Alkene Oxyamination Using Malonoyl Peroxides: Preparation of Pyrrolidines and Isoxazolidines

Article abstract of DOI:10.1021/acs.joc.8b00392

Treatment of homoallylic N-tosyl amines or allylic N-tosyl hydroxylamines with 1.5 equiv of a malonoyl peroxide provides a stereoselective method to access functionalized pyrrolidines and isoxazolidines. This metal free alkene oxyamination proceeds in 50-

Full text of DOI:10.1021/acs.joc.8b00392

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Alkene Oxyamination Using Malonoyl Peroxides: Preparation of
Pyrrolidines and Isoxazolidines
Carla Alamillo-Ferrer,† Jonathan M. Curle,† Stuart C. Davidson,† Simon C. C. Lucas,†,‡
Stephen J. Atkinson,‡ Matthew Campbell,‡ Alan R. Kennedy,† and Nicholas C. O. Tomkinson*,†
†WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral
Street, Glasgow, G1 1XL, United Kingdom
‡GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom
S
* Supporting Information
ABSTRACT: Treatment of homoallylic N-tosyl amines or allylic
N-tosyl hydroxylamines with 1.5 equiv of a malonoyl peroxide
provides a stereoselective method to access functionalized
pyrrolidines and isoxazolidines. This metal free alkene oxy-
amination proceeds in 50−85% yield and up to 13:1 trans-
selectivity. In addition, the relative stereochemistry of the oxygen
and nitrogen substituents can be inverted through an oxidation/
reduction sequence or inverting the stereochemistry of the starting
alkene. Mechanistic investigations show a higher reactivity for hydroxyl nucleophiles over sulfonamide nucleophiles revealing a
preference for dioxygenation over oxyamination.
he vicinal functionalization of alkenes is one of the most
lactone, respectively (Scheme 1). Encouraged by the success of
Tstudied transformations in organic synthesis. This is this work, we sought to discover if the overall strategy could be
particularly the case for the introduction of new carbon
heteroatom bonds generating up to two new stereogenic
centers. For example, exquisite success has been achieved in
dihydroxylation processes whereby the majority of alkene
building blocks can be transformed stereo- and enantioselec-
tively into the corresponding syn- or anti-diol using commercial
reagents under mild and efficient conditions.1−3
Scheme 1. Intramolecular Oxidative Cyclizations
While significant efforts have been devoted to the
dioxygenation of alkenes, methods for oxyamination are
substantially less developed, despite the accordant potential
for the products in pharmaceutical and agrochemical research.4
The majority of methods developed for oxyamination involve
the use of transition metal catalysts, including osmium,5,6
rhodium,7 palladium,8 copper,9 and iron.10 Metal free methods
have also been described and include both iodine(0)11 and
iodine(III)12 species as the reagent. Despite the extensive
inroads made in the development of effective methods for the
oxyamination of alkenes using these processes, significant
opportunities still exist in the area with regard to regio- and
stereoselectivity along with substrate scope and the use of more
environmentally benign catalysts, reagents, and reaction
conditions.
We have recently shown that malonoyl peroxide 1 and its
derivatives are versatile reagents for both the syn-13 and anti-
dioxygenation14,15 of alkenes. In the preparation of oxygen
heterocycles, transformations proceed through the reaction of
the substrate alkene 2 with the malonoyl peroxide to give a
dioxonium intermediate 3,16 which can react stereoselectively
in an intramolecular fashion with either an alcohol or a
carboxylic acid to give the corresponding tetrahydrofuran or γ-
applied to the preparation of nitrogen containing heterocycles
through the reaction of alkenes tethered directly to a nitrogen
nucleophile (e.g., 5). Within this paper, we describe the
development of a simple and effective intramolecular oxy-
amination procedure to deliver 2-hydroxypyrrolidine derivatives
7 in a stereoselective manner.
Our investigation began with the reaction of a homoallylic
amine 8a (R = Ts) with malonoyl peroxide 1 (Table 1).
Received: February 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00392
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the process (Table 2). Substitution on all positions of the
aromatic ring was tolerated with p- (entry 2; 66%; 1:7 cis/
Table 1. Influence of a Nitrogen Substituent
Table 2. Substrate Scope for the Oxyamination Procedure
b
conversion
yield
c
cis/
trans
b
entry reactant
R
solvent
(%)
(%)
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8b
8c
8d
8e
Ts
CHCl3
CH2Cl2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
16
8
Ts
Ts
100
100
100
100
100
27
69
71
1:9
d
Ts
1:13
Ac
Boc
Cbz
DNs
1:1
a
b
c
All reactions performed in duplicate at 0.5 M concentration for 5 h.
Determined by 1H NMR spectroscopy on the crude reaction mixture.
d
Isolated yield of the major isomer. Solvent dried over 3 Å molecular
sieves for 24 h prior to use. DNs = 2,4-dinitrophenylsufonyl.
Chlorinated solvents, which had proved effective in both the
syn- and anti-dioxygenation of alkenes,13,14 led to a slow
consumption of starting materials with no clear indication of
the desired pyrrolidine product 9a (R = Ts) (entries 1 and 2).
However, reaction of 8a with 1.5 equiv of malonoyl peroxide 1
at room temperature for 5 h in hexafluoroisopropanol (HFIP)
followed by hydrolysis of the product led to the desired trans-3-
hydroxypyrrolidine 9a in an excellent 69% isolated yield and a
1:9 cis/trans selectivity (entry 3). Drying the HFIP solvent over
3 Å molecular sieves for 24 h prior to use provided the product
in a similar yield and improved selectivity (entry 4; 71%; 1:13
cis/trans). Interestingly, despite extensive efforts to induce a
similar reactivity with alternative amide 8b (entry 5), carbamate
8c and 8d (entries 6 and 7), and sulfonamide 8e (entry 8)
substituents on the nitrogen nucleophile, similar reactivity
patterns could not be observed upon complete consumption of
starting material. In each of these transformations, numerous
1
products were present in the H NMR of the crude reaction
mixture with no clear evidence for the formation of the target
pyrrolidines. This suggests that both the electronics and sterics
of the nitrogen nucleophile are crucial to observing the desired
reactivity and that N-tosylsulfonamides provide the environ-
ment required to promote reactivity.
Confirmation of the structure of the cyclized pyrrolidine 10,
prior to hydrolysis, came from single crystal X-ray crystallog-
raphy (Figure 1). This structure clearly shows the trans-
relationship between the phenyl group from the alkene
substrate and the ester group from the malonoyl peroxide
reagent. Overall, this provides a convenient, mild, and effective
method for the anti-oxyamination of alkenes.
a
b
Yields quoted are isolated yields of the major isomer. Diaster-
eoselectivity determined by 1H NMR spectroscopy on the crude
reaction mixture. Reaction conducted at 50 °C for 20 h. (Z)-Alkene
substrate used.
c
d
Having established an efficient method for the oxyamination
of 8a (R = Ts), we went on to examine some of the scope of
trans), m- (entry 3; 71%; 1:6 cis/trans), and o-tolyl (entry 4;
72%) substrates effectively undergoing the intramolecular
oxyamination process. Chloride substitution was also well
tolerated (entries 6 and 7), providing the products in up to 67%
isolated yield, which could readily be diversified. Alternative
substitution on the aromatic ring that was also investigated
included a p-phenyl substituent (entry 5; 72%; 1:9 cis/trans)
and an acetal group (entry 8; 55%; 1:9 cis/trans).
Figure 1. Single crystal X-ray structure of pyrrolidine 10.
B
DOI: 10.1021/acs.joc.8b00392
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The Journal of Organic Chemistry
Note
Figure 2. Proposed mechanistic pathway for the intramolecular oxyamination procedure.
A limitation was encountered with the introduction of the
strongly electron withdrawing trifluoromethyl substituent,
which was significantly slower than the other substrates
examined. Conducting the reaction at a higher temperature of
50 °C for 20 h gave the product 20 in just 19% isolated yield
(entry 9). While 1H NMR spectroscopy supported the
structure of 20, it was not possible to determine the
stereoselectivity due to overlapping signals. Introduction of an
additional substituent on the alkene substrate was also possible
with the diphenyl-substituted pyrrolidine 21 being isolated in
an excellent 82% yield (entry 10), providing the most efficient
pyrrolidine synthesis examined within this study. Use of a (Z)-
alkene substrate gave the cis-pyrrolidine product 22 as a 5:1
mixture of cis- and trans-isomers (entry 11).
intermediate 32. We believe this product is formed due to the
increased steric encumbrance of carbon atom A, reducing the
reactivity of this center.
To expand the scope of the transformation to alternative
nitrogen containing heterocycles, we prepared the hydroxyl-
amine derivatives 33 and 35 and reacted each with 1.5 equiv of
1 (HFIP, 40 °C, 18 h) (Scheme 3). The elevated temperature
Scheme 3. Preparation of Isoxazolidines
Mechanistically we believe that the reaction is proceeding as
outlined in Figure 2. Nucleophilic attack of the substituted
alkene 23 on the peroxide 1 leads to 24, which cyclizes
intramolecularly to give the dioxonium species 25 as defined
previously for alkene dihydroxylation.16 Subsequent cyclization
of the nitrogen nucleophile forms the pyrrolidine ring 27 with a
trans-relationship of the newly formed C−O and C−N bonds.
This mechanistic pathway is consistent with previous
investigations into the reactivity of malonoyl peroxide 1 and
accounts for the stereoselectivities observed within the process.
In order to understand the mechanism of this transformation
further, we prepared the probe molecule 28, to ascertain if
differences in nucleophilicity between heteroatoms could
influence the outcome of the cyclization (Scheme 2).
and extended reaction times necessary to bring about reaction
suggest a reduced nucleophilicity of the nitrogen heteroatom
within these substrates. After treatment of the crude reaction
mixture with TMSCHN2, the isoxazolidines 34 (80%; 1:10 cis/
trans) and 36 (85%; 1:7 cis/trans) were isolated after
purification by column chromatography. This provides an
efficient and highly stereoselective method for the preparation
of the 4-hydroxyisoxazolidine framework from readily accessible
alkene substrates.
The structure of the isoxazolidine product 37, prior to
esterification, was confirmed by single crystal X-ray crystallo-
graphic analysis (Figure 3). In contrast to the structure of the
Scheme 2. Probe To Understand the Reaction Mechanism
Figure 3. Single crystal X-ray structure of isoxazolidine 37.
pyrrolidine analogue 10, the nitrogen atom adopts a tetrahedral
geometry in this structure, with the isoxazolidine ring having a
more puckered conformation. The apparent reduced nucleo-
philicity of the hydroxylamine derivatives 33 and 35 was
surprising. While we are unable to unequivocally explain this
observation, the X-ray structures of compounds 10 and 37
suggest that the conformation of the substrates may affect
reactivity.
Reaction of 3-hydroxypyrrolidine 9a with IBX (3 equiv) in
acetonitrile gave the pyrrolidinone 38 in 85% isolated yield
(Scheme 4). Reduction of this ketone with DIBAL-H in THF
at rt for 3 h gave the cis-substituted product 22 (6:1 cis/trans;
78%). This sequence provides an alternative access to the
Compound 28 is a tetrasubstituted alkene, which contains
both an alcohol and a sulfonamide nucleophile. Reaction of 28
under standard cyclization conditions followed by esterification
of the crude product gave tetrahydrofuran 29 (46%).
1
Pyrrolidine 30 was not detected by H NMR spectroscopy
on the crude reaction mixture. This shows that on formation of
a dioxonium ion intermediate 32 the more nucleophilic
pendant heteroatom reacts selectively through carbon atom
A. In addition, we also isolated a small amount of the bicyclic
compound 31 (7%), which results from direct cyclization of the
oxygen heteroatom on carbon atom B of the dioxonium
C
DOI: 10.1021/acs.joc.8b00392
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The Journal of Organic Chemistry
Note
General Procedure 1 (Heck Coupling).19 A dry three-neck flask
fitted with a condenser was charged with aryl iodide (1.1 equiv) and
Et3N (2.0 equiv) in MeCN (0.05 M). 2-(But-3-en-1-yl)isoindoline-1,3-
dione (1.0 equiv) was added followed by P(o-tol)3 (10 mol %) and
Pd(OAc)2 (5 mol %). The mixture was stirred at reflux until
completion by TLC. The solution was allowed to cool to room
temperature and was passed through a plug of Celite, and the solvent
was removed in vacuo. The crude residue was dissolved in EtOAc (100
mL) and washed with 2 M HCl (× 2) and H2O (× 2), dried over
MgSO4, and filtered, and the solvent was removed by rotary
evaporation. Purification by silica gel flash column chromatography
with hexane/EtOAc mixtures afforded the target compounds.
Scheme 4. Inverting Relative Stereochemistry of the
Pyrrolidine Ring
diastereomeric pyrrolidine product 22 without independent
preparation of the (Z)-alkene substrate enhancing the overall
use of the process described and the diversity of structures
accessed using this methodology.
