Insights into the Gold-Catalyzed Propargyl Ester Rearrangement/Tandem Cyclization Sequence: Radical versus Gold Catalysis - Myers-Saito- versus Schmittel-Type Cyclization

Article abstract of DOI:10.1002/chem.201501725

A detailed study of the gold-catalyzed tandem 1,3-carboxy migration/allene-enyne cycloisomerization was undertaken. It was found that after the initial allene formation the selectivity of the reaction is strongly influenced by the polarization of the remaining alkyne. Depending on the substitution pattern of the starting diynes, either a Schmittel- or a Myers-Saito-type cyclization was triggered. The 6-endo-dig Myers-Saito-type cyclization gave access to benzo[b]fluorenes, while the Schmittel pathway (5-exo-dig) delivered benzofulvenes as final products. In special cases a yet unknown pathway was opened by the ambiphilic nature of the allene moiety. In these cases completely different products were obtained by the nucleophilic attack of the alkyne moiety onto the allene that can also act as an electrophile. Mechanistic studies revealed that diradical pathways can be ruled out for this type of tandem cyclization reactions and it is shown that both steps of the reaction cascade are catalyzed by the gold complex.

Full text of DOI:10.1002/chem.201501725

DOI: 10.1002/chem.201501725
Full Paper
&
Catalysis
Insights into the Gold-Catalyzed Propargyl Ester Rearrangement/
Tandem Cyclization Sequence: Radical versus Gold Catalysis—
Myers–Saito- versus Schmittel-Type Cyclization
Eva Rettenmeier,[a] Max M. Hansmann,[a] Alexander Ahrens,[a] Katharina Rübenacker,[a]
Tapish Saboo,[a] Joy Massholder,[a] Christian Meier,[a] Matthias Rudolph,[a] Frank Rominger,[a]
and A. Stephen K. Hashmi*[a, b]
Abstract: A detailed study of the gold-catalyzed tandem
1,3-carboxy migration/allene–enyne cycloisomerization was
undertaken. It was found that after the initial allene forma-
tion the selectivity of the reaction is strongly influenced by
the polarization of the remaining alkyne. Depending on the
substitution pattern of the starting diynes, either a Schmittel-
or a Myers–Saito-type cyclization was triggered. The 6-endo-
dig Myers–Saito-type cyclization gave access to benzo[b]-
fluorenes, while the Schmittel pathway (5-exo-dig) delivered
benzofulvenes as final products. In special cases a yet un-
known pathway was opened by the ambiphilic nature of the
allene moiety. In these cases completely different products
were obtained by the nucleophilic attack of the alkyne
moiety onto the allene that can also act as an electrophile.
Mechanistic studies revealed that diradical pathways can be
ruled out for this type of tandem cyclization reactions and it
is shown that both steps of the reaction cascade are cata-
lyzed by the gold complex.
Introduction
a transition-metal-catalyzed 1,3-acyl migration of propargyl
esters.[8] In the case of a gold-catalyzed 1,3-acyl shift, carboxyal-
lenes are generated that can act as a nucleophile[9] or electro-
phile[10] for further applications in tandem reactions.[11,12]
Toste et al. and Oh and Kim et al. combined a silver or gold-
catalyzed allene formation by 1,3-acyl migration of nonterminal
propargylic esters with a Myers–Saito-type enyne–allene cycli-
zation to form highly functionalized aromatic compounds
(Scheme 1a).[9e,11p] Liu et al. published a similar reaction using
propargyl carbonates instead of the corresponding esters.[13]
Here the resulting oxocarbenium ion formed in the gold-cata-
lyzed 6-endo-dig cyclization step could be further attacked by
the aryl moiety, giving rise to a second cyclization reaction
(Scheme 1b). In the case of an aliphatic backbone, Malacria,
Gandon, and Fensterbank et al. showed that a Schmittel-type
5-exo-dig enyne–allene cyclization proceeds (Scheme 1c).[14]
Just recently Chen et al. published a platinum-catalyzed reac-
tion using a similar 1,3-acyl migration strategy to obtain ben-
zofulvenes also through a Schmittel-type enyne–allene cycliza-
tion (Scheme 1d).[15]
Cycloisomerization reactions are a powerful and efficient
method for atom economic[1]CÀC bond formations. Among the
many investigated reactions the diyne and yne-allene cycliza-
tion reactions play a significant role in organic synthesis.[2] Sev-
eral strategies exist for which in a tandem process highly reac-
tive enyne-allene intermediates are initially formed that can
then undergo subsequent cycloisomerization reactions to val-
uable products.[3] Yne-allenes have been demonstrated to un-
dergo two main thermal diradical cyclization pathways:
