Cycloaddition of metal-containing azomethine ylides for highly efficient synthesis of mitosene skeleton

Article abstract of DOI:10.1016/j.tet.2011.04.017

Efficient synthesis of tricyclic indole derivatives bearing a substituent at the 3-position of the indole nucleus was achieved by the [3+2] cycloaddition reaction of transition metal-containing azomethine ylides derived from N-(o-alkynylphenyl)imines with vinyl ethers. Third-row transition metal complexes, especially PtCl₂, turned out to be highly efficient for the reaction of internal alkynes and imidate substrates with wide generality. Moreover, as strong support for the reaction mechanism, the intermediate Pt-carbene complex was found to undergo intramolecular C-H bond insertion reaction to give tetracyclic indoline derivatives when benzyl vinyl ether was employed as a dipolarophile. This protocol provided a facile synthesis of highly functionalized tricyclic indole derivatives found as the basic skeleton of the mitosene family, such as mitomycin C.

Full text of DOI:10.1016/j.tet.2011.04.017

Tetrahedron 67 (2011) 4455e4466
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
[3þ2] Cycloaddition of metal-containing azomethine ylides for highly efficient
synthesis of mitosene skeleton
*
Jun Takaya, Yuichi Miyashita, Hiroyuki Kusama, Nobuharu Iwasawa
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthesis of tricyclic indole derivatives bearing a substituent at the 3-position of the indole
nucleus was achieved by the [3þ2] cycloaddition reaction of transition metal-containing azomethine
ylides derived from N-(o-alkynylphenyl)imines with vinyl ethers. Third-row transition metal complexes,
especially PtCl2, turned out to be highly efficient for the reaction of internal alkynes and imidate sub-
strates with wide generality. Moreover, as strong support for the reaction mechanism, the intermediate
Ptecarbene complex was found to undergo intramolecular CeH bond insertion reaction to give tetra-
cyclic indoline derivatives when benzyl vinyl ether was employed as a dipolarophile. This protocol
provided a facile synthesis of highly functionalized tricyclic indole derivatives found as the basic skeleton
of the mitosene family, such as mitomycin C.
Received 17 January 2011
Received in revised form 29 March 2011
Accepted 5 April 2011
Available online 13 April 2011
Keywords:
Indole synthesis
Azomethine ylide
Carbene complex
Electrophilic activation of alkyne
PtCl2
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The indole skeleton is an important core framework for phar-
maceuticals, insecticides etc., and the development of concise
methods for the synthesis of polycyclic indoles is highly desirable.1
We have previously reported a novel method for the construction
of polycyclic indole skeletons through W(CO)6-promoted genera-
tion and reaction of metal-containing azomethine ylides.2 These
novel azomethine ylide species A are generated by the reaction of
N-(o-ethynylphenyl)imine derivatives (R1¼Ph, OR) with a catalytic
amount of W(CO)6 under photoirradiation conditions, and they
undergo [3þ2] cycloaddition with electron-rich alkenes to give
tungsten carbene complexes B.3 1,2-Migration of the substituent R2
(R2¼H, alkyl, aryl) affords polycyclic indole derivatives with re-
generation of the tungsten catalyst (Scheme 1). Importantly, this
method is applicable to internal alkyne derivatives to give tricyclic
indoles bearing a substituent R2 at the 3-position of the indole
nucleus, which is the basic structure often found in natural prod-
ucts, such as mitomycins (Fig. 1).4,5 However, when internal alkyne
substrates were employed, the efficiency of the tungsten catalyst
was moderate and a stoichiometric amount of W(CO)6 was neces-
sary to bring the reaction to completion. Moreover, the reaction was
limited to aldimine type substrates and inapplicable to imidate
substrates, which would afford synthetically more useful products
A
B
Scheme 1.
* Corresponding author. Tel.: þ81 3 5734 2746; fax: þ81 3 5734 2931; e-mail
address: niwasawa@chem.titech.ac.jp (N. Iwasawa).
Fig. 1. Mitomycin C and its related compounds.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.017

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J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
possessing an N,O-acetal moiety (Fig. 2). Thus, it is highly desirable
to develop efficient catalytic reactions generally applicable to in-
ternal alkynes and imidate substrates. In this paper, we describe
excellent catalytic activity of third-row transition metal complexes,
especially PtCl2, for generation and reaction of metal-containing
azomethine ylides with wide generality including internal alkynes
and imidate substrates.6,7 Reaction of highly functionalized metal-
containing azomethine ylide and its synthetic application toward
mitomycin C are also described. Moreover, intramolecular CeH
insertion reaction of Ptecarbene intermediate to give tetracyclic
indoline derivative is also demonstrated as a strong support of the
reaction mechanism.
complexes, and the results are summarized in Table 1. Various
metal complexes, such as Re(I), Ir(I), Pd(II), Pt(II), and Au(III) were
found to catalyze this reaction efficiently, giving the [3þ2]
cyloaddition/1,2-Pr-migration product 3a in good to excellent
yields (entries 5,6,10,13,14,18,19).These metal complexes exhibited
much higher catalytic activity than the tungsten carbonyl complex.
The same mechanism is proposed for these reactions as that for
W(CO)5(L)-catalyzed reaction as depicted in Scheme 2. Electro-
philic activation of the internal alkyne moiety by these metals in-
duces nucleophilic, 5-endo cyclization of the imino nitrogen onto
the alkyne moiety to generate the corresponding metal-containing
azomethine ylides A. Successive [3þ2] cycloaddition and 1,2-alkyl
migration give tricyclic indole 3a with regeneration of the catalyst,
along with a small amount of formal [4þ2] cycloadduct 4a. In-
terestingly, the efficiency seemed to be roughly dependent on the
‘row’ and ‘valence’ of the metal complexes. Thus, molybdenum
carbonyl gave the desired product 3a in much lower yield than
tungsten (entries 1 and 3), and except for Pd(II), the reactions with
first- or second-row transition metal complexes, such as
MnBr(CO)5, Ru3(CO)12/hv, [RhCl(cod)]2, and NiCl2 resulted in no
formation of the desired [3þ2] cycloaddduct 3a (entries 4,8,9,
and 12).
Even with third-row metals, high valent metal complexes,
such as ReCl5 and IrCl3 tend to give hetero DielseAlder cyclo-
adduct 5a through electrophilic activation of aldimine moiety
(entries 7 and 11).8 In addition, PtCl4 showed lower catalytic
activity and product selectivity ([3þ2] vs [4þ2]) than those of
PtCl2 (entries 14 and 15).9 These results indicate that soft metal
complexes, that is, low valent and third-row transition metal
complexes, with moderate Lewis acidity activate the alkyne
moiety efficiently and selectively and are the catalyst of choice
for the present reaction.
Fig. 2. Limitation of tungsten-promoted reaction.
2. Results and discussion
2.1. Effect of various metal catalyst
We first investigated the reaction of a benzaldimine derivative
1a bearing an n-propyl group on the alkyne terminus with tert-
butyl vinyl ether 2a in toluene by using various transition metal
Table 1
Screening of metal complexes
Entry
Catalyst
Loading of catalyst
(mol %)
Time
(h)
Yield of 3a
(%)
cis:trans
(3a)
Yield of 4a
(%)
Yield of 5a
(%)
1a
W(CO)6/h
n
100
10
100
10
10
10
10
3.5
5.0
5.0
10
9.0
10
10
10
10
10
10
10
13
22
16
76
33
15
0
70
69
0
0
0
73
0
0
71
90
57
49
42
82
70
22:78
17:83
21:79
d
21d
d
4
0
d
2a
3
Mo(CO)6/h
Mn(CO)5Br/h
Re(CO)5Cl/h
Re(CO)5Br/h
ReCl5
n
0
0
0
0
94
0
0
0
13
0
0
0
0
0
0
0
0
4b
n
12.5
5.5
2.0
2.0
11.5
26
26
29.5
29
2.0
9.5
24.5
29
30
1.2
0.5
0
5
6
n
64:36
52:48
d
Trace
Trace
0
n
7
8b
Ru3(CO)12/h
n
d
0
9b,c
10
11b,c
12b,c
13
14
15
16
17b
18
19
[RhCl(cod)]2
[IrCl(cod)]2
IrCl3
NiCl2
PdCl2(CH3CN)2
PtCl2
PtCl4
AuCl
[Au(PPh3)]SbF6
AuCl3
AuBr3
d
0
19:81
d
5e
0
d
0
54:46
58:42
49:51
55:45
58:42
57:43
53:47
3e
0
29e
3e
2e
3e
6e
f
a
Compound 2a (10 equiv) was employed.
Compound 1a was recovered.
Hydrolysis of 1a proceeded to some extent.
dr¼94:6.
b
c
d
e
f
Single isomer.
Prepared from AuCl(PPh3) and AgSbF6 in situ.

