Bis(1-cyanovinyl acetate) Is a Linear Precursor to 3-Oxidopyrylium Ions

Article abstract of DOI:10.1021/acs.joc.6b02111

Herein we describe the first approach to 3-oxidopyrylium ions from a linear precursor. Heating bis(1-cyanovinyl acetate) in the presence of a trace amount of pyridinium p-toluenesulfonate results in a series of acyl group transfers and an intramolecular cyclization event to form a 3-oxidopyrylium ion that can be trapped by reaction with several dipolarophiles. When treated with dienes, the result is a sequential [5 + 2]/[4 + 2] cycloaddition reaction that provides sp³-rich products of high molecular complexity.

Full text of DOI:10.1021/acs.joc.6b02111

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Article
Bis(1-cyanovinyl acetate) is a Linear Precursor to 3-Oxidopyrylium Ions
Sidney Malik Wilkerson-Hill, Shota Sawano, and Richmond Sarpong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02111 • Publication Date (Web): 14 Oct 2016
Downloaded from http://pubs.acs.org on October 14, 2016
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Page 1 of 43
The Journal of Organic Chemistry
Bis(1-cyanovinyl acetate) is a Linear Precursor to 3-Oxidopyrylium Ions
1
2
3
4
Sidney Malik Wilkerson-Hill, ‡ Shota Sawano, ‡ and Richmond Sarpong*
5
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7
Department of Chemistry, University of California, Berkeley, California 94720, United States.
8
9
O
CN
NC
AcO
10
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19
O
MeCN, 0.10 M
OAc
CN
AcHN
R
+
PPTS (10 mol %)
reflux, 24 h
R
linear precursor to
3-oxidopyrylium ions
O
Ac2N
O
CN
electrophilic
3-oxidopyrylium ion
ABSTRACT
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Herein we describe the first approach to 3-oxidopyrylium ions from a linear precursor. Heating bis(1-
cyanovinyl acetate) in the presence of a trace amount of pyridinium p-toluenesulfonate results in a series
of acyl group transfers and an intramolecular cyclization event to form a 3-oxidopyrylium ion that can
be trapped by reaction with several dipolarophiles. When treated with dienes, the result is a sequential
[5+2]/[4+2] cycloaddition reaction that provides sp3-rich products of high molecular complexity.
INTRODUCTION
The rapid generation of molecular complexity (RGMC) from readily accessible precursors is a
long-standing goal in organic synthesis.1 Complexity-building reactions, which introduce new rings
(fused and bridging) as well as additional functional groups and stereogenic centers, are conceptually
and mechanistically interesting and are therefore of academic interest. From a practical perspective
(e.g., in preparing complex molecules), RGMC is especially pertinent because it can reduce the number
of steps needed to access architecturally intricate and functional group dense intermediates en route to a
desired target.2 Furthermore, the continuing emergence of unique sp3-rich chemotypes for medicinal
chemistry makes new modes for generating molecular complexity highly important.3,4
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Cycloaddition reactions constitute textbook examples of complexity building reactions that
convert relatively simple π-systems to more complex, ring-containing, compounds bearing multiple sp3
stereogenic centers in a regio- and diastereoselective manner. The Diels–Alder cycloaddition reaction
(Figure 1A) epitomizes these processes as it can construct a six-membered ring and up to four
contiguous stereogenic centers from acyclic precursors.
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R
R
A. Diels–Alder
cycloaddition reaction
R'
R'
cyclohexene
one 6-membered ring
up to four stereogenic centers
R'
R'
R
R
O
H
O
[3.2.1]-oxobicyclooctene
one 7-membered ring
enone fuctionality
R'
O
B. 3-oxidopyrylium ion
[5+2] cycloaddition reaction
O
up to four stereogenic centers
R'
H
3-oxidopyrylium ion
Figure 1. [4+2] atom and [5+2] atom cycloaddition reactions with alkenes and their resulting
cycloadducts.
The [5+2] cycloaddition reaction between 3-oxidopyrylium ions and dipolarophiles represents
another well-practiced complexity-building pericyclic reaction (Figure 1B).5 In this case [3.2.1]-
oxabicyclooctenes, which are otherwise difficult to access, are formed in a single step. As a result,
cycloaddition reactions between alkenes and 3-oxidopyrylium ions have been used extensively in
natural product synthesis; most notably by Wender and coworkers to access molecules such as
phorbol.5c,6
Though the cycloaddition reactivity of 3-oxidopyrylium ions is well-established,7 methods to
access functionalized precursors to these intermediates remain limited. In general, two strategies have
been employed in their preparation. 3-Oxidopyrylium ions can be generated from 3-hydroxy-4-
pyranones by a group transfer-type reaction from kojic acid derivatives (Scheme 1, Eq. 1).8
Alternatively, these reactive intermediates can be accessed through the base-mediated transformation of
pyranyl acetates, which may be obtained from the Achmatowicz rearrangement of furanyl alcohols
(Scheme 1, Eq. 2).9 Extensive work by the Padwa group has shown that [5+2] cycloaddition reactions
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The Journal of Organic Chemistry
can also be effected with carbonyl ylides generated from the rhodium(II)-catalyzed decomposition of
linear δ-diazoketones.10a Unfortunately, when attempts were made to extend this reaction to generate 3-
oxidopyrylium ions using linear precursors (Scheme 1, Eq. 3), the reactive intermediates could not be
trapped, and instead, an unidentifiable dimeric side-product was obtained.10b Herein, we report our
discovery of a method for generating a highly functionalized 3-oxidopyrylium ion from easily
synthesized bis(1-cyanovinyl acetate) (1), and we demonstrate its ability to undergo intermolecular
cycloaddition reactions with various dipolarophiles (Scheme 1, Eq. 4). To the best of our knowledge, 1
constitutes the first reported acyclic precursor to 3-oxidopyrylium ions.
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O
OH
OR
kojic acid
derivatization
RO
group
transfer
O
O
(1)
O
O
O
R
O
R
R
HO
1. oxidant
Achmatowicz
rearrangement
O
R
H
R
base
R
(2)
O
– baseH+
– AcO–
O
O
2. AcCl, pyridine
OAc
N2
MeO2C
MeO2C
O
CO2Me
Rh2(OAc)4
1. mCPBA
O
O
O
(3)
O
2. NsN3, Et3N
could not trap
intermediate
Ph
Ph
Ph
O
AcO
CN
O
Cl
NAc2
1. TMSCN, TMSCl
2. AcCl, pyridine
this work
(4)
O
NC
OAc
Cl
O
CN
3-oxidopyrylium ion
1
Scheme 1. Tactics for generating 3-oxidopyrylium ion intermediates.
RESULTS AND DISCUSSION
Bis(1-cyanovinyl acetate) (1) was first synthesized in 1992 by Oku and coworkers and was
studied in the context of photochemical [2+2] and olefin isomerization reactions.11 Since that time, diene
1 has wallowed in relative obscurity. We initially posited that 1 could serve as a masked bisketene
equivalent and might undergo a double Diels–Alder cycloaddition reaction with dienes such as
vinylindene 2a12 (Scheme 2) to give symmetrical tetrahydrofluorene dimers (e.g., 3).13,14 However, upon
heating diene 1 with vinylindene 2a, we found, much to our surprise, that diene 1 instead undergoes
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rearrangement and cycloaddition reactions (with 2 equiv of 2a) to give a diastereomeric mixture of a
bis-adduct (the connectivity of which was confirmed by X-ray crystallographic analysis of the major
diastereomer, 4a).15,16
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2
3
4
5
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8
MeO
MeO
9
NC
OAc
+
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AcO
CN
OAc
MeO AcO
OMe
OMe
CN
NC
MeO
1
2a
(2 equiv)
3
MeO
H
H
MeO
O
H
CN
O
AcHN
toluene, 180 °C µW, 2 h
OMe
4a
59%, dr 75:25
MeO
(major diastereomer)
Scheme 2. Unexpected [5+2]/[4+2] domino cycloaddition reaction between diene 1 and vinylindene 2a.
On the basis of this observation, we set out to extend this cycloaddition reaction to other
dipolarophiles. We quickly identified electron-rich styrenes such as 4-methoxystyrene (4-vinylanisole;
2b) as the most competent type of dipolarophile. Using 2b as a model dipolarophile, we surveyed
conditions to increase the yield of the corresponding [5+2] cycloadduct 4b (Table 1). Heating diene 1
and 2b (1 equiv) in toluene at 180 °C (microwave heating) gave a low yield (7% isolated) of adduct 4b.
Partly, this low yield might be attributed to the fact that 1 is only sparingly soluble in toluene (and also
in 1,4-dioxane), leading to intractable polymeric tars during the course of the reaction. Using other
solvents in which 1 was more soluble (e.g., acetonitrile), resulted in an increase in the isolated yield of
adduct 4b to 30% (Table 1, entry 1) with prolonged heating at lower temperatures (100 °C). Upon
investigating the effect of different additives on the efficiency of the reaction, we found that the addition
of acids or bases (5–10 mol %) significantly affects the efficiency of the overall process (entries 2–9).
Table 1. Optimization of reaction conditions with 4-vinylanisole (2b)a
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The Journal of Organic Chemistry
O
O
NC
AcO
CN
CN
O
O
additive (10 mol %)
OAc
CN
1
AcHN
AcHN
+
+
MeCN, 100 ºC, 39 h
OMe
2
1
2b (5 equiv)
3
endo-4b
exo-4b
OMe
OMe
4
5
6
7
8
entry
additive
none
yield (%)b
dr (endo:exo)
87:13
81:19
86:14
84:16
–
1
2
3
4
5
6
7
8
9
30
60
28
43
0
9
pyridine
DMAP
DBN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
K2CO3
AcOH
PyHCl
PPTS
40
73
83
83
85:15
81:19
74:26
74:26
PPTSc
26
a
Bis(1-cyanovinyl acetate) (1) (0.10 mmol), 4-vinylanisole (2b) (0.50 mmol), additive (10 µmol), and
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b
c
MeCN (1 mL). See Supporting Information for details. Isolated yields. 5.0 mol %. DMAP = N,N-
dimethyl-4-aminopyridine, DBN = 1,5-diazabicyclo[4.3.0]non-5-ene, PPTS = pyridinium p-
toluenesulfonate.