(E)-2-(4-Phenylbut-3-en-1-yl)isoindoline-1,3-dione.20 Phenyl io-
dide (1.7 mL, 14.8 mmol) and Et3N (3.7 mL, 26.8 mmol) were
dissolved in MeCN (270 mL) followed by the addition of 2-(but-3-en-
1-yl)isoindoline-1,3-dione (2.7 g, 13.4 mmol), P(o-tol)3 (407 mg, 1.3
mmol), and Pd(OAc)2 (150 mg, 0.7 mmol) according to General
Procedure 1, and the resulting mixture was heated at reflux for 16 h.
Purification by silica gel flash column chromatography (hexane/EtOAc
9:1) afforded the title compound (2.2 g, 7.9 mmol, 60%) as a white
solid: mp 138−139 °C (lit.20 133.5−135.5 °C); IR (ATR)/cm−1 3054,
3025, 2935, 1695; 1H NMR (500 MHz, CDCl3) δ 7.84−7.82 (m, 2H),
7.70−7.69 (m, 2H), 7.30−7.27 (m, 4H), 7.20−7.18 (m, 1H), 6.43 (d, J
= 15.8 Hz, 1H), 6.18 (dt, J = 15.8, 7.1 Hz, 1H), 3.85 (t, J = 7.1 Hz,
2H), 2.63−2.59 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 168.3,
137.3, 133.9, 132.6, 132.1, 128.5, 127.2, 126.2, 126.1, 123.2, 37.6, 32.2;
LRMS (ES + APCI) m/z 278.0 [M + H]+.
In summary, we have described a simple and effective
method for the intramolecular oxyamination of alkenes.
Through optimization of the nitrogen substituent, we have
shown that the oxyamination procedure can be induced at
room temperature by treatment of an alkene substrate with 1.5
equiv of malonoyl peroxide 1 in HFIP. The product can be
isolated in a good yield and up to a 13:1 trans/cis ratio. The
related isoxazolidines can also be prepared from the appropriate
hydroxylamine substrate. In addition, the relative stereo-
chemistry of the two newly formed carbonheteroatom
bonds can be changed by preparation of the (Z)-alkene
substrate or through a simple oxidation−reduction sequence,
further expanding the scope of this useful transformation. A
mechanistic probe showed there is a preference for reaction of
the dioxonium intermediate with an alcohol over a sulfonamide
nucleophile, revealing a preference for dioxygenation over
oxyamination. Current efforts are focused on developing an
intermolecular variant of this procedure, and we will report on
our findings in the near future.
(E)-2-(4-p-Tolyl)but-3-en-1-yl)isoindoline-1,3-dione.21 4-Iodoto-
luene (600 mg, 2.7 mmol) and Et3N (700 μL, 5.0 mmol) were
dissolved in MeCN (50 mL) followed by the addition of 2-(but-3-en-
1-yl)isoindoline-1,3-dione (500 mg, 2.5 mmol), P(o-tol)3 (75 mg, 0.3
mmol), and Pd(OAc)2 (28 mg, 0.1 mmol) according to General
Procedure 1, and the resulting mixture was heated at reflux for 24 h.
Purification by silica gel flash column chromatography (hexane/EtOAc
9:1) afforded the title compound (432 mg, 1.5 mmol, 60%) as a white
1
solid: mp 121−122 °C; IR (ATR)/cm−1 3023, 2922, 2854, 1708; H
NMR (500 MHz, CDCl3) δ 7.84−7.81 (m, 2H), 7.71−7.68 (m, 2H),
7.19 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.40 (d, J = 15.9 Hz,
1H), 6.12 (dt, J = 15.9, 7.2 Hz, 1H), 3.83 (t, J = 7.2 Hz, 2H), 2.62−
2.57 (m, 2H), 2.31 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 168.5,
137.1, 134.6, 134.0, 132.6, 132.3, 129.3, 126.2, 125.2, 123.4, 37.8, 32.4,
21.3; LRMS (ES + APCI) m/z 292.0 [M + H]+.
EXPERIMENTAL SECTION
■
Synthesis of Malonoyl Peroxide (1).15 Methane sulfonic acid
(30 mL) was placed in a round-bottom flask equipped with a large
magnetic stirrer bar and immersed in a bath of water at 22 °C. Urea
hydrogen peroxide (9.8 g, 104.0 mmol) was added in a single portion,
and the mixture was stirred for 30 s. Cyclopropane-1,1-dicarboxylic
acid (5.0 g, 38.5 mmol) was added in a single portion, and the reaction
was stirred vigorously for 18 h. The reaction mixture was poured into a
mixture of ice (80 g) and ethyl acetate (100 mL), and the layers were
separated. The aqueous layer was extracted with ethyl acetate (2 × 100
mL), and the combined organics were washed with NaHCO3 (2 × 50
mL) and brine (20 mL) and dried over MgSO4. Removal of the
solvent under reduced pressure gave the desired peroxide 1 (3.5 g,
(E)-2-(4-m-Tolyl)but-3-en-1-yl)isoindoline-1,3-dione.21 3-Iodoto-
luene (350 μL, 2.7 mmol) and Et3N (700 μL, 5.0 mmol) were
dissolved in MeCN (50 mL) followed by the addition of 2-(but-3-en-
1-yl)isoindoline-1,3-dione (500 mg, 2.5 mmol), P(o-tol)3 (75 mg, 0.3
mmol), and Pd(OAc)2 (28 mg, 0.1 mmol) according to General
Procedure 1, and the resulting mixture was heated at reflux for 20 h.
Purification by silica gel flash column chromatography (hexane/EtOAc
9:1) afforded the title compound (528 mg, 1.8 mmol, 73%) as a
colorless oil: IR (ATR)/cm−1 3055, 2940, 2857, 1712; 1H NMR (500
MHz, CDCl3) δ 7.84−7.82 (m, 2H), 7.70−7.68 (m, 2H), 7.16 (t, J =
7.4 Hz, 1H), 7.11 (s, 1H), 7.11−7.09 (m, 1H), 7.01 (d, J = 7.4 Hz,
1H), 6.40 (d, J = 15.8 Hz, 1H), 6.16 (dt, J = 15.8, 7.1 Hz, 1H), 3.84 (t,
J = 7.1 Hz, 2H), 2.63−2.58 (m, 2H), 2.31 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 168.5, 138.1, 137.3, 134.0, 132.8, 132.3, 128.5, 128.2,
127.0, 126.0, 123.43, 123.37, 37.8, 32.4, 21.5; LRMS (ES + APCI) m/z
292.0 [M + H]+.
27.3 mmol, 71%): mp 90 °C; IR (ATR)/cm−1 1827, 1798, 1358; H
1
NMR (500 MHz, CDCl3) δ 2.10 (s, 4H); 13C NMR (126 MHz,
CDCl3) δ 172.3, 23.7, 19.9.
Synthesis of 2-(But-3-en-1-yl)isoindoline-1,3-dione.17 A dry
three-neck flask was charged with potassium phthalimide (3.6 g, 19.2
mmol) in DMF (12 mL). 4-Bromobut-1-ene (1.5 mL, 14.8 mmol) was
added, and the mixture was stirred at reflux for 5 h. The mixture was
allowed to cool to room temperature, poured onto ice, and extracted
with CH2Cl2 (3 × 50 mL). The combined organics were washed with
0.2 M KOH (50 mL) and H2O (50 mL), dried over MgSO4, and
filtered, and the solvent was removed by rotary evaporation to afford
the title compound (2.8 g, 13.8 mmol, 93%) as a brown solid, which
was used without further purification: mp 49−51 °C (lit.18 52−53 °C);
(E)-2-(4-o-Tolyl)but-3-en-1-yl)isoindoline-1,3-dione.21 2-Iodoto-
luene (350 μL, 2.7 mmol) and Et3N (700 μL, 5.0 mmol) were
dissolved in MeCN (50 mL) followed by the addition of 2-(but-3-en-
1-yl)isoindoline-1,3-dione (500 mg, 2.5 mmol), P(o-tol)3 (75 mg, 0.3
mmol), and Pd(OAc)2 (28 mg, 0.1 mmol) according to General
Procedure 1, and the resulting mixture was heated at reflux for 16 h.
Purification by silica gel flash column chromatography (hexane/EtOAc
9:1) afforded the title compound (300 mg, 1.0 mmol, 42%) as a white
solid: mp 132−134 °C; IR (ATR)/cm−1 3056, 3017, 2939, 2855,
1
IR (ATR)/cm−1 3075, 2974, 2939, 1772, 1705; H NMR (500 MHz,
CDCl3) δ 7.85−7.81 (m, 2H), 7.72−7.68 (m, 2H), 5.79 (ddt, J = 17.1,
10.2, 6.9 Hz, 1H), 5.06 (dd, J = 17.1, 1.5 Hz, 1H), 5.01 (d, J = 10.2 Hz,
1H), 3.76 (t, J = 7.1 Hz, 2H), 2.47−2.42 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 168.5, 134.6, 134.0, 132.3, 123.3, 117.7, 37.5, 33.0;
LRMS (ES + APCI) m/z 202.1 [M + H]+.
1
1706; H NMR (500 MHz, CDCl3) δ 7.84−7.83 (m, 2H), 7.71−7.69
(m, 2H), 7.35 (d, J = 6.9 Hz, 1H), 7.14−7.06 (m, 3H), 6.59 (d, J =
15.6 Hz, 1H), 6.12 (dt, J = 15.6, 7.5 Hz, 1H), 3.86 (t, J = 7.0 Hz, 2H),
D
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The Journal of Organic Chemistry
Note
2.66−2.61 (m, 2H), 2.20 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
168.5, 136.6, 135.2, 134.1, 132.3, 130.8, 130.2, 127.7, 127.3, 126.2,
126.0, 123.4, 37.8, 32.6, 19.8; LRMS (ES + APCI) m/z 292.0 [M +
H]+.
(E)-2-(4-(4-Trifluoromethylphenyl)but-3-en-1-yl)isoindoline-1,3-
dione.24 1-Iodo-4-(trifluoromethyl)benzene (803 μL, 5.5 mmol) and
Et3N (1.4 mL, 9.9 mmol) were dissolved in MeCN (100 mL) followed
by the addition of 2-(but-3-en-1-yl)isoindoline-1,3-dione (1.0 g, 5.0
mmol), P(o-tol)3 (151 mg, 0.5 mmol), and Pd(OAc)2 (56 mg, 0.3
mmol) according to General Procedure 1, and the resulting mixture
was heated at reflux for 18 h. Purification by silica gel flash column
chromatography (hexane/EtOAc 9:1) afforded the title compound
(1.2 g, 3.5 mmol, 70%) as a white solid: mp 150 °C decomp; IR
(ATR)/cm−1 2997, 2866, 1699; 1H NMR (500 MHz, CDCl3) δ 7.84−
7.83 (m, 2H), 7.71−7.69 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.38 (d, J
= 8.1 Hz, 2H), 6.45 (d, J = 15.8 Hz, 1H), 6.31−6.25 (m, 1H), 3.87 (t, J
= 7.0 Hz, 2H), 2.66−2.62 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
168.5, 140.8, 134.2, 134.1, 132.2, 131.5, 129.3, 127.7 (JC−F = 348.5
Hz), 126.4, 125.6 (JC−F = 3.75 Hz), 123.4, 37.5, 32.4; LRMS (ES +
APCI) m/z 346.0 [M + H]+.
(E)-2-(4-(4-Chlorophenyl)but-3-en-1-yl)isoindoline-1,3-dione.22 1-
Chloro-4-iodobenzene (1.3 g, 5.5 mmol) and Et3N (1.4 mL, 10.0
mmol) were dissolved in MeCN (100 mL) followed by the addition of
2-(but-3-en-1-yl)isoindoline-1,3-dione (1.0 g, 4.97 mmol), P(o-tol)3
(151 mg, 0.5 mmol), and Pd(OAc)2 (56 mg, 0.3 mmol) according to
General Procedure 1, and the resulting mixture was heated at reflux for
42 h. Purification by silica gel flash column chromatography (hexane/
EtOAc 9:1) afforded the title compound (1.1 g, 3.4 mmol, 68%) as a
white solid: mp 130−131 °C (lit.22 130.5−132.0 °C); IR (ATR)/cm−1
1
3058, 3025, 3002, 2939, 1699; H NMR (500 MHz, CDCl3) δ 7.84−
7.82 (m, 2H), 7.71−7.69 (m, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.21 (d, J
= 8.8 Hz, 2H), 6.37 (d, J = 15.8 Hz, 1H), 6.15 (dt, J = 15.8, 7.1 Hz,
1H), 3.84 (t, J = 7.1 Hz, 2H), 2.62−2.58 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 168.5, 135.9, 134.1, 133.0, 132.2, 131.5, 128.8, 127.5,
127.1, 123.4, 37.6, 32.4; LRMS (ES + APCI) m/z 328.9 [M + NH4]+.
