Gold catalysis: β-ketonaphthalenes via molecular gymnastics of 1,6-diyne-4-en-3-ols

Article abstract of DOI:10.1002/adsc.201300396

1,6-Diyne-4-en-3-ols with one terminal alkyne were applied as test substrates for a possible dual catalyzed cyclization. Instead of a dual catalysis cycle, naphthyl ketone derivatives were obtained as single products. The regioselectivity of the obtained products is unprecedented. Instead of the expected naphthyl ketones bearing the keto group in the α-position, the keto group is positioned in the ss-position of the naphthyl skeleton by a complex rearrangement of the starting materials. Copyright

Full text of DOI:10.1002/adsc.201300396

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DOI: 10.1002/adsc.201300396
Gold Catalysis: b-Ketonaphthalenes via Molecular Gymnastics of
1,6-Diyne-4-en-3-ols
Tobias Lauterbach,a Sebastian Arndt,a Matthias Rudolph,a Frank Rominger,a
and A. Stephen K. Hashmia,b,*
a
Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢀt Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
Fax : (+49)-711-685-4205; e-mail: hashmi@hashmi.de
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
b
Received: May 6, 2013; Revised: May 17, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300396.
Abstract: 1,6-Diyne-4-en-3-ols with one terminal
alkyne were applied as test substrates for a possible
dual catalyzed cyclization. Instead of a dual cataly-
sis cycle, naphthyl ketone derivatives were obtained
as single products. The regioselectivity of the ob-
tained products is unprecedented. Instead of the ex-
pected naphthyl ketones bearing the keto group in
the a-position, the keto group is positioned in the
ß-position of the naphthyl skeleton by a complex
rearrangement of the starting materials.
philes were applied. Just recently Zhangꢁs and our
groups independently discovered a new reaction path-
way for diyne systems, which is based on a dual acti-
vation mode. The nucleophilicity of one of the alk-
AHCTUNGTREGyNNNU nes is increased via s-coordination (acetylide forma-
tion). This enables the attack onto the remaining
alkyne which is activated by a second cationic gold
fragment via the common p-activation mode. De-
pending on the backbone of the diyne system either
a 5-endo-dig cyclization or a 6-endo-dig cyclization
takes place leading to highly reactive vinylidene/car-
bene intermediates with a rich follow-up chemisty.[4]
So far only 1,5-diynes were used as starting materi-
als for these transformations. Now we have consid-
ered the easily available 1,6-diynes as starting materi-
als as well. The unexpected results of these experi-
ments are summarized in this contribution.
Keywords: cycloisomerization; diynes; gold cataly-
sis; rearrangement; regioselectivity
During the ongoing development of new synthetically
As test substrate we selected diyne 1a as it is close-
useful transformations catalyzed by homogeneous ly related to our previously published benzofulvene
gold catalysts,[1] substrates bearing two alkynyl moiet- synthesis.[4d] As depicted in Scheme 1, we expected
ies have attracted considerable interest in the recent the formation of a gold vinylidene intermediate I
À
past. Mainly two alternative reaction pathways can be which then could undergo a subsequent C H inser-
found. The majority of the reactions is initiated via tion reaction. In order to initiate a dual activation
a nucleophilic addition onto one of the triple bonds. mode, we employed a s,p-dinuclear propyne gold ace-
The double bond obtained then serves as a nucleo- tylide (dual activation catalyst), a catalyst that had
phile and a subsequent reaction with the remaining proven to be ideal for related reactions based on this
alkyne delivers the final products. For this process ex- reactivity.[5] Indeed we could monitor a complete con-
ternal[2] as well as intramolecularly[3] offered nucleo- version of the starting material even at room temper-
Scheme 1. Expected reactivity for substrate 1a.
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À
Table 1. Screening of reaction conditions.
ature, but to our surprise no C H activation took
place and the tert-butyl group was preserved in the
1
final molecule (easily detectable by H NMR). The
NMR assignment revealed a naphthalene structure,
but the substitution pattern of the product did not
match with related systems derived from the cycliza-
tion of the corresponding non-terminal alkynes as
starting materials; a reaction cascade that was report-
ed by the Liu group.[6] Most fortunately, we were able
to obtain single crystals suitable for an X-ray crystal
structure analysis.[7] The solid state molecular struc-
ture in Figure 1 shows the unexpected outcome of this
reaction. To our surprise the obtained naphthalene
derivative 2a contained the pivaloyl substituent in the
b-position and furthermore a migration of the tert-
butyl group must have taken place as the distance to
both of the anellation points contains three carbon
atoms!
