Facile synthesis of azaspirocycles via iron trichloride-promoted cyclization/chlorination of cyclic 8-Aryl-5-aza-5-tosyl-2-en-7-yn-1-ols

Article abstract of DOI:10.1021/ol300434m

A simple and efficient FeCl₃-promoted cyclization/chlorination of cyclic tosylamine-tethered 8-aryl-2-en-7-yn-1-ols was observed. The reaction proceeded instantaneously at 23 °C in air to afford (Z)-4- (arylchloromethylene)-substituted azaspiro

Full text of DOI:10.1021/ol300434m

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1830–1833
Facile Synthesis of Azaspirocycles via
Iron Trichloride-Promoted Cyclization/
Chlorination of Cyclic 8-Aryl-5-aza-5-tosyl-
2-en-7-yn-1-ols
Ming-Chang P. Yeh,* Cheng-Wei Fang, and Hsin-Hui Lin
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road,
Section 4, Taipei 11677, Taiwan, Republic of China
cheyeh@ntnu.edu.tw
Received February 22, 2012
ABSTRACT
A simple and efficient FeCl3-promoted cyclization/chlorination of cyclic tosylamine-tethered 8-aryl-2-en-7-yn-1-ols was observed. The reaction
proceeded instantaneously at 23 °C in air to afford (Z)-4-(arylchloromethylene)-substituted azaspirocycles in good to excellent yields. This
transformation can also be applied to the synthesis of spirocarbocyclic analogues from cyclic 8-aryl-2-en-7-yn-1-ols and FeCl3.
Azaspirocycles are important synthetic building blocks
in alkaloid chemistry because such ring skeletons are
present in many naturally occurring substances of biolo-
gical properties.1 Many synthetic methods, as the key step,
have been developed in pursuit of these structures, includ-
ing the platinum(II)-catalyzed intramolecular cyclization
of cyclic enesulfoamides bearing an alkyne tether,2a the
ene-type cyclization of cyclic nitrogen-tethered 1,7-enynes
catalyzed by the cationic palladium complex,2b the
samarium(II)-mediated cyclization of unsaturated
ketolactams,2c the intramolecular radical cyclization of cyclic
enamines carrying an alkylbromide,2d the palladium-cata-
lyzed transformation of 3,4-dihydro-2-pyridinones carrying
a
(2-bromophenyl)ethyl substituent,2e the ytterbium-
catalyzed intramolecular hydroamination of alkenes,2f the
zirconium-catalyzed cyclization of diallylamines,2g and the
1,3-dipolar cycloaddition reactions of azomethine ylides with
olefins and acetylenes.2hÀj Recently, iron complexes have
emerged as inexpensive and low-toxicity substitutes for pre-
cious metals allowing numerous synthetic transformations of
unsaturated systems into useful structure motifs.3 Although
iron(0)-ate complex-catalyzed cycloisomerization of enynes
with cyclic alkenes via an Alder-ene reaction affording
fused bicycles,4 iron-catalyzed redox radical cyclization
of 1,6-dienes and enynes producing five-membered carbo- or
(1) (a) Yang, L.; Morriello, G.; Prendergast, K.; Cheng, K.; Jacks, T.;
Chan, W. S.; Schleim, K. D.; Smith, R. G.; Patchett, A. A. Biorg. Med.
Chem. Lett. 1998, 8, 107. (b) Ma, Z.; Chu, D. T. W.; Cooper, C. S.; Li, Q.;
Fung, A. K. L.; Wang, S.; Shen, L. L.; Flamm, R. K.; Nilius, A. M.;
Alder, J. D.; Meulbroek, J. A.; Or, Y. S. J. Med. Chem. 1999, 42, 4202. (c)
Makovec, F.; Peris, W.; Revel, L.; Giovanetti, R.; Mennuni, L.; Rovati,
L. C. J. Med. Chem. 1992, 35, 28. (d) Dake, G. Tetrahedron 2006, 62,
3467. (e) Li, M; Dixon, D. J. Org. Lett. 2010, 12, 3784.
~
(3) (a) Correa, A.; Mancheno, O. G.; Bolm, C. Chem. Soc. Rev. 2008,
37, 1108. (b) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed.
