Homoallylic ketones and pyrroles by way of copper-catalyzed cascade additions of alkylsubstituted vinyl Grignard reagents to esters

Article abstract of DOI:10.1139/V07-114

Exploring the scope of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylic esters, a set of substituted homoallylic ketones (γ.δ-unsaturated ketones) have been synthesized in 11%-94% yields from treatment of methyl 4-methoxybenz

Full text of DOI:10.1139/V07-114

1006
Homoallylic ketones and pyrroles by way of
copper-catalyzed cascade additions of alkyl-
substituted vinyl Grignard reagents to esters
Aurélie A. Dörr and William D. Lubell
Abstract: Exploring the scope of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylic esters,
a set of substituted homoallylic ketones (γ,δ-unsaturated ketones) have been synthesized in 11%–94% yields from treat-
ment of methyl 4-methoxybenzoate and methyl N-Boc-β-alaninate with different methyl-, dimethyl-, and phenyl-
substituted vinyl Grignard reagents in the presence of catalytic amounts of CuCN in THF. The respective 2,4-di-, 2,3,5-
tri-, and 2,3,4,5-tetrasubstituted pyrroles were obtained in 47%–93% yields from the homoallylic ketones by a sequence
featuring ozonolysis followed by Paal–Knorr condensation with ammonium formate.
Key words: copper-catalyzed cascade addition, homoallylic ketone, alkyl-substituted vinyl Grignard reagents,
ozonolysis, pyrrole, γ,δ-unsaturated ketone.
Résumé : En étudiant l’étendue de la réaction d’addition en cascade de réactifs de Grignard vinyliques sur des esters
carboxyliques catalysée par des sels de cuivre, une série de cétones homoallyliques (cétones γ,δ-insaturées) substituées
a été synthétisée avec des rendements de 11%–94% à partir du 4-méthoxybenzoate de méthyle et du N-Boc-β-alaninate
de méthyle avec différents réactifs de Grignard vinyliques substitués par des groupements méthyle, diméthyle et phé-
nyle, dans le THF. Des pyrroles 2,4-di, 2,3,5-tri et 2,3,4,5-tétrasubstitués ont été obtenus avec des rendements de 47%–
93% à partir des cétones homoallyliques suite à une séquence réactionnelle incluant une ozonolyse suivie d’une
condensation de Paal–Knorr avec de l’ammonium formate.
Mots-clés : addition en cascade catalysée au cuivre, cétone homoallylique, réactif de Grignard vinylique substitués,
ozonolyse, pyrrole, cétone γ,δ-insaturée.
[Traduit par la Rédaction] Dörr and Lubell 1017
Introduction
conjugate additions to α,β-unsaturated ketones of alkenyl
Grignard reagents in the presence (15a–15h) and absence
(15i–15k) of catalytic copper salts, as well as the 1,4-
additions of alkenyl copper (16–19) and boron (20) reagents,
have all been used to make homoallylic ketones. Alternative
methods for making γ,δ-unsaturated carbonyl units include
the direct insertion of aroyl cyanides (21a) and aldehydes
(21b, 21c) to zirconacyclopentenes, the allylation of silyl
enol ethers (22), and various allylations of unsaturated com-
pounds under ruthenium (23), palladium (24), copper (25)
and nickel (26) catalysis. The Claisen–Cope (1m, 27) and
Carrol (28) rearrangements (29) and the Wittig (30) method-
ology have also found utility in the construction of γ,δ-
unsaturated carbonyl compounds.
Homoallylic ketones have been obtained by the reaction
of excess vinylmagnesium halide onto various carboxylic
acid derivatives, including carboxylic acids (31a–31c), esters
(31b, 32), acid anhydrides (31b), and acid halides (33). Low
yields and the competitive formation of side products, such
as tertiary alcohols and alkenyl ketones, have limited the
utility of this methodology (31b–31c, 33). Copper salts have
been utilized to enhance product formation in these cascade
addition processes. For example, CuCl was added to the cas-
cade reaction of excess vinylmagnesium chloride to fatty
carboxylic acids and esters to produce mixtures of 1,6-
diones and homoallylic ketones in 6%–47% yields (32). Sig-
nificantly improved yields of homoallylic ketone were
The γ,δ-unsaturated carbonyl unit is a structural compo-
nent of natural products (1) and an important intermediate in
the synthesis of terpenoids (2) and heterocycles such as
pyrroles (3), dihydropyrroles (3a, 4), pyridines (5), and
isoquinolines (5a). Moreover, homoallylic ketones (γ,δ-
unsaturated ketones) are particularly useful as precursors to
1,4-diketone intermediates for the preparation of
cyclopentanones (6), pyrroles (7), furans (7h–7k, 8),
thiophenes (7j–7k), and pyridazines (7k, 9).
In light of their broad utility for making compounds of bi-
ological and technological importance, the synthesis of γ,δ-
unsaturated carbonyl compounds has attracted considerable
interest. Among the methods for synthesizing γ,δ-unsatu-
rated systems (10–14), a notable one of choice has been the
1,4-addition of suitably substituted alkenyl metallic reagents
to an α,β-unsaturated carbonyl compound. For example,
Received 9 April 2007. Accepted 20 August 2007. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
25 October 2007.
A.A. Dörr and W.D. Lubell. Département de Chimie,
Université de Montréal, C.P. 6128. Succursale Centre-Ville,
Montréal, QC H3C 3J7, Canada.
1Corresponding author (e-mail: lubell@chimie.umontreal.ca).
Can. J. Chem. 85: 1006–1017 (2007)
doi:10.1139/V07-114
© 2007 NRC Canada

Dörr and Lubell
1007
Scheme 1. Cascade addition in the absence of copper salts.
achieved in the cascade reaction of excess vinylmagnesium
bromide to methyl esters by employing catalytic amounts of
Cu(OAc)2 or CuCN (34). This version of the copper-
catalyzed cascade addition proved effective for the synthesis
of the parent but-4-en-1-ones using a variety of methyl
carboxylates, including aromatic and aliphatic esters as well
as N-protected α-, β-, and γ-amino esters.
R1
R2
MgBr
R3
R2 R3
O
O
R3
R2
OMe
(400 mol%)
R1 R1
THF, -45 to 0 °C
MeO
MeO
Mixtures of homoallylic ketone and tertiary alcohol were
also isolated from cascade reactions using α-methyl-, β-
methyl-, and β,β-dimethyl substituted vinylmagnesium
halides in additions to carboxylic acids, esters, and acid an-
hydrides (35, 36) in the absence of copper. For example, the
treatment of methyl p-toluate with isopropenyl- and prop-1-
enyl-magnesium bromides gave, respectively, 2,4-dimethyl-
1-(p-tolyl)pent-4-en-1-one and 3-methyl-1-(p-tolyl)hex-4-en-
1-one in 65% and 54% yields, along with 7%–11% of the
corresponding tertiary alcohol resulting from two sequential
1,2-addition reactions of the alkenyl Grignard reagent onto
the ester carbonyl (35). On the other hand, treatment of ethyl
benzoate with 2-methylprop-1-enyl-magnesium bromide was
reported to produce exclusively the tertiary alcohol 2,6-
dimethyl-4-phenyl-heptadi-2,5-en-4-ol in 70% yield (36).
In considering these issues (35–36), and the success of the
copper-catalyzed cascade addition of vinyl Grignard reagent
to esters for preparing the parent but-4-en-1-ones (34), the
reactions of esters with various alkenyl Grignard reagents
and CuCN have now been investigated to provide substituted
homoallylic ketones. The scope of this reaction has been ex-
amined by employing a diverse set of methyl-, dimethyl-,
and phenyl-substituted vinyl Grignard reagents on two sub-
strates: methyl 4-methoxybenzoate and methyl N-Boc-β-
alaninate. Furthermore, the corresponding homoallylic ke-
tones 2–8, which were obtained in 11%–94% yields, were
subsequently used to provide a diverse set of substituted
pyrroles 9–13 in 47%–93% yields by a route featuring
ozonolysis of the olefin to provide 1,4-dione and 4-oxo alde-
hyde intermediates for Paal–Knorr condensations with am-
monium formate.
R1 R2 R3 (%)a
1a
3a
4a
5a
6a
H
H
Me
Me
Me Me 36
SM
SM
H
80
H
H
H
Me Me
a Isolated yield
ment with a solution of the ester. Condition B (Table 1)
employed more CuCN (60 mol%) and a longer premixing
time (2 h) with the Grignard reagent (400 mol%) in THF at
−45 °C before treatment with a solution of the ester. Condi-
tion C was identical to condition B except for the use of
more Grignard reagent (500 mol%).
Substituted homoallylic ketones 3–8 were usually ob-
tained in relatively higher yields (Table 1, 11%–94%) using
Condition B vs. Condition A (Table 1, 9%–88% yields).
This improvement was more evident in the synthesis of
homoallylic ketones from methyl 4-methoxybenzoate rather
than from N-Boc-β-alaninate, which seemed less sensitive to
the change. For example, the yields of homoallylic ketone
4a possessing a quaternary gem-dimethyl carbon were im-
proved from 66% to 75% yield using Condition B (Table 1,
entry 3); however, in the case of the N-Boc-β-alaninate-
derived counterpart 4b, they dropped from 25% to 20% (Ta-
ble 1, entry 10).
Some changes were observed using Condition C vs. Con-
dition B in the synthesis of homoallylic ketones from N-
Boc-β-alaninate. This amelioration was particularly evident
for the synthesis of homoallylic ketones 5b and 7b, respec-
tively, from using isopropenylmagnesium bromide and 2-
phenylvinylmagnesium bromide; the yields were improved
from 38% to 63%, respectively, and from 11% to 78%
(Table 1, entries 11 and 13). On the other hand, a minor 3%–
5% improvement in yield was observed in the synthesis of
homoallylic ketones 3b and 6b using 500 mol% of 1-
propenylmagnesium bromide or 1-methyl-1-propenyl-
magnesiumbromide, respectively, (Table 1, entries 9 and 12),
and no amelioration was observed in the case of the synthe-
sis of homoallylic ketones 4b and 8b from 2-methyl-1-
propenylmagnesium bromide and 1-phenylvinylmagnesium
bromide, respectively (Table 1, entries 10 and 14).
Olefins 3a, 3b, and 7b were isolated as mixtures of dou-
ble bond isomers from reactions employing the β-methyl-
and β-phenyl-substituted vinyl Grignard reagents, 1-
propenylmagnesium bromide and 2-phenylvinylmagnesium
bromide. On the other hand, (4Z)-1-(4-methoxyphenyl)-3,5-
diphenylpent-4-en-1-one (7a) was isolated in 61% yield as a
single isomer. The ratios of E/Z isomers 3a, 3b, and 7b were
measured by integration of the olefinic protons in their re-
Results and discussion
Methyl 4-methoxybenzoate and N-Boc-β-alanine methyl
ester were treated with a set of commercially available α-
and β-methyl and di-methyl substituted Grignard reagents, as
well as α- and β-phenylvinyl Grignard reagents that were
freshly prepared in-house. We first examined the cascade ad-
dition of 400 mol% of α- and β-methyl and dimethyl-
substituted Grignard reagents to methyl 4-methoxybenzoate
in the absence of copper salts (Scheme 1). Homoallylic ke-
tones 3a and 4a were obtained in 80% and 36% yields from
employing as Grignard reagent, respectively, 1-
propenylmagnesium
bromide
and
2-methyl-1-
propenylmagnesium bromide. Only starting methyl ester
was, however, recovered from the reactions using isopro-
penylmagnesium bromide and 1-methyl-1-propenyl-
magnesium bromide as Grignard reagent. The Cu-catalyzed
cascade additions of substituted vinyl Grignard reagents
were then performed using three types of conditions
(Scheme 2). Condition A (Table 1) featured premixing Grig-
nard reagent (400 mol%) and a catalytic amount of CuCN
(30%–40 mol%) in THF at −45 °C for 10 min before treat-
1
spective H NMR spectra as well as by LC-MS analysis in
the case of 3a. The E and Z geometry was assigned on the
basis of the characteristic coupling constants of the vinylic
protons (Table 1). Homoallylic ketones 3a and 3b were ob-
served to contain predominantly the Z-isomer (E/Z 35:65
© 2007 NRC Canada

