Synthesis of α-Cyano and α-Sulfonyl Cyclic Ethers via Intramolecular Reactions of Peroxides with Sulfone- And Nitrile-Stabilized Carbanions

Article abstract of DOI:10.1021/acs.joc.9b02112

The intramolecular reaction of carbon nucleophiles with oxygen-centered electrophiles has been little explored outside of nucleophilic epoxidation. We now report the synthesis of sulfonyl- and cyano-substituted oxacycles via intramolecular reaction of sul

Full text of DOI:10.1021/acs.joc.9b02112

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Article
Synthesis of #-cyano and #-sulfonyl cyclic ethers via intramolecular
reactions of peroxides with sulfone- and nitrile-stabilized carbanions
Alissa Horn, and Patrick H. Dussault
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02112 • Publication Date (Web): 08 Oct 2019
Downloaded from pubs.acs.org on October 13, 2019
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Synthesis of -cyano and -sulfonyl cyclic ethers via intramolecular reactions of
peroxides with sulfone- and nitrile-stabilized carbanions
Alissa Horn and Patrick H. Dussault
Department of Chemistry
University of Nebraska-Lincoln
Lincoln, NE 68588-0304
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pdussault1@unl.edu
ABSTRACT: The intramolecular reaction of carbon nucleophiles with oxygen-centered
electrophiles has been little explored outside of nucleophilic epoxidation. We now report the
synthesis of sulfonyl- and cyano-substituted oxacycles via intramolecular reaction of sulfone-
and nitrile-stabilized carbanions with dialkyl peroxides, triethylsilyl/alkyl peroxides, and
monoperoxyacetals. The cyclizations are successfully applied to synthesis of oxetanes,
tetrahydrofurans, and tetrahydropyrans but fail for oxepanes. Cyclizations involving the
relatively stabilized anion derived from a benzylic nitrile proceed in high yield for a variety of
peroxides, including those in which the electrophilic oxygen is formally isobutyl or neopentyl.
Corresponding cyclizations of an alkanenitrile are successful with both dialkyl and alkyl silyl
peroxides but demonstrate much greater variability in yield. Reactions of sulfone-containing
substrates are successful only with dialkyl peroxides. The success of reactions appears to be
strongly influenced by the rate of peroxide decomposition, which appears to be highest for
reactions involving poorly stabilized anions. The significant variation in diastereoselectivity
observed for different classes of peroxide on a common framework suggests the possibility of
substrate-dependent reaction mechanisms.
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Introduction: Cyclic ethers are important structural elements in organic chemistry, and can be
found at the core of molecules ranging from common solvents to complex natural products.1
The majority of synthetic approaches to cyclic ethers are based upon reactions of nucleophilic
oxygen with electrophilic carbon (Figure 1a-d). 2,3,4,5
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Figure 1: Selected approaches to intramolecular C-O bond formation
We recently described a synthesis of cyclic and spirocyclic ethers based upon intramolecular
5
reaction of ketone enolates and dialkyl peroxides. Extension of this chemistry to stabilized
anions derived from nitriles and sulfones would provide a means of accessing the rich chemistry
associated with these functional groups (Figure 1e).6,7 However, while intermolecular reactions
of nitrile- or sulfone-stabilized carbanions with simple oxygen electrophiles have been
demonstrated,8,9 the corresponding intramolecular reactions have not been reported outside of
3
-exo closures during nucleophilic epoxidations (eq 1).10,11,12 We now report a new approach to
functionalized oxetanes, tetrahydrofurans, and tetrahydropyrans based upon intramolecular
reactions of peroxides with metalated nitriles and sulfones.
Results: A series of secondary and tertiary peroxyalkylnitrile substrates were prepared via
monoalkylation of phenylacetonitrile or octanenitrile with bromoalkenes, followed by reductive
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oxygenation in the presence of Co(II) and triethylsilane (Table 1).13 Yields for the peroxidation
were lower than those later observed with substrates lacking a nitrile group (vide infra).
Table 1. Syntheses of peroxy-substituted nitriles.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
hexyl
R1
H
CH3
H
H
H
n
2
2
1
2
3
4
-
nitrile (%) peroxide (%)
1 (97)
2 (92)
3 (98)
4 (97)
5 (98)
6 (96)
7 (98)
1si (41)
2si (30)
3si (35)
4si (47)
5si (41)
6si (42)
7si (36)
"
"
Ph
Ph
Ph
Ph
Ph
H
CH3
Deprotection of silyl peroxide 4si furnished hydroperoxide 4h (eq 2), which was subjected to
acid-promoted acetalization with dihydropyran to furnish monoperoxyacetal 4thp.14
Preparation of the corresponding dialkyl peroxide substrates proved more challenging (Scheme
1). Although monoalkylation of phenylacetonitrile with 1,n-dihalides has been reported, we found
that reaction with 1-bromo-4-chlorobutane furnished a mixture of the desired chloroalkylnitrile
and a spirocyclopentane.15,16 An alternative route based upon alkylation with 1-iodo-4-t-
butylperoxybutane proceeded slowly and in low yield. The unexpectedly low reactivity of the
iodoalkyl peroxide was confirmed by a competition reaction with 4-bromo-1-butene. In contrast,
monoalkylation of octanenitrile with 1-chloro-3-bromopropane provided chloronitrile 8 in high
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yield, offering a simple pathway, via the iodide 9i, for synthesis of a dialkyl peroxide-substituted
alkyl nitrile (9bu).
0
1
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8
9
0
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1. Approaches to alkylperoxy nitriles.
a
approx. 50% recovered iodoperoxide
Clean alkylation of lithiated methyl phenyl sulfone with a 1,3-diodide or a 4-iodoperoxide also
17
proved unsuccessful despite precedent for similar reactions. A series of t-butyl/primary alkyl
peroxysulfones was instead prepared using the sequence shown in Scheme 2. Monoalkylation
of thiophenol with 1,n-chlorobromides furnished thioethers 10a-13a. Oxidation of the thioethers
to generate sulfones 10b-13b was followed by Finkelstein exchange to generate iodosulfones
10c-13c. Alkylation of t-butyl hydroperoxide with the iodosulfones furnished the corresponding
peroxysulfones, 10bu-13bu. Reaction of iodide 11c with 2-tetrahydropyranyl hydroperoxide,
18
generated from dihydropyran, generated peroxyacetal 11thp (Scheme 2). The reaction of 10c
to furnish peroxide 10bu was accompanied by spiroalkylation to form a cyclopropyl sulfone (not
shown).
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0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Synthesis of t-butylperoxyalkyl sulfones.
a
PhSO cycloC H also formed (46%)
2
3
5
Preparation of a series of secondary peroxides on a common sulfone framework is illustrated in
Scheme 3. Alkylation of thiophenol with 5-bromo-1-pentene generated the unsaturated thioether
14, which underwent Co(II)-promoted oxygenation in the presence of triethylsilane to produce
triethylsilyl peroxide 15; this appears to be the first application of Mukaiyama/Nojima
peroxidation in the presence of a thioether.13,19 Oxidation of the thioether with neat hydrogen
peroxide furnished sulfone 16si. Fluoride-mediated desilylation furnished hydroperoxide 16h,
which underwent methylation to furnish 16me or acetalization to produce monoperoxyacetal
16thp.
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0
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0
1
2
3
4
5
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2
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8
9
0
Scheme 3. Synthesis of secondary peroxyalkylsulfones.
Reactivity of nitriles
Table 2 illustrates base-promoted reactions of substrates combining a benzylic nitrile and 2° or
3° trialkylsilyl peroxides. The secondary peroxide (4si) underwent cyclization in good and
sometimes excellent yields to form tetrahydrofurans 17 with moderate selectivity for generation
of the diastereomer (17a) possessing a trans relationship of the C phenyl and C methyl (vide
2
5
infra); the only reagent that was unsuccessful was a phosphazene “superbase”. Encouragingly,
fragmentation of the peroxide to the ketone (Kornblum-De la Mare reaction) was not observed in
any of these reactions.20 Cyclizations of the corresponding tertiary peroxide (7si) were also
successful, generating the tertiary/tertiary ether 18 in yields only slightly lower yields than
observed with 4si.