1) Myers–Saito cyclization[4] and 2) Schmittel cyclization.[5] As
mentioned above, such substrates can be prepared in a stoi-
chiometric fashion[6] or by thermal rearrangement reactions.[7]
In addition there exist several reports on the transition-metal-
catalyzed formation of such yne-allene intermediates. One of
these strategies is the generation of the allene fragment by
[a] Dipl.-Chem. E. Rettenmeier, Dr. M. M. Hansmann, A. Ahrens, K. Rübenacker,
T. Saboo, J. Massholder, C. Meier, Dr. M. Rudolph, Dr. F. Rominger,+
Prof. Dr. A. S. K. Hashmi
Compared to the previously described reactions, which pro-
ceed through a tandem cyclization cascade in which both in-
dependent steps are postulated to be transition-metal-cata-
lyzed, Shi et al. reported a tandem reaction in which the
second step is an uncatalyzed radical Schmittel cyclization
(Scheme 2a).[16] In this case the pivotal intermediate, the
enyne-allene, is generated by a gold-catalyzed propargyl vinyl
rearrangement with a triazole gold catalyst. While most of the
starting materials are derived upon addition of a terminal
alkyne to benzaldehyde, propargyl esters containing the ester
Organisch-Chemisches Institut
Ruprecht-Karls-Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science, King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
[+] Crystallographic investigation
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501725.
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Results and Discussion
We started our investigation by
reacting propargyl acetate 1a
with 5 mol% of [IPrAuNTf2] in
CH2Cl2. In a fast reaction at room
temperature in less than 1 h we
could isolate a new product as
yellow solid. To our delight, we
were able to obtain single crys-
tals suitable for X-ray diffrac-
tion.[17] The solid-state structure
obtained by X-ray diffraction
analysis revealed a statistically
disordered isomer superposition
of 80% benzo[b]fluorene (2a)
and 20% benzofulvene (3a) (for
the visualization of the solid-
state structure of compound 2a,
see Figure 1). Based on 2D NMR
spectroscopic analysis we could
Scheme 1. Transition-metal-catalyzed tandem cyclization reactions of diyne acetates/carbonates.
functionality on the nonaromatic terminus, as depicted in
Scheme 2, are far less studied.
Herein we report a detailed study of such substituted prop-
argyl esters to form benzo[b]fluorenes and benzofulvenes by
a gold-catalyzed rearrangement/cyclization cascade. Compared
to the previous literature, one major focus is the electronic in-
fluence on the product distribution of Myers–Saito- and
Schmittel-type cyclization products as well as novel side path-
ways. Furthermore, the question if this transformation contains
two gold-catalyzed or a gold-catalyzed and a radical cyclization
step is addressed.
Figure 1. Solid-state molecular structure of compound 2a.
Scheme 2. Gold-catalyzed tandem cyclization reactions.
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ties of the phenyl group we observed varying product se-
lectivities. Using electron-donating substituents in the para
or ortho-position to the alkyne fragment shifted the ratio
between the two resulting isomers towards the Myers–
Saito-type product (isomer 2).
Table 1. Catalyst and solvent screening. Yields and isomeric ratio were deter-
mined by 1H NMR spectroscopic integration using 1,4-dioxane as an internal
standard.
Strong electron-donating substituents (OMe, 1c and 1d)
as well as weaker donating substituents (Me, 1e) induced
a significant shift towards the 6-endo-dig products 2c–
e (Table 2, entries 3–5). Importantly, the electron-rich sub-
strate containing three methyl groups on the phenyl
moiety gave rise to a single isomer 2 f (entry 6), which also
could be characterized by an X-ray single-crystal structure
analysis (Figure 2).[17] A methoxy group located at the ortho-
Entry Solvent
Catalyst
Yield [%] Isomeric ratio
1
2
3
4
5
6
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgOTf
[IPrAuCl]/AgPF6
[PPh3AuCl]/AgNTf2
[PPh3AuCl]/AgSbF6
87
70
83
81
5
80:20
79:21
77:23
76:24
76:24
80:20
21
7
CD2Cl2
traces
–
8
9
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
A/AgSbF6
11
47
54
17
–
42
5
8
81:19
57:43
58:42
74:26
–
86:14
74:26
69:31
–
[SPhosAuCl]/AgNTf2
[SPhosAuCl]/AgSbF6
AuCl3
10
11
12
13
14
15
16
[D8]toluene [IPrAuCl]/AgNTf2
[D8]toluene [IPrAuCl]/AgSbF6
CD3CN
CD3CN
CD2Cl2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgSbF6
AgNTf2
Figure 2. Solid-state molecular structure of compound 2 f. Hydrogen
atoms are omitted for clarity.
