A Silver-Catalyzed Modular Intermolecular Access to 6,6-Spiroketals

Article abstract of DOI:10.1002/adsc.201900988

A modular synthesis of 6,6-spiroketals via silver catalysis is reported. By combining an intermolecular Michael addition and a 6-endo-dig cyclization, this cascade reaction allows the modular preparation of highly substituted 6,6-spiroketals by combining two substrate molecules. Established methods accessing this interesting substructure are complemented by this new transformation. The protocol tolerates diverse substitution patterns and functional groups. (Figure presented.).

Full text of DOI:10.1002/adsc.201900988

Title: A Silver-Catalyzed Modular Intermolecular Access to 6,6-
Spiroketals
Authors: Alexander Ahrens, Niklas F. Heinrich, Simon R, Kohl, Martha
Hokamp, Matthias Rudolph, Frank Rominger, and A. Stephen
K. Hashmi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900988
Link to VoR: http://dx.doi.org/10.1002/adsc.201900988

10.1002/adsc.201900988
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Silver-Catalyzed Modular Intermolecular Access to 6,6-
Spiroketals
Alexander Ahrens,a Niklas F. Heinrich,a Simon R. Kohl,a Martha Hokamp,a Matthias
Rudolph,a Frank Rominger,a[+] A. Stephen K. Hashmia,b*
a
Organisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: (+49)-6221-54-4205; E-mail: hashmi@hashmi.de; Homepage: http://www.hashmi.de
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Crystallographic investigation
b
[+]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A modular synthesis of 6,6-spiroketals via silver
catalysis is reported. By combining an intermolecular
Michael addition and a 6-endo-dig cyclization, this cascade
reaction allows the modular preparation of highly
substituted 6,6-spiroketals by combining two substrate
molecules. Established methods accessing this interesting
substructure are complemented by this new transformation.
The protocol tolerates diverse substitution patterns and
functional groups.
Keywords: Spiroketals; Silver catalysis; Michael
addition; Enones; Alkynes
Introduction
The 6,6-spiroketal moiety is a structural motive of high
interest, which can be found in a variety of natural
products and other biologically active compounds
such as Reveromycines,[1] Rubromycines[2] and
Griseusines[3] (Figure 1). For example, Griseusin G
and especially F have been found to have cytostatic
properties with excellent efficiency against human cell
lines of melanoma, breast carcinoma, pancreatic
cancer, renal carcinoma and colon cancer.
Additionally, they possess antibacterial properties.[4]
Figure 1. Griseusin derivates found to have interesting
biological activity.
The development of synthetic methods towards
spiroketals has been an active field in organic
synthesis for decades. The most common and widely
used path towards spiroketals is based on the
intramolecular acid-assisted cyclization of dihydroxy
ketones. These intramolecular methods are mild and
tolerate a variety of other functional groups, which at
the same time limits the modularity of the synthetic
approach towards the target molecules; thus often
intermolecular convergent synthetic strategies are
used.[7] An alternative to this Brønsted acid based
approach is the intramolecular cyclization of
dihydroxy alkynes via π-acid catalysis.[8] This method
uses alkynes as less reactive surrogates for a ketone,
which enables the use in late stage steps in a complex
molecular environment and has been used in several
total synthesis, e.g. involving gold catalysis.[9]
Furthermore, several elegant and enantioselective
methods for 6,6-spiroketals have been published
Recently Brimble et al. published insightful reviews
on the potential of Griseusin derivates[3] and
spiroketals in natural products.[5] Still, predicting
structure-activity relation remains a challenge for
biological active molecules. This holds true for
Griseusin derivates, too.[6] In order to find efficient and
selective bioactive compounds which can be utilized
as drugs, derivatization of known compounds and
novel synthetic strategies enabling new substitution
patterns are needed.
1
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
recently,
using
different
metal
salts
or
organocatalysts.[10] Despite these advances, only a
limited number of intramolecular spiroketal
formations have been reported, which often require
highly reactive compounds such as organolithium
compounds or Grignard reagents, accompanied by a
low functional group tolerance. Here too, recent works
have improved the access to this moiety. Jiang et al.
introduced a silver salt-mediated transformations
using an 1-(2-ethynylphenyl)ethenone and Michael
acceptors.[11] The bimetallic and modular approach of
Feng et al. is also of note, combining a gold-catalyzed
cyclization with an enantioselective [4+2]
cycloaddition to unsaturated keto esters.[12]
Independently, Jiang et al. developed an analogous
synthetic cut, using silver and scandium synergistic
catalysis yielding racemic products.[13]
Beyond its appearance in natural products and
biologically active compounds of interest, the
6,6-spiroketal motif has been used as skeleton for
chiral ligands, enabling various transition-metal-
catalyzed asymmetric reactions.[14]
In this light, we set out to develop a mild transition
metal-catalyzed synthesis of the spiroketal
substructure via an intramolecular cyclization and an
intermolecular addition to yield the desired scaffold.
Results and Discussion
To access this, we envisioned that a Yamamoto-
type[15] π acid catalysis and a Michael addition might
deliver a partly unsaturated spiroketal. The cyclization
could either proceed as a 5-exo-dig or 6-endo-dig
transformation, with both possible modes contributing
a novel and convenient retrosynthetic disconnection
(Scheme 1).
Scheme 1. Schematic retrosynthetic disconnections of
spiroketals.
A strong nucleophile would assist the postulated
reactivity. Mayr et al. investigated the anions of 1,3-
diketones in this regard.[16] We deduced that dimedone
would be a suitable starting point for our desired
transformation. As acceptor a phenyl substituted 1-
propenone-5-ethynylbenzene was picked to explore
the reactivity.
Scheme 2. Initial finding of the desired reactivity.
With 5 mol% AuCl3 in DCM at room temperature a
full consumption of the starting material was observed
after 16 h. Column chromatography over silica gave
both the 5-exo-dig and 6-endo-dig products as a
mixture in an overall yield of 44%. They could be
identified by 1H and 13C NMR spectroscopy, as well as
HRMS. One of them was very clearly a major product,
however, a direct assignment proved difficult at that
point (Scheme 2).
Screenings were conducted to identify conditions for a
selective and efficient transformation, using
100 mg/ml 2a in absolute DCM with 1.2 equiv
dimedone and 4 Å molecular sieve under air. As keto-
enol tautomerism and Michael addition can be
influenced by acidic or basic conditions, different
additives were tested (Table 1).
2
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
Table 1. Screening of additives with 5 mol% AuCl3 as
Table 2. Screening of catalysts.
yield 8a)
yield 9aa)
catalyst.
