Copper-Catalyzed Addition of Alkylboranes to Iminoacetates: Access to α-Alkyl Branched α-Amino Acids

Article abstract of DOI:10.1002/adsc.201600248

A copper(I)-catalyzed addition of alkylborane reagents to α-iminoacetates has been developed to assemble both acyclic and cyclic α-branched α-amino carboxylic acid derivatives in good yields. A wide variety of unactivated alkenes are well tolerated in this transformation. (Figure presented.).

Full text of DOI:10.1002/adsc.201600248

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DOI: 10.1002/adsc.201600248
Copper-Catalyzed Addition of Alkylboranes to Iminoacetates:
Access to a-Alkyl Branched a-Amino Acids
Xinsheng Xiao,a Wei Zhang,a Xiaoxia Lu,b Yuanfu Deng,a Huangfeng Jiang,a
and Wei Zenga,*
a
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou 510641, Peopleꢀs Republic of China
Fax : (+86)-20-2223-6337; e-mail: zengwei@scut.edu.cn
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of China
b
Received: March 3, 2016; Revised: April 17, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600248.
Abstract: A copper(I)-catalyzed addition of alkylbor- wide variety of unactivated alkenes are well tolerat-
ane reagents to a-iminoacetates has been developed ed in this transformation.
to assemble both acyclic and cyclic a-branched a-
amino carboxylic acid derivatives in good yields. A Keywords: alkylboranes; a-amino acids; copper cat-
alysis; imino esters; unactivated monoalkenes
Introduction
remain in realizing the direct coupling of imines with
alkylboranes.[9]
Carbonyl alkylation belongs to an important class of
On the other hand, Umani-Ronchi and co-workers
3
3
[1]
À
Csp Csp bond forming reactions. In the past 100 have reported that the addition of stoichiometric al-
years, significant progress in the nucleophilic addition kylzinc-copper reagents to imines could smoothly pro-
of Grignard reagents to carbonyl compounds has ceed to afford a-branched chain aliphatic amines,
been achieved for constructing various carbon-carbon which indicated that active alkylcopper(I) intermedi-
bonds.[2] However, organomagnesium reagents are ates could not easily undergo the b-hydride elimina-
generally sensitive to moisture, oxygen and many tion process to form alkenes.[10] Recently, Ohmiya and
functional groups. In particular, alkylmagnesium com- Sawamura further found the cross-coupling reactivity
pounds are not easily available because the insertion between alkyl-9-BBN and alkenes, alkynes or allylic
À
of magnesium metal into the C X bond of alkyl hal- substrates could be significantly improved via boron-
ides generally suffers from highly reactive radical in- copper exchange.[11] These results imply that alkylbor-
termediates,[3] and these drawbacks inhibited their anes could possibly act as alkenyl equivalents to be
broader application to some degree. To surmount trapped by various coupling partners under copper
these limitations, various organometallic reagents catalytic system. Therefore, we herein report the first
have been developed to improve the reaction selectiv- example of copper(I)-catalyzed cross-coupling of ole-
ity under mild reaction conditions.[4] Among them, fins with imines under mild conditions, in which unac-
water-tolerant organoboranes have aroused growing tivated alkenes were firstly reduced to alkylboranes
interests in the past few decades because of their ver- by 9-BBN-H (Scheme 1).
satile functional group compatibilities in various
transformations.[5] In this regard, transition metal-cat-
alyzed cross-couplings of aryl-,[6] alkenyl-[6d,7] and al- Results and Discussion
lylboranes[8] with carbonyl compounds, including
imines, through boron-metal transmetalation process- Initially, we focused on exploring the effect of various
es, have been well established for assembling complex hydrogen donors on the CuOAc-catalyzed stepwise
alcohols and amines. In comparison, the nucleophilic reductive coupling of (4-methoxyphenylimino)acetic
addition of alkylboranes to carbonyl compounds has acid ethyl ester (1a) with phenyl ethylene (2a) using
rarely been reported, and enormous challenges still Na2CO3 as base at 708C for 24 h (Table 1, entries 1–
4). Previous works have already demonstrated that al-
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drides as reducing agents, could produce alkylcopper
species via a transmetalation process in the presence
of copper catalysts,[12,13,14] so we first employed zirco-
nocene hydrochloride (HZrCp2Cl), HSiMe2Ph and
HSiEt3 as hydrogen sources in our reaction system,
respectively. Unfortunately, no desired stepwise re-
ductive coupling product 3a was observed (entries 1–
3). On the contrary, when hydroborane was applied to
this reaction system, we quickly found that 9-BBN-H
could produce 2-(4-methoxyphenylamino)-4-phenyl-
butyric acid ethyl ester (3a) in 22% yield (compare
entries 1–3 with entry 4). Although the conversion of
1a was very low (entry 4), this positive result greatly
encouraged us to continue to evaluate various copper
catalysts such as CuBr, CuCl, CuI, and Cu(OAc)2,
Scheme 1. Copper-catalyzed addition of a-imino esters with
alkylboranes derived from unactivated monoalkenes.
kylzirconiums and alkylsilanes which generated in situ etc., for improving the stepwise reductive coupling
from alkenes using Schwartz reagent and silicon hy- yield. The corresponding copper salt screening indi-
Table 1. Optimization of the reaction parameters[a]
Entry
Catalyst
Reductant
Base
Additives
Yield (%)[b]
1
2
3
4
5
6
7
8
CuOAc
CuOAc
CuOAc
CuOAc
CuBr
HZrCp2Cl
HSiMe2Ph
HSiEt3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Li2CO3
t-BuOLi
t-BuONa
MeOLi
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOK
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0
0
0
22
19
18
24
5
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
9-BBN-H
CuCl
CuI
Cu(OAc)2
CuBr·SMe2
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuOAc
9
trace
29
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0[c]
37
37
38
48
30
53
trace
16
–
PivOH
AcOH
i-PrOH
H2O
H2O
H2O
1,10-Phen
64
75
33[d]
74[e]
36[15]
[a]
Unless otherwise noted, all the reactions were first carried out using styrene (2a) (0.15 mmol) with reductant (0.15 mmol)
in toluene (2.0 mL) under an argon atmosphere at 608C for 1 h in a sealed reaction tube. Then the reaction mixture was
cooled down to room temperature, and copper catalyst (10 mol%), base (15 mol%), additive (0.10 mmol) and a-imino
ester (1a) (0.10 mmol) were added and the corresponding mixture was stirred further at 708C for 24 h under argon.
Isolated yield.
Employing 1aa as substrate instead of 1a.
The reaction temperature is 608C.
The reaction temperature is 908C.
[b]
[c]
[d]
[e]
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cated that CuCN could serve as the most efficient cat- the CuCN/9-BBN-H/Cs2CO3 reaction system, and we
alyst for this transformation (compare entries 4–9 pleasingly found that H2O could afford the best yield
with entry 10). By the way, when a-imino ester 1a was of 3a (75% yield of 3a, entries 18–20 vs. entry 21). It
switched to N-Ts-substituted imine 1aa, we did not is worth noting that decreasing or increasing the reac-
obtain the corresponding stepwise reductive coupling tion temperature could not further improve the reac-
product 3aa (entry 11), possibly due to the fact that tion yield (entries 22 and 23 vs. entzry 21), and also
Lewis acid Cu(I) catalysts or borates could not effi- use of Sawamuraꢀs conditions[15] only led to a 36%
ciently activate the imino C=N bond in the absence of yield of the stepwise reductive coupling product 3a
a carbonyl chelating anchor. Subsequently, a further (entry 24).
significant improvement of the reaction (53% yield of
With the optimized conditions for the Cu(I)-cata-
3a) was achieved by employing cesium carbonate as lyzed stepwise reductive coupling transformation es-
base (entries 12–16 vs. entry 17). Finally, considering tablished, we next investigated the scope of the cur-
that a proper proton source is essential for enhancing rent procedure by testing various imino esters in the
this stepwise reductive coupling reaction, several reaction with phenylethylene (2a). As shown in
proton-donor additives including pivalic acid, acetic Table 2 (3a–3i), the reactivity of imino esters (1) was
acid, isopropyl alcohol and water were investigated in partly dependent on the electronic and structural
Table 2. Substrate scope.[a,b]
[a]
All the reactions were first carried out using alkene (2) (0.15 mmol) with 9-BBN-H (0.15 mmol) in toluene (2.0 mL)
under argon at 608C for 1 h in a sealed reaction tube. Then the reaction mixture was cooled down to room temperature,
and CuCN (10 mol%), Cs2CO3 (15 mol%), H2O (0.10 mmol) and a-imino ester (1) (0.10 mmol) were added and the cor-
responding mixture was stirred further at 708C for 24 h under argon.
Isolated yield.
Diastereomeric ratio (anti:syn).
