Electrophilic ipso-halocyclization of N-arylpropynamides with polyfluoroalkyl alcohols: Selective synthesis of 8-(polyfluoroalkoxy)azaspiro[4. 5]trienes

Article abstract of DOI:10.1055/s-0028-1087972

A novel and efficient method for the synthesis of 8-(polyfluoroalkoxy)-1- azaspiro[4.5]deca-3,6,9-trien-2-ones has been demonstrated via the electrophilic ipso-halocyclization of Narylpropynamides with polyfluoroalkyl alcohols. In the presence of N-halosu

Full text of DOI:10.1055/s-0028-1087972

PAPER
891
Electrophilic ipso-Halocyclization of N-Arylpropynamides with Polyfluoro-
alkyl Alcohols: Selective Synthesis of 8-(Polyfluoroalkoxy)azaspiro[4.5]trienes
S
elective Synth
h
esis of 8-(Po
i
lyfluor
o
-
alkoxy)
Q
azaspiro[4.5]triene
i
s
ang Wang,a Bo-Xiao Tang,a Hong-Ping Zhang,a,b Feng Wang,a Jin-Heng Li*a
a
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education),
College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, P. R. of China
Fax +86(731)8872101; E-mail: jhli@hunnu.edu.cn
b
Department of Biology and Chemical Engineering, Shaoyang University, Shaoyang 422000, P. R of China
Received 19 September 2008; revised 25 November 2008
afford selectively spiro[4.5]trienyl acetates in moderate to
good yields (Scheme 1, equation 3).3 This prompted us to
extend the new intramolecular electrophilic ipso-cycliza-
tion of (para-unsubstituted aryl)alkynes route to the syn-
Abstract: A novel and efficient method for the synthesis of 8-
(polyfluoroalkoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-ones
has
been demonstrated via the electrophilic ipso-halocyclization of N-
arylpropynamides with polyfluoroalkyl alcohols. In the presence of
N-halosuccinimides (NXS), a variety of N-arylpropynamides un- thesis of the important spiro[4.5]decanes.4 It is well
derwent an electrophilic ipso-halocyclization reaction with poly-
fluoroalkyl alcohols to afford the corresponding 8-
known that the trifluoromethyl group has a great effect on
biological activity and often confers significant changes
(polyfluoroalkoxy)spiro[4.5]trienes in good yields. Note that mo-
in chemical and physical properties.5 Thus, we expected
lecular sieves can improve the yield of the reaction.
to induce a trifluoromethyl group into the spirocyclic mo-
Key words: electrophilic ipso-halocyclization, N-arylpropyna-
tif using trifluoroacetic acid, but failed. Interestingly, we
mide, N-halosuccinimide, spiro[4.5]decane, polyfluoroalkoxy sub-
found that 2,2,2-trifluoroethanol was a suitable substrate
stitution
for this purpose. Here, we wish to report that para-unacti-
vated N-arylpropynamides can undergo electrophilic
ipso-cyclization with polyfluoroalkyl alcohols and N-ha-
The intramolecular electrophilic cyclization of aryla-
losuccinimides (NXS) to synthesize selectively 8-(poly-
lkynes has recently attracted much attention and it is now
fluoroalkoxy)azaspiro[4.5]trienes in good yields
widely recognized for its potential to synthesize a wide
(Scheme 1, equation 4).6,7
range of heterocycles and carbocycles under simple and
mild conditions.1–3 The electrophilic cyclization protocols
Ph
Ph
are generally worked between alkyne and ortho-arene
I
R2
I2, NaHCO3, MeCN, r.t.
or ICl, CH2Cl2, –78 °C
substituents to construct heterocycles and carbocycles.1
Recently, the reaction between alkynes and ipso-arene
substituents to give spirocyclic compound has been devel-
oped by the Fanghänel2a and Larock groups2b indepen-
O
(1)
N
R1
O
N
R1
O
R
2 = OMe, NMe2
R2
dently.
4-(4-Methoxyaryl)alk-1-ynes
or
4-[4-
R2
I
(dimethylamino)aryl]alk-1-ynes, for example, underwent
intramolecular electrophilic ipso-cyclization with iodine
monochloride or iodine/sodium hydrogen carbonate to
synthesize spiro[4.5]trienones in moderate to excellent
yields (Scheme 1, equation 1). We have also reported that
the intramolecular ipso-iodocyclization of 4-(4-alkyl-
aryl)alk-1-ynes with iodine monochloride or iodine pro-
ceeded smoothly, providing the corresponding 8-
methylene-1-azaspiro[4.5]trienes in moderate to good
yields (Scheme 1, equation 2).2c However, the above ipso-
cyclization method is limited to aryl compounds bearing
active para-substituents, such as methoxy, dimethylami-
no, and alkyl groups, on the aryl ring. Very recently, we
found that N-(para-unsubstituted aryl)propynamides and
phenyl 3-phenylpropynoate underwent the intramolecular
electrophilic ipso-iodocyclization/nucleophilic addition
process with N-iodosuccinimide (NIS) and acetic acid to
ICl, H2O, MeCN, –25 °C
or I2, MeCN, r.t.
(2)
(3)
N
O
N
R1
O
R3
R3
R1
R1
O
Y
NIS, AcOH
AcO
R2
r.t.
I
R3
R1
Y
O
Y = NMe, O
RFCH2OH
NXS
R2
R2
R2
X
X
molecular sieves
RFCH2O
+
(4)
80 °C
N
O
N
R1
O
R3
R3
R1
N
O
R3
X = I, Br, Cl
R1
Scheme 1
Stimulated by our previous studies on the electrophilic
ipso-iodocyclization of N-(para-unsubstituted aryl)pro-
pynamides with N-iodosuccinimide and acetic acid,3 we
investigated the feasibility of the electrophilic ipso-iodo-
cyclization of N-methyl-N,3-diphenylpropynamide (1a)
with 2,2,2-trifluoroethanol (2a) because it was reported as
SYNTHESIS 2009, No. 6, pp 0891–0902
x
x
.
x
x
.2
0
0
9
Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087972; Art ID: F20008SS
© Georg Thieme Verlag Stuttgart · New York

892
Z.-Q. Wang et al.
PAPER
a special nucleophilic reagent for ipso-cyclizations.6b,c,g tolerated a wide range of functional groups, such as meth-
We found that the reaction temperature has a fundamental yl, methoxy, chloro, bromo, iodo, and nitro groups in the
influence on the reaction. As shown in Table 1, trace aromatic nucleus. Initially, the reaction of substrate 1a
amounts of three products were detected by GC-MS anal- with another polyfluoroalkyl alcohol, 2,2,3,3,3-pentafluo-
ysis from the reaction of N-methyl-N,3-diphenylpropyn- ropropan-1-ol (2b), was tested, and the results showed
amide (1a) with 2,2,2-trifluoroethanol (2a) at room that it was still a suitable substrate to react with amide 1a
temperature (entry 1). At 80 °C, the target product 3aa in good yield (entry 1). Subsequently, both the electronic
was enhanced to 51% total yield together with an ortho- and steric properties of the N-aryl group on the ipso-io-
cyclized side-product 4aa in 23% yield (entry 2). Molec- docyclization process were evaluated. Substrates 1e–i,
ular sieves were found to improve the reaction, and the bearing electron-neutral or electron-rich groups on the N-
yield of 3aa was enhanced to 67% when 100 mg of 3 Å aryl group, all worked well with polyfluoroalkyl alcohol
molecular sieves were added (entry 3).8 However, trace 2a or 2b and N-iodosuccinimide in moderate to good
amounts of 3aa or 4aa were observed using iodine yields (entries 2–7). N-Methyl-N-(2-methylphenyl)-3-
monochloride instead of N-iodosuccinimide (entry 4) and phenylpropynamide (1e) bearing an ortho-methyl group
the product 4aa was obtained as the major product in the on the N-aryl ring, for instance, underwent the reaction
presence of iodine (entry 5). Ethanol in place of 2,2,2-tri- with 2a and N-iodosuccinimide smoothly in 75% total
fluoroethanol (2a) as the reaction partner was also tested, yield (entry 2). To our surprise, substrate 1f having a
but failed (entry 6).9 In the cases where the N-methyl meta-methyl group provided the ortho-cyclized product
group was replaced by N-benzyl or N-acetyl or an N-un- 4fa as the major product in 66% yield together with the
substituted group, however, the reaction did not proceed ipso-product 3fa in 28% yield (entry 4). We found that
and the starting material 1a was recovered in >95% yield substrates 1j–l bearing weakly electron-deficient halo
(entries 7–9).
groups also displayed high efficient for the ipso-iodocy-
clization reaction with N-iodosuccinimide and 2,2,2-tri-
fluoroethanol (2a) providing 3ja–la in good yields
(entries 8–10). However, the reaction of amide 1m, bear-
ing an acetyl group on the N-aryl ring, did not take place
under standard conditions (entry 11). N-Aryl groups bear-
ing some active para-substituents were also evaluated
(entries 12 and 13). N-Methyl-N-(4-methylphenyl)-3-phe-
nylpropynamide (1n) did not undergo the reaction and N-
(4-methoxyphenyl)-N-methyl-3-phenylpropynamide (1o)
provided the spiro[4.5]trien-8-one 5oa in 66% yield
(Figure 1).
A variety of substrates were examined by reacting with
polyfluoroalkyl alcohols and N-iodosuccinimide to exam-
ine the scope of this intramolecular electrophilic ipso-io-
docyclization process, and the results are summarized in
Table 2.8 We were pleased to find that the novel process
Table 1 Screening Optimal Conditions for the Electrophilic ipso-
Iodocyclization Reactiona
Ph
Ph
Ph
I
I
[I]
CF3CH2O
+ CF3CH2OH
+
N
O
N
R
O
N
O
2a
R
Next, substituents at the terminal of the C≡C bond of
anilines were also examined (entries 14–19). N-Methyl-
N-phenylpropynamide (1p), a terminal alkyne, was an un-
suitable substrate for the reaction with N-iodosuccinimide
at 80 °C (entry 14). We found that the terminally substi-
tuted alkynes, with either alkyl groups or aryl groups, all
worked well with N-iodosuccinimide to afford the corre-
sponding target products 3qa–ua in moderate yields (en-
tries 15–19). Substrate 1q having a methyl group at the
terminal of the C≡C bond, for instance, gave the cis- and
trans-spirocyclic products 3qa in 77% total yield together
with an ortho-cyclized byproduct in 15% yield (entry 15).
