Alkynenitriles: Stereoselective chelation controlled conjugate addition-alkylations

Article abstract of DOI:10.1016/S0040-4020(03)00765-8

Chelation-controlled conjugate addition of Grignard reagents to γ-hydroxyalkynenitriles stereoselectively generates tri- and tetra-substituted alkenenitriles. t-BuMgCl-initiated deprotonation of hydroxyalkynenitriles followed by addition of a second Grignard reagents triggers a facile conjugate addition leading to a cyclic magnesium chelate. Protonation of the chelate stereoselectively generates trisubstituted nitriles whereas the addition of t-BuLi causes conversion to an 'ate' complex that allows alkylation with aldehyde electrophiles. The chelation-controlled conjugate addition-alkylation generates tri- and tetra-substituted alkenenitriles that are otherwise difficult to synthesize.

Full text of DOI:10.1016/S0040-4020(03)00765-8

Tetrahedron 59 (2003) 5585–5593
Alkynenitriles: stereoselective chelation controlled conjugate
addition–alkylations
*
Fraser F. Fleming, Venugopal Gudipati and Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne University, Mellon Hall, Pittsburgh, PA 15282-1530, USA
Received 4 April 2003; revised 1 May 2003; accepted 14 May 2003
Abstract—Chelation-controlled conjugate addition of Grignard reagents to g-hydroxyalkynenitriles stereoselectively generates tri- and
tetra-substituted alkenenitriles. t-BuMgCl-initiated deprotonation of hydroxyalkynenitriles followed by addition of a second Grignard
reagents triggers a facile conjugate addition leading to a cyclic magnesium chelate. Protonation of the chelate stereoselectively generates
trisubstituted nitriles whereas the addition of t-BuLi causes conversion to an ‘ate’ complex that allows alkylation with aldehyde electrophiles.
The chelation-controlled conjugate addition–alkylation generates tri- and tetra-substituted alkenenitriles that are otherwise difficult to
synthesize. q 2003 Elsevier Science Ltd. All rights reserved.
1
. Introduction
addition through chelate 2 whereas cuprates are unreactive
toward cyclohexenecarbonitrile (1, HOvH).
1
Chelation provides a powerful means of bond construction.
Temporary chelation dramatically accelerates many reac-
tions by virtue of the close proximity imparted on the two
reactive centers, essentially harnessing the inherent entropic
The enhanced reactivity, and high stereoselectivity, of
chelation-controlled conjugate additions to alkenenitriles
suggested extending the strategy to alkynenitriles. The
attraction lies not only in enlarging chelation-controlled
conjugate additions to incorporate sp-hybridized
2
advantages of intramolecular reactions in a formal inter-
molecular process. Tethering the two reacting centers
generally imposes precise geometric constraints on the
transition state resulting in high stereoselectivity during
1
0
acceptors, but in stereoselectively assembling tri-substi-
3
11
tuted alkenenitriles (Scheme 2, R ¼H). Conceptually,
chelation-controlled conjugate addition, followed by inter-
cepting the intermediate vinyl organometallic 6 with carbon
3
bond formation, in some cases affording stereoisomers that
4
are otherwise difficult to access.
1
2
electrophiles, provides a concise route to tetra-substituted
13
5
6
Conjugate addition and carbometallation reactions,
especially, are dramatically enhanced by chelation. The
enhanced reactivity is readily apparent by comparing
alkenenitriles 7 for which few syntheses exist. This
account describes the scope of chelation-controlled con-
1
4
jugate additions to hydroxyalkynenitriles and the first
series of conjugate addition–alkylation reactions with
alkynenitriles. Collectively these chelation-controlled con-
jugate addition reactions stereoselectively assemble tri-
and tetra-substituted alkenenitriles that are otherwise
challenging synthetic targets.
7
8
chelation-controlled and organocopper conjugate
additions to alkenenitriles—substrates that are generally
recalcitrant acceptors in anionic conjugate addition reac-
9
tions. For example, sequential deprotonation of 1 with
t-BuMgCl (Scheme 1) and alkyl exchange from a variety of
Grignard reagents triggers a stereoselective conjugate
Scheme 1. Chelation-controlled conjugate addition.
Keywords: conjugate addition; alkynenitriles.
*
Corresponding author. Tel.: þ1-412-396-6031; fax: þ1-412-396-5683;
Scheme 2. Chelation-controlled conjugate addition–alkylation of
alkynenitriles.
e-mail: flemingf@duq.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00765-8

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F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
Table 1. Hydroxyalkynenitrile synthesis
Analogous lithiation–cyanations of alkynes 8b and 8c
generate the chromatographically stable alkynenitriles 4b
and 4c (Table 1, entries 2–3), with the sterically hindered
nitrile 4c imparting sufficient stability for direct double
lithiation–cyanation of the hydroxyalkyne 8c (Table 1,
entry 3).
