Exploration of the interrupted Fischer indolization reaction

Article abstract of DOI:10.1016/j.tet.2010.02.050

A convergent method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization sequence. The method is convergent, mild, operationally simple, broad in scope, and can be used to access enantioenriched products. In addition, our approach is amenable to the synthesis of furoindoline and pyrrolidinoindoline natural products as demonstrated by the concise formal total syntheses of physovenine and debromoflustramine B. The strategy will likely enable the synthesis of more complex targets such as the communesin alkaloids.

Full text of DOI:10.1016/j.tet.2010.02.050

Tetrahedron 66 (2010) 4687–4695
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploration of the interrupted Fischer indolization reaction
*
Alex W. Schammel, Ben W. Boal, Liansuo Zu, Tehetena Mesganaw, Neil K. Garg
University of California, Los Angeles, Department of Chemistry and Biochemistry, Los Angeles, CA 90095, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 January 2010
Received in revised form 10 February 2010
Accepted 10 February 2010
Available online 13 February 2010
A convergent method to access the fused indoline ring system present in a multitude of bioactive
molecules has been developed. The strategy involves the condensation of hydrazines with latent alde-
hydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization
sequence. The method is convergent, mild, operationally simple, broad in scope, and can be used to
access enantioenriched products. In addition, our approach is amenable to the synthesis of furoindoline
and pyrrolidinoindoline natural products as demonstrated by the concise formal total syntheses of
physovenine and debromoflustramine B. The strategy will likely enable the synthesis of more complex
targets such as the communesin alkaloids.
This manuscript is dedicated to Professor
Brian M. Stoltz on the occasion of his receipt
of the Tetrahedron Young Investigator
Award
Published by Elsevier Ltd.
Keywords:
Indoline
Natural products
Fischer indole synthesis
Total synthesis
Heterocycles
1. Introduction
The importance of indoline-containing compounds has
prompted the development of a number of methods to access such
The discovery of efficient methods to synthesize complex bio-
active molecules continues to be a vital area of research.1 A subset
of compounds that have received substantial interest due to their
medicinal properties and impressive structures are those that
possess a fused indoline motif, of the type 1 (Fig. 1 and Scheme 1).
The simplest of these compounds are the acetylcholinesterase in-
hibitors physovenine (2) and physostigmine (3),2,3 which are
composed of basic furo- and pyrrolidinoindoline motifs, re-
spectively (Fig. 1). Numerous relatives of pyrrolidinoindoline 3 have
been isolated, including bis(prenylated) derivatives,4 dimeric
structures,5 and compounds possessing a heteroatom substituent
at C3 (e.g., 4–7, respectively).6,7 Beyond these compounds, a variety
of more architecturally complex indoline containing natural prod-
ucts are known, such as the akuammiline alkaloids (e.g., 8–11),8,9
perophoramidine (12),10 the communesins (e.g., 13),11 diazo-
namide A (14),12 and bipleiophylline (15).13 Many of these mole-
cules possess interesting biological properties, which further
enhance their appeal as targets for total synthesis.
motifs, with numerous studies particularly in the area of pyrroli-
dinoindoline synthesis. In most cases, the fused indoline ring sys-
tems 1 are constructed by cyclization of precursors of the type 16,
which in turn are derived from substituted indole14 or oxindole15
intermediates (Scheme 1). Herein, we report the development of
a powerful cascade reaction that allows direct access to 1 (via 16)
from the coupling of two simple fragments.16 The transformation is
convergent, broad in scope, proceeds under mild reaction condi-
tions, and can be used to synthesize a variety of natural product
scaffolds.
Our approach to the indoline scaffold 1 of compounds 2–15 is
inspired by the classic Fischer indole synthesis,17,18 and is pre-
sented in Scheme 2. We envisioned that an arylhydrazine 17 and
an
a-disubstituted aldehyde 18 would react in the presence of
acid to afford enamine intermediate 19. Subsequent [3,3]-
sigmatropic rearrangement and re-aromatization would pro-
vide aniline 20, which in turn would cyclize with loss of NH3 to
furnish transient indolenine 16. Intramolecular attack by a prox-
imal heteroatom substituent (X¼NR or O) would deliver the
desired product 1. This interrupted Fischer indolization process
would allow for the formation of three new bonds, two hetero-
cyclic rings, and two stereogenic centers, one of which is qua-
ternary (C3).
* Corresponding author. Tel.: þ1 310 825 1536; fax: þ1 310 206 1843; e-mail
address: neilgarg@chem.ucla.edu (N.K. Garg).
