Taming Silylium Ions for Synthesis: N-Heterocycle Synthesis via Stereoselective C-C Bond Formation

Article abstract of DOI:10.1055/s-0036-1590967

Silylium ions (formally [R ₃ Si] ⁺) have long been the subject of investigations and significant debate in both theoretical and experimental chemistry, but few catalytic, synthetic applications have been reported due to the exception

Full text of DOI:10.1055/s-0036-1590967

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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A
en
B. S. Moyer, M. R. Gagné
Cluster
Synlett
Taming Silylium Ions for Synthesis: N-Heterocycle Synthesis via
Stereoselective C–C Bond Formation
[R3Si+]
catalyst
R3Si–Nu
ArSO2
ArSO2
Nu
Ar
Brandon S. Moyer
Michel R. Gagné*
N
Ar
N
*
0
0
0
0
0-
0
0
1
8-
4
2
4
5-
5
4
7
*
R
R
*
OSiR3
O
Department of Chemistry, The University of North Carolina at
Chapel Hill, Chapel Hill, NC, 27599, USA
mgagne@unc.edu
pyrrolidines
NH2
• New C–C bond(s)
• 2–3 new stereocenters
• Nu = H, allyl, N3, enol ethers
3 steps
12 examples;
up to 92% yield
and >98:2 d.r.
R
Published as part of the Cluster Silicon in Synthesis and Catalysis
OH
amino
alcohols
Ar
[R3Si+]
catalyst
ArSO2
ArSO2
Ar
N
N
Nu
*
*
R
R3Si–Nu
R
OSiR3
O
piperidines
Received: 08.05.2017
Accepted after revision: 28.06.2017
Published online: 16.08.2017
[R3Si(solvent)][B(C6F5)4] via simple Bartlett–Condon–
Schneider hydride abstraction from R3Si–H by the commer-
cially available salt [Ph3C][B(C6F5)4] (abbreviated herein as
trityl BArF20).5
DOI: 10.1055/s-0036-1590967; Art ID: st-2017-b0339-c
Abstract Silylium ions (formally [R3Si]+) have long been the subject of
investigations and significant debate in both theoretical and experi-
mental chemistry, but few catalytic, synthetic applications have been
reported due to the exceptionally high reactivity and Lewis acidity of
these elusive species. Results to be discussed include the application of
easily accessible silylium ion catalysts to the stereoselective synthesis of
various N-heterocyclic pyrrolidine and piperidine scaffolds. The tested
substrates are derived from the chiral pool and can be obtained in three
high-yielding steps from amino alcohols; subsequent stereoselective si-
lylium ion catalyzed Prins cyclization and trapping with R3Si–Nu nucleo-
philes (e.g., Nu = H, allyl, azide, and enol ethers) results in novel nitro-
gen-containing polycyclic scaffolds with potential medicinal chemistry
applications.
To date, catalytic applications of silylium ions in synthe-
sis include alkene hydrosilylation,6 carbonyl reduction,7
imine reduction,8 C–F bond activation (hydrodefluorina-
tion),9 and C–C bond formation (namely Diels–Alder reac-
tions).10 Other synthetic examples of note, albeit not tech-
nically catalytic or self-regenerative in silylium, include ap-
plications in C–C11 and Si–C12 bond formation ((sila)-
Friedel–Crafts reactions). Few examples exist in which si-
lylium ions are employed to catalyze the construction of
substantial molecular complexity; herein we report the ap-
plication of easily accessible silylium ion catalysts to the
stereoselective synthesis of various N-heterocyclic pyrroli-
dine and piperidine scaffolds from acyclic substrates.
Representative conditions for the silylium ion catalyzed
Prins cyclization are given below in Scheme 1; attempts to
further optimize the reaction with respect to trialkylhydro-
silane, solvent, concentration, and catalyst loading were un-
fruitful. Using 10 mol% of the in situ generated silylium ion
equivalent [Et3Si][B(C6F5)4] in CH2Cl2 at –78 °C, an appropri-
ately substituted aldehyde rapidly cyclizes and the resulting
carbocation is trapped by a silyl-protected nucleophile
(R3Si–Nu) to form a substituted piperidine derivative, fol-
lowing subsequent acid-catalyzed removal of the silyl resi-
due.
