Enantioselective copper-catalyzed alkynylation of benzopyranyl oxocarbenium ions

Article abstract of DOI:10.1021/acs.joc.5b00364

We have developed highly enantioselective, copper-catalyzed alkynylations of benzopyranyl acetals. By using a copper(I) catalyst equipped with a chiral bis(oxazoline) ligand, high yields and enantioselectivities are achieved in the alkynylation of widely

Full text of DOI:10.1021/acs.joc.5b00364

Article
pubs.acs.org/joc
Enantioselective Copper-Catalyzed Alkynylation of Benzopyranyl
Oxocarbenium Ions
Harathi D. Srinivas, Prantik Maity,† Glenn P. A. Yap, and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: We have developed highly enantioselective,
copper-catalyzed alkynylations of benzopyranyl acetals. By
using a copper(I) catalyst equipped with a chiral bis-
(oxazoline) ligand, high yields and enantioselectivities are
achieved in the alkynylation of widely available, racemic
isochroman and chromene acetals to deliver α-chiral oxygen
heterocycles. This method demonstrates that chiral organo-
metallic nucleophiles can be successfully used in enantiose-
lective additions to oxocarbenium ions.
enantioselective addition involving a cyclic oxocarbenium ion,
1. INTRODUCTION
Braun described a single example of allylation of dihydropyr-
anyl acetal catalyzed by a chiral titanium(IV) Lewis acid.5 These
additions are proposed to involve SN2 additions to diastereo-
meric titanium-bound acetals, which equilibrate via an
oxocarbenium ion. For substrates that form more stable
oxocarbenium ions, two distinct strategies have been used to
control enantioselectivity. In a seminal report, Jacobsen
developed conditions for the catalytic generation of a chiral
oxocarbenium electrophile by using chiral thiourea catalysts in
concert with 1-chloroisochroman substrates.6 The Jacobsen
group has now also demonstrated that chiral thiourea catalysts
can also control enantioselectivity in both intra- and
intermolecular cyclizations of pyrilium ion intermediates.7
Subsequently, Terada and Floreancig showed that phosphoric
acid catalysts can also be used to catalytically generate chiral
oxocarbenium ion electrophiles, which undergo enantioselec-
tive attack by hydride or allyl nucleophiles, respectively.8 In a
distinct strategy, Schaus has demonstrated the complementary
approach of catalytic generation of a chiral nucleophile via
tartarate-derived diol-catalysis of vinyl and aryl boronate esters.9
Rueping, Lou and Liu, and Cozzi have also shown that chiral
enamine nucleophiles, catalytically generated from amine
catalysts and aldehydes, add to oxocarbenium ions with high
enantioselectivities.10 These methods are powerful in delivering
specific classes of nucleophiles (allyl, vinyl, aryl, enolate
equivalents, and hydride) to cyclic oxocarbenium ion
intermediates and indeed demonstrate that catalytic asymmetric
additions to oxocarbenium ions are feasible.
Controlling enantioselectivity in additions to oxocarbenium
ions represents a long-standing challenge in asymmetric
catalysis. In terms of intermolecular additions to cyclic
oxocarbenium ions, few methods have been developed to
confront this problem, despite the power of such a trans-
formation to deliver α-chiral oxygen heterocycles, an important
class of biologically active compounds.1−4 The challenge−and
opportunity−of controlling enantioselectivity in additions to
these electrophiles stems in part from the fact that
oxocarbenium ions lack a Lewis basic site (except for the
counteranion, as discussed below). This fact distinguishes
oxocarbenium ions from other carbonyl substrates and
precludes the well-established strategy of using a chiral Lewis
acid catalyst to control enantioselectivity in additions to these
special C=X electrophiles. Furthermore, the high reactivity of
oxocarbenium ion intermediates can make decomposition
reactions competitive with desired addition pathways.
Recognizing these challenges, a select number of enantiose-
lective additions to cyclic oxocarbenium ion intermediates have
been developed. The majority relies on either organocatalysts
or Lewis acid catalysts (Scheme 1A). In the first report of an
Scheme 1. Enantioselective Additions to Cyclic
Oxocarbenium Ion Intermediates
Given the success of using catalytically generated chiral
nucleophiles for highly enantioselective additions to cyclic
oxocarbenium ions, we envisioned that the use of chiral
organometallic nucleophiles, generated in situ using a chiral
Received: February 15, 2015
© XXXX American Chemical Society
A
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metal catalyst, would provide an alternative strategy for
enantioselective additions to oxocarbenium ion intermediates.
In particular, inspired by zinc- and copper-catalyzed alkynyla-
tions of aldehydes,11 ketones,12 imines, and iminium ions,13 we
have focused on the addition of alkynes. Alkynes are a class of
nucleophiles not addressed by organo- or Lewis acid-catalyzed
methods, and provide a powerful functional group handle for
elaboration of the α-chiral oxygen heterocycle products. Herein,
we report our development of a copper(I)-catalyzed
alkynylation of benzopyranyl acetals, which represents the
first example of enantioselective addition of an organometallic
nucleophile to a prochiral cyclic oxocarbenium ion (Scheme
1B).14 Using a copper catalyst equipped with a bis(oxazoline)
ligand, we have achieved high yields and enantioselectivities in
the alkynylation of both isochroman and chromene substrates.
Scheme 3. Oxocarbenium Ion Alkynylation with Achiral
Catalysts
a
2. RESULTS AND DISCUSSION
2.1. Substrate Synthesis. One advantage of using
enantioselective additions to oxocarbenium ions to generate
α-chiral oxygen heterocycles is the wide availability of the
requisite acetal precursors. Isochroman acetals are readily
prepared in one step via oxidation of the isochroman precursor
(eq 1).6 Reduction of chromenones delivers chromene acetals
(Scheme 2).9 These acetal substrates are stable for months to
years when stored neat at −15 °C.
a
Conditions: Acetal 2a or 5b (1.0 equiv), ZnBr2 or CuI (10 mol %),
alkyne (1.0−1.3 equiv), Et3N (1.0−1.3 equiv), TMSOTf (1.1−1.2
equiv), Et2O or PhMe, rt, 12 h, unless otherwise noted. See
Supporting Information for specific conditions. Yields in parentheses
1
determined by H NMR analysis using 1,3,5-trimethoxybenzene as
internal standard. CH2Cl2 used as solvent.
b
Scheme 2. Synthesis of Chromene Acetals
2.3. Enantioselective Alkynylations. As reported in our
initial communication in this area, the copper-catalyzed
alkynylation of isochroman acetals is rendered enantioselective
by the addition of a bis(oxazoline) ligand.14 In particular, by
using a copper(I) catalyst generated from Cu(MeCN)4(PF6)
and BnBox, high yields and enantioselectivities were achieved
with a range of isochroman acetals and aryl-substituted alkynes
(Scheme 4). Notably, use of a noncoordinating counteranion in
the copper precatalyst was critical; CuI led to low
enantioselectivities. Further, despite the promising reactivity
of ZnBr2 to form racemic products, we have yet to identify a
chiral zinc catalyst capable of delivering high reactivity or
enantioselectivity.
Having established that enantioselective alkynylation of
oxocarbenium ion intermediates provides an efficient route to
enantioenriched α-chiral isochromans, we then sought to
demonstrate the generality of using catalytically generated,
chiral organometallic nucleophiles in enantioselective additions
to oxocarbenium ions. Herein, we describe our application of
this strategy to the preparation of enantioenriched α-alkynyl
chromenes. This work demonstrates that our alkynylation
strategy is effective in providing high enantioselectivity in
reactions of both benzylic and aromatic oxocarbenium ions.
We began by studying the reaction of phenyl acetylene and
chromene acetal 5a. Despite the similarities between the
benzylic cation of isochroman oxocarbenium ions and the
aromatic cation of chromene oxocarbenium ions, we quickly
discovered that they react differently in these alkynylations. In
our previous optimization of isochroman acetal 2, we had found
that use of Cu(I) catalysts with weakly coordinating counter-
ions was crucial for high enantioselectivity. In particular,
2.2. Alkynylations with Achiral Catalysts. Our first
challenge in developing a metal-catalyzed alkynylation of
oxocarbenium ion intermediates was to identify conditions to
generate the requisite oxocarbenium ion that would be
compatible with a metal acetylide intermediate. Specifically,
we were concerned that the Lewis acid used to ionize an acetal
substrate may quench the metal acetylide. However, Downey
had demonstrated that zinc-catalyzed alkynylations of alde-
hydes can be performed, and even accelerated, in the presence
of trimethylsilyl triflate (TMSOTf), suggesting that zinc
acetylides are compatible with TMSOTf.15
Encouraged by Downey’s report, we began by investigating
the use of achiral zinc(II) catalysts in the alkynylation of
benzopyranyl acetals. In the presence of either catalytic ZnBr2
or CuI, as well as trimethylsilyl triflate (TMSOTf) and Et3N,
both isochroman and chromene acetals indeed undergo
alkynylation in good yields (Scheme 3). Although a small
amount of trimethylsilyl acetylene byproducts are formed, only
a slight excess of alkyne (1.0−1.3 equiv) is required to achieve
high yields. Alkynes with a broad range of substituents,
including aryl, primary and secondary alkyl, trimethylsilyl, and
protected aminomethyl, can be used in this transformation.
These results demonstrate that organometallic nucleophiles,
catalytically generated in situ, indeed undergo efficient
additions to oxocarbenium ion intermediates.
B
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a
Scheme 4. Enantioselective Alkynylation of Isochroman
Acetals
Table 1. Identification of Catalyst
a
b
c
entry
[Cu]
ligand
yield (%)
ee (%)
1
Cu(MeCN)4PF6
BnBox
BnBox
BnBox
BnBox
BnBox
PhBox
i-PrBox
t-BuBox
L1
49
58
60
55
87
63
57
59
75
82
70
76
40
42
21
20
60
26
48
26
54
63
61
61
2
Cu(MeCN)4BF4
3
Cu(OAc)2
CuBr
CuI
4
5
6
CuI
7
CuI
8
CuI
9
CuI
10
11
12
CuI
L2
CuI
L3
CuI
L4
a
Conditions: Acetal 2 (0.30 mmol, 1.0 equiv), [Cu(MeCN)4]PF6
(0.030 mmol, 10 mol %), (S,S)-BnBox (0.036 mmol, 12 mol %),
alkyne (0.34 mmol, 1.1 equiv), i-Pr2NEt (0.396 mmol, 1.3 equiv),
TMSOTf (0.365 mmol, 1.2 equiv), Et2O, −22 °C, 12 h, unless
otherwise noted. Average isolated yields ( 3%) and ee’s ( 2%) from
duplicate experiments, unless otherwise noted. Yields in parentheses
determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as
internal standard. Ee’s determined by HPLC analysis using a chiral
a
Conditions: Acetal 5a (0.12 mmol, 1.0 equiv), [Cu] (0.012 mmol, 10
mol %), L* (0.014 mmol, 12 mol %), HCCPh (6a, 0.15 mmol, 1.2
equiv), Et3N (0.15 mmol, 1.2 equiv), TMSOTf (0.12 mmol, 1.0
b
equiv), PhMe (0.31 M), 0 °C, 15 h. Determined by 1H NMR analysis
b
c
stationary phase. TMSOTf (1.1 equiv), i-Pr2Net (1.2 equiv). ee not
c
d
e
using 1,3,5-trimethoxybenzene as internal standard. Determined by
HPLC analysis using a chiral stationary phase.
determined. Twenty mol % [Cu], 23 mol % BnBox, PhMe, 0 °C. 0.1
mmol scale, single experiment.
a
Table 2. Optimization of Reaction Conditions
Cu(MeCN)4PF6 had proven best. However, under similar
conditions to those optimal for the alkynylation of isochroman
acetal 2, low enantioselectivity (40% ee) of α-alkynyl chromene
8aa was observed (Table 1, entry 1). In examining the effect of
the Cu counterion, we were surprised to find that catalysts
derived from CuI provided much greater enantioselectivity
(60% ee) than Cu salts with other counterions (entries 1−5).
This result is in direct contrast to the alkynylation of
isochroman acetals, in which CuI provided some of the lowest
enantioselectivities.
Despite this difference, BnBox remained the best ligand. Our
efforts to improve the enantioselectivity by identifying an
alternative ligand were unsuccessful; we investigated a variety of
other chiral ligand scaffolds, but none provided higher
enantioselectivity than BnBox under these reaction conditions.
Other bis(oxazoline) ligands also resulted in lower enantiose-
lectivities (entries 6−8). Curious about the potential
importance of an aryl ring in the ligand, we investigated
bis(oxazoline) ligands with substituted benzyl substituents,
including those with greater steric bulk (L1, entry 9), increased
electron-donating ability (L2 and L4, entries 10 and 12), and
extended π-faces (L3 and L4, entries 11 and 12). Although p-
methoxybenzyl-substituted L2 resulted in slightly higher
enantioselectivity (63% ee), no significant improvements were
observed with these ligands. Because BnBox is commercially
available and easier to synthesize than L2, we pursued further
optimization with BnBox.
