Functionalization of diazotetronic acid and application in a stereoselective modular synthesis of pulvinone, aspulvinones A-E, G, Q and their analogues

Article abstract of DOI:10.1039/c8ob01511b

A modular synthesis of aspulvinones A, B, C, D, E, G and the recently isolated aspulvinone Q was developed. The methodology features a highly stereoselective aldol condensation of diazotetronic acid with aldehydes to provide 5-arylidene diazotetronates. S

Full text of DOI:10.1039/c8ob01511b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Manchoju, R. A.
Annadate, L. Desquien and S. V. Pansare, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01511B.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 13
View Article Online
DOI: 10.1039/C8OB01511B
Journal Name
ARTICLE
Functionalization of Diazotetronic Acid and Application in a
Stereoselective Modular Synthesis of Pulvinone, Aspulvinones A‐
E, G, Q and their Analogues
Received 00th January 20xx,
Accepted 00th January 20xx
Amarender Manchoju,a Ritesh A. Annadate,a Lise Desquiena§ and Sunil V. Pansare*a
DOI: 10.1039/x0xx00000x
A modular synthesis of aspulvinones A, B, C, D, E, G and the recently isolated aspulvinone Q was developed. The methodology
features a highly stereoselective aldol condensation of diazotetronic acid with aldehydes to provide 5‐arylidene
diazotetronates. Subsequent catalytic intermolecular C‐H insertion reactions of the arylidene tetronates with arenes provide
a series of naturally occurring aspulvinones including aspulvinones C, D and Q which have not been synthesized before.
Variation of the aldehyde and the arene components furnishes synthetic analogues of the aspulvinones.
www.rsc.org/
family, aspulvinones I‐CR to N‐CR from the culture broth of a
Aspergillus sp. (strain 05545) obtained from a marine sponge,9
aspulvinone O from the fungal strain Paecilomyces variotii,10
Introduction
The tetronic acid (4‐hydroxy‐5H‐furan‐2‐one) motif is a characteristic
structural unit in many fungal metabolites.1,2 Among these, the
pulvinones (hydroxylated versions of 3‐aryl‐4‐hydroxy‐5‐arylidene
furan‐2(5H)‐ones) constitute a major group of naturally‐occurring
tetronic acids, which were first isolated as yellow pigments from the
aspulvinone P from Aspergillus flavipes PJ03‐117 and aspulvinone R
from Aspergillus sp. CPCC 400735.11 These are all closely related to
their congeners in Figure 1 and the synthetic strategy described here
is potentially applicable to the entire family of pulvinones. The
biological profiles of a large number of naturally occurring as well as
synthetic pulvinones have been exhaustively investigated, and
several studies have identified pulvinones with anticoagulant,12
antibacterial,13 peptidoglycan biosynthesis inhibitory,14 anti‐
inflammatory,15 antidiabetic,16 anti‐epileptic17 and antifungal18
activities. In particular, members of the aspulvinone family have
antiviral,19 ‐glucosidase inhibitory20 and firefly luciferase inhibitory9
activity.
mushroom Larch Bolete (Suillus grevillei).3 Subsequently,
a
significant number of coloured metabolites were isolated from
cultures of Aspergillus terreus.4 These were named the aspulvinones
presumably because their structures were determined5,6 to be
similar to the pulvinones isolated earlier. Of these, the aspulvinones
that were selected for our synthetic studies are shown in Figure 1.
The targets are assembled by their structural similarity, and they
include pulvinone (1),3 aspulvinone E (2),4 aspulvinone G (3),4 3',4,4'‐
trihydroxypulvinone (4),3 aspulvinone Q (5),7 aspulvinone A (6),4
aspulvinone C (7),4 aspulvinone B (8)4 and aspulvinone D (9).4
The wide spectrum of biological activity exhibited by pulvinones
has contributed to extensive interest in their synthesis and several
approaches to the functionalized tetronic acid motif in pulvinones
are reported (Figure 2). The salient features of these approaches are:
1) installation of the C5‐arylidene portion by aldol reaction of 3‐aryl‐
4‐methoxytetronates with aryl aldehydes followed by dehydration
(Pattenden),21 2) olefination of a dioxolane phosphorane (Ramage),22
or a dioxolane phosphonate (Brückner)23 with aryl aldehydes
followed by Claisen condensation with arylacetic esters, 3) Wittig
reaction of
a 3‐aryltetronate‐derived phosphorane with aryl
aldehydes (Campbell),24 4) assembly of the lactone moiety by O‐ and
C‐acylation of ‐hydroxy dibenzyl ketones with carbonyl diimidazole
followed by oxidation of the C5 benzyl group (Gill),25 5) aldol
condensation of 3‐bromotetronates at C5 with aryl aldehydes and
subsequent introduction of the C3 aryl group by Suzuki coupling
(Antane),26 6) Heck reaction of 2‐acetoxy acrylates and iodoarenes to
Figure 1. Naturally occurring aspulvinones prepared in this study
provide
the
corresponding
cinnamates,
subsequent
Several other aspulvinones are known; aspulvinone F,4
aspulvinone H,8 and the more recent additions to the aspulvinone
transesterification with arylacetic acids and Dieckmann cyclization
(Brückner),27 7) Dieckmann condensation/elimination protocol with
functionalized esters of aryl acetic acids (Le Gall)28 8) silver catalyzed
lactonization of acetylenic acids (Brückner)29 and 9) silver catalyzed
incorporation of carbon dioxide into conjugated ynones under high
pressure (Yamada).30 The majority of these strategies rely on the
cyclization of a functionalized precursor to provide the tetronic acid
motif and only a few21,24,26 have relied on the synthesis of an
a. Department of Chemistry, Memorial University, St. John’s, Newfoundland,
Canada A1B 3X7.
§Undergraduate internship student from Institut
Universitaire de Technologie de Béthune, Université d’Artois, France.
†Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra for
all compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 13
View Article Online
DOI: 10.1039/C8OB01511B
ARTICLE
Journal Name
appropriate tetronic acid which is subsequently elaborated to the products, is also necessary (Figure 2). Herein, we report the
target. Notably, all of these approaches are limited by the implementation of this two‐step procedure for the synthesis of
requirement of starting materials that contain the substituted arene, pulvinones from 3‐diazotetronic acid (10).
or arenes, in the target pulvinones. In addition, some of the above
methods generate mixtures of E‐ and Z‐pulvinones.23,24,28 In this
context, it is noteworthy that the synthesis of aspulvinones C and D
(7, 9 Figure 1) is not yet reported, and the synthesis of pure
aspulvinone B (8, Figure 1) has been challenging.27 We therefore
chose to develop a synthesis of pulvinones that is not limited by the
availability of arene‐bearing starting materials and also provides only
the Z isomer that is found in all of the naturally occurring pulvinones.
The initial focus of our studies was the installation of an arylidene
functionality at C5 in diazotetronate 10, which is easily prepared
fromcommercially available tetronic acid in one step,32 to potentially
provide the immediate precursors of the target pulvinones and their
analogs. Our objective was to develop a method that would avoid
multistep protocols that were employed in previous studies with
tetronic acid derivatives (Figure 2). At the outset, an aldol reaction of
10 and p‐tolualdehyde was attempted with the titanium enolate of
10 (using the TiCl4‐Et3N reagent,33 Table 1, entry 1). Interestingly, this
directly provided the aldol condensation product34 11a as a single
diastereomer, but in low yield (41%). We therefore conducted an
optimization of the aldol condensation by employing selected
combinations of Lewis acids and bases. Replacing TiCl4 with BF3.OEt2
(Table 1, entry 2) provided only the aldol addition product 12 as a
mixture of diastereomers (dr = 1:1). Changing the base from
triethylamine to heteroaromatic bases such as pyridine, N‐
methylimidazole and 2,4,6‐collidine prevented the formation of 12
and also improved the yield of 11a. With N‐methylimidazole and
pyridine (Table 1, entries 3 and 4), 11a was obtained in good yields
(77% and 82% respectively) but the reaction was slow. However, the
reaction with 2,4,6‐collidine as the base not only provided 11a in
good yield (82%, Table 1, entry 5), but this reaction was significantly
faster (80 min) than those with N‐methylimidazole (~20 h) or
pyridine (~43 h) as the base.
We reasoned that
a strategy that relied on the direct
functionalization of tetronic acid could potentially address these
objectives.
Table 1. Optimization of the aldol condensation of 10 with
p‐tolualdehyde.
Entry
Conditions
11aa 12a
Figure 2. Previous synthetic approaches to pulvinones and our two
step strategy.
1
TiCl4, ‐78 oC, 20 min; Et3N, ‐78 oC, 40 min to
41
‐
‐
38
‐
0 oC, 1.5 h
Results and discussion
o
o
2
3
4
5
BF3.OEt2, ‐78 C, 20 min; Et3N, ‐78 C, 40
Our approach to pulvinones relies on the functionalization of 3‐
diazotetronic acid (10, Figure 2). We have previously shown that C5‐
functionalized diazotetronates react with arenes in the presence of
a metal catalyst and provide the corresponding 3‐aryl tetronates as
the products of a net C‐H insertion reaction of the diazotetronate and
the arene C‐H bond.31 This reaction presumably proceeds as an
electrophilic aromatic subsbstitution reaction of the arene with the
tetronate‐derived carbenoid intermediate, and hence it displays the
conventional regiochemistry that is anticipated for electrophilic
aromatic substitution reactions. Notably, all of the naturally
occurring pulvinones have a tetronic acid core that is substituted
with an electron rich arene at C3 (Figure 1) which is typically 2‐, 2,4‐
di, or 2,4,5‐tri substituted with hydroxy, alkoxy or alkyl groups in
relation to the aryl‐tetronate linkage. We therefore anticipated that
the regiochemistry of our tetronate‐arene C‐H insertion
methodology would be particularly useful for the synthesis of
naturally occurring pulvinones and their analogues. In order for the
proposed methodology to be successful, a stereoselective aldol
condensation at C5 in the diazotetronic acid (10), to generate only
the Z‐arylidene functionality found in the pulvinone natural
min; 0oC, 1 h; rt, 1 h
TiCl4, ‐78 oC, 20 min; N‐methylimidazole,
‐78 oC, 30 min; 0 oC, 80 min; rt, 18 h
77
82
82
o
o
TiCl4, ‐78 C, 20 min; pyridine, ‐78 C, 30
‐
min; 0oC, 2 h; rt, 41 h
TiCl4, ‐78 oC, 20 min; 2,4,6‐collidine, ‐78 oC,
‐
30 min; 0oC, 30 min
a Isolated yields
At this stage, 11a was assigned the Z stereochemistry35 on the
basis of selected 13C‐1H coupling constants. The 3JC(4)‐H(6) (three bond
13C‐1H coupling constant) for the exocyclic methine and the ketone
carbonyl in 11a is 3.9 Hz and JC(5)‐H(6) (two bond 13C‐1H coupling
2
constant) in 11a is 4.3 Hz. These values are in good agreement with
those reported36 for several Z‐aurones (3JC‐H = 3.1‐3.6 Hz; 2JC‐H = 3.7‐
4.7 Hz) that are structurally related to 11a. Notably, the reported
3JC‐H and 2JC‐H values for E‐aurones are higher (7.0‐8.5 Hz).
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 13
View Article Online
DOI: 10.1039/C8OB01511B
Journal Name
ARTICLE
The optimized conditions were employed for the aldol
condensation of 10 with a variety of aldehydes. Pleasingly, a precursors to aspulvinone
Encouraged by the conversion of 11b to 1, the synthesis of
(2), aspulvinone (3), 3',4,4'‐
E
G
selection of electron‐rich and electron‐deficient aromatic aldehydes, trihydroxypulvinone (4) and aspulvinone Q (5) was investigated
as well as aliphatic aldehydes, provided the 5‐arylidene‐3‐ employing C5‐arylidene diazotetronates in which the arene
diazofuran‐2,4(3H,5H)‐diones 11b‐p as single diastereomers in good substituent was suitable for the targeted natural product. These C‐H
yields (16 examples, Figure 3). Notably, the arylidene diazotetronates insertion reactions were conducted in a solvent, rather than the neat
11b, 11d, 11f, 11g, 11h and 11i, which are potential intermediates arene, and an excess (4 equiv) of an appropriately substituted arene
for the synthesis of aspulvinones, were all obtained in good yield (79‐ as the reacting partner. Thus, the Rh2(CF3CO2)4‐catalyzed C‐H
92%). The reactions with aliphatic aldehydes are less efficient;
cyclopentanecarboxaldehyde and pivalaldehyde provided 11o and
11p respectively in modest yield (40% and 43% respectively) and
hydrocinnamaldehyde did not provide any of the required product.
For reasons that are not clear at this time, the reaction of 10 with
pyridine‐4‐carboxaldehyde was also unsuccessful. The aldol
condensation products 11b‐p were assigned the Z stereochemistry
by analogy to 11a, and this was also confirmed by the diagnostic C‐H
coupling constants for 11b and 11p.36 Eventually, this stereochemical
assignment was confirmed by conversion of several C5‐arylidene
derivatives to naturally occurring pulvinones, thus providing
unambiguous evidence for their structure.
insertion reaction of 11d with anisole in ,,‐
trifluoromethylbenzene provided the regioisomeric insertion
products 13a and 13b (13a/13b = 3.5:1, 91%, Scheme 1). A similar
reaction of 11f provided 14a and 14b (14a/14b = 4.4:1, 67%, Scheme
1). The regioisomeric products (13a/b and 14a/b) were easily
separated by flash column chromatography. Although the C‐H
insertion reaction of 11d with 1,3‐dimethoxybenzene provided 15
(76%) under these conditions, a similar reaction of 11g with the TBS
ether of phenol provided a complex mixture in which the desired
product, 16, could not be detected. Changing the solvent to 1,2‐
dichloroethane and the use of Rh2(esp)2,37 was beneficial and the
insertion product 16 was obtained as the only isolable product (40%).
Interestingly, the regioisomeric product (ortho C‐H insertion, as in
13b and 14b) was not obtained in this case.
Scheme 1. Arene C‐H insertion reactions for the synthesis of
pulvinones 1, 13‐16.
Selected insertion products shown in Scheme 1 were readily
converted into
a series of naturally occurring aspulvinones.
Demethylation of 13a, 14a and 15 with BBr3, according to the
reported procedure,27 provided aspulvinone E (2, 84%), aspulvinone
G (3, 81%), and 3’,4,4’‐trihydroxypulvinone (4, 85%, Scheme 2).
Removal of the TBS protecting groups in 16 with TBAF provided
aspulvinone Q (5) in good yield (86%).
Figure 3. Aldol condensation products of 10 with selected aldehydes.