–
clearly assign this product to be an 80:20 mixture of 6-endo-
dig (Myers–Saito-type, 2a) and 5-exo-dig (Schmittel-type, 3a)
cyclization compounds.
position showed only little influence on the 2/3 isomeric ratio
(entry 7). A methoxy group in meta-position led to a mixture
of two sets of regioisomers in 48 and 43% yield—one pair
leading to 1,2,3-substitution on the aryl moiety in lower 2/3 se-
lectivity (2h, 3h), whereas the regioisomer with 1,3,4-substitu-
tion showed a high selectivity towards Myers–Saito-type cycli-
zation product 2h’ (entry 8). Similarly, we also obtained a high
selectivity of 91:9 towards 6-endo-dig cyclization product 2i in
the case of an electron-rich dimethoxy substitution (entry 9).
Switching to a bromide substituent in para-position showed
no significant influence on the selectivity of 81:19 (entry 10).
However, installing a methyl group at the ortho-position result-
ed in a clean formation of a single isomer (entry 11). Compar-
ing meta versus para-bromide substitution (1j vs. 1l) delivered
a similar high yield of 89% and a drop in selectivity that might
arise from the missing electron-donating mesomeric effect
(entry 12). Finally, installation of an electron-withdrawing
group (CF3, 1m) resulted in an increase of the Schmittel-type
cyclization product 3m (entry 13). Most of the reactions gave
moderate to excellent yields (60–91%, entries 1–2, 4–5, and 8–
13). In the case of a very strong electron-donating substituent,
the yield of the isomeric mixture decreased (13, 39, and 5%;
entries 3, 6, and 7) and a new byproduct was observed, which
in some cases could be isolated as the main product (entries 3
and 7; for a detailed discussion on this byproduct see below).
When switching from the acetyl to the pivaloyl ester, this side
We next performed
a catalyst and solvent screening
(Table 1). Different silver salts in the presence of [IPrAuCl] were
used for the pre-activation and tested in the cycloisomerization
reaction (Table 1, entries 1–4). Among the different counter
ions tested, AgNTf2 performed extraordinarily well to give an
80:20 (2a/3a) isomer mixture in 87% yield. Next we studied
the effect of different ligands on the reaction outcome (en-
tries 5–10). Except the SPhos-ligand (47, 54%; entries 9 and 10)
all other ligands tested performed poorly (entries 5–8). Gold(III)
was also able to catalyze the reaction in a similar isomeric ratio
as [IPrAuNTf2] but only in low yields (entry 11). As a next step,
different solvents were tested (entries 12–15). Even though in
toluene we could observe an increase in the isomeric ratio to-
wards the 6-endo-dig cyclization product (entry 13), the overall
obtained yield was not satisfying. In a control experiment just
AgNTf2 showed no desired product (entry 16). The optimized
conditions proved to be 5 mol% [IPrAuNTf2] in CH2Cl2. The in
situ generation of [IPrAuNTf2] with AgNTf2 and [IPrAuCl] gave
nearly identical results as employing the isolated, pre-activated
silver-free complex.
With the optimized conditions in hand, we investigated the
scope of the reaction. First, we varied the substituents on the
phenyl moiety (Table 2). Depending on the electronic proper-
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pathway could be completely
suppressed and a good yield of
79% was restored (entry 4).
Table 2. Synthesis of benzo[b]fluorene 2 and benzofulvene 3 under optimized reaction conditions. Reactions
were performed on a 0.25 mmol scale (0.13m in CH2Cl2). Isolated yields are indicated.
