A hetero Diels-Alder approach to the synthesis of chromans (3,4-dihydrobenzopyrans) using oxonium ion chemistry: The oxa-Povarov reaction

Article abstract of DOI:10.1021/jo302328s

An oxa analogue of the well-known Povarov reaction has been developed for the synthesis of 3,4-dihydrobenzopyrans (chromans). The reaction involves the formal inverse electron demand [4 + 2] cycloaddition reaction of in situ-generated cationic aryl 2-oxadiene oxocarbenium ions with alkenes. The oxonium ion intermediates are generated through Lewis acid (SnCl ₄)-promoted reactions of phenol-derived Rychnovsky-type mixed acetals. The yield and diastereoselectivity of the chroman products are found to depend upon the substitution pattern of the precursor alkene (i.e., monosubstituted, trans- or cis-disubstituted and cyclic alkenes). Generally, the reactions afford the endo-diastereomers as the major products, except for the reactions of trans-β-methylstyrene, which afford exo-chromans. A comparison of the product distributions from the reactions of trans- and cis-β-methylstyrene reveal that the reaction proceeds, at least in part, by a nonconcerted ionic pathway. Just as for the aza-Povarov reaction, there are two potential mechanisms for the reaction. The first mechanism involves a direct asynchronous [4 + 2] cycloaddition pathway, while the second occurs through the stepwise Prins addition of the alkene to the aryl 2-oxadiene oxonium ion, followed by an intramolecular aromatic substitution reaction of the resultant cation (i.e., a domino Prins/intramolecular Friedel-Crafts reaction).

Full text of DOI:10.1021/jo302328s

Article
pubs.acs.org/joc
A Hetero Diels−Alder Approach to the Synthesis of Chromans
(3,4-Dihydrobenzopyrans) Using Oxonium Ion Chemistry:
The Oxa-Povarov Reaction
Rivka R. R. Taylor and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada,
M5S 3H6
S
* Supporting Information
ABSTRACT: An oxa analogue of the well-known Povarov reaction has been developed for the synthesis of 3,4-
dihydrobenzopyrans (chromans). The reaction involves the formal inverse electron demand [4 + 2] cycloaddition reaction of
in situ-generated cationic aryl 2-oxadiene oxocarbenium ions with alkenes. The oxonium ion intermediates are generated through
Lewis acid (SnCl4)-promoted reactions of phenol-derived Rychnovsky-type mixed acetals. The yield and diastereoselectivity of
the chroman products are found to depend upon the substitution pattern of the precursor alkene (i.e., monosubstituted, trans- or
cis-disubstituted and cyclic alkenes). Generally, the reactions afford the endo-diastereomers as the major products, except for the
reactions of trans-β-methylstyrene, which afford exo-chromans. A comparison of the product distributions from the reactions of
trans- and cis-β-methylstyrene reveal that the reaction proceeds, at least in part, by a nonconcerted ionic pathway. Just as for the
aza-Povarov reaction, there are two potential mechanisms for the reaction. The first mechanism involves a direct asynchronous
[4 + 2] cycloaddition pathway, while the second occurs through the stepwise Prins addition of the alkene to the aryl 2-oxadiene
oxonium ion, followed by an intramolecular aromatic substitution reaction of the resultant cation (i.e., a domino Prins/
intramolecular Friedel−Crafts reaction).
include multicomponent,4 organocatalytic,5 and solid-supported
INTRODUCTION
■
reactions.6 The tetrahydroquinoline products can be oxidized to
Hetero Diels−Alder reactions and their formal equivalents pro-
vide a powerful means for the rapid construction of hetero-
give quinolones,7 and the reaction has been used both for the
production of diverse chemical libraries8 as well as in the
cyclic scaffolds. Oxa- and aza-hetero Diels−Alder variants have
been developed in which the dienophile and/or dienes can
incorporate the heterocomponents.1 One such aza-variant is the
Povarov reaction,2,3 originally developed 50 years ago, in which
N-arylimines (2-azadienes) 1 react with electron-rich alkenes in a
formal inverse electron demand [4 + 2] cycloaddition via 2 to
furnish tetrahydroquinolines 3 (Scheme 1). Modern variants
synthesis of a number of natural products.9
The key reaction intermediate in Povarov reactions are either
protonated or Lewis acid-coordinated N-arylimines 2 or N-
aryliminium ions. The cationic nature of these species increases
their electrophilicity and reactivity as electron-deficient dienes.
Given the considerable utility of the Povarov reaction, we were
interested to establish whether an O-aryl oxonium species 5,
which is equivalent to a cationic 2-oxadiene intermediate, would
undergo an analogous reaction to give 3,4-dihydrobenzopyrans
(chromans) 6 (Scheme 2). Despite the extensive research on 2-
azadienes,10 and the importance of oxonium ions as
intermediates in numerous reactions, the chemistry of O-aryl
oxonium species 5, or their corresponding precursors 4,11
including their cycloaddition chemistry remains virtually unex-
plored.12,13 Such oxonium ion species would be expected to be
more reactive than the corresponding iminium ions and capable
of undergoing either direct hetero Diels−Alder reaction or the
Scheme 1. The Povarov Reaction
Received: October 21, 2012
Published: December 11, 2012
© 2012 American Chemical Society
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Scheme 2. Chroman Formation via the Oxa-Povarov (domino
Prins/Friedel−Crafts) Reaction
Figure 1. Tetrahedral intermediates formed using the Rychnovsky
protocol.
knowledge there are no reported examples of reductive
acetylation of phenyl or aryl esters using the Rychnovsky
protocol.
To circumvent this problem, the formation of a more stable
tetrahedral intermediate is necessary. Accordingly the introduc-
tion of an appropriately positioned heteroatom should
sufficiently stabilize such an intermediate by chelation. The use
of a picolinate ester was therefore considered, because it would
lead to a tetrahedral intermediate 8c stabilized by the pyridyl
nitrogen in a five-membered ring chelate. The requisite aryl
picolinate precursors 9 were synthesized in good yields by
reaction of picolinic acid with oxalyl chloride/DMF, followed
by treatment of the resultant acid chloride with phenol and
triethylamine (Table 1). Reaction of phenyl picolinate 9a
equivalent stepwise Prins addition/intramolecular electrophilic
aromatic substitution reaction to give 6.
The chroman skeleton appears in a number of natural
products, including the tocopherols14 and flavans.15 They display
a diverse array of biological activities, including antioxidant,16
antiestrogen,17 antiviral,18 antihypertensive,19 and anticancer20
activity. Common approaches to the chroman skeleton21 include
hetero Diels−Alder reactions of o-quinone methides (1-oxadienes),22
additions of o-hydroxy acetophenones,23 and intramolecular
nucleophilic substitution of phenols.24 Alternative approaches
to the chroman skeleton are of considerable interest for the
formation of substituted chromans. Herein we describe the
development of the oxa-Povarov reaction and its application
to the diastereoselective synthesis of 2,3,4-substituted
chromans.25
Table 1. Synthesis of Aryl Picolinates 9
entry
R
product
yield (%)
RESULTS AND DISCUSSION
1
H
9a
9b
9c
9d
9e
9f
86
80
82
76
78
63
76
80
64
79
60
65
75
35
■
Establishing conditions suitable for the formation of the O-aryl
oxonium species 5 is perhaps the major challenge associated with
the development of an oxa-Povarov reaction. In general,
formation of 5 could be achieved by the selective ionization of
ArOCHXR 4 using a Lewis acid. Selective ionization of the X−
group from 4 rather than the ArO− group would be required
under these conditions. Synthetic approaches to suitably
substituted 4 are rather limited, but one approach investigated
was the use of Rychnovsky’s protocol for mixed acetal
synthesis.26 The Rychnovsky-type mixed acetals have found
widespread application as oxonium ion precursors. According to
the literature procedure, treatment of phenyl benzoate with
DIBAL at −78 °C, followed by quenching with acetic anhydride,
DMAP, and pyridine, afforded only phenyl acetate and benzyl
alcohol and none of the desired mixed acetal 7 (eq 1). Attempts
2
o-Me
3
m-Me
4
p-Me
5
o-Cl
6
m-Cl
7
p-Cl
9g
9h
9i
8
o-OMe
m-OMe
p-OMe
3,5-di-OMe
3,5-di-Me
m-NO2
3,5-di-Cl
9
10
11
12
13
14
9j
9k
9l
9m
9n
according to the standard reductive acetylation conditions
afforded the desired mixed acetal 10a in 58% yield (Table 2,
entry 1). A similar approach was utilized to synthesize other
mixed acetals 10 (Table 2). The success of this procedure was
sensitive to the pKa of the phenolic component of the ester 9.
Higher yields were obtained for the more electron-rich esters
such as 9b and 9j (phenol pKa of 10.22 and 10.21, respectively),
whereas a significant decline in yield was observed for electron-
deficient esters, 9f and 9g (phenol pKa of 9.08 and 9.38,
respectively). Esters derived from phenols with a pKa less than
8.50 (e.g., 9e, 9k, 9m, and 9n) afforded none of the desired mixed
acetal.
Optimization studies on the reaction of 10a with norbornene
as a dienophile revealed that only stoichiometric amounts of
either SnCl4 or TiCl4 would promote the reaction, although
better diastereoselectivity was obtained with SnCl4. Stoichio-
metric quantities of Yb(OTf)3, In(OTf)3, InCl3, or BF3·OEt2
to modify the reaction conditions with other hydride reducing
agents were unsuccessful. The failure of this reaction must result
from facile collapse of the tetrahedral alumino intermediate 8a
under the DIBAL conditions, leading to over-reduced products
(Figure 1). The more facile collapse of 8a is presumably due to
faster loss of phenoxide ion from 8a (pKa of phenol is 9.95)
relative to that of alkoxide loss (pKa of aliphatic alcohols are
approximately 15.5−17) from the standard Rychnovsky-type
tetrahedral intermediate 8b.27 Indeed, to the best of our
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substituent adopts a pseudoequatorial orientation.30 The identity
of the major exo-endo diastereomer 11a was confirmed by H
Table 2. Reductive Acetylation of Aryl Picolinates 9
1
NMR and X-ray crystallographic analysis.31 (see Supporting
Information). The H2−H3 and H3−H4 coupling constants
were observed to be 3.5 and 9.0 Hz, respectively, which are
consistent with a pseudoaxial orientation of H2 and a pseudoe-
quatorial orientation of H3. The X-ray crystal structure indicates
that the chroman ring adopts a distorted half-chair conformation,
with a syn relationship between the C2, C3, and C4 substituents.
The H2/H3 and H3/H4 dihedral angles of 52.5° and 8.2°,
respectively, correlate well with the coupling constants observed
by 1H NMR.
The major diastereomers of the chromans derived from the
acyclic styrenes (11b−d) showed H2−H3 and H3−H4 vicinal
coupling constants that are also consistent with the endo
stereoisomers. As a representative example, the styrene adduct
11b-endo shows a doublet of doublet at 5.33 ppm with coupling
constants of 11.5 and 2.0 Hz, corresponding to H2, and a peak at
4.40 ppm with coupling constants of 12.0 and 5.5 Hz,
corresponding to H4. The coupling constants for both sets of
peaks are characteristic of an axial−axial and axial−equatorial
relationship for both the H2−H3/H2−H3′ and H4−H3/H4−
H3′ pairs. This is consistent with a half chairlike conformation of
the chroman ring and a syn relationship of the H2 and H4
protons of 11b-endo, such that both the pyridyl and phenyl
substituents adopt pseudoequatorial orientations. The stereo-
chemistry for 11b-endo was also verified by X-ray crystallographic
analysis. The observed dihedral angles of 63.8° and 177.5° for
H2−C2−C3−H3/H3′ and 58.3° and 177.0° for H4−C4−C3−
H3/H3′ are also consistent with the observed vicinal coupling
constants.32 In general, the most diagnostic peak to identify the
exo-diastereoisomers was that for H4 which appears as an
apparent triplet (with, for example, a coupling constant of J =
5.0 Hz for 11b-exo).33,34
To examine stereoelectronic effects, ortho- and para-sub-
stituted acetyl esters 10 were allowed to react with both styrene
(Table 4) and norbornene (Table 5) under the optimized
conditions. Reaction of styrene as the dienophile with methyl-,
methoxy-, and chloro-substituted compounds 10 occurred to
give the chromans 12 as the major endo-isomers with moderate
to good diastereomeric ratios (2.0−7.6:1) (Table 4). For
reaction of the para-substituted compounds, the diastereomeric
ratio showed a modest decrease with increasing electron-
donating ability of the substituent (Cl > Me > MeO). Products
from the reaction of the ortho-substituted compounds showed
slightly increased selectivity relative to their para-substituted
counterparts. The observed preference for the formation of the
12-endo products parallels the results generally obtained for the
preferential formation of endo-tetrahydroquinolines in the aza-
Povarov reaction, although reactions of styrenes are known to
occur with both endo and exo selectivity.3
In general, the cycloaddition reactions of norbornene were
more effective than those for styrene (Table 5). The reactions of
ortho- and para-methyl, -methoxy, and -chloro-substituted
compounds 10 occurred to give the chromans 13. As for the
reactions with styrene the endo-products (i.e., 13-exo-endo) were
obtained as the major isomers with good to excellent diastereo-
meric ratios (10−30:1) (Table 5). The observed preference for
the formation of the 13-exo-endo products contrasts with the
results for comparable standard aza-Povarov reactions.35 In these
cases, the product tetrahydroquinolines were obtained with high
exo-exo selectivity, and the selectivity was attributed to reaction
occurring via a concerted [4 + 2] mechanism.36
entry
R
product
yield (%)
phenol pKa
1
H
10a
10b
10c
10d
10e
10f
58
67
62
66
0
9.97
10.22
10.10
10.19
8.48
2
o-Me
3
m-Me
4
p-Me
5
o-Cl
6
m-Cl
13
44
55
47
71
0
9.08
7
p-Cl
10g
10h
10i
9.38
8
o-OMe
m-OMe
p-OMe
3,5-di-OMe
3,5-di-Me
m-NO2
3,5-di-Cl
9.98
9
9.65
10
11
12
13
14
10j
10.21
9.35
10k
10l
63
0
10.19
8.35
10m
10n
0
8.19
afforded only recovered starting material. Furthermore, the
reaction required at least 1.2 equiv of SnCl4 to proceed, and the
best results were obtained with 2.0 equiv. This likely arises from
preferential complexation with the pyridine nitrogen over the
acetate carbonyl group.28 The reaction was further optimized,
and the best conditions were determined to be the use of 2.0
equiv of SnCl4 in dichloromethane at −15 °C for 24 h.
Reaction of the acetal 10 with a variety of electron-rich alkenes
using the optimized conditions of SnCl4 (2.0 equiv) and
dienophile (1.2−4.0 equiv) in dichloromethane at −15 °C for
24 h afforded cycloadducts in moderate to good yields (Table 3).
Reaction of 10a with norbornene led to the formation of
chroman 11a in high yield and diastereoselectivity, favoring the
exo-endo29 diastereomer (Table 3, entry 1). Reactions of styrenes
led to the formation of chromans 11b−d with approximately 5:1
diastereomeric ratios favoring the cis-2,4-endo diastereoisomers
(Table 3, entries 2−4). The reaction was intolerant of very
electron-rich alkenes such as ethyl vinyl ether, endocyclic ene-
carbamates, cyclopentadiene, or dihydrofuran, species that can
be used in the Povarov reaction. In these cases, the strong Lewis
acidic conditions resulted in competitive polymerization of the
alkenes. Less reactive cyclic alkenes such as cyclopentene and
cyclohexene are only rarely encountered in the Povarov reaction
but interestingly were capable of participating in the oxa-Povarov
reaction, to give chromans 11e and 11f, respectively, albeit in
lower yields than were obtained for the adducts of norbornene or
styrene (Table 3, entries 5 and 6). Again the reactions were found
to be diastereoselective favoring the endo-diastereoisomers. The
more reactive substrates 1,3-cyclohexadiene and indene also
underwent addition to give adducts 11g and 11h, respectively, in
modest yields (Table 3, entries 7 and 8).
The stereochemistry of each adduct was determined by
analysis of the H NMR spectra of the products. The major
1
diastereomers of the products derived from cyclic alkenes (11a
and 11e−h) could be identified on the basis of the peaks
corresponding to the H2 protons. For example, the isolated
norbornene adduct 11a-exo-endo shows a doublet at 4.93 ppm for
H2 with a coupling constant of 3.5 Hz, which is indicative of an
axial−equatorial-like coupling. This is consistent with the syn
relationship in the exo-endo diastereomer where the phenyl
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Table 3. Reaction of 10a with Various Alkenes
a
b
1
Only the major (endo) product is shown. 11-endo:11-exo ratio determined by analysis of the H NMR spectrum of the crude reaction mixture.
c
d
e
4.0 equiv of dienophile used. Only the major (exo-endo) product is shown. Reaction conducted at 0 °C for 24 h.
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Table 4. Reaction of Styrene with Substituted Aryl Acetals 10
a
entry
precursor
R
product
yield (%)
dr
1
2
3
4
5
6
10a
10b
10d
10g
10h
10j
H
11b
12b
12d
12g
12h
12j
64
66
59
28
45
58
4.8:1
4.9:1
4.0:1
7.6:1
6.0:1
2.0:1
o-Me
p-Me
p-Cl
o-OMe
p-OMe
a
1
12-endo:12-exo ratio determined by analysis of the H NMR spectrum of the crude reaction mixture.
Table 5. Reaction of Norbornene with Substituted Acetals 10
a
entry
precrusor
R
product
isolated yield, %
dr
1
2
3
4
5
6
10a
10b
10d
10g
10h
10j
H
11a
13b
13d
13g
13h
13j
80
82
79
58
68
65
20:1
11:1
20:1
18:1
30:1
10:1
o-Me
p-Me
p-Cl
o-OMe
p-OMe
a
1
13-exo-endo:13-exo-exo ratio determined by analysis of the H NMR spectrum of the crude reaction mixture.