Having established
a
general synthesis of 5‐arylidene
diazotetronates 11, we examined their C‐H insertion reactions with
a selection of arenes. Since our immediate objective was to confirm
the Z‐geometry of 11, a C‐H insertion reaction of 11b was conducted
in benzene in the presence of Rh2(OAc)4 to provide the known,
naturally occurring, pulvinone 1 (78%, Scheme 1). Spectroscopic data
(1H NMR, 13C NMR) of 1 and its acetate derivative24 were identical
with those reported in the literature.22,24,28 The chemical shift of the
methyl group in the acetate derived from Z‐1 is reported to be  2.35,
whereas in E‐1 it is  1.67.24 The observed chemical shift ( 2.42) of
the methyl group in the acetate of 1 prepared in our study confirmed
the Z stereochemistry for 1. This also supports our earlier conclusion
that 11b has the Z‐geometry.
Scheme 2. Synthesis of aspulvinones E, G, Q and 3’,4,4’‐
trihydroxypulvinone.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 13
View Article Online
DOI: 10.1039/C8OB01511B
ARTICLE
Having achieved the synthesis of the naturally occuring
Journal Name
pulvinones 2, 3, 4 and 5, we next targeted the naturally occurring
aspulvinone A (6), aspulvinone C (7), aspulvinone B (8) and
aspulvinone D (9). In initial studies, Rh2(CF3COO)4 and Rh2(OAc)4
were screened as catalysts in the C‐H insertion reactions of 11i with
chromane 1738 (4 equiv.) in PhCF3 as the solvent at 100 oC. However,
in both cases, poor yields (29%, 38% respectively) of 6 were
observed. Changing the catalyst to Rh2(esp)2 and lowering the
reaction temperature to 50 oC improved the yield of aspulvinone A
(6) to 60%. These conditions were also used for the insertion reaction
of 11i with the 7‐methoxy‐2,2‐dimethylchromane (18)39 to provide
the pulvinone 19 in good yield (85%, Scheme 3). Attempted
demethylation of 19 by treatment with BBr3 resulted in concomitant
C‐O bond cleavage in the chromane moieties to provide a bis‐tertiary
bromide intermediate. This material spontaneously cyclized40 back
to the bis‐chromane in CH2Cl2 solution at ambient temperature to
provide aspulvinone C (7) in 75% yield from 19.
Scheme 4. Synthesis of aspulvinones B and D.
Over the years, interest in the biological activity of pulvinones
and aspulvinones has resulted in intense investigation of the
synthesis of structural variants of the natural isolates.9,12‐20,42 It may
be noted that the described methodology is particularly amenable to
the synthesis of a wide variety of non‐natural pulvinones by variation
of the aldehyde component in the aldol condensation that provides
11 and subsequent variation of the arene component in the C‐H
insertion reactions of 11. The potential of this strategy was
demonstrated by the two‐step synthesis of the non‐natural
pulvinones 23 (from 11o and 17), 24 (from 11j and 17) and 25 (from
11i and 5‐bromoindole, Figure 4).
Scheme 3. Synthesis of aspulvinones A and C.
The synthesis of aspulvinones B and D was examined next using
the diazotetronate 11h as the starting material, and a notable
difference in the reactivities of 11i and 11h was immediately
apparent. A change of solvent from PhCF3 to 1,2‐dichloroethane, and
higher reaction temperature (100 oC) was necessary with 11h. With
these modifications, the C‐H insertion reaction of 11h and chromane
(17) provided 20 (59%). Subsequent removal of the TBS protection in
20 provided aspulvinone B (8, 56%). The synthesis of aspulvinone D
was first initiated with an insertion reaction of 11h and 7‐methoxy‐
2,2‐dimethylchromane (18). While this reaction was successful (44%
yield), subsequent demethylation of the insertion product was
complicated by unwanted side reactions, and hence the TBS‐
protected chromane derivative 2141 was employed as the insertion
partner. Thus the reaction of 11h and 21 provided 22 (43%), which
was deprotected to provide aspulvinone D (9, 83%, Scheme 4).
Figure 4. Non‐natural pulvinones prepared in this study.
Conclusion
In conclusion
a two‐step synthesis of 3‐aryl‐5‐arylidene
tetronates was developed from diazotetronic acid as the starting
material. The utility of the methodology was demonstrated by
application in the synthesis of two naturally occurring pulvinones (1
and 4, Figure 1), seven aspulvinones (2, 3, 5, 6, 7, 8 and 9, Figure 1)
as well as three non‐natural pulvinones. This strategy provides the
shortest route to functionalized tetronates and has potential for the
rapid synthesis of focused libraries of aspulvinone‐like natural
product analogues. Current efforts focus on these and other
applications of 10.
Experimental
General: All commercially available reagents were used without
purification. All reactions requiring anhydrous conditions were
performed under an atmosphere of dry nitrogen using oven dried
glassware. Commercially available ,,‐trifluorotoluene was used
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 13
View Article Online
DOI: 10.1039/C8OB01511B
Journal Name
ARTICLE
as received. CH2Cl2 and Cl(CH2)2Cl (DCE) were distilled from CaH2. 130.5 (ArC), 129.1 (2 × ArC), 111.9 (PhCH=C); HRMS (APPI, pos.): m/z
Commercial precoated silica gel plates were used for TLC. All melting 214.0378 (214.0378 calc. for C11H6N2O3, (M)+).
points are uncorrected. Silica gel for flash column chromatography
was 230‐400 mesh. IR spectra were recorded on a Bruker TENSOR 27 (Z)‐3‐Diazo‐5‐(3‐methoxybenzylidene)furan‐2,4(3H,5H)‐dione
FT‐IR instrument. 1H NMR and 13C NMR spectra were recorded on a (11c): The reaction of 10 (150 mg, 1.19 mmol), 3‐
Bruker AVANCE III 300 or an AVANCE 500 instrument. Mass spectra methoxybenzaldehyde (145 µL, 1.19 mmol), TiCl4 (0.39 mL, 3.6
were obtained on an Agilent 6200 LC/MSD (TOF) chromatographic mmol) and 2,4,6‐collidine (0.47 mL, 3.6 mmol) in CH2Cl2 (7 mL)
system.
according to the general procedure provided, after purification by
flash column chromatography on silica gel (hexanes/EtOAc, 9:1 to
3‐Diazofuran‐2,4(3H,5H)‐dione (10): To a solution of tetronic acid 7:3), 231 mg (79%) of 11c as a yellow solid.
o
(1.50 g, 15.0 mmol) in acetonitrile (20 mL) at 0 C was added tosyl Rf = 0.46 (hexanes/EtOAc, 7:3); mp: 159‐161°C; IR (neat): 2923, 2844,
azide (2.90 g, 15.0 mmol) followed by dropwise addition of 2132, 1764, 1705, 1647, 1582, 1357, 1302, 1215, 1176, 1092, 1074,
triethylamine (2.09 mL, 15.0 mmol) over 10 min at 0 °C. The mixture 1036, 981, 912 cm‐1; 1H NMR (300 MHz, CDCl3): δ 7.36‐7.31 (m, 2H,
gradually turned black and it was stirred at room temperature for 1 ArH), 7.31‐7.28 (m, 1H, ArH), 7.00‐6.92 (m, 1H, ArH), 6.65 (s, 1H,
h. Removal of the solvent under reduced pressure provided a black ArCH=C), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): δ 174.6 (C=O),
residue. This was applied to a column (3 cm x 17 cm) of flash silica gel 160.1 (OC=O or ArCipso), 159.8 (OC=O or ArCipso), 142.1 (O‐C=CHAr),
packed in dichloromethane and the column was eluted with 132.1 (ArCipso), 129.9 (ArC), 124.1 (ArC), 116.6 (ArC), 116.0 (ArC),
dichloromethane (~300 mL). The residue obtained by concentration 111.7 (ArCH=C), 55.4 (OCH3); HRMS (APPI, pos.): m/z 244.0481
of the eluate was purified by flash column chromatography on silica (244.0484 calc. for C12H8N2O4, (M)+).
gel (CH2Cl2/EtOAc, 98:2) to provide 773 mg (41%) of 10 as a white
solid. Rf = 0.41 (CH2Cl2/EtOAc, 9.5:0.5). Spectroscopic data for 10 is in (Z)‐3‐Diazo‐5‐(4‐methoxybenzylidene)furan‐2,4(3H,5H)‐dione
agreement with reported data.31
(11d): The reaction of 10 (126 mg, 1.00 mmol), 4‐
methoxybenzaldehyde (121 µL, 1.00 mmol), TiCl4 (0.32 mL, 3.0
General procedure for the aldol condensation of diazotetronate 10 mmol) and 2,4,6‐collidine (0.40 mL, 3.0 mmol) in CH2Cl2 (6 mL)
and aldehydes: To a solution of 10 (1.0 equiv) and aldehyde (1.0 according to the general procedure provided, after purification by
equiv) in CH2Cl2 was added TiCl4 (3.0 equiv) at ‐78 °C. The solution flash column chromatography on silica gel (hexanes/EtOAc, 9:1 to
was stirred for 20 min, 2,4,6‐collidine (3.0 equiv) was added and the 4:1), 224 mg (92%) of 11d as a yellow solid.
mixture was stirred at ‐78 °C for 30 min and at 0 °C for 30 min. Rf = 0.33 (hexanes/EtOAc, 7:3); mp: 141‐145 °C; IR (neat): 2970, 2917,
Saturated aqueous NH4Cl (~ 3 mL) was added followed by cold water 2845, 2158, 1774, 1690, 1646, 1598, 1565, 1508, 1366, 1341, 1305,
(~ 2 mL). The resulting mixture was extracted with CH2Cl2 (3 x 6 mL). 1250, 1174, 1134, 1070, 1021, 957 cm‐1; 1H NMR (300 MHz, CDCl3): δ
The combined organic layers were washed with brine, dried (Na2SO4) 7.72 (d, 2H, J = 8.8 Hz, ArH), 6.94 (d, 2H, J = 8.8 Hz, ArH), 6.66 (s, 1H,
and concentrated under reduced pressure. The residue was purified ArCH=C), 3.86 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): δ 174.6 (C=O),
by flash chromatography on silica gel to provide the arylidene‐ or 161.4 (OC=O or ArCipso), 160.4 (OC=O or ArCipso), 140.5 (O‐C=CHAr),
alkylidene diazotetronates 11a‐p.
133.4 (2 × ArC), 123.7 (ArCipso), 114.5 (2 × ArC), 112.0 (ArCH=C), 55.4
(OCH3); HRMS (APPI, pos.): m/z 244.0484 (244.0484 calc. for
(Z)‐3‐Diazo‐5‐(4‐methylbenzylidene)furan‐2,4(3H,5H)‐dione (11a): C12H8N2O4, (M)+).
The reaction of 10 (126 mg, 1.00 mmol), 4‐methylbenzaldehyde (118
(Z)‐3‐Diazo‐5‐(2‐methoxybenzylidene)furan‐2,4(3H,5H)‐dione
µL, 1.00 mmol), TiCl4 (0.32 mL, 3.0 mmol) and 2,4,6‐collidine (0.40
mL, 3.0 mmol) in CH2Cl2 (5 mL) according to the general procedure
provided, after purification by flash column chromatography on silica
gel (hexanes/EtOAc, 9:1), 188 mg (82%) of 11a as a white solid.
Rf = 0.32 (hexanes/EtOAc, 8.5:1.5); mp: 147‐150 °C; IR (neat): 2157,
1758, 1689, 1634, 1602, 1362, 1339, 1313, 1251, 1078, 1048, 962,
917 cm‐1; 1H NMR (300 MHz, CDCl3): δ 7.66 (d, 2H, J = 8.1 Hz, ArH),
7.23 (d, 2H, J = 8.1 Hz, ArH), 6.68 (s, 1H, ArCH=C), 2.39 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): δ 174.8 (C=O), 160.5 (OC=O), 141.6 (O‐
C=CHAr or ArCipso), 141.3 (O‐C=CHAr or ArCipso), 131.6 (2 × ArC), 129.9
(2 × ArC), 128.3 (ArCipso), 112.2 (ArCH=C), 21.8 (CH3); HRMS (APPI,
pos.): m/z 228.0537 (228.0535 calc. for C12H8N2O3, (M)+).
(11e): The reaction of 10 (75 mg, 0.59 mmol), 2‐
methoxybenzaldehyde (81 mg, 0.59 mmol), TiCl4 (0.2 mL, 1.78 mmol)
and 2,4,6‐collidine (0.2 mL, 1.78 mmol) in CH2Cl2 (5 mL) according to
the general procedure provided, after purification by flash column
chromatography on silica gel (hexanes/EtOAc, 9:1), 77 mg (53%) of
11e as a yellow solid.
Rf = 0.23 (hexanes/EtOAc, 9:1); mp: 210‐211 oC; IR (neat): 3080,
2923, 2840, 2152, 1775, 1699, 1648, 1592, 1483, 1462, 1359, 1305,
1283, 1254, 1233, 1193, 1138, 1070, 1045, 1018, 955 cm‐1; 1H NMR
(300 MHz, CDCl3):  8.05 (dd, 2H, J = 7.6, 1.7 Hz, ArH), 7.37 (ddd, 1H
J = 8.3, 7.6, 1.7 Hz), 7.28 (s, 1H, ArCH), 7.01 (br t, 1H, J = 7.6 Hz, ArH),
6.91 (br d, 1H, J = 8.3 Hz, ArH), 3.88 (s, 3H, OCH3); 13C NMR (75 MHz,
(Z)‐5‐Benzylidene‐3‐diazofuran‐2,4(3H,5H)‐dione
(11b):
The CDCl3):  174.7 (C=O), 160.5 (O‐C=O), 158.7 (ArCipso), 141.8 (ArCipso),
reaction of 10 (70 mg, 0.56 mmol), benzaldehyde (57 µL, 0.56 mmol), 132.1 (O‐C=CHAr), 131.7 (ArH), 121.0 (ArH), 119.9 (ArCH=C), 110.8
TiCl4 (0.18 mL, 1.7 mmol) and 2,4,6‐collidine (0.22 mL, 1.7 mmol) in (ArH), 106.2 (ArH), 55.6 (OCH3); HRMS (APPI, pos.): m/z 244.0847
CH2Cl2 (3 mL) according to the general procedure provided, after (244.0484 calc. for C12H8N2O4 (M+)), 245.0560 (245.0562 calc. for
purification by flash column chromatography on silica gel C12H9N2O4 (M+H)+).
(hexanes/EtOAc, 8.5:1.5), 104 mg (87%) of 11b as a white solid.
