Asymmetric Redox-Annulation of Cyclic Amines

Article abstract of DOI:10.1021/acs.joc.5b01384

Cyclic amines such as 1,2,3,4-tetrahydroisoquinoline undergo regiodivergent annulation reactions with 4-nitrobutyraldehydes. These redox-neutral transformations enable the asymmetric synthesis of highly substituted polycyclic ring systems in just two steps from commercial materials. The utility of this process is illustrated in a rapid synthesis of (-)-protoemetinol. Computational studies provide mechanistic insights and implicate the elimination of acetic acid from an ammonium nitronate intermediate as the rate-determining step.

Full text of DOI:10.1021/acs.joc.5b01384

Article
pubs.acs.org/joc
Asymmetric Redox-Annulation of Cyclic Amines
YoungKu Kang,† Weijie Chen,† Martin Breugst,*,‡ and Daniel Seidel*,†
†Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
‡Department fur Chemie, Universitat zu Koln, Greinstraße 4, 50939 Koln, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: Cyclic amines such as 1,2,3,4-tetrahydroisoqui-
noline undergo regiodivergent annulation reactions with 4-
nitrobutyraldehydes. These redox-neutral transformations
enable the asymmetric synthesis of highly substituted
polycyclic ring systems in just two steps from commercial
materials. The utility of this process is illustrated in a rapid synthesis of (−)-protoemetinol. Computational studies provide
mechanistic insights and implicate the elimination of acetic acid from an ammonium nitronate intermediate as the rate-
determining step.
Scheme 2. Redox-Annulation
INTRODUCTION
■
Tryptoline (tetrahydro-β-carboline) and 1,2,3,4-tetrahydroiso-
quinoline (THIQ) are substructures of numerous bioactive
natural products that contain additional fused rings (Scheme 1).1
Scheme 1. Selected Natural Products with THIQ and
Tryptoline Substructures
The desire to build such highly substituted polycyclic
compounds with complete stereocontrol has inspired the
development of numerous synthetic methods.2 Here, we report
a redox-neutral annulation strategy that enables the asymmetric
synthesis of relevant core structures from simple THIQ or
tryptoline and readily available, highly enantioenriched 4-
nitrobutyraldehydes.
As part of our ongoing efforts to develop practical methods for
the C−H functionalization of amines,3,4 we recently reported the
first examples of what may be termed a redox-annulation of
amines (Scheme 2).3b Conceptually, an amine such as THIQ
engages an aldehyde with a pendent carbon nucleophile to form
product 2 via reductive N-alkylation/oxidative C−C bond
formation in an overall redox-neutral process.5 Condensation
of the two components initially forms an azomethine ylide
intermediate 1 that, following proton transfer and ring closure,
provides product 2.6−9 For instance, THIQ and indole aldehyde
3 form annulation product 4 in 64% yield.3b While this is a clear
demonstration of the utility of this approach for the facile
preparation of polycyclic ring systems, the method requires
relatively high reaction temperatures. More serious limitations
are the need for using nonenolizable aldehydes and electron-rich
aromatic nucleophiles (e.g., indole, β-naphthol).
In order to be applicable to the synthesis of structures related
to those shown in Scheme 1, the redox-annulation would have to
proceed with enolizable aldehydes capable of installing a fully
saturated ring bearing variable substituents. These consider-
ations, coupled with our goal to perform amine redox-
annulations in asymmetric fashion, led to the identification of
4-nitrobutyraldehydes 5 as ideal reaction partners. These
precursors are easily prepared in a single step and nearly
enantiopure form from aldehydes and nitroalkenes by means of
well-established organocatalytic methods.10 The corresponding
annulation products 6 are equipped with substituents in relevant
positions and, due to the presence of a nitro group, offer
numerous opportunities for further product manipulation.11
Received: July 15, 2015
© XXXX American Chemical Society
A
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a
EXPERIMENTAL RESULTS AND DISCUSSION
Scheme 3. Scope of the Asymmetric Redox-Annulation
■
We began our investigation into the feasibility of the proposed
annulation process by employing 5a and THIQ as model
substrates (Table 1). The original annulation conditions
a
Table 1. Evaluation of Reaction Conditions
entry
acid (equiv)
temp (°C) time (min) yield (%) ratio 6a:7a
1
2
3
4
5
6
150 (μW)
150 (μW)
150 (μW)
150 (μW)
150 (μW)
150 (μW)
150 (μW)
120 (μW)
reflux
15
15
complex
complex
45
ND
ND
1.8:1
2:1
AcOH (1)
AcOH (5)
15
AcOH (10)
2-EHA (10)
PhCO2H (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
15
65
15
30
1:1
b
15
NR
c
7
15
65
71
71
62
1.8:1
1.8:1
c
8
c
2
d
9
1 h
15 h
2:1
a
c
Reactions were performed on a 0.6 mmol scale. For products 6a/7a−
10
60
2:1
a
6j/7j, yields correspond to combined, isolated yields of both
diastereomers. For products 6k−t, yields correspond to isolated yields
of the major diastereomer.
Reactions were performed with 5a (0.2 mmol) and THIQ (4 equiv).
1
Product ratios were determined by H NMR analysis of the crude
reaction mixture. Yields correspond to combined, isolated yields of
b
both diastereomers. ND: not determined. NR: no reaction. Partially
c
epimerized starting material was recovered (dr = 1:1). Performed
patterns readily underwent the title reaction, providing products
6/7 in moderate to good yields and with diastereoselectivities of
up to 5:1. Notably, in all cases, separation of the two
diastereomeric products was readily accomplished by standard
column chromatography. 4-Nitrobutyraldehydes without α-
substituents gave rise to products 6 with good to excellent levels
of diastereoselectivity.12 Importantly, the reaction of mono- and
disubstituted 4-nitrobutyraldehydes was also applicable to
substituted THIQs and tryptoline.
During the development of the title reaction, we occasionally
observed small amounts of the regioisomeric annulation
products 8 and 9 (Scheme 4). Following extensive experimenta-
tion, conditions were identified that provided 8 and 9 as the
major products with regioselectivities of up to nearly 9:1.13
Diastereoselectivities were similar to those observed in redox-
annulations that involve the benzylic position, with β-
with 5a (0.6 mmol) and 2 equiv of THIQ in the presence of 4 Å MS.
d
Both 6a and 7a were obtained with 95% ee.
developed for product 4 failed to provide any desired product
(entry 1). Addition of acetic acid (1 equiv), an additive previously
shown to be an excellent promoter for amine α-oxygenation3h
and α-sulfenylation,3j did not provide any improvements (entry
2). Gratifyingly, the use of 5 equiv of acetic acid under otherwise
identical conditions allowed for the isolation of the desired
product as a 1.8:1 mixture of diastereomers 6a and 7a in 45%
overall yield. The formation of 7a is readily rationalized by the
intermediacy of enamines, causing epimerization of the stereo-
genic center in α-position of the aldehyde prior to the annulation
step. Excess acetic acid apparently reduces the concentration of
enamine intermediates, facilitating the redox-isomerization and
minimizing undesired side reactions. Indeed, further increase of
the amount of acetic acid to 10 equiv led to an increase in yield to
65% (entry 4). With 2-ethylhexanoic acid (2-EHA), the product
yield was only 30% (entry 5). Remarkably, with benzoic acid,
previously shown to be an excellent catalyst for amine α-
functionalizations, no desired product was formed; only
epimerization of the starting material was observed (entry 6).
Addition of molecular sieves had a beneficial effect, and the
amount of THIQ could be lowered to 2 equiv (entry 7). A
reduction in temperature from 150 to 120 °C, while reducing the
reaction time from 15 to 2 min, led to a further increase in yield to
71% (entry 8). A reaction performed under simple reflux
conditions was completed in only 1 h and gave rise to nearly
identical results (entry 9). Even at a temperature of only 60 °C,
the reaction progressed in an efficient manner (entry 10). For the
sake of convenience and to keep reaction times brief, subsequent
experiments were performed under reflux in toluene.
Scheme 4. Divergent Regioselectivity in the Asymmetric
a
Redox-Annulation
The scope of the asymmetric redox-annulation of THIQ was
explored with a range of 4-nitrobutyraldehydes (Scheme 3). α,β-
Disubstituted 4-nitrobutyraldehydes 5 with various substitution
a
Reactions were performed on a 0.6 mmol scale.
B
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monosubstituted 4-nitrobutyraldehydes providing products 8 in
highly diastereoselective fashion. Key to accomplishing redox-
annulations at the less reactive α-C−H bond is performing the
reaction at higher temperature (reflux in xylenes) and to
maintain a low concentration of 5. This was achieved by syringe
pump addition of the corresponding 4-nitrobutyraldehyde. Best
results were obtained in the absence of molecular sieves.14
Redox-annulations of THIQ were also performed with parent
4-nitrobutyraldehyde 10 eqs 1 and 2. Regioselective annulation
Condensation of 6,7-dimethoxy-THIQ and 18 resulted in the
formation of 19 and two of its diastereomers in 61% overall yield.
The major diastereomer was converted to (−)-protoemetinol in
a single operation that served to remove both the nitro and
benzyl groups.
COMPUTATIONAL RESULTS AND DISCUSSION
■
To shed light on the mechanism of the redox-annulations
discussed above and to rationalize the high regioselectivities of
eqs 1 and 2, we carefully analyzed the reaction between THIQ
and 4-nitrobutyraldehyde (10) by DFT calculations [M06-2X-
D3/def2-QZVP/IEFPCM//M06-L-D3/6-31+G(d,p)/
IEFPCM]. Although the uncatalyzed reaction of THIQ and 10
results in complex mixtures, knowledge of this pathway is
important to understand any potential background reaction
(Scheme 6). Consequently, the uncatalyzed pathway was
evaluated first. In the first step of this transformation, THIQ
and 10 form the hemiaminal 20 in an almost thermoneutral
reaction. Water can be eliminated from 20 in two different
orientations yielding the azomethine ylides 21a and 21b in highly
endergonic transformations (ΔG = +18.9 and +30.1 kcal mol−1).
Due to the direct conjugation of the azomethine ylide with the
benzene ring, ylide 21a is significantly more stable than its isomer
21b. We were unable to locate any transition states for this
elimination, and all attempts starting from different transition
state guesses resulted in a barrierless addition of water to the
corresponding azomethine ylides. Therefore, it was concluded
that this reaction occurs without a significant barrier which can be
rationalized with the high reactivities of the formed azomethine
ylides. In principle, the hemiaminal 20 could also form the
corresponding enamine (not shown in Scheme 6) through
another elimination of water. This transformation is thermo-
neutral (ΔG = −0.1 kcal mol−1) and can account for the
epimerization of α-substituted aldehydes (Table1). Next, an
intramolecular proton transfer takes place between the nitro-
alkane moiety and the ylide. In both transition states TS01a and
TS01b, the proton transfers occur through five-membered
transition states and are very high in energy (ΔG⧧ = +42.9 and
+47.1 kcal mol−1). In an alternative pathway, the zwitterions 22
could also be formed via a zwitterionic intermediate with an
exocyclic double bond (not shown in Scheme 6). As this isomer
is formed in a highly endergonic step (ΔG = +25 kcal mol−1) and
requires a highly unfavorable 1,3-proton shift, this pathway seems
less likely. The zwitterions 22a and 22b subsequently undergo
intramolecular cyclization reactions to either form the
diastereomeric products 11 and 12 or the regioisomers 13 and
14. These reactions occur without a significant barrier, which can
be explained by the high reactivities of nitronate anions and
iminium cations.16 Our calculations predict a small thermody-
namic preference (ΔΔG = 0.9 kcal mol−1) for the cis-product 11
over the trans-product 12, which is in good agreement with the
experimental 2:1 ratio. A much stronger preference (ΔΔG = 2.0
kcal mol−1) for the cis-isomer was calculated for 13 compared to
14 in line with the exclusive isolation of 13.
was accomplished at either position through judicious choice of
reaction conditions. Diastereomeric products 11 and 12 were
obtained in a 2:1 ratio and 55% overall yield (eq 1). This appears
to correspond to the thermodynamic equilibrium ratio of these
two products.15 Notably, product 13 was obtained as a single
diastereo- and regioisomer in 61% yield (eq 2).
Products derived from the redox-annulation could be readily
modified. For instance, reduction of 8k with Zn/HCl provided
amine 15 in 83% yield (eq 3). Removal of the nitro group in 6k
via hydrogenolysis provided heterocycle 16 in 75% yield (eq 4.
Importantly, the enantiomeric purity of the material was not
affected by this transformation. Finally, compound 11 was
alkylated with methyl vinyl ketone in the presence of DBU to
yield product 17 as a single diastereomer in 69% yield (eq 5).
The asymmetric redox-annulation was applied to a short
synthesis of the natural product (−)-protoemetinol (Scheme 5).
As the intramolecular proton transfers yielding the zwitterions
22 are very high in energy, we were wondering whether acetic
acid could act as a proton shuttle to bypass TS1a and TS1b as
seen in related oxygenation and sulfenylation reactions.3h,j
However, starting from many different transition-state guesses,
we were unable to locate any transition states for such
mechanisms. Instead, these structures relaxed to hydrogen-
bonded adducts between acetic acid and different polar groups of
the azomethine ylides. Furthermore, acetic acid could also
Scheme 5. Synthesis of (−)-Protoemetinol
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Scheme 6. Calculated Free Energies for the Uncatalyzed and Acetic-Acid-Catalyzed Annulation Reactions and Selected Transition-
State Structures [kcal mol−1, M06-2X-D3/def2-QZVP/IEFPCM//M06-L-D3/6-31+G(d,p)/IEFPCM]
facilitate the formation of iminium ions as intermediates in these
transformations, but based on our calculations, iminium ions are
very high in energy (ΔG⧧ > 47 kcal mol−1; see the Supporting
Information for more details) and were thus ruled out. Instead,
we considered a concerted elimination of acetic acid from
acetylated hemiaminals (N,O-acetals) as an alternative mecha-
nism (e.g., 23, 24, and 27), as previously suggested by Yu and co-
workers in the formation of pyrroles from pyrroline and
aldehydes.17
According to the calculated free energy profile in Scheme 6,
the combination of THIQ, 10, and AcOH results in the
formation of the N,O-acetal 23 in a slightly endergonic reaction.