0040-4020/$ – see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.02.050

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A.W. Schammel et al. / Tetrahedron 66 (2010) 4687–4695
NHMe
Me
H
N
Me
N
H
R''
H
n
N
O
Me
X
3
X
NMe
O
N
N
Me
H
N
H
H
N
H
X
R'
NMe
X = O, physovenine (2)
1
X = NMe, physostigmine (3)
N
H
H
N
Me
N
H
n = 1,2
X = NR, O
H
N
X = Br, flustramine B (4)
meso-
X = H, debromoflustramine B (5)
chimonanthine (6)
MeHN
OHC
Cl
Me
psychotrimine (7)
N
O
Me
N
N
N
Me
Me
H
H
Me
OH
Me
CO2Me
N
HN
N
N
H
Me
CO2Me
OH
CO2Me
MeO2C
OH
H
H
H
N
N
MeO
aspidophylline A (8)
minfiensine (9)
echitamine chloride (10)
vincorine (11)
O
O
Me
HN
Me
O
Me
N
OH
Me
HO
Me
N
Me
Cl
N
N
H
N
N
H
O
O
O
Br
N
Cl
O
N
O
Cl
N
H
O
N
NH
NH
N
H
MeO2C
NH
N
Me
H
H
Me
Cl
O
H
communesin B (13)
perophoramidine (12)
diazonamide A (14)
bipleiophylline (15)
Figure 1. Parent indoline 1 and representative natural products 2–15.
Common
R''
R''
R''
n
n
n
Approach
n = 1,2
R''
R''
indoles or
oxindoles
n
n
XH
X = NR, O
X
XH
X
O
H
3
HO
O
X
18
21
22
A + B
N
H
N
H
H
R'
R'
(fragment
coupling)
Our
Scheme 3. Lactols and hemiaminals as latent aldehydes.
1
16
Approach
Scheme 1. Approach to indoline 1.
Only scattered examples of the interrupted Fischer indolization
process have been reported over the past fifty years.23–25 Most
notable are the seminal studies by Grandberg summarized in
Figure 2.23 In 1967, C2 substituted pyrrolidinoindoline 25 was
prepared by reacting phenylhydrazine (23) and 5-chloro-3-meth-
ylpentan-2-one (24).23a However, this method is not applicable to
the synthesis of furoindolines, or to the more complex ring systems
encountered in numerous natural products. It was later demon-
strated that furoindolines could be accessed by the acid-promoted
R''
n
R''
XH
n
+
1
NH2
XH
N
H
R'
O
H
N
H
R'
17
18
16
n = 1,2
X = NR, O
reaction of phenylhydrazines with a
-disubstituted lactones.23b For
XH
H
XH
H
example, reaction of hydrazine 26 and lactone 27 in HCl/iPrOH
afforded furoindoline 28 in 22% yield. This method bears limita-
tions, such as the modest yields of products, the use of strongly
acidic conditions, and the constraint to furoindoline ring systems.
n
n
R''
R''
NH
NH2
NH
N
H
R'
R'
Me
19
20
O
BuOH
t
+
2
Cl
NH
Me
Scheme 2. Proposed fragment coupling/cyclization cascade to access indoline 1.
NH2
Me
N
H
MeOH, heat
(70% yield)
N
H
Me
A key feature of our approach to 1 is the ready availability of
starting materials 17 and 18. The arylhydrazine coupling partners
17 could be easily prepared or accessed from commercial sources.19
23
24
25
Me
OHC
Me
Although the required a-branched aldehyde fragments 18 would
HCl (conc.)
iPrOH
O
+
not be obtainable commercially, isomeric lactols and hemiaminals
21 could likely serve as suitable aldehyde surrogates in the desired
transformation (Scheme 3).20,21 In turn, lactols and hemiaminals 21
could be accessed by reduction of readily available lactones or
lactams 22.22
NH2
N
Me
O
N
Me
H
O
(22% yield)
26
27
28
Figure 2. Grandberg’s syntheses of pyrrolidinoindoline 25 and furoindoline 28.

A.W. Schammel et al. / Tetrahedron 66 (2010) 4687–4695
4689
Despite these laudable efforts, and those of others,24,25 a general
Table 2
Variation of the hydrazine N-substituent
and mild method to access 1 using the interrupted Fischer indoli-
zation strategy outlined in Scheme 2 has remained elusive. More-
over, with the exception of our studies,16 the notion that such
a method could be used to prepare the indoline scaffold present in
a multitude of complex biologically important compounds has not
been realized.
Entrya
Hydrazine
Product
Me
Yieldc (%)
O
1
89
70
59
60
<5
<5
NH2
N
H
N
H
H
Me
2. Results and discussion
2b
O
NH2
N
Me
2.1. Synthesis of furoindolines
N
Me
H
The feasibility of the proposed cascade reaction sequence of
Scheme 2 was established in the context of furoindoline synthesis.
Thus, the reaction between commercially available phenyl-
hydrazine (23) and latent aldehyde 29 (1 equiv) was carried out
under a variety of acidic conditions (Table 1). Lewis acids were
examined and found to be ineffective (entries 1 and 2). However,
use of p-toluenesulfonic acid, trifluoroacetic acid, or HCl each
afforded the desired product 30 in modest yield (entries 3–5).
Sulfuric acid-mediated reaction conditions were also explored, and
ultimately provided the desired product in 87% yield (entry 6).
