Regio- and Stereocontrol in the Reactions of α-Halo-β,γ-enoates and α- O -Phosphono-β,γ-enenitriles with Organocuprates

Article abstract of DOI:10.1021/jo502111c

The reactions of (Z)- and (E)-ethyl 2-chloro-3-octenoate (4a and 17) and (E)- and (Z)-diethyl (1-cyano-2-heptenyl)phosphate (21a and 21b) with organocuprates were investigated as potential substrates for preparing γ-substituted α,β-enoates and enenitriles. In these copper-mediated allylic substitution reactions, the Z-isomer 4a displayed complete regio- and stereoselectivity (i.e., E:Z), while the regio- and stereoselectivity for E-isomer 17 varied as a function of solvent, cuprate reagent, transferable ligand, and cuprate counterion (e.g., Li⁺ vs MgX⁺). Excellent selectivities could be achieved with 17 and ⁿBuCuCNLi in Et₂O. Conditions for improved selectivities in the reactions of allylic cyanophosphates over those previously reported were found. A series of relative rate and competition experiments was performed, and the degree of regio- and stereoselectivity for each system was rationalized in the light of the current mechanistic understanding of cuprate-mediated allylic substitution reactions.

Full text of DOI:10.1021/jo502111c

Article
pubs.acs.org/joc
Regio- and Stereocontrol in the Reactions of α‑Halo-β,γ-enoates and
α‑O‑Phosphono-β,γ-enenitriles with Organocuprates
R. Karl Dieter* and Alfredo Picado
Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, South Carolina 29634-0973, United States
S
* Supporting Information
ABSTRACT: The reactions of (Z)- and (E)-ethyl 2-chloro-3-octenoate (4a and 17) and (E)- and (Z)-diethyl (1-cyano-2-
heptenyl)phosphate (21a and 21b) with organocuprates were investigated as potential substrates for preparing γ-substituted α,β-
enoates and enenitriles. In these copper-mediated allylic substitution reactions, the Z-isomer 4a displayed complete regio- and
stereoselectivity (i.e., E:Z), while the regio- and stereoselectivity for E-isomer 17 varied as a function of solvent, cuprate reagent,
transferable ligand, and cuprate counterion (e.g., Li+ vs MgX+). Excellent selectivities could be achieved with 17 and nBuCuCNLi
in Et2O. Conditions for improved selectivities in the reactions of allylic cyanophosphates over those previously reported were
found. A series of relative rate and competition experiments was performed, and the degree of regio- and stereoselectivity for
each system was rationalized in the light of the current mechanistic understanding of cuprate-mediated allylic substitution
reactions.
Organocuprate-mediated allylic substitution on dialkyl α-
cyano-β-alkenylphosphate derivatives was first performed on
enantioenriched (E)-allylic cyanohydrin O-phosphates to afford
α,β-conjugated nitriles,7 which were then hydrolyzed with
strong acids to yield the unsaturated esters after esterification.
The protocol always afforded alkene E:Z mixtures with poor
stereoselectivity. Subsequently, Posner and co-workers pre-
pared enantioenriched (E)-α-chloro-β,γ-enoates from (E)-γ-
seleno-α,β-enoates by modification of the protocol of Paulmier
and co-workers8 and explored organocopper-mediated allylic
substitution reactions on these substrates. Although the method
was used for the preparation of γ-methyl-α,β-enoates,5 γ-amino-
α,β-enoates,5 and rhodanines,9 the method was largely limited
to methylation using Me2CuMgBr. Cuprates with Ph, allyl, and
vinyl ligands gave no reaction, while Et-, Pr-, and Bu-derived
cuprates gave nonseparable mixtures of SN2 and SN2′
products.6 We now report our efforts to control the regio-
and stereoselectivity in the reactions of organocuprates with α-
nucleofuge-substituted-β,γ-enoates and nitriles through exami-
nation of solvent, temperature, leaving group, cuprate
composition, and alkene configuration (i.e., E vs Z) of the
substrate.
INTRODUCTION
■
Small, highly functionalized synthons provide opportunities for
divergent synthesis via chemo-, regio-, and stereocontrolled
reaction pathways and through tandem or sequential
reactions.1,2 The presence of multiple functional groups along
a connected sequence of carbon atoms also provides
opportunities for remote functionalization. Allylic systems
with additional functionality on the allylic position containing
the leaving group are attractive candidates for employing this
strategy. Although copper-mediated allylic substitution reac-
tions have been extensively studied and developed, control of
regio- and stereoselectivity is too often substrate- and reagent-
dependent and difficult to control.3 Much progress has been
made in the development of asymmetric allylic substitution
(AAS) reactions involving chiral substrates or chiral reagents.3,4
Enantioenriched α-alkylations have been achieved with α,β-
enoates with a leaving group in the γ-position,4e−h while
racemic vinyloxiranes2d and δ-acetoxy-γ-halo-α,β-enoates2f
afford excellent diastereoselectivity in a one-pot bis-allylic
substitution methodology. Mixtures of products with (SN2′)
and without (SN2) rearrangement of the double bond, present
as E:Z double bond isomers or as diastereomeric mixtures when
additional stereogenic centers are present, are often obtained,
and these mixtures are normally difficult to separate.2d,5−7
These difficulties have been recently reported in copper-
mediated alkylation of α-chloro-β,γ-unsaturated esters5,6 and
allylic cyanohydrin phosphates7 with organocopper reagents.
i
t
Received: September 12, 2014
Published: October 10, 2014
© 2014 American Chemical Society
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RESULTS
Table 1. Reaction of Allylic Substrates 5a−d and 4a,b
■
Containing Different Nucleofuges with Lithium Alkyl- and
Although α-chloro-β,γ-unsaturated esters have been em-
ployed10 for the allylation of aldehydes and imines via bis-
allylpalladium intermediates and photochemical studies have
been reported for α-fluoro derivatives,11 there are few methods
available for their preparation. They can be prepared from
trimethylsiloxy-α-diazocarbonyl esters but this method gives
mixtures of α- and γ-halo unsaturated esters.12 The trans-α-
chloro and -α-bromo-β,γ-unsaturated esters used in this study
were most easily prepared from γ-phenylseleno-α,β-unsaturated
esters,8 while the Z-isomers were prepared in two steps from
terminal alkynes (Scheme 1). Although alkynyl alcohol 2 has
Phenylcuprate Reagents
a
yield
c
Scheme 1. Synthesis of (Z)-Ethyl 2-Chloro-3-octenoate
a
b
entry
substrate
reagent (equiv)
nBuCuCNLi (1.2)
nBu2CuLi (1.0)
product
(%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5c
5c
5c
5d
5d
5d
5d
5d
4a
4a
4a
4a
4b
4b
4b
6a
6a
6b
6b
6a
6a
6b
6b
6c
6a
6b
6c
6d
6d
6a
6b
6c
6a
6b
6c
6d
6d
6a
6b
6c
6d
6a
6d
6d
76
73
55
53
75
71
56
55
18
88
63
20
22
11
78
68
33
82
65
38
58
26
95
88
63
75
98
53
40
MeCuCNLi (1.2)
Me2CuLi (1.0)
nBuCuCNLi (1.2)
nBu2CuLi (1.0)
MeCuCNLi (1.2)
Me2CuLi (1.0)
d
9
PhCuCNLi (1.2)
nBuCuCNLi (1.2)
MeCuCNLi (1.2)
PhCuCNLi (1.2)
e
10
e
11
de
,
12
13
14
15
16
17
18
19
20
a
n
Reagents and conditions: (a) (i) 1 (n equiv), BuLi (n equiv), THF,
e g
−
CH3N(Boc)CH2CuCNLi (1.2)
(CH3N(Boc)CH2)2CuLi (1.0)
nBuCuCNLi (1.2)
−78 °C, 1 h; (ii) ZnBr2 (n = 1, 2, 3:1.0, 0.5, 0.33 equiv, respectively);
(iii) MeLi (3 − n equiv), −60 to 25 °C, 1.5 h. (b) Freshly distilled
HOCCO2Et, PhMe, −60 to −20 °C (85%). (c) Lindlar catalyst,
quinoline (1.1 equiv), MeOH, H2, 25 °C, 4 h (88%). (d) PPh3 (1.3
equiv), CCl4, 75 °C, 1.5 h (85%). (e) PBr3 (2.0 equiv), DMF, −15 °C,
1 h (75%).
egh
,
d
d
,
MeCuCNLi (1.2)
PhCuCNLi (1.2)
nBuCuCNLi (1.2)
MeCuCNLi (1.2)
PhCuCNLi (1.2)
fgi
,
21 ,
CH3N(Boc)CH2CuCNLi(1.2)
(CH3N(Boc)CH2)2CuLi (1.0)
nBuCuCNLi (1.2)
been prepared in low yields by addition of alkynyl Grignard
reagents to esters of oxalic acid (28%),13 we developed a more
effective procedure using organozincate reagents. The
dialkynyl(methyl)zincate reagent proved to be most effective,
as it transferred both alkynyl ligands. Lindlar reduction14 of
alkyne 2 followed by conversion of alcohol 3 into chloride15 4a
completed the synthesis without double bond migration or E/
Z-isomerization of the Z-alkene. Allylic alcohol 3 has also been
prepared enantioselectively from ethyl glyoxylate and (Z)-1-
trimethylsilyl-1-hexene.16 Preparation of compound 4b from 3
with PBr3 afforded the E-isomer as a minor impurity.
gh
,
22
23
24
25
26
27
MeCuCNLi (1.2)
PhCuCNLi (0.9)
hi
,
CH3N(Boc)CH2CuCNLi (1.2)
nBuCuCNLi (1.2)
fg
28 ,
CH3N(Boc)CH2CuCNLi (1.2)
(CH3N(Boc)CH2)2CuLi (1.0)
gh
,
29
a
THF as solvent with a composition for the reaction of 10/1 solvent/
organometallic solvent unless otherwise noted. Cuprates were
prepared from THF-soluble CuCN·2LiCl. Reactions were performed
b
In pursuit of a synthetic objective, we attempted to couple
the N-Boc-2-pyrrolidinyl ligand with various (Z)-α-nucleofuge-
substituted-β,γ-enoates without success. Examination of these
substrates (i.e., 5a−d and 4a,b) was then undertaken in order
to understand their reactivity profile with lithium alkyl(cyano)-
(i.e., RCuCNLi) and dialkylcuprates (i.e., R2CuLi). The allylic
phosphates 5a,b,17 mesylate 5c,18 pentafluorobenzoate17b,19 5d,
and halides 4a,b all gave a single product in modest to good
yields with methyl and n-butylcuprates (Table 1). Higher yields
were obtained with the n-butylcuprates, and surprisingly, similar
yields were obtained with both RCuCNLi and R2CuLi reagents
(entries 1 vs 2, 3 vs 4, 5 vs 6, 7 vs 8) with phosphates 5a,b. In
situ generation of the phosphate ester gave slightly higher yields
than utilization of the preformed substrate (entries 10 vs 5, 11
vs 7). Yields were generally comparable along the series
−OPO(OR)2 ≈ −OMs ≈ −CO2C6F5 and slightly higher for
at −78 °C for 2 h and then warmed up to room temperature (rt) with
c
overall stirring of 8−12 h. Upon the basis of isolated material purified
d
by column chromatography. Biphenyl was the major product of this
e
f
reaction. Phosphate prepared in situ. Solvent THF:Et2O (1:2).
