Synthesis of α,ω-Bis-Enones by the Double Addition of Alkenyl Grignard Reagents to Diacid Weinreb Amides

Article abstract of DOI:10.1002/ejoc.201901043

An efficient double addition of substituted alkenylmagnesium bromides to bis-Weinreb amides has been developed, giving α,ω-bis-enones that are building blocks for certain drugs and polymers. Furthermore, reliable protocols for the preparation of the requi

Full text of DOI:10.1002/ejoc.201901043

A Journal of
Accepted Article
Title: Synthesis of α,ω-Bis-Enones by the Double Addition of Alkenyl
Grignard Reagents to Diacid Weinreb Amides
Authors: Stefan Wiesler, Michael Andreas Bau, Thomas Niepel, Sara
Laila Younas, Hieu-Trinh Luu, and Jan Streuff
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901043
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
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a w
Synthesis of , -Bis-Enones by the Double Addition of Alkenyl Grignard
Reagents to Diacid Weinreb Amides
Stefan Wiesler,[a] Michael A. Bau,[a] Thomas Niepel,[a] Sara L. Younas,[a] Hieu-Trinh Luu,[a] and Jan
Streuff*[a]
O
OH
Abstract:
An
efficient
double
addition
of
substituted
MeO
OMe
alkenylmagnesium bromides to bis-Weinreb amides has been
developed, giving a,w-bis-enones that are building blocks for certain
drugs and polymers. Furthermore, reliable protocols for the
preparation of the required substituted alkenyl magnesium reagents
from substituted non-activated alkenyl bromides are reported. The
double addition is demonstrated on 25 examples, including
enantiopure as well as conjugated and cross-conjugated bis-enones.
The addition to a cyclohexane-1,2-dicarboxamide was found to lead
curcumin
HO
O
OH
O
R1
O
R1
O
n
n
R2
R2
R1 R2 R2 R1
(cross-conjugated)
(conjugated)
This work:
O
O
to
a selective mono addition, giving access to cyclohexyl g-
R1
R1
O
O
R1
[Mg]
ketoamides that are core motifs of several pharmaceutical agents
and promising drug candidates.
X
MeO
+
OMe
2
N
X
N
double
addition
R2 R3 R3 R2
R2 R3
bis-enone
Scheme 1. Curcumin and examples of conjugated and cross-conjugated a,w-
bisenones (top). Envisioned double-Grignard addition to bis-Weinreb amides
(bottom).
Introduction
Symmetric a,w-bisenones have been of interest to researchers
over the past decades. Curcumin and related compounds
belonging to the family of the bis-chalcones, have been heavily
examined for potential biological properties, although it has
recently been uncovered that curcumin returns deceptively false
results (Scheme 1).[1,2] Furthermore, bis-chalcones are also
widely used as photosensitizers and precursors of organic
dyes.[3] While these compounds can be easily accessed via aldol
condensation reactions, the corresponding cross-conjugated bis-
enones exhibit a much higher reactivity and tendency to
polymerization and, hence, have been much less studied. Still,
such cross-conjugated bis-enones are of interest as precursors
in organic synthesis and polymer chemistry.[4]
More general methods to access bis-enone compounds are
scarce and do not always give satisfying results.[5] One
approach to double unsaturated 1,4-diketones with a saturated
C2-tether are oxidative coupling protocols, which unfortunately
cannot be transferred to the preparation of linked enones having
a longer connecting chain.[6] An alternative is the 1,2-addition of
aryl or alkyl Grignard and lithium reagents to bis-Weinreb
amides has been reported.[8,9] Recent studies further show that
such nucleophilic acyl substitution reactions can be even carried
out in protic media under air, efficiently suppressing the over-
addition in the addition of organometallic reagents to simple
N,N-dialkylamides.[10]
We have recently published a broadly applicable synthesis
of chiral ansa-metallocenes, which featured the double addition
of alkenyl Grignard reagents to a,w-bis-Weinreb amides for the
formation of the key bisenone intermediates.[11] Herein, the
development and scope of this double addition is reported,
including reliable methods for the preparation of substituted
alkenyl Grignard reagents.
Results and Discussion
alkenyllithium
and
Grignard
reagents
to
a,w-diacid
The alkenyl bromides for the formation of the Grignard
reagents were prepared from the corresponding ketones by
treatment with bromine, triphenylphosphite and triethylamine, if
not noted otherwise.[12] The bis-Weinreb amides were
conveniently synthesized either from the diesters by reaction
derivatives.[4,7] But since the preparation of Grignard reagents
from non-activated and substituted alkenylbromides is not
always straightforward,[7a] such double-additions have only been
reported with commercially available vinyl- or 2-propenyl-
magnesium bromide solutions and in typically low to moderate
yields.[4,7b,c] In this context, it should be noted that the addition of
with
N-methoxy-N-methylamine
hydrochloride
and
trimethylaluminum, or by a T3P-promoted amide formation using
the free diacid, or from the diacid chloride, HN(Me)OMe•HCl and
triethylamine.[13,14]
In order to achieve good yields for the envisioned double
addition reaction, the procedure for the formation of the required
Grignard reagents was optimized using cyclohexenyl bromide
(1) as test substrate.[15] In Table 1, the results of the condition
screening are given, each entry showing the result of the largest
scale reaction as indicated. In detail, common conditions using
Mg0 turnings and 5 mol-% of iodine for activation gave
1
[a]
S. Wiesler, M. A. Bau, T. Niepel, S. L. Younas, H.-T. Luu, Dr. J.
Streuff
Institut für Organische Chemie
Albert-Ludwigs-Universität Freiburg
Albertstr. 12, 79104 Freiburg im Breisgau, Germany
E-mail: jan.streuff@ocbc.uni-freiburg.de
Homepage: https://portal.uni-freiburg.de/streuff
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ejoc.201901043.
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
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Table 1. Optimization of the Grignard reagent formation.
metal
additives
Br
[M]
Et2O or THF
reflux, 2 h
1a
(5–100 mmol)
2a: [M] = MgBr•LiCl
[b]
Entry
Metal (equiv)
Additives (equiv)
Solvent
[M] =
c / M[a] (cmax
)
Conversion / %[c]
1
2
3
4
5
6
7
Mg0 turnings (1.00)
Mg0 turnings (1.00)
Mg0 powder (2.50)
Mg0 powder (2.50)
Mg0 powder (2.50)
iPrMgCl•LiCl
I2 (0.05)
THF
THF
THF
THF
Et2O
THF
THF
MgBr
0.34–0.40 (0.80)
0.42–0.63 (0.80)
0.28 (0.40)
0.35 (0.40)
0.06 (0.40)
-- (0.40)
43–50[d,e]
53–79[f]
70[g]
I2 (0.05), (BrCH2)2 (0.05), LiCl (1.25)
TMSCl (0.01), (BrCH2)2 (0.05), LiCl (1.25)
TMSCl (0.01), (BrCH2)2 (0.10), LiCl (1.25)
TMSCl (0.01), (BrCH2)2 (0.05), LiCl (1.25)
none
MgBr•LiCl
MgBr•LiCl
MgBr•LiCl
MgBr•LiCl
MgCl•LiCl
ZnBr•LiCl
88[h]
16[g]
0[g]
Zn0 powder (1.50)
TMSCl (0.01), (BrCH2)2 (0.05), LiCl (1.50)
-- (0.40)
0[g]
[a] Determined by titration against 2-hydroxybenzaldehyde-N-phenylhydrazone.[16] [b] cmax = theoretical maximum concentration. [c] Determined from c/cmax. [d]
Significant Wurtz-coupling was observed. [e] 10 mmol scale. The range in yield of several reactions is given. [f] 100 mmol scale. The range in yield of several
reactions is given. [g] 5 mmol scale. [h] 80 mmol scale.
cyclohexenylmagnesium bromide in yields of only 43–50%, the
main issue being the formation of undesired byproducts
(entry 1).[17] The reaction was more efficient in the presence of
dry lithium chloride, which is known to facilitate Grignard reagent
formation.[18] Small amounts of dibromoethane and iodine further
activated the magnesium metal and enabled the visualization of
the reaction initiation by the vanishing iodine color (entry 2).[19]
This protocol gave good and reproducible concentrations of the
alkenyl magnesium bromide lithium chloride 2a in a range of c =
0.42–0.63 M (theoretical maximum concentration: 0.8 M). As an
alternative procedure, an excess of Mg0 powder in combination
with lithium chloride and chlorotrimethylsilane / dibromoethane
for the activation was successful (entry 3). While the
concentrations of the reagent prepared this way varied on small
scale, this protocol gave reliably high concentrations and yields
of 2a on a 50–80 mmol scale (up to 88%, entry 4). In either case,
using THF as solvent for the preparation of 2a was crucial, since
the conversion was poor in diethyl ether (entry 5). Furthermore,
the purity of alkenyl bromide 1a was important for achieving a
high concentration of the reagent. We also briefly tested
alternative conditions via transmetallation from iPrMgCl•LiCl
(entry 6) and the formation of the corresponding oranozinc
species (entry 7), but the desired organometallic reagents were
required a careful optimization in order to achieve good results
for the double addition and, in particular, the choice of solvent
was important (Table 2). It was found that pure THF as solvent
was insufficient (entry 1). Preparing the organomagnesium
reagent in THF and adding it to a solution of the bis-Weinreb
amide in the same volume of diethyl ether, however, gave
satisfactory results (entry 2). The yield of diketone 4a was
further increased by
a
higher concentration of the
organomagnesium reagent and by increasing the amount to
three equivalents (based on 3a, = 1.5 equiv/amide). This way,
diketone 4a was received in 70% yield on an 8 mmol scale
(entry 3). Importantly, no mono addition product was observed
Table 2. Optimization of the addition of 2a to 3a.
O
O
2a
MeO
N
N
OMe
solvent
–10 ºC to 23 ºC
overnight
O
O
3a
[2a] / M
4a
Entry
Equiv 2a[a]
2.2
3a dissolved in
Yield / %[b]
1
2
3
4
0.21 in THF
0.21 in THF
0.37 in THF
0.06 in Et2O
THF
15
not formed.[7a,20] Following the conditions of entries
2
2.4
Et2O (THF:Et2O = 1:1)[c]
Et2O (THF:Et2O = 1:1)[c]
neat
54
(designated method A) or 4 (designated method B), non-
activated substituted alkenyl bromides could be efficiently
transformed into the corresponding alkenylmagnesium bromide
lithium chlorides with good conversion. The resulting solutions
were of suitable molarities for the subsequent double 1,2-
addition reactions.
3.0
70[d]
99
3.0
[a] Based on 3a. [b] Yield of isolated product. [c] Final THF/Et2O ratio (v/v)
after the addition. [d] Reaction on an 8 mmol scale.
We then investigated the addition of 2a to the bis-Weinreb
amide of succinic acid (3a) as limiting reagent. The reaction
2
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[Mg]
Table 3. Grignard reagent preparation.
R1
R1
R2
R2
O
Mg0
O
R2
2a–o (in THF)
method A or
MeO
N
N
OMe
Et2O
–10 ºC to 23 ºC
overnight
O
method B or
R1
R1
R1
O
4a–o
3a
method C
Br
[Mg]
R2
1a–o
THF, reflux
R2
n
O
O
2a–o
[c,d]
Entry
1
Reagent
2a
Method[a]
Additives[b]
[2] / M (cmax)
O
O
4a: 70%
n
4b (n = 1): 86%
4c (n = 3): 81%
4d (n = 4): 61%
B
B
B
B
A
A
A
B
C
B
C
C
A
A
A
TMSCl, (BrCH2)2
TMSCl, (BrCH2)2
TMSCl, (BrCH2)2
TMSCl, (BrCH2)2
I2, (BrCH2)2
I2, (BrCH2)2
I2, (BrCH2)2
TMSCl, (BrCH2)2
-
0.30–0.40 (0.41)
0.35–0.45 (0.70)
0.07–0.21 (0.41)
0.12–0.33 (0.41)
0.18 (0.50)
2
2b
2c
O
O
3
4
2d
2e
O
O
4e: 63%
4f: 62%
5
O
O
n
6
2f
0.38 (0.93)
7
2g
2h
2i
0.27 (0.53)
O
O
n
4g: 67%
4h (n = 1): 65%
4i (n = 2): 84%
8
0.24 (0.41)
O
O
9
0.78–0.81 (1.00)
0.41–0.43 (0.43)[e]
0.56 (1.00)
Ph
Ph
10
11
12
13
14
15
2j
TMSCl, (BrCH2)2
-
O
O
4j: 41%
4k: 73%
2k
O
O
Ph
2l
-
0.50–0.68 (1.00)
0.23 (0.56)
Ph
O
O
2m
2n
2o
I2, (BrCH2)2
I2, (BrCH2)2
I2, (BrCH2)2
4l: 86%
(E/E:E/Z:Z/Z = 1.0:2.9:3.8)
4m: 50%
0.17 (0.40)
O
O
O
O
O
O
0.40 (0.50)
O
O
4o: 57%
4n: 69%
[a] Method A: see Table 1, entry 2. Method B: see Table 1, entry 4. Method C:
Mg0 turnings (2.5 equiv), alkenyl bromide (1.0 equiv), THF, reflux, 2 h. [b] The
additives were added in quantities of 0.3–10 mol-% to start and maintain the
Grignard formation. See the experimental details. [c] Determined by titration
Scheme 2. Double-addition of various Grignard reagents to bis-Weinreb amide
3a.
against 2-hydroxybenzaldehyde-N-phenylhydrazone. [d] cmax
= theoretical
maximum concentration. [e] Using method C, reagent 2j was formed in a
concentration of c = 0.76 M (cmax = 1.00 M).
soluble and, hence, the addition to this intermediate would be
preferred over the addition to 3a.
To demonstrate the scope of the double addition, several
structurally diverse alkenyl Grignard reagents were prepared.
Table 3 shows the concentrations of the reagents that were
typically prepared on a 40–70 mmol scale. Several alkenyl
bromides, in particular those activated by conjugation, were
sufficiently reactive to form the Grignard reagent without the
addition of lithium chloride or other additives (designated method
C). The addition of each freshly prepared reagents to 3a then
led to a number of substituted bisenones (Scheme 2). In detail,
the reaction was tested for five- to eight-membered
alkenylmagnesium reagents resulting in isolated yields of 61–
86% (4a–d). A 4-tert-butyl substituted cyclohexenyl Grignard
reagent (2e) underwent the double addition in 63% yield giving
bisenone 4e and a gem-dimethyl substituted cyclohexene motif
could be double-added in 62% yield to give 4f. It was then tested
whether a conjugation of the alkene with an aromatic ring was
under these conditions. A longer reaction time of 72 h did not
further improve the reaction outcome. A reaction run in diethyl
ether as sole solvent, which was carried out by the addition of an
ethereal solution of 2a to neat 3a, was quantitative (entry 4). But
since the formation of Grignard reagent 2a was inferior in diethyl
ether, the conversion based on alkenyl bromide was low,
resulting in the impracticable requirement of a large excess of
the bromide. A corresponding addition of 2a prepared in THF to
neat 3a gave only 52% yield, further showing the importance of
Et2O as co-solvent. Overall, entry 3 provided the best conditions
for the addition step.
