Hydrazinium carbazate-H2O2: An ideal combination for diimide reduction of base-sensitive unsaturated peroxides

Article abstract of DOI:10.1055/s-0029-1218639

The utility of a hydrazinium carbazate (N₂H₃COON ₂H₅) and H₂O₂ combination for the double bond reduction of base-sensitive unsaturated 1,2,4-trioxanes, 1,2,4-trioxepanes, and their precursors β-andγ-hydroxyhydroperoxides is presented. The method is superior to the conventional diimide reduction using N₂H₄H₂O-H₂O₂ and catalytic hydrogenation.

Full text of DOI:10.1055/s-0029-1218639

1014
PAPER
Hydrazinium Carbazate–H2O2: An Ideal Combination for Diimide Reduction
of Base-Sensitive Unsaturated Peroxides1
D
ouble Bond
R
ed
h
uctionwith
a
H
ydraziniun2
m
C
arbazate
d
–HO2 an Singh,* Ajit Shankar Singh, Niraj Krishna Naikade, Ved Prakash Verma, Mohammad Hassam,
Nitin Gupta, Shilpi Pandey
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: chandancdri@yahoo.com
Received 9 September 2009; revised 10 November 2009
ed keto alcohols, which react with various amines and
Abstract: The utility of a hydrazinium carbazate (N2H3COON2H5)
and H2O2 combination for the double bond reduction of base-sensi-
tive unsaturated 1,2,4-trioxanes, 1,2,4-trioxepanes, and their pre-
cursors b- and g-hydroxyhydroperoxides is presented. The method
thiols to give Michael adducts (Scheme 2).Based on these
results we have earlier suggested that this facile formation
of a,b-unsaturated keto systems under basic conditions
is superior to the conventional diimide reduction using N2H4·H2O– and their equally facile reaction with amines and thiols
H2O2 and catalytic hydrogenation.
might have relevance to the mechanism of action of these
trioxanes as antimalarials.8 This suggestion naturally
Key words: diimide reduction, hydrazinium carbazate, hydrogen
peroxide, b-/g-hydroxyhydroperoxides, 1,2,4-trioxanes
makes the double bond the key group for the activity of
this group of 1,2,4-trioxanes and calls for the preparation
and antimalarial assessment of the corresponding saturat-
ed 1,2,4-trioxanes.
Artemisinin, a naturally occurring 1,2,4-trioxane from
Artemisia annua and its semi-synthetic derivatives such
as artemether and arteether (Figure 1) are currently the
drugs of choice for the treatment of malaria caused by
Plasmodium falciparum.2
ArHN
O
ArNH2
Ar
OH
R1
R2
O
O
O
base
O
Ar
O
RS
Ar
H
H
OH
OH
Ar
RSH
O
O
Scheme 2 Base mediated fragmentation of 1,2,4-trioxanes into a,b-
unsaturated keto alcohols and their entrapment by amines and thiols
O
O
O
O
H
H
O
O
In our efforts to achieve this objective, we have discov-
OR
O
ered
hydrazinium
carbazate/hydrogen
peroxide
artemisinin
artemether, R = Me
arteether, R = Et
(N2H3COON2H5–H2O2) as a new combination for the di-
imide reduction of these base-sensitive 1,2,4-trioxanes
and 1,2,4-trioxepanes and their precursors, b- and g-hy-
droxyhydroperoxides. In the present study, we demon-
strate the superiority of this new diimide reduction
method over the conventional diimide reduction using
N2H4·H2O–H2O29,10and catalytic hydrogenation.11 To-
wards this end, we first attempted catalytic hydrogenation
of trioxane 1a with hydrogen over platinum(IV) oxide at
room temperature and atmospheric pressure, which fur-
nished only diol 2 and ketone 3 in 64 and 89% yield, re-
spectively, and no trace of the corresponding saturated
trioxane was isolated12 (Scheme 3).
Figure 1 Artemisinin and its semi-synthetic derivatives
As a part of an endeavor to develop synthetic substitutes
for artemisinin and its derivatives, we have earlier report-
ed photooxygenation routes for the preparation of 1,2,4-
trioxanes3,4 and 1,2,4-trioxepanes5,6 (Scheme 1).
R1
R2
O
O
O
1O2
O
OH
OH
OH
R1COR2
H+
n
Ar
Ar
Ar
n
n
n = 1, 2
Scheme 1 Synthesis of 1,2,4-trioxanes (n = 1) and 1,2,4-triox-
epanes (n = 2) via photooxygenation of allylic and homoallylic alcohols
Further we attempted diimide reduction using a
N2H4·H2O–H2O2 combination (Method A). Thus, the re-
action of trioxane 1a with N2H4·H2O–30% H2O2 in a 1:1
mixture of THF–EtOH was complete within three days
and furnished the corresponding saturated trioxanes 4a
(less polar) and 5a (more polar) as a diastereomeric mix-
ture in 44% yield and in a ratio of 2:3. Reduction of the tri-
oxanes 1b–e under similar conditions furnished a mixture
of the corresponding saturated trioxanes 4b–e (less polar)
and 5b–e (more polar) in 36–58% yields. Similar reduc-
Several of the 6-arylvinyl-1,2,4-trioxanes prepared by this
method have shown promising antimalarial activity.7 We
have also shown that these trioxanes undergo a facile frag-
mentation under basic conditions to furnish a,b-unsaturat-
SYNTHESIS 2010, No. 6, pp 1014–1022
x
x
.
x
x
.2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218639; Art ID: T17709SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Double Bond Reduction with Hydrazinium Carbazate–H2O2
1015
H
O
O
O
OH
OH
PtO2, H2, EtOAc
O
+
H
1 atm pressure, r.t.
