Tandem nucleophilic addition/fragmentation of vinylogous acyl nonaflates for the synthesis of functionalized alkynes, with new mechanistic insight

Article abstract of DOI:10.1055/s-0031-1290945

Vinylogous acyl nonaflates, like the corresponding triflates, are subject to nucleophile-triggered fragmentation as part of a tandem process for generating functionalized alkynes. Advantages to the use of nonaflates in lieu of triflates include cost and s

Full text of DOI:10.1055/s-0031-1290945

1818▌
SPECIAL TOPIC
special topic
Tandem Nucleophilic Addition/Fragmentation of Vinylogous Acyl Nonaflates
for the Synthesis of Functionalized Alkynes, with New Mechanistic Insight
Tandem Addition/Fragmentation of Vinylogous Acyl Nonaflates
Paratchata Batsomboon, Brian A. Gold, Igor V. Alabugin, Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6448281; E-mail: gdudley@chem.fsu.edu
Received: 03.03.2012; Accepted: 07.03.2012
are also competent nucleofuges.11 In contrast, Coke
Abstract: Vinylogous acyl nonaflates, like the corresponding tri-
showed that chlorides participate in ring-opening frag-
flates, are subject to nucleophile-triggered fragmentation as part of
mentations only upon rather intense heating.12 Prior to our
work, Fleming reported that simultaneous release of car-
a tandem process for generating functionalized alkynes. Advantag-
es to the use of nonaflates in lieu of triflates include cost and stabil-
ity. Computational analysis supports a postulated fragmentation bon dioxide and metal triflate salts can drive the alkyno-
genic fragmentation of β-keto ester derivatives.13
Fleming’s decarboxylative elimination to alkynes was in
mechanism involving a closed (cyclic) transition state with concert-
ed extrusion of lithium sulfonate.
Key words: alkynes, fragmentation, nucleophilic addition, solvent
effects, tandem reaction
turn foreshadowed by Brummond’s LDA-mediated elim-
ination of vinyl triflates.14
Li•THFn
O
O
Tandem processes1 involve the coordinated execution of
two or more distinct reactions in one experimental proto-
col. Under the umbrella of tandem processes are cas-
cade/domino reactions,2 in which all reactions take place
without altering the experimental conditions, and consec-
utive/sequential processes that require additional input
(energy and/or reagents) to complete the process.3 Tan-
dem reactions are typically associated with reduced time,
effort, cost, and waste, especially as they pertain to avoid-
ing the need to isolate and purify intermediates. In addi-
tion, such processes expand the synthetic utility of
reactive intermediates for which isolation and purification
may not be appropriate.
Ph
Ph
Ph–Li
O
THF
fast
– LiOTf
slow
OTf
1a
3c, 93% yield
OTf
Scheme 1 Nucleophilic addition/C–C bond-cleaving fragmentation
of a vinylogous acyl triflate, with initial mechanistic hypothesis
An advantage of our tandem addition/fragmentation pro-
cess is versatility (Scheme 2). By varying the nature of the
nucleophile, one can generate alkynes optionally tethered
to aryl and alkylketones, β-keto esters and phospho-
nates,15 alcohols,16 and amides.4 Ring-expansion to cy-
cloalkynes is also possible.17 Likewise, varying the triflate
substrate leads to alternative fragmentation products. Het-
erocyclic triflates provide access to homopropargyl
alcohol18 and amine19 derivatives, and Williams20 and
Cramer21independently exploited deconjugated cyclohex-
enone triflates for the production of chiral allenes. On the
other hand, the use of triflate building blocks can be cost-
prohibitive, and some vinylogous acyl triflates are unsta-
ble to prolonged storage, as discussed herein.
We have been developing a tandem process based on vi-
nylogous acyl triflates in which C–C bond-forming addi-
tion of organometallic nucleophiles sets up a C–C bond-
cleaving fragmentation event, with release of metal tri-
flate salt, to generate functionalized alkynes (Scheme 1).4
The first stage of this tandem process – addition to a vi-
nylogous ester – is reminiscent of the Woods enone syn-
thesis,5 which is perhaps best known for its role in the
Stork–Danheiser alkylation strategy.6 The second stage
intersects with the classic Eschenmoser–Tanabe fragmen-
tation reaction.7
In this report, we focus on vinylogous acyl nonaflates as
an alternative to triflates (Figure 1). Nonaflates can pro-
vide certain specific advantages over triflates.22 Nonaflyl
fluoride (NfF) is produced industrially for surfactant ap-
plications, and as such it is inexpensive by pharmaceutical
standards. Enol nonaflates are regarded as being more sta-
ble to storage than analogous triflates, while providing
similar (if not greater) levels of reactivity.24 We had pre-
viously examined nucleofuges including bromide, mesyl-
ate, and benzenesulfonate in place of triflate,23but none of
these enabled the desired fragmentation process at tem-
peratures up to refluxing toluene. Our studies on the syn-
thesis, stability, and tandem addition/fragmentation
reactivity of vinylogous acyl nonaflates are disclosed
here.