Entry Catalyst (5 mol%)
Entry Additives
yield 8a)
yield 9aa)
1
AuBr3
4%
24%
23%
0%
1
2
3
none
10%
4%
34%
1%
2
Au(OAc)3
35%
0%
1 equiv Cs2CO3
3
IPrAu(bph)Cl/NaBArF
IPrAuCl3
10 mol% 2,6-di-tert-
butylpyridine
3%
33%
4
0%
0%
4
10 mol% HNTf2
4%
3%
0%
21%
26%
0%
5
IPrAu(MeCN)SbF6
(Ph)3PAu(MeCN)SbF6
0%
6%
5b)
6
10 equiv H2O
6
13%
4%
7
(RO3P)AuCl)b)/NaBArF 18%
30%
77%
0%
10 mol% Cs2CO3
a) Yield and quantity ratio of isomers were determined by
1H NMR spectroscopy with 1,4 dinitrobenzene as internal
standard in CDCl3, monitoring the peaks at 6.08 ppm for
product 8 and 6.72 ppm for product 9a. The protons of
interest are marked blue in Scheme 2. b) No molecular sieve
was added.
8
AgSbF6
1%
0%
0%
3%
0%
1%
0%
0%
9
IPrAgCl
10
11
12
13
14
15
IPrAgCl/NaBArF
Ag2CO3
98%
8%
AgNTf2
66%
72%
76%
55%
Neither the addition of a base nor Brønsted acid
additives gave the desired selectivity. Overall,
additives diminished the yield, especially with 1 equiv
of cesium carbonate as additive. For all reactions
(entries 1 to 4) conversions were completed within 16
h. Most likely, the additives induce side reactions or
decomposition of the enol ether products, which are
known to have a rich chemistry[17] and can easily
decompose via polymerization or fragmentation
reactions. If water was present (entry 5), a slight
decrease in yield but a better selectivity was observed.
HNTf2 alone decomposed the starting material over
the course of 16 h (entry 7), whereas base alone (entry
5) gave no conversion.
AgBF4
AgOTf
IPrCuCl/NaBArF
a) Yield and quantity ratio of isomers were determined by
1H NMR with 1,4-dinitrobenzene as internal standard in
CDCl3, monitoring the peaks at 6.08 ppm for product 8 and
6.72 ppm for product 9a. b) R = 2,4-di-tert-butylphenyl
With a selective method in hand, pure product could
be obtained by column chromatography and crystals
suitable for X-ray single crystal structure analysis were
gained by crystallization from DCM and pentane at
4 °C . The analysis enabled the assignment of 9a being
the 6-exo-dig product (Figure 2).[15]
Next, different gold(III), gold(I) catalysts as well as
other π-acidic transition metal complexes were tested
(Table 2).
Notably, gold(III) acetate (entry 2) gave a mixture with
poor selectivity, but with inverted major/minor
product ratio. None of the other applied gold(III)
compounds gave an improvement with respect to
gold(III) chloride. The same was true for gold(I)
complexes with varying electronic properties. In that
series the electron-poor phosphite complex (entry 7)
delivered the best yield but only a poor selectivity.
Next, different silver(I) salts were tested, which gave
good yields at high selectivity. To our delight, the
NHC complex IPrAgCl activated by NaBArF gave
almost quantitative conversion to a single isomer.
Copper(I) catalysts turned out to be less efficient than
the silver catalysts. With an optimized yield of 98%,
no further optimization was conducted.
Figure 2. Molecular structure of 9a in the crystal. Hydrogen
atoms were omitted for clarity.[15]
3
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
In addition, the other isomer could be crystallized from
a mixture of both products, obtained from a gold(III)-
catalyzed reaction, using DCM and pentane at 4 °C.
Allowing both compounds to by characterized by X-
ray single crystal structure analysis (Figure 3). [18]
(E)-chalcone was left to react with dimedone under
optimized conditions. (Scheme 3)
Scheme 3. Reaction of (E)-chalcone with dimedone under
conditions for catalysis.
No reaction was observed, as confirmed by TLC and
GCMS. On the basis of this experiment and the
obtained structures we postulate the following
mechanism (Scheme 4). After complexation of the
starting material by the carbophilic catalyst [M]+, the
carbonyl functionality can attack the activated alkyne,
giving intermediate II. This intermediate itself is a
cationic Michael system and can be attacked by the
enol form of dimedone. A proton is released in the
process, allowing the protodemetalation of the vinyl
metal species. Subsequently, the π-acidic metal cation
can now coordinate to and activate the novel enol ether
functionality of intermediate VI. The 1,3-diketone
substructure carries out a nucleophilic attack via its
oxygen atom on the enol ether, giving intermediate V.
After protodemetalation, the product is released and
the catalyst is regenerated and transferred to the next
substrate molecule.
Figure 3. Molecular structure of 8 in the crystal. Hydrogen
atoms omitted for clarity.[18]
The intramolecular Yamamoto-type cyclization[15] or
the intermolecular Michael addition could be the first
step of the transformation. Intramolecular reactions
should win over intermolecular ones. To confirm this,
Scheme 4. Postulated mechanism for the spiroketal
formation.
4
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
Next, we set out to determine the synthetic scope of
this new transformation. To test the functional group
tolerance, as well as the impact of steric and electronic
effects, two different strategies towards synthesizing
test substrates were applied. The variations of the
substitution of the alkyne R1 and alkene R2 start from
2-iodoacetophenone (Scheme 5). The alkyne is
introduced via a Sonogashira coupling. The cheaper
alternative 2-bromoacetophenone gave inferior yields
under the same conditions (less than 30%). Finally, a
cross aldol condensation forms the enone moiety.
Scheme 5. Synthesis of test substrates via aldol
condensation.
An alternative synthetic approach (Scheme 6) gave
access to a wider range of substitution patterns of the
enone, as some are not that easily accessible by an
aldol reaction. After a Sonogashira coupling, the olefin
is introduced by a Grignard addition. The resulting
alcohols 4 were then oxidized with Dess-Martin
periodinane. The slightly unstable ynone substrate 7
was synthesized in a similar fashion.
Figure 4. Synthesized test substrates and overall yields.
These test substrates were converted under the
optimized conditions in dry DCM with molecular
sieve (4 Å), 1.2 equiv of dimedone, but half of the
catalyst loading (Scheme 7). The reactions usually
took 16-20 h and the products could be purified by
column chromatography on silica gel.
Scheme
6.
Substrate
synthesis
via
Grignard
reaction/oxidation.
Overall, eleven test substrates were obtained (Figure
4) in acceptable to good overall yields.
5
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
sensitivity of the substrates and products which easily
decompose. The other examples demonstrate that the
transformation is highly tolerant towards steric and
electronic variations of the scaffold. Electron-donating
(9b and 9f), electron-withdrawing (9e and 9g) and
sterically demanding (9c) groups have little influence
on the yield. Alkyl-substituted products 9i can also be
obtained in good yields. Brominated compounds 9e
are also accessible in good yield, allowing further
functionalization e.g. by cross coupling reactions.
Although 5 mol% of NaBArF were used while
exploring the reaction scope, a later experiment using
substrate 2a confirmed that using 2.5 mol% IPrAgCl
and 2.5 mol% NaBArF affected neither the yield nor
the reaction time.
The products can be stored in a freezer for months.
However, they all show signs of slow decomposition
in solution at room temperature. Some products were
isolated as a mixture with a second unknown
compound with up to 5% impurity as determined by
1H NMR spectroscopy. This compound could not be
separated
by
column
chromatography,
recrystallization or preparative TLC and could also not
be identified.