2 (64%)
3 (89%)
1a
Scheme 3 Catalytic hydrogenation of unsaturated 1,2,4-trioxane 1a
H
H
O
O
O
Ar
method A
4a–c
O
O
O
EtOH–THF, r.t., 2–3 d, 36–44%
+
method B
EtOH–THF, r.t., 9–14 d, 92–97%
4/5 = 2:3 (for both the methods)
H
O
O
O
Ar
1a–c
a, Ar = Ph
Ar
H
b, Ar = 4-ClC6H4
c, Ar = 4-FC6H4
5a–c
H
H
O
O
Ar
O
n
method A
4d, e
O
O
O
EtOH–THF, r.t., 2–4 d, 37–58%
+
method B
EtOH–THF, r.t., 12–16 d, 89–91%
4/5 = 2:3 (for both the methods)
Ar
O
O
O
H
n
1d, e
d, Ar = Ph, n = 1
e, Ar = Ph, n = 2
H
Ar
n
n
5d, e
O
O
H
O
O
Ar
H
H
method A
O
O
7a–c
+
EtOH–THF, r.t., 2–3 d, 53–57%
n
method B
EtOH–THF, r.t., 6–8 d, 70–79%
7/8 = 2:3 (for both the methods)
O
Ar
O
O
H
n
6a–c
a, Ar = Ph, n = 1
b, Ar = 4-PhC6H4, n = 1
c, Ar = 4-PhC6H4, n = 2
Ar
8a–c
Scheme 4 Reduction of unsaturated 1,2,4-trioxanes 1a–e and 1,2,4-trioxepanes 6a–c by N2H4·H2O–30% H2O2 (method A) and
N2H3COON2H5–30% H2O2 (method B)
tion of the trioxepanes 6a–c furnished a mixture of the 79% yields (Scheme 4, Table 1). The diastereomers were
corresponding saturated trioxepanes 7a–c (less polar) and separated by column chromatography and characterized
8a–c (more polar) in 53-57% yields (Scheme 4, Table 1). individually.16
We believed that the poor yields in diimide reduction of The lower basicity of N2H3COON2H5 as compared with
trioxanes 1a–e, were due to the high basicity of N2H4 could be the main reason for the sluggishness of this
N2H4·H2O, which can lead to a fragmentation of the triox- reaction. The oxidation of N2H4 to N2H2, the actual reduc-
ane moiety by a mechanism similar to that shown in ing species, is known to be influenced by the pH of the re-
Scheme 2. On the other hand, hydrazine hydrate is known action; at pH <8 it is very slow.17
to react with CO2 to form hydrazinium carbazate
The difference in diimide reduction using N2H4·H2O–
(N2H3COON2H5), a 2:1 adduct of hydrazine and
H2O2 and N2H3COON2H5–H2O2 was found to be even
CO2.13,14A comparison of the pH values of aqueous solu-
more dramatic in the reduction of unsaturated b- and g-hy-
tions of N2H4·H2O and N2H3COON2H5, prepared in our
laboratory, showed that the latter was much less basic and
droxyhydroperoxides. The diimide reduction of b-hy-
droxyhydroperoxide
9
with N2H3COON2H5–H2O2
therefore more suitable for our work.15 In fact, the reaction
of trioxane 1a with N2H3COON2H5–30% H2O2 (method
B) took more time to complete, but gave a mixture of the
corresponding saturated trioxanes 4a and 5a in a 2:3 ratio
in 97% yield. Similarly, reduction of the trioxanes 1b–e
under these conditions furnished the corresponding satu-
rated trioxanes 4b–e and 5b–e in 89–95% yields. A simi-
lar reduction of the trioxepanes 6a–c furnished the
corresponding saturated trioxepanes 7a–c and 8a–c in 70–
furnished the saturated b-hydroxyhydroperoxide 10 as an
inseparable mixture of diastereomers in 50% yield togeth-
er with saturated diol 11 in 17% yield, also as an insepa-
rable mixture of diastereomers. Similarly, the reduction of
b-hydroxyhydroperoxide 13 under these conditions fur-
nished saturated b-hydroxyhydroperoxide 14 and diol 15
in 51 and 28% yield, respectively. Analogous reduction of
unsaturated g-hydroxyhydroperoxides 17 and 21 with
N2H3COON2H5–H2O2 furnished the corresponding satu-
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

1016
C. Singh et al.
PAPER
NaBH4, MeOH, 0 °C
H
H
O
OH
OH
OH
O
OH
OH
method B
+
EtOH–THF, r.t.
OH
Ar
Ar
Ar
H
H
11, 15
9, 13
10, 14
Ac2O, Et3N, DMAP,
CH2Cl2, r.t.
for 9–12, Ar = 2-naphthyl
for 13–16, Ar = 4-FC6H4
H
OAc
OAc
Ar
H
12, 16
H
H
O
OH
OH
OH
O
OH
OH
method B
NaBH4
OH
EtOH–THF, r.t.
MeOH
0 °C
Ar
Ar
Ar
H
H
19, 23
17, 21
18, 22
Ac2O, Et3N, DMAP,
CH2Cl2, r.t.
for 17–20, Ar = Ph
for 21–24, Ar = 4-PhC6H4
H
OAc
OAc
Ar
H
20, 24
Scheme 5
Reduction of b-hydroxyhydroperoxides 9 and 13 and g-hydroxyhydroperoxides 17 and 21 by N2H3COON2H5–30% H2O2
Table 2 Yield of Diimide Reduction of Unsaturated Hydroperox-
ides with N2H3COON2H5–30% H2O2
rated hydroperoxides 18 and 22 in 62 and 63% yield, re-
spectively; no corresponding diols were obtained in this
case (Scheme 5, Table 2).
