Cyclohexylcarbonitriles: Diastereoselective arylations with TMPZnCl·LiCl

Article abstract of DOI:10.1021/jo301127n

Deprotonating substituted cyclohexanecarbonitriles with TMPZnCl·LiCl affords zincated nitriles that diastereoselectively couple with aryl bromides in the presence of catalytic Pd(OAc)₂ and S-Phos. Steric and electronic effects influence the dia

Full text of DOI:10.1021/jo301127n

Note
pubs.acs.org/joc
Cyclohexylcarbonitriles: Diastereoselective Arylations with
TMPZnCl·LiCl
Robert J. Mycka,† Stephanie Duez,‡ Sebastian Bernhardt,‡ Johannes Heppekausen,‡ Paul Knochel,*,‡
́
and Fraser F. Fleming*,†
†Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, United States
‡Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377, Munchen, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Deprotonating substituted cyclohexanecarbonitriles
with TMPZnCl·LiCl affords zincated nitriles that diastereoselectively
couple with aryl bromides in the presence of catalytic Pd(OAc)2 and S-
Phos. Steric and electronic effects influence the diastereoselectivity; 4-t-
butyl-, 4-TBSO-, and 2-Me-cyclohexanecarbonitriles exert virtually
complete diastereocontrol whereas modest diastereoselectivity is observed with 4-i-Pr-, 4-Me-, and 3-Me-cyclohexanecarboni-
triles. The unusual diastereoselectivity trends should prove useful for synthesizing substituted cyclohexanecarbonitrile-containing
pharmaceuticals.
ubstituted arylacetonitriles are prevalent motifs embedded
within diverse pharmaceuticals (Figure 1).1 Typically the
bases11 in combination with palladium catalysts are particularly
efficacious for the direct arylation of aliphatic nitriles.
As a prelude to developing a diastereoselective cross coupling
of cyclohexanecarbonitriles, cyclohexanecarbonitrile (5a) was
deprotonated with the powerful base TMPZnCl·LiCl12 and
coupled with aryl halides (Scheme 1). During optimization with
S
Scheme 1. α-Arylation of Cyclohexanecarbonitrile (5)
Figure 1. Arylacetonitrile pharmaceuticals.
Pd(OAc)2 and S-Phos,13 4-iodobenzonitrile was found to afford
significant amounts of [1,1′-biphenyl]-4,4′-dicarbonitrile
whereas the corresponding bromide did not. The optimized
procedure involves deprotonating cyclohexanecarbonitriles with
TMPZnCl·LiCl for 20 min followed by the addition of S-Phos,
Pd(OAc)2, and aryl bromide and then heating to 50 °C. Under
the optimized conditions, 5a couples with the electron deficient
t-butyl 4-bromobenzoate (6a) to afford nitrile 7a and with the
hindered, electron-rich 1-bromo-2-methoxybenzene (6b) to
form 7b (Scheme 1). The coupling conditions tolerate the
presence of the t-butyl ester, although the corresponding ethyl
ester suffers competitive attack from the metalated nitrile.
nitrile-bearing carbon is fully substituted, as in the blockbuster
drug anastrazole (1)2 and the well-studied antiarrhythmic agent
verapamil (2).3 Conspicuous among nitrile-containing pharma-
ceuticals is the aryl-substituted cyclohexanecarbonitrile phar-
macophore as contained within the second-generation H1-
receptor antagonist levocabastine (3)4 and the antiasthmatic
cilomilast (4).5 Cilomilast (4) and related arylacetonitriles are
being pursued as inhibitors of phosphodiesterase 4.6
Several excellent methods access aryl-substituted nitriles
through Pd-catalyzed α-arylation.7 Typically palladated nitriles
are accessed by metalation-transmetalation sequences,8 decar-
boxylation,9 or cleavage of silylketenimines,7c followed by
coupling with an aryl halide and a catalyst-ligand combina-
tion.10 Among these approaches, tetramethylpiperidine (TMP)
Received: June 1, 2012
Published: August 16, 2012
© 2012 American Chemical Society
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Note
Table 1. Diastereoselective Cyclohexanecarbonitrile Coupling
a
b
c
1
No diastereomers were detected. Ratio determined by H NMR Spectroscopy. Ratio determined by GC.
