Prins cascade cyclization for the synthesis of 1,9-dioxa-4-azaspiro[5.5] undecane derivatives

Article abstract of DOI:10.1021/jo4027534

A novel Prins cascade process for the synthesis of 1,9-dioxa-4- azaspiro[5.5]undecane derivatives by the coupling of aldehydes with N-(4-hydroxy-2-methylenebutyl)-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide has been developed. This is the first report of the synthesis of spiromorpholinotetrahydropyran derivatives through a Prins bicyclization.

Full text of DOI:10.1021/jo4027534

Note
pubs.acs.org/joc
Prins Cascade Cyclization for the Synthesis of 1,9-Dioxa-4-
azaspiro[5.5]undecane Derivatives
B. V. Subba Reddy,*,† Durgaprasad Medaboina,† B. Sridhar,‡ and Kiran Kumar Singarapu§
†Natural Product Chemistry, ‡Laboratory of X-ray Crystallography, and §Centre for Nuclear Magnetic Resonance, Indian Institute of
Chemical Technology, Hyderabad-500 007, India
S
* Supporting Information
ABSTRACT: A novel Prins cascade process for the synthesis of 1,9-
dioxa-4- azaspiro[5.5]undecane derivatives by the coupling of aldehydes
with N-(4-hydroxy-2-methylenebutyl)-N-(2-hydroxyethyl)-4-methylben-
zenesulfonamide has been developed. This is the first report of the
synthesis of spiromorpholinotetrahydropyran derivatives through a Prins
bicyclization.
piroketal derivatives possessing a nitrogen atom have been
evaluated as tachykinin antagonists. In particular, spiro-
Scheme 1. Preparation of Starting Material 4
S
morpholine derivatives have been found to exhibit high affinity
and excellent central nervous system penetration.1 They are
known to display a broad spectrum of biological activities such
as antiproliferative, anti-HIV, and NK1 receptor antagonist
behavior (Figure 1).2,3 The Prins cyclization is a very useful
upon desilylation with TBAF gave the desired homoallyl
alcohol 4.
Initially, we attempted the coupling of diol 4 with p-
chlorobenzaldehyde in the presence of 30 mol % In(OTf)3.
However, the corresponding 1,9-dioxa-4-azaspiro[5.5]undecane
was obtained as a mixture of 6g and 7g in a 66:34 ratio (Table
1, entry a), which were unseparable by column chromatog-
raphy. Therefore, to improve the selectivity, the above reaction
was performed using various acid catalysts at different
temperatures, and the results are presented in Table 1. It was
observed that the 6g/7g ratio differs with temperature.
Interestingly, excellent selectivity for 6g was obtained at −50
°C in the presence of 1.2 equiv of BF3·OEt2. Under the
optimized conditions, the required product 6g was isolated in
excellent yield (95%) and selectivity (92:8) (Table 1, entry e).
Figure 1. Biologically active spirotetrahydropyrans.
strategy for the construction of the tetrahydropyran ring
system, which is a common structural unit in several natural
products.4 In particular, a tandem Prins reaction is a simple and
one-pot strategy for the stereoselective synthesis of heterobi-
cycles.5,6 In spite of its potential applications in the synthesis of
biologically active molecules,7 the scope of a tandem Prins
process for the synthesis of dioxaazaspiro[5.5]undecane
derivatives from a readily accessible hydroxy-tethered homo-
allylic alcohol has not yet been explored.
Following our interest in Prins-type cyclizations for the
synthesis of heterocycles,8 we herein report a novel and
efficient strategy for the synthesis of 1,9-dioxa-4-azaspiro[5.5]-
undecane derivatives through a cascade of Prins reactions.
The requisite homoallyl alcohol, N-(4-hydroxy-2-methylene-
butyl)-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide (4),
was prepared as shown in Scheme 1. Allyl alcohol 1 was
prepared according to the literature procedure.9 Accordingly,
the coupling of 1 with aminoethanol derivative 2 under
Mitsunobu conditions afforded the di-TBS derivative 3, which
1
The ratio of products was determined from the H NMR
spectrum of the crude mixture. However, the reaction did not
proceed at −60 °C even when the amount of Lewis acid was
increased from 1.2 to 2.4 equiv. Next, we examined the effect of
the solvent on the conversion. Among the various solvents
tested, such as dichloromethane, acetonitrile, tetrahydrofuran,
benzene, and dichloroethane, dichloromethane gave the best
results in terms of conversion.
The scope of this reaction was further evaluated using various
aldehydes containing different electron-withdrawing and
-donating substituents on the aromatic ring. As shown in
Table 2, the product obtained depends upon the nature of the
aldehyde and the electronic character of the substituent. It was
observed that activated aromatic aldehydes (Table 2, entries k
Received: December 16, 2013
Published: February 17, 2014
© 2014 American Chemical Society
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Note
Table 1. Optimization of the Reaction Conditions
a
b
Entry
Lewis acid
Equiv
Solvent
T (°C)
t (h)
Yield (%)
dr (6g:7g)
a
b
c
d
e
f
In(OTf)3
In(OTf)3
In(OTf)3
Sc(OTf)3
InBr3
0.3
0.3
0.3
0.3
0.5
0.5
1.2
1.2
1.2
1.2
2.4
1.2
1.2
1.2
1.2
2.4
DCM
DCM
DCE
rt
3
90
−
70
80
−
66:34
−
66:34
66:34
−
0
16
16
10
12
12
0.5
0.5
0.5
10
10
1
rt
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
rt
rt
InCl3
rt
−
−
g
h
i
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
TMSOTf
0
96
96
95
−
83:17
89:11
92:8
−
−20
−50
−60
−60
−50
−50
−50
−50
−60
j
k
l
−
−
80
60
−
−
−
92:8
92:8
−
−
−
m
n
o
p
benzene
THF
1
2
AcCN
DCM
2
10
a
b
1
Yields refer to the pure products after column chromatography. The product ratios were determined by H NMR analysis.
and l) gave the products in slightly lower yields than the
halogenated or alkyl-substituted aromatic counterparts. Surpris-
ingly, nitro-substituted benzaldehyde failed to give the desired
product at −50 °C. Though the above reaction was successful
at room temperature, the 6:7 selectivity was very low
(approximately a 1:1 ratio).