Key words silylium ion, silylium catalysis, Lewis acid, Prins cyclization,
Hosomi–Sakurai allylation, Si–X reagent, N-heterocycle, polycyclic scaf-
fold
The development of catalytic, synthetic applications of
silylium ions has been frustrated by the technicality that,
except for in the most extreme cases,1 they do not exist.2
Despite their apparent structural similarity to carbenium
ions and their reduced Pauling electronegativity (1.8 vs.
2.5), silylium ions are highly Lewis acidic.3 Their increased
size and longer bond lengths reduce the efficiency of stabi-
lizing π-conjugative and hyperconjugative effects, endow-
ing them with a high affinity for both σ- and π-Lewis bases,
including solvent molecules and counteranions. Therefore,
as silylium ionicity falls on a continuum, the most ‘free’ ex-
amples so far reported are paired with either [B(C6F5)4]–
(i.e., BArF20) or [HCB11R5X6]– (halogenated carboranes) as
weakly coordinating anions (WCAs) in aromatic or halocar-
bon solvents.4 In particular, the reactive [R3Si]+ equivalent is
readily accessible as the solvent-stabilized Lewis pair
ArSO2
Ar
Ar
trityl BArF20 (10 mol%),
Et3Si—H (12 mol%)
ArSO2
N
N
Nu
*
+
R3Si—Nu
R
CH2Cl2, –78 °C, 1 h;
then acidic resin in
1:1 CH2Cl2/MeOH, 22 °C, 1 h
*
R
O
(2.50 equiv)
OH
Scheme 1 Representative reaction conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
B. S. Moyer, M. R. Gagné
Cluster
Synlett
Bs
N
Ph
Ph
Br
2) DMP
3
O
CH2Cl2, 22 °C
Ph
Bs
Bs–Cl,
NEt3
75% yield
NH2
NH
1) K2CO3,
acetone, 65 °C
Ph
Ph
CH2Cl2, 22 °C
OH
OH
Br
92% yield
Bs
Ph
2) DMP
1
2
N
Ph
(S)-phenylalaninol
CH2Cl2, 22 °C
Ph
Bs = 4-bromobenzenesulfonyl
77% yield
4
O
Scheme 2 Representative substrate syntheses
Aldehyde substrates can be obtained in three high-
yielding linear steps starting from the corresponding amino
alcohols. Representative syntheses of (S)-phenylalaninol
derivatives 3 and 4 are illustrated in Scheme 2. First, (S)-
phenylalaninol (1) was sulfonylated with 4-bromobenzene-
sulfonyl chloride (Bs, brosyl) in the presence of triethyl-
amine to afford the Bs-amino alcohol 2 in 92% yield.13 Bs-
amino alcohol 2 was then alkylated with either cinnamyl
bromide or 2-phenylallyl bromide in the presence of potas-
sium carbonate to yield the corresponding N-alkylated Bs-
amino alcohols (not shown; see Supporting Information).
These were then oxidized with Dess–Martin periodinane
(DMP) to yield, respectively, the cinnamyl-amino aldehyde
3 in 75% yield (2 steps) and the 2-phenylallyl-amino alde-
hyde 4 in 77% yield (2 steps).
The trapping nucleophile (R3Si–Nu) scope of the silyli-
um-catalyzed Prins cyclization was investigated; the best
examples are listed in Table 1.14 Reaction of cinnamyl-ami-
no aldehyde 3 with Et3Si–H resulted in the formation of
pyrrolidine 5 in 77% yield as a mixture of three diastereo-
mers in 76:13:11 d.r. (Table 1, entry 1). The reaction of 2-
phenylallyl-amino aldehyde 4 with Et3Si–H resulted in
piperidine 6 in 92% yield and 60:21:19 d.r. (Table 1, entry 2).
