Carbene transfer - A new pathway for propargylic esters in gold catalysis

Article abstract of DOI:10.1002/adsc.201300572

Gold (homepage: http://www.hashmi.de) carbenes generated via 1,2-migration of a propargylic ester group can be transferred over a tethered alkyne. The use of aromatic backbones leads after a 1,7-carbene transfer to a benzyl-stabilized carbene as intermediate. A 1,2-shift of a methyl group delivers vinyl-substituted β-naphthol derivatives as the final products. Copyright

Full text of DOI:10.1002/adsc.201300572

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DOI: 10.1002/adsc.201300572
Carbene Transfer – A New Pathway for Propargylic Esters in
Gold Catalysis
Tobias Lauterbach,a Sabrina Gatzweiler,a Pascal Nçsel,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)-6221-54-4205; e-mail: hashmi@hashmi.de
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
b
+
Crystallographic investigation.
Received: May 9, 2013; Revised: June 27, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300572.
Abstract: Gold (homepage: http://www.hashmi.de)
carbenes generated via 1,2-migration of a propargyl-
ic ester group can be transferred over a tethered
alkyne. The use of aromatic backbones leads after
a 1,7-carbene transfer to a benzyl-stabilized carbene
as intermediate. A 1,2-shift of a methyl group deliv-
ers vinyl-substituted b-naphthol derivatives as the
final products.
The so formed vinyl carbenes can be accessed
under mild conditions which caught the attention of
the chemical community as the propargylic esters can
serve as substitutes for the hazardous and often explo-
sive diazo compounds that are frequently used as pre-
cursors for the corresponding a-oxo carbenes
(Scheme 1, upper part).[2] Based on this methodology,
a whole series of beautiful transformations was re-
ported recently and even various examples for appli-
cations in natural product synthesis can be found in
the literature.[3] Interestingly, when we started our
studies, no reports on the trapping of propargylic
esters-derived carbenoids with a tethered alkyne were
known. During the preparation of this manuscript one
exciting contribution of the groups of Hirao and Chan
Keywords: carbene transfer; diynes; gold catalysis;
2-naphthols; propargylic esters
In the emerging field of gold-catalyzed reactions[1] appeared, which reports on the synthesis of 2,4a-dihy-
one of the dominating aspects is the part which com- dro-1H-fluorenes. This reaction cascade consists of
prises the chemistry of gold carbenoids that can be a 1,2-migration of an acetoxy group followed by a car-
generated via a 1,2-acetate shift of a propargylic ester bene transfer over a pendent alkyne and finally a Naz-
moiety.
arov-type cyclization as terminating step.[4] The first
Scheme 1. The generation of metal carbenoids and carbenoid transfer with alkynes.
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example for a gold-catalyzed carbene transfer over an best choice (entry 4) but the GC yield of 44% was
alkyne was described by the Toste group who used still low. Next we investigated the effect of different
a diazo compound as carbene precursor.[5]
counter ions (entries 5–8) but unfortunately no large
If one considers the plethora of useful synthetic counter ion effect was observed and yields were in
transformations which are reported on metal-cata- the same moderate range. It is noteworthy that, by
lyzed carbene/alkyne transfer reactions based on the using the in situ activation with a silver salt, lower
decomposition of diazo compounds,[6] we believe that yields were obtained for the triflimide counter ion
there would be an immense impact if the more easily (entry 5). This can be rationalized by a competing de-
available carbene precursors could be applied for this composition of the starting material by the silver salt.
type of chemistry (Scheme 1, lower part).
Indeed the control experiment with only the silver
We envisioned that propargylic acetates might also salt showed a steady decomposition of the starting
be a perfect choice as starting materials since a 1,2- material. In order to circumvent this negative effect
migration often can take place under remarkably mild of the activation by silver, we switched back to isolat-
conditions and furthermore the synthesis of the start- ed pre-activated triflimide complexes.[7] Changing the
ing materials could be straightforward.
ligand to triphenylphosphane did not lead to an im-
We decided to use aromatic backbones for our test provement (entry 10). Using the IPr-NHC ligand at
substrates. The fixed geometry of the systems should room temperature delivered only 33% of the desired
enable clean reactions and, furthermore, the starting product (entry 11). Next we varied the concentration
materials are accessible by a short route of simple of the reaction mixture (entries 12 and 13). It became
transformations. A screening of the reaction condi- obvious that higher concentrations in combination
tions was performed with substrate 1a, the results of with the IPr-NHC ligand led to a significant improve-
the optimization are summarized in Table 1.
