Site-Specific Functionalization of 1,3-Dioxolane with Imines: A Radical Chain Approach to Masked α-Amino Aldehydes

Article abstract of DOI:10.1021/acs.joc.8b00715

A thiol-promoted site-specific addition of 1,3-dioxolane to imines through a radical chain process is described. This process represents a metal-free and redox-neutral way to convert inexpensive materials to a broad range of protected α-amino aldehydes in good to excellent yields using only a catalytic amount of radical precursor. Control experiments revealed that both the thiol and a small amount of oxygen from air are indispensable to the success of this reaction.

Full text of DOI:10.1021/acs.joc.8b00715

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Site-Specific Functionalization of 1,3-Dioxolane with Imines:
A Radical Chain Approach to Masked #-Amino Aldehydes
Haipeng Zeng, Sen Yang, Haotian Li, Dengfu Lu, Yuefa Gong, and Jin-Tao Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00715 • Publication Date (Web): 12 Apr 2018
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SiteꢀSpecific Functionalization of 1,3ꢀDioxolane with Imines: A
Radical Chain Approach to Masked αꢀAmino Aldehydes
Haipeng Zeng, Sen Yang, Haotian Li, Dengfu Lu*, Yuefa Gong* and JinꢀTao Zhu
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School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Rd.,
Wuhan, Hubei, 430074, China
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Supporting Information Placeholder
Abstract: A thiol promoted siteꢀspecific addition of 1,3ꢀdioxolane to imines through radical
chain process is described. This process represents a metalꢀfree and redoxꢀneutral way to convert
inexpensive materials to a broad range of protected αꢀamino aldehydes in good to excellent
yields using only catalytic amount of radical precursor. Control experiments revealed that both
the thiol and a small amount of oxygen from air are indispensable to the success of this reaction.
Introduction
Converting abundant ethers and alcohols to valuable building blocks through direct sp3 C–H
functionalization is a challenging endeavor in synthetic chemistry.1 Due to the αꢀeffect of the
adjacent oxygen atom, radical activation of the αꢀC–H bonds has emerged as a popular strategy,2
for example, the flourishing oxidative coupling reactions.1b,1dꢀg Within these methods, the C–H
bonds are prevailingly activated by strongly electronꢀdeficient oxygenꢀcentered radicals
generated from stoichiometric amounts of oxidants such as peroxides3 and persulfates.4 Besides
oxidative coupling processes, we noticed that numerous redoxꢀneutral reactions, e.g., radical
addition to multiple bonds, also require excess amount of radical precursors,5 probably due to the
irreversible generation of highly active radical species.
Scheme 1. Radical addition of 1,3ꢀdioxolane to imines
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Our lab has recently developed an azobisisobutyronitrile (AIBN) initiated radical chain
addition of cyclic ethers to imines, demonstrating that etheric radicals can be regenerated from
the reaction intermediate.6 This discovery led us to explore more general and synthetically useful
redoxꢀneutral radical functionalization methods. The functionalization of 1,3ꢀdioxolane with
imines7 is of special interest since it represents a practical route to masked amino aldehydes,
which are important building blocks in organic synthesis. However, the existing methods
developed by Alonso7a, Tomioka7bꢀc, and Shi7d et al. require either stoichiometric amount of
radical precursors or UV irradiation (Scheme 1, a). Meanwhile, due to the close dissociation
energy of the C–H bonds,8 the siteꢀselectivity of 1,3ꢀdioxolane remains a challenge with oxygenꢀ
centered radicals,3a,3d,3fꢀg,4b,5aꢀb,5h (usually from 1.5:1 to 6:1). A method that can regioselectively
convert 1,3ꢀdioxolane and imines to masked amino aldehydes without using a stoichiometric
radical precursor is highly desirable.
Most recently, Doyle8 reported a formylation of aryl chlorides which selectively activates the
2ꢀC–H bond of 1,3ꢀdioxolane with a chlorine radical. While in our radical chain reaction, an
exclusive 2ꢀC–H selectivity was also observed for 1,3ꢀdioxolane, despite a low conversion.6
Based on the mechanistic studies, it is assumed that this selectivity may stem from the inferior
reactivity of a stabilized nitrogen radical intermediate A (Scheme 1, b). However, compared to
tetrahydrofuran, the more complicated reactivity of 1,3ꢀdioxolane could increase the rate of chain
termination other than the effective propagation, thus the less reactive radical A may also be
responsible for the poor chain efficiency. Therefore, we envisioned to introduce a suitable radical
mediator to balance the reactivity and selectivity in the hydrogen atom transfer (HAT) step.
Inspired by the pioneering works of Roberts9 and Newcomb10 et al., we proposed that thiols
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could be potential candidates as they are reported to readily reduce nitrogen radicals and the
resulting thiyl radical is capable of Hꢀatom abstraction from specific C–H bonds.11 Herein we
report a thiol mediated radical chain addition of 1,3ꢀdioxolane to different types of imines with
exclusive siteꢀselectivity. (Scheme 1, c)
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Results and discussion
Table 1. Reaction condition optimizationa
Entry
Variations from the
standard conditions
none
Conv.b
Yield
(3aa)
62%
1
66%
<5%
34%
<5%
60%
62%
10%
36%
68%
52%
<5%
20%
2
without AIBN
20 mol% AIBN
without TDM
<5% c
3
33%
4
<5% c
55%
5
20 mol% TDM.
T1 instead of TDM
T2 instead of TDM
without 4Å MS
purified imine
reaction at 65 °C
under N2 or Ar
under O2
6
52%
<5% c
7
8
31%
9
63%
10 d
11
12
44%
<5% c
15% c
aUnless otherwise stated, the reactions were carried out under air in a 20 mL sealed tube with benzaldehyde (0.2
mmol), aniline (0.2 mmol) and 4Å molecular sieves (80 mg) in freshly distilled 1,3ꢀdioxolane (2 mL) in the presence
b
1
of AIBN (0.02 mmol) and TDM (0.02 mmol); The conversion was determined with crude H NMR by calculating
the remaining aldehyde and imine; cDetermined by 1H NMR; dReaction time: 24 h.
Starting with a relatively less reactive N,1ꢀdiphenylmethanꢀimine, after extensive screening of
the conditions, the reaction of inꢀsitu formed imine was able to achieve good conversion in the
presence of 10 mol % of AIBN and tertꢀdodecyl mercaptan (TDM) at 80 °C with 4 Å molecular
sieves, affording product 3aa in 62% yield as the only regioꢀisomer (Table 1, entry 1). A few
conditions that may be mechanistically important are described here. As previously observed, the
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reaction doesn’t occur in the absence of AIBN (entry 2). Interestingly, for this substrate, the
reaction hardly proceeds without TDM, while more of it doesn’t improve the yield either (entries
4ꢀ5). Aliphatic thiols are more effective than aromatic ones and the bulkiness of aliphatic thiols
may also play a role, presumably because of their potential nucleophilic addition to imines
(entries 6ꢀ7). Since the imine is formed inꢀsitu, 4 Å molecular sieves are essential to remove the
water, and the same yield was obtained with purified imine (entries 8ꢀ9). The reaction slows
down at 65 °C and the yield was not improved after extended reaction time (entry 10).
Surprisingly, product 3aa was hardly observed when the reaction was strictly conducted under
inert atmosphere (entry 11), implying the participation of O2. However, O2 atmosphere also
caused an inefficient transformation (entry 12).
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Table 2. Addition of 1,3ꢀdioxolane to N,1ꢀdiarylmethanꢀiminesa
Structure
Entry Substituent
Product
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
Yield
86%b
67%b
72%b
75%
79%
65%
60%
91%
84%
95%b
77%
95%b
74%
97%b
73%
55%
1
Ar1 = 4ꢀCO2MeꢀC6H4
2
Ar1 = 4ꢀMeꢀC6H4
Ar1 = 4ꢀMeOꢀC6H4
Ar1 = 4ꢀFꢀC6H4
3
4
5
Ar1 = 4ꢀClꢀC6H4
Ar1 = 3ꢀClꢀC6H4
Ar1 = 2ꢀClꢀC6H4
Ar1 = 2,4ꢀCl2ꢀC6H3
Ar1 = 2ꢀpyridyl
6
7
8
9
3ja
3ib
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16
Ar2 = 4ꢀMeꢀC6H4
Ar2 = 4ꢀMeOꢀC6H4
Ar2 = 4ꢀClꢀC6H4
Ar2 = 3ꢀClꢀC6H4
Ar2 = 4ꢀBrꢀC6H4
Ar2 = 4ꢀFꢀC6H4
3ic
3id
3ie
3if
3ig
Ar2 = 3,5ꢀ(CF3)2ꢀC6H3
3ih
aUnless otherwise stated, the reaction was performed under air in a 20 mL sealed tube with a corresponding
aldehyde (0.2 mmol), an amine (0.2 mmol) and 4Å molecular sieves (80 mg) in freshly distilled 1,3ꢀdioxolane (2 mL)
in the presence of AIBN (0.02 mmol) and TDM (0.02 mmol); bReaction performed with purified imine.
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After establishing the optimized condition, we tested a combination of various aromatic
aldehydes and aniline derivatives with 1,3ꢀdioxolane. Both electronꢀrich and electronꢀdeficient
aldehydes including heterocycles are well tolerated in combination with aniline to afford the
products 3baꢀ3ja regioselectively in good to excellent yields (Table 2, entries 1ꢀ9). Different
substituted anilines are also compatible with 2,4ꢀdichlorobenzaldehyde (entries 10ꢀ16). In cases
that imines are not formed inꢀsitu with sufficient efficiency and purity, purified imines are
employed to ensure reproducibility.
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While most reports of radical additions to imine are limited to N,1ꢀdiaryl substrates, the
functionality performance of this method encouraged us to explore more synthetically intriguing
aldehydes and amines (Table 3). The three component reaction of ethyl glyoxylate, aniline and
1,3ꢀdioxolane gives the αꢀamino ester 4a as a single regioꢀisomer with excellent yield (entry 1).
Several substituted anilines are also suitable for this “oneꢀpot” procedure (60%ꢀ96% yields,
entries 2ꢀ7). The α C–H bonds of amines are normally considered unstable towards radical
species. Surprisingly, aliphatic amines bearing very labile C–H bonds, such as benzylamine and
1ꢀphenylethylamine, are compatible with this process, leading to products 4h and 4i with
removable Nꢀprotecting groups (entries 8ꢀ9). The reaction of cyclohexylamine and amantadine
proceed smoothly to afford product 4j and 4k in moderate to good yields (entries 10ꢀ11).
Gratifyingly, amines with multiple functional groups are also well applied, offering densely
functionalized products 4l and 4m in practical yields (entries 12ꢀ13).
