Synthesis and Oxidative Cleavage of Oxazinocarbazoles: Atropselective Access to Medium-Sized Rings

Article abstract of DOI:10.1055/s-0034-1378530

Polycyclic systems can be converted into medium-sized-ring-containing compounds through the controlled oxidative cleavage of internal double bonds. This approach is particularly accessible in systems that contain a suitably substituted indole ring. Here, a robust approach to the synthesis of the understudied oxazinocarbazole system is reported. After regioselective incorporation of a carbonyl functional group, m-chloroperoxybenzoic acid (MCPBA) is used to cleave the indole 2,3-double bond that this system contains. This results in a competition between two processes, oxidative cleavage of the double bond and a pinacol-type rearrangement, both of which occur with very high diastereoselectivity. The balance between the two processes is studied as a function of the substrate structure. Extensive use of X-ray crystallographic analysis of the products enables detailed mechanistic conclusions to be drawn.

Full text of DOI:10.1055/s-0034-1378530

2808▌
PAPER
paper
Synthesis and Oxidative Cleavage of Oxazinocarbazoles: Atropselective
Access to Medium-Sized Rings
Synthesis and Oxidative Cleavage of Oxazinocarbazoles
Gu Liu,1 Christopher S. Lancefield,1 Magali M. Lorion, Alexandra M. Z. Slawin, Nicholas J. Westwood*
School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife,
UK
Fax +44(1334)462595; E-mail: njw3@st-andrews.ac.uk
Received: 27.03.2014; Accepted after revision: 27.06.2014
Dedicated to Professor Philip D. Magnus on the occasion of his 70th birthday
conditions to afford α-functionalised ketones 5 (n = 1–3).
Abstract: Polycyclic systems can be converted into medium-sized-
Japp–Klingemann modified Fisher indole synthesis9 us-
ring-containing compounds through the controlled oxidative cleav-
ing a range of anilines gave carbazol-1-ones 6b–j10a,11 via
age of internal double bonds. This approach is particularly accessi-
ble in systems that contain a suitably substituted indole ring. Here,
the corresponding hydrazones 7b–j10 in reasonable yields,
a robust approach to the synthesis of the understudied oxazinocar- with the exception of 6f12 (see Table 1 for substituent and
bazole system is reported. After regioselective incorporation of a
carbonyl functional group, m-chloroperoxybenzoic acid (MCPBA)
ring size). Selective N-alkylation of 6a–j under biphasic
reaction conditions gave 8a–j in good yields.10,11 Subse-
is used to cleave the indole 2,3-double bond that this system con-
quent reduction of 8a–j with NaBH4 led to the formation
tains. This results in a competition between two processes, oxida-
of the morpholine ring in one pot to give oxazinocarba-
tive cleavage of the double bond and a pinacol-type rearrangement,
zoles 2a–j.
both of which occur with very high diastereoselectivity. The bal-
ance between the two processes is studied as a function of the sub-
strate structure. Extensive use of X-ray crystallographic analysis of
the products enables detailed mechanistic conclusions to be drawn.
O
N
5+n
R
Key words: atropisomerism, diastereoselectivity, macrocycles, ep-
oxidation, heterocycles
n
n
N
N
N
N
O
O
R
1
2
Pyrazinocarbazoles of general structure 1 (Figure 1) are of
interest because of their reported biological activity, in
particular as monoamine oxidase A inhibitors.2 Given the
interest shown in this type of compound, it is perhaps sur-
prising that there are relatively few reports on the synthe-
sis and biological characterisation of the related
oxazinocarbazole systems with general structure 2.3 Here,
we address this issue and show that, as well as being inter-
esting molecules in their own right, oxazinocarbazoles
can be converted into substrates of a highly diastereose-
lective oxidative cleavage reaction.
3
Figure 1 Structures of the pyrazino- and oxazino-carbazole systems
1 and 2, respectively, and the polycyclic system 3, which was the fo-
cus of our recent asymmetric oxidative cleavage studies8
Use of the Corey–Bakshi–Shibata (CBS) catalyst enabled
asymmetric reduction of 8c to 9c in high yield and 98% ee
as judged by chiral HPLC analysis (Scheme 1 and
Figure S1).13 Subsequent cyclisation of 9c using potassi-
um tert-butoxide gave highly optically enriched (R)-2c.
The absolute configuration of 2c (and hence 9c) prepared
by this route was assigned based on the X-ray crystallo-
graphic analysis of 11c derived from (R)-2c as discussed
in more detail below. Oxazinocarbazole analogues con-
taining a five-membered ring (n = 0 in general structure 2,
Figure 1) could not be prepared by this route, with forma-
tion of the morpholine ring in the final step proving unsuc-
cessful (Scheme S1).
Oxidative cleavage of the indole 2,3-double bond has
been achieved by using a wide range of reagents including
ozone, metal-based and electrocatalytic methods, hyper-
valent iodine reagents, peroxidases, molecular oxygen
and peracids such as m-chloroperoxybenzoic acid
(MCPBA).4–6 In our case, MCPBA was used. Whilst exploring
the scope of this reaction, we observed a competing rear-
rangement reaction for some substrates.7 This work ex-
tends our previous studies on the oxidative cleavage of
compounds of general structure 3, providing additional in-
formation on the mechanism of this type of reaction.8
Having established a robust route to 2, we next explored
oxidation of the C(5+n) position in 2 (Figure 1). 2,3-Di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated
oxidation14 of 2a–j resulted in the formation of 10a–j (see
Table 1 for structures and yields) with X-ray crystallo-
graphic studies confirming the structures of a racemic
sample of 10c and its homologue 10h.15
Commercially available cyclic ketones 4 (n = 1–3,
Scheme 1) were treated with ethyl formate under basic
SYNTHESIS 2014, 46, 2808–2814
Advanced online publication: 30.07.2014
DOI: 10.1055/s-0034-1378530; Art ID: ss-2014-n0207-op
© Georg Thieme Verlag Stuttgart · New York
Conversion of 10a into the corresponding nine-mem-
bered-ring-containing compound 11a was achieved in
low yield on reaction with 2.5 equivalents of MCPBA
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PAPER
Synthesis and Oxidative Cleavage of Oxazinocarbazoles
2809
R
that, in all cases where 11 was produced, only one isomer
of 11 was formed and subsequently isolated. This oxida-
tive cleavage reaction is therefore highly diastereoselec-
tive. X-ray crystallographic analysis of 11c15 confirmed
that the relative configuration at C13 (n = 1) and C14 (n =
1) was as shown in Table 1 (Figure 2, A).