This method works not only with aromatic aldehydes but
also with acid-sensitive cinnamaldehyde and phenylacetalde-
hyde (Table 2, entries m and n) as well as sterically hindered 2-
naphthaldehyde (Table 2, entry e). The efficiency of this
method was also exemplified by performing the reaction with
aliphatic aldehydes (Table 2, entries q and r) and the
heterocyclic aldehyde thiophene-2-carboxaldehyde (Table 2,
entry p). Finally, we attempted to remove the tosyl protecting
group with lithium naphthalenide. Accordingly, treatment of N-
tosyl spiropyranomorpholine 6b with 10 equiv of lithium
naphthalenide in THF at −50 °C gave the desired free amine 8
in 80% yield (Scheme 2).
isomers, having H8 in an axial position and the aryl group in an
3
equatorial position. The large coupling constants JH8−H7′
=
3
12.0 Hz and JH11′−H10′ = 13.2 Hz for the major isomer and
3JH8−H7′ = 11.6 Hz for the minor isomer and the presence of
NOE cross-peaks between H8 and H10′(ax) and between
H7′(ax) and H11′(ax) indicate that the six-membered ring is in
9
the C6 chair conformation. The stereochemistry of the major
isomer at the spiro center was determined by the appearance of
NOE cross-peaks between H8 and H5, H8 and H5′(ax), H5′(ax)
and H7, H5 and H7, and H10′(ax) and H5, which indicate that
the oxygen is in the equatorial position and the methylene
group in the axial position on the six-membered tetrahydropyr-
an ring, as shown in Figure 2. The appearance of NOE cross-
peaks between H7′(ax) and H5′(ax), H11′(ax) and H5′(ax), and
H11 and H2 in the minor isomer supports the presence of
methylene in the equatorial position and oxygen in the axial
position on the tetrahydropyran ring.
In order to explain the stereochemical outcome of the Prins
cyclization, the reaction is proposed to proceed via the
formation of oxocarbenium ion A from the aldehyde and the
homoallylic alcohol, likely after activation with BF3·OEt2. The
oxocarbenium ion is attacked by the internal olefin, resulting in
the formation of tertiary carbocation B, which is simultaneously
trapped by the tethered hydroxyl group, leading to the
formation of the spirocycle as depicted in Scheme 3. The
exceptional diastereoselectivity in favor of the major isomer 6 is
believed to originate from the favorable trapping of the
carbocation from the less hindered equatorial side to overcome
the unfavorable 1,3-diaxial interactions, as shown in Scheme 3.
The interconversion of the chair conformation B to the less
favored conformation C in which the R group is placed in the
axial position is more rapid at room temperature than at low
temperature, which may be responsible for the formation of the
minor isomer 7 at room temperature.
Furthermore, we performed the reaction with homoallylic
substrates 9 and 10 bearing N-Boc and N-Cbz protecting
groups, respectively, instead of the N-Ts group, but no desired
product was obtained with either of these protecting groups.
These results clearly reveal that the reaction was successful only
with N-tosyl protection.
The structure of major isomer 6i was confirmed by X-ray
crystallography.10 Furthermore, the structure and stereo-
chemistry of 6g and 7g were established by detailed 1D and
2D NMR experiments (Figure 2). When the reaction was run
at room temperature using 30 mol % In(OTf)3, the
diastereomeric ratio of 6g and 7g was 10:4, which was
measured by integrating the isolated peaks at 4.36 and 4.60
ppm. The 3J coupling constants 3JH8−H7 = 2.3 Hz and 3JH8−H7′
=
12.0 Hz for the major isomer and 3JH8−H7 = 2.2 Hz and 3JH8−H7′
= 11.6 Hz for the minor isomer along with the presence of an
NOE cross-peak between H8 and H10′ for both isomers
indicate that the stereocenter at carbon C8 is the same in both
In conclusion, a novel Prins cascade strategy has been
developed for the synthesis of 1,9-dioxa-4-azaspiro[5.5]-
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Note
Table 2. Preparation of Azaspiro[5.5]undecane Scaffolds through a Prins Bicyclization
a
b
1
Yields refer to the pure products after column chromatoraphy. The product ratios were determined by H NMR analysis.
undecane derivatives. The reaction is highly diastereoselective
and proceeds in good yield in most cases. This method
provides direct access to the synthesis of pharmaceutically
interesting spirocyclic scaffolds, which are reported to have
antiproliferative and anti-HIV activity.
EXPERIMENTAL SECTION
■
General. All of the solvents were dried according to standard
literature procedures. Reactions were performed in oven-dried round-
bottom flasks fitted with rubber septa, and the reactions were
conducted under a nitrogen atmosphere. Glass syringes were used to
transfer solvents. Crude products were purified by column
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Note
of the starting material as indicated by TLC, the solvent was
evoporated on rotary evaporator, and the resulting crude product was
purified by column chromatography (silica gel, 60−120 mesh) using
an ethyl acetate/n-hexane gradient mixture to afford the pure product
3 in 70% yield as a colorless liquid. Yield: 1.84 g, 70%. 1H NMR (500
MHz, CDCl3): δ 7.70 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H),
4.96 (s, 2H), 3.78 (s, 2H), 3.71 (t, J = 6.7 Hz, 2H), 3.66 (t, J = 6.8 Hz,
2H), 3.17 (t, J = 6.8 Hz, 2H), 2.42 (s, 3H), 2.23 (t, J = 6.5 Hz, 2H),
0.88 (s, 9H), 0.84 (s, 9H), 0.05 (s, 6H), 0.0 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 143.0, 141.6, 136.9, 129.5, 127.1, 115.1, 61.6, 61.4,
54.6, 49.2, 36.2, 25.9, 25.8, 21.4, 18.2, 18.1, −5.3, −5.4. IR (KBr) ν
(cm−1): 3448, 2954, 2930, 2888, 2857, 1726, 1650, 1599, 1467, 1345,
1254, 1161, 1096, 1023, 931, 835, 776, 658, 549. MS-ESI: m/z 550 [M
+ Na]+. HRMS (Orbitrap ESI): calcd for C26H50O4NSSi2 [M + H]+,
528.2993; found, 528.2980.