Alkynogenic (alkyne-generating) fragmentations like this
one are rare compared to those that produce alkenes.8 For
generating alkynes, better nucleofuges9 and/or higher
temperatures are needed. Release of molecular nitrogen
(and a sulfinic acid) drives the Eschenmoser–Tanabe frag-
mentation; more recently, Brewer and co-workers have
exploited this most powerful nucleofuge in a variety of
novel alkynogenic fragmentation pathways.10 Selenones
SYNTHESIS 2012, 44, 1818–1824
Advanced online publication: 04.05.2012
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DOI: 10.1055/s-0031-1290945; Art ID: SS-2012-C0221-ST
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Addition/Fragmentation of Vinylogous Acyl Nonaflates
1819
O
Table 1 Synthesis of Vinylogous Acyl Nonaflates (VANs) 2a–f
(carbonyl extrusion)
R1
O
O
R2
O
R2
R2
R3
R3
R2
R2
R3
R3
1) HMDS, imidazole
reflux
OH
R1
O
R1
R2
R1
X
O
R1
2) NfF, CsF, THF
0 °C to r.t.
n
R2MgX
or R2Li
ONf
n
n
OTf
LiHMDS
then R2I
n
n
R4 R4
R4 R4
2
(X = CH2, NH)
MeMgBr
(X = O)
R1, R2, R3, R4
Yield (%)a
Entry
n
Nonaflate
EWG
OH
O
R1
Li
EWG
R1
DIBAL-H
1
2
3
4
5
6
0
1
1
1
1
1
Me, H, H, –
H, H, H, H
2a
2b
2c
2d
2e
2f
85
O
R1
X
stabilized
67
carbanions
OTf
n
OTf
n
n
(capable of fragmentation)
R2Li or LiBHEt3 (2 equiv)
Me, H, H, H
H, H, Me, H
H, Me, H, H
H, H, H, Me
73
R2NHLi
80
intramolecular
nucleophile
NHR1
O
54b
20b
R2 R2
OH R1
O
R1
a Isolated yield.
n
n
b Nonaflates 2e and 2f (entries 5 and 6) were prepared from 6,6-di-
methylcyclohexane-1,3-dione as a mixture of regioisomers, which
were then separated by chromatography.
n
m
Scheme 2 Versatility of the tandem addition/fragmentation process
for producing diverse alkyne building blocks
Tandem Nucleophilic Addition/Fragmentation Reac-
tions of Vinylogous Acyl Nonaflates
O
O
The central question of this study – Will VAN substrates
undergo the tandem addition/fragmentation process by
analogy to vinylogous acyl triflates? – is addressed in
Table 2. The best result was obtained in the reaction of
O
O
O O
S
S
O
CF3
O
CF2CF2CF2CF3
1a
vinylogous acyl triflate
2c
vinylogous acyl nonaflate
Table 2 Reaction of PhLi with Nonaflates 2a–f
Figure 1 Vinylogous acyl triflate 1a and nonaflate 2c
O
O
R2
R2
R3
R3
R2
R2
R3
R3
R1
Synthesis of Vinylogous Acyl Nonaflates
Ph
R1
PhLi
–78 to 100 °C
toluene, 60 min
Synthesis of the vinylogous acyl nonaflate (VAN) sub-
strates for tandem addition/fragmentation was carried out
from commercially available 1,3-diones by analogy to lit-
erature reports (Table 1).24 Direct dione sulfonylation was
impractical, but the two-step process of silylation fol-
lowed by TMS → Nf exchange provided general access to
the desired VANs. Entries 5 and 6 are actually the result
of a single experiment, in which a nonsymmetrical dione
was converted into regioisomeric nonaflates 2e (major)
and 2f (minor), which were then separated by chromatog-
raphy.