Unsaturated
Time (d)
Product
Yield (%)
hydroperoxide
Table 1 Comparative Yields of Diimide Reduction of 1,2,4-Triox-
anes 1a–e and 1,2,4-Trioxepanes 6a–ca
9
13
17
21
4
10
14
18
22
50
51
62
63
4
Unsaturated Method
peroxide
Time (d)
Products
Yield (%)b
3.5
3.5
1a
1b
1c
1d
1e
6a
6b
6c
A
B
3
9
4a + 5a
4a + 5a
44
97
A
B
2
14
4b + 5b
4b + 5b
36
95
Reduction of b-hydroxyhydroperoxides 9 and 13 and g-
hydroxyhydroperoxides 17 and 21 by the conventional
method using N2H4·H2O–H2O2 provided only the corre-
sponding saturated diols. Also, the catalytic reduction of
hydroperoxide 9 furnished only diol 11 in 97% yield and
no trace of the corresponding saturated hydroperoxide
was isolated. To the best of our knowledge, this is the first
report on the reduction of the unsaturated hydroxyhydro-
peroxides to the saturated hydroxyhydroperoxides.
A
B
2
10
4c + 5c
4c + 5c
36
92
A
B
2
12
4d + 5d
4d + 5d
37
89
A
B
4
16
4e + 5e
4e + 5e
58
91
A
B
2
6
7a + 8a
7a + 8a
57
79
The saturated hydroxyhydroperoxides 10, 14, 18, and 22
were reduced with NaBH4 to furnish saturated diols 11,
15, 19, and 23, which on acetylation furnished the corre-
sponding diacetates 12, 16, 20, and 24, respectively, as
inseparable mixtures of diastereomers.18
A
B
2
6
7b + 8b
7b + 8b
55
70
A
B
3
8
7c + 8c
7c + 8c
53
76
The comparative superiority of N2H3COON2H5–H2O2
over N2H4·H2O–H2O2 was also evident in the double bond
reduction of ascaridole (25). While the reaction of ascari-
dole (25) with N2H4·H2O–H2O2 furnished dihydroascari-
dole (26) in only 25% yield,19 the reaction with
a Method A: N2H4·H2O–30% H2O2; Method B: N2H3COON2H5–30%
H2O2.
b The ratio of the two diastereomers 4:5 and 7:8 is around 2:3 as seen
by 1H NMR spectra of the crude mixtures of the diastereomers.
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

PAPER
Double Bond Reduction with Hydrazinium Carbazate–H2O2
1017
1H NMR (300 MHz, CDCl3): d = 7.36–7.17 (m, 5 H), 3.79–3.75 (br
m, 1 H), 3.58–3.35 (br m, 1 H), 2.88 and 2.81 (2 quint, J = 7.2 Hz,1
H), 2.13–2.03 (br m, 4 H), 1.35 and 1.27 (2 d, J = 7.0, 7.1 Hz, 3 H ).
method A
EtOH–THF, r.t., 6 h
method B
EtOH–THF, r.t., 12 h
O
O
O
O
O
O
13C NMR (75 MHz, CDCl3): d = 142.4 (C), 141.8 (C), 127.5 (CH),
127.3 (CH), 126.7 (CH), 126.3 (CH), 125.6 (CH), 125.4 (CH), 76.2
(CH), 75.0 (CH), 63.30 (CH2), 63.27 (CH2), 41.7 (CH), 41.5 (CH),
16.5 (CH3), 16.1 (CH3).
ESI-MS: m/z = 167 [M + H+].
EI-HRMS: m/z calcd for C10H14O2 [M+]: 166.0994; found:
26 (25%)
25
26 (72%)
Scheme 6 Reduction of ascaridole (25) to dihydroascaridole (26) by
N2H4·H2O–30% H2O2 (method A) and N2H3COON2H5–30% H2O2
(method B)
166.0990.
N2H3COON2H5–H2O2 furnished the same compound in
72% yield (Scheme 6).
2-Adamantanone (3)
White solid; mp 256–259 °C.
FT-IR (KBr): 1717, 2920 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.53 (br s, 2 H), 2.12–1.95 (m, 12
H).
Since the objective of these studies was to figure out the
role of the double bond in the biological activity of the tri-
oxanes, we evaluated some of these saturated trioxanes
for antimalarial activity. Several of the saturated triox-
anes, particularly the less polar isomers, were found to be
several fold more active than the parent unsaturated triox-
anes. The details of the biological activity of the saturated
trioxanes will be disclosed elsewhere.
13C NMR (75 MHz, CDCl3): d = 217.7 (C), 46.7 (3 × CH2), 38.9
(3 × CH), 36.0 (CH), 27.2 (2 × CH2).
FAB-MS: m/z = 151 [M + H+].
Hydrazinium Carbazate Solution
A slow stream of CO2 gas was bubbled through ice cooled hydra-
zine hydrate (N2H4·H2O, 103 g, 2.06 mol) till the weight of reaction
mixture became constant (150 g, which corresponded to a 2:1 ad-
duct of N2H4·H2O and CO2). A small amount (1 g) of this highly vis-
cous material (density = 1.45 g/mL) was dissolved in H2O (100 mL)
for the measurement of pH, which was found to be 7.51, while the
pH value of 1% aq N2H4·H2O was found to be 9.79.