Next, we tested the applicability of a simple ketone
and a silyl enol ether (Figure 5).
Figure 5. Ketone and silyl enol ether tested as nucleophile.
Again, optimized conditions in dry DCM with
molecular sieve (4 Å) and half of the original catalyst
loading were used (Scheme 8). As no reaction took
place over the course of 16-20 h, additives were tested
(Table 3).
Table 3. Reaction conditions for nucleophiles.
Entry Nucleophile
Additive
Yield
1
2
3
acetone
acetone
none
0%
0%
0%
3 equiv Cs2CO3
TMSO-ethene 1.5 equiv CsF
4
TMSO-ethene 1.5 equiv MeOH 0%
Scheme 7. Catalysis and scope of products.
For all substrates the catalytic transformation was
successful and selective. The yields are mostly good,
with the exceptions of 8k and 8i with yields of 25%
and 15%, respectively. This can be explained by the
6
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
However, no improvement could be observed. Other
1,3-diketones were tested as nucleophiles under
optimized conditions (Scheme 8).
methodologies that are most often based on
intramolecular procedures. Our method tolerates a
variety of functional groups, allowing easy further
manipulation of the products. While some limitations
regarding the nucleophile are present, the
intermolecular construction of the spirocyclic core
should enable modular synthetic approaches which are
of high interest for medicinal chemistry. The found
reactivity can provide alternative synthetic pathways
towards interesting biological active targets such as
members of the griseusine family.
Experimental Section
General Procedure for a Silver Catalysis:
In a vial 1 equiv of the substrate, 2.5 mol% of IPrAgCl
and1.5 equiv of the nucleophile were dissolved in DCM.
Molecular sieve (4 Å) and 2.5 mol% of NaBArF were added
at room temperature and the reaction mixture was stirred
until the reaction was finished, as confirmed by TLC. The
solvent was removed under vacuum and the raw product
was purified using column chromatography with silica gel.
(Z)-3'-Benzylidene-7,7-dimethyl-4-phenyl-3,4,7,8-
tetrahydro-3'H-spiro[chromene-2,1'-isobenzofuran]-
5(6H)-one (8)
80 mg (260 µmol) of 2a was dissolved in 1.5 ml dry DCM.
54.6 mg of dimedone (390 µmol, 1.5 equiv), 84.5 mg of
Cs2CO3 (260 µmol, 1.0 equiv) and 7.88 mg (26.0 µmol, 10
mol%) AuCl3 were added successively and the reaction
mixture was stirred at room temperature for 16 h. After the
reaction was finished, as confirmed by TLC, the solvent was
removed in vacuo. Column chromatography using silica and
PE/EA 20/1 as eluent, gave the title compound as a colorless
crystalline sold (22 mg, 49.1 µmol, 10/1 8/9a mixture as
determined by 1H NMR spectroscopy, 16%).
Scheme 8. Catalysis and scope with 1,3-dicarbonyl
compounds as nucleophiles.
The catalysis works well with 1,3-diketones, however,
simple acetone – with and without base – showed no
conversion, which we attributed to the lower
nucleophilicity. The silyl vinyl ether also gave no
significant conversion, even in presence of classical
activation agents like methanol and fluoride. More
flexible 1,3-diketones like acetylacetone and
cycloheptane-1,3-dione gave lower yields than their
more rigid relatives. Additionally, for cycloheptane-
1,3-dione the formation of several unidentified side
products was observed.
R (PE/EA 5:1) = 0.44; 1H NMR (400 MHz, CD2Cl2,
f
25 °C, TMS): δ = 7.71 – 7.69 (m, 2H), 7.66 – 7.64 (m, 1H),
7.54 – 7.50 (m, 1H), 7.45 – 7.43 (m, 2H), 7.37 – 7.24(m,
6H), 7.22 – 7.18 (m, 1H), 6.12 (s, 1H), 4.19 (ddt, J = 11.7,
7.6, 2.1 Hz, 1H), 2.47 – 2.42 (m, 3H), 2.32 (dd, J = 17.5, 2.6
Hz, 1H), 2.25 (s, 2H), 1.19 (s, 3H), 1.08 (s, 3H) ppm;13C
NMR (100 MHz, CD2Cl2, 25 °C): δ = 196.7 (s, 1C), 169.7
(s, 1C), 152.3 (s, 1C), 145.8 (s, 1C), 139.1 (s,1C), 135.9 (s,
2C), 135.5 (s, 1C), 131.2 (d, 1C), 130.0 (d, 1C), 129.2 (d,
2C), 129.1 (d, 2C), 129.1 (d, 2C), 127.6 (d, 1C), 126.9 (d,
1C), 126.5 (d, 1C), 122.8 (s, 1C), 120.6 (s, 1C), 114.8 (s,
1C), 109.3 (s, 1C), 100.13 (d, C), 51.8 (t, 1C), 43.1 (t, 1C),
41.5 (t. 1C), 35.4 (d, 1C), 32.5 (s, 1C), 29.2 (q, 1C), 28.3 (q,
1C) ppm, IR (refl.): ṽ = 3058, 3024, 2956, 1661, 1623, 1600,
1493, 1467, 1451, 1426, 1375, 1360, 1286, 1214, 1188,
1159, 1116, 1102, 1076, 1058, 1015, 988, 955, 926, 902,
870, 827, 765, 746, 702, 618 cm-1; HRMS (EI(+), 70 eV):
[C31H28O3]+: calculated 448.2033, found 448.2038; mp =
139 °C.
Conclusion
In conclusion, we have developed a novel highly
selective method to prepare diversely substituted 6,6-
spiroketals by means of silver catalysis. Due to the
high importance as privileged structure in natural
products this completely different approach towards
this structure nicely complements existing
7
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
1659, 1625, 1510, 1495, 1456, 1372, 1300, 1287, 1246,
1215, 1176, 1161, 1103, 1069, 1042, 1026, 1042, 1026, 991,
958, 940, 909, 841, 761, 729, 691, 647 cm-1; HRMS
(DART(+)): [C32H30O4]+H+: calculated 479.2217, found
479.2215; mp = 180 °C.
7,7-Dimethyl-3’,4-diphenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1’-isochromen]-5(3H)-one
(9a)
60.0 mg (195 µmol) of 2a, 40.9 mg (292 µmol, 1.5 equiv)
of dimedone, 5.18 mg (9.80 µmol, 2.5 mol%) of IPrAgCl,
8.44 mg of (9.80 µmol, 2.5 mol%) of NaBArF and 500 µl
of DCM were used. After recrystallization from DCM/PE
the product was obtained as a yellow crystalline solid (80.2
mg, 179 µmol, 92%).
4-Mesityl-7,7-dimethyl-3'-phenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1'-isochromen]-5(3H)-one
(9c)
50.0 mg (143 µmol, 1.0 eq) of 2c, 24.0 mg (171 µmol,
1.2 equiv) of dimedone and 1.90 mg (3.60 µmol, 2.5 mol%)
of IPrAgCl were dissolved in 0.5 mL of DCM. Then
NaBArF (3.10 mg, 3.60 µmol, 2.5 mol%) were added and
the mixture was stirred for 18 h. Purification by preparative
TLC (PE:EA = 5:1, Rf = 0.43) gave the title product as
orange solid (50.2 mg, 106 µmol, 74 %).