Starting material was recovered. Solvent THF:Et2O (1:1). Reaction
conditions: −40 °C for 1 h and then slowly warmed to rt (−40 to 25
g
h
i
°C, 2 h, then 12 h at 25 °C).
15, 18, 23, and 27 and 3, 7, 11, 16, 19, 24). Phenyl(cyano)-
cuprates gave low yields with the phosphates (entries 9 and
12), mesylate (entry 17), and pentafluorobenzoate (entry 20)
due to biphenyl formation2b,20,21 and modest yields with the
chloride 4a (entry 25), suggesting a higher reactivity for the
latter substrate. In most cases, low yields were obtained with
the α-(N-carbamoyl)alkyl(cyano)cuprates (entries 13, 21, and
28), with chloride 4a giving the highest yield (entry 26) and the
n
the halides with the Bu- and methylcuprates (entries 1, 5, 10,
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Table 2. Reaction of (Z)-Ethyl 2-Chloro-3-octenoate with Organocuprate Reagents
a
b
c
d
entry
reagent (equiv)
nBu2CuLi (1.0)
yield (%)
product
6:7:8
1
2
75
6a
6a
6a
6a
8a
7a
6a
6a
6b
6b
6f
100:0:0
100:0:0
100:0:0
100:0:0
nBuCuCNLi (1.0−1.2)
nBuCuCNLi (1.2)
nBuCuCNLi (1.2)
nBuCuCNLi (1.2)
nBuCuCNLi (1.2)
nBuCuCNMgCl (1.2)
nBu2CuMgCl (1.0)
MeCuCNLi (1.2)
Me2CuLi (1.0)
85−95
76
e
3
f
g
4
31
h
i
5
17
8a major
7a major
94:0:6
j
i
6
23
7
77
8
78
92:0:8
9
88
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
99:0:1
10
11
12
13
59
sBuCuCNLi (1.2)
tBuCuCNLi (1.2)
tBu2CuLi (1.0)
57
81
6e
6e
6d
6c
6c
6g
6h
6i
50
kl
,
14
15
16
17
18
19
20
CH3N(Boc)CH2CuCNLi (1.0−1.2)
Ph2CuLi (1.0)
70−75
30
m
PhCuCNLi (0.9−1.2)
60−63
73
CH3OC6H4CuCNLi (1.2)
C10H8CuCNLi (1.2)
75
CH2CH−CH2CuCNMgCl (1.2)
(CH2CH−CH2)2CuMgCl (1.2)
66
52
6i
100:0:0
a
THF as solvent with a composition for the reaction of 10/1 solvent/organometallic solvent unless otherwise noted. Cuprates were prepared from
THF-soluble CuCN·2LiCl. Reactions were performed at −78 °C for 2 h and then warmed up to rt with overall stirring of 8−12 h. Upon the basis
of isolated material purified by column chromatography. Determined by H NMR integration of absorption peaks for the vinyl protons. Solvent
Et2O. Solvent CH2Cl2. Starting material recovered. Solvent DMF. Unidentified byproducts found. Solvent CH3CN. Solvent THF:Et2O (1:2).
Reaction was run at −78 (26%), −40 (75%), and 0 °C (58%) for 1 h and then slowly warmed to rt. Biphenyl was the major product of this
b
c
d
e
1
f
g
h
i
j
k
l
m
reaction.
Table 3. Catalytic Procedure for γ-Alkylation of (Z)-Ethyl 2-Chloro-3-octenoate
a
b
c
d
entry
reagent (equiv)
solvent
yield (%)
product
6:7:8
e
f
1
nBuMgCl, CuCN (0.15)
nBuLi, CuCN·2LiCl (0.33)
nBuMgCl, CuCN (0.33)
nBuLi, CuCN (0.33)
nBuMgCl, CuCN (0.33)
nBuLi, CuCN (0.33)
nBuMgCl, CuCN (0.33)
nBuLi, CuCN (0.33)
nBuMgCl, CuCN (0.33)
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
THF
THF
Et2O
70
72
88
67
81
81
97
56
76
44
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
94:0:6
e
f
2
100:0:0
e
f
3
91:0:9
e
f
4
100:0:0
e
f
5
98:0:2
g
h
h
6
100:0:0
98:0:2
g
7
g
8
100:0:0
74:0:16
88:0:12
g
9
g
10
MeMgBr, CuCN (0.33)
a
b
Cuprate reagent was prepared over 30 min from −60 to −30 °C from solid CuCN unless otherwise noted. Solvent with a composition for the
c
d
reaction of solvent/organometallic solvent of 10/1. Upon the basis of isolated material purified by column chromatography. Isomer ratios were
e
f
1
determined from integration of the H NMR absorption peaks for the vinyl protons. Reaction quenched after 4 h at −78 °C. Starting material
g
h
recovered. Reaction done for 1 h at −78 °C and then slowly warmed up to room temperature for an overall reaction time of 4 h. Unidentified
byproducts found.
bis α-(N-carbamoyl)alkylcuprates (entries 14, 22, and 29)
giving significantly lower yields. The coupling of N-Boc-2-
pyrrolidinylcuprates with substrates 5a−d and 4a,b could not
be accomplished. Formation of homocoupling products
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Table 4. Cuprate Allylic Alkylation of Methyl 2-Chloro-3-butenoate (9) and (Z)-Ethyl 2-Chloro-4-phenyl-3-butenoate (13)
a
b
c
d
entry
halide
reagent (equiv)
major isomer
yield (%)
10:11:12 or 14:15:16
e
1
2
3
4
9
nBuCuCNLi (1.2)
nBuCuCNLi (0.75)
nBuCuCNMgCl (0.75)
nBuCuCNLi (1.2)
10a
10a
10a
6c
35
38
31
93
76
62
80
67
88
53
91
89:11:0
e
9
91:9:0
e
9
88:12:0
13
13
13
13
13
13
13
13
55:0:45
75:0:25
f
5
nBuCuCNLi (1.2)
6c
f
e
6
nBuLi (1.2)/CuCN (0.33)
nBuCuCNMgCl (1.2)
nBuCuCNMgCl (1.2)
MeCuCNLi (1.2)
6c
85:0:15
7
16a
6c
30:0:70
f
g
8
51:0:49
9
14b
14b
16b
84:0:16
f
e
10
MeLi (1.2)/CuCN (0.33)
MeCuCNMgBr (1.35)
78:0:22
11
28:0:72
a
THF as solvent, unless otherwise noted, with a composition for the reaction of 10/1 solvent/organometallic solvent unless otherwise noted.
b
Cuprates were prepared from THF-soluble CuCN·2LiCl. Reactions were performed at −78 °C for 2 h and then warmed up to room temperature
c
d
with overall stirring of 8−12 h. Yields are based upon isolated products purified by column chromatography. Isomer ratios were determined from
e
f
1
integration of the H NMR absorption peaks of the vinyl protons. Unidentified byproducts found. Solvent Et2O. Cuprates were prepared from
solid, insoluble CuCN [from −70 °C (or −60 °C, substoichiometric CuCN) to −40 °C (or −30 °C, substoichiometric CuCN)], by stirring for 30
g
min before cooling to −78 °C. Starting material was recovered.
suggests that a single electron transfer (SET) reaction takes
place over the intended allylic substitution.20
pattern (entries 19 and 20), giving lower yields of 6i for the
diallylcuprate reagent.
Upon completion of the leaving group and cuprate
composition studies, we turned our attention to exploring the
scope of ligand efficacy in these allylic substitution reactions.
Although the phosphate, mesylate, and pentafluorobenzoate
leaving groups2,19 all gave comparable yields, ethyl (Z)-2-
chloro-3-octenoate (4a) was chosen for further study because it
afforded higher product yields upon reaction with PhCuCNLi
and CH3N(Boc)CH2CuCNLi (entries 25 and 26). Addition-
ally, 4a was easier to prepare and was stable to Z to E
isomerization in the refrigerator for 6 months.22
In pursuit of a catalytic procedure, several reactions were run
using 0.15−0.33 equiv of solid CuCN with either alkyl lithium
or magnesium reagents. Initially the reaction mixtures were
quenched at −74 °C, giving good yields of products 6a,b
(Table 3, entries 1−5) but accompanied by recovery of 10−
20% of starting material. The reactions could be brought to
completion by slowly allowing the reaction mixture to warm to
room temperature (entries 6−10), and with the magnesium
cuprate a yield of 97% could be achieved (entry 7) with the n-
butyl Grignard reagent. Utilization of Grignard reagents
generally gave lower SN2′:SN2-regioselectivity (entries 1, 3, 5,
7, 9, and 10), while regiospecificity was obtained with the
lithium reagents (entries 2, 4, 6, and 8). In accord with prior
studies,2e use of lithium reagents required a minimum of 0.33
equiv of a Cu(I) salts, while lower amounts of Cu(I) salts could
be employed with the Grignard reagents (entry 1). The stability
of these substrates to the presence of organolithium reagents is
noteworthy.
