Aromatic cations from oxidative carbon-hydrogen bond cleavage in bimolecular carbon-carbon bond forming reactions

Article abstract of DOI:10.1021/jo301185h

Chromenes and isochromenes react quickly with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ) to form persistent aromatic oxocarbenium ions through oxidative carbon-hydrogen cleavage. This process is tolerant of electron-donating and electron-withdrawing groups on the benzene ring and additional substitution on the pyran ring. A variety of nucleophiles can be added to these cations to generate a diverse set of structures.

Full text of DOI:10.1021/jo301185h

Article
pubs.acs.org/joc
Aromatic Cations from Oxidative Carbon−Hydrogen Bond Cleavage
in Bimolecular Carbon−Carbon Bond Forming Reactions
Dane J. Clausen and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Chromenes and isochromenes react quickly with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) to form persistent aromatic oxocarbenium
ions through oxidative carbon−hydrogen cleavage. This process is tolerant of
electron-donating and electron-withdrawing groups on the benzene ring and
additional substitution on the pyran ring. A variety of nucleophiles can be added
to these cations to generate a diverse set of structures.
These processes proceed effectively even when the substrates
contain electron-withdrawing groups. The intermediate cations
react with several nucleophiles including weakly nucleophilic
potassium trifluoroborates and prochiral allylsilanes. Suitable
substitution on the substrates creates the potential for facile
product diversification.
INTRODUCTION
■
Carbon−hydrogen bond functionalization reactions are becom-
ing increasingly common in chemical synthesis because of their
capacity to deliver increases in molecular complexity and
functional group content from readily available precursors with
minimal waste generation.1 While these processes are most
frequently achieved through transition metal-mediated catalysis,
a growing number of transformations proceed through cation
formation via carbon−hydrogen bond oxidation. We2 and
others3 have developed a number of stereoselective cyclization
reactions based on ether, amide, and sulfide oxidation by 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). These pro-
cesses proceed through the formation of stabilized carbocations
followed by intramolecular additions of π-nucleophiles.
Extending this approach to the development of oxidative
bimolecular reactions offers the enticing prospect of using
carbon−hydrogen functionalization as an entry to fragment
coupling in complex molecule synthesis. Indeed numerous
examples of bimolecular reactions that proceed through
oxidative carbon−hydrogen bond cleavage have been reported.
The challenges of preparing cations that have a sufficient
lifetime to engage in bimolecular reactions dictates that these
transformations employ readily oxidized substrates such as
electron-rich alkenes,4 isochromans and related alkoxybenzyl
ethers,5 xanthenes,6 and amines, with tetrahydroisoquinolines
being particularly common.7
RESULTS AND DISCUSSION
■
Mechanistic studies in our group9 showed that cation stability is
an important determinant in the rate of oxidative carbon−
hydrogen bond cleavage. This led us to consider aromaticity as
a stabilizing element in carbocation formation. Our initial
studies (Scheme 1) focused on the use of 2H-chromene (1) as
Scheme 1. Nucleophilic Addition to Chromene through
Oxidative Carbon−Hydrogen Bond Cleavage
The significant benefits of developing fragment coupling
reactions based on oxidative carbon−hydrogen bond cleavage
for devising convergent syntheses and for preparing structurally
diverse low molecular weight libraries for fragment-based
screening8 led us to consider new substrate designs for these
processes. Our objective was to develop substrates that undergo
facile oxidation to form cations that can react with a range of
nucleophiles while retaining a functional handle for additional
manipulations. In this manuscript we report that chromenes
and isochromenes react with DDQ to form aromatic cations.
a substrate. This structure and the majority of the chromenes in
this were efficiently accessed by treating aryl propargyl ethers
with Ph3PAuNTf2 through the Stratakis protocol.10 These
compounds are useful entries for this endeavor because their
substitution products can be converted to core subunits of
numerous biologically active benzopyran-containing natural
Received: June 8, 2012
© XXXX American Chemical Society
A
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products.11 Exposing 1 to DDQ in CH3CN at 0 °C resulted in
starting material disappearance within 30 min to form putative
intermediate 2. This transformation proceeded most smoothly
in the presence of 4 Å MS to prevent the formation of ether
dimers that result from reactions with water. LiClO4 was
incorporated in this step to promote the conversion of 2 to ion
pair 3. The addition of allyl trimethylsilane led to the rapid
formation of 4 in 74% yield. This reaction proceeded most
efficiently when conducted by generating a “cation pool”12
prior to nucleophilic addition rather than by adding the
nucleophile prior to oxidation. The process can also be
conducted in other solvents, such as CH2Cl2 or toluene with
minimal impact on efficiency.
The scope of the reaction was probed by perturbing the
structure of the chromene and by changing the nucleophile.
The results of varying the nucleophile are shown in Table 1.
Prochiral substituted allylic silanes are useful nucleophiles and
provide good to excellent levels of diastereocontrol (entries 1
and 2). Notably, changing the geometry of the alkene results in
a change of the major diastereomer. Enolsilanes are also
excellent nucleophiles (entry 3), although diastereocontrol is
low for the cyclohexanone-derived species. Interestingly, the
enolsilane of N-acetyl pyrrole provided the electrophilic
aromatic substitution product rather than the product of direct
enolate addition (entry 4). This result cannot be attributed to
cleavage of the enolsilane prior to addition since N-acetyl
pyrrole itself reacted far slower than its enolsilane. This
outcome could be attributed to a rapid enolsilane addition
followed by ionization and rearrangement steps. Potassium
alkynyl- and alkenyltrifluoroborates13 provide an effective
source of sp- and sp2-hybridized carbon nucleophiles (entries
5−7). While boron ate-complexes have been shown to be
effective nucleophiles for additions into oxocarbenium ions,14
to the best of our knowledge this is the first report of adding
these species to oxidatively generated electrophiles. Note that
the 1,1-disubstituted reagent proceeds through an unexpected
mode of addition to provide an allylated product (entry 7).
Potassium phenyl trifluoroborate was unreactive in this system
(entry 8).
These processes are sensitive to the steric demands of the
nucleophile, with the reactions of silanes 5 and 7 requiring 12 h
to reach completion, while the reaction with allyl trimethylsi-
lane only required 30 min. This accounts for the low reactivity
of potassium phenyl trifluoroborate and the unexpected
reaction of trifluoroborate 17. The proposed mechanism for
isomerization of 17 (Scheme 2) proceeds through a sterically
a
Table 1. Nucleophile Scope
Scheme 2. Rearrangement of 1,1-Disubstituted Vinyl
Trifluoroborate
dictated nucleophilic addition to form cation 20. Hydride
migration to form cation 21 and BF3 loss leads to 18 as a
mixture of geometrical isomers. Overman has reported a similar
reactivity pattern for intramolecular vinylsilane additions into
oxocarbenium ions.15
The stereochemical outcomes of the allylsilane additions also
merit discussion. Allylsilanes can react with oxocarbenium ions
through antiperiplanar or synclinal transition states.16 We
hypothesize that the preferred nucleophilic approach will place
the hydrogen underneath the ring, as shown in Figure 1. A
comparison of the synclinal (22) and antiperiplanar (23)
transition states for the addition of E-silane 5 into the
a
Representative protocol: DDQ (1.3 equiv) was added to a mixture of
2H-chromene (1 equiv, 0.1 M), LiClO4 (1 equiv), and 4 Å MS in
CH3CN at 0 °C. The mixture was stirred at 0 °C for 30 min, and then
the nucleophile was added. See the Supporting Information for details
b
on reaction times and purification protocols. Isolated yields of
c
purified materials. Stereochemical assignment based on a crystal
d
structure of a derivative. See subsequent discussion for details. The
stereochemistry was not assigned for this product mixture.
Figure 1. Approach trajectories for prochiral allylic silanes.