Given that the [5+2] cycloadduct (e.g., 4b) lacks one of the acetyl groups present in 1 and that
the N-atom in 4b is acetylated, we tested whether carbophilic amine bases that might facilitate acyl
transfers would result in higher yields (Table 1, entries 1–5). While the addition of pyridine (10 mol %)
boosted the yield significantly (to 60%; Table 1, entry 2), surprisingly, the addition of 10 mol % of
either 4-dimethylaminopyridine (DMAP) or 1,5-diazabicyclononene (DBN), which are well-recognized
‘carbon bases’,17 led to diminished yields (Table 1, entries 3 and 4) whereas K2CO3 resulted in only non-
specific decomposition of 1.18,19 From this survey of exogenous base and acid additives, pyridinium p-
toluenesulfonate (PPTS) proved to give the highest yields (Table 1, entries 8 and 9) and so these
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conditions have been adopted for exploring the scope of the cycloaddition process. In general, a mixture
of the endo- and exo- adducts is obtained, which was easily separated to facilitate unambiguous proof of
structure by X-ray crystallographic analysis (see Supporting Information). The cycloaddition reactions
are readily scaled up with only a slight reduction in isolated yield. For example, endo-4b and exo-4b are
formed in a combined 64% yield on 3 mmol scale.
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We have found that the 3-oxidopyrylium ion intermediate generated from compound 1 can be
trapped with a variety of styrenes in modest to good yields (Table 2). The efficiency of the
cycloaddition has been good using various styrene partners (see 4b–4h in Table 2). Tetra-substituted
centers can be generated as demonstrated by the cycloaddition with α-methylstyrene 2i (see 4i). Non-
styryl dipolarophiles such as electron-rich phenyl vinyl sulfide 2j and benzyl vinyl ether 2k also
undergo cycloaddition, but proceed to give moderate isolated yields (see 4j and 4k). Disubstituted
alkenes, albeit more strained (e.g., norbornene 2l), are also competent dienophiles and provide the
cycloadduct 4l in good yield and excellent diastereoselectivity. Finally, compound 1 also reacts with 1-
(p-toluenesulfonyl)-3-vinyl-indole (2m) to give adduct 4m (51% isolated yield) in an aza-variant of the
initial discovery described in Scheme 2. The structure of 4m is supported by X-ray crystallographic
analysis (see Supporting Information). Collectively, access to 4a and 4m demonstrate that additional
cycloaddition reactions are possible from the [5+2] dipolar cycloadducts.
Table 2. Substrate scope for [5+2] cycloaddition reaction with various dipolarophilesa
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NC
AcO
O
R2
PPTS (5.0 mol %)
OAc
CN
R2
O
+
1
2
AcHN
MeCN, 100 ºC, 24 h
R1
CN
2
(5 equiv)
R1
1
4
3
4
5
6
7
8
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22
O
AcHN
O
CN
O
CN
R
O
AcHN
R
R
R
=
2j
SPh
OBn
4j 60%, dr >95:5
4k 43%, dr >95:5d
2k
R
R
=
4b
4c
4d
4e
4f
2b
2c
2d
2e
2f
80%, dr 78:22
64%, dr 73:27
72%, dr 74:26
65%, dr 72:28
70%, dr 78:22
66%, dr 71:29
62%, dr 61:39
OMe
O
H
CN
O
Me
AcHN
H
i-Pr
t-Bu
OAc
CF3
H
4g
4h
2g
2h
2l
4l 50%, dr >95:5
O
TsN
H
CN
Me
Me
O
AcHN
O
H
CN
O
N
Ts
AcHN
2i
2m
NTs
4i 63%, dr 83:17b,c
4m 51%, dr >95:5e,f
23
a
Bis(1-cyanovinyl acetate) (1) (0.10 mmol), dipolarophile (0.50 mmol), PPTS (5.0 µmol), and MeCN
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(1 mL). See Supporting Information for details. b 1H NMR yield. 1,1,2,2-tetrachloroethane was used as
c
an internal standard. Bis(1-cyanovinyl acetate) (1) and α-methylstyrene 2i were stirred in i-
butylmethylketone without PPTS. d Bis(1-cyanovinyl acetate) (1) and benzyl vinyl ether 2k were stirred
e
in THF without PPTS. 2nd step: Crude products were stirred with TsOH·H2O in DCM at 40 ºC. 2
f
steps overall yield.
This newly discovered cycloaddition reaction is not without limitations. For example, thus far,
attempted cycloaddition reactions with dipolarophiles such as maleic anhydride, 2-vinylnaphthalene, 4-
phenylstyrene, stilbene, diphenylacetylene (tolan), N-vinylphthalimide, and vinylcyclohexane have
resulted in non-specific decomposition of diene 1 upon prolonged heating. These observations may be
rationalized by the steric encumbrance associated with cycloaddition to the 3-oxidopyrylium ion
intermediate as well as its electron-poor nature, and possibly suggests a stepwise [5+2] cycloaddition
reaction. The apparent electrophilicity of the intermediate 3-oxidopyrylium ion is unusual and is likely
imparted by the pendant cyano group. Other dipoles of this type not bearing cyano groups are known to
undergo cycloaddition reactions with both electron-rich and electron-poor dipolarophiles.5
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Our tentative hypothesis regarding a mechanism for the generation of the 3-oxidopyrylium
intermediate is outlined in Scheme 3. Diene (E,E)-1 likely undergoes a thermally promoted E- to Z-
isomerization to give diene (E,Z)-1 in line with the precedent of Oku and coworkers.11 At this stage, a
carbophilic base, which could either be acetonitrile (the solvent), the nitrile groups of 1, or pyridine
(from the PPTS additive), mediates deacylation to give enol A that is stabilized by ketenimine-like
tautomer B. Net acyl transfer to the N-atom will give acyl ketimine C, which may undergo formal 6π-
electrocyclic ring closure to provide oxidopyrylium ion precursor D. Another acyl transfer (via E)
would yield the reactive 3-oxidopyrylium ion (G) which undergoes [5+2] cycloaddition with
dipolarophile to afford cycloadducts. Alternatively, intermediate B could be transformed to bicyclic
intermediate H through the formation of C–N bond. Ring-opening of five membered ring would transfer
the acyl group from oxygen onto nitrogen with the generation of oxidopyrylium ion I. At this stage,
there is no direct proof to support the reaction mechanism.
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NC
AcO
E/Z
isomerization
CN
Z
E
E
PPTS
OAc
CN
AcO
OH
N
E
CN OAc
AcO
CN
(E,E)-1
(E,Z)-1
A
CN
CN
AcPy
AcO
CN
O
O
O
N
AcO
C
B
AcO
C
C
AcN
NH
H
Ac
D
–PPTS
HO
Ac
CN
AcO
AcN
CN
O
CN
O
O
O
N
Ac
N
Ac
H
E
Ac
OTs
OTs
F
G
CN
CN
O
CN
O
O
O
C
B
O
O
NH
H
N
NH
O
O
Me
Ac
Me
H
I
Scheme 3. A possible mechanism for formation of 3-oxidopyrylium ion from diene 1.
In a preliminary study, we have shown that the cycloadducts can be further elaborated to
generate products of even more molecular complexity. For example (Scheme 4), endo-4b undergoes
Johnson iodination of the enone moiety to provide iodide 5 (67% isolated yield) in preparation for
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The Journal of Organic Chemistry
various cross-coupling reactions.20 The enone double bond may also be simply removed under
hydrogenation conditions (see 6). Of note, compound 6 is formally a carbonyl ylide cycloadduct.
Adduct endo-4b can also be utilized in conjugate additions (see 7) or Diels–Alder cycloaddition
reactions (see 8). Furthermore, endo-4b undergoes highly chemo- and diastereoselective ionic reduction
of the enone carbonyl group (Et3SiH, TiCl4) to afford allylic alcohol 9, which may be employed in a
variety of hydroxyl-directed transformations.21 The bridgehead cyano group of endo-4b can also be
manipulated. For example, addition of excess phenyl magnesium bromide to endo-4b yields phenyl
ketone 10 whereas hydration of the nitrile group gives carboxamide 11.22
1
2
3
4
5
6
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9
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N(SiMe3
)
2
O
O
CN
O
CN
O
AcHN
AcHN
7
6
98%
I
OMe
50%, dr > 95:5
OMe
O
TsN
CN
(b)
O
H
(c)
H
AcHN
O
H
(a)
CN
O
O
AcHN
CN
(d)
5
O
67%
AcHN
OMe
8
74%, dr > 95:5
endo-4b
OMe
(g)
H
(e)
OMe
CN
HO
AcHN
O
(f)
NH2
O
O
AcHN
O
Ph
HO
AcHN
Ph
O
9
O
62%, dr > 95:5
OMe
11
94%
OMe
10
65%, dr > 95:5
OMe
Scheme 4. Derivatization of [5+2]-cycloaddition adduct endo-4b. a) I2, pyridine, DCM. b) Pd/C, H2,
THF. c) LHMDS, THF. d) 2m, MeCN. e) Et3SiH, TiCl4, DCM. f) PhMgBr, THF. g) RhCl(PPh3)3,
acetaldoxime, toluene. DCM = 1,1-dichloromethane, THF = tetrahydrofuran. See the Supporting
Information for details.
The rapid generation of molecular complexity afforded by these novel oxidopyrylium
cycloadducts is further powerfully illustrated by the cycloadditions of styrene derivatives 2n and 2o to
give 4n and 4o, respectively (Scheme 5). Subsequent intramolecular Heck and conjugate addition
reactions of the endo adducts 4n and 4o into the enone moiety yields multicyclic scaffolds 12 and 13,
respectively.