1008
Can. J. Chem. Vol. 85, 2007
Scheme 2. Synthesis of homoallylic ketones 2–8 by copper-catalyzed cascade addition.
R1
R2
MgBr
R3
R3
R2 R3
O
O
(400-500 mol%)
MeO
a: R =
R
R2
R
OMe
30–60 mol% CuCN
THF, -45 to 0 °C
R1 R1
1
2–8
b: R = BocHN
R1, R2, R3 = H, Me, Ph
and 29:71), and low selectivity was observed for olefin 7b
(E/Z 60:40). The influence of the reaction conditions on the
stereoselectivity of the olefin has yet to be investigated,
however the geometry of the double bond in the final prod-
uct does not reflect the geometry of the starting Grignard re-
agent. For example, when employing an isomeric mixture of
E- and Z-2-phenylvinylmagnesium bromide, only E-isomer
7a (Table 1, entry 6) was isolated from 4-methoxybenzoate
and a nearly equal ratio of two isomers 7b (Table 1, entry
13) was obtained from N-Boc-β-alanine methyl ester.
before the addition of the ester to produce a 4.6:2.8:2.6 ratio
of 14a/5a/2a (Table 2, entry 1). Then varying amounts of
the isopropenylmagnesium bromide and CuCN were pre-
mixed in THF for 2 h at −45 °C, prior to the addition of the
vinylmagnesium bromide (100 mol%) and methyl ester (Ta-
ble 2, entries 2–3). When 300 and 100 mol% of the methyl-
substituted vinyl Grignard reagent were, respectively,
premixed with 60 and 100 mol% of copper salt, homoallylic
ketones 14a/5a/2a were obtained in ratios of 4.1:4.4:1.6
(Table 2, entry 2) and 4.1:3.7:2.2 (Table 2, entry 3). To date,
our best results were obtained by premixing isopropenyl-
magnesium bromide (110 mol%) with 60 mol% of CuCN
prior to the addition of ester and vinylmagnesium bromide
(100 mol%), which provided ketones 14a/5a/2a in a
5.6:0.6:3.8 ratio (Table 2, entry 4). A sample of 4-methyl
ketone 14a was finally isolated by HPLC purification for
characterization purposes.
Pyrrole synthesis was next performed using the γ,δ-unsat-
urated ketones (Scheme 4). Previously, a library of 1,2,5-
trisubstituted pyrroles was synthesized from homoallylic ke-
tones that were obtained from the cascade reaction of vinyl
Grignard reagent by an approach featuring olefin oxidation
using the Tsuji–Wacker reaction and subsequent Paal–Knorr
condensation on the resulting 1,4-diones with different
amines (7a). With substituted homoallylic ketones 3 and 5–8
now in hand, we explored a similar olefin oxidation/Paal–
Knorr strategy to prepare 2,4-di-, 2,3,5-tri-, and 2,3,4,5-
tetra-substituted pyrroles 9–13 (Fig. 1). For the oxidation of
homoallylic ketones 3 and 5–8, ozonolysis in MeOH/CH2Cl2
at –78 °C, followed by treatment with Me2S and freeze-
drying gave crude 1,4-dicarbonyl compounds that were typi-
cally of sufficient purity for the subsequent condensation
step. The Paal–Knorr reaction was accomplished by treat-
ment of the crude 1,4-dicarbonyl compounds with ammo-
nium formate. In the synthesis of pyrroles 10, 11b, 12, and
13, the ozonolysis product was condensed with ammonium
formate in the presence of NaOAc/HOAc (100 mol% w/w)
in acetonitrile at 65 °C to give the desired targets in 47%–
93% yields from the corresponding homoallylic ketone (7a).
Alternatively, substituted pyrroles 9 and 11a were best ob-
tained in 59%–70% yields by treating the ozonolysis product
with ammonium formate and KOAc in a AcOH/CH3CN/H2O
mixture (1:1:1) at 80 °C.
Mixtures of isomers were also isolated from the reactions
using 1-methyl-1-propenylmagnesium bromide. Homoallylic
ketone 6a was isolated as a mixture of three isomers, which
were observed to exist in a 7.1:1.6:1.3 ratio, by LC-MS anal-
ysis of three peaks possessing the same molecular weight,
and in an 8.4:0.9:0.7 ratio, as esteemed by integration of the
sets of aromatic doublets in the 1H NMR spectrum.
Homoallylic ketone 6b was isolated as a mixture of two iso-
mers that were inseparable by analytical LC-MS and mea-
sured as an 8.5:1.5 ratio by integration of the vinyl protons
1
in the H NMR spectrum. Homoallylic ketones 6a and 6b
may exist as mixtures of syn and anti diastereomers as well
as cis and trans olefins, however their assignment could not
be made because of difficulties in separating pure isomers;
instead, the mixtures were used directly for pyrrole synthesis
as described below.
The ability to use mixtures of substituted vinyl organo-
metallic reagents in multi-component reactions would pro-
vide novel access to a greater diversity of γ,δ-unsaturated
ketones. The cascade addition of two different Grignard
reagents was thus explored by adding vinylmagnesium bro-
mide and isopropenylmagnesium bromide to 4-methoxy-
benzoate (Scheme 3, Table 2). In certain cases, the desired
4-methyl homoallylic ketone 14a, resulting from the 1,2-
addition of vinylmagnesium bromide to the ester followed
by the 1,4-addition of isopropenylmagnesium bromide to the
enone intermediate, was obtained as the major product, al-
beit in low yield. Homoallylic ketone 14a was contaminated
with 2,4-dimethyl homoallylic ketone 5a and the parent
homoallylic ketone 2a resulting from 1,2- and 1,4-additions
of only isopropenylmagnesium bromide or vinylmagnesium
bromide, respectively. Four conditions were explored to opti-
mize the production of 4-methyl product 14a. The resultant
crude product was then purified by column chromatography
to give an inseparable mixture of homoallylic ketones 14a,
5a, and 2a. The product ratio was determined by LC-MS
analysis of the purified mixture of homoallylic ketones. Ini-
tially, relatively equal amounts of the Grignard reagents
were premixed for 10 min at −45 °C with CuCN (30 mol%)
Conclusion
The scope of the copper-catalyzed cascade addition of
vinylmagnesium bromide to carboxylic esters for the synthe-
sis of homoallylic ketones has been expanded by the em-
© 2007 NRC Canada

Dörr and Lubell
Table 1. Reaction conditions and yields for the synthesis of homoallylic ketones 2–8.
1009
Isomeric
ratio
Isolated
yield
(%)
Reaction
conditions
J Hz
E / Z
(tR) a
Entry R1 R2 R3
Product
Ref
LC-MS
(1H NMR)
O
A
B
70
69
31a,c
37
2a
3a
4a
5a
1
2
3
4
H
H
H
H
H
—
—
—
MeO
MeO
MeO
MeO
Me
O
Me
A
B
88
94
N.d. /1.56,
10.01
35:65
(35:65 E/Z) 29.82
30.31,
Me
—
—
—
O
Me
Me
Me
Me
A
B
66
75
H
Me Me
—
—
—
—
—
O
O
100
(> 99:1)
A
B
46
81
Me
H
H
H
H
Me Me
Me
33.45,
32.63,
32.28
Me
Ph
A
B
9
71:16:13
(84:9:7)
6a
7a
5
6
Me Me
N.d.
—
—
24 (33)b
Me Me
Ph
MeO
MeO
O
O
1
6
100
(> 99:1
E/Z)
A
B
H
Ph
5.63, 15.90
—
28 (73)b
100
(> 99:1)
A
B
24 (49)b
50
8a
2b
3b
7
8
Ph
H
H
H
H
H
—
—
—
—
—
Ph Ph
MeO
O
A
94
—
7a
BocHN
A
B
C
55
71
74
Me
O
Me
N.d. / 1.65,
9.62
N.d.
(29:71 E/Z)
9
H
H
Me
H
27.51
—
BocHN
A
B
C
25
20
21
O
O
Me Me
Me
4b
5b
10
Me Me
—
—
—
—
—
—
—
Me
BocHN
BocHN
A
B
C
44
38
63
100
(> 99:1)
11 Me
H
H
H
Me Me
Me
O
A
B
C
15 (26)b
21 (34)b
26 (49)b
Me
N.d.
(85:15)
6b
12 Me Me
BocHN
N.d.
30.93
—
Me
Me
A
B
C
22 (31)b
11
78
Ph
O
O
6.21, 15.90 /
10.95, 11.47 (60:40 E/Z)
N.d.
7b
8b
13
H
Ph Ph
31.56
—
—
—
BocHN
BocHN
Ph
A
B
C
22
41
38
100
(> 99:1)
14 Ph
H
H
—
Ph Ph
Note: N.d. indicates Not determined.
aRetention time in minutes.
bYields based on recovered starting methyl ester.
© 2007 NRC Canada