O
O
O
N
i
ii
N
OH
n
n
n
H
4
7b–j 57–81%
5
Interestingly, the X-ray crystallographic analysis of 11c
also showed that the amide bond was twisted away from
the expected planar orientation, with a C11a-N12-C13-
O13 torsion angle of 17.9°. When (R)-2c was carried
through the two-step ketone incorporation/oxidative
cleavage sequence, highly optically enriched (R)-11c
(96% ee, Figure S2) was formed in 50% yield when 2.5
equivalents of MCPBA was used. Incorporation of a bro-
R
R
iii
n
n
iv
v
2a–j
67–89%
O
O
N
N
H
6a–j 55–67%
(except 6f)
Br
8a–j
55–66%
for
Br
vi
vii
94%
8c R = Br
(R)-2c
n = 1
Table 1 DDQ-Mediated Oxidation of 2a–j and Oxidative Cleavage
76%, 98% ee
of the Oxazinocarbazole Systema
OH
N
O
O
R
Br
9c
O
n
12+n
N
(5+n)a
O
C
(5+n)
13+n
Scheme 1 Synthesis of 2. Reaction conditions: (i) NaH, ethyl for-
mate, EtOH, THF, 0 °C to r.t., overnight; (ii) aniline, NaNO2, concd
HCl, H2O, 20 min, then 5 in MeOH–H2O–NaOAc, 15 min; yield (%):
7b (81), 7c (75), 7d (76), 7e (69), 7f (57), 7g (83), 7h (73), 7i (79), 7j
(67); (iii) HCl, AcOH, 120 °C, 25 min; yield (%): 6b (67), 6c (64), 6d
(61), 6e (55), 6f (12), 6g (66), 6h (66), 6i (55), 6j (67), 6a (prepared
according to Li and Vince11b in 65% yield); (iv) dibromoethane,
TBAB, 9 M NaOH (aq), r.t., overnight; yield (%): 8a (64), 8b (65), 8c
(55), 8d (61), 8e (62), 8f (65), 8g (65), 8h (66), 8i (64), 8j (64);
(v) NaBH4, EtOH, 60 °C, 6 h; yield (%): 2a (67), 2b (68), 2c (68), 2d
(68), 2e (77), 2f (69), 2g (81), 2h (89), 2i (86), 2j (89); (vi) (S)-oxaza-
borolidine, BH3·DMS, CH2Cl2, –20 °C, 3.5 h, 76%, 98% ee; (vii) t-
BuOH, t-BuOK, r.t., overnight, 94%.
O
R
7+n
i
ii
2a–j
11a–j
n
10+nN
(10+n)a
O
O
O
R
6
10a–j
n
7
H
3O
12e–j
N
Entry 10–12
R
n
MCPBA Yield (%)
(equiv)
10b
11c
12c
1
2
a
a
b
c
c
d
d
e
f
H
H
Cl
Br
Br
I
1
1
1
1
1
1
1
1
1
2
2
3
3
2.5
4.0
2.5
2.5
4.0
2.5
4.0
2.5
2.5
2.5
2.5
2.5
2.5
74
0
19
87
83
50
87
32
83
15
0
0
0
(Table 1, entry 1). However, increasing the number of
equivalents of MCPBA used in this reaction from 2.5 to 4,
resulted in increased conversion and hence significantly
improved isolated yield of 11a (entry 2). In-house purified
MCPBA was used throughout this study. Interestingly, in-
corporation of an 8-chloro substituent in 10b led to a sig-
nificant improvement in the efficiency of the cleavage
reaction, with 11b being formed from 10b in 83% isolated
yield even in the presence of 2.5 equivalents of MCPBA
(entry 3). Ketones 10c–e, 10i and 10j all gave the corre-
sponding oxidatively cleaved products 11c–e, 11i and 11j,
respectively (entries 4–8, 12 and 13). We5g,8 and others16
have reported that compounds containing medium-sized
rings of this general type can exhibit atropisomerism due
to the inability of the carbonyl group [C13 in the case of
11a–e (n = 1), C15 for 11i and 11j (n =3), Table 1] to pass
through the medium-sized ring. In this system, the results
of low-level computational studies were consistent with
this view, suggesting that compounds of type 11 contain
one stereogenic centre at the C13+n position and one axis
of chirality due to restricted rotation about the N-aryl
bond and could therefore exist as two diastereoisomers.
Interestingly, 1H NMR analysis of the crude reaction mix-
tures obtained on treatment of 10 with MCPBA showed
3
15
43
0
0
4
0
5
0
6
66
0
0
7
I
0
8
OMe
NO2
H
63
67
37
35
53
47
15
27
53
61
17
21
9
10
11
12
13
g
h
i
0
Br
0
H
17
23
j
Br
a Reaction conditions: (i) DDQ, THF–H2O, 0 °C to r.t. 2 h; yield (%):
10a (65%), 10b (68), 10c (65), 10d (61), 10e (66), 10f (57), 10g (64);
10h (67), 10i (65), 10j (61); (ii) MCPBA (2.5 or 4.0 equiv), CH2Cl2,
r.t. 18 h.
b Isolated yield of recovered starting material 10.
c Isolated yield of products 11 and/or 12.