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Br
OMe
O
O
AcHN
O
H
AcHN
H
O
1
2
Pd(OAc)2 (10 mol %)
PPh3 (30 mol %)
Et3N (1 equiv)
OMe
(5 equiv)
H
2n
PPTS (10 mol %)
NC
CN
Br
DMF, 120 °C, 12 h
3
4
5
6
7
8
9
MeCN , 100 ºC, 36 h
12 55%
endo-4n 41%
(exo-4n 31%)
MeO
MeO
NC
AcO
OMe
OMe
OAc
CN
1
O
NHAc
O
AcHN
H
O
H
LiHMDS (5 equiv)
THF, –78°C to rt, 1 h
H
PPTS (10 mol %)
MeCN, reflux, 36 h
CN
O
Ac
H
MeO
MeO
O
Ac
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OMe
endo-4o 26%
(exo-4o 28%)
MeO
13 25%
OMe
(5 equiv)
OMe
2o
Scheme 5. Synthetic sequences to access multi-cyclic scaffolds.
In conclusion, we report the generation of a novel 3-oxidopyrylium ion intermediate (G) from
bis(1-cyanovinyl acetate) (1). To our knowledge, this work represents the first reported generation of 3-
oxidopyrylium ions from a non-cyclic (i.e., linear) precursor. We have demonstrated that the dipole thus
generated undergoes cycloaddition reactions with various styryl dipolarophiles to give [3.1.0]-
oxabicyclooctenes, which can themselves be further functionalized. In addition, a vinyl sulfide and a
vinyl ether also serve as cycloaddition partners. Studies aimed at elucidating the mechanism of this
unusual transformation that would shed light on the acyl transfer events, as well as the fate of the acyl
group that is lost from the final product are underway. We are also investigating the possibility of
enantioselective versions of this transformation and applications to the total synthesis of natural
products.
EXPERIMENTAL SECTION
General Information. All reactions were run in flame-dried round-bottomed flasks, vials, or Schlenk
flasks under a nitrogen atmosphere. Reactions were monitored by thin layer chromatography on glass-
backed TLC plates (250 µm thickness, 60 Å porosity, F-254 indicator) and visualized using UV
irradiation and p-anisaldehyde (PAA), cerium molybdate (CeMo), 2,4-dinitrophenyl hydrazine (DNP),
KMnO4, or iodine (I2) stain respectively, and the TLC visualization stains were prepared using standard
procedures.23 Dry acetonitrile (MeCN), toluene, benzene, tetrahydrofuran (THF), and methanol (MeOH)
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were obtained by passing these previously degassed solvents through activated alumina columns.
Dichloromethane (DCM) was distilled over calcium hydride before use. Volatile solvents were removed
under reduced pressure on a rotary evaporator. All flash chromatography was conducted using standard
grade silica gel 60 Å, 230 x 400 mesh (40-63 µm). 1H NMR and 13C NMR spectra were collected using
400, 500, and 600 MHz (100, 125, and 150 MHz for 13C NMR) spectrometers in CDCl3, C6D6, or
CD3CN as noted. Chemical shifts were measured relative to the shift of the residual solvent (1H NMR,
CDCl3 δ = 7.26, C6D6 δ = 7.16 ppm; 13C NMR, CDCl3 δ = 77.2, C6D6 δ = 128.1 ppm, CD3CN δ = 1.32
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1
ppm). H NMR data are reported as follows: chemical shift (multiplicity, coupling constant,
integration). Splitting is reported with the following symbols: s = singlet, d = doublet, dd = doublet of
doublets, ddd = doublet of doublet of doublets, t = triplet, sept = septet, m = multiplet. FTIR spectra
were measured using the ATIR method. Spectra are reported in frequency of absorption in cm–1, and
only selected resonances are reported. High-resolution mass spectral data were obtained using
electrospray (ESI) or electron impact (EI) ionization and using linear ion trap analyzer. Microwave-
assisted reactions were performed using a Biotage® Initiator 2.5 reactor on low absorbance irradiation
setting with the fix-hold-time feature set to off.
(1E,3E)-1,4-dicyanonbuta-1,3-diene-1,4-diyl diacetate (1) was synthesized according to literature
procedures with slight modifications as described below and will be referred to as bis(1-cyanovinyl
acetate).11 1-(toluene-4-sulfonyl)-2-vinyl-1H-indole 2m was synthesized according to a literature
procedure.24 2-Vinyl-1H-indene 2a12, 4-isopropylstyrene 2e, 4-trifluoromethylstyrene 2h, benzyl vinyl
ether 2k, 2-bromo-4,5-dimethoxystyrene 2n, and 2-acetoxy-4,5-dibromostyrene 2o were synthesized as
described below. All other commercially available reagents were used as purchased (i.e., with
stabilizers).
Modification of procedure to synthesize bis(1-cyanovinyl acetate) (1). To a flamed-dried round-
bottomed flask containing a Teflon®-coated stir bar and fitted with a rubber septum was added succinyl
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chloride (1.9 mL, 17.3 mmol, 1.0 equiv) under a positive pressure of nitrogen. Trimethylsilyl cyanide
(5.2 mL, 41.6 mmol, 2.4 equiv), and trimethylsilyl chloride (270 µL, 2.1 mmol, 0.12 equiv) were added,
and the colorless homogenous solution was stirred for 3 days at room temperature. At this time, the
byproduct trimethylsilyl chloride was removed from the vessel under a slight vacuum using a Welch®
pump (model 2025) (~600 – 650 mm Hg at room temperature) to give crude succinyl cyanide as a
brown low melting solid, which was used immediately without further purification. To a stirred solution
of the crude succinyl cyanide and acetyl chloride (3.6 mL, 50.4 mmol, 2.9 equiv) in benzene (100 mL)
was added a solution of pyridine (4.1 mL, 49.6 mmol, 2.8 equiv) in benzene (120 mL) by cannula (over
~3 min). The solution turned purple and heterogeneous over time. After 1 h, the heterogeneous mixture
was diluted by water, extracted with ethyl acetate (x 3), washed with water and brine, dried with
MgSO4, and evaporated to give a dark red solid containing traces of pyridine hydrochloride. SiO2-gel
column chromatography (3:1 hexanes:ethyl acetate) gave a yellow solid which was rinsed with diethyl
ether (10 mL x 2) to give the desired product as a yellow solid (1.68 g, 7.6 mmol, 44%). The purified
material has a melting point range of 168 – 171 ºC, which matches the reported literature value (165 –
170 ºC). Notes: The Oku procedure11 (synthesis of compound 1 in their report) states that 9.06 g (6.66
mmol) of the diacid cyanide was used. For the diacid cyanide, 9.06 g actually corresponds to 66.6 mmol
of substrate and not 6.66 mmol. Using 6.66 mmol, the concentration of the reaction is 0.07 M (which we
used to prepare the title compound). The concentration (assuming Oku and coworkers used 9.06 g of the
dicyanide) would be 0.70 M in the initial report for the preparation of compound 1.
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Synthesis of indene 2a.12 To a flame-dried round-bottomed flask containing a Teflon®-coated stir bar
and fitted with a rubber septum was added solid 2,5-dimethoxy benzaldehyde (5.00 g, 30.0 mmol, 1
equiv). The flask was evacuated and backfilled with nitrogen gas (x 3). THF (300 mL) was added, and
the homogenous solution was cooled to 0 ºC. Ethynylmagnesium bromide (0.5 M in THF) (66.3 mL,
33.2 mmol, 1.1 equiv) was added dropwise over 5 minutes, and the solution was stirred at 0 ºC for 1 h
after which pivalolyl chloride (7.40 g, 60.1 mmol, 2.0 equiv) was added. The solution was then heated
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to 50 ºC with stirring and held at this temperature for 1 h. The resulting solution was cooled to room
temperature, diluted with diethyl ether (600 mL), and quenched with saturated aqueous NaHCO3 (300
mL). The biphasic mixture was then shaken and the aqueous layer separated. The aqueous layer was
extracted with diethyl ether (300 mL x 3). The combined organic layers were washed with brine (300
mL x 3), dried over Na2SO4, concentrated, and purified by SiO2-gel chromatography (5:1
hexanes:diethyl ether) to afford the propargylic ester S1; Rf = 0.53 (2:1 hexanes:ethyl acetate); The
product stains black with PAA; The product is isolated as a viscous yellow oil; Isolated yield 8.2 g,
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1
99%; H NMR (600 MHz, CDCl3) δ 7.22 (s, 1H), 6.86 (dd, J = 8.9, 3.1 Hz, 1H), 6.82 (d, J = 8.9 Hz,
13
1H), 6.70 (d, J = 2.2 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 2.56 (s, 1H), 1.22 (s, 9H); C NMR (150
MHz, CDCl3) δ 177.0, 153.7, 151.0, 126.2, 114.8, 114.4, 112.1, 80.6, 74.5, 60.3, 56.3, 55.9, 38.9, 27.2;
IR (ATIR) 3284, 2971, 2936, 2909, 2874, 2836, 1732 cm–1; HRMS (ESI) calcd for C16H20O4Na
(M+Na)+ m/z 299.1254 found 299.1253.
To a flame-dried Schlenk flask equipped with a Teflon®-coated stir bar was added the propargylic ester
S1 (2.76 g, 10.0 mmol, 1 equiv) from the previous step. The flask was then brought into a glove box and
di-µ-chloro-dichlorobis(ethylene)-diplatinum(II) (Zeise’s dimer) (294 mg, 0.50 mmol, 5 mol %) was
added. The sealed flask was then brought outside of the glove box and toluene (100 mL) was added
followed by trans-4-octene (448 mg, 4.0 mmol, 0.4 equiv) under nitrogen atmosphere. The flask was
resealed, heated to 100 ºC, and held at this temperature for 1 h. The flask was then cooled in a room
temperature water bath. The solution was concentrated under reduced pressure and the residue purified
by SiO2-gel chromatography (7:1 hexanes:ethyl acetate) to give the 2-indenylpivalate S2; Rf = 0.35
(10:1 hexanes:ethyl acetate); The product stains blue green with PAA; The product is isolated as a
yellow solid; Isolated yield 2.07 g, 75%; 1H NMR (500 MHz, CDCl3) δ 6.73 (d, J = 8.8 Hz, 1H), 6.67
13
(s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.53 (s, 2H), 1.31 (s, 9H); C NMR (125
MHz, CDCl3) δ 176.0, 155.3, 149.7, 148.0, 133.1, 125.8, 111.4, 110.3, 107.5, 56.4, 55.8, 39.4, 36.0,
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27.2; IR (ATIR) 2976, 2941, 2908, 2973, 2835, 1741, 1495 cm–1; HRMS (EI) calcd for C16H20O4 (M)•+
1
2
3
m/z 276.1362 found 276.1366.