n
n
ONf
R4 R4
2
R4 R4
3
R1, R2, R3, R4
Entry Concn
PhLi
(equiv)
n
Alkyne Yield
(%)a
1b
2b
3
72c
96c
63
76
72
68
68
56
66
76
0.28 M
55 mM
28 mM
28 mM
28 mM
28 mM
28 mM
55 mM
55 mM
28 mM
0.9
0.9
1.0
1.5
1.5
1.5
1.5
1.0
1.5
1.5
1
1
1
1
1
1
1
0
0
0
Me, H, H, H
Me, H, H, H
H, H, H, H
H, H, H, H
H, H, Me, H
H, Me, H, H
H, H, H, Me
Me, H, H, –
Me, H, H, –
Me, H, H, –
3c
3c
3b
3b
3d
3e
3f
4
There are advantages and disadvantages of this VAN syn-
thesis compared with the corresponding triflates. Our pre-
ferred triflate synthesis involves cryogenic conditions,
chlorinated solvent, and highly reactive (i.e., hazardous)
and expensive triflic anhydride.25 On the other hand, it
provides triflate 1a (Figure 1) in one step and 98% yield
(vs. 73% for nonaflate 2c, Table 1, entry 3). The VAN
synthesis is potentially more amenable to large-scale pro-
duction,24 with nonaflyl fluoride being cheaper and easier
to handle than triflic anhydride. Nonaflates also tend to be
more robust, as discussed herein.
5
6
7
8
3a
3a
3a
9
10
a Isolated yield.
b Temp: –78 to 0 °C over 75 min.
c Based on PhLi.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1818–1824

1820
P. Batsomboon et al.
SPECIAL TOPIC
phenyllithium with nonaflate 2c (→ 3c, Table 2, entry 2, with lithium reagents outperforming Grignards (Table 3,
96%) under dilute conditions in toluene. The analogous entries 1–5). Phosphonate17 anions are effective triggers
transformation of triflate 1a → 3c (93% yield) was for fragmentation (entries 6–8), but enolate addition to
achieved at a higher concentration in THF.4
VAN 2b produced alkyne 3m much less efficiently than
previously reported.16
The reactions of phenyllithium with nonaflates 2a–f are
highlighted in Table 2. Yields of alkynyl ketones 3 corre- Comparing Vinylogous Acyl Triflates and Nonaflates
late well with yields from our previous studies4 involving
We noted previously the cost advantages to nonaflates
vinylogous acyl triflates. Most yields here are slightly
over triflates.24 In addition, nonaflates generally provide
higher – the biggest improvement was in alkyne 3a (entry
enhanced stability over the corresponding triflates. Most
10, 76% vs. 61%4) – whereas the yield of 3d is dramati-
of our methodology has focused on reactions of triflate 1a
cally lower (entry 5, 72% vs. 96%4). Alkynes 3e and 3f
(Figure 1), which is indefinitely stable. In fact, triflate 1a
is easier to purify, store, and handle than the dione from
(entries 6 and 7) had not been reported previously.
Optimal conditions here involved toluene as solvent (in- which it is derived. However, the same cannot be said for
stead of THF) under more dilute conditions. Toluene triflate 1b (Figure 2), which must be freshly prepared for
emerged as the optimal solvent in previous studies involv- best results. In this case, the enhanced stability of VAN 2b
ing alkyl nucleophiles,15,20,21 which we rationalized based provides an advantage.
on aggregation effects with the organometallic partner,
and the impact of these effects on the initial carbonyl ad-
O
O
dition step. However, in this case we are unable to recon-
cile the experimental observation with our working
mechanistic hypothesis for the rate-determining fragmen-
tation (Scheme 1). Consequently, we have revised our
mechanistic model to account for the new observations
(vide infra).
O
O
O O
S
S
O
CF3
O
CF2CF2CF2CF3
1b
2b
Figure 2 Vinylogous acyl triflate 1b and nonaflate 2b
A brief scan of the scope of suitable nucleophiles for the
tandem addition/fragmentation of vinylogous acyl nonaf-
lates mostly parallels the previously studied triflates
(Table 3). Both aryl and alkyl carbanions are appropriate,
We prepared fresh samples of 1b and 2b and left them
overnight in the freezer (–25 °C). 1H NMR analysis of the
samples after 18 hours revealed that triflate 1b had de-
Table 3 Reaction of Nonaflates with Diverse Nucleophilesa
O
O
R1
R5–M (1.1 equiv)
R5
R1
solvent
conditions
ONf
2
3
R1
R5–M
Yield (%)b
Entry
Nonaflate 2
Conditions
Alkyne
n-BuLic
1
2
3
4
5
6
7
8
9
2c
2c
2c
2c
2c
2c
2b
2b
2b
Me
Me
Me
Me
Me
Me
H
–78 → 0 °C
–78 → 0 °C
0 → 60 °C
3g
3c
3g
3c
3h
3i
98
96
69
77
75
89
PhLic
n-BuMgClc
PhMgClc
0 → 60 °C
PhCH2MgClc
0 → 60 °C
(MeO)2(O)PCH2Li
(MeO)2(O)PCH2Li
(MeO)2(O)PCH(Me)Li
–78 → 60 °C
–78 → 60 °C
–78 → 60 °C
–78 → 60 °C
53d
85d
41
3j
H
3k
3m
e
H
PhC(OLi)=CH2
a Typical procedure: a solution of nonaflate 2 and R5–M nucleophile (55 mM in toluene for entries 1–5, in THF for entries 6–9) stirred at low
temperature for the initial addition, followed by warming to induce fragmentation; see ‘Conditions’ for specific temperatures.