In order to optimize the reaction conditions for this
transformation, we first intended to evaluate whether
a dual activation cycle or a classical p-activation
mode is present. Therefore we synthesized preformed
acetylide 3 and subjected it to catalytic amounts of
cationic gold catalyst (Scheme 2). The fact that abso-
lutely no conversion takes place indicates that a dual
activation is unlikely. As a consequence we concen-
Entry [M]
Additive Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
TDAC-PF6
–
DCM
DCM
DCM
acetone traces
MeCN
MeOH
77
77
92
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
AgPF6
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
traces
89
benzene 61
toluene
67
9
AgNTf2
DCM
13
10
11
12
13
15
16
BrettPhosAuCl AgNTf2
SPhosAuCl
XPhosAuCl
(Mes)3PAuCl
AgNTf2
FeCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
traces
16
traces
32
AgNTf2
AgNTf2
AgNTf2
–
–
–
–
–
–
traces
–
–
–
–
–
trated our efforts for catalyst optimization on cationic 17
gold species without additives for acetylide formation
(Table 1).
Results comparable to the dual activation catalyst
(entry 1) were obtained with IPrAuCl in combination
with the hexafluorophosphate counter ion (entry 2).
Even better results were obtained with the triflimide
counter ion. Under these conditions an excellent yield
CuTf2
18
19
20
DyTf3
YbTf3
p-TsOH
[a]
Yield determined by GC-MS using hexamethylbenzene
as internal standard.
was obtained (entry 3). Changing the solvent did not
improve the result. While only traces of product were
obtained in acetone and acetonitrile (entries 4 and 5),
methanol proved to be a suitable solvent, too
(entry 6). Non-polar solvents like benzene and tolu-
ene delivered only moderate yields (entries 7 and 8).
A short screening of different ligands at the gold
center did not improve the yield. Neither the acyclic
carbene complex 4 (entry 9) nor phosphane-based li-
gands (entries 10–13) showed acceptable results.
Other Lewis acids (entries 15–19) or simple para-tol-
uenesulfonic acid (entry 20) failed to catalyze the re-
action.
Figure 1. Solid state molecular structure of the product 2a.
With the optimized reaction conditions in hand we
focused on the evaluation of the substrate scope
(Table 2). Unfortunately, the isolated yield of the
final product 2a turned out to be only moderate
which indicates problems during purification
(entry 1). Substrates 1b and 1c bearing alkoxy groups
in the meta-position to the alkynyl substitutens deliv-
ered only poor yields (entries 2 and 3), whereas regio-
isomer 1d delivered acceptable results again. Elec-
tron-poor aromatic starting materials delivered better
Scheme 2. Gold acetylide 3 does not react in the presence of
active gold(I) catalyst.
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Table 2. Substrate scope.
Entry
1
Substrate
Product
Time
16 h
Yield [%]
59
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2
3
4
5
17 h
24 h
1 h
32
14
62
62
17 h
6
7
1f
1g
2f
2g
3 h
2 h
52
92
8
1h
2h
27 h
17
9
1i
1j
2i
2j
21 h
24 h
80
43
10
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Table 2. (Continued)
Entry
Substrate
Product
Time
24 h
Yield [%]
65
11
1k
1l
2k
2l
12
16 h
51
tion pattern no matter if there are electronically neu-
tral (entry 9), electron-donating (entry 10) or elec-
tron-withdrawing substitutents (entry 11) at the aro-
matic backbone. Substituents at the arene at the
alkyne terminus are also tolerated which was demon-
strated by substrate 2l (entry 12). In order to verify
the correct assignment of the obtained structures, ad-
ditional X-ray crystal structure analyses were per-
formed. Figure 2 shows the solid state molecular
structures of compounds 2c, 2k and 2l.[7] The structure
of 2l demonstrates that the same substitution pattern
is also obtained for aryl substitution at the internal
alkyne. Structure 2k demonstrates that the carbonyl is
placed next to the former terminal alkyne position.
In order to obtain further insight into the reaction
mechanism, deuterated substrate 1a-d was converted
under the standard reaction conditions (Scheme 3,
Figure 2. Solid state molecular structures of compounds 2c
(top), 2k (middle) and 2l (bottom).
yields and both fluoro and nitro substitutents were
tolerated (entries 5 and 6). The use of a sterically less
demanding unbranched alkyl chain as alkyne substitu-
ent was tolerated as well and product 2g was obtained
in excellent isolated yields (entry 7). Changing the ar-
omatic backbone to thiophene delivered significantly
lower yields than the corresponding benzene deriva-
tive (entry 8). Next we shifted to aromatic substitu-
ents at the alkyne terminus (entries 9–11). For all of
the test substrates yields were higher for this substitu- Scheme 3. Labelling experiments.
