C-H bond functionalization via hydride transfer: Formation of α-arylated piperidines and 1,2,3,4-tetrahydroisoquinolines via stereoselective intramolecular amination of benzylic C-H bonds

Article abstract of DOI:10.1021/jo300635m

We here report a study of the intramolecular amination of sp³ C-H bonds via the hydride transfer cyclization of N-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to N-toluenesulfonamide in the presence of BF₃?OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4- tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the N-tosylimine and the benzylic sp³ C-H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C-H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity.

Full text of DOI:10.1021/jo300635m

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C−H Bond Functionalization via Hydride Transfer: Formation of α-
Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via
Stereoselective Intramolecular Amination of Benzylic C−H Bonds
Paul A. Vadola,† Ignacio Carrera,† and Dalibor Sames*
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York, 10027
S
* Supporting Information
ABSTRACT: We here report a study of the intramolecular
amination of sp3 C−H bonds via the hydride transfer
cyclization of N-tosylimines (HT-amination). In this trans-
formation, 5-aryl aldehydes are subjected to N-toluenesulfona-
mide in the presence of BF3·OEt2 to effect imine formation and
HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-
tetrahydroisoquinolines in a one-pot procedure. We examined
the reactivity of a range of aldehyde substrates as a function of
their conformational flexibility. Substrates of higher conforma-
tional rigidity were more reactive, giving higher yields of the
desired products. However, a single substituent on the alkyl chain linking the N-tosylimine and the benzylic sp3 C−H bonds was
sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the
hydridic C−H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly
stereoselective; 2-substituted aldehydes yield cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-2,4-
disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the
arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the
axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity.
Scheme 1. Two Complementary Approaches to α-Arylated
Piperidines via C−H Bond Functionalization
INTRODUCTION
■
a
C−H bond functionalization represents a process of broad
synthetic potential owing to the ubiquity of C−H bonds in
organic compounds.1 As part of a broad program aimed at the
development of new approaches for the direct functionalization
of C−H bonds, we have been interested in the design of new
methods for the synthesis of arylated pyrrolidines and
piperidines.2,3 The wide ranging biological activity of such
compounds has granted them an important status in the fields
of organic and medicinal chemistry.4
To complement approaches initiated by transition-metal
insertion into C−H bonds2 and those relying on an external
oxidant,3 for preparation of α-arylpiperidines we considered an
alternative mode of reactivity based on the hydride-transfer
cyclization of imines (HT-amination, Scheme 1B).5 This
approach is based on a Lewis acid promoted hydride transfer
to an activated imine, followed by C−N bond formation. We
have previously demonstrated that the HT-cyclization effects
the coupling of a range of hydride acceptors, such as aldehydes,
enones, enals, vinyl acetals, and unactivated alkynes, with sp3
C−H bonds to deliver a diverse array of complex structural
scaffolds, under mild conditions (Figure 1).6 HT-cyclization has
since become an active area of research, which has led to the
development of a number of interesting transformations.7−12
In regard to HT-amination reactions, an early report by
Reinhoudt et al. describes the thermal-cyclization of o-
aminobenzaldimines of type I to aminals II (Scheme 2A).13
a
DG = directing group.
More recently, the research teams of Seidel14a and Akiyama14b
showed that triflic acid catalyzed this transformation, leading to
expansion of its scope and utility. Both the thermal and the
acid-catalyzed reactions of aromatic imines can be rationalized
by a sigmatropic hydrogen shift. However, a through-space
hydride transfer mechanism is also reasonable. In the context of
saturated substrates (where a through-space hydride transfer is
the only reasonable mechanistic rationale), Tietze and
colleagues have reported the HT-cyclization of imines within
Received: March 27, 2012
© XXXX American Chemical Society
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Scheme 3. One-Pot Condensation/HT-amination Protocol
Figure 1. Examples of diverse structures prepared by HT-cyclization in
our group. The bond formed during the process is highlighted in red.
E = CO2Me, E′ = CO2Et, Ar = 4-MeOC6H4.
Scheme 2. Formation of Cyclic Amines via the HT-
cyclization of Imines
After heating at 80 °C for 2 h, 1,2,3,4-tetrahydroisoquinoline 2
was isolated in 87% yield. Lewis acid optimization revealed that
BF3·OEt2 and TiF4 were the only reagents capable of
promoting complete conversion of aldehyde 3 to product 2
(see Table S1 in the Supporting Information for an extensive
screen). We also investigated the use of alternative amines in a
one-pot procedure with substrate 3. While aniline gave complex
product mixtures, 4-nitrobenzenesulfonamide led to a clean
reaction mixture. However, the rate of reaction was dramatically
slower than that with N-toluenesulfonamide, and incomplete
conversion of the aldehyde to the imine was a recurring
problem.
With the one-pot procedure in hand, we next directed our
attention toward aliphatic aldehyde substrates, which upon HT-
amination would yield α-arylated piperidines (Scheme 3). Our
investigation began with aldehyde 4, containing gem-dimethyl
substitution in the α-position, to promote the intramolecular
hydride transfer by increasing the rigidity of the substrate and
preventing the potential tautomerization of the imine to the
enamine. This substrate gave the 2-aryl-piperidine 5 in 96% yield
at room temperature in 1 h, the result that stimulated the
systematic examination of the aliphatic substrates. Attempts to
extend the HT-amination reactivity to ketone substrates of both
the aryl and aliphatic classes were unsuccessful, with complete
recovery of the starting ketone observed in all cases.
HT-amination of Aliphatic Aldehydes: Conforma-
tional Rigidity of the Substrate Backbone and Elec-
tronics of the Benzylic C−H Bonds. Preliminary studies
outlined above established that aliphatic aldehyde 4 exhibits
high reactivity in the one-pot HT-cyclization protocol.
Similarly, the cyclic aldehyde 6 afforded an excellent yield of
spirocyclic piperidine 7 under mild reaction conditions (Table
1, entry 2). Moving the gem-dimethyl substitution in the β-
position had no major effect; substrate 8 furnished the
corresponding product 9 in 95% yield under the same
conditions (Table 1, entry 3).
We next examined substrate 10, containing one methyl group
in the β-position, and substrate 12, containing no substitution
on the alkyl linker (Table 1, entries 4 and 5). Importantly, both
substrates afforded the corresponding products, demonstrating
the feasibility of HT-amination of aliphatic substrates with a
small conformational bias, albeit with significantly lower yield.
The efficiency of the HT-cyclization was improved by
optimization of reaction conditions as is described in the
following section (Table 2). Unfortunately, even under the
optimized conditions unsubstituted substrate 12 failed to
conformationally rigid steroidal substrates, giving access to
complex isoquinuclidines of type IV (Scheme 2B).15 This
reaction has recently been expanded to the corresponding
oximes and hydrozones.16
In this study, we examined the importance of conformational
rigidity for the HT-cyclization of imines in a systematic manner.
We explored the reactivity of aldehyde substrates with varying
degrees of conformational freedom, ranging from rigid aromatic
aldehydes to entirely unrestricted 5-arylpentanals. We found
that a single substituent on the alkyl chain connecting the N-
tosylimine (formed in situ from the aldehyde) and the benzylic
group is sufficient for an efficient HT-cyclization to occur.
Furthermore, we discovered that the HT-cyclization is highly
stereoselective, and we provide a mechanistic rationale for the
observed results.
RESULTS AND DISCUSSION
■
Initial Investigation of the HT-amination: One-Pot
Protocol. We first examined the aromatic N-tosylimine
substrate 1 considering the restricted conformational freedom
imparted by the aromatic core, which forces the hydride
acceptor (N-tosylimine) and the hydride donor (the benzylic
C−H bonds) into proximity and thereby should facilitate the
hydride transfer (Scheme 3). Moreover, substrates of type 1 are
readily accessible from commercially available materials and
provide a direct route to an attractive but medicinally
underexplored heterocyclic motif, the 3-aryl-1,2,3,4-tetrahy-
droisoquinoline (also see discussion below).
Substrate 1 was subjected to BF3·OEt2 (2 equiv) in DCE at
50 °C, and we were gratified to observe an efficient conversion
to the N-tosyl-1,2,3,4-tetrahydroisoquinoline 2 in 92% yield
(Scheme 3). As BF3·OEt2 is known to promote the
condensation of aldehydes and N-toluenesulfonamide, we
subjected the precursor aldehyde 3 to BF3·OEt2 (3 equiv), N-
toluenesulfonamide (2 equiv) and 4 Å molecular sieves (MS).17
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products. However, we have found that the presence of a
heteroatom in the backbone of various HT-cyclization
substrates is generally not tolerated and leads to decomposition
of the starting material.
Table 1. HT-amination Scope: Conformational Rigidity and
Electronics of Aldehyde Substrates
a
In the context of these substrates, we also explored the effect
of electronics of the benzylic C−H bonds and the arene ring. In
addition to the methoxy group, the carbamate-containing
substrate 14 provided 81% yield of product 15 (Table 1, entry
6). In addition, we were glad to find that substrate 16 with an
unsubstituted phenyl ring undergoes the cyclization, although
with lower efficiency (Table 1, entry 7). As expected, electron-
donating substituents are required to achieve high yields of the
desired products. This is a limitation pertinent to all HT-
cyclization reactions as the stabilization of the carbocation
intermediate, formed by the hydride transfer, is required
(Scheme 1B).
HT-amination of Aliphatic Aldehydes is Highly
Stereoselective. Examining the reactivity of substrate 10,
bearing one methyl group in the β-position, revealed that the
HT-cyclization is stereoselective (Scheme 4A). Optimization of
Scheme 4. HT-amination Is Stereoselective
a
Reactions performed at 0.05 M in dry DCE, with 2 equiv of TsNH2, 3
b
equiv of BF3·OEt2 and 4 Å MS 200% by wt Obtained as a 95:5 trans
/cis mixture. Reactions run in a sealed vial.
c
the reaction conditions revealed that elevating the temperature
to 80 °C and decreasing the substrate concentration (to
disfavor formation of side products stemming from intermo-
lecular reactions) led to a substantial improvement of the
reaction efficiency, from 37% to 85% yield (Table 2).
furnish the desired product in higher yield. We also considered
the incorporation of a heteroatom into the alkyl linker, which
upon HT-amination would afford morpholine and piperazine
a
Table 2. Optimization of the HT-Amination Protocol for Monosubstituted Substrates
b
entry
solvent
conc (M)
BF3·OEt2 (equiv)
T (°C)
time
yield (%)
trans/cis
1
2
DCE
DCE
DCE
DCE
DCM
toluene
MeCN
THF
DCE
DCE
DCE
DCE
DCE
0.05
3
3
23
23
23
23
23
23
23
23
80
80
80
80
80
80 min
80 min
80 min
80 min
100 min
100 min
19 h
37
46
70
70
55
50
7
95:5
95:5
94:6
90:10
95:5
95:5
95:5
0.025
0.012
0.006
0.012
0.012
0.012
0.012
0.012
0.012
0.012
0.012
0.012
3
3
4
3
5
3
6
3
7
3
8
3
10 h
0
9
3
2
15 min
30 min
30 min
30 min
150 min
85
80
81
85
84
93:7
93:7
92:8
92:8
95:5
10
11
12
1
0.5
c
13
0.5
a
b
c
1
2 equiv of TsNH2 employed, unless otherwise noted. Ratio determined by H NMR of the crude reaction. 1.1 equiv of TsNH2 employed.
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Figure 2. Mechanistic rationale for the observed diastereoselectivity. (A) The experimental data supports the thermodynamic control of the
stereoselectivity. The stereoisomer with the α-aryl group in the axial position is more stable due to the steric bulk of the N-tosyl group and its
position on a partially sp2-hybridized nitrogen. (B) The same rationale explains the formation of the cis-isomer of 2,5-disubstituted piperidine 19 as
the major product.
a
Modification of reaction conditions during optimization had a
small effect on the diastereoselectivity.
Table 3. Stereoselective HT-amination: Substrate Scope
Under optimized conditions (Table 2, entry 9), aldehyde 10
afforded two diastereoisomers in a 93:7 ratio as determined by
1H NMR of the crude mixture (Scheme 4A). The geometry of
the major trans-isomer was established by X-ray crystallography
(see the Supporting Information). However, aldehyde 18 with
the methyl group in the α-position afforded 2,5-disubstituted
piperidine 19 in 65% yield and high stereoselectivity favoring
the cis-isomer (dr 92:8, Scheme 4B). The structure and
geometry of the major isomer was again confirmed by X-ray
crystallographic analysis (see the Supporting Information). As
expected, substantial racemization occurs under the HT-
amination conditions when optically pure substrate 18 is used
(see the Supporting Information).
While we did observe similar results with a substoichiometric
amount of BF3·OEt2 (0.5 equiv, entries 12 and 13, Table 2),
these reaction conditions were not general and failed to effect
the HT-amination of other substrates in good yield.
Mechanistic Rationale for the Observed Stereo-
selectivity. To determine whether the diastereoselectivity of
the HT-amination is kinetically or thermodynamically driven, a
mixture of isomers 11 enriched in the minor cis-isomer (63:37
trans/cis ratio)18 was subjected to the reaction conditions
(Figure 2). The result was a shift in the ratio to 90:10 trans/cis,
which is very close to the product ratio found in the cyclization
reaction. Similar results were obtained for the 2,5-disubstituted
piperidines 19 when a 72:28 cis/trans ratio of products was
equilibrated under the reaction conditions to a 92:8 cis/trans
mixture. These results demonstrate the reversibility of the
cyclization step and support thermodynamic control as the
source of the observed high stereoselectivity. In both cases
(Figure 2A,B), the aryl ring prefers to adopt an axial position in
the chair of the piperidine ring to avoid the steric interaction
with the sulfonamide group. The propensity for axial preference
of substituents adjacent to sp2-hybridized nitrogens has been
termed “pseudo-allylic strain” and has previously been
proposed to explain conformation preferences of N-acyl- and
N-sulfonylpiperidines.19 Under circumstances where the
reaction would be controlled kinetically, the same pseudoallylic
strain rationale could be invoked in the corresponding
transition states.
a
Reactions performed at 0.012 M in dry DCE, with 2 equiv of TsNH2,
b
1
3 equiv of BF3·OEt2, and 4 Å MS 200% by wt dr determined by H
NMR of the crude reaction mixture.
entry 1). Similarly, compound 20 presenting a β-phenyl ring
also reacted well under the optimized conditions, affording the
diaryl piperidine 21 with excellent stereoselectivity (dr 92:8
favoring the trans-isomer) and modest yield (45%, Table 3,
entry 2).