The results demonstrated that both the electronic and ster-
ic properties of the aryl groups affected the chemoselec-
tivity of the reaction to some extent. Although the ortho-
cyclized product 4sa was obtained as the major product
from the reaction of the bulky substrate 1s, the spirocyclic
product 3sa was still isolated in 38% yield (entry 17).
Both the ipso-cyclized product 3ta and the ortho-cyclized
product 4ta were observed in the reaction of the electron-
rich substrate 1t (entry 18), but only the ipso-cyclized
product 3ua was isolated from the electron-deficient sub-
strate 1u (entry 19). However, another product, 3-iodo-1-
methyl-4-(thiophen-2-yl)-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (5va) (Figure 1), was isolated from the re-
R
1a
3aa
4aa
Entry
R
[I]
Isolated yield (%)
cis/trans-3
4
1b,c
2c
3
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Bn (1b)
Ac (1c)
H (1d)
NIS
NIS
NIS
ICl
trace (3aa)
26:25 (3aa)
30:37 (3aa)
trace (3aa)
trace (3aa)
0 (3aa)
trace (4aa)
23 (4aa)
19 (4aa)
4d
5
trace (4aa)
53 (4aa)
I2
6e
7f
8f
9f
NIS
NIS
NIS
NIS
trace (4aa)
trace (4ba)
trace (4ca)
trace (4da)
trace (3ba)
trace (3ca)
trace (3da)
a Reagents and conditions: 1a (0.3 mmol), 2a (2 mL), [I] (1.5 equiv),
3 Å MS (100 mg), 80 °C, 8 h.
b At r.t.
c Without molecular sieves.
d Messy results were observed at –40 °C.
e EtOH instead of CF3CH2OH; >95% of 1a was recovered.
f >95% of 1a was recovered.
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of 8-(Polyfluoroalkoxy)azaspiro[4.5]trienes
893
Table 2 Electrophilic ipso-Iodocyclizations of N-Arylpropyn-
action of the heteroarylalkyne substrate 1v with N-
iodosuccinimide in 2,2,2-trifluoroethanol (2a) (entry 20).
Unfortunately, amine 1w, ester 1x, and ether 1y were
found to be unsuitable substrates under the standard reac-
tion conditions (entries 21–23).
amides 1 with Polyfluoroalkyl Alcohols 2 in the Presence of
N-Iodosuccinimidea (continued)
R1
R1
I
R1
I
NIS
+
+ RFCH2OH
RFCH2O
Y
Y
Z
R2
Table 2 Electrophilic ipso-Iodocyclizations of N-Arylpropyn-
amides 1 with Polyfluoroalkyl Alcohols 2 in the Presence of
N-Iodosuccinimidea
Y
Z
Z
R2
R2
1
2a RF = CF3
2b RF = CH2CF3
3
4
R1
R1
R1
Entry Substrate
Alcohol Isolated yield (%)
I
I
cis/trans-3 4
NIS
+
+ RFCH2OH
RFCH2O
Y
Y
Z
R2
Y
Z
Z
R2
R2
I
1
2a RF = CF3
2b RF = CH2CF3
3
4
45:38
(3la)
trace
(3la)
10
1l
2a
2a
Me
N
O
Entry Substrate
Alcohol Isolated yield (%)
cis/trans-3 4
O
trace
(4ma
)
trace
(3ma)
11c 1m
Me
N
O
17:54
(3ab)
trace
(4ab)
1
1a
2b
Me
N
O
0
trace
(4na)
12c 1n
2a
2a
(3na)
38:37
(3ea)
trace
(4ea)
Me
N
O
2
3
1e
1e
2a
2b
Me
N
O
OMe
41:45
(3eb)
trace
(4eb)
0
0
13d 1o
(3oa)
(4oa)
Me
Me
Me
Me
Me
Me
Me
N
O
15:13
(3fa)
66
4
5
1f
2a
2a
(4fa)b
Me
N
O
trace
(3pa)
trace
(4pa)
14c 1p
15e 1q
16e 1r
2a
2a
2b
2a
2a
2a
N
O
35:28
(3ga)
trace
(4ga)
1g
32:45
(3qa)
15
(4qa)
Me
Me
N
O
N
O
55:42
(3ha)
trace
(4ha)
6
7
8
9
1h
1i
2a
2a
2a
2a
15:21
(3ra)
trace
(4ra)
N
O
N
O
C5H11
MeO
Me
44:33
(3ia)
trace
(3ia)
21:17
(3sa)
51
(4sa)
N
17
18
19
1s
1t
N
O
O
Cl
46:44
(3ja)
trace
(4ja)
1j
27:35
(3ta)
36
(4ta)
Me
N
N
O
O
OMe
Br
43:41
(3ka)
trace
(4ka)
1k
24:31
(3ua)
trace
(4ua)
Me
N
O
1u
N
O
NO2
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

894
Z.-Q. Wang et al.
PAPER
Table 2 Electrophilic ipso-Iodocyclizations of N-Arylpropyn-
amides 1 with Polyfluoroalkyl Alcohols 2 in the Presence of
N-Iodosuccinimidea (continued)
3-(thiophen-2-yl)propynamide (1v) with N-bromosuccin-
imide. Interestingly, amides substrates bearing a group at
the ortho-position of the N-aryl ring are still suitable sub-
strates for the reaction with N-bromosuccinimide or N-
chlorosuccinimide. For example, an 84% yield of the
ipso-bromocyclized product 6ja was obtained from the
substrate 1j having an ortho-chloro group.
R1
R1
R1
I
I
NIS
+
+ RFCH2OH
RFCH2O
Y
Y
Z
R2
Y
Z
Z
R2
R2
1
2a RF = CF3
3
4
2b RF = CH2CF3
A working mechanism as outlined in Scheme 3 was pro-
posed on the basis of the present results and the previously
reported mechanisms.1–3 Initially, the iodonium interme-
diate A is generated by the interaction of the electrophilic
N-iodosuccinimide with the alkyne moiety. The iodonium
intermediate A can proceed via two routes including: (1)
intramolecular electrophilic ortho-cyclization reaction to
afford 4, or (2) intramolecular electrophilic ipso-cycliza-
tion reaction to form intermediate B.1,2 The reaction of in-
termediate B with RFCH2OH occurs to yield both cis- and
trans-products 3. Based on the mechanism, we deduced
that both the steric hindrance and electron-withdrawing
groups disfavored the stability of intermediate B resulting
in lower yields.
Entry Substrate
Alcohol Isolated yield (%)
cis/trans-3 4
trace
(3va)
trace
(4va)
20f 1v
2a
2a
2a
2a
Me
N
O
S
trace
(3wa)
trace
(4wa)
21g 1w
Me
N
Ph
trace
(3xa)
trace
(4xa)
22g 1x
O
O
Ph
Ph
R2
R2
X
NXS
trace
(3ya)
trace
(4ya)
CF3CH2O
+ CF3CH2OH
23g 1y
N
2a
N
O
O
R1
R1
O
Me
Me
1
S
cis/trans
Ph
Ph
a Reagents and conditions: 1 (0.3 mmol), 2a (2 mL), 3 Å MS (100
mg), NIS (1.5 equiv), 80 °C, 8 h.
Br
O
Br
O
Br
CF3CH2O
CF3CH2O
CF3CH2O
cis/trans:
b 3-Iodo-1,5-dimethyl-4-phenylquinolin-2(1H)-one (4fa) and 3-iodo-
1,7-dimethyl-4-phenylquinolin-2(1H)-one (4fa¢); ratio 4fa/4fa¢ 1:3.
c Messy results were observed, which was determined by GC-MS
analysis.
N
N
N
O
Me
32% (3:2, 6va)
Me
Cl
26%/59% (6ja)
Me
35%/28% (6aa)
Ph
Ph
Cl
Cl
O
d Another product 5oa (Figure 1) was isolated in 66% yield.
e For 24 h.
CF3CH2O
CF3CH2O
O
N
N
f Another product 5va (Figure 1) was isolated in 47% yield.
g >95% of substrate 1 was recovered.
Me
40%/37% (7aa)
Me
42%/46% (7ea)
cis/trans:
Scheme 2 Electrophilic ipso-halocyclizations in the presence of N-
bromosuccinimide or N-chlorosuccinimide. Reagents and conditions:
1 (3 mmol), 2a (2 mL), 3 Å MS (100 mg), NXS (1.5 equiv), 80 °C, 8
h.
S
Ph
I
I
O
O
N
Me
N
Me
O
O
R1
5oa
5va
I
– H+
R1
R1
NIS
Figure 1
N
O
I
R2
I
4
Me
R1
As listed in Scheme 2, the two other N-halosuccinimides,
N-bromosuccinimide (NBS) and N-chlorosuccinimide
(NCS), were used as the electrophilic reagents to react
with anilines. To our delight, both N-bromosuccinimide
and N-chlorosuccinimide are efficient for the electrophilic
ipso-iodocyclizations. Substrate 1a, for instance, under-
went the electrophilic ipso-iodocyclization with either N-
bromosuccinimide or N-chlorosuccinimide successfully
to afford the corresponding ipso-cyclized products 6aa
and 7aa in 62% and 77% yields, respectively. Gratifying-
ly, a 32% yield of the corresponding desired product 6va
was still achieved in the reaction of N-methyl-N-phenyl-
N
O
N
O
R2
R2
Me
1
Me
A
N
O
O
R2
Me
B
N– + RFCH2OH
R1
I
O
RFH2CO
O
N
O
R2
Me
NH
3
O
Scheme 3 A working mechanism
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of 8-(Polyfluoroalkoxy)azaspiro[4.5]trienes
895
LR-MS (EI, 70 eV): m/z (%) = 461 (M+, 18), 362 (3), 334 (100), 129
(60).