Controlling the arylation diastereoselectivity in cross
Coupling a range of cyclohexanecarbonitriles 518 with 4-
bromobenzonitrile (6c) and 1-bromo-4-methoxybenzene (6d)
as representative electron deficient and electron rich aryl
bromides, respectively, provides insight into the diastereose-
lective arylation of substituted cyclohexanecarbonitriles (Table
1). 4-t-Butylcyclohexanecarbonitrile (5b) was employed as a
conformationally constrained prototype because extensive
alkylations provide stereoselectivity trends relating the hybrid-
couplings of substituted cyclic nitriles is a significant challenge.14
Related arylations of substituted cyclohexanones15 and cyclo-
hexylcarboxylate-derived enolates16 exhibit stereoselectivities in
which electronic effects of the substituent and the aryl halide
exert unusual diastereoselectivity trends that sometimes do not
correlate with the substituents’ steric demand.17
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Note
ization of the nucleophilic carbon to the alkylation ratio.19 The
arylation of 4-t-butylcyclohexanecarbonitrile (5b) with electron
deficient 6c is greater than 20:1 (7c, Table 1, entry 1) but is
diminished to 8.4:1 with the more electron rich aromatic 6d
(7d, Table 1, entry 2).20 In comparable couplings with 4-
bromobenzonitrile (6c), the steroidal nitrile 7e and the silyloxy
nitrile 7f are formed with essentially complete stereoselectivity
(Table 1, entries 3 and 4, respectively) whereas an analogous
arylation with 4-isopropylcyclohexanecarbonitrile (5e) pro-
ceeds with reduced diastereoselectivity (2.3:1 for 7g, Table 1,
entry 5).21
Coupling 4-methyl-cyclohexanecarbonitrile (5f) and 3-
methyl-cyclohexanecarbonitrile (5g) with electron rich and
electron deficient aryl bromides installs quaternary centers with
diastereoselectivities in the range of 3.5−6.2:1 (Table 1, entries
6−8). The diastereoselectivity is only modestly influenced by
the electronic character of the aryl bromide (compare entry 1
with entry 2 and entry 6 with entry 7) whereas the nature and
position of the substituent has a dramatic effect. Moving the
methyl group progressively closer to the nitrile-bearing carbon
increases the diastereoselectivity (Table 1, compare entry 6, 7h,
with entries 8 and 9, 7j and 7k, respectively), and is highest for
2-methyl-cyclohexanecarbonitrile (5h) which forms 7k bearing
adjacent tertiary and quaternary centers (Table 1, entry 9).
Mechanistically, the reaction most likely proceeds through
zincation,11 transmetalation to palladium, and reductive
elimination (Scheme 2).7 Deprotonating 5 with
diastereoselectivity difference not present in the corresponding
isopropyl and methyl analogs 5e and 5f, respectively.
Consistent with the relayed electronic influence from the
remote C-4 substituent is the virtually exclusive diastereocon-
trol for the 4-OTBS cyclohexanecarbonitrile (5d) which has a
significantly smaller steric demand than either a t-butyl or i-Pr
substituent (0.7, 4.2, and 2.2 kcal mol−1 for OTBS, t-Bu, and i-
Pr groups, respectively)26 and yet couples with virtually
complete diastereoselectivity.
The coupling of 2-methylcyclohexanecarbonitrile (5h) is
highly diastereoselective (Table 1, entry 9). Presumably the C-
palladated nitrile25 9 (R2 = Me) exerts a strong preference for
conformer 9a where the small nitrile and vicinal methyl groups
are gauche to avoid steric compression between a gauche
methyl group and the sterically demanding palladium-SPhos
complex (cf. 9b).
Deprotonating cyclohexanecarbonitriles with TMPZnCl·LiCl
and coupling with aryl bromides diastereoselectively affords
substituted cyclohexanecarbonitriles. The diastereoselectivity
trends are unusual in exhibiting a strong electronic dependence
on the nature of the aryl bromide and the substituents on the
cyclohexane ring. 4-t-Butyl-, 4-TBSO-, and 2-Me substituents
exert virtually complete stereocontrol whereas 4-i-Pr, 4-Me, and
3-Me substituents are significantly less selective. Collectively
these alkylations are the first diastereoselective arylations of
cyclic nitriles and establish unusual stereoelectronic effects that
should prove useful in synthesizing cyclohexanecarbonitrile-
containing pharmaceuticals.
Scheme 2. Metalated Nitrile Coupling Mechanism
EXPERIMENTAL SECTION
■
General Procedure for the Conversion of Ketones to
Nitriles. Modifying a known procedure,18 solid t-BuOK (1.2 equiv)
was added to a vigorously stirred, THF solution (0.1 M) of the ketone
(1 equiv). After 20 min solid toluenesulfonylmethyl isocyanide
(TosMIC, 1.2 equiv) was added. After 4 h, a saturated, aqueous
NH4Cl solution was added, the phases were separated, and the
aqueous phase was extracted with Et2O (3×). The combined organic
extracts were dried (Na2SO4), concentrated, and purified by silica gel
(230−400 mesh) chromatography to afford analytically pure material.
4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarbonitrile (5d).
Two portions of solid NaBH4 (360 mg, 9.51 mmol) were added to a 0
°C, methanolic solution (20 mL) of 4-oxocyclohexanecarbonitrile28
(585 mg, 4.75 mmol). After 30 min the ice bath was removed and after
1 h the solvent was under reduced pressure. The concentrate dissolved
in EtOAc (100 mL), extracted with water (100 mL), dried (Na2SO4),
and then the solvent was evaporated under reduced pressure. The
crude hydroxynitrile 270.7 mg (2.16 mmol) was dissolved in DMF (5
mL) and then TBSCl (244.8 mg, 1.62 mmol) and imidazole (229.4
mg, 3.36 mmol) were added. After 16 h a solution of aqueous,
saturated NH4Cl (20 mL) was added, the phases were separated, and
the aqueous phase extracted with ether (100 mL). The organic phase
was dried (Na2SO4), the solvent was evaporated under reduced
pressure, and the crude silyl ether nitrile was purified by column
chromatography (hexanes) to afford 318.3 mg (82% yield) of 5d as a
mixture of diastereomers:29 IR (neat) 2239 cm−1; 1H NMR (400
MHz, CDCl3) δ 3.81−3.74 (m, 1H), 2.63 (m, 1H), 2.09−1.99 (m,
2H), 1.89−1.76 (m, 1H), 1.72−1.52 (m, 4H), 1.49−1.33 (m, 1H),
0.89 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 122.32, 122.25, 67.45, 66.69, 32.12, 27.13, 25.71, 17.99, −4.87;
HRMS (ESI-TOF) m/z calcd for C13H25NOSiNa (M + Na) 262.1603;
found 262.1615.
TMPZnCl·LiCl affords a C-zincated nitrile22 that likely
equilibrates through a conducted tour C → N → C metal
migration sequence23 to 8 with zinc in the equatorial
orientation.24 Transmetalation of the zincated nitrile 8 with
an arylpalladium bromide would afford the C-palladated nitrile
9 with subsequent reductive elimination affording nitrile 7.25
Variations in the diastereomeric ratio for the same carbonitrile
with different aryl bromides (Table 1, entries 1−2 and 6−7)
implies that an equilibrium exists between axial and equatorial
C-palladated nitriles 9a and 9b. A similar electronic influence
on the equilibrium between 9a and 9b is implied from the
distinctly different diastereomeric ratios of the t-butyl- and
isopropylcyclohexane carbonitriles (Table 1, compare entries 1
and 5) which typically exert similar conformational restric-
tion.26 An electronic influence from the remote 4-t-butyl
substituent decreases the s character at the metalated carbon,
because of a bond angle distortion at C-4,27 causing a
4-Isopropylcyclohexanecarbonitrile (5e). Performing the gen-
eral cyanation procedure with 4-isopropylcyclohexanone (1.00 g, 7.13
mmol), t-BuOK (0.96 g, 8.56 mmol), and TosMIC (1.67 g, 8.55
mmol) gave the crude nitrile that was purified by column
chromatography (95:5, hexanes/EtOAc) to afford 0.865 g (80%
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Note
yield) of 5e as an oily mixture of diastereomers:30 IR (neat) 2230
cm−1; 1H NMR (400 MHz, CDCl3) δ 2.94−2.90 (m, 1H), 2.33 (tt, J =
4.0, 12.5 Hz, 1 H), 2.15−2.10 (m, 2H), 2.10−1.98 (m, 2H), 1.81−1.76
(m, 2H), 1.58−1.52 (m, 2H), 1.50−1.33 (m, 4H), 1.12−1.02 (m, 2H),
1.02−0.95 (m, 2H), 0.89 (d, J = 7.0 Hz, 6H), 0.85 (d, J = 6.5 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 122.84, 122.16, 43.22, 42.54, 32.39,
29.99, 28.51, 28.29, 27.14, 25.60, 19.60, 19.50; HRMS (ESI-TOF) m/z
calcd for C10H17NNa (M + Na) 174.1259; found 174.1246.