B
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intermediate oxocarbenium ion shows a steric clash for 23 that
is not present in 22, thereby accounting for the high observed
stereocontrol. No major steric clash is apparent in 24 and 25,
the synclinal and antiperiplanar transition states for the addition
of Z-silane 7 into the oxocarbenium ion. The selectivity for the
observed product suggests a slight inherent preference for the
antiperiplanar transition state that results from the oxygen
being less sterically demanding than the methine group. A
similar analysis of the nucleophilic approach of enolsilanes (not
shown) does not reveal an obvious preference, consistent with
the observation of little stereocontrol.
Brimble group.17 Isochromenes are also suitable substrates for
these reactions (entries 9 and 10).
As expected, the oxidation of electron-rich chromenes
proceeds more readily than the oxidation of electron-deficient
chromenes, which require heating for efficient cation formation.
The capacity to prepare a cyano-substituted cation, however,
highlights the utility of employing aromatic intermediates to
promote reactivity. Nucleophilic additions proceed more
efficiently into the cyano-substituted cations. Yields are higher
for these reactions, and nucleophiles that were unreactive
toward the parent 2H-chromene, such as potassium phenyl-
trifluoroborate (entry 5), proved to be reactive toward the less-
stable ions. These trends are also observed for the
isochromenes, where the oxidation of 40 proceeds instanta-
neously at −30 °C, while the oxidation of 42 proceeds over 25
min at −5 °C, but the yield of 43 is higher than the yield of 41.
The compatibility of a chloro-substituent with this protocol will
prove to be useful for further diversification reactions.
Variations in the substrate were also studied, and the results
are shown in Table 2. The methoxy group was incorporated as
a
Table 2. Substrate Scope
Crotylation product 32 (entry 4) was used to determine the
stereochemical outcome of the addition (Scheme 3). Attempts
Scheme 3. Structural Proof for the Crotylation Reaction
to crystallize this compound for X-ray diffraction analysis were
unsuccessful, so we prepared derivatives. Selective hydro-
boration of the terminal alkene with 9-BBN followed by a basic
peroxide workup provided the expected primary alcohol.
Acylation to form the common crystallization promoting p-
bromobenzoate and p-phenylbenzoate esters did not yield
suitable crystals. Therefore the alcohol was oxidized with the
Dess−Martin periodinane,18 and the resulting aldehyde was
converted to 2,4-dinitrophenylhydrazone 44 under standard
conditions. This product provided suitable crystals for the
diffraction study that led to unambiguous stereochemical
assignment and the transition state analysis in Figure 1.
a
Please see the Supporting Information for experimental details.
a representative electron-donating group (entries 1 and 2),
while a cyano group was incorporated as a representative
electron-withdrawing group (entries 3−5). Substitution is also
tolerated on the pyran section of the compounds, with methyl-
substituted substrate 34 and silyl-substituted substrate 36
reacting under standard conditions to yield 35 and 37,
respectively. Spirocycles can be prepared through intra-
molecular additions, as demonstrated by the conversion of 38
to 39 (entry 8) and in accord with recent results from the
The tolerance toward substitution in the pyran subunit is
critical for expanding the scope of this protocol. The silyl
substituent in 36 was selected because of its exceptional
capacity for conversion to other functional groups. Vinyl silanes
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General Procedure for the Oxidative Coupling. To a solution
of the benzopyran (1.0 equiv) in freshly distilled acetonitrile (0.1 M)
at 0 °C was added LiClO4 (1.5 equiv) and 4 Å MS (250 mg/mmol).
After 5 min, DDQ (1.3 equiv) was added to the reaction mixture, and
it was stirred until TLC analysis showed complete starting material
consumption. The nucleophile (2.0 equiv) was added, and the reaction
was stirred until completion (monitored via TLC analysis). The
reaction was quenched with 10% aqueous NaHCO3 solution (10 mL).
The reaction mixture was extracted with diethyl ether (3 × 10 mL),
dried over MgSO4, and concentrated under a vacuum. The crude
mixture was purified by flash chromatography.
can be converted to carbonyl groups through peroxide-
mediated oxidation19 and can be employed in cross-coupling
reactions,20 suggesting that compounds such as 37 can serve as
versatile progenitors to libraries for biological screening studies.
The kinetic impact of proceeding through aromatic cationic
intermediates is quite dramatic in the oxidation of isochromene
40. Previously reported DDQ-mediated oxidations of isochro-
man (45) to form oxocarbenium ion 465 required 24 h at rt for
complete starting material consumption, whereas the oxidation
of 40 proceeds to completion within minutes at −30 °C to
form 47 (Scheme 4).
2-Allyl-2H-chromene (4). The general procedure for the oxidative
coupling was followed using benzopyran 1 (264 mg, 2.00 mmol),
LiClO4 (319 mg, 3.00 mmol), 4 Å MS (500 mg), DDQ (590 mg, 2.60
mmol), and acetonitrile (20 mL). After 30 min the oxidation was
complete, and allyl trimethylsilane (457 mg, 4.00 mmol) was added.
The reaction was complete after 30 min and was purified using flash
chromatography (1−5% ethyl acetate in hexanes) to yield the
Scheme 4. Impact of Aromaticity on Oxidation Rate
1
substituted benzopyran (254 mg, 74%) as an oil: H NMR (CDCl3,
400 MHz) δ 7.02 (td, J = 7.6, 1.6 Hz, 1H), 6.88 (dd, J = 7.6, 1.6 Hz,
1H), 6.76 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 9.6
Hz, 1H), 5.82 (ddt, J = 17.2, 10.4, 7.2 Hz, 1H), 5.61 (dd, J = 9.6, 3.2
Hz, 1H), 5.07 (d, J = 9.6 Hz, 1H), 5.04 (s, 1H), 4.82−4.85 (m, 1H),
2.46−2.53 (m, 1H), 2.34−2.41 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 153.3, 133.3, 129.1, 126.4,125.0,124.2, 121.8, 121.0, 117.8,
115.9, 74.7, 39.7; IR (neat) 3075, 2934, 1640, 1605, 1486, 1271, 1206,
1041, 754 cm−1, HRMS (ESI) m/z calcd for C12H11O [M − H]+
171.0810, found 171.0813.
( )-(S)-2-((R)-Hept-1-en-3-yl)-2H-chromene (6). The general
procedure for the oxidative coupling was followed using benzopyran 1
(132 mg, 1.00 mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250
mg), DDQ (295 mg, 1.30 mmol), and acetonitrile (10 mL). After 30
min the oxidation was complete, and silane 5 (341 mg, 2.00 mmol)
was added. The reaction was complete after 16 h and was purified
using flash chromatography (1−5% ethyl acetate in hexanes) to yield
the substituted benzopyran (144 mg, 63%) as an oil: 1H NMR
(CDCl3, 400 MHz) δ 7.09 (td, J = 7.6, 1.6 Hz, 1H), 6.94 (dd, J = 7.2,
1.2 Hz, 1H), 6.83 (td, J = 7.2, 0.8 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H),
6.42 (dd, J = 10.0, 1.2 Hz, 1H), 5.68−5.76 (m, 1H), 5.66 (dd, J = 10.0,
3.2 Hz, 1H), 5.11 (dd, J = 10.0, 1.6 Hz, 1H), 5.06 (dd, J = 16.8, 1.2 Hz,
1H), 4.85−4.87 (m, 1H), 2.37 (sep, J = 4.8 Hz, 1H), 1.59−1.68 (m,
1H), 1.41−1.51 (m, 1H), 1.19−1.37 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 153.9, 138.0, 129.0, 126.4, 124.4,
124.3, 121.9, 120.8, 116.9, 115.7, 77.8, 49.6, 29.5, 29.4, 22.7, 14.0; IR
(neat) 3073, 2928, 2857, 1639, 1486, 1230, 1206, 1040, 915, 753;
HRMS (ESI) m/z calcd for C16H21O [M + H]+ 229.1592, found
229.1594.
