Palladium(II)-catalyzed synthesis of the formylcarbazole alkaloids murrayaline A-C, 7-methoxymukonal, and 7-methoxy-o-methylmukonal

Article abstract of DOI:10.1002/ejoc.201402201

We describe the synthesis of the naturally occurring 2,7-dioxygenated formylcarbazole alkaloids 7-methoxymukonal, 7-methoxy-O-methylmukonal, and the murrayalines A-C. The carbazole framework was constructed by a Buchwald-Hartwig amination and a subsequent palladium(II)-catalyzed oxidative cyclization. We describe the synthesis of the naturally occurring 2,7-dioxygenated formylcarbazole alkaloids 7-methoxymukonal, 7-methoxy-O-methylmukonal, and the murrayalines A-C. The carbazole framework was constructed by a Buchwald-Hartwig amination and a subsequent palladium(II)-catalyzed oxidative cyclization. Copyright

Full text of DOI:10.1002/ejoc.201402201

Job/Unit: O42201
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FULL PAPER
DOI: 10.1002/ejoc.201402201
Palladium(II)-Catalyzed Synthesis of the Formylcarbazole Alkaloids
Murrayaline A–C, 7-Methoxymukonal, and 7-Methoxy-O-methylmukonal[‡]
Ronny Hesse,[a] Micha P. Krahl,[a] Anne Jäger,[a] Olga Kataeva,[a] Arndt W. Schmidt,[a] and
Hans-Joachim Knölker*[a]
Keywords: Natural products / Alkaloids / Nitrogen heterocycles / C–H activation / Cyclization / Palladium
We describe the synthesis of the naturally occurring 2,7-di-
oxygenated formylcarbazole alkaloids 7-methoxymukonal,
7-methoxy-O-methylmukonal, and the murrayalines A–C.
The carbazole framework was constructed by a Buchwald–
Hartwig amination and a subsequent palladium(II)-catalyzed
oxidative cyclization.
onal (1) and 7-methoxy-O-methylmukonal (2). In 1996, Wu
and co-workers identified 1 as an inhibitor of rabbit platelet
aggregation.[8] Kongkathip and co-workers observed that 7-
methoxymukonal (1) displays weak antimycobacterial ac-
tivity against the H37Ra strain and weak antifungal activity
against Candida albicans.[9] Furthermore, cytotoxicity
against the MCF-7 cell line (breast cancer) and the KB cell
line (oral human epidermal carcinoma),[5,10] antimalarial
activity,[10a] weak antioxidant activity, and an inhibition of
lipid peroxidation have been described for 1.[11] In 2005,
Kongkathip and co-workers reported anti-HIV activity for
7-methoxy-O-methylmukonal (2).[12]
Introduction
Over the past decade, numerous carbazole alkaloids have
been obtained from various natural sources. Their bio-
logical activities as well as approaches towards their total
syntheses have been the focus of scientific research.[1] Natu-
rally occurring tricyclic carbazoles have been classified on
the basis of their oxygenation pattern.[1f,1p] Herein, we re-
port the total syntheses of the five 2,7-dioxygenated carba-
zolecarbaldehydes 7-methoxymukonal (1), 7-methoxy-O-
methylmukonal (2), and the murrayalines A–C (3–5) (see
Figure 1). 7-Methoxymukonal (1) was first isolated in 1988
by Pummangura and co-workers from the root bark of
Clausena harmandiana Pierre, which was collected in Thai-
land (see Figure 1).[2] These plants are used in folk medicine
for the treatment of stomach aches and fever. The structure
of 1 was assigned on the basis of its spectroscopic data. In
addition, 7-methoxymukonal (1) was isolated from the stem
bark of Clausena excavata Burm. F by Ito et al.,[3] from
Clausena vestita D. D. Tao by Zhao et al.,[4] and from
Clausena wallichii by Laphookhieo et al.[5] In 1990, Lange
et al. reported the first isolation of the corresponding
methyl ether, 7-methoxy-O-methylmukonal (2), from the
roots of Murraya siamensis, which was collected in Thai-
land.[6] Subsequently, compound 2 was also isolated from
Clausena excavata by Wu et al.,[7] from Clausena vestita
D. D. Tao by Zhao et al.,[4] and from the roots of Clausena
wallichii by Laphookhieo and co-workers.[5] A variety of
biological activities has been reported for 7-methoxymuk-
Figure 1. Naturally occurring 2,7-dioxygenated carbazolecarb-
aldehydes 1–5.
[‡] Transition Metals in Organic Synthesis, Part 115. Part 114: R.
Martin, C. Risacher, A. Barthel, A. Jäger, A. W. Schmidt, S.
Richter, M. Böhl, M. Preller, K. Chinthalapudi, D. J. Manstein,
H. O. Gutzeit, H.-J. Knölker, Eur. J. Org. Chem. 2014, DOI:
10.1002/ejoc.201402177.
Previously, we described the first total synthesis of 7-
methoxy-O-methylmukonal (2) by using an iron-mediated
route (three steps, 38% overall yield).[13] We also reported
the palladium-catalyzed synthesis of 7-hydroxy-O-meth-
ylmukonal (four steps, 51% overall yield), a regioisomer of
the natural product 7-methoxymukonal (1).[14] However, no
total synthesis of 1 has been reported so far.
[a] Department Chemie, Technische Universität Dresden,
Bergstrasse 66, 01069 Dresden, Germany
E-mail: hans-joachim.knoelker@tu-dresden.de
www.chm.tu-dresden.de/oc2/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402201.
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In 1986, the carbazole-8-carbaldehyde murrayaline A (3) a directed palladation that results from the coordination of
was first isolated by Furukawa et al. from the stem bark palladium(II) to the oxygen atom of the methoxy
of Murraya euchrestifolia Hayata, which was collected in group.[14,21] Oxidative cyclization in the absence of cupric
Taiwan.[15] Its structure was determined by spectroscopic acetate with smaller amounts of palladium acetate in the
data and confirmed by total synthesis (no experimental de- presence of potassium carbonate led exclusively to the de-
tails and yields were given).[15] In 1991, the murrayalines B sired regioisomer 13.
(4) and C (5) were both isolated by Furukawa et al. from
the acetone extract of the stem bark of Murraya euchresti-
folia Hayata, which was collected in Taiwan.[16] No synthe-
ses have yet been reported for the murrayalines B and C (4
and 5).
Results and Discussion
We devised an approach to the 2,7-dioxygenated carb-
azolecarbaldehydes 1–5 by using our palladium(II)-cata-
lyzed synthesis for carbazole alkaloids (see Scheme 1).[1i,17]
The key step of this approach is the oxidative cyclization of
diarylamine 6 through a double C–H bond activation by
using catalytic amounts of palladium(II) acetate. In 1994,
we demonstrated that this process, originally described by
Åkermark in 1975 using stoichiometric amounts of a palla-
dium(II) salt,[18] becomes catalytic with regard to the palla-
dium through the reoxidation of palladium(0), which is
formed during the reaction.[17a] The required diarylamine 6
is most conveniently prepared through a Buchwald–Hart-
wig coupling reaction between an appropriately substituted
aryl halide 7 and an arylamine 8.[19]
Scheme 2. Synthesis of the 2,7-dioxygenated carbazole 13. Reagents
and conditions: (a) BnBr (1.2 equiv.), K2CO3 (2.0 equiv.), acetone,
reflux, 17 h, 97%; (b) m-anisidine (1.3 equiv.), Pd(OAc)2 (5 mol-%),
2-dicyclohexylphosphino-2Ј,6Ј-dimethoxybiphenyl (SPhos, 10 mol-
%), Cs2CO3 (1.4 equiv.), toluene, 100 °C, 18 h, 97%; (c) m-bromo-
anisole (1.0 equiv.), 11 (1.3 equiv.), Pd(OAc)2 (5 mol-%), SPhos
(10 mol-%), Cs2CO3 (1.4 equiv.), toluene, 100 °C, 22 h, 94%;
(d) Pd(OAc)2 (8 mol-%), K2CO3 (10 mol-%), pivalic acid (PivOH),
100 °C, 24 h, air, 95% (for 13).
Table 1. Palladium(II)-catalyzed oxidative cyclization of the di-
arylamine 12.
Pd(OAc)2 Additive (equiv.) Conditions
[mol-%]
Yield [%]
13 14
15
11
Cu(OAc)2 (2.5) PivOH, 110 °C, MW,[a] 4 h, air 91
5
3
Cu(OAc)2 (0.1), PivOH, 100 °C, 29 h, air
K2CO3 (0.15)
72
8
K2CO3 (0.1)
PivOH, 100 °C, 24 h, air
95
–
Scheme 1. Palladium-catalyzed approach to carbazole alkaloids 1–5.
[a] MW = microwave.
For the synthesis of 7-methoxymukonal (1), we first pre-
pared diarylamine 12 by the Buchwald–Hartwig coupling
The carbazole 13 was converted into carbazole-3-carbal-
reaction of bromoarene 10 and meta-anisidine with a cata- dehyde 15 by treatment with 2,3-dichloro-5,6-di-
lytic amount of SPhos[19c] as ligand (see Scheme 2). Alter- cyano-1,4-benzoquinone (DDQ) in a mixture of methanol,
natively, under the same reaction conditions, compound 12 tetrahydrofuran (THF), and water (see Scheme 3).[22] The
was available in a similar high yield through the coupling removal of the benzyl group to gain access to 7-meth-
of the arylamine 11 and meta-bromoanisole. Compound 11 oxymukonal (1) proceeded with low yields under most con-
was prepared by the O-benzylation of 2-methyl-5-nitro- ditions and often was accompanied by benzylation at C-1
phenol and subsequent reduction reaction (two steps, 99% of the carbazole framework. Finally, cleavage of the benzyl
yield).[20] An oxidative cyclization of diarylamine 12 by ether was achieved by using overstoichiometric amounts of
heating in pivalic acid in the presence of a catalytic amount zinc bromide and 2,6-dimethoxytoluene as a benzyl scaven-
of palladium(II) acetate and a stoichiometric amount of cu- ger to provide 7-methoxymukonal (1) in 77% yield. Alter-
pric acetate provided the desired carbazole 13 along with natively, 1 was accessible in two steps from TIPS-protected
the undesired, sterically more hindered isomer 14 in a ratio carbazole 16 (TIPS = triisopropylsilyl), which served as an
of 18:1 and 96% combined yield (see Table 1). The forma- intermediate in our syntheses of the pyrayafolines A–E.[17e]
tion of the sterically more hindered 4-oxygenated carba- The oxidation of compound 16 by treatment with DDQ
zoles has been previously observed and can be explained by followed by desilylation afforded 7-methoxymukonal (1), al-
2
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Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
beit in only 26% yield over both steps. The spectroscopic in the presence of 2.5 equiv. of cupric acetate in air,[17a] pro-
data of synthetic 1 are in full agreement with those reported vided carbazole 19 in 62% yield. This yield could be im-
for the natural product.[2] The structure of 7-methoxymu- proved further by reducing the amount of cupric acetate to
konal (1) was also confirmed by single-crystal X-ray analy- 10 mol-%. Thus, using catalytic amounts of palladium(II)
sis (see Figure 2). Our palladium-catalyzed approach com- acetate and cupric acetate (10 mol-% each) under air pro-
pletes the first total synthesis of 7-methoxymukonal (1) and vided carbazole 19 in 67% yield. Replacing cupric acetate
provides the natural product in five steps and 60% overall by manganese(III) acetate dihydrate led to almost identical
yield based on the bromophenol 9.
results.[17c] The oxidative cyclization under oxygen, instead
of air, provided carbazole 19 in 55% yield when 10 mol-
% of palladium(II) acetate and cupric acetate were used.
However, under an oxygen atmosphere, the catalyst loading
could be further reduced to 5 mol-% of palladium(II) acet-
ate and cupric acetate without a significant decrease in the
yield. A further decrease of the amount of palladium(II)
acetate to 1 mol-% provided carbazole 19 in 45% yield
(equivalent to a turnover number of 45). The absence of any
co-oxidant resulted in a sharp decrease in the yield (23%).
Without a palladium(II) source, no cyclization, but partial
decomposition, was observed. Finally, the oxidation of di-
arylamine 19 by treatment with DDQ afforded 7-methoxy-
O-methylmukonal (2). In conclusion, our palladium(II)-cat-
alyzed approach provides 7-methoxy-O-methylmukonal (2)
in three steps and 42% overall yield and is superior to our
iron-mediated synthesis of 2 (three steps and 38% yield).[13]
Scheme 3. Synthesis of 7-methoxymukonal (1). Reagents and con-
ditions: (a) DDQ (2.5 equiv.), MeOH/THF/H2O (6:3:1), room
temp., 37 min, 87%; (b) ZnBr2 (15.0 equiv.), 2,6-dimethoxytoluene
(3.1 equiv.), 1,2-dichloroethane, 70 °C to reflux, 30 h, 77%;
(c) (1) DDQ (2.2 equiv.), MeOH/THF/H2O (10:5:1), room temp.,
1.5 h, 39%; (2) tetra-n-butylammonium fluoride (TBAF,
1.5 equiv.), N,N-dimethylformamide (DMF), –15 °C to room
temp., 13 min, 67%. For the synthesis of compound 16, see ref.[17e]
Scheme 4. Synthesis of 7-methoxy-O-methylmukonal (2). Reagents
and conditions: (a) m-bromoanisole (1.0 equiv.), 17 (1.25 equiv.),
Pd(OAc)2 (6 mol-%), rac-BINAP (5 mol-%), Cs2CO3 (1.2 equiv.),
toluene, reflux, 24 h, 85%; (b) Pd(OAc)2 (10 mol-%), Cu(OAc)2
(10 mol-%), AcOH, 90 °C, air, 5 h, 67%; (c) DDQ (4.2 equiv.),
MeOH/H2O (10:1), room temp., 80 min, 73%, see ref.[13b]
Figure 2. Molecular structure of 7-methoxymukonal (1) in the crys-
tal. ORTEP plot showing thermal ellipsoids at 50% probability
level.
Table 2. Palladium(II)-catalyzed oxidative cyclization of the di-
arylamine 18.