Substrate 18 with the methyl group in the α-position
exhibited relatively lower reactivity in comparison to the
regioisomeric aldehyde 10 (65% yield, Table 3, entry 3), but
the stereoselectivity was high and comparable between these
two substrates. The transposition of the methoxy group on the
arene to the ortho-position resulted in a decrease in yield and
diastereoselectivity (28% yield, 73:27 cis/trans; Table 3, entry
4). Positioning the methoxy group in the meta-position
disfavored the HT-cyclization and led to bicycle 25, the
product of a Friedel−Crafts hydroxyalkylation followed by
dehydration (Table 3, entry 5). We attribute this unexpected
result to the decreased stabilization of the ensuing carbocation
HT-amination of Monosubstituted Aliphatic Alde-
hydes: Substrate Scope. As discussed above, substrate 10
containing a methyl group in the β-position gave the trans-
isomer of 11 in excellent yield and stereoselectivity (Table 3,
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by the methoxy group in the meta-position, which thereby
decreases the hydridic character of the benzylic C−H bonds. In
addition, this placement of the methoxy group may deactivate
the hydridic C−H bonds via a sigma withdrawing effect. With
these effects in action the Friedel−Crafts hydroalkylation
pathway dominates, leading to cyclization at the electron rich
ortho-position of the methoxy group.
HT-amination of Aromatic Aldehydes: Substrate
Scope. We revisited the reactivity of o-(2-arylethyl)-
benzaldehydes in the HT-amination reaction since they afford
an interesting and underexplored class of heterocycles, 3-aryl-
1,2,3,4-tetrahydroisoquinolines (Table 4). While there are
numerous methods reported in the literature for the synthesis
of 1-substituted tetrahydroisoquinolines,20 there are only a few
general methods for the incorporation of the aryl substituents
at the 3-position.5,21 Following our approach based on the HT-
cyclization, 3-aryl-1,2,3,4-tetrahydroisoquinolines can be pre-
pared in four steps from commercially available 2-bromoben-
zaldehydes.
The introduction of either electron-donating (Table 2, entry
2) or -withdrawing groups (Table 2, entries 3−5) onto the
benzaldehyde ring (hydride acceptor) was well tolerated.
Extension of the π-system of the parent substrate 3 to a
naphthaldehyde afforded compound 35 in 85% yield, with an
extension of the reaction time to 5 h.
Directing our focus to the hydride donor portion of the
substrate, we found that the absence of the p-methoxy group
again was not tolerated under the standard reaction conditions.
While clean conversion to the imine was observed by 1H NMR,
only trace HT-amination product 37 was observed even after
heating at 120 °C for 72 h. However, a phenyl group in the 4-
position was tolerated, giving the biphenyl-substituted product
39 in 46% yield. The elevated reaction temperature of 120 °C
was required in order to promote the HT-cyclization. The
isolation of pure crystals of 39 permitted an X-ray analysis,
thereby affirming the proposed 3-aryl-1,2,3,4-tetrahydroisoqui-
noline structure of this and all related products (see the
Supporting Information). Substrate 40 was prepared in order to
investigate the effects of steric hindrance on the HT-amination,
given the potential for the o-methyl group to impede
cyclization. Such a steric effect was found to be minimal, with
product 41 being formed in 80% yield. The methoxynaph-
thalene derivative 42 was also reactive furnishing a 71% yield of
product 43 after an extended reaction time of 24 h.
Table 4. Synthesis of 3-Aryl-1,2,3,4-tetrahydroisoquinolines
a
via HT-amination
Deprotection of N-Tosyl Piperidines. Lastly, we
investigated the removal of N-tosyl group in the context of
the products discussed in this paper, which are all benzyl-
amines. After exploring several known procedures, we found
that sodium naphthalenide, prepared fresh in dimethoxyethane
(DME) at −78 °C, was effective. For example, compound 2
was deprotected to afford 3-aryl-1,2,3,4-tetrahydroisoquinoline
44 in 89% (Scheme 5).22 In addition, deprotection of substrate
19 was accomplished in 87% yield with minimal impact on the
stereochemical integrity of the product.
Scheme 5. Deprotection of the N-Tosyl Group
CONCLUSION
■
In this study, we examined the formation of α-arylpiperidines
via HT-cyclization of N-tosylimines formed in situ from the
corresponding aldehydes. We showed that conformationally
rigid aromatic aldehydes are readily converted to 3-aryl-1,2,3,4-
tetrahydroisoquinolines, an interesting class of heterocycles. In
a systematic manner, we examined the reactivity of aliphatic
aldehydes (5-arylpentanals). We found that a single substituent
on the alkyl chain connecting the N-tosylimine and the benzylic
a
Reactions performed at 0.05 M in dry DCE, with 2 equiv of TsNH2, 3
b
equiv of BF3·OEt2, and 4 Å MS 200% by wt Reactions run in a sealed
vial.
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General Sonogashira Coupling Protocol. A flame-dried flask
was charged with PdCl2(PPh3)2 (2.5 mol %) and CuI (2.5 mol %).
Freshly distilled triethylamine (0.25 M) was then added followed by
the appropriate aryl bromide (1 equiv) and alkyne (1.1 equiv). The
reaction was sealed under argon and heated to 50 °C. The reaction
was monitored by TLC. Upon consumption of the aryl bromide, the
mixture was cooled to room temperature and concentrated in vacuo.
The residue was then dissolved in EtOAc and washed with water and
NH4Cl (aq satd). The organic layer was then dried over MgSO4. The
suspension was filtered, and the filtrate was concentrated in vacuo. The
residue was chromatographed on silica gel to afford the pure product.
General Alkene/Alkyne Hydrogenation Protocol. To a
solution of the appropriate alkene or alkyne in EtOH (0.4 M) was
added 10% by wt Pd/C (20% by wt relative to alkyne/alkene). The
flask was equipped with a magnetic stir bar, and the suspension was
sealed with a septum under an atmosphere of H2 supplied via a
group is sufficient for an efficient HT-cyclization to occur.
Furthermore, we discovered that the HT-cyclization of these
substrates is highly stereoselective affording stereodefined 2,4-
and 2,5-disubstituted piperidines. In addition, we have shown
that the HT-cyclization of N-tosylimines is a reversible,
thermodynamically controlled process and the high stereo-
selectivity is ascribed to the pseudo-allylic strain between the N-
tosyl group and the arene ring in the 2-position. This study has
served to increase the understanding of the HT-amination
reaction and has expanded the scope of HT-transformations in
general.
EXPERIMENTAL SECTION
■
General Considerations. Argon was purified by passage through
Drierite. Nuclear magnetic resonance spectra were recorded at 300 K
on 300, 400, or 500 MHz NMR spectrometers. 1H NMR spectra
1
balloon. The reaction was stirred vigorously and monitored by H
NMR. Following complete hydrogenation, the suspension was filtered
recorded in CDCl3 solutions were referenced to TMS (0.00 ppm). 13
C
through a pad of Celite. The filtrate was concentrated in vacuo to
1
afford the product; the crude product was typically pure by H NMR
NMR spectra recorded in CDCl3 were referenced to the residual
solvent peak (77.16 ppm). High-resolution mass spectra (HRMS)
were obtained on a high resolution sector type double focusing mass
spectrometer (ionization mode: FAB+). Flash chromatography was
performed on silica gel (230−400 mesh). Reactions were monitored
by GC or TLC analysis using hexanes/ethyl acetate and hexanes/
diethyl ether mixtures as the eluent and visualized using permanganate
stain and/or cerric ammonium molybdate stain and/or UV light.
Chloroform-d1 was stored over 4 Å molecular sieves. Dichloroethane
and triethylamine were freshly distilled from CaH2. Substrates 1223a
and 3623b were prepared according to literature procedures.
General HT-amination Protocol. Activated 4 Å molecular sieves
(200% by wt relative to substrate) were added to an oven-dried flask
followed by toluenesulfonamide (2 equiv), the appropriate substrate,
and a magnetic stir bar. The mixture was sealed under a rubber septum
and backfilled with argon. DCE, freshly distilled from calcium hydride,
was then added via syringe, followed by addition of BF3·OEt2 (3
equiv) via microsyringe. The reaction was placed in an oil bath and
heated to 80 °C. The reaction was monitored by TLC, employing UV
and KMnO4 stain visualization; however, the N-tosylimine and
cyclized product often exhibited identical Rf values. As such, 1H
NMR may be required to ensure the reaction has gone to completion.
Following conversion of the starting material, the reaction was filtered
through a cotton plug and concentrated in vacuo. The resulting
residue was purified by flash column chromatography on silica gel.
Representative Procedure. To a solution of 1-(3-(4-
methoxyphenyl)propyl)cyclohexanecarbaldehyde (6) (66 mg, 0.3
mmol) in freshly distilled DCE (6 mL) were added TsNH2 (103
mg, 0.6 mmol) and 4 Å molecular sieves (132 mg). The reaction was
sealed with a septum under argon. BF3·OEt2 (113 μL, 0.9 mmol) was
then added via syringe, and the mixture was stirred at room
temperature. The reaction was monitored by TLC (30% Et2O/
Hex). Upon complete consumption of the starting material, the
mixture was filtered through a cotton plug and concentrated in vacuo.
The residue was chromatographed on silica gel, eluting with 25%
Et2O/Hex to afford 3-(4-methoxyphenyl)-2-tosyl-2-azaspiro[5.5]-
undecane (7) as a white solid (107 mg, 95%).
and employed directly in the next step.
General LiAlH4 Reduction Protocol. A flame-dried flask was
charged with LiAlH4 (1.5 equiv), followed by the addition of THF
(0.17 M based on ester). The suspension was then cooled to 0 °C in
an ice bath, and a solution of the appropriate ester in THF (0.24 M
based on ester) was added slowly. The reaction was then allowed to
warm to room temperature. The reaction was monitored by TLC.
After complete reduction of the starting material, the reaction was
cooled to 0 °C and quenched with water (3 mL/1 g LiAlH4), KOH
20% (9 mL/1 g LiAlH4), and finally water (15 mL/1 g LiAlH4). After
being stirred for 5 min, the suspension was filtered and the filtrate
dried over MgSO4 and concentrated in vacuo. The product alcohol
was typically pure by 1H NMR and employed directly in the next step.
General MnO2 Oxidation Protocol. To a solution of alcohol (1
equiv) in DCM (0.3 M) was added MnO2 (5 equiv). The suspension
was stirred vigorously and monitored by TLC. Upon complete
conversion of the starting material, the mixture was filtered through
Celite and the filtrate concentrated in vacuo. The residue was
chromatographed on silica gel to afford the pure aldehyde.
General Pyridinium Chlorochromate (PCC) Oxidation Pro-
tocol. To a solution of alcohol (1 equiv) in DCM (0.2 M) was added
PCC (2.25 equiv). The mixture was stirred and monitored by TLC.
Upon conversion of the starting material, the suspension was filtered
through a pad of silica gel. The filtrate was concentrated in vacuo and
the residue chromatographed on silica gel to afford the pure aldehyde.
General Swern Oxidation Protocol. A solution of DMSO (2.4
equiv) in dry DCM (1 M) was cooled to −78 °C under an argon
atmosphere. Oxalyl chloride (1.2 equiv, 2.0 M solution in DCM) was
added dropwise. The resulting solution was stirred at −78 °C for 30
min. A solution of the corresponding alcohol (1 equiv) in dry DCM (5
M) was added dropwise to the reaction mixture. The reaction was
stirred at −78 °C for 1 h. Triethylamine was then added to the
solution, and the mixture was allowed to warm to room temperature.
The reaction mixture was poured into water (3 × total volume of
DCM) and extracted four times with DCM. The combined organic
layers were then washed sequentially with saturated aqueous CuSO4
solution and brine and then dried over MgSO4. The suspension was
filtered and the filtrate concentrated in vacuo. The residue was then
chromatographed on silica gel to afford the pure aldehyde.
General Heck Reaction Protocol. A flame-dried Schlenk tube
was charged with Pd(OAc)2 (5 mol %), followed by the addition of
DMF (0.25 M). The appropriate alkene (1 equiv) and aryl iodide/
bromide (1.1 equiv) were subsequently added. Freshly distilled
triethylamine (1.1 equiv) was then added to the reaction mixture. The
vessel was equipped with a magnetic stir bar and sealed under argon.
The reaction was then heated to 80 °C and monitored by TLC. Upon
complete consumption of the alkene, the reaction was cooled to room
temperature and poured into water (3 × volume of DMF). The
resulting solution was extracted with EtOAc (4 × volume of DMF).
The combined organic layers were then washed twice with water and
once with brine and dried over MgSO4. The suspension was filtered,
and the filtrate was concentrated in vacuo. The residue was then
chromatographed on silica gel to afford the pure product.
N-(2-(4-Methoxyphenethyl)benzylidene)-4-methylbenzene-
sulfonamide (1). To a solution of 2-(4-methoxyphenethyl)-
benzaldehyde24 (720 mg, 6.0 mmol) in THF (6 mL) were added
TsNH2 (1.03 g, 6.0 mmol) and Ti(OEt)4 (1.9 mL, 9.0 mmol). The
reaction was sealed with a septum under argon and stirred for 24 h.