Scheme 2. . Removal of the p-Toluenesulfonyl Protecting
Group
N-(4-Hydroxy-2-methylenebutyl)-N-(2-hydroxyethyl)-4-methyl-
benzenesulfonamide (4). To a solution of 3 (1.58 g, 3 mmol) in THF
at 0 °C was added TBAF (7 mmol) dropwise, and the resulting
mixture was allowed to stir at rt for 1 h. After complete consuption of
the starting material as indicated by TLC, the reaction was quenched
with a saturated solution of NaHCO3, and the aqueous layer was
extracted with ethyl acetate. Removal of the solvent followed by
purification by silica gel column chromatography (silica gel, 60−120
mesh) using an ethyl acetate/n-hexane gradient mixture afforded the
pure product 4 in 95% yield as a colorless liquid. Yield: 0.851 g, 95%.
1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 8.3 Hz, 2H), 7.33 (d, J =
7.9 Hz, 2H), 5.07 (d, J = 3.7 Hz, 2H), 3.84−3.69 (m, 6H), 3.21 (t, J =
5.2 Hz, 2H), 2.44 (s, 3H), 2.39 (t, J = 6.0 Hz, 2H), 1.66 (br s, 2H). 13
C
Figure 2. Characteristic NOEs and energy-minimized structures of 6g
and 7g.
NMR (125 MHz, CDCl3): δ 143.6, 141.6, 135.4, 129.7, 127.2, 115.9,
60.9, 60.4, 55.3, 50.9, 35.9, 21.4. IR (neat) ν (cm−1): 3404 broad,
2928, 1650, 1598,1443, 1331, 1157, 1115, 1085, 1045, 920, 814, 757,
703, 657, 548. MS-ESI: m/z 322.06 [M + Na]+. HRMS (Orbitrap
ESI): calcd for C14H22O4NS [M + H]+, 300.1264; found, 300.1260.
Typical Procedure for Prins Bicyclization. To a mixture of 4
(0.5 mmol) and benzaldehyde (0.6 mmol) in anhydrous DCM (5 mL)
was added BF3·OEt2 (1.2 equiv) at −50 °C. The resulting mixture was
allowed to stir at the same temperature under a nitrogen atmosphere
for the specified time (Table 2). After completion of the reaction, the
reaction mixture was quenched with NaHCO3 solution (5 mL) and
then extracted with dichloromethane (2 × 5 mL). The organic phases
were washed with brine (3 × 2 mL), dried over anhydrous Na2SO4,
and concentrated on a rotary evaporator. The resulting crude product
was purified by silica gel column chromatography (100−200 mesh)
using an ethyl acetate/hexane gradient mixture to afford the pure
product 6a (Table 2, entry a).
Scheme 3. A Plausible Reaction Mechanism
8-Phenyl-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6a). White
1
solid; yield 174 mg, 90%; mp 116−118 °C. H NMR (500 MHz,
CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.39−7.27 (m, 7H), 4.38 (dd, J =
12.0, 2.2 Hz, 1H), 4.13 (ddd, J = 12.3, 5.3, 1.3 Hz, 1H), 3.86−3.80 (m,
2H), 3.64 (td, J = 13.1, 2.2 Hz, 1H), 3.23 (d, J = 11.4 Hz, 1H), 3.1−
3.04 (m, 2H), 3.03−2.96 (m, 1H), 2.46 (s, 3H), 2.28 (d, J = 13.1 Hz,
1H), 2.01 (d, J = 13.2 Hz, 1H), 1.78 (td, J = 13.1, 5.4 Hz, 1H), 1.64 (t,
J = 12.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 143.9, 141.6, 132.8,
129.8, 128.3, 127.6, 127.5, 125.8, 76.4, 71.3, 64.5, 59.3, 50.2, 45.7, 41.1,
33.8, 21.4. IR (KBr) ν (cm−1): 3446, 3061, 2927, 2856, 1739, 1598,
1452, 1346, 1283, 1166, 1089, 956, 912, 814, 755, 700, 658, 547. MS-
ESI: m/z 410.07 [M + Na]+. HRMS (Orbitrap ESI): calcd for
C21H26O4NS [M + H]+, 388.1577; found, 388.1572.
chromatography on silica gel of 60−120 or 100−200 mesh. Thin-layer
chromatography plates were visualized by exposure to ultraviolet light
and/or by exposure to iodine vapors and/or by exposure to a
methanolic acidic solution of p-anisaldehyde followed by heating (<1
min) on a hot plate (∼250 °C). Organic solutions were concentrated
on a rotary evaporator at 35−40 °C. IR spectra were recorded on an
FT-IR spectrometer. 1H and proton-decoupled 13C NMR spectra were
recorded in CDCl3 solvent on a 200, 300, 400, or 500 MHz NMR
spectrometer. Chemical shifts (δ) are reported in parts per million
with respect to TMS as an internal standard. Coupling constants (J)
are quoted in hertz. Mass spectra were recorded on a mass
spectrometer using electrospray ionization (ESI) or atmospheric-
pressure chemical ionization (APCI).
Preparation of the Starting Material 4. N-(4-((tert-
Butyldimethylsilyl)oxy)-2-methylenebutyl)-N-(2-((tert-
butyldimethylsilyl)oxy) ethyl)-4-methylbenzenesulfonamide (3). To
a premixed solution of 1 (1.08 g, 5 mmol), 2 (1.97 g, 6 mmol), and
triphenylphosphine (1.57 g, 6 mmol) in THF at 0 °C was added
diethyl azodicarboxylate (1.84 g, 6 mmol) dropwise over 5 min. The
resulting mixture was stirred at rt for 4 h. After complete consumption
8-(p-Tolyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6b).