An improved approach was developed for the synthesis
of 7-methoxy-O-methylmukonal (2) by following a similar
route. A Buchwald–Hartwig coupling reaction of meta-
bromoanisole and commercially available 3-methoxy-4-
methylaniline (17) using (Ϯ)-2,2Ј-bis(diphenylphosphino)-
1,1Ј-binaphthalene (rac-BINAP) as ligand provided di-
arylamine 18 (see Scheme 4). The oxidative cyclization of
compound 18 by treatment with a stoichiometric amount
of palladium(II) acetate in acetic acid at 90 °C provided the
desired carbazole 19 in 55% yield (see Table 2). We then
investigated a number of reagents for the re-oxidation of
the palladium(0) species. Using 10 mol-% of palladium(II)
acetate and either 1,4-benzoquinone or tert-butyl hydroper-
oxide as a co-oxidant led only to decomposition. Em-
ploying our original conditions for the palladium(II)-cata-
Pd(OAc)2
[mol-%]
Co-oxidant (equiv.)
Conditions[a]
Yield [%]
19
120
10
10
10
10
10
10
5
–
argon, 2 h
air, 3 h
air, 3 h
air, 2 d
air, 5 h
55
decomp.
decomp.
62
67
65
55
54
45
benzoquinone (2.5)
tBuOOH (2.5)
Cu(OAc)2 (2.5)
Cu(OAc)2 (0.1)
Mn(OAc)3 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.05)
Cu(OAc)2 (0.05)
–
air, 6 h
oxygen, 6 h
oxygen, 8 h
oxygen, 20 h
oxygen, 12 h
oxygen, 24 h
1
10
–
23
[b]
Cu(OAc)2 (0.1)
–
[a] Acetic acid, 90 °C. [b] Isolation of 77% of starting material.
Our approach to the murrayalines A–C (3–5) relies on a
lyzed oxidative cyclization, 10 mol-% palladium(II) acetate late-stage reduction of a cyano group to introduce the for-
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myl group at C-8. This strategy has already been applied to in our syntheses of pyrayafolines A–E.[17e] The palla-
generate the formyl group at C-3 in our synthesis of 7-hy- dium(0)-catalyzed coupling of 24 with benzonitrile 21 pro-
droxy-O-methylmukonal.[14] Thus, we first prepared benzo- vided diarylamine 25 in 85% yield. The structure of com-
nitrile 21 from commercially available 2-chloro-6-hydroxy- pound 25 was confirmed by an X-ray crystal structure
benzonitrile (20) by O-methylation with methyl iodide (see analysis (see Figure 4). The palladium(II)-catalyzed oxidat-
Scheme 5). The Buchwald–Hartwig coupling of 21 with an- ive cyclization of 25 afforded carbazolecarbonitrile 26 in
iline 17 led to diarylamine 22. The palladium(II)-catalyzed 87% yield. The reduction of the cyano group by treatment
oxidative cyclization of 22 by heating at 120 °C in pivalic with DIBAL-H to give a formyl group followed by cleavage
acid in air and in the presence of a catalytic amount of of the silyl ether with tetra-n-butylammonium fluoride pro-
palladium(II) acetate and potassium carbonate provided vided murrayaline B (4). The spectroscopic data of our syn-
carbazolecarbonitrile 23 in 87% yield. In comparison to thetic 4 were identical to those reported for the natural
our standard conditions,[17] we had to increase the amount product.[16] The single-crystal X-ray structure determi-
of palladium(II) catalyst slightly to achieve an efficient oxi- nation of murrayaline B (4) unambiguously confirmed the
dative cyclization of diarylamine 22. The reduction of the compound assignment (see Figure 5). The present route
cyano group by treatment with diisobutylaluminium hy- constitutes the first total synthesis of murrayaline B (4) and
dride (DIBAL-H)[23] in dichloromethane at low tempera- provides the natural product in six steps and 66% overall
ture provided murrayaline A (3) in four steps and 54% over- yield.
all yield. All spectroscopic data of 3 matched with those
reported for the natural product.[15] The structure of 3 was
also confirmed by single-crystal X-ray analysis (see Fig-
ure 3).
Scheme 6. Synthesis of murrayaline B (4). Reagents and conditions:
(a) 21 (1.0 equiv.), 24 (1.2 equiv.), Pd(OAc)2 (5 mol-%), SPhos
(10 mol-%), Cs2CO3 (1.4 equiv.), toluene, reflux, 18 h, 85%;
(b) Pd(OAc)2 (22 mol-%), Cu(OAc)2 (21 mol-%), K2CO3 (26 mol-
%), PivOH, 100 °C, air, 18.5 h, 87%; (c) DIBAL-H (3.0 equiv.),
CH2Cl2, –40 to –30 °C, 4 h; (d) TBAF (1.5 equiv.), DMF, –15 °C
to room temp., 10 min, 89% (two steps).
Scheme 5. Synthesis of murrayaline A (3). Reagents and conditions:
(a) MeI (6.0 equiv.), K2CO3 (5.1 equiv.), DMF, reflux, 19 h, 87%;
(b) 17 (1.27 equiv.), Pd(OAc)2 (6 mol-%), SPhos (13 mol-%),
Cs2CO3 (1.8 equiv.), toluene, reflux, 19.5 h, 100%; (c) Pd(OAc)2
(23 mol-%), K2CO3 (25 mol-%), PivOH, 120 °C, 15.5 h, air, 87%;
(d) DIBAL-H (2.5 equiv.), CH2Cl2, –55 to –25 °C, 4 h, 72%.
Figure 3. Molecular structure of murrayaline A (3) in the crystal.
ORTEP plot showing thermal ellipsoids at 50% probability level.
Figure 4. Molecular structure of diarylamine 25 in the crystal.
ORTEP plot showing thermal ellipsoids at 50% probability level.
The O-silyl-protected m-aminophenol 24 served as the
starting material for the synthesis of murrayaline B (4) (see
For our first attempt towards the synthesis of murraya-
Scheme 6). Compound 24 was already used as a precursor line C (5), we envisaged an oxidation of the C-3 methyl
4
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Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
carbazolecarbaldehyde 33 in 55% yield over four steps. The
structure of 33 was confirmed by single-crystal X-ray analy-
sis (see Figure 6). The formylation of compound 33 was ex-
pected to occur preferentially at the 6-position of the more
electron-rich benzene ring. However, several attempts to
achieve the formylation of 33 resulted in decomposition.
Figure 5. Molecular structure of murrayaline B (4) in the crystal.
ORTEP plot showing thermal ellipsoids at 50% probability level.
group of the benzyl-protected carbazole 28 to give a formyl
group (see Scheme 7). Benzyl protection was preferred to
silyl protection (as used for carbazole 26 in the synthesis
of 4), as we previously learned from our synthesis of 7-
methoxymukonal (1) that DDQ oxidation of a methyl
group ortho to a bulky silyl ether is difficult (cf. Scheme 3,
oxidation of 16 to 1). A Buchwald–Hartwig coupling of
compound 21 and aniline 11 followed by the palladium(II)-
catalyzed oxidative cyclization of diarylamine 27 afforded
carbazole 28 in 94% yield over both steps. Reduction of
the cyano into a formyl group by using DIBAL-H at low
temperature afforded benzyl-protected carbazolecarbal-
dehyde 29. Unfortunately, all efforts to convert 29 into di-
aldehyde 5 failed and led only to decomposition.
Scheme 8. Second approach to murrayaline C (5). Reagents and
conditions: (a) 21 (1.25 equiv.), Pd(OAc)2 (5 mol-%), SPhos
(10 mol-%), Cs2CO3 (1.4 equiv.), toluene, reflux, 23 h, 100%;
(b) Pd(OAc)2 (9 mol-%), Cs2CO3 (10 mol-%), PivOH, 110 °C, air,
50 h, 76%; (c) DIBAL-H (3.0 equiv.), CH2Cl2, –78 to –30 °C, 4 h;
(d) TBAF (1.5 equiv.), DMF, –8 °C to room temp., 10 min, 73%
(two steps).
Figure 6. Molecular structure of 7-hydroxy-2-methoxycarbazole-1-
carbaldehyde (33) in the crystal. ORTEP plot showing thermal el-
lipsoids at 50% probability level.
Finally, we decided to generate the C-3 formyl group of
murrayaline C (5) by reduction of an ester group. Thus,
carbazole 36 was prepared from commercially available
methyl 4-aminosalicylate (34) (see Scheme 9). Protection of
the hydroxy group and Buchwald–Hartwig amination led to
the diarylamine 35. The palladium(II)-catalyzed oxidative
cyclization of 35 under microwave conditions (110 °C) pro-
vided carbazole 36 in 77% yield. Although both aryl rings
of diarylamine 35 contained an electron-withdrawing
Scheme 7. First approach to murrayaline C (5). Reagents and con-
ditions: (a) 21 (1.0 equiv.), 11 (1.25 equiv.), Pd(OAc)2 (5 mol-%),
SPhos (10 mol-%), Cs2CO3 (1.4 equiv.), toluene, reflux, 20.5 h,
96%; (b) Pd(OAc)2 (20 mol-%), K2CO3 (19 mol-%), PivOH,
110 °C, air, 2 d, 98%; (c) DIBAL-H (3.5 equiv.), CH2Cl2, –40 to
–30 °C, 4 h, 56%.
In our second approach to murrayaline C (5), we pro- group, with the appropriate reaction conditions, the oxidat-
posed a Vilsmeier–Haack formylation of hydroxycarbazole ive cyclization was achieved in high yield by using only
33 (see Scheme 8). Compound 33 was prepared by a Buch- 7 mol-% of the palladium(II) catalyst. The DIBAL-H re-
wald–Hartwig coupling of aniline 30 with compound 21 to duction of 36 led to a 3-hydroxymethylcarbazole-8-carb-
give diarylamine 31, which by palladium(II)-catalyzed cycli- aldehyde, which was directly oxidized by using mangan-
zation gave carbazole 32. Subsequent DIBAL-H reduction ese(IV) oxide to afford the carbazole-3,8-dicarbaldehyde 37.
of the cyano group and cleavage of the silyl ether afforded Cleavage of the silyl ether by treatment with TBAF pro-
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H.-J. Knölker et al.
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vided synthetic murrayaline C (5) in six steps and 20% over-
all yield based on methyl 4-aminosalicylate (34). The spec-
troscopic data of our synthetic murrayaline C (5) were in
full agreement with those reported for the natural prod-
uct.[16]
Experimental Section
General Methods: All reactions were carried out in oven-dried
glassware under argon and with dry solvents unless stated other-
wise. Tetrahydrofuran was dried using a solvent purification system
(MBraun-SPS). Other chemicals were used as received from their
commercial sources. Flash chromatography was performed on a
Büchi Sepacore system that was equipped with an UV monitor,
and silica gel from Acros Organics (0.035–0.070 mm) was used.
Thin layer chromatography was performed with TLC plates from
Merck (60 F254), and UV light was used for the visualizations.
Melting points were measured with a Gallenkamp MPD 350 melt-
ing point apparatus. Ultraviolet spectra were recorded with a Per-
kin–Elmer 25 UV/Vis spectrometer. Infrared spectra were recorded
with a Thermo Nicolet Avatar 360 FTIR spectrometer using the
ATR method (attenuated total reflectance). The NMR spectro-
scopic data were recorded with Bruker Avance III 600 and DRX
500 spectrometers. Chemical shifts (δ) are reported in parts per
million with the nondeuterated residual solvent as the internal stan-
dard. The abbreviations that are used to report the data are s (sing-
let), d (doublet), t (triplet), sept (septet), m (multiplet), and br.
(broad). Mass spectrometry data were recorded with a Finnigan
MAT-95 spectrometer (electron impact, 70 eV) or through GC–MS
coupling with an Agilent Technologies 6890 N GC System
equipped with a 5973 mass selective detector (electron impact,
70 eV). Elemental analyses were determined with a EuroVector
EuroEA3000 elemental analyzer. X-ray crystal structure analyses
were performed with a Bruker-Nonius Kappa CCD that was
equipped with a 700 series Cryostream low temperature device
from Oxford Cryosystems. SHELXS-97,[24] SADABS version
2.10,[25] SHELXL-97,[26] POV-Ray for Windows version
3.6.2.msvc9.win64, and ORTEP-3 for Windows[27] were used for
processing and visualization.
Scheme 9. Synthesis of murrayaline C (5). Reagents and conditions:
(a) imidazole (ImH, 4.0 equiv.), TIPSCl (3.0 equiv.), DMF, 50 °C,
4 d, 65%; (b) 21 (1.2 equiv.), Pd(OAc)2 (5 mol-%), SPhos (10 mol-
%), Cs2CO3 (1.4 equiv.), toluene, reflux, 18 h, 85%; (c) Pd(OAc)2
(7 mol-%), K2CO3 (10 mol-%), Cu(OAc)2 (2.5 equiv.), PivOH, mi-
crowave, 110 °C, air, 5 h, 77%; (d) DIBAL-H (4.5 equiv.), CH2Cl2,
–78 to –35 °C, 4 h; (e) MnO2 (20 equiv.), CH2Cl2, room temp., 6 d;
(f) TBAF (1.5 equiv.), DMF, –10 °C to room temp., 10 min, 48%
(three steps).
2-Benzyloxy-4-bromotoluene (10): Benzyl bromide (2.28 mL, 3.28 g,
19.2 mmol) was added dropwise to a solution of 5-bromo-2-meth-
ylphenol (9, 2.99 g, 16.0 mmol) and potassium carbonate (4.43 g,
32.1 mmol) in acetone (40 mL), and the mixture was stirred and
heated at reflux for 17 h. The mixture was diluted with ethyl acet-
ate, and the resulting solution was washed with water and brine
several times. The aqueous layers were extracted with ethyl acetate.