One possible origin for the positive effect of Et2O on the
reaction yield and the high chemoselectivity towards the double
addition was the poor solubility of 3a in Et2O. The mono addition
intermediate, on the other hand, was expected to be more
3
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10.1002/ejoc.201901043
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tolerated. Gratifyingly, the addition of 2-indenylmagnesium
bromide lithium chloride (2g) took place and product 4g was
formed in 67% yield. The fully conjugated bis-enol tautomer of
4g was not observed. This was also the case for products 4h
and 4i that were obtained in 65% and 84% yield. The
corresponding organomagnesium precursors (2h,i) were
prepared from a-tetralone and benzosuberone, respectively, in a
three-step sequence. In analogy, the cross-conjugated bisenone
4j was prepared, albeit in a 41% yield. A plausible cause for this
reduced outcome was the increased steric demand of the
Grignard reagent. The formation of the aryl-conjugated Grignard
reagents was greatly facilitated and occurred readily in presence
of Mg0 turnings without further additives (method C). However, in
the case of 2j, a higher conversion of the alkenyl bromide (up to
>99%) could be achieved using method B (entry 10). Next,
acyclic alkenyl-Grignard reagents were examined. The linear
phenyl- and cyclohexyl-substituted bisenones 4k and 4l bearing
1,2-disubstituted alkene moieties were prepared from the
corresponding b-styryl and 2-cyclohexylethenyl reagents 2k,l in
good to excellent yield (73% and 86%). Since 2l was employed
as a mixture of double bond isomers, 4l was received as a
respectively. Hence, simultaneous variations of both reagents
were tolerated as well.
As an interesting exception, cyclohexane-1,2-dicarboxamide
3j turned out to be a poor substrate for the double addition.
Instead, a selective formation of the mono addition product rac-6
took place, which was isolated in 50% yield (Scheme 4).
Moreover, no reaction took place when the isolated mono
addition product rac-6 was resubmitted to the 1,2-addition
conditions. We hypothesized that an unusually stable
coordination complex involving both carbonyl groups may be
formed in these cases, hampering the second addition of the
organometallic reagent. This selective mono addition may be a
useful alternative for the preparation of analogous cyclohexyl g-
ketoamides.[21] These are central motifs of compounds with
various biological activities, ranging from potential agents
against chagas disease and hepatitis C, orexin receptor and
MCH antagonists, neuroleptic drug models, as well as FLAP and
Pin1 inhibitors, for example.[22] Attempts to further explore the
selective mono addition or even a sequential addition of two
different Grignard reagents to bis-Weinreb amide 3a were
unsuccessful.
1.0:2.9:3.8
(E/E:E/Z:Z/Z)
stereoisomeric
mixture.
For
MgBr•LiCl
O
O
characterization purposes, the isomers were successfully
separated by chromatography. For the preparation of cross-
conjugated bisenones, the Grignard reagents 2m–o were added
to 3a and, to our delight, the products 4m–o could be isolated in
moderate to good yields. However, these products were found to
be prone to polymerization, which required a rapid purification
and characterization. In the cases of 4m and 4o, this
polymerization tendency led to the slightly reduced yields of 50%
and 57%. Along these lines, it should be noted that the a- and b-
styryl based bromoalkene precursors for the arene-conjugated
Grignard reagents, in particular 1j,m,n, were also found to
polymerize easily. The corresponding bromoalkene precursors
had therefore to be used immediately after their preparation.
The scope of the bis-Weinreb amide was explored as well
and a number of aliphatic, aromatic, and chiral bis-amides were
prepared from the corresponding readily-available diacids
(Scheme 3). Here, elongating the central carbon chain to three
and four carbons led to high yields of >99% and 78% (5a,b). A
terephthalic acid derivative was also smoothly converted into the
bisenone product (5c). Importantly, the enantiopure 2,3-
dimethyldiacid derivative 3e could be converted in 60% yield into
bisenone 5d without any loss of enantiopurity. This encouraged
us to prepare further enantiopure 1,4-bisenones using tartaric
and malic acid-derived building blocks (5e–h). The dimethoxy
derivative 3f, prepared from a tartrate by methyl ether formation
with silver(I) oxide and subsequent amide formation, gave 5e in
73% yield. Particularly good yields of 86% and >99% were
achieved for the cyclic acetal-containing products (5f,g). The
double addition to the malic acid bisamide 3i gave 5h in a
moderate yield of 42%. For this product, it was confirmed again
that the reaction occurred without any erosion of the
enantiopurity. Finally, we prepared bis-enones 5i and 5j in 54%
and 80% yields by adding cyclopentenyl and dihydroindenyl
reagents 2b and 2j to bis-Weinreb amides 3h and 3b,
O
O
2a (3 equiv)
MeO
OMe
X
N
X
N
THF/Et2O (1:1)
–10 ºC to 23 ºC
overnight
5a–h
3b–i
O
O
O
O
5a: >99%
5b: 78%
O
O
O
O
5c: 52%
5d: 60%
(>99% ee)[a]
O O
O
OMe
OMe O
5e: 73%
O O
O
O
5f: 86%
OMe
O
O
O
O
5h: 42%
(>99% ee)[a]
5g: >99%
O
O
O
O
O
O
5i: 54%[b]
5j: 80%[c]
Scheme 3. Addition of 2a to various bis-Weinreb amides. [a] Determined by
chiral HPLC. [b] Prepared using 2b and 3h. [c] Prepared using 2j and 3b.
4
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
MeO
O O
OMe
N
O O
OMe
N
Nicolet iS10 FT-IR spectrometer equipped with a diamond ATR unit and
are reported in frequency of absorption. Low- and high-resolution mass
analyses were performed by the service department at the Institute for
Organic Chemistry and Biochemistry, Freiburg University using a Thermo
Finnigan TSQ 700 for electron impact ionization (EI) at 70 eV, 200 ºC.
High resolution mass analyses (HRMS) were carried out on a Thermo
Exactive spectrometer with Orbitrap-Analyzer using atmospheric
pressure chemical ionization (APCI) or electron spray ionization (ESI).
HPLC analyses were carried out by the HPLC Analytics Service of the
Institute of Organic Chemistry of the University of Freiburg using a Merck
Hitachi LaChrom HPLC system.
N
2a (0.23 M)
THF/Et2O
23 ºC then
reflux, 18 h
6: 50%
3j
Scheme 4. Observed selective mono addition to a substrate with both amides
in close proximity.
Conclusions
Preparation of alkenyl bromides 1a–o
A double Grignard addition strategy for the synthesis of
symmetrical a,w-bis-enones has been developed. The method
has been demonstrated on the synthesis of a range of aliphatic,
conjugated, and cross-conjugated a,w-bisenones and it can be
applied to enantiopure diacid building blocks without a loss of
enantiopurity. In contrast, the addition of cyclohexenyl
1-Bromocyclohex-1-ene (1a). Synthesized from cyclohexanone (19.6 g,
20.7 ml, 200 mmol) according to a literature procedure in 87% yield
(28.1 g, 174.5 mmol).[12] The analytical data matched the previously
published values. This compound is also commercially available. 1H NMR
(300.1 MHz, CDCl3): d = 1.58-1.64 (m, 2H), 1.71-1.77 (m, 2H), 2.05-2.10
(m, 2H), 2.36-2.43 (m, 2H), 6.03 (dddd, J = 1.8, 1.8, 4.0, 4.0 Hz, 1H).
magnesium reagent 2a to
a substrate with both amide
functionalities in close proximity leads to a selective mono
addition, giving the corresponding g-ketoamide. Since the
products obtained from these double- and mono addition
reactions are of potential interest as building blocks for biological
and polymer chemistry as well as dendralene synthesis, the
methods reported herein could find future applications in these
areas. The herein reported optimized protocols for the formation
of substituted alkenyl Grignard reagents from the corresponding
bromoalkenes may facilitate the future use of such substituted
alkenylmagnesium reagents in synthesis in general.
1-Bromocyclopent-1-ene (1b). Synthesized from cyclopentanone
(16.8 g, 17.7 ml, 200 mmol) according to a literature procedure in 43%
yield (12.5 g, 85.0 mmol).[12] The analytical data matched the previously
published values. 1H NMR (300.1 MHz, CDCl3): d = 1.91-2.01 (m, 2H),
2.27-2.35 (m, 2H), 2.52-2.60 (m, 2H), 5.80-5.84 (m, 1H).
1-Bromocyclohept-1-ene (1c). Synthesized from cycloheptanone
(22.4 g, 23.6 ml, 200 mmol) according to a literature procedure in 96%
yield (33.6 g, 192 mmol).[12] The analytical data matched the previously
published values. 1H NMR (300.1 MHz, CDCl3): d = 1.53-1.76 (m, 6H),
2.04-2.11 (m, 2H), 2.66-2.70 (m, 2H), 6.20 (tt, J = 0.7, 6.6 Hz, 1H).
1-Bromocyclooct-1-ene (1d). Synthesized from cyclooctanone (25.2 g,
200 mmol) according to a literature procedure in 75% yield (28.3 g,
150 mmol).[12] The analytical data matched the previously published
values. 1H NMR (300.1 MHz, CDCl3): d = 1.50-1.56 (m, 6H), 1.59-1.68 (m,
2H), 2.07-2.13 (m, 2H), 2.59-2.63 (m, 2H), 6.03 (t, J = 8.5 Hz, 1H).
Experimental Section
Materials and methods. All reactions have been carried out in flame-
dried Schlenk flasks equipped with a magnetic stir bar under argon
atmosphere (argon 5.0) using absolute solvents unless noticed otherwise.
For reactions run under refluxing conditions, the reaction vessel was
equipped with an appropriate reflux condenser. Absolute THF was dried
over potassium under argon atmosphere and freshly distilled prior to use.
Absolute Et2O was obtained from a M. Braun Solvent Purification System
800 equipped with activated molecular sieves (MS 2Å). Ethyl acetate and
cyclohexane for column chromatography were purchased in technical
1-Bromo-4-(tert-butyl)cyclohex-1-ene (1e). Synthesized from 4-(tert-
butyl)cyclohexanone (3.09 g, 20.0 mmol) following the literature for 1a–d
in 90% yield (3.91 g, 18.0 mmol).[12] The analytical data matched the
previously published values.[23] 1H NMR (300.1 MHz, CDCl3): d = 0.89 (s,
9H), 1.26-1.47 (m, 2H), 1.83-1.93 (m, 2H), 2.07-2.17 (m, 1H), 2.46-2.50
(m, 2H), 6.02-6.05 (m, 1H).
quality and purified by destillation with
Bromoindene (1g) was purchased from ChemPur, 2-bromopropene (1o)
was purchased from AlfaAesar. N,O-Dimethylhydroxylamine
a rotary evaporator. 2-
2,2-Dimethylcyclohexanone (7). 2-Methylcyclohexanone (39.3 g,
350 mmol) was methylated following a literature procedure.[24] A mixture
of 7, 2,6-dimethylcyclohexanone, 2,2,6-trimethylcyclohexanone, and
2,2,6,6-tetramethylcyclohexanone was received (>99%). Ketone 7 and
unreacted 2-methylcyclohexanone were then separated from the other
polymethylated ketones following a literature procedure consisting of a
selective formylation, an acid-base extraction, and a deformylation.
Fractional distillation under reduced pressure (bp 60 ºC at p = 19 mbar)
using a 20 cm Vigreux column gave pure 7 in 23% overall yield (10.2 g,
80.8 mmol).[25] The analytical data matched the previously published
hydrochloride was purchased from ChemPur and was freshly crystallized
from chloroform. Triethylamine was purified by distillation over calcium
hydride. Propylphosphonic anhydride (T3P) was purchased from
ChemPur. Glutaryl chloride was purchased from ChemPur. Lithium
chloride was purchased from VWR. Magnesium powder was purchased
from Grüssing and magnesium turnings were purchased from Roth. All
other chemicals were purchased from Aldrich, AlfaAesar, or Acros and
used as received unless noted otherwise. An IKAmag temperature
modulator in combination with an oil bath was used to control the
reaction temperatures. NMR spectra were recorded on a Bruker Avance
III 300 (300 MHz) or a Bruker Avance II 400 (400 MHz and 100 MHz)
spectrometer and reported to residual CHCl3 (1H: d = 7.26 ppm, 13C: d =
77.16 ppm), C6D5H (1H: d = 7.16 ppm, 13C: d = 128.00 ppm), or acetone-
d5 (1H: d = 2.05 ppm, 13C: d = 29.84 ppm). The following abbreviations
were used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet,
br = broad signal. IR spectra were recorded on a Thermo Scientific
1
values. H NMR (400.1 MHz, CDCl3): d = 1.11 (s, 6H), 1.63-1.68 (m, 2H),
1.70-1.77 (m, 2H), 1.79-1.86 (m, 2H), 2.37-2.43 (m, 2H).
6-Bromo-2,2-dimethylcyclohexanone (8). This compound was
literature-known but no preparation procedure or characterization data
could be found.[26] A flame-dried, argon-filled 500 ml Schlenk flask
equipped with
a
magnetic stir bar was charged with 2,2-
5
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
dimethylcyclohexanone (7) (2.52 g, 20.0 mmol, 1.0 equiv) followed by
addition of CH2Cl2 (240 ml) and MeOH (100 ml). Stirring was started and
tetrabutylammonium tribromide (10.61 g, 22.0 mmol, 1.1 equiv) was
added at room temperature. The mixture was further stirred until the
orange color turned yellow (about 2.5 h). The solvent was removed under
reduced pressure and the residue was extracted with Et2O (4 × 80 ml).
The ether extracts were combined, dried over Na2SO4, filtered, and the
solvent was removed under reduced pressure. The product was received
as a colorless solid in 94% yield (3.84 g, 18.7 mmol) and it was used
without further purification. 1H NMR (400.1 MHz, CDCl3): d = 1.21 (s, 3H),
1.21 (s, 3H), 1.67 (ddd, J = 4.4, 11.9, 13.5 Hz, 1H), 1.75-1.97 (m, 3H),
2.11 (ddd, J = 4.4, 11.9, 13.5 Hz, 1H), 2.54-2.62 (m, 1H), 4.87 (dd, J =
5.9, 11.9 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): d = 22.13, 25.45, 26.84,
39.77, 40.87, 46.64, 54.09, 206.6. MS (EI, 70 eV): m/z (%) = 204.0 [M]+
(10), 125.1 (11), 97.1 (56), 81.1 (19), 69.1 (51), 55.1 (100), 41.1 (88),
39.0 (67). HRMS (pos. APCI) calcd for C8H17ONBr+ [M+NH4]+: 222.0488,
found: 222.0486. IR (ATR): n [cm–1] = 2941, 2868, 1723, 1452, 1386,
1367, 1300, 1202, 1079, 1052, 991, 942, 863, 752, 711.
The crude product was purified by column chromatography (pentane)
and obtained as a colorless liquid in 51% yield (2.14 g, 11.3 mmol). Rf
(pentane) = 0.8. 1H NMR (400.1 MHz, CDCl3): d = 1.01 (s, 6H), 1.41-1.44
(m, 2H), 1.71-1.78 (m, 2H), 2.37 (dt, J = 1.8, 6.3 Hz, 2H), 5.81 (t, J =
1.8 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): d = 21.61, 29.45, 35.28,
35.58, 35.96, 121.14, 138.84. MS (EI, 70 eV): m/z (%) = 187.9 [M]+ (6),
109.0 (100), 93.0 (90), 81.0 (28), 77.0 (31), 67.0 (82), 53.0 (8), 41.0 (7),
39.0 (7). HRMS (pos. APCI) calcd for C8H12OBr+ [M+O–H]+: 203.0066,
found: 203.0067. IR (ATR): n [cm–1] = 2936, 2859, 1631, 1494, 1449,
1431, 1386, 1342, 1306, 1272, 1252, 1241, 1132, 1112, 972, 928, 891,
852, 829, 740, 695. The product was found to be unstable under the
conditions for the high-resolution mass analysis (APCI and ESI
conditions). The measured molecule mass matched the corresponding
enone (e.g. 2-bromo-6,6-dimethylcyclohex-2-en-1-one), which was
probably formed by an oxidation of the allylic CH2 group to a ketone.