To demonstrate the synthetic utility of this method, we tested two representative substrates on
gramꢀscale and obtained comparative yields (Table 3, entries 4 and 8). As shown in Scheme 2,
product 4h, for example, can be readily converted to key intermediate 5 that serves as a versatile
precursor to various unnatural amino acid derivatives. Products 6 and 7 are also typical
substrates for asymmetric hydrogenation to produce chiral amino acids.13
Table 3. Addition of 1,3ꢀdioxolane to ethyl glyoxylate iminesa
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Entry Substituent
Product Yield
1
2
3
4
5
6
7
R = Phb
96%
4a
4b
4c
4d
4e
4f
R = 4ꢀCO2MeꢀC6H4
R = 4ꢀMeꢀC6H4
R = 4ꢀOMeꢀC6H4
R = 4ꢀFꢀC6H4
R = 4ꢀClꢀC6H4
R = 3ꢀClꢀC6H4
60%
91%
96% (90%)d
60%
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85%
61%
4g
10
HN
O
EtO2C
O
4h, 62%c (55%)d
4i, 65%c dr 1.2:1
4j, 62%c
4k, 75%
4l, 45%
4m, 66%, dr 1.5:1
aUnless otherwise stated, the reaction was performed under air in a 20 mL sealed tube with ethyl glyoxylate (0.2
mmol), a corresponding amine (0.2 mmol) and 4Å molecular sieves (80 mg) in freshly distilled 1,3ꢀdioxolane (2
mL) in the presence of AIBN (0.02 mmol) and TDM (0.02 mmol); Aniline: 2 equiv; cReaction performed at 65 °C
without thiol; dReaction on 10 mmol scale.
b
Scheme 2. Product derivatizations
aCondition: AcCl (1.5 equiv.), NEt3 (1.5 equiv.), ClCH2CH2Cl, room temperature, 4 h; bCondition: AcOH/HI, 65 °C,
2 h.
To gather evidences for mechanistic insights of this transformation, a series of control
experiments were carried out.13 Firstly, the reaction of 1i and 2a in 1,3ꢀdioxolane was inhibited
by 20 mol% of the radical scavenger TEMPO ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxyl, Scheme
3, a). Secondly, the kinetic studies showed the reaction was significantly accelerated by thiol
and, unexpectly, a lower loading of thiol led to a more durable process (b). Thirdly, when a nonꢀ
activated alkene was mixed with TDM under the reaction conditions to capture the thiyl radical
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through the thiolꢀene process,14 the click product 9 was isolated under inert atmosphere, but not
detected in the presence of air (c). Then, in a 20 mL sealed tube (22ꢀ24 mL gas space), 5 mL of
O2 in otherwise N2 promoted the reaction most efficiently, which is consistent with its good
performance under air (d). Next, carbonate 10 was identified as a side product in aliphatic
amines participated reactions (about 15% yield based on imine), which possibly comes from the
O2 entrapment of a 1,3ꢀdioxolane radical. Interestingly, 10 was not observed in the reaction of
aromatic amines (e). In addition, the reaction of tetrahydrofuran revealed a similar thiolꢀ
accelerating trend, which indicates this is not an individual effect for 1,3ꢀdioxolane (f).
Furthermore, primary kinetic isotope effect was observed for THF under these conditions in both
intermolecular competition (kH/kD = 6.3) and parallel (kH/kD = 3.6±0.1) experiments.
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Scheme 3. Mechanistic related control experiments
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The above observations together with the results in table 1 reveal mechanistic information.
First, radical species are involved in this reaction, and AIBN, thiol and O2 are all essential to the
reaction. Then, according to the thiolꢀene reaction, thiol and AIBN should be able to generate
thiyl radical under inert atmosphere. So, the necessity of O2 suggests that the thiolꢀthiyl radical
pair alone could not promote the chain reaction efficiently as we proposed in the introduction. An
O2ꢀrelated species is highly likely involved in the radical chain propagation cycle. Additionally,
the generation of carbonate 10 reveals O2 could also act as a competing electrophile when imine
is not reactive enough. Furthermore, no matter which radical is the real abstracting species, it has
excellent regioselectivity, and the HAT process from the substrate is probably rateꢀdetermining.
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Scheme 4. Plausible reaction mechanism
Based on these results, we proposed a plausible reaction mechanism as illustrated in Scheme
4. In the initiation stage, AIBN firstly decomposes under heating condition to generate isobutyl
nitrile radical B, which is known15 to react with a thiol to yield a thiyl radical C and isobutyl
nitrile 12 (detected by GCꢀMS). Then, O2 could participate in two different ways: either
combines with radical B to form a peroxyl radical D (path I), or reacts with thiyl radical C to
furnish a thiylperoxyl radical RSOO·,16 which could be further converted to a series of
derivatives according to previous studies (path II), such as sulfonyl radical [RS(O)O·], sulfonyl
peroxyl radical [RS(OO·)O2] and sulfinyl [RSO·] radical. These species are presented as one
general formula [RSOn·] in Scheme 4.
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In the case of path I, the peroxyl radical D may abstract an Hꢀatom from 1,3ꢀdioxolane to
generate 13 (detected by GCꢀMS) and radical E, which would quickly add to an imine to furnish
a nitrogenꢀcentered radical F. This nitrogen radical would be readily reduced by one molecule of
thiol to afford the product and a thiyl radical C.10,17 Since RS–H and R’OO–H have very similar
bond dissociation energy (both around 87–88 kcal/mol),11,18 radical C may abstract an Hꢀatom
from peroxide 13 to regenerate the peroxyl radical D. On the other hind, thiyl peroxyl radical and
its derivatives [RSOn·] normally have mild reactivity and form weak O–H bonds. Therefore, they
may also be able to abstract a hydrogen atom from 1,3ꢀdioxolane and then reduce the nitrogen
radical G. However, in this scenario, there might multiple species (n = 1, 2 or 4) involved and we
currently cannot identify the real effective one (path II). Based on the evidence we have, neither
path I nor II could be ruled out, and maybe both of them contribute to the reaction. In addition,
although O2 is essential to the desired radical chain propagation, it also acts as a competing
electrophile toward radical E to cause a nonꢀproductive oxidation cycle to yield carbonate 10,
especially in the reactions of Nꢀaliphatic imines.
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Conclusion
In summary, we have developed an AIBN/thiol promoted siteꢀspecific and redoxꢀneutral
functionalization procedure of 1,3ꢀdioxolane with imines to synthesize masked amino aldehydes,
avoiding the use of stoichiometric amount of radical precursors. This method is scalable and
tolerates a range of functional groups, including those were normally incompatible with imine
radical additions. Mechanistic studies demonstrate this transformation proceeds through a thiol
and O2 promoted radical chain pathway with the initiation of AIBN. Further synthetic
applications and mechanistic studies of this reaction are ongoing in our laboratory.
Experimental Section
i. General procedures. All reactions were performed in ovenꢀdried roundꢀbottom flasks and
tubes. Solvents were dried and freshly distilled before use. 4 Å molecular sieves were freshly
activated before use. Aldehydes and amines are purified either by distillation or recrystallization
before use. Reactions were monitored by thin layer chromatography (TLC) using silica gel 60 Fꢀ
254 plates. TLC plates were normally visualized under UV irradiation (254 nm or 365 nm),
stained with basic KMnO4 or phosphomolybdic acid. Flash column chromatography was
performed using silica gel 60 (200−300 mesh).
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ii. Instrumentation. Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on Bruker Ascend 400 MHZ or 600 MHZ.
Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane
and are referenced to the NMR solvent residual peak (CHCl3: δ 7.26). Chemical shifts for
carbons are reported in parts per million downfield from tetramethylsilane and are referenced to
the carbon resonances of the NMR solvent (CDCl3: δ 77.0). Data are represented as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad), coupling constants in Hertz (Hz), and integration. HRMS was measured on a Bruker
SolariX 7.0 T spectrometer equipped with an ESI or APCI source.
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iii. Abbreviations used: TLC–thin layer chromatography; AIBN–azobisisobutyronitrile; TDM–
tertꢀdodecyl mercaptan; PE–Petroleum Ethers; TEMPO–2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl;
NOE–Nuclear Overhauser Effect.
iv. General procedures for Initiator evaluation and condition optimization (Table 1)
To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added benzaldehyde (21.2 mg,
0.2 mmol), aniline (18.6 mg, 0.2 mmol), AIBN (0.02 or 0.04 mmol) and freshly activated 4 Å
molecular sieves (80 mg, if any). Freshly distilled 1,3ꢀdioxolane (2 mL) was added through a
syringe followed by the addition of a corresponding thiol (0.02 or 0.04 mmol). The reaction tube
was then sealed with a septum under air, heated up to the indicated temperature and stirred for 12
hours. The reaction was then cooled down, filtered through a Celite® pad, washed with ether, and
1
the filtrate was concentrated in vacuo. The residue was submitted for H NMR analysis with
1,3,5ꢀtrimethoxybenzene as an internal standard. For reactions with decent conversions, yield of
3aa was obtained after purification through a silica gel column chromatography (PE:EtOAc from
20:1 to 10:1 ).
Nꢀ((1,3ꢀDioxolanꢀ2ꢀyl)(phenyl)methyl)aniline (3aa): compound 3aa was isolated through a silica
gel column chromatography (PE:EtOAc from 20:1 to 10:1) as a yellow solid (32 mg, 62% yield,
m.p. 76–78 °C), which is a known compound7d and the characterization data are in accordance
with the literature. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 6.9 Hz, 2H), 7.24 (t, J = 7.4 Hz,
2H), 7.20 – 7.15 (m, 1H), 7.00 (t, J = 7.8 Hz, 2H), 6.57 (t, J = 7.3 Hz, 1H), 6.48 (d, J = 7.9 Hz,
2H), 5.10 (d, J = 2.8 Hz, 1H), 4.49 (d, J = 2.8 Hz, 2H), 3.77 (m, 4H); 13C{1H}NMR (100 MHz,
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CDCl3) δ 147.0, 138.7, 129.1, 128.4, 127.7, 127.6, 117.7, 113.8, 105.5, 65.5, 65.3, 60.2; IR νmax
(neat)/cmꢀ1: 3361, 3027, 2876, 1603, 1505, 1294, 1123, 1031, 749, 700.
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v. Addition of 1,3ꢀdioxolane to N,1ꢀdiarylmethanimines (Table 2)
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Procedure A: To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added an
aldehyde (0.2 mmol), an amine (0.2 mmol), AIBN (3.3 mg, 0.02 mmol) and freshly activated 4 Å
molecular sieves (80 mg). The tube was sealed with a septum and 1,3ꢀdioxolane (2 mL, freshly
distilled) was added through a syringe, followed by the addition of TDM (5 ꢁL, 0.02 mmol). The
reaction mixture was stirred at 80 °C for indicated time and then cooled down, filtered through a
Celite® pad and washed with ether. After the filtrate was concentrated in vacuo, the resulting
residue was purified through a silica gel column chromatography to afford the corresponding
product 3.
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Procedure B: To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added a
corresponding purified imine (0.2 mmol), AIBN (3.3 mg, 0.02 mmol) and freshly activated 4 Å
molecular sieves (40 mg). The tube was sealed with a septum and 1,3ꢀdioxolane (2 mL, freshly
distilled) was added through a syringe, followed by the addition of TDM (5 ꢁL, 0.02 mmol). The
reaction mixture was stirred at 80 °C for indicated time and then cooled down, filtered through a
Celite® pad and washed with ether. After concentrated in vacuo, the resulting residue was
purified through a silica gel column chromatography to afford the corresponding product 3.
Methyl 4ꢀ((1,3ꢀdioxolanꢀ2ꢀyl)(phenylamino)methyl)benzoate (3ba) was prepared according to
procedure B through the reaction of methyl (E)ꢀ4ꢀ((phenylimino)methyl)benzoate in 1,3ꢀ
dioxolane for 12 hours. Compound 3ba was isolated through a silica gel column chromatography
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(PE: EtOAc from 20:1 to 10:1) as a yellow solid (54 mg, 86% yield, m.p. 79–81 °C). H NMR
(600 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 8.0 Hz, 2H),
6.68 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 8.8 Hz, 2H), 5.20 (d, J = 2.8 Hz, 1H), 4.64 (d, J = 2.8 Hz,
2H), 3.90 (s, 3H), 3.91 – 3.80 (m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 167.0, 146.6, 144.1,
129.7, 129.6, 129.2, 127.9, 118.0, 113.8, 105.0, 65.5, 65.4, 60.2, 52.1; IR νmax (neat)/cmꢀ1: 3376,
3027, 2878, 1722, 1605, 1510, 1315, 1125, 1033, 747, 695; HRMS (ESI/FTꢀICR, m/z): calcd for
C18H19NNaO4 [M + Na]+ 336.1206, found 336.1212
Nꢀ((1,3ꢀDioxolanꢀ2ꢀyl)(pꢀtolyl)methyl)aniline (3ca) was prepared according to procedure B
through the reaction of (E)ꢀNꢀphenylꢀ1ꢀ(pꢀtolyl)methanimine in 1,3ꢀdioxolane for 12 hours.
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Compound 3ca was isolated through a silica gel column chromatography (PE:EtOAc from 20:1
to 10:1) as a yellow solid (36 mg, 67% yield, m.p. 58–60 °C). 1H NMR (600 MHz, CDCl3) δ
7.32 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.09 (t, J = 7.8 Hz, 2H), 6.66 (t, J = 7.4 Hz,
1H), 6.57 (d, J = 7.4 Hz, 2H), 5.16 (d, J = 3.2 Hz, 1H), 4.55 (d, J = 3.2 Hz, 1H), 3.96 – 3.73 (m,
4H), 2.33 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 147.1, 137.2, 135.6, 129.2, 129.1, 127.5,
117.7, 113.8, 105.6, 65.4, 65.3, 60.0, 21.2; IR νmax (neat)/cmꢀ1: 3376, 3027, 2876, 1606, 1510,
1317, 1125, 1033, 746, 696; HRMS (ESI/FTꢀICR, m/z): calcd for C17H19NNaO2 [M + Na]+
292.1308, found 292,1315.
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Nꢀ((1,3ꢀDioxolanꢀ2ꢀyl)(4ꢀmethoxyphenyl)methyl)aniline (3da) was prepared according to
procedure B through the reaction of (E)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀNꢀphenylmethanimine in 1,3ꢀ
dioxolane for 12 hours. Compound 3da was isolated through a silica gel column chromatography
(PE:EtOAc from 20:1 to 10:1) as a yellow solid (41 mg, 72% yield, m.p. 81–83 °C). 3da is a
known compound7d and the characterization data are in accordance with the literature. 1H NMR
(400 MHz, CDCl3) δ 7.35 (d, J = 8.7 Hz, 2H), 7.14 – 7.05 (m, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.66
(t, J = 7.3 Hz, 1H), 6.57 (d, J = 7.9 Hz, 2H), 5.15 (d, J = 3.1 Hz, 1H), 4.56 (s, 1H), 4.52 (d, J =
3.1 Hz, 1H), 3.87 (m, 4H), 3.78 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 159.1, 147.1, 130.6,
129.1, 128.7, 117.6, 113.9, 113.8, 105.5, 65.4, 65.3, 59.7, 55.2; IR νmax (neat)/cmꢀ1: 3372, 3023,
2881, 1606, 1512, 1306, 1251, 1178, 1125, 1035, 746, 693.
Nꢀ((1,3ꢀDioxolanꢀ2ꢀyl)(4ꢀfluorophenyl)methyl)aniline (3ea) was prepared according to procedure
A through the reaction of 4ꢀfluoroꢀbenzaldehyde and aniline in 1,3ꢀdioxolane for 12 hours.
Compound 3ea was isolated through a silica gel column chromatography (PE:EtOAc from 20:1
to 10:1) as a yellow solid (41 mg, 75% yield, m.p. 44–47 °C). 1H NMR (600 MHz, CDCl3) δ
7.41 (td, J = 5.6, 2.3 Hz, 2H), 7.11 (t, J = 8.0 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 6.69 (t, J = 7.3
Hz, 1H), 6.55 (d, J = 7.6 Hz, 2H), 5.17 (d, J = 3.1 Hz, 1H), 4.56 (d, J = 3.1 Hz, 1H), 3.93 – 3.82
(m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 162.3 (d, J = 245.5 Hz), 146.8, 134.2 (d, J = 3.1
Hz), 129.3 (d, J = 8.1 Hz), 129.1, 117.9, 115.3 (d, J = 21.4 Hz), 113.8, 113.8, 105.2, 65.5, 65.4,
59.7; 19F NMR (376 MHz, CDCl3) δ ꢀ115.16 (tt, J = 8.8, 5.3 Hz); IR νmax (neat)/cmꢀ1: 3374, 3062,
2877, 1605, 1509, 1394, 1297, 1230, 1122, 1028, 748, 698; HRMS (ESI/FTꢀICR, m/z): calcd for
C16H16FNNaO2 [M + Na]+ 296.1057, found 296,1068.
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Nꢀ((4ꢀChlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline (3fa) was prepared according to
procedure A through the reaction of 4ꢀchloroꢀbenzaldehyde and aniline in 1,3ꢀdioxolane for 12
hours. Compound 3fa was isolated through a silica gel column chromatography (PE:EtOAc from
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20:1 to 10:1) as a yellow solid (46 mg, 79% yield, m.p. 58–60 °C). H NMR (600 MHz, CDCl3)
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7.38 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.11 (t, J = 7.7 Hz, 2H), 6.69 (t, J = 7.3 Hz,
1H), 6.54 (d, J = 7.9 Hz, 2H), 5.16 (d, J = 3.2 Hz, 1H), 4.55 (d, J = 3.2 Hz, 1H), 3.92 – 3.79 (m,
4H); 13C{1H}NMR (151 MHz, CDCl3) δ 146.7, 137.2, 133.4, 129.2, 129.2, 128.6, 118.0, 113.8,
105.1, 65.5, 65.4, 59.8; IR νmax (neat)/cmꢀ1: 3391, 3053, 2883, 1604, 1513, 1317, 1125, 1031,
749, 694 cm–1; HRMS (ESI/FTꢀICR, m/z): calcd for C16H16ClNNaO2 [M + Na]+ 312.0762,
found 312.0781.
Nꢀ((3ꢀChlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline (3ga) was prepared according to
procedure A through the reaction of 3ꢀchloroꢀbenzaldehyde and aniline in 1,3ꢀdioxolane for 12
hours. Compound 3ga was isolated through a silica gel column chromatography (PE:EtOAc
from 20:1 to 10:1) as a yellow solid (37 mg, 65% yield, m.p. 56–58 °C). 1H NMR (600 MHz,
CDCl3) δ 7.48 (s, 1H), 7.38 – 7.33 (m, 1H), 7.32 – 7.26 (m, 2H), 7.14 (t, J = 7.9 Hz, 2H), 6.72 (t,
J = 7.3 Hz, 1H), 6.58 (d, J = 7.9 Hz, 2H), 5.19 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 3.2 Hz, 1H), 3.95
– 3.85 (m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 146.7, 141.0, 134.4, 129.6, 129.2, 127.9,
127.9, 126.0, 118.0, 113.7, 105.1, 65.5, 65.4, 60.0; IR νmax (neat)/cmꢀ1: 3367, 3056, 2873, 1603,
1510, 1315, 1130, 1035, 749, 693; HRMS ESI/FTꢀICR, m/z): calcd for C16H16ClNNaO2 [M +
Na]+ 312.0762, found 312.0774.
Nꢀ((2ꢀChlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline (3ha) was prepared according to
procedure A through the reaction of 2ꢀchloroꢀbenzaldehyde and aniline in 1,3ꢀdioxolane for 12
hours. Compound 3ha was isolated through a silica gel column chromatography (PE:EtOAc
from 20:1 to 10:1) as a yellow solid (34 mg, 60% yield, m.p. 57–59 °C). 1H NMR (600 MHz,
CDCl3) δ 7.54 – 7.49 (m, 1H), 7.44 – 7.38 (m, 1H), 7.25 – 7.18 (m, 2H), 7.11 (t, J = 7.9 Hz, 2H),
6.68 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 5.22 (s, 2H), 4.04 – 3.86 (m, 4H);
13C{1H}NMR (151 MHz, CDCl3) δ 146.5, 136.2, 133.8, 129.5, 129.2, 128.9, 128.8, 127.1, 117.9,
113.5, 104.1, 65.6, 65.3, 55.8; IR νmax (neat)/cmꢀ1: 3358, 3020, 2900, 1602, 1523, 1498, 1318,
1112, 1028, 746, 693; HRMS (ESI/FTꢀICR, m/z): calcd for C16H16ClNNaO2 [M + Na]+
312.0762, found 312.0766.
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Nꢀ((2,4ꢀDichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline (3ia) was prepared according to
procedure A through the reaction of 2,4ꢀdichloro benzaldehyde and aniline in 1,3ꢀdioxolane for 8
hours. Compound 3ia was isolated through a silica gel column chromatography (PE:EtOAc from
20:1 to 10:1) as colorless oil (59 mg, 91% yield), which we have reported6 in a previous
publication. 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.40 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 (t,
J = 7.7 Hz, 2H), 6.69 (t, J = 7.4 Hz, 1H), 6.51 (m, 2H), 5.19 (d, J = 2.5 Hz, 1H), 5.16 (d, J = 2.5
Hz, 1H), 4.51 (s, 1H), 4.06 – 3.76 (m, 4H); 13C{1H}NMR (100 MHz, CDCl3) δ 146.2, 134.9,
134.5, 133.9, 130.0, 129.3, 129.3, 127.5, 118.2, 113.5, 103.8, 65.6, 65.4, 55.6; IR νmax (neat)/cmꢀ
1: 3402, 3027, 2873, 1602, 1514, 1317, 1125, 1033, 746, 696.
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Nꢀ((1,3ꢀdioxolanꢀ2ꢀyl)(pyridinꢀ2ꢀyl)methyl)aniline (3ja) was prepared according to procedure A
through the reaction of 2ꢀpyridinecarboxaldehyde and aniline in 1,3ꢀdioxolane for 12 hours.
Compound 3ja was isolated through a silica gel column chromatography (PE:EtOAc from 10:1
to 5:1 as a yellow solid (48 mg, 84% yield, m.p. 106–108 °C). 1H NMR (400 MHz, CDCl3) δ
8.63 (d, J = 6.1 Hz, 1H), 7.63 (td, J = 7.7, 1.9 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.5,
4.9 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 6.72 – 6.60 (m, 3H), 5.33 (d, J = 2.9 Hz, 1H), 4.96 (d, J =
13
6.7 Hz, 1H), 4.78 (dd, J = 6.7, 2.9 Hz, 1H), 4.01 – 3.83 (m, 4H); C{1H}NMR (100 MHz,
CDCl3) δ 158.3, 149.3, 147.2, 136.5, 129.2, 122.5, 122.5, 117.8, 113.7, 105.1, 65.5, 65.4, 61.2;
IR νmax (neat)/cmꢀ1: 3312, 3055, 2875, 1603, 1515, 1311, 1119, 1035, 748, 690; HRMS (ESI/FTꢀ
ICR, m/z): calcd for C15H16N2NaO2 [M + Na]+ 279.1104, found 279.1108.
Nꢀ((2,4ꢀDichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)ꢀ4ꢀmethylaniline
(3ib)
was
prepared
according to procedure B through the reaction of (E)ꢀ1ꢀ(2,4ꢀdichlorophenyl)ꢀNꢀ(pꢀ
tolyl)methanimine in 1,3ꢀdioxolane for 10 hours. Compound 3ib was isolated through a silica gel
column chromatography (PE:EtOAc from 20:1 to 10:1) as colorless oil (64 mg, 95% yield). 1H
NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 6.92 (d, J = 8.0
Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 5.18 (d, J = 2.8 Hz, 1H), 5.12 (d, J = 2.8 Hz, 1H), 4.49 (s, 1H),
4.04 – 3.79 (m, 4H), 2.19 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 143.9, 135.1, 134.5, 133.8,
130.0, 129.7, 129.2, 127.5, 127.3, 113.6, 103.9, 65.6, 65.4, 55.8, 20.4; IR νmax (neat)/cmꢀ1: 3407,
3022, 2889, 1617, 1520, 1313, 1110, 1028, 811, 733; HRMS (ESI/FTꢀICR, m/z): calcd for
C17H17Cl2NNaO2 [M + Na]+ 360.0529, found 360.0538.
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Nꢀ((2,4ꢀDichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)ꢀ4ꢀmethoxyaniline (3ic)
was prepared
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according to procedure A through the reaction of 2,4ꢀdichlorobenzaldehyde and 4ꢀanisidine in
1,3ꢀdioxolane for 10 hours. Compound 3ic was isolated through a silica gel column
chromatography (PE:EtOAc from 20:1 to 10:1) as colorless oil (54 mg, 77% yield). 1H NMR
(600 MHz, CDCl3) δ 7.48 – 7.40 (m, 2H), 7.20 (dd, J = 8.4, 2.2 Hz, 1H), 6.71 (d, J = 9.0 Hz, 2H),
6.47 (d, J = 9.0 Hz, 2H), 5.18 (d, J = 2.9 Hz, 1H), 5.09 (d, J = 2.9 Hz, 1H), 4.36 (s, 1H), 4.01 –
3.86 (m, 4H), 3.69 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 152.5, 140.3, 135.1, 134.6, 133.9,
130.0, 129.3, 127.5, 114.8, 114.7, 104.0, 65.6, 65.4, 56.3, 55.7; IR νmax (neat)/cmꢀ1: 3389, 3064,
2892, 1618, 1514, 1384, 1240, 1037, 820, 733; HRMS (ESI/FTꢀICR, m/z): calcd for
C17H17Cl2NNaO3 [M + Na]+ 376.0478, found 376.0490.
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4ꢀChloroꢀNꢀ((2,4ꢀdichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline
(3id)
was
prepared
according to procedure B through the reaction of (E)ꢀNꢀ(4ꢀchlorophenyl)ꢀ1ꢀ(2,4ꢀdichlorophenyl)
methanimine in 1,3ꢀdioxolane for 10 hours. Compound 3ia was isolated through a silica gel
column chromatography (PE:EtOAc from 20:1 to 10:1) as colorless oil (67 mg, 95% yield). 1H
NMR (400 MHz, CDCl3) δ 7.44 – 7.37 (m, 2H), 7.19 (dd, J = 8.5, 2.2 Hz, 1H), 7.05 (d, J = 8.8
Hz, 2H), 6.42 (d, J = 8.8 Hz, 2H), 5.16 (d, J = 2.7 Hz, 1H), 5.13 – 5.08 (m, 1H), 4.63 (d, J = 5.4
Hz, 1H), 4.02 – 3.82 (m, 4H); 13C{1H}NMR (100 MHz, CDCl3) δ 144.8, 134.5, 134.4, 134.1,
129.8, 129.4, 129.1, 127.6, 122.8, 114.6, 103.6, 65.6, 65.4, 55.6; IR νmax (neat)/cmꢀ1: 3421, 3068,
2890, 1599, 1500, 1315, 1121, 1027, 816, 734 cm–1; HRMS (ESI/FTꢀICR, m/z): calcd for
C16H14Cl3NNaO2 [M + Na]+ 379.9982, found 379.9993.
3ꢀChloroꢀNꢀ((2,4ꢀdichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline (3ie) was prepared according
to procedure A through the reaction of 2,4ꢀdichlorobenzaldehyde and 3ꢀchloro aniline in 1,3ꢀ
dioxolane for 10 hours. Compound 3ie was isolated through a silica gel column chromatography
(PE:EtOAc from 20:1 to 10:1) as colorless oil (53 mg, 74% yield). 1H NMR (600 MHz, CDCl3) δ
7.45 – 7.38 (m, 2H), 7.21 (dd, J = 8.4, 2.1 Hz, 1H), 7.01 (t, J = 8.1 Hz, 1H), 6.68 – 6.63 (m, 1H),
6.53 (t, J = 2.2 Hz, 1H), 6.37 – 6.32 (m, 1H), 5.16 (d, J = 2.6 Hz, 1H), 5.12 (d, J = 2.6 Hz, 1H),
4.69 (s, 1H), 4.01 – 3.86 (m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 147.4, 134.9, 134.4, 134.3,
134.2, 130.3, 129.8, 129.4, 127.6, 118.1, 113.5, 111.4, 103.6, 65.6, 65.4, 55.4; IR νmax (neat)/cmꢀ
1: 3421, 3068, 2890, 1598, 1500, 1324, 1120, 1028, 842, 766; HRMS (ESI/FTꢀICR, m/z): calcd
for C16H14Cl3NNaO2 [M + Na]+ 379.9982, found 379.9985.
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4ꢀBromoꢀNꢀ((2,4ꢀdichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)aniline (3if) was prepared according
to procedure B through the reaction of (E)ꢀNꢀ(4ꢀbromophenyl)ꢀ1ꢀ(2,4ꢀdichlorophenyl)
methanimine in 1,3ꢀdioxolane for 10 hours. Compound 3if was isolated through a silica gel
column chromatography (PE:EtOAc from 20:1 to 10:1) as colorless oil (77 mg, 97% yield). 1H
NMR (400 MHz, CDCl3) δ 7.45 – 7.34 (m, 2H), 7.23 – 7.14 (m, 3H), 6.37 (d, J = 8.7 Hz, 2H),
5.15 (d, J = 2.6 Hz, 1H), 5.09 (s, 1H), 4.63 (s, 1H), 4.04 – 3.83 (m, 4H); 13C{1H}NMR (100 MHz,
CDCl3) δ 145.2, 134.5, 134.3, 134.2, 132.0, 129.8, 129.4, 127.6, 115.1, 109.9, 103.6, 65.6, 65.3,
55.5; IR νmax (neat)/cmꢀ1: 3417, 3067, 2889, 1594, 1498, 1315, 1120, 1028, 815, 735; HRMS
(ESI/FTꢀICR, m/z): calcd for C16H14BrCl2NNaO2 [M + Na]+ 423.9477, found 423.9483.
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Nꢀ((2,4ꢀDichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)ꢀ4ꢀfluoroaniline (3ig) was prepared according
to procedure A through the reaction of 2,4ꢀdichlorobenzaldehyde and 4ꢀfluoroaniline in 1,3ꢀ
dioxolane for 12 hours. Compound 3ig was isolated through a silica gel column chromatography
(PE: EtOAc from 20:1 to 10:1) as colorless oil (50 mg, 73% yield). 1H NMR (600 MHz, CDCl3)
δ 7.45 – 7.40 (m, 2H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 6.81 (t, J = 8.7 Hz, 2H), 6.47 – 6.42 (m,
2H), 5.16 (d, J = 2.5 Hz, 1H), 5.08 (d, J = 2.5 Hz, 1H), 4.51 (s, 1H), 4.03 – 3.86 (m, 4H);
13C{1H}NMR (151 MHz, CDCl3) δ 156.1 (d, J = 235.7 Hz), 142.5, 134.6 (d, J = 18.1 Hz), 134.1,
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129.9, 129.3, 127.5, 115.7 (d, J = 22.5 Hz), 114.34 (d, J = 7.5 Hz), 103.8, 65.6, 65.4, 56.1; F
NMR (376 MHz, CDCl3) δ ꢀ127.2 (tt, J = 8.6, 4.3 Hz); IR νmax (neat)/cmꢀ1: 3421, 3063, 2891,
1612, 1513, 1312, 1220, 1120, 1028, 820, 733; HRMS (ESI/FTꢀICR, m/z): calcd for
C16H14Cl2FNNaO2 [M + Na]+ 364.0278, found 364.0286.
Nꢀ((2,4ꢀDichlorophenyl)(1,3ꢀdioxolanꢀ2ꢀyl)methyl)ꢀ3,5ꢀbis(trifluoromeꢀthyl)aniline (3ih) was
prepared according to procedure A through the reaction of 2,4ꢀdichlorobenzaldehyde and 3,5ꢀ
bis(trifluoromethyl)aniline in 1,3ꢀdioxolane for 16 hours. Compound 3ih was isolated through a
silica gel column chromatography (PE:EtOAc from 20:1 to 10:1) as a yellow solid (50 mg, 55%
yield, m.p. 93–95 °C). 1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 2.1 Hz, 1H), 7.40 (d, J = 8.4
Hz, 1H), 7.22 (dd, J = 8.4, 2.1 Hz, 1H), 7.14 (s, 1H), 6.88 (s, 2H), 5.20 (d, J = 2.4 Hz, 1H), 5.16
(d, J = 2.4 Hz, 1H), 5.07 (s, 1H), 4.04 – 3.85 (m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 147.0,
134.7, 134.5, 133.3, 132.5 (q, J = 32.8 Hz), 129.7, 129.5, 127.7, 123.4 (q, J = 272.7 Hz), 112.6
(m), 111.1(m), 103.3, 65.7, 65.4, 55.2; 19F NMR (376 MHz, CDCl3) δ ꢀ63.3 (s); IR νmax
(neat)/cmꢀ1: 3440, 3085, 2902, 1626, 1520, 1388, 1280, 1174, 1122, 1028, 852, 681; HRMS
(ESI/FTꢀICR, m/z): calcd for C18H13Cl2F6NNaO2 [M + Na]+ 482.0120, found 482.0131.
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vi. Addition of 1,3ꢀdioxolane to ethyl glyoxylate imines (Table 3)
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Procedure C: To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added ethyl
glyoxylate (40 ꢁL, 0.2 mmol, ~50% in toluene), a corresponding amine (0.2 mmol) and freshly
activated 4 Å molecular sieves (80 mg). The tube was sealed with a septum and freshly distilled
1,3ꢀdioxolane (1.5 mL) was added through a syringe. The mixture was stirred for 1 hour at room
temperature before the addition of AIBN (3.3 mg, 0.02 mmol, dissolved in 0.5 mL 1,3ꢀdioxolane)
and TDM (5 ꢁL, 0.02 mmol) through syringes. The reaction mixture was then heated up to 80 °C
and monitored by TLC. Upon completion, the solvent was removed in vacuo, and the resulting
residue was purified through a silica gel column chromatography to afford a corresponding
product 4.
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Procedure D: To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added ethyl
glyoxylate (40 ꢁL, 0.2 mmol, ~50% in toluene), a corresponding amine (0.2 mmol) and freshly
activated 4 Å molecular sieves (80 mg). The tube was sealed with a septum and freshly distilled
1,3ꢀdioxolane (1.5 mL) was added through a syringe. The mixture was stirred for 1 hour at room
temperature before the addition of AIBN (3.3 mg, 0.02 mmol, dissolved in 0.5 mL 1,3ꢀ
dioxolane) through a syringe. The reaction mixture was then heated up to 65 °C and monitored
by TLC. Upon completion, the solvent was removed in vacuo, and the resulting residue was
purified through a silica gel column chromatography to afford a corresponding product 4.
Ethyl 2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ(phenylamino)acetate (4a): was prepared according to procedure C
through the reaction of ethyl glyoxylate and aniline in 1,3ꢀdioxolane for 12 hours. Compound 4a
was isolated through a silica gel column chromatography (PE: EtOAc from 10:1 to 5:1) as a
yellowish solid (48 mg, 96% yield, m.p. 70–72 °C), which is a known compound3h and the
characterization data are in accordance with the literature. 1H NMR (600 MHz, CDCl3) δ 7.17 (t,
J = 7.9 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.71 (d, J = 7.8 Hz, 2H), 5.37 (d, J = 2.2 Hz, 1H), 4.31
(d, J = 2.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.12 – 4.06 (m, 1H), 4.03 – 3.97 (m, 1H), 3.95 –
3.89 (m, 2H), 3.28 (s, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H}NMR NMR (151 MHz, CDCl3) δ
170.4, 146.9, 129.4, 129.2, 118.7, 114.0, 103.4, 66.0, 65.6, 61.7, 60.3, 14.2; IR νmax (neat)/cmꢀ1:
3385, 3054, 2895, 1739, 1604, 1510, 1308, 1160, 1026, 755, 694.
Ethyl 4ꢀ((1ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀethoxyꢀ2ꢀoxoethyl)amino)benzoate (4b): was prepared
according to procedure C through the reaction of ethyl glyoxylate and ethyl 4ꢀaminobenzoate in
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1,3ꢀdioxolane for 12 hours. Compound 4b was isolated through a silica gel column
chromatography (PE: EtOAc from 10:1 to 5:1) as colorless oil (39 mg, 60% yield). 1H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 5.38 (d, J = 2.2 Hz, 1H),
4.85 (d, J = 8.4 Hz, 1H), 4.40 (dd, J = 8.4, 2.2 Hz, 1H), 4.36 – 4.20 (m, 4H), 4.12 – 3.99 (m, 1H),
3.97 – 3.86 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ 169.6, 166.7, 150.7, 131.4, 120.1, 112.5, 103.2, 66.0, 65.6, 62.0, 60.3, 59.1, 14.4, 14.2;
IR νmax (neat)/cmꢀ1: 3374, 3052, 2899, 1740, 1703, 1607, 1530, 1278, 1175, 1106, 1022, 772;
HRMS (ESI/FTꢀICR, m/z): calcd for C16H21NNaO6 [M + Na]+ 346.1261, found 346.1267.
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Ethyl 2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ(pꢀtolylamino)acetate (4c): was prepared according to general C
through the reaction of ethyl glyoxylate and 4ꢀtoluidine in 1,3ꢀdioxolane for 12 hours.
Compound 4c was isolated through a silica gel column chromatography (PE: EtOAc from 10:1
to 5:1) as colorless oil (48 mg, 91% yield); 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 8.1 Hz,
2H), 6.63 (d, J = 8.1 Hz, 2H), 5.36 (d, J = 2.3 Hz, 1H), 4.34 (d, J = 7.6 Hz, 1H), 4.31 – 4.18 (m,
3H), 4.13 – 4.05 (m, 1H), 4.05 – 3.97 (m, 1H), 3.97 – 3.88 (m, 2H), 2.23 (s, 3H), 1.27 (t, J = 7.1
Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 170.5, 144.6, 129.7, 127.9, 114.1, 103.5, 66.0, 65.6,
61.6, 60.7, 20.4, 14.2; IR νmax (neat)/cmꢀ1: 3388, 3033, 2887, 1735, 1616, 1522, 1302, 1167,
1030, 989, 808; HRMS (ESI/FTꢀICR, m/z): calcd for C14H19NNaO4 [M + Na]+ 288.1206, found
288.1211.
Ethyl 2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ((4ꢀmethoxyphenyl)amino)acetate (4d): was prepared according to
procedure C through the reaction of ethyl glyoxylate and 4ꢀanisidine in 1,3ꢀdioxolane for 12
hours. Compound 4d was isolated through a silica gel column chromatography (PE: EtOAc from
10:1 to 5:1) as colorless oil (54 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 9.0
Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 5.34 (s, 1H), 4.27 – 4.16 (m, 4H), 4.12 – 4.04 (m, 1H), 4.05 –
3.97 (m, 1H), 3.96 – 3.89 (m, 2H), 3.73 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (100
MHz, CDCl3) δ 170.7, 152.9, 141.0, 115.5, 114.8, 103.4, 65.9, 65.6, 61.6, 61.5, 55.7, 14.2; IR
νmax (neat)/cmꢀ1: 3373, 3023, 2898, 1739, 1621, 1516, 1240, 1159, 1035, 879; HRMS (ESI/FTꢀ
ICR, m/z): calcd for C14H19NNaO5 [M + Na]+ 304.1155, found 304.1159.
Ethyl 2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ((4ꢀfluorophenyl)amino)acetate (4e) was prepared according to
procedure C through the reaction of ethyl glyoxylate and 4ꢀfluoroaniline in 1,3ꢀdioxolane for 12
hours. Compound 4e was isolated through a silica gel column chromatography (PE:EtOAc from
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10:1 to 5:1) as yellow oil (32 mg, 60% yield) which is a known compound3h and the
characterization data are in accordance with the literature. 1H NMR (400 MHz, CDCl3) δ 6.87 (t,
J = 8.7 Hz, 2H), 6.65 (dd, J = 9.0, 4.3 Hz, 2H), 5.35 (d, J = 2.3 Hz, 1H), 4.35 (s, 1H), 4.28 – 4.18
(m, 3H), 4.13 – 4.05 (m, 1H), 4.04 – 3.97 (m, 1H), 3.97 – 3.89 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ 170.3, 156.5 (d, J = 236.1 Hz), 143.3 (d, J = 2.0 Hz), 115.6
(d, J = 22.4 Hz), 115.0 (d, J = 7.5 Hz), 103.3, 66.0, 65.6, 61.7, 61.0, 14.2; IR νmax (neat)/cmꢀ1:
3378, 3056, 2898, 1739, 1621, 1516, 1369, 1240, 1158, 1035, 825.
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Ethyl 2ꢀ((4ꢀchlorophenyl)amino)ꢀ2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)acetate (4f) was prepared according to
procedure C through the reaction of ethyl glyoxylate and 4ꢀchloroaniline in 1,3ꢀdioxolane for 12
hours. Compound 4f was isolated through a silica gel column chromatography (PE: EtOAc from
10:1 to 5:1) as a yellowish solid (48 mg, 85% yield, m.p. 48–49 °C) which is a known
compound3h and the characterization data are in accordance with the literature. 1H NMR (400
MHz, CDCl3) δ 7.11 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.36 (d, J = 2.3 Hz, 1H), 4.47
(d, J = 8.5 Hz, 1H), 4.29 – 4.18 (m, 3H), 4.13 – 4.03 (m, 1H), 4.01 – 3.86 (m, 3H), 1.27 (t, J =
7.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 170.1, 145.6, 129.0, 123.2, 115.0, 103.3, 66.0,
65.6, 61.8, 60.2, 14.2; IR νmax (neat)/cmꢀ1: 3383, 3036, 2898, 1736, 1620, 1522, 1357, 1242,
1152, 1042, 833.
Ethyl 2ꢀ((3ꢀchlorophenyl)amino)ꢀ2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)acetate (4g) was prepared according to
procedure C through the reaction of ethyl glyoxylate and 3ꢀchloroaniline in 1,3ꢀdioxolane for 12
hours. Compound 4g was isolated through a silica gel column chromatography (PE: EtOAc from
10:1 to 5:1) as colorless oil (35 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.9
Hz, 1H), 6.75 – 6.65 (m, 2H), 6.57 (dd, J = 8.1, 2.3 Hz, 1H), 5.37 (d, J = 2.3 Hz, 1H), 4.53 (d, J
= 8.5 Hz, 1H), 4.31 – 4.20 (m, 3H), 4.15 – 4.02 (m, 1H), 4.02 – 3.85 (m, 3H), 1.28 (t, J = 7.1 Hz,
3H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.9, 148.1, 134.9, 130.2, 118.5, 113.7, 112.1, 103.3,
66.0, 65.6, 61.9, 59.9, 14.2; IR νmax (neat)/cmꢀ1: 3388, 3060, 2895, 1738, 1611, 1527, 1355, 1247,
1148, 1047, 837; HRMS (ESI/FTꢀICR, m/z): calcd for C13H16ClNNaO4 [M + Na]+ 308.0660,
found 308.0667.
Ethyl 2ꢀ(benzylamino)ꢀ2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)acetate (4h) was prepared according to procedure D
through the reaction of ethyl glyoxylate and benzylamine in 1,3ꢀdioxolane for 4 hours.
Compound 4h was isolated through a silica gel column chromatography (PE: EtOAc from 5:1 to
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3:1) as colorless oil (33 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.11 (m, 5H), 5.10
(d, J = 3.5 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 4.01 – 3.90 (m, 2H), 3.87 – 3.77 (m, 3H), 3.66 (d, J
= 13.2 Hz, 1H), 3.42 (d, J = 3.5 Hz, 1H), 2.01 (s, 1H), 1.21 (t, J = 7.2 Hz, 3H); 13C{1H}NMR
(100 MHz, CDCl3) δ 171.5, 139.5, 128.4, 128.2, 127.1, 103.8, 65.6, 65.5, 63.6, 61.1, 52.3, 14.3;
IR νmax (neat)/cmꢀ1: 3339, 3062, 2893, 1736, 1457, 1190, 1158, 1028, 701; HRMS (ESI/FTꢀICR,
m/z): calcd for C14H19NNaO4 [M + Na]+ 288.1206, found 288.1217.
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Ethyl 2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ((1ꢀphenylethyl)amino)acetate (4i) was prepared according to
procedure D through the reaction of ethyl glyoxylate and (R)ꢀαꢀmethylbenzylamine in 1,3ꢀ
dioxolane for 4 hours. Compound 4i was isolated through a silica gel column chromatography
(PE: EtOAc from 5:1 to 3:1) as colorless oil (36 mg, 65% yield, dr = 1.2:1). 1H NMR (400 MHz,
CDCl3) (mixture of 2 diastereomers) δ 6.54 – 6.27 (m, 5H, major+minor), 4.27 (d, J = 3.6 Hz,
1H, minor), 4.20 (d, J = 3.4 Hz, 1H, major), 3.34 (q, J = 7.1 Hz, 2H, major), 3.25 – 2.94 (m, 6H,
major+minor), 2.89 (q, J = 6.5 Hz, 1H, major), 2.57 (d, J = 3.6 Hz, 1H, minor), 2.39 (d, J = 3.4
Hz, 1H, major), 0.48 (d, J = 6.5 Hz, 3H, major+minor), 0.40 (t, J = 7.1 Hz, 3H, major), 0.31 (t, J
= 7.1 Hz, 3H, minor); 13C{1H}NMR (100 MHz, CDCl3) δ 172.0 (major), 171.6 (minor), 145.1
(minor), 144.5 (major), 128.4 (major), 128.4 (minor), 127.1 (minor), 127.1 (major), 126.9
(major), 126.8 (minor), 104.3 (minor), 103.8 (major), 65.6 (minor), 65.5(major+minor), 65.5
(major), 62.3 (minor), 61.9 (major), 61.0 (minor), 61.0 (major), 57.2 (minor), 56.4 (major), 25.4
(major), 23.4 (minor), 14.3 (major), 14.1 (minor); IR νmax (neat)/cmꢀ1: 3338, 3062, 2891, 1736,
1450, 1190, 1159, 1026, 703; HRMS (ESI/FTꢀICR, m/z): calcd for C15H21NNaO4 [M + Na]+
302.1363, found 302.1369.
Ethyl 2ꢀ(cyclohexylamino)ꢀ2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)acetate (4j) was prepared according to
procedure D through the reaction of ethyl glyoxylate and cyclohexylamine in 1,3ꢀdioxolane for 8
hours. Compound 4j was isolated through a silica gel column chromatography (PE:EtOAc from
5:1 to 3:1) as colorless oil (32 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 5.07 (d, J = 3.8
Hz, 1H), 4.22 (q, J = 7.3 Hz, 2H), 4.07 – 3.94 (m, 2H), 3.94 – 3.83 (m, 2H), 3.55 (d, J = 3.8 Hz,
1H), 2.44 – 2.33 (m, 1H), 1.91 – 1.51 (m, 4H), 1.28 (t, J = 7.3 Hz, 3H), 1.27 – 0.97 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 172.3, 104.0, 65.4, 61.7, 61.0, 55.4, 34.0, 32.8, 26.0, 25.0, 24.7, 14.3;
IR νmax (neat)/cmꢀ1: 3329, 2935, 2893, 1736, 1471, 1371, 1190, 1159, 1032, 947; HRMS
(ESI/FTꢀICR, m/z): calcd for C13H23NNaO4 [M + Na]+ 280.1519, found 280.1526.
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Ethylꢀ2ꢀadamantanꢀ1ꢀyl)amino)ꢀ2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)acetate (4k) was prepared according to
procedure C through the reaction of ethyl glyoxylate and amantadine in 1,3ꢀdioxolane for 12
hours. Compound 4k was isolated through a silica gel column chromatography (PE:EtOAc from
8:1 to 5:1) as colorless oil (46 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 5.00 (d, J = 4.0
Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.07 – 3.92 (m, 2H), 3.91 – 3.81 (m, 2H), 3.57 (d, J = 4.0 Hz,
1H), 2.02 (s, 3H), 1.80 (s, 1H), 1.66 – 1.45 (m, 12H), 1.28 (t, J = 7.1 Hz, 3H).; 13C{1H}NMR
(100 MHz, CDCl3) δ 173.6, 104.9, 65.5, 65.4, 61.1, 56.9, 50.7, 42.9, 36.5, 29.5, 14.2; IR νmax
(neat)/cmꢀ1: 3330, 2905, 2850, 1738, 1451, 1247, 1164, 1144, 1027, 946; HRMS (ESI/FTꢀICR,
m/z): calcd for C17H27NNaO4 [M + Na]+ 332.1832, found 332.1836.
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Ethyl 2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)ꢀ2ꢀ((3ꢀhydroxypropyl)amino)acetate (4l) was prepared according to
procedure C through the reaction of ethyl glyoxylate and 3ꢀaminopropanol in 1,3ꢀdioxolane for
12 hours. Compound 4k was isolated through a silica gel column chromatography (PE:EtOAc
from 1:1 to 1:5) as colorless oil (21 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 5.12 (d, J =
3.0 Hz, 1H), 4.23 (q, J = 7.1, 2H), 4.04 – 3.94 (m, 2H), 3.94 – 3.83 (m, 2H), 3.79 (t, J = 5.4 Hz,
2H), 3.50 (d, J = 3.0 Hz, 1H), 3.07 – 2.95 (m, 1H), 2.74 – 2.62 (m, 1H), 1.75 – 1.60 (m, 2H),
1.28 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 171.2, 103.2, 65.7, 65.6, 63.8, 63.7,
61.3, 48.1, 30.9, 14.2; IR νmax (neat)/cmꢀ1: 3418, 2957, 2889, 1730, 1593, 1497, 1314, 1147,
1073, 1027, 813; HRMS (ESI/FTꢀICR, m/z): calcd for C10H19NNaO5 [M + Na]+ 256.1155,
found 256.1163.
Ethyl 2ꢀ(((2,2ꢀdimethylꢀ1,3ꢀdioxolanꢀ4ꢀyl)methyl)amino)ꢀ2ꢀ(1,3ꢀdioxolanꢀ2ꢀyl)acetate (4m): was
prepared according to procedure C through the reaction of ethyl glyoxylate and 2,2ꢀdimethylꢀ1,3ꢀ
dioxolaneꢀ4ꢀmethanamine in 1,3ꢀdioxolane for 12 hours. Compound 4m was isolated through a
silica gel column chromatography (PE:EtOAc from 5:1 to 3:1) as colorless oil (38 mg, 66%
yield, mixture of 2 diastereomers, dr = 1.5:1); 1H NMR (400 MHz, CDCl3) δ 5.14 (d, J = 3.4 Hz,
1H, major), 5.12 (d, J = 3.6 Hz, 1H, minor), 4.30 – 4.15 (m, 3H, major+minor), 4.08 – 3.93 (m,
3H, major+minor), 3.95 – 3.81 (m, 2H, major+minor), 3.75 – 3.61 (m, 1H, major+minor), 3.50
(d, J = 3.5 Hz, 1H, major), 3.45 (d, J = 3.6 Hz, 1H, minor), 2.87 – 2.76 (m, 1H, major+minor),
2.70 (dd, J = 12.1, 6.0 Hz, 1H, major), 2.62 (dd, J = 11.8, 4.5 Hz, 1H, minor), 2.00 (brs, 1H,
major+minor), 1.40 (s, 3H, minor), 1.39 (s, 3H, major), 1.33 (s, 3H, major+minor), 1.28 (t, J =
7.2 Hz, 3H, major+minor); 13C{1H}NMR (100 MHz, CDCl3) δ 170.3 (minor), 170.2 (major),
108.2 (minor), 108.1 (major), 102.7 (major), 102.6 (minor), 74.7 (minor), 74.5 (major), 66.5
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(minor), 66.4 (major), 64.6 (major), 64.6 (minor), 64.5 (major+minor), 63.8 (minor), 63.5
(major), 60.13 (major), 60.09 (minor), 50.5 (minor), 49.7 (major), 26.0 (minor), 25.8 (major),
24.5 (minor), 24.4 (major), 13.2 (major+minor); IR νmax (neat)/cmꢀ1: 3341, 2985, 2893, 1737,
1467, 1375, 1212, 1191, 1159, 1033, 798; HRMS (ESI/FTꢀICR, m/z): calcd for C13H23NNaO6
[M + Na]+ 312.1418, found 312.1422.
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Gramꢀscale preparation of 4d: To an ovenꢀdried sealable flask charged with a stir bar were
added ethyl glyoxylate (2.0 mL, 10.0 mmol, ~50% in toluene), anisidine (1.23 g, 10.0 mmol) and
freshly activated 4 Å molecular sieves (4 g). The flask was sealed with a septum and freshly
distilled 1,3ꢀdioxolane (70 mL) was added through a syringe. The mixture was stirred for 1 hour
at room temperature before the addition of AIBN (41 mg, 0.25 mmol for each) and TDM (59 ꢁL,
0.25 mmol for each). The reaction mixture was then heated up to 80 °C. Another three portions
of AIBN (41 mg, 0.25 mmol) and TDM (59 ꢁL, 0.25 mmol) were added every 12 hours. After
totally 48 hours, the reaction mixture was cooled down to room temperature, filtered through
Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo, and the residue was
purified through a silica gel column chromatography (PE:EtOAc from 10:1 to 5:1) to afford
product 4d as colorless oil (2.52 g, 90% yield).
Gramꢀscale preparation of 4h: To an ovenꢀdried sealable flask charged with a stir bar were
added ethyl glyoxylate (2.0 mL, 10.0 mmol, ~50% in toluene), benzylamine (1.09 mL, 10.0
mmol) and freshly activated 4 Å molecular sieves (4 g). The flask was sealed with a septum and
freshly distilled 1,3ꢀdioxolane (70 mL) was added through a syringe. The mixture was stirred for
1 hour at room temperature before the addition of AIBN (41 mg, 0.25 mmol). The reaction
mixture was then heated up to 65 °C. Another three portions of AIBN (41 mg, 0.25 mmol for
each) were added every 12 hours. After totally 48 hours, the reaction mixture was cooled down
to room temperature, filtered through Celite and washed with CH2Cl2. The filtrate was
concentrated in vacuo, and the residue was purified through a silica gel column chromatography
(PE:EtOAc from 5:1 to 3:1) to afford product 4h as colorless oil (1.37g, 55% yield).
vii. Product derivatization (Scheme 2)
Ethyl (E)ꢀ2ꢀ(Nꢀbenzylacetamido)ꢀ3ꢀhydroxyacrylate (5): To a stirred solution of 4h (1.06 g, 4
mmol) and Et3N (835 ꢁL, 6 mmol) in dry 1,2ꢀdichloroethane (50 mL) was added freshly distilled
acetyl chloride (427 uL, 6 mmol) dropꢀwise at 0 °C. The reaction mixture was warmed up to
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room temperature and stirred for 4h. Upon completion of the reaction, the insolubles were
removed by filtration and washed with ether. The filtrate is concentrated under reduced pressure
to afford the crude acetylated product which is subjected in next step without further purification.
The obtained crude product is dissolved in acetic acid (10 mL) in a 25 mL flask, followed by the
addition of hydriodic acid (45 mg, 57%, 0.2 mmol). After being stirred at 65 °C for 2 hours, the
reaction mixture was cooled to room temperature and diluted with CH2Cl2 (30 mL). The
resulting solution was washed with water (3 × 30 mL), dried with Na2SO4, and concentrated
under reduced pressure to afford a residue, which was purified through a silica gel column
chromatography (PE:acetone from 4:1 to 1:1) to give product 5 as a major isomer (725 mg, 83%
yield). 1H NMR (400 MHz, CDCl3) δ 11.32 (d, J = 13.0 Hz, 1H), 7.36 – 7.21 (m, 5H), 6.82 (d, J
= 13.0 Hz, 1H), 5.28 (d, J = 14.2 Hz, 1H), 4.34 – 4.18 (m, 2H), 3.98 (d, J = 14.2 Hz, 1H), 2.01
(s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 172.4, 169.6, 164.2, 136.9,
129.3, 128.5, 127.6, 110.7, 61.5, 51.7, 21.9, 14.2; IR νmax (neat)/cmꢀ1: 3349, 3064, 2983, 1744,
1710, 1637, 1413, 1219, 1148, 1039, 700; HRMS (ESI/FTꢀICR, m/z): calcd for C14H17NNaO4
[M + Na]+ 286.1050, found 286.1054. The double bond geometry of 5 was tentatively assigned
to be (E) by NOE analysis based on the correlation between the olefinic proton and the acetyl
group. This preferred geometry is presumably ascribed to the intramolecular hydrogen bonding.
The NOE spectrum was presented in the supporting information.
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Ethyl (E)ꢀ2ꢀ(Nꢀbenzylacetamido)ꢀ3ꢀ(butylamino)acrylate (6): A mixture of 5 (53 mg, 0.2 mmol)
and butylamine (22 mg, 0.3 mmol) in EtOH (2 mL) was heated under reflux for 12 hours. The
mixture was cooled to room temperature and concentrated under reduced pressure. The residue
was purified through a silica gel column chromatography (PE:EtOAc 5:1) to give the product 6
(55 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.34 (m, 2H), 7.31 – 7.23 (m, 4H), 5.38 (d,
J = 13.7 Hz, 1H), 4.21 – 4.03 (m, 3H), 3.78 (d, J = 13.7 Hz, 1H), 2.96 – 2.81 (m, 1H), 2.81 –
2.64 (m, 1H), 1.94 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.12 – 1.00 (m, 4H), 0.84 – 0.80 (m, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ 172.9, 166.1, 146.9, 139.0, 129.4, 128.5, 127.6, 102.9, 76.7,
59.8, 50.5, 47.8, 32.8, 21.3, 19.4, 14.6, 13.6; IR νmax (neat)/cmꢀ1: 3305, 3031, 2930, 2869, 1683,
1639, 1408, 1279, 1171, 1052, 731; HRMS (ESI/FTꢀICR, m/z): calcd for C18H26N2NaO3 [M +
Na]+ 341.1836, found 341.1840.
Diethyl (E)ꢀ2ꢀ(Nꢀbenzylacetamido)pentꢀ2ꢀenedioate (7): A solution of 5 (53.0 mg, 0.2 mmol) and
ethyl 2ꢀ(triphenylphosphanylidene) acetate (69 mg, 0.2 mmol) in dry 1,2ꢀdichloroethane (2 mL)
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was stirred at 80 C for 6 hours. The resulting mixture was cooled to room temperature and
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7
concentrated in vacuo. The residue was purified through a silica gel column chromatography
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(PE:EtOAc from 10:1 to 5:1) to give product 7 as colorless oil (60 mg, 90%). H NMR (400
8
9
MHz, CDCl3) δ 7.33 – 7.24 (m, 5H), 7.08 (t, J = 7.5 Hz, 1H), 5.26 (d, J = 14.1 Hz, 1H), 4.32 –
4.15 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.98 (d, J = 14.1 Hz, 1H), 2.81 (dd, J = 18.0, 8.1 Hz, 1H),
2.46 (dd, J = 18.0, 6.9 Hz, 1H), 1.92 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ 170.4, 168.9, 163.6, 136.9, 136.5, 133.8, 129.8, 128.5, 127.8,
61.8, 61.2, 50.2, 33.1, 21.6, 14.2, 14.1; IR νmax (neat)/cmꢀ1: 3064, 2983, 2906, 1724, 1672, 1655,
1444, 1393, 1254, 1184, 1030, 704; HRMS (ESI/FTꢀICR, m/z): calcd for C18H23NNaO5 [M +
Na]+ 356.1468, found 356.1473. Compound 7 is also isolated as a single isomer. However, the
geometry of the double bond seemed difficult to determine through NOE analysis.
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Diethyl acetylglutamate (8): To a 20 mL sealable tube equipped with a stir bar were added
compound 7 (33.3 mg, 0.1 mmol) and 10% palladium on charcoal (10 mg). The vial was
evacuated in vacuo and refilled with N2 three times and then was added ethanol (2 mL). The tube
was evacuated again and refilled with an H2 balloon, three times. The reaction mixture was
warmed up to 60 oC and stirred under H2 atmosphere for 24 h. The resulting mixture was cooled
to room temperature, filtered through a Celite® pad and concentrated in vacuo. The residue was
purified through a silica gel column chromatography (PE:EtOAc from 5:1 to 2:1) to give
compound 8 (18.4 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 6.26 (d, J = 7.3 Hz, 1H), 4.59 (td, J
= 7.3, 5.1 Hz, 1H), 4.25 – 4.13 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 2.48 – 2.27 (m, 2H), 2.25 –
2.12 (m, 1H), 2.01 (s, 3H), 1.99 – 1.89 (m, 1H), 1.32 – 1.20 (m, 6H); 13C{1H}NMR (100 MHz,
CDCl3) δ 172.9, 172.0, 170.0, 61.7, 60.7, 51.7, 30.3, 27.4, 23.1, 14.2, 14.1; IR νmax (neat)/cmꢀ1:
3288, 2983, 2935, 1737, 1658, 1543, 1376, 1259, 1200, 1026, 859; HRMS (ESI/FTꢀICR, m/z):
calcd for C11H19NNaO5 [M + Na]+ 268.1155, found 268.1158.
viii. Mechanistic related experiments (Scheme 3)
The inhibiting effect of TEMPO: To an ovenꢀdried 20 mL sealable tube charged with a stir bar
were added 2,4ꢀdichlorobenzaldehyde 1i (35 mg, 0.2 mmol), aniline 2a (18.6 mg, 0.2 mmol),
AIBN (3.3 mg, 0.02 mmol) and freshly activated 4 Å molecular sieves (80 mg). The tube was
sealed with a septum and 1,3ꢀdioxolane (2 mL, freshly distilled) was added through a syringe,
followed by the addition of TDM (5 ꢁL, 0.02 mmol). The reaction mixture was stirred at 80 °C
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for 10 hours and then cooled down. After concentrated in vacuo, the resulting residue was
1
submitted for H NMR analysis with 1,3,5ꢀtrimethoxybenzene as an internal standard. By
comparing the spectrum to authentic sample 3ia, no desired product was detected in this case
7
8
9
(<5%, Scheme 3a).
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Kinetic study with different thiol loadings: To an ovenꢀdried 20 mL sealable tube charged with
a stir bar were added (E)ꢀ1ꢀ(2,4ꢀdichlorophenyl)ꢀNꢀphenylmethanimine (50 mg, 0.2 mmol),
AIBN (3.3 mg, 0.02 mmol), methyl benzoate (25 ꢁL, 0.2 mmol, as an internal standard) and
freshly activated 4 Å molecular sieves (80 mg). The tube was sealed with a septum and 1,3ꢀ
dioxolane (2 mL, freshly distilled) was added through a syringe, followed by the addition of
TDM (0, 0.02, 0.06, and 0.1 mmol). The reaction mixture was stirred at 80 °C and 50 ꢁL of
reaction mixture was taken by a syringe at 0.5 h, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h and
10 h, respectively. The sample was diluted with 2 mL hexanes/iPrOH (9:1 mixture) and filtered
through a 0.45 ꢁm nylon membrane before submitted for HPLC analysis (Note: the response
factors of imine/internal standard and product/internal standard were determined first by mixing
specific amount of samples). The results are depicted in Scheme 3b.
Thiyl radical capturing through thiolꢀene reaction: To an ovenꢀdried sealable tube charged
with a stir bar were added allyl benzoate (32.4 mg, 0.2 mmol) and AIBN (3.3 mg, 0.02 mmol).
The tube was evacuated in vacuo and refilled with N2 three times. Then, 1,3ꢀdioxolane (2 mL,
freshly distilled) was added through a syringe, followed by the addition of TDM (50 ꢁL, 0.2
mmol). The sealed tubes were then heated up to 80 °C and kept stirring for 12 hours. After
concentrated in vacuo, the resulting residue was purified through a silica gel column
chromatography (PE: Et2O from 100:1 to 50:1) to afford the corresponding product 9 as colorless
oil (23 mg, 31% yield). 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 7.7 Hz, 2H), 7.56 (t, J = 7.5
Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.41 (t, J = 6.4 Hz, 2H), 2.63 (q, J = 7.4 Hz, 1H), 2.57 (q, J =
6.9 Hz, 1H), 2.03 (m, 1H), 1.50 – 1.07 (m, 13H), 1.00 – 0.71 (m, 12H); 13C{1H}NMR (151 MHz,
CDCl3) δ 166.5, 132.9, 130.3, 129.6, 128.4, 63.9, 45.6, 29.7, 29.1, 28.8, 24.3, 23.7, 23.7, 22.7,
17.5, 16.1, 14.5, 14.1, 12.2, 8.7.; HRMS (ESI/FTꢀICR, m/z): calcd for C22H36NaO2S [M + Na]+
387.2328, found 387.2329.
The oxygen effects: To an ovenꢀdried 20 mL sealable tube (22ꢀ24 mL gas space) charged with a
stir bar were added (E)ꢀ1ꢀ(2,4ꢀdichlorophenyl)ꢀNꢀphenylmethanimine (50 mg, 0.2 mmol), AIBN
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(3.3 mg, 0.02 mmol) and freshly activated 4 Å molecular sieves (80 mg). The tube was evacuated
in vacuo and refilled with N2 three times. Then, certain volume of N2 (1 mL, 2 mL, 5 mL, 10 mL,
respectively) was withdrawn from the reaction tubes (with a syringe) and they were refilled with
an O2 balloon immediately. 1,3ꢀDioxolane (2 mL, freshly distilled) was added through a syringe,
followed by the addition of TDM (5 ꢁL, 0.02 mmol). The sealed tubes were then heated up to
80 °C and kept stirring for 3 hours. After concentrated in vacuo, the resulting residue was
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submitted for H NMR analysis with 1,3,5ꢀtrimethoxybenzene as an internal standard. The
reaction results are presented in Scheme 3d.
The intermolecular competition kinetic isotope effect was studied with a 1:1 mixture of THF
and THFꢀd8. To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added 2,4ꢀ
dichlorobenzaldehyde (17.5 mg, 0.1 mmol), aniline (9.1 ꢁL, 0.1 mmol), AIBN (1.6 mg, 0.01
mmol) and freshly activated 4 Å molecular sieves (80 mg). The tube was sealed with a septum
and THF/THFꢀd8 (1 mL, 1:1 v/v) was added through a syringe, followed by the addition of TDM
(2.4 ꢁL, 0.01 mmol). The reaction mixture was stirred at 80 °C for 12 hours and then cooled
1
down. After concentrated in vacuo, the resulting residue was submitted for H NMR analysis.
The k
H
/k (11 + 11ꢀd1)/(11ꢀd7 + 11ꢀd8) was determined to be 6.3. (Detailed spectrum analysis is
D
presented in the Supporting Information)
The parallel kinetic isotope effect was studied through parallel reactions with THF and THFꢀd8
as solvent, respectively. To an ovenꢀdried 20 mL sealable tube charged with a stir bar were added
2,4ꢀdichlorobenzaldehyde (17.5 mg, 0.1 mmol), aniline (9.1 ꢁL, 0.1 mmol), AIBN (1.6 mg, 0.01
mmol) and freshly activated 4 Å molecular sieves (80 mg). The tube was sealed with a septum
and THF or THFꢀd8 (1 mL) was added through syringes, followed by the addition of TDM (2.4
ꢁL, 0.01 mmol). The reaction mixture was stirred at 80 °C for 4 or 8 hours and then cooled
1
down. After concentrated in vacuo, the resulting residue was submitted for H NMR analysis
with 1,3,5ꢀtrimethoxybenzene as an internal standard. The product ratio 11/11ꢀd8 are in good
agreement at different time point and the k
H
/k was determined to be 3.6±0.1.
D
Acknowledgments
Financial support from the National Natural Science Foundation of China (21472053) and the
Natural Science Foundation of Hubei Committee (2016CFA001) is gratefully acknowledged. We
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also thank Huazhong University of Science & Technology Analytical & Testing Center for
characterizing new compounds.
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Supporting Information
9
NMR spectra and for all compounds. (PDF) This file is available free of charge on the ACS
Publications website.
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References
(1) For selected reviews on C–H functionalization of ethers and alcohols: (a) Godula, K.; Sames, D. C–
H bond functionalization in complex organic synthesis. Science 2006, 312, 67; (b) Li, C.ꢀJ. Crossꢀ
dehydrogenative coupling (CDC): exploring C–C bond formations beyond functional group
transformations. Acc. Chem. Res. 2009, 42, 335; (c) Conejero, S.; Paneque, M.; Poveda, M. L.; Santos, L.
L.; Carmona, E. C–H bond activation reactions of ethers that generate iridium carbenes. Acc. Chem. Res.
2010, 43, 572; (d) Zhang, S.ꢀY.; Zhang, F.ꢀM.; Tu, Y.ꢀQ. Direct sp3 αꢀCꢀH activation and functionalization
of alcohol and ether. Chem. Soc. Rev. 2011, 40, 1937. (e) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang,
J.; Singh, A. K.; Lei, A. Recent advances in radical C–H activation/radical crossꢀcoupling. Chem. Rev.
2017, 117, 9016; (f) Guo, S.ꢀR.; Kumar, P. S.; Yang, M. Recent advances of oxidative radical crossꢀ
coupling reactions: direct αꢀC(sp3)–H bond functionalization of ethers and alcohols. Adv. Synth. Catal.
2017, 359, 2; (g) Lakshman, M. K.; Vuram, P. K. Crossꢀdehydrogenative coupling and oxidativeꢀ
amination reactions of ethers and alcohols with aromatics and heteroaromatics. Chem. Sci. 2017, 8, 5845.
(2) Selected examples of redoxꢀneutral catalytic radical functionalization of ethers and alcohols: (a)
Deng, H.ꢀP.; Fan, X.ꢀZ.; Chen, Z.ꢀH.; Xu, Q.ꢀH.; Wu, J. Photoinduced nickelꢀcatalyzed chemoꢀ and
regioselective hydroalkylation of internal alkynes with ether and amide αꢀhetero C(sp3)–H bonds. J. Am.
Chem. Soc. 2017, 139, 13579; (b) Hager, D.; MacMillan, D. W. C. Activation of C–H bonds via the
merger of photoredox and organocatalysis: a coupling of benzylic ethers with Schiff bases. J. Am. Chem.
Soc. 2014, 136, 16986; (c) Jeffrey, J. L.; Terrett, J. A.; MacMillan, D. W. C. O–H hydrogen bonding
promotes Hꢀatom transfer from α C–H bonds for Cꢀalkylation of alcohols. Science 2015, 349, 1532; (d)
Jin, J.; MacMillan, D. W. C. Alcohols as alkylating agents in heteroarene C–H functionalization. Nature
2015, 525, 87; (e) Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C. A General strategy for
organocatalytic activation of C–H bonds via photoredox catalysis: direct arylation of benzylic ethers. J.
Am. Chem. Soc. 2014, 136, 626; (f) Lahm, G.; Opatz, T. Selective C–H activation of methoxy groups in a
threeꢀcomponent photoreaction. J. Org. Chem. 2015, 80, 12711; (g) Zhang, M.; Zhao, Y.; Chen, W.
Peroxideꢀfree Co(OAc)2ꢀcatalyzed radical addition of sp3 C–H bonds to alkynes. Synthesis 2017, 49,
1342.
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(3) Selected examples of oxidative radical functionalization with peroxides: (a) Giordano, C.; Minisci,
F.; Vismara, E.; Levi, S. A general, selective, and convenient procedure of homolytic formylation of
heteroaromatic bases. J. Org. Chem. 1986, 51, 536; (b) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M.
Direct C2ꢀalkylation of azoles with alcohols and ethers through dehydrogenative crossꢀcoupling under
metalꢀfree conditions. Org. Lett. 2011, 13, 5016; (c) Wei, W.ꢀT.; Song, R.ꢀJ.; Li, J.ꢀH. Copperꢀcatalyzed
oxidative αꢀalkylation of αꢀamino carbonyl compounds with ethers via dual C(sp3)–H oxidative crossꢀ
coupling. Adv. Synth. Catal. 2014, 356, 1703; (d) Sun, W.; Xie, Z.; Liu, J.; Wang, L. Oxidative crossꢀ
coupling of pyridine Nꢀoxides and ethers between C(sp2)ꢀH/C(sp3)–H bonds under transitionꢀmetalꢀfree
conditions. Org. Biomol. Chem. 2015, 13, 4596; (e) Xu, Z.; Hang, Z.; Chai, L.; Liu, Z.ꢀQ. A freeꢀradicalꢀ
promoted siteꢀspecific crossꢀdehydrogenativeꢀcoupling of Nꢀheterocycles with fluorinated alcohols. Org.
Lett. 2016, 18, 4662; (f) Li, Y.; Wang, M.; Fan, W.; Qian, F.; Li, G.; Lu, H. Cobaltꢀcatalyzed crossꢀ
dehydrogenative coupling reactions of (benz)oxazoles with ethers. J. Org. Chem. 2016, 81, 11743; (g)
Feng, S.; Li, T.; Du, C.; Chen, P.; Song, D.; Li, J.; Xie, X.; She, X. Visibleꢀlightꢀmediated radical insertion
/cyclization cascade reaction: synthesis of phenanthridines and isoquinolines from isocyanides. Chem.
Commun. 2017, 53, 4585; (h) San Segundo, M.; Guerrero, I.; Correa, A. Coꢀcatalyzed C(sp3)–H oxidative
coupling of glycine and peptide derivatives. Org. Lett. 2017, 19, 5288; and references cited therein.
(4) Selected examples of oxidative radical functionalization with persulfates: (a) Xie, Z.; Cai, Y.; Hu, H.;
Lin, C.; Jiang, J.; Chen, Z.; Wang, L.; Pan, Y. Cuꢀcatalyzed crossꢀdehydrogenative coupling reactions of
(benzo)thiazoles with cyclic ethers. Org. Lett. 2013, 15, 4600; (b) Jin, J.; MacMillan, D. W. C. Direct α-
arylation of ethers through the combination of photoredox-mediated C–H functionalization and the
minisci reaction. Angew. Chem. Int. Ed. 2015, 54, 1565; (c) Devari, S.; Shah, B. A. Visible lightꢀpromoted
C–H functionalization of ethers and electronꢀdeficient arenes. Chem. Commun. 2016, 52, 1490; (d) Ji, P.ꢀY.;
Liu, Y.ꢀF.; Xu, J.ꢀW.; Luo, W.ꢀP.; Liu, Q.; Guo, C.ꢀC. Transitionꢀmetalꢀfree oxidative decarboxylative
cross coupling of α,βꢀunsaturated carboxylic acids with cyclic ethers under air conditions: mild synthesis
of αꢀoxyalkyl ketones. J. Org. Chem. 2017, 82, 2965; (e) Liu, S.; Liu, A.; Zhang, Y.; Wang, W. Direct Cαꢀ
heteroarylation of structurally diverse ethers via a mild Nꢀhydroxysuccinimide mediated crossꢀdehydrogenative
coupling reaction. Chem. Sci. 2017, 8, 4044; (f) Quattrini, M. C.; Fujii, S.; Yamada, K.; Fukuyama, T.;
Ravelli, D.; Fagnoni, M.; Ryu, I. Versatile crossꢀdehydrogenative coupling of heteroaromatics and hydrogen
donors viadecatungstate photocatalysis. Chem. Commun. 2017, 53, 2335.
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(5) Selected examples of redox neutral reactions that use stoichiometric amount of radical precursors: (a)
Yamada, K.ꢀI.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Radical addition of ethers to
imines initiated by dimethylzinc. Org. Lett. 2002, 4, 3509; (b) Yoshimitsu, T.; Arano, Y.; Nagaoka, H.
Radical αꢀCꢀH hydroxyalkylation of ethers and acetal. J. Org. Chem. 2005, 70, 2342; (c) Clerici, A.;
+
Cannella, R.; Panzeri, W.; Pastori, N.; Regolini, E.; Porta, O., TiCl3/PhN2 ꢀmediated radical addition of
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ethers to aldimines generated in situ under aqueous conditions. Tetrahedron Lett. 2005, 46, 8351; (d) A.
Clerici, R. Cannella, N. Pastori, W. Panzeri, O. Porta, A free radical Mannich type reaction: selective αꢀ
C–H aminomethylation of ethers by Ti(III)/tꢀBuOOH system under aqueous acidic conditions.
Tetrahedron 2006, 62, 5986; (e) Liu, Z.ꢀQ.; Sun, L.; Wang, J.ꢀG.; Han, J.; Zhao, Y.ꢀK.; Zhou, B. Freeꢀ
radicalꢀinitiated coupling reaction of alcohols and alkynes: not C–O but C–C bond formation. Org. Lett.
2009, 11, 1437; (f) Jung, J. C.; Kim, Y. H.; Lee, K. Practical βꢀmasked formylation and acetylation of
electronꢀdeficient olefins utilizing tetra(nꢀbutyl)ammonium peroxydisulfate. Tetrahedron Lett. 2011, 52,
4662; (g) Li, J.; Zhang, J.; Tan, H.; Wang, D. Z. Visibleꢀlightꢀpromoted vinylation of tetrahydrofuran with
alkynes through direct C–H bond functionalization. Org. Lett. 2015, 17, 2522; (h) Solvhoj, A.; Ahlburg,
A.; Madsen, R. Dimethylzincꢀinitiated radical coupling of βꢀbromostyrenes with ethers and amines.
Chem.ꢀEur. J. 2015, 21, 16272; (i) Lan, Y.; Fan, P.; Liu, X.ꢀW.; Meng, F.ꢀF.; Ahmad, T.; Xu, Y.ꢀH.; Loh,
T.ꢀP. An ironꢀcatalyzed hydroalkylation reaction of α,βꢀunsaturated ketones with ethers. Chem. Commun.
2017, 53, 12353.
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(6) Zeng, H.; Lu, D.; Gong, Y. Direct metal-free C–H functionalization of cyclic ethers with Schiff bases
through an azobisisobutyronitrile-initiated radical chain process. Eur. J. Org. Chem. 2017, 2017, 7231.
(7) (a) Fernandez, M.; Alonso, R. Diastereoselective intermolecular addition of the 1,3ꢀdioxolanyl
radical to Nꢀacyl aldohydrazones. Asymmetric synthesis of αꢀamino acid derivatives. Org. Lett. 2003, 5,
2461; (b) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K. Introduction of functionalized C1, C2,
and C3 units to imines through the dimethylzincꢀairꢀinitiated radical addition. J. Org. Chem. 2004, 69,
1531; (c) Yamada, K.; Umeki, H.; Maekawa, M.; Yamamoto, Y.; Akindele, T.; Nakano, M.; Tomioka, K.
Conjugate addition reaction of THFꢀ2ꢀyl radical with α,βꢀunsaturated Nꢀtosyl imines using a
dimethylzincꢀair initiator. Tetrahedron 2008, 64, 7258; (d) Zhang, L.; Deng, Y.; Shi, F. Light promoted
aqueous phase amine synthesis via threeꢀcomponent coupling reactions. Tetrahedron Lett. 2013, 54, 5217.
(8) Nielsen, M. K.; Shields, B. J.; Liu, J.; Williams, M. J.; Zacuto, M. J.; Doyle, A. G Mild, Redoxꢀ
neutral formylation of aryl chlorides through the photocatalytic generation of chlorine radicals. Angew.
Chem. Int. Ed. 2017, 56, 7191.
(9) P. Roberts, B. Polarityꢀreversal catalysis of hydrogenꢀatom abstraction reactions: concepts and
applications in organic chemistry. Chem. Soc. Rev. 1999, 28, 25.
(10) Musa, O. M.; Horner, J. H.; Shahin, H.; Newcomb, M. A kinetic scale for dialkylaminyl radical
reactions. J. Am. Chem. Soc. 1996, 118, 3862.
(11) Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev.
2014, 114, 2587.
(12) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. Preparation and use of C2ꢀsymmetric
bis(phospholanes): production of αꢀamino acid derivatives via highly enantioselective hydrogenation
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