Recognizing that a milder acid source would be more generally
useful, acetic acid was examined. Although the use of glacial acetic
acid afforded modest product yields (entry 7), employment of a 1:1
mixture of acetic acid and water at 60 ꢀC furnished indoline 30 in
89% isolated yield (entry 8).26
Me
O
3
NH2
N
Bn
N
Bn
H
Me
O
NH2
4
N
N
H
Me
O
5
NH2
N
Ac
N
Ac
H
Me
O
6
NH2
N
Boc
Table 1
N
Boc
H
Survey of acids to promote furoindoline formation
a
Conditions unless otherwise noted: lactol 29 (1 equiv), 1:1 AcOH/H2O, 60 ꢀC.
Me
b
c
Me
AcOH as solvent.
Isolated yield.
O
+
NH2
N
H
O
N
H
H
HO
The scope of the lactol component for furoindoline synthesis
23
29
30
was examined in the interrupted Fischer indolization process
(Table 4). Allyl and phenyl substituents were tolerated, thus pro-
viding fused indolines with alternate C3 substitution (entries 1 and
2). It should be noted, however, that substrates bearing either a tert-
butyl or a methyl ester substituent led only to trace amounts of
product formation (entries 3 and 4). Nonetheless, a six-membered
homolog of the furoindoline framework was accessible using this
methodology using our standard reaction conditions (entry 5).
Entry
Acid source
Conditions
Yielda (%)
1
2
3
4
5
6
7
8
PCl3
Benzene, 60 ꢀ
C
<5
<5
51
64
70
87
52
89b
ZnCl2
TsOH
TFA
5% HCl
4% H2SO4
AcOH
AcOH
EtOH, 100 ꢀ
C
EtOH, H2O, 60 ꢀ
C
CH3CN, 60 ꢀ
CH3CN, 60 ꢀ
CH3CN, 60 ꢀ
C
C
C
AcOH, 60 ꢀC
1:1 AcOH/H2O, 60 ꢀ
C
2.2. Synthesis of pyrrolidinoindolines
Unless otherwise noted, yields determined by 1H NMR analysis.
Isolated yield.
a
b
Having established the viability of the interrupted Fischer
indolization approach for the synthesis of furoindolines, we sought
to develop the corresponding transformation that would enable the
synthesis of pyrrolidinoindolines and related derivatives. Thus,
hemiaminal 31 was prepared from the corresponding lactam fol-
lowing a known procedure, and then subjected to phenylhydrazine
(23) in the presence of 1:1 H2O/AcOH (Scheme 4). To our delight,
the interrupted Fischer indolization reaction proceeded smoothly
at 100 ꢀC and delivered the desired indoline 32 in 88% yield.
Analogous to our studies in the area of furoindoline synthesis,
the interrupted Fischer indolization reaction was found to be an
effective means to access a range of pyrrolidinoindolines. As shown
in Table 5, a variety of arylhydrazines were tolerated in the trans-
formation. Reactions of N-substituted arylhydrazines furnished the
desired indoline products in good yield (entries 1–3), whereas
a range of arylhydrazines bearing benzenoid substitution were
deemed competent coupling partners (entries 4–9). Similar to the
results obtained in our furoindoline studies, use of p-(tri-
fluoromethyl)phenylhydrazine as a substrate led to low yields of
product (entry 10).
As shown in Table 2, a number of arylhydrazines bearing N-
substitution were examined in the interrupted Fischer indolization
reaction. In addition to parent arylhydrazine 23 (entry 1), N-
methyl,27 N-benzyl, and N-allyl substituted hydrazines were
deemed competent coupling partners (entries 2–4). Interestingly,
the use of N-acetyl and N-Boc phenylhydrazines (entries 5 and 6)
led predominantly to the recovery of unreacted starting
materials.28,29
Substitution on the aryl ring of the hydrazine component was
also investigated (Table 3). It was found that para, meta, and ortho
substituents were tolerated under the reaction conditions (entries
1–6). Importantly, use of chlorohydrazines furnished haloindolines
(entries 4 and 5), which could be further functionalized by transi-
tion metal-catalyzed cross-coupling chemistry. The transformation
proceeded smoothly with p-methoxyphenylhydrazine as a sub-
strate, thus affording C5-oxygenated products in good yields (entry 6).
However, use of p-(trifluoromethyl)phenylhydrazine as a substrate
led to low yields of product (entry 7).

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A.W. Schammel et al. / Tetrahedron 66 (2010) 4687–4695
Table 3
Table 4
Variation of the hydrazine aryl substituents
Variation of the lactol component
Entrya
Hydrazine
Product
Yieldb (%)
60
Entrya
Lactol
Product
Yieldb (%)
Me
Me
Me
Cl
Me
O
1
3
NH2
1
89
O
N
H
N
H
H
O
HO
N
H
H
Me
O
N
H
H
Me
2
75
3
+
O
Me
2
75 (4:3)
Me
NH2
O
N
H
H
HO
N
H
O
N
H
H
t-Bu
t-Bu
3
O
3
4
<5
<5
Me
O
N
H
H
HO
O
NH2
3
4
5
62
67
60
N
H
N
H
H
MeO2C
Me
MeO2C
Me
3
O
Me
O
N
H
H
HO
Cl
O
NH2
N
H
N
H
H
Me
Me
HO
Me
5
65
O
O
N
H
H
O
NH2
N
H
a
N
H
H
Conditions: hydrazine 23 (1 equiv), 1:1 AcOH/H2O, 60 ꢀC.