(E)-2-(4-(3-Chlorophenyl)but-3-en-1-yl)isoindoline-1,3-dione.23 1-
Chloro-3-iodobenzene (2.0 g, 8.4 mmol) and Et3N (2.1 mL, 15.2
mmol) were dissolved in MeCN (150 mL) followed by the addition of
2-(but-3-en-1-yl)isoindoline-1,3-dione (1.53 g, 7.6 mmol), P(o-tol)3
(232 mg, 0.8 mmol), and Pd(OAc)2 (86 mg, 0.4 mmol) according to
General Procedure 1, and the resulting mixture was heated at reflux for
48 h. Purification by silica gel flash column chromatography (hexane/
EtOAc 9:1) afforded the title compound (1.8 g, 5.8 mmol, 76%) as a
brown solid: mp 106−108 °C; IR (ATR)/cm−1 3056, 3025, 2935,
2854, 1708; 1H NMR (500 MHz, CDCl3) δ 7.85−7.81 (m, 2H),
7.72−7.68 (m, 2H), 7.26 (s, 1H), 7.21−7.14 (m, 3H), 6.36 (d, J = 15.8
Hz, 1H), 6.19 (dt, J = 15.8, 7.1 Hz, 1H), 3.84 (t, J = 7.1 Hz, 2H),
2.63−2.59 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 168.5, 139.2,
134.6, 134.1, 132.2, 131.5, 129.8, 128.0, 127.3, 126.3, 124.5, 123.4,
37.6, 32.2; LRMS (ES + APCI) m/z 329.0 [M + NH4]+.
Synthesis of 2-(4,4-Diphenylbut-3-en-1-yl)isoindoline-1,3-
dione..17,25−27 To a three-neck round-bottom flask dried and flushed
with argon was added (3 hydroxypropyl)triphenylphosphonium
bromide (2.6 g, 6.6 mmol) in anhydrous THF (12 mL). The resulting
suspension was cooled to −10 °C using a NaCl/ice bath. A 1 M
solution of LiHMDS (15 mL) was added dropwise, and the mixture
was stirred at −10 °C for 1 h. Benzophenone (1.0 g, 5.5 mmol) was
then added dropwise and stirred at −10 °C for 2 h. The mixture was
allowed to warm to rt and stirred for a further 18 h. A saturated
aqueous solution of NH4Cl (50 mL) was then added. The organic
layer was extracted with Et2O (2 × 100 mL), dried over MgSO4, and
filtered, and the solvent was removed under reduced pressure.
Purification by silica gel flash column chromatography (petroleum
ether (40−60 °C)/EtOAc 6:4) afforded 4,4 diphenylbut 3-en-1-ol (1.0
1
g, 4.5 mmol, 81%) as a colorless oil: H NMR (400 MHz, CDCl3) δ
7.40−7.36 (m, 2H), 7.34−7.26 (m, 2H), 7.25−7.19 (m, 6H), 6.15 (t, J
= 7.5 Hz, 1H), 3.75 (t, J = 6.5 Hz, 2H), 2.46−2.41 (m, 2H), 1.39 (bs,
1H); 13C NMR (101 MHz, CDCl3) δ 144.3, 142.4, 139.8, 129.9,
128.2, 128.1, 127.2, 127.1, 125.2, 62.6, 33.3.
(E)-2-(4-([1,1′-Biphenyl]-4-yl)but-3-en-1-yl)isoindoline-1,3-dione.
4-Iodo-1,1′-biphenyl (1.7 g, 6.1 mmol) and Et3N (1.5 mL, 11.0 mmol)
were dissolved in MeCN (110 mL) followed by the addition of 2-(but-
3-en-1-yl)isoindoline-1,3-dione (1.1 g, 5.5 mmol), P(o-tol)3 (168 mg,
0.6 mmol), and Pd(OAc)2 (62 mg, 0.3 mmol) according to General
Procedure 1, and the resulting mixture was heated at reflux for 72 h.
Purification by silica gel flash column chromatography (hexane/EtOAc
8:2) afforded the title compound (0.8 g, 2.3 mmol, 41%) as a white
solid: mp 198 °C (decomp); IR (ATR)/cm−1 2987, 2935, 2879, 1720;
1H NMR (400 MHz, CDCl3) δ 7.86−7.82 (m, 2H), 7.72−7.67 (m,
2H), 7.59−7.56 (m, 2H), 7.53−7.50 (m, 2H), 7.44−7.40 (m, 2H),
7.38−7.36 (m, 2H), 7.35−7.30 (m, 1H), 6.47 (d, J = 15.8 Hz, 1H),
6.22 (d, J = 15.8, 7.1 Hz, 1H), 3.87 (t, J = 7.1 Hz, 2H), 2.67−2.61 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 168.5, 140.9, 140.2, 136.5,
134.1, 132.31, 132.26, 128.9, 127.3, 127.1, 126.7, 126.5, 123.4, 37.7,
32.5 (1 carbon missing); LRMS (ES + APCI) m/z 371.1 [M + NH4]+;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C24H20NO2 354.1494,
found 354.1491.
To a solution of 4,4-diphenylbut-3-en-1-ol (300 mg, 1.3 mmol) in a
48% solution of HBr (1.6 mL) was added tetrabutylammonium
bromide (17 mg, 0.1 mmol). The mixture was stirred at reflux for 18 h.
The mixture was then allowed to cool to rt and diluted with CH2Cl2
(10 mL) and H2O (10 mL). The organic layer was extracted with
CH2Cl2 (2 × 20 mL), washed with NaHCO3 (50 mL) and brine (50
mL), dried over MgSO4, and filtered. The solvent was removed under
reduced pressure to afford (4-bromobut-1-ene-1,1-diyl)dibenzene
(350 mg, 1.2 mmol, 91%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) δ 7.44−7.27 (m, 5H), 7.25−7.22 (m, 3H), 7.19−7.17 (m,
2H), 6.09 (t, J = 7.3 Hz, 1H), 3.43 (t, J = 7.0 Hz, 2H), 2.71−2.66 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 144.3, 142.1, 139.6, 129.7,
128.3, 128.1, 127.29, 127.26, 125.7, 32.9, 32.6.
A dry three-neck flask was charged with potassium phthalimide
(360 mg, 1.9 mmol) in anhydrous DMF (10 mL). (4-Bromobut-1-
ene-1,1-diyl)dibenzene (558 mg, 1.9 mmol) was added, and the
mixture was stirred at reflux for 18 h. The mixture was allowed to cool
to rt, poured into ice, and extracted with CH2Cl2 (3 × 50 mL). The
organics were washed with 0.2 M KOH (50 mL) and H2O (50 mL),
dried over MgSO4, and filtered, and the solvent was removed under
reduced pressure. Purification by silica gel flash column chromatog-
raphy (petroleum ether (40−60 °C)/EtOAc 9:1) afforded the title
compound (600 mg, 1.7 mmol, 88%) as a white solid: mp 120−121
°C (lit.28 119−120 °C); IR (ATR)/cm−1 2967, 2921, 2908, 2872,
1718, 1701; 1H NMR (400 MHz, CDCl3) δ 7.83−7.78 (m, 2H),
7.71−7.66 (m, 2H), 7.27−7.18 (m, 8H), 7.02−6.99 (m, 2H), 6.07 (t, J
= 7.6 Hz, 1H), 3.81−3.78 (m, 2H), 2.57−2.52 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 168.3, 144.5, 142.5, 139.6, 134.0, 132.3, 129.8,
128.3, 128.2, 127.5, 127.2, 125.2, 123.3, 37.8, 29.0 (1 carbon missing);
LRMS (ES + APCI) m/z 354.0 [M + H]+.
(E)-2-(4-(4-(1,3-Dioxalan-2-yl)phenyl)but-3-en-1-yl)isoindoline-
1,3-dione. 2-(4-Iodophenyl)-1-dioxalane (3.0 g, 10.9 mmol) and Et3N
(2.8 mL, 19.7 mmol) were dissolved in MeCN (200 mL) followed by
the addition of 2-(but-3-en-1-yl)isoindoline-1,3-dione (2.0 g, 9.9
mmol), P(o-tol)3 (301 mg, 1.0 mmol), and Pd(OAc)2 (111 mg, 0.5
mmol) according to General Procedure 1, and the resulting mixture
was heated at reflux for 72 h. Purification by silica gel flash column
chromatography (hexane/EtOAc 9:1) afforded the title compound
(1.6 g, 4.6 mmol, 46%) as a white solid: mp 120−121 °C; IR (ATR)/
1
cm−1 3026, 2945, 2883, 1706; H NMR (500 MHz, CDCl3) δ 7.84−
7.80 (m, 2H), 7.71−7.67 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.30 (d, J
= 8.2 Hz, 2H), 6.42 (d, J = 15.8 Hz, 1H), 6.19 (dd, J = 15.8, 7.1 Hz,
1H), 5.78 (s, 1H), 4.12−4.10 (m, 2H), 4.04−4.00 (m, 2H), 3.85 (d, J
= 7.1 Hz, 2H), 2.63−2.59 (m, 2H); 13C NMR (101 MHz, CDCl3) δ
168.5, 138.4, 136.9, 134.1, 132.4, 132.2, 127.0, 126.8, 126.3, 123.4,
103.7, 65.4, 37.7, 32.4; LRMS (ES + APCI) m/z 350.0 [M + H]+;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H20NO4 350.1392,
found 350.1387.
General Procedure 2 (Removal of Phthalimide and
Tosylation).29 To a solution of (E)-2-(4-arylbut-3-en-1-yl)-
isoindoline-1,3-dione (1.0 equiv) in EtOH (0.3 M) was added
hydrazine monohydrate (2.0 equiv). The mixture was stirred at room
temperature for 10 min and at reflux for a further 30 min. After the
E
DOI: 10.1021/acs.joc.8b00392
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The Journal of Organic Chemistry
Note
mixture cooled to room temperature, a 2 M solution of NaOH was
added (50 mL). The solvent was evaporated before extracting the
organics with EtOAc (3 × 50 mL) and drying over MgSO4. The
solvent was removed by rotary evaporation to give the free amine
compound, which was used without further purification. The crude
reaction mixture was dissolved in anhydrous CH2Cl2 (0.3 M) under an
argon atmosphere, and Et3N (1.5 equiv) was added. The mixture was
cooled to 0 °C, and p-toluenesulfonyl chloride (1.0 equiv) and DMAP
(0.3 equiv) were added in one portion. The mixture was stirred at
room temperature for 24 h. The solution was diluted with CH2Cl2 and
washed with 2 M HCl (100 mL) and brine (100 mL). The organics
were dried over MgSO4, and the solvent was removed by rotary
evaporation to give a crude material, which was purified by silica gel
chromatography eluting with hexane/EtOAc mixtures to afford the
tosylated compound.
(E)-4-Methyl-N-(4-(o-tolyl)but-3-en-1-yl)benzenesulfonamide.21
To a solution of (E)-2-(4-(o-tolyl)but-3-en-1-yl)isoindoline-1,3-dione
(275 mg, 0.9 mmol) in EtOH (3.6 mL) was added hydrazine
monohydrate (92 μL, 1.9 mmol) according to General Procedure 2 to
give (E)-4-(o-tolylbut)-3-en-1-amine.
To a solution of (E)-4-(o-tolylbut)-3-en-1-amine (151 mg, 0.9
mmol) in CH2Cl2 (4.0 mL) was added Et3N (200 μL, 1.4 mmol)
followed by p-TsCl (179 mg, 0.9 mmol) and DMAP (35 mg, 0.3
mmol) according to General Procedure 2. Purification by silica gel
flash column chromatography (hexane/EtOAc 8:2) afforded the title
compound (64 mg, 0.2 mmol, 22%) as a colorless oil: IR (ATR)/cm−1
1
3272, 3021, 2922, 2865; H NMR (500 MHz, CDCl3) δ 7.76 (d, J =
8.1 Hz, 2H), 7.32−7.31 (m, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.15−7.11
(m, 3H), 6.58 (d, J = 15.7 Hz, 1H), 5.86 (dt, J = 15.7, 7.1 Hz, 1H),
4.65 (bs, 1H), 3.11 (t, J = 6.7 Hz, 2H), 2.42 (s, 3H), 2.42−2.37 (m,
2H), 2.30 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 143.6, 137.2,
136.1, 135.2, 131.2, 130.4, 129.8, 127.5, 127.4, 127.0, 126.2, 125.6,
42.8, 33.4, 21.6, 19.9; LRMS (ES + APCI) m/z 316.0 [M + H]+.
(E)-2-(4-([1,1′-Biphenyl]-4-yl)but-3-en-1-yl)-4-methylbenzenesul-
fonamide. To a solution of (E)-2-(4-([1,1′-biphenyl]-4-yl)but-3-en-1-
yl)isoindoline-1,3-dione (300 mg, 0.9 mmol) in EtOH (3.5 mL) was
added hydrazine monohydrate (82 μL, 1.7 mmol) according to
General Procedure 2 to give (E)-4-([1,1′-biphenyl]-4-yl)but-3-en-1-
amine.