1
White solid; yield 190 mg, 95%; mp 130−132 °C. H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.23 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.33 (dd, J = 12.0,
1.8 Hz, 1H), 4.11 (ddd, J = 12.2, 5.1, 1.2 Hz, 1H), 3.82 (t, J = 4.8 Hz,
2H), 3.62 (td, J = 12.9, 2.1 Hz, 1H), 3.19 (d, J = 11.5 Hz, 1H), 3.09 (d,
J = 11.5 Hz, 1H), 3.06−2.97 (m, 2H), 2.46 (s, 3H), 2.34 (s, 3H), 2.24
(d, J = 13.1 Hz, 1H), 2.02 (d, J = 13.1 Hz, 1H), 1.76 (td, J = 13.1, 5.4
Hz, 1H), 1.64 (t, J = 12.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
143.9, 138.6, 137.3, 132.7, 129.8, 129.0, 127.5, 125.7, 76.2, 71.3, 64.5,
59.3, 50.2, 45.7, 41.2, 33.7, 21.4, 21.0. IR (KBr) ν (cm−1): 3449, 2968,
2925, 2855, 1598, 1515, 1452, 1336, 1168, 1099, 1044, 1019, 975, 816,
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Note
764, 662, 550. MS-ESI: m/z 424.22 [M + Na]+. HRMS (Orbitrap
ESI): calcd for C22H28O4NS [M + H]+, 402.1733; found, 402.1734.
8-(4-Isopropylphenyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
H]+. HRMS (Orbitrap ESI): calcd for C21H25O4NClS [M + H]+,
422.1187; found, 422.1183.
8-(4-Bromophenyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
(6h). White solid; yield 209 mg, 90%; mp 135−137 °C. 1H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H),
7.37 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 4.34 (dd, J = 12.0,
2.1 Hz, 1H), 4.12 (ddd, J = 12.3, 5.3, 1.3 Hz, 1H), 3.86−3.78 (m, 2H),
3.62 (td, J = 12.9, 2.1 Hz, 1H), 3.25 (d, J = 11.5 Hz, 1H), 3.13−2.93
(m, 3H), 2.46 (s, 3H), 2.28 (d, J = 13.2 Hz, 1H), 1.99 (d, J = 13.1 Hz,
1H), 1.76 (td, J = 13.2, 5.4 Hz, 1H), 1.55 (t, J = 13.8 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 143.9, 140.7, 132.8, 131.4, 129.8, 127.5,
121.4, 75.7, 71.1, 64.5, 59.4, 50.2, 45.8, 41.0, 33.8, 21.5. IR (KBr) ν
(cm−1): 3448, 2925, 2854, 1739, 1632, 1598, 1487, 1453, 1346, 1254,
1166, 1092, 1016, 953, 814, 754, 658, 547. MS-ESI: m/z 490.2 [M +
Na]+. HRMS (Orbitrap ESI): calcd for C21H25O4NBrS [M + H]+,
466.0682; found, 466.0687.
8-(4-Fluorophenyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
(6i). White solid; yield 192 mg, 95%; mp 140−142 °C. 1H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.35−7.30 (m, 2H), 7.05−7.01 (m, 2H), 4.36 (dd, J = 11.9, 1.9 Hz,
1H), 4.12 (ddd, J = 12.3, 5.4, 1.3 Hz, 1H), 3.86−3.78 (m, 2H), 3.63
(td, J = 12.8, 2.1 Hz, 1H), 3.25 (d, J = 11.5 Hz, 1H), 3.11−2.94 (m,
3H), 2.46 (s, 3H), 2.28 (d, J = 13.1 Hz, 1H), 2.00 (d, J = 13.2 Hz, 1H),
1.71 (td, J = 13.2, 5.4 Hz, 1H), 1.62−1.56 (m, 1H). 13C NMR (75
MHz, CDCl3): δ 163.8, 160.5, 143.9, 137.4, 132.9, 129.8, 127.5, 115.3,
115.0, 75.7, 71.2, 64.6, 59.4, 50.2, 45.8, 41.1, 33.8, 21.5. IR (KBr) ν
(cm−1): 3447, 3068, 2955, 2864, 1924, 1735, 1603, 1512, 1454, 1344,
1223, 1165, 1086, 1045, 959, 818, 756, 658, 595, 547. MS-ESI: m/z
428 [M + Na]+. HRMS (Orbitrap ESI): calcd for C21H25O4NFS [M +
H]+, 406.1482; found, 406.1480.
1
(6c). Off-white solid; yield 193 mg, 90%; mp 142−145 °C. H NMR
(300 MHz, CDCl3): δ 7.68 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz,
2H), 7.31−7.17 (m, 4H), 4.34 (d, J = 10.9 Hz, 1H), 4.11 (dd, J = 11.8,
4.7 Hz, 1H), 3.83 (t, J = 4.9 Hz, 2H), 3.62 (td, J = 12.8, 1.5 Hz, 1H),
3.20 (d, J = 11.5 Hz, 1H), 3.13−2.97 (m, 3H), 2.95−2.84 (m, 1H),
2.46 (s, 3H), 2.26 (d, J = 13.2 Hz, 1H), 2.02 (d, J = 13.1 Hz, 1H), 1.77
(td, J = 13.2, 5.4 Hz, 1H), 1.67 (t, J = 12.6 Hz, 1H), 1.24 (d, J = 6.9
Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 148.4, 143.9, 138.7, 132.5,
129.7, 127.5, 126.3, 125.9, 76.3, 71.3, 64.5, 64.1, 59.2, 50.2, 45.7, 40.8,
33.7, 25.1, 23.8, 21.4. IR (KBr) ν (cm−1): 3448, 2961, 2927, 2858,
1598, 1512, 1459, 1336, 1214, 1168, 1096, 1047, 1018, 971, 833, 811,
660, 624, 548. MS-ESI: m/z 452.25 [M + Na]+. HRMS (Orbitrap
ESI): calcd for C24H32O4NS [M + H]+, 430.20466; found, 430.20464.
