A Serendipitous Synthesis of Bis-Heterocyclic Spiro 3(2 H)-Furanones

Article abstract of DOI:10.1021/acs.joc.5b02350

(Z) Enol triflates 6, 11b-d, (E) enol triflate 11e, and phenol triflate 11a, derived from β-keto esters or 2-carboalkoxy phenols, respectively, react with N-Boc 2-lithiopyrrolidine (5a), N-Boc N-methylaminomethyllithium (5b), or 2-lithio-1,3-dithiane (14) to afford 3(2H)-furanones in modest to good yields (38-81%). Product and carbanion reagent studies suggest that the 3(2H)-furanone is formed in a cascade of reactions involving nucleophilic acyl substitution, enolate formation, trifluoromethyl transfer, iminium or sulfenium ion formation, and subsequent ring closure to form the 3(2H)-furanone. The use of 2-lithio-1,3-dithiane affords a cyclic α-keto-S,S,O-orthoester in which the functionality can be selectively manipulated for synthetic applications. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02350

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Article
A Serendipitous Synthesis of Bis-Heterocyclic Spiro 3(2H)-Furanones
Alfredo Picado, ShengJian Li, and R. Karl Dieter
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02350 • Publication Date (Web): 12 Jan 2016
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A Serendipitous Synthesis of Bis-Heterocyclic Spiro 3(2H)-Furanones
Alfredo Picado, ShengJian Li, R. Karl Dieter*
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Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, SC 29634ꢀ0973
dieterr@clemson.edu
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ABSTRACT
(Z) Enol triflates 6, 11b-d, (E) enol triflate 11e and phenol triflate 11a, derived from βꢀketo
esters or 2ꢀcarboalkoxy phenols, respectively, react with NꢀBoc 2ꢀlithiopyrrodidine (5a), NꢀBoc
Nꢀmethylaminomethyllithium (5b) or 2ꢀlithioꢀ1,3ꢀdithiane (14) to afford 3(2H)ꢀfuranones in
modest to good yields (38ꢀ81%). Product and carbanion reagent studies suggest that the 3(2H)ꢀ
furanone is formed in a cascade of reactions involving nucleophilic acyl substitution, enolate
formation, trifluoromethyl transfer, iminium or sulfenium ion formation and subsequent ring
closure to form the 3(2H)ꢀfuranone. The use of 2ꢀlithioꢀ1,3ꢀdithiane affords a cyclic αꢀketoꢀ
S,S,Oꢀorthoester in which the functionality can be selectively manipulated for synthetic
applications.
INTRODUCTION
The 3(2H)ꢀfuranone core1 (Figure 1, 1) is present in several biologically active natural
products such as Eremantholide AꢀC,2 Geiparvarin,3 and Bullatenone.4 Jatrophone,5 Pseurotin
A,6 Armeniaspirole A (2), B, and C7a are related natural products containing a spiroꢀfuranone
core and they and their derivatives7b are also of pharmaceutical interest.7c Pioneering work on the
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syntheses of compounds containing the 3(2H)ꢀfuranone motif1 was reported in the early 1980s
by Smith and coworkers culminating in the synthesis of Jatrophone.5b,c A structurally related
class of natural products contain a spirocyclic 3(2H)ꢀbenzofuranone moiety8 illustrated by
Griseofulvin.8a In the intervening years, synthetic methodologies have been developed for the
regioselective introduction of varied substituents on the 3(2H)ꢀfuranone core,9 the synthesis of 5ꢀ
amino substituted derivatives,10 the intramolecular condensation of αꢀacyloxy ketones at high
temperature,11 the application of Green Chemistry approaches12 and the utilization of catalytic
amounts of transition metals.13
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The syntheses of spiro compounds has focused on carbocyclic spiro 3(2H)ꢀfuranones
(e.g., 3, Scheme 1) where one of the earliest reports came from Lehmann who prepared
butenolides from cyclic αꢀacyloxy ketones via intramoleculare ester enolate addition to the
ketone moiety.14 Akita and coꢀworkers15 employed a similar protocol to convert γ-acetoxyꢀβꢀ
ketoesters derived from 1ꢀalkynylꢀ1ꢀacetoxy derviatives to spiro 3(2H)ꢀfuranones. Using
transition metal catalysis in a protocol involving backbone rearrangement, the Kirsch group
prepared C5ꢀsubstituted spiro furanones from αꢀalkynylꢀαꢀhydroxy ketones16a and C4ꢀiodo C3-
substituted spiro furanones from αꢀalkynylꢀαꢀsilyloxy ketones.16b More recent strategies include
Au(I)ꢀcatalyzed intramolecular cyclization of γꢀacyloxyꢀα,βꢀalkynyl ketones,17 the intermolecular
cyclization of γꢀarylacyloxy18a or γꢀalkylacyloxyꢀβꢀketo18b nitriles derived from γꢀhydroxyꢀα,βꢀ
alkynyl nitriles and aryl or aliphatic carboxylic acids, and a copper mediated domino reaction
between nitriles and propargylic alcohols induced by CO2.19
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Figure 1. 3(2H)ꢀFuranone (1), Armeniaspirole A (2),7a Carbocyclic Spiro Furanone (3),17 and
(4).15
Spiro furanones in which both rings of the spiro fused system are heterocyclic (e.g., 2)
are few in number and have only recently been reported;7, 15,20 Among these compounds, the
Armeniaspiroles AꢀC and their derivatives display antibiotic activity against Gramꢀpositive
bacteria.7 During the course of our studies on the coupling of αꢀ(NꢀCarbamoyl)ꢀalkylcuprates21
(e.g., 5a) with enol triflates,22 we observed the formation of spiroꢀfuranone 7 instead of the
expected coupling product 8 (eq. 1). We now report a detailed study of the scope and limitations
in the reactions of organolithium reagents with (Z) enol triflates derived from βꢀketo esters as a
synthetic protocol for the synthesis of 3(2H)ꢀfuranones.
OTf
O
COOEt
N
O
6
CuCN 10 mol %
PdCl2 5 mol %,
Boc
+
(1)
7
SbPh3 10 mol%
COOEt
Li
N
THF, -78 to 25 0C
Boc
5a
N
Boc
8
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RESULTS AND DISCUSSION
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6
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8
Initially, the attempted palladium promoted coupling of NꢀBocꢀ2ꢀpyrrolidinyllithium 5a
with triflate 6 gave the 3(2H)ꢀfuranone derivative 7 instead of enoate 8 (eq. 1), which seemed
uncharacteristic of a palladium promoted reaction pathway. Control experiments wherein the
metals (i.e., CuCN, PdCl2) and ligands (i.e., SbPh3) were removed from the reaction mixture also
afforded 7 in comparable yields. A study of substrate, diamine additive and solvent was then
undertaken.
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Tosylate 10, prepared from ethyl salycilate, gave poor yields of spiro furanone 12 (Table
1, entries 1ꢀ6). Starting materials were the major components isolated from the crude reaction
mixture, which also yielded phenol 13. Switching from tosylate 10 to triflate 11a increased the
yield of 12 (Table 1, entries 7ꢀ16) and reduced considerably the amount of starting materials
recovered. Here, the combined effect of the diamine and the solvent does not afford the high
yields we observed when coupling αꢀ(Nꢀcarbamoyl)ꢀalkylcuprates with iodo vinylesters, enol
triflates, or other electrophiles in which the best results were obtained with mixtures of
THF/TMEDA or Et2O/(ꢀ)ꢀsparteine.22ꢀ23 In these prior experiments, the αꢀ(Nꢀ
o
carbamoyl)alkylcuprate reagents were generated at ꢀ78 C from the organolithium reagents and
when the cuprates were generated at higher temperatures and for various periods of time lower
and variable yields of products were obtained similar to those observed in the present reaction
(Table 1). These observations are consistent with prior reports on the thermal instability of Nꢀ
Boc 2ꢀlithiopyrrolidine.21,24
The highest yields of 12 were obtained in THF using (ꢀ)ꢀsparteine as an additive (entries
7 & 13), while lower yields were generally obtained with TMEDA (entries 8 & 12) and in less
polar solvents (e.g., Et2O, entry 15; tBuOMe, entry 9ꢀ10). It is intriguing that higher yields of 12
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were obtained with 2.2 equivalents of TMEDA in TBME than with 1.2 equivalents of (ꢀ)ꢀ
sparteine in the same solvent (entries 9ꢀ10), while 6.0 equivalents of either diamine in THF gave
comparable yields of 12 (entries 11ꢀ12) but lower than that obtained with 1.2 equivalents of
(ꢀ)ꢀsparteine in THF (entries 7 & 13). The yields of 12 obtained under these various conditions
suggest the influence of multiple factors such as efficacy of deprotonation of 9 and the reactivity
of 5a with 11a, which could be diminished by coordination of 5a with diamine (i.e., entries 9ꢀ
12). A diminished rate for reaction of 5a with 11a would allow for nonꢀproductive side reactions.