Table 2. Influence of base on a selected cyclization
subs
R
base
product
S,R*/
R,R*
8:1
6.5:1
6:1
3.5:1
3:1
3.1:1
(
% yield)
17 (95)
17 (93)
17 (91)
17 (72)
17 (83)
17 (30)
4si
4si
4si
4si
4si
4si
H
H
H
H
H
H
KOtBu
KDA
KH
LDA
n-BuLi
PhLi
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7
7
si
si
si
si
si
si
si
si
si
H
H
NaH
BTPP*
17 (94)
4.7:1
na
na
na
na
na
na
na
na
nr
Me KOtBu
18 (75)
18 (71)
18 (59)
18 (57)
18 (67)
18 (25)
18 (21)
Me
Me
Me
KDA
KH
LDA
Me n-BuLi
Me
Me
1
1
1
1
1
1
1
1
1
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3
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4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
PhLi
NaH
*
tert-butylimino-tri(pyrrolidino)phosphorane
Table 3 compares the application of a common set of cyclizations across a homologous series
of secondary triethylsilyl peroxides. Cyclizations to form the oxetane (19), tetrahydrofuran (17)
and tetrahydropyran (20) all proceeded at similar rates, but with major differences in yields. In
1
each case, one diastereomer predominated ( H NMR). Cyclization of 6si to form an oxepane
was unsuccessful, generating a mixture of recovered starting materials and byproducts (TLC).
Table 3. Cyclization yields vs. ring size.
subs
n
1
2
3
ring size
product (% yield)
19 (58)
17 (95)
3si
4si
5si
4
5
6
20 (37)
6si
4
7
nr (62% recov 6i)
We next explored the influence of the peroxide group on cyclizations generating a common
tetrahydrofuran (Table 4). Although superior yields were consistently obtained with the
triethylsilyl peroxide (4si), cyclizations of the peroxyacetal (4thp) gave good yields under some
conditions (KOtBu, NaH). The few trials attempted using the free hydroperoxide (4h) gave poor
yields. Interestingly, reactions of the silyl peroxide generally proceeded with moderate
stereoselectivity while the corresponding reactions of the hydroperoxide and monoperoxyacetal
proceeded with minimal diastereoselection.
Table 4. Influence of the class of peroxide on cyclization.
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0
1
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7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
subs
4si
base
yield (%)
95
17a/17b
8:1
4
4
4
ha
thp
si
KOtBu
15
85
72
28
39
83
47
91
1.5:1
1.1:1
3.5:1
1.6:1
1.4:1
3:1
1.6:1
6:1
1.1:1
4.7:1
1.2:1
4ha
LDA
n-BuLi
KH
4
4
4
thp
si
thp
4si
4
4
4
thp
si
thp
71
94
78
NaH
a2.0 equiv of base
The configuration of the major diastereomer was assigned based upon observation of nOe
enhancements between the ortho arene hydrogens and the tetrahydrofuranyl C -hydrogen in
5
butyl ketone 21 (eq. 3). Addition details can be found in Table S1.
Analogous cyclizations of the alkyl-peroxide in the nitrile series proved to be strongly dependent
upon choice of base (Table 5). The best yields, whether for reaction of a primary dialkyl
peroxide (9bu), a secondary silyl peroxide (1si), or a tertiary alkyl/silyl peroxide (2si), were
obtained using strong lithium bases. Use of KOtBu produced fragmentation of the primary
dialkyl and secondary alky/silyl peroxide substrates to form complex mixtures containing
aldehydes and ketones.20 Reactions of tertiary alkyl/silyl peroxides proceeded with remarkable
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sensitivity to base: LDA gave the best yield yet seen, while use of KOt-Bu or KH resulted in
1
complex product mixtures containing significant amounts ( H NMR) of the tertiary alcohol.
Interestingly, reactions of 1si appeared to generate one major diastereomer.
Table 5. Cyclization of peroxy-substituted alkyl nitriles.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
subs
base
KOtBu
KDA
product (% yield)
decompa
decompa
22 (27)
9bu
9bu
9bu
LDA
9bu
n-BuLi
PhLi
KOt-Bu
KDA
KH
LDA
22 (46)
9
1
1
bu
si
si
22 (60)
decompa
decompa
decompa
23 (67)
1si
1si
1si
1si
n-BuLi
NaH
23 (22)
recov 1si (82)
2si
KOtBu
KH
LDA
decompb
decompb
2si
si
2
24 (85)
2si
n-BuLi
PhLi
24 (54)
24 (29)
2si
2
si
NaH
recov 2si (86)
a
mixture including aldehyde or ketone;
mixture including 3° alcohol
b
The reactions described in Table 5 were conducted by mixing substrate and base at 0 °C,
followed by removal of the cooling bath. A seemingly minor change, addition of a hexane
solution of n-BuLi into a room temperature solution of tertiary peroxide 2si gave no cyclization
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5
6
product; instead we observed the hydroxyketone (25) derived from cleavage of the peroxide and
attack on the nitrile (eq 4).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cyclizations of t-butyl peroxyalkylsulfones were successful in the case of 4-, 5- and 6-
membered rings, but failed to generate an oxepane (Table 6). The cyclizations, which
demonstrated a strong and seemingly substrate-specific base dependence, were generally
slower than had been observed for the nitriles and significant amounts of starting materials were
often recovered. Although the use of a slight excess of base gave improved yields, continued
increase in base stoichiometry led to increased formation of decomposition products.
Application of some of the successful cyclization conditions to monoperoxyacetal 11thp resulted
only in decomposition.
Table 6: Cyclizations of peroxy- and monoperoxyacetal-substituted sulfones.
sub
base
eq.
T
°C)
t
prod
(%)
recov
s. mat
(
(h)
(%)
1
0bu
KOtBu
1.5
1.8
1.1
rt
rt
0
0
0
rt
rt
0
“
1
2
0.5
0.25
1
0.5
1
0.25
0.25
0.17
26 (13)
(25)
26 (24)
(29)
26 (41)
27 (34)
(67)
27 (33)
(22)
43
40
32
25
10
-
-
-
-
-
10bu
PhLi
1.2
1
1
0bu
1bu
n-BuLi
KOtBu
1.2
1.5
1.7
11bu
PhLi
1.1
1.2
1.6
“
(14)
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1
1bu
n-BuLi
1.1
“
“
“
“
“
“
“
“
rt
rt
rt
0
0
rt
66
rt
0
0
0
rt
rt
0
0
1
“
“
“
“
“
“
“
3
5
0.5
0.25
0.75
1
“
27 (<1)
(27)
(33)
dec
27 (9)
(21)
(47)
27 (52)
-
55
31
21
-
45
41
33
11
79
83
-
1.5
1.8
2.2
11bu
LDA
1.0
1
1
.2
.5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1bu LiHMDS 1.5
1bu
1bu
KH
NaH
2.0
2.0
1.6
1.2
1.3
1.5
-
11thp KOtBu
dec
dec
dec
28 (9)
(11)
(18)
28 (64)
28 (11)
(44)
-
11thp
PhLi
n-BuLi
KOtBu
-
-
11hp
12bu
42
32
37
24
31
15
77
81
1
2
.5
.0
“
0.25
1
“
3
12bu
PhLi
n-BuLi
1.1
1.2
12bu
1.5
12bu
12bu
13bu
NaH
CsOH
PhLi
2.6
2.5
1.2
1.2
3
-
-
-
a
74
13bu
n-BuLi
76a
a. Some decomp observed
Table 7 compares cyclizations of three different secondary peroxides on a common sulfone
framework. All attempts to achieve closure from the triethylsilyl peroxide (16si) were
unsuccessful, invariably generating the corresponding alcohol (30). Reaction of the
monoperoxyacetal (16thp) generated a complex mixture of products. The dialkyl peroxide
(
16me) underwent successful cyclization in the presence of a number of bases, but yields were
generally modest or poor. The reactions generated inseparable mixtures of diastereomers, with
the same major product generated from reaction with KOtBu (69:31) and PhLi (80:20).
Changing the solvent had limited impact on reaction yield.
Table 7. Influence of peroxide electrophile
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
subs
base
eq.