Although lithium di-n-butylcuprate and lithium n-butyl-
(cyano)cuprate reagents gave comparable yields of 6a in
THF and Et2O (Table 2, entries 1−3), low yields were
obtained in CH2Cl2 (entry 4), DMF (entry 5), or CH3CN
(entry 6). For the solvents CH2Cl2, DMF, and CH3CN, the
cuprate reagent was prepared by mixing RLi and CuCN·2LiCl
in THF and then adding the desired solvent. Utilization of
magnesium n-butylcuprate reagents afforded similar yields of 6a
but slightly reduced SN2′:SN2 regioselectivity (entries 7 and 8).
It is interesting to note that the SN2-regioisomer (i.e., 8a)
retained the alkene Z-configuration. Similar results were
Two additional substrates were examined to explore the
scope of the reaction. These included the γ-unsubstituted
analogue 923 and the phenyl-substituted derivative 1315,24
(Table 4). Allylic chloride 9 gave low yields of alkylation
products accompanied by an orange brown precipitate in the
reaction mixture, indicative of polymer formation,25 and
significant amounts of the Z-alkene stereoisomer 11a when
s
t
obtained for the Me, Bu, and Bu transferable ligands, giving
modest to good yields of 6b, 6f, and 6e, respectively, and
excellent regioselectivity (entries 9−13). Again, the alkyl-
(cyano)cuprates gave higher yields than the dialkylcuprate
reagents (entries 9 vs 10, and 12 vs 13). Good results were
obtained for the N-(tert-butoxycarbonyl)-N-methylaminome-
thylcuprate reagent to give 6d (entry 14) but the procedure
could not be extended to the 2-pyrrolidinylcuprate analogue.
The arylcuprates generally gave good chemical yields of 6c, 6g,
and 6h and excellent SN2′:SN2-regioselectivity (entries 16−18)
with the exception of Ph2CuLi (entry 15), which gave low
yields of 6c due to homocoupling and biaryl formation.20,21
The magnesium allylcuprate reagents displayed the same
n
reacted with BuCuCNM (M = Li, MgCl, entries 1−3). The
phenyl-substituted derivative 13 gave the SN2-substitution
products 16a,b either in significant amounts (entries 4−6 and
8−10) or as the major stereoisomer (e.g., entries 7 and 11). For
the lithium cuprates, higher SN2′-regioselectivity was achieved
in Et2O than in THF (entries 5 and 6 vs 4) and with
substoichiometric amounts of CuCN (entry 6), where R2CuLi
is presumed to be the active agent. The magnesium n-
butyl(cyano)cuprate gave the SN2-product 16a as the major
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Table 5. Reaction of (E)-Ethyl 2-Chloro-3-octenoate with Organocuprate Reagents
a
b
c
d
entry
reagent (equiv)
nBuCuCNLi (1.2)
nBuCuCNLi (1.2)
nBuCuCNLi (1.2)
nBu2CuLi (1.0)
nBuCuCNMgCl (1.2)
nBuCuCNMgCl (1.2)
nBuCuCNMgCl (1.2)
nBu2CuMgCl (1.0)
nBuCuCNMgCl (1.2)
yield (%)
product
6:7:18
1
70
83
9
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
6c
89:6:5
98:0:2
e
2
f
g
3
100:0:0
h
4
5
56
97
71
49
71
96
95
95
60
77
88
55
37
89
67
85
95
87
43
84:8:8
82:14:4
86:10:4
e
6
f
7
32:23:45
79:17:4
83:12:5
81:15:4
76:24:0
86:14:0
97:1:2
8
i
9
10
nBuMgCl (1.2), CuCN (0.15)
nBuMgCl (2.10), CuCN (1.05)
nBuMgCl (1.2), CuCN (0.15)
nBuLi (1.2), CuCN (0.33)
nBuMgCl (1.2), CuCN (0.33)
MeCuCNLi (1.2)
j
11
k
12
ek
,
13
14
15
16
17
18
19
20
21
22
ek
,
91:7:2
97:1:2
h
Me2CuLi (1.0)
100:0:0
MeCuCNMgBr (1.2)
84:3:13
94:2:4
88:3:9
98:1:1
100:0:0
Me2CuMgBr (1.0)
f
j
MeCuCNMgBr (1.2)
MeMgBr (1.2), CuCN (0.15)
MeMgBr (2.10), CuCN (1.05)
PhCuCNLi (1.1)
h
100:0:0
a
THF as solvent with a composition for the reaction of 10/1 solvent/organometallic solvent unless otherwise noted. Cuprates were prepared from
b
THF soluble CuCN·2LiCl. Reactions were performed at −78 °C for 2 h and then warmed up to room temperature with overall stirring for 8−12 h.
c
d
e
Yields are based upon isolated products purified by column chromatography. Ratios were determined by 13C NMR peak heights. Solvent Et2O.
Cuprates were prepared from solid insoluble CuCN [from −70 °C (or −60 °C, substoichiometric CuCN) to −40 °C (or −30 °C, substoichiometric
f
CuCN), stir for 30 min before cooling to −78 °C]. Solvent CH2Cl2. Cuprates prepared from CuCN·2LiCl in THF and then diluted 10 times with
g
h
i
CH2Cl2. Starting material recovered. Unidentified byproducts found. Reaction conditions: −40 °C for 1 h and then slowly warm to 25 °C.
j
Posner’s procedure: LiCl was not used. Cuprate formation and reaction conditions: 30 min at −78 °C, reaction mixture quenched at −78 °C 30 min
after the addition of the electrophile. Reaction quenched after 4 h at −78 °C.
k
regioisomer in THF (entry 7) and a nearly 1:1 mixture of
stereoisomers in Et2O (entry 8). The putative reagent Me2CuLi
gave a slightly lower SN2′-regioselectivity (entry 10) than
MeCuCNLi (entry 9), although different solvents were
employed. A less reactive magnesium methyl(cyano)cuprate
reagent gave the SN2-substitution product 16b as the major
isomer in THF (entry 11).
Posner and co-workers had reported the clean SN2′-
methylation of (E)-α-chloro-β,γ-unsaturated esters but noted
complex product mixtures for other alkylcuprate reagents.5 We
decided to reinvestigate this reaction in order to explore the
role of substrate E:Z geometry (Table 5). As observed by
Posner and co-workers, E-stereoisomer 17 afforded more
complex reaction mixtures upon reaction, with cuprate reagents
generally yielding mixtures of SN2′-derived E:Z stereoisomers
(i.e., 6 and 7) and the SN2-regioisomer 18. The highest regio-
and stereoselectivity for 6a was achieved with lithium n-
butyl(cyano)cuprate (entries 1−3). Although the greatest
selectivity was achieved in CH2Cl2 (entry 3), this solvent
afforded very low product yields. The magnesium n-
butylcuprates gave poor stereo- and regioselectivity (entries 5,
6, and 8−12) with the lowest yields and selectivities observed in
CH2Cl2 (entry 7). For both the lithium and magnesium
cuprates, utilization of substoichiometric amounts of CuCN
afforded excellent regio- and stereoselectivities (entries 13 and
14). Consistent with Posner and co-worker’s report,5 the
magnesium methylcuprates gave high chemical yields and
selectivities for 6b under both stoichiometric (entries 17−19,
21) and catalytic conditions (entry 20). The lithium cuprates
gave excellent selectivities but lower chemical yields (entries 15
and 16). The phenyl(cyano)cuprate gave modest chemical
yields of 6c but excellent regio- and E:Z-stereoselectivity (entry
22).
In an effort to gain some mechanistic insight into the regio-
and stereoselectivity of these reactions, several relative rate and
competition experiments were performed (eqs 1−4 in Chart 1).
Relative rate experiments on 4a (eq 1, Chart 1) revealed that
the lithium cuprate was only slightly faster than the magnesium
cuprate (i.e., 1% vs 12% recovered 4a after 30 min at −78 °C)
n
and that the BuCuCNLi reagent reacted with 4a faster than
the MeCuCNLi reagent. The former reagent, prepared from
CuCN, was only slightly faster in THF than in Et2O. These
experiments show that the relative rate of reaction of 4a with
these cuprates is comparable, regardless of the metal cation
(i.e., Li+ or MgCl+) or ethereal solvent (i.e., THF or Et2O). The
rate of allylic substitution is not sensitive to the electronic
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Chart 1
properties of the substituent at the 4-position of 4a or 13, since
both give comparable product yields and recovered starting
material in a competition experiment (eq 2, Chart 1).
Surprisingly, the trans isomer 17 reacted nearly twice as fast
as the cis isomer 4a, as evidenced by a competition experiment
(eq 3, Chart 1). Finally, 17 is roughly 5−7 times more reactive
than a mixture of allylic chlorides 19a,b (eq 4, Chart 1)
revealing the accelerating effect of the ester functionality.
In the light of these results, we decided to briefly re-examine
the α-cyano allylic phosphates originally studied by Najera and
co-workers.7 The cyanophosphates 21a and 21b,26 prepared by
an established procedure,27 exhibited SN2′-regiospecificity and
modest E:Z stereospecific alkylation (Table 6), with the E-
isomer 21a giving the Z-alkenylnitrile 23 preferentially (entries
1−5) and the Z-isomer 21b affording predominantly the E-
alkenylnitrile 22 (entries 6−10). For 21a, the highest E:Z-
stereoselectivity was achieved with the magnesium cuprate
prepared from CuBr·SMe2. The Z-isomer 21b gave E:Z
selectivity for both the lithium and magnesium cuprates
(entries 6−10) and the lowest selectivity for the lithium
cuprate prepared from CuBr·SMe2 (entry 9).