b Isolated yield based on limiting reagent.
c Amount used = 0.9 equiv.
d Estimated yield based on 1H NMR analysis.
e Amount of enolate = 2.2 equiv.
Synthesis 2012, 44, 1818–1824
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Addition/Fragmentation of Vinylogous Acyl Nonaflates
1821
composed beyond recognition, whereas VAN 2b re-
mained essentially unchanged. Typically, 2b is stored in a
lab freezer for up to a week before repurification is war-
ranted. The recommendation here is therefore to consider
the nonaflate analogue in cases where triflate stability is a
problem.
On the other hand, fragmentation of the nonaflate sub-
strates optimally involves toluene as solvent under higher
dilution than fragmentation of the triflates. Why are these
changes in protocol beneficial for the fragmentation of
nonaflates? Our initial mechanistic model (lithium ion
solvation aids fragmentation, Scheme 1) is inconsistent
with the positive effect of increasing the amount of tolu-
ene as the solvent for fragmentation. Therefore, we recon-
sider our initial hypothesis and now postulate a revised
mechanism.
Revised Mechanistic Hypothesis
Why is toluene an effective fragmentation solvent? Ac-
cording to gas-phase free-energy calculations at the
B3LYP/6-31(d) level of theory, the lithium alkoxide inter-
mediate adopts a bridged conformation in which the lithi-
um ion establishes points of contact with both the
alkoxide and one of the sulfonate oxygens (Scheme 3).
Such a chelate is likely strongest in nonpolar solvents and
at low concentration, with fewer external Lewis basic
sites available to compete with the sulfonate for coordina-
tion to lithium. In the gas phase, this cyclic eight-atom
chelate is predicted to be 10.9 kcal/more more stable than
the nonchelated structure.
Scheme 3 A revised mechanistic hypothesis for the tandem addi-
tion/fragmentation process, supported by gas-phase calculations at
the B3LYP/6-31(d) level of theory (bond lengths given in Ång-
stroms). The lithium alkoxide intermediate preferentially adopts a
bridging eight-atom ring chelate structure, which then undergoes ex-
trusion of lithium triflate via a ‘closed’ transition state. Compared to
the alternative release of lithium triflate as a solvent-separated ion
pair (cf. Scheme 1), this pathway enables favorable interactions be-
tween lithium and the triflate in the fragmentation transition state,
which provides an additional driving force for fragmentation.
The chelate structure offers the significant and specific
advantage of releasing lithium triflate directly as a contact
ion pair, through what we are calling a ‘closed’ transition
state. The calculated energy barrier (ΔG‡ =11.3 kcal/mol)
is consistent with fragmentation occurring below room
temperature as observed4 (cf. Table 2, entry 2).26 Note that
these values were calculated for the triflate, which is sim-
pler and easier to calculate than the nonaflate. Likewise in
solution, the additional rotational degrees of freedom (and
steric profile) of the nonaflate may disfavor the more or-
dered chelate structure, increasing the importance of a
nonpolar solvent and high dilution conditions.
probe this new mechanistic hypothesis experimentally,
but it is consistent with recent observations. Importantly,
the closed transition state model has predictive value for
expanding the scope of the tandem addition/fragmenta-
tion process. Such studies are now underway.