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7
8
To a 500 mL round-bottomed flask equipped with a Teflon®-coated stir bar was added the 2-
indenylpivalate S2 (2.41 g, 8.7 mmol, 1 equiv) from the previous step and potassium hydroxide (980
mg, 17.5 mmol, 2 equiv). MeOH (60 mL) was added, and the solution was stirred at room temperature
for 2 h. The solution was then diluted with water (50 mL) and 1N aqueous HCl (50 mL). The reaction
mixture was extracted with dichloromethane (100 mL x 3), washed with water (50 mL) and brine (50
mL), dried over MgSO4, and concentrated to give the crude 2-indanone, which was transferred to a
flame-dried 250 mL round-bottomed flask with a Teflon®-coated stir bar. The flask was evacuated and
backfilled with nitrogen gas (x 3). THF (50 mL) was added and the solution was cooled to 0 ºC. To the
cooled solution was slowly added t-BuOK (10.6 mL, 1.0 M in THF) and the solution was allowed to stir
at 0 ºC for 1 h. Solid Comin’s reagent25 (4.10 g, 10.4 mmol) was then added all at once at 0 ºC by
quickly removing and replacing the fitted septa. The homogenous solution was then allowed to stir for 1
h at room temperature. The resulting solution was then diluted with water (20 mL) and ethyl acetate (20
mL), transferred to a separatory funnel and shaken. The aqueous layer was then removed and the
organic layer was washed with 1 N aqueous NaOH (10 mL) and brine (20 mL). The organic layers were
dried over MgSO4, filtered, concentrated, and purified by SiO2-gel chromatography (7:1
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hexanes:dichloromethane) to give the desired indenyl-2-triflate S3; Rf
=
0.25 (4:1
hexanes:dichloromethane); The product is isolated as yellow oil; Isolated yield 752 mg, 27% (over two
1
steps); H NMR (500 MHz, CDCl3) δ 6.80 (s, 1H), 6.77 (d, J = 9.1 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H),
3.84 (m, 6H), 3.62 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 152.1, 149.4, 148.4, 130.0, 125.9, 118.8 (q,
JC–F = 319.6 Hz), 116.6, 110.2, 109.2, 56.1, 55.8, 36.0; IR (ATIR) 3005, 2946, 2910, 2838, 1498, 1423,
32
1204 cm–1; HRMS (EI) calcd for C12H11O5F3 S (M)•+ m/z 324.0279 found 324.0285.
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To a flame-dried 100 mL round-bottomed flask equipped with a Teflon®-coated stir bar was added
Pd(PPh3)4 (76.2 mg, 66.0 µmol, 3 mol %) inside a glove box. The sealed flask was then brought outside
of the glove box and the indenyl-2-triflate S3 (709 mg, 2.2 mmol, 1 equiv) from the previous step was
added as a solution in dimethoxyethane (22 mL). The solution was stirred at room temperature for 20
min. At that time, a solution of K2CO3 (608 mg, 4.4 mmol, 2 equiv) and vinylboroxine pyridine
complex26 (263 mg, 1.1 mmol, 0.5 equiv) in water (7 mL) was injected into the reaction mixture. The
solution was then heated to 100 ºC and stirred at that temperature for 14 h. After cooling to room
temperature, the reaction mixture was extracted with diethyl ether (20 mL x 3). The organic layers were
washed with water (10 mL) and brine (10 mL), dried over MgSO4, concentrated, and purified by SiO2-
gel chromatography (100:1 hexanes:ethyl acetate) to give 2-vinyl-1H-indene 2a; Rf = 0.24 (100:1
hexanes:ethyl acetate); The product is isolated as a yellow amorphous solid; Isolated yield 318 mg,
71%; 1H NMR (500 MHz, CDCl3) δ 6.83 (s, 1H), 6.74 (dd, J = 17.3, 10.6 Hz, 1H), 6.71 (d, J = 8.5 Hz,
1H), 6.65 (d, J = 8.0 Hz, 1H), 5.42 (d, J = 17.5 Hz, 1H), 5.15 (d, J = 10.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s,
3H), 3.51 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 149.9, 148.1, 145.7, 135.3, 133.2, 131.3, 127.1,
114.5, 109.8, 108.4, 56.2, 55.8, 35.1; IR (ATIR) 3085, 3047, 2997, 2939, 2903, 2831, 1796, 1618,
1491, 1251 cm–1; HRMS (EI) calcd for C13H14O2 (M)•+ m/z 202.0994 found 202.0998.
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General Procedure for the Synthesis of 4-isopropyl styrene 2e and 4-trifluoromethyl styrene 2h.
To a flame-dried round-bottomed flask equipped with a Teflon®-coated stir bar was added
methyltriphenylphosphonium iodide (1.3 equiv) and THF (13 mL/mmol). t-BuOK (1.9 equiv) was
added in one portion at 0 ºC under nitrogen atmosphere, and the resulting yellow solution was stirred at
room temperature for 1 h. The corresponding aldehyde (1 equiv) was added dropwise to the solution.
After the aldehyde was consumed, the solution was filtered over a one inch pad of Celite® and the
residue was washed with diethyl ether. The filtrate was concentrated and purified by SiO2-gel
chromatography (100% hexanes) to give the desired styrene; Spectroscopic data for these compounds
was identical to that previously reported.27,28
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4-isopropyl styrene 2e. Rf = 0.57 (hexanes only); The product is isolated as colorless oil; The product
stains purple with PAA; Isolated yield 1.13 g, 64%; 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.9 Hz,
2H), 7.20 (d, J = 7.9 Hz, 2H), 6.71 (dd, J = 17.7, 10.9 Hz, 1H), 5.72 (d, J = 17.6 Hz, 1H), 5.20 (d, J =
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10.8 Hz, 1H), 2.91 (sept, J = 6.5 Hz, 1H), 1.26 (d, J = 7.0 Hz, 6H); C NMR (125 MHz, CDCl3) δ
9
148.8, 136.8, 135.4, 126.7, 126.3, 113.0, 34.0, 24.1; IR (ATIR) 2959, 1612, 1511, 1407, 988, 900, 836
cm–1; HRMS (EI) calcd for C11H14 (M)•+ m/z 146.1096 found 146.1095.
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4-trifluoromethyl styrene 2h. Rf = 0.62 (hexanes only); The product is isolated as colorless oil; The
1
product stains yellow with KMnO4; Isolated yield 861 mg, 33%; H NMR (500 MHz, CDCl3) δ 7.58
(d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 6.75 (dd, J = 17.7, 10.9 Hz, 1H), 5.85 (d, J = 17.6 Hz, 1H),
5.39 (d, J = 10.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 141.1, 135.8, 129.8 (q, JC–F = 32.3 Hz),
126.5, 125.5 (q, JC–F = 37.5 Hz), 124.4 (q, JC–F = 270.4 Hz), 116.6; IR (ATIR) 3095, 1618, 1321, 1164,
1111, 1066, 844 cm–1; HRMS (EI) calcd for C9H7F3 (M)•+ m/z 172.0500 found 172.0499.
Synthesis of benzyl vinyl ether 2k. To a flame-dried 50 mL round-bottomed flask equipped with a
Teflon®-coated stir bar, t-BuOK (616 mg, 5.5 mmol, 2.4 equiv) and THF (3 mL) were added under
nitrogen atmosphere. The solution of 1-(benzyloxy)-2-bromoethane (485 mg, 2.25 mmol, 1 equiv) in
THF (2 mL) was added dropwise at 0 °C. The solution was stirred at room temperature for 2 h. At that
time, the reaction mixture was diluted with water (5 mL), extracted with diethyl ether (10 mL x 3),
washed with brine (5 mL), dried over Na2SO4, and concentrated to afford the crude product, which was
purified by SiO2-gel column chromatography (hexanes only) to give the benzyl vinyl ether 2k (210 mg,
1.57 mmol, 70%); Rf = 0.23 (100% hexanes); The product is isolated as colorless oil; The product stains
black with CeMo; 1H NMR (500 MHz, CDCl3) δ 7.42 – 7.30 (m, 5H), 6.58 (dd, J = 14.4, 6.8 Hz, 1H),
13
4.77 (s, 2H), 4.32 (dd, J = 14.4, 2.3 Hz, 1H), 4.10 (dd, J = 6.9, 2.3 Hz, 1H); C NMR (125 MHz,
CDCl3) δ 151.8, 137.0, 128.7, 128.1, 127.7, 87.5, 70.2; IR (ATIR) 3034, 2868, 1614, 1319, 1194, 815,
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734, 695 cm–1; HRMS (EI) calcd for C9H10O (M)•+ m/z 134.0732 found 134.0730. Spectroscopic data
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3
for this compound was identical to that previously reported.29
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5
Synthesis of 2-bromo-4,5-dimethoxystyrene 2n. To a 200 mL flame-dried round-bottomed flask
equipped with a Teflon®-coated stir bar was added methyltriphenylphosphonium iodide (9.70 g, 24.0
mmol, 1.2 equiv) and THF (100 mL). t-BuOK (2.80 g, 25.0 mmol, 1.3 equiv) was added in one portion
at 0 ºC under nitrogen atmosphere, and the resulting solution was stirred at 0 ºC for 20 min. A solution
of 6-bromoveratral30 (4.90 g, 20.0 mmol, 1 equiv) in THF (30 mL) was added slowly to the solution,
and warmed to room temperature. After stirring for 30 min, the solution was filtered over a pad of
Celite® and the residue was washed with diethyl ether (20 mL). The filtrate was concentrated and
purified by SiO2-gel chromatography (10:1 hexanes:ethyl acetate) to give 2-bromo-4,5-
dimethoxystyrene 2n; Rf = 0.21 (10:1 hexanes:ethyl acetate); The product is isolated as an off-white
solid; The product stains purple with PAA; Isolated yield 2.70 g, 56%; 1H NMR (600 MHz, CDCl3) δ
7.05 (s, 1H), 7.01 (s, 1H), 6.98 (dd, J = 17.4, 11.0 Hz, 1H), 5.59 (dd, J = 17.4, 0.9 Hz, 1H), 5.28 (dd, J =
10.9, 0.8 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 149.5, 148.7, 135.6, 129.6,
115.3, 114.7, 114.4, 108.8, 56.3, 56.1; IR (ATIR) 2998, 2934, 2906, 2837, 1498, 1255, 1207, 1160,
1024, 851, 793 cm–1; HRMS (EI) calcd for C10H11O279Br (M)•+ m/z 241.9942 found 241.9945.