In conclusion, we have discovered N2H3COON2H5–H2O2
as a new combination for the double bond reduction of
base-sensitive arylvinyl-1,2,4-trioxanes/trioxepanes and
their precursors b-/g-hydroxyhydroperoxides.20 This new
method is superior to the conventional diimide reduction
with N2H4·H2O–H2O2 and catalytic hydrogenation. While
there are several precedents in the literature on the double
bond reduction of unsaturated peroxides, to the best of our
knowledge, this is the first report on the preparation of sat-
urated hydroxyhydroperoxides from unsaturated hydroxy-
hydroperoxides.
Diimide Reduction of 1,2,4-Trioxanes/Trioxepanes, b-/g-Hy-
droxyhydroperoxides and Ascaridole Using Hydrazine Hydrate
and 30% H2O2; Typical Procedure for the Reduction of 1,2,4-
Trioxane 1a (Method A)
To a stirred and ice cooled solution of trioxane 1a (1.00 g, 3.205
mmol) and N2H4·H2O (3.2 mL, 20 equiv) in a 1:1 mixture of EtOH–
THF (50 mL) was added 30% H2O2 (10.89 mL, 30 equiv) dropwise
over 30 min and the reaction mixture was allowed to stir at r.t. for 3
d. The mixture was concentrated under vacuum, diluted with H2O
(20 mL) and extracted with Et2O (2 × 50 mL). The combined organ-
ic extracts were washed successively with aq 10% HCl (10 mL),
H2O (10 mL), and with sat. aq NaHCO3 (10 mL), dried (Na2SO4),
and concentrated under vacuum. The crude product was purified by
column chromatography over silica gel to furnish saturated triox-
anes 4a and 5a (0.440 g, 44%) as a mixture of diastereomers in ap-
proximately 2:3 ratio, which on flash chromatography furnished the
pure isomers 4a (less polar, oil) and 5a (more polar, white solid, mp
84–85 °C).
All glass apparatus were oven dried prior to use. Melting points
were recorded in open capillaries and are uncorrected. Compounds
were characterized by IR, 1H, 13C, 1H–1H COSY (correlation spec-
troscopy), HSQC (heteronuclear single quantum coherence spec-
tra), HMBC (heteronuclear multiple bond correlation spectra), ESI-
MS (electron spray ionization mass spectra), FAB-MS (fast atom
bombardment mass spectra), EI-HRMS (electron impact high-reso-
1
lution mass spectra), and elemental analysis (C, H). H and 13C
NMR spectra were obtained using CDCl3 as a solvent. TMS (d 0.00
ppm) served as an internal standard in 1H NMR and CDCl3 (d 77.0
ppm) in 13C NMR. Chemical shifts are reported in parts per million.
Column chromatography was performed over silica gel (particle
size: 60–120 mesh), or flash silica gel (particle size: 230–400
mesh).
Diimide Reduction of 1,2,4-Trioxanes/Trioxepanes, b-/g-Hy-
droxyhydroperoxides and Ascaridole Using Hydrazinium Car-
bazate and 30% H2O2; Typical Procedure for the Reduction of
1,2,4-Trioxane 1a (Method B)
To a stirred and ice cooled solution of trioxane 1a (3.00 g, 9.62
mmol) and hydrazinium carbazate (9.55 mL, 10 equiv) in a mixture
of EtOH–THF (1:1; 150 mL) was added 30% H2O2 (32.69 mL, 30
equiv) dropwise over 30 min and the reaction mixture was allowed
to stir at r.t. for 9 d. The mixture was worked up and the crude prod-
uct was chromatographed as above to furnish a mixture of 4a and
5a (2.92 g, 97%). No significant difference in yield and reaction
time was observed when 1a was reacted with a large excess of
N2H3COON2H5–H2O2.
Catalytic Hydrogenation of Trioxane 1a
A solution of 6-arylvinyl-1,2,4-trioxane 1a (0.200 g, 0.64 mmol) in
EtOAc (15 mL) was hydrogenated in the presence of Adam’s cata-
lyst (PtO2, 0.003 g) using a Parr shaker assembly at r.t. and atmo-
spheric pressure for 1.5 h. The reaction mixture was filtered over
Celite, concentrated under vacuum, and the crude product was pu-
rified by column chromatography over silica gel to furnish the sat-
urated diol 2 (0.060 g, 64%) as a colorless oil together with 2-
adamantanone (3; 0.080 g, 89%) as a white solid.
3-Phenylbutane-1,2-diol (2)
Oil.
Trioxane 4a
Oil.
FT-IR (neat): 1057, 1593, 2923, 3403 cm–1.
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

1018
C. Singh et al.
PAPER
FT-IR (neat): 763, 1025, 1117, 1223, 1602, 2914 cm–1.
FT-IR (neat): 772, 1111, 1653, 2925 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.18 (m, 5 H), 4.35 (dt,
J = 9.6, 2.6 Hz, 1 H), 3.62 (dd, J = 11.8, 9.6 Hz, 1 H), 3.34 (dd,
J = 11.8, 2.6 Hz, 1 H), 2.81 (s, 1 H), 2.76 (quint, J = 6.9 Hz, 1 H),
2.06–1.59 (m, 13 H), 1.39 (d, J = 6.9 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.16–6.96 (m, 4 H), 4.26 (dt,
J = 9.3, 2.6 Hz, 1 H), 3.58 (dd, J = 11.8, 9.3 Hz, 1 H), 3.32 (dd,
J = 11.8, 2.6 Hz, 1 H), 2.78 (br quint, 1 H), 2.75 (s, 1 H), 2.02–1.57
(m, 13 H), 1.35 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 142.0 (C), 128.9 (2 × CH), 127.8
(2 × CH), 127.3 (CH), 104.5 (C), 83.3 (CH), 61.2 (CH2), 41.0 (CH),
37.4 (CH2), 35.7 (CH), 33.7 (2 × CH2), 33.5 (CH2), 33.2 (CH2), 30.1
(CH), 27.4 (2 × CH), 18.6 (CH3).
