Straightforward access to hexahydropyrrolo[2,3-b]indole core by a regioselective c3-azo coupling reaction of arenediazonium compounds with tryptamines

Article abstract of DOI:10.1002/ejoc.201402088

A base-mediated regioselective electrophilic addition of arenediazonium salts at the C3-position of tryptamines followed by cyclization provides an efficient entry to C3-nitrogenated hexahydropyrrolo[2,3-b]indoles (HPIs) that can subsequently be transformed into 3-arylhexahydropyrrolo[2,3-b]indoles and other HPI derivatives. The reaction is the first example of a 1,2-diamination that utilizes easily accessible arenediazonium salts as nitrogenous electrophiles. Copyright

Full text of DOI:10.1002/ejoc.201402088

FULL PAPER
DOI: 10.1002/ejoc.201402088
Straightforward Access to Hexahydropyrrolo[2,3-b]indole Core by a
Regioselective C3-Azo Coupling Reaction of Arenediazonium Compounds with
Tryptamines
David E. Stephens[a] and Oleg V. Larionov*[a]
Keywords: Synthetic methods / Electrophilic addition / Diazo compounds / Hydrazines / Nitrogen heterocycles
A base-mediated regioselective electrophilic addition of ar-
enediazonium salts at the C3-position of tryptamines fol-
lowed by cyclization provides an efficient entry to C3-nitro-
genated hexahydropyrrolo[2,3-b]indoles (HPIs) that can sub-
sequently be transformed into 3-arylhexahydropyrrolo-
[2,3-b]indoles and other HPI derivatives. The reaction is the
first example of a 1,2-diamination that utilizes easily access-
ible arenediazonium salts as nitrogenous electrophiles.
Introduction
The hexahydropyrrolo[2,3-b]indole (HPI) framework is
widely represented among natural products. Over 1000 al-
kaloids and peptides containing this structural motif have
been isolated to date. The HPI natural products exhibit a
range of interesting biological activities; representatives are
known to serve as cytotoxins, neuroprotective agents, and
cholinesterase inhibitors (Figure 1).
These interesting properties, combined with their un-
usual structural features, have rendered these natural prod-
ucts attractive synthetic targets.[1] In particular, hexa-
hydropyrrolo[2,3-b]indoles bearing a C3–N bond have pre-
sented a notable synthetic challenge, due to the difficulties
associated with introduction of the nitrogenous substituents
in the C3-position of indoles.
Electrophilic addition, followed by cyclization, is a gene-
ral and efficient approach to synthesizing pyrroloindolines.
Toward this end, a number of electrophilic reagents have
recently been utilized for the construction of this tricyclic
core from tryptophans and tryptamines. Thus, Quing de-
scribed a trifluoromethylsulfanilation/cyclization cascade
mediated by CF3SNHPh.[2] Selenization of tryptamines has
also been extensively documented and employed in total
synthesis.[3] Fluoro-[4] chloro-[5] bromocyclizations[6] en
route to hexahydropyrrolo[2,3-b]indoles have been reported
as well. In addition, installation of the 3-hydroxy group has
been achieved by oxidatively-induced cyclizations of trypta-
mines with hypervalent iodine reagents,[7] singlet oxygen,[8]
DMDO.[9] Photochemical hydroxylation with heterocyclic
Figure 1. Representative hexahydropyrrolo[2,3-b]indole natural
products.
N-oxides has also been reported.[10] Some of the recent
methods that have been used to introduce a nitrogen sub-
stituent in the C3-position of hexahydropyrrolo[2,3-b]ind-
oles include reactions of tryptamines with i) N-iodosuccin-
imide and primary or secondary amines,[11] ii) iodine/tert-
butyl hydrogen peroxide/amine,[12] iii) azodicarboxylates,[13]
iv) sequential bromocyclization/base-mediated nucleophilic
substitution,[14] v) rhodium-catalyzed amidation,[15] vi) con-
densation with N-oxyindoles,[16] and vii) iodine azide-medi-
ated cyclization[17] (Scheme 1).
Arenediazonium compounds have recently emerged as
versatile reagents for a variety of C–C bond-forming reac-
tions. Some examples include the Heck–Matsuda reac-
tion,[18] palladium-catalyzed C–H-arylation,[19] as well as
Meerwein[20] and Sandmeyer-type reactions.[21] On the
other hand, examples of using arenediazonium compounds
[a] Department of Chemistry, University of Texas at
San Antonio,
San Antonio, Texas 78249, U.S.A.
E-mail: oleg.larionov@utsa.edu
www.utsa.edu/chem/larionov.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402088.
3662
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3662–3670

Facile Generation of Pyrroloindoles from Tryptamines
provement was observed at –78 °C (Table 1, Entries 2–4).
Subsequent screening of different bases demonstrated that
Cs2CO3 was superior to other basic alkali metal salts
(Table 1, Entries 5–9). Finally, the optimal yield of 3 was
obtained at –20 °C using lower concentrations of diazo-
nium salt 2 (Table 1, Entry 11) and Cs2CO3 as the base.
Interestingly, tert-butyldimethylsilyl-protected indole 4 also
proved to be a viable substrate and afforded product 3 as a
result of concomitant desilylation. Generally, the effects of
solvent, base and temperature (Table 1, Entries 12–19) on
the performance of substrate 4 were similar to those of un-
protected indole 1, although a higher yield of coupling
product 3 was obtained under optimized conditions
(Table 1, Entry 20).
Table 1. Diazonium-mediated pyrroloindoline synthesis.[a]
Entry Substrate
2
Base
Solvent
(temp. [°C])
Yield
[%][b]
[equiv.]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1
1
1
1
1
1
1
1
1
1
1
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
2
2
2
2
2
2
2
2
2
2
2
NaHCO3
CH2Cl2 (23)
10
40
0
NaHCO3 CH3CN (23)
NaHCO3 CH3OH (23)
NaHCO3 CH2Cl2 (–78)
Na2CO3
K2CO3
K3PO4
Li2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaHCO3 CH3CN (23)
NaHCO3 CH2Cl2 (23)
26
27
24
24
17
37
20
62
23
9
CH2Cl2 (–78)
CH2Cl2 (–78)
CH2Cl2 (–78)
CH2Cl2 (–78)
CH2Cl2 (–78)
CH2Cl2 (0)
Scheme 1. Construction of the pyrrolidinoindoline framework bear-
ing the C3–N linkage.
for the formation of C–N bonds are relatively rare. Thus,
Knochel described an efficient indazole synthesis from
functionalized organozinc reagents.[22] Aggarwal employed
arenediazonium compounds for stereospecific amination of
alkylboronates.[23] In addition, azo-coupling reactions with
arenes have been used for the synthesis of new dyes[24] and
as vehicles for tyrosine-specific bioconjugations.[25] Al-
though arenediazonium salts have previously been used as
electrophiles in reactions with electron-rich alkenes and silyl
enol ethers,[26] they have not been employed as electrophiles
for 1,2-diamination chemistry. Herein, we describe an azo-
coupling/cyclization cascade as a straightforward method
of constructing pyrrolidinoindolines bearing the C3–N link-
age, and their subsequent application for synthesis of fur-
ther HPI compounds.
CH2Cl2 (–20)
NaHCO3 CH3OH (23)
NaHCO3 CH2Cl2 (–78)
Cs2CO3
0
27
42
28
58
83
96
CH2Cl2 (–50)
NaHCO3 CH2Cl2 (–50)
Cs2CO3
Cs2CO3
Cs2CO3
CH3CN (–20)
CH2Cl2 (–20)
CH2Cl2 (0)
[a] Reaction conditions: 1 or 4 (0.25 mmol), base (5 equiv.), molecu-
1
lar sieves (3 Å, 150 mg), solvent (2.5 mL). [b] Determined by H
NMR spectroscopy.
We then proceeded with the study of the scope of the
reaction. Since synthetically useful yields were obtained for
both unprotected indole 1 and N-silylindole 4, the unpro-
tected tryptamines were used as substrates. Under the opti-
mized conditions a variety of diazonium compounds re-
acted readily with substituted tryptamines. In general, reac-
Results and Discussion
Initial experiments with N-acetyltryptamine (1) and tions with arenediazonium salts bearing electron-with-
benzenediazonium tetrafluoroborate (2) have shown that drawing substituents proceeded more cleanly and afforded
desired HPI product 3 can be formed, albeit in a low yield higher yields than their less electrophilic counterparts (Fig-
at room temperature in CH2Cl2 and with NaHCO3 as a ure 2). Thus, 3,5-bis(trifluoromethyl)benzenediazonium
base (Table 1, Entry 1). Acetonitrile proved to be a better tetrafluoroborate proved to be a particularly efficient rea-
medium than CH2Cl2 and MeOH, and a moderate im- gent. ortho-Substituted diazonium salts were somewhat less
Eur. J. Org. Chem. 2014, 3662–3670
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3663

D. E. Stephens, O. V. Larionov
FULL PAPER
Figure 2. Synthetic scope of the reaction of arenediazonium compounds with tryptamines, substituted tryptophan derivatives and related
3-substituted indoles. Reaction conditions: [a] ArN2BF4 (2 equiv.), molecular sieves (3 Å), CH3CN, –20 °C, 12 h. [b] 4, ArN2BF4 (2 equiv.),
molecular sieves (3 Å), CH2Cl2, 0 °C, 12 h. [c] ArN2BF4 (2 equiv.), molecular sieves (3 Å), CH3CN, 23 °C, 12 h. [d] ArN2BF4 (2 equiv.),
molecular sieves (3 Å), CH3CN/CH2Cl2 (1:1), 23 °C, 12 h.
reactive, requiring longer reaction times to give syntheti- Finally, the Boc-protected methyl ester of tryptophan re-
cally useful yields of pyrroloindolines (e.g. compounds 13, acted with diazonium compounds to give corresponding
16 and 19).
pyrroloindolines (19–21) in good yields.