R (PE/EA 5:1) = 0.44; 1H NMR (300 MHz, CD2Cl2,
f
25 °C): δ = 7.70 – 7.67, 7.47 – 7.27, 7.25 – 7.22, 6.72 (s,
1H), 4.36 – 4.29 (s, 1H), 2.82 – 2.64 (m, 2H), 2.32 – 2.06
(m, 4H), 1.11 (s, 3H); 0.93 (s, 3H) ppm; 13C NMR (100
MHz, CD2Cl2, 25 °C) δ 196.6 (s, 1C), 167.4 (s, 1C), 149.6
(s, 1C), 146.1 (s, 1C), 134.4 (s, 1C), 131.4 (s,1C), 130.5 (d,
1C), 129.8 (d, 1C), 129.3 (d, 2C), 129.0 (d, 2C), 127.8 (d,
2C), 127.8 (d, 2C), 126.6 (d, 1C), 125.8 (d, 1C), 125.4 (d,
2C), 124.3 (d, 1C), 114.9 (s, 1C), 101.7 (d, 1C), 99.6 (s,
1C), 51.7 (t, 1C), 42.9 (t, 1C), 40.8 (t, 1C), 35.6 (d, 1C),
32.1 (s, 1C), 29.3 (q, 1C), 28.0 (q, 1C) ppm; IR (refl.): ṽ =
3027, 2951, 2929, 2857, 1655, 1641, 1620, 1514, 1491,
1465, 1454, 1376, 1358, 1341, 1287, 1257, 1222, 1207,
1159, 1103, 1067, 1042, 1024, 990, 957, 940, 912, 902, 894,
851, 837, 810, 778, 756, 742, 698, 684, 664, 644, 628 cm-1;
HRMS (DART(+)): [C31H28O3]+H+: calculated 449.2111,
found 449.2117; mp = 165 °C.
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ =7.72 – 7.67
(m, 2H), 7.45 – 7.41 (m, 2H), 7.40 – 7.34 (m, 3H),
7.34 – 7.29 (m, 2H), 6.91 (bs, 1H), 6.81 (bs, 1H) 6.71 (s,
1H), 4.85 – 4.78 (m, 1H), 2.97 – 2.89 (m, 1H), 2.65 – 2.57
(m, 1H), 2.50 (s, 3H), 2.36 – 2.27 (m, 1H), 2.34 – 2.26 (m,
1H), 2.33 (s, 3H), 2.27 (s, 3H), 2.18 – 2.13 (m, 1H),
2.05 – 1.99 (m, 1H), 1.05 (s, 3H), 0.88 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3, 25 °C) δ = 197.0 (s, 1C), 165.6 (s,
1C), 149.1 (s, 1C), 137.2 (s, 1C), 136.6 (s, 1C), 135.5 (s,
1C), 134.6 (s, 1C), 134.1 (s, 1C), 131.1 (d, 1C), 131.0 (s,
1C), 130.2 (d, 1C), 129.7 (d, 1C), 129.4 (d, 1C), 128.9 (d,
2C), 128.4 (s, 1C), 127.6 (d, 1C), 125.6 (d, 1C), 124.9 (d,
2C), 123.8 (d, 1C), 116.1 (s, 1C), 101.5 (d, 1C), 99.6 (s, 1C),
51.3 (t, 1C), 42.7 (t, 1C), 34.6 (t, 1C), 32.4 (s, 1C), 29.5 (d,
1C), 29.4 (q, 1C), 28.3 (q, 1C), 21.4 (q, 1C), 21.1 (q, 1C),
20.5 (q, 1C) ppm; IR (relf.): ṽ = 2955, 2926, 2869, 1793,
1732, 1661, 1633, 1491, 1456, 1370, 1288, 1213, 1151,
1102, 1068, 1044, 1026, 990, 957, 932, 905. 852, 811, 762,
691, 615 cm-1; HRMS (DART(+)): [C34H34O3]+H+:
calculated 491.2581, found 491.2582; mp = 140 °C.
4-(4-Methoxyphenyl)-7,7-dimethyl-3'-phenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1'-isochromen]-5(3H)-one
(9b)
59.8 mg (176 µmol, 1.0 eq) of 2b, 29.7 mg (212 µmol,
1.2 eq) of dimedone and 2.40 mg (4.40 µmol, 2.5 mol%) of
IPrAgCl were dissolved in 0.5 mL of DCM. Then 3.80 mg
(4.40 µmol, 2.5 mol%) of NaBArF were added and the
mixture was stirred for 18 h. Purification by preparative
TLC (PE:EA = 5:1, Rf = 0.50) gave the title product as
orange solid (46.3 mg, 96.8 µmol, 55%).
7,7-Dimethyl-4-phenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1'-isochromen]-5(3H)-one
(9d)
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ = 7.70 – 7.65
(m, 2H), 7.44 – 7.40 (m, 3H), 7.38 – 7.35 (m, 2H),
7.33 – 7.29 (m, 2H), 7.26 – 7.22 (m, 2H), 6.92 – 6.87 (m,
2H), 6.69 (s, 1H), 4.38 – 4.31 (m, 1H), 3.82 (s, 1H),
2.83 – 2.77 (m, 1H), 2.74 – 2.66 (m, 1H), 2.31 – 2.26 (m,
1H), 2.26 – 2.21 (m, 1H), 2.20 – 2.15 (m, 1H), 2.14 – 2.08
(m, 1H), 1.12 (s, 3H), 0.94 (s, 3H, H) ppm; 13C NMR (100
MHz, CDCl3, 25 °C) δ = 196.9 (s, 1C), 167.1 (s, 1C),
158.3 (s, 1C), 149.2 (s, 1C), 137.3 (s, 1C), 134.1 (s, 1C),
131.0 (s, 1C), 130.2 (d, 1C), 129.4 (d, 1C), 129.0 (d, 2C),
128.3 (d, 2C), 128.2 (s, 1C), 127.5 (d, 1C), 125.5 (d, 1C),
125.1 (d, 2C), 123.9 (d, 1C), 115.0 (s, 1C), 114.4 (d, 2C),
101.5 (d, 1C), 99.4 (s, 1C), 55.5 (d, 1C), 51.5 (t, 1C), 42.7
(t, 1C), 40.6 (t, 1C), 34.4 (d, 1C), 31.9 (s, 1C), 29.3 (q, 1C),
27.9 (q, 1C) ppm; IR (refl.): ṽ = 2956, 2834, 2248, 1733,
50.5 mg (217 µmol, 1.0 eq) of 2d, 36.6 mg (261 µmol,
1.2 equiv) of dimedone and 2.9 mg (5.4 µmol, 2.5 mol%) of
IPrAgCl were dissolved in 0.5 mL of DCM. Then 4.6 mg
(5.4 µmol, 2.5 mol%) of NaBArF were added and the
mixture was stirred for 18 h. Purification by preparative
TLC (PE:EA = 2:1, Rf = 0.27) gave the title product as
orange solid (51.7 mg, 139 µmol, 64 %).
