Visible-Light-Mediated Ipso-Carboacylation of Alkynes: Synthesis of 3-Acylspiro[4,5]trienones from N-(p-Methoxyaryl)propiolamides and Acyl Chlorides

Article abstract of DOI:10.1021/acs.joc.7b03104

A novel visible-light-mediated ipso-carboacylation of N-(p-methoxyaryl)propiolamides with acyl chloride has been established for the synthesis of diverse 3-acylspiro[4,5]trienones with high selectivity and efficiency. This method represents a new difunctionalization of alkynes through cross coupling of the acyl chloride C-Cl bonds with an ipso-aromatic carbon by simultaneously forming two new carbon-carbon bonds and one carbon-oxygen double bond.

Full text of DOI:10.1021/acs.joc.7b03104

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Article
Visible-Light-Mediated Ipso-Carboacylation of Alkynes:
Synthesis of 3-Acylspiro[4,5]trienones from N-(p-
methoxyaryl)propiolamides and Acyl Chlorides
Yu Liu, Qiao-Lin Wang, Cong-Shan Zhou, Biquan Xiong,
Pan-Liang Zhang, Chang-An Yang, and Ke-Wen Tang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03104 • Publication Date (Web): 17 Jan 2018
Downloaded from http://pubs.acs.org on January 17, 2018
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Page 1 of 26
The Journal of Organic Chemistry
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Visible-Light-Mediated Ipso-Carboacylation of
Alkynes: Synthesis of 3-Acylspiro[4,5]trienones from
N-(p-methoxyaryl)propiolamides and Acyl Chlorides
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*
Yu Liu, Qiao-Lin Wang, Cong-Shan Zhou, Bi-Quan Xiong, Pan-Liang Zhang, Chang-an Yang, Ke-
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Wen Tang
†
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology,
Yueyang 414006, China
lyxtmj_613@163.com and tangkewen@sina.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract
A novel visible-light-mediated ipso-carboacylation of N-(p-methoxyaryl)propiolamides with acyl
chloride has been established for the synthesis of diverse 3-acylspiro[4,5]trienones with high selectivity
and efficiency. This method represents a new difunctionalization of alkynes through cross coupling of
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the acyl chloride C-Cl bonds with an ipso-aromatic carbon by simultaneously forming two new carbon-
carbon bonds and one carbon-oxygen double bond.
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Introduction
Spirocycles, including spiro[4,5]decatrienones, are very important scaffolds, and they often exist in
1
natural products and biologically active molecules. Among these compounds, spiroquinones are
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versatile intermediates that can be used for the synthesis of diverse framework. For this reason,
considerable efforts have been devoted to the development of novel and efficient ways for the synthesis
2
-6
of spiro[4,5]decatrienones. Generally, the spiro[4,5]decatrienones structures are constructed via the
3
electrophilic ipso-cyclization of 5-(4-methoxyaryl)-1-alkynes, transition-metal-catalyzed intramolecular
4
nucleophilic ipso-carbocyclization of 5-(4-hydroxyaryl)-1-alkynes or 5-(4-hydroxyaryl)-1-alkenes and
5
the oxidative ispo-cyclization of phenol derivatives. Recently, many approaches for the synthesis of
6
spiro[4,5]decatrienones via the oxidative radical coupling strategy were developed. Li and co-workers
6
e
6f
reported radical oxidative ipso-carbocyclization of alkynes with ethers or alkanes for the synthesis of
6
g
3-substituted spiro[4,5]decatrienones (Eq 1, Scheme 1). Liang’s group and Liu’s group developed
copper-catalyzed difunctionalization of activated alkynes leading to 3-trifluoromethyl
spiro[4,5]decatrienones by radical oxidation/dearomatization/tandem cyclization (Eq 2, Scheme 1).
As carbonyl groups are very active group, the introduction of a carbonyl group into the organic
compounds become one of the most popularly processes for organic chemists. The frequently utilized
method for the carbonyl group introduction is the carbonylation reaction that using the toxic CO gas as
7
the carbonyl source. However, these methods suffer from the storage and transport of the toxic CO gas,
that limiting their wide application in organic synthesis and industry. Therefore, the acylation reaction is
8
becoming a major topic in the carbonyl group introduction by acyl radical strategies. Li and co-
9
workers applied acyl radicals derived from simple aldehydes into the radical cascade cyclization of
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a
9b
9c
activated alkenes , N-arylpropiolamides (Eq 3, Scheme 1) and 1,n-enynes , which developed the
1
0
most rapid and atom-economic protocol for building fused polycyclic hydrocarbons. Wang’s group
11
and Wallentin’s group reported that acyl radicals derived from α-oxocarboxylic acids and aromatic
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carboxylic acids, respectively, have been used to initiate cyclization cascades to generate heterocyclic
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compounds. Recently, Xu and co-workers applied acyl radicals generated from commercially available
and abundant acyl chlorides into valuable cascade annulations reactions under visible-light-mediated
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photoredox catalysis. Inspired by these works, and based on our work on the development of visible-
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light photoredox catalysis reactions , we report a novel visible-light-mediated difunctionalizing
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acylation of activated alkynes in the synthesis of 3-acylspiro[4,5]decatrienones (Eq 4, Scheme 1). This
strategy involves a connection of the acyl group with the electron-deficient carbon-carbon triple bond to
generate the spiro[4,5]decatrienone skeleton via a tandem cyclization/dearomatization process.
a) Previous work:
R2
X = O or CH2
X
X
O
(
(
1)
2)
[Cu], TBHP
ref 6e and 6f
Y
O
R1
R1
R1
R2
NaSO CF
2
3
R2
CuCl, TBHP
NaOAc, MnO2
CF3
O
O
o
CH CN/H O, 60 C
Y
R1
Y
O
3
2
O
ref 6g
Y = NR, O
R2
O
R3
3
R CHO, TBHP
(
3)
n
o
BuOAc, 120 C
Y
O
ref 9b
b) This work:
R3
R4
R3
[Ir(ppy) ], 2,6-lutidine
3
MeO
O
O
H O
2
(
4)
O
+
R4
o
Cl
CH CN, Ar, 100 C
3
N
R2
R1
N
O
O
5
W blue LED light
R1
R2
Scheme 1. Oxidative Radical Difunctionalization of Alkyne Leading to Spiro[4,5]trienones.
Results and discussion
Initially, [Ir(ppy) ] (2 mol %) was chosen as the photocatalyst for the tandem reaction of N-(4-
3
methoxyphenyl)-N-methyl-3-phenylpropiolamide (1a) and benzoyl chloride (2a). To our delight, the
9b
desired spiro[4,5]decatrienone 3aa was afforded in 88% yield using 2,6-lutidine (0.4 mmol) as
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o
additive, H O (2 equiv) and CH CN (2 mL) as solvent at 100 C by irradiation with a 5 W blue LED
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light bulb for 24 h (Table1, entry 1). Given the potential utility of this protocol, we focused our attention
on optimizing the reaction conditions (Table 1). However, no spiro[4,5]decatrienone 3aa was observed
when Ru(bpy) Cl and Eosin Y were used instead of [Ir(ppy) ] (entries 2-3). Further experiments
2
2
3
demonstrated that either [Ir(ppy) ] or light was essential for the reaction (Table 1, entries 4-5). The
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amount of [Ir(ppy) ] was found to affect the reaction, as 2 mol% [Ir(ppy) ] was preferred (entry 1 versus
3
3
entry 6). However, the yield of 3aa decreased to 73% using 36 W compact fluorescent light instead of 5
W blue LED light (entry 1 versus entry 7). Compared with 2,6-lutidine as the additive, other base such
as Na CO , K CO , and Et N led to lower yields, and using pyridine obtained the target product 3aa in
2
3
2
3
3
67% yield (entry 1 versus entries 8-11). Therefore, 2,6-lutidine was the optimal additive used to afford
1
2
alkaline environment and also stabilize the acyl radical . In an attempt to improve the reaction
efficiency, a number of solvents were tested, and the results showed that others such as toluene, BuOAc,
THF, DMF, and DMSO gave poor reaction yields (entry 1 versus entries 12-16). Among the reaction
o
o
temperature examined, it turned out that the similar yield as that of 100 C was achieved at 120 C (entry
o
o
1
7), but the yield decreased from 88% at 100 C to 70% at 80 C (entry 18). We also tested effect of the
amount of H O, and the results showed that 2 equiv. of H O afforded the best result (entry 1 vs. entries
2
2
19-21). We were pleased to find that a 1 gram (3.77 mmol) of substrate 1a was successful in producing a
good yield (entry 22).