(Z)‐3‐Diazo‐5‐(3,4‐dimethoxybenzylidene)furan‐2,4(3H,5H)‐dione
(11f): The reaction of 10 (80 mg, 0.64 mmol), 3,4‐
dimethoxybenzaldehyde (106 mg, 0.640 mmol), TiCl4 (0.21 mL, 1.9
mmol) and 2,4,6‐collidine (0.25 mL, 1.9 mmol) in CH2Cl2 (4 mL)
according to the general procedure provided, after purification by
Rf = 0.51 (hexanes/EtOAc, 7:3); mp: 147‐154 °C; IR (neat): 2921, 2852,
2151, 1763, 1699, 1639, 1358, 1337, 1244, 1082, 1051, 963 cm‐1; 1H
NMR (300 MHz, CDCl3): δ 7.81‐7.72 (m, 2H, ArH), 7.49‐7.39 (m, 3H,
ArH), 6.69 (s, 1H, PhCH); 13C NMR (75 MHz, CDCl3): δ 174.8 (C=O),
160.3 (OC=O), 142.1 (PhHC=C‐O), 131.5 (2 × ArC), 131.0 (ArCipso),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 13
View Article Online
DOI: 10.1039/C8OB01511B
ARTICLE
Journal Name
flash column chromatography on silica gel (hexanes/EtOAc, 7:3 to Rf = 0.46 (hexanes/EtOAc, 7:3); mp: 156‐161 °C; IR (neat): 2979, 2926,
1:1), 161 mg (93%) of 11f as a yellow solid.
2163, 1774, 1702, 1641, 1598, 1570, 1490, 1364, 1308, 1269, 1116,
1
Rf = 0.19 (hexanes/EtOAc, 7:3); mp: 177‐183 °C; IR (neat): 2961, 2936, 1074, 1054, 948 cm‐1; H NMR (300 MHz, CDCl3): δ 7.53 (br s, 1H,
2913, 2836, 2143, 1779, 1693, 1643, 1594, 1513, 1360, 1321, 1266, ArH), 7.50 (dd, 1H, J = 8.3, 2.1 Hz, ArH), 6.81 (d, 1H, J = 8.3 Hz, ArH),
1
1219, 1145, 1129, 1081, 1063, 1018, 979, 916 cm‐1; H NMR (300 6.64 (s, 1H, ArCH=C), 2.81 (t, 2H, J = 6.7 Hz, ArCH2CH2), 1.83 (t, 2H, J
MHz, CDCl3): δ 7.36 (s, 1H, ArH), 7.35 (dd, 1H, J = 8.6, 2.0 Hz, ArH), = 6.7 Hz, ArCH2CH2), 1.36 (s, 6H, 2 × CH3); 13C NMR (75 MHz, CDCl3):
6.91 (d, 1H, J = 8.6 Hz, ArH), 6.66 (s, 1H, ArCH=C), 3.94 (s, 6H, 2 × δ 174.6 (C=O), 160.6 (OC=O), 156.6 (ArCipso), 140.1 (O‐C=CHAr), 133.3
OCH3); 13C NMR (75 MHz, CDCl3): δ 174.7 (C=O), 160.5 (OC=O), 151.4 (ArC), 131.4 (ArC), 122.6 (ArCipso), 121.7 (ArCipso), 118.1 (ArC), 112.7
(ArCipso), 149.3 (ArCipso), 140.7 (O‐C=CHAr), 126.2 (ArC), 124.1 (ArCH=C), 75.5 (Ar‐O‐C(CH3)2), 32.5 (ArCH2CH2), 26.9 (2 × CH3), 22.4
(ArCipso), 113.5 (ArC or ArCH=C), 112.4 (ArC or ArCH=C), 111.3 (ArC or (ArCH2CH2); HRMS (ESI, pos.): m/z 298.0939 (298.0954 calc. for
ArCH=C), 56.1 (2 × OCH3); HRMS (APPI, pos.): m/z 274.0597 C16H14N2O4, (M)+), 299.1012 (299.1032 calc. for C16H15N2O4, (M+H)+)
(274.0590 calc for C13H10N2O5 (M)+).
and 321.0827 (321.0851 calc. for C16H14N2NaO4, (M+Na)+).
(Z)‐5‐(4‐(tert‐butyldimethylsilyloxy)‐3‐methoxybenzylidene)‐3‐
(Z)‐3‐Diazo‐5‐(naphthalen‐2‐ylmethylene)furan‐2,4(3H,5H)‐dione
diazofuran‐2,4(3H,5H)‐dione (11g): The reaction of 10 (100 mg, 0.79 (11j): The reaction of 10 (150 mg, 1.19 mmol), 2‐naphthaldehyde
mmol), 4‐(tert‐butyldimethylsilyloxy)‐3‐methoxybenzaldehyde (211 (186 mg, 1.19 mmol), TiCl4 (0.39 mL, 3.6 mmol) and 2,4,6‐collidine
mg, 0.79 mmol), TiCl4 (0.25 mL, 2.38 mmol) and 2,4,6‐collidine (0.3 (0.47 mL, 3.6 mmol) in CH2Cl2 (7 mL) according to the general
mL, 2.38 mmol) in CH2Cl2 (5 mL) according to the general procedure procedure provided, after purification by flash column
provided, after purification by flash column chromatography on silica chromatography on silica gel (hexanes/EtOAc, 8.5:1.5 to 1:1), 292 mg
gel (hexanes/EtOAc, 9.2:0.8), 257 mg (87%) of 11g as a yellow solid.
(93%) of 11j as an orange‐yellow solid.
Rf = 0.30 (hexanes/EtOAc, 9.2:0.8); IR (neat): 2957, 2931, 2856, 2147, Rf = 0.40 (hexanes/EtOAc, 7:3); mp: 156‐160 °C; IR (neat): 2922, 2134,
1
1786, 1708, 1649, 1591, 1508, 1463, 1419, 1364, 1344, 1310, 1276, 1762, 1710, 1645, 1358, 1322, 1078, 1048, 976, 929 cm‐1; H NMR
1
1248, 1169, 1132, 1072 cm‐1; H NMR (300 MHz, CDCl3): δ 7.34 (d, (300 MHz, CDCl3): δ 8.22 (s, 1H, ArH), 7.94‐7.80 (m, 4H, ArH), 7.59‐
1H, J = 2.1 Hz, ArH), 7.24 (dd, 1H, J = 8.3, 2.1 Hz, ArH), 6.88 (d, 1H, J = 7.49 (m, 2H, ArH), 6.86 (s, 1H, ArCH=C); 13C NMR (75 MHz, CDCl3): δ
8.3 Hz, ArH), 6.65 (s, 1H, ArCH), 3.86 (s, 3H, OCH3), 1.00 (s, 9H, 174.7 (C=O), 160.4 (OC=O), 142.2 (O‐C=CHAr), 134.0 (ArCipso), 133.3
C(CH3)3), 0.18 (s, 6H, Si(CH3)2). 13C NMR (75 MHz, CDCl3): δ 174.7 (ArCipso), 132.6 (ArC), 129.0 (ArC), 128.9 (ArC), 128.6 (ArCipso), 128.0
(C=O), 160.5 (O‐C=O), 151.4 (ArCipso), 148.0 (ArCipso), 140.7 (ArCipso), (ArC), 127.9 (ArC), 127.4 (ArC), 126.9 (ArC), 112.2 (ArCH=C); HRMS
126.1 (ArC), 124.9 (O‐C=CHAr), 121.4 (ArH), 114.5 (ArCH), 112.6 (APPI, pos): m/z 264.0539 (264.0535 calc for C15H8N2O3 (M)+).
(ArC), 55.7 (OCH3), 25.8 (C(CH3)3), 18.7 (C(CH3)3), ‐4.4 (Si(CH3)2);
HRMS (ESI, pos.): m/z 374.1295 (374.1298 calc. for C18H22N2O5Si (Z)‐3‐Diazo‐5‐(4‐(trifluoromethyl)benzylidene)furan‐2,4(3H,5H)‐
(M)+), 397.1187 (397.1196 calc. for C18H22N2NaO5Si (M+Na)+).
dione (11k): The reaction of 10 (126 mg, 1.00 mmol), 4‐
(trifluoromethyl)benzaldehyde (134 µL, 1.00 mmol), TiCl4 (0.32 mL,
3.0 mmol) and 2,4,6‐collidine (0.40 mL, 3.0 mmol) in CH2Cl2 (5 mL)
(Z)‐5‐(4‐((tert‐Butyldimethylsilyl)oxy)‐3‐(3‐methylbut‐2‐en‐1‐
yl)benzylidene)‐3‐diazofuran‐2,4(3H,5H)‐dione (11h): The reaction according to the general procedure provided, after purification by
of 10 (350 mg, 2.78 mmol), 4‐((tert‐butyldimethylsilyl)oxy)‐3‐(3‐ flash column chromatography on silica gel (hexanes/EtOAc, 8.5:1.5
methylbut‐2‐en‐1‐yl)benzaldehyde (846 mg, 2.78 mmol), TiCl4 (0.90 to 4:1), 239 mg (85%) of 11k as a yellow solid.
mL, 8.3 mmol) and 2,4,6‐collidine (1.10 mL, 8.33 mmol) in CH2Cl2 (12 Rf = 0.56 (hexanes/EtOAc, 7:3); mp: 158‐162 °C; IR (neat): 3072, 2924,
mL) according to the general procedure provided, after purification 2168, 1783, 1710, 1653, 1355, 1317, 1170, 1120, 1045, 1013, 963
by flash column chromatography on silica gel (hexanes/EtOAc, 19:1), cm‐1; 1H NMR (300 MHz, CDCl3): δ 7.84 (d, 2H, J = 8.3 Hz, ArH), 7.65
902 mg (79%) of 11h as a yellow solid.
(d, 2H, J = 8.3 Hz, ArH), 6.67 (s, 1H, ArCH=C); 13C NMR (75 MHz,
Rf = 0.63 (hexanes/EtOAc, 7:3); mp: 118‐121 °C; IR (neat): 2961, 2929, CDCl3): δ 174.4 (C=O), 159.8 (OC=O), 143.4 (O‐C=CHAr), 134.3 (q, 5JC‐
2858, 2137, 1782, 1708, 1648, 1598, 1497, 1364, 1276, 1076, 931 cm‐ F = 1.4 Hz, ArCipso), 131.6 (q, 2JC‐F = 32.7 Hz, ArCipso), 131.3 (2 × ArC),
1; 1H NMR (300 MHz, CDCl3): δ 7.59 (dd, 1H, J = 8.4, 2.3 Hz, ArH), 7.49 125.85 (q, 3JC‐F = 3.8 Hz, 2 × ArC), 123.7 (q, 1JC‐F = 272.3 Hz, CF3), 109.5
(d, 1H, J = 2.3 Hz, ArH), 6.82 (d, 1H, J = 8.4 Hz, ArH), 6.66 (s, 1H, (ArCH=C); HRMS (APPI, neg.): m/z 282.0254 (282.0252 calc. for
ArCH=C), 5.24‐5.33 (m, 1H, (CH3)2C=CH), 3.30 (d, 2H, J = 7.1 Hz, C12H5F3N2O3, (M)‐).
C=CHCH2), 1.77 (br d, 3H, J = 1.0 Hz, CH3), 1.71 (br s, 3H, CH3), 1.02 (s,
9H, 3 × CH3), 0.27 (s, 6H, 2 × CH3); 13C NMR (75 MHz, CDCl3): δ 174.7 (Z)‐5‐(4‐Bromobenzylidene)‐3‐diazofuran‐2,4(3H,5H)‐dione (11l):
(C=O), 160.4 (OC=O), 156.0 (ArCipso), 140.4 (O‐C=CHAr), 133.61 (ArC), The reaction of 10 (150 mg, 1.19 mmol), 4‐bromobenzaldehyde (220
133.57 (ArCipso or (CH3)2C=CH), 133.1 (ArCipso or (CH3)2C=CH), 130.6 mg, 1.19 mmol), TiCl4 (0.39 mL, 3.6 mmol) and 2,4,6‐collidine (0.47
(ArC or (CH3)2C=CH), 123.9 (ArCipso or (CH3)2C=CH), 121.7 (ArC or mL, 3.6 mmol) in CH2Cl2 (7 mL) according to the general procedure
ArCH=C), 118.9 (ArC), 112.6 (ArCH=C), 28.4 (CH2), 25.7 (4 × CH3), 18.3 provided, after purification by flash column chromatography on silica
(Si‐C(CH3)3), 17.9 (CH3), ‐4.1 (2 × SiCH3); HRMS (APPI, pos.): m/z gel (hexanes/EtOAc, 8.5:1.5 to 4:1), 287 mg (82%) of 11l as a yellow
412.1827 (412.1818 calc. for C22H28N2O4Si, (M)+) and 413.1859 solid.
(413.1897 calc. for C22H29N2O4Si, (M+H)+).
Rf = 0.36 (hexanes/EtOAc, 7:3); mp: 214‐218 °C; IR (neat): 2163, 1780,
1702, 1638, 1579, 1484, 1354, 1306, 1244, 1131, 1064, 1045, 1003,
960 cm‐1; 1H NMR (300 MHz, CDCl3): δ 7.62 (d, 2H, J = 8.6 Hz, ArH),
(Z)‐3‐Diazo‐5‐((2,2‐dimethylchroman‐6‐yl)methylene)furan‐
2,4(3H,5H)‐dione (11i): The reaction of 10 (200 mg, 1.59 mmol), 2,2‐ 7.55 (d, 2H, J = 8.6 Hz, ArH), 6.62 (s, 1H, ArCH=C); 13C NMR (75 MHz,
dimethylchroman‐6‐carbaldehyde (302 mg, 1.59 mmol), TiCl4 (0.52 CDCl3): δ 174.4 (C=O), 159.9 (OC=O), 142.3 (O‐C=CHAr), 132.7 (2 ×
mL, 4.8 mmol) and 2,4,6‐collidine (0.63 mL, 4.8 mmol) in CH2Cl2 (9 ArC), 132.3 (2 × ArC), 129.8 (ArCipso), 125.0 (ArCipso), 110.4 (ArCH=C);
mL) according to the general procedure provided, after purification HRMS (APPI, pos.): m/z 291.9481 (291.9484 calc. for C11H579BrN2O3,
by flash column chromatography on silica gel (hexanes/EtOAc, 4:1 to (M)+) and 293.9455 (293.9463 calc. for C11H581BrN2O3, (M)+).
7:3), 430 mg (91%) of 11i as a yellow‐orange solid.
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 7 of 13
View Article Online
DOI: 10.1039/C8OB01511B
Journal Name
ARTICLE
(Z)‐3‐Diazo‐5‐(4‐nitrobenzylidene)furan‐2,4(3H,5H)‐dione (11m): Rf = 0.19 (hexanes/EtOAc, 9.5:0.5); IR (neat): 2963, 2907, 2870, 2148,
1
The reaction of 10 (75 mg, 0.59 mmol), 4‐nitrobenzaldehyde (90 mg, 1780, 1712, 1622, 1356, 1241, 1083, 988 cm‐1; H NMR (300 MHz,
0.59 mmol), TiCl4 (0.2 mL, 1.78 mmol) and 2,4,6‐collidine (0.2 mL, CDCl3): δ 5.91 (s, 1H, ((CH3)3C)‐CH), 1.23 (s, 9H, (CH3)3). 13C NMR (75
1.78 mmol) in CH2Cl2 (5 mL) according to the general procedure MHz, CDCl3): δ 175.2, (C=O), 160.3 (O‐C=O), 142.3 (O‐C=CH(C(CH3)3)),
provided, after purification by flash column chromatography on silica 124.8 (C(CH3)3CH=C), 33.0 (C(CH3)3), 29.7 (CH3)3; HRMS (APPI, pos.):
gel (hexanes/EtOAc, 4:1), 95 mg (62%) of 11m as a light brown solid. m/z 194.0699 (194.0691 calc. for C9H10N2O3 (M)+), 195.0769
Rf = 0.20 (hexanes/EtOAc, 4:1); mp: 188‐190 oC; IR (neat): 2922, (195.0770 calc. for C9H11N2O3 (M+H)+).
