Synthesis of α-Alkenyl α,β-Unsaturated Ketones via Dehydrogermylation of Oxagermacycles with Regeneration of the Germanium(II) Species

Article abstract of DOI:10.1021/acs.orglett.9b03454

The synthesis of α-alkenyl α,β-unsaturated ketones using germanium(II) salts is reported. Oxagermacycles derived from α,β-unsaturated ketones with germanium(II) salts and aldehydes can be transformed into α-alkenyl α,β-unsaturated ketones. Ammonium salts promoted the elimination of Ge(II) species to afford the two classes of α-alkenyl α,β-unsaturated ketones in good yields. The α-alkenyl α,β-unsaturated ketones are precursors for multisubstituted heterocycles.

Full text of DOI:10.1021/acs.orglett.9b03454

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α‑Alkenyl α,β-Unsaturated Ketones via
Dehydrogermylation of Oxagermacycles with Regeneration of the
Germanium(II) Species
Yohei Minami,† Akihito Konishi,*,†,‡ and Makoto Yasuda*,†
‡
†Department of Applied Chemistry and Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The synthesis of α-alkenyl α,β-unsaturated ketones using
germanium(II) salts is reported. Oxagermacycles derived from α,β-
unsaturated ketones with germanium(II) salts and aldehydes can be
transformed into α-alkenyl α,β-unsaturated ketones. Ammonium salts
promoted the elimination of Ge(II) species to afford the two classes of
α-alkenyl α,β-unsaturated ketones in good yields. The α-alkenyl α,β-
unsaturated ketones are precursors for multisubstituted heterocycles.
Scheme 1. Synthesis of α-Alkenyl α,β-Unsaturated Ketones
via (A) Combination of the Morita−Baylis−Hillman and
Wittig Reactions, (B) Palladium-Catalyzed Cross-Coupling,
and (C) Olefination of Oxagermacycles Used in This Work
n the field of organic synthesis, multisubstituted α,β-
Iunsaturated ketones are important building blocks that are
successfully employed in the syntheses of bioactive com-
pounds.1−3 The bifunctionality inherent in α,β-unsaturated
carbonyl and 1,3-diene moieties endows α-alkenyl α,β-
unsaturated carbonyls with synthetic values that make them
capable precursors for highly functionalized organic molecules.
The synthesis of α-alkenyl α,β-unsaturated carbonyls has been
accomplished via several methods.4−8 The synthesis of α-alkenyl
α,β-unsaturated carbonyls with strong electron-withdrawing
groups,9 such as esters10 and nitriles,11 has been established
using a combination of the Morita−Baylis−Hillman and Wittig
reactions to construct the diene structure (Scheme 1A).
Transition-metal-catalyzed cross-coupling reactions,12 as well
as the direct α-alkenylation of heterocyclic α,β-unsaturated
ketones,13−17 have attained modest success in the synthesis of
cyclic α-alkenyl α,β-unsaturated ketones (Scheme 1B). The α-
alkenylation of acyclic α,β-unsaturated ketones remains
undeveloped, however, and this has hampered the flexible and
broad-ranging utilization of α-alkenyl α,β-unsaturated carbon-
yls.
Metallacyclic compounds are important intermediates in
stoichiometric and/or catalytic carbon−carbon bond forma-
tions,18,19 metathesis reactions,20,21 and polymerizations.22
Oxidative cyclization of low-valent transition metals is one of
the well-developed methods for the formation of metalla-
cycles.23−30 A low-valent group of 14 species, each with an
oxidation state of +2, are used to perform oxidative cyclization
with unsaturated organic molecules to give the metallacycles
that are incorporated in this group of 14 metals (along with the
oxidation state changed into +4).31−36 Divalent silicons,37
germaniums,38,39 and tins39 readily react with α,β-unsaturated
carbonyls or 1,3-dienes to afford the corresponding five-
membered metallacycles. However, the high or inert reactivity
of divalent silicon and tin salts, respectively, interferes with the
synthetic applications of the metallacycles based on these
metals. For example, SiCl2 is a highly reactive intermediate, and
Received: September 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03454
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
SnCl2 is a bench-stable reductant in organic synthesis. On the
other hand, divalent germanium salts with moderate stability
and enough reduction capacity can provide the synthetic utility
of a low-valent metal. The allylations40 or aldol-type
reactions41−45 of carbonyl compounds have been accomplished
using low-valent germanium.46 Recently, we reported the
diastereoselective synthesis of oxagermacycles via the aldol
reactions of aldehydes with C,O-chelated germyl enolates
derived from Ge(II) salts and α,β-unsaturated ketones. The
oxagermacycles were transformed into triols bearing four
stereocenters with perfect disatereoselectivity.47 Further trans-
formation of the oxagermacycles is a promising strategy that
could be used to construct highly functionalized molecules in
short steps. Herein, we report the synthesis of α-alkenyl α,β-
unsaturated ketones via dehydrogermylation of oxagermacycles
(Scheme 1C). The addition of ammonium salts promoted the
initial dehydrogermylation and the subsequent elimination of a
Ge−O moiety. The obtained α-alkenyl α,β-unsaturated ketones
are applicable as a synthon for functionalized heterocyclic
compounds.
