One-pot cascade synthesis of azabicycles via the nitro-Mannich reaction and N -alkylation

Article abstract of DOI:10.1039/c7ob03104a

A one-pot, metal-free process for the synthesis of azabicycles is developed. The key transformations involved a cascade of double intramolecular cyclizations via the nitro-Mannich reaction and N-alkylation, providing various ring systems of azabicycles in

Full text of DOI:10.1039/c7ob03104a

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One-pot cascade synthesis of azabicycles via the nitro-Mannich
reaction and N-alkylation
Wannaporn Disadee*a and Somsak Ruchirawata,b,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A one-pot, metal-free process for the synthesis of azabicycles is annulation of cyclic amines having a reactive
developed. The key transformations involved a cascade of double nitroalkyl-tethered aldehydes6; and (d) de-carboxylative
intramolecular cyclizations via the nitro-Mannich reaction and N- annulation of amino acids with nitroalkyl-tethered
α-proton and
a
alkylation, providing various ring systems of azabicycles in yields aldehyde.7 Although these previously reported methodologies
up to 81% and an isomeric ratio of 62 : 1. This approach offers exhibit interesting chemistry, some approaches require
considerable advantages in terms of the handling of small intensively controlled reaction conditions with special
molecules, the flexibility to introduce a functionalized side chain, equipment, while others suffer from difficulty in the material
and gives direct access to various azabicycles.
preparation and limited substrate scope. These drawbacks
make these methods impractical for synthetic applications.
Azabicyclo[m,n,0]alkanes are well-known heterocycles that are
common core structures or sub-units of numerous natural
products and synthetic pharmaceutical lead substances (Fig.
1).1 In light of their versatile properties, a large number of
novel synthetic routes to these moieties have been
developed.2 These include multi-step transformations,
transannular ring contractions, reductive aminations, ylide
cyclizations, acyliminium cyclizations, radical cyclizations,
biomimetic cyclizations, aza-ene reactions, and cycloadditions.
A combination of the nitro-Mannich reaction and other
reactions in a tandem strategy has been developed as a
powerful tool in synthetic chemistry.3 A cascade annulation
between the nitroalkyl-tethered moiety and the cyclic iminium
OMe
Me
H
O
N
MeO
MeO
HO
C6H13
H
N
O
H
H
(-)-Lepadiformine A1b
H
N
H
O
Me
O
NH
H
Stemonine1a
O
(-)-Cryptopleurine1c
Me
Me
(+)-Laburnamine1d
N
Fig. 1 Examples of azabicycles as core- or sub-units
A) Previous works
segment of intermediate
A, Scheme 1A, has been used by
several research groups to prepare nitro-azabicycles, which are
important scaffolds for transformations to various
NO2
NO2
NO2
N
NH
heterocycles. In this regard, the iminium ion
A can be
(a)
(b)
(c)
X
generated in situ through a number of methods (Scheme 1A),
including: (a) the reaction of preformed cyclic imines and
nitroalkyl-tethered carboxylic acid derivatives or halides (X =
CO2R, CONR2, halides)4; (b) chemo-selective amide reduction
of nitroalkyl-tethered lactams5; (c) asymmetric redox-
N
N
O
X = CHO, CO2R,
CONR2, halogen
O
nitro-azabicycles
R
OH
A :R = H2 or O
NH
(d)
NH
B) Our work: One-pot approach for doubleintramolecular cyclizations
(Overall: new 2 C-N bonds, 1 C-C bond and 2rings formations)
via:Imine formation, nitro-Mannichreaction and N-Alkylation
NO2
O
O
O2
N
R
N
O
O
N
N
R
N
R
N
m
1
2
H2N
base
or
+
m
n
O
m
n
m
n
3: m, n = 1, 2...