© Georg Thieme Verlag Stuttgart · New York
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G. Liu et al.
PAPER
mo- or an iodo-substituent at the C8-position in 10 (n = 1) also achieved in the formation of 12e and 12g–j on reac-
had little observable effect on the outcome of the reaction tion of 12e and 12g–j, respectively.
when four equivalents of MCPBA was used, with 11c and
11d being formed in a similar yield to that of 11a (cf. Ta-
O
O
HO
ble 1, entries 2, 5 and 7). However, when 2.5 equivalents
of MCPBA was used, the reaction conversion followed a
clear trend with Cl > Br > I > H (cf. entries 3, 4, 6, 1). Be-
cause these four reactions were carried out under analo-
gous conditions, it is clear that the incorporation of a C8-
halogen substituent in 10 (n = 1) increased the rate of for-
mation of 11.
R
R
path b
(i)
n
n
N
N
X
X
10 X = O
13 X = O
path a
HO
15 X = CH2, R = Br
O
O
O
X
O
O
O
R
R
O
n
n
N
N
Grob
fragmentation
X
Cl
11a–e, i, j X = O
16 X = CH2, R = Br
14 X = O
Pinacol-type
O
O
rearrangement
R
6
7
X = O
H
3O
N
12e–j
Scheme 2 Proposed mechanism for the formation of 11 and 12 (a–f,
n = 1; g–h, n = 2; i–j, n = 3). Reaction conditions: (i) MCPBA (2.5 or
4.0 equiv), CH2Cl2, r.t. 18 h; see Table 1 for results with 10a–j; 15
was converted exclusively into 16 using MCPBA (2.5 equiv) in 67%
yield
In contrast to other related systems we have studied,8 this
system enables a much clearer picture of the mechanism
of the conversion of 10 into 11 and/or 12 to be deduced.
The formation of 11a–e can be rationalised by initial ep-
oxidation of 10a–e, leading to the formation of iminium
ion 13. Subsequent trapping of 13 with a second equiva-
lent of MCPBA then occurs to give 14, in line with previ-
ous reports of the directed addition of a nucleophile to an
iminium ion (Scheme 2, path a).18 Grob fragmentation can
still occur in 14, with the C6a–C11a bond being able to
adopt an antiperiplanar arrangement with the O–O bond.
This mechanism would predict that the C13 carbonyl
group in, for example 11c, should be anti to the C8-
alkoxy-substituent, which is consistent with the experi-
mental observation (Scheme 2 and Figure 2). The same
high diastereoselectivity was also observed when this re-
action was carried out on 15, an analogue of 10c in which
the oxygen was replaced by a methylene group. The oxi-
dative cleavage reaction of 15 gave exclusively 16
(Scheme 2 and Schemes S2 and S3 for further details of
the preparation of 15 and its conversion into 16). This ob-
servation supports the view that initial attack of MCPBA
on 10 is controlled by the sterically preferred approach of
the reagent from the opposite side to the C3-substituent.
Figure 2 Representations of the X-ray crystallographic analysis of
(A) (R)-11c and (B) 12c. For molecular formulae, crystal data, collec-
tion and analysis methods and selected bond lengths and angles see
the Supporting Information Tables S1–S6
One possible explanation for the role of the C8-halogen is
that mesomeric electron-donation leads to localisation of
additional electron density at N-11 in 10 (n = 1), rendering
the indole C6a–C11 double bond in 10 (n = 1) more elec-
tron-rich and prone to react with MCPBA (see Table 1 for
numbering). Within the halogen series, the observed trend
may reflect the relative ability of the various halogens to
donate electron density in this system.
Interestingly when a strong mesomerically electron-
donating C8-methoxy-substituent was introduced in 10e,
no increase in yield of 11e was observed compared with
the reaction of 10a to give 11a (cf. entries 8 and 1). How-
ever, a second product 12e (Scheme 2) with an unusual
structure17 was also isolated from this reaction. When a
strong electron-withdrawing C8-nitro-substituent was in-
corporated, none of the expected cleavage product 11f
was obtained, with the rearranged product 12f being the
only isolated product (entry 9). X-ray crystallographic
studies confirmed the structure of 12f.15 Detailed analysis
of the 1H NMR spectrum of the crude reaction mixture in-
dicated that the formation of 12f was a highly diastereose-
lective process (Scheme 2). High diastereoselectivity was
For substrates 10e–j, the corresponding rearranged prod-
uct 12e–j was observed either in almost equal quantities to
11 (12e, 12i, and 12j) or as the only product (12f, 12g, and
12h). The stereochemistry at the newly formed quaternary
Synthesis 2014, 46, 2808–2814
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Oxidative Cleavage of Oxazinocarbazoles
2811
in open capillaries with an Electrothermal 9100 melting point appa-
ratus. Values are quoted to the nearest 1 °C and are uncorrected. El-
emental microanalyses were performed with a Carlo Erba CHNS
analyser within the School of Chemistry at the University of St An-
drews. Infrared spectra were recorded with a Perkin Elmer Spec-
trum GX FT-IR spectrophotometer using either thin films on NaCl
plates (NaCl) or KBr discs (KBr) as stated. Absorption maxima are
reported as wavenumbers (cm–1) and intensities are quoted as strong
(s), medium (m), weak (w) and broad (br). Low-resolution (LR) and
high-resolution (HR) electrospray mass spectral (ES-MS) analyses
were acquired by electrospray ionisation (ESI), electron impact (EI)
or chemical ionisation (CI) within the School of Chemistry, Univer-
sity of St Andrews. Low- and high-resolution ESI MS were carried
out with a Micromass LCT spectrometer and low- and high-resolu-
tion CI MS were carried out with a Micromass GCT spectrometer
recorded with a high-performance orthogonal acceleration reflect-
ing TOF mass spectrometer, coupled to a Waters 2975 HPLC. Only
the major peaks are reported and intensities are quoted as percent-
ages of the base peak. NMR spectra were acquired with either a
Bruker Avance 300 (1H, 300 MHz; 13C, 75 MHz), Bruker Avance
400 (1H, 400 MHz; 13C, 100 MHz) or a Bruker Avance 500 (1H, 500
MHz; 13C, 125 MHz) spectrometer, in the deuterated solvent stated.