2850, 2162, 1767, 1706, 1643, 1504, 1362, 1338, 1296, 1240, 1070,
962, 911, 857, 828, 750 cm‐1; 1H NMR (500 MHz, DMSO‐d6):  8.34
(d, 2H, J = 8.9 Hz, ArH), 8.09 (d, 2H, J = 8.9 Hz, ArH), 6.92 (s, 1H, ArCH);
13C NMR (125 MHz, DMSO‐d6):  174.4 (C=O), 160.1 (O‐C=O), 147.2
(ArCipso), 144.5 (ArCipso), 137.8 (O‐C=CHAr), 131.7 (2 x ArH), 124.0 (2
x ArH), 106.5 (ArCH=C); HRMS (APPI, pos.): m/z 259.0224 (259.0229
calc. for C11H5N3O5 (M+)), 260.0296 (260.0307 calc. for C11H6N3O6
(M+H)+).
3‐Diazo‐5‐(hydroxy(p‐tolyl)methyl)furan‐2,4(3H,5H)‐dione
(12):
The reaction of 10 (126 mg, 1.00 mmol), tolualdehyde (0.14 mL, 1.20
mmol), BF3.OEt2 (0.37 mL, 3.0 mmol) and Et3N (0.43 mL, 3.0 mmol)
in CH2Cl2 (3 mL) according to the general procedure provided, after
purification by flash column chromatography on silica gel
(hexanes/EtOAc, 4:1), 83 mg (38%) of 12 (dr = 1.2/1) as a white gum.
Rf = 0.23 (hexanes/EtOAc, 4:1); IR: 3461, 2923, 2146, 1768, 1698,
1515, 1353, 1215, 1110, 1084, 1017 cm‐1; 1H NMR (500 MHz, CDCl3):
(Z)‐3‐Diazo‐5‐(furan‐2‐ylmethylene)furan‐2,4(3H,5H)‐dione (11n): Major diastereomer: δ 7.26 (d, 2H, J = 8.0 Hz, ArH), 7.18 (d, 2H, J =
The reaction of 10 (150 mg, 1.19 mmol), 2‐furaldehyde (99 µL, 1.2 8.0 Hz, ArH), 5.14 (d, 1H, J = 8.0 Hz, CHCO), 4.99 (d, 1H, J = 3.8 Hz,
mmol), TiCl4 (0.39 mL, 3.6 mmol) and 2,4,6‐collidine (0.47 mL, 3.6 CHOH), 2.67 (br s, 1H, OH), 2.35 (s, 3H, CH3); Minor diastereomer: δ
mmol) in CH2Cl2 (7 mL) according to the general procedure provided, 7.33 (d, 2H, J = 8.0 Hz, ArH), 7.20 (d, 2H, J = 8.0 Hz, ArH), 5.18 (br s,
after purification by flash column chromatography on silica gel 1H, CHCO), 4.84 (d, 1H, J = 2 Hz, CHOH), 2.36 (s, 3H, CH3); 13C NMR
(hexanes/EtOAc, 9:1 to 8.5:1.5), 227 mg (93%) of 11n as an orange‐ (125 MHz, CDCl3), Major diastereomer: δ 186.0 (C=O), 163.0 (O‐C=O),
yellow solid.
139.0 (ArCipso), 135.5 (ArCipso), 129.6 (2 × ArC), 126.9 (2 × ArC), 86.6
Rf = 0.29 (hexanes/EtOAc, 9:1); mp: 163‐167 °C; IR (neat): 2923, 2853, (CHCO), 73.6 (CHOH), 21.3 (CH3); minor diastereomer: δ 186.8 (C=O),
2166, 1761, 1698, 1641, 1353, 1315, 1242, 1070, 1014, 964 cm‐1; 1H 163.5 (O‐C=O), 138.9 (ArCipso), 133.5 (ArCipso), 129.5 (2 × ArC),
NMR (300 MHz, CDCl3): δ 7.58 (dd, 1H, J = 1.7, 0.5 Hz, ArH), 7.03 (br 126.6 (2 × ArC), 86.7 (CHCO), 72.5 (CHOH), 21.3 (CH3); HRMS (APPI,
dt, 1H, J = 3.5, 0.5 Hz, ArH), 6.70 (br s, 1H, ArCH=C), 6.57 (ddd, 1H, J pos.): m/z 228.0543 (228.0535 calc. for C12H8N2O3 ((M‐H2O)+),
= 3.5, 1.7, 0.5 Hz, ArH); 13C NMR (75 MHz, CDCl3): δ 173.8 (C=O), 160.0 229.0611 (229.0613 calc. for C12H9N2O3 (((M‐H2O)+H)+).
(OC=O), 147.5 (O‐C=CHAr or ArCipso), 145.6 (ArC), 139.8 (O‐C=CHAr or
ArCipso), 117.6 (ArC), 113.2 (ArC), 100.5 (ArCH=C); HRMS (APPI, pos.): General procedures for the insertion reactions of (Z)‐5‐
m/z 204.0168 (204.0171 calc. for C9H4N2O4, (M)+)
arylidene/alkylidene‐3‐diazofuran‐2,4(3H,5H)‐diones and arenes:
Method A: To a solution of (Z)‐5‐arylidene/alkylidene‐3‐diazofuran‐
2,4(3H,5H)‐dione (1 equiv) in the aromatic compound was added the
(Z)‐5‐(Cyclopentylmethylene)‐3‐diazofuran‐2,4(3H,5H)‐dione
(11o): To a solution of 10 (150 mg, 1.19 mmol) in CH2Cl2 (4 mL) was Rh(II) catalyst (1 mol%) at room temperature. The reaction mixture
added TiCl4 (0.39 mL, 3.57 mmol) at ‐78 °C and the solution was was then placed in a pre‐heated oil bath at 100 °C. The mixture was
stirred for 20 min. To the mixture was added 2,4,6‐collidine (0.47 mL, heated until complete consumption of the diazo compound (TLC),
3.6
cyclopentanecarboxaldehyde (127 µL, 1.19 mmol) in CH2Cl (2 mL) was purified by flash chromatography on silica gel.
over 5 min. The mixture was stirred at ‐78 °C for 20 min and then at Method B: To
suspension of (Z)‐5‐arylidene/alkylidene‐3‐
mmol)
followed
by
dropwise
addition
of then cooled to room temperature and concentrated. The residue
a
0 °C for 1 h. Saturated aqueous NH4Cl (~3 mL) was added followed by
cold water (~2 mL). The resulting mixture was extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(hexanes/EtOAc, 19:1) to provide 97 mg (40%) of 11o as a brown
gum.
Rf = 0.73 (hexanes/EtOAc, 7:3); IR (neat): 2953, 2868, 2145, 1777,
1709, 1663, 1347, 1273, 1125, 1072, 1058, 1020, 960 cm‐1; 1H NMR
(300 MHz, CDCl3): δ 5.93 (d, 1H, J = 9.9 Hz, C5H9CH=C), 3.03‐2.87 (m,
1H, CH2CHCH2), 2.00‐7.86 (m, 2H, CH2), 1.80‐1.56 (m, 4H, CH2), 1.47‐
1.32 (m, 2H, CH2); 13C NMR (75 MHz, CDCl3): δ 174.2 (C=O), 160.3
(OC=O), 143.2 (O‐C=CHC5H9), 121.2 (C5H9CH=C), 36.8 (CH2CHCH2),
33.1 (2 × CH2), 25.4 (2 × CH2); HRMS (ESI, neg.): m/z 178.0628
(178.0630 calc. for C10H10O3, (M‐N2)‐) and 223.0613 (223.0606 calc.
for C11H11O5, (M+HCOO‐N2)‐).
diazofuran‐2,4(3H,5H)‐dione (1 equiv) in ,,‐trifluorotoluene or
DCE was added the aromatic compound (4 equiv) followed by the
Rh(II) catalyst (1 mol%) at room temperature and the reaction
mixture was placed in an oil bath that was pre‐heated to 50 °C or to
100 °C. The mixture was heated until complete consumption of the
diazo compound (TLC), then cooled to room temperature and
concentrated. The residue was purified by flash chromatography on
silica gel.
(Z)‐5‐Benzylidene‐4‐hydroxy‐3‐phenylfuran‐2(5H)‐one (Pulvinone
(1)):15,30 The reaction of 11b (40 mg, 0.19 mmol), and benzene in the
presence of Rh2(OAc)4 (0.80 mg, 1.9 x 10‐3 mmol) in benzene (1.5 mL)
at reflux for 42 h according to Method A provided, after purification
by flash column chromatography on silica gel (hexanes/EtOAc, 7:3 to
1:1), 38 mg (78%, 81% based on recovery of 11b) of 1 as a yellow
solid.
Rf = 0.17 (hexanes/EtOAc, 7:3); mp: 247‐251 °C (Lit.24 250‐251 oC); IR
(neat): 3007 (br), 2920, 2851, 2632 (br), 1698, 1621, 1595, 1406,
1332, 1303, 1210, 1150, 1122, 1001 cm‐1; 1H NMR (300 MHz, DMSO‐
d6): δ 7.98‐7.91 (m, 2H, ArH), 7.80‐7.72 (m, 2H, ArH), 7.53‐7.27 (m,
6H, ArH), 6.75 (s, 1H, PhCH); 13C NMR (75 MHz, DMSO‐d6): δ 167.9
(C=O or C=COH), 163.8 (C=O or C=COH), 142.4 (O‐C=CHPh), 132.7
(ArCipso), 130.1 (2 × ArC), 129.8 (ArCipso), 129.0 (2 × ArC), 128.8 (ArC),
(Z)‐3‐Diazo‐5‐(2,2‐dimethylpropylidene)furan‐2,4(3H,5H)‐dione
(11p): The reaction of 10 (75 mg, 0.59 mmol), pivalaldehyde (64 μL,
0.59 mmol), TiCl4 (0.2 mL, 1.78 mmol) and 2,4,6‐collidine (0.23 mL,
1.78 mmol) in CH2Cl2 (5 mL) according to the general procedure
provided, after purification by flash column chromatography on silica
gel (hexanes/EtOAc, 9.5:0.5), 49 mg (43%) of 11p as a colourless gum.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 13
View Article Online
DOI: 10.1039/C8OB01511B
ARTICLE
Journal Name
128.3 (2 × ArC), 127.2 (2 × ArC), 127.1 (ArC), 107.6 (PhCH=C), 100.1 99.4 (ArCH=C), 55.6 (OCH3), 55.5 (OCH3), 55.1 (OCH3); HRMS (APPI,
(C=COH); HRMS (APPI, pos.): m/z 264.0796 (264.0786 calc. for pos.): m/z 354.1116 (354.1103 calc. for C20H18O6, (M)+) and 355.1189
C17H12O3, (M)+) and 265.0868 (265.0865 calc. for C17H13O3, (M+H)+).
(355.1182 calc. for C20H19O6, (M+H)+).
(Z)‐4‐Hydroxy‐5‐(4‐methoxybenzylidene)‐3‐(4‐
(Z)‐5‐(3,4‐Dimethoxybenzylidene)‐4‐hydroxy‐3‐(2‐
methoxyphenyl)furan‐2(5H)‐one (13a):27 The reaction of 11d (60 methoxyphenyl)furan‐2(5H)‐one (14b):
mg, 0.25 mmol) and anisole (107 µL, 0.980 mmol) in the presence of Rf = 0.43 (hexanes/EtOAc, 1:1); mp: 104‐108 °C; IR (neat): 3075 (br),
Rh2(CF3CO2)4 (1.6 mg, 2.5 x 10‐3 mmol) in ,,‐trifluorotoluene (2
mL) at 100 °C for 6 h according to Method B provided, after
purification by flash column chromatography on silica gel
(hexanes/EtOAc, 4:1 to 3:7), 56 mg (71%) of 13a as a brown solid and
16 mg (20%) of 13b as a yellow solid.
2954, 2923 (br), 2839, 1748, 1596, 1515, 1451, 1328, 1272, 1237,
1
1142, 1121, 1012, 966 cm‐1; H NMR (300 MHz, CDCl3): δ 8.09 (dd,
1H, J = 7.7, 1.7 Hz, ArH), 7.45 (d, 1H, J = 2.0 Hz, ArH), 7.40‐7.32 (m,
2H, ArH), 7.19 (td, 1H, J = 7.7, 1.1 Hz, ArH), 7.07 (dd, 1H, J = 8.3, 1.1
Hz, ArH), 6.89 (d, 1H, J = 8.3 Hz, ArH), 6.35 (s, 1H, ArCH=C), 4.04 (s,
3H, OCH3), 3.97 (s, 3H, OCH3), 3.93 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3): δ 168.3 (C=O or C=COH), 162.8 (C=O or C=COH), 154.7
(ArCipso), 150.1 (ArCipso), 149.2 (ArCipso), 140.5 (O‐C=CHAr), 130.2
(ArC), 129.4 (ArC), 126.1 (ArCipso), 124.6 (ArC), 123.3 (ArC), 119.4
(ArCipso), 113.0 (2 × ArC), 111.2 (ArC or ArCH=), 108.4 (ArC or ArCH=C),
99.2 (C=COH), 57.7 (OCH3), 56.2 (OCH3), 56.1 (OCH3); HRMS (APPI,
pos.): m/z 354.1100 (354.1103 calc. for C20H18O6, (M)+) and 355.1173
(355.1182 calc. for C20H19O6, (M+H)+).
Rf = 0.21 (hexanes/EtOAc, 1:1); mp: 241‐244 °C (Lit.15 250‐253 ºC); IR
(neat): 3003, 2954, 2833, 2601 (br), 1685, 1595, 1507, 1426, 1398,
1247, 1175, 1156, 1130, 1098, 1027, 1003 cm‐1; 1H NMR (300 MHz,
CDCl3/one drop DMSO‐d6): δ 7.90 (d, 2H, J = 8.9 Hz, ArH), 7.71 (d, 2H,
J = 8.8 Hz, ArH), 6.91 (d, 2H, J = 8.8 Hz, ArH), 6.87 (d, 2H, J = 8.9 Hz,
ArH), 6.47 (s, 1H, ArCH=C), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3); 13
C
NMR (75 MHz, CDCl3/one drop DMSO‐d6): δ 169.0 (C=O or C=COH),
162.3 (C=O or C=COH), 159.7 (ArCipso), 158.4 (ArCipso), 141.1 (O‐
C=CHAr), 131.8 (2 × ArC), 128.9 (2 × ArC), 125.8 (ArCipso), 122.6
(ArCipso), 114.1 (2 × ArC), 113.5 (2 × ArC), 107.3 (ArCH=C), 100.6
(C=COH), 55.2 (OCH3), 55.1 (OCH3); HRMS (APPI, pos.): m/z 324.0992
(324.0998 calc. for C19H16O5, (M)+) and 325.1064 (325.1076 calc. for
C19H17O5, (M+H)+).