4-Methylcyclohexanecarbonitrile (5f). Performing the general
cyanation procedure with 4-methylcyclohexanone (1.00 g, 7.13
mmol), t-BuOK (1.20 g, 10.7 mmol), and TosMIC (2.09 g, 10.7
mmol) gave the crude nitrile that was purified by column
chromatography (95:5, hexanes/EtOAc) to afford 0.829 g (75%
yield) of 5f as an oily mixture of diastereomers:31 1H NMR (400 MHz,
CDCl3) δ 2.99−2.94 (m, 1H), 2.43 (tt, J = 4.0, 12.4 Hz, 1 H), 2.09−
2.04 (m, 3H), 1.91−1.86 (m, 3H), 1.84−1.75 (m, 3H), 1.75−1.64 (m,
3H), 1.48−1.32 (m, 4H), 1.32−1.15 (m, 4H), 0.93 (d, J = 6.8 Hz,
3H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 122.74,
122.45, 37.89, 36.41, 34.01, 33.65, 31.78, 29.54, 28.28, 28.25, 27.20,
25.02, 22.17, 22.13, 21.82; HRMS (ESI-TOF) m/z calcd for
C8H10NNa (M − 3H + Na) 143.0694; found 143.0702.
3-Methylcyclohexanecarbonitrile (5g). Performing the reaction
according to the general cyanation procedure using 3-methylcyclohex-
anone (1.00 g, 7.13 mmol), t-BuOK (1.20 g, 10.69 mmol), and
TosMIC (2.09 g, 10.70 mmol) gave the crude nitrile that was purified
by column chromatography (85:15, pentane/ether) to afford 0.847 g
(77% yield) of the nitrile 5g as an oily mixture of diastereomers:32 1H
NMR (400 MHz, CDCl3) δ 2.98−2.94 (m, 1H), 2.43 (tt, J = 3.6, 12.4
Hz, 1 H), 2.11−2.00 (m, 3H), 1.95−1.87 (m, 2H), 1.85−1.75 (m,
3H), 1.74−1.65 (m, 4H), 1.50−1.40 (m, 2H), 1.30−1.14 (m, 4H),
0.93 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 122.73, 122.41, 37.92, 36.43, 36.43, 34.02, 33.66,
31.79, 29.56, 28.52, 2827, 25.03, 22.15, 21.79; HRMS (ESI-TOF) m/z
calcd for C8H14N (M + H) 124.1126; found 124.1096.
2-Methylcyclohexanecarbonitrile (5h). Performing the reaction
according to the general cyanation procedure using 2-methylcyclohex-
anone (2.03 g, 18.10 mmol), t-BuOK (2.48 g, 22.10 mmol), and
TosMIC (4.42 g, 22.64 mmol) gave the crude nitrile that was purified
by column chromatography (85:15, pentane/ether) to afford 1.86 g
(83% yield) of the nitrile 5h as an oily mixture of diastereomers
exhibiting spectral properties identical to that exhibited by previously
isolated material:33 1H NMR (400 MHz, CDCl3) δ 2.83−2.79 (m,
1H), 2.12−1.98 (m, 3H), 1.79−1.53 (m, 11H), 1.36−1.15 (m, 4H),
1.12 (d, J = 6.4 Hz), 1.08 (d, J = 6.4 Hz), 1.04−0.90 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 122.28, 120.66, 36.18, 35.29, 34.65, 33.82,
33.50, 30.65, 29.98, 28.70, 25.11, 25.03, 24.88, 21.93, 20.79, 20.07.
δ 165.09, 145.68, 131.61, 129.69, 125.48, 122.14, 81.22, 44.53, 37.20,
28.14, 24.86, 23.46; HRMS (ESI-TOF) m/z calcd. for C18H23NO2
(M+) 285.1728; found 285.1702.