The combined organic layers were dried with sodium sulfate, and
the solvent was evaporated. Purification of the residue by
chromatography on a silica gel column (petroleum ether/diethyl
ether, gradient from 1:0 to 5:1) provided 2-benzyloxy-4-bromotolu-
ene (10, 4.30 g, 97% yield) as a colorless oil. UV (MeOH): λ = 277,
Conclusions
283 nm. IR (ATR): ν = 3088, 3064, 3031, 2922, 2853, 1592, 1486,
˜
1457, 1419, 1397, 1378, 1304, 1238, 1189, 1125, 1083, 1015, 913,
877, 834, 799, 733, 694, 630 cm–1. 1H NMR (500 MHz, [D6]acet-
one): δ = 2.19 (s, 3 H), 5.17 (s, 2 H), 7.03 (dd, J = 7.9, 1.7 Hz, 1
H), 7.11 (d, J = 7.9 Hz, 1 H), 7.17 (d, J = 1.7 Hz, 1 H), 7.34 (t, J
= 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.51 (d, J = 7.5 Hz, 2
H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ = 16.09
(CH3), 70.71 (CH2), 115.70 (CH), 120.06 (C), 124.11 (CH), 126.82
(C), 128.22 (2 CH), 128.71 (CH), 129.34 (2 CH), 132.66 (CH),
138.06 (C), 158.55 (C) ppm. MS (EI, 70 eV): m/z (%) = 278 (46),
276 (44) [M]+, 197 (22), 181 (21), 91 (100). HRMS: calcd. for
C14H13BrO [M]+ 276.0150; found 276.0126.
We have developed the palladium(II)-catalyzed total syn-
theses of five naturally occurring 2,7-dioxygenated carb-
azolecarbaldehydes. 7-Methoxymukonal (1) and 7-meth-
oxy-O-methylmukonal (2) were obtained in five steps and
60% overall yield and three steps and 42% overall yield,
respectively. It has been shown that acceptor-substituted
carbazoles can be efficiently prepared through palladi-
um(II)-catalyzed oxidative cyclizations of diarylamines that
contain electron-withdrawing groups. Carbazolecarb-
aldehydes 3–5 were obtained from cyano-substituted di-
arylamines through short synthetic routes, which thus pro-
vided murrayaline A (3) in four steps and 54% overall yield,
murrayaline B (4) in six steps and 66% overall yield, and
murrayaline C (5) in six steps and 20% overall yield. 7-
Methoxymukonal (1), murrayaline B (4), and murrayaline C
(5) were obtained by total synthesis for the first time.
3-Benzyloxy-N-(3-methoxyphenyl)-4-methylaniline (12):
Method A: To a suspension of m-anisidine (174 mg, 1.41 mmol),
palladium acetate (12.1 mg, 53.9 μmol), SPhos (44.8 mg,
0.109 mmol), and cesium carbonate (493 mg, 1.51 mmol) in toluene
(10 mL) was added dropwise over a period of 2 h a solution of 2-
benzyloxy-4-bromotoluene (10, 300 mg, 1.08 mmol) in toluene
6
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Job/Unit: O42201
/KAP1
Date: 15-05-14 17:13:26
Pages: 16
Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
(10 mL) at 100 °C, and the mixture was stirred at 100 °C for 16 h
(total reaction time: 18 h). After cooling to room temperature, the
solvent was evaporated. Purification of the residue by chromatog-
raphy on a silica gel column (pentane/ethyl acetate, gradient from
1:0 to 7:1) provided 3-benzyloxy-N-(3-methoxyphenyl)-4-methylan-
iline (12, 337 mg, 97% yield) as a colorless solid; m.p. 82 °C. UV
(C), 119.13 (C), 120.51 (CH), 121.35 (CH), 128.10 (2 CH), 128.45
(CH), 129.28 (2 CH), 138.90 (C), 140.55 (C), 142.11 (C), 156.22
(C), 158.97 (C) ppm. MS (EI, 70 eV): m/z (%) = 317 (23) [M]+, 226
(100), 91 (11). HRMS: calcd. for C21H19NO2 [M]+ 317.1416; found
317.1427. C21H19NO2 (317.39): calcd. C 79.47, H 6.03, N 4.41;
found C 78.92, H 6.14, N 4.36.
(MeOH): λ = 283 nm. IR (ATR): ν = 3413, 3392, 3055, 3025, 2999,
˜
2-Benzyloxy-5-methoxy-3-methylcarbazole (14): A 10 mL micro-
wave tube was charged with diarylamine 12 (300 mg, 0.939 mmol),
palladium acetate (32.2 mg, 0.143 mmol), cupric acetate (427 mg,
2.35 mmol), and pivalic acid (1.5 g) under air. The tube was irradi-
ated in a microwave reactor at 110 °C and 300 W for 4 h. After
cooling to room temperature, the mixture was diluted with ethyl
acetate, and the resulting solution was washed with a saturated
solution of potassium carbonate and brine several times. The aque-
ous layers were extracted with ethyl acetate. The combined organic
layers were dried with sodium sulfate, and the solvent was evapo-
rated. Purification of the residue by chromatography on a silica gel
column (pentane/ethyl acetate, gradient from 10:1 to 2:5) provided
2-benzyloxy-7-methoxy-3-methylcarbazole (13, 271 mg, 91% yield,
for spectroscopic data see above) and the less polar 2-benzyloxy-5-
methoxy-3-methylcarbazole (14, 15.9 mg, 5% yield) as a brown so-
lid; m.p. 191–192 °C. UV (MeOH): λ = 240, 284 (sh), 294, 317,
330 nm. Fluorescence (MeOH): λex = 240 nm, λem = 340, 352 nm.
2922, 2850, 2826, 1591, 1510, 1490, 1473, 1456, 1395, 1366, 1336,
1262, 1203, 1169, 1154, 1127, 1079, 1037, 995, 975, 932, 860, 839,
1
826, 808, 745, 686, 630, 613 cm–1. H NMR (500 MHz, CDCl3): δ
= 2.34 (s, 3 H), 3.82 (s, 3 H), 5.08 (s, 2 H), 5.58 (br. s, 1 H), 6.54
(dd, J = 8.1, 2.0 Hz, 1 H), 6.63 (br. d, J = 8.1 Hz, 1 H), 6.65 (t, J
= 2.0 Hz, 1 H), 6.70 (dd, J = 7.9, 2.0 Hz, 1 H), 6.76 (d, J = 2.0 Hz,
1 H), 7.13 (d, J = 7.9 Hz, 1 H), 7.21 (t, J = 8.1 Hz, 1 H), 7.40 (t,
J = 7.2 Hz, 1 H), 7.44–7.51 (m, 4 H) ppm. 13C NMR and DEPT
(125 MHz, CDCl3): δ = 15.89 (CH3), 55.18 (CH3), 69.75 (CH2),
102.66 (CH), 103.55 (CH), 105.69 (CH), 109.48 (CH), 111.30 (CH),
120.35 (C), 127.14 (2 CH), 127.80 (CH), 128.58 (2 CH), 130.16
(CH), 131.12 (CH), 137.38 (C), 141.50 (C), 145.29 (C), 157.42 (C),
160.75 (C). GC–MS (70 eV): m/z (%) = 319 (57) [M]+, 228 (10),
200 (8), 91 (100). C21H21NO2 (319.40): calcd. C 78.97, H 6.63, N
4.39; found C 78.89, H 6.82, N 4.24.
Method B: To a mixture of 3-benzyloxy-4-methylaniline (11, 3.43 g,
16.1 mmol), palladium acetate (139 mg, 0.619 mmol), SPhos
(508 mg, 1.24 mmol), and cesium carbonate (5.71 g, 17.5 mmol) in
toluene (70 mL) was added dropwise over a period of 18 h a solu-
tion of m-bromoanisole (2.31 g, 12.4 mmol) in toluene (10 mL) at
100 °C, and the mixture was stirred at 100 °C for 4 h (total reaction
time: 22 h). The mixture was diluted with ethyl acetate, and the
resulting solution was washed with water and brine several times.
The aqueous layers were extracted with ethyl acetate. The com-
bined organic layers were dried with sodium sulfate, and the solvent
was evaporated. Purification of the residue by chromatography on
a silica gel column (pentane/ethyl acetate, gradient from 50:1 to
15:1) provided 3-benzyloxy-N-(3-methoxyphenyl)-4-methylaniline
(12, 3.71 g, 94% yield) as a colorless solid.
IR (ATR): ν = 3377, 3058, 3035, 2942, 2908, 2863, 2833, 2030,
˜
2007, 1970, 1947, 1631, 1604, 1580, 1504, 1475, 1457, 1434, 1401,
1342, 1313, 1272, 1216, 1163, 1143, 1097, 1020, 969, 894, 815, 781,
740, 725, 697, 615 cm–1. 1H NMR (500 MHz, [D6]acetone): δ =
2.38 (s, 3 H), 4.04 (s, 3 H), 5.20 (s, 2 H), 6.66 (d, J = 8.0 Hz, 1 H),
7.03 (d, J = 8.0 Hz, 1 H), 7.10 (s, 1 H), 7.20 (t, J = 8.0 Hz, 1 H),
7.33 (t, J = 7.3 Hz, 1 H), 7.41 (m, 2 H), 7.55 (m, 2 H), 8.00 (s, 1
H), 10.12 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
acetone): δ = 17.11 (CH3), 55.57 (CH3), 70.53 (CH2), 94.62 (CH),
100.58 (CH), 104.54 (CH), 113.15 (C), 116.60 (C), 119.10 (C),
124.71 (CH), 125.76 (CH), 128.12 (2 CH), 128.45 (CH), 129.28
(2 CH), 138.85 (C), 139.79 (C), 142.19 (C), 156.33 (C), 156.44
(C) ppm. MS (ESI, +25 V): m/z = 318.2 [M + H]+, 340.3
[M + Na]+, 635.5 [2M + H]+. MS (ESI, –25 V): m/z = 224.8 [M –
C7H7]–. MS (EI, 70 eV): m/z (%) = 317 (55) [M]+, 226 (100), 91
(10). HRMS: calcd. for C21H19NO2 [M]+ 317.1416; found
317.1428.
2-Benzyloxy-7-methoxy-3-methylcarbazole (13): To a mixture of di-
arylamine 12 (1.01 g, 3.16 mmol), potassium carbonate (44.3 mg,
0.321 mmol), and pivalic acid (3.1 g) in a 25 mL test tube under air
was added palladium acetate (36.2 mg, 0.161 mmol) at 100 °C. The
mixture was heated and vigorously stirred at 100 °C for 15 h, and
then an additional portion of palladium acetate (21.8 mg,
97.1 μmol) was added. The stirring was continued at 100 °C for
9 h (total reaction time: 24 h). The mixture was cooled to room
temperature, diluted with ethyl acetate, and the resulting solution
was washed with a saturated solution of potassium carbonate and
brine several times. The aqueous layers were extracted with ethyl
acetate. The combined organic layers were dried with sodium sulf-
ate, and the solvent was evaporated. Purification of the residue by
chromatography on a silica gel column (pentane/ethyl acetate, gra-
dient from 12:1 to 1:2) provided 2-benzyloxy-7-methoxy-3-methyl-
carbazole (13, 957 mg, 95% yield) as a brown solid; m.p. 252–
253 °C. UV (MeOH): λ = 236, 261, 312, 320 nm. Fluorescence
2-Benzyloxy-7-methoxycarbazole-3-carbaldehyde
(15):
DDQ
(484 mg, 2.13 mmol) was added to a solution of 2-benzyloxy-7-
methoxy-3-methylcarbazole (13, 271 mg, 0.854 mmol) in a mixture
of methanol (150 mL), THF (75 mL), and water (25 mL), and the
resulting mixture was vigorously stirred at room temperature for
37 min. Diethyl ether was added, and the mixture was washed with
aqueous potassium hydroxide (2 m) and brine several times. The
aqueous layers were extracted with diethyl ether. The combined
organic layers were dried with sodium sulfate, and the solvent was
evaporated. Purification of the residue by chromatography on a
silica gel column (pentane/ethyl acetate, gradient from 6:1 to 2:3)
provided 2-benzyloxy-7-methoxycarbazole-3-carbaldehyde (15,
247 mg, 87% yield) as yellow crystals; m.p. 196–199 °C. UV
(MeOH): λex = 261 nm, λem = 354 nm. IR (ATR): ν = 3402, 3064, (MeOH): λ = 240, 299, 346 nm. Fluorescence (MeOH): λex
=
˜
3028, 2992, 2942, 2836, 1619, 1500, 1469, 1450, 1389, 1339, 1308,
1264, 1233, 1216, 1197, 1179, 1160, 1138, 1018, 945, 911, 880, 853,
822, 803, 752, 736, 696, 632 cm–1. 1H NMR (500 MHz, [D6]acet-
one): δ = 2.37 (s, 3 H), 3.83 (s, 3 H), 5.19 (s, 2 H), 6.75 (dd, J =
299 nm, λem = 357, 519 nm. IR (ATR): ν = 3322, 2921, 2873, 2843,
˜
1659, 1633, 1601, 1577, 1541, 1506, 1456, 1409, 1388, 1346, 1311,
1270, 1246, 1225, 1211, 1149, 1032, 1019, 976, 936, 903, 864, 843,
1
820, 792, 730, 694, 626 cm–1. H NMR (500 MHz, [D6]acetone): δ
8.5, 2.3 Hz, 1 H), 6.96 (d, J = 2.3 Hz, 1 H), 7.08 (s, 1 H), 7.33 (t, = 3.86 (s, 3 H), 5.34 (s, 2 H), 6.85 (dd, J = 8.6, 2.3 Hz, 1 H), 7.03
J = 7.4 Hz, 1 H), 7.41 (m, 2 H), 7.54 (m, 2 H), 7.74 (s, 1 H), 7.83
(d, J = 8.5 Hz, 1 H), 9.98 (br. s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, [D6]acetone): δ = 17.05 (CH3), 55.68 (CH3), 70.60
(d, J = 2.3 Hz, 1 H), 7.22 (s, 1 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.43
(m, 2 H), 7.58 (m, 2 H), 8.01 (d, J = 8.6 Hz, 1 H), 8.41 (s, 1 H),
10.53 (br. s, 1 H), 10.54 (s, 1 H) ppm. 13C NMR and DEPT
(CH2), 95.16 (CH), 95.52 (CH), 108.27 (CH), 117.41 (C), 117.98 (125 MHz, [D6]acetone): δ = 55.79 (CH3), 71.34 (CH2), 95.33 (CH),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42201
/KAP1
Date: 15-05-14 17:13:26
Pages: 16
H.-J. Knölker et al.
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
FULL PAPER
96.13 (CH), 109.55 (CH), 117.87 (C), 118.55 (C), 119.79 (C), 120.24
(CH), 121.58 (CH), 128.41 (2 CH), 128.83 (CH), 129.43 (2 CH), request/cif.
137.92 (C), 142.95 (C), 146.44 (C), 160.09 (C), 160.71 (C), 188.65
Method B: DDQ (65.0 mg, 0.286 mmol) was added to a solution
(CHO) ppm. MS (ESI, +75 V): m/z = 332.2 [M + H]+, 347.3 [M +
NH4]+, 354.1 [M + Na]+, 685.2 [2M + Na]+. MS (ESI, –10 V): m/z
= 329.9 [M – H]–, 660.8 [2M – H]–. MS (EI, 70 eV): m/z (%) = 331
(51) [M]+, 240 (100), 91 (28). HRMS: calcd. for C21H17NO3 [M]+
331.1208; found 331.1222. C21H17NO3 (331.37): calcd. C 76.12, H
5.17, N 4.23; found C 75.81, H 5.45, N 4.27.
of 7-methoxy-3-methyl-2-triisopropylsilyloxycarbazole (16, 50.6 mg,
0.132 mmol) in a mixture of methanol (10 mL), THF (5 mL), and
water (1 mL), and the mixture was vigorously stirred at room tem-
perature for 90 min. Ethyl acetate was added, and the mixture was
washed with aqueous potassium hydroxide (2 m) and brine several
times. The aqueous layers were extracted with ethyl acetate. The
combined organic layers were dried with sodium sulfate, and the
solvent was evaporated. Purification of the residue by chromatog-
raphy on a silica gel column (pentane/ethyl acetate, 10:1) provided
7-methoxy-2-triisopropylsilyloxycarbazole-3-carbaldehyde (20.7 mg,
Crystal
Data
for
15:
C21H17NO3,
crystal
size:
0.35ϫ0.12ϫ0.08 mm3, M = 313.36 gmol–1, triclinic, space group:
¯
P1, a = 8.1299(5) Å, b = 8.3239(5) Å, c = 12.4639(7) Å, α =
103.061(3)°, β = 98.540(3)°, γ = 97.992(3)°, V = 799.39(8) Å3, Z =
2, ρcalcd. = 1.377 gcm–3, μ = 0.092 mm–1, T = 150(2) K, λ =
0.71073 Å, θ range: 1.71–28.00°, 38008 reflections collected, 3830
independent reflections (Rint = 0.0640), 231 parameters. The struc-
ture was solved by direct methods and refined by full-matrix least-
1
39% yield) as a yellow solid. H NMR (500 MHz, [D6]acetone): δ
= 1.18 (d, J = 7.6 Hz, 18 H), 1.45 (sept, J = 7.6 Hz, 3 H), 3.86 (s,
3 H), 6.85 (dd, J = 8.5, 2.3 Hz, 1 H), 7.03 (d, J = 2.3 Hz, 1 H),
7.04 (s, 1 H), 8.00 (d, J = 8.5 Hz, 1 H), 8.38 (s, 1 H), 10.40 (br. s,
1 H), 10.56 (s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
acetone): δ = 13.75 (3 CH), 18.37 (6 CH3), 55.81 (CH3), 96.21
(CH), 101.02 (CH), 109.47 (CH), 117.85 (C), 119.35 (C), 120.13
(CH), 121.31 (C), 121.65 (CH), 143.25 (C), 146.45 (C), 158.13 (C),
160.21 (C), 189.01 (CHO) ppm. To a solution of 7-methoxy-2-(tri-
isopropylsilyloxy)carbazole-3-carbaldehyde (71.8 mg, 0.181 mmol)
in DMF (8 mL) was added TBAF (1 m in THF, 0.27 mL,
0.27 mmol) at –15 °C. The cooling bath was removed, and the mix-
ture was stirred for 13 min and then diluted with ethyl acetate. The
resulting mixture was washed with water, a saturated aqueous solu-
tion of ammonium chloride, and brine. The aqueous layers were
extracted with ethyl acetate. The combined organic layers were
dried with sodium sulfate, and the solvent was evaporated. Purifica-
tion of the residue by chromatography on a silica gel column (pent-
ane/ethyl acetate, gradient from 4:1 to 5:2) provided 7-methoxy-
mukonal (1, 29.0 mg, 67% yield) as a yellow solid. For spectro-
scopic data of 1, see above.
squares on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0382, wR2
=
0.0926, maximal residual electron density: 0.247 eÅ–3. CCDC-
988852) contains the supplementary crystallographic data for 15.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
7-Methoxymukonal (1):
Method A: A mixture of 2-benzyloxy-7-methoxycarbazole-3-carb-
aldehyde (15, 50.2 mg, 0.151 mmol), zinc bromide (512 mg,
2.27 mmol), and 2,6-dimethoxytoluene (70.2 mg, 0.461 mmol) in
1,2-dichloroethane (10 mL) was heated at 70 °C for 2 h and then
at reflux for 28 h. After cooling to room temperature, the mixture
was diluted with ethyl acetate, and the solution was washed with
water and brine several times. The aqueous layers were extracted
with ethyl acetate. The combined organic layers were dried with
sodium sulfate, and the solvent was evaporated. Purification of the
residue by chromatography on a silica gel column (pentane/ethyl
acetate, gradient from 4:1 to 5:2) provided 7-methoxymukonal (1,
28.2 mg, 77% yield) as yellow crystals, m.p. 222 °C; ref.[2] m.p. 226–
227 °C. UV (MeOH): λ = 223, 237, 300, 338 nm. Fluorescence
3-Methoxy-N-(3-methoxyphenyl)-4-methylaniline (18): A solution
of m-bromoanisole (1.51 g, 8.07 mmol) in toluene (20 mL) was
added over a period of 10 h to a refluxing mixture of 3-methoxy-
4-methylaniline (17, 1.39 g, 10.1 mmol), cesium carbonate (3.18 g,
9.76 mmol), palladium acetate (110 mg, 0.490 mmol), and rac-
BINAP (251 mg, 0.403 mmol) in toluene, and the mixture was
heated at reflux for 14 h (total reaction time: 24 h). The suspension
was cooled to room temperature and then filtered through Celite®
(diethyl ether), and the solvent was evaporated. Purification of the
residue by chromatography on a silica gel column (petroleum ether/
acetone, 25:1) provided diarylamine 18 (1.67 g, 85% yield) as a red
(MeOH): λex = 299 nm, λem = 361 nm. IR (ATR): ν = 3254, 3015,
˜
2920, 2850, 1699, 1609, 1540, 1508, 1452, 1394, 1311, 1243, 1218,
1180, 1152, 1102, 1025, 944, 895, 842, 813, 762, 725, 701, 645 cm–1.
1H NMR (500 MHz, [D6]DMSO): δ = 3.83 (s, 3 H), 6.79 (dd, J =
8.5, 2.3 Hz, 1 H), 6.85 (s, 1 H), 6.94 (d, J = 2.3 Hz, 1 H), 7.93 (d,
J = 8.5 Hz, 1 H), 8.32 (s, 1 H), 10.12 (s, 1 H), 10.91 (br. s, 1 H),
11.42 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
DMSO): δ = 55.35 (CH3), 95.37 (CH), 96.33 (CH), 108.34 (CH),
115.68 (C), 116.40 (C), 117.07 (C), 120.67 (CH), 123.09 (CH),
142.07 (C), 145.95 (C), 158.49 (C), 159.32 (C), 192.51 (CHO) ppm.
GC–MS (70 eV): m/z (%) = 241 (100) [M]+, 226 (63), 198 (30), 140
(9). MS (EI, 70 eV): m/z (%) = 241 (100) [M]+, 226 (45), 198 (16).
HRMS: calcd. for C14H11NO3 [M]+ 241.0739; found 241.0732.
oil. UV (MeOH): λ = 283, 303 (sh) nm. IR (ATR): ν = 3386, 2998,
˜
2936, 2835, 1593, 1508, 1491, 1461, 1391, 1318, 1268, 1209, 1151,
1
1126, 1035, 995, 966, 829, 806, 759, 741, 687, 855 cm–1. H NMR
(500 MHz, [D6]acetone): δ = 2.10 (s, 3 H), 3.74 (s, 3 H), 3.77 (s, 3
H), 6.39 (m, 1 H), 6.64–6.68 (m, 3 H), 6.72 (d, J = 1.7 Hz, 1 H),
6.99 (d, J = 7.9 Hz, 1 H), 7.11 (t, J = 8.4 Hz, 1 H), 7.27 (br. s, 1
H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ = 15.70
(CH3), 55.27 (CH3), 55.47 (CH3), 102.24 (CH), 102.84 (CH), 105.90
(CH), 109.90 (CH), 110.72 (CH), 119.07 (C), 130.69 (CH), 131.48
(CH), 143.38 (C), 146.63 (C), 159.20 (C), 161.73 (C) ppm. MS (EI,
70 eV): m/z (%) = 243 (100) [M]+, 184 (45), 154 (16). HRMS: calcd.
for C15H17NO2 [M]+ 243.1259; found 243.1254. C15H17NO2
(243.30): calcd. C 74.05, H 7.04, N 5.76; found C 74.21, H 7.14, N
5.77.
Crystal Data for 1: C14H11NO3, M = 241.24 gmol–1, crystal size:
0.35ϫ0.03ϫ0.03 mm3, orthorhombic, space group: Pna21, a =
12.424(1) Å, b = 17.649(2) Å, c = 5.084(1) Å, V = 1114.8(3) Å3, Z
= 4, ρcalcd. = 1.437 gcm–3, μ = 0.102 mm–1, T = 150(2) K, λ =
0.71073 Å, θ range: 2.00–29.29°, 8197 reflections collected, 3010
independent reflections (Rint = 0.0771), 172 parameters. The struc-
ture was solved by direct methods and refined by full-matrix least-
squares on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0417, wR2
=
0.0557, maximal residual electron density: 0.186 eÅ–3. CCDC-
988849 contains the supplementary crystallographic data for 1.
These data can be obtained free of charge from The Cambridge
2,7-Dimethoxy-3-methylcarbazole (19): A mixture of diarylamine
18 (294 mg, 1.21 mmol), palladium acetate (27.0 mg, 0.120 mmol),
and cupric acetate (22.5 mg, 0.124 mmol) in acetic acid (7.5 mL)
8
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/KAP1
Date: 15-05-14 17:13:26
Pages: 16
Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
was heated at 90 °C and vigorously stirred under air for 5 h. The
mixture was cooled to room temperature and then filtered through
Celite® (diethyl ether), and the solvent was evaporated. Purification
of the residue by chromatography on a silica gel column (petroleum
ether/ethyl acetate, 4:1) provided 2,7-dimethoxy-3-methylcarbazole
(19, 195 mg, 67% yield) as a colorless solid; m.p. 243–244 °C. For
spectroscopic data and the transformation into 7-methoxy-O-meth-
ylmukonal (2), see ref.[13b]
1375, 1303, 1267, 1203, 1193, 1181, 1158, 1128, 1087, 1033, 988,
973, 846, 815, 772, 730, 651 cm–1. 1H NMR (500 MHz, [D6]acet-
one): δ = 2.14 (s, 3 H), 3.80 (s, 3 H), 3.91 (s, 3 H), 6.53 (d, J =
8.4 Hz, 1 H), 6.77 (dd, J = 7.9, 1.7 Hz, 1 H), 6.80 (d, J = 8.4 Hz,
1 H), 6.87 (d, J = 1.7 Hz, 1 H), 7.08 (d, J = 7.9 Hz, 1 H), 7.32 (br.
s, 1 H), 7.35 (t, J = 8.4 Hz, 1 H) ppm. 13C NMR and DEPT
(125 MHz, [D6]acetone): δ = 15.83 (CH3), 55.61 (CH3), 56.49
(CH3), 89.64 (C), 102.00 (CH), 105.58 (CH), 108.02 (CH), 114.18
(CH), 115.49 (C), 122.18 (C), 131.50 (CH), 135.34 (CH), 140.78
(C), 150.34 (C), 159.26 (C), 163.42 (C) ppm. GC–MS (70 eV): m/z
(%) = 268 (100) [M]+, 237 (7), 225 (16). C16H16N2O2 (268.31):
calcd. C 71.62, H 6.01, N 10.44; found C 71.90, H 6.18, N 10.27.
2-Chloro-6-methoxybenzonitrile (21): A mixture of 2-chloro-6-
hydroxybenzonitrile (20, 2.00 g, 13.0 mmol) and potassium carb-
onate (9.23 g, 66.8 mmol) in DMF (30 mL) was heated at reflux.
Methyl iodide (4.05 mL, 9.23 g, 65.1 mmol) was added dropwise at
that temperature over a period of 13 h. The mixture was heated at
reflux for an additional 4 h, and an additional portion of methyl
iodide (0.81 mL, 1.85 g, 13.0 mmol) was added. The mixture was
heated at reflux for an additional 2 h (total reaction time: 19 h).
The reaction mixture was cooled to room temperature and then
diluted with ethyl acetate, and the resulting solution was washed
several times with water, dilute hydrochloric acid, and brine. The
aqueous layers were extracted with ethyl acetate. The combined
organic layers were dried with sodium sulfate, and the solvent was
evaporated. Purification of the residue by chromatography on a
silica gel column (pentane/dichloromethane, gradient from 3:1 to
3:2) provided 2-chloro-6-methoxybenzonitrile (21, 1.90 g, 87%
yield) as colorless crystals; m.p. 114 °C. UV (MeOH): λ = 239, 246,
2,7-Dimethoxy-6-methylcarbazole-1-carbonitrile (23): To a mixture
of diarylamine 22 (135 mg, 0.503 mmol), potassium carbonate
(17.4 mg, 0.126 mmol), and pivalic acid (442 mg) in a 10 mL test
tube was added palladium acetate (25.5 mg, 0.114 mmol) at 120 °C,
and the mixture was heated at 120 °C for 15.5 h and vigorously
stirred under air. The mixture was cooled to room temperature and
then diluted with ethyl acetate, and the solution was washed with
a saturated solution of potassium carbonate and brine several
times. The aqueous layers were extracted with ethyl acetate. The
combined organic layers were dried with sodium sulfate, and the
solvent was evaporated. Purification of the residue by chromatog-
raphy on a silica gel column (petroleum ether/ethyl acetate, gradient
from
9:1
to
2:3)
provided
2,7-dimethoxy-6-methyl-
carbazole-1-carbonitrile (23, 116 mg, 87% yield) as a pale yellow
solid; m.p. 280–282 °C. UV (MeOH): λ = 219, 240, 286, 347 nm.
304 nm. IR (ATR): ν = 3106, 2992, 2956, 2847, 2232, 1591, 1572,
˜
1470, 1450, 1434, 1286, 1212, 1190, 1156, 1074, 1031, 973, 890,
858, 785, 772, 725, 645 cm–1. 1H NMR (500 MHz, CDCl3): δ =
3.94 (s, 3 H), 6.88 (d, J = 8.4 Hz, 1 H), 7.06 (dd, J = 8.4, 0.6 Hz, 1
H), 7.45 (t, J = 8.4 Hz, 1 H) ppm. 13C NMR and DEPT (125 MHz,
CDCl3): δ = 56.62 (CH3), 103.25 (C), 109.49 (CH), 113.73 (C),
121.82 (CH), 134.43 (CH), 138.14 (C), 162.72 (C) ppm. GC–MS
(70 eV): m/z (%) = 167 (100) [M]+, 139 (67), 138 (98), 124 (59), 100
(18), 88 (21),75 (22), 63 (23).
Fluorescence (MeOH): λex = 286 nm, λem = 414 nm. IR (ATR): ν
˜
= 3281, 2988, 2965, 2939, 2841, 2223, 1613, 1588, 1507, 1478, 1447,
1395, 1354, 1308, 1281, 1241, 1196, 1168, 1144, 1087, 1064, 1014,
999, 956, 890, 820, 804, 766,735, 661 cm–1. 1HNMR (500 MHz, [D6]-
acetone): δ = 2.30 (s, 3 H), 3.91 (s, 3 H), 4.01 (s, 3 H), 6.96 (d, J =
8.7 Hz, 1 H), 7.11 (s, 1 H), 7.79 (s, 1 H), 8.16 (d, J = 8.7 Hz, 1 H),
10.65 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acet-
one): δ = 16.84 (CH3), 55.81 (CH3), 57.01 (CH3), 83.73 (C), 94.08
(CH), 103.54 (CH), 115.48 (C), 116.37 (C), 119.17 (C), 120.45 (C),
121.74 (CH), 125.54 (CH), 141.15 (C), 142.69 (C), 158.24 (C),
160.46 (C) ppm. GC–MS (70 eV): m/z (%) = 266 (90) [M]+, 251
(100), 236 (12), 208 (17), 179 (12). C16H14N2O2 (266.30): calcd. C
72.16, H 5.30, N 10.52; found C 71.74, H 5.44, N 10.24.
Crystal Data for 21: C8H6ClNO, crystal size: 0.20ϫ0.09ϫ0.04 mm3,
M = 167.59 gmol–1, orthorhombic, space group: P212121, a =
3.948(1) Å, b = 6.902(1) Å, c = 28.272(4) Å, V = 770.4(2) Å3, Z =
4, ρcalcd. = 1.445 gcm–3, μ = 0.429 mm–1, T = 198(2) K, λ =
0.71073 Å, θ range: 3.04–25.39°, 17088 reflections collected, 1371
independent reflections (Rint = 0.0743), 101 parameters. The struc-
ture was solved by direct methods and refined by full-matrix least-
Murrayaline A (3): To a solution of carbonitrile 23 (121 mg,
0.454 mmol) in degassed dichloromethane (20 mL) was added di-
isobutylaluminium hydride (1 m in toluene, 1.13 mL, 1.13 mmol)
slowly at –78 °C, and the mixture was stirred for 4 h and then grad-
ually warmed from –55 to –25 °C. The excess amount of reagent
was quenched by the addition of ethyl acetate (1 mL) at –25 °C.
The mixture was warmed to room temperature and then diluted
with ethyl acetate. The resulting solution was washed several times
with water, dilute hydrochloric acid, and brine. The aqueous layers
were extracted with ethyl acetate. The combined organic layers were
dried with sodium sulfate, and the solvent was evaporated. Purifica-
tion of the residue by chromatography on a silica gel column (pe-
squares on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0608, wR2
=
0.1695, maximal residual electron density: 0.630 eÅ–3. CCDC-
988853 contains the supplementary crystallographic data for 21.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2-Methoxy-6-(3-methoxy-4-methylphenylamino)benzonitrile (22): A
solution of 2-chloro-6-methoxybenzonitrile (21, 913 mg,
5.45 mmol) in toluene (10 mL) was added dropwise over a period
of 5 h to a solution of 3-methoxy-4-methylaniline (17, 946 mg,
6.90 mmol), palladium acetate (77.6 mg, 0.346 mmol), SPhos troleum ether/dichloromethane/ethyl acetate, gradient from 90:10:1
(285 mg, 0.693 mmol), and cesium carbonate (3.21 g, 9.84 mmol)
in degassed toluene (60 mL) at reflux. The mixture was then heated
at reflux for an additional 14.5 h (total reaction time: 19.5 h). The
reaction mixture was cooled to room temperature, and the solvent
was evaporated. Purification of the residue by chromatography on
a silica gel column (petroleum ether/dichloromethane/ethyl acetate,
gradient from 60:5:1 to 45:5:1) provided diarylamine 22 (1.47 g,
100% yield) as a colorless solid; m.p. 160–163 °C. UV (MeOH): λ
to 20:10:1) provided murrayaline A (3, 88.4 mg, 72% yield) as yel-
low crystals, m.p. 271–272 °C; ref.[15] m.p. 248–250 °C. UV
(MeOH): λ = 223, 238 (sh), 255, 302, 380 nm. Fluorescence
(MeOH): λex = 302 nm, λem = 417 nm. IR (ATR): ν = 3370, 2979,
˜
2942, 2848, 1647, 1632, 1591, 1576, 1508, 1477, 1451, 1389, 1357,
1317, 1263, 1233, 1187, 1166, 1138, 1076, 1018, 999, 960, 918, 882,
1
824, 808, 772, 737, 683, 635 cm–1. H NMR (600 MHz, CDCl3): δ
= 2.35 (s, 3 H), 3.92 (s, 3 H), 4.00 (s, 3 H), 6.75 (d, J = 8.5 Hz, 1
H), 6.93 (s, 1 H), 7.69 (s, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 10.32 (br.
s, 1 H), 10.61 (s, 1 H) ppm. 13C NMR and DEPT (150 MHz,
= 262, 284 (sh), 340 nm. IR (ATR): ν = 3315, 3081, 3020, 3002,
˜
2957, 2928, 2851, 2214, 1593, 1577, 1504, 1473, 1450, 1435, 1397,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

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/KAP1
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Pages: 16
H.-J. Knölker et al.
FULL PAPER
CDCl3): δ = 16.88 (CH3), 55.75 (CH3), 56.41 (CH3), 93.34 (CH), pivalic acid (470 mg) were placed in a 10 mL test tube, and the
102.24 (CH), 108.76 (C), 114.99 (C), 118.68 (C), 120.32 (C), 121.02 mixture was heated at 100 °C. Palladium acetate (24.2 mg,
(CH), 127.37 (CH), 139.84 (C), 139.98 (C), 157.23 (C), 160.87 (C),
191.14 (CHO) ppm. GC–MS (70 eV): m/z (%) = 269 (100) [M]+,
254 (74), 226 (21), 211 (14), 183 (27), 154 (13). C16H15NO3 (269.30):
calcd. C 71.36, H 5.61, N 5.20; found C 71.14, H 5.69, N 5.38.
0.108 mmol) was added, and the mixture was vigorously stirred at
that temperature for 18.5 h under air. The mixture was cooled to
room temperature and then diluted with ethyl acetate, and the re-
sulting solution was washed with a saturated solution of potassium
carbonate and brine several times. The aqueous layers were ex-
tracted with ethyl acetate. The combined organic layers were dried
with sodium sulfate, and the solvent was evaporated. Purification
of the residue by chromatography on a silica gel column (pentane/
dichloromethane/ethyl acetate, gradient from 60:5:1 to 45:5:1) pro-
vided carbazolecarbonitrile 26 (177 mg, 87% yield) as pale yellow
crystals; m.p. 211 °C. UV (MeOH): λ = 221, 240 (sh), 286, 326 (sh),
349 nm. Fluorescence (MeOH): λex = 286 nm, λem = 403 nm. IR
Crystal Data for 3: C16H15NO3, M = 269.29 gmol–1, crystal size:
0.22ϫ0.15ϫ0.10 mm3, monoclinic, space group: P21/c,
a =
10.962(1) Å, b = 15.532(1) Å, c = 7.776(2) Å, β = 90.94(1)°, V =
1323.8(4) Å3, Z = 4, ρcalcd. = 1.351 gcm–3, μ = 0.094 mm–1, T =
198(2) K, λ = 0.71073 Å, θ range: 3.21–28.00°, 42436 reflections
collected, 3182 independent reflections (Rint = 0.1095), 188 param-
eters. The structure was solved by direct methods and refined by
full-matrix least-squares on F2, final R indices [I Ͼ 2σ(I)]: R1
0.0464, wR2 0.0941, maximal residual electron density:
=
(ATR): ν = 3294, 3018, 2941, 2864, 2219, 1614, 1505, 1473, 1396,
˜
=
1351, 1312, 1282, 1253, 1236, 1169, 1142, 1096, 1055, 996, 910,
0.241 eÅ–3. CCDC-988850 contains the supplementary crystallo-
graphic data for 3. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
1
883, 848, 789, 766, 733, 715, 672, 656 cm–1. H NMR (500 MHz,
CDCl3): δ = 1.15 (d, J = 7.5 Hz, 18 H), 1.37 (m, 3 H), 2.38 (s, 3
H), 3.99 (s, 3 H), 6.75 (d, J = 8.6 Hz, 1 H), 6.90 (s, 1 H), 7.68 (s,
1 H), 7.96 (d, J = 8.6 Hz, 1 H), 8.41 (br. s, 1 H) ppm. 13C NMR
and DEPT (125 MHz, CDCl3): δ = 13.19 (3 CH), 17.71 (CH3),
18.22 (6 CH3), 56.67 (CH3), 83.15 (C), 100.40 (CH), 102.70 (CH),
115.53 (C), 116.46 (C), 118.35 (C), 121.20 (CH), 122.66 (C), 124.72
(CH), 139.15 (C), 142.18 (C), 153.76 (C), 159.62 (C) ppm. GC–MS
(70 eV): m/z (%) = 408 (100) [M]+, 365 (72), 337 (30), 263 (26), 154
(25). C24H32N2O2Si (408.62): calcd. C 70.55, H 7.89, N 6.86; found
C 70.18, H 7.99, N 6.80.
2-Methoxy-6-[4-methyl-3-(triisopropylsilyloxy)phenylamino]benzo-
nitrile (25): 4-Methyl-3-(triisopropylsilyloxy)aniline (24, 1.00 g,
3.58 mmol), palladium acetate (34.2 mg, 0.152 mmol), SPhos
(127 mg, 0.309 mmol), and cesium carbonate (1.37 g, 4.20 mmol)
were dissolved in degassed toluene (15 mL), and the mixture was
heated at reflux. A solution of 2-chloro-6-methoxybenzonitrile (21,
502 mg, 3.00 mmol) in toluene (20 mL) was added dropwise over a
period of 15 h, and the mixture was heated at reflux for 3 h (total
reaction time: 18 h). The reaction mixture was cooled to room tem-
perature, and the solvent was evaporated. The residue was purified
by chromatography on a silica gel column (petroleum ether/di-
chloromethane/ethyl acetate, gradient from 60:5:1 to 45:5:1) to pro-
vide compound 25 (1.04 g, 85% yield) as colorless crystals; m.p.
142–143 °C. UV (MeOH): λ = 215, 259, 281 (sh), 340 nm. IR
Crystal
Data
for
26:
C24H32N2O2Si,
crystal
size:
0.38ϫ0.22ϫ0.20 mm3, M = 408.61 gmol–1, triclinic, space group:
¯
P1, a = 8.1619(4) Å, b = 8.5757(4) Å, c = 18.5198(9) Å, α =
81.623(2)°, β = 82.958(3)°, γ = 64.754(2)°, V = 1157.30(10) Å3, Z
= 2, ρcalcd. = 1.173 gcm–3, μ = 0.123 mm–1, T = 150(2) K, λ =
0.71073 Å, θ range: 1.11–26.00°, 28247 reflections collected, 4480
independent reflections (Rint = 0.0334), 274 parameters. The struc-
ture was solved by direct methods and refined by full-matrix least-
(ATR): ν = 3355, 2939, 2864, 2214, 1590, 1505, 1475, 1403, 1385,
˜
1362, 1331, 1274, 1205, 1176, 1131, 1087, 1011, 995, 981, 948, 918,
880, 845, 815, 777, 723, 697, 678, 661, 615 cm–1. 1H NMR
(500 MHz, [D6]acetone): δ = 1.12 (d, J = 7.5 Hz, 18 H), 1.32 (m, 3
H), 2.21 (s, 3 H), 3.91 (s, 3 H), 6.53 (d, J = 8.3 Hz, 1 H), 6.75–6.80
(m, 3 H), 7.11 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 8.4 Hz, 1 H), 7.43
(br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ
= 13.67 (3 CH), 16.69 (CH3), 18.39 (6 CH3), 56.49 (CH3), 89.96
(C), 102.14 (CH), 108.18 (CH), 112.55 (CH), 115.21 (CH), 115.46
(C), 124.20 (C), 132.04 (CH), 135.18 (CH), 140.72 (C), 150.31 (C),
155.59 (C), 163.50 (C) ppm. GC–MS (70 eV): m/z (%) = 410 (49)
[M]+, 367 (100). C24H34N2O2Si (410.63): calcd. C 70.20, H 8.35, N
6.82; found C 70.05, H 8.62, N 6.82.