Reaction of 4 with allyltrimethylsilane led to an 84%
yield of piperidine 7, which contains an all-carbon quater-
nary center (66:34 d.r., Table 1, entry 3); from a mechanis-
tic perspective, this transformation could be considered a
vinylogous analogue of the named Hosomi–Sakurai allyla-
tion.15 When trimethylsilyl azide (Me3Si–N3) was employed
as the trapping nucleophile, alkyl azide 8 was obtained in
78% yield and 79:21 d.r. (Table 1, entry 4). When chloro-
trimethylsilane (Me3Si–Cl) was employed as the trapping
nucleophile, no chloride-trapped product was observed
(<5%; 9, Table 1, entry 5); Me3Si–Cl is apparently insuffi-
ciently nucleophilic under these conditions, even upon
warming to room temperature.16 Fortuitously, the TiCl4-
promoted classic Prins cyclization (see Supporting Informa-
tion for details) is complementary in that it produces the
chloride-trapped piperidine 9 in 99% isolated yield and
85:9:6 d.r. favoring the vicinal cis diastereomer (3JCH–CH = 5.9 Hz).
With silyl enol ether trapping nucleophiles, various
novel hetero(poly)cyclic piperidines 13–19 are accessible in
fair to good yields and as single diastereomers (Table 2).
These novel bridged tricyclic piperidine scaffolds contain
two stereocenters, one of which is an all-carbon quaternary
center. The initial intramolecular Prins cyclization and in-
termolecular carbocation trapping create the two new C–C
bonds (red) in intermediate I; subsequent treatment of I
with Brønsted acid (e.g., Dowex resin 50W-X8) catalyzes
annulation (blue bond) and elimination to diastereomeri-
cally pure (>98:2 d.r.) tricyclic product. It is noteworthy
that the annulation selects for a single diastereomer of
trapped product; the yields likely reflect this.17
Entry 1 (Table 2) documents the effects of changing the
ring size of the silyl enol ether; cyclopentanone-derived 13
is obtained in only trace amounts (13C NMR and HRMS; see
Supporting Information), presumably due to ring strain,
while cyclohexanone and cycloheptanone derivatives 14
and 15 are obtained in 64% and 22% yields, respectively. Al-
aninol derivative 16 was obtained in 38% yield (Table 2, en-
try 2) and the more hindered valinol derivative was not ob-
tainable under any conditions (not shown; see S17 in the
Supporting Information). The presence of a conjugated aryl
group on the silyl enol ether is also not well tolerated; see
α-tetralone-derivative 17 (11% yield, Table 2, entry 3).18
Aryl iodide 11, showcasing aryl substitution on the 2-phen-
ylpropene fragment, undergoes cyclization and annulation
to 18 in 24% yield (Table 2, entry 4); such products could
potentially be employed in cross-coupling reactions for fur-
ther synthetic elaboration. Methyl-substituted 19, derived
from the corresponding 2-methylpropenyl-substituted
starting material 12, was obtained in 22% yield (Table 2, en-
try 5).
In light of the knowledge that deprotection of simple
aryl sulfonamides (e.g., tosyl (Ts), brosyl (Bs)) often requires
aggressive reagents,19 we endeavored to demonstrate re-
moval under mild conditions. The 2-naphthalene sulfon-
amide protected 20 was synthesized for this purpose (55%,
see Supporting Information), and employing a modification
of a previously reported reductive protocol20 provided free
amine 21 (91% yield, Scheme 3, a). It is also notable that the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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B. S. Moyer, M. R. Gagné
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Table 1 Scope of Trapping Nucleophiles (R3Si–Nu)a,b
trityl BArF20 (10 mol%),
Et3Si—H (12 mol%),
R3Si—Nu (2.50 equiv)
Ph
Nu
Bs
Ph
Bs
Bs
Nu
N
N
N
*
*
Ph
*
Ph
Ph
*
Ph
*
CH2Cl2, –78 °C, 1 h;
acidic resin
O
OH
4
OH
(or cinnamyl-
derivative 3)
6–9
5
Entry
1
Product
Yield (%, NMR)c
d.r.d
R3Si Nu
Bs
H
N
N
Ph
Ph
Et3Si
H
H
Ph
77
76:13:11
OH
5
Ph
Bs
H
2e
92
60:21:19
66:34
79:21
n.d.b
Et3Si
OH
6
Ph
Bs
N
Me3Si
3f–h
4h,i
5j
84
Ph
OH
7
Ph
N3
Bs
Bs
N
Ph
Ph
Me3Si N3
78
OH
8
Ph
Cl
N
Me3Si Cl
(<5)
OH
9
a Reactions were run in duplicate on a 0.05–0.1 mmol scale.