[b]
[c]
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properties of the N-substituted arenes. para-, meta- or were applied to this reaction system, the unexpected
ortho-Substitution of N-phenyl rings with electron-do- cyclic a-piperidinyl-substituted carboxylic acid esters
nating groups (Me, MeO) or electron-withdrawing 3y (59% yield) and 3z (62% yield) were obtained
groups (halogen, ester) does not significantly affect through a stepwise reductive coupling/cyclization pro-
the stepwise reductive coupling yields (50–75% yields cess. By the way, existing synthetic approaches to
for 3a–3i). For example, the electron-rich N-(4-meth- multisubstituted pipecolic acid derivatives generally
ylphenyl)imino ester underwent an efficient conver- need tedious reaction steps.[16] Finally, the structure of
sion to provide the desired stepwise reductive cou- the product 3r was already unambiguously assigned
pling product 3c in 65% yield, but the strong elec- by its single crystal X-ray analysis (see the Supporting
tron-withdrawing nitro group-containing imino ester Information for more details).
could also smoothly couple with 1-vinylnaphthalene
Furthermore, removal of the N-p-methoxyphenyl
to furnish the a-branched-chain a-amino acid deriva- (PMP) group of 3a occurred upon treatment with am-
tive (3j) in moderate yield (55% yield).
monium cerium nitrate (CAN) under mild conditions
À
On the other hand, the present stepwise reductive to produce the corresponding free (N H) a-phenyl-
coupling method was also successfully applied to ethyl-substituted a-amino acid ester in 62% yield.
a wide range of unactive monoalkenes with (4-me- The subsequent hydrolysis and reduction procedure
thoxyphenylimino)acetic acid ethyl ester (1a) as the provided a convenient approach to the a-branched-a-
coupling partner. It was revealed that the reaction ef- amino acid and the b-amino alcohol in 96% and 83%
ficiency was maintained irrespective of the type of yield (see Scheme 2a), respectively, and these amino
alkene substrate. As anticipated, various kinds of compounds are widely used in synthetic organic
phenyl-substituted monoalkenes, naphthyl-substituted chemistry.[17] Moreover, employing (4R,4’R)-2,2’-(pro-
olefins and even (2-furyl)-substituted ethylene could pane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) (L*)
efficiently produce the corresponding stepwise reduc- as chiral ligand could afford (S)-3a (53% yield), (S)-
tive coupling products (3k–3s) in good to excellent 3b (44% yield), (S)-3c (47% yield), (S)-3d (49%
yields. Remarkably, various alkyl-substituted monoal- yield), and (S)-3h (46% yield) with enantiomeric ex-
kenes could be readily converted to the corresponding cesses (ee) of 33%, 29%, 29%, 21%, and 25%, respec-
long-chain aliphatic amine derivatives (3t–3v) in 62– tively (see Scheme 2b).
72% yields; moreover, a 1,1-disubstituted terminal
We then conducted several control reactions to fur-
alkene and a 1,2-disubstituted internal alkene also al- ther investigate the primary mechanism of the present
lowed for this transformation and afforded the a- Cu(I)-catalyzed alkylation of imino esters with al-
highly branched a-amino acid derivatives 3w in 62% kenes (see Scheme 3). Firstly, the cross-coupling reac-
yield and 3x in 72% yield. More interestingly, when tion between a-imino ester (1a) and alkyl-9-BBN
alkenes bearing a bromo moiety such as 2p and 2q (2a–1) derived from phenylethylene (2a), was per-
Scheme 2. Synthetic applications of this transformation.
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Scheme 3. Control experiments.
formed in the presence of TEMPO (1.0 equiv.) under absence of copper salts using the NaCN/DABCO
our standard conditions, and a 58% yield of alkylated system, which ruled out that CuCN would deliver cya-
product 3a could be obtained (Scheme 3a). In con- nide ion to the alkylborane reagent to form a nucleo-
trast, employing the H2O2 reaction system[18] in which philic tetravalent boronate complex (Scheme 3d).
the alkylborane could be easily oxidized to alkyl radi- Moreover, FeCl3-catalyzed addition of alkylborane
cal intermediates, could not afford the desired prod- (2a-1) to imino ester (1a) only provided a 7% yield of
uct 3a (Scheme 3b). These findings demonstrated that alkylation product 3a, this result further demonstrated
a free radical process was not involved in this trans- that copper acted as a catalyst precursor to alkylcup-
formation. Subsequently, conducting the addition re- rates rather than as a soft Lewis acid to enhance the
action of 2a-1 to 1a in the absence of Cu(I) catalysts alkylation of a-imino ester (Scheme 3e). By the way,
under the H2O/Ar conditions could also lead to the the copper-free reaction variant at 1008C (10% yield)
formation of 3a (Scheme 3c, 12% yield), which im- was also performed to clarify that copper played
plied that the imino carbon could be directly attacked
a
unique catalytic role in this transformation
by nucleophilic alkylboranes to some degree; Mean- (Scheme 3f). At last, we directly employed n-butyl
while, we also could obtain an 8% yield of 3a in the cuprate[19] (4a) as starting material to react with imino
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[20]
ester (1a) in the presence of PhB(OH)2
for 24 h, sembly of cyclic 2-piperidinecarboxylic acid deriva-
and a 47% yield of the coupling product 3za was ob- tives via a stepwise reductive coupling/cyclization cas-
tained (Scheme 3g).[21] In comparison, n-butyl cuprate cade. We are currently exploring the asymmetric
(4a) only gave 9% yield of 3za in the absence of orga- version of this transformation, which will be reported
noboron compounds (Scheme 3h) possibly due to the in due course.
fact that organoboron derivatives[22] derived from 9-
BBN acted in the role of a Lewis acid to activate the
imino C=N bond.
Based on the above-mentioned results, two plausi-
ble reaction paths are involved in this transformation.
Initially, hydroboration of alkene 2 produced alkyl-9-
Experimental Section
BBN (A), and A could be further activated by
Cs2CO3 to form alkylborate B (Figure 1, path a).[23]
Then boron-Cu(I) transmetalation between borate B
and copper(I) salts with the assistance of H2O result-
ed in the alkylcopper species C and hydroxy-9-BBN
(B*).[22] Subsequently, the coordination of a-imino
ester 1 and alkylcopper C with the assistance of Lewis
acid B* formed p-complexes D, which would undergo
migratory insertion or nucleophilic attack to provide
N-copper intermediate E. Finally, metal-proton ex-
change of E furnished the desired a-branched a-
amino acid ester 3, regenerating the Cu(I) catalyst for
the next catalytic cycle. Alternatively, alkyl-9-BBN
(A) could also directly activate a-imino ester 1 via
complexation with the imine nitrogen in the absence
of copper catalysts, and followed by nucleophilic
attack[24] and protonation to afford 3 (path b).
General Information
Unless otherwise noted, all experiments were performed
under an argon atmosphere. Solvents were treated with 4ꢂ
molecular sieves or sodium and distilled prior to use. Flash
chromatography was performed on silica gel (40–63 mm) by
1
standard techniques. H and 13C NMR spectra were record-
1
ed on a 400 MHz NMR spectrometer (400 MHz for H and
13
100 MHz for C). Splitting patterns are designated as sin-
glet (s), doublet (d), triplet (t), quartet (q). Splitting patterns
that could not be interpreted or easily visualized are desig-
nated as multiplet (m). Low resolution mass spectra were
recorded using an HPLC mass spectrometer. High resolu-
tion exact mass measurements (HR-MS) were performed on
a TOF spectrometer. Infrared spectra (IR) were reported as
wavelength numbers (cmÀ1). Infrared spectra were recorded
by preparing a KBr pellet containing the title compound.
Crystal data were obtained by employing graphite mono-
chromated Mo-Ka radiation (l=1.54178 ꢂ) at 571 (2) K
and operating in the f-w scan mode. The structure was
solved by direct methods with SHELXS-97. a-Imino ester
substrates including (E)-ethyl 2-[(4-methoxyphenyl)imino]-
Conclusions
AHCTUNGTREGaNNUN cetate (1a), (E)-ethyl 2-[(2-methoxyphenyl)imino]acetate
(1b), (E)-ethyl 2-(p-tolylimino)acetate (1c), (E)-ethyl 2-(m-
tolylimino)acetate (1d), (E)-ethyl 2-(phenylimino)acetate
(1e), (E)-ethyl 2-(naphthalen-1-ylimino)acetate (1f), (E)-
ethyl 2-[(4-chlorophenyl)imino]acetate (1g), (E)-ethyl 2-[(4-
bromophenyl)imino]acetate (1h), (E)-ethyl 4-[(2-ethoxy-2-
oxoethylidene)amino]benzoate (1i), (E)-ethyl 2-[(4-nitrophe-
nyl)imino]acetate (1j) were prepared using the previously
reported procedure.[25] All the alkenes substrates are com-
In summary, we have reported the first copper(I)-cat-
alyzed stepwise reductive coupling between imines
and unactivated monoalkenes to furnish a-branched
a-amino carboxylic acid derivatives. The method is
compatible with a wide variety of unactive alkenes in-
cluding kinds of arylethenes, terminal mono- or disub-
stituted aliphatic alkenes and internal alkenes. Fur-
thermore, the procedure allows for the convenient as- mercially available.
