Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a highly active derivative of N,N-dimethylaminopyridine

Article abstract of DOI:10.1016/j.tetlet.2020.152047

1,1,7,7-Tetramethyl-9-azajulolidine (TMAJ), which theoretical studies have suggested as a highly active DMAP analog, was synthesized for the first time. The catalytic activity of TMAJ was confirmed by the acetylation reactions of various tert-alcohols. TMAJ showed much higher catalytic activity than DMAP and one of the highest activity levels among the conventional DMAP analogs. These experimental results were in good agreement with the previous theoretical studies.

Full text of DOI:10.1016/j.tetlet.2020.152047

Journal Pre-proofs
Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a
highly active derivative of N,N-dimethylaminopyridine
Tomohiro Tsutsumi, Arisa Saitoh, Tomoyo Kasai, MengYue Chu, Sangita
Karanjit, Atsushi Nakayama, Kosuke Namba
PII:
S0040-4039(20)30493-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152047
TETL 152047
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Tetrahedron Letters
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Revised Date:
Accepted Date:
15 April 2020
12 May 2020
14 May 2020
Please cite this article as: Tsutsumi, T., Saitoh, A., Kasai, T., Chu, M., Karanjit, S., Nakayama, A., Namba, K.,
Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a highly active derivative of N,N-
dimethylaminopyridine, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152047
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Tetrahedron Letters
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Synthesis and evaluation of 1,1,7,7-tetramethyl-9-azajulolidine (TMAJ) as a highly
active derivative of N,N-dimethylaminopyridine
Tomohiro Tsutsumi, Arisa Saitoh, Tomoyo Kasai, MengYue Chu, Sangita Karanjit, Atsushi Nakayama and
Kosuke Namba
Graduate School of Pharmaceutical Sciences and Research Cluster on “Innovative Chemical Sensing”, Tokushima University, 1-78-1 Shomachi, Tokushima
7
70-8505, Japan
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. Tel.: +81-88-633-7293; fax: +81-88-633-9575; e-mail: namba@tokushima-u.ac.jp
Article history:
Received
Received in revised form
Accepted
1,1,7,7-Tetramethyl-9-azajulolidine (TMAJ), which theoretical studies have suggested as a
highly active DMAP analog, was synthesized for the first time. The catalytic activity of TMAJ
was confirmed by the acetylation reactions of various tert-alcohols. TMAJ showed much higher
catalytic activity than DMAP and one of the highest activity levels among the conventional
DMAP analogs. These experimental results were in good agreement with the previous
theoretical studies.
Available online
Keywords:
N,N-Dimethylaminopyridine
1
,1,7,7-Tetramethyl-9-azajulolidine
2009 Elsevier Ltd. All rights reserved.
Acylation catalyst
Quinolizidine alkaloid
Cascade reaction
N,N-Dimethylaminopyridine (DMAP) is one of the most
widely used organocatalysts in the field of organic chemistry. In
neighboring position of the pyridine ring is generally difficult.
For example, the Friedel-Crafts-type reaction is not suitable for
the pyridine ring because pyridine is an electron-deficient
aromatic ring. The intramolecular radical cyclization reactions
and the Heck reactions were likely to preferentially proceed with
5-exo cyclizations. On the other hand, we recently reported the
concise synthesis of quinolizidine alkaloid (+)-epilupinine. As 1
also includes the quinolizidine skeleton, we considered that our
synthetic method for quinolizidine alkaloids can be applied to the
synthesis of 1. Herein, we report the first synthesis of TMAJ (1)
and assess its ability as an acylation catalyst.
1
particular, DMAP is the most common catalyst for condensation
reactions of various alcohols, amines, and so on. Thus, the
development of more active derivatives of DMAP has been a
2
subject of intensive research. The catalytic activity of DMAP
1
2
analogs tends to increase with the electron-donating properties of
the 4-substituent, and 4-pyrolidinopyridine (PPY) has been used
3
as a more reactive analog than DMAP. In 2003, Steglich et al.
reported that bis-six-membered DMAP analog 9-azajulolidine (9-
4
AJ), synthesized according to Yamanaka’s procedure, showed
about six times the catalytic activity of DMAP in the
5
esterification reaction of a tertiary alcohol. After that report,
6
N
N
N
N
Han’s group improved the synthesis of 9-AJ and developed an
7
aza-analog that is slightly better than 9-AJ. Wong’s group also
reported the improved synthesis of 9-AJ and its application to the
8
post-Ullmann reaction. Moreover, various aza-analogs of 9-AJ
N
N
N
N
9
were developed as highly nucleophilic pyridines. In these ways,
DMAP
PPY
9-AJ
TMAJ (1)
cyclic analogs of DMAP have been intensively studied. Among
them, the bis-six-membered analogs have exhibited the highest
catalytic activity so far. On the other hand, Zipse et al. vigorously
investigated the catalytically most active DMAP derivatives by
computational studies.10 They reported that 1,1,7,7-tetramethyl-9-
azajulolidine 1 (TMAJ), the tetramethylated analog of 9-AJ,
forms the most stable acylpyridinium cation intermediate next to
the Fu’s ferrocene analog11 in various DMAP analogs.10a
However, although various derivatives of 9-AJ have been
developed so far, TMAJ (1), which was suggested to be the most
efficient DMAP analog, has not yet been synthesized. The main
reason for this is probably the difficulty of synthesizing 1. In
particular, the introduction of quaternary carbon centers to the
Figure 1. Structures of DMAP analogs
Our synthesis of (+)-epilupinine was achieved by the cascade
reaction of 2. Treatment of 2 with PhSH and L-proline induced
sequential reactions consisted of a removal of nosyl group,
condensation of the resulting secondary amine with either
aldehyde, and an intramolecular asymmetric Mannich reaction to
give 3. Subsequent direct addition of NaBH and methanol to the
reaction mixture afforded (+)-epilupinine in one step from 2
(Scheme 1a). Based on this quinolizidine-forming reaction, we
designed 4 possessing tetramethyl groups and exomethylene
moiety as the precursor of a similar cascade reaction that would
4