1H and 13C NMR spectra were recorded on a 400 MHz spectrometer
using CDCl3 as the deuterated solvent. The chemical shifts (δ) are
reported in parts per million (ppm) relative to the residual CHCl3
peak (7.26 ppm for 1H NMR and 77.0 ppm for 13C NMR) and α,α,α-
trifluorotoluene (–63.72 ppm for 19F NMR spectra peak). The cou-
pling constants (J) are reported in hertz (Hz). IR spectra were re-
corded on a FT-IR spectrometer with diamond ATR accessory as
thin film. Mass spectra were recorded using electrospray ionization
(ESI) or electron impact (EI). Yields refer to isolated material
judged to be ≥95% pure by 1H NMR spectroscopy following silica
gel chromatography, unless otherwise noted. All chemicals were
used as received unless otherwise stated. Nonafluorobutanesulfonyl
fluoride (purity 98%) was obtained from Aldrich. All solvents, so-
lutions and liquid reagents were added via syringe. THF was puri-
fied by distillation over Na and benzophenone. CH2Cl2 was distilled
from CaH2. Toluene was dried over a column of molecular sieves
under N2. The n-BuLi solutions were titrated against a known
amount menthol dissolved in THF using 1,10-phenanthroline as the
indicator. All reactions were carried out under an inert N2 atmo-
sphere unless otherwise stated. The purifications were performed by
flash chromatography using silica gel F-254 (230–499 mesh parti-
cle size). Cartesian Coordinates: all stationary points have been
In conclusion, the tandem nucleophilic addition/fragmen-
tation reactions of vinylogous acyl nonaflates provide ac-
cess to alkyne-tethered ketones and β-keto phosphonates.
This chemistry follows logically from previous work in-
volving vinylogous acyl triflates, but with several distinc-
tions. In general, nonaflates are cheaper to prepare, more
stable to storage and handling, and at least equal in nu-
cleofugality compared to their triflate counterparts. These
advantages are expected to provide a positive impact for
large-scale applications and in cases of poor triflate stabil-
ity (e.g., 1b).
Preliminary computational analysis of the postulated frag-
mentation pathway revealed an alternative ‘closed’ transi-
tion state, in which precomplexation within the
intermediate lithium alkoxide leads to release of lithium
sulfonate as a contact ion pair. More work is needed to
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1818–1824

1822
P. Batsomboon et al.
SPECIAL TOPIC
shown to be either minima (zero imaginary frequencies) or first-or-
der saddle points (one imaginary frequency).
1H NMR (400 MHz): δ = 1.13 (s, 6 H), 2.31 (s, 2 H), 2.540 (s, 2 H),
2.543 (s, 2 H), 6.08 (s, 1 H).
13C NMR (100 MHz): δ = 27.9, 33.3, 42.3, 50.5, 118.2, 166.2,
197.5.
19F NMR (376 MHz): δ = –81.8 (t, J = 9.5 Hz, 3 F), –110.25 to
–110.33 (m, 2 F), –122.1 to –122.2 (m, 2 F), –127.0 to –127.1 (m, 2
Nonaflates 2; 3-Oxocyclohex-1-enyl Nonafluorobutanesulfo-
nate (2b); Typical Procedure
To a suspension of cyclohexane-1,3-dione (1.00 g, 8.92 mmol) in
HMDS (7.0 mL, 31.21 mmol) was added imidazole (36.4 mg, 0.54
mmol) at r.t. The resulting mixture was stirred at 130 °C for 3 h and
then cooled to r.t. The excess HMDS was distilled off under reduced
pressure to obtain a crude oil (TMS-enol ether), which was used fur-
ther without purification. To a solution of the TMS-enol ether in
THF (18 mL) was added CsF (271 mg, 1.78 mmol) at 0 °C. After
stirring for 10 min, perfluoro-1-butanesulfonyl fluoride (1.76 mL,
9.81 mmol) was added dropwise. The resulting mixture was slowly
warmed to r.t. and stirred for 18 h. The reaction mixture was
quenched with H2O (10 mL) and extracted with EtOAc (2 × 15mL).
The combined organic layers were washed with H2O (30 mL) and
brine (30 mL). The solution was dried (Na2SO4), filtered, and con-
centrated under reduced pressure to give an oil. Purification by col-
umn chromatography on silica gel (gradient elution from 10% to
15% EtOAc–hexanes) gave 2.36 g (67%) of 2b as a colorless oil
(See Table 1 for experimental modifications and yields for each en-
try).
F).
HRMS (EI+): m/z calcd for C12H11F9O4S (M)+: 422.0234; found:
422.0233.
2e
Yield: 1.64 g (54%); colorless oil.
IR (neat): 1690, 1653, 1428, 1353, 1226, 1198, 1142, 1055, 1030,
920 cm–1.