1-(2-Methoxyphenyl)cyclohexanecarbonitrile (7b). Perform-
ing the general coupling procedure with cyclohexanecarbonitrile (5a,
91.9 mg, 0.81 mmol), TMPZnCl·LiCl (1.30 M, 0.81 mL, 1.26 mmol),
SPhos (10.6 mg, 4 mol %), Pd(OAc)2 (2.9 mg, 2 mol %) and 2-
bromoanisole (0.80 mL, 0.647 mmol) and purification of the crude
nitrile by column chromatography (95:5, pentane/ether) afforded 88.5
mg (64% yield) of 7b36 as an oil: IR (neat) 2229 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.35−7.31 (m, 2H), 6.99−6.95 (m, 2H), 3.93 (s, 3H),
2.40 (br d, J = 1.2 Hz, 2H), 1.89−1.77 (m, 6H), 1.30−1.27 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 157.57, 129.14, 129.07, 125.94,
122.50, 120.80, 112.18, 55.57, 40.82, 34.55, 25.31, 23.34.
4-((1SR,4SR)-4-(tert-Butyl)-1-cyanocyclohexyl)benzonitrile
(7c). Performing the general coupling procedure with 4-(tert-
butyl)cyclohexanecarbonitrile (5b, 122 mg, 0.738 mmol),19
TMPZnCl·LiCl (1.25 M, 0.89 mL, 1.11 mmol), SPhos (9.3 mg, 4
mol %), Pd(OAc)2 (2.6 mg, 2 mol %) and 4-bromobenzonitrile (103.4
mg, 0.568 mmol) and purification of the crude nitrile by column
chromatography (95:5, pentane/ether) afforded 113.5 mg (75% yield)
of (1SR,4SR)-7c: IR (neat) 2230 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.70 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 2.26−2.19 (m,
2H), 2.00−1.93 (m, 2H), 1.81 (tt, J = 3.2, 12.8 Hz, 2H), 1.68−1.57
(m, 2H), 1.13 (tt, J = 3.2, 12.0 Hz, 1H), 0.94 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 146.33, 132.72, 126.58, 121.55, 118.22, 112.02, 47.00,
44.73, 37.56, 32.45, 27.44, 24.54; HRMS (ESI-TOF) m/z calcd for
C18H22N2 (M+) 266.1783; found 266.1763.
(1SR, 4SR)-4-(tert-Butyl)-1-(4-methoxyphenyl)-
cyclohexanecarbonitrile (7d). Performing the general coupling
procedure with 4-(tert-butyl)cyclohexanecarbonitrile19 (5b, 138 mg,
0.758 mmol), TMPZnCl·LiCl (1.25 M, 1.00 mL, 1.25 mmol), SPhos
(10.5 mg, 4 mol %), Pd(OAc)2 (2.9 mg, 2 mol %) and 4-bromoanisole
(0.08 mL, 0.637 mmol) gave the crude nitrile that was purified by
column chromatography (97:3, pentane/ether) to afford 103.6 mg
(60% yield) of (1SR,4SR)-7d as an oily mixture of diastereomers
(8.4:1 ratio) that were separated by preparative HPLC. For
1
(1SR,4SR)-7d: IR (neat) 2239 cm−1; H NMR (400 MHz, CDCl3)
δ 7.41 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.22
(br d, J = 10.8 Hz, 2H), 1.93 (br d, J = 12.8 Hz, 2H), 1.75 (dt, J = 2.8,
12.8 Hz, 2H), 1.66−1.54 (m, 2H), 1.10 (tt, J = 3.2, 12 Hz, 1H), 0.93
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.99, 133.37, 126.67,
122.92, 114.10, 55.3247.10, 43.46, 37.89, 32.42, 27.49, 24.70; HRMS
(ESI-TOF) m/z calcd for C18H25NONa (M + Na) 294.1834; found
294.1811. For (1RS,4SR)-7d: 1H NMR (400 MHz, CDCl3) δ 7.39 (d,
J = 9.2 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 2.75−2.67 (m,
2H), 2.13−2.03 (m, 2H), 1.72−1.63 (m, 2H), 1.17−1.05 (m, 2H),
0.93−0.85 (m, 1H), 0.77 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
158.85, 128.89, 128.42, 152.50, 114.35, 55.27, 47.21, 37.27, 35.27,
32.36, 27.27, 21.98; HRMS (ESI-TOF) m/z calcd for C18H25NONa
(M + Na) 294.1834; found 294.1832.