1H-NMR (300 MHz, CDCl3, 25 °C, TMS) δ = 7.40 – 7.33
(m, 2H), 7.32 – 7.28 (m, 2H), 7.28 – 7.24 (m, 3H),
3
7.20 – 7.15 (m, 2H), 6.61 (d, J = 6.0 Hz, 1H), 6.06 (d,
3J = 6.0 Hz, 1H), 4.14 – 4.07 (m, 1H), 2.70 – 2.63 (m, 1H),
2.58 – 2.50 (m, 1H), 2.31 – 2.28 (m, 2H), 2.22 (s, 2H), 1.16
(s, 3H), 1.07 (s, 3H) ppm;13C-NMR (100 MHz, CDCl3,
8
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10.1002/adsc.201900988
Advanced Synthesis & Catalysis
25°C) δ = 196.7 (s, 1C), 167.2 (s, 1C), 145.3 (s, 1C),
141.6 (d, 1C), 130.1 (d, 1C), 129.6 (s, 1C), 128.8 (d, 2C),
128.3 (s, 1C), 127.7 (d, 1C), 127.3 (d, 2C), 126.4 (d, 1C),
124.8 (d, 1C), 124.2 (d, 1C), 114.8 (s, 1C), 105.8 (d, 1C),
98.9 (s, 1C), 51.3 (t, 1C), 42.7 (t, 1C), 40.8 (t, 1C), 35.1 (d,
1C), 31.9 (s, 1C), 29.7 (q, 1C), 27.9 (q, 1C) ppm; IR (refl.):
ṽ = 3062, 3027, 2958, 2890, 2870, 2247, 1732, 1712, 1659,
1629, 1492, 1468, 1454, 1374, 1215, 1162, 1102, 1068,
1041, 990, 960, 941, 911, 881, 844, 772, 757, 732, 699, 659,
646, 612 cm-1; HRMS (DART(+)): [C25H24O3]+H+:
calculated 373.1798, found 373.1796; mp = 107 °C.
(m, 4H), 6.80 – 6.74 (m, 2H), 6.49 (s, 1H, H7), 4.70
– 4.59 (m, 1H), 3.24 (s, 3H), 2.64 – 2.58 (m, 2H), 2.10 (s,
2H), 2.05 – 1.92 (m, 2H), 0.80 (s, 3H), 0.58 (s, 3H)
ppm; 13C NMR (75 MHz, C6D6, 25 °C): δ = 194.9 (s, 1C),
166.0 (s, 1C), 161.2 (s, 1C), 149.5 (s, 1C), 145.9 (s, 1C),
131.8 (s, 1C), 129.9 (d, 1C), 128.8 (d, 1C), 128.3 (d, 1C),
128.2 (s, 1C), 127.8 (d, 2C), 126.9 (s 1C), 126.7 (d, 2C),
126.4 (d, 2C), 125.1 (d, 1C), 124.2 (d, 1C), 115.1 (s, 1C,
C18), 114.5 (d, 2C), 100.0 (d, 1C), 99.4 (s, 1C), 54.9 (q,
1C), 51.3 (t, 1C), 42.4 (t, 1C), 40.8 (t, 1C), 35.8 (d, 1C),
31.4 (s, 1C), 28.7 (t, 1C), 27.6 (t, 1C) ppm; IR (refl.): ν˜
= 2952, 1738, 1657, 1630, 1601, 1511, 1490, 1464,
1452, 1421, 1375, 1291, 1247, 1216, 1177, 1161, 1114,
1104, 1065, 1044, 1031, 989, 960, 937, 913, 841, 811,
799, 776, 754, 742, 703, 675, 643, 628 cm-1; HRMS
(EI(+)): calcd. for [C32H30O4]+: calculated 478.21386,
found 478.21263; mp = 183 °C.
4-(4-Bromophenyl)-7,7-dimethyl-3'-phenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1'-isochromen]-5(3H)-one
(9e)
20.7 mg (53.5 µmol, 1.0 equiv) of 2e, 8.99 mg (64.1 µmol,
1.2 eq) of dimedone and 0.7 0mg (1.40 µmol, 2.5 mol%) of
IPrAgCl were dissolved in 0.1 mL of DCM. Then 1.20 mg
(1.40 µmol, 2.5 mol) of NaBArF were added and the
mixture was stirred for 20 h. Purification by column
chromatography (PE:EA = 20:1, Rf = 0.41) gave the title
product as orange solid (23.3 mg, 44.4 µmol, 83%).
7,7-Dimethyl-4-phenyl-3’-(4-(trifluoromethyl)phenyl)-
4,6,7,8-tetrahydrospiro[chro- mene-2,1’-isochromen]-
5(3H)-one (9g)
48.7 mg (129 µmol, 1.0 equiv) of 2g, 27.2 mg (194 µmol,
1.5 equiv) of dimedone, 1.71 mg (3.33 µmol, 2.5 mol %) of
IPrAgCl, 2.88 mg (3.44 µmol, 2.5 mol %) of NaBArF and
500 µl of DCM were used. After recrystallization from
DCM/PE the product was obtained as a yellow crystalline
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ = 7.66 – 7.63
(m, 2H), 7.47 – 7.43 (m, 3H), 7.40 – 7.35 (m, 4H),
7.34 – 7.30 (m, 2H), 7.20 – 7.18 (m, 2H), 6.69 (s, 1H),
4.35 – 4.31 (m, 1H), 2.81 – 2.76 (m, 1H), 2.66 – 2.61 (m,
1H), 2.30 – 2.26 (m, 1H), 2.26 – 2.20 (m, 1H), 2.20 – 2.16
(m, 1H), 2.16 – 2.10 (m, 1H), 1.10 (s, 3H), 0.93 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3, 25 °C) δ = 196.9 (s, 1C), 167.7
(s, 1C), 149.1 (s, 1C), 144.1 (s, 1C), 133.9 (s, C), 132.0 (d,
2C), 131.0 (s, 1C), 130.4 (d, 1C), 129.5 (d, 1C), 129.1 (d,
2C), 129.0 (d, 2C), 127.8 (s, 1C), 127.6 (d, 1C), 125.6 (d,
1C), 125.0 (d, 2C), 123.9 (d, 1C), 120.1 (s, 1C) 114.2 (s, 1C),
101.5 (d, 1C), 99.2 (s, 1C), 51.3 (t, 1C), 42.6 (t, 1C), 40.2 (t,
1C), 34.8 (d, 1C), 32.0 (s, 1C), 29.3 (q, 1C), 27.9 (q, 1C)
ppm; IR (refl.): ṽ = 2962, 2926, 2846, 1640, 1615, 1510,
1480, 1464, 1373, 1358, 1338, 1292, 1265, 1222, 1205,
1113, 1076, 1053, 1021, 990, 958, 945, 916, 900, 850, 843,
812, 778, 758, 740, 700, 684, 662, 644 cm-1; HRMS (EI(+)):
[C31H27O3Br]: calculated 526.1144, 528.1123; found
526.1107; 528.1130; mp = 195 °C.
solid (55.5 mg, 120 µmol, 93%).