ment of the yield. Finally, we screened non-activated
In a first set of experiments we applied air stable gold sources for the transformation, too. To our sur-
IPrAuNTf2 in different solvents at a reaction tempera- prise even IPrAuCl led to a quantitative conversion
ture of 808C (entries 1–4). Indeed significant reactivi- after 16 h at 808C (entry 14). In addition, yields
ty was observed for all of the applied solvents. turned out to be high. Encouraged by this rather un-
Among the tested solvents DCE turned out to be the common reactivity we considered simple AuCl as cat-
alyst (entry 15). By using this gold source, the reac-
tion was speeded up remarkably and a full conversion
was detected after only 0.2 h. In addition, an excellent
Table 1. Screening of the reaction conditions.
yield of 97% was observed. It should be mentioned
that in the case of Hirao and Chanꢂs publication AuCl
was completely inefficient, which indicates a strong
catalyst dependency for these type of cyclizations.[4]
2-D-NMR analysis of the obtained product 2a re-
vealed the formation of an acetate protected naphthol
skeleton. As expected, the acetyl group performed
a 1,2-shift leading to the oxygen in the b-position of
the naphthol. Furthermore, the reaction must be ter-
minated by a 1,2-shift of one of the methyl groups of
the tert-butyl group, leading to a tetra-substituted
vinyl substituent next to the ring fusion.
With the best reaction conditions in hand, we fo-
cused our attention on the evaluation of the reaction
scope. At first, we briefly investigated the influence of
different substitution patterns on the aromatic back-
bone (Table 2). Similar to the non-substituted back-
bone (1a) (entry 1) good to excellent yields were ob-
tained for arene systems 1b–1e bearing oxygen donor
atoms (entries 2–5). An electron-donating methyl
group in para-position to the substituent bearing the
terminal alkyne was also well tolerated and the final
product 2f could be isolated in 85% yield (entry 6).
Only slightly lower yields were obtained for electron-
withdrawing substituents at the arene moiety, but
yields were still high, no matter if fluoro (entries 7
and 8) or nitro groups (entry 9) were transformed. A
Entry [Au]
AgX
Solvent Time Yield[a] [%]
[h]
1
IPrAuNTf2
–
–
–
–
benzene 0.5
toluene 0.5
27
23
2
3
4
5
6
7
8
9
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
–
MeCN
DCE
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
38
44
34
27
31
35
AgNTf2 DCE
AgPF6 DCE
AgSbF6 DCE
AgBF4 DCE
AgNTf2 DCE
–
–
–
–
–
–
decomposition
10
11[b]
12[c]
13[d]
14[d]
15[d]
PPh3AuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuCl
AuCl
DCE
DCE
DCE
DCE
DCE
DCE
41
33
57
65
84
97
0.5
0.5
16
0.2
[a]
Yield determined by GCMS using hexamethylbenzene as in-
ternal standard. (c=0.1 mol/L).
Reaction was run at room temperature.
0.25 mL solvent (0.19 mol/L).
[b]
[c]
[d]
0.125 mL solvent (0.38 mol/L).
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Carbene Transfer – A New Pathway for Propargylic Esters in Gold Catalysis
Table 2. Scope of the transformation.
Entry
1
Substrate
Product
Time [min]
15
Yield [%]
94
1a
1b
1c
2a
2b
2c
2
3
20
85
99
120
4
1d
2d
30
88
5
6
7
1e
1f
1g
2e
2f
2g
180
120
120
80
85
72
8
9
1h
1i
2h
2i
120
120
71
81
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Table 2. (Continued)
Entry
Substrate
Product
Time [min]
Yield [%]
[a]
10
1j
–
60
–
[a]
Starting material was recovered unchanged.
heteroaromatic thiophene backbone showed no con- step in gold-catalyzed reactions was previously de-
version at all (entry 10). One reason might be the scribed by the group of Davies, who reported on the
widened angle in the 5-membered ring which leads to intermolecular asymmetric cyclopropenation of inter-
a larger distance between the two reacting moieties.
nal alkynes with carbenoids derived from diazo com-
Other migrating groups were also tested (Table 3). pounds.[9] After gold-mediated ring opening of the cy-
A migration of a pivaloyl moiety is also possible clopropene unit,[10] benzyl cation V is formed. Break-
(entry 1), but the isolated yield for the product was ing of the cyclopropane bond then generates the aro-
slightly lower than for the corresponding acetyl deriv- matic naphthyl skeleton and a stabilized carbenoid/
ative. No selective reaction was observed in the case cation intermediate VI is formed.[11] After a 1,2-mi-
of
a trifluoroacetate group as migrating group gration of a methyl group, elimination of the gold cat-
(entry 2). This is not unexpected as to the best of our alyst closes the catalytic cycle under formation of the
knowledge no successful gold-catalyzed 1,2-shifts final product 2a.
have ever been reported for this moiety. Shifting to
In conclusion, we have demonstrated that propar-
a benzoyl moiety restored the selectivity and a high gylic esters in the presence of a tethered alkyne can
yield of benzoyl-protected naphthol 2m was obtained undergo a carbene transfer reaction which leads to
(entry 3). We were able to grow single crystals suita- a benzyl-stabilized carbenoid/cation if aromatic back-
ble for an X-ray crystal structure analysis. The solid bones are applied. The effective use of propargylic
state molecular structure which delivers the final esters as carbenoid source for this type of chemistry
proof for
a
correct assignment is depicted in should pave the way for further useful transforma-
tions. This process should be driven by the easier han-
Figure 1.[8]
Slightly lower yields were obtained with a para-ni- dling of the starting materials combined with a faster
trobenzoyl group which might be explained by the de-
creased nucleophilicity of the carbonyl oxygen
(entry 4).