Subsequently, acetic acid is eliminated in a concerted yet highly
asynchronous transition state (TS02, see the Supporting
Information) yielding the azomethine ylide 21a. Next, acetic
acid adds across the other terminus of the ylide (TS03), resulting
in the formation of the more stable isomeric N,O-acetal 24. This
intermediate can now react via two pathways to form either the
product 11 (or 12) or the regioisomer 13. For the formation of
11, the next step involves an intramolecular deprotonation of an
acidic proton in α-position of the nitro group. This reaction
proceeds through a six-membered transition state (TS04) and
yields the ammonium nitronate 25. This endergonic step is also
reflected in a very late transition state with a short N−H bond
(1.14 Å). Next, acetic acid is eliminated through TS05 (ΔG⧧ =
30.5 kcal mol−1), which is also the rate-determining step for the
formation of 11. This reaction proceeds in a concerted yet highly
asynchronous fashion in which the cleavage of the C−O bond
lacks behind the proton transfer. After cyclization of the
generated zwitterion 22a, the annulation product 11 is formed
in an overall exergonic reaction.
The alternate regioisomer 13 could also be obtained from
N,O-acetal intermediate 23. This pathway is identical to the one
discussed for the formation of 11 for the transformation of 23 to
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harmonic vibrational frequencies at the same level of theory for a
standard state of 1 mol L−1 and 298.15 K. Entropic contributions to the
reported free energies were derived from partition functions evaluated
with the quasiharmonic approximation by Truhlar and co-workers.24
Electronic energies were subsequently obtained from single-point
calculations of the M06-L-D3 geometries employing the meta-hybrid
M06-2X functional,25 Grimme’s dispersion-correction D3 (zero-damp-
ing), the large quadruple-ζ basis set def2-QZVP,26 and IEFPCM for
toluene, a level expected to give accurate energies.27 An ultrafine grid
was used throughout this study for numerical integration of the density.
All density functional theory calculations were performed with Gaussian
09.28
24. However, from there it continues with an almost isoenergetic
isomerization of the N,O-acetal 24 to the N,O-acetal 27. This
two-step process consists of elimination and subsequent addition
of acetic acid through transition states TS06 and TS07.18 In
principle, 27 could also be obtained in a sequence of elimination
and addition of AcOH (23 → 21b → 27, not shown in Scheme
6), and we have calculated the transition states (ΔG⧧ = 30.8 and
29.9 kcal mol−1, respectively, Supporting Information) for these
transformations as well. As they are significantly higher in energy
than the barriers for the pathway involving 26 (Scheme 6), we
have to conclude that the azomethine ylide 21b does not lie on
the reaction coordinate for the formation of either 11 or 13.
Next, the ammonium nitronate 28 is formed through TS08
before the rate-determining elimination of acetic acid takes place
(TS09, ΔG⧧ = +30.8 kcal mol−1). Alternatively, zwitterions 22
could also be obtained directly from the azomethine ylide 26
through an intramolecular proton transfer. However, these
reactions would occur with significantly higher barriers (ΔG⧧ =
+40.4 kcal mol−1 for 26 → 22a and ΔG⧧ = +37.6 kcal mol−1 for
26 → 22b) and thus appear to play no role in this transformation.
Finally, the thermodynamic product 13 is formed via cyclization
of the zwitterion 22b.
The calculated energy profile is in good qualitative agreement
with the experimental findings. The calculated barriers might be
slightly overestimated as in the experimental studies both acetic
acid and THIQ are used in excess. The results of eqs 1 and 2 can
also be rationalized using the computational data in Scheme 6.
Although the energetic difference between both rate-determin-
ing steps TS05 and TS09 is rather small, the formation of 11 and
12 is kinetically preferred. The conditions of eq 1 favor the
formation of the kinetically preferred products 11 and 12, while
the thermodynamically more stable product 13 is obtained
exclusively at higher temperatures and longer reaction times.
EXPERIMENTAL SECTION
■
General Information. Starting materials, reagents, and solvents
were purchased from commercial sources and used as received unless
stated otherwise. Propionaldehyde, isovaleraldehyde, hydrocinnamalde-
hyde, and trans-cinnamaldehyde were purified by distillation prior to
use. 1,2,3,4-Tetrahydroisoquinoline was distilled prior to use. Powdered
molecular sieves (4 Å) were activated before use by heating in a furnace
to 300 °C for 2 h and were stored in a desiccator. Nitroalkenes were
prepared according to previously reported procedures.29 Microwave
reactions were carried out in a CEM Discover reactor. Silicon carbide
(SiC) passive heating elements were purchased from Anton Paar.
Analytical thin-layer chromatography was performed on EM Reagent
0.25 mm silica gel 60 F254 plates. Visualization was accomplished with
UV light, potassium permanganate, and Dragendorff−Munier stains
followed by heating. Purification of reaction products was carried out by
flash column chromatography using Sorbent Technologies Standard
grade silica gel (60 Å, 230−400 mesh). Chemical shifts in proton nuclear
magnetic resonance spectra (1H NMR) are reported in ppm using the
solvent as an internal standard (CDCl3 at 7.26 ppm, CD2Cl2 at 5.30
ppm). Data are reported as app = apparent, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, comp = complex, br = broad; coupling
constant(s) in hertz. Chemical shifts in proton-decoupled carbon
nuclear magnetic resonance spectra (13C NMR) are reported in ppm
using the solvent as an internal standard (CDCl3 at 77.0 ppm, CD2Cl2 at
54.0 ppm). HRMS spectrometry data were recorded on a spectrometer
operating on ESI-FTICR (MeCN as solvent). Optical rotations were
measured using a 1 mL cell with a 1 dm path length at 589 nm and at 25
°C. (S)-Diphenylprolinol trimethylsilyl ether was prepared according to
a literature procedure.30
CONCLUSIONS
■
We have reported the first examples of asymmetric redox-
annulations of tetrahydroisoquinolines and tryptoline with
readily available, highly enantioenriched 4-nitrobutyraldehydes.
Reactions proceed under operationally convenient conditions
and do not require the use of expensive catalysts. This strategy
enabled the asymmetric preparation of polycyclic amines that
contain the core structure of various bioactive compounds in just
two steps from commercial materials. Simply by changing the
reaction conditions, regioselective redox-annulations can be
achieved at the nonbenzylic position of THIQ, enabling the rapid
exploration of new chemical space.
General Procedures for the Synthesis of Starting Materials.10
General Procedure A. To a stirred solution of nitroalkene (3 mmol, 1
equiv), (S)-diphenylprolinol trimethylsilyl ether (0.15 mmol, 5 mol %),
and p-nitrophenol (0.15 mmol, 5 mol %) in toluene (3 mL) was added
aldehyde (4.5 mmol, 1.5 equiv) at room temperature. The reaction
progress was monitored by TLC. After completion, the reaction was
quenched by the addition of 1 M HCl (10 mL) and the resulting mixture
extracted with EtOAc (2 × 10 mL). The combined organic layers were
dried over anhydrous Na2SO4. Solvent was removed under reduced
pressure and the residue purified by silica gel chromatography.
General Procedure B. To a stirred solution of trans-cinnamaldehyde
(3 mmol, 1 equiv), (S)-diphenylprolinol trimethylsilyl ether (0.3 mmol,
10 mol %), and benzoic acid (0.6 mmol, 20 mol %) in MeOH (6 mL)
was added nitromethane (9 mmol, 3 equiv) at room temperature. The
reaction progress was monitored by TLC. After completion, the reaction
was quenched by the addition of saturated NaHCO3 (10 mL) and the
resulting mixture extracted with EtOAc (2 × 10 mL). The combined
organic layers were dried over anhydrous Na2SO4. Solvent was removed
under reduced pressure and the residue purified by silica gel
chromatography.
COMPUTATIONAL METHODS
■
For the computational investigations, the conformational space for each
structure was explored using the OPLS-2005 force field19 and a modified
Monte Carlo search algorithm implemented in MacroModel 10.6.20 An
energy cutoff of 20 kcal mol−1 was employed for the conformational
analysis, and structures with heavy-atom root-mean-square deviations
(RMSD) less than 2 Å after the initial force field optimizations were
considered to be the same conformer. The remaining structures were
subsequently optimized with the dispersion-corrected M06-L func-
tional21 with Grimme’s dispersion-correction D322 and the double-ζ
basis set 6-31+G(d,p). Solvation by toluene was taken into account by
using the integral equation formalism polarizable continuum model
(IEFPCM)23 for all calculations. Vibrational analysis verified that each
structure was a minimum or transition state. Following the intrinsic
reaction coordinates (IRC) confirmed that all transition states
connected the corresponding reactants and products on the potential
energy surface. Thermal corrections were obtained from unscaled
General Procedure C. To a stirred solution of nitroalkene (3 mmol, 1
equiv) and (S)-diphenylprolinol trimethylsilyl ether (0.3 mmol, 10 mol
%) in dioxane (0.6 mL) was added acetaldehyde (30 mmol, 10 equiv) at
0 °C. The reaction mixture was stirred at room temperature, and the
reaction progress was monitored by TLC. After completion, the reaction
was quenched by the addition of 1 M HCl (10 mL) and the resulting
mixture extracted with EtOAc (2 × 10 mL). The combined organic
E
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layers were dried over anhydrous Na2SO4. Solvent was removed under
reduced pressure and the residue purified by silica gel chromatography.
(2R,3S)-2-Methyl-4-nitro-3-phenylbutanal. The title compound
was synthesized following general procedure A.10j The product was
obtained as a yellow oil in 78% yield (mixture of two diastereomers).
Compound 5a was previously reported, and its published character-
ization data matched our own in all respects.10j The enantiomeric excess
was determined by HPLC with Daicel Chiralcel OD-H: n-hexane/i-
PrOH = 90/10, flow rate = 1 mL/min, UV = 210 nm, tR = 22.4 min
(minor) and tR = 32.9 min (major), 96% ee.
(2R,3S)-3-(4-Fluorophenyl)-2-methyl-4-nitrobutanal. The title
compound was synthesized following general procedure A.10j The
product was obtained as a yellow oil in 78% yield (mixture of two
diastereomers). Compound 5b was previously reported, and its
published characterization data matched our own in all respects.10i
(2R,3S)-3-(4-Bromophenyl)-2-methyl-4-nitrobutanal. The title
compound was synthesized following general procedure A.10j The
product was obtained as a yellow solid in 70% yield (mixture of two
diastereomers). Compound 5c was previously reported, and its
published characterization data matched our own in all respects.10j
(2R,3S)-2-Methyl-4-nitro-3-(p-tolyl)butanal. The title compound
was synthesized following general procedure A.10j The product was
obtained as a yellow oil in 70% yield (mixture of two diastereomers).
Compound 5d was previously reported, and its published character-
ization data matched our own in all respects.10c
(2R,3S)-3-(4-Methoxyphenyl)-2-methyl-4-nitrobutanal. The title
compound was synthesized following general procedure A.10j The
product was obtained as a yellow oil in 68% yield (mixture of two
diastereomers). Compound 5e was previously reported, and its
published characterization data matched our own in all respects.10j
(2R,3R)-2-Methyl-3-(nitromethyl)-5-phenylpentanal. The title
compound was synthesized following general procedure A.10j The
product was obtained as a yellow oil in 57% yield (mixture of two
diastereomers). Compound 5f was previously reported, and its
published characterization data matched our own in all respects.10j
(2R,3S)-2-Benzyl-4-nitro-3-phenylbutanal. The title compound was
synthesized following general procedure A.10j The product was obtained
as a yellow oil in 66% yield (mixture of two diastereomers). Compound
5g was previously reported, and its published characterization data
matched our own in all respects.10j
(2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal. The title compound
was synthesized following general procedure A.10j The product was
obtained as a white solid in 57% yield (mixture of two diastereomers).
Compound 5h was previously reported, and its published character-
ization data matched our own in all respects.10j
(S)-4-Nitro-3-phenylbutanal. The title compound was synthesized
following general procedure B.10f The product was obtained as a yellow
oil in 74% yield. Compound 5k was previously reported, and its
published characterization data matched our own in all respects.10f The
product was reduced to the corresponding alcohol using NaBH4 for
HPLC analysis:31 Daicel Chiralcel OD-H, n-hexane/i-PrOH = 90/10,
flow rate = 1 mL/min, UV = 230 nm, tR = 17.2 min (minor) and tR = 21.9
min (major), 95% ee.
(S)-3-(4-Chlorophenyl)-4-nitrobutanal. The title compound was
synthesized following general procedure C.10h The product was
obtained as a yellow oil in 44% yield. Compound 5l was previously
reported, and its published characterization data matched our own in all
respects.10h
(S)-3-(4-Bromophenyl)-4-nitrobutanal. The title compound was
synthesized following general procedure C.10h The product was
obtained as a yellow oil in 34% yield. Compound 5m was previously
reported, and its published characterization data matched our own in all
respects.10h
reported, and its published characterization data matched our own in all
respects.10h
(S)-3-(Naphthalen-2-yl)-4-nitrobutanal. The title compound was
synthesized following general procedure C.10h The product was
obtained as a yellow solid in 69% yield. Compound 5p was previously
reported, and its published characterization data matched our own in all
respects.10h
(R)-3-(Furan-2-yl)-4-nitrobutanal. The title compound was synthe-
sized following general procedure C.10h The product was obtained as a
yellow oil in 42% yield. Compound 5q was previously reported, and its
published characterization data matched our own in all respects.10h
General Procedures for the Asymmetric Redox-Annulation.
General Procedure A. To a mixture of aldehyde (0.6 mmol, 1 equiv), 4 Å
MS (0.2 g) and AcOH (6 mmol, 10 equiv) in toluene (6 mL) was added
the amine (1.2 mmol, 2 equiv) at room temperature. The mixture was
heated under reflux for 1 h. Subsequently, the reaction mixture was
allowed to cool to room temperature, diluted with EtOAc (20 mL), and
washed with saturated aqueous NaHCO3 (3 × 10 mL). The combined
aqueous layers were extracted with EtOAc (2 × 10 mL) and the
combined organic layers dried over anhydrous Na2SO4. Solvent was
removed under reduced pressure and the residue purified by silica gel
chromatography.