1
R (PE/EA 5:1) = 0.48; H- NMR (300 MHz, C6D6, 25 °C,
f
TMS): δ = 7.56 – 7.52 (m, 2H), 7.40 – 7.36 (m, 2H), 7.35
– 7.26 (m, 4H), 7.22 – 7.17 (m, 1H), 7.15 – 6.92 (m, 4H),
6.46 (s, 1H), 4.58 – 4.50 (m, 1H), 2.57 (d, J=9.4 Hz, 2H),
2.10 – 1.78 (m, 4H), 0.77 (s, 3H), 0.51 (s, 3H) ppm;
13C NMR (75 MHz, C6D6, 25 °C): δ = 194.8 (s, 1C), 165.6
(s, 1C), 147.8 (s, 1C), 145.6 (s, 1C), 137.6 (s, 1C), 130.7
(s, 1C), 130.0 (d, 2C), 128.9 (d, 2C), 128.3 (d, 1C),
128.2 (s, 1C), 128.1 (d, 1C), 127.9 (s, 1C), 127.7 (d, 2C),
126.5 (d, 1C), 126.0 (s, 1C), 125.6 (d, 1C), 125.2 (d,
2C), 124.3 (d, 1C), 115.0 (s, 1C), 103.6 (d, 1C), 99.2
(s,1C), 51.3 (t, 1C), 42.3 (t, 1C), 40.7 (t, 1C), 35.7 (d,
1C), 31.5 (s, 1C), 28.4 (t, 1C), 27.7 (t, 1C) ppm; 19F
NMR (283 MHz, C6D6, 25 °C): δ = -62.29 (s) ppm; IR
(refl.): ṽ = 3052, 2980, 2876, 2860, 1732, 1725, 1660, 1625,
1495, 1470, 1458, 1370, 1220, 1174, 1100, 1065, 1040, 990,
958, 942, 912, 881, 845, 757, 730, 699, 658 cm-1; HRMS
(EI(+)): [C32H27O3F3]+: calculated 516.19068, found
516.19027; mp = 95 °C.
3’-(4-Methoxyphenyl)-7,7-dimethyl-4-phenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1’-isochromen]-5(3H)-one
(9f)
50.0 mg (148 µmol, 1.0 equiv) of 2f, 31.1 mg (222 µmol,
1.5 equiv) of dimedone, 1.90 mg (3.70 µmol, 2.5 mol %) of
IPrAgCl, 3.20 mg (3.70 µmol, 2.5 mol%) of NaBArF and
500 µlof DCM were used. After column chromatography
using PE/EA 10:1 and recrystallization from DCM/PE the
product was obtained as a white solid (61.5 mg, 128 µmol,
87%).
R (PE/EA 5:1) = 0.18; H NMR (300 MHz, C6D6, 25 °C,
f
TMS): δ = 7.72 – 7.66 (m, 2H), 7.41 – 7.35 (m, 2H),
7.32 – 7.25 (m, 2H), 7.22 – 7.18 (m, 1H), 7.14 – 6.91
7,7-Dimethyl-3'-phenyl-4,6,7,8-
tetrahydrospiro[chromene-2,1'-isochromen]-5(3H)-one
(9h)
40.0 mg (172 µmol, 1.0 eq) of 5a, 29.0 mg (207 µmol,
1.2 equiv) of dimedone and 2.30 mg (4.30 µmol, 2.5 mol%)
of IPrAgCl were dissolved in 0.1 mL of DCM. Then
3.70 mg (4.30 µmol, 2.5 mol%) of NaBArF was added and
the mixture was stirred for 20 h. Purification by column
chromatography (PE:EA = 5:1, Rf = 0.29) gave the title
product as lightly orange oil (9.80 mg, 26.3 µmol, 15%).
1
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900988
Advanced Synthesis & Catalysis
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ = 7.65 – 7.61
(m, 2H), 7.44 – 7.40 (m, 2H), 7.37 – 7.35 (m, 1H),
7.35 – 7.33 (m, 2H), 7.33 – 7.28 (m, 2H), 6.64 (s, 1H),
2.80 – 2.72 (m, 2H), 2.61 – 2.50 (m, 2H), 2.29 (d,
3J = 1.9 Hz, 2H), 2.21 – 2.05 (m, 2H), 1.02 (s, 3H), 0.95 (s,
3H) ppm;13C NMR (100 MHz, CDCl3, 25 °C) δ = 198.5 (s,
1C), 166.9 (s, 1C), 149.3 (s, 1C), 134.3 (s, 1C) 131.1 (s, 1C),
130.1 (d, 1C), 129.4 (d, 1C), 128.9 (d, 2C), 128.7 (s, 1C),
127.5 (d, 1C), 125.5 (d, 1C), 125.1 (d, 2C), 123.9 (d, 1C),
111.1 (s, 1C), 101.3 (d, 1C), 99.3 (s, 1C), 51.1 (t, 1C), 42.4
(t, 1C), 32.5 (s, 1C), 28.7 (q, 1C), 28.6 (t, 1C), 28.4 (q, 1C),
14.9 (t, 1C) ppm, IR (refl.): ṽ = 3050, 3022, 2980, 1660,
1618, 1597, 1492, 1465, 1450, 1363, 1355, 1280, 1216,
1190, 1149, 1123, 1102, 1066, 1015, 986, 953, 902, 865,
820, 763, 742, 700, 625 cm-1; HRMS (DART(+)):
[C25H24O3]+H+: calculated 373.1798, found 373.1798.
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ =7.65 – 7.6 (m,
2H), 7.36 – 7.29 (m, 3H, H), 7.24 (dt, 3J = 7.4 Hz,
4J = 1.2 Hz, 1H), 7.17 – 7.14 (m, 1H), 7.14 – 7.09 (m, 1H),
6.84 – 6.80 (m, 1H), 6.39 (s, 1H), 4.97 (d, 3J = 3.4 Hz 1H),
3
4.81 (d, J = 3.4 Hz 1H), 2.67 – 2.55 (m, 2H), 2.40 – 2.30
(m, 2H), 1.24 (s, 3H), 1.23 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3, 25 °C) δ = 191.8 (s, 1C), 176.1 (s, 1C), 164.8
(s, 1C), 150.3 (s, 1C), 135.4 (s, 1C), 130.8 (s, 1C), 129.8 (s,
1C), 128.9 (d, 1C), 128.9 (d, 1C), 128.5 (d, 2C), 127.4 (d,
1C), 125.6 (d, 2C), 125.2 (d, 1C), 125.1 (d, 1C), 116.1 (s,
1C), 100.9 (d, 1C), 94.6 (t, 1C), 84.1 (s, 1C), 52.2 (t, 1C),
37.9 (t, 1C), 34.4 (s, 1C), 29.0 (q, 1C), 28.9 (q, 1C) ppm; IR
(refl.): ṽ = 3065, 3030, 2956, 2892, 2871, 2245, 1730, 1715,
1662, 1625, 1482, 1464, 1450, 1380, 1214, 1160, 1103,
1067, 1040, 990, 960, 942, 911, 880, 843, 771, 760, 732,
701, 657, 646, 610 cm-1; HRMS (DART(+)):
[C22H23O3]+H+: calculated 371.1642, found 371.1641; mp =
117 °C.