2
Tetrahedron Letters
afford quinolizidine compound 5. The pyridine formation using
b) and the other hemiaminal formation leading to 16 (path c)
compete with the desired hemiaminal formation, and these
undesired reactions take precedence over the desired path a
aldehyde and exomethylene moiety as a foothold would afford
TMAJ (1) (Scheme 1b).
(
Scheme 3). The reaction mainly afforded 15 and 16 at the
(
a) Previous synthesis of (+)-epilupinine
beginning, and then was gradually obtained through
equilibrium. Thus, we needed to suppress the undesired paths b
and c to increase the yield of 5.
5
1
4
O
O
N
(a)
(b)
0%
N
H
N
H
7
Ns
H
O
O
H
CHO
8
3% ee OH
H
c
N
N
H
H
2
3
(+)-epilupinine
HO
N
(b) Synthetic plan of TMAJ
15
16
b
O
N
O
O
a
TMAJ
H
N
H
PhSH,
K2CO3
O
O
a
Ns
1
CHO
4
H
N
H
H
MeOH,
rt
OH
13
H
O
4
5
c
Scheme 1. Synthesis of (+)-epilupinine and synthetic plan of
1
0
b
12
3
days
. Reaction conditions; (a) PhSH, L-proline, Cs
°C. (b) NaBH , MeOH, 0 °C to rt.
2 3 3
CO , CHCl ,
4
N
N
We synthesized the cascade reaction precursor 4. Starting with
commercially available 6, the conjugate addition of the allyl
group followed by hydrolysis and decarboxylation afforded
carboxylic acid 7. The carboxylic acid moiety was reduced to
alcohol 8, and the resulting hydroxy group was converted into the
tosylate group as a leaving group to give 9. Next, commercially
available o-nosylamide was treated with 2.0 equiv of 9 as an
alkylating reagent to afford double-alkylated product 10 in 70%
yield. After ozonolysis of 10, treatment of the resulting
dialdehyde 11 with 1.0 equiv of formalin under basic conditions
afforded the desired cascade reaction precursor 4 (Scheme 2).
18%
CHO
HO
14
5
Scheme 3. The reaction pathway of the cascade reaction
leading to 5.
It was difficult to modify the olefin moiety to suppress path b
despite our efforts. On the other hand, the unconjugated aldehyde
was convertible into silyl enol ether 17 for the suppression of
path c. A similar reaction of 17 increased the yield of 5 to 47%,
although the reaction time was longer due to the unavoidable
path b and the stability of TIPS enol ether. Indeed, it was
confirmed that the 1,4-addition product was generated mainly in
the early stage, and that the isolated 1,4-adduct was returned to
enal under the reaction conditions. On the other hand, TBS enol
ether instead of the TIPS group converted readily back to
aldehyde before the removal of the nosyl group in the reaction
conditions.
1
)
MgBr
,
CuCI
1
2
) MeI, K CO3
DMF, rt
2
EtO C
Et2O, –40 °C to rt
2
HO C
2
) DIBAL
2
3
) 6 M NaOH aq
MeOH, 50 °C
) xylene, reflux
CO Et
2
CH Cl2
2
7
6
–78 °C
TsCl, NEt3
DMAP
HO
TsO
N
CH Cl2
2
8
9
0
°C to rt
4
6% (6 steps)
O
OTIPS
TIPSOTf
2
PhSH, K CO3
5
4
9
(2.0 equiv)
CH Cl2
H
N
O , CH Cl
2
–78 °C;
2
MeOH, 40 °C
2 weeks
3
2
Ns
K CO , DMF
0 °C to rt
2
3
NsNH2
17
N
PPh3
84% (E/Z = 1/3)
1
00 °C
47%
Ns
–
78 °C to rt
7
0%
N
Scheme 4. Cascade reaction of silyl enol ether 17.
1
0
7
3%
O
H
O
formalin, K CO3
2
With a sufficient amount of 5 in hand, we attempted the syn-
thesis of TMAJ (1). Treatment of 5 with O-methylhydroxyamine
afforded O-methyloxime 18 in excellent yield. We next applied
4
H
EtOH-H O, 70 °C
Ns
2
5
2% (brsm 95%)
11
the Polonovski reaction to introduce another double bond into
Scheme 2. Synthesis of the cascade reaction precursor 4.
15
1
8. The tertiary amine of 18 was oxidized by mCPBA to give
N-oxide 19. Subsequent treatment of crude 19 with
trifluoroacetic anhydride afforded the desired enamine 20, along
with inseparable regioisomers 20a and 20b. Although the desired
Having prepared the cascade reaction precursor, we tried the
cascade reaction of 4. Treatment of 4 with PhSH and K CO in
2 3
methanol for the removal of the nosyl group initially afforded
reactive secondary amine 12. Then, when the reaction was
extended for a long time, the desired 5 gradually appeared as a
single diastereomer.13 The reaction leading to 5 probably
consisted of the hemiaminal formation with the aldehyde on the
enal side (12 →13) and the generation of iminium cation (13 →
2
0 was a minor product, it was considered that major
regioisomers 20a and 20b could also be isomerized to the desired
16
isomer 20. Therefore, a mixture of the three isomers was heated
to 150 °C by microwave irradiation, and the desired TMAJ (1)
was obtained in 36% yield from 18.
1
4) followed by the intramolecular Mannich reaction (14 →5).
Although the desired quinolizidine skeleton 5 was obtained in
this cascade reaction, the yield of 5 had to be improved for
further conversion. The main reason for the low yield and long
reaction time is that the 1,4-addition reaction leading to 15 (path

3
by TMAJ (1) (entries 2 and 3). The reaction time was prolonged
O
N
in the order of alkyl, alkenyl, and alkynyl group, reflecting the
steric hindrance of these substituents. The reaction of tert-alcohol
at the -position of ketone 26 also gave the acetate in good yield,
i.e., TMAJ accelerated the reaction in the tert-alcohol possessing
strong electron with-drawing groups (entry 4). The case of cyclic
trialkyl tert-alcohol 27 similarly gave the desired acetates in
much higher yields than DMAP (entry 5). In addition, the
reaction of diol 28 with 4.0 equiv of acetic anhydride afforded
the corresponding diacetate in good yield (entry 6). Throughout,
TMAJ (1) showed much higher catalytic activity than DMAP.
N
mCPBA
NH OMe•HCl
2
5
CH Cl , rt
MeOH, 40 °C
2
2
9
7%
N
N
OMe
OMe
19
1
8
N
N
N
N
TFAA
+
+
CH Cl2
2
N
N
4
0 °C
OMe
OMe
OMe
Table 1. Comparison of DMAP and TMAJ in reactions of
various tert-alcohols.
2
0
20a
20b
(
20/20a+20b = 1/3)
Ac O (2.0 equiv), NEt (3.0 equiv)
catalyst (10 mol %)
N
2
3
M. W.
MeOH, 150 °C
6% (3 steps)
R1
R3
R1
R3
R2
OH
R2
OAc
3
CH2Cl2 (0.2 M), rt
N
1
yield (%)a
DMAP TMAJ
Scheme 5. Synthesis of TMAJ (1)
entry
substrate
OH
time (h)
Having established the synthesis of 1, we evaluated its
catalytic activity. The acetylation reaction of unreactive tertiary
alcohol 21 with acetic anhydride was adopted for the activity test
according to the conventional evaluation of DMAP analogs. The
progress of the reaction in the presence of 10 mol % of DMAP
1
1.3
46
83
23
1
analogs as catalysts was observed by H NMR spectroscopy. The
OH
OH
yields of acetate 22 were plotted over a time course as shown in
Figure 2. In comparison with DMAP and PPY, bis-six-membered
analogs showed much higher catalytic activity. In particular,
TMAJ (1) had the highest catalytic activity, ca. 1.5 times higher
2
3
7.0
11
51
51
84
84
2
4
5
,17
than 9-AJ.
These experimental results supported the
1
0a
theoretical studies reported by Zipse et al.
Ac O (2.0 equiv), NEt (3.0 equiv)
catalyst (10 mol %)
25
2
3
HO
AcO
CDCl (0.2 M), rt
OH
3
4
0.5
42
85
85
21
22
O
2
6
O
O
OH
5b
33
8
54
26
2
2
7
8
OH
6b
82
HO
a
b
NMR yield using pyrazine as an internal standard. 4.0 equiv
2 3
of Ac O and 6.0 equiv of NEt were used.
In conclusion, we achieved the first synthesis of TMAJ (1),
which has been proposed as a highly active DMAP analog in
theoretical studies. The catalytic activity of 1 was actually
confirmed by the acetylation reaction of various tert-alcohols,
and 1 showed much higher catalytic activity than DMAP and one
of the highest activity levels among the conventional DMAP
analogs. These experimental results were in good agreement with
the previous theoretical studies. TMAJ (1) is expected to be
widely used as an efficient catalyst for acylation reactions and
various other reactions such as carbamylation, silylation,
sulfonylation, lactonization, and so on. For this purpose, the
Figure 2. Time course of yield in the acetylation reaction of 21 using 10
mol % of DMAP analog catalyst: DMAP (▲), PPY (◆), 9-AJ (■), and
TMAJ (●).
Finally, the acetylation reactions of various tert-alcohols using
TMAJ as a catalyst were examined (Table 1). The reaction of
aliphatic alkynyl alcohol 23 proceeded smoothly to give the
desired acetate in 83% yield, while the use of DMAP
significantly decreased the yield (entry 1). The reactions of
alkenyl alcohol 24 and alkyl alcohol 25 also smoothly catalyzed

4
Tetrahedron Letters
synthesis of 1 still needs several improvements regarding the
positions instead of a dimethyl group. Although the cascade
reaction needs dimethyl groups so far, we are currently
undertaking the improvement of the cascade reaction so that the
reaction can be applied not only to the large-scale synthesis of
TMAJ (1) but also to the development of novel chiral DMAP
analogs.
number of steps, the yields, and the reaction time of the cascade
reaction. In addition, chiral DMAP analogs have recently been
developed and successfully applied to asymmetric syntheses.18
Our synthesis of 1 can be applied to the development of novel
chiral DMAP analogs that possess chiral centers at the 1- and 7-
1
2. T. Tsutsumi, S. Karanjit, A. Nakayama, K. Namba, Org. Lett., 21
2019) 2620–2624.
(
1
3. The single diastereomer is probably due to the epimerization of
aldehyde to more stable isomer as is the case of (+)-epilupinine
synthesis.
Acknowledgments
This work was partially supported by JSPS KAKENHI Grant
Numbers JP16H01156 in Middle Molecular Strategy,
JP18H04416, and JP19H02851. We acknowledge Tokushima
University for their financial support of the Research Clusters
program of Tokushima University (No. 1802001). T.T. is grateful
to Nagai Memorial Research Scholarship from the
Pharmaceutical Society of Japan (N-206305) for young scientists.
14. Although the yield of 5 was only 18%, other byproducts were not
isolated. The reactive 12 readily induced the intermolecular
reaction to give complex polymerized mixtures during the
equilibrium even under diluted conditions. Indeed, the desired 5
was not obtained under the undiluted condition.
1
5. (a) M. J. Polonovski, M. Polonovski, Bull. Soc. Chim. Fr., 41
(1927) 1927–1208; (b) J. Zhang, Y.-Q. Wang, X.-W. Wang, W.-D.
Z. Li, J. Org. Chem., 78 (2013) 6154–6162.
1
1
6. Similar isomerization in the Polonovski reaction, see: D. Grierson,
Org. React., 39 (1990) 85–295.
7. The catalytic activity of 1 was estimated by comparison of the
half-reaction times of each catalyst according to the report of
Steglich and Zipse.
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☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Declaration of interests
The authors declare that they have no known
☒
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.

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Synthesis and evaluation of 1,1,7,7-
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tetramethyl-9-azajulolidine (TMAJ) as a
highly active derivative of N,N-
Highlights
dimethylaminopyridine
Tomohiro Tsutsumi, Arisa Saitoh, Tomoyo Kasai, MengYue Chu, Sangita Karanjit, Atsushi Nakayama and
•
1,1,7,7,-tetramethyl-9-azajulolidine (TMAJ) has been
Kosuke Namba
proposed by theoretical studies as a highly active analog of
N
N
N
N,N-dimethylaminopyridine (DMAP).
•
TMAJ was first synthesized by a cascade reaction forming
DMAP
N
TMAJ
the quinolizidine skeleton followed by pyridine ring
formation.
•
The high catalytic activity of TMAJ was demonstrated in the
acylation reaction of sterically hindered tert-alcohols.