8-(4-(tert-Butyl)phenyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]-
undecane (6d). White solid; yield 199 mg, 90%; mp 186−188 °C. 1H
NMR (300 MHz, CDCl3): δ 7.67 (d, J = 8.1 Hz, 2H), 7.4−7.34 (m,
4H), 7.3−7.24 (m, 2H), 4.34 (d, J = 11.8 Hz, 1H), 4.11 (dd, J = 12.2,
4.1 Hz, 1H), 3.83 (t, J = 4.9 Hz, 2H), 3.62 (td, J = 13.0, 1.8 Hz, 1H),
3.24−2.98 (m, 4H), 2.46 (s, 3H), 2.26 (d, J = 13.2 Hz, 1H), 2.02 (d, J
= 13.4 Hz, 1H), 1.77 (td, J = 13.2, 5.2 Hz, 1H), 1.68 (t, J = 12.6 Hz,
1H), 1.30 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 150.7, 143.9,
138.4, 132.7, 129.8, 127.6, 125.7, 125.3, 76.2, 71.3, 64.6, 59.3, 50.2,
45.7, 40.8, 34.4, 33.7, 31.2, 21.5. IR (KBr) ν (cm−1): 3448, 2951, 2869,
1598, 1514, 1459, 1353, 1336, 1277, 1258, 1171, 1126, 1095, 1048,
970, 946, 907, 832, 764, 661, 549. MS-ESI: m/z 466.27 [M + Na]+.
HRMS (Orbitrap ESI): calcd for C25H34O4NS [M + H]+, 444.2203;
found, 444.2204.
8-(m-Tolyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6j).
White solid; yield 180 mg, 90%; mp 107−109 °C. H NMR (500
8-(Naphthalen-2-yl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
(6e). White solid; yield 185 mg, 85%; mp 150−152 °C. 1H NMR (300
MHz, CDCl3): δ 7.86−7.79 (m, 4H), 7.70 (d, J = 8.1 Hz, 2H), 7.50−
7.35 (m, 5H), 4.55 (dd, J = 11.7, 1.3 Hz, 1H), 4.19 (dd, J = 12.2, 4.3
Hz, 1H), 3.83 (t, J = 4.9 Hz, 2H), 3.70 (td, J = 12.8, 1.8, 1H), 3.29 (d,
J = 11.7 Hz, 1H), 3.15−2.95 (m, 3H), 2.46 (s, 3H), 2.38 (d, J = 13.2
Hz, 1H), 2.05 (d, J = 13.3 Hz, 1H), 1.83 (td, J = 13.0, 5.2 Hz, 1H),
1.72 (t, J = 12.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 143.9, 139.0,
133.1, 132.8, 132.6, 129.8, 128.1, 127.9, 127.5, 125.9, 125.7, 124.4,
123.9, 76.4, 71.3, 64.6, 59.3, 50.2, 45.7, 41.1, 33.8, 21.4. IR (KBr) ν
(cm−1): 3448, 3051, 2969, 2926, 2854, 1599, 1507, 1335, 1166, 1096,
975, 819, 764, 658, 546. MS-ESI: m/z 459.8 [M + Na]+. HRMS
(Orbitrap ESI): calcd for C25H28O4NS [M + H]+, 438.1733; found,
438.1734.
1
MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.25−7.21 (m, 1H), 7.17 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.10 (d, J =
7.4 Hz, 1H), 4.34 (dd, J = 12.0, 1.9 Hz, 1H), 4.12 (ddd, J = 12.2, 5.3,
1.3 Hz, 1H), 3.86−3.80 (m, 2H), 3.63 (td, J = 12.9, 2.1 Hz, 1H), 3.22
(d, J = 11.4 Hz, 1H), 3.09−2.96 (m, 3H), 2.46 (s, 3H), 2.35 (s, 3H),
2.27 (d, J = 13.1 Hz, 1H), 2.01 (d, J = 13.2 Hz, 1H), 1.78 (td, J = 13.1,
5.4 Hz, 1H), 1.64 (t, J = 12.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
143.9, 141.5, 138.0, 132.8, 129.8, 128.4, 128.3, 127.6, 126.5, 122.9,
71.3, 64.6, 59.3, 50.3, 45.8, 41.1, 33.8, 21.5, 21.4. IR (KBr) ν (cm−1):
3442, 2951, 2920, 2846, 1597, 1457, 1340, 1283, 1260, 1168, 1094,
962, 820, 757, 658, 546. MS-ESI: m/z 423.8 [M + Na]+. HRMS
(Orbitrap ESI): calcd for C22H28O4NS [M + H]+, 402.1733; found,
402.1739.
8-(Naphthalen-1-yl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
(6f). White solid; yield 179 mg, 82%; mp 162−164 °C. 1H NMR (300
MHz, CDCl3): δ 8.16 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H),
7.97 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.66−7.56 (m, 2H),
7.54−7.43 (m, 2H), 7.37 (d, J = 7.9 Hz, 2H), 5.17 (d, J = 11.3 Hz,
1H), 4.28−4.19 (m, 1H), 3.91−3.72 (m, 3H), 3.68 (d, J = 11.7 Hz,
1H), 3.26−3.16 (m, 1H), 2.94−2.79 (m, 2H), 2.70 (d, J = 13.2 Hz,
1H), 2.45 (s, 3H), 1.99−1.88 (m, 2H), 1.73 (t, J = 12.6 Hz, 1H). 13C
NMR (125 MHz, CDCl3): δ 143.9, 137.3, 133.6, 132.6, 130.0, 129.8,
128.7, 128.0, 127.6, 126.3, 125.5, 125.3, 123.2, 122.7, 73.6, 71.6, 64.8,
59.3, 50.4, 45.9, 39.7, 34.8, 21.5. IR (KBr) ν (cm−1): 3448, 3056, 2945,
2923, 2844, 1594, 1453, 1346, 1283, 1252, 1168, 1092, 956, 911, 802,
758, 657, 603, 543. MS-ESI: m/z 459.8 [M + Na]+. HRMS (Orbitrap
ESI): calcd for C25H28O4NS [M + H]+, 438.1733; found, 438.1738.