(2) (a) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9,
367. (b) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704. (c)
Guazzelli, G.; Duffy, L. A.; Procter, D. J. Org. Lett. 2008, 10, 4291. (d)
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2008, 47, 3317. (c) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.;
Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773. (d)
~
€
Aurrecoechea, J. M.; Coy, C. A.; Patino, O. J. J. Org. Chem. 2008, 73,
Furstner, A.; Martin, R. Chem. Lett. 2005, 34, 624. (e) Bolm, C.; Legros,
5194. (e) Satyanarayana, G.; Maier, M. E. J. Org. Chem. 2008, 73, 5410.
(f) Riegert, d.; Collin, J.; Meddour, A.; Schulz, E.; Trifonov, A. J. Org.
Chem. 2006, 71, 2514–2517. (g) Yamaura, Y.; Hyakutake, M.; Mori, M.
J. Am. Chem. Soc. 1997, 119, 7615. (h) Sureshbabu, A. R.;
Raghunathan, R.; Satiskumar, B. K. Tetrahedron Lett. 2009, 50, 2818.
(i) Prasad, T. A. A.; Vithiya, B. S. M.; Ignacimuthu, S. Pharma Chem.
2011, 3, 293. (j) Subramaniyan, G.; Raghunathan, R Tetrahedron 2001,
57, 2909.
J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217. (f) Sherry, B. D.;
Furstner, A. Acc. Chem. Res. 2008, 41, 1500. (g) Norinder, J.;
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Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2008,
130, 5858. (h) Volla, C. M. R.; Vogel, P. Angew. Chem., Int. Ed. 2008, 47,
1305. (i) Lu, Z.; Chai, G.; Ma, S. J. Am. Chem. Soc. 2007, 129, 14546. (j)
Langlotz, B. K.; Wadepohl, H.; Gade, L. H. Angew. Chem., Int. Ed.
2008, 47, 4670. (k) Shaikh, N. S.; Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem., Int. Ed. 2008, 47, 2497.
r
10.1021/ol300434m
Published on Web 03/28/2012
2012 American Chemical Society

heterocycles,5 FeCl3-promoted coupling of alkynes and al-
dehydes giving 1,5-dihalo-1,4-dienes,6 and ironhalide-pro-
moted cyclization/halogenation of alkynyl diethyl acetals
generating arylhalomethylene-substituted five-membered
cycles have been reported,7 a general iron trichloride-
promoted intramolecular cyclization of tosylamine-teth-
ered 8-aryl-2-en-7-yn-1-ols to produce azaspirocycles has
yet to be developed. We have now demonstrated that
FeCl3 can be applied toward the stereospecific synthesis
of (Z)-4-(arylchloromethylene)-substituted azaspirocycles
by treatment of cyclic 8-aryl-5-aza-5-tosyl-2-en-7-yn-1-ols
with 1.2 equiv of FeCl3. In this transformation, activation
of the hydroxyl group of the enynols by FeCl3 followed by
a subsequent anti-addition of the allylic group and a
chloride ion across the alkyne gave the azaspirocycles.
Moreover, the FeCl3-promoted cyclization/chlorination
can be extended to the synthesis of carbospirocyclic ana-
logues from cyclic 8-aryl-2-en-7-yn-1-ols.