T
t
h)
Prod
(% yield)
(
1
1
6si
6si
KOtBu
n-BuLi
LDA
1.5
1.2
1.5
1.5
1.5
1.2
1.2
1.5
1.3
1.3
1.4
1.0
rt
0°C
0
rt
rt
0°C
rt
“
“
“
0.5 30 (98)
0.5 30 (97)
1
“
0.5 decomp
0.5 decomp
1
“
16si
6si
30 (94)
30 (71)
1
KDA
16thp KOtBu
16thp
n-BuLi
KOtBu
"
16me
29 (13)
29 (33)
29 (9)
29 (7)
29 (10)
CH CN
“
“
“
3
DMSO
DMF
PhLi
“
16me
0°C
0°C
0.5 29 (18)
“
“
1
1
.1
.3
29 (19)
29 (21)
1
6me
6me
n-BuLi
1.0
.2
0°C
0°C
0°C
0°C
rt
0.5 29 (10)
0.5 29 (37)
1
2
18
18
1
1
LDA
KDA
KH
1.5
1.2
2.0
2.0
29 (48)
decomp
nr
16me
1
1
6me
6me
NaH
rt
nr
The reduction in yields seen at increased base stoichiometry led us to investigate the stability of
alkoxysulfones 27 and 29 to typical cyclization conditions (Table 8). Both were rapidly degraded
by phenyl lithium, which had proved effective as a base (Tables 6 and 7); 29 was recovered in
good yield following treatment with excess KOtBu.
Table 8. Stability of sulfonyl ether products.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
subs
base (equiv)
PhLi (1.3)
KOtBu(1.5)
PhLi (1.3)
T
0 °C
rt
yield
32%
85%
39%
2
2
7
9
“
0 °C
Discussion:
Nitriles and sulfones are capable of a rich suite of transformations, including generation and
functionalization of adjacent carbanions and used as precursors to other functional groups,
radicals, and hydrocarbons.6, 21,22,23 -Alkoxy nitriles and -Alkoxysulfones are both versatile
classes of synthetic intermediates.9, 24, 25 26 Cyanoethers have also been used as components in
fluorescent probes 27 and the core of a class of anti-viral nucleoside analogs.28
Nitrile and sulfone stabilized anions have been applied to intermolecular reactions with a variety
of heteroatom electrophiles, including some activated peroxides.8, 29,30 Our results demonstrate
that this class of anions undergoes intramolecular reaction with peroxides to generate
31
32
33
functionalized oxetanes, tetrahydrofurans, and tetrahydropyrans. However, as discussed
in the following paragraphs, yields vary greatly depending upon substrates and conditions.
Nature of the peroxide: Subject to limitations discussed below in relation to peroxide
decomposition, the reactions show no obvious dependence upon the nature of the peroxide. For
example, ring closures involving the benzylic nitrile were rapid and high-yielding for nearly all
peroxides tested, including one in which the electrophilic oxygen is effectively neopentyl. This is
a significant departure from reactions with highly reactive organometallics such as n-BuLi or
PhMgX, where reactivity of monoperoxyacetals > dialkyl peroxides >> alkyl trialkylsilyl
14
peroxides. However, the limited influence of the nature of the peroxide is consistent with the
successful reaction of dialkyl peroxide intermediates during nucleophilic epoxidations and in
cyclizations of peroxide-substituted ketone enolates.5,10-12
Peroxide stability. The rate of peroxide decomposition appears to play a major factor in the
success or failure of the cyclizations. Base-promoted Kornblum fragmentation, an often
exothermic analog of the E cb or E reactions involving elimination across a H-C-O-O unit of
1
2
20
peroxides, requires a C–H bond alpha to the peroxide. The Kornblum reaction is also favored
by a basic medium and/or activation of the peroxides by a conjugated electron-withdrawing
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
group.34 In our experience, dialkyl peroxides and monoperoxyacetals are often relatively stable
14
towards fragmentation. In the current work, Kornblum fragmentation products were never
observed in reactions of involving derivatives of benzyl nitrile (pKa ~22) but were observed for
the more basic anions derived from the alkyl nitrile (pKa ~ 32); a similar phenomenon is
discussed below for the phenylsulfones. The observation of moderate yields from a reaction of a
silyl/tertiary alkyl peroxide (2si, see Table 5) may reflect in part the inability of this substrate to
enter into Kornblum fragmentation. The corresponding reactions of alkyl nitriles were successful
in at least some cases for both dialkyl peroxides and triethylsilyl peroxides. Cyclizations
involving a sulfone-stabilized anion were successful only for dialkyl peroxides; as discussed
below, the failure to successfully cyclize onto silyl peroxides or monoperoxyacetals may reflect
less on the rate of cyclization than on the rate of peroxide decomposition. The formation of
alcohol during reactions of some triethylsilyl peroxides with anions derived from an alkyl nitrile or
phenylsulfones (pKa ~ 29) makes clear that a different class of fragmentation is open for these
substrates. We note that analogous products have been reported from reactions of
organometallics with a hindered alkyl silyl peroxide.14
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Nucleophile reactivity and basicity: Cycloalkylation of nitriles bearing -halo or sulfonate groups
has been shown to generate good yields of 4-, 5-, and 6-membered rings.15 There are fewer
35
reports describing comparable cyclizations of sulfones, but 3-exo attack of sulfone-stabilized
3
36
carbanions on sp C-Cl or C-Br linkage to form cyclopropanes is known. While there is
obvious risk in evaluating the reaction of carbanions and peroxides using scales developed for
carbon electrophiles, it is clear that the anions derived from benzylic nitriles are strong and
highly polarizable nucleophiles,3
7,38
whereas the anions derived from alkyl nitriles and alkyl
sulfones are more localized and more basic.39 However, the superior yields obtained with the
benzyl nitriles may also reflect their greater acidity, which results in a less basic reaction
medium and a higher effective concentration of nucleophile. Cyclizations of alkyl nitriles were
successful in the presence of bases (n-BuLi, PhLi, LDA) capable of rapidly generating
significant concentrations of the nitrile-stabilized carbanions; KOtBu, one of the most effective
bases with the benzyl nitriles, generated a mixture of recovered starting material and
decomposition byproducts. Cyclizations of sulfones were successful with multiple bases, with
some of the best yields coming from KOtBu; however, this may relate to the stability of the
sulfone products in the presence of this base.
During reactions of the benzyl nitriles, we observed successful cyclization in the presence of
different counterions (Table 2, Li, Na, or K), but no major differences in diastereoselection. This
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is in contrast to reports describing base-dependent diastereoselection of carbocyclizations
39
involving nitrile-stabilized anions. Attempts to achieve cyclizations of sulfone-stabilized
carbanions onto secondary alkyl silyl peroxides were unsuccessful regardless of base. The role
of the counterion remains to some degree a mystery. In our earlier work with ketones,
potassium enolates were found to be far more active than the corresponding sodium or lithium
species. However, for some substrates (e.g., the cyclization of 10si) all bases work well and
there is almost no difference between KH or NaH. For other substrates, for example
peroxyacetal 4thp, KOtBu is far more effective than either LDA or n-BuLi. Comparison of
diastereoselection within a common framework (Table 2), makes clear that the nature of the
base and counterion, while less impactful than the nature of the peroxide leaving group (Table
4), does have a discernible influence.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Steric influences: For the reactions of benzylic nitriles, the degree of substitution adjacent to the
electrophilic oxygen has little influence on either reactivity or yields. In the alkyl nitrile series,
superior yields were observed with a tertiary peroxide, perhaps as a consequence of removing a
pathway for Kornblum fragmentation. Within the sulfone series, somewhat better yields were
observed for reaction at a primary vs. secondary oxygen, although this may have also reflected
different stabilities towards fragmentation.