Figure 1. Possible mechanism for the transformation.
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Ethyl
2-[(4-methoxyphenyl)amino]-4-phenylbutanoate
1
Procedure for the Preparation of a-Imino Esters
(3a): Yellow oil; yield: 23.5 mg (75%); H NMR (400 MHz,
CDCl3): d=7.28 (t, J=7.3 Hz, 2H), 7.18 (d, J=7.2 Hz, 3H),
6.75 (d, J=7.9 Hz, 2H), 6.56 (d, J=7.8 Hz, 2H), 4.14 (q, J=
7.1 Hz, 2H), 3.97 (s, 1H), 3.91 (s, 1H), 3.71 (s, 3H), 2.77 (t,
J=7.7 Hz, 2H), 2.06 (ddd, J=27.9, 13.5, 6.9 Hz, 2H), 1.22
(t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=174.4,
152.8, 141.1, 128.6, 128.5, 126.2, 115.3, 114.9, 61.1, 57.4, 55.7,
34.8, 31.9, 14.3; HR-MS (ESI): m/z=314.1749, calcd. for
[M+1]+ C19H24NO3: 314.1751; IR (KBr): n=3452, 3171,
3000, 2389,1629, 1486, 1400, 1176, 540 cmÀ1.
All the a-imino esters (1) were synthesized according to the
reported procedures.[25]
A mixture of ethyl glyoxylate
(20.4 mg, 0.20 mmol), substituted amine (0.20 mmol) and an-
hydrous sodium sulfate (1.0 mmol) in 2 mL of toluene was
stirred for 0.5 hour at room temperature. The mixture was
then filtered and the solvent was removed under reduced
pressure to produce the corresponding a-imino esters. The
crude products were directly used for synthetic purposes
without further purification.
Ethyl
2-[(2-methoxyphenyl)amino]-4-phenylbutanoate
1
(3b): Yellow oil; yield: 21.0 mg (67%); H NMR (400 MHz,
CDCl3): d=7.30–7.26 (m, 2H), 7.19 (d, J=7.3 Hz, 3H),
6.82–6.76 (m, 2H), 6.70 (d, J=7.6 Hz, 1H), 6.49 (d, J=
7.7 Hz, 1H), 4.75 (d, J=6.9 Hz, 1H), 4.16 (q, J=7.1 Hz,
2H), 4.10–4.05 (m, 1H), 3.86 (s, 3H), 2.78 (t, J=7.8 Hz,
2H), 2.20 (dd, J=13.8, 7.2 Hz, 1H), 2.10 (dd, J=14.0,
7.0 Hz, 1H), 1.24 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d=174.0, 147.2, 141.0, 136.8, 128.5, 128.5, 126.1,
121.2, 117.5, 110.5, 109.9, 61.0, 55.9, 55.5, 34.6, 31.8, 14.2;
HR-MS (ESI): m/z=314.1750, calcd. for [M+1]+
C19H24NO3: 314.1751; IR (KBr): n=3468, 3106, 2998, 1612,
1400, 1175, 538 cmÀ1.
Synthesis of N-Benzylidene-4-methylbenzene-
sulfonamide (1aa)[26]
To a solution of benzaldehyde (2.54 mL, 25 mmol) and p-
toluenesulfonamide (4.28 g, 25 mmol) in toluene (76 mL) at
reflux using a Dean–Stark apparatus was added BF3·OEt2
(37 mL, 0.4 mmol, 0.016 equiv.). The reaction was stirred at
reflux until the theoretical amount of water was collected.
The reaction mixture was quenched with NaOH (2M in
H2O), extracted with EtOAc, dried (MgSO4) and concen-
trated under vacuum to give a crude reaction mixture. The
corresponding pure N-benzylidene-4-methylbenzenesulfon-
ACHTUNGTRENNUNGamide (1aa) was obtained as a white solid after recrystalliza-
Ethyl 4-phenyl-2-(p-tolylamino)butanoate (3c): Yellow
tion (EtOAc/isohexane); yield: 5.0 g (77%). 1H NMR
(400 MHz, CDCl3): d=9.06 (s, 1H), 7.93 (dd, J=13.2,
7.9 Hz, 4H), 7.64 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.5 Hz, 2H),
7.37 (d, J=7.9 Hz, 2H), 2.46 (s, 3H); MS (ESI): m/z=259.1
[M+].
1
oil; yield: 19.3 mg (65%); H NMR (400 MHz, CDCl3): d=
7.28 (d, J=7.2 Hz, 2H), 7.19 (d, J=7.4 Hz, 3H), 6.97 (d, J=
7.8 Hz, 2H), 6.52 (d, J=7.8 Hz, 2H), 4.16 (q, J=7.1 Hz,
2H), 4.03 (s, 2H), 2.76 (t, J=7.8 Hz, 2H), 2.22 (s, 3H), 2.15
(dd, J=14.0, 6.5 Hz, 1H), 2.03 (dd, J=13.9, 7.1 Hz, 1H),
1.24 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
174.2, 144.5, 141.0, 129.8, 128.5, 128.5, 127.6, 126.1, 113.8,
61.0, 56.5, 34.7, 31.8, 20.4, 14.2; HR-MS (ESI): m/z=
298.1802, calcd. for [M+1]+ C19H24NO2: 298.1802; IR
(KBr): n=3451, 3102, 3005, 2392, 1625, 1400, 1172,
540 cmÀ1.
Synthesis of n-C4H9Cu (4a)[19]
n-C4H9Cu (4a) (0.3 mmolmLÀ1 in THF): To a stirred suspen-
sion of CuBr (1.43 g, 0.01 mol) in THF (18.3 mL), a solution
of dry lithium bromide (0.87 g, 0.010 mol) in THF (5 mL)
was added at 208C. The homogeneous solution was cooled
Ethyl 4-phenyl-2-(m-tolylamino)butanoate (3d): Yellow
1
to À608C and
a solution of n-C4H9MgCl (10.0 mL,
oil; yield: 18.7 mg (63%); H NMR (400 MHz, CDCl3): d=
10.0 mmol, 1.0 mol/L in THF) was added dropwise. The
mixture was then stirred at À608C for 15 min, and used di-
rectly.
7.32 (t, J=7.2 Hz, 2H), 7.23 (t, J=7.8 Hz, 3H), 7.08 (t, J=
7.6 Hz, 1H), 6.59 (d, J=7.4 Hz, 1H), 6.43 (d, J=7.4 Hz,
2H), 4.17 (dt, J=30.1, 9.4 Hz, 4H), 2.80 (t, J=7.8 Hz, 2H),
2.28 (s, 3H), 2.20 (dd, J=13.7, 6.4 Hz, 1H), 2.11–2.06 (m,
1H), 1.28 (d, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=174.0, 146.8, 140.9, 139.1, 129.1, 128.5, 128.4, 126.1, 119.3,
114.4, 110.6, 61.1, 56.1, 34.7, 31.8, 21.5, 14.2; HR-MS (ESI):
m/z=298.1799, calcd. for [M+1]+ C19H24NO2: 298.1802; IR
(KBr): n=3437, 3104, 3005, 1634, 1400, 1171, 626, 538 cmÀ1.
Ethyl 4-phenyl-2-(phenylamino)butanoate (3e): Yellow
General Procedure for the Synthesis of Compounds
3a–3z
An oven-dried tube containing a magnetic stirring bar was
refreshed with argon for 5 min, and then sealed with a cap
equipped with a Teflon-coated silicon rubber septum. Firstly,
alkenes (0.15 mmol) and 9-BBN-H (0.30 mL, 0.5M in THF,
0.15 mmol) were sequentially injected inside through a sy-
ringe, and the mixture was stirred at 608C for 1 h to prepare
the alkylborane. After the reaction mixture was cooled
down to room temperature, Cs2CO3 (0.015 mmol, 5 mg) and
CuCN (0.01 mmol, 1.0 mg) were added, respectively, and
the corresponding mixture was stirred at 258C for 30 min.
Subsequently, a-imino ester (0.10 mmol) in dry toluene
(1.0 mL) and H2O (0.10 mmol) were added again. The reac-
tion mixture was stirred at 708C for another 24 h. Upon
completion as monitored by TLC, the reaction mixture was
filtered and concentrated under vacuum to leave a residue
which was purified by flash column chromatography on
silica gel to furnish the target products.
1
oil; yield: 17.0 mg (60%); H NMR (400 MHz, CDCl3): d=
7.31–7.27 (m, 2H), 7.23–7.13 (m, 5H), 6.73 (t, J=7.3 Hz,
1H), 6.59 (d, J=7.8 Hz, 2H), 4.17 (dd, J=14.1, 7.1 Hz, 3H),
4.07 (t, J=6.0 Hz, 1H), 2.77 (t, J=7.8 Hz, 2H), 2.18 (dd, J=
13.4, 6.3 Hz, 1H), 2.10–2.03 (m, 1H), 1.24 (d, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=173.9, 146.8, 140.9,
129.3, 128.5, 128.4, 126.1, 118.3, 113.6, 61.1, 56.1, 34.6, 31.8,
14.2; HR-MS (ESI): m/z=284.1646, calcd. for [M+1]+
C18H22NO2: 284.1645; IR (KBr): n=3482, 3001, 2393, 1631,
1480, 1400, 1172, 1134, 997, 624 cmÀ1.
Ethyl 2-(naphthalen-1-ylamino)-4-phenylbutanoate (3f):
Yellow oil; yield: 21.0 mg (63%); 1H NMR (400 MHz,
CDCl3): d=7.86–7.76 (m, 2H), 7.45 (d, J=4.7 Hz, 2H), 7.27
(s, 4H), 7.22 (s, 3H), 6.48 (d, J=5.9 Hz, 1H), 4.93 (s, 1H),
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7
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4.26 (s, 1H), 4.21 (d, J=7.0 Hz, 2H), 2.84 (t, J=7.2 Hz,
2H), 2.27 (ddd, J=29.5, 13.6, 6.9 Hz, 2H), 1.27 (t, J=
6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=174.0, 141.9,
140.9, 134.4, 128.6, 128.5, 128.5, 126.3, 126.1, 125.8, 124.9,
123.8, 120.1, 118.3, 105.2, 61.2, 56.2, 34.4, 31.8, 14.2; HR-MS
(ESI): m/z=334.1798, calcd. for [M+1]+ C22H24NO2:
334.1802; IR (KBr): n=3483, 3109, 3002, 1633, 1400, 1177,
854, 781, 539 cmÀ1.
(d, J=5.8 Hz, 1H), 4.00 (s, 1H), 3.74 (s, 3H), 3.23 (t, J=
7.8 Hz, 2H), 2.27 (dd, J=13.4, 7.3 Hz, 1H), 2.21–2.09 (m,
1H), 1.24 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=174.2, 152.8, 141.0, 137.2, 133.9, 131.7, 128.8, 126.9, 126.2,
125.9, 125.5, 123.6, 115.4, 114.9, 61.1, 57.7, 55.7, 34.0, 29.0,
14.2; HR-MS (ESI): m/z=364.1905, calcd. for [M+1]+
C23H26NO3: 364.1907; IR (KBr): n=3497, 3109, 3000, 1731,
1632, 1400, 1241, 1177, 784, 538 cmÀ1.
Ethyl 2-[(4-chlorophenyl)amino]-4-phenylbutanoate (3g):
Yellow oil; yield: 19.0 mg (60%); 1H NMR (400 MHz,
CDCl3): d=7.29 (t, J=7.3 Hz, 2H), 7.20 (dd, J=16.3,
7.2 Hz, 3H), 7.10 (d, J=8.3 Hz, 2H), 6.49 (d, J=8.3 Hz,
2H), 4.16 (dt, J=11.7, 5.9 Hz, 3H), 4.04–3.97 (m, 1H), 2.75
(t, J=7.8 Hz, 2H), 2.21–2.12 (m, 1H), 2.04 (dd, J=13.7,
7.0 Hz, 1H), 1.26 (d, J=6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=174.1, 152.9, 140.8, 139.9, 131.5, 130.3, 119.9,
115.3, 114.9, 61.1, 57.1, 55.7, 34.5, 31.2, 14.2; HR-MS (ESI):
m/z=318.1254, calcd. for [M+1]+ C18H21ClNO2: 318.1255;
IR (KBr): n=3483, 3108, 1626, 1486, 1400, 1134, 623 cmÀ1.
Ethyl 2-[(4-bromophenyl)amino]-4-phenylbutanoate (3h):
Yellow oil; yield: 20.6 mg (57%); 1H NMR (400 MHz,
CDCl3): d=7.24 (ddd, J=29.7, 18.3, 7.0 Hz, 7H), 6.45 (d,
J=7.5 Hz, 2H), 4.17 (d, J=7.4 Hz, 3H), 4.00 (d, J=6.4 Hz,
1H), 2.75 (t, J=7.3 Hz, 2H), 2.10 (ddd, J=50.6, 13.0,
6.8 Hz, 2H), 1.25 (t, J=6.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=173.6, 145.8, 140.7, 132.0, 128.5, 128.5, 126.2,
115.1, 110.0, 61.2, 56.0, 34.3, 31.7, 14.2; HR-MS (ESI): m/z=
362.0748, calcd. for [M+1]+ C18H21BrNO2: 362.0750; IR
(KBr): n=3472, 3180, 3003, 1634, 1485, 1400, 1174, 627,
540 cmÀ1.
Ethyl 4-[(1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino]ben-
zoate (3i): Yellow oil; yield: 17.8 mg (50%); 1H NMR
(400 MHz, CDCl3): d=7.85 (d, J=8.0 Hz, 2H), 7.28 (dd, J=
13.3, 6.0 Hz, 2H), 7.22 (d, J=6.7 Hz, 1H), 7.17 (d, J=
7.2 Hz, 2H), 6.52 (d, J=8.1 Hz, 2H), 4.62 (d, J=8.3 Hz,
1H), 4.36–4.29 (m, 2H), 4.17 (dt, J=15.7, 6.9 Hz, 3H), 2.74
(t, J=7.4 Hz, 2H), 2.26–2.02 (m, 2H), 1.35 (t, J=6.9 Hz,
3H), 1.27 (t, J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=173.1, 166.7, 150.4, 140.5, 131.5, 128.5, 128.4, 126.3, 119.8,
112.1, 61.4, 60.2, 55.3, 34.2, 31.6, 14.4, 14.2; HR-MS (ESI):
m/z=356.1853, calcd. for [M+1]+ C21H26NO4: 356.1856; IR
(KBr): n=2921, 2850, 1699, 1604, 1525, 1273, 1176, 1106,
1019, 766, 698 cmÀ1.
Ethyl 2-[(4-methoxyphenyl)amino]-4-(p-tolyl)butanoate
(3l): Yellow oil; yield: 27.8 mg (85%); H NMR (400 MHz,
1
CDCl3): d=7.09 (s, 4H), 6.75 (d, J=8.5 Hz, 2H), 6.57 (d,
J=8.4 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.97 (s, 1H), 3.87
(s, 1H), 3.73 (s, 3H), 2.73 (t, J=7.8 Hz, 2H), 2.32 (s, 3H),
2.13–1.97 (m, 2H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=174.3, 152.7, 141.0, 137.9, 135.6,
129.1, 128.3, 115.2, 114.8, 61.0, 57.3, 55.7, 34.9, 31.4, 21.0,
14.2; HR-MS (ESI): m/z=328.1910, calcd. for [M+1]+
C20H26NO3: 328.1907; IR (KBr): n=3460, 3184, 2998, 1668,
1400, 1136, 858, 533 cmÀ1.
Ethyl 2-[(4-methoxyphenyl)amino]-4-(m-tolyl)butanoate
1
(3m): Yellow oil; yield: 22.2 mg (68%); H NMR (400 MHz,
CDCl3): d=7.17 (t, J=7.3 Hz, 1H), 7.00 (t, J=8.8 Hz, 3H),
6.75 (d, J=8.6 Hz, 2H), 6.57 (d, J=8.6 Hz, 2H), 4.15 (q, J=
7.1 Hz, 2H), 3.97 (t, J=6.3 Hz, 1H), 3.88 (s, 1H), 3.73 (s,
3H), 2.73 (t, J=7.8 Hz, 2H), 2.32 (s, 3H), 2.17–2.00 (m,
2H), 1.23 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=174.3, 152.8, 141.0, 140.9, 138.0, 129.3, 128.3, 126.8, 125.5,
115.2, 114.8, 61.0, 57.4, 55.7, 34.8, 31.8, 21.3, 14.2; HR-MS
(ESI): m/z=328.1899, calcd. for [M+1]+ C20H26NO3:
328.1907; IR (KBr): n=3437, 3104, 3005, 1734, 1635, 1400,
1171, 626, 538 cmÀ1.
Ethyl 4-[4-(tert-butyl)phenyl]-2-[(4-methoxyphenyl)ami-
no]butanoate (3n): Yellow oil; yield: 28.4 mg (77%);
1H NMR (400 MHz, CDCl3): d=7.31 (d, J=7.9 Hz, 2H),
7.12 (d, J=7.9 Hz, 2H), 6.75 (d, J=8.6 Hz, 2H), 6.61 (d, J=
8.5 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.99 (t, J=6.4 Hz,
1H), 3.74 (s, 3H), 2.74 (t, J=7.8 Hz, 2H), 2.18–2.00 (m,
2H), 1.31 (s, 9H), 1.22 (d, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=174.2, 152.8, 148.9, 140.8, 137.9,
128.1, 125.3, 115.3, 114.8, 61.0, 57.5, 55.7, 34.6, 34.3, 31.4,
31.3, 14.2; HR-MS (ESI): m/z=370.2363, calcd. for [M+1]+
C23H32NO3: 370.2377; IR (KBr): n=3482, 3176, 2386, 1625,
1400, 1176, 627, 539 cmÀ1.
Ethyl 4-(naphthalen-1-yl)-2-[(4-nitrophenyl)amino]buta-
noate (3j): Yellow oil; yield: 20.1 mg (55%); 1H NMR
(400 MHz, CDCl3): d=8.05 (d, J=8.2 Hz, 2H), 7.89 (dd, J=
18.2, 6.9 Hz, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.47 (s, 2H), 7.39
(t, J=7.0 Hz, 1H), 7.30 (d, J=6.2 Hz, 1H), 6.49 (d, J=
8.2 Hz, 2H), 5.08 (d, J=6.9 Hz, 1H), 4.25 (d, J=6.3 Hz,
3H), 3.32–3.09 (m, 2H), 2.32 (d, J=44.8 Hz, 2H), 1.30 (t,
J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.4,
151.7, 138.9, 136.2, 133.9, 131.5, 129.0, 127.3, 126.4, 126.3,
126.1, 125.7, 125.5, 123.2, 111.8, 61.9, 55.4, 33.0, 28.5, 14.2;
HR-MS (ESI): m/z=379.1655, calcd. for [M+1]+
C22H23N2O4: 379.1652; IR (KBr): n=3637, 3350, 2922, 1729,
1595, 1503, 1313, 1185, 1106, 835, 782 cmÀ1.
Ethyl 4-(4-methoxyphenyl)-2-[(4-methoxyphenyl)amino]-
butanoate (3o): Yellow oil; yield: 27.1 mg (79%); H NMR
1
(400 MHz, CDCl3): d=7.11 (d, J=8.2 Hz,2H), 6.83 (d, J=
8.2 Hz, 2H), 6.75 (d, J=8.6 Hz, 2H), 6.57 (d, J=
8.6 Hz,2H), 4.15 (q, J=7.1 Hz, 2H), 3.96 (d, J=5.6 Hz,
1H), 3.86 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 2.72 (t, J=
7.8 Hz, 2H), 2.10 (dd, J=13.6, 5.9 Hz, 1H), 1.99 (dd, J=
14.1, 7.2 Hz, 1H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d=174.3, 158.0, 152.8, 141.0, 133.0,
129.4, 115.2, 114.8, 113.9, 60.9, 57.2, 55.7, 55.2, 35.0, 30.9,
14.2; HR-MS (ESI): m/z=344.1854, calcd. for [M+1]+
C20H26NO4: 344.1856; IR (KBr): n=3459, 3104, 3001, 2393,
1624, 1399, 1171, 537 cmÀ1.
Ethyl 2-[(4-methoxyphenyl)amino]-4-(naphthalen-1-yl)bu-
tanoate (3k): Yellow oil; yield: 25.8 mg (71%); 1H NMR
(400 MHz, CDCl3): d=7.98 (d, J=7.0 Hz,1H), 7.88–7.82 (m,
1H), 7.72 (d, J=8.0 Hz, 1H), 7.50–7.45 (m, 2H), 7.38 (t, J=
7.5 Hz, 1H), 7.33 (d, J=6.7 Hz, 1H), 6.77 (d, J=7.9 Hz,
2H), 6.62 (d, J=8.2 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 4.09
Ethyl 4-(3,4-dimethoxyphenyl)-2-[(4-methoxyphenyl)ami-
no]butanoate (3p): Yellow oil; yield: 21.6 mg (58%);
1H NMR (400 MHz, CDCl3): d=6.82–6.70 (m, 5H), 6.57 (d,
J=7.4 Hz, 2H), 4.16 (q, J=6.6 Hz, 2H), 3.95 (s, 1H), 3.86
(s, 4H), 3.82 (s, 3H), 3.73 (s, 3H), 2.73 (t, J=7.3 Hz, 2H),
2.14–1.98 (m, 2H), 1.23 (t, J=7.6 Hz, 3H); 13C NMR
Adv. Synth. Catal. 0000, 000, 0 – 0
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(100 MHz, CDCl3): d=174.4, 152.8, 148.9, 147.4, 141.0,
133.5, 120.3, 115.2, 114.8, 111.9, 111.3, 61.0, 57.1, 55.9, 55.7,
55.7, 34.9, 31.4, 14.2; HR-MS (ESI): m/z=374.1970, calcd.
for [M+1]+ C21H27NO5: 374.1962; IR (KBr): n=3744, 2930,
2855, 1729, 1511, 1455, 1238, 1155, 1026, 816 cmÀ1.
Ethyl 4-(4-chlorophenyl)-2-[(4-methoxyphenyl)amino]bu-
tanoate (3q): Yellow oil; yield: 25.4 mg (65%); 1H NMR
(400 MHz, CDCl3): d=7.25 (d, J=6.8 Hz, 2H), 7.12 (d, J=
8.0 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.57 (d, J=8.5 Hz,
2H), 4.15 (q, J=7.1 Hz, 2H), 3.94 (s, 1H), 3.86 (s, 1H), 3.74
(s, 3H), 2.75 (t, J=7.7 Hz, 2H), 2.14–1.97 (m, 2H), 1.23 (t,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=174.1,
152.9, 140.8, 139.9, 131.5, 130.3, 119.9, 115.3, 114.9, 61.1,
57.1, 55.7, 34.5, 31.2, 14.2; HR-MS (ESI): m/z=392.0848,
calcd. for [M+1]+ C19H23BrNO3: 392.0856; IR (KBr): n=
3443, 2920, 2850, 2381, 1731, 1635, 1512, 1239, 1027, 816,
673 cmÀ1.
158.8, 152.8, 140.9, 129.4, 120.7, 115.2, 114.9, 114.5, 67.1,
61.0, 57.6, 55.7, 29.8, 25.6, 14.2; HR-MS (ESI): m/z=
344.1853, calcd. for [M+1]+ C20H26NO4: 344.1856; IR
(KBr): n=3465, 3175, 3005, 1634, 1400, 1178, 626, 537 cmÀ1.
Ethyl 4-cyclohexyl-2-[(4-methoxyphenyl)amino]butanoate
1
(3v): Yellow oil; yield: 23.0 mg (72%); H NMR (400 MHz,
CDCl3): d=6.76 (d, J=7.5 Hz, 2H), 6.59 (d, J=7.6 Hz, 2H),
4.16 (d, J=7.0 Hz, 2H), 3.92 (s, 1H), 3.83 (s, 1H), 3.73 (s,
3H), 1.68 (d, J=10.7 Hz, 7H), 1.25 (ddd, J=30.4, 19.7,
11.8 Hz, 9H), 0.88 (d, J=11.0 Hz, 2H); 13C NMR (101 MHz,
CDCl3): d=174.5, 152.6, 141.1, 115.1, 114.8, 60.8, 58.1, 55.7,
37.4, 33.2, 33.1, 30.6, 26.6, 26.2, 14.2; HR-MS (ESI): m/z=
320.2215, calcd. for [M+1]+ C19H30NO3: 320.2220; IR
(KBr): n=3447, 3109, 3002, 1630, 1400, 1174, 855, 539 cmÀ1.
Ethyl
2-[(4-methoxyphenyl)amino]-4-phenylpentanoate
1
(3w): Yellow oil; yield: 20.3 mg (62%); H NMR (400 MHz,
CDCl3): d=7.31 (d, J=6.4 Hz, 2H), 7.22 (t, J=8.5 Hz, 3H),
6.75–6.67 (m, 2H), 6.46 (t, J=7.0 Hz, 2H), 4.08 (td, J=14.3,
7.0 Hz, 2H), 3.86 (t, J=6.9 Hz, 1H), 3.71 (s, 3H), 3.01 (ddd,
J=40.5, 14.4, 6.8 Hz, 1H), 2.09–1.89 (m, 2H), 1.34–1.27 (m,
3H), 1.23–1.14 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
174.7, 174.5, 152.8, 152.7, 146.3, 145.7, 141.2, 140.8, 128.5,
128.5, 127.2, 127.1, 126.4, 115.5, 115.1, 114.8, 114.7, 60.9,
60.8, 56.7, 56.3, 55.7, 55.6, 41.7, 36.4, 36.4, 22.6, 22.2, 14.2,
14.2; HR-MS (ESI): m/z=328.1919, calcd. for [M+1]+
C20H26NO3: 328.1907; IR (KBr): n=2931, 1729, 1510, 1239,
1029, 821, 759, 699 cmÀ1.
Ethyl 4-(4-chlorophenyl)-2-[(4-chlorophenyl)amino]buta-
noate (3r): White solid; yield: 25.3 mg (72%); mp 107–
1
1088C; H NMR (400 MHz, CDCl3): d=7.25 (d, J=6.9 Hz,
2H), 7.10 (d, J=7.9 Hz, 4H), 6.50 (d, J=7.5 Hz, 2H), 4.17
(dd, J=13.1, 6.3 Hz, 3H), 3.97 (s, 1H), 2.72 (t, J=7.5 Hz,
2H), 2.07 (ddd, J=51.6, 13.6, 7.1 Hz, 2H), 1.24 (t, J=
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=173.5, 145.3,
139.1, 132.0, 129.8, 129.2, 128.6, 123.1, 114.7, 61.3, 55.9, 34.2,
31.0, 14.2; HR-MS (ESI): m/z=352.0874, calcd. for [M+1]+
C18H20Cl2NO2: 352.0866; IR (KBr): n=3373, 2926, 2859,
1731, 1599, 1496, 1309, 1182, 1092, 1017, 815 cmÀ1. CCDC
1411146 contains the supplementary crystallographic data
for compound 3r in this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Ethyl 2-[(4-methoxyphenyl)amino]-4-(thiophen-2-yl)buta-
noate (3s): Yellow oil; yield: 11.8 mg (37%); 1H NMR
(400 MHz, CDCl3): d=7.14 (d, J=4.6 Hz, 1H), 6.93 (s, 1H),
6.82 (s, 1H), 6.76 (d, J=7.5 Hz, 2H), 6.59 (d, J=7.7 Hz,
2H), 4.16 (q, J=6.8 Hz, 2H), 4.04–3.98 (m, 2H), 3.74 (s,
3H), 3.01 (t, J=7.5 Hz, 2H), 2.18 (dd, J=14.1, 7.1 Hz, 1H),
2.08 (dt, J=13.8, 7.0 Hz, 1H), 1.26–1.22 (m, 3H); 13C NMR
(100 MHz, CDCl3): d=174.1, 152.8, 143.6, 140.9, 126.8,
124.7, 123.4, 115.3, 114.8, 61.1, 57.2, 55.7, 35.0, 26.0, 14.2;
HR-MS (ESI): m/z=320.1317, calcd. for [M+1]+
C17H22NO3S: 320.1315; IR (KBr): n=3482, 3108, 1628, 1400,
1175, 541 cmÀ1.
Ethyl
2-cyclohexyl-2-[(4-methoxyphenyl)amino]acetate
1
(3x): Yellow oil; yield: 20.9 mg (72%); H NMR (400 MHz,
CDCl3): d=6.75 (d, J=8.3 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H),
4.15 (q, J=7.1 Hz, 2H), 3.85 (s, 1H), 3.75 (d, J=6.0 Hz,
1H), 3.73 (s, 3H), 1.86 (d, J=12.1 Hz, 1H), 1.77 (d, J=
11.5 Hz, 3H), 1.67 (d, J=11.6 Hz, 2H), 1.31–1.15 (m, 8H);
13C NMR (100 MHz, CDCl3): d=174.0, 152.6, 141.6, 115.22,
114.8, 63.4, 60.6, 55.7, 41.3, 29.6, 29.2, 26.2, 26.1, 26.0, 14.3;
HR-MS (ESI): m/z=292.1906, calcd. for [M+1]+
C17H25NO3: 292.1907; IR (KBr): n=3450, 2401, 2290, 1598,
1474, 1394, 723, 624 cmÀ1.
Ethyl 1-(4-methoxyphenyl)-4-methylpiperidine-2-carbox-
ylate (3y): Yellow oil; yield: 16.4 mg (59%); 1H NMR
(400 MHz, CDCl3): d=6.82 (dd, J=20.6, 8.6 Hz, 4H), 4.47
(s, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.75 (s, 3H), 3.40 (d, J=
11.3 Hz, 2H), 2.26–1.97 (m, 2H), 1.78 (d, J=12.7 Hz, 1H),
1.57 (s, 2H), 1.16 (t, J=7.0 Hz, 3H), 0.96 (d, J=5.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=173.2, 152.9, 145.0,
117.3, 114.3, 60.2, 59.4, 55.5, 44.9, 36.3, 33.9, 26.6, 21.9, 14.2;
HR-MS (ESI): m/z=278.1752, calcd. for [M+1]+
C16H24NO3: 278.1751; IR (KBr): n=2927, 2855, 1738, 1636,
1514,1473, 1243, 1179, 1033, 821, 723, 624 cmÀ1.
Ethyl 1-(4-methoxyphenyl)piperidine-2-carboxylate (3z):
Yellow oil; yield: 16.3 mg (62%); 1H NMR (400 MHz,
CDCl3): d=6.90 (d, J=8.3 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H),
4.24 (t, J=4.4 Hz, 1H), 4.07 (dd, J=13.4, 6.5 Hz, 2H), 3.75
(s, 3H), 3.38 (t, J=9.5 Hz, 1H), 3.19–3.12 (m, 1H), 2.07 (d,
J=4.2 Hz, 1H), 2.00–1.93 (m, 1H), 1.80 (s, 1H), 1.67 (s,
1H), 1.50 (d, J=11.9 Hz, 1H), 1.13 (t, J=7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=173.2, 153.6, 145.5, 118.8,
114.3, 60.6, 60.2, 55.5, 48.0, 28.7, 25.6, 21.0, 14.1; HR-MS
(ESI): m/z=264.1589, calcd. for [M+1]+ C15H22NO3:
264.1594; IR (KBr): n=2925, 2852, 2326, 1733, 1635, 1514,
1242, 1181, 1034, 821 cmÀ1.
Ethyl 2-[(4-methoxyphenyl)amino]octanoate (3t): Yellow
1
oil; yield: 21.1 mg (72%); H NMR (400 MHz, CDCl3): d=
6.76 (d, J=8.7 Hz, 2H), 6.59 (d, J=8.6 Hz, 2H), 4.16 (q, J=
7.1 Hz, 2H), 3.94 (t, J=6.4 Hz, 1H), 3.81 (d, J=4.0 Hz,
1H), 3.73 (s, 3H), 1.82–1.70 (m, 2H), 1.42 (s, 2H), 1.33–1.26
(m, 6H), 1.23 (t, J=7.1 Hz, 3H), 0.88 (t, J=6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=174.6, 152.6, 141.1, 115.1,
114.8, 60.8, 57.9, 55.7, 33.2, 31.6, 29.0, 25.6, 22.5, 14.2, 14.0;
HR-MS (ESI): m/z=294.2063, calcd. for [M+1]+
C17H28NO3: 294.2064; IR (KBr): n=3462, 2923, 2854, 2362,
2324, 1734, 1633, 1514, 1466, 1239, 1185, 1036, 820, 671 cmÀ1.
Ethyl 2-[(4-methoxyphenyl)amino]-5-phenoxypentanoate
1
(3u): Yellow oil; yield: 21.3 mg (62%); H NMR (400 MHz,
CDCl3): d=7.30–7.25 (m, 2H), 6.94 (t, J=7.3 Hz, 1H), 6.88
(d, J=8.1 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.60 (d, J=
8.6 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 4.00 (dd, J=11.3,
6.0 Hz, 2H), 3.90 (s, 1H), 3.73 (s, 3H), 2.03–1.89 (m, 4H),
1.26–1.21 (m, 3H); 13C NMR (100 MHz, CDCl3): d=174.2,
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Synthetic Applications
Synthesis of Compounds (S)-3a, (S)-3b, (S)-3c, (S)-3d,
(S)-3h
Synthesis of ethyl 2-amino-4-phenylbutanoate (3a-1): A
CH3CN (5.0 mL) solution of ethyl 2-[(4-methoxyphenyl)
amino)]-4-phenylbutanoate (3a, 62.6 mg, 0.2 mmol) was
cooled to 08C, an aqueous solution of ammonium cerium ni-
trate (CAN, 484 mg, 0.88 mmol, 3.0 mL of H2O) was added
directly, and the corresponding mixture was stirred at ambi-
ent temperature for 12 h, and then its pH was adjusted to 2–
3 using aqueous HCl solution (2N). After the aqueous
phase was washed with EtOAc (3ꢃ8 mL) and brought to
basic by the addition of saturated NaHCO3, the resulting
suspension was extracted with CH2Cl2 (3ꢃ12 mL) and dried
over anhydrous Na2SO4, and then the crude product was pu-
rified directly by silica gel column chromatography to afford
3a-1 as a colorless oil; yield: 25.7 mg (62%). 1H NMR
(400 MHz, CDCl3): d=7.30 (t, J=7.2 Hz, 2H), 7.22 (d, J=
7.7 Hz, 3H), 4.18 (q, J=7.0 Hz, 2H), 3.46 (t, J=6.4 Hz,
1H), 2.75 (dd, J=14.6, 6.2 Hz, 2H), 2.09 (dt, J=14.8,
6.3 Hz, 1H), 1.88 (dt, J=13.9, 7.1 Hz, 1H), 1.29 (t, J=
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=175.9, 141.3,
128.4, 128.4, 126.0, 60.8, 54.0, 36.5, 31.9, 14.2; HR-MS (ESI):
m/z=208.1333, calcd. for [M+1]+ C12H18NO2: 208.1332; IR
An oven-dried tube (A) containing a magnetic stirring bar
was refreshed with argon for 5 min, and then sealed with
a cap equipped with a Teflon-coated silicon rubber septum.
First, alkenes (0.15 mmol) and 9-BBN-H (0.30 mL, 0.5M in
THF, 0.15 mmol) were sequentially injected through a sy-
ringe, and the mixture was stirred at 608C for 1 h to prepare
the alkylborane. Meanwhile, the mixture of (4R,4’R)-
2,2’-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole)
(0.015 mmol, 10 mg), Li2CO3 (0.15 mmol, 11.4 mg) and
Cu(OTf)2 (0.01 mmol, 3.6 mg) was stirred in 0.5 mL of tolu-
ene at 508C for 1 h in another oven-dried tube (B). After
the reaction mixture from tube B was cooled down to room
temperature, the alkylborane in tube (A) was transferred to
tube (B). Subsequently, a-imino ester (0.10 mmol) in dry
toluene (1.0 mL) was added again. The reaction mixture was
stirred under argon conditions at 708C for another 24 h.
Upon completion as monitored by TLC, the reaction mix-
ture was filtrated and concentrated under vacuum to leave
a residue which was purified by flash column chromatogra-
phy on silica gel to furnish the target products.
(KBr): n=3667, 3482, 3001, 2393, 1631, 1480, 1400, 1172,
Ethyl
2-[(4-methoxyphenyl)amino]-4-phenylbutanoate
À1
[(S)-3a]: Yellow oil; yield: 16.6 mg (53%); [a]2D0: +20.78 (c=
0.022, acetone); ee=33%, determined by HPLC [Phenom-
enex Lux 5u cellulose-1 (250ꢃ4.6 mm), hexanes/i-PrOH
1134, 997, 624 cm
.
Synthesis of 2-amino-4-phenylbutanoic acid (3a-2):[27]
Ethyl 2-amino-4-phenylbutanoate (3a-1, 20.7 mg, 0.10 mmol)
was refluxed in hydrochloric acid (1.5 mL, 4.0M) for 2.5 h
under an argon atmosphere. Then the mixture was washed
with diethyl ether and concentrated under vacuum to give
3a-2 as a colorless solid; yield: 20.6 mg (96%). 1H NMR
(400 MHz, D2O): d=7.35 (t, J=7.2 Hz, 2H), 7.28 (d, J=
7.2 Hz, 3H), 4.04 (t, J=6.1 Hz, 1H), 2.84–2.68 (m, 2H),
2.32–2.12 (m, 2H); 13C NMR (100 MHz, D2O): d=171.9,
140.1, 128.8, 128.5, 126.7, 52.4, 31.5, 30.3; MS (ESI): m/z=
(2.5/1), 0.7 mLminÀ1 flow rate, 254 nm UV lamp]:
t
(major)=9.684 min, t (minor)=9.185 min.
Ethyl
2-[(2-methoxyphenyl)amino]-4-phenylbutanoate
[(S)-3b]: Yellow oil; yield: 13.8 mg (44%); [a]2D0: +35.28 (c=
0.027, acetone); ee=29%, determined by HPLC [Phenom-
enex Lux 5u cellulose-1 (250ꢃ4.6 mm), hexanes/i-PrOH
(2.5/1), 0.7 mLminÀ1 flow rate, 254 nm UV lamp]:
t
(major)=38.552 min, t (minor)=7.767 min.
202.1 [MÀHCl+Na+]; IR (KBr): n=3668, 2549, 1736, 1449,
Ethyl
4-phenyl-2-(p-tolylamino)butanoate
[(S)-3c]:
À1
Yellow oil; yield: 14.0 mg (47%); [a]2D0: +21.48 (c=0.028,
acetone); ee=29%, determined by HPLC [Phenomenex
Lux amylose-2 (250ꢃ4.6 mm), hexanes/i-PrOH (2.5/1),
0.7 mLminÀ1 flow rate, 254 nm UV lamp]: t (major)=
7.153 min, t (minor)=14.531 min.
1208, 986, 700 cm
.
Synthesis of 2-amino-4-phenylbutan-1-ol (3a-3): A metha-
nol (6 mL) solution of ethyl 2-amino-4-phenylbutanoate (3a-
1, 55.9 mg, 0.27 mmol) was cooled to 08C, and then NaBH4
(55 mg, 1.62 mmol) was added in one portion. The resulting
solution was stirred under ambient temperature for 24 h.
After the reaction was complete (monitored by TLC), the
organic solvents were evaporated under vacuum. Water
(5 mL) was added, and after phase separation the corre-
sponding aqueous phase was extracted with EtOAc (3ꢃ
3 mL). The combined organic extracts were washed with
brine, dried (Na2SO4), and then concentrated under high
vacuum. The crude product was purified directly by silica
gel column chromatography to give 3a-3 as a colorless oil;
Ethyl
4-phenyl-2-(m-tolylamino)butanoate
[(S)-3d]:
Yellow oil; yield: 14.5 mg (49%); [a]2D0: +18.98 (c=0.029,
acetone); ee=21%, determined by HPLC [Phenomenex
Lux 5u cellulose-1 (250ꢃ4.6 mm), hexanes/i-PrOH (2.5/1),
0.7 mLminÀ1 flow rate, 254 nm UV lamp]: t (major)=
9.439 min, t (minor)=7.997 min.
Ethyl 2-[(4-bromophenyl)amino]-4-phenylbutanoate [(S)-
3h]: Yellow oil; yield: 17.0 mg (46%); [a]2D0: +24.58 (c=
0.034, acetone); ee=25%, determined by HPLC [Phenom-
enex Lux 5u cellulose-1 (250ꢃ4.6 mm), hexanes/i-PrOH
1
yield: 37.0 mg (83%); H NMR (400 MHz, CDCl3): d=7.26
(2.5/1), 0.7 mLminÀ1 flow rate, 254 nm UV lamp]:
t
(t, J=7.2 Hz, 2H), 7.16 (d, J=7.0 Hz, 3H), 3.59 (d, J=
9.4 Hz, 1H), 3.32 (t, J=9.0 Hz, 1H), 2.85 (s, 1H), 2.73–2.60
(m, 2H), 2.53 (s, 2H), 1.79–1.68 (m, 1H), 1.60 (dd, J=14.2,
7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=141.7, 128.4,
128.3, 125.9, 66.5, 52.4, 35.8, 32.4; HR-MS (ESI): m/z=
166.1227, calcd. for [M+1]+ C10H16NO: 166.1226; IR (KBr):
n=3740, 3350, 3028, 2924, 2858, 1584, 1453 cmÀ1.
(major)=9.278 min, t (minor)=8.667 min.
Mechanistic Studies
Procedure for the addition of alkylboranes to a-imino ester
(1a) in the presence of TEMPO (Scheme 3a): An oven-
dried tube containing a magnetic stirring bar was refreshed
with argon for 5 min, and then sealed with a cap equipped
with a Teflon-coated silicon rubber septum. First, styrene
(0.15 mmol) and 9-BBN (0.30 mL, 0.5M in THF, 0.15 mmol)
were sequentially injected inside through a syringe, and the
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mixture was stirred at 608C for 1 h to prepare the alkylbor-
ane. After the reaction mixture was cooled down to room
temperature, Cs2CO3 (0.015 mmol, 5 mg) and CuCN
(0.01 mmol, 1.0 mg) were added, respectively, and the corre-
sponding mixture was stirred at 258C for 30 min. Subse-
quently, the a-imino ester (0.10 mmol) in dry toluene
(1.0 mL), TEMPO (1.0 equiv.) and H2O (0.10 mmol) were
added again. The reaction mixture was stirred at 708C for
another 24 h. Then, the reaction mixture was filtered and
concentrated under vacuum to leave a residue which was
purified by flash column chromatography on silica gel to fur-
nish the target product 3a; yield: 18.2 mg (58%).
Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the presence of H2O2 (Scheme 3b): An oven-
dried tube containing a magnetic stirring bar was refreshed
with argon for 5 min, and then sealed with a cap equipped
with a Teflon-coated silicon rubber septum. First, styrene
(0.15 mmol) and 9-BBN-H (0.30 mL, 0.5M in THF,
0.15 mmol) were sequentially injected through a syringe,
and the mixture was stirred at 608C for 1 h to prepare the
alkylborane. After the reaction mixture was cooled down to
room temperature, a-imino ester (0.10 mmol) in dry toluene
(1.0 mL), H2O2 (1.0 equiv.) and H2O (0.10 mmol) were
added again. The reaction mixture was stirred at 708C for
another 24 h. The target product 3a was not detected by
TLC and GC-MS analysis.
Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the absence of Cu(I) catalysts (Scheme 3c): An
oven-dried tube containing a magnetic stirring bar was re-
freshed with argon for 5 min, and then sealed with a cap
equipped with a Teflon-coated silicon rubber septum. First,
styrene (0.15 mmol) and 9-BBN (0.30 mL, 0.5M in THF,
0.15 mmol) were sequentially injected through a syringe,
and the mixture was stirred at 608C for 1 h to prepare alkyl-
borane. After the reaction mixture was cooled down to
room temperature, a-imino ester (0.10 mmol) in dry toluene
(1.0 mL) and H2O (0.10 mmol) were added again. The reac-
tion mixture was stirred at 708C for another 24 h. Then, the
reaction mixture was filtered and concentrated under
vacuum to leave a residue which was purified by flash
column chromatography on silica gel to furnish the target
product 3a; yield: 3.7 mg (12%).
Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the presence of NaCN (Scheme 3d): An oven-
dried tube containing a magnetic stirring bar was refreshed
with argon for 5 min, and then sealed with a cap equipped
with a Teflon-coated silicon rubber septum. First, styrene
(0.15 mmol) and 9-BBN-H (0.30 mL, 0.5M in THF,
0.15 mmol) were sequentially injected inside through a sy-
ringe, and the mixture was stirred at 608C for 1 h to prepare
the corresponding alkylborane starting material. After the
reaction mixture was cooled down to room temperature,
DABCO (0.1 mmol, 11.2 mg) and NaCN (0.01 mmol,
0.5 mg) were added, respectively, and the corresponding
mixture was stirred at 258C for 30 min. Subsequently, a-
imino ester (0.10 mmol) in dry toluene (1.0 mL) and H2O
(0.10 mmol) were added. The reaction mixture was stirred
at 708C for another 24 h. Then, the reaction mixture was fil-
tered and concentrated under vacuum to leave a residue
which was purified by flash column chromatography on
silica gel to furnish the target product 3a; yield: 2.5 mg
(8%).
Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the presence of FeCl3 (Scheme 3e): An oven-
dried tube containing a magnetic stirring bar was refreshed
with Ar for 5 min, and then sealed with a cap equipped with
a
Teflon-coated silicon rubber septum. First, styrene
(0.15 mmol) and 9-BBN-H (0.30 mL, 0.5M in THF,
0.15 mmol) were sequentially injected inside through a sy-
ringe, and the mixture was stirred at 608C for 1 h to prepare
alkylborane. After the reaction mixture was cooled down to
room temperature, Cs2CO3 (0.015 mmol, 5 mg) and FeCl3
(0.01 mmol, 1.6 mg) were added, respectively, and the corre-
sponding mixture was stirred at 258C for 30 min. Subse-
quently, a-imino ester (0.10 mmol) in dry toluene (1.0 mL)
and H2O (0.10 mmol) were added. The reaction mixture was
stirred at 708C for another 24 h. Then, the reaction mixture
was filtered and concentrated under vacuum to leave a resi-
due which was purified by flash column chromatography on
silica gel to furnish the target product 3a; yield: 2.8 mg
(9%).
Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the absence of Cu(I) catalysts at 1008C
(Scheme 3f): An oven-dried tube containing a magnetic stir-
ring bar was refreshed with Ar for 5 min, and then sealed
with a cap equipped with a Teflon-coated silicon rubber
septum. First, styrene (0.15 mmol) and 9-BBN (0.30 mL,
0.5M in THF, 0.15 mmol) were sequentially injected through
a syringe, and the mixture was stirred at 608C for 1 h to pre-
pare the the corresponding alkylborane starting material.
After the reaction mixture was cooled down to room tem-
perature, a-imino ester (0.10 mmol) in dry toluene (1.0 mL)
and H2O (0.10 mmol) were added. The reaction mixture was
stirred at 1008C for 24 h. Then, the reaction mixture was fil-
tered and concentrated under vacuum to leave a residue
which was purified by flash column chromatography on
silica gel to furnish the target product 3a; yield: 3.1 mg
(10%).
Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the presence of PhB(OH)2 (Scheme 3g): An
oven-dried tube containing Cs2CO3 (0.015 mmol, 5.0 mg)
was refreshed with argon for 5 min, and then sealed with
a cap equipped with a Teflon-coated silicon rubber septum.
Then, n-C4H9Cu (4a, 0.50 mL, 0.30 mmolmLÀ1 in THF) was
injected through a syringe. The corresponding mixture was
stirred at 258C for 30 min. Subsequently, imine (1a,
0.10 mmol) in dry toluene (1.0 mL), PhB(OH)2 (0.15 mmol)
and H2O (0.10 mmol) were added. The reaction mixture was
stirred at 708C for 24 h. Upon completion as monitored by
TLC, the crude material was concentrated under vacuum to
leave a residue which was purified by flash column chroma-
tography on silica gel to furnish the target product ethyl 2-
[(4-methoxyphenyl)amino]hexanoate (3za) as a yellow oil;
1
yield: 12.5 mg (47%). H NMR (400 MHz, CDCl3): d=6.76
(d, J=8.2 Hz, 2H), 6.59 (d, J=8.2 Hz, 2H), 4.16 (q, J=
7.0 Hz, 2H), 3.95 (t, J=6.4 Hz, 1H), 3.84 (s, 1H), 3.73 (s,
3H), 1.82–1.69 (m, 2H), 1.45–1.33 (m, 5H), 1.23 (t, J=
7.1 Hz, 3H), 0.91 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=174.6, 152.7, 141.2, 115.1, 114.9, 60.8, 57.9, 55.7,
32.9, 27.7, 22.4, 14.2, 13.9; HR-MS (ESI): m/z=266.1762,
calcd. for [M+1]+ C15H24NO3: 266.1751; IR (KBr): n=3376,
2945, 2853, 2065, 1734, 1617, 1516, 1457, 1374, 1242, 1033,
821, 749, 520 cmÀ1.
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Procedure for the addition of alkylboranes to iminoace-
tate (1a) in the absence of organoboranes (Scheme 3h): An
oven-dried tube containing Cs2CO3 (0.015 mmol, 5.0 mg)
was refreshed with argon for 5 min, and then sealed with
a cap equipped with a Teflon-coated silicon rubber septum.
Then, n-C4H9Cu (4a, 0.50 mL, 0.3 mmolmLÀ1 in THF) was
injected through a syringe. The corresponding mixture was
stirred at 258C for 30 min. Subsequently, imine (1a,
0.10 mmol) in dry toluene (1.0 mL), and H2O (0.10 mmol)
were added. The reaction mixture was stirred for 24 h at
708C. Upon completion as monitored by TLC, the crude
material was concentrated under vacuum to leave a residue
which was purified by flash column chromatography on
silica gel to furnish the target product 3za; yield: 2.3 mg
(9%).
4659; d) K. Osakama, M. Nakajima, Org. Lett. 2016,
18, 236; e) M. Hatano, S. Suzuki, K. Ishihara, J. Am.
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[3] M. A. Reichle, B. Breit, Angew. Chem. 2012, 124, 5828;
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[4] For selected examples, see: a) K. Kubota, J. C. Leight-
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Marti, G. Rihs, P. Rothe-Streit, F. Schwarzenbach, J.
Am. Chem. Soc. 1992, 114, 2321; c) C. H. Burgos, E.
Canales, K. Matos, J. Soderquist, J. Am. Chem. Soc.
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kashima, A. Ishiba, H. Yamamoto, J. Am. Chem. Soc.
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101, 757; h) B. C. Hong, J. H. Hong, Y. C. Tsai, Angew.
Chem. 1998, 110, 482; Angew. Chem. Int. Ed. 1998, 37,
468.
GC-MS analysis of the reductive coupling of a-imino
ester (1a) with phenylethylene (2a): a-Imino ester (1a) was
reacted with phenyl ethylene (2a) using our standard proce-
dure. Then the reaction mixture was analyzed by GC-MS
and TLC method. Finally, the by-product was purified by
flash column chromatography on silica gel to furnish the
target product cyclooctanone (3zc)[28] as a colorless oil;
1
yield: 16.6 mg (88%). H NMR (400 MHz, CDCl3): d=2.53–
[5] For selected reviews, see: a) K. Tanaka, Y. Tajima, Eur.
J. Org. Chem. 2012, 2012, 3715; b) P. Knochel, A.
Boudier, L. O. Bromm, E. Hupe, J. A. Varela, A. Ro-
driguez, C. Koradin, T. Bunlaksananusorn, H. Laaziri,
F. Lhermitte, Pure Appl. Chem. 2000, 72, 1699; c) B.
Wrackmeyer, Coord. Chem. Rev. 1995, 145, 125; d) A.
Suzuki, Acc. Chem. Res. 1982, 15, 178; e) G. M. L.
Cragg, K. R. Koch, Chem. Soc. Rev. 1977, 4, 393.
2.34 (m, 4H), 1.99–1.81 (m, 4H), 1.65–1.49 (m, 4H), 1.43–
1.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d=218.13,
41.87, 27.12, 25.60, 24.67; MS (ESI): m/z=126.03 [M+].
Acknowledgements
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The authors thank the NSFC (No.21372085) and Science and
Technology Program of Guangzhou (No.156300075) for fi-
nancial support.
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14 Copper-Catalyzed Addition of Alkylboranes to
Iminoacetates: Access to a-Alkyl Branched a-Amino Acids
Adv. Synth. Catal. 2016, 358, 1 – 14
Xinsheng Xiao, Wei Zhang, Xiaoxia Lu, Yuanfu Deng,
Huangfeng Jiang, Wei Zeng*
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!