The diamines are employed to facilitate deprotontion of the carbamate, and although Campos
and coꢀworkers25 have reported the deprotonation of NꢀBoc heterocycles in THF without
diamine, we could not reproduce or apply this diamineꢀfree deprotonation protocol to this
reaction. In general, spiro furanone 12 could be prepared in moderate yields accompanied by
starting material and phenol 13 (approx. 20%).
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Table 1. Solvent and Additive Effects on the Yield of 3(2H)-furanone 12.
5
6
O
O
OX
7
8
9
O
O
Boc
10 , X = Tosyl
11a, X = Triflic
1. Diamine
N
+
N
Li
N
2. sec-BuLi 1.2 equiv.
THF, -78 oC, 2 h
-78 oC to rt, overnight
N
O
10
11
12
13
14
15
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17
18
19
20
21
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HO
Boc
Boc
Boc
9 (1.0 equiv.)
5a
12
13
entry
1
diamine (eq)
substrate (eq) solventa yield of 12 (%)b yield of 13 (%)b
TMEDA (2.2)
TMEDA (2.2)
TMEDA (2.2)
(ꢀ)ꢀsparteine (1.2)
(ꢀ)ꢀsparteine (1.2)
(ꢀ)ꢀsparteine (1.2)
(ꢀ)ꢀsparteine (1.2)
TMEDA (2.2)
(ꢀ)ꢀsparteine (1.2)
TMEDA (2.2)
(ꢀ)ꢀsparteine (6.0)
TMEDA (6.0)
(ꢀ)ꢀsparteine (1.2)
(ꢀ)ꢀsparteine (1.2)
(ꢀ)ꢀsparteine (1.2)
—
10 (0.9)
10 (0.5)
10 (0.5)
10 (0.9)
10 (0.5)
THF
THF
Et2O
THF
THF
Et2O
THF
THF
TBME
TBME
THF
THF
THF
THF
Et2O
THF
8
10
4
7
7
25
23
—
25
28
—
11
—
—
17
—
—
24
—
—
—
2
3c
4
5
6c
10 (0.5)
4
7
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
11a (0.5)
65
30
31
52
47
44
65
42
30
16
8c
9c
10
11c
12c
13d
14c,e
15c
16c
aSolvent with a composition for the reaction of 10/1 solvent/organometallic solvent
b
(cyclohexane/hexane) unless otherwise noted. Determined from isolated material purified by
c
d
column chromatography. The yield of product 13 was not determined. Upon reaching room
e
temperature, the reaction mixture was heated at reflux for 2 h. SbPh3 (0.15 equiv.) was added
along with the diamine.
The scope of the reaction was briefly examined with a combination of carbanions and
enol or phenol triflates (Table 2). Lithiocarbamate 5a gave lower yields of furanones 7 and 16,
respectively, with cyclohexenyl triflate 6 and acyclic triflate 11b (entries 1ꢀ2) than furnanone 12
with triflate 11a (Table 1). Two additional αꢀlithiocarbamates derived from NꢀBocꢀ
dimethylamine and NꢀBoc piperidine were then examined. These amines were αꢀlithiated with
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secꢀBuLi in the presence of TMEDA or (ꢀ)ꢀsparteine, to generate αꢀlithiated carbamates 5b-c,
respectively (Table 2, entries 3ꢀ5).
7
8
9
While the secondary αꢀlithiocarbamate 5c afforded very low yields of furanone 18 (entry
5), the primary carbanion 5b gave a good yield of the 2ꢀcarbamoylfuranone 17 when generated
in the presense of (ꢀ)ꢀsparteine (entry 3) but not with TMEDA (entry 4). Good yields of spiroꢀ
furanones could be obtained with 2ꢀlithioꢀ1,3ꢀdithiane 14 and cyclic triflates 6, 11a (entries 6ꢀ7
& 9), although low yields of 19 were obtained in a THF/Et2O solvent mixture (entry 8). For
triflate 11a and dithiane 14, comparable yields of furnanone 19 were obtained with either 2.0 or
1.2 equivalents of 2ꢀlithioꢀ1,3ꢀdithiane (i.e., 14, entry 6 vs. 7). Recovery of starting sulfonate
ester and low yields of 19 resulted when tosylate 10 or the corresponding mesylate were used in
place of triflate 11a. Carbanion 14 gave good yields of furanone 20 with cyclic triflate 6 (entry 9)
but modest to low yields of furanones 21ꢀ22 (entries 10ꢀ11) with acyclic triflates 11b-c,
respectively. Closer examination of the product mixture from reaction of 14 with 11b indicated
that E2 elimination, nucleophilic acyl substitution, and ketone 1,2ꢀnucleophilic addition reactions
occurred competitively even when sequential reactions were involved in product formation
(Table 3). The product distribution could be subtly altered by change of reaction conditions but
no conditions were found to afford the furanone exclusively. The major product obtained with
triflate 11c, methyl 3ꢀphenylproynoate, arises via a base induced elimination of triflic acid.
10
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12
13
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Table 2. Heterocyclic 3(2H)-furanones.
5
6
7
8
9
O
O
R1
R2
R3
R4
R3
OR5
R1
R2
THF or THF/Et2O
-78 oC to rt
M
+
R4
OTf
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.0 equiv.
1.0 equiv.
5a-c, 14-15
6, 11a-e
7, 16-24
Carbanions (R1R2M)
Enol/phenol triflates
S
Li
Li
R
R
6
R3 = R4 = -(CH2)4-,
R5 = Et
R5 = Et
R5 = Me
S
N
Li
11a R3 = R4 = -(CH)4-,
11b R3 = H, R4 = Et,
11c R3 = H, R4 = Ph,
Boc
14
O
R5 = Et
11d R3 = PhCH2, R4 = Ph, R5 = Et
11e R3 = Cl, R4 = Ph, R5 = Et
15
enol/phenol
yield
entrya carbanion
triflate
product
(%)b
1
43
5a
6
7
O
2
38
72
5a
11b
N
O
Boc
16
3c
5b
11a
17
17
4d
5e
25
11
5b
5c
11a
6
18
6f
14
75
11a
19
19
19
7g
8h
68
33
14
14
11a
11a
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14
6
7
8
20
9
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13
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19
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10i
11j
12
40
15k
71
14
14
14
11b
21
11c
22
O
S
Ph
11d
O
S
Ph
23
23
13l
50
68
14
14
11d
11e
O
Cl
S
S
14m
O
Ph
24
15
nBuLi
68
11a
25
25
16n
17o
nBuLi
40
—
11a
11a
nBuMgCl
—
18p
15
—
—
11a
aTHF was used as solvent with a composition for the reaction
of 10/1 solvent/organometallic solvent (hexanes) unless
otherwise noted. Reactions were run from ꢀ78 °C for 2 h then
o
slowly warmed up to 25 C for a total of 8ꢀ12 h; with 2.0
equiv. of R1R2 M (M = Li, MgCl) and 1.0 equiv of enol or
phenol triflate. When a protected amine was employed, 1.2
equiv. of (ꢀ)ꢀsparteine was used unless otherwise noted.
