Differential nitrogen-carbon bond cleavages in architecturally complex molecular scaffolds containing a bridge-head nitrogen atom

Article abstract of DOI:10.1016/j.crci.2014.04.006

Application of an N-C bond cleavage reaction in various structurally complex molecular frameworks containing bridge-head nitrogen atom offered differential outcomes that were attempted to rationalize invoking both steric and electronic factors.

Full text of DOI:10.1016/j.crci.2014.04.006

C. R. Chimie 18 (2015) 127–131
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Preliminary communication/Communication
Differential nitrogen–carbon bond cleavages in
architecturally complex molecular scaffolds containing a
bridge-head nitrogen atom
1
*
Sankar Chatterjee , Maurice Shamma
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Application of an N–C bond cleavage reaction in various structurally complex molecular
frameworks containing bridge-head nitrogen atom offered differential outcomes that
were attempted to rationalize invoking both steric and electronic factors.
Received 8 April 2014
Accepted after revision 18 April 2014
Available online 13 January 2015
´
ß 2014 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Heterocyclic
Benzazepine
Tetrahydroprotoberberine
Steric
Electronic
1. Introduction
dark to generate compound 5 (method b, Fig. 2) had been
also reported [5,6].
During
a synthetic program aimed at generating
biologically active novel neurological agents, we sought
to carry out synthetic transformations from structurally
complex bridge-head heterocyclic indoline fused benza-
zepine class of compound 1 to compound 2 (Fig. 1).
Our anticipation was based on a literature reported
similar N–C8 bond cleavage reaction. For example, reflux-
ing biologically active natural product tetrahydroproto-
berberine class of compounds 3 in ethyl chloroformate
generated compound 4 (method a, Fig. 2; note the
numbering systems in compounds 1 and 3 and afterwards
maintain the same pattern for the uniformity in the
2. Chemistry
Compound 1 was accessed by following a literature
reported procedure [7]. Once in hand, refluxing the
compound 1 with excess ethyl chloroformate over a period
of 24 h resulted in no appreciable change of the starting
material. On the other hand, treatment of compound 1 in
acetone with ethyl chloroformate in the presence of sodium
iodide resulted in exclusive cleavage, not at expected C8–N
bond but at C6–N bond generating compound 6, instead of
the anticipated compound 2 (Scheme 1).
discussion) [1–4].
compound 3 in acetone with ethyl chloroformate in the
presence of sodium iodide at room temperature and in
A
modified procedure of treating
The mode of cleavage was proven by reduction of
compound 6, with lithium aluminum hydride, to the
corresponding tertiary base 7. The 1H NMR spectrum of
compound 7 displayed a three-proton triplet at
d 1.14 with
a coupling constant of 7.5 Hz and a two-proton quartet at
d
*
2.57 with a coupling constant of 7.5 Hz representing the
aromatic –CH2CH3 group. The spectrum also exhibited
Corresponding author. 1375 Indian Creek Dr., Wynnewood, PA
19096-3321, USA.
E-mail address: Sankar.Chatterjee24@gmail.com (S. Chatterjee).
three-proton singlet at
d 2.49 for the N–CH3 group.
1
Professor Emeritus.
http://dx.doi.org/10.1016/j.crci.2014.04.006
1631-0748/ß 2014 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.

