Redox Property of Enamines

Article abstract of DOI:10.1021/acs.joc.9b02003

Enamines are electron-rich compounds bearing intriguing redox properties. Herein, a series of secondary enamines condensed from primary amine and β-ketocarbonyls were synthesized and their electrochemical oxidation properties were systematically studied by cyclic voltammetry. Furthermore, theoretical calculation of oxidation potentials of enamines, particularly those catalytic intermediates, was also conducted to further broaden the scope investigated. Possible structural factors on oxidation and the nature of the resulted radical cation intermediates were revealed and discussed. Correlation of redox potentials with molecular properties such as highest occupied molecular orbital energies and natural population analysis charge were explored, and there appears no simple linear correlation. On the other hand, a good correlation with Mayr's nucleophilicity parameter N was noted among a range of catalytically relevant enamines. Spin population analysis disclosed that enamine radical cations mainly exhibit the carbon-center free radical feature. Taking experimental and computation data together, a comprehensive picture about the redox property of enamines is presented, which would provide guidance in the development of oxidative enamine catalysis and transformations.

Full text of DOI:10.1021/acs.joc.9b02003

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Article
Redox Property of Enamines
Yao Li, Dehong Wang, Long Zhang, and Sanzhong Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02003 • Publication Date (Web): 23 Aug 2019
Downloaded from pubs.acs.org on August 24, 2019
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Redox Property of Enamines
Yao Li,†,§ Dehong Wang,‡,§ Long Zhang, †,‡ and Sanzhong Luo*,†,‡
†
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua
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University, Beijing 100084, China
‡
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
E-mail: luosz@tsinghua.edu.cn
Oxidation Potential Scale of Enamines
-
H OTf
N
N
N
N
N
N
NH
O
NH
O
NH
O
NH
O
NH
O
NH
O
OEt
OEt
OEt
CF3
OEt
Cl
Exp. Ep
(V vs. SCE)
0
.80
0.90
1.00
1.10
1.20
O
Ph
Ph
Ar
-OTf
O
N
N
H
N
Ph
Ph
OTMS
Ar
OTMS
Ar = 3,5-diCF3Ph
N
COOH
N
N
N
N
Bn
OH
N
Bn
N
NH
NH
Cal. Eox
V vs. SCE)
(
0.50
0.60
0.70
0.80
0.90
ABSTRACT: Enamines are electron-rich compounds bearing intriguing redox properties. Herein, a
series of secondary enamines condensed from primary amine and β-ketocarbonyls were synthesized
and their electrochemical oxidation properties were systematically studied by cyclic voltammetry.
Furthermore, theoretical calculation of oxidation potentials of enamines, particularly those catalytic
intermediates, was also conducted to further broaden the scope investigated. Possible structural factors
on oxidation as well as the nature of the resulted radical cation intermediates were revealed and
discussed. Correlation of redox potentials with molecular properties such as HUMO energies, NPA
charge were explored, and there appears no simple linear correlation. On the other hand, a good
correlation with Mayr’s nucleophilicity parameter N was noted among a range of catalytically relevant
enamines. Spin population analysis disclosed that enamine radical cations mainly exhibit
carbon-center free radical feature. Taking experimental and computation data together, a
comprehensive picture about the redox property of enamines is presented, which would provide
guidance in the development of oxidative enamine catalysis and transformations.
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INTRODUCTION
Enamines chemistry is a classical yet fundamental tool in carbonyl transformations. In the field of
organocatalysis, enamine has been extensively explored as a nucleophilic intermediate, known as
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HOMO-enhancing enamine activation (Scheme 1). On the other hand, the redox property of enamine,
2
especially their single-electron oxidation via chemical or electrochemical or photo process, is also
quite intriguing. Such processes lead to open shell enamine intermediates such as enamine radical
cation (Scheme 1), also known as SOMO activation, 2s,3 or -iminio radical from secondary
enamine,2c which lay the basis for a plethora of oxidative enamine transformations beyond the
classical HOMO-activation pathway.3a,4 Hence, redox properties of enamine are highly desirable in
the pursuit of oxidation enamine transformations. Unfortunately, unlike the well-investigated
5
nucleophilicity of enamines, information on the redox properties are only sparsely available and has
6
not been systematically investigated, particularly in the context of enamine catalysis (Scheme 2). Half
a century ago, Fritsch et al. investigated the electrolytic oxidations of N,N-dimethylaminoalkenes.6a,6b
Besides, factors affecting the lifetimes of the cation radicals were also discussed.6b In 1984, Masui et
al. explored the electrochemical properties of 2-cyano-2-phenylvinylamines and reported the anodic
dimerization of these enamines.6c A few years later, Schoeller et al. and Renaud et al.6d,6e studied the
redox properties of enamines derived from cyclic ketones and cyclic amines and irreversible oxidation
processes were found. In 1995, Cossy et al.6f investigated the redox properties of several types of
amidoenamines bearing unsaturated groups, i.e. allyl, propargyl, in an attempt to achieve
electrochemical cyclization. In the same year, Tabaković disclosed anodic oxidation of enaminones
and the dimerization of corresponding radical cations.6g
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Typical enamine catalysis: HOMO activation
O
N
E
+
E: electrophile
E
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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Oxidative enamine catalysis: SOMO activation
O
[O]
Nu: nucleophile
N
Nu
+
Nu
SET
R
H+
-
N
N
R = H
Enamine
radical cation

-iminio radical
Scheme 1. Aminocatalytic mode.
X
m
R4
H
O
N
N
X = CH2, m = 1-3
X = O, NH, m = 1
O
CN R2
N
N
N
N
N
N
R5
N
R3
R7
R6
n
n = 0-3
R1
Fritsch
Masui
1984
Schoeller, Renaud
Cossy
Tabakovic
1968, 1970
1988, 1990
1995
1995
Scheme 2. Previous systematical studies of enamines’ redox properties.
Herein, we wish to present our systematic studies on the redox property of enamines using both
experimental and computational approaches. Stabilized enamines such as secondary enamines derived
from β-ketocarbonyls were synthesized and analyzed by cyclic voltammetry (CV). The obtained
experimental data were then served as bench mark on which DFT calculations on those catalytically
interesting enamine intermediates could be formulated. Taken together, we aim to provide a coherent
picture of one-electron oxidation chemistry of enamines. We also discussed the possible structural
effect on redox properties as well as the structure of the resulted enamine radical cation intermediates.
EXPERIMENTAL METHODS
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1
. Synthesis and characterization of enamines
All secondary enamines were synthesized from corresponding primary amines (1-6) with
β-ketocarbonyls (A-D) using the protocol described in literature (Scheme 3).7
R1
NH
O
O
O
0
1
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0
Fe(OTf)3
neat
R2
R1 NH2
R2
R
+
R
R3
R3
Amines
NH2
NH2
N
NH2
N
NH2
HOTf
NH2
NH2
1
2
3
4
6
R -NH2 =
1
5

-ketocarbonyls
2
2
2
3
O
A1, n = 1, R = OEt
B , R = OEt
C , R = OEt, R = Cl
O
O
1
1
2
O
O
2
O
O
A , n = 2, R = OEt
B , R = Ph
2
3
D1, n = 2
D2, n = 1
2
2
C , R = OEt, R = Me
2
R2 A3, n = 3, R = OEt
2
R2 B , R = Me
2
R2 C ,
2
3
3
3 R = Et, R = Me
2
2
R3
n
n
A4, n = 1, R = NHPh
B4, R = CF
3
2
2
O
A , n = 1, R = NHBn
B , R = NHPh
A
5
B
5
C
D
2
B , R = NHBn
6
Secondary enamines
R1
R1
XA1, n = 1, R = OEt R1
2
XB , R = OEt R1
2
2
3
NH
XC
NH
1
1
, R = OEt, R = Cl
O
2
NH
O
2
NH
O
XA , n = 2, R = OEt
XB , R = Ph
2
3
XD1, n = 2
XD2, n = 1
2
2
XC , R = OEt, R = Me
2
R2 XA , n = 3, R = OEt
2
R2
2
R2
XC , R = Et, R = Me
3
2
3
3
XB , R = Me
3
2
2
R3
n
n
XA4, n = 1, R = NHPh
XB4, R = CF
3
2
2
O
XA , n = 1, R = NHBn
XB , R = NHPh
5
5
X = 1-6
R -NH2 = 1-6
1
2
XB , R = NHBn
6
Scheme 3. Secondary enamines investigated in electrochemical study.