( )-(S)-2-((S)-Hept-1-en-3-yl)-2H-chromene (8). The general
procedure for the oxidative coupling was followed using benzopyran 1
(132 mg, 1.00 mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250
mg), DDQ (295 mg, 1.30 mmol), and acetonitrile (10 mL). After 30
min the oxidation was complete, and silane 7 (341 mg, 2.00 mmol)
was added. The reaction was complete after 16 h and was purified
using flash chromatography (1−5% ethyl acetate in hexanes) to yield
the substituted benzopyran (6:1 anti:syn) (117 mg, 51%) as an oil: 1H
NMR (CDCl3, 500 MHz) δ 7.09 (td, J = 8.0, 1.5 Hz, 1H), 6.95 (dd, J
= 7.0, 1.5 Hz, 1H), 6.83 (td, J = 7.5, 1.0 Hz, 1H), 6.77 (d, J = 8.0 Hz,
1H), 6.41 (dd, J = 10.0, 1.0 Hz, 1H), 5.65−5.72 (m, 2H), 5.11 (dd, J =
10.5, 2.0 Hz, 1H), 5.07 (dd, J = 17.0, 1.0 Hz, 1H), 4.74−4.76 (m, 1H),
2.37−2.43 (m, 1H), 1.72−1.78 (m, 1H), 1.16−1.38 (m, 5H), 0.89 (t, J
= 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 153.6, 138.1, 129.1,
126.4, 124.5, 124.2, 122.0, 120.8, 117.4, 115.8, 77.7, 49.6, 29.3, 29.1,
22.7, 14.0; IR (neat) 3073, 2919, 2852, 1638, 1485, 1229, 1038, 750;
HRMS (ESI) m/z calcd for C16H21O [M + H]+ 229.1592, found
229.1586.
CONCLUSIONS
■
We have shown that DDQ-mediated oxidative carbon−
hydrogen bond cleavage reactions proceed quite efficiently to
provide aromatic carbocations. These intermediates possess a
sufficient lifetime to engage in bimolecular reactions with a
number of stable nucleophiles, leading to useful fragment-
coupling protocols. Transition state models for the addition of
prochiral nucleophiles have been developed, which will be
useful in predicting the capacity for absolute stereochemical
induction with chiral reagents. The procedure is tolerant of
electron-withdrawing groups on the substrate, leading to a
useful substrate scope expansion for oxidative cation gen-
eration. Defining new substrates for this process will be
essential for the impact of this increasingly common protocol to
progress.
EXPERIMENTAL SECTION
■
General Procedures. Proton (1H NMR) and carbon (13C NMR)
nuclear magnetic resonance spectra were recorded at 300, 400, or 500
MHz and 75, 100, or 125 MHz, respectively. The chemical shifts are
given in parts per million (ppm) on the delta (δ) scale.
Tetramethylsilane (TMS) or the solvent peak was used as a reference
1
value, for H NMR: TMS (in CDCl3) = 0.00 ppm, for 13C NMR:
TMS (in CDCl3) = 0.00. Data are reported as follows: s = singlet; d =
doublet; t = triplet; q = quartet; dd = doublet of doublets; dt = doublet
of triplets; br = broad. Samples for IR were prepared as a thin film on a
NaCl plate by dissolving the compound in CH2Cl2 and then
evaporating the CH2Cl2. Analytical TLC was performed on precoated
(25 mm) silica gel 60F-254 plates. Visualization was done under UV
(254 nm). Flash chromatography was done using 32−63 60 Å silica
gel. Methylene chloride was distilled under N2 from CaH2. Reagent
grade ethyl acetate, diethyl ether, pentane and hexanes (commercial
mixture) were used as purchased for chromatography. Benzene was
dried with 4 Å molecular sieves. THF was distilled from sodium. Other
reagents were obtained from commercial sources without further
purification. Substrates 1, 26, 28, and 30 were prepared following the
Stratakis protocol.10 Substrate 40 was prepared following Descotes
protocol.21 Substrate 42 was prepared through the Saa
́
route.22
2-(2H-Chromen-2-yl)cyclohexanone (10). The general proce-
dure for the oxidative coupling was followed using benzopyran 1 (132
mg, 1.00 mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250 mg),
DDQ (295 mg, 1.30 mmol), and acetonitrile (10 mL). After 30 min
the oxidation was complete, and enol silane 9 (341 mg, 2.00 mmol)
Nucleophile 11 was prepared according to the Simchen protocol.23
Nucleophile 15 was prepared according to Molander’s protocol.24 All
reactions were performed in oven or flame-dried glassware with
magnetic stirring unless otherwise noted.
D
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was added. The reaction was complete after 30 min and was purified
using flash chromatography (5−15% ethyl acetate in hexanes) to yield
was complete, and trifluoroborate 17 (492 mg, 2.00 mmol) was added.
The reaction was complete after 30 min and was purified using flash
chromatography (1−5% ethyl acetate in hexanes) to yield the
substituted benzopyran (5:1 olefin mixture) (179 mg, 66%) as an
1
the substituted benzopyran (dr 1:1.6) (162 mg, 71%) as an oil: H
NMR (CDCl3, 400 MHz) δ 7.03−7.12 (m, 1H), 6.92−6.97 (m, 1H),
6.83−6.86 (m, 1H), 6.78 (d, J = 8.4 Hz, 0.38H), 6.72 (d, J = 8.0 Hz,
0.62H), 6.39−6.45 (m, 1H), 5.86 (dd, J = 10.0, 3.6 Hz, 0.38H), 5.69
(dd, J = 10.0, 3.2 Hz, 0.62H), 5.47−5.50 (m, 0.62H), 5.17 (ddd, J =
7.6, 4.0, 1.2 Hz, 0.38H), 2.87−2.93 (m, 0.62H), 2.67−2.74 (m,
0.38H), 2.22−2.47 (m, 2.62H), 2.04−2.12 (m, 1H), 1.86−1.94 (m,
1.38H), 1.55−1.76 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.8,
210.6, 153.8, 152.9, 129.1, 126.4, 126.4, 125.4, 124.7, 123.8, 123.0,
121.8, 121.3, 121.1, 120.9, 115.9, 115.4, 73.8, 73.2, 55.7, 55.3, 42.6,
42.2, 29.6, 27.9, 27.6, 27.4, 24.5, 24.4; IR (neat) 3044, 2938, 2862,
1707, 1605, 1485, 1454, 1271, 1230, 1037, 778; HRMS (EI) m/z calcd
for C15H16O2 [M]+ 228.1150, found 228.1173.
1-(2-(2H-Chromen-2-yl)-1H-pyrrol-1-yl)ethanone (12). The
general procedure for the oxidative coupling was followed using
benzopyran 1 (26 mg, 0.20 mmol), LiClO4 (32 mg, 0.30 mmol), 4 Å
MS (50 mg), DDQ (59 mg, 0.26 mmol), and acetonitrile (2.0 mL).
After 30 min the oxidation was complete, and enol silane 11 (72 mg,
0.400 mmol) was added. The reaction was complete after 30 min and
was purified using flash chromatography (5−15% ethyl acetate in
hexanes) to yield the substituted benzopyran (22 mg, 47%) as an oil:
1H NMR (CDCl3, 500 MHz) δ 7.13 (dd, J = 3.0, 1.5 Hz, 1H), 7.10
(td, J = 7.5, 1.5 Hz, 1H), 7.00 (dd, J = 7.5, 1.5 Hz, 1H), 6.85 (td, J =
7.5, 1.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 4.0 Hz, 1H),
6.52 (d, J = 10.0 Hz, 1H), 6.37−6.38 (m, 1H), 6.16 (t, J = 3.0 Hz, 1H),
5.93 (dd, J = 10.0, 4.0 Hz, 1H), 2.61 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 169.0, 153.0, 134.4, 129.2, 126.5, 124.1, 123.3, 122.1, 121.5,
121.1, 116.2, 115.0, 111.8, 69.8, 24.1; IR (neat) 3043, 2921, 1721,
1484, 1226, 1126, 1037, 939, 756; HRMS (ESI) m/z calcd for
C15H13NO2Na [M + Na]+ 262.0844, found 262.0851.