OTs
B
OTs
C
R= H, alkyl
n
R
Scheme 1 A) Selected approaches for generating cyclic iminium ions A, and B) Our
proposed method for the synthesis of azabicycle 3
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Designing convenient and efficient one-pot processes with [6,7]-ring systems could be synthesized in moderate to good
atom and step economy remains a topic of interest for yields with isomeric ratios up to 62:1 under mild reactions
synthetic chemists. Herein, we present a one-pot process (Table 2, entries 2, 4–6, and 8–14). However, no reaction was
giving easy access to nitro-azabicycle
systems and substituted groups from simple and easily the case of the eight-membered ring formation, N-alkylation
accessible materials and (Scheme 1B). The key provided the desired product 3d in low yield (24%), along with
3 having various ring observed for the [5,5]-ring system of 3b (Table 2, entry 1). In
1
2
transformations involved a cascade of double intramolecular a non-cyclization product 3d’ in 58% yield (Table 2, entry 3).
cyclizations of the nitro-Mannich reaction and N-alkylation via No intramolecular nitro-Mannich reaction occurred for a
an imine B or a cyclic iminium ion C depending on the mode of medium ring 3h, even after increasing the reaction
ring-size annulation.8 Furthermore, this process might be temperature to 80 °C (Table 2, entry 7). The substitution
useful for the preparation of biologically active natural product patterns also affected the stability and reactivity of substrates
cores.
1 and 2. Secondary nitroalkylamine 1 gave the corresponding
After the preliminary experiments (see the SI), several azabicycles 3j in moderate yield with a fair diastereomeric
inorganic and organic bases were further screened against the ratio (Table 2, entry 9). The azabicycle with an angular methyl
in situ generated 3-nitro-1-propylamine9 from precursors 1a at a bridged carbon atom 3k was successfully prepared from
and 2a in alcoholic solvents (Table 1). The reactivity of each the corresponding ketone
base was compared by Gas Chromatography Mass improved chemical yields of 3n and 3o were observed from
Spectrometry (GC–MS) analysis of product 3a. We found that the more stable aldehydes when the reaction temperature
MeOH provided a higher chemical yield than those of EtOH was increased to 80 °C for 3 h (Table 2, entries 13 and 14). The
and 2-PrOH (Table 1, entries 1–3). When the reaction was use of an easily prepared 2,3-diaryl-4-nitro-butylamine
2
(Table 2, entry 10).11 The
−
2
4
treated with 2 equiv. of K2CO3, no notable improvement of the afforded an indolizidine derivative 3p in good yield (Scheme 2).
chemical yield was observed (Table 1, entry 4). Increasing In addition, we found that instead of the amine group,
reaction temperatures to 80 and 100 °C for 1–3 h resulted in phosphazene could function as an amine surrogate via the aza-
lower chemical yields (Table 1, entries 5–7) owing to the
Table 1 Conditions for optimization of the one-pot process of 3a
stability of product 3a and a competing intramolecular self-
cyclization of aldehyde 2a as a side reaction pathway under
the thermal basic conditions. Thus, the challenge of this
process was to find suitable conditions that would enhance
nitronate formation and cyclization, while avoiding aldehyde
self-cyclization and isomerization of the desired products.
% Yield of
Entry Base
Solvent T (°C)
t (h)
drb
Alkali metal carbonate and phosphate bases gave the optimal
yields of 3a (Table 1, entries 8–10 and 17), while bicarbonate
bases gave lower yields (Table 1, entries 15–16). Surprisingly,
carbonate bases of alkaline earth and transition metals
provided poor yields (Table 1, entries 12–14), possibly because
of their low solubility in methanol.10 Other non-metal
carbonate and hydroxide bases also gave reasonable yields
(Table 1, entries 11 and 18). Strong bases, such as NaOMe and
KOtBu, were ineffective, leading to considerable
decomposition of the aldehyde (data not shown). Tertiary
amine bases with moderate basicity all showed comparable
reactivity (Table 1, entries 19–20). Among the various
screening bases, K2CO3 was the most effective for this process.