bBased upon isolated material purified by column
c
chromatography unless otherwise noted. Deprotonation for 1
h at ꢀ78 °C with 1.2 equiv. of (ꢀ)ꢀsparteine. dDeprotonation
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for 1.5 h at ꢀ78 °C with 2.4 equiv. of TMEDA. eDeprotonation
3
4
5
6
f
for 4 h at ꢀ78 °C with 2.2 equiv. of TMEDA. Byproducts
7
8
9
formed included 1,3ꢀdithianꢀ2ꢀyl 2ꢀhydroxymethyl ketone
g
(9%) and ethyl 2ꢀhydroxybenzoate (2%). Employing 1.22
10
11
12
13
14
15
16
17
18
19
20
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equiv.
of
2ꢀlithioꢀ1,3ꢀdithiane,
1,3ꢀdithianꢀ2ꢀyl
2ꢀ
hydroxymethyl ketone (9%) and ethyl 2ꢀhydroxybenzoate
(3%) were formed as byproducts. hThe solvent ratio THF:Et2O
i
was 1:2. Starting materials were recovered. 2ꢀLithioꢀ1,3ꢀ
dithiane 14 (1.2 equiv.) in a solvent mixture of THF:Et2O
(1/2) was employed. The elimination product, methyl 2ꢀ
j
pentynoate (31%) was formed as a major byproduct. 1.2
k
equiv. of 14 was employed. Molar ratio estimated from the
1HꢀNMR spectrum of the crude reaction mixture. The major
product formed was the elimination product ethyl 3ꢀ
phenylpropynoate. Same result was obtained when the
l
reaction mixture was quenched at ꢀ78 °C after 2 h. 2ꢀLithioꢀ
m
1,3ꢀdithiane was employed at 1.2 equivalents. 2ꢀLithioꢀ1,3ꢀ
dithiane was employed at 1.0 equiv., reaction mixture was
kept at ꢀ78 °C for 2.5 h and quenched with brine at ꢀ78 °C.
nEmploying 1.25 equiv. of nBuLi, triflate 11a (35%) and ethyl
o
2ꢀhydroxybenzoate (3%) were recovered. Starting material
11a was recovered in 85%. p2ꢀLithio tetrahydropyran was
generated from 2ꢀphenylthiotetrahyropyran with 1.0 equiv. of
lithium napthalenide (LN) or 2.0 equiv. of lithium 1ꢀ
(dimethylamino)naphthalenide (LNMAN) respectively.
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Table 3. Product Distribution from Reaction of 14 with 11b.
5
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9
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15
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19
20
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productsb
21:26:27:28:29
ꢀ :65: ꢀ : ꢀ : ꢀ
THF:Et2O, 1:3 22:25:25: ꢀ : ꢀ
THF 13: ꢀ : ꢀ :30:33
14
entrya equiv. solvent, ratio
1
2
3
4
5
1.2
1.2
2.0
2.0
2.0
THF
THF:Et2O, 1:2 40: ꢀ : ꢀ : 5:31
THF:Et2O, 1:5 37: ꢀ : ꢀ : 5:33
aSolvent with a composition for the reaction of 10/1
solvent/organometallic
solvent
(hexanes).
bDetermined from isolated material purified by
column chromatography
Xꢀray crystallographic data were obtained for compounds 7, 12, 19 and 20 confirming the
structure of these heterocyclic spiro compounds and the ORTEP drawing for 19 is shown in
Figure 2.
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Figure 2. ORTEP Drawing of Spiro 3(2H)-furanone 19 at 50% ellipsoid contour.
Furanones were not obtained with several carbanions. Reaction of triflate 11a with αꢀ
7
8
9
thioꢀstabilized carbanions did afford initial nucleophilic acyl substitution but with allylic
rearrangement of the carbanion moiety (i.e., E2’) (eq. 2) or olefination of the resultant
phenylthiomethyl ketone via 1,2ꢀnucleophilic addition and loss of water (eq. 3). When triflate
10
11
12
13
14
15
16
17
18
19
20
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n
11a was reacted with BuLi, nucleophilic acyl substitution followed by intramolecular sulfonyl
migration occurred to give ketone 25 (Table 2, entry 15) and the yield of 25 was diminished
n
when only 1.25 equivalents of BuLi was employed (entry 16). No major products were isolated
n
upon reaction of BuMgCl. In an attempt to expand this methodology to oxygen containing
heterocycles, αꢀlithio ether 15 was prepared26ꢀ27 by lithiation of 2ꢀ(phenylthio)tetrahydropyran28
with lithium naphthalide or lithium dimethylaminonaphthalide.29
Reaction of 2ꢀ
lithiotetrahydropyran (15, entry 18) with triflate 11a afforded PhSꢀSPh, recover starting
materials, and unidentified byꢀbroducts of high molecular weight even though 15 was
successfully reacted with benzophenone to give the tertiary alcohol (50% yield).
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Several competition experiments were performed using two different nucleophiles.
Reaction of triflate 11a with equimolar amounts of 14 and nBuLi gave similar yields of furanone
19 and ketone 25 (eq. 4), while equimolar amounts of 14 and tBuLi gave comparable yields of 19
and the tertꢀbutyl ketone 33 (eq. 5). In both cases, very minor amounts of the desulfonated
product 32 was obtained suggesting that intermolecular desulfonation is not competitive with the
intramolecular pathway and that the nucleophilic acyl substitution reaction is only slightly
sensitive to carbanion nucleophilicity and steric hindrance.
10
11
12
13
14
15
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18
19
20
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The reaction of 14 with triflate 11a displayed an informative temperature profile (Table
4). As the temperature at which 11a was added to 14 was raised, the yield of 19 decreased
(entries 1ꢀ3). Surprisingly, the highest yield of 19 was obtained when the reaction mixture was
o
quenched at ꢀ78 C after 30 minutes (entry 5) and no diminution of yield was observed upon
o
longer reaction times at ꢀ78 C (entry 4). In these high yielding reactions, the 2ꢀlithioꢀ1,3ꢀ
dithiane was generated at ꢀ40 to ꢀ20 oC. When 14 was generated at 0 oC, and the reaction mixture
maintained at ꢀ78 oC a roughly 3:1 ratio of 34:19 was generated (entries 6ꢀ7) and the ratio shifted
completely to product when the solution was warmed to room temperature (entry 8). These
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results implicate the thermal stability of 14 and a role of the lithium ethoxide generated in the
5
6
nucleophilic acyl substitution reaction.
7
8
9
Table 4. Temperature and Time Dependence
in the Formation of 19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
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% yield 19
entry rxn cond. oC (h)a
or 34:19b
75
1
2
3
4
5
ꢀ78 (2), to 25 (12)
ꢀ40 (1), to 25 (12)
0 (1), to 25 (12)
ꢀ78 (1.33)
43
38
80c
ꢀ78 (0.5)
81c
6d ꢀ78 (1.33)
72:28
68:32
0:100
7d ꢀ78 (1.33)
8d ꢀ78 (4), to 25 (12)
aThe 2ꢀlithioꢀ1,3ꢀdithiane was prepared at ꢀ40 to
o
ꢀ20 C for 40 min unless otherwise noted.
bYields are based upon isolated products
purified by column chromatography. Product
ratios were estimated from the ionꢀcurrent trace
c
obtained from GCꢀMS analysis. The phenol
d
derived from 34 was formed in 2ꢀ3%. The 2ꢀ
lithioꢀ1,3ꢀdithiane was prepared at 0 oC for 1 h.
The synthetic utility of 19 was briefly examined through functional group
transformations (Scheme 1). Attempted deprotection of the O,S,Sꢀorthoester in 19 with
HgO/HgCl2 afforded the O,O,Oꢀorthoester 35 and minor amounts of αꢀketoester 36 arising from
ring opening, while utilization of Nꢀchlorosuccinimide and AgNO3 afforded αꢀketolactone 37 in
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modest yield. Desulfurization of 19 with Raney Nickel gave furanone 38 in moderate yield with
minor amounts of alcohol 39 arising from over reduction. Ketolactone 37 (i.e., coumaranꢀ2,3ꢀ
dione) has previously been used in a variety of synthetic applications30 and is generally prepared
in four steps from isatin in 50% overall yield.