1
oil: H NMR (CDCl3, 500 MHz) δ 7.11 (td, J = 7.0, 0.8 Hz, 1H),
6.95−6.97 (m, 1H), 6.83−6.86 (m, 1H), 6.77 (d, J = 8.0 Hz, 1H),
6.40−6.42 (m, 1H), 5.70 (dd, J = 9.5, 3.0 Hz, 1H), 5.53−5.58 (m,
1H), 5.45−5.51 (m, 1H), 4.86−4.91 (m, 1H), 2.46−2.54 (m, 1.67H),
2.37−2.42 (m, 0.33H), 1.93−2.05 (m, 2H), 1.22−1.34 (m, 10H), 0.89
(t, J = 6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 153.4, 153.4,
134.3, 133.2, 129.1, 129.0, 126.4, 126.3, 125.4, 125.3, 124.3, 124.1,
124.0, 123.5, 122.0, 121.8, 120.9, 120.9, 115.9, 74.9, 74.9, 38.7, 33.4,
32.6, 31.8, 29.5, 29.4, 29.2, 29.2, 29.2, 29.1, 27.4, 22.7, 14.1; IR (neat)
3011, 2925, 2853, 1638, 1468, 1457, 1230, 1112, 753; HRMS (ESI)
m/z calcd for C19H27O [M + H]+ 271.2062, found 271. 2050.
2-Allyl-6-methoxy-2H-chromene (27). The general procedure
for the oxidative coupling was followed using benzopyran 26 (162 mg,
1.00 mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250 mg), DDQ
(295 mg, 1.30 mmol), and acetonitrile (10 mL). After 30 min the
oxidation was complete, and allyl trimethylsilane (229 mg, 2.00 mmol)
was added. The reaction was complete after 30 min and was purified
using flash chromatography (1−10% ethyl acetate in hexanes) to yield
the substituted benzopyran (129 mg, 64%) as an oil: 1H NMR
(CDCl3, 400 MHz) δ 6.73 (d, J = 8.8 Hz, 1H), 6.67 (dd, J = 8.4, 2.8
Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 6.39 (d, J = 10.0 Hz, 1H), 5.90 (ddt,
J = 17.2, 10.4, 7.2, 1H), 5.75 (dd, J = 9.6, 3.2 Hz, 1H), 5.15 (d, J = 8.8
Hz, 1H), 5.12 (s, 1H), 4.85 (m, 1H), 3.76 (s, 3H), 2.54−2.61 (m, 1H),
2.41−2.48 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 153.9, 147.1,
133.4, 126.1, 124.3, 122.5, 117.8, 116.5, 114.2, 111.6, 74.3, 55.6, 39.4;
IR (neat) 3075, 2936, 2832, 1577, 1491, 1432, 1268, 1045, 920, 708;
HRMS (ESI) m/z calcd for C13H15O2 [M + H]+ 203.1072, found
203.1069.
(E)-2-(Dec-1-enyl)-2H-chromene (14). The general procedure
for the oxidative coupling was followed using benzopyran 1 (132 mg,
1.00 mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250 mg), DDQ
(295 mg, 1.30 mmol), and acetonitrile (10 mL). After 30 min the
oxidation was complete, and trifluoroborate 13 (492 mg, 2.00 mmol)
was added. The reaction was complete after 30 min and was purified
using flash chromatography (1−5% ethyl acetate in hexanes) to yield
the substituted benzopyran (176 mg, 65%) as an oil: 1H NMR
(CDCl3, 400 MHz) δ 7.12 (td, J = 7.2, 1.2 Hz, 1H), 6.98 (dd, J = 7.2,
0.8 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.43 (d,
J = 9.6 Hz, 1H), 5.81 (dt, J = 15.2, 6.8 Hz, 1H), 5.65−5.71 (m, 2H),
5.27−5.29 (m, 1H), 2.07 (q, J = 6.8 Hz, 2H), 1.28−1.40 (m, 12H),
0.91 (t, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 153.2, 134.5,
129.1, 127.8, 126.4, 124.7, 123.7, 121.6, 120.9, 116.0, 75.8, 32.1, 31.8,
29.4, 29.2, 29.1, 28.9, 22.7, 14.1; IR (neat) 3042, 2924, 2853, 1638,
1485, 1456, 1227, 1036, 768; HRMS (ESI) m/z calcd for C19H25O [M
− H]+ 269.1905, found 269.1899.
2-Allyl-5-methoxy-2H-chromene (29). The general procedure
for the oxidative coupling was followed using benzopyran 28 (140 mg,
0.863 mmol), LiClO4 (138 mg, 1.29 mmol), 4 Å MS (200 mg), DDQ
(252 mg, 1.11 mmol), and acetonitrile (8.6 mL). After 30 min the
oxidation was complete, and allyl trimethylsilane (197 mg, 1.72 mmol)
was added. The reaction was complete after 30 min and was purified
using flash chromatography (1−10% ethyl acetate in hexanes) to yield
the substituted benzopyran (80 mg, 46%) as an oil: 1H NMR (CDCl3,
500 MHz) δ 7.06 (t, J = 8.5 Hz, 1H), 6.76 (d, J = 10.0 Hz, 1H), 6.46
(d, J = 8.5 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.91 (ddt, J = 17.0, 10.0,
7.0 Hz, 1H), 5.66 (dd, J = 10.0, 3.0 Hz, 1H), 5.15 (d, J = 17.0 Hz, 1H),
5.13 (d, J = 9.5 Hz, 1H), 4.85−4.87 (m, 1H), 3.83 (s, 3H), 2.56−2.61
(m, 1H), 2.43−2.48 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 155.2,
154.1, 133.4, 129.0, 123.2, 118.9, 117.8, 111.3, 109.1, 103.3, 74.1, 55.6,
39.5; IR (neat) 3074, 2934, 1634, 1580, 1310, 1101, 917, 749; HRMS
(ESI) m/z calcd C13H13O2 [M − H]+ 201.0916, found 201. 0918.
2-Allyl-2H-chromene-6-carbonitrile (31). To a solution of
benzopyran 30 (31 mg, 0.20 mmol) in freshly distilled acetonitrile
(2.0 mL) at rt was added LiClO4 (32 mg, 0.30 mmol) and 4 Å MS
(50.0 mg). After 5 min, DDQ (59 mg, 0.260 mmol) was added, and
the reaction was warmed to 75 °C for 2 h. The reaction was cooled to
rt, allyl trimethylsilane (46 mg, 0.40 mmol) was added, and the
reaction was stirred for 15 min. The solution was quenched with 10%
aqueous NaHCO3 solution (5 mL). The reaction mixture was
extracted with diethyl ether (3 × 5 mL), dried over MgSO4, and
concentrated under a vacuum. The crude residue was purified using
flash chromatography (3−12% ethyl acetate in hexanes) to yield the
substituted benzopyran (36 mg, 92%) as an oil: 1H NMR (CDCl3, 400
MHz) δ 7.38 (dd, J = 8.4, 1.6 Hz, 1H), 7.23 (d, J = 1.2 Hz, 1H), 6.81
(d, J = 8.4 Hz, 1H), 6.38 (d, J = 10.0 Hz, 1H), 5.87 (ddt, J = 17.6, 10.8,
7.2 Hz, 1H), 5.78 (dd, J = 10.0, 3.2 Hz, 1H), 5.17 (d, J = 6.4 Hz, 1H),
5.14 (s, 1H), 5.06 (m, 1H), 2.47−2.61 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 157.1, 133.4, 132.3, 130.2, 126.6, 122.5, 122.2, 119.1,
118.7, 116.8, 104.1, 75.4, 40.1; IR (neat) 3078, 2926, 2225, 1640,
1488, 1251, 1130, 1021, 830, 715; HRMS (ESI) m/z calcd for
C13H12NO [M + H]+ 198.0919, found 198.0917.
2-(Dec-1-ynyl)-2H-chromene (16). The general procedure for
the oxidative coupling was followed using benzopyran 1 (132 mg, 1.00
mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250 mg), DDQ (295
mg, 1.30 mmol), and acetonitrile (10 mL). After 30 min the oxidation
was complete, and trifluoroborate 15 (488 mg, 2.00 mmol) was added.