The azo-cyclization reaction appears to exhibit a broad
Photoinduced extrusion of nitrogen from unsymmetrical
scope with respect to tryptamine counterparts. The general azo compounds was recently exploited by Movassaghi as
requirement of the nucleophilic N-terminus was found to a general and powerful strategy for making heterodimeric
be the presence of an electron-withdrawing group on the hexahydropyrroloindoles.[27] We reasoned that the azo-cou-
C3-side chain nitrogen; no azo-cylization products were ob- pling/cyclization cascade and subsequent photochemical ni-
served with tryptamines bearing N-alkyl groups or with un- trogen extrusion may provide a transition metal-free two-
protected tryptamine. On the other hand, carbamides, sulf- step shortcut to 3-aryl-substituted hexahydropyrroloind-
onamides and carbamates gave desired products (e.g. 6, 7, oles.
9, and 12) in good yields. In addition to 3-amidoalkyl side
The HPI subunit[28] bearing a C3-aryl group is present
chains, substrates with O-termini in the C3-side chain also in a number of natural products such as asperazine[29] (Fig-
gave rise to diazenes. Thus, both tryptophol and 3-indole- ure 1), naseseazines A and B,[30] and pestalazine A.[31]
acetic acid afforded products 8 and 18 in excellent yields.
Indeed, irradiation of tryptophol-derived compound 8 in
Substrates expected to give rise to products with a six-mem- tert-butanol afforded nitrogen extrusion product 22 in 42%
bered C-ring did not afford diazenes in isolable quantities. yield (Table 2). Similarly, tryptophan-derived diazene 21
3664
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3662–3670

Facile Generation of Pyrroloindoles from Tryptamines
produced 3-phenyl-substituted product 23 in 41% yield.
To gain insight into the mechanism of the reaction, the
Attempts to use diazenes bearing substituents on the aro- influence of electronic factors on the reaction of tryptamine
matic ring (e.g. 7, 15, and 19), as well as phenyl-substituted 5a with arenediazonium compounds was studied (Figure 3).
diazenes 11 and 12 with N-tosyl and endocyclic amido The Hammett plot of the reaction afforded a ρ value of
groups led to scission of the C-ring, and only precursors 5 0.59. This ρ value is substantially lower than Hammett reac-
were isolated, highlighting the intricate balance of elec- tion constants observed for the reactions of indole, as well
tronic effects during the solvent-caged photochemical pro- as 2- and 3-methylindole (ρ = 3–3.3).[36] The large ρ values
cess.
for these substrates were explained by the formation of the
Wheland intermediate in the rate-limiting step.
Table 2. Photoinduced nitrogen extrusion from 3-phenylazopyrrolo-
indolines 8 and 21.[a]
Substrate
X
R1
Product
Yield [%][b]
8
21
O
H
22
23
42
41
NHBoc
CO2CH3
[a] Reaction conditions: low-pressure Hg lamp (254 nm), 0.06 m (8)
or 0.05 m (21) solution in tert-butanol, 23 °C, 12 h. [b] Isolated yield
after column chromatography.
Substituted hydrazines are important molecular scaffolds
in drug discovery. A number of hydrazines are currently in
use or are being investigated for the treatment of psychiatric
disorders,[32] tuberculosis,[33] and cancer.[34] We therefore
studied the reduction of 3-arylazopyrroloindolines to their
corresponding substituted hydrazine derivatives (Table 3). It
was found that unsymmetrical hydrazines 24–28 can be
formed efficiently from precursor diazenes 3, 9, 10, 12, and
13 in high yields using hydrazine hydrate as a reducing
agent.[35] On the other hand, attempts to induce reductive
cleavage of the N–N bond to 3-aminohexahydropyrroloin-
doles led to exclusive formation of ring-scission products 5
with zinc and indium metals as reducing agents under
acidic conditions (acetic acid in THF and HCl in CH3OH).
Figure 3. Hammett plot for the reaction of tryptamine 5a with arene-
diazonium compounds.
On the other hand, studies by Jackson and Lynch point
to the second step (proton abstraction) as the rate-limiting
step.[37] Based on the relatively small Hammett reaction
constant observed for the azo-cyclization of 5a, the mecha-
nism appears to be better described by the Jackson–Lynch
model. This is consistent with recent mechanistic observa-
tions highlighting the reversibility of the initial phenylselen-
ation step in the phenylselenation/cyclization cascade reac-
tion of tryptamines.[38]
Table 3. Hydrazine-mediated reduction of 3-arylazopyrroloindol-
ines.[a]
Conclusions
In summary, we have developed an arenediazonium-in-
duced cyclization cascade of tryptamines, tryptophan deriv-
atives and related 3-substituted indoles. The reaction af-
fords 3-arylazohexahydropyrrolo[2,3-b]indoles in good to
excellent yields, and in combination with photoinduced
nitrogen extrusion, provides a simple transition metal-free
two-step entry to arylhexahydropyrrolo[2,3-b]indoles re-
lated to asperazine and other secondary metabolites with
the pyrroloindoline framework. Additionally, we have
Substrate
R1
R2
Ph
Product Yield
[%][b]
3
9
10
12
13
C(O)CH3
24
25
26
27
28
99
99
98
76
99
C(O)OBn 3,5-bis(trifluoromethyl)phenyl
C(O)OtBu
SO2Tol
2,4,5-trifluorophenyl
Ph
2-bromophenyl
C(O)OtBu
[a] Reaction conditions: N2H4·H2O, EtOH (0.05–0.1 m), 50 °C, 3–
12 h. [b] Isolated yield.
Eur. J. Org. Chem. 2014, 3662–3670
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3665

D. E. Stephens, O. V. Larionov
FULL PAPER
(572 mg, 1.76 mmol, 5 equiv.) in acetonitrile (4 mL) was treated
with 3,5-bis(trifluoromethyl)benzenediazonium tetrafluoroborate
(238 mg, 0.728 mmol, 2 equiv.) at –20 °C. The crude product was
purified to yield HPI 6 (127 mg, 69 %) as a red oil. 1H NMR
(500 MHz): δ = 3.31 (d, J = 17.5 Hz, 1 H), 3.46 (d, J = 17.5 Hz, 1
H), 4.41–4.50 (m, 1 H), 4.97 (d, J = 15 Hz, 1 H), 5.88 (s, 1 H), 6.77
(d, J = 9 Hz, 1 H), 7.03–7.48 (m, 8 H), 7.79–8.04 (m, 2 H), 8.16 (s,
1 H), 8.31 (s, 1 H) ppm. 13C NMR (125 MHz): δ = 40.4, 44.4, 78.6,
83.0, 110.5, 120.0, 122.6, 123.0, 127.4, 128.1, 129.1, 132.7, 135.6,
146.8, 151.3, 152.6, 153.1, 170.4 ppm. 19F NMR (282 MHz): δ =
found that unsymmetrical diazenes can also be reduced to
the corresponding hydrazo compounds in high yields.
Experimental Section
General Methods: Anhydrous dichloromethane were collected un-
der argon from an LC Technologies solvent purification system.
Acetonitrile was dried with molecular sieves (4 Å). 3 Å Molecular
sieves were freshly dried at 100 °C and cooled to room temperature
under positive argon pressure before use. All chemicals were used
as commercially available (Sigma–Aldrich, Acros, Alfa Aesar,
Combi-Blocks, Strem). Arenediazonium salts have been prepared
according to the literature procedure.[39] All reactions were con-
ducted with continuous magnetic stirring under an atmosphere of
argon in oven-dried glassware. Low-temperature experiments were
conducted using a Neslab Cryotrol CB-80 cryostat. Reactions were
monitored by TLC until deemed complete using silica gel-coated
glass plates (Merck Kieselgel 60 F254) and neutral alumina plates.
Plates were visualized under ultraviolet light (254 nm). Column
chromatography was performed using a CombiFlash Rf-200 (Tele-
dyne-Isco) automated flash chromatography system. 1H, 13C, 19F
NMR spectra were recorded at 300 and 500 (1H), and 75.5 and
125 MHz (13C), 282 MHz (19F) in CDCl3 solutions if not otherwise
specified. Chemical shifts (δ) are reported in parts per million
(ppm) from the residual solvent peak and coupling constants (J) in
Hz. Infrared measurements were carried out neat with a Bruker
Vector 22 FT-IR spectrometer fitted with a Specac diamond atten-
uated total reflectance (ATR) module. Specific optical rotations
were measured with a Rudolph Research Analytical Autopol IV
digital polarimeter using a 1 dm cell.
–62.9 ppm. IR: ν = 1043, 1146, 1252, 1381, 1498, 2871, 2964 cm–1.
˜
MS ESI: 503.1, calcd: 503.1312, HRMS found: 503.1311 [M + H]+.