128
S. Chatterjee, M. Shamma / C. R. Chimie 18 (2015) 127–131
5
5
6
4
4
3
2
6
7
3
2
7
RO
O
O
8
N
B
A
B
A
C
9
N
C
OMe
OMe
RO
8
9
13
14
1
14
D
1
OR
OR
12
13
10
D
11
12
1
10
3
11
Method a
or
Method b
O
O
N
COOEt
D
B
A
RO
RO
COOEt
OMe
N
X
X
OMe
OR
OR
2 X = halogen
Fig. 1. Anticipated transformations from compound 1 to compound 2.
4) X = Cl
5) X = I
Concurrently, we were also developing
a total
Fig. 2. Reported ring fragmentation procedures.
synthesis of the novel tetrahydrohomoprotoberberine
compound 8 (Scheme 2). Commercially available com-
pound 9 was converted to compound 10 [5]. Compound
10, on treatment with sodium cyanide, produced
compound 11 that underwent basic hydrolysis (sodium
hydroxide) to generate compound 12 without affecting
The difference in behavior of compounds 1 and 3 in the
bond cleavage reactions as well as the availability of
compound 8 at this stage prompted us to explore its behavior
in the same paradigm. Treatment of compound 8 in refluxing
ethylchloroformate [Scheme 3, step (a) (i)] overnightresulted
in the production of a compound (50% yield), displaying a
deep blue fluorescence under short UV light. The same
product was also generated in 90% yield when Ro¨nsch
protocol [Scheme 3, step (a) (ii)] was followed. The 1H NMR
spectrumofthe compound revealed two one-proton doublets
the N-ethoxycarbonyl group. Its removal needed
a
harsher condition with careful monitoring by heating
compound 12 at a high temperature in a sealed tube in
the presence of potassium hydroxide to generate
compound 13. Subsequent internal cyclization of the
amino acid 13 to lactam 14 was carried out in hot
decalin. Compound 14 was reduced by lithium alumi-
num hydride to generate the free base 8.
at
d 6.81 and d 6.85, respectively, with a coupling constant of
13.5 Hz, indicating two vicinal protons of an olefinic moiety of
6
6
I
7
O
O
O
O
N
8
COOEt
7
a
OMe
OMe
N
8
OMe
1
6
X
a
OMe
b
6
CH3
COOEt
O
I
N
O
O
8
H3C
7
OMe
OMe
O
N
OMe
2
7
OMe
Scheme 1. Reagents and conditions. (a) Ethyl chloroformate, NaI, acetone, dark, room temperature, 72 h, 70%; (b) LAH, ether, heat, 1 h, 65%.

S. Chatterjee, M. Shamma / C. R. Chimie 18 (2015) 127–131
129
O
O
O
10) X = I, Y = CO2Et
a
OMe
OMe
7
Y
N
N
b
X
8
O
11) X = CN, Y = CO2Et
12) X = CO2H, Y = CO2Et
13) X = CO2H, Y = H
OMe
OMe
c
d
9
e
5
4
1
3
2
6
O
O
O
O
7
8
f
O
N
N
15
14
13
9
10
OMe
OMe
OMe
14
11
8
OMe
12
Scheme 2. Reagents and conditions. (a) Ethyl chloroformate, NaI, acetone, dark, room temperature, 72 h, quantitative; (b) NaCN, DMSO, room temp., 1 h,
quantitative; (c) NaOH, EtOH–H2O, reflux, overnight, 80%; (d) KOH, EtOH–H2O, sealed tube, 140 8C, overnight, 70%; (e) decalin, 180 8C, 2 h, 90%; (f) LAH,
ether, reflux, 1 h, 90%.
O
O
O
O
O
Me
COOEt
OMe
N
N
b
N
a
O
H
H
15
H
H
OMe
OMe
OMe
OMe
OMe
15
8
16
Scheme 3. Reagents and conditions. (a) (i) Ethyl chloroformate, reflux, overnight, 50%; or (ii) Ethyl chloroformate, NaI, acetone, dark, room tempearture,
overnight, 90%; (b) LAH, ether, heat, 1 h, 90%.
a trans-stilbene system indicating the product might be the
compound 15. This was further proven by reduction of
compound 15, with lithium aluminum hydride, to corre-
sponding tertiary base 16. In the 1H NMR spectrum of
compound 16, the vicinal protons around the olefinic moiety
3. Discussion
It had been proposed in the literature [4] that for ring
cleavage in compound 3, the reaction is initiated by the
nucleophilic attack by the lone pair of electrons on
nitrogen in compound 3 at the electrophilic carbethoxy
group generating the reactive acyl ammonium intermedi-
ate A (Fig. 3).
appeared as two doublets at
d6.82 and 6.89, respectively with
a coupling constant of 16.2 Hz. The spectrum also displayed a
singlet at
d
2.37 for the N–CH3 group.
RO
RO
6
COOEt
N
Method a
COOEt
(+)
N
RO
X
3
X(-)
[
]
RO
14
or
OR
OR
8
OR
OR
Method b
4) X = Cl
5) X = I
A
Fig. 3. Proposed mechanism for compound 3.