(E)-4-Methyl-N-(4-phenylbut-3-en-1-yl)benzenesulfonamide
(8a).29 To a solution of (E)-2-(4-phenylbut-3-en-1-yl)isoindoline-1,3-
dione (2.2 g, 7.4 mmol) in EtOH (32 mL) was added hydrazine
monohydrate (771 μL, 15.8 mmol) according to General Procedure 2
to give (E)-4-phenylbut-3-en-1-amine.
To a solution of (E)-4-phenylbut-3-en-1-amine (1.2 g, 7.9 mmol) in
CH2Cl2 (65 mL) was added Et3N (2.3 mL, 16.2 mmol) followed by p-
TsCl (1.8 g, 9.8 mmol) and DMAP (0.6 g, 4.9 mmol) according to
General Procedure 2. Purification by silica gel flash column
chromatography (hexane/EtOAc 9:1) afforded title compound 8a
(1.8 g, 6.0 mmol, 74%) as a white solid: mp 52−54 °C; IR (ATR)/
cm−1 3272, 3058, 3023, 2922; 1H NMR (500 MHz, CDCl3) δ 7.75 (d,
J = 8.2 Hz, 2H), 7.31−7.27 (m, 6H), 7.24−7.21 (m, 1H), 6.36 (d, J =
15.9 Hz, 1H), 5.98 (dt, J = 15.9, 7.1 Hz, 1H), 4.43 (bs, 1H), 3.13−3.09
(m, 2H), 2.43 (s, 3H), 2.39−2.35 (m, 2H); 13C NMR (126 MHz,
CDCl3) δ 143.6, 137.2, 136.9, 133.5, 129.9, 128.7, 127.7, 127.3, 126.3,
125.6, 42.7, 33.2, 21.7; LRMS (ES + APCI) m/z 319.1 [M + NH4]+.
(E)-4-Methyl-N-(4-(p-tolyl)but-3-en-1-yl)benzenesulfonamide.30
To a solution of (E)-2-(4-(p-tolyl)but-3-en-1-yl)isoindoline-1,3-dione
(430 mg, 1.5 mmol) in EtOH (6.0 mL) was added hydrazine
monohydrate (143 μL, 3.0 mmol) according to General Procedure 2
to give (E)-4-(p-tolylbut)-3-en-1-amine.
To a solution of (E)-4-(p-tolylbut)-3-en-1-amine (165 mg, 1.0
mmol) in CH2Cl2 (4.0 mL) was added Et3N (210 μL, 1.5 mmol)
followed by p-TsCl (190 mg, 1.2 mmol) and DMAP (37 mg, 0.3
mmol) according to General Procedure 2. Purification by silica gel
flash column chromatography (hexane/EtOAc 8:2) afforded the title
compound (192 mg, 0.6 mmol, 61%) as a white solid: mp 82−84 °C;
IR (ATR)/cm−1 3276, 3047, 3017, 2939; 1H NMR (500 MHz,
CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.17 (d, J
= 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.32 (d, J = 15.8 Hz, 1H), 5.97
(dt, J = 15.8, 7.1 Hz, 1H), 4.37 (t, J = 5.4 Hz, 1H), 3.12−3.08 (m, 2H),
2.43 (s, 3H), 2.37−2.34 (m, 2H), 2.33 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 143.6, 137.5, 137.2, 134.1, 133.4, 129.9, 129.4, 127.3, 126.2,
124.5, 42.7, 33.1, 21.7, 21.3; LRMS (ES + APCI) m/z 316.0 [M + H]+.
(E)-4-Methyl-N-(4-(m-tolyl)but-3-en-1-yl)benzenesulfonamide.21
To a solution of (E)-2-(4-(m-tolyl)but-3-en-1-yl)isoindoline-1,3-dione
(340 mg, 1.2 mmol) in EtOH (4.5 mL) was added hydrazine
monohydrate (113 μL, 2.3 mmol) according to General Procedure 2
to give (E)-4-(m-tolylbut)-3-en-1-amine.
To a solution of (E)-4-([1,1′-biphenyl]-4-yl)but-3-en-1-amine (189
mg, 0.9 mmol) in CH2Cl2 (3.0 mL) was added Et3N (177 μL, 1.3
mmol) followed by p-TsCl (162 mg, 0.9 mmol) and DMAP (31 mg,
0.3 mmol) according to General Procedure 2. Purification by silica gel
flash column chromatography (hexane/EtOAc 9:1) afforded the title
compound (75 mg, 0.2 mmol, 23%) as a white solid: mp 126−128 °C;
1
IR (ATR)/cm−1 3276, 3051, 3025, 2922, 2865; H NMR (500 MHz,
CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 7.54 (d, J
= 8.2 Hz, 2H), 7.44 (at, J = 7.6 Hz, 2H), 7.36−7.34 (m, 3H), 7.30 (d, J
= 8.0 Hz, 2H), 6.40 (d, J = 15.9 Hz, 1H), 6.03 (dt, J = 15.9, 7.1 Hz,
1H), 4.59 (t, J = 6.0 Hz, 1H), 3.14−3.10 (m, 2H), 2.42 (s, 3H), 2.41−
2.37 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 143.6, 140.8, 140.4,
137.1, 136.0, 132.9, 129.9, 128.9, 127.5, 127.4, 127.3, 127.0, 126.7,
125.8, 42.7, 33.2, 21.7; LRMS (ES + APCI) m/z 378.0 [M + NH4]+;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H24NO2S 378.1528,
found 378.1522.
(E)-N-(4-(4-Chlorophenyl)but-3-en-1-yl)-4-methylbenzenesulfo-
namide.31 To a solution of (E)-2-(4-(4-chlorophenyl)but-3-en-1-
yl)isoindoline-1,3-dione (444 mg, 1.4 mmol) in EtOH (5.5 mL) was
added hydrazine monohydrate (138 μL, 2.8 mmol) according to
General Procedure 2 to give (E)-4-(4-chlorophenyl)but-3-en-1-amine.
To a solution of (E)-4-(4-chlorophenyl)but-3-en-1-amine (150 mg,
0.8 mmol) in CH2Cl2 (3.0 mL) was added Et3N (172 μL, 1.2 mmol)
followed by p-TsCl (157 mg, 0.8 mmol) and DMAP (30 mg, 0.3
mmol) according to General Procedure 2. Purification by silica gel
flash column chromatography (hexane/EtOAc 8:2) afforded the title
compound (57 mg, 0.2 mmol, 20%) as a white solid: mp 90−92 °C;
IR (ATR)/cm−1 3360, 3250, 2947, 2826; 1H NMR (500 MHz,
CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.23 (d, J
= 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 15.9 Hz, 1H), 5.96
(dt, J = 15.9, 7.0 Hz, 1H), 4.78 (t, J = 5.9 Hz, 1H), 3.10−3.07 (m, 2H),
2.41 (s, 3H), 2.37−2.33 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
143.6, 137.1, 135.5, 133.1, 132.0, 129.9, 128.8, 127.5, 127.2, 126.6,
42.6, 33.1, 21.6; LRMS (ES + APCI) m/z 336.0 [M + H]+.
To a solution of (E)-4-(m-tolylbut)-3-en-1-amine (189 mg, 1.2
mmol) in CH2Cl2 (4.0 mL) was added Et3N (245 μL, 1.8 mmol)
followed by p-TsCl (223 mg, 1.2 mmol) and DMAP (43 mg, 0.4
mmol) according to General Procedure 2. Purification by silica gel
flash column chromatography (hexane/EtOAc 8:2) afforded the title
compound (145 mg, 0.5 mmol, 39%) as a colorless oil: IR (ATR)/
cm−1 3277, 3023, 2919, 2861; 1H NMR (500 MHz, CDCl3) δ 7.75 (d,
J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.10
(s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.33 (d, J =
15.8 Hz, 1H), 5.97 (dt, J = 15.8, 7.0 Hz, 1H), 4.66 (t, J = 5.8 Hz, 1H),
3.11−3.07 (m, 2H), 2.42 (s, 3H), 2.38−2.33 (m, 2H), 2.33 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 143.5, 138.2, 137.1, 136.9, 133.4,
(E)-N-(4-(3-Chlorophenyl)but-3-en-1-yl)-4-methylbenzenesulfo-
namide. To a solution of (E)-2-(4-(3-chlorophenyl)but-3-en-1-
yl)isoindoline-1,3-dione (1.8 g, 5.8 mmol) in EtOH (22 mL) was
added hydrazine monohydrate (560 μL, 11.5 mmol) according to
General Procedure 2 to give (E)-4-(3-chlorophenyl)but-3-en-1-amine.
To a solution of (E)-4-(3-chlorophenyl)but-3-en-1-amine (1.1 g, 5.8
mmol) in CH2Cl2 (20 mL) was added Et3N (1.2 μL, 8.7 mmol)
followed by p-TsCl (1.1 g, 5.8 mmol) and DMAP (0.2 g, 1.7 mmol)
according to General Procedure 2. Purification by silica gel flash
column chromatography (hexane/EtOAc 8:2) afforded the title
compound (0.4 g, 1.2 mmol, 21%) as a colorless oil: IR (ATR)/
129.8, 128.6, 128.4, 127.3, 127.0, 125.5, 123.4, 42.7, 33.1, 21.6, 21.5;
LRMS (ES + APCI) m/z 316.0 [M + H]+.
cm−1 3272, 3060, 3025, 2921, 2870; H NMR (500 MHz, CDCl3) δ
1
F
DOI: 10.1021/acs.joc.8b00392
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The Journal of Organic Chemistry
Note
7.74 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.24 (m, 1H), 7.21−
7.17 (m, 2H), 7.13 (d, J = 7.1 Hz, 1H), 6.29 (d, J = 15.9 Hz, 1H), 5.99
(dt, J = 15.9, 7.0 Hz, 1H), 4.68 (bs, 1H), 3.12−3.08 (m, 2H), 2.42 (s,
3H), 2.39−2.35 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 143.6,
138.8, 137.1, 134.6, 131.9, 129.9, 127.5, 127.4, 127.3, 126.1, 124.6,
42.6, 33.1, 21.7 (1 carbon missing); LRMS (ES + APCI) m/z 352.9
[M + NH4]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C17H1935lNO2S 336.0825, found 336.0823.
(E)-N-(4-(4-(1,3-Dioxalan-2-yl)phenyl)but-3-en-1-yl)-4-methyl-
benzenesulfonamide. To a solution of (E)-2-(4-(4-(1,3-dioxalan-2-
yl)phenyl)but-3-en-1-yl)isoindoline-1,3-dione (400 mg, 1.1 mmol) in
EtOH (4.5 mL) was added hydrazine monohydrate (111 μL, 2.3
mmol) according to General Procedure 2 to give (E)-(4-(4-(1,3-
dioxalan-2-yl)phenyl)but-3-en-1-yl)-1-amine.
To a solution of (E)-(4-(4-(1,3-dioxalan-2-yl)phenyl)but-3-en-1-
yl)-1-amine (250 mg, 1.1 mmol) in CH2Cl2 (4.0 mL) was added Et3N
(240 μL, 1.7 mmol) followed by p-TsCl (217 mg, 1.1 mmol) and
DMAP (42 mg, 0.3 mmol) according to General Procedure 2.
Purification by silica gel flash column chromatography (hexane/EtOAc
6:4) afforded the title compound (260 mg, 0.7 mmol, 61%) as a
colorless oil: IR (ATR)/cm−1 3264, 3026, 2948, 2883; 1H NMR (500
MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H),
7.30−7.27 (m, 4H), 6.36 (d, J = 15.9 Hz, 1H), 5.99 (dt, J = 15.8, 7.1
Hz, 1H), 5.79 (s, 1H), 4.43 (t, J = 5.8 Hz, 1H), 4.15−4.11 (m, 2H),
4.05−4.01 (m, 2H), 3.13−3.08 (m, 2H), 2.42 (s, 3H), 2.39−2.34 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 143.6, 137.8, 137.3, 137.1,
133.0, 130.0, 127.3, 126.9, 126.33, 126.26, 103.7, 65.4, 42.6, 33.2, 21.7;
LRMS (ES + APCI) m/z 374.0 [M + H]+; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C20H24NO4S 374.1426, found 374.1420.