General Procedure B. A solution of amine (1.2 mmol, 2 equiv) and 2-
EHA (6 mmol, 10 equiv) in xylenes (6 mL) was heated under reflux. The
aldehyde (0.6 mmol, 0.12 M solution in xylenes) was delivered through
the top of the reflux condenser over 15 h via syringe pump. The reaction
was then kept under reflux for a further 0.5−1 h at which time the
aldehyde was consumed as judged by TLC analysis. Subsequently, the
reaction mixture was allowed to cool to room temperature, diluted with
EtOAc (20 mL), and washed with saturated aqueous NaHCO3 (3 × 20
mL). The combined aqueous layers were extracted with EtOAc (2 × 10
mL) and the combined organic layers dried over anhydrous Na2SO4.
Solvent was removed under reduced pressure and the residue purified by
silica gel chromatography.
General Procedure C. A 10 mL microwave reaction tube was charged
with a 10 × 8 mm SiC passive heating element, aldehyde (0.6 mmol, 1
equiv), toluene (6 mL), amine (1.2 mmol, 2 equiv), 3 Å MS (0.2 g), and
AcOH (6 mmol, 10 equiv). The reaction tube was sealed with a Teflon-
lined snap cap and heated in a microwave reactor at 120 °C (0−15 psi)
for 3 min. After being cooled with compressed air flow, the reaction
mixture was diluted with EtOAc (20 mL) and washed with saturated
aqueous NaHCO3 (3 × 20 mL). The combined aqueous layers were
extracted with EtOAc (2 × 10 mL) and the combined organic layers
dried over anhydrous Na2SO4. Solvent was removed under reduced
pressure and the residue purified by silica gel chromatography.
Products 6a and 7a. Following general procedure A, products 6a
and 7a were obtained in a 2:1 ratio (71% combined yield). The relative
stereochemistry was determined by GCOSY and NOESY NMR.
Characterization data for 6a: yellowish oil; Rf = 0.32 in 20%
EtOAc/Hex; [α]D25 − 31.9 (c 0.5, CHCl3); IR (KBr) 3063, 3028, 2959,
2927, 2828, 1539, 1492, 1452, 1311, 1264, 1153, 1094, 750, 703 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.33−7.28 (comp, 2H), 7.27−7.25 (m,
1H), 7.19−7.15 (comp, 4H), 7.07 (app t, J = 7.5 Hz, 1H), 6.87 (app d, J
= 7.8 Hz, 1H), 4.97 (dd, J = 11.2, 9.8 Hz, 1H), 4.39 (d, J = 9.8 Hz, 1H),
3.34 (ddd, J = 11.4, 9.8, 4.9 Hz, 1H), 3.19 (dd, J = 13.7, 4.1 Hz, 1H), 3.11
(app t, J = 11.4 Hz, 1H), 3.05 (dd, J = 9.6, 6.7 Hz, 1H), 3.00−2.98 (m,
1H), 2.96−2.92 (comp, 2H), 2.30−2.23 (m, 1H), 0.73 (d, J = 6.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 138.2(2), 134.2(1), 132.9, 129.5,
129.1, 128.1, 128.0, 127.0, 126.3, 91.7, 77.6, 77.3, 77.1, 63.0, 62.1, 56.0,
46.5, 31.2, 29.9, 16.7; HRMS (ESI) m/z calcd for C20H23N2O2 [M + H]+
323.1754, found 323.1765; HPLC Daicel Chiralcel OD-H, n-hexane/i-
PrOH = 90/10, flow rate = 1 mL/min; UV = 230 nm, tR = 7.1 min
(major) and tR = 8.0 min (minor), 95% ee.
(S)-4-Nitro-3-(p-tolyl)butanal. The title compound was synthesized
following general procedure C.10h The product was obtained as a yellow
solid in 72% yield. Compound 5n was previously reported, and its
published characterization data matched our own in all respects.10h
(S)-3-(4-Methoxyphenyl)-4-nitrobutanal. The title compound was
synthesized following general procedure C.10h The product was
obtained as a yellow oil in 56% yield. Compound 5o was previously
Characterization data for 7a. yellowish solid; mp 180−182 °C; Rf =
0.46 in 20% EtOAc/Hex; [α]D25 −130.8 (c 0.5, CHCl3); IR (KBr) 3061,
3031, 2957, 2957, 2927, 2893, 2811, 2767, 1546, 1489, 1452, 1351,
1299, 1146, 1111, 738, 696 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.32−
7.29 (comp, 2H), 7.27−7.20 (comp, 2H), 7.20−7.14 (comp, 3H), 7.11
(app t, J = 7.6 Hz, 1H), 6.90 (app d, J = 7.9 Hz, 1H), 5.09 (dd, J = 11.7,
9.0 Hz, 1H), 4.20 (d, J = 9.0 Hz, 1H), 3.82 (dd, J = 11.7, 5.0 Hz, 1H),
F
DOI: 10.1021/acs.joc.5b01384
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The Journal of Organic Chemistry
Article
3.25 (dd, J = 12.2, 3.5 Hz, 1H), 3.12 (ddd, J = 14.8, 9.4, 5.0 Hz, 1H), 3.05
(app dt, J = 10.9, 4.4 Hz, 1H), 2.98 (dd, J = 12.2, 1.8 Hz, 1H), 2.86 (ddd,
J = 11.1, 9.4, 3.5 Hz, 1H), 2.76 (app dt, J = 15.4, 3.5 Hz, 1H), 2.18−2.09
(m, 1H), 0.95 (d, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
138.5, 136.0, 133.0, 129.5, 128.7, 128.2, 127.6, 127.5, 126.5, 126.3, 88.3,
66.0, 62.0, 52.7, 50.8, 35.8, 31.2, 15.2; m/z (ESI-MS) 323.2 [M + H]+;
HPLC Daicel Chiralcel OD-H, n-hexane/i-PrOH = 90/10, flow rate = 1
mL/min; UV = 230 nm, tR = 6.3 min (minor) and tR = 6.9 min (major),
95% ee.
Characterization data for 6d: yellowish oil; Rf = 0.35 in 20%
EtOAc/Hex; [α]D25 −34.8 (c 0.5, CHCl3); IR (KBr) 3056, 3021, 2972,
2925, 2905, 2878, 2809, 2767, 1548, 1509, 1492, 1445, 1371, 1346,
1296, 1267, 1254, 1151, 1114, 1037, 951, 832, 802, 733 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.22−7.18 (m, 1H), 7.17−7.14 (m, 1H), 7.13−
7.09 (comp, 2H), 7.09−7.04 (comp, 3H), 6.87 (app d, J = 7.9 Hz, 1H),
4.94 (dd, J = 11.2, 9.8 Hz, 1H), 4.38 (d, J = 9.8 Hz, 1H), 3.34 (ddd, J =
11.2, 9.6, 4.9 Hz, 1H), 3.18 (dd, J = 13.7, 4.1 Hz, 1H), 3.11−3.01 (comp,
2H), 3.00−2.91 (comp, 3H), 2.31 (s, 3H), 2.28−2.21 (m, 1H), 0.73 (d, J
= 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 137.5, 135.2, 134.2,
133.0, 129.8, 129.5, 128.1, 127.0, 126.3, 105.0, 91.8, 63.0, 62.1, 55.7,
46.4, 31.2, 29.9, 21.3, 16.7; m/z (ESI-MS) 337.2 [M + H]+.
Characterization data for 7d: yellowish oil; Rf = 0.52 in 20%
EtOAc/Hex; [α]D25 −157.6 (c 0.5, CHCl3); IR (KBr) 3056, 3024, 2962,
2920, 2895, 2809, 2767, 1546, 1509, 1494, 1450, 1368, 1348, 1294,
1264, 1148, 1114, 1039, 948, 837, 800, 726 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.23−7.19 (m, 1H), 7.17−7.14 (m, 1H), 7.12−7.10 (comp,
3H), 7.09−7.05 (comp, 2H), 6.90 (app d, J = 7.9 Hz, 1H), 5.07 (dd, J =
11.7, 9.0 Hz, 1H), 4.18 (d, J = 9.0 Hz, 1H), 3.78 (dd, J = 11.7, 4.9 Hz,
1H), 3.23 (dd, J = 12.2, 3.3 Hz, 1H), 3.12 (ddd, J = 14.8, 9.3, 4.9 Hz, 1H),
3.04 (app dt, J = 11.1, 4.4 Hz, 1H), 2.97 (dd, J = 12.2, 1.8 Hz, 1H), 2.85
(ddd, J = 11.1, 9.3, 3.5 Hz, 1H), 2.75 (app dt, J = 15.5, 3.5 Hz, 1H), 2.31
(s, 3H), 2.13−2.10 (m, 1H), 0.96 (d, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 137.1, 136.1, 135.5, 133.2, 129.5, 129.4, 128.1, 127.6,
126.5, 126.3, 88.5, 66.0, 62.0, 52.4, 50.8, 35.9, 31.3, 21.3, 15.2; m/z (ESI-
MS) 337.2 [M + H]+.
Products 6b and 7b. Following general procedure A, products 6b
and 7b were obtained in a 2:1 ratio (68% combined yield).
Characterization data for 6b: yellowish oil; Rf = 0.32 in 20%
EtOAc/Hex; [α]D25 −32.6 (c 0.5, CHCl3); IR (KBr) 3066, 3033, 2959,
2920, 2843, 1608, 1543, 1509, 1457, 1363, 1311, 1225, 1161, 1096, 733
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.23−7.18 (m, 1H), 7.16−7.13
(comp, 3H), 7.07 (app t, J = 7.5 Hz, 1H), 7.01−6.98 (comp, 2H), 6.85
(app d, J = 7.8 Hz, 1H), 4.90 (dd, J = 11.2, 9.8 Hz, 1H), 4.37 (d, J = 9.8
Hz, 1H), 3.32 (ddd, J = 11.2, 9.4, 4.9 Hz, 1H), 3.18 (dd, J = 13.7, 4.1 Hz,
1H), 3.10 (app t, J = 11.2 Hz, 1H), 3.03 (dd, J = 9.8, 6.7 Hz, 1H), 2.99−
2.90 (comp, 3H), 2.25−2.17 (m, 1H), 0.72 (d, J = 6.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 162.4 (d, J = 246.2 Hz), 134.2, 134.0 (d, J =
3.3 Hz), 132.8, 129.6, 128.2, 126.9, 126.4(0), 126.3(6), 116.1 (d, J = 21.5
Hz), 91.8, 63.0, 62.0, 55.3, 46.5, 31.3, 29.9, 16.6; m/z (ESI-MS) 341.1
[M + H]+.
Characterization data for 7b. Yellowish solid; mp 100−103 °C; (Rf
= 0.47 in 20% EtOAc/Hex); [α]D25 −126.5 (c 0.5, CHCl3); IR (KBr)
3063, 2969, 2935, 2910, 2814, 2769, 1608, 1546, 1506, 1427, 1348,
1299, 1222, 1161, 1109, 842, 812, 753, 696 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.21 (app t, J = 7.3 Hz, 1H), 7.18−7.09 (comp, 4H), 7.01−
6.98 (comp, 2H), 6.88 (app d, J = 7.9 Hz, 1H), 5.02 (dd, J = 11.7, 9.0 Hz,
1H), 4.17 (d, J = 9.0 Hz, 1H), 3.80 (dd, J = 11.7, 4.9 Hz, 1H), 3.22 (dd, J
= 12.2, 3.2 Hz, 1H), 3.12 (ddd, J = 14.6, 9.3, 4.6 Hz, 1H), 3.02 (app dt, J
= 10.9, 4.6 Hz, 1H), 2.96 (dd, J = 12.2, 1.7 Hz, 1H), 2.84 (app td, J =
10.9, 3.2 Hz, 1H), 2.74 (app dt, J = 15.5, 3.2 Hz, 1H), 2.15−2.05 (m,
1H), 0.94 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.2 (d,
J = 245.9 Hz), 136.1, 134.2(9), 134.2(6), 133.0, 129.7 (d, J = 8.0 Hz),
129.5, 127.6, 126.5, 126.2, 115.7 (d, J = 21.4 Hz), 88.6, 66.0, 61.9, 52.1,
50.8, 35.8, 31.2, 15.0; m/z (ESI-MS) 341.1 [M + H]+.
Products 6e and 7e. Following general procedure A, products 6e and
7e were obtained in a 1.5:1 ratio (65% combined yield).
Characterization data for 6e: yellowish solid; mp 110−113 °C; Rf =
0.24 in 20% EtOAc/Hex; [α]D25 −24.5 (c 0.5, CHCl3); IR (KBr) 2954,
2932, 2902, 2833, 2804, 1615, 1546, 1541, 1462, 1380, 1249, 1175,
1116, 1035, 837, 740 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.21−7.17
(m, 1H), 7.16−7.14 (m, 1H), 7.09−7.05 (comp, 3H), 6.86−6.82
(comp, 3H), 4.90 (dd, J = 11.0, 9.8 Hz, 1H), 4.37 (d, J = 9.8 Hz, 1H),
3.77 (s, 3H), 3.33 (ddd, J = 11.3, 9.8, 4.9 Hz, 1H), 3.18 (dd, J = 13.7, 4.1
Hz, 1H), 3.09−3.01 (comp, 2H), 2.99−2.90 (comp, 3H), 2.26−2.17 (m,
1H), 0.73 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 159.2,
134.1, 132.9, 130.2, 129.5, 128.1, 126.9, 126.3, 114.5, 91.9, 62.9, 62.1,
55.4, 55.2, 46.5, 31.3, 29.9, 16.7; m/z (ESI-MS) 353.2 [M + H]+.
Characterization data for 7e: yellowish solid; mp 120−122 °C; Rf =
0.41 in 20% EtOAc/Hex; [α]D25 −178.1 (c 0.5, CHCl3); IR (KBr) 2954,
2927, 2833, 1613, 1543, 1506, 1452, 1361, 1341, 1247, 1180, 1027, 820,
745 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.22−7.18 (m, 1H), 7.16−
7.15 (m, 1H), 7.12−7.09 (comp, 3H), 6.89 (app d, J = 7.9 Hz, 1H),
6.85−6.81 (comp, 2H), 5.03 (dd, J = 11.5, 9.2 Hz, 1H), 4.19 (d, J = 9.2
Hz, 1H), 3.78 (s, 3H), 3.76 (dd, J = 8.0, 4.9 Hz, 1H), 3.24−3.22 (m, 1H),
3.11 (ddd, J = 14.6, 9.1, 4.7 Hz, 1H), 3.08−3.02 (m, 1H), 2.98−2.95 (m,
1H), 2.87−2.84 (m, 1H), 2.78−2.75 (m, 1H), 2.15−2.04 (m, 1H), 0.95
(d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.9, 136.0, 133.2,
130.5, 129.5, 129.2, 127.6, 126.5, 126.3, 114.1, 88.6, 65.9, 61.9, 55.4,
52.0, 50.8, 35.9, 31.1, 15.2; m/z (ESI-MS) 353.1 [M + H]+.
