Synthesis of α-alkenyl-β-hydroxy adducts by α-addition of unprotected 4-bromocrotonic acid and amides with aldehydes and ketones by chromium(II)-mediated reactions

Article abstract of DOI:10.1002/aoc.3488

The regioselective and diastereoselective chromium(II)-mediated reactions of 4-bromocrotonic acid or amides with aldehydes and ketones can proceed without the need to protect protic sites to generate the respective α-alkenyl-β-hydroxy adducts, i.e. formally the addition of the α-anion of a carboxylic acid or amide to an oxo-compound is featured.

Full text of DOI:10.1002/aoc.3488

Full paper
Received: 13 November 2015
Revised: 11 February 2016
Accepted: 9 March 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3488
Synthesis of α-alkenyl-β-hydroxy adducts by
α-addition of unprotected 4-bromocrotonic
acid and amides with aldehydes and ketones
by chromium(II)-mediated reactions
Ludger A. Wessjohanna,b*, Harry Wildb, Leonildo A. Ferreirac
and Henri S. Schrekkera,c*
The regioselective and diastereoselective chromium(II)-mediated reactions of 4-bromocrotonic acid or amides with aldehydes and
ketones can proceed without the need to protect protic sites to generate the respective α-alkenyl-β-hydroxy adducts, i.e. formally
the addition of the α-anion of a carboxylic acid or amide to an oxo-compound is featured. Copyright © 2016 John Wiley & Sons,
Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: allyl and enolate complexes; regio- and chemoselectivity; chromium; diastereoselectivity; Grignard-type reaction
Generally, aldol reactions of crotonate derivatives under
Reformatsky conditions result in a mixture of α- and predominantly
Introduction
The application of chromium(II) reagents in organic chemistry has
resulted in a wide variety of methods for coupling organic halides
with aldehydes.[1] These reactions are characterized by mild condi-
tions and an excellent chemoselectivity towards aldehydes in the
presence of many other electrophilic functional groups. This has
rendered them indispensable in many complex total syntheses such
as the preparation of viridiofungin derivatives.[2] Particularly attrac-
tive methods are the chromium(II)-mediated Nozaki–Hiyama–Kishi
and Reformatsky reactions which can be performed with
polyfunctional substrates.[1,3] For instance, α-halo oxazolidones
(Evans-type imides) result in high diasteroselectivity and enantio-
selectivity by chromium(II)-mediated Reformatsky reactions that
allowed the development of an innovative method towards the
total synthesis of tonantzitlolone and epothilones.[1,4] Also, α-halo
ketones, esters, nitriles, N,N′-dialkylamides and 4-bromocrotonates
can be coupled to aldehydes in excellent yields.[1,4] The Nozaki–
Hiyama–Kishi reaction was recently used in the synthesis of
enantioenriched α-exo-methylene γ-butyrolactones, in a two-step
sequence, using chromium catalysis.[5]
γ-substituted products. For example, preparation of zinc carboxyl-
ates by coupling of allylzinc bromide with several electrophiles
gave the respective allylic alcohols in 21–81% yield with 12–100%
γ-regioselectivity.[2] For the α-products, a mix of the syn and anti di-
astereoisomers was obtained.[2,7]
Alternatively, crotonic acids can be transformed into their
dienolates by treatment with strong bases such as lithium
naphthalide[8] or lithium diisopropylamide.[9] Subsequent reactions
with aldehydes generate mainly the α-substituted alcohol (50–94%)
in low to moderate yields (9–50%), but ketones still give predomi-
nantly γ-products.[6]
Hence, halo-crotonic acids must be transformed into their
corresponding esters to favor syn allylic carbonyl compounds by α-
addition.[2] This protection–deprotection strategy involves two extra
steps if unprotected alkenyl-β-hydroxy acid or amide is desired.