CH2Cl2 (6 mL) was added Et3N (206 μL, 2.0 mmol) followed by the
addition of acetyl chloride (97 μL, 1.4 mmol). The resultant mixture
was then stirred at rt for 18 h, before washing with a 1 M HCl solution
(20 mL) followed by a 1 M NaOH solution (20 mL) and brine (20
mL). The organic layer was dried over MgSO4 and filtered, and the
solvent was removed by rotary evaporation affording title compound
1
8b (190 mg, 1.0 mmol, 72%) as a yellow semisolid: H NMR (400
MHz, CDCl3) 7.35−7.28 (m, 4H), 7.22 (t, J = 7.1 Hz, 1H), 6.45 (d, J
= 15.8 Hz, 1H), 6.14 (dt, J = 15.8, 7.1 Hz, 1H), 5.62 (bs, 1H), 3.42−
3.37 (m, 2H), 2.45−2.39 (m, 2H), 1.96 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 170.2, 137.3, 132.5, 128.7, 127.5, 127.0, 126.2, 39.1, 33.2,
23.5; LRMS (ES + APCI) m/z 190.1 [M + H]+.
tert-Butyl (E)-(4-Phenylbut-3-en-1-yl)carbamate (8c).33 To a
solution of (E)-4-phenylbut-3-en-1-amine (316 mg, 2.1 mmol) in
CH2Cl2 (4 mL) was added K2CO3 (591 mg, 4.3 mmol) followed by
the addition of di-tert-butyl dicarbonate (468 mg, 2.1 mmol). The
resultant mixture was then stirred at 40 °C for 18 h, before the
addition of H2O (20 mL), and the stirring was extended for an extra
hour. Layers were separated, and the organic layer was washed with
brine (30 mL), dried over MgSO4, and filtered. The solvent was
removed by rotary evaporation. Purification by silica gel flash column
chromatography (hexane/EtOAc 9:1) afforded title compound 8c
1
(441 mg, 1.8 mmol, 83%) as a colorless oil: H NMR (400 MHz,
CDCl3) δ 7.35−7.34 (m, 2H), 7.30 (at, J = 7.5 Hz, 2H), 7.21 (t, J = 7.1
Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.15 (dt, J = 15.8, 7.1 Hz, 1H),
4.59 (bs, 1H), 3.30−3.25 (m, 2H), 2.43−2.38 (m, 2H), 1.44 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 156.1, 137.4, 132.4, 128.7, 127.4,
127.2, 126.2, 40.2, 33.7, 28.6 (1 carbon missing); LRMS (ES + APCI)
m/z 248.1 [M + H]+.
Benzyl (E)-(4-Phenylbut-3-en-1-yl)carbamate (8d).21 To a sol-
ution of (E)-4-phenylbut-3-en-1-amine (308 mg, 2.1 mmol) in H2O
(10 mL) and acetone (21 mL) was added NaHCO3 (200 mg, 2.4
mmol) followed by the addition of benzyl chloroformate (335 μL, 2.4
mmol). The resultant mixture was then stirred at rt for 18 h, before
evaporation of the solvent, and the precipitate was filtered affording
title compound 8d (498 mg, 1.8 mmol, 85%) as a white solid: mp 90−
(E)-4-Methyl-N-(4-(4-trifluoromethyl)phenyl)but-3-en-1-yl)-
benzenesulfonamide. To
a solution of (E)-2-(4-(4-
trifluoromethylphenyl)but-3-en-1-yl)isoindoline-1,3-dione (1.0 g, 2.9
mmol) in EtOH (11 mL) was added hydrazine monohydrate (280 μL,
5.8 mmol) according to General Procedure 2 to give (E)-4-(4-
(trifluoro)phenyl)but-3-en-1-amine.
To a solution of (E)-4-(4-(trifluoro)phenyl)but-3-en-1-amine (623
mg, 3.0 mmol) in CH2Cl2 (9.6 mL) was added Et3N (604 μL, 4.3
mmol) followed by p-TsCl (551 mg, 2.9 mmol) and DMAP (106 mg,
0.9 mmol) according to General Procedure 2. Purification by silica gel
flash column chromatography (hexane/EtOAc 8:2) afforded the title
compound (409 mg, 1.1 mmol, 38%) as a white solid: mp 121−122
1
92 °C; H NMR (400 MHz, CDCl3) δ 7.35−7.28 (m, 9H), 7.24−7.1
(m, 1H), 6.45 (d, J = 15.9 Hz, 1H), 6.14 (dt, J = 15.9, 7.3 Hz, 1H),
5.10 (s, 2H), 4.83 (bs, 1H), 3.38−3.34 (m, 2H), 2.46−2.41 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 156.3, 137.1, 136.6, 132.5, 128.6,
128.5, 128.5, 128.1, 127.3, 126.6, 126.1, 66.6, 40.5, 33.5; LRMS (ES +
1
°C; IR (ATR)/cm−1 3330, 3244, 2991, 2875; H NMR (500 MHz,
APCI) m/z 282.1 [M + H]+.
CDCl3) δ 7.74 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.37 (d, J
= 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.40 (d, J = 15.9 Hz, 1H),
6.14−6.08 (m, 1H), 4.39 (t, J = 5.9 Hz, 1H), 3.15−3.11 (m, 2H), 2.42
(s, 3H), 2.42−2.39 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 143.7,
140.4, 137.1, 132.0, 129.9, 129.4 (d, JC−F = 33.1 Hz), 128.7, 127.3,
126.4, 125.6 (q, JC−F = 3.7 Hz), 124.3 (d, JC−F = 272.0 Hz), 42.6, 33.3,
21.6; LRMS (ES + APCI) m/z 370.0 [M + H]+.
N-(4,4-Diphenylbut-3-en-1-yl)-4-methylbenzenesulfonamide. To
a solution of 2-(4,4-diphenylbut-3-en-1-yl)isoindoline-1,3-dione (280
mg, 0.8 mmol) in EtOH (3.0 mL) was added hydrazine monohydrate
(77 μL, 1.6 mmol) according to General Procedure 2 to give 4,4-
diphenylbut-3-en-1-amine.
(E)-2,4-Dinitro-N-(4-phenylbut-3-en-1-yl)benzenesulfonamide
(8e). To a cooled (0 °C) solution of (E)-4-phenylbut-3-en-1-amine
(200 mg, 1.4 mmol) in CH2Cl2 (14 mL) was added Et3N (284 μL, 2.0
mmol) followed by the addition of 2,4-dinitrobenzenesulfonyl chloride
(471 mg, 1.8 mmol). The resultant mixture was then stirred at rt for
18 h, before quenching with a saturated solution of NH4Cl (20 mL).
The organic layer was extracted with CH2Cl2 (3 × 50 mL), washed
with brine (100 mL), dried over MgSO4, and filtered, and the solvent
was removed by rotary evaporation. Purification by silica gel flash
column chromatography (hexane/EtOAc 8:2) afforded title com-
pound 8e (502 mg, 1.3 mmol, 98%) as a yellow solid: mp 130−132
°C; 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.36−8.34 (m, 1H),
8.27−8.24 (m, 1H), 7.24−7.15 (m, 3H), 7.11−7.08 (m, 2H), 6.29 (d, J
= 15.8 Hz, 1H), 5.83 (dt, J = 15.8, 7.3 Hz, 1H), 5.41 (bt, J = 5.6 Hz,
1H), 3.46−3.42 (m, 2H), 2.46−2.41 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 149.2, 147.7, 139.8, 136.2, 133.8, 131.9, 128.6, 128.1, 127.0,
125.9, 125.1, 120.7, 43.9, 33.5; LRMS (ES + APCI) m/z 378.1 [M +
H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H16N3O6S
378.0760, found 378.0746.
General Procedure 3 (Oxyamination Procedure for the
Synthesis of Pyrrolidines). Malonoyl peroxide 1 (1.5 equiv) was
added to a solution of alkene 11 (1.0 equiv) in HFIP (0.5 M). The
mixture was stirred at rt for 5 h. The solvent was removed by rotary
evaporation, and the resulting residue was directly treated with 1 M
NaOH/THF (1:1 (0.1 M)). The solution was stirred at 60 °C for 18 h
and allowed to cool to rt, and the aqueous phase was extracted with
EtOAc (× 3). The combined organics were washed with brine and
dried over MgSO4. Removal of the solvent under reduced pressure
To a solution of 4,4-diphenylbut-3-en-1-amine (176 mg, 0.8 mmol)
in CH2Cl2 (2.6 mL) was added Et3N (165 μL, 1.2 mmol) followed by
p-TsCl (166 mg, 0.9 mmol) and DMAP (29 mg, 0.2 mmol) according
to General Procedure 2. Purification by silica gel flash column
chromatography (hexane/EtOAc 8:2) afforded the title compound
(200 mg, 0.5 mmol, 67%) as a colorless oil: IR (ATR)/cm−1 3281,
3053, 3023, 2922; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz,
2H), 7.38−7.29 (m, 3H), 7.27−7.22 (m, 5H), 7.20−7.15 (m, 2H),
7.12−7.10 (m, 2H), 5.97 (t, J = 7.4 Hz, 1H), 4.76 (bs, 1H), 3.07−3.02
(m, 2H), 2.41 (s, 3H), 2.30−2.24 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 144.7, 143.4, 142.1, 139.6, 137.0, 129.8, 128.4, 128.2,
127.35, 127.31, 127.2, 124.7, 43.1, 29.9, 21.6; LRMS (ES + APCI) m/z
378.1 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C23H24NO2S 378.1528, found 378.1521.
(E)-(4-Phenylbut-3-en-1-yl)acetamide (8b).32 To a cooled (0 °C)
solution of (E)-4-phenylbut-3-en-1-amine (200 mg, 1.4 mmol) in
G
DOI: 10.1021/acs.joc.8b00392
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
afforded the crude pyrrolidine product. Purification by silica gel flash
column chromatography eluting with hexane/EtOAc mixtures afforded
target compound 12.
( )-2-([1,1′-Biphenyl]-4-yl)-1-tosylpyrrolidin-3-ol (16). Reaction of
(E)-2-(4-([1,1′-biphenyl]-4-yl)but-3-en-1-yl)-4-methylbenzenesulfo-
namide (40 mg, 0.11 mmol) and malonoyl peroxide 1 (20 mg, 0.16
mmol) in HFIP (0.2 mL) according to General Procedure 3 followed
by hydrolysis in 1 M NaOH/THF (1.0 mL, 1:1) gave the crude
alcohol (1:9 cis/trans). Purification by silica gel flash column
chromatography (hexane/EtOAc 4:6) gave title compound 16 (30
mg, 0.08 mmol, 72%) as a white solid: mp 190−192 °C (decomp); IR
(ATR)/cm−1 3450, 3010, 2947, 2920; 1H NMR (500 MHz, CDCl3) δ
7.76 (d, J = 8.1 Hz, 2H), 7.50−7.47 (m, 4H), 7.45−7.40 (m, 4H),
7.29−7.23 (m, 3H), 4.70 (bs, 1H), 4.22 (bs, 1H), 3.77−3.73 (m, 1H),
3.55 (dt, J = 16.8, 8.5 Hz, 1H), 2.43 (s, 3H), 2.11−2.05 (m, 1H),
1.79−1.75 (m, 1H), 1.50 (bs, 1H); 13C NMR (126 MHz, CDCl3) δ
143.7, 140.9, 140.7, 139.0, 134.7, 129.7, 128.9, 127.9, 127.5, 127.3,
126.8, 79.1, 71.8, 46.9, 31.6, 21.7 (missing 1 carbon); LRMS (ES +
APCI) m/z 394.0 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C23H24NO3S 394.1477, found 394.1472.
( )-2-(4-Chlorophenyl)-1-tosylpyrrolidin-3-ol (17). Reaction of
(E)-N-(4-(4-chlorophenyl)but-3-en-1-yl)-4-methylbenzenesulfona-
mide (100 mg, 0.30 mmol) and malonoyl peroxide 1 (57 mg, 0.45
mmol) in HFIP (0.6 mL) according to General Procedure 3 followed
by hydrolysis in 1 M NaOH/THF (2.6 mL, 1:1) gave the crude
alcohol (1:9 cis/trans). Purification by silica gel flash column
chromatography (hexane/EtOAc 4:6) gave title compound 17 (69
mg, 0.20 mmol, 67%) as a white solid: mp 169−171 °C; IR (ATR)/
cm−1 3558, 3499, 2937, 2889; 1H NMR (500 MHz, CDCl3) δ 7.72 (d,
J = 7.7 Hz, 2H), 7.31−7.26 (m, 6H), 4.60 (bs, 1H), 4.11 (bs, 1H),
3.72−3.69 (m, 1H), 3.52−3.47 (m, 1H), 2.42 (s, 3H), 2.02−1.95 (m,
1H), 1.75−1.72 (m, 1H), 1.58 (bs, 1H); 13C NMR (126 MHz,
CDCl3) δ 143.8, 138.6, 134.4, 129.8, 128.8, 128.9, 127.9, 127.7, 78.9,
71.4, 46.9, 31.5, 21.7; LRMS (ES + APCI) m/z 351.9 [M]+; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C17H1935ClNO3S 352.0774, found
352.0772.