With the optimized conditions in hand, a variety of α,β-
unsaturated ketones and aliphatic aldehydes was applied in the
reaction to give the corresponding α-alkenyl α,β-unsaturated
ketones 4 (Scheme 2). The reaction with the linear aldehydes
Scheme 2. Substrate Scope of α,β-Unsaturated Ketones and
a
Aliphatic Aldehydes
In an initial study, in order to activate a germanium center of 3
via coordination of a ligand, tetrabutylammonium salts were
utilized. The treatment of oxagermacycle 3aa, which is derived
from the Ge(II)-mediated aldol reaction47 of 4-methyl-3-
penten-2-one 1a and 3-phenylpropanal 2a, with Bu4NBr gave
the α-alkenyl α,β-unsaturated ketones 4aa/5aa in 76% yield
(90:10 selectivity) (entry 1 in Table 1). Those results prompted
a
Yields were determined via 1H NMR measurement with 1,1,2,2-
tetrachloroethane as an internal standard. Isolated yields are in
parentheses. Due to the adsorption of the products on silica gel, the
isolated yields decreased. Ratios of 4/5 for the E/Z mixtures were
determined by 1H NMR measurement of the crude reaction mixture.
2a−2d selectively afforded the products 4aa−4ad with an
internal butadiene framework in good yields. The employment
of an α-branched aldehyde 2e also gave the diene 4ae as the
main product, but the generation of 5ae with a terminal
butadiene framework was slightly increased. Several unsaturated
ketones (1b−1f) were applicable to the reaction. Products 4ba−
4fa were generated as E/Z mixtures with respect to the carbon−
carbon double bond adjacent to the carbonyl group.
Presumably, the observed ratios depend on the thermodynamic
stability between the two isomers. A perfect E-selectivity for the
carbon−carbon double bond derived from aldehyde was found
in 4. This result suggests that the E2-type mechanism involves
the formation of the carbon−carbon double bond.
Next, we examined the reaction of 1a with aromatic aldehydes
2f−2m (Scheme 3). For aromatic aldehydes, the obtained
butadienes 5af−5am proved to be the terminal versions as E/Z
mixtures. In these cases, prolonged reaction times resulted in
sufficient yields. The benzaldehyde derivatives bearing electron-
donating (2g) and electron-withdrawing (2h, 2i, 2j) groups and
Table 1. Optimization of the Reaction Conditions
b
c
entry
base
time (h)
yield (%)
4aa/5aa
1
2
3
4
5
6
7
8
Bu4N+Br−
Bu4N+Cl−
Bu4N+I−
Bu4N+HSO3
KOAc
Cs2CO3
Et3N
pyridine
Bu4N+Br−
Bu4N+Br−
24
24
24
24
24
24
24
24
1
76
90:10
91:9
81:19
88:12
>99:1
-
69
54
58
29
0
−
0
0
-
-
a
9
10
74 (48)
69
95:5
86:14
d
24
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), GeCl2-dioxane
b
(0.6 mmol), base (2.5 mmol), MeCN (2 mL), 80 °C. Yields were
determined by 1H NMR measurement using 1,1,2,2-tetrachloroethane
a
c
Scheme 3. Substrate Scope of Aromatic Aldehydes
as an internal standard. Isolated yield is in parentheses. The ratio of
4aa/5aa was determined by 1H NMR measurement of the crude
d
reaction mixture. GeBr2-dioxane was used instead of GeCl2-dioxane.
