Synthesis of a novel tetracyclic azaindolo[2,1-c][1,4]benzoxazine ring system

Article abstract of DOI:10.1016/j.tetlet.2011.02.020

Synthesis of a series of novel fused tetracyclic mono- and diazaindolo[2,1-c][1,4]benzoxazine heterocyclic compounds 3a-o has been achieved in a two-step one-pot reaction set up starting from commercially available or easily accessible inputs. For example

Full text of DOI:10.1016/j.tetlet.2011.02.020

Tetrahedron Letters 52 (2011) 1874–1877
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Tetrahedron Letters
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Synthesis of a novel tetracyclic azaindolo[2,1-c][1,4]benzoxazine ring system
Santosh Kurhade a, Rahul D. Kaduskar a, Bhavesh Dave a, Parimi Atchuta Ramaiah b, Venkata P. Palle a,
Debnath Bhuniya a,
⇑
a Drug Discovery Facility, Advinus Therapeutics Ltd, Quantum Towers, Plot-9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune 411 057, India
b Department of Organic Chemistry, Andhra University, Visakhapatnam 530 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a series of novel fused tetracyclic mono- and diazaindolo[2,1-c][1,4]benzoxazine heterocy-
clic compounds 3a–o has been achieved in a two-step one-pot reaction set up starting from commercially
available or easily accessible inputs. For example, reaction of di-lithiated (N-Boc)-2-amino-3-methylpyr-
idine Li2–2a with Weinreb amide of 2-(2,4-difluorophenoxy)-2,2-dimethylacetic acid 1a, followed by TFA
treatment furnished the tetracyclic compound 3a, which is essentially a fusion of 7-azaindole and 3,4-
dihydro[1,4]benzoxazine, in 70% isolated yield. A competitive elimination by-product 4a was also
observed (24% isolated yield) in this case. Based on our initial results, a structural basis and molecular
mechanism have been suggested to explain these two parallel reactions. Consequently, with appropriate
structural tuning of 1, formation of the individual products can be controlled.
Received 16 December 2010
Revised 1 February 2011
Accepted 7 February 2011
Available online 4 March 2011
Keywords:
Azaindolo[2,1-c][1,4]benzoxazine
Diazaindolo[2,1-c][1,4]benzoxazine
(N-Boc)-2-amino-3-methylpyridine
2-(2,4-Difluorophenoxy)-2,2-dimethylacetic
acid
Ó 2011 Elsevier Ltd. All rights reserved.
Weinreb amide
Design and effective synthesis of new fused heterocyclic sys-
tems are highly appreciated in medicinal chemistry as often very
specific drug–receptor interactions are achieved through pre-dis-
posing such heterocycles in the molecular design.1 While working
in medicinal chemistry, we embarked on the synthesis of a fused
tetracyclic ring system, for example, 3a (Scheme 1) which is essen-
from (N-Boc)-2-amino-3-picoline 2a, with Weinreb amide of 2-
(2,4-difluorophenoxy)acetic acid 1a (Scheme 1, Eq. 3).
Reaction6,7 of Weinreb amide of 2-(2,4-difluorophenoxy)acetic
acid 1a with di-lithium salt of (N-Boc)-2-aminopicoline Li2–2a at
low temperature, followed by a treatment with excess TFA indeed
furnished the benzoxazino derived tetra cyclic ring system 3a8 in
70% isolated yield along with minor amounts (24% isolated yield)
of 2-alkenyl azaindole 4a9 as an eliminated product (Scheme 2).
Independent reaction of 1a with Li2–2a, and omitting the TFA
treatment led to isolation of intermediates 6a10 and 7a (70% and
25% isolated yield), presumably via the formation of a common
intermediate like 5. Thus, the formation of 6a can be explained
via an initial nucleophilic substitution at Weinreb amide carbonyl
center (in 1a) triggered by the lithiated carbanion (of 2a) to form
the reactive intermediate 5a, followed by an intramolecular aro-
matic nucleophilic substitution of fluoride by carbamate nitrogen
centered anion (indicated by blue colored arrow movements). A
competitive nucleophilic attack of the carbamate anion onto car-
bonyl-carbon in structure 5a can explain the formation of the
2-hydroxy-azaindoline intermediate 7a (indicated by red colored
arrow movement). Subsequent treatment of intermediates 6a and
7a with excess TFA furnished 3a and 4a, respectively in quantita-
tive yield, presumably via deprotection of N-Boc group to form
intermediates 8 and 9, followed by TFA-mediated elimination of
water in case of 8, and of water as well as 2,4-difluorophenol in
case of 9 (Scheme 2).
