Hauser-Heck: Efficient Synthesis of γ-Aryl-β-ketoesters en Route to Substituted Naphthalenes

Article abstract of DOI:10.1021/acs.orglett.5b02952

γ-Aryl-β-ketoesters can be prepared in one step from aryl bromides and bis(trimethylsilyl) enol ethers using catalytic amounts of Pd(dba)₂/t-Bu₃P and stoichiometric amounts of Bu₃SnF. The wide range of γ-(hetero)aryl-β-ketoesters that can be obtained illustrate the scope and limitations of this novel Hauser-Heck combination. γ-Aryl-β-ketoesters with a 1,3-dioxane acetal in the ortho position can easily be transformed into the hydroxy naphthoate in very good yield. Aqueous formic acid at 65 °C provides optimal conditions for this deprotective aromatization.

Full text of DOI:10.1021/acs.orglett.5b02952

Letter
pubs.acs.org/OrgLett
Hauser−Heck: Efficient Synthesis of γ‑Aryl-β-ketoesters en Route to
Substituted Naphthalenes
Frederic Wagner, Klaus Harms, and Ulrich Koert*
Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse 4, D-35043 Marburg, Germany
S
* Supporting Information
ABSTRACT: γ-Aryl-β-ketoesters can be prepared in one step from aryl bromides and bis(trimethylsilyl) enol ethers using
catalytic amounts of Pd(dba)2/t-Bu3P and stoichiometric amounts of Bu3SnF. The wide range of γ-(hetero)aryl-β-ketoesters that
can be obtained illustrate the scope and limitations of this novel Hauser−Heck combination. γ-Aryl-β-ketoesters with a 1,3-
dioxane acetal in the ortho position can easily be transformed into the hydroxy naphthoate in very good yield. Aqueous formic
acid at 65 °C provides optimal conditions for this deprotective aromatization.
Scheme 1. Regioselective γ-Substitution of β-Keto-esters
γ-Aryl-β-ketoesters of type 1 are valuable intermediates for the
synthesis of complex target molecules.1 So far, they have been
synthesized from phenylacetone 2 or phenyl acetic acid 3
precursors.2 A one-step approach using an aryl halide 4 and a β-
ketoester 5 could make use of the large number of aryl halides
commercially available and could provide an efficient alternative
to access compounds of type 1. Here, we disclose a general
solution to this challenge.3 The substitution of β-ketoester in
the γ-position can be achieved via reaction of the dienolate 6
with appropriate electrophiles (6 → 7). The observed γ-
regioselectivity follows Hauser’s rule (Scheme 1).4 If carbonyl
compounds are used as electrophiles and bis(trimethylsilyl)
enol ethers 8 as substrates, the products of a vinylogous aldol
reaction (8 → 9) can be obtained.5 For 1,3 dienes (10) a Heck
reaction with aryl halides results in the formation of γ-arylated
dienes (11).6 The transition-metal catalyzed cross-coupling
reaction of enolates with aryl halides (enolate arylation) is an
established reaction but carries with it the disadvantage of high
enolate basicity,7 which can be avoided by using silyl enol
ethers as enolate equivalents. Following the pioneering work of
Kuwajima on the Pd-mediated regioselective arylation of silyl
enol ethers,8 optimized conditions that use metal fluoride
additives have been reported.9 Following a careful consid-
eration of the methodology known for Hauser’s selectivity,
enolate-equivalent arylation, and Heck reaction, we considered
it worthwhile to examine the Pd-mediated γ-arylation of
bis(trimethylsilyl) enol ethers (12 → 13). This process might
be denoted as a Hauser−Heck-type reaction. Here, we disclose
the Pd-catalyzed coupling of various (hetero)aryl halides with
bis(trimethyl)silyl enol ethers in the γ-position and its
application in the synthesis of substituted naphthalenes.
(dba)2/t-Bu3P gave the desired product in good yield (entry 1).
The use of RuPhos Pd-G2 also resulted in good yields, but only
for selected substrates, it lacking in overall generality (entry 3).