Isolated yield.
Cl
b
Cl
Me
6
7
X¼OMe; 75
X¼CF3; <5
X
5
X
Me
O
Me
NH2
H2O, AcOH
N
H
NTs
+
N
H
H
NH2
N
H
100 °C
N
Ts
N
H
H
HO
a
Conditions: lactol 29 (1 equiv), 1:1 AcOH/H2O, 60 ꢀC.
Isolated yield.
(88% yield)
b
23
31
32
Scheme 4. Synthesis of pyrrolidinoindoline 32.
The scope of the hemiaminal component was also investigated
(Table 6). C3-allylated and -phenylated pyrrolidinoindolines could
be accessed without difficulty (entries 1 and 2). Of note, these
pyrrolidinoindoline motifs are present in an array of medicinally
important compounds, such as debromoflustramine B (5, Fig. 1)4a
and the hodgkinsine alkaloids.30 Furthermore, a six-membered
homolog was prepared in 81% yield (entry 3) reminiscent of the
communesin and perophoramidine core structures. Finally, it was
determined that a carbamylated hemiaminal could be employed in
place of a sulfonamide (entry 4).
As shown in Figure 3, the N-substituents of our pyrrolidi-
noindoline products can easily be manipulated. The sulfonamide
group of 33 was removed upon treatment with Mg and NH4Cl in
MeOH31 to provide pyrrolidinoindoline 34 in 79% yield.32 Addi-
tionally, carbamate 35 was converted to the corresponding N-
methylated product 36 when reacted with Red-Al. The latter of
these results is particularly notable given that many pyrrolidi-
noindoline natural products possess this N-methylated substitution
pattern (e.g., Fig. 1, 3–7).
newly discovered transformation has been utilized to achieve
a concise formal total synthesis of the furoindoline natural product
physovenine (2).33 Reaction of hydrazine 3734 with lactol 29 in
AcOH furnished furoindoline 38 in 77% yield, which has previously
been converted to physovenine (2) in two additional steps.15a Al-
though asymmetric routes to intermediate 38 have previously been
reported, our single step route to (ꢁ)-38 is substantially shorter
(one step compared to 7,15a or 1833g steps). Furthermore phys-
ovenine (2) can be optically resolved, on preparative scale, using
column chromatography with cellulose triacetate.33o
The interrupted Fischer indolization reaction could also be used
to complete a formal total synthesis of the pyrrolidinoindoline
natural product debromoflustramine B (5).35 Pyrrolidinone 3936
was elaborated to hemiaminal 40 using a standard two-step se-
quence. Treatment of 40 with 1-allyl-1-phenylhydrazine in H2O/
AcOH at 100 ꢀC facilitated the key condensation/sigmatropic rear-
rangement to deliver bis(allylated)pyrrolidinoindoline 41. In turn,
41 was reacted with 2-methyl-2-butene in the presence of Grubbs’
second generation catalyst to afford bis(prenylated) derivative 42,37
which was converted to 5 by reduction with Red-Al (Scheme 6).
Finally, we explored the scope and limitations of our method-
ology in the context of the communesin natural products (Scheme
7).38 Known sulfonamide 4339 was reacted with 1-ethoxypropene
in the presence of Cs2CO3 to afford hetero-Diels–Alder product 44,
following the general procedure described by Corey.39 Exposure of
44 to N-methylphenylhydrazine (26) in 1:1 AcOH/H2O delivered
2.3. Formal total syntheses of physovenine and
debromoflustramine B, and assembly of the communesin
indoline scaffold
Having developed a powerful means to synthesize fused indo-
line ring systems, we examined the scope and limitations of our
methodology in more complex settings. As shown in Scheme 5, the

A.W. Schammel et al. / Tetrahedron 66 (2010) 4687–4695
4691
Table 5
Table 6
Variation of the hydrazine component
Variation of the hemiaminal component
Entrya
Hydrazine
Product
Yieldd (%)
81
Entrya
Hemiaminal
Product
Yieldb (%)
Me
1b
NTs
NH2
3
1
68
70
N
Me
NTs
N
Me
H
N
HO
Ts
N
H
H
Me
NTs
2
83
NH2
N
Bn
N
Bn
H
2
3
3
NTs
Me
N
Ts
HO
N
H
H
NTs
NH2
3
4
70
71
N
N
H
Me
Me
81
88
NTs
Me
Me
Me
Cl
N
Ts
HO
Me
N
H
H
NTs
NH2
N
H
N
H
H
Me
Me
NCO2Me
4
Me
N
HO
N
H
H
CO2Me
NTs
a
Conditions: hydrazine 23 (1 equiv), 1:1 AcOH/H2O, 100 ꢀC.
Isolated yield.
N
H
H
Me
b
+
Me
5
55 (4:3)
Me
NH2
N
H
Me
Me
NTs
Mg, NH4Cl
MeOH, 23 °C
(79% yield)
N
H
H
NH
NTs
N
Me
H
N
Me
H
Me
34
33
NTs
NH2
6
7
8
73
77
84
N
H
N
H
H
Me
Me
Me
Me
Red-Al
NMe
N
Me
CO2Me
toluene, 110 °C
N
H
H
Cl
N
H
H
NTs
(92% yield)
NH2
N
H
36
35
N
H
H
Figure 3. Manipulation of the N-substituent.
Me
NTs
NH2
Me
MeO
N
H
Me
MeO
N
H
H
AcOH
O
Cl
+
Cl
NH2
100 °C
N
Me
O
N
Me
H
HO
9c
10
X¼OMe; 70
X¼CF3; <5
Me
X
(77% yield)
X
37
29
38
NTs
NH2
N
H
N
H
H
Me
H
N
O
2 steps
ref 15a
a
Me
O
Conditions unless otherwise noted: hemiaminal 31 (1 equiv), 1:1 AcOH/H2O,
100 ꢀC.
O
N
Me
H
b
23 ꢀC, AcOH as solvent.
75 ꢀC.
c
physovenine (2)
d
Isolated yield.
Scheme 5. Formal total synthesis of physovenine (2).
indoline 45, which possesses the tetracyclic 6,5,6,6-ring system of
the communesin alkaloids.40 As noted earlier, the previously de-
scribed [3,3]-sigmatropic rearrangement strategies for the syn-
thesis of fused indoline ring systems are not amenable to this
complex scaffold.
achieve this goal would involve asymmetric catalysis. Thus, efforts
were put forth to carry out the interrupted Fischer indolization
reaction in the presence of chiral non-racemic phosphoric acids.41
As shown in Scheme 8, this asymmetric transformation proved
challenging. Despite an extensive survey of reaction conditions
(e.g., variations in substrates, phosphoric acid promoter, stoichi-
ometry, solvent, and temperature), only modest levels of enantio-
selectivity could be obtained. For example, reaction of hydrazine 23
and lactol 29 in the presence of 1.2 equiv of phosphoric acid 46
(prepared from (R)-BINOL)42 in benzene at 40 ꢀC provided furo-
indoline 30 in 62% yield and 28% ee.43 Similar results were obtained
when hemiaminal substrates were employed in place of lactols.
2.4. Access to enantioenriched indoline products
Having demonstrated that the interrupted Fischer indolization
reaction provides an effective means to access indoline scaffolds,
we hoped to uncover a variant that would give access to enan-
tioenriched indoline products. The most appealing scenario to

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A.W. Schammel et al. / Tetrahedron 66 (2010) 4687–4695
NH2
1. NaH, THF, 0 °C
then ClCO2Me
NH2
N
Pd(OAc)2, BINAP
NH
Me
NaOt-Bu
2.
i-Bu2AlH
CH2Cl2, –78 °C
+
N
H
N
Me
O
HO
CO2Me AcOH, H2O
100 °C
toluene, 80 °C
(97% yield)
Br
39
40
(54% yield, 2 steps)
(86% yield)
47
(–)-48
49
NH2
N
NCO2Me
NCO2Me
1. NaNO2, HCl(aq), 0
2. LiAlH4, Et2O, 40 °C
23 °C
Grubbs II
Me
N
H
N
H
CH2Cl2, 23 °C
(83% yield)
(81% yield, 2 steps)
41
42
50
Scheme 9. Synthesis of arylhydrazine 50.
debromo-
flustramine B
(5)
Red-Al
NMe
The utility of arylhydrazine 50 in our interrupted Fischer indo-
lization process was evaluated in the context of furoindoline syn-
thesis (Fig. 4). Gratifyingly, the reaction of 50 and lactol 29
proceeded smoothly under a variety of acidic conditions. When the
reaction was carried out in the presence of 3 equiv of chloroacetic
acid in benzene at 40 ꢀC, an 80% yield of diastereomeric indoline
products 51 and 52 was obtained (dr¼2.4:1).47 The isomers were
easily separable using conventional flash column chromatography
on silica gel. The major isomer 51 was treated with Pd(OH)2 and 1,4-
cyclohexadiene in EtOH to remove the auxiliary and deliver opti-
cally enriched indoline 30.48,49 The ee of 30 was found to be 97%,22
thus demonstrating that our methodology can be utilized to access
enantioenriched products. The absolute configuration of 30 was
determined based on correlation to known data,33c and was found
to be as depicted in Figure 4.
toluene, 80 °C
(70% yield)
N
H
Scheme 6. Formal total synthesis of debromoflustramine B (5).
Me
Cl
TsHN
EtO
Me
EtO
N
Cs2CO3
Ts
CH2Cl2, –78 °C
43
44
(70% yield)
26
Me
NH2
N
Me
Me
Me
N
Ts
AcOH, H2O
80 °C
29
N
Me
H
ClAcOH
(3 equiv)
NH2
O
O
+
N
(70% yield)
45
N
H
N
H
40 °C
Me
Scheme 7. Synthesis of communesin indoline scaffold 45.
benzene
Me
Me
(80% yield
d.r. = 2.4:1)
50
51
52
Me
+
Me
NH2
CF3
Me
N
H
O
Pd(OH)2
HO
O
1,4-cyclohexadiene
O
97% ee
N
H
23
29
EtOH, 80 °C
N
H
H
CF3
Me
46 (1.2 equiv)
(80% yield)
O
P
O
O
benzene, 40 °C
(+)-30
51
OH
Me
CF3
Figure 4. Synthesis of enantioenriched 30.