1H NMR (400 MHz): δ = 1.13 (s, 6 H), 1.92 (t, J = 6.2 Hz, 2 H), 2.70
(td, J = 6.2, 1.3 Hz, 2 H), 5.98 (s, 1 H).
13C NMR (100 MHz): δ = 23.5, 26.2, 34.3, 40.8, 117.6, 165.6,
202.1.
19F NMR (376 MHz): δ = –81.6 (t, J = 9.6 Hz, 3 F), –110.0 to –110.1
(m, 2 F), –121.8 to –121.9 (m, 2 F), –126.8 to –126.9 (m, 2 F).
HRMS (EI+): m/z calcd for C12H11F9O4S (M)+: 422.0234; found:
422.0215.
IR (neat): 1693, 1646, 1428, 1353, 1224, 1197, 1141, 1069, 1033,
910 cm–1.
1H NMR (400 MHz): δ = 2.10 (quint, J = 6.5 Hz, 2 H), 2.43 (t, J =
6.7 Hz, 2 H), 2.66 (t, J = 6.2 Hz, 2 H), 6.05 (d, J = 1.2 Hz, 1 H).
13C NMR (100 MHz): δ = 20.7, 28.4, 36.3, 119.1, 167.6, 197.4.
2f
Yield: 0.59 g (20%); colorless oil.
IR (neat): 1694, 1632, 1420, 1228, 1197, 1142, 1019, 1884 cm–1.
19F NMR (376 MHz): δ = –81.8 (t, J = 9.7 Hz, 3 F), –110.25 to
–110.30 (m, 2 F), –121.08 to –121.16 (m, 2 F), –127.1 to –127.1 (m,
2 F).
HRMS (EI+): m/z calcd for C10H7F9O4S (M)+: 393.9921; found:
393.9935.
1H NMR (400 MHz): δ = 1.30 (s, 6 H), 1.96 (dd, J = 6.9, 5.8 Hz, 2
H), 2.50 (dd, J = 7.4, 6.2 Hz, 2 H), 6.02 (s, 1 H).
13C NMR (100 MHz): δ = 24.9, 33.9, 35.8, 36.2, 116.1, 172.9,
197.4.
19F NMR (376 MHz): δ = –81.8 (t, J = 9.6 Hz, 3 F), –110.4 to –110.5
(m, 2 F), –122.1 to –122.2 (m, 2 F), –127.0 to –127.1 (m, 2 F).
HRMS (EI+): m/z calcd for C12H11F9O4S (M)+: 422.0234; found:
2a
Yield: 2.99 g (85%); colorless oil.
422.0221.
IR (neat): 1724, 1680, 1429, 1225, 1142, 1083, 1052, 1033, 901
cm–1.
Reaction of VANs 2 with PhLi; 1-Phenylhex-5-yn-1-one (3b);
Typical Procedure
1H NMR (400 MHz): δ = 1.78 (app t, J = 2.2 Hz, 1 H), 2.64–2.66
(m, 2 H), 2.91–2.93 (m, 2 H).
13C NMR (100 MHz): δ = 6.7, 26.9, 129.7, 172.4, 203.2.
19F NMR (376 MHz): δ = –81.6 (t, J = 9.5 Hz, 3 F), –110.2 to –110.3
(m, 2 F), –121.78 to –121.82 (m, 2 F), –126.7 to –126.8 (m, 2 F).
HRMS (EI+): m/z calcd for C10H7F9O4S (M)+: 393.9921; found:
393.9008.
PhLi (0.28 mL, 0.50 mmol; 1.8 M in Bu2O) was added dropwise to
nonaflate 2b (0.27 g, 1.02 mmol) in toluene (25 mL) at –78 °C un-
der N2. The resulting mixture was stirred at –78 °C for 15 min,
warmed to r.t., and then heated at 100 °C for 45 min. H2O (15 mL)
was added to quench the reaction and then the mixture was extract-
ed with EtOAc (2 × 10 mL). The combined organic layers were
washed with H2O (20 mL), dried (Na2SO4), filtered, and concentrat-
ed under reduced pressure to give an oil, which was purified by col-
umn chromatography on silica (gradient elution from 10% to 15%
EtOAc–hexanes) to give 89.5 g (76%) of 3b as a colorless oil (see
Table 2 for experimental modifications and yields for each entry).
2c
Yield: 2.36 g (73%); colorless oil.
IR (neat): 1690, 1669, 1420, 1344, 1223, 1195, 1142, 1026, 914
cm–1.