tially
a fusion of two well known heterocycles: 3,4-dihy-
dro[1,4]benzoxazine2 and pyrrolo[2,3-b]pyridine (7-azaindole).3
To the best of our knowledge, synthesis of such heterocyclic core
is unprecedented in the literature.
Synthetic strategy for such fused ring systems was derived from
two independent methodologies known in the literature. The first
one is the synthesis of pyrrolo[2,1-c][1,4]benzoxazines via intra-
molecular nucleophilic substitution of aromatic fluoride as ele-
gantly demonstrated by Pujol’s group (Scheme 1, Eq. 1).4 The
second one is from Hands et al. who have described the syntheses
of 2-substituted-6-azaindoles via condensation of Li2-(N-Boc)-3-
amino-4-picoline with appropriately chosen Weinreb amides
(Scheme 1, Eq. 2).5a Subsequently, this methodology has been very
effectively modified by Song et al. to synthesize a variety of 2-
substituted-azaindole analogs essentially in one-pot two-step syn-
thesis.5b,c Based on the above literature, we envisaged that a fused
tetracyclic 7-azaindolo[2,1-c][1,4]benzoxazine scaffold as in 3a
could be obtained from reactions of di-lithiated reagent, generated
Interestingly, the reaction of 1b with Li2–2a followed by TFA
treatment, as shown in Scheme 2, led to exclusive formation of
⇑
Corresponding author. Tel.: +91 20 66539600; fax: +91 20 66539620.
E-mail address: debnath.b@advinus.com (D. Bhuniya).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.020

S. Kurhade et al. / Tetrahedron Letters 52 (2011) 1874–1877
1875
ing the described typical procedure.6 Based on the results (Table 1,
entries 1–10), we infer that an additional halogen (X = F, Cl) substi-
tution para to 2-fluorophenoxy moiety (X in structure 1) was nec-
essary to promote an intramolecular aromatic nucleophilic
substitution of the 2-fluoro group to construct the 1,4-benzoxazine
core as otherwise exclusive elimination product 4a was formed
from substrates like 1b, 1c, and 1e (entries 2, 3 and 5). We rational-
ize that the para halogen substitution could offer the phenoxy ring
the required electron deficiency to trigger the aromatic nucleo-
philic substitution reaction at its ortho-F position. Unfortunately,
non-halogen and strong electron withdrawing substitutions like
–NO2, –CN, –SO2Me led to uncontrolled reactions (data not shared
here), otherwise the hypothesis could have been confirmed further.
It was encouraging to note that the methodology provided us
consistent results even when R1 and R2 groups were varied from
di-methyl to either mono or unsubstituted cases (compare entry
1 vs 7–8, 13; examples 3a vs 3g–h, 3m, respectively) or to cyclic
substitutions like 1,6-cyclohexylene and 1,5-cyclopentylene (com-
pare entry 1 vs 9–10; examples 3a vs 3i–j, respectively).
NaH, DMF,
60 oC, 12h
N
O
N
F
78%
HO
Eq. 1: Intramolecular aromatic nucleophilic substitution
(Pujol et al.; Ref: 4)
1. THF, -30 oC to RT
N
O
N
2. 5.5 M HCl
OMe
+
Ph
N
HN
50% (2 steps)
Me
Boc
N
CH2Li
Li
Ph
Eq. 2: Pyrrole ring construction (Hands, D. et al.; Ref: 5a)
N
O
F
N
N
OMe
O
5
+
6
10
N
N
F
3a
4
3
Me
Boc
Me
F
H
2a
7
2
9
O
1
Another structural feature, namely, the gem-di-substitution (R1
and R2 in 1) was found to be critical toward the formation of phe-
nol-eliminated side product, for example, 4a, 4d–g, 4i. On the con-
8
1a
Eq. 3: Synthetic strategy adopted in the present work
trary, 1g with one
a-CH led to 2-(1-hydroxyethyl)azaindole 4b as
Scheme 1. Conceiving the idea.
side product (compare entry 7 vs 1). In case of 1h, having no
a-
C-substitutions (R1 = R2 = H), the phenolic group remained intact
in the by-product, for example, 4c and 4h. These observations
are explained in Scheme 3 by invoking oxonium and carbonium
intermediates 10 and 11, and following fundamental principles of
reaction mechanism for elimination versus substitution pathways.