130
S. Chatterjee, M. Shamma / C. R. Chimie 18 (2015) 127–131
I(-)
X
I
6
O
O
COOEt
N
COOEt
8
O
O
Method b
N
[
]
1
(+)
OMe
OMe
OMe
13
B
6
OMe
Fig. 4. Suggested mechanism for compound 1.
O
O
O
6
COOEt
O
O
COOEt
N
COOEt
8
N
H
O
N
X
(+)
15
H
Method a
-HX
H
]
H
[
8
or
OMe
OMe
X(-)
OMe
OMe
OMe
Method b
OMe
15
D (X = Cl or I)
C (X = Cl or I)
Fig. 5. Suggested mechanism for compound 8.
Nucleophilic halide anion (XÀ) then attacks the
intermediate B (Fig. 4). However, due to the constrained
nature of the five-member indoline ring fused to a seven-
member azepine ring with a bridge-head nitrogen atom,
primary benzylic position 8 assumes an envelop form
getting steric resistance from the newly-attached car-
bethoxy group. Thus, this position becomes less accessible
to a nucleophilic attack. Same is true for the sterically
congested tertiary benzylic position 13. However, in order
to relieve the steric congestion in the newly formed
cationic species, the iodide anion, a superior nucleophile
sterically less hindered primary benzylic position 8 over
sterically congested tertiary benzylic position 14, thus,
cleaving the N–C8 bond in an SN2 fashion producing
compounds 4 or 5. Thus, the course of the reaction is
guided by both electronic and steric factors.
For compound 1, it appears that the initial step also
involves the nucleophilic attack by the lone pair of
electrons on nitrogen in compound 1 at the electrophilic
carbethoxy group generating the reactive acyl ammonium
MeO
MeO
MeO
4
5
3
6
7
MeO
MeO
N
N
MeO
b
A
B
Me
COOEt
8
N
8
2
15
14
1
9
C
Major
a
Me
D
I
10
13
12
11
20
17
18
MeO
MeO
Me
MeO
MeO
N
H
COOEt
N
H
b
15
H
H
14
Minor
21
19
Scheme 4. Reagents and conditions. (a) (i) Ethyl chloroformate, reflux, overnight, 50%; or (ii) Ethyl chloroformate, NaI, acetone, dark, room temp., 72 h, 90%;
(b) LAH, ether, heat, 1 h, 90%.

S. Chatterjee, M. Shamma / C. R. Chimie 18 (2015) 127–131
131
then finds the remaining available position 6, though it is
not benzylic in nature. Note the fragmentation did not
take place in neat ethyl chloroformate where counter
anion was less nucleophilic chloride anion. Thus, the
course of the reaction in this case is guided by steric factor.
For compound 8, the similar initial step provides the
intermediate C (Fig. 5). Note in the intermediate C,
position 8 is no longer benzylic in nature, but position
15 remains so.
The inherent flexibility of the seven-member ring
accommodates the anion (X(À)) to interact with sterically
congested position 15 over non-benzylic but sterically
accessible position 6 (cf. intermediate B in Fig. 4) affording
the second intermediate D. Intermediate D then under-
goes concomitant in situ trans-dehydrohalogenation
reaction generating the final compound 15. Thus, the
course of the reaction in this case is guided mainly by
electronic factor with accommodation from steric factor.
Interestingly, the fragmentation pattern also allowed an
entry to generate an 11-membered flexible cyclic system,
that itself might be a driving force in the outcome of the
cleavage.
additionally characterized by reducing them to corre-
sponding bases 20 and 21, respectively. As can be seen
from the ratio of the initial cleavage products (18 and
19), though both available benzylic sites took part in
the ultimate outcome, the attack by the nucleophile at
sterically favored primary benzylic position 8 predomi-
nated over sterically congested benzylic position 15. The
same ratio of products, but with a lower total yield (50%)
was obtained when compound 17 was heated in neat
ethyl chloroformate.2
Acknowledgements
Authors wish to acknowledge Mr. Greg Hostetler for
his help with literature search.
References
[1] K. Nagami, T. Imanishi, M. Hanaoka, Heterocycles 12 (1979) 497.
[2] M. Inoue, S. Yasuda, T. Imanishi, M. Hanaoka, Heterocycles 14 (1980)
1791.
[3] K. Nagami, T. Imanishi, M. Hanaoka, Chem. Pharm. Bull. 27 (1979) 1947.
[4] K. Nagami, S. Horima, T. Imanishi, M. Hanaoka, Heterocycles 15 (1981)
297.
[5] H.Z. Ro¨nsch, Phytochem. 16 (1977) 691.
[6] H. Ro¨nsch, Z. Chem. 19 (1979) 447.
[7] S. Teitel, W. Klo¨tzer, J. Borgese, A. Brossi, Can. J. Chem. 50 (1972) 2002.
[8] M. Shamma, The Isoquinoline Alkaloids, Academic Press, New York,
1972, p. 486.
After completion of our previous efforts, we located
compound 17 from our chemical library [8]. Interest-
ingly, the treatment of compound 17 in acetone with
ethyl chloroformate in the presence of sodium iodide
generated both compounds 18 and 19 in 5:1 ratio, in a
total yield of 90% (Scheme 4). Both of them were
2
Compound 15. To
a
solution of compound
8
(0.106 g,
0.3 Â 10À3 mmol) in acetone (10 mL) at room temperature was slowly
added a mixture of sodium iodide (0.45 g, 3 Â 10À3 mmol) in acetone
(15 mL) followed by drop wise addition of ethyl chloroformate (2 mL) in a
dark chamber. The reaction mixture was stirred overnight, concentrated
and partitioned between water (20 mL) and Et2O (3 Â 20 mL). The
combined organic layer was dried (MgSO4), concentrated and purified via
preparative chromatography (eluant: 1% MeOH in CH2Cl2) to generate
compound 15 (0.115 g, 90%) as a colorless oil. 1H NMR (200 MHz; CDCl3)
d
1.32 (t, J 7.1 Hz, 3H, –COOCH2CH3), 2.18–3.62 (m, 8H), 3.85 (s, 3H, –OCH3),
3.89 (s, 3H, –OCH3), 4.19 (q, J 7.1 Hz, 2H, –COOCH2CH3), 5.96 (s, 2H, –
OCH2O–), 6.71 (s, 1H, ArH), 6.80 (s, 1H, ArH), 6.81 (d, J 13.5 Hz, 1H, –
CH5CH–), 6.82 (d, J 8.5 Hz, 1H, ArH), 6.85 (d, J 13.5 Hz, 1H, –CH5CH–),
7.06 (d, J 8.5 Hz, 1H, ArH). MS. m/e 426 (M+H).
Compound 16. A solution of compound 15 (0.043 g, 0.1 Â 10À3 mmol)
in anhydrous Et2O (10 mL) was slowly added to a refluxing suspension of
lithium aluminum hydride (0.015 g, 0.4 Â 10À3 mmol) in anhydrous Et2O
(100 mL). Heating was continued for another 1 h. After cooling to 0 8C, the
reaction mixture was carefully quenched with the slow addition of a
saturated aq. Na2SO4 solution. The supernatant was decanted and the
inorganic residue was well-washed with Et2O (3 Â 10 mL). The combined
organic layer was washed successively with water and brine, dried
(MgSO4), concentrated and purified via preparative chromatography
(eluant: 90% CH2Cl2 10% 7 N methanolic ammonia) to generate compound
17 as a colorless oil (0.030 g, 80%). 1H NMR (200 MHz; CDCl3)
d 2.37 (s, 3H,
–NCH3), 3.83 (s, 3H, –OCH3), 3.88 (s, 3H, –OCH3), 5.93 (s, 2H, –OCH2O-),
6.67 (s, 1H, ArH), 6.79 (d, J 8.4 Hz, 1H, ArH), 6.82 (d, J 16.2 Hz, 1H, –
CH5CH–), 6.88 (s, 1H, ArH), 6.89 (d, J 16.2 Hz, 1H, –CH = CH–), 7.05 (d, J
8.4 Hz, 1H, ArH). MS. m/e 368 (M+H).