of the resulting enones with NaBH4 in MeOH at 0 °C
provided 1 in 43% overall yields.8 The reaction conditions
were optimized for the cyclization/chlorination of the parent
compound 1a as shown in Table 1. The reaction of 1a with
1.2 equiv of FeCl3 in CH2Cl2 at 23 °C under an atmosphere
of nitrogen took place rapidly to produce 4-(chloro(phenyl)-
methylene)-2-tosyl-2-azaspiro[4.5]dec-6-ene (2a) with (Z)-
configuration in 84% isolated yield. The (Z)-configuration
of 2a was confirmed by X-ray diffraction analysis. If in
the air, the reaction also proceeded instantaneously at 23 °C
and afforded 2a in 83% yield (Table 1, entry 1). Thus,
the following screening of the reaction conditions was
conducted in the air. Lowering the temperature to 0 °C
increased the reaction time to 3 min and allowed for the
isolation of 2a in 72% yield (Table 1, entry 2). Moreover, the
reaction of 1a with 1.2 equiv of FeBr3 in CH2Cl2 at 23 °C
produced a 74% yield of the bromine-incorporated spiro-
pyrrolidine 3(Figure 1). Theuseof AlCl3 in CH2Cl2 at 23 °C
decreased the yield of 2a to 67% (Table 1, entry 3) and 2a
was formed as a mixture of Z- and E-isomers in a ratio of
6:1. Of other Lewis acids tested, TiCl4 and SnCl4 were less
efficient and provided 2a in 179 and 27% isolated yields,
respectively (Table 1, entries 4 and 5), whereas ZnCl2 and
Table 1. Optimizing the Reaction Conditions
Fe(NO3)3 9H2O were completely ineffectively even after
3
prolonged reaction at 23 °C (Table 1, entries 6 and 7). In the
presence of FeCl3, the use of 1,2-dichloroethane (DCE) and
1,2-dibromoethane (DBE) as solvents gave yields compar-
able with CH2Cl2 (Table 1, entries 8 and 9). On the other
hand, the more coordinating solvent, such as THF, required
extended reaction time (26 h) at 23 °C, and the desired 2a
was isolated in 23% yield (Table 1, entry 10). Moreover, no
desired product was observed when CH3CN was used
(Table 1, entry 11). Thus, the use of FeCl3 (1.2 equiv) in
CH2Cl2 at 23 °C in the air was found to be efficient and was
chosen as the standard reaction conditions. Transition
metals, such as platinum,10 rhodium,11 and palladium,12
are well-known catalysts of choice for synthesis of pyrroli-
dine ring skeletons from enynes. However, these protocols
required longer reaction times (3À24 h) and higher reaction
temperatures (70À100 °C). Furthermore, cycloisomeriza-
tion of compound 1a using 5 mol % of PPh3AuCl/AgOTf in
CH2Cl2 at 40 °C under nitrogen for 15 min produced
azaspiro[4.5]decenone 4 (Figure 1) in 67% yield as a mix-
ture of two diastereomers.8a The current approach for the
construction of azaspirocyclic ring systems is achieved with-
out the use of complex catalysts or removable of air and
moisture, only requiring 1.2 equiv of FeCl3 in CH2Cl2 at
room temperature in the air for 1 min.
entry
Lewis acid
FeCl3
solvent temp (°C) time yield (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
23
0
1 min
3 min
1 min
0.5 h
0.5 h
48 h
83
72
67a
17b
27
0
2
FeCl3
AlCl3
TiCl4
SnCl4
ZnCl2
3
23
23
23
23
23
23
23
23
23
4
5
6
7
Fe(NO3)3 9H2O CH2Cl2
48 h
0
3
8
FeCl3
FeCl3
FeCl3
FeCl3
DCE
1 min
2 h
74
72
23
0
9
DBE
10
11
THF
26 h
CH3CN
a Z/E = 6:1 (determined by 400 MHz 1H NMR analysis of the crude
reaction mixture). b Z/E = 13:1 (determined by 400 MHz 1H NMR
analysis of the crude reaction mixture).
The requisite cyclic 8-aryl-5-aza-5-tosyl-2-en-7-yn-1-ols
1were prepared starting from addition of lithiated dimethyl-
sufide to 3-isobutoxycyclohex-2-en-1-one in THF at room
temperature to generate 3-((methylthio)methyl)cyclohex-
2-en-1-one. Treatment of the resultant thioether with methyl
iodide in CH2Cl2 at reflux afforded 3-(iodomethyl)-
cyclohexe-2-en-1-one. Reaction of the corresponding aryl-
propagylsulfonamide with 3-(iodomethyl)cyclohexe-2-en-
1-one in acetone at room temperature followed by reduction
With the optimal reaction conditions, we next examined
the substrate scope of the FeCl3-promotedtransformation.
(8) (a) Yeh, M. C. P.; Pai, H. F.; Hsiow, C. Y.; Wang, Y. R.
Organometallics 2010, 29, 160. (b) Lin, M. N.; Wu, S. H.; Yeh,
M. C. P. Adv. Synth. Catal. 2011, 353, 3290.
(9) A mixture of Z- and E-isomers was formed in a ratio of 13:1.
(10) (a) Miura, T.; Shimada, M.; Murakami, M. J. Am. Chem. Soc.
2005, 127, 1094. (b) Matsuda, T.; Kadowaki, S.; Murakami, M. Helv.
Chim. Acta 2006, 89, 1672.
(11) (a) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc.
2004, 126, 7601. (b) Wang, J.; Tong, X.; Xie, X.; Zhang, Z. Org. Lett.
2010, 12, 5370.
€
(4) (a) Furstner, A.; Martin, R.; Majima, K. J. Am. Chem. Soc. 2005,
€
´
127, 12236. (b) Furstner, A.; Majima, K.; Martın, R.; Krause, H.;
Kattnig, E.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008,
130, 1992.
(5) Taniguchi, T.; Goto, N.; Nishibata, A.; Ishibashi, H. Org. Lett.
2010, 12, 112.
ꢀ
(6) Miranda, P. O.; Dı
´
az, D. D.; Padron, J. I.; Ramırez, M. A.;
´
Martın, V. S. J. Org. Chem. 2005, 70, 57–62.
´
(7) Xu, T.; Yu, Z.; Wang, L. Org. Lett. 2009, 11, 2113.
(12) Hatano, M.; Mikami, K. Org. Biomol. Chem. 2003, 1, 3871.
Org. Lett., Vol. 14, No. 7, 2012
1831

Table 2. FeCl3-Promoted Cyclization/Chlorination of Various
Cyclic 8-Aryl-5-aza-5-tosyl-2-en-7-yn-1-ols
entry substrate
R1
R2 product yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
phenyl
H
2a
2b
2c
2d
2e
2f
83
80
83
89
89
90
97
4-methylphenyl
4-nitrophenyl
3-carbethoxyphenyl
4-phenylphenyl
4-bromophenyl
phenyl
H
H
H
H
Figure 1. Structures of 3, 4, 1j, and 2j.
H
1g
1h
1i
CH3
H
2g
Results of the cyclization/chlorination of cyclic 8-aryl-5-
aza-5-tosyl-2-en-7-yn-1-ols 1aÀg to produce (Z)-4-(aryl-
chloromethylene)-substituted spiro[4.5]pyrrolidines 2aÀg
are listed in Table 2. Both electron-neutral and electron-
deficient arenes at the alkyne terminus were proven to
be good substrates under the standard reaction conditions,
as the yields of desired spiropyrrolidines 2aÀg ranged
from 80 to 97% (Table 2, entries 1À7). In all cases, the
4-methoxyphenyl
H
H
Scheme 1. Plausible Mechanism
1
(E)-products were not detected on 400 MHz H NMR
spectra of crude mixtures. It is worth mentioning that FeCl3-
mediated intermolecular coupling reactions of benzylic alco-
hols and arylalkynes afforded alkenyl chlorides as a mix-
ture of E- and Z-isomers, and no reaction took place when
arylalkynes bearing a nitro group were used.13 However,
compound 1c containing a nitro group at the para position of
the phenyl ring produced the corresponding spiropyrrodine
2c in 83% yield (Table 2, entry 3). In addition, a bromine
atom on the phenyl ring, for example, 1f, did not inhibit the
activity of FeCl3, as evidenced by the good yield of 2f (90%
yield, Table 2, entry 6). A double substituted methyl group at
the C-5 position of the cyclohexenol ring, for example, 1g,
achieved the highest yield (Table 2, entry 7). However,
substrate 1h containing an methoxy group at the C-4 posi-
tion of the phenyl ring inhibited the activity of FeCl3, and
the reaction failed to give any desired products. A mixture
of unidentified products was formed. Unfortunately, the
reaction of the substrate with a terminal alkyne, for example,
1i, resulted in decomposition of the starting substrate. Inter-
estingly, substrate 1j (Figure 1), bearing an o-carbethoxy-
phenyl substituent on the alkyne, reacted smoothly with
FeCl3 to afford azaspirocyclic lactone 2j (Figure 1) in 80%
isolated yield.
of 1a by FeCl3 led to the allylic carbonium 5 (path a).