2
. Cyclic voltammetric details
We evaluated the redox properties of the enamines by cyclic voltammetry. Our setup comprised
of an undivided cell, a glassy carbon working electrode (3mm diameter), a platinum wire counter
electrode, and a saturated Ag/AgCl reference electrode. Each cyclic voltammogram (CV) was
measured at a sweep rate of 100 mV/s. Measurements were carried out with 0.01 M enamines in dry
CH CN using Bu NPF (0.10 M) as the supporting electrolyte.
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4
6
CALCULATION METHODS
Theoretical approaches have been found to give a precise prediction of electrochemistry
8
properties in solution, we also explored similar methods to predict the oxidation potentials of
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enamines by using Gaussian09. After benchmarked several conventional functions, we found that
Truhlar’s M06-2X hybrid functional provided accurate predictions of oxidation potentials.11 Geometry
optimizations and frequency computations were performed at the M06-2X/6-311G(d,p) level of
theory, in conjunction with the IEF-PCM model to account for the solvation effects of acetonitrile.12
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13
The calculated oxidation potentials were scaled to saturated calomel electrode (SCE). Free energies
−1
include unscaled zero-point vibrational energies. Low frequencies (<100 cm ) were corrected in the
vibrational component of the entropy using a free rotor approximation according to the method of
Grimme et al., since entropy associated with these loose vibrational modes was the most prone to
computational error.14 The quasi-harmonic oscillator corrections were obtained using the
GoodVibes.15 The Natural Bond Orbital (NBO) analysis was conducted at the same level of geometry
optimization using NBO package build-in Gaussian 09.16
RESULTS AND DISCUSSION
1
. Cyclic voltammetric investigations of stabilized secondary enamines
Irreversible oxidation peaks were observed in the CVs of each enamine species, and typical
examples (1A -6A ) are shown in Figure 1. The voltammograms of all investigated enamines show
1
1
well defined anodic current maxima, but no corresponding cathodic wave on the reverse scan, even at
rate up to 50 V/s (the second oxidation peak of 1A may be attributed to the oxidation of tertiary
1
amine moiety). The irreversibility is likely ascribed to the highly unstable cation radical generated by
one-electron oxidation on anode. Due to the irreversibility electro-oxidation, the anodic peak
potentials were selected for comparison. The reported oxidation peak potentials are converted from
Ag/AgCl as reference electrode into saturated calomel electrode (SCE).17 A summary of the oxidation
peak potentials (E ) is presented in Table 1 and an E scale-map of these enamines is given in Figure
p
p
2
1
. The peak potentials of the enamines investigated vary greatly from the lowest 0.68 V to the highest
.87 V which highly depend on the structures of the enamines as indicated in Table 1.
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1A1
2A1
0
0
0
0
0
0
.25
.20
.15
.10
.05
.00
N
3A1
NH
O
NH
NH
4A1
O
O
5
6
A1
A1
OEt
OEt
OEt
1
A1
2A1
3A1
0
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0
HOTf
N
NH
NH
O
O
NH
O
OEt
OEt
OEt
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
4A1
5A1
6A1
Potential/V vs. Ag/AgCl
Figure 1. CVs of representative secondary enamines 1A -6A (0.01 M in acetonitrile-0.1 M Bu NPF ,
1
1
4
6
sweep rate ν 100 mV/s, 3 mm diameter glassy carbon electrode).
As can be seen in Table 1, both the primary amines and the carbonyls showed significant
influences on the oxidative potential of enamines. With cyclic β-ketone amide A , the corresponding
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E increased from 0.68 V to 0.98 V when varying the primary amine from 1 to 6 (Table 1, 1A -6A ).
p
5
5
The enamine derived from other carbonyls showed similar trends (Table 1). Generally, the enamine
based on aliphatic amines give smaller E values than those with aromatic amines. The primary
p
tertiary diamine derived enamines always give the lowest oxidative peak potentials (Table 1, 1A-1C),
due to the intramolecular electron-donating effect of the vicinal tertiary amines, which could
significantly stabilize the in-situ formed radical cations after one-electron oxidation. Instead, the
protonation of this tertiary amine moiety could completely destroy this stabilization effect and the
corresponding E raised to a much higher level (Table 1, 6A-6C).
p
Table 1. Oxidation peak potentials of secondary enamines in acetonitrile (E /V vs. SCE)
p
NH2
NH2
NH2
N
N
HOTf
1
NH2
NH2
3
NH2
2
R -NH =
4
1
6
5
2
R1
2
n = 1, R = OEt
1A
1
0.85 2A
1
0.97 3A
1
0.99 4A
1
1.00 5A
1
1.11 6A
1
1.20
NH
O
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n = 2, R = OEt
1A
1A
2
3
4
5
0.80 2A
0.79 2A
2
3
0.95 3A
2
0.90 4A
0.86 4A
0.81 4A
0.77 4A
2
3
4
5
1.02 5A
0.93 5A
0.86 5A
0.83 5A
2
3
4
5
1.06 6A
1.02 6A
0.89 6A
0.86 6A
2
3
4
5
1.15
1.10
1.08
0.98
1.41
1.46
1.43
1.87
2
n = 3, R = OEt
0.86 3A
0.80 3A
0.76 3A
3
2
n = 1, R = NHPh 1A
0.73 2A
0.68 2A
4
4
2
n = 1, R = NHBn 1A
5
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
R = OEt
1B
1B
1B
1B
1
2
3
4
0.95 2B
0.97 2B
0.95 2B
1.09 2B
2B
1
1.16 3B
1.28 3B
1.21 3B
1.64 3B
0.92 3B
0.92
1
2
3
4
5
1.17 4B
1.30 4B
1.24 4B
1.63 4B
1.00 4B
4B
1
2
3
4
5
6
1.19 5B
1.16 5B
1.27 5B
1.68 5B
0.97
1
2
3
4
1.34 6B
1.34 6B
1.40 6B
1.72 6B
1
2
3
4
2
R = Ph
2
R1
2
NH
O
R = Me
3
4
5
6
R2
2
R = CF
3
2
/a
/
R = NHPh
/
/
/
/
2
R = NHBn
2B
/
0.96
R1
2
3
1
2
3
1
2
3
1
1
2
3
1
1
2
3
1
1
1
2
3
R = OEt, R = Cl 1C
0.96 2C
0.79 2C
0.83 2C
2D
1.11 3C
0.86 3C
0.87 3C
1.20 3D
1.13 4C
0.87 4C
0.88 4C
1.22 4D
1.16 5C
0.93
1.22 6C
6C
1.37
1.10
1.10
NH
O
2
3
R = OEt, R =
Me
R2
1C
1C
/
/
R3
2
3
R = Et, R = Me
0.93
6C
R1
n = 2
/
/
1.31 5D
1
2
1.35
/
/
NH
n = 1
2D
2
1.33
/
4D
2
1.46 5D
1.42
n
O
a
“
/”indicates the corresponding enamines are not available.
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Oxidation peak potentials scale of secondary enamines in acetonitrile.
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The structure of the carbonyl moiety also contributed significantly to the oxidative potentials.
Generally, the enamines derived from α-alkyl substituted β-ketocarbonyls showed lower E values
p
than the unsubstituted ones (Table 1, 1C -6C vs. 1B -6B , Figure 3, A). The α-chloro substituted
2
2
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
enamines also exhibited minor yet noticeable more negative E in comparison with those unsubstituted
p
ones (Table 1, 2C -6C vs. 2B -6B ), which highlights the contribution of α-substituents on stabilizing
1
1
1
1
the corresponding enamine radical cations. The enamines with β-ketoesters give higher E values than
p
that with β-ketoamides (Table 1, 1A -6A vs. 1A -6A , 1A -6A ; 2B -2B vs. 2B and 4B -4B vs.
1
1
4
4
5
5
5
6
1
5
6
4
B ). Further increasing the electron-withdrawing nature of the carbonyls caused significant increase
1
in E s (Table 1, 1B -6B , 1B -6B and Figure 3, B).
p
2
2
4
4
A
1
2
3
4
5
6
B
1
2
3
4
5
6
1.5
2.0
1
1
1
1
1
0
.4
.3
.2
.1
.0
.9
1
1
1
.8
.6
.4
1.2
1.0
0.8
0
.8
B3
B1
C1
C2
C3
B5
B1
B3
B2
B4
β-ketocarbonyls
β-ketocarbonyls
R1
R1
R1
R1
NH
O
NH
O
NH
O
NH
O
1
R -NH2
OEt
Ph
= 1-6,
N
OEt
H
X = 1-6
XB1
XB3
XB5
XB1
R1
R1
R1
NH
O
NH
O
NH
O
R1
R1
R1
NH
O
NH
O
NH
O
OEt
OEt
Cl
Ph
CF3
XC1
XC2
XC3
XB3
XB2
XB4
Figure 3. The influence of substituents of β-ketocarbonyls on the oxidation peak potentials.
We also observed a ring size effect of the ketone esters on the E of enamines. As can be seen in
p
Figure 3, the oxidation peak potentials are mainly in the order XA < XA < XA (X = 1-6), which
3
2
1
means larger rings generally possess lower E values, with only one observed exception (Figure 4, 4A
p
2
vs. 4A1).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
3
4
5
6
1
1
.2
.1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.0
0
0
0
.9
.8
.7
A3
A2
A1
β-ketone ester
R1
R1
R1
O
NH
NH
O
NH
O
OEt
OEt
1
OEt
XA1
R -NH2 = 1-6
X = 1-6
XA3
XA2
Figure 4. The influence of ring size on the oxidation peak potentials.
2
. DFT Calculations studies
Besides the redox potentials of secondary enamines examined above, the E evaluation of other
p
types of enamines are also urgently needed, especially for those enamines derived from simple
aldehydes and ketones. However, it was very difficult to experimentally determine the reliable
oxidation potentials of these enamines as they are generally unstable and cannot be isolated in the
context of aminocatalysis. Since theory calculation have been found to give a precise prediction of
8
electrochemistry properties in solution, we carried out quantum chemical calculations to further
broaden the enamine scope investigated. We first calculated oxidation potentials of simple enamines
(
deriving from pyrrolidine, morpholine and cyclohexanone) and benchmarked with the experimental
data (Table S1).6d On this basis, the most accurate calculation method was reached and a very good
linear correlation was found between the experimental oxidation peak potentials (of the known
enamines our synthetic enamines deriving from β-ketocarbonyls) and calculated oxidation potentials
(
Figure 5 and Table S2).17 This correlation indicated that the method is applicable for both secondary
1
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enamines and tertiary enamines. With this method in hand, we started to investigate other types of
enamines.
2
1
1
1
.0
.8
.6
.4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5B4
5D2
y = 1.024x + 0.031
2
R = 0.971
3B 3D1
1
3C1
3B2
5
C2
A2
3B3
2C2
1.2
.0
0.8
4
5A1
1
A1
3
A3
1
1C2
6C2
3A1
3
C3
1
A5
3
A 3C
4
2
0
0
0
.6
.4
.2
O
N
N
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Experimental E (V vs. SCE)
p
Figure 5. Correlation of experimental E and calculated E .
p
ox
The enamines deriving from various amines (1-17) and aldehydes or ketones (E-J) were
evaluated (Figure 6). Besides those primary amines mentioned above, prevalent chiral aminocatalysts
(7-8, 11-17) as well as the model cyclic amines (9 and 10) were also selected for evaluation (Figure
6).
NH2
NH2
Amines
N
NH2
N
NH2
HOTf
NH2
NH2
1
2
3
4
5
6
Ph
Ph
Ph
N
COOH
N
N
H
N
H
Ph
N
N
H
NH2
NH2
H
OH
7
8
9
10
11
12
Ar
O
O
O
Ph
N
N
N
Ar
N
Ph
OTMS
N
H
OTMS
Ar = 3,5-diCF3Ph
t-Bu
Bn
H
N
Bn
N
t-Bu
N
H
H
H
13
14
15
16
17
O
O
O
Aldehydes
O
O
O
and ketones
H
H
H
Ph
Ph
Ph
E
F
G
H
I
J
Figure 6. Enamines precursors investigated in DFT calculations.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
.1 Enamine geometry
Unlike secondary enamines of β-ketocarbonyls, which are stabilized by intramolecular
H-bonding and have relatively rigid conformation, most enamines are conformationally flexible. To
obtain a more reliable prediction of oxidation potentials, we first explored the Z/E configurations of
enamines. It has been reported in the literatures that tertiary enamines from simple aldehydes (E and
F) favor E-configured double bonds,18a-e while for secondary enamines (e.g. those from E and G),
Z-configured double bond are generally favored.18f-i Our calculations for enamines deriving simple
aldehydes and ketones (E-G) are in good agreement with previous reports18 and the relative free
energies between Z-enamines and E-enamines are briefly illustrated in Figure 7 (for details, see Table
S3). It should be noted that Z-type enamines are more favored with chiral primary amine catalyst such
as primary-tertiary diamines 1, 6, 7 and 8. For 2-phenylacetaldehyde, both primary amine and
secondary amine significantly prefer E-enamine geometry, likely a result of phenyl conjugation effect.
For α-branched aldehyde and ketones (G and I), no obvious trend was observed but primary amine
catalysts tend to form E-enamine with I and J.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH
NH
NH
NH
NH
NH
Secondary
enamine
Ph
Ph
0.0

G (Kcal/mol) 0.2-0.6
0.0
0.4-2.4
0.5-2.6
0.0
Tertiary
enamine
N
N
N
N
N
N
Ph
Ph
0.0

G (Kcal/mol) 0.0
0.6-4.5
0.8-6.5
0.0
0.6-3.8
Figure 7. Calculated relative free energies of Z/E-enamines.
.2 Calculated oxidation potentials of enamine intermediates
We have evaluated oxidation potentials of both Z-configured and E-configured enamines
2
deriving from E, F, G, I and J. Compared with enamines in stable configurations, the oxidation
potentials of enamines in unstable configurations can be higher or lower. The oxidation potentials of
enamines in their relative stable configurations (Figure 7) were shown in Table 2 (for oxidation
potentials of enamines in less stable configurations, see Table S3).
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As shown in Table 2, the calculated oxidation potentials of the enamines vary greatly from the
lowest 0.22 V to the highest 0.90 V. The oxidation potentials of enamines deriving from simple
aldehydes or ketones are significantly lower than those derived from β-ketocarbonyls. The electronic
effect of the carbonyl group showed a significant effect on the oxidative potentials of these enamines.
For example, the oxidation potentials with butanone G are generally lower than those derived from its
aldehyde analogue propionaldehyde E (Table 2, 1G-17G vs. 1E-17E), and enamines derived from
α-branch aldehydes are easier to be oxidized than those with simple aldehydes (E-F) (Table 2, 1I-17I
vs. 1E-17E and 1F-17F).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The nature of amine also showed significant influence on the oxidative potentials. The enamines
based on aliphatic primary amines (2-3) were of lower oxidation potentials than those with aromatic
primary amines (4-5). And the enamines deriving from primary tertiary diamines 1 or 7 demonstrated
relative lower oxidation potentials comparing with those deriving from other primary amines. The
protonation of tertiary amine moiety caused significant increase in the oxidation potentials (ca.
2
00-300 mv). For enamines with conventional chiral secondary amines, MacMillan catalysts (15-17)
show higher oxidation potentials than proline-derived catalysts (11-14). Enamines derived from
prolinol 12 are usually easier to be oxidized than those derived from prolinol silyl ether 13. Enamines
derived from the electron-deficient prolinol silyl ether 14 showed much higher oxidation potentials,
which were even higher than proline 11, probably due to the negative hyperconjugation effect. 5c,19-20
This result indicated that remote electronic effects may also have an impact on redox properties of
enamines.
a
Table 2. Calculated oxidation potentials of enamines in acetonitrile (E /V vs. SCE).
ox
1
2
R , R =
(CH -,
R = H
1
2
1
2
1
2
1
2
1
2
Secondary
enamines
R = H, R = H,
R = H, R =
R = Me, R =
R = H, R =
R = Me, R =
-
2 4
)
3
3
3
3
3
R = Me
Ph, R = H
H, R = Me
Ph, R = Me
Ph, R = Me
3
N
1
E
0.52
1F 0.51
2F 0.64
1G 0.48
2G 0.52
1H 0.39
2H 0.47
1I 0.41b
1J 0.35c
NH
R3
R1
R2
NH
0.62b
2I 0.54b
2J 0.45b
2
E
R3
R1
R2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NH
R3
3E 0.60
3F 0.54
3G 0.44
3H 0.40
3I 0.47b
3J 0.36c
R1
R2
Bn
R1
Ph
NH
R3
4I 0.63b
5I 0.76b
4J 0.55c
5J 0.68c
4E 0.75
5E 0.84b
4F 0.73
5F 0.82
4G 0.65
5G 0.80
4H 0.70
5H 0.78
R2
NH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R3
R1
R2
HOTf
N
6E 0.87
7E 0.59
6F 0.76
7F 0.53
6G 0.79
7G 0.46
6H 0.74
7H 0.39
6I 0.73b
7I 0.44b
6J 0.71b
7J 0.36b
NH
R3
R1
R2
N
NH
R3
R1
R2
Ph
Ph
N
NH
8E 0.72
8F 0.60
8G 0.54
8H 0.47
8I 0.57b
8J 0.42b
R3
R1
R2
1
2
R , R =
(CH -,
R = H
1
2
1
2
1
2
1
2
1
2
Tertiary
enamines
R = H, R =
R = H, R =
R = Me, R =
R = H, R =
R = Me, R =
-
2 4
)
3
3
3
3
3
Me, R = H
Ph, R = H
Me, R = H
Ph, R = Me
Ph, R = Me
3
N
R3
9E 0.45
9F 0.51
9G 0.31
9H 0.32
9I 0.42c
9J 0.22c
R1
R2
N
10I 0.40c
10J 0.36c
1
0E 0.53
10F 0.53
10G 0.49
10H 0.49
R3
R1
R2
COOH
N
N
R3
11E
0.64
11F 0.64
12F 0.55
11G 0.55
12G 0.42
11H 0.52
12H 0.43
11I 0.61c
12I 0.48b
11J 0.49c
12J 0.47b
R1
R2
Ph
Ph
R3
OH
12E 0.52
R1
R2
Ph
Ph
N
N
R3
OTMS
13E 0.56
14E 0.77
13F 0.60
14F 0.77
13G 0.36
14G 0.61
13H 0.45
14H 0.62
13I 0.55c
14I 0.68b
13J 0.38b
14J 0.57b
R1
R2
Ar
Ar
R3
OTMS
R1
N
R2
O
N
15E 0.84
16E 0.89
15F 0.82
16F 0.84
15G 0.80
16G 0.89
15H 0.81
16H 0.90
15I 0.78
b
15J 0.82
b
R3
R1
R2
O
N
Bn
16I 0.82c
16J 0.87c
N
R3
R1
R2
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O
N
Bn
R3
17I 0.75c
17J 0.87b
N
17E 0.85
17F 0.79
17G 0.75
17H 0.75
R1
R2
Unless otherwise noted, the reported oxidation potentials correspond to enamines’ configurations drawn in column. b
a
c
E-configured enamine. Z-configured enamine.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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6
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 8. Calculated oxidation potentials scale of enamines in acetonitrile.
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To obtain a better comparison, we constructed a calculated oxidation potentials scale for those
catalytic enamines in Figure 8.
2
.3 Correlation of calculated oxidation potentials with molecular properties
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Previous work showed that there were certain connections between Hammett substituent
constants, ionization potentials, electron affinities, HOMO and LUMO energies and the redox
potentials.21 Therefore, the relationship between the molecular properties and oxidation potentials
were then explored. Initially, the relationships between HOMO energies and oxidation potentials of
enamines deriving from propionaldehyde (E) and various amines (1-17) were investigated.
2
Unfortunately, poor correlation was found (Figure 9, A, labeled in red square, R = 0.22). Changing
2
enamines to 1I-17I gave a moderate correlation (Figure 9, A, labeled as black triangle, R = 0.49).
Enamines derived from the same amine (1) and different carbonyl compounds (E-J) were also
examined and no overall correlation with their HOMO energies could be found. When limited to only
2
ketones (G, H and J), a clear trend was noted (Figure 9, B, labeled in red triangle, R = 0.97).
We next tried to reduce variations in structures and simple enamines deriving from pyrrolidine
2
and cyclic ketones were investigated. A good linear correlation (R = 0.87) was found between the
HOMO energies of enamines and oxidation potentials (Figure 10, A). Further expanding the scope of
2
to include acyclic ketones (9P and 9G, as red dots) also gave good correlation (R = 0.89). It seems
that enamines with small rings display higher oxidation potentials than those with larger ring (Figure
1
0), which is consistent with our experimental data of cyclic ketoesters.
Since the oxidation of enamines mainly involve the loss of electron from nitrogen atom, we
suspected that the oxidation potentials may have certain connections with the electronic density of
nitrogen atom of enamines. To verify the hypothesis, the Natural Population Analysis (NPA) charges
of enamines were evaluated.16 A good linear correlation was found between the calculated oxidation
potentials and NPA charge of nitrogen atom for enamines (9H and 9K-9O) (Figure 10, B). The result
2
was slightly better than using HOMO energies for this series of enamines (R = 0.93). But expanding
2
the scopes to include acyclic ketones (9P and 9G, as red stars) resulted in a worse correlation (R =
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0
.87).
A
B
-5.2
-
5.20
y = -0.69x - 5.07
R2 = 0.49
1I
y = -1.59x - 4.55
R2 = 0.52
-5.3
-5.4
-5.5
-5.6
-5.25
-5.30
-5.35
-5.40
1F
0
1
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3
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8
9
0
1
2
3
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9
0
1
2
3
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
J
-
-
-
5.45
5.50
5.55
1E
-5.7
y = -0.52x - 5.31
R2 = 0.22
1H
y = -1.65x - 4.81
R2 = 0.97
-
5.8
5.9
1
G
-
-5.60
0
.34 0.36 0.38 0.40 0.42 0.44 0.46 0.48 0.50 0.52 0.54
0.4
0.5
0.6
0.7
0.8
0.9
Eox (V vs. SCE)
Eox (V vs. SCE)
Figure 9. A) Correlation between HOMO energies and calculated oxidation potentials of enamines
E-17E and 1I-17I. B) Correlation between HOMO energies and calculated oxidation potentials of
enamines (1E-1J)
1
N
N
N
N
N
N
N
N
9K
9L
9M
9H
9N
9O
9P
9G
Eox(V vs. SCE)
NPA(N)
0.75
-0.499
0.49
-0.510
0.37
-0.516
0.32
-0.517
0.32
0.513
0.30
-0.520
0.62
0.31
-
0.501
0.512
B
A
-0.495
-5.35
-5.40
-5.45
-5.50
-5.55
9M
9N
-0.500
y = -0.37x - 5.27
R2 = 0.87
9P
9
K
9
9
G
O
9H
-0.505
9L
y = 0.043x - 0.53
R2 = 0.93
-0.510
9
G
9
L
9
N
-0.515
9
P
9M
9H
9K
-0.520
9
O
0.3
0.4
0.5
0.6
0.7
0.8
0
.3
0.4
0.5
0.6
0.7
0.8
Eox (V vs. SCE)
Eox (V vs. SCE)
Figure 10. Correlation between calculated oxidation potentials and HOMO energies/NPA charges of
nitrogen atom for pyrrolidine derived enamines.
1
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2
.4 Spin density and spin density distributions of enamine radical cation
To further gain insight into the nature of radical cations of enamine, an active single
electron-oxidation intermediate, spin population analysis was conducted. Two spin population
methods, Mulliken spin population and Becke spin population, were used and the results are similar.25
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The analysis of enamine radical cation 1C and 9E showed that the single electron is mainly located at
2
the α-C-center and N-center free radical is less populated (Figure 11), which is in consistence with the
previous calculated results of radical cation of enamine reported by Houk and MacMillan.26 The spin
analysis of enamines derived from other amines and carbonyls also gave the same results. Although
the term ‘enamine radical cation’ has been widely used, our calculation indicated that it is mainly a
carbon radical plus an iminium cation, which is also consistent with the previous electron spin
resonance (ESR) studies reported by Fritsch et al. In this study, it was shown that unpaired electrons
tend to polarize away from the dimethylamino groups in monocationic radicals.6b
-
0.032
-0.036
0.412
-0.099
N
0
.666
N
0.280
Me
0
.080
-0.055
NH
O
-0.059
Mulliken spin
distribution
O
0.763
-0.119
N
0.345
-0.049
0.515
Mulliken spin
distribution
Me
Becke spin
distribution
1C2
9E
Figure 11. Spin density plot and spin density distributions of enamine radical cation 1C and 9E.
2
Recently, we have reported the oxidative enamine catalysis via -imino radical by the primary
-
tertiary diamine catalyst.2c This strategy was further utilized to achieve oxidative enamine
functionalization.2e-f Due to the strong acidity of radical cations in 1C2,27 the intramolecular proton
transfer from enamine nitrogen to tertiary amine nitrogen is significantly favored (Figure 12) leading
to the formation of α-imino radical. In this equilibration, spin population is slightly shifted toward
α-carbon in α-imino radical. Similar equilibration toward α-imino radical has also been observed with
aldehyde enamine radical cation 1I in both its E- and Z- isomer. Thus, for single-electron oxidation of
secondary enamines, especially for those deriving from primary-tertiary diamines, α-iminio radical
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1
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1
1
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2
2
2
2
2
2
2
2
3
3
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may be the actual reactive intermediate.2c,2e-f
N
N
H
0.234
0
NH
.280

G = -4.7 kcal/mol
N
O
0
1
2
3
4
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8
9
0
1
2
3
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9
0
1
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9
0
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9
0
1
2
3
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6
7
8
9
0
O
O
O
0.834
0.763
enamine radical cation
C2
-iminio radical
1
Mulliken spin distribution
N
N
H
N
N
0.235
H
0
.287
NH
N 0.354
N 0.356
NH
Ph
0.586
Ph
0.561
0.660
0.658
Ph
Ph

G = -3.5 kcal/mol
G = -2.8 kcal/mol
E-1I
Z-
1I
Figure 12. Free energy differences and spin density distributions of enamine radical cation 1C/1I and
their related α-iminio radicals.
2
.5 Application in organocatalysis
Our experimental and calculated oxidation potentials for enamines could be used to explain the
previous results in enamines oxidation transformations. For example, Macmillan’s catalysts derived
enamines have relative higher oxidation potentials (E (15E) = 0.84 V, E (16E) = 0.89 V vs. SCE in
ox
ox
MeCN). That’s why strong oxidant, such as ceric ammonium nitrate (CAN) (E [Ce(IV)/(III)] = 0.68
p
V vs. Fc /Fc in MeCN ) and [Fe(phen) ] • (PF ) (E [Fe(III)/(II)] = 1.10 V vs. SCE in MeCN28b),
+
28a
3
6 3
1/2
3
29
were used in SOMO catalysis. For direct β-alkylation of aldehydes reported by Macmillan,
photocatalyst Ir(ppy) (E [Ir (III)/(II)] = 0.31 V vs. SCE in MeCN30a) gave very low yield (7%),
*
3
1/2
*
30b
while Ru(bpy) Cl (E [Ru (III)/(II)] = 0.77 V vs. SCE in MeCN ) and Ir(ppy) (dtbbpy)PF (E
1/2
3
2
1/2
2
6
Ir (III)/(II)] = 0.66 V vs. SCE in MeCN30c) gave moderate yield (50% and 52%, respectively) under
*
[
the similar condition. These results can be rationalized by the calculated oxidation potentials of
enamine 9E (E (9E) = 0.45 V vs. SCE in MeCN), which indicted that oxidation of enamine similar to
ox
9
E by excited-state Ir(ppy) should be unfavored and oxidation of enamine by excited-state
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Ru(bpy) Cl and excited-state Ir(ppy) (dtbbpy)PF should be favored. Besides application in
3
2
2
6
explaining previous results, we hope that enamines oxidation potentials will be helpful for mechanism
consideration in enamines oxidation transformations.
Mayr and coworkers recently developed a nucleophilicity (N) scale for a series of enamine
intermediates. 22 Previously, it has also been shown that oxidation potential could serve as a measure
of the reactivity of nucleophiles. 23 In this study, we evaluated the correlation of calculated oxidation
potentials with experimental nucleophilicity of enamines. It was found that the calculated oxidation
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
potentials of enamines are in good consistence (Figure 13 A, R = 0.87) with Mayr’s nucleophilicity
5
parameters N in acetonitrile. The oxidation potentials also exhibited a good correlation with log k
2
2
(
Figure 13 B, R = 0.86), which are calculated by the Mayr-Patz equation (log k (20 ºC)= s (N + E))
2
N
+
24
for the reactions of enamines with (Me N-C H ) CH (E = -7.02). The above correlations, which
2
6
4 2
cover more than eleven orders of magnitude, indicated that the oxidation potentials of enamines would
also provide a guide for their nucleophilic reactivities.
A
B
20
18
16
14
12
10
8
6
4
y = -16.29x + 21.22
R2 = 0.87
10
8
y = -15.63x + 10.55
R2 = 0.86
11H'
11H'
9H
CO2Me
9H
N
CO2Me
N
CO2
N
CO2
N
11H''
11H''
6
10H
9F
11H''
11H'
11H''
4
11H'
10F
9F
10H
10F
2
13F
13F
0
17F
-
2
4
17F
1
6F
-
16F
0.0
0.2
0.4
Eox (V vs. SCE)
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
Eox (V vs. SCE)
Figure 13. Correlation of calculated oxidation potentials with nucleophilicity parameters N and
logarithm of rate constants (log k2).
CONCLUSIONS
In summary, a broad series of secondary enamines, including those prepared from primary
amines and β-ketoesters, β-ketoamides or 1,3-diketones, were synthesized and their redox properties
were systematically investigated by cyclic voltammetry. All of the synthetic enamines showed
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2
2
2
2
2
2
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6
irreversible oxidation process. The electronic nature as well as the ring size of enamines showed
significant effects on E values. Accurate DFT calculations were then performed to predict the
p
oxidation potentials of a series of unstable and catalytically relevant enamines. The calculations
provided effective supplement to the experimental oxidation potentials. Spin population analysis
indicated that the resulted enamine radical cations mainly display C-center free radical property. Our
calculations indicated that α-iminio radical may be the actual reactive intermediate in single-electron
oxidation of primary-tertiary diamines derived secondary enamines. These electrochemical studies and
theoretical calculations would provide guidance in exploring oxidative enamine transformations and
aminocatalysis.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
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0
1
2
3
4
5
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9
0
EXPERIMENTAL SECTION
General information. H NMR and 13C NMR spectra were measured on Bruker spectrometers
1
1
(
at 400 and 500 MHz for H NMR, 101 and 126 MHz for 13C NMR). Tetramethylsilane (TMS) served
as the internal standard for H NMR, and CDCl /DMSO-d served as the internal standard for 13C
1
3
6
NMR. The following abbreviations were used to express the multiplicities: s = singlet; d = doublet; t =
triplet; q = quartet; m = multiplet; br = broad. IR spectra were recorded on a Thermo Fischer Nicolet
–
1
6
700 FT-IR spectrometer and are reported in terms of frequency absorption (cm ). HRMS was
obtained using electrospray ionization (ESI) mass spectrometer, and the mass analyzer of the HRMS
was orbitrap. Cyclic voltammograms were collected with a Shanghai Chenhua CH1600D potentiostat.
Unless otherwise noted, materials were obtained from commercial suppliers and used without further
purification. Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates.
Materials. Chiral primary amine 131 and β-ketocarbonyls A3,32a A , A , C332c were prepared
32b
32b
4
5
according to the literature.
General procedure for synthesis of secondary enamines. All secondary enamines were
7
synthesized according to procedure reported in the literature. Fe(OTf) (0.1 mmol, 50.2 mg) was
3
added to a mixture of primary amines (10 mmol) and β-ketocarbonyls compounds (11 mmol) in a 25
mL round-bottom flask and the mixtures were allowed to stir at ambient temperature. The completion
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of the reaction was monitored by TLC. The pure enamines were obtained by passing them directly
through alkaline alumina column chromatography using hexanes/ethyl acetate. Some Enamines
X-5X (X = A-D) are known compounds that have been reported in literature.33-38
2
Ethyl
(S)-2-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)cyclopent-1-ene-1-carboxylate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1A1). This compound was prepared according to the general procedure using
1
1
(
S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
1.72
g)
and
ethyl
2
-oxocyclopentane-1-carboxylate (11 mmol, 1.72 g). Purification by alkaline alumina column
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 62% yield (1.92 g).
1
H NMR (400 MHz, CDCl ) δ 7.60 (s, 1H), 4.23 – 4.06 (m, 2H), 3.06 – 2.85 (m, 1H), 2.77 – 2.58 (m,
3
2
7
5
H), 2.56 – 2.32 (m, 7H), 2.27 (dd, J = 13.7, 9.7 Hz, 1H), 1.79 (dd, J = 14.3, 6.9 Hz, 2H), 1.27 (t, J =
.1 Hz, 3H), 1.00 – 0.88 (m, 15H). 13C{ H} NMR (126 MHz, CDCl ) δ 168.7, 166.4, 91.0, 63.8, 58.2,
1
3
+
5.7, 48.0, 34.6, 32.7, 29.1, 26.7, 21.2, 14.8, 12.3. HRMS (ESI-Orbitrap) m/z: [M + H] calcd for
+
-1
C H N O 311.2693, found 311.2694. IR (KBr, cm ): 2965, 2868, 1654, 1602, 1465, 1264, 1096.
1
8
35
2
2
Ethyl
(S)-2-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)cyclohex-1-ene-1-carboxylate
(
1A2).33a This compound was prepared according to the general procedure using
1
1
(
S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
1.72
g)
and
ethyl
2
-oxocyclohexane-1-carboxylate (11 mmol, 1.87 g). Purification by alkaline alumina column
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 69% yield (2.23 g).
1
H NMR (400 MHz, CDCl ) δ 9.22 (d, J = 10.7 Hz, 1H), 4.18 – 4.00 (m, 2H), 3.31 – 3.03 (m, 1H),
3
2
3
.62 (dd, J = 13.6, 2.2 Hz, 1H), 2.59 – 2.44 (m, 3H), 2.39 (dq, J = 14.0, 7.0 Hz, 2H), 2.32 – 2.24 (m,
H), 2.24 – 2.11 (m, 1H), 1.67 – 1.48 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 1.02 – 0.89 (m, 15H). 13C{ H}
1
NMR (101 MHz, CDCl ) δ 171.0, 160.9, 87.6, 60.2, 58.3, 56.4, 48.0, 34.7, 26.9, 26.8, 24.1, 23.1, 22.6,
3
+
+
1
4.7, 12.4. HRMS (ESI-Orbitrap) m/z: [M + H] calcd for C H N O 325.2850, found 325.2849. IR
19 37 2 2
-1
(
KBr, cm ): 2967, 2933, 2868, 1644, 1600, 1455, 1234, 1095, 1065.
Ethyl (S)-2-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)cyclohept-1-ene-1-carboxylate
1A3). This compound was prepared according to the general procedure using
(
1
1
(
S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
1.72
g)
and
ethyl
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2
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5
5
6
2
-oxocycloheptane-1-carboxylate (11 mmol, 2.02 g). Purification by alkaline alumina column
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 72% yield (2.44 g).
1
H NMR (400 MHz, CDCl ) δ 9.59 (d, J = 10.1 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.21 (td, J = 10.2, 2.1
3
Hz, 1H), 2.64 (dd, J = 13.7, 2.1 Hz, 1H), 2.57 – 2.36 (m, 8H), 2.29 (dd, J = 13.7, 9.4 Hz, 1H), 1.79 –
0
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0
1
.60 (m, 4H), 1.61 – 1.49 (m, 1H), 1.49 – 1.40 (m, 3H), 1.25 (t, J = 7.1 Hz, 3H), 0.99 – 0.90 (m, 15H).
13
1
C{ H} NMR (101 MHz, CDCl ) δ 170.7, 168.6, 92.5, 61.8, 58.4, 56.0, 48.0, 34.6, 31.7, 28.8, 28.8,
3
+
+
2
6.9, 26.0, 25.5, 14.8, 12.1. HRMS (ESI-Orbitrap) m/z: [M + H] calcd for C H N O 339.3006,
20 39 2 2
-1
found 339.3005. IR (KBr, cm ): 2968, 2923, 2848, 1635, 1600, 1467, 1254, 1204, 1140, 1097, 1050.
S)-2-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)-N-phenylcyclopent-1-ene-1-carboxamid
(1A4). This compound was prepared according to the general procedure using
(
e
1
1
(S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
1.72
g)
and
2
-oxo-N-phenylcyclopentane-1-carboxamide (11 mmol, 2.24 g). Purification by alkaline alumina
column chromatography (30% EtOAc/hexanes) provided the compound as colorless oil in 65% yield
1
(2.33 g). H NMR (500 MHz, CDCl ) δ 8.32 (d, J = 11.0 Hz, 1H), 7.54 – 7.40 (m, 2H), 7.37 – 7.19
3
(m, 2H), 7.07 – 6.84 (m, 1H), 6.56 (s, 1H), 3.01 – 2.84 (m, 1H), 2.76 (dt, J = 15.8, 7.7 Hz, 1H), 2.67 –
2
.56 (m, 3H), 2.48 (dddt, J = 19.9, 14.1, 12.9, 7.1 Hz, 5H), 2.31 (dd, J = 13.7, 9.6 Hz, 1H), 1.96 – 1.85
m, 2H), 1.01 – 0.89 (m, 15H). 13C{ H} NMR (126 MHz, CDCl ) δ 167.0, 165.2, 139.3, 128.8, 122.6,
1
(
3
1
19.7, 92.1, 64.1, 55.9, 48.0, 34.6, 32.6, 29.5, 26.8, 20.9, 12.3. HRMS (ESI-Orbitrap) m/z: [M + H]+
+
-1
calcd for C H N O 358.2853, found 358.2855. IR (KBr, cm ): 3336, 2964, 2868, 1636, 1594,
2
2
36
3
1
517, 1310, 1236.
S)-N-benzyl-2-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)cyclopent-1-ene-1-carboxamide
1A5). This compound was prepared according to the general procedure using
(
(
1
1
(S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
1.72
g)
and
N-benzyl-2-oxocyclopentane-1-carboxamide (11 mmol, 2.39 g). Purification by alkaline alumina
column chromatography (30% EtOAc/hexanes) provided the compound as colorless oil in 62% yield
1
(2.32 g). Colorless oil, 2.32 g, 62% yield. H NMR (500 MHz, CDCl ) δ 8.19 (d, J = 11.1 Hz, 1H),
3
7
.34 – 7.28 (m, 4H), 7.25 – 7.21 (m, 1H), 5.05 (t, J = 5.4 Hz, 1H), 4.51 (ddd, J = 84.6, 14.9, 5.8 Hz,
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8
9
2
H), 2.99 – 2.85 (m, 1H), 2.72 (dt, J = 15.8, 7.8 Hz, 1H), 2.63 (dd, J = 13.7, 2.2 Hz, 1H), 2.56 – 2.39
m, 7H), 2.30 (dd, J = 13.7, 9.6 Hz, 1H), 1.91 – 1.80 (m, 2H), 1.01 – 0.91 (m, 15H). 13C{ H} NMR
1
(
(126 MHz, CDCl ) δ 168.9, 163.6, 139.9, 128.5, 127.6, 127.0, 91.8, 63.7, 56.0, 48.0, 42.8, 34.7, 32.4,
3
+
+
2
3
9.3, 26.8, 20.9, 12.3. HRMS (ESI-Orbitrap) m/z: [M + H] calcd for C H N O 372.3009, found
23 38 3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
72.3007. IR (KBr, cm ): 3342, 2964, 2868, 1628, 1589, 1517, 1270, 698.
Ethyl (S,Z)-3-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)but-2-enoate
compound was prepared according to the general procedure
(1B1).
This
using
1
1
(S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine (10 mmol, 1.72 g) and ethyl 3-oxobutanoate (11
mmol, 1.43 g). Purification by alkaline alumina column chromatography (10% EtOAc/hexanes)
1
provided the compound as colorless oil in 69% yield (1.96 g). H NMR (500 MHz, CDCl ) δ 8.79 (d,
3
J = 8.9 Hz, 1H), 4.37 (s, 1H), 4.14 – 4.01 (m, 2H), 3.19 – 3.03 (m, 1H), 2.61 (dd, J = 13.7, 2.1 Hz,
1
1
1
H), 2.52 (tt, J = 14.4, 7.2 Hz, 2H), 2.40 (dq, J = 14.0, 7.0 Hz, 2H), 2.30 (dd, J = 13.7, 9.8 Hz, 1H),
.94 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.00 – 0.93 (m, 15H). 13C{ H} NMR (126 MHz, CDCl ) δ 170.8,
1
3
63.1, 80.9, 61.8, 58.0, 55.8, 48.1, 34.5, 26.7, 20.1, 14.7, 12.3. HRMS (ESI-Orbitrap) m/z: [M + H]+
+
-1
calcd for C H N O 285.2537, found 285.2539. IR (KBr, cm ): 2967, 2871, 1647, 1609, 1263,
1
6
33
2
2
1
173, 1107, 784.
S,Z)-3-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)-1-phenylbut-2-en-1-one (1B2). This
compound was prepared according to the general procedure using
(
1
1
(S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine (10 mmol, 1.72 g) and 1-phenylbutane-1,3-dione
(11 mmol, 1.78 g). Purification by alkaline alumina column chromatography (10% EtOAc/hexanes)
1
provided the compound as colorless oil in 67% yield (2.12 g). H NMR (500 MHz, CDCl ) δ 11.87 (d,
3
J = 10.3 Hz, 1H), 8.03 – 7.76 (m, 2H), 7.48 – 7.32 (m, 3H), 5.64 (s, 1H), 3.29 (td, J = 10.5, 2.0 Hz,
1
2
1
H), 2.70 (dd, J = 13.8, 2.0 Hz, 1H), 2.55 (tt, J = 14.3, 7.2 Hz, 2H), 2.43 (qd, J = 7.0, 5.1 Hz, 3H),
.14 (s, 3H), 1.04 (s, 9H), 0.98 (t, J = 7.1 Hz, 6H). 13C{ H} NMR (126 MHz, CDCl ) δ 186.8, 166.0,
1
3
40.8, 130.1, 128.1, 126.9, 91.6, 62.9, 55.9, 48.2, 34.3, 26.8, 20.1, 12.3. HRMS (ESI-Orbitrap) m/z:
+
+
-1
[M + H] calcd for C H N O 316.2515, found 316.2517. IR (KBr, cm ): 2966, 1599, 1556, 1326,
20 32 2
1
297, 1086, 1064, 731.
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8
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
(
S,Z)-4-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)pent-3-en-2-one (1B ). This compound
3
was
prepared
according
to
the
general
procedure
using
1
1
(
S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine (10 mmol, 1.72 g) and pentane-2,4-dione (11
mmol, 1.10 g). Purification by alkaline alumina column chromatography (10% EtOAc/hexanes)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
provided the compound as colorless oil in 61% yield (1.55 g). H NMR (500 MHz, CDCl ) δ 11.28 (d,
3
J = 9.7 Hz, 1H), 4.90 (s, 1H), 3.17 (td, J = 10.5, 2.0 Hz, 1H), 2.61 (dd, J = 13.8, 2.1 Hz, 1H), 2.51 (tt,
J = 14.4, 7.2 Hz, 2H), 2.45 – 2.28 (m, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 0.99 – 0.91 (m, 15H). 13C{1H}
NMR (126 MHz, CDCl ) δ 193.8, 164.4, 94.5, 62.4, 55.8, 48.1, 34.2, 28.6, 26.6, 19.5, 12.3. HRMS
3
+
+
-1
(
ESI-Orbitrap) m/z: [M + H] calcd for C H N O 255.2431, found 255.2435. IR (KBr, cm ): 2966,
15 31 2
2
873, 1608, 1582, 1310, 1191, 733.
S,Z)-4-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)-1,1,1-trifluoropent-3-en-2-one (1B4).
(
This
compound
was
prepared
according
to
the
general
procedure
1.72 g)
using
and
1
1
(
S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
1
,1,1-trifluoropentane-2,4-dione (11 mmol, 1.69 g). Purification by alkaline alumina column
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 70% yield (2.16 g).
1
H NMR (500 MHz, CDCl ) δ 11.56 (s, 1H), 5.29 (s, 1H), 3.31 (td, J = 10.4, 2.0 Hz, 1H), 2.67 (dd, J
3
=
13.9, 2.0 Hz, 1H), 2.60 – 2.49 (m, 2H), 2.39 (ddd, J = 13.6, 9.7, 6.7 Hz, 3H), 2.14 (s, 3H), 1.01 (s,
1
9
H), 0.95 (t, J = 7.1 Hz, 6H). 13C{ H} NMR (126 MHz, CDCl ) δ 174.6 (q, J = 32.6 Hz), 170.4, 118.0
3
(
q, J = 288.0 Hz), 89.1, 63.8, 55.5, 48.2, 33.9, 26.5, 19.9, 12.2. HRMS (ESI-Orbitrap) m/z: [M + H]+
+
-1
calcd for C H F N O 309.2148, found 309.2145. IR (KBr, cm ): 2969, 2873, 1596, 1262, 1181,
1
5
28
3
2
1
137, 1086, 1100.
Ethyl (S,E)-2-chloro-3-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)but-2-enoate (1C1).
This
compound
was
prepared
according
to
the
general
1.72
procedure
g) and
using
ethyl
1
1
(
S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
2
-chloro-3-oxobutanoate (11 mmol, 1.81 g). Purification by alkaline alumina column chromatography
1
(
10% EtOAc/hexanes) provided the compound as colorless oil in 58% yield (1.85 g). H NMR (500
MHz, CDCl ) δ 9.39 (d, J = 10.2 Hz, 1H), 4.29 – 4.11 (m, 2H), 3.20 (td, J = 10.3, 2.1 Hz, 1H), 2.68 –
3
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8
9
2
2
1
+
.58 (m, 1H), 2.55 – 2.46 (m, 2H), 2.38 (dq, J = 14.0, 7.0 Hz, 2H), 2.29 (dd, J = 13.7, 9.9 Hz, 1H),
.21 (s, 3H), 1.31 (td, J = 7.1, 3.9 Hz, 3H), 0.99 – 0.91 (m, 15H). 13C{ H} NMR (126 MHz, CDCl ) δ
1
3
67.7, 161.5, 90.8, 63.0, 59.9, 55.8, 48.0, 34.4, 26.7, 17.3, 14.6, 12.2. HRMS (ESI-Orbitrap) m/z: [M
+
+
-1
H] calcd for C H ClN O 319.2147, found 319.2149. IR (KBr, cm ): 2968, 2871, 1636, 1597,
1
6
32
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
448, 1258, 1074, 770.
Ethyl (S,Z)-3-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)-2-methylbut-2-enoate (1C2).33b
This
compound
was
prepared
according
to
the
general
1.72
procedure
g) and
using
ethyl
1
1
(S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine
(10
mmol,
2
-methyl-3-oxobutanoate (11 mmol, 1.59 g). Purification by alkaline alumina column chromatography
1
(10% EtOAc/hexanes) provided the compound as colorless oil in 66% yield (1.97 g). H NMR (500
MHz, CDCl ) δ 9.53 (d, J = 10.4 Hz, 1H), 4.16 – 4.01 (m, 2H), 3.19 (td, J = 10.6, 2.2 Hz, 1H), 2.62
3
(dd, J = 13.6, 2.2 Hz, 1H), 2.50 (tt, J = 14.3, 7.2 Hz, 2H), 2.45 – 2.35 (m, 2H), 2.29 (dd, J = 13.6, 9.6
Hz, 1H), 1.98 (s, 3H), 1.80 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.98 – 0.92 (m, 15H). 13C{ H} NMR (126
1
MHz, CDCl ) δ 171.2, 161.1, 84.8, 61.7, 58.4, 56.1, 48.0, 34.7, 26.8, 16.0, 14.7, 12.9, 12.2. HRMS
3
+
+
-1
(ESI-Orbitrap) m/z: [M + H] calcd for C H N O 299.2693, found 299.2691. IR (KBr, cm ): 2968,
17 35 2 2
2
871, 1640, 1602, 1465, 1256, 1099, 782.
S,Z)-5-((1-(diethylamino)-3,3-dimethylbutan-2-yl)amino)-4-methylhex-4-en-3-one (1C ). This
(
3
compound
was
prepared
according
to
the
general
procedure
using
1
1
(S)-N ,N -diethyl-3,3-dimethylbutane-1,2-diamine (10 mmol, 1.72 g) and 3-methylhexane-2,4-dione
(11 mmol, 1.41 g). Purification by alkaline alumina column chromatography (10% EtOAc/hexanes)
1
provided the compound as colorless oil in 63% yield (1.78 g). H NMR (500 MHz, CDCl ) δ 12.47 (d,
3
J = 9.8 Hz, 1H), 3.27 (td, J = 10.1, 2.2 Hz, 1H), 2.63 (dd, J = 13.7, 2.2 Hz, 1H), 2.53 – 2.43 (m, 2H),
2
9
.43 – 2.34 (m, 2H), 2.33 – 2.25 (m, 1H), 2.00 (s, 3H), 1.85 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H), 0.96 (s,
H), 0.92 (t, J = 7.1 Hz, 6H) (enamine). 3.20 (td, J = 9.9, 2.2 Hz, 1H), 2.12 (s, 3H), 1.85 (s, 3H), 0.97
s, 9H) (imine). 13C{ H} NMR (126 MHz, CDCl ) δ 196.6, 163.4, 96.4, 62.4, 56.2, 48.0, 34.4, 32.9,
1
(
3
1
3
1
2
5
6.8, 15.8, 14.4, 12.2, 9.7 (enamine). C{ H} NMR (126 MHz, CDCl ) δ 193.6, 168.6, 95.9, 62.5,
3
+
6.6, 48.1, 34.2, 28.3, 21.6, 14.3, 12.1, 11.7 (imine). HRMS (ESI-Orbitrap) m/z: [M + H] calcd for
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
-1
C H N O 283.2744, found 283.2742. IR (KBr, cm ): 2967, 2871, 1596, 1466, 1233, 1083, 830.
1
7
35
2
Ethyl 2-(cyclohexylamino)cyclopent-1-ene-1-carboxylate (2A1).34a,b This compound was prepared
according to the general procedure using cyclohexanamine (10 mmol, 0.99 g) and ethyl
-oxocyclopentane-1-carboxylate (11 mmol, 1.72 g). Purification by alkaline alumina column
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 72% yield (1.71 g).
1
H NMR (400 MHz, CDCl ) δ 7.46 (s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.17 (qd, J = 9.5, 4.7 Hz, 1H),
3
2
.56 (t, J = 7.6 Hz, 2H), 2.53 – 2.47 (m, 2H), 1.91 – 1.79 (m, 4H), 1.79 – 1.69 (m, 2H), 1.63 – 1.51
1
(
m, 1H), 1.38 – 1.16 (m, 8H). 13C{ H} NMR (101 MHz, CDCl ) δ 168.5, 163.9, 92.0, 58.3, 53.3, 34.6,
3
3
1.9, 28.9, 25.4, 24.8, 21.1, 14.8.
Ethyl 2-(cyclohexylamino)cyclohex-1-ene-1-carboxylate (2A2).34c This compound was prepared
according to the general procedure using cyclohexanamine (10 mmol, 0.99 g) and ethyl
-oxocyclohexane-1-carboxylate (11 mmol, 1.87 g). Purification by alkaline alumina column
2
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 70% yield (1.76 g).
1
H NMR (400 MHz, CDCl ) δ 9.04 (d, J = 8.5 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.44 – 3.18 (m, 1H),
3
2
.34 (t, J = 6.3 Hz, 2H), 2.27 (t, J = 6.2 Hz, 2H), 1.85 (d, J = 10.6 Hz, 2H), 1.80 – 1.70 (m, 2H), 1.65
1
(
(
dt, J = 12.2, 6.3 Hz, 2H), 1.56 (ddd, J = 11.3, 7.8, 4.0 Hz, 3H), 1.37 – 1.17 (m, 8H). 13C{ H} NMR
101 MHz, CDCl ) δ 170.9, 158.7, 88.9, 58.6, 50.3, 34.6, 26.9, 26.3, 25.6, 24.9, 23.9, 22.8, 22.4, 14.7.
3
Ethyl 2-(cyclohexylamino)cyclohept-1-ene-1-carboxylate (2A ). This compound was prepared
3
according to the general procedure using cyclohexanamine (10 mmol, 0.99 g) and ethyl
-oxocycloheptane-1-carboxylate (11 mmol, 2.03 g). Purification by alkaline alumina column
2
chromatography (10% EtOAc/hexanes) provided the compound as colorless oil in 68% yield (1.80 g).
1
H NMR (400 MHz, CDCl ) δ 9.37 (d, J = 6.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.34 (dd, J = 7.9, 3.9
3
Hz, 1H), 2.48 (dd, J = 10.7, 5.0 Hz, 4H), 1.86 (dd, J = 8.8, 4.4 Hz, 2H), 1.72 (ddd, J = 14.8, 11.8, 7.5
1
3
1
Hz, 4H), 1.58 (dt, J = 10.2, 5.0 Hz, 3H), 1.51 – 1.39 (m, 2H), 1.37 – 1.14 (m, 8H). C{ H} NMR (101
MHz, CDCl ) δ 170.7, 166.8, 93.4, 58.5, 51.5, 34.8, 31.9, 28.8, 28.5, 25.8, 25.5, 24.7, 14.8. HRMS
3
+
+
-1
(
ESI-Orbitrap) m/z: [M + H] calcd for C H NO 266.2115, found 266.2113. IR (KBr, cm ): 2978,
16 28 2
2
926, 2851, 1639, 1593, 1451, 1251, 1203, 1097, 1048, 786.
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2
-(cyclohexylamino)-N-phenylcyclopent-1-ene-1-carboxamide (2A4). This compound was
prepared according to the general procedure using cyclohexanamine (10 mmol, 0.99 g) and
-oxo-N-phenylcyclopentane-1-carboxamide (11 mmol, 2.24 g). Purification by alkaline alumina
2
column chromatography (30% EtOAc/hexanes) provided the compound as white solid in 55% yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(
1.56 g). Mp 126-127 ˚C. H NMR (500 MHz, CDCl ) δ 8.18 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.1 Hz,
3
2
7
1
1
H), 7.36 – 7.20 (m, 2H), 7.01 (td, J = 7.4, 1.1 Hz, 1H), 6.59 (s, 1H), 3.24 – 3.02 (m, 1H), 2.62 (t, J =
.5 Hz, 2H), 2.57 (t, J = 7.0 Hz, 2H), 1.92 (ddd, J = 24.1, 11.9, 4.9 Hz, 4H), 1.76 (d, J = 9.3 Hz, 2H),
.58 (d, J = 9.9 Hz, 1H), 1.35 – 1.11 (m, 5H). 13C{ H} NMR (126 MHz, CDCl ) δ 167.0, 163.0,
1
3
39.0, 128.8, 122.9, 119.0, 92.9, 53.5, 34.8, 31.8, 29.3, 25.4, 25.0, 20.9. HRMS (ESI-Orbitrap) m/z:
+
+
-1
[
M + H] calcd for C H N O 285.1961, found 285.1957. IR (KBr, cm ): 2928, 2851, 1637, 1593,
18 25 2
1
516, 1429, 1309, 1235, 1074, 749.
N-benzyl-2-(cyclohexylamino)cyclopent-1-ene-1-carboxamide (2A5). This compound was
prepared according to the general procedure using cyclohexanamine (10 mmol, 0.99 g) and
N-benzyl-2-oxocyclopentane-1-carboxamide (11 mmol, 2.39 g). Purification by alkaline alumina
column chromatography (30% EtOAc/hexanes) provided the compound as yellowish solid in 61%
1
yield (1.82 g). Mp 105-108 ˚C. H NMR (500 MHz, CDCl ) δ 8.03 (d, J = 9.0 Hz, 1H), 7.36 – 7.28
3
(
m, 4H), 7.28 – 7.21 (m, 1H), 5.12 (s, 1H), 4.50 (d, J = 5.8 Hz, 2H), 3.13 (qd, J = 9.5, 4.7 Hz, 1H),
2
2
1
.58 (t, J = 7.6 Hz, 2H), 2.47 – 2.35 (m, 2H), 1.87 (dt, J = 14.5, 7.4 Hz, 4H), 1.75 (dd, J = 8.7, 4.1 Hz,
H), 1.61 – 1.49 (m, 1H), 1.37 – 1.11 (m, 5H). 13C{ H} NMR (126 MHz, CDCl ) δ 168.7, 161.2,
1
3
39.7, 128.6, 127.7, 127.1, 92.7, 53.2, 42.8, 34.8, 31.7, 29.1, 25.5, 24.9, 20.9. HRMS (ESI-Orbitrap)
+
+
-1
m/z: [M + H] calcd for C H N O 299.2118, found 299.2112. IR (KBr, cm ): 2928, 2851, 1629,
1
9
27
2
1
588, 1513, 1451, 1282, 1243, 698.
Ethyl (Z)-3-(cyclohexylamino)but-2-enoate (2B1).34d This compound was prepared according to
the general procedure using cyclohexanamine (10 mmol, 0.99 g) and ethyl 3-oxobutanoate (11 mmol,
1
.43 g). Purification by alkaline alumina column chromatography (10% EtOAc/hexanes) provided the
1
compound as yellowish oil in 82% yield (1.73 g). H NMR (400 MHz, CDCl ) δ 8.61 (d, J = 6.7 Hz,
3
1
H), 4.36 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.38 – 3.17 (m, 1H), 1.91 (s, 3H), 1.84 (dd, J = 9.8, 3.5 Hz,
29
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