O
N
H
H
3. Conclusions
46
CF3
30
In summary, we have developed an efficient method to access
the fused indoline ring systems present in a variety of natural
products. Our interrupted Fischer indolization strategy involves the
condensation of readily available hydrazines with latent aldehydes
to deliver indoline-containing products by way of a tandem [3,3]-
sigmatropic rearrangement/cyclization cascade sequence. The
method is convergent, mild, operationally simple, broad in scope,
and can be used to access enantioenriched products. In addition,
our approach is amenable to the synthesis of furoindoline and
pyrrolidinoindoline natural products as demonstrated by the con-
cise formal total syntheses of physovenine and debromoflustr-
amine B. We expect that the interrupted Fischer indolization
strategy will enable the synthesis of more complex targets such as
(62% yield, 28% ee)
Scheme 8. Furoindoline synthesis using phosphoric acid promoter 46.
Given the difficulty in achieving a reagent or catalyst-controlled
asymmetric interrupted Fischer indolization, we turned to an
auxiliary-based approach.44 Thus, Nishida’s enantioenriched arylhy-
drazine 50 was prepared using the sequence shown in Scheme 9.25e,45,46
Bromobenzene (47) was coupled with commercially available
enantioenriched amine (ꢂ)-48 under Pd catalysis to provide aniline
49. Using a standard protocol, aniline 49 was converted to the tar-
geted hydrazine 50 in 81% yield over two steps.

A.W. Schammel et al. / Tetrahedron 66 (2010) 4687–4695
4693
the communesins and akuammiline alkaloids. Such studies in the
realm of natural product synthesis are currently underway in our
laboratory.
chromatography, under the same conditions. The stereochemical
configurations of 51 and 52 were inferred after the conversion of 51
to (þ)-30. Indoline 51: Rf 0.5 (4:1 hexanes/EtOAc); 1H NMR
(500 MHz, CDCl3):
d
8.23 (d, J¼8.0, 1H), 7.96 (d, J¼7.5, 1H), 7.82 (t,
4. Experimental
J¼8.0, 2H), 7.60 (t, J¼7.0, 1H), 7.56 (t, J¼7.5, 1H), 7.49 (t, J¼8.0, 1H),
7.11 (d, J¼7.5, 1H), 6.91 (t, J¼7.5, 1H), 6.03 (d, J¼7.5, 1H), 5.65 (s, 1H),
5.56 (q, J¼7.0, 1H), 4.03 (t, J¼8.0, 1H), 3.70–3.75 (m, 1H), 2.28 (dd,
J¼11.5, 4.5, 1H), 1.86 (d, J¼6.5, 3H), 1.58 (s, 3H); 13C NMR (125 MHz,
4.1. Representative experimental procedure for furoindoline
synthesis (Table 2, entry 1)
CDCl3):
d 149.1, 139.4, 134.5, 133.9, 130.8, 129.1, 127.8, 127.5, 125.9,
Lactol 29 (126 mg, 1.22 mmol) was dissolved in a 1:1 mixture of
acetic acid and water (6 mL). Phenylhydrazine (23) (0.121 mL,
1.23 mmol) was added to the resulting mixture. The reaction was
heated to 60 ꢀC for 4.5 h, then cooled to 23 ꢀC, and quenched with
a solution of satd aq NaHCO3 (15 mL). The resulting mixture was
extracted with EtOAc (3ꢃ15 mL). The combined organic layers were
dried over MgSO4. Evaporation of the solvent under reduced
pressure afforded the crude product. Purification by flash chro-
matography (7:1 hexanes/EtOAc) afforded indoline 30 (196 mg, 89%
125.8, 125.2, 123.6, 122.5, 122.4, 117.3, 106.0, 101.4, 66.7, 52.3, 51.7,
41.9, 25.8, 19.0; IR (neat): 3046, 2963, 2852, 1606, 1594, 1487, 1459,
1395, 1298, 1236, 1013 cmꢂ1; HRMS-ESI (m/z): [MþNa]þ calcd for
24.4
C23H23NONa, 352.1677; found, 352.1686; [
a
]
D
þ125.4 (c 1.0,
CHCl3). Indoline 52: Rf 0.5 (4:1 hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3):
d
7.95 (d, J¼8.5, 1H), 7.90 (d, J¼8.0, 1H), 7.84 (d, J¼8.5, 1H),