Table 6. Reaction of Norbornene with Meta-Substituted Acetals 10
a
ab
,
entry
R1
R2
product
isolated yield, %
ratio (13-A:13-B)
dr
1
2
3
4
Me
Cl
H
13c
13f
13i
13l
81
55
57
1.7:1
2.2:1
2.1:1
−
20:1
H
15:1
OMe
Me
H
15:1
Me
66
b
≥40:1
a
1
Determined by analysis of the H NMR spectrum of the crude reaction mixture. 13-exo-endo:13-exo-exo determined for 13-A.
For the reactions of meta-substituted substrates 10, issues of
in relation to the corresponding Diels−Alder reaction. More
recent studies have demonstrated that a stepwise manifold is
often operative,3,38 with a Mannich-type addition of the alkene to
the activated imine, followed by cyclization via intramolecular
Friedel−Crafts reaction. In some instances, however, exper-
imental results are better rationalized with a concerted
mechanism.3,39 An analogous mechanistic dichotomy is also
possible for the oxa-Povarov reaction, with either stepwise or
concerted [4 + 2] cycloaddition cationic pathways leading to the
chroman products. The concerted [4 + 2] cycloaddition pathway
proceeds via 14 to give cation 15, which then loses a proton to
give chroman 6 (Figure 2). The stepwise mechanism involves
both regio- and diastereoselectivity arise. To examine these
selectivity issues, norbornene was chosen as a model dienophile
(Table 6). In all cases the products 13 were obtained favoring
isomer 13-A (with the substituent para to the norbornyl ring)
over 13-B (ortho) (1.7−2.2:1), and with high diastereomeric
ratios favoring the exo-endo-diastereoisomers.37
MECHANISTIC STUDIES
■
When first reported, the aza-Povarov reaction was presumed to
proceed via a concerted [4 + 2] cycloaddition mechanism, and
the possible diastereomeric products were designated endo or exo
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Figure 2. Concerted and stepwise reaction pathways for the Oxa-Povarov reaction.
Table 7. Reactions of cis- and trans-β-Methylstyrene with 10
a
a
entry
precursor styrene
precursor styrene
R
product
yield (%)
dr (endo:exo)
dr (endo-trans:exo-trans:endo-cis:exo-cis)
1
2
3
4
5
6
10a
10d
10j
trans
trans
trans
cis
H
18a
18d
18j
29
46
63
28
34
56
1.0:6.3
1.0:3.7
1.0:2.2
8.1:1.0
7.8:1.0
3.6:1.0
1.0:6.3:−:−
1.0:3.7:−:−
6.7:16.7:1.0:−
25:3.0:7.5:1.0
14.3:2.1:10:1.0
5.0:1.8:5.0:1.0
p-Me
p-OMe
H
10a
10d
10j
18a
18d
18j
cis
p-Me
p-OMe
cis
a
1
Determined by analysis of the H NMR spectrum of the crude reaction mixture.
initial Prins-type40 addition of the alkene to the E-configured aryl
oxocarbenium ion 541 via 16, followed by intramolecular
Friedel−Crafts alkylation of the resultant cation 17 to give 15
and finally rearomatization to give 6.42,43
The stereochemistry of the cycloadducts 18 was determined
by 1H NMR analysis, in particular through a consideration of the
H2 and H4 protons. An illustrative example is provided with
1
selected NMR data for product 18j (Table 8). The H NMR
One probe of whether a stepwise of concerted mechanism
occurs is to examine the reactions of stereochemically defined
trans- and cis-dienophiles, because the stereochemical relation-
ship of the dienophile substituents should be retained in the case
of a concerted [4 + 2] cycloaddition pathway (i.e., the reaction
should be stereospecific with respect to alkene geometry),
whereas reaction via a stepwise pathway can lead to stereo-
chemical scrambling resulting from C3−C4 bond rotation of
intermediate 17. Reaction of 10 with either cis- or trans-β-
methylstyrene under the standard conditions led to a mixture of
diastereomeric products (Table 7). For example, the reaction of
trans-β-methylstyrene and 10j afforded 18j as a mixture of the
endo-trans, exo-trans, and endo-cis isomers in an 6.7:16.7:1.0
ratio. For the reactions of cis-β-methylstyrene, all four isomeric
products were isolated in each case.
spectrum of 18j-endo-trans shows that both H2 and H4 have large
vicinal couplings to H3 (J = 10.0 and 11.0 Hz), consistent with an
axial−axial relationship between each of these protons and H3.
2D NOESY experiments show strong H2−H4 as well as methyl-
H2 and methyl-H4 NOE enhancements, indicative of a syn
relationship between H2, H4 and the methyl group. The exo-
trans and endo-cis isomers were distinguished on the basis of
observed NOE’s for H2, H4 and the methyl group. The endo-cis
isomer shows strong H2−H4, as well as H2−H3 and H3−H4
NOE enhancements, indicating a syn relationship between all
three of these protons. The absence of NOE enhancements
between either H2 or H4 and the methyl protons is also
consistent with the endo-cis stereochemistry, given the anti
relationship between both of these protons and the methyl
group. The observed vicinal coupling constants of 1.0 Hz for
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Table 8. Selected NMR Data for Diastereoisomers of 18j
a
Strong interactions are shown in blue, and weak interactions are shown in red.
JH2−H3 and 5.5 Hz for JH3−H4 are also consistent with the axial−
equatorial relationship between these pairs of protons. NOE data
for the exo-trans isomer show methyl-H4 and H2−H3 NOE
enhancements, indicating a syn relationship between these pairs,
while the absence of an H2 and H4 NOE enhancement is
consistent with an anti relationship between these protons. The
1H NMR data of the exo-cis isomer44 is consistent with a trans-
diaxial relationship between H2 and H3, and an axial−equatorial
relationship between H3 and H4.
Because the reaction is not stereospecific with respect to
alkene geometry, and scrambling of alkene geometry does not
occur in the absence of 10, the oxa-Povarov reaction must
proceed through a stepwise path (Figure 2),45 at least for those
cases where scrambling was observed (Table 7, entries 3−6).
Initial stepwise Prins-type addition of the activated alkene to the
oxonium generates carbocation intermediates A, B, and C, which
can have endo/exo and trans/cis relative stereochemistry 19
(Figure 3). Intermediates A and C are formed through a synclinal
approach of the oxonium ion to the alkene, whereas intermediate
B is formed through an anticlinal approach. Intermediates A and
B must undergo C2−C3 bond rotation to generate intermediate
C from which Friedel−Crafts cyclization to the products occur. A
concerted hetero Diels−Alder mechanism would proceed via a
synclinal orientation analogous to C. For reactions of styrene, the
favored products have endo stereochemistry (19, R = H), while
for reactions of trans-β-methylstyrene, there is a reversal of
selectivity in favor of the exo stereochemistry products (19,
R = Me). However, for the reactions of cis-β-methylstyrene
(R = Me), significant amounts of cis to trans scrambled products
are observed (the endo-trans isomers are the major products),
consistent with slow cyclization of the exo-cis intermediates
relative to C3−C4 bond rotation. There is also partial scrambling
of the endo-cis to the exo-trans intermediates. The overall
product distributions for the reactions of cis-β-methylstyrene
show that initial C2−C3 bond formation in the Prins step occurs
with only modest selectivity (i.e., the product ratio of endo-trans +
exo-cis:exo-trans + endo-cis).46
The relative C2/C3 stereochemistry should be set in the initial
addition step of the oxonium ion for the reactions of both cis and
trans-β-methylstyrene substrates, assuming that reaction occurs
via an irreversible stepwise mechanism. The stereoselectivity of
this C2−C3 bond formation can be compared to the additions of
alkenes to oxonium ions, such as occur in carbonyl ene47 and
crotylsilylation reactions.48 A combined experimental (using
TMSOTf as a Lewis acid) and computational study (at the
B3LYP/6-31+G(d) level of theory) revealed that reactions
between unbranched aliphatic aldehydes and E-crotylsilanes
occurred preferentially to give syn products, whereas Z-
crotylsilanes react preferentially to give the corresponding anti
products.48 These observations were rationalized using the
synclinal transition state model 20 and anticlinal transition state
model 21, respectively (Figure 4). The stereochemistry of TS 20
corresponds to the transition state exo-trans-A (Figure 3), and
predicts the same relative stereochemistry for both reactions (i.e.,
the syn-crotylsilylation corresponds to the C2/C3 stereocontrol
in the oxa-Povarov reaction). Similarly the analogous stereo-
chemistry of TS 21 and TS exo-cis-B results in the same relative
stereochemistry for the oxa Povarov and Z-crotylation products.
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Figure 3. Rationale for the formation of scrambled products from 10 and β-methylstyrene showing reaction intermediates involved in a stepwise
pathway.
occurs as a result of steric effects, particularly for transition states
exo-cyc-TS-A and exo-cyc-TS-B (corresponding to exo-cis-A and
B) (Figure 5). Similar destabilizing steric effects for endo-cyc-TS-A
may suggest that reactions of cyclic alkenes occur through either
the anticlinal transition state endo-cyc-TS-B or the Diels−Alder
like synclinal transition state endo-cyc-TS-C.
The Povarov reaction using protic acid catalysis49 has been
shown to operate via a stepwise mechanism, although its cationic
variant50 has been shown to be stereospecific with respect to
β-methylstyrene geometry, indicating a concerted mechanism.
Figure 4. Calculated transition state model48 for the reactions of
oxonium ions with E- and Z-crotylsilanes (M = CH3 and SiR3 = SiH3).
Related cycloaddition chemistry of α-thionium ion dienes to give
the corresponding thiochromans, however, appears to operate
by a stepwise mechanism.51 The aza-Povarov reaction has been
shown to be very sensitive to reaction conditions in terms of both
yield and selectivity. For example, a complete reversal of endo/exo
selectivity can be realized by changing from Lewis to protic acids
in the case of reactions of cyclic enamide-type dienophiles.52
For Povarov reactions using styrene as the dienophile, modest
exo selectivity is generally observed under protic acid-catalyzed
conditions;53 however, endo selectivity is often observed with
more reactive imine precursors.54 Interestingly, Povarov
reactions of trans-β-methylstyrenes occur with high levels of
endo selectivity.55 In contrast the oxa-Povarov reactions of trans-
β-methylstyrene occur with exo selectivity, while the reactions of
The higher selectivity obtained for the reactions of trans-β-
methylstyrene compared to the cis isomer are also paralleled in
the reactions of crotylsilanes. The similarity between these
reactions may suggest that transition states exo-trans-A and exo-
cis-B are relevant for the oxa-Povarov reaction.
Reactions with cyclic alkenes (i.e., also cis-configured alkenes)
such as norbornene, cyclohexene, and indene proceed with high
endo selectivity (≥10:1 for all cases studied). The C2/C3 relative
stereochemistry of the products is thus opposite to that for the
major isomers obtained from the reactions of cis-β-methylstyr-
ene. Destabilization of the exo Prins transition states presumably
Figure 5. Prins transition states for the reactions of cyclic alkenes.
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Peak multiplicities are designated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; J,
coupling constant in hertz. Mass spectra were obtained on a TOF mass
spectrometer.
styrene and cis-β-methylstyrene occur in an endo-selective fas-
hion. A similar comparison can be made for the reactions of
norbornene, for which exo-exo selectivity is observed in the aza-
Povarov reactions,35 but exo-endo selectivity in the oxa-Povarov
reaction. A key difference between the intermediates for these
reactions is the presence of the Lewis acid (bound to the imine
nitrogen) in the Povarov reaction, compared to a vacant site at
the E-configured oxocarbenium oxygen in the oxa-Povarov
reaction. While there is no definitive transition state model for
either the aza- or oxa-Povarov reactions, this difference and its
effect on the mode of approach of the dienophile with the
oxocarbenium ion relative to that obtained with an iminium ion is
presumably a major factor underlying the opposite diastereo-
selectivities obtained in the oxa-Povarov versus the standard aza-
Povarov reaction.
General Procedure for Picolinate Ester Synthesis (9). A slurry
of picolinic acid (4.0 mmol) in ether (30 mL) was cooled to 0 °C. Oxalyl
chloride (4.4 mmol) was added, followed by DMF (50 μL). The
reaction was stirred at 0 °C and warmed to room temperature over 16 h.
The solvent was then evaporated with protection from moisture, and the
resulting acid chloride was dissolved in CH2Cl2 (40 mL) and cooled to
0 °C. The appropriate phenol (4.4 mmol) was added, followed by
triethylamine (12.0 mmol). The reaction was stirred at 0 °C and warmed
to ambient temperature over 5 h. Saturated aqueous sodium bicarbonate
(10 mL) and CH2Cl2 (20 mL) were added, and the reaction was stirred
rapidly. The organic phase was collected and washed with saturated
sodium bicarbonate, water, and brine. After being dried over Na2SO4,
the reaction was concentrated under reduced pressure and purified by
silica gel column chromatography to afford the picolinate ester.
Phenyl picolinate 9a. Flash chromatography (30% ethyl acetate/
hexanes) gave 9a as a white solid (0.685 g, 86% yield). Rf = 0.23 (30%
ethyl acetate/hexanes); mp 78−79 °C (hexanes/ethyl acetate); IR (thin
film, CH2Cl2) νmax 3070, 1751, 1581, 1483, 1302, 1277, 1235, 1193,
1115, 1073, 924, 819, 749, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.86 (1H, ddd, J = 1.0, 1.5, 4.5 Hz), 8.31 (1H, ddd, J = 1.0, 1.0, 8.0 Hz),
7.93 (1H, ddd, J = 1.5, 7.5, 8.0 Hz), 7.57 (1H, ddd, J = 1.0, 4.5, 7.5 Hz),
7.45 (2H, dd, J = 8.0, 8.0 Hz), 7.26−7.33 (3H, m); 13C NMR (100 MHz,
CDCl3) δ 163.9, 151.0, 150.2, 147.6, 137.3, 129.6, 127.5, 126.2, 125.9,
121.7; MS (EI) m/z 199 (16) [M]+, 170 (4), 155 (100), 115 (4), 106
(31), 94 (8), 78 (64), 65 (17), 51 (8); HRMS (EI) calcd for [M]+
C12H9NO2 199.0633; found 199.0633.
2-Methylphenyl picolinate 9b. Flash chromatography (30% ethyl
acetate/hexanes) gave 9b as a white solid (0.681 g, 80% yield). Rf = 0.21
(30% ethyl acetate/hexanes); mp 48−49 °C (hexanes/ethyl acetate); IR
(thin film, CH2Cl2) νmax 3057, 2926, 1736, 1582, 1491, 1304, 1290,
1244, 1174, 1117, 1078, 993, 768, 746, 700 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.86 (1H, ddd, J = 0.5, 1.5, 4.5 Hz), 8.29 (1H, ddd, J = 0.5, 1.0,
8.0 Hz), 7.92 (1H, ddd, J = 1.5, 7.5, 8.0 Hz), 7.56 (1H, ddd, J = 1.0, 4.5,
7.5 Hz), 7.24−7.30 (2H, m), 7.15−7.22 (2H, m), 2.26 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 163.5, 150.2, 149.6, 147.4, 137.3, 131.3,
130.2, 127.5, 127.1, 126.4, 125.8, 121.9, 16.3; MS (EI) m/z 213 (2, M+),
184 (12), 169 (100), 156 (4), 129 (3), 106 (25), 91 (3), 78 (65), 51
(15); HRMS (EI) calcd for [M]+ C13H11NO2 213.0790; found
213.0794.
3-Methylphenyl picolinate 9c. Flash chromatography (30% ethyl
acetate/hexanes) gave 9c as a white solid (0.597 g, 70% yield). Rf = 0.18
(30% ethyl acetate/hexanes); mp 51−52 °C (hexanes/ethyl acetate); IR
(thin film, CH2Cl2) νmax 3063, 2916, 2855, 1751, 1604, 1582, 1427,
1303, 1227, 1142, 1111, 1072, 1049, 995, 918, 787, 748, 687 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.84 (1H, dd, J = 1.0, 4.5 Hz), 8.27 (1H, dd,
J = 0.5, 8.0 Hz), 7.90 (1H, ddd, J = 1.5, 7.5, 8.0 Hz), 7.54 (1H, dd, J = 4.5,
7.5 Hz), 7.31 (1H, dd, J = 7.5, 7.5 Hz), 7.02−7.11 (3H, m), 2.39 (3H, s);
13C NMR (100 MHz, CDCl3) δ 164.0, 150.9, 150.2, 147.6, 139.7, 137.2,
129.3, 127.4, 127.0, 125.8, 122.3, 118.7, 21.4; MS (EI+) m/z 213 (2, M+),
184 (4), 169 (100), 156 (2), 129 (1), 106 (37), 91 (1), 78 (72), 51 (13);
HRMS (EI) calcd for [M]+ C13H11NO2 213.0790; found 213.0792.
4-Methylphenyl picolinate 9d. Flash chromatography (30% ethyl
acetate/hexanes) gave 9d as a white solid (0.648 g, 76% yield). Rf = 0.18
(30% ethyl acetate/hexanes); mp 85−86 °C (hexanes, ethyl acetate); IR
(thin film, CH2Cl2) νmax 3055, 2955, 2916, 2862, 1751, 1574, 1505,
1304, 1281, 1234, 1188, 1165, 1111, 1072, 995, 880, 802 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.84 (1H, ddd, J = 1.0, 1.5, 4.5 Hz), 8.27 (1H, dd,
J = 1.0, 8.0 Hz), 7.90 (1H, ddd, J = 1.5, 7.5, 8.0 Hz), 7.55 (1H, ddd, J =
1.5, 4.5, 7.5 Hz), 7.23 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 2.37
(3H, s); 13C NMR (100 MHz, CDCl3) δ 164.2, 150.2, 148.8, 147.7,
137.3, 135.9, 130.2, 127.5, 125.9, 121.5, 21.0; MS (ESI+) m/z 236 (36,
[M + Na]+), 214 (100, [M + H]+), 124 (9), 106 (7), 96 (35); HRMS
(ESI+) calcd for [M + H]+ C13H12NO2 214.0862; found 214.0872.