J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
4457
Scheme 2.
Table 3
Further optimization of reaction conditions with reduced load-
Reaction of various internal alkyne derivativesa
ing of the catalyst disclosed that ReBr(CO)5, PtCl2, and AuBr3 have
excellent catalytic activity in terms of product yield and reaction
time.10e12 The reaction was complete within 2.5 h at room tem-
perature using only 3 mol % of ReBr(CO)5/hn or AuBr3 to give the
desired product 3a in 77 or 80% yield (Table 2, entry 1 and 3).The
loading of the catalyst was further reduced to 1 mol % without
decreasing the yield of 3a albeit a much longer reaction time (42 h)
was required for completion with AuBr3 catalyst (entry 2 and 4).
PtCl2-catalyzed reaction proceeded very slowly at room tempera-
ture with reduced loading of the catalyst (entry 5), and therefore
the reaction was carried out at 50 ꢀC with 3 mol % or 1 mol % of the
catalyst to afford the product 3a in high yield within an acceptable
reaction time (entries 6 and 7). Importantly, product selectivity was
also excellent and only a small amount of [4þ2] cycloadduct 4a was
obtained in these reactions (less than 4%).
Entry
R
ReBr(CO)5/h
n
AuBr3 at rt
PtCl2 at 50 ꢀC
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
1
2
3
4
Me
1b
1a
1c
1d
3.0
2.5
3.0
d
89
77
0
22
81
80
89
62
3.5
6.0
35
88
89
84b
84
n-Pr
c-Hex
Ph
2.5
2.0
0.5
d
7.0
a
The dr of 3 varied in the range of cis:trans¼23:77 to 73:27.
b
Vinyl ether (10 equiv) was employed.
Table 2
Optimized conditions using ReBr(CO)5, AuBr3 or PtCl2
employable as a migrating group (entry 4). It should be noted that
the rate of AuBr3-catalyzed reaction increased as the substituent
became bulkier, whereas the inverse tendency was observed in the
PtCl2-catalyzed reaction. This behavior may be suggestive of
a change in rate-limiting step between these two catalysts since
a bulkier substituent is expected to retard the formation of metal-
containing azomethine ylide (Me<n-Pr<c-Hex), whereas 1,2-alkyl
(or aryl) migration to the electron deficient carbene center would
be accelerated by a more electron-rich substituent, such as sec-
ondary alkyl or especially aryl group (Me<n-Pr<c-Hex<Ph) (Fig. 3).
On the other hand, ReBr(CO)5-catalyzed reaction of cyclohexyl-
substituted derivative 1c resulted in no formation of the desired
Entry
Catalyst
x
Temp
(ꢀC)
Time
(h)
Yield of 3a
(%)
cis:trans
(3a)
1
ReBr(CO)5/h
ReBr(CO)5/h
AuBr3
AuBr3
PtCl2
n
3.0
1.0
3.0
1.0
3.0
3.0
1.0
rt
rt
rt
rt
rt
50
50
2.5
2.5
2.5
42
72
6
77
69
80
81
81
89
74
56:44
57:43
58:42
56:44
54:46
51:46
38:62
2a
3
n
4b
5
Ph
Ph
6
PtCl2
PtCl2
formation of metal-containing
+
7a
16.5
N
N
azomethine ylide
R
a
0.3 M.
0.03 M.
b
slower with bulky R
rate : R = Me > n-Pr > c-Hex
M
–
R
2.2. Generality of the substituent on the alkyne terminus
rate-limiting step when cat. = PtCl2
Ph
N
Ph
N
With the efficient catalysts and reaction conditions in hand,
generality of the substituent on the alkyne terminus of the aldimine
was investigated. AuBr3 and PtCl2 catalyst showed wide generality
of substrates under the same reaction conditions described above,
and the results are summarized in Table 3. The reactions of methyl-
substituted derivative 1b (entry 1) and bulky cyclohexyl derivative
1c (entry 3) proceeded smoothly to give tricyclic indoles possessing
the corresponding alkyl group at the 3-position of the indole
nucleus in high yield. In addition to alkyl, phenyl was also
1,2-R2-migration
O-t-Bu
O-t-Bu
R
M
R
faster with electron rich R
rate : R = Me < n-Pr < c-Hex < Ph
rate-limiting step when cat. = AuBr3
Fig. 3. Possible explanation of the effect of substituent at the alkyne terminus on the
reaction rate.

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J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
[3þ2] cycloadduct at all although the reaction of Me-derivative 1b
proceeded without problem. It is likely that bulky tetracarbonyl
ligands on rhenium would be unfavorable for coordination of the
alkyne moiety bearing a sterically demanding c-Hex group, and
would inhibit the generation of a Re-containing azomethine ylide.
Since primary and secondary alkyl groups as well as phenyl group
were successful as a migrating group with AuBr3 and PtCl2 catalysts,
we further investigated 1,2-migration of a functionalized substituent
to expand the scope of this reaction, and a siloxymethyl group was
chosen considering application to mitomycin synthesis. Gratifyingly,
the desired [3þ2] cycloaddition and 1,2-migration of the siloxy-
methyl group was found to proceed smoothly by the use of PtCl2 as
a catalyst at 50 ꢀC, affording the corresponding tricyclic indole 3e in
good yield (Scheme 3). Use of AuBr3 caused complication of the re-
action including desilylation of the TIPSO-moiety of the product
probably due to its stronger Lewis acidity and harder character than
PtCl2. Thus, it was demonstrated that PtCl2 catalyst greatly expanded
generality and improved efficiency of the reaction of internal alkynes
compared to W(CO)6 system to realize facile synthesis of tricyclic
indoles bearing various substituents at the 3-position.
desired-position of the indole nucleus with an easily functionalizable
N,O-acetal moiety, and thus, would be a highly useful synthetic pre-
cursor to mitomycins and their analogues.
Table 4
Reaction of imidate 6a
Entry Catalyst
x
Additive Temp Time Yield of 7aa Yield of 8
(ꢀC)
(h)
(%)
(%)
1b
2
3
4
5
ReBr(CO)5/h
n
10
10
10
MS4A
MS4A
MS4A
rt
rt
rt
50
19.5 Trace
1.0 60
Trace
12
27
AuBr3
PtCl2
PtCl2
PtCl2
22
4
71
62
3.0 MS4A
3.0 MS4A
K2CO3
18
c
50
50
11
2
32
95
23
0
6
PtCl2
3.0 MS5A
a
The dr of 7a varied in the range of cis:trans¼58:42 to 68:32.
Compound 2a (4 equiv) was employed.
10 mol %.
b
c
Scheme 3.
Fig. 4. Possible mechanism for the formation of N-formylindole derivative 8.
2.3. Reaction of metal-containing azomethine ylide derived
from imidate derivatives
Application of this methodology not only to aldimine
derivatives but also to imidates would be useful since the resulting
indole derivatives possess an N,O-acetal moiety, which facilitates
further functionalization of the products.13 After screening several
substrates and reaction conditions, imidate 6a derived from
o-(pent-1-ynyl)aniline and tri(iso-propyl) orthoformate was found
to be employable as a precursor of the metal-containing azome-
thine ylide, which underwent [3þ2] cycloaddition with vinyl ether
2a (Table 4). In this case, the PtCl2-catalyzed reaction gave superior
results as compared with the ReBr(CO)5- or AuBr3-catalyzed one,
leading to a tricyclic indole derivative 7a with N,O-acetal moiety in
good yield (entries 1e3) although N-formylindole derivative 8,
Scheme 4.
possibly generated by base-promoted b-deprotonation of metal-
containing azomethine ylide was also produced as a byproduct
(Fig. 4). Further optimization of reaction conditions disclosed that
use of slightly acidic MS5A instead of MS4A completely suppressed
the formation of 8, and dramatically improved the yield of 7a by the
use of 3.0 mol % of PtCl2 at 50 ꢀC (entry 6).
Scheme 5.
Transformation of this N,O-acetal moiety was briefly demon-
The reaction of 6a also proceeded with p-methoxybenzyl vinyl
ether 2b as a dipolarophile to give indole 9a, which possessed an
easilyremovablebenzylgroup, inhighyield(Scheme4).Furthermore,
high synthetic utility of this methodology was demonstrated by the
reaction of imidate 6b bearing a siloxymethyl group on the alkyne
terminus with PMB-vinyl ether 2b, affording tricyclic indole de-
rivative 9b bearing three oxygen functionalities in a single operation
(Scheme 5). This product contains a hydroxymethyl equivalent at the
strated in Scheme 6. Thus, reductive cleavage of the N,O-acetal
proceeded smoothly by treatment of trans-7a with 2 equiv of
NaBH3CN and 1 equiv of p-toluenesulfonic acid in DMF at room
temperature to give tricyclic indole derivative 10 in high yield.14
The reaction proceeds through in situ generation of an iminium
ion followed by NaBH3CN-mediated reduction. It should be noted
that this method is a good alternative to the [3þ2] cycloaddition of

J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
4459
metal-containing azomethine ylide derived from methyleneamine
as a precursor, which is difficult to isolate and handle due to its
instability (Fig. 5).
Scheme 6.
H
OR'
H
H
H
N
N
1) [3+2]
N
Scheme 7.
OR''
2) N,O-acetal
reduction
R
R
R
unstable
Fig. 5. Imidate substrate as a synthetic equivalent to methyleneamine precursor.
generated from 15 with paraformaldehyde and TIPS-protection of
the resulting hydroxy group. Removal of the pivaloyl group on the
nitrogen was carried out by treating 17 with DIBAL at ꢁ95 ꢀC to give
aniline 18 in good yield. Finally, the reaction of 18 with tri(iso-
propyl) orthoformate at 80 ꢀC in the presence of MS4A afforded the
desired imidate 12 in moderate yield, which was purified by bulb-
to-bulb distillation.
2.4. Synthetic study toward mitomycin C. Generation and
reaction of metal-containing azomethine ylide from highly
oxygenated imidate derivative
Since the reaction of imidate derivative 6b, in which siloxy-
With the desired substrate in hand, we tried generation and
[3þ2] cycloaddition of metal-containing azomethine ylide from 12
using PtCl2 as a catalyst. After several trials, we were pleased to find
that treatment of 12 and 10 equiv of tert-butyl vinyl ether with
10 mol % of PtCl2 afforded the desired tricyclic indole derivative 11
bearing the N,O-acetal, siloxymethyl moiety, and two methoxy
groups on the benzene ring in good yield (Scheme 8). This com-
pound possesses the basic carbon skeleton of mitomycin C with five
oxygen functionalities, which would be suitable for further trans-
formations toward mitomycin C. This result also demonstrates that
the present reaction is applicable to highly oxygenated substrates,
indicating the wide generality and high synthetic utility of this
method.
methyl group underwent 1,2-migration, enabled construction of
the mitosene skeleton efficiently, we started
a preliminary
investigation toward mitomycin C (Fig. 1) utilizing the [3þ2]
cycloaddition of metal-containing azomethine ylide. We proposed
tricyclic indole derivative 11 as a potential key intermediate,
possessing two methoxy groups on the benzene ring for the
construction of the quinone moiety (Fig. 6). The N,O-acetal was
reduced as in Scheme 6 to form methylene moiety at 3-position
and the aziridine moiety of the target compound could be con-
structed by utilizing the t-BuO-function. Our purpose in this
preliminary study is to establish methodology to access this in-
termediate 11 by the [3þ2] cycloaddition of metal-containing
azomethine ylide derived from highly oxygenated imidate de-
rivative 12, and demonstrate the high synthetic utility of this
protocol.
Fig. 6. Synthetic application of this protocol toward mitomycin C.
The precursor 12 was synthesized in six steps starting from
N-pivaloyl-2-iodo-3,6-dimethoxyaniline 13 as shown in Scheme 7.
Sonogashira coupling reaction of 13 with trimethylsilylacetylene
followed by removal of the TMS group afforded o-ethynylaniline
derivative 15 in high yield. The siloxymethyl moiety on the alkyne
terminus was introduced by the reaction of the alkynyllithium
Scheme 8.