7.74 (d, J¼7.5, 1H), 7.45–7.54 (m, 3H), 7.14 (t, J¼8.0, 1H), 7.10 (d,
J¼7.0, 1H), 6.75 (d, J¼7.0, 1H), 6.51 (d, J¼7.5, 1H), 5.52 (q, J¼7.0, 1H),
4.69 (s, 1H), 3.93 (t, J¼7.5, 1H), 3.53 (ddd, J¼13.0, 8.5, 4.5, 1H), 2.18
(dd, J¼12.0, 4.5, 1H), 1.98 (ddd, J¼11.5, 11.5, 7.0, 1H), 1.90 (d, J¼6.5,
yield). Rf 0.7 (1:1 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3):
d 7.08
(d, J¼7.2, 1H), 7.05 (t, J¼7.5, 1H), 6.76 (t, J¼7.5, 1H), 6.59 (d, J¼7.8,
1H), 5.28 (s,1H), 3.96 (ddd, J¼8.4, 7.2, 1.8, 1H), 3.56 (ddd, J¼10.8, 8.4,
5.1, 1H), 2.13 (ddd, J¼11.7, 5.4, 1.5, 1H), 2.07 (ddd, J¼11.7, 7.2, 4.2, 1H),
3H), 1.24 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 148.8, 136.3, 134.7,
133.8, 131.7, 128.7, 128.1, 128.0, 126.2, 125.5, 125.4, 124.2, 123.2,
122.7, 117.3, 105.0, 101.0, 67.0, 52.2, 49.3, 41.2, 24.7, 18.1; IR (film):
1.47 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
148.8, 133.9, 127.9, 122.9,
3681, 2973, 2845, 1605, 1487, 1215, 1059 cmꢂ1; HRMS-ESI (m/z):
24.2
118.8, 108.8, 99.5, 67.3, 53.8, 41.4, 24.7; IR (film): 2967, 2845, 1611,
[MþNa]þ calcd for C23H23NONa, 352.1677; found, 352.1680; [
ꢂ54.6 (c 1.0, CHCl3).
a]
D
1486, 1265, 1055 cmꢂ1
C11H14NO, 176.1075; found, 176.1078.
;
HRMS-ESI (m/z): [MþH]þ calcd for
4.4. Synthesis of indoline (D)-30
4.2. Representative experimental procedure for
pyrrolidinoindoline synthesis (Table 6, entry 1)
A
mixture of indoline 51 (32.9 mg, 0.1 mmol), 1,4-cyclo-
hexadiene (80.0 mg, 1.0 mmol), and palladium hydroxide (20% wt
on carbon, 10.0 mg) in ethanol (1 mL) was heated at 80 ꢀC for 6 h.
The reaction mixture was cooled to 23 ꢀC, filtered through Celite,
washed with CH2Cl2 (10 mL), and the solvent was removed under
reduced pressure. Purification by flash chromatography (5:1 hex-
3-Allyl-1-tosylpyrrolidin-2-ol22 (105 mg, 0.37 mmol) was dis-
solved in a 1:1 mixture of acetic acid and water (1.8 mL). Phenyl-
hydrazine 23 (0.036 mL, 0.36 mmol) was added to the resulting
mixture. The reaction was heated to 100 ꢀC for 1 h 40 min, cooled to
23 ꢀC, and then diluted with Et2O (20 mL). The reaction mixture
was then quenched with satd aq NaHCO3 (20 mL), and the layers
were separated. The aqueous layer was extracted with Et2O
(3ꢃ20 mL). The combined organic layers were washed with brine
(20 mL), dried over MgSO4, and concentrated in vacuo to afford the
crude indoline product. Purification by flash chromatography
(18:1:1 benzene/Et2O/CH2Cl2) afforded the 3-allyl-indoline (Table
6, entry 1) as a yellow oil (88.0 mg, 68% yield). Rf 0.6 (8:1:1 ben-
anes/EtOAc) furnished furoindoline (þ)-30 (14.0 mg, 80% yield, 97%
24.3
ee). [
a
]
þ124.5 (c 1.0, CHCl3), SFC (CHIRALPAK AS-H, CO2/
D
MeOH¼9/10, flow 1.5 mL/min, at 23 ꢀC, detection at 254 nm) tR
3.06 min (major) and tR 4.43 min (minor). The absolute configura-
tion of 30 was determined based on correlation to known data.33c
Acknowledgements
zene/Et2O/CH2Cl2); 1H NMR (500 MHz, CDCl3):
d
7.75 (d, J¼8.0, 2H),
The authors are grateful to the NIH-NIGMS (R00 GM079922),
the University of California, Los Angeles and Boehringer Ingelheim
for financial support. We also thank Materia Inc. for the donation of
chemicals, the Garcia–Garibay laboratory (UCLA) for the generous
access to instrumentation, Dr. John Greaves (UC Irvine) for mass
spectra, and Professors Ken Houk (UCLA), Patrick Harran (UCLA),
and Jon Antilla (University of South Florida) for fruitful discussions.
