A catalyst-free, one-pot three-component aminomethylation of α-substituted nitroacetates: Theoretical and experimental studies into the rate-accelerating effects of the solvent methanol

Full text of DOI:10.1002/asia.201300053

COMMUNICATION
DOI: 10.1002/asia.201300053
A Catalyst-Free, One-Pot Three-Component Aminomethylation of a-
Substituted Nitroacetates: Theoretical and Experimental Studies into the
Rate-Accelerating Effects of the Solvent Methanol
Cong-Bin Ji,[a] Zhong-Yan Cao,[a] Xin Wang,*[b] De-Yin Wu,[c] and Jian Zhou*[a]
During the past decades, several organic solvents have
been found to serve as powerful catalyst-free reaction media
for some transformations.[1] For example, N,N-dimethylfor-
mamide (DMF) enabled a highly efficient allylation of ben-
zoylhydrazones by using allyltrichlorosilane[1a] and cyanosily-
lation of aldehydes and ketones.[1b] Alcoholic solvents could
promote hetero-Diels–Alder reactions of unactivated keto-
nes[1c] or imines.[1d] Ethylene glycol allowed a catalyst-free
Strecker reaction of a-CF2H or a-CF3 ketimines with
TMSCN (TMS=trimethylsilyl).[1e] Noticeably, some cata-
lyst-free reactions enabled by a certain organic solvent can
be more efficient than the corresponding process catalyzed
by an acid or base catalyst.[1e] However, detailed mechanistic
studies into the origin of the efficiency of catalyst-free reac-
tions in a given medium (or solvent) are very limited.
We have found that alcoholic solvents such as MeOH and
ethylene glycol are powerful catalyst-free reaction media for
the cyanation of ketimines,[1e–f] and the major role of the al-
cohol was believed to be the activation of ketimines through
H-bonding interactions. Herein, we wish to report a one-
pot,[2] catalyst-free, three-component aminomethylation re-
action of a-substituted nitroacetates, formalin, and amines
in MeOH; this method allows the efficient and diverse syn-
thesis of a,b-diamino acid derivatives. Most importantly,
NMR spectroscopic analysis, together with theoretical stud-
ies, casted some light on the role of MeOH as a solvent to
accelerate the reaction.
Owing to the ubiquitous nature of a,b-diamino acids as
key structural fragments in bioactive compounds,[3] the in-
corporation of conformationally constrained Ca-tetrasubsti-
tuted a,b-diamino acids becomes a fruitful method in the
design of peptides with enhanced properties.[4] In addition,
cyclic ureas, imidazolines, and b-lactam antibiotics derived
from a-alkyl-a,b-diamino acids showed versatile bioactivi-
ties.[5] While several methods for the synthesis of a-alkyl-
a,b-diaminopropionic acids are available,[6] methods for a-
aryl-a,b-diamino acids are scarce. In light of this, it is highly
desirable to develop facile methods for the synthesis of both
a-alkyl- and a-aryl-substituted a,b-diamino acid derivatives.
During our efforts in the synthesis of compounds that
have a tetrasubstituted carbon center for biological evalua-
tion,[7] we were interested in the functionalization of a-sub-
stituted nitroacetates,[8] owing to the rich chemistry associat-
ed with nitro groups. In this context, we have developed the
first catalytic asymmetric hydroxymethylation and amination
of a-substituted nitroacetates.[9] We noticed that no amino-
methylation reaction[10] of a-substituted nitroacetates had
been reported that would be a straightforward method for
the synthesis of a,b-diamino acid precursors, even though
the Mannich reaction of a-alkyl nitroacetates and N-protect-
ed aldimines has been intensively studied.[8a–h] Therefore, the
reaction of nitroacetate 1a, with 2.0 equivalents of formalin
(2), and 2.0 equivalents of p-anisidine (3a) was carried out
in CH2Cl2 at 408C. Base catalysts were first tested, and it
was found that the desired aminomethylation product 4a
could be obtained in moderate yield, accompanied with the
hydroxymethylation product 5 (Table 1, entries 1–3). The
[a] C.-B. Ji, Z.-Y. Cao, Prof. Dr. J. Zhou
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes
Department of Chemistry
East China Normal University
3663N, Zhongshan Road, Shanghai 200062 (China)
E-mail: jzhou@chem.ecnu.edu.cn
1
ratio of 4a to 5 was determined by H NMR spectroscopy of
the crude mixture.