In summary, we have developed a novel and efficient
electrophilic ipso-halocyclization method for the synthe-
sis of 8-(polyfluoroalkoxy)azaspiro[4.5]trienes. In the HRMS (EI): m/z [M]+ calcd for C18H15F3INO2: 461.0100; found:
461.0099.
presence of N-halosuccinimides, a variety of N-arylprop-
ynamides underwent the electrophilic ipso-halocycliza-
tion reaction with polyfluoroalkyl alcohols to afford the
cis-3-Iodo-1-methyl-8-(2,2,3,3,3-pentafluoropropoxy)-4-phe-
nyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ab)
corresponding 8-(polyfluoroalkoxy)-1-azaspiro[4.5]deca-
Yellow solid; mp 100.1 °C.
3,6,9-trien-2-ones in good yields. Based on the results,
IR (KBr): 1672 cm–1.
two features were established: (1) The scope of the elec-
1H NMR (500 MHz): d = 7.40–7.37 (m, 3 H), 7.26 (d, J = 8.0 Hz, 2
trophilic ipso-halocyclization method was extended to
H), 6.21 (d, J = 10.0 Hz, 2 H), 5.66 (d, J = 10.0 Hz, 2 H), 4.16 (s, 1
H), 3.88 (t, J = 12.5 Hz, 2 H), 2.95 (s, 3 H).
13C NMR (125 MHz): d = 167.1, 161.9, 133.1, 130.9, 129.4, 128.7,
substrates having no active para-substituents. (2) A wide
range of functional groups, such as methyl, methoxy,
chloro, bromo, iodo, and nitro groups, in the aromatic nu-
128.3, 127.8, 118.6 (tt, J = 285.0, 35.0 Hz, 1 C), 113.7 (tq,
cleus were tolerated well under the present reaction con-
J = 233.8, 37.5 Hz, 1 C), 96.7, 69.3, 69.2, 63.5 (q, J = 26.3 Hz, 1 C),
26.5.
LR-MS (EI, 70 eV): m/z (%) = 511 (M+, 3), 384 (100), 129 (71).
HRMS (EI): m/z [M]+ calcd for C19H15F5INO2: 511.0068; found:
ditions. Efforts to explore new electrophilic ipso-
halocyclization route and apply these protocols in organic
synthesis are underway in our laboratory.
511.0065.
NMR spectroscopy was performed on an Inova-400 (Varian), or a
Bruker-500 spectrometer operating at 400 MHz (1H NMR) and 100
trans-3-Iodo-1-methyl-8-(2,2,3,3,3-pentafluoropropoxy)-4-phe-
nyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ab)
Yellow solid; mp 159.2–160.0 °C.
IR (KBr): 1679 cm–1.
1H NMR (500 MHz): d = 7.40–7.37 (m, 3 H), 7.24 (d, J = 8.0 Hz, 2
H), 6.20 (d, J = 10.0 Hz, 2 H), 5.74 (d, J = 10.0 Hz, 2 H), 4.70 (s, 1
H), 3.00 (t, J = 12.5 Hz, 2 H), 2.85 (s, 3 H).
13C NMR (125 MHz): d = 167.0, 162.5, 133.1, 131.4, 130.3, 129.7,
128.4, 128.0, 118.5 (tt, J = 284.0, 35.0 Hz, 1 C), 113.0 (tq,
J = 235.0, 37.5 Hz, 1 C), 97.1, 68.7, 67.9, 60.7 (q, J = 26.3 Hz, 1 C),
26.3.
MHz (13C NMR), or 500 MHz (1H NMR) and 125 MHz (13C NMR).
TMS was used an internal standard and CDCl3 was used as the sol-
vent. MS analysis was performed on GC-MS analysis (Shimadzu
GCMS-QP2010). Melting points are uncorrected.
Electrophilic ipso-Halocyclization; General Procedure
A mixture of aniline 1 (0.3 mmol), polyfluoroalkyl alcohol 2 (2
mL), NXS (1.5 equiv), and 3Å molecular sieve (100 mg) was stirred
at 80 °C for the desired time (Table 2) until complete consumption
of starting material (TLC and GC-MS analysis). The mixture was
washed with sat. Na2S2O3 soln and extracted with Et2O. The com-
bined organic layers were dried (anhyd Na2SO4) and evaporated un-
der vacuum; the residue was purified by flash column
chromatography (hexane or hexane–EtOAc) to afford the desired
product.
LR-MS (EI, 70 eV): m/z (%) = 511 (M+, 121), 385 (23), 384 (100),
129 (69).
HRMS (EI): m/z [M]+ calcd for C19H15F5INO2: 511.0068; found:
511.0068.
cis-3-Iodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-aza-
spiro[4.5]deca-3,6,9-trien-2-one (cis-3aa)
cis-3-Iodo-1,6-dimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ea)
Pale yellow solid; mp 93.0–94.5 °C.
IR (KBr): 1698 cm–1.
1H NMR (500 MHz): d = 7.32–7.27 (m, 3 H), 7.22 (d, J = 8.0 Hz, 2
H), 6.14 (d, J = 10.0 Hz, 1 H), 5.87 (s, 1 H), 5.52 (d, J = 10.0 Hz, 1
H), 4.14 (s, 1 H), 3.74–3.69 (m, 2 H), 2.79 (s, 3 H), 1.51 (s, 3 H).
13C NMR (125 MHz): d = 167.6, 161.2, 133.7, 132.9, 130.7, 129.6,
129.0, 128.8, 128.5, 127.9, 127.6, 124.9, 123.8 (q, J = 277.5 Hz, 1
C), 96.6, 71.7, 70.6, 64.4 (q, J = 28.0 Hz, 1 C), 26.3, 17.0.
Pale yellow solid; mp 105.0–106.4 °C.
IR (KBr): 1695 cm–1.
1H NMR (400 MHz): d = 7.40–7.34 (m, 3 H), 7.26 (d, J = 8.0 Hz, 2
H), 6.21 (d, J = 10.0 Hz, 2 H), 5.64 (d, J = 10.0 Hz, 2 H), 4.13 (s, 1
H), 3.83–3.77 (m, 2 H), 2.94 (s, 3 H).
13C NMR (100 MHz): d = 167.2, 162.0, 133.2, 131.2, 129.4, 128.5,
128.4, 127.9, 123.8 (q, J = 276.6 Hz, 1 C), 96.8, 69.4, 69.3, 65.0 (q,
J = 34.4 Hz, 1 C), 26.6.
LR-MS (EI, 70 eV): m/z (%) = 461 (M+, 3), 362 (2), 334 (100), 129
(66).
LR-MS (EI, 70 eV): m/z (%) = 475 (M+, 32), 460 (16), 376 (5), 349
HRMS (EI): m/z [M]+ calcd for C18H15F3INO2: 461.0100; found:
(23), 348 (100), 129 (61).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO2: 475.0256; found:
461.0098.
475.0254.
trans-3-Iodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3aa)
Yellow solid; mp 179.6–180.4 °C.
IR (KBr): 1681 cm–1.
1H NMR (400 MHz): d = 7.39–7.37 (m, 3 H), 7.22 (d, J = 8.0 Hz, 2
H), 6.20 (d, J = 10.0 Hz, 2 H), 5.71 (d, J = 10.0 Hz, 2 H), 4.69 (s, 1
H), 2.89–2.85 (m, 2 H), 2.83 (s, 3 H).
13C NMR (100 MHz): d = 167.0, 162.6, 133.2, 131.7, 130.1, 129.7,
128.5, 128.1, 125.0, 123.6 (q, J = 276.1 Hz, 1 C), 97.1, 68.8, 67.9,
61.5 (q, J = 34.4 Hz, 1 C), 26.3.
trans-3-Iodo-1,6-dimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ea)
Pale yellow solid; mp 154.5–155.3 °C.
IR (KBr): 1674 cm–1.
1H NMR (500 MHz): d = 7.34–7.29 (m, 3 H), 7.21 (d, J = 8.0 Hz, 2
H), 6.12 (d, J = 10.0 Hz, 1 H), 5.90 (s, 1 H), 5.58 (d, J = 10.0 Hz, 1
H), 4.63 (s, 1 H), 2.98–2.90 (m, 2 H), 2.70 (s, 3 H), 1.56 (s, 3 H).
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

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Z.-Q. Wang et al.
PAPER
13C NMR (125 MHz): d = 167.4, 161.7, 135.5, 132.9, 131.0, 130.4,
129.9, 128.7, 128.6, 127.9, 123.8 (q, J = 276.3 Hz, 1 C), 97.2, 71.4,
69.5, 61.9 (q, J = 27.0 Hz, 1 C), 25.9, 17.3.
1H NMR (400 MHz): d = 7.39–7.35 (m, 3 H), 7.16 (d, J = 8.0 Hz, 2
H), 6.14 (d, J = 10.0 Hz, 1 H), 5.70 (d, J = 10.0 Hz, 1 H), 5.42 (s, 1
H), 4.54 (s, 1 H), 2.81 (s, 3 H), 2.72–2.52 (m, 2 H), 1.83 (s, 3 H).
LR-MS (EI, 70 eV): m/z (%) = 475 (M+, 52), 460 (17), 376 (6), 348
(100), 129 (66).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO2: 475.0256; found:
475.0256.
13C NMR (100 MHz): d = 166.9, 163.1, 139.3, 133.5, 131.2, 130.3,
129.6, 128.6, 128.5, 128.1, 127.8, 127.7, 125.3, 123.7 (q, J = 275.9
Hz, 1 C),, 96.8, 70.8, 70.1, 60.5 (q, J = 34.4 Hz, 1 C), 26.5, 15.9.
LR-MS (EI, 70 eV): m/z (%) = 475 (M+, 10), 376 (2), 348 (100), 129
(47).
cis-3-Iodo-1,6-dimethyl-8-(2,2,3,3,3-pentafluoropropoxy)-4-
phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3eb)
Pale yellow solid; mp 86.1 °C.
HRMS (EI): m/z [M]+ calcd for C19H17F3INO2: 475.0256; found:
475.0253.
IR (KBr): 1699 cm–1.
cis-3-Iodo-1,6,7-trimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ga)
Yellow solid; mp 100.2–101.5 °C.
IR (KBr): 1687 cm–1.
1H NMR (400 MHz): d = 7.40–7.32 (m, 3 H), 7.20 (d, J = 8.0 Hz, 2
H), 6.14 (d, J = 10.0 Hz, 1 H), 5.57 (d, J = 10.0 Hz, 1 H), 4.10 (s, 1
H), 3.72–3.58 (m, 2 H), 2.84 (s, 3 H), 1.78 (s, 3 H), 1.49 (s, 3 H).