Entry
1
Alkyne
Method
Alkynenitrile
Yield (%)
84
Hydroxyalkynenitriles 4a and 4c react with a range of
Grignard reagents in an efficient chelation-controlled
conjugate addition (Table 2). Experimentally, t-BuMgCl
deprotonates the g-hydroxyalkynenitriles permitting con-
jugate addition upon addition of a slight excess of a second,
potentially more valuable, Grignard reagent. t-BuMgCl is
AþB
2
3
AþB
76
80
2
0
an excellent sacrificial base for the initial deprotonation
A
since no transfer of the t-butyl group occurs during
deprotonation at 2788C, whereas warming to ambient
temperature with excess t-BuMgCl efficiently induces
conjugate addition of the t-butyl group (Table 2, entry 4).
High steric demand is tolerated in the Grignard reagent and
in the alkynenitrile, although the reaction efficiency is
reduced relative to reactions with less-substituted counter-
parts (compare Table 2, entry 1 with entries 4 and 9; entry 1
with entry 2; and entry 5 with entry 6).
2
. Results and discussion
A prerequisite for chelation-controlled conjugate addition
reactions is an efficient synthesis of diverse hydroxy-
alkynenitriles. A general route to hydroxyalkynenitriles
must overcome the instability of the parent 4-hydroxy-
1
5
butynenitrile (4a) toward base and silica gel chromato-
1
6
graphy
electrophilicity imparted by the proximal hydroxyl
that stems partly from the enhanced
Chelation-controlled conjugate additions of alkyl, vinyl,
aryl, and alkynyl Grignards exclusively generate E-alkene-
1
7
21
group, and partly from the accessibility of the electro-
philic b-carbon. Moderating the reactivity by THP protec-
tion of the hydroxyl group proved admirable in allowing a
high yielding deprotonation–cyanation route to the
chromatographically stable THP-protected alkynenitrile
that was subsequently converted to spectroscopically pure
nitriles. Modest halogen, silicon, and sulfur functionality
is tolerated in the Grignard reagent (Table 2, entries 10–12)
1
8
22
although the instability of the Grignard prepared from
23
3-chloropropyl phenylsulfide (Table 2, entry 11) causes
1
9
concomitant formation of 7l, presumably through conjugate
addition of PhSMgCl formed by cyclization of the Grignard
reagent.
4
a on exposure to Dowex 50-X4 (Table 1, entry 1).
Table 2. Conjugate additions to alkynenitriles
Entry
1
Alkynenitrile
Grignard reagent
MeMgCl
Alkenenitrile
Yield (%)
92
2
3
MeMgCl
70
87
i-PrMgBr
4
5
t-BuMgCl
60
92
PhMgCl

F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
5587
Table 2 (continued)
Entry
Alkynenitrile
Grignard reagent
Alkenenitrile
Yield (%)
6
7
PhMgCl
66
87
8
9
85
70
3
(n-Bu) SnMgCl
1
1
0
1
78
42
5
3
12
Me SiCH
3
2
MgCl
38
1
9
Chelate 6 is surprisingly unreactive toward alkylation—
2
alkoxide 5 that triggers the key anionic conjugate addition.
Alkyl transfer from 5 requires overlap of the s carbon–
4
even being unreactive toward benzaldehyde! The low
nucleophicity of chelate 6 is consistent with the inability of
p
p
magnesium bond with the p -LUMO where the p -node
2
7
6
to act as a vinyl Grignard reagent in a second chelation-
controlled conjugate addition with alkynenitrile 9a
Scheme 3). Competitive conjugate addition of the chelate
is only observed with Me SiCH MgCl (Table 1, entry 12),
precludes a concerted addition as does the large distance
between the magnesium and a-carbon atoms. Alkyl transfer
(
6
from 5, with activation of the nitrile by MgX , leads directly
2
2
8
to the magnesiated alkenenitrile 10 that will equilibrate to
29
3
2
2
5
presumably reflecting formation of the silicate 11n from
10n which unmasks a more reactive C–Mg bond that
competes with the hindered Me SiCH MgCl for 9a.
the cyclic chelate 6. Subsequent protonation of 6 generates
the corresponding alkenenitrile 7 with retention of stereo-
26
6
chemistry.
3
2
Mechanistically, the stepwise chelation controlled conju-
gate addition directly parallels the analogous reactions of
Chelation is essential for the conjugate addition. A control
experiment in which the THP-protected alkynenitrile 4a
HOvOTHP is exposed to n-BuMgCl leads to 90% recovery
of unreacted nitrile. Similarly, positioning the hydroxyl
group two atoms removed from the alkynenitrile prevents
7
hydroxyalkenenitriles. t-BuMgCl-induced deprotonation
of the g-hydroxyalkynenitrile followed by halogen–alkyl
5
b
exchange (Scheme 3), leads to the alkylmagnesium

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F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
Scheme 3. Chelation-controlled conjugate addition mechanism.