13C NMR (75 MHz, CDCl3): d = 162.0 (C, d, JC,F = 244 Hz), 137.8
(C), 129.2 (2 × CH, d, JC,F = 7.5 Hz), 115.8 (2 × CH, d, JC,F = 21
Hz), 104.6 (C), 83.2 (CH), 61.0 (CH2), 40.2 (CH), 37.4 (CH2), 35.6
(CH), 33.7 (2 × CH2), 33.5 (CH2), 33.2 (CH2), 30.2 (CH), 27.4
(2 × CH), 18.6 (CH3).
FAB-MS: m/z = 315 [M + H+].
FAB-MS: m/z = 333 [M + H+].
Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C, 76.10; H,
8.40.
EI-HRMS: m/z calcd for C20H25FO3 [M+]: 332.1788; found:
332.1786.
Trioxane 5a
White solid; mp 84–85 °C.
Trioxane 5c
White solid; mp 80–81 °C.
FT-IR (KBr): 767, 1113, 1637, 2923 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–6.98 (m, 4 H), 4.41 (br ddd,
1 H), 3.85–3.75 (m, 2 H), 2.86 (quint, J = 7.2 Hz, 1 H), 2.73 (s, 1
H), 2.07–1.55 (m, 13 H), 1.26 (d, J = 7.2 Hz, 3 H).
FT-IR (KBr): 759, 1029, 1086, 1113, 1219, 1604, 2914 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.23 (m, 5 H), 4.35 (ddd,
J = 9.6, 7.6, 3.4 Hz, 1 H), 3.83 (dd, J = 11.6, 9.6 Hz,1 H), 3.77 (dd,
J = 11.6, 3.4 Hz, 1 H), 2.87 (quint, J = 7.2 Hz, 1 H), 2.77 (s, 1 H),
2.08–1.55 (m, 13 H), 1.29 (d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 142.5 (C), 128.7 (2 × CH), 127.8
(2 × CH), 126.9 (CH), 104.60 (C), 82.6 (CH), 60.9 (CH2), 40.7
(CH), 37.4 (CH2), 36.1 (CH), 33.7 (CH2), 33.6 (CH2), 33.3 (CH2),
33.2 (CH2), 29.7 (CH), 27.33 (CH), 27.29 (CH), 17.5 (CH3).
13C NMR (75 MHz, CDCl3): d = 161.8 (C, d, JC,F = 242 Hz), 138.2
(C, d, JC,F = 3 Hz), 129.2 (2 × CH, d, JC,F = 7.5 Hz), 115.4 (2 × CH,
d, JC,F = 21 Hz), 104.64 (C), 82.5 (CH), 60.9 (CH2), 40.0 (CH), 37.4
(CH2), 36.0 (CH), 33.6 (CH2), 33.5 (CH2), 33.3 (CH2), 33.2 (CH2),
29.8 (CH), 27.30 (CH), 27.26 (CH), 17.7 (CH3).
FAB-MS: m/z = 333 [M + H+].
EI-HRMS: m/z calcd for C20H25FO3 [M+]: 332.1788; found:
FAB-MS: m/z = 315 [M + H+].
Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C, 76.37; H,
7.96.
332.1781.
Trioxane 4b
White solid; mp 92–94 °C.
8-(1-Phenylethyl)-6,7,10-trioxaspiro[4.5]decane (4d)
Oil.
FT-IR (KBr): 768, 1091, 1112, 1217, 1655, 29117 cm–1.
FT-IR (neat): 760, 1063, 1118, 1604, 2970 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29 (d, J = 8.4 Hz, 2 H), 7.13 (d,
J = 8.4 Hz, 2 H), 4.28 (dt, J = 9.1, 2.3 Hz, 1 H), 3.59 (dd, J = 11.7,
9.4 Hz, 1 H), 3.36 (dd, J = 11.8, 2.5 Hz, 1 H), 2.83–2.77 (m, 2 H),
2.03–1.60 (m, 13 H), 1.36 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 140.6 (C), 133.0 (C), 129.14
(2 × CH), 129.08 (2 × CH), 104.6 (C), 83.0 (CH), 60.9 (CH2), 40.3
(CH), 37.4 (CH2), 35.5 (CH), 33.6 (2 × CH2), 33.4 (CH2), 33.2
(CH2), 30.2 (CH), 27.3 (2 × CH), 18.5 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.33–7.16 (m, 5 H), 4.34 (dt,
J = 9.0, 2.9 Hz, 1 H), 3.52 (dd, J = 11.8, 9.0 Hz, 1 H), 3.41 (dd,
J = 11.8, 2.9 Hz, 1 H), 2.80 (quint, J = 6.9 Hz, 1 H), 2.37–2.32 (m,
1 H), 1.85–1.63 (m, 7 H), 1.36 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 142.0 (C), 128.9 (2 × CH), 127.8
(2 × CH), 127.2 (CH), 114.4 (C), 83.2 (CH), 63.9 (CH2), 40.7 (CH),
36.6 (CH2), 33.4 (CH2), 24.7 (CH2), 23.6 (CH2), 18.4 (CH3).