Products 6c and 7c. Following general procedure A, products 6c and
7c were obtained in a 2:1 ratio (71% combined yield).
Characterization data for 6c: yellowish solid; mp 130−132 °C; Rf =
0.37 in 20% EtOAc/Hex; [α]D25 −38.6 (c 0.5, CHCl3); IR (KBr) 3058,
3024, 2954, 2920, 2831, 1731, 1546, 1484, 1452, 1371, 1304, 1245,
1143, 1099, 1074, 1012, 958, 889, 817, 738, 674 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.45−7.40 (comp, 2H), 7.20 (app t, J = 7.4 Hz, 1H),
7.17−7.13 (m, 1H), 7.09−7.05 (comp, 3H), 6.85 (app d, J = 7.9 Hz,
1H), 4.90 (app t, J = 9.7 Hz, 1H), 4.36 (d, J = 9.7 Hz, 1H), 3.31 (ddd, J =
11.6, 10.9, 4.5 Hz, 1H), 3.18 (dd, J = 13.7, 3.9 Hz, 1H), 3.09 (app t, J =
11.6 Hz, 1H), 3.05−3.01 (m, 1H), 2.99−2.89 (comp, 3H), 2.25−2.16
(m, 1H), 0.72 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
137.3, 134.2, 132.7, 132.3, 129.6, 128.2, 126.9, 126.4, 121.9, 91.5, 63.0,
62.0, 55.5, 46.5, 31.2, 29.9, 16.6; m/z (ESI-MS) (79Br) 401.1 [M + H]+,
(81Br) 403.1 [M + H]+.
Characterization data for 7c: yellowish solid; mp 185−190 °C; Rf =
0.48 in 20% EtOAc/Hex; [α]D25 −134.9 (c 0.5, CHCl3); IR (KBr) 3061,
3026, 2964, 2927, 2895, 2809, 2764, 1541, 1492, 1447, 1425, 1351,
1291, 1148, 1109, 1072, 1037, 1007, 837, 807, 731 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.45−7.41(comp, 2H), 7.21 (app t, J = 7.4 Hz, 1H),
7.17−7.14 (m, 1H), 7.11 (app t, J = 7.6 Hz, 1H), 7.07−7.03 (comp, 2H),
6.87 (app d, J = 7.9 Hz, 1H), 5.02 (dd, J = 11.6, 9.0 Hz, 1H), 4.18 (d, J =
9.0 Hz, 1H), 3.78 (dd, J = 11.6, 4.9 Hz, 1H), 3.22 (dd, J = 12.2, 3.2 Hz,
1H), 3.11 (ddd, J = 14.8, 9.3, 4.7 Hz, 1H), 3.07−3.00 (m, 1H), 2.98−
2.94 (m, 1H), 2.89−2.81 (m, 1H), 2.78−2.70 (m, 1H), 2.14−2.06 (m,
1H), 0.94 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 137.6,
136.1, 132.9(0), 131.9(2), 129.9, 129.6, 127.7, 126.5, 126.2, 121.5, 88.3,
66.0, 61.9, 52.3, 50.8, 35.7, 31.2, 15.0; m/z (ESI-MS) (79Br) 401.1 [M +
H]+, (81Br) 403.1 [M + H]+.
Products 6f and 7f. Following general procedure A, products 6f and
7f were obtained in a 1:1 ratio (48% combined yield).
Characterization data for 6f: yellowish oil; Rf = 0.28 in 10% EtOAc/
Hex; [α]D25 −37.4 (c 0.5, CHCl3); IR (KBr) 3061, 3024, 2952, 2920,
2870, 1598, 1541, 1497, 1452, 1371, 1314, 1272, 1143, 1096, 941, 750,
1
698 cm−1; H NMR (500 MHz, CDCl3) δ 7.30−7.26 (comp, 2H),
7.24−7.17 (comp, 2H), 7.18−7.12 (comp, 3H), 7.10 (app td, J = 7.6, 1.5
Hz, 1H), 6.89 (app d, J = 7.8 Hz, 1H), 4.82 (dd, J = 11.2, 9.9 Hz, 1H),
4.30 (d, J = 9.9 Hz, 1H), 3.17 (ddd, J = 11.4, 9.9, 4.6 Hz, 1H), 3.09−2.99
(comp, 2H), 2.92 (app dt, J = 16.3, 3.9 Hz, 1H), 2.88−2.81 (comp, 2H),
2.64−2.50 (comp, 2H), 2.21−2.15 (m, 1H), 2.06−1.96 (m, 1H), 1.94−
1.85 (m, 1H), 1.62−1.55 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 141.7, 134.2, 133.2, 129.6, 128.7, 128.5, 128.1,
126.9, 126.3, 89.5, 62.8, 62.0, 47.4, 46.2, 30.9, 30.8, 29.8, 27.5, 16.3; m/z
(ESI-MS) 351.2 [M + H]+.
Characterization data for 7f: yellowish oil; Rf = 0.42 in 10% EtOAc/
Hex; [α]D25 −91.8 (c 0.5, CHCl3); IR (KBr) 3063, 3031, 2930, 2891,
2809, 2767, 1605, 1536, 1498, 1455, 1356, 1299, 1245, 1146, 1104, 736,
Products 6d and 7d. Following general procedure A, products 6d
and 7d were obtained in a 2:1 ratio (69% combined yield).
1
694 cm−1; H NMR (500 MHz, CDCl3) δ 7.29−7.32 (comp, 2H),
G
DOI: 10.1021/acs.joc.5b01384
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The Journal of Organic Chemistry
Article
7.23−7.20 (m, 1H), 7.19−7.17 (comp, 3H), 7.13−7.09 (comp, 2H),
6.91 (app d, J = 7.9 Hz, 1H), 4.41 (dd, J = 11.0, 9.2 Hz, 1H), 4.05 (d, J =
9.2 Hz, 1H), 3.09−3.03 (m, 1H), 3.00 (dd, J = 12.2, 3.4 Hz, 1H), 2.98−
2.94 (m, 1H), 2.90 (dd, J = 12.2, 2.3 Hz, 1H), 2.81−2.74 (comp, 2H),
2.74−2.67 (m, 1H), 2.54−2.48 (m, 1H), 2.48−2.40 (m, 1H), 2.21−2.15
(m, 1H), 1.71−1.62 (m, 1H), 1.60−1.53 (m, 1H), 1.12 (d, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 141.4, 136.1, 133.6, 129.5, 128.7,
128.5, 127.5, 126.5, 126.3, 125.9, 91.5, 77.5, 77.3, 77.0, 65.2, 61.8, 50.9,
44.7, 32.3, 31.1, 30.4, 29.9, 13.8; m/z (ESI-MS) 351.2 [M + H]+.
Products 6g and 7g. Following general procedure A, products 6g
and 7g were obtained in a 1.8:1 ratio (70% combined yield).
CDCl3) δ 7.31−7.28 (comp, 2H), 7.27−7.21 (m, 1H), 7.18−7.15
(comp, 2H), 6.81 (app d, J = 8.2 Hz, 1H), 6.68−6.66 (comp, 2H), 5.05
(dd, J = 11.6, 9.0 Hz, 1H), 4.13 (d, J = 9.0 Hz, 1H), 3.80 (dd, J = 10.2, 5.0
Hz. 1H), 3.78 (s, 3H), 3.22 (dd, J = 12.2, 3.0 Hz, 1H), 3.09 (ddd, J =
14.8, 9.2, 4.5 Hz, 1H), 3.05−2.99 (m, 1H), 2.96 (app d, J = 12.2 Hz, 1H),
2.83 (ddd, J = 12.2, 10.2, 3.3 Hz, 1H), 2.74−2.66 (m, 1H), 2.16−2.07
(m, 1H) 0.94 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.8,
138.6, 137.6, 128.7, 128.2, 127.5, 127.4, 125.4, 114.4, 112.2, 88.5, 65.8,
62.0, 55.4, 52.6, 50.7, 35.9, 31.5, 15.1; m/z (ESI-MS) 353.1 [M + H]+.
Products 6j and 7j. Following general procedure A, products 6j and
7j were obtained in a 2:1 ratio (42% combined yield).
Characterization data for 6g: yellowish solid; mp 64−66 °C; Rf =
0.27 in 10% EtOAc/Hex; [α]D25 −61.4 (c 0.5, CHCl3); IR (KBr) 3063,
3026, 2917, 2851, 2754, 1600, 1543, 1492, 1452, 1368, 1311, 1257,
1143, 1099, 738, 696 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.35
(comp, 2H), 7.31−7.23 (comp, 5H), 7.20−7.17 (comp, 2H), 7.14−7.11
(m, 1H), 7.07 (app t, J = 7.5 Hz, 1H), 7.01−6.99 (comp, 2H), 6.86 (app
d, J = 7.8 Hz, 1H), 4.94 (app t, J = 10.4 Hz, 1H), 4.36 (d, J = 9.7 Hz, 1H),
3.29 (app t, J = 11.4 Hz, 1H), 3.21−3.16 (m, 1H), 3.09 (dd, J = 13.7, 4.0
Hz, 1H), 2.98−2.87 (comp, 3H), 2.75 (app dt, J = 10.6, 5.0 Hz, 1H),
2.60 (dd, J = 13.7, 2.8 Hz, 1H), 2.50−2.38 (m, 1H), 2.16 (dd, J = 13.7,
10.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.4, 138.0, 134.4,
132.8, 129.5, 129.3, 129.0, 128.7, 128.3, 128.0, 126.8, 126.5, 126.4, 92.5,
63.1, 59.4, 54.7, 46.7, 38.3, 37.8, 29.9; m/z (ESI-MS) 399.2 [M + H]+.
Characterization data for 7g: yellowish oil; Rf = 0.48 in 10%
EtOAc/Hex; [α]D25 −156.6 (c 0.5, CHCl3); IR (KBr) 3061, 3024, 2952,
2927, 2902, 2804, 2754, 1600, 1546, 1492, 1452, 1356, 1299, 1252,
1143, 760, 701 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−7.34 (comp,
2H), 7.31−7.21 (comp, 6H), 7.21−7.17 (comp, 2H), 7.17−7.11 (m,
1H), 6.97−6.95 (comp, 2H), 6.91 (d, J = 7.9 Hz, 1H), 5.16 (dd, J = 11.7,
8.9 Hz, 1H), 4.21 (d, J = 8.9 Hz, 1H), 3.97 (dd, J = 11.7, 4.9 Hz, 1H),
3.26 (ddd, J = 14.7, 10.7, 4.9 Hz, 1H), 2.87 (dd, J = 7.9, 3.0 Hz, 1H), 2.84
(dd, J = 6.9, 2.5 Hz, 1H), 2.83−2.79 (comp, 2H), 2.78−2.70 (comp,
2H), 2.46 (dd, J = 13.0, 3.5 Hz, 1H), 2.23−2.17 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 140.9, 138.1, 136.3, 133.2, 129.6, 129.2, 128.9, 128.6,
128.3, 127.7, 127.6, 126.6, 126.3, 126.1, 89.2, 66.5, 57.1, 52.9, 50.8, 43.3,
33.2, 31.6; m/z (ESI-MS) 399.2 [M + H]+.
Characterization data for 6j: yellowish oil; Rf = 0.36 in 20% EtOAc/
Hex; [α]D25 −17.5 (c 0.5, CHCl3); IR (KBr) 3407, 3058, 3026, 2952,
2905, 2838, 2806, 1724, 1548, 1492, 1450, 1378, 1361, 1267, 1165, 740,
698 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.59 (br s, 1H), 7.50 (app d, J
= 7.5 Hz, 1H), 7.35−7.32 (comp, 3H), 7.31−7.27 (m, 1H), 7.19−7.14
(comp, 3H), 7.13−7.07 (m, 1H), 4.91−4.87 (m, 1H), 4.26 (d, J = 9.4
Hz, 1H), 3.23−3.18 (m, 2H), 3.05−2.93 (comp, 2H), 2.90−2.81 (comp,
2H), 2.69−2.61 (m, 1H), 2.35−2.21 (m, 1H), 0.77 (d, J = 6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 137.5, 136.8, 129.2, 128.3, 126.7, 122.7,
120.0, 118.5, 111.6, 111.2, 93.2, 62.7, 61.8, 56.5, 51.3, 34.9, 22.1, 16.9;
HRMS (ESI) m/z calcd for C22H24N3O2 [M + H]+ 362.1863, found
362.1875.
Characterization data for 7j: yellowish solid; mp 160−163 °C; Rf =
0.40 in 20% EtOAc/Hex; [α]D25 −25.7 (c 0.5, CHCl3); IR (KBr) 3409,
3061, 3031, 2964, 2898, 2838, 2774, 1697, 1632, 1541, 1452, 1343,
1269, 1170, 1114, 1072, 1007, 968, 736, 696 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.61 (br s, 1H), 7.51 (app d, J = 7.8 Hz, 1H), 7.35−7.32
(comp, 2H), 7.28 (app d, J = 7.3 Hz, 1H), 7.24−7.21 (comp, 2H), 7.20−
7.15 (m, 1H), 7.13−7.09 (m, 1H), 5.28 (dd, J = 11.8, 9.4 Hz, 1H), 4.18−
4.12 (m, 1H), 3.72 (dd, J = 11.8, 4.5 Hz, 1H), 3.15−3.07 (comp, 2H),
3.06−2.97 (comp, 2H), 2.88−2.74 (comp, 2H), 2.22−2.14 (m, 1H),
1.01 (d, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 136.9, 128.8,
128.4, 127.8, 126.7, 122.7, 120.0, 118.5, 111.6, 87.7, 63.8, 62.1, 52.9,
52.7, 35.9, 22.1, 14.5; m/z (ESI-MS) 362.2 [M + H]+.