DISCUSSION
■
The primary control element in cuprate -mediated allylic
substitution reactions is the preference for anti-SN2′-substitu-
tion pathways,28 which are enhanced by use of alkyl- or
aryl(cyano)cuprate reagents,2d,29 magnesium cuprates,2d,29 and
phosphate leaving groups.2d The greater SN2′-regioselectivity
observed for RCuCNLi reagents has been attributed to a trans
effect with the more electron rich R-group on the cuprate
reagent preferring (i.e., lower transition state energy) to be
trans to the substrate leaving group (cf. Scheme 4).29
Predominant formation of the E-diastereomer reflects the
influence of A1,3-strain30 in the transition state of the substrate−
cuprate interaction (Scheme 2).2d,3a For Z-substrate 4a, the
nBu/CO2Et A1,3-strain in the transition state arising from
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Table 6. γ-Alkylation of Allylic Cyanohydrin Phosphates
a
b
c
d
entry
substrate
reagent (equiv)
nBuCuCNLi (1.2)
nBuCuCNLi (1.2)
yield (%)
major isomer
22:23
e
1
21a
21a
21a
21a
21a
21b
21b
21b
21b
21b
60
66
63
68
62
69
70
75
72
68
23
23
23
23
23
22
22
22
22
22
20:80
32:68
40:60
20:80
2
3
4
5
nBuLi (1.2)/CuCN (0.33)
nBuLi (1.2)/CuBr·Me2S (1.2)
nBuMgCl (1.2)/CuBr·Me2S (1.2)
nBuCuCNLi (1.2)
nBuLi (1.2)/CuCN (1.2)
nBuCuCNLi (1.2)
f
8:92
e
g
f
6
70:30
85:15
88:12
67:33
82:18
7
8
g
9
nBuLi (1.2)/CuBr.Me2S (1.2)
nBuCuCNMgCl (1.2)
10
a
THF as solvent with a composition for the reaction of 10/1 solvent/organometallic solvent unless otherwise noted. Cuprates were prepared from
THF-soluble CuCN·2LiCl unless otherwise noted. Cuprates (entries 1−2, 6−7) were prepared from solid, insoluble CuCN (from −70 to −40 °C,
b
c
stir for 30 min before cooling to −78 °C). Reactions done at −78 °C for 2 h then warmed up to rt with overall stirring of 8−12 h. Isolated yield.
d
e
f
1
E:Z isomer ratios were determined by integration of the H NMR absorption peaks for the vinyl protons. Solvent Et2O. Starting material
g
recovered. Unidentified byproducts found.
Scheme 2. Model for SN2′-Regioselectivity in the Reactions of (Z)-α-Chloro-β,γ-unsaturated Esters with Organocuprates
conformer 24 and leading to 7 is sufficiently greater31 than the
nBu/H A1,3-strain in the transition state arising from 25 and
leading to 6 such that only the E-diastereomer 6 is observed in
these reactions (Tables 1−3). Although no SN2-substitution
product is observed for the lithium cuprate reagents (Tables
1−3) except in DMF (Table 2, entry 5), small amounts are
observed for magnesium cuprates (Tables 2 and 3), where
utilization of magnesium cuprates gives greater amounts of SN2-
product in THF than in Et2O (Table 2, entries 7 and 8; Table
3, entries 3 vs 5, and 9 vs 7 for THF vs Et2O). These results
suggest that complexation phenomena2d (cf., TSZ‑enoate in
Scheme 3) are not playing a role here, since the experimental
results are inconsistent with solvent, cation (i.e., Li vs Mg), and
trans effects.2d A slower reductive elimination step for the
magnesium cuprates would allow sufficient time for equilibra-
tion between two σ-allyl copper(III) complexes32 via a π-allyl
copper(III) complex (cf. Scheme 4)4d,32a,33,34 that is facilitated
by THF.34a The propensity of magnesium cuprates to favor
SN2′-selectivity generally occurs under conditions that favor
formation of RCuXMgX (X = heteroatom)33a,34a and the
influence of the trans-effect (i.e, oxidative addition step) and
does not mitigate against the additional influence of rates of
reductive elimination upon SN2′:SN2 selectivity ratios. Fast
reductive elimination from the π-allyl copper(III) or enyl[σ +
π] complex should favor greater SN2′-regioselectivity.29,33a,34
The single-point rate experiments (eq 1, Chart 1) are
inconclusive, revealing that these reactions are very fast and
the failure of the magnesium cuprates to go to completion may
reflect the difficulty of accurate titration of Grignard reagent
concentration. If the rate-determining step is oxidative addition,
the influence of the rate of reductive elimination cannot be
probed by kinetic studies. The increased formation of SN2
byproducts with methyl magnesium cuprate even in Et2O
(Table 3, entry 10) is consistent with the speculative influence
of reductive elimination rates.
Similar consideration of allylic strain can account for the
lower E:Z-diastereoselectivity observed in the allylic substitu-
tion reactions of the E-substrate 17. Here the combination of
A1,3- and A1,2-strain30 in the transition state is such that a
mixture of E (i.e., 6) and Z-diastereomers (i.e., 7) are formed
(Scheme 3). As expected, A1,3-strain predominates30b as a
controlling factor and the E-enoate 6 is formed as the major
isomer. In the reactions of the E-diasteromer 17, magnesium
cuprates give larger amounts of the Z-diastereomeric product 7
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Scheme 3. Model for SN2′-Regioselectivity in Reactions of (E)-α-Chloro-β,γ-unsaturated Esters with Organocuprates
than the lithium cuprates. Although it is tempting to invoke a
complexation model (e.g., TSZ‑enoate, Scheme 3) given the
ubiquity of coordination effects invoked in computational
models29,34,35 of cuprate reactions, solution NMR studies,36 and
cuprate X-ray structure determinations,37 this model is
inconsistent with the greater E-selectivity observed in Et2O
than in THF. The solvent and counterion (i.e., Li+ vs MgCl+)
effects are more consistent with a solvent-induced isomer-
ization34a of the C2-stereogenic center attached to the Cu-atom
in an intermediate σ-copper(III) complex (e.g., 29 of Scheme 3,
Nakamura model). Isomerization (i.e., 29 to 30) will be
enhanced in THF, where cuprate reagents can form solvent-
separated ion pairs (SSIP), in contrast to Et2O, where they tend
to exist as contact ion pairs (CIP).36a,b Although it is tempting
to attribute the greater amounts of isomerization observed for
the magnesium cuprates to slower reductive elimination rates,
attempts to gauge the relative rates of lithium vs magnesium
cuprates were inconclusive (eq 1, Chart 1).38
fact observed for the nBu cuprates (Table 5, entries 1 vs 4, and
5 vs 8) but not for the less reactive methylcuprates (entries 15
vs 16, and 17 vs 18), although the differences are very small and
within experimental error.
The excellent regioselectivity observed for 17 is consistent
with computational studies that show that the activation energy
for reductive elimination increases for electron-withdrawing
groups alpha to the Cu center34a and should be greater for 32
than for either 31 or 33, consistent with the observed product
ratios in THF and Et2O (Table 5). Dichloromethane provides
an exception where the SN2-product is the major isomer (Table
5, entry 7). It is interesting to note that the faster reaction rate
of 17 relative to those of 19a/19b in competition experiments
(eq 4, Chart 1) must be manifest in the oxidative addition step.
Allylic chloride 9 gave no SN2-substitution products and
mixtures of E:Z geometrical isomers (Table 4) arising from
SN2′-allylic substitution, consistent with the trans effect (i.e., R
group on copper trans to the Cl leaving group in TSR,Cl(trans)
)
The fact that trans isomer 17 reacts nearly twice as fast as the
cis isomer 4a and 5−7 times faster than 19a/19b with both the
magnesium and lithium n-butyl(cyano)cuprate reagents (eq 3,
Chart 1) indicates that steric factors (i.e., A1,3- and A1,2-strain)
are not insignificant. Significantly, although enantioenriched
chiral α-(N-carbamoyl)alkylcuprate reagents show good con-
figurational stability, isomerization is observed in slow reactions
and is faster in THF than in Et2O.39 RCuCNM reagents
undergo faster reductive elimination29 than R2CuM reagents
and would be expected to display higher E-selectivity. This is in
and lack of substituents on C4. For C1-monosubstituted π-
allylcopper complexes, the transition state energy for reductive
elimination is always greater for C1 than for C3, and both
energies are raised by electron-withdrawing groups (EWG).34a
The lower E:Z-stereoselectivity for 9 vs 4a reflects the relative
A-value of the H and nBu substituents in 9 and 4a, respectively.
For allylic chloride 13 containing a 4-phenyl substituent, the
trans effect should render TSR,Cl(trans) more stable than
TSCN,Cl(trans) and this should normally lead to significantly
enhanced SN2′-regioselectivity for RCuCNM (M = Li, MgX)
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Scheme 4. Model for SN2′ and SN2 Regioselectivity in the Reactions of Lithium and Magnesium Cuprates with (Z)-α-Chloro-
β,γ-enoates 9 and 13
Scheme 5. Models for E:Z Diastereoselectivity in the Reactions of Magnesium Cuprates with E-Cyanohydrin Phosphate 21a and
Z-Cyanohydrin Phosphate 21b
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reagents,29 contrary to our observations (Table 4). For the nBu
cuprates, reaction of the Li-cuprate in THF gives large amounts
of the SN2-product (45%), while the Mg-cuprate is SN2-
selective (70%) in THF (SN2′-selective in Et2O, 51%),
consistent with conversion of a σ-enyl complex 34 to a π-allyl
complex 36 via solvent participation.34a π-Allyl complex 36
provides a mechanistic pathway for equilibration of σ-
complexes 37 and 38. The magnesium counterion increases
the amount of SN2-product observed, perhaps by decreasing the
rate of product formation (cf. competition experiment, eq 1,
Chart 1), thereby allowing equilibration of the two σ-complexes
(i.e., 37 and 38) by a coordination effect with the ester
functionality in 38 or by subtle changes in the cuprate structure.