To expand the scope of the reaction substrate 3 was
reacted under the optimized conditions (Scheme 2).
Surprisingly, even though two competing pathways
(hydride shift vs. methyl shift) are possible, only prod-
uct 4 was observed. Under the same conditions that
were applied previously only a low yield of 24% and
no complete conversion were achieved. Even pro-
longed reaction times (20 h compared to 15 min for
the corresponding tert-butyl substrate 1a) did not de-
liver full conversion. The product was obtained as an
inseparable mixture of 4 and the remaining starting
material (3:4=2:1).
Our mechanistic proposal, as exemplified for 1a, is
depicted in Scheme 3. The first step of the reaction
cascade starts with the well known 1,2-migration of
an acetyl group which is known to be favoured for
terminal alkynes. The so formed vinyl carbene III can
then undergo an intramolecular cyclopropenation
event which might be assisted by the fixed geometry
of intermediate III. The feasibility of this elementary Figure 1. Solid state molecular structure of compound 2m.
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Carbene Transfer – A New Pathway for Propargylic Esters in Gold Catalysis
Table 3. Variation of the migrating group.
Entry
1
Substrate
Product
Time [min]
240
Yield [%]
85
1k
1l
2k
2l
[a]
2
3
60
–
1m
1n
2m
2n
20
88
42
4[b]
180
[a]
Unselective reaction.
10 mol% AuCl were employed.
[b]
purification system MB SPS-800. Oxygen-free, anhydrous
reactions were carried out under an atmosphere of nitrogen.
Reaction steps involving the synthesis of phosphorous li-
gands were carried out using dry and degassed solvents. To
degas the solvents, nitrogen was bubbled through them for
at least 1 hour.
access to potential starting materials. The search for
other synthetically useful transformations based on
this principle is ongoing in our laboratories.
Experimental Section
General Procedure 1 (GP1): Sonogashira Coupling
General Remarks
The aryl halide, 5 mol% of copper(I) iodide and 2.5 mol%
Chemicals were purchased from commercial suppliers and
used as delivered. Dry solvents were dispensed from solvent
of PdCl2ACHTNUGTRENUNG(PPh3)2 were dissolved in freshly degassed triethyla-
mine under an atmosphere of nitrogen. After stirring for
10 min a small excess of the terminal alkyne was added. The
resulting mixture was stirred at the mentioned temperature
until the reaction was completed. The solvent was removed
under reduced pressure and the crude product was purified
by column chromatography on silica gel.
General Procedure 2 (GP2): Grignard Reaction
Under an atmosphere of nitrogen the aldehyde was dis-
solved in THF. An excess of Grignard reagent was added
Scheme 2. Reaction of isopropyl substituted substrate 3.
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Scheme 3. Proposed mechanism.
and the mixture was stirred at room temperature until the References
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.
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General Procedure 3 (GP3): Introduction of an
Acetyl Protecting Group
The diyne-ol, 1.10 equiv. DMAP and 1.10 equiv. NEt3 were
dissolved in DCM and 1.10 equiv. acetic anhydride were
added under vigorous stirring. The reaction was monitored
by TLC. After complete conversion of the starting material
the reaction was quenched with a saturated solution of
NaHCO3. The aqueous layer was extracted with DCM and
the combined organic layers were dried with MgSO4, fil-
tered and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography
on silica gel.
General Procedure 4 (GP4): Gold Catalysis
400 mmol diyne were dissolved in 1 mL DCE. 20.0 mmol
(5 mol%) AuCl were added under vigorous stirring and the
mixtrure was heated to 808C. After complete consumption
of the starting material the solvent was removed under re-
duced pressure and the crude product was purified by
column chromatography.
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Acknowledgements
The authors thank Umicore AG & Co. KG for the generous
donation of gold salts. This work was supported by the DFG
(SFB 623).
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Carbene Transfer – A New Pathway for Propargylic Esters in Gold Catalysis
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8 Carbene Transfer – A New Pathway for Propargylic Esters
in Gold Catalysis
Adv. Synth. Catal. 2013, 355, 1 – 8
Tobias Lauterbach, Sabrina Gatzweiler, Pascal Nçsel,
Matthias Rudolph, Frank Rominger,
A. Stephen K. Hashmi*
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