1H NMR (400 MHz): δ = 1.88 (t, J = 1.2 Hz, 3 H), 2.08 (quint, J =
6.5 Hz, 2 H), 2.49 (t, J = 6.8 Hz, 2 H), 2.72–2.76 (m, 2 H).
Characterization data for 3e and 3f are provided; data for 3a (entry
10, 134 mg, 76%), 3b (entry 4, 134 mg, 76%), 3c (entry 2, 182 mg,
96%), and 3d (entry 5, 157 mg, 72%) match our previous report.4
13C NMR (100 MHz): δ = 9.3, 20.6, 28.7, 36.6, 128.2, 162.2, 197.7.
19F NMR (376 MHz): δ = –81.6 (t, J = 9.6 Hz, 3 F), –110.75 to
3e
Yield: 65 mg (68%); colorless oil.
–110.85 (m, 2 F), –121.7 to –121.8 (m, 2 F), –126.8 to –126.9 (m, 2
F).
IR (neat): 3297, 2969, 1671, 1598, 1472, 1390, 1261, 1200, 1180
cm–1.
HRMS (EI+): m/z calcd for C11H9F9O4S (M)+: 408.0078; found:
408.0079.
1H NMR (400 MHz): δ = 1.25 (s, 6 H), 1.85 (app t, J = 2.6 Hz, 1 H),
1.95–2.00 (m, 2 H), 2.04–2.07 (m, 2 H), 7.30–7.34 (m, 2 H), 7.36–
7.40 (m, 1 H), 7.58–7.60 (m, 2 H).
13C NMR (100 MHz): δ = 14.3, 25.8, 39.5, 47.3, 68.5, 84.0, 127.6,
128.1, 131.0, 138.5, 208.0.
HRMS (EI+): m/z calcd for C14H16O (M)+: 200.1201; found:
200.1197.
2d
Yield: 2.41 g (80%); colorless oil.
IR (neat): 1689, 1648, 1429, 1350, 1224, 1199, 1142, 1051, 951
cm–1.
Synthesis 2012, 44, 1818–1824
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Addition/Fragmentation of Vinylogous Acyl Nonaflates
1823
3f
3j
Yield: 65 mg (68%); colorless oil.
Yield: 64 mg of a pale yellow oil, which based on 1H NMR analysis
comprised 58 mg of 3j (85% estimated yield) and 5 mg of dimethyl
methylphosphonate.
IR (neat): 3297, 2971, 1683, 1598, 1449, 1364, 1289, 1215, 1003
cm–1.
IR (neat): 2960, 1671, 1423, 1353, 1237, 1203, 1145, 1037, 914
cm–1.
1H NMR (400 MHz): δ = 1.81 (quint, J = 7.0 Hz, 2 H), 1.96 (t, J =
2.7 Hz, 2 H), 2.24 (td, J = 6.9, 2.6 Hz, 2 H), 2.77 (t, J = 7.1 Hz, 2
H), 3.11 (d, 2JH,P = 22.7 Hz, 2 H), 3.79 (d, 3JH,P = 11.2 Hz, 6 H).
1H NMR (400 MHz): δ = 1.25 (s, 6 H), 1.85 (app t, J = 2.6 Hz, 1 H),
1.95–2.00 (m, 2 H), 2.04–2.07 (m, 2 H), 7.30–7.34 (m, 2 H), 7.36–
7.40 (m, 1 H), 7.58–7.60 (m, 2 H).
13C NMR (100 MHz): δ = 29.0, 30.6, 35.0, 36.9, 68.7, 90.8, 128.0,
128.5, 132.9, 136.8, 200.0.
HRMS (EI+): m/z calcd for C14H16O (M)+: 200.1201; found:
200.1209.
13C NMR (100 MHz): δ = 17.5, 22.0, 42.5, 42.0, 40.7, 53.1 (d,
2JC,P = 6.4 Hz), 69.1, 83.3, 201.3 (d, 2JC,P = 6.5 Hz).
HRMS (ESI+): m/z calcd for C9H15O4P + Na (M + Na)+: 241.0606;
found: 241.0604.
Spectroscopic data match the data reported previously for 3j.27
Reaction of VANs 2 with Organometallic Nucleophiles; Undec-
9-yn-5-one (3g); Typical Procedure
n-BuLi (0.29 mL, 0.45 mmol; 1.5 M in hexane) was added dropwise
to 2c (0.20 g, 0.49 mmol) in toluene (9 mL) at –78 °C under N2. The
resulting mixture was stirred at –78 °C for 15 min, then at 0 °C for
60 min. H2O (15 mL) was added to quench the reaction, and the
mixture was extracted with EtOAc (2 × 10 mL). The combined or-
ganic layers were washed with H2O (20 mL), dried (Na2SO4), fil-
tered, and concentrated under reduced pressure to give an oil, which
was purified by column chromatography on silica (gradient elution
from 10% to 15% EtOAc–hexanes) to give 73 g (98%) of 3g as a
colorless oil (see Table 3 for modifications and yields for each en-
try).