The reaction was then diluted with EtOAc, and the resulting solution
was poured into brine. The suspension was filtered through Celite, and
the filtrate was extracted with EtOAc. The combined organic layers
were dried over MgSO4. The suspension was filtered, and the filtrate
was concentrated in vacuo. The residue was then crystallized from
Et2O/Hex, affording 1 as a pale yellow solid (611 mg, 52%): 1H NMR
F
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(CDCl3, 300 MHz) δ 2.43 (s, 3H), 2.79 (t, J = 8.4 Hz, 2H), 3.19 (d, J
= 8.4 Hz, 2H), 3.79 (s, 3H), 6.81 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7
Hz, 2H), 7.34−7.23 (m, 4H), 7.49 (dt, J = 9.0 Hz, J = 1.5 Hz, 1H),
7.85 (d, J = 8.4 Hz, 2H), 7.99 (dd, J = 7.8 Hz, J = 1.2 Hz, 1H), 9.19 (s,
1H); 13C NMR (CDCl3, 75 MHz) δ 21.7, 35.4, 37.7, 55.3, 114.0,
126.9, 128.1, 129.6, 129.9, 130.1, 131.1, 131.2, 132.5, 134.7, 135.4,
144.6, 146.0, 158.2, 168.5; HRMS (FAB+) calcd for C23H24NO3S+
3H), 6.15 (d, J = 16.2 Hz, 1H), 6.28 (d, J = 16.2 Hz, 1H), 6.83 (d, J =
8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H). The resulting alkene (2.16 g,
8.70 mmol) was hydrogenated according to the hydrogenation
protocol employing 10% by wt Pd/C (432 mg, 20% by wt) in
EtOH (20 mL) to afford methyl 5-(4-methoxyphenyl)-3,3-dimethyl-
1
pentanoate as a colorless oil (1.47 g, 67%): H NMR (CDCl3, 300
MHz) δ 1.06 (s, 6H), 1.58 (bt, J = 8.1 Hz, 2H), 2.28 (s, 2H), 2.54 (d, J
= 8.1 Hz, 2H), 3.66 (s, 3H), 3.78 (s, 3H), 6.82 (d, J = 7.8 Hz, 2H),
7.10 (d, J = 7.5 Hz, 2H). The resulting ester (1.47 g, 5.86 mmol) was
reduced according to the LiAlH4 reduction protocol employing LiAlH4
(335 mg, 8.80 mmol) in THF (36 + 24 mL) followed by direct
oxidation of the crude product alcohol according to the PCC oxidation
protocol to afford aldehyde 8 (733 mg, 57% over two steps) as a
colorless oil following chromatography on silica gel, eluting with 8%
+
394.1471 , measured 394.1483 [M + 1].
5-(4-Methoxyphenyl)-2,2-dimethylpentanal (4). Prepared ac-
cording to the Heck protocol from ethyl 2,2,-dimethylpent-4-enoate25
(1.7 g, 10.9 mmol), 4-iodoanisole (2.63 g, 11.0 mmol), and Pd(OAc)2
(122 mg, 0.55 mmol, 5 mol %), in DMF (50 mL) and TEA (1.54 mL),
followed by direct hydrogenation according to the alkene hydro-
genation protocol to afford ethyl 2,2-dimethyl-5-phenylpentanoate as a
1
1
colorless oil (1.39 g, 76% over two steps): H NMR (CDCl3, 300
Et2O/Hex: H NMR (CDCl3, 300 MHz) δ 1.12 (s, 6H), 1.58−1.64
MHz) δ 1.14 (s, 6H), 1.22 (t, J = 7.2 Hz, 3H), 1.54 (apparent d, J =
3.6 Hz, 4H), 2.52 (bt, J = 6.6 Hz, 2H), 3.78 (s, 3H), 4.09 (quart, J =
7.2 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H). The
resulting ester (1.39 g, 5.29 mmol) was reduced according to the
LiAlH4 reduction protocol employing LiAlH4 (302 mg, 7.93 mmol) in
THF (32 + 22 mL) to afford pure product alcohol 2,2-dimethyl-5-
(m, 2H), 2.32 (s, 2H), 2.51−2.57 (m, 2H), 3.77 (s, 3H), 6.82 (d, J =
8.7 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 9.86 (t, J = 3.0 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 27.6, 29.7, 33.7, 45.2, 54.8, 55.3, 114.0,
+
129.2, 134.6, 157.9, 203.4; HRMS (FAB+) calcd for C14H21O2
221.1536 [M + 1], measured 221.1538 [M + 1].
5-(4-Methoxyphenyl)-3-methylpentanal (10). Triethyl phos-
phonoacetate (0.916 g, 4.08 mmol) was weighed into a flame-dried,
two-neck round-bottom flask equipped with a magnetic bar. Dry THF
(3 mL, 2 M) was added under an argon atmosphere. NaH (60%
suspension in mineral oil, 120 mg) was washed properly and added to
the reaction vessel. The reaction mixture was stirred at room
temperature for 30 min. 4-(4-Methoxyphenyl)butan-2-one (0.73 g,
4.09 mmol) in a solution of THF (2 mL, 2 M) was added dropwise to
the reaction mixture. The reaction was monitored by TLC. After 18 h,
the mixture was concentrated in vacuo. The residue was then dissolved
in diethyl ether (30 mL) and washed with saturated NaHCO3 (10
mL). The organic layer was dried over NaSO4. The suspension was
filtered, and the filtrate was concentrated in vacuo. The residue was
chromatographed on silica gel and eluted with EtOAc/Hex (5:95) to
afford the corresponding ester (0.64 g, 63%) as a colorless oil. This
ester was then subjected to the alkene hydrogenation protocol
employing Pd/C 10% by wt (64 mg) dissolved in EtOH (7 mL) to
afford ethyl 5-(4-methoxyphenyl)-3-methylpentanoate (0.511 g, 2.05
mmol, 50% yield over two steps), which was employed directly in the
1
phenylpentan-1-ol (1.17 g, 99%) as a colorless oil: H NMR (CDCl3,
300 MHz) δ 0.86 (s, 6H), 1.30−1.25 (m, 3H), 1.58−1.50 (m, 2H),
2.53 (t, J = 7.8 Hz, 2H), 3.30 (s, 2H), 3.78 (s, 3H), 6.82 (d, J = 8.4 Hz,
2H), 7.10 (d, J = 8.4 Hz, 2H). The resulting alcohol (1.16 g, 5.23
mmol) was oxidized according to the PCC oxidation protocol
employing PCC (2.54 g, 11.8 mmol) in DCM (25 mL) to afford
aldehyde 4 (888 mg, 77%) as a colorless oil following chromatography
on silica gel, eluting with 5% Et2O/Hex: 1H NMR (CDCl3, 300 MHz)
δ 1.03 (s, 6H), 1.53−1.45 (bm, 4H), 2.53−2.51 (bm, 2H), 3.78 (s,
3H), 6.82 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 9.42 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 21.4, 26.4, 35.5, 36.8, 45.8, 55.3, 113.9,
129.3, 134.1, 157.9, 206.4; HRMS (FAB+) calcd for C14H20O2
220.1463 [M], measured 220.1463 [M].
1-(3-(4-Methoxyphenyl)propyl)cyclohexanecarbaldehyde
(6). Prepared according to the Heck protocol from methyl 1-
allylcyclohexanecarboxylate (1.82 g, 10.0 mmol), 4-iodoanisole (2.58
g, 11.0 mmol), and Pd(OAc)2 (67 mg, 0.30 mmol, 3 mol %), in DMF
(50 mL), to afford (E)-methyl 1-(3-(4-methoxyphenyl)allyl)-
1
1
cyclohexanecarboxylate as a pale yellow oil (1.62 g, 56%): H NMR
next step; H NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz, 2H),
(CDCl3, 300 MHz) δ 1.34−1.18 (m, 6H), 1.62−1.54 (m, 2H), 2.12−
2.06 (m, 2H), 2.36 (d, J = 7.5 Hz, 2H), 3.67 (s, 3H), 3.79 (s, 3H),
5.89−6.00 (m, 1H), 6.30 (d, J = 15.9 Hz, 1H), 6.82 (d, J = 8.7 Hz,
2H), 7.25 (d, J = 8.7 Hz, 2H). The resulting alkene (1.62 g, 5.60
mmol) was hydrogenated according to the hydrogenation protocol
employing 10% by wt Pd/C (324 mg, 20% by wt) in EtOH (15 mL)
to a fford m ethy l 1- (3-( 4-metho xy pheny l)p ro py l)-
cyclohexanecarboxylate as a colorless oil (1.53 g, 94%): 1H NMR
(CDCl3, 300 MHz) δ 1.33−1.12 (m, 6H), 1.52−1.48 (m, 6H), 2.05
(bd, J = 12.0 Hz, 2H), 2.49 (bs, 2H), 3.65 (s, 3H), 3.78 (s, 3H), 6.81
(d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H). The resulting ester (1.53
g, 5.26 mmol) was reduced according to the LiAlH4 reduction
protocol employing LiAlH4 (300 mg, 7.89 mmol) in THF (30 + 20
mL) followed by direct oxidation of the crude product alcohol
according to PCC oxidation protocol to afford aldehyde 6 (980 mg,
72% over two steps) as a colorless oil following chromatography on
6.82 (d, J = 8.7 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 2.48−
2.67 (m, 2H), 2.34 (dd, J = 14.7, 6.2 Hz, 1H), 2.15 (dd, J = 14.8, 8.0
Hz, 1H), 2.00 (sext, J = 6.2 Hz, 1H), 1.59−1.65 (m, 1H), 1.47−1.52
(m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H). The ester
(0.492 g, 1.97 mmol) was reduced according to the LiAlH4 reduction
protocol employing LiAlH4 (0.112 g, 2.95 mmol) in THF (11 + 8 mL)
to afford pure 5-(4-methoxyphenyl)-3-methylpentan-1-ol (0.376 g,
92%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.10 (d, J = 8.7
Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.65−3.72 (m, 2H),
2.47−2.67 (m, 2H), 1.56−1.68 (m, 3H), 1.37−1.48 (m, 3H), 0.96 (d, J
= 6.3 Hz, 3H). The intermediate alcohol (0.346 g, 1.66 mmol) was
then oxidized according to the Swern oxidation protocol employing
(COCl)2 (0.99 mL of 2.0 M solution in DCM), DMSO (0.311 g, 3.98
mmol), and TEA (0.672 g, 6.65 mmol) in DCM (2 + 4 mL). The
crude material was purified by silica gel column chromatography (8%
Et2O/Hex) to afford the pure aldehyde 10 (0.250 g, 73%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.74 (t, J = 2.2 Hz, 1H),
7.09 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 2.54−
2.63 (m, 2H), 2.44 (ddd, J = 16.0, 5.7, 2.0 Hz, 1H), 2.27 (ddd, J =
16.1, 7.9, 16.1 Hz, 1H), 2.08−2.13 (m, 1H), 1.51−1.66 (m, 2H), 1.02
(d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.3, 158.2,
134.4; 129.6, 129.6, 114.2, 114.2, 55.7, 51.4, 39.3, 32.7, 28.1, 20.2;
HRMS (FAB+) calcd for C13H18O2 207.1307 [M], measured 206.1324
[M].
1
silica gel, eluting with 8% Et2O/Hex: H NMR (CDCl3, 400 MHz) δ
1.31−1.21 (m, 4H), 1.53−1.42 (m, 8H), 1.88−1.85 (m, 2H), 2.50 (t, J
= 6.8 Hz, 2H), 3.78 (s, 3H), 6.81 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8
Hz, 2H), 9.39 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 22.7, 25.6,
25.9, 31.1, 35.5, 36.1, 49.8, 55.4, 113.9, 129.3, 134.1, 157.9, 207.3;
HRMS (FAB+) calcd for C17H24O2 260.1776 [M], measured 260.1767
[M].
5-(4-Methoxyphenyl)-3,3-dimethylpentanal (8). Prepared ac-
cording to the Heck protocol from methyl 3,3-dimethylpent-4-enoate
(2.13 g, 15.0 mmol), 4-iodoanisole (3.86 g, 16.5 mmol), and
Pd(OAc)2 (100 mg, 0.45 mmol, 3 mol %), in DMF (75 mL) and
TEA (2.3 mL) to afford (E)-methyl 5-(4-methylphenyl)-3,3-
dimethylpent-4-enoate as a colorless oil (2.16 g, 58%): 1H NMR
(CDCl3, 300 MHz) δ 1.23 (s, 6H), 2.38 (s, 2H), 3.62 (s, 3H), 3.78 (s,
Methyl 4-(3,3-Dimethyl-5-oxopentyl)phenylcarbamate (14).
Prepared according to the Heck protocol from methyl 3,3-
dimethylpent-4-enoate (1.30 g, 9.09 mmol), aryl iodide methyl 4-
iodophenylcarbamate (2.77 g, 10.0 mmol), and Pd(OAc)2 (102 mg,
0.45 mmol, 5 mol %), in DMF (45 mL) and TEA (2.5 mL) to afford
methyl 5-(4-methoxycarbonylamino)phenyl)-3,3-dimethylpentenoate
G
dx.doi.org/10.1021/jo300635m | J. Org. Chem. XXXX, XXX, XXX−XXX

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1
as a colorless oil (1.38 g, 52%): H NMR (CDCl3, 300 MHz) δ 1.23
according to the LiAlH4 reduction protocol employing LiAlH4 (0.222
g, 5.85 mmol) in THF (22 + 16 mL) to afford pure 5-(4-
methoxyphenyl)-2-methylpentan-1-ol (0.722 g, 3.71 mmol, 95%) as
a colorless oil following silica gel column chromatography, eluting with
20% EtOAc/Hex: 1H NMR (300 MHz, CDCl3) δ 7.03 (d, J = 8.4 Hz,
2H), 6.77 (d, J = 8.5 Hz, 2H), 3.72 (s, 3H), 3.33−3.48 (m, 2H), 2.49
(ddd, J = 8.8, 8.8, 2.6 Hz, 2H), 1.50−1.63 (m, 3H), 1.22−1.44 (m,
1H), 1.15 (bs, 1H), 1.03−1.10 (m, 1H), 0.85 (d, J = 6.7 Hz, 3H). The
resulting alcohol (0.70 g, 3.36 mmol) was oxidized according to the
Swern oxidation protocol employing (COCl)2 (2.02 mL of 2.0 M
solution in DCM), DMSO (0.630 g, 8.07 mmol), TEA (1.36 g, 13.4
mmol) in DCM (2 + 4 mL). The crude material was purified by silica
gel column chromatography eluting with 5% EtOAc/Hex to afford the
(s, 6H), 2.40 (s, 2H), 3.63 (s, 3H), 3.75 (s, 3H), 6.32−6.18 (m, 2H),
7.08 (bs, 1H), 7.33−7.27 (m, 4H). The resulting alkene (918 mg, 3.15
mmol) was hydrogenated according to the hydrogenation protocol
employing 10% by wt Pd/C (100 mg, 20% by wt) in EtOH (10 mL)
to afford methyl 5-(4-methoxycarbonylamino)phenyl)-3,3-dimethyl-
1
pentanoate as a colorless oil (877 mg, 95%): H NMR (CDCl3, 300
MHz) δ 1.06 (s, 6H), 1.61−1.55 (m, 2H), 2.28 (s, 2H), 2.58−2.52 (m,
2H), 3.66 (s, 3H), 3.76 (s, 3H), 6.65 (bs, 1H), 7.12 (d, J = 8.4 Hz,
2H), 7.28 (d, J = 8.7 Hz, 2H). A flame-dried flask was charged with
LiBH4 (196 mg, 9.0 mmol, 3 equiv), followed by the addition of THF
(7 mL). The suspension was then cooled to 0 °C in an ice bath, and a
solution of methyl 5-(4-methoxycarbonylamino)phenyl)-3,3-dimethyl-
pentanoate in THF (3 mL) was added slowly. The reaction was then
allowed to warm to room temperature and was stirred overnight. After
complete reduction of the starting material, the mixture was diluted
with water (50 mL) followed by the slow addition of 10% HCl (aq).