3-Bromo-1,2-dihydronaphthalene (1h). Synthesized from a-tetralone
(8.77 g, 60.0 mmol) following a three-steps literature procedure in 87%
yield (10.9 g, 52.1 mmol).[28] The analytical data matched the previously
published values. 1H NMR (300.1 MHz, CDCl3): d = 2.75-2.81 (m, 2H),
2.96 (t, J = 8.3 Hz, 2H), 6.80 (s, 1H), 6.95-7.01 (m, 1H), 7.06-7.20 (m,
3H).
cis-6-Bromo-2,2-dimethylcyclohexanol (9a) and trans-6-Bromo-2,2-
dimethylcyclohexanol (9b) (4:1 mixture). These compounds were
literature-known but no preparation procedure or characterization data
could be found.[26] A flame-dried, argon-filled 250 ml Schlenk flask
equipped with a magnetic stir bar was charged with a solution of 6-
bromo-2,2-dimethylcyclohexanone (8) (5.01 g, 24.4 mmol, 1.0 equiv) in
THF (25.0 ml) and MeOH (14.4 ml). The solution was cooled to 0 ºC and
NaBH4 (0.92 g, 24.4 mmol, 1.0 equiv) was added in small portions. After
stirring the reaction mixture for 15 min at 0 ºC, it was allowed to warm to
room temperature and then stirred for additional 40 min. Then, aq. HCl
(1 M, 100 ml) was added to the mixture. The layers were separated and
the aqueous layer was extracted with Et2O (3 × 50 ml). The combined
organic layers were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The bromohydrins 9a and 9b were
isolated as a 4:1 cis/trans mixture in form of a colorless oil in 91% yield
(4.60 g, 22.2 mmol). The NMR data is reported for the 9a/9b, 4:1 mixture.
1H NMR (500.2 MHz, CDCl3): d = 0.91 (s, 0.6H, trans), 0.96 (s, 2.4H, cis),
1.05 (s, 2.4H, cis), 1.08 (s, 0.6H, trans), 1.12-1.16 (m, 0.8H, trans), 1.44-
1.66 (m, 3.2H, cis), 1.82-1.91 (m, 0.2H, trans) , 1.93-1.98 (m, 0.8H, cis),
2.06-2.14 (m, 1.6H, cis), 2.31-2.36 (m, 0.4H, trans), 3.32 (dd, J = 2.3,
10.1 Hz, 0.2H, trans), 3.52 (s, 0.8H, cis), 4.14 (ddd, J = 4.6, 10.1, 12.5 Hz,
8-Bromo-6,7-dihydro-5H-benzo[7]annulene (1i).[11] This compound
was literature known, but the characterization data was incomplete.[29] It
was synthesized from 1-benzosuberone (20.8 g, 130 mmol) in analogy to
1h via the same literature procedure in 95% yield (27.5 g, 123.3 mmol, 3
steps).[28] 1H NMR (400.1 MHz, CDCl3): d = 1.97-2.02 (m, 2H), 2.87-2.89
(m, 2H), 2.96 (t, J = 6.5 Hz, 2H), 7.01 (s, 1H), 7.10-7.22 (m, 4H). 13C
NMR (100.6 MHz, CDCl3): d = 27.31, 35.22, 43.04, 126.32, 127.47,
128.56, 129.30, 131.00, 133.26, 134.39, 141.14. MS (EI, 70 eV): m/z (%)
= 224.0 [M]+ (35), 222.0 (38), 143.1 (100), 128.1 (61), 115.0 (33), 89.0 (5).
HRMS (pos. APCI) calcd for C11H11Br+ [M]+: 222.0039, found: 222.0036.
IR (ATR): n [cm–1] = 3056, 3017, 2929, 2859, 1633, 1572, 1491, 1446,
1421, 1378, 1343, 1255, 1197, 1161, 1110, 1076, 1038, 938, 883, 866,
856, 832, 747, 726, 594, 572.
4-Bromo-1,2-dihydronaphthalene (1j). Synthesized from 1-tetralone
(29.2 g, 200 mmol) according to a literature procedure in 75% yield
(31.4 g, 150.2 mmol).[23] The analytical data matched the previously
published values. 1H NMR (300.1 MHz, CDCl3): d = 2.35-2.42 (m, 2H),
2.86 (dd, J = 8.1, 8.1 Hz, 2H), 6.46 (dd, J = 4.8, 4.8 Hz, 1H), 7.10-7.13
(m, 1H), 7.18-7.29 (m, 2H), 7.57 (dd, J = 1.7, 7.5 Hz, 1H).
0.2H, trans), 4.56 (ddd,
J =
2.3, 4.6, 12.5 Hz, 0.8H). 13C NMR
(125.8 MHz, CDCl3): d = 18.07, 22.97, 23.09, 24.54, 28.66, 29.91, 31.09,
31.45, 37.13, 37.31, 37.87, 39.16, 58.74, 60.54, 77.82, 81.83. MS (CI):
m/z (%) = 224.0 [M+NH4]+ (16), 144.1 (18), 126.1 (11), 109.1 (100).
HRMS (pos. APCI) calcd for C8H19ONBr+ [M+NH4]+: 224.0645, found:
224.0639. IR (ATR): n [cm–1] = 2938, 2866, 1449, 1351, 1278, 1226,
1200, 1177, 1116, 1008, 985, 957, 937, 913, 846, 699.
(E)-(2-Bromovinyl)benzene (1k). Synthesized from (E)-cinnamic acid
(1.48 g, 10.0 mmol) according to a literature procedure in 76% yield
(1.39 g, 7.59 mmol).[30] The analytical data matched previously published
values.[23] 1H NMR (300.1 MHz, CDCl3): d = 6.78 (d, J = 13.9 Hz, 1H),
7.12 (d, J = 13.9 Hz, 1H), 7.27-7.37 (m, 5H).
1-Bromo-3,3-dimethylcyclohexene (1f). This compound was literature-
known but no preparation procedure or characterization data could be
found.[26] It was synthesized following a modified dehydration procedure
from the literature as follows.[27] A flame-dried, argon-filled 1000 ml
Schlenk flask equipped with a magnetic stir bar was charged with a
solution of cis/trans 6-bromo-2,2-dimethylcyclohexanol (9a/9b, 4:1)
(4.60 g, 22.2 mmol, 1.0 equiv) in CH2Cl2 (222 ml). Stirring was started
and the mixture was cooled to 0 ºC. DMAP (270 mg, 2.22 mmol, 10 mol-
%) and Tf2O (6.89 g, 24.4 mmol, 1.1 equiv) were added and stirring was
continued for 10 min. Then, pyridine (8.96 ml, 111 mmol, 5.0 equiv) was
added and the mixture was allowed to slowly warm to room temperature.
The reaction was stirred for an additional 16 h and then quenched by
addition of H2O (300 ml). After the transfer to a separation funnel, the
organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (4 × 80 ml). The combined organic phases were dried over
MgSO4, filtered and the solvent was removed under reduced pressure.
(2-Bromovinyl)cyclohexane (1l), E/Z mixture. A flame-dried, argon-
filled 500 ml Schlenk flask equipped with a magnetic stir bar was charged
with (bromomethyl)triphenylphosphonium bromide (17.4 g, 40.0 mmol,
2.0 equiv) and THF (130 ml). The resulting suspension was stirred,
cooled to –78 ºC, and KOt-Bu (4.04 g, 36.0 mmol, 1.8 equiv) was added.
After 30 min, a solution of cyclohexanecarbaldehyde (2.24 g, 20.0 mmol,
1.0 equiv) in THF (32 ml) was added dropwise to the yellow reaction
mixture. The cooling bath was slowly warmed to –20 ºC (over 2 h). The
reaction mixture was diluted with Et2O (160 ml) and filtered over silica
(hexanes/EtOAc, 9:1). The solvent was removed under reduced pressure
and purification by column chromatography (hexanes) gave 1l as a
mixture of E/Z isomers (1:1.6) as a colorless liquid in 56% yield (2.12 g,
11.19 mmol). The NMR data is reported for the mixture. A partially
assignment to the double bond isomers was possible. The NMR data
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
matched the previously reported values for the E and the Z isomer.[31] 1
H
A sample of the resulting solution of the Grignard reagent was titrated
against 2-hydroxybenzaldehyde-N-phenylhydrazone.[16] The Grignard
reagent was used immediately.
NMR (300.1 MHz, CDCl3): d = 1.04-1.40 (m, 5.0H), 1.61-1.77 (m, 5.0H),
1.95-2.07 (m, 0.4H, E), 2.45-2.57 (m, 0.6H, Z), 5.92 (dd, J = 7.0, 8.8 Hz,
0.6H, Z), 5.99 (dd, J = 1.1, 13.6 Hz, 0.4H, E), 6.04 (dd, J = 0.9, 7.0 Hz,
0.6H, Z), 6.14 (dd, J = 7.1, 13.6 Hz, 0.4H, E).
Method C (Mg turnings): A flame-dried, argon-filled 100 ml three-necked
flask equipped with a magnetic stir bar and a reflux condenser was
charged with Mg-turnings (608 mg, 25.0 mmol, 2.5 equiv), and stirred
overnight. Then, abs. THF (6.7 ml) was added and the alkenyl bromide
(10.0 mmol, 1.0 equiv, in total) was weighed into a separate vessel. A
small amount was added neat (about 0.3 g) and then the remaining
alkenyl bromide was added as a solution in abs. THF (3.3 ml). The
reaction mixture was refluxed for 2 h and then allowed to cool to room
temperature. A sample of the resulting solution of the Grignard reagent
was titrated with 2-hydroxybenzaldehyde-N-phenylhydrazone.[16] The
Grignard reagent was used immediately.
(1-Bromovinyl)benzene (1m). Synthesized from acetophenone (9.61 g,
9.33 ml, 80.0 mmol) following the literature procedure for the synthesis of
1a in 47% yield (6.86 g, 37.5 mmol).[12] The analytical data matched the
previously published values.[32] 1H NMR (300.1 MHz, CDCl3): d = 5.79 (d,
J = 2.0 Hz, 1H), 6.13 (d, J = 2.0 Hz, 1H), 7.32-7.39 (m, 3H), 7.57-7.62 (m,
2H).
5-(1-Bomovinyl)benzodioxole (1n). Synthesized from benzo-1,3-dioxol-
5-yl methyl ketone (4.6 g, 28.0 mmol) following the literature procedure
for the synthesis of 1a in 52% yield (3.29 g, 14.5 mmol).[12] The analytical
data matched the previously published values.[33] 1H NMR (400.1 MHz,
CDCl3): d = 5.67 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 5.99 (s, 2H),
6.77 (dd, J = 0.4, 8.2 Hz, 1H), 7.07 (dd, J = 0.4, 2.0 Hz, 1H), 7.11 (dd, J =
2.0, 8.2 Hz, 1H).
Cyclohexen-1-ylmagnesium bromide lithium chloride (2a).[11]
Prepared following method
B
on scales of 30-100 mmol. The
concentration determined by titration was in the range of c = 0.3–0.4 M.
Cyclopenten-1-ylmagnesium bromide lithium chloride (2b). Prepared
following method B on scales of 10-50 mmol. The amount of THF was
Preparation of Grignard reagents 2a–o.
adjusted to give a theoretical maximum reagent concentration of cmax
=
0.7 M. The concentration determined by titration was in the range of c =
0.35–0.45 M.
Method A (Mg turnings, LiCl, I2, dibromoethane): A 250 ml 3-necked
flask, equipped with a magnetic stir bar, a reflux condenser, a stopper,
and a septum, was charged with magnesium turnings (1.22 g, 50.0 mmol,
1.00 equiv) and with LiCl (2.65 g, 62.5 mmol, 1.25 equiv). Stirring was
started and the solids were dried in vacuo for 20 min using a heat gun.
After cooling down to room temperature (23 ºC), THF (46 ml) was added,
followed by iodine (32 mg, 0.13 mmol, 0.3 mol-%). The stopper was
replaced by an internal thermometer and the orange-brown suspension
was heated to 40 ºC (internal temperature). The alkenyl bromide
(50.00 mmol, 1.00 equiv) was weighed out in a separate vessel and
about 0.25 ml of the alkenyl bromide were then added in one portion
using a syringe. Stirring was continued at 40 ºC (internal temperature)
and 1,2-dibromoethane (58 µl, 0.68 mmol, 1.4 mol-%) was added. Once
the mixture turned colorless (indicating the initiation of the reaction), the
remaining alkenyl bromide was added neat via syringe over 50 min while
keeping the internal temperature between 40 ºC and 50 ºC. The used
vessels and syringes were rinsed with additional THF (4 ml, total THF
volume = 50 ml) into the reaction mixture. The reaction was then heated
to a gentle reflux (80 ºC oil bath temperature) for 30 min and then cooled
to room temperature. A sample of the resulting solution of the Grignard
Cyclohepten-1-ylmagnesium bromide lithium chloride (2c).[11]
Prepared following method
B
on scales of 30–50 mmol. The
concentration determined by titration was in the range of c = 0.07–0.21 M.
Cycloocten-1-ylmagnesium bromide lithium chloride (2d).[11]
Prepared following method
B
on scales of 30–70 mmol. The
concentration determined by titration
(4-(tert-Butyl)cyclohexen-1-yl)magnesium bromide lithium chloride
(2e). Prepared following method A on scales of 10-40 mmol. The amount
of THF was adjusted to give
a theoretical maximum reagent
concentration of cmax = 0.50 M. The concentration determined by titration
was in the range of c = 0.12–0.20 M.
(3,3-Dimethylcyclohexen-1-yl)magnesium bromide lithium chloride
(2f). Prepared following method A on a 10.5 mmol scale. The amount of
THF was adjusted to give a theoretical maximum reagent concentration
of cmax = 0.93 M. The concentration determined by titration was c =
0.38 M.
reagent
was
titrated
against
2-hydroxybenzaldehyde-N-
phenylhydrazone.[16] The Grignard reagent was used immediately.
Method B (Mg powder, LiCl, TMSCl, dibromoethane): A flame-dried,
argon-filled 500 ml three-necked flask equipped with a magnetic stir bar
and a reflux condenser was charged with LiCl (3.71 g, 87.5 mmol, 1.25
equiv) and heated under high vacuum with a heat gun until the LiCl was
dry (no further gas evolution visible, the powder stopped moving; ca. 15-
20 min). Then, the flask was back-filled with argon and magnesium
powder (4.25 g, 175 mmol, 2.50 equiv) was added. The flask was again
heated under high vacuum for about 10 min. After cooling to room
temperature, abs. THF (155 ml) and TMSCl (89 µl, 0.7 mmol, 1 mol-%)
were added. While stirring, the suspension was heated to reflux for 1 min
and then allowed to cool down for 5 min. Then, 1,2-dibromoethane (5–10
mol-%) was added dropwise. At this point, a vigorous reaction occurred
and the solvent started to reflux (if no reaction was observed, gentle
warming with a heat gun would usually initiate the reaction). The alkenyl
bromide (70.0 mmol, 1.0 equiv) was added slowly by syringe in such way
that a gentle reflux was maintained. The syringe was rinsed with abs.
THF (20 ml, total THF volume = 175 ml). The reaction mixture was
heated to reflux for 4–6 h and then allowed to cool to room temperature.
(1H-Inden-2-yl)magnesium bromide lithium chloride (2g). Prepared
following method A on scales of 10-30 mmol. The amount of THF was
adjusted to give a theoretical maximum reagent concentration of cmax
0.50 M. The concentration determined by titration was c = 0.25–0.27 M.
=
(3,4-Dihydronaphthalen-2-yl)magnesium bromide (2h). Prepared
following method B on scales of 30 mmol scale. The concentration
determined by titration was c = 0.24 M.
