Exploring the Steric and Electronic Factors Governing the Regio- and Enantioselectivity of the Pd-Catalyzed Decarboxylative Generation and Allylation of 2-Azaallyl Anions

Article abstract of DOI:10.1021/acs.joc.8b00491

The impact of the steric and electronic factors in both the para-substituted benzaldimine and 2,2-diarylglycine components on the regioselectivity and enantioselectivity of the palladium-catalyzed decarboxylative allylation of allyl 2,2-diarylglycinate aryl imines was explored. These studies revealed that using 2,2-di(2-methoxyphenyl)glycine as the amino acid linchpin allowed for the exclusive synthesis of the desired homoallylic benzophenone imine regioisomers, independent of the nature of the imine moiety, in typically high yields. The resulting enantiomeric ratios, however, are slightly decreased in comparison to the transformations involving the corresponding allyl 2,2-diphenylglycinate imines, but this is more than balanced out by the increases in yield and regioselectivity. Overall, these studies suggest a general strategy for the highly regioselective functionalization of 2-azaallyl anions.

Full text of DOI:10.1021/acs.joc.8b00491

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Exploring the Steric and Electronic Factors Governing
the Regio- and Enantioselectivity of the Pd-Catalyzed
Decarboxylative Generation and Allylation of 2-Azaallyl Anions
Shuaifei Wang, Xiaoyan Qian, Yuanyu Chang, Jiayue Sun,
Xiujing Xing, Wendy Fields Ballard, and Jason J. Chruma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00491 • Publication Date (Web): 20 Mar 2018
Downloaded from http://pubs.acs.org on March 22, 2018
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The Journal of Organic Chemistry
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Exploring the Steric and Electronic Factors Governing the Regioꢀ
and Enantioselectivity of the PdꢀCatalyzed Decarboxylative Generaꢀ
tion and Allylation of 2ꢀAzaallyl Anions
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Shuaifei Wang,† Xiaoyan Qian,† Yuanyu Chang,† Jiayue Sun,† Xiujing Xing,† Wendy F. Ballard,‡,§ Jaꢀ
son J. Chruma*,†
†Key Laboratory of Green Chemistry & Technology (MOE), College of Chemistry and SinoꢀBritish Materials Research Institute, College
of Physical Sciences & Technology, Sichuan University, Chengdu, Sichuan, 610064, P. R. China
‡Department of Chemistry, University of Virginia, Charlottesville, VA 22904ꢀ4319, U.S.A.
ABSTRACT: The impact of the steric and electronic factors in both the paraꢀsubstituted benzaldimine and 2,2ꢀdiarylglycine comꢀ
ponents on the regioselectivity and enantioselectivity of the palladiumꢀcatalyzed decarboxylative allylation of allyl 2,2ꢀ
diarylglycinate aryl imines was explored. These studies revealed that using 2,2ꢀdi(2ꢀmethoxyphenyl)glycine as the amino acid
linchpin allowed for the exclusive synthesis of the desired homoallylic benzophenone imine regioisomers, independent of the nature
of the imine moiety, in typically high yields. The resulting enantiomeric ratios, however, are slightly decreased in comparison to the
transformations involving the corresponding allyl 2,2ꢀdiphenylglycinate imines, but this is more than balanced out by the increases
in yield and regioselectivity. Overall, these studies suggest a general strategy for the highly regioselective functionalization of 2ꢀ
azaallyl anions.
Scheme 1. Complementary Methods for the PdꢀCatalyzed
Decarboxylative Generation and Allylation of 2ꢀAzaallyl
INTRODUCTION
For over a century, the 2ꢀazaallyl anion has attracted signifiꢀ
Anions
cant attention as a nucleophilic imine umpolung.1 A unifying
concern for such processes is controlling the regioselectivity and
potential enantioselectivity of the key C–C bondꢀforming step.
Traditionally, 2ꢀazaallyl anions are generated by deprotonation of
the conjugate acid with strong amide bases,2 though very recent
reports indicate that such a tactic can lead to concomitant forꢀ
mation of 2ꢀazaallyl radicals.3 Decarboxylation is a relatively
recent alternative strategy for the generation of 2ꢀazaallyl aniꢀ
ons with at least two aromatic substituents (a.k.a. semiꢀ
stabilized 2ꢀazaallyl anions).4 For example, Burger and Tunge
disclosed a palladiumꢀcatalyzed decarboxylative generation
and allylation of semiꢀstabilized 2ꢀazaallyl anions from the
allyl esters of various αꢀbenzophenonimino acids (1, Scheme
1).4a Not long after, our group reported a complementary stratꢀ
egy starting from allyl diphenylglycinate imines (2);4b an
ate readily upon dissolution in aprotic coordinating media.4d
asymmetric variant of this transformation using the chiral ligꢀ
and (S,S)ꢀfꢀbinaphane5 was reported much later.4c Zhao and
Under otherwise identical conditions, all three approaches
coꢀworkers advanced an “intermolecular” modification startꢀ
ing from lithium diphenylglycinate imines (3), several of
which are stable complexes in protic solvents but decarboxylꢀ
afford essentially identical ratios of regioisomeric products 4
and 5, strongly indicating that all three transformations proꢀ
ceed via the same delocalized 1,1ꢀdiphenylꢀ2ꢀazaallyl anion
(A) and cationic πꢀallylPd(II) (B) intermediates. Previous
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mechanistic studies revealed a positive linear Hammett correꢀ
Table 1. Regioꢀ and Enantioselectivity for the PdꢀCatalyzed
Asymmetric DcA of Imino Esters 2
1
2
3
lation between the regioisomeric ratio [rr, log(4/5)] and theꢀ
Hammett resonance constant (σ─ )6 for the Pdꢀcatalyzed deꢀ
p
carboxylative allylation (DcA) of imino esters 2 in which the
R groups were various paraꢀsubstituted phenyl moieties.7 That
is to say that electronꢀdeficient aromatic R groups demonstratꢀ
ed a significantly higherꢀtoꢀexclusive preference for homoalꢀ
lylic imines 4 over aldimines 5, whereas electronꢀrich R
groups afforded only modest preferences for ketimines 4. A
roughly linear positive Hammett correlation was also observed
for the enantiomeric ratio (er) values of the resulting benzoꢀ
phenone imines (S)ꢀ4 in the asymmetric Pdꢀcatalyzed DcA of
allyl imino esters 2,4c though this relationship appeared to be
complicated by steric interactions between the R groups and
the chiral ligand. Herein is disclosed a more detailed investiꢀ
gation into the steric and electronic factors governing both the
regioꢀ and enantioselectivity for the Pdꢀcatalyzed DcA of allyl
2,2ꢀdiarylglycinate imines. These studies reveal that switching
the amino acid linchpin to 2,2ꢀdi(2ꢀmethoxyphenyl)glycine
completely solves the regioselectivity issue, affording the deꢀ
sired ketimines as the sole products in higher isolated yields
compared to the 2,2ꢀdiphenylglycine analogs. While the enanꢀ
tioselectivities of the Pdꢀcatalyzed DcAs suffered slight but
general decreases upon switching to 2,2ꢀdi(2ꢀmethoxyphenyl)ꢀ
glycine as the linchpin amino acid, the enatiopurity of the final
products could be enriched by single recrystallization. Overall,
these studies suggest a general strategy for the highly regioseꢀ
lective functionalization of semiꢀstabilized 2ꢀazaallyl anions.
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σ ꢀ a
νb
entry
1
R
rr (4:5)c er (S:R)d
p
NO2 (2a)
CN (2b)
CO2Me (2c)
CF3 (2d)
I (2e)
1.27
1.00
0.75
0.65
0.27
0.25
0.19
0.00
ꢀ0.03
ꢀ0.12f
ꢀ0.13
ꢀ0.17
ꢀ0.19
ꢀ0.26
NA
>20:1e
>20:1e
>20:1e
>20:1
15.5:1
14.1:1
10.5:1
7.2:1
94.7:5.3e
93.5:6.5e
93.9:6.1e
88.9:11.1
87.1:12.9
90.2:9.8e
86.3:13.7
86.2:13.8e
86.9:13.1e
83.9:16.1
79.7:20.3
89.5:10.5e
82.7:17.3
82.7:17.3
2
NA
3
NA
4
0.91
0.78
0.65
0.55
0.00
0.27
0.98
1.24
0.52
0.56
NA
5
RESULTS AND DISCUSSION
6
Br (2f)
Initial reports on the racemic Pdꢀcatalyzed DcA of diphenylꢀ
glycinate imino esters 2 using Pd(dba)2 (10 mol %) and dppf (10
mol %) in MeCN revealed a strong positive linear Hammett corꢀ
relation between regioselectivity [log(4/5)] and the Hammett resꢀ
onance coefficient for para substituents (σ ─p).4b,7 Later studies
using the chiral ligand (S,S)ꢀfꢀbinaphane in DMSO showed a
much rougher positive linear correlation between enantioselectiviꢀ
7
Cl (2g)
H (2h)
8
9
F (2i)
5.4:1
10
11
12
13
14
iꢀBu (2j)
tꢀBu (2k)
Me (2l)
Et (2m)
MeO (2n)
3.3:1
2.9:1
ty {log[(S)ꢀ4/(R)ꢀ4]} and σ ─ for electronꢀwithdrawing or elecꢀ
p
2.9:1
tronꢀneutral R groups (Table 1, 2a, 2b, 2c, 2f, and 2h), but with
an apparent inflection point at 2h (R = H) and a negative linear
correlation for R groups with negative σ ─p values, such as 2i (R =
F) and 2l (R = Me).4c Inflection points in Hammett plots typically
indicate a change in mechanism, but with regard to enantioselecꢀ
tivity it can also signify that a much more complicated relationꢀ
ship between both electronic and steric factors governs asymmetꢀ
ric induction.8 If there is a significant change in the mechanistic
pathway for the asymmetric DcA of imino esters 2 upon switchꢀ
ing from electronꢀwithdrawing to electronꢀdonating para substitꢀ
uents, then an inflection point would also be expected in the
Hammett plot for regioselectivity. While it was noted that strongꢀ
ly electronꢀwithdrawing substituents (2aꢀc) only provided the
corresponding benzophenone imines (4aꢀc), the regioselectivities
for the asymmetric DcA of other αꢀimino esters 2, regrettably,
were not determined in our previous study.4c
3.0:1
1.7:1
aHammett resonance coefficient for para substituent (ref 6).
bCharton steric coefficient (ref 9). Determined by 1H NMR analꢀ
ysis of the crude reaction mixture; average of three runs. Deterꢀ
mined by chiral HPLC analysis; average of three runs. From ref
4c. fThe reported value for nꢀBu was used (see text).
c
d
e
To address this question, a larger substrate screen was performed
for the Pdꢀcatalyzed asymmetric DcA of allyl diphenyglycinate
imines 2; both the regioisomeric ratio (rr) and enantiomeric ratio
(er) were determined (Table 1). In addition to theseven paraꢀ
substituted benzaldimines investigated in our previous report,4d
three more electronꢀwithdrawing R groups (trifluoromethyl (2d),
iodo (2e), and chloro (2g)) and four electronꢀdonating substituents
(isobutyl (2j), tertꢀbutyl (2k), ethyl (2m), and methoxy (2n)) were
included. The substrates are arranged in descending σ ─ values
(electronꢀwithdrawing to electronꢀdonating) in Table 1. It should
p
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be noted that the reported σ ─ value for the isobutyl moiety
group (4k) appears to be “too big” (ν = 1.24), resulting in a sigꢀ
p
(0.01)10 is inexplicably and drastically different from the values of
nificant decrease in observed enantioselectivity versus expectaꢀ
tion based on consideration of electronic factors alone. Overall,
using the data in Table 1 it is possible to construct a predictive
linear free energy relationship between the electronic and steric
factors in the paraꢀsubstituted benzaldimines 2 and the enantioꢀ
meric ratios of the corresponding products 4 in the asymmetric
Pdꢀcatalyzed DcA using (S,S)ꢀfꢀbinaphane as a chiral ligand; efꢀ
forts toward this end are detailed in the Supporting Information.
1
2
3
4
5
6
7
8
related substituents, such as isopropyl (ꢀ0.16), tertꢀbutyl (ꢀ0.13),
and nꢀbutyl (ꢀ0.12).6 Accordingly, the σ ─ value for an nꢀbutyl
p
group was used in our analysis. Since the observed er values
might be influenced by steric as well as electronic factors, Charꢀ
ton coefficients (
also provided in Table 1 for reference. An attempt was made to
have a wide range of both σ ─p and
values so as to best extrapoꢀ
ν
),9 which are classical steric parameters, are
ν
9
late the importance of each factor. Regretfully, Charton coeffiꢀ
cients for most strongly electronꢀwithdrawing (nitro (2a), cyano
(2b), and methyl carboxy (2c)) and electronꢀdonating (methoxy,
2n) groups are not available. In these cases, different steric paꢀ
rameters are available (see Supporting Information).8
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1.30
I
Br
Cl
1.10
0.90
0.70
0.50
0.30
0.10
A Hammett plot of the observed rr values versus σ ─ for the
p
asymmetric DcA of imino esters 2eꢀn shows a strong (R2 = 0.97)
positive linear correlation, similar to our previous studies using an
achiral ligand (Figure 1).4b,d This suggests that there is not a
change in mechanism as the R groups switch from electronꢀ
withdrawing to electronꢀdonating when the chiral ligand and
DMSO are employed. This conclusion is strengthened with the
expanded Hammett plot of er values versus σ ─p (Figure 2). There
is more substantial offꢀdiagonal scatter (R2 = 0.79) in this plot, but
the positive linear relationship is still evident throughout the seꢀ
ries of substrates. The higherꢀthanꢀexpected er value previously
observed for methylꢀsubstituted 4l is now balanced out by the
four newly included electronꢀrich products 4j (iꢀBu), 4k (tꢀBu),
4m (Et), and 4n (MeO). The observed er value for methylꢀ
substituted 4l is noticeably higher than the corresponding ethylꢀ
and tertꢀbutylꢀsubstituted products (4m and 4k, respectively),
H
F
iꢀBu
tꢀBu
Et
Me
MeO
R² = 0.97
0.2 0.3
ꢀ0.3
ꢀ0.2
ꢀ0.1
0
0.1
Hammett resonance coefficient (σ ─
)
p
Figure 1. Hammett plot of the regioselectivity of the Pdꢀcatalyzed
asymmetric DcA of imino ester 2eꢀn [log(4/5)] versus the correꢀ
sponding Hammett resonance coefficients for para substituents
(σ─p);6 see Table 1, entries 5ꢀ14. Log(4/5) values were determined
despite relatively similar σ ─ values for the associated R groups
p
(average ꢀσ ─ = 0.03). This difference could be a result of steric
p
1
from HꢀNMR analysis and are an average of three runs; error
factors in which the methyl substituent is just the right size (ν =
0.52) for optimal interactions with the chiral ligand upon apꢀ
bars are ± standard deviation (corrected with Student’s T test).
The reported R2 value was determine by standard linear regresꢀ
sion line fitting.
proaching the πꢀallylPd(II) electrophile. Conversely, the tertꢀbutyl
1.3
CO2Me
CN
NO2
Br
1.0
Me
Cl
CF3
F
H
I
Et
iꢀBu
MeO
0.7
0.4
tꢀBu
R² = 0.79
ꢀ0.3
ꢀ0.1
0.1
0.3
0.5
0.7
0.9
1.1
1.3
Hammett Resonance Constant (σ ─
)
p
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Figure 2. Hammett plot of the enantioselectivity of the Pdꢀcatalyzed asymmetric DcA of imino esters 2aꢀn [log(S/R)] versus the correꢀ
sponding Hammett resonance coefficients for para substituents (σ ─p);6 see Table 1. Log(er) 4 values determined from chiral HPLC analyꢀ
sis and are an average of three runs; error bars are ± standard deviation (uncorrected). The reported R2 value was determine by standard
linear regression line fitting.
1
2
3
4
5
6
7
8
The formation of regioisomers 4 and 5 in the Pdꢀcatalyzed
DcA of allyl diphenylglycinate imines 2 arises from the allylation
of either 2ꢀazaallyl anion resonance isomers A1 or A2, respectiveꢀ
ly (Scheme 2A). As evidenced by the results in Table 1 and Figꢀ
ure 1, the electronic nature of the R group greatly influences this
regioselectivity, with electronꢀdonating R groups increasing the
relative amount of allylation at the more sterically hindered diꢀ
phenylmethine position in A2. Alternatively, changing the steric
and electronic elements in the 2,2ꢀdiarylglycine amino acid linchꢀ
pin should also impact this regioselectivity. For example, Yoriꢀ
mitsu and Oshima observed that switching to xanthone imines 6
from the corresponding benzophenone imines resulted in signifiꢀ
cantly improved arylation at the less hindered position to afford
diarylmethylimines 7 in the Pdꢀcatalyzed arylation of 2ꢀazaallyl
anions (Scheme 2B).11 The situation is more complex for fluꢀ
orenoneꢀbased systems (Scheme 2C). Buchwald reported that the
Pdꢀcatalyzed asymmetric arylation of fluorenoneꢀbased 2ꢀazaallyl
anions of alkyl imines 8 (R = alkyl) proceeds with exlcusive regiꢀ
oselective arylation at the less substituted position to afford fluꢀ
orenone imines 9.12 Niu and coꢀworkers, on the other hand, deterꢀ
mined that asymmetric allylation of 2ꢀazaallyl anions derived
from (hetero)aryl imines 8 (R = (hetero)aryl) under Irꢀcatalysis
initially occurred at the more substituted position followed by
rapid [3,3]ꢀsigmatropic rearrangement under the reaction condiꢀ
tions to afford homoallylic imines 10 in high yield and enantioꢀ
meric excess.13 Similarly, in previously unpublished studies, we
determined that the Pdꢀcatalyzed allylation of the 2ꢀazaallyl anion
derived from deprotonation of 10,10ꢀdioxothioxanthene 11 proꢀ
ceeded exclusively at the more substituted carbon to afford benꢀ
zaldimine 12 in modest yield (Scheme 2D).