8-(4-Chlorophenyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
(6g). White solid; yield 200 mg, 95%; mp 145−147 °C. 1H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H),
7.33−7.26 (m, 4H), 4.36 (dd, J = 11.9, 1.9 Hz, 1H), 4.12 (ddd, J =
12.3, 5.3, 1.2 Hz, 1H), 3.85−3.79 (m, 2H), 3.62 (td, J = 12.9, 2.2 Hz,
1H), 3.25 (d, J = 11.5 Hz, 1H), 3.12−3.07 (m, 1H), 3.05−2.94 (m,
2H), 2.46 (s, 3H), 2.28 (d, J = 13.1 Hz, 1H), 1.99 (d, J = 13.1 Hz, 1H),
1.77 (td, J = 13.2, 5.4 Hz, 1H), 1.56 (t, J = 12.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 143.9, 140.2, 133.3, 132.7, 129.8, 128.5, 127.5,
127.1, 75.7, 71.2, 64.5, 59.3, 50.2, 45.7, 41.0, 33.8, 21.5. IR (KBr) ν
(cm−1): 3447, 2957, 2925, 2852, 1741, 1598, 1492, 1453, 1348, 1283,
1166, 1089, 1042, 957, 818, 756, 659, 549. MS-ESI: m/z 422.06 [M +
8-(3,4-Dimethoxyphenyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]-
undecane (6k). White solid; yield 185 mg, 83%; mp 140−142 °C. 1H
NMR (300 MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3
Hz, 2H), 6.95−6.81 (m, 3H), 4.33 (dd, J = 12.0, 1.5 Hz, 1H), 4.12
(dd, J = 12.0, 4.5 Hz, 1H), 3.95−3.81 (m, 8H), 3.63 (td, J = 12.8, 2.2
Hz, 1H), 3.22−3.00 (m, 4H), 2.46 (s, 3H), 2.25 (d, J = 13.5 Hz, 1H),
2.04 (d, J = 12.8 Hz, 1H), 1.78 (td, J = 12.8, 5.2 Hz, 1H), 1.67 (t, J =
12.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 148.9, 148.5, 143.9,
134.1, 132.6, 129.8, 127.5, 118.2, 110.8, 109.1, 76.2, 71.3, 64.6, 59.3,
55.9, 55.8, 50.2, 45.7, 41.1, 33.6, 21.5. IR (KBr) ν (cm−1): 3449, 3084,
2990, 2928, 2850, 1596, 1518, 1461, 1423, 1349, 1262, 1233, 1164,
1090, 1029, 976, 952, 870, 820, 756, 660, 599, 550. MS-ESI: m/z
470.06 [M + Na]+. HRMS (Orbitrap ESI): calcd for C23H30O6NS [M
+ H]+, 448.1788; found, 448.1790.
4-Tosyl-8-(3,4,5-trimethoxyphenyl)-1,9-dioxa-4-azaspiro[5.5]-
1
undecane (6l). White solid; yield 202 mg, 85%; mp 152−154 °C. H
NMR (500 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.3
Hz, 2H), 6.59 (s, 2H), 4.33 (dd, J = 12.0, 1.9 Hz, 1H), 4.12 (dd, J =
12.3, 4.7 Hz, 1H), 3.91−3.80 (m, 11H), 3.63 (td, J = 12.8, 1.9 Hz,
1H), 3.23 (d, J = 11.4 Hz, 1H), 3.10−2.96 (m, 3H), 2.47 (s, 3H), 2.29
(d, J = 13.1 Hz, 1H), 2.02 (d, J = 13.1 Hz, 1H), 1.78 (td, J = 13.2, 5.4
Hz, 1H), 1.66 (t, J = 12.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ
153.1, 143.9, 137.3, 137.2, 132.6, 129.8, 127.5, 102.9, 76.5, 71.2, 64.5,
60.7, 59.3, 56.0, 50.2, 45.7, 41.0, 33.7, 21.5. IR (KBr) ν (cm−1): 3447,
2931, 2871, 2845, 1741, 1593, 1508, 1459, 1424, 1347, 1239, 1168,
2293
dx.doi.org/10.1021/jo4027534 | J. Org. Chem. 2014, 79, 2289−2295

The Journal of Organic Chemistry
Note
1123, 1094, 1016, 950, 826, 762, 657, 547. MS-ESI: m/z 478.21 [M +
H]+. HRMS (Orbitrap ESI): calcd for C24H32O7NS [M + H]+,
478.1894; found, 478.18865.
(Orbitrap ESI): calcd for C19H30O4NS [M + H]+, 368.1890; found,
368.1895.
8-Propyl-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6r). Color-
1
less liquid; yield 141 mg, 80%. H NMR (500 MHz, CDCl3): δ 7.64
8-((E)-Styryl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6m).
1
(d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.95 (dd, J = 12.0, 5.0
Hz, 1H), 3.81 (t, J = 5.0 Hz, 2H), 3.43 (td, J = 12.9, 1.8 Hz, 1H),
3.33−3.27 (m, 1H), 3.09−2.92 (m, 4H), 2.45 (s, 3H), 1.97 (d, J = 13.1
Hz, 2H), 1.61 (td, J = 13.1, 5.3 Hz, 1H), 1.55−1.43 (m, 2H), 1.41−
1.25 (m, 3H), 0.92 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 143.8, 132.5, 129.7, 127.6, 73.8, 71.1, 64.1, 59.2, 50.4, 45.7, 39.6,
38.3, 33.7, 21.5, 18.6, 14.0. IR (neat) ν (cm−1): 3456, 2957, 2929,
2851, 1726, 1597, 1453, 1351, 1166, 1093, 955, 815, 758, 660, 549.
MS-ESI: m/z 376.23 [M + Na]+. HRMS (Orbitrap ESI): calcd for
C18H28O4NS [M + H]+, 354.1733; found, 354.1735.
Removal of the Tosyl Protecting Group To Give 8. Lithium
granules (8.72 mg, 1.24 mmol, 10 equiv) were added to a vigorously
stirred solution of naphthalene (159 mg, 1.24 mmol, 10 equiv) in
tetrahydrofuran (3 mL) at 30 °C, and the resulting green suspension
was allowed to stir for 3 h at 30 °C. A solution of N-tosyl
pyranomorpholine 6b (50 mg, 0.124 mmol, 1 equiv) in tetrahydrofur-
an (2 mL) was then added at −50 °C, and the resulting mixture was
stirred at the same temperature for 40 min. Saturated aqueous
ammonium chloride solution (4 mL) was then added to this solution
at −50 °C. The suspension was stirred at −50 °C for 5 min and then
was allowed to warm to rt. The solution was then partitioned between
ethyl acetate and brine. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The organic layer was
dried over sodium sulfate and concentrated on a rotary evaporator.