FAB-MS: m/z = 349 [M + H+].
FAB-MS: m/z = 249 [M + H+].
Anal. Calcd for C20H25ClO3: C, 68.86; H, 7.22. Found: C, 68.69; H,
6.99.
EI-HRMS: m/z calcd for C15H20O3 [M+]: 248.14125; found:
248.13959.
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C 72.32; H,
7.95.
Trioxane 5b
White solid; mp 114–115 °C.
FT-IR (KBr): 772, 1089, 1113, 1220, 1636, 2918 cm–1.
8-(1-Phenylethyl)-6,7,10-trioxaspiro[4.5]decane (5d)
Oil.
1H NMR (300 MHz, CDCl3): d = 7.29 (d, J = 8.3 Hz, 2 H), 7.16 (d,
J = 8.3 Hz, 2 H), 4.41 (br ddd, 1 H), 3.80–3.78 (m, 2 H), 2.84 (quint,
J = 7.2 Hz, 1 H), 2.71 (s, 1 H), 2.06–1.55 (m, 13 H), 1.26 (d, J = 7.2
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 141.1 (C), 132.7 (C), 129.2
(2 × CH), 128.8 (2 × CH), 104.7 (C), 82.5 (CH), 60.9 (CH2), 40.2
(CH), 37.4 (CH2), 35.9 (CH), 33.7 (CH), 33.6 (CH2), 33.4 (CH2),
33.2 (CH2), 29.9 (CH), 27.4 (CH), 27.3 (CH), 17.7 (CH3).
FT-IR (neat): 701, 1031, 1110, 1603, 2966 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.20 (m, 5 H), 4.48 (ddd,
J = 9.8, 7.6, 2.8 Hz, 1 H), 3.82 (dd, J = 11.5, 2.8 Hz, 1 H), 3.69 (dd,
J = 11.5, 9.8 Hz, 1 H), 2.86 (quint, J = 7.2 Hz, 1 H), 2.34–2.29 (m,
1 H), 1.78–1.60 (m, 7 H), 1.27 (d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 142.2 (C), 128.5 (2 × CH), 127.8
(2 × CH), 126.8 (CH), 114.4 (C), 82.5 (CH), 63.6 (CH2), 40.5 (CH),
36.9 (CH2), 33.0 (CH2), 24.7 (CH2), 23.5 (CH2), 17.4 (CH3).
FAB-MS: m/z = 349 [M + H+].
Anal. Calcd for C20H25ClO3: C, 68.86; H, 7.22. Found: C, 68.78; H,
6.88.
FAB-MS: m/z = 249 [M + H+].
EI-HRMS: m/z calcd for C15H20O3 [M+]: 248.1413; found:
248.1413.
Trioxane 4c
Oil.
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

PAPER
Double Bond Reduction with Hydrazinium Carbazate–H2O2
1019
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.90; H,
8.50.
13C NMR (50 MHz, CDCl3): d = 143.7 (C), 128.7 (2 × CH), 128.4
(2 × CH), 126.9 (CH), 118.2 (C), 88.0 (CH), 62.3 (CH2), 43.4 (CH),
36.5 (CH2), 35.2 (CH2), 35.0 (CH2), 24.4 (2 × CH2), 18.1 (CH3).
3-(1-Phenylethyl)-1,2,5-trioxaspiro[5.5]undecane (4e)
Oil.
FT-IR (neat): 764, 1023, 1097, 1602, 2935 cm–1.
ESI-MS: m/z = 269 [M + Li+], 285 [M + Na+], 301 [M + K+].
EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found:
262.1593.
1H NMR (300 MHz, CDCl3): d = 7.33–7.16 (m, 5 H), 4.30 (dt,
J = 9.2, 2.1 Hz, 1 H), 3.62 (dd, J = 11.8, 9.2 Hz, 1 H), 3.33 (dd,
J = 11.8, 2.1 Hz, 1 H), 2.80 (br quint, 1 H), 2.13–2.07 (m, 1 H),
1.91–1.84 (m, 1 H), 1.64–1.44 (m, 8 H), 1.37 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 142.0 (C), 128.9 (2 × CH), 127.8
(2 × CH), 127.3 (CH), 102.5 (C), 83.3 (CH), 61.6 (CH2), 40.9 (CH),
34.2 (CH2), 29.7 (CH2), 25.7 (CH2), 22.5 (CH2), 22.47 (CH2), 18.5
(CH3).
8-(1-Biphenyl-4-ylethyl)-6,7,11-trioxaspiro[4.6]undecane (7b)
White solid; mp 76–79 °C.
FT-IR (KBr): 1041, 1158, 1605, 2945 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.59–7.23 (m, 9 H), 4.26 (dt,
J = 9.6, 3.8 Hz, 1 H), 3.82 (dt, J = 12.2, 1.8 Hz, 1 H), 3.69 (td,
J = 12.2, 3.7 Hz, 1 H), 2.81 (quint, J = 6.9 Hz, 1 H), 2.16–1.47 (m,
10 H), 1.41 (d, J = 6.9 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 143.5 (C), 141.2 (C), 139.9 (C),
129.2 (2 × CH), 128.5 (2 × CH), 127.7 (CH), 127.6 (2 × CH), 127.4
(2 × CH), 118.3 (C), 88.7 (CH), 62.4 (CH2), 43.5 (CH), 36.8 (CH2),
36.5 (CH2), 34.9 (CH2), 24.4 (2 × CH2), 19.2 (CH3).
