45–1.54 (m, 1 H), 1.57–1.66 (m, 1 H), 1.80 (dd, J
= 14.2, 8.0 Hz, 1 H), 1.92 (dd, J = 14.2, 5.4 Hz, 1 H), 2.99–3.07
(m, 1 H), 7.19–7.32 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 9.1, 23.5, 24.1, 34.0, 37.0, 37.3, 46.7, 124.1, 126.4, 127.0, 128.6,
147.1 ppm. MS (CI): m/z = 201 [M + H+]. HRMS (EI): calcd. for
1.03 (d, J = 6.5 Hz, 3 H), 1.05 (d, J = 6.5 Hz, 3 H), 1.30 (d, J =
6.8 Hz, 3 H), 1.70–1.77 (m, 1 H), 1.82–1.89 (m, 1 H), 1.90–1.98 (m,
1 H), 2.43–2.48 (m, 1 H), 2.89–2.98 (m, 1 H), 7.19–7.34 (m, 5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 18.2, 20.9, 21.2, 29.5, 36.9,
37.4, 38.5, 120.8, 126.5, 126.8, 128.7, 145.8 ppm. HRMS (EI):
calcd. for C14H19NK+ 240.1155; found 240.1169. For the second
C14H19NNa+ 224.1415; found 224.1436. For the minor dia- eluting diastereomer 27b: IR (film): ν = 2235 cm–1. 1H NMR
˜
stereomer 23b: IR (film): ν = 2231 cm–1. 1H NMR (400 MHz, (500 MHz, CDCl3): δ = 0.96 (d, J = 6.8 Hz, 3 H), 1.00 (d, J =
˜
CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.27 (s, 3 H), 1.35 (d, J =
6.8 Hz, 3 H), 1.32 (d, J = 6.8 Hz, 3 H), 1.67–1.70 (m, 2 H), 1.87–
7.0 Hz, 3 H), 1.55–1.63 (m, 1 H), 1.78 (dd, J = 14.2, 5.5 Hz, 1 H), 1.93 (m, 1 H), 2.04–2.18 (m, 1 H), 2.89–3.03 (m, 1 H), 7.19–7.33
2.00 (dd, J = 14.2, 7.6 Hz, 1 H), 2.96–3.03 (m, 1 H), 7.20–7.32 (m,
5 H) ppm. MS (CI): m/z = 201 [M + H+]. HRMS (EI): calcd. for
C14H19NK+ 240.1149; found 240.1153.
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.7, 20.8, 23.1,
30.4, 37.3, 38.3, 38.4, 121.1, 126.6, 126.9, 128.8, 144.9 ppm. HRMS
(EI): calcd. for C14H19NNa+ 224.1415; found 224.1463.
2-(2-Phenylpropyl)nonanenitrile (26): The general deprotonation–al-
kylation procedure was employed with 18 (191 mg, 1.2 mmol) and
iodoheptane (315 mg, 1.4 mmol) to afford, after purification by ra-
dial chromatography (EtOAc/hexanes, 1:50), 262 mg (85%) of 26
as an oily mixture of diastereomers. For the first eluting dia-
Methyl (2S*,4R*)-2-Cyano-2-isopropyl-4-phenylpentanoate (29a)
and Methyl (2R*,4R*)-2-Cyano-2-isopropyl-4-phenylpentanoate
(29b): The general deprotonation–alkylation procedure was em-
ployed with 27 (80 mg, 0.4 mmol) and methyl cyanoformate
(41 mg, 0.48 mmol) and with the modification of substituting Li-
stereomer 26a: IR (film): ν = 2235 cm–1. 1H NMR (500 MHz, NEt2 for LDA, to afford, after purification by radial chromatog-
˜
CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.29 (d, J = 7.0 Hz, 3 H),
1.27–1.59 (m, 12 H), 1.72–1.80 (m, 1 H), 1.93–2.00 (m, 1 H), 2.45–
2.51 (m, 1 H), 2.90–2.99 (m, 1 H), 7.18–7.34 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.0, 21.3, 22.6, 27.0, 29.0, 29.0,
29.5, 31.7, 31.9, 37.3, 40.6, 122.2, 126.6, 126.8, 128.7, 145.6 ppm.