[5]
temp
yield
b
ee
c
entry
(M)
base
Et3N
Lewis acid
(°C)
(%)
(%)
1
2
3
4
5
0.31
0.08
0.08
0.08
0.08
0.08
TMSOTf
TMSOTf
TMSOTf
BF3·OEt2
BF3·OEt2
BF3·OEt2
0
0
(71)
56
63
73
77
80
83
83
Et3N
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
0
45
0
40
−22
−22
31
d
6
(74)
a
Conditions: Acetal 5a (0.12 mmol, 1.0 equiv), CuI (0.14 mmol, 10
mol %), BnBox (0.014 mmol, 12 mol %), HCCPh (6a, 0.15 mmol, 1.2
equiv), base (0.15 mmol, 1.2 equiv), Lewis acid (0.12 mmol, 1.0
b
equiv), PhMe, unless otherwise noted. Determined by 1H NMR
analysis using 1,3,5-trimethoxybenzene as internal standard. Numbers
in parentheses are isolated yields. Determined by HPLC analysis
using a chiral stationary phase. 1.75 equiv BF3·OEt2 was used.
c
d
further increases in enantioselectivity. However, the overall
reaction concentration influenced the enantioselectivity. By
reducing the [5a] to 0.08 M, 73% ee of 8aa was achieved
(Table 2, entry 2). Under these more dilute conditions,
optimization of the base and Lewis acid revealed that the use of
dicyclohexyl methyl amine (Cy2NMe) and BF3·OEt2 resulted
in even higher enantioselectivity (entries 3−4). At a reaction
temperature to −22 °C, chromene 8aa was formed in 83% ee,
but at the cost of yield (entry 5). Increasing the equivalents of
BF3·OEt2 led to synthetically useful yields of chromene 8aa in
Having identified CuI/BnBox as the best catalyst system, we
undertook a systematic evaluation of the other reaction
variables. By lowering the reaction temperature to 0 °C,
chromene 8aa was formed in 71% yield and 63% ee (Table 2,
entry 1). Lowering the temperature more did not result in
C
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a
equivalent enantioselectivity (entry 6). Under these optimal
conditions, chromene 8aa was formed in 74% yield and 83% ee.
Under these optimized conditions, a variety of chromene
acetal substrates underwent alkynylation in high yields and
enantioselectivities (Scheme 5). In particular, alkynylation of
Scheme 6. Scope of Alkyne
a
Scheme 5. Scope of Chromene Acetal
a
Conditions: Acetal 5 (0.25 mmol, 1.0 equiv), CuI (0.025 mmol, 10
mol %), (R,R)-BnBox (0.030 mmol, 12 mol %), HCCPh (6a, 0.31
mmol, 1.2 equiv), Cy2NMe (0.31 mmol, 1.2 equiv), BF3·OEt2 (0.44
mmol, 1.8 equiv), PhMe (0.08 M), 24 h, unless otherwise noted.
Average yields ( 7%) and ee’s ( 1%) of isolated products of duplicate
reactions. ee determined by HPLC analysis using a chiral stationary
b
phase. HCCPh (0.38 mmol, 1.5 equiv), BF3·OEt2 (0.36 mmol, 1.5
c
equiv). Reaction set up outside glovebox, HCCPh (0.38 mmol, 1.5
equiv).
chromene acetals substituted with electron-donating groups
resulted in high enantioselectivies (8ba, 8ca). 4-Aryl chromene
products were also formed in high ee’s (8ea−8ia). Notably, a
number of biologically active chromene natural products
contain this 4-aryl substituent.16 In this 4-aryl-substituted
series, the importance of electronic effects is clear; substrates
with more electron-donating 4-aryl substituents result in higher
enantioselectivities (discussed in detail below). The highest ee’s
are observed for chromene acetals with both an electron-
donating R1 and a 4-phenyl substituent (8ja, 8ka). In contrast
with the beneficial effect of 4-aryl substitution, 3-phenyl
chromene acetal underwent reaction with phenyl acetylene in
only 30% ee, and 4-methyl chromene acetal decomposed under
the reaction conditions (not shown). For convenience, we set
up our reactions in an inert-atmosphere glovebox. However,
these reactions can also be set up on the benchtop with little
change in the yield or enantioselectivity (see 8ea).
a
Conditions: acetal 5 (0.25 mmol, 1.0 equiv), CuI (0.025 mmol, 10
mol %), (R,R)-BnBox (0.030 mmol, 12 mol %), alkyne 6 (0.31 mmol,
1.2 equiv), Cy2NMe (0.31 mmol, 1.2 equiv), BF3·OEt2 (0.44 mmol,
1.8 equiv), PhMe (0.08 M), 24 h, unless otherwise noted. Average
yields ( 3%) and ee’s ( 1%) of isolated products of duplicate
reactions. ee determined by HPLC analysis using a chiral stationary
phase.
of functional groups was well-tolerated, including ether (8em,
8fx), chloride (8eo, 8et, 8ft), bromide (8es), fluoride (8eu,
8fu), trifluoromethyl (8ej, 8fj), nitrile (8eq, 8ev), and ester
(8fw) groups. However, reactions of alkynes with vinyl or
aliphatic substituents result in lower yields and enantioselectiv-
ities. For example, cyclohexene 8el is formed in only 49% yield
and 70% ee, and the analogous reaction of cyclopropylacetylene
provides product in only 43% ee (not shown). Although we do
not currently understand this trend, it mirrors observations
with isochroman acetal substrates. Although alkyl-substituted
Wide scope was also observed with respect to the alkyne
(Scheme 6). Both electron-rich and electron-poor aryl-
substituted alkynes were effective. In addition, a wide range
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alkynes undergo reaction in the presence of achiral Zn and Cu
catalysts, they fail when chiral Cu(BnBox) catalysts are
employed.
Reduction of these 2-alkynyl chromene products readily
delivers 2-alkyl chromans with high levels of stereochemical
fidelity. For example, hydrogenation of alkyne 8aa, prepared in
83% ee using (R,R)-BnBox as ligand, resulted in 2-
phenethylchroman (9) in 87% yield and 82% ee (eq 2).
Figure 1. Molecular diagram of [(S,S)-BnBox]CuI with ellipsoids at
30% probability. H atoms omitted for clarity.
Comparison of the optical rotation of chroman 9 to reported
values confirmed that the absolute configuration of alkyne 8aa
is S.9 In addition, the absolute configuration of products 8ea
and 8eo were also determined to be S by crystallography.17
These absolute configurations confirm that the copper acetylide
adds to the Re face of the oxocarbenium ion when (R,R)-BnBox
is used.
As discussed above, there is a strong correlation between the
stability of the oxocarbenium ion intermediate and the
enantioselectivity. As shown by the Hammett correlation
between σ+ values of substituents on the chromene acetal
and the enantiomeric ratio of the products (Figure 2),19 higher
2.4. Mechanistic Hypothesis and Model for Enan-
tioinduction. We propose that these alkynylations of both
isochroman and chromene acetals proceed via a catalytic cycle
as shown in Scheme 7 (illustrated with chromene acetal 5a).
Scheme 7. Proposed Catalytic Cycle
Figure 2. Hammett Plot of Substituent Effects of 4-Aryl-Substituted
Chromene Acetals vs Enantioselectivity.
enantioselectivities are observed for substrates with electron-
donating substituents, which stabilize oxocarbenium ion 12. In
general, electron-donating substituents on isochroman sub-
strates also lead to higher enantioselectivies, but the Hammett
correlation is less conclusive, suggesting other factors also affect
enantioselectivity in this case.17 These trends are consistent
with the C−C bond formation being enantiodetermining; a
more stable oxocarbenium ion intermediate will undergo a later
transition state in the addition of copper acetylide 11 to
oxocarbenium ion 12. A later transition state will have a shorter
C−C distance in the nascent bond, resulting in greater
interaction of the oxocarbenium ion with the chiral catalyst.
Focusing on C−C bond formation as the probable
enantiodetermining step, our current model for enantioinduc-
tion is largely based on minimization of steric interactions
between the oxocarbenium ion and the benzyl substituents of
the catalyst. We assume that copper acetylide 11 adopts a
pseudotetrahedral geometry at copper in the C−C bond-
forming transition state. We also propose that the copper
Combination of BnBox and Cu(MeCN)4PF6 or CuI leads to
formation of copper(I) species 10. Consistent with this
proposal, a crystal structure of [(S,S)-BnBox]CuI shows
bidentate coordination of BnBox to a trigonal planar copper(I)
center (Figure 1).17 Importantly, consistent and high
enantioselectivitives are only observed when the copper salt
and ligand are stirred for at least 30 min at room temperature
prior to the addition of other reagents, suggesting that the
ligation event is slow. Addition of alkyne and base likely lead to
formation of chiral copper acetylide 11. Simultaneously, acetal
5a undergoes Lewis acid-promoted ionization to deliver
oxocarbenium ion 12. Nucleophilic attack of copper acetylide
11 onto oxocarbenium ion 12 would then form the new C−C
bond and stereogenic center.18 Subsequent release of product
8aa frees catalyst 10 to re-enter the catalytic cycle.
acetylide approaches the oxocarbenium ion from a Burgi−
̈
Dunitz-like angle. Within these constraints, addition of the
copper acetylide to the Re face of the oxocarbenium ion would
be disfavored by a significant steric interaction between the
benzene of the oxocarbenium ion and the benzyl substitutent of
the catalyst (15, Figure 3). This destabilizing interaction is
absent in attack of the Si face of the oxocarbenium ion (14).
This model correctly predicts the observed major enantiomer
in the alkynylation of isochroman acetals using (S,S)-BnBox as
E
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enantioselectivities. For example, in the alkynylation of
chromene acetals, PhBox, i-PrBox, and t-BuBox give 26, 48
and 26% ee, respectively, under conditions where BnBox
provides 60% ee (see Table 1, entries 5−8). Similar trends are
observed with isochroman acetals. Further, the identity of the
Lewis acid, base, and copper counteranion affect enantiose-
lectivity. However, the optimal Lewis acid, base, and copper
counteranion differ for the two acetal classes, hindering the
development of a straightforward explanation of their effects.
These observations suggest that the mechanism and,
particularly, the enantiodetermining transition state are more
complicated than our current understanding. Experiments are
underway to increase the sophistication of our mechanistic
understanding of this highly enantioselective transformation.
CONCLUSIONS
■
We have developed an efficient, enantioselective, copper-
catalyzed alkynylation of benzopyranyl acetals. This method
enables formation of highly enantioenriched α-chiral oxygen
heterocycles from widely available, racemic isochroman and
chromene acetal substrates. This reaction relies on the use of a
copper/BnBox catalyst and demonstrates that chiral organo-
metallic nucleophiles can be used in highly enantioselective
additions to cyclic oxocarbenium ions. Ongoing efforts in our
laboratory are directed toward establishing the generality of
using chiral organometallic nucleophiles in enantioselective
additions to oxocarbenium ions and toward developing a
sophisticated understanding of the mechanism of this class of
reactions.
Figure 3. Putative stereochemical rationale. Shown with (S,S)-BnBox
ligand.
the ligand. With respect to chromene oxocarbenium ions, steric
hindrance between the benzene of the oxocarbenium ion and
the benzyl of the catalyst disfavors addition to the Re face (17),
which is consistent with the observed major enantiomer when
(S,S)-BnBox is used. However, in this case, maintenance of a
EXPERIMENTAL SECTION
Burgi−Dunitz-like approach rotates the benzene of the
̈
■
oxocarbenium ion away from the benzyl group of the catalyst,
leading to somewhat less steric hindrance (15 vs 17),
potentially explaining why chromene acetal 5a undergoes
alkynylation in lower enantioselectivities than isochroman
acetals 2 under identical conditions (see Table 1, entry 1). As
noted above, 4-aryl chromene acetals generally undergo
alkynylation in higher enantioselectivities. This effect of 4-aryl
substituents may be due to a later transition state in the C−C
bond formation due to stabilization of the oxocarbenium ion
intermediate via conjugation to the aryl ring. It may also occur
partially due to a steric interaction between the 4-aryl
substituent and the benzyl group of the catalyst (17). This
model is also consistent with the formation of racemic product
in the alkynylation of benzaldehyde dimethyl acetal (20, eq 3).
General Information. Reactions were performed either in a N2-
atmosphere glovebox or in round-bottomed flasks. Flasks were fitted
with rubber septa, and reactions were conducted under a positive
pressure of N2. Syringes were used to transfer air- and moisture-
sensitive liquids. Flash chromatography was performed on silica gel 60
(40−63 μm, 60 Å). Thin layer chromatography (TLC) was performed
on glass plates coated with silica gel 60 with F254 indicator.
Commercial reagents were purchased and used as received with the
following exceptions: toluene, CH2Cl2, and Et2O were dried by passing
through drying columns.20 Toluene was then degassed by sparging
with N2 and stored over activated 4 Å MS in a N2-atmosphere
glovebox. Et3N and Cy2NMe were distilled from CaH2. MeOH was
distilled from CaH2. BF3·OEt2 was purchased in sure sealed bottles
and used as such. CDCl3 was stored over oven-dried potassium
carbonate. Alkynes were degassed before use by either freeze−pump−
thaw cycles or sparging with N2. Proton nuclear magnetic resonance
(1H NMR) spectra and carbon nuclear magnetic resonance (13C
NMR) spectra were recorded on 400 MHz and 600 Mz spectrometers.
Chemical shifts for protons are reported in parts per million downfield
from tetramethylsilane and are referenced to residual protium in the
NMR solvent (CHCl3 = δ 7.28) and [(CD3)2CO = δ 2.05]. Chemical
shifts for carbon are reported in parts per million downfield from
tetramethylsilane and are referenced to the carbon resonance of the
solvent (CDCl3 = δ 77.07) and (CD3)2CO = δ 28.94). Data are
represented as follows: chemical shift, multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants in Hertz (Hz), integration. Infrared (IR) spectra were
obtained using FTIR spectrophotometers with material loaded onto a
NaCl plate. Optical rotations were measured using a 2.5 mL cell with a
0.1 dm path length. BOX ligands were prepared as described in the
literature.21 Alkynes 6j,22 6q,23 6r,24 6s,25 6v,26 6w,27 and 6x28 were
prepared as described in the literature.
In this case, the oxocarbenium ion likely adopts an E
configuration, instead of the Z configuration enforced for
cyclic oxocarbenium ions. Little difference would then be
expected between additions to the Re versus Si face of the
oxocarbenium ion (Figure 3C).