General Coupling Procedure.
A THF solution of
TMPZnCl·LiCl34 (1.5 equiv) was added, dropwise, to a THF solution
(2 mL) of the nitrile in a 25 mL Schlenk-tube. After 20 min, complete
deprotonation was checked by removing an aliquot and treating with
allyl bromide and a catalytic amount CuCN·2LiCl solution (1 M in
THF).35 Upon complete metalation, SPhos (4 mol %),13 Pd(OAc)2 (2
mol %) and the electrophile (0.6 equiv) were added and then the
reaction mixture was placed in an oil bath at 50 °C. Reaction progress
was checked by GC analysis of aliquots quenched with a solution of
NH4Cl. Upon completion, saturated, aqueous NH4Cl was added, the
phases were separated, and the aqueous phase was extracted with
ether. The combined organic phase was dried (Na2SO4), the solvent
was evaporated under reduced pressure, and the crude nitrile was then
purified by silica gel flash chromatography or radial chromatography.
tert-Butyl 4-(1-cyanocyclohexyl)benzoate (7a). Performing the
general coupling procedure with cyclohexanecarbonitrile (5a, 91.9 mg,
0.842 mmol), TMPZnCl·LiCl (1.30 M, 0.81 mL, 1.26 mmol), SPhos
(10.6 mg, 4 mol %), Pd(OAc)2 (2.9 mg, 2 mol %) and t-butyl 4-
bromobenzoate (166.4 mg, 0.647 mmol) and purification of the crude
nitrile by column chromatography (95:5, pentane/ether) afforded
128.1 mg (75% yield) of 7a as a white solid (mp 93−96 °C): IR (neat)
2235, 1706 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.8 Hz,
2H), 7.55 (d, J = 8.8 Hz, 2H), 2.18−2.13 (m, 2H), 1.93−1.73 (m,
6H), 1.59 (s, 9H), 1.35−1.24 (m, 2H); 13C NMR (100 MHz, CDCl3):
(3S,5R,8S,9R,10R,13S,14R,17S)-3-(4-Cyanophenyl)-10,13-di-
methyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1H-
cyclopenta[a]phenanthrene-3-carbonitrile (7e). Performing the
general coupling procedure with (5R,8S,9R,10R,13S,14R,17S)-10,13-
dimethyl-17-((R)-6-methylheptan-2-yl)hexadeca-hydro-1H-
cyclopenta[a]phenanthrene-3-carbonitrile18 (61.6 mg, 0.155 mmol),
TMPZnCl·LiCl (2.0 M, 0.77 mL, mmol), SPhos (4.0 mg, 4 mol %),
Pd(OAc)2 (1.2 mg, 2 mol %) and 4-bromobenzonitrile (29.1 mg,
0.160 mmol) gave the crude nitrile that was purified by column
1
chromatography (hexanes) to afford 92.7 mg (72% yield) of 7e: H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0
Hz, 2H), 2.05−0.97 (m, H), 0.91 (d, J = 8.0 Hz, 3H), 0.88 (s, 3H),
0.89 × 2 (d, J = 8.0 Hz, 3H), 0.67 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 146.32, 132.73, 126.59, 122.19, 118.27, 111.93, 56.25, 56.13,
53.65, 45.28, 43.42, 42.54, 39.78, 39.48, 38.81, 36.11, 35.79, 35.58,
35.44, 35.37, 32.93, 31.52, 28.19, 28.00, 27.99, 24.13, 23.81, 22.83,
22.55, 20.95, 18.64, 12.20, 12.07. HRMS (ESI-TOF) m/z calcd for
C35H50N2Na (M + Na) 521.3872; found 521.3836.