MS (CI): m/z = 258 [M + H+]. HRMS (EI): calcd. for C18H27NNa+
280.2041; found 280.2011. For the second eluting diastereomer 26b:
raphy (EtOAc/hexanes, 1:9), 51 mg (49%) of 29 as an oily 2.7:1
mixture of diastereomers: IR (film): ν = 2241, 1743 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 0.94 (d, J = 6.5 Hz, 3 H each), 0.99 (d, J
= 6.7 Hz, 3 H each), 1.09 (d, J = 6.8 Hz, 3 H each), 1.12 (d, J =
6.7 Hz, 3 H each), 1.22 (d, J = 7.0 Hz, 3 H each), 1.34 (d, J =
7.0 Hz, 3 H each), 2.03–2.31 (m, 3 H each), 2.93–3.07 (m, 1 H
each), 3.18 (s, 3 H each), 3.82 (s, 3 H each), 7.21–7.34 (m, 5 H
each) ppm. 13C NMR (100 MHz, CDCl3): δ = (17.9), 18.7, 21.5,
(23.7), 36.2, (36.3), 37.7, (38.1), (42.6), 42.8, (52.5), 53.0, 54.3,
IR (film): ν = 2235 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.86
˜
(t, J = 6.9 Hz, 3 H), 1.31 (d, J = 7.0 Hz, 3 H), 1.19–1.58 (m, 12
H), 1.68–1.75 (m, 1 H), 1.86–1.93 (m, 1 H), 2.10–2.17 (m, 1 H), (54.9), 117.4, (118.2), (126.6), (126.7), 127.0, (127.8), (128.2), 128.6,
706
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Eur. J. Org. Chem. 2009, 699–708

Metalated Nitriles: Internal 1,3-Asymmetric Induction
1
(144.0), 145.8, 170.1 ppm. MS (CI): m/z = 260 [M + H+]. HRMS
stereomers in the ratio of 7.1:1 as an oil: H NMR: δ = 0.90# (s, 9
(EI): calcd. for C16H21NO2K+ 298.1204; found 298.1189.
H), 0.95* (s, 9 H), 0.88–0.93# (m, 3 H), 0.88–0.93* (m, 3 H), 1.17*
(d, J = 6.4 Hz, 3 H), 1.30# (d, J = 6.4 Hz, 3 H), 1.31–1.95* (m, 23
H), 1.31–1.95# (m, 23 H), 3.63* (q, J = 6.4 Hz, 1 H), 3.63# (q, J =
6.4 Hz, 1 H) ppm. 13C NMR: δ = 14.0, 15.3, (17.2), 21.4, (21.4),
(21.4), 21.5, 22.6, (25.5), 25.6, (25.9), 26.3, (26.4), 26.4, 29.0, (29.0),
30.2, (30.3), 31.7, 31.8, 31.8, (32.0), (32.0), 33.8, (34.4), 35.5, (36.0),
76.1, (76.6), 80.5, (81.0), 82.3, (84.6), (119.3), 119.5 ppm.