(Z)‐3‐(2,4‐Dimethoxyphenyl)‐4‐hydroxy‐5‐(4‐
methoxybenzylidene)furan‐2(5H)‐one (15):27 The reaction of 11d
(65 mg, 0.27 mmol) and 1,3‐dimethoxybenzene (139 µL, 1.06 mmol)
in the presence of Rh2(CF3CO2)4 (1.7 mg, 2.7 x 10‐3 mmol) in ,,‐
trifluorotoluene (2 mL) at 100 °C for 22 h according to Method B
provided, after purification by flash column chromatography on silica
gel (hexanes/EtOAc, 7:3), 72 mg (76%) of 15 as a yellow solid.
(Z)‐4‐Hydroxy‐5‐(4‐methoxybenzylidene)‐3‐(2‐
methoxyphenyl)furan‐2(5H)‐one (13b):
Rf = 0.40 (hexanes/EtOAc, 7:3); mp: 109‐115 R °C; IR (neat): 2922 (br), Rf = 0.19 (hexanes/EtOAc, 7:3); mp: 176‐178 °C (Lit.2 180‐183 °C); IR
2838 (br), 1708, 1593, 1511, 1451, 1428, 1302, 1244, 1175, 1145, (neat): 3258 (br), 2926 (br), 2841, 1751, 1603, 1577, 1508, 1327,
1
1125, 1098, 1024, 983, 922 cm‐1; 1H NMR (300 MHz, CDCl3): δ 9.12 (s, 1299, 1253, 1210, 1160, 1096, 1023, 963, 932 cm‐1; H NMR (300
1H, OH), 8.09 (dd, 1H, J = 7.8, 1.1 Hz, ArH), 7.78 (d, 2H, J = 8.8 Hz, MHz, CDCl3): δ 8.92 (s, 1H, OH), 8.01 (d, 1H, J = 8.7 Hz, ArH), 7.76 (d,
ArH), 7.35 (ddd, 1H, J = 7.8, 7.5, 1.2 Hz, ArH), 7.18 (br td, 1H, J = 7.8, 2H, J = 8.8 Hz, ArH), 6.92 (d, 2H, J = 8.8 Hz, ArH), 6.70 (dd, 1H, J = 8.7,
1.1 Hz, ArH), 7.06 (dd, 1H, J = 8.2, 1.1 Hz, ArH), 6.93 (d, 2H, J = 8.8 Hz, 2.4 Hz, ArH), 6.59 (d, 1H, J = 2.4 Hz, ArH), 6.31 (s, 1H, ArCH=C), 4.00
ArH), 6.37 (s, 1H, ArCH=C), 4.03 (s, 3H, OCH3), 3.85 (s, 3H, OCH3); 13
C
(s, 3H, OCH3), 3.84 (s, 6H, 2 × OCH3); 13C NMR (75 MHz, CDCl3): δ
NMR (75 MHz, CDCl3): δ 168.4 (C=O or C=COH), 162.8 (C=O or C=COH 168.6 (C=O or C=COH), 161.3 (C=O or C=COH or ArCipso), 160.7 (C=O
or ArCipso), 160.3 (C=O or C=COH or ArCipso), 154.7 (ArCipso), 140.3 (O‐ or C=COH or ArCipso), 160.1 (C=O or C=COH or ArCipso), 155.8 (ArCipso),
C=CHAr), 132.4 (2 × ArC), 130.2 (ArC), 129.3 (ArC), 125.7 (ArCipso), 140.3 (O‐C=CHAr), 132.1 (2 × ArC), 130.8 (ArC), 125.7 (ArCipso), 114.3
123.3 (ArC), 119.4 (ArCipso), 114.4 (2 × ArC), 113.0 (ArC), 108.3 (2 × ArC), 111.7 (ArCipso), 107.5 (ArC), 107.1 (ArC), 100.3 (ArCH=C),
(ArCH=C), 99.2 (C=COH), 57.7 (OCH3), 55.5 (OCH3); HRMS (APPI, pos.): 99.0 (C=COH), 57.3 (OCH3), 55.6 (OCH3), 55.3 (OCH3); HRMS (APPI,
m/z 324.0986 (324.0998 calc. for C19H16O5, (M)+) and 325.1058 pos.): m/z 354.1108 (354.1103 calc. for C20H18O6, (M)+) and 355.1181
(325.1076 calc. for C19H17O5, (M+H)+).
(355.1182 calc. for C20H19O6, (M+H)+).
(Z)‐5‐(3,4‐Dimethoxybenzylidene)‐4‐hydroxy‐3‐(4‐
(Z)‐5‐(4‐(tert‐Butyldimethylsilyloxy)‐3‐methoxybenzylidene)‐3‐(4‐
methoxyphenyl)furan‐2(5H)‐one (14a):27 The reaction of 11f (90 mg, (tert‐butyldimethylsilyloxy)phenyl)‐4‐hydroxyfuran‐2(5H)‐one
0.33 mmol) and anisole (142 µL, 1.31 mmol) in the presence of (16): The reaction of 11f (150 mg, 0.40 mmol) and tert‐
Rh2(CF3CO2)4 (1.2 mg, 3.3 x 10‐3 mmol) in ,,‐trifluorotoluene (3
mL) at 100 °C for 22 h according to Method B provided, after
purification by flash column chromatography on silica gel
(hexanes/EtOAc, 7:3 to 3:7), 61 mg (53%) of 14a as a brown solid and
16 mg (14%) of 14b as a yellow solid.
butyldimethyl(phenoxy)silane (334 mg, 1.60 mmol) in the presence
of Rh2(esp)2 (3 mg, 0.004 mmol) in DCE at reflux for 3 h according to
Method
B provided, after purification of by flash column
chromatography on silica gel (hexanes/EtOAc, 9.2:0.8), 29 mg (40%)
of 16 as a yellow solid.
Rf = 0.19 (hexanes/EtOAc, 9.2:0.8); mp: 201‐203 oC; IR (neat): 3012,
2950, 2927, 2884, 2855, 1693, 1658, 1627, 1597, 1510, 1468, 1426,
Rf = 0.22 (hexanes/EtOAc, 1:1); mp: 215‐219 °C (Lit.2 219‐222 °C); IR
(neat): 3216 (br), 2959, 2921, 2851, 1693, 1657, 1625, 1595, 1510,
1464, 1443, 1425, 1401, 1242, 1139, 1096, 1018, 987 cm‐1; 1H NMR
(300 MHz, CDCl3/CD3OD, 97:3): δ 7.81 (d, 2H, J = 8.8 Hz, ArH), 7.45
(d, 1H, J = 1.7 Hz, ArH), 7.30 (dd superimposed on CHCl3 s, 1H, J = 8.2,
1.7 Hz, ArH), 6.96 (d, 2H, J = 8.8 Hz, ArH), 6.87 (d, 1H, J = 8.2 Hz, ArH),
6.34 (s, 1H, ArCH=C), 3.95 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.84 (s,
3H, OCH3); 13C NMR (75 MHz, DMSO‐d6): δ 168.1 (C=O or C=COH),
162.7 (C=O or C=COH), 158.1 (ArCipso), 149.6 (ArCipso), 148.7 (ArCipso),
141.0 (O‐C=CHAr), 128.4 (2 × ArC), 125.6 (ArCipso), 123.8 (ArC), 122.4
(ArCipso), 113.8 (2 × ArC), 113.0 (ArC), 112.0 (ArC), 107.3 (C=COH),
1
1399, 1360, 1292, 1264, 1248, 1149, 1130, 967, 911 cm‐1; H NMR
(300 MHz, DMSO‐d6): δ 7.88‐7.82 (m, 2H, ArH), 7.34 (d, 1H, J = 2.0 Hz,
ArH), 7.25 (dd, 1H, J = 8.4, 2.0 Hz, ArH), 6.95‐6.89 (m, 3H, ArH), 6.63
(s, 1H, ArCH), 3.82 (s, 3H, OCH3), 0.97 (s, 9H, Si‐C(CH3)3), 0.96 (s, 9H,
Si‐C(CH3)3), 0.21 (s, 6H, Si(CH3)2), 0.16 (s, 6H, Si(CH3)2). 13C NMR (75
MHz, DMSO‐d6): δ 168.0 (C=O or C=COH), 162.6 (C=O or C=COH),
154.1 (ArCipso), 150.6 (ArCipso), 145.3 (O‐C=CHAr), 141.0 (ArCipso),
128.5 (2 × ArC), 126.8 (ArCipso), 123.7 (ArC), 123.2 (ArCipso), 120.9
(ArC), 119.7 (2 × ArC), 113.7 (ArC), 107.4 (Ar‐CH), 99.6 (C=COH), 55.4
8 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 9 of 13
View Article Online
DOI: 10.1039/C8OB01511B
Journal Name
ARTICLE
(OCH3), 25.6 (C(CH3)3), 25.5 (C(CH3)3), 18.2 (C(CH3)3), 18.0 (C(CH3)3), ‐ tert‐Butyl(2,2‐dimethylchroman‐7‐yloxy)dimethylsilane (21): To a
4.5 (Si(CH3)2), ‐4.7 (Si(CH3)2); HRMS (ESI, pos.): m/z 554.2508 solution of 2,2‐dimethylchroman‐7‐ol41 (650 mg, 3.65 mmol) in DMF
(554.2520 calc. for C30H42O6Si2 (M)+), 555.2581 (555.2598 calc. for (8 mL) at ambient temperature was added imidazole (348 mg, 5.11
C30H43O6Si2 (M+H)+), 577.2400 (577.2418 calc. for C30H42NaO6Si2 mmol) followed by TBSCl (715 mg, 4.74 mmol) and the mixture was
(M+Na)+).
stirred for 2 h. Cold water (8 mL) was added and the resulting mixture
was extracted with ethyl acetate (3 × 20 mL). The combined organic
layers were washed with water (1 × 10 mL), brine, dried (Na2SO4) and
(Z)‐5‐((2,2‐Dimethylchroman‐6‐yl)methylene)‐4‐hydroxy‐3‐(7‐
methoxy‐2,2‐dimethylchroman‐6‐yl)furan‐2(5H)‐one (19): The concentrated under reduced pressure to provide 850 mg (80%) of 21
reaction of 11i (60 mg, 0.20 mmol) and 1839 (155 mg, 0.800 mmol) in as a colourless liquid.
the presence of Rh2(esp)2 (1.30 mg, 2.01 x 10‐3 mmol) in ,,‐
trifluorotoluene (2 mL) at 50 °C for 2 h according to Method B
provided, after purification by flash column chromatography on silica
gel (hexanes/EtOAc, 9:1 to 8.5:1.5), 79 mg (85%) of 19 as a yellow
solid.
Rf = 0.6 (hexanes/EtOAc, 9:1); IR (neat): 2974, 2929, 2895, 2857,
1617, 1576, 1501, 1472, 1344, 1307, 1281, 1253, 1168, 1149, 1120,
1106, 999, 836, 777 cm‐1; 1H NMR (500 MHz, CDCl3): δ 6.88 (d, 1H, J
= 8.2 Hz), 6.33 (dd, 1H, J = 8.2, 2.4 Hz, ArH), 6.29 (d, 1H, J = 2.4 Hz,
ArH), 2.69 (t, 2H, J = 6.8 Hz, ArCH2CH2), 1.77 (t, 2H, J = 6.8 Hz,
ArCH2CH2) 1.31 (s, 6H, 2 × CH3), 0.97 (s, 9H, C(CH3)3), 0.18 (s, 6H,
Si(CH3)2); 13C NMR (125 MHz, CDCl3): δ 155.2 (ArCipso), 155.0
(ArCipso), 130.0 (ArC), 114.2 (ArCipso), 112.4 (ArC), 108.9 (ArC), 74.5
(Ar‐O‐C(CH3)2), 33.4 (ArCH2CH2), 27.3 (2 × CH3), 26.1 (C(CH3)3), 22.3
(Si‐C(CH3)3), 18.6 (ArCH2CH2), ‐4.0 (Si(CH3)2); HRMS (APPI, pos.): m/z
292.1865 (292.1858 calc. for C17H28O2Si (M)+) and 293.1944
(239.1937 calc. for C17H29O2Si (M+H)+).
Rf = 0.26 (hexanes/EtOAc, 9.5:0.5); mp: 200‐204 °C; IR (neat): 3277
(br), 2976, 2933 (br), 2848, 1742, 1605, 1578, 1492, 1451, 1309,
1
1260, 1151, 1117, 1089, 1017, 976, 945 cm‐1; H NMR (300 MHz,
CDCl3): δ 8.98 (s, 1H, OH), 7.78 (s, 1H, ArH), 7.60 (br d, 1H, J = 1.8 Hz,
ArH), 7.51 (dd, 1H, J = 8.5, 1.8 Hz, ArH), 6.79 (d, 1H, J = 8.5 Hz, ArH),
6.49 (s, 1H, ArH), 6.27 (s, 1H, ArCH=C), 3.96 (s, 3H, OCH3), 2.82 (t, 2H,
J = 6.7 Hz, ArCH2CH2), 2.80 (t, 2H, J = 6.7 Hz, ArCH2CH2) (overlapping
triplets), 1.83 (t, 2H, J = 6.7 Hz, ArCH2CH2), 1.82 (t, 2H, J = 6.7 Hz,
ArCH2CH2), 1.35 (s, 12H, 4 × CH3); 13C NMR (75 MHz, CDCl3): δ 168.8
(C=O or C=COH), 161.3 (C=O or C=COH), 155.0 (ArCipso), 154.9
(ArCipso), 154.2 (ArCipso), 139.9 (O‐C=CHAr), 131.9 (ArC), 130.5 (ArC),
130.2 (ArC), 124.8 (ArCipso), 121.3 (ArCipso), 117.7 (ArC), 115.5
(ArCipso), 110.7 (ArCipso), 107.8 (ArC), 101.6 (ArCH=C), 99.0 (C=COH),
75.2 (Ar‐O‐C(CH3)2), 75.0 (Ar‐O‐C(CH3)2), 57.3 (OCH3), 32.8
(ArCH2CH2), 32.7 (ArCH2CH2), 26.94 (2 × CH3), 26.86 (2 × CH3), 22.5
(ArCH2CH2), 21.8 (ArCH2CH2); HRMS (APPI, pos.): m/z 462.2042
(462.2042 calc. for C28H30O6, (M)+) and 463.2114 (463.2121 calc. for
C28H31O6, (M+H)+).
