Total Synthesis of Olivacine and Ellipticine via a Lactone Ring-Opening and Aromatization Cascade

Article abstract of DOI:10.1021/acs.joc.9b00706

Effective preparation of olivacine and ellipticine via late-stage D-ring cyclization is described. Key features of the synthetic routes include trifluoroacetic acid-mediated formation of a lactone that is fused to a tetrahydrocarbazole derivative and its one-pot two-step ring opening and aromatization mediated by para-toluenesulfonic acid and palladium on carbon, respectively.

Full text of DOI:10.1021/acs.joc.9b00706

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Article
Total Synthesis of Olivacine and Ellipticine via a
Lactone Ring-Opening and Aromatization Cascade
Ömer Dilek, Süleyman Patir, Tahir Tilki, and Erkan Ertürk
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
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Total Synthesis of Olivacine and Ellipticine via a Lactone Ring-Opening and
Aromatization Cascade
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Ömer Dilek,†,‡ Süleyman Patir,† Tahir Tilki,‡ Erkan Ertürk*,†
†Institute of Chemical Technology, TÜBITAK Marmara Research Center, 41470 Gebze, Kocaeli, Turkey
‡Department of Chemistry, Süleyman Demirel University, 32260 Isparta, Turkey
Corresponding Author’s E-mail: erkan.erturk@tubitak.gov.tr
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TABLE of CONTENTS GRAPHIC
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ABSTRACT: Effective preparation of olivacine and ellipticine via late-stage D-ring cyclization is
described. Key features of the synthetic routes include trifluoroacetic acid-mediated formation of a
lactone that is fused to a tetrahydrocarbazole derivative and its one-pot two-step ring opening and
aromatization mediated by para-toluenesulfonic acid and palladium on carbon, respectively.
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INTRODUCTION
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Natural products have historically been the main arsenal of medicines.1,2 In the same way, carbazole alkaloids
continue to play an important role in the drug development.3,4 They have also become a source of inspiration for
the design of potential drugs, so that carbazole skeleton itself is regarded as a privileged building block for
identification of new pharmacophores.5 Olivacine6 and ellipticine7 (Figure 1), the most prominent representatives
of the pyrido[4,3-b]carbazole alkaloids, are still attracting much attention from both medicinal and synthetic
standpoints although their isolations date back to the late 1950s.8 This is because these structural isomers and
their derivatives exhibit diverse biological activities, by topoisomerase II inhibition, intercalation with DNA,
affecting cell-cycles etc.9 Consequently, a number of their derivatives have found application in clinical use. For
instance, N-2-methyl-9-hydroxy-ellipticinium acetate (Figure 1) has been used for the treatment of myeloblastic
leukemia, advanced breast cancer, and other solid tumors.
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HO
R3 R1
N
N
OAc
N
H
N
H
R2
1
2
3
Olivacine:
Ellipticine:
R = R = Me; R = H
N-2-Methyl-9-hydroxy-
ellipticinium acetate
2
3
1
R = R = Me; R = H
Figure 1. Structures of olivacine and ellipticine as well as a biologically important ellipticine derivative.
Since 1960s, total synthesis of olivacine and ellipticine has been a subject of many publications, as discussed in
several review articles.3,4,8,10–12 The majority of the methods for their syntheses rely on the late-stage D-ring
cyclization,13–22 whereas the late-stage C-ring23–29 and B-ring cyclization strategies30 have been rarely reported. In
their report in 1962, Cranwell and Saxton presented an effective and concise synthesis of ellipticine through the
late-stage cyclization of the D-ring from lower rim.15 Cranwell–Saxton synthesis of ellipticine was later frequently
utilized for the generation of ellipticine derivatives.8,22 However, the scope of Cranwell–Saxton methodology is
limited to the synthesis of ellipticine and its some derivatives, because it depends on the use of hexane-2,5-dione
as the starting material. On the other hand, Schmutz and Wittwer13 as well as Wenkert and Dave14 introduced the
late-stage cyclization of D-ring from upper rim for the synthesis of olivacine, in early 1960s. A closer and deeper
evaluation of those works hinted that the late-stage cyclization of D-ring from upper rim can not only be effective,
but also allow access to of pyrido[4,3-b]carbazole derivatives conveniently. Accordingly, our retrosynthetic
analysis for pyrido[4,3-b]carbazoles was formulated as depicted in Scheme 1. The key steps were the lactone
formation after R2 addition to the THC compound and a lactone ring-opening and aromatization cascade giving the
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desired carbazole derivative. Then, the D-ring cyclization of the carbazol-2-yl-ethaneamine would eventually
afford the pyrido[4,3-b]carbazole skeleton as described by Schmutz and Wittwer.13 Although our synthetic
proposal at first glance seemed to have drawbacks inherent in any linear synthesis, it could make the synthesis of
a specific carbazole derivative possible, by allowing step-by-step installation of the substituents. It should be
mentioned that some of us recently used a lactone similar to that shown in Scheme 1 as an intermediate for the
synthesis of dasycarpidol and dasycarpidone.31,32
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Scheme 1. Retrosynthesis of pyrido[4,3-b]carbazole alkaloids.
R5
R5
R1
9
10
R3
11
R3
C
D-Ring
cyclization
1
8
A
A
2
3
N
NH2
B
B
N
H
C
D
7
6 N
R4
5
R2
4
R2
Carbazole
derivative
Pyrido[4,3-b]carbazole
skeleton
Lactone ring-opening
and aromatization
R5
A
R2 addition
and lactone
formation
R5
NH2
R5
R3
R3
THC
formation
R3
+
A
A
B
N
H
B
N
H
C
C
C
EtO
2
R
O
O
CO2H
O
O
O
Tetrahydrocarbazole (THC)
derivative
Lactone
RESULTS AND DISCUSSION
Our route to olivacine and ellipticine started with the Japp-Klingemann condensation of aniline with ethyl 2-
oxocyclohexanecarboxylate (1a) and ethyl 5-methyl-2-oxocyclohexanecarboxylate (1b), respectively (Scheme 2).
Both keto-hydrazones 2a and 2b were obtained in 88% yield. The Fischer cyclization of 2a mediated by aqueous
sulfuric acid in acetonitrile (ACN) occurred to give tetrahydrocarbazole-1-one (3a) with high yield (92%),
according to the procedure of Hillier and co-workers.33 However, cyclization of 2b under the same reaction
conditions gave a mixture of isomers consisting of 4-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3b) and 3-
methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one, based on NMR spectroscopy. Fortunately, Fischer indolization of
the keto-hydrazone 2b could be achieved by p-toluenesulfonic acid monohydrate (p-TsOH·H2O) in anhydrous
benzene, thus furnishing 4-methyl-tetrahydrocarbazole-1-one (3b) selectively.20 The ketones 3a and 3b were
subjected to the aldol condensation with diethyl oxalate to give enols 4a and 4b that were then mesylated with
methanesulfonyl chloride and reduced with zinc-acetic acid couple, consecutively, to give the ester 5a and 5b/6b-
1
esters mixture, respectively. Structural elucidations of the esters 5b and 6b were made on the basis of H, 13C,
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COSY, HSQC spectral data (see Exp. Sect. as well as Table S2). All H NMR signals were assigned with the aid of
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COSY and HSQC. At this point, we examined possible conformations of the structures 5b and 6b which are actually
tetrahydrocarbazole derivatives. As is well known, tetrahydrocarbazoles usually assume half-chair conformation,
depending on the type of substituents. Strong correlations between the methine proton at δ 3.22–3.17 (m, H-2)
and the methine proton at δ 3.46–3.41 (m, H-4), one of the methylene protons at δ 2.30 (td, J = 12.9, 4.3 Hz, Ha-3),
and one of the methylene protons at δ 3.10 (dd, J = 16.4, 5.5 Hz, H-10) were determined by NOE-DIFF experiments.
Thus, cis-configuration for the major diastereomer (5b) was deduced from NOE-DIFF spectra. The 80:20 cis/trans
diastereomeric ratio (5b/6b) could be easily calculated from 1H NMR spectra as usual. The carboxylic acid 7a and
7b/8b-mixture were readily obtained from the corresponding esters through saponification with KOH in aqueous
methanol. Methylation and the Brønsted acid-catalyzed cyclization cascade to the lactone 9a was achieved by
methyllithium addition to the carboxylic acid 7a in the presence of Et3N and quenching the reaction mixture with
trifluoroacetic acid. Note that the use of hydrochloric acid instead of CF3CO2H did not afford 9a. Under the same
conditions, the 7b/8b mixture could also be converted into the corresponding mixture of lactones 9b/10b. The
relative stereochemistry of 9a (cis-configuration of the lactone ring) was explicitly determined by NOE-DIFF
spectroscopy. The diastreomers 9b and 10b could be individually separated by column chromatography on silica
gel. Assignment of correct skeletons of 9b and 10b as well as chemical shifts of all protons were in turn made by
1H, 13C, COSY and HSQC NMR spectra. Relative stereochemistries of 9b and 10b were also elucidated by NOE-DIFF
experiments (see Exp. Sect., as well as Table S3 and Table S4). All in all, syn-configuration for 9b and anti-
configuration for 10b were assigned. It is noteworthy that the configuration of the lactone ring was determined to
be cis. Formation of 9b and 10b from 7b and 8b mixture is a three-step reaction, i.e. methyllithium addition, acid-
catalyzed elimination, and ring-closure. After all these processes, however, the stereochemistry of the starting
materials (7b and 8b) are preserved, i.e. the lactone formation proceeds in a stereospecific manner. Approx. 80:20
diasteromeric ratio of 9b/10b was determined. Accordingly, we might give a mechanistic proposal for the
transformation of 7b to 9b which sequentially includes (i) the formation of the addition product 11, (ii) the acid-
catalyzed dehydration of 11 to give the 1,6-conjugated iminium cation 12, and (iii) the ring-closure of 12 to deliver
9b (at the bottom of Scheme 2).
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Scheme 2. Synthesis of the lactone intermediates 9a for olivacine and 9b/10b for ellipticine.
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4
HCl, NaNO2
5
6
7
8
NH2
Method A:
H2SO4 (10%)
ACN, 90 °C, 5 h
R1
R1
5 °C, 2 h
1) NaH, THF
rt, 1 h
O
N
O
CO2Et
OH
N
or
N
H
2) Et2C2O4
70 °C, 3 h
N
H
H
CO2Et
Method B:
p-TsOH (2.01 equiv)
benzene, rt, 3 h
1) NaOH, H2O
0 °C, 72 h
9
O
3a
O
R1
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4a
4b
(88%)
(quant.)
2a
2b
(88%)
(88%)
Method A
Method B


(92%)
2) HCl(aq)
(pH = 5.5)
0 °C, 1 h
R1
(85%)
3b
1a 1b
or
1) Et3N, MeSO2Cl
THF, 0 °C to rt, 4 h
2) Zn, AcOH, THF
0 °C to rt, 16 h
1
1
a:
b:
R = H;
R = Me
R1
R1
R1
R1
O
+
CO2R2
1) Et3N, MeLi
THF, 0 °C to rt, 2–16 h
CO2R2
N
N
H
H
O
6
+
N
H
O
N
H
5
2) TFA, 0 °C to rt, 2 h
O
1
2
5a
(65%): R = H, R = Et
O
O
1
2
5b 6b
5b/6b
+
(67%),
= 80:20: R = Me, R = Et
9
10
9a
(65%)
KOH (25%), MeOH – H2O
9b 10b
9b/10b
= 80:20
+
(63%),
7a
or
7
8
7b/8b
mixture
1
2
7a
(96%): R = R = H
1
2
7b 8b
+
(94%): R = Me, R = H
Plausible mechanism for the lactone formation:
1) MeLi
9b
7b
CO2H
N
N
2) CF3CO2H
H
– H
– H2O
H
H
OH2
O
O
11
12
The next obstacle to overcome was the lactone ring-opening (Scheme 3). We first treated the lactone 9a with
dimethylaluminum amide (Me2AlNH2), hoping the formation of the ring-opened product (a carboxylic acid amide)
as happened to a very similar lactone in our previous work.31 But, no formation of the expected product was
observed in this case. To our delight, catalytic hydrogenation over palladium hydroxide on carbon (Pearlman’s
catalyst) yielded the carboxylic acid 13 quantitatively. To the best of our knowledge, this is one of the rare
examples of the lactone ring-opening through hydrogenolysis.34–36 The high reactivity of the lactone 9a in the
hydrogenolysis can in turn be attributed to the presence of the benzylic carbon atom attached to the lactone ring.
Extensive structural investigation by NMR spectroscopy (1H, 13C, COSY, HSQC and NOE-DIFF; see Exp. Sec. and
Table S1) showed that the carboxylic acid 13 is cis-configured. A plausible mechanism for the formation of the cis-
product (13) is also depicted in Scheme 3 (at the bottom): Similar to the established mechanism of the
debenzylation reaction through hydrogenolysis,36 an oxidative addition of palladium(0) to the lactone ring can
take place, which lead to the formation of the palladacycle 18. Coordination of hydrogen and subsequent
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protonation might give the organopalladium 19 which must be prone to beta-hydride elimination to form alkene
20. Then, hydrogenation of 20 delivers the cis-product 13 exclusively. Treatment of 13 with ethyl iodide in the
presence of K2CO3 gave the ester 14 (92%) which was then converted into the carbazole 15a through
aromatization over palladium carbon in boiling decalin. As an alternative to the lactone ring-opening via the
hydrogenation, 9a could be directly converted into 15a via a one-pot two-step reaction cascade: The lactone 9a
was first treated with EtOH in the presence of an over-stoichiometric amount of p-TsOH·H2O (1.40 equiv) in p-
xylene to give likely the intermediate 16, and 16 was then converted to the carbazole-ester 15a through
aromatization on Pd/C. This furnished 15a from 9a directly, in 74% yield. Interestingly, the lactone ring-opening
with EtOH (9a  16) took place only in p-xylene among the solvents employed which include mixture of xylenes,
mesitylene, toluene, and decalin. Thereafter, 15a was converted into the corresponding carboxamide 17 in 80%
yield, by applying the sodium methoxide-mediated amidation procedure of esters with formamide.37 We aimed at
reducing 17 to the corresponding amine, the well-known precursor for olivacine. However, all the hydridic
reducing agents (LiAlH4, Red-Al, NaBH(OAc)3, and BH3·SMe2) employed for this purpose were determined to be
inadequate because product mixtures were obtained in all cases. When 17 was treated with the
polymethylhydrosiloxane–Ti(OiPr)438 couple, no conversion was observed.
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Scheme 3. Ring-opening of the lactone 9a.
H2 (1 atm)
Pd(OH)2/C (2 mol%)
Pd/C
CO2R
CO2Et
N
H
N
H
N
MeOH, rt, 2 h
Decalin
H
O
210 °C, 48 h
O
13:
14:
R = H (quant.)
R = Et (92%)
75%
15a
C2H5I, K2CO3
DMF, rt, 2 h
9a
HCONH2 (6.70 equiv)
NaOMe (2.30 equiv)
DMF, 105 °C, 3 h
1) p-TsOH·H2O (1.40 equiv)
MS 4Å
74%
p-Xylene – EtOH (4:1)
90 °C, 16 h
CO2Et
N
H
O
2) Pd/C, Decalin
210 °C, 48 h
OH
N
NH2
H
16
LiALH4, Red-Al®,
·
NaBH(OAc)3, BH3 SMe2,
17
(80%)
or PMHS/Ti(OiPr)4
No formation of the desired amine!
Plausible mechanism for the palladium-catalyzed hydrogenolysis of the lactone 9a:
Pd0
H
 Pd0
hydrogenation
13
CO2H
9a
N
H
N
H
N
CO2H
oxidative
addition
-hydride
elimination
H
PdII
H
PdII
H
PdII
H
O
H
19
18
20
O
H
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On the other hand, the lactones 9b and 10b did not undergo the ring-opening through hydrogenation over
Pd(OH)2/C catalyst. No conversion was detected at all. The presence of an extra methyl group at the C-4 carbon of
the tetrahydrocarbazole moiety in 9b and 10b would disturb alignment of the C–O bond in question with the
indole pi-system, which might preclude the hydrogenolysis of 9b and 10b. Fortunately, the alternative procedure
via one-pot two-step reaction cascade afforded the desired carbazole ester 15b in 71% yield (Scheme 4).
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Scheme 4. Ring-opening of the lactones 9b and 10b.
1) p-TsOH·H2O (1.40 equiv)
Pd/C, MS 4Å
p-Xylene – EtOH (4:1)
CO2Et
90 °C, 2 h
N
H
9b/10b
(80:20 mixture)
2) p-Xylene
15b
140 °C, 48 h
(71%)
Next, reduction of the esters 15a and 15b were effected with lithium aluminum hydride, to give the alcohols
21a and 21b in high yields (Scheme 5). Alcohols 21a and 21b were then converted into the azides 23a and 23b
by exploiting the conventional techniques, i.e. the mesylation with methanesulfonyl chloride and the azidation
with sodium azide through an SN2 reaction. Reduction of the azides by catalytic hydrogenation over platinum
allowed to isolate the primary amines 24a and 24b after simple filtration through celite. It should be mentioned
that reductions of the azides 23a and 23b to 24a and 24b with comparable yields were also achieved with lithium
aluminum hydride in Et2O at ambient temperatures. However, the former was practically more favorable.
Scheme 5. Synthesis of olivacine and ellipticine.a
R1
R1
a
b
b
c
c
LiAlH4
2
2
2
22a:
22b:
24a:
24b:
R = OMs
23a:
23b:
R = NH2 (90%)
R = N3 (86%)
CO2Et
THF
0 °C, 2 h
N
R2
N
a
H
H
2
2
2
R = OMs
R = NH2 (94%)
R = N3 (92%)
2
15a 15b
or
21a:
21b:
R = OH (97%)
1
1
a:
b:
R = H;
R = Me
2
R = OH (88%)
aReagents and conditions: (a) MsCl, Et3N, THF, rt, 1 h; (b) NaN3, DMF, 50 °C, 16 h; (c) H2 (1 atm), PtO2, MeOH, rt, 6 h.
Having prepared the key intermediates 24a and 24b for olivacine and ellipticine, respectively, we focused to
investigate the last steps (Scheme 6). 24a was easily converted into the acetamide 25 in 89% yield, by treating it
with acetic anhydride in the presence of Et3N. The Bischler-Napieralski cyclization of 25 mediated by
phosphorus(V) oxychloride delivered dihydroolivacine (26) with nearly quantitative yield (97%). Aromatization
of 26 was carried out over Pd/C at 210 °C in decalin. Thus, olivacine was obtained in 78% yield. The crude olivacine
was purified by reactive extraction, instead of the usual Soxhlet extraction with chloroform: The reaction mixture
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of the last step was cooled down to 0 °C and filtered. The solid residue was washed with 20% aqueous acetic acid
and the filtrate that contained the acetate salt of olivacine was then made alkaline by the addition of aqueous
ammonia (28%). The resulting mixture was extracted with warm chloroform. By such means, NMR-pure olivacine
was obtained in a straightforward manner. From the practical point of view it is also noteworthy that all the
intermediates for olivacine prepared herein, save the lactone 9a, did not require any column chromatographic
purification; they could be obtained in their NMR-pure forms either by simple precipitation, washing, or
recrystallization.
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The primary amine 24b that was already used as an intermediate of ellipticine by Bäckvall and Plobeck21 was
formylated with formic acid mediated by DCC and HOBt, in 86% yield (Scheme 6). The Bischler-Napieralski
cyclization of 27 with the aid of phosphorus(V) oxychloride as usual furnished dihydroellipticine (28) in 78%
yield. For its aromatization, 28 needed to be heated at 210 °C for 48 h, over Pd/C in decalin. The yield of the last
step was 50%.
Scheme 6. Synthesis of olivacine and ellipticine.
POCl3
Ac2O, Et3N
THF, rt, 2 h
Pd/C
N
O
24a
Olivacine
(R1 = H; R2 = Me)
N
H
Decalin
210 °C, 2 h
Toluene
120 °C, 2 h
N
N
H
H
78%
50%
R1 R2
26
(97%)
25
(89%)
N
N
H
DCC, HOBt
HCO2H
Ellipticine
(R1 = Me; R2 = H)
POCl3
Pd/C
O
N
24b
Decalin
210 °C, 48 h
Toluene
120 °C, 6 h
THF
0 °C to rt
16 h
N
N
H
N
H
H
H
27
28
(78%)
(86%)
After the synthesis of olivacine and ellipticine, we turned our attention to identify a common intermediate for
their synthesis. The olivacine intermediate 14 seemed to be the most suitable for this purpose (Scheme 7). 14 was
reduced with LiAlH4 to the alcohol 29 which was then acylated with acetic anhydride mediated by 4-
dimethylaminopyridine (DMAP), thus providing the ester 30 in 96% overall yield after two steps. It should be
noted that 29 and 30 are not stable on silica gel. 30 was oxidized to 31 in 53% yield by treatment with 2.00
equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in aqueous THF. N-Tosyl-derivative 32 was obtained
from 31 in 93% yield under the phase-transfer conditions. Note that the N-unprotected 4-
oxotetrahydrocarbazoles generally behave like amides; therefore, addition of main group organometallics to those
compounds is not possible, i.e. deprotonation of N-hydrogen takes place. However, a tosyl substituent at the
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nitrogen atom increases the electrophilicity of the 4-oxo functionality, thus causing the carbonyl group to exhibit
a more ketone-like character. So, addition of MeMgBr to 32 proceeded smoothly to yield the dihydroxy compound
33 which was then immediately acylated with acetic anhydride in the presence of Et3N as the base and DMAP as
the catalyst, thereby giving 34 in high yield. Note that treatment of 32 with MeLi resulted in the formation of 33
in lower yields than that of achieved with MeMgBr. Upon heating of 34 at 200 °C over Pd/C in decalin for 16 h, the
carbazole 35 was obtained in 35% yield. Surprisingly, aromatization and detosylation took place at the same time.
After saponification of the carbazole ester 35 with KOH in aqueous methanol, 21b that was herein already
identified to be a useful precursor for ellipticine was produced in quantitative yield. As a result, a divergent total
synthesis of olivacine and ellipticine was accomplished.
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Scheme 7. A common intermediate (14) for the synthesis of olivacine and ellipticine.
p-TsCl
O
NaOH(aq) (50%)
nBu4N(HSO4)
LiAlH4
DDQ
CO2Et
THF
0 °C, 2 h
N
H
N
H
H2O – CHCl3
rt, 2 h
N
H
THF – H2O (9:1)
rt, 2 h
OR
OAc
29:
R = H (96%)
31
(53%)
14
Ac2O, DMAP
Et3N, THF, rt,1 h
30:
R = Ac (quant.)
O
OR
Pd/C
Decalin
MeMgBr
THF
KOH(aq) (25%)
21b
(quant.)
N
H
N
N
OAc
OAc
OR
200 °C, 16 h
60 °C to rt
MeOH – H2O
THF
Ts
Ts
2 h
rt, 2 h
33:
35
R = H (94%)
(35%)
32
(93%)
Ac2O, DMAP
Et3N, THF, rt,1 h
34:
R = Ac (85%)
CONCLUSIONS
The procedures disclosed here are high yielding and practical, thus allow effective synthesis of olivacine and
ellipticine. For instance, 1.2 g of olivacine and 700 mg of ellipticine were prepared at a one-batch cycle.
Additionally, both alkaloids could be prepared from a common intermediate, whereby a divergent synthesis of
them was exemplified. En-route to them, a number of carbazole compounds having interesting substitution
patterns were generated. We believe that our synthetic route enables the synthesis of particular carbazole
compounds. Furthermore, we might note that by following the procedures detailed herein we have also
successfully synthesized 9-trifluoromethylellipticine, a hitherto unknown derivative of ellipticine, which will be
the subject of a prospective publication on medicinal chemistry soon. This can be regarded as a true indication of
the utility of our syntheses.
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EXPERIMENTAL SECTION
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General Information. All air-sensitive reactions were performed under an inert atmosphere of dry nitrogen (N2)
using oven-dried glassware. All reagents and solvents were transferred using gas-tight syringe and cannula
techniques under N2. Reactions were monitored by thin layer chromatography (TLC) on aluminum sheets that
were pre-coated with silica gel SIL G/UV254 from MN GmbH & Co., in which the spots were visualized in UV-light (λ
= 254 nm) and/or by staining with phosphomolybdic acid solution in EtOH (10%, w/v). Chromatographic
separations were performed using silica gel (230–400 mesh). All melting points were determined in open glass
capillary tube and values are uncorrected. Infrared (FT-IR) spectra were recorded on a PerkinElmer Spectrum One
FT-IR spectrometer, ṽmax in cm−1. Bands are characterized as broad (br), strong (s), medium (m), and weak (w). 1H
and 13C{1H} NMR spectra were recorded on a 500 MHz or 600 MHz NMR spectrometer. Chemical shifts δ are
reported in parts per million (ppm) relative to the residual protons in the NMR solvent (CHCl3: δ 7.26) and carbon
resonance of the solvent (CDCl3: δ 77.00). NMR peak multiplicities were given as follows: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad. High resolution electrospray ionization mass spectra (HR-ESI-
MS) were obtained with MeOH on a Bruker micrOTOF-Q.
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Tetrahydrofuran (THF) was freshly distilled under N2 from sodium/benzophenone prior to use under nitrogen
atmosphere. N,N-Dimethylformamide (DMF) was distilled under reduced pressure from calcium hydride (CaH2).
Dichloromethane (DCM) and triethylamine (TEA) were dried by distillation over CaH2 under N2. All other
chemicals were purchased from the commercial suppliers and used as received. 2-(2-
Phenylhydrazono)cyclohexan-1-one (2a)33, 4-methyl-2-(2-phenylhydrazono)cyclohexan-1-one (2b)33, 2,3,4,9-
tetrahydro-1H-carbazol-1-one (3a)33, 4-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3b)20, ethyl 2-(1-oxo-
2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetate (5a)14,32, and 2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetic
acid (7a)14,32 were prepared according to the literature procedures. All chiral compounds are in their racemic
forms. The directions of the wedged bonds and hashed wedged bonds in the drawings are used to denote just the
relative stereochemistries of the chiral molecules.
O
N
N
H
2a
2-(2-Phenylhydrazono)cyclohexan-1-one (2a).33 Ethyl 2-oxocyclohexanecarboxylate (1a; 44.8 g, 0.25 mol, 1.00
equiv) and 600 mL water were added into 1 L two-jacketed reactor that was equipped with a mechanical stirrer
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and a thermo-circulator. The mixture was cooled down to 2 °C with the aid of the thermo-circulator and 110 mL
of a 2.50 M aqueous NaOH solution were added dropwise into the reactor. After the addition was completed, the
mixture was stirred at 2 °C for 2 hours and left in a refrigerator at 4 °C for 72 hours. Then, the mixture was extracted
with tert-butyl methyl ether (MTBE) and the organic phase was discharged. The pH value of the aqueous phase
was adjusted to 5.50 by adding 18% aqueous HCl at 5–10 °C and the mixture was stirred at 5–10 °C for 2 hours.
Aniline (23.28 g, 22.78 mL, 0.25 mol, 1.00 equiv), 37% aqueous HCl (62.70 mL, 0.75 mol, 3.00 equiv) and 600 mL
water were added into a 1 L two-jacketed reactor that was equipped with a mechanical stirrer and a thermo
circulator. A solution of sodium nitrite (NaNO2, 17.25 g, 0.25 mol, 1.00 equiv) in water (165 mL) was added into
the reactor dropwise. After the addition was completed, the mixture was stirred 2 hours at −5 °C and so, the
formation of the diazonium salt was accomplished. The already prepared carboxylic acid solution of 1a was added
into a 5 L beaker containing crushed ice for maintaing cooling and equipped with a mechanical stirrer. Then, the
diazonium salt solution was carefully added dropwise into the 5 L beaker. After the addition was completed, the
mixture was stirred 3 hours at 0 °C. The precipitate was filtered and dried in air. The title compound (2a) was
obtained as an orange solid (44.50 g, 0.22 mol, 88%). Mp: 185–186 °C. TLC: Rf = 0.6 (silica gel; hexanes/EtOAc,
8:2). FTIR (KBr): ṽmax (cm−1) =3466 (br, w, N-H), 3245 (s), 3124 (s), 3048 (s), 3008 (s), 2942 (s), 1661 (s, C=O),
1604 (s, C=N). 1H NMR (600 MHz, CDCl3):  = 13.79 (s, 1H), 7.32 – 7.27 (m, 2H), 7.26 – 7.22 (m, 2H), 7.02 – 6.96 (m,
1H), 2.70 (dd, J = 6.5, 2.4 Hz, 2H), 2.54 – 2.46 (m, 2H), 1.84 (dt, J = 6.9, 3.5 Hz, 4H). 13C{1H} NMR (APT, 150 MHz,
CDCl3):  = 197.2 (C=O), 143.2 (C), 132.4 (C), 129.3 (CH), 122.7 (CH), 114.3 (CH), 39.8 (CH2), 32.0 (CH2), 23.5 (CH2),
22.3 (CH2). GCMS: tR = 17.79 min, m/z (%): 202 ([M]+, 100), 93 (35). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C12H15N2O 203.1179; Found 203.1178.
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N
H
O
3a
2,3,4,9-Tetrahydro-1H-carbazol-1-one (3a).33 An oven-dried 2 L round-bottomed two necked flask that was
equipped with a magnetic stirring bar, a glass stopper and a reflux condenser was charged with 2-(2-
phenylhydrazono)cyclohexan-1-one (2a; 40.45 g, 0.2 mol, 1.00 equiv). The flask was evacuated for 15 minutes,
and back-filled with N2. Then, CH3CN (500 mL) and aqueous H2SO4 (334 mL, 10%) were added into flask
consequtively, by means of a dropping funnel. The reaction flask was heated to 90 °C and stirred at this
temperature for 5 h. After the conversion was completed (TLC), the mixture was poured into a 5 L beaker
containing 2 L cold water. The precipitate was filtered, washed with distilled water, and dried. The title compound
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(3a) was obtained as a pale pink solid (34.04 g, 0.184 mol, 92%). Mp: 170–171 °C. TLC: Rf = 0.32 (silica gel;
hexanes/EtOAc, 8:2). FTIR (KBr): ṽmax (cm−1) = 3386 (br, s, N-H), 3284 (s), 2928 (s), 1647 (s, C=O). 1H NMR (600
MHz, CDCl3):  = 9.89 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.54 – 7.49 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.8,
7.2 Hz, 1H), 3.02 (t, J = 6.1 Hz, 2H), 2.73 – 2.69 (m, 2H), 2.31 – 2.25 (m, 2H). 13C{1H} NMR (APT, 150 MHz, CDCl3): 
= 191.7 (C=O), 138.2 (C), 131.2 (C), 129.6 (C), 126.9 (CH), 125.7 (C), 121.2 (CH), 120.2 (CH), 112.8 (CH), 38.2 (CH2),
25.0 (CH2), 21.4 (CH2). GCMS: tR = 30.67 min, m/z (%): 185 ([M]+, 100), 125 (84). HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C12H11NNaO 208.0733; Found 208.0732.
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CO2Et
N
H
O
5a
Ethyl 2-(1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetate (5a).14,32 A 2 L two-jacketed reactor that was equipped
with a mechanical stirrer, a dropping funnel, and a reflux condenser was charged with 2,3,4,9-tetrahydro-1H-
carbazol-1-one (3a; 30.0 g, 0.162 mol, 1.00 equiv). The reactor was evacuated for 15 minutes, back-filled with dry
N2. Then, dry THF (600 mL) was added into the reactor by means of a funnel under positive pressure of dry
nitrogen. Upon addition of THF, the starting material was dissolved. Then, NaH (16.2 g of 60% dispersion in
mineral oil, 0.402 mol, 2.50 equiv NaH) was added into the solution within 1 hour and the mixture was stirred at
room temperature for 1 hour. Diethyl oxalate (35.51 g, 32.90 mL, 0.243 mol, 1.50 equiv) was dropwise added into
the reaction mixture at room temperature, by means of a dropping funnel. After the addition of diethyl oxalate was
completed, the mixture was heated to 70 °C by means of thermo-circulator and stirred at this temperature for 3 h.
The conversion was followed by TLC. The reactor was cooled down to room temperature and the reaction mixture
was poured into 2 L beaker containing 250 mL 10% HCl. THF was removed by rotary evaporation under reduced
pressure. The precipitate was filtered, washed with distilled water, dried and washed with some methyl tert-butyl
ether. Thus, the compound 4a was obtained as a yellow solid (40.67 g, 0.142 mol, 88%). This compound was used
directly in the next step without further purification.
An oven-dried 1 L round-bottomed two necked flask that was equipped with a magnetic stirring bar, a glass
stopper was charged with 4a (57.00 g, 0.2 mol, 1.00 equiv). The flask was evacuated for 15 minutes, back-filled
with dry N2 and the glass stopper was replaced with a rubber septum under positive pressure of dry nitrogen.
Solid particles were dissolved by adding dry THF (600 mL) and triethylamine (TEA; 40.48 g, 55.45 mL, 0.40 mol,
2.00 equiv). The flask was cooled down to 0 °C in an ice-bath and methanesulfonyl chloride (MeSO2Cl; 45.82 g,
30.96 mL, 0.40 mol, 2.00 equiv) was added into the flask dropwise at this temperature. The mixture was then
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stirred for 16 h while the temperature was allowed to rise to room temperature. The conversion was followed by
TLC. The flask was cooled down to 0 °C and zinc dust (130.8 g, 2.0 mol, 10.00 equiv) was added into flask at this
temperature and the resulting mixture was stirred for 1 hour. Then, AcOH (168,14 g, 160.13 mL, 2.80 mol, 14.00
equiv) was dropwise added into the flask at 0 °C. After completion of the reaction (at room temperature for 2h),
the mixture was filtered and solid particles were removed. THF was removed by rotary evaporation under reduced
pressure. The precipitate was filtered, washed with distilled water, dried and purified by column chromatography
to give 35.23 g (0.13 mol, 65%) of the title compound (5a) as a white solid. Mp: 143–144 °C. TLC: Rf = 0.34 (silica
gel; hexanes/EtOAc, 8:2). FTIR (KBr): ṽmax (cm−1) = 3430 (br, w, N-H), 3257 (s), 2977 (s), 2929 (s), 1728 (s, C=O),
1649 (s, C=O). 1H NMR (600 MHz, CDCl3):  = 9.63 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.51 – 7.44 (m, 1H), 7.42 – 7.34
(m, 1H), 7.20 – 7.11 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.27 – 2.97 (m, 4H), 2.48 (dd, J = 16.3, 7.4 Hz, 1H), 2.43 – 2.33
(m, 1H), 2.19 – 2.05 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (APT, 150 MHz, CDCl3):  = 191.7 (C=O), 172.6
(C=O), 138.4 (C), 130.7 (C), 129.2 (C), 127.0 (CH), 125.7 (C), 121.2 (CH), 120.4 (CH), 112.7 (CH), 60.6 (CH2), 44.0
(CH), 34.8 (CH2), 31.2 (CH2), 21.1 (CH2), 14.2 (CH3). GCMS: tR = 35.91 min, m/z (%): 271 ([M]+, 74), 184 (100).
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H17NNaO3 294.1101; Found 294.1106.
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CO2H
N
H
O
7a
2-(1-Oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetic acid (7a).14,32 An oven-dried 500 mL round-bottomed one
necked flask that was equipped with a magnetic stirring bar was charged with ethyl 2-(1-oxo-2,3,4,9-tetrahydro-
1H-carbazol-2-yl)acetate (5a; 20.3 g, 75.0 mmol, 1.00 equiv). Then, THF (100 mL) and 150 g of 25% KOH ( 37.5 g
KOH + 82.5 g MeOH + 30 g H2O) solution were added into the flask consecutively. The resulting mixture was stirred
at room temperature for 1 h. After the conversion was completed (TLC), the pH value of the mixture was adjusted
to 1.5 with 10% HCl solution. The precipitate was filtered, washed with distilled water, and dried. Recrystallization
from MTBE afforded 17.50 g (72.0 mmol, 96%) of the title compound 7a as a white solid. Mp: 237-238 °C. TLC: Rf
= 0.58 (silica gel; EtOAc/MeOH, 8:2). FTIR (KBr): ṽmax (cm−1) =3281 (s, O-H), 2938 (m), 1708 (s, C=O), 1617 (s,
C=O). 1H NMR (500 MHz, DMSO-d6):  = 12.12 (s, 1H), 11.51 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H),
7.30 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.08 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 3.06 (ddd, J = 16.5, 4.8, 3.0 Hz, 1H), 3.02 – 2.87
(m, 2H), 2.79 (dd, J = 16.5, 5.2 Hz, 1H), 2.42 (dd, J = 16.5, 7.0 Hz, 1H), 2.33 – 2.21 (m, 1H), 2.06 (dt, J = 12.5, 7.5 Hz,
1H). 13C{1H} NMR (APT, 125 MHz, DMSO-d6):  = 190.9 (C=O), 173.3 (C=O), 138.2 (C), 130.7 (C), 127.6 (C), 126.0
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(CH), 125.1 (C), 121.0 (CH), 119.6 (CH), 112.7 (CH), 43.7 (CH), 34.2 (CH2), 30.5 (CH2), 20.4 (CH2). HRMS (ESI-TOF)
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m/z: [M + H]+ Calcd for C14H14NO3 244.0968; Found 244.0957.
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2b
4-Methyl-2-(2-phenylhydrazono)cyclohexan-1-one (2b).33 Ethyl 5-methyl-2-oxocyclohexanecarboxylate (1b)
(55.2 g, 0.3 mol, 1.00 equiv) and 720 mL water were added into a 1 L two-jacketed reactor that was equipped with
a mechanical stirrer and a thermo-circulator. The mixture was cooled down to 2 °C with the aid of the thermo-
circulator and 132 mL of a 2.50 M aqueous NaOH solution were added dropwise into the reactor. After the addition
was completed, the mixture was stirred at 2 °C for 2 hours and was left in a refrigerator at 4 °C for 72 hours. Then,
the mixture was extracted with MTBE and the organic phases were discharged. The pH value of the aqueous phase
was adjusted to 5.5 by adding 18% aqueous HCl at 5–10 °C and the mixture was stirred at 5–10 °C for 2 hours.
Aniline (28.00 g, 27.45 mL, 0.3 mol, 1.00 equiv), 37% aqueous HCl (75.2 mL, 0.9 mol, 3.00 equiv) and 720 mL water
were added into a 1 L two-jacketed reactor that was equipped with a mechanical stirrer and thermo circulator.
The resulting mixture in the reactor was cooled down to −5 °C and NaNO2 (20.7 g, 0.3 mol, 1.00 equiv) solution in
200 mL water was added into the reactor dropwise. After the addition was completed, the mixture was stirred 2
hours at −5 °C and so, formation of the diazonium salt was accomplished. The already prepared carboxylic acid
solution of 1b was added into a 5 L beaker containing crushed ice for maintaing cooling and equipped with a
mechanical stirrer. Then, the diazonium salt solution was carefully added dropwise into the 5 L beaker. After the
addition was completed, the mixture was stirred at 0 °C for 3 hours. The precipitate was filtered and dried in air.
The title compound (2b) was obtained as an yellow solid (57.0 g, 0.26 mol, 88%). Mp: 144–145 °C. TLC: Rf = 0.73
(silica gel; hexanes/EtOAc, 8:2). FTIR (KBr): ṽmax (cm−1) = 3436 (br, w, N-H), 3241 (s), 2955 (m), 2928 (m), 1666
(m), 1601 (s, C=N). 1H NMR (600 MHz, CDCl3):  = 13.80 (s, 1H), 7.29 (ddd, J = 9.0, 5.6, 1.8 Hz, 2H), 7.26 – 7.22 (m,
2H), 6.99 (tt, J = 7.3, 1.2 Hz, 1H), 2.79 (ddd, J = 16.0, 4.5, 2.4 Hz, 1H), 2.58 (ddd, J = 18.8, 5.8, 3.4 Hz, 1H), 2.52 – 2.42
(m, 1H), 2.33 (dd, J = 16.0, 11.2 Hz, 1H), 1.97 (dddd, J = 9.7, 7.7, 5.5, 2.8 Hz, 1H), 1.89 (dddd, J = 12.4, 9.7, 6.2, 3.2
Hz, 1H), 1.51 (dtd, J = 13.3, 11.1, 5.8 Hz, 1H), 1.10 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (APT, 150 MHz, CDCl3):  = 197.0
(C=O), 143.2 (C), 131.8 (C), 129.3 (CH), 122.7 (CH), 114.3 (CH), 40.4 (CH2), 38.8 (CH2), 30.3 (CH2), 29.9 (CH), 21.3
(CH3). GCMS: tR = 30.44 min, m/z (%): 216 ([M]+, 100), 93 (42). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H17N2O
217.1335; Found 217.1315.
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4-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3b).20 An oven-dried 2 L round-bottomed two necked flask that
was equipped with a magnetic stirring bar and a Dean-Stark apparatus was charged with p-TsOH·H2O (107.00 g,
0.56 mol, 2.01 equiv), capped with a glass stopper was evacuated for 15 min and back-filled with dry nitrogen. The
glass stopper was replaced with a rubber septum, under a positive pressure of nitrogen. Dry benzene (1.2 L) was
added into the flask and the mixture was heated to reflux in an oil bath under N2 and stirred under reflux for 24
hours. After the mixture was cooled down to ambient temperature, 600 mL of 0.463 M 4-methyl-2-(2-
phenylhydrazono)cyclohexan-1-one (2b) in dry benzene (60.0 g, 0.278 mol, 1.00 equiv of hydrazone) were added
into the flask at ambient temperature and the resulting mixture was stirred at ambient temperatures for 3 hours.
The conversion was followed by TLC. Then, the resulting mixture was poured into 5 L beaker containing 2 L of
aqueous NaHCO3 (7.5%) stirred 15 minutes with a mechanical stirrer. The phases were seperated by means of a
separatory funnel and the aqueous phase was shaken with CHCl3 (3 × 250 mL). The combined organic phases were
dried over Na2SO4, filtered, and concentrated by rotary evaporation in vacuo. The residue was then purified by
column chromatography to afford 47.0 g (0.236 mol, 85%) of the title compound (3b) as a white solid. Mp: 134–
136 °C. TLC: Rf = 0.42 (silica gel; hexanes/EtOAc, 8:2). FTIR (KBr): ṽmax (cm−1) = 3467 (br, w, N-H), 3268 (s), 2931
(w), 1635 (s, C=O). 1H NMR (600 MHz, CDCl3):  = 9.45 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.37
(ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 7.20 – 7.12 (m, 1H), 3.47 – 3.37 (m, 1H), 2.81 (ddd, J = 17.1, 9.5, 4.5 Hz, 1H), 2.61 (ddd,
J = 17.1, 7.6, 4.6 Hz, 1H), 2.39 (ddd, J = 18.3, 9.5, 4.8 Hz, 1H), 2.06 – 2.00 (m, 1H), 1.52 (d, J = 7.1 Hz, 3H). 13C{1H}
NMR (APT, 150 MHz, CDCl3):  = 191.4 (C=O), 138.2 (C), 133.7 (C), 130.4 (C), 126.7 (CH), 125.5 (C), 121.9 (CH),
120.3 (CH), 112.8 (CH), 35.4 (CH2), 32.7 (CH2), 27.8 (CH), 19.8 (CH3). GCMS: tR = 30.97 min, m/z (%): 199 ([M]+,
73), 184 (100). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H14NO 200.1070; Found 200.1056.
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H3C
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CH3
H
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4a
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H
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8a
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9a
9a
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Hb
H
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O
O
O
5b
6b
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CH3
CH3
O
O
O
13
13
cis- and trans-ethyl 2-(4-methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetate (5b [cis] and 6b [trans]). An
oven-dried 1 L two-jacketed reactor that was equipped with a mechanical stirrer, dropping funnel and reflux
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condenser was charged with 4-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3b) (19.9 g, 0.1 mol, 1.00 equiv).
The reactor was evacuated for 15 minutes, back-filled with dry N2. Then, dry THF (400 mL) was added into the
reactor by means of a funnel under positive pressure of dry nitrogen. Upon addition of THF, the starting material
was dissolved. Then, NaH (10.2 g of 60% dispersion in mineral oil, 0.25 mol, 2.50 equiv) was added into the
solution within 1 hour and the mixture was stirred 1 hour at room temperature. Diethyl oxalate (21.92 g, 20.30
mL, 0.15 mol, 1.50 equiv) was dropwise added into the reaction mixture at room temperature, by means of a
dropping funnel. After the addition of diethyl oxalate was completed, the reactor was heated to 70 °C by means of
a thermo-circulator and was stirred at this temperature for 3 h. The conversion was followed by TLC. The reactor
was cooled down to room temperature and the reaction mixture was poured into 2 L beaker containing 200 mL
10% HCl. THF was removed by rotary evaporation under reduced pressure. Then, the organic components were
extracted with EtOAc (3 × 250 mL). The combined organic extracts were dried over Na2SO4, filtered, and
concentrated by rotary evaporation in vacuo. The remaining solid was filtered, washed with n-hexane and dried.
Thus, the compound 4b was obtained as a green solid (29.9 g, 0.1 mol, quant.) and it was used directly in the next
step without further purification. An oven-dried 1 L round-bottomed two necked flask that was equipped with a
magnetic stirring bar, a glass stopper was charged with 4b (29.9 g, 0.1 mol, 1.00 equiv). The flask was evacuated
for 15 minutes, back-filled with dry N2 and the glass stopper was replaced with a rubber septum under positive
pressure of dry nitrogen. Solid particles were dissolved by adding dry THF (300 mL) and TEA (30.36 g, 41.58 mL,
0.30 mol, 3.00 equiv). The flask was cooled down to 0 °C in an ice-bath and MeSO2Cl (34.37 g, 23.22 mL, 0.30 mol,
3.00 equiv) was added into the flask dropwise at this temperature. The mixture was then stirred for 16 h while the
temperature was allowed to rise to room temperature. The conversion was followed by TLC. The flask was cooled
down to 0 °C and zinc dust (32.7 g, 0.50 mol, 5.00 equiv) was added into flask at this temperature and it was stirred
for 1 hour. Then, AcOH (84.0 g, 80.0 mL, 1.40 mol, 14.00 equiv) was dropwise added into the flask at 0 °C. After
completion of the reaction, the mixture was filtered and solid particles were removed. THF was removed by rotary
evaporation under reduced pressure. The precipitate was filtered, washed with distilled water, dried and purified
by column chromatography to give 19.0 g (0.065 mol, 67%) of a mixture the title compounds (5b/6b
diastereomeric ratio: 80:20) as a white solid. 5b and 6b could not be sepatared from each other by column
chromatography. Mp: 146–147 °C. TLC: Rf = 0.34 (silica gel; hexanes/EtOAc, 8:2). FTIR (KBr): ṽmax (cm−1) = 3452
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(br, w, N-H), 3298 (s), 2981 (w), 2959 (w), 1736 (s, C=O), 1638 (s, C=O). H NMR of the major diastereomer 5b
(600 MHz, CDCl3):  = 9.70 (s, 1H, N-H), 7.87 (d, J = 8.2 Hz, 1H, H-7), 7.49 (dd, J =11.2, 3.6 Hz, 1H, H-8), 7.36 (t, J =
7.8 Hz, 1H, H-6), 7.13 (t, J = 7.5 Hz, 1H, H-5), 4.22 (q, J = 7.1 Hz, 2H, H-12), 3.46 – 3.41 (m, 1H, H-4), 3.22 – 3.17 (m,
1H, H-2), 3.10 (dd, J = 16.4, 5.5 Hz, 1H, H-10), 2.44 (dd, J = 16.4, 7.2 Hz, 1H, H-10), 2.30 (td, J = 12.9, 4.3 Hz, 1H, Ha-
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3), 1.84 (m, 1H, Hb-3), 1.61 (d, J = 6.8 Hz, 3H, H-14), 1.30 (t, J = 7.1 Hz, 3H, H-13). 13C{1H} NMR of the major
diastereomer 5b (APT, 150 MHz, CDCl3):  = 192.0 (C, C=O, C-1), 172.8 (C, C=O, C-11), 138.77 (C, C-8a or C-9a),
132.9 (C, C-8a or C-9a), 130.4 (C, C-4b), 126.7 (CH, C-6), 125.7 (C, C-4a), 122.8 (CH, C-7), 120.4 (CH, C-5), 113.1 (CH,
C-8), 60.76 (CH2, C-12), 43.7 (CH, C-2), 41.0 (CH2, C-3), 34.8 (CH2, C-10), 30.1 (CH, C-4), 20.9 (CH3, C-14), 14.4 (CH3,
C-13). 1H NMR of the minor diastereomer 6b (600 MHz, CDCl3):  = 9.70 (s, 1H, N-H), 7.67 (d, J = 8.2 Hz, 1H, H-7),
7.48 (m, 1H, H-8), 7.39 (t, J = 7.8 Hz, 1H, H-6), 7.15 (t, J = 7.5 Hz, 1H, H-5), 4.22 (q, J = 7.1 Hz, 2H, H-12), 3.51 – 3.46
(m, 1H, H-2), 3.46 – 3.41 (m, 1H, H-4), 3.06 (dd, J = 16.4, 5.6 Hz, 1H, H-10), 2.44 (dd, J = 16.4, 7.2 Hz, 1H, H-10), 2.35
(td, J = 13.0, 5.3 Hz, 1H, Ha-3 of Hb-3), 2.12 (ddd, J = 13.2, 4.3, 2.4 Hz, 1H, Ha-3 of Hb-3), 1.50 (d, J = 7.2 Hz, 3H, H-14),
1.30 (t, J = 7.1 Hz, 3H, H-13). 13C{1H} NMR of the minor diastereomer 6b (APT, 150 MHz, CDCl3):  = 191.7 (C, C=O,
C-1), 172.7 (C, C=O, C-11), 138.72 (C, C-8a or C-9a), 133.9 (C, C-8a or C-9a), 129.7 (C, C-4b), 127.1 (CH, C-6), 125.4
(C, C-4a), 121.4 (CH, C-7), 120.5 (CH, C-5), 113.0 (CH, C-8), 60.75 (CH2, C-12), 39.5 (CH, C-2), 38.2 (CH2, C-3), 35.0
(CH2, C-10), 26.4 (CH, C-4), 19.5 (CH3, C-14), 14.4 (CH3, C-13). GCMS (6b): tR = 35.26 min, m/z (%): 285 ([M]+, 48),
198 (100). GCMS (5b): tR = 35.67 min, m/z (%): 285 ([M]+, 100), 196 (88). HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C17H20NO3 286.1443; Found 286.1428.
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CO2H
CO2H
N
N
H
H
O
O
7b
8b
Diastereomeric mixture of 2-(4-methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetic acid (7b and 8b). An oven-
dried 500 mL round-bottomed one necked flask that was equipped with a magnetic stirring bar was charged with
diastereomeric mixture of ethyl 2-(4-methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetate (5b/6b) (17.5 g,
61.4 mmol, 1.00 equiv). Then, THF (100 mL) and 150 g of 25% KOH (37.5 g KOH + 82.5 g MeOH + 30 g H2O) solution
were added into the flask respectively and the resulting mixture was stirred at rt for 1 h. The conversion was
followed by TLC. After the conversion was completed, the pH value of the mixture was adjusted to 1.5 with 10%
HCl solution. The precipitate was filtered, washed with distilled water, dried and afforded 14.85 g (57.72 mmol,
94%) of the title compound (diastereomeric mixture of 7b/8b, 80:20) as a white solid. Mp: 225–226 °C. TLC: Rf =
0.58 (silica gel; EtOAc/MeOH, 8:2). FTIR (KBr): ṽmax (cm−1) =3307 (br, s, O-H), 2909 (m), 1708 (s, C=O), 1642 (s,
C=O). 1H NMR (600 MHz, DMSO-d6): 20% minor isomer, 80% major ısomer. 13C{1H} NMR (Minor Isomer, APT, 150
MHz, DMSO-d6):  = 190.8 (C=O), 173.4 (C=O), 138.3 (C), 131.9 (C), 129.6 (C), 126.0 (CH), 124.7 (C), 121.1 (CH),
119.7 (CH), 112.9 (CH), 39.0 (CH), 37.2 (CH2), 34.2 (CH2), 25.5 (CH3), 19.5 (CH3). 13C{1H} NMR (Major Isomer, APT,
150 MHz, DMSO-d6):  = 191.2 (C=O), 173.4 (C=O), 138.4 (C), 130.9 (C), 130.4 (C), 125.7 (CH), 125.0 (C), 122.4
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(CH), 119.6 (CH), 113.0 (CH), 43.2 (CH), 40.2 (CH2), 34.0 (CH2), 29.3 (CH3), 20.7 (CH3). HRMS (ESI-TOF) m/z: [M +
2
3
4
H]+ Calcd for C15H16NO3 258.1130; Found 258.1155.
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Hb
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Ha
H
4b
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CH3
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10 Hb
Hb
H
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9a
O
10b-Methyl-3,3a,4,5,10,10b-hexahydro-2H-furo[2,3-a]carbazol-2-one (9a). An oven-dried 250 mL two-jacketed
reactor that was equipped with a magnetic stirrer and dropping funnel was charged with 2-(1-oxo-2,3,4,9-
tetrahydro-1H-carbazol-2-yl)acetic acid (7a) (5.28 g, 21.67 mmol, 1.00 equiv). The reactor was evacuated for 15
minutes, back-filled with dry N2. Then, dry THF (90 mL) and TEA (2.19 g, 3.00 mL, 21.67 mmol, 1.00 equiv) were
added into reactor respectively by means of a gas-tight syringe. Solid particles were dissolved upon addition of
THF and TEA. The reaction mixture was cooled down to 0 °C by means of a thermo circulator and 20.97 mL of 3.10
M methyllithium solution in diethoxymethane (65.0 mmol, 3.30 equiv of MeLi) were dropwise added into the
mixture. After the addition of MeLi was completed, the mixture was stirred at 0 ˚C for 2 hours. The conversion was
followed by TLC. After the conversion was completed, 11 mL of CF3COOH were dropwise added into the reaction
mixture via gas-tight syringe and it was stirred for 2 h while the temperature was allowed to rise to room
temperature. After the conversion was completed, the mixture poured into 500 mL beaker containing 250 mL 10%
aqueous K2CO3. THF was removed by rotary evaporation under reduced pressure. The precipitate was filtered,
washed with distilled water, dried and recrystallization from methanol afforded 3.40 g (14.1 mmol, 65%) of the
title compound (9a) as a white solid. Mp: 199–201 °C. TLC: Rf = 0.2 (silica gel; hexanes/EtOAc 8:2). FTIR (KBr):
ṽmax (cm−1) = 3319 (br, s, N-H), 2921 (s), 2892 (s), 2848 (s), 1756 (s, C=O). 1H NMR (600 MHz, DMSO-d6):  = 11.21
(s, 1H, NH), 7.47 (d, J = 7.8 Hz, 1H, H-7), 7.34 (d, J = 8.1 Hz, 1H, H-8), 7.15 – 7.07 (m, 1H, H-6), 6.99 (t, J = 7.4 Hz, 1H,
H-5), 2.82 (dd, J = 17.5, 8.4 Hz, 1H, Ha-10), 2.77 (ddd, J = 15.8, 8.0, 5.1 Hz, 1H, Ha-4), 2.70 (qd, J = 7.6, 4.0 Hz, 1H, H-
2), 2.65 (dt, J = 15.9, 5.5 Hz, 1H, Hb-4), 2.42 (dd, J = 20.6, 10.3 H, 1H, Hb-10), 1.97 (m, 1H, Ha-3), 1.82 – 1.72 (m, 1H,
Hb-3), 1.72 (s, 3H, H-12). 13C{1H} NMR (150 MHz, DMSO-d6):  = 175.7 (C, C=O), 136.6 (C, C-8a or C-9a), 133.0 (C, C-
8a or C-9a), 125.6 (C, C-4), 122.1 (CH, C-6), 118.9 (CH, C-7), 118.6 (CH, C-5), 111.4 (CH, C-8), 110.5 (C, C-4a), 81.6
(C, C-1), 40.7 (CH, C-2), 32.9 (CH2, C-10), 25.4 (CH3, C-12), 24.4 (CH2, C-3), 17.0 (CH2, C-4). HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C15H16NO2 242.1181; Found 242.1168.
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4b
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4a
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H
Ha
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10 Hb
Ha
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CH3
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10 Hb
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syn- and anti-5,10b-dimethyl-3,3a,4,5,10,10b-hexahydro-2H-furo[2,3-a]carbazol-2-one (9b [syn] and 10b [anti]). An
oven-dried 250 mL two-jacketed reactor that was equipped with a magnetic stirrer and dropping funnel was
charged with diastereomeric mixture of 2-(4-methyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetic acid
(7b/8b) (5.14 g, 20.0 mmol, 1.00 equiv). The reactor was evacuated for 15 minutes, back-filled with dry N2. Then
dry THF (80 mL) and TEA (2.02 g, 2.77 mL, 20.0 mmol, 1.00 equiv) were consecutively added into the reactor by
means of a gas-tight syringe. Solid particles were dissolved upon addition of THF and TEA. The homogenous
mixture was cooled down to 0 ˚C with a thermo circulator and 21.30 mL of 3.10 M methyllithium solution in
diethoxymethane (66.0 mmol, 3.30 equiv of MeLi) were dropwise added into the mixture by means of a dropping
funnel. After the addition of MeLi was completed, the mixture was stirred at 0 ˚C for 16 hours. After the conversion
was completed, 11 mL of CF3COOH were dropwise added into the reaction mixture via gas-tight syringe and it was
stirred for 2 h while the temperature was allowed to rise to room temperature. After the conversion was
completed, the mixture poured into 500 mL beaker containing 250 mL 10% aqueous K2CO3. THF was removed by
rotary evaporation under reduced pressure. The aqueous residue was extracted with EtOAc (3 × 250 mL). The
combined organic extracts were dried over Na2SO4, filtered, and concentrated by rotary evaporation in vacuo.
Then, the residue was purified by column chromatography, which afforded 2.5 g (10.0 mmol, 50%) of 9b and 0.7
g (2.75 mmol, 13%) of 10b. Compound 9b: White solid, mp: 225–227 °C. TLC: Rf = 0.49 (silica gel; hexanes/EtOAc,
7:3). FTIR (KBr): ṽmax (cm−1) = 3350 (br, s, N-H), 2972 (m), 2931 (m), 1745 (s, C=O). 1H NMR (600 MHz, DMSO-d6):
 = 11.28 (s, 1H, N-H), 7.67 (d, J = 8.0 Hz, 1H, H-7), 7.36 (t, J = 8.1 Hz, 1H, H-8), 7.11 (t, J = 7.3 Hz, 1H, H-6), 6.97 (t, J
= 7.3 Hz, 1H, H-5), 3.23 (dd, J = 17.6, 7.8 Hz, 1H, Ha-10), 2.99 –2.95 (m, 1H, H-4), 2.56 –2.50 (m, 1H, H-2), 2.25 (d, J
= 17.5 Hz, 1H, Hb-10), 1.92 (td, J = 13.3, 4.4 Hz, Ha-3), 1.69 (s, 3H, H-12), 1.43 (d, J = 6.8 Hz, 3H, H-13), 1.22 – 1.16
(m, 1H, Hb-3). 13C{1H} NMR (APT, 150 MHz, DMSO-d6):  = 175.8 (C, C=O, C-11), 136.9 (C, C-8a or C-9a), 132.2 (C,
C-8a or C-9a), 125.2 (C, C-4b ), 121.8 (CH, C-6), 120.6 (CH, C-7), 118.6 (CH, C-5), 116.3 (C, C-4a), 111.6 (CH, C-8),
80.5 (C, C-1), 40.0 (CH, C-2), 37.5 (CH2, C-3), 35.4 (CH2, C-10), 27.4 (CH, C-4), 25.1 (CH3, C-12), 20.7 (CH3, C-13).
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H18NO2 256.1338; Found 256.1326. Compound 10b: White solid, mp:
200–202 °C. TLC: Rf = 0.58 (silica gel; hexanes/EtOAc, 7:3). FTIR (KBr): ṽmax (cm−1) = 3314 (br, s, N-H), 2978 (w),
2959 (w), 2916 (m), 1752 (s, C=O). 1H NMR (600 MHz, DMSO-d6):  = 11.22 (s, 1H, N-H), 7.57 (d, J = 7.9 Hz, 1H, H-
7), 7.34 (d, J = 8.1 Hz, 1H, H-8), 7.11 (t, J = 7.4 Hz, 1H, H-6), 6.99 (t, J = 7.5 Hz, 1H, H-5), 3.17 – 3.14 (m, 1H, H-4),
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2.91 (dd, J = 17.6, 8.3 Hz, 1H, Ha-10), 2.75 (m, 1H, H-2), 2.36 (dd, J = 17.6, 6.4 Hz, 1H, Hb-10), 1.85 – 1.81 (m, 1H,
Hb-3), 1.76 (s, 3H, H-12), 1.71 – 1.67 ((m, 1H, Ha-3), 1.31 (d, J = 6.9 Hz, 3H, H-13). 13C{1H} NMR (APT, 150 MHz,
DMSO-d6):  = 175.8 (C=O), 136.8 (C, C-8a or C-9a), 132.3 (C, C-8a or C-9a), 125.2 (C, C-4b), 121.9 (CH, C-6), 119.6
(CH, C-7), 118.6, CH, C-5), 115.4 (C, C-4a), 111.5 (CH, C-8), 81.2 (C, C-1), 38.5 (CH, C-2), 33.6 (CH2, H-10), 33.4 (CH2,
C-3), 25.3 (CH3, C-12), 24.1 (CH, C-4), 20.6 (CH3, C-13). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H18NO2
256.1338; Found 256.1326.
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cis-2-(-1-Methyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetic acid (13). An oven-dried 500 mL round-bottomed
three necked flask that was equipped with a magnetic stirring bar, a punch balloon containing hydrogen gas, and
a vacuum adaptor was charged with (3a,10b)-10b-methyl-3,3a,4,5,10,10b-hexahydro-2H-furo[2,3-a]carbazol-2-
one (9a) (2.41 g, 10.0 mmol, 1.00 equiv), 400 mg Pd(OH)2/C and capped with a glass stopper. The flask was
evacuated for 15 minutes, back-filled with dry N2, then the flask was evacuated for 15 minutes again and back-
filled with H2. The glass stopper was replaced with a rubber septum under positive pressure of dry hydrogen.
Anhydrous methanol (150 mL) was added by means of a gas-tight syringe and the resulting heterogenous dark
mixture was vigorously stirred at ambient temperatures for 2 hours, under hydrogen aymosphere (ca. 1 atm). The
conversion was followed by TLC. After the conversion was completed, the mixture was filtered through a short
plug of celite. After metanol was removed by rotary evaporation under reduced pressure, the title compound (13)
(2.43 g, 10.0 mmol, quant.) was obtained as a white solid. Note that this compound is extremely instable. It
decomposes not only in solution in a couple of days, but also in its solid state within a month. Mp: 167–168 °C.
TLC: Rf = 0.28 (silica gel; hexanes/EtOAc 3:2). FTIR (KBr): ṽmax (cm−1) = 3400 (br, w, N-H), 2965 (s), 2929 (s), 1555
(s, C=O). 1H NMR (600 MHz, DMSO-d6):  = 10.70 (s, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.95 (dd, J
= 11.2, 3.9 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 3.04 (qd, J = 12.4, 6.3 Hz, 1H, H-1), 2.69 – 2.60 (m, 1H, H-4), 2.57 – 2.51
(m, 1H, H-4), 2.34 (d, J = 3.7 Hz, 1H, H-2), 2.11 (dd, J = 14.3, 7.1 Hz, 1H, H-10), 2.01 (dd, J = 14.3, 7.8 Hz, 1H, H-10),
1.75 – 1.68 (m, 1H, H-3), 1.59 (dd, J = 10.9, 4.3 Hz, 1H, H-3), 1.11 (d, J = 7.0 Hz, 3H, H-12). 13C{1H} NMR (APT, 150
MHz, DMSO-d6):  = 176.7 (C=O), 140.6 (C, Caryl), 135.9 (C, Caryl), 127.0 (C, Caryl), 119.8 (CH, Caryl), 117.7 (CH, Caryl),
117.2 (CH, Caryl), 110.6 (CH, Caryl), 106.9 (C, Caryl), 41.0 (CH2, C-10), 35.7 (CH, C-2), 30.7 (CH, C-1), 24.8 (CH2, C-3),
20.6 (CH2, C-4), 15.6 (CH3, C-12). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H18NO2 244.1338; Found 244.1326.
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Ethyl 2-(1-methyl-9H-carbazol-2-yl)acetate (15a) from 14. An oven-dried 250 mL round-bottomed two necked
flask that was equipped with a magnetic stirring bar, a glass stopper was charged with 2-(-1-methyl-2,3,4,9-
tetrahydro-1H-carbazol-2-yl)acetic acid (13) (2.43 g, 10.0 mmol, 1.00 equiv) and K2CO3 (2.76 g, 20.0 mmol, 2.00
equiv). The flask was evacuated for 15 minutes, back-filled with dry N2 and the glass stopper was replaced with a
rubber septum under positive pressure of dry nitrogen. Anhydrous DMF (50 mL) and ethyl iodide (3.12 g, 1.61
mL, 20.00 mol, 2.00 equiv) were added sequentially by means of gas-tight syringes and the resulting heterogenous
mixture was stirred ambient temperature for 2 hours. The conversion was followed by TLC. After the conversion
was completed, 50 mL water were added into the flask. The organic components were extracted with Et2O (3 × 75
mL). The combined organic phases were dried over Na2SO4, filtered, concentrated by rotary evaporation in vacuo
and the compound 14 was obtained. This compound was used directly in the next step without further purification.
An oven-dried 100 mL round-bottomed two necked flask that was equipped with a magnetic stirring bar, a glass
stopper was charged with 1.0 g Pd/C (containing 5% Pd) and the compound 14. The flask was evacuated for 15
minutes, back-filled with dry N2, the glass stopper was replaced with a rubber septum under positive pressure of
dry nitrogen and decalin (50 mL) was added by means of gas-tight syringes. The resulting mixture was heated to
210 °C in an oil-bath and stirred at this temperature for 48 h. The conversion was followed by TLC. After the
conversion was completed, the flask was cooled down to the ambient temperatures and 50 mL CHCl3 were added
into the flask. The mixture was filtered through a short plug of celite. The filtrate was concentrated by rotary
evaporation under reduced pressure. The precipitate was filtered, washed with hexanes, and dried under vacuum.
Thus, the title compound (15a) (1.87 g, 7.0 mmol, 70%) was obtained as a white solid. Mp: 143–145 °C. TLC: Rf =
0.32 (silica gel; hexanes/EtOAc 8:2). FTIR (KBr): ṽmax (cm−1) = 3346 (br, s, N-H), 2987 (s), 2954 (w), 1708 (s, C=O).
1H NMR (600 MHz, CDCl3):  = 8.03 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 7.9 Hz, 1H). 7.40 (ddd, J = 9.7, 9.1, 4.3 Hz, 2H),
7.22 (ddd, J = 7.9, 6.7, 1.4 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 2.48 (s, 3H), 1.27 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (APT, 150 MHz, CDCl3):  = 171.9 (C=O), 139.7 (C), 139.4 (C), 129.8 (C), 125.5 (CH),
123.8 (C), 122.1 (CH), 120.3 (CH), 119.4 (CH), 118.5 (C), 117.7 (CH), 110.6 (CH), 60.8 (CH2), 39.4 (CH2), 14.2 (CH3),
13.4 (CH3). GCMS: tR = 35.77 min, m/z (%): 267 ([M]+,54), 194 (100). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H18NO2 268.1338; Found 268.1334.
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Ethyl 2-(1-methyl-9H-carbazol-2-yl)acetate (15a) from 9a. An oven-dried 500 mL round-bottomed two necked
flask that was equipped with a magnetic stirring bar, a glass stopper and a reflux condenser was charged with
(3a,10b)-10b-methyl-3,3a,4,5,10,10b-hexahydro-2H-furo[2,3-a]carbazol-2-one (9a) (2.41 g, 10.0 mmol, 1.00
equiv), p-TsOH·H2O (2.66 g, 14.0 mmol, 1.40 equiv), and 5.0 g of active molecular sieve (4 Å). The flask was
evacuated for 15 minutes, back-filled with dry N2. Absolute ethanol (40 mL) and p-xylene (160 mL) were added
into the flask by means of a funnel under positive pressure of dry nitrogen. The mixture was heated to 90 °C under
N2 and was stirred at this temperature for 16 h. The conversion was followed by TLC. After the conversion was
completed, the flask cooled down to ambient temperature. Solid particles were filtered off. Ethanol and p-xylene
were removed by rotary evaporation under reduced pressure and the intermediate 16 was obtained. An oven-
dried 100 mL round-bottomed two necked flask that was equipped with a magnetic stirring bar, glass stopper was
charged with 1.0 g Pd/C (containing 5% Pd) and the intermediate 16. The flask was evacuated for 15 minutes,
back-filled with dry N2, the glass stopper was replaced with a rubber septum under positive pressure of dry
nitrogen and decalin (50 mL) was added by means of gas-tight syringes. The flask was heated to 210 °C in an oil-
bath and was stirred at this temperature for 48 h. The conversion was followed by TLC. After the conversion was
completed, the flask was cooled down to the ambient temperatures and 50 mL CHCl3 were added into the flask.
The mixture was filtered through a short plug of celite. Chloroform was removed by rotary evaporation under
reduced pressure. The precipitate was filtered, dried and purified by column chromatography to afford 1.98 g (7.4
mmol, 74%) of the title compound (15a) as a white solid.
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Ethyl 2-(1,4-dimethyl-9H-carbazol-2-yl)acetate (15b). An oven-dried 500 mL round-bottomed two necked flask
that was equipped with a magnetic stirring bar, a glass stopper and a reflux condenser was charged with
diastereomeric mixtures of (3a,10b)-5,10b-dimethyl-3,3a,4,5,10,10b-hexahydro-2H-furo[2,3-a]carbazol-2-one
(9b/10b, 80:20) (7.85 g, 30.8 mmol, 1.00 equiv), p-TsOH·H2O (2.66 g, 14.0 mmol, 1.40 equiv), 10.0 g molecular
sieves (4 A˚) and 6.16 g Pd/C (contain 10% Pd). The flask was evacuated for 15 minutes, back-filled with dry N2.
Absolute ethanol (123 mL) and p-xylene (492 mL) were added into the flask by means of a funnel under positive
pressure of dry nitrogen. The flask was heated to 90 ˚C and was stirred at this temperature for 2 h. The conversion
was followed by TLC. After the conversion was completed, ethanol was removed by distillation under nitrogen
atmosphere. Then the flask was heated to 140 ˚C for 48 h. The conversion was followed by TLC. After the
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conversion was completed, the flask was cooled down to the ambient temperatures and 50 mL CHCl3 were added
into the flask. The mixture was filtered through a short plug of celite. CHCl3 and p-xylene were removed by rotary
evaporation under reduced pressure. The precipitate was filtered, dried and purified by column chromatography
to afford 6.14 g (21.85 mmol, 71%) of the title compound (15b) as a white solid. Mp: 134–136 °C. TLC: Rf = 0.38
(silica gel; hexanes/EtOAc, 8:2). FTIR (KBr): ṽmax (cm−1) = 3380 (br, s, N-H), 2967 (m), 2955 (m), 1709 (s, C=O). 1H
NMR (600 MHz, CDCl3):  = 8.11 (d, J = 7.9 Hz, 1H), 8.08 (s, 1H), 7.40 (ddd, J = 11.1, 8.8, 4.3 Hz, 2H), 7.25 – 7.20 (m,
1H), 6.89 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 2.78 (s, 3H), 2.45 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(APT, 150 MHz, CDCl3):  = 172.1 (C=O), 139.7 (C), 139.4 (C), 130.5 (C), 129.4 (C), 124.8 (CH), 124.4 (C), 123.4
(CH), 122.3 (CH), 120.7 (C), 119.3 (CH), 115.7 (C), 110.4 (CH), 60.8 (CH2), 39.2 (CH2), 20.3 (CH3), 14.2 (CH3), 13.1
(CH3). GCMS: tR = 36.36 min, m/z (%): 281 ([M]+, 71), 208 (100). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H20NO2
282.1494; Found 282.1475.
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NH2
H
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2-(1-Methyl-9H-carbazol-2-yl)acetamide (17). An oven-dried 100 mL round-bottomed two necked flask that was
equipped with a magnetic stirring bar, glass stopper and reflux condenser was charged with ethyl 2-(1-methyl-
9H-carbazol-2-yl)acetate (15a) (1.07 g, 4.0 mmol, 1.00 equiv). The flask was evacuated for 15 minutes, back-filled
with dry N2, the glass stopper was replaced with a rubber septum under positive pressure of dry nitrogen. 16 mL
dry DMF were added by means of a gas-tight syringe. Upon dissolution of the solid particles, formamide (1.21 g,
1.07 mL, 26.8 mmol, 6.70 equiv) was added into the flask flask by means of a gas-tight syringe. The flask was heated
to 105 ˚C in an oil-bath and was stirred at this temperature for 1 hour. Then, 4 mL of 2.31 M NaOMe in methanol
(9.24 mmol, 2.31 equiv of NaOMe) were dropwise added into the flask at 105 ˚C, within 15 minutes. The resulting
mixture was stirred at this temperature for 3 hours. The conversion was followed by TLC. After the conversion
was completed, the flask was cooled down to the ambient temperatures and 50 mL water were added. The organic
components were extracted with EtOAc (3 × 75 mL). The combined organic phases were dried over Na2SO4,
filtered, concentrated by rotary evaporation in vacuo. The precipitate was washed with Et2O and dried in vacuo
overnight, which afforded 763 mg (3.2 mmol, 80%) of the title compound (17) as a white solid. Mp: 267–268 °C.
TLC: Rf = 0.25 (silica gel; EtOAc ). FTIR (KBr): ṽmax (cm−1) = 3433 (s, N-H), 3365 (s, N-H), 2921 (s), 1631 (s, C=O).
1H NMR (500 MHz, DMSO-d6):  = 11.08 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 8.1 Hz,
1H), 7.41 – 7.32 (m, 2H), 7.13 (dd, J = 11.0, 3.8 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 3.60 (s, 2H), 2.51 (s,
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3H). 13C{1H} NMR (APT, 125 MHz, DMSO-d6):  = 172.5 (C=O), 140.0 (C), 139.7 (C), 131.8 (C), 125.0 (CH), 122.9 (C),
121.4 (CH), 120.7 (C), 119.9 (CH), 118.9 (C), 118.3 (CH), 117.0 (CH), 110.9 (CH), 40.1 (CH2), 13.5 (CH3). HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H15N2O 239.1184; Found 239.1172.
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2-(1-Methyl-9H-carbazol-2-yl)ethan-1-ol (21a). An oven-dried 100 mL Schlenk flask that was equipped with a
magnetic stirring bar and a glass stopper was evacuated for 15 minutes, back-filled with dry N2. The glass stopper
opened, LiAlH4 (570 mg, 15.0 mmol, 2.50 equiv) was added into flask and the glass stopper was replaced with a
rubber septum under positive pressure of dry nitrogen. 10 mL dry THF were added into flask by means of a gas-
tight syringe and the flask was cooled down to 0 ˚C in an ice-bath, 25 mL of 0.24 M ethyl 2-(1-methyl-9H-carbazol-
2-yl)acetate (15a) (1.60 g, 6.0 mmol, 1.00 equiv) in THF were dropwise added into the flask. The resulting mixture
was then stirred for 1 h while the temperature was allowed to rise to room temperature. The conversion was
followed by TLC. After the conversion was completed, 20 mL of 3.0 M KOH were dropwise added into the flask at
ambient temperatures. Organic components were extracted with EtOAc (3 × 50 mL). The combined organic phases
were dried over Na2SO4, filtered, concentrated by rotary evaporation in vacuo. Purification of the residue by flash
column chromatography on silica gel gave 1.31 g (5.82 mmol, 97%) of the title compound (21a) as a white solid.
Mp: 116–117 °C. TLC: Rf = 0.28 (silica gel; hexanes/EtOAc, 1:1). FTIR (KBr): ṽmax (cm−1) = 3434 (s, N-H), 3305 (br,
s, O-H), 2945 (m), 2873 (m), 1928 (s). 1H NMR (500 MHz, CDCl3):  = 8.05 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.87 (d, J
= 7.9 Hz, 1H), 7.42 (ddd, J = 10.7, 9.1, 4.5 Hz, 2H), 7.26 – 7.22 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H), 3.90 (t, J = 6.8 Hz, 2H),
3.09 (t, J = 6.8 Hz, 2H), 2.50 (s, 3H). 13C{1H} NMR (APT, 125 MHz, CDCl3):  = 139.69 (C), 139.65 (C), 133.6 (C), 125.5
(CH), 123.9 (C), 121.8 (CH), 121.6 (C), 120.2 (CH), 119.5 (CH), 118.1 (C), 117.7 (CH), 110.6 (CH), 63.4 (CH2), 36.5
(CH2), 13.0 (CH3). GCMS: tR = 35.07 min, m/z (%): 225 ([M]+,34), 194 (100). HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C15H16NO 226.1232; Found 226.1220.
N
OH
H
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2-(1,4-Dimethyl-9H-carbazol-2-yl)ethan-1-ol (21b). An oven-dried 250 mL Schlenk flask that was equipped with a
magnetic stirring bar and a glass stopper was evacuated for 15 minutes, back-filled with dry N2. The glass stopper
was opened, LiAlH4 (3.80 g, 0.10 mol, 5.00 equiv) was added into the flask and the glass stopper was replaced with
a rubber septum under positive pressure of dry nitrogen. 20 mL dry THF was added by means of a gas-tight syringe
and the flask cooled down to 0 °C in an ice-bath. 60 mL of 0.33 M ethyl 2-(1,4-dimethyl-9H-carbazol-2-yl)acetate
(15b) (5.62 g, 20.0 mmol, 1.00 equiv) in THF were dropwise added into the flask. The mixture was then stirred for
1 h while the temperature was allowed to rise to room temperature. The conversion was followed by TLC. After
the conversion was completed, 50 mL 3.0 M KOH were dropwise added into the flask at ambient temperatures.
Organic components were extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over
Na2SO4, filtered, concentrated by rotary evaporation in vacuo. Purification of the residue by flash column
chromatography on silica gel gave 4.21 g (17.6 mmol, 88%) of the title compound (21b) as a white solid. Mp: 153–
155 °C. TLC: Rf = 0.3 (silica gel; hexanes/EtOAc, 3:2). FTIR (KBr): ṽmax (cm−1) = 3532 (s, N-H), 3269 (s, O-H), 2936
(w), 2880 (w). 1H NMR (600 MHz, CDCl3):  = 8.15 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H),
7.26 (t, J = 7.5 Hz, 1H), 6.87 (s, 1H), 3.90 (t, J = 6.8 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.83 (s, 3H), 2.47 (s, 3H). 13C{1H}
NMR (APT, 150 MHz, CDCl3):  = 139.6 (C), 139.5 (C), 133.2 (C), 130.5 (C), 124.8 (CH), 124.4 (C), 123.1 (CH), 122.3
(CH), 120.1 (C), 119.3 (CH), 115.3 (C), 110.4 (CH), 63.4 (CH2), 36.4 (CH2), 20.3 (CH3), 12.8 (CH3). GCMS: tR = 36.36
min, m/z (%): 239 ([M]+, 32), 208 (100). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H18NO 240.1388; Found
240.1373.
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2-(2-Azidoethyl)-1-methyl-9H-carbazole (23a). An oven-dried 100 mL round-bottomed two necked flask that was
equipped with a magnetic stirring bar and the glass stopper was charged with 2-(1-methyl-9H-carbazol-2-
yl)ethan-1-ol (21a) (1.13 g, 5.0 mmol, 1.00 equiv). The flask was evacuated for 15 minutes, back-filled with dry N2,
the glass stopper was replaced with a rubber septum under positive pressure of dry nitrogen. Upon addition of 50
mL dry THF by means of a gas-tight syringe, the solid particles were dissolved. The flask was cooled down to 0 °C
in an ice-bath. TEA (1.01 g, 1.39 mL, 10.0 mmol, 2.00 equiv) and MeSO2Cl (601 mg, 406.0 µL, 5.25 mmol, 1.05 equiv)
were consecutively added into the flask by using gas-tight syringes. The mixture was then stirred for 1 h while the
temperature was allowed to rise to room temperature. The conversion was followed by TLC. After the conversion
was completed, 50 mL aqueous saturated NaHCO3 were dropwise added into the flask at ambient temperatures.
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Organic components were extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over
Na2SO4, filtered, concentrated by rotary evaporation in vacuo and the intermediate 22a was obtained. An oven-
dried 100 mL round-bottomed two necked flask that was equipped with a magnetic stirring bar and a glass stopper
was charged with the intermediate 22a and NaN3 (1.63 g, 25.0 mmol, 5.00 equiv). The flask was evacuated for 15
minutes, back-filled with dry N2, the glass stopper was replaced with a rubber septum under positive pressure of
dry nitrogen. 40 mL dry DMF were added into the flask by means of a gas-tight syringe and the resulting
heterogenous mixture was stirred at 50 °C in an oil bath for 16 hours. The conversion was followed by TLC. After
the conversion was completed, the flask was cooled down to the ambient temperatures and 40 mL water were
added. Organic components were extracted with Et2O (3 × 100 mL). The combined organic phases were dried over
Na2SO4, filtered, concentrated by rotary evaporation in vacuo. Purification of the residue by flash column
chromatography on silica gel gave 1.08 g (4.3 mmol, 86%) of the title compound (23a) as a white solid. Mp: 70–
71 °C. TLC: Rf = 0.23 (silica gel; hexanes/EtOAc, 9:1). FTIR (KBr): ṽmax (cm−1) = 3441 (s, N-H), 2935 (m), 2090 (s,
N3). 1H NMR (500 MHz, CDCl3):  = 8.06 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.48 – 7.38 (m, 2H), 7.26 (ddd, J
= 8.0, 5.0, 1.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 3.55 (t, J = 7.6 Hz, 2H), 3.13 (t, J = 7.6 Hz, 2H), 2.52 (s, 3H). 13C{1H}
NMR (APT, 125 MHz, CDCl3):  = 139.8 (C), 139.6 (C), 133.3 (C), 125.6 (CH), 124.0 (C), 122.0 (C), 121.5 (CH), 120.3
(CH), 119.6 (CH), 117.9 (CH), 117.8 (C), 110.7 (CH), 52.3 (CH2), 32.8 (CH2), 12.9 (CH3).
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2-(2-Azidoethyl)-1,4-dimethyl-9H-carbazole (23b). An oven-dried 500 mL round-bottomed two necked flask that
was equipped with a magnetic stirring bar and a glass stopper was charged with 2-(1,4-dimethyl-9H-carbazol-2-
yl)ethan-1-ol (21b) (4.60 g, 19.2 mmol, 1.00 equiv). The flask was evacuated for 15 minutes, back-filled with dry
N2, the glass stopper was replaced with a rubber septum under positive pressure of dry nitrogen. Upon addition
of 190 mL dry THF by means of a gas-tight syringe, the solid particles were dissolved. The flask cooled down to 0
˚C in an ice-bath. TEA (3.89 g, 5.33 mL, 38.4 mmol, 2.00 equiv) and MeSO2Cl (2.31 g, 1.56 mL, 20.16 mmol, 1.05
equiv) were consecutively added into the flask by using gas-tight syringes. The mixture was then stirred for 1 h
while the temperature was allowed to rise to room temperature. The conversion was followed by TLC. After the
conversion was completed, 50 mL aqueous saturated NaHCO3 were dropwise added into the flask at ambient
temperatures. Organic components were extracted with EtOAc (3 × 150 mL). The combined organic phases were
dried over Na2SO4, filtered, concentrated by rotary evaporation in vacuo and the intermediate 22b was obtained.
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An oven-dried 500 mL round-bottomed two necked flask that was equipped with a magnetic stirring bar and a
glass stopper was charged with the intermediate 22b and NaN3 (6.24 g, 96.00 mmol, 5.00 equiv). The flask was
evacuated for 15 minutes, back-filled with dry N2, the glass stopper was replaced with a rubber septum under
positive pressure of dry nitrogen. 150 mL dry DMF were added into the flask by means of a gas-tight syringe and
the resulting heterogenous mixture was stirred 50 ˚C in an oil-bath for 16 hours. The conversion was followed by
TLC. After the conversion was completed, the flask was cooled down to ambient temperatures and 40 mL water
were added into the flask. Organic components were extracted with Et2O (3 × 200 mL). The combined organic
phases were dried over Na2SO4, filtered, concentrated by rotary evaporation in vacuo. Purification of the residue
by flash column chromatography on silica gel gave 4.67 g (17.66 mmol, 92%) of the title compound (23b) as a
white solid. Mp: 74–75 °C. TLC: Rf = 0.32 (silica gel; hexanes/EtOAc, 9:1). FTIR (KBr): ṽmax (cm−1) = 3359 (s, N-H),
2921 (m), 2090 (s, N3). 1H NMR (600 MHz, CDCl3):  = 8.16 (d, J = 7.9 Hz, 1H), 7.98 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H),
7.43 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 3.53 (t, J = 7.7 Hz, 2H), 3.09 (t, J = 7.7 Hz, 2H), 2.85 (s, 3H), 2.49 (s,
3H). 13C{1H} NMR (APT, 125 MHz, CDCl3):  = 139.6 (C), 139.4 (C), 132.9 (C), 130.7 (C), 124.9 (CH), 124.4 (C), 122.8
(CH), 122.3 (CH), 120.4 (C), 119.5 (CH), 115.0 (C), 110.4 (CH), 52.2 (CH2), 32.7 (CH2), 20.3 (CH3), 12.7 (CH3). HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H15N4 263.1297; Found 263.1321.
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2-(1-Methyl-9H-carbazol-2-yl)ethan-1-amine (24a).13,14,21 An oven-dried 100 mL round-bottomed three necked
flask that was equipped with a magnetic stirring bar, a punch balloon that was containing hydrogen gas, and a
vacuum adaptor was charged with 2-(2-azidoethyl)-1-methyl-9H-carbazole (23a) (1.50 g, 6.0 mmol, 1.00 equiv),
68 mg PtO2 (5%) and capped with a glass stopper. The flask was evacuated for 15 minutes, back-filled with dry N2,
then the flask was evacuated for 15 minutes again and back-filled with H2. The glass stopper was replaced with a
rubber septum under positive pressure of hydrogen. Anhydrous methanol (48 mL) was added by means of a gas-
tight syringe and the resulting heterogenous mixture was vigorously stirred for 6 hours at ambient temperatures
under hydrogen atmosphere (ca. 1 atm). The conversion was followed by TLC. After the conversion was completed,
the mixture was carefully filtered through a short plug of celite. Methanol was removed by rotary evaporation
under reduced pressure and the remaining solid was dried overnight in vacuo. Thus, the title compound (24a)
(1.21 g, 5.4 mmol, 90%) was obtained as a white solid. Mp: 168–171 °C. TLC: Rf = 0.6 (silica gel; TEA/MeOH, 1:1).
FTIR (KBr): ṽmax (cm−1) = 3437 (br, w, N-H), 3350 (s, N-H), 2882 (m). 1H NMR (500 MHz, DMSO-d6):  = 10.92 (s),
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8.01 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.41 – 7.24 (m, 1H), 7.18 – 7.06 (m, 1H), 6.99
(d, J = 7.9 Hz, 1H), 2.94 – 2.76 (m, 4H), 2.52 (s, 3H). 13C{1H} NMR (APT, 125 MHz, DMSO-d6):  = 139.9 (C), 139.8
(C), 135.4 (C), 124.8 (CH), 123.0 (C), 120.8 (CH), 120.2 (C), 119.8 (CH), 118.3 (CH), 117.9 (C), 117.1 (CH), 110.9
(CH), 43.4 (CH2), 37.7 (CH2), 13.1 (CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H17N2 225.1392; Found
225.1387.
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2-(1,4-Dimethyl-9H-carbazol-2-yl)ethan-1-amine (24b). An oven-dried 250 mL round-bottomed three necked
flask that was equipped with a magnetic stirring bar, a punch balloon that was containing hydrogen gas, and a
vacuum adaptor was charged with 2-(2-azidoethyl)-1,4-dimethyl-9H-carbazole (23b) (4.28 g, 16.20 mmol, 1.00
equiv), 184 mg PtO2 (5%) and capped with a glass stopper. The flask was evacuated for 15 minutes, back-filled
with dry N2, then the flask was evacuated for 15 minutes again and back-filled with H2. The glass stopper was
replaced with a rubber septum under positive pressure of hydrogen. Anhydrous methanol (130 mL) was added
by means of a gas-tight syringe and the resulting heterogenous mixture was vigorously stirred at ambient
temperatures for 6 hours under hydrogen atmosphere (ca. 1atm). The conversion was followed by TLC. After the
conversion was completed, the mixture was carefully filtered through a short plug of celite. Methanol was removed
by rotary evaporation under reduced pressure and the remaining solid was dried overnight in vacuo. Thus, the
title compound(24b) (3.47 g, 14,6 mmol, 90%) was obtained as a white solid. Mp: 195–200 °C (Decomp.). TLC: Rf
= 0.6 (silica gel; TEA/MeOH, 1:1). FTIR (KBr): ṽmax (cm−1) = 3410 (br, w, N-H), 3348 (s, N-H), 3288 (w), 3153 (m),
3086 (m), 2927 (m). 1H NMR (600 MHz, DMSO-d6):  = 11.05 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H),
7.34 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.77 (s, 1H), 2.78 (td, J = 11.2, 6.9 Hz, 4H), 2.72 (s, 3H), 2.47 (s, 3H).
13C{1H} NMR (APT, 150 MHz, DMSO-d6):  = 139.9 (C), 139.8 (C), 135.1 (C), 128.9 (C), 124.2 (CH), 123.5 (C), 122.2
(CH), 121.6 (CH), 118.8 (C), 118.4 (CH), 115.2 (C), 110.7 (CH), 43.5 (CH2), 37.6 (CH2), 20.1 (CH3), 12.9 (CH3). HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H19N2 239.1548; Found 239.1538.
O
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