Product 6k. Following general procedure A, product 6k was obtained
in 61% yield. The relative stereochemistry was determined by GCOSY
and NOESY NMR.
Products 6h and 7h. Following general procedure A, products 6h
and 7h were obtained in a 5:1 ratio (37% combined yield).
Characterization data for 6k: yellowish solid; mp 150−152 °C; Rf =
0.42 in 30% EtOAc/Hex; [α]D25 −56.3 (c 0.5, CHCl3); IR (KBr) 3059,
3028, 2931, 2862, 2862, 2834, 1714, 1630, 1551, 1489, 1447, 1364,
1036, 1143, 1108, 1081, 752, 700 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.33−7.30 (comp, 2H), 7.29−7.19 (comp, 4H), 7.18−7.14 (m, 1H),
7.08 (app t, J = 7.3 Hz, 1H), 6.87 (app d, J = 7.8 Hz, 1H), 4.97 (dd, J =
11.1, 9.8 Hz, 1H), 4.37 (d, J = 9.8 Hz, 1H), 3.56 (app td, J = 12.7, 4.4 Hz,
1H), 3.38−3.22 (comp, 3H), 3.07 (ddd, J = 15.8, 9.3, 6.3 Hz, 1H), 2.98
(app dt, J = 16.4, 4.1 Hz, 1H), 2.90 (ddd, J = 9.9, 6.1, 3.6 Hz, 1H), 2.17−
2.09 (m, 1H), 1.83−1.77 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
139.9, 134.2, 133.0, 129.5, 129.2, 128.1, 128.0, 127.5, 127.0, 126.3, 91.0,
63.1, 54.5, 49.0, 45.9, 29.8, 28.2; m/z (ESI-MS) 309.1 [M + H]+; HPLC
Daicel Chiralcel OD-H, n-hexane/i-PrOH = 90/10, flow rate = 1 mL/
min, UV = 230 nm, tR = 11.1 min (major) and tR = 13.9 min (minor),
94% ee.
Characterization data for 6h: yellowish solid; mp 180−184 °C; Rf =
0.45 in 20% EtOAc/Hex; [α]D25 −23.0 (c 0.5, CHCl3); IR (KBr) 3063,
3026, 2952, 2922, 2868, 2823, 1546, 1497, 1450, 1368, 1306, 1141,
1099, 1005, 750, 726, 696 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.32−
7.29 (comp, 2H), 7.25−7.23 (m, 1H), 7.21−7.14 (comp, 4H), 7.07 (app
t, J = 7.5 Hz, 1H), 6.85 (app d, J = 7.9 Hz, 1H), 4.92 (app t, J = 9.8 Hz,
1H), 4.35 (d, J = 9.8 Hz, 1H), 3.42 (app t, J = 11.6 Hz, 1H), 3.38−3.29
(m, 1H), 3.19 (dd, J = 13.4, 3.7 Hz, 1H), 3.13−2.96 (comp, 3H), 2.94−
2.87 (m, 1H), 2.24−2.15 (m, 1H), 1.50−1.44 (m, 1H), 0.90 (d, J = 7.0
Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 138.0,
134.2, 132.9, 129.5, 129.2, 128.1, 128.0, 126.9, 126.4, 93.0, 62.9, 54.1,
52.2, 46.7, 40.3, 29.9, 26.6, 21.5, 15.6; m/z (ESI-MS) 351.2 [M + H]+.
Products 6i and 7i. Following general procedure A, products 6i and
7i were obtained in a 1.5:1 ratio (66% combined yield).
Characterization data for 6i: yellowish solid; mp 145−148 °C; Rf =
0.35 in 30% EtOAc/Hex; [α]D25 −11.9 (c 0.5, CHCl3); IR (KBr) 3063,
3026, 3001, 2957, 2922, 2902, 2828, 1610, 1539, 1504, 1452, 1378,
1309, 1252, 1146, 1035, 859, 817, 760, 743, 701 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.31−7.28 (comp, 2H), 7.27−7.21 (m, 1H), 7.17−7.16
(comp, 2H), 6.78 (app d, J = 8.6 Hz, 1H), 6.68−6.65 (m, 1H), 6.62 (dd,
J = 8.6, 2.5 Hz, 1H), 4.92 (dd, J = 11.2, 9.8 Hz, 1H), 4.32 (d, J = 9.7 Hz,
1H), 3.75 (s, 3H), 3.35−3.26 (m, 1H), 3.17 (dd, J = 13.7, 4.1 Hz, 1H),
3.08 (app t, J = 11.4 Hz, 1H), 3.05−2.98 (m, 1H), 2.97−2.87 (comp,
3H), 2.30−2.18 (m, 1H), 0.71 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.2, 138.2, 135.7, 129.1, 128.0, 128.0, 125.3, 114.4, 112.2,
91.9, 62.6, 62.1, 55.9, 55.4, 46.4, 31.2, 30.2, 16.7; m/z (ESI-MS) 353.1
[M + H]+.
Product 6l. Following general procedure A, product 6l was obtained
in 51% yield.
Characterization data for 6l: yellowish solid; mp 150−152 °C; Rf =
0.31 in 30% EtOAc/Hex; [α]D25 −50.1 (c 0.5, CHCl3); IR (KBr) 3021,
2941, 2914, 2845, 2824, 1644, 1541, 1485, 1369, 1309, 1143, 1102,
1067, 1105, 811, 766, 755 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.31−
7.27 (comp, 2H), 7.24−7.19 (m, 1H), 7.17−7.15 (comp, 3H), 7.08 (app
t, J = 7.2 Hz, 1H), 6.85 (app d, J = 7.8 Hz, 1H) 4.91 (app t, J = 9.6 Hz,
1H), 4.37 (d, J = 9.6 Hz, 1H), 3.54 (app td, J = 12.8, 4.4 Hz, 1H), 3.37−
3.22 (comp, 3H), 3.11−3.03 (m, 1H), 3.01−2.97 (m, 1H), 2.91 (ddd, J
= 10.1, 5.9, 3.9 Hz, 1H), 2.15−2.05 (m, 1H), 1.83−1.76 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 138.2, 134.1, 133.9, 132.5, 129.6, 129.4,
128.8, 128.3, 126.9, 126.4, 90.9, 63.0, 54.4, 48.3, 46.1, 29.7, 28.1; m/z
(ESI-MS) (35Cl) 343.2 [M + H]+, (37Cl) 345.2 [M + H]+.
Characterization data for 7i: yellowish solid; mp 130−133; Rf = 0.45
25
in 30% EtOAc/Hex; [α]D −102.0 (c 0.5, CHCl3); IR (KBr) 3061,
3028, 2959, 2932, 2907, 2863, 2806, 2767, 1613, 1546, 1494, 1455,
Product 6m. Following general procedure A, product 6m was
obtained in 55% yield.
1356, 1269, 1151, 1116, 1039, 827, 743, 698 cm−1; 1H NMR (500 MHz,
H
DOI: 10.1021/acs.joc.5b01384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Characterization data for 6m: yellowish solid; mp 150−153 °C; Rf
128.2, 127.0, 126.2, 110.5, 106.7, 88.9, 62.7, 53.8, 45.4, 41.8, 29.7, 24.8;
m/z (ESI-MS) 299.2 [M + H]+.
Product 6r. Following general procedure A, product 6r was obtained
25
= 0.31 in 30% EtOAc/Hex; [α]D −48.9 (c 0.5, CHCl3); IR (KBr)
3021, 2941, 2914, 2855, 2824, 1644, 1541, 1485, 1451, 1364, 1309,
1
1143, 1102, 1067, 1105, 811, 766, 749 cm−1; H NMR (500 MHz,
in 44% yield.
CDCl3) δ 7.46−7.40 (comp, 2H), 7.24−7.18 (m, 1H), 7.16 (d, J = 7.1
Hz, 1H), 7.12−7.05 (comp, 3H), 6.84 (app d, J = 7.8 Hz, 1H), 4.89 (dd,
J = 11.2, 9.6 Hz, 1H), 4.34 (d, J = 9.6 Hz, 1H), 3.53 (app td, J = 12.8, 4.4
Hz, 1H), 3.34−3.18 (comp, 3H), 3.04 (ddd, J = 15.5, 9.1, 6.2 Hz, 1H),
2.97 (app dt, J = 16.3, 4.2 Hz, 1H), 2.92−2.85 (m, 1H), 2.11−2.02 (m,
1H), 1.79−1.75 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 138.9, 134.2,
132.8, 132.3, 129.6, 129.2, 128.2, 126.9, 126.3, 121.9, 90.8, 63.1, 54.4,
48.5, 46.0, 29.8, 28.2; m/z (ESI-MS) (79Br) 387.1 [M + H]+, (81Br)
389.1 [M + H]+.
Characterization data for 6r: yellowish solid; mp 150−152 °C; Rf =
0.29 in 30% EtOAc/Hex; [α]D25 −35.1 (c 0.5, CHCl3); IR (KBr) 3062,
3024, 2997, 2927, 2858, 2834, 1610, 1541, 1506, 1454, 1364, 1306,
1271, 1250, 1143, 1032, 763, 693 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.32−7.29 (comp, 2H), 7.25 (d, J = 7.1 Hz, 1H), 7.24−7.20 (comp, 2H),
6.79 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H), 6.63 (dd, J = 8.6, 2.6
Hz, 1H), 4.92 (dd, J = 11.1, 9.7 Hz, 1H), 4.31 (d, J = 9.7 Hz, 1H), 3.76 (s,
3H), 3.54 (app td, J = 12.6, 4.3 Hz, 1H), 3.33−3.25 (comp, 2H), 3.23
(ddd, J = 13.7, 4.5, 1.8 Hz, 1H), 3.03 (ddd, J = 15.7, 9.2, 6.3 Hz, 1H), 2.94
(app dt, J = 15.7, 4.0 Hz, 1H), 2.89−2.85 (m, 1H), 2.15−2.06 (m, 1H),
1.84−1.74 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 159.2, 140.0, 135.7,
129.2, 128.1, 127.9, 127.5, 125.4, 114.4, 112.1, 91.3, 62.8, 55.4, 54.5,
48.9, 45.9, 30.2, 28.3; m/z (ESI-MS) 339.1 [M + H]+.
Product 6n. Following general procedure A, product 6n was obtained
in 64% yield.
Characterization data for 6n: yellowish solid; mp 154−156 °C; Rf =
0.48 in 30% EtOAc/Hex; [α]D25 −29.6 (c 0.5, CHCl3); IR (KBr) 3021,
2948, 2917, 2855, 2824, 1648, 1548, 1510, 1364, 1306, 1140, 1102,
1067, 1036, 942, 804, 752 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.23−
7.20 (m, 1H), 7.19−7.16 (m, 1H), 7.14−7.11 (comp, 4H), 7.08 (app t, J
= 7.5 Hz, 1H), 6.88 (app d, J = 7.9 Hz, 1H), 4.99−4.89 (m, 1H), 4.37 (d,
J = 9.6 Hz, 1H), 3.58−3.48 (m, 1H), 3.36−3.30 (m, 1H), 3.28 (dd, J =
13.2, 2.1 Hz, 1H), 3.26−3.21 (m, 1H), 3.10−3.04 (m, 1H), 3.02−2.95
(m, 1H), 2.91−2.87 (m, 1H), 2.32 (s, 3H), 2.17−2.06 (m, 1H), 1.83−
1.73 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 137.6, 137.0, 134.2,
133.1, 129.9, 129.5, 128.1, 127.3, 127.0, 126.3, 91.2, 63.1, 54.5, 48.6,
45.9, 29.9, 28.3, 21.3; m/z (ESI-MS) 323.1 [M + H]+.
Product 6s. Following general procedure A, product 6s was obtained
in 52% yield.
Characterization data for 6s: yellowish solid; mp 148−151 °C; Rf =
0.42 in 50% EtOAc/Hex; [α]D25 −18.9 (c 0.5, CHCl3); IR (KBr) 3059,
3028, 2990, 2945, 2921, 2889, 2883, 2855, 2834, 1610, 1544, 1520,
1447, 1354, 1261, 1226, 1143, 1112, 1019, 873, 759, 704 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.30−7.28 (comp, 2H), 7.25−7.22 (m, 1H),
7.22−7.18 (comp, 2H), 6.61 (s, 1H), 6.37 (s, 1H), 4.89 (dd, J = 11.2, 9.6
Hz, 1H), 4.27 (d, J = 9.6 Hz, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 3.51 (app
td, J = 12.7, 4.3 Hz, 1H), 3.30−3.18 (comp, 3H), 2.99−2.91 (m, 1H),
2.89−2.83 (comp, 2H), 2.10 (ddd, J = 15.1, 12.7, 4.8 Hz, 1H), 1.78 (app
ddt, J = 13.7, 4.3, 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 148.7,
147.3, 139.8, 129.1, 128.0, 127.4, 126.6, 125.1, 111.8, 109.8, 91.7, 63.0,
56.0(1), 55.9(9), 54.5, 49.0, 46.2, 29.5, 28.2; m/z (ESI-MS) 369.1 [M +
H]+.
Product 6o. Following general procedure A, product 6o was obtained
in 41% yield.
Characterization data for 6o: yellowish solid; mp 120−124 °C; Rf =
0.26 in 30% EtOAc/Hex; [α]D25 −31.3 (c 0.5, CHCl3); IR (KBr) 3063,
3031, 2999, 2927, 2860, 2833, 1610, 1546, 1514, 1452, 1366, 1306,
1
1249, 1175, 1143, 1101, 1035, 827, 731 cm−1; H NMR (500 MHz,
Product 6t. Following general procedure A, product 6t was obtained
CDCl3) δ 7.22−7.17 (m, 1H), 7.17−7.10 (comp, 3H), 7.06 (app t, J =
7.5 Hz, 1H), 6.89−6.80 (comp, 3H), 4.88 (dd, J = 11.2, 9.7 Hz, 1H),
4.34 (d, J = 9.7 Hz, 1H), 3.77 (s, 3H), 3.54−3.45 (m, 1H), 3.34−3.18
(comp, 3H), 3.05 (ddd, J = 15.7, 9.3, 6.3 Hz, 1H), 2.96 (app dt, J = 16.4,
4.1 Hz, 1H), 2.92−2.85 (m, 1H), 2.09 (ddd, J = 15.0, 12.8, 4.7 Hz, 1H),
1.80−1.74 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 159.2, 134.2, 133.0,
132.0, 129.5, 128.5, 128.1, 127.0, 126.3, 114.5, 91.4, 63.1, 55.4, 54.5,
48.2, 45.9, 29.8, 28.3; m/z (ESI-MS) 339.2 [M + H]+.
in 37% yield.