10
11
12
13
14
15
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18
19
20
21
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25
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40
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59
60
Scheme 1. Functional Group Transformations of 19
DISCUSSION
Plausible mechanistic pathways are outlined in Scheme 2 each of which begins with
nucleophilic acyl substitution to give a ketone intermediate (e.g., 34). The second equivalent of
carbanion acts as a base to convert the intermediate ketone into an enolate (e.g., 40), which can
either attack the oxygen atom displacing the triflate anion directly forming the furanone (path 1)
or attack the sulfur atom to transfer the trifluoromethylsulfonyl group from the oxygen atom to
the carbon atom (path 2) forming an intermediate αꢀtrifluoromethylsulfonylketone intermediate
(i.e. 41). The adjacent heteroatom can then expel the excellent leaving group affording a
sulfenium (or iminium) cation 42 that is then trapped by the oxyanion (i.e., phenoxide or
n
enolate). The experimental data is more consistent with the latter pathway. When BuLi is
employed as the nucleophile/base reactant the reaction stops at the αꢀtrifluorosulfonylketone
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stage (i.e., 25) because there are no adjacent heteroatoms to assist in the displacement of the
trifluorosulfonyl leaving group. Similarly, the low yields obtained with enol tosylates or
mesylates reflect the poorer leaving group ability of the pꢀtoluenesulfonyl or methanesulfonyl
10
11
12
13
14
15
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18
19
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n
groups. The failure of BuMgCl may reflect its lack of nucleophilicity and basicity. Reaction of
phenylthiomethyllithium with triflate 11a gives 31 (eq. 3) arising from successful nucleophilic
acyl substitution followed by 1,2ꢀnucleophilic addition to the resultant ketone and subsequent
dehydration that could be aided by sulfonyl transfer from the phenol oxygen to the alkoxide. The
utilization of 2ꢀlithiotetrahydropyran (15) gives a complex mixture of products from which no
major product was isolated. This pattern of reactivity suggests that a complex interplay of
relative rates involving the sequential and/or competitive reactions of nucleophilic acyl
substitution, enolization, 1,2ꢀnucleophilic addition to intermediate ketones, intramolecular
sulfonyl transfer, sulfenium or iminium ion formation and elimination reactions (e.g., substrates
11bꢀc) where possible play a crucial role in the eventual outcome of carbanion and triflate
combinations. This perspective is supported by the competition experiments (eqs. 4ꢀ5) where 2ꢀ
lithioꢀ1,3ꢀdithiane and the alkyllithium reagents give the respective products in roughly
equimolar amounts across a range of basicities, nucleophilicities, and steric hindrance. It is also
consistent with the temperature dependence observed for reaction of triflate 11a with 14 where
11a is sufficiently stable so that at higher temperatures the generated lithium ethoxide can
function as the base to deprotonate 34 and drive the reaction to completion (Table 4, entries 6ꢀ8).
Successful formation of 19 with 1.22 equivalents of 14 (Table 2, entry 7) also suggests
deprotonation of the intermediate ketone by lithium ethoxide.
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Scheme 2. Plausible Mechanistic Pathways for the
Formation of Heterocyclic Spiro-furanone 19.
6
7
8
9
EtO-
O
O
S
S
S
Li
EtO
TfO
+
S
H
TfO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
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45
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48
49
50
51
52
53
54
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59
60
RLi
11a
34
14
O
O
S
S
S
-
-
OR
S
O
O
40
O
S
O
40
O
S
O
CF3
CF3
Path 2
Tf -
Path 1
O
O
S
S
S
S
O
Tf
-O
19
41
O
S
S
-O
Tf -
42
CONCLUSIONS
We have developed a new method for the one pot synthesis of heterocyclic spiro 3(2H)ꢀ
furanones that can be prepared from triflates of βꢀketo esters or 2ꢀcarboalkoxy phenols and αꢀ
heteroatom stabilized carbanions containing either one nitrogen atom or two sulfur atoms. The
product is most likely formed through a cascade of reactions involving nucleophilic acyl
substitution, enolate formation, trifluoromethyl transfer, iminium or sulfenium ion formation and
subsequent ring closure to form the 3(2H)ꢀfuranone. Consequently, the 3(2H)ꢀfuranone chemical
yields are dependent upon the rates of the sequential reactions as well as competing side
reactions and thus on temperature and solvent as well. For acyclic enol triflates (i.e., 11b-c),
competitive E2 elimination of triflic acid arising from deprotonation of the αꢀhydrogen atom
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(Table 2, entries 10ꢀ11) is faster than nucleophilic acyl substitution on the ester moiety,
producing methyl 2ꢀpentynoate and ethyl 3ꢀphenylpropynoate respectively. This unwanted side
reaction can be diminished by the use of THF/Et2O mixtures, which increases the nucleophilic
acyl substitution on 11b or 11c relative to the elimination reaction but increasing the Et2O:THF
ratio to more than 5 to 1 results in nucleophilic 1,2ꢀaddition of the lithiated nucleophile 14 to the
intermediate ketone formed in situ from the initial nucleophilic acyl substitution reaction.
Similarly, αꢀsulfur stabilized carbanions containing one sulfur atom lead to products arising from
initial nucleophilic acyl substitution followed by nucleophilic 1,2ꢀaddition to the resultant
ketone. Utilization of 2ꢀlithioꢀ1,3ꢀdithiane affords αꢀketoꢀO,S,Sꢀorthoesters in which the
functionality can be manipulated for further synthetic applications.
10
11
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14
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19
20
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34
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60
EXPERIMENTAL SECTION
General. NMR spectra were recorded as CDCl3 solutions on a 500 MHz or a 300 MHz
1
instrument. The H NMR chemical shits are reported as δ values in parts per million (ppm)
relative to tetramethylsilane (TMS, δ = 0.00). The residual chloroform signal, CHCl3 (δ = 7.28)
was used as reference. 13C NMR chemical shifts are reported as δ values in parts per million
(ppm) relative to TMS and CDCl3 signal (triplet, centerline δ = 77.0) as reference. Infrared (IR)
spectra were recorded as neat samples (films on NaCl plates). Gas chromatography mass
spectrometry (GCꢀMS) measurements were performed on equipment coupled to a mass
spectrometer with a quadrupole detector at 70 eV. Analytical thin layer chromatography (TLC)
was performed on silica gel plates, 200 ꢁm with F254 indicator, visualization was accomplished
by UV light (254 nm), 5% ethanol solution of ninhydrin or 3% ethanol solution of
phosphomolybdic acid. Flash column chromatography was performed with 200ꢀ400 ꢁm silica.
Yields are reported as pure material after isolation by column chromatography. Compounds for
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high resolution mass spectrometry (HRMS) were analyzed by positive mode electron ionization
(EI) or electrospray ionization (ESI) using TOF detector.
7
8
9
Crystals were grown by slow evaporation of CH2Cl2 solutions. After microscopic evaluation, Xꢀ
ray quality crystals were selected and mounted on glass fibers using epoxy glue. Xꢀray data
were collected using a diffractometer equipped with a Mercury CCD area detector and Mo Kα
radiation (λ = 0.7071 Å). Diffraction data were collected in 0.5 ° oscillations of ω at 200 K.