Continuing our interest in the development of chemo- and
diastereoselective methodologies based on chromium(II)/(III)
4-Bromocrotonate derivatives are believed to react more readily
through allylchromium(III) intermediates, instead of the thermody-
namically favored chromium(III) dienolate (Scheme 1). Thus, the
functional group attached to the allylchromium(III) species might
be of secondary importance. Therefore, a carboxylic acid might pro-
duce allylchromium(III) in the course of the reaction which does not
equilibrate fast with chromium(III) dienolate. Furthermore, the ex-
traordinary stability of alkylchromium(III) complexes to hydrolysis
enables carbon–carbon coupling in the presence of water,[1,6]
suggesting a slow protonation of the allylchromium(III) adduct by
inter- or intramolecular proton transfer in comparison with car-
bonyl electrophilic reactions.
*
Correspondence to: Ludger A. Wessjohann Leibniz Institute of Plant Biochemistry,
Weinberg 3, D-06120 Halle (Saale), Germany. E-mail: wessjohann@ipb-halle.de; or
Henri S. Schrekker Universidade Federal do Rio Grande do Sul, Institute of
Chemistry, Av. Bento Gonçalves 9500, Porto Alegre-RS, CEP: 91.501-970, Brazil.
E-mail: henri.schrekker@ufrgs.br
a Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120, Halle (Saale),
Germany
b Ludwig Maximilians Universität München, Butenandtstrasse 5-13, D-081377
München, Germany
c
Universidade Federal do Rio Grande do Sul, Institute of Chemistry, Av. Bento
Gonçalves 9500, Porto Alegre - RS, CEP: 91.501-970, Brazil
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

L. A. Wessjohann et al.
Figure 1. Dianionic Cr(III) chelate complex with the aldolate–carboxylate
product
its ligands, the chelation might provoke considerable product loss
during protonation and aqueous work-up.
Surprisingly, the syn-4a aldol adduct was isolated in similar yields
switching from salt 2 to its original acid 1. This result was achieved
by slowly adding solid acid 1 to an aldehyde/chromium(II) chloride
suspension in aprotic solvent, thus keeping the proton concentra-
tion in the medium low. It is also noted that acetonitrile gives
slightly better yield than tetrahydrofuran (THF) (Table 1, entries 1
and 2), together with total regioselectivity. Based on these prelimi-
nary results, instead of transforming 1 into its respective lithium
salt 2, simply adding a removable organic base might further
improve the result. Hence, 1 was reacted with 3a in the presence
Scheme 1. Chromium(III) intermediates (R = H or alkyl)
species,[10] we herein report the direct coupling of 4-
bromocrotonic acid with aldehydes and ketones by chromium
(II)-mediated Nozaki–Hiyama–Kishi reactions to give exclusively
the syn α-alkenyl-β-hydroxy adducts, without the necessity of
protection such as with a methyl- or silylester[1,11] or Zn salt.[12]
Furthermore, Nozaki–Hiyama–Kishi and Reformatsky reactions of
the corresponding primary and secondary amides are reported.
Table 1. Chromium(II)-mediated Nozaki–Hiyama–Kishi reaction of
4-bromocrotonic acid (1) with benzaldehyde (3a) in the presence of ter-
tiary aminesa
Results and discussion
Influenced by the literature, we initially assumed the requirement
of decreasing the acidity of the substrate in the reaction medium
in order to avoid protonation of any prospective allylchromium(III)
intermediate and to favor α-addition. Therefore, we started our
study by transforming 4-bromocrotonic acid (1) to its respective
lithium salt (lithium 4-bromocrotonate, 2). Treatment of 1 with lith-
ium t-butoxide in t-butanol gave 2 in 99% yield.[13] This salt was
then subjected to the chromium(II)-mediated Nozaki–Hiyama–Kishi
reaction with benzaldehyde (3a) in acetonitrile to generate exclu-
sively the α-syn-aldol product syn-4a in 32% yield after 0.5 h
(Scheme 2). Apparently, the reaction follows an anionic path rather
than a radical one via ketyl/allyl radical cross-coupling, since no
typical radical byproducts were found, like dimers of the oxo-
compound.[14]
It is postulated that the trans-allylchromium(III) species does not
equilibrate with the chromium(III) dienolate and attacks the si benz-
aldehyde (3a) face in a Zimmerman–Traxler transition state (ZT-TS)
model to generate the syn-aldol adduct exclusively (Scheme 1).