(2S*,4R*)-2-(Hydroxymethyl)-2-methyl-4-phenylpentanenitrile (34a)
and (2R*,4R*)-2-(Hydroxymethyl)-2-methyl-4-phenylpentanenitrile
(34b): The general deprotonation–alkylation procedure was em-
ployed except with 2.2 equiv. of LDA and with 30 (76 mg,
0.4 mmol) and methyl iodide (62 mg, 0.44 mmol) to afford, after
purification by radial chromatography (EtOAc/hexanes, 1:8), 61 mg
(75%) of 34 as an oily, 1.5:1 mixture of diastereomers. For 34a: IR
2-(Hydroxydiphenylmethyl)-2-(1,2,2-trimethylpropoxy)nonanenitrile
(40a and 40b): The general procedure was employed with 36
(105 mg, 0.44 mmol) and benzophenone (89 mg, 0.49 mmol) to af-
ford, after purification by radial chromatography (EtOAc/hexanes,
1:10), 130 mg (70%) of 40a and 40b as a inseparable mixture of
(film): ν = 3451, 2236 cm–1. 1H NMR (400 MHz, CDCl ): δ = 1.07
˜
3
(s, 3 H), 1.38 (d, J = 6.8 Hz, 3 H), 1.78–1.85 (m, 1 H), 2.07 (dd, J
= 14.1, 5.3 Hz, 1 H), 3.03–3.08 (m, 1 H), 3.52 (d, J = 6.8 Hz, 2 H),
7.23–7.34 (m, 5 H) ppm; (100 MHz, CDCl3): δ = 22.6, 24.7, 37.3,
39.2, 43.3, 67.2, 122.8, 126.9, 126.9, 128.9, 146.2 ppm. HRMS (EI):
calcd. for C13H17NONa+ 226.1202; found 226.1196. For 34b: IR
diastereomers in the ratio 9.8:1 of as an oil: H NMR: δ = 0.64#
1
(s, 9 H), 0.88–0.93*# (m, 3 H), 0.88* (s, 9 H), 1.05*# (d, J = 6.0 Hz,
3 H), 1.10–2.10*# (m, 12 H), 3.18* (br. s, 1 H), 3.27# (br. s, 1 H),
3.69*# (q, J = 6.4 Hz, 3 H), 7.25–7.40*# (m, 3 H), 7.60–7.72*# (m,
2 H), 7.75–7.82*# (m, 12 H) ppm. 13C NMR: δ = 14.0, 14.6, 17.2,
22.5, 25.8, (25.8), (26.1), 26.4, 28.8, (28.8), 29.8, (29.9), 31.6, (31.6),
35.6, (35.6), (77.2), 77.3, 81.4, (81.5), (81.8), 82.1, (119.0), 119.5,
127.5, 127.6, (127.6), 127.7, 127.7, 127.8, 127.8, 127.9, 128.2 ppm.
MS (CI): m/z = 421 [M+].
(film): ν = 3479, 2239 cm–1. 1H NMR (400 MHz, CDCl ): δ = 1.34
˜
3
(d, J = 7.0 Hz, 3 H), 1.35 (s, 3 H), 1.44 (t, J = 6.8 Hz, 1 H), 1.75–
1.80 (m, 1 H), 2.07–2.13 (m, 1 H), 3.03–3.10 (m, 1 H), 3.26–3.41
(m, 2 H), 7.23–7.34 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 20.8, 24.1, 37.2, 39.6, 43.1, 69.0, 123.2, 126.6, 127.0, 128.7,
146.7 ppm. MS (CI): m/z = 204 [M + H+]. HRMS (EI): calcd. for
C13H17NONa+ 226.1202; found 226.1212.
(2R*,4R*)-2-(2-Hydroxyethyl)-2-methyl-4-phenylpentanenitrile (35a)
and (2S*,4R*)-2-(2-Hydroxyethyl)-2-methyl-4-phenylpentanenitrile
(35b): The general deprotonation–alkylation procedure was em-
ployed except with 2.2 equiv. of LDA and with 31 (81 mg,
0.4 mmol) and methyl iodide (62 mg, 0.44 mmol) to afford, after
purification by radial chromatography (EtOAc/hexanes, 1:8), 47 mg
Supporting Information (see also the footnote on the first page of
this article): 1H NMR and 13C NMR spectra for all new com-
pounds, experimental procedures for chemical correlation of inter-
mediates, and procedures for the synthesis of 13, 30, 31 and 36.
(54%) of 35 as an oily 2.6:1 mixture of diastereomers: IR (film): ν
˜
Acknowledgments
= 3421, 2238 cm–1. Although the major diastereomer was not sepa-
rable, enriched fractions allowed complete NMR assignments. For
the major diastereomer 35a: 1H NMR (400 MHz, CDCl3): δ = 1.33
(s, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.54–1.60 (m, 1 H), 1.70–1.90
(m, 2 H), 2.05 (dd, J = 14.3, 8.1 Hz, 1 H), 2.98–3.05 (m, 1 H),
3.69–3.78 (m, 2 H), 7.20–7.32 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.3, 25.4, 34.6, 37.0, 41.1, 47.5, 59.0, 124.0, 126.5,
127.0, 128.6, 146.5 ppm. HRMS (EI): calcd. for C14H19NOK+
256.1104; found 256.1154. For the minor diastereomer 35b: 1H
NMR (400 MHz, CDCl3): δ = 1.13 (s, 3 H), 1.36 (d, J = 7.3 Hz, 3
H), 1.70–1.90 (m, 3 H), 1.97 (dd, J = 14.2, 5.4 Hz, 1 H), 3.01 (br.
s, 1 H), 3.81 (t, J = 6.9 Hz, 2 H), 7.20–7.32 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.2, 24.4, 34.7, 37.1, 42.7, 47.3,
59.0, 124.1, 126.4, 126.9, 128.6, 146.8 ppm.