Although this stereochemical model is satisfying in its
rationalization of the observed major enantiomers and its
simplicity, there are several results it does not explain. Notably,
this model is predicated on minimization of steric hindrance,
but ligand substituents larger than benzyl result in lower
General Procedure for Preparation of Chromene Acetal
Substrates. 2-Methoxy-2H-chromene (5a). This procedure was
adapted from literature.9 To a flame-dried, 250 mL round-bottomed
F
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The Journal of Organic Chemistry
Article
flask was added coumarin (6.0 g, 41.1 mmol, 1.0 equiv) and CH2Cl2
(60 mL). The solution was cooled to −78 °C and DIBAL-H (1.2 M in
PhMe, 36.0 mL, 43.1 mmol, 1.05 equiv) was added via syringe over 15
min. The solution was then stirred for an additional 2 h at −78 °C and
then allowed to warm to 0 °C and stirred for 15 min. The solution was
then diluted with EtOAc (200 mL) and quenched with H2O (200
mL). The resulting mixture was vigorously stirred for 1 h and then
filtered through Celite. The aqueous layer was extracted with EtOAc
(2 × 200 mL). The combined organic layers were washed with satd
NaCl (200 mL), dried (Na2SO4), filtered, and concentrated. The
hemiacetal was used in the subsequent step without further
purification.
(NaCl, thin film): 2928, 2827, 1637, 1636, 1604, 1483, 1483, 1452,
1219, 1045 cm−1. LRMS (EI+): [M]+ calculated for C16H14O2, 238.1;
found, 238.1.
2-Methoxy-4-(4-methoxyphenyl)-2H-chromene (5f). Prepared via
the general procedure described above on a 3.98 mmol scale. 4-(4-
Methoxyphenyl) coumarin was prepared as reported in the literature.30
The crude product was purified by silica gel chromatography (7−8%
Et2O/hexanes with 5% Et3N; Rf = 0.33) to give 5f (810 mg, 76%) as a
1
white solid (mp 79−82 °C). H NMR (400 MHz, CDCl3): δ 7.34−
7.31 (m, 2H), 7.26−7.22 (m, 1H), 7.17−7.14 (m, 1H), 7.08−7.06 (m,
1H), 6.95−6.90 (m, 3H), 5.81 (d, J = 4.2 Hz, 1H), 5.62 (d, J = 4.1 Hz,
1H), 3.85 (s, 3H), 3.53 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
159.6, 151.6, 138.3, 130.1, 129.9, 129.4, 126.3, 121.9, 121.4, 117.3,
117.1, 113.7, 95.9, 55.3, 55.2. FTIR (NaCl, thin film): 2930, 2833,
1696, 1636, 1606, 1573, 1612, 1452, 1248, 1095, cm−1. LRMS (EI+):
[M]+ calculated for C17H16O3, 268.1; found, 268.1.
The crude hemiacetal was dissolved in MeOH (50 mL).
Trifluoroacetic acid (95.4 μL, 1.2 mmol, 3 mol %) was added, and
the solution was stirred for 4 h at room temperature. K2CO3 (228 mg,
1.65 mmol, 0.04 equiv) was added. The mixture was filtered, and the
filtrate was concentrated. The resulting residue was purified by silica
gel chromatography (2−4% Et2O/hexanes with 5% Et3N; Rf = 0.44 to
afford 5a (5.65 g, 85%) as pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.24−7.20 (m, 1H), 7.15−7.13 (m, 1H), 7.00−6.94 (m,
2H), 6.74 (d, J = 9.6 Hz, 1H), 5.87 (dd, J = 9.7, 3.8 Hz, 1H), 5.60 (d, J
= 3.8 Hz, 1H), 3.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 151.3,
129.4, 127.1, 126.7, 121.6, 120.7, 119.7, 116.6, 95.9, 55.1; FTIR (NaCl,
thin film): 2912, 2830, 1642, 1606, 1488, 1457, 1403, 1205 cm−1;
LRMS (EI+): [M]+ calculated for C10H10O2, 162.07; found, 162.1.
2-Methoxy-6-methyl-2H-chromene (5b). Prepared via the general
procedure described above on a 31.0 mmol scale. The crude product
was purified by silica gel chromatography (3−4% Et2O/hexanes with
2-Methoxy-4-(p-tolyl)-2H-chromene (5g). Prepared via the general
procedure described above on a 3.26 mmol scale. 4-(p-Tolyl)
coumarin was prepared as reported in the literature.30 The crude
product was purified by silica gel chromatography (3−4% Et2O/
hexanes with 5% Et3N; Rf = 0.45) to give 5g (517 mg, 63%) as a white
solid (mp 85−88 °C). 1H NMR (400 MHz, CDCl3): δ 7.33−7.21 (m,
5H), 7.16−7.14 (m, 1H), 7.09−7.07 (m, 1H), 6.94−6.90 (m, 1H),
5.86 (d, J = 4.2 Hz, 1H), 5.66 (d, J = 4.1 Hz, 1H), 3.55 (s, 3H), 2.42
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 151.5, 138.7, 137.9, 134.6,
129.4, 129.1, 128.7, 126.4, 121.8, 121.4, 117.5, 117.1, 95.8, 55.2, 21.2.
FTIR (NaCl, thin film): 2923, 2827, 1639, 1603, 1558, 1484, 1452,
1220, 1095, 1045, cm−1. LRMS (EI+): [M]+ calculated for C17H16O2,
252.2; found, 252.1.
1
5% Et3N; Rf = 0.5) to give 5b (5.1 g, 93%) as colorless oil. H NMR
(400 MHz, CDCl3): δ 7.03−7.01 (m, 1H), 6.96−6.94 (m, 1H), 6.90−
6.88 (m, 1H), 6.70 (d, J = 9.6 Hz, 1H), 5.85 (dd, J = 9.6, 3.8 Hz, 1H),
5.56 (d, J = 3.8 Hz, 1H), 3.48 (s, 3H), 2.28 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 149.1, 130.8, 130.0, 127.4, 126.7, 120.4, 119.7, 116.3,
95.8, 54.9, 20.6. FTIR (NaCl, thin film): 2914, 1641, 1493, 1083, 1023
cm−1. LRMS (EI+): [M]+ calculated for C11H12O2, 176.08; found,
176.1.
4-(4-Chlorophenyl)-2-methoxy-2H-chromene (5h). Prepared via
the general procedure described above on a 1.75 mmol scale. 4-(4-
Chlorophenyl) coumarin was prepared as reported in the literature.31
The crude product was purified by silica gel chromatography (5%
Et2O/hexanes with 5% Et3N; Rf = 0.44) to give 5h (286 mg, 60%) as a
white solid (mp 99−102 °C): 1H NMR (400 MHz, CDCl3) 7.41−7.33
(m, 4H), 7.25−7.29 (m, 1H), 7.08−7.10 (m, 2H) 6.96−6.92 (m, 1H),
5.84 (d, J = 4.2 Hz, 1H), 5.64 (d, J = 4.1 Hz, 1H), 3.54 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 146.3, 132.6, 130.8, 128.9, 125.02, 124.5,
123.4, 120.8, 116.3, 116.2, 113.0, 112.01, 90.5, 50.1. FTIR (NaCl, thin
film): 2926, 2827, 1652, 1636, 1558, 1483, 1455, 1219, 1088, 1045,
cm−1. LRMS (EI+): [M]+ calculated for C16H13ClO2, 272.1; found,
272.1.
2,6-Dimethoxy-2H-chromene (5c). Prepared via the general
procedure described above on a 12.5 mmol scale. 6-Methoxy coumarin
preparation method was adapted from literature.29 The crude product
was purified by silica gel chromatography (10% Et2O/hexanes with 5%
1
Et3N; Rf = 0.4) to give 5c (1.96 g, 82%) as a colorless oil. H NMR
(400 MHz, CDCl3): δ 6.93 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 8.8, 3.0
Hz, 1H), 6.70−6.68 (m, 2H), 5.90 (dd, J = 9.7, 3.8 Hz, 1H), 5.53 (d, J
= 3.8 Hz, 1H), 3.77 (s, 3H), 3.48 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 154.2, 145.2, 126.6, 121.2, 120.4, 117.2, 115.3, 111.5, 95.8,
55.8, 55.1. FTIR (NaCl, thin film): 2932, 2831, 1611, 1604, 1578,
1492, 1263, 1207 cm−1. LRMS (EI+): [M]+ calculated for C11H12O3,
192.08; found, 192.1.
2-Methoxy-4-(3-methoxyphenyl)-2H-chromene (5i). Prepared via
the general procedure described above on a 2.78 mmol scale. 4-(3-
Methoxyphenyl) coumarin was prepared as reported in the literature.30
The crude product was purified by silica gel chromatography (6−7%
Et2O/hexanes with 5% Et3N; Rf = 0.34) to give 5i (469 mg, 63%) as a
1
white solid (mp 87−90 °C): H NMR (400 MHz, CDCl3): δ 7.34−
2,7-Dimethoxy-2H-chromene (5d). Prepared via the general
procedure described above on a 12.5 mmol scale. 7-Methoxy coumarin
was prepared as reported in the literature.29 The crude product was
purified by silica gel chromatography (10% Et2O/hexanes with 5%
7.23 (m, 2H), 7.17−7.15 (m, 1H), 7.09−7.07 (m, 1H), 6.99−6.90 (m,
4H), 5.87 (d, J = 4.1 Hz, 1H), 5.65 (d, J = 4.1 Hz, 1H), 3.82 (s, 3H),
3.54 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 159.5, 151.4, 139.03,
138.8, 129.5, 129.4, 126.3, 121.70, 121.5, 121.3, 117.8, 117.1, 114.1,
113.9, 95.8, 55.3, 55.2. FTIR (NaCl, thin film): 2931, 2831, 1636,
1604, 1577, 1483, 1453, 1218, 1097, 1045, cm−1. LRMS (EI+): [M]+
calculated for C17H16O3, 268.1; found, 268.1.
1
Et3N; Rf = 0.42) to give 5d (1.46g, 61%) as colorless oil. H NMR
(400 MHz, CDCl3): δ 7.04 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 9.7 Hz,
1H), 6.59−6.48 (m, 2H), 5.73 (dd, J = 9.6, 3.7 Hz, 1H), 5.58 (d, J =
3.7 Hz, 1H), 3.80 (s, 3H), 3.49 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 160.8, 152.6, 127.8, 126.4, 116.9, 114.1, 107.8, 102.09, 96.2,
55.4, 54.9. FTIR (NaCl, thin film): 2933, 2830, 1641, 1615, 1569,
1506, 1274 cm−1. LRMS (EI+): [M]+ calculated for C11H12O3, 192.08;
found, 192.1.
2-Methoxy-6-methyl-4-phenyl-2H-chromene (5j). Prepared via
the general procedure described above on a 2.39 mmol scale. 6-
Methyl-4-phenyl coumarin was prepared as reported in the literature.32
The crude product was purified by silica gel chromatography (4%
Et2O/hexanes with 5% Et3N; Rf = 0.45) to give 5j (500 mg, 83%) as a
1
2-Methoxy-4-phenyl-2H-chromene (5e). Prepared via the general
procedure described above on a 4.86 mmol scale. 4-Phenyl coumarin
was prepared as reported in the literature.30 The crude product was
purified by silica gel chromatography (3−4% Et2O/hexanes with 5%
Et3N; Rf = 0.45) to give 5e (856 mg, 74%) as a white solid (mp 81−83
white solid (mp 89−92 °C): H NMR (400 MHz, CDCl3): δ 7.47−
7.40 (m, 5H), 7.09−7.07 (m, 1H), 7.02−7.00 (m, 1H), 6.96−6.94 (m,
1H), 5.87 (d, J = 4.2 Hz, 1H), 5.64 (d, J = 4.2 Hz, 1H), 3.55 (s, 3H),
2.25 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 149.2, 138.9, 137.8,
130.7, 130.1, 128.9, 128.4, 128.08, 126.5, 121.5, 118.03, 116.8, 95.7,
55.2, 20.8. FTIR (NaCl, thin film): 2923, 2827, 1637, 1489, 1445,
1227, 1093, 1045 cm−1. LRMS (EI+): [M]+ calculated for C17H16O2,
252.1; found, 252.1.
1
°C). H NMR (400 MHz, CDCl3): δ 7.42−7.37 (m, 5H), 7.28−7.24
(m, 1H), 7.14 (dd, J = 7.8, 1.6 Hz, 1H), 7.10−7.08 (m, 1H), 6.95−
6.91 (m, 1H), 5.86 (d, J = 4.2 Hz, 1H), 5.66 (d, J = 4.1 Hz, 1H), 3.54
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 151.5, 138.8, 137.6, 129.5,
128.8, 128.4, 128.1, 126.3, 121.7, 121.4, 117.9, 117.0, 95.8, 55.2. FTIR
2,7-Dimethoxy-4-phenyl-2H-chromene (5k). Prepared via the
general procedure described above on a 1.50 mmol scale. 7-
G
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The Journal of Organic Chemistry
Article
Methoxy-4-phenyl coumarin was prepared as reported in the
literature.32 The crude product was purified by silica gel chromatog-
raphy (7−8% Et2O/hexanes with 5% Et3N; Rf = 0.4) to give 5k (210
mg, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.44−7.42
(m, 5H), 7.07 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.52 (dd, J
= 8.6, 2.6 Hz, 1H), 5.74 (d, J = 4.1 Hz, 1H), 5.67 (d, J = 4.1 Hz, 1H),
3.84 (s, 3H), 3.57 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 160.8,
152.9, 138.7, 137.8, 128.8, 128.3, 128.1, 127.2, 115.2, 115.11, 107.6,
102.4, 96.3, 55.4, 55.1. FTIR (NaCl, thin film): 2925, 2830, 1612,
1567, 1504, 1444, 1157, 1043 cm−1. LRMS (EI+): [M]+ calculated for
C17H16O3, 268.1; found, 268.1.