A similar SN2-regioselectivity for nBuCuCNMgCl (30:70,
THF) and MeCuCNMgCl (28:72, THF) points to a chelation
effect (e.g., Mg+ coordination of the CN and ester groups)
favoring σ-complex 38, since the two cuprates are expected to
have different steric and reactivity profiles (cf. eq 1, Chart 1).
Although chelation effects are generally more manifest in Et2O
than in THF,2d THF is expected to facilitate the equilibration
between σ-complexes34a 37 and 38, and 38 may either be
stabilized34a,40 relative to 37 by electronic effects (i.e., the ester
EWG raises the energy of activation for reductive eliminatio-
n34a) or by chelation. Computational studies34a indicate that
the transition state leading from enyl[σ + π] complex 34 should
be lower in energy, affording SN2′-product 6c, which is formed
in modest but diminished selectivity compared to 4a in ether
and for lithium cuprates. Increased amounts of SN2-products
are observed in THF and for magnesium cuprates, suggesting
that these conditions favor reaction through σ-complex 38 or
enyl[σ + π] complex 35. In this regard, an α-EWG reduces the
rate of reductive elimination (i.e., 35 should be slower than 34),
but alkene π-donation to the cuprate p-orbital should favor 35
over 34.34a The increased formation of SN2-products from 13 is
inconsistent with the computational prediction34a,40 of
substituent electronic effects (e.g., Ph vs CO2Et), suggesting
that steric factors (i.e., alkene substituents and cuprate
structure) are playing a role in the transition state for reductive
elimination. Allylic chlorides 4a (SN2′-regioselective) and 13
(nonregioselective) display comparable rates in competition
experiments for both the lithium and magnesium cuprates (cf.
eq 2, Chart 1), and the SN2-regioselectivity for the magnesium
cuprate with 13 nearly doubles compared to that of the lithium
cuprate. The importance of the trans effect in the reactions of
13 can be seen in the slightly greater SN2′-selectivity of
MeCuCNLi in THF (i.e., 84:16), vs the combination of MeLi
(1.2 equiv)/CuCN (0.33 equiv) presumably forming Me2CuLi
(SN2′:SN2, 78:22, Table 4, entries 9 vs 10), even though the
latter reaction was conducted in Et2O. The greater SN2′:SN2-
regioselectivity for reaction of 13 with MeCuCNLi (84:16) vs
nBuCuCNLi (55:45) in THF again suggests that steric
interactions between the phenyl substituent and cuprate ligand
40).37a,b The high Z-selectivity achieved with CuBr·SMe2 on E-
21a suggests that the Br-ligand on copper can play the same
role as the cyanide ligand in bridging the magnesium cation
between the allylic substrate and the cuprate reagent (i.e.,
39a,b). Previous studies [RMgX (3.0 equiv), CuX (1.5 equiv)]
only examined the E-isomer (i.e., an analogue of 21a) and
concluded that steric factors involving the transferable ligand
were unimportant in determining the Z-selectivity.7 Slightly
higher Z-stereoselectivity is achieved in Et2O than in THF for
21a (Table 6, entries 1 vs 2), with use of CuBr·SMe2 for
preparation of the lithium cuprates (entries 4 vs 2) and with
magnesium rather than lithium cuprates (entries 5 vs 4),
consistent with complexation phenomena.2d A1,3-strain gen-
erally leads to formation of the E-diasteromeric alkene product,
and formation of the Z-isomer is often accounted for on the
basis of intramolecular cuprate complexation to a heteroatom
moiety within the substrate.
Coherently, the preference of Z-isomer 21b for formation of
E-enenitrile 22 is controlled by A1,3-strain (i.e., nBu, CN) in the
transition state, and the stereoselectivity is relatively consistent
n
across cuprate reagents. The use of Et2O, BuLi/CuBr·SMe2,
and magnesium cuprates gave lower E:Z-selectivity for 21b
than nBuCuCNLi (Table 6, entries 6, 9, and 10, respectively, vs
7 and 8) as expected for conditions that should favor cuprate
nitrile (i.e., substrate) complexation and reaction from
conformer 41. Again, the examination of both E-21a and Z-
21b revealed the varied importance of A1,3-strain in the
transition state of the oxidative addition step.
CONCLUSIONS
■
In summary, cuprate alkylation of β,γ-unsaturated esters and
nitriles containing an α-nucleofuge substituent provides
opportunities for remote C−C bond formation in the product
enoates and enenitriles with control of regio- and stereo-
chemistry dependent upon the alkene geometry in the
substrate. The Z-alkenyl esters display complete regio- and
stereoselectivity, while the E-alkenyl esters display diminished
selectivities that can be enhanced by use of lithium instead of
magnesium cuprates and in some cases by use of substoichio-
metric amounts of Cu(I) salts. In an asymmetric protocol, the
E- and Z-alkenyl esters will afford enantiomeric products,
allowing enantiodifferentiation to be achieved by either altering
the configuration at the stereogenic center containing the
leaving group or by changing the alkene configuration. The
100% regioselectivity in the SN2′ vs SN2 pathway can be
achieved with the combination of alkyl or aryl lithium cuprates
and α-nucleofuge-substituted-Z-β,γ-unsaturated esters. The E-
and Z-allylic cyanohydrin phosphates display modest regiospe-
cificity arising from the ability of the nitrile functionality to
effectively complex with the cuprate reagent in the E-isomer
21a. The present work significantly extends the range of
cuprate reagents and opportunities for regio- and stereocontrol
in cuprate-mediated allylic substitutions in this class of
substrates. Enantioenriched α-hydroxy-Z-β,γ-unsaturated esters
can be prepared by the reduction of acetylenic α,β-ketoesters
with alpine borane, providing access to an enantioselective
protocol.14
n
(e.g., Me vs Bu) are also playing a role.
The cyanohydrin phosphates 21a,b displayed modest
regiospecificity with E-21a affording Z-enenitrile 23 and Z-
21b affording E-enenitrile 22 predominantly. The E-isomer 21a
has accessible a gauche conformer (with respect to the vinyl
and CN substituents) with low A1,3-strain (i.e., vinyl H, CN)
that allows for magnesium complexation to the nitrile N-atom41
and copper complexation to the alkene (i.e., complex 39,
Scheme 5). In the solid state, alkyl(cyano)cuprates exist as
oligomers where the monomeric units reveal the propensity of
metal cation coordination through the cyano ligands (e.g.,
EXPERIMENTAL SECTION
■
General. NMR spectra were recorded as CDCl3 solutions on a 500
MHz instrument. The 1H NMR chemical shits are reported as δ values
in parts per million (ppm) relative to tetramethylsilane (TMS, δ =
0.00). The residual chloroform signal (CHCl3 δ = 7.28) was used as
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reference. 13C NMR chemical shifts are reported as δ values in parts
per million (ppm) relative to TMS and the CDCl3 signal (triplet,
centerline δ = 77.0) as reference. Infrared (IR) spectra were recorded
as neat samples (liquid films on NaCl plates). Gas chromatography
mass spectrometry (GC−MS) measurements were performed on
equipment coupled to a mass spectrometer with a quadrupole detector
at 70 eV. Analytical thin layer chromatography (TLC) was performed
on silica gel plates (200 μm with F254 indicator). Flash column
chromatography was performed with 200−400 μm silica or with
silica−AgNO3 (10% by weight). Yields are reported as pure material
after isolation by column chromatography. Compounds for high-
resolution mass spectrometry (HRMS) were analyzed by positive
mode electron ionization (EI) using a Q-TOF detector.
dissolved and there was no indication of decomposition. The reaction
mixture was cooled down to −78 °C, and the Z-α-chloro-β,γ-
unsaturated ester 4a (0.85 mmol, 173 mg) was added quickly
dropwise. The mixture was kept at −78 °C over 4 h and quenched at
this temperature for entries 1−5 (Table 3), and for entries 6−10
(Table 3), it was kept 1 h at −78 °C and then warmed up slowly to
room temperature for a total stirring time of 4 h. It was quenched with
a saturated aqueous solution of NH4Cl, extracted with Et2O three
times, concentrated in vacuo, and purified (silica gel, 5% Et2O/95%
hexanes).
General Procedure C. SN2′ γ-Alkylation of Cyanohydrin
Phosphates (Table 6) 21a and 21b. These compounds were
synthesized by adapting procedures from Hoover and Stahl26 and
Najera and co-workers.27 Alkylcyanocuprates were prepared as
described in general procedure A. Cyanohydrin phosphate 21a or
21b (0.50 mmol) was quickly added dropwise to a −78 °C solution of
nBuCuLM (0.60 mmol, L = CN, Br; M = Li, MgCl) in the
Materials. Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from sodium/benzophenone. All other solvents were dried
over 4 Å molecular sieves. Commercially available alkyllithium
solutions were titrated with sec-butyl alcohol and 1,10-phenanthro-
line.42 Commercially available Grignard solutions were titrated with
menthol and 1,10-phenanthroline.43 Cuprates were made from CuCN
dried under vacuum over P2O5 into an Abderhalden’s drying tube and
flame-dried LiCl. Cuprates in Table 2 (entries 4−6) were prepared
first in THF and then diluted 10 times with the corresponding solvent
(CH2Cl2, DMF, or CH3CN). The glassware was flame-dried and
cooled under nitrogen. Low-temperature baths (−78 °C) were made
from dry ice and 2-propanol. All the reactions were carried out under
positive pressure of nitrogen passed over a trap of desiccant agent
(Drierite). Silica−AgNO3 (10% by weight) was prepared with 30 g of
200−400 μm silica and 3.3 g of AgNO3 dissolved in 8 mL of H2O. The
silver nitrate solution was added to the silica, and the mixture was
ground with a mortar and pestle, dried for 2−3 h in an oven at 170 °C,
and then stored and protected from light.
corresponding solvent (5.0 mL). The reaction mixture was stirred for 2
h at −78 °C and then allowed to warm slowly to room temperature
overnight. It was quenched with brine, extracted with Et2O three
times, concentrated in vacuo, and purified (silica gel with silver nitrate,
5% Et2O/95% hexanes).