6
a
the conjugate addition. The inability of alkynenitrile 4b to
undergo chelation controlled conjugate addition is surpris-
ing given the related carbometallation of butynols with
Grignard reagents, and the apparently more favorable
proximity achieved by increasing the length of the tether
alkylation through a cyclic ate complex (Table 3). The
overall sequence of t-BuMgBr deprotonation, RMgX
conjugate addition, t-BuLi ate activation, and alkylation
is remarkably efficient for several Grignard reagents and
even with the potentially enolizable aldehyde 3-phenyl-
propanal (Table 3, entries 3–6). Collectively, the three
component coupling stereoselectively generates tetra-
substituted alkenenitriles that are otherwise difficult to
synthesize.
6
(
controlled conjugate addition with 4b may stem from an
Eq. (1)). Although speculative, the inability of a chelation-
3
0
31
interaction between magnesium and the p-bond which
positions the alkyl group away from the alkyne and
deactivates the alkynenitrile nitrogen toward complexation
with magnesium dihalide.
ð1Þ
The poor nucleophilicity of the chelate 6 is surprising for a
formal ‘dianion.’ Efforts to activate the chelate 6 by
2
weakening the Mg-sp bond focused on the addition of
t-BuLi for conversion to the more reactive magnesium ate
3
2
species 13 (Scheme 4). Although not proof for the
intermediacy of an ate complex, the addition of t-BuLi
3
3
sufficiently activates 6 for a stereoselective alkylation
3
with aldehydes that is consistent with a retentive
4
Scheme 4. Chelation-controlled conjugate addition–alkylations.
Table 3. Alkynenitrile conjugate addition–alkylations
Entry
Alkynenitrile
Grignard Reagent
PhMgCl
Aldehyde
PhCHO
Alkenenitrile
Yield (%)
1
60
2
i-PrMgBr
PhCHO
72

F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
5589
Table 3 (continued)
Entry
Alkynenitrile
Grignard Reagent
Aldehyde
Alkenenitrile
Yield (%)
6
5
3
4
5
6
i-PrMgBr
PhMgCl
PhMgCl
MeMgCl
57
57
61
Temporary chelation of Grignard reagents to g-hydroxy-
alkynenitriles triggers a facile conjugate addition reaction.
t-BuMgCl-initiated deprotonation of g-hydroxyalkyne-
nitriles and addition of a slight excess of a second Grignard
reagent causes a stepwise conjugate addition resulting in the
formation of a cyclic magnesium chelate. Protonation of the
chelate stereoselectively generates tri-substituted alkene-
nitriles whereas addition of t-BuLi generates a more
reactive ate complex that alkylates aromatic and aliphatic
aldehydes with complete stereochemical fidelity. Collec-
tively the chelation-controlled conjugate addition–alkyl-
ation generates a range of tri- and tetra-substituted
alkenenitriles that are otherwise difficult to synthesize.
3.1.2. 4-Hydroxy-but-2-ynenitrile (4a). An anhydrous
methanolic solution (15 mL) of 5-(tetrahydro-pyran-2-
yloxy)-pent-2-ynenitrile (0.6 g) and Dowex (pre washed
with anhydrous methanol) was stirred at room temperature
for 1.5 h. The reaction was then filtered, the residue
concentrated, and retreated with Dowex for 1.5 h to yield
295 mg (100%) of 4a as oil: IR (film) 3447, 2308,
2
1 1
2245 cm ; H NMR d 2.39 (br, 1H), 4.40 (s, 2H), 2.38
1
(s, 1H); C NMR d 50.6, 59.6, 83.1, 104.6.