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Synthesis of 2-acetoxy-4,5-dimethoxystyrene 2o. To a flame-dried 200 mL flask equipped with a
Teflon®-coated stir bar was added 1-(2-bromo-4,5-dimethoxyphenyl)ethanone31 (2.59 g, 10.0 mmol, 1
equiv), Pd(PPh3)4 (578 mg, 0.50 mmol, 5 mol %), and DME (60 mL). This solution was stirred at room
temperature for 20 min undernitrogen atmosphere. To this reaction mixture, a solution of vinylboroxine
pyridine complex26 (900 mg, 3.7 mmol, 0.40 equiv) and K2CO3 (1.38 g, 10.0 mmol, 1 equiv) in water
(20 mL) was injected and the flask was warmed to 80 ºC. This solution was stirred for 11 h at that
temperature. After cooling to room temperature, the reaction mixture was extracted with diethyl ether
(20 mL x 3). The organic layers were washed with water (20 mL) and brine (20 mL), dried over MgSO4,
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concentrated, and purified by SiO2-gel chromatography (5:1 hexanes:ethyl acetate) to give 2-acetoxy-
4,5-dimethoxystyrene 2o; Rf = 0.10 (5:1 hexanes:ethyl acetate); The product is isolated as an off-white
solid; Isolated yield 1.72 g, 83%; 1H NMR (600 MHz, CDCl3) δ 7.24 (dd, J = 17.3, 10.9 Hz, 1H), 7.17
(s, 1H), 7.00 (s, 1H), 5.55 (dd, J = 17.3, 1.2 Hz, 1H), 5.31 (dd, J = 10.9, 1.1 Hz, 1H), 3.96 (s, 3H), 3.93
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(s, 3H), 2.56 (s, 3H); C NMR (150 MHz, CDCl3) δ 200.2, 151.9, 148.2, 136.4, 132.9, 130.0, 115.6,
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112.1, 110.1, 56.3, 56.1, 30.0; IR (ATIR) 2965, 2943, 2852, 1662, 1510, 1335, 1266, 1202, 1187, 1147,
922, 875 cm–1; HRMS (EI) calcd for C12H14O3 (M)•+ m/z 206.0943 found 206.0935.
Procedure for intermolecular [5+2] cycloaddition reaction with indene 2a. To a flame-dried 0.2 –
0.5 mL Biotage® microwave vial was added bis(1-cyanovinyl acetate) (1) (11.0 mg, 0.050 mmol, 1
equiv) and indene 2 (20.2 mg, 0.10 mmol, 2 equiv). The vial was sealed, evacuated and backfilled with
nitrogen gas (x 3). Toluene (1.0 mL) was added and the heterogeneous solution was heated to 180 ºC in
the microwave and held at this temperature for 2 h. The resulting solution was concentrated and purified
by SiO2-gel chromatography (50:3 hexanes:ethyl acetate to 100% ethyl acetate) to afford a
diastereomeric mixture of adduct 4a; Isolated yield 17.3 mg, 59% (dr 75:25); Rf = 0.56 (1:2
1
hexanes:ethyl acetate); The product stains purple with DNP; Spectral data reported endo-4a H NMR
(600 MHz, CDCl3) δ 7.17 (s, 1H), 6.79 – 6.76 (m, 2H), 6.71 (d, J = 8.6 Hz, 1H), 6.65 (d, J = 8.6 Hz,
1H), 6.62 (d, J = 8.7 Hz, 1H), 5.57 (s, 1H), 4.55 (dd, J = 5.6, 5.6 Hz, 1H), 4.43 (dd, J = 12.0, 7.1 Hz,
1H), 3.87 (s, 3H), 3.86 – 3.76 (m, 11H), 3.65 – 3.49 (m, 4H), 2.81 (dd, J = 15.1, 8.2 Hz, 1H), 2.65 –
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2.56 (m, 1H), 2.52 – 2.44 (m, 1H), 2.39 (dd, J = 13.3 Hz, 7.1 Hz, 1H), 1.97 (s, 3H); C NMR (150
MHz, CDCl3) δ 199.5, 170.0, 150.6, 150.3, 150.0, 147.9, 141.2, 139.6, 133.9, 132.0, 131.9, 130.8,
126.5, 117.6, 117.1, 109.8, 109.0, 108.8, 108.4, 91.5, 79.2, 56.0, 55.8, 55.7, 55.6, 49.4, 45.1, 43.6, 40.9,
39.8, 35.0, 32.1, 25.7, 24.5; IR (ATIR) 3375, 2951, 2912, 2852, 1743, 1696, 1495, 1461, 1254 cm–1;32
HRMS (ESI) calcd for C34H35O7N2 (M+H)+ 583.2439 found 583.2440; Melting point of an amorphous
solid is 237 – 241 ºC; X-ray quality crystal of the endo- adduct was obtained as follows: Ethanol was
added to the diastereomeric mixture to precipitate the product and the solution was heated to the point of
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reflux and allowed to slowly cool to room temperature to give a white powder. The resulting powder
was then filtered over glass wool, washed with hexanes, and then collected as a solution by washing
with DCM to dissolve the solids and concentrated. The resulting solid was then recrystallized by vapor
diffusion (hexanes into ethyl acetate).
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Experimental procedure (Table 1). To a flame-dried 4 mL vial equipped with a Teflon®-coated stir
bar was added bis(1-cyanovinyl acetate) 1 (22.0 mg, 0.10 mmol), 4-methoxystyrene 2b (0.50 mmol, 5
equiv), additive (10 µmol, 10 mol %), and dry acetonitrile (1 mL). The vial was then capped, the
reaction mixture was heated to reflux (100 ºC, oil bath temperature) and stirred for 39 h. At this time,
the solution was concentrated and purified by SiO2-gel chromatography (2:1 hexanes:ethyl acetate) to
afford the desired cycloaddition products endo- and exo-4b.
General procedure for intermolecular [5+2] cycloaddition reaction (Table 2). To a flame-dried 4
mL vial equipped with a Teflon®-coated stir bar was added bis(1-cyanovinyl acetate) 1 (22.0 mg, 0.10
mmol), the dipolarophile 2 (0.50 mmol, 5 equiv), PPTS (1.2 mg, 5.0 µmol, 5 mol %), and dry
acetonitrile (1 mL). The vial was then capped, the reaction mixture was heated to reflux (100 ºC, oil
bath temperature) and stirred for 24 h. At this time, the solution was concentrated and purified by SiO2-
gel chromatography to afford the desired cycloaddition products 4.
N-(5-cyano-6-(4-methoxyphenyl)-2-oxo-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide
(4b).
Purification by SiO2-gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for
both diastereomers is 25.1 mg, 80% (dr 78:22).
endo- diastereomer Rf = 0.43 (1:2 hexanes:ethyl acetate); The product stains red with PAA; The product
1
is isolated as an orange amorphous solid; Isolated yield 19.6 mg, 63%; H NMR (600 MHz, C6D6) δ
6.75 (d, J = 10.4 Hz, 2H), 6.61 (d, J = 10.5 Hz, 2H), 6.31 (s, 1H), 5.81 (d, J = 11.8 Hz, 1H), 5.57 (d, J =
11.8 Hz, 1H), 4.37 (dd, J = 10.8, 10.8 Hz, 1H), 3.49 (dd, J = 16.1, 11.4 Hz, 1H), 3.26 (s, 3H), 1.73 (dd,
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13
J = 16.0, 10.4 Hz, 1H), 1.33 (s, 3H); C NMR (150 MHz, C6D6) δ 189.9, 169.2, 160.3, 148.1, 129.7,
127.2, 125.1, 116.4, 114.5, 91.4, 77.4, 54.9, 52.2, 31.5, 23.2; IR (ATIR) 3305, 3054, 2959, 2928, 2840,
1718, 1684, 1515, 1252, 1032 cm–1; HRMS (EI) calcd for C17H16N2O4 (M)•+ m/z 312.1110 found
312.1111; Melting point of an amorphous solid is 155 – 158 ºC; X-ray quality crystals were grown by
vapor diffusion of ethyl acetate into hexanes dissolving ~4.3 mg of endo-4b in 0.5 mL ethyl acetate.
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exo- diastereomer Rf = 0.22 (1:2 hexanes:ethyl acetate); The product stains faint purple/red with PAA;
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The product is isolated a yellow amorphous solid; Isolated yield 5.5 mg, 18%; H NMR (600 MHz,
CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 6.76 (s, 1H), 6.24
(d, J = 9.8 Hz, 1H), 3.82 (s, 3H), 3.67 (dd, J = 9.3, 4.0 Hz, 1H), 3.39 (dd, J = 14.3, 4.0 Hz, 1H), 2.41
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(dd, J = 14.2, 9.4 Hz, 1H), 2.15 (s, 3H); C NMR (150 MHz, CDCl3) δ 190.1, 170.0, 159.9, 150.7,
130.8, 129.9, 125.3, 114.8, 114.5, 93.0, 79.1, 55.4, 52.5, 33.9, 24.4; IR (ATIR) 3302, 3040, 2957, 2923,
1717, 1679, 1513, 1251, 1052, 1032 cm–1; HRMS (EI) calcd for C17H16N2O4 (M)•+ m/z 312.1110 found
312.1111; Melting point of an amorphous solid is 208 – 212 ºC; X-ray quality crystals of exo-4b were
grown by slow evaporation from a solution of isopropyl alcohol (~10 mg in 500 µL solvent).
N-(5-cyano-2-oxo-6-phenyl-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide (4c). Purification by SiO2-
gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for both diastereomers is
18.1 mg, 64% (dr 73:27).