2-Chlorophenyl picolinate 9e. Flash chromatography (30% ethyl
acetate/hexanes) gave 9e as a white solid (0.730 g, 78% yield). Rf = 0.13
(30% ethyl acetate/hexanes); mp 80−81 °C (hexanes, ethyl acetate); IR
CONCLUSIONS
■
A hetero Diels−Alder approach to 2,3,4-substituted chromans
has been developed. The reaction proceeds via a formal [4 + 2]
cycloaddition between an electron-rich alkene and an extremely
rare cationic 2-oxadiene intermediate. Aryl picolinate mixed
acetals serve as precursors to these intermediates, such that
chromans are formed on reaction with 2 equiv of SnCl4 and
electron-rich alkenes. Norbornene and styrene afforded
moderate to good yields of chromans, whereas lower yields
were obtained with other carbocyclic alkenes such as cyclohexene
and cyclohexadiene. Endo-selective reactions occurred from the
reactions of norbornene (≥10:1) and styrene (approximately 5:1 dr).
Reactions of trans-β-methylstyrene occurred with exo selectivity,
whereas the reactions of cis-β-methylstyrene occurred with endo
selectivity. The reactions of cis-β-methylstyrene were also found
to be nonstereospecific with respect to the styrene geometry,
indicating that a sequential Prins/Friedel−Crafts-type mecha-
nism occurs for the reactions of this substrate. The relative endo/
exo stereochemistry observed in the oxa-Povarov reactions was
generally found to be opposite to that observed for the com-
parable standard Povarov reactions.
Through the course of this study, the first example of a
reductive acetylation procedure for the synthesis of phenol-sub-
stituted mixed acetals was also developed. The use of picolinate
esters was essential to achieve selective DIBAL reduction.
Further studies will be required to expand the scope of oxonium
precursors and alkenes amenable to the reaction, as well as to
provide additional mechanistic data to rationalize the observed
selectivity differences for chroman formation.
EXPERIMENTAL SECTION
■
General Procedure. All reactions were performed under nitrogen
or argon in flame-dried glassware. Ether was freshly distilled from
sodium/benzophenone ketyl under nitrogen. Dichloromethane was
freshly distilled from calcium hydride under nitrogen. All other solvents
were obtained as ACS grade or better from commercial suppliers and
used as received. All reagents were used as received from commercial
suppliers. Flash chromatography on silica gel (60 Å, 230−400 mesh)
was performed with reagent grade solvents. Analytical thin-layer
chromatography (TLC) was performed on precoated silica gel plates,
visualized with a UV254 lamp, and stained with vanillin. Solvent ratios for
chromatography and Rf values are reported as v/v ratios. Melting points
are uncorrected and obtained on compounds purified through flash
chromatography with further recrystallization. 1H and 13C NMR spectra
were obtained as solutions in deuterated solvents. Chemical shifts are
reported in δ ppm values. Proton chemical shifts were internally referenced
to tetramethylsilane (δ 0.00 ppm). Carbon chemical shifts were inter-
nally referenced to the solvent resonances in CDCl3 (δ 77.00 ppm).
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(thin film, CH2Cl2) νmax 3061, 3030, 3009, 1736, 1586, 1574, 1474, 1449,
1303, 1284, 1240, 1205, 1097, 1058, 1030, 995, 945, 882, 747 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.87 (1H, ddd, J = 1.0, 2.0, 4.5 Hz), 8.32
(1H, d, J = 8.0 Hz), 7.93 (1H, dd, J = 8.0, 8.5 Hz), 7.57 (1H, ddd, J = 1.0,
4.5, 8.5 Hz), 7.50 (1H, d, J = 1.5 Hz), 7.30−7.36 (2H, m), 6.97 (1H, dd,
J = 7.0, 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 162.9, 150.4, 147.3,
147.0, 137.4, 130.5, 128.0, 127.7, 127.5, 126.2, 123.8; MS (ESI+) m/z
234 (90, [M + H]+), 124 (100); HRMS (ESI+) calcd for C12H9ClNO2
[M + H]+: 234.0322, found 234.0314.
3-Chlorophenyl picolinate 9f. Flash chromatography (30% ethyl
acetate/hexanes) gave 9f as a white solid (0.590 g, 63% yield). Rf = 0.13
(30% ethyl acetate/hexanes); mp 85−86 °C (hexanes, ethyl acetate); IR
(thin film, CH2Cl2) νmax 3065, 3036, 3014, 1755, 1591, 1478, 1431,
1304, 1279, 1234, 1204, 1115, 1069, 1047, 991, 912, 881, 756, 752,
700 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, ddd, J = 1.0, 2.0, 5.0
Hz), 8.26 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.92 (1H, ddd, J = 1.5, 7.5, 8.0
Hz), 7.56 (1H, ddd, J = 1.0, 4.5, 7.5 Hz), 7.36 (1H, dd, J = 8.0, 8.0 Hz),
7.31 (1H, dd, J = 2.0, 2.0 Hz), 7.27 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 7.18
(1H, ddd, J = 1.0, 2.0, 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 163.7,
151.5, 150.4, 147.3, 137.4, 135.0, 130.4, 127.8, 126.7, 126.1, 122.6; MS
(ESI+) m/z 234 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+
C12H9ClNO2 234.0322; found 234.0314.
4-Chlorophenyl picolinate 9g. Flash chromatography (30% ethyl
acetate/hexanes) gave 9g as a white solid (0.711 g, 76% yield). Rf = 0.13
(30% ethyl acetate/hexanes); mp 91−91 °C (hexanes, ethyl acetate); IR
(thin film) νmax 3092, 3051, 3036, 1759, 1582, 1485, 1437, 1404, 1304,
1283, 1244, 1198, 1157, 1117, 1078, 1012, 995, 889, 814, 746, 721, 698,
650, 621 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, ddd, J = 1.0,
1.5, 4.5 Hz), 8.27 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.92 (1H, ddd, J = 1.5,
8.0, 8.0 Hz), 7.57 (1H, ddd, J = 1.0, 4.5, 8.0 Hz), 7.40 (2H, ddd, J = 2.0,
2.0, 9.0 Hz), 7.21 (2H, ddd, J = 2.0, 2.0, 9.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 163.9, 150.4, 149.6, 147.4, 137.4, 131.8, 129.8, 127.8, 126.1,
123.3; MS (ESI+) m/z 356 (57, [M + Na]+), 234 (100), 124 (18), 106
(24), 96 (77); HRMS (ESI+) calcd for [M + H]+ C12H9NO2Cl
234.0316; found 234.0322.
2-Methoxyphenyl picolinate 9h. Flash chromatography (30% ethyl
acetate/hexanes) gave 9h as a white solid (0.733 g, 80% yield). Rf = 0.11
(30% ethyl acetate/hexanes); mp 83−84 °C (hexanes, ethyl acetate); IR
(thin film, CH2Cl2) νmax 3071, 3021, 2974, 1748, 1609, 1505, 1462,
1377, 1303, 1281, 1257, 1234, 1195, 1123, 1042, 1026, 991, 821, 767,
702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.85 (1H, ddd, J = 1.0, 2.0,
4.5 Hz), 8.28 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.89 (1H, ddd, J = 2.0, 8.0,
8.0 Hz), 7.54 (1H, ddd, J = 1.0, 4.5, 8.0 Hz), 7.20−7.27 (2H, m), 6.97−
7.03 (2H, m), 3.81 (3H, s); 13C NMR (100 MHz, CDCl3) δ 163.4,
151.3, 150.3, 147.6, 140.1, 137.3, 127.4, 127.3, 126.0, 123.0, 120.9, 112.6,
56.0; MS (EI) m/z 229 (2, M+), 198 (8), 184 (86), 170 (7), 155 (12),
131 (4), 106 (41), 95 (6), 84 (34), 78 (100), 65 (5), 51 (13); HRMS
(EI) calcd for [M]+ C13H11NO3 229.0739; found 229.0736.
3-Methoxyphenyl picolinate 9i. Flash chromatography (30% ethyl
acetate/hexanes) gave 9i as a white solid (0.586 g, 64% yield). Rf = 0.21
(30% ethyl acetate/hexanes); mp 77−79 °C (hexanes, ethyl acetate); IR
(thin film, CH2Cl2) νmax 3022, 2843, 2855, 1747, 1582, 1504, 1431,
1304, 1279, 1260, 1196, 1119, 1074, 821, 748, 702 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.81 (1H, ddd, J = 1.0, 1.5, 4.5 Hz), 8.25 (1H, ddd, J =
1.0, 1.0, 7.0 Hz), 7.87 (1H, ddd, J = 1.5, 7.0, 7.5 Hz), 7.51 (1H, ddd, J =
1.5, 4.5, 7.5 Hz), 7.17−7.24 (2H, m), 7.94−7.02 (2H, m), 3.78 (3H, s);
13C NMR (100 MHz, CDCl3) δ 164.0, 150.9, 150.2, 147.6, 139.7, 137.2,
129.3, 127.4, 127.0, 125.8, 122.3, 118.7, 21.4; MS (ESI+) m/z 230 (100,
[M + H]+); HRMS (ESI+) calcd for [M + H]+ C13H12NO3 230.0817;
found 230.0871.
4-Methoxyphenyl picolinate 9j. Flash chromatography (30% ethyl
acetate/hexanes) gave 9j as a white solid (0.724 g, 79% yield). Rf = 0.11
(30% ethyl acetate/hexanes); mp 88−89 °C (hexanes, ethyl acetate); IR
(thin film, CH2Cl2) νmax 3065, 2952, 2855, 1751, 1579, 1508, 1440,
1304, 1290, 1236, 1194, 1114, 1074, 1028, 993, 874, 818, 754, 702 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.85 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 8.28
(1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.91 (1H, ddd, J = 1.5, 7.5, 8.0 Hz), 7.55
(1H, ddd, J = 1.0, 5.0, 7.5 Hz), 7.18 (2H, d, J = 9.0 Hz), 6.94 (2H, d, J =
9.0 Hz), 3.81 (3H, s); 13C NMR (100 MHz, CDCl3) δ 164.3, 157.6,
150.2, 147.7, 144.5, 137.3, 127.5, 125.9, 122.5, 114.7, 55.7; MS (EI) m/z
229 (12, M+), 185 (100), 170 (6), 158 (4), 130 (2), 106 (46), 95 (7), 78
(99), 65 (2), 51 (6); HRMS (EI) calcd for [M]+ C13H11NO3 229.0739;
found 229.0736.
3,5-Dimethoxyphenyl picolinate 9k. Flash chromatography (30%
ethyl acetate/hexanes) gave 9k as a white solid (0.622 g, 60% yield). Rf =
0.10 (30% ethyl acetate/hexanes); mp 73−74 °C (hexanes, ethyl acetate);
IR (thin film, CH2Cl2) νmax 3082, 3011, 2845, 1734, 1618, 1597, 1466,
1441, 1304, 1292, 1244, 1207, 1132, 1096, 1042, 991, 954, 922, 829, 745,
682, 646 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.84 (1H, ddd, J = 1.0,
2.0, 4.5 Hz), 8.27 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 7.90 (1H, ddd, J = 2.0,
8.0, 8.0 Hz), 7.56 (1H, ddd, J = 1.5, 4.5, 8.0 Hz), 6.44 (2H, d, J = 2.0),
6.39 (1H, d, J = 2.5), 3.80 (6H, s); 13C NMR (100 MHz, CDCl3) δ
163.9, 161.4, 152.6, 150.3, 147.7, 137.4, 127.6, 126.0, 100.5, 98.9, 48.0;
MS (ESI+) m/z 260 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+
C14H14NO4 260.0923; found 260.0919.
3,5-Dimethylphenyl picolinate 9l. Flash chromatography (30%
ethyl acetate/hexanes) gave 9l as a colorless oil (0.590 g, 65% yield). Rf =
0.15 (30% ethyl acetate/hexanes); IR (thin film, CH2Cl2) νmax 3055,
3013, 2951, 1755, 1732, 1620, 1589, 1470, 1435, 1308, 1285, 1242,
1142, 1099, 1045, 995, 903, 868, 826, 745, 721, 702 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.84 (1H, ddd, J = 1.0, 2.0, 4.5 Hz), 8.26 (1H, ddd, J =
1.0, 1.0, 8.0 Hz), 7.90 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.54 (1H, ddd, J =
1.0, 4.5, 8.0 Hz), 6.88 (1H, s), 6.87 (2H, s), 2.34 (6H, s); 13C NMR (100
MHz, CDCl3) δ 164.2, 150.5, 150.2, 147.8, 139.5, 137.3, 128.0, 127.4,
125.9, 119.3, 21.4; MS (ESI+) m/z 228 (100, [M + H]+); HRMS (ESI+)
calcd for [M + H]+ C14H14NO2 228.1025; found 228.1021.
3-Nitrophenyl picolinate 9m. Flash chromatography (50% ethyl
acetate/hexanes) gave 9m as a white solid (0.735 g, 75% yield). Rf = 0.05
(40% ethyl acetate/hexanes); mp 115−116 °C (hexanes, ethyl acetate);
IR (thin film, CH2Cl2) νmax 3092, 3049, 1734, 1586, 1526, 1474, 1439,
1354, 1290, 1271, 1242, 1213, 1103, 1074, 991, 899, 814, 799, 739, 714,
696. 664 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.87 (1H, ddd, J = 1.0,
1.5, 4.5 Hz), 8.30 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 8.15−8.20 (2H, m),
7.96 (1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.60−7.68 (3H, m); 13C NMR (100
MHz, CDCl3) δ 163.5, 151.3, 150.4, 149.0, 146.7, 137.6, 130.3, 128.4,
128.1, 126.3, 121.3, 117.7; MS (ESI+) m/z 245 (16, ([M + H]+); HRMS
(ESI+) calcd for [M + H]+ C12H9N2O4 245.0562; found 245.0564.
3,5-Dichlorophenyl picolinate 9n. Flash chromatography (30%
ethyl acetate/hexanes) gave 9n as a white solid (0.482 g, 45% yield). Rf =
0.15 (30% ethyl acetate/hexanes); mp 88−89 °C (hexanes, ethyl
acetate); IR (thin film, CH2Cl2) νmax 3093, 3057, 1763, 1582, 1439,
1310, 1289, 1244, 1105, 1044, 997, 924, 891, 854, 839, 802, 744, 694,
664 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.81 (1H, ddd, J = 1.0, 2.0, 4.5
Hz), 8.22 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.90 (1H, ddd, J = 2.0, 8.0, 8.0
Hz), 7.54 (1H, ddd, J = 1.0, 4.5, 8.0 Hz), 7.27 (2H, dd, J = 2.0, 2.0 Hz),
7.20 (1H, d, J = 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 163.3, 151.2,
150.4, 146.8, 137.5, 135.5, 127.09, 126.8, 126.2, 121.2; MS (ESI+) m/z
268 (100, [M + H]+), 124 (5); HRMS (ESI+) calcd for [M + H]+
C12H8Cl2NO2 267.9932; found 267.9935.
General Procedure for α-Acetoxy Ester Synthesis (10). A
solution of 9 (2.0 mmol) in CH2Cl2 (10 mL) was cooled to −78 °C.
DIBAL (2.4 mmol, 1.0 M in hexanes) was added over 2 h, and the
reaction was stirred until consumption of 9 was observed by TLC.
Pyridine (6.0 mmol), DMAP (2.4 mmol, in 2 mL CH2Cl2), and Ac2O
(8.0 mmol) were added sequentially, and the reaction was stirred at
−78 °C to room temperature for 10 h. Saturated sodium bicarbonate (5 mL)
and saturated Rochelle’s salt (10 mL) were added, and the reaction was
stirred rapidly for 45 min. The crude mixture was extracted with
dichloromethane, washed with cold 1 M sodium bisulfate (5 mL),
sodium bicarbonate (5 mL), water, and brine. After being dried over
Na2SO4, the reaction mixture was concentrated at reduced pressure.
Purification by silica gel column chromatography afforded the desired
product.
Phenoxy(pyridin-2-yl)methyl acetate 10a. Flash chromatography
(25% ethyl acetate/hexanes) gave 10a as a colorless oil (0.309 g, 58%
yield). Rf = 0.25 (30% ethyl acetate/hexanes); IR (neat) νmax 3065, 2955,
1751, 1589, 1493, 1439, 1371, 1240, 1206, 1105, 1071, 1013, 995, 962
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (1H, ddd, J = 1.0, 1.5, 4.5
Hz), 7.78 (1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.70 (1H, ddd, J = 1.0, 1.0, 8.0
Hz), 7.39 (1H, s), 7.28−7.34 (3H, m), 7.94−7.12 (3H, m), 2.14 (3H, s);
1413
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13C NMR (100 MHz, CDCl3) δ 169.8, 156.1, 155.6, 149.7, 137.2, 129.0,
124.4, 123.2, 121.4, 117.1, 94.9, 21.2; MS (ESI+) m/z 266 (9, [M +
Na]+), 266 (9), 184 (100), 156 (27), 108 (10); HRMS (ESI+) calcd for
[M + Na]+ C14H13NO3Na 266.0787; found 266.0777.
(2-Methoxyphenoxy)(pyridin-2-yl)methyl acetate 10h. Flash chro-
matography (40% ethyl acetate/hexanes) gave 10h as a colorless oil
(0.300 g, 55% yield). Rf = 0.16 (40% ethyl acetate/hexanes); IR (thin
film) νmax 3067, 3013, 2943, 2839, 1748, 1593, 1574, 1439, 1370, 1261,
1
1231, 1204, 1177, 1126, 957, 887, 748 cm−1; H NMR (400 MHz,
(2-Methylphenoxy)(pyridin-2-yl)methyl acetate 10b. Flash chro-
matography (25% ethyl acetate/hexanes) gave 10b as a colorless oil
(0.345 g, 67% yield). Rf = 0.22 (30% ethyl acetate/hexanes); IR (neat)
νmax 3060, 3024, 2951, 1745, 1593, 1496, 1439, 1370, 1300, 1242, 1215,
CDCl3) δ 8.65 (1H, ddd, J = 1.5, 1.5, 4.5 Hz), 7.72−7.79 (2H, m,), 7.34
(1H, s), 7.29 (1H, ddd, J = 2.5, 5.0, 8.0 Hz), 7.14 (1H, dd, J =1.5, 8.0 Hz),
7.06 (1H, ddd, 1.5, 7.5, 7.5 Hz), 6.92 (1H, dd, J = 1.0, 8.0 Hz), 6.88 (1H,
ddd, J = 1.5, 7.5, 7.5 Hz), 3.84 (3H, s), 2.10 (3H, s); 13C NMR (100
MHz, CDCl3) δ 169.8, 155.8, 151.1, 149.5, 145.2, 137.0, 124.8, 124.2,
121.6, 120.9, 120.1, 112.6, 96.0, 56.0, 21.2; MS (ESI+) m/z 296 (13,
[M + Na]+), 214 (100), 199 (7), 182 (11), 170 (4), 156 (5), 121 (5),
110 (12), 108 (9), 92 (15); HRMS(ESI) calcd for [M + Na]+
C15H15NO4Na 296.0893; found 296.0902.