Ring size: Cyclizations of peroxide-substituted benzyl nitriles successfully generated four- to six-
membered oxacycles, with yields decreasing 5>4>6 (Table 9). Yields for cyclizations involving
sulfone-stabilized anions with dialkyl peroxides followed a trend of 5 ~ 6 > 4; different bases
were optimal in each case. Cyclizations to form seven-membered rings were not successful in
either series, again consistent with results from ketone enolates.5
Table 9. Relative yields of ring closures in nitrile and sulfones
EWG
CN
CN
CN
CN
n
1
2
3
4
1
2
3
R
R1
X
base yield
Me Ph SiEt3 KOtBu 58%
Me Ph SiEt3 KOtBu 95%
Me Ph SiEt3 KOtBu 37%
Me Ph SiEt3 KOtBu nr
H
H
H
SO Ph
H
H
H
t-Bu n-BuLi 41%
t-Bu KOtBu 67%
t-Bu
2
SO Ph
2
SO Ph
PhLi
64%
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
SO Ph
4
H
H
t-Bu
PhLi
nr
2
Stability of the reaction products: Evaluation of the relative efficiency of cyclization in the sulfone
series is complicated by decomposition of the products in the presence of an organolithium
2
6
reagent, an unreported variant of a known transformation. The only example of similar
decomposition in the nitrile series (equation 4) involves the use of a strong nucleophile (n-BuLi)
under conditions in which intermolecular attack by the reagent appears to compete with
deprotonation of the substrate.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mechanism: Several pathways can be envisaged for intramolecular reactions of peroxides with
carbanions (Figure 2). Early work on cleavage of a series of dialkyl peroxides with
14
organometallics displayed trends consistent with S 2-type pathways, and the 3-exo closure of
N
3-peroxy-2-enols/enolates during nucleophilic epoxidation has been described as a low-barrier
40
substitution. However, a direct displacement is not consistent with the high yields observed for
attack of a nitrile-stabilized anion on the isobutyl and neopentyl-like oxygen atoms of secondary
and tertiary peroxides. Reactions of organometallic reagents with peroxides have often been
interpreted in terms of intermediate alkoxy radicals derived through single-electron transfer
(SET).41 Earlier work in our lab on intermolecular reactions of organolithium and -magnesium
reagents with dialkyl and alkyl silyl peroxides incorporating alkoxy radical “clocks” gave some
evidence for SET processes; whereas reactions of more reactive THP monoperoxyacetals
appeared to involve direct insertion.14
Figure 2. Possible mechanisms/intermediates
Our results, and in particular, the observation of peroxide-dependent diastereoselection,
suggests the possibility of multiple mechanisms. Although the data on conformational
42
preferences in 2,2,5-trisubstituted tetrahydrofurans is limited, there is evidence that the major
diastereomer observed in our reactions is also the thermodynamically favored product, placing
the C -methyl group trans to the C -phenyl and cis to the C nitrile. The contrast between the
5
2
2
moderate diastereoselection observed during cyclizations of triethylsilyl peroxides and the
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minimal diastereoselection observed during reactions of the more reactive acetals or
peroxyanions, may support reactions of the silyl peroxides via SET and a product-like diradical
intermediate, whereas the more reactive peroxyanion and peroxyacetal substrates might react
14,43
through an early transition state involving an S 2 or insertion (Figure 3).
Similar levels of
N
diastereoselection were observed in the sulfone series, but we were not able to assign the
relative stereochemistry.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Possible intermediates and products
Dampening effect of peroxide: We were surprised by the unexpectedly low intermolecular
reactivity of electrophiles attached to a peroxide-containing alkyl chain. For example, 4-
iodoalkyl t-butyl peroxide, a substrate we had employed in tandem C-C/C-O bond-forming
5
reaction, is poorly reactive towards a deprotonated nitrile and fails to react with lithiated phenyl
methyl sulfone. The reduced rate of nucleophilic substitution on carbons adjacent to sigma
44
electron-withdrawing groups is well-known (e.g. trifluoroethyl); however we are unaware when
this effect has been observed across a three- or four-methylene span.
Conclusion:
Intramolecular reactions of peroxides with nitrile- and sulfone-stabilized carbanions offer a new
approach to a range of functionalized oxacycles, including oxetanes, tetrahydrofurans, and
tetrahydropyrans. The cyclizations, which can be conducted using several different classes of
peroxide, enable synthesis of secondary or tertiary ether linkages. Key factors in the success of
the reaction are the basicity of the reagents required and the propensity of the peroxide towards
decomposition. The nature of the substituent on the departing peroxide oxygen also appears to
strongly influence the reaction mechanism.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Experimental:
General Methods: All reagents and solvents were used as purchased except for DMF, which was
distilled from CaH at reduced pressure, and THF, which was distilled from Na/benzophenone.
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Except as noted, all reactions were conducted under an atmosphere of N in flame-dried
2
glassware. Thin layer chromatography (TLC) was performed on 0.25 mm hard-layer silica plates
visualized with a UV lamp or by developing with one of the following dips: 2.5% ammonium
molybdate and 0.5% ceric sulfate in 10% aqueous sulfuric acid (general stain, after heating); 1%
potassium permanganate in water (general stain, heating sometimes required); 1% N,N-dimethyl-
p-phenylenediamine in 1:20:100 acetic acid/ water/ methanol (hydroperoxides give a color change
45
upon contact; other peroxides can be visualized after heating); or a solution composed of 3 g of
vanillin and 3 mL sulfuric acid in 97 mL ethanol (general stain requiring heating). Unless otherwise
described, column chromatography refers to flash column chromatography on silica gel. Unless
1
13
noted, H NMR and C NMR spectra were acquired in CDCl . Chemical shifts are reported
3
1
relative to residual chloroform (7.26/77.16 ppm). H spectra are reported as chemical shift
(multiplicity, J couplings in, number of protons). IR spectra were recorded as neat films on a ZrSe
-1
crystal; selected absorbances are reported in cm . High resolution mass spectra (HRMS) were
obtained at the Nebraska Center for Mass Spectrometry at UNL. Melting points are uncorrected.
Abbreviations: hexane = Hex; THF = tetrahydrofuran; EtOH = ethanol; DCM = dichloromethane;
EA = ethyl acetate; n-BuLi = n-butyl lithium; KOtBu = potassium tert-butoxide; LDA = lithium
diisopropyl amide; LHMDS = lithium hexamethyldisilazide; TBAF = tetra-n-butylammonium
fluoride; sat = saturated.
Preparation of LDA (example: actual scale varies): To a solution of diisopropylamine (5.90 mL,
42.1 mmol, 1.0 equiv) in THF 100 mL was added n-BuLi (26.0 mL, 41.6 mmol, 1.0 equiv, 1.6 M
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in hexanes) at -78 °C. The resulting solution, nominally, 0.33 M in LDA was stirred for 30 min at
-78 °C and immediately used.
Nitrile alkylation was based upon an adaptation of a reported procedure.15a To a solution of
benzyl cyanide (4.0 mL, 35 mmol) in THF (50 mL) was added freshly prepared LDA (42 mmol,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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1.2 equiv), followed by bromoalkene (41.6 mmol, 1.2 equiv). After stirring for 1 h, the reaction
was quenched with sat. aq. NH Cl (50 mL) and the resulting mixture extracted with DCM (50 mL
4
x 3). The combined organic layers were dried with Na SO and concentrated under reduced
2
4
pressure. The residue was purified by column chromatography (typically 5% EA/Hex).
2-(But-3-en-1-yl)octanenitrile (1) was prepared as a yellow-orange oil (4.52 g, 97%) from
octanenitrile (4.0 mL, 25.9 mmol) and 4-bromobutene (3.17 mL, 31.2 mmol, 1.2 equiv) using the
1
nitrile alkylation procedure described above: R = 0.53 (10% EA/Hex); H (400 MHz) δ 5.77
f
(dddd, J = 6.6, 10.1, 13.3, 16.7, 1H), 5.09 (d, J = 17.1, 1H), 5.04 (d, J = 11.0, 1H), 2.54 (ddd, J =
4.9, 9.3, 14.0, 1H), 2.31 (m, 1H), 2.19 (m, 1H), 1.50-1.68 (4H), 1.21-1.38 (8H), 0.89 (t, J = 6.6,
13
1
3H); C{ H} (100 MHz) δ 136.6, 122.3, 116.4, 32.3, 31.6, 31.5, 31.3, 31.1, 28.9, 2.2, 22.6, 14.1;
-1
+
IR: 2928, 2859, 2237, 1642, 1456, 1379, 994, 914, 724, 647, 554 cm ; HRMS (ESI , TOF)
+
calcd for C H NNa (M + Na) : 202.1572; found: 202.1575.
12
21
2-(3-Methylbut-3-en-1-yl)octanenitrile (2) was prepared as a light yellow/orange oil (4.63 g,
92%) from octanenitrile (4.0 mL, 26.0 mmol) and 4-iodo-2-methylbutene (5.61 g, 28.6 mmol, 1.1
1
equiv) using the general procedure described above: R = 0.55 (10% EA/Hex); H (400 MHz) δ
f
4.78 (s, 1H), 4.73 (s, 1H), 2.52 (ddd, J = 5.2, 9.0, 14.1, 1H), 2.18 (m, 2H), 1.73 (s, 3H), 1.49-
13
1
1
.64 (4H), 1.24-1.38 (8H), 0.89 (t, J = 7.0, 3H); C{ H} (100 MHz) δ 143.7, 122.2, 111.3, 35.1,
32.2, 31.5, 31.1, 30.3, 28.8, 27.1, 22.5, 22.2, 14.0; IR: 2928, 2858, 2238, 1650, 1456, 1377,
-1
+
+
889, 724 cm ; HRMS (ESI , TOF) calcd for C H NNa (M + Na) : 216.1728; found: 216.1733.
13
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2
-Phenylpent-4-enenitrile (3) was prepared (5.35 g, 98%) from 3-bromo-1-propene (41.6
mmol, 5.03 g) by the procedure described above. Spectral details matched those previously
46
1
reported: R = 0.45 (10% EA/Hex); H (400 MHz) δ 7.29-7.42 (m, 5H), 5.83 (m, 1H), 5.23 (m,
f
0
1
2
3
4
5
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7
8
9
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13
1
1H), 5.20 (m, 1H), 3.86 (t, J = 7.2, 1H), 2.67 (m, 2H); C{ H} (100 MHz) δ 135.3, 132.7, 129.2,
128.3, 127.5, 120.4, 119.5, 40.0, 37.7.
2-Phenylhex-5-enenitrile (4) was prepared (5.74 g, 97%) from 4-bromo-1-butene (41.6 mmol,
.62 g) by the procedure described above. Spectral details matched those previously reported:47
5
1
R = 0.46 (10% EA/Hex); H (400 MHz ) δ 7.31-7.41 (m, 5H), 5.78 (ddt, J = 6.7, 10.2, 17.0, 1H),
f
3
13
1
5.09 (m, 2H), 3.81 (dd, J = 6.3, 8.6, 1H), 2.25 (q, J = 7.1, 2H), 2.00 (m, 2H); C{ H} (100 MHz) δ
136.1, 135.8, 129.1, 128.1, 127.3, 120.7, 116.7, 36.5, 34.9, 30.9
2-Phenylhept-6-enenitrile (5) was prepared (6.28 g, 98%) from 5-bromo-1-pentene (41.6
1
mmol, 6.20 g) by the procedure described above: R = 0.48 (10% EA/Hex); H (400 MHz) δ
f
7.30-7.40 (m, 5H), 5.78 (m, 1H), 5.02 (m, 2H), 3.78 (dd, J = 6.4, 8.4, 1H), 2.13 (app q, J = 7.2,
13
1
2H), 1.93 (m, 2H), 1.61 (m, 2H); C{ H} (100 MHz) δ 137.7, 136.0, 129.2, 128.2, 127.3, 120.9,
115.6, 37.4, 35.3, 33.0, 26.2; IR: 3065, 2930, 2861, 2239, 1640, 1495, 1455, 994, 911, 755,
-1
+
+
698, 519 cm ; HRMS (ESI , TOF) calcd for C H NNa (M + Na) : 208.1102; found: 208.1102.
13
15
2-Phenyloct-7-enenitrile (6) was prepared (6.64 g, 96%) from 6-bromo-1-hexene (41.6 mmol,
1
6.78 g) by the procedure described above: R = 0.49 (10% EA/Hex); H (400 MHz) δ 7.30-7.40
f
(m, 5H), 5.80 (m, 1H), 4.89-5.02 (m, 2H), 3.77 (dd, J = 6.4, 8.4, 1H), 2.08 (app q, J = 6.7, 2H),
13
1
1.93 (m, 2H), 1.27-1.59 (4H); C{ H} (100 MHz) δ 138.4, 136.1, 129.2, 128.1, 127.3, 121.0,
115.0, 37.5, 35.9, 33.5, 28.3, 26.6; IR: 3065, 2930, 2861, 2239, 1640, 1495, 994, 911, 755, 698,
+
+
519; HRMS (ESI , TOF) calcd for C H NNa (M + Na) : 222.1259; found: 222.1266.
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-Methyl-2-phenylhex-5-enenitrile (7) was prepared as a light yellow oil (6.30 g, 98%) from
benzyl cyanide (4.0 mL, 34.7 mmol) and 1-bromo-3-methyl-2-butene (38.1 mmol, 1.1 equiv)
1
using the general procedure for alkylation: R = 0.50 (10% EA/Hex); H (400 MHz) δ 7.29-7.41
f
1
1
1
1
1
1
1
1
1
1
2
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(m, 5H), 5.21 (t, J= 7.4, 1H), 3.79 (t, J = 7.1, 1H), 2.64 (m, 2H), 1.75 (s, 3H), 1.69 (s, 3H);
13
1
C{ H} (100 MHz) δ 136.8, 135.8, 129.1, 128.1, 127.5, 120.9, 118.6, 38.0, 34.6, 25.9, 18.0; IR:
-1
+
2971, 2915, 2240, 1673, 1600, 1497, 1454, 1378, 844, 755, 697, 515 cm ; HRMS (ESI , TOF)
+
calcd for C H NNa (M + Na) : 208.1102; found 208.1104.
13
15
Reductive deoxygenation to form triethylsilylperoxides: The reductive dioxygenation of alkenes
to generate the corresponding triethylsilyl peroxides was adapted from reported procedures.13ab
To a solution of alkene (10.0 mmol) in EtOH (80 mL) was added triethylsilane (20.0 mmol, 2
equiv), followed by Co(acac) (1.0 mmol, 0.1 equiv). The reaction was stirred at room
2
temperature under O (1 atm, balloon) for 18 hrs. The reaction solution was concentrated under
2
reduced pressure and the residue purified by column chromatography (5% EA/Hex) to yield a
colorless oil.
2-(3-((Triethylsilyl)peroxy)butyl)octanenitrile (1si) was prepared as an inseparable 1:1
mixture of diastereomers (1.67 g, 41%) from nitrile 1 (2.22 g, 12.4 mmol) using the procedure
1
described above. The product was a colorless oil: R = 0.56 (10% EA/Hex); H (400 MHz) δ
f
4.03-4.11 (m, 2H), 2.51-2.62 (m, 2H), 1.51-1.76 (14H), 1.41-1.49 (m, 2H), 1.26-1.40 (m, 12H),
13
1
1.22-1.25 (m, 6H), 0.98-1.04 (m, 18H), 0.89-0.92 (m, 6H), 0.67-0.74 (m, 12H); C{ H} (100
MHz) δ 122.4, 122.3, 80.9, 80.2, 32.4, 32.3, 32.2, 32.0, 31.8, 31.7, 28.9, 28.7, 27.9, 27.2, 22.6,
-
1
18.6, 18.4, 14.1, 6.9, 3.9; IR: 2955, 2931, 2876, 2237, 1459, 1377, 1239, 1006, 795, 727 cm ;
+
+
HRMS (ESI , TOF) calcd for C H NNaO Si (M + Na) : 350.2491; found: 350.2495.
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-(3-Methyl-3-((triethylsilyl)peroxy)butyl)octanenitrile (2si) was prepared as a colorless oil
(1.05 g, 30%) from nitrile 2 (2.0 g, 10 mmol) using the reductive dioxygenation procedure
1
described above: R = 0.57 (10% EA/Hex); H (400 MHz) δ 2.52 (m, 1H), 1.59-1.70 (m, 4H),
f
1
6
2
.51-.159 (m, 2H), 1.23-1.38 (8H), 1.19 (s, 3H), 1.17 (s, 3H), 0.98 (t, J = 7.9, 9H), 0.89 (t, J =
0
1
2
3
4
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7
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9
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8
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8
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3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
13
.9, 3H), 0.66 (q, J = 7.9, 6H); C (100 MHz) δ 122.6, 81.6, 36.1, 32.4, 32.0, 31.7, 28.9, 27.2,
6.8, 24.8, 24.2, 22.6, 14.1, 6.9, 4.0; IR: 2955, 2932, 2876, 2237, 1458, 1413, 1379, 1364,
-1
+
+
1239, 1006, 855, 804, 728 cm ; HRMS (ESI , TOF) calcd for C H NNaO Si (M + Na) :
19
39
2
364.2648; found: 364.2654.
(
R,R* and R*,S*) 2-Phenyl-4-((triethylsilyl)peroxy)pentanenitrile (3si) was prepared as a
nearly inseparable 1:1 mixture of diastereomers (1.65 g, 35%) from 2-phenylpent-4-enenitrile (3,
5.4 mmol, 2.42 g) using the reductive dioxygenation procedure described above. The product
was a colorless oil: R = 0.58 (10% EA/Hex); IR: 2956, 2913, 2877, 2241, 1456, 1375, 1239,
1
f
-1
+
+
1005, 823, 793, 730, 697 cm ; HRMS (ESI , TOF) calcd for C H NNaO Si (M + Na) :
17 27 2
328.1709; found 328.1711. Individual peak assignments are based upon the isolation of a very
small quantity of one diastereomer in pure form.
1
Diastereomer 1: H (400 MHz) δ 7.37 (d, J = 6.5, 2H), 7.34 (t, J = 6.9, 2H), 7.32 (t, J = 6.9, 1H),
4
1
1
.02 (t, J = 6.8, 1H), 3.96 (m, 1H), 2.44 (ddd, J = 6.7, 7.5, 14.2, 2H), 1.98 (ddd, J =4.8, 8.6, 13.5,
13
1
H), 1.24 (d, J = 6.3, 3H), 1.00 (t, J = 8.0, 9H), 0.71 (q, J = 8.1, 6H) C{ H} (100 MHz) δ 135.7,
29.2, 128.3, 127.8, 121.4, 78.5, 40.2, 33.2, 18.4, 6.8, 3.9.
1
Diastereomer 2: H (400 MHz) δ 7.41 (d, J = 7.7, 2H), 7.39 (t, J = 7.3, 2H), 7.35 (t, J = 7.4, 1H),
4.38 (m, 1H), 4.21 (dd, J = 4.6, 11.1, 1H), 2.17 (ddd, J = 4.7, 9.5, 14.3, 2H), 2.00 (ddd, J =4.5,
13
1
8.1, 13.6, 1H), 1.30 (d, J = 6.2, 3H), 1.04 (t, J = 8.0, 9H), 0.76 (q, J = 8.0, 6H); C{ H} (100
MHz) δ 136.3, 129.3, 128.1, 127.2, 120.9, 78.5, 41.9, 34.8, 18.4, 6.9, 3.9.
(R,R* and R*,S*) 2-Phenyl-5-((triethylsilyl)peroxy)hexanenitrile (4si) was prepared as an
inseparable 1:1 mixture of diastereomers (2.04 g, 47%) from nitrile 4 (13.6 mmol, 2.33 g) using
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the reductive dioxygenation procedure described above: R = 0.59 (10% EA/Hex); H (400 MHz)
f
δ 7.37-7.40 (m, 4H), 7.31-7.34 (m, 6H), 3.99-4.13 (m, 2H), 3.81-3.89 (m, 2H), 1.92-2.09 (m, 4H),
1
.63-1.81 (m, 4H), 1.20 (d, J = 6.1, 3H), 1.19 (d, J = 6.2, 3H), 0.96-1.00 (m, 18H), 0.65-0.70 (m,
13
1
1
2H); C{ H} (100 MHz) δ 135.9, 129.2, 128.2, 127.4, 120.9, 80.7, 80.2, 37.5, 37.3, 32.0, 31.9,
1
1
1
1
1
1
1
1
1
1
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2
2
2
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5
6
0
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9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1.7, 31.6, 18.6, 18.4, 6.9, 3.9; IR: 2956, 2877, 2241, 1495, 1455, 1413, 1375, 1239, 1005, 836,
-1
+
+
7
92, 729, 697 cm ; HRMS (ESI , TOF) calcd for C H NNaO Si (M + Na) : 342.1865; found
18 29 2
342.1866.
(
R,R* and R*,S*) 2-Phenyl-6-((triethylsilyl)peroxy)heptanenitrile (5si) was prepared as an
inseparable 1:1 mixture of diastereomers (1.68 g, 41%) from nitrile 5 (12.3 mmol, 2.28 g) using
1
the reductive dioxygenation procedure described above: R = 0.55 (10% EA/Hex); H (400 MHz)
f
δ 7.36-7.39 (m, 4H), 7.32-7.33 (m, 6H), 3.95-4.02 (m, 2H), 3.77-3.80 (m, 2H), 1.83-2.01 (m, 4H),
1
1
3
.39-1.70 (m, 8H), 1.18 (d, J = 6.0, 3H), 1.18 (d, J = 6.1, 3H), 0.95-0.99 (m, 18H), 0.64-0.70 (m
13
1
2H); C{ H} (100 MHz) δ 135.9, 129.2, 128.2, 127.3, 120.9, 81.2, 81.0, 37.4, 36.0, 35.9, 33.7,
3.3, 33.2, 23.1, 23.0, 18.4, 18.2, 6.9, 6.7, 5.9, 3.9; IR: 2954, 2912, 2876, 2240, 1495, 1456,
-1
+
1414, 1375, 1239, 1005, 826, 729, 698, 509 cm ; HRMS (ESI , TOF) calcd for C H NNaO Si
1
9
31
2
+
(M + Na) : 356.2022; found 356.2025.
(
R,R* and R*,S*) 2-Phenyl-7-((triethylsilyl)peroxy)octanenitrile (6si) was prepared as an
inseparable 1:1 mixture of diastereomers (872.9 mg, 42%) from nitrile 6 (5.99 mmol, 1.19 g)
1
using the reductive dioxygenation procedure described above: R = 0.57 (10% EA/Hex); H (400
f
MHz) δ 7.37-7.40 (m, 4H), 7.31-7.34 (m, 6H), 3.75-4.01 (m, 2H), 3.76-3.79 (m, 2H), 1.83-1.99
(
m, 4H), 1.46-1.66 (m, 4H), 1.33-1.46 (m, 8H), 1.18 (d, J = 6.1, 6H), 0.97-1.01 (m, 18H), 0.65-
13
1
0
.71 (m, 12H); C{ H} (100 MHz) δ 136.0, 129.2, 128.1, 127.3, 121.0, 81.2, 81.2, 37.5, 35.9,
34.1, 34.1, 27.2, 24.9, 24.9, 6.9, 6.7, 5.9, 3.9; IR: 2952, 2876, 2240, 1494, 1456, 1413, 1374,
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5
5
5
5
5
5
6
-1
+
1
239, 1005, 832, 794, 728, 698, 509 cm ; HRMS (ESI , TOF) calcd for C H NNaO Si (M +
20 33 2
+
Na) : 370.2178; found: 370.2180.
5
-Methyl-2-phenyl-5-((triethylsilyl)peroxy)hexanenitrile (7si) was prepared as a colorless oil
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
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7
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9
0
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2
3
4
5
6
7
8
9
0
(
1.24 g, 36%) from nitrile 7 (1.91 g, 10.3 mmol) using the general procedure for reductive
1
deoxygenation described earlier: R = 0.63 (10% EA/Hex); H (400 MHz) δ 7.30-7.40 (m, 5H),
f
3.82 (t, J = 7.3, 1H), 1.94-2.00 (m, 2H), 1.71-1.75 (m, 2H), 1.18 (s, 3H), 1.15 (s, 3H), 0.97 (t, J =
13
1
7.9, 9H), 0.65 (q, J = 7.9, 6H); C{ H} (100 MHz) δ 136.2, 129.1, 128.1, 127.4, 121.1, 81.6,
3
7.7, 35.9, 30.5, 24.8, 24.3, 6.9, 4.0; IR: 2956, 2876, 2241, 1739, 1495, 1455, 1412, 1364,
-1
+
1
239, 1046, 1006, 856, 802, 730, 697, 525 cm ; HRMS (ESI , TOF) calcd for C H NNaO Si
19
31
2
+
(M + Na) : 356.2022; found: 356.2026.