(Z)‐3‐(7‐(tert‐Butyldimethylsilyloxy)‐2,2‐dimethylchroman‐6‐yl)‐5‐
(4‐(tert‐butyldimethylsilyloxy)‐3‐(3‐methylbut‐2‐
enyl)benzylidene)‐4‐hydroxyfuran‐2(5H)‐one (22): The reaction of
11h (47 mg, 0.11 mmol) and 21 (133 mg, 0.45 mmol), Rh2(esp)2 (0.8
mg, 0.001 mmol) in DCE at reflux for 6 h according to Method B
provided, after purification of by flash column chromatography on
silica gel (hexanes/EtOAc, 9.7:0.3), 29 mg (38%, 43% based on
recovered SM) of 22 as a yellow solid.
o
Rf = 0.18 (hexanes/EtOAc, 9.7:0.3); mp: 67‐69 C; IR (neat): 2955,
2929, 2857, 1753, 1611, 1600, 1495, 1471, 1325, 1276, 1254, 1119,
1091, 837 cm‐1; 1H NMR (300 MHz, CDCl3): δ 8.73 (s, 1H, OH), 7.68
(dd, J = 8.5, 2.4 Hz, ArH), 7.60 (br s, 1H, ArH), 7.49 (d, 1H, J = 2.4 Hz,
ArH), 6.83 (d, 1H, J = 8.5 Hz, ArH), 6.39 (s, 1H, ArH), 6.27 (s, 1H, ArCH),
5.36‐5.28 (m, 1H, (CH3)2C=CH), 3.33 (d, 2H, J = 7.2 Hz, CH2CH=(CH3)2),
2.78 (t, 2H, J = 6.8 Hz, ArCH2CH2), 1.80 (t, 2H, J = 6.8 Hz, ArCH2CH2),
1.77 (s, 3H, CH=C(CH3)2), 1.73 (s, 3H, CH=C(CH3)2), 1.33 (s, 6H,
C(CH3)2) 1.02 (s, 9H, C(CH3)3), 0.96 (s, 9H, C(CH3)3), 0.26 (s, 6H,
Si(CH3)2), 0.20 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): δ 168.7
(C=O or C=COH), 161.6 (C=O or C=COH), 154.9 (ArCipso), 154.5
(ArCipso), 150.4 (ArCipso), 140.4 (O‐C=CHAr), 133.1 (ArCipso or
(CH3)2C=C) , 132.8 (ArCipso or (CH3)2C=C), 132.5 (ArC), 130.4 (ArC),
129.5 (ArC), 126.2 (ArCipso), 122.4 ((CH3)2C=C), 119.0 (ArC), 116.7
(ArCipso), 113.3 (ArCipso), 109.2 (Ar‐CH) , 107.8 (ArC) , 100.3 (C=COH),
75.1 (C(CH3)2), 32.9 (CH2), 28.7 (CH2), 27.0 ((O‐C(CH3)2), 25.9 (2 × (Si‐
C(CH3)3), 1 × C=C(CH3)2), 22.0 (CH2). 18.53 (Si‐C(CH3)2), 18.48 (Si‐
C(CH3)2), 18.1 (1× C=C(CH3)2), ‐3.9 (Si(CH3)2), ‐4.2 (Si(CH3)2); HRMS
(APPI, pos.): m/z 676.3616 (676.3615 calc. for C39H56O6Si2 (M)+) and
677.3686 (677.3694 calc. for C39H57O6Si2 (M+H)+).
(Z)‐5‐(4‐(tert‐Butyldimethylsilyloxy)‐3‐(3‐methylbut‐2‐
enyl)benzylidene)‐3‐(2,2‐dimethylchroman‐6‐yl)‐4‐hydroxyfuran‐
2(5H)‐one (20): The reaction of 11h (50 mg, 0.12 mmol) and 17 (78
mg, 0.48 mmol) in the presence of Rh2(esp)2 (0.9 mg, 0.001 mmol) in
DCE at reflux for 2 h according to Method B provided, after
purification of by flash column chromatography on silica gel
(hexanes/EtOAc, 9:1), 39 mg (59%) of 20 as a yellow solid.
Rf = 0.19 (hexanes/EtOAc, 9:1); mp: 116‐118 oC; IR (neat): 2929, 2856,
1711, 1599, 1495, 1258, 1223, 1156, 1117, 991, 935, 890 cm‐1; H
1
NMR (300 MHz, CDCl3): δ 7.64 (dd, 1H, J = 8.4, 2.1 Hz, ArH), 7.46 (d,
1H, J = 2.0 Hz, ArH) 7.39 (br s, 1H, ArH), 7.34 (br dd, 1H, J = 8.4, 1.8
Hz, ArH), 6.84 (d, 1H, J = 8.4 Hz, ArH), 6.79 (d, 1H, J = 8.5 Hz, ArH),
6.71‐6.54 (bs, 1H, OH), 6.26 (s, 1H, ArCH), 5.34‐5.25 (m, 1H,
(CH3)2C=CH), 3.32 (d, 2H, J = 7.0 Hz, CH2CH=(CH3)2), 2.80 (t, 2H, J = 6.7
Hz, ArCH2CH2), 1.80 (t, 2H, J = 6.7 Hz, ArCH2CH2), 1.76 (s, 3H,
CH=C(CH3)2), 1.71 (s, 3H, CH=C(CH3)2), 1.33 (s, 6H, O‐C(CH3)2), 1.02 (s,
9H, C(CH3)3), 0.26 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): δ 169.1
(C=O or C=COH), 160.6 (C=O or C=COH), 154.8 (ArCipso), 154.3
(ArCipso), 140.1 (O‐C=CHAr), 133.1 (ArCipso or (CH3)2C=C), 132.9 (ArCipso
or (CH3)2C=C), 132.7 (ArC), 129.6 (ArC), 129.2 (ArCipso), 126.9 (ArC),
125.8 (ArC), 122.4 (ArCipso), 122.0 (ArCipso), 119.9 ((CH3)2C=CH), 119.0
(ArC), 118.1 (ArC), 108.7 (Ar‐CH), 103.1 (C=COH), 74.9 (O‐C(CH3)2),
32.8 (CH2), 28.7 (CH2), 27.0 ((O‐C(CH3)2), 25.9 ((Si‐C(CH3)3) and 1 ×
C=C(CH3)2), 22.6 (CH3), 18.5 ((Si‐C(CH3)3), 18.0 (1 × C=C(CH3)2), ‐4.0
(Si(CH3)2); HRMS (ESI, pos.): m/z 546.2799 (546.2802 calc. for
C33H42O5Si (M)+) and 547.2872 (547.2880 calc. for C33H43O5Si (M+H)+)
and 569.2690 (569.2699 calc. for C33H42NaO5Si (M+Na)+).
General procedure for the demethylation of aryl methyl ethers 13a,
14a and 15: To a solution of methoxypulvinones in CH2Cl2 was added
BBr3 (1M in CH2Cl2) at 0 °C. The mixture was warmed to room
temperature, stirred for 20 min and then heated to reflux until
consumption of the starting material (TLC). The mixture was then
cooled to 0 °C and water (3 mL) was added. The resulting suspension
was extracted with ethyl acetate (5 x 4 mL) and the combined organic
layers were dried (Na2SO4) and concentrated under reduced
pressure. The crude product was dissolved in dichloromethane with
the aid of methanol and a few drops of hexanes were added. The
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 13
View Article Online
DOI: 10.1039/C8OB01511B
ARTICLE
Journal Name
mixture was left for a day at room temperature and the precipitated provided, after purification by flash column chromatography on silica
product (yellow solid) was isolated by filtration. This material was gel (CH2Cl2/EtOAc, 9.8:0.2 to 9:1), 63 mg (60%) of 6 as a yellow solid.
pure by 1H NMR.
Rf = 0.12 (hexanes/EtOAc, 7:3); mp: 244‐247 °C (Lit.2 241‐243 °C); IR
(neat): 2973 (br), 2928 (br), 1690, 1624, 1605, 1572, 1495, 1390,
(Z)‐4‐Hydroxy‐5‐(4‐hydroxybenzylidene)‐3‐(4‐
hydroxyphenyl)furan‐2(5H)‐one (Aspulvinone
1300, 1259, 1234, 1154, 1121, 947 cm‐1; 1H NMR (300 MHz,
E
(2)):27,43 The CDCl3/DMSO‐d6, 95:5): δ 10.99 (br, 1H, OH), 7.70 (s, 1H, ArH), 7.68
reaction of 13a (80 mg, 0.25 mmol), BBr3 (1.5 mL 1.5 mmol, 1.0 M in (dd, 1H, J = 8.6. 2.0 Hz, ArH), 7.56 (br d, 1H, J = 2.0 Hz, ArH), 7.48 (dd,
CH2Cl2) in dichloromethane (3 mL) for 3 h, according to the general 1H, J = 8.6. 2.0 Hz, ArH), 6.79 (dd, 1H, J = 8.6. 2.0 Hz, ArH), 6.76 (d,
procedure, provided 61 mg (84%) of 2 as a brown solid.
1H, J = 8.6 Hz, ArH), 6.47 (s, 1H, ArCH=C), 2.83 (br t, 2H, J = 6.7 Hz,
Rf = 0.27 (EtOAc/hexanes, 3:2); mp: 261‐266 °C (Lit.2 >250 °C); IR ArCH2CH2), 2.82 (br t, 2H, J = 6.7 Hz, ArCH2CH2), 1.83 (t, 2H, J = 6.7 Hz,
(neat): 3202 (br), 2923, 2853, 1695, 1602, 1509, 1443, 1408, 1340, ArCH2CH2), 1.82 (t, 2H, J = 6.7 Hz, ArCH2CH2), 1.35 (s, 6H, 2 × CH3),
1248, 1194, 1158 cm‐1; 1H NMR (300 MHz, CD3OD): δ 7.74 (d, 2H, J = 1.34 (s, 6H, 2 × CH3); 13C NMR (75 MHz, DMSO‐d6): δ 168.1 (C=O or
8.7 Hz, ArH), 7.65 (d, 2H, J = 8.7 Hz, ArH), 6.82 (d, 4H, J = 8.7 Hz, ArH), C=COH), 162.0 (C=O or C=COH), 154.5 (ArCipso), 152.8 (ArCipso), 140.4
6.40 (s, 1H, ArCH=C); 13C NMR (75 MHz, CD3OD): δ 171.2 (C=O or (O‐C=CHAr), 131.6 (ArC), 129.6 (ArC), 128.4 (ArC), 126.4 (ArC), 124.4
C=COH), 163.3 (C=O or C=COH), 159.7 (ArCipso), 157.9 (ArCipso), 141.8 (ArCipso), 121.5 (ArCipso), 121.3 (ArCipso), 120.6 (ArCipso), 117.5 (ArC),
(O‐C=CHAr), 133.3 (2 × ArC), 130.3 (2 × ArC), 125.9 (ArCipso), 122.3 116.6 (ArC), 107.3 (O‐C=CHAr), 99.7 (C=COH), 74.9 (Ar‐O‐C(CH3)2),
(ArCipso), 116.8 (2 × ArC), 116.1 (2 × ArC), 108.9 (ArCH=C), 102.5 74.3 (Ar‐O‐C(CH3)2), 32.1 (ArCH2CH2), 31.9 (ArCH2CH2), 26.6 (4 × CH3),
(C=COH); HRMS (APPI, pos.): m/z 296.0690 (296.0685 calc. for 22.0 (ArCH2CH2), 21.8 (ArCH2CH2); HRMS (APPI, pos.): m/z 432.1921
C17H12O5, (M)+) and 297.0763 (297.0763 calc. for C17H13O6, (M+H)+).
(432.1937 calc for C27H28O5 (M)+) and 433.1993 (433.2015 calc for
C27H29O5 (M+H)+).
(Z)‐3‐(2,4‐Dihydroxyphenyl)‐4‐hydroxy‐5‐(4‐
hydroxybenzylidene)furan‐2(5H)‐one (Aspulvinone G (3)):27 The (Z)‐5‐((2,2‐Dimethylchroman‐6‐yl)methylene)‐4‐hydroxy‐3‐(7‐
reaction of 14a (60 mg, 0.17 mmol), BBr3 (1.5 mL, 1.5 mmol, 1.0 M in hydroxy‐2,2‐dimethylchroman‐6‐yl)furan‐2(5H)‐one (Aspulvinone
CH2Cl2) in dichloromethane (3 mL) for 2 h, according to the general C (7)):5,43 To a solution of compound 19 (50 mg, 0.11 mmol) in CH2Cl2
procedure, provided 43 mg (81%) of 3 as a yellow solid.
(2 mL) was added BBr3 (0.32 mL, 0.32 mmol, 1.0 M in CH2Cl2) at ‐78
Rf = 0.25 (EtOAc/hexanes, 3:2); mp: 243‐248 °C (Lit.2 >250 °C); IR °C and the mixture was stirred for 40 min. The reaction mixture was
(neat): 3151 (br), 1729, 1603, 1513, 1464, 1443, 1376, 1343, 1307, then warmed to 0 °C and stirred for 20 min. Water (2 mL) was added.
1256, 1226, 1174, 1118, 1093, 983 cm‐1; 1H NMR (300 MHz, CD3OD): The resulting mixture was extracted with ethyl acetate (3 x 4 mL) and
δ 7.64 (d, 2H, J = 8.7 Hz, ArH), 7.60 (d, 1H, J = 8.2 Hz, ArH), 6.82 (d, the combined organic layers were dried (Na2SO4) and concentrated.
2H, J = 8.7 Hz, ArH), 6.43 (dd, 1H, J = 8.2, 2.1 Hz, ArH), 6.42 (s, 1H, The residue was dissolved in dichloromethane (3 mL), a few drops of
ArH), 6.32 (s, 1H, ArCH=C); 13C NMR (75 MHz, CD3OD): δ 171.4 (C=O hexanes were added, and the mixture was allowed to stand at room
or C=COH), 163.6 (C=O or C=COH), 159.9 (ArCipso), 159.7 (ArCipso), temperature for 22 h to provide 36 mg (75%) of 6 (Aspulvinone C) as
1
155.7 (ArCipso), 141.8 (O‐C=CHAr), 133.3 (2 × ArC), 131.7 (ArC), 126.1 a yellow solid that was isolated by filtration. This was pure by H
(ArCipso), 116.8 (2 × ArC), 109.6 (ArCipso), 109.1 (ArC), 108.5 (ArC), NMR.
103.9 (ArCH=C), 100.1 (C=COH); HRMS (APPI, pos.): m/z 312.0635 Rf = 0.61 (EtOAc/hexanes, 7:3); mp: 224‐230 °C; IR (neat): 3065 (br),
(312.0634 calc. for C17H12O6, (M)+) and 313.0708 (313.0712 calc. for 2973, 2924 (br), 1709, 1602, 1494, 1428, 1343, 1284, 1263, 1229,
C17H13O6, (M+H)+).