(3-Methoxyphenoxy)(pyridin-2-yl)methyl acetate 10i. Flash chro-
matography (40% ethyl acetate/hexanes) gave 10i as a colorless oil
(0.257 g, 47% yield). Rf = 0.19 (40% ethyl acetate/hexanes); IR (thin
film) νmax 3067, 3009, 2940, 2835, 1748, 1589, 1454, 1439, 1370, 1285,
1265, 1219, 1011, 857, 841 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67
(1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.79 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.68
(1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.37 (1H, s), 7.32 (1H, ddd, J = 1.0, 5.0,
8.0 Hz), 7.20 (1H, dddd, J = 2.0, 2.0, 8.5, 8.5 Hz), 6.66−6.70 (2H, m),
6.62 (1H, ddd, J = 1.0, 2.5, 8.5 Hz), 3.80 (3H, s), 2.18 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 169.7, 161.1, 157.2, 155.5, 149.7, 137.2, 130.3,
124.4, 121.4, 109.1, 108.8, 103.3, 94.8, 55.5, 21.2; MS (EI) m/z 273
(2, M+), 214 (4), 183 (1), 166 (19), 124 (100), 108 (16), 94 (6), 78 (3),
52 (2); HRMS (EI) calcd for [M]+ C15H15NO4 273.1001; found
273.1025.
(4-Methoxyphenoxy)(pyridin-2-yl)methyl acetate 10j. Flash chro-
matography (40% ethyl acetate/hexanes) gave 10j as a white solid
(0.389 g, 71% yield). Rf = 0.19 (40% ethyl acetate/hexanes); mp 45−46
°C (hexanes, ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 3050,
2994, 2963, 2835, 1740, 1593, 1508, 1424, 1366, 1289, 1238, 1188,
1076, 995, 950, 883, 822, 787, 741 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.66 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.78 (1H, ddd, J = 2.0, 8.0, 8.0 Hz),
7.68 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.32 (1H, ddd, J = 1.0, 5.0, 7.5 Hz),
7.26 (1H, s), 7.05 (2H, d, J = 9.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 3.77 (3H,
s), 2.13 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.9, 155.83, 155.80,
150.1, 149.7, 137.2, 124.4, 121.4, 119.0, 114.9, 96.1, 55.8, 21.2; MS (EI)
m/z 273 (0.3, M+), 214 (3), 199 (0.7), 186 (3), 166 (8), 124 (100), 108
(27), 95 (1), 78 (4), 65 (0.7), 51 (1); HRMS (EI) calcd for [M]+
C15H15NO4 273.1001; found 273.0995.
(3,5-Dimethylphenoxy)(pyridin-2-yl)methyl acetate 10l. Flash
chromatography (25% ethyl acetate/hexanes) gave 10l as a colorless
oil (0.257 g, 63% yield). Rf = 0.31 (40% ethyl acetate/hexanes); IR (thin
film) νmax 3055, 3017, 2947, 2862, 1740, 1613, 1593, 1474, 1439, 1370,
1296, 1219, 1150, 1107, 1080, 1011, 995, 957, 837, 775, 748, 683 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.65 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.77
(1H, ddd, J = 1.0, 7.5, 7.5 Hz), 7.68 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.35
(1H, s), 7.30 (1H, ddd, J = 1.0, 4.5, 7.5 Hz), 6.76 (3H, m), 2.28 (6H, s),
2.14 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.9, 156.2, 155.8, 149.7,
139.6, 137.2, 125.0, 124.3, 121.3, 114.7, 95.0, 21.6, 21.3; MS (ESI+) m/z
272 (60, ([M + H]+), 230(20), 212 (100), 190 (22), 183 (31), 154 (5),
108 (4); HRMS (ESI+) calcd for [M + H]+ C16H18NO3 272.1287; found
272.1292.
1
1184, 1126, 1068, 995, 957, 752, 714 cm−1; H NMR (400 MHz,
CDCl3) δ 8.65 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.77 (1H, ddd, J = 1.5, 7.5,
7.5 Hz), 7.72 (1H, ddd, J = 1.0, 1.0, 7.5 Hz), 7.36 (1H, s), 7.30 (1H, ddd,
J = 1.5, 5.0, 7.5 Hz), 7.12−7.18 (2H, m), 7.06 (1H, d, J = 7.5 Hz), 6.97
(1H, ddd, J = 1.0, 7.5, 7.5 Hz), 2.29 (3H, s), 2.11 (3H, s); 13C NMR (100
MHz, CDCl3) δ 169.7, 155.9, 154.4, 149.6, 137.1, 131.2, 128.4, 127.1,
124.2, 123.1, 121.2, 115.4, 95.3, 21.2, 16.5; MS (ESI+) m/z 280 (6, (M +
Na)+), 198 (100), 183 (10), 170 (24), 108 (7); HRMS (ESI+) calcd for
[M + Na]+ C15H15NO3Na 280.0944; found 280.0932.
(3-Methylphenoxy)(pyridin-2-yl)methyl acetate 10c. Flash chro-
matography (25% ethyl acetate/hexanes) gave 10c as a colorless oil
(0.319 g, 62% yield). Rf = 0.23 (30% ethyl acetate/hexanes); IR (neat)
νmax 3030, 2924, 1740, 1589, 1506, 1439, 1368, 1236, 1205, 1179, 1105,
1
1009, 995, 954, 817, 773 cm−1; H NMR (400 MHz, CDCl3) δ 8.67
(1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.78 (1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.69
(1H, ddd, J = 1.0, 1.0, 7.5 Hz), 7.37 (1H, s), 7.32 (1H, ddd, J = 1.0, 5.0,
7.5 Hz), 7.18 (1H, dd, J = 8.0, 8.0 Hz), 6.84−6.94 (3H, m), 2.37 (3H, s),
2.16 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.8, 156.1, 155.7, 149.6,
139.9, 137.1, 129.5, 124.3, 124.0, 121.3, 117.9, 113.8, 94.9, 21.5, 21.2;
MS (EI) m/z 257 (2, M+), 214 (2), 198 (8), 183 (2), 170 (2), 150 (22),
108 (100), 91 (2), 78 (8), 65 (2), 51 (2); HRMS (EI) calcd for [M]+
C15H15NO3 257.1052; found 257.1051.
(4-Methylphenoxy)(pyridin-2-yl)methyl acetate 10d. Flash chro-
matography (25% ethyl acetate/hexanes) gave 10d as a colorless oil
(0.339 g, 66% yield). Rf = 0.23 (30% ethyl acetate/hexanes); IR (neat)
νmax 3061, 3030, 2924, 1748, 1593, 1510, 1439, 1371, 1240, 1204, 1179,
1105, 1011, 995, 955, 773 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.66
(1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.77 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.68
(1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.34 (1H, s) 7.31 (1H, ddd, J = 1.0, 5.0,
7.5 Hz), 7.10 (2H, d, J = 9.0 Hz), 6.98 (2H, d, J = 9.0 Hz), 2.14 (3H, s),
2.05 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.9, 155.7, 154.0, 149.7,
137.2, 132.7, 130.3, 124.3, 121.4, 117.2, 95.3, 21.2, 20.8; MS (EI) m/z
257 (2, M+), 214 (4), 198 (20), 170 (3), 150 (15), 108 (100), 91 (5), 78
(10), 65 (3), 51 (7); HRMS (EI) calcd for [M]+ C15H15NO3 257.1052;
found 257.1049.
3-Chlorophenoxy)(pyridin-2-yl)methyl acetate 10f. Flash chroma-
tography (20% ethyl acetate/hexanes) gave 10f as a colorless oil (0.072
g, 13% yield). Rf = 0.19 (30% ethyl acetate/hexanes); IR (neat) νmax
3068, 3024, 2930, 1751, 1593, 1474, 1439, 1370, 1236, 1206, 1103,
1076, 1012, 995, 943, 889, 771 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.66 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.79 (1H, ddd, J = 2.0, 4.5, 4.5 Hz),
7.66 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.32−7.35 (2H, m), 7.22 (1H, dd,
J = 8.0, 8.0 Hz), 7.11 (1H, dd, J = 2.0, 2.0 Hz), 7.04 (1H, ddd, J = 1.0, 2.0,
8.0 Hz), 6.99 (1H, ddd, J = 1.0, 2.5, 8.0 Hz), 2.16 (3H, s); 13C NMR (100
MHz, CDCl3) δ 169.7, 156.8, 155.2, 149.8, 137.3, 135.2, 130.6, 124.6,
123.5, 121.3, 118.1, 115.2, 94.9, 21.2; MS (ESI+) m/z 277.1 (5, [M]+),
218 (6), 190 (1), 183 (31), 170 (7) 154 (2), 150 (7), 128 (39) 108
(100), 78 (6); HRMS (ESI+) calcd for [M]+ C14H12NO3Cl 277.0506;
found 277.0502.
4-Chlorophenoxy)(pyridin-2-yl)methyl acetate 10g. Flash chro-
matography (30% ethyl acetate/hexanes) gave 10g as a colorless oil
(0.244 g, 44% yield). Rf = 0.28 (40% ethyl acetate/hexanes); IR (thin
film) νmax 3094, 3063, 3021, 2994, 1748, 1593, 1489, 1439, 1370, 1242,
1204, 1173, 1072, 991, 964, 899 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.65 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.78 (1H, ddd, J = 2.0, 8.0, 8.0 Hz),
7.66 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.30−7.34 (2H, m), 7.25 (2H, ddd, J
= 2.5, 2.5, 9.0 Hz), 7.04 (2H, ddd, J = 2.5, 2.5, 9.0 Hz), 2.14 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 169.5, 155.1, 154.6, 149.5, 137.1, 129.6,
128.1, 124.4, 121.1, 118.4, 94.9, 21.0; MS (ESI+) m/z 300 (15, [M +
Na]+), 218 (100), 190 (22), 183 (31), 154 (5), 108 (4); HRMS (ESI+)
calcd for [M + Na]+ C14H12NO3ClNa 300.0404; found 300.0397.
General Procedure for Oxa-Povarov Reaction. A solution of 10
(1.0 mmol) and dienophile (1.1 to 4.0 mmol) in CH2Cl2 (6.6 mL) was
cooled to −78 °C. SnCl4 (2.0 mmol, 1 M in CH2Cl2) was added slowly,
and the reaction was warmed to −15 °C and then stirred for 24 h under
an argon atmosphere. The reaction was then quenched with saturated
NaHCO3 (2 mL) and warmed to room temperature. The reaction was
extracted with CH2Cl2, and the combined extracts were washed with
water and brine. After drying over Na2SO4 and evaporation of the
solvent at reduced pressure, the products were purified by silica gel
column chromatography.
Chroman 11a. Flash chromatography (20% ethyl acetate/hexanes)
gave 11a as a white solid (0.213 g, 77% yield). Rf = 0.19 (10% ethyl
acetate/hexanes); mp 83−85 °C (hexanes, ethyl acetate); IR (thin film,
CH2Cl2) νmax 3063, 2955, 2870, 1589, 1489, 1435, 1366, 1335, 1250,
1235, 1111, 1080, 995, 748 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.58
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(1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.75 (1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.69
(1H, d, J = 7.0 Hz), 7.16−7.22 (2H, m), 7.10 (1H, ddd, J = 2.0, 8.0, 8.0
Hz), 6.91−6.99 (2H, m), 4.92 (1H, d, J = 4.0 Hz), 3.09 (1H, d, J = 9.0
Hz), 2.58 (1H, dd, J = 3.0, 8.5 Hz), 2.19 (1H, d, J = 4.5 Hz), 1.79 (1H, d,
J = 3.0), 1.59 (1H, tt, J = 4.0, 12.0 Hz), 1.28−1.49 (3H, m), 1.19 (1H, tt,
J = 3.0, 8.5 Hz), 0.84 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3)
δ 160.7, 156.7, 149.2, 136.6, 130.0, 129.7, 126.8, 122.2, 122.1, 120.9,
117.6, 80.6, 48.3, 47.9, 45.4, 37.1, 34.6, 31.3, 28.4; MS (ESI+) m/z 278
(100, [M + H]+); HRMS (ESI+) calcd for [M + H]+ C19H20NO
278.1539; found 278.1547.
155.2, 149.3, 143.2, 137.2, 132.6, 130.1, 129.9, 129.0, 128.2, 125.5, 123.0,
121.1, 120.3, 117.3, 78.6, 42.8, 39.5; MS (ESI+) m/z 322 (100, [M +
H]+), 183 (4); HRMS (ESI+) calcd for [M + H]+ C20H17ClNO
322.0999; found 322.0999.
2-((2R*,4R*)-4-(4-Chlorophenyl)chroman-2-yl)pyridine 11d-exo.
Rf = 0.21 (10% ethyl acetate/hexanes); mp 94−95 °C (ether); IR
(thin film) νmax 3063, 3021, 2955, 2870, 1582, 1485, 1454, 1358, 1227,
1107, 984, 752 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (1H, ddd, J =
1.0, 2.0, 5.0 Hz), 7.70 (1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.67 (1H, d, J =
7.5 Hz), 7.27 (2H, d, J = 8.5 Hz) 7.18−7.24 (2H, m), 7.04−7.08 (3H, m),
6.86−6.92 (2H, m), 5.16 (1H, dd, J = 3.0, 9.0 Hz), 4.13 (1H, t, J = 5.0
Hz), 2.40−2.55 (2H, m); 13C NMR (100 MHz, CDCl3) δ 160.7, 154.9,
149.3, 144.3, 137.0, 132.6, 130.8, 130.3, 128.9, 128.6, 123.4, 122.8, 121.0,
120.8, 117.4, 74.4, 39.4, 36.5; MS (ESI+) m/z 322 (100, [M + H]+);
HRMS (ESI+) calcd for [M + H]+ C20H17ClNO 322.0999; found
322.0994.
11b. Flash chromatography (15% ethyl acetate/hexanes) gave 11b as
a white solid (0.184 g, 64% yield). Additional flash chromatography
(10% to 25% ethyl acetate/hexanes gradient) afforded pure samples of
11b-endo and 11b-exo.
2-((2S*,4R*)-4-Phenylchroman-2-yl)pyridine 11b-endo. Rf = 0.10
(10% ethyl acetate/hexanes); mp 140−141 °C (ether); IR (thin film,
CH2Cl2) νmax 3024, 2916, 2870, 1574, 1481, 1450, 1435, 1234, 1111,
Chroman 11e. Flash chromatography (10% ethyl acetate/hexanes)
gave 11e as a white solid (0.105 g, 42% yield). Rf = 0.15 (10% ethyl
acetate/hexanes); IR (thin film) νmax 3063, 3021, 2955, 2870, 1582,
1
1072, 995, 918, 756, 702 cm−1; H NMR (400 MHz, CDCl3) δ 8.56
(1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.76 (1H, ddd, J = 2.0, 7.5, 7.5 Hz), 7.67
(1H, d, J = 8.0 Hz), 7.30 (2H, tt, J = 1.0, 6.5 Hz), 7.28−7.35 (4H, m),
7.15 (1H, ddd, J = 1.0, 2.5, 6.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 6.80−6.82
(2H, m), 5.33 (1H, dd, J = 2.0, 11.5 Hz), 4.40 (1H, dd, J = 5.5, 12.0 Hz),
2.70 (1H, ddd, J = 2.0, 5.5, 13.5 Hz), 2.16 (1H, ddd, J = 11.5, 12.0, 13.5
Hz); 13C NMR (100 MHz, CDCl3) δ 160.6, 155.2, 149.2, 144.7, 137.1,
130.1, 128.8, 128.0, 126.9, 126.1, 122.9, 121.0, 120.3, 117.2, 78.8, 43.4,
39.6; MS (ESI+) m/z 288 (100, [M + H]+), 183 (7), 106 (5); HRMS
(ESI+) calcd for [M + H]+ C20H18NO 288.1382; found 288.1380.
2-((2R*,4R*)-4-Phenylchroman-2-yl)pyridine 11b-exo. Rf = 0.16
(10% ethyl acetate/hexanes); mp 116−117 °C (ether); IR (thin film,
CH2Cl2) νmax 3059, 3024, 2920, 1589, 1497, 1435, 1343, 1238, 1126,
1
1485, 1454, 1358, 1227, 1107, 984, 752 cm−1; H NMR (400 MHz,
CDCl3) δ 8.58 (1H, ddd, J = 1.0, 1.5, 3.5 Hz), 7.76 (1H, ddd, J = 1.0, 8.0,
8.0 Hz), 7.69 (1H, d, J = 7.5 Hz), 7.18−7.22 (2H, m), 7.12 (1H, ddd, J =
1.5, 7.5, 7.5 Hz), 6.92−6.98 (2H, m), 5.25 (1H, d, J = 2.5 Hz), 3.58 (1H,
t, J = 7.5 Hz), 2.85−3.00 (1H, m), 2.10−2.20 (1H, m), 1.80−1.88 (1H, m),
1.42−1.58 (3H, m), 1.20−1.30 (1H, m); 13C NMR (100 MHz, CDCl3)
δ 160.7, 155.0, 149.0, 136.7, 129.4, 127.9, 127.0, 122.3, 121.8, 120.4,
117.4, 78.4, 43.6, 39.6, 35.0, 23.8, 23.5; MS (ESI+) m/z 252 (100, [M +
H]+); HRMS (ESI+) calcd for [M + H]+ C17H18NO 252.1382; found
252.1383.