(
R,R* and R*,S*) 5-Hydroperoxy-2-phenylhexanenitrile (4h) was prepared using an
adaptation of reported procedures.48 To a solution of alkene 4si (896.2 mg, 2.8 mmol) in THF
40 mL) was added TBAF (3.4 mL, 3.4 mmol, 1.2 equiv, nominally 1.0 M in THF). The reaction
(
was stirred at room temperature for 10 min. The reaction was diluted with water (15 mL) and
extracted with EA (20 mL x 3). The combined organic layers were dried with Na SO and
2
4
filtered. The residue obtained after concentration under reduced pressure and purified by
column chromatography (10% EA/Hex) to yield 505.6 mg (88%) of hydroperoxide 4h as a
colorless oil; the product was formed as an inseparable 1:1 mixture of diastereomers: R = 0.20
f
1
(
20% EA/Hex); H (400 MHz) δ 8.27 (s, 2H), 7.32-7.40 (m, 10H), 4.06-4.15 (m, 2H), 3.81-3.87
(
m, 2H), 1.93-2.07 (m, 2H), 1.65-1.82 (m, 2H), 1.23 (d, J = 6.2, 3H), 1.22 (d, J = 6.3, 3H);
13
1
C{ H} (100 MHz) δ 135.7, 135.7, 129.3, 128.3, 127.4, 127.4, 80.8, 80.4, 37.5, 37.2, 31.9, 31.5,
3
1.5, 31.3, 18.3, 18.2; IR: 3376, 2977, 2935, 2243, 1492, 1455, 1375, 1185, 1095, 1057, 915,
-1
+
+
761, 743, 698 cm ; HRMS (ESI , TOF) calcd for C H NNaO (M + Na) : 228.1000; found:
12
15
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228.1004.
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(
R,R* and R*,S*) 2-Phenyl-5-(tetrahydro-2H-pyran-2-yl)peroxy hexanenitrile (4thp): The
conversion of the hydroperoxide to the tetrahydropyranyl peroxyacetal employed a reported
14
procedure. To hydroperoxide 4h (768.4 mg, 3.74 mmol) was added dihydropyran (0.35 mL,
1
1
1
1
1
1
1
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0
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0
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7
8
9
0
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.16 mmol, 1.1 equiv), followed by a solution of 10% H SO in THF (0.1 mL). The reaction was
2
4
stirred at room temperature for 18 h. The reaction was diluted with EA (30 mL) and the organic
layer was extracted with water (25 mL x 3). The dried organic layer (Na SO ) was concentrated
2
4
under reduced pressure and the residue purified by column chromatography (10-20% EA/Hex)
to yield 802.9 mg (74%) of the tetrahydropyranyl peroxyacetal as a light orange oil as an
1
inseparable 1 : 1.14 mixture of diastereomers: R = 0.33 (20% EA/Hex); H (400 MHz) δ 7.30-
f
7
.39 (10H), 5.11 (m, 1H), 5.06 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.96 (m, 2H), 3.84 (m, 2H),
13
1
3
.60 (m, 2H), 1.97-2.08 (m, 4H), 1.65-1.83 (8H), 1.46-1.63 (8H), 1.21-1.25 (6H); C{ H} (100
MHz) δ 135.9, 129.2, 128.2, 127.4, 120.9, 101.4, 101.0, 79.8, 79.1, 62.8, 37.5, 37.4, 37.2, 36.9,
3
2.1, 32.0, 31.9, 31.8, 31.7, 31.6, 31.5, 28.0, 25.2, 19.9; IR: 2955,2925, 2877, 2243, 1496,
-1
+
1
454, 1202, 1131, 1105, 1078, 996, 969, 904, 874, 814, 738, 698, 430 cm ; HRMS (ESI , TOF)
+
calcd for C H NNaO (M + Na) : 312.1576; found: 312.1578.
17
23
3
2
-(3-Chloropropyl)octanenitrile (9) was prepared using a modification of a reported
49
procedure. To a solution of octanenitrile (3.0 mL, 19.5 mmol) in THF (20 mL) was added a
freshly prepared solution of LDA in THF (23.6 mmol, 1.2 equiv; prepared as described earlier),
followed by 1-bromo-3-chloropropane (2.3 mL, 23.3 mmol, 1.2 equiv). The reaction was stirred
at room temperature for 1 h. The reaction was quenched with sat. aq. NH Cl (50 mL) and
4
extracted with DCM (60 mL X 3). The combined organic layers were dried with Na SO and the
2
4
residue concentrated under reduced pressure to yield 3.86 g (98%) of the chloroalkyl nitrile as a
1
yellow oil: R = 0.52 (10% EA/Hex); H (400 MHz) δ 3.58 (t, J = 6.4, 2H), 2.57 (m, 1H), 2.04 (m,
f
1H), 1.91 (m, 1H), 1.77 (m, 2H), 1.59 (m, 2H), 1.45 (m, 2H), 1.23-1.38 (6H), 0.89 (t, J = 6.8, 3H);
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13
1
C{ H} (100 MHz) δ 121.9, 44.2, 32.4, 31.6, 31.2, 30.0, 29.7, 28.8, 27.2, 22.6, 14.1; IR: 2955,
-1
+
2928, 2858, 2237, 1459, 1379, 1308, 725, 654 cm ; HRMS (ESI , TOF) calcd for C H ClNNa
11 20
+
(M + Na) : 224.1182; found: 224.1182.
0
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9
0
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0
2
-(3-(tert-Butylperoxy)propyl)octanenitrile (9bu) was prepared via the intermediate iodide. 50
To a solution of 2-(3-chloropropyl)octanenitrile (3.81 g, 18.9 mmol) in acetone (150 mL) was
added sodium iodide (15.58 g, 104.0 mmol, 5.5 equiv); the reaction was held at reflux for 18 h.
The cooled reaction was then diluted with water (50 mL) and extracted with hexanes (50 mL X
3). The combined organic layers were dried with Na SO and the residue concentrated under
2 4
reduced pressure to yield 5.22 g (94%) of 2-(3-iodopropyl)octanenitrile (9i) as a yellow/orange
1
oil which was used without purification: R = 0.53 (10% EA/Hex); H (400 MHz) δ 3.23 (t, J = 6.6,
f
2
3
2
H), 2.57 (m, 1H), 2.07 (m, 1H), 1.96 (m, 1H), 1.50-1.79 (4H), 1.23-1.40 (8H), 0.91 (t, J = 6.3,
13
1
H); C{ H} (100 MHz) δ 121.9, 33.1, 32.3, 31.6, 30.9, 30.7, 28.8, 27.2, 22.6, 14.1, 5.2; IR:
-1
+
927, 2857, 2236, 1457, 1378, 1291, 1223, 1174, 724, 505 cm ; HRMS (ESI , TOF) calcd for
+
C H INNa (M + Na) : 316.0538; found: 316.0539.
11 20
The conversion of the iodide to peroxide 9bu was based upon reported procedures.5, 51 To a
solution of CsOH monohydrate (2.18 g, 14.7 mmol, 1.2 equiv) in DMF (125 mL) at 0 °C was
added dropwise tert-butyl hydroperoxide (3.33 mL, 18.3 mmol, 1.5 equiv, nominally 5.5 M in
decane). After the solution had stirred for 30 min, 2-(3-iodopropyl)octanenitrile (3.58 g, 12.2
mmol) was added. The reaction was allowed to slowly warm to room temperature. After 5 h, the
reaction was quenched with water (50 mL) and extracted with hexanes (50 mL X 3). The
combined organic layers were dried with Na SO , concentrated under reduced pressure and the
2
4
residue purified by column chromatography (5% EA/Hex) pressure to yield 1.68 g (54%) of
1
peroxide 9bu as a colorless oil: R = 0.55 (10% EA/Hex); H (400 MHz) δ 3.96 (m, 2H), 2.55 (m,
f
13
1
1H), 1.62-1.78 (4H), 1.47-1.60, 4H), 1.25-1.36 (6H), 1.23 (s, 9H), 0.88 (t, J = 6.6, 3H); C{ H}
(100 MHz) δ 122.3, 80.4, 74.1, 32.4, 31.7, 31.6, 29.4, 28.9, 27.2, 26.4, 25.9, 22.6, 14.1; IR:
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929, 2860, 2237, 1458, 1385, 1362, 1242, 1196, 1059, 1023, 878, 756, 724, 546 cm ; HRMS
+
+
(ESI , TOF) calcd for C H NNaO (M + Na) : 278.2096: found; 278.2099.