The crude product was purified by flash column chromatography using
a MeOH/DCM gradient to afford the detosylated product 8 as a
yellow oil (24 mg, 80%).
8-(p-Tolyl)-1,9-dioxa-4-azaspiro[5.5]undecane (8). Yellow liquid;
yield 24 mg, 80%. 1H NMR (500 MHz, CDCl3): δ 7.24 (d, J = 8.0 Hz,
2H), 7.15 (d, J = 7.9 Hz, 2H), 4.30 (dd, J = 12.0, 1.9 Hz, 1H), 4.09
(ddd, J = 12.0, 5.3, 1.3 Hz, 1H), 3.74 (t, J = 4.8 Hz, 2H), 3.58 (td, J =
13.4, 2.1 Hz, 1H), 3.08 (d, J = 12.3 Hz, 1H), 3.03 (d, J = 12.3 Hz, 1H),
2.89−2.84 (m, 2H), 2.65−2.46 (bs, 1H), 2.33 (s, 3H), 2.32−2.29 (m,
1H), 2.09 (dd, J = 13.1, 1.6 Hz, 1H), 1.75 (td, J = 13.2, 5.4 Hz, 1H),
1.64 (t, J = 12.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 139.0,
137.2, 128.9, 125.8, 76.5, 70.6, 64.8, 60.9, 50.7, 46.1, 41.7, 34.3, 21.0.
IR (neat) ν (cm−1): 3424, 2924, 2853, 1642, 1566, 1515, 1451, 1364,
1256, 1088, 1046, 1016, 814, 594. MS-ESI: m/z 248.21 [M + Na]+.
HRMS (Orbitrap ESI): calcd for C15H22O2N [M + H]+, 248.1645;
found, 248.1647.
Pale-yellow solid; yield 154 mg, 75%; mp 86−88 °C. H NMR (500
MHz, CDCl3): δ 7.66 (d, J = 8.22 Hz, 2H), 7.4−7.34 (m, 4H), 7.33−
7.29 (m, 2H), 7.25−7.22 (m, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.18 (dd,
J = 16.0, 5.7 Hz, 1H), 4.10−4.0 (m, 2H), 3.84 (t, J = 4.7 Hz, 2H), 3.56
(td, J = 12.6, 2.2 Hz, 1H), 3.10−2.99 (m, 4H), 2.46 (s, 3H), 2.15 (d, J
= 13.1 Hz, 1H), 2.0 (d, J = 13.1 Hz, 1H), 1.7 (td, J = 12.9, 5.3 Hz,
1H), 1.54 (t, J = 12.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): 143.9,
136.7, 132.2, 130.5, 129.7, 129.6, 128.4, 127.7, 127.5, 126.4, 72.4, 70.0,
62.6, 59.5, 55.1, 45.8, 38.4, 32.0, 21.5. IR (KBr) ν (cm−1): 3446, 3026,
2955, 2923, 2852, 1735, 1597, 1494, 1453, 1351, 1284, 1167, 1089,
1028, 969, 934, 815, 755, 657, 547. MS-ESI: m/z 436.15 [M + Na]+.
HRMS (Orbitrap ESI): calcd for C23H27O4NNaS [M + Na]+,
436.1553; found, 436.1558.
8-Benzyl-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6n). Sticky
solid; yield 140 mg, 70%. 1H NMR (500 MHz, CDCl3): δ 7.61 (d, J =
8.2 Hz, 2H), 7.35−7.19 (m, 7H), 3.96 (ddd, J = 12.2, 5.2, 1.4 Hz, 1H),
3.85−3.73 (m, 2H), 3.60−3.54 (m, 1H), 3.41 (td, J = 12.7, 2.0 Hz,
1H), 3.13 (d, J = 11.6 Hz, 1H), 3.10−3.04 (m, 1H), 2.90−2.80 (m,
3H), 2.71 (dd, J = 13.9, 5.2 Hz, 1H), 2.43 (s, 3H), 2.02 (d, J = 13.0 Hz,
1H), 1.93 (d, J = 13.1 Hz, 1H), 1.61 (td, J = 13.1, 5.4 Hz, 1H), 1.39 (t,
J = 12.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 143.8, 138.0, 132.6,
129.7, 129.3, 128.2, 127.6, 126.2, 74.7, 71.1, 64.1, 59.3, 50.3, 45.7, 42.6,
39.5, 33.2, 21.5. IR (KBr) ν (cm−1): 3448, 3062, 3026, 2926, 2854,
1738, 1598, 1495, 1453, 1345, 1281, 1222, 1164, 1086, 1025, 946, 814,
757, 701, 655, 549. MS-ESI: m/z 423.8 [M + Na]+. HRMS (Orbitrap
ESI): calcd for C22H28O4NS [M + H]+, 402.17336; found, 402.17332.
8-(o-Tolyl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6o).
1
White solid; yield 170 mg, 85%; mp 153−155 °C. H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 7.4 Hz, 1H),
7.37 (d, J = 8.0 Hz, 2H), 7.24−7.13 (m, 3H), 4.59 (dd, J = 11.9, 1.8
Hz, 1H), 4.13 (ddd, J = 12.2, 5.3, 1.3 Hz, 1H), 3.9−3.83 (m, 1H),
3.80−3.74 (m, 1H), 3.65 (td, J = 12.5, 2.4 Hz, 1H), 3.49 (d, J = 11.4
Hz, 1H), 3.20−3.14 (m, 1H), 2.87−2.79 (m, 2H), 2.46 (s, 3H), 2.43−
2.39 (m, 1H), 2.39 (s, 3H), 1.9 (d, J = 13.1 Hz, 1H), 1.83 (td, J = 12.9,
5.3 Hz, 1H), 1.56 (t, J = 12.3 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ 143.9, 139.7, 134.4, 132.4, 130.3, 129.8, 127.6, 127.3, 126.2, 125.1,
73.4, 71.3, 64.6, 59.2, 50.3, 45.8, 39.3, 34.5, 21.5, 18.9. IR (KBr) ν
(cm−1): 3448, 3024, 2956, 2919, 2869, 2845, 1597, 1490, 1349, 1297,
1278, 1169, 1096, 1023, 960, 913, 817, 758, 659, 602, 548. MS-ESI:
m/z 423.8 [M + Na]+. HRMS (Orbitrap ESI): calcd for C22H28O4NS
[M + H]+, 402.1733; found, 402.1728.