4460
J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
2.5. Mechanistic considerations. Evidence for intermediacy of
the Ptecarbene complex
These results strongly support the existence of Ptecarbene complex
as an intermediate in the reaction sequence, and indicate possibility
of utilizing the intermediate for further CeC bond forming
transformations.
We disclosed that PtCl2 was the best catalyst for the reaction of
internal alkynes and imidate substrates in terms of efficiency and
generality of the reaction. Concerning the mechanism of this pro-
cess, it is postulated that a Pt-containing azomethine ylide un-
dergoes [3þ2]-cycloaddition reaction with vinyl ethers to give
a metal carbene complex intermediate, which undergoes 1,2-mi-
gration of the substituent R2 to the electrophilic Ptecarbene center
(Fig. 7). In our previous investigation on the reaction of internal
alkyne derivatives using a stoichiometric amount of W(CO)6, one of
the stereoisomers of the intermediate tungsten carbene complex
was successfully isolated due in part to moderate stability of group
6 metal carbene complexes having carbonyl ligands.3 Even though
the corresponding Ptecarbene complex seems to be highly un-
stable, it is desirable to confirm the intermediacy of the Ptecarbene
complex to support the mechanism of the reaction.
Fig. 7. Proposed key intermediate, Ptecarbene complex.
During investigation of the reaction of aldimine derivatives with
various vinyl ethers, we fortunately found that the intermediate
Ptecarbene complexes can be captured by an intramolecular CeH
bond insertion reaction with the appropriate choice of substrates.
Thus, treatment of aldimine 1a and 4 equiv of benzyl vinyl ether 2c
with 3 mol % of PtCl2 under standard reaction conditions afforded
tetracyclic indoline derivative 20a in 14% yield as a single stereo-
isomer along with 42% of 1,2-migration product 19a (entry 1,
Table 5). Furthermore, the yield of the tetracyclic indoline was in-
creased by the combination of aldimine 1b bearing Me-substituent
on the alkyne terminus and p-methoxybenzyl vinyl ether 2b as
substrates, affording 41% of indoline 20b and 43% of indole 19b
Fig. 8. ORTEP drawing of 20b at 50% probability level.
(entry 2). The structures of these tetracycles were assigned by 1H,13
C
and various 2D NMR techniques, and confirmed by X-ray analysis in
the case of 20b (Fig. 8). The formation of tetracyclic indoline de-
rivative was reasonably explained by considering intramolecular
insertion of Ptecarbene complex 21 into the benzylic CeH bond
before 1,2-n-Pr-migration (Fig. 9).15 The lower electron donating
ability of Me-substituent compared to n-Pr is expected to retard the
1,2-migration and the bond dissociation energy of the benzylic CeH
bond becomes smaller due to the electron-rich aromatic ring, and
therefore the relative rate of CeH insertion to 1,2-migration in-
creased to give the indoline derivative more efficiently in entry 2.
Fig. 9. CeH insertion versus 1,2-migration.
3. Conclusion
In conclusion, we have successfully established the generality
and efficiency of the [3þ2] cycloaddition reaction of transition
metal-containing azomethine ylides. Third-row transition metal
complexes, especially PtCl2, proved to be the most efficient catalyst
for the reaction of internal alkynes and imidate substrates. Highly
functionalized tricyclic indole derivatives with oxygen functional-
ities, the basic skeleton of the mitosene family (e.g., mitomycin C),
were easily accessible by this method. Furthermore, the key in-
termediate Ptecarbene complex was found to undergo intra-
molecular CeH bond insertion to give a tetracyclic indoline
derivative. The present results demonstrate novel aspects of tran-
sition metal-containing dipoles and their high utility for the con-
struction of various synthetically valuable indole derivatives.
Table 5
Formation of tetracyclic indoline derivative 20
Entry R1
R2
Yield of 19 cis:trans of 19 Yield of 20
(%)
(%)
1
2
n-Pr (1a) Ph (2c)
Me (1b)
42 (19a)
53:47
70:30
14 (20a)
41 (20b)
p-MeOC6H4 (2b) 43 (19b)

J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
4461
4. Experimental section
4.1. General
2866, 2225, 1615, 1493, 1090 cmꢁ1
;
1H NMR (400 MHz)
d
¼1.08e1.23 (m, 21H), 4.13e4.27 (br s, 2H), 4.66 (s, 2H), 6.64e7.01
(m, 2H), 7.11 (ddd, J¼7.6, 7.6, 1.6 Hz, 1H), 7.26 (dd, J¼7.6, 1.6 Hz, 1H);
13C NMR (100 MHz)
d
¼12.1, 18.0, 52.6, 81.1, 93.3, 107.6, 114.2, 117.7,
All operations were performed under an argon atmosphere. 1H
and 13C NMR spectra were recorded on a Bruker DRX-500 (500 MHz
for 1H and 125 MHz for 13C), a JEOL AL-400 (400 MHz for 1H and
100 MHz for 13C) or a JEOL Lambda-400 (400 MHz for 1H and
100 MHz for 13C) spectrometer in CDCl3 (99.8% atom enriched,
Acros Co., Ltd.). Chemical shifts are expressed in parts per million
(ppm) downfield from tetramethylsilane and are referenced to re-
129.5, 132.2, 147.8; Anal. Calcd for C18H29NOSi: C, 71.23; H, 9.63; N,
4.61. Found: C, 71.01, H, 9.42, N, 4.50.
The aldimine 1e was prepared according the procedure
described for the preparation of 1c using 2-(3-triisopropylsilox-
yprop-1-ynyl)aniline (185 ꢀC/0.05 mmHg). The geometry was
confirmed to be E by the observation of an NOE between the aldi-
mine proton and the C-6 aromatic proton. IR (neat) 3063, 2941,
sidual CHCl3
(
dH 7.26) for 1H and CDCl3
(
dC 77.0) for 13C spectra. IR
2230, 1633, 1190, 1106 cmꢁ1
;
1H NMR (400 MHz)
d¼1.01e1.16 (m,
spectra were recorded on an IR-810 or an FT/IR-460 plus (JASCO Co.,
Ltd.). Photoirradiation was performed with a 250 W super high-
pressure mercury lamp (USHIO INC.). Silica gel 60 (Kanto Chem-
ical Co., Inc.) or aluminum oxide 90 active neutral (activity I,
0.063e0.200 mm, Merck) was used for flash column chromatog-
raphy. Merck Kieselgel 60 F254 (0.25 mm thickness, coated on
20ꢂ20 cm2 glass plate) was used for thin layer chromatography
(TLC), and Wakogel B-5F coated on glass in a thickness of 0.7 mm
was used for preparative TLC. All solvents were distilled according
to the usual procedures and stored over molecular sieves. MS4A
and MS5A were heated by heat-gun under reduced pressure before
use. High-resolution mass analyses (FAB) were performed on a JEOL
JMS-700 mass spectrometer using 2-nitrophenyl octyl ether as
a matrix. Elemental analyses were performed on a PerkineElmer
2400 instrument. Aldimines 1a, 1b, 1d were prepared according to
our previously reported procedure.2a 1H NMR spectral data of
cycloadducts 3a, 3b, 3d, and 4a were identical to those in our
previous report.2a
21H), 4,57 (s, 2H), 7.01 (dd, J¼7.6, 1.2 Hz, 1H), 7.13 (ddd, J¼7.6, 7.6,
1.2 Hz, 1H), 7.32 (ddd, J¼7.6, 7.6, 1.2 Hz, 1H), 7.36e7.56 (m, 4H), 7.93
(dd, J¼7.6, 1.6 Hz, 2H), 8.44 (s, 1H); 13C NMR (100 MHz)
¼12.1, 18.0,
d
52.6, 82.1, 92.1, 115.9, 119.4, 124.9, 128.6, 128.9, 129.0, 131.4, 133.1,
136.0, 153.9, 161.8; Anal. Calcd for C25H33NOSi: C, 76.67; H, 8.49; N,
3.58. Found: C, 76.38, H, 8.75, N, 3.42.
4.3. Preparation of imidate
4.3.1. (E)-Isopropyl N-(2-(1-pentynyl)phenyl)formimidate (6a).
A mixture of 2-(pent-1-ynyl)aniline (437 mg, 2.74 mmol), triiso-
propyl orthoformate (2.5 mL, 11 mmol) and MS5A (4.2 g) in toluene
(8.5 mL) was heated at 80 ꢀC. After 15 h, the mixture was filtered
through a short pad of CeliteÒ and the filtrate was concentrated
under reduced pressure. The resulting residue was purified by
bulb-to-bulb distillation to give the imidate 6a (105 ꢀC/0.01 mmHg,
547 mg, 2.38 mmol, 87%). The geometry was confirmed to be E by
the observation of an NOE between the formimidic proton and the
C-6 aromatic proton. IR (neat) 2966, 2229, 1644 cmꢁ1
(400 MHz)
;
1H NMR
4.2. Preparation of aldimines derived from 2-(1-alkynyl)
anilines and benzaldehyde
d
¼1.03 (t, J¼7.6 Hz, 3H), 1.39 (d, J¼6.0 Hz, 6H), 1.55e1.66
(m, 2H), 2.38 (t, J¼7.2 Hz, 2H), 5.19e5.33 (m, 1H), 6.84 (br d,
J¼7.6 Hz, 1H), 7.01 (ddd, J¼7.6, 7.6, 1.6 Hz, 1H), 7.19 (ddd, J¼7.6, 7.6,
1.6 Hz, 1H), 7.39 (dd, J¼7.6, 1.6 Hz, 1H), 7.65 (s, 1H); 13C NMR
4.2.1. (E)-N-Benzylidene-2-(2-cyclohexylethynyl)aniline (1c). To
a
stirred mixture of 2-(2-cyclohexylethynyl)aniline16 (578 mg,
2.90 mmol) and MS5A (1.5 g) in toluene (2.0 mL) was added
benzaldehyde (0.35 mL, 3.4 mmol) at room temperature. After 5
days, the reaction mixture was filtered through a short pad of
CeliteÒ and the filtrate was concentrated under reduced pressure.
The resulting residue was purified by bulb-to-bulb distillation to
give 1c (170 ꢀC/0.03 mmHg, 786 mg, 2.71 mmol, 94%) as a single
isomer. The geometry was confirmed to be E by the observation of
an NOE between the aldimine proton and the C-6 aromatic proton.
(100 MHz)
d
¼13.6, 21.7, 21.8, 22.3, 69.4, 78.5, 93.7,117.1,120.9,123.5,
128.2, 132.6, 149.6, 155.0; Anal. Calcd for C15H19NO: C, 78.56; H,
8.35; N, 6.11. Found: C, 78.28, H, 8.48, N, 5.82.
4.3.2. (E)-Isopropyl
N-((3-triisopropylsiloxyprop-1-ynyl)-phenyl)-
formimidate (6b). The imidate 6b was prepared according to the
procedure described for the preparation of 6a using 2-(3-triiso-
propylsiloxyprop-1-ynyl)aniline in 85% yield (155 ꢀC/0.05 mmHg).
The geometry was confirmed to be E by the observation of an NOE
between the formimidic proton and the C-6 aromatic proton. IR
IR (neat) 3061, 2929, 2223, 1633 cmꢁ1 1H NMR (400 MHz)
;
d
¼1.20e1.35 (m, 3H), 1.37e1.55 (m, 3H), 1.61e1.84 (m, 4H),
(neat) 3065, 2943, 2232, 1645, 1189, 1108 cmꢁ1
(400 MHz)
;
1H NMR
2.54e2.65 (m, 1H), 7.02 (br d, J¼6.0 Hz, 1H), 7.11 (ddd, J¼7.6, 7.6,
1.2 Hz, 1H), 7.27 (ddd, J¼7.6, 7.6, 1.2 Hz, 1H), 7.42e7.60 (m, 4H),
d
¼1.06e1.17 (m, 21H), 1.38 (d, J¼6.0 Hz, 6H), 4.60 (s,
2H), 5.17e5.28 (m, 1H), 6.85 (br d, J¼7.6 Hz, 1H), 7.03 (br dd, J¼7.6,
7.6 Hz, 1H), 7.23 (br dd, J¼7.6, 7.6 Hz, 1H), 7.42 (br d, J¼7.6 Hz, 1H),
7.89e7.97 (m, 2H), 8.47 (s, 1H); 13C NMR (100 MHz)
d
¼24.6, 26.0,
29.7, 32.6, 78.3, 98.7, 116.6, 119.6, 124.8, 128.2, 128.6, 128.8, 131.3,
132.7, 136.1, 153.7, 161.7; Anal. Calcd for C21H21N: C, 87.76; H, 7.36;
N, 4.87. Found: C, 87.71, H, 7.38, N, 4.65.
7.63 (s, 1H); 13C NMR (100 MHz)
d
¼12.1, 18.0, 21.7, 52.6, 69.6, 82.4,
91.4, 116.3, 120.9, 123.6, 129.0, 132.9, 149.9, 155.0; Anal. Calcd for
C22H35NOSi: C, 70.73; H, 9.44; N, 3.75. Found: C, 70.48, H, 9.32, N,
3.52.
4.2.2. (E)-N-Benzylidene-2-(3-triisopropylsiloxyprop-1-ynyl)-aniline
(1e). 2-(3-Triisopropylsiloxyprop-1-ynyl)aniline, the precursor of
aldimine 1e, was prepared as follows. To a stirred mixture of 2-(3-
hydroxyprop-1-ynyl)aniline17 (2.07 g, 14.1 mmol) and imidazole
(2.39 g, 35.2 mmol) in DMF (5 mL) was added chloro-
triisopropylsilane (3.1 mL, 14.5 mmol) at room temperature and the
mixture was stirred for 1 h. The reaction was quenched with 1 N
HCl, and then the aqueous layer was extracted with ether three
times and the combined extracts were washed with brine, and
dried (MgSO4). The solvent was removed under reduced pressure
and the residue was purified by silica-gel column chromatography
(hexane/ethyl acetate¼5:1) to give 2-(3-triisopropylsiloxyprop-1-
ynyl)aniline (4.00 g, 13.2 mmol, 94%); IR (neat) 3478, 3384, 2943,
4.4. Preparation of functionalized imidate 12 (Scheme 5)
4.4.1. N-(3,6-Dimethoxy-2-(2-(trimethylsilyl)ethynyl)phenyl)-piv-
alamide (14). To a mixture of N-(2-iodo-3,6-dimethoxyphenyl)
pival-amide18
13
(1.31
g,
3.6
mmol),
dichlorobis(-
triphenylphosphine)-palladium(II) (251 mg, 0.36 mmol) and cop-
per(I) iodide (141 mg, 0.74 mmol) in diethylamine (10 mL) was
added ethynyltrimethylsilane (1.0 mL, 7.1 mmol) at room tempera-
ture and the mixture was heated at 80 ꢀC. After 3.5 h, the reaction
was quenched with saturated aq NH4Cl. The aqueous layer was
extracted with ether (3ꢂ) and the combined extracts were washed
with brine, and dried (MgSO4). The solvent was removed under