General Procedure for the Enantioselective, Copper-Cata-
lyzed Alkynylation of Chromene Acetals. In a N2-atmosphere
glovebox, CuI (4.8 mg, 0.025 mmol, 10 mol %) was weighed into a 10
mL round-bottomed flask. (+)-2,2′-Isopropylidene[(4R)-4-benzyl-2-
oxazoline] (BnBox, 11.0 mg, 0.030 mmol, 12 mol %) and toluene (3.2
mL, 0.08 M) were added. The round-bottomed flask was sealed with a
septum. The mixture was stirred for 60 min at room temperature.
Then the alkyne (0.305 mmol, 1.2 equiv), dicyclohexylmethyl amine
(65.5 μL, 0.305 mmol, 1.2 equiv), and chromene acetal (0.254 mmol,
1.0 equiv) were added. The flask was again sealed with a septum,
removed from the glovebox, and cooled to −22 °C. After 10 min, BF3·
OEt2 (55.0 μL, 0.444 mmol, 1.75 equiv) was added via syringe, and the
reaction mixture was stirred for 24 h at −22 °C. The reaction mixture
was quenched MeOH (3.0 mL), allowed to warm to room
temperature, diluted with Et2O (10 mL), and filtered through a
short plug of silica gel, which was then washed with Et2O (10 mL).
The filtrate was concentrated and purified by silica gel chromatog-
raphy.
run 2:88% ee) by chiral HPLC analysis (CHIRALPAK IC, 0.8 mL/
min, 2% i-PrOH/hexane, λ = 254 nm); tR(major) = 9.21 min,
24
1
tR(minor) = 10.71 min. [α]D = −173.1° (c 1.6, CHCl3). H NMR
(400 MHz, CDCl3): δ 7.42−7.40 (m, 2H), 7.29−7.26 (m, 3H), 6.85
(d, J = 8.7 Hz, 1H), 6.72 (dd, J = 8.8, 3.0 Hz, 1H), 6.61 (d, J = 3.0 Hz,
1H), 6.49 (d, J = 9.6, 1H), 5.89 (dd, J = 9.6, 4.1 Hz, 1H), 5.74−5.73
(m, 1H), 3.77 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 154.5, 146.3,
131.9, 128.6, 128.2, 124.8, 123.1, 122.2, 122.1, 117.1, 114.6, 111.8,
86.0, 85.6, 65.0, 55.7. FTIR (NaCl, thin film): 2935, 2832, 2216, 1635,
1609, 1577, 1489, 1450, 1269, 1199 cm−1. HRMS (EI+): [M]+
calculated for C18H14O2: 262.0993; found, 262.0988.
(S)-7-Methoxy-2-(phenylethynyl)-2H-chromene (8da). Prepared
via the general procedure. The crude material was purified by silica
gel chromatography (4% Et2O/hexanes, Rf = 0.4) to give 8da (run
1:56.3 mg, 85%; run 2:48 mg, 72%) as a light yellow oil. After the
column fractions were concentrated, HPLC and NMR analysis were
immediately performed on compound 8da. When stored neat at room
temperature, compound 8da begins to decompose within minutes but
can be stored in solution in CHCl3 below −5 °C for days. The
enantiomeric excess was determined to be 91% (run 1:90% ee; run
2:91% ee) by chiral HPLC analysis (CHIRALPAK IC, 0.8 mL/min,
2% i-PrOH/hexane, λ = 254 nm); tR(major) = 10.14 min, tR(minor) =
24
1
9.53 min. [α]D = −110.8° (c 1.2, CHCl3). H NMR (600 MHz,
CDCl3): δ 7.45 (d, J = 7.2 Hz, 2H), 7.34−7.28 (m, 3H), 6.97 (d, J =
8.1 Hz, 1H), 6.52−6.48 (m, 3H), 5.80−5.79 (m, 1H), 5.73 (dd, J =
9.6, 4.0 Hz, 1H), 3.81 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 160.9,
153.7, 131.9, 128.6, 128.2, 127.5, 124.3, 122.2, 119.1, 114.7, 107.7,
102.3, 86.2, 85.5, 65.2, 55.3. FTIR (NaCl, thin film): 2932, 2830, 2213,
1635, 1612, 1550, 1481, 1269 cm−1. HRMS (EI+): [M]+ calculated for
C18H14O2, 262.0993; found, 262.0985.
(S)-2-(Phenylethynyl)-2H-chromene (8aa). Chromene 8aa was
prepared according to the general procedure described above, except
that 1.5 equiv of alkyne and 1.45 equiv BF3·OEt2 were used. The crude
material was purified by silica gel chromatography (3% Et2O/hexanes,
Rf = 0.40) to give 8aa (run 1:39.3 mg, 67%; run 2:36.9 mg, 63%) as a
colorless oil. The enantiomeric excess was determined to be 84% (run
1:84% ee; run 2:83% ee) by chiral HPLC analysis (CHIRALPAK IB,
0.8 mL/min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 10.9 min,
(S)-4-Phenyl-2-(phenylethynyl)-2H-chromene (8ea). Prepared via
the general procedure. The crude material was purified by silica gel
chromatography (3% Et2O/hexanes, Rf = 0.40) to give 8ea (run 1:60.0
mg, 77%; run 2:64.0 mg, 82%) as a white solid (mp 111−114 °C).
The enantiomeric excess was determined to be 91% (run 1:91% ee;
run 2:90% ee) by chiral HPLC analysis (CHIRALPAK IC, 0.8 mL/
min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 7.66 min,
24
1
24
1
tR(minor) = 10.30 min. [α]D = −110.1° (c 1.0, CHCl3). H NMR
(400 MHz, CDCl3): δ 7.43−7.41 (m, 2H), 7.34−7.26 (m, 3H), 7.20−
7.14 (m, 1H), 7.07−7.03 (m, 1H), 6.96−6.90 (m, 2H), 6.53 (d, J = 9.5
Hz, 1H), 5.87−5.81 (m, 2H). 13C NMR (151 MHz, CDCl3): δ 152.4,
131.9, 129.5, 128.7, 128.2, 126.8, 124.6, 122.15, 122.10, 121.8, 121.4,
116.5, 86.0, 85.7, 65.0. HRMS (EI+): [M]+ calculated for C17H12O,
232.0888; found, 232.0895. The spectral data for this compound
matches that reported in the literature.14
tR(minor) = 7.30 min. [α]D = −103.7° (c 1.6, CHCl3). H NMR
(600 MHz (CD3)2CO): δ 7.48−7.33 (m, 10H), 7.25 (t, J = 7.8, Hz,
1H), 7.04 (d, J= 7.6 Hz, 1H), 7.00 (d, 1 J = 8.1 Hz, 1H), 6.95 (t, J =
7.5 Hz 1H), 5.98 (d, J = 4.7 Hz, 1H), 5.95 (d, J = 4.6, 1H). 13C NMR
(151 MHz, (CD3)2CO): δ 153.1, 137.6, 136.7, 131.6, 129.6, 128.8,
128.6, 128.54, 128.51, 128.1, 125.8, 122.7, 122.1, 121.6, 120.4, 116.9,
86.2, 85.1, 64.5. FTIR (NaCl/thin film): 2922, 2850, 2215, 1629,
1601, 1573, 1481, 1451, 1214, 1110 cm−1. HRMS (EI+): [M]+
calculated for C23H16O, 308.1201; found, 308.1191. X-ray quality
crystals were obtained from an Et2O/hexanes mixture cooled to −18
°C. The crystal structure demonstrated that the absolute configuration
is S.
Product 8ea was also prepared in a reaction set up outside a N2-
atmosphere glovebox. In a flame-dried, 10 mL round-bottomed flask,
CuI (4.8 mg, 0.025 mmol, 10 mol %) and (+)-2,2′-isopropylidene-
[(4R)-4-benzyl-2-oxazoline] (BnBox, 11.0 mg, 0.0305 mmol, 12 mol
%) were combined. The flask was sealed with a septum. The flask was
evacuated and refilled with N2 three times before PhMe (3.18 mL, 0.08
M) was added. The solution was stirred for 60 min at room
temperature. Then phenyl acetylene (38.9 mg, 0.381 mmol, 1.5 equiv),
dicyclohexylmethyl amine (65.5 μL, 0.305 mmol, 1.2 equiv) and
chromene acetal 5e (60.5 mg, 0.254 mmol, 1.0 equiv) were added. The
flask was cooled to −22 °C. After 10 min, BF3·OEt2 (55.0 μL, 0.444
mmol, 1.75 equiv) was added via syringe, and the reaction mixture was
stirred at −22 °C for 24 h. MeOH (3.0 mL) was then added. After
warming to room temperature, the mixture was diluted with Et2O (10
mL) and filtered through a short plug of silica gel, which was then
washed with Et2O (10 mL). The filtrate was concentrated. The crude
product was purified by silica gel chromatography (3% Et2O/hexanes,
Rf = 0.40) to give 8ea (run 1:54.3 mg, 69%; run 2:53.0 mg, 68%) as a
white solid. The enantiomeric excess was determined to be 93% (run
1:93% ee; run 2:93% ee) by chiral HPLC analysis (CHIRALPAK IC,
0.8 mL/min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 7.10 min,
(S)-6-Methyl-2-(phenylethynyl)-2H-chromene (8ba). Prepared via
the general procedure. The crude material was purified by silica gel
chromatography (2−3% Et2O/hexanes, Rf = 0.5) to give 8ba (run
1:52.8 mg, 84%; run 2:48 mg, 77%) as a colorless oil. The
enantiomeric excess was determined to be 89% (run 1:89% ee; run
2:89% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
1% i-PrOH/hexane, λ = 254 nm); tR(major) = 11.00 min, tR(minor) =
24
1
10.24 min. [α]D = −223.5° (c 1.4, CHCl3). H NMR (400 MHz,
CDCl3): δ 7.45−7.43 (m, 2H), 7.35−7.27 (m, 3H), 6.98 (dd, J = 8.2,
1.7 Hz, 1H), 6.88−6.87 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.52−6.49
(m, 1H), 5.86 (dd, J = 9.5, 4.0 Hz, 1H), 5.79 (dd, J = 4.0, 1.6 Hz, 1H),
2.29 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 150.2, 131.9, 131.1,
129.9, 128.6, 128.2, 127.2, 124.8, 122.2, 122.1, 121.2, 116.2, 86.1, 85.5,
65.0, 20.6. FTIR (NaCl, thin film): 2918, 2830, 2214, 1725, 1665,
1632, 1586, 1487, 1442, 1206, 1022 cm−1. HRMS (EI+): [M]+
calculated for C18H14O, 246.1044; found, 246.1048.
(S)-6-Methoxy-2-(phenylethynyl)-2H-chromene (8ca). Prepared
via the general procedure. The crude material was purified by silica
gel chromatography (5% Et2O/hexanes, Rf = 0.38) to give 8ca (run
1:51 mg, 77%; run 2:54 mg, 81%) as a colorless oil. After the column
fractions were concentrated, HPLC and NMR analysis were
immediately performed on compound 8ca. When stored neat at
room temperature, compound 8ca begins to decompose within
minutes, but can be stored in solution in CHCl3 below −5 °C for days.
The enantiomeric excess was determined to be 89% (run 1:89% ee;
H
DOI: 10.1021/acs.joc.5b00364
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
tR(minor) = 6.77 min. The spectral data for this compound matches
that reported above.
154 °C). The enantiomeric excess was determined to be 94% (run
1:93% ee; run 2:95% ee) by chiral HPLC analysis (CHIRALPAK IB,
0.8 mL/min, 2% i-PrOH/hexane, λ = 254 nm); tR(major) = 7.38 min,
tR(minor) = 6.21 min. [α]D24 = −80.6° (c 1.6, CHCl3). 1H NMR (400
MHz, (CD3)2CO): δ 7.48−7.34 (m, 10H), 7.06 (d, J = 8.2 Hz, 1H),
6.89 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 5.96 (d, J = 4.6 Hz, 1H), 5.90
(d, J = 4.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
150.9, 137.8, 137.3, 131.9, 131.0, 130.09, 128.8, 128.6, 128.4, 128.2
128.03, 126.4, 122.6, 122.2, 120.2, 116.7, 86.1, 85.7, 65.1, 20.8. FTIR
(NaCl, thin film): 2922, 2830, 2217, 1683, 1635, 1601, 1481, 1456,
1213 cm−1. HRMS (EI+): [M]+ calculated for C24H18O, 322.1357;
found, 322.1363.
(S)-4-(4-Methoxyphenyl)-2-(phenylethynyl)-2H-chromene (8fa).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (5% Et2O/hexanes, Rf = 0.4) to give 8fa
(run 1:70 mg, 81%; run 2:65.8 mg, 77%) as a white solid (mp 94−97
°C). The enantiomeric excess was determined to be 93% (run 1:93%
ee; run 2:92% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/
min, 3% i-PrOH/hexane, λ = 254 nm); tR(major) = 8.67 min,
24
1
tR(minor) = 7.38 min. [α]D = −140.5° (c 1.0, CHCl3). H NMR
(400 MHz, (CD3)2CO): δ 7.45−7.33 (m, 7H), 7.29−7.25 (m, 1H),
7.10 (dd, J = 7.7, 1.7 Hz, 1H), 7.05−6.96 (m, 4H), 6.00−5.94 (m,
2H), 3.85 (s, 3H). 13C NMR (101 MHz, (CD3)2CO): δ 159.8, 153.2,
136.2, 131.6, 129.8, 129.7, 129.5, 128.8, 128.5, 125.9, 122.9, 122.2,
121.6, 119.5, 116.9, 113.8, 86.3, 84.9, 64.5, 54.7. FTIR (NaCl, thin
film): 2929, 2832, 2216, 1608, 1571, 1481, 1450, 1346, 1247, 1213
cm−1. HRMS (EI+): [M]+ calculated for C24H18O2, 338.1306; found,
338.1300.