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Note
4-((1SR, 4SR)-4-((tert-Butyldimethylsilyl)oxy)-1-
cyanocyclohexyl)benzonitrile (7f). Performing the general cou-
pling procedure with 4-((tert-butyldimethylsilyl)oxy)-
cyclohexanecarbonitrile (5d, 109.4 mg, 0.457 mmol), TMPZnCl·LiCl
(0.86M, 0.89 mL, 0.685 mmol), SPhos (7.5 mg, 4 mol %), Pd(OAc)2
(2.1 mg, 2 mol %) and 4-bromobenzonitrile (55.3 mg, 0.304 mmol)
gave the crude nitrile that was purified by radial chromatography
(92:8, hexanes/EtOAc) to afford 73.5 mg (71% yield) of (1SR,4SR)-
7f: IR (neat) 2232 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
8.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 3.70−3.62 (m, 1H), 2.21−2.15
(m, 2H), 2.05−1.99 (m, 2H), 1.68−1.57 (m, 2H), 1.97−1.92 (m, 1H),
1.91−1.82 (m, 3H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 145.49, 132.76, 126.60, 121.23, 118.12, 112.18, 69.51, 43.68,
35.59, 32.83, 25.76, 18.07, −4.63; HRMS (ESI-TOF) m/z calcd for
C20H28N2OSiNa (M + Na) 363.1869; found 363.1852.
4-((1SR,4SR)-1-Cyano-4-isopropylcyclohexyl)benzonitrile
(7g). Performing the general coupling procedure with 4-isopropylcy-
clohexanecarbonitrile (5e, 103.8 mg, 0.686 mmol), TMPZnCl·LiCl
(1.04M, 1.00 mL, 1.04 mmol), SPhos (11.3 mg, 4 mol %), Pd(OAc)2
(3.1 mg, 2 mol %) and 4-bromobenzonitrile (123.6 mg, 0.679 mmol)
gave the crude nitrile that was purified by column chromatography
(95:5, pentane/ether) to afford 123.7 mg (72% yield) of 7g as an oily
mixture of diastereomers (2.3:1 ratio): IR (neat) 2230 cm−1; HRMS
(ESI-TOF) m/z calcd for C17H20N2Na (M + Na) 275.1524; found
275.1501. For (1SR,4SR)-7g: 1H NMR (500 MHz, CDCl3) δ 7.69 (d,
J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 2.24−2.16 (m, 2H), 1.94−
1.87 (m, 2H), 1.79 (dt, J = 3.5, 13.5 Hz, 2H), 1.64−1.52 (m, 3H),
1.21−1.11 (m, 1H), 0.94 (d, J = 7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 146.311, 132.70, 126.56, 118.23, 111.94, 44.78, 42.82, 37.24,
32.42, 26.74, 19.73. For (1RS,4SR)-7g: 1H NMR (500 MHz, CDCl3)
δ 2.04−1.98 (m, 2H), 1.89−1.84 (m, 2H), 1.35−1.30 (m, 1H), 0.89
(d, J = 6.5, 6H); 13C NMR (100 MHz, CDCl3) δ 146.38, 132.75,
127.19, 118.20, 111.98, 44.78, 42.82, 37.24, 32.89, 24.92.
2 mol %) and 4-bromobenzonitrile (198.9 mg, 1.093 mmol) gave the
crude nitrile that was purified by column chromatography (90:10,
pentane/ether) to afford 171 mg (70% yield) of 7j as a mixture of
diastereomers (6.2:1 ratio). For (1SR,3SR)-7j: IR (neat) 2230 cm−1;
1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.62 (d, J =
7.8 Hz, 2H), 2.15−2.07 (m, 2H), 2.04−1.94 (m, 1H), 1.93−1.85 (m,
3H), 1.67 (dt, J = 4.2, 12.6 Hz), 1.39 (dd, J = 12.0, 12.6 Hz, 1H), 1.01
(d, J = 6.4 Hz, 3H), 1.05−0.98 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 146.29, 132.64, 126.48, 121.70, 118.14, 111.89, 44.97, 36.68,
36.61, 33.47, 29.87, 23.32, 21.89; HRMS (ESI-TOF) m/z calcd for
C15H16N2 (M+) 224.1313; found 224.1312. For (1RS,3SR)-7j: 1H
NMR (400 MHz, CDCl3) δ 2.54−2.42 (m, 2H), 1.71−1.61 (m, 1H),
1.45−1.30 (m, 1H), 1.21−1.11 (m, 1H), 1.00 (d, J = 6.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 143.65, 132.79, 127.94, 123.8, 112.01,
42.60, 39.19, 34.69, 33.11, 27.26, 21.52, 20.57; HRMS (ESI-TOF) m/z
calcd for C15H16N2 (M+) 224.1313; found 224.1312.
4-((1RS,2SR)-1-Cyano-2-methylcyclohexyl)benzonitrile (7k).
Performing the general coupling procedure with 2-methylcyclohex-
anecarbonitrile (5h, 165.0 mg, 1.34 mmol), TMPZnCl·LiCl (1.40 M,
1.44 mL, 2.02 mmol), SPhos (5.0 mg, 4 mol %), Pd(OAc)2 (17.0 mg,
2 mol %) and 4-bromobenzonitrile (187.7 mg, 1.031 mmol), except
performing the deprotonation at 50 °C for 12 h, gave the crude nitrile
that was purified by column chromatography (90:10, pentane/ether)
to afford 117.6 mg (51% yield) of (1RS, 2SR)-7k: IR (neat) 2230
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.61
(d, J = 8.4 Hz, 2H), 2.08−1.77 (m, 6H), 1.62−1.52 (m, 2H), 1.44−
1.38 (m, 1H), 0.79 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 145.45, 132.68, 126.85, 119.79, 118.25, 111.80, 51.77, 40.12, 39.12,
31.81, 25.44, 23.41, 17.72; HRMS (ESI-TOF) m/z calcd for
C15H16N2Na (M + Na) 247.1206; found 247.1200.
ASSOCIATED CONTENT
■
S
* Supporting Information
4-((1SR,4SR)-1-Cyano-4-methylcyclohexyl)benzonitrile (7h).
Performing the general coupling procedure with 4-methylcyclohex-
anecarbonitrile (5f, 90.0 mg, 0.731 mmol), TMPZnCl·LiCl (1.25 M,
0.88 mL, 1.10 mmol), SPhos (9.2 mg, 4 mol %), Pd(OAc)2 (2.5 mg, 2
mol %) and 4-bromobenzonitrile (102.3 mg, 0.679 mmol) gave the
crude nitrile that was purified by column chromatography (90:10,
pentane/ether) to afford 85.8 mg (68% yield) of 7h as a mixture of
diastereomers (3.5:1 ratio): IR (neat) 2231 cm−1; 13C NMR (100
MHz, CDCl3) δ 146.28, 132.67, 126.91, 126.55, 121.54, 118.16,
111.97, 111.95, 44.39, 37.13, 31.81, 31.52, 28.82, 21.95, 21.86; HRMS
(ESI-TOF) m/z calcd for C15H16N2Na (M + Na) 247.1211; found
247.1206. For (1SR,4SR)-7h: 1H NMR (600 MHz, CDCl3) δ 7.69 (d,
J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 2.17−2.13 (m, 2H), 1.90−
1.85 (m, 2H), 1.81 (dt, J = 3.6, 13.2 Hz, 2H), 1.03 (d, J = 6.0 Hz, 3H).
1H NMR, and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Paul.Knochel@cup.uni-muenchen.de; flemingf@duq.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
For (1RS,4SR)-7h: H NMR (400 MHz, CDCl3) δ 2.06−1.95 (m,
Financial support for this research from The Center for
Advanced Studies, Ludwig Maximilians University (Munich)
and the NSF (CHE 0808996 and 1111406 and CHE 0614785
for NMR facilities) is gratefully acknowledged.
2H), 1.01 (d, J = 6.6, 3H).
(1SR,4SR)-1-(4-Methoxyphenyl)-4-methylcyclohexanecarbo-
nitrile (7i). Performing the general coupling procedure with 4-
methylcyclohexanecarbonitrile (5f, 68.0 mg, 0.552 mmol),
TMPZnCl·LiCl (1.25M, 0.67 mL, 0.838 mmol), SPhos (7.9 mg, 4
mol %), Pd(OAc)2 (2.2 mg, 2 mol %) and 4-bromoanisole (0.06 mL,
0.478 mmol) gave the crude nitrile that was purified by radial
chromatography (95:5, hexanes/EtOAc) to afford 79.8 mg (68%
yield) of 7i as a mixture of diastereomers (4.8:1 ratio): 13C NMR (100
MHz, CDCl3) δ 158.98, 158.96, 133.44, 133.36, 127.70, 127.16,
126.68, 123.57, 122.96, 114.19, 114.10, 55.31, 43.16, 37.50, 32.13,
31.70, 29.06, 22.06; HRMS (ESI-TOF) m/z calcd for C15H19NOK (M
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7675
dx.doi.org/10.1021/jo301127n | J. Org. Chem. 2012, 77, 7671−7676

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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on August 16, 2012. Minor
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