7.32 (d, J¼8.0, 2H), 7.08 (t, J¼7.5, 1H), 7.00 (d, J¼7.0, 1H), 6.75 (t,
J¼7.5, 1H), 6.62 (d, J¼7.5, 1H), 5.55 (ddt, J¼16.8, 10.0, 7.5, 1H), 5.13 (s,
1H), 4.96–5.00 (m, 2H), 4.84 (s, 1H), 3.43 (ddd, J¼10.0, 8.0, 2.0, 1H),
3.13 (ddd, J¼10.5, 10.5, 6.0, 1H), 2.44 (s, 3H), 2.31 (ddd J¼19.5, 13.5,
7.5, 2H), 2.07 (ddd, J¼6.,5, 6.0, 2.0, 1H), 1.84 (ddd, J¼10.5, 8.0, 6.5,
1H); 13C NMR (125 MHz, CDCl3):
d 149.1, 143.7, 136.4, 133.5, 131.4,
130.0 128.8, 127.3 123.2, 119.3, 118.8, 109.7, 82.7, 58.0, 47.6, 42.3,
36.2, 21.7; IR (neat): 3391, 3076,1611,1485,1337,1160 cmꢂ1; HRMS-
ESI (m/z): [MþNa]þ calcd for C20H22N2O2SNa, 377.1300; found,
377.1298.
Supplementary data
Supplementary data associated with this article, includes ex-
perimental procedures, characterization data, and NMR spectra.
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2010.02.050.
4.3. Synthesis of indoline diastereomers 51 and 52
To a mixture of arylhydrazine 50 (52.4 mg, 0.20 mmol), lactol 29
(20.6 mg, 0.20 mmol), and benzene (1 mL) was added chloroacetic
acid (56.7 mg, 0.60 mmol). The resulting mixture was heated at
40 ꢀC for 24 h. The reaction mixture was cooled to 23 ꢀC, diluted
with CH2Cl2 (20 mL), washed with satd aq NaHCO3 (5 mL) and
extracted with CH2Cl2 (10 mL). The combined organic layers were
dried over MgSO4 and evaporated to dryness. Purification by flash
chromatography (15:1/10:1 hexanes/EtOAc) afforded a mixture of
diastereomers as an orange solid (53.0 mg, 80% yield, 2.4:1 dr). To
separate the diastereomers the mixture was repurified by flash
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35. For syntheses of 5, see Ref. 14d and the following: (a) Rivera-Becerril, E.;
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Joseph-Nathan, P.; Pe´rez-Alvarez, V. M.; Morales-Rı´os, M. S. J. Med. Chem. 2008,
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22. See Supplementary data for details.
23. (a) Grandberg, I. I.; Zuyanova, T. I.; Afonina, N. I.; Ivanova, T. A. Dokl. Akad. Nauk
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24. Takano et al. has synthesized a pyrrolidinoindoline product using an inter-
rupted Fischer indolization reaction; see: (a) Takano, S.; Moriya, M.; Iwabuchi,
Y.; Ogasawara, K. Chem. Lett. 1990, 109–112; (b) Takano, S.; Ogasawara, K.;
Iwabuchi, R.; Moriya, M. JP 03112989 A 19910514, 1991.
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2002, 58, 587–593; (b) Britten, A. Z.; Bardsley, W. G.; Hill, C. M. Tetrahedron
1971, 27, 5631–5639; (c) Rosenmund, P.; Sadri, E. Liebigs Ann. Chem. 1979, 927–
943; (d) Rosenmund, P.; Gektidis, S.; Brill, H.; Kalbe, R. Tetrahedron Lett. 1989,
30, 61–62; (e) Nishida, A.; Ushigome, S.; Sugimoto, A.; Arai, S. Heterocycles
2005, 66, 181–185.
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36. Khoukhi, N.; Vaultier, M.; Carrie´, R. Tetrahedron 1987, 43, 1811–1822.
37. 42 has previously been converted to debromoflustramine B (5) by reduction
with LiAlH4; see Ref. 35e.

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4695
38. For the total synthesis of communesin F, see: Yang, J.; Wu, H.; Shen, L.; Qin, Y.
J. Am. Chem. Soc. 2007, 129, 13794–13795.
39. Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928–1931.
40. Indoline 45 has previously been prepared by an intermolecular aza-Diels–Alder
strategy; see Ref. 31.
45. Although experimental procedures for the synthesis of 50 were not reported
previously, the synthetic route shown in Scheme 9 parallels that described by
Nishida (see Ref. 25e). Experimental details for the synthesis of 50 are included
in the Supplementary data that accompanies this manuscript.
46. Nishida has utilized 50 to synthesize an optically enriched pyrrolidinone, albeit
in modest yield.
41. (a) Terada, M. Chem. Commun. 2008, 4097–4112; (b) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520–1543.
47. The stereochemical configurations of 51 and 52 were inferred after the con-
version of 51 to (þ)-30.
42. Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583–2585.
43. The enantiomer formed in excess is believed to have the (R,R) configuration, as
depicted in Scheme 8, based on correlation to known data (see Ref. 33c).
44. Takano has shown that a proximal stereogenic center can be used to induce
diastereoselectivity in a Fischer indolization reaction see Ref. 24a.
48. 30 can be converted to physovenine (2) in four steps; see Ref. 33c.
49. Numerous attempts to cleave the auxiliary using H2 with various metal catalysts
led to reduction of the N,O-acetal linkage, a problem that was not encountered
when cleaving the auxiliary from a pyrrolidinoindoline derivative (see Ref. 25e).