Ethyl 2-Hydroxy-3-octynoate (2). A round-bottom flask
equipped with septum and a magnetic stir bar was flame-dried
under N2. THF (20 mL) and 1-hexyne (1) (2.3 mL, 20 mmol) were
n
added, the mixture was cooled down to −78 °C, BuLi (2.5 M in
hexanes, 8.0 mL, 20 mmol) was slowly added, and the mixture was
kept at this temperature over 1 h to complete the deprotonation of the
alkyne. After this period, the solution was brought to −60 °C. In
another flask, flame-dried ZnBr2 (2.3 g, 10 mmol) was dissolved in
THF (10 mL) and slowly added by cannula to the previous solution at
−60 °C; once added, this new reaction mixture was allowed to warm
from −60 to 0 °C over 45 min and was then kept at 0 °C over another
15 min. MeLi (1.5 M in Et2O, 6.7 mL, 10 mmol) was then slowly
added to the dialkylzinc solution. At this point the reaction mixture
was stirred at 0 °C over 30 and 15 min at room temperature and then
it was cooled down to −60 °C. Fleshly distilled ethyl glyoxylate (45
mmol) in toluene was added to the just prepared triorganoalkyl zincate
solution. The mixture was allowed to stir over 2 h from −60 to −20
°C (it is important not to go over −20 °C to avoid the formation of
byproducts), quenched at this temperature with a saturated aqueous
solution of NH4Cl, extracted with Et2O three times, concentrated in
vacuo, and purified (silica gel, eluding first with 50−75 mL of hexanes
to remove the remaining toluene and then with 15% EtOAc/85%
hexanes). After purification, a pale yellow oil was obtained (3.1 g,
85%): IR (neat) 3474 (br, s), 2960 (s), 2936 (s), 2874 (m), 2293 (w),
2237 (m), 1745 (s), 1633 (w), 1467 (m), 1369 (m), 1263 (m), 1205
(m), 1144 (m), 1073 (m), 731 (w) cm−1; 1H NMR (500 MHz,
CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H), 1.33 (t, J = 7.3 Hz, 3H), 1.37−1.44
(m, 2H), 1.46−1.54 (m, 2H), 2.22 (dt, J = 1.8, 7.3 Hz, 2H), 3.07 (d, J
= 7.3 Hz, 1H), 4.31 (q, J = 7.3 Hz, 2H), 4.81 (dt, J = 1.8, 7.3 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 13.5, 14.0, 18.3, 21.8, 30.2, 61.6, 62.5,
75.5, 86.6, 170.8; mass spectrum m/z (relative intensity) EI 184 (0.10,
M+), 142 (5), 111 (100), 96 (12), 77 (12), 67 (11), 55 (39), 41 (25).
(Z)-Ethyl 2-Hydroxy-3-octenoate (3). A round-bottom flask
provided with a magnetic stir bar and septum was loaded with the α-
hydroxy-β,γ-acetylenic ester 2 (3.7 g, 20 mmol), Lindlar catalyst (Pd/
BaSO4/Pb, 200 mg), quinoline (2.6 mL, 22 mmol), and methanol (30
mL). A needle attached to a continuous source of H2 was inserted
deep inside the reaction mixture to allow positive flow of H2; another
needle was set in the septum to allow evacuation of the excess gas.
This mixture was vigorously stirred and kept under slow but
continuous flow of H2 for 4−5 h. After this period, all the material
was reduced to allylic alcohol 3, and no evidence of over-reduced
product was found. The reaction crude material was filtrated over a
small layer of silica gel to remove the palladium catalyst and then
eluted with 50% Et2O/50% hexanes. Concentration in vacuo and
purification (silica gel, 15% EtOAc/85% hexanes) gave a pale yellow
oil (3.3 g, 88%): IR (neat) 3473 (br, s), 3011 (m), 2959 (s), 2931 (s),
2873 (m), 1736 (s), 1655 (w), 1466 (m), 1369 (m), 1201 (s), 1085
1
For compounds 2, 3, 6b, and 14b, 13C NMR, H NMR, GC−MS,
and IR data reductions are included. These compounds have been fully
characterized and reported.13,16,44,45 For new compounds 4a, 6a, 6c,
6d, 6e, 6g, 6h, 6i, 13, 16a, 22, and 23, 13C NMR, 1H NMR, GC−MS,
IR, and HRMS data reductions are provided.
General Procedure A. Synthesis of γ-Substituted-α,β-
unsaturated Esters Using Alkyl(cyano)- or Dialkylcuprates
(Tables 1 and 2). A round-bottom flask with a magnetic stir bar and
with LiCl (2.0 mmol, 85 mg) was flame-dried and cooled under
vacuum, CuCN (1.0 equiv, 1.0 mmol, 90 mg) was added inside of an
AtmosBag (trade mark of Sigma-Aldrich) filled with N2, and the flask
was sealed with a rubber septum. The flask was connected to a N2 line
and then loaded with THF (6.0 mL), and the mixture stirred at room
temperature for 20−30 min. This solution of CuCN·2LiCl was cooled
at −78 °C and the alkyllithium or Grignard solution was added
dropwise (for the preparation of cyanocuprates, RCuCNM, 1.0 equiv
of alkyllithium or Grignard was added, and for the dialkylcuprates,
R2CuM, 2.0 equiv of alkyllithium or Grignard was used; M = Li, MgX).
This mixture was allowed to stir for 30−45 min at −78 °C. For the
formation of ArCuCNLi or Ar2CuLi, the cuprate was stirred only for
15 min at −78 °C to avoid the formation of the byproduct, Ar−Ar.
After this period, the Z-α-substituted-β,γ-unsaturated ester, 4a,b or
5a−d (0.85 mmol), was added quickly dropwise to the reaction
mixture at −78 °C, the temperature was kept for 2 h at −78 °C, and
then the reaction was allowed to warm to room temperature slowly for
a total stirring time of 8−12 h. The mixture was quenched with a
saturated aqueous solution of NH4Cl, extracted with Et2O three times,
concentrated in vacuo, and purified (silica gel, 5% Et2O/95% hexanes
for products 6a−c,e−i and 10% EtOAc/90% hexanes for product 6d).
General Procedure B. Catalytic Procedure. Synthesis of γ-
Substituted-α,β-unsaturated Esters from α-Chloro-β,γ-unsatu-
rated Esters (Table 3). A round-bottom flask equipped with a
magnetic stir bar and septum was flame-dried under N2. CuCN (0.15−
0.33 mmol) was added inside an AtmosBag, and the flask was sealed
with a rubber septum; the flask was then connected to a N2 line and
the solvent (6.0 mL) was added. This mixture was cooled down to
−60 °C and the alkyllithium (1.0 equiv, 1.0 mmol) or alkylmagnesium
(1.0 equiv, 1.0 mmol) was added dropwise. The mixture was allowed
to warm to −30 °C (30 min), and after this period, all the solid was
11135
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Article
(s), 1040 (m), 925 (w), 810 (w), 743 (w) cm−1; 1H NMR (500 MHz,
CDCl3) δ 0.92 (t, J = 7.3 Hz, 3H), 1.27−1.45 (m, 7H), 2.17−2.25 (m,
2H), 3.00 (d, J = 6.0 Hz, 1H), 4.20−4.29 (m, 2H), 4.92 (dd, J = 0.9,
6.0 Hz, 1H), 5.31−5.38 (m, 1H), 5.70 (dt, J = 0.9, 7.3 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 13.9, 14.0, 22.3, 27.6, 31.4, 61.9, 67.6,
126.1, 136.0, 147.2; mass spectrum m/z (relative intensity) EI 186
(0.20, M+), 168 (4.5), 157 (1), 140 (1), 113 (45), 95 (66), 83 (6), 57
(100), 55 (11).
(2), 204 (18), 189 (8), 172 (9), 158 (40), 143 (41), 133 (38), 115
(100), 91 (36), 77 (8), 55 (10), 41 (11). HRMS (EI) calcd for
[C16H22O2]+ 246.1620, found 246.1622.
(E)-Ethyl 4-(N-tert-Butoxycarbamoyl-N-methylamino)-2-oc-
tenoate (6d). Compound 6d was prepared using general procedure
A. After purification (silica gel, 10% EtOAc/90% hexanes), a clear oil
was obtained (200 mg, 75%): IR (neat) 2961 (m), 2932 (m), 2974
(w), 2966 (w) 1721 (s), 1698 (s), 1654 (w), 1463 (m), 1394 (m),
1367 (m), 1268 (m), 1152 (m), 1043 (m), 983 (w), 879 (w), 771 (w)
cm−1; 1H NMR (500 MHz, CDCl3) (minor rotamer) δ 0.82−0.90 (br,
s, 3H), 1.14−1.34 (m, 9H), 1.36−1.46 (br, s, 9H), 2.42−2.57 (br, m,
1H), (2.73) 2.81 (s, 3H), (3.07−3.17) 3.19−3.31 (m, 2H), 4.16 (q, J =
7.3 Hz, 2H), 5.77 (d, J = 15.6 Hz, 1H), 6.68−6.78 (m, 1H); 13C NMR
(125 MHz, CDCl3) (minor rotamer) δ 13.8, 14.2, 22.6, 28.3, 29.2,
31.4, 34.7 (35.2), (42.0) 42.2, (52.6) 53.1, 60.2, (79.3) 79.5, 122.4,
150.5 (150.7), 155.4 (155.8), 166.2; mass spectrum m/z (relative
intensity) EI 313 (0.03, M+), 240 (5), 194 (4), 170 (28), 144 (44),
127 (21), 99 (13), 88 (14), 57 (78), 44 (100), 41 (23); HRMS (EI)
calcd for [C17H31NO4]+ 313.2253, found 313.2258.