Neither the γ-alcohol 5 nor the anti-allylic carboxylic acid anti-4a
were observed in the crude 1H NMR spectrum. Despite the low iso-
lated yield of the desired α-adduct syn-4a, the result is quite inspir-
ing since this diastereoselectivity has not been accomplished with
any other Nozaki–Hiyama–Kishi reaction. The low yield may be ex-
plained by the strong chelating character of the product as
depicted in Fig. 1. Since chromium(III) is difficult to separate from
Entry
Base
Solvent Time
(h)
Ratio α:γ
Ratio Yield
α
syn:αanti (%)b
1
2
—
CH3CN 2.00
100:0
95:5
95:5
42
—
THF
THF
2.00
1.00
1.00
1.00
1.00
1.00
0.50
0.50
0.50
1.00
1.00
1.00
>97:3 31
>97:3 62
3
4
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
>97:3
>95:5
CH3CN
DMF
CH2Cl2
Et2O
THF
>95:5 56
c
c
5
—
—
32d
6
85:15
>95:5 27
c
c
7
—
—
11
85:15 24
49
8
59:41
9
TMEDA
DBU
THF
—
—
e
e
e
10
THF
—
—
—
64
67
59
11 (À)-quinidine THF
12 (À)-sparteine THF
13 (À)-sparteine CH3CN
94:6
>98:2
96:4
96:4
95:5
96:4
14f
—
CH3CN 0.50
92:8
78f
> 97:3
aFor specific details and exact amounts refer to the experimental
section. Product distributions are based on crude product
(hydrolysis and filtered through silica to remove paramagnetic
chromium)
bIsolated yield of isomeric mixture based on minor component
cChromium(III) traces in the crude product caused line broadening in
the 1H NMR spectrum not allowing determination of the product
distribution
dWork-up resulted in product loss
eDecomposition of 1
fReference reaction of methyl 4-bromocrotonate (6) to main product
7 (Table 2) according to Schrekker et al[10]
Scheme 2. Chromium(II)-mediated Nozaki–Hiyama–Kishi reaction of
4-bromocrotonate (2) with benzaldehyde (3a) to syn-4a. Isomers in
brackets were not found (NMR) starting from lithium salt 2
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Chemoselective C-C cross-couplings of complex substrates
Table 2. Chromium(II)-mediated Nozaki–Hiyama–Kishi reaction of 4-bromocrotonic acid (1) with aldehydes and ketones (3a–e) in the presence of
DIPEA. Comparison with methyl ester 6 as starting materiala
Entry
3
R1
R2
Products
R
Solvent
Time (h)
α:γ
αsyn:αanti
Yield (%)b
1
2
a
Ph
Et
H
H
4, 5
4, 5
7, 8
4, 5
7, 8
4, 5
4, 5
7, 8
4, 5
4,5
H
THF
THF
0.5
1.0
2.0
0.5
3.0
2.0
2.0
1.0
2.0
1.0
1.0
>97:3
>99:1
89:11
100:0
91:9
>97:3
>99:1
82:18
62
88
64
73
56
68
44
95
7
b
b
c
H
Me
H
3c
Et
H
CH3CN
THF
4
i-Pr
i-Pr
Et
H
>99:1
5c
6
c
H
Me
H
i-PrCN
THF
90:10
d
d
d
e
e
e
Me
Me
Me
Me
Me
Me
100:0
100:0
95:5
60:40d
60:40d
60:40
7
8c
Et
H
CH3CN
Butanone
THF
Et
Me
H
9
Ph
Ph
Ph
100:0
100:0
95:5
50:50d
85:15d
65:35
10
11c
H
CH3CN
CH3CN
32
46
7, 8
Me
aFor specific details and exact amounts refer to the experimental section
bYield of isomeric mixture based on minor component
cReference reaction of methyl 4-bromocrotonate (6) to main product 7 according to Wessjohann and Scheid[1]
dAssignment of diastereomers is based on chemical shifts and coupling constants reported for the analogous ester[10]
of tertiary amines, chromium(II) chloride and aprotic solvents at
20 °C (Table 1).
tetramethylethylenediamine (TMEDA) is suitable but clearly less ef-
ficient than DIPEA (Table 1, entry 9). Consequently, DIPEA is identi-
fied as the best additive in this reference reaction. The regio- and
diastereoselectivity are comparable to the results obtained with
the corresponding methyl ester as starting material; yields are only
a little lower (Table 1, entries 3, 4, 11, 12 versus 14). Possibly, the
DIPEA efficiency is threefold: efficient deprotonation of 1 without
deactivation of the chromium species through complexation or
participation in the decomposition of the substrate via nucleophilic
attack at Cγ (Scheme 3).