13C NMR spectra were acquired by using the PENDANT or DEPTQ
pulse sequences. All NMR spectra were acquired by using the deu-
terated solvent as the lock. Coupling constants (J) are quoted in Hz,
and are recorded to the nearest 0.1 Hz. The following abbreviations
are used; s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet
of doublets of doublets; dt, doublet of triplets; t, triplet; m, multi-
plet; q, quartet; quint, quintet; and br, broad.
centre in 12 was assigned based on X-ray crystallographic
analysis of not only 12f, as discussed above, but also 12c
(Figure 2, B), and 12h.15 The formation of 12 can be ra-
tionalised by iminium ion 13 undergoing a pinacol-type
rearrangement with acyl group migration (Scheme 2, path
b). This mechanism is consistent with the highly diastereo-
selective formation of isomer 12. Whilst it is difficult to
rationalise fully the subtle impact of remote substituents
on the formation of 12 (cf. entries 1 with 8 and 9), a dra-
matic difference in behaviour was observed on changing
the size of the C-ring in 10 (Table 1). When n = 2 in 10
(entries 10 and 11) then the only products observed result
from path b, giving 12g and 12h in reasonable yield. This
contrasts with the situation in which n = 1 for 10 (only
cleavage to give 11, entries 1 and 4) and n = 3 for 10 (both
processes, entries 12 and 13). One possible explanation is
that as the size of the C-ring changes subtle steric con-
straints may hinder attack of the second equivalent of
MCPBA and hence block the conversion of 13 into 14.
This, in turn, would be expected to promote the pinacol-
type rearrangement to give 12. The fact that 10c was con-
verted into 12c in 95% yield on reaction with dimethyldi-
oxirane (DMDO), which is an epoxidising agent that is
capable of generating 13 but not converting it into 14, im-
plies that in the absence of a nucleophile (or when nucle-
ophilic attack is slowed for steric reasons) rearrangement
to 12 occurs.
The protocols used for the synthesis of 6 from 4 are known,10,11 with
modifications, and analytical data to support the assigned structures
are provided in the Supporting Information.
Whilst oxidative cleavage of the indole 2,3-double bond
has been extensively studied, it remains rare for complex
substrates that raise interesting stereochemical questions
to be used in this reaction. Here, we address this issue by
using the understudied oxazinocarbazole class of indole-
General Alkylation Procedure
Compound 6 (10.0 mmol) was suspended in 1,2-dibromoethane (10
mL) or 1,3-dibromopropane (10 mL), and 9 M aq NaOH (10 mL)
and tetra-n-butyl ammonium bromide (TBAB; 0.086 g, 3.00 mmol,
0.03 equiv) were added. The mixture was stirred at r.t. for 18 h, then
containing structures. A robust five-step approach to the diluted with CH2Cl2 (30 mL) and H2O (30 mL), the organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(3 × 30 mL). The combined organic extracts were dried over Mg-
SO4, filtered and concentrated in vacuo. The crude product was pu-
rified by flash column chromatography by silica gel (EtOAc–
synthesis of the required substrates 10a–j is described.
These substrates differ in both the nature of the C-8 sub-
stituent and the size of the C-ring. Reaction of 10 with
MCPBA results in almost all cases in the highly diastere-
hexanes, 1:19) to afford product 8. The preparation of 8a–f has been
reported previously.10a,11b Compounds 8g–j are novel, with full
characterisation being provided here for 8j as an example. Analyti-
cal data to support the structural assignment of 8g–i are provided in
the Supporting Information.
oselective oxidative cleavage to deliver medium-sized-
ring-containing compounds 11. The relative stereochem-
istry of these cleaved products enables a detailed mecha-
nistic insight to be gained. In addition, a competing
pinacol-type rearrangement occurs for some substrates,
leading to complex spirocycles of type 12 with high dias-
tereocontrol. Further investigations into the biological ac-
tivity of the reported oxazinocarbazoles, medium-sized-
ring-containing derivatives and spirocycles will be report-
ed in the near future.
2-Bromo-5-(2-bromoethyl)-8,9,10,11-tetrahydro-5H-cyclooc-
ta[b]indol-6(7H)-one (8j)
Yield: 2.04 g (6.40 mmol, 64%); light-brown solid; mp 119–
120 °C.
IR (KBr): 2967 (m), 2855 (m, Ar-H), 1629 (s, C=O), 819 (m, C-Br),
730 (Ar-H) cm–1.
4
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 2.0 Hz, 1 H, H-1),
7.25 (dd, 3J = 9.0 Hz, 4J = 2.0 Hz, 1 H, H-3), 7.13 (d, 3J = 9.0 Hz,
1 H, H-4), 4.82 (t, 3J = 7.0 Hz, 2 H, H-1′), 3.61 (t, 3J = 7.0 Hz, 2 H,
H-2′), 3.27 (t, 3J = 7.0 Hz, 2 H, H-11), 2.97 (t, 3J = 7.5 Hz, 2 H, H-
7), 1.66–1.83 (m, 4 H, H-10, H-8), 1.33–1.41 (m, 2 H, H-9).
Chemicals and reagents were obtained from either Aldrich or Alfa-
Aesar and were used as received unless otherwise stated. All reac-
tions involving moisture-sensitive reagents were performed in
oven-dried glassware under a positive pressure of argon. Tetrahy-
drofuran (THF), dichloromethane (CH2Cl2) and toluene were ob-
tained anhydrous from a solvent purification system (MBraun, SPS-
800). Dimethyldioxirane (DMDO) was prepared by using a report-
ed procedure.19 Thin-layer chromatography was performed by us-
ing glass plates coated with silica gel (with fluorescent indicator
UV254) (Aldrich). Developed plates were air-dried and analysed un-
der a UV lamp. Flash column chromatography was performed using
silica gel (40–63 μm) (Fluorochem). Melting points were recorded
13C NMR (100 MHz, CDCl3): δ = 195.6 (C6), 137.4 (C4a), 134.8
(C5a), 129.4 (C3), 128.3 (C11b), 123.6 (C1), 123.4 (C11a), 113.6
(C2), 112.0 (C4), 47.0 (C1′), 42.2 (C7), 30.8 (C2′), 25.5 (C9), 24.02
(C10), 23.99 (C8), 22.6 (C11).
MS (ES+): m/z (%) = 397.97 (100) [M + H]+, 399.97 (100) [M + H]+.
HRMS (ES+): m/z [M + H]+ calcd for C16H18NO79Br2: 397.9677;
found: 397.9677.
© Georg Thieme Verlag Stuttgart · New York
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2812
G. Liu et al.
PAPER
Sodium Borohydride-Mediated Reduction of 8; General Proce-
dure
MS (ES+): m/z (%) = 373.95 (100) [M + H]+, 371.83 (60) [M + H]+.
HRMS (ES+): m/z [M + H]+ calcd for C14H16NO79Br: 373.9506;
Ketone 8 (5.0 mmol, 1.0 equiv) was dissolved in EtOH (100 mL)
and NaBH4 (0.57 g, 15.0 mmol, 3.0 equiv) was added. The reaction
mixture was heated at 60 °C for 6 h, then the solvent was removed
in vacuo and the residue was partitioned between CH2Cl2 (50 mL)
and H2O (50 mL). The aqueous layer was extracted with CH2Cl2
(3 × 50 mL) and the combined organic extracts were dried (MgSO4)
and concentrated in vacuo. The crude mixture was purified by using
flash column chromatography over silica gel (EtOAc–hexanes, 3:7)
to afford 2. Compounds 2a–j are novel, with full characterisation
being provided here for 2j as a representative example. Analytical
data to support the structural assignment of 2a–i are provided in the
Supporting Information.
found 373.9511.
DDQ-Mediated Oxidation; General Procedure
To a solution of 2 (1.0 mmol, 1.0 equiv) in THF–H2O (11 mL, 9:1)
at 0 °C, was added a solution of DDQ (0.454 g, 2.00 mmol, 2.0
equiv) in THF (4 mL) dropwise with stirring under a nitrogen atmo-
sphere. The reaction mixture was stirred for 1 h and then concen-
trated in vacuo. The resulting solid was partitioned between H2O
(50 mL) and EtOAc (50 mL), and the aqueous phase was extracted
with EtOAc (3 × 20 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated in vacuo to give a red solid,
which was purified by flash column chromatography over alumini-
um oxide eluting with EtOAc to yield the title compound. Com-
pounds 10a–j are novel, with full characterisation being provided
here for 10j as a representative example. Analytical data to support
the structural assignment of 10a–i are provided in the Supporting
Information.
10-Bromo-1,2,3a,4,5,6,7,8-octahydro-3-oxa-12b-azacyclooc-
ta[jk]fluorene (2j)
Yield: 1.42 g (4.45 mmol, 89%); pale-yellow solid; mp 107–
108 °C.
IR (KBr): 2926 (m, Ar-H), 1103 (s, C-O), 1606 (m, C=C Ar), 790
(m, C-Br), 739 (m, C-H Ar) cm–1.
10-Bromo-1,2,4,5,6,7-hexahydro-3-oxa-12b-azacyclooc-
ta[jk]fluoren-8(3aH)-one (10j)
Yield: 0.20 g (0.61 mmol, 61%); white solid; mp 200–201 °C.
4
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 2.0 Hz, 1 H, H-9),
7.25 (dd, 3J = 9.0 Hz, 4J = 2.0 Hz, 1 H, H-11), 7.13 (d, 3J = 9.0 Hz,
3
IR (KBr): 2940 (m), 2851 (m, Ar-H), 1625 (s, C=O), 1106 (s, C-O),
1433 (m), 1444 (m, CH2), 796 (m, C-Br) cm–1.
1 H, H-12), 5.12 (dd, J = 9.5, 5.0 Hz, 1 H, H-3a), 4.21–4.39 (m,
1 H, H-2a), 3.91–4.10 (m, 3 H, H-2b, H-1), 2.68–2.95 (m, 2 H, H-
8), 2.00–2.22 (m, 2 H, H-4), 1.52–1.86 (m, 6 H, H-7, H-6, H-5).
13C NMR (100 MHz, CDCl3): δ = 134.9 (C13a), 133.8 (C12a),
129.5 (C8a), 123.6 (C11), 120.8 (C9), 112.7 (C10), 110.0 (C12),
109.0 (C8a), 73.7 (C3a), 61.1 (C2), 42.2 (C1), 35.2 (C4), 27.7 (C7),
26.1 (C6), 22.0 (C5), 21.2 (C8).
1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 2.0 Hz, 1 H, H-9),
4
7.37 (dd, 3J = 8.5 Hz, 4J = 2.4 Hz, 1 H, H-11), 7.17 (d, 3J = 8.5 Hz,
3
1 H, H12), 5.83 (dd, J = 10.5, 7.5 Hz, 1 H, H3a), 4.22–4.32 (m,
1 H, H-2a), 4.06–4.16 (m, 3 H, H-2b, H-1), 2.65–2.84 (m, 2 H, H-
7), 1.90–2.19 (m, 3 H, H-4, H-5a), 1.50–1.83 (m, 3 H, H-5b, H-6).
13C NMR (100 MHz, CDCl3): δ = 195.6 (C8), 141.5 (C13a), 134.6
(C11a), 127.6 (C8b), 125.9 (C11), 125.2 (C9), 116.8 (C10), 115.2
(C8a), 109.9 (C12), 73.0 (C3a), 58.8 (C2), 42.1 (C7), 41.9 (C2),
31.6 (C4), 23.8 (C5), 22.5 (C6).
MS (ES+): m/z (%) = 342.06 (100) [M + Na]+, 344.05 (95) [M +
Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C16H18NOBrNa: 342.0572;
found: 342.0577.
MS (ES+): m/z (%) = 355.93 (100) [M + Na]+, 357.94 (80) [M +
Na]+.
Synthesis of (R)-6-Bromo-9-(2-bromoethyl)-2,3,4,9-tetrahydro-
1H-carbazol-1-ol [(R)-9c]
HRMS (ES+): m/z [M + Na]+ calcd for C16H16NO2Na79Br:
356.0258; found: 356.0262; m/z [M + Na]+ calcd for C16H16NO2-
Na81Br: 358.0239; found: 358.0242.
To a solution of 2c (0.37 g, 1 mmol, 1.0 equiv) in CH2Cl2 (20 mL)
at –20 °C was added (S)-oxazaborolidine (0.277 g, 1 mmol, 1.0
equiv). The solution was stirred for 20 min, then BH3·DMS (95 μL,
1.0 equiv) was added dropwise over 10 min. The mixture was then
stirred for 3.5 h at –20 °C, then the reaction was quenched by addi-
tion of isopropyl alcohol (2 mL) and warmed to r.t. The solvent was
removed in vacuo and the crude material was passed through a plug
of silica eluting with dichloromethane. The organic washings were
concentrated in vacuo and the resulting solid was recrystalised from
EtOAc–hexane to give the desired product. The optical purity of
(R)-9c prepared by this method was determined to be 98% ee by chi-
ral HPLC analysis (see Figure S1 in the Supporting Information).
The assignment of the absolute configuration of (R)-9c was based
on the absolute stereochemistry of the stereogenic centre present in
11c, which was determined by small-molecule X-ray crystallo-
graphic analysis of 11c.
10-Bromo-2,3,3a,4,5,6-hexahydro-1H-pyrido[3,2,1-jk]carbazol-
1-one (15)
Yield: 0.20 g (0.65 mmol, 65%); white solid; mp 235 °C (dec.).
1H NMR (400 MHz, CDCl3): δ = 8.34 (d, 4J = 2.0 Hz, 1 H, H-11),
7.35 (dd, 3J = 8.5 Hz, 4J = 2.0 Hz, 1 H, H-9), 7.14 (d, 3J = 8.5 Hz,
1 H, H-8), 4.24 (q, 3J = 6.5 Hz, 1 H, H-6a), 3.80 (dt, 2J = 13.0 Hz,
3J = 6.0 Hz, 1 H, H-6b), 2.97–3.01 (m, 1 H, H-3a), 2.59–2.65 (m,
2 H, H-2), 2.10–2.41 (m, 4 H, H-5, H-4a, H-3a), 1.76–1.90 (m, 1 H,
H-3b), 1.35–1.50 (m, 1 H, H-4b).
13C NMR (100 MHz, CDCl3): δ = 193.1 (C1), 139.0 (C3b), 136.6
(C7a), 128.7 (C11a), 125.6 (C9), 124.2 (C11), 116.4 (C10), 110.6
(C8), 109.9 (C11b), 41.9 (C6), 38.8 (C2), 33.6 (C3a), 31.4 (C3),
26.9 (C4), 22.6 (C5).
20
Yield: 0.28 g (0.76 mmol, 76%); white solid; mp 167–168 °C; [α]D
MS (ES+): m/z (%) = 326.08 (100) [M + Na]+, 328.08 (100) [M +
77.0 (c = 0.004, CH2Cl2).
Na]+.
IR (KBr): 3325 (br, O-H), 2927 (m), 2868 (m), 1478 (m), 1405 (m),
815 (m, C-Br) cm–1.
HRMS (ES+): m/z [M + Na]+ calcd for C15H14NONa79Br: 326.0156;
found: 326.0154; m/z [M + Na]+ calcd for C15H14NONa81Br:
328.0136; found: 328.0139.
4
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 2.0 Hz, 1 H, H-5),
7.34 (dd, 3J = 9.0 Hz, 4J = 2.0 Hz, 1 H, H-7), 7.22 (d, 3J = 9.0 Hz,
1 H, H-8), 4.98–5.05 (m, 1 H, H-1), 4.48–4.70 (m, 2 H, H-1′), 3.59–
3.78 (m, 2 H, H-2′), 2.76–2.86 (m, 1 H, H-2a), 2.53–2.65 (m, 1 H,
H-2b), 2.00–2.18 (m, 2 H, H-4), 1.90–1.99 (m, 2 H, H-5).
MCPBA-Mediated Oxidative Fragmentation; General Proce-
dure
Compound 10 (0.5 mmol, 1.0 equiv) was dissolved in anhydrous
CH2Cl2 (50 mL) and purified MCPBA (0.344 g, 2.0 mmol, 4.0
equiv) was added to the solution. The reaction mixture was stirred
at r.t. under N2 for 16 h, then sat. Na2S2O3 solution (10 mL) fol-
lowed by sat. NaHCO3 solution (20 mL) were added and the reac-
tion mixture was extracted with CH2Cl2 (3 × 20 mL). The combined
13C NMR (100 MHz, CDCl3): δ = 121.9 (C5), 125.3 (C7), 110.5
(C8), 62.0 (C1), 44.9 (C1′), 29.4 (C2′), 21.0 (C2), 33.4 (C4), 18.4
(C3), 112.7 (C6), 106.2 (C4a), 134.7 (C9a), 131.2 (C8a), 128.3
(C4b).
Synthesis 2014, 46, 2808–2814
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Oxidative Cleavage of Oxazinocarbazoles
2813
organic layers were dried (MgSO4), filtered and concentrated in
vacuo to give a brown solid, which was purified by flash column
chromatography (EtOAc–CH2Cl2, 3:7) to give the product.
10-Bromo-2,3,4,5,6,7-hexahydro-1,5-methanobenzo[b][1]-
azacycloundecine-7,8,14-trione (16)
Yield: 0.11 g (0.34 mmol, 67%); yellow solid; mp 139–140 °C.
IR (KBr): 2861 (m), 2920 (m, Ar-H), 1682 (s), 1648 (s, C=O), 1466
(s), 1419 (s, CH2), 836 (s, C-Br) cm–1.
Compounds 11a–e, 11i, 11j and 12e–j are novel, with full charac-
terization being provided here for 11c and 12f as representative ex-
amples. Analytical data to support the structural assignment of 11a,
11b, 11d, 11e, 11i, 11j and 12e–j are provided in the Supporting In-
formation.
4
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 2.5 Hz, 1 H, H-9),
7.76 (dd, 3J = 8.5 Hz, 4J = 2.5 Hz, 1 H, H-11), 7.12 (d, 3J = 8.5 Hz,
1 H, H-12), 3.82–3.90 (m, 1 H, H-1a), 3.27–3.36 (m, 2 H, H-1b,
H6a), 2.84–2.97 (m, 1 H, H-4), 2.54–2.63 (m, 1 H, H-6b), 2.39–
2.50 (m, 1 H, H-3a), 2.05–2.22 (m, 3 H, H-3b, H-5a, H-2a), 1.77–
1.94 (m, 2 H, H-5b, H-2b).
11-Bromo-6,7-dihydro-2H-1,5-methanobenzo[e][1,4]oxaazacy-
cloundecine-8,9,14(3H,5H)-trione (11c)
Compound 11c was afforded when MCPBA (2.5 equiv) was used.
Recrystallisation from acetone afforded analytically pure 11c suit-
able for small-molecule X-ray crystallographic analysis.
13C NMR (100 MHz, CDCl3): δ = 204.7 (C7), 191.2 (C8), 174.7
(C14), 142.0 (C12a), 137.2 (C11), 136.6 (C8a), 132.9 (C9), 124.8
(C12), 120.7 (C10), 50.0 (C1), 40.7 (C4), 35.3 (C6), 28.9 (C3), 25.4
(C5), 18.7 (C2).
Yield: 0.084 g (0.25 mmol, 50%); pale-yellow solid; mp 205–
206 °C.
MS (ES+): m/z (%) = 357.85 (100) [M + Na]+, 359.85 (95) [M +
IR (KBr): 2861 (m), 2920 (m), 1682 (s, C=O), 1648 (s, C=O), 1710
(s, C=O), 1466 (s), 1429 (s), 1102 (s, C-O), 836 (m, C-Br) cm–1.
Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C15H14NO3Na79Br:
358.0057; found: 358.0055; m/z [M + Na]+ calcd for C15H14NO3-
Na81Br: 360.0041; found: 360.0034.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, 4J = 2.5 Hz, 1 H, H-10),
7.71 (dd, 3J = 8.5 Hz, 4J = 2.5 Hz, 1 H, H-12), 7.11 (d, 3J = 8.5 Hz,
1 H, H-9), 4.50 (d, 3J = 6.0 Hz, 1 H, H-5), 4.02–4.08 (m, 1 H, H-3a),
3.77–3.86 (m, 1 H, H-3b), 3.67–3.72 (m, 1 H, H-2a), 3.28–3.38 (m,
1 H, H-2b), 3.12–3.20 (m, 1 H, H-7a), 2.63–2.73 (m, 1 H, H-7b),
2.48–2.60 (m, 1 H, H-6a), 2.26–2.36 (m, 1 H, H-6b).
13C NMR (100 MHz, CDCl3): δ = 202.3 (C9), 190.3 (C8), 173.3
(C14), 139.7 (C11), 136.9 (C12), 135.7 (C9a), 133.3 (C10), 126.1
(C13), 122.0 (C13a), 77.3 (C5), 62.2 (C3), 49.4 (C2), 34.2 (C7),
29.7 (C6).
Anal. Calcd for C14H12NO4Br: C, 53.59; H, 4.20; N, 4.17. Found: C,
53.73; H, 3.99; N, 4.19.
9-Bromo-3,3a,5,6-tetrahydro-1H-cyclopenta[2,3][1,4]oxizi-
no[4,3-a]indole-1,12(2H)-dione (12c)
Compound 10c (0.500 g, 1.63 mmol, 1 equiv) was dissolved in an-
hydrous CH2Cl2 (10 mL) and dimethyl dioxirane acetone solution
(0.01 M, 81.5 mL, 5 equiv) was added dropwise. The mixture was
stirred at r.t. for 30 min, then concentrated in vacuo and purified by
flash column chromatography (EtOAc–hexane, 3:7).
MS (ES+): m/z (%) = 359.89 (100) [M + Na]+, 361.89 (90) [M +
Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C14H12NO4Na79Br:
359.9847; found: 359.9845; m/z [M + Na]+ calcd for C14H12NO2-
Na81Br: 361.9827; found: 361.9831.
Yield: 0.500 g (1.56 mmol, 95%); yellow solid; mp 196–197 °C.
IR (KBr): 2861 (m), 2920 (m), 1682 (s, C=O), 1648 (s, C=O), 1466
(s), 1429 (s), 1132 (s, C-O), 813 (C-Br) cm–1.
4
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 2.0 Hz, 1 H, H-8),
Anal. Calcd for C14H12NO4Br: C, 49.73; H, 3.58; N, 4.14. Found: C,
49.64; H, 3.41; N, 4.19.
7.56 (dd, 3J = 9.0 Hz, 4J = 2.0 Hz, 1 H, H-10), 6.79 (d, 3J = 9.0 Hz,
1 H, H-11), 4.03 (d, 3J = 4.5 Hz, 1 H, H-3a), 3.86–3.92 (m, 1 H, H-
2a), 3.60–3.66 (m, 1 H, H-1a), 3.30–3.45 (m, 2 H, H-1b, H-2b),
2.75–2.89 (m, 1 H, H-4a), 2.64–2.75 (m, 1 H, H-5a), 2.52–2.64 (m,
1 H, H-5b), 2.16–2.26 (m, 1 H, H-4b).
Compound (M,R)-11c was prepared in an analogous manner. Chiral
HPLC analysis (Figure S2) indicated that the prepared sample of
(M,R)-11c had 96% ee.
10-Nitro-3,3a,5,6-tetrahydro-1H-cyclopenta[2,3][1,4]oxazi-
no[4,3-a]indole-1,12(2H)-dione (12f)
Compound 12f was afforded when MCPBA (2.5 equiv) was used.
Recrystallisation from acetone afforded analytically pure 12f,
which was suitable for small-molecule X-ray crystallographic anal-
ysis.
13C NMR (100 MHz, CDCl3): δ = 208.6 (C6), 191.4 (C7), 159.1
(C11a), 140.1 (C10), 127.8 (C8), 121.1 (C7a), 111.0 (C11), 110.4
(C9), 80.5 (C6a), 78.2 (C3a), 65.2 (C2), 41.7 (C1), 33.3 (C5), 24.4
(C4).
MS (ES+): m/z (%) = 343.84 (100) [M + Na]+, 345.84 (90) [M +
Na]+.
Yield: 0.04 g (0.14 mmol, 27%); yellow solid; mp 115–116 °C.
HRMS (ES+): m/z [M + Na]+ calcd for C14H12NO3Na79Br:
343.9885; found: 343.9898; m/z [M + Na]+ calcd for C14H12NO3-
Na81Br: 345.9892; found: 345.9878.
IR (KBr): 3041 (m), 2955 (m), 2876 (m, Ar-H), 1650 (s, C=O),
1640 (s, C=O), 1557 (s), 1340 (s) (NO2), 1102 (s, C-O) cm–1.
4
1H NMR (400 MHz, CDCl3): δ = 8.46 (d, J = 2.0 Hz, 1 H, H-2),
Anal. Calcd for C14H12NO3Br: C, 52.20; H, 3.75; N, 4.35. Found: C,
52.39; H, 3.56; N, 4.38.
8.38 (dd, 3J = 9.5 Hz, 4J = 2.0 Hz, 1 H, H-4), 6.90 (d, 3J = 9.5 Hz,
1 H, H-5), 4.13 (d, 3J = 4.0 Hz, 1 H, H-9a), 3.97–4.02 (m, 1 H, H-
8a), 3.70–3.76 (m, 1 H, H-7a), 3.38–3.54 (m, 2 H, H-8b, H-7b),
2.80–2.92 (m, 1 H, H-10a), 2.54–2.79 (m, 2 H, H-11), 2.22–2.32
(m, 1 H, H-10b).
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 206.7 (C12), 190.5 (C1), 161.8
(C5a), 139.4 (C3), 132.7 (C4), 122.7 (C2), 119.0 (C1a), 108.5 (C5),
81.5 (C12a), 78.3 (C9a), 65.4 (C8), 41.7 (C7), 32.9 (C11), 24.5
(C10).
MS (ES+): m/z (%) = 311.26 (100) [M + Na]+.
HRMS (ES+): m/z [M + Na]+ calcd for C14H12N2O5Na: 311.0699;
We wish to thank the EPSRC UK National Mass Spectrometry fa-
cility at Swansea University, Carolyn Horsburgh, Sylvia William-
son, Tomas Lebl and Melanja Smith for extensive analytical
support. The School of Chemistry at St Andrews (G.L.), EPSRC
(C.S.L.) and the Royal Society (N.J.W. held a URF when this work
was started) provided funding for this work. We would also like to
thank Sabrina Pereira.
found: 311.0695.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2808–2814

2814
G. Liu et al.
PAPER
(8) Jones, A. M.; Liu, G.; Lorion, M. M.; Patterson, S.; Lebl, T.;
Slawin, A. M. Z.; Westwood, N. J. Chem. Eur. J. 2011, 17,
5714.
Supporting Information for this article is available online
at http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
o
o
nr
i
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