FAB-MS: m/z = 263 [M + H+].
EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found:
262.1569.
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.35; H,
8.50.
ESI-MS: m/z = 339 [M + H+].
EI-HRMS: m/z calcd for C22H26O3 [M+]: 338.1882; found:
338.1834.
3-(1-Phenylethyl)-1,2,5-trioxaspiro[5.5]undecane (5e)
Oil.
FT-IR (neat): 765, 1030, 1091, 1602, 2940 cm–1.
8-(1-Biphenyl-4-ylethyl)-6,7,11-trioxaspiro[4.6]undecane (8b)
White solid; mp 100–104 °C.
FT-IR (KBr): 1036, 1163, 1609, 2950 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.20 (m, 5 H), 4.44 (ddd,
J = 9.9, 7.8, 3.2 Hz, 1 H), 3.82 (dd, J = 11.7, 9.9 Hz, 1 H), 3.73 (dd,
J = 11.7, 3.2 Hz, 1 H), 2.86 (quint, J = 7.3 Hz, 1 H), 2.11–2.03 (m,
1 H), 1.87–1.79 (m, 1 H), 1.61–1.38 (m, 8 H), 1.27 (d, J = 7.3 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 142.3 (C), 128.7 (2 × CH), 127.9
(2 × CH), 126.9 (CH), 102.6 (C), 82.7 (CH), 61.4 (CH2), 40.7 (CH),
34.6 (CH2), 29.4 (CH2), 25.7 (CH2), 22.5 (CH2), 22.4 (CH2), 17.5
(CH3).
1H NMR (200 MHz, CDCl3): d = 7.60–7.26 (m, 9 H), 4.37 (ddd,
J = 10.5, 6.8, 4.1 Hz, 1 H), 3.89 (dt, J = 11.9, 1.9 Hz, 1 H), 3.77 (td,
J = 12.1, 3.8 Hz, 1 H), 2.92 (quint, J = 7.2 Hz, 1 H), 2.15–1.65 (m,
10 H), 1.32 (d, J = 7.2 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 142.9 (C), 141.5 (C), 139.7 (C),
129.1 (2 × CH), 128.7 (2 × CH), 127.5 (5 × CH), 118.2 (C), 88.0
(CH), 62.3 (CH2), 43.0 (CH), 36.4 (CH2), 35.3 (CH2), 34.9 (CH2),
24.4 (2 × CH2), 18.2 (CH3).
FAB-MS: m/z = 263 [M + H+].
EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found:
ESI-MS: m/z = 339 [M + H+], 377 [M + K]+.
262.1534.
EI-HRMS: m/z calcd for C22H26O3 [M+]: 338.1882; found:
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.10; H,
8.70.
338.1886.
9-(1-Biphenyl-4-ylethyl)-7,8,12-trioxaspiro[5.6]dodecane (7c)
White solid; mp 70–73 °C.
8-(1-Phenylethyl)-6,7,11-trioxaspiro[4.6]undecane (7a)
Oil.
FT-IR (KBr): 1010, 1153, 1611, 2930 cm–1.
FT-IR (neat): 1023, 1100, 1607, 2920 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.60–7.22 (m, 9 H), 4.22 (dt,
J = 12.3, 3.5 Hz, 1 H), 3.87 (t, J = 11.4 Hz, 1 H), 3.68–3.62 (m, 1
H), 2.80 (br m, 1 H), 1.81–1.56 (m, 12 H), 1.40 (d, J = 6.8 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 143.5 (C), 141.3 (C), 139.9 (C),
129.2 (2 × CH), 128.5 (2 × CH), 127.7 (CH), 127.6 (2 × CH), 127.4
(2 × CH), 106.8 (C), 88.5 (CH), 60.5 (CH2), 43.4 (CH), 36.9 (CH2),
34.4 (CH2), 32.0 (CH2), 25.9 (CH2), 23.4 (CH2), 23.2 (CH2), 19.1
(CH3).
1H NMR (200 MHz, CDCl3): d = 7.33–7.16 (m, 5 H), 4.22 (dt,
J = 9.7, 3.8 Hz, 1 H), 3.80 (dt, J = 12.0, 1.2 Hz, 1 H), 3.67 (td,
J = 12.2, 3.7 Hz, 1 H), 2.75 (quint, J = 6.9 Hz, 1 H), 2.15–1.47 (m,
10 H), 1.37 (d, J = 6.8 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 144.5 (C), 128.9 (2 × CH), 128.1
(2 × CH), 126.9 (CH), 118.3 (C), 88.8 (CH), 62.5 (CH2), 43.9 (CH),
36.8 (CH2), 36.5 (CH2), 34.9 (CH2), 24.4 (2 × CH2), 19.3 (CH3).
ESI-MS: m/z = 263 [M + H+], 285 [M + Na+].
ESI-MS: m/z = 353 [M + H+], 371 [M + NH4 ].
+
EI-HRMS: m/z calcd for C16H22O3 [M+]: 262.1569; found:
EI-HRMS: m/z calcd for C23H28O3 [M+]: 352.2039; found:
262.1583.
352.2036.
8-(1-Phenylethyl)-6,7,11-trioxaspiro[4.6]undecane (8a)
Oil.
9-(1-Biphenyl-4-ylethyl)-7,8,12-trioxaspiro[5.6]dodecane (8c)
White solid; mp 76–80 °C.
FT-IR (neat): 1020, 1150, 1615, 2925 cm–1.