(Z)-Ethyl 2-Chloro-3-octenoate (4a). The Z-allylic alcohol 3 was
chlorinated by adapting the procedure from Calzada and Hooz:15 To a
round-bottom flask equipped with a magnetic stir bar and septum was
added the Z-α-hydroxy-β,γ-unsaturated ester 3 (4.0 g, 21.5 mmol) and
CCl4 (18 mL), and this mixture was stirred for 15−20 min at room
temperature. Then PPh3 (7.3 g, 28 mmol) was added in two portions
and the mixture stirred for 15 min to ensure a complete dissolution of
all the solid. A condenser was attached and the reaction mixture was
heated in an oil bath up to 75 °C (external temperature). Higher
temperatures should be avoided to prevent mixtures of cis and trans
products. The reaction was followed by TLC and normally after 1.5 h
it is complete; a bulky precipitated was present at this point. Once
cooled down to room temperature, the reaction crude was filtered over
a small layer of SiO2, eluted with 20% Et2O/80% hexanes,
concentrated in vacuo, and purified (silica gel 3% Et2O/97% hexanes).
After purification, a pale yellow oil was obtained (3.7 g, 85%): IR
(neat) 3032 (w), 2961 (m), 2933 (m), 2874 (m), 1747 (s), 1651 (w),
1466 (m), 1312 (m), 1262 (m), 1162 (s), 1027 (m), 819 (s) cm−1; 1H
NMR (500 MHz, CDCl3) δ 0.93 (t, J = 6.9 Hz, 3H), 1.29−1.45 (m,
7H), 2.12−2.22 (m, 2H), 4.25 (q, J = 6.9 Hz, 2H), 5.09 (d, J = 9.6 Hz,
1H), 5.66−5.79 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 13.8, 13.9,
22.2, 27.3, 31.2, 52.4, 62.2, 124.1, 163.9, 168.6; mass spectrum m/z
(relative intensity) EI 204 (0.10, M+), 169 (55), 141 (17), 125 (22),
95 (100), 81 (26), 67 (28), 55 (36), 41 (26); HRMS (EI) calcd for
[C10H17ClO2]+ 204.0917, found 204.0915.
(E)-Ethyl 4-Butyl-2-octenoate (6a). Compound 6a was prepared
using general procedure A. After purification (silica gel, 5% Et2O/95%
hexanes), a colorless oil was obtained (182 mg, 95%): IR (neat) 2959
(s), 2930 (s), 2860 (s), 1722 (s), 1652 (m), 1466 (m), 1369 (m),
1307 (m), 1266 (m), 1216 (m), 1176 (m), 1144 (m), 1043 (m), 988
(m), 864 (w), 730 (w) cm−1; 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J
= 7.3 Hz, 3H), 1.16−1.48 (m, 15H), 2.08−2.18 (m, 1H), 4.20 (q, J =
7.3 Hz, 2H), 5.77 (d, J = 15.6 Hz, 1H), 6.75 (dd, J = 9.2, 15.6 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 14.0, 14.3, 22.7, 29.4, 34.2, 42.7, 60.1,
120.8, 154.0, 166.8; mass spectrum m/z (relative intensity) EI 226
(3.5, M+), 197 (2), 184 (25), 181 (39), 155 (18), 138 (67), 123 (28),
110 (37), 96 (200), 81 (56), 47 (69), 55 (85), 41 (10); HRMS (EI)
calcd for [C14H26O2]+ 226.1933, found 226.1932.
(E)-Ethyl 4-Methyl-2-octenoate (6b). Compound 6b was
prepared using general procedure A. After purification (silica gel, 5%
Et2O/95% hexanes), a colorless oil was obtained (137 mg, 88%): IR
(neat) 2961 (m), 2931 (m), 2874 (m), 1722 (s), 1652 (m), 1461 (m),
1266 (m), 1181 (m), 1040 (m), 985 (w), 864 (w), 725 (w) cm−1; 1H
NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 3H), 1.04 (d, J = 6.9
Hz, 3H), 1.21−1.41 (m, 9H), 2.24−2.34 (m, 1H), 4.19 (q, J = 7.3 Hz,
2H), 5.77 (d, J = 15.6 Hz, 1H), 6.86 (dd, J = 7.8, 15.6 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 13.9, 14.2, 19.4, 22.7, 29.3, 35.7, 36.5,
60.1, 119.5, 154.7, 166.9; mass spectrum m/z (relative intensity) EI
184 (4.5, M+), 169 (1.5), 155 (7), 142 (80), 139 (60), 113 (45), 96
(98), 81 (43), 69 (93), 55 (100), 41 (53).
(E)-Ethyl 4-Phenyl-2-octenoate (6c). Compound 6c was
prepared using general procedure A. After purification (silica gel, 5%
Et2O/95% hexanes), a clear oil was obtained (132 mg, 63%): IR (neat)
3063 (w), 3029 (w), 2959 (m), 2932 (s), 2860 (m), 1720 (s), 1650
(m), 1602 (w), 1494 (w), 1454 (m), 1368 (m), 1309 (m), 1267 (m),
1171 (m), 1043 (m), 985 (m), 867 (w), 761 (w), 700 (m), 560 (w)
cm−1; 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 3H), 1.20−
1.37 (m, 7H), 1.73−1.86 (m, 2H), 3.36−3.43 (m, 1H), 4.19 (q, J = 7.3
Hz, 2H), 5.80 (dd, J = 0.9, 15.6 Hz, 1H), 7.08 (dd, J = 7.8, 15.6 Hz,
1H), 7.17−7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 13.9, 14.2,
22.5, 29.6, 34.6, 48.5, 60.2, 120.6, 126.7, 127.7, 128.6, 142.4, 152.0,
166.7; mass spectrum m/z (relative intensity) EI 246 (14, M+), 217
(E)-Ethyl 4-(1,1-Dimethyl ethyl)-2-octenoate (6e). Compound
6e was prepared using general procedure A. After purification (silica
gel, 5% Et2O/95% hexanes), a clear oil was obtained (156 mg, 81%):
IR (neat) 2961 (s), 2871 (m), 1722 (s), 1651 (m), 1468 (m), 1368
(m), 1344 (m), 1266 (m), 1212 (m), 1162 (m), 1137 (m), 1040 (m),
1
992 (m), 864 (w), 730 (w) cm−1; H NMR (500 MHz, CDCl3) δ
0.82−0.92 (m, 12H), 0.98−1.08 (m, 1H), 1.16−1.36 (m, 7H), 1.51−
1.60 (m, 1H), 1.81 (dt, J = 2.3, 10.5 Hz, 1H), 4.20 (q, J = 7.3 Hz, 2H),
5.75 (d, J = 15.6 Hz, 1H), 6.78 (dd, J = 10.5, 15.6 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.0, 14.2, 22.7, 27.7, 28.2, 30.4, 33.1, 53.7, 60.1,
122.4, 151.6, 166.5; mass spectrum m/z (relative intensity) EI 170
(100, M+ − tBu), 127 (79), 99 (57), 81 (18), 57 (40), 41 (24); HRMS
(EI) calcd for [C14H26O2 + H]+ 227.2011, found 227.2014.
(E)-Ethyl 4-(2-Methoxyphenyl)-2-octenoate (6g). Compound
6g was prepared using general procedure A. After purification (silica
gel, 5% Et2O/95% hexanes), a clear oil was obtained (171 mg, 73%):
IR (neat) 3032 (w), 2958 (s), 2933 (s), 2861 (m), 2839 (m), 1717
(s), 1650 (m), 1599 (m), 1493 (m), 1464 (m), 1440 (m), 1368 (m),
1
1244 (s), 1176 (s), 1032 (s), 867 (w), 754 (s), 574 (w) cm−1; H
NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 3H), 1.19−1.37 (m,
7H), 1.73−1.84 (m, 2H), 3.83 (s, 3H), 3.88−3.93 (m, 1H), 4.18 (q, J
= 7.3 Hz, 2H), 5.79 (dd, J = 1.4, 15.6 Hz, 1H), 6.88 (d, J = 8.3 Hz,
1H), 6.95 (t, J = 6.9 Hz, 1H), 7.10 (dd, J = 7.8, 15.6 Hz, 1H), 7.15 (dd,
J = 1.4, 7.3 Hz, 1H), 7.22 (dt, J = 1.4, 7.8 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 13.9, 14.2, 22.6, 29.7, 33.4, 40.8, 55.4, 60.1, 110.7,
120.3, 120.7, 127.5, 127.9, 130.6, 152.0, 157.0, 167.0; mass spectrum
m/z (relative intensity) EI 276 (46, M+), 231 (25), 219 (44), 188
(22), 175 (52), 145 (100), 115 (35), 91 (29), 77 (14), 55 (9), 41 (9);
HRMS (EI) calcd for [C17H24O3]+ 276.1725, found 276.1725.
(E)-Ethyl 4-(1-Naphthyl)-2-octenoate (6h). Compound 6h was
prepared using general procedure A. After purification (silica gel, 5%
Et2O/95% hexanes), a clear oil was obtained (189 mg, 75%): IR (neat)
3049 (m), 2958 (s), 2932 (s), 2861 (m), 1936 (w), 1716 (s), 1650
(m), 1598 (w), 1510 (w), 1465 (m), 1368 (m), 1309 (m), 1269 (s),
1177 (s), 1072 (m), 986 (m), 860 (w), 798 (m), 779 (s), 733 (w)
cm−1; 1H NMR (500 MHz, CDCl3) δ 0.78 (t, J = 6.9 Hz, 3H), 1.14−
1.32 (m, 7H), 1.83−1.93 (m, 1H), 4.06 (q, J = 6.9 Hz, 2H), 4.14−4.20
(m, 1H), 5.74 (dd, J = 0.9, 15.6 Hz, 1H), 7.10−7.18 (m, 1H), 7.29−
7.46 (m, 4H), 7.67 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.97
(d, J = 8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 14.2, 22.7,
29.9, 34.4, 42.8, 60.3, 121.0, 123.0, 124.4, 125.4, 125.5, 126.0, 127.2,
129.0, 131.6, 134.0, 138.4, 151.7, 166.7; mass spectrum m/z (relative
intensity) EI 296 (25, M+), 251 (7), 239 (13), 223 (6), 208 (5), 179
(6), 165 (100), 153 (10), 128 (4), 115 (4), 55 (3), 41 (4) ; HRMS
(EI) calcd for [C20H24O2]+ 296.1776, found 296.1776.