[b] Prof. Dr. X. Wang
College of Chemistry
Sichuan University
We had previously found that bases such as 1,4-
diazabicycloACTHNUGTRNEUNG[2.2.2]octane (DABCO) were efficient catalysts
for the hydroxymethylation reaction,[9a] therefore we next
tried the catalyst-free version to suppress this side reaction,
and found that only the desired Mannich reaction took
place without any base, thereby affording the desired prod-
uct 4a in 91% yield after 5 h (Table 1, entry 4). We further
checked the influence of the ratio of nitroacetate 1a/formal-
in 2/p-anisidine 3a (Table 1, entries 4–6), and found that
when only 1.2 equivalents of formalin 2 and 1.0 equivalent
of p-anisidine 3a were used, the reaction still worked well to
Chengdu, 610064 (China)
E-mail: wangxin@scu.edu.cn
[c] Prof. Dr. D.-Y. Wu
State Key Laboratory of Physical Chemistry of Solid Surfaces and
Department of Chemistry
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen, 361005 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300053.
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Jian Zhou, Xin Wang et al.
Table 1. Reaction development.[a]
Table 2. The scope of the a-substituted nitroacetate 1.[a]
Entry
R1
R2
4
t [h]
Yield [%][b]
Entry
1a/2/3a
Solvent Catalyst
t [h]
4a/5
Yield [%][c]
1
2
3
4
5
6
7
Me (1a)
Me (1b)
Me (1c)
Et (1d)
nBu (1e)
iBu (1 f)
iPr
Et
4a
4b
4c
4d
4e
4 f
4g
0.5
0.7
1.0
2.5
2.5
2.5
2.5
94
93
73
82
77
57
81
1
2
3
4
5
6
7
8
1.0:2.0:2.0 CH2Cl2
1.0:2.0:2.0 CH2Cl2
1.0:2.0:2.0 CH2Cl2
1.0:2.0:2.0 CH2Cl2
1.0:2.0:1.0 CH2Cl2
1.0:1.2:1.0 CH2Cl2
1.0:1.2:1.0 CHCl3
1.0:1.2:1.0 toluene
1.0:1.2:1.0 EtOAc
1.0:1.2:1.0 THF
K3PO4
DABCO
DBU
0.5
0.5
0.5
5.0
4.5
11.0
5.5
7.0
4.0
4.0
7.0
3.0
0.5
4.0
4.0
5.5:1
7.1:1
16.7:1 61
38
65
tBu
iPr
iPr
iPr
iPr
[b]
–
–
–
–
–
–
–
–
–
–
–
–
–
91
74
85
72
65
76
89
57
86
94
91
70
[b]
8.3:1
[b]
CH3ACHTNUTRGNE(UNG CH2)6 (1g)
–
–
–
–
–
–
–
–
–
–
[b]
8
iPr
Et
Et
4h
4i
9.0
8.0
2.0
66
73
80
[b]
[b]
9
9
Bn (1i)
[b]
10
11
12
13
14
15
[b]
10
4j
1.0:1.2:1.0 Et2O
1.0:1.2:1.0 MeCN
1.0:1.2:1.0 MeOH
1.0:1.2:1.0 EtOH
[b]
[b]
11
12
Et
Et
4k
4l
2.0
1.0
76
87
[b]
[b]
1.0:1.2:1.0
H2O
[a] Reaction was run on a 0.25 mmol scale; [b] No catalyst; [c] Yield of
isolated product 4a. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
AHCTUNGTRENNUNG
13
14
iPr
4m
4n
9.0
1.0
86
84
G
Et
afford product 4a in 85% yield (Table 1, entry 6). The eval-
uation of the solvent effects demonstrated that MeOH
could significantly accelerate this catalyst-free reaction
(Table 1, entries 7–15), and the reaction reached completion
within 30 min to afford 4a in 94% yield, and no hydroxyme-
thylation reaction was detected. The reaction in water could
also afford product 4a in 70% yield (Table 1, entry 15), but
the poor solubility of 1a in water prevented its full conver-
sion and required an extraction procedure for purification.
Accordingly, the optimal reaction conditions were in
MeOH at 408C, with the ratio of nitroacetate 1a/formalin 2/
p-anisidine 3a being 1.0:1.2:1.0. The substrate scope of the
a-substituted nitroacetates was then examined (Table 2).
The ester group of the nitroacetates 1 had little effect on
the reactivity. Isopropyl, ethyl, and tert-butyl esters 1a–c all
afforded the corresponding products 4a–c in excellent yield
(Table 2, entries 1–3). Gratifyingly, both a-aliphatic and a-
aryl nitroacetates were viable substrates under these reac-
tion conditions. Generally, both a-aliphatic nitroacetates
1a–g and aryl-substituted a-aliphatic nitroacetates 1h–q
worked well to provide the desired products 4a–q in good
to excellent yields (Table 2, entries 1–17). The a-aryl-substi-
tuted nitroacetates 1r–v afforded the corresponding adducts
4r–v in lower yields (Table 2, entries 18–22), and especially,
the nature and position of the substituent at the a-phenyl
group greatly influenced the reaction outcome. No reaction
took place in the case of o-chlorophenyl-substituted nitroa-
cetate 1w (Table 2, entry 23).
15
Et
4o
2.0
99
16
17
iPr
4p
4q
1.0
2.0
71
85
Et
18
19
20
21
22
23
Ph (1r)
Et
iPr
Et
iPr
Et
iPr
4r
4s
4t
4u
4v
4w
1.0
8.0
4.0
4.0
20.0
24
57
56
53
61
p-FC6H4 (1s)
p-ClC6H4 (1t)
m-BrC6H4 (1u)
p-MeOC6H4 (1v)
o-ClC6H4 (1w)
32
NR[c]
[a] Reaction was run on a 0.25 mmol scale; [b] Yield of isolated product;
[c] No reaction.
benzyl amine 3e provided product 6d in 56% yield after
10 h (Table 3, entry 4). All of the aniline derivatives 3 f–j
were excellent reaction partners, either with electron-donat-
ing or electron-withdrawing substituents, thus giving prod-
ucts 6e–i in high to excellent yields (Table 3, entries 5–9).
Chiral primary amines 3k,l also afforded the corresponding
products 6j–l in good yields (Table 3, entries 10–12), albeit
with poor diastereoselectivity (up to 1.0:1.5), even though
several reaction parameters such as temperature and the
structure of the chiral amines were optimized. When ammo-
nium acetate was used as the amine source, a double Man-
nich reaction took place to afford amine 6m in 70% yield
and 1.7:1 d.r. (Scheme 1).
A wide range of structurally diverse amines were tolerat-
ed with this protocol, as shown in Table 3. Secondary
amines such as piperidine, morpholine, and 3-piperazinoben-
zisothiazole gave the desired products 6a–c in reasonable
yields (Table 3, entries 1–3). The less reactive aliphatic
The practicability of this method was shown by the fol-
lowing preparative scale synthesis. For example, the reaction
of nitroacetate 1a, formalin 2, and p-anisidine 3a readily
furnished the product 4a in 92% yield, while the reaction
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Jian Zhou, Xin Wang et al.
Table 3. The scope of amines.[a]
Entry
R2
3
6
t [h]
Yield [%][b]
Scheme 3. Synthetic procedure for the synthesis of 8a and 8r. Reaction
conditions: a) Zn/HOAC, iPrOH; b) triphosgene (1.0 equiv)/Et3N (1.0
equiv); c) CAN, CH3CN/H2O (3:1 or 1:1 v/v). CAN=ammonium ceriu-
m(IV) nitrate.
1
2
iPr
iPr
piperidine (3b)
morpholine (3c)
6a
6b
0.5
0.5
30
61
3
iPr
6c
1.0
64
4
5
6
7
8
9
iPr
iPr
iPr
iPr
iPr
iPr
BnNH2 (3e)
6d
6e
6 f
6g
6h
6i
10
56
94
97
90
80
80
peaks of nitroacetate 1b at 5.19 and 1.80 ppm remained
during the reaction course (Figure 1A). In sharp contrast,
the characteristic peak at 5.46 ppm gradually disappeared
within 30 min and the doublet peak at 1.73 ppm, corre-
sponding to the a-methyl group of 1b, simultaneously
emerged into a singlet peak at 1.84 ppm when run in
CD3OD (Figure 1,B). Similar results were obtained when
p-MeC6H4NH2 (3 f)
m-MeC6H4NH2 (3g)
p-FC6H4NH2 (3h)
m-ClC6H4NH2 (3i)
p-BrC6H4NH2 (3j)
1.0
1.0
1.0
23
17
62
10[c]
iPr
6j
3.0
1.0:1.3 d.r.
78
11[c]
12[c]
iPr
6k
6l
0.5
4.0
1.0:1.3 d.r.
tBu
ACHTUNGTRENNUNG(3l)
54
1.0:1.5 d.r.
[a] Reaction run on a 0.25 mmol scale; [b] Yield of isolated product;
[c] at À108C.
Scheme 1. Synthetic procedure for the synthesis of 6m.
with nitroacetate 1r furnished the product 4r in 83% yield
(Scheme 2).
Scheme 2. Gram-scale synthesis of 4a and 4r.
The versatility of the Mannich adduct 4 was demonstrated
by the facile transformation into the corresponding a,b-
amino acid-derived imidazolidinone
(Scheme 3).
8 in good yield
To understand the rate-accelerating effect observed when
using MeOH as the solvent, we conducted NMR spectro-
scopic studies to investigate the reaction mechanism, by
using CDCl3 or CD3OD as the solvent. The catalyst-free re-
action in CDCl3 proceeded slowly, and the characteristic
Figure 1. 1H NMR spectroscopic analysis: (A) the reaction of 1b, 2, and
3a in CDCl3; (B) the reaction of 1b, 2, and 3a in CD3OD.