9
10
11
12
13
14
15
16
17
18
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20
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Scheme 2. Regioselectivity in the Transition Metalꢀ
Mediated Alkylation/Arylation of 2ꢀAzaallyl Anions
In regard to the regioselectivity observed for the Pdꢀcatalyzed
DcA of allyl 2,2ꢀdiarylglycinate imines like 2, changing the steric
and electronic factors in the amino acid linchpin should also have
a profound impact. To explore this hypothesis, we first syntheꢀ
sized the allyl esters of 2,2ꢀdi(4ꢀmethoxyphenyl)glycine (13) and
2,2ꢀdi(2ꢀmethoxyphenyl)glycine (14) following a modification of
procedures recently reported by Bertus and coꢀworkers (see Supꢀ
porting Information)14 and then condensed these amines with a
series of paraꢀsubstituted benzaldehydes to afford a collection of
imines 15 and 16, respectively (Scheme 3). The para substituent
(R group) in these benzaldimines was varied to span the range of
highly electronꢀwithdrawing (R = CN) to electronꢀdonating (R =
OMe). Imino esters 15 and 16 were next subjected to our previꢀ
ously reported racemic Pdꢀcatalyzed DcA reaction conditions and
the resulting regioisomeric ratios (rr) were compared to the rr
values obtained with the analogous 2,2ꢀdiphenylglycinate imino
esters 2 (Table 2). Throughout the whole series of 2,2ꢀdi(4ꢀ
methoxyphenyl)glycinates 15 (entries 2, 5, 8, 11, & 14), the reꢀ
sulting rr values (17:18) were consistently higher than those obꢀ
tained from 2,2ꢀdiphenylglycinates 2 (4:5, entries 1, 4, 7, 10, and
13), without a substantial drop in isolated yield. As expected, the
electronꢀdonating character of the paraꢀmethoxy substituents in
the amino acid linchpin of 15 pushes electron density away from
the more substituted carbon in the 2ꢀazaallyl anion intermediate
(i.e., A2 → A1, Scheme 2A), thus providing stronger preference
for the desired homoallylic imine products 17 over the regioisoꢀ
mers 18. This is most pronounced for the 4ꢀmethoxybenzaldimine
15n, in which there is an 86% increase in the rr versus that seen
for analogous imine 2n (4.1:1 vs 2.2:1, respectively).
Moving the methoxy groups to the ortho positions in the 2,2ꢀ
diarylglycine linchpin should introduce a new steric drive for
allylation at the less substituted position of the corresponding 2ꢀ
azaallyl anions, in addition to the electronic push provided by the
electronꢀdonating nature of the methoxy groups. In accord with
this hypothesis, all of the allyl 2,2ꢀdi(2ꢀmethoxyphenyl)glycinate
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imines (16) tested in the racemic Pdꢀcatalyzed DcA transforꢀ
Scheme 3. Synthesis of New Allyl 2,2ꢀDiarylglycinate
1
2
3
mation (Table 2, entries 3, 6, 9, 12, & 15) exclusively afforded the
Imines
desired homoallylic imines 19 as the sole regioisomeric products.
1
resultant broadening in the 1H NMR spectra, H NMR analysis of
4
5
6
7
the crude reaction mixtures for the Pdꢀcatalyzed DcA of imines
16 could not be used to determine the rr values of 19 versus 20.
Instead, the filtered crude reaction mixtures were first treated with
NaBH3CN in MeOH to reduce the imine groups and the resultant
1
8
amines 21 were then analyzed by H NMR spectroscopy to deꢀ
9
termine the rr values (Scheme 4). In all cases, only the diphenylꢀ
methylamine products 21 were observed without any trace of the
corresponding regioisomeric product arising from benzaldimines
20. In short, switching to the 2,2ꢀdi(2ꢀmethoxyꢀphenyl)glycine
linchpin (i.e. 2 → 16) completely solved the regioselectivity issue
for the corresponding Pdꢀcatalyzed DcA reactions. Moreover, in
all but one case (2h versus 16h), the Pdꢀcatalyzed DcA of imines
16 proceeded in notably higher isolated yields versus the correꢀ
sponding 2,2ꢀdiphenylglycinates 2. This is most pronounced when
comparing the pꢀmethoxybenzaldimines 16n and 2n (Table 2,
entries 15 and 13, respectively), in which the former exclusively
provides the corresponding homoallylic imine 19n in 93% isolatꢀ
ed yield, whereas the latter generates homoallylic imine 4n as a
2.2:1 mixture with regioisomer 5n in 52% combined isolated
yield.
Table 2. Effect of the 2,2ꢀDiarylglycine Linchpin on the
Regioselectivity of the PdꢀCatalyzed DcA
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Reduction of Imines 19 to Amines 21
Arb
Yieldc rrd
σ ꢀ a
entry
1
R
p
CN
1.00
Ph (2b)
91%e
96%
>98%
96%e
84%
89%
97%e
79%
>98%
80%e
80%
88%
52%
74%
93%
>20:1e
2
PMP (15b)
OMP (16b)
Ph (2h)
>20:1
3
>20:1f
6.1:1.0e
10.1:1.0
>20:1f
5.5:1.0e
6.3:1.0
>20:1f
3.1:1e
4
H
0.00
Having determined that addition of methoxy groups at either the
para or ortho positions of the amino acid linchpin improves the
regioselectivity of the Pdꢀcatalyzed DcA of allyl 2,2ꢀ
diarylglycinate imines, the influence of these electronꢀdonating
substituents on the er for the corresponding asymmetric transforꢀ
mations using (S,S)ꢀfꢀbinaphane as a chiral ligand was next exꢀ
plored. Initial comparisons focused on the pꢀcyanobenzaldimines
2b, 15b, and 16b (Scheme 5). In our previous report, 2b proved to
be one of the best substrates for the asymmetric Pdꢀcatalyzed
DcA reaction, affording (S)ꢀ4b in essentially quantitative isolated
yield with an er of 93.5:6.5.4c This er value could be improved to
at least 98:2 (and 88% isolated yield) by selective crystallization
of the racemate of 4b from hexanes and concentration of the reꢀ
sultant mother liquor. Following otherwise identical reaction conꢀ
ditions (2.5 mol % Pd2(dba)3, 5 mol % (S,S)ꢀfꢀbinaphane, 0.1 M in
DMSO, 25 °C), imino esters 15b and 16b converted to the correꢀ
sponding homoallylic imines 17b and 19b in equally high isolated
yield (98% and 93%, respectively). The resultant er values, howꢀ
ever, were lower than that observed for benzophenone imine 4b.
The di(4ꢀmethoxyphenyl)ketimine 17b was obtained with an avꢀ
erage er value of 90.6:9.4, whereas the more sterically congested
di(2ꢀmethoxyphenyl)ketimine 19b was isolated with an even lowꢀ
er average er (89.1:10.9) in comparison to the parent compound
benzophenone imine 4b. This modest reduction in er is not surꢀ
prising. As outlined above (Table 1 & Figure 2), addition of elecꢀ
tronꢀdonating groups into the πꢀnetwork of the 2ꢀazaallyl anion
5
PMP (15h)
OMP (16h)
Ph (2i)
6
7
F
ꢀ0.03
ꢀ0.17
ꢀ0.26
8
PMP (15i)
OMP (16i)
Ph (2l)
9
10
11
12
13
14
15
Me
MeO
PMP (15l)
OMP (16l)
Ph (2n)
5.7:1.0
>20:1e
2.2:1
PMP (15n)
OMP (16n)
4.1:1
>20:1f
aHammett resonance coefficient for para substituent (ref 6). bPMP
= 4ꢀOMeꢀC6H4, OMP = 2ꢀOMeꢀC6H4. cAverage isolated comꢀ
d
1
bined yield over three runs. Determined by H NMR analysis of
the crude reaction mixture; average of three runs and is written in
4:5 (Ar = Ph), 17:18 (Ar = (4ꢀMeO)Ph), or 19:20 (Ar = (2ꢀ
e
f
MeO)Ph). From ref 4b. Regioisomeric ratio (rr) determined by
1H NMR analysis after reduction of the imine to the correspondꢀ
ing amine 21 with NaBH3CN (Scheme 4).
It should be noted that, due to hindered rotation about the arylꢀ
C(imine) bonds in the di(2ꢀmethoxyphenyl)ketimines 19 and the
ACS Paragon Plus Environment

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Page 6 of 19
intermediate generally results in decreased enantioselectivity.
Table 3. PdꢀCatalyzed Asymmetric DcA of Allyl 2,2ꢀDi(2ꢀ
methoxyphenyl)glycinate Benzaldimines.
1
2
3
4
Accordingly, while introduction of the electronꢀdonating methoxy
groups into the 2,2ꢀdiarylglycine linchpin framework has a posiꢀ
tive impact on regioselectivity, it also has a slightly negative imꢀ
pact on enantioselectivity.
5
6
7
8
Scheme 5. Effect of Diarylaglycine Linchpin on Enantioseꢀ
lectivity for the PdꢀCatalyzed Asymmetric DcA of pꢀ
Cyanobenzaldimines
entry
1
R
Product
Yieldb
erc
σ ꢀ a
p
9
CN
1.00
0.25
0.00
ꢀ0.03
ꢀ0.17
ꢀ0.26
93%
(61%)d
89.1:10.9
(98.7:1.3)e
19b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
4
5
6
Br
85%
(64%)d
86.8:13.2
(90.4:9.6)e
19f
19h
19i
19l
19n
H
87%
(38%)d
83.2:17.1
(88.3:11.7)e
F
84%
(44%)d
77.5:22.5
(86.3:13.7)e
We next explored the generality of the relationship between
the nature of the 2,2ꢀdiarylglycine linchpin and the resultant er
value for the asymmetric DcA transformation. Unfortunately, all
chiral di(4ꢀmethoxyphenyl)ketimines 17, with the exception of
benzonitrile 17b, proved to be prohibitively challenging to sepaꢀ
rate into individual enantiomers by chiralꢀphase analytical HPLC.
This phenomenon, in combination with the superior regioselectivꢀ
ities observed for the Pdꢀcatalyzed DcA of allyl 2,2ꢀdi(2ꢀmethꢀ
oxyphenyl)glycinate imines 16, inspired us to focus exclusively
on the asymmetric synthesis of di(2ꢀmethoxyphenyl)ketimines 19,
as summarized in Table 3. In most cases, the homoallylic imines
19 were obtained with lower er values (5ꢀ11% decrease) in comꢀ
parison to the corresponding benzophenone imines 4 (compare
with Table 1, entries 2, 6, 8, 9, 12, & 14). One remarkable excepꢀ
tion is with pꢀmethoxybenzaldimine 16n, which converted excluꢀ
sively to 19n in 71% isolated yield and an average er of 87.6:12.4
(Table 3, entry 6). The analogous 2,2ꢀdiphenylglycinate 2n transꢀ
formed under otherwise identical reaction conditions to a 1.7:1
mixture of chiral benzophenone imine 4n (er 82.7:17.3) and alꢀ
dimine 5n in 68% combined yield (Table 1, entry 14). The enanꢀ
tiopurity of all imines 19 could be improved substantially by seꢀ
lective removal of the racemates by crystallization from hexanes.
The configuration of pꢀbromoꢀsubstituted 19f was confirmed to
be (S) by hydrolysis of the imine and comparison of the optical
rotation value of the resultant amine 22f with literature reports
(Scheme 6);15 the configurations of the other products 19 were
assumed to also be (S) by analogy.
Me
MeO
81%
(43%)d
80.9:19.1
(84.5:15.5)e
71%
(66%)d
87.6:12.4
(92.5:7.5)e
aHammett resonance coefficient for para substituent (ref. 6). bAvꢀ
erage isolated yield over three runs. Determined by chiralꢀphase
HPLC analysis; average of three runs. dIsolated yield after recrysꢀ
tallization from hexane. Er of concentrated mother liquor after
recrystallizing out the racemate from hexanes.
c
e
Scheme 6. Hydrolysis of Imine (S)ꢀ19f
Figure 3. Other substrates and products
and 16p (Figure 3). Subjection of oꢀbromoꢀsubstituted aldimine
15o to our racemic reaction conditions (10 mol % Pd(dba)2, 10
mol % dppf, MeCN, 25 °C)4b afforded racemic 17o exclusively
(without any of the potential regioisomer 18o) in moderate isolatꢀ
ed yield (50%). When 2ꢀfuranyl imine 15p was subjected to
theracemic reaction conditions, however, 17p was generated as a
6.8:1 mixture with the aldimine regioisomer 18p in 68% comꢀ
As a final exploration of the generality of using methoxylated
2,2ꢀdiarylglycines as amino acid linchpins in the synthesis of
homoallylic amines via Pdꢀcatalyzed DcA reactions, we conꢀ
densed 2ꢀbromopiperonal and 2ꢀfuranaldehyde with allyl 2,2ꢀdi(4ꢀ
methoxyphenyl)glycine (13) and allyl 2,2ꢀdi(2ꢀmethoxyphenyl)ꢀ
glycine (14) to afford the corresponding imines 15o, 15p, 16o,
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The Journal of Organic Chemistry
bined yield. Exposure of 2,2ꢀdi(2ꢀmethoxyphenyl)glycinate 16o
homoallylic imines 4f, 4h, 4i, and 4l matched reported proceꢀ
dures.4c Melting points are uncorrected. Infrared spectra were
obtained using a thin film deposited on freshly made KBr disks;
only strong and functional groupꢀspecific peaks are reported (in
cmꢀ1). Optical rotation was determined in a 10 cm length polarꢀ
imeter cell; all [α]D values are given in 10ꢀ1 degcm2gꢀ1 at the indiꢀ
cated temperature; concentrations listed in mg/mL. All NMR
spectra were taken on a 400 MHz spectrometer at 300 K, as indiꢀ
1
2
3
4
5
6
7
8
to our asymmetric reaction conditions (2.5 mol % Pd2(dba)3, 5
mol % (S,S)ꢀfꢀbinaphane, DMSO, 25 °C)4c generated homoallylic
imine (S)ꢀ19o in 83% isolated yield and moderate er (87.6:12.4).
The corresponding 2ꢀfuranyl imine 16p afforded (S)ꢀ19p excluꢀ
sively in identical isolated yield (83%) but reduced enantiopurity
(er 71.5:28.5). These results further highlight that 2,2ꢀdi(2ꢀ
methoxyphenyl)glycine is a superior amino acid linchpin in reꢀ
gards to regioselectivity, but further optimization of the reaction
conditions (most likely in the nature of the chiral ligand) is still
required to afford a truly general method for the Pdꢀcatalyzed
asymmetric DcA of allyl 2,2ꢀdiarylglycinate imines.
cated. Chemical shifts are reported in
δ (ppm) units using residual
solvent peak as a standard.17 Initial regioisomeric ratios (rr) deꢀ
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
termined from H NMR analysis of the crude reaction mixtures.
High resolution mass spectra obtained using an LCMSꢀITꢀTOF.
In summary, we have explored the electronic and steric facꢀ
tors (within the imine component and the amino acid linchpin)
governing the regioselectivity and enantioselectivity of the Pdꢀ
catalyzed asymmetric DcA of allyl 2,2ꢀdiarylglycinate imines
using (S,S)ꢀfꢀbinaphane as a chiral ligand. These expanded studies
strongly reaffirm the positive linear Hammett correlations beꢀ
tween the electronic nature of the paraꢀsubstituted benzaldimine
component in the substrate and the regioselectivity and enantioseꢀ
lectivity of the transformation. The results indicate that a change
in reaction mechanism does not occur as the imines become more
electronꢀrich. More importantly, our efforts identified 2,2ꢀdi(2ꢀ
methoxyphenyl)glycine as a superior amino acid linchpin for the
transformations with regards to isolated yield and regioselectivity.
The oꢀmethoxy groups provide both an electronic push and a
steric influence that lead to exclusive allylation of the less substiꢀ
tuted carbon of the 2ꢀazaallyl anion intermediate, regardless of
other factors. This combination of steric and electronic driving
forces can be applied immediately as a general strategy for the
highly regioselective functionalization of 2ꢀazaallyl anion imine
umpolungs;1,2 further studies toward this end are currently in proꢀ
gress.
General Procedures for the Condensation of Allyl 2,2ꢀ
Diarylglycinate Imines 2, 15, and 16.4bꢀc,7 To a flameꢀdried
round bottom flask equipped with a magnetic stir bar and a Deanꢀ
Starke trap was added the appropriate allyl 2,2ꢀdiarylglycinate
(1.00 equiv) and the requisite aldehyde (0.95ꢀ0.98 equiv) in toluꢀ
ene (0.2 M). The reaction mixture was heated to reflux
(130 ꢀ 150 °C) and stirred at that temperature until completion, as
determined by TLC. Concentration in vacuo and purification by
flash chromatography with the indicated eluent afforded the corꢀ
responding imines 2, 15, or 16, respectively.
General Procedures for the Racemic PdꢀCatalyzed DcA of
Allyl 2,2ꢀDiphenylglycinate Imines 2, 15, and 16 [Procedure
A].4b To a flameꢀdried screwꢀcap (with septum) vial equipped
with a magnetic spin vane was added imine 2, 15, or 16 (1 equiv),
dppf (10 mol %), and Pd(dba)2 (10 mol %). The vial was deoxyꢀ
genated with three vacuum/Arꢀfill cycles and the solids were then
dissolved in dry MeCN (0.1 M). The resulting reaction mixture
was stirred at 25 °C for 24 h and then passed through a short plug
of silica gel using the indicated eluent to remove catalyst and
1
ligand. The regioisomeric ratio (rr) was determined by H NMR
analysis of the resulting concentrated crude reaction mixture. For
characterization purposes of new compounds, an analytical samꢀ
ple of homoallylic imines 4 or 17 were obtained by several purifiꢀ
cations via flash chromatography. Due to hindered rotation about
the 2ꢀMeOPhꢀC(imine) bond in imines 19, peak resolution in
EXPERIMENTAL SECTION
General Methods. All nonꢀaqueous reactions were performed
in ovenꢀdried flasks or vials under an atmosphere of dried and
deoxygenated argon with dry solvents and magnetic stirring, unꢀ
less stated otherwise. All solvents were dried by storing over actiꢀ
vate 3Å molecular sieves for at least 48 h and sparged with dried
and deoxygenated argon gas for at least 30 min.16 OꢀAllyl 2,2ꢀ
diphenylglycinate was synthesized according to reported proceꢀ
dures.4bꢀc,7 Allyl esters 13 and 14 were synthesized following a
modification of procedures reported by Bertus and coꢀworkers.15
Imino esters 2f, 2h, 2i, 2l, and 2n were generated following reꢀ
ported procedures.4b,c Benzaldehyde was filtered through basic
alumina and distilled under reduced pressure immediately prior to
use. Allyl bromide was filtered through a pipette of basic alumina
immediately prior to use. All other reagents were purchased from
commercial sources and used as received. All chromatography
was performed with indicated solvents and 60Å 230ꢀ400 mesh
silica gel. Unless otherwise noted, all yields in the main text refer
to average isolated yields after column chromatography of at least
two separate runs at different scales. Accordingly, these yields
may differ from the specific examples provided below. Enantioꢀ
meric ratios (er) were determined from samples separated on a
Chiral Technologies Diacel ODꢀH chiral column (PDA/UV detecꢀ
tion) and compared to a racemic standard; elution protocol for
1
most H NMR were not suitable for determining rr values. Acꢀ
cordingly, imines 19 were reduced to the corresponding amines
21 prior to analysis (see below).