15 29 2
Syntheses of [(chloroalkyl)thio]benzenes was based upon a modification of a reported
1
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0
52
procedure. To a solution of thiophenol (4.69 mL, 46 mmol) in DMF (100 mL) was added K CO
2
3
(
8.29 g, 60 mmol, 1.3 equiv), followed by the 1,n-bromochloroalkane (46 mmol). The reaction
was stirred at room temperature for 1 h and then diluted with water (30 mL). The combined
hexane extracts (3 x 25 mL) were dried with Na SO and the residue concentrated under
2
4
reduced pressure to yield a colorless oil which was used without further purification.
3-Chloropropyl-phenyl sulfide (10a) was prepared (8.40 g, 98%) from 1-bromo-3-
chloropropane (4.55 mL, 46.0 mmol) using the general procedure described above. Spectral
53
1
details matched those previously reported: R = 0.66 (10% EA/Hex); H (400 MHz) δ 7.39 (d, J
f
=
2
7.1, 2H), 7.33 (t, J = 7.4, 2H) 7.23 (t, J = 7.3, 1H), 3.70 (t, J = 6.3, 2H), 3.11 (t, J = 7.0, 2H),
13
1
.10 (p, J = 6.6, 2H); C{ H} (100 MHz) δ 135.7, 129.6, 129.0, 126.3, 43.4, 31.7, 30.8.
4-Chlorobutyl-phenyl sulfide (11a) was prepared (9.03 g, 98%) from 1-bromo-4-chlorobutane
5.30 mL, 46.0 mmol) using the procedure described above. Spectral details matched those
(
52
1
previously reported. R = 0.65 (10% EA/Hex); H (400 MHz) δ 7.36 (d, J = 7.8, 2H), 7.31 (t, J =
f
7
2
3
.4, 2H), 7.21 (t, J = 7.2, 1H), 3.57 (t, J = 6.5, 2H), 2.97 (t, J = 7.1, 2H), 1.95 (app tt, J = 6.3, 7.6,
13
1
H), 1.82 (app tt, J = 7.0, 7.6, 2H); C{ H} (100 MHz) δ 136.6, 129.7, 129.3, 126.4, 44.8, 33.4,
1.7, 26.7.
5-Chloropentyl-phenyl sulfide (12a) was prepared (9.79 g, 99%) from 1-bromo-5-
chloropentane (6.06 mL, 46.0 mmol) using the general procedure described above. Spectral
details matched those previously reported.54 R = 0.66 (10% EA/Hex); H (400 MHz) δ 7.39 (d, J
1
f
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=
1
7.8, 2H), 7.34 (t, J = 7.6, 2H), 7.23 (t, J = 7.3, 1H), 3.55 (t, J = 6.7, 2H), 2.97 (t, J = 7.2, 2H),
13
1
.82 (p, J = 7.3, 2H), 1.72 (app tt, J = 7.2, 7.6, 2H), 1.62 (app tt, J = 6.7, J = 7.6, 2H); C{ H}
(100 MHz) δ 136.8, 129.1, 129.0, 44.9, 33.4, 32.2, 28.8, 28.5, 26.2.
0
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0
6-Chlorohexyl-phenyl sulfide (13a) was prepared (10.1 g, 96%) from 1-bromo-6-chlorohexane
(6.86 mL, 46.0 mmol) using the procedure described above. Spectral details matched those
54
1
previously reported. R = 0.66 (10% EA/Hex); H (400 MHz) δ 7.36 (d, J = 7.3, 2H), 7.31 (t, J =
f
7.3, 2H), 7.20 (t, 7.2, 1H), 3.55 (t, J = 6.7, 2H), 2.95 (t, J = 7.2, 2H), 1.79 (p, J = 6.9, 2H), 1.70
13
1
(p, J = 7.3, 2H), 1.47-1.52 (m, 4H); C{ H} (100 MHz) δ 136.9, 129.0, 128.9, 125.8, 45.0, 33.5,
32.3, 29.0, 28.0, 26.5.
Syntheses of chloroalkyl sulfonyl benzenes: Oxidation of the sulfides followed a published
procedure.55 To the neat sulfide (6.0 mmol) was added 30% aq. H O (30 mmol, 5.0 equiv).
2
2
The stirred mixture was heated to 75 °C for 5 h. The reaction was allowed to cool and was then
diluted with water (20 mL). The combined EA extracts (20 mL X 3) were dried with Na SO and
2
4
the residue concentrated under reduced pressure to yield a colorless oil which was used without
further purification.
3-Chloropropyl-sulfonyl benzene (10b) was prepared (1.60 g, 97%) from 3-chloropropyl-
phenyl sulfide (1.40 g, 7.5 mmol) by the procedure described above. Spectral details matched
those previously reported:52 R = 0.36 (25% EA/Hex); H (400 MHz) δ 7.92 (d, J = 7.7, 2H), 7.68
1
f
(t, J = 7.3, 1H), 7.59 (t, J = 7.3, 2H), 3.62 (t, J = 6.2, 2H), 3.27 (t, J = 7.6, 2H), 2.22 (app p, J =
13
1
6.6, 2H); C{ H} (100 MHz) δ 139.0, 134.1, 129.6, 128.1, 53.7, 42.8, 25.9.
4-Chlorobutyl-sulfonyl benzene (11b) was prepared (1.58 g, 95%) from 4-chlorobutyl-phenyl
sulfide (1.41 g, 7.0 mmol) by the procedure described above. Spectral details matched those
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previously reported:52 R = 0.35 (25% EA/Hex); H (400 MHz) δ 7.92 (d, J = 7.7, 2H), 7.68 (t, J =
1
f
7
.4, 1H), 7.59 (t, J = 7.6, 2H), 3.52 (t, J = 5.5, 2H), 3.13 (t, J = 7.1, 2H), 1.89-1.91 (m, 4H);
13
1
C{ H} (100 MHz) δ 139.3, 134.2, 129.7, 128.4, 55.7, 44.2, 31.2, 20.7.
1
1
1
1
1
1
1
1
1
1
2
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2
2
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0
1
2
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7
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9
0
5
-Chloropentyl-sulfonyl benzene (12b) was prepared (1.35 g, 94%) from 5-chloropentyl-
phenyl sulfide (1.25 g, 5.8 mmol) by the procedure described above. Spectral details matched
those previously reported:52 R = 0.36 (25 % EA/Hex); H (400 MHz) δ 7.88 (d, J = 7.9, 2H), 7.64
1
f
(t, J = 7.3, 1H), 7.55 (t, J = 7.6, 2H), 3.46 (t, J = 6.5, 2H), 3.08 (t, J = 8.0, 2H), 1.72 (app p, J =
13
1
6
.9, 4H), 1.49 (m, 2H) ; C{ H} (100 MHz) δ 139.0, 133.8. 129.4, 128.0, 56.1, 44.4, 31.9, 25.6,
22.0.
6
-Chlorohexyl-sulfonyl benzene (13b) was prepared (1.52 g, 96%) from 6-chlorohexyl-phenyl
sulfide (1.37 g, 6.0 mmol) by the procedure described above. Spectral details matched those
56
1
previously reported: R = 0.36 (25% EA/Hex); H (400 MHz) δ 7.91 (d, J = 7.3, 2H), 7.66 (t, J =
f
7
.5, 1H), 7.57 (t, J = 7.6, 2H), 3.49 (t, J = 6.6, 2H), 3.09 (app dt, J = 5.5, 7.9, 2H), 1.70-1.77 (m,
13
1
4H), 1.38-1.43 (m, 4H); C{ H} (100 MHz) δ 139.3, 133.8, 129.4, 128.1, 56.3, 44.9, 32.2, 27.7,
26.4, 22.7.
Syntheses of [iodoalkylsulfonyl] benzenes was performed as described for the synthesis of 9bu.
To a solution of chloroalkyl sulfonyl benzene (30.0 mmol) in acetone (165 mL) was added
sodium iodide (24.7 g, 165 mmol, 5.5 equiv). The reaction was stirred under reflux for 18 h. The
reaction was allowed to cool and then diluted with water (50 mL). The combined hexane
extracts (60 mL X 3) were dried over Na SO and the residue concentrated under reduced
2
4
pressure to yield a yellow solid.
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