b Bs = 4-bromo-benzenesulfonyl; n.d. = not determined.
c Dimethylformamide (DMF) used as 1H NMR internal standard.
d d.r. after purification.
e 1.20 equiv Et3Si–H provided 6 in 69% NMR yield and 51:29:20 d.r.
f The reaction was warmed from –78 °C to –30 °C overnight.
g 1.10 equiv Me3Si–allyl provided 7 in 57% NMR yield and 58:42 d.r.
h The relative configurations of 7 and 8 were assigned in analogy to the X-ray crystal structure of 20 (vide infra).
i 1.10 equiv R3Si–N3; 2.50 equiv provided 8 in 85% yield and 62:38 d.r.
j The reaction was slowly warmed from –78 to 22 °C over 8 h.
more potent Na-naphthalenide reductant was able to effect
the Bs deprotection of 14 (93% yield, see Supporting Infor-
mation). X-ray analysis of 20 (Scheme 3, b) confirmed the
relative stereochemistry of the C–O bond and amino R
group to be cis (axial-equatorial), respectively, consistent
with 3JCH–CH = 3 Hz.21
Based on the similarity in reactivity and observed vici-
nal cis-diastereoselectivity in the products resulting from
both our putative silylium ion manifold and classical TiCl4-
promoted Prins cyclization conditions (vide supra), we sug-
gest the mechanism in Scheme 4 (a): The strongly Lewis
acidic silylium ion catalyst [R3Si][B(C6F5)4] activates the al-
dehyde to nucleophilic attack by the appended alkene via
chairlike transition states TS and TS′;22 experimentation
has shown TS′ to be favored to arrive at the cis-diastereo-
mer II′. The ensuing trap of II and II′ by R3Si–Nu regenerates
the [R3Si][B(C6F5)4] catalyst.23 The multiple observed diaste-
reomers can be explained by invoking high facial discrimi-
nation in II via a 1,3-diaxial interaction, whereas II′ con-
tains almost no inherent facial bias.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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B. S. Moyer, M. R. Gagné
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Table 2 Silyl Enol Ethers as Trapping Nucleophilesa,b
OSiMe3
via:
trityl BArF20 (10 mol %),
Et3Si—H (12 mol %)
Ar
Ar
Bs
Bs
Bs
Ar
N
N
N
*
+
CH2Cl2, –78 °C, 1 h;
Dowex resin
*
R
R
R
n
O
O
I
n
n
2.50 equiv
R3SiO
O
4;
>98:2 d.r.
10–12
13–19
Entry
1
Substrate
Product
Yield (%, NMR)c
Ph
Bs
N
Bs
Ph
N
n = 0: 13; (trace)
n = 1: 14; 64d
n = 2: 15; 22
Ph
Ph
O
13-15
n
O
4
Ph
Bs
Bs
Ph
N
N
2
3
38
Me
Me
O
O
N
10
16
Ph
Bs
Bs
Ph
N
Ph
Ph
11 (17)
O
O
4
17
I
I
Bs
Bs
Bs
Bs
N
N
N
N
4e
24
22
Ph
Ph
Ph
Ph
O
O
O
11
18
Me
Me
5e
O
12
19
a Reactions were run in duplicate on a 0.05–0.1 mmol scale.
b Bs = 4-bromo-benzenesulfonyl.
c Dimethylformamide (DMF) used as 1H NMR internal standard.
d Compound 14 was obtained in 52% yield using 1.10 equiv of silyl enol ether.
e The reaction was warmed from –78 to –30 °C overnight, which increased yield and reproducibility.