(6,7-Dihydro-5H-benzo[7]annulen-8-yl)magnesium bromide (2i).[11]
Prepared following method
C on scales of 36–123 mmol. The
concentration of the Grignard reagent was in the range of c = 0.78–
0.81 M.
(3,4-Dihydronaphthalen-1-yl)magnesium bromide lithium chloride
(2j). Prepared following method B on scales of 15–30 mmol. The amount
7
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
of THF was adjusted to give
concentration of cmax = 0.43 M. The concentration determined by titration
was in the range c = 0.41–0.43 M.
a
theoretical maximum reagent
to 3a in 95% yield (4.76 g, 18.9 mmol). The analytical data matched the
previously published values.[34] 1H NMR (300.1 MHz, CDCl3): d = 3.37 (s,
6H), 3.54 (s, 6H), 7.70 (s, 4H).
(E)-Styrylmagnesium bromide (2k). Prepared following method C on a
30 mmol scale. The concentration determined by titration was c = 0.56 M.
(R,R)-2,3-Dimethylsuccinic acid (10). Synthesized from propionyl
chloride (4.39 ml, 50.3 mmol) according to
a three-step literature
procedure involving
a dimerization in 60% overall yield (2.20 g,
15.1 mmol).[37] The analytical data matched the previously published
(2-Cyclohexylvinyl)magnesium bromide (2l). Prepared following
method C on scales of 10-23 mmol. The concentration determined by
titration was in the range of c = 0.50–0.68 M.
25
values. [a]D = +7.8º (c 1.02, H2O). 1H NMR (400.1 MHz, CD3OD): d =
1.14-1.18 (m, 6H), 2.71-2.79 (m, 2H), 4.82 (br, 2H). 13C NMR (100.6 MHz,
CD3OD): d = 14.12, 42.97, 179.19.
(1-Phenylvinyl)magnesium bromide lithium chloride (2m). Prepared
following method A on a 30 mmol scale. The amount of THF was
(R,R)-N,N’-Dimethoxy-N,N’,2,3-tetramethylsuccinamide (3e).[11]
A
flame-dried and argon-filled 250 ml Schlenk flask was charged with
(R,R)-2,3-dimethylsuccinic acid (10) (1.572 g, 10.76 mmol) and with
freshly recrystallized N,O-dimethylhydroxylammonium chloride (3.147 g,
32.26 mmol, 3.0 equiv). While stirring, the flask was evacuated and
backfilled with argon three times. The solids were suspended in THF
adjusted to give a theoretical maximum reagent concentration of cmax
0.56 M. The concentration determined by titration was c = 0.23 M.
=
(1-(Benzodioxol-5-yl)vinyl)magnesium bromide lithium chloride (2n).
Prepared following method A on a 8.4 mmol scale. The amount of THF
was adjusted to give a theoretical maximum reagent concentration of cmax
= 0.40 m. The concentration determined by titration was c = 0.17 M.
(65 ml) and the suspension was cooled to 0 ºC.
A solution of
propylphosphonic anhydride (T3P, 50% w/w in toluene, 10.54 g,
16.56 mmol, 1.5 equiv) in THF (24 ml) was added dropwise and
subsequently freshly dried and distilled diisopropylethylamine (12.5 ml,
9.50 g, 73.5 mmol, 6.8 equiv) was added dropwise, the mixture was
stirred for 5 min at 0 ºC, the cooling bath was removed and the mixture
(1-Propen-2-ylmagnesium bromide lithium chloride (2o). Prepared
following method A on a 10 mmol scale. The amount of THF was
adjusted to give a theoretical maximum reagent concentration of cmax
0.50 M. The concentration determined by titration was c = 0.40 M.
=
was stirred for further 18.5
h at room temperature. Additional
diisopropylethylamine (3.0 ml, 2.3 g, 18 mmol, 1.7 equiv) was added and
the mixture was stirred for 2 h and 20 min at room temperature.
Afterwards, the reaction mixture was cooled to 0 ºC, the reaction was
quenched by addition of a saturated aq. solution of NaHCO3 (100 ml)
(gas evolution!) and then diluted with H2O (50 ml). The organic solvent
(THF) was removed from the mixture under reduced pressure. Otherwise
no proper separation of the organic and aqueous was achieved in the
next step. The remaining contents of the flask were transferred to a
separatory funnel followed by rinsing with CH2Cl2 and H2O. The mixture
was then extracted with CH2Cl2 (5 × 40 ml). The combined organic layers
were consecutively washed with saturated aq. NH4Cl (50 ml), H2O (2 ×
50 ml) and brine (50 ml) and then dried over Na2SO4. After filtration, the
solvent was removed under reduced pressure and the residue was
purified by column chromatography (EtOAc). The title compound was
obtained as a colorless oil, which solidified upon removal of the solvents
by freeze-drying in 72% yield (1.789 g, 7.702 mmol). Rf (EtOAc) = 0.2.
Mp 55 ºC. [a]D25 = +12.7º (c 1.00, CHCl3). 1H NMR (400.1 MHz, CDCl3): d
= 1.12-1.15 (m, 6H), 3.09 (br, 2H), 3.15 (br, 6H), 3.80 (br, 6H). 13C NMR
(100.6 MHz, CDCl3): d = 14.83, 32.21 (br), 38.53, 61.45, 177.23 (br). MS
(CI): m/z (%) = 233.2 [M+H]+ (100), 172.1 (27). HRMS (APCI) calcd for
C10H21N2O4 [M+H]+: 233.1496, found: 233.1494. IR (ATR): n [cm–1] =
2977, 2942, 2908, 2881, 1652, 1457, 1422, 1386, 1365, 1178, 1086, 987,
733, 562.
Preparation of Weinreb amides 3a–j.
N,N’-Dimethoxy-N,N’-dimethylsuccinamide (3a). This compound was
literature known.[34] A flame-dried, argon-filled 100 ml Schlenk flask
equipped with
a
magnetic stir bar was charged with N,O-
dimethylhydroxylamine hydrochloride (1.18 g, 12.0 mmol, 3.0 equiv,
freshly crystallized from chloroform), DMAP (48 mg, 0.4 mmol, 10 mol-%)
and CH2Cl2 (10 ml). Then, freshly distilled succinyl chloride (440 µl,
4.0 mmol, 1.0 equiv) was added. Stirring was started and the mixture
was cooled to –10 ºC. Then, freshly distilled triethylamine (1.7 ml,
24.0 mmol, 6.0 equiv) was added slowly. The reaction was quenched by
addition of sat. aq. NaHCO3 solution (60 ml) and the mixture was
transferred into a separation funnel. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (4 × 35 ml). The
combined organic layers were washed with aq. HCl (1 M, 60 ml) and
brine (60 ml). After drying over Na2SO4 and filtration, the solvent was
removed under reduced pressure. The crude product 3a was of sufficient
purity and used as such in the next step (696 mg, 3.41 mmol, 85%). The
reaction was repeated on a 70 mmol scale and 3a was received in 75%
yield (10.7 g, 52.5 mmol). The analytical data matched the previously
published values.[34] 1H NMR (300.1 MHz, CDCl3): d = 2.75 (s, 4H), 3.16
(s, 6H), 3.71 (s, 6H).
Diethyl (R,R)-2,3-dimethoxysuccinate (11). This compound was
literature-known and prepared according to a modified procedure as
follows:[38] A flame-dried and argon-filled 100 ml Schlenk flask was
charged with MeI (20 ml, 46 g, 320 mmol, 12.8 equiv) and the liquid was
cooled to 0 ºC. While stirring, (+)-diethyl (R,R)-L-tartrate (4.3 ml, 5.2 g,
25 mmol) was added dropwise, followed by a portion-wise addition of
Ag2O (26.14 g, 112.8 mmol, 4.5 equiv). The reaction mixture was heated
to reflux for 19 h and after cooling to room temperature the remaining
MeI was removed by vacuum condensation. Et2O (200 ml) was added to
the residue and the obtained suspension was filtered through a plug of
diatomaceous earth, followed by rinsing with additional Et2O (300 ml).
The solvent was removed under reduced pressure and the title
compound was obtained as a colorless liquid in 96% yield (5.628 g,
24.03 mmol). The analytical data matched the previously published
values.[39] 1H NMR (400.1 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 6H), 3.43
N,N'-Dimethoxy-N,N'-dimethylglutaramide (3b). Synthesized from
glutaryl chloride (9.45 ml, 74 mmol) according to a literature procedure in
88% yield (14.25 g, 65.3 mmol).[9a] The analytical data matched the
previously published values.[34] 1H NMR (300.1 MHz, CDCl3): d = 1.91
(quint, J = 7.2 Hz, 2H), 2.46 (t, J = 7.2 Hz, 4H), 3.12 (s, 6H), 3.62 (s, 6H).
N,N’-Dimethoxy-N,N’-dimethyladipamide (3c). Synthesized from
adipoyl chloride (7.27 ml, 50 mmol) according to a literature procedure in
65% yield (7.59 g, 32.7 mmol).[35] The analytical data matched the
previously published values.[36] 1H NMR (300.1 MHz, CDCl3): d = 1.66-
1.71 (m, 6H), 2.42-2.49 (m, 6H), 3.17 (s, 8H), 3.68 (s, 8H).
N,N’-Dimethoxy-N,N’-dimethylterephthalamide (3d). This compound
was prepared from terephthaloyl chloride (4.06 g, 20.0 mmol) in analogy
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
(s, 6H), 4.18 (s, 2H), 4.16-4.31 (m, 4H). 13C NMR (100.6 MHz, CDCl3): d
= 14.31, 59.67, 61.31, 81.29, 169.22. MS (EI, 70 eV): m/z (%) = 234.1
[M]+ (1), 173.1 (14), 161.1 (23), 133.1 (80), 117.1 (100), 89.1 (41), 77.1
(21), 61.0 (36), 45.1 (53). HRMS (APCI) calcd for C10H22NO6 [M+NH4]+:
252.1442, found: 252.1443. IR (ATR): n [cm–1] = 2984, 2937, 2833, 1754,
1730, 1447, 1369, 1267, 1185, 1149, 1108, 1026, 923, 858, 703.
(300.1 MHz, CDCl3): d = 1.48 (s, 6H), 3.19 (s, 6H), 3.66 (s, 6H), 5.13 (s,
2H).
(S)-Dimethyl-2-hydroxysuccinate (13). Synthesized from commercially
available L-malic acid (6.70 g, 50.0 mmol) according to a literature
procedure in 92% yield (7.47 g, 46.1 mmol).[42] The analytical data
matched the previously published values. 1H NMR (300.1 MHz, CDCl3): d
= 2.70-2.86 (m, 2H), 3.65 (s, 3H), 3.75 (s, 3H), 4.44 (dd, J = 4.6, 6.1 Hz,
1H).
(R,R)-N,N’,2,3-Tetramethoxy-N,N’-dimethylsuccinamide (3f). A flame-
dried and argon-filled 50 ml Schlenk flask was charged with freshly
recrystallized
N,O-dimethylhydroxylammonium
chloride
(1.114 g,
11.42 mmol, 4.6 equiv) and evacuated and backfilled with argon with
stirring three times. CH2Cl2 (12.5 ml) was added and the resulting
suspension was cooled to 0 ºC. Within 5 min trimethylaluminum (2.0 m
solution in n-hexane, 5.7 ml, 11 mmol, 4.4 equiv) was added dropwise
and the obtained homogeneous, colorless solution was stirred for 5 min
at 0 ºC, then 5 min at room temperature and was then cooled to -18 ºC.
(S)-Dimethyl-2-methoxysuccinate (14). Synthesized from (S)-dimethyl-
2-hydroxysuccinate (13, 2.81 g, 17.3 mmol) according to a literature
procedure in 92% yield (2.83 g, 16.0 mmol).[43] The analytical data
matched the previously published values. 1H NMR (300.1 MHz, CDCl3): d
= 2.73 (dd, J = 7.7, 16.2 Hz, 1H), 2.80 (dd, J = 5.1, 16.1 Hz, 1H), 3.46 (s,
3H), 3.71 (s, 3H), 3.78 (s, 3H), 4.20 (dd, J = 5.1, 7.7 Hz, 1H).
A
solution of diethyl (R,R)-2,3-dimethoxysuccinate (11) (587 mg,
2.51 mmol) in CH2Cl2 (1.5 ml) was added dropwise and the mixture was
stirred for 4 h between -18 ºC and -10 ºC. Afterwards, the mixture was
stirred for 1 h at room temperature and it was then poured carefully on aq.
HCl (1 M, 15 ml). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10 ml). The combined organic layers were
washed with brine (25 ml), dried over Na2SO4, filtered, and the solvents
were removed under reduced pressure. The residue was purified by
column chromatography (EtOAc/MeOH, 20:1) and the title compound
was obtained as a colorless solid in 72% yield (478 mg, 1.81 mmol). Rf
(S)-2-Methoxysuccinic acid (15). Synthesized from (S)-dimethyl-2-
methoxysuccinate (14, 1.68 g, 9.51 mmol) according to
a literature
procedure in 73% yield (1.02 g, 6.90 mmol).[44] The analytical data
matched the previously published values.[45] 1H NMR (300.1 MHz,
acetone-d6): d = 2.64 (dd, J = 8.2, 16.2 Hz, 1H), 2.80 (dd, J = 4.4,
16.2 Hz, 1H), 3.39 (s, 3H), 4.16 (dd, J = 4.4, 8.2 Hz, 1H).
(S)-N,N’,2-Trimethoxy-N,N’-dimethylsuccinamide (3i). A flame-dried,
argon-filled 25 ml Schlenk tube was charged with (S)-2-methoxysuccinic
acid (15) (148 mg, 1.0 mmol, 1.0 equiv) and with freshly recrystallized
N,O-dimethylhydroxylammonium chloride (292 mg, 3.0 mmol, 3.0 equiv).
While stirring, the vessel was evacuated and backfilled with argon three
times. The solids were suspended in THF (6 ml) and the suspension was
cooled to 0 ºC. A solution of propylphosphonic anhydride (T3P, 50% w/w
in toluene, 1.9 g, 3.0 mmol, 3.0 equiv) in THF (1.5 ml) was added
dropwise and then subsequently freshly dried and distilled
diisopropylethylamine (1.4 ml, 8.0 mmol, 8.0 equiv) was added dropwise.
The mixture was stirred for 5 min at 0 ºC, then the cooling bath was
removed and the mixture was stirred for further 15 h at room temperature.
The reaction mixture was then cooled to 0 ºC and saturated aq. NaHCO3
solution (10 ml) (gas evolution!) was added. The mixture was diluted with
H2O (5 ml) and extracted with CH2Cl2 (5 × 5 ml). The combined organic
layers were consecutively washed with saturated aq. NH4Cl (5 ml), H2O
(2 × 5 ml) and brine (5 ml) and dried over Na2SO4. After filtration and
concentration, the product was purified by column chromatography
(CH2Cl2/MeOH, 20:1) and obtained as a colorless oil in 73% yield
1
(EtOAc/MeOH, 20:1) = 0.3. Mp 82 ºC. [a]D25 = +78.0º (c 1.49, CDCl3). H
NMR (500.2 MHz, CDCl3): d = 3.18 (br, 6H), 3.51 (s, 6H), 3.79 (s, 6H),
4.59 (br, 2H). 13C NMR (125.8 MHz, CDCl3): d = 32.00, 59.17, 61.58,
77.72, 169.66. MS (ESI, 70 eV): m/z (%) = 287.1 [M+Na]+ (100), 168.1
(74), 138.1 (6), 74.1 (42). HRMS (ESI) calcd for C10H20N2O6Na [M+Na]+:
287.1214, found: 287.1214. IR (ATR): n [cm–1] = 2940, 2830, 1655, 1442,
1389, 1330, 1179, 1098, 1062, 984, 937, 823, 721, 628.