Characterization data for 6t: yellowish solid; mp 144−146 °C; (Rf =
0.31 in 30% EtOAc/Hex); [α]D25 −38.5 (c 0.5, CHCl3); IR (KBr) 3409,
3056, 3031, 2947, 2917, 2846, 2806, 2757, 1729, 1598, 1546, 1492,
1455, 1356, 1311, 1264, 1168, 738, 701 cm−1; H NMR (500 MHz,
1
CDCl3) δ 7.65 (br s, 1H), 7.55−7.50 (m, 1H), 7.39−7.33 (comp, 2H),
7.33−7.29 (m, 1H), 7.27−7.21 (comp, 3H), 7.17 (app td, J = 7.6, 1.3 Hz,
1H), 7.14−7.10 (m, 1H), 4.88 (dd, J = 11.2, 9.5 Hz, 1H), 4.25 (d, J = 9.5
Hz, 1H), 3.44−3.33 (m, 1H), 3.25−3.18 (comp, 2H), 3.05−2.93 (comp,
2H), 2.92−2.78 (comp, 2H), 2.21−2.13 (m, 1H), 1.99 (app ddt, J =
13.6, 4.7, 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.1, 136.8,
130.2, 129.3, 128.3, 127.5, 126.7, 122.7, 120.0, 118.5, 111.6, 111.2, 92.8,
61.9, 55.1, 51.3, 49.7, 31.5, 22.1; m/z (ESI-MS) 348.2 [M + H]+.
Products 8a and 9a. Following general procedure B, products 8a
and 9a were obtained in a 1.2:1 ratio (62% combined yield). The relative
stereochemistry was determined by GCOSY and NOESY NMR.
Characterization data for 8a: yellowish oil; Rf = 0.37 in 20%
EtOAc/Hex; [α]D25 +24.8 (c 0.5, CHCl3); IR (KBr) 3066, 3031, 2977,
2895, 2816, 2776, 2757, 2678, 1546, 1494, 1452, 1375, 1289, 1151,
1119, 1072, 1039, 751, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36−
7.30 (comp, 2H), 7.29−7.27 (m, 1H), 7.21−7.12 (comp, 4H), 7.08−
7.03 (comp, 2H), 4.66 (dd, J = 11.1, 8.2 Hz, 1H), 4.03 (d, J = 15.2 Hz,
1H), 3.56 (d, J = 15.2 Hz, 1H), 3.19 (dd, J = 18.5, 10.4 HZ, 1H), 3.01−
2.92 (comp, 2H), 2.93−2.85 (m, 1H), 2.84−2.77 (m, 1H), 2.26−2.13
(comp, 2H), 0.78 (d, J = 6.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
137.6, 132.9, 131.3, 129.0, 128.2, 127.9, 126.8, 126.3, 125.8, 96.2, 62.8,
60.6, 57.4, 54.0, 34.3, 32.8, 16.9; HRMS (ESI) m/z calcd for
C20H23N2O2 [M + H]+ 323.1754, found 323.1765.
Product 6p. Following general procedure A, product 6p was obtained
in 60% yield.
Characterization data for 6p: Yellowish solid; mp > 190 °C; Rf =
0.45 in 30% EtOAc/Hex; [α]D25 −12.5 (c 0.5, CHCl3); IR (KBr) 3055,
3017, 2927, 2855, 2810, 1600, 1537, 1496, 1440, 1357, 1309, 1140,
1102, 1063, 939, 856, 745 cm−1; 1H NMR (500 MHz, CD2Cl2) δ 7.86−
7.85 (comp, 3H), 7.71 (s, 1H), 7.56−7.45 (comp, 2H), 7.40 (app d, J =
8.4 Hz, 1H), 7.26−7.22 (comp, 2H), 7.09 (app t, J = 6.2 Hz, 1H), 6.86
(app d, J = 7.8 Hz, 1H), 5.11 (app t, J = 9.6 Hz, 1H), 4.43 (d, J = 9.6 Hz,
1H), 3.75 (app td, J = 12.4, 4.3 Hz, 1H), 3.41 (app td, J = 11.2, 4.6 Hz,
1H), 3.38−3.33 (m, 1H), 3.29 (dd, J = 13.0, 3.2 Hz, 1H), 3.15−2.99
(comp, 2H), 2.99−2.88 (m, 1H), 2.29−2.21 (m, 1H), 1.87−1.85 (m,
1H); 13C NMR (125 MHz, CD2Cl2) δ 137.6, 134.8, 133.7, 133.3, 133.0,
129.6, 128.9, 128.0, 127.9, 127.8, 126.9, 126.5(8), 126.5(5), 126.2,
126.0, 125.1, 91.0, 63.1, 54.3, 49.1, 45.7, 29.8, 28.0; m/z (ESI-MS) 359.2
[M + H]+.
Product 6q. Following general procedure A, product 6q was obtained
in 50% yield.
Characterization data for 6q: yellowish solid; mp 128−130 °C; Rf =
0.35 in 30% EtOAc/Hex; [α]D25 −35.2 (c 0.5, CHCl3); IR (KBr) 3118,
3062, 3021, 2952, 2921, 2858, 1548, 1496, 1454, 1361, 1309, 1146,
1102, 1081, 1012, 932, 742 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−
7.30 (m, 1H), 7.22−7.17 (m, 1H), 7.16−7.12 (m, 1H), 7.07 (app t, J =
7.5 Hz, 1H), 6.84 (app d, J = 7.8 Hz, 1H), 6.26 (dd, J = 3.3, 1.9 Hz, 1H),
6.11 (app d, J = 3.3 Hz, 1H), 4.92 (app t, J = 9.8 Hz, 1H), 4.32 (d, J = 9.8
Hz, 1H), 3.74 (app td, J = 12.6, 4.4 Hz, 1H), 3.36−3.17 (comp, 3H),
3.05 (ddd, J = 16.3, 9.9, 6.5 Hz, 1H), 2.93 (app dt, J = 16.4, 3.6 Hz, 1H),
2.86 (ddd, J = 11.3, 6.4, 2.9 Hz, 1H), 2.22−2.14 (m, 1H), 1.90−1.83 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 152.9, 142.5, 134.1, 132.7, 129.5,
Characterization data for 9a: yellowish solid; mp 182−185 °C; Rf =
0.48 in 20% EtOAc/Hex; [α]D25 −31.6 (c 0.5, CHCl3); IR (KBr) 3068,
3028, 2975, 2895, 2813, 2778, 2763, 1546, 1494, 1455, 1375, 1364,
1289, 1156, 1115, 1032, 750, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.35−7.32 (comp, 2H), 7.28−7.23 (comp, 3H), 7.20−7.13 (comp, 2H),
7.12−7.02 (comp, 2H), 5.09 (dd, J = 12.3, 9.1 Hz, 1H), 3.96 (d, J = 15.1
Hz, 1H), (dd, J = 12.3, 4.5 Hz, 1H), 3.53 (d, J = 15.1 Hz, 1H), 3.16−3.02
(comp, 2H), 2.92−2.82 (comp, 2H), 2.70 (dd, J = 11.5, 3.2 Hz, 1H),
2.31−2.14 (m, 1H), 1.00 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
I
DOI: 10.1021/acs.joc.5b01384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) δ 138.1, 133.2, 131.5, 128.6, 128.2, 127.7, 127.5, 126.7, 126.2,
125.8, 89.7, 62.0, 61.7, 57.8, 49.8, 35.0, 33.1, 13.3; m/z (ESI-MS) 323.2
[M + H]+.
Products 8c and 9c. Following general procedure B, products 8c and
9c were obtained in a 1.2:1 ratio (49% combined yield).
Characterization data for 8c: yellow solid; mp 180−182 °C; Rf =
0.31 in 20% EtOAc/Hex; [α]D25 +36.7 (c 0.5, CHCl3); IR (KBr) 3068,
3026, 2962, 2930, 2883, 1971, 1929, 1897, 1714, 1650, 1546, 1489,
1452, 1375, 1262, 1153, 1007, 815, 758, 738 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.49−7.43 (comp, 2H), 7.20−7.12 (comp, 2H), 7.09−7.04
(comp, 4H), 4.59 (dd, J = 11.4, 8.4 Hz, 1H), 4.02 (d, J = 15.1 Hz, 1H),
3.55 (d, J = 15.1 Hz, 1H), 3.21−3.13 (m, 1H), 3.04−2.73 (comp, 4H),
2.24−2.06 (comp, 2H), 0.78 (d, J = 6.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 136.6, 132.7, 132.1, 131.1, 128.2, 126.7, 126.3, 125.8, 121.8,
95.9, 62.6, 60.5, 57.2, 53.4, 34.2, 32.7, 16.7; m/z (ESI-MS) (79Br) 401.1
[M + H]+, (81Br) 403.1 [M + H]+.
Product 8l. Following general procedure B, product 8l was obtained
in 43% yield.
Characterization data for 8l: yellow solid; mp 165−167 °C; Rf =
0.48 in 30% EtOAc/Hex; [α]D25 +18.2 (c 0.5, CHCl3); IR (KBr) 3042,
2965, 2928, 2894, 2821, 2762, 2680, 1959, 1902, 1796, 1593, 1543,
1495, 1373, 1362, 1351, 1255, 1093, 1085, 1011, 933, 818, 745 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.34−7.29 (comp, 2H), 7.18−7.13 (comp,
4H), 7.10−7.04 (comp, 2H), 4.56 (dd, J = 11.3, 8.6 Hz, 1H), 4.03 (d, J =
15.2 Hz, 1H), 3.58 (d, J = 15.2 Hz, 1H), 3.29 (app td, J = 11.4, 5.5 Hz,
1H), 3.25−3.18 (m, 1H), 3.02−2.91 (comp, 2H), 2.87−2.79 (comp,
2H), 2.47 (app td, J = 11.6, 4.4 Hz, 1H), 2.10−1.99 (comp, 2H); 13C
NMR (125 MHz, CDCl3) δ 137.6, 133.7, 132.8, 131.1, 129.2, 128.5,
128.1, 126.7, 126.2, 125.7, 95.4, 60.4, 57.3, 54.9, 46.5, 32.8, 30.7; m/z
(ESI-MS) (35Cl) 343.2 [M + H]+, (37Cl) 345.2 [M + H]+.
Product 8n. Following general procedure B, product 8n was obtained
in 61% yield.
Characterization data for 9c: yellow solid; mp >200 °C; Rf = 0.53 in
20% EtOAc/Hex; [α]D25 −32.2 (c 0.5, CHCl3); IR (KBr) 3066, 3025,
2964, 2928, 2896, 2811, 2762, 1892, 1730, 1652, 1546, 1489, 1456,
1377, 1363, 1306, 1287, 1257, 1153, 1108, 1073, 1009, 825, 800, 749
Characterization data for 8n: yellow solid; mp 175−178 °C; Rf =
0.51 in 30% EtOAc/Hex; [α]D25 +19.4 (c 0.5, CHCl3); IR (KBr) 3021,
2947, 2922, 2894, 2820, 2759, 2687, 2356, 1924, 1897, 1548, 1515,
1
1496, 1456, 1376, 1351, 1256, 1152, 811, 748 cm−1; H NMR (400
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.51−7.44 (comp, 2H), 7.20−
MHz, CDCl3) δ 7.21−7.12 (comp, 6H), 7.11−7.05 (comp, 2H), 4.61
(dd, J = 11.4, 8.7 Hz, 1H), 4.04 (d, J = 15.2 Hz, 1H), 3.59 (d, J = 15.2 Hz,
1H), 3.29 (dd, J = 11.8, 4.7 Hz, 1H), 3.23 (app dt, J = 11.8, 3.2 Hz, 1H),
3.04−2.93 (comp, 2H), 2.86 (dd, J = 13.7, 7.0 Hz, 1H), 2.48 (app td, J =
11.8, 3.5 Hz, 1H), 2.34 (s, 3H), 2.15−1.99 (comp, 2H); 13C NMR (75
MHz, CDCl3) δ 137.6, 136.2, 132.9, 131.3, 129.7, 128.2, 127.0, 126.8,
126.3, 125.8, 95.8, 60.6, 57.5, 55.1, 46.8, 32.9, 30.9, 21.1; m/z (ESI-MS)
323.1[M + H]+.
Products 11 and 12. Following general procedure C, products 11
and 12 were obtained in a 2:1 ratio (55% combined yield). The relative
stereochemistry was determined by GCOSY and NOESY NMR.
Characterization data for 11: yellowish oil; Rf = 0.40 in 50%
EtOAc/Hex; IR (KBr) 3056, 3033, 2932, 2851, 2804, 2754, 1529, 1489,
1452, 1368, 1306, 1143, 740 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.12
(app t, J = 7.4 Hz, 1H), 7.05 (app d, J = 7.5 Hz, 1H), 7.00 (app t, J = 7.5
Hz, 1H), 6.78 (app d, J = 7.5 Hz, 1H), 4.74−4.62 (m, 1H), 4.20 (d, J =
9.3 Hz, 1H), 3.15−3.07 (m, 1H), 3.04−2.93 (comp, 2H), 2.90−2.85
(comp, 2H), 2.75 (app dt, J = 11.1, 5.3 Hz, 1H), 2.30−2.23 (comp, 2H)
1.82−1.72 (m, 1H), 1.63−1.55 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 134.4, 133.3, 129.6, 127.9, 126.6, 126.3, 86.0, 62.6, 53.8, 46.6, 31.1,
29.3, 20.0; m/z (ESI-MS) 233.2 [M + H]+.