Due to the positive influence of tertiary bases in the previous re-
action, it was decided to check if optically active amines such as
(À)-quinidine and (À)-sparteine would affect the diastereomeric ra-
tio of the allylic products.[15,16] Both bases afford aldol products 4a
with slightly improved yields (Table 1, entries 11–13), but no consid-
erable effect on the selectivities is observed.
To determine the scope and limitations of the almost exclusive
formation of the α-addition products, the method was expanded
to aliphatic aldehydes and ketones in the presence of DIPEA
(Table 2). The regioselectivities, diasteroselectivities and yields ob-
tained from reactions of 4-bromocrotonic acid with aliphatic alde-
hydes surprisingly are superior even to those obtained with the
corresponding methyl ester 6 (Table 2, entries 2 versus 3 and en-
tries 4 versus 5). Also, the coupling of 1 with ketones in the
Amines have a considerable influence on the reaction yield and
regioselectivity, but have little effect on the diastereoselectivity.
When applying N,N-diisopropylethylamine (DIPEA; Hünig’s base)
as base, polar aprotic solvents such as THF and acetonitrile are best
for this C-C coupling as has been reported previously for methyl
crotonates.[1,10] Dimethylformamide (DMF; Table 1, entry 5) as a
highly polar solvent can improve the solubility of Cr(II)Cl2, and
consequently can result in higher yields, as sometimes does dichlo-
romethane (for unknown reasons). Ethyl ether turns out to be not a
suitable alternative solvent because traces of paramagnetic Cr(III)
present in the crude product result in the necessity of performing
further purification, which causes significant product loss (Table 1,
entry 7). Also, triethylamine is not effective yielding an almost equi-
molar mixture of α and γ products in just 24% yield (Table 1, entry
8). Thus, steric hindrance seems to be important considering that
Et3N and DIPEA have similar pΚa values. Hence, the highly hindered
base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was also tested. The
solution turned dark immediately after the addition of this amine
and no further reaction was noticed (Table 1, entry 10). The reason
behind this observation was not pursued, but it is likely that, be-
cause of its higher basicity, DBU decomposes the starting material
1 into unknown compounds. The weaker diamino base N,N,N′,N′-
Scheme 3. Role of DIPEA in the Cr-mediated reaction of 4-bromocrotonic
acid with aldehydes and ketones
Scheme 4. Chromium(II)-mediated Nozaki–Hiyama–Kishi reaction of the
chiral secondary amide 9 with benzaldehyde (3a)
Appl. Organometal. Chem. (2016)
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L. A. Wessjohann et al.
Table 3. Chromium(II)-mediated Reformatsky reaction of primary and
secondary α-halo-amides 11a–d with aldehydes and acetophenone
(3e)a
3a results in the β-hydroxycarboxamide 12a in 98% yield after
2.5 h at 55 °C (Table 3, entry 1). It was expected that the reaction
of iodocarboxamide 11d with 3a would give the respective α-
addition product in high yield. Although TLC indicated the sole for-
mation of 12e, only 15% of the expected secondary amide could
be isolated. This can be explained by the high water solubility
and better chromium ion complexation of the product, implying
that most of product 12e is lost during the aqueous work-up. Sim-
ilar behavior is noted after the reaction of the primary amide 11d
with 2-phenylpropanal (12f, 22%) and isobutyraldehyde (12 g,
16%). Hence, the α-adduct must be sufficiently apolar to allow its
separation from chromium salt by extraction into the organic
phase during work-up. This can be accomplished by the presence
of alkyl substituents such as in 11a (R3 and R4 = ethyl) or through a
lipophilic amine portion like in (S)-(À)-α-methylbenzylamides 11b
and 11c.
The chiral amides 11c and 11d do not influence the
enantioselectivity of the reaction towards the β-hydro-
xycarboxamides 12c and 12d (Table 3, entries 3 and 4). Expectedly,
3e, when reacted with the primary amide 11a, gives a lower yield of
the β-hydroxycarboxamide 12b. However, if one considers the
steric bulk around the adjacent quarternary centers formed in
aldol-type reactions, the yield is very good.[1]
Entry 3
R1
R2 11 X R3 R4
R5
Time 12 Yield
(h)
(%)b
1
2
3
4
5
6
7
a
e
a
a
a
Ph
Ph
Ph
Ph
Ph
H
Me
H
a
a
Br Et Et
Br Et Et
H
H
2.5
1.0
a
93
25
b
bc Br H Me Ph(Me)CH 1.0 cd 79
H
cc Br H
H
H
H
H
Ph(Me)CH 1.0
d
e
f
71
H
d
d
d
I
I
I
H
H
H
H
H
H
0.5
1.2
0.5
15e
22e
f (S)-Ph(Me)CH
i-Pr
H
,
c
H
g
16e f
aFor specific details and exact amounts refer to the experimental
section.
bIsolated yield based on minor component
cNo asymmetric induction with (S)-phenylethylamide
dSyn/anti ratio = 64:36
eReduced yields due to high water solubility of the products
fWithout lithium iodide
In contrast to the carboxamides and 4-bromocrotonic acid,
α-halocarboxylic acids are unsuitable Reformatsky substrates. All
attempts to react them in chromium-mediated Reformatsky
reactions almost exclusively afforded the corresponding
dehalogenated carboxylic acid products.
presence of DIPEA results exclusively in the α-alkenyl-β-hydroxy
acids, albeit in slightly lower yields than those accomplished with
methyl ester 6 (Table 2, entries 6 versus 8, 10 versus 11).
Noteworthy is the superior diasteroselectivity of the free acid 1
achieved with phenyl methyl ketone 3e when compared to the re-
action of ester 6 (Table 2, entries 10 versus 11).
Influence of proton concentration and mobility
In order to study the influence of free protons in a more general
way, methyl bromocrotonate (6) was reacted with 3a in the pres-
ence of protic solvents, namely either methanol or t-butanol
(10%) as extremes in ether (Scheme 5). t-Butanol is highly hindered
and 100 times less acidic than methanol. The reaction in t-butanol
(10 vol.% in ether) gives a 9:1 mixture of α-7:γ-8 in 34% yield and
a diastereoselectivity of 90:10 of syn versus anti isomers. When
methanol is used, methyl crotonate 13 and minor amounts of
chloromethyl crotonate 14 are formed; the latter by nucleophilic
substitution with chloride, but no coupling product is isolated.
Thus, protons do not easily interfere in the chromium-mediated
Nozaki–Hyama–Kishi reaction unless they are very mobile (acidic).
The same behavior is expected to occur for the Reformatsky
reaction.
The effective utilization of 1 and its in situ generated ammonium
salts in chromium(II)-mediated Reformatsky reactions prompted us
to extend the method to the coupling of amides. As a start,
the reaction of enantiomerically pure 4-bromocrotonyl
N-phenylethylamide (9) with 3a was chosen (Scheme 4). This reac-
tion is 100% regio- and diasteroselective, and the α-syn isomer is
the only product. The (S)-(À)-α-methylbenzylamine unit of sub-
strate 9 does not promote preference between the two possible
syn isomers, which results in the isolation of the purified α-syn-10
isomers in 34 and 33% yield.
The exclusive α-addition observed in the formation of syn-10 in-
stigated us to extend our studies to the chromium-mediated
Reformatsky reaction of simpler, non-vinylogous primary and sec-
ondary α-halo-amides with aldehydes (3a, c, f) and acetophenone
(3e) (Table 3). Seemingly, the α-addition of the amides 11 proceeds
through a chromium(III) enolate intermediate, in contrast to the
carboxylates 1 and 2 (with an allylchromium intermediate pro-
posed). The coupling of the primary bromocarboxamide 11a with
Conclusions
Unprotected protic vinylogous halo acids and amides react in chro-
mium(II)-mediated Nozaki–Hiyama–Kishi reactions with aldehydes
in good to excellent yields to result in α-alkenyl-β-hydroxy adducts,
if proton mobility and acidity are controlled, e.g. by using DIPEA as
base. The Reformatsky reaction of simple primary and secondary α-
halo carbox amides with aldehydes (or ketones to give sterically
highly congested molecules) in the presence of chromium(II) chlo-
ride expands the scope of these Cr(II)-mediated reactions. Especially
in reactions of complex natural products, be it in total or semi syn-
thesis or for derivatization, it is important to have a portfolio of
methods that do not require protection–deprotection strategies.
The method herein described certainly can contribute to this
Scheme 5. Chromium(II)-mediated Nozaki–Hiyama–Kishi reaction of
methyl 4-bromocrotonate (6) with benzaldehyde (3a) in the presence of
protic solvents
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Chemoselective C-C cross-couplings of complex substrates
portfolio, since several biomolecules contain β-hydroxy-α-alkenoic
acid or amide moieties, e.g. viridiofungin derivatives.
diazomethane esterification was applied.[9,22] The combined or-
ganic extracts were dried on sodium or magnesium sulfate, filtered
and the solvent removed using a rotary evaporator. The crude prod-
uct was used to determine the product distribution, usually by NMR,
and eventually purified by column chromatography on silica.
Experimental
All reactions were carried out under an argon atmosphere in flame-
dried glassware using standard syringe and septa techniques.
The commercial reagents 6, 11a, 11d, lithium t-butoxide, crotonic
General procedure for chromium(II)-mediated
Nozaki–Hiyama–Kishi reaction of 4-bromocrotonic acid in
presence of amines
acid,
N-bromosuccinimide,
2,2′-azobis(2-methylpropionitrile)
(AIBN), oxalyl chloride, 2-bromopropionyl bromide, (S)-(À)-α-
methylbenzylamine, bromoacetyl bromide, (À)-quinidine, (À)-spar-
teine, DBU, TMEDA, triethylamine, DIPEA, lithium iodide and
chromium(II) chloride (99.9% from Strem Chemicals) were used as
To chromium(II) chloride (2.3–2.5 equiv.) and lithium iodide
(0.10–0.42 equiv.) was added solvent (1.5–8 ml) under vigorous
stirring at 20 °C. After 5 min, aldehyde (1.5–5.1 equiv.)/ketone
(9.2–13 equiv.) and a solution formed of 1 (145–220 mg,
0.88–1.33 mmol, 1.0 equiv.), amine (1.04–1.10 equiv.) and sol-
vent (1.5–4.0 ml) were added to the reaction flask. Work-up,
if required after addition of phosphoric instead of citric acid,
is stated as above or described individually.
purchased. Diazomethane was synthesized according to
a
literature procedure.[17] THF and diethylether were distilled from
potassium/benzophenone. Absolute DMF and t-butanol were pur-
chased from Fluka. Acetonitrile was distilled from Sicapent (Merck)
and flushed with argon. Dichloromethane and carbon tetrachloride
were filtered through basic aluminium oxide. Aldehydes 3a–c, 3f
and ketones 3d and 3e were distilled from calcium chloride under
an argon atmosphere and stored over a 0.4 nm molecular sieve.
Spectral data of known compounds were either in accordance with
those of the literature (1,[18] syn-4a,[13] anti-4a,[13] syn-4b,[19]
syn-4c,[11] 5,[13] syn-7,[10] anti-7,[10] 8,[20] 12e[21] and 14[22]) or the
commercial substance (13). TLC was carried out with Merck silica
60/F-254 aluminium-backed plates. Flash chromatography was per-
formed using Merck silica gel 60 (40–60 μm). 1H NMR and 13C NMR
spectra were recorded in CDCl3 or CD3OD, and tetramethylsilane
was used as internal standard. Chemical shifts are quoted in ppm,
and coupling constants J are given in Hz.
Acknowledgment
H.S.S. was supported by the state of Saxony-Anhalt (HWP).
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