Next, we investigated the in-
fluence of different substituents
at the backbone of the proparg-
yl ester (R3; Table 3). Here, the
electron-donating
methoxy
group shifted the reaction to-
wards the 5-exo-dig cyclization
product and we obtained a 1:1
ratio of the two isomers (Table 3,
entry 1). Increasing the electron
density by adding another me-
thoxy group resulted in a favored
Schmittel-type cyclization and
for the first time we isolated
isomer 3 as our major product
(entry 2). As expected, changing
to electron-withdrawing groups
the 6-endo-dig cyclization prod-
uct was again favored and ob-
tained with an isomeric ratio of
up to 93:7 (entries 3–6). Taking
into account the high selectivity
of the favored 6-endo-dig cycliza-
tion with electron-rich aryl
groups (R2) and electron-defi-
cient backbones (R3), we com-
bined these trends in synthesiz-
ing compounds 1t–w. The cycli-
zation of propargyl esters con-
taining an acetyl group resulted
mainly (4t) and in two cases
even exclusively (4v, 4w) in the
formation of the byproduct as
mentioned earlier (entries 7, 9,
and 10). We were able to fully
characterize this side product
and to obtain crystals suitable
for X-ray diffraction proving the
exact connectivity (Figure 3).[17]
This side product arises from
the formal addition of acetic
acid, which is generated by elim-
ination of another molecule of
starting material. In the case of
the original cyclization reaction
we observed a high selectivity
for the Myers–Saito-type cycliza-
tion reaction isolating 2t as the
single isomer (Table 3, entry 7).
However, changing the acetyl
group by a pivaloyl group again
suppressed the side-product for-
mation and increased the yield
of 2u to 83% (entry 8).
Entry Product
Yield [%] Side product
85, 80:20
Yield [%]
1
2
3
91, 76:24
13, 92:8
26
4
5
79, 90:10
63, 89:11
6
7
39
32
31
5, 83:17
48, 76:24
43, 90:10
8
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Our proposed mechanism for
the reaction starts with the gold-
catalyzed 1,3-acyl shift forming
the enyne-allene I. Activation of
the lower alkyne unit by gold
coordination initiates two poten-
tial cyclization pathways: 1) 6-
endo-dig cyclization to form
naphthyl intermediate III (path a)
or 2) 5-exo-dig cyclization to
generate fulvene intermediate IV
(path b). In both cases, electro-
philic aromatic substitution gen-
erates the benzo[b]fluorene and
benzofulvene core V and VI fol-
lowed by aromatization and pro-
todeauration to close the cata-
lytic cycle (Scheme 3). Interest-
ingly, after the 1,3-acyl shift gold
can also activate the electron-
rich allene moiety rather than
the alkyne fragment. In this case
the alkyne acts as the nucleo-
phile to attack the gold-activat-
ed allenyl acetate to form inter-
mediate VII (path c). This species
is trapped by acetate presuma-
bly generated by the elimination
of HOAc from another molecule
of starting material to give rise
to the byproduct 4. The attack
of acetate proceeds exclusively
from the sterically less hindered
and not from the gem-dimethyl
side to give rise to a single
Table 2. (Continued)
Entry Product
Yield [%] Side product
Yield [%]
9
78, 91:9
10
11
12
84, 81:19
60
89, 67:33
13
60, 62:38
isomer. This mechanism is in accordance with the generation
of diacetate 4 in the case of electron-rich aryl groups as these
represent stronger nucleophiles and are superior in stabilizing
the vinyl cation VII. In addition, this pathway could be sup-
pressed by the installation of a sterically more demanding piv-
aloyl moiety that prevents the nucleophilic attack onto the
vinyl cation. Furthermore, the selectivity for the two cyclization
pathways (a and b) can be explained by the polarization of the
alkyne fragment. In the case of an electron-rich aryl group and
an electron-deficient backbone gold preferentially coordinates
towards the backbone controlling the selectivity for the 6-endo
cyclization pathway (path a) and vice versa.
To support our mechanism we synthesized propargyl esters
1x–z. Under optimized conditions, we isolated the elimination
products 5x–z (Scheme 4). In these cases, the addition to the
carbenium ion III is inhibited as either both ortho-positions are
substituted (1x, 1y) or the aryl moiety is substituted by an
alkyl chain (1z) giving rise to the elimination products 5x–z. In
case of 1x, the diacetate byproduct (4x) was obtained as the
major product and could also be isolated in trace amounts in
the case of the pivaloate 1y.
Figure 3. Solid-state molecular structure of compound 4w. Hydrogen atoms
are omitted for clarity.