To address the suitability of the methodology for structural
diversity in 2, two more analogs 2b and 2c were considered (op-
tional nitrogen in place of u, v, w as shown in Table 1, entries
11–15). As illustrated in entries 11–14, di-lithiated 2b and 2c re-
acted with 1a, 1e, and 1h (only representative combinations
the eliminated product 4a. This was also independently confirmed
by the isolation of intermediate 7b11 exclusively in the absence of
TFA treatment. We explain this result by invoking that, for 1b, aro-
matic ring could be deactivated for nucleophilic substitution when
X is H.
To explore the synthetic utility of the above mentioned new
protocol, several Weinreb amides of optionally
a-substituted 2-
(2-fluorophenoxy)acetic acids (1c–h or 1i–j, respectively; Table 1)
were reacted with (N-Boc)-2-amino-3-methylpyridine 2a follow-
O
n-BuLi (2.5 eq.), THF,
O
N
H
2a
N
-15 oC, 30 min.
1. THF, -15 oC to RT, 90 min.
N
Li
2. TFA (excess), CH2Cl2,
0 oC to RT, 30 min.
N
F
O
Li
O
N
N
H
O
O
+
N
+
F
O
O
N
N
One pot
X
4a
Li2-2a
-H2O
3a
1
N
N
OH
X
-H2O
TFA
HN
O
THF, -15 oC to RT,
90 min.
HN
F
H
OH
O
O
TFA
O
O
X
X
H
F
8
Li
O
N
N
9
O
N
N
H
O
N
O
N
+
O
OH
O
7 (% yield)
7a (25)
6 (% yield)
6a (70)
1
O
F
O
H
1a
1b
X
X=F
X=H
F
O
X
7b (85)
6b (00)
6
7
5
X
Scheme 2. Synthesis of 7-azaindolo[2,1-c][1,4]benzoxazine in a model reaction set up.

1876
S. Kurhade et al. / Tetrahedron Letters 52 (2011) 1874–1877
Table 1
Diverse examples generated from reactions between 1a–j and 2a–ca
V
U
1. THF, -15 oC to RT,
90 min.
W
W
Li
F
Y
O
V
2. TFA (excess), CH2Cl2,
X
Y
N
0 oC to RT, 30 min.
OMe
Li
W
U
O
U
O
N
+
R2
R2
R1
R1
+
N
H
O
R3
Me
V
O
N
z
X
z
4a-i
Li2-2a-c
1a-j
3a-o
Entry
1
X, Y, Z
R1, R2
2
U, V, W
3 (yield, %)b
R3
4 (yield, %)b
1
2
1a
1b
F, H, H
H, H, H
Me, Me
Me, Me
2a
2a
N, CH, CH
N, CH, CH
3a (70)c
3b (00)
4a (24)c
4a (84)
3
1c
H, F, H
Me, Me
2a
N, CH, CH
3c (00)
4a (85)
4
5
6
1d
1e
1f
F, H, F
H, H, F
Cl, H, H
Me, Me
Me, Me
Me, Me
2a
2a
2a
N, CH, CH
N, CH, CH
N, CH, CH
3d (70)c
3e (00)
3f (65)
4a (20)
4a (80)
4a (30)
Me
7
1g
F, H, H
Me, H
2a
N, CH, CH
3g (70)
4b (25)
OH
O
8
1h
F, H, H
H, H
2a
N, CH, CH
3h (73)
4c (22)
F
F
9
10
11
1i
1j
1a
F, H, H
F, H, H
F, H, H
–(CH2)5–
–(CH2)4–
Me, Me
2a
2a
2b
N, CH, CH
N, CH, CH
CH, N, CH
3i (75)c
3j (75)
4d (20)c
4e (20)
4f (20)
3k (70)c
12
13
1a
1e
F, H, H
H, H, F
Me, Me
Me, Me
2c
2c
N, CH, N
N, CH, N
3l (74)
3m (00)
4g (15)
4g (85)
O
F
14
15
1h
1j
F, H, H
F, H, H
H, H
2c
2c
N, CH, N
N, CH, N
3n (70)
3o (20)
4h (23)
4i (72)
F
–(CH2)4–
a
b
c
Reactions were carried out following the typical procedure described in Ref. 6.