Corroboration of our proposed mechanism was ob-
tained by running the Prins cyclization in the absence of
suitable trapping nucleophiles; upon warming to room
temperature, elimination (an effective carbonyl-ene reac-
tion) occurs to yield cis- and trans-tetrahydropyridine dias-
tereomers 22 and 23, respectively (58% yield, 83:17 d.r.,
Scheme 4, b).24 Intriguingly, application of the neutral
Lewis acid B(C6F5)3 at room temperature provides trans-23
in 99% yield.25 We attribute this reversal of diastereoselec-
tivity to the larger steric environment (and lower reactivi-
ty) of B(C6F5)3 only allowing for activation of the aldehyde
in an exclusively trans-diaxial conformation (TS).
In summary, we have developed a straightforward syn-
thetic protocol that utilizes readily accessible, in situ gener-
ated silylium ions to stereoselectively catalyze the conver-
sion of acyclic amino alcohol derived substrates into stereo-
defined N-heterocyclic pyrrolidine and piperidine
derivatives.26 This represents an early and nascent example
of how silylium ions can be harnessed in complexity-gener-
ating organic transformations. We hope that their high re-
activity can be further modulated to better control and in-
crease their selectivity. Investigations into the applications
of silylium catalysis to organic synthesis are ongoing in our
laboratory.
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B. S. Moyer, M. R. Gagné
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References and Notes
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Scheme 3 Deprotection (a) and X-ray structure (b) of piperidine 20
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Funding Information
This work was financially supported by the DOE (Basic Energy Scienc-
es, DE-FG02-05ER15630)
Bacsi
E
n
e
gr
y
S
ecin
c
es
D(E-F
G
0
2-0
5
E
R
1
5
6
3
0)
Acknowledgment
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6643.
We thank the UNC Chemistry Department Mass Spec Core Laboratory
(Dr. Brandie Ehrmann) and Jared Lowe for solving the X-ray struc-
tures.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590967.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
a) Prins cyclization diastereoselectivity
LA
LA
PG
PG
PG
Ar
Ar Nu–SiR3
LA = SiR3
O
O
N
N
BArF
R
H
N
3
O
Ar
Ar
(cyclization)
ring flip;
H+
trans
(minor)
H
H
TS
II
Nu
Nu
R
R
B(C6F5)4
Ar
PG
PG
PG
Ar Nu–SiR3
LA = SiR3
H
H
N
N
R
N
(cyclization)
ring flip;
H+
cis
(major)
O
O
TS’
II’
OH
R
R
LA
LA
b) Cyclization in the absence of a trapping nucleophile
A) trityl BArF20 (10 mol%),
Et3Si–H (12 mol%),
Bs
Ph
Bs
Ph
Bs
Ph
N
N
N
CH2Cl2, –78 to 22 °C, 8 h
+
Ph
Ph
Ph
B) B(C6F5)3 (10 mol%),
CH2Cl2, 22 °C, 1 h
O
(X-ray)
OH
4
OH
22
23
cis
trans
A: 58% yield; d.r.:
B: 99% yield; d.r.:
83
2
:
17
:
>98
Scheme 4 Proposed mechanism of the silylium-catalyzed Prins cyclization
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
B. S. Moyer, M. R. Gagné
Cluster
Synlett
(10) (a) Hara, K.; Akiyama, R.; Sawamura, M. Org. Lett. 2005, 7, 5621.
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G.; Hilt, G.; Oestreich, M. Organometallics 2014, 33, 302.
(d) Rohde, V. H. G.; Pommerening, P.; Klare, H. F. T.; Oestreich,
M. Organometallics 2014, 33, 3618. (e) Rohde, V. H. G.; Müller,
M. F.; Oestreich, M. Organometallics 2015, 34, 3358.
(f) Shaykhutdinova, P.; Oestreich, M. Organometallics 2016, 35,
2768. (g) Schmidt, R. K.; Klare, H. F. T.; Fröhlich, R.; Oestreich, M.
Chem. Eur. J. 2016, 22, 5376.
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2010, 24, 533. (b) Duttwyler, S.; Douvris, C.; Nathanael, C. D.;
Fackler, L. P.; Tham, F. S.; Reed, C. A.; Baldridge, K. K.; Siegel, J. S.