a
Table 1. Screening Optimal Conditions
Entry
1
2
Variation from the standard conditions
none
yield (%)
88
0
b
[Ru(bpy) Cl ] instead of [Ir(ppy) ]
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b
b
b
3
4
5
Eosin Y instead of [Ir(ppy)3]
without [Ir(ppy)3]
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without additional light
6
[Ir(ppy) ] (5 mol %)
89
73
53
47
51
67
32
61
54
0
3
c
7
none
8
9
10
1
2
3
Na CO instead of 2,6-lutidine
2
3
K CO instead of 2,6-lutidine
2 3
Et N instead of 2,6-lutidine
3
1
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pyridine instead of 2,6-lutidine
toluene instead of CH CN
3
BuOAc instead of CH CN
3
14
THF instead of CH CN
3
b
1
1
1
5
6
DMF instead of CH CN
3
b
DMSO instead of CH CN
0
3
o
7
at 120 C
86
70
trace
72
70
80
o
18
at 80 C
b
1
2
2
9
Without H O
2
0
H O (1 equiv)
2
1
H O (3 equiv)
2
d
22
none
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Ir(ppy) ] (2 mol %),
,6-lutidine (2.0 equiv), CH CN (2 mL), 100 C, argon, 5 W blue LED light
and 24 h. Most of raw material 1a was recovered, and the rest was
decomposed, and over 70% of benzil generated from homocoupling of
benzoyl chloride according the GC-MS analysis.
fluorescent light instead of 5 W blue LED light. 1a (1.0 g, 3.77 mmol) for
3
o
2
3
b
c
36 W compact
d
72 h.
Having established the standard reaction conditions, we first investigated the scope of N-(p-
methoxyaryl)propiolamides (1) with respect to benzoyl chloride (2a) for this new ipso-carboacylation
2
process (Table 2). Firstly, we investigated the effect of the substituent at nitrogen (R ). Whereas we
were pleased to find that propiolamides 1b-1d, having a benzyl group, a 2-iodobenzyl group, or an
allylic group on the nitrogen atom, were suitable for accessing spiro[4,5]decatrienone 3ba-3da in the
2
presence of benzoyl chloride (2a), [Ir(ppy) ], 2,6-lutidine, H O, and CH CN. However, substrate 1e (R
3
2
3
= H) only gave a trace amount of the desired product, substrate 1f with an electron withdraw group (Ac)
on the nitrogen atom afforded the corresponding product 3fa in 69% yield. Subsequently, the
substitution effect of the N-aryl moiety was tested (products 3ga-3ka). For example, substrate 1, bearing
an o-Me group, a m-OMe group or a m-Me group on the aromatic ring of the N-aryl moiety, were
successfully reacted with benzoyl chloride 2a in 67%, 61% and 64% yield (product 3ga, 3ia and 3ja),
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respectively. Importantly, the ipso-carboarcylation protocol was applicable to o-iodo- or m-chloro-
substituted propiolamides 1h and 1k, thus providing the opportunities for further modifications of
products at the halogenated positions (product 3ha and 3ka). Extensive screening revealed that a series
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of substituents, including Me, Et, t-Bu, OMe, F, Cl, CF , and Ac groups, on the aromatic ring at the
3
terminal alkyne were tolerated well (substrate 1l-1u), and the electron-withdraw groups shown lower
reactivity than the electron-donating groups in terms of the yields (products 3la-3ua). Nevertheless, the
steric factor also affected the ipso-carboacylation process according to the yields of products 3la, 3ma,
and 3oa. Gratifyingly, the alkyl alkyne 1v was also tolerated well, and giving the corresponding product
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va in 61% yield. Naphthalen-1yl alkyne 1w was also viable to furnish 3wa. Notably, the ipso-
cyclization method was extended to heteroaryl alkynes (1x and 1y) leading to 3xa and 3ya in 65% and
7% yields, respectively. Unfortunately, attempted to ipso-carboacylation of terminal alkyne failed to
assemble spiro[4,5]decatrienone.
5
a
Table 2. Screening Scope of N-(p-methoxyaryl)propiolamides (1)
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2
Ph
Ph
R = Bn, 3ba, 83%
Ph
Ph
Ph
1
2
3
4
5
6
7
8
9
Ph
2
R = 2-I-Bn, 3ca, 76%
O
O
O
O
O
2
R = allyl, 3da, 70%
O
O
O
O
O
2
N
N
3ea, 0%
O
O
N
R2
R = H,
O
2
I
R = Ac, 3fa, 69%
3
ga, 67%
3ha, 72%
Ph
Ph
Ph
Ph
Ph
Ph
O
O
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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0
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N
N
ja, 64%
O
O
O
Cl
MeO
3
ka, 64%
3
3ia, 61%
Ph
n-C H
Ph
5
11
3
R = 2-Et, 3la, 60%
O
3
O
R = 3-Me, 3ma, 70%
R3
Ph
O
O
3
R = 3,5-diMe, 3na, 83%
N
O
N
3
O
R = 4-Me, 3oa, 86%
3
va, 61%
3
3wa, 72%
R = 4-t-Bu, 3pa, 88%
O
N
3
O
R = 4-OMe, 3qa, 85%
N
3
O
R = 4-F, 3ra, 78%
S
Ph
Ph
3
R = 4-Cl, 3sa, 80%
O
O
3
R = 4-CF , 3ta, 74%
3
O
O
3
R = 4-Ac, 3ua, 75%
N
N
O
O
3
xa, 65%
3ya, 57%
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [Ir(ppy) ] (2 mol %), 2,6-
3
o
lutidine (2.0 equiv), CH CN (2 mL), 100 C, Ar, 5 W blue LED light and 24 h.
3
As shown in Table 3, We next set out to examine the scope of acyl chloride 2 in the presence of N-(p-
methoxyaryl)propiolamides (1), [Ir(ppy) ], 2,6-lutidine, H O, and CH CN. We As shown in Table 3, we
3
2
3
are pleased to find this process could be applied to ispo-carboacylation of a wide range of aroyl
chlorides 2b-2n, including substituted benzoyl chlorides and heterocyclic acyl chlorides. The results
demonstrated that aroyl chlorides bearing both electron-donating and electron-withdrawing substituents
were all viable substrates for the cyclization. Electron-rich aroyl chlorides generally gave higher yields
than electron-poor ones, aroyl chloride bearing no substituents afforded the highest yield (product 3aa)
and 4-nitrobenzoyl chloride (2k) was inert and could not afford the desired product 3ak in this
transformation. Meanwhile, the position of substituents also have significantly affect on the product
yields (products 3ab, 3ad and 3af).
a
Table 3. Screening Scope of acyl chlorides (2)
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
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6
R
O
O
O
O
O
Ph
Ph
Ph
R
0
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3
4
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O
O
O
N
N
N
O
3
aa, 88%
R = Me, 3ab, 75%
R = F, 3ac, 58%
R = Me, 3ad, 79%
R = Cl, 3ae, 60%
R = Me, 3af, 86%
O
R = OMe, 3ag,85%
R = F, 3ah,80%,
R = Cl, 3ai,78%
R = Br, 3aj, 66%
R = NO , 3ak, 0%
R = CF , 3al, 70%
O
Ph
Ph
Ph
O
O
O
R
N
N
O
O
O
2
3
am, 0%
3
O
O
O
Ph
Ph
Ph
Cl
S
Bn
O
O
N
N
N
O
O
Cl
3
an, 60%
3ao, 73%
3ap, 0%
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), [Ir(ppy) ] (2 mol %), 2,6-
lutidine (2.0 equiv), CH CN (2 mL), 100 C, Ar, 5 W blue LED light and 24 h.