tert-Butyl (4-Hydroxy-2-methylenebutyl)(2-hydroxyethyl)-
1
carbamate (9). Colorless liquid; yield 980 mg, 80%. H NMR (500
8-(Thiophen-2-yl)-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane
1
MHz, CDCl3): δ 4.96 (d, J = 14.3 Hz, 2H), 3.88 (s, 2H), 3.77−3.70
(m, 4H), 3.40−3.35 (m, 2H), 2.26 (t, J = 6.2 Hz, 2H), 1.46 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 157.1, 156.0, 142.0, 112.7, 80.4, 61.9,
(6p). Yellow solid; yield 147 mg, 75%; mp 85−87 °C. H NMR (300
MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H),
7.28−7.24 (m, 1H), 7.01−6.93 (m, 2H), 4.64 (dd, J = 12.0, 2.2 Hz,
1H), 4.10 (dd, J = 12.0, 4.5 Hz, 1H), 3.88−3.80 (m, 2H), 3.65 (td, J =
12.8, 1.5 Hz, 1H), 3.16 (d, J = 12.0 Hz, 1H), 3.10−2.97 (m, 3H), 2.45
(s, 3H), 2.36 (d, J = 12.8 Hz, 1H), 2.07 (d, J = 12.8 Hz, 1H), 1.86−
1.73 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 144.6, 144.0, 132.5,
129.8, 127.6, 126.4, 124.9, 123.9, 72.1, 71.0, 64.6, 59.4, 50.2, 45.7, 41.0,
33.3, 21.5. IR (KBr) ν (cm−1): 3449, 3067, 2957, 2924, 2851, 2736,
1923, 1735, 1597, 1452, 1349, 1282, 1256, 1166, 1090, 1024, 950, 906,
819, 756, 704, 659, 613, 547. MS-ESI: m/z 416.07 [M + Na]+. HRMS
(Orbitrap ESI): calcd for C19H24O4NS2 [M + H]+, 394.1141; found,
394.1145.
60.5, 52.8, 52.4, 49.5, 36.5, 28.2. IR (neat) ν (cm−1): 3401, 2975, 2933,
1672, 1464, 1413, 1367, 1250, 1168, 1132, 1050, 949, 889, 773, 676.
MS-ESI: m/z 268.29 [M + Na]+. HRMS (Orbitrap ESI): calcd for
C12H23O4NNa [M + Na]+, 268.1519; found, 268.1521.
Benzyl (4-Hydroxy-2-methylenebutyl)(2-hydroxyethyl)carbamate
(10). Colorless liquid; yield 1.185 g, 85%. 1H NMR (500 MHz,
CDCl3): δ 7.40−7.29 (m, 5H), 5.14 (s, 2H), 5.01−4.91 (m, 2H),
4.03−3.91 (m, 2H), 3.81−3.58 (m, 4H), 3.43 (s, 2H), 2.27−2.17 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 157.2, 156.6, 141.8, 141.6,
136.2, 134.7, 128.4, 127.8, 128.0, 127.5, 112.8, 67.4, 60.7, 60.4, 52.5,
49.7, 48.8, 36.5, 36.3, 26.4. IR (neat) ν (cm−1): 3404, 2939, 1681,
1474, 1422, 1366, 1232, 1126, 1050, 985, 907, 864, 743, 699, 608, 508.
MS-ESI: m/z 302.24 [M + Na]+. HRMS (Orbitrap ESI): calcd for
C15H21O4NNa [M + Na]+, 302.1362; found, 302.1360.
8-Isobutyl-4-tosyl-1,9-dioxa-4-azaspiro[5.5]undecane (6q). Col-
orless liquid; yield 156 mg, 85%. 1H NMR (500 MHz, CDCl3): δ 7.65
(d, J = 7.1 Hz, 2H), 7.36 (d, J = 7.4 Hz, 2H), 3.95 (dd, J = 12.2, 5.1
Hz, 1H), 3.81 (t, J = 4.2 Hz, 2H), 3.43 (t, J = 12.6 Hz, 1H), 3.39−3.33
(m, 1H), 3.09−2.93 (m, 4H), 2.45 (s, 3H), 1.99−1.93 (m, 2H), 1.84−
1.74 (m, 1H), 1.61 (td, J = 12.9, 5.0 Hz, 1H), 1.52−1.45 (m, 1H),
1.33−1.24 (m, 1H), 1.22−1.14 (m, 1H), 0.9 (d, J = 6.7 Hz, 6H). 13C
NMR (125 MHz, CDCl3): δ 143.9, 132.6, 129.7, 127.6, 72.3, 71.1,
64.1, 59.2, 50.4, 45.8, 45.3, 40.0, 33.7, 24.3, 23.1, 22.3, 21.5. IR (neat) ν
(cm−1): 3455, 2955, 2926, 2851, 1733, 1597, 1453, 1351, 1166, 1094,
948, 815, 757, 660, 549. MS-ESI: m/z 390.25 [M + Na]+. HRMS
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray data for compound 6i as a CIF file and an ORTEP
diagram; NOESY and DQFCOSY study of the 10:4 6g:7g
mixture; and copies of 1H and 13C NMR spectra of 6a−r, 3, 4,
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dx.doi.org/10.1021/jo4027534 | J. Org. Chem. 2014, 79, 2289−2295

The Journal of Organic Chemistry
Note
8, 9, and 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: basireddy@iict.res.in. Fax: 0091-40-27160512.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
D.M. thanks CSIR, New Delhi for the award of a fellowship.
■
REFERENCES
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