(R,R)-Dimethyl-1,3-dioxolane-4,5-dicarboxylate (12). Synthesized
from (+)-dimethyl (R,R)-L-tartrate (8.92 g, 50 mmol) according to
a
literature procedure in 87% yield (8.26 g, 43.4 mmol).[40] The analytical
data matched previously published values.[41] 1H NMR (400.1 MHz,
CDCl3): d = 3.81 (s, 6H), 4.75 (s, 2H), 5.24 (s, 2H). 13C NMR (100.6 MHz,
CDCl3): d = 52.93, 76.84, 97.60, 169.70.
(R,R)-N,N’-Dimethoxy-N,N’-dimethyl-1,3-dioxolane-4,5-
dicarboxamide (3g). This compound was prepared from (R,R)-dimethyl-
1,3-dioxolane-4,5-dicarboxylate (12) (380 mg, 2.00 mmol) following the
procedure for diamide 3f with the following modification: The dropwise
addition of 12 was carried out over 1.5 h at temperatures between -18 ºC
and -10 ºC. Afterwards, stirring was continued for 30 min at room
temperature. The crude product was purified by column chromatography
(CH2Cl2/MeOH 30:1) giving the title compound as a yellow oil in 77%
25
(172 mg, 0.73 mmol). Rf (CH2Cl2/MeOH, 20:1) = 0.4. [a]D = –4.0º (c
1.00; CHCl3). 1H NMR (400.1 MHz, CDCl3, 333K): d = 2.78 (dd, J = 5.8,
16.2 Hz, 1H), 2.85 (dd, J = 7.1, 16.2 Hz, 1H), 3.12 (s, 3H), 3.18 (s, 3H),
3.33 (s, 3H), 3.66 (s, 3H), 3.72 (s, 3H), 4.65 (dd, J = 5.8, 7.1 Hz, 1H). 13C
NMR (100.6 MHz, CDCl3, 333K): d = 32.33, 32.62, 34.54, 57.52, 61.33,
61.50, 74.22, 171.12, 171.88. MS (EI, 70 eV): m/z (%) = 174.0 [M–
C2H4O2+] (97), 146.0 (100), 142.0 (73), 113.0 (10), 104.0 (100), 85.0 (12),
72.0 (7), 60.0 (20), 58.0 (13). HRMS (pos. ESI) calcd for C9H18N2O5Na+
[M+Na]+: 257.1108, found: 257.1109. IR (ATR): n [cm–1] = 2939, 2826,
1653, 1422, 1386, 1325, 1275, 1177, 1101, 986, 945, 845, 732, 700, 616.
25
yield (382 mg, 1.54 mmol). Rf (CH2Cl2/MeOH 30:1) = 0.3. [a]D = -22.2º
(c 1.73, CHCl3). 1H NMR (400.1 MHz, CDCl3): d = 3.20 (br s, 6H), 3.67 (s,
6H), 5.07 (br s, 2H), 5.15 (s, 2H). 13C NMR (100.6 MHz, CDCl3): d =
32.48, 61.75, 74.67, 97.07, 169.56. MS (EI, 70eV): m/z (%) = 248.1 [M]+
(3), 217.1 (7), 186.1 (16), 160.1 (48), 142.1 (13), 130.1 (20), 102.1 (100),
88.1 (29), 71.1 (30), 60.1 (30), 42.1 (22). HRMS (APCI) calcd for
C9H17N2O6 [M+H]+: 249.1081, found: 249.1082. IR (ATR): n [cm–1] =
2977, 2942, 1667, 1463, 1443, 1391, 1332, 1169, 1119, 1083, 1053, 988,
935, 856.
rac-3i was prepared as follows:
N-Tolyl maleimide (16). Synthesized from para-toluidine (5.36 g,
50.0 mmol) according to a literature procedure in 89% yield (8.29 g,
44.3 mmol).[46] If necessary, the product can be recrystallized from hot
i-PrOH. The analytical data matched the previously published values.[45]
1H NMR (300.1 MHz, CDCl3): d = 2.40 (s, 3H), 6.82 (s, 2H), 7.21-7.24 (m,
2H), 7.27-7.30 (m, 2H).
(R,R)-N,N’-Dimethoxy-N,N’-2,2-tetramethyl-1,3-dioxolane-4,5-
dicarboxamide (3h). Synthesized from commercially available (R,R)-
diethyl-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (4.93 g, 20.0 mmol)
according to a literature procedure in 91% yield (5.01 g, 18.1 mmol).[9c]
The analytical data matched the previously published values. 1H NMR
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
rac-2-Methoxysuccinic acid (rac-15). Synthesized from N-tolyl
maleimide (16, 2.81 g, 15.0 mmol) according to a literature procedure in
75% yield (1.67 g, 11.28 mmol).[45] The following modification was
applied: 9 mol-% of K2CO3 were used. The analytical data matched the
previously published values. 1H NMR (300.1 MHz, acetone-d6): d = 2.63
(dd, J = 8.2, 16.2 Hz, 1H), 2.80 (dd, J = 4.4, 16.2 Hz, 1H), 3.39 (s, 3H),
4.17 (dd, J = 4.4, 8.2 Hz, 1H).
product was purified by column chromatography (n-pentane/EtOAc, 20:1)
and obtained as a colorless solid in 70% yield (1.402 g, 5.69 mmol). Rf
(n-pentane/EtOAc, 6:1) = 0.3. 1H NMR (400.1 MHz, CDCl3): d = 1.55-
1.65 (m, 8H), 2.19-2.26 (m, 8H), 2.95 (s, 4H), 6.97-6.99 (m, 2H). 13C
NMR (100.6 MHz, CDCl3): d = 21.74, 22.13, 23.33, 26.20, 31.26, 139.16,
139.92, 200.08. MS (EI, 70 eV): m/z (%) = 246.1 [M]+ (11), 165.1 (9),
137.1 (25), 109.1 (100), 91.1 (6), 81.1 (61), 79.0 (49), 77.0 (11), 55.1 (10),
+
53.1 (19), 41.2 (9). HRMS (pos. APCI) calcd for C16H23O2 [M+H]+:
247.16926, found: 247.16949. IR (ATR): n [cm–1] = 2935, 1660, 1638,
rac-N,N’-2-Trimethoxy-N,N’-dimethylsuccinamide
(rac-3i).
This
1423, 1387, 1262, 1214, 1168, 1135, 1097, 994, 923, 746, 667.
compound was prepared from rac-2-methoxysuccinic acid (rac-15,
603 mg, 4.07 mmol) in analogy to (S)-N,N’,2-trimethoxy-N,N’-
dimethylsuccinamide (3i). The product was purified by column
chromatography (CH2Cl2/MeOH, 20:1, Rf = 0.4) and obtained as a
colorless oil in 69% yield (655 mg, 2.79 mmol). 1H NMR (400.1 MHz,
CDCl3, 333K): d = 2.78 (dd, J = 5.8, 16.2 Hz, 1H), 2.85 (dd, J = 7.1,
16.2 Hz, 1H), 3.12 (s, 3H), 3.18 (s, 3H), 3.33 (s, 3H), 3.66 (s, 3H), 3.72 (s,
3H), 4.65 (dd, J = 5.8, 7.1 Hz, 1H). 13C NMR (100.6 MHz, CDCl3, 333K):
d = 32.33, 32.62, 34.54, 57.52, 61.33, 61.50, 74.22, 171.12, 171.88. MS
(CI): m/z (%) = 235.1 [M+H]+ (100), 174.0 (53), 146.0 (6), 142.0 (6),
1,4-Di(cyclopent-1-en-1-yl)butane-1,4-dione (4b). This compound was
prepared in analogy to 4a using bis-Weinreb amide 3a (2.37 g,
11.6 mmol) and Grignard reagent 2b (70 ml, 0.45 M in THF, 31.5 mmol,
2.7 equiv). The product was purified by column chromatography
(hexanes/EtOAc, 10:1) and obtained as a colorless solid in 86% yield
(2.19 g, 10.0 mmol). Rf (hexanes/EtOAc, 10:1)
=
0.1. 1H NMR
(400.1 MHz, CDCl3): d = 1.87-1.94 (m, 4H), 2.50-2.58 (m, 8H), 2.99 (m,
4H), 6.79-6.81 (s, 2H). 13C NMR (100.6 MHz, CDCl3): d = 22.93, 30.84,
32.96, 34.09, 143.66, 145.49, 197.63. MS (EI, 70 eV): m/z (%) = 218.1
[M]+ (20), 123.1 (22), 95.0 (100), 67.1 (11), 41.1 (7). HRMS (pos. APCI)
calcd for C14H19O2+ [M+H]+: 219.1380, found: 219.1379. IR (ATR): n [cm–
1] = 2955, 2324, 2162, 2050, 1980, 1663, 1614, 1412, 1368, 1307, 1259,
1163, 1039, 980, 944, 903, 801, 615.
+
131.0 (5), 104.0 (6). HRMS (pos. APCI) calcd for C9H19N2O5 [M+H]+:
235.1288, found: 235.1287. IR (ATR): n [cm–1] = 2939, 2826, 1655, 1423,
1386, 1324, 1178, 1103, 989, 917, 844, 726, 646, 608.
rac-trans-Cyclohexane-1,2-dicarbonyldichloride (17). Synthesized
from commercially available rac-trans-cyclohexane-1,2-dicarboxylic acid
(1.72 g, 10.0 mmol) according to a literature procedure with the following
modification: the reaction time was shortened to 16 h.[47] The crude diacid
dichloride was used immediately in the next step. The analytical data
matched the previously published values. 1H NMR (300.1 MHz, CDCl3): d
= 1.32-1.52 (m, 4H), 1.87-1.97 (m, 2H), 2.35-2.44 (m, 2H), 3.03-3.12 (m,
2H).
1,4-Di(cyclohept-1-en-1-yl)butane-1,4-dione (4c).[11] This compound
was prepared in analogy to 4a using bis-Weinreb amide 3a (204 mg,
1.0 mmol) and Grignard reagent 2c (38.6 ml, 0.07 M in THF, 2.7 mmol,
2.7 equiv). The product was purified by column chromatography (n-
pentane/EtOAc, 20:1) and obtained as a colorless solid in 81% yield
(223 mg, 0.81 mmol). Rf (n-pentane/EtOAc, 10:1)
=
0.3. 1H NMR
(400.1 MHz, CDCl3): d = 1.41-1.47 (m, 4H), 1.51-1.57 (m, 4H), 1.73-1.79
(m, 4H), 2.31-2.36 (m, 4H), 2.46-2.49 (m, 4H), 2.96 (s, 4H), 7.14 (t, J =
6.7 Hz, 2H). 13C NMR (100.6 MHz, CDCl3): d = 25.86, 25.93, 26.26,
29.21, 31.70, 32.33, 144.39, 146.02, 200.04. MS (EI, 70 eV): m/z (%) =
276.3 (19), 275.2 [M]+ (100), 274 (13), 257.2 (3), 179.2 (4), 151.2 (7),
rac-trans-N,N'-Dimethoxy-N,N'-dimethylcyclohexane-1,2-
dicarboxamide (3j). This compound was prepared from rac-trans-
cyclohexane-1,2-dicarbonyldichloride (17, 2.09 g, 10.0 mmol) in analogy
to 3a. The desired bis-Weinreb amide was obtained in analytically pure
form as a yellow solid in 82% yield (2.114 g, 8.184 mmol). The product
can be recrystallized by slow evaporation at room temperature of a
saturated solution in Et2O/n-pentane = 4:1 (v/v). Mp 56-58 ºC. 1H NMR
(400.1 MHz, CDCl3): d = 1.23-1.36 (m, 4H), 1.72-1.82 (m, 2H), 1.90-2.04
(m, 2H), 2.99-3.20 (m, 8H), 3.79 (br, 6H). 13C NMR (100.6 MHz, CDCl3):
d = 25.76, 28.71, 32.08 (br), 41.73, 61.54, 176.05 (br). MS (CI): m/z (%)
= 276.2 [M+NH4]+ (9), 259.2 [M+H]+ (100), 229.2 (20), 198.2 (72), 168.1
(16), 142.1 (9), 75.1 (6), 62.1 (19). HRMS (ESI) calcd for C12H22N2O4Na
[M+Na]+: 281.1472, found: 281.1473. IR (ATR): n [cm–1] = 2933, 2857,
1652, 1468, 1446, 1385, 1178, 1130, 984, 918, 731.
+
123.1 (27), 95.0 (12), 67.1 (5). HRMS (pos. APCI) calcd for C18H27O2
[M+H]+: 275.2006, found: 275.2003. IR (ATR): n [cm–1] = 2919, 2850,
1662, 1636, 1448, 1387, 1330, 1299,1276, 1234, 1215, 1187, 1173,
1132, 1101, 1077, 1025, 968, 917, 856, 778, 732, 649.
1,4-Di(cyclooct-1-en-1-yl)butane-1,4-dione (4d).[11] This compound
was prepared in analogy to 4a using bis-Weinreb amide 3a (511 mg,
2.5 mmol) and Grignard reagent 2d (56 ml, 0.12 M in THF, 6.75 mmol,
2.7 equiv). The product was purified by column chromatography (n-
pentane/EtOAc, 20:1) and obtained as a colorless solid in 61% yield
(464 mg, 1.53 mmol). Rf (n-pentane/EtOAc, 10:1)
(400.1 MHz, CDCl3): d = 1.39-1.55 (m, 12H), 1.59-1.65 (m, 4H), 2.31-
2.36 (m, 4H), 2.43-2.46 (m, 4H), 3.00 (s, 4H), 6.96 (t, J = 8.4 Hz, 2H). 13
=
0.2. 1H NMR
Grignard addition reactions.
C
NMR (100.6 MHz, CDCl3): d = 23.87, 26.28, 26.75, 27.64, 29.21, 29.37,
31.67, 142.48, 142.59, 199.90. MS (EI, 70 eV): m/z (%) = 302.3 [M]+ (28),
193.2 (33), 165.2 (58), 137.1 (100), 109.1 (16), 81.1 (23), 67.1 (88), 55.1
(33), 41.2 (21). HRMS (pos. APCI) calcd for C20H31O2+ [M+H]+: 303.2319,
found: 303.2318. IR (ATR): n [cm-1] = 2922, 2851, 1662, 1636, 1465,
1446, 1402, 1383, 1358, 1324, 1265, 1189, 1167, 1089, 1026, 976, 896,
847, 777.
1,4-Di(cyclohex-1-en-1-yl)butane-1,4-dione (4a).[11]
A
flame-dried,
argon-filled 250 ml Schlenk flask equipped with a magnetic stir bar was
charged with the bis-Weinreb amide 3a (1.67 g, 8.18 mmol, 1.0 equiv)
and evacuated and backfilled with argon three times while stirring. The
solid was suspended in Et2O (88 ml) and cooled to 0 ºC with stirring. A
solution of the freshly titrated Grignard reagent 2a (88 ml, 0.28 M in THF,
24.6 mmol, 3.0 equiv) was added. After 10 minutes, the reaction mixture
was allowed to warm to room temperature and stirring was continued for
14–20 h. Then, saturated aq. NH4Cl solution (35 ml) was added and the
mixture was transferred into a separation funnel. The phases were
separated and the org. phase was washed with aq. HCl (1 M, 3 × 50 ml).