squares on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0360, wR2
=
0.0885, maximal residual electron density: 0.425 eÅ–3. CCDC-
988855 contains the supplementary crystallographic data for 26.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Murrayaline B (4): To a solution of carbazolecarbonitrile 26
(100 mg, 0.245 mmol) in dry, degassed dichloromethane (12 mL)
was slowly added diisobutylaluminium hydride (1 m in hexane,
0.734 mL, 0.734 mmol) at –78 °C. The reaction mixture was stirred
at –40 to –30 °C for 4 h and then quenched with ethyl acetate
(1 mL) at that temperature. The mixture was washed with water,
dilute hydrochloric acid, and brine. The aqueous layers were ex-
tracted with ethyl acetate. The combined organic layers were dried
with sodium sulfate, and the solvent was evaporated. The crude
product was dried under high vacuum to provide 2-methoxy-6-
methyl-7-(triisopropylsilyloxy)carbazole-1-carbaldehyde as yellow
crystals; m.p. 211 °C. UV (MeOH): λ = 225, 257, 303, 382 nm. IR
Crystal Data for 25: C24H34N2O2Si, M = 410.62 gmol–1, crystal
size: 0.36ϫ0.10ϫ0.07 mm3, monoclinic, space group: C2/c, a =
24.940(5) Å, b = 7.632(2) Å, c = 26.616(5) Å, β = 115.65(3)°, V =
4566.9(17) Å3, Z = 8, ρcalcd. = 1.194 gcm–3, μ = 0.125 mm–1, T =
198(2) K, λ = 0.71073 Å, θ range: 3.08–27.00°, 65253 reflections
collected, 4990 independent reflections (Rint = 0.0890), 274 param-
eters. The structure was solved by direct methods and refined by
(ATR): ν = 3386, 2961, 2942, 2865, 1647, 1631, 1606, 1575, 1509,
˜
full-matrix least-squares on F2, final R indices [I Ͼ 2σ(I)]: R1
0.0422, wR2 0.0948, maximal residual electron density:
=
1472, 1392, 1355, 1319, 1256, 1232, 1179, 1138, 1083, 1069, 996,
937, 883, 852, 807, 768, 739, 716, 677, 636 cm–1. 1H NMR
(500 MHz, [D6]acetone): δ = 1.16 (d, J = 7.5 Hz, 18 H), 1.43 (sept,
J = 7.5 Hz, 3 H), 2.38 (s, 3 H), 4.02 (s, 3 H), 6.91 (d, J = 8.5 Hz,
1 H), 7.35 (s, 1 H), 7.79 (s, 1 H), 8.19 (d, J = 8.5 Hz, 1 H), 10.58
(s, 1 H), 10.99 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz,
[D6]acetone): δ = 13.76 (3 CH), 17.79 (CH3), 18.49 (6 CH3), 56.82
(CH3), 102.08 (CH), 103.10 (CH), 109.46 (C), 116.73 (C), 119.45
=
0.258 eÅ–3. CCDC-988854 contains the supplementary crystallo-
graphic data for 25. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
2-Methoxy-6-methyl-7-(triisopropylsilyloxy)carbazole-1-carbonitrile
(26): Diarylamine 25 (205 mg, 0.499 mmol), potassium carbonate
(18.0 mg, 0.130 mmol), cupric acetate (19.4 mg, 0.107 mmol), and (C), 121.57 (CH), 122.24 (C), 128.04 (CH), 140.34 (C), 141.36 (C),
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 15-05-14 17:13:26
Pages: 16
Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
153.90 (C), 161.76 (C), 190.17 (CHO) ppm. GC–MS (70 eV): m/z
stirred and heated at reflux for 20.5 h. The mixture was cooled to
(%) = 411 (100) [M]+, 368 (55), 340 (22), 266 (15), 156 (18). room temperature and then diluted with ethyl acetate. The resulting
C24H33NO3Si (411.62): calcd. C 70.03, H 8.08, N 3.40; found C
70.14, H 8.21, N 3.50. The crude 2-methoxy-6-methyl-7-(triiso-
propylsilyloxy)carbazole-1-carbaldehyde was dissolved in degassed
solution was washed several times with water, a saturated aqueous
solution of ammonium chloride (containing a small portion of di-
lute hydrochloric acid), a saturated aqueous solution of potassium
DMF (10 mL), and TBAF (1 m in THF, 0.37 mL, 0.37 mmol) was carbonate, and brine. The aqueous layers were extracted with ethyl
added at –15 °C. The reaction was warmed to room temperature
and then stirred for 10 min. Water (10 mL) was added, and the
mixture was diluted with diethyl ether. The resulting solution was
washed with water and brine, and the aqueous layers were extracted
with diethyl ether. The combined organic layers were dried with
sodium sulfate, and the solvent was evaporated. Purification of the
residue by column chromatography (pentane/ethyl acetate, gradient
from 6:1 to 3:1) provided murrayaline B (4, 55.6 mg, 89% yield)
acetate. The combined organic layers were dried with sodium sulf-
ate, and the solvent was evaporated. Purification of the residue by
chromatography on a silica gel column (pentane/dichloromethane/
ethyl acetate, gradient from 34:5:1 to 24:5:1) provided diarylamine
27 (2.12 g, 96% yield) as a colorless solid. 1H NMR (500 MHz,
CDCl3): δ = 2.28 (s, 3 H), 3.90 (s, 3 H), 5.07 (s, 2 H), 6.28 (br. s, 1
H), 6.30 (d, J = 8.2 Hz, 1 H), 6.54 (d, J = 8.5 Hz, 1 H), 6.70 (d, J
= 2.1 Hz, 1 H), 6.71 (br. s, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 7.18 (t,
as yellow crystals, m.p. 248–250 °C; ref.[17] m.p. 240–242 °C. UV J = 8.4 Hz, 1 H), 7.35 (m, 1 H), 7.38–7.44 (m, 4 H) ppm. 13C NMR
(MeOH): λ = 223, 259, 272 (sh), 303, 383 nm. Fluorescence and DEPT (125 MHz, CDCl3): δ = 16.12 (CH3), 56.14 (CH3), 69.92
(MeOH): λex = 303 nm, λem = 354, 418 nm. IR (ATR): ν = 3448, (CH2), 87.84 (C), 100.50 (CH), 106.00 (CH), 106.97 (CH), 114.89
˜
3360, 2969, 2916, 2848, 1648, 1626, 1580, 1506, 1485, 1454, 1385,
(CH), 115.72 (C), 123.67 (C), 127.16 (2 CH), 127.96 (CH), 128.72
1350, 1319, 1234, 1216, 1167, 1140, 1110, 1081, 1061, 982, 923, 882, (2 CH), 131.31 (CH),134.60 (CH), 137.17 (C), 138.41 (C), 149.33
1
803, 766, 729, 682, 622 cm–1. H NMR (500 MHz, [D6]acetone): δ
= 2.33 (s, 3 H), 4.01 (s, 3 H), 6.88 (d, J = 8.5 Hz, 1 H), 7.20 (s, 1
H), 7.73 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.38 (s, 1 H), 10.57 (s,
1 H), 10.80 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
acetone): δ = 16.73 (CH3), 56.80 (CH3), 98.38 (CH), 102.94 (CH),
109.43 (C), 115.73 (C), 118.93 (C), 119.72 (C), 121.63 (CH), 127.66
(CH), 140.19 (C), 141.50 (C), 155.35 (C), 161.49 (C), 190.22
(CHO) ppm. GC–MS (70 eV): m/z (%) = 255 (100) [M]+, 240 (38),
212 (22), 184 (34). C15H13NO3 (255.27): calcd. C 70.58, H 5.13, N
5.49; found C 70.31, H 5.17, N 5.54.
(C), 157.41 (C), 162.50 (C) ppm.
7-Benzyloxy-2-methoxy-6-methylcarbazole-1-carbonitrile (28): To a
mixture of diarylamine 27 (1.00 g, 2.90 mmol), potassium carb-
onate (75.5 mg, 0.546 mmol), and pivalic acid (5.0 g) in a 25 mL
test tube was added palladium acetate (32.6 mg, 0.145 mmol) at
110 °C, and the mixture was vigorously stirred at 110 °C under air.
Additional palladium acetate was added after 9 h (33.4 mg,
0.149 mmol), after 24 h (32.4 mg, 0.144 mmol), and after 32 h
(32.7 mg, 0.146 mmol). After a total reaction time of 48 h, the mix-
ture was cooled to room temperature and then diluted with ethyl
acetate. The resulting solution was washed several times with water,
a saturated aqueous solution of potassium carbonate, and brine.
The aqueous layers were extracted with ethyl acetate. The com-
bined organic layers were dried with sodium sulfate, and the solvent
was evaporated. Purification of the residue by chromatography on
a silica gel column (pentane/ethyl acetate/ethanol, gradient from
100:1:1 to 66:16:1) provided carbazolecarbonitrile 28 (975 mg, 98%
yield) as a brown solid. 1H NMR (500 MHz, [D6]acetone): δ = 2.38
(s, 3 H), 4.01 (s, 3 H), 5.23 (s, 2 H), 6.96 (d, J = 8.7 Hz, 1 H), 7.20
(s, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.55
(d, J = 7.5 Hz, 2 H), 7.83 (s, 1 H), 8.18 (d, J = 8.7 Hz, 1 H), 10.68
(br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]acetone): δ
= 17.04 (CH3), 57.02 (CH3), 70.65 (CH2), 95.63 (CH), 103.58 (CH),
115.45 (C), 116.70 (C), 119.10 (C), 120.83 (C), 121.85 (CH), 125.63
(CH), 128.18 (2 CH), 128.57 (CH), 129.33 (2 CH), 136.32 (C),
138.58 (C), 140.88 (C), 142.63 (C), 157.19 (C), 160.54 (C) ppm. MS
(ESI, +10 V): m/z = 343.1 [M + H]+. MS (ESI, –10 V): m/z = 340.9
[M – H]–.
Crystal Data for 2-Methoxy-6-methyl-7-(triisopropylsilyloxy)-
carbazole-1-carbaldehyde:
C24H33NO3Si,
crystal
size:
0.74ϫ0.23ϫ0.21 mm3, M = 411.60 gmol–1, triclinic, space group:
P1, a = 7.928(1) Å, b = 15.421(1) Å, c = 19.187(3) Å, α = 86.95(1)°,
β = 81.90(1)°, γ = 86.56(1)°, V = 2315.8(5) Å3, Z = 4, ρcalcd.
¯
=
1.181 gcm–3, μ = 0.125 mm–1, T = 198(2) K, λ = 0.71073 Å, θ
range: 3.13–27.00°, 87761 reflections collected, 9931 independent
reflections (Rint = 0.0805), 529 parameters. The structure was
solved by direct methods and refined by full-matrix least-squares
on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0490, wR2 = 0.1008,
maximal residual electron density: 0.305 eÅ–3. CCDC-988856 con-
tains the supplementary crystallographic data for 2-methoxy-6-
methyl-7-(triisopropylsilyloxy)carbazole-1-carbaldehyde.
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
These
Crystal Data for 4·Me2CO: C18H19NO4, M = 313.34 gmol–1, crys-
tal size: 0.41ϫ0.27ϫ0.21 mm , triclinic, space group: P1, a =
3
¯
7.853(1) Å, b = 10.277(2) Å, c = 11.504(1) Å, α = 65.21(1)°, β =
7-Benzyloxy-2-methoxy-6-methylcarbazole-1-carbaldehyde (29): To
a solution of carbonitrile 28 (174 mg, 0.508 mmol) in degassed
dichloromethane (20 mL) was added diisobutylaluminium hydride
(1 m in hexane, 1.78 mL, 1.78 mmol) slowly at –78 °C, and the mix-
ture was stirred for 4 h and then gradually warmed from –40 to
–30 °C. The excess amount of reagent was quenched by the ad-
dition of ethyl acetate (2 mL) at –30 °C. The mixture was warmed
to room temperature and then diluted with ethyl acetate, and the
resulting solution was washed several times with water, a saturated
solution of aqueous ammonium chloride, dilute hydrochloric acid,
and brine. The aqueous layers were extracted with ethyl acetate.
79.16(1)°, γ = 69.55(1)°, V = 788.8(2) Å3, Z = 2, ρcalcd.
=
1.319 gcm–3, μ = 0.093 mm–1, T = 198(2) K, λ = 0.71073 Å, θ
range: 3.01–25.40°, 22791 reflections collected, 2907 independent
reflections (Rint = 0.0489), 221 parameters. The structure was
solved by direct methods and refined by full-matrix least-squares
on F2, final R indices [I Ͼ 2σ(I)]: R1 = 0.0420, wR2 = 0.0930,
maximal residual electron density: 0.167 eÅ–3. CCDC-988851 con-
tains the supplementary crystallographic data for 4·Me2CO. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
2-[3-(Benzyloxy)-4-methylphenylamino]-6-methoxybenzonitrile (27): The combined organic layers were dried with sodium sulfate, and
A suspension of 3-benzyloxy-4-methylaniline (11, 1.70 g, 7.97 mmol),
2-chloro-6-methoxybenzonitrile (21, 1.07 g, 6.38 mmol), palladium
the solvent was evaporated. Purification of the residue by
chromatography on a silica gel column (petroleum ether/dichloro-
acetate (71.3 mg, 0.318 mmol), SPhos (265 mg, 0.646 mmol), and methane/ethyl acetate, gradient from 500:4:1 to 15:4:1) provided
cesium carbonate (2.91 g, 8.93 mmol) in toluene (20 mL) was
carbaldehyde 29 (98.2 mg, 56% yield) as a colorless solid. 1H NMR
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

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/KAP1
Date: 15-05-14 17:13:26
Pages: 16
H.-J. Knölker et al.
FULL PAPER
(500 MHz, [D6]acetone): δ = 2.38 (s, 3 H), 4.03 (s, 3 H), 5.22 (s, 2
perature and then diluted with ethyl acetate. The resulting solution
H), 6.93 (d, J = 8.5 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.40 (s, 1 was washed with a saturated aqueous solution of potassium carb-
H), 7.42 (m, 2 H), 7.55 (d, J = 7.5 Hz, 2 H), 7.81 (s, 1 H), 8.21 (d,
J = 8.5 Hz, 1 H), 10.59 (s, 1 H), 10.94 (br. s, 1 H) ppm. 13C NMR
and DEPT (125 MHz, [D6]acetone): δ = 17.08 (CH3), 56.86 (CH3),
70.59 (CH2), 96.22 (CH), 103.29 (CH), 109.49 (C), 115.99 (C),
119.36 (C), 120.65 (C), 121.57 (CH), 128.06 (CH), 128.23 (2 CH),
onate and brine several times. The aqueous layers were extracted
with ethyl acetate. The combined organic layers were dried with
sodium sulfate, and the solvent was evaporated. Purification of the
residue by chromatography on a silica gel column (pentane/di-
chloromethane/ethyl acetate, gradient from 60:5:1 to 40:5:1) pro-
128.54 (CH), 129.30 (2 CH), 138.64 (C), 140.12 (C), 141.31 (C), vided carbazole-1-carbonitrile 32 (241 mg, 76% yield) as a pale yel-
156.87 (C), 161.72 (C), 190.25 (CHO) ppm. MS (ESI, +25 V): m/z
low solid; m.p. 197 °C. UV (MeOH): λ = 221, 234 (sh), 282, 321
(sh), 348 nm. Fluorescence (MeOH): λex = 282 nm, λem = 386 nm.
= 346.2 [M + H]+.
IR (ATR): ν = 3338, 2943, 2889, 2866, 2218, 1612, 1586, 1542,
˜
3-(Triisopropylsilyloxy)aniline (30): Chlorotriisopropylsilane (4.59 g,
23.8 mmol) was added to a solution of 3-aminophenol (2.01 g,
18.4 mmol) and imidazole (2.49 g, 36.6 mmol) in THF (18 mL),
and the reaction mixture was stirred at room temperature for 20 h.
The mixture was diluted with diethyl ether, and the solution was
washed with water and brine several times. The aqueous layers were
extracted with diethyl ether. The combined organic layers were
dried with sodium sulfate, and the solvent was evaporated. Purifica-
tion of the residue by chromatography on a silica gel column (pent-
ane/dichloromethane/ethyl acetate, gradient from 80:5:1 to 35:5:1)
provided 3-(triisopropylsilyloxy)aniline (30, 4.72 g, 97% yield) as a
light red oil. 1H NMR (500 MHz, CDCl3): δ = 1.10 (d, J = 7.4 Hz,
18 H), 1.25 (m, 3 H), 3.75 (br. s, 2 H), 6.26 (t, J = 2.1 Hz, 1 H),
6.30 (dt, J = 2.1, 7.9 Hz, 2 H), 6.98 (t, J = 7.9 Hz, 1 H) ppm. 13C
NMR and DEPT (125 MHz, CDCl3): δ = 12.81 (3 CH), 18.08 (6
CH3), 107.27 (CH), 108.50 (CH), 110.68 (CH), 130.00 (CH), 147.43
(C), 157.21 (C) ppm. GC–MS (70 eV): m/z (%) = 265 (63) [M]+,
222 (100), 194 (50), 166 (60), 152 (47).
1507, 1456, 1441, 1391, 1366, 1309, 1285, 1264, 1243, 1219, 1160,
1119, 1091, 1071, 1013, 994, 970, 952, 898, 881, 849, 837, 801, 774,
722, 683, 653, 606 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.13 (d,
J = 7.4 Hz, 18 H), 1.31 (sept, J = 7.4 Hz, 3 H), 4.00 (s, 3 H), 6.78
(d, J = 8.7 Hz, 1 H), 6.84 (dd, J = 8.4, 2.1 Hz, 1 H), 6.96 (d, J =
2.1 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 1 H),
8.39 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ
= 12.84 (3 CH), 18.10 (6 CH3), 56.73 (CH3), 83.34 (C), 102.16
(CH), 102.98 (CH), 114.38 (CH), 115.36 (C), 117.07 (C), 118.33
(C), 120.39 (CH), 124.95 (CH), 140.90 (C), 142.33 (C), 155.42 (C),
159.87 (C) ppm. GC–MS (70 eV): m/z (%) = 394 (100) [M]+, 351
(90), 323 (45), 295 (58), 281 (42), 249 (35), 147 (48). C23H30N2O2Si
(394.59): calcd. C 70.01, H 7.66, N 7.10; found C 69.82, H 7.68, N
6.88.
7-Hydroxy-2-methoxycarbazole-1-carbaldehyde (33): To a solution
of carbazolecarbonitrile 32 (119 mg, 0.302 mmol) in dichlorometh-
ane (11 mL) was added diisobutylaluminium hydride (1 m in hex-
ane, 0.907 mL, 0.907 mmol) slowly at –78 °C. The reaction mixture
was stirred at –40 to –30 °C for 4 h and then quenched at –30 °C
by the addition of ethyl acetate (1 mL). The mixture was warmed to
room temperature and then diluted with ethyl acetate. The resulting
solution was washed several times with water, a saturated aqueous
solution of ammonium chloride (containing a small portion of di-
lute hydrochloric acid), and brine. The aqueous layers were ex-
tracted with ethyl acetate. The combined organic layers were dried
with sodium sulfate, and the solvent was evaporated. The crude
product was dried under high vacuum to provide 2-methoxy-7-(tri-
isopropylsilyloxy)carbazole-1-carbaldehyde (133 mg) as a yellow
solid of sufficient purity, m.p. 204–206 °C. UV (MeOH): λ = 225,
2-Methoxy-6-[3-(triisopropylsilyloxy)phenylamino]benzonitrile (31):
A mixture of 3-(triisopropylsilyloxy)aniline (30, 1.01 g, 3.80 mmol),
2-chloro-6-methoxybenzonitrile (21, 508 mg, 3.03 mmol), palla-
dium acetate (34.4 mg, 0.153 mmol), SPhos (124 mg, 0.302 mmol),
and cesium carbonate (1.38 g, 4.24 mmol) in degassed toluene
(14 mL) was heated at reflux for 23 h. The mixture was cooled to
room temperature and then diluted with diethyl ether. The resulting
mixture was filtered through Celite® (ethyl acetate), and the solvent
was evaporated. Purification of the residue by chromatography on a
silica gel column (pentane/dichloromethane/ethyl acetate, gradient
from 140:5:1 to 70:5:1) provided diarylamine 31 (1.21 g, 100%
yield) as a colorless solid; m.p. 94 °C. UV (MeOH): λ = 214, 258,
237 (sh), 256 (sh), 280, 378 nm. Fluorescence (MeOH): λex
=
281, 338 nm. IR (ATR): ν = 3325, 2944, 2865, 2216, 1593, 1578,
˜
225 nm, λem = 345 nm. IR (ATR): ν = 3387, 2941, 2889, 2864,
˜
1508, 1492, 1470, 1439, 1398, 1293, 1265, 1181, 1159, 1089, 988,
1649, 1607, 1575, 1542, 1498, 1453, 1394, 1357, 1320, 1236, 1183,
1145, 1119, 1084, 1015, 994, 957, 932, 880, 858, 844, 804, 782, 743,
722, 673, 629, 606 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.13 (d,
J = 7.4 Hz, 18 H), 1.31 (sept, J = 7.4 Hz, 3 H), 4.00 (s, 3 H), 6.75
(d, J = 8.5 Hz, 1 H), 6.83 (dd, J = 8.4, 2.1 Hz, 1 H), 6.97 (d, J =
2.1 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H),
10.30 (br. s, 1 H), 10.61 (s, 1 H) ppm. 13C NMR and DEPT
(125 MHz, CDCl3): δ = 12.85 (3 CH), 18.11 (6 CH3), 56.40 (CH3),
102.30 (CH), 102.35 (CH), 108.73 (C), 114.17 (CH), 116.35 (C),
118.67 (C), 120.15 (CH), 127.53 (CH), 140.46 (C), 141.48 (C),
155.04 (C), 161.04 (C), 191.10 (CHO) ppm. GC–MS (70 eV): m/z
(%) = 397 (100) [M]+, 354 (64), 326 (34), 298 (25), 284 (21), 252
(14), 224 (21), 149 (22). C23H31NO3Si (397.59): calcd. C 69.48, H
7.86, N 3.52; found C 69.34, H 7.98, N 3.62. To a solution of the
carbazolecarbaldehyde in DMF (10 mL) was added TBAF (1 m in
THF, 0.454 mL, 0.454 mmol) at –10 °C, and the cooling bath was
removed. The mixture was stirred for 10 min, and water (10 mL)
was added. The mixture was diluted with diethyl ether, and the
resulting solution was washed with water and brine several times.
The aqueous layers were extracted with diethyl ether. The com-
bined organic layers were dried with sodium sulfate, and the solvent
1
942, 880, 830, 769, 720, 683, 612 cm–1. H NMR (500 MHz, [D6]-
acetone): δ = 1.11 (d, J = 7.4 Hz, 18 H), 1.29 (sept, J = 7.4 Hz, 3
H), 3.92 (s, 3 H), 6.59 (d, J = 8.4 Hz, 1 H), 6.63 (m, 1 H), 6.85–
6.89 (m, 3 H), 7.21 (t, J = 8.1 Hz, 1 H), 7.40 (dt, J = 8.4, 0.8 Hz,
1 H), 7.51 (br. s, 1 H) ppm. 13C NMR and DEPT (125 MHz, [D6]-
acetone): δ = 13.34 (3 CH), 18.25 (6 CH3), 56.54 (CH3), 90.89 (C),
102.86 (CH), 108.96 (CH), 113.16 (CH), 114.63 (CH), 115.33 (C),
115.47 (CH), 130.87 (CH), 135.25 (CH), 143.52 (C), 149.62 (C),
157.81 (C), 163.51 (C) ppm. GC–MS (70 eV): m/z (%) = 396 (28)
[M]+, 353 (100), 281 (8), 267 (10), 253 (10), 223 (18), 126 (13).
C23H32N2O2Si (396.60): calcd. C 69.95, H 8.13, N 7.06; found C
69.97, H 8.44, N 7.12.
2-Methoxy-7-(triisopropylsilyloxy)carbazole-1-carbonitrile (32): To
a mixture of diarylamine 31 (319 mg, 0.804 mmol), cesium carb-
onate (26 mg, 80 μmol), and pivalic acid (510 mg) in a 10 mL test
tube was added palladium acetate (5.8 mg, 26 μmol) at 110 °C, and
the mixture was vigorously stirred at 110 °C under air. Additional
palladium acetate was added after 14 h (3.4 mg, 15 μmol), after
25 h (3.6 mg, 16 μmol), and after 39 h (3.6 mg, 16 μmol). After a
total reaction time of 50 h, the mixture was cooled to room tem-
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42201
/KAP1
Date: 15-05-14 17:13:26
Pages: 16
Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
was evaporated. Purification of the residue by chromatography on
a silica gel column (pentane/ethyl acetate, gradient from 3:1 to 2:1)
ylsilyloxy)benzoate (555 mg, 1.72 mmol), 2-chloro-6-methoxy-
benzonitrile (21, 344 mg, 2.05 mmol), palladium acetate (19.0 mg,
84.6 μmol), SPhos (72.0 mg, 0.175 mmol), and cesium carbonate
provided
7-hydroxy-2-methoxycarbazole-1-carbaldehyde
(33,
53.4 mg, 73% yield) as yellow crystals; m.p. 265–267 °C. UV (779 mg, 2.39 mmol) in toluene (12 mL) was stirred and heated at
(MeOH): λ = 223, 237 (sh), 255, 298, 378 nm. Fluorescence reflux for 18 h. The reaction mixture was cooled to room tempera-
(MeOH): λex = 298 nm, λem = 350, 405 nm. IR (ATR): ν = 3443, ture and then filtered through Celite® (ethyl acetate), and the sol-
˜
3318, 3023, 2921, 2850, 1639, 1616, 1581, 1525, 1498, 1451, 1387,
vent was evaporated. Purification of the residue by chromatography
1345, 1310, 1205, 1184, 1170, 1145, 1125, 1079, 948, 922, 821, 805, on a silica gel column (pentane/dichloromethane/ethyl acetate, gra-
767, 733, 680, 631 cm–1. 1H NMR (500 MHz, [D6]acetone): δ =
4.02 (s, 3 H), 6.78 (dd, J = 8.4, 2.2 Hz, 1 H), 6.91 (d, J = 8.5 Hz,
1 H), 7.20 (d, J = 2.2 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 8.18 (d,
dient from 35:5:1 to 25:5:1) provided diarylamine 35 (660 mg, 85%
yield) as a pale yellow solid; m.p. 131–132 °C. UV (MeOH): λ =
231 (sh), 272, 299, 326 (sh), 341 nm. IR (ATR): ν = 3299, 3183,
˜
J = 8.5 Hz, 1 H), 8.45 (s, 1 H), 10.58 (s, 1 H), 10.90 (br. s, 1 H) ppm. 3091, 3025, 2943, 2864, 2221, 1771, 1724, 1699, 1684, 1651, 1612,
13C NMR and DEPT (125 MHz, [D6]acetone): δ = 56.83 (CH3),
1579, 1518, 1475, 1455, 1401, 1335, 1312, 1260, 1235, 1207, 1148,
1075, 1008, 969, 946, 921, 882, 847, 829, 814, 774, 708, 686, 663,
98.86 (CH), 103.21 (CH), 109.49 (C), 110.42 (CH), 115.96 (C),
119.69 (C), 120.98 (CH), 127.78 (CH), 140.38 (C), 143.31 (C), 610 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.11 (d, J = 7.4 Hz,
157.29 (C), 161.61 (C), 190.26 (CHO) ppm. GC–MS (70 eV): m/z
18 H), 1.29 (m, 3 H), 3.85 (s, 3 H), 3.93 (s, 3 H), 6.37 (br. s, 1 H),
(%) = 241 (100) [M]+, 226 (42), 198 (17), 170 (39). C14H11NO3 6.46 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 2.1 Hz, 1 H), 6.72 (dd, J =
(241.25): calcd. C 69.70, H 4.60, N 5.81; found C 69.93, H 4.42, N
5.15.
8.5, 2.1 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.33 (t, J = 8.4 Hz, 1
H), 7.79 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR and DEPT
(125 MHz, CDCl3): δ = 13.25 (3 CH), 18.05 (6 CH3), 51.80 (CH3),
56.28 (CH3), 90.54 (C), 102.78 (CH), 108.38 (CH), 110.76 (CH),
112.13 (CH), 115.22 (C), 116.88 (C), 133.67 (CH), 134.53 (CH),
145.04 (C), 146.77 (C), 157.49 (C), 162.66 (C), 166.84 (C=O) ppm.
GC–MS (70 eV): m/z (%) = 411 (100) [M – C3H7]+, 309 (3), 205
(4). C25H34N2O4Si (454.64): calcd. C 66.05, H 7.54, N 6.16; found
C 66.36, H 7.75, N 6.17.
Crystal Data for 33: C14H11NO3, M = 241.24 gmol–1, crystal size:
0.57ϫ0.21ϫ0.16 mm3, monoclinic, space group: P21/c,
a =
10.859(1) Å, b = 14.173(2) Å, c = 7.067(1) Å, β = 94.762(9)°, V =
1083.9(2) Å3, Z = 4, ρcalcd. = 1.478 gcm–3, μ = 0.105 mm–1, T =
198(2) K, λ = 0.71073 Å, θ range: 3.23–25.40°, 19319 reflections
collected, 1993 independent reflections (Rint = 0.0714), 168 param-
eters. The structure was solved by direct methods and refined by
full-matrix least-squares on F2, final R indices [I Ͼ 2σ(I)]: R1
0.0453, wR2 0.1013, maximal residual electron density:
=
Methyl
8-Cyano-7-methoxy-2-(triisopropylsilyloxy)carbazole-3-
carboxylate (36): A 10 mL microwave tube was charged with di-
arylamine 35 (101 mg, 0.222 mmol), palladium acetate (3.4 mg,
15 μmol), potassium carbonate (3.1 mg, 22 μmol), cupric acetate
(101 mg, 0.556 mmol), and pivalic acid (400 mg) under air. The
tube was irradiated in a microwave reactor at 110 °C and 300 W
for 5 h. The mixture was cooled to room temperature and then
diluted with ethyl acetate. The resulting solution was washed with
a saturated solution of potassium carbonate and brine several
times. The aqueous layers were extracted with ethyl acetate. The
combined organic layers were dried with sodium sulfate, and the
solvent was evaporated. Purification of the residue by chromatog-
raphy on a silica gel column (pentane/dichloromethane/ethyl acet-
ate, 28:5:1) provided methyl carbazole-3-carboxylate 36 (77.2 mg,
77% yield) as a colorless solid; m.p. 227 °C. UV (MeOH): λ = 217,
249, 287, 326, 331, 347 nm. Fluorescence (MeOH): λex = 287 nm,
=
0.216 eÅ–3. CCDC-988857 contains the supplementary crystallo-
graphic data for 33. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Methyl 4-Amino-2-(triisopropylsilyloxy)benzoate: To a degassed
solution of methyl 4-amino-2-hydroxybenzoate (34, 2.00 g,
12.0 mmol) and imidazole (3.27 g, 48.0 mmol) in DMF (50 mL)
was added chlorotriisopropylsilane (4.70 mL, 4.23 g, 21.9 mmol) at
50 °C, and the mixture was stirred at 50 °C for 3 d. A second batch
of chlorotriisopropylsilane (3.00 mL, 2.70 g, 14.0 mmol) was
added, and the mixture was stirred for 1 d (total reaction time 4 d).
The mixture was cooled to room temperature and then diluted with
diethyl ether. The resulting solution was washed several times with
water, dilute hydrochloric acid, and brine. The aqueous layers were
extracted with diethyl ether. The combined organic layers were
dried with sodium sulfate, and the solvent was evaporated. Purifica-
tion of the residue by chromatography on a silica gel column (pent-
ane/dichloromethane/ethyl acetate, gradient from 45:5:1 to 35:5:1)
provided methyl 4-amino-2-(triisopropylsilyloxy)benzoate (2.50 g,
65% yield) as a slightly red oil. UV (MeOH): λ = 212 (sh), 233,
λem = 378 nm. IR (ATR): ν = 3300, 2942, 2863, 2222, 1734, 1689,
˜
1612, 1570, 1507, 1459, 1433, 1396, 1349, 1318, 1283, 1240, 1170,
1087, 1050, 1015, 978, 905, 883, 817, 782, 735 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.15 (d, J = 7.5 Hz, 18 H), 1.38 (m, 3 H),
3.91 (s, 3 H), 4.01 (s, 3 H), 6.82 (d, J = 8.7 Hz, 1 H), 6.93 (s, 1 H),
8.03 (d, J = 8.7 Hz, 1 H), 8.42 (s, 1 H), 8.62 (br. s, 1 H) ppm. 13C
NMR and DEPT (125 MHz, CDCl3): δ = 13.29 (3 CH), 18.11 (6
CH3), 52.02 (CH3), 56.78 (CH3), 83.74 (C), 101.99 (CH), 103.70
(CH), 115.08 (C), 116.60 (C), 116.75 (C), 118.12 (C), 124.04 (CH),
125.45 (CH), 142.93 (C), 143.09 (C), 155.24 (C), 160.32 (C), 167.87
(C=O) ppm. GC–MS (70 eV): m/z (%) = 409 (100) [M – C3H7]+,
307 (5), 279 (6), 264 (5). C25H32N2O4Si (452.62): calcd. C 66.34, H
7.13, N 6.19; found C 66.33, H 7.26, N 6.17.
280, 300 (sh) nm. Fluorescence (MeOH): λex = 280 nm, λem
=
335 nm. IR (ATR): ν = 3473, 3368, 3230, 2945, 2866, 1699, 1677,
˜
1653, 1599, 1565, 1506, 1453, 1397, 1345, 1319, 1278, 1247, 1209,
1139, 1083, 992, 963, 920, 881, 839, 772, 681, 642, 612 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 1.11 (d, J = 7.4 Hz, 18 H), 1.30 (m,
3 H), 3.80 (s, 3 H), 4.40 (br. s, 2 H), 6.15 (d, J = 2.2 Hz, 1 H), 6.28
(dd, J = 8.5, 2.2 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR
and DEPT (125 MHz, CDCl3): δ = 13.33 (3 CH), 18.10 (6 CH3),
51.46 (CH3), 106.27 (CH), 107.99 (CH), 112.58 (C), 134.14 (CH),
150.73 (C), 158.06 (C), 167.16 (C=O) ppm. GC-MS (70 eV): m/z
(%) = 280 (100) [M – C3H7]+, 194 (8). C17H29NO3Si (323.51): calcd.
C 63.12, H 9.04, N 4.33; found C 63.06, H 9.27, N 4.60.
6-(Hydroxymethyl)-2-methoxy-7-(triisopropylsilyloxy)carbazole-1-
carbaldehyde: To a solution of methyl 8-cyano-7-methoxy-2-tri-
isopropylsilyloxy-9H-carbazole-3-carboxylate
(36,
100 mg,
0.221 mmol) in dichloromethane (20 mL) was slowly added diiso-
butylaluminium hydride (1 m in toluene, 0.99 mL, 0.99 mmol) at
–78 °C, and the mixture was stirred at –40 to –35 °C for 4 h. The
reaction was quenched at low temperature with ethyl acetate (1 mL)
and then diluted with diethyl ether, and the resulting mixture was
Methyl
4-[(2-Cyano-3-methoxyphenyl)amino]-2-(triisopropylsilyl-
oxy)benzoate (35): A suspension of methyl 4-amino-2-(triisoprop-
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H.-J. Knölker et al.
FULL PAPER
washed several times with water, a saturated aqueous solution of
ammonium chloride (containing a small portion of dilute hydro-
chloric acid), and brine. The aqueous layers were extracted with
diethyl ether. The combined organic layers were dried with sodium
sulfate, and the solvent was evaporated. The residue was dried un-
der high vacuum to provide crude 6-(hydroxymethyl)-2-methoxy-7-
10.02 (s, 1 H), 10.58 (s, 1 H), 11.36 (br. s, 1 H), 11.40 (s, 1 H) ppm.
13C NMR and DEPT (125 MHz, [D6]acetone): δ = 57.03 (CH3),
99.05 (CH), 104.99 (CH), 110.00 (C), 117.04 (C), 117.32 (C), 118.87
(C), 127.53 (CH), 128.60 (CH), 141.53 (C), 147.85 (C), 161.55 (C),
162.53 (C), 190.28 (CHO), 196.91 (CHO) ppm. GC–MS (70 eV):
m/z (%) = 269 (100) [M]+, 254 (27), 226 (12), 198 (23). C15H11NO4
(triisopropylsilyloxy)carbazole-1-carbaldehyde (94.5 mg, 100% (269.26): calcd. C 66.91, H 4.12, N 5.20; found C 67.15, H 4.45, N
yield); m.p. 145–146 °C. UV (MeOH): λ = 228, 257 (sh), 302, 352
(sh), 380 nm. Fluorescence (MeOH): λex = 228 nm, λem = 392 nm.
4.84.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all compounds and
data for the X-ray crystal structure analyses of 2-methoxy-6-
methyl-7-(triisopropylsilyloxy)carbazole-1-carbaldehyde and com-
pounds 15, 21, and 26.
IR (ATR): ν = 3384, 2942, 2865, 1650, 1631, 1606, 1575, 1508,
˜
1472, 1436, 1389, 1355, 1319, 1255, 1232, 1145, 1087, 995, 948, 882,
1
851, 798, 773, 722, 677 cm–1. H NMR (600 MHz, [D6]acetone): δ
= 1.16 (d, J = 7.6 Hz, 18 H), 1.44 (m, 3 H), 3.93 (t, J = 6.0 Hz, 1
H), 4.04 (s, 3 H), 4.84 (d, J = 6.0 Hz, 2 H), 6.94 (d, J = 8.5 Hz, 1
H), 7.36 (s, 1 H), 8.06 (s, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 10.59 (s,
1 H), 11.04 (br. s, 1 H) ppm. 13C NMR and DEPT (150 MHz, [D6]-
acetone): δ = 13.76 (3 CH), 18.50 (6 CH3), 56.87 (CH3), 61.16
(CH2), 101.89 (CH), 103.31 (CH), 109.56 (C), 116.66 (C), 119.10
(CH), 119.69 (C), 126.95 (C), 128.11 (CH), 140.44 (C), 141.77 (C),
152.83 (C), 161.83 (C), 190.19 (CHO) ppm. MS (ESI, +25 V): m/z
= 410.3 [M – OH]+, 877.6 [2M + Na]+. MS (ESI, –25 V): m/z =
425.9 [M – H]–. MS (EI, 70 eV): m/z (%) = 427 (100) [M]+, 424
(35), 384 (77), 381 (37), 342 (33), 314 (32), 311 (28), 280 (40), 253
(24). HRMS: calcd. for C24H33NO4Si [M]+ 427.2179; found
427.2163.
Acknowledgments
The authors are grateful to Müge Fuchsenberger, Philipp Linning
and Heinrich L. Schnitzler for experimental support.
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2-Methoxy-7-(triisopropylsilyloxy)carbazole-1,6-dicarbaldehyde
(37): A suspension of the crude hydroxymethylcarbazole and man-
ganese dioxide (191 mg, 2.20 mmol) in degassed dichloromethane
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to provide crude 2-methoxy-7-(triisopropylsilyloxy)carbazole-1,6-
dicarbaldehyde (37, 94.1 mg, 100% yield). 1H NMR (500 MHz,
CDCl3): δ = 1.17 (d, J = 7.5 Hz, 18 H), 1.42 (m, 3 H), 4.02 (s, 3
H), 6.83 (d, J = 8.6 Hz, 1 H), 6.89 (s, 1 H), 8.11 (d, J = 8.6 Hz, 1
H), 8.44 (s, 1 H), 10.46 (br. s, 1 H), 10.58 (s, 1 H), 10.59 (s, 1
H) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ = 13.20 (3
CH), 18.18 (6 CH3), 56.49 (CH3), 100.86 (CH), 103.66 (CH),
109.06 (C), 117.11 (C), 118.45 (C), 120.36 (CH), 121.70 (C), 128.29
(CH), 141.26 (C), 145.59 (C), 158.53 (C), 161.65 (C), 190.18
(CHO), 191.13 (CHO) ppm. MS (ESI, +25 V): m/z = 426.4 [M +
H]+. MS (ESI, –50 V): m/z = 424.0 [M – H]–.
Murrayaline C (5): Without further purification, dicarbaldehyde 37
was dissolved in degassed DMF (15 mL), and TBAF (1 m in THF,
0.33 mL, 0.33 mmol) was added at –10 °C. The reaction was
warmed to room temperature and then stirred for 10 min. Water
(5 mL) was added, and the mixture was diluted with diethyl ether.
The resulting mixture was washed with water and brine several
times. The aqueous layers were extracted with ethyl acetate. The
combined organic layers were dried with sodium sulfate, and the
solvent was evaporated. Purification of the residue by chromatog-
raphy on a silica gel column (pentane/ethyl acetate, gradient from
5:1 to 7:2) provided murrayaline C (5, 28.3 mg, 48% yield) as a
yellow solid, m.p. 273 °C; ref.[17] no m.p. (yellow powder). UV
(MeOH): λ = 257, 266 (sh), 305 (sh), 327, 330 nm. Fluorescence
(MeOH): λex = 266 nm, λem = 358 nm. IR (ATR): ν = 3357, 2921,
˜
2850, 1735, 1700, 1658, 1643, 1594, 1509, 1462, 1432, 1394, 1327,
1
1253, 1230, 1183, 1082, 932, 880, 822, 798, 719, 678, 631 cm–1. H
NMR (500 MHz, [D6]acetone): δ = 4.07 (s, 3 H), 7.06 (d, J =
8.6 Hz, 1 H), 7.21 (s, 1 H), 8.33 (d, J = 8.6 Hz, 1 H), 8.42 (s, 1 H),
14
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Palladium(II)-Catalyzed Synthesis of Formylcarbazole Alkaloids
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Received: March 5, 2014
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H.-J. Knölker et al.
FULL PAPER
Total Synthesis
We describe the synthesis of the naturally
occurring 2,7-dioxygenated formylcarb-
azole alkaloids 7-methoxymukonal, 7-meth-
oxy-O-methylmukonal, and the murray-
alines A–C. The carbazole framework was
constructed by a Buchwald–Hartwig amin-
ation and a subsequent palladium(II)-cata-
lyzed oxidative cyclization.
R. Hesse, M. P. Krahl, A. Jäger,
O. Kataeva, A. W. Schmidt,
H.-J. Knölker* ................................ 1–16
Palladium(II)-Catalyzed Synthesis of the
Formylcarbazole Alkaloids Murraya-
line A–C, 7-Methoxymukonal, and 7-
Methoxy-O-methylmukonal
Keywords: Natural products / Alkaloids /
Nitrogen heterocycles / C–H activation /
Cyclization / Palladium
16
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