us to further optimize the reaction conditions for the synthesis of
diene 4. Bu4NCl, Bu4NI, Bu4NHSO3, and KOAc were also
productive, but the yields of the product were insufficient
(entries 2−5). The size of halide was crucial, either smaller or
larger than bromide is not suitable (entries 2 and 3). Other
typical bases such as Cs2CO3, Et3N, and pyridine promoted the
dissociation of 3aa to 1a and 2a (entries 6−8). An improvement
in the selectivity of 4aa/5aa was afforded when the reaction time
was shortened from 24 to 1 h (entry 9). Instead of GeCl2-
dioxane, GeBr2-dioxane worked to give slightly lower yield
(entry 10).
a
1
Yields were determined by H NMR measurement using 1,1,2,2-
tetrachloroethane as an internal standard. Isolated yields are in
parentheses. Due to the adsorption of the products on silica gel, the
isolated yields decreased. The E/Z ratio was determined by 1H NMR
measurement of the crude reaction mixture.
B
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Letter
2-naphthaldehyde (2k) were applicable to the reaction, but 2j
possessed a strong electron-withdrawing nitro group that
suppressed the yield. The ratio between E- and Z-isomers
remained relatively constant among products 5af−5ak.
Heteroaromatic aldehydes (2l, 2m) were utilized in this
reaction. For the diene 5al from 2-thiophenecarboxaldehyde
2l, the ratio of the E-isomer was slightly increased presumably
because of the electrostatic repulsion between the carbonyl
group and the sulfur atom.
the presence of both a Lewis acid and Bu4NBr (entry 1 in Table
S1). The absence of either Bu4NBr or Ge(II) salts gave none of
product 5ai (entries 2 and 3 in Table S1). Because the
combination of either GeCl4 or BF3−Et2O with Bu4NBr also
succeeded (entries 4 and 5, respectively), the utility of Lewis
acids and Bu4NBr was expected to promote the elimination of
the Ge−O moiety. We also attempted to observe the germanium
alkoxide intermediate 6aa or trap the alcohol 7aa derived from
the aliphatic aldehyde 2a, but the fast olefination of 3aa into 4aa
under the same conditions hampered these trials (Scheme 4C).
We postulated that the alkoxygermanium intermediate 6 was
formed as a key intermediate in the initial step of the reaction,
which was followed by the elimination of the Ge−O moiety to
give α-alkenyl α,β-unsaturated ketones 4 and 5.
1
The reaction mixture was monitored by H NMR spectros-
copy to investigate the reaction mechanism. The NMR
measurement of the reaction of 3ai with Bu4NBr in
acetonitrile-d3 showed that a singlet signal appeared at 5.74
ppm after being mixed for 0.5 h at 80 °C (Scheme 4A). The
After the completion of the reaction, we examined the
structure of the germanium species. When tetraphenylphos-
phonium salt was utilized instead of Bu4NBr, the highly
crystalline nature of the Ph4P+ ions facilitated the isolation of
germanium salts after the reaction. The treatment of the
oxagermacycle 3ai with an equimolar amount of tetraphenyl-
phosphonium chloride quantitatively gave 5ai with
Ph4P+[GeCl3]− 8. The structure of Ph4P+[GeCl3]− 8 was
confirmed by X-ray crystallographic analysis (Scheme 4D). The
regeneration of the germanium(II) species suggested that the
intermediate 6ai was formed not via direct β-hydride
elimination, but rather by the base-promoted 1,2-elimination
of the germanium moiety. The base-promoted 1,2-elimination
can be found in the reaction of a β-stannyl ketone.48 Although
regeneration of the germanium(II) species might be unusual, the
bistability of the two oxidation states of germanium (Ge(II)/
Ge(IV)) enabled the dissociation of the Ge−C bond. The
stepwise change in the oxidative state of the germanium center
may have led to a catalytic reaction. The regenerated
germanium(II) species 8 did not show catalytic activity due to
the formation of an inert tricoordinated germanate(II) complex.
Further investigation of the catalytic condition of Ge(II) salt is
ongoing in our group.
a
Scheme 4. Mechanistic Studies
Although details of the reaction mechanism remain uncertain,
we believe that Scheme 5 offers a plausible mechanism for the
transformation of the oxagermacycle 3 into dienes. Initially, the
treatment of an oxagermacycle intermediate 3 with Bu4NBr
Scheme 5. Plausible Reaction Mechanism
a
Conditions: (A) 1H NMR spectra (400 MHz, acetonitrile-d3)
showing the progress of the transformation of 3ai to 5ai via 6ai at 80
°C by Bu4NBr; (B) transformation of 3ai to 5ai via 6ai and
protonation of the reaction intermediate; (C) transformation of 3aa
to 4aa via 6aa; and (D) determination of the germanium species after
the completion of the reaction.
observed singlet signal should be assigned to the benzylic
proton. Quenching the reaction in 30 min with saturated
aqueous NH4Cl gave the benzylic alcohol 7ai in 59% yield,
which strongly suggests that the observed singlet signals at 5.74
ppm should be from an intermediate, 6ai (Scheme 4B). Actually,
the ESI-MS measurement directly detected a molecular ion for
6ai in the reaction mixture (Figures S4 and S5). The isolated
alcohol 7ai was quantitatively transformed into the diene 5ai in
C
DOI: 10.1021/acs.orglett.9b03454
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Letter
triggered the deprotonation of an α-proton of the carbonyl
group. The generated enolate 9 cleaved the Ge−C bond to
afford the alkoxygermanium species 6 in situ. For the aliphatic
aldehydes (path A), the deprotonation at the β position of 6 led
to elimination of the Ge−O moiety of 10 to primarily give diene
4. When the main product was 4 rather than 5, this suggested
that the 1,2-elimination of the Ge−O moiety would proceed via
an E2-type mechanism. In contrast, for the aromatic aldehyde
(path B), the 1,4-elimination of the Ge−O moiety of 11
selectively gave the E-isomer of 5 as a kinetically controlled
product. A gradual isomerization was observed to afford an E/Z
mixture (see Figure S3). Because the 1,4-elimination was slower
than the 1,2-elimination, intermediate 6ai was observed by
NMR spectroscopy.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03454.
■
S
Experimental procedures, characterization of products,
and spectroscopic data (PDF)
Accession Codes
CCDC 1953429−1953430 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
The obtained α-alkenyl α,β-unsaturated ketones were applied
to the synthesis of 1,5-diphenyl-3-methylpyrazole derivatives 12
and 13 (Scheme 6). The analogues of 1,5-diphenyl-3-
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: a-koni@chem.eng.osaka-u.ac.jp.
*E-mail: yasuda@chem.eng.osaka-u.ac.jp.
Scheme 6. Synthesis of 1,5-Diphenyl-3-methylpyrazole
Derivatives
ORCID
Yohei Minami: 0000-0001-5246-418X
Akihito Konishi: 0000-0002-3438-786X
Makoto Yasuda: 0000-0002-6618-2893
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the JSPS KAKENHI (Grant Nos.
JP15H05848 in Middle Molecular Strategy, JP18H01977,
JP18K19079, and JP18K14201). M.Y. acknowledges support
from the JSPS Fellowship for Young Scientists (19J10386). A.K.
would like to thank the Iketani Science and Technology
Foundation for their financial support. We thank Dr. N.
Kanehisa (Osaka University) for valuable advice regarding X-
ray crystallography. Thanks are due to the Analytical
Instrumentation Facility, Graduate School of Engineering,
Osaka University.
methylpyrazole have shown potential for use as HIV-1 reverse
transcriptase inhibitors.49,50 The treatment of 4da with
phenylhydrazine hydrochloride afforded the 1,5-diphenyl-3-
methylpyrazole derivative 12 in 61% yield.51 The 1,5-diphenyl-
3-methylpyrazole derivative 13 was synthesized from 5af via the
treatment of phenylhydrazine followed by oxidation with
DDQ.52 The formation of 13 was confirmed by X-ray
crystallographic analysis.
In conclusion, we have developed a method for the synthesis
of α-alkenyl α,β-unsaturated ketones from α,β-unsaturated
ketones with aldehydes using germanium(II) salts. Highly
substituted α,β-unsaturated ketones were successfully synthe-
sized. Various aldehydes, such as aromatic, heteroaromatic, and
alkyl versions, are applicable to the reaction. The internal
butadienes were obtained from aliphatic aldehydes. On the
other hand, the terminal butadienes were formed from aromatic
aldehydes. From a mechanistic perspective, tetrabutylammo-
nium bromide worked as a base, which promoted dehydro-
germylation to give a germanium alkoxide intermediate with the
regeneration of divalent germanium species. The intermediate
was transformed to α-alkenyl α,β-unsaturated ketones in the
presence of germanium salts and tetrabutylammonium salts.
The internal dienes 4 and the terminal dienes 5 were formed via
the 1,2-elimination and the 1,4-elimination of the Ge−O
moiety, respectively. The 2-acyl-1,3-butadiene derivatives 4 and
5 could be transformed into highly substituted pyrazoles.
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