1154, 1109, 1088 cm‐1; 1H NMR (300 MHz, DMSO‐d6): δ 7.50 (s, 1H,
ArH), 7.48 (dd, 1H, J = 8.9, 2.1 Hz, ArH), 7.11 (s, 1H, ArH), 6.77 (d, 1H,
J = 8.9 Hz, ArH), 6.28 (s, 1H, ArH or ArCH=C), 6.24 (s, 1H, ArH or
(Z)‐5‐(3,4‐Dihydroxybenzylidene)‐4‐hydroxy‐3‐(4‐
hydroxyphenyl)furan‐2(5H)‐one (3',4,’4‐Trihydroxypulvinone (4)):27 ArCH=C), 2.78 (t, 2H, J = 6.6 Hz, ArCH2CH2), 2.64 (t, 2H, J = 6.6 Hz,
The reaction of 15 (55 mg, 0.16 mmol), BBr3 (1.6 mL, 1.6 mmol, 1.0 ArCH2CH2), 1.79 (t, 2H, J = 6.6 Hz, ArCH2CH2), 1.73 (t, 2H, J = 6.6 Hz,
M in CH2Cl2) in dichloromethane (2 mL) for 4 h, according to general ArCH2CH2), 1.30 (s, 6H, 2 × CH3), 1.27 (s, 6H, 2 × CH3); 13C NMR (75
procedure, provided 41 mg (85%) of 4 as a brown solid.
MHz, DMSO‐d6): δ 168.6 (C=O or C=COH), 163.6 (C=O or C=COH),
Rf = 0.31 (EtOAc/hexanes, 3:2); mp: 277‐283 °C (Lit.7 289‐291 °C); IR 154.20 (ArCipso), 154.19 (ArCipso), 154.1 (ArCipso), 141.3 (O‐C=CHAr),
(neat): 3304 (br), 2921, 2628 (br), 1693, 1597, 1509, 1443, 1407, 131.4 (ArC), 130.6 (ArC), 129.4 (ArC), 124.7 (ArCipso), 121.3 (ArCipso),
1
1326, 1241, 1156, 1129, 1098, 1015, 964 cm‐1; H NMR (300 MHz, 117.3 (ArC), 111.5 (ArCipso), 108.8 (ArCipso), 105.5 (ArC or ArCH=C),
acetone‐d6): δ 10.43 (br s, 1H, OH), 8.51 (s, 1H, OH), 8.36 (s, 1H, OH), 103.4 (ArC or ArCH=C), 97.9 (C=COH), 74.8 (Ar‐O‐C(CH3)2), 74.1 (Ar‐
8.24 (s, 1H, OH), 7.83 (d, 2H, J = 8.8 Hz, ArH), 7.47 (d, 1H, J = 2.0 Hz, O‐C(CH3)2), 32.4 (ArCH2CH2), 32.0 (ArCH2CH2), 26.62 (2 × CH3), 26.59
ArH), 7.09 (dd, 1H, J = 8.2, 2.0 Hz, ArH), 6.89 (d, 1H, J = 8.8 Hz, ArH), (2 × CH3), 21.8 (ArCH2CH2), 21.2 (ArCH2CH2); HRMS (ESI, pos.): m/z
6.87 (d, 1H, J = 8.2 Hz, ArH), 6.44 (s, 1H, ArCH=C); 13C NMR (75 MHz, 448.1866 (448.1886 calc for C27H28O6 (M)+) and 471.1755 (471.1784
CD3OD): δ 171.4 (C=O or C=COH), 163.4 (C=O or C=COH), 158.0 calc for C27H28NaO6 (M+Na)+).
(ArCipso), 148.2 (ArCipso), 146.7 (ArCipso), 141.8 (O‐C=CHAr), 130.3 (2 ×
ArC), 126.4 (ArCipso), 124.9 (ArC), 122.4 (ArCipso), 118.0 (ArC), 116.5 General procedure for the deprotection of TBS ethers 16, 19, 20, 22:
(ArC), 116.1 (2 × ArC), 109.4 (ArCH=C), 102.5 (C=COH); HRMS (APPI, To a solution of the TBS protected substrate in THF was added TBAF
pos.): m/z 312.0628 (312.0634 calc. for C17H12O6, (M)+) and 313.0704 (1M in THF) at 0 oC. The mixture was warmed to room temperature
(313.0712 calc. for C17H13O6, (M+H)+).
and stirred until consumption of the starting material (TLC). The
solvent was removed under educed pressure, the residue suspended
in water and the mixture was extracted with EtOAc. The combined
(Z)‐3‐(2,2‐Dimethylchroman‐6‐yl)‐5‐((2,2‐dimethylchroman‐6‐
yl)methylene)‐4‐hydroxyfuran‐2(5H)‐one (Aspulvinone A (6)):27,43 organic layers were dried over anhydrous sodium sulphate and
The reaction of 11i (60 mg, 0.21 mmol) and 17 (134 mg, 0.830 mmol) concentrated. The residue was purified by flash chromatography on
in the presence of Rh2(esp)2 (1.6 mg, 2.1 x 10‐3 mmol) in ,,‐
silica gel.
trifluorotoluene (2 mL) at 50 °C for 6 h according to Method B
10 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 11 of 13
View Article Online
DOI: 10.1039/C8OB01511B
Journal Name
ARTICLE
(Z)‐4‐Hydroxy‐5‐(4‐hydroxy‐3‐methoxybenzylidene)‐3‐(4‐
C=CHAr), 131.8 (ArCipso or (CH3)2C=C), 131.6 (ArC), 130.7 (ArC), 129.2
hydroxyphenyl)furan‐2(5H)‐one (Aspulvinone Q (5)):11 The reaction (ArC), 128.0 (ArCipso or (CH3)2C=C), 124.0 (ArCipso), 122.5 ((CH3)2C=C),
16 (75 mg, 0.135 mmol) and TBAF (0.40 ml, 0.40 mmol) in THF (2 mL) 115.3 (ArC), 111.6 (ArCipso), 108.7 (ArCipso), 106.1 (Ar‐CH), 103.4 (ArC),
according to the general procedure provided, after purification by 98.0 (C=COH), 74.1 (O‐C(CH3)2), 32.4 (CH2), 27.9 (CH2), 26.6 (C(CH3)2),
flash column chromatography on silica gel (hexanes/EtOAc, 3:2 1% 25.5 (C=C(CH3)2), 21.2 (CH2), 17.7 (C=C(CH3)2); HRMS (ESI, pos.): m/z
AcOH), 38 mg (86%) of 5 as a yellow solid.
448.1890 (448.1886 calc. for C27H28O6 (M)+), 449.1963 (449.1964
Rf = 0.23 (hexanes/EtOAc, 3:2, 1% vol AcOH); mp: 223‐225 C; IR calc. for C27H29O6 (M+H)+), 471.1778 (471.1784 calc. for C27H28NaO6
(neat): 3300 (br), 3129, 2931, 1692, 1624, 1592, 1512, 1432, 1406, (M+Na)+).
o
1277, 1234, 1148, 1130, 1095 cm‐1; 1H NMR (500 MHz, DMSO‐d6): δ
9.49 (bs, 2H, OH), 7.80 (d, 2H, J = 8.7 Hz, ArH), 7.30 (s, 1H, ArH), 7.18 (Z)‐5‐(Cyclopentylmethylene)‐3‐(2,2‐dimethylchroman‐6‐yl)‐4‐
(dd, 1H, J = 8.1, 2.0 Hz,), 6.86 (d, 1H, J = 8.1 Hz, ArH), 6.80 (d, 2H, J = hydroxyfuran‐2(5H)‐one (23): The reaction of 11o (56 mg, 0.27
8.7 Hz, ArH), 6.53 (br s, 1H, ArCH), 3.80 (s, 3H, OCH3). 13C NMR (75 mmol) and 17 (176 mg, 1.08 mmol) in the presence of Rh2(esp)2 (1.8
mg, 2.7 x 10‐3 mmol) in ,,‐trifluorotoluene (2 mL) at 50 °C for 22
h according to Method B provided, after purification by flash column
chromatography on silica gel (hexanes/EtOAc, 9:1 to 7:3), 54 mg
(58%) of 23 as a white solid.
MHz, DMSO‐d6): δ 168.6 (C=O or C=COH), 163.6 (C=O or C=COH),
156.1 (ArCipso), 147.7 (ArCipso), 147.6 (ArCipso), 141.0 (O‐C=CHAr),
128.1 (2 × ArC), 124.6 (ArCipso), 124.0 (ArC), 121.5 (ArCipso), 115.9
(ArC), 115.0 (2 × ArC), 113.7 (ArC), 106.7 (Ar‐CH), 98.5 (C=COH), 55.6
(OCH3); HRMS (APPI, pos.): m/z 326.0781 (326.0790 calc. for C18H14O6
(M)+), 327.0853 (327.0869 calc. for C18H15O6 (M+H)+).
Rf = 0.21 (hexanes/EtOAc, 7:3); mp: 176‐179 °C; IR (neat): 2942 (br),
2865 (br), 1697, 1670, 1627, 1613, 1576, 1497, 1438, 1395, 1370,
1253, 1223, 1155, 1120, 1099, 1003 cm‐1; 1H NMR NMR (300 MHz,
CDCl3/CD3OD, 95:5): δ 7.60 (br s, 1H, ArH), 7.57 (dd, 1H, J = 8.3, 2.2
Hz, ArH), 6.78 (d, 1H, J = 8.3, Hz, ArH), 5.56 (d, 1H, J = 9.7 Hz,
C5H9CH=C), 3.16‐3.00 (m, 1H, CH2CHCH2), 2.81 (t, 2H, J = 6.7 Hz,
ArCH2CH2), 2.02‐1.87 (m, 2H, CH2), 1.81 (t, 2H, J = 6.7 Hz, ArCH2CH2),
1.77‐1.56 (m, 4H, CH2), 1.48‐1.24 (m, 2H, CH2), 1.34 (s, 6H, 2 × CH3);
13C NMR (75 MHz, CDCl3/CD3OD, 95:5): δ 169.9 (C=O or C=COH),
160.8 (C=O or C=COH), 153.4 (ArCipso), 142.9 (O‐C=CHAr), 129.1 (ArC),
127.2 (ArC), 121.2 (ArCipso), 121.0 (ArCipso), 117.1 (ArC or O‐C=CHAr),
115.6 (ArC or O‐C=CHAr), 102.6 (C=COH), 74.7 (Ar‐O‐C(CH3)2), 37.1
(CH(CH2)2), 33.7 (2 × CH2), 32.9 (CH2), 26.9 (2 × CH3), 25.4 (2 × CH2),
22.5 (CH2); HRMS (APPI, pos.): m/z 340.1667 (340.1675 calc. for
C21H24O4, (M)+) and 341.1739 (341.1753 calc. for C21H25O4, (M+H)+).
(Z)‐3‐(2,2‐Dimethylchroman‐6‐yl)‐4‐hydroxy‐5‐(4‐hydroxy‐3‐(3‐
methylbut‐2‐enyl)benzylidene)furan‐2(5H)‐one (Aspulvinone
B
(8)):27 The reaction of 20 (50 mg, 0.091 mmol) and TBAF (0.18 ml,
0.18 mmol) in THF (2 mL) according to the general procedure for 1 h.
provided, after purification by flash column chromatography on silica
gel (hexanes/EtOAc, 7.5:2.5, 1% AcOH), 22 mg (56%) of 8 as a yellow
solid.
Rf = 0.23 (hexanes/EtOAc, 7.5:2.5, 1% vol AcOH); mp: 146‐149 oC; IR
(neat): 3310 (br), 2973, 2927, 1704, 1598, 1496, 1434, 1261, 1221,
1
1156, 1116, 989 cm‐1; H NMR (300 MHz, DMSO‐d6): δ 9.87 (s, 1H,
OH), 7.70‐7.63 (m, 2H, ArH), 7.47‐7.41 (m, 2H, ArH), 6.87 (d, 1H, J =
8.2, ArH), 6.75 (d, 1H, J = 8.5 Hz, ArH), 6.54 (s, 1H, ArCH) 5.29 (br t,
1H, J = 7.4 Hz, CH2CH=(CH3)2), 3.24 (d, 2H, J = 7.4 Hz, CH2CH=(CH3)2),
2.76 (br t, 2H, J = 6.7 Hz, ArCH2CH2), 1.78 (br t, 2H, J = 6.7 Hz,
ArCH2CH2) 1.72 (s, 3H, CH=(CH3)2), 1.70 (s, 3H, CH=(CH3)2), 1.29 (s,
6H, C(CH3)2); 13C NMR (75 MHz, DMSO‐d6): δ 168.3 (C=O or C=COH),
162.6 (C=O or C=COH), 156.0 (ArCipso), 152.6 (ArCipso), 140.1 (O‐
C=CHAr), 131.9 (ArCipso or (CH3)2C=C), 131.6 (ArC), 129.3 (ArC), 128.2
(ArC), 128.0 (ArCipso or (CH3)2C=C), 126.2 (ArC), 123.9 (ArCipso), 122.4
((CH3)2C=C), 121.6 (ArCipso), 120.5 (ArCipso), 116.5 (ArC), 115.4 (ArC),
107.5 (ArCH), 99.1 (C=COH), 74.3 (O‐C(CH3)2), 32.2 (CH2), 27.8 (CH2),
26.6 ((O‐C(CH3)2), 25.5 (C=C(CH3)2), 22.0 (CH2), 17.7 (C=C(CH3)2);
HRMS (APPI, pos.): m/z 432.1929 (432.1937 calc. for C27H28O5 (M)+),
433.2001 (433.2015 calc. for C27H29O5 (M+H)+).
(Z)‐3‐(2,2‐Dimethylchroman‐6‐yl)‐4‐hydroxy‐5‐(naphthalen‐2‐
ylmethylene)furan‐2(5H)‐one (24): The reaction of 11j (70 mg, 0.27
mmol) and 17 (175 mg, 1.08 mmol) in the presence of Rh2(esp)2 (1.8
mg, 2.7 x 10‐3 mmol) in ,,‐trifluorotoluene (2 mL) at 70 °C for 5 h
according to Method B provided, after purification by flash column
chromatography on silica gel (hexanes/EtOAc, 4:1 to 1:1), 44 mg
(42%) of 24 as a yellow solid.