( )-2-(3-Chlorophenyl)-1-tosylpyrrolidin-3-ol (18). Reaction of
(E)-N-(4-(3-chlorophenyl)but-3-en-1-yl)-4-methylbenzenesulfona-
mide (60 mg, 0.18 mmol) and malonoyl peroxide 1 (34 mg, 0.27
mmol) in HFIP (0.4 mL) according to General Procedure 3 followed
by hydrolysis in 1 M NaOH/THF (0.4 mL, 1:1) gave the crude
alcohol (1:6 cis/trans). Purification by silica gel flash column
chromatography (hexane/EtOAc 4:6) gave title compound 18 (33
mg, 0.09 mmol, 52%) as a white solid: mp 96−98 °C; IR (ATR)/cm−1
3489, 3062, 2952, 2922, 2954; 1H NMR (500 MHz, CDCl3) δ 7.72 (d,
J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.25−7.21 (m,
3H), 4.63 (bs, 1H), 4.12 (bs, 1H), 3.70 (td, J = 9.3, 2.3 Hz, 1H), 3.52
(td, J = 9.9, 6.9 Hz, 1H), 2.42 (s, 3H), 2.06−1.96 (m, 1H), 1.77−1.73
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 143.9, 142.2, 134.6, 134.5,
130.0, 129.9, 129.8, 127.8, 126.5, 124.6, 78.9, 71.4, 46.9, 31.6, 21.7;
LRMS (ES + APCI) m/z 351.9 [M]+; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C17H1935ClNO3S 352.0774, found 352.0770.
( )-2-Phenyl-1-tosylpyrrolidin-3-ol (9a).34 Reaction of (E)-4-
methyl-N-(4-phenylbut-3-en-1-yl)benzenesulfonamide 8a (25 mg,
0.08 mmol) and malonoyl peroxide 1 (16 mg, 0.12 mmol) in HFIP
(0.2 mL) according to General Procedure 3 followed by hydrolysis in
1 M NaOH/THF (0.8 mL, 1:1) gave the crude alcohol (1:13 cis/
trans). Purification by silica gel flash column chromatography (hexane/
EtOAc 4:6) gave title compound 9a (18 mg, 0.06 mmol, 71%) as a
white solid: mp 148−149 °C (lit.34 155−156 °C); IR (ATR)/cm−1
3474, 3065, 3034, 2929, 2892; 1H NMR (500 MHz, CDCl3) δ 7.75 (d,
J = 8.1 Hz, 2H), 7.34−7.33 (m, 4H), 7.31 (d, J = 8.1 Hz, 2H), 7.28−
7.26 (m, 1H), 4.66 (bs, 1H), 4.18 (bs, 1H), 3.73 (td, J = 9.4, 2.1 Hz,
1H), 3.53 (td, J = 9.9, 7.0 Hz, 1H), 2.43 (s, 3H), 2.07−2.00 (m, 1H),
1.77−1.73 (m, 1H), 1.37−1.38 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 143.7, 139.9, 134.7, 129.7, 128.7, 128.9, 127.7, 126.3, 79.1,
72.0, 46.8, 31.5, 21.7; LRMS (ES + APCI) m/z 318.0 [M + H]+.
( )-2-(p-Tolyl)-1-tosylpyrrolidin-3-ol (13). Reaction of (E)-4-
methyl-N-(4-(p-tolyl)but-3-en-1-yl)benzenesulfonamide (100 mg,
0.32 mmol) and malonoyl peroxide 1 (61 mg, 0.48 mmol) in HFIP
(0.7 mL) according to General Procedure 3 followed by hydrolysis in
1 M NaOH/THF (3.2 mL, 1:1) gave the crude alcohol (1:7 cis/trans).
Purification by silica gel flash column chromatography (hexane/EtOAc
4:6) gave title compound 13 (69 mg, 0.21 mmol, 66%) as a white
1
solid: mp 135−136 °C; IR (ATR)/cm−1 3401, 3029, 2960, 2899; H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0
Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 4.62 (bs,
1H), 4.13 (bs, 1H), 3.70 (ddd, J = 9.3, 8.6, 2.4 Hz, 1H), 3.50 (td, J =
9.9, 6.9 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.07−1.97 (m, 1H), 1.75−
1.69 (m, 1H), 1.54 (bs, 1H); 13C NMR (101 MHz, CDCl3) δ 143.6,
137.3, 137.1, 134.7, 129.7, 129.3, 127.9, 126.2, 79.0, 71.8, 46.8, 31.5,
21.7, 21.2; LRMS (ES + APCI) m/z 332.0 [M + H]+; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C18H22NO3S 332.1320, found
332.1316.
( )-2-(m-Tolyl)-1-tosylpyrrolidin-3-ol (14). Reaction of (E)-4-
methyl-N-(4-(m-tolyl)but-3-en-1-yl)benzenesulfonamide (50 mg,
0.16 mmol) and malonoyl peroxide 1 (30 mg, 0.24 mmol) in HFIP
(0.3 mL) according to General Procedure 3 followed by hydrolysis in
1 M NaOH/THF (1.9 mL, 1:1) gave the crude alcohol (1:6 cis/trans).
Purification by silica gel flash column chromatography (hexane/EtOAc
4:6) gave title compound 14 (37 mg, 0.11 mmol, 71%) as a white
solid: mp 102−104 °C; IR (ATR)/cm−1 3525, 3489, 3478. 3462,
3447, 2950, 2921; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz,
2H), 7.29 (d, J = 8.3 Hz, 2H), 7.21 (at, J = 7.5 Hz, 1H), 7.12−7.10 (m,
2H), 7.06 (d, J = 7.4 Hz, 1H), 4.63 (bs, 1H), 4.14 (bs, 1H), 3.71 (ddd,
J = 9.4, 8.5, 2.4 Hz, 1H), 3.53 (td, J = 9.9, 6.9 Hz, 1H), 2.42 (s, 3H),
2.32 (s, 3H), 2.07−1.98 (m, 1H), 1.76−1.70 (m, 1H), 1.55 (bd, J = 2.6
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 143.6, 139.9, 138.3, 134.8,
129.7, 128.6, 128.4, 127.8, 127.0, 123.4, 79.0, 72.0, 46.9, 31.5, 21.7,
21.6; LRMS (ES + APCI) m/z 332.0 [M + H]+; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C18H22NO3S 332.1320, found 332.1316.
( )-2-(o-Tolyl)-1-tosylpyrrolidin-3-ol (15). Reaction of (E)-4-
methyl-N-(4-(o-tolyl)but-3-en-1-yl)benzenesulfonamide (100 mg,
0.32 mmol) and malonoyl peroxide 1 (61 mg, 0.48 mmol) in HFIP
(0.6 mL) according to General Procedure 3 followed by hydrolysis in
1 M NaOH/THF (3.2 mL, 1:1) gave the crude alcohol (1:4.6 cis/
trans). Purification by silica gel flash column chromatography (hexane/
EtOAc 4:6) gave title compound 15 (76 mg, 0.23 mmol, 72%) as a
white solid: mp 173−175 °C; IR (ATR)/cm−1 3504, 3064, 2948,
2922, 2854; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 2H),
7.36−7.34 (m, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.20−7.12 (m, 3H), 4.85
(bs, 1H), 4.06 (bs, 1H), 3.76 (td, J = 8.9, 1.6 Hz, 1H), 3.54 (ddd, J =
11.0, 9.3, 6.7 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H), 2.10−2.01 (m, 1H),
1.79−1.74 (m, 1H), 1.59 (bs, 1H); 13C NMR (150 MHz, CDCl3) δ
143.6, 138.2, 134.8, 134.4, 130.5, 129.7, 127.8, 127.5, 126.4, 126.2,
77.6, 69.7, 46.9, 31.5, 21.7, 19.6; LRMS (ES + APCI) m/z 332.0 [M +
H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H22NO3S
332.1320, found 332.1317.
( )-2-(4-(1,3-Dioxalan-2-yl)phenyl)-1-tosylpyrrolidin-3-ol (19).
Reaction of (E)-N-(4-(4-(1,3-dioxalan-2-yl)phenyl)but-3-en-1-yl)-4-
methylbenzenesulfonamide (200 mg, 0.54 mmol) and malonoyl
peroxide 1 (103 mg, 0.80 mmol) in HFIP (1.1 mL) according to
General Procedure 3 followed by hydrolysis in 1 M NaOH/THF (5.3
mL, 1:1) gave the crude alcohol (1:9 cis/trans). Purification by silica
gel flash column chromatography (hexane/EtOAc 1:1) gave title
compound 19 (115 mg, 0.30 mmol, 55%) as a white solid: mp 146−
1
148 °C; IR (ATR)/cm−1 3517, 3054, 2922, 2887, 2852, 1702; H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2
Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.79 (s,
1H), 4.66 (bs, 1H), 4.13−4.07 (m, 3H), 4.05−4.00 (m, 2H), 3.71−
3.66 (m, 1H), 3.51 (dt, J = 9.9, 6.9 Hz, 1H), 2.41 (s, 3H), 2.01−1.92
(m, 1H), 1.73−1.75 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 143.7,
141.1, 137.4, 134.7, 129.7, 127.9, 126.8, 126.4, 103.6, 78.9, 71.8, 65.4,
46.9, 31.4, 21.7; LRMS (ES + APCI) m/z 390.0 [M + H]+; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C20H24NO5S 390.1375, found
390.1370.
( )-1-Tosyl-2-(4-(trifluoromethyl)phenyl)pyrrolidine-3-ol (20). Re-
action of (E)-4-methyl-N-(4-(4-trifluoromethyl)phenyl)but-3-en-1-yl)-
benzenesulfonamide (50 mg, 0.1 mmol) and malonoyl peroxide 1 (35
H
DOI: 10.1021/acs.joc.8b00392
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The Journal of Organic Chemistry
Note
mg, 0.3 mmol) in HFIP (0.6 mL) according to General Procedure 3,
warming up to 50 °C, followed by hydrolysis in 1 M NaOH/THF (2.6
mL, 1:1) gave the crude alcohol. Purification by silica gel flash column
chromatography (hexane/EtOAc 4:6) gave title compound 20 (10 mg,
0.03 mmol, 19%) as a white solid: mp 119−120 °C; IR (ATR)/cm−1
3541, 2996, 2888; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz,
2H), 7.57 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0
Hz, 2H), 4.69 (bs, 1H), 4.15 (bs, 1H), 3.74−3.70 (m, 1H), 3.55−3.50
(m, 1H), 2.42 (s, 3H), 2.01−1.95 (m, 1H), 1.78−1.74 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 144.1, 144.0, 134.3, 130.0 (JC−F = 13.8
Hz), 129.8, 127.9, 126.8, 125.7 (JC−F = 3.6 Hz), 124.2 (JC−F = 272.0
Hz), 78.9, 71.5, 47.0, 31.6, 21.7; LRMS (ES + APCI) m/z 386.0 [M +
H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H19F3NO3S
386.1038, found 386.1030.
2-(3-(Diphenylmethylene)pent-4-en-1-yl)isoindoline-1,3-dione.
To a solution of 2-(3-bromo-4,4-diphenylbut-3-en-1-yl)isoindoline-
1,3-dione (1.0 g, 2.3 mmol) in degassed EtOH (10 mL) were added
potassium vinyltrifluoroborate (0.4 g, 2.8 mmol) and Pd(dppf)Cl2 (0.2
g, 0.2 mmol) under a N2 atmosphere. The resulting mixture was
stirred at rt before the addition of Et3N (0.8 mL, 5.6 mmol). The
mixture was then heated to 120 °C, and stirring was continued for 48
h. The reaction was allowed to cool to room temperature, and the
solvent was removed under reduced pressure. The resulting solid was
dissolved in CH2Cl2 (20 mL), washed with H2O (20 mL), dried over
MgSO4, and filtered, and the solvent was removed by rotary
evaporation. Purification by silica gel flash column chromatography
(petroleum ether (40−60 °C)/EtOAc 9:1) afforded the title
compound (350 mg, 0.9 mmol, 40% (80% pure)) as a cream solid:
1
mp 135−137 °C; IR (ATR)/cm−1 3024, 1696, 1399, 1104, 988; H
( )-2,2-Diphenyl-1-tosylpyrrolidin-3-ol (21). Reaction of N-(4,4-
diphenylbut-3-en-1-yl)-4-methylbenzenesulfonamide (80 mg, 0.21
mmol) and malonoyl peroxide 1 (41 mg, 0.32 mmol) in HFIP (0.4
mL) according to General Procedure 3 followed by hydrolysis in 1 M
NaOH/THF (2.1 mL, 1:1) gave the crude alcohol. Purification by
silica gel flash column chromatography (hexane/EtOAc 6:4) gave title
compound 21 (68 mg, 0.17 mmol, 82%) as a white solid: mp 153−154
NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 7.70 (dd, J
= 5.5, 3.0 Hz, 2H), 7.37−7.14 (m, 8H), 7.09 (dd, J = 6.5, 3.1 Hz, 2H),
6.58 (dd, J = 17.5, 11.0 Hz, 1H), 5.61 (d, J = 17.5 Hz, 1H), 5.19 (d, J =
11.0 Hz, 1H), 3.89 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H); 13C
NMR (101 MHz, CDCl3) δ 168.1, 144.4, 142.2, 141.9, 136.0, 133.7,
132.3, 130.2, 129.1, 128.9, 128.5, 128.2, 127.9, 126.9, 123.1, 114.5,
37.5, 28.1; LCMS (ES + APCI) m/z = 380.5 [M + H]+; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C26H22NO2 380.1651, found 380.1638.