3
3.1.3. 5-(Tetrahydro-pyran-2-yloxy)-pent-2-ynenitrile. A
hexanes solution (1.6 M) of n-BuLi (0.52 mL, 0.84 mmol)
3
6
was added to a 2788C, THF solution of 8b (0.13 g,
.84 mmol) followed, after 15 min, by a THF solution of
0
PhOCN (1.3 equiv.). The cooling bath was removed and,
after 15 min, aqueous NaOH (6 M) was added and followed
by ether extraction. The combined extracts were washed
sequentially with NaOH (6 M), and saturated NaCl, passed
through a short plug of silica gel (5£1 cm column), dried
3
5
3
. Experimental
.1. Data for compounds
.1.1. 4-(Tetrahydro-pyran-2-yloxy)-but-2-ynenitrile. A
3
3
over NaSO , concentrated and, purified by radial chroma-
4
hexanes solution of n-BuLi (5.4 mL, 8.6 mmol) was added
1
to a 2788C, THF solution of 8a (1.2 g, 8.6 mmol)
tography (1:10 EtOAc/hexanes) to yield 0.12 g (80%) of
5-(tetrahydro-pyran-2-yloxy)-pent-2-ynenitrile as oil: IR
8
1
9
21 1
followed, after 15 min, by a THF solution of PhOCN
1.3 equiv.). The cooling bath was removed and, after
5 min, aqueous NaOH (6 M) was added and followed by
(film) 2314, 2261 cm ; H NMR d 1.57–1.84 (m, 6H),
2.65–2.69 (m, 2H), 3.52–3.65 (m, 2H), 3.81–3.92 (m, 2H),
(
1
1
3
4.64 (brs, 1H); C NMR d 19.2, 20.6, 25.3, 30.4, 55.9, 62.3,
63.7, 84.7, 99.0, 105.1; MS e/m 178 (M2H).
ether extraction. The combined extracts were washed
sequentially with NaOH (6 M), and saturated NaCl, passed
through a short plug of silica gel (5£1 cm column), dried
3.1.4. 5-Hydroxy-pent-2-ynenitrile (4b). A methanolic
solution (10 mL) of 5-(Tetrahydro-pyran-2-yloxy)-pent-2-
ynenitrile (0.12 g) and Dowex (pre-washed with anhydrous
methanol) was stirred at room temperature for 1.5 h. The
reaction was then filtered, the residue concentrated, and
retreated with Dowex for 1.5 h to yield 63 mg (100%) of
over NaSO , concentrated, and purified by radial chroma-
4
tography (1:9 EtOAc/hexanes) to yield 1.3 g (92%) of
4
-(tetrahydro-pyran-2-yloxy)-but-2-ynenitrile as oil: IR
2
1
1
(
film) 2304, 2265 cm
;
.54–3.58 (m, 1H), 3.75–3.83 (m, 1H), 4.37 (s, 2H), 4.76
H NMR 1.52–1.84 (m, 6H),
3
1
3
21 1
(
s, 1H); C NMR d 18.6, 25.0, 29.9, 53.6, 59.7, 62.0, 81.6,
7.7, 104.6; MS m/e 164 (M2H).
4b as an oil: IR (film) 3434, 2315, 2263 cm ; H NMR
d 2.12 (s, 1H), 2.65–2.61 (s, J¼6.0 Hz, 2H), 3.82 (s,
9

5590
F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
1
3
2
H); C NMR d 23.0, 56.1, 59.3, 85.0, 105.0 MS m/e 95
3.2.5. (2E)-4-Hydroxy-3-phenylbut-2-enenitrile (7e).
(
MþH).
Performing the general conjugate addition procedure with a
THF solution (5 mL) of 4a (15 mg) and PhMgCl provided,
after purification by radial chromatography (3:7 EtOAc/
3
.1.5. 4-Hydroxy-4-methyl-pent-2ynenitrile (4c).
A
3
8
hexanes solution (1.6 M) of n-BuLi (2.96 mL, 4.75 mmol)
was added to a 2788C, THF solution of 8c (0.4 g,
4
PhOCN (1.3 equiv.). The cooling bath was removed and,
after 15 min, aqueous NaOH (6 M) was added and followed
by ether extraction. The combined extracts were washed
sequentially with NaOH (6 M), and saturated NaCl, dried
hexanes), 27 mg (92%) of 7e as an oil: IR (Film) 3446, 3060,
2221, 1623 cm2 ; H NMR d2.37(brs, 1H), 4.52(s, 2H), 5.78
1 1
1
3
.75 mmol) followed, after 15 min, by a THF solution of
(s, 1H), 7.43 (s, 5H); C NMR d 64.6, 94.2, 117.4, 127.2,
128.9, 130.1, 134.7, 163.6; MS m/e 159.
3.2.6. (2E)-4-Hydroxy-4-methyl-3-phenylpent-2-ene-
nitrile (7f). Performing the general conjugate addition
procedure with a THF solution (5 mL) of 4c (20 mg) and
PhMgCl, provided after purification by radial chromato-
graphy (1:4 EtOAc/hexanes), 22.6 mg (66%) of 7f as a light
over NaSO , concentrated and, purified by radial chroma-
4
tography (1:9 EtOAc/hexanes) to yield 0.41 g (80%) of 4c
7
3
as oil, identical to material previously synthesized.