Chroman 11f. Flash chromatography (10% ethyl acetate/hexanes)
gave 11f as a white solid (0.067 g, 25% yield). Rf = 0.16 (10% ethyl
acetate/hexanes); IR (thin film) νmax 3060, 3021, 2955, 2870, 1589,
1
1073, 995, 918, 756, 702 cm−1; H NMR (400 MHz, CDCl3) δ 8.54
(1H, d, J = 5.0 Hz), 7.69 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.54 (1H, d, J =
8.0 Hz), 7.30 (2H, t, J = 7.5 Hz), 7.12−7.24 (5H, m), 7.05 (1H, dd, J =
1.0, 9.0 Hz), 6.95 (1H, dd, J = 1.5, 7.5 Hz), 6.87 (1H, ddd, J = 1.0, 7.0, 7.0
Hz), 5.20 (1H, dd, J = 3.5, 9.0 Hz), 4.15 (1H, t, J = 5.0 Hz), 2.44−2.56
(2H, m); 13C NMR (100 MHz, CDCl3) δ 160.9, 154.9, 149.3, 145.8,
136.9, 130.9, 128.9, 128.7, 128.3, 126.7, 123.9, 122.7, 120.9, 120.8, 117.2,
74.5, 39.9, 36.5; MS (ESI+) m/z 288 (100, [M + H]+); HRMS (ESI+)
calcd for [M + H]+ C20H18NO 288.1388; found 288.1384.
2-((2S*,4R*)-4-(p-Tolyl)chroman-2-yl)pyridine 11c-endo. Flash
chromatography (15% ethyl acetate/hexanes) gave 11c as a white
solid (0.060 g, 20% yield). Further purification by flash chromatography
(10% ethyl acetate/hexanes) afforded pure 11c-endo. Rf = 0.12 (10%
ethyl acetate/hexanes); mp 98−99 °C (ethyl acetate/hexanes); IR (thin
film, CH2Cl2) νmax 3059, 3024, 2920, 2862, 1589, 1474, 1339, 1273,
1242, 1219, 1123, 1072, 1049, 995, 883, 814, 760, 702 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.57 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.76 (1H, ddd,
J = 2.0, 7.5, 7.5 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.22 (1H, ddd, J = 1.0, 4.5,
7.5 Hz), 7.08−7.16 (4H, m), 6.98−7.04 (2H, m), 6.80 (1H, d, J = 4.5
Hz.), 5.33 (1H, dd, J = 2.0, 11.5 Hz), 4.36 (1H, dd, J = 6.0, 12.5 Hz), 2.66
(1H, ddd, J = 2.0, 6.0, 13.5 Hz), 2.33 (3H, s), 2.15 (1H, ddd, J = 11.5,
12.5, 13.5 Hz); 13C NMR (100 MHz, CDCl3) δ 160.7, 155.2, 149.2,
144.7, 137.1, 130.1, 128.8, 128.0, 126.9, 126.1, 122.9, 121.0, 120.3, 117.2,
78.8, 43.4, 39.6; MS (EI) m/z 301 (8, M+), 282 (4), 197 (100), 165 (3),
152 (2), 93 (4); HRMS (EI) calcd for [M]+ C21H19NO 301.1467; found
301.1470.
11d. Flash chromatography (15% ethyl acetate/hexanes) gave 11d as
a white solid (0.173 g, 54% yield). Further purification by flash chro-
matography (10% ethyl acetate/hexanes) afforded pure 11d-endo and
11d-exo.
2-((2S*,4R*)-4-(4-Chlorophenyl)chroman-2-yl)pyridine 11d-
endo. Rf = 0.11 (10% ethyl acetate/hexanes); mp 124−125 °C
(ether); IR (thin film, CH2Cl2) νmax 3061, 3026, 1593, 1582, 1485, 1452,
1435, 1292, 1236, 1113, 993, 914, 829, 754 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.57 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.77 (1H, ddd, J = 1.5, 8.0,
8.0 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.17−7.28 (3H, m), 7.12−7.19 (3H,
m), 7.00 (1H, dd, J = 1.0, 8.0 Hz), 6.83 (1H, ddd, J = 1.5, 8.0, 8.0 Hz),
6.76 (1H, ddd, J = 1.5, 1.5, 7.5 Hz), 5.31 (1H, dd, J = 1.5, 11.5 Hz), 4.39
(1H, dd, J = 5.5, 12.0 Hz), 2.68 (1H, ddd, J = 2.0, 6.0, 13.5 Hz), 2.12 (1H,
ddd, J = 11.5, 12.0, 13.5 Hz); 13C NMR (100 MHz, CDCl3) δ 160.4,
1
1485, 1459, 1358, 1227, 1105, 984, 752 cm−1; H NMR (400 MHz,
CDCl3) δ 8.60 (1H, ddd, J = 1.0, 1.5, 3.5 Hz), 7.74 (1H, ddd, J = 1.0, 8.0,
8.0 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.14−7.22 (2H, m), 7.02 (1H, d, J =
7.5 Hz), 6.93−6.98 (2H, m), 5.24 (1H, d, J = 2.0 Hz), 3.46 (1H, d, J =
3.0 Hz), 2.48−2.50 (2H, m), 1.76 (1H, tt, J = 4.0, 13.0 Hz), 1.55 (1H, d,
J = 2.5 Hz), 1.42 (1H, dd, J = 3.5, 11.0 Hz), 1.08−1.21 (4H, m); 13C
NMR (100 MHz, CDCl3) δ 159.7, 156.4, 148.5, 137.1, 129.7, 127.3,
122.7, 121.3, 121.2, 120.4, 115.7, 80.9, 38.1, 35.5, 28.5, 25.5, 20.6, 20.1;
MS (ESI+) m/z 266 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+
C18H20NO 266.1522; found 266.1519.
Chroman 11g. Flash chromatography (10% ethyl acetate/hexanes)
gave 11g as a white solid (0.070 g, 27% yield). Rf = 0.14 (10% ethyl
acetate/hexanes); mp 94−95 °C (ether); IR (thin film, CH2Cl2) νmax
3140, 3063, 3028, 2932, 2909, 2862, 2839, 1651, 1593, 1578, 1489,
1454, 1435, 1354, 1304, 1265, 1111, 1076, 1049, 995, 752, 733 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.60 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.75
(1H, ddd, J = 2.0, 7.5, 7.5 Hz), 7.69 (1H, d, J = 7.5 Hz), 7.30 (1H, d, J =
7.5 Hz), 7.20 (1H, ddd, J = 1.5, 5.0, 7.5 Hz.), 7.13 (1H, dddd, J = 1.0, 1.5,
7.5, 7.5 Hz), 6.95 (2H, d, J = 7.5 Hz), 6.22 (1H, dddd, J = 2.0, 5.5, 10.0,
12.0 Hz), 5.76−5.82 (1H, m), 5.27 (1H, d, J = 2.0 Hz), 3.83 (1H, t, J =
5.5 Hz), 2.60−2.64 (1H, m), 1.90−1.98 (2H, m), 1.34−1.46 (1H, m),
1.20 (1H, dd, J = 3.0, 13.5 Hz); 13C NMR (100 MHz, CDCl3) δ 159.5,
153.1, 149.2, 136.4, 128.9, 128.4, 128.0, 127.1, 125.9, 122.3, 121.4, 121.0,
117.2, 80.6, 36.1, 25.6, 25.2, 17.1; MS (EI) m/z 263 (10, M+), 262 (12),
244 (1), 234 (3), 183 (100), 155 (18), 130 (3), 117 (4), 93 (8), 78(2);
HRMS (EI) calcd for [M]+ C18H17NO 263.1310; found 263.1311.
Chroman 11h. Flash chromatography (10% ethyl acetate/hexanes)
gave 11h as a white solid (0.044 g, 15% yield). Rf = 0.15 (10% ethyl
acetate/hexanes); isolated as a colorless oil in 15% yield; IR (thin film,
CH2Cl2) νmax 3059, 3009, 2936, 2889, 1589, 1578, 1485, 1474, 1434,
1358, 1308, 1227, 1208, 1184, 1115, 1084, 961, 903, 764, 748 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.61 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.75−
7.83 (2H, m), 7.55 (1H, d, J = 7.5 Hz), 7.45 (1H, d, J = 7.5 Hz), 7.25
(1H, ddd, J = 1.5, 5.0, 9.0 Hz), 7.17 (1H, dd, J = 7.5, 7.5 Hz), 7.08−7.13
(2H, m), 7.04 (1H, d, J = 7.5 Hz), 6.91−6.98 (2H, m), 5.40 (1H, d, J =
2.5 Hz), 4.64 (1H, d, J = 8.5 Hz), 3.59−3.67 (1H, m), 3.05 (1H, dd, J =
11.0, 16.0 Hz), 2.44 (1H, dd, J = 8.0, 15.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 159.9, 154.4, 149.2, 145.8, 142.5, 136.9, 129.6, 127.5, 127.4,
1415
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Article
126.8, 125.2, 125.1, 122.6, 122.0, 120.5, 117.9, 78.2, 44.8, 44.7, 30.5; MS
(ESI+) m/z 300 (100, [M + H]+), 124 (6); HRMS (ESI+) calcd for [M +
H]+ C21H18NO 300.1388; found 300.1391.
12b. Flash chromatography (15% ethyl acetate/hexanes) gave 12b as
a white solid (0.198 g, 66% yield). Further purification by flash chro-
matography (10% to 20% ethyl acetate/hexanes) afforded pure 12b-endo
and 12b-exo.
3059, 3024, 2920, 1589, 1497, 1435, 1343, 1304, 1238, 1126, 1072,
1030, 995, 922, 814, 760, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.57
(1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.76 (1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.64
(1H, ddd, J = 1.5, 1.5, 6.5 Hz), 7.32 (2H, dddd, J = 1.5, 1.5, 7.0, 7.0 Hz),
7.17−7.26 (4H, m), 7.10 (1H, ddd, J = 1.0, 2.5, 8.5 Hz), 6.93 (1H, d, J =
9.0 Hz), 6.77 (1H, dd, J = 1.0, 2.5 Hz), 5.29 (1H, dd, J = 2.0 Hz, 11.5 Hz),
4.34 (1H, dd, J = 6.0, 12.0 Hz), 2.68 (1H, ddd, J = 2.0, 6.0, 13.5 Hz), 2.15
(1H, ddd, J = 13.5, 11.5, 12.0 Hz); 13C NMR (100 MHz, CDCl3) δ
160.1, 153.9, 149.3, 143.7, 137.2, 129.6, 129.0, 128.7, 128.1, 127.8, 127.3,
125.8, 123.0, 120.3, 118.6, 79.0, 43.4, 39.1; MS (ESI+) m/z 301 (100,
[M + H]+); HRMS (ESI+) calcd for [M + H]+ C20H17ClNO 322.0999;
found 322.0999.
2-((2R*,4R*)-6-Chloro-4-phenylchroman-2-yl)pyridine 12g-exo.
mp 102−104 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax
3059, 3024, 2924, 1593, 1477, 1435, 1223, 1123, 1072, 1030, 995, 818,
748, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.57 (1H, ddd, J = 1.0,
2.0, 5.0 Hz), 7.68 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.48 (1H, d, J = 8.0 Hz),
7.30 (2H, dd, J = 7.5, 7.5 Hz), 7.05−7.22 (5H, m), 6.98 (1H, d, J = 8.5
Hz), 6.91 (1H, dd, J = 0.5, 2.5 Hz), 5.18 (1H, dd, J = 3.5, 9.0 Hz), 4.09
(1H, t, J = 5.5 Hz), 2.40−2.55 (2H, m); 13C NMR (100 MHz, CDCl3) δ
160.4, 153.6, 149.4, 145.0, 137.0, 130.3, 128.9, 128.8, 128.4, 127.0, 125.7,
125.6, 122.8, 120.9, 118.6, 74.8, 39.8, 36.0; MS (ESI+) m/z 301 (100,
[M + H]+); HRMS (ESI+) calcd for [M + H]+ C20H17ClNO 322.0999;
found 322.0996.
2-((2S*,4R*)-8-Methoxy-4-phenylchroman-2-yl)pyridine 12b-
endo. mp 136−137 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2)
νmax 3063, 3013, 2963, 2924, 1589, 1466, 1435, 1335, 1300, 1261, 1211,
1180, 1084, 1045, 995, 914, 787, 768, 702, cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.60 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.71−7.78 (2H, m), 7.28
(2H, dddd, J = 1.5, 1.5, 7.5, 7.5 Hz), 7.18−7.23 (4H, m), 7.03 (1H, ddd,
J = 1.0, 1.0, 7.0 Hz), 6.71 (1H, dd, J = 8.0, 8.0 Hz), 6.64 (1H, d, J = 8.0
Hz), 5.33 (1H, dd, J = 1.5, 11.5 Hz), 4.40 (1H, dd, J = 6.0, 12.0 Hz), 2.75
(1H, ddd, J = 2.0, 6.0, 13.5 Hz), 2.28 (3H, s), 2.10 (1H, ddd, J = 11.5,
12.0, 13.5 Hz); 13C NMR (100 MHz, CDCl3) δ 161.1, 153.2, 149.1,
144.9, 137.1, 129.1, 128.8, 128.7, 127.7, 126.8, 126.2, 125.6, 122.7, 120.2,
120.0, 78.5, 43.6, 39.7, 16.5; MS (EI) m/z 301 (4, [M]+), 197 (100), 169
(26), 165 (4), 152 (3), 115 (1), 106 (3), 93 (4); HRMS (EI) calcd for
[M]+ C21H19NO 301.1467; found 301.1470.
2-((2R*,4R*)-8-Methoxy-4-phenylchroman-2-yl)pyridine 12b-
exo. mp 115−117 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2)
νmax 3059, 3024, 2934, 1589, 1483, 1435, 1343, 1238, 1126, 1073, 1030,
995, 922, 813, 759, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (1H,
ddd, J = 1.0, 2.0, 5.0 Hz), 7.71 (1H, ddd, J = 2.0, 7.5, 7.5 Hz), 7.58 (1H, d,
J = 8.0 Hz), 7.29 (2H, dd, J = 7.5, 7.5 Hz), 7.17−7.22 (2H, m), 7.14 (2H,
d, J = 7.5 Hz), 7.08 (1H, dd, J =2.5, 6.5 Hz), 6.78−6.83 (2H, m), 5.21
(1H, dd, J = 3.0, 9.5 Hz), 4.16 (1H, t, J = 5.0 Hz), 2.41−2.57 (2H, m),
2.36 (3H, s); 13C NMR (100 MHz, CDCl3) δ 161.4, 153.0, 149.1, 146.0,
136.9, 129.4, 129.0, 128.6, 128.5, 126.6, 126.2, 123.3, 122.5, 120.5, 120.2,
74.4, 40.1, 36.6, 16.5; MS (ESI+) m/z 302 (100, [M + H]+); HRMS
(ESI+) calcd for [M + H]+ C21H20NO 302.1545; found 302.1555.
12d. Flash chromatography (15% ethyl acetate/hexanes) gave 12d as
a white solid (0.179 g, 59% yield). Further purification by flash chromato-
graphy (10% to 30% ethyl acetate/hexanes) afforded pure 12d-endo and
12d-exo.
2-((2S*,4R*)-6-Methyl-4-phenylchroman-2-yl)pyridine 12d-endo.
mp 146−148 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax
3059, 3024, 2920, 2862, 1589, 1474, 1339, 1273, 1242, 1219, 1123,
1072, 1049, 995, 883, 814, 760, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ 8.56 (1H, ddd, J = 1.0, 1.5, 5.0 Hz), 7.75 (1H, ddd, J = 2.0, 8.0, 8.0 Hz),
7.66 (1H, ddd, J = 1.5, 1.5, 8.0 Hz), 7.30 (2H, dddd, J = 1.5, 1.5, 7.5, 7.5
Hz), 7.18−7.26 (4H, m), 6.96 (1H, ddd, J = 1.0, 1.5, 7.5 Hz), 6.90 (1H,
d, J = 8.5 Hz), 6.61 (1H, d, J = 0.5 Hz), 5.28 (1H, dd, J = 1.0, 11.5 Hz),
4.36 (1H, dd, J = 5.5, 12.0), 2.67 (1H, ddd, J = 2.0, 6.0, 13.5 Hz), 2.09−
2.19 (4H, m); 13C NMR (100 MHz, CDCl3) δ 160.7, 153.1, 149.2,
144.8, 137.1, 130.3, 130.1, 128.8, 128.7, 128.6, 126.8, 125.7, 122.8, 120.3,
117.0, 78.8, 43.5, 39.9, 20.8; MS (EI) m/z 301 (6, M+), 282 (2), 197
(100), 169 (23), 165 (3), 152 (2), 93 (4); HRMS (EI) calcd for [M]+
C21H19NO 301.1467; found 301.1472.
2-((2R*,4R*)-6-Methyl-4-phenylchroman-2-yl)pyridine 12d-exo.
mp 93−96 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax
3059, 3024, 2920, 1589, 1497, 1435, 1343, 1238, 1126, 1073, 1030, 995,
922, 813, 759, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, ddd,
J = 1.0, 2.0, 5.0 Hz), 7.69 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.54 (1H, ddd,
J = 1.0, 1.0, 8.0 Hz), 7.30 (2H, dddd, J = 1.0, 1.0, 7.5, 7.5 Hz), 7.14−7.23
(4H, m), 7.02 (1H, dd, J = 2.0, 8.5 Hz), 6.95 (1H, d, J = 8.0 Hz), 6.76
(1H, d, J = 1.0 Hz), 5.17 (1H, dd, J = 3.5, 5.5 Hz), 4.12 (1H, t, J =
5.0 Hz), 2.42−2.54 (2H, m), 2.21 (3H, s); 13C NMR (100 MHz, CDCl3) δ
161.0, 152.8, 149.2, 145.9, 136.9, 131.0, 130.0, 129.0, 128.9, 128.6, 126.6,
123.4, 122.6, 120.9, 116.9, 74.4, 40.0, 36.6, 20.7; MS (EI) m/z 301 (100,
M+), 282 (27), 195 (14), 178 (2), 165 (6), 152 (5), 115 (2), 93 (65);
HRMS (EI) calcd for [M]+ C21H19NO 301.1467; found 301.1466.