13C NMR (100 MHz): d = 167.6, 161.9, 133.3, 133.1, 130.4, 129.5,
128.4, 127.5, 127.1, 123.9 (q, J = 276.2 Hz, 1 C), 96.5, 73.0, 72.7,
63.3 (q, J = 34.4 Hz, 1 C), 26.3, 15.7, 12.4.
1H NMR (500 MHz): d = 7.40–7.35 (m, 3 H), 7.29 (d, J = 8.0 Hz, 2
H), 6.20 (d, J = 10.0 Hz, 1 H), 5.94 (s, 1 H), 5.60 (d, J = 10.0 Hz, 1
H), 4.23 (s, 1 H), 3.86 (t, J = 12.5 Hz, 2 H), 2.87 (s, 3 H), 1.59 (s, 3
H).
13C NMR (125 MHz): d = 167.6, 161.0, 133.8, 132.8, 130.5, 129.6,
129.1, 128.4, 127.6, 127.5, 118.6 (tt, J = 284.0 Hz, 35.0 Hz, 1 C),
114.1 (tq, J = 271.1 Hz, 36.3 Hz, 1 C), 96.5, 71.6, 70.4, 63.0 (t,
J = 26.3 Hz, 1 C), 26.2, 17.0.
LR-MS (EI, 70 eV): m/z (%) = 525 (M+, 11), 398 (38), 249 (10), 207
(13), 129 (40), 43 (100).
HRMS (EI): m/z [M]+ calcd for C20H17F5INO2: 525.0224; found:
LR-MS (EI, 70 eV): m/z (%) = 489 (M+, 38), 390 (7), 362 (100), 129
(55).
525.0224.
HRMS (EI): m/z [M]+ calcd for C20H19F3INO2: 489.0413; found:
489.0412.
trans-3-Iodo-1,6-dimethyl-8-(2,2,3,3,3-pentafluoropropoxy)-4-
phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3eb)
Pale yellow solid; mp 152.9–153.4 °C.
IR (KBr): 1699 cm–1.
trans-3-Iodo-1,6,7-trimethyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ga)
Pale yellow solid; mp 155.1–155.2 °C.
1H NMR (500 MHz): d = 7.40–7.35 (m, 3 H), 7.29 (d, J = 10.0 Hz,
2 H), 6.18 (d, J = 10.0 Hz, 1 H), 5.96 (s, 1 H), 5.66 (d, J = 10.0 Hz,
1 H), 4.71 (s, 1 H), 3.16–3.09 (m, 2 H), 2.77 (s, 3 H), 1.64 (s, 3 H).
13C NMR (125 MHz): d = 167.3, 161.6, 135.6, 132.7, 130.7, 130.4,
129.8, 128.5, 128.4, 127.7, 118.5 (tt, J = 284.0 Hz, 35.0 Hz, 1 C),
113.9 (tq, J = 271.1 Hz, 36.3 Hz, 1 C), 97.2, 71.2, 69.4, 60.8 (t,
J = 26.3 Hz, 1 C), 25.9, 17.3.
LR-MS (EI, 70 eV): m/z (%) = 525 (M+, 43), 398 (100), 129 (71),
43 (62).
HRMS (EI): m/z [M]+ calcd for C20H17F5INO2: 525.0224; found:
525.0224.
IR (KBr): 1693 cm–1.
1H NMR (400 MHz): d = 7.38–7.34 (m, 3 H), 7.14 (d, J = 8.0 Hz, 2
H), 6.12 (d, J = 10.0 Hz, 1 H), 5.63 (d, J = 10.0 Hz, 1 H), 4.54 (s, 1
H), 2.74 (s, 3 H), 2.71–2.59 (m, 2 H), 1.79 (s, 3 H), 1.55 (s, 3 H).
13C NMR (100 MHz): d = 167.4, 163.1, 134.1, 133.4, 130.5, 130.4,
129.8, 128.6, 128.5, 127.8, 123.8 (q, J = 276.0 Hz, 1 C), 97.3, 72.6,
72.3, 60.5 (q, J = 34.4 Hz, 1 C), 26.0, 15.5, 12.8.
LR-MS (EI, 70 eV): m/z (%) = 489 (M+, 57), 390 (10), 362 (100),
129 (68).
HRMS (EI): m/z [M]+ calcd for C20H19F3INO2: 489.0413; found:
489.0413.
cis-3-Iodo-1,7-dimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3fa)
Pale yellow solid; mp 149.5–150.7 °C.
IR (KBr): 1696 cm–1.
1H NMR (400 MHz): d = 7.40–7.33 (m, 3 H), 7.22 (d, J = 8.0 Hz, 2
H), 6.15 (d, J = 10.0 Hz, 1 H), 5.61 (d, J = 10.0 Hz, 1 H), 5.36 (s, 1
H), 4.03 (s, 1 H), 3.77–3.65 (m, 2 H), 2.91 (s, 3 H), 1.85 (s, 3 H).
13C NMR (100 MHz): d = 167.1, 162.6, 138.9, 133.3, 130.7, 129.4,
129.0, 128.6, 128.3, 127.8, 123.8, 123.7 (q, J = 276.9 Hz, 1 C),
122.4, 96.4, 72.0, 70.3, 64.0 (q, J = 34.4 Hz, 1 C), 26.6, 19.5.
LR-MS (EI, 70 eV): m/z (%) = 475 (M+, 49), 376 (7), 349 (23), 348
(100), 129 (84).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO2: 475.0256; found:
475.0256.
cis-3-Iodo-1,6,9-trimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ha)
Yellow solid; mp 152.8–153.4 °C.
IR (KBr): 1672 cm–1.
1H NMR (400 MHz): d = 7.40–7.33 (m, 3 H), 7.25 (d, J = 8.0 Hz, 2
H), 5.87 (s, 1 H), 5.31 (s, 1 H), 4.09 (s, 1 H), 3.75–3.62 (m, 2 H),
2.84 (s, 3 H), 1.84 (s, 3 H), 1.55 (s, 3 H).
13C NMR (100 MHz): d = 167.6, 161.9, 138.6, 134.1, 133.0, 129.6,
128.8, 128.7, 127.7, 127.6, 124.3, 123.9 (q, J = 276.6 Hz, 1 C),
96.2, 73.1, 72.7, 63.5 (q, J = 34.4 Hz, 1 C), 26.3, 19.2, 16.7.
LR-MS (EI, 70 eV): m/z (%) = 489 (M+, 23), 390 (6), 362 (100), 129
(54).
HRMS (EI): m/z [M]+ calcd for C20H19F3INO2: 489.0413; found:
489.0413.
trans-3-Iodo-1,7-dimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3fa)
Pale yellow solid; mp 160.4–160.9 °C.
IR (KBr): 1695 cm–1.
trans-3-Iodo-1,6,9-trimethyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ha)
Pale yellow solid; mp 165.7–166.6 °C.
IR (KBr): 1674 cm–1.
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of 8-(Polyfluoroalkoxy)azaspiro[4.5]trienes
IR (KBr): 1700 cm–1.
897
1H NMR (400 MHz): d = 7.38–7.35 (m, 3 H), 7.19 (d, J = 8.0 Hz, 2
H), 5.90 (s, 1 H), 5.35 (s, 1 H), 4.55 (s, 1 H), 2.85–2.78 (m, 1 H),
2.74 (s, 3 H), 2.70–2.63 (m, 1 H), 1.82 (s, 3 H), 1.62 (s, 3 H).
13C NMR (100 MHz): d = 167.3, 162.3, 138.7, 135.7, 133.3, 129.8,
128.6, 128.4, 127.8, 125.6, 123.8 (q, J = 276.1 Hz, 1 C), 97.1, 72.6,
72.3, 60.8 (q, J = 34.4 Hz, 1 C), 26.0, 19.2, 17.1.
1H NMR (500 MHz): d = 7.44–7.41 (m, 3 H), 7.28 (d, J = 8.0 Hz, 2
H), 6.34 (s, 1 H), 6.18 (d, J = 10.0 Hz, 1 H), 5.76 (d, J = 10.0 Hz, 1
H), 4.86 (s, 1 H), 2.85 (s, 3 H), 2.82–2.80 (m, 2 H).
13C NMR (125 MHz): d = 167.3, 160.3, 133.5, 132.5, 130.7, 130.5,
130.0, 129.9, 128.7, 123.4 (q, J = 276.3 Hz, 1 C), 98.8, 71.8, 70.3,
61.5 (q, J = 35.0 Hz, 1 C), 26.1.
LR-MS (EI, 70 eV): m/z (%) = 489 (M+, 28), 390 (5), 362 (100), 129
(52).
LR-MS (EI, 70 eV): m/z (%) = 497 (M+ + 2, 9), 495 (M+, 29), 460
(M – Cl, 30), 368 (54), 129 (100).
HRMS (EI): m/z [M]+ calcd for C20H19F3INO2: 489.0413; found:
489.0411.
HRMS (EI): m/z [M]+ calcd for C18H14ClF3INO2: 494.9710; found:
494.9709.
cis-3-Iodo-6-methoxy-1-methyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ia)
Yellow solid; mp 76.0 °C.
IR (KBr): 1700 cm–1.
cis-6-Bromo-3-iodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ka)
Pale yellow solid; mp 117.8–119.5 °C.
1H NMR (500 MHz): d = 7.41–7.34 (m, 3 H), 7.18 (d, J = 8.0 Hz, 2
H), 6.14 (d, J = 10.0 Hz, 1 H), 5.51 (d, J = 10.0 Hz, 1 H), 5.09 (s, 1
H), 4.51 (s, 1 H), 3.83–3.73 (m, 2 H), 3.59 (s, 3 H), 2.87 (s, 3 H).
13C NMR (125 MHz): d = 167.9, 160.7, 151.9, 132.8, 130.7, 129.5,
129.3, 128.3, 127.8, 127.6, 129.2 (q, J = 276.0 Hz, 1 C), 98.8, 96.6,
71.9, 70.6, 63.6 (q, J = 33.4 Hz, 1 C), 54.9, 26.3.
IR (KBr): 1697 cm–1.