(E)-Ethyl 4-[1-(2-Propenyl)]-2-octenoate (6i). Compound 6i
was prepared using general procedure A. After purification (silica gel,
5% Et2O/95% hexanes), a colorless oil was obtained (118 mg, 66%):
IR (neat) 3079 (w), 2960 (m), 2930 (m), 2860 (w), 1722 (s), 1654
(m), 1466 (w), 1369 (m), 1308 (m), 1267 (m), 1221 (m), 1176 (m),
1
1142 (m), 1043 (m), 987 (m), 914 (m), 862 (w), 726 (w) cm−1; H
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NMR (500 MHz, CDCl3) δ 0.81 (t, J = 7.3 Hz, 3H), 1.08−1.44 (m,
9H), 2.02−2.20 (m, 3H), 4.12 (q, J = 7.3 Hz, 2H), 4.90−4.99 (m,
2H), 5.59−5.68 (m, 1H), 5.70 (d, J = 15.6 Hz, 1H), 6.70 (dd, J = 8.7,
15.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 14.2, 22.6, 29.2,
33.4, 38.7, 42.3, 60.1, 116.5, 121.1, 135.9, 152.8, 166.7; mass spectrum
m/z (relative intensity) EI 210 (0.70, M+), 169 (50), 165 (15), 136
(22), 123 (23), 95 (100), 81 (65), 67 (35), 55 (50), 41 (29); HRMS
(EI) calcd for [C13H22O2]+ 210.1620, found 210.1619.
(Z)-Ethyl 2-Chloro-4-phenyl-3-butenoate (13). Compound 13
was prepared by adapting the procedure from Calzada and Hooz15 for
ethyl (3Z)-2-hydroxy-4-phenylbut-3-enoate using Z-PhCHCHCH-
(OH)COOEt as starting material. After purification (silica gel, 3%
Et2O/97% hexanes), a pale yellow oil was obtained (3.8 g, 80%): IR
(neat) 3060 (w), 3029 (w), 2984 (m), 2939 (w), 2907 (w), 1961 (w),
1887 (w), 1746 (s), 1641 (w), 1494 (m), 1447 (m), 1369 (m), 1317
(s), 1262 (s), 1177 (s), 1026 (m), 818 (m), 770 (m), 700 (s), 526
(w), 486 (w) cm−1; 1H NMR (500 MHz, CDCl3) δ 1.33 (t, J = 7.3 Hz,
3H), 4.29 (q, J = 7.3 Hz, 2H), 5.22 (t, J = 10.5 Hz, 1H), 6.00 (t, J =
11.0 Hz, 1H), 6.81 (d, J = 11.5 Hz, 1H), 7.33−7.46 (m, 5H); 13C
NMR (125 MHz, CDCl3) δ 13.9, 53.1, 62.4, 125.2, 128.1, 128.6, 128.7,
134.7, 135.1, 168.3; mass spectrum m/z (relative intensity) EI 224
(0.60, M+), 189 (90), 151 (45), 115 (100), 105 (5), 89 (16), 63 (10),
51 (7); HRMS (EI) calcd for [C12H13ClO2]+ 224.0604, found
224.0604.
(Z)-4-Butyl-2-octenenitrile (23). Compound 23 was prepared
using general procedure C. Initial purification over silica gel (5%
Et2O/95% hexanes) yielded a mixture of E and Z isomers (55 mg,
62%). A second purification done with SiO2−AgNO3 (5% Et2O/95%
hexanes) to isolate the Z-isomer 23 gave a colorless oil: IR (neat) 3068
(w), 2959 (s), 2930 (s), 2860 (m), 2220 (m), 1621 (m), 1466 (m),
1380 (w), 755 (m) cm−1; 1H NMR (500 MHz, CDCl3) δ 0.90 (t, J =
7.3 Hz, 6H), 1.22−1.38 (m, 10H), 1.45−1.55 (m, 2H), 2.59−2.69 (m,
1H), 5.33 (d, J = 11.0 Hz, 1H), 6.21 (dd, J = 10.5, 11.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 13.9, 22.6, 29.3, 34.4, 42.6, 99.0, 116.4,
159.9; mass spectrum m/z (relative intensity) EI 179 (0.25, M+), 178
(1.5), 164 (5), 150 (10), 136 (11), 124 (20), 110 (57), 94 (32), 80
(100), 69 (38), 55 (54), 41 (67); HRMS (EI) calcd for [C12H21N]+
179.1674, found 179.1674.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for 2, 3, 4a, 6a−e, 6g−i, 13, 14b, 16a,
22, and 23 are provided. This material is available free of charge
via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail: dieterr@clemson.edu.
■
(E)-Ethyl 4-Phenyl-2-pentenoate (14b). Compound 14b was
prepared using general procedure A, with Z-α-chloro-β,γ-unsaturated
ester 13 (0.75 mmol) as starting material. Initial purification over silica
gel (5% Et2O/95% hexanes) yielded a mixture of E and Z isomers
(128 mg, 84%). A second purification done with SiO2−AgNO3 (3%
Et2O/97% hexanes) to isolate the E-isomer 14b gave a clear oil: IR
(neat) 3065 (w), 3029 (m), 2960 (m), 2931 (s), 1721 (s), 1650 (m),
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of the NSF Chemical Instrumentation Program for
purchase of a JEOL 500 MHz NMR instrument is gratefully
acknowledged (CHE-9700278). A.P. thanks the Ministry of
Science and Technology of Costa Rica (MICIT) for partial
support.
1
1460 (m), 1170 (s), 1040 (m), 700 (m) cm−1; H NMR (500 MHz,
CDCl3) δ 1.29 (t, J = 6.9 Hz, 3H), 1.45 (d, J = 6.9 Hz, 3H), 3.61−3.67
(m, 1H), 4.20 (q, J = 6.9 Hz, 2H), 5.82 (dd, J = 1.4, 15.6 Hz, 1H), 7.13
(dd, J = 6.9, 15.6 Hz, 1H), 7.21−7.39 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 13.9, 20.0, 41.9, 60.3, 120.1, 126.7, 127.3, 128.7, 143.0,
152.6, 166.5; mass spectrum m/z (relative intensity) EI 204 (21, M+),
158 (5), 131 (100), 115 (10), 91 (27), 77 (5), 65 (4), 53 (3).
(Z)-Ethyl 2-Butyl-4-phenyl-3-butenoate (16a). Compound 16a
was prepared using general procedure A, with Z-α-chloro-β,γ-
unsaturated ester 13 (0.35 mmol) as starting material. Initial
purification over silica gel (5% Et2O/95% hexanes) yielded a mixture
of E and Z isomers (69 mg, 80%). A second purification done with
SiO2−AgNO3 (3% Et2O/97% hexanes) to isolate the Z-isomer 16a
gave a clear oil: IR (neat) 3060 (w), 3025 (m), 2959 (s), 2933 (s),
2862 (m), 1733 (s), 1494 (w), 1448 (m), 1255 (m), 1224 (m), 1172
(s), 1031 (m), 768 (m), 701 (m) cm−1; 1H NMR (500 MHz, CDCl3)
δ 0.80 (t, J = 7.3 Hz, 3H), 1.09−1.29 (m, 7H), 1.69−1.79 (m, 1H),
3.47−3.55 (m, 1H), 4.14 (q, J = 7.3 Hz, 2H), 5.61 (dd, J = 11.0, 11.5
Hz, 1H), 6.55 (d, J = 11.5 Hz, 1H), 7.18−7.33 (m, 5H); 13C NMR
(125 MHz, CDCl3) δ 13.9, 14.2, 22.4, 29.1, 33.0, 44.7, 60.5, 127.0,
128.3, 128.7, 130.0, 131.1, 136.8, 174.3; mass spectrum m/z (relative
intensity) EI 246 (27, M+), 203 (4), 190 (6), 173 (52), 157 (4), 131
(18), 117 (100), 91 (54), 69 (6), 41 (8); HRMS (EI) calcd for
[C16H22O2]+ 246.1620, found 246.1622.
REFERENCES
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(E)-4-Butyl-2-octenenitrile (22). Compound 22 was prepared
using general procedure C. Initial purification over silica gel (5%
Et2O/95% hexanes) yielded a mixture of E and Z isomers (67 mg,
75%). A second purification done with SiO2−AgNO3 (5% Et2O/95%
hexanes) to isolate the E-isomer 22 gave a colorless oil: IR (neat) 3052
(w), 2959 (s), 2931 (s), 2860 (m), 2224 (m), 1632 (m), 1466 (m),
1
1380 (w), 973 (m), 731 (w) cm−1; H NMR (500 MHz, CDCl3) δ
0.89 (t, J = 7.3 Hz, 6H), 1.14−1.36 (m, 10H), 1.39−1.50 (m, 2H),
2.08−2.18 (m, 1H), 5.28 (d, J = 16.5 Hz, 1H), 6.50 (dd, J = 9.2, 16.5
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 22.6, 29.2, 33.7, 44.0,
99.1, 117.6, 160.7; mass spectrum m/z (relative intensity) EI 179
(0.25, M+), 178 (1.25), 164 (6), 150 (11), 124 (23), 110 (61), 94
(37), 80 (97), 56 (60), 55 (95), 41 (100); HRMS (EI) calcd for
[C12H21N]+ 179.1674, found 179.1692.
11137
dx.doi.org/10.1021/jo502111c | J. Org. Chem. 2014, 79, 11125−11138

The Journal of Organic Chemistry
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