12g. Flash chromatography (15% ethyl acetate/hexanes) gave 12g as
a white solid (0.089 g, 28% yield). Further purification by flash chroma-
tography (10% to 20% ethyl acetate/hexanes) afforded pure 12g-endo
and 12g-exo.
12h. Flash chromatography (25% ethyl acetate/hexanes) gave 12h as
a white solid (0.142 g, 45% yield). Further purification by flash chroma-
tography (10% to 40% ethyl acetate/hexanes) afforded pure 12h-endo
and 12h-exo.
2-((2S*,4R*)-8-Methoxy-4-phenylchroman-2-yl)pyridine 12h-
endo. mp 137−139 °C (hexanes, ethyl acetate); IR (thin film, CH2Cl2)
νmax 3061, 3025, 2931, 2835, 1593, 1474, 1454, 1263, 1217, 1092, 1020,
993, 916, 781, 761, 735, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.52
(1H, ddd, J = 1.5, 4.5, 4.5 Hz), 7.72−7.74 (2H, m), 7.16−7.30 (6H, m),
6.72−6.79 (2H, m), 6.40 (1H, ddd, J = 1.0, 2.5, 7.0 Hz), 5.35 (1H, dd, J =
2.0, 11.5 Hz), 4.16 (1H, dd, J = 6.0, 12.0 Hz), 3.89 (3H, s), 2.71 (1H,
ddd, J = 2.0, 6.0, 13.5), 2.16 (1H, ddd, J = 11.5, 12.0, 13.5); 13C NMR
(100 MHz, CDCl3) δ 160.6, 149.1, 148.8, 144.9, 144.7, 137.2, 128.7,
126.9, 122.8, 126.8, 122.8, 121.9, 120.4, 120.2, 110.0, 78.9, 56.3, 43.4,
39.6; MS (ESI+) m/z 318 (100, [M + H]+); HRMS (ESI+) calcd for
[M + H]+ C21H20NO2 318.1494; found 318.1502.
2-((2R*,4R*)-8-Methoxy-4-phenylchroman-2-yl)pyridine 12h-
exo. Colorless oil; IR (thin film, CH2Cl2) νmax 3061, 3025, 2931, 2835,
1589, 1493, 1473, 1263, 1251, 1092, 1026, 995, 926, 781, 761, 735, 702
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, ddd, J = 1.0, 2.0, 4.5
Hz), 7.68 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.57 (1H, d, J = 8.0 Hz), 7.29
(2H, dd, J = 7.5, 7.5 Hz), 7.13−7.23 (4H, m), 6.78−6.84 (2H, m), 6.51
(1H, ddd, J = 1.0, 2.5, 7.0 Hz), 5.21 (1H, dd, J = 3.5, 8.5 Hz), 4.08 (1H, t,
J = 5.5 Hz), 3.95 (3H, s), 2.47−2.61 (2H, m); 13C NMR (100 MHz,
CDCl3) δ 160.8, 149.2, 148.8, 145.5, 144.3, 137.0, 128.9, 128.7, 126.7,
125.0, 122.6, 122.5, 120.9, 120.2, 109.9, 75.0, 56.2, 39.7, 36.2; MS (ESI+)
m/z 318 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+
C21H20NO2 318.1494; found 318.1506.
12j. Flash chromatography (25% ethyl acetate/hexanes) gave 12j as a
white solid (0.183 g, 58% yield). Further purification by flash
chromatography (10% to 40% ethyl acetate/hexanes) afforded pure
12j-endo and 12j-exo.
2-((2S*,4R*)-6-Methoxy-4-phenylchroman-2-yl)pyridine 12j-
endo. mp 104−106 °C (hexanes/ethyl acetate); IR (thin film,
CH2Cl2) νmax 3063, 3028, 2947, 2832, 1589, 1474, 1435, 1338, 1265,
1211, 1150, 1099, 1072, 1057, 1038, 926, 872, 818, 733, 702 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.56 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.75
(1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.29 (2H, dddd,
J = 1.0, 1.0, 7.5, 7.5 Hz), 7.18−7.24 (4H, m), 6.94 (1H, d, J = 9.0 Hz),
6.74 (1H, ddd, J = 1.0, 3.0, 9.0 Hz), 6.34 (1H, dd, J = 1.0, 3.0 Hz), 5.26
(1H, dd, J = 1.5 Hz, 11.5 Hz), 4.37 (1H, dd, J = 6.0, 12.0 Hz), 3.81 (3H, s),
2.67 (1H, ddd, J = 2.0, 6.0, 13.5 Hz), 2.14 (1H, ddd, J = 13.5, 11.5, 12.0
Hz); 13C NMR (100 MHz, CDCl3) δ 160.7, 153.8, 149.5, 149.2, 144.6,
137.1, 128.9, 128.8, 127.0, 126.7, 122.9, 120.3, 117.8, 114.8, 114.0, 78.8,
55.9, 43.7, 39.8; MS (ESI+) m/z 318 (100, [M + H]+); HRMS (ESI+)
calcd for [M + H]+ C21H20NO2 318.1494; found 318.1508.
2-((2S*,4R*)-6-Chloro-4-phenylchroman-2-yl)pyridine 12g-endo.
mp 116−117 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax
1416
dx.doi.org/10.1021/jo302328s | J. Org. Chem. 2013, 78, 1404−1420

The Journal of Organic Chemistry
Article
2-((2R*,4R*)-6-Methoxy-4-phenylchroman-2-yl)pyridine 12j-exo.
mp 99−101 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax
3059, 2916, 1591, 1493, 1271, 1217, 1202, 1152, 1072, 1044, 851, 766,
702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, ddd, J = 1.0, 2.0, 5.0
Hz), 7.67 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.29
(2H, dddd, J = 1.0, 1.0, 7.5, 7.5 Hz), 7.13−7.23 (4H, m), 6.99 (1H, d, J =
9.0 Hz), 6.80 (1H, ddd, J = 2.5, 7.0, 7.0 Hz), 6.47 (1H, d, J = 3.0 Hz),
5.16 (1H, dd, J = 3.0, 9.5 Hz), 4.13 (1H, t, J = 5.0 Hz), 3.65 (3H, s),
2.42−2.55 (2H, m); 13C NMR (100 MHz, CDCl3) δ 161.0, 153.7, 149.3,
149.1, 145.7, 136.9, 128.9, 128.7, 126.7, 124.3, 122.6, 120.9, 117.8, 114.9,
114.8, 74.4, 55.9, 40.3, 36.6; MS (ESI+) m/z 318 (100, [M + H]+), 132
(63); HRMS (ESI+) calcd for C21H20NO2 [M + H]+ 318.1494; found
318.1510.
(1H, tt, J = 3.0, 8.5 Hz), 0.86 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 160.8, 154.5, 149.1, 136.6, 131.3, 130.3, 129.3, 127.5, 122.1,
120.9, 117.3, 80.7, 48.2, 47.9, 45.4, 37.2, 34.7, 31.3, 28.5, 21.0; MS (EI)
m/z 291 (100, M+), 262 (16), 250 (7), 224(15), 197 (85), 169 (6), 146
(23), 130 (8), 117 (4), 93 (13); HRMS (EI) calcd for [M]+ C20H21NO
291.1623 found 291.1624.
Chroman 13f. Flash chromatography (15% ethyl acetate/hexanes)
gave 13f as a colorless oil (0.170 g, 55% yield). Further purification by
flash chromatography (5% to 20% ethyl acetate/hexanes) afforded pure
13f-A and 13f-B.
13f-A. colorless oil; IR (thin film, CH2Cl2) νmax 3063, 2955, 1589,
1474, 1359, 1247, 1191, 1123, 1076, 957, 899, 764, 687 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.59 (1H, ddd, J = 1.0, 1.5, 4.5 Hz), 7.77 (1H, ddd,
J = 2.0, 7.5, 7.5 Hz), 7.66 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 7.22 (1H, dddd,
J = 0.5, 1.0, 4.5, 7.5 Hz), 7.14 (1H, d, J = 9.0 Hz), 6.94−6.97 (2H, m),
4.90 (1H, d, J = 4.0 Hz), 3.07 (1H, d, J = 9.0 Hz), 2.60 (1H, ddd, J = 1.0,
3.5, 8.5 Hz), 2.18 (1H, d, J = 4.5 Hz), 1.80 (1H, d, J = 4.0 Hz), 1.60 (1H,
tt, J = 4.5, 12.5 Hz), 1.30−1.46 (3H, m), 1.20 (1H, tt, J = 3.0, 8.5 Hz),
0.87 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 160.2, 157.2,
149.2, 136.8, 131.8, 130.9, 128.2, 122.5, 122.3, 120.8, 117.8, 80.8, 48.2,
47.6, 44.9, 37.1, 34.6, 31.2, 28.3; MS (ESI+) m/z 312 (100, [M + H]+);
HRMS (ESI+) calcd for [M + H]+ C19H19ClNO 312.1155; found
312.1153.
13f-B. colorless oil; IR (thin film, CH2Cl2) νmax 3059, 2953, 2909,
2970, 2834, 1591, 1483, 1453, 1333, 1264, 1221, 1188, 1109, 1094,
1084, 991, 837, 774, 741; 1H NMR (400 MHz, CDCl3) δ 8.58 (1H, ddd,
J = 1.0, 1.5, 5.0 Hz), 7.74 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.65 (1H, d, J =
8.0 Hz), 7.20 (1H, ddd, J = 1.5, 5.0, 8.5 Hz), 7.03 (2H, d, J = 4.5 Hz),
6.86 (1H, dd, J = 4.5, 4.5 Hz), 4.86 (1H, d, J = 4.0 Hz), 3.28 (1H, d, J =
9.0 Hz), 2.61 (1H, dd, J = 3.5, 9.0 Hz), 2.40 (1H, d, J = 4.0 Hz), 1.81 (1H,
d, J = 2.5 Hz), 1.60 (1H, tt, J = 4.0, 12.5 Hz), 1.40−1.50 (2H, m), 1.36
(1H, tt, J = 2.0, 10.0 Hz), 1.20 (1H, tt, J = 3.0, 9.5 Hz), 0.87 (1H, d, J =
10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 160.1, 157.8, 149.2, 136.7,
134.7, 128.0, 127.2, 123.3, 122.3, 120.8, 116.5, 80.9, 48.0, 45.4, 43.6,
37.6, 35.0, 31.1, 28.6; MS (ESI+) m/z 312 (100, [M + H]+); HRMS
(ESI+) calcd for [M + H]+ C19H19ClNO 312.1155; found 312.1150.
Chroman 13g. Flash chromatography (15% ethyl acetate/hexanes)
gave 13g as a white solid (0.180 g, 58% yield). mp 95−96 °C (hexanes/
ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 2955, 1589, 1474, 1362,
1254, 1184, 1123, 1076, 957, 899, 817, 764, 687 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.60 (1H, ddd, J = 3.5, 4.5, 6.0 Hz), 7.76 (1H, ddd, J =
2.0, 7.5, 7.5 Hz), 7.66 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 7.19−7.23 (2H, m),
7.06 (1H, ddd, J = 0.5, 2.5, 4.5 Hz), 6.87 (1H, d, J = 8.5 Hz), 4.89 (1H, d,
J = 4.0 Hz), 3.60 (1H, d, J = 9.0 Hz), 2.58 (1H, ddd, J = 1.0, 3.5, 8.5 Hz),
2.21 (1H, d, J = 4.5 Hz), 1.80 (1H, d, J = 4.0 Hz), 1.60 (1H, tt, J = 4.5,
12.5 Hz), 1.30−1.46 (3H, m), 1.23 (1H, tt, J = 3.0, 8.5 Hz), 0.87 (1H, d,
J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 160.2, 155.2, 149.2, 136.7,
131.3, 129.6, 126.9, 126.8, 122.3, 120.8, 118.9, 80.8, 48.2, 47.6, 45.3,
37.1, 34.6, 31.2, 28.3; MS (ESI+) m/z 312 (100, [M + H]+); HRMS
(ESI+) calcd for [M + H]+ C19H19ClNO 312.1155; found 312.1169.
Chroman 13h. Flash chromatography (20% ethyl acetate/hexanes)
gave 13h as a white solid (0.208 g, 68% yield). mp 120−122 °C (hexanes/
ethyl acetate); IR (thin film, CH2Cl2) νmax 3059, 2953, 2909, 2970, 2834,
1591, 1483, 1453, 1333, 1264, 1221, 1188, 1109, 1094, 1084, 991, 837,
774, 741; 1H NMR (400 MHz, CDCl3) δ 8.58 (1H, ddd, J = 0.5, 1.0, 4.5
Hz), 7.74−7.81 (2H, m), 7.19 (1H, ddd, J = 1.5, 5.0, 8.5 Hz), 6.92 (1H,
dd, J = 8.0, 7.5 Hz), 6.84 (1H, dd, J = 1.5, 7.5 Hz), 6.73 (1H, dd, J = 1.5,
8.0 Hz), 4.93 (1H, d, J = 4.0 Hz), 3.85 (3H, s), 3.11 (1H, d, J = 9.0 Hz),
2.61 (1H, dd, J = 3.5, 9.0 Hz), 2.21 (1H, d, J = 4.5 Hz), 1.81 (1H, d, J =
2.5 Hz), 1.60 (1H, tt, J = 4.0, 12.5 Hz), 1.30−1.52 (3H, m), 1.22 (1H, tt,
J = 3.0, 9.5 Hz), 0.86 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3)
δ 160.7, 149.1, 149.0, 146.2, 136.8, 130.6, 122.1, 121.9, 121.6, 121.0,
109.4, 80.9, 56.3, 48.1, 47.8, 45.4, 37.1, 34.7, 31.2, 28.4; MS (ESI+) m/z
308 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+ C20H22NO2
308.1651 found 308.1656.
Chroman 13b. Flash chromatography (10% ethyl acetate/hexanes)
gave 13b as a white solid (0.238 g, 82% yield); mp 136−138 °C
(hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 3052, 2953,
2924, 2870, 1589, 1572, 1472, 1433, 1362, 1335, 1258, 1215, 1109, 991,
1
774, 748; H NMR (400 MHz, CDCl3) δ 8.60 (1H, ddd, J = 1.5, 1.5,
5.0 Hz), 7.76−7.82 (2H, m), 7.21 (1H, ddd, J = 0.5, 3.5, 8.5 Hz), 7.07
(1H, d, J = 7.5 Hz), 6.99 (1H, d, J = 7.5 Hz), 6.88 (1H, dd, J = 7.5, 7.5
Hz), 4.90 (1H, d, J = 4.0 Hz), 3.11 (1H, d, J = 9.0 Hz), 2.65 (1H, dd, J =
3.0, 8.0 Hz), 2.28 (3H, s), 2.19 (1H, d, J = 4.5 Hz), 1.77 (1H, d, J =
3.0 Hz), 1.59 (1H, tt, J = 4.0, 12.0 Hz), 1.30−1.49 (3H, m), 1.23 (1H, tt,
J = 3.0, 8.5 Hz), 0.84 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3)
δ 161.1, 154.8, 149.1, 136.6, 129.2, 127.9, 127.5, 126.6, 122.1, 121.5,
120.7, 80.4, 48.3, 47.8, 45.5, 37.2, 34.6, 31.3, 28.5, 16.0; MS (ESI+) m/z
292 (100, [M+H]+); HRMS (ESI+) calcd for [M + H]+ C20H22NO
292.1701 found 292.1707.
Chroman 13c. Flash chromatography (10% ethyl acetate/hexanes)
gave 13c as a white solid (0.236 g, 81% yield). Pure samples of 13c-A and
13c-B were obtained by semipreparative reverse phase HPLC (Eclipse
XDB-C18 (5 μm) 9.4 × 250 mm, 20 to 95% acetonitrile/water).
13c-A. mp 129−130 °C; IR (thin film, CH2Cl2) νmax 3063, 2955,
2924, 2870, 1591, 1573, 1472, 1435, 1359, 1261, 1130, 1105, 991, 804,
765; 1H NMR (400 MHz, CDCl3) δ 8.60 (1H, ddd, J = 1.0, 2.0, 5.0 Hz),
7.77 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.59 (1H, d, J = 7.5 Hz), 7.20 (1H,
ddd, J = 1.0, 3.5, 6.0 Hz), 7.10 (1H, d, J = 8.0 Hz), 6.81 (1H, d, J =
9.0 Hz), 6.78 (1H, s), 4.91 (1H, d, J = 4.0 Hz), 3.07 (1H, d, J = 9.0 Hz),
2.57 (1H, dd, J = 4.0, 9.0 Hz), 2.30 (3H, s), 2.19 (1H, d, J = 4.5 Hz), 1.79
(1H, d, J = 3.0 Hz), 1.59 (1H, tt, J = 4.0, 12.0 Hz), 1.29−1.50 (3H, m),
1.23 (1H, tt, J = 3.0, 8.5 Hz), 0.85 (1H, d, J = 10.0 Hz); 13C NMR (100
MHz, CDCl3) δ 160.8, 156.5, 149.1, 136.7, 136.6, 129.7, 126.5, 123.1,
122.1, 120.9, 118.0, 80.6, 48.2, 47.8, 45.5, 37.1, 34.6, 31.3, 28.4, 21.3; MS
(ESI+) m/z 292 (100, [M + H]+). HRMS (ESI+) calcd for [M + H]+
C20H22NO 292.1701 found 292.1702.
13c-B. mp 76−78 °C; IR (thin film, CH2Cl2) νmax 3067, 3005, 2959,
2870, 1589, 1574, 1497, 1474, 1439, 1366, 1335, 1242, 1227, 1134,
1107, 1080, 991, 818, 787, 768, 694, 656; 1H NMR (400 MHz, CDCl3) δ
8.60 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.78 (1H, ddd, J = 1.5, 8.0, 8.0 Hz),
7.72 (1H, d, J = 1.0 Hz), 7.21 (1H, ddd, J = 1.0, 5.0, 8.0 Hz), 7.03 (1H,
dd, J = 8.0, 8.0 Hz), 6.85 (1H, d, J = 7.5 Hz), 6.81 (1H, d, J = 8.0 Hz),
4.88 (1H, d, J = 4.0 Hz), 3.12 (1H, d, J = 9.0 Hz), 2.63 (1H, dd, J = 3.0,
8.0 Hz), 2.37 (3H, s), 2.20 (1H, d, J = 4.5 Hz), 1.80 (1H, d, J = 3.0 Hz),
1.60 (1H, tt, J = 4.0, 12.0 Hz), 1.32−1.49 (3H, m), 1.24 (1H, tt, J = 3.0,
8.5 Hz), 0.88 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ
160.5, 156.7, 148.9, 137.6, 136.4, 128.0, 126.2, 123.8, 121.9, 120.7, 115.4,
80.3, 48.3, 45.3, 42.7, 37.2, 35.0, 30.9, 28.5, 19.1; MS (ESI+) m/z 292
(100, [M + H]+); HRMS (ESI+) calcd for [M + H]+ C20H22NO
292.1701 found 292.1707.
Chroman 13d. Flash chromatography (10% ethyl acetate/hexanes)
gave 13d as a white solid (0.229 g, 79% yield). mp 129−131 °C (hexanes/
ethyl acetate); IR (thin film, CH2Cl2) νmax 3067, 3005, 2959, 2870, 1589,
1574, 1497, 1474, 1439, 1366, 1335, 1242, 1227, 1134, 1107, 1080, 991,
818, 787, 768, 694, 656; 1H NMR (400 MHz, CDCl3) δ 8.60 (1H, ddd,
J = 1.0, 1.5, 4.5 Hz), 7.76 (1H, ddd, J = 2.0, 7.5, 7.5 Hz), 7.70 (1H, d, J =
8.0), 7.20 (1H, ddd, J = 1.0, 5.0, 7.5 Hz), 7.03 (1H, d, J = 1.5 Hz), 6.92
(1H, dd, J = 2.0, 8.5 Hz), 6.83 (1H, d, J = 8.0 Hz), 4.88 (1H, d, J = 3.5
Hz), 3.06 (1H, d, J = 9.0 Hz), 2.57 (1H, dd, J = 3.5, 9.0 Hz), 2.31 (3H, s),
2.22 (1H, d, J = 4.0 Hz), 1.79 (1H, d, J = 3.0 Hz), 1.60 (1H, tt, J =
4.0, 12.0 Hz), 1.49 (1H, td, J = 2.0, 10.0 Hz), 1.30−1.46 (2H, m), 1.19
Chroman 13i. Flash chromatography (15% ethyl acetate/hexanes)
gave 13i as a white solid (0.174 g, 57% yield). Further purification by
flash chromatography (5% to 30% ethyl acetate/hexanes) afforded pure
13i-A and 13i-B.
1417
dx.doi.org/10.1021/jo302328s | J. Org. Chem. 2013, 78, 1404−1420

The Journal of Organic Chemistry
Article
13i-A. mp 102−122 °C (hexanes/ethyl acetate); IR (thin film, CH2Cl2)
νmax 3063, 2953, 1618, 1582, 1502, 1453, 1360, 1267, 1161, 1113, 1038,
993, 835, 766; 1H NMR (400 MHz, CDCl3) δ 8.60 (1H, ddd, J = 1.0, 1.5,
4.5 Hz), 7.77 (1H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.69 (1H, d, J = 8.0 Hz),
7.22 (1H, ddd, J = 1.0, 5.0, 9.0 Hz), 7.10 (1H, d, J = 8.0 Hz), 6.59 (1H,
dd, J = 2.5, 8.5 Hz), 6.51 (1H, d, J = 2.5 Hz), 4.94 (1H, d, J = 3.5 Hz),
3.77 (3H, s), 3.06 (1H, d, J = 9.0 Hz), 2.55 (1H, dd, J = 3.0, 8.5 Hz), 2.16
(1H, d, J = 4.5 Hz), 1.79 (1H, d, J = 3.0 Hz), 1.58 (1H, tt, J = 4.0, 12.0
Hz), 1.28−1.47 (3H, m), 1.14−1.21 (1H, m), 0.85 (1H, d, J = 10 . 0 Hz);
13C NMR (100 MHz, CDCl3) δ 160.7, 158.9, 157.4, 149.2, 136.6, 130.4,
J = 1.0, 8.5 Hz), 6.78 (1H, ddd, J = 1.0, 7.5, 7.5 Hz), 6.67 (1H, ddd, J =
1.0, 1.0, 8.0 Hz), 4.94 (1H, d, J = 10.0 Hz), 3.85 (1H, d, J = 11.0 Hz),
2.40−2.51 (1H, m), 0.64 (3H, d, J = 6.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 159.3, 155.2, 149.4, 143.8, 137.1, 130.4, 129.7, 128.7, 127.7,
126.9, 126.5, 123.5, 122.5, 120.9, 116.9, 84.9, 51.0, 40.4, 15.4; MS (ESI+)
m/z 302 (100, [M + H]+), 183 (5), 120 (5); HRMS (ESI+) calcd for
[M + H]+ C21H20NO 302.1539; found 302.1552.
2-((2S*,3R*,4S*)-3-Methyl-4-phenylchroman-2-yl)pyridine 18a-
exo-trans. isolated as a white solid, mp 96−98 °C (ether); IR (thin
film, CH2Cl2) νmax 3059, 3024, 2920, 1589, 1497, 1435, 1343, 1238,
1126, 1073, 1030, 995, 922, 813, 759, 702 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.51 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.76 (1H, ddd, J = 2.0, 7.5,
7.5 Hz), 7.52 (1H, d, J = 7.5 Hz), 7.32 (2H, dd, J = 7.5, 7.5 Hz), 7.12−
7.27 (5H, m), 7.09 (1H, dd, J = 1.0, 8.2 Hz), 7.04 (1H, dd, J = 1.5, 7.5
Hz), 6.93 (1H, ddd, J = 1.0, 7.5, 7.5 Hz), 5.15 (1H, d, J = 2.5 Hz), 4.04
(1H, d, J = 2.0 Hz), 2.71 (1H, tq, J = 2.5, 7.0 Hz), 0.84 (3H, d, J = 7.0
Hz); 13C NMR (100 MHz, CDCl3) δ 160.1, 154.6, 149.0, 146.5, 136.5,
132.0, 129.1, 128.7, 128.2, 126.6, 122.3, 122.2, 121.3, 121.2, 116.9, 75.5,
48.6, 38.8, 13. 9; MS (ESI+) m/z 302 (100, [M + H]+), 183 (5), 120 (5);
HRMS (ESI+) calcd for [M + H]+ C21H20NO 302.1539; found 302.1552.
18d. Flash chromatography (10% ethyl acetate/hexanes) gave 18d as
a white solid (0.144 g, 46% yield). Further purification by flash chroma-
tography (5% to 20% ethyl acetate/hexanes) afforded pure 18d-endo-
trans and 18d-exo-trans.
2-((2S*,3S*,4R*)-3,6-Dimethyl-4-phenylchroman-2-yl)pyridine
18d-endo-trans. isolated as a white solid, mp 149−150 °C (hexanes/
ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 3024, 2920, 2962, 1589,
1474, 1339, 1273, 1242, 1219, 1123, 1072, 1049, 883, 814, 759 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.63 (1H, ddd, J = 1.0, 1.5, 4.5 Hz), 7.75
(1H, ddd, J = 1.5, 7.5, 7.5 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.32 (2H, dddd,
J = 1.0, 1.0, 7.0, 7.0 Hz), 7.24−7.28 (2H, m), 7.20 (2H, ddd, J = 1.5, 6.5,
6.5Hz), 6.91(1H, dd, J = 2.0, 8.0 Hz), 6.82 (1H, d, J = 9.0 Hz), 6.47 (1H, s),
4.89 (1H, d, J = 10.0 Hz), 3.81 (1H, d, J = 10.5 Hz), 2.48−2.50 (1H, m),
2.12 (3H, s), 0.63 (3H, d, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ
159.5, 153.1, 149.4, 144.0, 137.1, 130.5, 130.1, 129.7, 128.7, 128.4, 126.9,
126.1, 123.4, 122.5.2, 116.7, 84.9, 51.1, 40.7, 20.8, 15.5; MS (ESI+) m/z
316 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+ C22H22NO
316.1707; found 316.1705.
2-((2S*,3R*,4S*)-3,6-Dimethyl-4-phenylchroman-2-yl)pyridine
18d-exo-trans. isolated as a white solid, mp 93−94 °C (hexanes/ethyl
acetate); IR (thin film, CH2Cl2) νmax 3059, 3024, 2956, 1591, 1493,
1426, 1343, 1238, 1126, 1055, 1030, 926, 816, 702, 687 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.49 (1H, ddd, J = 1.0, 1.5, 4.5 Hz), 7.70 (1H, ddd,
J = 2.0, 8.0, 8.0 Hz), 7.65 (1H, ddd, J = 1.0, 1.5, 3.0 Hz), 7.28 (2H, dddd,
J = 0.5, 0.5, 7.5, 7.5 Hz), 7.19 (1H, tt, J = 1.0, 7.5 Hz), 7.10−7.15 (3H,
m), 7.02 (1H, dd, J = 2.0, 8.0 Hz), 6.96 (1H, d, J = 8.0 Hz), 6.82 (1 H, d,
J = 1.5 Hz), 5.10 (1H, d, J = 2.5 Hz), 3.97 (1H, d, J = 1.5 Hz), 2.68 (1H,
tq, J = 2.0, 7.0 Hz), 2.23 (3H, s), 0.81 (3H, d, J = 7.0 Hz); 13C δ NMR
(100 MHz, CDCl3) 160.3, 152.4, 149.0, 146.7, 136.5, 132.1, 130.3,
129.1, 129.0, 128.6, 126.6, 122.2, 121.8, 121.3, 116.6, 75.4, 48.7, 38.9,
20.8, 13.9; MS (ESI+) m/z 316 (100, [M + H]+); HRMS (ESI+) calcd for
[M + H]+ C22H22NO 316.1707; found 316.1701.
122.2, 121.7, 120.9, 109.2, 102.4, 80.8, 55.5, 48.1, 47.7, 44.7, 37.1, 34.5,
31.3, 28.2; MS (ESI+) m/z 308 (100, [M + H]+). HRMS (ESI+) calcd for
[M + H]+ C20H22NO2 308.1651 found 308.1649.
Chroman 13i-B. mp 95−96 °C (hexanes/ethyl acetate); IR (thin
film, CH2Cl2) νmax 3059, 2953, 2909, 2970, 2834, 1591, 1483, 1453,
1333, 1264, 1221, 1188, 1109, 1094, 1084, 991, 837, 774, 741; 1H NMR
(400 MHz, CDCl3) δ 8.59 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.76 (1H, ddd,
J = 2.0, 8.0, 8.0 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.22 (1H, ddd, J = 1.0, 5.0,
7.0 Hz), 7.08 (1H, dd, J = 8.0, 8.0 Hz), 6.60 (1H, d, J = 8.0 Hz), 6.53 (1H,
d, J = 8.0 Hz), 4.90 (1H, d, J = 4.0 Hz), 3.86 (3H, s), 3.24 (1H, d, J =
9.0 Hz), 2.56 (1H, dd, J = 4.0, 9.0 Hz), 2.28 (1H, d, J = 4.5 Hz), 1.78 (1H,
d, J = 3.0 Hz), 1.57 (1H, tt, J = 4.0, 12.0 Hz), 1.40−1.44 (2H, m), 1.33
(1H, tt, J = 4.5, 12.0 Hz), 1.20 (1H, tt, J = 3.5, 8.0 Hz), 0.85 (1H, d, J =
10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 160.8, 158.2, 157.7, 149.1,
136.6, 126.7, 122.2, 120.9, 118.4, 110.5, 103.8, 80.6, 55.7, 47.6, 45.2,
40.2, 37.3, 35.2, 31.3, 28.5; MS (ESI+) m/z 308 (100, [M + H]+); HRMS
(ESI+) calcd for [M + H]+ C20H22NO2 308.1651 found 308.1656.
Chroman 13j. Flash chromatography (20% ethyl acetate/hexanes)
gave 13j as a white solid (0.199 g, 65% yield). mp 113−115 °C (hexanes/
ethyl acetate); IR (thin film, CH2Cl2) νmax 3053, 2953, 2924, 2870, 1593,
1572, 1472, 1435, 1362, 1338, 1288, 1252, 1213, 1155, 1103, 991, 812,
764, 747; 1H NMR (400 MHz, CDCl3) δ 8.59 (1H, ddd, J = 1.0, 2.0, 5.0
Hz), 7.76 (1 H, ddd, J = 2.0, 8.0, 8.0 Hz), 7.69 (1H, d, J = 8.0), 7.20 (1H,
ddd, J = 1.0, 5.0, 7.5 Hz), 6.87 (1H, d, J = 9.0 Hz), 6.76 (1H, d, J = 3.0
Hz), 6.68 (1H, dd, J = 3.0, 9.0 Hz), 4.88 (1H, d, J = 4.0 Hz), 3.19 (3H, s),
3.07 (1H, d, J = 9.0 Hz), 2.56 (1H, dd, J = 3.5, 9.0 Hz), 2.23 (1H, d, J =
4.5 Hz), 1.79 (1H, d, J = 3.0 Hz), 1.60 (1H, tt, J = 4.0, 12.5 Hz), 1.51
(1H, dt, J = 2.0, 10.0 Hz), 1.30−1.46 (2H, m), 1.20 (1H, tt, J = 3.0, 9.0
Hz), 0.87 (1 H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 160.8,
154.7, 150.7, 149.1, 136.6, 130.3, 122.1, 120.9, 118.2, 114.3, 112.8, 80.8,
55.8, 48.2, 47.8, 45.9, 37.1, 34.7, 31.2, 28.5; MS (ESI+) m/z 308 (100,
[M + H]+). HRMS (ESI+) calcd for [M + H]+ C20H22NO2 308.1651
found 308.1651.
Chroman 13l. Flash chromatography (15% ethyl acetate/hexanes)
gave 13l as a white solid (0.200 g, 66% yield). IR (thin film, CH2Cl2) νmax
3055, 3005, 2959, 2924, 2870, 1590, 1573, 1489, 1474, 1439, 1366,
1335, 1242, 1227, 1126, 1012, 995, 889, 814, 746, 721, 698, 650, 621; 1H
NMR (400 MHz, CDCl3) δ 8.58 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.75
(1H, ddd, J = 2.0, 2.0, 7.5 Hz), 7.69 (1H, ddd, J = 0.5, 1.5, 3.0 Hz), 7.19
(1H, dddd, J = 0.5, 1.3, 5.0, 6.5 Hz), 6.66 (2H, d, J = 12.0 Hz), 4.84 (1H,
d, J = 4.0 Hz), 3.07 (1H, d, J = 9.0 Hz), 2.59 (1H, ddd, J = 1.0, 4.0, 8.0
Hz), 2.32 (3H, s), 2.25 (3H, s), 2.18 (1H, d, J = 4.5 Hz), 1.78 (1H, d,
J = 1.5 Hz), 1.51−1.59 (2H, m), 1.31−1.45 (2H, m), 1.20 (1H, tt, J = 3.0,
8.5 Hz), 0.86 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ
160.8, 156.8, 149.1, 137.2, 136.6, 136.2, 125.1, 125.0, 122.1, 120.9, 116.1,
80.6, 48.4, 45.6, 42.7, 37.4, 35.2, 31.1, 28.7, 21.1, 16.0; MS (ESI+) m/z
306 (100, [M + H]+); HRMS (ESI+) calcd for [M + H]+ C21H24NO
306.1858; found 306.1866.
18j. Flash chromatography (20% ethyl acetate/hexanes) gave 18j as a
white solid (0.207 g, 63% yield). Further purification by flash
chromatography (10% to 25% ethyl acetate/hexanes) afforded pure
18j-endo-trans, 18a-exo-trans, and 18j-endo-cis.
2-((2S*,3S*,4R*)-6-Methoxy-3-methyl-4-phenylchroman-2-yl)-
pyridine 18j-endo-trans. isolated as a white solid, mp 124−125 °C
(hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 2964, 2927,
18a. Flash chromatography (15% ethyl acetate/hexanes) gave 18a as
a white solid (0.087 g, 29% yield). Further purification by flash chroma-
tography (5% to 20% ethyl acetate/hexanes) afforded pure 18a-endo-
trans and 18a-exo-trans.
2-((2S*,3S*,4R*)-3-Methyl-4-phenylchroman-2-yl)pyridine 18a-
endo-trans. isolated as a white solid, mp 140−141 °C (ether); IR
(thin film, CH2Cl2) νmax 3063, 3013, 2963, 2924, 1589, 1466, 1435,
1335, 1300, 1261, 1211, 1180, 1084, 1045, 995, 914, 787, 768 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.64 (1H, ddd, J = 0.5, 1.5, 5.0 Hz), 7.76
(1H, ddd, J = 2.0, 7.5, 7.5 Hz), 7.52 (1H, ddd, J = 1.0, 1.0, 8.0 Hz), 7.32
(2H, dddd, J = 1.0, 1.0, 7.0, 7.0 Hz), 7.24−7.28 (2H, m), 7.20 (2H, dd,
J = 1.5, 8.5 Hz), 7.11 (1H, dddd, J = 1.0, 1.5, 7.0, 7.0 Hz), 6.92 (1H, dd,
1
1591, 1490, 1342, 1270, 1214, 1151, 1028, 819, 700 cm−1; H NMR
(400 MHz, CDCl3) δ 8.63 (1H, ddd, J = 1.0, 2.0, 5.0 Hz), 7.75 (1H, ddd,
J = 2.0, 7.5, 7.5 Hz), 7.50 (1H, d, J = 8.0 Hz), 7.18−7.33 (6H, m), 6.86
(1H, d, J = 9.0 Hz), 6.68 (1H, ddd, J = 1.0, 3.0, 9.0 Hz), 6.21 (1H, dd, J =
1.0, 3.0 Hz), 4.87 (1H, d, J = 10.0 Hz), 3.82 (1H, d, J = 11.0 Hz), 3.59
(3H, s), 2.39−2.49 (1H, m), 0.63 (3H, d, J = 6.5 Hz); 13C NMR (100
MHz, CDCl3) δ 159.4, 153.8, 149.5, 149.4, 143.7, 137.1, 129.7, 128.7,
127.2, 127.0, 123.4, 125.5, 117.5, 115.2, 113.6, 84.9, 55.8, 51.4, 40.6,
15.5; MS (ESI+) m/z 332 (100, [M + H]+); HRMS (ESI+) calcd for
[M + H]+ C22H22NO2 332.1656; found 332.1655.