The solution was then neutralized with saturated NaHCO3, and the
resulting solution was extracted with EtOAc. The combined organic
layers were washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude intermediate alcohol was employed directly in the
next step. The alcohol was then subjected to the Swern oxidation
protocol employing DMSO (0.51 mL, 7.20 mmol), oxalyl chloride 2
M in DCM (1.80 mL, 3.60 mmol), and triethylamine (1.70 mL, 12
mmol) in DCM (10 mL) to afford aldehyde 14 (603 mg, 76% over
two steps) as a colorless oil following chromatography on silica gel,
1
pure aldehyde 18 (0.506 g, 2.45 mmol, 73%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 9.58 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 8.5
Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.77 (s, 3H), 2.56 (t, J = 7.3 Hz,
2H), 2.33 (dsext, J = 6.9; 1.9 Hz, 1H), 1.57−1.76 (m, 3H), 1.34−1.43
(m, 1H), 1.08 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
205.5, 158.2, 134.4; 129.7, 129.6, 114.2, 114.2, 55.6, 46.6, 35.3, 30.4,
29.3, 13.7; HRMS (FAB+) calcd for C13H18O2 206.1307 [M],
measured 206.1321 [M].
5-(4-Methoxyphenyl)-3-phenylpentanal (20). Prepared ac-
cording to the procedure for compound 10 from triethyl
phosphonoacetate (0.821 g, 2.66 mmol), NaH from 60% mineral oil
suspension (0.140 g), and 3-(4-methoxyphenyl)-1-phenylpropan-1-
one (0.80 g, 3.33 mmol) in THF (4 + 4 mL). After purification using
silica gel column chormatography (5% EtOAc/Hex) the correspond-
ing ester was submitted to direct hydrogenation according to the
hydrogenation protocol using Pd/C 10% by wt (80 mg) in EtOH (10
mL) to afford ethyl 5-(4-methoxyphenyl)-3-phenylpentanoate (0.52 g,
1.66 mmol, 50% over two steps) which was employed directly in the
1
eluting with 30% Et2O/Hex: H NMR (CDCl3, 300 MHz) δ 1.13 (s,
6H), 1.64−1.58 (m, 2H), 2.34 (d, J = 3.0 Hz, 2H), 2.58−2.53 (m,
2H), 3.76 (s, 3H), 6.63 (bs, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.29 (d, J =
8.4 Hz, 2H), 9.87 (t, J = 3.0 Hz, 1H); HRMS (FAB+) calcd for
C15H21NO3 263.1521 [M], measured 263.1528 [M].
1
2,2-Dimethyl-5-phenylpentanal (16). Prepared according to the
Heck protocol from ethyl 2,2,-dimethylpent-4-enoate25 (1.56 g, 10.0
mmol), 4-iodobenzene (1.3 mL, 11.0 mmol), and Pd(OAc)2 (67 mg,
0.30 mmol, 3 mol %) in DMF (50 mL) to afford (E)-ethyl 3,3-
dimethyl-5-phenylpent-4-enoate as a pale yellow oil (1.85 g, 80%): 1H
NMR (CDCl3, 300 MHz) δ 1.22 (s, 6H), 1.25 (t, J = 7.2 Hz, 3H), 2.43
(dd, J = 7.5 Hz, J = 0.9 Hz, 2H), 4.13 (quart, J = 7.2 Hz, 2H), 6.20−
6.09 (m, 1H), 6.40 (d, J = 15.9 Hz, 1H), 7.34−7.20 (m, 5H). The
resulting alkene (1.85 g, 7.97 mmol) was hydrogenated according to
the hydrogenation protocol employing 10% by wt Pd/C (370 mg, 20%
by wt) in EtOH (20 mL) to afford ethyl 3,3-dimethyl-5-phenyl-
next step: H NMR (300 MHz, CDCl3) δ 7.31−7.34 (m, 2H), 7.19−
7.28 (m, 3H), 7.01 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 4.02
(q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.12−3.23 (m, 1H), 2.60 (t, J = 6.1
Hz, 2H), 2.40 (t, J = 8.4 Hz, 2H), 1.86−1.97 (m, 2H), 1.12 (t, J = 6.9
Hz, 3H). The crude ester (0.75 g, 2.40 mmol) was reduced according
to the LiAlH4 reduction protocol employing LiAlH4 (0.14 g, 3.61
mmol) in THF (14 + 10 mL) to afford pure 5-(4-methoxyphenyl)-3-
1
phenylpentan-1-ol (0.616 g, 2.28 mmol, 95%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz, 2H), 7.20 (dd, J = 5.5,
4.1 Hz, 3H), 7.01 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 3.77 (s,
3H), 3.43−3.56 (m, 2H), 2.72 (t, J = 7.9 Hz, 1H), 2.40 (t, J = 7.9 Hz,
2H), 1.86−1.99 (m, 4H), 1.56 (brs, 1H). The intermediate alcohol
(0.53 g, 1.95 mmol) was oxidized according to the Swern oxidation
protocol employing (COCl)2 (1.17 mL of 2.0 M solution in DCM),
DMSO (0.37 g, 4.68 mmol), TEA (0.79 g, 7.80 mmol) in DCM (2 + 4
mL). The crude product was purified by silica gel column
chromatography 5% EtOAc/Hex to afford the pure aldehyde 20
1
pentanoate as a colorless oil (1.70 g, 91%): H NMR (CDCl3, 300
MHz) δ 1.15 (s, 6H), 1.22 (t, J = 7.2 Hz, 3H), 1.56 (bs, 4H), 2.59 (bs,
2H), 4.09 (quart, J = 7.2 Hz, 2H), 7.27−7.15 (m, 5H). The
intermediate ester (1.70 g, 7.25 mmol) was reduced according to the
LiAlH4 reduction protocol employing LiAlH4 (413 mg, 10.88 mmol)
in THF (42 + 28 mL) followed by direct oxidation of the crude
product alcohol according to the PCC oxidation protocol to afford
aldehyde 16 (1.11 g, 81% over two steps) as a colorless oil following
1
(0.37 g, 1.36 mmol, 70%) as a colorless oil: H NMR (300 MHz,
CDCl3) δ 9.63 (t, J = 2.1 Hz, 1H), 7.33 (t, J = 6.5 Hz, 2H), 7.21−7.23
(m, 3H) 7.01 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 3.77 (s,
3H), 3.19 (quintet, J = 7.4 Hz, 1H), 2.72 (ddd J = 7.4, 2.1, 1.3 Hz,
2H), 2.42 (ddd, J = 9.0, 9.0, 1.8 Hz, 2H), 1.90−1.99 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 202.1, 158.2, 143.8; 134.1, 129.6, 129.6,
129.1, 129.1, 128.0, 128.0, 127.1, 114.2, 114.2, 55.6, 51.1, 39.9, 38.7,
32.0; HRMS (FAB+) calcd for C18H20O2 268.1463 [M], measured
268.1476 [M].
1
chromatography on silica gel, eluting with 5% Et2O/Hex: H NMR
(CDCl3, 300 MHz) δ 1.03 (s, 6H), 1.55−1.51 (bm, 4H), 2.60 (t, J =
6.9 Hz, 2H), 7.30−7.14 (m, 5H), 9.42 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 21.4, 26.2, 36.5, 36.9, 45.9, 126.0, 128.5, 128.7, 142.1, 206.4;
HRMS (FAB+) calcd for C13H18O 190.1358 [M], measured 190.1371
[M].
5-(4-Methoxyphenyl)-2-methylpentanal (18). Prepared ac-
cording to the Heck protocol from ethyl 2-methylpent-4-enoate
(1.00 g, 7.03 mmol), 4-iodoanisole (1.81 g, 7.74 mmol), and
PdCl2(PPh3)2 (24 mg, 5 mol %) in DMF (28 mL) and TEA (0.78
g, 7.7 mmol) to afford (E)-ethyl-5-(4-methoxyphenyl)-2-methylpent-
4-enoate as a pale yellow oil. The resulting alkene was hydrogenated
according to the hydrogenation protocol employing Pd/C 10% by wt
(99.0 mg) in EtOH (10.0 mL) to afford ethyl 5-(4-methoxyphenyl)-2-
methylpentanoate (1.12 g, 4.5 mmol, 64% over two steps) which was
5-(2-Methoxyphenyl)-2-methylpentanal (22). Prepared ac-
cording to the Heck protocol from ethyl 2-methylpent-4-enoate
(1.00 g, 7.03 mmol), 2-iodoanisole (1.81 g, 7.74 mmol), and
PdCl2(PPh3)2 (24 mg, 5 mol %) in DMF (28 mL) and TEA (0.78
g, 7.7 mmol). The resulting alkene was submitted to the hydro-
genation protocol using EtOH (10 mL) and Pd/C 10% by wt (100
mg) to afford ester ethyl 5-(2-methoxyphenyl)-2-methylpentanoate
(0.88 g, 3.52 mmol, 50% over two steps) which was used directly in
1
1
employed directly in the next step: H NMR (300 MHz, CDCl3) δ
the next step: H NMR (300 MHz, CDCl3) δ 7.16 (ddd, J = 9.6, 7.8,
7.08 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.12 (q, J = 8.7 Hz,
2H), 3.79 (s, 3H), 2.55 (t, J = 7.4 Hz, 2H), 2.43 (t, J = 7.4 Hz, 1H),
1.54−1.73 (m, 3H), 1.43−1.49 (m, 1H), 1.24 (t, J = 7.3 Hz, 3H), 1.13
(d, J = 6.9 Hz, 3H). The crude ester (0.975 g, 3.90 mmol) was reduced
1.8 Hz, 1H), 7.11 (dd, J = 7.4, 1.6 Hz, 1H), 6.82−6.89 (m, 2H), 4.12
(q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 2.45 (sext, J
= 7.0 Hz, 1H), 1.65−1.73 (m, 1H), 1.56−1.61 (m, 2H), 1.40−1.50 (m,
1H), 1.24 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 6.9 Hz, 3H). The crude ester
H
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Featured Article
(0.87 g, 3.46 mmol) was reduced according to the LiAlH4 reduction
protocol employing LiAlH4 (0.197 g, 5.19 mmol) in THF (17 + 14
mL) to afford pure 5-(2-methoxyphenyl)-2-methylpentan-1-ol (0.633
g, 3.04 mmol, 88%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.12−7.20 (m, 2H), 6.83−6.93 (m, 2H), 3.82 (s, 3H), 3.51 (dd, J =
10.4, 6.0 Hz, 1H), 3.42 (dd, J = 10.2, 6.6 Hz, 1H), 2.60 (ddd, J = 8.8,
6.9, 2.3 Hz, 2H), 1.41−1.70 (m, 4H), 1.30 (brs, 1H), 1.17−1.23 (m,
1H), 0.93 (d, J = 6.7 Hz, 3H). The intermediate alcohol (0.77 g, 3.70
mmol) was oxidized according to the Swern oxidation protocol
employing (COCl)2 (2.21 mL of 2.0 M solution in DCM), DMSO
(0.693 g, 8.90 mmol), TEA (1.50 g, 14.7 mmol) in DCM (3 + 6 mL).
The crude product was purified by silica gel column chromatography
eluting with 10% EtOAc/Hex to afford the pure aldehyde 22 (0.412 g,
2.0 mmol, 54%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.57
(d, J = 2.0 Hz, 1H), 7.06−7.16 (m, 2H), 6.78−6.87 (m, 2H), 3.76 (s,
3H), 2.62 (t, J = 7.4 Hz, 2H), 2.33 (dsext, J = 7.0, 1.9 Hz, 1H), 1.59−
1.73 (m, 3H), 1.36−1.42 (m, 1), 1.05 (d, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 205.6, 157.8, 130.7; 130.2, 127.6, 120.8, 110.7,
55.6, 46.6, 30.6, 30.6, 27.6, 13.7; HRMS (FAB+) calcd for C13H18O2
206.1307 [M], measured 206.1311 [M].
Hz, 2H), 3.76 (s, 3H), 6.80 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.8 Hz,
2H), 7.17−7.15 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 10.09 (s, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 34.0, 37.7, 55.3, 113.9, 116.9 (d, J = 21.6
Hz), 120.9 (d, J = 21.1 Hz), 129.6, 132.7, 133.1 (d, J = 6.9 Hz), 135.3
(d, J = 5.5 Hz), 140.2, 158.2, 161.5 (d, J = 245.8 Hz), 190.5; HRMS
(FAB+) calcd for C16H15FO2 258.1056 [M], measured 258.1054 [M].
4-Fluoro-2-(4-methoxyphenethyl)benzaldehyde (30). Pre-
pared according to the Sonogashira conditions from methyl 2-
bromo-4-fluorobenzoate (1.6 mL, 6.88 mmol), 4-ethynylanisole (1.0 g,
7.57 mmol), PdCl2(PPh3)2 (91 mg, 0.13 mmol, 2 mol %), and CuI (25
mg, 0.13 mmol, 2 mol %) in freshly distilled triethylamine (23 mL) to
afford methyl 4-fluoro-2-((4-methoxyphenyl)ethynyl)benzoate as a
yellow solid (1.81 g, 93%) following chromatography on silica gel,
1
eluting with 20% Et2O/Hex: H NMR (CDCl3, 300 MHz) δ 3.81 (s,
3H), 3.94 (s, 3H), 6.88 (d, J = 9.0 Hz, 2H), 7.03 (dt, J = 7.8 Hz, J = 2.4
Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.98 (dd, J
= 6.0 Hz, J = 3.0 Hz, 1H). The intermediate alkyne (1.81 g, 6.37
mmol) was hydrogenated according to the hydrogenation protocol
employing 10% by wt Pd/C (362 mg, 20% by wt) in EtOH (22 mL)
to afford methyl 4-fluoro-2-(4-methoxyphenylethyl)benzoate as a
colorless oil (1.77 g, 96%): 1H NMR (CDCl3, 300 MHz) δ 2.84 (dd, J
= 8.4 Hz, J = 5.7 Hz, 2H), 3.22 (dd, J = 8.4 Hz, J = 5.7 Hz, 2H), 3.79
(s, 3H), 3.89 (s, 3H), 6.83 (d, J = 8.4 Hz, 2H), 6.95−6.84 (m, 2H),
7.13 (d, J = 8.4 Hz, 2H), 7.94 (dd, J = 8.7 Hz, J = 6.0 Hz, 1H). The
resulting ester (1.75 g, 6.06 mmol) was reduced according to the
LiAlH4 reduction protocol employing LiAlH4 (345 mg, 9.09 mmol) in
THF (36 + 24 mL) followed by direct oxidation of the crude product
alcohol according to the manganese dioxide oxidation protocol to
afford aldehyde 30 (1.19 g, 76% over two steps) as a white solid
following chromatography on silica gel, eluting with 15% EtOAc/Hex:
1H NMR (CDCl3, 300 MHz) δ 2.83 (t, J = 8.1 Hz, 2H), 3.27 (t, J =
8.1 Hz, 2H), 3.75 (s, 3H), 6.80 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 9.3 Hz,
1H), 7.09−6.99 (m, 3H), 7.81 (t, J = 7.8 Hz, 1H), 10.08 (s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 34.9, 37.0, 55.2, 113.9 (d, J = 21.5 Hz),
113.9, 118.0 (d, J = 21.4 Hz), 129.5, 130.5, 132.8, 135.1 (d, J = 9.9
Hz), 147.9 (d, J = 8.8 Hz), 158.2, 165.7 (d, J = 254.9 Hz), 190.5;
HRMS (FAB+) calcd for C16H15FO2 258.1056 [M], measured
258.1049 [M].
5-(3-Methoxyphenyl)-2-methylpentanal (24). Prepared ac-
cording to the Heck protocol from ethyl 2-methylpent-4-enoate
(1.00 g, 7.03 mmol), 2-iodoanisole (1.81 g, 7.74 mmol), and
PdCl2(PPh3)2 (24 mg, 5 mol %) in DMF (28 mL) and TEA (0.78
g, 7.7 mmol). The resulting alkene was submitted to the hydro-
genation protocol using EtOH (10 mL) and Pd/C 10% by wt (100
mg) to afford ethyl 5-(3-methoxyphenyl)-2-methylpentanoate (0.65 g,
2.60 mmol, 37% over two steps) which was used directly in the next
1
step; H NMR (300 MHz, CDCl3) δ 7.19 (ddd, J = 7.4, 7.4, 2.0 Hz,
1H), 6.72−6.77 (m, 4H), 4.12 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.59
(t, J = 7.4 Hz, 2H), 2.43 (sext, J = 6.8 Hz, 1H), 1.56−1.72 (m, 3H),
1.42−1.50 (m, 1H), 1.24 (t, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H).
The crude ester (0.65 g, 2.60 mmol) was reduced according to the
LiAlH4 reduction protocol employing LiAlH4 (0.150 g, 3.95 mmol) in
THF (13 + 11 mL) to afford pure 5-(3-methoxyphenyl)-2-
1
methylpentan-1-ol (0.285 g, 1.37 mmol, 53%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 7.17−7.22 (m, 1H), 6.72−6.79 (m, 3H),
3.80 (s, 3H), 3.42−3.49 (m, 2H), 2.59 (td, J = 7.9, 2.7 Hz, 2H), 1.60−
1.68 (m, 2H), 1.57 (s, 1H), 1.42−1.46 (m, 1H), 1.18−1.25 (m, 2H),
0.92 (d, J = 6.7 Hz, 3H). The intermediate alcohol (0.510 g, 2.45
mmol) was oxidized according to the Swern oxidation protocol
employing (COCl)2 (1.50 mL of 2.0 M solution in DCM), DMSO
(0.459 g, 5.87 mmol), TEA (0.99 g, 9.80 mmol) in DCM (2.5 + 1.5
mL). The crude product was purified by silica gel column
chromatography eluting with 10% EtOAc/Hex to afford the pure
4,5-Difluoro-2-(4-methoxyphenethyl)benzaldehyde (32).
Prepared according to the Sonogashira conditions from methyl 2-
bromo-4,5-difluorobenzoate (1.72 mL, 6.88 mmol), 4-ethynylanisole
(1.0 g, 7.57 mmol), PdCl2(PPh3)2 (91 mg, 0.13 mmol, 2 mol %), and
CuI (25 mg, 0.13 mmol, 2 mol %) in freshly distilled triethylamine (23
mL) to afford methyl 4,5-difluoro-2-((4-methoxyphenyl)ethynyl)-
benzoate as a yellow solid (1.68 g, 81%) following chromatography
1
aldehyde 24 (0.430 g, 2.08 mmol, 85%) as a colorless oil: H NMR
1
on silica gel, eluting with 8% EtOAc/Hex: H NMR (CDCl3, 300
(300 MHz, CDCl3) δ 9.60 (dd, J = 1.9, 0.8 Hz, 1H), 7.20 (t, J = 7.5
Hz, 1H), 6.72−6.78 (m, 3H), 3.80 (s, 3H), 2.61 (t, J = 7.3 Hz, 2H),
2.35 (dsext, J = 7.0, 1.9 Hz, 1H), 1.63−1.71 (m, 3H), 1.48−1.41 (m,
1H), 1.09 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 204.9,
159.7, 143.6; 129.3, 120.8, 114.2, 111.1, 55.0, 46.2, 35.9, 30.0, 28.6,
13.3; HRMS (FAB+) calcd for C13H18O2 206.1307 [M], measured
206.1311 [M].
MHz) δ 3.83 (s, 3H), 3.95 (s, 3H), 6.89 (d, J = 8.7 Hz, 2H), 7.40 (dd,
J = 10.8 Hz, J = 7.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.81 (dd, J =
10.8 Hz, J = 8.4 Hz, 1H). The intermediate alkyne (1.68 g, 5.57 mmol)
was hydrogenated according to the hydrogenation protocol employing
10% by wt Pd/C (337 mg, 20% by wt) in EtOH (19 mL) to afford
methyl 4,5-difluoro-2-(4-methoxyphenethyl)benzoate as a white solid
(1.70 g, 99%): 1H NMR (CDCl3, 300 MHz) δ 2.81 (dd, J = 8.4 Hz, J =
5.7 Hz, 2H), 3.20 (dd, J = 8.4 Hz, J = 5.7 Hz, 2H), 3.79 (s, 3H), 3.89
(s, 3H), 6.83 (d, J = 8.4 Hz, 2H), 6.96 (dd, J = 11.1 Hz, J = 7.8 Hz,
1H), 7.10 (d, J = 8.4 Hz, 2H), 7.77 (dd, J = 11.1 Hz, J = 8.1 Hz, 1H).
The resulting ester (1.70 g, 5.57 mmol) was reduced according to the
LiAlH4 reduction protocol employing LiAlH4 (320 mg, 8.36 mmol) in
THF (33 + 22 mL) followed by direct oxidation of the crude product
alcohol according to the manganese dioxide oxidation protocol to
afford aldehyde 32 (842 mg, 55% over two steps) as a white solid
following recrystallization from Et2O/Hex: 1H NMR (CDCl3, 300
MHz) δ 2.84 (t, J = 8.4 Hz, 2H), 3.24 (t, J = 8.1 Hz, 2H), 3.78 (s, 3H),
6.80 (d, J = 8.7 Hz, 2H), 7.04−6.97 (m, 3H), 7.64 (dd, J = 10.5 Hz, J =
8.4 Hz, 1H), 10.03 (d, J = 2.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
33.9, 37.4, 55.4, 114.1, 119.6 (d, J = 17.3 Hz), 120.0 (d, J = 17.3 Hz),
129.6, 130.8, 132.2, 142.5, 149.8 (dd, J = 332.1 Hz, J = 13.1 Hz), 153.2
(dd, J = 340.5 Hz, J = 12.9 Hz), 158.4, 189.0; HRMS (FAB+) calcd for
C16H14F2O2 276.0962 [M], measured 276.0949 [M].
5-Fluoro-2-(4-methoxyphenethyl)benzaldehyde (28). Pre-
pared according to the Sonogashira conditions from 2-bromo-5-
fluorobenzaldehyde (1.40 g, 6.88 mmol), 4-ethynylanisole (1.0 g, 7.57
mmol), PdCl2(PPh3)2 (91 mg, 0.13 mmol, 2 mol %), and CuI (25 mg,
0.13 mmol, 2 mol %) in freshly distilled triethylamine (27 mL) to
afford 5-fluoro-2-((4-methoxyphenyl)ethynyl)benzaldehyde as a white
solid (1.63 g, 93%) following chromatography on silica gel, eluting
1
with 10% Et2O/Hex: H NMR (CDCl3, 300 MHz) δ 3.84 (s, 3H),
6.90 (d, J = 8.7 Hz, 2H), 7.31−7.24 (m, 1H), 7.49 (d, J = 8.7 Hz, 2H),
7.63−7.58 (m, 2H), 10.58 (s, 1H). The intermediate alkyne (1.53 g,
6.00 mmol) was hydrogenated according to the hydrogenation
protocol employing 10% by wt Pd/C (300 mg, 20% by wt) in
EtOH (15 mL), followed by direct oxidation of the crude product
alcohol according to the manganese dioxide oxidation protocol to
afford aldehyde 28 (1.21 g, 78% over two steps) as a white solid
following chromatography on silica gel, eluting with 5% Et2O/Hex: 1H
NMR (CDCl3, 400 MHz) δ 2.82 (t, J = 8.4 Hz, 2H), 3.24 (t, J = 8.0
I
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Featured Article
1-(4-Methoxyphenethyl)naphthalene-2-carbaldehyde (34).
Prepared according to the Sonogashira conditions from 1-
bromonaphthalene-2-carboxaldehyde (1.35 g, 5.73 mmol), 4-ethyny-
lanisole (832 mg, 6.30 mmol), PdCl2(PPh3)2 (97 mg, 0.14 mmol, 2.5
mol %), and CuI (27 mg, 0.14 mmol, 2.5 mol %) in freshly distilled
triethylamine (23 mL) to afford 1-((4-methoxyphenyl)ethynyl)-
naphthalene-2-carboxaldehyde as a yellow solid (1.18 g, 72%)
following chromatography on silica gel, eluting with 10% Et2O/Hex:
1H NMR (CDCl3, 300 MHz) δ 3.88 (s, 3H), 6.97 (dd, J = 6.9 Hz, J =
2.1 Hz, 2H), 7.69−7.62 (m, 4H), 7.91−7.84 (m, 2H), 7.98 (d, J = 8.7
Hz, 1H), 8.61 (dd, J = 6.3 Hz, J = 3.6 Hz, 1H), 10.89 (s, 1H). The
intermediate alkyne (1.18 g, 4.12 mmol) was hydrogenated according
to the hydrogenation protocol employing 10% by wt Pd/C (236 mg,
20% by wt) in EtOH (15 mL), followed by direct oxidation of the
crude alcohol according to the manganese dioxide oxidation protocol
to afford 34 (464 mg, 39%, across two steps) as a white solid following
NMR (CDCl3, 100 MHz) δ 19.6, 33.9, 34.9, 55.3, 111.3, 115.9, 126.8,
130.3, 131.4, 131.6, 132.1, 133.9, 134.0, 137.4, 144.7, 158.1, 192.3;
HRMS (FAB+) calcd for C17H18O2 254.1307 [M], measured 254.1317
[M].
2-(2-(6-Methoxynaphthalen-2-yl)ethyl)benzaldehyde (42).
Prepared according to the Sonogashira conditions from 2-
bromobenzaldehyde (1.17 mL, 10.0 mmol), 2-ethynyl-6-methoxy-
naphthalene (2 g, 11.0 mmol), PdCl2(PPh3)2 (140 mg, 0.20 mmol, 2
mol %), and CuI (38 mg, 0.20 mmol, 2 mol %) in freshly distilled
triethylamine (40 mL) to afford 2-((6-methoxynaphthalen-2-yl)-
ethynyl)benzaldehyde as a white solid (1.90 g, 66%) following
1
chromatography on silica gel, eluting with 20% Et2O/Hex: H NMR
(CDCl3, 400 MHz) δ 3.92 (s, 3H), 7.11 (d, J = 2.0 Hz, 1H), 7.18 (dd,
J = 9.2 Hz, J = 2.4 Hz, 1H), 7.43 (dt, J = 8.0 Hz, J = 0.8 Hz, 1H),
7.59−7.53 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.8 Hz, J =
2.4, 2H), 7.96 (d, J = 0.8 Hz, 1H), 8.00 (s, 1H), 10.70 (s, 1H). The
intermediate alkyne (1.85 g, 6.74 mmol) was hydrogenated according
to the hydrogenation protocol employing 10% by wt Pd/C (370 mg,
20% by wt) in EtOH (17 mL) followed by direct oxidation of the
crude alcohol via the manganese dioxide oxidation protocol to afford
aldehyde 42 (1.40 g, 75% over two steps) following chromatography
on silica gel, eluting with 15% Et2O/Hex: 1H NMR (CDCl3, 300
MHz) δ 3.01 (t, J = 8.4 Hz, 2H), 3.37 (t, J = 8.4 Hz, 2H), 3.89, (s,
3H), 7.13−7.10 (m, 2H), 7.22 (d, J = 7.2 Hz, 1H), 7.39−7.31 (m,
2H), 7.48−7.43 (m, 1H), 7.52 (s, 1H), 7.68−7.63 (m, 2H), 7.82 (dd, J
= 7.5 Hz, J = 0.9, 1H), 10.22 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
35.1, 38.3, 55.4, 105.7, 118.8, 126.6, 126.8, 126.9, 127.9, 129.0, 129.1,
131.4, 132.7, 133.2, 133.9, 136.5, 144.4, 157.3, 192.6; HRMS (FAB+)
calcd for C20H18O2 290.1307 [M], measured 290.1312 [M].
1
chromatography on silica gel, eluting with 15% Et2O/Hex: H NMR
(CDCl3, 300 MHz) δ 2.99 (t, J = 6.3 Hz, 2H), 3.82−3.77 (m, 2H,
eclipsed by singlet at 3.79), 3.79 (s, 3H), 6.85 (dd, J = 6.6 Hz, J = 1.8
Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 7.65−7.62 (m, 2H), 7.81 (d, J = 8.7
Hz, 1H), 7.93−7.88 (m, 2H), 8.32−8.28 (m, 1H), 10.41 (s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 29.0, 37.2, 55.4, 114.1, 124.6, 125.0, 127.1,
127.4, 128.6, 129.1, 129.5, 131.0, 131.9, 132.0, 136.4, 143.6, 158.3,
+
191.6; HRMS (FAB+) calcd for C20H19O2 291.1380 [M + 1],
measured 291.1385 [M + 1].
2-(2-(Biphenyl-4-yl)ethyl)benzaldehyde (38.). To a flame-dried
flask equipped with a magnetic stir bar was added 95% NaH (288 mg,
12.0 mmol) followed by DMF (40 mL). The resulting suspension was
cooled to 0 °C and triphenyl-(2-carbomethoxybenzyl)phosphonium
bromide26 (5.88 g, 12 mmol) was added portionwise. Upon complete
addition, the mixture was warmed to room temperature and stirred for
30 min. 4-Biphenyl carboxaldehyde (1.82 g, 10 mmol) was then added
in one portion, and the mixture was stirred at room temperature for 12
h. Upon complete consumption of the aldehyde, the reaction mixture
was poured into water (200 mL) and extracted with EtOAc. The
combined organic layers were then washed twice with water and once
with brine. The organic layer was dried over MgSO4, and the resulting
suspension was filtered. The filtrate was concentrated in vacuo, and the
residue was then chromatographed on silica gel, eluting with 20%
EtOAc/Hex, to afford (E)-methyl 2-(2-(biphenyl-4-yl)vinyl)benzoate
as a white solid (3.14 g, 99%): 1H NMR (CDCl3, 400 MHz) δ 3.93 (s,
3H), 7.04 (d, J = 16.4 Hz, 1H), 7.36−7.29 (m, 2H), 7.44 (t, J = 7.2 Hz,
2H), 7.51 (t, J = 7.2 Hz, 1H), 7.63−7.58 (m, 6H), 7.73 (d, J = 8.0 Hz,
1H), 7.93 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 16.4 Hz, 1H). The
intermediate alkene (3.14 g, 9.99 mmol) was hydrogenated according
to the hydrogenation protocol employing 10% by wt Pd/C (640 mg,
20% by wt) in EtOH (25 mL), followed by direct reduction of the
crude product ester according to the LiAlH4 reduction protocol. The
resulting crude alcohol was subjected to the manganese dioxide
oxidation protocol to afford aldehyde 38 (1.74 g, 61% over three
steps) as a white solid following chromatography on silica gel, eluting
with 15% Et2O/Hex: 1H NMR (CDCl3, 300 MHz) δ 2.93 (dd, J = 8.4
Hz, J = 6.0 Hz, 2H), 3.34 (dd, J = 8.4 Hz, J = 5.7 Hz, 2H), 7.52−7.20
(m, 10H), 7.58 (d, J = 8.7 Hz, 2H), 7.82 (dd, J = 7.8 Hz, J = 1.2 Hz,
1H), 10.21 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 35.1, 38.0, 126.9,
127.1, 127.2, 127.2, 128.8, 129.1, 131.4, 132.9, 133.9, 139.2, 140.5,
141.1, 144.3, 192.6; HRMS (FAB+) calcd for C21H18O 286.1358 [M],
measured 286.1367 [M].
3-(4-Methoxyphenyl)-2-tosyl-1,2,3,4-tetrahydroisoquinoline
(2). Purification by flash column chromatography on silica gel afforded
1
2 as a white solid, eluting with 15% EtOAc/Hex: H NMR (CDCl3,
500 MHz) δ 2.36 (s, 3H), 3.05−3.03 (m, 2H), 3.73 (s, 3H), 4.14 (d, J
= 17 Hz, 1H), 4.68 (d, J = 16.5 Hz, 1H), 5.37 (bs, 1H), 6.72 (d, J = 8.5
Hz, 2H), 6.99−6.97 (m, 1H), 7.05−7.03 (m, 1H), 7.13−7.10 (m, 4H),
7.16 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3,
75 MHz) δ 21.6, 32.2, 43.9, 54.1, 55.3, 113.8, 126.0, 126.5, 127.1,
127.2, 128.6, 128.8, 129.6, 131.8, 132.5, 132.7, 137.4, 143.3, 158.9;
HRMS (FAB+) calcd for C23H24NO3S 394.1471 [M + 1], measured
394.1483 [M + 1].
2-(4-Methoxyphenyl)-5,5-dimethyl-1-tosylpiperidine (5). Pu-
rification by flash column chromatography on silica gel afforded 5 as a
white solid, eluting with 25% Et2O/Hex: 1H NMR (CDCl3, 300 MHz)
δ 0.79 (s, 6H), 1.28−1.22 (bm, 2H), 2.10−2.03 (bm, 2H), 2.39 (s,
3H), 2.84 (d, J = 13.5 Hz, 1H), 3.37 (d, J = 13.2 Hz, 1H), 3.77 (s, 3H),
5.16 (s, 1H), 6.77 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.22
(d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ 21.6, 24.2, 25.7, 28.7, 30.4, 32.6, 52.5, 55.0, 55.3, 113.8, 127.1,
128.2, 129.5, 130.8, 138.7, 142.8, 158.4; HRMS (FAB+) calcd for
C21H28NO3S+ 374.1784 [M + 1], measured 374.1798 [M + 1].
3-(4-Methoxyphenyl)-2-tosyl-2-azaspiro[5.5]undecane (7).
Purification by flash column chromatography on silica gel afforded 7
1
as a white solid, eluting with 15% Et2O/Hex: H NMR (CDCl3, 400
MHz) δ 1.21−1.07 (m, 4H), 1.43−1.31 (m, 8H), 2.03−1.97 (m, 2H),
2.38 (s, 3H), 2.76 (d, J = 13.6 Hz, 1H), 3.69 (d, J = 13.6 Hz, 1H), 5.14
(t, J = 3.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H),
7.20 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 21.5, 21.6, 25.0, 26.5, 30.9, 31.9, 32.7, 37.8, 50.0, 55.3,
113.8, 127.0, 128.2, 129.4, 130.9, 138.6, 142.7, 158.4; HRMS (FAB+)
calcd for C24H32NO3S+ 414.2097 [M + 1], measured 414.2092 [M +
1].
2-(4-Methoxyphenyl)-4,4-dimethyl-1-tosylpiperidine (9). Pu-
rification by flash column chromatography on silica gel afforded 9 as a
white solid, eluting with 15% Et2O/Hex: 1H NMR (CDCl3, 300 MHz)
δ 0.58 (s, 3H), 0.80 (s, 3H), 1.25 (t, J = 3.6 Hz, 2H), 1.49 (dd, J = 14.1
Hz, J = 5.7 Hz, 1H), 1.91 (dd, J = 14.1 Hz, J = 4.8 Hz, 1H), 2.41 (s,
3H), 3.46−3.37 (m, 1H), 3.69−3.63 (m, 1H), 3.77 (s, 3H), 4.93 (t, J =
4.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.24
(d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ 21.6, 27.3, 28.9, 31.1, 37.3, 40.2, 42.7, 55.3, 113.6, 127.2,
2-(4-Methoxy-2-methylphenethyl)benzaldehyde (40). Pre-
pared according to the hydrogenation protocol from alkyne 2-((4-
methoxy-2-methylphenyl)ethynyl)benzaldehyde27 (1.51 g, 6.00 mmol)
and 10% by wt Pd/C (302 mg, 20% by wt) in EtOH (15 mL) followed
by direct oxidation of the crude alcohol via the manganese dioxide
oxidation protocol to afford aldehyde 40 (813 mg, 53% over two
steps) following chromatography on silica gel, eluting with 8% Et2O/
1
Hex: H NMR (CDCl3, 400 MHz) δ 2.25 (s, 3H), 2.84 (dd, J = 8.4
Hz, J = 6.0 Hz, 2H), 3.25 (dd, J = 8.4 Hz, J = 6.0 Hz, 2H), 3.77 (s,
3H), 6.70−6.65 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 7.6 Hz,
1H), 7.38 (dt, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.49 (dt, J = 7.6 Hz, J = 1.6
Hz, 1H), 7.82 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 10.17 (s, 1H); 13C
J
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127.5, 129.5, 132.9, 138.0, 142.9, 158.3; HRMS (FAB+) calcd for
C21H28NO3S+ 374.1784 [M + 1], measured 374.1798 [M + 1].
trans-2-(4-Methoxyphenyl)-4-methyl-1-tosylpiperidine (11).
Purification by flash column chromatography on silica gel, eluting with
5% EtOAc/Hex, afforded 11 as a 93:7 trans/cis mixture. The major
diastereomer was isolated by recrystallization of the mixture from
diethyl ether with slow vapor diffusion of pentane. This material was
CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.29 (d, J
= 9.0 Hz, 2H), 7.25 (t, J = 7.0 Hz, 2H), 7.18 (ddd, J = 7.3, 1.3, 1.3 Hz,
1H), 6.97 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.40 (d, J = 4.6
Hz, 1H), 4.00 (d, J = 14.2 Hz, 1H), 3.81 (s, 3H), 3.12 (ddd, J = 14.7,
12.9, 3.1 Hz, 1H), 2.71 (ddd, J = 12.6, 3.4, 3.4 Hz, 1H), 2.46 (s, 3H),
2.35 (d, J = 13.9 Hz, 1H), 1.79 (ddd, J = 13.4, 13.4, 5.3 Hz, 1H), 1.57−
1.55 (m, 1H), 1.45 (ddd, J = 17.3, 12.8, 4.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 159.0, 145.6, 143.6, 139.2, 130.8, 130.2, 130.2, 129.0,
129.0, 128.4, 128.4, 127.5, 127.5, 127.0, 127.0, 126.9, 114.6, 114.6,
55.7, 55.4, 42.1, 36.8, 34.6, 32.2, 21.9; HRMS (FAB+) calcd for
C25H28NO3S+ 422.1784 [M + 1], measured 422.1790 [M + 1].
cis-2-(2-Methoxyphenyl)-5-methyl-1-tosylpiperidine (Major
Diastereomer cis-23). Purification by flash column chromatography
on silica gel, eluting with 10% EtOAc/Hex afforded 23 as a 73:27
trans/cis mixture. The major diastereomer cis-23 was isolated by
recrystallization of the mixture from diethyl ether with slow vapor
diffusion of pentane. This material was used for characterization
1
used for characterization purposes: H NMR (300 MHz, CDCl3) δ
7.75 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.3 Hz,
2H), 6.84 (d, J = 8.2 Hz, 2H), 5.27 (d, J = 5.0 Hz, 1H), 3.86 (d, J =
13.9 Hz, 1H), 3.79 (s, 3H), 2.97 (ddd, J = 13.5, 13.5, 2.6 Hz, 1H), 2.43
(s, 3H), 2.14 (d, J = 13.8 Hz, 1H), 1.61−1.48 (m, 1H), 1.37 (d, J =
13.1 Hz, 1H), 1.25 (ddd, J = 12.6, 12.6, 5.4 Hz, 1H), 0.90 (ddd, J =
16.8, 12.6, 4.5 Hz, 1H), 0.79 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 158.8, 143.3, 139.2, 131.4, 130.0, 130.0, 128.4, 128.4, 127.4,
127.4, 114.3, 114.3, 55.7, 55.3, 42.8, 36.0, 33.3, 25.5, 22.6, 21.9; HRMS
(FAB+) calcd for C20H26NO3S+ 360.1628 [M + 1], measured
360.1630 [M + 1]. An X-ray structure was also obtained; see the
Supporting Information.
1
purposes: H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 7.6 Hz, 2H),
7.20−7.06 (m, 4H), 6.81 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.5 Hz, 1H),
5.50 (d, J = 5.8 Hz, 1H), 3.95 (dd, J = 13.3, 4.5 Hz, 1H), 3.79 (s, 3H),
2.96 (dd, J = 13.2, 11.7 Hz, 1H), 2.38 (s, 3H), 2.17−2.12 (m, 1H),
1.75−1.64 (m, 2H), 1.55−1-.42 (m, 2H), 0.95−0.91 (m, 1H), 0.83 (d,
J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.6, 143.0, 138.7,
129.9, 129.7, 129.7, 128.2, 128.1, 127.3, 127.3, 120.3, 110.9, 55.5, 51.7,
50.3, 30.8, 29.7, 28.1, 21.8, 19.5; HRMS (FAB+) calcd for
C20H26NO3S+ 360.1628 [M + 1], measured 360.1647 [M + 1].
trans-2-(2-Methoxyphenyl)-5-methyl-1-tosylpiperidine
(Minor Diastereomer trans-23). Purification by flash column
chromatography on silica gel afforded trans-23 as a white solid,
eluting with 10% EtOAc/Hex. The minor diastereomer was isolated
after several silica gel chromatography columns. This material was used
for characterization purposes: 1H NMR (300 MHz, CDCl3) δ 7.41 (d,
J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 1H), 7.12 (m, 3H), 6.80 (ddd, J =
7.7, 7.7, 1.0 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.75 (dd, J = 7.9, 4.6
Hz, 1H), 3.88 (dd, J = 12.5, 4.2 Hz, 1H), 3.70 (s, 3H), 2.84 (dd, J =
12.7, 7.7 Hz, 1H), 2.37 (s, 3H), 1.98−1.95 (m, 2H), 1.85−1.83 (m,
1H), 1.73−1.68 (m, 1H), 1.10−1.07 (m, 1H), 0.94 (d, J = 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 142.4, 136.4, 129.3, 129.1,
128.9, 128.9, 128.1, 127.5, 127.5, 119.9, 110.0, 55.0, 54.6, 52.1, 29.5,
29.5, 29.5, 21.5, 18.9; HRMS (FAB+) calcd for C20H26NO3S+
360.1628 [M + 1], measured 360.1637 [M + 1].
2-(4-Methoxyphenyl)-1-tosylpiperidine (13). Purification by
flash column chromatography on silica gel afforded 13 as a colorless
oil, eluting with 10% Et2O/Hex: 1H NMR (CDCl3, 300 MHz) δ
1.48−1.29 (m, 5H), 2.16 (bd, J = 12.6 Hz, 1H), 2.44 (s, 3H), 2.99 (dt,
J = 14.7 Hz, J = 3.3 Hz, 1H), 3.83−3.77 (m, 4H), 5.21 (s, 1H), 6.86
(d, J = 8.7 Hz, 2H), 7.31−7.24 (m, 4H), 7.75 (d, J = 8.4 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) δ 19.1, 21.7, 24.5, 27.4, 41.9, 55.0, 55.4,
114.1, 127.2, 128.4, 129.8, 131.0, 139.0, 143.0, 158.6; HRMS (FAB+)
calcd for C19H24NO3S+ 346.1471 [M + 1], measured 346.1482 [M +
1].
Methyl 4-(4,4-Dimethyl-1-tosylpiperidin-2-yl)-
phenylcarbamate (15). Purification by flash column chromatog-
raphy on silica gel afforded 15 as a white solid, eluting with 40% Et2O/
Hex: 1H NMR (CDCl3, 300 MHz) δ 0.57 (s, 3H), 0.80 (s, 3H), 1.28−
1.23 (m, 2H), 1.52 (dd, J = 10.5 Hz, J = 4.2 Hz, 1H), 1.92 (dd, J = 10.5
Hz, J = 3.3 Hz, 1H), 2.42 (s, 3H), 3.42−3.35 (m, 1H), 3.68 (dt, J =
10.5 Hz, J = 3.3 Hz, 1H), 3.77 (s, 3H), 4.96 (t, J = 3.6 Hz, 1H), 6.56
(bs, 1H), 7.19 (d, J = 6.6 Hz, 2H), 7.29−7.25 (m, 4H), 7.65 (d, J = 6.3
Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.6, 27.2, 29.0, 31.3, 37.3,
40.2, 42.6, 52.4, 55.4, 118.6, 127.1, 127.3, 129.6, 136.2, 136.5, 138.0,
143.1, 154.1; HRMS (FAB+) calcd for C22H29N2O4S+ 417.1843 [M +
1], measured 417.1849 [M + 1].
5,5-Dimethyl-2-phenyl-1-tosylpiperidine (17). Purification by
(Z)-1-Methoxy-8-methyl-6,7-dihydro-5H-benzo[7]annulene
(25). Purification by flash column chromatography on silica gel
afforded 25, eluting with 5% EtOAc/Hex: 1H NMR (300 MHz,
CDCl3) δ 7.01 (d, J = 8.3 Hz, 1H), 6.69−6.63 (m, 2H), 6.21 (s, 1H),
3.79 (s, 3H), 2.78−2.75 (m, 2H), 2.30 (t, J = 6.8 Hz, 2H), 1.98−1.94
(m, 2H), 1.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.6, 142.7,
137.7; 131.5, 129.6, 125.4, 114.6, 110.7, 55.2, 36.6, 35.8, 27.1, 27.0;
HRMS (FAB+) calcd for C13H17O+ 189.1274 [M + 1], measured
189.1290 [M + 1].
flash column chromatography on silica gel afforded 17 as a golden oil,
1
eluting with 5% Et2O/Hex: H NMR (CDCl3, 300 MHz) δ 0.80 (s,
6H), 1.26−1.21 (m, 2H), 2.12−2.08 (m, 2H), 2.40 (s, 3H), 2.86 (d, J
= 13.5 Hz, 1H), 3.41 (d, J = 13.5 Hz, 1H), 5.23 (bs, 1H), 7.27−7.14
(m, 7H), 7.65 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ
21.6, 24.2, 25.8, 28.8, 30.5, 32.6, 52.7, 55.5, 126.8, 127.1, 127.2, 128.6,
129.5, 138.7, 139.0, 142.9; HRMS (FAB+) calcd for C20H25NO2S
343.1606 [M], measured 343.1610 [M].
7-Fluoro-3-(4-methoxyphenyl)-2-tosyl-1,2,3,4-tetrahydroi-
soquinoline (29). Purification by flash column chromatography on
silica gel afforded 29 as a white solid, eluting with 15% EtOAc/Hex:
1H NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.99 (bd, J = 4.0 Hz,
cis-2-(4-Methoxyphenyl)-5-methyl-1-tosylpiperidine (19).
Purification by flash column chromatography on silica gel, eluting
with 10% EtOAc/Hex, afforded 19 as a 92:8 cis/trans mixture. The
major diastereomer was isolated by recrystallization of the mixture
from diethyl ether with slow vapor diffusion of pentane. This material
2H), 3.71 (s, 3H), 4.08 (d, J = 16.8 Hz, 1H), 4.66 (d, J = 16.8 Hz, 1H),
5.35 (t, J = 4.4 Hz, 1H), 6.68 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.72
(dd, J = 6.8 Hz, J = 2.0 Hz, 2H), 6.82 (dt, J = 8.8 Hz, J = 2.8 Hz, 1H),
7.00 (dd, J = 8.4 Hz, J = 6.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.17 (d,
J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ 21.5, 31.2, 43.7, 54.0, 55.3, 122.6 (d, J = 21.7 Hz), 113.8,
114.3 (d, J = 21.3 Hz), 127.1, 128.3, 128.5, 129.6, 130.2 (d, J = 7.8
Hz), 131.3, 134.2 (d, J = 7.0 Hz), 137.3, 143.4, 159.0, 161.2 (d, J =
243.7 Hz); HRMS (FAB+) calcd for C23H23FNO3S+ 412.1377 [M +
1], measured 412.1375 [M + 1].
1
was used for characterization purposes: H NMR (300 MHz, CDCl3)
δ 7.75 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.7
Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.21 (d, J = 4.6 Hz, 1H), 3.80 (s,
3H), 3.79−3.75 (m, 1H), 2.53 (dd, J = 14.3, 11.7 Hz, 1H), 2.43 (s,
3H), 2.18 (ddd, J = 14.0, 5.2, 3.1 Hz, 1H), 1.64 (dddd, J = 14.0, 14.0,
5.4, 3.7 Hz, 1H), 1.50−1.37 (m, 2H), 1.07 (ddd, J = 13.5, 12.0, 3.3 Hz,
1H), 0.70 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9,
143.3, 139.2, 131.0, 130.0, 130.0, 128.5, 128.5, 127.4, 127.4, 114.3,
114.3, 55.6, 54.3, 48.5, 30.3, 28.1, 27.5, 21.9, 19.3; HRMS (FAB+)
calcd for C20H26NO3S+ 360.1628 [M + 1], measured 360.1637 [M +
1]. An X-ray structure was also obtained; see the Supporting
Information.
6-Fluoro-3-(4-methoxyphenyl)-2-tosyl-1,2,3,4-tetrahydroi-
soquinoline (31). Purification by flash column chromatography on
silica gel afforded 31 as a white solid, eluting with 20% EtOAc/Hex:
1H NMR (CDCl3, 300 MHz) δ 2.35 (s, 3H), 3.00 (s, 2H), 3.71 (s,
trans-2-(4-Methoxyphenyl)-4-phenyl-1-tosylpiperidine (21).
Purification by flash column chromatography on silica gel afforded 21
as a white solid, eluting with 10% EtOAc/Hex: H NMR (300 MHz,
3H), 4.09 (d, J = 16.5 Hz, 1H), 4.66 (d, J = 16.5 Hz, 1H), 5.35 (t, J =
3.9 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.84−6.77 (m, 2H), 6.96−6.92
1
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(m, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.63 (d, J
= 8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.5, 32.1, 43.3, 53.6,
55.2, 113.6 (d, J = 21.1 Hz), 113.8, 115.2 (d, J = 21.7 Hz), 127.1, 127.4
(d, J = 8.2 Hz), 128.4, 129.4, 129.6, 131.3, 135.0 (d, J = 7.7 Hz), 137.3,
143.3, 159.0, 161.6 (d, J = 243.9 Hz); HRMS (FAB+) calcd for
C23H23FNO3S+ 412.1377 [M + 1], measured 412.1375 [M + 1].
6,7-Fluoro-3-(4-methoxyphenyl)-2-tosyl-1,2,3,4-tetrahydroi-
soquinoline (33). Purification by flash column chromatography on
silica gel afforded 33 as a white solid, eluting with 10% EtOAc/Hex:
1H NMR (CDCl3, 300 MHz) δ 2.38 (s, 3H), 2.97 (bd, J = 3.6 Hz,
2H), 3.74 (s, 3H), 4.00 (d, J = 16.8 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H),
5.35 (t, J = 4.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 6.90−6.78 (m, 2H),
7.08 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz,
2H); 13C NMR (CDCl3, 75 MHz) δ 21.5, 31.1, 43.0, 53.5, 55.3, 114.0,
114.7 (d, J = 17.8 Hz), 117.3 (d, J = 17.0 Hz), 127.2, 128.4, 128.8,
129.3, 129.7, 130.9, 137.3, 143.6, 148.8 (dd, J = 244.7 Hz, J = 11.5
Hz), 149.4 (dd, J = 243.0, Hz, J = 9.4 Hz), 159.1; HRMS (FAB+)
calcd for C23H21F2NO3S 429.1210 [M], measured 429.1214 [M].
3-(4-Methoxyphenyl)-2-tosyl-1,2,3,4-tetrahydrobenzo[f]-
isoquinoline (35). Purification by flash column chromatography on
silica gel afforded 35 as a white solid, eluting with 30% Et2O/Hex: 1H
NMR (CDCl3, 300 MHz) δ 2.25 (s, 3H), 3.20 (dd, J = 17.1 Hz, J = 6.3
Hz, 1H), 3.57 (d, J = 17.1 Hz, 1H), 3.67 (s, 3H), 4.18 (d, J = 17.4 Hz,
1H), 4.81 (d, J = 17.7 Hz, 1H), 5.61 (d, J = 6.3 Hz, 1H), 6.66 (d, J =
8.4 Hz, 2H), 7.11−7.03 (m, 5H), 7.53−7.44 (m, 2H), 7.67−7.62 (m,
3H), 7.87−7.88 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.5, 27.1,
43.6, 53.3, 55.3, 113.8, 122.5, 124.2, 125.7, 126.6, 126.9, 127.1, 127.6,
128.8, 129.6, 131.0, 131.8, 132.7, 137.7, 143.3, 159.0; HRMS (FAB+)
calcd for C27H26NO3S+ 444.1628 [M + 1], measured 444.1616 [M +
1].
3H), 4.19 (d, J = 16.5 Hz, 1H), 4.73 (d, J = 16.8 Hz, 1H), 5.53−5.50
(m, 1H), 6.99−6.96 (m, 1H), 7.15−7.05 (m, 7H), 7.36 (dd, J = 8.7
Hz, J = 1.8 Hz, 1H), 7.44, (s, 1H), 7.47 (d, J = 16.2 Hz, 1H), 7.60 (d, J
= 8.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ 21.6, 32.1, 44.2, 54.8, 55.4, 105.6, 118.9, 126.0, 126.1, 126.5, 127.2,
128.5, 128.8, 129.6, 132.5, 132.7, 133.9, 134.9, 137.4, 143.3, 157.9;
HRMS (FAB+) calcd for C27H25NO3S 443.1555 [M], measured
443.1557 [M].
3-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (44).
Napthalene (0.274 g, 2.14 mmol) was dissolved in dry DME (1.5
M), and sodium (0.039 g, 1.69 mmol) was added in portions. The
mixture was stirred at room temperature for 1 h. It was then added
dropwise to a solution of the tosylamine 2 (0.060 g, 0.152 mmol) in
DME (0.09 M) at −78 °C until a green color persisted. Saturated
NaHCO3 was added, and the mixture was extracted with EtOAc. The
combined organic layers were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (80% EtOAc/MeOH) to
1
afford 44 (0.039 g, 0.135 mmol, 89%) as pale yellow oil: H NMR
(300 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.16−7.10 (m, 4H),
6.91 (d, J = 8.7 Hz, 2H), 3.97 (t, J = 7.2 Hz, 1H), 3.82 (s, 3H), 2.96 (d,
J = 7.1 Hz, 2H), 1.99 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 159.0,
136.3, 135.0, 134.9, 129.2, 127.8, 127.8, 126.4, 126.3, 114.1, 114.1,
58.0, 55.4, 49.3, 37.7, 29.8; HRMS (FAB+) calcd for C16H17NO
239.1310 [M], measured 239.1315 [M].
cis-2-(4-Methoxyphenyl)-5-methylpiperidine (45). Naptha-
lene (0.464 g, 3.62 mmol) was dissolved in dry DME (1.5 M), and
sodium (0.065 g, 2.83 mmol) was added in portions. The mixture was
stirred at room temperature for 1 h. It was added dropwise to a
solution of the tosylamine 19 (0.093 g, 0.260 mmol) in DME (0.09
M) at −78 °C until a green color persisted. Saturated NaHCO3 was
added, and the mixture was extracted with EtOAc. The combined
organic layers were extracted with HCl 10%. The resulting aqueous
layers were combined and washed with ethyl acetate. The aqueous
layer was then neutralized with NaOH 1 N and subsequently extracted
with EtOAc. The organic layers were dried over Na2SO4 and
concentrated under reduced pressure to afford 45 (0.046 g, 0.226
mmol, 87%) as a pale yellow oil that was pure by NMR analysis
(mixture of diastereomers 90:10 cis/trans): 1H NMR (300 MHz,
CDCl3) δ 7.30 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.79 (s,
3H), 3.58 (d, J = 9.2 Hz, 1H), 2.98 (dd, J = 11.7, 3.3 Hz, 1H), 2.84 (d,
J = 11.7 Hz, 1H), 1.79−1.73 (m, 4H), 1.58 (d, J = 10.1 Hz, 2H), 1.14
(d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9, 137.9,
128.1, 128.1, 114.1, 114.1, 61.3, 55.6, 52.7, 31.1, 29.8, 28.1, 17.6;
HRMS (FAB+) calcd for C13H20NO+ 206.1539 [M + 1], measured
206.1544 [M + 1].