7.14 (comp, 2H), 7.14−7.03 (comp, 4H), 5.02 (dd, J = 12.3, 8.9 Hz,
1H), 3.96 (d, J = 15.1 Hz, 1H), 3.61 (dd, J = 12.3, 4.5 Hz, 1H), 3.52 (d, J
= 15.1 Hz, 1H), 3.12−3.01 (comp, 2H), 2.94−2.80 (comp, 2H), 2.68
(dd, J = 11.6, 3.2 Hz, 1H), 2.24−2.13 (m, 1H), 0.98 (d, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 137.1, 133.1, 131.8, 131.4, 129.4, 128.2,
126.7, 126.3, 125.8, 121.5, 89.5, 61.8, 61.6, 57.7, 49.3, 34.8, 33.1, 13.2;
m/z (ESI-MS) (79Br) 401.2 [M + H]+, (81Br) 403.2 [M + H]+.
Products 8e and 9e. Following general procedure B, products 8e and
9e were obtained in a 1.3:1 ratio (54% combined yield).
Characterization data for 8e: yellow solid; mp 115−117 °C; Rf =
0.28 in 20% EtOAc/Hex; [α]D25 +25.1 (c 0.5, CHCl3); IR (KBr) 3024,
2965, 2928, 2894, 2821, 2762, 2680, 1959, 1902, 1796, 1593, 1545,
1495, 1373, 1362, 1255, 1093, 1011, 933, 818, 745 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.18−7.13 (comp, 2H), 7.12−7.07 (comp, 2H), 7.09−
7.02 (comp, 2H), 6.88−6.84 (comp, 2H), 4.59 (dd, J = 11.4, 8.7 Hz,
1H), 4.01 (d, J = 15.2 Hz, 1H), 3.78 (s, 3H), 3.54 (d, J = 15.2 Hz, 1H),
3.23−3.13 (m, 1H), 2.99−2.88 (comp, 2H), 2.96−2.80 (comp, 2H),
2.22−2.10 (comp, 2H), 0.78 (d, J = 6.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.3, 133.1, 131.5, 129.7, 128.5, 127.0, 126.5, 126.1, 114.5,
96.7, 63.1, 60.8, 57.6, 55.4, 53.5, 34.6, 33.1, 17.1; m/z (ESI-MS) 353.2
[M + H]+.
Characterization data for 12: yellowish oil; Rf = 0.50 in 50%
EtOAc/Hex; IR (KBr) 3061, 3026, 2932, 2865, 2799, 2749, 1721, 1650,
Characterization data for 9e: yellow solid; mp >200 °C; (Rf = 0.45
in 20% EtOAc/Hex); [α]D −31.6 (c 0.5, CHCl3); IR (KBr) 3026,
1
1541, 1437, 1366, 1240, 1141, 1141, 738 cm−1; H NMR (500 MHz,
25
CDCl3) δ 7.22−7.13 (comp, 3H), 7.12−7.09 (m, 1H), 5.18 (app dt, J =
4.5, 2.3 Hz, 1H), 3.68 (s, 1H), 3.16 (ddd, J = 16.9, 12.2, 5.3 Hz, 1H),
3.12−3.07 (m, 1H), 3.00 (ddd, J = 11.1, 5.3, 1.7 Hz, 1H), 2.69−2.60
(comp, 2H), 2.59−2.50 (m, 1H), 2.41 (app td, J = 12.0, 3.0 Hz, 1H),
2.26−2.15 (m, 1H), 1.94 (ddd, J = 18.5, 9.3, 4.9 Hz, 1H), 1.72−1.61 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 135.9, 133.8, 129.4, 126.8, 126.2,
124.4, 82.7, 65.6, 56.5, 52.7, 29.5, 28.9, 21.1; m/z (ESI-MS) 233.2 [M +
H]+.
3013, 2992, 2969, 2955, 2899, 2835, 2780, 2761, 1966, 1922, 1884,
1613, 1548, 1512, 1456, 1442, 1399, 1380, 1355, 1310, 1300, 1254,
1178, 1028, 829, 748 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.19−7.13
(comp, 4H), 7.11−7.06 (m, 1H), 7.06−7.02 (m, 1H), 6.89−6.85 (comp
2H), 5.03 (dd, J = 12.3, 9.2 Hz, 1H), 3.95 (d, J = 15.1 Hz, 1H), 3.79 (s,
3H), 3.58 (dd, J = 12.3, 4.5 Hz, 1H), 3.52 (d, J = 15.1 Hz, 1H), 3.12−
3.00 (comp, 2H), 2.93−2.79 (comp, 2H), 2.68 (dd, J = 11.5, 3.2 Hz,
1H), 2.21−2.13 (m, 1H), 1.00 (d, J = 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.1, 133.4, 131.7, 130.3, 129.0, 128.4, 126.9, 126.4, 126.0,
114.3, 90.2, 62.2, 61.9, 58.0, 55.5, 49.3, 35.3, 33.4, 13.6; m/z (ESI-MS)
353.2 [M + H]+.
Product 13. Following general procedure B (5 equiv of 2-EHA was
used), product 13 was obtained in 61% yield. The relative stereo-
chemistry was determined by GCOSY and NOESY NMR.
Characterization data for 13: yellowish solid; mp 75−77 °C; (Rf =
0.43 in 50% EtOAc/Hex); IR (KBr) 3066, 3028, 2950, 2820, 2754,
2687, 2361, 2329, 1964, 1919, 1842, 1805, 1546, 1496, 1463, 1455,
Product 8k. Following general procedure B, product 8k was obtained
in 48% yield. The relative stereochemistry was determined by GCOSY
and NOESY NMR.
1
1357, 1347, 1277, 1237, 1218, 1117, 1105, 744 cm−1; H NMR (400
Characterization data for 8k: yellow solid; mp 160−163 °C; Rf =
0.47 in 30% EtOAc/Hex; [α]D25 +27.2 (c 0.5, CHCl3); IR (KBr) 3061,
3026, 2932, 2865, 2799, 2749, 1721, 1650, 1541, 1437, 1366, 1240,
MHz, CDCl3) δ 7.17−7.10 (comp, 2H), 7.08−6.99 (comp, 2H), 4.45−
4.40 (m, 1H), 3.95 (d, J = 15.2 Hz, 1H), 3.53 (d, J = 15.2 Hz, 1H), 3.12−
3.05 (m, 1H), 2.91−2.80 (comp, 3H), 2.40−2.32 (m, 1H), 2.27 (app td,
J = 12.1, 2.8 Hz, 1H), 2.09−1.99 (m, 1H), 1.95−1.87 (m, 1H), 1.78
(ddd, J = 16.3, 8.4, 3.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 133.0,
131.5, 128.2, 126.6, 126.2, 125.8, 89.8, 59.9, 57.5, 54.7, 32.7, 30.1, 22.8;
m/z (ESI-MS) 233.2 [M + H]+.
Product 15. Compound 8k was reduced following an adapted
literature procedure.32 To a stirred solution of 8k (0.09 mmol, 0.053 g)
in i-PrOH (2 mL) was added 1 M HCl (1.8 mmol, 1.8 mL) followed by
Zn dust (5.45 mmol, 0.356 g). The reaction mixture was stirred at room
1
1141, 1141, 738 cm−1; H NMR (400 MHz, CDCl3) δ 7.37−7.30
(comp, 2H), 7.30−7.27 (m, 1H), 7.25−7.20 (comp, 2H), 7.19−7.13
(comp, 2H), 7.09−7.02 (comp, 2H), 4.62 (dd, J = 11.4, 8.6 Hz, 1H),
4.03 (d, J = 15.1 Hz, 1H), 3.58 (d, J = 15.1 Hz, 1H), 3.30 (app td, J =
11.8, 4.8 Hz, 1H), 3.23 (app dt, J = 11.8, 3.0 Hz, 1H), 3.02−2.91 (comp
2H), 2.89−2.78 (m, 1H), 2.49 (app td, J = 11.8, 3.6 Hz, 1H), 2.16−1.95
(comp, 2H); 13C NMR (75 MHz, CDCl3) δ 139.2, 132.9, 131.3, 129.0,
128.2, 128.0, 127.2, 126.8, 126.3, 125.8, 95.7, 60.6, 57.5, 55.1, 47.2, 32.9,
30.9; m/z (ESI-MS) 309.1 [M + H]+.
J
DOI: 10.1021/acs.joc.5b01384
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The Journal of Organic Chemistry
Article
temperature for 2 h. The reaction was then quenched by addition of
saturated NaHCO3 (aq). The resulting mixture was stirred vigorously
for 20 min and then filtered through a plug of Celite and washed with
EtOAc. The filtrate was extracted with EtOAc, and the combined
organic layers were dried over Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified by flash chromatography to
give the title compound as a white solid in 83% yield.
layers were dried over anhydrous Na2SO4. Solvent was removed under
reduced pressure and the residue purified by silica gel chromatography
to give the title compound as a colorless oil in 73% yield (dr = 6.5:1).
Characterization data for 18 (major diastereomer): colorless oil; Rf
25
= 0.35 in 10% EtOAc/Hex; [α]D +3.76 (c 0.25, CHCl3); IR (KBr)
3032, 2967, 2876, 2735, 1722, 1555, 1496, 1454, 1382, 1204, 1100,
1027, 739, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.67 (d, J = 1.2 Hz,
1H), 7.38−7.28 (m, 5H), 4.62 (dd, J = 12.8, 6.6 Hz, 1H), 4.46−4.45
(comp, 2H), 4.42 (dd, J = 12.8, 6.5 Hz, 1H), 3.51 (t, J = 5.8 Hz, 2H),
2.90−2.84 (m, 1H), 2.49−2.40 (m, 1H), 1.86−1.62 (comp, 3H), 1.54−
1.46 (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
202.9, 137.8, 128.4, 127.7(4), 127.6(8), 76.9, 73.1, 67.4, 54.0, 34.5, 29.1,
18.5, 12.1; m/z (ESI-MS) 280.2 [M + H]+; HPLC Daicel Chiralcel OJ-
H, n-hexane/i-PrOH = 90/10, flow rate =1 mL/min, UV = 230 nm, tR =
78.2 min (major) and tR = 96.4 min (minor), 99% ee.
Product 19. A solution of the amine (0.232 g, 1.2 mmol, 2 equiv) and
AcOH (0.346 mL, 6 mmol, 10 equiv) in toluene (6 mL) was heated
under reflux. 4-Nitrobutyraldehyde 18 (0.167 g, 0.6 mmol, 0.12 M
solution in toluene) was delivered through the top of the reflux
condenser over 15 h via syringe pump. The reaction was then kept under
reflux for a further 0.5−1 h at which time the aldehyde was consumed as
judged by TLC analysis. Subsequently, the reaction mixture was allowed
to cool to room temperature, diluted with EtOAc (20 mL), and washed
with saturated aqueous NaHCO3 (3 × 20 mL). The combined aqueous
layers were extracted with EtOAc (2 × 10 mL), and the combined
organic layers were dried over anhydrous Na2SO4. Solvent was removed
under reduced pressure and the residue purified by silica gel
chromatography. Products 19, 19′, and 19″ were obtained in a 2:2:1
ratio, 61% combined yield.
Characterization data for 15: mp 122−125 °C; Rf = 0.25 in 5%
25
MeOH/EtOAc; [α]D +66.8 (c 0.5, CHCl3); IR (KBr); 3409, 3061,
3024, 2919, 2801, 2755, 1949, 1599, 1588, 1553, 1493, 1453, 1362,
1346, 1120, 1096, 1011, 863, 748 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.38−7.32 (comp, 2H), 7.30−7.24 (comp, 3H), 7.17−7.10 (comp, 3H),
7.07−7.02 (m, 1H), 3.95 (d, J = 15.2 Hz, 1H), 3.50 (d, J = 15.2 Hz, 1H),
3.31 (dd, J = 16.5, 4.4 Hz, 1H), 3.19 (app dt, J = 11.5, 3.3 Hz, 1H), 2.87−
2.77 (comp, 2H), 2.49−2.41 (m, 1H), 2.38 (app td, J = 12.2, 2.8 Hz,
1H), 2.23 (app dq, J = 10.5 Hz, 4.3 Hz, 1H), 2.05 (app qd, J = 12.8, 3.7
Hz, 1H), 1.93−1.86 (m, 1H), 1.24 (br s, 2H); 13C NMR (125 MHz,
CDCl3) δ 143.2, 133.6, 133.3, 128.8, 128.3, 127.8, 126.9, 126.4, 125.8,
125.7, 64.8, 59.6, 58.1, 55.8, 51.3, 34.0, 32.2; m/z (ESI-MS) 279.2 [M +
H]+.
Product 16. Compound 6k was denitrated following an adapted
literature procedure.33 To a stirred solution of 6k (31 mg, 0.1 mmol,
94% ee) in EtOH (2 mL) was added Pd(OH)2/C (20 wt %, 75 mg). The
reaction mixture was purged twice with hydrogen gas and then placed
under 1 bar of hydrogen gas at 60 °C for 14 h. After being cooled to
room temperature, the mixture was filtered through a Celite pad and
washed with ethyl acetate. The solvent was removed under reduced
pressure, and the crude material purified by flash chromatography to
give the desired product as an off-white solid in 75% yield.
Characterization data for 16: mp 124−127 °C; Rf = 0.41 in 40%
EtOAc/Hex; [α]D25 −27.2 (c 0.5, CHCl3); IR (KBr) 3058, 3032, 2942,
2915, 2801, 2742, 1598, 1494, 1450, 1348, 1296, 1151, 1131, 1104,
1064, 1039, 963, 758, 733, 696 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.36−7.27 (comp, 4H), 7.25−7.18 (comp, 2H), 7.16−7.09 (comp, 3H),
3.32 (app d, J = 11.0 Hz, 1H), 3.23 (ddd, J = 17.0, 12.1, 6.1 Hz, 1H), 3.15
(app dt, J = 11.4, 3.1 Hz, 1H), 3.06 (dd, J = 11.4, 6.0 Hz, 1H), 2.87−2.72
(comp, 2H), 2.60 (app td, J = 11.6, 3.9 Hz, 1H), 2.54−2.49 (comp, 2H),
2.03−1.87 (comp, 2H), 1.70 (app q, J = 12.4 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 146.4, 138.1, 134.7, 129.2, 128.7, 127.2, 126.5, 126.3,
126.0, 125.0, 63.5, 57.1, 52.6, 43.7, 39.2, 33.3, 29.9; m/z (ESI-MS) 264.3
[M + H]+; HPLC Daicel Chiralcel OD-H, n-hexane/i-PrOH/diethyl-
amine = 94.95/5/0.05, flow rate = 1 mL/min, UV = 254 nm, tR = 6.2 min
(major) and tR = 22.1 min (minor), 94% ee.