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At this stage we could not
rule out a mechanism, which
Table 3. Synthesis of benzo[b]fluorene 2 and benzofulvene 3 under optimized conditions. Reactions were per-
formed on a 0.25 mmol scale (0.13m in CH2Cl2). Isolated yields are indicated.
proceeds through
a
domino
gold-catalyzed 1,3-acyl shift fol-
lowed by a radical Schmittel cyc-
lization as demonstrated by Shi
et al.[16] To prove our hypothesis
of a tandem gold-catalyzed reac-
tion rather than a gold-catalyzed
transformation followed by a rad-
ical cyclization, we independent-
ly synthesized allenyl acetate 6a
and 6x by copper-mediated
conjugate addition to the corre-
sponding yne-one.[18] Interesting-
ly, these compounds undergo
a very clean and selective radical
Schmittel cyclization to afford
the fulvenes 7a and 7x as single
isomers in quantitative yield
(Scheme 5). Remarkably, in the
case of yne-allene 6a, the gener-
ated diradical intermediate does
not undergo a further radical
cyclization but undergoes elimi-
nation to give the five-mem-
bered ring compound 7a. In the
case of compound 7x, we were
able to obtain single crystals for
X-ray diffraction clearly proving
the connectivity (Figure 4).[17]
The formation of the C2–C6
Schmittel products and not the
Entry
1
Product
Yield [%]
88, 50:50
Side product
Yield [%]
2
3
4
68, 12:88
83, 93:7
96, 86:14
5
6
87, 93:7
80, 85:15
corresponding
Myers–Saito
products is in agreement with
similar substrates bearing aryl
substitution on the alkyne frag-
ment.[5a,b,18,19]
7
8
9
18
83
32
However, reacting allenyl ace-
tate 6a under our optimized
gold catalysis conditions gave in
a very fast reaction rise to the
same product mixture of ben-
zo[b]fluorene 2a and benzoful-
vene 3a as previously observed
(Scheme 5a). In the case of allen-
yl acetate 6x under gold cataly-
sis we detected the formation of
the 6-endo cyclization/elimina-
tion product 5x (Scheme 5b). As
the thermal/radical reactions
give rise to different cyclization
products, these experiments
clearly demonstrate a domino
gold-catalyzed reaction and not
a domino gold/radical cyclization
with an allenyl acetate inter-
47
44
10
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Scheme 3. Proposed reaction mechanism.
Conclusion
We demonstrated a domino gold-catalyzed formation
of benzo[b]fluorenes and benzofulvenes from prop-
argyl esters. This involves the generation of allenyl
acetates by an 1,3-acyl shift followed by a gold-cata-
lyzed cyclization reaction. We studied the influence
of substitution on the aryl as well as on the back-
bone and could control Schmittel- and Myers–Saito-
type cyclization pathways by different polarizations
of the alkyne fragment. In specific cases, we were
able to change the selectivity towards the exclusive
formation of one cyclization product. Furthermore, new side
products, which arise from activation of the allene by gold co-
ordination could be isolated and fully characterized. This
switch in nucleophilic/electrophilc nature of the allene could
be controlled by substitution of the starting material and by
the choice of the migrating ester moiety. Mechanistically, a radi-
cal cyclization pathway could be ruled out by synthesizing in-
dependently the corresponding allene intermediates.
Scheme 4. Synthesis of cyclization/elimination products 5x–z.
mediate being involved. However, we were interested in using
triazole catalyst [Ph3PAu(triazole)OTf], which is known for gen-
erating the allene intermediate from propargylic esters without
catalyzing following cyclization reactions.[20] Unfortunately, this
reaction was unselective and based on in situ NMR spectra we
could identify small amounts of a twofold gold-catalyzed
domino transformation as well as the gold/radical cyclization
product.
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fçrderung) is acknowledged for a PhD scholarship of
E.R. M.M.H. is grateful to the Fonds der chemischen
Industrie for a Chemiefonds scholarship and to the
Studienstiftung des deutschen Volkes.
Keywords: alkynes · allenes · benzo[b]fluorenes ·
gold · propargylic carboxylates
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Acknowledgements
The authors thank Umicore AG & Co. KG for the generous don-
ation of gold salts. The LGFG Heidelberg (Landesgraduierten-
Chem. Eur. J. 2015, 21, 14401 – 14409
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Full Paper
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Received: May 3, 2015
Published online on August 20, 2015
Chem. Eur. J. 2015, 21, 14401 – 14409
www.chemeurj.org
14409
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim