Experimental and computational study of intermolecular migration of N,N-dimethylcarbamoyl group from N(7) to N(1) on a 7-azaindoline derivative

Article abstract of DOI:10.1016/j.tet.2013.09.024

N,N-Dimethylcarbamoylation of the anilinic nitrogen atom N(1) on the spiro 7-azaindoline consists of two steps. The first step is N,N- dimethylcarbamoylation of the pyridyl nitrogen atom N(7), leading to the formation of an isolable intermediate. The second step is intermolecular migration of the N,N-dimethylcarbamoyl group from the pyridyl nitrogen atom N(7) to the anilinic nitrogen atom N(1). We accomplished optimization of the reaction conditions based on the revealed reaction mechanism and a large scale synthesis of compound 3 in quantitative yield.

Full text of DOI:10.1016/j.tet.2013.09.024

Tetrahedron 69 (2013) 9675e9681
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Experimental and computational study of intermolecular migration
of N,N-dimethylcarbamoyl group from N(7) to N(1) on
a 7-azaindoline derivative
Yoshiharu Uruno , Akio Tanaka , Kazuki Hashimoto , Shinya Usui , Yasunao Inoue ,d,
a
b
c
a
a
a
a
a
c
a
Yasuko Konishi , Atsushi Suwa , Kentaro Takai , Wataru Katoda , Norio Fujiwara ,
Takaaki Sumiyoshi
Drug Research Division, Dainippon Sumitomo Pharma Co. Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan
Organic Synthesis Research Laboratory, Sumitomo Chemical Co. Ltd., 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan
Process Chemistry Research & Development Laboratories, Dainippon Sumitomo Pharma Co. Ltd., 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka
a,
*
a
b
c
5
54-8558, Japan
d
R & D Department, DSP Gokyo Food & Chemical Co. Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2013
Received in revised form 6 September 2013
Accepted 7 September 2013
Available online 14 September 2013
N,N-Dimethylcarbamoylation of the anilinic nitrogen atom N(1) on the spiro 7-azaindoline consists of
two steps. The first step is N,N-dimethylcarbamoylation of the pyridyl nitrogen atom N(7), leading to the
formation of an isolable intermediate. The second step is intermolecular migration of the N,N-dime-
thylcarbamoyl group from the pyridyl nitrogen atom N(7) to the anilinic nitrogen atom N(1). We ac-
complished optimization of the reaction conditions based on the revealed reaction mechanism and
a large scale synthesis of compound 3 in quantitative yield.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
7-Azaindoline
N,N-Dimethylcarbamoylation
Intermolecular migration
Muscarinic acetylcholine receptors agonist
DFT calculation
1. Introduction
These findings support the idea that azaindoline derivatives are
useful scaffolds for identification of ligands with high pharmaco-
Indoline is one of the common scaffolds used in medicinal
chemistry. In particular, spiroindoline is frequently used to identify
logical activity and low ADRs. On the other hand, replacement of
indolines by azaindolines is also reported to lower reactivity of the
anilinic nitrogen atoms. In addition, there are only few reports
1
4
ligands for G-protein-coupled receptors as well as various en-
zymes.2 Pfizer medicinal chemists have recently reported that
transformation of indolines to azaindolines can minimize the risk
of adverse drug reactions (ADRs) associated with the use of indo-
lines.3 This report suggests that replacement of indolines by
azaindolines reduces electron density and reactivity of the benzene
ring and suppresses N-nitrosation and oxidation of reactive me-
tabolites (Fig. 1).
describing metabolic modification of azaindolines anilinic nitro-
5
gens. Even with these drawbacks, it is still important to develop
new synthetic methods for the preparation of azaindolines as
scaffolds for safer drug candidates.
In our drug discovery program, we have found the 7-azaindoline
derivative 1 as a muscarinic acetylcholine receptors (mAChRs) ag-
onist selective for M
Clinical trials with xanomeline demonstrated that M
1
and M
4
mAChRs over M
2
, M
3
and M
5
(Fig. 2).
and M
1
4
mAChRs are attractive therapeutic targets for Alzheimer’s disease
6
and schizophrenia.
In our synthesis of compound 1, we found that formation of urea
at the anilinic nitrogen atom of 7-azaindoline provided a low yield.
To overcome this problem, we focused on clarifying the mechanism
of carbamoylation by isolation of the reaction intermediate and
calculation of density functional theory (DFT). Here we describe
a rational optimization of the reaction conditions for practical
Fig. 1. Plausible metabolic pathways for indolines ADRs.
*
Corresponding author. Tel.: þ81 6 6337 5906; e-mail address: takaaki-su-
miyoshi@ds-pharma.co.jp (T. Sumiyoshi).
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.024

9676
Y. Uruno et al. / Tetrahedron 69 (2013) 9675e9681
Fig. 2. Structures of xanomeline and compound 1.
synthesis of compound 1. Our efforts revealed that intermolecular
migration of the N,N-dimethylcarbamoyl group from the pyridyl
nitrogen atom to the anilinic nitrogen atom is a rate-determining
step. Based on this finding, we optimized reaction concentrations
and temperature effectively and used the optimized procedure to
large scale synthesis of compound 1.
A
B
2
. Results and discussion
The initial synthetic route of compound 1 is shown in Scheme 1.
Reaction of the known 7-azaindoline compound 2 (1.0 equiv) with
N,N-dimethylcarbamoyl chloride (1.2 equiv) in the presence of
ꢀ
triethylamine (3.0 equiv) in toluene (0.2 M) at 90 C for 24 h
Fig. 3. TLC analysis (A) and HPLC analysis (B) of N,N-dimethylcarbamoylation. TLC
afforded compound 3 in only 28% isolated yield. When excess
amounts of reagents were used, i.e., N,N-dimethylcarbamoyl chlo-
analysis conditions (Silicagel: FUJI SILYSIA, TLC Plates NH, eluent: ethyl acetate); HPLC
conditions (Column: Eclipse Plus C18 4.6ꢁ100 mm, 3.5
mm; flow 1.0 mL/min; Eluent:
Gradient 10e90% methanol in water containing 0.01% TFA).
ride (4.0 equiv) and triethylamine (8.0 equiv) in toluene (0.2 M) at
ꢀ
9
0 C for 24 h, the yield of compound 3 increased to 68%. However,
reproducibility of this yield was poor.
Scheme 2. Isolation of the Key Intermediate 4. Reagents and conditions: (a) N,N-Di-
ꢀ
methylcarbamoyl chloride (1.5 equiv), toluene, 90 C (51%); (b) Na
CO
2 3
2
, H O, rt (99%).
in the 1H NMR spectrum of compound 3 (Fig. 4C). These results
strongly indicate that intermediate 4 was produced through N,N-
carbamoylation of the pyridyl nitrogen atom on 7-azaindoline. As
migration of the N,N-dimethylcarbamoyl group must have hap-
pened to allow production of compound 3 from compound 2
through compound 4, we investigated whether this migration was
1 4
Scheme 1. Synthesis of the selective M and M mAChRs agonist 1.Reagents and
conditions: (a) N,N-Dimethylcarbamoyl chloride (1.2 equiv), triethylamine (3.0 equiv),
ꢀ
toluene (0.2 M), 90 C (28%); (b) HCOONH
4
, 10% Pd/C, CH
3
OH, reflux (99%); (c) Ethyl 4-
Cl , rt (75%).
formylpiperidine-1-carboxylate, NaBH(OCOCH
3
)
3
, CH COOH, CH
3
2
2
Thin layer chromatography (TLC) analysis (Fig. 3A) revealed that
the reaction consisted of two steps. In the first step, the spot of the
7
intramolecular or intermolecular by DFT calculation (Fig. 5).
8
DFT calculation was carried out using the Gaussian09 package.
starting material 2 (R
¼0.2). In the second step, the polar spot decreased gradually,
giving rise to the spot of the target compound 3 (R
f
¼0.4) was quickly converted to a polar spot
9
10
The hybrid functional B3LYP combined with 6-31þG(d,p) basis
set specifying 6d functions was used to fully optimize the geometry
of stable molecules and transition state structures. All transition
states were confirmed by IRC calculation. In order to reduce cal-
culation cost, 3-spiro-linked piperidyl-7-azaindoline (SM1) was
used as a model substrate (Fig. 6). Through careful exploration of
rearrangement pathways from compound SM1 to TM1, four
mechanistic pathways were identified (Fig. 6). The structures of
the transition states and intermediates are also shown in
Supplementary data (Fig. S1).
(R
f
f
¼0.6). The polar
unknown compound was also observed in HPLC analysis (Fig. 3B).
LCMS analysis indicated that both compound 3 and the in-
termediate had the same molecular weight (m/z¼351). In order to
determine the structure of the intermediate, we tried to isolate it.
Fortunately, base-free conditions enabled isolation of 2HCl salt of
intermediate compound 4 in 51% yield (Scheme 2).
1
H NMR spectrum of the intermediate 4 shows no aromatic ring
structure. Chemical shifts of the protons at the pyridine ring of
compound 2 shifted from 7.8, 7.3 and 6.5 ppm to 6.7, 6.3 and
In the intramolecular pathway, mechanistic route 1 shows
SM1 carbamoyl group migration via TS1 to form TM1 (Fig. 6).
The Gibbs activation energy was calculated as 41.21 kcal/mol,
which indicates an energetically difficult rearrangement (Fig. 7).
5
.6 ppm, respectively, in the spectrum of compound 4 (Fig. 4A and
B). These lower chemical shifts shifted back to 8.1, 7.4 and 6.8 ppm

Y. Uruno et al. / Tetrahedron 69 (2013) 9675e9681
9677
in the caged eight-membered ring. The steric hindrance and dis-
tortion cancel the thermodynamic advantage of intermolecular
concerted mechanism. The route 4 is a stepwise carbamoyl group
exchange between a pair of SM1 (Fig. 6). The pathway consists of
three transition states (TS5, TS6 and TS7) and two intermediates
(IM2 and IM3). Initially, the pyridyl N-carbamoyl group in SM1 is
nucleophilically attacked by an unsubstituted anilinic nitrogen in
another SM1 via TS5 to form the zwitterionic intermediate IM2.
Following that, the anionic oxygen in IM2 attacks the intra-
molecular urea carbon via TS6 with six-membered ring structure to
form the carbamate IM3, which is finally transformed into a pair of
TM1 via TS7 with six-membered ring structure. Reaction barriers of
the three transition states TS5, TS6 and TS7 with reference to SM1
were much lower than those of the other three routes 1, 2 and 3
(24.58, 27.73 and 23.73 kcal/mol, Fig. 8). In other words, route 4 was
the most plausible mechanism in the investigated pathways. The
important transition states TS6 and TS7 were N-carbonyl migration
from the pyridyl nitrogen atom to the anilinic nitrogen atom with
a six-membered ring conformation. In the two intermolecular
mechanisms, the reaction barrier of the concerted route 3 was
higher because of repulsion between the two caged tetrahedral
carbons in TS4. In contrast, route 4 avoids steric distortion by
stepwise N-carbamoyl exchange via TS6 and TS7 to reduce reaction
barrier. To confirm the proposed mechanism, we performed addi-
tional calculations to estimate the reaction barriers for TS1, TS4 and
11
TS5 using M06-2X/6-31þG(d,p) ,that is, the method to treat dis-
persion interactions (Fig. S2 and Table S1). The results showed the
barrier of the stepwise intermolecular migration (TS5) was over
10 kcal/mol lower than of the intramolecular (TS1) and the con-
certed intermolecular mechanism (TS4), which indicated the sim-
ilar fashion of the result of B3LYP method.
Since DFT calculation suggested that the reaction proceeded by
an intermolecular process, we initially tried to optimize the re-
action concentrations. First, a suitable concentration for the syn-
Fig. 4. 1H NMR Spectra of compounds 2 (A), 4 (B) and 3 (C).
Fig. 5. Migration of the N,N-dimethylcarbamoyl group via intramolecular (path A) or intermolecular (path B) reaction.
The N,N-dimethylcarbamoyl group of TS1 had four-membered cy-
clic structure to raise the reaction barrier (Fig. S1). Route 2 shows
a stepwise N-carbamoylation of SM1 with additional N,N-dime-
thylcarbamoyl chloride via TS2 to form intermediate IM1, followed
by elimination of N,N-dimethylcarbamoyl chloride via TS3 to pro-
vide TM1 (Fig. 6). The Gibbs activation energy values of SM1 to TS2
and IM1 to TS3 were 38.30 and 25.85 kcal/mol, respectively (Fig. 7).
In the two intermolecular migration mechanisms, route 3 is
a concerted pathway of carbamoyl group exchange between a pair
of SM1 via TS4 to form a pair of TM1 (Fig. 6). The Gibbs free acti-
vation energy for this pathway was estimated to be 38.53 kcal/mol,
which is almost the same as the energy for the intramolecular
mechanisms (Fig. 7). TS4 is composed of an asymmetric eight-
thesis of compound 3 from compound 4 was explored in toluene at
90 C (Table 1). Under high dilution conditions (0.002 M), the mi-
ꢀ
gration reaction did not proceed (Table 1, entry 1). As concentra-
tions of the reaction increased (0.1 M to neat), the conversion ratio
of compound 4 to compound 3 increased (Table 1, entries 2e6).
Treatment of 4 under neat conditions afforded a conversion ratio of
compound 3:compound 2¼90:10. Under neat condition, the con-
version of compound 4 to compound 3 was also observed at room
temperature (entry 7). These results and LCMS monitoring study
(Scheme S1) indicate that N,N-dimethylcarbamoyl group of in-
termediate 4 is migrated via intermolecular mechanism.
Second, we explored a suitable reaction temperature. As a result,
the conversion ratio of compound 3 increased under reflux condi-
tions (Table 1, entries 8 and 9). It is because high reaction tem-
perature increases molecular movements. NMR monitoring study
showed that compound 2 was smoothly converted to compound 4
membered ring structure with formation of two bonds (1.61 and
ꢀ
2
.14 A) as indicated by dash lines in Fig. S1. The asymmetry stems
from steric distortion between the two nearby tetrahedral carbons

9678
Y. Uruno et al. / Tetrahedron 69 (2013) 9675e9681
Fig. 6. Four possible pathways explored by computational study.
(Table 2, entry 1) and compound 4 was transformed to compound 3
3. Conclusion
via intermolecular migration of N,N-dimethylcarbamoyl group
(
Table 2, entries 2e4).
Finally, based on the results described above, we optimized the
In summary, we have successfully improved the yield of the
original synthesis of compound 3 through identification of the re-
action mechanism, which involves intermolecular migration of
N,N-dimethylcarbamoyl group as indicated by isolation of in-
termediate 4 and DFT calculation. Taking advantage of this method,
we accomplished a large scale synthesis of the promising antipsy-
chotic compound 1.
reaction conditions as shown in Table 3. We determined the opti-
mal reaction concentration to be 2.0 M; at higher concentration
agitation/mixing is insufficient for application at large scale. Re-
action temperature and base were changed, from 90 C to reflux
condition, and from triethylamine to N,N-diisopropylethylamine
ꢀ
ꢀ
(
DIPEA) since triethylamine boiling point was only 88.8 C as
ꢀ
compared to 127 C for DIPEA. As expected, the modified reaction
conditions afforded the desired compound 3 in 99% yield (<1 g
scale) (Table 3, entry 1). However, in case of large scale synthesis
4. Experimental section
4.1. General information
(>20 g), the isolated yield of compound 3 decreased to 84%, and the
starting material 2 was recovered (Table 3, entry 2). Because of low
thermal efficiency in large scale synthesis, compound 4 might de-
compose to the starting material 2. To complete the reaction,
All reagents and solvents were purchased from commercial
suppliers and used without further purification. Nuclear Magnetic
Resonance (NMR) spectra were recorded at ambient temperature,
operating at 400 MHz for H NMR and 100 MHz for C NMR.
Chemical shifts were expressed in parts per million and referenced
1
13
0
.3 equiv of N,N-dimethylcarbamoyl chloride and 0.6 equiv of
DIPEA were added to the reaction mixture after 3 h to obtain
compound 3 in quantitative yield (Table 3, entry 3).
3
to tetramethylsilane (TMS) in CDCl and residual solvent peak in

Y. Uruno et al. / Tetrahedron 69 (2013) 9675e9681
9679
TS1
5
4
3
2
1
0
0
0
0
0
0
41.21
(40.82)
TS3
28.07
TS2
TS4
(
13.31)
3
8.30
38.53
(30.01)
(
24.66)
IM1
2
.23
(
-9.87)
SM1
.00
(0.00)
0
-
-
-
10
20
30
Route 1
Route 2
Route 3
TM1
-17.89
-18.34)
(
Reaction coordinate
Fig. 7. Reaction coordinates for rearrangement of SM1 to TM1 in the mechanistic routes 1, 2 and 3. Upper numbers indicate relative Gibbs free energy, and the numbers in pa-
rentheses are relative enthalpies in units of kcal/mol.
5
4
3
2
1
0
0
0
0
0
0
TS1
TS2, TS4
TS6
TS5
IM2
2
7.73
2
4.58
17.11)
TS7
24.53
(
18.91)
(
23.73
15.40)
(
16.87)
(
IM3
13.96
(
6.39)
SM1
.00
0.00)
0
(
-
-
-
10
20
30
TM1
-
17.89
-18.34)
(
Reaction coordinate
Fig. 8. Reaction coordinate of the intermolecular stepwise rearrangement mechanism (route 4) from SM1 to TM1. The upper numbers indicate relative Gibbs free energy, and the
numbers in parentheses are relative enthalpies in units of kcal/mol.
CDCl
3
or DMSO-d
6
for 1H NMR and 13C NMR. Splitting pattern
4.2. Synthesis
designed as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br s, broad singlet; and dd, double doublet. Mass spectra
were obtained using Electro Spray Ionization. ESI mass spectra (for
HRMS) were measured on a hybrid linear ion trapeOrbitrap mass
0
0
0
4.2.1. 1-Benzyl-1 ,2 -dihydrospiro[piperidine-4,3 -pyrrolo[2,3-b]pyri-
dine] (2). Preparation of compound 2 had been described in pre-
ꢀ
1
vious reports (Refs. 5a,b). White solid; mp 124e126 C; H NMR
(400 MHz, CDCl 1.72e1.75 (m, 2H), 1.85e1.94 (m, 2H), 2.10e2.15
ꢂ1
spectrometer. IR spectra are reported in wavenumbers (cm ). TLC
3
) d
analysis was performed on TLC Plates NH. Column chromatography
(m, 2H), 2.82e2.85 (m, 2H), 3.45 (s, 2H), 3.55 (s, 2H), 4.42 (br s, 1H),
6.53 (dd, J¼7.1, 5.1 Hz, 1H), 7.21e7.34 (m, 6H), 7.84 (dd, J¼5.1, 1.5 Hz,
ꢀ
was carried out using prepacked amino silica gel (40
mm, 60 A).

9680
Y. Uruno et al. / Tetrahedron 69 (2013) 9675e9681
Table 1
in toluene (247 mL) was added N,N-dimethylcarbamoyl chloride
52 mL, 564 mmol) at room temperature and the mixture was stirred
under reflux for 3 h. After addition of N,N-diisopropylethylamine
32 mL, 226 mmol) and N,N-dimethylcarbamoyl chloride (10 mL,
13 mmol), the reaction mixture was stirred for 3 h under reflux. The
Effect of reaction concentrations to migration of N,N-dimethylcarbamoyl group
(
(
1
reaction mixture was cooled to room temperature, quenched with
water and extracted with EtOAc. Organic layer was washed with
saturated aqueous NaHCO and brine, dried over Na SO and fil-
3 2 4
tered. The filtrate was concentrated in vacuo to give solid. The solid
was triturated with n-hexane to give 3 (119 g, 99%) as a pale yellow
ꢀ
Ratioa
Entry
Temperature ( C)
Concentration (M)
ꢀ
1
3
solid. Mp 128e129 C; H NMR (400 MHz, CDCl ) d 1.70e1.73 (m,
4
3
2
2
H), 1.89e1.96 (m, 2H), 2.15e2.21 (m, 2H), 2.84e2.87 (m, 2H), 3.03
1
2
3
4
5
6
7
8
9
90
90
90
90
90
90
rt
Reflux
Reflux
0.002
0.1
0.2
1
>99
57
65
<1
<1
<1
14
<1
<1
<1
17
21
56
70
90
69
<1
26
14
44
30
10
17
<1
<1
(s, 6H), 3.56 (s, 2H), 3.78 (s, 2H), 6.75 (dd, J¼7.3, 5.4 Hz, 1H),
7.26e7.35 (m, 5H), 7.36 (dd, J¼7.3, 1.7 Hz, 1H), 8.05 (dd, J¼5.4, 1.7 Hz,
13
1H); C NMR (100 MHz, CDCl
3
),
d
35.5, 38.1, 39.7, 50.1, 57.5, 63.3,
2
116.2, 127.1, 128.2, 129.2, 130.3, 132.1, 137.8, 146.4, 157.3, 157.6: IR 702,
Neat
Neat
0.2
2
ꢂ1
þ
7
44, 771, 1366, 1416, 1655 cm ; MS (ESI, positive) m/z 351 (MþH) ;
þ
>99
>99
HRMS (ESI, positive) m/z calcd for C21
H
27ON
(MþH) 351.2179,
4
found 351.2183; Anal. Calcd for C21
Found: C, 72.03; H, 7.58; N, 16.07.
26 4
H N O: C, 71.97; H, 7.48; N,15.99.
aReaction ratio was determined by 1H NMR.
0
0
0
4
.2.3. Ethyl 4-{[1 -(dimethylcarbamoyl)-1 ,2 -dihydro-1H-spiro[pi-
Table 2
0
peridine-4,3 -pyrrolo[2,3-b]pyridin]-1-yl]methyl}piperidine-1-
NMR monitoring studies
carboxylate (1). To a solution of 3 (27.5 g, 78.5 mmol) in methanol
(
82 mL) were added HCOONH
dium on carbon (5.5 g). The mixture was stirred under reflux for
h, cooled to room temperature and filtered. The filtrate was
concentrated in vacuo. The residue was diluted with CHCl and
washed with water, saturated aqueous NaHCO and brine. The or-
ganic layer was dried over Na SO , filtered and concentrated in
4
(24.7 g, 392 mmol) and 10% palla-
7
3
3
2
4
vacuo to give a pale yellow amorphous (20.4 g, 99%). To a solution of
the amorphous (20.4 g, 78.2 mmol) acetic acid (6.7 mL, 117 mmol)
and ethyl 4-formylpiperidine-1-carboxylate (14.5 g, 78.2 mmol) in
dichloromethane (390 mL) was added sodium triacetoxyborohy-
dride (24.8 g, 117 mmol) at room temperature and the mixture was
Ratioa
Entry
Time (h)
2
4
3
1
2
3
4
0.25
1
3
11
12
6
82
56
37
<1
7
32
57
ꢀ
stirred for 2 h. The reaction mixture was cooled to 0 C and
24
<1
>99
quenched with saturated aqueous NaHCO
washed with water and brine, dried over Na
3
. The organic layer was
SO , filtered and
a
Reaction ratio was determined by 1H NMR. The reaction was performed at
2
4
a 0.7 mmol scale of compound 2.
concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexaneeAcOEt) to afford 1 (25.3 g, 75%) as
ꢀ
1
a white solid; mp 120e122 C; H NMR (400 MHz, CDCl
1.04e1.18 (m, 2H), 1.26 (t, J¼7.3 Hz, 3H), 1.65e1.82 (m, 8H),
1.84e1.95 (m, 2H), 2.11 (t, J¼10.7 Hz, 2H), 2.21 (d, J¼7.3 Hz, 2H),
.71e2.83 (m, 4H), 3.78 (s, 2H), 3.56 (s, 2H), 3.78 (s, 2H), 4.13 (q,
3
)
Table 3
d
Optimization of large scale synthesis of compound 3
2
J¼7.3 Hz, 2H), 4.13e4.17 (m, 1H), 6.76 (dd, J¼7.3, 5.4 Hz, 1H), 7.37
1
3
(
(
6
1
dd, J¼7.3, 1.5 Hz, 1H), 8.06 (dd, J¼5.4, 1.5 Hz, 1H); C NMR
100 MHz, CDCl 14.7, 30.7, 33.7, 35.7, 38.2, 39.9, 43.9, 50.8, 57.5,
1.1, 64.9, 116.2, 130.4, 132.2, 146.5. 155.6, 157.3, 157.7; IR 768, 1080,
3
) d
ꢂ1
þ
111, 1361, 1420 cm ; MS (ESI, positive) m/z 430 (MþH) ; HRMS
þ
(
4
ESI, positive) m/z calcd for C23
30.2824; Anal. Calcd for C23
Found: C, 64.15; H, 8.33, N, 16.22.
H
36
O
3
N
5
(MþH) 430.2813, found
35
H N
5
O
3
: C, 64.31; H, 8.21; N, 16.30.
Entry
A (equiv)
DIPEA (equiv)
Yield (%)
Scale (g)
1
2
3
1.5
1.5
1.5þ0.3
2.0
2.0
2.0þ0.6
99
84
>99
<1
>20
>20
0
4.2.4. 1-Benzyl-N,N-dimethylspiro[piperidine-4,3 -pyrrolo[2,3-b]pyr-
0
0
idine]-7 (2 H)-carboxamide dihydrochloride (4$2HCl). To a solution
of compound 2 (200 mg, 0.72 mmol) in toluene (0.7 mL) was added
N,N-dimethylcarbamoyl chloride (99 mL, 1.1 mmol) at 60 C and the
mixture was stirred for 4 h. The precipitate was collected by fil-
tration and washed with diethyl ether to give 4$2HCl (157 mg, 51%)
ꢀ
1
1
1
H); 13C NMR (100 MHz, CDCl
27.1, 128.2, 129.2, 129.7, 129.9, 138.2, 146.4, 163.5; IR 694, 744, 771,
3
)
d
36.4, 42.7, 50.2, 54.0, 63.5, 113.4,
ꢂ1
þ
612 cm ; MS (ESI, positive) m/z 280 (MþH) ; HRMS (ESI, posi-
þ
ꢀ
1
tive) m/z calcd for C18
H
22
N
3
(MþH) 280.1808, found 280.1813;
as a pale yellow solid; mp 193e194 C; H NMR (400 MHz, DMSO-
2.01 (d, J¼13.7 Hz, 2H), 2.32e2.45 (m, 2H), 2.92 (s, 3H), 3.07 (s,
3H), 3.08e3.29 (m, 4H), 3.86 (s, 2H), 4.31 (s, 2H), 6.86 (t, J¼6.8 Hz,
H), 7.42e7.48 (m, 4H), 7.64e7.51 (m, 2H), 7.88 (d, J¼6.6 Hz, 1H),
Anal. Calcd for C18
H, 7.67, N, 15.06.
H
21
N
3
: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.16;
6
d ) d
1
0
13
4
.2.2. 1-Benzyl-N,N-dimethylspiro[piperidine-4,3 -pyrrolo[2,3-b]pyr-
idine]-1 (2 H)-carboxamide (3). To a solution of N,N-diisopropyle-
thylamine (105 mL, 752 mmol) and compound 2 (105 g, 376 mmol)
6
10.4 (br s, 1H), 11.6 (br s, 1H); C NMR (100 MHz, DMSO-d ) d 32.3,
0
0
37.2, 38.1, 40.7, 47.6, 55.5, 58.7, 112.5, 128.7, 129.3, 130.0, 131.3, 131.9,
133.8, 138.3, 149.5, 152.7; IR 768, 1080, 1111, 1203, 1362, 1420,

Y. Uruno et al. / Tetrahedron 69 (2013) 9675e9681
9681
ꢂ1
1
667 cm ; MS (ESI, positive) m/z 351; HRMS (ESI, positive) m/z
E.; Leventhal, L.; Whiteside, G. T.; Kennedy, J. D.; Trybulski, E. J. J. Med. Chem.
2010, 53, 2051e2062; (b) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44,
þ
calcd for C21
for C21
Found: C, 56.85; H, 6.90; N, 12.54; Cl, 15.81.
H27ON
4
(MþH) 351.2179, found 351.2188; Anal. Calcd
4
47e457; (c) Marquis, K. L.; Sabb, A. L.; Sheree, F. L.; Brennan, J. A.; Piesla, M. J.;
26 4 2
H N O$2HCl$H O: C, 57.14; H, 6.85; N, 12.69; Cl, 16.06.
Comery, T. A.; Grauer, S. M.; Ashby, C. R., Jr.; Nguyen, H. Q.; Dawson, L. A.; Barret,
J. E.; Stack, G.; Meltzer, H. Y.; Harrison, B. L.; Rosenzweig-Lipson, S. J. Pharmacol.
Exp. Ther. 2007, 320, 486e496; (d) Khan, P. M.; Correa, R. G.; Divlianska, D. B.;
Peddibhotla, S.; Sessions, E. H.; Magnuson, G.; Brown, B.; Suyama, E.; Yuan, H.;
Mangravita-Novo, A.; Vicchiarelli, M.; Su, Y.; Vasile, S.; Smith, L. H.; Diaz, P. W.;
Reed, J. C.; Roth, G. P. ACS Med. Chem. Lett. 2011, 2, 780e785; (e) Boal, B. W.;
Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458e3461.
. (a) Pong, S.-S.; Chaung, L.-Y. P.; Dean, D. C.; Nargund, R. P.; Patchett, A. A.; Smith,
R. G. Mol. Endocrinol. 1996, 10, 57e61; (b) Sakamoto, T.; Moriya, M.; Tsuge, H.;
Takahashi, T.; Haga, Y.; Nonoshita, K.; Okamoto, O.; Takahashi, H.; Sakuraba, A.;
Hirohashi, T.; Shibata, T.; Kanno, T.; Ito, J.; Iwaasa, H.; Gomori, A.; Ishihara, A.;
Fukuroda, T.; Kanatani, A.; Fukami, T. Bioorg. Med. Chem. 2009, 17, 5015e5026;
0
.2.5. 1-Benzyl-N,N-dimethylspiro[piperidine-4,3 -pyrrolo[2,3-b]pyr-
4
0
0
idine]-7 (2 H)-carboxamide (4). An aqueous solution of 4$2HCl
157 mg, 0.37 mmol) was basified with saturated aqueous Na CO
The mixture was stirred for 5 min and extracted with AcOEt. The
organic layer was dried over Na SO , filtered, and concentrated in
vacuo to give 4 (129 mg, 99%) as a pale yellow oil. H NMR
400 MHz, CDCl 1.56e1.82 (m, 4H), 2.02e2.15 (m, 2H),
.76e2.86 (m, 2H), 3.05 (br s, 6H), 3.52 (s, 2H), 3.72 (s, 2H), 5.64 (t,
J¼6.2 Hz, 1H), 6.29 (d, J¼6.2 Hz, 1H), 6.71 (dd, J¼7.3, 1.3 Hz, 1H),
(
2
3
.
2
2
4
1
(
2
3
) d
(c) Horton, D. A.; Severinsen, R.; Kofod-Hansen, M.; Bourne, G. T.; Smythe, M. L.
J. Comb. Chem. 2005, 7, 421e435; (d) Ong, H. H.; Profitt, J. A.; Fortunato, J.;
Glamkowski, E. J.; Ellis, D. B.; Geyer, H. M., III; Wilker, J. C.; Burghard, H. J. Med.
Chem. 1983, 26, 981e986; (e) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M.-
H.; Barakat, K. J.; Johnston, D. B. R.; Cheng, K.; Chan, W. W.-S.; Butler, B.; Hickey,
G.; Jacks, T.; Schleim, K.; Pong, S.-S.; Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.;
Leung, K. H.; Chiu, S.-H. L.; Smith, R. G. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
7001e7005.
. Piatnitski Chekler, E. L.; Khan, T. A.; Mamidala, R.; Anderson, J. T.; Tangirala, R.
S.; Verhoest, P. R.; Gilbert, A. M. Tetrahedron Lett. 2012, 53, 377e379.
. (a) Norberto, F.; Santos, S.; Silva, D.; Herv eꢁ s, P.; Miguel, A. S.; Vilela, F. J. Chem.
.23e7.36 (m, 5H); 1 C NMR (100 MHz, CDCl
0.2, 63.5, 65.8, 103.9, 121.4, 127.0, 128.2, 128.9, 129.1, 138.3, 145.9,
55.0, 157.9; IR 698, 736, 1115, 1173, 1207, 1238, 1385, 1589,
3
7
5
1
1
3
) d 35.6, 36.3, 42.8,
ꢂ1
694 cm ; MS (ESI, positive) m/z 351; HRMS (ESI, positive) m/z
3
4
calcd for C21
H
27
N
4
O (MþH)þ 351.2179, found 351.2187.
Soc., Perkin Trans. 2 2002, 1162e1165; (b) Schneider, C.; Gueyrard, D.; Popowycz,
F.; Joseph, B.; Goekjian, P. G. Synlett 2007, 2237e2241; (c) Schmid, S.; R o€ ttgen,
4
.3. Computational methods
M.; Thewalt, U.; Austel, V. Org. Biomol. Chem. 2005, 3, 3408e3421; (d) Bolhofer,
W. A.; Deana, A. A.; Habecker, C. N.; Hoffman, J. M.; Gould, N. P.; Pie-
truszkiewicz, A. M.; Prugh, J. D.; Torchiana, M. L.; Cragoe, E. J., Jr.; Hirschmann,
R. J. Med. Chem. 1983, 26, 544e548.
. (a) Ito, F.; Hayashi, S.; Hashizume, Y.; Mihara S. PCT Int. Appl. WO/2005/016913,
2005. (b) Gao, Y.-D.; Macneil, D. J.; Yang, L.; Morin, N. R.; Fukami, T.; Kanatani,
A.; Fukuroda, T.; Ishii, Y.; Morin, M. PCT Int. Appl. WO/2000/027845, 2000. (c)
Cassayre, J.; Molleyres, L.-P.; Maienfisch, P.; Cederbaum, F. PCT Int. Appl. WO/
DFT calculation was carried out using the Gaussian09 package.
The hybrid functional B3LYP combined with 6-31þG(d,p) basis set
specifying 6d functions was used to fully optimize the geometry of
stable molecules and transition state structures. Vibrational fre-
quency analyses were used to search for transition state structures
and to estimate thermochemical kinetics. Intrinsic reaction co-
ordinate (IRC) calculation was also executed for all transition state
structures to verify first-order saddle points on potential energy
5
2005/061512, 2005.
6. (a) Bodick, N. C.; Offen, W. W.; Levey, A. I.; Cutler, N. R.; Gauthier, S. G.; Satlin,
A.; Shannon, H. E.; Tollefson, G. D.; Rasmussen, K.; Bymaster, F. P.; Hurley, D. J.;
Potter, W. Z.; Paul, S. M. Arch. Neurol. 1997, 54, 465e473; (b) Shekhar, A.; Potter,
W. Z.; Lightfoot, J.; Lienemann, J.; Dub eꢁ , S.; Mallinckrodt, C.; Bymaster, F. P.;
McKinzie, D. L.; Felder, C. C. Am. J. Psychiatry 2008, 165, 1033e1039.
7. DFT calculation of acyl transfer from pyridyl nitrogen atom to other atoms, see:
Larionov, E.; Mahesh, M.; Spivey, A. C.; Wei, Y.; Zipse, H. J. Am. Chem. Soc. 2012,
12
surface between two local minima. All DFT calculations took into
account a solvation model of the polarizable continuum model
using the integral equation formalism variant (IEFPCM) with united
13
atom-for-HartreeeFock (UAHF) radii. Toluene was specified as the
134, 9390e9399.
reaction solvent for execution inputs.
8
. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K.
N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
Acknowledgements
We really thank Keiko Bando for elemental analyses and Nao-
hiro Nishimura and Sayo Takayama for HRMS analyses.
Supplementary data
€
1H and 13C NMR spectra for compounds 1e4 and 4$2HCl, Fig-
nenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian: Wallingford, CT.
ures, Schemes, Tables and Additional materials for DFT calculations.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.024.
9. Becke, A. B. J. Chem. Phys. 1993, 98, 5648e5652.
1
0. (a) Petersson, G. A.; Bennett, A.; Tensfeldt, T. G.; Al-Laham, T. G.; Shirley, W. A.;
Mantzaris, J. J. Chem. Phys. 1988, 89, 2193e2218; (b) Petersson, G. A.; Al-Laham,
M. A. J. Chem. Phys. 1991, 94, 6081e6090.
1
1. Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215e241.
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