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Gold Catalysis: b-Ketonaphthalenes via Molecular Gymnastics of 1,6-Diyne-4-en-3-ols
upper part). The deuterium labelling was completely reaction under dry conditions in the presence of
preserved in the product with the deuterium labelling 10 equivalents of H218O (Scheme 3, lower part). Even
in the b-position of the naphthalene system next to in the presence of the great excess of oxgen labelled
the carbonyl carbon atom. In addition we converted water, only minor amounts were incorporated in the
substrate 1i-c with 13C-labelling at the alkyne termi- final product. This strongly indicates that the oxygen
nus. As depicted in Scheme 3 (middle part) the la- is transferred in an intramolecular process.
belled carbon is transferred to the carbonyl position
Finally, we examined the reaction with trimethyl-
of the final product 2i-c (the position of the 13C-la- silyl-protected alkynol 5 (Scheme 4). For this type of
belled carbon was confirmed by an intense peak at substrate no cyclization took place which underlies
198.1 ppm in the carbon NMR; in addition the label- the importance of the hydroxy moiety for the rear-
ling was confirmed by mass spectrometry by the in- rangement.
creased intensity of the molecule peak at m/z=233
Our mechanistic proposal is depicted in Scheme 5.
and its characteristic fragmentations at m/z=156 For the first part of the transformation two different
[C1013CH7O]+ and 106 [C613CH5O]+; fragmentation pathways are reasonable.[8] Pathway 1 is initiated by
ions without the CO of the carbonyl group match a nucleophilic attack of the propargylic hydroxy
with the natural 13C distribution. To evaluate the group onto the non-terminal alkyne leading to inter-
origin of the oxygen in the product, we conducted the mediate IIa. The next step involves a cleavage of the
ether bond under formation of stabilized cation IIIa.[9]
The benzylic cation can then be trapped by a molecule
of water which stems from the reaction solvent. This
overall process of a SN1-type propargylic substitution
is a well known process in gold chemistry.[10] The so
formed intermediate IV contains a nucleophilic eno-
late moiety which can attack the p-actitvated terminal
Scheme 4. No reaction with TMS-protected substrate 5.
alkyne under formation of key intermediate V. The
Scheme 5. Mechanistic proposal.
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mine under an atmosphere of nitrogen. After stirring for
10 min 1.2 equivalents of the terminal alkyne were added.
The resulting mixture was stirred at the mentioned tempera-
ture until the reaction was completed. The solvent was re-
moved under reduced pressure and the crude product was
purified by column chromatography on silica gel.
same key intermediate V could also be formed via
pathway 2. The initial reaction steps for this pathway
are akin to those proposed by the Liu group.[6,11] The
hydroxy moiety in the starting material might direct
the cationic gold fragment to the internal position of
the terminal alkyne which then enables a 6-endo-dig
attack of the non-terminal alkyne. The so formed cat-
ionic vinyl gold species IIIb[9] reacts with traces of
water in the solvent which after tautermerization also
delivers ketone V as key intermediate. It should be
mentioned that in the case of labelled water in the re-
action media two different positions in intermediate
V are labelled. Pathway 1 should put the labelled
oxygen in the benzylic position while a nucleophilic
attack of water onto cation IIIb would place the la-
belled oxgen at the carbonyl position. The next step
of the cascade comprises the nucleophilic attack of
the carbonyl oxygen onto the benzylic position. It is
reasonable that gold is also involved in this step and
that the cationic gold fragment triggers the release of
the hydroxy group under formation of a gold hydroxy
complex. The so formed oxonium intermediate VI is
then attacked by the adjacent double bond. Unsubsti-
tuted naphthalene by-products VII could also be ob-
served in small amounts. These by-products were also
observed by the Liu group and can be explained by
water induced decomposition of intermediate VI
under elimination of a molecule of organic acid. It re-
mains unclear why this reaction step only occurs in
traces and cannot be forced to be the major pathway
for our substrates (even in the presence of 10 equiva-
lents of water). Instead of the elimination pathway
mainly charged intermediate VIII is formed which
then undergoes rearrangement to the aromatic prod-
ucts under release of a proton. If one consideres the
labelling experiments both of the pathways are in line
with the carbon and deuterium labelling, but the re-
sults of the oxygen labelling which underline that an
intramolecular oxygen transfer takes place strongly
favour pathway 1.
General Procedure for the Grignard Reaction
Under an atmosphere of nitrogen the aldehyde was dis-
solved in THF. An excess of Grignard reagent was added
and the mixture was stirred at room temperature until the
reaction was completed. The reaction was quenched with
aqueous saturated NaHCO3 solution, extracted with DCM
and dried over MgSO4. The suspension was filtered and the
solvent was removed under reduced pressure. The crude
product was purified by column chromatography on silica
gel.
General Procedure for the Gold Catalysis
The diynol was dissolved in a small amount of DCM.
5 mol% IPrAuCl and 5 mol% AgNTf2 were added under
vigorous stirring and the reaction was monitored by TLC.
After complete consumption of the starting material the sol-
vent was removed under reduced pressure and the crude
product was purified by column chromatography.
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Experimental Section
General Procedure for the Sonogashira Coupling
The aryl halide, 5 mol% of copper(I) iodide and 2.5 mol%
of PdCl2ACHTUNGTRENNUNG(PPh3)2 were dissolved in freshly degassed triethyla-
6
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8 Gold Catalysis: b-Ketonaphthalenes via Molecular
Gymnastics of 1,6-Diyne-4-en-3-ols
Adv. Synth. Catal. 2013, 355, 1 – 8
Tobias Lauterbach, Sebastian Arndt, Matthias Rudolph,
Frank Rominger, A. Stephen K. Hashmi*
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