(S)-7-Methoxy-4-phenyl-2-(phenylethynyl)-2H-chromene (8ka).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography using N2 to pressurize the column (3−5%
Et2O/hexanes, Rf = 0.42) to give 8ka (run 1:59 mg, 69%; run 2:54 mg,
63%) as a colorless oil. After the column fractions were concentrated,
HPLC and NMR analysis were immediately performed on compound
8ka. When stored neat at room temperature, compound 8ka begins to
decompose within minutes but can be stored in solution in CHCl3
under a N2 atmosphere below −5 °C for at least 12 h. The
enantiomeric excess was determined to be 95% (run 1:95% ee; run
2:94% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
3% i-PrOH/hexane, λ = 254 nm); tR(major) = 8.35 min, tR(minor) =
(S)-2-(Phenylethynyl)-4-(p-tolyl)-2H-chromene (8ga). Prepared
via the general procedure. The crude material was purified by silica
gel chromatography (3% Et2O/hexanes, Rf = 0.5) to give 8ga (run
1:70 mg, 86%; run 2:67.7 mg, 83%) as a colorless oil. The
enantiomeric excess was determined to be 89% (run 1:89% ee; run
2:89% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
1% i-PrOH/hexane, λ = 254 nm); tR(major) = 10.45 min, tR(minor) =
24
7.11 min. [α]D = −66.2° (c 1.6, CHCl3). 1H NMR (600 MHz,
24
7.32 min. [α]D = −38.3° (c 1.6, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.44−7.36 (m, 7H), 7.33−7.27 (m, 3H), 6.98 (d, J = 8.6
Hz, 1H), 6.61−6.60 (m, 1H), 6.47 (dd, J = 8.6, 2.5 Hz, 1H), 5.84 (d, J
= 4.2 Hz, 1H), 5.73 (d, J = 4.2 Hz, 1H), 3.80 (s, 3H). 13C NMR (151
MHz, CDCl3): δ 160.8, 154.5, 137.9, 137.1, 132.0, 128.7, 128.6, 128.3,
128.2, 128.0, 127.0, 122.2, 117.2, 116.1, 107.7, 102.5, 86.1, 85.6, 65.4,
55.4. FTIR (NaCl, thin film): 2930, 2835, 2215, 1630, 1602, 1480,
1450, 1348, 1213 cm−1. HRMS (EI+): [M]+ calculated for C24H18O2,
338.1306; found, 338.1298.
CDCl3): δ 7.46−7.44 (m, 2H), 7.34−7.28 (m, 5H), 7.25−7.21 (m,
3H), 7.11 (dd, J = 7.7, 1.6 Hz, 1H), 7.05−7.03 (m, 1H), 6.95−6.91
(m, 1H), 5.88−5.85 (m, 2H), 2.43 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 153.1, 137.9, 137.1, 134.7, 131.9, 129.5, 129.1, 128.7, 128.6,
128.2, 126.1, 122.9, 122.2, 121.6, 119.6, 116.9, 86.1, 85.7, 65.1, 21.2.
FTIR (NaCl, thin film): 2920, 2826, 2230, 1683, 1635, 1601,1481,
1456, 1213 cm−1. HRMS (EI+): [M]+ calculated for C24H18O,
322.1357; found, 322.1360.
(S)-2-((4-Methoxyphenyl)ethynyl)-4-phenyl-2H-chromene (8em).
Prepared via the general procedure. The crude material was purified by
silica gel chromatography (7% Et2O/hexanes, Rf = 0.35) to give 8em
(run 1:61.5 mg, 72%; run 2:65.8 mg, 77%) as a colorless oil. The
enantiomeric excess was determined to be 86% (run 1:85% ee; run
2:86% ee) by chiral HPLC analysis (CHIRALPAK IC, 0.8 mL/min,
2% i-PrOH/hexane, λ = 254 nm); tR(major) = 8.69 min, tR(minor) =
(S)-4-(4-Chlorophenyl)-2-(phenylethynyl)-2H-chromene (8ha).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (3% Et2O/hexanes, Rf = 0.45) to give 8ha
(run 1:75.4 mg, 87%; run 2:68.7 mg, 79%) as a colorless oil. The
enantiomeric excess was determined to be 80% (run 1:80% ee; run
2:80% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
3% i-PrOH/hexane, λ = 254 nm); tR(major) = 8.62 min, tR(minor) =
24
8.18 min. [α]D = −72.9° (c 1.4, CHCl3). 1H NMR (400 MHz,
24
6.47 min. [α]D = −31.0° (c 2.0, CHCl3). 1H NMR (400 MHz,
(CD3)2CO): δ 7.51−7.34 (m, 7H), 7.28−7.24 (m, 1H), 7.06 (dd, J=
7.7 Hz, 1.7 Hz, 1H), 7.01−6.90 (m, 4H), 5.99 (d, J = 4.6 Hz, 1H), 5.94
(d, J = 4.6 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, (CD3)2CO): δ
160.2, 153.2, 137.6, 136.5, 133.2, 129.6, 128.6, 128.5, 128.1, 125.8,
122.8, 121.6, 120.6, 116.9, 114.1, 114.0, 85.2, 84.7, 64.6, 54.8. FTIR
(NaCl, thin film): 2928, 2836, 2216, 1604, 1570, 1480, 1451, 1249
cm−1. HRMS (EI+): [M]+ calculated for C24H18O2, 338.1306; found,
338.1315.
(CD3)2CO): δ 7.54−7.51 (m, 2H), 7.48−7.33 (m, 7H), 7.30−7.26
(m, 1H), 7.06−6.94 (m, 3H), 6.04 (d, J = 4.7 Hz, 1H), 5.96 (d, J = 4.7
Hz, 1H). 13C NMR (101 MHz, (CD3)2CO): δ 153.1, 136.3, 135.5,
133.5, 131.6, 130.3, 129.8, 128.9, 128.6, 128.5, 125.7, 122.3, 122.1,
121.8, 120.9, 117.0, 86.0, 85.2, 64.4. FTIR (NaCl, thin film): 2924,
2840, 2216, 2235, 1635, 1658, 1506, 1488, 1481, 1213, 1110, 1088
cm−1. HRMS (EI+): [M]+ calculated for C23H15OCl, 342.0811; found,
342.0804.
(S)-4-Phenyl-2-(p-tolylethynyl)-2H-chromene (8en). Prepared via
the general procedure. The crude material was purified by silica gel
chromatography (3% Et2O/hexanes, Rf = 0.5) to give 8en (run 1:64
mg, 78%; run 2:58.8 mg, 72%) as a white solid (mp 147−149 °C).
The enantiomeric excess was determined to be 89% (run 1:89% ee;
run 2:89% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/
min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 10.89 min,
(S)-4-(3-Methoxyphenyl)-2-(phenylethynyl)-2H-chromene (8ia).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (5% Et2O/hexanes, Rf = 0.4) to give 8ia
(run 1:68.5 mg, 80%; run 2:73.5 mg, 86%) as a white solid (mp 97−
100 °C). The enantiomeric excess was determined to be 87% (run
1:87% ee; run 2:86% ee) by chiral HPLC analysis (CHIRALPAK IB,
0.8 mL/min, 3% i-PrOH/hexane, λ = 254 nm); tR(major) = 8.00 min,
tR(minor) = 7.16 min. [α]D24 = −123° (c 1.2, CHCl3). 1H NMR (400
MHz, (CD3)2CO): δ 7.43−7.33 (m, 6H), 7.28−7.23 (m, 1H), 7.09
(dd, J = 7.7, 1.6 Hz, 1H), 7.00−6.94 (m, 5H), 6.01 (d, J = 4.6 Hz, 1H),
5.95 (d, J = 4.6 Hz, 1H), 3.83 (s, 3H). 13C NMR (101 MHz,
(CD3)2CO): δ 159.9, 153.1, 138.9, 136.5, 131.6, 129.6, 129.5, 128.9,
128.5, 125.9, 122.6, 122.1, 121.7, 120.8, 120.3, 116.9, 114.0, 113.7,
86.2, 85.1, 64.5, 54.7. FTIR (NaCl, thin film): 2929, 2843, 2217, 1597,
1481, 1451, 1211 cm−1. HRMS (EI+): [M]+ calculated for C24H18O2,
338.1306; found, 338.1310.
24
1
tR(minor) = 7.23 min. [α]D = −117.0° (c 0.8, CHCl3). H NMR
(600 MHz, (CD3)2CO): δ 7.47−7.38 (m, 5H), 7.30 (d, J = 7.8 Hz,
2H), 7.25 (t, J= 7.7 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 7.7
Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 5.97 (d, J =
4.6 Hz, 1H), 5.93 (d, J = 4.6 Hz, 1H), 2.31 (s, 3H). 13C NMR (151
MHz, (CD3)2CO): δ 153.2, 139.0, 137.7, 136.6, 131.6, 129.6, 129.2,
128.6, 128.5, 128.1, 125.8, 122.8, 121.6, 120.5, 119.2, 116.9, 85.6, 85.3,
64.6, 20.5. FTIR (NaCl/thin film): 2916, 2848, 2214, 1635, 1508,
1450, 1453, 1212 cm−1. HRMS (EI+): [M]+ calculated for C24H18O,
322.1357; found, 322.1365.
(S)-6-Methyl-4-phenyl-2-(phenylethynyl)-2H-chromene (8ja).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (4% Et2O/hexanes, Rf = 0.6) to give 8ja
(run 1:73 mg, 89%; run 2:73.4 mg, 90%) as a white solid (mp 152−
(S)-2-((4-Chlorophenyl)ethynyl)-4-phenyl-2H-chromene (8eo).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (6% Et2O/hexanes, Rf = 0.5) to give 8eo
(run 1:63.4 mg, 73%; run 2:65.3 mg, 75%) as a light yellow solid (mp
I
DOI: 10.1021/acs.joc.5b00364
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The Journal of Organic Chemistry
Article
142−145 °C). The enantiomeric excess was determined to be 89%
(run 1:89% ee; run 2:89% ee) by chiral HPLC analysis (CHIRALPAK
IB, 0.8 mL/min, 2% i-PrOH/hexane, λ = 254 nm); tR(major) = 7.24
(CD3)2CO): δ 7.51−7.41 (m, 5H), 7.30−7.20 (m, 5H), 7.07−6.95
(m, 3H), 6.00 (d, J = 4.7 Hz, 1H), 5.97 (d, J = 4.7 Hz, 1H), 2.31 (s,
3H). 13C NMR (101 MHz, (CD3)2CO): δ 153.1, 138.2, 137.6, 136.6,
132.1, 129.7, 129.6, 128.7, 128.58, 128.56, 128.4, 128.1, 125.8, 122.7,
122.0, 121.6, 120.4, 116.9, 85.8, 85.2, 64.5, 20.1. FTIR (NaCl, thin
film): 2920, 2823, 2216, 1601, 1481, 1451, 1341, 1294, 1214 cm−1.
HRMS (EI+): [M]+ calculated for C24H18O, 322.1357; found,
322.1352.
24
1
min, tR(minor) = 6.46 min. [α]D = −134.2° (c 0.8, CHCl3). H
NMR (400 MHz, (CD3)2CO): δ 7.51−7.40 (m, 9H), 7.30−7.25 (m,
1H), 7.07−6.95 (m, 3H), 5.97−6.00 (m, 2H). 13C NMR (101 MHz,
(CD3)2CO): δ 153.0, 137.5, 136.7, 134.4, 133.3, 129.7, 128.8, 128.57,
128.56, 128.2, 125.8, 122.7, 121.7, 120.9, 120.1, 116.9, 87.3, 83.8, 64.4.
FTIR (NaCl, thin film): 2921, 2820, 2240, 1659, 1631, 1481, 1452,
1214 cm−1. HRMS (EI+): [M]+ calculated for C23H15OCl, 342.0811;
found, 342.0808. X-ray quality crystals were obtained from an Et2O/
hexanes mixture cooled to −18 °C. The enantiomeric excess of these
crystals was determined to be >99% by chiral HPLC analysis. The
crystal structure demonstrated that the absolute configuration is S.
(S)-4-Phenyl-2-((4-(trifluoromethyl)phenyl)ethynyl)-2H-chromene
(8ej). Prepared via the general procedure. The crude material was
purified by silica gel chromatography (4% Et2O/hexanes, Rf = 0.55) to
give 8ej (run 1:72.3 mg, 76%; run 2:69.2 mg, 73%) as a light yellow
solid (mp 123−126 °C). The enantiomeric excess was determined to
be 83% (run 1:82% ee; run 2:83% ee) by chiral HPLC analysis
(CHIRALPAK IB, 0.8 mL/min, 1% i-PrOH/hexane, λ = 254 nm);
(S)-2-((3-Bromophenyl)ethynyl)-4-phenyl-2H-chromene (8es).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (4% Et2O/hexanes, Rf = 0.5) to give 8es
(run 1:72.4 mg, 74%; run 2:74 mg, 76%) as a yellow oil. The
enantiomeric excess was determined to be 87% (run 1:87% ee; run
2:86% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
2% i-PrOH/hexane, λ = 254 nm); tR(major) = 7.03 min, tR(minor) =
24
6.43 min. [α]D = −129° (c 1.0, CHCl3). 1H NMR (400 MHz,
(CD3)2CO): δ 7.58−7.56 (m, 2H), 7.48−7.39 (m, 6H), 7.34−7.24
(m, 2H), 7.05−6.94 (m, 3H), 6.00−5.96 (m, 2H). 13C NMR (101
MHz, (CD3)2CO): δ 153.0, 137.5, 136.8, 134.1, 132.0, 130.6, 130.5,
129.7, 128.59, 128.57, 128.2, 125.9, 124.3, 122.7, 121.8, 121.7, 120.0,
116.9, 87.7, 83.40, 64.4. FTIR (NaCl, thin film): 2919, 2849, 2214,
1589, 1554, 1480, 1349, 1213, 1110 cm−1. HRMS (EI+): [M]+
calculated for C23H15O Br, 386.0306; found, 386.0302.
24
tR(major) = 8.30 min, tR(minor) = 6.98 min. [α]D = −81.2° (c 1.6,
CHCl3); 1H NMR (600 MHz, (CD3)2CO): δ 7.71 (d, J = 8.1 Hz, 2H),
7.63 (d, J = 8.1 Hz, 2H), 7.48−7.40 (m, 5H), 7.26 (t, J = 7.6 Hz, 1H),
7.05 (d, J = 6.0 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.97 (t, J = 7.6 Hz,
1H), 6.05−6.00 (m, 2H). 13C NMR (151 MHz, (CD3)2CO): δ 153.0,
137.5, 137.0, 129.9 (q, JC−F = 31.7 Hz), 129.7,129.2 128.4, 128.2,127.8,
126.3, 125.9, 125.4 (q, JC−F = 3.0 Hz), 124.0 (q, JC−F = 271.8 Hz),
122.7, 121.8, 119.9, 116.9, 88.9, 83.6, 64.4. FTIR (NaCl, thin film):
2925, 2820, 2232, 1615, 1481, 1452 cm−1. HRMS (EI+): [M]+
calculated for C24H15OF3, 376.1075; found, 376.1070.
(S)-2-((3-Chlorophenyl)ethynyl)-4-phenyl-2H-chromene (8et).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (4% Et2O/hexanes, Rf = 0.4) to give 8et
(run 1:70.3 mg, 81%; run 2:73 mg, 84%) as a yellow oil. The
enantiomeric excess was determined to be 89% (run 1:90% ee; run
2:88% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
1% i-PrOH/hexane, λ = 254 nm); tR(major) = 8.58 min, tR(minor) =
24
7.32 min. [α]D = −71.2° (c 0.8, CHCl3). 1H NMR (600 MHz,
(S)-4-((4-Phenyl-2H-chromen-2-yl)ethynyl)benzonitrile (8eq). Pre-
pared via the general procedure. The crude material was purified by
silica gel chromatography (9% Et2O/hexanes, Rf = 0.3) to give 8eq
(run 1:62.2 mg, 74%; run 2:63.8 mg, 76%) as light yellow oil. The
enantiomeric excess was determined to be 85% (run 1:85% ee; run
2:85% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
3% i-PrOH/hexane, λ = 254 nm); tR(major) = 13.24 min, tR(minor) =
11.74 min. [α]D = −106.7° (c 0.8, CHCl3). H NMR (600 MHz,
(CD3)2CO): δ 7.77 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H),
7.48−7.40 (m, 5H), 7.27 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H),
7.01 (d, J = 8.1 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.07−5.99 (m, 2H).
13C NMR (151 MHz, (CD3)2CO): δ 152.9, 137.5, 137.1, 132.4, 132.3,
(CD3)2CO): δ 7.48−7.36 (m, 9H), 7.26 (t, J = 7.7 Hz, 1H), 7.05 (d, J
= 7.7 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 5.98
(m, 2H). 13C NMR (151 MHz, (CD3)2CO): δ 153.0, 137.5, 136.9,
133.8, 131.2, 130.3, 130.2, 129.7, 129.08, 128.59, 128.55, 128.2, 125.8,
124.09, 122.7, 121.7, 120.1, 116.9, 87.3, 83.8, 64.4. FTIR (NaCl, thin
film): 2922, 2832, 2215, 1683, 1652, 1558, 1540, 1506, 1521, 1457,
1436 cm−1. HRMS (EI+): [M]+ calculated for C23H15OCl, 342.0811;
found, 342.0821.
24
1
(S)-2-((3-Fluorophenyl) ethynyl)-4-phenyl-2H-chromene (8eu).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (4% Et2O/hexanes, Rf = 0.4) to give 8eu
(run 1:65 mg, 79%; run 2:60.2 mg, 73%) as a colorless oil. The
enantiomeric excess was determined to be 93% (run 1:93% ee; run
2:92% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
2% i-PrOH/hexane, λ= 220 nm); tR(major) = 6.64 min, tR(minor) =
129.7, 128.6, 128.5, 128.2, 126.8, 125.9, 122.7, 121.8, 119.7, 117.9,
116.9, 112.2, 90.3, 83.5, 64.4. FTIR (NaCl, thin film): 2924, 2853,
2228, 2235, 1717, 1683, 1652, 1603, 1558, 1480, 1213 cm−1. HRMS
(EI+): [M]+ calculated for C24H15ON, 333.1153; found, 333.1148.
(S)-2-((3,5-Dimethylphenyl)ethynyl)-4-phenyl-2H-chromene
(8er). Prepared via the general procedure. The crude material was
purified by silica gel chromatography (2−3% Et2O/hexanes, Rf = 0.57)
to give 8er (run 1:68 mg, 80%; run 2:73.3 mg, 86%) as a colorless oil.
The enantiomeric excess was determined to be 91% (run 1:90% ee;
run 2:92% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/
min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 10.59 min,
24
1
6.12 min. [α]D = −180.0° (c 0.4, CHCl3). H NMR (600 MHz,
(CD3)2CO): δ 7.48−7.38 (m, 6H), 7.27−7.24 (m, 2H), 7.18−7.15
(m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.96 (t, J =
7.5 Hz, 1H), 5.99−5.96 (m, 2H). 13C NMR (151 MHz, (CD3)2CO): δ
162.3 (d, JC−F = 246.1 Hz), 153.1, 137.5, 136.8, 130.6 (d, JC−F = 7.6
Hz), 129.7, 128.6, 128.5, 128.1, 127.8 (d, JC−F = 3.02 Hz), 125.8, 124.1
(d, JC−F = 10.5 Hz), 122.7, 121.7, 120.1, 118.1(d, JC−F = 22.6 Hz),
116.9, 116.1(d, JC−F = 21.1 Hz), 87.3, 83.7(d, JC−F = 3.02 Hz), 64.4.
FTIR (NaCl, thin film): 2916, 2848, 2224, 1601, 1581, 1481, 1452,
1264 cm−1. HRMS (EI+): [M]+ calculated for C23H15OF, 326.1107;
found, 326.1106.
24
1
tR(minor) = 7.63 min. [α]D = −214.5° (c 0.4, CHCl3). H NMR
(400 MHz, (CD3)2CO): δ 7.51−7.41 (m, 5H), 7.29−7.25 (m, 1H),
7.07−6.94 (m, 6H), 5.99 (d, J = 4.7 Hz, 1H), 5.96 (d, J = 4.7 Hz, 1H),
2.26 (s, 6H). 13C NMR (101 MHz, (CD3)2CO): δ 153.1, 138.1, 137.6,
136.5, 130.5, 129.6, 129.2, 128.6, 128.5, 128.1, 125.8, 122.7, 121.8,
121.6, 120.4, 116.9, 85.49, 85.48, 64.5, 20.1. FTIR (NaCl, thin film):
2917, 2820, 2212, 1637, 1599, 1481, 1452, 1214 cm−1. HRMS (EI+):
[M]+ calculated for C25H20O, 336.1514; found, 336.1509.
(S)-3-((4-Phenyl-2H-chromen-2-yl) ethynyl) benzonitrile (8ev).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (8% Et2O/hexanes, Rf = 0.33) to give 8ev
(run 1:65.8 mg, 78%; run 2:63.2 mg, 75%) as a colorless oil. The
enantiomeric excess was determined to be 88% (run 1:87% ee; run
2:89% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
3% i-PrOH/hexane, λ = 254 nm); tR(major) = 12.66 min, tR(minor) =
(S)-4-Phenyl-2-(m-tolylethynyl)-2H-chromene (8eh). Prepared via
the general procedure. The crude material was purified by silica gel
chromatography (3% Et2O/hexanes, Rf = 0.5) to give 8eh (run 1:70.3
mg, 86%; run 2:65 mg, 80%) as a white solid (mp 98−102 °C). The
enantiomeric excess was determined to be 90% (run 1:90% ee; run
2:89% ee) by chiral HPLC analysis (CHIRALPAK IC, 0.8 mL/min,
1% i-PrOH/hexane, λ = 254 nm); tR(major) = 7.35 min, tR(minor) =
24
1
11.59 min). [α]D = −140.8° (c 1.2, CHCl3). H NMR (600 MHz,
(CD3)2CO): δ 7.81 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.9
Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.48−7.40 (m, 5H), 7.28−7.25 (m,
1H), 7.05 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.97 (t, J = 7.5
Hz, 1H), 6.00−5.98 (m, 2H). 13C NMR (151 MHz, (CD3)2CO): δ
153.0, 137.5, 137.0, 135.9, 134.8, 132.2, 129.8, 129.7, 128.59, 128.55,
24
1
6.78 min. [α]D = −126.6° (c 1.2, CHCl3). H NMR (400 MHz,
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Article
128.2, 125.9, 123.6, 122.7, 121.8, 119.8, 117.5, 116.9, 112.9, 88.5, 82.9,
64.4. FTIR (NaCl, thin film): 2924, 2853, 2226, 2232, 1600, 1572,
1451, 1293 cm−1. HRMS (EI+): [M]+ calculated for C24H15ON,
333.1153; found, 333.1149.
1573, 1511, 1480 cm−1. HRMS (EI+): [M]+ calculated for C25H20O3,
368.1412; found, 368.1404.
(S)-2-((3-Chlorophenyl)ethynyl)-4-(4-methoxyphenyl)-2H-chro-
mene (8 ft). Prepared via the general procedure. The crude material
was purified by silica gel chromatography (4% Et2O/hexanes, Rf = 0.5)
to give 8 ft (run 1:75.7 mg, 80%; run 2:70.8 mg, 75%) as a light yellow
solid (mp 112−115 °C). The enantiomeric excess was determined to
be 91% (run 1:91% ee; run 2:90% ee) by chiral HPLC analysis
(CHIRALPAK IB, 0.8 mL/min, 1% i-PrOH/hexane, λ = 254 nm);
tR(major) = 11.23 min, tR(minor) = 10.17 min. [α]D24 = −70.8° (c 1.2,
(S)-2-(Cyclohex-1-en-1-ylethynyl)-4-phenyl-2H-chromene (8el).
Prepared via the general procedure. The crude material was purified
by silica gel chromatography (2−3% Et2O/hexanes, Rf = 0.5) to give
8el (run 1:40.1 mg, 51%; run 2:36.2 mg, 46%) as a colorless oil. The
enantiomeric excess was determined to be 70% (run 1:70% ee; run
2:70% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/min,
1% i-PrOH/hexane, λ = 254 nm); tR(major) = 6.74 min, tR(minor) =
1
CHCl3). H NMR (400 MHz, (CD3)2CO): δ 7.45−7.33 (m, 6H),
24
6.15 min. [α]D = −82.0° (c 1.0, CHCl3). 1H NMR (400 MHz,
7.30−7.25 (m, 1H), 7.10 (dd, J = 7.7, 1.7 Hz, 1H), 7.06−6.96 (m,
4H), 6.00−5.94 (m, 2H), 3.86 (s, 3H). 13C NMR (101 MHz,
(CD3)2CO): δ 159.8, 153.1, 136.4, 133.8, 131.1, 130.3, 130.1, 129.7,
129.62, 129.61, 129.1, 125.9, 124.1, 122.9, 121.7, 119.1, 116.9, 113.9,
87.8, 83.3, 64.3, 54.7. FTIR (NaCl, thin film): 2930, 2832, 2216, 2235,
1608, 1627, 1529, 1560, 1480, 1214 cm−1. HRMS (EI+): [M+]
calculated for C24H17O2Cl, 372.0917; found, 372.0913.
CDCl3): δ 7.42−7.35 (m, 5H), 7.21−7.17 (m, 1H), 7.04−7.02 (m,
1H), 6.99−6.98 (m, 1H), 6.90−6.87 (m, 1H), 6.15−6.13 (m, 1H),
5.81 (d, J = 4.1 Hz, 1H), 5.76 (d, J = 4.1 Hz, 1H), 2.28−2.08 (m, 4H),
1.69−1.47 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 153.2, 137.7,
136.9, 136.5, 129.5, 128.8, 128.4, 128.0, 126.0, 122.9, 121.5, 120.6,
119.8, 116.9, 87.8, 83.2, 65.2, 29.0, 25.7, 22.2, 21.4. FTIR (NaCl, thin
film): 2925, 2855, 2214, 1630, 1602, 1480, 1450, 1348, 1213 cm−1.
HRMS (EI+): [M]+ calculated for C23H20O, 312.1514; found,
312.1522.
(S)-2-((3-Fluorophenyl)ethynyl)-4-(4-methoxyphenyl)-2H-chro-
mene (8fu). Prepared via the general procedure. The crude material
was purified by silica gel chromatography (4% Et2O/hexanes, Rf = 0.4)
to give 8fu (run 1:77.6 mg, 86%; run 2:81.3 mg, 90%) as a colorless
oil. The enantiomeric excess was determined to be 91% (run 1:91%
ee; run 2:91% ee) by chiral HPLC analysis (CHIRALPAK IB, 0.8 mL/
min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 11.07 min,
(S)-Ethyl-4-((4-(4-methoxyphenyl)-2H-chromen-2-yl)ethynyl)-
benzoate (8fw). Prepared via the general procedure. The crude
material was purified by silica gel chromatography (12% Et2O/
hexanes, Rf = 0.33) to give 8fw (run 1:88 mg, 85%; run 2:89.8 mg,
86%) as a colorless oil. The enantiomeric excess was determined to be
89% (run 1:88% ee; run 2:89% ee) by chiral HPLC analysis
(CHIRALPAK IA, 0.8 mL/min, 3% i-PrOH/hexane, λ = 254 nm);
tR(major) = 17.69 min, tR(minor) = 14.33 min. [α]D24 = −105° (c 0.8,
24
1
tR(minor) = 9.84 min. [α]D = −115.7° (c 1.4, CHCl3). H NMR
(600 MHz, (CD3)2CO): δ 7.45−7.41 (m, 1H), 7.36 (d, J = 8.2 Hz,
2H), 7.29−7.26 (m, 2H), 7.20−7.18 (m, 2H), 7.12 (d, J = 7.6 Hz,
1H), 7.05−6.98 (m, 4H), 5.98−5.95 (m, 2H), 3.88 (s, 3H). 13C NMR
(151 MHz, (CD3)2CO): δ 162.3 (d, JC−F = 247.6 Hz), 159.9, 153.1,
1
CHCl3). H NMR (400 MHz, (CD3)2CO): δ 8.03−8.00 (m, 2H),
136.4, 130.6 (d, JC−F = 9.06 Hz), 129.7, 129.6, 129.5, 127.8 (d, JC−F
=
7.58−7.55 (m, 2H), 7.39−7.37 (m, 2H), 7.32−7.28 (m, 1H), 7.11 (dd,
J = 7.7, 1.6 Hz, 1H), 7.08−6.99 (m, 4H), 6.03−5.98 (m, 2H), 4.36 (q,
J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, (CD3)2CO): δ 165.1, 159.8, 153.1, 136.4, 131.7, 130.5, 129.7,
129.63, 129.60, 129.3, 126.6, 125.9, 122.9, 121.7, 119.1, 116.9, 113.8,
89.3, 84.1, 64.4, 60.8, 54.7, 13.6. FTIR (NaCl, thin film): 2931, 2835,
2232, 1716, 1678, 1606, 1572, 1511, 1481 cm−1. HRMS (EI+): [M]+
calculated for C27H22O4, 410.1518; found, 410.1527.
3.0 Hz), 125.9, 124.2 (d, JC−F = 10.57 Hz), 122.9, 121.7, 119.2, 118.1
(d, JC−F = 24.16 Hz), 116.8, 116.07 (d, JC−F = 21.1 Hz), 113.9, 87.5,
83.6 (d, JC−F = 3.0 Hz), 64.5, 54.8. FTIR (NaCl, thin film): 2930,
2835, 2222, 1667, 1580, 1510, 1481, 1463, 1450, 1247, 1213 cm−1.
HRMS (EI+): [M]+ calculated for C24H17O2F, 356.1212; found,
356.1203.
(R)-2-Phenethylchroman (9). Alkyne 8aa (25.0 mg, 0.107 mmol,
83% ee, prepared from acetal 5a and phenylacetylene using (R,R)-
BnBox as ligand) and MeOH (2.5 mL) were combined in a flame-
dried, 10 mL round-bottomed flask fitted with a 3-way adapter with a
T-bore stopcock. Via this adapter, the reaction vessel was connected to
a N2/vacuum manifold and to an H2-filled balloon. The flask was
evacuated and refilled with nitrogen three times. 10% Pd/C (3.0 mg,
0.0028 mmol, 0.026 equiv) was added, and the flask was again
evacuated and refilled with nitrogen three times. The flask was then
evacuated and refilled with H2 five times. The reaction mixture was
stirred under H2 (1 atm) for 12 h. After consumption of alkyne 8aa as
determined by TLC analysis, the mixture was filtered through a short
pad of Celite, which was then washed with Et2O (10 mL). The filtrate
was concentrated, and the crude material was purified by silica gel
chromatography (1−3% Et2O/hexanes, Rf = 0.4) to give 9 (22.3 mg,
87%) as colorless oil. The enantiomeric excess was determined to be
82% by chiral HPLC analysis (CHIRALPAK IA, 0.8 mL/min, 0.5% i-
PrOH/hexane, λ = 254 nm); tR(major) = 7.72 min, tR(minor) = 8.6
min. [α]D24 = +43.1° (c 0.8, CHCl3). The sign of observed rotation is
opposite to that of (S)-9 reported in literature,9 allowing assignment of
the absolute configuration of 9 as R via our synthesis. The absolute
configuration of alkyne 8aa is thus assigned as S. 1H NMR (600 MHz,
CDCl3): δ 7.32−7.29 (m, 4H), 7.22−7.20 (m, 1H), 7.12 (t, J = 7.8 Hz,
1H), 7.06 (d, J = 7.5 Hz, 1H), 6.87−6.84 (m, 2H), 4.01−3.99 (m,
1H), 2.95−2.76 (m, 4H), 2.13−2.07 (m, 1H), 2.02−2.00 (m, 1H),
1.95−1.89 (m, 1H), 1.83−1.76 (m, 1H). 13C NMR (151 MHz,
CDCl3): δ 155.0, 141.9, 129.5, 128.6, 128.4, 127.2, 125.8, 122.1, 120.0,
116.8, 74.8, 37.1, 31.5, 27.5, 24.8. HRMS (EI+): [M]+ calculated for
C17H18O, 238.1357; found, 238.1353.
(S)-4-(4-Methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)ethynyl)-
2H-chromene (8fj). Prepared via the general procedure. The crude
material was purified by silica gel chromatography (6% Et2O/hexanes,
Rf = 0.33) to give 8fj (run 1:76.4 mg, 74%; run 2:81.3 mg, 79%) as a
colorless oil. The enantiomeric excess was determined to be 87% (run
1:87% ee; run 2:87% ee) by chiral HPLC analysis (CHIRALPAK IB,
0.8 mL/min, 1% i-PrOH/hexane, λ = 254 nm); tR(major) = 11.72 min,
24
1
tR(minor) = 10.55 min. [α]D = −19.2° (c 1.0, CHCl3). H NMR
(400 MHz, (CD3)2CO): δ 7.72 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.2
Hz, 2H), 7.36−7.31 (m, 2H), 7.29−7.24 (m, 1H), 7.09 (dd, J = 1.6,
7.7 Hz, 1H), 7.05−6.95 (m, 4H), 6.02−5.90 (m, 2H), 3.85 (s, 3H).
13C NMR (151 MHz, CDCl3): δ 159.6, 153.1, 137.0, 132.2, 130.3 (q,
JC−F = 33.2 Hz), 129.9, 129.86, 129.6, 126.2, 126.1 125.1 (q, JC−F
=
3.02 Hz), 123.8 (q, JC−F = 271.8 Hz), 123.0, 121.8 118.7, 116.9, 113.9,
88.6, 84.2, 64.9, 55.4. FTIR (NaCl, thin film): 2929, 2834, 2226, 1608,
1570, 1511, 1481, 1451, 1323, 1290, 1248 cm−1. HRMS (EI+): [M]+
calculated for C25H17O2F3, 406.1180; found, 406.117.
(S)-4-(4-Methoxyphenyl)-2-((3-methoxyphenyl)ethynyl)-2H-chro-
mene (8fx). Prepared via the general procedure. The crude material
was purified by silica gel chromatography (8% Et2O/hexanes, Rf = 0.3)
to give 8fx (run 1:80.7 mg, 86%; run 2:77.0 mg, 82%) as a colorless oil.
The enantiomeric excess was determined to be 90% (run 1:90% ee;
run 2:89% ee) by chiral HPLC analysis (CHIRALPAK IA, 0.8 mL/
min, 2% i-PrOH/hexane, λ = 254 nm); tR(major) = 16.46 min,
24
1
tR(minor) = 13.94 min. [α]D = −56.8° (c 1.0, CHCl3). H NMR
(400 MHz, (CD3)2CO): δ 7.37−7.33 (m, 2H), 7.30−7.242 (m, 2H),
7.09 (dd, J = 7.7, 1.6 Hz, 1H), 7.05−6.95 (m, 7H), 5.96−5.93 (m,
2H), 3.87 (s, 3H), 3.80 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
159.5, 159.2, 153.2, 136.7, 130.0, 129.9 129.5, 129.3, 126.1, 124.5,
123.2, 123.06, 121.7, 119.3, 116.9, 116.6, 115.4, 113.8, 85.9, 85.6, 65.1,
55.36, 55.31. FTIR (NaCl, thin film): 2928, 2832, 2228, 2221, 1604,
1-(Oct-1-yn-1-yl)isochroman (7ab). In a N2-atmosphere glovebox,
ZnBr2 (9.0 mg, 0.04 mmol, 10 mol %) was weighed into a 1 dram vial.
1-Octyne (6b, 57.3 mg, 0.52 mmol, 1.3 equiv) and Et2O (1.0 mL, 0.4
M) were added. Then triethyl amine (72.5 μL, 0.52 mmol, 1.3 equiv)
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and isochroman acetal 2a (65.7 mg, 0.4 mmol, 1.0 equiv) were added.
The vial was sealed and removed from the glovebox. After 10 min,
TMSOTf (87.5 μL, 0.48 mmol, 1.2 equiv) was added via syringe, and
the reaction mixture was stirred for 12 h at rt. The reaction mixture
was quenched MeOH (1.0 mL), diluted with Et2O (5.0 mL), and
filtered through a short plug of silica gel, which was then washed with
Et2O (5.0 mL). The filtrate was concentrated and purified by silica gel
chromatography (1−2% Et2O/hexanes, Rf = 0.50) to give product 7ab
hexanes, Rf = 0.50) to give product 7ae (76.2 mg, 83%) as a colorless
oil. H NMR (400 MHz, CDCl3): δ 7.30−7.28 (m, 1H), 7.24−7.22
1
(m, 2H), 7.14−7.10 (m, 1H), 5.55 (s, 1H), 4.29−4.23 (m, 1H), 3.99−
3.94 (m, 1H), 2.89−2.91 (m, 2H), 0.20 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 134.6, 132.7, 128.8, 127.2, 126.3, 126.0, 104.1, 90.4, 67.4,
62.9, 27.9, 0.14. FTIR (NaCl, thin film): 2961, 2899, 2166, 1652, 1558,
1492, 1452, 1426, 1426, 1249, 1093 cm−1. HRMS LIFDI: [M]+
calculated for C14H18OSi, 230.1127; found, 230.1106.
1
(90.1 mg, 93%) as a colorless oil: H NMR (400 MHz, CDCl3): δ
2-(3-(Isochroman-1-yl)prop-2-yn-1-yl)isoindoline-1,3-dione (7af).
In a N2-atmosphere glovebox, ZnBr2 (9.0 mg, 0.04 mmol, 10 mol %)
was weighed into a 1 dram vial. Propargyl phthalimide (6f, 96.3 mg,
0.52 mmol, 1.3 equiv) and CH2Cl2 (1.0 mL, 0.4 M) were added. Then
triethyl amine (72.5 μL, 0.52 mmol, 1.3 equiv) and isochroman acetal
2a (65.7 mg, 0.4 mmol, 1.0 equiv) were added. The vial was sealed and
removed from the glovebox. After 10 min, TMSOTf (87.5 μL, 0.48
mmol, 1.2 equiv) was added via syringe, and the reaction mixture was
stirred at rt for 12 h. The reaction mixture was quenched MeOH (1.0
mL), diluted with Et2O (5.0 mL), and filtered through a short plug of
silica gel, which was then washed with Et2O (5.0 mL). The filtrate was
concentrated and purified by silica gel chromatography (40% Et2O/
hexanes, Rf = 0.30) to give product 7af (95.2 mg, 75%) as a white solid
7.31−7.27 (m, 1H), 7.22−7.21 (m, 2H), 7.15−7.13 (m, 1H), 5.55 (s,
1H), 4.27−4.24 (m, 1H), 3.98−3.95 (m, 1H), 2.90−2.87 (m, 2H),
2.27−2.24 (m, 2H), 1.58−1.50 (m, 2H), 1.41−1.26 (m, 6H), 0.91−
0.88 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 135.6, 132.6, 128.8,
127.0, 126.2, 125.9, 86.7, 79.0, 67.2, 62.6, 31.3, 28.58, 28.53, 28.1, 22.5,
18.8, 14.06. HRMS LIFDI: [M]+ calculated for C17H22O, 242.1671;
found, 242.1694. The spectra matches with that reported in the
literature.14
1-(Cyclopentylethynyl)isochroman (7ac). In a N2-atmosphere
glovebox, ZnBr2 (9.0 mg, 0.04 mmol, 10 mol %) was weighed into
a 1 dram vial. Cyclopentylacetylene (6c, 90%, 54.4 mg, 0.52 mmol, 1.3
equiv) and Et2O (1.0 mL, 0.4 M) were added. Then triethyl amine
(72.5 μL, 0.52 mmol, 1.3 equiv) and isochroman acetal 2a (65.7 mg,
0.4 mmol, 1.0 equiv) were added. The vial was sealed and removed
from the glovebox. After 10 min, TMSOTf (87.5 μL, 0.48 mmol, 1.2
equiv) was added via syringe, and the reaction mixture was stirred at rt
for 12 h. The reaction mixture was quenched MeOH (1.0 mL), diluted
with Et2O (5.0 mL) and filtered through a short plug of silica gel,
which was then washed with Et2O (5.0 mL). The filtrate was
concentrated and purified by silica gel chromatography (3−4% Et2O/
hexanes, Rf = 0.40) to give product 7ac (72.4 mg, 80%) as a colorless
1
(mp 158−162 °C). H NMR (400 MHz, CDCl3): δ 7.90−7.88 (m,
2H), 7.76−7.74 (m, 2H), 7.26−7.20 (m, 3H), 7.12−7.11 (m, 1H),
5.55 (s, 1H), 4.53 (s, 2H), 4.24−4.18 (m, 1H), 3.99−3.93 (m, 1H),
2.90−2.79 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 167.0, 134.3,
134.1, 132.7, 132.03, 128.9, 127.2, 126.3, 126.0, 123.5, 82.1, 79.2, 66.6,
62.4, 27.8, 27.3. FTIR (NaCl, thin film): 2927, 2240, 1771, 1719, 1611,
1491, 1467, 1426, 1452, 1391, 1344, 1190, 1116 cm−1. HRMS: LIFDI
[M]+ calculated for C20H15NO3, 317.1052; found, 317.1064.