3,4,7,7-Tetramethyl-3'-phenyl-4,6,7,8-tetrahydrospiro
[chromene-2,1'-isochromen]-5(3H)-one (9i)
50.0 mg (192 µmol, 1.0 eq) of 5b, 32.3 mg (230 µmol,
1.2 equiv) of dimedone and 2.60 mg (5.00 µmol, 2.5 mol%)
of IPrAgCl were dissolved in 0.5 mL of DCM. Then
4.33 mg (5.00 µmol, 2.5 mol%) of NaBArF were added and
the mixture was stirred for 18 h. Purification by preparative
TLC (PE:EA = 4:1, Rf = 0.41) gave the title product as
colorless solid (67.6 mg, 168 µmol, 89%).
1-(6’-Methyl-3,4’-diphenyl-3’,4’-
dihydrospiro[isochromene-1,2’-pyran]-5’-yl)ethan-1-
one (9l)
50.0 mg (162 µmol. 1.0 equiv) of 2a, 24.4 mg (243 µmol,
25.0 µl) of pentane-2,4-dione, 2.15 mg (4.05 µmol, 2.5
mol %) of IPrAgCl, 3.50 mg (4.05 µmol, 2.5 mol%) of
NaBArF and 500 µl of DCM were used. After column
chromatography using PE/EA 5:1 and recrystallization
from DCM/PE the product was isolated as a yellow
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ = 7.61 – 7.57
(m, 2H), 7.44 – 7.39 (m, 2H), 7.35 – 7.31 (m, 3H),
7.31 – 7.287 (m, 2H), 6.59 (s, 1H), 2.83 – 2.74 (m, 1H),
2.53 – 2.44 (m, 1H), 2.31 – 2.24 (m, 1H), 2.21 – 2.15 (m,
1H), 2.15 – 2.10 (m, 1H), .02 – 1.95 (m, 1H), 1.44 (d,
crystalline solid (26.4 mg, 64.8 µmol, 40%).
1
R (PE/EA 5:1) = 0.28; H NMR (300 MHz, C6D6, 25 °C,
f
TMS): δ = 7.82 – 7.76 (m, 2H), 7.38 –7.33 (m, 2H), 7.23
– 7.18 (m, 2H), 7.13 – 6.91 (m, 6H), 6.86 – 6.79 (m, 1H),
6.75 – 6.70 (m, 1H), 5.98 (s, 1H), 5.37 – 5.26 (m, 2H),
4.25 – 4.19 (m, 1H), 2.04 (s, 3H), 1.67 (s, 3H) ppm;
13C NMR (75 MHz, C6D6, 25 °C): δ = 202.4 (s, 1C), 202.3
(s, 1C), 151.9 (s, 1C), 149.1 (s, 1C), 142.6 (s, 1C), 133.8
(s, 1C), 130.8 (s, 1C), 129.4 (d, 1C), 129.1 (d, 2C), 128.9
(d, 2C), 128.3 (s, 1C), 128.2 (d, 2C), 127.9 (s, 1C), 127.8
(d, 1C), 127.1 (d, 1C), 125.7 (d, 1C), 125.1 (d, 2C), 123.0
(d, 1C), 102.0 (d, 1C), 100.5 (d, 1C), 75.8 (d, 1C), 41.9 (t,
3
3J = 6.5 Hz, 1H5), 1.14 (d, J = 6.5 Hz, 1H), 1.03 (s, 3H),
0.89 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C) δ =
198.1 (s, 1C), 165.1 (s, 1C), 149.3 (s, 1C), 134.2 (s, 1C),
131.6 (s, 1C), 129.9 (d, 1C), 129.3 (d, 1C), 128.9 (d, 2C),
127.5 (s, 1C), 127.4 (d, 1C), 125.7 (d, 1C), 124.9 (d, 2C),
124.7 (d, 1C), 117.6 (s, 1C), 102.0 (s, 1C), 100.5 (d, 1C),
51.8 (t, 1C), 42.5 (t, 1C), 41.7 (d, 1C), 31.7 (s, 1C), 30.2 (d,
1C), 29.4 (q, 1C), 27.4 (q, 1C), 18.7 (q, 1C), 15.9 (q, 1C)
ppm; IR (refl.): ν˜ = 3025, 1690, 1653, 1634, 1558, 1492,
1C), 30.4 (q, 1C), 27.8 (q, 1C ) ppm; IR (refl.): ν˜ = 3028,
1450, 1353, 1260, 1177, 1150, 1120, 1067, 1023, 868, 811,
754, 730, 682 cm-1; HRMS (DART(+)): [C27H29O3]+H+:
calculated 401.2111, found 401.2108; mp = 78 °C.
1689, 1655, 1629, 1559, 1490, 1453, 1353, 1258, 1178,
1149, 1121, 1077, 1025, 866, 811, 754, 731, 684 cm-1;
HRMS (EI(+), 70 eV): [C28H24O3]+: calculated 408.17200,
found 408.17082; mp = 86 °C.
7,7-Dimethyl-3'-phenyl-7,8-dihydrospiro[chromene-
2,1'-isochromen]-5(6H)-one (9j)
101 mg (440 µmol, 1.0 equiv) of 7, 74.1 mg (528 µmol,
1.2 equiv) of dimedone and 5.8 mg (11 µmol, 2.5 mol%) of
IPrAgCl were dissolved in 0.1 mL of DCM. Then 10.0 mg
(11.0 µmol, 2.5 mol%) of NaBArF was added and the
mixture was stirred for 20 h. Purification by column
chromatography (PE:EA = 10:1, Rf = 0.33) gave the title
product as orange solid (40.7 mg, 110 µmol, 25%).
3',4-Diphenyl-6,7-dihydro-3H-
spiro[cyclopenta[b]pyran-2,1'-isochromen]-5(4H)-one
(9m)
50.0 mg (162 µmol. 1.0 equiv) of 2a, 23.8 mg (243 µmol)
of cyclopentane-1,3-dione, 2.15 mg (4.05 µmol, 2.5 mol %)
of IPrAgCl, 3.50 mg (4.05 µmol, 2.5 mol%) of NaBArF and
500 µl of DCM were used. After column chromatography
using PE/EA 7:1 and recrystallization from DCM/PE the
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900988
Advanced Synthesis & Catalysis
product was isolated as a colorless crystalline solid (55.2
mg, 136 µmol, 83%).