1010
Can. J. Chem. Vol. 85, 2007
Table 2. Conditions for the addition of two different Grignard reagents to methyl p-methoxybenzoate.
Reaction
conditions
CuCN
(mol%)
Vinylmagnesium
bromide (mol%)
Isopropenylmagnesium
bromide (mol%)
Premixed
time
Ratio
Yield of
14a (%)
Entry
14a/5a/2aa
1
2
3
4
D
E
F
30
60
100
60
100
100
100
100
120
300
100
110
10 min
2 h
2 h
4.6:2.8:2.6
4.0:4.4:1.6
4.1:3.7:2.2
5.6:0.6:3.8
15 (17)b
30
13 (16)b
17 (27)b
G
1 h
aDetermined by LC-MS analysis of the isolated mixture.
bYields based on recovered starting methyl ester.
Scheme 3. Addition of two different Grignard reagents to methyl
p-methoxybenzoate.
Fig. 1. Yields of polysubstituted pyrroles 9–13 (see ref. 38 for
12a).
Me
2,4-disubstituted
O
O
MgBr
MgBr
Me
Me
+
OMe
Me
MeO
O
MeO
CuCN, THF, -45°C
MeO
MeO
MeO
BocHN
N
N
1a
14a
H
H
9a
(65 %)
9b
(59 %)
O
+
+
Me Me
MeO
MeO
5a
2a
BocHN
N
H
N
H
Scheme 4. Synthesis of 2,4-di-, 2,3,5-tri-, and 2,3,4,5-tetra-
substituted pyrroles 9–13.
12a
12b
(76%)
(60%)
2,3,5-trisubstituted
1) O3, MeOH/CH2Cl2, –78 °C R1
2) Me2S
R2
R2 R3
O
R3
Me
Me
R
R2
R
R1
3) NH4CO2H, HOAc
65–80 °C
N
H
Me
Me
BocHN
R1 R1
N
H
N
H
9–13
R1, R2, R3, R4 = H, Me, Ph
3, 5–8
10b
(56 %)
10a
(47 %)
a: R=
b: R=
BocHN
BocHN
N
H
N
H
MeO
MeO
13a
13b
(77 %)
(93 %)
ployment of substituted vinyl Grignard reagents. Substituted
γ,δ-unsaturated ketones were synthesized in 11%–94%
yields on respective treatments of methyl 4-methoxy-
benzoate and methyl N-Boc-β-alaninate with methyl-,
dimethyl-, and phenyl-substituted vinyl Grignard reagents in
the presence of catalytic CuCN in THF. A series of diverse
substituted pyrroles were then prepared in two steps from
the substituted γ,δ-unsaturated ketones, by employing an ole-
fin ozonolysis/Paal–Knorr condensation procedure. 2,4-Di-,
2,3,5-tri-, and 2,3,4,5-tetra-substituted pyrroles 9–13 were
synthesized in 47%–93% overall yields from their respective
homoallylic ketones. Moreover, a cursory investigation of
the addition of a combination of isopropenyl- and vinyl-
magnesium bromides onto methyl 4-methoxybenzoate dem-
onstrated that two different vinyl Grignard reagents may be
used in this cascade reaction to broaden the diversity of
homoallylic ketone products.
2,3,4,5-tetrasubstituted
Me Me
Me
Me
Me
Me
BocHN
MeO
N
H
N
H
11a
11b
(58 %)
(70 %)
under a positive pressure of argon using anhydrous solvents
that were transferred by syringe. Anhydrous solvents (THF,
CH3CN, MeOH) were dried by passage through solvent fil-
tration systems (GlassContour, Irvine, California). Final re-
action mixture solutions were dried over MgSO4.
Chromatography was on a 230–400 mesh silica gel,
and TLC was on aluminium-backed silica plates. Mass
spectrometry data were obtained at the Université de
Montréal Mass Spectrometry facility. The ratios of isomers
of homoallylic ketones 3–8 were determined by analytical
LC-MS (Prevail column from Alltech, Inc, 4.6 × 250 mm, 5
µm, C18) with a flow rate of 0.5 mL/min using CH3CN
(0.1% TFA)/H2O (0.1% TFA) from 20:80 to 80:20 in
45 min. The retention times (tR) are reported in minutes. The
product ratios of homoallylic ketones 14a/5a/2a were deter-
Experimental
General
For reactions performed under anhydrous conditions,
glassware was flame-dried, and the reaction was performed
© 2007 NRC Canada

Dörr and Lubell
1011
mined by analytical LC-MS (Gemini from Phenomenex Inc.,
4.6 × 50 mm, 5 µm, C18) with a flow rate of 0.5 mL/min us-
ing CH3CN (0.1% TFA)/H2O (0.1% TFA) from 20:80 to
with Et2O (2 ×). The combined organic extracts were
washed with saturated NaHCO3 solution and brine, dried
(MgSO4), filtered, and evaporated to give the homoallylic
ketone. The crude product was then purified as specified.
1
80:20 in 14 min. H NMR spectra were measured in CDCl3
or acetone-d6 at 400 and 300 MHz and referenced to CDCl3
(7.26 ppm) or acetone-d6 (2.05). 13C NMR were measured in
CDCl3 at 100 and 75 MHz and referenced to CDCl3
(77.0 ppm) or acetone-d6 (29.92). Methyl 4-
methoxybenzoate 1a was purchased from Sigma-Aldrich and
N-Boc-β-alanine methyl ester 1b was prepared from β-
alanine by Boc-protection (di-tertbutyl dicarbonate/Na2CO3
in dioxane/H2O) followed by esterification using acetyl
chloride in MeOH (7a). Except for α- and β-phenylvinyl
Grignard reagents, which were freshly prepared in-house be-
fore use, Grignard reagents and copper (I) cyanide (99%)
were all purchased from Sigma-Aldrich and used as received.
The chemical shifts for the carbons and the protons of the
minor isomers are respectively reported in parentheses and
in brackets.
Condition B for the synthesis of homoallylic ketone
A solution of Grignard reagent (400 mol%) in THF was
added to a flame-dried flask containing CuCN (60 mol%) at
−45 °C under argon atmosphere. The slurry was stirred for
2 h and then treated dropwise with a solution of ester
(100 mol%) in dry THF (2.0 mL per 1.0 mmol of ester). The
resultant mixture was stirred for 1 h at −45 °C and treated as
described in Condition A. The crude product was then puri-
fied as specified.
Condition C for the synthesis of homoallylic ketone
A solution of Grignard reagent (500 mol%) in THF was
employed as described for Condition B.
1-(4-Methoxy-phenyl)-pent-4-en-1-one (2a)
N-(Boc)-␤-alanine methyl ester (1b)
According to procedure A, the treatment of methyl 4-
methoxybenzoate (2.0 g, 12 mmol) with vinylmagnesium
bromide (1.3 mol/L in THF, 37.0 mL, 3.41 mmol) in the
presence of CuCN (321 mg, 3.61 mmol) gave a crude oil
that was purified using column chromatography (10% ethyl
acetate in hexane) to give homoallylic ketone 2a (1.6 g,
70%) as a pale yellow oil. TLC Rf 0.36 (10:90 EtOAc/Hexane).
1H NMR (300 MHz, CDCl3) δ: 2.49 (q, J = 6.74 Hz, 2H),
3.04 (t, J = 7.44 Hz, 2H), 3.88 (s, 3H), 4.97–5.14 (m, 2H),
5.84–6.00 (m, 1H), 6.90–7.00 (m, 2H), 7.91–8.00 (m, 2H).
13C NMR (75 MHz, CDCl3) δ: 198.2, 163.5, 137.6, 130.4,
130.1, 115.3, 113.8, 55.6, 37.5, 28.5. HRMS m/z 191.1073
[M + H+, calcd. for [C12H15O2]+: 191.1066].
A stirred suspension of β-alanine (26.7 g, 300 mmol) in
dry MeOH (100 mL) was added dropwise to a premixed so-
lution of acetyl chloride (27.7 mL, 400 mmol) in dry MeOH
(100 mL, and the components were premixed at 5 °C and
stirred in an ice bath for 30 min) at 8–10 °C. After 3 h the
ice bath was removed and stirring was continued overnight.
The solution was poured into Et2O (600 mL) and cooled for
2 h. The precipitate was collected and the mother liquor was
evaporated to a residue that yielded more product after addi-
tion of MeOH (50 mL) and Et2O (70 mL). β-Alaninate
methyl ester hydrochloride (33.5 g, 240 mmol) was dis-
solved in dioxane/H2O (2:1, 260 mL) and treated with solid
Na2CO3 (27.6 g, 260 mmol), cooled to 0 °C, treated with
(Boc)2O (57.6 g, 260 mmol), stirred at room temperature
(RT) overnight and evaporated to a residue, which was taken
up in Et2O. Water was added to the residue and the aqueous
phase was extracted with Et2O. The organic phases were
combined and washed with water, dried (MgSO4), filtered
1-(4-Methoxy-phenyl)-3-methyl-hex-4-en-1-one (3a)
According to procedure B, the treatment of methyl 4-
methoxybenzoate (332 mg, 2.00 mmol) with 1-
propenylmagnesium bromide (0.5 mol/L in THF, 16 mL,
8.0 mmol) in the presence of CuCN (107 mg, 1.20 mmol)
gave a crude oil that was purified using column chromatog-
raphy (10% ethyl ether in hexane) to give homoallylic
ketone 3a (411 mg, 94%) as a pale yellow oil. TLC Rf 0.27
1
and evaporated to give a pale yellow gum (47.9 g, 98%). H
NMR (300 MHz, CDCl3) δ: 1.41 (s, 9H), 2.50 (t, J = 6.1 Hz,
2H), 3.31–3.42 (m, 2H), 3.67 (s, 3H), 5.05 (br s, 1H). 13C
NMR (75 MHz, CDCl3) δ: 173.0, 155.9, 79.4, 51.8, 36.1,
34.5, 28.4. HRMS m/z 226.1052 [M + Na, calcd. for
[C9H17NO4Na]: 226.1050].
1
(10:90 Et2O/Hexane). LC-MS and H NMR analysis showed
1
a 6.5:3.5 mixture of 2 isomers. H NMR (300 MHz, CDCl3)
δ: 1.00–1.03 (2d partially overlapped, J = 6.39, 6.67 Hz,
3H), 1.56–1.67 (dd partially overlapped with m, J = 1.61,
6.70, 3H), 2.75–3.00 (m, 2.2 H), 3.11–3.28 (m, 0.8H), 5.19–
5.30 (m, 0.8H), 5.32–5.47 (m, 1.2H), 6.91–7.00 (m, 2H),
7.91–8.00 (m, 2H). 13C NMR (75 MHz, CDCl3) δ: (198.4)
198.4, 163.4, (136.1) 135.6, 130.6, 130.5, (123.6) 123.3,
113.8, 55.6, 45.7 (45.6), (33.2) 28.5, 21.2 (20.6), (18.1)
13.1. HRMS m/z 219.1378 [M + H+, calcd. for [C14H19O2]+:
219.1380].
Condition A for the synthesis of homoallylic ketone
A flask containing CuCN (30–40 mol%) was flame-dried
and filled with dry THF (2.0 mL per 1.0 mmol of CuCN).
The suspension was cooled to −45 °C under argon atmo-
sphere and treated via syringe with the vinyl Grignard re-
agent (400 mol%). The slurry was stirred for 10 min and
then treated dropwise with a solution of ester (100 mol%) in
dry THF (2.0 mL per 1.0 mmol of ester). The resultant mix-
ture was stirred for 1 h at −45 °C. The cold bath was re-
moved and replaced with an ice bath and the reaction
mixture was allowed to stir and warm slowly to RT over-
night. The reaction mixture was quenched by treatment with
NaH2PO4 solution (200% v/v based on total reaction vol-
ume; 1 mol/L aqueous) at 0 °C. After vigorous shaking, the
layers were separated, and the aqueous phase was extracted
1-(4-Methoxy-phenyl)-3,3,5-trimethyl-hex-4-en-1-one
(4a)
According to procedure B, the treatment of methyl 4-
methoxybenzoate (332 mg, 2.00 mmol) with 2-methyl-1-
propenylmagnesium bromide (0.5 mol/L in THF, 16 mL,
8.0 mmol) in the presence of CuCN (107 mg, 1.20 mmol)
gave a crude oil that was purified using column chromatog-
© 2007 NRC Canada

1012
Can. J. Chem. Vol. 85, 2007
raphy (10% ethyl ether in hexane) to give homoallylic
(m, 2H), 7.16–7.38 (m, 10H), 7.93–8.02 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ: 196.8, 163.6, 143.6, 137.4, 132.9,
130.5, 130.4, 130.1, 128.8, 128.6, 127.9, 127.3, 126.7,
126.4, 113.9, 55.6, 44.3, 44,2. HRMS m/z 365.1510 [M +
Na, calcd. for [C24H22O2Na]: 365.1512].
ketone 4a (369 mg, 75%) as a yellow oil. TLC Rf 0.33
1
(10:90 Et2O/Hexane). H NMR (300 MHz, CDCl3) δ: 1.25
(s, 6H), 1.63 (d, J = 1.24 Hz, 3H), 1.69 (d, J = 1.15 Hz, 3H),
3.00 (s, 2H), 3.85 (s, 3H), 5.21–5.28 (m, 1H), 6.87–6.96 (m,
2H), 7.87–8.00 (m, 2H). 13C NMR (75 MHz, CDCl3) δ:
198.5, 163.2, 133.4, 131.6, 130.8, 130.6, 113.5, 55.5, 49.8,
35.4, 29.6 (2C), 28.2, 19.1. HRMS m/z 247.1692 [M + H+,
calcd. for [C16H23O2]+: 247.1693].
1-(4-Methoxy-phenyl)-2,4-diphenyl-pent-4-en-1-one (8a)
According to procedure B, the treatment of methyl 4-
methoxybenzoate (332 mg, 2.00 mmol) with α-
phenylvinylmagnesium bromide (0.5 mol/L in THF, 16 mL,
8.0 mmol) in the presence of CuCN (107 mg, 1.20 mmol)
gave a crude oil that was purified using column chromatog-
raphy (10% ethyl acetate in hexane) to give homoallylic
ketone 8a (343 mg, 50%) as an orange oil. TLC Rf 0.47
(20:80 EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ: 2.97
(ddd, J = 0.82, 6.97, 14.65 Hz, 1H), 3.52 (ddd, J = 0.87,
7.32, 14.62 Hz, 1H), 3.81 (s, 3H), 4.67 (t, J = 7.16 Hz, 1H),
4.93 (d, J = 1.21 Hz, 1H), 5.19 (d, J = 1.25 Hz, 1H), 6.80–
6.86 (m, 2H), 7.17–7.41 (m, 10H), 7.82–7.88 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ: 197.5, 162.9, 145.4, 140.5,
139.2, 130.6, 129.3, 128.4, 128.0, 127.8, 127.1, 126.6,
126.0, 114.4, 113.2, 55.0, 51.0, 39.2. HRMS m/z 343.1693
[M + H+, calcd. for [C24H23O2]+: 343.1688].
1-(4-Methoxy-phenyl)-2,4-dimethyl-pent-4-en-1-one (5a)
According to procedure B, the treatment of methyl 4-
methoxybenzoate (332 mg, 2.00 mmol) with isopropenyl-
magnesium bromide (0.5 mol/L in THF, 16 mL, 8.0 mmol)
in the presence of CuCN (107 mg, 1.20 mmol) gave a crude
oil that was purified using column chromatography (10%
ethyl ether in hexane) to give homoallylic ketone 5a
(354 mg, 81%) as a colorless oil. TLC Rf 0.32 (10:90
1
Et2O/Hexane). H NMR (300 MHz, CDCl3) δ: 1.18 (d, J =
6.87 Hz, 3H), 1.75 (s, 3H), 2.11 (dd, J = 7.69, 14.46 Hz,
1H), 2.54 (dd, J = 6.33, 14.43 Hz, 1H), 3.57–3.71 (m, 1H),
3.88 (s, 3H), 4.69 (s, 1H), 4.76 (s, 1H), 6.89–7.03 (m, 2H),
7.89–8.05 (m, 2H). 13C NMR (75 MHz, CDCl3) δ: 202.5,
163.5, 143.4, 130.7, 129.5, 113.9, 112.1, 55.6, 41.6, 38.3,
22.8, 17.5. HRMS m/z 219.1383 [M + H+, calcd. for
[C14H19O2]+: 219.1380].
tert-Butyl-3-oxo-hept-6-enylcarbamate (2b)
Prepared according to procedure A. NMR data was con-
sistent with the literature (7a).
1-(4-Methoxy-phenyl)-2,3,4-trimethyl-hex-4-en-1-one (6a)
According to procedure B, the treatment of methyl 4-
methoxybenzoate (332 mg, 2.00 mmol) with 1-methyl-1-
propenylmagnesium bromide (0.5 mol/L in THF, 16 mL,
8.0 mmol) in the presence of CuCN (107 mg, 1.20 mmol)
gave a crude oil that was purified using column chromatog-
raphy (5% ethyl ether in hexane) to give homoallylic ketone
6a [116 mg, 24% (33% based on recovered starting material)]
tert-Butyl-5-methyl-3-oxo-oct-6-enylcarbamate (3b)
According to procedure C, the treatment of β-alanine
methyl ester (203 mg, 1.00 mmol) with 1-propenylmag-
nesium bromide (0.5 mol/L in THF, 10 mL, 5.0 mmol) in
the presence of CuCN (54 mg, 0.60 mmol) gave a crude oil
that was purified using column chromatography (20% ethyl
acetate in hexane) to give homoallylic ketone 3b (189 mg,
74%) as a pale yellow oil. TLC Rf 0.35 (20:80 EtAc/Hexane).
1H NMR (300 MHz, CDCl3) measurement of olefinic sig-
nals showed a 7.1:2.9 mixture of 2 isomers, δ: 0.92–1.00 (2d
partially overlapped, J = 6.68, 6.70 Hz, 3H), 1.42 (s, 9H),
1.61 (dd, J = 1.74, 6.81, 3H), 2.35 (d, J = 7.09 Hz, 2H), 2.61
(t, J = 5.65 Hz, 2H), 2.95–3.11 (m, 1H), 3.32 (q, J =
5.89 Hz, 2H), 4.99 (br s, 1H), 5.14 (tq, J = 1.65, 9.62 Hz,
1H), 5.22–5.44 (m, 1H). 13C NMR (75 MHz, CDCl3) δ:
210.1, 156.0, (135.4) 135.0, (124.1) 123.7, 79.3, 50.4, 43.4,
35.2 (33.0), 28.5, 28.1, 21.1 (20.7), (18.0) 13.0. HRMS m/z
278.1724 [M + Na, calcd. for [C14H25NO3Na]: 278.1727].
1
as a pale orange oil. TLC Rf 0.32 (10:90 Et2O/Hexane). H
NMR (300 MHz, CDCl3) measurement of aromatic signals
showed a 8.4:0.9:0.7 mixture of 3 isomers, δ: 0.89–0.92 (m,
2.5H), 0.99–1.08 (m, 3H) [1.18–1.23 (m, 0.5H)], 1.55–1.70
(m, 6H), 3.02–3.55 (m, 1.8H) [2.45–2.72 (m, 0.1H), 4.25–
4.44 (m, 0.1H)], 3.89 (s, 2.5H) [3.87 (s, 0.5H)], 5.30–5.43
(m, 0.8H) [5.00–5.30 (m, 0.1H) 5.50–5.65 (m, 0.1H)], 6.90–
7.00 (m, 2H), [7.82–7.89 (m, 0.15H), 7.92–7.99 (m, 0.15H)]
8.00–8.08 (m, 1.7H). 13C NMR (75 MHz, CDCl3) δ: 203.9,
163.6, 137.3, 130.9 (130.8), (132.2) 130.6 (130.4), 121.4
(120.7), 113.9 (113.8) (113.6), 55.6, 43.2 (43.4), 36.9 (35.6),
18.5 (18.6), 17.7 (17.5), 17.1 (16.1), 13.3. HRMS m/z
247.1698 [M + H+, calcd. for [C16H23O2]+: 247.1693].
tert-Butyl-5,5,7-trimethyl-3-oxo-oct-6-enylcarbamate (4b)
According to procedure A, the treatment of β-alanine
methyl ester (246 mg, 1.21 mmol) with 2-methyl-1-
propenylmagnesium bromide (0.5 mol/L in THF, 9.70 mL,
4.84 mmol) in the presence of CuCN (43 mg, 0.48 mmol)
gave a crude oil that was purified using column chromatog-
raphy (15% ethyl acetate in hexane) to give homoallylic
ketone 4b (86 mg, 25%) as a pale orange oil. TLC Rf 0.40
(20:80 EtOAc/Hexane). 1H NMR (300 MHz, CDCl3) δ: 1.17
(s, 6H), 1.42 (s, 9H), 1.68 (d, J = 1.24 Hz, 3H), 1.71 (d, J =
1.15 Hz, 3H), 2.49 (s, 2H), 2.60 (t, J = 5.60, 2H), 3.30 (q,
J = 5.80 Hz, 2H), 5.02 (br s, 1H), 5.12–5.15 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ: 210.4, 156.0, 132.5, 131.7, 79.2,
55.2, 44.5, 35.2, 35.2, 29.6, 28.5 (2C), 28.1, 19.1. HRMS
1-(4-Methoxy-phenyl)-3,5-diphenyl-pent-4-en-1-one (7a)
According to procedure A, the treatment of methyl 4-
methoxybenzoate (166 mg, 1.00 mmol) with β-phenyl-
vinylmagnesium bromide (0.5 mol/L in THF, 8 mL, 4 mmol)
in the presence of CuCN (36 mg, 0.40 mmol) gave a crude
mixture that was triturated in Et2O/Hexane (1:1) to give
homoallylic ketone 7a (209 mg, 61%) as a white crystaline
solid, mp 107–110 °C. TLC Rf 0.21 (20:80 Et2O/Hexanes).
1H NMR (400 MHz, CDCl3) δ: 3.40–3.53 (dd, J = 6.70,
16.35 Hz, 1H) partially overlapped with (dd, J = 7.39,
16.35 Hz, 1H), 3.88 (s, 3H), 4.30–4.40 (m, 1H), 6.39 (d, J =
15.90 Hz, 1H), 6.45 (dd, J = 5.63, 15.99 Hz, 1H), 6.93–7.01
© 2007 NRC Canada

Dörr and Lubell
1013
m/z 306.2039 [M
306.2040].
+
Na, calcd. for [C16H29NO3Na]:
130.2, 129.9, 129.0, 128.9, 128.7, 128.6, 128.4, 127.7,
127.5, 127.3, 127.2, 126.9, 126.8, 126.4, 79.4, 79.4, 50.6,
48.9, 44.1, 43.6, 43.3, 39.7, 35.1, 35.1, 28.5, 28.5. HRMS
m/z 402.2040 [M
402.2042].
+ Na, calcd. for [C24H29NO3Na]:
tert-Butyl-4,6-dimethyl-3-oxo-hept-6-enylcarbamate (5b)
According to procedure C, the treatment of β-alanine
methyl ester (203 mg, 1.00 mmol) with isopropenyl-
magnesium bromide (0.5 mol/L in THF, 10 mL, 5.0 mmol)
in the presence of CuCN (54 mg, 0.60 mmol) gave a crude
oil that was purified using column chromatography (10%
ethyl acetate in hexane) to give homoallylic ketone 5b
(160 mg, 63%) as a colorless oil. TLC Rf 0.35 (20:80
EtOAc/Hexane). 1H NMR (300 MHz, CDCl3) δ: 1.06 (d, J =
6.94 Hz, 3H), 1.42 (s, 9H), 1.77 (s, 3H), 2.00 (dd, J = 7.52,
14.22 Hz, 1H), 2.37 (dd, J = 7.10, 14.20 Hz, 1H), 2.60–2.77
(m, 3H), 3.35 (q, J = 5.91 Hz, 2H), 4.66 (s, 1H), 4.77 (s,
1H), 5.00 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ: 214.0,
156.0, 142.9, 112.6, 79.3, 44.6, 41.1, 40.9, 35.3, 28.5, 22.4,
tert-Butyl-4,6-diphenyl-3-oxo-hept-6-enylcarbamate (8b)
According to procedure B, the treatment of β-alanine
methyl ester (406 mg, 2.00 mmol) with α-phenylvinyl-
magnesium bromide (0.5 mol/L in THF, 16 mL, 8.0 mmol)
in the presence of CuCN (107 mg, 1.20 mmol) gave a crude
oil that was purified using column chromatography (10%
ethyl acetate in hexane) to give homoallylic ketone 8b
(309 mg, 41%) as a sticky orange oil. TLC Rf 0.35 (20:80
1
EtOAc/Hexane). H NMR (300 MHz, CDCl3) δ: 1.42 (s,
9H), 2.40–2.65 (m, 2H), 2.86 (dd, J = 6.98, 14.32 Hz, 1H),
3.20–3.32 (m, 2H), 3.40 (dd, J = 7.02, 14.25 Hz, 1H), 3.78
(t, J = 7.29 Hz, 1H), 4.28 (br s, 1H), 4.95 (d, J = 1.09 Hz,
1H), 5.20 (d, J = 1.17 Hz, 1H), 7.11–7.17 (m, 2H), 7.25–
7.42 (m, 8H). 13C NMR (75 MHz, CDCl3) δ: 156.1, 145.8,
140.6, 138.2, 129.0, 128.6, 128.4, 127.8, 127.6, 126.5,
115.0, 79.3, 57.3, 42.2, 38.3, 38.1, 35.3, 28.5. HRMS m/z
402.2043 [M + Na, calcd. for [C24H29NO3Na]: 402.2040].
16.3. HRMS m/z 278.1724 [M
+
Na, calcd. for
[C14H25NO3Na]: 278.1727].
tert-Butyl-4,5,6-trimethyl-3-oxo-oct-6-enylcarbamate (6b)
According to procedure C, the treatment of β-alanine
methyl ester (203 mg, 2.00 mmol) with 1-methyl-1-
propenylmagnesium bromide (0.5 mol/L in THF, 10 mL,
5.0 mmol) in the presence of CuCN (54 mg, 0.60 mmol)
gave a crude oil that was purified using column chromatog-
raphy (10% ethyl acetate in hexane) to give homoallylic
ketone 6b [74 mg, 26% (49% based on recovered starting
material)] as a pale orange oil. TLC Rf 0.38 (10:90
Condition D for the synthesis of homoallylic ketone
with two different Grignard reagents
A solution of vinylmagnesium bromide (0.8 mol/L in
THF, 1.25 mL, 1.00 mmol) and isopropenylmagnesium bro-
mide (0.5 mol/L in THF, 2.40 mL, 1.20 mmol) was added to
a flame-dried flask containing CuCN (27 mg, 0.30 mmol) at
−45 °C under argon atmosphere. The slurry was stirred for
10 min and then treated dropwise with a solution of ester
(166 mg, 1.00 mmol) in dry THF (2 mL). The resultant mix-
ture was stirred for 1 h at −45 °C and treated as described in
Condition A. The crude product was then purified using col-
umn chromatography (10% ethyl acetate in hexane) to give
98 mg of a mixture of 14a/5a/2a in a ratio of 4.6:2.8:2.6 as
determined by LC-MS analysis.
1
EtOAc/Hexane). H NMR (300 MHz, CDCl3) measurement
of olefinic signals showed a 8.5:1.5 mixture of 2 isomers, δ:
0.87 (d, J = 6.76 Hz, 2.6 H) [0.97, (d, J = 7.12 Hz, 0.4H)],
0.91 (d, J = 6.93 Hz, 2.6H) [1.06 (d, J = 6.82 Hz, 0.4H)],
1.42 (s, 9H), 1.50–1.57 (m, 3H), 1.57–1.64 (m, 3H), 2.40–
2.97 (m, 4H), 3.20–3.40 ((q, J = 5.87 Hz) partially over-
lapped with [q, J = 5.75 Hz], 2H), 4.90–5.11 (br s, 1H),
[5.11–5.20 (m, 0.1H)] 5.24–5.35 (m, 0.9H). 13C NMR
(75 MHz, CDCl3) δ: 215.3, 156.1, 136.7, 121.5, 79.3, 50.1
(49.4), 42.3, (36.7) 36.4, 35.3, 28.5, (18.9) 18.2, 17.4 (16.6),
15.7 (15.0), 13.2 (13.1). HRMS m/z 306.2040 [M + Na,
calcd. for [C16H29NO3Na]: 306.2040].
Condition E for the synthesis of homoallylic ketone
with two different Grignard reagents
A solution of isopropenylmagnesium bromide (0.5 mol/L
in THF, 6.00 mL, 3.00 mmol) was added to a flame-dried
flask containing a suspension of CuCN (54 mg, 0.60 mmol)
at −45 °C under argon atmosphere. The slurry was stirred
for 2 h and then treated dropwise with a solution of vinyl-
magnesium bromide (1 mol/L in THF, 1.00 mL, 1.00 mmol)
and ester (166 mg, 1.00 mmol) in dry THF (2 mL). The re-
sultant mixture was stirred for 1 h at −45 °C and treated as
described in Condition A. The crude product was then puri-
fied using column chromatography (10% ethyl acetate in
hexane) to give 170 mg of a mixture of 14a/5a/2a in a ratio
of 4.1:4.4:1.6 as determined by LC-MS analysis.
tert-Butyl-5,7-diphenyl-3-oxo-hept-6-enylcarbamate (7b)
According to procedure C, the treatment of β-alanine
methyl ester (406 mg, 2.00 mmol) with β-phenylvinyl-
magnesium bromide (0.5 mol/L in THF, 20 mL, 10 mmol) in
the presence of CuCN (107 mg, 1.20 mmol) gave a crude
mixture that was purified using column chromatography
(20% ethyl acetate in hexane) to give homoallylic ketone 7b
(590 mg, 78%) as a pale yellow oil. TLC Rf 0.30 (20:80
1
EtOAc/Hexane). H NMR (300 MHz, CDCl3) measurement
of olefinic signals showed a 3:2 mixture of 2 isomers, δ:
1.38–1.50 (s partially overlapped with s, 9H), 2.35–2.70 (m,
2H), 2.77 (dd, J = 7.56, 15.62 Hz, 0.5H), 2.87 (dd, J = 6.95,
15.59 Hz, 0.5H), 2.94 (d, J = 7.33 Hz, 1H), 3.20–3.35 (m
partially overlapped with m, 2H), 4.09 (q, J = 6.93 Hz,
0.5H), 4.35–4.48 (m, 0.5H), 4.91 (br d, J = 5.95 Hz, 1H),
5.83 (t, J = 10.95 Hz, 0.5H), 6.32 (dd, J = 6.21, 15.89 Hz,
0.5H), 6.40 (d, J = 15.93 Hz, 0.5H), 6.54 (d, J = 11.47 Hz,
0.5H), 7.15–7.40 (m, 10H). 13C NMR (75 MHz, CDCl3) δ:
208.7, 156.0, 143.6, 142.8, 137.1, 136.9, 133.6, 132.3,
Condition F for the synthesis of homoallylic ketone
with two different Grignard reagents
The reaction was performed as described for condition E
with isopropenylmagnesium bromide (0.5 mol/L in THF,
2.00 mL, 1.00 mmol), CuCN (90 mg, 1.0 mmol), vinyl-
magnesium bromide (1 mol/L in THF, 1.00 mL, 1.00 mmol),
and ester (166 mg, 1.00 mmol) in dry THF (2 mL) to give
© 2007 NRC Canada

1014
Can. J. Chem. Vol. 85, 2007
98 mg of a mixture of 14a/5a/2a in a ratio of 4.1:3.7:2.2 as
determined by LC-MS analysis.
equimolar quantities of NaOAc and HOAc). The mixture
was heated at 65 °C until complete consumption of the start-
ing material was observed by TLC. After cooling to RT, the
reaction mixture was partitioned between Et2O/CH2Cl2 (2:1)
and pH 6.8 sodium phosphate buffer. The layers were sepa-
rated, and the organic phase was washed with pH 6.8 so-
dium phosphate buffer. The aqueous phase was extracted
twice with Et2O/CH2Cl2 (2:1), and the combined organic
phases were dried (MgSO4). Volatiles were removed by suc-
cessive rotary evaporation and lyophilization to give crude
pyrrole product, which was purified as specified.
Condition G for the synthesis of homoallylic ketone
with two different Grignard reagents
A solution of isopropenylmagnesium bromide (0.5 mol/L
in THF, 2.20 mL, 1.10 mmol) was added to a flame-dried
flask containing CuCN (54 mg, 0.60 mmol) at −45 °C under
argon atmosphere. The slurry was stirred for 1 h and then
treated dropwise with a solution of ester (166 mg,
1.00 mmol) in dry THF (2 mL) and vinylmagnesium bro-
mide (1 mol/L in THF, 1.00 mL, 1.00 mmol). The resultant
mixture was stirred for 10 min at −45 °C and treated as de-
scribed in Condition A. The crude product was then purified
using column chromatography (10% ethyl acetate in hexane)
to give 123 mg of a mixture of 14a/5a/2a in a ratio of
5.6:0.6:3.8 as determined by LC-MS analysis.
2-(4-Methoxy-phenyl)-4-methyl-1H-pyrrole (9a)
Prepared from homoallylic ketone 3a (30 mg, 0.14 mmol)
according to procedure H to yield crude product (19.4 mg),
which was purified using column chromatography (20%
ethyl acetate in hexane) to give pyrrole 9a (17 mg, 65%) as a
1
mauve gum. TLC Rf 0.40 (20:80 EtOAc/Hexane). H NMR
1-(4-Methoxy-phenyl)-3-methyl-hex-4-en-1-one (14a)
A sample of 14a was obtained by HPLC purification per-
formed on a reverse-phase Prevail column from Alltech Inc.
(22 × 250 mm, 5 µm, C18) with a flow rate of 10 mL/min us-
ing CH3CN (0.1% TFA)/H2O (0.1% TFA) from 40:60 to
(300 MHz, CDCl3) δ: 2.16 (s, 3H), 3.83 (s, 3H), 6.26 (s,
1H), 6.59 (s, 1H), 6.85–6.95 (m, 2H), 7.33–7.42 (m, 2H),
8.08 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ: 158.2, 132.2,
126.2, 125.2, 120.6, 116.1, 114.4, 106.6, 55.4, 12.1. HRMS
m/z 188.1070 [M + H+, calcd. for [C12H14NO]+: 188.1065].
1
80:20 in 50 min. H NMR (400 MHz, CDCl3) δ: 1.80 (s,
3H), 2.45 (t, J = 7.68 Hz, 2H), 3.08 (t, J = 7.70 Hz, 2H),
3.88 (s, 3H), 4.73 (s, 1H), 4.77 (s, 1H), 6.90–7.00 (m, 2H),
7.90–8.00 (m, 2H). 13C NMR (75 MHz, CDCl3) δ: 198.5,
163.5, 145.0, 130.7, 130.5, 113.9, 110.2, 55.6, 36.6, 32.2,
22.9. HRMS m/z 205.1223 [M + H+, calcd. for [C13H17O2]+:
205.1221].
2-(4-Methoxy-phenyl)-3,5-dimethyl-1H-pyrrole (10a)
Prepared from homoallylic ketone 5a (55.4 mg,
0.250 mmol) according to procedure I to yield crude product
(43.5 mg) that was purified using column chromatography
(15% ethyl acetate in hexane) to give pyrrole 10a (24 mg,
47%) as a deep purple gum. TLC Rf 0.43 (20:80
EtOAc/Hexane). 1H NMR (300 MHz, CDCl3) δ: 2.20 (s,
3H), 2.29 (s, 3H), 3.82 (s, 3H), 5.82 (d, J = 2.60 Hz, 1H),
6.90–7.00 (m, 2H), 7.28–7.36 (m, 2H), 7.75 (br s, 1H). 13C
NMR (75 MHz, CDCl3) δ: 157.8, 127.6, 127.0, 126.9, 126.8,
115.4, 114.2, 109.9, 55.4, 13.1, 12.4. HRMS m/z 202.1226
[M + H+, calcd. for [C13H16NO]+: 202.1217].
General procedure H: pyrrole synthesis
A
solution of homoallylic ketone (100 mol%) in
CH2Cl2/MeOH (1:5, 13.5 mL per 1.00 mmol of homoallylic
ketone) was treated with ozone bubbles at –78 °C until a
blue color persisted, purged with a stream of argon bubbles,
treated with dimethyl sulphide (500 mol%), and stirred over-
night, after which time the bath temperature had warmed to
RT. Removal of the volatiles by rotary evaporation gave
crude 1,4-dicarbonyl product, which was taken up into a so-
lution of AcOH/H2O/MeCN (1:1:1, 10 mL per 1.0 mmol of
homoallylic ketone) and treated with ammonium formate
(500 mol%) and KOAc (6 000 mol%). The mixture was
heated at 80 °C until complete consumption of starting ma-
terial was observed by TLC. After cooling to RT, the reac-
tion mixture was partitioned between an organic phase of
Et2O/CH2Cl2 (2:1) and Na2CO3 solution (5% aq.). The lay-
ers were separated, and the aqueous phase was extracted
twice with Et2O/CH2Cl2 (2:1). The combined organic phases
were washed with pH 6.8 phosphate buffer and dried
(MgSO4). Volatiles were removed by successive rotary evap-
oration and lyophilization to give the crude pyrrole product,
which was purified as specified.
2-(4-Methoxy-phenyl)-3,4,5-trimethyl-1H-pyrrole (11a)
Prepared from homoallylic ketone 6a (23 mg,
0.090 mmol) according to procedure H to yield crude prod-
uct (19.2 mg) that was purified using column chromatogra-
phy (20% ethyl acetate in hexane) to give pyrrole 11a
(14 mg, 70%) as a purple gum. TLC Rf 0.49 (20:80
EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ: 1.99 (s,
3H), 2.13, (s, 3H), 2.23 (s, 3H), 3.84 (s, 3H), 6.90–6.97 (m,
2H), 7.28–7.36 (m, 2H), 7.60 (br s, 1H). 13C NMR
(400 MHz, CDCl3) δ: 157.9, 127.8, 127.4, 126.6, 115.6,
114.8, 114.2, 114.0, 55.4, 11.3, 10.4, 9.3.
2-(4-Methoxy-phenyl)-4-phenyl-1H-pyrrole (12a)
Prepared from homoallylic ketone 7a (50.8 mg,
0.150 mmol) according to procedure I (ozonolyzis carried
out in CH2Cl2) to yield crude product that was purified using
column chromatography (20% ethyl acetate in hexane) to
give pyrrole 12a (28.3 mg, 76%) as a blue gum. TLC Rf 0.30
(20:80 EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ: 3.82
(s, 3H), 5.95 (s. 0.5H), 6.60 (d, J = 2.72 Hz, 1H), 6.85–6.93
(m, 2H), 7.11–7.40 (m, 10H), 8.00 (br s, 1H). HRMS m/z
250.1222 [M + H+, calcd. for [C17H16NO]+: 250.1226].
General procedure I — pyrrole synthesis
As described in general procedure H, crude 1,4-dicarbonyl
product was produced by ozonolysis of the homoallylic
ketone (100 mol%). It was then taken up into a solution of
acetonitrile (12.5 mL per 1.00 mmol of homoallylic ketone)
containing ammonium formate (500 mol%) and
NaOAc/AcOH (100 mol% w/w, prepared by mixing
© 2007 NRC Canada

Dörr and Lubell
1015
2H), 3.31–3.46 (m, 2H), 4.84 (br s, 1H), 5. 88 (s. 0.5H),
2-(4-Methoxy-phenyl)-3,5-diphenyl-1H-pyrrole (13a)
Prepared from homoallylic ketone 8a (81 mg, 0.24 mmol)
according to procedure I to yield crude product (70.7 mg)
that was purified using column chromatography (15% ethyl
acetate in hexane) to give pyrrole 13a (59.5 mg, 77%) as a
beige powder. TLC Rf 0.40 (20:80 EtOAc/Hexane). 1H NMR
(300 MHz, CDCl3) δ: 3.84 (s, 3H), 6.71 (br s, 1H), 6.83–
6.94 (m, 2H), 7.13–7.65 (m, 12H), 8.39 (br s, 1H). 13C NMR
(100 MHz, CDCl3) δ: 158.9, 136.6, 129.1, 128.4, 128.4,
126.5, 125.9, 123.8, 123.1, 114.3, 108.4, 55.4. HRMS m/z
326.1539 [M + H+, calcd. for [C23H20NO]+: 326.1530].
6.11 (d, J = 2.52 Hz, 1H), 7.05–7.27 (m, 8H), 8.48 (br s,
1H). HRMS m/z 287.1754 [M
+
H+, calcd. for
[C17H23N2O2]+: 287.1759].
tert-Butyl-[2-(3,5-diphenyl-1H-pyrrol-2-yl)]ethylcarbamate
(13b)
Prepared from homoallylic ketone 8b (91.8 mg,
0.242 mmol) according to procedure I to yield crude product
(86.2 mg) that was purified using column chromatography
(15% ethyl acetate in hexane) to give pyrrole 13b (81.1 mg,
93%) as a beige powder. TLC Rf 0.26 (20:80 EtOAc/Hexane).
1H NMR (300 MHz, CDCl3) δ: 1.44 (s, 9H), 3.07 (t, J =
6.22 Hz, 2H), 3.43–3.60 (m, 2H), 4.84 (br s, 1H), 6.65 (d,
J = 2.65 Hz, 1H), 7.15–7.65 (m, 10H), 9.51 (br s, 1H). 13C
NMR (100 MHz, CDCl3) δ: 156.9, 136.9, 132.7, 131.0,
128.9, 128.8, 128.6, 127.9, 126.6, 125.9, 125.6, 123.6,
106.3, 80.1, 39.6, 28.5, 28.3. HRMS m/z 385.1886 [M +
Na+, calcd. for [C23H26N2O2Na]: 385.1880].
tert-Butyl-[2-(4-methyl-1H-pyrrol-2-yl)]ethylcarbamate
(9b)
Prepared from homoallylic ketone 3b (32.5 mg,
0.120 mmol) according to procedure H to yield crude prod-
uct (24.3 mg) that was purified using column chromatogra-
phy (20% ethyl acetate in hexane) to give pyrrole 9b (16 mg,
59%) as a brown gum. TLC Rf 0.20 (20:80 EtOAc/Hexane).
1H NMR (300 MHz, acetone-d6) δ: 1.38 (s, 9H), 1.98 (s,
3H), 2.68 (t, J = 7.43 Hz, 2H), 3.15–3.31 (m, 2H), 5.66 (s,
1H), 5.87 (br s, 1H), 6.36 (s, 1H), 9.42 (br s, 1H). 13C NMR
(75 MHz, acetone-d6) δ: 156.8, 130.0, 118.3, 115.0, 107.8,
78.4, 41.5, 28.6, 12.1. HRMS m/z 247.1417 [M + Na+,
calcd. for [C12H20N2O2Na]: 247.1414].
Acknowledgement
This research was supported by the Natural Sciences and
Engineering Research Council (NSERC) of Canada as well
as the Fond Québecois de Recherche sur la Nature et les
Technologies (FQRNT) of Québec. We thank the Université
de Montréal Mass Spectroscopy facility for mass spectral
analyses.
tert-Butyl-[2-(3,5-dimethyl-1H-pyrrol-2-yl)]ethylcarbamate
(10b)
Prepared from homoallylic ketone 5b (70 mg, 0.27 mmol)
according to procedure I to yield crude product (63.8 mg)
that was purified using column chromatography (20% ethyl
acetate in hexane) to give pyrrole 10b (36.3 mg, 56%) as a
References
1. (a) Y. Li, J.-P. Feng, W.-H. Wang, J. Chen, and X.-P. Cao. J.
Org. Chem. 72, 2344 (2007); (b) H.-J. Zhang, C. Ma, N.V.
Hung, N.M. Cuong, G.T. Tan, B.D. Santarsiero, A.D. Mesecar,
D.D. Soejarto, J.M. Pezzuto, and H.H.S. Fong. J. Med. Chem.
49, 693 (2006); (c) U. Albrecht, M. Lalk, and P. Langer.
Bioorg. Med. Chem. 13, 1531 (2005); (d) A. Bhatt, C.B.W.
Stark, B.M. Harvey, A.R. Gallimore, Y.A. Demydchuk, J.B.
Spencer, J. Staunton, and P.F. Leadlay. Angew. Chem. Int. Ed.
44, 7075 (2005); (e) C. Campagnuolo, E. Fattorusso, A.
Romano, O. Taglialatela-Scafati, N. Basilico, S. Parapini, and
D. Taramelli. Eur. J. Org. Chem. 5077 (2005); (f) A.V.
Baranovskii, R.P. Litvinovskaya, and V.A. Khripach. Russ. J.
Org. Chem. 40, 1608 (2004); (g) A.A. Cossé, R.J. Bartelt, and
B.W. Zilkowski. J. Nat. Prod. 65, 1156 (2002); (h) T.
Agatsuma, H. Ogawa, K. Akasaka, A. Asai, Y. Yamashita, T.
Mizukami, S. Akinaga, Y. Saitoh. Bioorg. Med. Chem. 10,
3445 (2002); (i) A. Rueda, E. Zubía, M.J. Ortega, J.J. Salvá. J.
Nat. Prod. 64, 401 (2001); (j) Y. Yang, K. Kinoshita, K.
Koyama, K. Takahashi, T. Tai, Y. Nunoura, and K.J. Watanabe.
J. Nat. Prod. 62, 1672 (1999); (k) P. Rüngeler, V. Castro, G.
Mora, N. Gören, W. Vichnewski, H.L. Pahl, I. Merfort, and
T.J. Schmidt. Bioorg. Med. Chem. 7, 2343 (1999); (l) K. Pari,
P.J. Rao, B. Subrahmanyam, J.N. Rasthogi, and C. Devakumar.
Phytochemistry, 49, 1385 (1998); (m) T. Masso, A. Portella,
and E. Rus. Perfum. Flavor. 15, 42 (1990); (n) I. Yamamoto, S.
Tanaka, T. Fujimoto, and K. Ohta. J. Org. Chem. 54, 747
(1989); (o) A. Evidente. J. Nat. Prod. 50, 173 (1987); (p) J.E.
Hochlowski, and D.J. Faulkner. J. Org. Chem. 49, 3838
(1984); (q) M. Johnston, R. Raines, M. Chang, N. Esaki, K.
Soda, and C. Walsh. Biochemistry, 20, 4325 (1981); (r) Atta-
ur-Rahman. In Natural product chemistry. Edited by Atta-ur-
Rahman. Springler-Verlag, Berlin, Germany. 1986. p. 330; (s)
1
brown gum. TLC Rf 0.22 (20:80 EtOAc/Hexane). H NMR
(300 MHz, acetone-d6) δ: 1.39 (s, 9H), 1.90 (s, 3H), 2.10 (s,
3H), 2.62 (t, J = 7.43 Hz, 2H), 3.11–3.21 (m, 2H), 5.46 (s,
1H), 5.96 (br s, 1H), 9.17 (br s, 1H). 13C NMR (75 MHz, ac-
etone-d6) δ: 156.6, 125.5, 124.1, 114.6, 108.2, 78.4, 41.6,
28.6, 27.2, 12.9, 11.1. HRMS m/z 239.1766 [M + H+, calcd.
for [C13H23N2O2]+: 239.1754].
tert-Butyl-[2-(3,4,5-trimethyl-1H-pyrrol-2-yl)]ethylcarba-
mate (11b)
Prepared from homoallylic ketone 6b (42.7 mg,
0.150 mmol) according to procedure I to yield crude product
(29.1 mg) that was purified using column chromatography
(20% ethyl acetate in hexane) to give pyrrole 11b (22 mg,
58%) as a brown gum. TLC Rf 0.24 (20:80 EtOAc/Hexane).
1H NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.92 (s, 3H),
1.93 (s, 3H), 2.14 (s, 3H), 2.71 (t, J = 6.61 Hz, 2H), 3.23–
3.36 (m, 2H), 4.66 (br s, 1H), 7.66 (br s, 1H). 13C NMR
(75 MHz, CDCl3) δ: 156.3, 122.1, 121.8, 114.9, 113.9, 79.5,
40.6, 28.5, 26.9, 11.1, 9.3, 9.2. HRMS m/z 253.1910 [M +
H+, calcd. for [C14H25N2O2]+: 253.1909].
tert-Butyl-[2-(4-phenyl-1H-pyrrol-2-yl)]ethylcarbamate (12b)
Prepared from homoallylic ketone 7b (140 mg,
0.370 mmol) according to procedure I to yield crude product
that was purified using column chromatography (20%–30%
ethyl acetate in hexane) to give pyrrole 12b (63.4 mg, 60%)
1
as a pink foam. TLC Rf 0.08 (20:80 EtOAc/Hexane). H
NMR (400 MHz, CDCl3) δ: 1.35 (s, 9H), 2.70–2.83 (m,
© 2007 NRC Canada

1016
R.R. Schmidt. In Natural product chemistry. Edited by Atta-ur-
Can. J. Chem. Vol. 85, 2007
Organometallics, 9, 3178 (1990); (f) T.R. Hoye, A.S. Magee,
and R.E. Rosen. J. Org. Chem. 49, 3224 (1984); (g) H. Mori
and R. Ohuchi. Chem. Pharm. Bull. 23, 980 (1975); (h) H.
Mori and R. Ohuchi. Chem. Pharm. Bull. 23, 559 (1975);
(i) G.L. Larson, I. Montes de López-Cepero, and L.E. Torres.
Tetrahedron Lett. 25, 1673 (1984); (j) S, Watanabe, K. Suga,
and T. Fujita. Isr. J. Chem. 11, 71 (1973); (k) G. Cahiez, P.
Venegas, C.E. Tucker, T.N. Majid, and P. Knochel. J. Chem.
Soc. Chem. Commun. 1406 (1992).
Rahman. Springler-Verlag, Berlin, Germany. 1986. p. 383.
2. C.H. Heathcock, S. Graham, M.C. Pirrung, F. Plavac, and C.T.
White. In The total synthesis of natural products. Vol. 5.
Edited by J. ApSimon. Wiley, New York. 1983. Chap. 2.
3. (a) M. Yoshida, M. Kitamura, and K. Narasaka. Bull. Chem.
Soc. Jpn. 76, 2003 (2003); (b) H. Tsuitsui, M. Kitamura, and
K. Narasaka. Bull. Chem. Soc. Jpn. 75, 1451 (2002); (c) H.
Tsuitsui and K. Narasaka. Chem Lett. 45 (1999).
4. (a) M. Kitamura, Y. Mori, and K. Narasaka. Tetrahedron Lett.
46, 2373 (2005); (b) M. Yoshida, M. Kitamura, and K.
Narasaka. Chem Lett. 144 (2002); (c) Y. Koganemaru, M.
Kitamura, and K. Narasaka. Chem Lett. 784 (2002); (d) K.
Uchiyama, Y. Hayashi, and K. Narasaka. Chem Lett. 1261
(1998); (e) T. Mikami and K. Narasaka. Chem Lett. 338
(2000).
5. (a) H. Tsuitsui and K. Narasaka. Chem. Lett. 526 (2001);
(b) M. Tingoli, M. Tiecco, L. Testaferri, R. Andrenacci, and R.
Balducci. J. Org. Chem. 58, 6097 (1993); (c) T. Hosokawa, N.
Shimo, K. Maeda, A. Sonoda, and S.-I. Murahashi. Tetrahe-
dron Lett. 17, 383 (1976).
16. (a) F. Näf and P. Degen. Helv. Chim. Acta, 54, 1939 (1971);
(b) R.E. Ireland and P. Wipf. J. Org. Chem. 55, 1425 (1990).
17. J. Hooz and R.B. Layton. Can. J. Chem. 48, 1626 (1970).
18. (a) W.X. Zheng and X. Huang. Synthesis, 2497 (2002); (b) A.
El-Batta, T.R. Hage, S. Ploktin, and M. Bergdahl. Org. Lett. 6,
107 (2004).
19. A. Barbero, F.J. Pulido, J.A. Rincó, P. Cuadrado, D. Galisteo,
and H. Martínez-Garciá. Angew. Chem. Int. Ed. 40, 2101
(2001).
20. (a) S. Hara, S. Hyuga, M. Aoyama, M. Sato, and A. Suzuki.
Tetrahedron Lett. 31, 247 (1990); (b) E. Takada, S. Hara, and
A. Suzuki. Tetrahedron Lett. 34, 7067 (1993); (c) S. Hara, S.
Ishimura, and A. Suzuki. Synlett, 993 (1996); (d) Y. Satoh, H.
Serizawa, S. Hara, and A. Suzuki. J. Am. Chem. Soc. 107,
5225 (1985); (e) P. Jacob and H.C. Brown. J. Am. Chem. Soc.
98, 7832 (1976).
21. (a) S. Zhou, B. Yan, and Y. Liu. J. Org. Chem. 70, 4006
(2005); (b) C. Zhao, J. Yan, and Z. Xi. J. Org. Chem. 68, 4355
(2003); (c) C. Zhao, T. Yu, and Z. Xi. Chem. Commun. (Cam-
bridge), 142 (2002).
22. (a) T. Mukaiyama, H. Nagaoka, M. Ohshima, and M.
Murakami. Chem. Lett. 1009 (1986); (b) K. Kudo, K. Saigo,
Y. Hashimoto, H. Houchigai, and M. Hasegawa. Tetrahedron
Lett. 32, 4311 (1991); (c) K. Kudo, Y. Hashimoto, H.
Houchigai, M. Hasegawa, and K. Saigo. Bull. Chem. Soc. Jpn.
66, 848 (1993); (d) T. Ishihara, T. Shinozaki, and M.
Kuroboshi. Chem. Lett. 1369 (1989).
23. (a) B.M. Trost, J.A. Martinez, R.J. Kulawiec, and A.F.
Indolese. J. Am. Chem. Soc. 115, 10402 (1993); (b) S. Dérien
and P.H. Dixneuf. J. Chem. Soc. Chem. Commun. 2551 (1994).
24. (a) A.R. Katritzky, Z. Huang, and Y. Fang. J. Org. Chem. 64,
7625 (1999); (b) L. Zhao and X. Lu. Org. Lett. 4, 3903 (2002);
(c) Z. Wang and X. Lu. Chem. Commun. (Cambridge), 535
(1996); (d) Z. Wang and X. Lu. J. Org. Chem. 61, 2254
(1996); (e) J. Tsuji, I. Miniami, and I. Shimizu. Chem. Lett.
1325 (1983).
6. R.A. Ellison. Synthesis, 397 (1973).
7. (a) K.A. Hansford, V. Zanzavora, A. Dörr, and W.D. Lubell. J.
Comb. Chem. 6, 893 (2004); (b) K.A. Hansford, S.A.P.
Guarin, W.G. Skene, W.D. Lubell. J. Org. Chem. 70, 7996
(2005); (c) B. Jolicoeur and W.D. Lubell. Org. Lett. 8, 6107
(2006); (d) R. Dhawan, and B.A. Arndtsen. J. Am. Chem. Soc.
126, 468 (2004); (e) B.K. Banik, S. Samajdar, and I. Banik. J.
Org. Chem. 69, 213 (2004); (f) R.U. Braun, K. Zeitler, and T.J.
Muller. J. Org. Lett. 3, 3297 (2001); (g) E. Baltazzi and L.I.
Krimen. Chem. Rev. 63, 511 (1963); (h) H. Chochois, M.
Sauthier, E. Maerten, Y. Castaner, and A. Mortreux. Tetrahe-
dron, 62, 11740 (2006); (i) G. Minetto, L.F. Raveglia, and M.
Taddei. Org. Lett. 6, 389 (2004); (j) D.S. Mortensen, A.L. Ro-
driguez, K.E. Carlson, J. Sun, B.S. Katzenellenbogen, and J.A.
Katzenellenbogen. J. Med. Chem. 44, 3838 (2001); (k) S,
Raghavan, and K. Anuradha. Synlett, 5, 711 (2003).
8. (a) H.S.P. Rao and S. Jothilingam. J. Org. Chem. 68, 5392
(2003); (b) B.W. Greatrex, M.C. Kimber, D.K. Taylor, and
E.R.T. Tiekink. J. Org. Chem. 68, 4239 (2003); (c) W.C.
Christopfel, and L.L. Miller. J. Org. Chem. 51, 4169 (1986);
(d) P. Bosshard and C.H. Eugster. Adv. Heterocycl. Chem. 7,
377 (1966).
9. A. Dörr and W.D. Lubell. Biopolymers (Peptide Science), 88,
290 (2007).
10. (a) A.R. Katritzky, M.V. Voronkov, and D. Toader. J. Org.
Chem. 63, 9987 (1998); (b) A.R. Katritzky, and D. Toader. J.
Am. Chem. Soc. 119, 9321 (1997).
25. M. Yasuda, S. Tsuji, Y. Shigeyoshi, and A. Baba. J. Am.
Chem. Soc. 124, 7440 (2002).
26. S. Condon-Gueugnot, D. Dupré, J.-Y. Nédélec, and J.
Périchon. Synthesis, 1457 (1997).
11. S. Takano, S. Tomita, M. Takahashi, and K. Ogasawara. Chem.
Lett. 1569 (1987).
12. T. Fujiwara, T. Iwasaki, and T. Takeda. Chem. Lett. 1321
(1993).
13. D.V. Avilov, M.G. Malusare, E. Arslancan, and D.C. Dittmer.
Org. Lett. 6, 2225 (2004).
14. D. Imao, A. Itoi, A. Yamasaki, M. Shirakura, R. Ohtoshi, K.
Ogata, Y. Ohmori, T. Ohta, Y. Ito. J. Org. Chem. 72, 1652
(2007).
15. (a) S.M. Allin, J.S. Khera, C.I. Thomas, J. Witherington, K.
Doyle, M.R.J. Elsegood, and M. Edgar. Tetrahedron Lett. 47,
1961 (2006); (b) D. Giomi, M. Piacenti, and A. Brandi. Eur. J.
Org. Chem. 4649 (2005); (c) K. Totani, T. Nagatsuka, K.-I.
Takao, S. Ohba, and K.-I. Tadano. Org. Lett. 1, 1447 (1999);
(d) Y. Han and V.J. Hruby. Tetrahedron Lett. 38, 7317 (1997);
(e) K.-H.A. Ahn, B.R. Klassen, and S.J. Lippard.
27. (a) G. Saucy and R. Marbet. Helv. Chim. Acta, 50, 2091
(1967); (b) M. Koreeda and J.I. Luengo. J. Am. Chem. Soc.
107, 5572 (1985); (c) M. Morita, S. Sakaguchi, and Y. Ishii. J.
Org. Chem. 71, 6285 (2006); (d) T. Higashino, S. Sakaguchi,
and Y. Ishii. Org. Lett. 2, 4193 (2000); (e) G. Nordmann and
S.L. Buchwald. J. Am. Chem. Soc. 125, 4978 (2003); (f) H.
Tamio, Y. Akihiro, and I. Yoshihiko. Synth. Commun. 19,
2109 (1989); (g) G. Büchi and D.E. Vogel. J. Org. Chem. 50,
4664 (1985); (h) R.M. Roberts and R.G. Landolt. J. Am.
Chem. Soc. 87, 2281 (1965); (i) T. Masso, A. Portella, and E.
Rus. Perfum. Flavor. 15, 39 (1990); (j) W. Giersch and I.
Farris. Helv. Chim. Acta, 87, 1601 (2004); (k) S.-I. Murahashi,
Y. Makabe, and K. Kunita. J. Org. Chem. 53, 4489 (1988).
28. (a) W. Kimmel and A.C. Cope. J. Am. Chem. Soc. 65, 1992
(1943); (b) M.F. Carroll. J. Chem. Soc. 704 (1940); (c) J.
© 2007 NRC Canada

Dörr and Lubell
Tsuji, I. Minami, and I. Shimizu. Chem. Lett. 1721 (1984);
(d) E.C. Burger and J.A. Tunge. Org. Lett. 6, 2603, 2004).
29. J. Nowicki. Molecules, 2000, 1420 (2000).
30. (a) T. Nishiyama, J.F. Woodhall, E.N. Lawson, and W.
Kitching. J. Org. Chem. 54, 2183 (1989); (b) C.A. Cornish and
S. Warren. J. Chem. Soc. Perkin Trans. 1, 2585 (1985);
(c) C.A. Cornish and S. Warren. Tetrahedron. Lett. 25, 2603
(1983); (d) T.H. Kim and S. Isoe. J. Chem. Soc. Chem.
Commun. 730 (1983).
31. (a) K. Suga, S. Watanabe, Y. Yamaguchi, and M. Tohyama.
Synthesis, 189 (1970); (b) K. Suga, S. Watanabe, T. Fujita, and
Y. Takahashi. Aust. J. Chem. 26, 2123 (1973); (c) S.
Watanabe, K. Suga, and Y. Yamaguchi. J. Appl. Chem.
Biotechnol. 22, 43 (1972).
1017
33. K. Suga, T. Fujita, S. Watanabe, and Y. Takahashi. Synthesis,
133 (1974).
34. K.A. Hansford, J. Dettwiler, and W.D. Lubell. Org. Lett. 5,
4887 (2003).
35. S. Watanabe, K. Suga, T. Fujita, and N. Saito. Aust. J. Chem.
30, 427 (1977).
36. N. Boccara and P. Maitte. Bull. Soc. Chim. Fr. 4, 1448 (1972).
37. (a) H. Ikeda, T. Minegishi, T. Miyashi, P.S. Lakkaraju, R.R.
Sauers, and H.D. Roth. J. Phys. Chem. B, 109, 2504 (2005);
(b) E.N. Marvell and T.H.-C. Li. J. Am. Chem. Soc. 100, 883
(1978); (c) J.M. Watson, J.L. Irvine, and R.M. Roberts. J. Am.
Chem. Soc. 95, 3348 (1973).
38. (a) W. Zhao and E.M. Carreira. Chem. Eur. J. 12, 7254 (2006);
(b) M.J. Hall, S.O. McDonnell, J. Killoran, and D.F. O’Shea.
J. Org. Chem. 70, 5571 (2005).
32. S. Watanabe, K. Suga, T. Fujita, and I. Takahashi. Can. J.
Chem. 50, 2786 (1972).
© 2007 NRC Canada