Product 17. Alkylation of 11 was achieved following an adapted
literature procedure.34 To a stirred solution of 11 (0.1 mmol, 0.023 g)
and methyl vinyl ketone (0.13 mmol, 0.01 mL) in MeCN (1 mL) was
added DBU (0.1 mmol, 0.015 mL) at room temperature. The reaction
mixture was stirred for 15 h at room temperature. Solvent was removed
under reduced pressure, and the crude material purified by flash
chromatography to give the title compound as a colorless oil in 69%
yield.
Characterization Data for 19 (1S,2R,3R,11bR)-2-(2-(Benzyloxy)-
ethyl)-3-ethyl-9,10-dimethoxy-1-nitro-2,3,4,6,7,11b-hexahydro-1H-
pyrido[2,1-a]isoquinoline). The relative stereochemistry was deter-
mined by GCOSY and NOESY NMR: brown oil; Rf = 0.45 in 50%
EtOAc/Hex; [α]D25 −16.4 (c 0.25, CHCl3); IR (KBr) 3061, 2959, 2865,
2831, 1741, 1682, 1631, 1539, 1519, 1467, 1356, 1262, 1225, 1143,
1111, 740 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.19 (comp, 5H),
6.58 (s, 1H), 6.34 (s, 1H), 4.88−4.77 (m, 1H), 4.47 (d, J = 12.0 Hz, 1H),
4.43 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 9.8 Hz, 1H), 3.83 (s, 3H), 3.76 (s,
3H), 3.48 (t, J = 6.6 Hz, 2H), 3.13 (dd, J = 13.5, 4.0 Hz, 1H), 3.02−2.97
(m, 1H), 2.92−2.85 (m, 1H), 2.81−2.62 (comp, 3H), 2.25−2.18 (m,
1H), 1.89−1.82 (m, 1H), 1.80−1.58 (comp, 3H), 1.23−1.09 (m, 1H),
0.90 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.7, 147.2,
138.4, 128.6, 127.7(7), 127.7(5), 126.4, 125.4, 111.8, 109.8, 91.2, 73.3,
67.0, 62.8, 59.0, 56.1, 56.0, 46.1, 43.6, 33.8, 29.4, 28.2, 23.3, 11.0; m/z
(ESI-MS) 455.1 [M + H]+.
Characterization Data for 19′ ((1S,2R,3S,11bR)-2-(2-(Benzyloxy)-
ethyl)-3-ethyl-9,10-dimethoxy-1-nitro-2,3,4,6,7,11b-hexahydro-1H-
pyrido[2,1-a]isoquinoline). The relative stereochemistry was deter-
mined by GCOSY and NOESY NMR: brown oil; Rf = 0.42 in 20%
EtOAc/Hex; [α]D25 −69.9 (c 0.25, CHCl3); IR (KBr) 3026, 3009, 2937,
2865, 2806, 1726, 1608, 1551, 1462, 1363, 1269, 1225, 1096,1010, 876,
743, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.26 (comp, 5H),
6.56 (s, 1H), 6.41 (s, 1H), 4.52 (d, J = 11.9 Hz, 1H), 4.44 (d, J = 11.9 Hz,
1H), 4.39−4.30 (m, 1H), 4.01 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.75 (s,
3H), 3.50−3.43 (comp, 2H), 3.00−2.94 (comp, 2H), 2.88 (ddd, J =
11.0, 4.9, 3.0 Hz, 1H), 2.79−2.68 (comp, 2H), 2.59−2,54 (comp, 2H),
1.74−1.53 (comp, 4H), 1.52−1.42 (m, 1H), 1.42−1.31 (m, 1H), 0.88 (t,
J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 148.1, 147.4, 138.4,
128.6, 128.4, 127.9(2), 127.8(5), 125.8, 111.8, 108.8, 92.4, 73.1, 67.0,
65.0, 57.0, 56.0, 51.3, 42.7, 37.2, 30.4, 28.2, 18.9, 12.5; m/z (ESI-MS)
455.1 [M + H]+.
Characterization data for 17. The relative stereochemistry was
determined by GCOSY and NOESY NMR: Rf = 0.32 in 20% EtOAc/
Hex; IR (KBr) 3073, 3021, 2962, 2900, 2814, 2759, 1719, 1645, 1521,
1
1450, 1358, 1299, 1252, 1141, 1106, 1052, 745 cm−1; H NMR (400
MHz, CDCl3) δ 7.19−7.11 (m, 1H), 7.08−7.03 (comp, 2H), 6.69 (app
d, J = 7.9 Hz, 1H), 4.27 (s, 1H), 3.18−3.06 (m, 1H), 3.03−2.99 (m, 1H),
2.90 (app dd, J = 10.8, 3.0 Hz, 1H), 2.79−2.63 (comp, 2H), 2.59−2.45
(comp, 4H), 2.36−2.21 (m, 1H), 2.15−2.02 (comp, 4H), 1.95−1.87
(m, 1H), 1.80−1.61 (comp, 2H); 13C NMR (75 MHz, CDCl3) δ 207.6,
137.4, 132.1, 129.2, 127.0, 126.2, 125.6, 94.5, 69.7, 55.7, 51.1, 37.8, 34.7,
30.9, 30.0, 22.5, 22.4; m/z (ESI-MS) 303.2 [M + H]+.
Product 18. To a stirred solution of (E)-(((4-nitrobut-3-en-1-
yl)oxy)methyl)benzene (0.858 g, 4.14 mmol, 1 equiv), (S)-
diphenylprolinol trimethylsilyl ether (0.135 g, 0.414 mmol, 10 mol
%), and p-nitrophenol (0.028 g, 0.207 mmol, 5 mol %) in toluene (4.14
mL) was added n-butyraldehyde (1.12 mL, 12.42 mmol, 3 equiv) at
room temperature. The reaction mixture was stirred for 14 h and
quenched by the addition of 1 M HCl (10 mL), and the resulting
mixture was extracted with EtOAc (2 × 10 mL). The combined organic
Characterization data for 19″ (1R,2R,3S,11bS)-2-(2-(benzyloxy)-
ethyl)-3-ethyl-9,10-dimethoxy-1-nitro-2,3,4,6,7,11b-hexahydro-1H-
pyrido[2,1-a]isoquinoline): brown oil; Rf = 0.55 in 50% EtOAc/Hex;
[α]D25 +49.4 (c 0.25, CHCl3); IR (KBr) 3063, 3033, 2959, 2932, 2860,
2801, 2754, 1734, 1615, 1541, 1519, 1363, 1264, 1104, 740, 696 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.40−7.26 (comp, 5H), 6.56 (s, 1H),
6.50 (s, 1H), 5.53 (app t, J = 2.1 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.56
(d, J = 12.0 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 1H), 3.80−3.73 (m, 1H),
3.72−3.67 (m, 1H), 3.55 (s, 3H), 3.20−3.07 (m, 1H), 3.07−2.95 (m,
K
DOI: 10.1021/acs.joc.5b01384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 2.86 (dd, J = 10.8, 3.0 Hz, 1H), 2.81−2.70 (m, 1H), 2.59−2.46
(comp, 2H), 2.39−2.19 (comp, 2H), 1.92−1.74 (comp, 2H), 1.35−1.23
(comp, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
147.6, 147.2, 137.8, 128.5, 127.9, 127.8, 127.5, 125.5, 111.6, 107.2, 86.0,
73.5, 70.1, 59.8, 56.9, 55.8, 55.7, 52.7, 39.8, 36.3, 28.9, 25.1, 23.1, 11.5;
m/z (ESI-MS) 455.1 [M + H]+.
(−)-Protoemetinol. To a stirred solution of starting material 19 (91
mg, 0.2 mmol) in EtOH (4 mL) was added Pd(OH)2/C (20 wt %, 112
mg). The reaction mixture was purged twice with hydrogen gas and then
placed under 1 bar of hydrogen gas at 70 °C for 30 h. After being cooled
to room temperature, the mixture was filtered through a Celite pad and
washed with ethyl acetate. The solvent was removed under reduced
pressure and the crude material purified by flash chromatography to give
the desired product as a yellow oil in 64% yield. (−)-Protoemetinol was
previously reported, and its published characterization data matched our
own in all respects.2g,l
(e) Nuhant, P.; Raikar, S. B.; Wypych, J.-C.; Delpech, B.; Marazano, C. J.
Org. Chem. 2009, 74, 9413. (f) English, B. J.; Williams, R. M. J. Org.
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52, 1154. (l) Lin, S.; Deiana, L.; Tseggai, A.; Cordova, A. Eur. J. Org.
Chem. 2012, 2012, 398. (m) Lebold, T. P.; Wood, J. L.; Deitch, J.;
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(n) Moon, H.; An, H.; Sim, J.; Kim, K.; Paek, S.-M.; Suh, Y.-G.
Tetrahedron Lett. 2015, 56, 608.
(3) Examples from our laboratory: (a) Zhang, C.; De, C. K.; Mal, R.;
Seidel, D. J. Am. Chem. Soc. 2008, 130, 416. (b) Zhang, C.; Das, D.;
Seidel, D. Chem. Sci. 2011, 2, 233. (c) Ma, L.; Chen, W.; Seidel, D. J. Am.
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Lett. 2014, 16, 3556.
(4) Selected recent reviews on amine α-functionalization, including
redox-neutral approaches: (a) Campos, K. R. Chem. Soc. Rev. 2007, 36,
1069. (b) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem. - Eur. J. 2010, 16, 2654. (c) Mitchell, E. A.; Peschiulli,
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Characterization data for (−)-protoemetinol: yellow oil; Rf = 0.45
in 30% MeOH/EtOAc; [α]D25 −46.5 (c 0.6, CHCl3); IR (KBr) 3422,
2956, 2931, 2874, 2868, 2751, 1610, 1510, 1463, 1365, 1330, 1253,
1
1230, 1148, 1100, 1040, 1000, 867, 767, 732; H NMR (500 MHz,
CDCl3) δ 6.67 (s, 1H), 6.56 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.79−
3.69 (comp, 2H), 3.14−3.00 (comp, 3H), 2.99−2.93 (m, 1H), 2.61 (app
d, J = 15.9 Hz, 1H), 2.47 (app td, J = 11.5, 3.9 Hz, 1H), 2.33 (app d, J =
12.8 Hz, 1H), 2.05−1.97 (m, 1H), 1.93 (app dt, J = 11.1, 7.8 Hz, 1H),
1.70−1.63 (m, 1H), 1.49−1.36 (comp, 3H), 1.28−1.18 (m, 1H), 1.16−
1.06 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
147.4, 147.1, 130.0, 126.7, 111.5, 108.3, 62.7, 61.4, 60.6, 56.1, 55.8, 52.5,
41.3, 37.6, 37.3, 35.9, 29.1, 23.5, 11.1; HRMS (ESI) m/z calcd for
C19H30NO3 [M + H]+ 320.2220, found 320.2225.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01384.
■
S
X-ray crystal structure of compound 6c (CIF)
X-ray crystal structure of compound 7c (CIF)
X-ray crystal structure of compound 8 (CIF)
NMR spectra for all reported compounds; 2D-NMR
spectra for selected compounds; Cartesian coordinates,
energies of all calculated structures, and details of
computational methods (PDF)
(5) Additional reviews covering various aspects of redox-neutral
chemistry Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854. (b) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res.
2014, 47, 696. (c) Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische,
M. J. Angew. Chem., Int. Ed. 2014, 53, 9142. (d) Huang, H.; Ji, X.; Wu,
W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mbreugst@uni-koeln.de.
*E-mail: seidel@rutchem.rutgers.edu.
(6) The intermediacy of azomethine ylides has been established in
related processes. For instance, see ref 3e,h.
■
(7) Examples of other recent redox-neutral amine α-C−H
functionalizations that likely involve azomethine ylides as intermediates:
(a) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889.
(b) Zheng, Q.-H.; Meng, W.; Jiang, G.-J.; Yu, Z.-X. Org. Lett. 2013, 15,
5928. (c) Lin, W.; Cao, T.; Fan, W.; Han, Y.; Kuang, J.; Luo, H.; Miao,
B.; Tang, X.; Yu, Q.; Yuan, W.; Zhang, J.; Zhu, C.; Ma, S. Angew. Chem.,
Int. Ed. 2014, 53, 277. (d) Haldar, S.; Mahato, S.; Jana, C. K. Asian J. Org.
Chem. 2014, 3, 44. (e) Rahman, M.; Bagdi, A. K.; Mishra, S.; Hajra, A.
Chem. Commun. 2014, 50, 2951. (f) Li, J.; Wang, H.; Sun, J.; Yang, Y.;
Liu, L. Org. Biomol. Chem. 2014, 12, 2523.
(8) Selected recent reviews on azomethine ylides: (a) Padwa, A.;
Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Wiley: Chichester,
U. K., 2002; Vol. 59. (b) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105,
2765. (c) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106,
4484. (d) Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 2006, 2873.
(e) Najera, C.; Sansano, J. M. Top. Heterocycl. Chem. 2008, 12, 117.
(f) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (g) Nyerges,
M.; Toth, J.; Groundwater, P. W. Synlett 2008, 2008, 1269. (h) Burrell,
A. J. M.; Coldham, I. Curr. Org. Synth. 2010, 7, 312. (i) Anac, O.;
Gungor, F. S. Tetrahedron 2010, 66, 5931.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NIH−NIGMS (R01GM101389) and
the Fonds der Chemischen Industrie (Liebig Scholarship to
M.B.) is gratefully acknowledged. We thank Dr. Tom Emge for
crystallographic analysis. This work used the Cologne High
Efficiency Operating Platform for Sciences (CHEOPS).
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diastereomer when exposed to the reaction conditions. Partial
isomerization to the apparently thermodynamically more stable major
isomer may also occur during column-chromatographic purification.
The absolute and relative configurations of all compounds were
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8a/9a and vice versa have been unsuccessful under a variety of
conditions, including the reaction conditions that allow for the selective
formation of either regioisomeric pair.
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M
DOI: 10.1021/acs.joc.5b01384
J. Org. Chem. XXXX, XXX, XXX−XXX