.2. General conjugate addition procedure
brown solid: IR (film) 3440, 3060, 2229, 1614 cm2 ; H
1 1
3
NMR d 1.39 (s, 6H), 1.86 (s, 1H), 5.97 (s, 1H), 7.19–7.44
1
3
(
m, 5H); C NMR d 28.7, 73.6, 97.1, 116.9, 127.7, 128.4,
þ
þ
A THF solution of t-BuMgCl (1.0 equiv., 1–2 M) was
added to a 2788C, THF solution of the g-hydroxyalkyne-
nitrile (1 equiv.) followed, after 5 min, by a THF solution of
the appropriate Grignard reagent (1.1 equiv., 1–3 M). After
128.7; HRMS (ESI) calcd for (MþNa ) C H NONa
1
2 13
210.0889, found 210.08933.
3.2.7. (2E)-3-(Hydroxymethyl) penta-2, 4-dienenitrile
(7g). Performing the general conjugate addition procedure
with a THF solution (5 mL) of 4a (21.3 mg) and vinyl
magnesium bromide provided, after purification by radial
chromatography (1:4 EtOAc/hexanes), 25 mg (87%) of 7g
as an oil: IR (film) 3423, 2218, 1635, 1582 cm2 , H NMR d
2.08 (s, 1H), 4.51 (s, 2H), 5.54 (d, J¼11 Hz, 1H), 5.58 (d,
45 min, the reaction mixture was allowed to warm to room
temperature (15 min) and then saturated aqueous NH Cl
4
was added. The crude reaction mixture was extracted
with EtOAc the combined organic extracts were dried
(
column), concentrated, and purified by radial
chromatography.
1 1
Na SO ), passed through a short plug of silica gel (2£1 cm
2
4
1
3
J¼17 Hz, 1H), 5.69 (s, 1H), 6.87 (dd, J¼17, 11 Hz, 1H);
C
NMR: 61.0, 95.7, 116.6, 120.9, 131.4, 158.0; MS m/e 109.
3
.2.1. 4-Hydroxy-3-but-2-enenitrile (7a). Performing the
general conjugate addition procedure with a THF solution
5 mL) of 4a (20 mg) and MeMgCl provided, after
3.2.8. (2E)-3-(Hydroxymethyl)-5-phenylpent-2-en-4-yne-
nitrile (7h). Performing the general conjugate addition
procedure with a THF solution (5 mL) of 4a (30 mg) and
PhCuCMgCl provided, after purification by radial
chromatography (1:3 EtOAc/hexanes), 57.6 (85%) mg of
(
purification by radial chromatography (1:4 EtOAc/
hexanes), 22 mg (92%) of 7a spectrally identical to material
previously synthesized.
3
9
2
1a
7
h as an oil: IR (film) 3347, 3067, 2224, 2192, 1589 cm2
;
1
1
3
(
.2.2. (2E)-4-Hydroxy-3,4-dimethylpent-2-enenitrile
7b). Performing the general conjugate addition procedure
H NMR d 2.36 (s, 1H), 4.39 (s, 2H), 5.93 (s, 2H), 7.36–
1
3
8.74 (m, 5H); C NMR: 64.1, 83.2, 100.9, 102, 116.7,
þ
with a THF solution (5 mL) of 4c (20 mg) and MeMgCl
provided, after purification by radial chromatography (1:4
EtOAc/hexanes), 16.1 mg (70%) of 7b as an oil: IR (film)
121.2, 128.5, 129.9, 132.3, 145.8 MS m/e 183 (M ).
3.2.9. (2Z)-4,4-Dibutyl-3-(hydroxymethyl)-4-stannaoct-
2-enenitrile (7i). Performing the general conjugate addition
procedure with a THF solution (5 mL) of 4a (10 mg) and
2
1 1
3
(
1
410, 2932, 2215, 1601 cm ; H NMR d 1.37 (s, 6H), 2.08
1
3
s, 3H), 5.63 (s, 1H); C NMR d 17.8, 28.5, 73.6, 94.1,
17.5, 169.6; MS e/m 126 (MþH).
4
0
(Bu) SnMgCl
provided, after purification by radial
chromatography (1:4 EtOAc/hexanes), 32 mg (70%) of 7i
3
1 1
3
.2.3. (2E)-3-(Hydroxymethyl)-4-methylpent-2-ene-
as oil: IR (film) 3422, 2217, 1654 cm2 ; H NMR d 0.91 (t,
nitrile (7c). Performing the general conjugate addition
procedure with a THF solution (5 mL) of 4a (12.9 mg) and
i-PrMgBr provided, after purification by radial chromato-
graphy (3:7 EtOAc/hexanes), 17.3 mg (87%) of 7c as an oil:
J¼7.0 Hz, 9H), 1.12–1.64 (m, 18H), 4.42 (s, 2H), 6.26 (s,
1
3
1H); C NMR d 10.1, 13.6, 27.2, 29.0, 68.1, 105.5, 118.9,
176.7; MS m/e 373 (M ).