The use of this carbonate was also advantageous for the
purification process. Several by-products, including hydrazide
and tosylate, could be easily separated as potassium salts by
normal filtration. In addition, the carbonate behaved as a
desiccant removing water from the alcohol solvent to promote
the imine formation step. Thus, K2CO3 was found to be the
best choice for subsequent studies.
3ac,d
1
K2CO3
K2CO3
K2CO3
EtOH
MeOH
2-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
RT
RT
RT
RT
80
80
100
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
14
14
14
14
1
3.4 : 1
4.2 : 1
3.0 : 1
3.8 : 1
3.0 : 1
3.0 : 1
3.0 : 1
2.7 : 1
3.2 : 1
3.6 : 1
2.7 : 1
4.5 : 1
3.2 : 1
2.5 : 1
2.8 : 1
2.9 : 1
3.1 : 1
3.0 : 1
2.7 : 1
2.8 : 1
84
2
86 (67)
56
3
e
4
K2CO3
88 (70)
56
5
K2CO3
6
K2CO3
3
57
7
K2CO3
1
38
8
Li2CO3
14
14
14
14
14
14
14
14
14
14
14
14
14
52
9
Na2CO3
Cs2CO3
(NH4)2CO3
CaCO3
Tl2CO3
Ag2CO3
NaHCO3
KHCO3
K3PO4
64
10
11
12
13
14
15
16
17
18
19
20
63
55
8
5
35
32
35
58
28% aq.NH3
NEt3
72
65
DIPEA
63
Having established the optimal conditions, we turned our
attention to varying the ring-size and substituents on the
substrates for these intramolecular cyclizations. We found that
various chain lengths and substitution patterns of the
a All reactions were performed with 1a (0.35 mmol), 2a (1.1 equiv.), and base (1.1
b
equiv.) in 1.3 mL of MeOH. Isomeric ratio of 3a from crude reaction was
c
determined by GCMS analysis. Yield was calculated by GCMS analysis with an
d
internal calibration method and N-butyl piperidine as the internal standard.
homologation synthons
1
and
2
underwent these cascade Numbers in parentheses referred to isolated yield of inseparable diastereomeric
mixtures of 3a. Where a major diastereomer was shown; the other isomers were
not assigned. e Two equiv. of base were used.
reactions to afford products
3
in variable chemical yields and
isomeric ratios. Structures including [5,6]-, [5,7]-, [6,6]-, and
2 | J. Name., 2012, 00, 1-3
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Table 2 Variation of ring sizes and substituents on substrates
1
and 2a
drd
drd
drd
Entry
1
3b-o
entry
3b-o
entry
10
3b-o
% yielde
% yielde
% yielde
62 : 1
72
3 : 2
69
NR
5
6
12 : 1
51
7 : 1
45
9 : 4 : 1
67
11
12
2
37 : 1
24
ND
75
7b
NR
3b
3 : 1
58
6 : 3 : 1
68
ND
79
8
13c
14c
4 : 1
65
1 : 1
67
7 : 1
81
9
4
a Reactions were performed with 1 (0.35 mmol), 2 (1.1 equiv.), and K2CO3 (1.1 equiv.) in 1.3 mL of MeOH at room temperature for 14 h. b Reaction was performed at
room temperature for 14 h and then 80 °C for 3 h. c Reaction was performed at 80 °C for 3 h. d Isomeric ratio of 3 was determined from crude products using GC–MS
analysis (entries 2–11) or 1H NMR analysis (entries 12–14). e Isolated yield of 3 as isomeric mixtures (entries 2–11 and 14) or as a pure isomer (entries 12 and 13).
the use of previously reported conditions.14 Polyhydroxylated
azabicycles (7–8) were synthesized by varying the hydrogen
pressure, catalyst, and temperature for selective reduction of
the nitro group and hydrogenolysis of an O-benzyl ether
protective group. Crispine A oxime (9) was obtained by a
reductive Nef reaction15 of 3o with the use of in situ
generation of chromium (II) chloride in MeOH. A complex
molecule of decahydro-[1,7]-naphthyridine
(10) could be
prepared in a straightforward manner over two steps from 3p
via the reduction of nitroalkane and Pictet–Spengler reaction.