The combined aq. layers were extracted with Et2O (3 × 75 ml) and the
combined org. layers were washed with saturated aq. NaHCO3 (1 ×
100 ml) and brine (1 × 100 ml). The organic layer was dried over Na2SO4,
filtered and the solvent was removed under reduced pressure. The
1,4-Bis(4-(tert-butyl)cyclohexen-1-yl)butane-1,4-dione
(4e).
This
compound was prepared in analogy to 4a using bis-Weinreb amide 3a
(98 mg, 0.48 mmol) and Grignard reagent 2e (14 ml, 0.09 M in THF,
1.3 mmol, 3.0 equiv). The product was purified by column
chromatography (hexanes/EtOAc, 9:1) and obtained as a colorless solid
in 63% yield (108 mg, 0.30 mmol). Rf (hexanes/ ethyl acetate, 9:1) = 0.4.
1H NMR (400.1 MHz, CDCl3): d = 0.89 (s, 18H), 1.04-1.14 (m, 2H), 1.23-
10
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
1.31 (m, 2H), 1.88-1.93 (m, 2H), 1.96-2.09 (m, 4H), 2.27-2.34 (m, 2H),
2.52-2.57 (m, 2H), 2.96 (s, 4H), 6.99-7.01 (m, 2H). 13C NMR (100.6 MHz,
CDCl3): d = 23.62, 24.86, 27.28, 28.01, 31.39, 32.31, 43.64, 139.08,
140.43, 199.92. MS (EI, 70 eV): m/z (%) = 358.3 [M]+ (100), 343.3 (22),
301.2 (36), 193.3 (11), 165.3 (36), 57.1 (9). HRMS (pos. APCI) calcd for
C24H39O2+ [M+H]+: 359.2945, found: 359.2936. IR (ATR): n [cm–1] = 2958,
2868, 1658, 1642, 1420, 1385, 1364, 1320, 1288, 1246, 1184, 1159,
1020, 977, 915, 765.
solid in 84% yield (827 mg, 2.23 mmol). Rf (n-pentane/EtOAc, 10:1) = 0.4.
1H NMR (400.1 MHz, CDCl3): d = 2.06-2.12 (m, 4H), 2.59 (ddd, J = 1.1,
6.2, 6.2 Hz, 4H), 2.78-2.81 (m, 4H), 3.26 (s, 4H), 7.16-7.21 (m, 2H), 7.22-
7.27 (m, 4H), 7.31-7.35 (m, 2H), 7.67 (s, 2H). 13C NMR (100.6 MHz,
CDCl3): d = 28.35, 28.92, 32.29, 34.99, 126.30, 129.01, 129.58, 132.30,
134.94, 139.71, 141.46, 143.20, 200.68. MS (EI, 70 eV): m/z (%) = 370.1
[M]+ (80), 226.0 (17), 198.2 (8), 171.0 (100), 143.2 (18), 128.1 (54), 118.0
(11). HRMS (pos. ESI) calcd for C26H26O2Na+ [M+Na]+: 393.1825, found:
393.1829. IR (ATR): n [cm–1] = 3060, 3015, 2926, 2859, 1659, 1627,
1570, 1492, 1447, 1417, 1340, 1303, 1283, 1260, 1224, 1188, 1152,
1109, 1079, 1044, 949, 907, 868, 798, 754, 731.
1,4-Bis(3,3-dimethylcyclohexen-1-yl)butane-1,4-dione
(4f).
This
compound was prepared in analogy to 4a using bis-Weinreb amide 3a
(293 mg, 1.43 mmol) and Grignard reagent 2f (11 ml, 0.38 M in THF,
4.3 mmol, 3.0 equiv). The product was purified by column
chromatography (hexanes/EtOAc, 9:1) and obtained as a colorless oil in
62% yield (268 mg, 0.89 mmol). Rf (hexanes/ ethyl acetate, 9:1) = 0.4. 1H
NMR (400.1 MHz, CDCl3): d = 1.07 (s, 12H), 1.43-1.46 (m, 4H), 1.60-
1.67 (m, 4H), 2.18 (td, J = 1.7, 6.2 Hz, 4H), 2.97 (s, 4H), 6.64 (t, J =
1.7 Hz, 2H). 13C NMR (100.6 MHz, CDCl3): d = 19.30, 23.53, 29.36,
31.39, 32.87, 36.61, 136.77, 148.82, 200.65. MS (EI, 70 eV): m/z (%) =
303.2 [M]+ (6), 193.1 (32), 177.0 (13), 165.1 (67), 151.1 (11), 147.1 (14),
137.0 (83), 133.1 (31), 109.0 (100), 93.0 (14), 79.0 (18), 67.0 (49), 55.0
1,4-Bis(3,4-dihydronaphthalen-1-yl)butane-1,4-dione
(4j).
This
compound was prepared in analogy to 4a using bis-Weinreb amide 3a
(204 mg, 1.0 mmol) and Grignard reagent 2j (4.5 ml, 0.67 M in THF,
3.0 mmol, 3.0 equiv). The product was purified by column
chromatography (n-pentane/EtOAc, 10:1) and obtained as a colorless
solid in 41% yield (139 mg, 0.41 mmol). Rf (n-pentane/EtOAc, 10:1) = 0.2.
1H NMR (400.1 MHz, CDCl3): d = 2.43-2.48 (m, 4H), 2.78 (t, J = 7.9 Hz,
4H), 3.22 (s, 4H), 7.08 (t, J = 4.9 Hz, 2H), 7.17-7.26 (m, 6H), 7.68-7.70
(m, 2H). 13C NMR (100.6 MHz, CDCl3): d = 23.55, 27.45, 34.01, 126.36,
126.44, 127.53, 127.60, 130.99, 136.36, 137.57, 139.07, 200.49. MS (EI,
70 eV): m/z (%) = 342.3 [M]+ (18), 314.3 (56), 211.1 (100), 183.2 (18),
172.2 (52), 157.2 (97), 141.2 (10), 128.2 (57), 102.1 (7), 77.1 (10), 55.1
+
(7). HRMS (pos. APCI) calcd for C20H31O2 [M+H]+: 303.2319, found:
303.2314. IR (ATR): n [cm–1] = 2954, 2929, 2864, 1665, 1635, 1469,
1453, 1391, 1360, 1339, 1298, 1268, 1214, 1154, 1062, 1035, 1000, 990,
937, 870, 591.
+
(9). HRMS (pos. ESI) calcd for C24H23O2 [M+H]+: 343.1693, found:
343.1693. IR (ATR): n [cm–1] = 3058, 2937, 2886, 2831, 2248, 1670,
1613, 1598, 1567, 1483, 1450, 1424, 1380, 1327, 1242, 1191, 1139,
1093, 1044, 1020, 956, 911, 873, 817, 787, 763, 735, 679.
1,4-Di(1H-inden-2-yl)butane-1,4-dione (4g). This compound was
prepared in analogy to 4a using bis-Weinreb amide 3a (131 mg,
0.64 mmol) and Grignard reagent 2g (7.0 ml, 0.28 M in THF, 1.9 mmol,
3.0 equiv). The product was purified by column chromatography
(hexanes/EtOAc, 9:1) and obtained as a colorless oil in 67% yield
(E,E)-1,8-diphenylocta-1,7-diene-3,6-dione (4k). This compound was
prepared in analogy to 4a using bis-Weinreb amide 3a (515 mg,
2.52 mmol) and Grignard reagent 2k (11.3 ml, 0.56 M in THF, 6.3 mmol,
2.5 equiv). The product was purified by column chromatography (n-
pentane/EtOAc, 10:1 to 5:1) and obtained as a colorless solid in 73%
yield (536 mg, 1.85 mmol). Rf (n-pentane/EtOAc, 3:1) = 0.2. 1H NMR
(400.1 MHz, CDCl3): d = 3.09 (s, 4H), 6.79 (d, J = 16.3 Hz, 2H), 7.37-7.41
(m, 4H), 7.53-7.58 (m, 4H), 7.62 (d, J = 16.3 Hz, 2H). 13C NMR
(100.6 MHz, CDCl3): d = 34.53, 126.22, 128.40, 129.02, 130.54, 134.62,
142.87, 198.63. MS (EI, 70 eV): m/z (%) = 290.2 [M]+ (9), 272.1 (7),
180.1 (5), 159.1 (5), 144.1 (23), 131.1 (100), 103.1 (38), 77.1 (14).
HRMS (pos. ESI) calcd for C20H19O2+ [M+H]+: 291.1380, found: 291.1380.
IR (ATR): n [cm–1] = 3056, 3032, 2906, 1690, 1668, 1613, 1576, 1494,
1449, 1395, 1361, 1236, 1192, 1164, 1097, 1086, 1009, 979, 970, 944,
903, 783, 743, 688.
(135 mg, 0.43 mmol). Rf (hexanes/EtOAc, 9:1)
=
0.4. 1H NMR
(400.1 MHz, CDCl3): d = 3.38 (s, 4H), 3.61 (d, J = 2.1 Hz, 4H), 7.27 (td, J
= 1.2, 7.4 Hz, 2H), 7.32-7.36 (m, 2H), 7.48-7.50 (m, 2H), 7.53 (t, J =
2.1 Hz, 2H), 8.20 (dt, J = 0.9, 7.7 Hz, 2H). 13C NMR (100.6 MHz, CDCl3):
d = 33.61, 38.87, 123.53, 123.80, 125.94, 126.87, 141.03, 143.27, 143.30,
144.19, 196.91. MS (EI, 70 eV): m/z (%) = 314.0 [M]+ (31), 286.1 (67),
271.0 (6), 240.9 (6), 199.0 (100), 171.1 (14), 157.1 (8). 143.1 (26), 129.1
(10), 115.2 (69), 55.2 (6). HRMS (pos. APCI) calcd for C22H19O2+ [M+H]+:
315.1380, found: 315.1379. IR (ATR): n [cm–1] = 3074, 2917, 1709, 1674,
1662, 1604, 1581, 1561, 1461, 1455, 1398, 1387, 1375, 1296, 1246,
1205, 1189, 1086, 1019, 910, 885, 791, 763, 722, 716.
1,4-Bis(3,4-dihydronaphthalen-2-yl)butane-1,4-dione
(4h).
This
compound was prepared in analogy to 4a using bis-Weinreb amide 3a
(476 mg, 2.33 mmol) and Grignard reagent 2h (26.8 ml, 0.235 M in THF,
6.3 mmol, 2.7 equiv). The product was purified by column
chromatography (n-pentane/EtOAc, 10:1) and obtained as a colorless
solid in 65% yield (518 mg, 1.51 mmol). Rf (n-pentane/EtOAc, 10:1) = 0.1.
1H NMR (400.1 MHz, CDCl3): d = 2.62 (t, J = 8.2 Hz, 4H), 2.85 (t, J =
8.2 Hz, 4H), 3.23 (s, 4H), 7.17-7.29 (m, 8H), 7.54 (s, 2H). 13C NMR
(100.6 MHz, CDCl3): d = 21.40, 27.61, 31.65, 126.87, 127.84, 128.88,
129.91, 132.72, 136.58, 137.59, 137.70, 199.30. MS (EI, 70 eV): m/z (%)
= 342.3 [M]+ (13), 211.2 (20), 185.2 (13), 172.1 (100), 157.2 (52), 128.2
1,8-Dicyclohexylocta-1,7-diene-3,6-dione, mixture of double bond
isomers (4l). This compound was prepared in analogy to 4a on using
bis-Weinreb amide 3a (204 mg, 1.0 mmol) and Grignard reagent 2l
(4.4 ml, 0.68 M in THF, 3.0 mmol, 3.0 equiv). The product was purified by
column chromatography (hexanes/EtOAc, 25:1) and obtained as
a
colorless solid in 86% yield (259 mg, 0.86 mmol) as a mixture of double
bond isomers (E/E : E/Z : Z/Z = 1.0:2.9:3.8). For characterization
purposes the olefin isomers were separated using an Interchim Puriflash
system equipped with a normal phase silica gel column (type PF-
SIHP/12g, 30 µm particle size) eluting with hexanes/EtOAc, 50:1→25:1.
E/E isomer: Rf (hexanes/EtOAc, 10:1) = 0.43. 1H NMR (400.1 MHz,
C6D6): d = 0.87-1.12 (m, 6H), 1.18-1.33 (m, 4H), 1.47-1.62 (m, 6H), 1.70-
1.78 (m, 4H), 2.49 (s, 4H), 3.40-3.54 (m, 2H), 5.60 (dd, J = 9.6, 11.4 Hz,
2H), 5.81 (dd, J = 1.0, 11.4 Hz, 2H). 13C NMR (100.6 MHz, C6D6): d =
25.83, 26.31, 32.75, 37.69, 37.85, 125.24, 152.76, 198.46. MS (EI, 70
eV): m/z (%) = 302.2 [M]+ (16), 208.1 (10), 193.1 (45), 175.1 (18), 165.1
(25), 157.1 (7), 147.1 (15), 133.1 (46), 119.1 (5), 113.1 (32), 105.1 (6),
95.1 (29), 81.0 (100), 67.0 (25), 55.0 (8). HRMS (pos. ESI) calcd for
C20H31O2+ [M+H]+: 303.2319, found: 303.2321. IR (ATR): n [cm–1] = 2922,
+
(28), 77.1 (6). HRMS (pos. ESI) calcd for C24H23O2 [M+H]+: 343.1693,
found: 343.1695. IR (ATR): n [cm–1] = 3016, 2931, 2835, 1655, 1622,
1567, 1485, 1452, 1439, 1384, 1345, 1313, 1297, 1269, 1249, 1206,
1189, 1171, 1154, 1107, 1030, 1011, 945, 892, 851, 756, 724.
1,4-Bis(6,7-dihydro-5H-benzo[7]annulen-8-yl)butane-1,4-dione (4i).[11]
This compound was prepared in analogy to 4a using bis-Weinreb amide
3a (544 mg, 2.66 mmol) and Grignard reagent 2i (32 ml, 0.29 M in THF,
9.3 mmol, 3.5 equiv). The product was purified by column
chromatography (n-pentane/EtOAc, 20:1) and obtained as a colorless
11
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10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
2850, 2206, 1787, 1683, 1620, 1448, 1407, 1349, 1273, 1185, 1073,
1029, 962, 891, 838, 817, 762, 687. E/Z isomer: Rf (hexanes/EtOAc,
10:1) = 0.41. 1H NMR (400.1 MHz, C6D6): d = 0.82-1.11 (m, 8H), 1.26 (tq,
J = 3.2, 12.6 Hz, 2H), 1.47-1.61 (m, 8H), 1.71-1.80 (m, 3H) 2.57-2.65 (m,
4H), 3.44-3.54 (m, 1H), 5.62 (dd, J = 9.6, 11.4 Hz, 1H), 5.85 (dd, J = 1.0,
11.4 Hz, 1H), 5.99 (dd, J = 1.4, 16.0 Hz, 1H), 6.66 (dd, J = 6.8, 16.0 Hz,
1H). 13C NMR (100.6 MHz, C6D6): d = 25.84, 26.00, 26.22, 26.31, 31.90,
32.77, 34.00, 37.72, 37.91, 40.60, 125.29, 128.22, 151.21, 152.79,
197.60, 198.65. MS (EI, 70 eV): m/z (%) = 302.2 [M]+ (9), 208.1 (6),
193.1 (24), 175.0 (6), 165.1 (5), 150.1 (9), 133.0 (12), 111.0 (100), 99.0
(qd, J = 0.7, 1.5 Hz, 2H), 6.05 (quint, J = 0.9 Hz, 2H). 13C NMR
(100.6 MHz, CDCl3): d = 17.74, 31.68, 124.77, 144.42, 200.53.