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Jian Zhou, Xin Wang et al.
the nitroacetate 1b, formalin, and PMP-NH2 (PMP=p-me-
thoxyphenyl) were added all at once. These changes could
be explained by H/D exchange of the a proton of 1b by
13C NMR spectroscopy analysis, as the characteristic peak of
the a carbon at 83.30 was split into a triplet peak at
82.48 ppm (see the Supporting Information). These results
suggested that in MeOH, nitroacetate was activated by de-
protonation for H/D exchange. Interestingly, when imine 9,
prepared from formalin and PMP-NH2, was used to react
with nitroacetate 1b in CD3OD, the peaks of nitroacetate
1b at 5.46 and 1.70 ppm could be detected even after 40 h.
These results suggested that 3a, rather than the in situ
formed imine 9, was responsible for the activation of nitroa-
cetate 1b. In addition, 1H NMR spectroscopic analysis of
the formation of imine 9 in CDCl3, CD3OD, or CD3CN
demonstrated that imine formation was very fast, and was
not the rate-determining step of this reaction. Accordingly,
it was postulated that the rate-acceleration effect in MeOH
was possibly due to the H-bonding interactions[11] between
nitroacetate and MeOH, which facilitated the deprotonative
activation[12] of nitroacetate by PMP-NH2, a kind of dual ac-
tivation. For further NMR data, please see the Supporting
Information.
tance of MeOH are 13.4 and 23.6 kcalmolÀ1, respectively.
The formation of hydrogen bonds can decrease the reaction
barriers significantly. Interestingly, although hydrogen bonds
might be expected between the MeOH and nitroacetates
(with multiple H-bond acceptors), the optimized H-bonding
À
interactions consisted of three O H···O hydrogen bonds be-
tween two MeOH molecules and the reactants; this stabiliz-
es the TS and lowers the energy barriers, as shown in
Figure 2. The formation of H-bonding interactions between
two MeOH molecules led to the enhanced H-bond activa-
tion, a form of Brønsted acid-assisted Brønsted acid cataly-
sis that was proposed by Yamamoto, Rawal, and co-worker-
s.[11e,f] Considering the solvent effects, we calculated the
free-energy barrier and the total free-energy barrier in
MeOH to be 15.4 and 18.9 kcalmolÀ1, respectively; these
values are significantly lower than those in CHCl3 (22.8 and
24.5 kcalmolÀ1, respectively), which provided a possible ex-
planation for the rate-acceleration effect when using MeOH
as the solvent.
In conclusion, to the best of our knowledge, we have de-
veloped the first example of a highly efficient aminomethy-
lation of both a-alkyl- and a-aryl-substituted nitroacetates
under catalyst-free conditions. The versatility of the prod-
ucts was demonstrated by their facile conversion into the
corresponding a,b-amino acid-derived imidazolidinones.
NMR spectroscopy studies and theoretical calculations re-
vealed that the high efficiency of this catalyst-free transfor-
mation is owed to the dual activation of 1b through the H-
bonding interactions with MeOH and the deprotonative ac-
tivation of 1b by PMP-NH2. The detailed reaction mecha-
nism and the development of a catalytic asymmetric ver-
sion[13] are now in progress in our laboratory.
Because of the pervasive H-bond donors in MeOH and
considering that the nitroacetate has four oxygen atoms as
H-bond acceptors, we further performed theoretical calcula-
tions to study the proton-transfer processes with or without
the assistance of MeOH, and the patterns of H-bonding in-
teractions between MeOH and the nitroacetate. The opti-
mized transition state (TS) structures are shown in Figure 2,
Acknowledgements
The financial support from NSFC (21222204), innovation program of
SMEC (12ZZ046) and the Fundamental Research Funds for the Central
Universities (East China Normal University 11043) are highly appreciat-
ed.
Keywords: aminomethylation · diastereoselectivity · solvent
effects · a,b-amino acids · a-substituted nitroacetates
Figure 2. Optimized structures of the TS in the proton-transfer process
from 1b to PMP-NH2. TSI and TSII are the TSs without and with
MeOH, respectively. The bond distances of the optimized structures are
in angstroms.
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Jian Zhou, Xin Wang et al.
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[13] Despite extensive screening of a variety of easily available chiral
Brønsted bases for the reaction of nitroacetate 1a and preformed
imine 9 under the indicated reaction conditions, 4a was obtained in
only 3% ee.
Received: January 14, 2013
Published online: March 5, 2013
Chem. Asian J. 2013, 8, 877 – 882
882
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim