Palladium-Catalyzed Synthesis of Pyrayaquinones, Murrayaquinones, and Murrayafoline-B

SYNTHESIS

0

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1

4

3

7

-

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2016, 48, A–R

paper

A

S. K. Kutz et al.

Paper

Synthesis

Palladium-Catalyzed Synthesis of Pyrayaquinones, Murraya-

quinones, and Murrayafoline-B

O

Sebastian K. Kutz

N

Pd(II)-catalyzed

oxidative cyclization

Arndt W. Schmidt

KO₃S

SO₃K

O

Hans-Joachim Knölker*

N

O

H

Department Chemie, Technische Universität Dresden,

Bergstraße 66, 01069 Dresden, Germany

hans-joachim.knoelker@tu-dresden.de

O

pyrayaquinone-C

O

N

H

OTs

O

N

Dedicated to Professor Dieter Enders on the occasion of

his 70^thbirthday.

KO₃S

SO₃K

DIBAL-H

HO

N

O

H

murrayaquinone-D

Received: 08.08.2016

Accepted after revision: 06.09.2016

Published online: 11.10.2016

(2)⁹and in 1987, the same authors reported an alternative

route to 2 and a synthetic access to pyrayaquinone-A (1).¹⁰

Pyrayaquinone-C (3) was isolated by Furukawa and co-

workers in 1988 from the same natural source as com-

pounds 1 and 2.¹¹The first isolation of murrayaquinone-B

(5) was communicated by Furukawa and co-workers in

1983.¹²Full details of the extraction and purification were

reported in 1985 together with the isolation and structural

elucidation of murrayaquinone-A (4), -C (7), and -D (8).¹³

Murrayaquinone-E (6) was first described by the same

group six years later.¹⁴In contrast to compounds 1–5, 7, and

8, compound 6 was not obtained from the root bark, but

from the stem bark of M. euchrestifolia.

DOI: 10.1055/s-0036-1588322; Art ID: ss-2016-m0558-op

Abstract We describe the total synthesis of murrayafoline-B and seven

carbazole-1,4-quinone alkaloids. A palladium(II)-catalyzed oxidative cy-

clization is used to construct the carbazole skeleton. Pyran annulation

and oxidation provide pyrayaquinone-A, -B, and -C. DIBAL-H-promoted

reductive ring opening of pyrano[3,2-a]carbazole precursors leads to

the prenylated and geranylated carbazole-1,4-quinone alkaloids mur-

rayaquinone-B, -C, -D, and -E and to murrayafoline-B.

Key words carbazole, alkaloids, quinones, natural products, total syn-

thesis, palladium, Frémy’s salt, ring opening

Various approaches to murrayaquinone-A (4) have been

developed,^1b,1f,15the first one being reported by Kapil in

1987.¹⁰We described an iron-mediated and a palladium-

catalyzed synthesis of murrayaquinone-A (4) in 1993 and

2003, respectively.¹⁶The groups of Moody and Kapil de-

scribed synthetic routes to murrayaquinone-B (5) in 1985

and 1986.¹⁷Only recently, Norcott and McErlean reported

the total synthesis of the carbazolequinones 2, 3, and 5–8.¹⁸

Herein, we describe our route to the carbazole-1,4-quinone

alkaloids pyrayaquinone-A–C (1–3) and murrayaquinone-

B–E (5–8) utilizing a common precursor.

Our projected route relies on late-stage oxidation of a 1-

hydroxycarbazole to the corresponding quinoid natural

products 5–8 (Scheme 1). The prenylated or geranylated

carbazoles 9 would be generated by our recently developed

DIBAL-H-mediated reductive pyran ring opening of pyrano-

carbazoles 10.¹⁹The latter also represent the precursors to

the pyrayaquinones 2 and 3 and are available by pyran ring

annulation at the hydroxycarbazole 13, which in turn is

synthesized by palladium(II)-catalyzed oxidative cycliza-

tion of the corresponding diarylamine. Pyrayaquinone-A (1)

would be available by regioselective pyran ring annulation

Carbazole alkaloids have been the topic of scientific in-

terest due to their unique chemical and medicinal proper-

ties.¹Various methods have been developed for construc-

tion of the carbazole skeleton, with many relying on transi-

tion-metal-mediated and -catalyzed reactions.²We

previously developed iron-mediated³and palladium-cata-

lyzed approaches to carbazole alkaloids.⁴The latter relies

on a palladium(II)-catalyzed oxidative cyclization of diaryl-

amines by double C–H bond activation.⁵The feasibility of

this reaction had been first demonstrated on a carbazole-

1,4-quinone.^4aSeveral quinoid carbazoles have been isolat-

ed from natural sources and their promising pharmacologi-

cal potential, e.g., anti-TB activity, has induced scientific in-

terest.^1f,6The carbazole-1,4-quinones 1–8 have been ob-

tained from Murraya euchrestifolia (Rutaceae), one of the

main natural sources of carbazole alkaloids (Figure 1). Pyra-

yaquinone-A (1) and -B (2) were isolated first in 1985 by

Furukawa and co-workers from the acetone extract of the

root bark of Murraya euchrestifolia Hayata collected in Tai-

wan.⁷The structures were assigned based on spectroscopic

data and confirmed by total synthesis.^7,8In 1986, Ramesh

and Kapil outlined the first synthesis of pyrayaquinone-B

B

S. K. Kutz et al.

Paper

Synthesis

at the C-6–C-7 linkage of the hydroxycarbazole 13 and sub-

sequent oxidation (not shown). Analogously to our previous

syntheses of other oxygenated pyrano[3,2-a]carbazoles, we

initially used the triisopropylsilyloxycarbazole 18 for pyran

annulation (Scheme 2).^4d,4f,19aCopper(I)-catalyzed Ullmann-

type coupling²⁰of 3-(benzyloxy)iodobenzene (14b) and the

hydroxyaniline 15a was followed by O-silylation to provide

the diarylamine 17b in high yield. This sequence proved to

be superior to the Buchwald–Hartwig amination of the bro-

moarene 16b and the triisopropylsilyl-protected aniline

15b, which provided the desired diarylamine 17b only in

very low yield (probably due to steric hindrance). Palladi-

um(II)-catalyzed oxidative cyclization and hydrogenolytic

benzyl ether cleavage afforded the desired carbazole 18 in

good yield (71%). However, attempts at pyran annulation

with hydroxycarbazole 18 using either Casiraghi’s [Ti(Oi-

Pr)₄/prenal]^21aor Dufresne’s method [PhB(OH)₂/propionic

acid/prenal]^21bprovided mixtures of compounds, while

O

N

H

N

H

O

pyrayaquinone-A (1)

pyrayaquinone-B (2)

O

N

O

H

pyrayaquinone-C (3)

murrayaquinone-A (4)

O

RO

N

H

O

H

Godfrey’s

protocol

[CuCl₂/DBU/1,1-dimethylpropargyl

methyl carbonate (11)]²²induced migration of the silyl

group.^4f,21The latter reaction parallels the DBU-induced

cleavage of phenolic silyl ethers that was reported by Kim

and co-workers in 2007.²³

murrayaquinone-B (5)

R = Me

murrayaquinone-C (7)

R = Me

murrayaquinone-E (6)

R = H

murrayaquinone-D (8)

R = H

Due to the difficulties associated with the silyl group of

the hydroxycarbazole 18, we decided to replace both pro-

tecting groups and used instead the 7-methoxycarbazol-1-

Figure 1 Naturally occurring carbazole-1,4-quinone alkaloids

O

RO

b

R¹O

HO

+

N

H

N

H

OH

BnO

N

H

O

OPG

I

NH₂

15a

OH

5 R¹= Me, R²= H

6 R¹= H, R²= H

7 R¹= Me, R²= prenyl

8 R¹= H, R²= prenyl

9

14a, R = H

14b, R = Bn

17a

R²

R²= H, prenyl

a

c

reductive

ring-

opening

RO

DIBAL-H

d

+

OR

BnO

N

H

O

Br

16a, R = H

16b, R = Bn

NH₂

15a, R = H

15b, R = TIPS

OTIPS

17b

a

c

O

N

H

O

OPG

H

R²

2 R²= H

10

e, f

3 R²= prenyl

R

²= H, prenyl

HO

O

N

H

OTIPS

H

O

18

19

6

O

OMe

4b 4a

3

O

OMe

Scheme 2 Synthesis of the 7-hydroxy-1-(silyloxy)carbazole 18. Re-

agents and conditions: (a) BnBr (1.5 equiv), K₂CO₃(1.5 equiv), acetone,

r.t., 6 h (14b: 99%; 16b: 73%); (b) 14b (1.0 equiv), 15a (2.0 equiv), CuI

(20 mol%), K₃PO₄(2.0 equiv), DMF, 80 °C, 18 h (85%); (c) TIPSCl (1.2

equiv), ImH (1.2 equiv), DMF, 50 °C, 24 h (15b: 84%; 17b: 96%); (d) 16b

(1.0 equiv), 15b (1.3 equiv), Pd(OAc)₂(6 mol%), XPhos (12 mol%), tolu-

ene, reflux, 25 h (9%); (e) Pd(OAc)₂(15 mol%), Cu(OAc)₂(2.5 equiv),

AcOH, 130 °C, microwave (300 W), 30 min; (f) H₂(1 atm), Pd/C (2 wt%),

EtOAc, r.t., 3 d (71%, 2 steps).

or

+

HO

7

1

8a

9a

N

H

8

OPG

11

12

13

Scheme 1 Retrosynthetic analysis of the carbazole-1,4-quinones 2, 3,

and 5–8

C

S. K. Kutz et al.

Paper

Synthesis

yl tosylate 22 for our synthesis (Scheme 3). Copper(I)-cata-

lyzed Ullmann-type coupling of m-iodoanisole (20) and the

aminocresol 15a provided the diarylamine 21a in high

yield. O-Tosylation and treatment of the resulting tosyl-pro-

tected diarylamine 21b with catalytic amounts of palladi-

um(II) acetate and potassium carbonate in pivalic acid at

100 °C led to the desired 7-methoxycarbazole 22. The

methyl ether was cleaved by heating of 22 in a mixture of

acetic acid and hydrobromic acid to provide the 7-hydroxy-

carbazole 23 in good yield. The pyran ring was then annu-

lated using Godfrey’s method.²²Treatment of compound 23

with 1,1-dimethylpropargyl methyl carbonate (11) in the

presence of catalytic amounts of copper(II) chloride and

DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) gave the propar-

gyloxycarbazole 24, thermally-induced rearrangement of

which finally provided the pyrano[3,2-a]carbazole 25. Lith-

ium aluminum hydride induced cleavage of the tosyl group

afforded the hydroxycarbazole 26, which already had been

an intermediate in Kapil’s synthesis of pyrayaquinone-B

(2).⁹Oxidation using Frémy’s salt²⁴provided compound 2 in

46% yield, which is superior to the oxidation with PCC (30%

yield)⁹as reported by Kapil. Our route led to natural product

2 in eight steps and 27% overall yield.

OMe

a

+

I

H₂N

MeO

N

H

OH

OR

20

15a

21a, R = H

b

21b, R = Ts

c

d

MeO

HO

N

H

N

H

OTs

OH

OTs

22

23

e

f

O

N

H

N

H

OTs

24

25

O

g

h

O

N

H

N

H

O

Pyrayaquinone-C (3) was synthesized following the

same route using a C₁₀-unit for the pyran annulation

(Scheme 4). Copper(II)-catalyzed treatment of the 2-hy-

droxycarbazole 23 with 3,7-dimethyloct-6-en-1-yn-3-yl

methyl carbonate (12) and DBU followed by thermally in-

duced rearrangement afforded the homoprenyl-substituted

pyranocarbazole 28. Base-induced cleavage of the sulfonic

ester and oxidation led to pyrayaquinone-C (3) in eight

steps and 30% overall yield. Unfortunately, compound 23

could not be transformed into the pyrano[2,3-b]carbazole,

pyrayaquinone-A (1). Various conditions for pyran annula-

tion using 23 following either Godfrey’s,²²Casiraghi’s,^21aor

Dufresne’s methods^21bprovided mainly the [3,2-a] annulat-

ed product 25, and at best trace amounts of 30, the poten-

tial precursor to compound 1.^4f,21Substitution at the nitro-

gen atom with bulky protecting groups did not significantly

change the regioselectivity.^4d,25Alternative methods, e.g.,

lithiation/prenal addition, Friedel–Crafts acylation or esteri-

fication/Fries rearrangement failed as well.²⁶Finally, we de-

cided to use a prenylation/cyclization approach (Scheme 5).

Regioselective bromination at C-6 of the tosyl-protected

7-methoxycarbazole 22 and prenylation of the resulting 6-

bromocarbazole 31 by Suzuki–Miyaura coupling with pren-

ylboronic acid pinacol ester provided the 6-prenylcarbazole

32.²⁷In agreement with Choshi and Hibino,^27bbut in con-

trast to Ma,^27awe observed, isolated, and characterized the

tert-prenylated isomer 32a as a side product (ratio of

32/32a = 3:1). Treatment of 32 with pyridinium chloride in-

duced cleavage of the methyl ether and subsequent pyran

ring closure, probably by intramolecular electrophilic addi-

tion at the prenyl double bond, to afford the tetrahydropy-

26

pyrayaquinone-B (2)

Scheme 3 Synthesis of pyrayaquinone-B (2). Reagents and conditions:

(a) 20 (1.0 equiv), 15a (2.1 equiv), CuI (26 mol%), K₃PO₄(2.0 equiv),

DMF, 80 °C, 8.5 h (90%); (b) TsCl (1.1 equiv), Na₂CO₃(20 mol%), Bu₄N⁺Cl^–

(2 mol%), NaOH (4.1 equiv), PhCl–H₂O (3:4), r.t., 3 h (100%); (c) Pd(OAc)₂

(20 mol%), K₂CO₃(19 mol%), PivOH, 100 °C, 22 h (85%); (d) HBr (aque-

ous, 48%), AcOH, reflux, 2 h (90%); (e) CuCl₂·2H₂O (0.85 mol%), DBU

(2.0 equiv), 1,1-dimethylpropargyl methyl carbonate (11) (2.0 equiv),

MeCN, r.t., 28 h; (f) toluene, reflux, 19 h (85%, 2 steps); (g) LiAlH₄(6.6

equiv), THF, reflux, 2 h; (h) (KSO₃)₂NO (3.0 equiv), acetone–H₂O (1:1),

r.t., 2.5 h (46%, 2 steps).

a

b

HO

O

N

H

N

H

OTs

O

23

27

d

O

N

H

N

OR

O

H

pyrayaquinone-C (3)

28 R = Ts

29 R = H

c

Scheme 4 Synthesis of pyrayaquinone-C (3). Reagents and conditions:

(a) CuCl₂·2H₂O (2.7 mol%), DBU (2.2 equiv), 3,7-dimethyloct-6-en-1-

yn-3-yl methyl carbonate (12) (2.2 equiv), MeCN, r.t., 45 h (69%); (b)

toluene, reflux, 22 h (100%); (c) NaOH (57 equiv), EtOH–H₂O (5:1), re-

flux, 2.5 h; (d) (KSO₃)₂NO (3.7 equiv), acetone–H₂O (1:1), r.t., 18 h

(64%, 2 steps).

D

S. K. Kutz et al.

Paper

Synthesis

amino)quinone 38 and the regioisomer 39.^8,16bThe quinone

38 was selectively synthesized by Buchwald–Hartwig ami-

nation of the bromoquinone 41, available in three steps

from the hydroquinone 40, and the silyloxyaniline 36. Palla-

dium(II)-catalyzed oxidative cyclization of 38 in acetic acid

at reflux using copper(II) acetate as the oxidant, our original

conditions for the palladium(II)-catalyzed oxidative cycliza-

tion,^4a,16bprovided the silyloxy-substituted carbazole-1,4-

quinone 42 in good yield. TBAF-induced cleavage of the silyl

ether finally led to the desired hydroxycarbazolequinone

HO

O

N

H

N

H

OTs

23

30

Br

a

b

MeO

N

H

N

H

OTs

22

31

OTBS

O

R¹

R²

a

+

MeO

NH₂

TBSO

N

H

N

H

OTs

O

38 R¹= Me, R²= H

39 R¹= H, R²= Me

36

37

32

32a

ratio 32/32a = 3:1

c

OH

O

b–d

e

d

Br

TBSO

N

H

O

N

H

OH

N

H

OTs

OH

40

41

38

33

34

O

f

RO

O

e

f

N

H

N

H

O

N

H

N

H

O

42 R = TBS

43 R = H

pyrayaquinone-B (2)

g

35

pyrayaquinone-A (1)

Scheme 5 Synthesis of pyrayaquinone-A (1). Reagents and conditions:

(a) N-bromosuccinimide (NBS) (1.0 equiv), CH₂Cl₂, r.t., 3 d (94%); (b) 3-

methyl-2-butenylboronic acid pinacol ester [Me₂C=CHCH₂B(pin)] (1.9

equiv), (Ph₃P)₄Pd (10 mol%), NaOH (40 equiv), toluene–H₂O (1:1), r.t.,

21 h (32: 74%; 32a: 25%); (c) Py·HCl (39 equiv), neat, 170 °C, 5 h (80%);

(d) LiAlH₄(10.6 equiv), THF, reflux, 14 h; (e) (KSO₃)₂NO (6.9 equiv), ace-

tone–H₂O (1:1), r.t., 40 min (60%, 2 steps); (f) DDQ (2.2 equiv), toluene,

100 °C, 3.5 h (86%).

OTBS

OMe

h

+

TBSO

N

NH₂

Br

H

OMe

36

44

45

MeO

TBSO

rano[2,3-b]carbazole 33. Cleavage of the sulfonic ester fol-

lowed by oxidation with Frémy’s salt and dehydrogenation

finally provided pyrayaquinone-A (1) in nine steps and 22%

overall yield.

N

H

OMe

46

Scheme 6 An attempted alternative approach to the pyrayaquinones-

A–C (1–3). Reagents and conditions: (a) 36 (1.0 equiv), 37 (2.0 equiv),

H₂O–MeOH–AcOH (15:5:1), –4 °C, 48 h (compound mixture, purifica-

tion of which provided 38 in 29% yield); (b) Me₂SO₄(3.0 equiv), K₂CO₃

(5.0 equiv), acetone, r.t., 3 h; (c) bromine (1.1 equiv), NaOAc (2.0

equiv), AcOH, r.t., 85 min; (d) cerium ammonium nitrate (CAN) (2.5

equiv), MeCN–H₂O (7:2), r.t., 1 h (97%, 3 steps); (e) 36 (1.2 equiv),

Pd(OAc)₂(12 mol%), XPhos (25 mol%), Cs₂CO₃(1.5 equiv), toluene,

100 °C, 2 h (62%); (f) Pd(OAc)₂(33 mol%), Cu(OAc)₂(2.5 equiv), AcOH,

100 °C, 5 h (74%); (g) TBAF (1.3 equiv), THF, 0 °C, 10 min (90%); (h) 44

(1.0 equiv), 36 (1.3 equiv), Pd(OAc)₂(6 mol%), XPhos (12 mol%),

Cs₂CO₃(1.2 equiv), toluene, reflux, 20 h (97%).

We also explored alternative routes to the pyranocarba-

zoles 1–3. In an early approach, we thought to apply a pyran

ring annulation to the hydroxycarbazole-1,4-quinone 43

(Scheme 6). Our first route to the latter compound started

with reaction of the aniline 36 and two equivalents of 2-

methyl-1,4-benzoquinone (37). The silyloxyaniline 36 was

synthesized from m-nitrophenol by O-silylation and subse-

quent iron/acetic acid mediated reduction of the nitro

group. The addition/oxidation reaction of 36 and 37 provid-

ed an almost inseparable mixture of the desired (phenyl-

E

S. K. Kutz et al.

Paper

Synthesis

43. Unfortunately, all attempts to annulate a pyran ring at

43 failed. We suspect that the electron-poor quinoid ring

system was responsible for this failure. Finally, we envis-

aged the synthesis of the 1,4-dimethoxycarbazole 46

(Scheme 6). Buchwald–Hartwig amination of the aniline 36

and bromoarene 44, the precursor of the quinone 41, pro-

vided diarylamine 45. Since our attempts to achieve an oxi-

dative cyclization of the electron-rich diarylamine 45 led

only to decomposition, this route was abandoned.

We then turned our attention to the prenyl- and gera-

nyl-substituted carbazole-1,4-quinones 5–8 (Schemes 7–9).

DIBAL-H-mediated reductive pyran ring opening¹⁹of com-

pound 25 by treatment with an excess of silicon tetrachlo-

ride and DIBAL-H in toluene at –78 °C followed by warming

to room temperature provided the 7-hydroxy-8-prenylcar-

bazole 47 in 77% yield (Scheme 7). Removal of the tosyl

group and oxidation using Frémy’s salt led to murrayaqui-

none-E (6) in 75% yield (9 steps, 34% overall yield). The cor-

responding 7-O-methyl derivative, murrayaquinone-B (5),

was obtained following the same route. O-Methylation of

the carbazole 47 and subsequent detosylation led to mur-

rayafoline-B (50), a natural product that like the carbazole-

quinones 1–8 has been isolated from M. euchrestifolia.¹³Our

approach constitutes only the second synthesis of murraya-

foline-B (50) and led to the natural product in nine steps

and 40% overall yield. The only other route known so far,

published by Kapil in 1986, provided this natural product in

less than 1% overall yield.^17cTreatment of murrayafoline-B

(50) with Frémy’s salt afforded murrayaquinone-B (5) in

68% yield (10 steps, 27% overall yield).

Application of the reaction conditions for our DIBAL-H-

mediated pyran ring-opening reaction to the homoprenyl-

substituted pyrano[3,2-a]carbazole 28 surprisingly did not

provide the desired geranylcarbazole 51, but instead the

isochromeno[4,3-a]carbazole 52 in up to 60% yield (Scheme

8). The cis-relationship of C4a-H and C13c-H was assigned

based on comparison of the ¹H NMR data with those of re-

lated structures.²⁸The geranylated carbazole-1,4-quinones

7 and 8 were finally synthesized using a Claisen rearrange-

ment as the key step (Scheme 9). Partial hydrogenation of

the propargyloxycarbazole 27, the direct precursor to pyra-

nocarbazole 28, followed by thermally induced Claisen re-

arrangement provided compound 54 as a mixture of double

bond isomers (ratio E/Z = 1.3:1). Removal of the tosyl group,

oxidation with Frémy’s salt, and separation of the isomers

led to murrayaquinone-D (8) and the corresponding Z-iso-

mer 56. Murrayaquinone-C (7) was synthesized from inter-

mediate 54 by initial O-methylation to give 55 followed by

detosylation and oxidation. The two stereoisomers 7 and 57

(ratio = 3:1) could not be separated in this case. However, a

pure sample of the E-isomer, murrayaquinone-C (7), was

prepared by O-methylation of murrayaquinone-D (8) fol-

lowing Norcott and MacErlean’s procedure,¹⁸who de-

scribed the sequential treatment of 3.5 mg of 8 with an

equimolar amount of butyllithium and an excess of io-

domethane at –78 °C to provide 2.5 mg of murrayaquinone-

C (7) (70% yield). In our hands this transformation proved to

be difficult and provided murrayaquinone-C (7) in 59%

yield (10 mg scale).

a

O

HO

a

N

H

N

H

O

RO

OTs

N

H

N

H

OTs

28

51

25

47, R = H

(desired product)

b

48, R = Me

O

8

9

47

or

48

c

d

O

11

RO

13

a

H

13a

N

H

OTs

13c

OH

O

4a

H

1

H

3

(

)-52

49

murrayaquinone-E (6)

R = H

Scheme 8 DIBAL-H-promoted reaction of the pyrano[3,2-a]carbazole

28. Reagents and conditions: (a) DIBAL-H (4.0 equiv), SiCl₄(4.0 equiv),

CH₂Cl₂, –78 °C to r.t., 20 h (60%).

murrayafoline-B (50)

R = Me

murrayaquinone-B (5)

R = Me

Scheme 7 Synthesis of murrayafoline-B (50), murrayaquinone-B (5),

and murrayaquinone-E (6). Reagents and conditions: (a) DIBAL-H (6.6

equiv), SiCl₄(6.6 equiv), toluene, –78 °C to r.t., 22 h (77%); (b) Me₂SO₄

(5.0 equiv), K₂CO₃(4.7 equiv), acetone, r.t. to 40 °C, 16 h (94%); (c)

LiAlH₄(6.8 equiv), THF, reflux, (16 h, 49; 18 h, 50: 94%) (d) (KSO₃)₂NO

(5.6 equiv), acetone–H₂O (1:1), r.t., (68 h, 6: 75%, 2 steps; 3 d, 5: 68%).

The pyranocarbazolequinones pyrayaquinone-A (1), -B

(2), and -C (3), the prenylated or geranylated carbazolequi-

nones murrayaquinone-B (5), -C (7), -D (8), and -E (6), and

murrayafoline-B (50) were synthesized from 7-methoxy-3-

F

S. K. Kutz et al.

Paper

Synthesis

methyl-1-tosyloxycarbazole (22) as a common precursor,

which was obtained in three steps and 77% overall yield

based on commercially available compounds. Pyran annula-

tion and oxidation provided pyrayaquinone-A (1) in nine

steps and 22% overall yield, pyrayaquinone-B (2) in eight

steps and 27% overall yield, and pyrayaquinone-C (3) in

eight steps and 30% overall yield. DIBAL-H-mediated ring

opening of an intermediate pyrano[3,2-a]carbazole led to

murrayaquinone-E (6) in nine steps and 34% overall yield

and to murrayaquinone-B (5) in 10 steps and 27% overall

yield. Murrayafoline-B (50) (9 steps, 40% yield) was ob-

tained en route to murrayaquinone-B (5). Claisen rear-

rangement of a pyrayaquinone-C (3) precursor provided

murrayaquinone-C (7) in 10 steps and 8% overall yield and

murrayaquinone-D (8) in nine steps and 14% overall yield.

Our route provided the latter compounds, 7 and 8, for the

first time as pure diastereoisomers. Moreover, the superior-

ity of our palladium-catalyzed approach is emphasized by a

comparison of the overall yields for our syntheses of the

pyrayaquinones-A–C (1–3), the murrayaquinones-B–E (5–

8), and murrayafoline-B (50) with those of the alternative

routes described in the literature (Table 1).

a

O

N

H

N

H

OTs

27

53

b

c

HO

MeO

N

H

N

H

OTs

54

55

O

54

or

55

d, e

RO

+

RO

N

H

N

O

H

murrayaquinone-D (8)

56, R = H

R = H

f

57, R = Me

murrayaquinone-C (7)

All reactions were carried out in oven-dried glassware using anhy-

drous solvents under an argon atmosphere, unless stated otherwise.

CH₂Cl₂, MeCN, THF, and toluene were dried using a solvent purifica-

tion system (MBraun-SPS). Petroleum ether (PE) refers to the hydro-

carbon mixture with a boiling range of 40–65 °C. Pd(OAc)₂was re-

crystallized from glacial AcOH. All other chemicals were used as re-

ceived from commercial sources. Flash chromatography was

performed using silica gel from Acros Organics (0.035–0.070 mm),

occasionally on a Büchi Sepacore system equipped with a UV monitor.

TLC was performed with TLC plates from Merck (60 F254) using UV

light for visualization. A CEM Discover microwave reactor was utilized

for reactions taking place under microwave irradiation. Melting

R = Me

Scheme 9 Synthesis of murrayaquinone-C (7), and murrayaquinone-D

(8). Reagents and conditions: (a) H₂(1 atm), Lindlar catalyst (10 wt%),

EtOAc, r.t., 22 h; (b) DMF, 180 °C, microwave (300 W), 1 h (79%, 2 steps;

ratio of E/Z = 1.3:1); (c) Me₂SO₄(5.2 equiv), K₂CO₃(4.7 equiv), acetone,

r.t. to 50 °C, 17.5 h (92%); (d) LiAlH₄(10 equiv), THF, reflux, 22 h; (e)

(KSO₃)₂NO (14 equiv), acetone–H₂O (1:1), r.t. (22 h, 8: 37%, 2 steps; 56:

19%, 2 steps; 64 h, 7 and 57: 62%, 2 steps, ratio of 7/57 = 3:1); (f) BuLi

(1.0 equiv), MeI (50 equiv), THF, –78 °C to r.t., 22 h (59%).

Table 1 Comparison of the Different Synthetic Routes to the Pyrayaquinones 1–3, the Murrayaquinones 5–8, and Murrayafoline-B (50)

Carbazole alkaloid

No. of steps

Overall yield (%)

Previous total syntheses

No. of steps

Overall yield (%)

pyrayaquinone-A (1)

pyrayaquinone-B (2)

9

8

22

27

2¹⁰

5⁸

2.9^a

0.5

6¹⁸

2¹⁰

5⁸

7

2.9^a

0.7

pyrayaquinone-C (3)

murrayaquinone-B (5)

8

30

27

6¹⁸

12

10

6¹⁸

10

8^17a,17b

0.9^a

0.2^a

7^17c

murrayaquinone-C (7)

10

9

8

6¹⁸

5¹⁸

6^17c

9

murrayaquinone-D (8)

14

34

40

12

murrayaquinone-E (6)

9

10

murrayafoline-B (50)

9

0.8^a

^aBased on non-commercial starting material.

G

S. K. Kutz et al.

Paper

Synthesis

points were measured on a Gallenkamp MPD 350 melting point appa-

ratus. Ultraviolet spectra were recorded on a PerkinElmer 25 UV/Vis

spectrometer. Fluorescence spectra were obtained using a Varian

Cary Eclipse spectrometer. IR spectra were recorded on a Thermo Ni-

colet Avatar 360 FT-IR spectrometer using the ATR method (attenuat-

ed total reflectance). NMR spectra were recorded on Bruker DRX 500

and Avance III 600 spectrometers. ACD/NMR Processor Academic Edi-

tion and Bruker TopSpin V2.1 were used for processing. Chemical

shifts (δ) are reported in parts per million with the solvent signal as

internal standard. Standard abbreviations were used to denote the

multiplicities of the signals. Mass spectra were recorded on a Fin-

nigan MAT-95 spectrometer (electron impact, 70 eV) or by GC/MS-

coupling using an Agilent Technologies 6890 N GC System equipped

with a 5973 Mass Selective Detector (electron impact, 70 eV). ESI-MS

spectra were recorded on an Esquire LC with an ion trap detector

from Bruker. Positive and negative ions were detected. Elemental

analyses were measured on a EuroVector EuroEA3000 elemental ana-

lyzer.

¹H NMR (500 MHz, CDCl₃): δ = 2.32 (s, 3 H), 4.98 (s, 2 H), 5.96 (br s, 1

H), 6.34–6.40 (m, 2 H), 6.49 (ddd, J = 8.2, 2.4, 0.8 Hz, 1 H), 6.69 (ddd,

J = 7.9, 1.9, 0.6 Hz, 1 H), 6.82 (d, J = 1.3 Hz, 1 H), 7.04 (d, J = 7.9 Hz, 1

H), 7.11 (t, J = 8.0 Hz, 1 H), 7.28–7.41 (m, 5 H).

¹³C NMR (125 MHz, CDCl₃): δ = 21.37 (CH₃), 70.05 (CH₂), 102.54 (CH),

106.50 (CH), 108.69 (CH), 116.17 (CH), 121.75 (CH), 125.36 (C),

126.31 (CH), 127.71 (2 CH), 128.08 (CH), 128.69 (2 CH), 130.34 (CH),

137.05 (C), 137.75 (C), 147.41 (C), 151.94 (C), 160.16 (C).

MS (EI): m/z (%) = 306 (15), 305 (68) [M⁺], 214 (8), 186 (17), 184 (8),

171 (5), 170 (5), 92 (8), 91 (100), 77 (8), 65 (17), 39 (5).

Anal. Calcd for C₂₀H₁₉NO₂: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.84;

H, 6.32; N, 4.64.

N-[3-(Benzyloxy)phenyl]-4-methyl-2-[(triisopropylsilyl)oxy]ani-

line (17b)

A mixture of diarylamine 17a (2.67 g, 8.74 mmol), TIPSCl (2.03 g, 10.5

mmol), imidazole (714 mg, 10.5 mmol), and DMF (20 mL) was stirred

under air at 50 °C for 24 h. A saturated aqueous solution of NH₄Cl was

added and the mixture was extracted with Et₂O. The combined or-

ganic layers were dried (MgSO₄) and the solvent was evaporated. Pu-

rification by column chromatography (silica gel, isohexane–EtOAc,

10:1 to 3:1) provided diarylamine 17b (3.86 g, 8.36 mmol, 96%) as a

highly viscous orange oil.

1-(Benzyloxy)-3-iodobenzene (14b)

K₂CO₃(4.71 g, 34.1 mmol) and benzyl bromide (4.05 mL, 5.83 g, 34.0

mmol) were added to a solution of 3-iodophenol (14a) (5.00 g, 22.7

mmol) in acetone (30 mL) at r.t. under an argon atmosphere and the

mixture was stirred at r.t. for 6 h. Methanol (75 mL) and aqueous

NH₄OH (25%, 75 mL) were added and stirring was continued for an-

other 5 h. The mixture was extracted with Et₂O, the combined organ-

ic layers were dried (MgSO₄) and the solvent was evaporated. Column

chromatography (silica gel, isohexane–EtOAc, 3:1 to 1:1) provided

compound 14b (6.98 g, 22.5 mmol, 99%) as a colorless solid.

UV (MeOH): 278, 309 (sh) nm.

IR (ATR): 3424, 3032, 2943, 2865, 1595, 1558, 1520, 1494, 1457, 1406,

1265, 1213, 1177, 1155, 1123, 1027, 997, 969, 881, 806, 734, 681 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.11 (d, J = 7.6 Hz, 18 H), 1.25–1.36 (m,

3 H), 2.26 (s, 3 H), 5.04 (s, 2 H), 6.53 (dd, J = 8.2, 2.5 Hz, 1 H), 6.64–6.70

(m, 3 H), 6.75 (t, J = 2.2 Hz, 1 H), 7.15 (t, J = 8.2 Hz, 1 H), 7.21 (d, J = 8.5

Hz, 1 H), 7.29–7.45 (m, 5 H).

Mp 50.8–51.8 °C.

UV (MeOH): 210, 226 (sh), 277, 284 nm.

¹³C NMR (125 MHz, CDCl₃): δ = 12.99 (3 CH), 18.17 (6 CH₃), 21.14

(CH₃), 70.07 (CH₂), 103.81 (CH), 106.78 (CH), 110.30 (CH), 117.30

(CH), 119.25 (CH), 121.76 (CH), 127.66 (2 CH), 128.05 (CH), 128.71 (2

CH), 130.15 (CH), 130.76 (C), 130.92 (C), 137.24 (C), 144.75 (C),

145.34 (C), 159.98 (C).

ESI-MS (+25 V): m/z = 462.4 [M + H]⁺.

ESI-MS (–25 V): m/z = 460.0 [M – H]^–.

IR (ATR): 2934, 1582, 1562, 1520, 1475, 1460, 1415, 1398, 1381, 1323,

1302, 1273, 1235, 1158, 1059, 1008, 988, 918, 867, 842, 824, 773,

750, 698, 678 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 5.03 (s, 2 H), 6.94 (ddd, J = 8.5, 2.5, 0.9

Hz, 1 H), 7.00 (t, J = 8.2 Hz, 1 H), 7.30 (dt, J = 7.6, 1.3 Hz, 1 H), 7.32–

7.37 (m, 2 H), 7.37–7.44 (m, 4 H).

¹³C NMR (125 MHz, CDCl₃): δ = 70.28 (CH₂), 94.49 (C), 114.62 (CH),

124.18 (CH), 127.65 (2 CH), 128.29 (CH), 128.79 (2 CH), 130.25 (CH),

130.94 (CH), 136.53 (C), 159.45 (C).

7-Hydroxy-3-methyl-1-[(triisopropylsilyl)oxy]carbazole (18)

MS (EI): m/z (%) = 310 (15) [M⁺], 92 (13), 91 (100), 65 (13), 64 (7), 63

(10).

A 10 mL microwave tube was charged with diarylamine 17b (100 mg,

0.217 mmol), Pd(OAc)₂(7.3 mg, 33 μmol), Cu(OAc)₂(99.0 mg, 0.543

mmol), and glacial acetic acid (1 mL). The mixture was irradiated in a

microwave reactor (300 W, 130 °C) for 30 min. An aqueous solution of

K₂CO₃was added and the mixture was extracted with EtOAc. The

combined organic layers were dried (MgSO₄) and the solvent was

evaporated.

Anal. Calcd for C₁₃H₁₁IO: C, 50.35; H, 3.58. Found: C, 50.92; H, 3.58.

2-{[3-(Benzyloxy)phenyl]amino}-5-methylphenol (17a)

A 25 mL round-bottom flask was charged with iodoarene 14b (3.00 g,

9.67 mmol), 2-amino-5-methylphenol (15a) (2.38 g, 19.3 mmol),

K₃PO₄(4.11 g, 19.4 mmol), CuI (368 mg, 1.93 mmol), and DMF (14 mL)

under an argon atmosphere. The reaction mixture was stirred for 18 h

at 80 °C, diluted with EtOAc and washed with 2 M hydrochloric acid.

The aqueous layer was extracted with EtOAc, the combined organic

layers were dried (MgSO₄) and the solvent was evaporated. Purifica-

tion by column chromatography (silica gel, isohexane–EtOAc, 8:1)

provided diarylamine 17a (2.51 g, 8.22 mmol, 85%) as a brown oil.

The residue was dissolved in EtOAc (5 mL) and Pd/C (10%, 20 mg) was

added. The mixture was vigorously stirred for 3 d at r.t. under a hy-

drogen atmosphere. The solvent was evaporated and the residue was

purified by column chromatography (silica gel, isohexane–EtOAc, 4:1

to 1:1) to provide hydroxycarbazole 18 (56.5 mg, 0.153 mmol, 71%) as

a highly viscous brown oil.

UV (MeOH): 241, 302 nm.

UV (MeOH): 211, 277, 296 (sh) nm.

Fluorescence (MeOH, exc. 250 nm): 364 nm.

IR (ATR): 3504, 3462, 3379, 3034, 2919, 1593, 1493, 1451, 1391, 1319,

1290, 1257, 1221, 1178, 1149, 1112, 1082, 1013, 972, 945, 911, 850,

IR (ATR): 3477, 3388, 2942, 2865, 2053, 2030, 1997, 1630, 1584, 1499,

1453, 1392, 1341, 1314, 1283, 1211, 1159, 1132, 1102, 1070, 1007,

821, 772, 745, 693, 624 cm^–1

.

957, 921, 881, 831, 785, 684, 644 cm^–1

.

H

S. K. Kutz et al.

Paper

Synthesis

¹H NMR (500 MHz, CDCl₃): δ = 1.16 (d, J = 7.6 Hz, 18 H), 1.39 (sept, J =

7.6 Hz, 3 H), 2.45 (s, 3 H), 6.65 (d, J = 0.9 Hz, 1 H), 6.70 (dd, J = 8.2, 2.2

Hz, 1 H), 6.88 (d, J = 2.2 Hz, 1 H), 7.34–7.37 (m, 1 H), 7.81 (br s, 1 H),

7.81 (d, J = 8.5 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 13.08 (3 CH), 18.23 (6 CH₃), 21.88

(CH₃), 97.09 (CH), 108.47 (CH), 112.39 (CH), 114.71 (CH), 118.25 (C),

121.40 (CH), 125.07 (C), 129.76 (C), 130.06 (C), 140.86 (C), 141.03 (C),

154.60 (C).

¹H NMR (500 MHz, CDCl₃): δ = 2.26 (s, 3 H), 2.31 (s, 3 H), 3.75 (s, 3 H),

5.65 (br s, 1 H), 6.26 (t, J = 2.2 Hz, 1 H), 6.33 (dd, J = 7.7, 1.7 Hz, 1 H),

6.42 (dd, J = 8.2, 2.2 Hz, 1 H), 6.94 (ddd, J = 8.2, 1.9, 0.6 Hz, 1 H), 7.00

(d, J = 1.6 Hz, 1 H), 7.07 (t, J = 8.0 Hz, 1 H), 7.13–7.17 (m, 3 H), 7.65–

7.68 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 20.75 (CH₃), 21.75 (CH₃), 55.28 (CH₃),

103.02 (CH), 106.16 (CH), 110.04 (CH), 119.49 (CH), 124.41 (CH),

128.34 (CH), 128.45 (2 CH), 129.80 (2 CH), 129.97 (CH), 131.44 (C),

132.26 (C), 133.04 (C), 139.44 (C), 143.89 (C), 145.72 (C), 160.57 (C).

ESI-MS (+25 V): m/z = 370.3 [M + H]⁺.

ESI-MS (–25 V): m/z = 368.1 [M – H]^–, 737.2 [2M – H]^–.

ESI-MS (+25 V): m/z = 384.3 [M + H]⁺.

ESI-MS (–25 V): m/z = 382.0 [M – H]^–.

2-[(3-Methoxyphenyl)amino]-5-methylphenol (21a)

Anal. Calcd for C₂₁H₂₁NO₄S: C, 65.78; H, 5.52; N, 3.65; S, 8.36. Found:

C, 66.41; H, 5.95; N, 3.68; S 8.19.

A 100 mL round-bottom flask was charged with 3-iodoanisole (20)

(5.03 g, 21.5 mmol), 2-amino-5-methylphenol (15a) (5.58 g, 45.3

mmol), K₃PO₄(9.12 g, 42.9 mmol), CuI (995 mg, 5.52 mmol), and DMF

(30 mL) under an argon atmosphere. The reaction mixture was stirred

for 8.5 h at 80 °C, then diluted with EtOAc and washed with 2 M hy-

drochloric acid. The aqueous layer was extracted with EtOAc, the

combined organic layers were dried (MgSO₄) and the solvent was

evaporated. Purification by column chromatography (silica gel, iso-

hexane–EtOAc, 8:1) provided diarylamine 21a (4.43 g, 19.3 mmol,

90%) as a colorless solid.

7-Methoxy-3-methyl-9H-carbazol-1-yl 4-Methylbenzenesulfonate

(22)

A 100 mL round-bottom flask was charged with diarylamine 21b (500

mg, 1.30 mmol), Pd(OAc)₂(59.0 mg, 0.263 mmol), K₂CO₃(35.0 mg,

0.253 mmol), and pivalic acid (5.00 g) under air. The reaction mixture

was stirred for 22 h at 100 °C, then diluted with EtOAc and washed

with 2 M aqueous NaOH solution. After separation, the aqueous layer

was extracted with EtOAc. The combined organic layers were dried

(MgSO₄) and the solvent was evaporated. Purification by column

chromatography (silica gel, isohexane–EtOAc, 5:1) provided the 7-

methoxycarbazole 22 (420 mg, 1.10 mmol, 85%) as a colorless solid.

Mp 77.5–78.0 °C.

UV (MeOH): 206 (sh), 212, 276, 299 (sh) nm.

IR (ATR): 3413, 3344, 3008, 2980, 2913, 1598, 1501, 1458, 1331, 1315,

1295, 1262, 1239, 1207, 1152, 1084, 1029, 956, 936, 868, 829, 770,

Mp 167.5–168.0 °C.

683, 631 cm^–1

.

UV (MeOH): 221 (sh), 237, 251 (sh), 303, 317 (sh) nm.

Fluorescence (MeOH, exc. 237 nm): 374 nm.

IR (ATR): 3389, 2922, 1624, 1492, 1450, 1365, 1344, 1306, 1276, 1190,

¹H NMR (500 MHz, CDCl₃): δ = 2.32 (s, 3 H), 3.74 (s, 3 H), 5.88 (br s, 1

H), 6.27 (t, J = 2.2 Hz, 1 H), 6.34 (dd, J = 8.2, 2.0 Hz, 1 H), 6.42 (dd, J =

8.2, 2.2 Hz, 1 H), 6.70 (dd, J = 8.4, 1.7 Hz, 1 H), 6.83 (d, J = 1.6 Hz, 1 H),

7.06 (d, J = 7.9 Hz, 1 H), 7.11 (t, J = 8.0 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 21.37 (CH₃), 55.31 (CH₃), 101.49 (CH),

105.37 (CH), 108.18 (CH), 116.07 (CH), 121.75 (CH), 125.52 (C),

126.38 (CH), 130.33 (CH), 137.66 (C), 147.69 (C), 152.05 (C), 160.96

(C).

1170, 1076, 1029, 974, 880, 852, 803, 780, 879, 663 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 2.35 (s, 3 H), 2.44 (s, 3 H), 3.90 (s, 3 H),

6.55 (s, 1 H), 6.84 (dd, J = 8.5, 2.2 Hz, 1 H), 6.89 (d, J = 1.9 Hz, 1 H), 7.31

(d, J = 7.9 Hz, 2 H), 7.61 (s, 1 H), 7.73–7.78 (m, 2 H), 7.84 (d, J = 8.5 Hz,

1 H), 8.29 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 21.31 (CH₃), 21.88 (CH₃), 55.76 (CH₃),

95.01 (CH), 109.04 (CH), 116.83 (C), 118.50 (CH), 118.89 (CH), 121.24

(CH), 126.97 (C), 128.79 (2 CH), 129.52 (C), 129.93 (2 CH), 130.60 (C),

131.95 (C), 133.83 (C), 141.57 (C), 145.84 (C), 159.67 (C).

MS (EI): m/z (%) = 229 (100) [M⁺], 212 (13), 198 (16), 197 (16), 186 (9),

184 (9), 77 (16), 65 (11), 63 (9).

2-[(3-Methoxyphenyl)amino]-5-methylphenyl 4-Methylbenzene-

sulfonate (21b)

ESI-MS (+25 V): m/z = 382.3 [M + H]⁺, 404.3 [M + Na]⁺, 785.4 [2M +

Na]⁺.

Tosyl chloride (730 mg, 3.83 mmol) was added to a mixture of diaryl-

amine 21a (806 mg, 3.52 mmol), Na₂CO₃(74.0 mg, 698 μmol),

Bu₄N⁺Cl^–(23.0 mg, 82.8 μmol), NaOH (573 mg, 14.3 mmol), H₂O (20

mL) and chlorobenzene (15 mL) under air. The reaction mixture was

stirred for 3 h at r.t. and then diluted with CH₂Cl₂and 2 M HCl. After

separation, the aqueous layer was extracted with EtOAc. The com-

bined organic layers were dried (MgSO₄) and the solvent was evapo-

rated. Purification by column chromatography (silica gel, isohexane–

EtOAc, 5:1 to 2:1) provided diarylamine 21b (1.37 g, 3.57 mmol,

100%) as a colorless solid.

ESI-MS (–25 V): m/z = 380.1 [M – H]^–.

Anal. Calcd for C₂₁H₁₉NO₄S: C, 66.12; H, 5.02; N, 3.67; S, 8.40. Found:

C, 66.58; H, 5.27; N, 3.68; S, 8.29.

7-Hydroxy-3-methyl-1-(tosyloxy)carbazole (23)

A mixture of the carbazole 22 (2.32 g, 6.08 mmol), acetic acid (70 mL),

and 48% aqueous hydrobromic acid (35 mL) was refluxed for 2 h un-

der air. After diluting with H₂O and EtOAc, the layers were separated

and the aqueous layer was extracted with EtOAc. The combined or-

ganic layers were dried (MgSO₄) and the solvent was evaporated. Pu-

rification by column chromatography (silica gel, isohexane–EtOAc,

3:1) provided the 7-hydroxycarbazole 23 (2.02 g, 5.50 mmol, 90%) as

a colorless solid.

Mp 85.0–85.5 °C.

UV (MeOH): 222 (sh), 281, 294 (sh) nm.

IR (ATR): 3404, 2970, 1601, 1515, 1493, 1375, 1307, 1182, 1153, 1084,

1042, 948, 931, 883, 815, 778, 739, 695, 661 cm^–1

.

Mp 184.5–185.5 °C.

UV (MeOH): 221 (sh), 238, 252 (sh), 304 nm.

Fluorescence (MeOH, exc. 237 nm): 358 nm.

I

S. K. Kutz et al.

Paper

Synthesis

IR (ATR): 3350, 2922, 1732, 1698, 1626, 1582, 1493, 1452, 1348, 1318,

1237, 1204, 1163, 1073, 976, 884, 849, 812, 773, 732, 666 cm^–1

¹H NMR (500 MHz, CDCl₃): δ = 2.35 (s, 3 H), 2.44 (s, 3 H), 6.56 (d, J =

0.9 Hz, 1 H), 6.74 (dd, J = 8.5, 2.2 Hz, 1 H), 6.81 (d, J = 1.9 Hz, 1 H),

7.28–7.33 (m, 2 H), 7.60 (s, 1 H), 7.74–7.78 (m, 2 H), 7.81 (s, 1 H), 8.26

(br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 21.30 (CH₃), 21.87 (CH₃), 97.31 (CH),

109.22 (CH), 117.12 (C), 118.48 (CH), 118.96 (CH), 121.42 (CH),

126.92 (C), 128.77 (2 CH), 129.55 (C), 129.94 (2 CH), 130.65 (C),

131.92 (C), 133.82 (C), 141.59 (C), 145.91 (C), 155.38 (C).

Method B (from 23)

.

DBU (1.04 g, 6.83 mmol) and CuCl₂·2H₂O (5.0 mg, 29 μmol) were add-

ed to a stirred solution of the 7-hydroxycarbazole 23 (1.25 g, 3.40

mmol) in MeCN (15 mL) under air at r.t. Subsequently, 1,1-dimethyl-

propargyl methyl carbonate (11) (967 mg, 6.80 mmol) in MeCN (5

mL) was added. The mixture was stirred at r.t. for 28 h, then the sol-

vent was evaporated and the mixture was filtered over a short pad of

silica gel (isohexane–EtOAc, 3:1).

The solvent was evaporated, the crude mixture was dissolved in tolu-

ene (25 mL) and refluxed for 19 h under air. Evaporation of the solvent

and subsequent column chromatography (silica gel, isohexane–EtO-

Ac, 4:1 to 1:1) provided pyranocarbazole 25 (1.26 g, 2.91 mmol, 85%)

as a colorless solid.

ESI-MS (+10 V): m/z = 368.2 [M + H]⁺.

ESI-MS (–25 V): m/z = 366.0 [M – H]^–, 732.6 [2M – H]^–.

Anal. Calcd for C₂₀H₁₇NO₄S: C, 65.38; H, 4.66; N, 3.81; S, 8.73. Found:

C, 65.84; H, 4.85; N, 3.89; S, 8.18.

Mp 199.0–201.0 °C.

UV (MeOH): 230, 236, 278 (sh), 287, 326, 352 nm.

Fluorescence (MeOH, exc. 287 nm): 405 nm.

3-Methyl-7-[(2-methylbut-3-yn-2-yl)oxy]-1-(tosyloxy)carbazole

(24)

IR (ATR): 3425, 3386, 2955, 2915, 2030, 1976, 1639, 1597, 1580, 1484,

1451, 1402, 1366, 1341, 1302, 1282, 1255, 1213, 1189, 1175, 1151,

1115, 1090, 1051, 1010, 984, 967, 898, 852, 803, 779, 754, 721, 690,

DBU (22.0 μL, 22.4 mg, 0.147 mmol) and CuCl₂·2H₂O (1.0 mg, 5.9

μmol) were added to a stirring solution of the 7-hydroxycarbazole 23

(41.0 mg, 0.112 mmol) in MeCN (3 mL) at 0 °C under an argon atmo-

sphere. Subsequently, 1,1-dimethylpropargyl methyl carbonate (11)

(20.6 mg, 0.145 mmol) in MeCN (1 mL) was added. The mixture was

stirred at 0 °C for 3 h, then it was allowed to warm to r.t. After 20 h, an

additional portion of 1,1-dimethylpropargyl methyl carbonate (11)

(20.6 mg, 0.145 mmol) was added and the mixture was stirred for 3 d

at the same temperature. Evaporation of the solvent and subsequent

column chromatography (silica gel, isohexane–EtOAc, 4:1) provided

propargyloxycarbazole 24 (37.8 mg, 87.3 μmol, 78%) as a colorless

solid.

661 cm^–1

.

¹H NMR (600 MHz, DMSO-d₆): δ = 1.41 (s, 6 H), 2.32 (s, 3 H), 2.34 (s, 3

H), 5.79 (d, J = 9.8 Hz, 1 H), 6.59 (d, J = 8.3 Hz, 1 H), 6.74–6.77 (m, 1 H),

7.07 (d, J = 10.2 Hz, 1 H), 7.34–7.39 (m, 2 H), 7.68 (s, 1 H), 7.74 (d, J =

8.3 Hz, 1 H), 7.78–7.83 (m, 2 H), 11.09 (s, 1 H).

¹³C NMR (150 MHz, DMSO-d₆): δ = 20.87 (CH₃), 21.10 (CH₃), 27.44 (2

CH₃), 75.84 (C), 104.89 (C), 109.26 (CH), 116.32 (C), 117.65 (CH),

117.71 (CH), 118.14 (CH), 120.52 (CH), 126.15 (C), 128.14 (C), 128.66

(2 CH), 129.13 (CH), 129.82 (2 CH), 130.07 (C), 131.48 (C), 133.69 (C),

136.97 (C), 145.73 (C), 151.38 (C).

Mp 116.5–118.0 °C.

ESI-MS (+25 V): m/z = 434.3 [M + H]⁺.

ESI-MS (–25 V): m/z = 432.1 [M – H]^–.

UV (MeOH): 238, 248 (sh), 258 (sh), 299 nm.

Fluorescence (MeOH, exc. 238 nm): 361 nm.

Anal. Calcd for C₂₅H₂₃NO₄S: C, 69.26; H, 5.35; N, 3.23; S, 7.40. Found:

C, 69.24; H, 5.43; N, 3.25; S, 6.90.

IR (ATR): 3392, 3280, 2986, 2920, 2111, 1622, 1583, 1486, 1451, 1398,

1360, 1336, 1304, 1272, 1260, 1217, 1190, 1173, 1133, 1077, 1000,

972, 866, 850, 825, 806, 779, 690, 663 cm^–1

.

Pyrayaquinone-B (2)

¹H NMR (500 MHz, CDCl₃): δ = 1.70 (s, 6 H), 2.36 (s, 3 H), 2.44 (s, 3 H),

2.62 (d, J = 0.9 Hz, 1 H), 6.57 (s, 1 H), 7.06 (ddd, J = 8.5, 2.0, 0.8 Hz, 1 H),

7.31 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 2.2 Hz, 1 H), 7.63 (s, 1 H), 7.76 (d,

J = 8.2 Hz, 2 H), 7.84 (d, J = 8.5 Hz, 1 H), 8.32 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 21.31 (CH₃), 21.88 (CH₃), 29.82 (2

CH₃), 73.04 (C), 74.09 (CH), 86.49 (C), 103.94 (CH), 115.26 (CH),

118.79 (CH), 119.34 (CH), 120.50 (CH), 124.86 (C), 126.81 (C), 128.80

(2 CH), 129.45 (C), 129.93 (2 CH), 130.92 (C), 131.94 (C), 133.89 (C),

140.81 (C), 145.86 (C), 155.13 (C).

LiAlH₄(2.4 M in THF, 0.20 mL, 0.48 mmol) was added to a solution of

pyranocarbazole 25 (31.3 mg, 72.2 μmol) in THF (7 mL) under an ar-

gon atmosphere at r.t. The solution was refluxed for 2 h and subse-

quently quenched with H₂O at 0 °C. After extraction with EtOAc, the

combined organic layers were dried (MgSO₄), the solvent was evapo-

rated and the residue was filtered over a short pad of silica gel (iso-

hexane–EtOAc, 4:1) to yield crude 10-hydroxy-3,3,8-trimethyl-3,11-

dihydropyrano[3,2-a]carbazole (26) (13.3 mg, 47.6 μmol).

The crude hydroxycarbazole 26 (12.4 mg, 44.4 μmol) was dissolved in

acetone (7 mL) under air. Subsequently, potassium nitrosodisulfonate

(Frémy’s salt) (35.7 mg, 0.133 mmol) in H₂O (7 mL) was added and the

mixture was stirred vigorously at r.t. for 2.5 h. The mixture was dilut-

ed with EtOAc. After extraction with EtOAc, the combined organic

layers were dried (MgSO₄). Evaporation of the solvent and subsequent

column chromatography (silica gel, isohexane–EtOAc, 4:1) provided

pyrayaquinone-B (2) (9.1 mg, 31 μmol, 46%) as a dark purple solid.

ESI-MS (+10 V): m/z = 434.3 [M + H]⁺.

Anal. Calcd for C₂₅H₂₃NO₄S: C, 69.26; H, 5.35; N, 3.23; S, 7.40. Found:

C, 69.92; H, 5.47; N, 3.39; S, 7.00.

3,3,8-Trimethyl-10-(tosyloxy)-3,11-dihydropyrano[3,2-a]carba-

zole (25)

Mp 225–230 °C (sublimed) [Lit.⁷244 °C (dec.)].

UV (MeOH): 247, 268 (sh), 317, 409 nm.

Fluorescence (MeOH, exc. 247 nm): 361 nm.

Method A (from 24)

A solution of propargyloxycarbazole 24 (37.0 mg, 85.5 μmol) in tolu-

ene (3 mL) was refluxed for 16 h under air. Evaporation of the solvent

and subsequent column chromatography (silica gel, isohexane–

EtOAc, 20:1) provided pyranocarbazole 25 (36.9 mg, 85.3 μmol, 100%)

as a colorless solid.

IR (ATR): 3275, 3084, 2975, 2921, 2056, 2030, 2009, 1975, 1734, 1717,

1699, 1629, 1605, 1578, 1539, 1498, 1466, 1420, 1399, 1376, 1356,

1323, 1265, 1211, 1156, 1135, 1117, 1053, 1021, 993, 942, 898, 848,

825, 767, 725, 694 cm^–1

.

J

S. K. Kutz et al.

Paper

Synthesis

¹H NMR (500 MHz, pyridine-d₅): δ = 1.48 (s, 6 H), 2.07 (d, J = 1.6 Hz, 3

H), 5.69 (d, J = 9.8 Hz, 1 H), 6.49 (q, J = 1.6 Hz, 1 H), 7.12 (dd, J = 8.5, 0.6

Hz, 1 H), 7.15 (dd, J = 9.8, 0.6 Hz, 1 H), 8.31 (d, J = 8.5 Hz, 1 H), 13.72

(br s, 1 H).

Anal. Calcd for C₃₀H₃₁NO₄S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found:

C, 71.97; H, 6.53; N, 2.70; S, 5.93.

3,8-Dimethyl-3-(4-methylpent-3-enyl)-10-(tosyloxy)-3,11-dihy-

¹H NMR (600 MHz, CDCl₃): δ = 1.47 (s, 6 H), 2.14 (d, J = 1.5 Hz, 3 H),

5.71 (d, J = 9.8 Hz, 1 H), 6.45 (q, J = 1.6 Hz, 1 H), 6.58 (d, J = 9.8 Hz, 1 H),

6.86 (d, J = 8.7 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 9.22 (br s, 1 H).

¹³C NMR (125 MHz, pyridine-d₅): δ = 15.80 (CH₃), 27.65 (2 CH₃), 76.69

(C), 106.96 (C), 115.73 (CH), 117.58 (CH), 117.70 (C), 119.70 (C),

123.14 (CH), 130.24 (CH), 132.26 (CH), 136.67 (C), 147.49 (C), 152.35

(C), 180.03 (C=O), 183.99 (C=O); 1 C not visible due to signal overlap

with solvent peaks.

¹³C NMR (150 MHz, CDCl₃): δ = 16.28 (CH₃), 27.80 (2 CH₃), 76.87 (C),

105.69 (C), 116.00 (CH), 116.21 (CH), 117.85 (C), 119.05 (C), 123.28

(CH), 130.64 (CH), 131.73 (CH), 134.24 (C), 134.78 (C), 148.35 (C),

152.64 (C), 179.98 (C=O), 183.93 (C=O).

ESI-MS (+10 V): m/z = 294.2 [M + H]⁺, 609.1 [2M + Na]⁺.

ESI-MS (–10 V): m/z = 291.9 [M – H]^–.

dropyrano[3,2-a]carbazole (28)

A solution of propargyloxycarbazole 27 (74.0 mg, 0.148 mmol) in tol-

uene (4 mL) was refluxed for 22 h under air. Evaporation of the sol-

vent and subsequent column chromatography (silica gel, isohexane–

EtOAc, 15:1) provided pyranocarbazole 28 (74.0 mg, 0.148 mmol,

100%) as a yellow solid.

Mp 149.0–151.0 °C.

UV (MeOH): 226 (sh), 233, 238, 279 (sh), 288, 326, 336 (sh), 352 nm.

Fluorescence (MeOH, exc. 237 nm): 365 nm.

IR (ATR): 3383, 2971, 2923, 2846, 2030, 1640, 1581, 1485, 1474, 1448,

1371, 1340, 1304, 1275, 1213, 1187, 1175, 1122, 1087, 1051, 1008,

982, 969, 911, 887, 850, 805, 784, 757, 719, 666 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.45 (s, 3 H), 1.62 (s, 3 H), 1.66 (d, J =

1.3 Hz, 3 H), 1.72 (ddd, J = 13.9, 11.0, 6.0 Hz, 1 H), 1.80 (ddd, J = 13.9,

10.4, 6.6 Hz, 1 H), 2.11–2.20 (m, 2 H), 2.36 (s, 3 H), 2.43 (s, 3 H), 5.11

(tsept, J = 7.3, 1.3 Hz, 1 H), 5.68 (d, J = 9.8 Hz, 1 H), 6.56–6.60 (m, 2 H),

6.71 (dd, J = 8.5, 0.6 Hz, 1 H), 7.28–7.33 (m, 2 H), 7.57 (d, J = 0.6 Hz, 1

H), 7.67 (d, J = 8.5 Hz, 1 H), 7.73–7.78 (m, 2 H), 8.05 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 17.79 (CH₃), 21.32 (CH₃), 21.88 (CH₃),

22.88 (CH₂), 25.82 (CH₃), 26.18 (CH₃), 41.01 (CH₂), 78.71 (C), 104.95

(C), 110.23 (CH), 117.09 (C), 117.21 (CH), 118.47 (CH), 119.04 (CH),

120.63 (CH), 124.18 (CH), 127.36 (C), 128.78 (2 CH), 128.98 (CH),

129.78 (C), 129.99 (2 CH), 130.53 (C), 131.93 (C), 132.09 (C), 133.99

(C), 136.97 (C), 145.94 (C), 152.45 (C).

Anal. Calcd for C₁₈H₁₅NO₃: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.26;

H, 5.40; N, 4.68.

7-[(3,7-Dimethyloct-6-en-1-yn-3-yl)oxy]-3-methylcarbazol-1-yl

4-Methylbenzenesulfonate (27)

DBU (160 μL, 163 mg, 1.07 mmol) and CuCl₂·2H₂O (2.5 mg, 15 μmol)

were added to a stirring solution of the 7-hydroxycarbazole 23 (201

mg, 0.548 mmol) in MeCN (4 mL) at 0 °C under an argon atmosphere.

Subsequently, 3,7-dimethyloct-6-en-1-yn-3-yl methyl carbonate (12)

(230 mg, 1.09 mmol) in MeCN (2 mL) was added. The mixture was al-

lowed to warm to r.t. After 21 h, additional portions of 3,7-dimethyl-

oct-6-en-1-yn-3-yl methyl carbonate (12) (20.0 mg, 95.1 μmol) and

DBU (20 μL, 0.13 mmol) were added and the mixture was stirred for

24 h at the same temperature. EtOAc and 2 M hydrochloric acid were

added, the layers were separated and the aqueous layer was extracted

with EtOAc. The combined organic layers were dried (MgSO₄). Evapo-

ration of the solvent and subsequent column chromatography (silica

gel, isohexane–EtOAc, 15:1) provided propargyloxycarbazole 27 (190

mg, 0.379 mmol, 69%) as a yellow solid.

ESI-MS (+10 V): m/z = 502.5 [M + H]⁺, 524.6 [M + Na]⁺.

ESI-MS (–25 V): m/z = 500.1 [M – H]^–.

Anal. Calcd for C₃₀H₃₁NO₄S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found:

C, 72.02; H, 6.38; N, 2.75; S, 6.08.

Pyrayaquinone-C (3)

A mixture of pyrano[3,2-a]carbazole 28 (74.0 mg, 0.148 mmol), NaOH

(340 mg, 8.5 mmol), ethanol (4.7 mL), and H₂O (1.0 mL) was refluxed

for 2.5 h. EtOAc was added, the layers were separated and the aqueous

layer was extracted with EtOAc. The combined organic layers were

dried (MgSO₄) and the solvent was evaporated. The residue was sub-

jected to filtration over a short pad of silica gel (isohexane–EtOAc,

15:1) to provide crude hydroxycarbazole 29 (44.4 mg, 0.130 mmol).

Mp 130.0–131.0 °C.

UV (MeOH): 222 (sh), 238, 249 (sh), 299, 323, 337 (sh) nm.

Fluorescence (MeOH, exc. 237 nm): 365 nm.

IR (ATR): 3393, 3304, 2972, 2917, 2853, 1733, 1621, 1584, 1492, 1450,

1397, 1370, 1337, 1304, 1267, 1214, 1176, 1151, 1078, 972, 906, 876,

The crude hydroxycarbazole 29 (35.3 mg, 0.102 mmol) was dissolved

in acetone (4 mL) under air. Subsequently, potassium nitrosodisulfon-

ate (Frémy’s salt) (101.7 mg, 0.379 mmol) in H₂O (4 mL) was added

and the mixture was stirred vigorously at r.t. for 18 h. The mixture

was diluted with EtOAc. After extraction with EtOAc, the combined

organic layers were dried (MgSO₄). Evaporation of the solvent and

subsequent column chromatography (silica gel, isohexane–EtOAc,

2:1) provided pyrayaquinone-C (3) (26.7 mg, 74.0 μmol, 64%) as a

dark purple solid.

Mp 218.0–220.0 °C (dec.) [Lit.¹¹223 °C (dec.)].

UV (MeOH): 248, 270 (sh), 320, 410 nm.

Fluorescence (MeOH, exc. 247 nm): 375 nm.

848, 803, 772, 664 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.63 (s, 3 H), 1.65 (s, 3 H), 1.71 (d, J =

0.9 Hz, 3 H), 1.89 (ddd, J = 13.6, 11.7, 5.4 Hz, 1 H), 1.99 (ddd, J = 13.6,

11.7, 5.0 Hz, 1 H), 2.23–2.41 (m, 2 H), 2.36 (s, 3 H), 2.44 (s, 3 H), 2.64

(s, 1 H), 5.17 (tsept, J = 7.2, 1.4 Hz, 1 H), 6.55–6.57 (m, 1 H), 7.05 (dd,

J = 8.5, 2.2 Hz, 1 H), 7.29–7.32 (m, 2 H), 7.33 (d, J = 1.9 Hz, 1 H), 7.63 (s,

1 H), 7.74–7.78 (m, 2 H), 7.84 (d, J = 8.5 Hz, 1 H), 8.31 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 17.84 (CH₃), 21.31 (CH₃), 21.88 (CH₃),

23.35 (CH₂), 25.85 (CH₃), 27.10 (CH₃), 42.69 (CH₂), 75.35 (C), 76.08 (C),

85.50 (CH), 103.92 (CH), 115.30 (CH), 118.64 (C), 118.78 (CH), 119.30

(CH), 120.47 (CH), 123.66 (CH), 126.83 (C), 128.80 (2 CH), 129.43 (C),

129.93 (2 CH), 130.90 (C), 131.95 (C), 132.33 (C), 133.88 (C), 140.81

(C), 145.86 (C), 155.16 (C).

IR (ATR): 3257, 3085, 2966, 2914, 2846, 2438, 2055, 2030, 2009, 1978,

1661, 1630, 1606, 1580, 1541, 1501, 1468, 1421, 1405, 1370, 1305,

1261, 1208, 1169, 1134, 1082, 1056, 1022, 991, 942, 909, 865, 847,

ESI-MS (+25 V): m/z = 502.5 [M + H]⁺, 524.5 [M + Na]⁺.

ESI-MS (–25 V): m/z = 500.1 [M – H]^–.

823, 781, 731, 703 cm^–1

.

K

S. K. Kutz et al.

Paper

Synthesis

¹H NMR (500 MHz, CDCl₃): δ = 1.44 (s, 3 H), 1.57 (s, 3 H), 1.65 (d, J =

0.9 Hz, 3 H), 1.71 (ddd, J = 13.9, 11.0, 6.0 Hz, 1 H), 1.78 (ddd, J = 13.9,

10.1, 6.6 Hz, 1 H), 2.07–2.21 (m, 2 H), 2.15 (d, J = 1.9 Hz, 3 H), 5.09

(tsept, J = 7.3, 1.3 Hz, 1 H), 5.68 (d, J = 10.1 Hz, 1 H), 6.45 (d, J = 1.6 Hz,

1 H), 6.61 (d, J = 9.8 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 7.94 (d, J = 8.5 Hz,

1 H), 9.28 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 16.28 (CH₃), 17.78 (CH₃), 22.84 (CH₂),

25.81 (CH₃), 26.30 (CH₃), 41.08 (CH₂), 79.26 (C), 105.48 (C), 116.12

(CH), 116.40 (CH), 117.85 (C), 118.93 (C), 123.23 (CH), 123.97 (CH),

129.70 (CH), 131.74 (CH), 132.10 (C), 134.29 (C), 134.73 (C), 148.32

(C), 152.89 (C), 180.00 (C), 183.95 (C).

Fluorescence (MeOH, exc. 239 nm): 373 nm.

IR (ATR): 3415, 3028, 2969, 2923, 2840, 1734, 1717, 1698, 1684, 1623,

1595, 1579, 1485, 1456, 1376, 1334, 1294, 1230, 1216, 1190, 1175,

1162, 1118, 1093, 1063, 1017, 961, 876, 842, 816, 786, 764, 705 cm^–1

.

¹H NMR (600 MHz, CDCl₃): δ = 1.76 (d, J = 0.8 Hz, 3 H), 1.78 (d, J = 1.1

Hz, 3 H), 2.35 (s, 3 H), 2.44 (s, 3 H), 3.43 (d, J = 6.8 Hz, 2 H), 3.92 (s, 3

H), 5.39 (tsept, J = 7.2, 1.5 Hz, 1 H), 6.49–6.55 (m, 1 H), 6.86 (s, 1 H),

7.30 (s, 2 H), 7.60 (dd, J = 1.5, 0.8 Hz, 1 H), 7.68 (s, 1 H), 7.72–7.78 (m,

2 H), 8.25 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃,): δ = 17.94 (CH₃), 21.29 (CH₃), 21.86 (CH₃),

26.04 (CH₃), 28.94 (CH₂), 55.77 (CH₃), 93.16 (CH), 116.04 (C), 118.42

(CH), 118.49 (CH), 120.49 (CH), 123.29 (CH), 123.59 (C), 127.18 (2

CH), 128.79 (2 CH), 129.22 (C), 129.90 (C), 130.41 (C), 132.06 (C),

132.37 (C), 133.90 (C), 140.00 (C), 145.75 (C), 157.68 (C).

ESI-MS (+25 V): m/z = 362.4 [M + H]⁺, 745.4 [2M + Na]⁺.

ESI-MS (–25 V): m/z = 360.1 [M – H]^–, 743.3 [2M + Na – 2 H]^–.

HRMS: m/z [M]⁺calcd for C₂₃H₂₃NO₃: 361.1678; found: 361.1662.

ESI-MS (+10 V): m/z = 450.4 [M + H]⁺.

ESI-MS (–10 V): m/z = 448.2 [M – H]^–.

6-Bromo-7-methoxy-3-methyl-1-(tosyloxy)carbazole (31)

N-Bromosuccinimide (234 mg, 1.31 mmol) was added to a solution of

the carbazole 22 (500 mg, 1.31 mmol) in CH₂Cl₂(30 mL) under an ar-

gon atmosphere. The reaction mixture was stirred for 3 d at r.t., then

the solvent was evaporated. Purification by column chromatography

(silica gel, isohexane–EtOAc, 8:1 to 6:1) provided bromocarbazole 31

(566 mg, 1.23 mmol, 94%) as a colorless solid.

Anal. Calcd for C₂₆H₂₇NO₄S: C, 69.46; H, 6.05; N, 3.12; S, 7.13. Found:

C, 69.45; H, 6.25; N, 3.06; S, 6.87.

tert-Prenylcarbazole 32a

Mp 193.0–194.5 °C.

IR (ATR): 3397, 2998, 2969, 2949, 2917, 2866, 1628, 1597, 1580, 1496,

1454, 1366, 1292, 1254, 1195, 1169, 1087, 1062, 1014, 976, 904, 884,

Mp 200.0–201.0 °C.

UV (MeOH): 238, 263 (sh), 306, 324 (sh), 337 (sh) nm.

Fluorescence (MeOH, exc. 306 nm): 384 nm.

855, 809, 782, 714, 657, 633 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.54 (s, 6 H), 2.34 (s, 3 H), 2.44 (s, 3 H),

3.88 (s, 3 H), 4.96 (dd, J = 17.3, 1.4 Hz, 1 H), 4.97 (dd, J = 10.7, 1.4 Hz, 1

H), 6.27 (dd, J = 17.3, 10.7 Hz, 1 H), 6.50 (s, 1 H), 6.89 (s, 1 H), 7.30 (d,

J = 7.9 Hz, 2 H), 7.62 (s, 1 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.85 (s, 1 H), 8.29

(s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 21.31 (CH₃), 21.88 (CH₃), 27.95 (2

CH₃), 40.87 (C), 55.51 (CH₃), 94.59 (CH), 109.79 (CH₂), 115.72 (C),

118.31 (CH), 118.54 (CH), 118.58 (CH), 127.47 (C), 128.80 (2 CH),

129.32 (C), 129.90 (2 CH), 130.22 (C), 130.52 (C), 131.93 (C), 133.90

(C), 140.12 (C), 145.77 (C), 148.81 (CH), 158.77 (C).

IR (ATR): 3424, 2972, 2945, 2919, 2853, 1621, 1491, 1454, 1397, 1364,

1333, 1289, 1215, 1198, 1171, 1079, 1036, 973, 873, 845, 813, 803,

779, 753, 703, 661 cm^–1

.

¹H NMR (600 MHz, CDCl₃): δ = 2.34 (s, 3 H), 2.45 (s, 3 H), 3.97 (s, 3 H),

6.51–6.59 (m, 1 H), 6.92 (s, 1 H), 7.32 (d, J = 8.7 Hz, 2 H), 7.57 (d, J = 0.8

Hz, 1 H), 7.71–7.83 (m, 2 H), 8.10 (s, 1 H), 8.43 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃): δ = 21.30 (CH₃), 21.89 (CH₃), 56.61 (CH₃),

94.66 (CH), 104.10 (C), 117.66 (C), 118.68 (CH), 119.48 (CH), 124.77

(CH), 126.04 (C), 128.80 (2 CH), 129.98 (2 CH), 130.20 (C), 130.76 (C),

131.83 (C), 133.88 (C), 140.45 (C), 145.96 (C), 155.18 (C).

ESI-MS (+25 V): m/z = 450.3 [M + H]⁺.

ESI-MS (+25 V): m/z = 460.2/462.2 [M + H]⁺.

ESI-MS (–50 V): m/z = 457.8/459.8 [M – H]^–.

Anal. Calcd for C₂₆H₂₇NO₄S: C, 69.46; H, 6.05; N, 3.12; S, 7.13. Found:

C, 68.62; H, 5.99; N, 3.07; S, 6.82.

Anal. Calcd for C₂₁H₁₈BrNO₄S: C, 54.79; H, 3.94; N, 3.04; S, 6.96.

Found: C, 55.17; H, 3.87; N, 3.09; S, 7.23.

2,2,7-Trimethyl-9-(tosyloxy)-2,3,4,10-tetrahydropyrano[2,3-b]car-

bazole (33)

A 1.5 mL GC-vial was charged with prenylcarbazole 32 (30.0 mg, 66.7

μmol) and pyridinium chloride (300 mg, 2.60 mmol). The mixture

was stirred at 170 °C for 5 h, then H₂O was added and the mixture

was extracted with EtOAc. Evaporation of the solvent and subsequent

column chromatography (silica gel, isohexane–EtOAc, 8:1) provided

the tetrahydropyrano[2,3-b]carbazole 33 (23.3 mg, 53.5 μmol, 80%) as

a colorless solid.

7-Methoxy-3-methyl-6-(3-methylbut-2-enyl)-1-(tosyloxy)carba-

zole (32) and 6-(1,1-Dimethylprop-2-enyl)-7-methoxy-3-methyl-

1-(tosyloxy)carbazole (32a)

A mixture of bromocarbazole 31 (50.0 mg, 0.109 mmol), 3-methyl-2-

butenylboronic acid pinacol ester (40.0 mg, 0.204 mmol), (PPh₃)₄Pd

(13.0 mg, 11.2 μmol), NaOH (175 mg, 4.38 mmol), toluene (2 mL), and

H₂O (2 mL) was vigorously stirred at r.t. under an argon atmosphere.

After 21 h, H₂O was added and the mixture was extracted with EtOAc.

Evaporation of the solvent and subsequent column chromatography

(silica gel, isohexane–EtOAc, 8:1) provided prenylcarbazole 32 (36.2

mg, 80.5 μmol, 74%), and tert-prenylcarbazole 32a (12.1 mg, 26.9

μmol, 25%) both as colorless solids.

Mp 167.5–168.5 °C.

UV (MeOH): 220, 236 (sh), 242, 254 (sh), 310, 326 (sh), 340 (sh) nm.

Fluorescence (MeOH, exc. 242 nm): 375 nm.

IR (ATR): 3415, 2969, 2922, 2846, 2054, 2030, 2010, 1640, 1580, 1494,

1455, 1436, 1368, 1336, 1291, 1255, 1217, 1175, 1153, 1118, 1094,

1065, 973, 940, 848, 812, 770 cm^–1

.

Prenylcarbazole 32

¹H NMR (500 MHz, CDCl₃): δ = 1.38 (s, 6 H), 1.87 (t, J = 6.8 Hz, 2 H),

2.35 (s, 3 H), 2.43 (s, 3 H), 2.95 (t, J = 6.6 Hz, 2 H), 6.58 (s, 1 H), 6.75 (s,

1 H), 7.27–7.32 (m, 2 H), 7.55 (s, 1 H), 7.63 (s, 1 H), 7.75 (s, 2 H), 8.02

(br s, 1 H).

Mp 141.0–141.5 °C.

UV (MeOH): 239, 251 (sh), 263 (sh), 305, 323 (sh), 335 (sh) nm.

L

S. K. Kutz et al.

Paper

Synthesis

¹³C NMR (125 MHz, CDCl₃): δ = 21.31 (CH₃), 21.86 (CH₃), 22.94 (CH₂),

27.09 (2 CH₃), 33.25 (CH₂), 74.70 (C), 98.46 (CH), 114.48 (C), 116.77

(C), 118.31 (CH), 118.85 (CH), 120.52 (CH), 126.98 (C), 128.73 (2 CH),

129.11 (C), 129.89 (2 CH), 130.79 (C), 132.13 (C), 133.78 (C), 140.41

(C), 145.77 (C), 154.06 (C).

ESI-MS (+10 V): m/z = 436.4 [M + H]⁺.

ESI-MS (–25 V): m/z = 434.1 [M – H]^–.

IR (ATR): 3177, 3133, 2976, 2928, 2140, 2048, 2030, 2009, 1975, 1716,

1659, 1630, 1604, 1573, 1534, 1490, 1471, 1457, 1442, 1376, 1360,

1320, 1295, 1272, 1216, 1188, 1154, 1116, 1085, 1039, 1007, 979,

905, 888, 867, 849, 768, 741, 694 cm^–1

.

¹H NMR (600 MHz, DMSO-d₆): δ = 1.39 (s, 6 H), 2.02 (d, J = 1.9 Hz, 3

H), 5.84 (d, J = 9.8 Hz, 1 H), 6.52 (q, J = 1.5 Hz, 1 H), 6.60 (d, J = 9.8 Hz,

1 H), 6.77 (s, 1 H), 7.68 (s, 1 H), 12.54 (s, 1 H).

¹³C NMR (150 MHz, DMSO-d₆): δ = 15.46 (CH₃), 27.64 (2 CH₃), 76.42

(C), 99.23 (CH), 116.00 (C), 118.34 (C), 118.73 (CH), 119.97 (C), 122.45

(CH), 131.51 (CH), 131.61 (CH), 135.09 (C), 138.48 (C), 147.12 (C),

152.26 (C), 179.17 (C=O), 183.07 (C=O).

Anal. Calcd for C₂₅H₂₅NO₄S: C, 68.94; H, 5.79; N, 3.22; S, 7.36. Found:

C, 68.98; H, 5.89; N, 3.25; S, 7.41.

2,2,7-Trimethyl-2,3,4,10-tetrahydropyrano[2,3-b]carbazole-6,9-

dione (35)

MS (EI): m/z (%) = 293 (13) [M⁺], 278 (100), 250 (4), 222 (4).

Anal. Calcd for C₁₈H₁₅NO₃: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.88;

H, 5.63; N, 4.55.

Lithium aluminum hydride (2.4 M in THF, 0.50 mL, 1.2 mmol) was

added to a solution of compound 33 (49.0 mg, 0.113 mmol) in THF (8

mL) under an argon atmosphere at r.t. The solution was refluxed for

14 h and subsequently quenched with H₂O at 0 °C, then a saturated

aqueous solution of sodium potassium tartrate was added. After ex-

traction with EtOAc, the combined organic layers were dried (MgSO₄),

the solvent was evaporated and the residue was filtered over a short

pad of silica gel (isohexane–EtOAc, 1:1). The solvent was evaporated

and the residue was dissolved in acetone (7 mL).

3-[(tert-Butyldimethylsilyl)oxy]aniline (36)

A solution of 3-nitrophenol (500 mg, 3.59 mmol), TBSCl (2.00 g, 15.9

mmol), and imidazole (1.50 g, 22.0 mmol) in DMF (10 mL) was stirred

under an argon atmosphere for 24 h at r.t. The mixture was diluted

with EtOAc and H₂O and the layers were separated. The aqueous layer

was extracted with EtOAc, and the combined organic layers were

washed with brine and dried (Na₂SO₄). The solvent was evaporated

and the residue was purified by column chromatography (silica gel,

PE–EtOAc, 6:1) to provide tert-butyldimethyl-(3-nitrophenoxy)silane

(825 mg, 3.26 mmol, 92%).

This solution was added to a stirred solution of potassium nitrosodi-

sulfonate (Frémy’s salt) (210 mg, 0.783 mmol) in H₂O (7 mL) at r.t. un-

der air. The mixture was stirred vigorously at the same temperature

for 40 min. The mixture was diluted with EtOAc. After extraction with

EtOAc, the combined organic layers were dried (MgSO₄). Evaporation

of the solvent and subsequent column chromatography (silica gel, iso-

hexane–EtOAc, 7:1) provided the tetrahydropyrano[2,3-b]carbazole-

dione 35 (20.0 mg, 67.7 mmol, 60%) as a dark purple solid.

A mixture of tert-butyldimethyl-(3-nitrophenoxy)silane (400 mg,

1.58 mmol), EtOH (20 mL), and Pd/C (10%, 80 mg) was vigorously

shaken in a Parr hydrogenation apparatus under a hydrogen atmo-

sphere (4 bar) for 8 h. Filtration over a short pad of Celite (EtOAc) and

evaporation of the solvent provided the aniline 36 (348 mg, 1.56

mmol, 99%) as a brown oil.

¹H NMR (400 MHz, CDCl₃): δ = 0.19 (s, 6 H), 0.98 (s, 9 H), 3.56–3.60

(br s, 2 H), 6.19 (td, J = 2.3, 0.4 Hz, 1 H), 6.25 (ddd, J = 8.0, 2.3, 0.8 Hz, 1

H), 6.29 (ddd, J = 8.0, 2.3, 0.8 Hz, 1 H), 6.99 (td, J = 2.3, 0.4 Hz, 1 H).

Mp 225–230 °C (sublimed).

UV (MeOH): 232, 265, 293 (sh), 425 nm.

Fluorescence (MeOH, exc. 232 nm): 343 nm.

IR (ATR): 3244, 3183, 2969, 2925, 1658, 1626, 1604, 1574, 1559, 1532,

1498, 1458, 1439, 1398, 1378, 1338, 1295, 1268, 1243, 1216, 1154,

1120, 1092, 1005, 976, 927, 898, 879, 857, 841, 750, 720, 680, 664,

For further spectroscopic data, see ref. 29.

606 cm^–1

.

2-Bromo-5-methylcyclohexa-2,5-diene-1,4-dione (41)

¹H NMR (500 MHz, CDCl₃): δ = 1.37 (s, 6 H), 1.86 (t, J = 6.9 Hz, 2 H),

2.14 (d, J = 1.6 Hz, 3 H), 2.96 (t, J = 6.9 Hz, 2 H), 6.43 (q, J = 1.6 Hz, 1 H),

6.82 (s, 1 H), 7.90 (s, 1 H), 9.12 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 16.25 (CH₃), 23.11 (CH₂), 27.15 (2

CH₃), 32.99 (CH₂), 75.24 (C), 99.05 (CH), 116.94 (C), 118.51 (C), 121.02

(C), 122.81 (CH), 131.76 (CH), 134.89 (C), 137.54 (C), 148.20 (C),

154.84 (C), 179.98 (C=O), 184.01 (C=O).

K₂CO₃(27.6 g, 200 mmol) and Me₂SO₄(11.5 mL, 15.2 g, 121 mmol)

were added to solution of toluhydroquinone (40) (5.00 g, 40.3 mmol)

in acetone (30 mL) at r.t. under an argon atmosphere. The mixture

was stirred at the same temperature for 3 h. H₂O and Et₂O were add-

ed, the layers were separated, and the aqueous layer was extracted

with Et₂O. The combined organic layers were dried (MgSO₄) and the

solvent was evaporated.

ESI-MS (+25 V): m/z = 296.3 [M + H]⁺, 613.2 [2M + Na]⁺.

ESI-MS (–50 V): m/z = 293.9 [M – H]^–.

The residue and NaOAc (6.62 g, 80.7 mmol) were dissolved in glacial

acetic acid (40 mL) and bromine (2.28 mL, 7.10 g, 44.4 mmol) was

added over a period of 25 min under air at r.t. The mixture was stirred

for another 60 min. A saturated aqueous solution of NaHCO₃was add-

ed slowly and the mixture was extracted with EtOAc. The combined

organic layers were washed with brine, dried (MgSO₄), and the sol-

vent was evaporated.

Pyrayaquinone-A (1)

A mixture of compound 35 (20.0 mg, 67.7 μmol), DDQ (33.8 mg, 0.149

mmol) and toluene (3 mL) was stirred at 100 °C under air. After 3.5 h,

the solvent was removed and the residue was subjected to column

chromatography (silica gel, isohexane–EtOAc, 1:1) to provide pyraya-

quinone-A (1) (17.0 mg, 58.0 μmol, 86%) as a dark purple solid.

The residue was dissolved in MeCN (70 mL). Ceric ammonium nitrate

(54.8 g, 100 mmol) and H₂O (20 mL) were added at r.t. under air and

the mixture was stirred vigorously for 1 h. Et₂O and H₂O were added,

the layers were separated and the aqueous layer was extracted with

Et₂O. The combined organic layers were dried (MgSO₄), the solvent

was evaporated and the residue was purified by column chromatogra-

phy (silica gel, isohexane–EtOAc, 15:1) to provide the quinone 41

(7.85 g, 39.1 mmol, 97%) as a yellow solid.

Mp 225–230 °C (dec.) [Lit.⁷222 °C (dec.)].

UV (MeOH): 214, 250, 459 nm.

Fluorescence (MeOH, exc. 250 nm): 360 nm.

M

S. K. Kutz et al.

Paper

Synthesis

Mp 97.0–98.5 °C.

7-Hydroxy-3-methyl-1H-carbazole-1,4(9H)-dione (43)

¹H NMR (300 MHz, CDCl₃): δ = 2.08 (d, J = 1.6 Hz, 3 H), 6.80 (q, J = 1.6

Hz, 1 H), 7.28 (s, 1 H).

TBAF (1 M in THF, 255 μL, 0.255 mmol) was added to a solution of the

carbazolequinone 42 (67.0 mg, 0.196 mmol) in THF (5 mL) at 0 °C un-

der an argon atmosphere, and the mixture was stirred for 10 min. H₂O

was added and the mixture was extracted with EtOAc. The combined

organic layers were dried (MgSO₄), the solvent was evaporated and

the residue was purified by column chromatography (silica gel, iso-

hexane–EtOAc, 3:1 to 1:1) to provide hydroxycarbazolequinone 43

(40.0 mg, 0.176 mmol, 90%) as a dark purple solid.

For additional spectroscopic data, see ref. 30.

2-({3-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-5-methylcy-

clohexa-2,5-diene-1,4-dione (38)

A solution of quinone 41 (75 mg, 0.37 mmol) in toluene (3 mL) was

added using a syringe pump to a stirred mixture of the aniline 36

(100 mg, 0.448 mmol), Cs₂CO₃(176 mg, 0.540 mmol), Pd(OAc)₂(10

mg, 44 μmol), and XPhos (45 mg, 94 μmol) in toluene (20 mL) at

100 °C under an argon atmosphere within 1 h. The mixture was

stirred at the same temperature for another 1 h. The solvent was

evaporated and the residue was purified by column chromatography

(silica gel, isohexane–EtOAc, 20:1 to 15:1) to provide compound 38

(79 mg, 0.23 mmol, 62%) as a dark red solid.

Mp >300 °C.

UV (MeOH): 228, 262, 288 (sh), 403 nm.

Fluorescence (MeOH, exc. 262 nm): 364 nm.

IR (ATR): 3514, 3201, 1659, 1621, 1601, 1533, 1517, 1473, 1419, 1380,

1256, 1213, 1181, 1155, 1139, 1100, 1010, 974, 953, 879, 843, 816,

783, 744, 694 cm^–1

.

¹H NMR (500 MHz, DMSO-d₆): δ = 2.03 (d, J = 1.6 Hz, 3 H), 6.52 (q, J =

1.6 Hz, 1 H), 6.80–6.85 (m, 2 H), 7.81 (d, J = 9.5 Hz, 1 H), 9.75 (br s, 1

H), 12.39 (br s, 1 H).

Mp 108.5–109.5 °C.

UV (MeOH): 215, 263, 500 nm.

¹³C NMR (125 MHz, DMSO-d₆): δ = 15.51 (CH₃), 97.44 (CH), 115.40

(CH), 116.04 (C), 116.97 (C), 122.45 (CH), 131.56 (CH), 134.67 (C),

139.25 (C), 147.06 (C), 156.91 (C), 179.45 (C), 183.37 (C).

MS (EI): m/z (%) = 227 (100) [M⁺], 199 (47), 170 (37), 159 (22), 130

(14), 103 (14), 76 (16), 39 (11).

IR (ATR): 3248, 3055, 2952, 2928, 2857, 2056, 1643, 1575, 1525, 1483,

1422, 1358, 1256, 1190, 1122, 983, 863, 834, 775, 681 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 0.21 (s, 6 H), 0.98 (s, 9 H), 2.09 (d, J =

1.6 Hz, 3 H), 6.17 (s, 1 H), 6.56 (q, J = 1.6 Hz, 1 H), 6.63–6.69 (m, 2 H),

6.81 (dd, J = 8.1, 1.6 Hz, 1 H), 7.20 (br s, 1 H), 7.22 (t, J = 8.1 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = –4.23 (2 CH₃), 16.62 (CH₃), 18.35 (C),

25.78 (3 CH₃), 101.40 (CH), 114.02 (CH), 115.09 (CH), 117.24 (CH),

129.40 (CH), 130.44 (CH), 138.74 (C), 142.97 (C), 149.81 (C), 156.90

(C), 183.96 (C=O), 186.85 (C=O).

MS (EI): m/z (%) = 343 (87) [M⁺], 286 (41), 271 (26), 258 (100), 243

(11), 242 (11), 212 (22), 75 (19), 73 (10).

For additional spectroscopic data, see ref. 18.

N-{3-[(tert-Butyldimethylsilyl)oxy]phenyl}-2,5-dimethoxy-4-

methylaniline (45)

A solution of compound 44 (1.17 g, 5.05 mmol) in toluene (10 mL)

was added using a syringe pump to a stirred mixture of the aniline 36

(1.48 g, 6.62 mmol), Cs₂CO₃(1.96 g, 6.00 mmol), Pd(OAc)₂(67.0 mg,

298 μmol), and XPhos (286 mg, 600 μmol) in toluene (50 mL) at reflux

under an argon atmosphere within 2 h. The mixture was stirred at the

same temperature for another 18 h. The reaction mixture was al-

lowed to cool to r.t. and filtered over Celite (EtOAc). Removal of the

solvent and purification of the residue by column chromatography

(silica gel, isohexane–EtOAc, 99:1 to 85:15) afforded compound 45

(1.83 g, 4.90 mmol, 97%) as a colorless oil.

Anal. Calcd for C₁₉H₂₅NO₃Si: C, 66.44; H, 7.34; N, 4.08. Found: C,

66.72; H, 7.56; N, 3.80.

7-[(tert-Butyldimethylsilyl)oxy]-3-methyl-1H-carbazole-1,4(9H)-

dione (42)

A mixture of compound 38 (70.0 mg, 0.204 mmol), Pd(OAc)₂(15 mg,

67 μmol), Cu(OAc)₂(91 mg, 0.50 mmol), and glacial acetic acid (1.5

mL) was stirred at 100 °C under air for 5 h. An aqueous solution of

K₂CO₃was added and the mixture was extracted with EtOAc. The

combined organic layers were dried (MgSO₄) and the solvent was

evaporated. Column chromatography (silica gel, isohexane–EtOAc,

15:1 to 5:1) provided the carbazolequinone 42 (51.6 mg, 0.151 mmol,

74%) as a dark purple solid.

IR (ATR): 3417, 2949, 2930, 2856, 1594, 1492, 1465, 1393, 1254, 1204,

1176, 1155, 1044, 983, 837, 778, 690 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 0.20 (s, 6 H), 0.98 (s, 9 H), 2.19 (s, 3 H),

3.74 (s, 3 H), 3.82 (s, 3 H), 5.98 (br s, 1 H), 6.40 (dd, J = 8.0, 1.9 Hz, 1 H),

6.63 (t, J = 2.2 Hz, 1 H), 6.69–6.70 (m, 1 H), 6.70 (s, 1 H), 6.90 (s, 1 H),

7.10 (t, J = 8.1 Hz, 1 H).

Mp >300 °C (dec.).

¹³C NMR (125 MHz, CDCl₃): δ = –4.11 (2 CH₃), 16.03 (CH₃), 18.41 (C),

25.91 (3 CH₃), 56.41 (CH₃), 56.66 (CH₃), 101.07 (CH), 109.58 (CH),

111.21 (CH), 112.68 (CH), 114.36 (CH), 117.99 (C), 130.13 (CH),

130.89 (C), 142.79 (C), 144.75 (C), 151.86 (C), 156.90 (C).

UV (MeOH): 214, 264, 500 nm.

Fluorescence (MeOH, exc. 264 nm): 298 nm.

IR (ATR): 3180, 2953, 2927, 2855, 2056, 2030, 1627, 1603, 1569, 1537,

1432, 1241, 1161, 1101, 965, 869, 832, 777, 664, 639 cm^–1

.

MS (EI): m/z (%) = 373 (92) [M⁺], 358 (100), 269 (8), 75 (9), 73 (10).

¹H NMR (500 MHz, DMSO-d₆): δ = 0.22 (s, 6 H), 0.97 (s, 9 H), 2.05 (d,

J = 1.6 Hz, 3 H), 6.58 (q, J = 1.6 Hz, 1 H), 6.82–6.99 (m, 2 H), 7.91 (d, J =

9.1 Hz, 1 H), 12.55 (s, 1 H).

Anal. Calcd for C₂₁H₃₁NO₃Si: C, 67.52; H, 8.36; N, 3.75. Found: C,

67.80; H, 8.42; N, 3.81.

¹³C NMR (125 MHz, DMSO-d₆): δ = –4.48 (2 CH₃), 15.55 (CH₃), 18.00

(C), 25.57 (3 CH₃), 102.96 (CH), 115.76 (C), 118.57 (CH), 118.79 (C),

122.56 (CH), 131.60 (CH), 135.51 (C), 138.71 (C), 147.38 (C), 154.21

(C), 179.63 (C=O), 183.24 (C=O).

7-Hydroxy-3-methyl-8-(3-methylbut-2-en-1-yl)-1-(tosyloxy)car-

bazole (47)

Silicon tetrachloride (432 mg, 2.54 mmol) and DIBAL-H (1 M in n-

hexane, 2.50 mL, 2.50 mmol) were added slowly to a solution of pyra-

nocarbazole 25 (165 mg, 0.381 mmol) in toluene (50 mL) under an ar-

gon atmosphere at –78 °C. The mixture was allowed to warm to r.t.

and was stirred for 22 h. After quenching slowly with H₂O at 0 °C,

MS (EI): m/z (%) = 341 (33) [M⁺], 285 (36), 284 (100).

Anal. Calcd for C₁₉H₂₃NO₃Si: C, 66.83; H, 6.79; N, 4.10. Found: C,

66.63; H, 7.04; N, 4.01.

N

S. K. Kutz et al.

Paper

Synthesis

EtOAc and saturated aqueous sodium potassium tartrate solution

were added. The aqueous layer was extracted with EtOAc and the

combined organic layers were dried (MgSO₄). Evaporation of the sol-

vent and subsequent column chromatography (silica gel, isohexane–

EtOAc, 10:1 to 5:1) provided prenylcarbazole 47 (128 mg, 0.294

mmol, 77%) as a colorless solid.

Murrayafoline-B (50)

Lithium aluminum hydride (2.4 M in THF, 1.95 mL, 4.68 mmol) was

added to a solution of the carbazole 48 (300 mg, 0.667 mmol) in THF

(30 mL) under an argon atmosphere at r.t. The solution was refluxed

for 18 h and subsequently quenched with H₂O at 0 °C, then a saturat-

ed aqueous solution of sodium potassium tartrate was added. After

extraction with EtOAc, the combined organic layers were dried (Mg-

SO₄), the solvent was evaporated and the residue was subjected to

column chromatography (silica gel, isohexane–EtOAc, 15:1) which

provided murrayafoline-B (50) (186 mg, 0.630 mmol, 94%) as a brown

solid.

Mp 127.0–127.5 °C.

UV (MeOH): 226, 243, 253 (sh), 304, 319 (sh) nm.

Fluorescence (MeOH, exc. 243 nm): 364 nm.

IR (ATR): 3507, 3402, 2954, 2917, 1622, 1492, 1451, 1420, 1398, 1352,

1282, 1227, 1204, 1187, 1171, 1091, 1020, 972, 853, 803, 778, 737,

Mp 121.0–123.0 °C (Lit.¹³syrup; Lit.^17c212–214 °C).

UV (MeOH): 232 (sh), 245, 253 (sh), 283, 300, 322, 335 nm.

Fluorescence (MeOH, exc. 245 nm): 366 nm.

663 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.83 (d, J = 1.3 Hz, 3 H), 1.94 (s, 3 H),

2.36 (s, 3 H), 2.44 (s, 3 H), 3.57 (d, J = 7.3 Hz, 2 H), 5.16 (br s, 1 H), 5.36

(tsept, J = 7.1, 1.4 Hz, 1 H), 6.54 (s, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 7.30

(d, J = 7.9 Hz, 2 H), 7.58 (s, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.74 (d, J = 8.2

Hz, 2 H), 8.23 (s, 1 H).

IR (ATR): 3432, 3298, 2960, 2910, 2835, 2050, 2030, 2010, 1973, 1620,

1589, 1535, 1512, 1490, 1455, 1417, 1373, 1351, 1313, 1291, 1253,

1220, 1172, 1082, 1031, 995, 974, 953, 875, 833, 809, 788, 694 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.74 (d, J = 1.3 Hz, 3 H), 1.89 (s, 3 H),

2.45 (s, 3 H), 3.63 (d, J = 6.9 Hz, 2 H), 3.93 (s, 3 H), 5.02 (br s, 1 H), 5.32

(tsept, J = 6.9, 1.3 Hz, 1 H), 6.58 (s, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 7.37 (s,

1 H), 7.78 (d, J = 8.5 Hz, 1 H), 7.97 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.13 (CH₃), 21.61 (CH₃), 24.06 (CH₂),

25.84 (CH₃), 56.82 (CH₃), 104.89 (CH), 111.52 (CH), 111.57 (C), 112.63

(CH), 118.16 (C), 118.49 (CH), 122.43 (CH), 126.05 (C), 127.40 (C),

129.60 (C), 132.97 (C), 140.56 (C), 140.64 (C), 155.66 (C).

¹³C NMR (125 MHz, CDCl₃): δ = 18.21 (CH₃), 21.32 (CH₃), 21.88 (CH₃),

24.47 (CH₂), 25.95 (CH₃), 108.89 (C), 109.81 (CH), 117.15 (C), 118.51

(CH), 118.90 (CH), 118.91 (CH), 121.10 (CH), 127.44 (C), 128.77 (2

CH), 129.48 (C), 129.91 (2 CH), 130.73 (C), 132.06 (C), 133.97 (C),

135.63 (C), 140.91 (C), 145.76 (C), 152.94 (C).

ESI-MS (+25 V): m/z = 436.6 [M + H]⁺, 458.4 [M + Na]⁺.

ESI-MS (–25 V): m/z = 434.1 [M – H]^–.

Anal. Calcd for C₂₅H₂₅NO₄S: C, 68.94; H, 5.79; N, 3.22; S, 7.36. Found:

C, 68.59; H, 6.39; N, 3.21; S, 6.84.

MS (EI): m/z (%) = 295 (100) [M⁺], 280 (49), 264 (17), 249 (10), 240

(65), 210 (28).

Anal. Calcd for C₁₉H₂₁NO₂: C, 77.26; H, 7.17; N, 4.74. Found: C, 76.98;

H, 7.26; N, 4.61.

7-Methoxy-3-methyl-8-(3-methylbut-2-en-1-yl)-1-(tosyloxy)car-

bazole (48)

K₂CO₃(310 mg, 2.24 mmol) and Me₂SO₄(225 μL, 299 mg, 2.37 mmol)

were added to a solution of the hydroxycarbazole 47 (206 mg, 0.473

mmol) in acetone (10 mL) under an argon atmosphere at r.t. The mix-

ture was stirred at the same temperature for 14 h, then it was stirred

at 40 °C for another 2 h. H₂O was added and the mixture was extract-

ed with EtOAc. The combined organic layers were dried (MgSO₄) and

the solvent was evaporated. Subsequent column chromatography (sil-

ica gel, isohexane–EtOAc, 4:1) provided the carbazole 48 (199 mg,

0.443 mmol, 94%) as a colorless solid.

Murrayaquinone-E (6)

Lithium aluminum hydride (2.4 M in THF, 0.80 mL, 1.9 mmol) was

added to a solution of prenylcarbazole 47 (122 mg, 0.280 mmol) in

THF (35 mL) under an argon atmosphere at r.t. The solution was re-

fluxed for 16 h and subsequently quenched with H₂O at 0 °C, then a

saturated aqueous solution of sodium potassium tartrate was added.

After extraction with EtOAc, the combined organic layers were dried

(MgSO₄), the solvent was evaporated and the residue was filtered over

a short pad of silica gel (isohexane–EtOAc, 10:1 to 5:1). The solvent

was evaporated to provide the crude, very air-sensitive dihydroxycar-

bazole 49.

Mp 133.0–134.5 °C.

UV (MeOH): 223, 244, 254 (sh), 303, 321 (sh), 333 (sh) nm.

Fluorescence (MeOH, exc. 223 nm): 368 nm.

A solution of compound 49 in acetone (3 mL) was added to a stirred

solution of potassium nitrosodisulfonate (Frémy’s salt) (420 mg, 1.57

mmol) in H₂O (35 mL) at r.t. under air. Subsequently, acetone (32 mL)

was added and the mixture was stirred vigorously at the same tem-

perature for 68 h. The mixture was diluted with EtOAc. After ex-

traction with EtOAc, the combined organic layers were dried (MgSO₄).

Evaporation of the solvent and subsequent column chromatography

(silica gel, isohexane–EtOAc, 5:1) provided murrayaquinone-E (6)

(61.9 mg, 0.210 mmol, 75%) as a dark purple solid.

IR (ATR): 3445, 3405, 3379, 2955, 2916, 2860, 2830, 1729, 1617, 1484,

1455, 1435, 1358, 1293, 1268, 1216, 1188, 1172, 1083, 1019, 970,

848, 802, 762, 738, 673 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.79 (d, J = 0.9 Hz, 3 H), 1.94 (s, 3 H),

2.35 (s, 3 H), 2.43 (s, 3 H), 3.59 (d, J = 7.3 Hz, 2 H), 3.92 (s, 3 H), 5.30

(tsept, J = 7.3, 1.3 Hz, 1 H), 6.53–6.57 (m, 1 H), 6.86 (d, J = 8.5 Hz, 1 H),

7.27–7.31 (m, 2 H), 7.59–7.60 (m, 1 H), 7.74 (d, J = 8.2 Hz, 2 H), 7.76

(d, J = 8.5 Hz, 1 H), 8.25 (s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 18.13 (CH₃), 21.31 (CH₃), 21.87 (CH₃),

23.99 (CH₂), 25.93 (CH₃), 56.79 (CH₃), 105.20 (CH), 111.75 (C), 117.53

(C), 118.42 (CH), 118.60 (CH), 119.02 (CH), 121.94 (CH), 127.29 (C),

128.75 (2 CH), 129.28 (C), 129.88 (2 CH), 131.07 (C), 132.11 (C),

133.60 (C), 133.95 (C), 141.11 (C), 145.70 (C), 156.15 (C).

Mp 201.0 °C (dec.) (Lit.¹⁴brown oil; Lit.¹⁸88–89 °C).

UV (MeOH): 231, 263, 283, 412 nm.

Fluorescence (MeOH, exc. 230 nm): 360 nm.

IR (ATR): 3371, 3273, 2976, 2914, 2851, 1602, 1527, 1466, 1419, 1374,

1289, 1246, 1168, 1139, 1031, 1013, 991, 949, 873, 853, 813, 794,

ESI-MS (+10 V): m/z = 450.4 [M + H]⁺.

ESI-MS (–25 V): m/z = 448.2 [M – H]^–.

772, 699, 658 cm^–1

.

O

S. K. Kutz et al.

Paper

Synthesis

¹H NMR (500 MHz, CDCl₃): δ = 1.79 (d, J = 1.3 Hz, 3 H), 1.87 (s, 3 H),

2.14 (d, J = 1.6 Hz, 3 H), 3.57 (d, J = 6.9 Hz, 2 H), 5.20–5.45 (m, 1 H),

6.45 (q, J = 1.6 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 7.94 (d, J = 8.5 Hz, 1 H),

8.92 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 16.29 (CH₃), 18.26 (CH₃), 24.26 (CH₂),

25.88 (CH₃), 109.54 (C), 115.77 (CH), 117.70 (C), 119.01 (C), 120.68

(CH), 121.67 (CH), 131.70 (CH), 134.80 (C), 136.22 (C), 138.01 (C),

148.32 (C), 153.13 (C), 179.92 (C=O), 183.97 (C=O).

Hz, 1 H), 6.49 (s, 1 H), 6.72 (d, J = 8.5 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 2 H),

7.55 (s, 1 H), 7.69 (d, J = 8.2 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 2 H), 8.62 (s, 1

H).

¹³C NMR (125 MHz, CDCl₃): δ = 20.36 (CH₂), 21.31 (CH₃), 21.87 (CH₃),

23.73 (CH₃), 25.65 (CH₃), 26.29 (CH₃), 30.18 (CH₂), 32.23 (CH), 39.98

(CH), 76.43 (C), 107.69 (C), 111.59 (CH), 116.94 (C), 118.17 (CH),

118.48 (CH), 119.16 (CH), 120.11 (CH), 127.47 (C), 128.81 (2 CH),

129.43 (C), 129.88 (2 CH), 130.30 (C), 131.79 (C), 133.89 (C), 138.08

(C), 140.46 (C), 145.71 (C), 152.07 (C).

MS (EI): m/z (%) = 295 (66) [M⁺], 280 (12), 265 (10), 252 (6), 240 (100),

211 (6), 183 (6), 154 (7).

ESI-MS (+50 V): m/z = 502.4 [M + H]⁺, 524.4 [M + Na]⁺, 1025.4 [2M +

Na]⁺.

ESI-MS (–25 V): m/z = 500.3 [M – H]^–.

Murrayaquinone-B (5)

A solution of potassium nitrosodisulfonate (Frémy’s salt) (187 mg,

0.698 mmol) in H₂O (7 mL) was added to a solution of murrayafoline-

B (50) (29.4 mg, 99.7 μmol) in acetone (7 mL) and the mixture was

stirred vigorously at r.t. under air for 3 d. The mixture was diluted

with EtOAc. The aqueous layer was separated, extracted with EtOAc,

and the combined organic layers were dried (MgSO₄). Evaporation of

the solvent and subsequent column chromatography (silica gel, iso-

hexane–EtOAc, 10:1) provided murrayaquinone-B (5) (20.8 mg, 67.3

μmol, 68%) as a dark purple solid.

8-(3,7-Dimethylocta-2,6-dienyl)-7-hydroxy-3-methyl-1-(tosyl-

oxy)carbazole (54)

A mixture of propargyloxycarbazole 27 (198 mg, 0.395 mmol),

Lindlar catalyst (10%, 20 mg), and EtOAc (10 mL) was vigorously

stirred at r.t. under a hydrogen atmosphere for 22 h. After filtration

(EtOAc) and removal of the solvent, the residue was dissolved in DMF

(3 mL) in a 10 mL microwave tube and irradiated in a microwave reac-

tor (300 W, 180 °C) for 60 min. After cooling to r.t., H₂O was added

and the mixture was extracted with EtOAc. The combined organic

layers were dried (MgSO₄) and the solvent was evaporated. Subse-

quent column chromatography (silica gel, isohexane–EtOAc, 5:1) pro-

vided the hydroxycarbazole 54 as a mixture of diastereoisomers [ratio

E/Z = 1.3:1 (determined by ¹H NMR)] (157 mg, 0.312 mmol, 79%) as a

yellow solid. Further column chromatography (48 mg) using a Büchi

Sepacore apparatus [silica gel, isohexane–EtOAc, 100:0 (20 min) to

isohexane–EtOAc, 85:15 (80 min)] afforded 3 fractions in which one

or the other diastereoisomer was enriched (E/Z as determined by ¹H

NMR given in parentheses): 11.0 mg (1:10); 10.7 mg (1:1.3); 25.7 mg

(3:1).

Mp 220.5–221.0 °C (Lit.¹²221–223 °C).

UV (MeOH): 231, 263, 404 nm.

Fluorescence (MeOH, exc. 230 nm): 368 nm.

IR (ATR): 3284, 2960, 2916, 2853, 2134, 2048, 2030, 2009, 1977, 1641,

1608, 1558, 1536, 1513, 1469, 1439, 1416, 1372, 1331, 1289, 1257,

1170, 1141, 1083, 1033, 993, 951, 875, 842, 805, 787, 705, 678 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.75 (d, J = 0.9 Hz, 3 H), 1.85 (s, 3 H),

2.14 (d, J = 1.9 Hz, 3 H), 3.57 (d, J = 6.9 Hz, 2 H), 3.91 (s, 3 H), 5.25

(tsept, J = 6.7, 1.6 Hz, 1 H), 6.44 (q, J = 1.6 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1

H), 8.01 (d, J = 8.8 Hz, 1 H), 8.96 (br s, 1 H).

¹H NMR (500 MHz, CDCl₃): δ = 1.59 (E, s) and 1.67 (Z, s, 3 H), 1.66 (E,

s) and 1.73 (Z, s, 3 H), 1.83 (Z, d, J = 1.3 Hz) and 1.93 (E, s, 3 H), 2.08–

2.19 (E, m, 4 H) and 2.20–2.27 (Z, m, 2 H) and 2.32–2.40 (Z, m, 2 H),

2.35 (s, 3 H), 2.44 (s, 3 H), 3.57 (d, J = 6.9 Hz, 2 H), 5.00–5.15 (E, m) and

5.17–5.27 (Z, m, 1 H), 5.33–5.41 (m, 1 H), 6.55 (s, 1 H), 6.73 (Z, d, J =

8.5 Hz) and 6.74 (E, d, J = 8.5 Hz, 1 H), 7.26–7.33 (m, 2 H), 7.58 (s, 1 H),

7.685 (Z, d, J = 8.5 Hz) and 7.687 (E, d, J = 8.5 Hz, 1 H), 7.74 (d, J = 8.2

Hz, 2 H), 8.20 (E, s) and 8.23 (Z, s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 16.59 (E) and 23.63 (Z, CH₃), 17.86 (E)

and 17.91 (Z, CH₃), 21.33 (CH₃), 21.88 (CH₃), 24.21 (Z) and 24.46 (E,

CH₂), 25.82 (E) and 25.93 (Z, CH₃), 26.55 (Z) and 26.58 (E, CH₂), 32.36

(Z) and 39.82 (E, CH₂), 108.84 (E) and 108.88 (Z, C), 109.85 (Z) and

109.97 (E, CH), 117.08 (E) and 117.11 (Z, C), 118.49 (CH), 118.89 (CH),

118.94 (CH), 120.82 (E) and 121.69 (Z, CH), 123.91 (Z) and 123.97 (E,

CH), 127.44 (Z) and 127.48 (E, C), 128.77 (2 CH), 129.48 (Z) and 129.50

(E, C), 129.91 (2 CH), 130.67 (E) and 130.69 (Z, C), 132.08 (C), 132.13

(E) and 132.60 (Z, C), 133.97 (C), 139.46 (E) and 139.62 (Z, C), 140.82

(Z) and 140.84 (E, C), 145.75 (C), 153.06 (Z) and 153.22 (E, C).

¹³C NMR (125 MHz, CDCl₃): δ = 16.28 (CH₃), 18.17 (CH₃), 23.82 (CH₂),

25.83 (CH₃), 56.81 (CH₃), 110.87 (CH), 112.66 (C), 117.34 (C), 119.12

(C), 121.26 (CH), 121.68 (CH), 131.63 (CH), 134.15 (C), 135.22 (C),

138.07 (C), 148.33 (C), 156.12 (C), 179.99 (C=O), 183.90 (C=O).

MS (EI): m/z (%) = 309 (100) [M⁺], 294 (41), 279 (39), 266 (13), 264

(14), 254 (59), 241 (14), 224 (18).

2,5,5,10-Tetramethyl-12-(tosyloxy)-3,4,4a,5,13,13c-hexahydroiso-

chromeno[4,3-a]carbazole (52)

SiCl₄(136 mg, 800 μmol) and then DIBAL-H (1 M in hexane, 0.80 mL,

0.80 mmol) were added slowly at –78 °C to a solution of the pyra-

no[3,2-a]carbazole 28 (100 mg, 0.199 mmol) in CH₂Cl₂(17 mL). The

cooling was removed and the mixture was stirred for 20 h. The mix-

ture was cooled to 0 °C, quenched by the addition of H₂O and EtOAc,

and the layers were separated. The organic layer was washed with a

saturated aqueous solution of sodium potassium tartrate. The aque-

ous layer was extracted with EtOAc. The combined organic layers

were dried (MgSO₄) and the solvent was evaporated. Purification of

the residue by column chromatography (silica gel, isohexane–EtOAc,

15:1) provided the isochromeno[4,3-a]carbazole 52 (60.0 mg, 0.120

mmol, 60%) as a highly viscous colorless oil.

ESI-MS (+25 V): m/z = 504.3 [M + H]⁺, 526.3 [M + Na]⁺.

Anal. Calcd for C₃₀H₃₃NO₄S: C, 71.54; H, 6.60; N, 2.78; S, 6.37. Found:

C, 71.38; H, 7.21; N, 2.77; S, 5.74.

UV (MeOH): 229, 238, 278 (sh), 288, 309 (sh), 353 (sh) nm.

Fluorescence (MeOH, exc. 238 nm): 368 nm.

¹H NMR (500 MHz, CDCl₃): δ = 1.34 (s, 3 H), 1.48 (s, 3 H), 1.49–1.66

(m, 2 H), 1.78 (s, 3 H), 1.82 (ddd, J = 11.9, 5.6, 3.0 Hz, 1 H), 1.94–2.12

(m, 2 H), 2.33 (s, 3 H), 2.43 (s, 3 H), 3.72–3.88 (m, 1 H), 6.18 (d, J = 4.4

8-(3,7-Dimethylocta-2,6-dien-1-yl)-7-methoxy-3-methyl-1-(tosyl-

oxy)carbazole (55)

K₂CO₃(130 mg, 0.940 mmol) and Me₂SO₄(90 μL, 0.13 g, 0.99 mmol)

were added to a solution of the hydroxycarbazole 54 (ratio E/Z =

1.3:1) (100 mg, 0.199 mmol) in acetone (5 mL) under an argon atmo-

sphere at r.t. The mixture was stirred at the same temperature for 15

P

S. K. Kutz et al.

Paper

Synthesis

h, then Me₂SO₄(36 μL, 50 mg, 0.40 mmol) was added and the mixture

was stirred at 50 °C for a further 2.5 h. H₂O was added and the mix-

ture was extracted with EtOAc. The combined organic layers were

dried (MgSO₄) and the solvent was evaporated. Subsequent column

chromatography (silica gel, isohexane–EtOAc, 4:1) provided the car-

bazole 55 [ratio E/Z = 1.3:1 (determined by ¹H NMR)] (94.9 mg, 0.183

mmol, 92%) as a colorless solid.

¹H NMR (600 MHz, CDCl₃): δ = 1.57 (E, s) and 1.68 (Z, s, 3 H), 1.62 (E,

d, J = 0.6 Hz) and 1.73 (Z, d, J = 0.9 Hz, 3 H), 1.81 (Z, d, J = 1.3 Hz) and

1.95 (E, d, J = 0.6 Hz, 3 H), 2.06–2.16 (E, m, 4 H) and 2.20–2.27 (Z, m, 2

H) and 2.37–2.41 (Z, m, 2 H), 2.36 (s, 3 H), 2.43 (s, 3 H), 3.61 (d, J = 6.9

Hz, 2 H), 3.92 (Z, s) and 3.93 (E, s, 3 H), 5.05–5.12 (E, m) and 5.23–5.28

(Z, m, 1 H), 5.28–5.37 (m, 1 H), 6.53–6.61 (m, 1 H), 6.86 (Z, d, J = 8.5

Hz) and 6.87 (E, d, J = 8.5 Hz, 1 H), 7.27–7.31 (m, 2 H), 7.58–7.62 (E, m)

and 7.60 (Z, d, J = 0.6 Hz, 1 H), 7.71–7.81 (m, 3 H), 8.23 (E, br s) and

8.27 (Z, br s, 1 H).

¹H NMR (600 MHz, CDCl₃): δ = 1.58 (s, 3 H), 1.65 (d, J = 1.1 Hz, 3 H),

1.87 (d, J = 1.1 Hz, 3 H), 2.07–2.13 (m, 4 H), 2.14 (d, J = 1.9 Hz, 3 H),

3.58 (d, J = 6.8 Hz, 2 H), 5.05 (tsept, J = 6.8, 1.5 Hz, 1 H), 5.29–5.41 (m,

2 H), 6.45 (q, J = 1.5 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 1 H), 7.94 (d, J = 8.7 Hz,

1 H), 8.96 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃): δ = 16.27 (CH₃), 16.62 (CH₃), 17.86 (CH₃),

24.29 (CH₂), 25.80 (CH₃), 26.53 (CH₂), 39.75 (CH₂), 109.50 (C), 115.89

(CH), 117.70 (C), 119.01 (C), 120.49 (CH), 121.68 (CH), 123.72 (CH),

131.69 (CH), 132.34 (C), 134.80 (C), 138.02 (C), 140.01 (C), 148.32 (C),

153.32 (C), 179.86 (C=O), 183.96 (C=O).

ESI-MS (+25 V): m/z = 364.3 [M + H]⁺, 386.4 [M + Na]⁺, 749.5 [2M +

Na]⁺.

ESI-MS (–50 V): m/z = 362.1 [M – H]^–, 747.2 [2M + Na – 2 H]^–.

Anal. Calcd for C₂₃H₂₅NO₃: C, 76.01; H, 6.93; N, 3.85. Found: C, 75.91;

H, 7.18; N, 3.76.

¹³C NMR (150 MHz, CDCl₃): δ = 16.53 (E) and 23.64 (Z, CH₃), 17.81 (E)

and 17.88 (Z, CH₃), 21.31 (CH₃), 21.85 (CH₃), 23.70 (Z) and 23.86 (E,

CH₂), 25.78 (E) and 25.90 (Z, CH₃), 26.73 (Z) and 26.78 (E, CH₂), 32.36

(Z) and 39.83 (E, CH₂), 56.70 (Z) and 56.78 (E, CH₃), 105.12 (Z) and

105.21 (E, CH), 111.72 (Z) and 111.81 (E, C), 117.48 (E) and 117.52 (Z,

C), 118.40 (CH), 118.57 (CH), 119.02 (E) and 119.05 (Z, CH), 121.67 (E)

and 122.48 (Z, CH), 124.36 (Z) and 124.38 (E, CH), 127.25 (Z) and

127.27 (E, C), 128.72 (2 CH), 129.28 (C), 129.87 (2 CH), 131.02 (C),

131.57 (C), 132.04 (Z) and 132.14 (E, C), 133.93 (C), 137.09 (E) and

137.59 (Z, C), 141.08 (C), 145.67 (C), 156.11 (Z) and 156.16 (E, C).

8-[(Z)-3,7-Dimethylocta-2,6-dien-1-yl]-7-hydroxy-3-methyl-1H-

carbazole-1,4(9H)-dione (56)

Mp 163.0–165.0 °C.

UV (MeOH): 231, 263, 412 nm.

Fluorescence (MeOH, exc. 263 nm): 363 nm.

IR (ATR): 3409, 3273, 3159, 2963, 2920, 2854, 2056, 2030, 2009, 1716,

1699, 1639, 1593, 1526, 1469, 1376, 1281, 1250, 1159, 1138, 1041,

952, 896, 875, 811, 719, 690 cm^–1

.

¹H NMR (600 MHz, CDCl₃): δ = 1.64 (s, 3 H), 1.69 (d, J = 1.1 Hz, 3 H),

1.80 (q, J = 1.4 Hz, 3 H), 2.14 (d, J = 1.9 Hz, 3 H), 2.16–2.23 (m, 2 H),

2.27–2.33 (m, 2 H), 3.58 (dd, J = 7.0, 0.9 Hz, 2 H), 5.17 (tsept, J = 7.2,

1.5 Hz, 1 H), 5.30–5.38 (m, 2 H), 6.45 (q, J = 1.5 Hz, 1 H), 6.88 (d, J = 8.7

Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 9.00 (br s, 1 H).

¹³C NMR (150 MHz, CDCl₃): δ = 16.26 (CH₃), 17.87 (CH₃), 23.52 (CH₃),

24.01 (CH₂), 25.87 (CH₃), 26.38 (CH₂), 32.33 (CH₂), 109.59 (C), 115.81

(CH), 117.70 (C), 119.03 (C), 121.30 (CH), 121.68 (CH), 123.65 (CH),

131.71 (CH), 132.86 (C), 134.80 (C), 138.02 (C), 140.09 (C), 148.31 (C),

153.21 (C), 179.89 (C=O), 183.96 (C=O).

ESI-MS (+10 V): m/z = 518.4 [M + H]⁺.

ESI-MS (–10 V): m/z = 516.1 [M – H]^–.

Murrayaquinone-D (8) and 8-[(Z)-3,7-Dimethylocta-2,6-dien-1-

yl]-7-hydroxy-3-methyl-1H-carbazole-1,4(9H)-dione (56)

LiAlH₄(2.4 M in THF, 1.44 mL, 3.46 mmol) was added to a solution of

carbazole 54 (ratio E/Z = 1.3:1) (174.5 mg, 0.347 mmol) in THF (22

mL) under an argon atmosphere at r.t. The solution was heated at re-

flux for 22 h and quenched with H₂O at 0 °C. A saturated aqueous

solution of sodium potassium tartrate was added and the mixture

was extracted with EtOAc. The organic layers were combined and the

solvent was evaporated.

ESI-MS (+25 V): m/z = 364.3 [M + H]⁺, 749.5 [2M + Na]⁺.

ESI-MS (–50 V): m/z = 362.1 [M – H]^–, 747.2 [2M + Na – 2 H]^–.

The residue was dissolved in acetone (19 mL), a solution of potassium

nitrosodisulfonate (Frémy’s salt) (804 mg, 3.00 mmol) in H₂O (19 mL)

was added at r.t. under air and the mixture was stirred vigorously for

3.5 h. An additional portion of Frémy’s salt (500 mg, 1.86 mmol) was

added and the mixture was stirred for another 18.5 h. The mixture

was extracted with EtOAc and the combined organic layers were

dried (MgSO₄). Evaporation of the solvent and subsequent multiple

column chromatography (silica gel, isohexane–EtOAc, 8:1) provided

murrayaquinone-D (8) (47.4 mg, 0.130 mmol, 37%) as the more polar

fraction and the corresponding Z-isomer 56 (23.9 mg, 65.8 μmol, 19%)

as the less polar fraction. Murrayaquinone-D (8) and the Z-isomer 56

were obtained as dark purple solids.

Murrayaquinone-C (7) and 8-[(Z)-3,7-Dimethylocta-2,6-dienyl]-7-

methoxy-3-methyl-1H-carbazole-1,4(9H)-dione (57)

Method A: Synthesis of 7 from Carbazole 55

Lithium aluminum hydride (2.4 M in THF, 0.60 mL, 1.4 mmol) was

added to a solution of carbazole 55 (ratio E/Z = 3:1) (83.9 mg, 0.162

mmol) in THF (10 mL) under an argon atmosphere at r.t. The solution

was refluxed for 18 h and subsequently quenched with H₂O at 0 °C,

then a saturated aqueous solution of sodium potassium tartrate was

added. After extraction with EtOAc, the organic layers were combined

and the solvent was evaporated. Filtration of the residue (silica gel,

isohexane–EtOAc, 15:1) afforded a crude material (58.8 mg, 0.162

mmol), which was partly (40.0 mg, 0.108 mmol) dissolved in acetone

(7 mL).

Murrayaquinone-D (8)

Mp 175.0–177.0 °C (Lit.¹³164–168 °C).

UV (MeOH): 231, 263, 412 nm.

A solution of potassium nitrosodisulfonate (Frémy’s salt) (207 mg,

0.772 mmol) in H₂O (7 mL) was added at r.t. under air. After stirring

vigorously for 64 h, the mixture was extracted with EtOAc and the

combined organic layers were dried (MgSO₄). Evaporation of the sol-

vent and subsequent column chromatography (silica gel, isohexane–

EtOAc, 10:1) provided the compounds 7 and 57 in a ratio of 3:1 (25.4

mg, 67.4 μmol, 62%) as a dark purple solid.

Fluorescence (MeOH, exc. 263 nm): 363 nm.

IR (ATR): 3261, 2962, 2919, 2030, 2010, 1980, 1716, 1658, 1604, 1529,

1469, 1419, 1377, 1311, 1287, 1246, 1140, 1014, 992, 951, 874, 816,

699, 669 cm^–1

.

Q

S. K. Kutz et al.

Paper

Synthesis

Method B: Synthesis of 7 from Murrayaquinone-D (8)

References

A solution of butyllithium (2.5 M in hexane, 11.6 μL, 29.0 μmol) was

added to a solution of murrayaquinone-D (8) (10.5 mg, 28.9 μmol) in

THF (2 mL) at –78 °C under an argon atmosphere. Subsequently,

methyl iodide (90 μL, 1.4 mmol) was added and the mixture was al-

lowed to warm to r.t. After 22 h, H₂O was added and the mixture was

extracted with EtOAc. The combined organic layers were dried

(MgSO₄). Evaporation of the solvent and subsequent column chroma-

tography (silica gel, isohexane–EtOAc, 4:1) provided murrayaqui-

none-C (7) (6.3 mg, 17 μmol, 59%) as a dark purple solid and reisolat-

ed murrayaquinone-D (8) (3.0 mg, 8.3 μmol, 29%).

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Mp 156.0–158.0 °C (Lit.¹³158–159 °C).

UV (MeOH): 202, 231, 263, 405, 516 (sh) nm.

Fluorescence (MeOH, exc. 231 nm): 367 nm.

IR (ATR): 3283, 2967, 2918, 2852, 2055, 2031, 2008, 1641, 1606, 1538,

1512, 1461, 1442, 1417, 1373, 1331, 1287, 1256, 1171, 1141, 1086,

1035, 995, 951, 876, 808, 790, 709, 629 cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 1.57 (s, 3 H), 1.62 (s, 3 H), 1.86 (s, 3 H),

2.02–2.13 (m, 4 H), 2.14 (d, J = 1.6 Hz, 3 H), 3.60 (d, J = 6.9 Hz, 2 H),

3.92 (s, 3 H), 4.98–5.13 (m, 1 H), 5.27 (dt, J = 1.3, 6.9 Hz, 1 H), 6.44 (q,

J = 1.6 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 8.94

(br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 16.29 (CH₃), 16.56 (CH₃), 17.83 (CH₃),

23.80 (CH₂), 25.78 (CH₃), 26.69 (CH₂), 39.75 (CH₂), 56.85 (CH₃), 110.91

(CH), 112.69 (C), 117.30 (C), 119.15 (C), 121.26 (CH), 121.54 (CH),

124.02 (CH), 131.63 (CH), 131.91 (C), 135.24 (C), 137.86 (C), 138.12

(C), 148.34 (C), 156.14 (C), 179.93 (C=O), 183.93 (C=O).

ESI-MS (+25 V): m/z = 378.3 [M + H]⁺.

ESI-MS (–25 V): m/z = 376.3 [M – H]^–.

8-[(Z)-3,7-Dimethylocta-2,6-dienyl]-7-methoxy-3-methyl-1H-car-

bazole-1,4(9H)-dione (57)

¹H NMR (500 MHz, CDCl₃): δ = 1.64 (s, 3 H), 1.68 (s, 3 H), 1.76 (d, J =

1.3 Hz, 3 H), 2.14 (d, J = 1.3 Hz, 3 H), 2.16–2.21 (m, 2 H), 2.26–2.32 (m,

2 H), 3.54–3.63 (m, 2 H), 3.91 (s, 3 H), 5.14–5.23 (m, 1 H), 5.23–5.31

(m, 1 H), 6.44 (d, J = 1.6 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 8.02 (d, J = 8.8

Hz, 1 H), 8.99 (br s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 16.27 (CH₃), 17.85 (CH₃), 23.50 (CH₃),

23.56 (CH₂), 25.84 (CH₃), 26.51 (CH₂), 32.30 (CH₂), 56.77 (CH₃), 110.83

(CH), 112.68 (C), 117.30 (C), 119.14 (C), 121.26 (CH), 122.26 (CH),

124.02 (CH), 131.64 (CH), 132.39 (C), 135.23 (C), 137.80 (C), 138.09

(C), 148.32 (C), 156.09 (C), 179.93 (C=O), 183.91 (C=O).

Acknowledgment

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We would like to thank Max Kaulfuß, Adrian Kishonti, Vicky Langer,

Alexander Purtsas, and Patrick Zimdars for experimental support.

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Supporting Information

Supporting information for this article is available online at

http://dx.doi.org/10.1055/s-0036-1588322.

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Article Doi

Palladium-Catalyzed Synthesis of Pyrayaquinones, Murrayaquinones, and Murrayafoline-B

DOI: 10.1055/s-0036-1588322

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