Rf = 0.30 (1:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as a
1
yellow amorphous solid; Isolated yield 13.2 mg, 47%; H NMR (600 MHz, CDCl3) δ 7.04 – 6.95 (m,
3H), 6.84 – 6.79 (m, 2H), 6.32 (s, 1H), 5.70 (d, J = 9.8 Hz, 1H), 5.53 (d, J = 9.8 Hz, 1H), 4.34 (dd, J =
9.1, 9.1 Hz, 1H), 3.46 (dd, J = 12.8, 10.1 Hz, 1H), 1.74 (dd, J = 12.9, 8.7 Hz, 1H), 1.34 (s, 3H); 13C
NMR (150 MHz, CD3CN) δ 190.0, 171.2, 147.5, 134.4, 130.2, 129.8, 129.6, 129.5, 117.4, 93.3, 78.2,
54.0, 34.4, 23.5; IR (ATIR) 3298, 3051, 3033, 1718, 1681, 1526, 1501, 1373, 1274, 1188 cm–1; HRMS
(EI) calcd for C16H14N2O3 (M)•+ m/z 282.1004 found 282.1004.
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Rf = 0.15 (1:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as an
orange amorphous solid; Isolated yield 4.9 mg, 17%;1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 7.5
Hz, 2H), 7.47 – 7.41 (m, 3H), 7.37 (t, J = 7.4 Hz, 1H), 6.75 (s, 1H), 6.27 (d, J = 9.8 Hz, 1H), 3.70 (dd, J
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= 9.2, 3.8 Hz, 1H), 3.44 (dd, J = 14.2, 3.9 Hz, 1H), 2.44 (dd, J = 14.1, 9.4 Hz, 1H), 2.16 (s, 3H); C
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NMR (125 MHz, CDCl3) δ 190.0, 170.0, 150.6, 138.7, 129.2, 128.8, 128.6, 125.5, 114.7, 93.0, 78.8,
53.1, 34.0, 24.4; IR (ATIR) 3303, 3060, 3034, 2928, 2251, 1717, 1681, 1527, 1371, 1052 cm–1; HRMS
(EI) calcd for C16H14N2O3 (M)•+ m/z 282.1004 found 282.1000.
N-(5-cyano-2-oxo-6-(p-tolyl)-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide (4d). Purification by SiO2-
gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for both diastereomers is
21.2 mg, 72% (dr 74:26).
Rf = 0.22 (2:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as a
1
yellow amorphous solid; Isolated yield 15.5 mg, 52%; H NMR (600 MHz, CDCl3) δ 7.21 (d, J = 7.9
Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 6.80 (s, 1H), 6.75 (d, J = 9.8 Hz, 1H), 6.34 (d, J = 9.8 Hz, 1H), 4.39
(dd, J = 9.1, 9.1 Hz, 1H), 3.60 (dd, J = 13.7, 9.5 Hz, 1H), 2.35 (s, 3H), 2.23 (dd, J = 13.6, 8.6 Hz, 1H),
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2.12 (s, 3H); C NMR (150 MHz, CDCl3) δ 189.8, 170.1, 148.3, 138.9, 129.9, 129.8, 128.3, 127.5,
115.8, 91.2, 77.1, 52.4, 31.6, 24.3, 21.2; IR (ATIR) 3373, 2920, 2855, 1720, 1694, 1503, 1252, 1171,
993 cm–1; HRMS (EI) calcd for C17H16N2O3 (M)•+ m/z 296.1161 found 296.1165.
Rf = 0.08 (2:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as an
1
orange amorphous solid; Isolated yield 5.7 mg, 19%; H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.6
Hz, 2H), 7.42 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 2H), 6.73 (s, 1H), 6.26 (d, J = 9.8 Hz, 1H), 3.66
(dd, J = 9.7, 4.0 Hz, 1H), 3.36 (dd, J = 14.2, 4.2 Hz, 1H), 2.43 (dd, J = 13.9, 9.1 Hz, 1H), 2.36 (s, 3H),
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2.15 (s, 3H); C NMR (125 MHz, CDCl3) δ 190.1, 170.0, 150.6, 138.5, 135.7, 129.9, 128.5, 125.5,
114.8, 93.0, 79.0, 52.7, 34.2, 24.3, 21.4; IR (ATIR) 3290, 2956, 2922, 2853, 1719, 1672, 1515, 1455,
1373, 1053 cm–1; HRMS (EI) calcd for C17H16N2O3 (M)•+ m/z 296.1161 found 296.1162.
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N-(5-cyano-6-(4-isopropylphenyl)-2-oxo-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide
(4e).
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Purification by SiO2-gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for
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both diastereomers is 21.2 mg, 65% (dr 72:28).
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Rf = 0.22 (2:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as a
yellow amorphous solid; Isolated yield 15.2 mg, 47%; 1H NMR (600 MHz, C6D6) δ 6.94 (d, J = 8.0 Hz,
2H), 6.85 (d, J = 8.0 Hz, 2H), 6.33 (s, 1H), 5.76 (d, J = 9.8 Hz, 1H), 5.57 (d, J = 9.8 Hz, 1H), 4.39 (dd, J
= 9.1, 9.1 Hz, 1H), 3.50 (dd, J = 13.4, 9.5 Hz, 1H), 2.66 (sept, J = 6.6 Hz, 1H), 1.81 (dd, J = 13.4, 8.6
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Hz, 1H), 1.35 (s, 3H), 1.11 (d, J = 6.9 Hz, 6H); C NMR (150 MHz, C6D6) δ 189.9, 169.2, 149.3,
148.0, 130.8, 128.7, 127.11, 127.07, 116.4, 91.4, 77.3, 52.4, 34.1, 31.4, 24.0, 23.2; IR (ATIR) 3266,
3046, 2959, 1715, 1670, 1538, 1371, 1337, 1199, 1078 cm–1; HRMS (EI) calcd for C19H20N2O3 (M)•+
m/z 324.1474 found 324.1471.
Rf = 0.09 (2:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as an
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orange amorphous solid; Isolated yield 6.0 mg, 18%; H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 8.2
Hz, 2H), 7.42 (d, J = 9.8 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 6.75 (s, 1H), 6.25 (d, J = 9.8 Hz, 1H), 3.67
(dd, J = 9.3, 3.9 Hz, 1H), 3.36 (dd, J = 14.4, 4.1 Hz, 1H), 2.92 (sept, J = 6.9 Hz, 1H), 2.43 (dd, J = 14.1,
9.3 Hz, 1H), 2.15 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 190.1, 170.0, 150.6,
149.3, 136.0, 128.5, 127.2, 125.5, 114.8, 93.0, 78.9, 52.7, 34.3, 33.9, 24.3, 24.1, 24.0; IR (ATIR) 3281,
3057, 2961, 1719, 1673, 1539, 1373, 1331, 1206, 1184, 1052 cm–1; HRMS (EI) calcd for C19H20N2O3
(M)•+ m/z 324.1474 found 324.1472.
N-(6-(4-(tert-butyl)phenyl)-5-cyano-2-oxo-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide
(4f).
Purification by SiO2-gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for
both diastereomers is 23.8 mg, 70% (dr 78:22).
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Rf = 0.26 (2:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as an
orange amorphous solid; Isolated yield 18.6 mg, 55%; 1H NMR (600 MHz, C6D6) δ 7.13 (d, J = 8.4 Hz,
2H), 6.89 (d, J = 8.3 Hz, 2H), 6.37 (s, 1H), 5.78 (d, J = 9.8 Hz, 1H), 5.61 (d, J = 9.8 Hz, 1H), 4.41 (dd, J
= 9.1, 9.1 Hz, 1H), 3.52 (dd, J = 13.3, 9.8 Hz, 1H), 1.85 (dd, J = 13.5, 8.6 Hz, 1H), 1.38 (s, 3H), 1.19 (s,
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9H); C NMR (150 MHz, C6D6) δ 189.9, 169.3, 151.5, 148.0, 130.5, 128.4, 127.1, 126.0, 116.4, 91.5,
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77.3, 52.4, 34.5, 31.4, 31.1, 23.3; IR (ATIR) 3299, 3053, 2961, 2904, 2867, 1718, 1679, 1515, 1369,
1269, 1187 cm–1; HRMS (EI) calcd for C20H22N2O3 (M)•+ m/z 338.1630 found 338.1630.
Rf = 0.09 (2:1 hexanes:ethyl acetate); The product stains orange with DNP; The product is isolated as a
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red amorphous solid; Isolated yield 5.6 mg, 15%; H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz,
2H), 7.45 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 9.8 Hz, 1H), 6.75 (s, 1H), 6.25 (d, J = 9.8 Hz, 1H), 3.68 (dd, J
= 9.4, 4.0 Hz, 1H), 3.37 (dd, J = 14.2, 4.1 Hz, 1H), 2.43 (dd, J = 14.0, 9.4 Hz, 1H), 2.15 (s, 3H), 1.32 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 190.1, 170.0, 151.5, 150.6, 135.7, 128.3, 126.1, 125.4, 114.8, 92.9,
78.9, 52.6, 34.7, 34.3, 31.4, 24.3; IR (ATIR) 3300, 3053, 2963, 2867, 1718, 1514, 1370, 1269, 1052
cm–1; HRMS (EI) calcd for C20H22N2O3 (M)•+ m/z 338.1630 found 338.1629.
4-(1-acetamido-5-cyano-2-oxo-8-oxabicyclo[3.2.1]oct-3-en-6-yl)phenyl acetate (4g). Purification by
SiO2-gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for both diastereomers
is 22.3 mg, 66% (dr 71:29).
Rf = 0.18 (2:1 hexanes:ethyl acetate); The product stains red/purple with PAA; The product is isolated
as a red amorphous solid; Isolated yield 15.8 mg, 46%; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 6.8
Hz, 2H), 7.11 (d, J = 6.8 Hz, 2H), 6.80 (d, J = 7.9 Hz, 2H), 6.79 (s, 1H), 6.37 (d, J = 7.8 Hz, 1H), 4.43
(dd, J = 7.3, 7.3 Hz, 1H), 3.64 (dd, J = 10.9, 7.6 Hz, 1H), 2.31 (s, 3H), 2.21 (dd, J = 10.9, 6.8 Hz, 1H),
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2.13 (s, 3H); C NMR (100 MHz, CD3CN) δ 189.9, 171.2, 170.4, 152.0, 147.3, 132.0, 130.7, 130.3,
123.2, 117.3, 93.2, 78.1, 53.5, 34.6, 23.5; IR (ATIR) 3315, 3056, 2927, 1754, 1719, 1691, 1510, 1197,
1170 cm–1; HRMS (EI) calcd for C18H16N2O5 (M)•+ m/z 340.1059 found 340.1062.