Attack of the alkyne at the allylic carbon generated the
vinylic cation 6.14 The vinylic cation may be stabilized by
delocalization of the positive charge through the adjacent
CÀC double bond. Trapping of 6 with a chloride ion
from the less hindered side produced the spiropyrrolidine
2a with Z selectivity. However, from the observed good
yield in the cyclization/chlorination of a strong electron-
deficient nitro-substituted substrate 1c (Table 1, entry 3),
it could be suggested that no vinylic cation was formed in
Stepwise (path a) and concerted (path b) pathways are
speculatedin Scheme 1. Detachment of the hydroxyl group
(13) (a) Liu, Z.; Wang, J.; Han, J.; Zhao, Y.; Zhou, B. Tetrahedon
Lett. 2009, 50, 1240. (b) Biswas, S.; Maiti, S.; Jana, U. Eur. J. Org. Chem.
2009, 14, 2354. (c) Liu, Z.; Wang, J.; Zhao, Y.; Zhou, B. Adv. Synth.
Catal. 2009, 351, 371.
(14) (a) Jin, T.; Uchiyama, J.; Himuro, M.; Yamamoto, Y. Tetra-
hedron Lett. 2011, 52, 2069. (b) Jin, T.; Himuro, M.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2009, 48, 5893. (c) Jin, T.; Himuro, M.;
Yamamoto, Y. J. Am. Chem. Soc. 2010, 132, 5590.
1832
Org. Lett., Vol. 14, No. 7, 2012

this reaction. A concerted reaction pathway is suggested
(path b, Scheme 1). Substrate 1a was activated by FeCl3
toform aniron intermediate7 and HCl. A subsequent anti-
addition of the allylic group and a chloride ion (from the
less hindered side) across the alkyne produced the spir-
opyrrolidine derivative 2a with Z selectivity. In the case
of 1j (Figure 1), anti-addition of the carbethoxy group and
the allylic group across the alkyne gave the azaspirocyclic
lactone 2j (Figure 1).
Scheme 3. FeCl3-Promoted Cylization/Chlorination of 10
The chemistry can be applied to the synthesis of (Z)-
4-(arylchloromethylene)-2-tosyl-2-azaspiro[4.4]non-6-ene
derivatives from five-membered ring substrates. Thus,
treatment of cyclic 8-aryl-5-aza-5-tosyl-2-en-7-yn-1-ols 8a
and 8b with 1.2 molar equiv of FeCl3 using the standard
reaction conditions (CH2Cl2, 23 °C, 1 min, air) afforded
spiropyrrolidines 9a (84%) and 9b (64%), respectively
(Scheme 2). Moreover, the chemistry is general for synth-
esis of the carbospirocyclic analogues. Aliphatic carbon
linked cyclic 8-aryl-2-en-7-yn-1-ols 10aÀf were prepared
starting from addition of the corresponding 5-lithio-1-
arylpent-1-yne to 3-methoxycyclohex-2-en-1-one followed
by reduction of the resulting enones with NaBH4 in MeOH
to afford cyclic enynols 10aÀf in good overall yields.
Substrates 10aÀf reacted with 1.2 equiv of FeCl3 efficiently
to generate chlorinated carbospirocycles 11aÀf in 58À86%
yields under the standard reaction conditions (Scheme 3).
In summary, we have developed an efficient and con-
venient method for the synthesis of (Z)-4-(arylchloro-
methylene)-substituted spiropyrrolidines from cyclic
8-aryl-5-tosyl-5-aza-2-en-7-yn-1-ols and nontoxic and inex-
pensive iron trichloride. The reaction has many advantages:
they are virtually instantaneous, even in the presence of air,
the required FeCl3 loading is 1.2 molar equiv, no extra ligand
is necessary, and the yields are good to excellent. This FeCl3-
promoted cyclization/chlorination can be applied to the
formation of carbospirocycles. The easy formation of spiro-
cycles in an efficient way under mild reaction conditions may
have further applications.
Acknowledgment. This research was supported by grants
from the National Science Council (NSC 98-2119-M-003-
004-MY3, NSC 98-2119-M-003-001-MY2) and National
Taiwan Normal University.
Scheme 2. FeCl3-Promoted Cylization/Chlorination of 8
Supporting Information Available. Experimental details,
analytical data, copies of NMR spectra, and X-ray crystal-
lographic information files for compounds 2a, 2c, 9a, 11b,
11c, and 11d. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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