1H NMR (500 MHz): d = 7.35–7.30 (m, 3 H), 7.23 (d, J = 8.0 Hz, 2
H), 6.48 (s, 1 H), 6.16 (d, J = 10.0 Hz, 1 H), 5.65 (d, J = 10.0 Hz, 1
H), 4.14 (s, 1 H), 3.77–3.72 (m, 2 H), 2.85 (s, 3 H).
13C NMR (125 MHz): d = 167.3, 159.8, 133.8, 132.3, 130.2, 129.7,
128.5, 127.8, 127.7, 124.0, 123.4 (q, J = 276.3 Hz, 1 C), 98.3, 72.3,
71.9, 64.9 (q, J = 33.8 Hz, 1 C), 26.2.
LR-MS (EI, 70 eV): m/z (%) = 491 (M+, 34), 392 (24), 377 (19), 364
(18), 129 (100).
LR-MS (EI, 70 eV): m/z (%) = 541 (M+ + 2, 9), 539 (M+, 10), 461
(12), 460 (M – Br, 58), 412 (10), 332 (52), 333 (22), 234 (9), 129
(100).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO3: 491.0205; found:
491.0204.
HRMS (EI): m/z [M]+ calcd for C18H14BrF3INO2: 538.9205; found:
538.9205.
trans-3-Iodo-6-methoxy-1-methyl-4-phenyl-8-(2,2,2-trifluoro-
ethoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ia)
White solid; mp 147.0–148.6 °C.
IR (KBr): 1696 cm–1.
1H NMR (500 MHz): d = 7.39–7.38 (m, 3 H), 7.11 (d, J = 8.0 Hz, 2
H), 6.09 (d, J = 10.0 Hz, 1 H), 5.56 (d, J = 10.0 Hz, 1 H), 5.06 (s, 1
H), 4.98 (s, 1 H), 3.62 (s, 3 H), 2.78 (s, 3 H), 2.74–2.64 (m, 2 H).
13C NMR (125 MHz): d = 167.7, 161.6, 153.1, 133.0, 131.0, 129.6,
129.1, 128.5, 127.8, 129.0 (q, J = 276.1 Hz, 1 C), 99.5, 97.0, 70.7,
70.4, 59.9 (q, J = 33.8 Hz, 1 C), 54.8, 26.1.
trans-6-Bromo-3-iodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ka)
Pale yellow solid; mp 164.6–165.8 °C.
IR (KBr): 1699 cm–1.
1H NMR (500 MHz): d = 7.35–7.34 (m, 3 H), 7.24 (d, J = 8.0 Hz, 2
H), 6.50 (s, 1 H), 6.12 (d, J = 10.0 Hz, 1 H), 5.73 (d, J = 10.0 Hz, 1
H), 4.67 (s, 1 H), 2.79–2.77 (m, 5 H).
13C NMR (125 MHz): d = 167.2, 160.4, 134.0, 132.5, 130.4, 130.0,
129.8, 128.8, 128.6, 128.2, 125.4, 123.1 (q, J = 276.1 Hz, 1 C),
99.0, 72.2, 70.6, 61.7 (q, J = 35.0 Hz, 1 C), 26.1.
LR-MS (EI, 70 eV): m/z (%) = 491 (M+, 36), 460 (21), 392 (26), 364
(24), 234 (7), 129 (100).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO3: 491.0205; found:
491.0205.
LR-MS (EI, 70 eV): m/z (%) = 541 (M+ + 2, 23), 539 (M+, 26), 461
(2), 460 (M – Br, 9), 412 (11), 333 (22), 332 (52), 234 (9), 129
(100).
cis-6-Chloro-3-iodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ja)
Pale yellow solid; mp 92.9–94.0 °C.
HRMS (EI): m/z [M]+ calcd for C18H14BrF3INO2: 538.9205; found:
538.9205.
IR (KBr): 1697 cm–1.
cis-3,6-Diiodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3la)
Pale yellow solid; mp 114.0–115.2 °C.
IR (KBr): 1691 cm–1.
1H NMR (400 MHz): d = 7.43–7.35 (m, 3 H), 7.26 (d, J = 8.0 Hz, 2
H), 6.32 (s, 1 H), 6.21 (d, J = 10.0 Hz, 1 H), 5.67 (d, J = 10.0 Hz, 1
H), 4.31 (s, 1 H), 3.84–3.78 (m, 2 H), 2.91 (s, 3 H).
13C NMR (100 MHz): d = 167.5, 159.7, 132.4, 132.2, 130.2, 129.8,
129.6, 128.8, 127.9, 127.8, 123.6 (q, J = 276.8 Hz, 1 C), 98.2, 71.9,
71.7, 65.0 (q, J = 33.4 Hz, 1 C), 26.2.
1H NMR (500 MHz): d = 7.44–7.39 (m, 3 H), 7.35 (d, J = 8.0 Hz, 2
H), 6.87 (s, 1 H), 6.30 (d, J = 10.0 Hz, 1 H), 5.81 (d, J = 10.0 Hz, 1
H), 4.11 (s, 1 H), 3.86–3.80 (m, 2 H), 2.92 (s, 3 H).
LR-MS (EI, 70 eV): m/z (%) = 497 (M+ + 2, 9), 495 (M+, 29), 460
(M – Cl, 30), 396 (4), 368 (50), 332 (31), 129 (100).
HRMS (EI): m/z [M]+ calcd for C18H14ClF3INO2: 494.9710; found:
494.9709.
13C NMR (125 MHz): d = 167.1, 160.3, 141.8, 132.3, 130.3, 129.7,
128.4, 127.8, 123.5 (q, J = 277.5 Hz, 1 C), 102.7, 98.5, 73.0, 71.9,
64.9 (q, J = 33.8 Hz, 1 C), 26.3.
LR-MS (EI, 70 eV): m/z (%) = 588 (M+, 3), 587 (15), 460 (100), 333
(25), 250 (29), 234 (20), 129 (96).
trans-6-Chloro-3-iodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ja)
Pale yellow solid; mp 162.1–163.3 °C.
HRMS (EI): m/z [M]+ calcd for C18H14F3I2NO2: 586.9066; found:
586.9065.
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

898
Z.-Q. Wang et al.
PAPER
trans-3,6-Diiodo-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-
1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3la)
Pale yellow solid; mp 164.6–165.8 °C.
trans-3-Iodo-1-methyl-8-(2,2,3,3,3-pentafluoropropoxy)-4-pen-
tyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3rb)
Yellow oil.
IR (KBr): 1699 cm–1.
IR (KBr): 1699 cm–1.
1H NMR (500 MHz): d = 7.44–7.41 (m, 3 H), 7.39–7.37 (m, 2 H),
6.91 (s, 1 H), 6.27 (d, J = 10.0 Hz, 1 H), 5.89 (d, J = 10.0 Hz, 1 H),
4.63 (s, 1 H), 2.94–2.90 (m, 2 H), 2.84 (s, 3 H).
13C NMR (125 MHz): d = 166.9, 160.8, 143.0, 132.4, 130.5, 130.0,
128.8, 128.5, 128.3, 127.9, 123.4 (q, J = 276.3 Hz, 1 C), 104.4,
99.2, 72.8, 70.6, 61.8 (q, J = 33.8 Hz, 1 C), 26.1.
LR-MS (EI, 70 eV): m/z (%) = 588 (M+, 9), 587 (43), 503 (5), 460
(25), 333 (25), 250 (21), 129 (77), 57 (100).
HRMS (EI): m/z [M]+ calcd for C18H14F3I2NO2: 586.9066; found:
586.9066.
1H NMR (500 MHz): d = 6.33 (d, J = 11.0 Hz, 2 H), 5.50 (d,
J = 11.0 Hz, 2 H), 4.63 (s, 1 H), 3.94 (t, J = 13.0 Hz, 2 H), 2.75 (s,
3 H), 2.021–2.12 (m, 2 H), 1.49–1.40 (m, 2 H), 1.31–1.25 (m, 4 H),
0.89 (t, J = 6.5 Hz, 3 H).
13C NMR (125 MHz): d = 167.2, 164.1, 130.5, 130.0, 118.5 (tt,
J = 283.8, 35.0 Hz, 1 C), 113.9 (tq, J = 271.3, 36.3 Hz, 1 C), 94.6,
69.1, 68.5, 63.6 (t, J = 27.5 Hz, 1 C), 31.6, 29.8, 27.5, 26.0, 21.9,
13.6.
LR-MS (EI, 70 eV): m/z (%) = 505 (M+, 17), 434 (100).
HRMS (EI): m/z [M]+ calcd for C18H21F5INO2: 505.0537; found:
505.0537.
cis-3-Iodo-1,4-methyl-8-(2,2,2-trifluoroethoxy)-1-aza-
spiro[4.5]deca-3,6,9-trien-2-one (cis-3qa)
Yellow solid; mp 84.1–85.9 °C.
IR (KBr): 1699 cm–1.
1H NMR (500 MHz): d = 6.29 (d, J = 12.5 Hz, 2 H), 5.48 (d,
J = 12.5 Hz, 2 H), 4.65 (s, 1 H), 3.89–3.84 (m, 2 H), 2.91 (s, 3 H),
1.81 (s, 3 H).
13C NMR (125 MHz): d = 167.3, 160.7, 130.6, 129.2, 123.7 (q,
J = 276.3 Hz, 1 C), 94.5, 69.0, 68.7, 64.2 (q, J = 35.0 Hz, 1 C), 26.6,
15.4.
LR-MS (EI, 70 eV): m/z (%) = 399 (M+, 44), 587 (15), 272 (44), 111
(31), 97 (45), 57 (89), 43 (100).
HRMS (EI): m/z [M]+ calcd for C13H13F3INO2: 398.9943; found:
398.9943.
cis-3-Iodo-1-methyl-4-(2-methylphenyl)-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3sa)
Pale yellow solid; mp 118.4 °C.
IR (KBr): 1694 cm–1.
1H NMR (500 MHz): d = 7.28 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 7.5
Hz, 1 H), 7.14 (t, J = 7.5 Hz, 1 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.27 (d,
J = 12 Hz, 1 H), 6.05 (d, J = 12 Hz, 1 H), 5.70 (d, J = 12 Hz, 1 H),
5.65 (d, J = 12 Hz, 1 H), 3.84 (s, 1 H), 3.77–3.72 (m, 2 H), 2.97 (s,
3 H), 2.19 (s, 3 H).
13C NMR (125 MHz): d = 167.1, 163.0, 135.9, 1, 129.8, 129.1,
128.0, 127.7, 125.1, 123.7 (q, J = 276.3 Hz, 1 C), 98.5, 70.7, 69.3,
64.5 (q, J = 33.8 Hz, 1 C), 26.9, 20.0.
LR-MS (EI, 70 eV): m/z (%) = 475 (M+, 21), 376 (4), 348 (100).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO2: 475.0256; found:
trans-3-Iodo-1,4-methyl-8-(2,2,2-trifluoroethoxy)-1-aza-
spiro[4.5]deca-3,6,9-trien-2-one (trans-3qa)
Yellow solid; mp 88.6 °C.
IR (KBr): 1694 cm–1.
1H NMR (500 MHz): d = 6.36 (d, J = 12.5 Hz, 2 H), 5.48 (d,
J = 12.5 Hz, 2 H), 4.63 (s, 1 H), 3.92–3.88 (m, 2 H), 2.78 (s, 3 H),
1.90 (s, 3 H).
13C NMR (125 MHz): d = 167.2, 160.6, 131.1, 129.9, 123.5 (q,
J = 276.3 Hz, 1 C), 69.3, 68.3, 64.8 (q, J = 35.0 Hz, 1 C), 26.2, 15.8.
LR-MS (EI, 70 eV): m/z (%) = 399 (M+, 17), 300 (4), 503 (5), 272
(28), 111 (37), 57 (100).
HRMS (EI): m/z [M]+ calcd for C13H13F3INO2: 398.9943; found:
398.9941.
475.0256.
trans-3-Iodo-1-methyl-4-(2-methylphenyl)-8-(2,2,2-trifluoro-
ethoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3sa)
Pale yellow solid; mp 163.3–164.1 °C.
IR (KBr): 1682 cm–1.
1H NMR (500 MHz): d = 7.32–7.26 (m, 2 H), 7.21 (t, J = 7.5 Hz, 1
H), 6.93 (d, J = 7.5 Hz, 1 H), 6.25 (d, J = 12 Hz, 1 H), 6.09 (d,
J = 12 Hz, 1 H), 5.82 (d, J = 10 Hz, 1 H), 5.76 (d, J = 10 Hz, 1 H),
4.74 (s, 1 H), 2.90 (s, 3 H), 2.61–2.57 (m, 1 H), 2.46–2.42 (m, 1 H),
2.26 (s, 3 H).
13C NMR (125 MHz): d = 166.8, 163.1, 135.8, 132.0, 131.8, 131.0,
130.7, 130.5, 129.7, 128.4, 125.3, 123.5 (q, J = 276.3 Hz, 1 C),
98.8, 70.0, 67.5, 60.1 (q, J = 33.8 Hz, 1 C), 26.6, 19.9.
LR-MS (EI, 70 eV): m/z (%) = 475 (M+, 3), 376 (2), 348 (100).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO2: 475.0256; found:
cis-3-Iodo-1-methyl-8-(2,2,3,3,3-pentafluoropropoxy)-4-pentyl-
1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3rb)
Yellow oil.
475.0255.
IR (KBr): 1699 cm–1.
cis-3-Iodo-4-(4-methoxyphenyl)-1-methyl-8-(2,2,2-trifluoro-
ethoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ta)
Yellow solid; mp 133.3–135.0 °C.
IR (KBr): 1697 cm–1.
1H NMR (500 MHz): d = 7.23 (d, J = 7.0 Hz, 2 H), 6.88 (d, J = 7.0
Hz, 2 H), 6.21 (d, J = 10.5 Hz, 2 H), 5.69 (d, J = 10.5 Hz, 2 H), 4.68
(s, 1 H), 3.78 (s, 3 H), 3.05–3.00 (m, 2 H), 2.81 (s, 3 H).
13C NMR (125 MHz): d = 167.2, 162.1, 160.6, 131.4, 130.3, 129.6,
125.1, 123.6 (q, J = 277.5 Hz, 1 C), 113.9, 96.4, 68.8, 68.0, 61.9 (q,
J = 33.8 Hz, 1 C), 55.2, 26.3.
1H NMR (500 MHz): d = 6.28 (d, J = 11.0 Hz, 2 H), 5.49 (d,
J = 11.0 Hz, 2 H), 4.68 (s, 1 H), 3.92 (t, J = 13.0 Hz, 2 H), 2.86 (s,
3 H), 2.09–2.05 (m, 2 H), 1.49–1.40 (m, 2 H), 1.29–1.25 (m, 4 H),
0.88 (t, J = 6.5 Hz, 3 H).
13C NMR (125 MHz): d = 167.4, 164.3, 130.3, 129.2, 118.6 (tt,
J = 284.0, 35.0 Hz, 1 C), 114.0 (tq, J = 233.8, 36.3 Hz, 1 C), 94.5,
69.0, 68.8, 63.1 (t, J = 27.5 Hz, 1 C), 31.8, 29.5, 27.4, 26.3, 22.0,
13.6.
LR-MS (EI, 70 eV): m/z (%) = 505 (M+, 7), 434 (100).
HRMS (EI): m/z [M]+ calcd for C18H21F5INO2: 505.0537; found:
LR-MS (EI, 70 eV): m/z (%) = 491 (M+, 36), 364 (69), 159 (100).
505.0535.
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

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Selective Synthesis of 8-(Polyfluoroalkoxy)azaspiro[4.5]trienes
899
HRMS (EI): m/z [M]+ calcd for C19H17F3INO3: 491.0205; found:
IR (KBr): 1644 cm–1.
491.0205.
1H NMR (400 MHz): d = 7.41–7.35 (m, 4 H), 7.26 (d, J = 6.8 Hz,
0.31 H), 7.13–7.08 (m, 4 H), 6.92 (d, J = 6.4 Hz, 0.69 H), 6.86 (d,
J = 5.6 Hz, 0.28 H), 6.80 (d, J = 6.8 Hz, 0.72 H), 3.81 (s, 0.29 H),
3.78 (s, 0.71 H), 2.38 (s, 3 H).
13C NMR (100 MHz): d = 159.2, 158.7, 156.2, 156.0, 146.0, 142.0,
141.6, 140.8, 139.0, 137.0, 128.7, 128.4, 127.1, 123.8, 119.8, 119.4,
114.4, 113.3, 105.3, 99.8, 32.8, 31.7, 24.9, 22.2.
trans-3-Iodo-4-(4-methoxyphenyl)-1-methyl-8-(2,2,2-trifluoro-
ethoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ta)
Yellow solid; mp 135.0 °C.
IR (KBr): 1682 cm–1.
1H NMR (500 MHz): d = 7.28 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 8.5
Hz, 2 H), 6.22 (d, J = 10.0 Hz, 2 H), 5.62 (d, J = 10.0 Hz, 2 H), 4.24
(s, 1 H), 3.83–3.81 (m, 5 H), 2.92 (s, 3 H).
LR-MS (EI, 70 eV): m/z (%) = 375 (M+, 100).
13C NMR (125 MHz): d = 167.3, 161.4, 160.4, 130.9, 129.3, 128.9,
125.2, 123.8 (q, J = 277.5 Hz, 1 C), 113.8, 95.9, 69.4, 69.1, 64.6 (q,
J = 33.8 Hz, 1 C), 55.3, 26.9.
LR-MS (EI, 70 eV): m/z (%) = 491 (M+, 44), 364 (69), 265 (11), 253
(6), 159 (100).
3-Iodo-1,4-dimethylquinolin-2(1H)-one (4qa)1
Yellow solid; mp 121.0 °C.
IR (KBr): 1633 cm–1.
1H NMR (500 MHz): d = 7.83 (d, J = 8.0 Hz, 1 H), 7.62 (t, J = 8.0
Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1 H), 7.28–7.25 (m, 1 H), 2.83 (s, 3
H), 2.82 (s, 3 H).
HRMS (EI): m/z [M]+ calcd for C19H17F3INO3: 491.0205; found:
491.0205.
13C NMR (100 MHz): d = 150.8, 139.0, 130.9, 129.1, 126.0, 122.4,
120.6, 114.4, 102.7, 31.6, 26.2.
cis-3-Iodo-1-methyl-4-(4-nitrophenyl)-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-3ua)
Yellow solid; mp 175.5–176.3 °C.
IR (KBr): 1690 cm–1.
1H NMR (500 MHz): d = 8.17 (d, J = 9.0 Hz, 2 H), 7.40 (d, J = 8.5
Hz, 2 H), 6.21 (d, J = 10.5 Hz, 2 H), 5.59 (d, J = 10.5 Hz, 2 H), 4.08
(s, 1 H), 3.79–3.74 (m, 2 H), 2.89 (s, 3 H).
13C NMR (125 MHz): d = 166.4, 159.7, 148.2, 139.7, 131.7, 129.1,
127.7, 123.7, 123.6 (q, J = 276.3 Hz, 1 C), 99.1, 69.1 (2 C), 65.0 (q,
J = 35.0 Hz, 1 C), 26.6.
LR-MS (EI, 70 eV): m/z (%) = 299 (M+, 100).
3-Iodo-1-methyl-4-(2-methylphenyl)quinolin-2(1H)-one (4sa)
Pale yellow solid; mp 109.6–121.0 °C.
IR (KBr): 1637 cm–1.
1H NMR (500 MHz): d = 7.61 (t, J = 8.5 Hz, 1 H), 7.46–7.41 (m, 2
H), 7.36 (t, J = 8.0 Hz, 2 H), 7.10–7.04 (m, 3 H), 3.91 (s, 3 H), 2.05
(s, 3 H).
13C NMR (125 MHz): d = 159.1, 156.3, 140.5, 139.4, 134.8, 131.1,
130.3, 128.8, 128.2, 128.0, 126.3, 122.5, 120.9, 114.3, 101.5, 31.6,
19.3.
LR-MS (EI, 70 eV): m/z (%) = 375 (M+, 100).
HRMS (EI): m/z [M]+ calcd for C17H14INO: 375.0120; found:
LR-MS (EI, 70 eV): m/z (%) = 506 (M+, 3), 406 (3), 379 (100).
HRMS (EI): m/z [M]+ calcd for C18H14F3IN2O4: 505.9950; found:
505.9950.