4462
J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
reduced pressure and the residue was purified by silica-gel column
chromatography (hexane/ethyl acetate¼2:1) to give anilide 14
toluene (1.0 mL) was added diisobutylaluminum hydride (1.0 M in
toluene, 0.44 mL, 0.44 mmol) at ꢁ95 ꢀC and the mixture was stirred
at this temperature for 3 h. The reaction was quenched with satu-
rated aqueous solution of potassium sodium (þ)-tartrate at ꢁ95 ꢀC
and the mixture was stirred at room temperature until the biphasic
solution became clear. The aqueous layer was extracted with ethyl
acetate (3ꢂ) and the combined extracts were washed with brine,
and dried (MgSO4). The solvent was removed under reduced
pressure and the residue was purified by PTLC (hexane/ethyl
acetate¼5:1) to give aniline 18 (31.6 mg, 60%) along with N-neo-
pentyl-3,6-dimethoxy-2-(3-triisopropylsiloxyprop-1-ynyl)-aniline
(10.0 mg, 16%) as a byproduct and the staring material 17 (16.7 mg,
(1.10 g, 92%). IR (KBr) 2959, 2835, 2147, 1691, 1270 cmꢁ1 1H NMR
;
(400 MHz)
d
¼0.25 (s, 9H), 1.35 (s, 9H), 3.79 (s, 3H), 3.83 (s, 3H), 6.71
(d, J¼8.8 Hz,1H), 6.86 (d, J¼8.8 Hz,1H), 7.09e7.20 (br s,1H); 13C NMR
(100 MHz)
d¼0.2, 27.8, 39.6, 56.6, 56.7, 79.8, 97.4, 104.1, 110.7, 113.3,
129.1, 148.6, 154.8, 176.0; Anal. Calcd for C18H27NO3Si: C, 64.83; H,
8.16; N, 4.20. Found: C, 65.03, H, 8.33, N, 4.30.
4.4.2. N-(3,6-Dimethoxy-2-ethynylphenyl)pivalamide (15). To a sol-
ution of anilide 14 (670 mg, 2.0 mmol) in THF/MeOH (1:1, 6.0 mL)
was added tetra-n-butylammonium fluoride (1.0 M in THF, 3.0 mL,
3.0 mmol) at 0 ꢀC. After the mixture was stirred for 2 h at room
temperature, the reactionwas quenched with pH 7 phosphate buffer
and the product was extracted with ethyl acetate (3ꢂ). The com-
bined extracts were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by silica-gel column chroma-
tography (hexane/ethyl acetate¼2:1) to give the title compound 15
(531 mg,100%). IR (KBr) 3092, 2971, 2842, 2100,1762 cmꢁ1; 1H NMR
26%). IR (KBr) 3482, 3373, 2940, 2863, 2218, 1615, 1493, 1057 cmꢁ1
1H NMR (400 MHz)
¼1.16e1.23 (m, 21H), 3.78 (s, 3H), 3.80 (s, 3H),
;
d
4.35e4.48 (br s, 2H), 4.71 (s, 2H), 6.12 (d, J¼8.8 Hz, 1H), 6.65 (d,
J¼8.8 Hz, 1H); 13C NMR (100 MHz)
¼12.1, 18.0, 52.8, 55.9, 56.0,
d
77.6, 97.4, 97.9, 100.5, 110.5, 139.9, 141.0, 154.7; Anal. Calcd for
C20H33NO3Si: C, 66.07; H, 9.15; N, 3.85. Found: C, 65.85, H, 9.19, N,
3.70.
(400 MHz)
d
¼1.34 (s, 9H), 3.50 (s, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 6.73
(d, J¼9.2 Hz,1H), 6.88 (d, J¼9.2 Hz,1H), 7.10e7.21 (br s,1H); 13C NMR
4.4.6. (E)-Isopropyl N-(3,6-dimethoxy-2-(3-triisopropylsiloxy-prop-
1-ynyl)phenyl)formimidate (12). This compound was prepared
according to the procedure described for the preparation of 6a
using aniline 18 in 36% yield (170 ꢀC/0.05 mmHg). The product was
contaminated with a small amount of aniline 18 (less than 5%), and
analytically pure sample was not obtained. The geometry was de-
duced to be E since the chemical shift of formimidic proton is
similar to those of imidate 6a and 6b; 1H NMR (400 MHz)
(100 MHz)
d
¼27.7, 39.4, 56.5, 56.6, 76.8, 86.1, 108.8, 110.0, 113.0,
129.3, 148.3, 155.0, 176.3; Anal. Calcd for C15H19NO3: C, 68.94; H,
7.33; N, 5.36. Found: C, 68.70, H, 7.39, N, 5.47.
4.4.3. N-(3,6-Dimethoxy-2-(3-hydroxyprop-1-ynyl)phenyl)pival-am-
ide (16). To a stirred solution of 15 (230 mg, 0.880 mmol) in THF
(1.0 mL) was added n-butyllithium (1.53 M in THF, 1.20 mL,
1.83 mmol, 2.1 equiv) at 0 ꢀC and the reaction mixture was stirred at
room temperature for 0.5 h. The reaction mixture was cooled to
d
¼1.00e1.62 (m, 21H), 1.39 (d, J¼6.4 Hz, 6H), 3.73 (s, 3H), 3.80 (s,
3H), 4.62 (s, 2H), 5.24e5.32 (m, 1H), 6.49 (d, J¼8.8 Hz, 1H), 6.77 (d,
0
ꢀC, paraformaldehyde (139 mg, 4.63 mmol) was added, and the
J¼8.8 Hz, 1H), 7.64 (s, 1H); 13C NMR (100 MHz)
¼12.1, 18.0, 21.7,
d
reaction mixture was stirred for 8 h at room temperature. The re-
action mixture was quenched with pH 7 phosphate buffer and the
product was extracted with ethyl acetate (3ꢂ), and the combined
extracts were dried (MgSO4). After removal of solvent under re-
duced pressure, the residue was purified by silica-gel column
chromatography (hexane/ethyl acetate¼1:1 then ethyl acetate) to
give the title compound 16 (186 mg, 72%) along with starting ma-
52.7, 56.1, 56.6, 69.3, 78.4, 95.5, 105.2, 106.7, 112.3, 141.1, 145.7, 155.1,
156.6.
4.5. Procedure for PtCl2-, AuBr3-, or ReBr(CO)5-catalyzed
reaction of imine and imidate derivatives with vinyl ether
Procedure for the 3.0 mol % PtCl2-catalyzed reaction of 1a with
2a was described (entry 6, Table 2) as a representative example. To
a stirred suspension of a mixture of an imine 1a (31.2 mg,
terial 15 (23 mg, 10%). IR (KBr) 3651, 2957, 2836, 1656, 1038 cmꢁ1
1H NMR (400 MHz)
¼1.35 (s, 9H),1.92 (t, J¼5.6 Hz,1H), 3.79 (s, 3H),
;
d
3.84 (s, 3H), 4.50 (d, J¼5.6 Hz, 2H), 6.71 (d, J¼9.2 Hz, 1H), 6.85 (d,
0.126 mmol), vinyl ether 2a (67 ml, 0.51 mmol) and MS4A (251 mg)
J¼9.2 Hz, 1H), 7.19e7.24 (br s, 1H); 13C NMR (100 MHz)
d
¼27.7, 39.5,
in toluene (1.2 mL) was added PtCl2 (1.0 mg, 0.0038 mmol) at room
temperature. The mixture was heated at 50 ꢀC for 6 h. After dis-
appearance of 1a was confirmed by TLC, the reaction was quenched
with saturated aq NaHCO3 and the reaction mixture was filtered
through a short pad of CeliteÒ. The filtrate was extracted with ethyl
acetate (3ꢂ) and the combined organic layers were washed with
brine, and dried (MgSO4). The solvent was removed under reduced
pressure and the residue was purified by preparative TLC (toluene/
hexane¼2:1, Rf¼0.4) to afford a tricyclic indole derivative 3a
(39.9 mg, 89%).
51.7, 56.4, 56.5, 79.0, 96.9, 108.6, 110.5, 112.2, 128.9, 148.0, 154.3,
176.5; Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
66.02, H, 7.23, N, 4.64.
4.4.4. N-(3,6-Dimethoxy-2-(3-triisopropylsiloxyprop-1-ynyl)-phe-
nyl)pivalamide (17). To
a stirred mixture of 16 (182.3 mg,
0.626 mmol) and imidazole (106.3 mg, 1.56 mmol) in DMF (1 mL)
was added chlorotriisopropylsilane (0.15 mL, 0.70 mmol) at room
temperature and the mixture was stirred overnight. The reaction
was quenched with 1 N HCl, and then the aqueous layer was
extracted with ether (3ꢂ) and combined extracts were washed
with brine, and dried (MgSO4). The solvent was removed under
reduced pressure and the residue was purified by silica-gel column
chromatography (hexane/ethyl acetate¼2:1) to give the title com-
pound 17 (250.7 mg, 89%). IR (KBr) 2944, 2865, 2238, 1664,
4.5.1. 1-tert-Butoxy-9-cyclohexyl-2,3-dihydro-3-phenyl-1H-pyrr-olo
[1,2-a]indole (3c). The stereochemistry of trans-3c was determined
by X-ray structure analysis as shown below (Fig. 10).
cis-3c; IR (neat) 3046, 2972, 2924, 2850, 1456, 1363 cmꢁ1 1H
;
NMR (500 MHz)
d
¼1.39e1.48 (m, 3H), 1.34 (s, 9H), 1.75e1.81 (m,
1084 cmꢁ1; 1H NMR (400 MHz)
d
¼1.03e1.20 (m, 21H), 1.34 (s, 9H),
1H),1.86e2.05 (m, 6H), 2.47 (ddd, J¼13.2, 7.3, 5.2 Hz,1H), 2.97e3.06
(m, 1H), 3.25 (ddd, J¼13.2, 7.3, 7.3 Hz, 1H), 5.16 (dd, J¼7.3, 7.3 Hz,
1H), 5.31 (dd, J¼7.3, 5.2 Hz, 1H), 6.66 (br d, J¼8.1 Hz, 1H), 6.89 (ddd,
J¼8.1, 8.1, 1.0 Hz, 1H), 6.96 (ddd, J¼8.1, 8.1, 1.0 Hz, 1H), 7.27e7.37 (m,
3H), 7.37e7.41 (m, 2H), 7.70 (br d, J¼8.1 Hz, 1H); 13C NMR
3.78 (s, 3H), 3.79 (s. 3H), 4.65 (s, 2H), 6.69 (d, J¼9.2 Hz, 1H), 6.84 (d,
J¼9.2 Hz, 1H), 7.07e7.18 (br s, 1H); 13C NMR (100 MHz)
¼12.0, 18.0,
d
27.7, 39.4, 52.7, 56.4, 56.6, 77.2, 97.2, 109.0, 110.7, 112.7, 128.8, 148.5,
154.6, 176.2; Anal. Calcd for C25H41NO4Si: C, 67.07; H, 9.23; N, 3.13.
Found: C, 67.08, H, 9.35, N, 2.92.
(125 MHz)
d
¼26.4, 27.37, 27.39, 28.9, 33.2, 33.9, 36.1, 49.7, 59.7, 68.0,
74.4, 110.5, 114.2, 118.4, 120.2, 120.6, 127.0, 127.7, 128.7, 131.8, 132.2,
140.3, 141.2; Anal. Calcd for C27H33NO: C, 83.68; H, 8.58; N, 3.61.
Found: C, 83.43; H, 8.56; N, 3.33.
4.4.5. 3,6-Dimethoxy-2-(3-triisopropylsiloxyprop-1-ynyl)aniline
(18). To a stirred solution of anilide 17 (65.2 mg, 0.146 mmol) in