3-(Biphenyl-4-yl)-2-tosyl-1,2,3,4-tetrahydroisoquinoline
(39). Purification by flash column chromatography on silica gel
1
afforded 39 as a white solid, eluting with 20% Et2O/Hex: H NMR
(CDCl3, 300 MHz) δ 2.36 (s, 3H), 3.10 (d, J = 4.2 Hz, 2H), 4.25 (d, J
= 16.5 Hz, 1H), 4.72 (d, J = 16.5 Hz, 1H), 5.43 (t, J = 4.5 Hz, 1H),
7.03−7.00 (m, 1H), 7.08−7.05 (m, 1H), 7.18−7.13 (m, 4H), 7.28−
7.25 (m, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.44−7.38 (m, 4H), 7.51 (d, J
= 6.9 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
δ 21.6, 32.6, 44.3, 54.7, 126.0, 126.6, 127.1, 127.2, 127.3, 127.4, 127.8,
128.8, 128.9, 129.7, 132.6, 132.7, 137.4, 139.0, 140.4, 140.8, 143.3;
HRMS (FAB+) calcd for C28H26NO2S+ 440.1679 [M + 1], measured
440.1680 [M + 1]. The X-ray structure was also obtained; see the
Supporting Information.
3-(4-Methoxy-2-methylphenyl)-2-tosyl-1,2,3,4-tetrahydroi-
soquinoline (41). Purification by flash column chromatography on
silica gel afforded 41 as a white solid, eluting with 20% EtOAc/Hex.
The product was isolated as a 3:1 mixture of rotomers. Elevated
temperature 1H NMR failed to result in coalescence of the signals. For
the purposes of spectral characterization the major and minor
Chiral Substrate (S)-5-(4-Methoxyphenyl)-2-methylpentanal
(S5). To a suspension of (4S)-4-benzyl-oxazolidin-2-one (S1) (0.131
g, 0.739 mmol), DMAP (0.012 g, 0.098 mmol), and 5-(4-
methoxyphenyl)pentanoic acid23a (0.20 g, 0.96 mmol) in DCM
(0.75 M in oxazolidinone) at 0 °C under an argon atmosphere was
added DCC (0.200 g, 1.00 mmol) in one portion. The reaction was
warmed to room temperature after 10 min, and stirring was continued
until no starting material was detected by TLC. The suspension was
filtered through Celite, and the precipitate was washed with DCM.
The filtrate was washed with sat. NaHCO3, dried over Na2SO4, and
concentrated at reduced pressure. The resulting residue was purified
by silica gel chromatography, eluting with 20% EtOAc/Hex to afford
(S)-4-benzyl-3-(5-(4-methoxyphenyl)pentanoyl)oxazolidin-2-one (S2)
1
rotomers designated as a and b, respectively: H NMR (CDCl3, 300
MHz) δ 2.19 (s, 0.91Hb), 2.30 (s, 3Ha), 2.41 (s, 0.97Hb), 2.50 (s,
3Ha), 2.85−2.77 (m, 1Ha + 0.44Hb), 3.07−3.01 (m, 1Ha + 0.67Hb),
3.17 (dd, J = 11.1 Hz, J = 4.8 Hz, 0.32Hb), 3.53 (s, 0.96Hb), 3.72 (s,
3Ha), 4.13 (d, J = 12.0 Hz, 0.32Hb), 4.21 (d, J = 12.3 Hz, 1Ha), 4.63
(d, J = 12.6 Hz, 1Ha), 4.76 (d, J = 11.7 Hz, 0.30Hb), 5.43−5.41 (m,
1Ha + 0.31Hb), 6.04 (d, J = 1.5 Hz, 0.29Hb), 6.44 (dd, J = 6.3 Hz, J =
2.1 Hz, 0.98Hb), 6.51 (d, J = 1.8 Hz, 0.35Hb), 6.70 (d, J = 2.1 Hz,
1Ha), 6.77 (d, J = 6.6 Hz, 1Ha), 6.93−6.91 (m, 1H + 0.39Hb), 7.19−
7.00 (m, 6Ha + 1.5Hb), 7.29 (d, J = 6.0 Hz, 0.69Hb), 7.53 (d, J = 6.0
Hz, 2Ha), 7.78 (d, J = 6.0 Hz, 0.63Hb); 13C NMR (CDCl3, 75 MHz)
δ18.6, 20.0, 21.5, 32.4, 41.7, 45.0, 50.4, 52.4, 52.7, 55.2, 105.1, 110.8,
116.4, 116.9, 125.5, 125.9, 126.5, 126.6, 126.8, 127.3, 127.4, 127.7,
127.8, 128.1, 128.3, 128.7, 129.2, 129.9, 131.2, 131.6, 133.2, 133.4,
134.8, 136.0, 136.8, 137.7, 138.0, 140.2, 143.1, 143.5, 158.8, 159.5;
HRMS (FAB+) calcd for C24H26NO3S+ 408.1628 [M + 1], measured
408.1652 [M + 1].
1
(0.243 g, 0.662 mmol, 69%) as a colorless oil: H NMR (300 MHz,
CDCl3) δ 7.36−7.33 (m, 3H), 7.23 (d, J = 7.1 Hz, 2H), 7.14 (d, 8.7
Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 4.68 (oct, J = 8.3 Hz, 1H), 4.19−
4.18 (m, 2H), 3.81 (s, 3H), 3.31 (dd, J = 13.4, 3.1 Hz, 1H), 3.01−2.98
(m, 2H), 2.79 (dd, J = 13.4, 9.6 Hz, 1H), 2.65 (t, J = 7.2 Hz, 2H),
1.76−1.74 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 173.2, 157.8,
153.5, 135.4, 134.2, 129.5, 129.5, 129.3, 129.3, 129.0, 129.0, 127.3,
114.8, 113.8, 113.8 66.2, 55.3, 55.1, 37.9, 35.4, 34.7, 31.1, 23.9. To a
stirred solution of N,N-diisopropylamine (0.275, 2.72 mmol) in
anhydrous THF (0.4 M) at −78 °C was added a 2.5 M solution of n-
BuLi in hexanes (1.8 mL). After stirring for 15 min at −78 °C, S2
3-(6-Methoxynaphthalen-2-yl)-2-tosyl-1,2,3,4-tetrahydroi-
soquinoline (43). Purification by flash column chromatography on
silica gel afforded 43 as a white solid, eluting with 20% Et2O/Hex: 1H
NMR (CDCl3, 300 MHz) δ 2.33 (s, 3H), 3.19−3.06 (m, 2H), 3.88 (s,
L
dx.doi.org/10.1021/jo300635m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(0.833 g, 2.26 mmol) in THF (0.8 M) was added dropwise. The
mixture was stirred for 30 min after which methyl iodide (1.29 g, 0.09
mmol) was added. The reaction mixture was stirred overnight at room
temperature. The reaction was then quenched with 0.1 M aqueous
HCl solution and extracted four times with Et2O. The extract was
washed once with brine, dried over Na2SO4 and concentrated under
reduced pressure to furnish the crude product, which was purified by
silica gel chromatography, eluting with 15% EtOAc/Hex to afford (S)-
4-benzyl-3-((S)-5-(4-methoxyphenyl)-2-methylpentanoyl)oxazolidin-
55.2, 50.5, 37.0, 35.1, 35.1, 29.3, 22.1, 19.1; HRMS (FAB+) calcd for
C19H31N2O2 319.2386 [M + 1], measured 319.2379 [M + 1].
+
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of HT-amination substrates and
products, X-ray data for compounds 11, 19, and 39 (CIF), and
discussion of the reactivity of chiral substrates. This material is
available free of charge via the Internet at http://pubs.acs.org
1
2-one (S3) (0.632 g, 1.66 mmol, 73%) as a colorless oil: H NMR
(300 MHz, CDCl3) δ 7.34−7.24 (m, 3H), 7.20 (d, J = 7.5 Hz, 2H),
7.08 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.68−4.59 (m, 1H),
4.15−4.13 (m, 2H), 3.77 (s, 3H), 3.74 (q, J = 6.7 Hz, 1H), 3.24 (dd, J
= 13.4, 3.1 Hz, 1H), 2.76 (dd, J = 13.4, 9.6 Hz, 1H), 2.65 (dd, J = 12.9,
7.1 Hz, 2H), 1.83−1.76 (m, 1H), 1.66−1.56 (m, 2H), 1.47−1.45 (m,
1H), 1.21 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5,
158.2, 153.4, 135.7, 134.7, 129.8, 129.8, 129.7, 129.3, 129.3, 127.7,
114.1, 114.1, 66.4, 55.7, 55.6, 38.3, 38.0, 35.3, 33.4, 29.6, 17.9; HRMS
(FAB+) calcd for C23H28NO4+ 382.2013 [M + 1], measured 382.2029
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sames@chem.columbia.edu.
Author Contributions
†P.A.V. and I.C. contributed equally to this work.
ACKNOWLEDGMENTS
[M
+ 1]. (S)-4-Benzyl-3-((S)-5-(4-methoxyphenyl)-2-
■
methylpentanoyl)oxazolidin-2-one (S3) (0.60 g, 1.57 mmol) was
dissolved in dry THF (0.3 M in ester) under an argon atmosphere and
cooled to 0 °C. EtOH was added (101 uL), followed by LiBH4 (0.041
g, 1.88 mmol). The mixture was then stirred overnight. Following the
disappearance of the starting material as detected by TLC, EtOAc was
added followed by the careful addition of saturated NH4Cl. The
aqueous layer was extracted with EtOAc. The combined organic layers
were dried over Na2SO4 and concentrated under reduced pressure to
yield (S)-5-(4-methoxyphenyl)-2-methylpentan-1-ol (S4) (0.274 g,
1.31 mmol) as a colorless oil following purification by silica gel column
This work was supported by the National Institute of General
Medical Sciences (GM60326). We also thank the Parkin
research group for X-ray crystal analysis. The National Science
Foundation (CHE-0619638) is thanked for acquisition of an X-
ray diffractometer.
REFERENCES
■
(1) Godula, K.; Sames, D. Science 2006, 312, 67−72.
(2) (a) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc.
1
chromatography, eluting with 20% EtOAc/Hex: H NMR (300 MHz,
2006, 128, 14220−14221. (b) Gribkov, D. V.; Pastine, S. J.; Schnurch,
̈
CDCl3) δ 7.09 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.78 (s,
3H), 3.45 (s, 2H), 2.55 (ddd, J = 8.8, 8.8, 2.6 Hz, 2H), 1.63−1.50 (m,
3H), 1.44−1.32 (m, 1H), 1.22 (bs, 1H), 1.15−1.03 (m, 1H), 0.91 (d, J
= 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 158.1, 135.2, 129.6,
129.6, 114.1, 114.1, 68.6, 55.6, 36.1, 35.7, 33.2, 29.5, 17.0. Oxidation
was carried out according to the Swern oxidation protocol from (S)-5-
(4-methoxyphenyl)-2-methylpentan-1-ol (S4) (0.439 g, 2.11 mmol)
and (COCl)2 (1.26 mL of 2.0 M solution in DCM), DMSO (0.395 g,
5.06 mmol), TEA (0.853 g, 8.44 mmol) in DCM (2 + 4 mL). The
crude reaction residue was purified by silica gel column chromatog-
raphy 5% EtOAc/Hex to afford the pure (S)-5-(4-methoxyphenyl)-2-
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1
methylpentanal (S5) (0.305 g, 1.49 mmol, 70%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 9.58 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 8.5
Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.77 (s, 3H), 2.56 (t, J = 7.3 Hz,
2H), 2.33 (dsext, J = 6.9; 1.9 Hz, 1H), 1.76−1.57 (m, 3H), 1.43−1.34
(m, 1H), 1.08 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
205.5, 158.2, 134.4; 129.7, 129.6, 114.2, 114.2, 55.6, 46.6, 35.3, 30.4,
+
29.3, 13.7; HRMS (FAB+) calcd for C13H19O2 207.1380 [M + 1],
measured 207.1390 [M + 1].
(S)-2-(Methoxymethyl)-N-((S)-5-(4-methoxyphenyl)-2-
methylpentylidene)pyrrolidin-1-amine (S6). The enantiomeric
excess of aldehyde S5 was determined by conversion of the aldehyde
to the 1-amino-2-(methoxymethyl)pyrrolidine (SAMP) imine. SAMP
(0.054 g, 0.415 mmol) was added to S5 (0.103 g, 0.500 mmol) at 0 °C
in the absence of solvent. After 1 h, the reaction mixture was dissolved
in DCM, dried over Na2SO4, and concentrated under reduced
pressure. The resulting residue was analyzed by 1H NMR, which
indicated a diastereomeric ratio of >99:1. The residue was purified by
silica gel column chromatography eluting with 20% EtOAc/Hex to
afford (S)-2-(methoxymethyl)-N-((S)-5-(4-methoxyphenyl)-2-
methylpentylidene)pyrrolidin-1-amine (S6) (0.137 g, 0.430 mmol,
86%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.08 (d, J = 7.1
Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 6.5 Hz, 1H), 3.77 (s,
3H), 3.57 (ddd, J = 8.9, 3.5, 1.7 Hz, 1H), 3.44−3.32 (m, 6H), 2.69
(quintet, J = 8.7 Hz, 1H), 2.54 (t, J = 7.0 Hz, 2H), 2.33 (septet, J = 6.8
Hz, 1H), 1.93−1.88 (m, 4H), 1.61 (quintet, J = 7.6 Hz, 2H), 1.45−
1.37 (m, 2H), 1.03 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
157.6, 144.2, 144.2, 134.8, 129.3, 129.3, 113.7, 113.7, 74.8, 63.6, 59.2,
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dx.doi.org/10.1021/jo300635m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
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