Data were collected, processed and corrected for absorption and Lorentz and polarization effects
using the CrystalClear software package.31 The structures were solved by direct methods and
refined by least squares refinement on F2 using the SHELXL software package.32 All nonꢀ
hydrogen atoms were refined anisotropically. Hydrogen atoms were constrained to idealized
geometries and treated as riding atoms.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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46
47
48
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50
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59
60
Materials. Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from
sodium/benzophenone. All other solvents were dried over 4Å molecular sieves. Commercially
available alkyllithium solutions were titrated with secꢀbutyl alcohol and 1,10ꢀphenanthroline.33
Commercially available Grignard solutions were titrated with menthol and 1,10ꢀ
phenanthroline.34 The glassware was flameꢀdried and cooled under nitrogen. Lowꢀtemperature
baths (ꢀ78 °C) were made from dry ice and 2ꢀpropanol. All the reactions were carried out under
positive pressure of N2 passed over a trap of desiccant agent (Drierite). Trifluoromethanesulfonic
anhydride (triflic anhydride), Sulfuryl chloride, Raney®ꢀNickel activated catalyst 50 % slurry in
water (CAS 7440ꢀ02ꢀ0), Methanesulfonyl chloride, ethyl 2ꢀcyclohexanonecarboxylate, methyl
propionylacetate, ethyl salicylate, Ethyl benzoylacetate, and NaH 57ꢀ63% oil dispersion were
purchased from commercial sources and used as received. Tosyl chloride and 1,3ꢀdithiane were
dried under vacuum over P2O5 into an Abderhalden's drying tube overnight. 3,4ꢀDihydroꢀ2Hꢀ
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pyran was dried over 4 Å molecular sieves. N,N,N′,N′ꢀTetramethylethylenediamine (TMEDA)
5
6
was distilled and stored over 4 Å molecular sieves. (ꢀ)ꢀSparteine was distilled and stored over 4
7
8
9
Å molecular sieves and kept in the fridge at 4 °C.
NꢀChlorosuccinimide was purified by
10
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42
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48
49
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51
52
53
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recrystallization in benzene. AgNO3, HgO, HgCl2 were used without any further purification. Nꢀ
Boc protected amines were prepared according to the protocol from Varala.35 (Z)ꢀβꢀEnol/phenol
triflates 6, 11a-d and (E)ꢀβꢀenol triflate 11e were prepared from βꢀketo esters: ethyl 2ꢀ
cyclohexanone carboxylate, ethyl salicylate, methyl propionylacetate, ethyl benzoylacetate, ethyl
2ꢀbenzylꢀ3ꢀoxoꢀ3ꢀphenylpropanoate and ethyl 2ꢀchloroꢀ3ꢀoxoꢀ3ꢀphenylpropanoate respectively
using the general protocol described below. (Z)ꢀβꢀEnol tosylate 10 from ethyl salicylate was
prepared adapting this procedure but using tosyl chloride instead triflic anhydride.
Compounds 6,22 11a,22 11b,36 11c,37 13,38 26,39 33,40 35,41 36,42 37,43 38,44 and 39,45 have been
reported and characterized. Data reductions are included for 11d,46 11e,47 13, 35, 37, 38.
1
For new compounds 7, 12, 16-25, 27-31 and 34 13CꢀNMR, HꢀNMR, 19FꢀNMR, GCꢀMS, IR,
elemental analysis or HRMS data reductions are reported.
General Synthesis of (Z)-β-enol/phenol triflates (6, 11a-d) and (E)-β-enol triflate 11e. NaH
60% oil dispersion (1.3 equiv, 6.5 mmol, 260mg) was weighted into a 100 ml round bottom
flask, it was rinsed with hexanes (3 x 10 ml) and flushed with N2, then a magnetic stirrer and 25
ml of CH2Cl2 were added, capped with rubber septa and provided with N2. The flask was placed
into an ice bath and after 5 minutes the βꢀketo ester (1.0 equiv, 5.0 mmol) was added dropwise in
three portions over a 5 minutes period. This reaction mixture was stirred for 15ꢀ20 minutes at
0°C to complete deprotonation and then cooled down to ꢀ78°C. Trifluoromethanesulfonic
anhydride (1.35 equiv, 6.75 mmol, 1.13 ml) were added dropwise while keeping a strong stirring
then let to warm up slowly overnight from 8ꢀ12 h. It was quenched with brine, extracted with
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CH2Cl2 three times, concentrated in vacuo and purified over silica gel with 5% Et2O and 95%
hexanes. For compounds 6, 11b-d, no mixtures of Z and E βꢀenol triflates were found with this
methodology. The yields obtained for these substrates are as follow 6 (1.25 g, 83%), 11a (1.35g,
90%), 11b (1.15g, 88%), 11c (1.38g, 85%), 11d (1.55 g, 75%), 11e (1.18g, 66%).
10
11
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General procedure A. Synthesis of 3(2H)-furanone spiro from N-Boc protected amines
(Table 1 and Table 2). A roundꢀbottom flask with a magnetic stir bar and septum was flameꢀ
dried under N2, NꢀBoc protected amine (1.0 equiv, 2.0 mmol), (ꢀ)ꢀsparteine (1.2 equiv, 2.4 mmol,
560 mg) and THF (9.0 mL) were mixed at room temperature and stirred for 5 min, then the
solution was cooled down to ꢀ78 °C and secꢀBuLi (1.03 M, 1.2 equiv, 2.4 mmol, 2.35 mL) was
added dropwise. The mixture was stirred at ꢀ78 °C for 2 h to complete the αꢀdeprotonation of the
protected amine and then the corresponding enol/phenol triflate 6, 11a-b (1.0 equiv, 1.0 mmol)
was added in one portion. The reaction mixture was kept for 2 h at ꢀ78 °C and then warmed up
slowly to room temperature for a total time of 8ꢀ12 h. It was quenched with a saturated aqueous
solution of NH4Cl, extracted with Et2O three times, concentrated in vacuo and purified over
silica gel.
General procedure B. Synthesis of 3(2H)-furanone spiro from 1,3-dithiane (Table 2). A
roundꢀbottom flask with a magnetic stir bar and septum was flameꢀdried under N2. 1,3ꢀDithiane
(2.0 equiv, 2.0 mmol, 240 mg) was added inside an AtmosBag®, and the flask was sealed with a
rubber septum; the flask was then connected to a N2 line and the solvent THF (9.0 mL) was
added. This solution was cooled down to ꢀ40 °C and nꢀBuLi (2.50 M, 2.1 equiv, 2.1 mmol, 0.84
mL) was added dropwise and the mixture was stirred for 40 min from ꢀ40 to ꢀ20°C. The reaction
mixture was then cooled down to ꢀ78 °C and the corresponding enol/phenol triflate 6, 11a-e (1.0
equiv, 1.0 mmol) was added in one portion. The mixture was kept for 2 h at ꢀ78 °C and then
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warmed up slowly to room temperature for a total time of 8ꢀ12 h. It was quenched with brine,
extracted with Et2O three times, concentrated in vacuo and purified over silica gel.
Preparation of 14 at higher temperatures than ꢀ20 °C resulted in diminished yields.
10
11
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13
14
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tert-butyl
3-oxo-4,5,6,7-tetrahydro-1'H,3H-spiro[1-benzofuran-2,2'-pyrrolidine]-1'-
carboxylate (7). Prepared using general procedure A. After purification (silica gel, eluding first
with 7% EtOAc / 93% hexanes followed by 20% EtOAc / 80% hexanes), a transparent solid was
obtained (150 mg, 43%). Recrystallization was done from a CH2Cl2 solution which was left for
slow evaporation of the solvent over 3 weeks period at room temperature. Melting point 146.0ꢀ
148.5 °C. IR (neat) 2977 (m), 2935 (m), 2889 (m), 2856 (m), 1711(s), 1630 (s), 1383 (s), 1156
(m), 919 (m), 737 (w), 534 (w) cmꢀ1; 1H NMR (500 MHz, CDCl3) (minor rotamer) δ 1.36 (1.44)
(s, 9H), 1.60ꢀ1.90 (m, 4H), 1.95ꢀ2.45 (m, 8H), 3.50ꢀ3.60 (m, 1H), (3.68) 3.77 (t, J = 8.7 Hz, 1H);
13C NMR (125 MHz, CDCl3) (minor rotamer) δ (18.1) 18.3, 21.5, 21.6, 21.8 (22.5), 25.5, 28.0
(28.2), (38.4) 39.1, 48.2 (48.6), (80.5) 80.9, 98.5 (98.9), 111.2 (111.8), (152.1) 152.2, 184.7,
(198.2) 198.4; mass spectrum m/z (relative intensity) EI 293 (5, M+), 237 (10), 193 (14), 176 (7),
86 (12), 70 (100), 57 (62), 41 (32). Elemental analysis calcd for C16H23NO4: C, 65.51; H, 7.90.
Found: C, 65.51, H, 7.91.
Ethyl
(2Z)-2-benzyl-3-phenyl-3-{[(trifluoromethyl)sulfonyl]oxy}prop-2-enoate
(11d).
Prepared using the general synthesis of βꢀenol triflates. Purification was done by filtration of the
crude over silica with 5% Et2O and 95% hexanes giving an pale orange liquid (solidifies after
cooling in the fridge) and used without further purification (770 mg, 75%): IR (neat) 3060 (w),
2970 (m), 2915 (m), 1730 (s), 1618 (m), 1425 (s), 1220 (s), 1125 (m), 1062 (m), 760 (m), 680
(m), 580 (m) cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 1.14 (t, J = 7.3 Hz, 3H), 3.64 (s, 2H), 4.17 (q,
J = 7.3 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 7.12ꢀ7.24 (m, 4H), 7.32ꢀ7.42 (m, 4H); 13C NMR (125
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MHz, CDCl3) δ 13.7, 35.6, 61.9, CF3 q (114.2, 116.7, 119.3, 121.8), 126.7, 128.0, 128.5, 128.6,
128.7, 129.0, 130.8, 131.0, 137.1, 148.7, 164.8; 19F NMR (282 MHz, CDCl3) δ ꢀ74.3 (s, 3F);
mass spectrum m/z (relative intensity) EI 355 (6), 281 (6), 264 (40), 191 (100), 165 (14), 94 (6).
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Ethyl
(2E)-2-chloro-3-phenyl-3-{[(trifluoromethyl)sulfonyl]oxy}prop-2-enoate
(11e).
Prepared using the general synthesis of βꢀenol triflates, with the following modifications: after
the addition of trifluoromethanesulfonic anhydride, the reaction mixture was allowed for slow
warm up from ꢀ78 °C to 0 °C for 4 h and quenched at this temperature. This procedure gives a
mixture of 75:25 E to Z stereoisomers of the βꢀenol triflate. Purification of the Eꢀstereoisomer
11e was done over silica with 5% Et2O and 95% hexanes giving a pale liquid (235 mg, 66%): IR
(neat) 3068 (w), 2983 (m), 2942 (w), 2905 (w), 1735 (s), 1627 (m), 1431 (s), 1222 (s), 1138 (s),
1062 (m), 991 (s), 809 (s), 766 (m), 697 (s), 598 (s) cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 1.34 (t,
J = 7.3 Hz, 3H), 4.36 (q, J = 7.3 Hz, 2H), 7.38ꢀ7.46 (m, 3H), 7.50 (d, J = 6.4 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 13.9, 63.5, CF3 q (114.2, 116.7, 119.2, 121.7), 121.3, 128.5, 129.1, 130.3,
131.4, 149.4, 160.8; 19F NMR (282 MHz, CDCl3) δ ꢀ73.7 (s, 3F); mass spectrum m/z (relative
intensity) EI 358 (34, M+), 313 (8), 265 (5), 197 (18), 169 (18), 125 (15), 105 (100), 77 (58), 51
(17).
tert-butyl 3-oxo-1'H,3H-spiro[1-benzofuran-2,2'-pyrrolidine]-1'-carboxylate (12). Prepared
using general procedure A. After purification (silica gel, eluding first with 15% EtOAc / 85%
hexanes followed by 25% EtOAc / 75% hexanes), a transparent solid was obtained (70 mg,
65%). Recrystallization was done from a CH2Cl2 solution which was left for slow evaporation of
the solvent over 3 weeks period at room temperature. Melting point 112.6ꢀ115.0 °C. IR (neat)
2979 (m), 2962 (w), 2890 (w), 1709 (s), 1616 (s), 1464 (m), 1381 (s), 1322 (w), 1244 (m), 1154
(s), 918 (m), 757 (m) cmꢀ1; H NMR (500 MHz, CDCl3) (minor rotamer) δ 1.07 (1.42) (s, 9H),
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2.03ꢀ2.33 (m, 4H), 3.54ꢀ3.64 (m, 1H), (3.75) 3.85 (t, J = 8.7 Hz, 1H), 7.00ꢀ7.10 (m, 2H), 7.58ꢀ
7.73 (m, 2H); 13C NMR (125 MHz, CDCl3) (minor rotamer) δ 22.2 (22.9), 27.5 (28.2), (37.7)
38.5, 48.0 (48.3), (81.0) 81.7, 98.9 (99.6), 112.7, 120.5, 121.5 (121.6), 124.4 (124.5), (137.9)
138.1, 152.1 (152.5), (169.4) 169.7, (197.5) 198.1; mass spectrum m/z (relative intensity) EI 289
(17, M+), 233 (33), 189 (33), 161 (83), 121 (18), 106 (78), 57 (100), 41 (46). Anal. Calcd for
C16H19NO4: C, 66.42; H, 6.62. Found: C, 66.35, H, 6.62.
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tert-butyl 2-(2-hydroxybenzoyl)pyrrolidine-1-carboxylate (13). Prepared using general
procedure A. After purification (silica gel, 30% EtOAc / 70% hexanes and preparative TLCꢀ
silica with 20% EtOAc / 80% hexanes), a pale yellow solid was obtained (73 mg, 25%). Melting
point 108.2ꢀ111.6 °C. IR (neat) 2972 (w), 2917 (w), 2864 (w), 1699 (s), 1643 (m), 1613 (w),
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1446 (w), 1401 (s), 1292 (w), 1156 (m), 1120 (w), 768 (m) cmꢀ1; H NMR (500 MHz, CDCl3)
(minor rotamer) δ 1.28 (1.45) (s, 9H), 1.90ꢀ2.04 (m, 3H), 2.33ꢀ2.50 (m, 1H), 3.47ꢀ3.72 (m, 2H),
5.21ꢀ5.28 (m, 0.5H), 5.35ꢀ5.42 (m, 0.5H), 6.86ꢀ6.96 (m, 1H), 6.97ꢀ7.07 (m, 1H), 7.46ꢀ7.56 (m,
1H), 7.74ꢀ7.82 (m, 1H), (12.11) 12.19 (s, 0.7H); 13C NMR (125 MHz, CDCl3) (minor rotamer) δ
23.7 (24.2), 28.1 (28.4), (30.4) 31.4, 46.6 (46.8), (60.5) 60.7, (79.9) 80.0, 117.5 (117.6), (118.6)
118.7, (118.9) 119.0, 129.1 (129.5), (136.4) 136.5, 153.6 (154.4), 162.8 (162.9), (204.2) 204.9;
mass spectrum m/z (relative intensity) EI 291 (0.5, M+), 235 (2.5), 218 (7), 170 (25), 114 (71), 70
(100), 57 (57), 41 (22).
tert-butyl 2-ethyl-4-oxo-1-oxa-6-azaspiro[4.4]non-2-ene-6-carboxylate (16). Prepared using
general procedure A. After purification (silica gel, 10% Et2O / 90% hexanes), a pale yellow oil
was obtained (102 mg, 38%): IR (neat) 2978 (s), 2939 (m), 2881 (w), 1700 (s), 1397 (s), 1163 (s)
cmꢀ1; 1H NMR (300 MHz, CDCl3) (minor rotamer) δ 1.15 (t, J = 7.5 Hz, 3H), 1.34 (s, 6H), 1.39
(s, 3H), 1.53ꢀ2.03 (m, 3H), 2.03ꢀ2.28 (m, 1H), 2.31 (q, J = 5.1 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H),
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4.14 (4.31) (m, 1H); 13C NMR (75 MHz, CDCl3) (minor rotamer) δ 12.6, 23.5 (24.0), 28.0, 28.3,
29.0, 30.1, 46.4 (46.6), (66.3) 66.5, (79.6) 80.1, (97.1) 97.7, 153.6 (154.0), (188.0) 188.2; mass
spectrum m/z (relative intensity) EI 195 (1), 179 (0.8), 170 (17), 150 (5), 70 (100), 57 (70).
Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92. Found: C,62.75; H, 7.90.
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tert-butyl methyl(3-oxo-2,3-dihydro-1-benzofuran-2-yl)carbamate (17). Prepared using
general procedure A. After purification (silica gel, eluding first with 7% EtOAc / 93% hexanes
followed by 20% EtOAc / 80% hexanes), a white solid was obtained (180 mg, 72%). Melting
point 86.8ꢀ89.4 °C. IR (neat) 2979 (m), 2934 (w), 1717 (s), 1616 (s), 1464 (s), 1318 (s), 1151
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(s), 1004 (w), 928 (m), 760 (m), 507 (w) cmꢀ1; H NMR (500 MHz, CDCl3) (minor rotamer)
δ 1.30 (1.52) (br s, 9H), 2.80 (2.98) (br s, 3H), 5.40ꢀ6.30 (br s, 1H), 7.08ꢀ7.14 (m, 2H), 7.63ꢀ7.71
(m, 2H); 13C NMR (125 MHz, CDCl3) (minor rotamer) δ 27.8, 28.0, (81.7) 82.2, 89.6 (90.6),
113.0 (113.3), 120.3, 122.0, 124.5, 138.6, 154.0 (155.3), 170.9 (171.5), 195.7 (196.3); mass
spectrum m/z (relative intensity) EI 263 (1, M+), 207 (58), 163 (10), 134 (59), 121 (29), 94 (47),
57 (100), 42 (53). HRMS (ESI) calcd for [C14H17NO4+H]+ 264.1159, found 264.1151.
tert-butyl
3-oxo-4,5,6,7-tetrahydro-1'H,3H-spiro[1-benzofuran-2,2'-piperidine]-1'-
carboxylate (18). Prepared using general procedure A. After purification (silica gel, 25%
EtOAc / 85% hexanes), a white solid was obtained (34 mg, 11%). Melting point 141.1ꢀ142.5 °C.
IR (neat) 2983 (w), 2947 (m), 2869 (w), 1705 (s), 1633 (m), 1368 (m), 1151 (m) cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ 1.30 (s, 9H), 1.50ꢀ1.75 (m, 7H), 1.75ꢀ1.94 (m, 3H), 2.06ꢀ2.25 (m, 2H),
2.25ꢀ2.47 (m, 2H) 2.97ꢀ3.22 (m, 1H), 3.75ꢀ3.93 (m, 1H); 13C NMR (75 MHz, CDCl3) 18.5, 18.8,
21.7, 21.8, 23.3, 25.5, 28.1, 33.8, 42.7, 81.6, 93.9, 110.4, 154.4, 183.0, 199.4; mass spectrum m/z
(relative intensity) EI 307 (12, M+), 251 (16), 234 (12), 207 (35), 190 (15), 178 (19), 164 (54), 84
(100), 57 (64). Anal. calcd for C17H25NO4: C, 66.43; H, 8.20. Found: C, 66.24, H, 8.17.
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3H-spiro[1-benzofuran-2,2'-[1,3]dithian]-3-one (19). Prepared using general procedure B.
After purification (silica gel, 10% Et2O/90% hexanes) a white solid was obtained (50 mg, 75%).
Recrystallization was done from a CH2Cl2 solution which was left for slow evaporation of the
solvent over 3 weeks period at room temperature. Melting point 105.7ꢀ108.0 °C. IR (neat) 2920
(m), 1719 (s), 1612 (s), 1476 (m), 1461 (m), 1298 (m), 1197 (m), 920 (m), 883 (m), 749 (m), 518
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(w) cmꢀ1; H NMR (500 MHz, CDCl3) δ 2.20ꢀ2.36 (m, 2H), 3.20ꢀ3.27 (m, 2H), 3.36ꢀ3.44 (m,
2H), 7.12ꢀ7.19 (m, 2H), 7.69 (t, J = 8.7 Hz, 1H), 7.76 (d, 7.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 23.9, 27.2, 91.0, 113.7, 118.7, 122.9, 125.7, 138.6, 169.1, 194.2; mass spectrum m/z
(relative intensity) EI 238 (74, M+), 205 (27), 173 (100), 163 (87), 121 (37), 104 (33), 76 (47), 41
(22). HRMS (ESI) calcd for [C11H10O2S2 + H]+ 239.0200, found 239.0204.
4,5,6,7-tetrahydro-3H-spiro[1-benzofuran-2,2'-[1,3]dithian]-3-one
(20). Prepared using
general procedure B. After purification (silica gel, eluding first with 10% EtOAc / 90% hexanes
followed by 25% EtOAc / 75% hexanes) a transparent solid was obtained (165 mg, 68%).
Recrystallization was done from a CH2Cl2 solution which was left for slow evaporation of the
solvent over 3 weeks period at room temperature.
Melting point 183.0ꢀ186.6 °C
(decomposition). IR (neat) 2938 (m), 2854 (w), 1703 (s), 1628 (s), 1425 (m), 1411 (m), 1204
(m), 912 (m), 816 (w), 467 (w) cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 1.68ꢀ1.75 (m, 2H), 1.84ꢀ1.91
(m, 2H), 2.21ꢀ2.31 (m, 4H), 2.49 (t, J = 6.0 Hz, 2H), 2.99ꢀ3.06 (m, 2H), 3.37ꢀ3.45 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 18.4, 21.5, 21.6, 23.7, 25.9, 27.2, 91.1, 111.6, 185.5, 195.2; mass
spectrum m/z (relative intensity) EI 242 (34, M+), 209 (30), 117 (100), 118 (53), 85 (50), 79 (37),
42 (62). HRMS (EI) calcd for [C11H14O2S2]+ 242.0435, found 242.0433.
2-ethyl-1-oxa-6,10-dithiaspiro[4.5]dec-2-en-4-one (21). Prepared using general procedure B.
After purification (silica gel, 10% EtOAc / 90% hexanes), a clear liquid was obtained (86 mg,
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40%). IR (neat) 2974 (w), 2920 (w), 1703 (s), 1593 (s), 1421 (w), 1275 (w), 1018 (w), 910 (m),
802 (w) cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 1.27 (t, J = 7.3 Hz, 3H), 2.20ꢀ2.28 (m, 2H), 2.56 (q,
J = 7.3 Hz, 2H), 3.00ꢀ3.80 (m, 2H), 3.34ꢀ3.42 (m, 2H), 5.56 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 9.9, 23.7, 24.2, 27.1, 91.6, 101.0, 191.9, 196.9; mass spectrum m/z (relative intensity)
EI 216 (27, M+), 183 (13), 159 (24), 151 (100), 118 (60), 85 (64), 71 (35), 42 (90). HRMS (ESI)
calcd for [C9H12O2S2 + H]+ 217.0357, found 217.0360.
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2-phenyl-1-oxa-6,10-dithiaspiro[4.5]dec-2-en-4-one. (22). Prepared using general procedure B.
After purification (silica gel, 10% EtOAc / 90% hexanes) a pale orange solid was obtained (25
mg, 9%): Melting point 115.7ꢀ118.5 °C. IR (neat) 2956 (w), 2921 (w), 1700 (s), 1605 (s), 1562
(s), 1450 (w), 1346 (m), 1285 (w), 1045 (w), 768 (w), 689 (w) cmꢀ1; 1H NMR (500 MHz, CDCl3)
δ 2.27ꢀ3.35 (m, 2H), 3.09ꢀ3.16 (m, 2H), 3.46ꢀ3.54 (m, 2H), 6.15 (s, 1H), 7.51ꢀ7.56 (m, 2H), 7.61
(t, J = 7.3 Hz, 1H), 7.86ꢀ7.90 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 23.7, 27.4, 92.2, 99.3,
127.4, 128.3, 128.9, 133.2, 182.1, 196.2; mass spectrum m/z (relative intensity) EI 264 (20, M+),
231 (16), 199 (70) 118 (22), 102 (100), 77 (25), 42 (30). HRMS (ESI) calcd for
[C13H12O2S2+H]+ 265.0357, found 265.0359.