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Rf = 0.09 (2:1 hexanes:ethyl acetate); The product stains red/purple with PAA; The product is isolated
as a white amorphous solid; Isolated yield 6.5 mg, 19%; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2
Hz, 2H), 7.42 (d, J = 9.8 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 6.76 (s, 1H), 6.26 (d, J = 9.8 Hz, 1H), 3.71
(dd, J = 9.4, 3.9 Hz, 1H), 3.41 (dd, J = 14.1, 3.9 Hz, 1H), 2.43 (dd, J = 14.2, 9.3 Hz, 1H), 2.30 (s, 3H),
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2.15 (s, 3H); C NMR (125 MHz, CDCl3) δ 189.8, 170.1, 169.5, 150.8, 150.2, 136.3, 129.8, 125.7,
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122.3, 114.7, 92.9, 78.7, 52.4, 34.3, 24.3, 21.4; IR (ATIR) 3304, 3051, 2952, 2928, 1758, 1717, 1691,
1507, 1371, 1197, 1170 cm–1; HRMS (EI) calcd for C18H16N2O5 (M)•+ m/z 340.1059 found 340.1057.
N-(5-cyano-2-oxo-6-(4-(trifluoromethyl)phenyl)-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide (4h).
Purification by SiO2-gel chromatography (2:1 hexanes:ethyl acetate); Combined isolated yield for
both diastereomers is 21.6 mg, 62 % (dr 61:39).
Rf = 0.20 (2:1 hexanes:ethyl acetate); The product stains yellow with KMnO4; The product is isolated as
1
an orange amorphous solid; Isolated yield 13.2 mg, 38%; H NMR (600 MHz, CDCl3) δ 7.64 (d, J =
8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.87 (s, 1H), 6.74 (d, J = 9.8 Hz, 1H), 6.38 (d, J = 9.8 Hz, 1H),
4.48 (dd, J = 9.1, 9.1 Hz, 1H), 3.67 (dd, J = 13.7, 9.5 Hz, 1H), 2.26 (dd, J = 13.7, 8.6 Hz, 1H), 2.13 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 189.4, 170.3, 147.3, 137.0, 131.4 (q, JC–F = 32.7 Hz), 128.9, 128.0,
126.3 (q, JC–F = 3.8 Hz), 123.9 (q, JC–F = 270.5 Hz), 115.4, 91.2, 76.7, 52.4, 31.5, 24.2; IR (ATIR) 3374,
2925, 2853, 1728, 1684, 1503, 1325, 1165, 1133, 1119 cm–1; HRMS (EI) calcd for C17H13N2O3F3 (M)•+
m/z 350.0878 found 350.0877.
Rf = 0.09 (2:1 hexanes:ethyl acetate); The product stains yellow with KMnO4; The product is isolated as
a red amorphous solid; Isolated yield 8.4 mg, 24%; 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.9 Hz,
2H), 7.71 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 9.7 Hz, 1H), 6.80 (s, 1H), 6.29 (d, J = 9.7 Hz, 1H), 3.75 (dd, J
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= 9.4, 3.7 Hz, 1H), 3.50 (dd, J = 14.2, 3.7 Hz, 1H), 2.44 (dd, J = 14.3, 9.4 Hz, 1H), 2.16 (s, 3H); C
NMR (150 MHz, CDCl3) δ 189.8, 170.1, 150.3, 142.5, 130.9 (q, JC–F = 32.3 Hz), 129.3, 126.2 (q, JC–F
=
3.8 Hz), 125.5, 124.2 (q, JC–F = 270.5 Hz), 114.5, 92.8, 78.2, 52.8, 33.2, 24.5; IR (ATIR) 3272, 3047,
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The Journal of Organic Chemistry
1726, 1671, 1535, 1324, 1168, 1113, 1070, 1053 cm–1; HRMS (EI) calcd for C17H13N2O3F3 (M)•+ m/z
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350.0878 found 350.0876.
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N-(5-cyano-6-methyl-2-oxo-6-phenyl-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide (4i). Procedure To
a flame-dried 4 mL vial equipped with a Teflon®-coated stir bar was added bis(1-cyanovinyl acetate) 1
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(22.0 mg, 0.10 mmol), α-methylstyrene 2i (59.0 mg, 0.50 mmol, 5 equiv), and i-butylmethylketone (1
mL). The reaction mixture was heated (100 ºC, oil bath temperature) and stirred for 24 h. At this time,
the solution was cooled, concentrated, and purified by SiO2-gel chromatography (2:1 hexanes:ethyl
acetate) to afford the desired products; Rf = 0.32 (1:1 hexanes:ethyl acetate); The product stains orange
with DNP; The product is isolated as an orange amorphous solid; Isolated yield of endo-4i 14.7 mg,
50%; 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.4 Hz, 2H), 7.36 (dd, J = 8.0, 8.0 Hz, 2H), 7.29 (t, J =
7.3 Hz, 1H), 6.93 (d, J = 9.9 Hz, 1H), 6.79 (s, 1H), 6.02 (d, J = 9.9 Hz, 1H), 3.42 (d, J = 13.5 Hz, 1H),
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2.57 (d, J = 13.5 Hz, 1H), 2.14 (s, 3H), 2.09 (s, 3H); C NMR (150 MHz, CDCl3) δ 189.8, 170.0,
150.1, 142.5, 129.3, 127.8, 126.2, 125.1, 116.1, 90.5, 80.0, 55.7, 36.1, 30.8, 24.5; IR (ATIR) 3374,
3198, 3061, 2926, 1722, 1694, 1679, 1498, 1374, 1267, 1180, 1059, 961 cm–1; HRMS (EI) calcd for
C17H16N2O3 (M)•+ m/z 296.1161 found 296.1165; exo-4i is easily decomposed by SiO2-gel column
chromatography; Combined NMR yield for both diastereomers is 63 % (dr 83:17).
N-(5-cyano-2-oxo-6-(phenylthio)-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide (4j). Purification by
SiO2-gel chromatography (2:1 hexanes:ethyl acetate); The product stains yellow with KMnO4; The
product is isolated as an orange amorphous solid; Isolated yield 18.8 mg, 60% (dr >95:5); Rf = 0.19
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(2:1 hexanes:ethyl acetate); H NMR (400 MHz, CDCl3) δ 7.60 – 7.53 (m, 2H), 7.39 – 7.34 (m, 3H),
7.31 (d, J = 9.9 Hz, 1H), 6.81 (s, 1H), 6.34 (d, J = 9.9 Hz, 1H), 4.43 (dd, J = 9.7, 8.0 Hz, 1H), 3.75 (dd,
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J = 13.8, 9.6 Hz, 1H), 2.06 (s, 3H), 1.85 (dd, J = 13.8, 8.0 Hz, 1H); C NMR (100 MHz, CDCl3)
δ 189.1, 170.2, 148.0, 133.2, 131.9, 129.7, 129.2, 127.4, 115.0, 90.6, 75.6, 53.9, 33.7, 24.2; IR (ATIR)
3284, 3069, 1718, 1693, 1662, 1525, 1441, 1363, 1275, 1102 cm–1; HRMS (EI) calcd for C16H14N2O3S
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(M)•+ m/z 314.0726 found 314.0725; The stereochemistry was determined by (1H,1H) NOESY analysis
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of hydrogenated product as described below.