þ
2
1
1
IR (film) 3447, 2221, 1628 cm ; H NMR d 1.16 (d,
J¼7.2 Hz, 6H), 1.21 (br s, 1H), 3.10 (sept, J¼7 Hz, 1H),
3.2.10. (2E)-7-Chloro-3-(hydroxymethyl)-hept-2-eneni-
trile(7j). Performingthegeneralconjugateadditionprocedure
with a THF solution (5 mL) of 4a (15 mg) and chlorobutyl-
1
3
4
1
.30 (s, 2H), 5.53 (s, 1H); C NMR d 20.5, 32.2, 61.0, 91.9,
16.9, 172.1; MS m/e 126 (MþH).
4
1
magnesium bromide provided, after purification by radial
chromatography (3:7 EtOAc/hexanes), 25 mg (78%) of 7j as
an oil: IR (Film) 3435, 2220, 1639 cm2 , H NMR d 1.63–
1 1
3
.2.4. (2E)-3-(Hydroxymethyl)-4,4-dimethylpent-2-ene-
nitrile (7d). Performing the general conjugate addition
procedure with a THF solution (5 mL) of 4a (16.2 mg) and
t-BuMgCl provided, after purification by radial chromato-
graphy (1:4 EtOAc/hexanes), 16.5 mg (60%) of 7d as an oil:
1.73 (m, 2H), 1.80–1.89 (m, 2H), 2.42 (t, J¼7.5 Hz, 2H), 3.57
1
3
(t, J¼6.0 Hz, 2H), 4.26 (s, 2H), 5.59 (s, 1H); C NMR: 25.3,
31.2, 31.6, 44.3, 63.9, 94.3, 116.8, 166.2; MS m/e 173 (MþH).
2
1 1
IR (film) 3483, 2219, 1636 cm ; H NMR d 1.32 (s, 9H),
1
3.2.11. (2E)-3-(Hydroxymethyl)-6-phenylthiohex-2-ene-
nitrile (7k) and (2Z)-4-hydroxy-3-phenylthiobut-2-ene-
nitrile (7l). Performing the general conjugate addition
3
1
3
.75 (s, 1H), 4.32 (s, 2H), 5.72 (s, 1H); C NMR d 28.9,
6.2, 62.4, 91.4, 118.0, 173.2; MS m/e 140 (MþH).

F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
5591
procedure with a THF solution (5 mL) of 4a (16 mg) and
2
EtOAc/hexanes), 41.1 mg (72%) of 7p as an oil: IR (Film)
2
21 1
PhS(CH ) MgCl provided, after purification by radial
2
3414, 2217, 1603 cm ; H NMR d 1.09 (d, J¼6.7 Hz, 3H),
1.15 (d, J¼7.1 Hz, 3H), 2.64 (s, 1H), 3.13–3.22 (m, 1H), 3.45
(s, 1H), 4.30(ABq, Dn¼31.5 Hz, J¼12.3 Hz, 2H), 5.79 (s, 1H),
3
chromatography (3:7 EtOAc/hexanes), 19.3 mg (42%) of 7k
and 20 mg (53%) of 7l as an oils. For 7k IR (film) 3426,
2
1
1
13
3
1
060, 2219, 1632, 1584 cm ; H NMR d 1.60 (br s, 1H),
.78–1.88 (m, 2H), 2.51 (dd, J¼8 Hz, 2H), 2.95 (t,
7.32–7.45 (m, 5H); C NMR d 20.2, 20.3, 35.2, 57.0, 70.0,
116.5, 117.0 126.0, 128.7, 140.1, 163.4 MS m/e 231 (M2H).
J¼7.3 Hz, 2H), 4.20 (s, 2H), 5.57 (s, 1H), 7.17–7.60 (m,
1
3
5
1
2
(
1
H); C NMR d 27.6, 31.0, 33.5, 64.0, 94.6, 126.4, 129.0,
29.8, 165.7; MS e/m 233. For 7l IR (film) 3438, 3058,
216, 1579 cm2 ; H NMR d 2.03 (s, 1H), 4.07 (s, 2H), 5.81
3.3.3. (2Z)-3-(Hydroxymethyl)-2-(1-hydroxy-3-phenyl-
propyl)-4-methylpent-2-enenitrile (7q). Performing the
general conjugate addition–alkylation procedure with a
THF solution (5 mL) of 4a (12 mg), i-PrMgCl and
3-phenylpropanal provided, after purification by radial
chromatography (3:7 EtOAc/hexanes), 24.9 mg (65%) of
1 1
1
3
s, 1H), 7.27- 7.55 (m, 5H); C NMR d 64.1, 93.6, 127.9,
þ
29.9, 134.7, 162; MS m/e 191 (M ).