3-benzyl-2-phenyl-1-oxa-6,10-dithiaspiro[4.5]dec-2-en-4-one (23). Prepared using general
procedure B. After purification (silica gel, eluding first with 10% EtOAc / 90% hexanes followed
by 25% EtOAc / 75% hexanes) a pale orange solid was obtained (100 mg, 71%). Melting point
127.7ꢀ130.5 °C. IR (neat) 3061 (w), 3027 (w), 2920 (w), 1698 (s), 1610 (s), 1493 (m), 1423
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(m), 1386 (s), 1131 (m), 918 (m), 726 (m), 695 (m) cmꢀ1; H NMR (500 MHz, CDCl3) δ 2.22ꢀ
2.36 (m, 2H), 3.11ꢀ3.20 (m, 2H), 3.43ꢀ3.51 (m, 2H), 3.85 (s, 2H), 7.15ꢀ7.21 (m, 3H), 7.25ꢀ7.31
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(m, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.74 (t, J = 7.3 Hz, 2H); C NMR
(125 MHz, CDCl3) δ 23.9, 27.4, 27.6, 89.3, 112.1, 126.3, 127.8, 128.1, 128.6, 128.7, 129.3,
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132.1, 138.3, 177.8, 197.7; mass spectrum m/z (relative intensity) EI 354 (14, M+), 321 (20), 289
(80), 192 (100), 165 (11), 119 (10), 105 (29), 77 (32), 42 (24); HRMS (ESI) calcd for
[C20H18O2S2 + H]+ 355.0826, found 355.0819.
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3-chloro-2-phenyl-1-oxa-6,10-dithiaspiro[4.5]dec-2-en-4-one (24). Prepared using general
procedure B with the following modifications: 1.0 equiv. of 14 and 1.05 equiv of 11e were used.
11e was dissolved in 1.0 ml of THF and cooled to ꢀ78 °C before adding it by a cannula over the
reaction flask. The reaction mixture was kept at ꢀ78 °C for 2.5 h and quenched with brine at this
temperature. After purification (silica gel, 10% Et2O/90% hexanes) an orange solid was
obtained (65 mg, 68%). Melting point 128.5ꢀ131.0 °C. IR (neat) 2950 (w), 2921 (w), 2900 (w),
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1716 (s), 1602 (m), 1588 (m), 1568 (s), 1346 (s), 1045 (m), 891 (m), 687 (m) cmꢀ1; H NMR
(500 MHz, CDCl3) δ 2.24ꢀ2.34 (m, 2H), 3.13ꢀ3.23 (m, 2H), 3.40ꢀ3.50 (m, 2H), 7.56 (t, J = 7.8
Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 8.19 (d, J = 7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 23.5,
27.3, 90.1, 107.1, 127.6, 128.3, 128.7, 133.3, 173.9, 190.7; mass spectrum m/z (relative intensity)
EI 298 (14, M+), 265 (16), 233 (100), 193 (12), 136 (89), 105 (52), 77 (55), 42 (65); HRMS
(ESI) calcd for [C13H11ClO2S2+H]+ 298.9967, found 298.9967.
1-(2-hydroxyphenyl)-2-[(trifluoromethyl)sulfonyl]pentan-1-one (25). Prepared using general
procedure B, using 2.0 equiv of nꢀBuLi instead 14. After purification (silica gel, eluding first
with 7 % EtOAc / 93% hexanes followed by 10% EtOAc / 90% hexanes), a white solid was
obtained (63 mg, 68%). Melting point 80.4ꢀ81.4 °C. IR (neat) 2967 (m), 2879 (w), 1636 (s),
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1453 (w), 1361 (s), 1194 (s), 1116 (s), 959 (w), 753 (m), 496 (m) cmꢀ1; H NMR (500 MHz,
CDCl3) δ 0.98 (t, J = 7.3 Hz, 3H), 1.32ꢀ1.47 (m, 2H), 2.18ꢀ2.28 (m, 1H), 2.48ꢀ2.58 (m, 1H), 5.25
(dd, J = 11.0, 3.2 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.63 (t, J = 7.3 Hz,
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1H), 7.70 (d, J = 8.7 Hz, 1H), 11.72 (s, 0.8H); C NMR (125 MHz, CDCl3) δ 13.6, 20.2, 29.4,
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64.8, CF3 q (115.7, 118.3, 120.9, 123.6), 119.3, 119.5, 119.8, 129.9, 138.6, 163.6, 193.8. 19F
NMR (282 MHz, CDCl3) δ ꢀ74.3 (s, 3F); mass spectrum m/z (relative intensity) EI 310 (9, M+),
268 (8), 199 (5), 147 (7), 134 (9), 121 (100), 93 (14), 65 (18); HRMS (EI) calcd for
[C12H13F3O4S]+ 310.0487, found 310.0488.
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(2Z)-1,1-di(1,3-dithian-2-yl)-1-hydroxypent-2-en-3-yl
trifluoromethanesulfonate
(27).
Prepared using general procedure B, with a ratio of solvents THF/Et2O : 1/2. After purification
(silica gel, eluding first with 7 % Et2O / 93% hexanes followed by 12% Et2O / 88% hexanes), a
pale solid was obtained (55 mg, 25%). Melting point 142.5ꢀ145.9 (decomposition) °C. IR
(neat) 3011 (w), 2923 (w), 2875 (w), 1699 (w), 1417 (s), 1207 (s), 1142 (s), 901 (m), 591 (w)
1
cmꢀ1; H NMR (500 MHz, CDCl3) δ 1.20 (t, J = 7.3 Hz, 3H), 1.94ꢀ2.03 (m, 2H), 2.03ꢀ2.12 (m,
2H), 2.44 (q, J = 7.3 Hz, 2H), 2.73ꢀ2.83 (m, 4H), 3.07ꢀ3.17 (m, 4H), 3.51 (s, 1H), 4.43 (s, 2H),
5.32 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 11.1, 25.3, 28.0, 29.0, 29.2, 53.4, 83.4, 119.0,
153.1. 19F NMR (282 MHz, CDCl3) δ ꢀ74.7 (s, 3F); mass spectrum m/z (relative intensity) EI
320 (1), 213 (7), 201 (23), 173 (1), 159 (1), 119 (100), 85 (5), 75 (7), 45 (14); HRMS (ESI) calcd
for [C14H21F3O4S5+Na]+ 492.9893, found 492.9891.
1-(1,3-dithian-2-yl)pent-2-yn-1-one (28). Prepared using general procedure B. After
purification (silica gel, 5 % Et2O / 95% hexanes), a pale yellow solid was obtained (30 mg,
30%): Melting point 91.4ꢀ94.0 (decomposition) °C. IR (neat) 2924 (m), 2853 (w), 2208 (m),
1670 (s), 1656 (s), 1259 (w), 1144 (w), 1001 (w) cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 1.24 (t, J =
7.5 Hz, 3H), 1.98ꢀ2.20 (m, 2H), 2.43 (q, J = 7.5 Hz, 2H), 2.55ꢀ2.65 (m, 2H), 3.19ꢀ3.31 (m, 2H),
4.29 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.5, 12.9, 24.9, 25.8, 48.3, 78.9, 97.1, 179.1; mass
spectrum m/z (relative intensity) EI 200 (8, M+), 172 (1), 144 (2), 119 (100), 85 (8), 75 (10), 53
(15), 45 (18); HRMS (EI) calcd for [C9H12OS2]+ 200.0330, found 200.0336.
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