% Yields are the isolated yields of analytically pure products after column chromatography or prep. TLC.
For analytical data of these representative examples, please see: Refs. 8,9,12–15.
Elimination
chosen) in an expected fashion. For substrates with X = F, the tetra-
cyclic compounds 3k–l, 3n were obtained in 70–74% isolated
yields along with the respective side products 4f–h in 15–23% iso-
lated yields (entries 11–12, 14). Once again, in the case of X = H, 4g
was found to be the exclusive product (entry 13). Unfortunately
the reaction of 2c with 1j led to elimination as a major path as
shown in entry 15 (4i; 72%) which was surprising in the light of
the result from entry 10.
by-product
N
H
4a
N
H+
R1=R2=H
TFA
R1=R2=Me
N
N
At this preliminary stage of developing this new methodology,
we believe that this Letter will provide synthetic chemists an easy
access to these novel tetracyclic mono- and diazaindolo[2,1-
c][1,4]benzoxazine heterocycles. In addition, an appropriate sub-
strate choice will also allow the chemists to use this methodology
for quick synthesis of 2-(isopropenyl)azaindole and its analogs.
HN
TFA
R2
R1
HN
R1
H O
+
R2
+
F
OH
F
11
R1=Me; R2=H
H2O
H+
F
Acknowledgments
10
F
Authors are grateful to Drs. Rashmi Barbhaiya, and Kasim A.
Mookhtiar for their support and encouragement. S.K. would like
to thank Professor Y. L. N. Murthy (Andhra University) for his help.
Mahesh Mone (Analytical Dept.), Drs. D. Srinivas Reddy and Umesh
Singh are being acknowledged for various help during this work.
Advinus Publication No. ADV-A-011.
Substituted
by-product
HO
N
H
4b
N
Scheme 3. Effect of R1 and R2 on the nature of by-product 4.

S. Kurhade et al. / Tetrahedron Letters 52 (2011) 1874–1877
1877
42.28, 82.75, 86.56, 114.79 (d, J = 23.1 Hz), 116.83 (d, J = 23.8 Hz), 123.72,
126.42 (d, J = 8.9 Hz), 132.20, 136.06 (d, J = 9.7 Hz), 138.89, 146.08, 148.26,
152.70, 159.30 (d, J = 243.2 Hz), 206.29 (2C). HPLC purity: 100%. LC–MS (m/z):
387.1 [M+1]. HRMS calcd for the [M+1]+: 387.1720, found: 387.1722.
11. Compound 7b: 2-[1-(2-Fluoro-phenoxy)-1-methyl-ethyl]-2-hydroxy-2,3-dihydro-
pyrrolo[2,3-b]pyridine-1-carboxylic acid, tert-butyl ester. Rf-value: 0.35 (30%
ethyl acetate in hexanes). Mp: 52–53 °C. 1H NMR (400 MHz; DMSO-d6;
assignment given for major rotamer): d 1.36 (s, 9H), 1.41 (s, 6H), 4.20 (s,
2H), 7.05–7.15 (aromatics, 3H), 7.21 (dd, J = 7.3, 4.9 Hz, 1H), 7.24–7.30
(aromatics, 1H), 7.61 (d, J = 7.3 Hz, 1H), 8.26 (d, J = 4.9 Hz, 1H), 9.11 (s, 1H).
13C NMR (100 MHz; CD3OD): d 24.18 (2C), 28.63 (3C), 40.24, 81.48, 87.79,
117.53, 117.74, 122.82, 125.56, 125.90 (d, J = 7.0 Hz), 127.95, 142.58, 143.28 (d,
J = 3.8 Hz), 147.79, 151.29, 155.60, 157.17 (d, J = 243.9 Hz), 210.21. HPLC
purity: 99%. LC–MS (m/z): 389.1 [M+1]. HRMS calcd for the [M+1]+: 389.1876,
found: 389.1876.
12. Compound 3d: 7-Azaindolo[2,1-c]-(6,8-difluoro-2,2-dimethyl)-[1,4]benzoxazine.
Rf-value: 0.7 (30% ethyl acetate in hexanes). Mp: 59–60 °C. 1H NMR (400 MHz;
CDCl3): d 1.75 (s, 6H), 6.37 (s, 1H), 6.71 (dt, J = 10.3, 3.0 Hz, 1H), 7.17 (dd, J = 7.7,
4.8 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 3.5 Hz, 1H), 8.74 (app. d,
J = 10 Hz, 1H). 13C NMR (100 MHz; CDCl3): d 27.04 (2C), 75.82, 96.02, 100.38
(dd, J = 27.1, 21.6 Hz), 101.89 (dd, J = 28.6, 3.0 Hz), 118.02, 122.17, 128.12 (dd,
J = 14, 5.4 Hz), 128.30, 129.46 (m, 1C), 139.15, 143.87, 147.84, 152.54 (dd,
J = 244.6, 13.9 Hz), 156.79 (dd, J = 238.5, 12.4 Hz). HPLC purity: 99%. LC–MS (m/
z): 287.2 [M+1]. Structure of 3d was further confirmed using single crystal X-
ray analysis (CCDC-785444; www.ccdc.cam.ac.uk). The ORTEP view is shown
here:
Supplementary data
A complete list of analytical characterization data of 3a, 3d, 3f–l,
3n, 3o, 4a–i, 6a, 7a and 7b, and single crystal X-ray crystallo-
graphic data of 3d. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2011.
02.020.
References and notes
1. For reviews and conceptual articles on heterocycle and drug design, please see:
(a) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887–2893; (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930; (c) Andrews,
P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648–1657; (d) Broughton,
H. B.; Watson, I. A. J. Mol. Graphics Modell. 2005, 23, 51–58.
2. (a) Ilas, J.; Anderluh, P. S.; Dolenc, M. S.; Kikelj, D. Tetrahedron 2005, 61, 7325–
7348; (b) Bromidge, S. M.; Arban, R.; Bertani, B.; Bison, S., et al J. Med. Chem.
2010, 53, 5827–5843.
3. (a) Popowycz, F.; Routier, S.; Joesph, B.; Mérour, J.-Y. Tetrahedron 2007, 63,
1031–1064; (b) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120–1132.
4. Sánchez, I.; Pujol, M. D. Tetrahedron 1999, 55, 5593–5598.
5. (a) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.; Wright, S. H.
B. Synthesis 1996, 877–882; (b) Song, J. J.; Tan, Z.; Reeves, J. T.; Fandrick, D. R.;
Lee, H.; Yee, N. K.; Senanayake, C. H. Tetrahedron Lett. 2009, 50, 3952–3954; (c)
Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.; Senanayake, C. H. J. Org. Chem.
2005, 70, 6512–6514.
6. In a typical synthesis, n-BuLi (1.6 M in hexane, 3.75 mL, 7.21 mmol, 2.5 equiv)
was added dropwise to a solution of (N-Boc)-2-aminopicoline 2a (500 mg,
2.40 mmol, 1 equiv) in 10 mL dry THF at À15 °C to generate the di-anion (dark
red appearance). After stirring for 30 min, 2-(2,4-difluorophenoxy)-N-methoxy-
N-methyl-2-methylpropionamide 1a (560 mg, 2.16 mmol, 0.9 equiv), dissolved
in 5 mL dry THF, was added to the reaction mixture followed by continuation of
stirring for 1.5 h (À15 °C to rt). The reaction mixture was concentrated to
remove THF; the resultant mass was then taken in dry dichloromethane (5 mL)
and was treated with 5 mL TFA at 0 °C. The reaction mixture was stirred at rt
for 30 min to de-protect the N-Boc group and promote cyclization and
elimination process. The resultant reaction mixture was concentrated and
neutralized with aq satd NaHCO3 solution. The organic mass was extracted
with ethyl acetate (20 mL Â 3). The combined organic layer was given a brine
wash (50 mL), dried over anhydrous sodium sulfate, and finally concentrated
on rotavapour to afford the crude product, which was then purified by silica-
gel column chromatography (60–120 mesh, eluents: hexanes to 30% ethyl
acetate in hexanes) to obtain analytically pure 3a (406 mg, 70%) along with
minor amount of 2-(propen-2-yl)-7-azaindole 4a (70 mg, 24%).
7. In addition to Ref. 5, the below literature was consulted to come up with the
typical procedure described here in Ref. 6: Caulkett, P. W. R.; Mckerrecher, D.;
Newcombe, N. J.; Pike, K. G.; Robb, G. R.; Waring, M. J. in PCT Publication No.
WO 2007/031739 A1.
13. Compound 3i: 7-Azaindolo[2,1-c]-(6-fluoro-2,2-spirocyclohexyl)-[1,4]benzoxazine.
Rf-value: 0.7 (30% ethyl acetate in hexanes). Semi-solid mass. 1H NMR
(400 MHz; CDCl3):
d 1.63–1.70 (m, 2H), 1.72–1.86 (m, 6H), 2.12–2.16
8. Compound 3a: 7-Azaindolo[2,1-c]-(6-fluoro-2,2-dimethyl)-1,4]benzoxazine. Rf-
value: 0.7 (30% ethyl acetate in hexanes). Semi-solid mass. 1H NMR (400 MHz;
CDCl3): d 1.70 (s, 6H), 6.34 (s, 1H), 6.80 (dt, J = 8.5, 3.0 Hz, 1H), 6.99 (dd, J = 8.8,
5.0 Hz, 1H), 7.15 (dd, J = 7.8, 4.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 8.39 (dd,
J = 4.8, 1.7 Hz, 1H), 8.89 (dd, J = 10, 3.2 Hz, 1H). 13C NMR (100 MHz; CDCl3): d
26.90 (2C), 74.61, 95.05, 106.23 (d, J = 29.4 Hz), 110.96 (d, J = 23.2 Hz), 117.49,
118.48 (d, J = 8.5 Hz), 122.02, 126.75 (d, J = 11.6 Hz), 128.89, 139.28, 140.30 (d,
J = 3.1 Hz), 143.40, 147.50, 157.78 (d, J = 237.70 Hz). HPLC purity: 99%. LC–MS
(m/z): 269.2 [M+1] base peak. HRMS calcd for the [M+1]+: 269.1090, found:
269.1086.
9. Compound 4a: 2-Isopropenyl-1H-pyrrolo[2,3-b]pyridine. Rf-value: 0.35 (30%
ethyl acetate in hexanes). Mp: 65–66.5 °C. 1H NMR (400 MHz, DMSO-d6): d
2.11 (s, 3H), 5.15 (s, 1H), 5.76 (s, 1H), 6.49 (d, J = 2.0 Hz, 1H) 7.01 (dd, J = 8.0,
5.2 Hz, 1H), 7.88 (dd, J = 7.6, 1.2 Hz, 1H), 8.18 (dd, J = 5.2, 1.6 Hz, 1H), 11.79 (br
s, 1H). 13C NMR (100 MHz; DMSO-d6): d 20.50, 99.03, 113.05, 116.07, 120.92,
128.36, 134.70, 139.69, 143.56, 149.96. HPLC purity: 99%. LC–MS (m/z): 159.1
[M+1] base peak.
(m, 1H), 2.16–2.21 (m, 1H), 6.33 (s, 1H), 6.80 (dt, J = 8.4, 2.9 Hz, 1H), 7.05
(dd, J = 8.8, 5.6 Hz, 1H), 7.15 (dd, J = 7.6, 4.8 Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz,
1H), 8.39 (dd, J = 4.8, 1.4 Hz, 1H), 8.86 (dd, J = 10, 2.8 Hz, 1H). 13C NMR
(100 MHz; CDCl3):
d 21.08 (2C), 25.21, 34.28 (2C), 75.31, 94.95, 106.15
(d, J = 29.4 Hz), 110.70 (d, J = 23.0 Hz), 117.24, 118.28 (d, J = 8.6 Hz), 121.95,
127.02 (d, J = 12.4 Hz) 128.67, 139.69, 139.74, 143.17, 147.26, 157.65
(d, J = 236.8 Hz). HPLC purity: 99%. LC–MS (m/z): 309.2 [M+1]. HRMS calcd
for the [M+1]+: 309.1403, found: 309.1417.
14. Compound 4d. 2-Cyclohex-1-enyl-1H-pyrrolo[2,3-b]pyridine. Rf-value: 0.40 (30%
ethyl acetate in hexanes). Mp: 89–91 °C. 1H NMR (400 MHz; CDCl3): d 1.68–
1.76 (m, 2H), 1.78–1.84 (m, 2H), 2.28–2.34 (m, 2H), 2.45–2.52 (m, 2H), 6.37 (s,
1H), 6.37–6.41 (m, 1H), 7.02 (dd, J = 7.8, 4.8 Hz, 1H), 7.84 (dd, J = 7.8, 1.3 Hz,
1H), 8.20 (dd, J = 4.8, 1.3 Hz, 1H), 10.5 (br s, 1H). 13C NMR (100 MHz; CDCl3): d
22.17, 22.56, 25.71, 25.81, 96.25, 115.61, 122.11, 125.06, 128.16, 129.03,
141.12, 141.50, 149.42. HPLC purity: 98%. LC–MS (m/z): 199.0 [M+1]. HRMS
calcd for the [M+1]+: 199.1235, found: 199.1228.
15. Compound 3k. 6-Azaindolo[2,1-c]-(6-fluoro-2,2-dimethyl)-[1,4]benzoxazine. Rf-
value: 0.6 (30% ethyl acetate in hexanes). Mp: 91–92 °C. 1H NMR (400 MHz;
acetone-d6): d 1.72 (s, 6H), 6.68 (s, 1H), 7.00 (dt, J = 8.6, 2.7 Hz, 1H), 7.18 (dd,
J = 8.8, 5.4 Hz, 1H), 7.63 (d, J = 4.9 Hz, 1H), 7.91 (dd, J = 9.3, 2.9 Hz, 1H), 8.33 (d,
J = 4.9 Hz, 1H), 9.42 (s, 1H). 13C NMR (100 MHz; acetone-d6): d 26.01 (2C),
75.26, 97.30, 104.53 (d, J = 28.7 Hz), 111.24 (d, J = 22.4 Hz), 115.48, 119.71 (d,
J = 9.3 Hz), 127.13 (d, J = 10.8 Hz), 131.36, 133.89, 134.74, 140.62, 141.21 (d, J
=3.1 Hz), 143.07, 157.89 (d, J = 236.9 Hz). HPLC purity: 99%. LC–MS (m/z): 269.0
[M+1]. HRMS calcd for the [M+1]+: 269.1090, found: 269.1079.
10. Compound 6a. 11-Fluoro-7,7-dimethyl-6-oxo-6,7-dihydro-5H-8-oxa-1,13-diaza-
dibenzo[a,d]cyclononene-13-carboxylic acid, tert-butyl ester. Mp: 58–60 °C. Rf-
value: 0.4 (30% ethyl acetate in hexanes). 1H NMR (400 MHz; CDCl3): d 1.32 (s,
3H), 1.42 (s, 3H), 1.46 (s, 9H), 3.73 (br s, 1H), 4.25 (br s, 1H), 6.82–6.88
(aromatics, 3H), 7.22 (dd, J = 7.4, 4.9 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 8.35 (d,
J = 4.6 Hz, 1H). 1H NMR (400 MHz; DMSO-d6): d 1.38 (br s, 15H), 3.96 (br s, 1H),
4.10 (br s, 1H), 6.98 (dd, J = 8.8, 5.8 Hz, 1H), 7.05 (dt, J = 9.1, 3.2 Hz, 1H), 7.32
(dd, J = 9.3, 3.0 Hz, 1H), 7.30–7.38 (aromatics, 1H), 7.87 (d, J = 7.4 Hz, 1H), 8.26
(br. d, J = 2.0 Hz, 1H). 13C NMR (100 MHz; CDCl3): d 23.24, 26.49, 28.47 (3C),