Claisen-Type Condensation of VAN 2b with the Lithium Eno-
late of Acetophenone; 1-Phenyl-oct-7-yne-1,3-dione (3m); Typ-
ical Procedure (Table 3, entry 9)
To a stirred solution of LDA [prepared by treating a solution of i-
Pr2NH (0.15 mL, 1.07 mmol) in THF (8 mL) with n-BuLi (0.70 mL,
1.07 mmol; 1.5 M in hexane) at 0 °C] was added dropwise aceto-
phenone (0.13 mL, 1.07 mmol) at –78 °C. After 30 min, a solution
of nonaflate 2b (0.19 g, 0.49 mmol) in THF (2 mL) was added. The
resulting solution was stirred at –78 °C for 20 min, at r.t. for 40 min,
and at 60 °C for 30 min. The solution was diluted with sat. aq NH4Cl
(10 mL) and extracted with EtOAc (2 × 15 mL). The combined or-
ganic layers were washed with brine (30 mL), dried (Na2SO4), fil-
tered, and concentrated to an oil, which was purified by column
chromatography on silica gel (gradient elution from 15% to 20%
EtOAc–hexanes) to afford 43.1 mg (41%) of 3m. Characterization
data for 3m match our previous report.16
Characterization data for 3c (entry 2, 80 mg, 96% and entry 4, 64
mg, 77%), 3g (entry 1, 73 mg, 98% and entry 3, 51 mg, 69%), and
3h (entry 5, 67 mg, 75%) match our previous report.4
Claisen-Type Condensation of VANs 2 with Phosphonate Nu-
cleophiles; Dimethyl 1-Methyl-2-oxohept-6-ynylphosphonate
(3k); Typical Procedure
A THF solution (10 mL) of diethyl ethylphosphonate (0.10 mL,
0.61 mmol) was treated with n-BuLi (0.35 mL, 0.56 mmol; 1.6 M
solution in hexanes,) at –78 °C. After 20 min, a solution of nonaflate
2b (0.20 g, 0.50 mmol) in THF was added dropwise. The resulting
solution was stirred at –78 °C for 10 min, warmed to r.t., stirred for
40 min, and then heated at 60 °C for 30 min. The reaction mixture
was diluted with sat. aq NH4Cl (10 mL) and then extracted with
EtOAc (2 × 15 mL). The combined organic layers were washed
with sat. aq NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4),
filtered, and concentrated reduced pressure to give an oil, which
was purified by column chromatography on silica (gradient elution
from 80% to 100% EtOAc–hexanes) to afford 124 mg of a pale yel-
low oil. Based on 1H NMR analysis, this mixture comprised 112 mg
of 3k (85% estimated yield) and 12 mg of diethyl ethylphosphonate
(see Table 3 for experimental modifications and yields for each en-
try).
Acknowledgment
This research was supported in part by the Florida State University
and in part by grants from the National Science Foundation (Dudley
Lab: NSF-CHE 0749918; Alabugin Lab: NSF-CHE 0848686). We
thank Dr. Jumreang Tummatorn (Chulabhorn Research Instituted,
Thailand) for helpful discussions and suggestions.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
1
are copies of H, 13C, and 19F NMR spectra and Cartesian coordi-
nates and energies for calculations.omnorinfaIntgonimornifSIart
u
npotgiSutpor
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI: mD
Characterization data for 3j and 3k are provided; data for 3i (101
mg, 89%) match our previous report.4
1y
Prtat 0.4125/pd0027th.
m
iyPrDaZneht11alCy
0
r
hem
ts
i
3k
IR (neat): 3945, 2987, 1715, 1456, 1355, 1237, 1136, 1053, 967
cm–1.
References
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19.9, 7.1 Hz, 3 H), 1.81 (quint, J = 7.2 Hz, 2 H), 1.95 (t, J = 2.6 Hz,
1 H), 2.22 (app tq, J = 6.9, 1.4 Hz, 2 H), 2.66 (app dt, J = 18.4, 7.1
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1818–1824

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Synthesis 2012, 44, 1818–1824
© Georg Thieme Verlag Stuttgart · New York