1-((3aR,8aS)-3a-{[3,5-Bis(trifluoromethyl)phenyl]diazenyl}-5-meth-
oxy-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-1(2H)-yl)ethanone (7):
According to GP1, melatonin (200 mg, 0.862 mmol), cesium carb-
onate (1.4 g, 4.31 mmol, 5 equiv.), and molecular sieves (3 Å,
200 mg) in acetonitrile (8.6 mL) were treated with 3,5-bis(trifluoro-
methyl)benzenediazonium tetrafluoroborate (565 mg, 1.72 mmol,
2 equiv.) at –20 °C. The crude product was purified by column
chromatography to yield HPI 7 (215 mg, 55%) as a red oil. 1H NMR
(500 MHz): δ = 1.68 (s, 1 H), 2.11 (s, 3 H), 2.67–2.70 (m, 1 H), 3.52
(q, J = 2.5 Hz, 1 H), 3.78 (s, 3 H), 5.17 (s, 1 H), 6.16 (s, 1 H), 6.64
(d, J = 8.5 Hz, 1 H), 6.80 (dd, J = 2.5, 8.5 Hz, 1 H), 6.87 (d, J =
2.5 Hz, 1 H), 7.97 (s, 1 H), 8.18 (s, 2 H) ppm. 13C NMR (75 MHz):
δ = 22.4, 34.2, 46.8, 56.0, 78.5, 89.5, 111.0 (d, J = 22.5 Hz), 115.8,
122.4 (d, J = 3 Hz), 124.3 (d, J = 3 Hz), 126.7, 132.6 (q, J = 34.5 Hz),
144.2, 151.8, 153.7, 170.4 ppm. 19F NMR (282 MHz): δ =
–62.9 ppm. IR: ν = 1025, 1133, 1345, 1465, 2988, 3026 cm–1. MS
˜
ESI: 471.1, calcd: 471.1261, HRMS found: 471.1263 [M]–.
(3aR,8aS)-3a-(Phenyldiazenyl)-3,3a,8,8a-tetrahydro-2H-furo-
[2,3-b]indole (8): According to GP1, tryptophol (300 mg,
1.86 mmol), molecular sieves (3 Å, 250 mg), cesium carbonate (3 g,
9.31 mmol, 5 equiv.) in acetonitrile (18 mL) were treated with
benzenediazonium tetrafluoroborate (714 mg, 3.72 mmol, 2 equiv.)
at –20 °C. The crude product was purified by column chromatog-
raphy to yield HPI 8 (470 mg, 96 %) as a red oil. 1H NMR
(300 MHz): δ = 2.57 (dd, J = 4, 12.5 Hz, 1 H), 2.76–2.86 (m, 1 H),
3.90–3.99 (m, 1 H), 4.24 (t, J = 7 Hz, 1 H), 5.07 (d, J = 2 Hz, 1 H),
6.35 (d, J = 3 Hz, 1 H), 6.73 (d, J = 8 Hz, 1 H), 6.88 (t, J = 7 Hz,
1 H), 7.19–7.54 (m, 5 H), 7.81–7.85 (m, 2 H) ppm. 13C NMR
(75 MHz): δ = 38.6, 67.3, 91.5, 96.3, 109.3, 119.3, 122.6, 125.5, 128.5,
General Procedure 1 (GP1) for the Synthesis of Pyrroloindolines 3,
6–21: To
a solution of indole derivative 4, 5a–f (100 mg,
0.352 mmol, 1 equiv.), molecular sieves (3 Å, 50 mg), and cesium
carbonate (572 mg, 1.76 mmol, 5 equiv.) in the appropriate solvent
[CH3CN, CH2Cl2, or CH3CN/CH2Cl2 (1:1)] (4 mL) at –20, 0 or
23 °C was added diazonium salt (230 mg, 0.704 mmol, 2 equiv.).
The reaction was allowed to stir for 12 h then filtered through celite
and the solids were washed with dichloromethane (3ϫ 5 mL). After
concentrating under reduced pressure, the crude product was puri-
fied by column chromatography [hexanes/EtOAc, on neutral alu-
mina] to yield the desired product.
129.1, 129.9, 131.0, 150.5, 152.0 ppm. IR: ν = 1123, 1325, 1413,
˜
2998, 3036 cm–1. MS ESI: 266.1, calcd: 266.1288, HRMS found:
266.1285 [M + H]+.
1-[(3aR,8aS)-3a-(Phenyldiazenyl)-3,3a,8,8a-tetrahydropyrrolo-
[2,3-b]indol-1(2H)-yl]ethanone (3): According to GP1, N-{2-[1-(tert-
butyldimethylsilyl)-1H-indol-3-yl]ethyl}acetamide (4) (500 mg,
2.47 mmol), molecular sieves (3 Å, 600 mg), and cesium carbonate
(4.0 g, 12.37 mmol, 5 equiv.) in acetonitrile (25 mL) were treated
with benzenediazonium tetrafluoroborate (948 mg, 4.94 mmol,
2 equiv.) at –20 °C for 12 h. The crude product was purified by
(3aR,8aS)-Benzyl 3a-{[3,5-Bis(trifluoromethyl)phenyl]diazenyl}-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (9): Ac-
cording to GP1, benzyl [2-(1H-indol-3-yl)ethyl]carbamate (5d)
(300 mg, 1.02 mmol), cesium carbonate (1.66 g, 5.01 mmol, 5 equiv.),
molecular sieves (3 Å, 250 mg) in acetonitrile (10 mL) were treated
with 3,5-bis(trifluoromethyl)benzenediazonium tetrafluoroborate
(669 mg, 2.04 mmol, 2 equiv.) at –20 °C. The crude product was
purified by column chromatography to yield HPI 9 (340 mg, 88%)
1
column chromatography to yield 3 (701 mg, 93%) as a red oil. H
NMR (500 MHz): δ = 2.08 (s, 3 H), 3.44–3.50 (m, 2 H), 3.69–3.77
(m, 2 H), 6.19 (s, 1 H), 6.67 (d, J = 7.5 Hz, 1 H), 6.80 (dt, J = 1,
7.5 Hz, 1 H), 7.17 (dt, J = 1, 8 Hz, 1 H), 7.30 (dd, J = 1, 7.5 Hz,
1 H), 7.41–7.50 (m, 3 H), 7.70–7.73 (m, 2 H) ppm. 13C NMR
(125 MHz): δ = 22.4, 34.5, 46.9, 77.9, 88.4, 109.8, 119.0, 122.6,
124.9, 126.5, 128.3, 129.0, 130.1, 131.0, 150.1, 151.7, 170.8 ppm.
1
as an orange oil. H NMR (500 MHz, rotamers): δ = 2.60–2.69 (m,
2 H), 3.37–3.42 (m, 1 H), 3.88–3.99 (m, 1 H), 4.85 (br. s, 0.5 H),
5.16–5.32 (m, 2 H), 6.10 (s, 0.5 H), 6.14 (s, 0.5 H), 6.79 (dd, J = 7.5,
29 Hz, 2 H), 6.84 (t, J = 7.5 Hz, 1 H), 7.19–7.48 (m, 6 H), 7.97 (s,
1 H), 8.19 (s, 2 H) ppm. 13C NMR (125 MHz, rotamers): δ = 34.0,
34.7, 45.3, 45.6, 67.1, 67.4, 77.5, 78.1, 89.9, 91.0, 109.9, 110.1, 119.3,
119.6, 121.8, 122.5, 122.9, 124.0, 124.2, 125.0, 125.5, 125.6, 128.0,
128.0, 128.2, 128.2, 128.3, 128.4, 128.4, 128.5, 128.6, 128.7, 130.5,
IR: ν = 1128, 1282, 1361, 1415, 2893, 3026 cm–1. MS ESI: 307.2,
˜
calcd: 307.1553, HRMS found: 307.1554 [M + H]+.
(3aR,8aS)-1-Benzyl-3a-{[3,5-bis(trifluoromethyl)phenyl]diazenyl}-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2(1H)-one (6): According to
GP1, N-benzyl-2-(1H-indol-3-yl)acetamide (5b) (100 mg,
0.364 mmol), molecular sieves (3 Å, 50 mg), cesium carbonate
130.6, 132.5, 132.8, 136.3, 149.8, 150.1, 151.9, 154.1, 155.0 ppm. 19
NMR (282 MHz): δ = –62.9 ppm. IR: ν = 1144, 1183, 1280, 1369,
F
˜
3666
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3662–3670

Facile Generation of Pyrroloindoles from Tryptamines
1422, 1699, 2896, 3024 cm–1. MS ESI: 533.1, calcd: 533.1418,
HRMS found: 533.1951 [M]–.
column chromatography to yield 13 (160 mg, 95%) as an orange oil.
1H NMR (500 MHz, rotamers): δ = 1.52 (s, 4.5 H), 1.59 (s, 4.5 H),
2.55–2.68 (m, 2 H), 3.30–3.37 (m, 2 H), 3.75 (dt, J = 1, 8.5 Hz, 1
H), 3.88 (dt, J = 1, 8.5 Hz, 1 H), 4.84 (br. s, 1 H), 5.28 (br. s, 1 H),
6.08 (s, 1 H), 6.13 (s, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 6.82 (q, J =
8 Hz, 1 H), 7.19–7.44 (m, 4 H), 7.70–7.72 (m, 2 H) ppm. 13C NMR
(125 MHz, rotamers): δ = 28.5, 28.7, 34.1, 34.3, 45.2, 45.7, 78.5, 78.7,
80.1, 80.5, 89.9, 91.0, 109.7, 109.9, 118.0, 118.1, 119.0, 119.4, 124.4,
125.2, 125.2, 126.3, 126.4, 127.9, 127.9, 128.6, 130.1, 130.2, 131.8,
(3aR,8aS)-tert-Butyl 3a-[(2,4,5-Trifluorophenyl)diazenyl]-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (10): According to
GP1, tert-butyl [2-(1H-indol-3-yl)ethyl]carbamate (5a) (200 mg,
0.769 mmol), cesium carbonate (1.25 g, 3.84 mmol, 5 equiv.), and
molecular sieves (3 Å, 200 mg) in acetonitrile (7.7 mL) were treated
with 2,4,5-trifluorobenzenediazonium tetrafluoroborate (378 mg,
1.54 mmol, 2 equiv.) at –20 C. The crude product was purified by
131.8, 133.5, 133.5, 149.1, 149.9, 150.2, 153.7, 154.7 ppm. IR: ν =
˜
1
column chromatography to yield 10 (198 mg, 62%) as a red oil. H
1028, 1071, 1208, 1308, 1366, 1468, 1553, 1683, 2883, 2977,
3055 cm–1. MS ESI: 441.0, calcd: 441.0932, HRMS found:
440.0997 [M]–.
NMR (500 MHz): δ = 1.56 (s, 4.5 H), 1.63 (s, 4.5 H), 3.31–3.66 (m,
2 H), 3.76–3.90 (m, 2 H), 4.88 (br. s, 0.5 H), 5.31 (br. s, 0.5 H), 6.02–
6.10 (m, 2 H), 6.74–7.31 (m, 6 H) ppm. 13C NMR (125 MHz): δ =
14.2, 21.0, 28.5, 28.5, 28.7, 34.0, 34.3, 36.7, 45.3, 45.7, 60.5, 78.5,
78.6, 80.2, 80.5, 81.4, 89.2, 90.2, 101.7, 102.0, 103.9, 104.1, 104.2,
106.0, 106.2, 106.3, 106.4, 106.6, 109.8, 109.9, 111.1, 111.1, 111.1,
119.1, 119.5, 125.0, 125.1, 126.9, 126.9, 128.2, 128.3, 128.3, 128.6,
128.6, 128.9, 130.1, 130.2, 130.2, 132.0, 135.6, 135.7, 145.7, 145.8,
147.4, 147.5, 147.6, 147.7, 147.8, 149.4, 150.0, 150.00, 150.4, 150.4,
153.8, 154.8, 156.4, 158.4, 171.2 ppm. 19F NMR (282 MHz): δ =
(3aR,8aS)-tert-Butyl 3a-(Phenyldiazenyl)-3,3a,8,8a-tetrahydropyr-
rolo[2,3-b]indole-1(2H)-carboxylate (14): According to GP1, tert-
butyl [2-(1H-indol-3-yl)ethyl]carbamate (5a) (200 mg, 0.769 mmol),
cesium carbonate (1.25 g, 3.84 mmol, 5 equiv.), and molecular sieves
(3 Å, 200 mg) in acetonitrile (7.7 mL) was treated with benzenedia-
zonium tetrafluoroborate (295 mg, 1.54 mmol, 2 equiv.) at –20 °C.
The crude product was purified by column chromatography to yield
1
–126.1, –127.6, –137.6, –138.2, –139.8 ppm. IR: ν = 1159, 1207,
˜
14 (207 mg, 74%) as a red oil. H NMR (300 MHz, rotamers): δ =
1286, 1411, 1527, 1631, 2999, 3053 cm–1. MS ESI: 417.2, calcd:
417.2446, HRMS found: 417.1544 [M]–.
1.45–1.60 (m, 9 H), 2.56–2.69 (m, 3 H), 3.25–3.37 (m, 1 H), 3.70–
3.90 (m, 1 H), 5.99 (br. s, 1 H), 6.10 (s, 1 H), 6.71 (d, J = 8.5 Hz, 1
H), 6.76–6.83 (m, 1 H), 7.14–7.51 (m, 5 H), 7.68 (m, 1 H), 7.91 (d,
J = 8 Hz, 1 H) ppm. 13C NMR (125 MHz, rotamers): δ = 27.4, 28.5,
28.5, 28.7, 34.0, 34.4, 45.2, 45.6, 78.1, 80.1, 80.5, 88.5, 89.1, 90.1,
109.0, 109.8, 109.8, 109.9, 111.3, 119.3, 122.0, 122.1, 122.5, 122.6,
122.6, 122.7, 122.7, 122.8, 125.0, 125.0, 128.2, 128.9, 128.9, 129.0,
129.0, 129.1, 129.8, 130.0, 130.9, 131.2, 151.6, 151.7, 151.8, 153.7,
(3aR,8aS)-1-Benzyl-3a-(phenyldiazenyl)-3,3a,8,8a-tetrahydropyr-
rolo[2,3-b]indol-2(1H)-one (11): According to GP1, N-benzyl-2-(1H-
indol-3-yl)acetamide (5b) (1.0 g, 3.64 mmol), molecular sieves (3 Å,
300 mg), cesium carbonate (5.95 g, 18.20 mmol, 5 equiv.) in aceto-
nitrile (36 mL) were treated with benzenediazonium tetrafluoro-
borate (1.40 g, 7.28 mmol, 2 equiv.) at –20 °C. The crude product
was purified by column chromatography to yield 11 (1.18 g, 88%)
154.7 ppm. IR: ν = 1121, 1164, 1252, 1307, 1393, 1456, 1515, 1604,
˜
1695, 2890, 2978, 3061 cm–1. MS ESI: 363.1, calcd: 363.1826,
HRMS found: 363.1710 [M]–.
1
as a red oil. H NMR (500 MHz): δ = 3.23 (d, J = 17.5 Hz, 1 H),
3.47 (d, J = 17.5 Hz, 1 H), 4.38 (d, J = 15 Hz, 1 H), 5.10 (d, J =
15 Hz, 1 H), 5.81 (d, J = 4 Hz, 1 H), 6.78 (d, J = 8 Hz, 1 H), 6.95
(t, J = 8.5 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.34–7.50 (m, 9 H),
7.72–7.75 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3/[D6]DMSO):
δ = 39.4, 41.8, 76.7, 81.7, 109.8, 118.2, 120.2, 121.2, 123.8, 126.2,
(3aR,8aS)-tert-Butyl 3a-{[3,5-Bis(trifluoromethyl)phenyl]diazenyl}-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (15): Ac-
cording to GP1, tert-butyl [2-(1H-indol-3-yl)ethyl]carbamate (5a)
(200 mg, 0.769 mmol), cesium carbonate (1.25 g, 3.84 mmol,
5 equiv.), molecular sieves (3 Å, 200 mg) in acetonitrile (8 mL) were
treated with 3,5-bis(trifluoromethyl)benzenediazonium tetra-
fluoroborate (500 mg, 1.53 mmol, 2 equiv.) at –20 °C. The crude
product was purified by column chromatography to yield 15
(373 mg, 97%) as an orange oil. 1H NMR (500 MHz): δ = 1.52–1.62
(m, 18 H), 2.61–2.67 (m, 1 H), 2.72–2.75 (m, 2 H), 3.22–3.41 (m, 2
H), 3.78–4.00 (m, 3 H), 5.87 (br. s, 1 H), 6.11 (s, 1 H), 6.20 (s, 1 H),
7.73–7.98 (m, 4 H), 8.10–8.31 (m, 3 H) ppm. 13C NMR (125 MHz,
rotamers): δ = 28.3, 28.6, 34.2, 34.7, 45.0, 45.4, 77.9, 78.1, 80.9, 81.2,
82.3, 90.3, 108.9, 110.0, 118.0, 119.2, 119.5, 120.0, 121.4, 121.4,
121.8, 122.1, 122.4, 122.9, 123.0, 124.0, 124.0, 124.3, 124.4, 125.0,
125.1, 125.3, 125.7, 125.8, 126.1, 126.5, 126.9, 127.0, 129.8, 129.9,
130.4, 130.5, 130.6, 131.7, 133.5, 145.9, 146.1, 150.0, 150.3, 151.3,
151.6, 151.8, 152.0, 153.3, 153.3, 154.1, 154.5 ppm. 19F NMR
127.3, 127.7, 128.9, 130.0, 135.1, 148.5, 149.9, 169.4 ppm. IR: ν =
˜
1057, 1162, 1306, 1440, 2899, 3025 cm–1. MS ESI: 369.1, calcd:
369.1710, HRMS found: 369.1712 [M + H]+.
(3aR,8aS)-3a-(Phenyldiazenyl)-1-tosyl-1,2,3,3a,8,8a-hexahydropyr-
rolo[2,3-b]indole (12): According to GP1, N-[2-(1H-indol-3-yl)ethyl]-
4-methylbenzenesulfonamide6 (5c) (100 mg, 0.318 mmol), molecular
sieves (3 Å, 50 mg), cesium carbonate (516 mg, 1.59 mmol, 5 equiv.)
in acetonitrile (3 mL) were treated with benzenediazonium tetra-
fluoroborate (122 mg, 0.636 mmol, 2 equiv.) at –20 °C. The crude
product was purified by column chromatography to yield 12 (84 mg,
64%) as an orange oil. 1H NMR (300 MHz): δ = 2.41 (s, 3 H), 2.43–
2.56 (m, 1 H), 3.17–3.23 (m, 1 H), 3.40–3.54 (m, 1 H), 4.29–4.35 (m,
1 H), 5.06 (br. s, 1 H), 6.14 (s, 1 H), 6.73 (d, J = 8 Hz, 1 H), 6.83
(t, J = 7.5 Hz, 1 H), 7.07–7.51 (m, 9 H), 7.57–7.72 (m, 2 H), 7.82–
7.89 (m, 2 H) ppm. 13C NMR (75 MHz): δ = 21.5, 35.5, 47.2, 80.4,
90.5, 110.1, 119.4, 122.2, 124.7, 127.4, 128.4, 129.0, 129.8, 130.2,
(282 MHz): δ = –62.9 ppm. IR: ν = 1058, 1107, 1177, 1279, 1368,
˜
1481, 1610, 2938, 3031 cm–1. MS ESI: 499.1 [M]–, calcd: 522.1466,
HRMS found: 522.1474 [M + Na]+.
131.2, 135.6, 143.7, 149.5, 151.4 ppm. IR: ν = 1046, 1161, 1305,
˜
1401, 1439, 1598, 1610, 1702, 2973, 3063 cm–1. MS ESI: 417.0, calcd:
417.1391, HRMS found: 417.1429 [M]–.
(3aR,8aS)-tert-Butyl 3a-[(4-Methoxy-2-nitrophenyl)diazenyl]-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (16): Ac-
(3aR,8aS)-tert-Butyl 3a-[-(2-Bromophenyl)diazenyl]-3,3a,8,8a-tetra- cording to GP1, tert-butyl [2-(1H-indol-3-yl)ethyl]carbamate (5a)
hydropyrrolo[2,3-b]indole-1(2H)-carboxylate (13): According to GP1, (50 mg, 0.192 mmol), cesium carbonate (315 mg, 0.960 mmol,
tert-butyl [2-(1H-indol-3-yl)ethyl]carbamate (5a) (100 mg, 5 equiv.), and molecular sieves (3 Å, 100 mg) in acetonitrile (2 mL)
0.384 mmol), cesium carbonate (630 mg, 1.92 mmol, 5 equiv.), and were treated with 4-methoxy-2-nitrobenzenediazonium tetrafluoro-
molecular sieves (3 Å, 100 mg) in acetonitrile (4 mL) were treated
with 2-bromobenzenediazonium tetrafluoroborate (207 mg,
0.768 mmol, 2 equiv.) at –20 °C. The crude product was purified by 63%) as purple oil. H NMR (500 MHz, rotamers): δ = 1.49 (s, 4.5
borate (102 mg, 0.384 mmol, 2 equiv.) at –20 °C. The crude product
was purified by column chromatography to yield HPI 16 (53 mg,
1
Eur. J. Org. Chem. 2014, 3662–3670
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3667

D. E. Stephens, O. V. Larionov
FULL PAPER
H), 1.57 (s, 4.5 H), 2.45–2.64 (m, 2 H), 3.23–3.32 (m, 1 H), 3.71–
3.89 (m, 2 H), 3.91 (s, 3 H), 4.72–4.85 (br. s, 1 H), 5.22–5.26 (br. s,
1 H), 5.30 (d, J = 1.5 Hz, 1 H), 5.95 (s, 1 H), 6.01 (s, 1 H), 6.69 (d,
J = 7.5 Hz, 1 H), 6.78 (q, J = 8 Hz, 1 H), 7.08 (d, J = 9 Hz, 1 H),
7.15–7.40 (m, 4 H) ppm. 13C NMR (125 MHz, rotamers): δ = 14.1,
22.7, 28.4, 28.6, 33.6, 45.2, 45.2, 45.8, 56.2, 78.3, 78.8, 80.2, 80.5,
(2S,3R,8S)-1-tert-Butyl 2-Methyl 3a-[(4-Iodophenyl)diazenyl]-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate (20):
According to GP1, (S)-Boc-Trp-OMe (5f) (75 mg, 0.235 mmol), mo-
lecular sieves (3 Å, 100 mg), and cesium carbonate (381 mg,
1.17 mmol, 5 equiv.) in acetonitrile (2.5 mL) were treated with 4-
iodobenzenediazonium tetrafluoroborate (297 mg, 0.940 mmol,
89.7, 90.8, 108.3, 109.7, 109.8, 119.0, 119.1, 119.4, 119.8, 119.8, 4 equiv.) at 23 °C. The crude product was purified by column
125.1, 126.0, 128.3, 130.2, 130.2, 138.3, 138.4, 148.4, 149.9, 150.3,
chromatography to yield 20 (68 mg, 53%) as an orange oil. [α]2D3
=
153.6, 154.6, 161.2, 161.2 ppm. IR: ν = 1120, 1254, 1356, 1440, 2983, +35 (c = 0.6, CHCl3). 1H NMR (500 MHz, rotamers): δ = 1.43–1.58
˜
3044 cm–1. MS ESI: 438.0, calcd: 438.1783, HRMS found:
438.1678 [M]–.
(m, 9 H), 2.76–3.02 (m, 2 H), 3.67 (s, 3 H), 4.31–4.38 (m, 1 H), 5.45
(br. s, 1 H), 6.22 (s, 1 H), 6.71–6.80 (m, 1 H), 7.08–7.45 (m, 3 H),
7.70 (dd, J = 3, 9 Hz, 2 H), 7.80 (dd, J = 3, 9 Hz, 2 H) ppm. 13C
NMR (125 MHz, rotamers): δ = 28.2, 37.4, 37.8, 52.1, 59.3, 80.1,
81.2, 87.8, 97.9, 110.0, 110.2, 119.2, 119.8, 124.2, 124.3, 124.3, 124.5,
124.5, 126.7, 128.4, 128.5, 128.5, 130.2, 138.3, 138.3, 139.3, 149.5,
{(3aR,8aS)-3a-[3,5-Bis(trifluoromethyl)phenyl]diazenyl}-5-chloro-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-1(2H)-yl(phenyl)methanone
(17): According to GP1, N-[2-(5-Chloro-1H-indol-3-yl)ethyl]benza-
mide (5e) (30 mg, 0.105 mmol), cesium carbonate (171 mg,
0.528 mmol, 5 equiv.), and molecular sieves (3 Å, 50 mg) in aceto-
nitrile (1 mL) were treated with 3,5-bis(trifluoromethyl)benzenedi-
azonium tetrafluoroborate (68 mg, 0.210 mmol, 2 equiv.) at –20 °C.
The crude product was purified by column chromatography to yield
150.8, 154.1, 172.7 ppm. IR: ν = 1212, 1299, 1448, 1515, 2931, 2999,
˜
3042 cm–1. MS ESI: 546.0, calcd: 547.0848, HRMS found:
547.3660 [M]–.
(2S,3aR,8aS)-1-tert-Butyl 2-Methyl 3a-Phenyldiazenyl-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate (21): According
to GP1, (S)-Boc-Trp-OMe (5f) (1.28 g, 3.14 mmol), molecular sieves
(3 Å, 1.2 g), and cesium carbonate (5.10 g, 15.7 mmol, 5 equiv.) in
acetonitrile (31 mL) was treated with benzenediazonium tetrafluoro-
borate (1.93 g, 10.0 mmol, 3.2 equiv.) at –20 °C. The crude product
was purified by column chromatography to yield 21 (1.28 g, 96%)
1
17 (38 mg, 88%) as a yellow oil. H NMR (500 MHz): δ = 1.27 (s,
1 H), 1.65–1.70 (br. s, 1 H), 2.63 (q, J = 5 Hz, 1 H), 3.61 (q, J =
10 Hz, 1 H), 3.82 (q, J = 5 Hz, 1 H), 5.45 (s, 1 H), 6.48 (s, 1 H),
6.66 (d, J = 8 Hz, 1 H), 7.19 (d, J = 8 Hz, 1 H), 7.27 (s, 1 H), 7.40–
7.54 (m, 5 H), 7.99 (s, 1 H), 8.21 (s, 1 H) ppm. 13C NMR (125 MHz):
δ = 35.0, 48.6, 78.2, 89.0, 110.8, 121.8, 123.0 (d, J = 3 Hz), 123.9 (d,
J = 25 Hz) 124.4, 125.3, 126.9, 127.1, 128.3, 128.4, 130.6, 132.8 (q,
J = 34 Hz), 135.4, 149.0, 151.7, 170.2 ppm. 19F NMR (282 MHz): δ
1
as a red oil. H NMR (300 MHz, rotamers): δ = 1.42 (s, 9 H), 1.56
(s, 3 H), 2.74–3.05 (m, 2 H), 4.30–4.40 (m, 1 H), 5.45 (br. s, 1 H),
6.23 (s, 1 H), 6.70–6.79 (m, 2 H), 7.11–7.70 (m, 4 H) ppm. 13C NMR
(125 MHz): δ = 28.3, 37.9, 52.2, 59.4, 78.9, 80.2, 81.1, 87.7, 110.2,
119.2, 122.6, 122.6, 124.6, 127.0, 128.4, 129.0, 130.2, 131.1, 149.6,
= –62.9 ppm. IR: ν = 1088, 1107, 1177, 1369, 1448, 1577, 1624,
˜
2924, 2995, 3088, 3326 cm–1. MS ESI: 527.1, calcd: 537.0922,
HRMS found: 537.0901 [M]–.
151.6, 154.1, 172.7 ppm. IR: ν = 1013, 1146, 1215, 1345, 2890, 2993,
˜
(3aR,8aS)-3a-{[3,5-Bis(trifluoromethyl)phenyl]diazenyl}-3,3a,8,8a-
tetrahydro-2H-furo[2,3-b]indol-2-one (18): Indole-3-acetic acid
(200 mg, 1.14 mmol), cesium carbonate (1.85 g, 5.70 mmol, 5 equiv.),
and molecular sieves (3 Å, 200 mg) in acetonitrile (11 mL) and
dichloromethane (11 mL) were treated with 3,5-bis(trifluoromethyl)-
benzenediazonium tetrafluoroborate (747 mg, 2.28 mmol, 2 equiv.)
at 23 °C. The crude product was purified by column chromatography
3026 cm–1. MS ESI: 421.2, calcd: 421.1881, HRMS found:
421.1880 [M]–.
(3R,8S)-3a-Phenyl-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indole (22):[40]
Diazene 8 (80 mg, 0.300 mmol) in tert-butanol (5 mL) was irradiated
with UV light using low-pressure Hg lamp in a quartz photoreactor
for 12 h. The crude product was purified by column chromatography
1
to yield 18 (380 mg, 84%) as an orange oil. H NMR (500 MHz): δ
1
to yield 22 (30 mg, 42%) as an orange oil. H NMR (500 MHz): δ
= 3.38 (d, J = 19 Hz, 1 H), 3.72 (d, J = 19 Hz, 1 H), 7.41–7.58 (m,
2 H), 7.74–8.24 (m, 4 H), 8.46 (s, 2 H) ppm. 13C NMR (75 MHz): δ
= 29.7, 37.6, 83.1, 117.6, 119.2, 120.9, 121.0, 121.4, 121.9, 123.1,
123.6, 124.5, 125.3, 125.8, 127.2 132.0, 132.3, 132.8, 133.3, 133.8,
149.9, 151.0, 152.1, 171.6 ppm. 19F NMR (282 MHz): δ =
= 2.57 (dd, J = 4.5, 12 Hz, 1 H), 2.80 (dd, J = 7.5, 11 Hz, 1 H), 3.73
(dd, J = 7.5, 11 Hz, 1 H), 4.17–4.33 (m, 1 H), 4.68 (br. s, 1 H), 5.67
(s, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 6.80 (d, J = 7 Hz, 1 H), 7.07 (d,
J = 7 Hz, 1 H), 7.14 (t, J = 8 Hz, 1 H), 7.30–7.40 (m, 5 H) ppm.
13C NMR (125 MHz): δ = 40.5, 62.3, 68.3, 100.5, 108.7, 119.3, 124.6,
–63.1 ppm. IR: ν = 1092, 1135, 1263, 1369, 1442, 1516, 2801, 2963,
˜
126.1, 126.7, 128.4, 128.7, 132.7, 144.0, 149.4 ppm. IR: ν = 1033,
˜
3033 cm–1. MS ESI: 546.9, calcd: 546.9732, HRMS found:
546.9678 [M + Cs]+.
1282, 1384, 2845, 2975, 3051 cm–1.
(2S,3R,8S)-1-tert-Butyl 2-Methyl 3a-Phenyl-3,3a,8,8a-tetrahydropyr-
rolo[2,3-b]indole-1,2(2H)-dicarboxylate (23): Diazene 21 (118 mg,
0.279 mmol) in tert-butanol (5 mL) was irradiated with UV light
using low-pressure Hg lamp in a quartz photoreactor for 12 h. The
crude product was purified by column chromatography [hexanes/
(2S,3R,8S)-1-tert-Butyl 2-Methyl 3a-(Naphthalen-1-yldiazenyl)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate (19):
According to GP1, (S)-Boc-Trp-OMe (5f) (75 mg, 0.235 mmol),
cesium carbonate (381 mg, 1.17 mmol, 5 equiv.), molecular sieves
(3 Å, 100 mg), in acetonitrile (2.5 mL) was treated with naphthalene-
1-diazonium tetrafluoroborate (227 mg, 0.940 mmol, 4 equiv.) at
23 °C. The crude product was purified by column chromatography
to yield 19 (83 mg, 75%) as a red oil. [α]D23 = +111 (c = 1.35, CHCl3).
1H NMR (500 MHz, rotamers): δ = 1.46 (s, 9 H), 1.59 (s, 3 H), 2.80–
3.36 (m, 4 H), 3.63 (s, 3 H), 5.51 (s, 1 H), 6.36 (s, 1 H), 6.74–6.81
(m, 2 H), 7.13–7.96 (m, 8 H), 8.66–8.69 (m, 1 H) ppm. 13C NMR
(125 MHz, rotamers): δ = 28.2, 28.6, 29.7, 37.5, 38.0, 52.2, 52.4, 59.6,
59.6, 80.3, 81.2, 88.5, 109.7, 110.2, 112.4, 119.2, 120.8, 123.1, 124.6,
125.5, 125.8, 126.3, 126.5, 126.9, 127.0, 127.9, 128.3, 128.5, 130.2,
1
EtOAc/silica gel] to yield 23 (45 mg, 41%) as brown oil. H NMR
(500 MHz): δ = 1.41–1.47 (m, 9 H), 1.54–1.60 (m, 3 H), 2.71–3.05
(m, 4 H), 3.21 (s, 1 H), 3.75 (s, 3 H), 5.53 (br. s, 1 H), 5.65 (s, 1 H),
6.68–6.83 (m, 2 H), 6.99–7.79 (m, 7 H) ppm. 13C NMR (125 MHz,
rotamers): δ = 33.5, 33.6, 45.1, 45.5, 67.1, 67.3, 76.6, 78.0, 110.1,
110.2, 112.2, 119.4, 119.5, 123.6, 123.9, 126.7, 127.8, 128.0, 128.1,
128.3, 128.3, 128.3, 128.5, 128.7, 130.4, 132.2, 136.2, 149.9, 150.1,
150.7, 150.9, 154.1, 155.1 ppm. IR: ν = 1156, 1228, 1369, 1480, 1695,
˜
2726, 2877, 2983, 3050 cm–1. MS ESI: 395.8 [M + H]+, calcd:
393.1820, HRMS found: 393.1660 [M]–.
131.4, 134.1, 146.6, 149.6, 154.1, 172.7 ppm. IR: ν = 1144, 1165,
˜
1257, 1317, 1456, 1506, 1694, 2950, 2974, 3050 cm–1. MS ESI:
473.9 [M + H]+, calcd: 471.2038, HRMS found: 471.1363 [M]–.
General Procedure 2 (GP2) for the Synthesis of Hydrazines 24–28:
To a solution of diazene in EtOH was added hydrazine hydrate and
3668
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3662–3670

Facile Generation of Pyrroloindoles from Tryptamines
the reaction mixture was heated at 50 °C for 3–12 h. The solution
was then concentrated under reduced pressure and purified by col-
NMR(125 MHz): δ = 21.5, 25.5, 29.7, 34.8, 43.0, 47.1, 78.1, 80.4,
102.7, 103.0, 103.5, 103.7, 105.2, 105.4, 105.6, 109.2, 110.1, 110.3,
umn chromatography [hexanes/EtOAc/silica gel] to yield the desired 111.3, 111.6, 118.5, 119.5, 122.3, 122.6, 123.3, 126.6, 127.0, 127.2,
product.
128.3, 129.6, 129.9, 130.5, 135.2, 144.0, 149.9 ppm. IR: ν = 1094,
˜
1159, 1216, 1305, 1325, 1458, 1529, 2875, 3041 cm–1.
1-[(3aR,8aS)-3a-(2-Phenylhydrazinyl)-3,3a,8,8a-tetrahydropyrrolo-
[2,3-b]indol-1(2H)-yl]ethanone (24): According to GP2, 3 (200 mg,
0.653 mmol) and hydrazine hydrate (1 mL) in EtOH (5 mL) were
heated to 50 °C. The product was isolated after 12 h by concentrat-
ing under reduced pressure to yield 24 (199 mg, 99%) as a yellow
(3aR,8aS)-tert-Butyl 3a-[2-(2-Bromophenyl)hydrazinyl]-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (28): According to
GP2, diazene 13 (100 mg, 0.226 mmol) was treated with hydrazine
hydrate (500 μL) in EtOH (5 mL) at 50 °C for 4 h. The product was
1
1
oil. H NMR (500 MHz, rotamers): δ = 2.35 (s, 3 H), 3.28–3.45 (m,
azeotroped to yield hydrazine 28 (99 mg, 99%) as a yellow oil. H
4 H), 3.75 (br. s, 1 H), 4.93 (br. s, 1 H), 5.31 (s, 1 H), 5.71 (br. s, 1
H), 6.72 (d, J = 8 Hz, 1 H), 6.88 (d, J = 7.5 Hz, 1 H), 7.12–7.83 (m,
7 H) ppm. 13C NMR (125 MHz, rotamers): δ = 21.5, 34.6, 47.1,
78.3, 80.1, 106.7, 110.4, 119.4, 119.4, 119.4, 122.2, 123.5, 124.9,
125.7, 126.4, 126.8, 127.2, 127.3, 127.4, 128.3, 128.7, 129.7, 129.8,
NMR (500 MHz, rotamers): δ = 1.46–1.51 (m, 9 H), 2.18–2.44 (m,
4 H), 3.08–3.17 (m, 2 H), 3.62 (dt, J = 2, 8.5 Hz, 1 H), 3.75 (dt, J
= 2, 8.5 Hz, 1 H), 3.89 (br. s, 1 H), 3.94 (br. s, 1 H), 4.66 (s, 1 H),
5.18 (br. s), 5.23 (s, 1 H), 5.30 (s, 1 H), 5.72 (s, 1 H), 5.76 (s, 1 H),
6.64 (dt, J = 1, 8 Hz, 2 H), 6.67 (s, 1 H), 6.69 (s, 1 H), 6.81–6.86 (m,
2 H), 7.12 (q, J = 7.5 Hz, 3 H), 7.30–7.37 (m, 5 H) ppm. 13C NMR
(125 MHz, rotamers): δ = 14.8, 17.9, 25.1, 25.1, 28.4, 28.6, 33.0, 33.4,
45.1, 45.4, 76.5, 77.6, 78.2, 80.0, 80.4, 107.2, 110.1, 110.2, 114.4,
114.5, 119.0, 119.3, 119.6, 119.6, 123.5, 123.8, 127.4, 127.6, 128.2,
128.3, 130.1, 132.1, 146.3, 146.4, 149.9, 150.2, 153.7, 154.7,
130.3, 134.0, 135.1, 143.5, 144.0, 150.0 ppm. IR: ν = 1014, 1174,
˜
1315, 1396, 1555, 2875, 3053 cm–1. MS ESI: 305.1, calcd: 305.1408,
HRMS found: 305.1372 [M]–.
(3aR,8aS)-Benzyl 3a-{2-[3,5-Bis(trifluoromethyl)phenyl]hydrazinyl}-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (25): Ac-
cording to GP2, diazene 9 (63 mg, 0.117 mmol) was treated with
hydrazine hydrate (37 μL, 1.17 mmol, 10 equiv.) in EtOH (1 mL) at
50 °C. After 8 h, the solvent was removed under reduced pressure to
yield 25 (63 mg, 99%) as a yellow oil. 1H NMR (500 MHz): δ =
2.31–2.38 (m, 2 H), 3.17–3.22 (m, 1 H), 3.75–3.84 (m, 1 H), 4.02 (s,
1 H), 5.08–5.30 (m, 2 H), 5.37 (s, 1 H), 5.56 (br. s, 1 H), 5.77 (s, 1
H), 6.58–6.65 (m, 2 H), 6.80–6.83 (m, 1 H), 7.16–7.37 (m, 9 H) ppm.
13C NMR (125 MHz): δ = 33.4, 44.6, 45.1, 45.5, 67.1, 67.3, 76.6,
77.6, 78.0, 110.1, 110.2, 112.0, 112.0, 112.0, 112.0, 112.2, 119.4,
119.5, 122.4, 123.6, 123.9, 124.6, 126.4, 126.7, 127.8, 128.0, 128.1,
128.3, 128.3, 128.4, 128.5, 128.7, 130.4, 131.9, 132.2, 136.2, 136.3,
149.9, 150.1, 150.7, 150.9, 154.1, 155.1 ppm. 19F NMR (282 MHz):
159.7 ppm. IR: ν = 1166, 1237, 1322, 1408, 1646, 2863, 2927, 3045,
˜
3293 cm–1. MS ESI: 441.1, calcd: 443.1088, HRMS found:
441.1171 [M]–.
General Procedure 3 for Kinetic Experiments (GP3): To a solution of
5a (50 mg, 0.192 mmol, 1 equiv.), cesium carbonate (312 mg,
0.961 mmol, 5 equiv.), and molecular sieves in acetonitrile (3 Å,
2 mL) at 23 °C was added arenediazonium salt (0.192 mmol,
1 equiv.) in one portion. An aliquot was drawn at 2 min., concen-
trated under reduced pressure, and conversion of 5a was determined
by 1H NMR spectroscopy. Each experiment was repeated in quadru-
plet, and the average was used for the Hammett plot.
Supporting Information (see footnote on the first page of this article):
δ = –62.7 ppm. IR: ν = 1047, 1130, 1266, 1278, 1357, 1457, 1621,
˜
1
Copies of H and 13C NMR spectra of key compounds.
2889, 3038 cm–1. MS ESI: 535.1, calcd: 535.1574, HRMS found:
535.1205 [M]–.
Acknowledgments
(3aR,8aS)-tert-Butyl 3a-[2-(2,4,5-Trifluorophenyl)hydrazinyl]-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (26): Ac-
cording to GP2, 10 (90 mg, 0.217 mmol) and hydrazine hydrate
(500 μL) in EtOH (3 mL) was heated to 50 °C. The product was
isolated after 12 h by concentrating under reduced pressure to yield
The authors thank the Welch Foundation (AX-1788), the Max and
Minnie Tomerlin Voelcker Fund and the University of Texas at San
Antonio for financial support. Mass spectroscopic analysis was sup-
ported by a grant from the National Institute on Minority Health
and Health Disparities (G12MD00751).
1
26 (89 mg, 98%) as a yellow oil. H NMR (500 MHz, rotamers): δ
= 1.41–2.26 (m, 9 H), 3.05–3.26 (m, 4 H), 3.58–3.79 (m, 4 H), 3.94
(br. s, 1 H), 4.00 (br. s, 1 H), 4.71 (br. s, 1 H), 5.21–5.51 (m, 2 H),
6.53–7.41 (m, 5 H) ppm. 13C NMR (125 MHz, rotamers): δ = 17.8,
25.0, 28.4, 33.3, 45.3, 78.0, 80.1, 80.5, 102.8–105.4, 110.0, 110.1,
110.4 (d, J = 6 Hz), 110.5 (d, J = 6 Hz), 111.2 (d, J = 3 Hz), 111.4
(d, J = 3 Hz), 113.7, 116.0–116.3 (m), 117.9–118.2 (m), 119.0, 119.3,
123.8 (d, J = 16 Hz), 126.2, 127.1 (d, J = 16 Hz), 128.3, 130.2, 135.6–
135.9 (m), 144.6, 145.7–148.0, 149.9, 150.3, 153.6, 154.7, 159.7 ppm.
19F NMR (282 MHz): δ = –147.2, –141.9, –139.3, –138.4, –136.3,
[1] a) L. M. Repka, S. E. Reisman, J. Org. Chem. 2013, 78, 12314–
12320; b) P. Ruiz-Sanchis, S. A. Savina, F. Albericio, M. Álvarez,
Chem. Eur. J. 2011, 17, 1388–1408; c) M. Somei, F. Yamada,
Nat. Prod. Rep. 2004, 21, 278–311; d) S. Peddibhotla, Curr.
Bioact. Compd. 2009, 5, 20–38; e) S. Hibino, T. Choshi, Nat.
Prod. Rep. 2002, 19, 148–180.
[2] Y. Yang, X. Jiang, F.-L. Qing, J. Org. Chem. 2012, 77, 7538–
7547.
–130.0 ppm. IR: ν = 1094, 1159, 1216, 1305, 1325, 1458, 1529, 2875,
˜
[3] a) S. P. Marsden, K. M. Depew, S. J. Danishefsky, J. Am. Chem.
Soc. 1994, 116, 11143–11144; b) K. M. Depew, S. P. Marsden,
D. Zatorska, A. Zatorski, W. G. Bornmann, S. J. Danishefsky, J.
Am. Chem. Soc. 1999, 121, 11953–11963; c) Q. Wei, Y.-Y. Wang,
Y.-L. Du, L.-Z. Gong, Beilstein J. Org. Chem. 2013, 9, 1559–
1564; d) D. Crich, X. Huang, J. Org. Chem. 1999, 64, 7218–
7223.
[4] a) N. Shibata, T. Tarui, Y. Doi, K. L. Kirk, Angew. Chem. Int.
Ed. 2001, 40, 4461–4463; Angew. Chem. 2001, 113, 4593; b) O.
Lozano, G. Blessley, T. Martinez del Campo, A. L. Thompson,
G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V. Gouvern-
eur, Angew. Chem. Int. Ed. 2011, 50, 8105–8109; Angew. Chem.
2011, 123, 8255; c) Q. Wei, Y.-Y. Wang, Y.-L. Du, L.-Z. Gong,
3041 cm–1. MS ESI: 420.1, calcd: 420.1773, HRMS found:
420.1558 [M]–.
(3aR,8aS)-3a-(2-Phenylhydrazinyl)-1-tosyl-1,2,3,3a,8,8a-hexahydro-
pyrrolo[2,3-b]indole (27): According to GP2, 12 (110 mg,
0.263 mmol) was treated with hydrazine hydrate (500 μL) in EtOH
(5 mL) at 50 °C for 12 h. The crude product was purified by column
1
chromatography to yield 27 (84 mg, 76%) as a yellow oil. H NMR
(500 MHz): δ = 2.07–2.22 (m, 2 H), 2.44 (s, 3 H), 2.94 (t, J = 6.5 Hz,
1 H), 3.26–3.49 (m, 3 H), 3.84 (br. s, 1 H), 4.91 (br. s, 1 H), 5.24 (s,
1 H), 5.26 (br. s, 1 H), 5.39 (s, 1 H), 5.24 (s, 1 H), 5.26 (br. s, 1
H), 5.39 (s, 1 H), 6.70–7.09 (m, 7 H), 7.19–7.34 (m, 4 H) ppm. 13C
Eur. J. Org. Chem. 2014, 3662–3670
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3669

D. E. Stephens, O. V. Larionov
FULL PAPER
Beilstein J. Org. Chem. 2013, 9, 1559–1564; d) D. Crich, X. Hu-
ang, J. Org. Chem. 1999, 64, 7218–7223.
[5] a) M. Taniguchi, A. Gonsho, M. Nakagawa, T. Hino, Chem.
Pharm. Bull. 1983, 31, 1856–1865; b) D. Tu, L. Ma, X. Tong,
X. Deng, C. Xia, Org. Lett. 2012, 14, 4830–4833; c) J. A.
González-Vera, M. T. García-López, R. Herranz, J. Org. Chem.
2007, 72, 5395–5398.
[6] P. Ventosa-Andrés, J. A. González-Vera, Á. M. Valdivielso,
M. T. García-López, R. Herranz, Bioorg. Med. Chem. 2008, 16,
9313–9322.
[7] D. Kajiyama, T. Saitoh, S. Yamaguchi, S. Nishiyama, Synthesis
2012, 44, 1667–1671.
[8] a) P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc.
2003, 125, 5628–5629; b) H. Tian, L. Ermolenko, M. Gabant,
C. Vergne, C. Moriou, P. Retailleau, A. Al-Mourabit, Adv.
Synth. Catal. 2011, 353, 1525–1533; c) H. Droste, T. Wieland,
Liebigs Ann. Chem. 1987, 11, 901–910.
[9] a) T. M. Kamenecka, S. J. Danishefsky, Angew. Chem. Int. Ed.
1998, 37, 2995–2998; Angew. Chem. 1998, 110, 3166; b) D.
Schwaebisch, K. Tchabanenko, R. M. Adlington, A. M. Cowley,
J. E. Baldwin, Chem. Commun. 2004, 22, 2552–2553; c) O. R.
Suarez-Castillo, M. Sanchez-Zavala, M. Melendez-Rodriguez,
L. E. Castelan-Duarte, M. S. Morales-Rios, P. Joseph-Nathan,
Tetrahedron 2006, 62, 3040–3051.
[21]
a) A. S. Sigeev, I. P. Beletskaya, P. V. Petrovskii, A. S. Peregudov,
Russ. J. Org. Chem. 2012, 48, 1055–1058; b) J. Zhang, X. Wang,
H. Yu, J. Ye, Synlett 2012, 23, 1394–1396.
B. Haag, Z. Peng, P. Knochel, Org. Lett. 2009, 11, 4270–4273.
R. Larouche-Gauthier, T. G. Elford, V. K. Aggarwal, J. Am.
Chem. Soc. 2011, 133, 16794–16797.
W. Wu, G. Xu, C. Li, G. Yu, Y. Liu, C. Ye, J. Qin, Z. Li, Chem.
Eur. J. 2013, 19, 6874–6888.
J. Gavrilyuk, H. Ban, M. Nagano, W. Hakamata, C. F.
[22]
[23]
[24]
[25]
[26]
Barbas III, Bioconjugate Chem. 2012, 23, 2321–2328.
a) H. Mayr, M. Hartnagel, K. Grimm, Liebigs Ann. Recueil
1997, 55–69; b) H. Mayr, K. Grimm, J. Org. Chem. 1992, 57,
1057–1059.
a) S. P. Lathrop, M. Movassaghi, Chem. Sci. 2014, 5, 333–340;
b) M. Movassaghi, O. K. Ahmad, S. P. Lathrop, J. Am. Chem.
Soc. 2011, 133, 13002–13005.
For further recent examples of assembly of the hexahydropyr-
rolo[2,3-b]indole core with an all-carbon C3-stereocenter, see: a)
M. Movassaghi, M. A. Schmidt, Angew. Chem. Int. Ed. 2007,
46, 3725–3728; Angew. Chem. 2007, 119, 3799; b) L. Shen, M.
Zhang, Y. Wu, Y. Qin, Angew. Chem. Int. Ed. 2008, 47, 3618–
3621; Angew. Chem. 2008, 120, 3674; c) W. Zi, W. Xie, D. Ma,
J. Am. Chem. Soc. 2012, 134, 9126–9129; d) L. Furst, J. M. R.
Narayanam, C. R. J. Stephenson, Angew. Chem. Int. Ed. 2011,
50, 9655–9659; Angew. Chem. 2011, 123, 9829; e) Y. Sun, R. Li,
W. Zhang, A. Li, Angew. Chem. Int. Ed. 2013, 52, 9201–9204;
Angew. Chem. 2013, 125, 9371.
a) S. P. Govek, L. E. Overman, Tetrahedron 2007, 63, 8499–8513;
b) S. P. Govek, L. E. Overman, J. Am. Chem. Soc. 2001, 123,
9468–9469; c) M. Varoglu, T. H. Corbett, F. A. Valeriote, P.
Crews, J. Org. Chem. 1997, 62, 7078–7079.
a) R. Raju, A. M. Piggott, M. Conte, W. G. L. Aalbersberg, K.
Feussner, R. J. Capon, Org. Lett. 2009, 11, 3862–3865; b) S. Tad-
ano, Y. Mukaeda, H. Ishikawa, Angew. Chem. Int. Ed. 2013, 52,
7990–7994; Angew. Chem. 2013, 125, 8148; c) M. E. Kieffer,
K. V. Chuang, S. E. Reisman, J. Am. Chem. Soc. 2013, 135,
5557–5560; d) J. Kim, M. Movassaghi, J. Am. Chem. Soc. 2011,
133, 14940–14943.
[27]
[28]
[10] M. Nakagawa, T. Kaneko, H. Yamaguchi, T. Kawashima, T.
Hino, Tetrahedron 1974, 30, 2591–2600.
[11] a) T. Newhouse, P. S. Baran, J. Am. Chem. Soc. 2008, 130,
10886–10887; b) T. Newhouse, C. A. Lewis, P. S. Baran, J. Am.
Chem. Soc. 2009, 131, 6360–6361; c) T. Newhouse, C. A. Lewis,
K. J. Eastman, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 7119–
7137; d) K. Foo, T. Newhouse, I. Mori, T. Hiromitsu, P. S. Ba-
ran, Angew. Chem. Int. Ed. 2011, 50, 2716–2719; Angew. Chem.
2011, 123, 2768.
[12] Z.-J. Cai, S.-Y. Wang, S.-J. Ji, Org. Lett. 2013, 15, 5226–5229.
[13] a) P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5,
1999–2001; b) Z. Zhang, J. C. Antilla, Angew. Chem. Int. Ed.
2012, 51, 11778–11782; Angew. Chem. 2012, 124, 11948.
[14] a) V. R. Espejo, J. D. Rainier, J. Am. Chem. Soc. 2008, 130,
12894–12895; b) V. R. Espejo, X.-B. Li, J. D. Rainier, J. Am.
Chem. Soc. 2010, 132, 8282–8284; c) I. Villanueva-Margalef,
D. E. Thurston, G. Zinzalla, Org. Biomol. Chem. 2010, 8, 5294–
5303; d) V. R. Espejo, J. D. Rainier, Org. Lett. 2010, 12, 2154–
2157.
[15] S. Beaumont, V. Pons, P. Retailleau, R. H. Dodd, P. Dauban,
Angew. Chem. Int. Ed. 2010, 49, 1634–1637; Angew. Chem. 2010,
122, 1678.
[16] T. Hayashi, W. Peng, Y.-Y. Nakai, K. Yamada, M. Somei, Het-
erocycles 2002, 57, 421–424.
[17] a) M. Ikeda, K. Ohno, M. Katsura, M.-W. Chun, Y. Tamura, J.
Chem. Soc. Perkin Trans. 1 1979, 12, 3061–3063; b) M. Ikeda,
F. Tabusa, Y. Nishimura, S. Kwon, Y. Tamura, Tetrahedron Lett.
1976, 27, 2347–2350.
[29]
[30]
[31] G. Ding, L. Jiang, L. Guo, X. Chen, H. Zhang, Y. Che, J. Nat.
Prod. 2008, 71, 1861–1865.
[32] a) T. S. Gardner, E. Wenis, J. Lee, J. Med. Chem. 1960, 2, 133;
b) N. Yamada, S. Takahashi, K. G. Todd, G. B. Baker, P. R. Pa-
etsch, J. Pharm. Sci. 1993, 82, 934–937.
[33] G. S. Timmins, V. Deretic, Mol. Microbiol. 2006, 62, 1220–1227.
[34] G. M. Housey, Housey Pharmaceuticals, Inc., USA,
WO2005115992A1.
[35] M. Somei, A. Tanimoto, H. Orita, F. Yamada, T. Ohta, Synth.
Commun. 2001, 31, 425–432.
[36] H. A. Albar, A. S. Shavali’, M. A. Abdallah, Can. J. Chem. 1993,
71, 2144–2149.
[18] a) E. W. Werner, T.-S. Mei, A. J. Burckle, M. S. Sigman, Science
2012, 338, 1455–1458; b) D. A. Barancelli, A. G. Salles, J. G.
Taylor, C. R. D. Correia, Org. Lett. 2012, 14, 6036–6039; c) C.
Soldi, A. V. Moro, M. G. Pizzolatti, C. R. D. Correia, Eur. J.
Org. Chem. 2012, 19, 3607–3616.
[19] D. Kalyani, K. B. McMurtrey, S. R. Neufeldt, M. S. Sanford, J.
Am. Chem. Soc. 2011, 133, 18566–18569.
[20] a) H. Jiang, C. Huang, J. Guo, C. Zeng, Y. Zhang, S. Yu, Chem.
Eur. J. 2012, 18, 15158–15166; b) M. Hartmann, Y. Li, A.
Studer, J. Am. Chem. Soc. 2012, 134, 16516–16519.
[37] A. H. Jackson, P. P. Lynch, J. Chem. Soc. Perkin Trans. 2 1987,
12, 1483–148.
[38] C. Silva López, C. Pérez-Balado, P. Rodríguez-Graña, Á. R.
de Lera, Org. Lett. 2008, 10, 77–80.
[39] L. Li, X.-L. Zhou, Hecheng Huaxue 2007, 15, 503–505.
[40] S. Zhu, D. W. C. MacMillan, J. Am. Chem. Soc. 2012, 134,
10815–10818.
Received: February 16, 2014
Published Online: April 17, 2014
3670
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3662–3670