Ipso -Iodocyclization of ethoxyethyl ethers to alkynes at the ortho -position: An efficient synthesis of functionalized spiro compounds

Article abstract of DOI:10.1055/s-0029-1218569

An efficient approach to the synthesis of azaspiro compounds having dissymmetric dienone cores was achieved by ipso-iodocyclization of ethoxyethyl ether to alkynes. When the linker was an ether or an ester, domino iodocyclizaion/Diels-Alder reaction proceeded to afford the dimer, which can be transformed into the bridgehead-spiro connection ring system by a domino retro-Diels-Alder/Diels-Alder process.

Full text of DOI:10.1055/s-0029-1218569

LETTER
203
ipso-Iodocyclization of Ethoxyethyl Ethers to Alkynes at the ortho-Position:
An Efficient Synthesis of Functionalized Spiro Compounds
i
pso-
Iodocycliza
a
tion of
E
th
k
oxyethyl
E
th
a
ers to Alky
s
nes hi Okitsu,a Daisuke Nakazawa,a Akihiro Kobayashi,a Masahiro Mizohata,a Yasuko In,b Toshimasa Ishida,b
Akimori Wada*a
a
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi,
Higashinada-ku, Kobe 658-8558, Japan
Fax +81(78)4417562; E-mail: a-wada@kobepharma-u.ac.jp
Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka 569-1094, Japan
b
Received 15 October 2009
the construction of practical building blocks for the syn-
Abstract: An efficient approach to the synthesis of azaspiro com-
thesis of spiro compounds and for further development of
our iodocyclization project, we extended the ipso-iodo-
cyclization of aryl ethoxyethyl ether 1a, which has two at-
pounds having dissymmetric dienone cores was achieved by ipso-
iodocyclization of ethoxyethyl ether to alkynes. When the linker
was an ether or an ester, domino iodocyclizaion/Diels–Alder reac-
tion proceeded to afford the dimer, which can be transformed into oms as a linker between an alkyne and an aromatic ring at
the bridgehead-spiro connection ring system by a domino retro-
Diels–Alder/Diels–Alder process.
the ortho position, to obtain 1-azaspiro[4.5]decane-3,7,9-
trien-6-one (2a; Table 1). Our aims were as follows: (1)
the produced dissymmetric dienone ring would be amena-
ble to further functionalization by cycloaddition; (2) no
toxic halomethanes should be produced (which is possible
using this approach because the precursor 1a is an ethoxy-
Key words: iodocyclization, spiro compounds, heterocycles, dom-
ino reaction, Diels–Alder reaction
Iodocyclization has become very important in recent ethyl ether derivative rather than an anisole derivative).
years because of the low cost and high performance of Although the construction of a spirocyclic compound con-
iodinating reagents, the possibility of environmentally taining a dissymmetric dienone core by ipso-iodocycliza-
friendly reactions, and the natural abundance of iodine.1,2 tion has been reported, there is only one example.4b
Especially, iodocyclizaton of compounds containing a tri- Therefore, an optimized and general method for the syn-
ple bond produces aryl and vinyl iodides, which can be thesis of dissymmetric dienones was required. The condi-
further utilized for metal-catalyzed coupling reactions. tions tested to optimize the ipso-iodocyclization are
We recently achieved a versatile synthesis of 3-iodoben- shown in Table 1. First, we chose bis(2,4,6-collidine)io-
zo[b]furans by iodocyclization of ethoxyethyl ethers, donium(I) hexafluorophosphate [I(coll)2PF6] as an iodi-
which act as oxygen nucleophiles, to alkynes.3 The ethoxy- nating reagent because this worked well in our previous
ethyl ether moiety serves not only as a protecting and a di- studies.3 The presence of BF3·OEt2 as an additive was cru-
recting group for the preparation of precursors, but also cial for the iodocyclization (Table 1, entries 1 and 2) and
acts as a leaving group in the iodocyclization. Further- reaction temperature was tuned to –40 °C to achieve bet-
more, whereas the iodocyclization of anisole derivatives ter results (entries 2–5). Four equivalents of iodinating re-
as substrates produces carcinogenic halomethanes,2h,4a our agent were found to be essential (entries 4, 6, and 7). We
method produces less toxic byproducts based on the oxo- also found that the combination of N-iodosuccinimide
nium ion (Scheme 1).
(NIS) and BF3·OEt2 proceeded best to afford 2a in 89%
yield (entry 9).6 Using the combination of NIS and n-Bu3P
in place of NIS/BF3·OEt2 was not efficient and only led to
deprotection of ethoxyethyl ether (entry 10).7
1-Aza- and 1-oxaspiro[4.5]decane are important and
unique frameworks found in natural products.5 However,
whereas the 1-azaspiro[4.5]deca-3,6,9-triene skeleton has
been constructed by ipso-halocyclizations, most of its Once the optimized reaction conditions were established,
products are limited to the symmetric dienone unit.4 For the scope of usable substrates was next examined
(Table 2). Various aryl and vinylic substituents on the
R
alkyne were available with the trifluoroacetamide as a
protecting group (Table 2, entries 1–5). Unfortunately,
alkyl (n-Bu and t-Bu) groups on the alkyne as substrates
were not suitable under our conditions, and no cyclized
products were obtained (entries 6 and 7).
I
I(coll)2PF6
BF3⋅OEt2
+
R
OEt
CH2Cl2
r.t., 10 min
O
O
less toxic
OEt
Next, we examined substrates containing a range of amide
groups (Table 3). Whereas N-methyl and N-benzyl amide
groups as linkers were also effective for the ipso-iodocy-
clization (entries 1 and 2), substrates containing a second-
ary (NH) amide failed to generate the corresponding
Scheme 1
SYNLETT 2010, No. 2, pp 0203–0206
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218569; Art ID: U10509ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

204
T. Okitsu et al.
LETTER
Table 1 Optimization of ipso-Iodocyclization
Table 3 ipso-Iodocyclization of Amides 1i–la
Ac
N
Ph
Ac
Entry Amide 1
Product 2
Time Yield
(h) (%)b
[I+]
(4 equiv)
N
I
CH2Cl2
Me
Ph
O
Ph
O
O
N
Me
N
2a
OEt
1a
I
1
2
3.0 60
O
O
Ph
Entry [I+] Source
Additivea
Temp
(°C)
Time
(h)
Yield
(%)b
O
OEt
2i
1i
1j
Bn
N
Ph
1
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
I(coll)2PF6
ICl
none
r.t.
0.5
0.1
2.5
3.0
3.0
3.0
3.0
1.5
3.0
24
0
O
Bn
N
2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
none
r.t.
31
60
74
68
64
50
49
89
0
I
4.0 89
O
O
3
–20
–40
–60
–40
–40
–40
–40
–40
Ph
O
OEt
4
2j
5
Bn
N
Ph
O
Bn
N
6c
7c
8
I
3
4
2.5 83
O
O
Ph
O
OEt
2k
1k
9
NIS
BF3·OEt2
n-Bu3P
O
Bn
N
Ph
Bn
10
NIS
N
I
a Equivalents of additive was the same as that of the [I+] source.
b Isolated yield.
2.5 80
O
O
Ph
c 3 equiv (entry 6) and 5 equiv (entry 7) of both reagents were used.
O
OEt
1l
Table 2 Synthesis of 1-Azaspiro[4.5]decane-3,6,8-trien-5-ones 2b–h
2l
COCF3
N
R
a Reaction conditions: NIS (4 equiv), BF3·OEt2 (4 equiv), CH2Cl2 (0.1
F3COC
4 equiv NIS
4 equiv BF3⋅OEt2
CH2Cl2
–40 °C, 1.5 h
M), –40 °C.
N
I
b Isolated yield.
O
R
O
Table 4 ipso-Iodocyclization of Ethers 1m–q
2b–h
OEt
I
R
1b–h
4 equiv NIS
4 equiv BF3⋅OEt2
O
O
R
O
I
R
O
Entry
Alkyne 1
R
Product 2 Yield (%)a
O
CH2Cl2
–40 °C, 1.5 h
O
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
Ph
2b
2c
2d
2e
2f
62
58
54
68
59
0
OEt
1m–q
4-MeOC6H4
2-thienyl
3-thienyl
1-cyclohexenyl
n-Bu
2m–q
Entry
Alkyne 1
R
Product 2 Yield (%)a
1
2
3
4
5
1m
1n
1o
1p
1q
Ph
2m
2n
2o
90
94
87
83
67
4-MeOC6H4
2-thienyl
3-thienyl
1-cyclohexenyl
1g
1h
2g
2h
t-Bu
0
2p
2q
a Isolated yield.
a Isolated yield.
product. Naphthalene derivatives 1k and 1l could also be
used, giving tricyclic spiroamides 2k and 2l in good yields
(entries 3 and 4).
(Table 4). The structure of 2m was unambiguously as-
signed by single-crystal X-ray analysis (Figure 1).8 This
architecture was also afforded in high yield by the reac-
tion of ester 1r as a substrate (Scheme 2).
It is noteworthy that compounds with an ether linker
generated the pentacyclic dispiro compounds 2m–q
Synlett 2010, No. 2, 203–206 © Thieme Stuttgart · New York

LETTER
ipso-Iodocyclization of Ethoxyethyl Ethers
205
Based on the outcomes of these reactions, we developed a
plausible reaction mechanism (Scheme 3). In this postu-
lated mechanism, the reaction of NIS and BF3·OEt2 gen-
erates the active iodonium species A. The anti attack of
electrophile A and the electron-rich aromatic ring, fol-
lowed by elimination of an oxonium ion from C, affords
the spiro compound E. In no case was 6-exo-cyclization
initiated by the attack of the phenolic oxygen atom ob-
served, although the reason for this is unknown. The oxo-
nium ion might be trapped by imide salt B to generate the
N,O-acetal D. In compounds with ether and ester linkages
(X = O), Diels–Alder (DA) dimerization of E occurs due
to the fact that oxygen linkers are less hindered than those
containing nitrogen. The [4+2] cycloaddition of F pro-
ceeds in the sterically least hindered manner to generate
dimer G. The regio- and stereochemistry of G is the same
as for the related DA adducts of cyclohexadienones.9 Al-
though oxidative ortho-quinol formation followed by self
dimerization is well known,9 to the best of our knowledge,
this is the first report of a domino reaction involving io-
docyclization and DA reactions.
Figure 1 ORTEP drawing of compound 2m
I
O
Ph
4 equiv NIS
4 equiv BF3⋅OEt2
CH2Cl2
–40 °C, 0.5 h
O
O
Ph
O
I
Ph
O
O
O
O
O
These interesting results prompted us to apply the DA
dimer to the domino reaction of a retro-DA/DA reaction.10
Thus, this domino process was performed using the reac-
tion of 2m and N-phenylmaleimide in mesitylene at
OEt
1r
2r 93%
Scheme 2
BF3
BF3
O
O
O
NIS
+
BF3⋅OEt2
N
N
N
I
OEt
O
O
A
O
B
D
R1
I
I
I
R1
X
OEt
X
R1
I
R1
X
O
I
R1
O
[4 + 2]
X = O
O
R1
O
O
O
O
O
O
O
E
O
I
OEt
OEt
X = N–R2
G
R1
C
F
Scheme 3
Bu3Sn
OH
Ph
Pd2(dba)3⋅CHCl3
Ph3As, CsF
OH
O
Ph
N
I
Ph
DMF
50 °C, 3.5 h
O
O
Ph
N
Ph
O
O
O
I
I
Ph
O
O
O
O
Ph
4a 49%
N
mesitylene
160 °C, 2 h
O
O
TMS
TMS
O
PdCl2(PPh3)2
CuI, Et2NH
O
Ph
O
2m
3 98%
Ph
N
DMF
r.t., 3.5 h
O
O
O
4b 73%
Scheme 4
Synlett 2010, No. 2, 203–206 © Thieme Stuttgart · New York

206
T. Okitsu et al.
LETTER
Larock, R. C. J. Org. Chem. 2006, 71, 62. (k) Yao, T.;
Larock, R. C. J. Org. Chem. 2005, 70, 1432. (l) Yao, T.;
Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511.
(m) Khan, Z. A.; Wirth, T. Org. Lett. 2009, 11, 229.
(3) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org.
Lett. 2008, 10, 4967.
160 °C, to afford the cycloadduct 3 in 98% yield
(Scheme 4). Another advantage of our methodology is
that it accepts the C–C bond formation at the C–I bond by
Pd-catalyzed reactions. Thus, we were able to extend the
carbon-skeleton of 3 by either CsF-promoted Stille cou-
pling,11 or Sonogashira coupling, to provide 4a and 4b in
good yields. Three steps from 1m to 4a and 4b involve
dearomatizing iodocyclization, a domino DA reaction,
and a coupling reaction to achieve efficient molecular
transformations and allow the construction of a unique
bridgehead-spiro connection ring system.
(4) (a) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
12230. (b) Tang, B.-X.; Tang, D.-J.; Tang, S.; Yu, Q.-F.;
Zhang, Y.-H.; Liang, Y.; Zhong, P.; Li, J.-H. Org. Lett.
2008, 10, 1063. (c) Yu, Q.-F.; Zhang, Y.-H.; Yin, Q.; Tang,
B.-X.; Tang, R.-Y.; Zhong, P.; Li, J.-H. J. Org. Chem. 2008,
73, 3658. (d) Tang, B.-X.; Yin, Q.; Tang, R.-Y.; Li, J.-H.
J. Org. Chem. 2008, 73, 9008. (e) Wang, Z.-Q.; Tang,
B.-X.; Zhang, H.-P.; Wang, F.; Li, J.-H. Synthesis 2009, 891.
(5) (a) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.;
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M.
J. Antibiot. 1996, 49, 37. (b) Biard, J. F.; Guyot, S.;
Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.;
Boukef, K. Tetrahedron Lett. 1994, 35, 2691. (c) Imai, H.;
Suzuki, K.; Morioka, M.; Numasaki, Y.; Kadota, S.; Nagai,
K.; Sato, T.; Iwanami, M.; Saito, T. J. Antibiot. 1987, 40,
1475. (d) Bister, B.; Bischoff, D.; Ströbele, M.; Riedlinger,
J.; Reicke, A.; Wolter, F.; Bull, A. T.; Zähner, H.; Fiedler,
H.-P.; Süssmuth, R. D. Angew. Chem. Int. Ed. 2004, 43,
2574.
(6) General Procedure for ipso-Iodocyclization: To a solution
of 1a (51.0 mg, 0.150 mmol) in anhydrous CH2Cl2 (1.5 mL)
was added NIS (142 mg, 0.600 mmol) followed by BF3·OEt2
(74 mL, 0.600 mmol) at –40 °C. When the reaction was
complete, the mixture was diluted with sat. aq Na2S2O3 and
the mixture was extracted with CH2Cl2. The organic layer
was dried over Na2SO4, filtered, and evaporated in vacuo.
The residue was purified by flash column chromatography
on silica gel (hexane–EtOAc = 1:1) to give 2a (52.8 mg,
89%). N-Acetyl-3-iodo-4-phenyl-1-azaspiro[4,5]deca-
3,7,9-trien-6-one (2a): yellow amorphous solid. IR (CHCl3):
3017, 1676, 1655 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.35–7.27 (3 H, m), 7.03–7.01 (2 H, m), 6.71 (ddd, J = 10.0,
4.5, 3.0 Hz, 1 H), 6.23–6.22 (m, 2 H), 6.01 (d, J = 9.5 Hz,
1 H), 4.78 (d, J = 13.5 Hz, 1 H), 4.61 (d, J = 13.5 Hz, 1 H),
2.12 (s, 3 H). 13C NMR (125 MHz, CDCl3): d = 197.2, 167.5,
145.9, 141.1, 138.9, 132.6, 128.9, 128.8, 128.0, 126.9,
123.5, 91.2, 77.7, 62.9, 21.8. HRMS (EI): m/z [M]+ calcd for
C17H14INO2: 391.0069; found: 391.0080.
In summary, we have constructed 1-aza-3-iodo-
spiro[4.5]deca-3,7,9-trien-6-ones through the ipso-iodo-
cyclization of ethoxyethyl ether to alkynes. When the
linker between the aromatic ring and the triple bond was
an ether or an ester, a domino reaction of ipso-iodo-
cyclization and DA reaction occurred. In addition, an oxa-
cyclic compound could be further functionalized by
domino retro-DA/DA reactions to construct a novel
bridgehead-spiro connection ring system. Further Pd-cat-
alyzed reactions escalated the molecular complexity and
diversity. This strategy may expand the scope of research
into bioactive compounds that are difficult to synthesize
by other methods. Determining the scope and limitations
of our synthetic methodology and further applications are
ongoing.
Acknowledgment
We thank Dr. Miyoko Kamigauchi for help with the recrystallizati-
on of 2m for X-ray crystallography. This work was supported in
part by a Grant-in-Aid for Encouragement of Young Scientists from
the Ministry of Education, Culture, Sports, Science and Technolo-
gy.
References and Notes
(1) For reviews, see: (a) Togo, H.; Iida, S. Synlett 2006, 2159.
(b) Larock, R. C. Acetylene Chem. 2005, 51. (c) French,
A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33, 354.
(2) For selected papers on the iodocyclizations of alkynes, see:
(a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.;
Yamamoto, Y. Angew. Chem. Int. Ed. 2007, 46, 4764.
(b) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C.
J. Org. Chem. 2007, 72, 1347. (c) Halim, R. H.; Scammells,
P. J.; Flynn, B. L. Org. Lett. 2008, 10, 1967. (d) Barluenga,
J.; Palomas, D.; Rubio, E.; González, J. M. Org. Lett. 2007,
9, 2823. (e) Garud, D. R.; Koketsu, M. Org. Lett. 2008, 10,
3319. (f) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.;
Huang, S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9,
397. (g) Barluenga, J.; Trincado, M.; Rubio, E.; González,
J. M. Angew. Chem. Int. Ed. 2006, 45, 3140. (h) Yue, D.;
Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292.
(i) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M.
Angew. Chem. Int. Ed. 2003, 42, 2406. (j) Yue, D.; Yao, T.;
(7) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
(8) CCDC 731726 (2m) contains the supplementary
crystallographic data for this paper. This data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(9) (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev.
2004, 104, 1383. (b) Kürti, L.; Szilágyi, L.; Antus, S.;
Nógrádi, M. Eur. J. Org. Chem. 1999, 2579. (c)Bérubé,A.;
Drutu, I.; Wood, J. L. Org. Lett. 2006, 8, 5421.
(10) (a) Chittimalla, S. K.; Shiao, H.-Y.; Liao, C.-C. Org. Biomol.
Chem. 2006, 4, 2267. (b) Dong, S.; Hamel, E.; Bai, R.;
Covell, D. G.; Beutler, J. A.; Porvo, J. A. Jr. Angew. Chem.
Int. Ed. 2009, 48, 1494.
(11) Okitsu, T.; Iwatsuka, K.; Wada, A. Chem. Commun. 2008,
6330.
Synlett 2010, No. 2, 203–206 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.