2-(3-(Diphenylmethylene)-5-hydroxypentyl)isoindoline-1,3-
dione. To a solution of 2-(3-(diphenylmethylene)pent-4-en-1-yl)-
isoindoline-1,3-dione (220 mg, 0.6 mmol) in anhydrous THF (2 mL)
was added BH3 (1.0 M in THF, 0.9 mL, 0.9 mmol) under a N2
atmosphere. The resulting solution was stirred at rt for 4 h. After this
time, a 2 M solution of NaOH (2 mL) was added followed by H2O2
(28% w/w, 2 mL), and the mixture was further stirred for 2 h. Upon
completion, the reaction was quenched by the addition of a 2 M
solution of HCl (10 mL), and the organic layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organics were washed with a
saturated solution of Na2S2O5 (2 × 10 mL), dried over MgSO4, and
filtered, and the solvent was removed by rotary evaporation.
Purification by silica gel flash column chromatography (petroleum
ether (40−60 °C)/EtOAc 1:1) afforded the title compound (80 mg,
0.2 mmol, 33%) as a cream solid: mp 137−139 °C; IR (ATR)/cm−1
1
°C; IR (ATR)/cm−1 3502, 3054, 2980, 2954; H NMR (400 MHz,
CDCl3) δ 7.49−7.47 (m, 2H), 7.43−7.34 (m, 3H), 7.30−7.25 (m,
3H), 7.20−7.17 (m, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.86−6.83 (m,
2H), 4.79 (dd, J = 7.9, 6.0 Hz, 1H), 4.04 (ddd, J = 9.4, 8.4, 3.9 Hz,
1H), 3.62 (ddd, J = 9.4, 8.4, 7.2 Hz, 1H), 2.33 (s, 3H), 2.17−2.10 (m,
1H), 1.77−1.67 (m, 1H), 1.43 (bs, 1H); 13C NMR (101 MHz,
CDCl3) δ 142.3, 139.0, 138.5, 138.2, 130.8, 130.0, 128.9, 127.93,
127.89, 127.7, 126.6, 79.2, 77.1, 46.4, 30.6, 21.5 (1 carbon missing);
LRMS (ES + APCI) m/z 394.0 [M + H]+; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C23H24NO3S 394.1477, found 394.1471.
( )-2-Phenyl-1-tosylpyrrolidin-3-ol (22). Malonoyl peroxide 1 (45
mg, 0.35 mmol) was added to a solution of (Z)-4-methyl-N-(4-(p-
tolyl)but-3-en-1-yl)benzenesulfonamide21 (70 mg, 0.23 mmol) in
HFIP (0.5 mL), and the mixture was stirred at rt for 5 h. The solvent
was removed by rotary evaporation, and the resulting residue was
directly treated with 1 M NaOH/THF (2 mL (1:1)). The solution was
stirred at 60 °C for 18 h and allowed to cool to rt, and the aqueous
phase was extracted with EtOAc (3 × 50 mL). The combined organics
were washed with brine (100 mL) and dried over MgSO4. Removal of
the solvent under reduced pressure afforded the crude pyrrolidine
product (4:1 cis/trans). Purification by silica gel flash column
chromatography (EtOAc/hexane 4:6) gave title compound 22 (37
mg, 0.11 mmol, 50%), as a white solid: mp 114−116 °C; IR (ATR)/
1
3434, 2964, 1685, 1399, 1043; H NMR (400 MHz, CDCl3) δ 7.79
(dd, J = 5.4, 3.2 Hz, 2H), 7.70 (dd, J = 5.4, 3.2 Hz, 2H), 7.31−7.24 (m,
2H), 7.21−7.07 (m, 4H), 7.06−7.00 (m, 2H), 6.87−6.83 (m, 2H),
3.81 (t, J = 6.5 Hz, 2H), 3.75 (t, J = 6.7 Hz, 2H), 2.68 (t, J = 6.5 Hz,
2H), 2.62 (t, J = 6.7 Hz, 2H), 1.77 (bs, 1H); 13C NMR (101 MHz,
CDCl3) δ 168.1, 143.7, 142.6, 142.1, 133.8, 132.4, 131.5, 129.0, 128.9,
128.2, 128.1, 126.5, 126.4, 123.1, 61.3, 36.4, 35.7, 30.6; LCMS (ES +
APCI) m/z = 398.3 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+
calcd for C26H24NO3 398.1756, found 398.1755.
N-(3-(Diphenylmethylene)-5-hydroxypentyl)-4-methylbenzene-
sulfonamide (28). To a solution of 2-(3-(diphenylmethylene)-5-
hydroxypentyl)isoindoline-1,3-dione (120 mg, 0.3 mmol) in EtOH (2
mL) was added hydrazine monohydrate (30 μL, 0.6 mmol) according
to General Procedure 2 to give 5-amino-3-(diphenylmethylene)-
pentan-1-ol.
To a solution of 5-amino-3-(diphenylmethylene)pentan-1-ol in
CH2Cl2 (2.0 mL) was added Et3N (60 μL, 0.3 mmol) followed by p-
TsCl (58 mg, 0.3 mmol) and DMAP (11 mg, 0.09 mmol) according to
General Procedure 2. Purification by silica gel flash column
chromatography (cyclohexane/EtOAc 7:3) afforded the title com-
pound 28 (67 mg, 0.2 mmol, 53%) as a colorless gum: IR (ATR)/
cm−1 2878, 1322, 1153, 700; 1H NMR (600 MHz, CDCl3) δ 7.66 (d, J
= 8.1 Hz, 2H), 7.29−7.23 (m, 6H), 7.21−7.17 (m, 2H), 7.16−7.12 (m,
2H), 7.10−7.06 (m, 2H), 4.96 (t, J = 5.9 Hz, 1H), 3.64 (t, J = 7.0 Hz,
2H), 2.98 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.42−2.38 (m, 4H), 1.75
(bs, 1H); 13C NMR (151 MHz, CDCl3) δ 143.6, 143.2, 142.4, 137.0,
131.4, 129.6, 129.5, 128.9, 128.8, 128.4, 128.2, 127.0, 126.6, 126.6,
61.0, 41.7, 35.2, 32.0, 21.6; LCMS (ES + APCI) m/z = 422.3 [M +
H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for C25H28NO3S
422.1790, found 422.1786.
1
cm−1 3452, 2974, 2872, 1325, 1156; H NMR (400 MHz, CDCl3) δ
7.69−7.64 (m, 2H), 7.39−7.28 (m, 7H), 4.74 (d, J = 5.6 Hz, 1H),
4.25−4.15 (m, 1H), 3.80−3.70 (m, 1H), 3.64 (ddd, J = 10.7, 7.7, 4.9
Hz, 1H), 2.43 (s, 3H), 1.89 (ddt, J = 16.3, 6.5, 4.9 Hz, 1H), 1.80−1.69
(m, 1H), 1.09 (d, J = 4.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
143.7, 136.5, 135.0, 129.8, 128.8, 128.7, 128.3, 127.9, 127.7, 126.3,
73.7, 67.7, 47.2, 32.5, 21.7; LRMS (ES + APCI) m/z 318.0 [M + H]+.
2-(3-Bromo-4,4-diphenylbut-3-en-1-yl)isoindoline-1,3-dione. Bro-
mine (0.3 mL, 5.7 mmol) was added dropwise to a solution of 2-(4,4-
diphenylbut-3-en-1-yl)isoindoline-1,3-dione (1.0 g, 2.8 mmol) in 1,2-
DCE (5 mL) at room temperature. The resulting solution was stirred
for 15 h before the solvent was removed under reduced pressure. The
residue was dissolved with a solution of KOH (0.6 g, 11.3 mmol) in
MeOH (10 mL) and stirred for 30 min. The solids were then
separated by filtration, and the filtrate was concentrated under reduced
pressure affording the title compound (1.2 g, 2.7 mmol, 98%) as a
cream solid that was used without further purification: mp 192−193
1
°C; IR (ATR)/cm−1 2942, 1699, 1123, 695; H NMR (400 MHz,
CDCl3) δ 7.88−7.81 (m, 2H), 7.78−7.71 (m, 2H), 7.38−7.24 (m,
5H), 7.23−7.17 (m, 1H), 7.16−7.09 (m, 2H), 7.01−6.95 (m, 2H),
4.02 (t, J = 6.3 Hz, 2H), 3.08 (t, J = 6.3 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 168.0, 144.4, 142.9, 139.8, 133.9, 132.3, 129.0, 128.5,
128.6, 128.1, 127.4, 127.4, 123.3, 122.9, 37.7, 37.0; LCMS (ES +
APCI) m/z 331.9, 434.0 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+
calcd for C24H1979BrNO2 432.0599, found 432.0589.
Oxidative Heterocyclization with a Probe Compound (28).
Reaction of N-(3-(diphenylmethylene)-5-hydroxypentyl)-4-methyl-
I
DOI: 10.1021/acs.joc.8b00392
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
benzenesulfonamide 28 (170 mg, 0.4 mmol) and malonoyl peroxide 1
(77 mg, 0.8 mmol) in HFIP (1.0 mL) according to General Procedure
5 to give a crude material. The crude was dissolved in PhMe (1.0 mL)
and MeOH (0.5 mL) before the addition of TMS-CHN2 (2 M in
Et2O, 1.0 mL, 2.02 mmol) according to General Procedure 5.
Purification by silica gel flash column chromatography (cyclohexane/
EtOAc 3:1) afforded the cyclized furan compound 29 (104 mg, 0.2
mmol, 46% over 2 steps) as a colorless gum and bicycle product (16
mg, 0.03 mmol, 7%) as a colorless gum.
134.3, 134.2, 128.9, 128.8, 128.1, 123.5, 122.8, 78.4; LRMS (ES +
APCI) m/z 314.0 [M + H]+; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C17H1335ClNO3 314.0584, found 314.0583.
N-(Cinnamyloxy)-4-methylbenzenesulfonamide (33).37 To a
solution of 2-(cinnamyloxy)isoindoline-1,3-dione (4.5 g, 16.1 mmol)
in EtOH (62 mL) was added hydrazine monohydrate (1.6 mL, 33.8
mmol) according to General Procedure 2 to give O-cinnamylhydroxyl-
amine.
To a solution of crude O-cinnamylhydroxylamine (16.1 mmol) in
CH2Cl2 (65 mL) was added Et3N (27 mL, 19.3 mmol) followed by p-
TsCl (3.4 g, 17.7 mmol) and DMAP (0.6 g, 4.8 mmol) according to
General Procedure 2. Purification by silica gel flash column
chromatography (hexane/EtOAc 8:2) afforded title compound 33
(2.9 g, 9.6 mmol, 60%) as a white solid: mp 109−110 °C (lit.37 103
1-Methyl 1-(3-(2-((4-Methylphenyl)sulfonamido)ethyl)-2,2-diphe-
nyltetrahydrofuran-3-yl)cyclopropane-1,1-dicarboxylate (29): IR
1
(ATR)/cm−1 2954, 1722, 1438, 1323; H NMR (600 MHz, CDCl3)
δ 7.63 (t, J = 7.5 Hz, 4H), 7.54 (d, J = 7.5 Hz, 2H), 7.31−7.16 (m,
8H), 4.69 (bs, 1H), 4.12−4.02 (m, 2H), 3.76 (s, 3H), 2.86−2.76 (m,
1H), 2.77−2.64 (m, 2H), 2.45 (s, 3H), 2.36−2.29 (m, 1H), 2.20 (ddd,
J = 15.0, 8.0, 6.5 Hz, 1H), 2.06 (dt, J = 15.0, 7.5 Hz, 1H), 1.61−1.55
(m, 1H), 1.49−1.45 (m, 1H), 1.41−1.35 (m, 1H), 1.20−1.14 (m, 1H);
13C NMR (151 MHz, CDCl3) δ (ppm) 170.0, 168.6, 143.1, 142.6,
142.0, 137.0, 129.5, 127.9, 127.8, 127.2, 127.2, 127.0, 126.9, 126.1,
90.3, 88.7, 64.0, 52.6, 39.1, 35.9, 34.4, 28.8, 21.5, 16.7, 16.5; LCMS (ES
+ APCI) m/z = 586.3 [M + Na]+; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C31H33NNaO7S 586.1875, found 586.1873.
1
°C); IR (ATR)/cm−1 3220, 3058, 3026, 2924, 2870; H NMR (500
MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.38−7.25 (m, 7H), 6.91
(bs, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.22 (dt, J = 15.9, 6.8 Hz, 1H),
4.61 (d, J = 6.8, 2H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
145.1, 136.3, 136.0, 133.8, 129.9, 128.77, 128.75, 128.4, 126.9, 122.9,
78.1, 21.8; LRMS (ES + APCI) m/z 321.0 [M + NH4]+.
(E)-N-((3-(4-Chlorophenyl)allyl)oxy)-4-methylbenzenesulfona-
mide (35). To a solution of (E)-2-((3-(4-chlorophenyl)allyl)oxy)-
isoindoline-1,3-dione (202 mg, 0.6 mmol) in EtOH (2.3 mL) was
added hydrazine monohydrate (61 μL, 1.3 mmol) according to
General Procedure 2 to give (E)-O-(3-(4-chlorophenyl)allyl)-
hydroxylamine.
Methyl 1-(5-(2-((4-Methylphenyl)sulphonamide)ethyl)-6,6-di-
phenyl-2,7,8-trioxabicyclo[3.2.1]octan-1-yl)cyclopropane-1-carbox-
1
ylate (31): IR (ATR)/cm−1 2954, 1723, 1328, 1161, 1040; H NMR
(600 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 2H), 7.41−7.37 (m, 2H),
7.32−7.21 (m, 8H), 5.14 (dd, J = 7.3, 3.2 Hz, 1H), 3.85 (s, 3H), 3.75−
3.67 (m, 1H), 3.58 (dd, J = 11.3, 6.8 Hz, 1H), 3.14−3.07 (m, 1H),
2.99 (dt, J = 8.6, 4.2 Hz, 1H), 2.45 (s, 3H), 2.00 (td, J = 12.9, 7.0 Hz,
1H), 1.92−1.87 (m, 1H), 1.82−1.74 (m, 1H), 1.54 (dd, J = 13.6, 3.8
Hz, 1H), 1.50−1.45 (m, 1H), 1.41−1.32 (m, 3H); 13C NMR (151
MHz, CDCl3) δ 171.7, 143.3, 141.1, 139.8, 136.8, 129.7, 128.5, 127.8,
127.7, 127.7, 127.1, 118.1, 90.7, 86.1, 59.2, 52.5, 39.3, 35.1, 29.3, 29.1,
21.5, 14.6, 13.4; LCMS (ES + APCI) m/z = 586.3 [M + Na]+; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C31H33NNaO7S 586.1875, found
586.1872.
General Procedure 4 (Mitsunobu Reaction). A dry three-neck
flask was charged with cinnamyl alcohol (1.0 equiv), PPh3 (1.1 equiv),
and N-hydroxyphthalimide (1.1 equiv) in anhydrous THF (0.25 M).
The solution was cooled to 0 °C, and diethyl azodicarboxylate (2.2 M
in PhMe, 1.1 equiv) was added dropwise. The mixture was warmed to
rt and stirred for 2.5 h. The solvent was removed by rotary evaporation
before purification by silica gel flash column chromatography with
hexane/EtOAc mixtures to afford the target compound.
To a solution of crude (E)-O-(3-(4-chlorophenyl)allyl)-
hydroxylamine(0.6 mmol) in CH2Cl2 (2.2 mL) was added Et3N
(120 μL, 0.8 mmol) followed by p-TsCl (107 mg, 0.6 mmol) and
DMAP (22 mg, 0.2 mmol) according to General Procedure 2.
Purification by silica gel flash column chromatography (hexane/EtOAc
8:2) afforded title compound 35 (102 mg, 0.3 mmol, 54%) as a white
1
solid: mp 116−118 °C; IR (ATR)/cm−1 3216, 3064, 2922, 2852; H
NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0
Hz, 2H), 7.27−7.25 (s, 4H), 7.04 (bs, 1H), 6.54 (d, J = 15.9 Hz, 1H),
6.17 (dt, J = 15.9, 6.7 Hz, 1H), 4.57 (bd, J = 6.7 Hz, 2H), 2.41 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 145.0, 134.7, 134.4, 133.9, 133.7,
129.8, 128.8, 128.6, 127.9, 123.6, 77.6, 21.7; LRMS (ES + APCI) m/z
355.0 [M + NH4]+; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C16H1735ClNO3S 338.0618, found 338.0616.
General Procedure 5. Oxidative cyclization for the synthesis of
isoxazolidines. Malonoyl peroxide 1 (1.5 equiv) was added to a
solution of alkene 33 or 34 (1.0 equiv) in HFIP (0.5 M). The mixture
was stirred at 40 °C for 18 h before removal of the solvent by rotary
evaporation. The residue was dissolved in PhMe (0.2 M) and MeOH
(0.5 M) and a solution of TMS-CHN2 in Et2O (2.0 equiv) was added
dropwise. The resulting mixture was stirred at rt for 2 h before the
solvents were evaporated under reduced pressure. Purification of the
crude material by silica gel flash column chromatography with
petroleum ether (40−60 °C):Et2O mixtures afforded the target
compounds.
2-(Cinnamyloxy)isoindoline-1,3-dione.35 Cinnamyl alcohol (2.2 g,
16.0 mmol), PPh3 (4.6 g, 17.6 mmol), and N-hydroxyphthalimide (2.9
g, 17.6 mmol) were dissolved in anhydrous THF (64 mL) before the
dropwise addition of diethyl azodicarboxylate (2.2 M in PhMe, 8.0 mL,
17.6 mmol) according to the General Procedure 4. Purification by
silica gel flash column chromatography (hexane/EtOAc 8:2) afforded
the title compound (4.3 g, 15.4 mmol, 96%) as a white solid: mp 148−
150 °C (lit.36 116−118 °C); IR (ATR)/cm−1 3058, 3028, 2948, 1790;
1H NMR (500 MHz, CDCl3) δ 7.82−7.80 (m, 2H), 7.74−7.71 (m,
2H), 7.39−7.37 (m, 2H), 7.32−7.29 (m, 2H), 7.27−7.24 (m, 1H),
6.67 (d, J = 15.9 Hz, 1H), 6.47 (dt, J = 15.9, 7.1 Hz, 1H), 4.87 (d, J =
7.1 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 164.0, 137.7, 136.0,
134.6, 129.0, 128.8, 128.6, 127.1, 123.7, 122.2, 78.8; LRMS (ES +
APCI) m/z 297.0 [M + NH4]+.
(
)-1-(((3-Phenyl-2-tosylisoxazolidin-4-yl)oxy)carbonyl)-
cyclopropane-1-carboxylic Acid (37). To a solution of N-
(cinnamyloxy)-4-methylbenzenesulfonamide 33 (151 mg, 0.50
mmol) in HFIP (1.0 mL) was added malonoyl peroxide 1 (96 mg,
0.75 mmol) according to General Procedure 5 (without the TMS-
CHN2 methyl ester formation) to give crude isoxazolidine (1:10 cis/
trans). Purification by silica gel flash column chromatography (EtOAc
then EtOAc/AcOH 0.5%) afforded title compound 37 (178 mg, 0.41
mmol, 83%) as a white solid for characterization and X-ray analysis
purposes: mp 137−139 °C; IR (ATR)/cm−1 3550, 2930, 2852,1716,
1660; 1H NMR (500 MHz, CDCl3) δ 12.19 (bs, 1H), 7.88 (d, J = 8.3
Hz, 2H), 7.44−7.34 (m, 7H), 5.61 (ddd, J = 6.0, 3.1, 0.7 Hz, 1H), 5.54
(bs, 1H), 4.44 (dd, J = 9.6, 3.1 Hz, 1H), 4.39 (dd, J = 9.6, 6.0 Hz, 1H),
2.47 (s, 3H), 2.18−2.14 (m, 1H), 2.06−2.03 (m, 1H), 1.99−1.93 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 176.3, 170.0, 145.5, 136.3,
133.7, 129.9, 129.2, 129.1, 128.7, 126.5, 84.9, 74.6, 66.9, 25.6, 23.5,
23.2, 21.9; LRMS (ES + APCI) m/z 432.0 [M + H]+; HRMS (ESI-
TOF) m/z [M − H]− calcd for C21H20NO7S 430.0960, found
430.0954.
(E)-2-((3-(4-Chlorophenyl)allyl)oxy)isoindoline-1,3-dione. (E)-3-
(4-Chlorophenyl)prop-2-en-1-ol (300 mg, 1.8 mmol), PPh3 (513
mg, 2.0 mmol), and N-hydroxyphthalimide (320 mg, 2.0 mmol) were
dissolved in anhydrous THF (7.0 mL) before the dropwise addition of
diethyl azodicarboxylate (2.2 M in PhMe, 0.9 mL, 1.96 mmol)
according to General Procedure 4. Purification by silica gel flash
column chromatography (hexane/EtOAc 8:2) afforded the title
compound (200 mg, 0.6 mmol, 35%) as a white solid: mp 138−140
1
°C; IR (ATR)/cm−1 3050, 2948, 1788, 1742; H NMR (400 MHz,
CDCl3) δ 7.83−7.81 (m, 2H), 7.74−7.72 (m, 2H), 7.32−7.27 (m,
4H), 6.63 (d, J = 15.9 Hz, 1H), 6.44 (dt, J = 15.9, 7.0 Hz, 1H), 4.85 (d,
J = 7.0, 2H); 13C NMR (101 MHz, CDCl3) δ 163.8, 136.0, 134.5,
J
DOI: 10.1021/acs.joc.8b00392
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
( )-1-Methyl 1-((3R,4S)-3-Phenyl-2-tosylisoxazolidin-4-yl)-
cyclopropane-1,1-dicarboxylate (34). To a solution of N-(cinnamy-
loxy)-4-methylbenzenesulfonamide 33 (185 mg, 0.43 mmol) in HFIP
(0.9 mL) was added malonoyl peroxide 1 (82 mg, 0.65 mmol)
according to General Procedure 5 to give crude isoxazolidine (1:10 cis/
trans), which was dissolved in PhMe (2.2 mL) and MeOH (0.9 mL)
before the addition of TMS-CHN2 (2 M in Et2O, 0.43 mL, 0.86
mmol) according to General Procedure 5. Purification by silica gel
flash column chromatography (petroleum ether (40−60 °C)/EtOAc
6:4) afforded title compound 34 (154 mg, 0.35 mmol, 80% over two
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00392.
■
S
NMR spectra for all compounds reported, X-ray data for
10 and 36 and DSC data for 1 (PDF)
Crystal data for 10 and 36 (CIF)
1
steps) as a colorless oil: IR (ATR)/cm−1 3028, 3062, 2954, 1727; H
AUTHOR INFORMATION
Corresponding Author
*E-mail: Nicholas.Tomkinson@strath.ac.uk.
ORCID
Alan R. Kennedy: 0000-0003-3652-6015
Nicholas C. O. Tomkinson: 0000-0002-5509-0133
Notes
■
NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 7.3
Hz, 2H), 7.38−7.35 (m, 4H), 7.31 (t, J = 7.3 Hz, 1H), 5.52 (ddd, J =
6.1, 4.1, 1.7 Hz, 1H), 5.56 (bs, 1H), 4.38 (dd, J = 9.3, 6.1 Hz, 1H),
4.34 (dd, J = 9.3, 4.1 Hz, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 1.67−1.51
(m, 4H); 13C NMR (126 MHz, CDCl3) δ 169.9, 169.4, 145.2, 137.3,
133.9, 129.8, 129.2, 129.0, 128.3, 126.6, 83.8, 74.4, 67.0, 53.0, 27.9,
21.9, 17.6, 17.5; LRMS (ES + APCI) m/z 463.0 [M + NH4]+; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C22H24NO7S 446.1273, found
446.1266.
The authors declare no competing financial interest.
( )-1-((3R,4S)-3-(4-Chlorophenyl)-2-tosylisoxazolidin-4-yl) 1-
Methylcyclopropane-1,1-dicarboxylate (36). To a solution of (E)-
N-((3-(4-chlorophenyl)allyl)oxy)-4-methylbenzenesulfonamide 35
(66 mg, 0.20 mmol) in HFIP (0.4 mL) was added malonoyl peroxide
1 (38 mg, 0.29 mmol) according to General Procedure 5 to give crude
isoxazolidine (1:7 cis/trans), which was dissolved in PhMe (1.0 mL)
and MeOH (0.4 mL) before the addition of TMS-CHN2 (2 M in
Et2O, 0.2 mL, 0.40 mmol) according to General Procedure 5.
Purification by silica gel flash column chromatography (petroleum
ether (40−60 °C)/EtOAc 6:4) afforded title compound 36 (80 mg,
0.17 mmol, 85% over 2 steps) as a white solid: mp 110−112 °C; IR
ACKNOWLEDGMENTS
■
The authors thank Sean Lynn for NMR characterization of 31,
the EPSRC and GlaxoSmithKline for financial support, and the
EPSRC Mass Spectrometry Service, Swansea, for high-
resolution spectra.
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