Scheme 2 Nitro-azabicycles 3p and 3q from the corresponding synthons 4 and 5
Conclusions
A novel one-pot methodology for alternative access to various
Wittig reaction to generate the imine moiety.12 Thus, a chiral azabicycles containing five- to eight-membered-ring systems
moiety.12 Thus, a chiral quinolizidine (-)-3q could be prepared was developed through a cascade nitro-Mannich reaction and
from (-)-5 in good yield without racemization under thermal N-alkylation. Our new strategy is attractive owing to the ease
basic conditions (Scheme 2).
of handling reagents and products and the ability to introduce
Modification of the stereocenters and functional groups various functional groups into the substrates. Additionally, no
around the cores can alter the potency and efficacy of lead special treatments were required, no racemization of chiral
compounds for drug development.13 Thus, we attempted to substrates occurred under the thermal basic treatment
transform theses nitro-azabicycles
biologically active analogues 10
Epiquinamide derivative (
3
to functionalized, condition. Therefore, the present procedure provides
a
(
6–
)
(Scheme 3). epi- convenient and simple way to access various biologically active
6
) could be prepared from (-)-3q with azabicycle analogues.
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Scheme 3 Synthetic elaboration of nitro-azabicycles
3 to biologically active analogues 6–10
Acknowledgements
We gratefully acknowledge financial support from Chulabhorn
Research Institute, Mahidol University, the Institute for the
Promotion of Teaching Science and Technology through the
Research Fund for DPST Graduate with First Placement (Grant
No. 010/2557 to W.D.), and the Science and Technology
Research Grants from the Thailand Toray Science Foundation.
5
A. W. Gregory, A. Chambers, A. Hawkins, P. Jakubec and D. J.
Dixon, Chem. Eur. J., 2015, 21, 111.
Y. Kang, W. Chen, M. Breugst and D. Seidel, J. Org. Chem.,
2015, 80, 9628.
Y. Kang and D. Seidel, Org. Lett., 2016, 18, 4277.
A review on macro-cyclization reactions, see: V. Marti-
Centelles, M. D. Pandey, M. I. Burguete and S. V. Luis, Chem.
Rev., 2015, 115, 8736.
6
7
8
9
P. G. M. Wuts, Protective Groups in Organic Synthesis, 5th
ed., John Wiley & Sons, 2014.
Conflicts of interest
The authors declare no conflict of financial interest.
10 For solubility of inorganic bases in methanol, see: (a) V. A.
Stenger, J. Chem. Eng. Data, 1996, 41, 1111. (b) A. Y.
Platonov, A. N. Evdokimov, A. V. Kurzin and H. D. Maiyorova,
J. Chem. Eng. Data, 2002, 47, 1175.
11 For details on the effects of methylation in drug discovery,
see: (a) E. J. Barreiro, A. E. Kümmerle and C. A. M. Fraga,
Chem. Rev., 2011, 111, 5215. (b) H. Schӧnherr and T. Cernak,
Angew. Chem. Int. Ed., 2013, 52, 2.
12 For examples of the aza-Wittig reaction between
phosphazenes and aldehydes, see: (a) F. P. Cossío, C. Alonso,
B. Lecea, M. Ayerbe, G. Rubiales and F. Palacios, J. Org.
Chem., 2006, 71, 2839. (b) F. Palacios, C. Alonso, D. Aparicio,
Notes and references
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(a) R. W. Fitch, G. D. Sturgeon, S. R. Patel, T. F. Spande, H. M.
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4 | J. Name., 2012, 00, 1-3
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One-pot cascade synthesis of azabicycles via the nitro-Mannich reaction and N-alkylation
Wannaporn Disadee* and Somsak Ruchirawat
A cascade of double intramolecular cyclizations via the nitro-Mannich reaction and N-alkylation provides direct
access to various ring systems of azabicycles.