With regard to reaction temperature, a minimum of 65 °C was
optimal for a satisfying yield (entries 1, 4, 5, 6). As described for
The reaction of bromobenzene 14 with the bis-
(trimethylsilyl) enol ether 1510 to obtain the γ-phenyl-β-
ketoester 16 was chosen as a test reaction for our optimization
studies (Table 1). Among three Pd-catalysts screened, Pd-
Received: October 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02952
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Table 1. Optimization of Reaction Conditions
a
entry cat.
additive
solvent
temp (°C) yield (%)
1
2
A
B
C
A
A
A
A
A
A
A
Bu3SnF (1.4 equiv)
Bu3SnF (1.4 equiv)
Bu3SnF (1.4 equiv)
Bu3SnF (1.4 equiv)
Bu3SnF (1.4 equiv)
Bu3SnF (1.4 equiv)
Bu3SnF (1.2 equiv)
Bu3SnF (1.4 equiv)
ZnF2 (0.5 equiv)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
85
85
85
65
45
25
65
65
80
65
69
65
70
73
5
3
4
5
6
0
7
46
76
69
0
8
9
DMF
10
Bu3SnF (1.4 equiv)
CsF (1.4 equiv)
toluene
a
Isolated yields. Catalyst A: Pd(dba)2 (5 mol %)/t-Bu3P (6 mol %).
Catalyst B: Pd(OAc)2 (5 mol %)/t-Bu3P (9 mol %). Catalyst C:
RuPhos Pd-G2 (5 mol %).
simple enol ethers,8,9 Bu3SnF as a stoichiometric additive was
important in all cases but no synergistic effect9a of two metal
fluorides was observed (entry 10). Besides toluene, THF was
found to be a suitable solvent (entry 8). In DMF as solvent,
ZnF2 could be used as an additive (entry 9).9c
The optimized reaction conditions were utilized to perform
the reaction with a variety of different (hetero)aryl halides 14
and two bis(trimethylsilyl) enol ethers 15 and 18; they yielded
the γ-aryl-β-ketoesters 16 and 17 with the results summarized
in Figure 1. The arylation products were formed in moderate to
very good yields. Steric encumbrance in the case of the
electron-rich 2-bromotoluene turned out to be of no
significance (16c, 17c). A highly electron-donating amine
lowered the yields as expected (16d, 17d), whereas the
electron-withdrawing nitro group (16e, 17e) was tolerated just
like an ester, (16f, 17f) which remained untouched if exposed
to the reaction conditions. With respect to heteroaromatic
compounds, 2-bromothiophene (16h, 17h) as well as the
nitrogen-containing compounds 3-bromopyridine and 3-
bromoquinoline (16g, 16i, 17g, 17i) were determined to be
suitable reaction partners. As shown in the optimization studies,
the reaction can be carried out using toluene as a solvent, which
has proven to be superior in some cases. With respect to aryl
chlorides, the yields obtained were around 10%. The use of 1-
bromo-4-iodobenzene resulted in a complex mixture of
products.
Figure 1. Scope and limitations. Reactions were conducted with 1
equiv of aryl halide and 1.4 equiv of bis(trimethylsilyl) enol ether.
a Toluene was used. All yields are isolated yields.
Scheme 2. Retrosynthetic Approach to Substituted
Naphthalenes
Our motivation for an efficient synthetic access to γ-aryl-β-
ketoester arose from a material-science-directed project dealing
with the synthesis of oligo(pent)acenes.11a Key intermediates
for the synthesis of these target molecules are 3-hydroxy-
naphthyl-2-carboxylates11b of type 19 (Scheme 2). Retro-
synthetically, naphthalene 19 could be obtained by an
intramolecular aldol condensation from the β-ketoester
aldehyde 20 where the latter would be accessible from the γ-
arylation of the bis(trimethylsilyl) enol ether 12 with the aryl
bromide 21. Because of the incompatibility of an aldehyde with
the optimized Hauser−Heck conditions, an aldehyde equiv-
alent had to be used instead.
A first attempt for an aldehyde equivalent focused on a
protected alcohol for the Pd-mediated γ-arylation of the
bis(trimethylsilyl) enol ether (Scheme 3). The starting point
was the aryl bromide 22.12 The γ-arylation with the
bis(trimethylsilyl) enol ether 23 gave the β-ketoester 24 in
good yield. Deprotection of the THP ether resulted in
formation of the hemiacetal 25, which was in equilibrium
with its hydroxyketone. Therefore, we submitted this
equilibrium mixture to a Dess-Martin oxidation resulting in
the formation of the desired naphthalene 27 in a mere 8% yield,
B
DOI: 10.1021/acs.orglett.5b02952
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optimized conditions gave β-ketoesters 34 and 35 in very good
yield. For the case of the electron-rich dimethoxy substrate 33,
a satisfactory 58% yield of the arylation product 36 was
obtained. The final deprotective aromatization of the β-
ketoester acetal to the hydroxy naphthoate under acidic
conditions needed extensive optimization (vide infra). Aqueous
formic acid at 65 °C was identified as the optimal set of
conditions for this step. For hydroxy naphthoates 37 and 38
very good yields were achieved (79 and 88%), while for the
dimethoxy naphthol 39, a lower yield (45%) was obtained. The
structure of the substituted naphthalenes was proven by X-ray
crystal structures for 38 and 39 (Figure 2) as well as for 27 (see
Scheme 3. First Attempts in the Synthesis of Naphthalene 27
Starting from the Protected Alcohol 22
with dehydration of 25 to the isochromene 26 being the major
product.
Based on the previous results, we considered it advantageous
to use an aryl bromide for the γ-arylation where the oxidation
state of the aldehyde was already set. We therefore chose an
acetal as an aldehyde equivalent, which was subjected to our
optimized reaction conditions. We expected the resulting
diketo-acetal to undergo cyclization and aromatization when
exposed to aqueous acidic media. Toward this end, three
different bromo aldehydes 28, 29, and 30 were converted into
the corresponding acetals 31, 32, and 33 (Scheme 4). The γ-
arylation with the bis(trimethylsilyl) enol ether 15 using the
Figure 2. X-ray structures of naphthalenes 38 and 39.
Supporting Information). The successful deprotective aroma-
tization of the β-ketoester acetal moiety to the hydroxy
naphthoate was the result of an intensive optimization study
which is summarized for 35 → 38 in Table 2. A 1,3-dioxane was
chosen as the acetal because it could be hydrolyzed more easily
than a 5,5-dimethyl-1,3-dioxane or a dioxolane.13
Aqueous acetic acid at elevated temperatures is a typical
reagent for the deprotection of 1,3-dioxanes.14 Reaction
temperatures between 75 and 100 °C gave the desired
deprotection and intramolecular aldol condensation (35 →
Scheme 4. Access to Substituted Naphthalenes
a
Table 2. Test Reactions for the Ring Closing Reaction
time
(h)
temp
(°C)
b
entry
reagent
solvent
yield (%)
1
2
3
4
5
AcOH/piperidine benzene
24
24
24
24
6
80
100
90
decomp.
80% AcOH
80% AcOH
80% AcOH
p-TsOH (cat.)
H2O
H2O
H2O
27
45
32
75
toluene/
H2O
120
no reaction
6
37% HCl
(5 equiv)
THF
3
45
decomp.
7
8
TFA
THF
H2O
6
3
45
65
decomp.
88
80% HCO2H
a
b
Test reactions were run in 50 mg scale. Yield of isolated product.
C
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In summary, we have developed an efficient one-step
synthesis of γ-aryl-β-ketoesters from aryl bromides and
bis(trimethylsilyl) enol ethers. Catalytic amounts of Pd-
(dba)2/Pt-Bu3 and stoichiometric amounts of Bu3SnF were
optimal conditions for this novel Hauser−Heck combination.
Scope and limitations of the new method have been described
for a series of aromatic and heteroaromatic examples. γ-Aryl-β-
ketoesters with a 1,3-dioxane acetal in the ortho position can be
converted efficiently into substituted naphthalenes using
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02952.
Crystallographic data for 27, 38, and 39 (CIF)
Experimental details; spectroscopic and analytical data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: koert@chemie.uni-marburg.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Deutsche Forschungsgemeinschaft
(DFG, SFB 1083) and Fonds der Chemischen Industrie is
gratefully acknowledged.
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D
DOI: 10.1021/acs.orglett.5b02952
Org. Lett. XXXX, XXX, XXX−XXX