R (PE/EA 2:1) = 0.42; H NMR (400 MHz, C6D6, 25 °C,
f
3',4-diphenyl-6,7,8,9-tetrahydro-3H-
spiro[cyclohepta[b]pyran-2,1'-isochromen]-5(4H)-one
(9o)
1
50.0 mg (162 µmol. 1.0 equiv) of 2a, 20.6 mg (243 µmol)
of cycloheptane-1,3-dione, 2.15 mg (4.05 µmol, 2.5 mol %)
of IPrAgCl, 3.50 mg (4.05 µmol, 2.5 mol%) of NaBArF and
500 µl of DCM were used. After column chromatography
using PE/EA 7:1 and recrystallization from DCM/PE the
product was isolated as a yellow solid (39.4 mg, 90.7 µmol,
56%), containing an unknown contamination that could not
be separated.
TMS): δ = 7.70 – 7.64 (m, 2H), 7.28 – 7.17 (m, 5H), 7.15
– 7.10 (m, 3H), 7.08 – 7.02 (m, 2H), 6.99 (td, J = 7.4, 1.3
Hz, 1H), 6.93 (dd, J = 7.7, 1.4 Hz, 1H), 6.50 (s, 1H), 4.44
(ddt, J = 10.6, 6.4, 2.1 Hz, 1H), 2.54 – 2.34 (m, 2H), 2.04 –
1.84 (m, 4H) ppm; 13C NMR (100 MHz, C6D6, 25 °C): δ =
199.8 (s, 1C), 181.0 (s, 1C), 149.5 (s, 1C), 142.1 (s, 1C),
134.4 (s, 1C), 131.2 (s, 1C), 130.1 (d, 1C), 129.5 (d, 1C),
129.1 (d, 2C), 128.4 (d, 1C), 128.8 (d, 2C), 128.2 (d, 2C),
127.4 (d, 1C), 127.0 (d, 1C), 125.5 (d, 1C), 125.2 (d, 2C),
124.2 (d, 1C), 117.5 (s, 1C), 101.8 (s, 1C), 101.8 (d, 1C),
40.2 (t, 1C), 34.6 (s, 1C), 33.8 (t, 1C), 26.2 (t, 1C) ppm;
1
R (PE/EA 2:1) = 0.48; H NMR (400 MHz, C6D6, 25 °C,
f
TMS): δ = 7.77 (dd, J = 8.4, 1.3 Hz, 2H), 7.37 – 7.32 (m,
2H), 7.24 (dd, J = 8.5, 6.8 Hz, 3H), 7.12 – 6.99 (m, 5H),
6.55 (s, 1H), 4.79 (dd, J = 10.2, 8.9 Hz, 1H), 2.58 – 2.49 (m,
2H), 2.32 – 2.19 (m, 2H), 2.15 – 2.06 (m, 2H), 1.38 (dt, J =
7.4, 4.5 Hz, 2H), 1.31 – 1.25 (m, 2H) ppm; 13C NMR (100
MHz, C6D6, 25 °C): δ = 200.0 (s, 1C), 163.5 (s, 1C), 149.5
(s, 1C), 146.1 (s, 1C), 134.6 (s, 1C), 131.5 (s, 1C), 129.8 (d,
1C), 129.4 (d, 1C), 129.0 (d, 2C), 128.8 (d, 2C), 128.4 (d,
2C), 128.0 (s, 1C), 127.9 (d, 1C), 127.2 (d, 1C), 126.4 (d,
1C), 125.3 (d, 2C), 124.2 (d, 1C), 119.4 (s, 1C), 101.6 (d,
1C), 98.7 (s, 1C), 42.3 (t, 1C), 40.2 (t, 1C), 38.1 (d, 1C),
IR (refl.): ν˜ = 3052, 3032, 2969, 2937, 2898, 1692, 1631,
1603, 1566, 1493, 1455, 1438, 1455, 1438, 1375, 1360,
1291, 1258, 1207, 1155, 1099, 1078, 1062, 1041, 1024, 962,
950, 906, 877, 849, 810, 763, 735, 718, 701, 690, 639 cm-1;
HRMS (EI(+), 70 eV): [C28H22O3]+: calculated 406.15635,
found 406.15474; mp = 156 °C.
3',4-Diphenyl-3,4,7,8-tetrahydrospiro[chromene-2,1'-
isochromen]-5(6H)-one (9n)
32.0 (t, 1C), 23.6 (t, 1C), 21.2 (t, 1C) ppm; IR (refl.): ν˜ =
3060, 3027, 2935, 2866, 1953, 1723, 1697, 1633, 1602,
1493, 1454, 1343, 1289, 1216, 1172, 1124, 1099, 1074,
1043, 1027, 99, 972, 946, 910, 865, 814, 754, 699, 640 cm-
1; HRMS (EI(+), 70 eV): [C29H24O3]+: calculated 434.18765,
found 434.18905; mp = 78 °C.
50.0 mg (162 µmol. 1.0 equiv) of 2a, 27.2 mg (243 µmol)
of cyclohexane-1,3-dione, 2.15 mg (4.05 µmol, 2.5 mol %)
of IPrAgCl, 3.50 mg (4.05 µmol, 2.5 mol%) of NaBArF and
500 µl of DCM were used. After column chromatography
using PE/EA 7:1 and recrystallization from DCM/PE the
product was isolated as a colorless crystalline solid (61.9
mg, 147 µmol, 91%).
R (PE/EA 2:1) = 0.51; H NMR (400 MHz, C6D6, 25 °C,
f
1
References
TMS): δ = 7.73 – 7.67 (m, 2H), 7.33 – 7.23 (m, 4H), 7.15
– 7.10 (m, 3H), 7.09 – 6.90 (m, 4H), 6.52 (s, 1H), 4.59 (ddd,
J = 10.6, 8.1, 2.3 Hz, 1H), 2.60 – 2.50 (m, 2H), 2.15 (dtd, J
= 17.0, 4.4, 1.2 Hz, 1H), 2.00 – 1.88 (m, 2H), 1.79 (dddd, J
= 18.0, 10.9, 4.9, 2.8 Hz, 1H), 1.52 – 1.36 (m, 1H), 1.23 (dt,
J = 13.2, 4.5 Hz, 1H) ppm; 13C NMR (100 MHz, C6D6,
25 °C): δ = 194.7 (s, 1C), 167.7 (s, 1C), 149.5 (s, 1C), 145.8
(s, 1C), 134.5 (s, 1C), 131.4 (s, 1C), 129.9 (d, 1C), 129.4 (d,
1C), 129.0 (d, 2C), 128.8 (d, 2C), 128.7 (s, 1C), 128.4 (d,
1C), 127.9 (s, 1C), 127.6 (d, 1C), 127.3 (d, 1C), 126.4 (d,
1C), 125.4 (d, 1C), 125.2 (d, 2C), 124.2 (d, 1C), 116.7 (s,
1C), 101.8 (d, 1C), 99.2 (d, 1C), 40.7 (t, 1C), 37.2 (t, 1C),
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Advanced Synthesis & Catalysis
FULL PAPER
A Silver-Catalyzed Modular Intermolecular Access
to 6,6-Spiroketals
Adv. Synth. Catal. Year, Volume, Page – Page
Alexander Ahrens, Niklas F. Heinrich, Simon R.
Kohl, Martha Hokamp, Matthias Rudolph, Frank
Rominger, A. Stephen K. Hashmi*
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