375.0120.
trans-3-Iodo-1-methyl-4-(4-nitrophenyl)-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-3ua)
Yellow solid; mp 121.9–123.4 °C.
IR (KBr): 1682 cm–1.
1H NMR (500 MHz): d = 8.19 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.5
Hz, 2 H), 6.24 (d, J = 10.0 Hz, 2 H), 5.65 (d, J = 9.0 Hz, 2 H), 4.55
(s, 1 H), 3.15–3.10 (m, 2 H), 2.79 (s, 3 H).
13C NMR (125 MHz): d = 166.4, 159.7, 148.2, 139.4, 132.0, 129.4,
129.0, 123.6, 123.4 (q, J = 277.5 Hz, 1 C), 99.0, 68.7, 68.3, 63.2 (q,
J = 35.0 Hz, 1 C), 26.3.
3-Iodo-4-(4-methoxyphenyl)-1-methylquinolin-2(1H)-one (4ta)
Yellow solid; mp 145.1 °C.
IR (KBr): 1631 cm–1.
1H NMR (500 MHz): d = 7.26 (t, J = 8.0 Hz, 1 H), 7.21 (d, J = 8.0
Hz, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 10.5 Hz, 2 H), 7.07–
7.05 (m, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H).
13C NMR (125 MHz): d = 159.8, 159.1, 156.2, 139.6, 133.6, 130.9,
129.8, 129.0, 122.3, 121.8, 114.1, 102.1, 55.3, 31.7.
LR-MS (EI, 70 eV): m/z (%) = 391 (M+, 100).
HRMS (EI): m/z [M]+ calcd for C17H14INO2: 391.0069; found:
LR-MS (EI, 70 eV): m/z (%) = 506 (M+, 3), 407 (3), 380 (20), 379
(100).
HRMS (EI): m/z [M]+ calcd for C18H14F3IN2O4: 505.9950; found:
391.0069.
505.9948.
3-Iodo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-
dione (5oa)3
White solid; mp 195.6–197.3 °C.
IR (KBr): 1699, 1662, 1361 cm–1.
3-Iodo-1-methyl-4-phenylquinolin-2(1H)-one (4aa)1
Pale yellow solid; mp 173.2 °C.
IR (KBr): 1737, 1637, 1597 cm–1.
1H NMR (400 MHz): d = 7.40–7.34 (m, 3 H), 7.28 (d, J = 8.0 Hz, 2
H), 6.52, 6.46 (dd, J = 10.4 Hz, 10.4 Hz, 4 H), 2.95 (s, 3 H).
13C NMR (100 MHz): d = 183.8, 167.4, 158.0, 144.1, 133.3, 131.9,
130.1, 128.7, 127.7, 98.2, 70.4, 27.1.
1H NMR (400 MHz): d = 7.62–7.50 (m, 4 H), 7.43 (d, J = 8.4 Hz, 1
H), 7.22 (d, J = 6.8 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.08 (t,
J = 7.2 Hz, 1 H), 3.90 (s, 3 H).
13C NMR (100 MHz): d = 159.1, 156.3, 141.2, 139.6, 131.1, 128.8,
128.9, 128.6, 128.4, 122.4, 121.5, 65.8, 31.7.
LR-MS (EI, 70 eV): m/z (%) = 377 (M+, 14), 248 (94), 129 (100).
LR-MS (EI, 70 eV): m/z (%) = 361 (M+, 100).
3-Iodo-1-methyl-4-(thiophen-2-yl)-1-azaspiro[4.5]deca-3,6,9-
triene-2,8-dione (5va)
White solid; mp 179.3–180.1 °C.
IR (KBr): 1695, 1662 cm–1.
3-Iodo-1,5-dimethyl-4-phenylquinolin-2(1H)-one (4fa) and 3-
Iodo-1,7-dimethyl-4-phenylquinolin-2(1H)-one (4fa¢)
Pale yellow solid; ratio 4fa/4fa¢ 1:3.
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

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Z.-Q. Wang et al.
PAPER
1H NMR (500 MHz): d = 7.68 (s, 1 H), 7.53 (d, J = 5.0 Hz, 2 H),
7.10 (d, J = 5.0 Hz, 2 H), 6.62–6.53 (m, 4 H) 2.93 (s, 3 H).
13C NMR (125 MHz): d = 183.9, 167.6, 149.5, 145.1, 133.2, 132.7,
129.7, 129.4, 127.5, 93.5, 69.1, 26.3.
LR-MS (EI, 70 eV): m/z (%) = 383 (M+, 27), 256 (18), 135 (100).
HRMS (EI): m/z [M]+ calcd for C14H10INO2S: 382.9477; found:
1H NMR (500 MHz): d = 7.43–7.34 (m, 5 H), 6.36 (d, J = 10.0 Hz,
1 H), 6.21 (t, J = 10.0 Hz, 1 H), 5.75 (d, J = 10.0 Hz, 1 H), 4.86 (s,
1 H), 2.98–2.94 (m, 2 H), 2.82 (s, 3 H).
13C NMR (125 MHz): d = 165.7, 153.2, 132.3, 130.8, 130.4, 130.0,
129.6, 129.4, 128.5, 127.6, 123.5 (q, J = 276.3 Hz, 1 C), 120.4,
71.3, 70.0, 61.9 (q, J = 35.0 Hz, 1 C), 25.6.
LR-MS (EI, 70 eV): m/z (%) = 451 (5), 450 (4), 449 (M+ + 2, 15),
448 (4), 447 (M+, 9), 414 (9), 368 (13), 332 (10), 268 (7), 234 (10),
129 (90), 77 (9), 43 (100).
382.9477.
cis-3-Bromo-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-6aa)
Pale yellow solid; mp 88.2 °C.
HRMS (EI): m/z [M]+ calcd for C18H14BrClF3NO2: 446.9849;
found: 446.9848.
IR (KBr): 1697 cm–1.
3-Bromo-1-methyl-4-(thiophen-2-yl)-8-(2,2,2-trifluoroethoxy)-
1-azaspiro[4.5]deca-3,6,9-trien-2-one (6va)
Yellow solid; ratio cis/trans 3:2; mp 147.2 °C.
IR (KBr): 1694 cm–1.
1H NMR (500 MHz): d = 7.66–7.36 (m, 2 H), 7.12–7.05 (m, 1 H),
6.40–6.36 (m, 2 H), 5.67–5.63 (m, 2 H), 4.75–4.72 (m, 1 H), 3.98–
3.93 (m, 2 H), 2.91 (s, 1.9 H), 2.89 (m, 1.1 H).
13C NMR (125 MHz): d = 165.5, 165.2, 147.1, 146.2, 134.0, 132.4,
131.2, 131.0, 130.2, 130.0, 129.9, 129.7, 129.6, 129.1, 127.3, 123.8
(q, J = 276.3 Hz, 1 C), 117.4, 115.3, 114.9, 70.1, 69.9, 66.0–64.8
(qq, 2 C), 25.9, 25.8.
1H NMR (500 MHz): d = 7.39–7.35 (m, 5 H), 6.25 (d, J = 10.0 Hz,
2 H), 5.64 (d, J = 10.0 Hz, 2 H), 4.27 (s, 1 H), 3.85–3.80 (m, 2 H),
2.92 (s, 3 H).
13C NMR (125 MHz): d = 165.6, 154.8, 131.2, 130.3, 129.5, 128.9,
128.4, 127.8, 123.7 (q, J = 276.3 Hz, 1 C), 118.4, 69.2, 67.2, 64.6
(q, J = 33.8 Hz, 1 C), 26.2.
LR-MS (EI, 70 eV): m/z (%) = 415 (M+ + 2, 3), 413 (M+, 3), 334
(100), 129 (42).
HRMS (EI): m/z [M]+ calcd for C18H15BrF3NO2: 413.0238; found:
413.0237.
LR-MS (EI, 70 eV): m/z (%) = 422 (7), 421 (M+ + 2, 38), 420 (9),
419 (M+, 36), 375 (2), 341 (13), 340 (66), 241 (21), 204 (19), 135
(100), 77 (21).
HRMS (EI): m/z [M]+ calcd for C16H13BrF3NO2S: 418.9803; found:
418.9800.
trans-3-Bromo-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (trans-6aa)
White solid; mp 173.9–174.7 °C.
IR (KBr): 1693 cm–1.
1H NMR (500 MHz): d = 7.42–7.36 (m, 3 H), 7.32 (d, J = 7.0 Hz, 2
H), 6.24 (d, J = 10.0 Hz, 2 H), 5.73 (d, J = 10.0 Hz, 2 H), 4.72 (s, 1
H), 3.02–3.00 (m, 2 H), 2.82 (s, 3 H).
13C NMR (125 MHz): d = 165.5, 155.3, 131.8, 131.2, 129.9, 129.8,
128.4, 128.3, 123.6 (q, J = 276.3 Hz, 1 C), 118.8, 73.1, 66.8, 62.0
(q, J = 33.8 Hz, 1 C), 25.9.
LR-MS (EI, 70 eV): m/z (%) = 415 (M+ + 2, 12), 413 (M+, 12), 334
(100), 129 (64).
HRMS (EI): m/z [M]+ calcd for C18H15BrF3NO2: 413.0238; found:
413.0238.
cis-3-Chloro-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (cis-7aa)
Yellow solid; mp 73.0 °C.
IR (KBr): 1700 cm–1.
1H NMR (400 MHz): d = 7.41–7.26 (m, 5 H), 6.26 (d, J = 10.0 Hz,
2 H), 5.61 (d, J = 10.0 Hz, 2 H), 4.35 (s, 1 H), 3.87–3.80 (m, 2 H),
2.89 (s, 3 H).
13C NMR (100 MHz): d = 165.0, 150.6, 131.2, 130.3, 129.6, 128.7,
128.4, 127.9, 127.0, 123.7 (q, J = 277.0 Hz, 1 C), 69.3, 65.5, 64.7
(q, J = 34.3 Hz, 1 C), 27.8.
LR-MS (EI, 70 eV): m/z (%) = 371 (M+ + 2, 3), 369 (M+, 9), 334 (M
– Cl, 100).
HRMS (EI): m/z [M]+ calcd for C18H15ClF3NO2: 369.0743; found:
369.0741.
cis-3-Bromo-6-chloro-1-methyl-4-phenyl-8-(2,2,2-trifluoro-
ethoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-6ja)
Yellow oil.
IR (KBr): 1716 cm–1.
1H NMR (500 MHz): d = 7.41–7.33 (m, 5 H), 6.35 (d, J = 7.5 Hz, 1
H), 6.24 (t, J = 7.5 Hz, 1 H), 5.68 (d, J = 7.5 Hz, 1 H), 4.11 (d,
J = 7.5 Hz, 1 H), 3.85–3.83 (m, 2 H), 2.90 (s, 3 H).
13C NMR (100 MHz): d = 166.0, 152.7, 132.2, 130.6, 130.3, 129.8,
129.7, 128.6, 128.0, 127.8, 123.5 (q, J = 276.9 Hz, 1 C), 120.0,
71.6, 70.1, 64.9 (q, J = 35.1 Hz, 1 C), 25.9.
LR-MS (EI, 70 eV): m/z (%) = 451 (6), 450 (5), 449 (M+ + 2, 25),
448 (5), 447 (M+, 18), 414 (40), 368 (33), 332 (16), 312 (13), 268
(19), 234 (19), 129 (100).
HRMS (EI): m/z [M]+ calcd for C18H14BrClF3NO2: 446.9849;
found: 446.9849.
trans-3-Chloro-1-methyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-1-
azaspiro[4.5]deca-3,6,9-trien-2-one (trans-7aa)
Yellow solid; mp 129.7 °C.
IR (KBr): 1719 cm–1.
1H NMR (400 MHz): d = 7.40–7.36 (m, 5 H), 6.26 (d, J = 10.0 Hz,
2 H), 5.71 (d, J = 10.0 Hz, 2 H), 4.72 (s, 1 H), 31.8–3.11 (m, 2 H),
2.80 (s, 3 H).
13C NMR (100 MHz): d = 164.9, 151.0, 131.8, 130.1, 129.9, 129.8,
128.6, 128.4, 128.3, 127.3, 123.6 (q, J = 276.1 Hz, 1 C), 68.0, 65.2,
62.3 (q, J = 34.3 Hz, 1 C), 25.6.
LR-MS (EI, 70 eV): m/z (%) = 371 (M+ + 2, 11), 369 (M+, 33), 334
(M – Cl, 100).
HRMS (EI): m/z [M]+ calcd for C18H15ClF3NO2: 369.0743; found:
trans-3-Bromo-6-chloro-1-methyl-4-phenyl-8-(2,2,2-trifluoro-
ethoxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-6ja)
Yellow solid; mp 94.9 °C.
369.0743.
IR (KBr): 1708 cm–1.
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of 8-(Polyfluoroalkoxy)azaspiro[4.5]trienes
901
cis-3-Chloro-1,6-dimethyl-4-phenyl-8-(2,2,2-trifluoroethoxy)-
1-azaspiro[4.5]deca-3,6,9-trien-2-one (cis-7ea)
Yellow solid; mp 90.0 °C.
IR (KBr): 1699 cm–1.
1H NMR (400 MHz): d = 7.44–7.36 (m, 5 H), 6.24 (d, J = 10.0 Hz,
1 H), 6.00 (s, 1 H), 5.58 (d, J = 10.0 Hz, 1 H), 4.43 (s, 1 H), 3.86–
3.80 (m, 2 H), 2.82 (s, 3 H), 1.55 (s, 3 H).
13C NMR (100 MHz): d = 165.4, 149.8, 134.1, 130.6, 129.7, 129.3,
128.7, 128.5, 128.0, 127.9, 127.6, 123.8 (q, J = 276.9 Hz, 1 C),
70.6, 67.8, 64.5 (q, J = 34.4 Hz, 1 C), 25.6, 16.9.
Ed. 2003, 42, 2406. (o) Barluenga, J.; Trincado, M.; Rubio,
E.; Gonzalez, J. M. Angew. Chem. Int. Ed. 2006, 45, 3140.
(p) Barluenga, J.; Palomas, D.; Rubio, E.; Gonzalez, J. M.
Org. Lett. 2007, 9, 2823. (q) Greger, H. Planta Med. 2006,
72, 99.
(2) (a) Appel, T. R.; Yehia, N. A. M.; Baumeister, U.; Hartung,
H.; Kluge, R.; Ströhl, D.; Fanghänel, E. Eur. J. Org. Chem.
2003, 47. (b) Zhang, X.; Larock, R. C. J. Am. Chem. Soc.
2005, 127, 12230. (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.
(3) We have also developed a general and selective protocol for
the synthesis of spiro[4.5]trienyl acetates via intramolecular
electrophilic ipso-cyclization of N-arylpropynamides with
NIS and AcOH, in which no any active substituents at the
para-position of the N-aryl ring were required, see: 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.
(4) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac,
F.; White, C. T. The Total Synthesis of Natural Products,
Vol. 5; Apsimon, J., Ed.; Wiley-Interscience: New York,
1983, 264–313. (b) Yoneda, K.; Yamagata, E.; Nakanishi,
T.; Nagashima, T.; Kawasaki, I.; Yoshida, T.; Mori, H.;
Miura, I. Phytochemistry 1984, 23, 2068. (c) Sakamoto, K.;
Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996,
49, 37. (d) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J.
F.; Vercauteren, J.; Weber, J. F.; Boukef, K. Tetrahedron
Lett. 1994, 35, 2691. (e) Blackman, A. J.; Li, C.; Hockless,
D. C. R.; Skelton, B. W.; White, A. H. Tetrahedron 1993,
49, 8645. (f) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463;
and references cited therein. (g) Amagata, T.; Minoura, K.;
Numata, A. J. Nat. Prod. 2006, 69, 1384. (h) Galliford, C.
V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748.
(5) (a) Magueur, G.; Crousse, B.; Charneau, S.; Grellierm, P.;
Begue, J. P.; Bonnet-Delpon, D. J. Med. Chem. 2004, 47,
2694. (b) Gryshuk, A.; Chen, Y.; Goswami, L. N.; Pandey,
S.; Missert, J. R.; Ohulchanskyy, T.; Potter, W.; Prasad, P.
N.; Oseroff, A.; Pandey, R. K. J. Med. Chem. 2007, 50,
1754. (c) Gimenez, D.; Andreu, C.; Olmo, M. L.; Varea, T.;
Diaz, D.; Asensio, G. Bioorg. Med. Chem. 2006, 14, 6971.
(d) Large-Radix, S.; Billard, T.; Langlois, B. R. J. Fluorine
Chem. 2003, 124, 147. (e) Welch, J. T. Tetrahedron 1987,
43, 3123. (f) Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M.
T.; Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593.
(6) For selected papers on the synthesis of the spiro[4.5]decane
skeleton by intramolecular oxidative ipso-cyclization
reactions of aryl nitrenium ions, see: (a) Kawashima, T.;
Naganuma, K.; Okazaki, R. Organometallics 1998, 17, 367.
(b) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053.
(c) Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. J. Org.
Chem. 2003, 68, 5429. (d) Kikugawa, Y.; Nagashima, A.;
Sakamoto, T.; Miyazawa, E.; Shiiya, M. J. Org. Chem. 2003,
68, 6739. (e) Wardrop, D. J.; Landrie, C. L.; Ortíz, J. A.
Synlett 2003, 1352. (f) Wardrop, D. J.; Burge, M. S. J. Org.
Chem. 2005, 70, 10271. (g) Dohi, T.; Maruyama, A.;
Minamitsuji, Y.; Takenaga, N.; Kita, Y. Chem. Commun.
2007, 1224; and references cited therein.
LR-MS (EI, 70 eV): m/z (%) = 385 (M+ + 2, 7), 383 (M+, 21), 348
(M – Cl, 22), 284 (7), 234 (7), 207 (14), 129 (13), 77 (8), 43 (100).
HRMS (EI): m/z [M]+ calcd for C19H17ClF3NO2: 383.0900; found:
383.0899.
trans-3-Chloro-1,6-dimethyl-4-phenyl-8-(2,2,2-trifluoroeth-
oxy)-1-azaspiro[4.5]deca-3,6,9-trien-2-one (trans-7ea)
Yellow solid; mp 182.1 °C.
IR (KBr): 1720 cm–1.
1H NMR (400 MHz): d = 7.43–7.40 (m, 2 H), 7.36–7.30 (m, 3 H),
6.19 (d, J = 10.0 Hz, 1 H), 5.97 (s, 1 H), 5.57 (d, J = 10.0 Hz, 1 H),
3.28–3.24 (m, 2 H), 2.67 (s, 3 H), 1.53 (s, 3 H).
13C NMR (100 MHz): d = 165.3, 150.1, 135.3, 131.0, 130.1, 130.0,
129.9, 128.7, 128.5, 128.2, 128.0, 123.7 (q, J = 276.9 Hz, 1 C),
69.7, 67.6, 62.8 (q, J = 34.3 Hz, 1 C), 25.2, 17.2.
LR-MS (EI, 70 eV): m/z (%) = 385 (M+ + 2, 6), 383 (M+, 17), 348
(M – Cl, 15), 284 (8), 207 (20), 129 (12), 77 (9), 43 (100).
HRMS (EI): m/z [M]+ calcd for C19H17ClF3NO2: 383.0900; found:
383.0900.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (No. 20572020 and 20872112), Scientific Research Fund of
Hunan Provincial Education Department (No. 08A037), and Pro-
gram for New Century Excellent Talents in University (No. NCET-
06-0711) for financial support.
References
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Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York

902
Z.-Q. Wang et al.
PAPER
at the 8-position of the spirocyclic motif according to the
reported authoritative data of the corresponding analogues,
see refs. 6b, 6c, and 6g.
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(9) A set of other reagents, including NaOEt, NaOAc, NH4Cl, 4-
nitrophenol, and TfOH, instead of TFA were examined. The
results showed that no reaction was observed using NaOEt,
NaOAc, NH4Cl, or 4-nitrophenol, and the electrophilic
ortho-cyclization product 4aa was obtained in 90% yield in
the presence of TfOH.
(8) The structures and the cis/trans configuration of the products
are determined on the basis of the chemical shift of hydrogen
Synthesis 2009, No. 6, 891–902 © Thieme Stuttgart · New York