The reaction was complete after 30 min and was purified using flash
chromatography (1−5% ethyl acetate in hexanes) to yield the
1
substituted benzopyran (176 mg, 66%) as an oil: H NMR (CDCl3,
300 MHz) δ 7.15 (td, J = 7.8, 1.5 Hz, 1H), 7.02 (dd, J = 7.2, 1.2 Hz,
1H), 6.91 (t, J = 7.5 Hz, 1H) 6.88 (d, J = 8.1 Hz, 1H), 6.46 (d, J = 9.6
Hz, 1H), 5.76 (dd, J = 9.6, 3.9 Hz, 1H), 5.56 (q, J = 1.8 Hz, 1H), 2.21
(td, J = 6.9, 1.8 Hz, 2H), 1.49 (quin, J = 7.2 Hz, 2H), 1.26−1.34 (m,
10H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 152.6,
129.3, 126.6, 124.2, 123.0, 121.6, 121.5, 116.4, 87.1, 77.2, 64.9, 31.8,
29.1, 29.0, 28.8, 28.4, 22.6, 18.8, 14.1; IR (neat) 3045, 2925, 2854,
2277, 2219, 1606, 1485, 1293, 1198, 1111, 754; HRMS (EI) m/z calcd
for C19H24O [M]+ 268.1827, found 268.1864.
2-(Dec-2-enyl)-2H-chromene (18). The general procedure for
the oxidative coupling was followed using benzopyran 1 (132 mg, 1.00
mmol), LiClO4 (160 mg, 1.50 mmol), 4 Å MS (250 mg), DDQ (295
mg, 1.30 mmol), and acetonitrile (10 mL). After 30 min the oxidation
(
)-(S)-2-((R)-But-3-en-2-yl)-2H-chromene-6-carbonitrile
(33). To a solution of benzopyran 30 (314 mg, 2.00 mmol) in freshly
E
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distilled acetonitrile (20 mL) at rt was added LiClO4 (319 mg, 3.00
mmol) and 4 Å MS (500 mg). After 5 min, DDQ (590 mg, 2.60
mmol) was added, and the reaction was warmed to 80 °C for 2 h. The
reaction was cooled to rt, (E)-crotyl trimethylsilane (513 mg, 4.00
mmol) was added, and the reaction was stirred for 16 h. The solution
was quenched with 10% aqueous NaHCO3 solution (20 mL). The
reaction mixture was extracted with diethyl ether (3 × 20 mL), dried
over MgSO4, and concentrated under a vacuum. The crude residue
was purified using flash chromatography (2−15% ethyl acetate in
hexanes) to yield the substituted benzopyran (312 mg, 74%) as an oil:
1H NMR (CDCl3, 400 MHz) δ 7.37 (dd, J = 8.4, 1.6 Hz, 1H), 7.21 (d,
J = 1.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 10.0 Hz, 1H),
5.78−5.87 (m, 1H), 5.73 (dd, J = 10.4, 3.2 Hz, 1H), 5.13 (d, J = 0.8
Hz, 1H), 5.09 (d, J = 7.2 Hz, 1H), 4.95−4.98 (m, 1H), 2.62 (sex, J =
6.8 Hz, 1H), 1.14 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
157.4, 137.8, 133.3, 129.9, 125.0, 122.9, 122.0, 118.9, 116.3, 116.1,
103.7, 79.3, 43.0, 14.2; IR (neat) 2971, 2868, 2224, 1640, 1573, 1488,
1251, 1232, 1012, 920; HRMS (ESI) m/z calcd for C14H14NO [M +
H]+ 212.1075, found 212.1077.
2-Phenyl-2H-chromene-6-carbonitrile (33). To a solution of
benzopyran 30 (157 mg, 1.00 mmol) in freshly distilled acetonitrile
(10 mL) at rt was added LiClO4 (160 mg, 1.50 mmol) and 4 Å MS
(250 mg). After 5 min, DDQ (295 mg, 1.30 mmol) was added, and the
reaction was warmed to 70 °C for 2 h. The reaction was cooled to rt,
trifluoroborate 19 (368 mg, 2.00 mmol) was added, and the reaction
was warmed to 70 °C for 16 h. The solution was cooled to rt and
quenched with 10% aqueous NaHCO3 solution (10 mL). The reaction
mixture was extracted with diethyl ether (3 × 10 mL), dried over
MgSO4, and concentrated under a vacuum. The crude residue was
purified using flash chromatography (2−10% ethyl acetate in hexanes)
to yield the substituted benzopyran (104 mg, 45%) as an oil: 1H NMR
(CDCl3, 400 MHz) δ 7.36−7.41 (m, 6H), 7.30 (s, 1H), 6.81 (d, J =
8.4 Hz, 1H), 6.53 (d, J = 10.0 Hz, 1H), 6.03 (m, 1H), 5.90 (dd, J =
10.0, 3.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 156.6, 139.6, 133.6,
130.2, 128.8, 128.8, 126.9, 126.2, 122.1, 121.6, 119.0, 116.8, 104.2,
77.9; IR (neat) 3061, 3032, 2221, 1649, 1602, 1488, 1251, 1128, 1026,
849, 718; HRMS (ESI) m/z calcd for C16H12NO [M + H]+ 234.0919,
found 234.0927.
2-Allyl-3-methyl-2H-chromene (35). The general procedure for
the oxidative coupling was followed using benzopyran 34 (175 mg,
1.20 mmol), LiClO4 (191 mg, 1.80 mmol), 4 Å MS (300 mg), DDQ
(354 mg, 1.56 mmol), and acetonitrile (12 mL). After 30 min the
oxidation was complete, and allyl trimethylsilane (274 mg, 2.40 mmol)
was added. The reaction was complete after 30 min and was purified
using flash chromatography (1−5% ethyl acetate in hexanes) to yield
the substituted benzopyran (134 mg, 60%) as an oil: 1H NMR
(CDCl3, 400 MHz) δ 7.06 (td, J = 7.6, 1.6 Hz, 1H), 6.91 (dd, J = 7.2,
1.6 Hz, 1H), 6.84 (td, J = 7.2, 1.2 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H),
6.18 (s, 1H), 5.88−5.98 (m, 1H), 5.11−5.13 (m, 1H), 5.08 (t, J = 1.2
Hz, 1H), 4.71 (dd, J = 8.4, 3.6 Hz, 1H), 2.46−2.54 (m, 1H), 2.33−
2.41 (m, 1H), 1.85 (d, J = 0.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 151.3, 134.0, 133.6, 128.2, 125.5, 122.6, 121.0, 119.6, 117.5, 115.9,
78.2, 37.2, 19.7; IR (neat) 3074, 2913, 1640, 1578, 1442, 1240, 1104,
916, 752; HRMS (ESI) m/z calcd for C13H13O [M − H]+ 185.0966,
found 185.0962.
2-Allyl-4-(dimethylphenylsilyl)-2H-chromene (36). The gen-
eral procedure for the oxidative coupling was followed using
benzopyran 37 (266 mg, 1.00 mmol), LiClO4 (160 mg, 1.50 mmol),
4 Å MS (250 mg), DDQ (295 mg, 1.30 mmol), and acetonitrile (10
mL). After 2 h the oxidation was complete, and allyl trimethylsilane
(229 mg, 2.00 mmol) was added. The reaction was complete after 1 h
and was purified using flash chromatography (1−5% ethyl acetate in
hexanes) to yield the substituted benzopyran (216 mg, 71%) as an oil:
1H NMR (CDCl3, 400 MHz) δ 7.55−7.58 (m, 2H), 7.34−7.41 (m,
3H), 7.06 (td, J = 8.0, 1.6 Hz, 1H), 7.00 (dd, J = 7.6, 1.6 Hz, 1H), 6.82
(dd, J = 8.0, 1.2 Hz, 1H), 6.74 (td, J = 7.2, 1.2 Hz, 1H), 6.05 (d, J = 3.6
Hz, 1H), 5.86−5.96 (m, 1H), 5.15−5.17 (m, 1H), 5.12 (t, J = 1.2 Hz,
1H), 4.80 (ddd, J = 6.8, 5.6, 3.2 Hz, 1H), 2.56−2.63 (m, 1H), 2.43−
2.50 (m, 1H), 0.50 (s, 3H), 0.49 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 152.7, 137.8, 137.1, 134.0, 133.5, 133.0, 129.2, 128.6, 127.8,
127.4, 124.3, 120.9, 117.9, 116.6, 73.8, 39.0, −2.1, −2.1; IR (neat)
3068, 2956, 1641, 1595, 1482, 1450,1227, 1114, 814; HRMS (ESI) m/
z calcd for C20H21OSi [M − H]+ 305.1362, found 305.1364.