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Int. Ed. 2017, 56, 52. For selected examples, see: (b) Furukawa,
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Soc. 2016, 138, 7868.
(13) The choice of arylsulfonyl protecting group was based on yield
and general ease of substrate synthesis. Other N-protecting
groups (e.g., Boc, Ac, Bz, TFA, and p-Ns) were found to be diffi-
cult to install in satisfactory yields and so were not investigated
for compatibility in the Prins cyclization.
(22) DFT calculations (ωB97X-D//6-311+G**//CPCM:CH2Cl2) on 2-
methyl-1-(phenylsulfonyl)piperidine show the lowest energy
axial conformer to be 3.3 kcal/mol more stable than the lowest
energy equatorial conformer. We speculate that this is paral-
leled in TS and TS′.
(23) Interestingly, 10 mol% HBArF24 ([H(OEt2)2][B(C6H3(CF3)2)4],
Brookhart’s acid) as catalyst provided hydride-trapped 6 in an
inferior 47% NMR yield but 45:36:19 d.r. favoring the same dia-
stereomers as those resulting from the putative silylium ion
catalysis (cf. Table 1, entry 2; see Supporting Information). This
suggests that the reaction can be catalyzed by Brønsted acid and
that co-catalysis could be operative via adventitious water. See:
Schmidt, R. K.; Muether, K.; Mueck-Lichtenfeld, C.; Grimme, S.;
Oestreich, M. J. Am. Chem. Soc. 2012, 134, 4421.
(24) The relative stereochemistry of cis- and trans-tetrahydropyri-
dine products was determined via X-ray crystallography and
comparison of 1H NMR and 13C NMR data (see S19 in the Sup-
porting Information).
(25) (a) Attempts to intercept the carbocation with R3Si–Nu using
BCF have been unsuccessful; Et3Si–H hydrosilylates the alde-
hyde in 32% NMR yield, along with 44% of 23, and 7% and 12%,
respectively, of minor isomers B and C of 6. (b) Aldehyde hydro-
silylation has been well documented, see: Oestreich, M.;
Hermeke, J.; Mohr, J. Chem. Soc. Rev. 2015, 44, 2202.
(26) Representative Procedure for the Synthesis of Piperidine 20
In a dry, N2-filled glove box, aldehyde S16 (0.150 mmol, 68.3
mg, 1.00 equiv) and trityl BArF20 (0.0150 mmol, 13.8 mg, 0.10
equiv) were weighed into a screw-cap 1 dram vial equipped
with a stir bar and sealed with a septum cap. In a separate vial,
Et3SiH (0.0180 mmol, 2.9 μL, 0.12 equiv) and cyclohexanone-
derived silyl enol ether (0.375 mmol, 72 μL, 2.50 equiv) were
dissolved in 3.00 mL of CH2Cl2 and the vial sealed with a septum
cap. Both vials were removed from the glove box, and the vial
containing the aldehyde and trityl BArF20 was cooled to –78 °C
in an acetone/CO(s) bath. The room-temperature solution in
CH2Cl2 was syringed dropwise and slowly down the side of the
vial into the vigorously stirring solution over 5–10 min. The
reaction was stirred for an additional 2 h at –78 °C, quenched
with 50 μL Et3N, and warmed to r.t. The solution was repeatedly
washed with CH2Cl2 (3×; to remove excess base) and dried in
vacuo. The resulting residue was taken up in 2 mL of 1:1
CH2Cl2/MeOH, approximately 10–20 beads of Dowex resin
(50W-X8) were added, and the reaction was stirred at 22 °C for
3 h. The mixture was then filtered through a cotton/sand plug,
rinsed with 1 mL CH2Cl2 (2×), and concentrated in vacuo. The
crude residue was purified by silica gel chromatography (Rf =
0.5, n-pentane/EtOAc = 5:1), providing heterocycle 20 as a crys-
talline white solid in 55% yield (44.3 mg). 1H NMR (600 MHz,
CDCl3): δ = 8.50 (d, 1 H J = 1.9 Hz), 8.01 (d, 1 H, J = 8.7 Hz), 7.99
(d, 1 H, J = 8.2 Hz), 7.95 (d, 1 H, J = 8.0 Hz), 7.90 (dd, 1 H, J = 8.7,
1.9 Hz), 7.67 (ddd, 1 H, J = 8.2, 6.9, 1.4 Hz), 7.63 (ddd, 1 H, J = 8.2,
6.8, 1.4 Hz), 7.37 (t, 2 H, J = 7.7 Hz), 7.29 (dd, 2 H, J = 8.2, 1.3 Hz),
7.27–7.22 (m, 3 H), 7.18 (d, 1 H, J = 7.4 Hz), 7.16 (dd, 2 H, J = 7.1,
1.6 Hz), 4.69 (dd, 1 H, J = 11.4, 2.7 Hz), 3.89 (dt, 1 H, J = 4.0, 1.9
Hz), 3.57 (dd, 1 H, J = 12.7, 3.5 Hz), 3.40 (d, 1 H, J = 11.5 Hz), 3.30
(ddd, 1 H, J = 11.6, 3.6, 1.8 Hz), 2.85 (t, 1 H, J = 12.8, 11.6 Hz),
2.39–2.32 (m, 2 H), 2.24–2.19 (m, 1 H), 1.94–1.90 (m, 1 H),
1.72–1.53 (m, 6 H). 13C NMR (151 MHz, CDCl3): δ = 150.1, 143.5,
139.6, 138.2, 134.8, 132.4, 129.8, 129.4, 129.3, 128.9, 128.6,
128.6, 128.1, 127.8, 127.7, 126.7, 126.6, 126.4, 122.5, 106.3,
67.4, 65.5, 54.1, 39.1, 39.0, 35.8, 27.8, 24.8, 23.4, 23.1. HRMS
(ESI+): m/z calcd for C34H34NO3S+ [M + H]+: 536.2260; found:
536.2259. [α]D26 +11.7 (c 1.70, CH2Cl2, l = 100 mm).
(14) Other R3Si–Nu sources, including TMS–I, TMS–CN, and TMS–
OAc, provided complex mixtures of products by 1H NMR and 13
NMR analyses.
C
(15) For a review, see: (a) Hosomi, A. Acc. Chem. Res. 1988, 21, 200.
For selected modern asymmetric examples, see: (b) Mahlau, M.;
García-García, P.; List, B. Chem. Eur. J. 2012, 18, 16283. (c) Sai,
M.; Yamamoto, H. J. Am. Chem. Soc. 2015, 137, 7091. (d) Kaib, P.
S. J.; Schreyer, L.; Lee, S.; Properzi, R.; List, B. Angew. Chem. Int.
Ed. 2016, 55, 13200.
(16) The substrate is consumed; in the absence of a suitable trapping
nucleophile, catalytic [Et3Si][B(C6F5)4] leads to a 54% NMR yield
of eliminated products 22 and 23 in 78:22 cis/trans d.r.
(17) Analysis of crude pre- and post-annulation 13C NMR suggests
the reason for exclusively high d.r. but low yield is most likely
due to double diastereo-differentiation during annulation of
intermediate I; diastereomers with a trans-configuration of the
C–O and C–Nu bonds decompose and/or are easily separated
away from the cis-bridged products. We have not attempted to
isolate or characterize the intermediate ketone diastereomers I.
(18) Reaction with the corresponding acyclic acetophenone-derived
silyl enol ether yielded only trace cyclized product (see Sup-
porting Information).
(19) Wuts, P. G. M.; Greene, T. W. N-Sulfonyl Derivatives: R2NSO2R′, In
Greene’s Protective Groups in Organic Synthesis; John Wiley and
Sons: Hoboken, NJ, 2007, 4th ed. 851–868.
(20) (a) Nyasse, B.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S.;
Ragnarsson, U. J. Org. Chem. 1999, 64, 7135. (b) Grehn, L.;
Ragnarsson, U. J. Org. Chem. 2002, 67, 6557.
(21) CCDC 1548662 contains the supplementary crystallographic
data for this structure. The data can be obtained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F