Financial support for this research from the National Science
Foundation (NSF) (CHE 0515715, CRIF 024872 for X-ray facili-
ties, CHE 0421252 for HRMS instrumentation, and CHE 0614785
for NMR facilities) is gratefully acknowledged.
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4.5:1 as an oil: IR (film): ν = 2959, 2928, 2872, 1082 cm–1. 1H
˜
NMR: δ = 0.88 (t, J = 6.6 Hz, 3 H)#, 0.88 (t, J = 6.6 Hz, 3 H)*,
0.89 (s, 9 H)#, 0.89 (s, 9 H)*, 0.95 (t, J = 7.4 Hz, 3 H)#, 0.95 (t, J
= 7.4 Hz, 3 H)*, 1.17 (d, J = 6.3 Hz, 3 H)#, 1.17 (d, J = 6.3 Hz, 3
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29.6, 31.7, (31.7), 35.5, (35.5), 37.9, (38.6), 40.0, (40.7), 77.4, (77.5),
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88 mg (82%) of 39a and 39b as a inseparable mixture of dia-
Eur. J. Org. Chem. 2009, 699–708
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
707

F. F. Fleming, W. Liu
FULL PAPER
[12]
[27] The configuration of the major diastereomer was determined
by chemoselectively reducing the ester functionality in 20a, es-
terifying the resulting alcohol with para-nitrobenzoyl chloride
(PNBCl), and using X-ray crystallographic analysis to unequiv-
ocally assign the stereochemistry in the resulting ester (CCDC-
689492). Experimental details and spectroscopic data are pro-
vided in the Supporting Information.
[28] Differentiating between C- and N-metalated transition struc-
tures is experimentally challenging. Evolution of the ground
state C-magnesiated nitrile to an N-magnesiated transition
structure is virtually impossible to detect without recourse to
computational modeling but seems highly unlikely given the
divergent reactivity preferences of C- and N-metalated nitriles:
a) F. F. Fleming, Z. Zhang, W. Liu, P. Knochel, J. Org. Chem.
2005, 70, 2200–2205; b) F. F. Fleming, S. Gudipati, Z. Zhiyu,
W. Liu, O. W. Steward, J. Org. Chem. 2005, 70, 3845–3849.
[29] Ratios were obtained by analyzing the crude reaction mixtures
by 1H NMR (Scheme 4 in the Supporting Information). Iso-
lated yields were only obtained for the cases shown in Table 1
for which the isolated ratios were essentially identical to those
obtained by 1H NMR integration of the crude reaction mix-
ture.
The conformation shown for 5a was determined from molecu-
lar mechanics calculations using Chem3D Pro. 11.0.
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[19] The authors have deposited the crystallographic data with the
Cambridge Crystallographic Data Center (CCDC-689493).
The data can be obtained, on request, from the Director, Cam-
bridge Crystallographic Data Center, 12 Union Road, Cam-
bridge, CB2 1EZ, UK.
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0.2 kcalmol–1, and while the corresponding A value for an N-
lithiated nitrile has not been determined, the steric demand is
likely to be similar; a) F. R. Jensen, C. H. Bushweller, B. H.
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[22] Performing the alkylation of 7 (Scheme 1) with iPrI followed
by the same reduction, iodination and alkylation sequence pro-
vided the isopropyl-bearing nitrile 13. A detailed Scheme is
provided in the Supporting Information
[23] For an overview of metalated nitrile structures and alkylation
preferences see: F. F. Fleming, S. Gudipati, Eur. J. Org. Chem.
2008, 29, 5365–5374.
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hindered nitrile necessitating the use of LiNEt2.
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Received: October 27, 2008
Published Online: December 19, 2008
708
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 699–708