4′,5′-Dihydro-3′H-spiro[chromene-2,2′-furan] (39). To a
solution of benzopyran 38 (85 mg, 0.45 mmol) in freshly distilled
acetonitrile (4.4 mL) at 0 °C was added LiClO4 (71 mg, 0.67 mmol)
and 4 Å MS (100 mg). After 5 min, DDQ (130 mg, 0.581 mmol) was
added to the reaction mixture, and it was stirred for 15 min before
being quenched with 10% aqueous NaHCO3 solution (5 mL). The
reaction mixture was extracted with diethyl ether (3 × 5 mL), dried
over MgSO4, and concentrated under a vacuum. The crude residue
was purified using flash chromatography (5−10% ethyl acetate in
hexanes) to yield the substituted benzopyran (77 mg, 93%) as an oil:
1H NMR (CDCl3, 300 MHz) δ 7.19 (td, J = 7.5, 1.5 Hz, 1H), 7.14 (d,
J = 7.2 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.72
(d, J = 9.6 Hz, 1H), 5.76 (d, J = 9.6 Hz, 1H), 4.12−4.19 (m, 1H), 3.98
(q, J = 7.5 Hz, 1H), 2.32−2.44 (m, 2H), 1.96−2.14 (m, 2H); 13C
NMR (CDCl3, 125 MHz) δ 151.7, 129.1, 126.8, 126.8, 122.5, 121.1,
120.3, 116.4, 105.2, 68.2, 39.1, 24.5; IR (neat) 3047, 2955, 1624, 1571,
1254, 1065, 1016, 988, 756; HRMS (EI) m/z calcd for C12H12O2 [M]+
188.0837, found 188.0874.
1-Allyl-1H-isochromene (40). To a solution of benzopyran 41
(132 mg, 1.00 mmol) in freshly distilled CH2Cl2 (10 mL) at −35 °C
was added LiClO4 (160 mg, 1.50 mmol) and 4 Å MS (250 mg). After
5 min, DDQ (295 mg, 1.30 mmol) was added, and the reaction was
warmed to −30 °C over 10 min. Allyl tributyltin (662 mg, 2.00 mmol)
was added, and the reaction was warmed to rt over 30 min. The
solution was quenched with 10% aqueous NaHCO3 solution (5 mL).
The reaction mixture was extracted with CH2Cl2 (3 × 5 mL), dried
over MgSO4, and concentrated under a vacuum. The crude residue
was purified using flash chromatography (1% ethyl acetate in hexanes)
to yield the substituted benzopyran (135 mg, 79%) as an oil: 1H NMR
(CDCl3, 400 MHz) δ 7.23 (td, J = 7.6, 1.2 Hz, 1H), 7.17 (td, J = 7.6,
1.2 Hz, 1H), 7.00 (d, J = 4.0 Hz, 1H), 6.98 (d, J = 3.6 Hz, 1H), 6.52
(d, J = 5.6 Hz, 1H), 5.93 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H), 5.78 (d, J =
6.0 Hz, 1H), 5.16−5.21 (m, 2H), 5.14 (s, 1H), 2.79−2.86 (m, 1H),
2.51−2.57 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 144.1, 134.1,
130.7, 129.5, 127.9, 126.4, 124.2, 123.3, 117.6, 104.5, 76.9, 38.5; IR
(neat) 3069, 2937, 2829, 1626, 1488, 1452, 1226, 1051, 917, 769;
HRMS (EI) m/z calcd for C12H12O [M]+ 172.0888, found 172.0920.
1-Allyl-7-chloro-1H-isochromene (43). To a solution of
benzopyran 42 (33.3 mg, 0.200 mmol) in freshly distilled CH2Cl2
(2.0 mL) at −20 °C was added LiClO4 (31.9 mg, 0.300 mmol) and 4
Å MS (50 mg). After 5 min, DDQ (59.0 mg, 0.260 mmol) was added,
and the reaction was warmed to −5 °C over 25 min. Allyl tributyltin
(132 mg, 0.400 mmol) was added, and the reaction was warmed to rt
over 30 min. The solution was quenched with 10% aqueous NaHCO3
solution (5 mL). The reaction mixture was extracted with CH2Cl2 (3
× 5 mL), dried over MgSO4, and concentrated under a vacuum. The
crude residue was purified using flash chromatography (1% ethyl
acetate in hexanes) to yield the substituted benzopyran (37.4 mg,
1
91%): H NMR (CDCl3, 400 MHz) δ 7.17 (dd, J = 8.0, 2.0 Hz, 1H),
6.96 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 6.0 Hz,
1H), 5.83−5.93 (m, 1H), 5.73 (d, J = 5.6 Hz, 1H), 5.10−5.17 (m,
3H), 2.74−2.82 (m, 1H) 2.48−2.54 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 144.4, 133.6, 132.3, 131.6, 128.2, 127.9, 124.5, 118.0, 103.8,
76.5, 38.4; IR (neat) 3073, 2929, 2849, 1626, 1484, 1226, 1086, 919,
827; HRMS (ESI) m/z calcd for C12H12OCl [M + H]+ 207.0577,
found 207.0611.
1-(2-Methylallyloxy)-2-(prop-1-enyl)benzene. To a solution of
2-(prop-1-enyl)phenol (6:1 E:Z mixture) (1.40 g, 10.4 mmol) and
K2CO3 (1.73 g, 12.5 mmol) in DMF (20 mL) at 0 °C was added 3-
bromo-2-methylprop-1-ene (1.70 g, 12.5 mmol). The reaction was
warmed to rt and was stirred for 16 h. The reaction was quenched with
H2O (20 mL), extracted with diethyl ether (3 × 20 mL), dried over
MgSO4, and was concentrated under a vacuum. The crude residue was
purified using flash chromatography (5% ethyl acetate in hexanes) to
1
yield the diene (6:1 E:Z mixture) (1.74 g, 89%) as an oil: H NMR
(CDCl3, 400 MHz) δ 7.42 (dd, J = 7.6, 1.2 Hz, 0.83H), 7.29 (d, J = 7.2
Hz, 0.17H), 7.21 (t, J = 8.0 Hz, 0.17H), 7.16 (td, J = 8.4, 1.6 Hz,
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0.83H), 6.83−6.96 (m, 2H), 6.78 (dd, J = 15.6, 1.2 Hz, 0.83H), 6.61
(d, J = 11.6 Hz, 0.17H), 6.25 (dq, J = 16.0, 6.8 Hz, 0.83H), 5.84 (dq, J
= 11.6, 6.8 Hz, 0.17H), 5.12 (s, 1H), 5.01 (s, 0.83H), 4.99 (s, 0.17H),
4.47 (s, 2H), 1.91 (dd, J = 6.4, 1.6 Hz, 3H), 1.86 (s, 2.49H), 1.81 (s,
0.51H). These data are consistent with literature values.25
100 MHz) δ 153.1, 129.1, 126.4, 125.6, 124.0, 121.8, 121.0, 115.8,
74.9, 62.4, 31.6, 28.1; IR (neat) 3375, 3042, 2919, 1637, 1604, 1485,
1271, 1205, 1038, 932, 753; HRMS (ESI) m/z calcd for C12H14O2
[M]+ 190.0994, found 190.0975.