General Procedures for the Asymmetric PdꢀCatalyzed
DcA of Allyl 2,2ꢀDiphenylglycinate Imines 2, 15, and 16 [Proꢀ
cedure B].4c To a flameꢀdried screwꢀcap (with septum) vial
equipped with a magnetic spin vane was added imine 2, 15, or 16
(1 equiv), Pd2(dba)3 (2.5 mol %), and (S,S)ꢀfꢀbinaphane (5
mol %).5 The vial was deoxygenated with three vacuum/Arꢀfill
cycles and the solids were then dissolved in dry DMSO (0.1 M).
The resulting reaction mixture was stirred at 25 °C for 24 h and
then passed through a short plug of silica gel using the indicated
eluent to remove catalyst and ligand. The regioisomeric ratio (rr)
was determined by 1H NMR analysis of the resulting concentrated
crude reaction mixture. The resulting enantiomeric (and frequentꢀ
ly regioisomeric) mixtures for 4, 17, and 19 were then analyzed
by chiral HPLC and compared to racemic samples using the indiꢀ
cated eluents and flow rates to determine the corresponding er
values.
Allyl (E)ꢀ2ꢀ((4ꢀ(trifluoromethyl)benzylidene)amino)ꢀ2,2ꢀdiꢀ
phenylꢀ2ꢀacetate (2d). Imine 2d was synthesized by condensation
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
+
between allyl 2,2ꢀdiphenylglycinate and 4ꢀ(trifluoromethyl)ꢀ
Found 412.2271; m/z: [M+Na]+ Calcd for C28H29NNaO2
1
2
3
4
5
6
7
8
benzaldehyde and was purified by flash chromatography (1%
Et3N in 2% EtOAc/hexanes) to afford a yellow solid (0.30 g, 0.71
mmol, 78%): Rf = 0.19 (1% Et3N in 2% EtOAc/hexanes); mp
74.4 ꢀ 75.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.3 Hz,
3H), 7.67 (d, J = 8.2 Hz, 2H), 7.45 – 7.29 (m, 10H), 5.85 (ddt, J =
17.1, 10.7, 5.4 Hz, 1H), 5.16 (dtt, J = 10.5, 2.6, 1.4 Hz, 2H), 4.70
(dt, J = 5.4, 1.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 171.6,
434.2091; Found 434.2033
Allyl (E)ꢀ2ꢀ((4ꢀ(tertꢀbutyl)benzylidene)amino)ꢀ2,2ꢀdiphenylꢀ
acetate (2k). Imine 2k was synthesized by condensation between
allyl 2,2ꢀdiphenylglycinate and 4ꢀ(tertꢀbutyl)benzaldehyde and
was purified by flash chromatography (1% Et3N in 2%
EtOAc/hexanes) to afford a yellow solid (0.49 g, 1.19 mmol,
86%): Rf
= 0.21 (1% Et3N in 2% EtOAc/hexanes); mp
1
162.1, 142.2, 131.6, 129.4, 129.1, 128.2, 127.9, 125.7 (q, JCꢀF
=
157.3 ꢀ 158.7 °C; H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H),
7.81 – 7.73 (m, 2H), 7.49 – 7.27 (m, 12H), 5.86 (ddt, J = 17.2,
10.7, 5.4 Hz, 1H), 5.17 (tq, J = 10.4, 1.5 Hz, 2H), 4.70 (dt, J = 5.4,
1.5 Hz, 2H), 1.34 (d, J = 2.9 Hz, 9H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 163.2, 154.7, 142.7, 134.0, 131.8, 129.4, 128.7,
9
3.9 Hz), 118.5, 79.8, 66.4; IR (thin film) ν 3099, 2901, 2346,
1747, 1647, 1318; HRMS (ESI+) m/z: [M+H]+ Calcd for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
C25H21F3NO2 424.1519; Found 424.1547; m/z: [M+Na]+ Calcd
for C25H20F3NNaO2+ 446.1338; Found 446.1319.
Allyl (E)ꢀ2ꢀ((4ꢀiodobenzylidene)amino)ꢀ2,2ꢀdiphenylacetate
(2e). Imine 2e was synthesized by condensation between allyl 2,2ꢀ
diphenylglycinate and 4ꢀiodobenzaldehyde and was purified by
flash chromatography (1% Et3N in 2% EtOAc/hexanes) to afford
a white solid (0.59 g, 1.23 mmol, 92%): Rf = 0.31 (1% Et3N in
128.1, 127.6, 125.7, 118.4, 79.5, 66.3, 35.1, 31.4; IR (thin film)
3475, 3046, 2957, 2366, 1734, 1632 1201; HRMS (ESI+) m/z:
[M+H]+ Calcd for C28H30NO2 412.2271; Found 412.2274; m/z:
ν
+
[M+Na]+ Calcd for C28H29NNaO2+ 434.2091; Found 434.2048.
Allyl (E)ꢀ2ꢀ((4ꢀethylbenzylidene)amino)ꢀ2,2ꢀdiphenylacetate
(2m). Imine 2m was synthesized by condensation between allyl
2,2ꢀdiphenylglycinate and 4ꢀethylbenzaldehyde and was purified
by flash chromatography (1% Et3N in 2% EtOAc/hexanes) to
afford a yellow oil (0.42 g, 1.10 mmol, 75%): Rf = 0.28 (1% Et3N
in 2% EtOAc/hexanes);1H NMR (400 MHz, CDCl3) δ 7.89 (s,
1H), 7.75 (d, J = 8.0 Hz, 2H), 7.47 – 7.17 (m, 13H), 5.95 – 5.77
(m, 1H), 5.25 – 5.09 (m, 2H), 4.70 (dd, J = 4.0, 1.4 Hz, 2H), 2.69
(q, J = 7.6 Hz, 2H), 1.25 (dd, J = 7.9, 7.3 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 172.1, 163.3, 147.9, 142.7, 134.3, 131.7, 129.4,
128.9, 128.2, 128.1, 127.6, 118.3, 79.5, 66.3, 29.1, 15.6; IR (thin
1
2% EtOAc/hexanes); mp 71.2 − 73.4 °C; H NMR (400 MHz,
CDCl3)
δ 7.81 (s, 1H), 7.79 – 7.74 (m, 2H), 7.57 – 7.52 (m, 2H),
7.40 – 7.28 (m, 10H), 5.85 (ddt, J = 17.1, 10.7, 5.4 Hz, 1H), 5.17
(dq, J = 9.4, 1.4 Hz, 1H), 5.14 (dq, J = 2.7, 1.4 Hz, 1H), 4.69 (dt,
J = 5.4, 1.5 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ
171.7, 162.5,
142.3, 137.9, 135.9, 131.6, 130.3, 129.4, 128.2, 127.8, 118.4,
98.1, 79.6, 66.4; IR (thin film)
ν 3443, 1733, 1644, 1218, 1196;
+
HRMS (ESI+) m/z: [M+H]+ Calcd for C24H21INO2 482.0611;
Found 482.0616; m/z: [M+Na]+ Calcd for C24H20INNaO2
+
504.0431; Found 504.0389 .
film)
ν 2369, 1729, 1643, 1448, 1208; HRMS (ESI+) m/z:
Allyl (E)ꢀ2ꢀ((4ꢀchlorobenzylidene)amino)ꢀ2,2ꢀdiphenylacetate
(2g). Imine 2g was synthesized by condensation between allyl
2,2ꢀdiphenylglycinate and 4ꢀchlorobenzaldehyde and purified by
flash chromatography (1% Et3N in 3% EtOAc/hexanes) to afford
a yellow oil (0.42 g, 1.08 mmol, 87%): Rf = 0.45 (1% Et3N in 3%
[M+H]+ Calcd for C26H26NO2 384.1958; Found 384.1956; m/z:
+
[M+Na]+ Calcd for C26H25NNaO2 406.1778; Found 406.1727.
+
Nꢀ(Diphenylmethylene)ꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)butꢀ3ꢀ
enꢀ1ꢀamine (4d). Enantioenriched (S)ꢀ4d was synthesized from 2d
(95.3 mg, 0.25 mmol) following the general procedures described
above [Procedure B]. Passed through a small plug of silica gel
(eluent: 1% Et3N in 1% EtOAc/hexanes) to afford imino ester 4d
as a yellow oil (67.6 mg, 0.18 mmol, 79%; average er 88.9:11.1).
An analytical sample of pure 4c was obtained by repetitive flash
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.85 (s, 1H),
7.79 – 7.75 (m, 2H), 7.42 – 7.29 (m, 12H), 5.85 (ddt, J = 17.2,
10.7, 5.4 Hz, 1H), 5.18 (dq, J = 9.5, 1.4 Hz, 1H), 5.14 (dq, J =
2.7, 1.4 Hz, 1H), 4.70 (dt, J = 5.4, 1.5 Hz, 2H); 13C NMR (101
MHz, CDCl3)
δ 171.8, 162.1, 142.3, 137.2, 135.0, 131.6, 130.0,
chromatography: Rf = 0.31 (1% Et3N in 1% EtOAc/hexanes);
129.4, 129.0, 128.2, 127.8, 118.4, 79.6, 66.4; IR (thin film)
ν
[α]16.8 ꢀ33.1 (c 9.1 x 10ꢀ3, EtOAc); H NMR (400 MHz, CDCl3)
1
3441, 2923, 1734, 1644, 1217, 1198; HRMS (ESI+) m/z: [M+H]+
D
+
Calcd for C24H21ClNNaO2 390.1255; Found 390.1265; m/z:
δ 7.77 – 7.64 (m, 2H), 7.64 – 7.53 (m, 2H), 7.52 – 7.31 (m, 8H),
7.13 – 7.02 (m, 2H), 5.67 (ddt, J = 17.6, 10.4, 7.1 Hz, 1H), 5.07 –
4.95 (m, 2H), 4.52 (dd, J = 7.6, 5.6 Hz, 1H), 2.71 (dt, J = 14.0, 7.5
Hz, 1H), 2.60 (ddd, J = 13.7, 6.8, 5.7 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 167.8, 148.7, 140.0, 137.1, 135.3, 130.4, 128.9,
128.7, 128.7, 128.3, 128.0, 127.7, 125.4 (q, JCꢀF = 3.8 Hz), 117.5,
[M+Na]+ Calcd for C24H20ClNNaO2+ 412.1041; Found 412.1041.
Allyl (E)ꢀ2ꢀ((4ꢀisobutylbenzylidene)amino)ꢀ2,2ꢀdiphenylaceꢀ
tate (2j). Imine 2j was synthesized by condensation between allyl
2,2ꢀdiphenylglycinate and 4ꢀisobutylbenzaldehyde and was puriꢀ
fied by flash chromatography (1% Et3N in 2% EtOAc/hexanes) to
66.4, 44.1; IR (thin film)
ν 3086, 2915, 2330,1618, 1447,1347;
afford a yellow oil (0.51 g, 1.24 mmol, 98%): Rf = 0.44 (1% Et3N
HRMS (ESI+) m/z: [M+H]+ Calcd for C24H21F3N+ 380.1621;
Found 380.1609; Chrial HPLC conditions: eluent: 100% hexanes,
flow rate: 0.5 mL/min, average (S)ꢀ4d retention time = 12.18 min,
average (R)ꢀ4d retention time = 13.82 min.
1
in 2% EtOAc/hexanes); H NMR (400 MHz, CDCl3)
δ 7.89 (s,
1H), 7.74 (d, J = 8.1 Hz, 2H), 7.41 (ddd, J = 5.7, 3.9, 2.2 Hz, 4H),
7.39 – 7.27 (m, 6H), 7.20 (d, J = 8.1 Hz, 2H), 5.86 (ddt, J = 17.2,
10.7, 5.4 Hz, 1H), 5.17 (dq, J = 26.2, 1.5 Hz, 1H), 5.16 (dt, J =
3.0, 1.4 Hz, 1H), 4.71 (dt, J = 5.4, 1.5 Hz, 2H), 2.51 (d, J = 7.2
Hz, 2H), 1.88 (dp, J = 13.6, 6.8 Hz, 1H), 0.91 (d, J = 6.6 Hz, 6H);
Nꢀ(1ꢀ(4ꢀIodophenyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀdiphenylmethanimine
(4e). Enantioenriched (S)ꢀ4e was synthesized from 2e (104.3 mg,
0.22 mmol) following the general procedures described above
[Procedure B]. Passed through a small plug of silica gel (eluent:
1% Et3N in 1% EtOAc/hexanes) to afford a yellow oil (average
15.5:1 mixture with aldimine regioisomer 5e, 74.5 mg, 0.17
mmol, 77% combined yield; average er 87.1:12.9). An analytical
13C NMR (101 MHz, CDCl3)
131.7, 129.5, 129.4, 128.7, 128.1, 127.6, 118.4, 79.5, 66.3, 45.5,
30.4, 22.5; IR (thin film) 3024, 2955, 1736, 1642, 1218, 1198;
HRMS (ESI+) m/z: [M+H]+ Calcd for C28H30NO2 412.2271;
δ 172.1, 163.4, 145.4, 142.7, 134.2,
ν
+
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Page 9 of 19
The Journal of Organic Chemistry
sample of pure 4e was obtained by repetitive flash chromatogꢀ
mL/min, average (S)ꢀ4j retention time = 4.33 min, average (R)ꢀ4j
retention time = 4.71 min.
raphy: Rf = 0.31 (1% Et3N in 1% EtOAc/hexanes); [α]16.0 ꢀ29.3
1
2
3
4
5
6
7
8
D
1
(c 0.067, EtOAc); H NMR (400 MHz, CDCl3)
δ 7.71 – 7.57 (m,
Nꢀ(1ꢀ(4ꢀTertꢀbutylphenyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀdiphenylmethanꢀ
imine (4k). Enantioenriched (S)ꢀ4k was synthesized from 2k
(74.5 mg, 0.20 mmol) following the general procedures described
above [Procedure B]. Passed through a small plug of silica gel
(eluent:1% Et3N in 1% EtOAc/hexanes) to afford a yellow oil
(average 3.3:1 mixture with aldimine regioisomer 5k, 75.0 mg,
0.20 mmol, 88% combined yield; average er 79.7:20.3). An anaꢀ
lytical sample of pure 4k was obtained by repetitive flash chromaꢀ
4H), 7.47 – 7.39 (m, 3H), 7.39 – 7.30 (m, 3H), 7.11 – 7.00 (m,
4H), 5.63 (ddt, J = 17.3, 10.3, 7.1 Hz, 1H), 5.03 – 4.91 (m, 2H),
4.38 (dd, J = 7.6, 5.6 Hz, 1H), 2.64 (dt, J = 14.9, 7.5 Hz, 1H),
2.58 – 2.48 (m, 1H); 13C NMR (101 MHz, CDCl3)
139.8, 137.4, 137.0, 135.3, 130.0, 129.2, 128.6, 128.4, 128.0,
δ 167.2, 144.2,
127.8, 117.0, 92.0, 66.0, 43.8; IR (thin film)
ν 3059 2926, 1624,
1482, 1446; HRMS (ESI+) m/z: [M+H]+ Calcd for C23H21IN+
438.0713; Found 438.0711; m/z: [M+Na]+ Calcd for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tography: Rf
=
0.25 (1% Et3N in 1% EtOAc/hexanes);
+
1
[α]16.8 ꢀ13.4 (c 2.8 x 10ꢀ3, EtOAc); H NMR (400 MHz, CDCl3)
C24H20INNaO2 504.0431; Found 504.0389; Chiral HPLC condiꢀ
D
tions: eluent: 0.2:99.8 2ꢀPrOH/hexane, flow rate: 1 mL/min, averꢀ
age (S)ꢀ4e retention time = 5.49 min, average (R)ꢀ4e retention
time = 6.02 min.
δ 7.69 – 7.63 (m, 2H), 7.43 (ddd, J = 10.1, 4.6, 2.0 Hz, 3H), 7.37
– 7.28 (m, 5H), 7.27 – 7.22 (m, 2H), 7.12 – 7.06 (m, 2H), 5.64
(ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 5.04 – 4.91 (m, 2H), 4.41 (dd, J
= 8.1, 5.3 Hz, 1H), 2.69 (dt, J = 15.3, 7.8 Hz, 1H), 2.57 (ddd, J =
13.6, 6.6, 5.5 Hz, 1H), 1.31 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 166.3, 149.6, 141.5, 137.3, 136.1, 129.9, 128.7, 128.7, 128.4,
128.4, 128.2, 128.1, 126.9, 125.3, 116.7, 66.3, 43.9, 34.6, 31.7; IR
Nꢀ(1ꢀ(4ꢀChlorophenyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀdiphenylmethanimꢀ
ine (4g). Enantioenriched (S)ꢀ4g was synthesized from 2g (86.3
mg, 0.22 mmol) following the general procedures described
above [Procedure B]. Passed through a small plug of silica gel
(eluent: 1% Et3N in 1% EtOAc/hexanes) to afford a yellow oil
(average 10.5 : 1 mixture with aldimine regioisomer 5g, 70.0 mg,
0.20 mmol, 91% combined yield, average er 86.3:13.7). An anaꢀ
lytical sample of pure 4g was obtained by repetitive flash chromaꢀ
(thin film)
ν 3072, 2986, 2374, 1605, 1463,1277; HRMS (ESI+)
m/z: [M+H]+ Calcd for C27H30N+ 368.2373; Found 368.2358;
Chiral HPLC conditions: eluent: 0.2:99.8 2ꢀPrOH/hexane, flow
rate: 1 mL/min, average (S)ꢀ4k retention time = 4.33 min, average
(R)ꢀ4k retention time = 4.61 min.
tography: Rf = 0.58 (1% Et3N in 1% EtOAc/hexanes); [α]16.8
D
1
─21.7 (c 3.4 x 10ꢀ3, EtOAc); H NMR (400 MHz, CDCl3)
δ
7.70
Nꢀ(1ꢀ(4ꢀTolyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀdiphenylmethanimine (4l).
Racemic 4l synthesized from 2l following the general procedures
mentioned above [Procedure B]. Passed through a small plug of
silica gel to afford a mixture of ketimine 4l and aldimine 5l (averꢀ
age 2.9:1 mixture with aldimine regioisomer 5l, 81% combined
yield). Characterization data matched reported values for enantiꢀ
omerically enriched 4l.4c
– 7.65 (m, 2H), 7.44 (tt, J = 3.9, 1.8 Hz, 3H), 7.41 – 7.31 (m, 3H),
7.30 – 7.23 (m, 4H), 7.05 (ddd, J = 7.2, 5.0, 3.4 Hz, 2H), 5.64
(ddt, J = 17.3, 10.2, 7.1 Hz, 1H), 5.02 – 4.97 (m, 1H), 4.97 – 4.94
(m, 1H), 4.42 (dd, J = 7.7, 5.6 Hz, 1H), 2.71 – 2.61 (m, 1H), 2.60
s– 2.51 (m, 1H); 13C NMR (101 MHz, CDCl3)
140.0, 137.1, 135.4, 132.4, 130.2, 130.2, 128.7, 128.6, 128.5,
128.5, 128.2, 128.1, 127.9, 117.2, 65.9, 44.0; IR (thin film)
δ 167.2, 143.1,
ν
Nꢀ(Diphenylmethylene)ꢀ1ꢀ(4ꢀethylphenyl)butꢀ3ꢀenꢀ1ꢀamine
(4m). Enantioenriched (S)ꢀ4m was synthesized from 2m (63.3 mg,
0.17 mmol) following the general procedures described above
[Procedure B]. Passed through a small plug of silica gel (eluent: 1%
Et3N in 1% EtOAc/hexanes) to afford a yellow oil (average 3.3:1
mixture with aldimine regioisomer 5m, 48.8 mg, .0.14 mmol, 87%
combined yield; average er 82.7:17.3). An analytical sample of
pure 4m was obtained by repetitive flash chromatography: Rf =
0.22 (1% Et3N in 1% EtOAc/hexanes); [α]16.8D ꢀ11.8 (c 3.3 x 10ꢀ3,
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m, 2H), 7.43
(ddd, J = 10.1, 4.6, 2.0 Hz, 3H), 7.37 – 7.28 (m, 5H), 7.27 – 7.22
(m, 2H), 7.12 – 7.06 (m, 2H), 5.64 (ddt, J = 17.2, 10.1, 7.1 Hz,
1H), 5.04 – 4.91 (m, 2H), 4.41 (dd, J = 8.1, 5.3 Hz, 1H), 2.69 (dt,
J = 15.3, 7.8 Hz, 1H), 2.57 (ddd, J = 13.6, 6.6, 5.5 Hz, 1H), 1.31
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 166.3, 149.6, 141.5, 137.3,
136.1, 129.9, 128.7, 128.7, 128.4, 128.4, 128.2, 128.1, 126.9,
3436, 3060, 2928, 1624, 1490; HRMS (ESI+) m/z: [M+H]+ Calcd
for C23H21ClN+ 346.1357; Found 346.1340; Chiral HPLC condiꢀ
tions: eluent: 0.2:99.8 2ꢀPrOH/hexane, flow rate: 1 mL/min, averꢀ
age (S)ꢀ4g retention time = 5.21 min, average (R)ꢀ4g retention
time = 5.78 min.
Nꢀ(1ꢀ(4ꢀIsobutylphenyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀdiphenylmethanimꢀ
ine (4j). Enantioenriched (S)ꢀ4j was synthesized from 2j (87.6 mg,
0.21 mmol) following the general procedures described above
[Procedure B]. Passed through a small plug of silica gel (eluent:1%
Et3N in 1% EtOAc/hexanes) to afford a yellow oil (average 3.3:1
mixture with aldimine regioisomer 5j, 75.0 mg, .0.20 mmol, >98%
combined yield; average er 83.9:16.1). An analytical sample of
pure 4j was obtained by repetitive flash chromatography: Rf =
0.65 (1% Et3N in 1% EtOAc/hexanes); [α]16.7 ꢀ9.1 (c 6.1 x 10ꢀ3,
D
EtOAc); 1H NMR (400 MHz, CDCl3)
δ 7.69 – 7.63 (m, 2H), 7.43
125.3, 116.7, 66.3, 43.9, 34.6, 31.6; IR (thin film)
ν 3044, 2901,
– 7.38 (m, 3H), 7.35 – 7.27 (m, 3H), 7.21 (d, J = 7.9 Hz, 2H),
7.10 – 7.03 (m, 4H), 5.64 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 4.97
(ddd, J = 27.8, 2.2, 1.2 Hz, 1H), 4.95 (t, J = 2.5 Hz, 1H), 4.40 (dd,
J = 8.0, 5.4 Hz, 1H), 2.68 (dt, J = 14.1, 7.6 Hz, 1H), 2.61 – 2.52
(m, 1H), 2.43 (d, J = 7.2 Hz, 2H), 1.84 (dp, J = 13.6, 6.8 Hz, 1H),
2345, 1647, 1463,1292; HRMS (ESI+) m/z: [M+H]+ Calcd for
C25H26N+ 340.2060; Found 340.2037; Chiral HPLC conditions:
eluent: 0.2:99.8 2ꢀPrOH/hexane, flow rate: 1 mL/min, average
(S)ꢀ4m retention time = 4.48min, average (R)ꢀ4m retention time =
5.01 min.
0.89 (d, J = 6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 166.6,
Nꢀ(1ꢀ(4ꢀMethoxyphenyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀdiphenylmethanꢀ
imine (4n) Enantioenriched (S)ꢀ4n was synthesized from 2n (91.1
mg, 0.20 mmol) following the general procedures described
above [Procedure B]. Passed through a small plug of silica gel
(eluent:1% Et3N in 1% EtOAc/hexanes) to afford a yellow oil
141.8, 140.3, 140.2, 137.3, 136.1, 129.9, 129.1, 128.7, 128.4,
128.3, 128.1, 126.9, 116.7, 66.4, 45.3, 44.1, 30.4, 22.6, 22.6; IR
(thin film)
ν 3058, 2955, 2924, 1622, 1442; HRMS (ESI+) m/z:
[M+H]+Calcd for C27H30N+ 368.2373; Found 368.2357; Chiral
HPLC conditions: eluent: 0.2:99.8 2ꢀPrOH/hexane, flow rate: 1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
(average 1.7 : 1 mixture with aldimine regioisomer 5n, 55.8 mg,
016 mmol, 69% combined yield; average er 82.7:17.3). An anaꢀ
lytical sample of pure 4n was obtained by repetitive flash chromaꢀ
0.46 (20% EtOAc/hexanes); H NMR (400 MHz, CDCl3)
(s, 1H), 7.33 – 7.20 (m, 4H), 6.96 – 6.87 (m, 4H), 6.07 (s, 1H),
3.82 (s, 6H), 1.51 – 1.04 (m, 9H); 13C NMR (101 MHz, CDCl3)
193.0, 159.4, 154.0, 132.3, 129.8, 128.9, 113.9, 113.5, 80.0, 70.7,
δ 9.52
1
2
3
4
δ
1
tography: Rf = 0.21 (1% Et3N in 1% EtOAc/hexanes); H NMR
and 13C NMR spectra matched literature reports for the racemic
55.3, 53.5, 28.2; IR (thin film)
HRMS (ESI+) m/z: [M+Na]+ Calcd for C21H25NNaO5 394.1625;
ν 3404, 2719, 1717, 1254, 1179;
material:4b [α]16.3 ꢀ10.1 (c 9.02 x 10ꢀ3, EtOAc); Chiral HPLC
+
5
D
6
7
8
conditions: eluent: 0.2:99.8 2ꢀPrOH/hexane, flow rate: 1 mL/min,
average (S)ꢀ4n retention time = 6.70 min, average (R)ꢀ4n retenꢀ
tion time = 8.22 min.
Found 394.1610.
To a solution of the resulting aldehyde (5.05 g, 13.6 mmol) in 1:1
MeCN/H2O (140 mL, 0.2 M) were added successively NaH2PO4
(3.26 g, 27.2 mmol, 2.0 equiv), H2O2 (30 w/v %, 0.95 g, 2 equiv),
and NaClO2 (1.94 g, 21.4 mmol, 1.5 equiv). The resulting reacꢀ
tion mixture was stirred at 25 °C until complete as determined by
TLC. Solid Na2SO3 then was added to the mixture, which was
then stirred at rt for 3 h. The resulting quenched reaction was
diluted with sat. aq NaHCO3 (20 mL) and extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with
brine, dried (MgSO4), filtered and concentrated in vacuo. The
resulting residue was purified by flash chromatography (eluent:
10% MeOH/CH2Cl2) to afford 2((tertꢀbutoxycarbonyl)amino)ꢀ
2,2ꢀbis(4ꢀmethoxyphenyl)acetate) as a white solid (4.49 g, 11.6
mmol, 85%): Rf = 0.29 (10% MeOH/CH2Cl2). NMR spectra
matched published reports.14
9
9ꢀ(Benzylideneamino)ꢀ9Hꢀthioxanthene 10,10ꢀdioxide (11).
To a stirred solution of 9Hꢀthioxanthenꢀ9ꢀone 10.10ꢀdioxide (1.0
g, 4.1 mmol) and benzylamine (2.02 mL, 18.5 mmol) in toluene
(15 mL) at 0 °C was added dropwise via addition funnel a soluꢀ
tion of TiCl4 (0.34 mL, 3.1 mmol) in toluene (5 mL). The resultꢀ
ing mixture was stirred at rt for 30 min, then heated to reflux and
stirred at that temperature overnight. After cooling to rt, the mixꢀ
ture was filtered through Celite, concentrated in vacuo, and crysꢀ
talized from Et2O to afford benzaldimine 11 as a white powder
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(772 mg, 2.3 mmol, 56%): Rf = 0.46 (20% EtOAc/hexanes); mp
1
289.9 ꢀ 290.3 °C; H NMR (300 MHz, CDCl3)
δ 8.66 (s, 1H),
8.14 (tt, J = 4.9, 2.5 Hz, 2H), 8.08 ꢀ 8.01 (m, 2H), 7.62 ꢀ 7.46 (m,
9H), 5.93 (s, 1H); 13C NMR (75 MHz, CDCl3)
167.5, 141.6,
136.5, 135.3, 132.5, 132.2, 129.2, 129.1, 127.9, 126.2, 124.1, 66.6;
IR (thin film) 3457, 2930, 2346, 1647, 1643, 1292, 1292, 1163;
δ
To a slurry of the resulting carboxylic acid (3.16 g, 8.15 mmol) in
EtOH (40 mL, 0.2M) was added KOH (0.51 g, 9.10 mmol, 1.1
equiv) and the mixture was stirred at 25 °C. After complete dissoꢀ
lution of solids, the solvent was removed by rotary evaporation.
The resulting yellow oil was dissolved in DMF (40 mL, 0.2M)
and to the resulting solution was added dropwise via addition
funnel allyl bromide (0.75 mL, 8.66 mmol, 1.1 equiv). After stirꢀ
ring at 25 °C overnight, the reaction mixture was diluted with a
combination of DI H2O (20 mL) and brine (20 mL) and extracted
with EtOAc (3 × 40 mL). The combined organic layers were
washed with 10 w/v % aq LiCl (2 × 15 mL) to remove any residꢀ
ual DMF, then dried (Na2SO4), filtered and concentrated in vacuo.
The resulting residue was purified by flash chromatography (eluꢀ
ent: 10% EtOAc/hexanes) to afford allyl 2ꢀ((tertꢀbutoxycarbonꢀ
yl)amino)ꢀ2,2ꢀbis(4ꢀmethoxyphenyl)acetate as a yellow oil (3.35
ν
HRMS （ESI+） m/z: [M+H]+ Calcd for C20H16NO2S+ 334.0896;
Found 334.0892; m/z: [M+Na]+ Calcd for C20H16NNaO2S+
356.0716; Found 356.0682.
9ꢀAllylꢀ9ꢀ(benzylideneamino)ꢀ9Hꢀthioxanthane 10,10ꢀdioxide
(12). To a slurry of benzaldimine 11 (30 mg, 0.09 mmol), tetrabuꢀ
tylammonium bromide (2.9 mg, 9.0 ꢁmol), Pd(PPh3)4 (10.4 mg,
9.0 ꢁmol), and KOH (10 mg, 0.18 mmol) in toluene (1 mL) at rt
was added in one portion via syringe allyl acetate (0.02 mL, 0.23
mmol) and the resulting mixture was stirred vigorously at rt for 5
h then concentrated in vacuo. The resulting residue was purified
by flash chromatography (5% → 10% EtOAc/hexanes) to afford
the allylated product 12 as an offꢀwhite solid (13 mg, 0.04 mmol,
1
40%): Rf = 0.40 (10% EtOAc/hexanes); mp 236.7 ꢀ 237.3 °C; H
1
g, 7.85 mmol, 96%): Rf = 0.67 (20% EtOAc/hexanes); H NMR
NMR (400 MHz, CDCl3)
δ 8.48 (s, 1H), 8.31 – 8.12 (m, 2H),
(400 MHz, CDCl3)
δ 7.33 (d, J = 8.8 Hz, 4H), 6.84 (d, J = 8.9 Hz,
8.01 – 7.77 (m, 2H), 7.67 – 7.45 (m, 6H), 7.44 – 7.33 (m, 2H),
4H), 6.06 (s, 1H), 5.83 (ddd, J = 22.7, 10.9, 5.6 Hz, 1H), 5.24 –
5.13 (m, 2H), 4.66 (d, J = 5.6 Hz, 2H), 3.78 (s, 6H), 1.57 – 1.11
5.63 (ddt, J = 17.3, 10.3, 7.1 Hz, 1H), 4.95 (dd, J = 23.2, 6.0 Hz,
2H), 3.32 (d, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ
(m, 9H); 13C NMR (101 MHz, CDCl3)
δ
171.8, 158.9, 154.1,
165.6, 142.9, 136.3, 132.9, 132.5, 132.0, 129.1, 129.0, 128.8,
128.3, 123.7, 119.6, 66.7, 47.9; IR (thin film) 3457, 3086, 2902,
132.4, 131.4, 129.5, 118.7, 113.5, 113.2, 79.9, 68.5, 66.7, 55.2,
ν
28.3; IR (thin film)
ν 3430, 1723, 1648, 1253, 1180; HRMS
2359, 1618, 1292, 1149; HRMS (ESI+) m/z: [M+H]+ Calcd for
C23H20NO2S+ 374.1209; Found 374.1220; m/z: [M+Na]+ Calcd
for C23H19NNaO2S+ 396.1029; Found 396.1001.
+
(ESI+) m/z: [M+Na]+ Calcd for C24H29NNaO6 450.1887; Found
450.1882.
Finally, the resulting allyl ester (2.95 g, 6.90 mmol) was dissolved
in 1 M HCl in EtOAc (prepared by bubbling dry HCl gas into dry
EtOAc then diluting to 1 M with additional EtOAc, 5 equiv of
HCl) and the resulting reaction mixture was stirred at 25 °C until
complete disappearance of starting material, as determined by
TLC. The resulting mixture then was diluted with sat. aq NaHCO3
(80 mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layer was washed with brine, dried (MgSOs4), filtered,
and concentrated in vacuo. The resulting residue was purified by
flash chromatography (eluent: 20% EtOAc/hexanes) to afford
amine 13 as a yellow oil (2.24 g, 6.85 mmol, >98%): Rf = 0.44
Allyl 2ꢀaminoꢀ2,2ꢀbis(4ꢀmethoxyphenyl)acetate (13). To a
solution of tertꢀbutyl (2ꢀhydroxyꢀ1,1ꢀbis(4ꢀmethoxyphenyl)ethyl)ꢀ
carbamate (0.52 g, 1.39 mmol)14 in DMSO (10 mL. 0.2 M) was
added in one portion IBX (0.47 g, 1.68 mmol, 1.2 equiv) and the
reaction was stirred at 25 °C for 3 h. The resulting mixture was
then diluted with sat. aq NaHCO3 (10 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The resulting resiꢀ
due was purified by flash chromatography (eluent: 20%
EtOAc/hexanes) to afford tertꢀbutyl(1,1ꢀbis(4ꢀmethoxyphenyl)ꢀ2ꢀ
oxoethyl)carbmate as a yellow oil (0.45 g, 1.21 mmol, 87%): Rf =
(20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.34 – 7.27
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The Journal of Organic Chemistry
(m, 4H), 6.89 – 6.81 (m, 4H), 5.93 – 5.79 (m, 1H), 5.24 – 5.14
(m, 2H), 4.67 (ddd, J = 8.4, 4.9, 1.4 Hz, 2H), 3.80 (s, 6H), 2.21 (s,
2H); 13C NMR (101 MHz, CDCl3)
175.0, 158.9, 136.1, 131.6,
raphy (eluent: 10% EtOAc/hexane) to afford tertꢀbutyl(1,1ꢀbis(2ꢀ
methoxyphenyl)ꢀ2ꢀoxoethyl)carbamate as a white solid (1.96 g,
1
2
3
4
5
6
7
8
5.28 mmol, 84%): Rf = 0.28 (10% EtOAc/hexane); mp 90.6 −
δ
1
92.6 °C; H NMR (400 MHz, CDCl3)
δ (mixture of rotational
129.5, 128.8, 118.6, 113.4, 67.5, 66.3, 55.3; IR (thin film)
ν 3387,
3318, 1729, 1647; HRMS (ESI+) m/z: [M+Na]+ Calcd for
isomers) 9.82 (s, 1H), 7.35 – 7.26 (m, 2H), 7.22 (d, J = 7.6 Hz,
2H), 7.01 – 6.92 (m, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.42 (br s,
1H), 3.66 (s, 6H), 1.41 – 1.04 (br m, 10H); 13C NMR (101 MHz,
C19H21NNaO4+ 350.1363; Found 350.1356.
Allyl 2ꢀaminoꢀ2,2ꢀbis(2ꢀmethoxyphenyl)acetate (14). To a
stirred solution of cyanomethyl 1ꢀnaphthoate (6.02 g, 28.5
mmol)14 in THF (140 mL) at 0 °C was added dropwise via addiꢀ
tion funnel a solution of (2ꢀmethoxy)phenylmagnesium bromide
(32 mL, 2M in THF, 2.2 equiv). The resulting reaction mixture
was stirred at 0 °C for 30 min, then 1M aq HCl (50 mL) and
EtOAc (50 mL) were added successively. The resulting aqueous
later was extracted with more EtOAc (2 × 50 mL) and the comꢀ
bined organic layers were wash with brine, dried (MgSO4), filꢀ
tered, and concentration in vacuo. The resulting residue was puriꢀ
fied by flash chromatography (eluent: 30% EtOAc/hexanes) to
CDCl3)
δ (mixture of rotational isomers) 195.2, 158.4, 156.3,
132.7, 130.8, 130.5, 129.6, 125.6, 120.8, 120.4, 111.5, 79.2, 69.7,
9
55.8, 55.5, 28.3, 27.7; IR (thin film)
ν 3409, 1716, 1244, 1165;
+
HRMS (ESI+) m/z: [M+Na]+ Calcd for C21H25NNaO5 394.1625;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Found 394.1616.
To a solution of the resulting aldehyde (1.09 g, 2.93 mmol) in 1:1
MeCN/H2O (20 mL, 0.2M) were added successively NaH2PO4
(0.70 g, 5.83 mmol, 2.0 equiv), H2O2 (30 w/v %, 0.68 g, 2 equiv),
and NaClO2 (0.49 g, 5.41 mmol, 1.5 equiv). The resulting reacꢀ
tion mixture was stirred at 25 °C until complete as determined by
TLC. Solid Na2SO3 then was added to the mixture, which was
then stirred at 25 °C for 4 d. The resulting quenched reaction was
diluted with sat. aq NaHCO3 (20 mL) and extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with
brine, dried (MgSO4), filtered and concentrated in vacuo. The
resulting residue was purified by flash chromatography (eluent:
10% MeOH/CH2Cl2) to afford 2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ
2,2ꢀbis(2ꢀmethoxyphenyl)acetic acid as a white solid (0.91 g, 2.35
mmol, 80%): Rf = 0.29 (30% EtOAc/hexane); mp 62.7 − 64.0 °C;
afford
Nꢀ(2ꢀhydroxyꢀ1,1ꢀbis(2ꢀmethoxyphenyl)ethylꢀ1ꢀnaphthꢀ
amide as a white solid (4.21 g, 9.85 mmol, 35%): Rf = 0.31 (30%
1
EtOAc/hexanes); mp 140.1 − 141.3 °C; H NMR (400 MHz,
CDCl3)
δ 8.45 – 8.38 (m, 1H), 7.98 (br s, 1H), 7.92 (d, J = 8.3 Hz,
1H), 7.90 – 7.85 (m, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.56 – 7.50
(m, 2H), 7.50 – 7.43 (m, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.34 –
7.27 (m, 2H), 7.02 – 6.90 (m, 4H), 5.49 (dd, J = 8.1, 4.8 Hz, 1H),
4.79 (d, J = 6.9 Hz, 2H), 3.60 (s, 6H); 13C NMR (101 MHz,
CDCl3)
δ 169.6, 157.2, 135.5, 134.0, 130.8, 130.4, 130.2, 129.2,
1H NMR (400 MHz, CDCl3)
δ 7.37 – 7.29 (m, 2H), 7.13 (br s,
129.1, 128.4, 127.2, 126.6, 125.8, 125.0, 124.9, 120.9, 112.6,
2H), 7.00 – 6.96 (m, 2H), 6.93 (t, J = 7.5 Hz, 2H), 6.43 (br s, 1H),
3.76 (s, 6H), 1.35 (br s, 9H); 13C NMR (101 MHz, CDCl3) δ
171.4, 156.7, 130.5, 130.1, 125.3, 120.8, 112.3, 80.7, 60.4, 55.9,
69.4, 66.0, 55.7; IR (thin film)
ν 3392, 3361, 3307, 1645; HRMS
(ESI+) m/z: [M+H]+ Calcd for C27H26NO4 428.1856; Found
+
428.1860; [M+Na]+ Calcd for C27H25NNaO4 450.1676; Found
+
28.3; IR (thin film)
ν 3419, 2969, 1733, 1249, 1165; HRMS
450.1634.
+
(ESI+) m/z: [M+Na]+ Calcd for C21H25NNaO6 410.1574; Found
A solution of the resulting naphthamide (4.21 g, 9.85 mmol) and
NaOH (1.14 g, 28.5 mmol, 3.0 equiv) in EtOH (50 mL, 0.2 M)
was stirred at 135 °C for 2 h in a high pressure glass reaction
bottle. After cooling to rt, (Boc)2O (6.8 mL, 29.6 mmol, 3 equiv)
was added and the resulting solution was stirred at 40 °C for 7 d.
The resulting reaction mixture was partitioned between H2O (50
mL) and Et2O (50 mL). The aqueous phase was extracted with
more Et2O (2 × 50 mL) and the combined organic layers were
dried (MgSO4), filtered and concentrated in vacuo. The resulting
residue was purified by flash chromatography (eluent: 15%
EtOAc/hexanes) to afford tertꢀbutylꢀ(2ꢀhydroxyꢀ1,1ꢀbis(2ꢀmethꢀ
oxyphenyl)ethyl)carbamate as a yellow solid (2.34 g, 6.27 mmol,
64%): Rf = 0.33 (15% EtOAc/hexanes); mp 108.5 − 109.1 °C; 1H
410.1567.
To a vigorously stirred slurry of the resulting carboxylic acid
(2.67 g, 6.89 mmol) in EtOH (35 mL, 0.2M) was added KOH
(0.46 g, 8.21 mmol, 1 equiv). After complete dissolution of solids,
the solvent was removed by rotary evaporation and the resultant
yellow oil was redissolved in DMF (35 mL, 0.2M). To this stirred
solution was added dropwise via addition funnel allyl bromide
(1.02g, 8.43 mmol, 1 equiv). After stirring at 25 °C overnight, the
reaction mixture was diluted with a combination of DI H2O (15
mL) and brine (15 mL) and extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with 10 w/v % aq LiCl
(2 × 10 mL) to remove any residual DMF, dried (Na2SO4), filꢀ
tered and concentrated in vacuo. The resulting residue was puriꢀ
fied by flash chromatography (eluent: 20% EtOAc/hexanes) to
afford the corresponding allyl ester as a white solid (2.77 g, 6.49
mmol, 94%): Rf = 0.64 (20% EtOAc/hexanes); mp 111.6 − 112.3
°C; 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.7 Hz, 4H), 6.96 –
6.81 (m, 4H), 6.40 (s, 1H), 5.86 (ddt, J = 16.1, 10.7, 5.5 Hz, 1H),
5.13 (dq, J = 11.8, 1.3 Hz, 2H), 4.66 (d, J = 5.2 Hz, 2H), 3.62 (s,
6H), 1.65 – 1.00 (m, 9H)；13C NMR (101 MHz, CDCl3) δ 171.2,
171.1, 157.3, 154.2, 132.0, 130.3, 129.0, 127.7, 120.0, 117.9,
NMR (400 MHz, CDCl3)
δ 7.32 (d, J = 7.6 Hz, 2H), 7.25 – 7.18
(m, 2H), 6.91 (dd, J = 11.2, 4.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H),
6.33 (s, 1H), 4.71 (br s, 1H), 4.61 (d, J = 6.6 Hz, 2H), 3.50 (s,
6H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ
157.0, 156.1,
131.4, 128.4, 120.5, 112.6, 79.5, 66.5, 65.0, 55.6, 28.4; IR (thin
film)
ν 3569, 3405, 1711, 1250, 1158; HRMS (ESI+) m/z:
[M+Na]+ Calcd for C21H27NNaO5+ 396.1781; Found 396.1767.
To a solution of the resulting alcohol (2.34 g, 6.27 mmol) in
DMSO (20 mL, 0.2M) was added in one portion IBX (2.11 g,
7.54 mmol, 1.2 equiv) and the reaction was stirred at rt for 3 d.
The resulting reaction mixture was then diluted with sat. aq Naꢀ
HCO3 (20 mL) and extracted with EtOAc (3 × 20 mL). The comꢀ
bined organic layers were dried (MgSO4), filtered and concentratꢀ
ed in vacuo. The crude residue was purified by flash chromatogꢀ
112.0, 79.1, 67.4, 66.2, 60.4, 55.7, 28.3； IR (thin film)
ν 3443,
3072, 2972, 1723, 1253, 1160; HRMS (ESI+) m/z: [M+Na]+
Calcd for C24H29NNaO6+ 450.1887; Found 450.1875.
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The Journal of Organic Chemistry
Page 12 of 19
10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.85 – 7.79
Finally, the resulting allyl ester (2.77 g, 6.49 mmol) was dissolved
1
2
3
4
5
6
7
8
in 1 M HCl in EtOAc (prepared by bubbling dry HCl gas into dry
EtOAc then diluting to 1 M with additional EtOAc, 5 equiv of
HCl) and the resulting reaction mixture was stirred at 25 °C until
complete disappearance of starting material, as determined by
TLC. The resulting mixture then was diluted with sat. aq NaHCO3
(80 mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with brine, dried (MgSOs4), filtered,
and concentrated in vacuo. The resulting residue was purified by
flash chromatography (eluent: 5% MeOH/CH2Cl2) to afford
amine 14 as a pale yellow solid (2.01 g, 6.14 mmol, 95%): Rf =
(m, 3H), 7.33 – 7.27 (m, 4H), 7.14 – 7.06 (m, 2H), 6.91 – 6.84
(m, 4H), 5.86 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H), 5.22 – 5.13 (m,
2H), 4.68 (dt, J = 5.4, 1.5 Hz, 2H), 3.82 (s, 6H); 13C NMR (101
MHz, CDCl3)
δ 172.3, 164.7 (d, JCꢀF = 251.1 Hz), 161.4, 159.0,
134.6, 132.9 (JCꢀF = 3.0 Hz), 131.8, 130.8 (JCꢀF = 8.7 Hz), 130.6,
118.4, 115.8 (JCꢀF = 21.8 Hz), 113.4, 78.7, 66.3, 55.4; IR (thin
film)
ν 3440, 2934, 1732, 1644, 1252, 1178; HRMS (ESI+) m/z:
[M+Na]+ Calcd for C26H24FNNaO4+ 456.1582; Found 456.1576.
9
Allyl (E)ꢀ2ꢀ((4ꢀmethylbenzylidene)amino)ꢀ2,2ꢀbis(4ꢀmethoxyꢀ
phenyl)acetate (15l). Imine 15l was synthesized by condensation
between amino ester 13 and 4ꢀmethylbenzaldehyde following the
general procedures described above. Purified by flash chromatogꢀ
raphy (eluent: 1% Et3N in 10% EtOAc/hexanes) to afford a yelꢀ
low oil (0.86 g, 2.00 mmol, 89%): Rf = 0.36 (1% Et3N in 10%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
0.56 (10% MeOH/CH2Cl2); mp 64.5 − 66.1 °C; H NMR (400
MHz, CDCl3)
δ 7.29 (tt, J = 9.9, 2.1 Hz, 2H), 7.09 (dd, J = 7.8,
1.7 Hz, 2H), 6.95 (dd, J = 8.2, 0.9 Hz, 2H), 6.89 (td, J = 7.6, 1.1
Hz, 2H), 5.96 – 5.81 (m, 1H), 5.16 (dq, J = 6.1, 1.5 Hz, 1H), 5.12
(t, J = 1.4 Hz, 1H), 4.66 (dt, J = 5.6, 1.4 Hz, 2H), 3.78 (s, 6H),
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.83 (s, 1H),
2.60 (br s, 2H); 13C NMR (101 MHz, CDCl3)
132.4, 130.8, 129.1, 120.8, 117.8, 111.6, 66.4, 65.8, 55.6; IR (thin
δ 175.5, 157.6,
7.71 (d, J = 8.1 Hz, 2H), 7.33 – 7.28 (m, 4H), 7.22 (d, J = 7.9 Hz,
2H), 6.90 – 6.84 (m, 4H), 5.86 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H),
5.20 (ddd, J = 17.2, 3.1, 1.6 Hz, 1H), 5.15 (ddd, J = 10.5, 2.7, 1.3
Hz, 1H), 4.69 (dt, J = 5.4, 1.5 Hz, 2H), 3.82 (s, 6H), 2.39 (s, 3H);
film)
ν
3389, 2973, 1746, 1244; HRMS (ESI+) m/z: [M+H]+
Calcd for C19H22NO4+ 328.1543; Found 328.1527.
13C NMR (101 MHz, CDCl3)
134.0, 131.8, 130.6, 129.4, 128.8, 118.3, 113.4, 78.6, 66.2, 55.4,
δ 172.5, 162.6, 158.9, 141.5, 134.8,
Allyl (E)ꢀ2ꢀ((4ꢀcyanobenzylidene)amino)ꢀ2,2ꢀbis(4ꢀmethoxyꢀ
phenyl)acetate (15b). Imine 15b was synthesized by condensation
between amino ester 13 and 4ꢀformylbenzonitrile following the
general procedures described above. Purified by flash chromatogꢀ
raphy (eluent: 1% Et3N in 13% EtOAc/hexanes) to afford a yelꢀ
low solid (0.54 g, 1.23 mmol, 87%): Rf = 0.23 (1% Et3N in 10%
21.7; IR (thin film)
ν 3439, 3001, 2933, 1732, 1642, 1251, 1178;
HRMS (ESI+) m/z: [M+H]+ Calcd for C27H28NO5 446.1962;
+
Found 446.1965; m/z: [M+Na]+ Calcd for C27H27NNaO5
+
468.1781; Found 468.1744.
1
EtOAc/hexanes); mp 97.3−98.1 °C; H NMR (400 MHz, CDCl3)
Allyl
(E)ꢀ2,2ꢀbis(4ꢀmethoxyphenyl)ꢀ2ꢀ((4ꢀmethoxybenzyliꢀ
δ
7.92 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H),
dene)amino)acetate (15n). Imine 15n was synthesized by condenꢀ
sation between amino ester 13 and 4ꢀmethoxybenzaldehyde folꢀ
lowing the general procedures described above. Purified by flash
chromatography (eluent: 1% Et3N in 15% EtOAc/hexanes) to
7.31 – 7.26 (m, 4H), 6.92 – 6.85 (m, 4H), 5.85 (ddt, J = 17.1,
10.7, 5.4 Hz, 1H), 5.19 (dq, J = 10.9, 1.4 Hz, 1H), 5.15 (dq, J =
4.0, 1.4 Hz, 1H), 4.68 (dt, J = 5.4, 1.4 Hz, 2H), 3.82 (s, 6H); 13C
NMR (101 MHz, CDCl3)
δ 171.9, 161.1, 159.1, 140.3, 134.1,
afford a yellow oil (1.31 g, 2.94 mmol, 79%): Rf = 0.38 (1% Et3N
132.5, 131.6, 130.6, 129.2, 118.7, 118.5, 114.3, 113.5, 79.0, 66.4,
1
in 15% EtOAc/hexanes); H NMR (400 MHz, CDCl3)
δ 7.79 (s,
55.4; IR (thin film)
ν 3434, 3071, 2995, 1729, 1643, 1254, 1179;
1H), 7.78 – 7.74 (m, 2H), 7.32 – 7.27 (m, 4H), 6.95 – 6.90 (m,
2H), 6.89 – 6.84 (m, 4H), 5.86 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H),
5.19 (ddd, J = 17.5, 3.3, 1.7 Hz, 1H), 5.14 (ddd, J = 10.5, 2.8, 1.4
Hz, 1H), 4.68 (dt, J = 5.4, 1.5 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 6H);
+
HRMS (ESI+) m/z: [M+Na]+ Calcd
for C27H24N2NaO4
463.1628; Found 463.1623.
Allyl (E)ꢀ2ꢀ(benzylideneamino)ꢀ2,2ꢀbis(4ꢀmethoxyphenyl)aceꢀ
tate (15h). Imine 15h was synthesized by condensation between
amino ester 13 and benzaldehyde following the general proceꢀ
dures described above. Purified by flash chromatography (eluent:
1% Et3N in 5% EtOAc/hexanes) to afford a white solid (1.02 g,
13C NMR (101 MHz, CDCl3)
130.6, 130.5, 129.7, 118.3, 114.0, 113.4, 78.5, 66.2, 55.5, 55.4; IR
δ 172.6, 162.0, 158.9, 135.0, 131.9,
(thin film)
ν 3446, 3002, 1732, 1641, 1252, 1165; HRMS (ESI+)
+
m/z: [M+H]+ Calcd for C27H28NO4 430.2013; Found 430.2012;
m/z: [M+Na]+ Calcd for C27H27NNaO4 452.1832; Found
+
2.45 mmol, 78%): Rf = 0.35 (1% Et3N in 10% EtOAc/hexanes);
1
mp 77.7−79.3 °C; H NMR (400 MHz, CDCl3)
δ 7.86 (s, 1H),
452.1814.
7.84 – 7.79 (m, 2H), 7.46 – 7.38 (m, 3H), 7.33 – 7.28 (m, 4H),
6.90 – 6.84 (m, 4H), 5.86 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H), 5.20
(ddd, J = 17.2, 3.1, 1.6 Hz, 1H), 5.15 (ddd, J = 10.5, 2.7, 1.3 Hz,
1H), 4.69 (dt, J = 5.4, 1.5 Hz, 1H), 3.82 (s, 6H); 13C NMR (101
Allyl (E)ꢀ2ꢀ(((6ꢀbromobenzo[d][1,3]dioxolꢀ5ꢀyl)methylene)ꢀ
amino)ꢀ2,2ꢀbis(4ꢀmethoxyphenyl)acetate (15o). Imine 15o was
synthesized by condensation between amino ester 13 and 6ꢀ
bromopiperonal following the general procedures described above.
Purified by flash chromatography (eluent: 1% Et3N in 10%
EtOAc/hexanes) to afford a clear colorless oil (0.33 g, 0.61 mmol,
53%): Rf = 0.23 (1% Et3N in 10% EtOAc/hexanes); 1H NMR
MHz, CDCl3)
δ 172.4, 162.8, 158.9, 136.6, 134.7, 131.8, 131.1,
130.6, 128.9, 128.7, 118.4, 113.4, 78.7, 66.2, 55.4; IR (thin film)
ν
3000, 2937, 1728, 1646, 1254, 1224; HRMS (ESI+) m/z:
[M+Na]+ Calcd for C26H25NNaO4+ 438.1676; Found 438.1661.
(400 MHz, CDCl3)
δ 8.15 (s, 1H), 7.77 (s, 1H), 7.31 – 7.26 (m,
Allyl (E)ꢀ2ꢀ((4ꢀfluorobenzylidene)amino)ꢀ2,2ꢀbis(4ꢀmethoxyꢀ
phenyl)acetate (15i). Imine 15i was synthesized by condensation
between amino ester 13 and 4ꢀfluorobenzaldehyde following the
general procedures described above. Purified by flash chromatogꢀ
raphy (eluent: 1% Et3N in 10% EtOAc/hexanes) to afford a clear
offꢀwhite oil (0.52 g, 1.20 mmol, 98%): Rf = 0.42 (1% Et3N in
4H), 6.95 (s, 1H), 6.90 – 6.85 (m, 4H), 6.02 (s, 2H), 5.87 (ddt, J =
17.1, 10.7, 5.5 Hz, 1H), 5.24 – 5.13 (m, 2H), 4.69 (dt, J = 5.5, 1.4
Hz, 2H), 3.82 (s, 6H); 13C NMR (101 MHz, CDCl3)
δ 172.3,
161.6, 159.0, 150.8, 147.9, 134.5, 131.8, 130.5, 129.0, 118.5,
118.4, 113.5, 112.6, 108.2, 102.3, 78.9, 66.3, 55.4; IR (thin film)
ν
3442, 2932, 1732, 1250, 1178; HRMS (ESI+) m/z: [M+Na]+
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Page 13 of 19
The Journal of Organic Chemistry
+
Calcd for C27H24BrNNaO6 560.0679
560.0652 & 562.0643.
&
562.0659; Found
7.35 (dd, J = 7.8, 1.7 Hz, 2H), 7.29 (dd, J = 1.7, 0.6 Hz, 1H), 7.29
1
2
3
4
5
6
7
8
(dd, J = 15.5, 1.7 Hz, 1H), 6.94 (td, J = 7.6, 1.2 Hz, 2H), 6.88 (dd,
J = 8.2, 1.0 Hz, 2H), 5.87 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H), 5.16
(dq, J = 17.2, 1.6 Hz, 1H), 5.11 (ddd, J = 10.5, 2.8, 1.4 Hz, 1H),
4.68 (dt, J = 5.4, 1.5 Hz, 1H), 3.59 (s, 6H); 13C NMR (101 MHz,
Allyl (E)ꢀ2ꢀ((furanꢀ2ꢀylmethylene)amino)ꢀ2,2ꢀbis(4ꢀmethoxyꢀ
phenyl)acetate (15p). Imine 15p was synthesized by condensation
between amino ester 13 and 2ꢀfuranaldehyde following the genꢀ
eral procedures described above. Purified by flash chromatogꢀ
raphy (eluent: 1% Et3N in 15% EtOAc/hexanes) to afford a brown
oil (0.33 g, 0.81 mmol, 80%): Rf = 0.13 (1% Et3N in 10%
CDCl3)
δ 171.5, 161.2, 157.5, 137.0, 132.5, 130.7, 130.7, 129.3,
129.1, 128.8, 128.6, 120.4, 117.6, 112.0, 65.8, 55.6; IR (thin film)
ν
3465, 3065, 2995, 1774, 1639, 1248, 1191; HRMS (ESI+) m/z:
[M+H]+ Calcd for C26H26NO4+ 416.1856; Found 416.1856.
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.61 (s, 1H),
9
7.56 (d, J = 1.6 Hz, 1H), 7.30 – 7.24 (m, 4H), 6.90 – 6.83 (m,
4H), 6.79 (dd, J = 3.4, 0.5 Hz, 1H), 6.48 (dd, J = 3.4, 1.8 Hz, 1H),
5.86 (ddt, J = 17.2, 10.7, 5.5 Hz, 1H), 5.24 – 5.12 (m, 2H), 4.72 –
Allyl (E)ꢀ2ꢀ((4ꢀfluorobenzylidene)amino)ꢀ2,2ꢀbis(2ꢀmethoxyꢀ
phenyl)acetate (16i). Imine 16i was synthesized by condensation
between amine 14 (0.57 g, 1.74 mmol) and 4ꢀfluorobenzaldehyde
(0.21 g, 1.69 mmol, 0.95 equiv) as described above. Purified by
flash chromatography (eluent: 1% Et3N in 10% EtOAc/hexanes)
to afford a white solid (0.72 g, 1.67 mmol, >98%): Rf = 0.29 (1%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.66 (m, 2H), 3.82 (s, 6H); 13C NMR (101 MHz, CDCl3)
159.0, 152.2, 151.5, 145.3, 134.1, 131.8, 130.6, 128.9, 118.5,
δ 172.2,
115.4, 113.5, 113.4, 111.9, 78.9, 66.4, 55.4; IR (thin film)
ν 2934,
1
1732, 1644, 1252, 1179; HRMS (ESI+) m/z: [M+Na]+ Calcd for
Et3N in 10% EtOAc/hexanes); mp 137.3 − 138.3 °C; H NMR
C24H23NNaO5+ 428.1468; Found 428.1449.
(400 MHz, CDCl3) δ 8.02 (s, 1H), 7.86 – 7.77 (m, 2H), 7.45 –
7.26 (m, 5H), 7.12 – 7.03 (m, 2H), 6.98 – 6.85 (m, 4H), 5.86 (ddt,
J = 17.2, 10.7, 5.4 Hz, 1H), 5.13 (ddq, J = 15.3, 10.5, 1.5 Hz, 2H),
4.68 (dt, J = 5.4, 1.5 Hz, 2H), 3.59 (s, 6H); 13C NMR (101 MHz,
Allyl (E)ꢀ2ꢀ((4ꢀcyanobenzylidene)amino)ꢀ2,2ꢀbis(2ꢀmethoxyꢀ
phenyl)acetate (16b). Imine 16b was synthesized by condensation
between amine 14 (0.52 g, 1.59 mmol) and 4ꢀcyanobenzaldehyde
(0.20 g, 1.52 mmol, 0.95 equiv) as described above. Purified by
flash chromatography (eluent: 1% Et3N in 13% EtOAc/hexanes)
to afford a white solid (0.68 g, 1.54 mmol, >98%): Rf = 0.22 (1%
CDCl3) δ 171.6, 164.5 (d, JCꢀF = 250.5 Hz), 157.5, 133.3 (d, JCꢀF
=
2.9 Hz), 132.4, 130.63 (d, JCꢀF = 8.6 Hz), 130.61, 129.14, 129.08,
120.4, 117.7, 115.6 (d, JCꢀF = 21.8 Hz), 112.0, 65.8, 55.6.; IR (thin
1
film)
ν 3442, 3080, 3054, 2996, 1731, 1633, 1251, 1224; HRMS
Et3N in 13% EtOAc/hexanes); mp 134.2 − 134.5 °C; H NMR
(ESI+) m/z: [M+H]+ Calcd for C26H25FNO4 434.1762; Found
434.1760.
+
(400 MHz, CDCl3)
δ 8.08 (s, 1H), 7.96 – 7.88 (m, 2H), 7.76 –
7.64 (m, 2H), 7.36 – 7.25 (m, 5H), 7.00 – 6.86 (m, 4H), 5.86 (ddt,
Allyl (E)ꢀ2,2ꢀbis(2ꢀmethoxyphenyl)ꢀ2ꢀ((4ꢀmethylbenzylidene)ꢀ
amino)acetate (16l). Imine 16l was synthesized by condensation
between amine 14 (0.92 g, 2.81 mmol) and 4ꢀmethylbenzaldehyde
(0.33 g, 2.75 mmol, 0.95 equiv) as described above. Purified by
flash chromatography (eluent: 1% Et3N in 13% EtOAc/hexanes)
to afford a white solid (1.09 g, 2.54 mmol, 92%): Rf = 0.33 (1%
J = 17.2, 10.7, 5.4 Hz, 1H), 5.20 – 5.09 (m, 2H), 4.69 (dt, J = 5.4,
1.5 Hz, 2H), 3.59 (s, 6H); 13C NMR (101 MHz, CDCl3)
δ
171.2,
159.3, 157.3, 140.7, 132.3, 132.1, 130.4, 129.3, 129.0, 128.4,
120.4, 117.7, 111.9, 77.8, 65.9, 55.4; IR (thin film)
ν 3369, 2974,
1736, 1640, 1249, 1228; HRMS (ESI+) m/z: [M+H]+ Calcd for
C27H25N2O4+ 441.1809; Found 441.1808; m/z: [M+Na]+ Calcd for
C27H24N2NaO5+ 463.1628; Found 463.1610.
1
Et3N in 13% EtOAc/hexanes); mp 141.2 − 142.8 °C; H NMR
(400 MHz, CDCl3)
δ 8.02 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 8.1 Hz,
Allyl (E)ꢀ2ꢀ((4ꢀbromobenzylidene)amino)ꢀ2,2ꢀbis(2ꢀmethoxyꢀ
phenyl)acetate (16f). Imine 16f was synthesized by condensation
between amine 14 (0.33 g, 1.01 mmol) and 4ꢀbromobenzaldehyde
(0.17 g, 0.91 mmol, 0.95 equiv) as described above. Purified by
flash chromatography (eluent: 1% Et3N in 20% EtOAc/hexanes)
to afford a pale yellow solid (0.41 g, 0.83 mmol, 83%): Rf = 0.22
(1% Et3N in 10% EtOAc/hexanes); mp 156.3 ꢀ 167.0 °C; 1H
NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H),
7.53 (d, J = 8.4 Hz, 2H), 7.38 – 7.23 (m, 4H), 6.92 (ddd, J = 19.0,
12.8, 4.5 Hz, 4H), 5.94 – 5.78 (m, 1H), 5.23 – 5.07 (m, 2H), 4.68
(dt, J = 5.4, 1.4 Hz, 2H), 3.58 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 171.4, 160.0, 157.4, 135.9, 132.4, 131.8, 130.6, 130.2,
129.2, 129.0, 125.2, 120.5, 117.7, 112.00, 65.9, 55.6; IR (thin
2H), 7.37 – 7.25 (m, 5H), 7.21 (d, J = 7.9 Hz, 2H), 6.97 – 6.84 (m,
4H), 5.86 (ddt, J = 17.2, 10.6, 5.4 Hz, 1H), 5.13 (ddq, J = 21.2,
10.5, 1.5 Hz, 2H), 4.68 (dt, J = 5.4, 1.5 Hz, 2H), 3.59 (s, 6H), 2.38
(s, 3H); 13C NMR (101 MHz, CDCl3)
134.3, 132.4, 130.6, 129.2, 129.2, 128.9, 128.6, 120.3, 117.4,
δ 171.5, 160.9, 157.4, 140.9,
111.8, 65.6, 55.5, 21.6; IR (thin film)
ν 3444, 3063, 3014, 2934,
1732, 1642, 1250, 1208; HRMS (ESI+) m/z: [M+H]+ Calcd for
C27H28NO4+ 430.2013; Found 430.2013.
Allyl (E)ꢀ2ꢀ((4ꢀmethoxybenzylidene)amino)ꢀ2,2ꢀbis(2ꢀmethꢀ
oxyphenyl)acetate (16n). Imine 16n was synthesized by condenꢀ
sation between amine 14 (0.43 g, 1.31 mmol) and 4ꢀmethoxyꢀ
benzaldehyde (0.18 g, 1.30 mmol, 0.98 equiv) as described above.
Purified by flash chromatography (eluent: 1% Et3N in 13%
EtOAc/hexanes) to afford a white solid (0.51 g, 1.15 mmol, 88%):
Rf = 0.22 (1% Et3N in 13% EtOAc/hexanes); mp 93.4 − 94.4 °C;
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 5.2 Hz, 1H), 7.80 –
7.72 (m, 2H), 7.36 (dd, J = 7.8, 1.7 Hz, 2H), 7.31 – 7.25 (m, 3H),
6.97 – 6.84 (m, 6H), 5.93 – 5.79 (m, 1H), 5.21 – 5.05 (m, 2H),
film)
ν 2944, 2857, 2374, 1747, 1585, 1476, 1234; HRMS (ESI+)
+
m/z: [M+H]+ Calcd for C26H25BrNO4 494.0967 & 496.0946;
Found 494.0983 & 496.0968.
Allyl (E)ꢀ2ꢀ(benzylideneamino)ꢀ2,2ꢀbis(2ꢀmethoxyphenyl)aceꢀ
tate (16h). Imine 16h was synthesized by condensation between
amine 14 (0.51 g, 1.56 mmol) and benzaldehyde (0.17 g, 1.60
mmol, 1.02 equiv) as described above. Purified by flash chromaꢀ
tography (eluent: 1% Et3N in 10% EtOAc/hexanes) to afford a
white solid (0.56 g, 1.35 mmol, 87%): Rf = 0.29 (1% Et3N in 10%
EtOAc/hexanes); mp 96.6 − 97.3 °C; 1H NMR (400 MHz, CDCl3)
4.67 (ddd, J = 7.2, 4.4, 2.9 Hz, 2H), 3.84 (s, 3H), 3.58 (s, 6H); 13
NMR (101 MHz, CDCl3) 171.5, 161.7, 160.3, 157.4, 132.4,
130.6, 130.2, 129.4, 128.8, 120.2, 117.4, 113.8, 111.9, 65.6, 55.5,
C
δ
55.4; IR (thin film)
ν 3069, 2998, 1732, 1631, 1245, 1162; HRMS
+
(ESI+) m/z: [M+H]+ Calcd for C27H28NO5 446.1962; Found
δ
8.07 (s, 1H), 7.82 (td, J = 4.7, 2.9 Hz, 2H), 7.43 – 7.38 (m, 3H),
446.1961.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
Allyl (E)ꢀ2ꢀ(((6ꢀbromobenzo[d][1,3]dioxolꢀ5ꢀyl)methylene)ꢀ
(eluent: 10% EtOAc/hexanes) to afford a yellow oil (average 10:1
1
2
3
4
5
6
7
8
amino)ꢀ2,2ꢀbis(2ꢀmethoxyphenyl)acetate (16o). Imine 16o was
synthesized by condensation between amine 14 (0.46 g, 1.41
mmol) and 6ꢀbromopiperonal (0.31 g, 1.35 mmol, 0.95 equiv) as
described above. Purified by flash chromatography (eluent: 1%
Et3N in 15% EtOAc/hexanes) to afford a white solid (0.59 g, 1.09
mmol, 81%): Rf = 0.24 (1% Et3N in 15% EtOAc/hexanes); mp
126.7 − 128.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.2
Hz, 1H), 7.71 (s, 1H), 7.33 – 7.28 (m, 2H), 7.21 (dd, J = 7.8, 1.6
Hz, 2H), 7.00 – 6.86 (m, 5H), 6.00 (s, 2H), 5.95 – 5.82 (m, 1H),
5.14 (ddq, J = 13.3, 10.5, 1.5 Hz, 2H), 4.70 (dt, J = 5.5, 1.4 Hz,
mixture with aldimine regioisomer 18h, 47.2 mg, 0.13 mmol, 81%
combined yield). An analytical sample of pure 17h was obtained
by repetitive flash chromatography: Rf
=
0.49 (10%
1
EtOAc/hexanes); H NMR (400 MHz, CDCl3)
δ 7.62 (d, J = 8.8
Hz, 2H), 7.31 (dt, J = 15.0, 7.5 Hz, 4H), 7.24 – 7.18 (m, 1H), 6.96
(dd, J = 22.2, 8.8 Hz, 4H), 6.88 – 6.81 (m, 2H), 5.65 (ddt, J = 17.2,
10.2, 7.1 Hz, 1H), 4.96 (t, J = 13.8 Hz, 2H), 4.45 (dd, J = 7.7, 5.6
Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 2.75 – 2.62 (m, 1H), 2.61 –
2.50 (m, 1H); 13C NMR (101 MHz, CDCl3)
136.0, 130.2, 129.4, 128.9, 128.3, 127.2, 126.6, 116.5, 113.6,
δ 161.1, 159.4, 144.9,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2H), 3.64 (s, 6H); 13C NMR (101 MHz, CDCl3)
δ 171.5, 159.9,
113.3, 66.3, 55.3, 55.3, 44.1; IR (thin film)
ν 3067, 3003, 2931;
+
HRMS (ESI+) m/z: [M+H]+ Calcd for C25H26NO2 372.1958;
157.4, 150.4, 147.7, 132.3, 130.4, 129.4, 129.1, 128.6, 120.4,
117.8, 117.7, 112.4, 111.7, 108.4, 102.1, 77.8, 65.8, 55.4; IR (thin
Found 372.1943.
film)
ν 3441, 3076, 2962, 1727, 1621, 1246, 1167; HRMS (ESI+)
Nꢀ1ꢀ(4ꢀFluorophenyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀbis(4ꢀmethoxyphenꢀ
yl)methanimine (17i). Racemic 17i was synthesized from imino
ester 15i (78.6 mg, 0.18 mmol) following the general procedures
described above [Procedure A]. Passed through a short plug of
silica gel (eluent: 10% EtOAc/hexanes) to afford a clear colorless
oil (average 6.3:1 mixture with aldimine regioisomer 18i, 43.8 mg,
0.11 mmol, 61% combined yield). An analytical sample of pure
17i was obtained by repetitive flash chromatography: Rf = 0.23
(10% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J =
8.7 Hz, 2H), 7.32 – 7.24 (m, 3H), 7.00 – 6.91 (m, 6H), 6.84 (d, J
= 8.9 Hz, 2H), 5.62 (ddt, J = 17.3, 10.2, 7.1 Hz, 1H), 4.95 (dd, J =
13.7, 7.2 Hz, 2H), 4.46 – 4.38 (m, 1H), 3.87 (s, 3H), 3.81 (s, 3H),
2.62 (dt, J = 14.2, 7.1 Hz, 1H), 2.57 – 2.47 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ 166.2, 161.7 (JCF = 244.0 Hz), 161.2, 159.5,
140.7 (JCꢀF = 3.1 Hz), 135.8, 133.4, 130.3, 129.5, 129.4, 129.1
128.7 (JCF = 7.8 Hz), 128.52, 116.9, 115.1 (d, JCꢀF = 21.0 Hz),
+
m/z: [M+H]+ Calcd for C27H25BrNO6 538.0860 & 540.0840;
Found 538.0861 & 540.0841.
Allyl (E)ꢀ2ꢀ((furanꢀ2ꢀylmethylene)amino)ꢀ2,2ꢀbis(2ꢀmethoxyꢀ
phenyl)acetate (16p). Imine 16p was synthesized by condensation
between amine 14 (0.46 g, 1.40 mmol) and 2ꢀfuranaldehyde (0.13
g, 1.35 mmol, 0.95 equiv) as described above. Purified by flash
chromatography (eluent: 1% Et3N in 20% EtOAc/hexanes) to
afford a pale yellow solid (0.53 g, 1.31 mmol, 97%): Rf = 0.30 (1%
1
Et3N in 20% EtOAc/hexanes); mp 135.2 − 136.2 °C; H NMR
(400 MHz, CDCl3) δ 7.83 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.34 –
7.20 (m, 3H), 6.91 (ddt, J = 9.1, 8.2, 2.6 Hz, 2H), 6.82 – 6.74 (m,
1H), 6.46 (dd, J = 3.4, 1.8 Hz, 1H), 5.93 – 5.79 (m, 1H), 5.21 –
5.07 (m, 1H), 4.68 (tt, J = 6.5, 2.1 Hz, 1H), 3.60 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 171.4, 157.4, 152.4, 149.9, 144.8,
132.3, 130.7, 129.1, 128.5, 120.4, 117.6, 114.5, 111.9, 111.6, 77.7,
65.8, 55.4; IR (thin film)
1249，1219; HRMS (ESI+) m/z: [M+H]+ Calcd for C24H24NO5
ν
3406，3103，2999，1712，1647，
113.8, 113.4, 65.7, 55.5, 55.4, 44.3; IR (thin film)
ν 3071, 3003,
+
2932, 1461; HRMS (ESI+) m/z: [M+H]+ Calcd for C25H25FNO2 :
+
390.1864; Found 390.1848.
406.1649; Found 406.1647.
1,1ꢀBis(4ꢀmethoxyphenyl)ꢀNꢀ(1ꢀ(pꢀtolyl)butꢀ3ꢀenꢀ1ꢀyl)methanꢀ
imine (17l). Racemic 17l was synthesized from imino ester 15l
(91.8 mg, 0.21 mmol) following the general procedures described
above [Procedure A]. Passed through a short plug of silica gel
(eluent: 10% EtOAc/hexanes) to afford a yellow oil (average
5.7:1 mixture with aldimine regioisomer 18l, 62.7 mg, 0.16 mmol,
76% combined yield). An analytical sample of pure 8d was obꢀ
4ꢀ(1ꢀ((Bis(4ꢀmethoxyphenyl)methylene)amino)butꢀ3ꢀenꢀ1ꢀyl)ꢀ
benzonitrile (17b). Racemic 17b was synthesized from imino
ester 15b (99.3 mg, 0.23 mmol) following the general procedures
described above [Procedure A]. Passed through a short plug of
silica gel (eluent: 10% EtOAc/hexanes) to afford a clear colorless
oil (83.6 mg, 0.21 mmol, 91%). Enantioenriched (S)ꢀ17b was
synthesized from 15b following the general procedures described
above [Procedure B] to afford a yellow oil (average er 90.6 :
tained by repetitive flash chromatography: Rf = 0.53 (10%
1
9.4, >98% yield): Rf = 0.33 (10% EtOAc/hexanes); [α]16.3 ꢀ37.5
EtOAc/hexanes); H NMR (400 MHz, CDCl3)
δ 7.60 (t, J = 10.1
D
1
Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.99 (t,
J = 5.5 Hz, 2H), 6.94 (t, J = 5.5 Hz, 2H), 6.87 – 6.80 (m, 2H),
5.65 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 4.95 (dd, J = 20.4, 10.1 Hz,
2H), 4.42 (dd, J = 7.7, 5.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H),
2.72 – 2.61 (m, 1H), 2.60 – 2.49 (m, 1H), 2.33 (s, 3H); 13C NMR
(c 0.033, EtOAc); H NMR (400 MHz, CDCl3) δ 7.65 – 7.55 (m,
4H), 7.43 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz, 4H), 6.88 –
6.81 (m, 2H), 5.67 – 5.54 (m, 1H), 4.99 – 4.91 (m, 2H), 4.48 (dd,
J = 7.5, 5.7 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.61 (dt, J = 13.8,
7.4 Hz, 1H), 2.52 (ddd, J = 13.7, 6.9, 5.8 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 167.2, 161.3, 159.5, 150.4, 134.9, 132.9, 132.2,
130.3, 129.2, 129.0, 128.0, 119.2, 117.3, 113.8, 113.4, 110.4, 65.9,
(101 MHz, CDCl3)
δ 165.8, 161.0, 159.4, 141.9, 136.1, 133.5,
130.2, 129.4, 129.0, 127.0, 116.4, 113.6, 113.2, 66.0, 55.3, 55.3,
44.0, 21.1; IR (thin film)
ν 3435, 3072, 3002, 2931, 1463; HRMS
55.4, 55.3, 43.9; IR (thin film)
ν 3401, 3072, 3004, 2934, 1462;
+
(ESI+) m/z: [M+H]+ Calcd for C26H28NO2 386.2115; Found
HRMS (ESI+) m/z: [M+H]+ Calcd for C26H25N2O2 397.1911;
Found 397.1896 . Chiral HPLC conditions: eluent: 0.5:99.5 2ꢀ
PrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ17b retention
time = 22.91 min, average (R)ꢀ17b retention time = 26.37 min.
1,1ꢀBis(4ꢀmethoxyphenyl)ꢀNꢀ(1ꢀphenylbutꢀ3ꢀenꢀ1ꢀyl)methanꢀ
imine (17h). Racemic 17h was synthesized from imino ester 15h
(64.4 mg, 0.16 mmol) following the general procedures described
above [Procedure A]. Passed through a short plug of silica gel
+
386.2103.
1,1ꢀBis(4ꢀmethoxyphenyl)ꢀNꢀ(1ꢀ(4ꢀmethoxyphenyl)butꢀ3ꢀenꢀ1ꢀ
yl)methanimine (17n). Racemic 17n was synthesized from imino
ester 15n (69.7 mg, 0.16 mmol) following the general procedures
described above [Procedure A]. Passed through a short plug of
silica gel (eluent: 10% EtOAc/hexanes) to afford a yellow oil
(average 4.1:1 mixture with aldimine regioisomer 18n, 37.6 mg,
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
0.09 mmol, 56% combined yield). An analytical sample of pure
aryl–C(imine) bond (see below); IR (thin film)
ν 3400, 3070,
2991, 1625, 1490, 1463; HRMS (ESI+) m/z: [M+H]+ Calcd for
1
2
8e was obtained by repetitive flash chromatography: Rf = 0.36 (10%
1
+
EtOAc/hexanes); H NMR (400 MHz, CDCl3)
δ 7.65 – 7.57 (m,
C26H25N2O2 397.1916; Found 397.1903. Chiral HPLC condiꢀ
3
4
5
6
7
8
9
2H), 7.28 – 7.21 (m, 2H), 6.98 (dq, J = 13.5, 8.7 Hz, 4H), 6.88 –
6.80 (m, 4H), 5.65 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.01 – 4.89
(m, 2H), 4.41 (dd, J = 7.7, 5.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H),
3.79 (s, 3H), 2.64 (dt, J = 14.9, 7.5 Hz, 1H), 2.59 – 2.50 (m, 1H);
tions: eluent: 0.5:99.5 2ꢀPrOH/hexane, flow rate: 1 mL/min, averꢀ
age (S)ꢀ19b retention time = 23.98 min, average (R)ꢀ19b retention
time = 25.92 min.
Due to hindered rotation about arylꢀimine bond, 1H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21b. Specifically, to a solution of imine 19b
(46.6 mg, 0.12 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (29.9 mg, 0.47 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6 d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) affording amine 21b
as a yellow solid (30.1 mg, 0.08 mmol, 67%): Rf = 0.29 (10%
EtOAc/hexane); mp 103.7 – 104.8 °C; [α]16.6D +41.0 (c 6.3 x 10ꢀ3,
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.54 (m, 2H), 7.40
(d, J = 8.2 Hz, 2H), 7.30 (dt, J = 11.6, 5.8 Hz, 1H), 7.24 – 7.11 (m,
2H), 7.00 – 6.89 (m, 1H), 6.89 – 6.72 (m, 3H), 5.73 – 5.57 (m,
1H), 5.10 (d, J = 7.1 Hz, 2H), 5.05 (dd, J = 6.0, 1.8 Hz, 1H), 3.67
(t, J = 6.1 Hz, 6H), 2.76 (s, 1H), 2.46 – 2.31 (m, 2H);13C NMR
(101 MHz, CDCl3) δ 157.5, 156.8, 150.2, 135.0, 131.9, 131.6,
130.3, 128.9, 128.5, 128.4, 127.8, 127.7, 120.3, 119.3, 118.0,
13C NMR (101 MHz, CDCl3)
136.1, 133.5, 130.2, 129.6, 129.4, 128.1, 116.4, 113.7, 113.6,
113.3, 65.6, 55.3, 55.3, 55.2, 44.1; IR (thin film) 3001, 2932，
δ 165.6, 161.0, 159.4, 158.3, 137.1,
ν
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2836, 1604, 1509, 1410, 1304, 1247, 1174; HRMS (ESI+) m/z:
[M+H]+ Calcd for C26H28NO3+ 402.2064; Found 402.2055.
Nꢀ(1ꢀ(6ꢀBromobenzo[d][1,3]dioxolꢀ5ꢀyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀ
bis(4ꢀmethoxyphenyl)methanimine (17o). Racemic 17o was synꢀ
thesized from imino ester 15o (54.5 mg, 0.10 mmol) following the
general procedures described above [Procedure A]. Passed
through a short plug of silica gel (eluent: 10% EtOAc/hexanes) to
afford a yellow oil (26.6 mg, 0.05 mmol, 50%): Rf = 0.48 (10%
1
EtOAc/hexanes); H NMR (400 MHz, CDCl3)
δ 7.66 – 7.60 (m,
2H), 7.36 (s, 1H), 6.99 – 6.93 (m, 4H), 6.92 (s, 1H), 6.88 – 6.82
(m, 2H), 5.95 (dd, J = 6.1, 1.4 Hz, 2H), 5.67 (ddt, J = 17.2, 10.1,
7.1 Hz, 1H), 5.00 – 4.91 (m, 2H), 4.85 (dd, J = 7.2, 5.6 Hz, 1H),
3.86 (s, 3H), 3.82 (s, 3H), 2.54 – 2.43 (m, 2H); 13C NMR (101
MHz, CDCl3)
δ 167.0, 161.3, 159.6, 147.5, 146.8, 137.7, 135.6,
133.4, 130.4, 129.5, 129.4, 116.8, 113.9, 113.4, 112.5, 112.3,
109.6, 101.7, 64.4, 55.5, 55.4, 43.2; IR (thin film)
ν 3440, 3073,
3002, 2930, 1473; HRMS (ESI+) m/z: [M+H]+ Calcd for
+
C26H25BrNO4 494.0961
496.0931.
& 496.0941; Found 494.0949 &
110.8, 110.7, 110.4, 59.6, 55.2, 55.2, 53.7, 42.9; IR (thin film)
ν
3327, 3056, 3003, 2962, 2227, 1640, 1493, 1460; HRMS (ESI+)
m/z: [M+H]+ Calcd for C26H27N2O2+ 399.2073; Found 399.2063.
Nꢀ(Bis(2ꢀmethoxyphenyl)methylene)ꢀ1ꢀ(4ꢀbromophenyl)butꢀ3ꢀ
enꢀ1ꢀamine (19f). Racemic 19f was synthesized from imino ester
6f (109.0 mg, 0.22 mmol) following the general procedures deꢀ
scribed above [Procedure A]. Passed through a short plug of silica
gel to remove catalyst and ligand (eluent: 10% EtOAc/hexanes) to
afford imine 19f as a yellow solid (83.3 mg, 0.19 mmol, 86%).
Enantioenriched (S)ꢀ19f was synthesized from 16f following the
general procedures described above [Procedure B] to afford a
colorless oil (average er 86.8:13.2, 85%): Rf = 0.23 (10%
EtOAc/hexanes); mp 145.8 – 147.1 °C; poor peak resolution in 1H
and 13C NMR due to hindered rotation about the aryl–C(imine)
Nꢀ1ꢀ(Furanꢀ2ꢀyl)butꢀ3ꢀenꢀ1ꢀyl)ꢀ1,1ꢀbis(4ꢀmethoxyphenyl)ꢀ
methanimine (17p). Racemic 17p was synthesized from imino
ester 15p (70.7 mg, 0.17 mmol) following the general procedures
described above [Procedure A]. Passed through a short plug of
silica gel (eluent: 10% EtOAc/hexanes) to afford a yellow oil
(average 6.8:1 mixture with aldimine regioisomer 18p, 39.9 mg,
0.11 mmol, 65% combined yield). An analytical sample of pure
8g was obtained by repetitive flash chromatography: Rf = 0.29 (10%
1
EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 7.65 – 7.57 (m,
2H), 7.38 – 7.33 (m, 1H), 7.18 – 7.11 (m, 2H), 7.01 – 6.94 (m,
2H), 6.87 – 6.77 (m, 2H), 6.34 – 6.28 (m, 1H), 6.16 (dt, J = 3.2,
0.7 Hz, 1H), 5.67 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 5.09 – 4.94 (m,
2H), 4.59 (dd, J = 7.3, 6.0 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H),
2.76 – 2.62 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 168.0, 161.2,
159.5, 156.6, 141.4, 135.3, 133.2, 130.4, 129.6, 129.1, 117.0,
bond (see below); IR (thin film)
ν 3072，2930, 2830，2374,
1605, 1490, 1276; HRMS (ESI+) m/z: [M+H]+ Calcd for
+
C25H25BrNO2 450.1069
& 452.1048; Found 450.1058 &
113.7, 113.3, 110.0, 105.4, 60.1, 55.4, 55.3, 39.9; IR (thin film)
ν
3441, 3073, 3002, 1641, 1463; HRMS (ESI+) m/z: [M+H]+ Calcd
for C23H24NO3+ 362.1751; Found 362.1739.
452.1.31. Chiral HPLC conditions: eluent: 0.5:99.5 2ꢀ
PrOH/hexane, flow rate:1 mL/min, average (S)ꢀ19f retention time
= 8.13 min, average (R)ꢀ19f retention time = 9.98 min.
4ꢀ(1ꢀ((Bis(2ꢀmethoxyphenyl)methyl)amino)butꢀ3ꢀenꢀ1ꢀyl)benꢀ
zonitrile (19b) Racemic 19b was synthesized from imino ester
16b (101.9 mg, 0.23 mmol) following the general procedures
described above [Procedure A]. Passed through a short plug of
silica gel to remove catalyst and ligand (eluent: 10%
EtOAc/hexanes) to afford imine 19b as a yellow solid (95.1 mg,
0.22 mmol, >98%). Enantioenriched (S)ꢀ19b was synthesized
from 16b following the general procedures described above [Proꢀ
cedure B] to afford a yellow solid (average er 89.1 : 10.9, 93%):
Rf = 0.29 (10% EtOAc/hexanes); mp 134.8 – 135.7 °C; poor peak
1
Due to hindered rotation about arylꢀimine bond, H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21f. Specifically, to a solution of imine 19f
(58.1 mg, 0.13 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (33.1 mg, 0.53 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
1
resolution in H and 13C NMR due to hindered rotation about the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
filtered, and concentrated in vacuo. The resulting residue was
(s, 1H), 5.04 (ddd, J = 11.1, 2.4, 1.1 Hz, 2H), 3.62 (d, J = 4.9 Hz,
6H), 3.57 (dt, J = 9.8, 4.9 Hz, 1H), 2.69 – 2.33 (m, 3H); 13C NMR
(101 MHz, CDCl3) 157.7, 157.0, 144.3, 136.1, 132.1, 131.0,
129.2, 128.7, 128.0, 127.7, 127.6, 127.5, 126.7, 120.3, 120.2,
117.1, 110.9, 110.8, 59.8, 55.3, 55.2, 53.6, 43.1; IR (thin film)
1
2
3
4
5
6
7
8
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) afforded amine 21f
as a yellow solid (28.0 mg, 0.06 mmol, 48%): Rf = 0.17 (10%
δ
EtOAc/hexanes); mp 167.8 ꢀ 168.3; [α]16.5 +35.1 (c 4.58 x 10ꢀ3,
ν
D
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.45 (m, 1H), 7.43
– 7.20 (m, 6H), 7.16 – 7.03 (m, 3H), 7.01 – 6.85 (m, 3H), 5.89 –
5.73 (m, 1H), 5.29 (s, 1H), 5.18 (dd, J = 13.5, 7.2 Hz, 2H), 3.78 (d,
J = 5.1 Hz, 6H), 3.74 – 3.66 (m, 1H), 2.79 – 2.32 (m, 3H);13C
NMR (101 MHz, CDCl3) δ 157.4, 156.8, 144.0, 135.9, 131.9,
130.7, 129.0, 128.5, 127.8, 127.4, 127.3, 127.3, 126.5, 120.0,
3329, 3062, 3026, 3003, 1642, 1491, 1465; HRMS (ESI+) m/z:
[M+H]+ Calcd for C25H28NO2+ 374.2115; Found 374.2111.
Nꢀ(Bis(2ꢀmethoxyphenyl)methyl)ꢀ1ꢀ(4ꢀfluorophenyl)butꢀ3ꢀenꢀ
1ꢀamine (19i) Racemic 19i was synthesized from imino ester 16i
(101.9 mg, 0.23 mmol) following the general procedures deꢀ
scribed above [Procedure A]. Passed through a short plug of silica
gel to remove catalyst and ligand (eluent: 10% EtOAc/hexanes) to
afford imine 19i as a yellow solid (88.9 mg, 0.23 mmol, >98%).
Enantioenriched 19i was synthesized from 16i following the genꢀ
eral procedures described above [Procedure B] to afford a yellow
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
120.0, 116.9, 110.6, 110.5, 59.5, 55.1, 55.0, 53.4.; IR (thin film)
ν
3457, 2956, 1647, 1642, 1292,1116; HRMS (ESI+) m/z: [M+H]+
+
Calcd for C27H27BrNO2 452.1225 & 454.1205; Found 452.1163
& 454.1190.
Nꢀ(Bis(2ꢀmethoxyphenyl)methyl)ꢀ1ꢀphenylbutꢀ3ꢀenꢀ1ꢀamine
(19h). Racemic 19h was synthesized from imino ester 16h (97.9
mg, 0.24 mmol) following the general procedures described
above [Procedure A]. Passed through a short plug of silica gel to
remove catalyst and ligand (eluent: 10% EtOAc/hexanes) to afꢀ
ford imine 19h as a yellow solid (79.7 mg, 0.21 mmol, 91%).
Enantioenriched (S)ꢀ19h was synthesized from 16h following the
general procedures described above [Procedure B] to afford a
yellow solid (average er 83.2:16.8, 87%): Rf = 0.38 (10%
EtOAc/hexanes); mp 87.3 ꢀ 88.9 °C; 1H NMR (400 MHz, CDCl3,
poor peak resolution due to hindered rotation about the aryl–
solid (average er 77.5:22.5, 84%): Rf
EtOAc/hexanes); mp 88.3 – 90.4 °C; poor peak resolution in H
and 13C NMR due to hindered rotation about the aryl–C(imine)
=
0.22 (10%
1
bond (see below); IR (thin film)
ν 3435, 3071, 3004, 1619, 1489;
HRMS (ESI+) m/z: [M+H]+ Calcd for C25H25FNO2 390.1869;
Found 390.1858. Chiral HPLC conditions: eluent: 0.5:99.5 2ꢀ
PrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ19i retention time
= 7.84 min, average (R)ꢀ19i retention time = 9.45 min.
+
Due to hindered rotation about arylꢀimine bond, 1H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21i. Specifically, to a solution of imine 19i
(43.5 mg, 0.11 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (26.0 mg, 0.42 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) afforded amine 21i
as a white solid (26.1 mg, 0.06 mmol, 55%): Rf = 0.22 (10%
C(imine) bond)
δ 7.55 (br d, J = 7.2 Hz, 1H), 7.34 – 7.10 (br m,
8H), 7.01 – 6.71 (br m, 4H), 5.70 (br s, 1H), 5.09 – 4.85 (br m,
2H), 4.35 (br s, 1H), 3.80 (br s, 1.5H), 3.55 (br s, 3H), 3.50 (br s,
3H), 3.30 (br s, 1.5H), 2.89 – 2.48 (br m, 2H); 13C NMR (101
MHz, CDCl3, peaks doubled due to hindered rotation about the
aryl–C(imine) bond)
δ 165.1, 157.4, 155.8, 144.5, 144.1, 139.4,
136.4, 132.0, 130.3, 130.1, 129.6, 129.3, 128.7, 128.6, 128.5,
128.4, 128.1, 128.1, 127.4, 127.2, 126.4, 120.7, 120.0, 116.5,
115.9, 112.1, 111.1, 110.3, 66.9, 66.4, 55.8, 55.4, 54.8, 44.0, 43.1;
IR (thin film)
ν 3431, 3071, 3026, 3003, 1618, 1490, 1460;
+
HRMS (ESI+) m/z: [M+H]+ Calcd for C25H26NO2 372.1958;
Found 372.1948. Chiral HPLC conditions: eluent: 0.5:99.5 2ꢀ
PrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ19h retention
time = 7.68 min, average (R)ꢀ17h retention time = 9.84 min.
Due to hindered rotation about arylꢀimine bond, 1H NMR analysis
of the resulting product could not be used to determine the regioiꢀ
someric ratio. Accordingly, the imine was reduced to the correꢀ
sponding amine 21h. Specifically, to a solution of imine 19h
(73.9 mg, 0.19 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (53.1 mg, 0.84 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6 d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) afforded amine 21h
as a yellow solid (38.4 mg, 0.10 mmol, 53%): Rf = 0.33 (10%
EtOAc/hexanes); mp 107.2 – 108.5 °C; [α]16.2 +10.5 (c 0.013,
D
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 7.5, 1.7 Hz,
1H), 7.30 – 7.18 (m, 4H), 7.13 (tt, J = 16.4, 8.2 Hz, 1H), 7.05 –
6.91 (m, 3H), 6.89 – 6.74 (m, 3H), 5.77 – 5.61 (m, 1H), 5.16 (s,
1H), 5.11 – 5.02 (m, 2H), 3.67 (d, J = 6.0 Hz, 6H), 3.63 – 3.55 (m,
1H), 2.61 – 2.31 (m, 3H);13C NMR (101 MHz, CDCl3) δ 161.9 (d,
JCꢀF = 243.6 Hz), 157.7, 157.0, 139.9 (d, JCꢀF = 2.8 Hz), 135.9,
132.0, 130.8, 129.2, 129.1 (d, JCꢀF = 7.9 Hz), 128.7, 127.73,
127.68, 120.4, 120.3, 117.4, 114.8 (JCꢀF = 21.0 Hz), 110.94,
110.87, 59.1, 55.4, 55.3, 53.7, 43.3; IR (thin film)
ν 3340, 3064,
2996, 1639, 1489, 1461; HRMS (ESI+) m/z: [M+H]+ Calcd for
C25H27FNO2+ 392.2026; Found 392.2013.
Nꢀ(Bis(2ꢀmethoxyphenyl)methyl)ꢀ1ꢀ(pꢀtolyl)butꢀ3ꢀenꢀ1ꢀamine
(19l) Racemic 19l was synthesized from imino ester 16l (101.0
mg, 0.23 mmol) following the general procedures described
above [Procedure A]. Passed through a short plug of silica gel to
remove catalyst and ligand (eluent: 10% EtOAc/hexanes) to afꢀ
ford imine 19l as a yellow solid (84.8 mg, 0.22 mmol, 96%). Enꢀ
antioenriched (S)ꢀ19l was synthesized from 16l following the
general procedures described above [Procedure B] to afford a
yellow solid (average er 80.9:19.1, 91%): Rf = 0.33 (10%
EtOAc/hexanes); mp 84.9 – 85.4 °C; [α]20 +6.15 (c 0.011,
D
EtOAc); 1H NMR (400 MHz, CDCl3)
δ 7.38 (dd, J = 7.5, 1.7 Hz,
1H), 7.32 – 7.15 (m, 7H), 7.10 (tt, J = 8.0, 4.0 Hz, 1H), 6.93 (td, J
= 7.4, 1.0 Hz, 1H), 6.85 – 6.70 (m, 3H), 5.77 – 5.62 (m, 1H), 5.20
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The Journal of Organic Chemistry
1
EtOAc/hexanes); mp 77.9 – 78.7 °C; poor peak resolution in H
of CH2Cl2). The combined organic layers were dried (Na2SO4),
and 13C NMR due to hindered rotation about the aryl–C(imine)
bond (see below); IR (thin film) 3439, 3065, 3002, 1619, 1489,
1460; HRMS (ESI+) m/z: [M+H]+ Calcd for C26H28NO2
386.2120; Found 386.2105. Chiral HPLC conditions: eluent:
0.5:99.5 2ꢀPrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ19l
retention time = 7.94 min, average (R)ꢀ19l retention time = 9.37
min.
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 15% EtOAc/hexanes) afforded amine 21n
as a yellow solid (48.6 mg, 0.12 mmol, 80%): Rf = 0.31 (15%
1
2
3
4
5
6
7
8
ν
+
EtOAc/hexanes); mp 91.8 – 92.5 °C; [α]16.6 +19.6 (c 0.024,
D
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 7.5, 1.6 Hz,
1H), 7.27 – 7.08 (m, 6H), 7.00 – 6.92 (m, 1H), 6.89 – 6.81 (m,
4H), 6.76 (t, J = 7.3 Hz, 1H), 5.78 – 5.63 (m, 1H), 5.20 (s, 1H),
5.07 (t, J = 13.5 Hz, 2H), 3.80 (d, J = 10.4 Hz, 3H), 3.73 – 3.63
(m, 6H), 3.59 – 3.51 (m, 1H), 2.70 – 2.31 (m, 3H); 13C NMR (101
MHz, CDCl3) δ 158.4, 157.6, 157.0, 136.3, 136.2, 132.1, 130.9,
129.3, 128.7, 128.6, 127.5, 127.5, 120.2, 120.2, 117.0, 113.3,
Due to hindered rotation about arylꢀimine bond, 1H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21l. Specifically, to a solution of imine 19l
(41.3 mg, 0.12 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (25.9 mg, 0.41 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) afforded amine 21l
as a white solid (20.2, 0.05 mmol, 42%). Rf = 0.33 (10%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
110.8, 110.7, 59.0, 55.3, 55.2, 55.2, 53.7, 43.1.; IR (thin film)
ν
3329, 3061, 2997, 1639, 1489, 1460; HRMS (ESI+) m/z: [M+H]+
Calcd for C26H30NO3+ 404.2226; Found 404.2212.
Nꢀ(Bis(2ꢀmethoxyphenyl)methyl)ꢀ1ꢀ(6ꢀbromobenzo[d][1,3]diꢀ
oxolꢀ5ꢀyl)butꢀ3ꢀenꢀ1ꢀamine (19o) Racemic 19o was synthesized
from imino ester 16o (102.6 mg, 0.19 mmol) following the genꢀ
eral procedures described above [Procedure A]. Passed through a
short plug of silica gel to remove catalyst and ligand (eluent: 10%
EtOAc/hexanes) to afford imine 19o as a clear oil (95.3 mg, 0.19
mmol, >98%). Enantioenriched (S)ꢀ19o was synthesized from 16o
following the general procedures described above [Procedure B]
to afford a colorless oil (average er 87.6:12.4, 83%): Rf = 0.11 (10%
EtOAc/hexanes); mp 111.3 – 113.4 °C; [α]16.7 +17.0 (c 0.02,
D
EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 7.5, 1.7 Hz,
1H), 7.27 – 7.10 (m, 7H), 7.00 – 6.92 (m, 1H), 6.87 – 6.75 (m,
3H), 5.79 – 5.64 (m, 1H), 5.22 (s, 1H), 5.13 – 5.01 (m, 2H), 3.67
(d, J = 5.9 Hz, 6H), 3.57 (dd, J = 7.8, 6.0 Hz, 1H), 2.59 – 2.22 (m,
6H); 13C NMR (101 MHz, CDCl3) δ 157.6, 157.0, 141.2, 136.3,
136.1, 132.1, 130.9, 129.3, 128.7, 128.7, 127.5, 127.5, 120.2,
120.2, 117.0, 110.8, 110.7, 59.3, 55.3, 55.2, 53.7, 43.1, 21.2; IR
1
EtOAc/hexane poor peak resolution in H and 13C NMR due to
hindered rotation about the aryl–C(imine) bond (see below); IR
(thin film)
ν
3072, 2934, 1620, 1472; HRMS (ESI+) m/z: [M+H]+
+
Calcd for C26H25BrNO4 494.0967 & 496.0946; Found 494.0961
& 496.0946. Chiral HPLC conditions: eluent: 0.5:99.5 2ꢀ
PrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ19o retention
time = 16.32 min, average (R)ꢀ19o retention time = 47.35 min.
Due to hindered rotation about arylꢀimine bond, 1H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21o. Specifically, to a solution of imine 19o
(37.8 mg, 0.07 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (14.8 mg, 0.24 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) afforded amine 21o
(thin film)
ν 3325, 3056, 3004, 2963, 1641, 1492, 1462; HRMS
+
(ESI+) m/z: [M+H]+ Calcd for C26H30NO2 388.2277; Found
388.2263.
Nꢀ(Bis(2ꢀmethoxyphenyl)methyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)butꢀ3ꢀ
enꢀ1ꢀamine (19n). Racemic 19n was synthesized from imino ester
16n (100.4 mg, 0.23 mmol) following the general procedures
described above [Procedure A]. Passed through a short plug of
silica gel to remove catalyst and ligand (eluent: 15%
EtOAc/hexanes) to afford imine 19n as a yellow solid (84 mg,
0.21 mmol, 93%). Enantioenriched (S)ꢀ19n was synthesized from
16n following the general procedures described above [Procedure
B] to afford a yellow solid (average er 87.6:12.4, 71%): Rf = 0.31
(15% EtOAc/hexane); mp 77.0 – 77.4 °C; poor peak resolution in
1H and 13C NMR due to hindered rotation about the aryl–C(imine)
bond (see below); IR (thin film)
ν 3450, 3069, 3002, 2934, 1489,
1461; HRMS (ESI+) m/z: [M+H]+ Calcd for C26H28NO3
402.2069; Found 402.2051. Chiral HPLC conditions: eluent:
0.5:99.5 2ꢀPrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ19n
retention time = 14.36 min, average (R)ꢀ19n retention time =
16.03 min.
+
as a colorless oil (23.8 mg, 0.04 mmol, 57%): Rf = 0.11 (10%
1
EtOAc/hexanes); [α]16.7 ꢀ20.5 (c 0.018, EtOAc); H NMR (400
D
MHz, CDCl3) δ 7.39 – 7.30 (m, 1H), 7.28 – 7.09 (m, 4H), 6.99 –
6.90 (m, 2H), 6.89 – 6.73 (m, 3H), 5.96 (dd, J = 18.4, 1.4 Hz, 2H),
5.71 (dddd, J = 16.2, 10.2, 8.4, 5.8 Hz, 1H), 5.14 (s, 1H), 5.12 –
5.03 (m, 2H), 4.03 (dd, J = 8.6, 4.7 Hz, 1H), 2.52 – 1.80 (m,
4H);13C NMR (101 MHz, CDCl3) δ 157.6, 156.9, 147.5, 146.8,
136.5, 135.6, 132.0, 130.8, 129.2, 128.5, 127.6, 127.5, 120.2,
120.2, 117.4, 114.1, 112.1, 110.7, 110.6, 108.8, 101.5, 57.7, 55.3,
Due to hindered rotation about arylꢀimine bond, 1H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21n. Specifically, to a solution of imine 19n
(62.2 mg, 0.15 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (38.4 mg, 0.61 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
55.2, 53.4, 41.9, 29.7; IR (thin film)
ν 3348, 3072, 3001, 1638,
+
1470; HRMS (ESI+) m/z: [M+H]+ Calcd for C26H27BrNO4
496.1123 & 498.1103; Found 496.1155 & 498.1077.
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The Journal of Organic Chemistry
Page 18 of 19
Nꢀ(Bis(2ꢀmethoxyphenyl)methyl)ꢀ1ꢀ(furanꢀ2ꢀyl)butꢀ3ꢀenꢀ1ꢀ
Linear free energy relationship analyses, NMR spectra for new
1
2
3
4
5
6
7
8
amine (19p). Racemic 19p was synthesized from imino ester 16p
(103.9 mg, 0.26 mmol) following the general procedures deꢀ
scribed above [Procedure A]. Passed through a short plug of silica
gel to remove catalyst and ligand (eluent: 10% EtOAc/hexanes) to
afford imine 19p as a yellow solid (82.1 mg, 0.23 mmol, 88%).
Enantioenriched (S)ꢀ19p was synthesized from 16p following the
general procedures described above [Procedure B] to afford a
colorless oil (average er 71.5:28.5, 83%): Rf = 0.17 (10%
compounds, and chiralꢀphase HPLC traces (PDF). This material is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
§ Formerly Wendy H. Fields
Corresponding Author
* Eꢀmail: chruma@scu.edu.cn
1
9
EtOAc/hexanes); mp 55.4 – 55.9 °C poor peak resolution in H
and 13C NMR due to hindered rotation about the aryl–C(imine)
ORCID
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Jason J. Chruma: 0000ꢀ0002ꢀ3669ꢀ4863
bond (see below); IR (thin film)
ν 3426, 3070, 2996, 1620, 1488,
+
1460; HRMS (ESI+) m/z: [M+H]+ Calcd for C23H24NO3
362.1756; Found 362.1745. Chiral HPLC conditions: eluent:
0.5:99.5 2ꢀPrOH/hexane, flow rate: 1 mL/min, average (S)ꢀ19p
retention time = 11.58 min, average (R)ꢀ19p retention time =
14.95 min.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support provided by the NSFC (No. 21372159). Comꢀ
pound characterization (NMR, HRMS, IR) was performed by the
Comprehensive Specialized Laboratory Training Platform, Colꢀ
lege of Chemistry, Sichuan University.
Due to hindered rotation about arylꢀimine bond, 1H NMR
analysis of the resulting product could not be used to determine
the regioisomeric ratio. Accordingly, the imine was reduced to the
corresponding amine 21p. Specifically, to a solution of imine 19p
(36.5 mg, 0.10 mmol) in MeOH (0.5 mL) was added in one porꢀ
tion NaBH3CN (25.8 mg, 0.41 mmol, 4 equiv) and the resulting
solution was stirred at rt under Ar for 6 d. The resulting reaction
mixture then was diluted with CH2Cl2 and washed with 1N aq
NaOH (the aqueous layer was extracted with two more portions
of CH2Cl2). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was
passed through a short plug of silica gel to remove any unreacted
starting imine (eluent: 10% EtOAc/hexanes) afforded amine 21p
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as a colorless oil (19.8 mg, 0.05 mmol, 50%): Rf = 0.17 (10%
EtOAc/hexanes); [α]16.8 +20.6 (c 5.4 x 10ꢀ3, EtOAc); H NMR
1
D
(400 MHz, CDCl3) δ 7.52 (ddd, J = 9.2, 6.5, 2.5 Hz, 1H), 7.36 (dt,
J = 5.6, 2.8 Hz, 1H), 7.27 – 7.09 (m, 4H), 6.97 (td, J = 7.4, 0.9 Hz,
1H), 6.87 – 6.75 (m, 3H), 6.31 (dd, J = 3.1, 1.8 Hz, 1H), 6.13 (d, J
= 3.0 Hz, 1H), 5.72 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 5.46 (s, 1H),
5.13 – 5.08 (m, 1H), 5.07 – 4.99 (m, 1H), 3.72 (t, J = 4.7 Hz, 5H),
3.67 (dd, J = 8.0, 5.9 Hz, 1H), 2.66 – 2.48 (m, 2H), 2.39 – 2.15 (m,
1H);13C NMR (101 MHz, CDCl3) δ 157.6, 157.1, 156.6, 141.3,
135.5, 131.7, 130.7, 129.0, 128.8, 127.7, 127.7, 120.3, 120.3,
117.1, 110.8, 110.7, 109.8, 106.5, 55.4, 53.7, 52.7, 39.4; IR (thin
film)
ν 3342, 3071, 3000, 2933, 1640, 1489, 1462; HRMS (ESI+)
m/z: [M+H]+ Calcd for C23H26NO3 364.1913; Found 364.1891.
Hydrolysis of Imine 19f: To a stirred solution of imine (S)ꢀ
19f (74% ee, 43 mg, 96 ꢁmol) in 1:1 THF/H2O (1.0 mL) at rt was
added TFA (0.1 mL) and the resulting solution was stirred vigorꢀ
ously at rt for 3 d and monitored by TLC. Upon completion, volaꢀ
tiles were removed by rotary evaporation and the resulting aqueꢀ
ous solution was diluted with H2O (3.0 mL). After washing the
Et2O (3 x 2 mL), the aqueous layer was made basic by addition of
solid NaHCO3 and then extracted with EtOAc (3 x 2 mL). The
combined organic phase was concentrated by rotary evaporation
to afford amine 22f as a yellow oil (16 mg, 72 ꢁmol, 75%):
[α]16.7D ꢀ5.67 (c 4.6 x 10ꢀ3, EtOAc) compared with literature value
of [α]23D ꢀ40.1 (c 1.16, CHCl3, 98% ee).15
+
ASSOCIATED CONTENT
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The Journal of Organic Chemistry
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