Synthesis of decahydropyrrolo[2,1,5-cd]indolizine derivatives through RuCl3/AgOTf induced alkene-alkene and alkene-arene double cycloisomerizations

Article abstract of DOI:10.1016/j.tet.2011.10.071

In the presence of RuCl₃/AgOTf, pyrrolizidine derivative with styrenyl substituents at the 3,5-positions undergo a 6-exo-trig cyclization and subsequent intramolecular Friedel-Crafts reactions to form decahydropyrrolo[2,1, 5-cd]indolizine or de

Full text of DOI:10.1016/j.tet.2011.10.071

Tetrahedron 68 (2012) 152e158
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of decahydropyrrolo[2,1,5-cd]indolizine derivatives through RuCl3/
AgOTf induced alkeneealkene and alkeneearene double cycloisomerizations
,b,
Peipei Cui a, Liang Xu a, Hao Cheng a, Liangbing Gan a
*
a Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of RuCl3/AgOTf, pyrrolizidine derivative with styrenyl substituents at the 3,5-positions
undergo a 6-exo-trig cyclization and subsequent intramolecular FriedeleCrafts reactions to form deca-
hydropyrrolo[2,1,5-cd]indolizine or decahydrocycl[3.2.2]azine derivatives. The cycloisomerization is
highly stereoselective. Presence of electron donating groups on the styrenyl substituents inhibits the
double cycloisomerization process and results in a trans to cis epimerization instead. No reaction takes
place when electron withdrawing groups are present on the styrenyl substituents. Possible mechanisms
are proposed for the observed reactions.
Received 6 September 2011
Received in revised form 11 October 2011
Accepted 21 October 2011
Available online 28 October 2011
Keywords:
Cyclazine
Indolizine
Ó 2011 Elsevier Ltd. All rights reserved.
Pyrrolizidine
Cycloisomerization
Catalysis
1. Introduction
Pyrrolo[2,1,5-cd]indolizine or cycl[3.2.2]azine refers to 5-5-6
tricyclic compounds with an internal nitrogen atom. The word
‘cyclazine’ was originally proposed by Boekelheide in 1958 to de-
note ‘the general case of a conjugated unsaturated cycle held planar
by three covalent bonds to an internal nitrogen atom’.1 Compounds
with three six cycles would be named as cycl[3.3.3]azine according
to Boekelheide’s suggestion. Later Leaver suggested to move the
numerals into the front and to list the numerals in increasing order
rather than decreasing order, such as [2.2.3]cyclazine.2 Pyrrolo
[2,1,5-cd]indolizine is the name of [2.2.3]cyclazine according to the
IUPAC nomenclature.
N
N
Cycl[3,2,2]azine
Cycl[3,3,3]azine
H
N
Myrmicarin 430A
The first cyclazine, cycl[3.2.2]azine, was synthesized through atwo-
step cyclization procedure starting from indolizine by Boekelheide.1
Due to its aromatic properties, the nitrogen doped-tricyclic com-
pound has attracted much attention from both theoretical and syn-
thetic chemists. A number of different synthetic methods have been
reported for its synthesis.3e6 The most popular method is the (8þ2)-
cycloaddition of indolizine with an electron-deficient acetylene, such
as DMAD (dimethyl acetylenedicarboxylate).7e9 The cycl[3.2.2]azine
family has been shown to have pharmacological activity in binding
N
H
oestrogen receptor.10 Some cycl[3.2.2]azine derivatives are highly ef-
ficient fluorescent materials and can be used as light emitters.11,12
Partially hydrogenated cycl[3.2.2]azine derivatives have been
found in several natural products, such as the Myrmicarins, which
were isolated from the poison gland of the African ant species
Myrmicaria opaciventris.13,14 Several groups have prepared some
simple members of the Myrmicarin alkaloids.15e20 Compared to the
* Corresponding author. E-mail address: gan@pku.edu.cn (L. Gan).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.071

P. Cui et al. / Tetrahedron 68 (2012) 152e158
153
R1
synthesis of aromatic and partially hydrogenated cycl[3.2.2]azine,
fully hydrogenated cycl[3.2.2]azine has received little attention.21
In the case of other cyclazines, fully hydrogenated derivatives
have been well studied, such as the azaphenalene with three six-
membered rings or fully hydrogenated cycl[3.3.3]azine22 and aza-
triquinane with three five-membered rings or fully hydrogenated
cycl[2.2.2]azine.23
We have been interested in the synthesis of nitrogen containing
oligocyclic compounds.24e26 Recently we reported a highly ster-
eoselective synthesis of a fully hydrogenated cycl[3.2.2]azine de-
rivative through a ICl induced 6-exo-trig cyclization method.27
Further exploration of the method indicated that Lewis acid could
induce a double cyclization process affording oligocyclic derivative
with good stereoselectivity.28 Here we report the synthesis of
hexacyclic derivatives containing a fully hydrogenated cycl[3.2.2]
azine framework through consecutive [2þ3] cycloadditions and
RuCl3/AgOTf induced cyclization.
Ph
N
N
N
O
O
O
O
R1=R2=R3=H H3COOC
H3COOC
O
Ph
Cl
O
N
ICl
38%
N
N
O
R3
Ph
Ph
R1
O
I
2
R2
1
RuCl3
AgOTf
R1
R1
N
N
2. Results and discussion
N
N
O
H3COOC
O
O
O
H3COOC
O
O
2.1. Preparation of fully hydrogenated cycl[3.2.2]azine
derivatives
N
R3
N
O
R1
R1
O
Partially hydrogenated cycl[3.2.2]azine derivatives are currently
synthesized mainly through three pathways: (1) synthesis of pi-
perazine or pyridine derivatives with suitable functional groups at
the 2,6-positions, followed by two cyclization steps to form the
other two five-membered cycles;15,23,29 (2) synthesis of pyrrole
derivatives with suitable functional groups at the 2,5-positions,
followed by two cyclization steps to form the six- and five-
membered cycles;16,18 and (3) synthesis of suitable pyrrolizidine
derivative followed by a cyclization step to form the remaining six-
membered cycle.21,27
We have reported that the pyrrolizidine derivative 1a with two
alkenyl groups can react with ICl through a 6-exo-trig cyclization to
form the fully hydrogenated cycl[3.2.2]azine 2 with a total of 11
stereogenic carbons (Scheme 1). To investigate the mechanism of
the reaction, we treated 1a with various Lewis acids. It was found
that a combination of RuCl3 and AgOTf gave the best yield of
product 3a (87%).30 Another minor product was also detected in the
formation of 3a, but could not be fully characterized because its
yield was too low. In the reaction of 1b and 1c with a methoxy and
an isopropyl group on the amide phenyl group, respectively, yields
of the minor products 4b (2%) and 4c (4%) were high enough for
isolation and characterization.
The formation of compounds 4b and 4c were unexpected. The
conversion from 1 to 4 is just an epimerization process at one of the
pyrrolizidine carbon with styrenyl group. Unlike the trans-isomer 3,
the cis-isomer 4 does not undergo further cyclization reactions
under all the conditions tested including ICl. Interestingly, the se-
lectivity for products 3 and 4 could be switched completely when
one or two methoxyl groups were present on the styrenyl group.
Thus compounds 4d and 4e were obtained as the major product
with no detectable cyclazine derivative. The Lewis acid B(C6F5)3
could also induce the formation of 4d and 4e. In contrast, no re-
action was observed when one or two electron withdrawing nitro
groups were present on the styrenyl group as in the case of com-
pounds 3f and 3g.
R2
3
4
Entry
1a
1b
1c
1d
1e
1f
R1
R2
H
H
H
R3
Yield of 3 Yield of 4
H
OMe
iPr
H
H
H
H
H
87
42
34
-
-
-
-
2
4
OMe
OMe OMe
NO2
NO2
82 (96a)
H
H
H
77 (87a)
H
NO2
-
-
-
1g
(–) not detected; (a) using 1 eq. B(C6F5)3 as catalyst
Scheme 1. Reactions of compound 1.
obtain crystals for the dimeric complex 5.31 Treatment of 5 with
hexafluoroacetyl acetone afforded the monomeric complex 6. Slow
evaporation of a solution of 6 in CH2Cl2/iPrOH resulted in single
crystals suitable for X-ray diffraction analysis. The structure of 6
(Scheme 2) confirmed the relative stereochemistry of the styrenyl
groups as the trans-isomer. The rhodium atom and the two oxygen
and three carbon atoms in the acetyl ligand form a planar six-
membered ring. The two tricycles formed through the two
alkenyl ligands and rhodium atom are almost orthogonal to the six-
membered ring. The dihedral angles between the two tricycles and
ꢀ
the six-membered ring are 84.2 and 78.5 A respectively. The two
tricycles are also nearly orthogonal with each other (83.60 A).
ꢀ
To furtherexplore theepimerizationprocessof 1 to 4, we prepared
pyrrolizidine derivatives 7 and 9 following the same two-step [2þ3]
cycloaddition procedure used for compounds 1. Both 7 and 9 are
analogous to compound 1 and they also exhibit the epimerization
phenomenon. Treatment of 7 under the same conditions for the for-
mation of 4 afforded the epimer8. A basic conditionwas necessary for
the conversion of 9 to 10 as a result of the electron withdrawing ester
group. Single crystal structures of compounds 7, 9 and 10 were ob-
tained and confirmed the structure as depicted in Scheme 3.
2.2. Reactions and X-ray structures related to compound 1
and 4
The pyrrolizidine derivatives 1 and 4 showed the same HRMS as
expected for stereoisomers. To determine their stereochemistry, we
treated 1a with [Rh(CH2CH2)Cl]2 hoping that the metal complex
would be easier to grow single crystals. But it was not possible to
2.3. Characterization of compounds 3
Spectroscopic data are in agreement with the structural as-
signments for compounds 3. 1He1H COSY, DEPT, HMQC spectra

154
P. Cui et al. / Tetrahedron 68 (2012) 152e158
Ph
N
O
O
H3COOC
O
Ph
N
N
Ph
O
Ph
1a
Benzene
quant
[RhCl2(C2H4)2]2
O
Ph
O
Ph
N
N
N
N
Ph
Ph
Rh
O
O
Cl
Cl
H3COOC
COOCH3
N
Rh
N
O
O
Ph
Ph
Ph
O
O
Ph
5
DCM,
94%
(CF3CO)2CH2
Ph
O
N
N
Ph
CF3
O
O
H3COOC
N
Rh
O
O
CF3
Ph
Ph
O
6
Scheme 3. Epimerization of compounds 7 and 9 and X-ray crystal structures of 7, 9
and 10 (Blue N, Red O, Grey C).
Table 1
1H and 13C NMR chemical shifts for compound 3a (numbered as in Fig. 1)
1H
d
(ppm)
13C
d(ppm)
1a/1b
2
3
4
5
6
7
8
1.91/2.4
3.96
3.64
4.58
/
4.97
3.25
3.38
3.85
3.67
4.06
1
2
3
4
5
6
7
8
9
27.6
59.3
50.6
51.0
80.2
47.1
47.1
65.2
47.9
42.4
56.6
Scheme 2. Synthesis and X-ray crystal structure of rhodium complex 6 (Green F, Blue
N, Red O, Purple Rh, Grey C).
9
10
11
10
11
were obtained for both compounds 3a and 3b. These spectra helped
to assign all the non-aromatic proton and carbon chemical shifts
(see Supplementary data for complete lists). The chemical shifts in
the aromatic region are very close to each other and cannot be
assigned conclusively. The only CH2 group was readily identified
from the DEPT spectrum and served as the starting point in ana-
lyzing the spectra. Based on the chemical shifts of the CH2 group,
other signals were assigned according to correlation signals shown
on the 1He1H COSY and HMQC (Table 1). Stereochemistry of com-
pound 3a was determined from its NOESY spectrum. The spectrum
showed the expected NOE signals for the structure shown in Fig. 1.
2.4. Mechanism considerations
Two possible pathways are proposed for the cycloisomerization
Fig. 1. NOE signals for compound 3a.
of 1a to 3a (Scheme 4).28,30 The first step in pathway (1) is

P. Cui et al. / Tetrahedron 68 (2012) 152e158
155
Ph
N
the nitrogen is favoured because the phenylallenyl cation in-
termediate H is stabilized by the electron donating group. Recon-
nection of the broken nitrogen carbon bond in H and dissociation of
the ruthenium species then forms the epimer product (Scheme 5).
The epimerization of 7 to 8 should follow a similar pathway. The
electron withdrawing groups in compounds 1f and 1g probably
decrease the coordination ability of the alkene and thus inhibiting
both cyclization and isomerization. The Lewis acid B(C6F5)3 cata-
lyzed epimerization of 1d and 1e to 4d and 4e may go through
a similar CeN cleavage and reformation mechanism. In this case,
the Lewis acid just interacts with the pyrrolizidine nitrogen.
Ph
N
O
O
O
O
Friedel
Crafts
H3COOC
O
H3COOC
O
H
N
N
N
N
Ph
Ph
O
O
[Ru]
[Ru]
B
C
- H+
6-exo-trig
Ph
N
Ph
N
O
O
1 or 7
4 or 8
O
O
H3COOC
O
H3COOC
O
RuCl3 AgOTf
- [Ru]
N
N
N
Ph
N
Ar
N
Ph
Ar
N
O
O
O
O
[Ru]
O
O
[Ru]
H3COOC
O
+ H+
H3COOC
O
D
R1
R1
(1)
A
N
N
N
[Ru]
N
[Ru]
RuCl3
AgOTf
[Ru]
Alkene
Ar
Ar
1a
3a
+
Insertion
O
O
(2)
Ph
N
Ph
N
O
O
G
H
O
O
R2
R2
[Ru]
H3COOC
O
[Ru]
H3COOC
O
- H+
Scheme 5. Possible mechanism for epimerization.
N
N
N
N
Ph
Friedel
Crafts
Ph
The driving force for the epimerization should be mainly due to
steric effect. The cis-epimer 4, 8 and 10 are thermodynamically
more stable than the trans-epimer. The conversion of 9 to 10
should be a simple deprotonation and protonation process. The
easy conversion of 9 to 10 at rt provided convincing evidence for
their relative thermostability. Single crystal analysis data of both 9
and 10 unambiguously confirmed their structure as shown in
Scheme 3.
O
O
E
F
Scheme 4. Possible mechanisms for ruthenium catalyzed double cyclization process.
coordination of ruthenium to the less hindered styrenyl double
bond to form intermediate A. Addition of AgOTf is necessary to
activate the ruthenium species by forming RuCl2(OTf) and AgCl. A
6-exo-trig cyclization process involving the other styrenyl group cis
to the ester group then takes place to form intermediate B. The
benzyl cation in B adds to the adjacent phenyl group through
a FriedeleCrafts reaction to form intermediate C. Finally aromati-
zation and hydrolysis converts C to the cyclized product 3a. In the
ICl induced formation of compound 2,27 the initial process involves
the formation of a benzyl cation intermediate similar to B, which
was attacked by the nucleophilic chloride ion, preventing further
FriedeleCrafts reaction as in the present case.
In summary, an efficient method has been reported for the syn-
thesis of fully hydrogenated cycl[3.2.2]azine derivatives based on
Lewis acid induced cycloisomerization of pyrrolizidine derivatives
with styrenyl groups at the 3,5-positions. The method is formally an
intramolecular [2þ3] process. The mechanism involves a 6-exo-trig
cyclization and intramolecular FriedeleCrafts sequence. Sub-
stituents on the phenyl ring of the styrenyl group play an important
role in the double cyclization process. Presence of both the electron
donating OMe and electron withdrawing NO2 groups inhibits the
cyclization process. Further work is in progress in applying the
method to other pyrrolizidine derivatives with different sub-
stituents to synthesize new cycl[3.2.2]azine derivatives.
From the X-ray structure of compound 6, it is clear that both
styrenyl groups can coordinate to a metal atom. Thus instead of the
styrenyl group trans to the ester group, the ruthenium catalyst may
also coordinate to the styrenyl group cis to the ester group to form
intermediate E and induces an intramolecular hydroarenation to
form F as shown in pathway (2) in Scheme 4. Intramolecular alkene
insertion then converts F to D. But in this second pathway, the
presence of a trans alkene moiety on the nine-membered ring of F
is energetically unfavorable. Whereas in pathway (1) discussed
above, a six-membered and a five-membered rings are formed
sequentially. So, pathway (1) should be the dominant route leading
to compound 3.
3. Experimental section
All reagents were used as received. Dichloromethane (DCM) was
distilled over phosphorus pentoxide. Toluene and benzene was
distilled from sodium. Other solvents were used as received. The
reactions were carried out in air except for the preparation of
compounds 5 and 6, which were under nitrogen. Compounds 1
were prepared according to the procedure reported before.27 (see
Supplementary data for experimental procedure).
Besides the styrenyl group, the ruthenium catalyst could also
coordinate to the pyrrolizidine nitrogen atom to form intermediate
G. For compounds 1d and 1e with an electron donating methoxy
group on the para-position of the styrenyl group, coordination to
3.1. Compound 3a
A mixture of RuCl3$xH2O (100 mg, 0.32 mmol) and AgOTf
(240 mg, 0.94 mmol) in ClCH2CH2Cl (2.5 mL) was stirred vigorously

156
P. Cui et al. / Tetrahedron 68 (2012) 152e158
for 1 h. To the resulting solution was added compound 1a (100 mg,
0.15 mmol) in ClCH2CH2Cl (2.5 mL). The reaction mixture was
stirred at 80 ꢀC overnight. The product 3a was purified via silica gel
flash column chromatography (eluent: petroleum ether/ethyl ace-
tate, 4:1 v/v) as a white solid (87 mg, 87% yield). 1H NMR (500 MHz,
J¼24.1, 13.5 Hz, 1H), 1.28 (s, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H).
13C NMR (100 MHz, CDCl3)
176.5, 175.0, 174.8, 173.4, 170.2, 149.9,
d
149.4, 145.9, 144.5, 141.8, 129.2, 128.9, 128.8 (2C), 128.4 (2C), 127.5
(2C),127.3,127.1 (2C),126.9,126.3 (2C),125.5 (2C),124.7,124.2, 80.2,
65.1, 59.2, 56.6, 53.6, 51.0, 50.6, 47.9, 47.1, 47.1, 42.4, 33.9, 33.8, 29.6,
27.8, 23.7 (4C). FT-IR: 3025, 2959, 2927, 2870, 2854, 1739, 1713,
CDCl3)
d
7.52 (t, J¼7.7 Hz, 2H), 7.51e7.10 (m, 17H), 6.88 (d, J¼7.5 Hz,
1H), 4.97 (d, J¼8.0 Hz, 1H), 4.58 (d, J¼8.4 Hz, 1H), 4.06 (d, J¼9.2 Hz,
1H), 3.96 (dd, J¼18.3, 9.7 Hz, 1H), 3.85 (dd, J¼17.7, 8.9 Hz, 1H), 3.73
(s, 3H), 3.69e3.62 (m, 2H), 3.38 (dd, J¼8.7, 6.8 Hz, 1H), 3.25 (m, 1H),
2.43e2.27 (m, 1H), 1.91 (td, J¼13.5, 10.4 Hz, 1H). 13C NMR (125 MHz,
1515, 1384, 1220, 1187, 1130, 1055, 1102, 832, 810, 755, 700 cmꢁ1
.
ESI-HRMS: calcd for C47H46N3O6 [MþH]þ 748.3381, found
748.3380. Compound 4c 1H NMR (400 MHz, CDCl3)
d 7.43e7.21 (m,
18H), 6.57 (d, J¼15.7 Hz, 2H), 6.38 (dd, J¼15.7, 8.2 Hz, 1H), 6.10 (dd,
J¼16.0, 4.8 Hz, 1H), 4.86 (d, J¼8.5 Hz, 1H), 4.75 (d, J¼8.4 Hz, 1H),
4.47 (s, 1H), 3.80e3.67 (m, 3H), 3.5 (m, 3H), 1.31 (s, 3H), 1.29 (s, 3H),
CDCl3):
d 176.3, 174.8, 174.6, 173.2, 170.2, 131.7, 131.4, 130.8, 129.4
(2C), 129.1 (2C), 129.0, 128.8 (3C), 128.7, 128.5 (2C), 127.3, 127.2,
126.9, 126.6 (2C), 125.7 (2C), 124.7, 124.2, 65.2, 59.3, 56.6, 53.7, 51.0,
50.6, 47.9, 47.1, 47.1, 42.4; FT-IR: 3066, 3025, 2953, 2845, 1737, 1713,
1.27 (s, 3H), 1.25 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 176.9, 176.3,
174.7, 173.5, 170.6, 150.0, 149.6, 136.0, 135.9, 134.8, 131.1, 129.3, 129.1,
128.9, 128.6 (2C),128.5 (2C),128.2, 127.9,127.6 (2C),127.3 (2C),127.1
(2C), 126.4 (2C), 126.2 (2C), 125.7, 125.5 (2C), 81.6, 76.6, 70.2, 67.3,
53.4, 51.5, 51.1, 49.7, 47.1, 34.0, 33.9, 23.8 (4C). FT-IR: 3027, 2960,
2928, 2871, 2855, 1777, 1713, 1515, 1496, 1385, 1262, 1202, 1185,
1111, 966, 752, 694 cmꢁ1; ESI-HRMS: calcd for C47H46N3O6 [MþH]þ
748.3381, found 748.3386.
1498, 1382 cmꢁ1
664.2442, found 664.2446.
;
ESI-HRMS: calcd for C41H34N3O6 [MþH]þ
3.2. Compound 3b and Compound 4b
A mixture of RuCl3$xH2O (100 mg, 0.32 mmol) and AgOTf
(240 mg, 0.94 mmol) in ClCH2CH2Cl (3 mL) was stirred vigorously
for 1 h. To the resulting solution was added the compound 1b
(404 mg, 0.56 mmol) in ClCH2CH2Cl (2 mL). The reaction mixture
was stirred at 80 ꢀC overnight. The reaction mixture was purified
via silica gel flash column chromatography (eluent: dichloro-
methane/ethyl acetate, 20:1 v/v) to give the main product 3b
(169 mg, 42% yield) and another minor product 4b (8.5 mg, 2%
3.4. Compound 4d
To a solution of compound 1d (232 mg, 0.33 mmol) in DCM
(23 mL) was added B(C6F5)3 (171 mg, 0.33 mmol). After stirring at rt
for 2 h, the reaction mixture was concentrated in vacuum and pu-
rified via silica gel flash column chromatography (eluent: petro-
leum ether/ethyl acetate, 4:1 v/v) to give 4d as a white solid
yield). Compound 3b 1H NMR (500 MHz, CDCl3)
d 7.30e6.89 (m,
16H), 6.81 (d, J¼7.5 Hz, 1H), 4.88 (d, J¼8.0 Hz, 1H), 4.48 (d, J¼8.4 Hz,
1H), 3.99 (d, J¼9.2 Hz, 1H), 3.88 (dd, J¼18.3, 9.7 Hz, 1H), 3.81 (s, 3H),
3.78 (d, J¼8.8 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.62e3.58 (s, 1H),
3.57e3.53 (m, 1H), 3.28 (m, 1H), 3.16 (m, 1H), 2.31e2.25 (m, 2H),
(222 mg, 96% yield) 1H NMR (400 MHz, CDCl3):
d 7.51e7.20 (m,
17H), 6.82 (d, J¼8.6 Hz, 2H), 6.56 (d, J¼15.7 Hz, 1H), 6.49 (d,
J¼15.9 Hz, 1H), 6.38 (dd, J¼15.7, 8.1 Hz, 1H), 5.94 (dd, J¼15.9, 5.0 Hz,
1H), 4.84 (d, J¼8.6 Hz, 1H),4.74 (d, J¼8.4 Hz, 1H), 4.46 (t, J¼4.8 Hz,
1H), 3.77 (s, 3H), 3.72 (t, J¼8.0 Hz, 1H), 3.66 (dd, J¼8.4, 2.3 Hz, 1H),
3.59 (d, J¼8.2 Hz, 1H), 3.56 (s, 3H); 13C NMR (100 MHz, CDCl3):
1.82 (dd, J¼24.0, 13.5 Hz, 1H). 13C NMR (125 MHz, CDCl3)
d 176.5,
175.0, 174.8, 173.4, 170.2, 159.7, 159.5, 145.8, 144.4, 141.8, 128.7 (2C),
128.4 (2C), 127.7 (2C), 127.2, 127.1, 126.9 (2C), 126.8, 124.6, 124.3,
124.2, 123.9, 114.7 (2C), 114.3 (2C), 80.1, 65.0, 59.1, 56.5, 55.4, 55.3,
53.6, 50.9, 50.5, 47.9, 47.0 (2C), 42.3, 27.6. FT-IR: 3062, 3023, 3003,
2954, 2935, 2841, 1738, 1709, 1610, 1590, 1513, 1455, 1443, 1388,
1301, 1252, 1221, 1193, 1166, 1031, 831, 734 cmꢁ1. ESI-HRMS: calcd
for C43H38N3O8 [MþH]þ 724.2653, found 724.2667. Compound 4b
d
176.8, 176.2, 174.5, 173.4, 170.6, 135.8, 134.7, 131.7, 131.5, 130.5,
129.5 (2C), 129.1 (2C), 129.1, 128.8, 128.7, 128.5 (2C), 128.2, 127.6
(3C), 127.0 (2C), 126.5, 126.4 (2C), 125.8 (2C), 125.6, 114.0 (2C), 81.5,
70.1, 67.2, 55.2, 53.4, 51.4, 51.1, 49.7, 47.0; FT-IR: 3033, 2953, 2928,
2852, 1777, 1713, 1607, 1512, 1499, 1456, 1435, 1382, 1302, 1250,
1196, 1177, 1100, 1031, 966, 739, 692, 621 cmꢁ1; ESI-HRMS: calcd for
C42H36N3O7 [MþH]þ 694.2547, found 694.2537.
1H NMR (400 MHz, CDCl3)
2H), 6.37 (dd, J¼15.7, 8.2 Hz, 1H), 6.09 (dd, J¼15.9, 4.7 Hz, 1H), 4.84
(d, J¼8.5 Hz, 1H), 4.73 (d, J¼8.4 Hz, 1H), 4.46 (s, 1H), 3.87 (s, 3H),
3.82 (s, 3H), 3.78e3.66 (m, 3H), 3.58 (s, 3H). 13C NMR (100 MHz,
d
7.43e6.98 (m, 18H), 6.56 (d, J¼15.6 Hz,
3.5. Compound 4e
CDCl3)
d
177.0, 176.4, 174.7, 173.6, 170.6, 159.9, 159.7, 136.0, 135.9,
To a solution of compound 1e (396 mg, 0.55 mmol) in DCM
(40 mL) was added B(C6F5)3 (280 mg, 0.55 mmol). After stirring at
rt for 2 h, the reaction mixture was purified via silica gel flash
column chromatography (eluent: petroleum ether/ethyl acetate,
4:1 v/v) to give 4e as a white solid (344 mg, 87% yield). 1H NMR
134.7, 131.1, 128.9, 128.6 (2C), 128.5 (2C), 128.2, 127.9, 127.6 (2C),
127.1 (2C), 127.0 (2C), 126.4 (2C), 125.7, 124.4, 124.1, 114.9 (2C), 114.5
(2C), 81.6, 70.2, 67.3, 55.5, 55.5, 53.4, 51.5, 51.1, 49.7, 47.1. FT-IR:
3058, 3025, 2954, 2927, 2851, 1712, 1611, 1513, 1445, 1388, 1301,
1253, 1182, 1110, 1032, 966, 830, 753, 696 cmꢁ1; ESI-HRMS: calcd
for C43H38N3O8 [MþH]þ 724.2653, found 724.2638.
(400 MHz, CDCl3):
d
7.55e7.22 (m, 14H), 6.82(d, J¼8.3 Hz, 4H), 6.49
(d, J¼15.5 Hz, 2H), 6.23 (dd, J¼15.6, 8.3 Hz, 1H), 5.94 (dd, J¼15.9,
5.1 Hz, 1H), 4.83 (d, J¼8.5 Hz, 1H), 4.75 (d, J¼8.4 Hz, 1H), 4.47 (t,
J¼4 Hz, 1H), 3.78 (s, 3H), 3.78 (s, 3H), 3.71e3.65 (m, 2H), 3.56 (s,
3.3. Compound 3c and compound 4c
3H); 13C NMR (100 MHz, CDCl3):
d 176.9, 176.3, 174.6, 173.4, 170.7,
A
mixture of RuCl3$xH2O (80 mg, 0.25 mmol) and AgOTf
159.6, 159.4, 134.3, 131.7, 131.5, 130.5, 129.5 (2C), 129.2 (2C), 129.1,
128.8, 128.7, 128.6, 128.3 (2C), 127.6 (2C), 126.5, 126.4 (2C), 125.8
(2C), 123.2, 114.0 (2C), 113.9 (2C), 81.5, 70.3, 67.1, 55.2 (2C), 53.4,
51.4, 51.1, 49.7, 47.0; FT-IR: 3055, 2954, 2928, 2837, 1777, 1713, 1607,
1512, 1499, 1456, 1381, 1301, 1251, 1176, 1109, 1072, 1032, 966, 819,
739, 691, 620 cmꢁ1; ESI-HRMS: calcd for C43H38N3O8 [MþH]þ
724.2653, found 724.2625.
(192 mg, 0.75 mmol) in ClCH2CH2Cl was stirred vigorously for 1 h.
To the resulting solution was added the compound 1c (300 mg,
0.40 mmol) in ClCH2CH2Cl. The reaction mixture was stirred at
80 ꢀC overnight. The reaction mixture was purified via silica gel
flash column chromatography (eluent: dichloromethane/ethyl ac-
etate, 20:1 v/v) to give the main product 3c (102 mg, 34% yield) and
another minor product 4c (11 mg, 4% yield). Compound 3c 1H NMR
(400 MHz, CDCl3)
d
7.38e7.04 (m, 16H), 6.81 (d, J¼7.4 Hz, 1H), 4.91
3.6. Compound 5
(d, J¼8.0 Hz, 1H), 4.52 (d, J¼8.4 Hz, 1H), 3.99 (d, J¼9.3 Hz, 1H), 3.91
(dd, J¼18.4, 9.8 Hz, 1H), 3.78 (q, J¼8.9 Hz, 1H), 3.68 (s, 3H), 3.59 (m,
2H), 3.33 (m, 1H), 3.18 (t, J¼7.3 Hz, 1H), 2.28 (m, 1H), 1.82 (dd,
Rh2Cl2(C2H4)4 (124 mg, 0.32 mmol) was dissolved in benzene
(20 mL) under N2 atmosphere, then the benzene (20 mL) solution

P. Cui et al. / Tetrahedron 68 (2012) 152e158
157
of 1a (352 mg, 0.32 mmol) was added. The reaction mixture was
stirred at rt for 0.5 h and then the reaction solution was filtered
through Celite. The filtrate was concentrated to give the crude
product 5 (420 mg, containing unreacted Rh2Cl2(C2H4)4). 1H NMR
in ClCH2CH2Cl (2 mL). The reaction mixture was stirred at 80 ꢀC
overnight. The reaction mixture was purified via silica gel flash
column chromatography (eluent: petroleum ether/ethyl acetate,
5:1 v/v) to give a white solid 8 (42 mmol, 40%). 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
7.752e7.156(m, 40H), 6.826 (d, J¼7.2 Hz, 4H),
CDCl3):
d
7.56e7.21 (m, 15H), 6.81 (dd, J¼16.0, 2.0 Hz, 1H), 6.20 (dd,
5.680 (d, J¼12.0 Hz, 2H), 5.411 (d, J¼12.4 Hz, 2H), 5.278 (d,
J¼12.4 Hz, 2H), 4.696 (d, J¼8.2 Hz, 2H), 4.397e4.314 (m, 6H), 3.743
(s, 6H), 3.687 (t, J¼8.8 Hz, 2H), 3.604 (t, J¼8.8 Hz, 2H), 3.466 (d,
J¼16.0, 4.1 Hz, 1H), 4.91 (d, J¼8.5 Hz, 1H), 4.70 (d, J¼8.3 Hz, 1H),
4.40e4.36 (m, 1H), 3.87 (d, J¼7.7 Hz, 1H), 3.82 (s, 3H), 3.79 (d,
J¼7.8 Hz, 1H), 3.68 (dd, J¼8.3, 2.9 Hz, 1H), 3.46 (s, 3H). 13C NMR
J¼8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d
176.0 (2C), 174.7 (2C),
(100 MHz, CDCl3):d176.4, 176.0, 173.7, 173.6, 170.0, 168.3, 136.004,
173.9 (2C), 173.0 (2C), 169.5 (2C), 139.5 (2C), 137.9 (2C), 131.9 (2C),
131.1 (2C), 129.4 (4C), 129.3 (4C), 128.9 (4C), 128.9 (2C),128.8 (4C),
128.5 (4C), 128.4 (2C), 128.2 (6C), 127.7 (2C), 125.9 (4C), 125.8 (4C),
81.5 (2C), 79.1 (d, J¼5.1 Hz), 70.0 (d), 65.6 (d, J¼6.8 Hz), 63.9 (2C),
62.2 (2C), 53.4 (2C), 53.0 (d, J¼8.9 Hz), 50.8 (2C), 47.6 (2C), 47.2 (2C),
46.6 (2C); FT-IR: 3067, 3022, 3002, 2963, 1779, 1713, 1597, 1499,
1382, 1260, 1195, 1177, 1088, 1071, 1028, 756, 691 cmꢁ1; ESI-HRMS:
calcd for C82H66N6O12Rh2Cl [MꢁCl]þ 1567.2531, found 1567.2485.
131.8, 131.5, 131.2, 129.5 (2C), 129.2 (2C), 129.2, 128.9, 128.6 (2C),
128.0, 127.9, 126.6 (2C), 126.3 (2C), 125.9 (2C), 81.2, 68.6, 68.0, 53.5,
52.6, 51.5, 51.0, 47.9, 46.7. FT-IR: 3025, 2953, 2920, 2850, 1737, 1713,
1598, 1498, 1456, 1435, 1385, 1315, 1261, 1210, 1154, 969, 746,
692 cmꢁ1. ESI-HRMS: calcd for C35H30N3O8 [MþH]þ 660.2027,
found 620.2027.
3.10. Compound 9
3.7. Compound 6
Compound 9 was prepared with a procedure similar to com-
pound 1.27 (see Supplementary data for experimental procedure)
1H NMR(400 MHz, CDCl3):
d 7.52e7.43 (m, 6H), 7.29e7.22 (m, 4H),
To a solution of compound 5 (100 mg, 0.15 mmol) in DCM
(20 mL) was added hexafluroacetylacetone (100 mL, 0.15 mol). After
4.83 (d, J¼8.8 Hz, 1H), 4.43 (d, J¼8.0 Hz, 1H), 4.38 (dd, J¼9.2 Hz, 8.8,
2H), 3.78 (s, 3H), 3.76 (s,3H), 3.74 (s, 3H), 3.73e3.67 (m, 2H). 13C
NMR (100 MHz, CDCl3): 175.0, 174.1, 173.5, 173.4, 169.4, 169.3, 168.2,
131.5, 131.3, 129.5 (2C), 129.3 (2C), 129.2, 129.0, 129.5 (2C), 126.0
(2C), 82.3, 63.6, 63.4, 53.9, 52.9, 52.4, 50.4, 49.4, 48.1, 46.2. FT-IR:
1745, 1716 cmꢁ1.ESI-MS; C29H25N3O10 [MþH]þ 576. Anal. Calcd for
C 60.51%, H 4.38%, N 7.30%; Found C 60.00%, H 4.15%, N 7.05%.
Single crystals were obtained from slow evaporation of 9 in
DCM/EtOH. Crystal data for 9 C29H25N3O10, Mw¼621.59 g/mol,
T¼293(2) K, Trigonal, space group Rꢁ3, Unit cell dimensions:
stirring at rt for 0.5 h, the product 6 was purified via silica gel flash
column chromatography (eluent: petroleum ether/ethyl acetate,
4:1 to 3:1 v/v) as an orange solid (109 mg, 90% yield). FT-IR: 3058,
3024, 2959, 2928, 2855, 1716, 1626, 1499, 1381, 1257, 1212, 1152,
1104, 692 cmꢁ1; ESI-HRMS: calcd for C46H35F6N3O8Rh [MþH]þ
974.1377, found 974.1413.
Single crystals were obtained from slow evaporation of 6 in
DCM/iPrOH. Crystal data for 6 C46H35F6N3O8Rh, Mw¼1058.60 g/mol,
T¼173(2) K, Triclinic, space group Pꢁ1, Unit cell dimensions:
a¼12.988(3) A, b¼12.188(2) A, c¼23.837(5) A,
b
¼105.9000(10)ꢀ.
ꢀ
ꢀ
ꢀ
a¼38.457(2) A, b¼38.457(2) A, c¼12.712(1) A,
b
¼90ꢀ. V¼16,282(5)
ꢀ
ꢀ
ꢀ
3
V¼2189.2(8) A . Z¼2, rcalcd¼1.606 Mg mꢁ1. Reflections collected/
3
ꢀ
ꢀ
A . Z¼18, rcalcd¼1.141 Mg mꢁ1. Reflections collected/unique 37,709/
unique 29,227/9982 [R(int)¼0.0425]. Final R indices [I>2
s(I)]
6583 [R(int)¼0.0832]. Final
wR2¼0.2070. CCDC-190938.
R
indices [I>2
s
(I)] R1¼0.0792,
R1¼0.0604, wR2¼0.1549. CCDC-841587 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif (the same is true for the fol-
lowing compounds 7, 9 and 10).
3.11. Compound 10
To a solution of compound 9 (200 mg, 0.6 mmol) in THF, sodium
methoxide (40 mg, 0.7 mmol) was added and the solution was
stirred at rt. The reaction was monitored by TLC. After 2 days the
reaction mixture was concentrated in vacuum and the residue was
dissolved in dichloromethane and purified via silica gel flash col-
umn chromatography (eluent: petroleum ether/ethyl acetate, 4:1 v/
v) to give 10 as a white solid (106 mg, 92% yield). 1H NMR (400 MHz,
3.8. Compound 7
Compound 7 was prepared with a procedure similar to com-
pound 1.27 (see Supplementary data for experimental procedure)
1H NMR(400 MHz, CDCl3):
d
7.57e7.24 (m, 15H), 6.83 (d, J¼15.5 Hz,
1H), 6.16 (dd, J¼15.5 Hz, 1H), 4.81(d, J¼8.6 Hz, 1H), 4.47e4.40 (m,
2H), 4.09 (d, J¼9.8 Hz, 1H), 3.85 (s, 3H), 3.71e3.66 (m, 1H),
CDCl3):
d
7.53e7.39 (m, 6H), 7.28e7.23 (m, 4H), 4.87 (d, J¼8.0 Hz,
1H), 4.69 (d, J¼8.5 Hz, 1H), 4.23 (d, 1H). 13C NMR (100 MHz, CDCl3):
3.63e3.59 (m, 1H), 3.47 (s, 3H). 13C NMR(100 MHz, CDCl3):
d175.7,
d
175.5, 175.4, 173.1, 173.0, 169.8, 169.4, 168.8, 167.8, 131.4, 169.4,
174.1, 173.5, 173.3, 169.6, 169.5, 139.1, 135.6, 131.4, 131.3, 129.6 (2C),
129.3 (2C), 129.1, 128.6 (4C), 126.9 (2C), 126.6 (2C), 125.9 (2C), 119.2,
81.7, 65.9, 64.6, 53.9, 52.8, 52.0, 49.9, 47.9, 47.4. FT-IR: 1750,
1709 cmꢁ1. Anal. Calcd for C35H29N3O8: C 67.83%, H 4.72%, N 6.78%;
Found: C 67.55%, H 4.77%, N 6.60%.
169.8, 168.8, 167.8, 131.4, 131.0, 129.5 (2C), 129.2, 129.1 (2C), 128.9,
126.3 (2C), 125.8 (2C), 82.0, 68.7, 68.6, 53.5, 53.3, 52.7, 50.9, 48.9,
47.1, 47.0. FT-IR: 1744, 1716 cmꢁ1. ESI-HRMS: calcd for C29H25N3O10
[MþH]þ 576.1618, Anal. Calcd for C 60.51%, H 4.38%, N 7.30%; Found
C 60.63%, H 4.53%, N 7.25%.
Single crystals were obtained from slow evaporation of 7 in
DCM/iPrOH. Crystal data for 7 C35H29N3O8, Mw¼711.75 g mol,
T¼293(2) K, Monoclinic, space group P 2(1)/n, Unit cell dimensions:
Single crystals were obtained from slow evaporation of 10 in
DCM/iPrOH. Crystal data for 10 C29H25N3O10, Mw¼575.52 g/mol,
T¼293(2) K, Monoclinic, space group P2(1)/n, Unit cell dimensions:
a¼16.218(3) A, b¼11.577(2) A, c¼19.753(2) A,
¼103.709(4)ꢀ.
ꢀ
ꢀ
ꢀ
b
ꢀ
ꢀ
ꢀ
3
a¼11.833(2) A, b¼18.329(4) A, c¼13.246(3) A,
b
¼108.70(3)ꢀ.
V¼3603.1(12) A . Z¼4, rcalcd¼1.312 Mg mꢁ1. Reflections collected/
ꢀ
V¼2721.2(10) A . Z¼4, rcalcd¼1.405 Mg mꢁ1. Reflections collected/
3
ꢀ
unique 30,717/6305 [R(int)¼0.0741]. Final
R1¼0.0720, wR2¼0.1557. CCDC-841586.
R indices [I>2s(I)]
unique 22,930/5935 [R(int)¼0.0566]. Final R indices [I>2
R1¼0.0478, wR2¼0.1055. CCDC-190939.
s(I)]
3.9. Compound 8
Acknowledgements
A mixture of RuCl3$xH2O (30 mg, 0.09 mmol) and AgOTf (70 mg,
0.27 mmol) in ClCH2CH2Cl (3 mL) was stirred vigorously for 1 h. To
the resulting solution was added compound 7 (106 mg, 0.17 mmol)
This work is supported by NSFC and the Major State Basic Re-
search Development Program.

158
P. Cui et al. / Tetrahedron 68 (2012) 152e158
14. Schroder, F.; Sinnwell, V.; Baumann, H.; Kaib, M.; Francke, W. Angew. Chem., Int.
Supplementary data
Ed. 1997, 36, 77.
15. Schroder, F.; Francke, W. Tetrahedron 1998, 54, 5259.
16. Sayah, B.; Pelloux-Leon, N.; Vallee, Y. J. Org. Chem. 2000, 65, 2824.
17. Sayah, B.; Pelloux-Leon, N.; Milet, A.; Pardillos-Guindet, J.; Vallee, Y. J. Org.
Chem. 2001, 66, 2522.
18. Movassaghi, M.; Ondrus, A. E. Org. Lett. 2005, 7, 4423.
19. Snyder, S. A.; ElSohly, A. M.; Kontes, F. Angew. Chem., Int. Ed. 2010, 49, 9693.
20. Ondrus, A. E.; Kaniskan, H. U.; Movassaghi, M. Tetrahedron 2010, 66, 4784.
21. Diaz-Gavilan, M.; Galloway, W. R. J. D.; O’Connell, K. M. G.; Hodkingson, J. T.;
Spring, D. R. Chem. Commun. 2010, 776.
Spectroscopic data for compounds not listed above. Supple-
mentary data associated with this article can be found, in the online
version, at doi:10.1016/j.tet.2011.10.071.
References and notes
1. Boekelheide, V.; Windgassen, R. J. J. Am. Chem. Soc. 1958, 80, 2020.
2. Leaver, D. Pure Appl. Chem. 1986, 58, 143.
3. Gibson, W. K.; Leaver, D.; Roff, J. E.; Cummings, C. W. J. Chem. Soc., Chem.
22. Gerasyuto, A. I.; Hsung, R. P. J. Org. Chem. 2007, 72, 2476.
23. Jevric, M.; Zheng, T.; Meher, N. K.; Fettinger, J. C.; Mascal, M. Angew. Chem., Int.
Ed. 2011, 50, 717.
Commun. 1967, 214.
24. Shi, Y. R.; Gan, L. B.; Wei, X. L.; Jin, S.; Zhang, S.; Meng, F. Y.; Wang, Z. M.; Yan, C.
4. Babaev, E. V.; Simonyan, V. V.; Pasichnichenko, K. Y.; Nosova, V. M.; Kisin, A. V.;
Jug, K. J. Org. Chem. 1999, 64, 9057.
5. Gogoi, S.; Dutta, M.; Gogoi, J.; Boruah, R. C. Tetrahedron Lett. 2011, 52, 813.
6. Hu, J. X.; Jiang, X.; He, T.; Zhou, J.; Hu, Y. F.; Hu, H. W. J. Chem. Soc., Perkin Trans. 1
2001, 1820.
7. Galbraith, A.; Small, T.; Barner, R. A.; Boekelheide, V. J. Am. Chem. Soc.1961, 83, 453.
8. Matsumoto, K.; Uchida, T.; Yoshida, H.; Toda, M.; Kakehi, A. J. Chem. Soc., Perkin
Trans. 1 1992, 2437.
9. Tominaga, Y.; Sasaki, K.; Castle, R. N. J. Heterocycl. Chem. 1998, 35, 1219.
10. (a) Kanstrup, A.; Thorpe, S. M.; Bain, S.; Naerum, L.; Wassermann, K. Bioorg.
Med. Chem. Lett. 2000, 10, 399; (b) Jorgensen, A. S.; Jacobsen, P.; Christiansen, L.
B.; Bury, P. S.; Kanstrup, A.; Thorpe, S. M.; Naerum, L.; Wassermann, K. Bioorg.
Med. Chem. Lett. 2000, 10, 2383.
H. Org. Lett. 2000, 2, 667.
25. Cheng, H.; Gan, L. B.; Shi, Y. R.; Wei, X. L. J. Org. Chem. 2001, 66, 6369.
26. Zhang, G. H.; Huang, S. H.; Xiao, Z.; Chen, Q.; Gan, L. B.; Wang, Z. M. J. Am. Chem.
Soc. 2008, 130, 12614.
27. Cui, P. P.; Xu, L.; Shi, Z. J.; Gan, L. B. J. Org. Chem. 2011, 66, 6369.
28. For reviews on transition metal catalyzed cycloisomerization reactions see: (a)
Trost, B. M.; Krische, M. J. Synlett 1998, 1; (b) Shen, H. C. Tetrahedron 2008, 64,
7847; (c) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A.
Chem. Rev. 2011, 111, 1954.
29. Kanemasa, S.; Takenaka, S.; Watanabe, H.; Tsuge, O. J. Org. Chem. 1989, 54, 420.
30. For examples, of ruthenium catalyzed intramolecular cycloisomerizations see:
(a) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581; (b) Ohta, T.;
Kataoka, Y.; Miyoshi, A.; Oe, Y.; Furukawa, I.; Ito, Y. J. Organomet. Chem. 2007,
692, 671.
31. The structure of 5 was assumed as the dimer shown in Scheme 2 by comparison
to analogous rhodium complexes Crabtree, R. H. The Organometallic Chemistry
of the Transition Metals; Wiley: New York, NY, 1994.
11. Mitsumori, T.; Bendikov, M.; Dautel, O.; Wudl, F.; Shioya, T.; Sato, H.; Sato, Y. J.
Am. Chem. Soc. 2004, 126, 16793.
12. Shen, Y. M.; Grampp, G.; Leesakul, N.; Hu, H. W.; Xu, J. H. Eur. J. Org. Chem. 2007,
22, 3718.
13. Schroder, F.; Sinnwell, V.; Baumann, H.; Kaib, M. Chem. Commun. 1996, 2139.