1,5-Di(cyclohex-1-en-1-yl)pentane-1,5-dione (5a).[11] This compound
was prepared in analogy to 4a using bis-Weinreb amide 3b (611 mg,
2.8 mmol) and Grignard reagent 2a (21.6 ml, 0.35 M in THF, 7.56 mmol,
2.7 equiv). The product was purified by column chromatography (n-
pentane/EtOAc, 20:1) and obtained as a colorless solid in quantitative
yield (>99%, 727 mg, 2.79 mmol). Rf (n-pentane/EtOAc, 10:1) = 0.2. 1H
NMR (400.1 MHz, CDCl3): d = 1.46-1.57 (m, 8H), 1.81 (quint, J = 7.1 Hz,
2H), 2.09-2.17 (m, 8H), 2.58 (t, J = 7.1 Hz, 4H), 6.81-6.83 (m, 2H). 13C
NMR (100.6 MHz, CDCl3): d = 19.75, 21.54, 21.94, 23.07, 25.99, 36.15,
139.02, 139.72, 200.92. MS (EI, 70 eV): m/z (%) = 260.2 [M]+ (22), 207.0
(7), 179.1 (8), 151.2 (19), 136.1 (24), 124.1 (15), 109.1 (100), 91.1 (9),
81.1 (62), 79.1 (41), 67.1 (6), 53.1 (17), 41.1 (13). HRMS (pos. APCI)
+
(20), 83.0 (8), 67.0 (12), 55.0 (8). HRMS (pos. ESI) calcd for C20H31O2
[M+H]+: 303.2319, found: 303.2319. IR (ATR): n [cm–1] = 2922, 2850,
2206, 1787, 1683, 1620, 1448, 1407, 1349, 1273, 1185, 1073, 1029, 962,
891, 838, 817, 762, 687. Z/Z isomer: Rf (hexanes/EtOAc, 10:1) = 0.39. 1H
NMR (400.1 MHz, C6D6): d = 0.81-1.12 (m, 10H), 1.46-1.58 (m, 10H),
1.73-1.82 (m, 2H), 2.74 (s, 4H), 6.02 (dd, J = 9.6, 11.4 Hz, 2H), 6.69 (dd,
J = 1.0, 11.4 Hz, 2H). 13C NMR (100.6 MHz, C6D6): d = 26.01, 26.23,
31.91, 34.07, 40.63, 128.30, 151.28, 197.84. MS (EI, 70 eV): m/z (%) =
302.1 [M]+ (26), 208.1 (8), 193.1 (22), 165.0 (32), 150.1 (48), 147.1 (12),
137.0 (100), 119.0 (21), 111.0 (82), 95.0 (26), 83.0 (19), 67.0 (31), 55.0
+
calcd for C17H25O2 [M+H]+: 261.1849, found: 261.1848. IR (ATR):
n [cm-1] = 2933, 2860, 2251, 1660, 1636, 1449, 1434, 1423, 1386, 1344,
1312, 1269, 1249, 1204, 1136, 1082, 990, 909, 843, 828, 792, 727, 647.
1,6-Di(cyclohex-1-en-1-yl)hexane-1,6-dione (5b). This compound was
prepared in analogy to 4a using bis-Weinreb amide 3c (1.56 g, 6.7 mmol)
and Grignard-reagent 2a (33.5 ml, 0.60 M, 20.1 mmol, 3.0 equiv). The
product was purified by column chromatography (petroleum ether/EtOAc,
10:1) and obtained as a colorless solid in 78% yield (1.44 g, 5.24 mmol).
Rf (hexanes/EtOAc, 10:1) = 0.3. 1H-NMR (400.1 MHz, CDCl3): d = 1.57-
1.65 (m, 12H), 2.19-2.26, M, 8H), 2.62-2.66 (m, 4H), 6.87-6.89 (m, 2H).
13C-NMR (100.6 MHz, CDCl3): d = 21.75, 22.15, 23.31, 24.71, 26.22,
37.00, 139.36, 139.78, 201.45. MS (EI, 70 eV): m/z (%) = 274.2 [M]+ (25),
256.2 (10), 150.1 (60), 148.2 (15), 124.1 (30), 109.1 (100), 91.2 (5), 81.2
(50), 53.2 (10). HRMS (pos. ESI) m/z [M+Na]+ calcd for C18H26O2Na
297.1825, found: 297.1821. IR (ATR): n [cm–1] = 2927, 2857, 1686, 1659,
1638, 1617, 1462, 1432, 1414, 1387, 1354, 1271, 1271, 1250, 1173,
1140, 1075, 986, 938, 901, 849, 796, 732, 708.
+
(89). HRMS (pos. ESI) calcd for C20H31O2 [M+H]+:303.2319, found:
303.2320. IR (ATR): n [cm–1] = 2922, 2850, 2206, 1787, 1683, 1620,
1448, 1407, 1349, 1273, 1185, 1073, 1029, 962, 891, 838, 817, 762, 687.
2,7-Diphenylocta-1,7-diene-3,6-dione (4m). This compound was
prepared in analogy to 4a using bis-Weinreb amide 3a (843 mg,
4.13 mmol) and Grignard reagent 2m (54 ml, 0.23 M in THF, 12.4 mmol,
3.0 equiv). The product was purified by column chromatography
(hexanes/EtOAc, 6:1) and obtained as a colorless solid in 50% yield
(595 mg, 2.05 mmol). Rf (hexanes/EtOAc, 6:1)
=
0.2. 1H NMR
(400.1 MHz, CDCl3): d = 3.14 (s, 4H), 5.93 (d, J = 0.6 Hz, 2H), 6.22 (d, J
= 0.6 Hz, 2H), 7.32-7.40 (m, 10H). 13C NMR (100.6 MHz, CDCl3): d =
33.86, 124.60, 128.20, 128.30, 128.49, 137.30, 149.28, 200.34. MS (EI,
70 eV): m/z (%) = 290.2 [M]+ (1) 261.9 (100), 187.0 (16), 159.0 (8), 142.1
(11), 131.1 (9), 117.1 (8), 105.1 (7), 103.1 (51), 77.2 (13). HRMS (pos.
APCI) calcd for C20H19O2+ [M+H]+: 291.1380, found: 291.1375. IR (ATR):
n [cm–1] = 3077, 2905, 1672, 1603, 1503, 1487, 1441, 1364, 1354, 1155,
1114, 1037.
1,4-Phenylenebis(cyclohexen-1-ylmethanone) (5c). This compound
was prepared in analogy to 4a using bis-Weinreb amide 3d (499 mg,
1.98 mmol) and Grignard reagent 2a (13.5 ml, 0.44 M in THF, 5.94 mmol,
3.0 equiv). The product was purified by column chromatography
(hexanes/EtOAc, 9:1) and obtained as a colorless solid in 52% yield
(301 mg, 1.02 mmol). Rf (hexanes/EtOAc, 9:1)
=
0.4. 1H NMR
2,7-Bis(benzodioxol-5-yl)octa-1,7-diene-3,6-dione
(4n).
This
compound was prepared in analogy to 4a using bis-Weinreb amide 3a
(127 mg, 0.62 mmol) and Grignard reagent 2n (10 ml, 0.17 M in THF,
1.7 mmol, 2.7 equiv). The product was purified by column
chromatography (hexanes/EtOAc, 9:1) and obtained as a colorless solid
in 69% yield (163 mg, 0.43 mmol). Rf (hexanes/EtOAc, 9:1) = 0.2. 1H
NMR (400.1 MHz, CDCl3): d = 3.11 (s, 4H), 5.86 (d, J = 0.4 Hz, 2H), 5.96
(s, 4H), 6.11 (d, J = 0.4 Hz, 2H), 6.78-6.83 (m, 6H). 13C NMR (100.6 MHz,
CDCl3): d = 33.98, 101.29, 108.29, 109.12, 122.34, 123.80, 131.24,
147.66, 147.80, 148.91, 200.64. MS (EI, 70 eV): m/z (%) = 378.1 [M]+ (8),
349.9 (79), 320.0 (12), 201.0 (9), 186.0 (44), 147.1 (100), 117.0 (13),
89.2 (22), 63.2 (5). HRMS (pos. APCI) calcd for C22H22O6N+ [M+NH4]+:
396.1442, found: 396.1442. IR (ATR): n [cm–1] = 3079, 2919, 1670, 1626,
1603, 1503, 1493, 1444, 1408, 1344, 1262, 1229, 1167, 1148, 1121,
1081, 1031, 939, 935, 867, 822, 811, 753, 736.
(400.1 MHz, CDCl3): d = 1.64-1.76 (m, 8H), 2.24-2.29 (m, 4H), 2.39-2.43
(m, 4H), 6.58-6.60 (m, 2H), 7.62 (s, 4H). 13C NMR (100.6 MHz, CDCl3): d
= 21.72, 22.06, 23.88, 26.34, 128.73, 138.89, 141.19, 145.27, 197.65.
MS (EI, 70 eV): m/z (%) = 294.3 [M]+ (41), 277.2 (8), 266.2 (24), 248.1
(24), 238.1 (11), 213.2 (19), 198.1 (23), 185.0 (100), 157.0 (38), 143.0
(42), 129.0 (41), 115.0 (17), 109.0 (39), 91.0 (8), 81.0 (49), 79.0 (32),
+
53.0 (9). HRMS (pos. APCI) calcd for C20H23O2 [M+H]+: 295.1693,
found: 295.1693. IR (ATR): n [cm–1] = 3054, 2931, 1630, 1496, 1448,
1431, 1421, 1401, 1344, 1307, 1265, 1251, 1237, 1132, 1114, 1013, 972,
932, 893, 853, 824, 733, 702, 605.
(R,R)-1,4-Di(cyclohex-1-en-1-yl)-2,3-dimethylbutane-1,4-dione
(5d).[11] It was observed that the yield of this reaction was reduced by
>10% if it was run on a larger scale than 4.0 mmol. Hence, two identical
reactions were set up in parallel and then combined in the workup
procedure as follows: Two flame-dried, argon-filled 250 ml Schlenk flasks
equipped with magnetic stir bars were charged with bis-Weinreb amide
2e (930 mg, 4.00 mmol, 1.0 equiv each flask) and evacuated and
backfilled with argon three times while stirring. Stirring was started, the
solid was dissolved in Et2O (55 ml each flask) and the mixtures were
cooled to 0 ºC. A solution of the freshly titrated Grignard reagent 2a
(24.5 ml, 0.49 M in THF, 12.0 mmol, 3.0 equiv) was added to each flask.
After 10 minutes, the reaction mixtures were allowed to warm to room
temperature and stirring was continued for 16 h. Then, saturated aq.
2,7-Dimethylocta-1,7-diene-3,6-dione (4o). This product was literature
known.[4] This compound was prepared in analogy to 4a using bis-
Weinreb amide 3a (408 mg, 2.0 mmol) and Grignard reagent 2o (15 ml,
0.40 M in THF, 6.0 mmol, 3.0 equiv). The product was purified by column
chromatography (hexanes/EtOAc, 9:1) and obtained as a colorless solid
in 57% yield (190 mg, 1.14 mmol). The NMR data matched the
previously reported values. Rf (hexanes/EtOAc, 9:1) = 0.4. 1H NMR
(400.1 MHz, CDCl3): d = 1.88 (dd, J = 0.9, 1.5 Hz, 6H), 3.03 (s, 4H), 5.78
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
+
NH4Cl solution (50 ml) and H2O (25 ml) were added to each flask and the
mixtures were combined in a separation funnel. The remaining workup
was performed as described for diketone 4a. Purification of the crude
mixture by column chromatography (cyclohexane/EtOAc, 20:1) gave the
title compound as a yellow oil in 60% yield (1.314 g, 4.789 mmol). The
enaniomeric purity was determined to be >99% ee by chiral HPLC
(8), 81.1 (30), 53.1 (6). HRMS (pos. APCI) calcd for C19H27O4 [M+H]+:
319.1904, found: 319.1903. IR (ATR): n [cm–1] = 2987, 2934, 2861, 1666,
1634, 1449, 1435, 1381, 1257, 1200, 1157, 1073, 987, 923, 877, 849,
820, 695, 610.
(S)-1,4-Di(cyclohexen-1-yl)-2-methoxybutane-1,4-dione (5h). This
compound was prepared in analogy to diketone 4a using bis-Weinreb
amide 3i (117 mg, 0.5 mmol) and Grignard reagent 2a (7.1 ml, 0.21 M in
THF, 1.5 mmol, 3.0 equiv). The product was purified by column
chromatography (hexanes/EtOAc, 10:1) and obtained as a colorless solid
in 42% yield (57 mg, 0.21 mmol). The enaniomeric purity was determined
to be >99% ee by chiral HPLC (Chiralcel LC-4, heptane/EtOH= 95:5,
(Chiralpak AD-3, heptane/2-propanol = 99:1, 0.5 ml min–1, 22 ºC, tmajor
=
12.85 min, tminor = 11.76 min).[11] Rf (cyclohexane/EtOAc, 20:1) = 0.2.
[a]D = +90.6º (c 1.41; CHCl3). 1H NMR (500.2 MHz, CDCl3): d = 1.06-
25
1.11 (m, 6H), 1.55-1.66 (m, 8H), 2.05-2.28 (m, 8H), 3.44-3.52 (m, 2H),
6.93-6.95 (m, 2H). 13C NMR (100.6 MHz, CDCl3): d = 16.19, 21.70, 22.15,
23.48, 26.22, 42.32, 138.06, 139.66, 205.54. MS (EI, 70eV): m/z (%) =
274.1 [M]+ (27), 193 (5), 165.1 (25), 109.1 (100), 81.2 (25), 53.2 (5).
HRMS (ESI) calcd for C18H26O2Na [M+Na]+: 297.1825, found: 297.1827.
IR (ATR): n [cm–1] = 2970, 2930, 2875, 2859, 1657, 1636, 1449, 1433,
1385, 1267, 1211, 1187, 1171, 1135, 933, 915, 843, 734, 690.
0.5 ml min–1
,
22 ºC, tmajor
=
11.72 min, tminor = 13.92 min). Rf
(hexanes/EtOAc, 10:1) = 0.2. [a]D = –35.5º (c 1.02; CHCl3). 1H NMR
(400.1 MHz, CDCl3): d = 1.58-1.66 (m, 8H), 2.20-2.30 (m, 8H), 2.86 (dd,
J = 4.7, 16.6 Hz, 1H), 3.08 (dd, J = 7.5, 16.6 Hz, 1H), 3.30 (s, 3H), 5.01
(dd, J = 4.7, 7.5 Hz, 1H), 6.91-6.94 (m, 1H), 7.03-7.07 (m, 1H). 13C NMR
(100.6 MHz, CDCl3): d = 21.65, 22.03, 22.04, 23.24, 23.37, 26.32, 26.37,
39.75, 57.67, 77.28, 138.09, 139.48, 141.43, 141.70, 198.00, 199.50. MS
(CI): m/z (%) = 277.1 [M+H]+ (100), 262.1 (14), 245.1 (77), 109.0 (49),
81.0 (5). HRMS (pos. ESI) calcd for C17H24O3Na+ [M+Na]+: 299.1618,
found: 299.1619. IR (ATR): n [cm–1] = 2932, 2860, 1663, 1634, 1449,
1434, 1422, 1387, 1344, 1286, 1272, 1190, 1117, 993, 908, 729, 647.
25
(R,R)-1,4-Di(cyclohex-1-en-1-yl)-2,3-dimethoxybutane-1,4-dione (5e).
A flame-dried and argon-filled Schlenk flask was charged with bis-
Weinreb amide 3f (1.182 g, 4.473 mmol) and evacuated and backfilled
with argon three times while stirring. Et2O (61 ml) was added and the
mixture was cooled to 0 ºC with stirring. Then, cyclohexenylmagnesium
bromide lithium chloride adduct 2a (59.0 ml, 0.23 M in THF, 13.6 mmol,
3.0 equiv) was added. The rest of the reaction was performed following
the general procedure for double Grignard additions. After
chromatographic purification of the crude mixture (hexanes/EtOAc, 9:4),
the title compound (1.005 mg, 3.280 mmol, 73%) was obtained as a
yellow oil. Rf (hexanes/EtOAc, 9:4) = 0.3. [a]D25 = +28.7º (c 1.16; CHCl3).
1H NMR (500.2 MHz, CDCl3): d = 1.55-1.67 (m, 8H), 2.02-2.11 (m, 2H),
2.21-2.32 (m, 6H), 3.36 (s, 6H), 4.65 (s, 2H), 7.04-7.06 (m, 2H). 13C NMR
(125.8 MHz, CDCl3): d = 21.56, 21.96, 23.25, 26.38, 58.63, 82.68, 138.47,
143.07, 198.18. MS (EI, 70eV): m/z (%) = 306.3 [M]+ (1), 197.1 (5), 166.1
(17), 135.1 (24), 109.1 (100), 88.1 (7), 81.1 (32), 53.1 (9). HRMS (ESI)
calcd for C18H26O4Na [M+Na]+: 329.1723, found 329.1723. IR (ATR): n
[cm–1] = 2935, 1722, 1670, 1632, 1450, 1193, 1105.
rac-1,4-Di(cyclohexen-1-yl)-2-methoxybutane-1,4-dione (rac-5h). This
compound was prepared in analogy to diketone 4a using bis-Weinreb
amide rac-3i (234 mg, 1.0 mmol) and Grignard reagent 2a (10.5 ml,
0.285 M in THF, 3.0 mmol, 3.0 equiv). The product was purified by
column chromatography (hexanes/EtOAc, 10:1) and obtained as
a
colorless solid in 45% yield (125 mg, 0.45 mmol). Rf (hexanes/EtOAc,
10:1) = 0.2. 1H NMR (400.1 MHz, CDCl3): d = 1.58-1.66 (m, 8H), 2.20-
2.30 (m, 8H), 2.86 (dd, J = 4.7, 16.6 Hz, 1H), 3.08 (dd, J = 7.5, 16.6 Hz,
1H), 3.30 (s, 3H), 5.01 (dd, J = 4.7, 7.5 Hz, 1H), 6.91-6.94 (m, 1H), 7.03-
7.07 (m, 1H). 13C NMR (100.6 MHz, CDCl3): d = 21.65, 22.03, 22.04,
23.24, 23.37, 26.32, 26.37, 39.75, 57.67, 77.28, 138.09, 139.48, 141.43,
141.70, 198.00, 199.50. MS (CI): m/z (%) = 277.1 [M+H]+ (100), 262.1
(12), 245.1 (71), 109.0 (55), 81.1 (6). HRMS (pos. ESI) calcd for
C17H24O3Na+ [M+Na]+: 299.1618, found: 299.1619. IR (ATR): n [cm–1] =
2931, 2860, 1663, 1635, 1449, 1434, 1423, 1387, 1344, 1312, 1272,
1191, 1119, 993, 922, 836, 798, 730.
(R,R)-(1,3-Dioxolane-4,5-diyl)bis(cyclohex-1-en-1-ylmethanone) (5f).
This compound was synthesized in analogy to diketone 5e using bis-
Weinreb amide 3g (750 mg, 3.02 mmol) as starting material and
cyclohexenylmagnesium bromide lithium chloride adduct (14.0 ml, 0.65
M in THF, 9.10 mmol, 3.0 equiv). After chromatographic purification of
the crude mixture (cyclohexane/EtOAc, 10:1), the title compound
(R,R)-(2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(cyclopent-1-en-1-
ylmethanone) (5i). This compound was prepared in analogy to diketone
4a using bis-Weinreb amide 3h (501 mg, 1.81 mmol) and Grignard
reagent 2b (14 ml, 0.35 M in THF, 4.9 mmol, 2.7 equiv). The product was
purified by column chromatography (hexanes/EtOAc, 10:1) and obtained
as a colorless oil in 54% yield (285 mg, 0.98 mmol). Rf (hexanes/EtOAc,
(756 mg, 2.60 mmol, 86%) was obtained as
a light yellow oil. Rf
(cyclohexane/EtOAc, 10:1) = 0.2. [a]D = -131.5º (c 2.05; CHCl3). 1H
NMR (400.1 MHz, CDCl3): d = 1.54-1.68 (m, 8H), 2.20-2.37 (m, 8H), 5.12
(s, 2H), 5.31 (s, 2H), 7.12 (dddd, J = 1.6, 1.6, 3.9, 3.9 Hz, 2H). 13C NMR
(100.6 MHz, CDCl3): d = 21.54, 21.86, 23.27, 26.50, 77.48, 97.09, 137.76,
144.61, 195.77. MS (EI, 70eV): m/z (%) = 181.1 [M–C7H9O]+ (11), 151.1
(6), 109.1 (100), 81.1 (41), 53.1 (10). HRMS (ESI) calcd for C17H22O4Na
[M+Na]+: 313.1410, found: 313.1412. IR (ATR): n [cm–1] = 2933, 2861,
1729, 1664, 1632, 1449, 1434, 1421, 1387, 1345, 1272, 1213, 1196,
1163, 1089, 985, 940, 874, 729, 696.
25
10:1) = 0.2. [a]D25 = -48º (c 1.00; CHCl3). H NMR (400.1 MHz, CDCl3): d
1
= 1.42 (s, 6H), 1.86-1.94 (m, 4H), 2.56-2.63 (m, 8H), 5.26 (s, 2H), 7.05-
7.07 (m, 2H). 13C NMR (100.6 MHz, CDCl3): d = 22.38, 26.73, 31.10,
34.66, 79.48, 112.81, 143.56, 148.01, 194.44. MS (EI, 70 eV): m/z (%) =
290.0 [M]+ (1), 232.0 (5), 195.1 (18), 137.0 (29), 95.0 (100), 67.0 (4), 41.0
(5). HRMS (pos. ESI) calcd for C17H23O4 [M+H]+: 291.1591, found:
+
(R,R)-(2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(cyclohex-1-en-1-
ylmethanone) (5g). This compound was prepared in analogy diketone
4a using bis-Weinreb amide 3h (1.66 g, 6.0 mmol) and Grignard reagent
2a (60 ml, 0.25 M in THF, 15 mmol, 2.5 equiv). The product was purified
by column chromatography (n-pentane/EtOAc, 10:1) and obtained as a
colorless oil in >99% yield (1.91 g, 6.0 mmol). Rf (n-pentane/EtOAc, 10:1)
291.1593. IR (ATR): n [cm–1] = 2939, 1665, 1609, 1457, 1431, 1381,
1372, 1297, 1259, 1212, 1179, 1155, 1104, 1063, 1041, 980, 896, 857,
809, 782, 727, 611.
1,5-Bis(3,4-dihydronaphthalen-1-yl)pentane-1,5-dione
(5j).
This
compound was prepared in analogy to diketone 2a using bis-Weinreb
amide 3b (655 mg, 3.0 mmol) and Grignard reagent 2j (18.1 ml, 0.415 M
in THF, 7.5 mmol, 2.5 equiv). The product was purified by column
chromatography (hexanes/EtOAc, 10:1) and obtained as a colorless solid
in 80% yield (860 mg, 2.41 mmol). Rf (hexanes/EtOAc, 10:1) = 0.5. 1H
NMR (400.1 MHz, CDCl3): d = 2.11 (quint, J = 7.1 Hz, 2H), 2.42 (td, J =
25
= 0.2. [a]D = -43.0º (c 0.35; CHCl3). 1H NMR (400.1 MHz, CDCl3): d =
1.43 (s, 6H), 1.58-1.68 (m, 8H), 2.22-2.32 (m, 8H), 5.36 (s, 2H), 7.14-
7.17 (m, 2H). 13C NMR (100.6 MHz, CDCl3): d = 21.55, 21.86, 23.24,
26.44, 26.65, 77.55, 112.50, 137.90, 144.57, 196.32. MS (EI, 70 eV): m/z
(%) = 318.1 [M]+ (2), 260.0 (6), 209.1 (25), 151.0 (31), 109.0 (100), 85.0
13
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901043
European Journal of Organic Chemistry
FULL PAPER
4.9, 7.9 Hz, 4H), 2.75 (t, J = 7.9 Hz, 4H), 2.90 (t, J = 7.1 Hz, 4H), 6.96 (t,
J
L. D. Chiaradia-Delatorre, C. Gauthier, R. A. Yunes, R. J. Nunes, T. B.
Creczynski-Pasa, A. Di Pietro, J. Med. Chem. 2014, 57, 2930–2941.
For examples, see: a) S. Pai, M. Moos, M. H. Schreck, C. Lambert, D.
G. Kurth, Inorg. Chem. 2017, 56, 1418–1432; b) N. Li; P. Wang, S.-L.
Lai, W. Liu, C.-S. Lee, S.-T. Lee, Z. Liu, Adv. Mater. 2010, 22, 527–
530; c) C. B. Nielsen, J. Arnbjerg, M. Johnson, M. Jørgensen, P. R.
Ogilby, J. Org. Chem. 2009, 74, 9094–9104; d) A. Khatyr, H. Maas, G.
Calzaferri, J. Org. Chem. 2002, 67, 6705–6710.
= 4.9 Hz, 2H), 7.15-7.23 (m, 6H), 7.62-7.64 (m, 2H). 13C NMR
(100.6 MHz, CDCl3): d = 19.85, 23.71, 27.58, 38.90, 126.40, 126.58,
127.74, 127.81, 131.05, 136.58, 137.96, 139.18, 201.90. MS (EI, 70 eV):
m/z (%) = 356.1 [M]+ (100), 338.2 (31), 296.1 (6), 225.1 (42), 197.2 (15),
186.2 (42), 174.2 (13), 165.1 (16), 157.2 (60), 141.1 (15), 128.1 (96),
115.1 (8). HRMS (pos. ESI) calcd for C25H25O2+ [M+H]+: 357.1849, found:
357.1851. IR (ATR): n [cm–1] = 3059, 2938, 2831, 2248, 1671, 1612,
1483, 1450, 1425, 1379, 1325, 1241, 1139, 1094, 1044, 1021, 944, 909,
834, 764, 728, 689, 647, 568.
[3]
[4]
[5]
M. Sibrian-Vazquez, D. A. Spivak, Macromolecules 2003, 36, 5105–
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L. Liu, H.-T. Yu, W.-X. Zhang, Z. Xi, Chem. Eur. J. 2018, 24, 19122–
19135. For the addition of vinylmagnesium bromide to bis-Weinreb
amides, see: b) T. Shibuguchi, H. Mihara, A. Kuramochi, S. Sakuraba,
T. Ohshima, M. Shibasaki, Angew. Chem. Int. Ed. 2006, 45, 4635–
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rac-trans-2-(Cyclohex-1-ene-1-carbonyl)-N-methoxy-N-
methylcyclohexane-1-carboxamide (6). A flame-dried and argon-filled
25 ml Schlenk flask was charged with bis-Weinreb amide 3j (103 mg,
0.40 mmol, 1.0 equiv). While stirring, the vessel was evacuated and
backfilled with argon three times. Et2O (5.6 ml) was added and the
solution was cooled to 0 ºC. A freshly prepared solution of reagent 2a
(0.23 M in THF, 5.3 ml, 1.2 mmol, 3.0 equiv) was added over 5 min.
During the addition, the mixture turned turbid first and then clear again.
The mixture was heated to reflux for 21 h (oil bath temperature = 65 ºC)
and the reaction was quenched after cooling to room temperature by
addition of saturated aq. NH4Cl (5 ml), followed by H2O (5 ml) and Et2O
(5 ml). The biphasic mixture was stirred for 5 min at room temperature,
the layers were separated and the organic layer was washed with aq.
HCl (1 M, 3 x 10 ml). The combined aqueous layers were extracted with
Et2O (3 x 15 ml), and the combined organic layers were then washed
with saturated aq. NaHCO3 solution (25 ml) and brine (25 ml), dried over
Na2SO4 and filtered. The solvents were removed under reduced pressure
and the residue was purified by column chromatography
(cyclohexane/EtOAc, 2:1→0:100). The title compound (55.2 mg,
[6]
[7]
0.198 mmol, 50%) was obtained as
a
colorless oil. Rf
(cyclohexane/EtOAc, 2:1) = 0.3. 1H NMR (400.1 MHz, CDCl3): d = 1.12-
1.43 (m, 4H), 1.53-1.65 (m, 4H), 1.73-1.82 (m, 2H), 1.89-2.11 (m, 3H),
2.20-2.32 (m, 3H), 3.12 (br, 4H), 3.44 (ddd, J = 3.4, 10.6, 10.6 Hz, 1H),
3.82 (br, 3H), 6.98-7.02 (m, 1H). 13C NMR (100.6 MHz, CDCl3): d = 21.65,
22.10, 23.44, 25.87, 26.00, 26.21, 28.86, 30.87, 32.04 (br), 41.63, 45.65,
61.52, 137.79, 140.07, 176.11 (br), 204.73. MS (EI, 70eV): m/z (%) =
249.3 (5), 219.2 [M–C2H6NO]+ (100), 191.2 (11), 109.1 (72), 81.1 (27),
79.1 (17), 53.1 (6), 41.1 (7). HRMS (ESI) calcd for C16H25NO3Na
[M+Na]+: 302.1727, found: 302.1726. IR (ATR): n [cm–1] = 2930, 2857,
1657, 1448, 1384, 1342, 1248, 1186, 1119, 1000, 981.
[8]
[9]
S. Balasubramaniam, I. Singh Aidhen, Synthesis 2008, 3707–3738.
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[10] a) S. Ghinato, G. Dilauro, F. M. Perna, V. Capriati, M. Blangetti, C.
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Acknowledgments
[11] S. Wiesler, M. A. Bau, S. L. Younas, H.-T. Luu, D. Kratzert, J. Streuff,
Chem. Eur. J. 2018, 24, 16532–16536.
[12] F. Zhan, G. Liang, Angew. Chem. Int. Ed. 2013, 52, 1266–1269; Angew.
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This work was funded by the Deutsche Forschungsgemeinschaft
(DFG) – projects 333382543 and 408295365.
[13] a) J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. 1982, 12, 989–
993; b) A. Basha, M. Lipton, S. M. Weinreb, Tetrahedron Lett. 1977, 48,
4171–4174.
Keywords: alkenyl bromides • double addition • enones •
Grignard reaction • Weinreb amides
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Entry for the Table of Contents
FULL PAPER
• optimized formation
• polysubstituted
• conjugated
Bis-enone Synthesis*
• succinic • glutaric • adipic
• tartaric • malic • terephthalic
R'
Stefan Wiesler, Michael A. Bau, Thomas
Niepel, Sara L. Younas, Hieu-Trinh Luu,
Jan Streuff*
O
O
R
2
R'
R
[Mg]
O
N
N
R
O
X
X
>20 examples
R'
O
O
up to >99% yield
Page No. – Page No.
The synthesis of bis-enones from alkenyl bromides and a,w-bis-Weinreb amides via
a double Grignard reaction is reported. The work contains reliable protocols for the
double addition and the efficient generation of the required substituted alkenyl
Grignard reagents from alkenyl bromide precursors.
a w
Synthesis of , -Bis-Enones by the
Double Addition of Alkenyl Grignard
Reagents to Diacid Weinreb Amides
16
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