Rf = 0.15 (hexanes/EtOAc, 3:2); mp: 164‐169 °C; IR (neat): 3053 (br),
2974 (br), 2929 (br) 2849, 1695, 1621, 1495, 1386, 1314, 1267, 1222,
1156, 1118, 1020, 943 cm‐1; 1H NMR (300 MHz, DMSO‐d6): δ 8.20 (s,
1H, ArH), 8.04‐7.88 (m, 4H, ArH), 7.70 (s, 1H, ArH), 7.70‐7.65 (br s,
1H, ArH), 7.60‐7.57 (m, 2H, ArH), 6.83 (s, 1H, ArCH=C), 6.78 (d, 1H, J
= 8.3 Hz, ArH), 2.78 (t, 2H, J = 6.7 Hz, ArCH2CH2), 1.79 (t, 2H, J = 6.7
Hz, ArCH2CH2), 1.30 (s, 6H, 2 × CH3); 13C NMR (75 MHz, DMSO‐d6): δ
168.1 (C=O or C=COH), 162.2 (C=O or C=COH), 152.9 (ArCipso), 142.9
(O‐C=CHAr), 133.0 (ArCipso), 132.6 (ArCipso), 130.6 (ArCipso), 129.7
(ArC), 128.5 (2 × ArC), 128.3 (ArC), 127.6 (ArC), 127.0 (ArC), 126.9
(ArC), 126.7 (ArC), 126.5 (ArC), 121.2 (ArCipso), 120.6 (ArCipso), 116.7
(ArC), 106.8 (O‐C=CHAr), 100.3 (C=COH), 74.4 (Ar‐O‐C(CH3)2), 32.1
(ArCH2CH2), 26.6 (2 × CH3), 22.0 (ArCH2CH2); HRMS (APPI, pos.): m/z
398.1509 (398.1518 calc. for C26H22O4, (M)+) and 399.1580 (399.1596
calc. for C26H23O4, (M+H)+).
(Z)‐4‐Hydroxy‐3‐(7‐hydroxy‐2,2‐dimethylchroman‐6‐yl)‐5‐(4‐
hydroxy‐3‐(3‐methylbut‐2‐enyl)benzylidene)furan‐2(5H)‐one
(Aspulvinone D (9)):5,43 The reaction of 22 (165 mg, 0.243 mmol) and
TBAF (0.70 ml, 0.73 mmol) in THF (3 mL) according to the general
procedure provided, after purification by flash column
chromatography on silica gel (hexanes/EtOAc, 8.0:2.0, 1% AcOH), 90
mg (83%) of 9 as a yellow solid.
o
Rf = 0.20 (hexanes/EtOAc, 8.0:2.0, 1% vol AcOH); mp: 199‐201 C
(decomp.); IR (neat): 3300 (br), 2973, 2925, 1696, 1662, 1589, 1505,
1
1425, 1344, 1276, 1229, 1157, 1090, 990 cm‐1; H NMR (500 MHz,
DMSO‐d6): δ 9.81 (bs, 1H, OH), 7.47 (br d, 1H, J = 1.9 Hz, ArH), 7.45
(br dd, 1H, J = 8.3, 1.9 Hz, ArH), 7.10 (s, 1H, ArH), 6.86 (d, 1H, J = 8.3
Hz, ArH), 6.27 (s, 1H, ArH or ArCH), 6.24 (s, 1H, ArCH or ArH), 5.29 (br
t, 1H, J = 6.7 Hz, CH2CH=(CH3)2), 3.24 (d, 2H, J = 6.7 Hz, CH2CH=(CH3)2),
2.64 (br t, 2H, J = 6.5 Hz, ArCH2CH2), 1.73 (t, 2H, J = 6.5 Hz, ArCH2CH2),
1.72 (s, 3H, CH=C(CH3)2), 1.70 (s, 3H, CH=C(CH3)2), 1.27 (s, 6H,
C(CH3)2); 13C NMR (75 MHz, DMSO‐d6): δ 168.6 (C=O or C=COH),
163.3 (C=O or C=COH), 155.8 (ArCipso), 154.1 (2 × ArCipso), 140.6 (O‐
(Z)‐3‐(5‐Bromo‐1H‐indol‐3‐yl)‐5‐((2,2‐dimethylchroman‐6‐
yl)methylene)‐4‐hydroxyfuran‐2(5H)‐one (25): The reaction of 11i
(50 mg, 0.16 mmol) and 5‐bromoindole (131 mg, 0.67 mmol) in the
presence of Rh2(esp)2 (1.2 mg, 0.001 mmol) in PhCF3 at 50 oC for 24
h according to the general procedure provided, after purification by
flash column chromatography on silica gel (hexanes/EtOAc, 1:1), 70
mg (90 %) of 25 as a green solid.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 11
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 12 of 13
View Article Online
DOI: 10.1039/C8OB01511B
ARTICLE
Journal Name
Rf = 0.2 (hexanes/EtOAc, 3:2); mp: 243‐245 oC; IR (neat): 3427, 2972,
2926, 1711, 1605, 1574, 1531, 1496, 1453, 1295, 1264, 1254, 1153,
1116 cm‐1; 1H NMR (500 MHz, DMSO‐d6): δ 11.57 (s, 1H, OH), 8.22 (s,
1H, ArH), 7.78 (s, 1H, ArH), 7.50‐7.42 (m, 2H, ArH), 7.39 (d, 1H, J = 8.5
Hz, ArH), 7.24 (d, 1H, J = 8.5 Hz, ArH), 6.80 (s, 1H, J = 8.5 Hz, ArH),
6.47 (s, 1H, ArCH), 2.79 (br t, 2H, J = 6.8 Hz, CH2), 1.80 (br t, 2H, J =
6.8 Hz, CH2), 1.30 (s, 6H, (CH3)2); 13C NMR (75 MHz, DMSO‐d6): δ
168.6 (C=O or C=COH), 161.5 (C=O or C=COH), 154.2 (ArCipso), 141.5
(O‐C=CHAr), 134.7 (ArCipso), 131.4 (ArC), 129.4 (ArC), 127.2 (ArCipso),
126.5 (ArC), 124.7 (ArCipso), 124.0 (ArC), 123.8 (ArC), 121.4 (ArCipso),
117.4 (ArC), 113.6 (ArC), 111.4 (ArCipso), 106.2 (ArCH), 104.2 (C=COH),
96.7 (ArCipso), 74.9 (O‐C(CH3)2), 32.0 (CH2), 26.6 (CH3)2, 21.8 (CH2);
HRMS (ESI, pos.): m/z 465.0589 (465.0576 calc. for C24H20Br79NO4
(M)+), 466.0662 (467.0654 calc. for C24H21Br79NO4 (M+H)+), 468.0646
(469.0633 calc. for C24H21Br81NO4 (M+H)+), 488.0482 (488.0473 calc.
for C24H20Br79NNaO4 (M+Na)+), 490.0465 (491.0452 calc. for
C24H20Br81NNaO4 (M+Na)+).
16 D. Peter and R. Brückner, Chem. Eur. J., 2017, 23, 12104.
17 C. L. Zhang, S. S. Chatterjee, U. Stein and U. Heinemann, N.‐S.
Arch. Pharmacol., 1992, 345, 85.
18 K. Luk and S. A. Readshaw, J. Chem. Soc., Perkin Trans. 1, 1991,
1641.
19 H. Gao, W. Guo, Q. Wang, L. Zhang, M. Zhu, T. Zhu, Q. Gu, W.
Wang and D. Li, Bioorg. Med. Chem. Lett., 2013, 23, 1776.
20 R. T. Dewi, S. Tachibana, S. Fajriah and M. Hanafi, Med. Chem.
Res., 2015, 24, 737.
21 D. W. Knight and G. Pattenden, J. Chem. Soc., Perkin Trans. 1,
1979, 70.
22 R. Ramage, G. J. Griffiths and F. E. Shutt, J. Chem. Soc., Perkin
Trans. 1, 1984, 1539.
23 N. Kaczybura and R. Brückner, Synthesis, 2007, 118.
24 A. C. Campbell, M. S. Maidment, J. H. Pick and D. F. M.
Stevenson, J. Chem. Soc., Perkin Trans. 1, 1985, 1567.
25 M. Gill, M. J. Kiefel, D. A. Lally and A. Ten, Aust. J. Chem., 1990,
43, 1497.
26 S. Antane, C. E. Caufield, W. Hu, D. Keeney, P. Labthavikul, K.
Morris, S. M. Naughton, P. J. Petersen, B. A. Rasmussen, G.
Singh and Y. Yang, Bioorg. Med. Chem. Lett., 2006, 16, 176.
27 D. Bernier and R. Brückner, Synthesis, 2007, 2249.
28 B. Nadal, J. Rouleau, H. Besnard, P. Thuéry, and T. Le Gall,
Tetrahedron 2011, 67, 2605.
Conflicts of interest
There are no conflicts to declare.
29 D. Hermann, D. Arican and R. Brückner, Synthesis, 2017, 326.
30 Y. Sadamitsu, K. Komatsuki, K. Saito and T. Yamada, Org. Lett.,
2017, 19, 3191.
Acknowledgements
These investigations were supported by the Natural Sciences and
Engineering Research Council of Canada and the Canada Foundation
for Innovation.
31 (a) A. Manchoju and S. V. Pansare, Org. Lett., 2016, 18, 5952.
For selected reports on arene C‐H insertion reactions of
diazocarbonyl compounds, see: (b) X. Hu, X. Chen, Y. Shao, H.
Zhie, Y. Deng, Z. Ke, H. Jiang and W. Zheng, ACS Catal. 2018,
8
, 1308. (c) D. Zhao, J. H. Kim, L. Stegemann, C. A. Strassert
and F. Glorius, Angew. Chem., Int. Ed. 2015, 54, 4508. (d) E.
Tayama, T. Yanaki, H. Iwamoto and E. Hasegawa, Eur. J. Org.
Chem. 2010, 6719. (e) J.‐M. Yang, Y. Cai, S.‐F. Zhu and Q.‐L.
Zhou, Org. Biomol. Chem. 2016, 14, 5516.
Notes and references
1
2
3
4
5
6
7
L. Vieweg, S. Reichau, R. Schobert, P. F. Leadlay and R. D.
Süssmuth, Nat. Prod. Rep., 2014, 31, 1554.
R. Schobert, R and A. Schlenk, Bioorg. Med. Chem., 2008, 16
,
32 (a) Studies on O‐H bond insertion: H. D. Stachel, H.
Poschenrieder, J. Redlin, J. Schachtner and K. Zeitler, Liebigs
Ann. Chem., 1994, 129. (b) P. V. Murphy, T. J. O'Sullivan, B. D.
Kennedy and N. W. A. Geraghty, J. Chem. Soc. Perkin Trans. 1,
2000, 13, 2121.
33 Review: M. Periasamy, ARKIVOC, 2002, (vii), 151.
34 The TiCl4‐Et3N reagent system typically provides aldol addition
4203.
R. L. Edwards and M. Gill, J. Chem. Soc. Perkin Trans., 1 1973,
1921.
N. Ojima, S. Takenaka and S. Seto, Phytochemistry, 1973, 12
,
2527.
N. Ojima, S. Takenaka and S. Seto, Phytochemistry, 1975, 14,
573.
products when used in reactions of ‐diazo ‐ketoesters and
aromatic aldehydes; M. A. Calter and C. Zhu, J. Org. Chem.,
1999, 64, 1415.
M. J. Begley, D. R. Gedge, D. W. Knight and G. Pattenden, J.
Chem. Soc. Perkin Trans. 1, 1979, 77.
L.‐H. Zhang, B.‐M. Feng, Y.‐Q. Zhao, Y. Sun, B. Liu, F. Liu, G.
Chen, J. Bai, H.‐M. Hua, H.‐F. Wang and Y.‐H. Pei, Bioorg. Med.
Chem. Lett., 2016, 26, 346.
35 For Z‐selective aldol condensations of glycolic acid derivatives
and of azlactones with aromatic aldehydes, see: (a) Z. Cai, J.
Feng, Y. Guo, P. Li, Z. Shen, F. Chu and Z. Guo, Bioorg. Med.
Chem., 2006, 14, 866. (b) L. Shi, L. Wang, Z. Wang, H.‐L. Zhu
and Q. Song, Eur. J. Med. Chem., 2012, 47, 585.
8
9
N. Ojima, I. Takahashi, K. Ogura, S. Seto, Tetrahedron
Lett., 1976, 17, 1013.
P. G. Cruz, D. S. Auld, P. J. Schultz, S. Lovell, K. P. Battaile, R.
MacArthur, M. Shen, G. Tamayo‐Castillo, J. Inglese and D. H.
Sherman, Chem. Biol., 2011, 18, 1442.
36 M. Hoffmann, S. Miaskiewicz, J.‐M. Weibel, P. Pale and A.
Blanc, RSC Adv., 2015, 5, 37138.
37 K. W. Fiori and J. Du Bois, J. Am. Chem. Soc., 2007, 129, 562.
38 T. T. Dang, F. Boeck and L. Hintermann, J. Org. Chem., 2011,
76, 9353.
10 P. Zhang, X.‐M. Li, J. N. Wang, X. Li and B.‐G. Wang,
Phytochem. Lett., 2015, 11, 85.
11 X. Pang, J.‐Y. Zhao, X.‐M. Fang, T. Zhang, D.‐W. Zhang, H.‐Y.
Liu, J. Su, S. Cen and L.‐Y. Yu, J. Nat. Prod., 2017, 80, 2595.
12 K. Rehse and J. Lehmke, Arch. Pharm., 1985, 318, 11 and
references therein.
13 H.‐W. Xu, C. Xu, Z.‐Q. Fan, L. J. Zhao, and H.‐M. Liu, Bioorg.
Med. Chem. Lett., 2013, 23, 737.
14 T. S. Mansour, C. E. Caufield, B. Rasmussen, R. Chopra, G.
Krishnamurthy, K. M. Morris, K. Svenson, J. Bard, C. Smeltzer,
S. Naughton, S. Antane, Y. Yang, A. Severin, D. Quagliato, P. J.
39 M. M. Naik, D. P. Kamat, S. G. Tilve and V. P. Kamat,
Tetrahedron, 2014, 70, 5221.
40 For a similar cyclization, see: H. E. Zaugg, J. E. Leonard, R. W.
DeNet and D. L. Andersen, J. Het. Chem., 1974, 11, 797.
41 V. K. Ahluwalia, K. K. Arora and R. S. Jolly, J. Chem. Soc. Perkin
Trans. 1, 1982, 335.
42 C. E. Caufield, S. A. Antane, K. M. Morris, S. M. Naughton, D.
A. Quagliato, P. M. Andrae, A. Enos and J. F. Chiarello, US
20050054721 A1, March 10, 2005.
43 H. Sugiyaman, B. Ojima, M. Kobayashyi, S. Senda, J.‐I. Ishiyama
and S. Seto, Agric. Biol. Chem., 1979, 43, 403.
Petersen and G. Singh, ChemMedChem, 2007, 2, 1414 and
references therein.
15 F. R. Foden, J. McCormick and D. M. O’Mant, J. Med. Chem.,
1975, 18, 199.
12 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 13 of 13
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01511B
Diastereoselective aldol condensation of diazotetronic acid and a subsequent arene C-H insertion
provides an efficient route to the aspulvinone motif.