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2-((2S*,3R*,4S*)-6-Methoxy-3-methyl-4-phenylchroman-2-yl)-
pyridine 18j-exo-trans. isolated as a white solid, mp 105−106 °C
(hexanes/ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 2962, 1594,
1490, 1356, 1276, 1224, 1153, 1035, 964, 885, 821, 755, 703 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.50 (1H, ddd, J = 0.9, 1.7, 4.8 Hz), 7.70
(1H, ddd, J = 1.8, 7.8, 7.8 Hz), 7.65 (1H, d, J = 8.0 Hz), 7.30 (1H, t, J =
7.5 Hz), 7.20 (2H, dddd, J = 2.0, 2.0, 7.5, 7.5 Hz), 7.12−7.16 (3H, m),
7.01 (1H, d, J = 9.0 Hz), 6.83 (1H, dd, J = 3.1, 9.0 Hz), 6.55 (1H, d, J =
3.0 Hz), 5.10 (1H, d, J = 2.3 Hz), 4.00 (1 H, d, J = 1.6 Hz), 3.71 (3H, s),
2.68 (1H, app. tq, J = 2.3, 6.0 Hz), 0.83 (3H, d, J = 7.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 160.7, 154.1, 149.1, 148.7, 146.4, 136.5, 129.1,
128.7, 126.7, 122.7, 122.2, 121.3, 117.6, 115.7, 115.0, 75.5, 55.9, 49.1,
38.9, 14.0; MS (ESI+) m/z 332 (100, [M + H]+); HRMS (ESI+) calcd for
[M + H]+ C22H22NO2 332.1656; found 332.1654.
2-((2S*,3R*,4R*)-6-Methoxy-3-methyl-4-phenylchroman-2-yl)-
pyridine 18j-endo-cis. isolated as white solid, mp 109−110 °C (hexanes/
ethyl acetate); IR (thin film, CH2Cl2) νmax 3063, 2963, 1591, 1491, 1270,
1214, 1122, 1031, 924, 815, 743; 1H NMR (400 MHz, CDCl3) δ 8.60
(1H, ddd, J = 0.9, 1.7, 4.8 Hz), 7.70−7.78 (2H, m), 7.21−7.35 (6H, m),
6.97 (1H, d, J = 9.0 Hz), 6.78 (1H, dd, J = 3.1, 9.0 Hz), 6.57 (1H, d, J =
3.0 Hz), 5.40 (1H, d, J = 1.0 Hz), 4.79 (1H, d, J = 5.5 Hz), 3.66 (3H, s),
2.66−2.74 (1H, m), 0.46 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 160.0, 153.8, 149.3, 149.1, 141.8, 136.7, 130.2, 128.3, 127.0,
124.5, 122.4, 120.9, 117.8, 115.2, 114.2, 81.2, 55.9, 48.9, 37.4, 7.8; MS
(ESI+) m/z 332 (100, [M + H]+), 132 (63); HRMS (ESI+) calcd for [M
+ H]+ C22H22NO2 332.1651; found 332.1657.
(7) Vinvente-Garcia, E.; Ramon
Org. Chem. 2011, 7, 980−987.
́
, R.; Preciado, S.; Lavilla, R. Beilstein J.
(8) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977−
8978.
(9) For examples of the Povarov reaction in total synthesis, see:
(a) Toyota, M.; Komori, C.; Ihara, M. J. Org. Chem. 2000, 65, 7110−
7113. (b) Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913−4916.
(c) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2004, 126,
1352−1353. (d) Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74,
6728−6734.
(10) Monbaliu, J. M.; Masschelein, K. G. R.; Stevens, C. V. Chem. Soc.
Rev. 2011, 40, 4708−4739.
(11) Examples of cyclic variants exist in the literature, see: (a) Moquist,
P. N.; Kodama, T.; Schaus, S. E. Angew. Chem., Int. Ed. 2010, 49, 7096−
7100. (b) Watson, M. P; Maity, P. Synlett 2012, 1705−1708.
(12) There are rare examples of 2-oxadienes in synthesis; see: Mori, K.;
Kawasaki, T.; Sueoka, S.; Akiyama, T. Org. Lett. 2010, 12, 1732−1735.
(13) A recent example of the cycloaddition chemistry of vinyl
diazoacetates with cationic 2-oxadienes to give chromans has been
reported; see: Jadhav, A. M.; Pagar, V. V.; Liu, R.-S. Angew. Chem., Int.
Ed. 2012, 51, 11809−11813.
(14) KamaI-Eldin, A.; Appelqvist, L. A. Lipids 1996, 31, 671−701.
(15) Tapas, A. R.; Sakarkar, D. M.; Kakde, R. B. Trop. J. Pharm. Res.
2008, 7, 1089−1099.
(16) (a) Jacobsen, E. J.; VanDoornik, F. J.; Ayer, D. E.; Belonga, K. L.;
Braughler, J. M.; Hall, E. D.; Houser, D. J. J. Med. Chem. 1992, 35, 4464−
4472. (b) Terao, K.; Niki, E. J. Free Rad. Biol. Med. 1986, 2, 193−201.
(c) Grisar, J. M.; Petty, M. A.; Bolkenius, F. N.; Dow, J.; Wagner, J.;
Wagner, E. R.; Haegele, K. D.; Jong, W. D. J. Med. Chem. 1991, 34, 257−
260.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra, ORTEP X-ray crystal
structure displays, and CIF files for 11a-exo-endo and 11b-endo.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Lal, J. Contraception 2010, 81, 275−280.
(18) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioka,
T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-
Natschke, S. L.; Lee, K.-H. Tetrahedron 2001, 57, 1559−1563.
(19) Cassidy, F.; Evans, J. M.; Hadley, M. S.; Haladij, A. H.; Leach, P.
E.; Stemp, G. J. Med. Chem. 1992, 35, 1623−1627.
AUTHOR INFORMATION
Corresponding Author
*Phone/fax: (416)-978-5059. E-mail: rbatey@chem.utoronto.
■
(20) (a) Pouget, C.; Fagnere, C.; Basly, J.-P.; Leveque, H.; Chulia, A.-J.
Tetrahedron 2000, 56, 6047−6052. (b) Seeram, N. P.; Jacobs, H.;
McLean, S.; Reynolds, W. F. Phytochemistry 1998, 49, 1389−1391.
(21) Shen, H. C. Tetrahedron 2009, 65, 3931−3952.
(22) (a) Van de Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367−5405. (b) Korthals, K. A.; Wulff, W. D. J. Am. Chem. Soc. 2008,
130, 2898−2899. (c) Inoue, T.; Inoue, S.; Sato, K. Bull. Chem. Soc. Jpn.
1990, 63, 1647−1652.
(23) Ko, S. K.; Jang, H. J.; Kim, E.; Park, S. B. Chem. Commun. 2006,
2962−2964.
(24) (a) Kotame, P.; Hong, B.-C.; Liao, J. H. Tetrahedron Lett. 2009,
50, 704−707. (b) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen,
R. Org. Lett. 2009, 11, 991−994. (c) Mente, N. R.; Neighbors, J. D.;
Wiemer, D. F. J. Org. Chem. 2008, 73, 7963−7970.
(25) Taylor, R. R. R.; Batey, R. A. Studies on the oxo-Povarov reaction.
Presented in part at Pacifichem 2010, Dec 15−20, 2010, Honolulu, HI,
Abstract 1214.
ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support through the Natural Science
and Engineering Research Council (NSERC) of Canada via a
Discovery Grant for R.A.B., and a PGS-D scholarship to R.R.R.T.
We thank Dr. Alan J. Lough for X-ray crystallographic analysis.
REFERENCES
■
(1) (a) Cherkasov, V. M.; Kapran, N. A. Chem. Heterocycl. Compd.
1992, 28, 1101−1108. (b) Nicolaou, K. C.; Snyder, S. A.; Montagnon,
T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668−1698.
(2) (a) Grigos, V. I.; Povarov, L. S.; Mikhailov, B. M. Russ. Chem. Bull.,
Int. Ed. (Engl. Transl.) 1965, 12, 2163−2172. (b) Povarov, L. S.; Grigos,
V. I.; Mikhailov, B. M. Russ. Chem. Bull., Int. Ed. (Engl. Transl.) 1966, 1,
144−145.
(26) Kopecky, D .J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191−
198.
(27) Sergeant, E. P.; Dempsey, B. Ionization constants of organic acids in
aqueous solution; Pergamon Press: New York, 1979.
(28) Similar effects have been observed for Povarov reactions of N-(3-
pyridyl)aldimines; see: Palacios, F.; Alonso, C.; Arrieta, A.; Cossio, F. P.;
Ezpeleta, J. M.; Fuertes, M.; Rubiales, G. Eur. J. Org. Chem. 2010, 2019−
2099.
(3) For reviews on the Povarov reaction, see: (a) Povarov, L. S. Russ.
Chem. Rev. 1967, 36, 656−670. (b) Glushkov, V. A.; Tolstikov, A. G.
Russ. Chem. Rev. 2008, 2, 137−159. (c) Kouznetsov, V. V. Tetrahedron
2009, 65, 2721−2750.
(29) The following notation is used to distinguish the possible
diastereomers. The first term refers to the mode of facial selectivity to
the norbornene system (endo or exo), while the second term (endo or
exo) is defined on the basis of the Diels−Alder reaction, where H2 and
H4 have a cis or trans relationship, respectively.
́
(4) (a) Vicente-García, E.; Ramon, R.; Preciado, S.; Lavilla, R. Beilstein
J. Org. Chem. 2011, 7, 980−987. (b) Powell, D.; Batey, R. A. Org. Lett.
2002, 4, 2913−2916.
(5) Bergonzini, G.; Gramigna, L.; Mazzanti, L.; Fochi, M.; Bernardi, L.;
Ricci, A. Chem. Commun. 2010, 327−329.
(30) The minor isomer was identified from the 1H NMR spectrum of
the crude reaction mixtures. The H2 proton appeared at 4.54 ppm,
slightly upfield compared to the endo isomer, with a large coupling
(6) Kiselyov, A. S.; Smith, L., II; Armstrong, R. W. Tetrahedron 1998,
54, 5089−5096.
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constant of 9.6 Hz. The relatively large coupling constant, as well as the
upfield shift of these protons, is consistent with that of the exo-exo
stereoisomers observed for the products of aza-Povarov reactions of
norbornene (ref 35.).
(31) See Supporting Information for ORTEP X-ray crystal structure
displays of 11a-exo-endo and 11b-endo.
alkylation), isomerization was not detected when 18j-endo-trans, 18j-
exo-trans, or 18j-endo-cis were resubjected to the reaction conditions.
(46) One of the closest mechanistic comparisons to rationalize the
relative stereoselectivity (C2/C3) obtained in a stepwise oxa-Povarov
reaction is to consider stereoselective Prins reactions between 1,2-
disubsituted alkenes and aldehydes RCHO. However, most Prins
reactions utilize monosubstituted alkenes and formaldehyde as
substrates. One rare example is the iodine-promoted reaction of trans-
β-methylstyrene and propanal, which was recently described to give a
pure adduct in 88% yield (no dr was reported). The relative
stereochemistry of this adduct corresponds to the major diastereomer
18-exo-trans obtained for the oxa-Povarov reaction of trans-β-
methylstyrene. See: Yadav, J. S.; Subba Reddy, B. V.; Hara Gopal, A.
V.; Narayana Kumar, G. G. K. S.; Madavi, C.; Kunwar, A. C. Tetrahedron
Lett. 2008, 49, 4420−4423.
(47) Lewis acid-promoted carbonyl-ene reactions display variable
diastereoselectivity depending on the Lewis acid, aldehyde and alkene
components. (a) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J.
Am. Chem. Soc. 1982, 104, 555−563. (b) Yamanaka, M.; Mikami, K.
Helv. Chim. Acta 2002, 85, 4264−4269.
(48) Tietze, L. F.; Kinzel, T.; Schmatz, S. J. Am. Chem. Soc. 2006, 128,
11483−11495.
(49) He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14,
3158−3161.
(32) Coupling constants for 4-substituted flavans have been previously
shown to adhere well to the Karplus equation, see: Whalley, W. B. The
Chemistry of Flavonoid Compounds; Pergamon Press: London, 1962.
(33) Similar observations were made for the related styrene-derived
compounds 11c-exo and 11d-exo (see Table 3), as well as the 12-exo
series (see Table 4).
(34) Trans-2,4-disubstituted flavans show a characteristic triplet for H4
in their 1H NMR spectra; see: Bolger, B. J.; Hairwe, A.; Marathe, K. G.;
Philbin, E. M.; Vickars, M. A.; Lillya, C. P Tetrahedron 1966, 22, 621−
628.
(35) Smith, C. D.; Gavrilyuk, J. I.; Lough, A. J.; Batey, R. A. J. Org.
Chem. 2010, 75, 702−715.
(36) The [4 + 2] Povarov exo-transition state for the reaction of
norbornene is analogous to the oxa-Povarov transition state exo-cyc-TS-C
(Figure 5).
(37) The corresponding aza-Povarov reactions using norbornene
occur with modest selectivity to give the regioisomer having the
substituent at the 7-position of the tetrahydroquinoline ring system
using 3,4-dimethylaniline (3:2 ratio), and at the 5-position (64:36 ratio)
using m-chloroaniline (see ref 35). The 7-substituted tetrahydroquino-
lines were obtained exclusively as the exo-exo diastereomers and the 5-
substituted isomers were obtained as the exo-endo diastereomers. A
concerted [4 + 2] mechanism was proposed to account for the exo-exo
diastereomers and a stepwise mechanism for the exo-endo diaster-
eomers. The change in mechanism from concerted to stepwise for the
formation of the exo-endo 5-substituted tetrahydroquinolines was
attributed to additional unfavorable steric interactions that occur
between norbornene and the R1 substituents present in the exo-exo
transition states. The preference for the formation exo-endo-
norbornene-derived adducts in the oxa-Povarov reaction may reflect a
similar steric effect and either an earlier transition state for the oxa-
Povarov reaction or shorter C−O compared to C−N bond lengths in
the respective transition states.
(50) (a) Beifuss, U.; Ledderhouse, S. J. Chem. Soc., Chem. Commun.
1995, 2137−2138. (b) Katritzky, A. R.; Nichols, D. A.; Qi, M.; Yang, B. J.
Heterocycl. Chem. 1997, 34, 1259−1262.
(51) Katritzky, A. R; Button, M. A. C. J. Org. Chem. 2001, 66, 5595−
5600.
(52) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913−2916.
(53) (a) Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org.
Chem. 2008, 73, 7451−7456. (b) Xie, M.; Liu, X.; Zhu, Y.; Zhao, X.; Xia,
Y.; Lin, L.; Feng, X. Chem.Eur. J. 2011, 17, 13800−13805.
́ ́
(54) (a) Crousse, B.; Begue, J.-P.; Bonnet-Delpon, D. J. Org. Chem.
2000, 65, 5009−5013. (b) Palacios, F.; Alonso, C.; Fuertes, M.;
Ezpeleta, J. M.; Rubiales, G. Eur. J. Org. Chem. 2011, 4318−4326.
́
(55) (a) Kouznetsov, V. V.; Arenas, D. R. M.; Bohorquez, A. R. R.
Tetrahedron Lett. 2008, 49, 3097−3100. (b) He, L.; Bekkaye, M.;
Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158−3161. (c) One
endo-selective example with 2-hydroxystyrenes has been reported, see:
Shi, F.; Xing, G.-J.; Tao, Z.-L.; Luo, S.-W.; Tu, S.-J.; Gong, L.-Z. J. Org.
Chem. 2012, 77, 6970−6979.
(38) Bello, D.; Ramon, R.; Lavilla, R. Curr. Org. Chem. 2010, 14, 332−
356.
(39) Kudale, A. A.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org.
Biomol. Chem. 2011, 9, 7196−7206.
(40) For reviews on the Prins reaction, see: (a) Pastor, I. M.; Yus, M.
Curr. Org. Chem 2012, 16, 1277−1312. (b) Adams, D. R.; Bhatnagar, S.
P. Synthesis 1977, 661−672.
(41) Reaction via a Z-configured oxocarbenium ion is also, in principle,
possible but is unlikely because of the greater steric hindrance of such a
species.
(42) Examples of intramolecular Friedel−Crafts-terminated Prins
reactions are known; see: (a) Li, B.; Lai, Y.-C.; Zhao, Y.; Wong, Y.-H.;
Shen, Z. L.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 10619−10623.
(b) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Reddy, P. P.; Kunwar, A. C.;
Sridhar, B.; Gree
(c) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Gree
J. Org. Lett. 2011,
́
, R. Org. Biomol. Chem. 2012, 10, 1349−1358.
́
, R. J. Org.
Chem. 2011, 76, 7677−7690. (d) Fenster, E.; Aube,
́
13, 2614−2617. (e) Basavaiah, D.; Reddy, K. R. Org. Lett. 2007, 9, 57−
60.
(43) For the formation of a chromans via Prins reactions, see for
example: (a) Yang, X. F.; Wang, M. W.; Zhang, Y. H.; Li, C. J. Synlett
2005, 1912−1916. (b) Spivey, A. C.; Laraia, L.; Bayly, A. R.; Rzepa, H.
S.; White, A. J. P. Org. Lett. 2010, 12, 900−903. (c) Reddy, B. V. S.; Jalal,
S.; Borkar, P.; Yadav, J. S.; Reddy, P. P.; Kunwar, A. C.; Sridhar, B. Org.
Biomol. Chem. 2012, 10, 6562−6568.
(44) Pure samples of this compound were unobtainable; however, it
could be identified in the 1H NMR spectra of the crude reaction
mixtures.
(45) While cis/trans scrambling is also conceivable through isomer-
ization of the chroman products (e.g., via a reversible Friedel−Crafts
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