3
o
3
To our surprise, thiophene-2-carbonyl chloride (2o) was well tolerated under the optimal conditions
to obtain the desired product 3ao in a yield of 73%. However, it seems that the reaction conditions are
not ideal for the substrate of phenylacetyl chloride (2p). It should be the phenylacetyl radical could not
form easily from phenylacetyl chloride (2p) or the formed acyl radical was unstable, and that the same
as cinnamoyl chloride (2m).
It is believed that the ipso-carboacylation proceeded via a radical-type pathway on the basis of
12
previously reported literature. Then, the control experiments with radical inhibitors 2,6-di-tert-
butylphenol or TEMPO were performed as shown in Scheme 2. The results show that the transformation
was found to be inhibited and only trace amounts of the product were detected [Eq (1) and Eq (2)].
1
8
These results imply that the tandem reaction includes a radical process. Then, O-labeled experiments
18
were performed to explore the source of the oxygen atom of the newly-formed carbonyl, and 90% O-
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The Journal of Organic Chemistry
1
8
labeled product was obtained when 5 equiv H O was added into the reaction. In the light of these
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
results, we propose that the oxygen atom of the newly formed carbonyl mainly comes from H O [Eq (3)].
2
When dodecane-1-sulfonyl chloride (2q) was used to react with N-(p-methoxyaryl)propiolamides under
our conditions, 3-(dodecylsulfonyl)-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3aq)
could be obtained in 21% yield [Eq (4)].
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
BHT (3 equiv)
Ph
Ph
Ph
O
[Ir(ppy) ] (2 mol %)
3
MeO
O
2
,6-lutidine (2 equiv)
(1)
+
+
Cl
Cl
Ph
O
O
o
CH CN (2 mL), Ar, 100 C
3
N
O
N
O
O
5
W blue LED light, 24 h
3
aa, trace
1a
2a
Ph
TEMPO (3 equiv)
Ph
Ph
O
[Ir(ppy) ] (2 mol %)
3
MeO
MeO
O
2,6-lutidine (2 equiv)
(2)
Ph
o
CH CN (2 mL), Ar, 100 C
3
N
N
O
5
W blue LED light, 24 h
3
aa, trace
1
a
2a
1
8
H O (5 equiv)
Ph
2
mainly 18
O
Ph
Ph
O
[Ir(ppy) ] (2 mol %)
3
O
2,6-lutidine (2 equiv)
(
(
3)
4)
+ Cl
Ph
O
o
CH CN (2 mL), Ar, 100 C
3
N
N
O
O
5
W blue LED light, 24 h
3aa, 65%
1
a
2a
Ph
n
Ph
O
C H
12 25
[
Ir(ppy) ] (2 mol %)
3
S
MeO
2,6-lutidine (2 equiv)
O
+ nC H SO Cl
O
1
2
25
2
o
CH CN (2 mL), Ar, 100 C
5
3
N
N
O
O
W blue LED light, 24 h
3aq, 21%
1a
2q
Scheme 2. Control Experiments.
Consequently, we proposed a working mechanism as outline in Scheme 3 on the basis of the present
6
,8,9,12
III
results and the literatures.
Under visible-light irradiation, photocatalyst Ir (ppy) is excited to form
3
*
III
the strong reductant Ir (ppy) , which reduces benzoyl chloride 2a to deliver radical anion A and
3
IV
Ir (ppy) via single-electron transfer (SET). Subsequently, radical addition of acyl radical B, resulted
3
from the fragmentation of radical anion A, to C-C triple bond of amide 1a forms the first new C-C bond
to yield vinyl radical intermediate C, which is stabilized by the phenyl group. Then the radical
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intermediate D is obtained by selective ipso-carbocyclization and dearomatization. Subsquently, the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hydroxyl ion coming from hydrolysis of H O under the action of 2,6-lutidine attacks the radical carbon
2
of radical intermediate D to generate the intermediate E. Next, the removal of methoxyl of intermediate
E generates the intermediate F. Eventually, single electron oxidation and deprotonation of intermediate
III
F affords the final product 3aa along with Ir (ppy) .
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Possible mechanisms.
Conclusions
In summary, we have illustrated a novel visible-light-mediated ipso-carboacylation of alkyne with
aroyl chloride through sequential acylation, ipso-carbocyclization, dearomatization, and hydroxyl group
oxidation processes for the construction of a wide range of 3-acylspiro[4,5]-trienones, incorporating a
spirocycle unit that is a common structural motif in many pharmaceuticals and natural products.
Importantly, this method is the first example of an electron-deficient alkyne difunctionalization to
simultaneously form two carbon-carbon bonds and one carbon-oxygen double bond using visible-light
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The Journal of Organic Chemistry
photoredox catalysis strategy and provide valuable access to 3-acylspiro[4,5]-trienones. Studies on the
application of this new methodology to synthesize interesting biologically active compounds are
currently underway in our laboratory.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General Considerations:
1
13
The H and C NMR spectra were recorded in CDCl solvent on a NMR spectrometer using TMS as
3
internal standard. LRMS was performed on a GC-MS instrument and HRMS was measured on an
electrospray ionization (ESI) apparatus using time-of-flight (TOF) mass spectrometry. Melting points
are uncorrected.
Preparation of N-(p-methoxyaryl)propiolamides (1):
15
All N-(p-methoxyaryl)propiolamides (1) were synthesized according to the known methods.
3
ꢀ(2ꢀEthylphenyl)ꢀNꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylpropiolamide (1l): Yield: 410.2 mg, 70%; Yellow oil;
1
H NMR (400 MHz, CDCl ) δ: 7.31-7.24 (m, 4H), 7.12-7.06 (m, 2H), 6.96-6.92 (m, 2H), 3.83 (s, 3H),
3
13
1
3
.34 (s, 3H), 2.29-2.23 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 159.1,
3
154.7, 147.3, 136.2, 133.5, 130.1, 128.7, 127.7, 125.6, 119.7, 114.5, 89.7, 86.0, 55.5, 36.8, 26.9, 14.7.
+
HRMS (ESI-TOF) m/z: C H NO (M + H) calcd for 294.1489, found 294.1496.
1
9
20
2
3
ꢀ(3,5ꢀDimethylphenyl)ꢀNꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylpropiolamide (1n): Yield: 451.2 mg, 77%;
1
yellow oil; H NMR (400 MHz, CDCl ) δ: 7.27-7.22 (m, 2H), 6.97-6.93 (m, 3H), 6.78 (s, 2H), 3.84 (s,
3
1
3
1
3
H), 3.34 (s, 3H), 2.21 (s, 6H); C{ H}NMR (100 MHz, CDCl ) δ: 158.9, 154.6, 137.8, 136.1, 131.7,
3
+
1
29.9, 128.5, 120.0, 114.2, 91.4, 82.0, 55.4, 36.4, 20.9. HRMS (ESI-TOF) m/z: C H NO (M + H)
1
9
20
2
calcd for 294.1489, found 294.1496.
3
ꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀNꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylpropiolamide (1p): Yield: 539.3 mg, 84%;
1
yellow oil; H NMR (400 MHz, CDCl ) δ: 7.28-7.25 (m, 4H), 7.13-7.11 (m, 2H), 6.96-6.94 (m, 2H),
3
1
3
1
3.84 (s, 3H), 3.34 (s, 3H), 1.26 (s, 9H); C{ H}NMR (100 MHz, CDCl ) δ: 158.8, 154.5, 153.2, 136.0,
3
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1
32.1, 128.4, 125.2, 117.3, 114.1, 91.1, 82.1, 55.4, 36.3, 34.7, 30.8. HRMS (ESI-TOF) m/z: C H NO
21 24 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(M + H) calcd for 322.1802, found 322.1809.
Nꢀ(4ꢀMethoxyphenyl)ꢀNꢀmethylꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)propiolamide (1t): Yield: 519.5 mg, 78%;
1
yellow oil; H NMR (400 MHz, CDCl ) δ: 7.51 (d, J = 8.4 Hz, 2H), 7.29-7.25 (m, 4H), 6.98-6.94 (m,
3
1
3
1
2
H), 3.85 (s, 3H), 3.36 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 159.2, 154.0, 135.8, 132.5, 131.5,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
131.2, 128.5, 126.7, 125.3, 125.2, 125.2, 125.2, 124.3, 114.5, 114.3, 88.8, 84.3, 55.5, 36.6. HRMS (ESI-
+
TOF) m/z: C H F NO (M + H) calcd for 334.1049, found 334.1057.
1
8
15
3
2
Typical Experimental Procedure for the Visible-Light-Mediated Synthesis of 3-
Acylspiro[4,5]trienones from N-(p-methoxyaryl)propiolamides and Acyl Chloride:
To a Schlenk tube were added 1 (0.2 mmol), 2 (0.4 mmol), [Ir(ppy) ] (2 mol %, 0.004 mmol), 2,6-
3
o
lutidine (0.4 mmol), H O (2 equiv), CH CN (2 mL). Then the mixture was stirred at 100 C (oil bath
2
3
temperature) in argon atmosphere (1 atm) under 5 W blue LED light for 24 h until complete
consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was
finished, the reaction mixture was washed with brine. The aqueous phase was re-extracted with EtOAc
(3×10 mL). The combined organic extracts were dried over Na SO and concentrated in vacuum. The
2 4
residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 3:1) to afford the
desired products 3.
3
ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3aa): Yield: 62.5 mg, 88%;
o
1
yellow solid; mp 108.5-110.3 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.84 (d, J = 7.6 Hz, 2H),
3
7
.52 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.6 Hz, 3H), 7.18 (t, J = 7.6 Hz, 2H), 6.70
1
3
1
(d, J = 9.6 Hz, 2H), 6.58 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.2,
3
1
2
83.7, 167.1, 154.4, 144.6, 136.0, 135.5, 134.1 133.4, 130.4, 130.0, 129.3, 128.7, 128.6, 127.7, 67.2,
-1
+
5.8; IR (KBr, cm ) 1573, 1599, 1667, 1694; LRMS (EI, 70 eV) m/z (%): 355 (M , 27), 233 (17), 105
+
(100); HRMS (ESI-TOF) m/z: C H NO (M+ H) calcd for 356.1281, found 356.1272.
23 18
3
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3
ꢀBenzoylꢀ1ꢀbenzylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ba): Yield: 71.5 mg, 83%;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
yellow solid; mp 130.2-131.5 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.84 (d, J = 7.6 Hz, 2H),
3
7.52 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.27 (s, 5H), 7.22-7.12 (m, 5H), 6.52 (d, J = 9.2 Hz,
13
1
2
1
H),6.34 (d, J = 8.8 Hz, 2H), 4.59 (s, 2H); C{ H}NMR (100 MHz, CDCl ) δ: 191.1, 183.9, 167.3,
3
55.1, 144.7, 137.1, 135.9, 135.5, 134.1, 132.6, 130.4, 129.8, 129.4, 128.8, 128.6 (2C), 128.5, 127.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
127.7, 67.7, 44.6; IR (KBr, cm ) 1622, 1670, 1712; LRMS (EI, 70 eV) m/z (%): 431 (M , 12), 135
+
(100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 432.1594, found 432.1599.
2
9
22
3
3
ꢀBenzoylꢀ1ꢀ(2ꢀiodobenzyl)ꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ca): Yield: 84.7 mg,
o
1
76%; yellow solid; mp 222.2-224.3 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.87 (d, J = 7.6 Hz,
3
2
H), 7.77 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 3H), 7.28 (t, J = 7.6 Hz, 1H),
.21 (t, J = 6.4 Hz, 3H), 7.14 (t, J = 7.6 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 9.6 Hz, 2H), 6.32
7
1
3
1
(d, J = 9.2 Hz, 2H), 4.75 (s, 2H); C{ H}NMR (100 MHz, CDCl ) δ: 191.1, 184.0, 167.3, 155.6, 144.0,
3
1
6
39.6, 139.5, 135.8, 135.6, 134.3, 133.0, 130.5, 130.3, 129.9, 129.7, 129.5, 128.8, 128.7, 127.9. 99.5,
-1
+
7.7, 49.0; IR (KBr, cm ) 1629, 1660, 1696; LRMS (EI, 70 eV) m/z (%): 557 (M , 9), 430 (34), 135
+
(100); HRMS (ESI-TOF) m/z: C H INO (M+H) calcd for 558.0561, found 558.0571.
2
9
21
3
1
ꢀAllylꢀ3ꢀbenzoylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3da): Yield: 53.3 mg, 70%;
1
yellow oil; H NMR (400 MHz, CDCl ) δ: 7.83 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.38 (t, J =
3
7.2 Hz, 2H), 7.25 (t, J = 8.8 Hz, 3H), 7.18 (t, J = 7.2 Hz, 2H), 6.72 (d, J = 10.0 Hz, 2H), 6.51 (t, J = 9.6
1
3
1
Hz, 2H), 5.89-5.79 (m, 1H), 5.17 (d, J = 13.2 Hz, 2H), 3.98 (d, J = 6.0 Hz, 2H); C{ H}NMR (100
MHz, CDCl ) δ: 191.1, 183.9, 166.9, 154.9, 144.9, 133.0, 132.8, 130.4, 129.4, 128.7, 128.6, 127.8,
3
-1
+
118.9, 67.5, 43.4; IR (KBr, cm ) 1655, 1671, 1708; LRMS (EI, 70 eV) m/z (%): 381 (M , 15), 340 (21),
+
1
35 (100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 382.1438, found 382.1430.
2
5
20
3
1
ꢀAcetylꢀ3ꢀbenzoylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3fa): Yield: 52.9 mg, 69%;
o
1
yellow solid; mp 247.2-249.4 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.78 (d, J = 7.6 Hz, 2H),
3
7
.53 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.19-7.18 (m, 4H), 6.74 (d, J
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1
3
1
=
9.6 Hz, 2H), 6.48 (d, J = 10.0 Hz, 2H), 2.62 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 189.6, 183.8,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
68.8, 165.8, 158.5, 143.3, 135.6, 135.1, 134.5, 132.7, 130.8, 129.3, 128.7, 128.6, 128.5, 128.0, 67.5,
-1
+
25.7; IR (KBr, cm ) 1643, 1655, 1670, 1705; LRMS (EI, 70 eV) m/z (%): 383 (M , 11), 340 (19), 135
+
(100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 384.1230, found 384.1238.
2
4
18
4
3
ꢀBenzoylꢀ6ꢀmethyꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ga): Yield: 49.5 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
67%; yellow oil; H NMR (400 MHz, CDCl ) δ: 7.86 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.41
3
(t, J = 8.0 Hz, 2H), 7.28-7.20 (m, 5H), 6.67 (d, J = 9.6 Hz, 1H), 6.59 (d, J = 9.6 Hz, 1H), 6.45 (s, 1H),
1
3
1
2
.83 (s, 3H), 1.90 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.4, 184.5, 167.6, 154.7, 153.0, 144.9,
3
136.7, 135.6, 134.2, 132.9, 132.1, 130.7, 129.8, 129.4, 128.9, 128.7, 127.5, 69.3, 25.4, 18.0; IR (KBr,
-1
+
cm ) 1643, 1662, 1695; LRMS (EI, 70 eV) m/z (%): 369 (M , 8), 249 (31), 150 (100); HRMS (ESI-
+
TOF) m/z: C H NO (M+H) calcd for 370.1438, found 370.1431.
2
4
20
3
3ꢀBenzoylꢀ6ꢀiodoꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ha): Yield: 69.3 mg,
o
1
7
2%; yellow solid; mp 193.4-195.6 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.83 (d, J = 7.6 Hz,
3
2
H), 7.54 (t, J = 7.2 Hz, 1H), 7.49 (s, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.28 (d, J = 6.4 Hz, 1H), 7.22 (s, 4H),
1
3
1
6.74 (d, J = 9.6 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H), 2.96 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ:
3
1
90.9, 177.7, 166.9, 153.4, 152.3, 145.2, 136.3, 135.4, 134.3, 130.7, 130.3, 129.6, 129.4, 128.9, 128.7,
-1
+
1
27.7, 108.3, 70.3, 26.1; IR (KBr, cm ) 1633, 1641, 1680; LRMS (EI, 70 eV) m/z (%):481 (M , 15),
+
354 (54), 135 (100); HRMS (ESI-TOF) m/z: C H INO (M+H) calcd for 482.0248, found 482.0259.
2
3
17
3
3
ꢀBenzoylꢀ7ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ia): Yield: 47.0
o
1
mg, 61%; yellow solid; mp 203.9-205.6 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.86 (d, J =
3
7.2 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H), 7.27-7.24 (m, 3H), 7.20-7.17 (m, 2H),
6
.71 (d, J = 9.6 Hz, 1H), 6.58 (d, J = 10.0 Hz, 1H), 5.51 (s, 1H), 3.71 (s, 3H), 2.92 (s, 3H);
1
3
1
C{ H}NMR (100 MHz, CDCl ) δ: 191.4, 179.3, 166.8, 155.5, 154.1, 145.4, 135.6, 135.6, 134.2, 132.7,
3
-1
130.4, 130.1, 129.4, 128.7 (2C), 127.7, 127.0, 110.8, 68.8, 55.6, 25.6; IR (KBr, cm ) 1655, 1668, 1699;
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LRMS (EI, 70 eV) m/z (%): 385 (M , 15), 234 (28), 165 (100); HRMS (ESI-TOF) m/z: C H NO
2
4
20
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(
M+H) calcd for 386.1387, found 386.1396.
3ꢀBenzoylꢀ7ꢀmethylꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ja): Yield: 47.4 mg,
1
6
4%; yellow oil; H NMR (400 MHz, CDCl ) δ: 7.86-7.83 (m, 2H), 7.55-7.51 (m, 1H), 7.41-7.37(m,
3
2
H), 7.27-7.2 (m, 3H), 7.20-7.16 (m, 2H), 6.67-6.64 (m, 1H), 6.55 (d, J = 10.0 Hz, 1H), 6.47-6.46 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
1H), 2.90 (s, 3H), 2.00 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.4, 184.6, 167.2, 154.9, 144.5,
3
1
40.7, 139.3, 135.8, 135.5, 134.1, 133.2, 130.3, 130.1, 129.4, 128.7, 128.6, 127.7, 67.7, 25.8, 15.9; IR
-1
+
(
KBr, cm ) 1640, 1665, 1692; LRMS (EI, 70 eV) m/z (%): 369 (M , 8), 249 (31), 150 (100); HRMS
+
(ESI-TOF) m/z: C H NO (M+H) calcd for 370.1438, found 370.1431.
2
4
20
3
3
ꢀBenzoylꢀ7ꢀchloroꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ka): Yield: 49.8
o
1
mg, 64%; yellow solid; mp 185.3-187.2 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.83 (d, J =
3
7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.28 (s, 1H), 7.22 (t, J = 4.0 Hz, 4H), 6.92
1
3
1
(
s, 1H), 6.73 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 10.0 Hz, 1H); 2.95 (s, 3H); C{ H}NMR (100 MHz,
CDCl ) δ: 190.9, 176.9, 166.8, 153.8, 145.2, 140.2, 136.8, 136.3, 135.3, 134.3, 132.3, 130.7, 129.5,
3
-1
129.4, 128.9, 128.7, 127.6, 69.0, 26.1; IR (KBr, cm ) 1625, 1657, 1701; LRMS (EI, 70 eV) m/z (%):
+
+
+
3
3
3
6
90 (M +1, 5), 389 (M , 16), 170 (100); HRMS (ESI-TOF) m/z: C H ClNO (M+H) calcd for
23 17 3
90.0891, found 390.0899.
ꢀBenzoylꢀ4ꢀ(2ꢀethylphenyl)ꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3la): Yield: 46.0 mg,
1
0%; yellow oil; H NMR (400 MHz, CDCl ) δ: 7.78 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.37
3
(
t, J = 7.2 Hz, 2H), 7.20-7.13 (m, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.70 (s, 2H),
1
3
1
6
.46 (s, 2H), 2.99 (s, 3H), 2.45 (d, J = 7.2 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H); C{ H}NMR (100 MHz,
CDCl ) δ: 190.1, 183.5, 167.1, 156.5, 144.0, 142.0, 138.2, 135.5, 134.0, 133.6, 129.7, 129.4, 128.5,
3
-1
1
28.4, 128.3, 127.5, 124.7, 69.3, 26.6, 25.8, 14.7; IR (KBr, cm ) 1630, 1655, 1690; LRMS (EI, 70 eV)
+
+
m/z (%): 383 (M , 7), 278 (30), 135 (100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for
25 22
3
3
84.1594, found 384.1604.
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ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀ(mꢀtolyl)ꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ma): Yield: 51.8 mg, 70%;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
yellow oil; H NMR (400 MHz, CDCl ) δ: 7.84 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.38 (t, J =
3
7.2 Hz, 2H), 7.05 (d, J = 6.8 Hz, 4H), 6.70 (d, J = 9.6 Hz, 2H), 6.58 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H),
13
1
2
.16 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.3, 183.7, 167.1, 154.7, 144.7, 138.4, 135.7, 135.5,
3
-1
1
34.0, 133.3, 131.2, 129.9, 129.3, 128.6, 128.5, 128.4, 124.6, 67.1, 25.8, 21.1; IR (KBr, cm ) 1642,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1658, 1697; LRMS (EI, 70 eV) m/z (%): 369 (M , 8), 249 (31), 150 (100); HRMS (ESI-TOF) m/z:
+
C H NO (M+H) calcd for 370.1438, found 370.1431.
2
4
20
3
3
ꢀBenzoylꢀ4ꢀ(3,5ꢀdimethylphenyl)ꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3na): Yield:
o
1
63.6 mg, 83%; yellow solid; mp 180.7-182.0 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.83 (d, J
3
=
7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 10.0 Hz, 3H), 6.69 (d, J =
1
3
1
1
1
6
1
0.0 Hz, 2H), 6.58 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H), 2.12 (s, 6H); C{ H}NMR (100 MHz, CDCl ) δ:
3
91.4, 183.8, 167.3, 155.0, 144.8, 138.2, 135.6, 135.5, 134.0, 133.3, 132.2, 129.9, 129.3, 128.5, 125.4,
-1
+
7.2, 25.8, 21.0; IR (KBr, cm ) 1618, 1644, 1682; LRMS (EI, 70 eV) m/z (%): 383 (M , 7), 278 (30),
+
35 (100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 384.1594, found 384.1604.
2
5
22
3
3ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀ(pꢀtolyl)ꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3oa): Yield: 63.5 mg, 86%;
o
1
yellow solid; mp 134.0-135.5 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.87-7.84 (m, 2H), 7.56-
3
7
.52 (m, 1H), 7.42-7.38 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.71-6.67 (m, 2H),
1
3
1
6.60-6.57 (m, 2H), 2.91 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.6, 183.9, 167.3, 154.4, 144.9,
3
-1
1
41.0, 135.5, 135.3, 134.2, 133.3, 129.5 (2C), 128.7, 127.7, 127.2, 67.1, 25.8, 21.2; IR (KBr, cm ) 1633,
+
1
666, 1710; LRMS (EI, 70 eV) m/z (%): 369 (M , 8), 249 (31), 150 (100); HRMS (ESI-TOF) m/z:
+
C H NO (M+H) calcd for 370.1438, found 370.1431.
2
4
20
3
3
ꢀBenzoylꢀ4ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3pa): Yield:
o
1
7
2.3 mg, 88%; yellow solid; mp 169.3-171.1 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.87 (d, J
3
= 7.6 Hz, 2H), 7.54 (t, J = 7.2. Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.27-7.18 (m, 4H), 6.71 (d, J = 9.2 Hz,
13
1
2
H), 6.60 (d, J = 9.6 Hz, 2H), 2.90 (s, 3H), 1.20 (s, 9H); C{ H}NMR (100 MHz, CDCl ) δ: 191.8,
3
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3
83.9, 167.4, 154.2, 154.0, 145.1, 135.6, 135.2, 134.1, 133.2, 129.4, 128.7, 127.6, 127.0, 125.8, 66.9,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
4.7, 30.8, 25.7; LRMS (EI, 70 eV) m/z (%): 411 (M , 10), 306 (25), 135 (100); HRMS (ESI-TOF) m/z:
+
C H NO (M+H) calcd for 412.1907, found 412.1916.
2
7
26
3
3
ꢀBenzoylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3qa): Yield: 65.5
o
1
mg, 85%; yellow solid; mp 211.8-213.6 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.86 (d, J =
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.0
1
3
1
Hz, 4H), 6.60 (d, J = 9.6 Hz, 2H), 3.71 (s, 3H), 2.90 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.9,
3
1
83.9, 167.4, 161.2, 153.8, 145.2, 135.5, 134.2, 133.2, 129.4 (2C), 128.7, 122.3, 114.2, 66.9, 55.2, 25.7;
-1
+
IR (KBr, cm ) 1633, 1661, 1694; LRMS (EI, 70 eV) m/z (%): 385 (M , 15), 234 (28), 165 (100);
+
HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 386.1387, found 386.1396.
2
4
20
4
3
ꢀBenzoylꢀ4ꢀ(4ꢀfluorophenyl)ꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ra): Yield: 58.2
o
1
mg, 78%; yellow solid; mp 220.9-223.0 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.84 (d, J= 7.6
3
Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 6.4 Hz, 2H), 6.90 (t, J = 8.8 Hz,
1
3
1
2
H), 6.69 (d, J = 9.6 Hz, 2H), 6.59 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ:
3
191.2, 183.5, 167.0, 164.9, 153.3, 144.5, 136.2, 135.4, 134.4, 133.6, 130.0, 129.9, 129.4, 128.7, 126.1,
119
-1
1
1
16.2, 116.0, 67.2, 25.9; F NMR (282 MHz, CDCl ): δ: -108.4 (s, 1F); IR (KBr, cm ) 1632, 1660,
3
+
+
702; LRMS (EI, 70 eV) m/z (%): 374 (M +1, 5), 373 (M , 13), 135 (100); HRMS (ESI-TOF) m/z:
+
C H FNO (M+H) calcd for 374.1187, found 374.1195.
2
3
17
3
3
ꢀBenzoylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3sa): Yield: 62.2
o
1
mg, 80%; yellow solid; mp 178.3-179.9 C (uncorrected); H NMR (400 MHz, DCl ) δ: 7.84 (d, J = 7.6
3
Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.23-7.17 (m, 4H), 6.68 (d, J = 9.2 Hz, 2H),
13
1
6
1
.59 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.1, 183.5, 166.9, 153.1,
3
-1
44.3, 136.8, 136.6, 135.3, 134.4, 133.6, 129.4, 129.1 (2C), 128.8, 128.4, 67.1, 25.9; IR (KBr, cm )
+
+
1632, 1664, 1709; LRMS (EI, 70 eV) m/z (%): 390 (M +1, 5), 389 (M , 16), 170 (100); HRMS (ESI-
+
TOF) m/z: C H ClNO (M+H) calcd for 390.0891, found 390.0899.
2
3
17
3
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ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione
(3ta):
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
Yield: 62.6 mg, 74%; yellow solid; mp 241.1-243.5 C (uncorrected); H NMR (400 MHz, CDCl ) δ:
3
7.84 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 8.8 Hz, 2H), 7.40 (d, J = 8.0 Hz, 4H), 6.71
13
1
(d, J = 9.6 Hz, 2H), 6.59 (d, J = 10.0 Hz, 2H), 2.94 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 190.7,
3
1
83.3, 166.6, 152.9, 143.9, 137.8, 135.3, 134.5, 133.8, 133.4, 132.2, 129.4, 128.8, 128.2, 125.7, 125.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
-1
6
7.3, 25.9; F NMR (282 MHz, CDCl ): δ: -63.18(s, 1F); IR (KBr, cm ) 1611, 1668, 1712; LRMS (EI,
3
+
+
+
7
0 eV) m/z (%): 424 (M +1, 5), 423 (M , 17), 135 (100); HRMS (ESI-TOF) m/z: C H F NO (M+H)
24 17 3 3
calcd for 424.1155, found 424.1164.
4ꢀ(4ꢀAcetylphenyl)ꢀ3ꢀbenzoylꢀ1ꢀmethylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ua): Yield: 59.6
o
1
mg, 75%; yellow solid; mp 212.1-214.0 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.84 (d, J =
3
8
2
1
.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.42-7.36 (m, 4H), 6.72 (d, J = 9.6 Hz,
1
3
1
H), 6.59 (d, J = 9.6 Hz, 2H), 2.94 (s, 3H), 2.50 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 196.8,
3
90.7, 183.4, 166.7, 153.3, 144.1, 137.9, 137.4, 135.2, 134.4, 134.2, 133.7, 129.3, 128.7, 128.4, 128.1,
-1
+
67.2, 26.4, 25.9; IR (KBr, cm ) 1631, 1650, 1678, 1722; LRMS (EI, 70 eV) m/z (%): 397 (M , 9), 292
+
(26), 135 (100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 398.1387, found 398.1395.
2
5
20
4
3
ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀpentylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3va): Yield: 42.6 mg, 61%;
1
yellow oil; H NMR (400 MHz, CDCl ) δ: 7.88 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.50 (t, J =
3
7
.6 Hz, 2H), 6.62 (d, J = 9.6 Hz, 2H), 6.51 (d, J = 9.6 Hz, 2H), 2.89 (s, 3H), 2.18 (t, J = 8.0 Hz, 2H),
13
1
1
.27 (d,J = 10.8 Hz, 6H), 0.73 (d, J = 5.2 Hz, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.4, 183.9,
3
167.8, 160.0, 144.8, 136.2, 136.0, 134.1, 133.6, 129.4, 128.7, 68.2, 31.6, 29.6, 29.1, 26.4, 21.8, 13.6; IR
-1
+
(KBr, cm ) 1622, 1667, 1702; LRMS (EI, 70 eV) m/z (%): 349 (M , 10), 244 (27), 1351 (100); HRMS
+
(ESI-TOF) m/z: C H NO (M+H) calcd for 350.1751, found 350.1758.
2
2
24
3
3
7
7
ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀnaphthaleneꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3wa): Yield: 58.3 mg,
o
1
2%; yellow solid; mp 186.5-188.0 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.71-7.68 (m, 5H),
3
13
1
.41 (d, J = 7.2 Hz, 3H), 7.26-7.23 (m, 4H), 6.86-6.68 (m, 3H), 6.13 (s, 1H), 3.03 (s, 3H); C{ H}NMR
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(
100 MHz, CDCl ) δ: 190.1, 183.4, 167.0, 154.7, 143.8, 138.9, 135.2, 133.8, 133.1, 130.5, 130.1, 129.2,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
1
28.5, 128.1, 126.9, 126.5 (2C), 126.2, 124.7, 123.9, 69.14, 26.6; IR (KBr, cm ) 1630, 1662, 1694;
+
LRMS (EI, 70 eV) m/z (%): 405 (M , 17), 300 (21), 135 (100); HRMS (ESI-TOF) m/z: C H NO
2
7
20
3
+
(M+H) calcd for 406.1438, found 406.1447.
3
ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀthiopheneꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3xa): Yield: 46.9 mg, 65%;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
yellow solid; mp 156.1-158.3 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.93 (d, J = 8.4 Hz, 2H),
3
7
.60 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 5.2 Hz, 1H), 7.23-7.22 (m, 1H), 6.92-6.90
1
3
1
(m, 1H), 6.73-6.65 (m, 4H), 2.9 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 191.9, 183.8, 167.1, 146.2,
3
-1
145.0, 135.4, 134.5, 133.7, 132.5, 131.0, 130.5, 130.4, 129.4, 128.9, 127.9, 66.3, 25.6; IR (KBr, cm )
+
1
633, 1664, 1694; LRMS (EI, 70 eV) m/z (%):361 (M , 12), 256 (24), 135 (100); HRMS (ESI-TOF) m/z:
+
C H NO S (M+H) calcd for 362.0845, found 362.0855.
2
1
16
3
3ꢀBenzoylꢀ1ꢀmethylꢀ4ꢀpyridineꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ya): Yield: 40.1 mg, 57%;
o
1
yellow solid; mp 177.6-179.4 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 8.51 (d, J = 7.6 Hz, 2H),
3
7
.84 (d, J = 8.4 Hz, 2H), 7.63-7.56 (m, 2H), 7.45-7.41 (m, 2H), 7.20-7.17 (m, 1H), 6.69 (d, J = 10.0 Hz,
1
3
1
2H), 6.61 (d, J = 10.0 Hz, 2H), 2.96 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 190.5, 183.2, 166.7,
3
1
51.4, 151.3, 148.1, 143.8, 138.2, 135.3, 135.1, 134.6, 134.0, 129.5, 128.9, 126.3, 123.3, 67.3, 26.1; IR
-1
+
(KBr, cm ) 1620, 1667, 1689; LRMS (EI, 70 eV) m/z (%): 356 (M , 11), 251 (30), 135 (100); HRMS
+
(ESI-TOF) m/z: C H N O (M+H) calcd for 357.1234, found 357.1246
2
2
17
2
3
1
ꢀMethylꢀ3ꢀ(2ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ab): Yield: 55.4
o
1
mg, 75%; yellow solid; mp 167.6-169.2 C (uncorrected); H NMR (400 MHz, DCl ) δ: 7.54 (d, J = 8.0
3
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.28-7.14 (m, 7H), 6.66 (d, J = 9.6 Hz, 2H), 6.56 (d, J = 9.6 Hz, 2H),
13
1
2
1
.92 (s, 3H), 2.56 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 193.0, 183.7, 167.2, 154.4, 144.6, 140.0,
3
37.6, 135.4, 133.5, 132.7, 132.1, 131.2, 130.3, 130.0, 128.6, 127.7, 125.6, 67.2, 25.9, 21.5; IR (KBr,
-1
+
cm ) 1631, 1658, 1695; LRMS (EI, 70 eV) m/z (%): 369 (M , 8), 249 (31), 150 (100); HRMS (ESI-
+
TOF) m/z: C H NO (M+H) calcd for 370.1438, found 370.1431.
2
4
20
3
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3
ꢀ(2ꢀFluorobenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ac): Yield: 43.3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
mg, 58%; yellow solid; mp 192.1-194.0 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.84 (t, J =
3
7.6 Hz, 1H), 7.53-7.48 (m, 1H), 7.26-7.21 (m, 6H), 7.03 (t, J = 9.6 Hz, 1H), 6.65 (d, J = 9.6 Hz, 2H),
13
1
6
1
2
.54 (d, J = 9.6 Hz, 2H), 2.91 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 187.2, 183.7, 166.8, 163.3,
3
60.8, 154.6, 144.3, 135.8, 135.7, 133.4, 130.8, 130.2, 128.5, 127.9, 124.6, 124.6, 116.5, 116.3, 67.2,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
-1
5.8; F NMR (282 MHz, CDCl ): δ: -110.58 (s, 1F); IR (KBr, cm ) 1639, 1668, 1700; LRMS (EI, 70
3
+
+
+
eV) m/z (%): 374 (M +1, 5), 373 (M , 13), 135 (100); HRMS (ESI-TOF) m/z: C H FNO (M+H)
2
3
17
3
calcd for 374.1187, found 374.1195.
1ꢀMethylꢀ3ꢀ(3ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ad): Yield: 58.3
o
1
mg, 79%; yellow solid; mp 177.1-178.9 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.69 (s, 1H),
3
7
.60 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.2 Hz, 4H), 7.19 (t, J = 7.2 Hz, 2H), 6.70
1
3
1
(d, J = 9.6 Hz, 2H), 6.58 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H), 2.34 (s, 3H); C{ H}NMR (100 MHz,
CDCl ) δ: 191.4, 183.7, 167.2, 154.2, 144.7, 138.5, 136.2, 135.5, 135.0, 133.4, 130.4, 130.1, 129.5,
3
-1
128.7, 128.5, 127.7, 127.0, 67.2, 25.8, 21.2; IR (KBr, cm ) 1634, 1656, 1697; LRMS (EI, 70 eV) m/z
+
+
(%): 369 (M , 8), 249 (31), 150 (100); HRMS (ESI-TOF) m/z: C H NO (M+H) calcd for 370.1438,
24 20 3
found 370.1431.
3
ꢀ(3ꢀChlorobenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ae): Yield: 46.7
o
1
mg, 60%; yellow solid; mp 145.2-147.5 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.80 (s, 1H),
3
7
.69 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.34-7.19 (m, 6H), 6.70 (d, J = 9.6 Hz, 2H), 6.58 (d, J
1
3
1
=
9.2 Hz, 2H), 2.93 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 189.9, 183.6, 166.8, 155.5, 144.3,
3
1
37.0, 135.3, 134.9, 134.0, 133.5, 130.6, 129.9, 129.8, 129.1, 128.8, 127.7, 127.6, 67.2, 25.9; IR (KBr,
-1
+
+
cm ) 1630, 1664, 1694; LRMS (EI, 70 eV) m/z (%): 390 (M +1, 5), 389 (M , 16), 170 (100); HRMS
+
(ESI-TOF) m/z: C H ClNO (M+H) calcd for 390.0891, found 390.0899.
23 17
3
1ꢀMethylꢀ3ꢀ(4ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3af): Yield: 63.5
o
1
mg, 86%; yellow solid; mp 123.1-124.8 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.74 (d, J =
3
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7
2
.6 Hz, 2H), 7.28 (J = 7.2 Hz, 3H), 7.19 (t, J = 6.8 Hz, 4H), 6.70 (d, J = 9.2 Hz, 2H), 6.58 (d, J = 9.2 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
H), 2.92 (s, 3H), 2.36 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 190.9, 183.8, 167.2, 154.0, 145.4,
3
-1
144.8, 136.2, 133.4, 133.1, 130.4, 130.1, 129.6, 129.4, 128.7, 127.7, 67.1, 25.8, 21.7; IR (KBr, cm )
+
1
589, 1645, 1660, 1691; LRMS (EI, 70 eV) m/z (%): 369 (M , 20), 247 (25), 119 (100); HRMS (ESI-
+
TOF) m/z: calcd for C H NO (M+ H) calcd for 370.1438, found 370.1425.
2
4
20
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3ꢀ(4ꢀMethoxybenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ag): Yield: 65.3
o
1
mg, 85%; yellow solid; mp 171.9-173.0 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.82 (d, J =
3
8
.4 Hz, 2H), 7.27 (t, J = 8.8 Hz, 3H), 7.19 (t, J = 7.2 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 9.2
1
3
1
Hz, 2H), 6.57 (d, J = 9.6 Hz, 2H), 3.82 (s, 3H), 2.91 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 189.6,
3
1
2
83.7, 167.3, 164.4, 153.6, 144.8, 136.3, 133.3, 131.9, 130.3, 130.1, 128.7, 127.7, 113.9, 67.1, 55.4,
-1
+
5.8; IR (KBr, cm ) 1622, 1655, 1690; LRMS (EI, 70 eV) m/z (%): 385 (M , 13), 384 (8), 263 (25), 135
+
(100); HRMS (ESI-TOF) m/z: C H NO (M+ H) calcd for 386.1387, found 386.1403.
2
4
20
4
3
ꢀ(4ꢀFluorobenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ah): Yield: 59.7
o
1
mg, 80%; yellow solid; mp 188.9-190.3 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.87 (t, J =
3
6.4 Hz, 2H), 7.30-7.25 (m, 3H), 7.20 (t, J = 7.2 Hz, 2H), 7.05 (t, J = 8.4 Hz, 2H), 6.70 (d, J = 9.6 Hz,
13
1
2
H), 6.58 (d, J = 9.2 Hz, 2H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 189.5, 183.6, 167.5,
3
1
67.0, 165.0, 154.8, 144.4, 135.7, 133.5, 132.2, 132.1, 132.0, 130.6, 129.9, 128.8, 127.7, 116.0, 115.8,
1
9
-1
67.2, 25.8; F NMR (282 MHz, CDCl ): δ: -102.56 (s, 1F); IR (KBr, cm ) 1631, 1660, 1690; LRMS
3
+
+
(EI, 70 eV) m/z (%): 374 (M +1, 5), 373 (M , 13), 135 (100); HRMS (ESI-TOF) m/z: C H FNO
23 17 3
+
(M+H) calcd for 374.1187, found 374.1195.
3ꢀ(4ꢀChlorobenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ai): Yield: 60.7
o
1
mg, 78%; yellow solid; mp 201.4-203.6 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.77 (d, J =
3
8
2
1
.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.28-7.19 (m, 5H), 6.69 (d, J = 10.0 Hz, 2H), 6.58 (d, J = 10.0 Hz,
1
3
1
H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 189.9, 183.6, 166.9, 155.1, 144.4, 140.7, 135.5,
3
-1
33.8, 133.5, 130.7, 130.6, 129.8, 129.0, 128.8, 127.7, 67.2, 25.8; IR (KBr, cm ) 1636, 1660, 1696;
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+
+
LRMS (EI, 70 eV) m/z (%): 390 (M +1, 5), 389 (M , 16), 170 (100); HRMS (ESI-TOF) m/z:
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
C H ClNO (M+H) calcd for 390.0891, found 390.0899.
2
3
17
3
3ꢀ(4ꢀBromobenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3aj): Yield: 57.2
o
1
mg, 66%; yellow solid; mp 138.3-139.9 C (uncorrected); H NMR (400 MHz, CDCl ) δ: 7.69 (d, J =
3
8
.0 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.31-7.19 (m, 5H), 6.68 (d, J = 10.0 Hz, 2H), 6.58 (d, J = 9.6 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
2H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 190.2, 183.6, 166.9, 155.2, 144.4, 135.5, 134.3,
3
-1
1
33.5, 132.0, 130.8, 130.7, 129.8, 129.6, 128.8, 127.7, 67.2, 25.9; IR (KBr, cm ) 1638, 1664, 1699;
+
+
LRMS (EI, 70 eV) m/z (%): 434 (M +1, 4), 433 (M , 16), 135 (100); HRMS (ESI-TOF) m/z:
+
C H BrNO (M+H) calcd for 434.0386, found 434.0397.
2
3
17
3
1
ꢀMethylꢀ4ꢀphenylꢀ3ꢀ(4ꢀ(trifluoromethyl)benzoyl)ꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione
(3al):
o
1
Yield: 59.2 mg, 70%; yellow solid; mp 214.6-216.7 C (uncorrected); H NMR (400 MHz, CDCl ) δ:
3
7.94 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.30-7.22 (m, 5H), 6.69 (d, J = 9.6 Hz, 2H), 6.60 (d, J
13
1
=
9.6 Hz, 2H), 2.94 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 190.2, 183.6, 166.8, 156.1, 144.2,
3
1
9
1
39.7, 138.1, 135.4, 133.7, 130.8, 129.7, 129.7, 128.9, 127.7, 125.8, 125.7, 67.3, 25.9; F NMR (282
-1
MHz, CDCl ): δ: -63.29(s, 1F); IR (KBr, cm ) 1625, 1663, 1704; LRMS (EI, 70 eV) m/z (%): 424
3
+
+
+
(
M +1, 5), 423 (M , 17), 135 (100); HRMS (ESI-TOF) m/z: C H F NO (M+H) calcd for 424.1155,
24 17 3 3
found 424.1164.
3ꢀ(3,5ꢀDichlorobenzoyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3an): Yield:
o
1
5
0.8 mg, 60%; yellow solid; mp 187.4-189.3 C (uncorrected); H NMR (400 MHz, DCl ) δ: 7.94 (d, J
3
=
2.0 Hz, 1H), 7.64 (s, 2H), 7.49 (s, 1H), 7.35-7.31 (m, 1H), 7.27-7.25 (m, 2H), 7.23-7.22 (m, 2H), 6.68
1
3
1
(d, J = 10.0 Hz, 2H), 6.60 (d, J = 10.0 Hz, 2H), 2.94 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 188.6,
3
1
83.6, 166.7, 156.6, 144.0, 137.8, 135.7, 135.3, 134.8, 133.8, 133.7, 131.0, 129.6, 129.0, 128.4, 127.7
-1
+
+
(
2C), 67.4, 26.0; IR (KBr, cm ) 1632, 1663, 1697; LRMS (EI, 70 eV) m/z (%): 424 (M +1, 5), 423 (M ,
+
19), 135 (100); HRMS (ESI-TOF) m/z: C H Cl NO (M+H) calcd for 424.0502, found 424.0510.
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1
ꢀMethylꢀ4ꢀphenylꢀ3ꢀ(thiopheneꢀ2ꢀcarbonyl)ꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3ao): Yield:
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o
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2.7 mg, 73%; yellow solid; mp 161.4-163.3 C (uncorrected); H NMR (400 MHz, DCl ) δ: 7.65 (d, J
3
= 4.8 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 7.2 Hz, 3H),7.29-7.21 (m, 2H), 7.03 (d, J = 3.6 Hz, 1H), 6.67 (d,
13
1
J = 10.0 Hz, 2H), 6.58 (d, J = 9.6 Hz, 2H), 2.92 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 183.7,
3
1
82.8, 166.8, 154.6, 144.5, 142.7, 135.8, 135.0, 133.5, 130.6, 130.0, 128.8, 128.3, 127.8, 67.1, 25.9; IR
0
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-1
+
(KBr, cm ) 1635, 1661, 1698; LRMS (EI, 70 eV) m/z (%): 361 (M , 12), 256 (24), 135 (100); HRMS
+
(ESI-TOF) m/z: C H NO S (M+H) calcd for 362.0845, found 362.0855.
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ꢀ(Dodecylsulfonyl)ꢀ1ꢀmethylꢀ4ꢀphenylꢀ1ꢀazaspiro[4.5]decaꢀ3,6,9ꢀtrieneꢀ2,8ꢀdione (3aq): Yield: 20.3
1
mg, 21%; yellow oil; H NMR (400 MHz, DCl ) δ: 7.43 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz,
3
2
1
1
2
H),7.22 (d, J = 7.2 Hz, 2H), 6.51 (s, 4H), 3.49 (t, J = 8.0 Hz, 2H), 2.93 (s, 3H), 1.77-1.73 (m, 2H),
1
3
1
.25-1.21 (m, 18H), 0.88 (t, J = 7.2 Hz, 3H); C{ H}NMR (100 MHz, CDCl ) δ: 183.1, 164.1, 162.8,
3
42.1, 134.8, 134.4, 130.7, 128.1, 128.0, 127.9, 68.3, 53.7, 31.8, 29.5 (2C), 29.4, 29.3, 29.2, 29.0, 28.2,
-1
6.4, 22.6, 21.6, 14.1; IR (KBr, cm ) 1622, 1652, 1677, 1690; HRMS (ESI-TOF) m/z: C H NO S
2
8
38
4
+
(M+H) calcd for 484.2516, found 484.2524.
Acknowledgments. We thank the Scientific Research Fund of Hunan Provincial Education
Department (No. 16A087) and National Natural Science Foundation of China (No. 21602056) for
financial support.
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8
Supporting Information Available: The O -labelled control experiment and the copies of spectra.
This material is available free of charge via the Internet at http://pubs.acs.org.
References and notes
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