7q as an oil: IR (film) 3410, 2214, 1603 cm2 ; H NMR d
1.07 (d, J¼6.4 Hz, 3H), 1.15 (d, J¼6.3 Hz, 3H), 1.70 (br s,
1H), 1.97–2.21 (m, 2H), 2.32 (br s, 1H), 2.74 (t, J¼7.5 Hz,
2H), 3.14–3.23 (m, 1H), 4.14 (s, 2H), 4.55 (t, J¼6.8 Hz, 1H),
1 1
3
2
.2.12. (2Z)-3-(Hydroxymethyl)-5,5-dimethyl-5-silahex-
-enenitrile (7m) and (2E)-1-[1-(2,2-dimethyl-2-sila-
propyl)-2-hydroxyethylidene]-2-(hydroxymethyl)prop-
-ene-1,3-dicarbonitrile (7n). Performing the general
conjugate addition procedure with a THF solution (5 mL)
2
1
3
7.12–7.31 (m, 5H); C NMR d 20.2, 20.4, 31.8, 35.1, 36.8,
of 4a (20 mg) and (CH ) SiCH MgCl provided, after
3
57.0, 67.4, 116.3, 117.1, 126.2, 128.4, 128.5, 140.8, 164.3.
3
2
purification by radial chromatography (3:7 EtOAc/
hexanes), 16 mg (38.3%) of 7m and 14 mg (19.4) of 7n as
3.3.4. (2E)-4-Hydroxy-2-(1-hydroxy-3-phenylpropyl)-3-
phenylbut-2-enenitrile (7r). Performing the general con-
jugate addition–alkylation procedure with a THF solution
(5 mL) of 4a (15 mg), PhMgCl and 3-phenylpropanal
provided, after purification by radial chromatography (3:7
EtOAc/hexanes), 30.9 mg (57%) of 7r as an oil. IR (film)
1
an oils. For 7m: IR (Film) 3456, 2215, 1620; H NMR d
1
3
0
NMR d 21.0, 24.6, 65.3, 89.2, 118.1, 166.7; MS m/e 169.
.12 (s, 9H), 1.94 (s, 2H), 4.13 (s, 2H), 5.39 (s, 1H);
C
2
1 1
For 7n: IR (Film) 3456, 2221, 1630 cm ; H NMR d 0.22
s, 9H), 2.38 (s, 2H), 4.27 (s, 2H), 4.36 (s, 2H), 5.84 (s, 1H);
(
1
3
21
1
C NMR d-0.8, 28.0, 62.4, 63.3, 100.2, 100.6, 116.3, 157.1,
67.5; MS m/e 250 (MþH).
3386, 2216, 1602 cm ; H NMR d 2.1–2.24 (m, 2H),
2.74–2.78 (m, 2H), 3.20 (brs, 2H), 4.39 (AB , Dn¼40.0 Hz,
1
q
J¼13.4 Hz, 2H), 4.69 (t, J¼7 Hz, 1H), 7.20–7.38 (m, 10H);
1
3
3
.3. General conjugate addition–alkylation procedure
C NMR: 31.7, 37.1, 62.3, 67.6, 116.9, 118.2, 126.3, 127.8,
28.4, 128.6, 128.8, 129.6, 137.5, 140.6, 157.4.
1
A THF solution of t-BuMgCl (1.0 equiv., 1–2 M) was added
to a 2788C, THF solution of the g-hydroxyalkynenitrile
3.3.5. (2Z)-4-Hydroxy-2-(1-hydroxy-3-phenylpropyl)-4-
methyl-3-phenylpent-2-enenitrile (7s). Performing the
general conjugate addition–alkylation procedure with a
THF solution (5 mL) of 4c (17 mg), PhMgCl and 3-phenyl-
propanal provided, after purification by radial chromato-
graphy (3:7 EtOAc/hexanes), 28.5 mg (57%) of 7s as an oil;
(
1 equiv.) followed, after 5 min, by a THF solution of the
appropriate Grignard reagent (1.1 equiv., 1–3 M). After
5 min, the reaction mixture was allowed to warm to room
4
temperature (15 min), re-cooled to 2788C, and then a hexanes
solution of t-BuLi (1.2 equiv., 1.5 M) was added. The cooling
bath was then removed, and after 15 min neat aldehyde
IR (film) 3434, 2215, 1602 cm2 ; H NMR d 1.25 (s, 3H),
1 1
(
aqueous saturated NH Cl. The crude reaction mixture was
1.5 equiv.) was added, followed, after a further 30 min, by
1.36 (s, 3H), 1.40–1.60 (m, 2H), 2.01–2.27 (m, 2H), 2.72–
1
3
2.92 (s, 2H), 5.22–5.27 (m, 1H), 7.20–7.71 (m, 10H);
C
4
extracted with EtOAc, the combined extracts were passed
through a short plug of silica gel (2£1 cm column),
concentrated, and purified by radial chromatography.