6-Methyl-2-(oct-1-yn-1-yl)-2H-chromene (8bb). In a N2-atmos-
phere glovebox, ZnBr2 (6.4 mg, 0.028 mmol, 10 mol %) was weighed
into a 1 dram vial. 1-Octyne (6b, 34.4 mg, 0.312 mmol, 1.1 equiv) and
toluene (916 μL, 0.31 M) were added. Then triethyl amine (50.0 μL,
0.355 mmol, 1.25 equiv) and chromene acetal 5b (50.0 mg, 0.284
mmol, 1.0 equiv) were added. The vial was sealed and removed from
the glovebox. After 10 min, TMSOTf (56.9 μL, 0.312 mmol, 1.1
equiv) was added via syringe, and the reaction mixture was stirred at rt
for 12 h. The reaction mixture was quenched MeOH (1.0 mL), diluted
with Et2O (5.0 mL), and filtered through a short plug of silica gel,
which was then washed with Et2O (5.0 mL). The filtrate was
concentrated and purified by silica gel chromatography (1−2% Et2O/
1
oil. H NMR (400 MHz, CDCl3): δ 7.31−7.28 (m, 1H), 7.23−7.20
(m, 2H), 7.13−7.11 (m, 1H), 5.55 (s, 1H), 4.28−4.22 (m, 1H), 3.97−
3.92 (m, 1H), 2.91−2.86 (m, 2H), 2.70−2.66 (m, 1H), 1.95−1.91 (m,
2H), 1.73−1.55 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 136.3,
133.2, 129.3, 127.5, 126.7, 126.5, 91.3, 79.04, 67.9, 63.3, 34.3, 30.7,
28.6, 25.5. FTIR (NaCl, thin film): 2959, 2868, 2160, 1729, 1491,
1451, 1289, 1085 cm−1. HRMS LIFDI: [M]+ calculated for C16H18O,
226.1358; found, 226.1332.
1-(Cyclopropylethynyl)isochroman (7ad). In a N2-atmosphere
glovebox, ZnBr2 (9.0 mg, 0.04 mmol, 10 mol %) was weighed into
a 1 dram vial. Cyclopropylacetylene (6d, 34.4 mg, 0.52 mmol, 1.3
equiv) and Et2O (1.0 mL, 0.4 M) were added. Then triethyl amine
(72.5 μL, 0.52 mmol, 1.3 equiv) and isochroman acetal 2a (65.7 mg,
0.4 mmol, 1.0 equiv) were added. The vial was sealed and removed
from the glovebox. After 10 min, TMSOTf (87.5 μL, 0.48 mmol, 1.2
equiv) was added via syringe, and the reaction mixture was stirred at rt
for 12 h. The reaction mixture was quenched MeOH (1.0 mL), diluted
with Et2O (5.0 mL), and filtered through a short plug of silica gel,
which was then washed with Et2O (5.0 mL). The filtrate was
concentrated and purified by silica gel chromatography (1−2% Et2O/
hexanes, Rf = 0.4) to give product 7ad (68.2 mg, 86%) as a colorless
1
hexanes, Rf = 0.40) to give 8bb (46.9 mg, 65%) as a colorless oil: H
NMR (400 MHz, CDCl3): δ 6.96 (dd, J = 8.12, 1.8 Hz, 1H), 6.85−
6.84 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.43 (dd, J = 9.6, 1.1 Hz, 1H),
5.76 (dd, J = 9.6, 3.8 Hz, 1H), 5.54−5.52 (m, 1H), 2.28 (s, 3H), 2.23−
2.19 (m, 2H), 1.51−1.46 (m, 2H) 1.38−1.23 (m, 6H), 0.89 (t, J = 6.9,
3H). 13C NMR (101 MHz, (CD3)2CO): δ 150.3, 130.6, 129.5, 127.1,
123.7, 123.3, 121.6, 115.9, 85.9, 77.7, 64.3, 31.1, 28.2, 28.1, 22.3, 19.6,
18.1, 13.4. FTIR (NaCl, thin film): 3077, 2990, 2812, 2338, 2311,
2281, 1900, 1719, 1623, 1547, 1271, 1088 cm−1. HRMS (EI+): [M]+
calculated for C18H22O, 254.1671; found, 254.1686.
1
oil. H NMR (400 MHz, CDCl3): δ 7.29−7.27 (m, 1H), 7.22−7.20
2-(Cyclopentylethynyl)-6-methyl-2H-chromene (8bc). In a N2-
atmosphere glovebox, ZnBr2 (3.2 mg, 0.014 mmol, 10 mol %) was
weighed into a 1 dram vial. Cyclopentylacetylene (6c, 90%, 18.5 μL,
0.142 mmol, 1.0 equiv) and toluene (460 μL, 0.31 M) were added.
Then triethyl amine (24.8 μL, 0.177 mmol, 1.25 equiv) and chromene
acetal 5b (25.0 mg, 0.142 mmol, 1.0 equiv) were added. The vial was
sealed and removed from the glovebox. After 10 min, TMSOTf (28.5
μL, 0.156 mmol, 1.1 equiv) was added via syringe, and the reaction
mixture was stirred for 12 h at rt. The reaction mixture was quenched
MeOH (1.0 mL), diluted with Et2O (5.0 mL), and filtered through a
short plug of silica gel, which was then washed with Et2O (5.0 mL).
The filtrate was concentrated and purified by silica gel chromatography
(1−2% Et2O/hexanes, Rf = 0.40) to give 8bc (31.4 mg, 93%) as a
(m, 2H), 7.13−7.10 (m, 1H), 5.51 (s, 1H), 4.27−4.21 (m, 1H), 3.97−
3.92 (m, 1H), 2.88 (t, J = 5.7 Hz, 2H), 1.32−1.27 (m, 1H), 0.81−0.73
(m, 4H). 13C NMR (101 MHz, CDCl3): δ 135.4, 132.6, 128.8, 127.1,
126.2, 125.9, 89.6, 74.2, 67.2, 62.6, 28.05, 8.3, 8.2. HRMS LIFDI: [M]+
calculated for C14H14O, 198.1044; found, 198.1045. The spectra
matches with that reported in the literature.14
(Isochroman-1-ylethynyl)trimethylsilane (7ae). In a N2-atmos-
phere glovebox, ZnBr2 (9.0 mg, 0.04 mmol, 10 mol %) was weighed
into a 1 dram vial. Trimethylsilylacetylene (6e, 51.1 mg, 0.52 mmol,
1.3 equiv) and Et2O (1.0 mL, 0.4 M) were added. Then triethyl amine
(72.5 μL, 0.52 mmol, 1.3 equiv) and isochroman acetal 2a (65.7 mg,
0.4 mmol, 1.0 equiv) were added. The vial was sealed and removed
from the glovebox. After 10 min, TMSOTf (87.5 μL, 0.48 mmol, 1.2
equiv) was added via syringe, and the reaction mixture was stirred for
12 h at rt. The reaction mixture was quenched MeOH (1.0 mL),
diluted with Et2O (5.0 mL), and filtered through a short plug of silica
gel, which was then washed with Et2O (5.0 mL). The filtrate was
concentrated and purified by silica gel chromatography (1% Et2O/
1
colorless oil. H NMR (400 MHz, CDCl3): δ 6.96 (dd, J = 8.12, 1.8
Hz, 1H), 6.84−6.83 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.42 (dd, J =
9.6, 1.5 Hz, 1H), 5.74 (dd, J = 9.6, 3.7 Hz, 1H), 5.56−5.54 (m, 1H),
2.68−2.60 (m, 1H), 2.27 (s, 3H), 1.95−1.88 (m, 2H), 1.75−1.66 (m,
2H) 1.65−1.47 (m, 4H). 13C NMR (101 MHz, (CD3)2CO): δ 150.4,
130.5, 129.5, 127.1, 123.7, 123.4, 121.5, 115.9, 90.0, 77.2, 64.4, 33.42,
L
DOI: 10.1021/acs.joc.5b00364
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
33.41, 24.5, 19.6. FTIR (NaCl, thin film): 3077, 2958, 2868, 2311,
2222, 1652, 1558, 1489, 1209, 1125, 1024 cm−1. HRMS (EI+): [M]+
calculated for C17H18O, 238.1358; found, 238.1381.
A.; Leblanc, G.; Martel, C.; Simard, J.; Merand, Y.; Belanger, A.;
Labrie, C.; Labrie, F. J. Med. Chem. 1997, 40, 2117.
(2) For routes towards racemic α-substituted benzopyrans, see:
(a) Correia, C. A.; Li, C.-J. Heterocycles 2010, 82, 555. (b) Zhang, Y.;
Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242. (c) Hayashi, M.; Inubushi,
A.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1988, 61, 4037. (d) Mitchell,
T. A.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 18057. (e) Vieira, A. S.;
Fiorante, P. F.; Hough, T. L. S.; Ferreira, F. P.; Ludtke, D. S.; Stefani,
H. A. Org. Lett. 2008, 10, 5215. (f) Vo, C.-V. T.; Mitchell, T. A.; Bode,
J. W. J. Am. Chem. Soc. 2011, 133, 14082. (g) Chen, W.; Xie, Z.;
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7586.
Trimethyl((6-methyl-2H-chromen-2-yl)ethynyl)silane (8be). In a
N2-atmosphere glovebox, CuI (5.4 mg, 0.028 mmol, 10 mol %) was
weighed into a 1 dram vial. Trimethylsilylacetylene (6e, 40.0 μL, 0.283
mmol, 1.0 equiv) and toluene (912 μL, 0.31 M) were added. Then
triethyl amine (50.0 μL, 0.354 mmol, 1.25 equiv) and chromene acetal
5b (50.0 mg, 0.283 mmol, 1.0 equiv) were added. The vial was sealed
and removed from the glovebox. After 10 min, TMSOTf (56.8 μL,
0.312 mmol, 1.1 equiv) was added via syringe, and the reaction
mixture was stirred at rt for 12 h. The reaction mixture was quenched
MeOH (1.0 mL), diluted with Et2O (5.0 mL) and filtered through a
short plug of silica gel, which was then washed with Et2O (5.0 mL).
The filtrate was concentrated and purified by silica gel chromatography
(1% Et2O/hexanes, Rf = 0.5) to give 8be (58.5 mg, 85%) as a white
(3) For enantioselective additions to acyclic oxocarbenium ions (or
acetals), see: (a) Evans, D.; Thomson, R. J. Am. Chem. Soc. 2005, 127,
1
10506. (b) Coric,
́
I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132,
I.; List, B. Nature 2012, 483, 315. (d) Coric, I.;
solid (mp 72−75 °C). H NMR (400 MHz, CDCl3): δ 6.96 (dd, J =
8536. (c) Coric,
́
́
8.12, 1.9 Hz, 1H), 6.84−6.83 (m, 2H), 6.79 (d, J = 8.1 Hz, 1H), 5.74
(dd, J = 9.6, 1.6 Hz, 1H), 5.57−5.55 (m, 1H), 2.28 (s, 3H), 0.18 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 150.2, 131.0, 129.9, 127.2,
124.7, 122.2, 121.1, 116.1, 102.1, 90.8, 65.1, 20.5, −0.21. FTIR (NaCl,
thin film): 2966, 2896, 2167, 1684, 1652, 1489, 1250, 1206, 1026
cm−1. HRMS (EI+): [M]+ calculated for C15H18OSi, 242.1127; found,
242.1148.
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(8) (a) Terada, M.; Li, F.; Toda, Y. Angew. Chem., Int. Ed. 2014, 53,
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ASSOCIATED CONTENT
* Supporting Information
NMR and HPLC spectra of new compounds and X-ray crystal
structures of 8ea, 8eo, and [(S,S)-BnBox]CuI. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: mpwatson@udel.edu.
Present Address
■
†(P.M.) Senior Research Investigator, Biocon Bristol Mayer
Squibb Research Center (BBRC), Biocon Limited, Bommasan-
dra-Jgani Link Rd., Bangalore-560100, India. E-mail: prantik.
maity@syngeneintl.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgement is gratefully made to the National Science
Foundation (CAREER CHE 1151364) and the University of
Delaware Research Fund for support of this research. NMR and
other data were acquired at UD on instruments obtained with
the assistance of NSF and NIH funding (NSF CHE 0421224,
CHE 1229234, and CHE 0840401; NIH P20 GM103541 and
S10 RR02682).
(9) Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew. Chem., Int. Ed.
2010, 49, 7096.
(10) (a) Hsiao, C.-C.; Liao, H.-H.; Sugiono, E.; Atodiresei, I.;
Rueping, M. Chem.Eur. J. 2013, 19, 9775. (b) Rueping, M.; Volla, C.
M. R.; Atodiresei, I. Org. Lett. 2012, 14, 4642. (c) Meng, Z.; Sun, S.;
Yuan, H.; Lou, H.; Liu, L. Angew. Chem., Int. Ed. 2014, 53, 543.
(d) Benfatti, F.; Benedetto, E.; Cozzi, P. G. Chem.Asian J. 2010, 5,
2047.
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