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N-(6-(benzyloxy)-5-cyano-2-oxo-8-oxabicyclo[3.2.1]oct-3-en-1-yl)acetamide (4k). To a flame-dried 4
mL vial equipped with a Teflon®-coated stir bar was added bis(1-cyanovinyl acetate) 1 (22.0 mg, 0.10
mmol, 1 equiv), benzyl vinyl ether 2k (67.1 mg, 0.50 mmol, 5 equiv), and dry THF (1 mL). The vial
was sealed, and then heated to reflux (80 ºC, oil bath temperature) for 96 h. After this time, the solution
was cooled to room temperature and concentrated to afford the crude cycloaddition product;
Purification by SiO2-gel chromatography (2:1 hexanes:ethyl acetate); Rf = 0.26 (1:1 hexanes:ethyl
acetate); The product stains red with PAA; The product is isolated as an orange amorphous solid;
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Isolated yield 13.5 mg, 43% (dr >95:5); 1H NMR (600 MHz, CDCl3) δ 7.39 – 7.29 (m, 5H), 7.19 (d, J
= 10.0 Hz, 1H), 6.72 (s, 1H), 6.34 (d, J = 9.9 Hz, 1H), 4.94 (dd, J = 8.9, 5.6 Hz, 1H), 4.74 (d, J = 11.6
Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 3.53 (dd, J = 13.5, 8.8 Hz, 1H), 2.06 (s, 3H), 1.77 (dd, J = 13.5, 5.7
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Hz, 1H); C NMR (150 MHz, CDCl3) δ 189.7, 170.0, 147.8, 136.4, 128.9, 128.6, 128.0, 127.6, 116.1,
90.4, 83.2, 74.1, 73.8, 32.4, 24.2; IR (ATIR) 3286, 3047, 2922, 2872, 1719, 1670, 1536, 1306, 1267,
1178, 1122, 1060, 1035 cm–1; HRMS (ESI) calcd for C17H17N2O4 (M+H)+ m/z 313.1188 found
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313.1185; The stereochemistry was determined by (1H, H) NOESY analysis as shown; It was also
assigned by analogy using the previous report describing the [5+2] cycloaddition reaction of
oxidopyrylium ions with vinyl ethers to provide endo-adduct.33
N-(9-cyano-6-oxo-1,2,3,4,4a,6,9,9a-octahydro-5H-5,9-epoxy-1,4-methanobenzo[7]annulen-5-yl)
acetamide (4l). Purification by SiO2-gel chromatography (2:1 hexanes:ethyl acetate); The product
stains yellow with KMnO4; The product is isolated as an orange amorphous solid; Isolated yield 13.7
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mg, 50% (dr >95:5); Rf = 0.22 (1:2 hexanes:ethyl acetate); H NMR (500 MHz, CDCl3) δ 7.25 (d, J =
9.3 Hz, 1H), 6.33 (s, 1H), 6.27 (d, J = 9.7 Hz, 1H), 2.80 – 2.77 (m, 1H), 2.46 – 2.43 (m, 1H), 2.36 (d, J
= 6.8 Hz, 1H), 2.10 (s, 3H), 2.07 (d, J = 6.9 Hz, 1H), 1.98 – 1.94 (m, 1H), 1.69 – 1.63 (m, 2H), 1.28 –
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The Journal of Organic Chemistry
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1.16 (m, 3H); C NMR (125 MHz, CDCl3) δ 189.4, 169.9, 148.5, 129.0, 115.3, 94.5, 76.4, 56.4, 49.8,
39.9, 37.4, 34.1, 28.2, 27.9, 23.2; IR (ATIR) 3368, 2994, 2975, 2870, 1720, 1674, 1498, 1428, 1367,
1213, 1170, 1063, 999 cm–1; HRMS (ESI) calcd for C15H17N2O3 (M+H)+ m/z 273.1234 found 273.1232;
The stereochemistry was assigned by analogy using the previous report describing [5+2] cycloaddition
reaction of oxidopyrylium ions with norbornene.34
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Sequential [5+2]/[4+2] cycloaddition reaction of 1-(p-toluenesulfonyl)-3-vinyl-1H-indole (2m) with
bis(1-cyanovinyl acetate) (1). To a flame-dried 4 mL vial equipped with a Teflon®-coated stir bar was
added bis(1-cyanovinyl acetate) 1 (44.0 mg, 0.20 mmol), vinylindole 2m (297.4 mg, 1.0 mmol, 5
equiv), PPTS (2.5 mg, 0.010 mmol), and dry acetonitrile (2 mL). The solution was heated to reflux (100
ºC, oil bath temperature) for 36 h. At this time, the solution was concentrated and purified by SiO2-gel
chromatography (2:1 hexanes:ethyl acetate) to afford the double cycloaddition product 4m as a mixture
with its aromatized tautomer (tautomer of 4m:4m 90:10). Both adducts (tautomer of 4m and 4m) were
treated with TsOH･H2O (57.1 mg, 0.30 mmol, 1.5 equiv) in DCM (5 mL) for 12 h at 40 ºC to induce
aromatization to give the sole product 4m, which was then purified by SiO2-gel chromatography (2:1
hexanes:ethyl acetate); Rf = 0.16 (2:1 hexanes:ethyl acetate); The product stains black with CeMo; The
1
product is an off-white amorphous solid; Isolated yield 78.7 mg, 51%; H NMR (500 MHz, CDCl3) δ
8.10 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H), 7.80 – 7.75 (m, 3H), 7.69 (d, J = 8.5 Hz, 2H), 7.46 – 7.34 (m,
3H), 7.31 – 7.21 (m, 4H), 6.96 (s, 1H), 6.75 (d, J = 8.0 Hz, 2H), 5.49 (d, J = 5.8 Hz, 1H), 4.90 (dd, J =
12.0, 8.0 Hz, 1H), 4.08 (dd, J = 13.1, 13.1 Hz, 1H), 2.86 (dd, J = 17.0, 5.2 Hz, 1H), 2.70 (dd, J = 13.8,
7.7 Hz, 1H), 2.44 – 2.16 (m, 4H), 2.26 – 2.16 (m, 2H), 2.12 (s, 3H), 2.01 – 1.91 (m, 1H), 1.95 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 196.6, 170.3, 145.3, 136.5, 135.8, 135.7, 134.6, 130.1, 129.9, 129.8,
128.6, 128.5, 127.3, 126.7, 126.1, 125.3, 124.6, 124.1, 123.5, 121.4, 119.4, 119.0, 117.9, 117.7, 114.3,
114.1, 90.9, 79.1, 46.7, 44.8, 42.1, 32.3, 24.6, 22.0, 21.8, 21.4, 19.8; IR (ATIR) 3394, 2948, 1744,
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1702, 1509, 1451, 1352, 1175, 1135 cm–1; HRMS (ESI) calcd for C42H36O7N4Na32S2 (M+Na)+ m/z
795.1918 found 795.1911; Melting point of the amorphous solid is 267 – 270 ºC.
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Experimental procedure for large scale synthesis of 4b. To a flame-dried 100 mL Schlenk flask
equipped with a Teflon®-coated stir bar was added bis(1-cyanovinyl acetate) 1 (660 mg, 3.0 mmol, 1
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equiv), 4-vinylanisole 2b (2.01 g, 15.0 mmol, 5 equiv), PPTS (37.7 mg, 15 µmol, 5 mol %), and dry
acetonitrile (30 mL). This reaction mixture was heated to reflux (100 ºC, oil bath temperature) and
stirred for 24 h. At this time, the solution was concentrated and purified by SiO2-gel chromatography
(3:2 hexanes:ethyl acetate) to provide the desired cycloaddition products endo-4b (460 mg, 1.47 mmol,
49%) and exo-4b (138 mg, 0.44 mmol, 15%).
Functionalization of [5+2] cycloaddition reaction product endo-4b (Scheme 3)
Johnson iodination of endo-4b. To a flame-dried 4 mL dram vial equipped with a Teflon®-coated stir
bar was added endo-4b (21.9 mg, 0.070 mmol, 1 equiv). The vial was then fitted with a rubber septum,
carefully evacuated and backfilled with nitrogen gas (x 3), and then DCM (175 µL) was added. The
resulting homogenous solution was cooled to –5 ºC (brine/ice bath), and anhydrous pyridine (175 µL)
was added under nitrogen gas. I2 (35.6 mg, 0.14 mmol, 2 equiv) was added as a solid all at once by
quickly removing and refitting the rubber septum under a high stream of nitrogen gas at 0 ºC. The
initially heterogeneous orange solution was stirred at –5 ºC for 1 h after which the solution turned
homogeneous and purple. The solution was then taken up in diethyl ether (5 mL) while still cold and
washed with 1 N aqueous HCl (5 mL x 2) while warming to room temperature. The organic layers were
washed with saturated aqueous Na2SO3 (5 mL x 2), dried over MgSO4, concentrated, and purified by
SiO2-gel chromatography (1:1 hexanes:ethyl acetate) to afford iodoenone 5; Rf = 0.10 (2:1
hexanes:ethyl acetate); The product stains purple with DNP; The product is isolated as an off-white
amorphous solid; Isolated yield 20.8 mg, 67%; 1H NMR (600 MHz, CDCl3) δ 7.39 (s, 1H), 7.19 (d, J =
8.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 4.30 (dd, J = 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.60 (dd,
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J = 13.7, 9.4 Hz, 1H), 2.16 (dd, J = 13.6, 8.5 Hz, 1H), 2.13 (s, 3H); C NMR (150 MHz, CDCl3) δ
185.1, 170.0, 160.2, 155.5, 129.4, 124.1, 114.8, 114.7, 99.6, 90.3, 79.2, 55.5, 52.5, 32.3, 24.3; IR
(ATIR) 3266, 3213, 3063, 3007, 2928, 2832, 1717, 1669, 1549, 1515, 1304, 1249, 1181, 1090, 1042
cm–1; HRMS (EI) calcd for C17H15N2O4I (M)•+ m/z 438.0077 found 438.0074.
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Hydrogenation of endo-4b under Pd/C catalysis. To a flame-dried 25 mL round-bottomed flask
equipped with a Teflon®-coated stir bar was added endo-4b (31.2 mg, 0.10 mmol, 1 equiv), 10 wt. %
dried Pd/C (5.3 mg, 0.010 mmol, 5 mol % Pd), and THF (3 mL) under nitrogen atmosphere. The flask
was evacuated and backfilled with hydrogen gas, fitted with a balloon and the solution was stirred at
room temperature for 12 h. After this time, the reaction mixture was filtered over a pad of Celite® and
concentrated to afford the desired product 6; Rf = 0.16 (1:1 hexanes:ethyl acetate); The product stains
black with CeMo; The product is an off-white amorphous solid; Isolated yield 30.8 mg, 98%; 1H NMR
(500 MHz, CDCl3) δ 7.38 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 4.41 (dd, J = 11.9,
9.0 Hz, 1H), 3.83 (s, 3H), 3.45 (dd, J = 12.6, 12.6 Hz, 1H), 2.72 (ddd, J = 17.8, 17.8, 9.3 Hz, 1H), 2.62
(ddd, J = 17.2, 17.2, 8.8 Hz, 1H), 2.42 (ddd, J = 14.2, 9.3, 9.3 Hz, 1H), 2.33 (dd, J = 13.8, 8.7 Hz, 1H),
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2.10 – 2.04 (m, 4H); C NMR (100 MHz, CDCl3) δ 199.3, 170.2, 159.7, 128.7, 126.0, 118.3, 114.8,
90.8, 77.5, 55.5, 50.8, 32.7, 31.7, 31.1, 24.2; IR (ATIR) 3391, 2919, 2846, 1738, 1682, 1518, 1495,
1249, 1026 cm–1; HRMS (ESI) calcd for C17H19N2O4 (M+H)+ m/z 315.1339 found 315.1336.
1,4-Addition of lithium hexamethyldisilazide. To a flame-dried 4 mL vial equipped with a Teflon®-
coated stir bar was added endo-4b (31.2 mg, 0.10 mmol) and THF (1 mL) under nitrogen atmosphere.
The solution was then cooled to –78 ºC. LHMDS (0.20 mL, 0.20 mmol, 2 equiv, 1.0 M THF solution)
was then added dropwise to the resulting solution at –78 ºC, and the reaction mixture was warmed to
room temperature. After 1 h, saturated aqueous NH4Cl (0.5 mL) was added slowly at 0 ºC, and the
mixture was extracted with ethyl acetate (5 mL x 3), washed with water (5 mL) and brine (5 mL), dried
over MgSO4, and evaporated. The crude product was purified by SiO2-gel column chromatography (2:1
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