(E)-1-(Trimethylsilyl)-hept-2-ene (5). To a flask containing E-1-
iodo-1-hexene (7.50 g, 35.7 mmol) in dry, degassed THF (100 mL) at
0 °C was added Pd(PPh3)4 (1.03 g, 0.893 mmol) and a 1.0 M solution
of (trimethylsilyl)methylmagnesium chloride in diethyl ether (46.4
mL, 46.4 mmol). After 2 h, the reaction was quenched with H2O (50
mL) and a saturated solution of NH4Cl (50 mL). The aqueous layer
was extracted with hexanes (3 × 50 mL), dried over MgSO4, and
concentrated under a vacuum. The crude residue was purified using
flash chromatography (100% hexanes) to yield the silane (5.28 g, 87%)
3-Methyl-2H-chromene (34). To a solution of the diene from the
previous protocol (3.12 g, 16.5 mmol) in CH2Cl2 (150 mL) was added
Hoveyda−Grubbs second generation catalyst (50 mg, 0.080 mmmol).
The reaction mixture was heated to 50 °C and stirred for 2 d. More
Hoveyda−Grubbs second generation catalyst (50 mg, 0.080 mmmol)
was added and stirred for an additional 2 d. The reaction mixture was
cooled to rt and concentrated under a vacuum. The crude residue was
purified using flash chromatography (1% ethyl acetate in hexanes) to
1
1
as an oil: H NMR (CDCl3, 300 MHz) δ 5.33−5.43 (m, 1H), 5.19−
yield the benzopryran (1.97 g, 82%) as an oil: H NMR (CDCl3, 300
5.29 (m, 1H),1.98 (q, J = 8.8 Hz, 2H), 1.39 (d, J = 10.4 Hz, 2H),
1.28−1.32 (m, 4H), 0.89 (t, J = 8.8 Hz, 3H), −0.01 (s, 9H). These
data are consistent with literature values.27
MHz) δ 7.05 (td, J = 7.8, 1.8 Hz, 1H), 6.91 (dd, J = 7.2, 1.5 Hz, 1H),
6.84 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.16 (s, 1H), 4.69 (s,
2H), 1.80 (s, 3H). These data are consistent with literature values.25
1-(Allyloxy)-2-(1-dimethylphenylsilylvinyl)benzene. To a sol-
ution of (1-bromovinyl)dimethyl(phenyl)silane26 (3.98 g, 18.6 mmol)
in dry, degassed THF (35 mL) at 0 °C was added magnesium ribbon
(0.809 g, 33.3 mmol) and LiCl (0.926 g, 21.8 mmol). After stirring for
3 h, the Grignard reagent was cannulated off the excess magnesium
ribbon into a different flask. FeCl3 (0.084 g, 0.520 mmol) was added to
a vial under an inert atmosphere in a glovebox. The vial was removed
from the glovebox, and THF (2.0 mL) and TMEDA (0.242 g, 2.08
mmol) were added prior to cannulating the solution into the flask
containing the Grignard reagent. 1-(Allyloxy)-2-bromobenzene (2.50
g, 10.4 mmol) was added, and the flask was stirred for 3 h. Another
1.00 equiv of Grignard reagent was prepared in the same manner as
described above and added to the solution via cannulation. After
stirring for 16 h, the reaction mixture was quenched with a saturated
solution of NaHCO3 (50 mL). The solution was extracted with diethyl
ether (3 × 50 mL), dried over MgSO4, and concentrated under a
vacuum. The crude residue was purified using MPLC (2−10% toluene
(Z)-1-(Trimethylsilyl)-hept-2-ene (7). To a flask containing
sodium borohydride (0.149 g, 3.93 mmol) in ethanol (4.75 mL)
was added a 1.0 M aqueous solution of NaOH (0.25 mL). This
solution was sonicated for 5 min, and the remaining solids were
filtered away. This NaBH4 solution was then added to a flask
containing Ni(OAc)2·4H2O (1.03 g, 4.15 mmol) in ethanol (300 mL).
After stirring for 5 min, ethylenediamine (0.55 mL, 8.28 mmol) was
added. After stirring for an additional 5 min, 1-(trimethylsilyl)-hept-2-
yne28 (3.50 g, 20.7 mmol) was added, and the N2 atmosphere was
replaced with an H2 atmosphere using a balloon. The reaction mixture
stirred vigorously for 3 h and was then quenched with H2O (300 mL).
The solution was extracted with hexanes (3 × 200 mL), dried over
MgSO4, and was concentrated under a vacuum. The crude residue was
purified using flash chromatography (2% diethyl ether in pentanes) to
yield the silane (3.31 g, 94%) as an oil: 1H NMR (CDCl3, 500 MHz) δ
5.36−5.42 (m, 1H), 5.24−5.30 (m, 1H), 1.97−2.01 (2H, m), 1.47 (dt,
J = 8.5, 0.5 Hz, 2H), 1.27−1.36 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H), 0.01
(s, 9H). These data are consistent with literature values.27
1
in hexanes) to yield the diene (1.00 g, 33%) as an oil: H NMR
Potassium (E)-Dec-1-enyltrifluoroborate (13). To a solution of
(E)-2-(dec-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane29 (1.50 g,
5.63 mmol) in acetonitrile (14 mL) was added KHF2 (1.55 g, 19.9
mmol) and H2O (4.6 mL). The solution was stirred for 2 h and was
concentrated. The resulting solid was dissolved in hot acetone and
filtered to remove undesired salts. The filtrate was concentrated and
dissolved in a minimal volume of hot acetone to dissolve the solid
completely. Adding diethyl ether to the solution solidified the desired
product. The solid was collected by vacuum filtration to yield the
trifluoroborate salt (0.831 g, 60%) as a white solid: 1H NMR (DMSO-
d6, 400 MHz) δ 5.44 (dt, J = 17.2, 6.0 Hz, 1H), 5.15−5.22 (m, 1H),
1.85 (q, J = 6.0 Hz, 2H), 1.21−1.29 (m, 12H), 0.85 (t, J = 6.8 Hz,
3H); 13C NMR (DMSO-d6, 125 MHz) δ 112.2, 112.2, 36.3, 31.5, 29.6,
29.3, 28.9, 28.5, 22.2,14.0; 11B NMR (DMSO-d6, 125 MHz) δ 2.62;
19F NMR (DMSO-d6, 376 MHz) δ −140.9; IR (neat) 2917, 2849,
1577, 1540, 1466, 1422, 1155, 1107; HRMS (ESI) m/z calcd for
C10H19BF3K [M]+ 246.1169, found 246.1148; mp >245 °C. These
data are consistent with literature values.30
(E)-Crotyl Trimethylsilane. To a suspension of LAH (6.51 g, 171
mmol) in dimethoxyethane (100 mL) at 0 °C was added 2-butyn-1-ol
(10.0 g, 142 mmol) via dimethoxyethane (25 mL) over 20 min. The
reaction was warmed to rt and stirred for 48 h before cooling to 0 °C
and quenching carefully with H2O (6.5 mL), 15% aqueous NaOH (6.5
mL), and H2O (19.5 mL). The remaining solids were filtered off using
diethyl ether to wash the solid, and the solution was concentrated at 0
°C under minimal pressure to avoid loss of desired product. The
resulting oil was used in the next step without further purification.
To a solution of the crude E-crotyl alcohol (10.1 g, 140 mmol) in
diethyl ether (150 mL) at 0 °C was added PBr3 (7.98 mL, 84.0 mmol)
dropwise. After 1 h, the reaction was quenched by pouring the solution
into a beaker of iced H2O. The resulting biphasic mixture was
extracted with diethyl ether (3 × 150 mL) and dried over MgSO4. The
solution was concentrated at 0 °C under minimal pressure to avoid
loss of the desired product. The resulting oil was used in the next step
without further purification.