NMR: 30.6, 31.4, 32.1, 37.2, 67.1, 74.9, 116.8, 120.1, 126.1,
127.1, 127.9, 128.5, 139.4, 141.2, 165.1; HRMS (ESI) calcd
þ
for (MþNa ) C H NO 344.1621, found 344.1611.
2
1
23
2
3.3.1. (2Z)-4-Hydroxy-2-(hydroxyphenylmethyl)-3-
phenylbut-2-enenitrile (7o). Performing the general con-
jugate addition–alkylation procedure with a THF solution
3.3.6. (2Z)-4-Hydroxy-2-(1-hydroxy-3-phenylpropyl)-
3,4-dimethylpent-2-enenitrile (7t). Performing the general
conjugate addition–alkylation procedure with a THF
solution (5 mL) of 4c (20 mg), MeMgCl and 3-phenyl-
propanal, provided after purification by radial chromato-
graphy (3:7 EtOAc/hexanes), 29 mg (61%) of 7t as an oil:
(
5 mL) of 4a (10 mg), PhMgCl and PhCHO provided, after
purification by radial chromatography (3:7 EtOAc/
hexanes), 19.6 mg (60%) of 7o as a light brown solid (mp
23–1258C): IR (film) 3388, 2219, 1595 cm2 ; H NMR d
1
1
IR (film) 3433, 2211, 1602 cm ; H NMR d 1.21–1.37 (m,
1H), 1.34 (s, 3H), 1.42 (s, 3H), 1.94–2.20 (m, 2H), 2.09 (s,
3H), 2.65–2.85 (m, 3H), 5.07–5.12 (m, 1H), 7.18–7.46 (m,
21 1
1
4
.55–4.57 (m, 2H), 5.40–5.42 (m, 1H, exchanges with
D O), 5.94–5.96 (m, 1H), 6.21 (d, J¼4.0 Hz, 1H,
2
1
3
13
exchanges with D O), 7.26–7.50 (m, 10H); C NMR d
2
5H); C NMR: 22.0, 29.7, 30.3, 32.0, 37.3, 66.8, 75.2,
116.5, 117.7, 125.9, 128.4 (doubled), 141.3, 161.8; MS m/e
259 (M2OH).
6
1
0.6, 67.6, 117.4, 118.2, 125.9, 127.3, 128.1, 138.5, 141.6,
56.0 MS m/e 247 (M2H O).
2
3
.3.2. (2Z)-3-(Hydroxymethyl)-2-(hydroxyphenyl-
methyl)-4-methylpent-2-enenitrile (7p). Performing the
general conjugate addition–alkylation procedure with a THF
solution (5 mL) of 4a (20 mg), i-PrMgCl and PhCHO
provided, after purification by radial chromatography (4:6
Acknowledgements
Financial support of this research from NIH, and travel
funds from NSF, are gratefully acknowledged.

5592
F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
demand in the THP-protected alkynenitrile, or locating the
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1
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1
2
4
(
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4
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a
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a
(
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2
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8
7
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1
1
1
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assignment with the Z-stereochemistry of 7p–7t being
assigned by analogy. The authors have deposited the crystal-
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Data Center (CCDC 177267). The data can be obtained, on
request, from the Director, Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge, CB2 1EZ, UK.
1971, 30, 682.
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able absorption on the silica gel.
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with an adjacent hydroxyl group whereas the increased steric
34. No alkylation was observed with MeI, allyl bromide, TMSCl,

F. F. Fleming et al. / Tetrahedron 59 (2003) 5585–5593
5593
PhCOCl or MeOCOCl although alkylation of related
38. An unusually high CuN frequency and minor discrepancies in
NMR shifts were previously reported for nitrile 7e: Tanyeli,
C.; Demir, A. S.; Akhmedov, I. M.; Ozgiil, E.; Kandemir, C. G.
Synth. Commun. 1996, 26, 2967.
a-magnesioalkenenitrile is possible by conversion to the
2
corresponding cuprate.
6a
3
5. For general experimental procedures see: Fleming, F. F.;
Hussain, Z.; Weaver, D.; Norman, R. E. J. Org. Chem. 1997,
6
39. Prepared by reacting 1.5 equiv. of phenylacetylene with
1.5 equiv. of MeMgCl at 08C for 15 min.
2, 1305. The high-resolution mass spectra were recorded at
4
0. Prepared by reacting (Bu) SnH (1.3 equiv.) with MeMgCl
3
The Ohio State University Campus Chemical Instrumentation
Center.
(1.3 equiv.) at 08C for 10 min.
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3
6. Commercially available from Aldrich Chemical Co.
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J. Organomet. Chem. 1975, 93, 129.