J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
4463
132.7, 141.4, 141.5.l; Anal. Calcd for C31H45NO2Si: C, 75.71; H, 9.22;
N, 2.85. Found: C, 75.44; H, 9.49; N, 2.66.
4.5.3. 4-Methoxy-2-phenyl-8-(prop-1-ynyl)-1,2,3,4-tetrahydro-quin-
oline (5a). NMR (400 MHz)
d
¼0.94 (t, J¼7.3 Hz, 3H), 1.33 (s, 9H),
1.48e1.61 (m, 2H), 2.06 (dd, J¼23.4, 12.1 Hz, 1H), 2.23e2.31 (m, 1H),
2.64 (t, J¼7.1 Hz, 2H), 4.68 (dd, J¼12.1, 3.2 Hz, 1H), 4.80 (br s, 1H),
4.87 (dd, J¼10.7, 5.1 Hz, 1H), 6.61 (t, J¼7.6 Hz, 1H), 7.14 (d, J¼7.6 Hz,
1H), 7.27e7.50 (m, 6H).
4.5.4. 1-tert-Butoxy-2,3-dihydro-3-isopropoxy-9-propyl-1H-pyrrolo
[1,2-a]indole (7a). The stereochemistry of the products was
determined by the observation of NOEs as shown below.
Fig. 10. ORTEP plot of trans-3c at 50% probability level (hydrogen atoms are omitted
for clarity).
trans-3c; IR (neat) 3047, 2973, 2926, 2850, 1455, 1364 cmꢁ1
1H NMR (500 MHz)
;
cis-7a; IR (neat) 3050, 2972, 2930, 2870, 1456, 1365 cmꢁ1
NMR (400 MHz)
;
1H
d
¼1.32e1.50 (m, 3H), 1.33 (s, 9H), 1.77e1.82
(m, 1H), 1.87e2.03 (m, 6H), 2.70 (ddd, J¼12.6, 6.5, 6.4 Hz, 1H),
2.92e3.10 (m, 2H), 5.36 (dd, J¼6.4, 3.0 Hz, 1H), 5.54 (dd, J¼7.0,
6.5 Hz, 1H), 6.65 (br d, J¼8.1 Hz, 1H), 6.87e6.92 (m, 1H),
6.95e7.00 (m, 1H), 7.07e7.11 (m, 2H), 7.27e7.34 (m, 3H), 7.72 (br
d
¼0.96 (t, J¼7.2 Hz, 3H), 1.06 (d, J¼6.0 Hz, 3H), 1.26
(d, J¼6.0 Hz, 3H), 1.35 (s, 9H), 1.63e1.78 (m, 2H), 2.42 (ddd, J¼14.0,
2.4, 2.4 Hz,1H), 2.71e2.77 (m, 2H), 3.02 (ddd, J¼14.0, 7.0, 7.0 Hz,1H),
4.02e4.12 (m,1H), 5.06 (dd, J¼7.0, 2.4 Hz,1H), 5.76 (dd, J¼7.0, 2.4 Hz,
1H), 7.08 (dd, J¼8.0, 8.0 Hz, 1H), 7.14 (dd, J¼8.0, 8.0 Hz, 1H), 7.37 (d,
d, J¼8.1 Hz, 1H); 13C NMR (125 MHz)
¼26.4, 27.35, 27.37, 28.9,
d
J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz)
¼14.3,
d
33.3, 33.7, 36.4, 50.3, 59.2, 67.2, 74.5, 110.7, 114.2, 118.3, 120.4,
120.7, 126.3, 127.7, 128.8, 131.8, 132.3, 140.2, 141.6; Anal. Calcd
for C27H33NO: C, 83.68; H, 8.58; N, 3.61. Found: C, 83.42; H, 8.85;
N, 3.33.
23.3, 23.5, 24.2, 26.1, 28.7, 46.7, 65.2, 68.1, 74.3, 83.8, 108.9, 110.4,
119.2, 119.3, 121.0, 132.0, 133.3, 140.0; Anal. Calcd for C21H31NO2: C,
76.55; H, 9.48; N, 4.25. Found: C, 76.27; H, 9.77; N, 3.97.
trans-7a; IR (neat) 3051, 2972, 2931, 2870, 1456, 1364 cmꢁ1; 1H
4.5.2. 1-tert-Butoxy-2,3-dihydro-9-triisopropylsiloxymethyl-3-phe-
nyl-1H-pyrrolo[1,2-a]indole (3e). The stereochemistry was de-
termined by the observation of NOEs as shown below.
NMR (500 MHz)
d
¼0.98 (t, J¼7.4 Hz, 3H), 1.17 (d, J¼6.1 Hz, 3H), 1.24
(d, J¼6.1 Hz, 3H), 1.33 (s, 9H), 1.64e1.78 (m, 2H), 2.62 (ddd, J¼13.4,
6.5, 6.0 Hz, 1H), 2.75e2,80 (m, 2H), 2.82 (dd, J¼13.4, 6.5 Hz, 1H),
3.94e4.01 (m, 1H), 5.49 (dd, J¼6.5, 6.5 Hz, 1H), 5.88 (d, J¼6.0 Hz,
1H), 7.08 (dd, J¼7.9, 7.9 Hz, 1H), 7.13 (dd, J¼7.9, 7.9 Hz, 1H), 7.30 (d,
J¼7.9 Hz, 1H), 7.54 (d, J¼7.9 Hz, 1H); 13C NMR (125 MHz)
¼14.3,
d
22.5, 23.1, 24.4, 25.7, 28.6, 48.9, 67.0, 69.9, 74.3, 83.2, 109.6, 109.9,
119.1, 119.3, 121.0, 132.2, 133.6, 139.9; Anal. Calcd for C21H31NO2: C,
76.55; H, 9.48; N, 4.25. Found: C, 76.32; H, 9.70; N, 4.06.
4.5.5. N-Formyl-2-propylindole (8). 1H NMR (400 MHz)
d
¼1.07 (t,
J¼7.3 Hz, 3H), 1.79 (sextet, J¼7.3 Hz, 2H), 2.36e2.95 (m, 2H), 6.39 (s,
1H), 7.25e7.31 (m, 2H), 7.46e7.50 (m, 2H), 9.30 (br s, 1H).
cis-3e (minor); IR (neat) 3049, 2965, 2942, 2865, 1456, 1364,
1192, 1060 cmꢁ1
;
1H NMR (400 MHz)
d¼1.09e1.31 (m, 21H), 1.34
4.5.6. 2,3-Dihydro-3-isopropoxy-1-(4-methoxybenzyloxy)-9-tri-iso-
propylsiloxymethyl-1H-pyrrolo[1,2-a]indole (9b). The stereochem-
istry of the major product was determined to be cis by the observed
NOEs shown below. Therefore, the minor product was assigned to
be the corresponding trans isomer.
(s, 9H), 2.45 (ddd, J¼12.8, 7.2, 6.0 Hz, 1H), 3.30 (ddd, J¼12.8, 7.2,
6.0 Hz, 1H), 5.09 (d, J¼12.0 Hz, 1H), 5.14 (d, J¼12.0 Hz, 1H), 5.22
(dd, J¼7.2, 7.2 Hz, 1H), 5.36 (dd, J¼6.0, 6.0 Hz, 1H), 6.65 (d,
J¼8.0 Hz, 1H), 6.91 (dd, J¼8.0, 8.0 Hz, 1H), 7.02 (dd, J¼8.0, 8.0 Hz,
1H), 7.27e7.38 (m, 5H), 7.78 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz)
d
¼12.2, 18.3, 28.8, 49.9, 56.9, 59.9, 67.8, 74.4, 108.0, 110.3, 119.1,
120.5, 120.7, 126.9, 127.8, 128.7, 132.0, 132.6, 140.9, 141.3; Anal.
Calcd for C31H45NO2Si: C, 75.71; H, 9.22; N, 2.85. Found: C, 75.47;
H, 9.45; N, 3.02.
trans-3e (major); IR (neat) 3050, 2964, 2942, 2865, 1456, 1365,
1191, 1059 cmꢁ1
;
1H NMR (500 MHz)
d
¼1.11e1.16 (m, 18H),
cis-9b; IR (neat) 2941, 2865, 1457, 1368 cmꢁ1
;
1H NMR
¼0.90e1.41 (m, 21H), 1.19 (d, J¼6.0 Hz, 3H), 1.25
1.17e1.26 (m, 3H), 1.36 (s, 9H), 2.75 (ddd, J¼13.3, 6.7, 5.5 Hz, 1H),
2.95 (ddd, J¼13.3, 7.7, 3.7 Hz, 1H), 5.09 (d, J¼11.8 Hz, 1H), 5.15 (d,
J¼11.8 Hz, 1H), 5.39 (dd, J¼6.7, 3.7 Hz, 1H), 5.58 (dd, J¼7.7, 5.5 Hz,
1H), 6.69 (d, J¼8.0 Hz, 1H), 6.94 (dd, J¼8.0, 8.0 Hz, 1H), 7.04 (dd,
J¼8.0, 8.0 Hz, 1H), 7.07e7.12 (m, 2H), 7.27e7.35 (m, 3H), 7.80 (d,
(400 MHz)
d
(d, J¼6.0 Hz, 3H), 2.62 (d, J¼14.4 Hz, 1H), 2.94 (ddd, J¼14.4, 6.8,
6.4 Hz, 1H), 3.80 (s, 3H), 4.07e4.18 (m, 1H), 4.53 (d, J¼11.2 Hz, 1H),
4.65 (d, J¼11.2 Hz, 1H), 4.98 (d, J¼12.0 Hz, 1H), 5.05 (d, J¼12.0 Hz,
1H), 5.09 (d, J¼6.8 Hz, 1H), 5.77 (d, J¼6.4 Hz, 1H), 6.86 (d, J¼8.4 Hz,
2H), 7.13 (dd, J¼7.6, 7.6 Hz, 1H), 7.20 (dd, J¼7.6, 7.6 Hz, 1H), 7.28
J¼8.0 Hz,1H); 13C NMR (125 MHz)
¼12.2,18.2, 28.7, 50.4, 57.1, 59.4,
d
67.0, 74.4, 108.2, 110.4, 119.1, 120.6, 120.9, 126.3, 127.7, 128.8, 132.2,

4464
J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
(d, J¼8.4 Hz, 2H), 7.38 (d, J¼7.6 Hz, 1H), 7.73 (d, J¼7.6 Hz, 1H); 13C
d
¼14.5, 24.0, 27.0, 45.7, 59.2, 70.6, 73.5, 109.5, 110.4, 118.8, 119.6,
NMR (100 MHz)
d
¼12.2, 18.2, 22.9, 23.3, 43.8, 55.3, 57.5, 69.1, 69.7,
121.1, 126.6, 127.50, 127.54, 127.6, 128.3, 128.6, 132.3, 132.5, 138.2,
139.9, 141.5; Anal. Calcd for C27H27NO: C, 85.00; H, 7.13; N, 3.67.
Found: C, 84.80; H, 7.03; N, 3.47.
71.1, 83.2, 110.0, 113.6, 119.9, 120.5, 122.0, 129.4, 130.5, 132.0, 132.7,
139.0, 159.0; Anal. Calcd for C32H47NO4Si: C, 71.46; H, 8.81; N, 2.60.
Found: C, 71.25; H, 9.04; N, 2.49.
trans-19a; IR (neat) 2955, 1604, 1455, 1358 cmꢁ1 1H NMR
;
trans-9b; IR (neat) 2941, 2865, 1456, 1367 cmꢁ1
;
1H NMR
(400 MHz)
d
¼1.03 (t, J¼7.6 Hz, 3H), 1.74e1.89 (m, 2H), 2.68 (ddd,
(400 MHz)
d
¼1.04e1.19 (m, 21H), 1.22 (d, J¼5.6 Hz, 3H), 1.23 (d,
J¼13.6, 7.2, 6.0 Hz, 1H), 2.78e2.95 (m, 2H), 3.11 (ddd, J¼13.6, 7.2,
1.6 Hz, 1H), 4.62 (s, 2H), 5.24 (dd, J¼6.0, 1.6 Hz, 1H), 5.58 (dd, J¼7.2,
7.2 Hz, 1H), 6.58 (d, J¼7.6 Hz, 1H), 6.94 (dd, J¼7.6, 7.6 Hz, 1H), 7.04
(dd, J¼7.6, 7.6 Hz, 1H), 7.14e7.21 (m, 2H), 7.28e7.40 (m, 8H), 7.62
J¼5.6 Hz, 1H), 2.73e2.79 (m, 2H), 3.81 (s, 3H), 3.93e4.05 (m, 1H),
4.55 (s, 2H), 5.05 (s, 2H), 5.37 (dd, J¼5.6, 5.6 Hz, 1H), 5.96 (dd,
J¼4.4, 4.4 Hz, 1H), 6.88 (d, J¼8.4 Hz, 2H), 7.12 (dd, J¼7.6, 7.6 Hz,
1H), 7.18 (dd, J¼7.6, 7.6 Hz, 1H), 7.28 (d, J¼8.4 Hz, 2H), 7.31 (d,
(d, J¼7.6 Hz, 1H); 13C NMR (100 MHz)
¼14.5, 24.1, 27.2, 47.8, 59.9,
d
J¼7.6 Hz, 1H), 7.75 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz)
d¼12.2,
70.4, 73.1, 109.7, 110.7, 118.6, 119.7, 121.1, 126.7, 127.6, 127.8, 127.9,
128.4, 128.8, 132.1, 132.4, 138.1, 138.7, 140.5.; HRMS calcd for
C27H28NO: MHþ382.2172. Found: m/z 382.2151.
18.2, 22.7, 23.0, 45.4, 55.3, 57.2, 70.3, 70.6, 84.3, 109.7, 110.2, 113.8,
119.7, 120.5, 121.6, 129.4, 130.1, 132.3, 132.5, 139.0, 159.2; Anal.
Calcd for C32H47NO4Si: C, 71.46; H, 8.81; N, 2.60. Found: C, 71.17;
H, 9.11; N, 2.60.
4.5.9. Tetracyclic indoline (20a). IR (neat) 2959, 2925, 2866, 1601,
1481, 1274, 1026 cmꢁ1; 1H NMR (500 MHz)
d¼1.00 (t, J¼7.3 Hz, 3H),
4.5.7. 1-tert-Butoxy-2,3-dihydro-5,8-dimethoxy-3-phenyl-9-tri-iso-
propylsiloxymethyl-1H-pyrrolo[1,2-a]indole (11). The stereochem-
istry of the minor product was determined to be trans by the
observed NOEs shown below. Therefore, the major product was
assigned to be the corresponding cis isomer.
1.35e1.47 (m, 1H), 1.63e1.47 (m, 1H), 1.77e1.86 (m, 2H), 2.10
(ddd, J¼14.1, 10.3, 3.6 Hz, 1H), 2.87 (dd, J¼14.1, 7.1 Hz, 1H), 3.57
(d, J¼6.8 Hz, 1H), 4.33 (d, J¼3.6 Hz, 1H), 4.62 (dd, J¼10.3, 7.1 Hz, 1H),
5.13 (d, J¼6.8 Hz, 1H), 5.87 (d, J¼7.6 Hz, 1H), 6.35e6.42 (m, 2H), 6.88
(dd, J¼7.6, 7.6 Hz, 1H), 6.95e6.99 (m, 2H), 7.15e7.23 (m, 3H), 7.29
(dd, J¼7.4, 7.4 Hz, 1H), 7.40 (dd, J¼7.4, 7.4 Hz, 2H), 7.52 (d, J¼7.4 Hz,
2H); 13C NMR (125 MHz)
d¼14.7, 18.0, 40.3, 42.1, 57.7, 70.4, 85.4,
86.7, 87.3, 112.0, 120.2, 125.8, 126.2, 126.6, 126.8, 127.4, 127.6, 128.0,
128.6, 131.1, 137.1, 145.6, 156.1; Anal. Calcd for C27H27NO: C, 85.00;
H, 7.13; N, 3.67. Found: C, 85.07; H, 7.34; N, 3.50.
4.5.10. 2,3-Dihydro-1-(4-methoxybenzyloxy)-9-methyl-3-phenyl-
1H-pyrrolo[1,2-a] indole (19b). This compound was obtained as an
inseparable mixture of diastereomers.
cis-11; IR (neat) 2968, 2938, 2865, 1465, 1366, 1111 cmꢁ1
NMR (500 MHz)
;
1H
IR (neat) 2933, 2860, 1612, 1455, 1358 cmꢁ1; 1H NMR (400 MHz)
d
¼0.87e1.22 (m, 27H), 1.35 (s, 9H), 2.36 (d,
J¼14.1 Hz, 1H), 2.84 (ddd, J¼14.1, 6.5, 5.9 Hz, 1H), 3.81 (s, 3H), 3.86
(s, 3H), 3.98e4.08 (m, 1H), 4.91 (d, J¼11.2 Hz, 1H), 5.13 (d, J¼6.5 Hz,
1H), 5.33 (d, J¼11.2 Hz, 1H), 5.95 (d, J¼5.9 Hz, 1H), 6.32 (d, J¼8.4 Hz,
d
¼2.39 (s, 2.25H), 2.42 (s, 0.75H), 2.53e2.67 (m, 1H), 3.03 (ddd,
J¼13.6, 6.4,1.2 Hz, 0.25H), 3.23 (ddd, J¼15.6, 8.8, 6.8 Hz, 0.75H), 3.75
(s, 2.25H), 3.76 (s, 0.75H), 4.46e4.60 (m, 2H), 5.11 (dd, J¼6.8, 2.5 Hz,
0.75H), 5.14 (dd, J¼6.0, 1.2 Hz, 0.25H), 5.28 (dd, J¼8.8, 4.0 Hz,
0.75H), 5.53 (dd, J¼8.4, 6.4 Hz, 0.25H), 6.51 (d, J¼8.0 Hz, 0.25H),
6.79e6.87 (m, 2.75H), 6.90 (br d, J¼8.0 Hz, 0.25H), 6.95e7.06 (m,
1.75H), 7.11e7.15(m, 0.5H), 7.16e7.32 (m, 6.5H), 7.51e7.56 (m, 1H);
1H), 6.42 (d, J¼8.4 Hz, 1H); 13C NMR (125 MHz)
¼12.2, 18.1, 23.1,
d
23.2, 28.7, 46.7, 55.1, 55.5, 56.7, 65.2, 68.5, 74.0, 85.4, 99.1, 101.4,
109.3, 123.4, 123.7, 141.8,142.0, 149.2.; HRMS calcd for C30H52NO5Si:
MHþ534.3615. Found: m/z 534.3607.
trans-11; IR (neat) 2967, 2940, 2865, 1465, 1366, 1114 cmꢁ1 1H
;
13C NMR (100 MHz)
d¼9.3, 9.6, 45.8, 48.2, 55.3, 59.2, 60.0, 70.2, 72.6,
NMR (500 MHz)
d
¼0.92e1.20 (m, 27H), 1.35 (s, 9H), 2.52 (ddd,
72.9, 104.1, 104.2, 110.3, 110.6, 113.7, 113.8, 118.6, 118.9, 119.2, 119.3,
121.2, 121.3, 126.6, 126.7, 127.5, 127.9, 128.6, 128.7, 129.1, 129.4,
130.26, 130.29, 132.0, 132.3, 132.88, 132.94, 140.0, 140.1, 140.3, 141.6,
159.0, 159.1 (2C missing); Anal. Calcd for C26H25NO2 (cis and trans
mixture): C, 81.43; H, 6.57; N, 3.65. Found: C, 81.64; H, 6.79; N, 3.35.
J¼12.9, 6.7, 5.5 Hz, 1H), 2.77 (dd, J¼12.9, 6.7 Hz, 1H), 3.80 (s, 3H),
3.87 (s, 3H), 3.94e4.03 (m, 1H), 4.98 (d, J¼10.9 Hz, 1H), 5.27 (d,
J¼10.9 Hz, 1H), 5.54 (dd, J¼6.7, 6.7 Hz, 1H), 6.07 (d, J¼5.5 Hz, 1H),
6.31 (d, J¼8.4 Hz, 1H), 6.42 (d, J¼8.4 Hz, 1H); 13C NMR (125 MHz)
d
¼12.3, 18.1, 22.4, 23.2, 28.8, 49.2, 54.9, 55.2, 56.0, 67.5, 69.1, 74.1,
84.7, 98.9, 101.1, 110.1, 123.3, 123.8, 141.4, 141.8, 149.2.
4.5.11. Tetracyclic indoline (20b). The stereochemistry of indoline
20b was determined by X-ray analysis as shown in Fig. 8.
IR (neat) 3066, 2956, 2927, 2833, 1602, 1482, 1245, 1037 cmꢁ1
;
4.5.8. 1-Benzyloxy-2,3-dihydro-3-phenyl-9-propyl-1H-pyrrolo-[1,2-
a]indole (19a). The stereochemistry of the products was
determined by the observation of NOEs as shown below.
1H NMR (400 MHz)
d¼1.62 (s, 3H), 2.12, (ddd, J¼14.0, 10.4, 3.2 Hz,
1H), 2.85 (dd, J¼14.0, 7.2 Hz, 1H), 3.43 (d, J¼6.8 Hz, 1H), 3.78 (s,
3H), 4.27 (d, J¼3.2 Hz, 1H), 4.61 (dd, J¼10.4, 7.2 Hz, 1H), 5.12 (d,
J¼6.8 Hz, 1H), 5.96 (d, J¼7.6 Hz, 1H), 6.39 (d, J¼7.6 Hz, 1H), 6.47 (d,
J¼7.6 Hz, 1H), 6.73 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H), 6.93
(dd, J¼7.6, 7.6 Hz, 1H), 7.30 (dd, J¼7.6, 7.6 Hz, 1H), 7.40 (dd, J¼7.6,
7.6 Hz, 2H), 7.54 (d, J¼7.6 Hz, 2H); 13C NMR (100 MHz)
¼24.4,
d
42.2, 55.2, 60.0, 70.5, 83.7, 84.9, 87.4, 112.0, 112.9, 120.3, 126.3,
126.4, 126.8, 127.9, 128.0, 128.5, 129.1, 130.7, 145.3, 155.3, 158.9;
Anal. Calcd for C26H25NO2: C, 81.43; H, 6.57; N, 3.65. Found: C,
81.67; H, 6.76; N, 3.60.
cis-19a; IR (neat) 3064, 2966, 1609, 1456, 1360 cmꢁ1
(400 MHz)
(ddd, J¼14.0, 4.0, 3.2 Hz, 1H), 2.79e2.93 (m, 2H), 3.30 (ddd, J¼14.0,
8.8, 6.8 Hz, 1H), 4.64 (s, 2H), 5.20 (dd, J¼6.8, 3.2 Hz, 1H), 5.34 (dd,
J¼8.8, 4.0 Hz, 1H), 6.86 (d, J¼7.6 Hz, 1H), 6.98e7.08 (m, 2H),
7.27e7.38 (m, 10H), 7.62 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz)
;
1H NMR
d
¼1.02 (t, J¼7.6 Hz, 3H), 1.73e1.86 (m, 2H), 2.66
4.6. Procedure for PtCl2-catalyzed reaction of imidate 6a with
p-methoxybenzyl vinyl ether
To a mixture of p-methoxybenzyl vinyl ether 2b (82 mg,
5.0 mmol), activated MS5A (200 mg), and PtCl2 (1.0 mg,

J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
4465
0.003 mmol) in toluene (2.5 mL) was added an imidate 6a (28.5 mg,
0.125 mmol) in toluene (1.5 mL) over 2 h at 50 ꢀC. After heating for
further 6.5 h, the reaction was quenched with saturated aq NaHCO3
and the reaction mixture was filtered through a short pad of Cel-
iteÒ. The filtrate was extracted with ethyl acetate (3ꢂ) and the
combined organic layer was washed with brine, and dried (MgSO4).
The solvent was removed under reduced pressure and the residue
was purified by preparative TLC (toluene/ethyl acetate¼40:1) to
give 9a (42.6 mg, 87% (cis:trans¼45:55)).
7.04 (br dd, J¼7.6, 7.6 Hz, 1H), 7.11 (br dd, J¼7.6, 7.6 Hz, 1H), 7.20 (br
d, J¼7.6 Hz, 1H), 7.55 (br d, J¼7.6 Hz, 1H); 13C NMR (100 MHz)
d
¼14.4, 24.6, 26.2, 28.7, 39.0, 41.9, 67.5, 74.3, 108.3, 109.4, 118.3,
119.3, 120.5, 132.3, 132.5, 140.3.; HRMS calcd for C18H26NO: MHþ
272.2005. Found: m/z 272.2010.
5. Crystallographic data
Crystallographic data for the structural analyses have been
deposited with the Cambridge Crystallographic Data Center,
CCDC no. 819184 for compound 20b, CCDC no. 606158
for compound trans-3c. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or e-mail: deposit@
ccdc.cam.ac.Uk).
4.6.1. cis-2,3-Dihydro-3-isopropoxy-1-(4-methoxybenzyloxy)-9-pro-
pyl-1H-pyrrolo[1,2-a]indole (9a). The stereochemistry of the minor
product was determined to be cis by the observed NOEs shown
below. Therefore, the major product was assigned to be the corre-
sponding trans isomer.
Acknowledgements
This research was partly supported by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan. We thank Ms. Sachiyo Kubo for
performing X-ray analysis.
cis-9a (minor); IR (neat) 3050, 2959, 2930, 2869, 1612, 1514,
1455, 1328, 1247 cmꢁ1
;
1H NMR (500 MHz)
d¼0.98 (t, J¼7.3 Hz,
Supplementary data
3H), 1.21 (d, J¼6.0 Hz, 3H), 1.25 (d, J¼6.0 Hz, 3H), 1.68e1.80 (m,
2H), 2.62 (br d, J¼14.1 Hz, 1H), 2.71e2.83 (m, 2H), 2.95 (ddd,
J¼14.1, 6.8, 6.8 Hz, 1H), 3.81 (s, 3H), 4.08e4.17 (m, 1H), 4.51 (d,
J¼11.4 Hz, 1H), 4.63 (d, J¼11.4 Hz, 1H), 5.08 (br d, J¼6.8 Hz, 1H),
5.76 (br d, J¼6.8 Hz, 1H), 6.89 (br d, J¼8.6 Hz, 2H), 7.12 (br dd,
J¼8.0, 8.0 Hz, 1H), 7.20 (br dd, J¼8.0, 8.0 Hz, 1H), 7.31 (br d,
J¼8.6 Hz, 2H), 7.38 (br d J¼8.0 Hz, 1H), 7.59 (br d, J¼8.0 Hz, 1H);
1HNMR spectra of5a, 8, cis- and trans-11, cis- and trans-19, cis-and
trans-9a, and 10. Supplementary data related to this article can be
found online at doi:10.1016/j.tet.2011.04.017.
References and notes
13C NMR (125 MHz)
d¼14.4, 22.8, 23.2, 23.6, 26.8, 43.7, 55.3, 69.1,
1. For reviews on the synthesis of indole derivatives, see: (a) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045e1075; (b) Cacchi, S.; Fabrizi, G. Chem. Rev.
69.3, 71.0, 83.0, 110.3, 110.6, 113.7, 119.5, 119.8, 121.7, 129.3, 130.7,
132.7, 132.8, 138.9, 159.1.; HRMS calcd for. C25H31NO3, M 393.2304.
Found m/z 393.2300.
~
ꢀ
2005, 105, 2873e2920; (c) Barluenga, J.; Rodríguez, F.; Fananas, F. J. Chem.
dAsian J. 2009, 4, 1036e1048.
2. (a) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2002,124,11592e11593 See
also: (b) Kusama, H.; Suzuki, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 895e897.
3. Takaya, J.; Kusama, H.; Iwasawa, N. Chem. Lett. 2004, 33, 16e17.
4. (a) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.; Shen, B. Chem.
Rev. 2005, 105, 739e758; (b) Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98,
2723e2795 For recent total synthesis of mitomycins, see: (c) Wang, Z.; Jimenez,
L. S. Tetrahedron Lett. 1996, 37, 6049e6052 and references cited therein. See
also; (d) Andrez, J.-C. Beilstein J. Org. Chem 2009, 5 No. 33.
trans-9a (major); IR (neat) 3050, 2960, 2930, 2869, 1612,
1514, 1456, 1328, 1248 cmꢁ1
;
1H NMR (500 MHz)
d
¼0.99 (t,
J¼7.4 Hz, 3H), 1.23 (d, J¼6.1 Hz, 6H), 1.68e1.79 (m, 2H),
2.72e2.87 (m, 4H), 3.80 (s, 3H), 3.95e4.04 (m, 1H), 4.52 (d,
J¼11.2 Hz, 1H), 4.55 (d, J¼11.2 Hz, 1H), 5.35 (dd, J¼6.3, 4.9 Hz,
1H), 5.95 (dd, J¼5.4, 3.2 Hz, 1H), 6.91 (br d, J¼8.5 Hz, 2H), 7.11
(dd, J¼8.0, 8.0 Hz, 1H), 7.17 (dd, J¼8.0, 8.0 Hz, 1H), 7.31 (br d,
J¼8.5 Hz, 2H), 7.35 (d, J¼8.0 Hz, 1H), 7.58 (d, J¼8.0 Hz, 1H); 13C
5. For recent examples of the preparation of mitosene skeletons, see: (a) Gubler,
D. A.; Williams, R. M. Tetrahedron Lett. 2009, 50, 4265e4267 and references
ꢀ
ꢀ
cited therein; (b) Perez-Serrano, L.; Domínguez, G.; Perez-Castells, J. J. Org.
Chem. 2004, 69, 5413e5418; (c) Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org.
Chem. 2004, 69, 7309e7316; (d) Tsuboike, K.; Guerin, D. J.; Mennen, S. M.;
Miller, S. J. Tetrahedron 2004, 60, 7367e7374; (e) Kim, M.; Vedejs, E. J. Org.
Chem. 2004, 69, 7262e7265 and references cited therein.
NMR (125 MHz)
d
¼14.3, 22.8, 23.0, 23.9, 26.5, 45.1, 55.3, 70.3,
70.4, 72.8, 84.2, 110.1, 110.3, 113.9, 119.3, 119.7, 121.4, 129.3,
130.3, 132.2, 133.2, 138.5, 159.3.; HRMS calcd for. C25H31NO3, M
393.2304. Found m/z 393.2309.
6. Part of this work has been communicated previously. See: Kusama, H.;
Miyashita, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 289e292.
7. There are some reports on generation and cycloaddition of azomethine
ylides through transition metal-catalyzed electrophilic activation of al-
kynes. See: (a) Su, S.; Porco, J. A. J. Am. Chem. Soc. 2007, 129, 7744e7745;
(b) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47,
7040e7043.
4.7. Reduction of N,O-acetal moiety of trans-7a
NaBH3CN (3.6 mg, 0.057 mmol) was added to a mixture of tri-
cyclic indole trans-7a (9.5 mg, 0.029 mmol) and p-toluenesulfonic
acid monohydrate (5.3 mg, 0.028 mmol) in DMF (0.33 mL) at room
temperature. After 20 h, the reaction mixture was quenched by
saturated aq NaHCO3, and the aqueous layer was extracted with
ethyl acetate (3ꢂ) and the combined extracts were washed with
brine, and dried (MgSO4). The solvent was removed under reduced
pressure and the residue was purified by PTLC (hexane/ethyl
acetate¼5:1) to give 10 (7.0 mg, 90%).
8. It is likely that these high valent metals are harder than the corresponding low
valent metals and preferentially activate the aldimine part, which is more basic
and harder than the alkyne moiety.
9. This product selectivity could be explained by considering higher nucleophi-
licity at the
b-position of the zwitterionic alkenylmetal intermediate A of
platinum(II) than that of platinum(IV).
10. For recent reviews on Pt- and Au-catalyzed synthetic reactions through elec-
trophilic activation of CeC multiple bonds, see: (a) Shapiro, N. D.; Toste, F. D.
Synlett 2010, 675e691; (b) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010,
€
692e706; (c) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208e3221; (d) Li, Z.;
Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239e3265; (e) Arcadi, A. Chem. Rev.
2008, 108, 3266e3325; (f) Shen, H. C. Tetrahedron 2008, 64, 3885e3903;
€
(g) Kirsch, S. F. Synthesis 2008, 3183e3204; (h) Furstner, A.; Davies, P. W. Angew.
4.7.1. 1-tert-Butoxy-2,3-dihydro-9-propyl-1H-pyrrolo[1,2-a]-indole
Chem., Int. Ed. 2007, 46, 3410e3449.
(10). IR (neat) 3051, 2971, 2930, 2870, 1614, 1459, 1364 cmꢁ1 1H
;
11. For examples of catalytic reactions through electrophilic activation of al-
kynes by Re(I) complexes, see: (a) Chatani, N.; Kataoka, K.; Murai, S.;
Furukawa, N.; Seki, Y. J. Am. Chem. Soc. 1998, 120, 9104e9105; (b) Hua, R.;
NMR (400 MHz)
d
¼0.98 (t, J¼7.6 Hz, 3H), 1.35 (s, 9H), 1.60e1.80 (m,
2H), 2.45e2.55 (m, 1H), 2.76 (t, J¼7.6 Hz, 2H), 2.79e2,91 (m, 1H),
3.90e3.99 (m, 1H), 4.18e4.26 (m, 1H), 5.25 (dd, J¼6.8, 3.6 Hz, 1H),
€
Tian, X. J. Org. Chem. 2004, 69, 5782e5784; (c) Ouh, L. L.; Muller, T. E.; Yan,
Y. K. J. Organomet. Chem. 2005, 690, 3774e3782; (d) Kuninobu, Y.; Kawata,

4466
J. Takaya et al. / Tetrahedron 67 (2011) 4455e4466
R1
Ph
A.; Takai, K. Org. Lett. 2005, 7, 4823e4825; (e) Kusama, H.; Yamabe, H.;
Onizawa, Y.; Hoshino, T.; Iwasawa, N. Angew. Chem., Int. Ed. 2005, 44,
468e470; (f) Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem.
Int. Ed. 2008, 47, 4906e4909; (g) Saito, K.; Onizawa, Y.; Kusama, H.;
Ph
N
R1
H
Ph
H
N
N
H
H
,
O
O
O
O
[Pt]
R1
[Pt]
Iwasawa, N. Chem.dEur. J. 2010, 16, 4716e4720.
R2
12. It should be noted that the reactions of a terminal alkyne substrate with
a catalytic amount of PtCl2 or AuBr3 were rather sluggish, while the corre-
sponding tungsten-catalyzed reaction gave the desired tricyclic indole in high
yield as previously reported.2a
13. For examples of Lewis acid-promoted, nucleophilic substitution reaction onto
N,O-acetals, see: Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 12510e12517 and references cited therein.
14. Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546e5549.
15. It should be noted that the CeH insertion product 20 was formed stereo-
selectively, whereas the 1,2-migration product was obtained as a mixture of
stereoisomers, and this difference could be explained as follows. First,
among four possible stereoisomers of the Ptecarbene intermediate 21, A and
B in which R1 and OR are located cis are not suitable for CeH insertion since
they give highly strained trans-fused 5-5 bicycles (Fig. 11). Concerning iso-
mer C, its stable conformation would be Cb since both substituents, Ph and
OR, are located in pseudo-equatorial position, where the benzylic proton and
the carbene moiety are too widely separated to undergo CeH insertion. On
the other hand, isomer D would favor the conformation Da, which is suit-
able for CeH insertion. This would avoid a large steric repulsion of Ph at
pseudo-axial position in Db, and afford the CeH insertion product stereo-
selectively (Fig. 12). Furthermore, the CeH insertion reaction proceeds ster-
eoselectively via TS E due to large steric repulsion between R2 and the [Pt]
moiety in TS F (Fig. 13).
[Pt]
R2
R2
C
Ca
Cb
favored
facile C-H insertion
Ph
N
R1
R1
H
Ph
N
H
N
H
H
Ph
O
[Pt]
[Pt]
too far for C-H
R1
O
R2
[Pt]
R2
Da
R2
insertion
D
Db
favored
Fig. 12. Reaction of the stereoisomers C and D.
Fig. 13. Origin of diastereoselectivity in the C-H insertion.
16. Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662e5663.
17. Villemin, D.; Goussu, D. Heterocycles 1989, 29, 1255e1261.
ꢀ
18. Fourquez, J. M.; Godard, A.; Marsais, F.; Queguiner, G. J. Heterocycl. Chem. 1995,
Fig. 11. Reaction of the stereoisomers A and B.
32, 1165e1170.