(CDCl3, 500 MHz) δ 7.52−7.55 (m, 2H), 7.30−7.35 (m, 3H), 7.16
(td, J = 8.0, 2.0 Hz, 1H), 7.00 (dd, J = 7.5, 1.5 Hz, 1H), 6.89 (td, J =
7.5, 1.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H),
5.86 (ddt, J = 17.0, 10.5, 5.0 Hz, 1H), 5.67 (d, J = 3.0 Hz, 1H), 5.28
(dq, J = 17.0, 1.5 Hz, 1H), 5.20 (dq, J = 10.5, 1.5 Hz, 1H), 4.34 (dt, J =
5.0, 1.5 Hz, 2H), 0.36 (s, 6H).
4-(Dimethylphenylsilyl)-2H-chromene (36). To a solution of 1-
(allyloxy)-2-(1-dimethylphenylsilylvinyl)benzene (107 mg, 0.363
mmol) in CH2Cl2 (5.0 mL) was added Hoveyda−Grubbs second
generation catalyst (2.3 mg, 0.004 mmmol). The reaction mixture was
heated to 50 °C and stirred for 6 h. The reaction mixture was cooled
to rt and concentrated under a vacuum. The crude residue was purified
using flash chromatography (2−5% ethyl acetate in hexanes) to yield
the benzopryran (69 mg, 72%) as an oil: 1H NMR (CDCl3, 400 MHz)
δ 7.56−7.59 (m, 2H), 7.35−7.38 (m, 3H), 7.07 (td, J = 7.6, 1.2 Hz,
1H), 7.01 (dd, J = 7.6, 1.2 Hz, 1H), 6.82 (dd, J = 8.0, 0.8 Hz, 1H), 6.76
(td, J = 7.6, 0.8 Hz, 1H), 6.15 (t, J = 4.0 Hz, 1H), 4.73 (d, J = 3.6 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ 153.6, 137.8, 134.0, 134.0,
133.7, 129.2, 128.6, 127.9, 127.5, 124.8, 121.1, 116.2, 65.2, −2.1; IR
(neat) 3067, 2957, 2919, 1704, 1602, 1484, 1427, 1252, 1220, 1115,
1013, 912, 815, 777, 702; HRMS (ESI) m/z calcd for C17H17OSi [M
− H]+ 265.1049, found 265.1049.
3-(2H-Chromen-2-yl)propan-1-ol (40). To a solution of terminal
alkene 4 (130 mg, 0.75 mg) in THF (2.0 mL) was added 9-BBN dimer
(124 mg, 0.52 mmol). After stirring for 1 h, the reaction was cooled to
0 °C. A solution of 2.0 M aqueous NaOH (0.75 mL) and 30% aqueous
H2O2 (0.75 mL) was added, and the reaction was warmed to rt. After
30 min, the mixture was extracted with CH2Cl2 (3 × 10 mL), dried
over MgSO4, and concentrated under a vacuum. The crude residue
was purified using flash chromatography (2−25% ethyl acetate in
1
hexanes) to yield the primary alcohol (92 mg, 65%) as an oil: H
NMR (CDCl3, 400 MHz) δ 7.11 (td, J = 7.6, 1.6 Hz, 1H), 6.97 (dd, J
= 7.6, 1.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H),
6.41 (d, J = 10.0 Hz, 1H), 5.68 (dd, J = 9.6 3.2 Hz, 1H), 4.91−4.93 (m,
1H), 3.72 (t, J = 6.0 Hz, 2H), 1.76−2.06 (m, 4H); 3C NMR (CDCl3,
G
dx.doi.org/10.1021/jo301185h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CuCl (0.354 g, 3.56 mmol) was placed into a flask under an inert
atmosphere in a glovebox. The flask was sealed and removed from the
glovebox, where dry, degassed diethyl ether (75 mL) and triethylamine
(26.3 mL, 190 mmol) were added at 0 °C. The crude E-crotyl bromide
(16.0 g, 119 mmol) was added over 20 min before the reaction was
stirred for 1 h at 0 °C and 1 h at rt. The resulting solids were removed
by passing the solution through a pad of Celite via diethyl ether. The
solution was concentrated at 0 °C under minimal pressure to avoid
loss desired product. The resulting oil was used in the next step
without further purification.
130.3, 130.0, 129.9, 129.5, 128.7, 128.2, 125.0, 124.7, 123.7, 123.4,
123.3, 123.2, 121.9, 121.8, 118.8, 116.7, 116.5, 116.4, 104.4, 104.2,
79.6, 79.4, 37.2, 34.6, 15.9, 15.5; mp 138−141 °C.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds and coordinates
for the crystallographic analysis (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
To a flask containing diethyl ether (100 mL) at 0 °C was added a
3.0 M solution methylmagnesium iodide in diethyl ether (130 mL, 389
mmol). The crude E-crotyl trichlorosilane (16.4 g, 86.5 mmol) was
added dropwise over 30 min. The resulting solution was refluxed at 40
°C for 16 h. The reaction was cooled to 0 °C and quenched carefully
with a saturated solution of NH4Cl (100 mL). The biphasic mixture
was extracted with diethyl ether (3 × 50 mL) and dried over MgSO4.
The solution was concentrated at 0 °C under minimal pressure to
avoid loss of desired product. The resulting oil was distilled (114 °C)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: florean@pitt.edu.
Notes
The authors declare no competing financial interest.
1
to obtain pure E-crotyl silane (6.62 g, 36% over 4 steps) as an oil: H
ACKNOWLEDGMENTS
■
NMR (CDCl3, 300 MHz) δ 5.35−5.46 (m, 1H), 5.20−5.32 (m, 1H),
1.65 (dd, J = 6.0, 1.2 Hz, 3H), 1.39 (dt, J = 7.5, 1.2 Hz, 2H), −0.01 (s,
9H). These data are consistent with literature values.31
We thank the National Institutes of Health (GM062924) for
generous support of this work and for a grant (1S10RR031789-
01) for a diffractometer purchase. We thank Dr. Steve Geib for
crystallographic studies.
( )-(R)-2-((R)-4-Hydroxybutan-2-yl)-2H-chromene-6-carbon-
itrile. To a solution of terminal alkene 32 (312 mg, 1.48 mg) in THF
(2.0 mL) was added 9-BBN dimer (285 mg, 1.03 mmol). After stirring
for 1 h the reaction was cooled to 0 °C. A solution of 3.0 M aqueous
NaOH (1.5 mL) and 30% aqueous H2O2 (1.5 mL) was added, and the
reaction was warmed to rt. After 30 min, the mixture was extracted
with CH2Cl2 (3 × 10 mL), dried over MgSO4, and concentrated under
a vacuum. The crude residue was purified using flash chromatography
(2−25% ethyl acetate in hexanes) to yield the primary alcohol (242
mg, 72%) as an oil: 1H NMR (CDCl3, 500 MHz) δ 7.37 (dd, J = 8.5,
2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.42
(dd, J = 10.0, 2.0 Hz, 1H), 5.76 (dd, J = 10.0, 3.0 Hz, 1H), 4.94−4.96
(m, 1H), 3.75−3.79 (m, 1H), 3.68−3.73 (m, 1H), 2.04−2.09 (m, 1H),
1.88−1.92 (m, 1H), 1.45−1.51 (m, 1H), 1.06 (d, J = 7.0 Hz, 3H).
( )-(R)-2-((R)-4-Oxobutan-2-yl)-2H-chromene-6-carbonitrile.
To a mixture of the hydroboration product (125 mg, 0.550 mmol) and
NaHCO3 (92 mg, 1.1 mmol) in CH2Cl2 (5.5 mL) was added Dess−
Martin periodinane (350 mg, 0.825 mmol). After 1 h, the reaction was
quenched with H2O (5 mL), extracted with CH2Cl2 (3 × 5 mL), dried
over MgSO4, and concentrated under a vacuum. The crude residue
was purified using flash chromatography (10−20% ethyl acetate in
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́
, R. Org. Biomol.
(CDCl3, 400 MHz) δ 9.79 (s, 1H), 7.39 (dd, J = 8.0, 1.6 Hz, 1H), 7.24
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