FT-IR (KBr): 1008, 1150, 1615, 2935 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.33–7.20 (m, 5 H), 4.40–4.29 (m,
1 H), 3.87–3.72 (m, 2 H), 2.93 (quint, J = 7.2 Hz, 1 H), 2.14–1.57
(m, 10 H), 1.29 (d, J = 7.2 Hz, 3 H).
1H NMR (200 MHz, CDCl3): d = 7.60–7.24 (m, 9 H), 4.32 (ddd,
J = 10.9, 10.2, 3.5 Hz, 1 H), 3.93 (dt, J = 12.0, 0.9 Hz, 1 H), 3.70
(td, J = 12.3, 3.3 Hz, 1 H), 2.99 (quint, J = 7.2 Hz, 1 H), 1.86–1.39
(m, 12 H), 1.33 (d, J = 7.2 Hz, 3 H).
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

1020
C. Singh et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 142.7 (C), 141.4 (C), 139.7 (C),
129.1 (2 × CH), 128.8 (2 × CH), 128.5 (CH), 127.4 (4 × CH), 106.8
(C), 87.9 (CH), 60.6 (CH2), 42.9 (CH), 35.1 (CH2), 34.6 (CH2), 31.8
(CH2), 25.9 (CH2), 23.5 (CH2), 23.1 (CH2), 17.8 (CH3).
13C NMR (50 MHz, CDCl3): d = 143.3 (C), 142.7 (C), 141.3 (C),
139.7 (C), 129.2 (CH), 128.8 (CH), 128.7 (CH), 127.5 (CH), 127.4
(CH), 89.3 (CH), 89.1 (CH), 61.0 (CH2), 42.7 (CH), 42.0 (CH), 33.2
(CH2), 32.4 (CH2), 30.1 (CH2), 29.8 (CH2), 18.7 (CH3), 16.5 (CH3).
ESI-MS: m/z = 353 [M + H+].
ESI-MS: m/z = 273 [M + H+].
EI-HRMS: m/z calcd for C23H28O3 [M+]: 352.2039; found:
352.2052.
1-Isopropyl-4-methyl-2,3-dioxabicyclo[2,2,2]octane (Dihydro-
ascaridole, 26)
Oil.
2-Hydroperoxy-3-naphthalen-2-ylbutan-1-ol (10)
Oil.
FT-IR (neat): 1039, 1116, 2965 cm–1.
FT-IR (neat): 750, 820, 1063, 1599, 2928, 3405 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.97–1.81 (br m, 4 H), 1.75–1.63
(br m, 5 H), 1.11 (s, 3 H), 0.87 (d, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 79.1 (C), 74.4 (C), 34.4 (CH), 30.8
(2 × CH2), 26.1 (2 × CH2), 24.1 (CH3), 16.9 (2 × CH3).
ESI-MS: m/z = 171 [M + H+].
EI-HRMS: m/z calcd for C10H18O2 [M+]: 170.1307; found:
1H NMR (300 MHz, CDCl3): d = 9.72 (br m, 1 H, OOH), 7.77–7.21
(m, 7 H), 4.15–4.02 (m, 1 H), 3.74 (dd, J = 12.3, 2.3 Hz) and 3.50
(dd, J = 12.2, 2.9 Hz, 1 H total), 3.66 (dd, J = 12.3, 6.2 Hz) and 3.42
(dd, J = 12.2, 6.4 Hz, 1 H total), 3.09 (br quint, J = 7.2 Hz) and 2.20
(quint, J = 7.2 Hz, 1 H total), 1.40 (d, J = 7.0 Hz) and 1.28 (d,
J = 7.2 Hz, 3 H total).
13C NMR (75 MHz, CDCl3): d = 140.0 (C), 139.4 (C), 133.7 (C),
132.8 (C), 132.7 (C), 128.7 (CH), 128.4 (CH), 127.9 (CH), 127.83
(CH), 127.78 (CH), 126.6 (CH), 126.5 (CH), 126.4 (CH), 126.14
(CH), 126.11 (CH), 125.9 (CH), 125.7 (CH), 83.2 (CH), 82.6 (CH),
61.2 (CH2), 61.0 (CH2), 41.04 (CH), 40.98 (CH), 18.8 (CH3), 17.8
(CH3).
170.1284.
Borohydride Reduction of Saturated b-Hydroxyhydroperox-
ides and g-Hydroxyhydroperoxides; Typical Procedure for the
Reduction of Saturated b-Hydroxyhydroperoxide 10
To a stirred and ice cooled solution of b-hydroxyhydroperoxide 10
(0.100 g, 0.431 mmol) in MeOH (5 mL), was added NaBH4 (0.033
g, 2 equiv) and the reaction mixture was allowed to stir for 5 min.
The mixture was quenched with glacial AcOH (0.5 mL), concen-
trated under vacuum, diluted with H2O (5 mL), and extracted with
EtOAc (3 × 10 mL). The combined organic extracts were washed
with brine (5 mL), concentrated, and the crude product was purified
by column chromatography over silica gel to furnish the saturated
diol 11 (0.090 g, 97%) as a colorless oil.
ESI-MS: m/z = 255 [M + Na+].
3-(4-Fluorophenyl)-2-hydroperoxybutan-1-ol (14)
Oil.
FT-IR (neat): 841, 1045, 1603, 2932, 3405 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.73 (br m, 1 H, OOH), 7.22–6.98
(m, 4 H), 4.05 and 3.96 (2 m, 1 H), 3.89 (dd, J = 12.3, 2.6 Hz) and
3.56 (dd, J = 12.2, 2.8 Hz, 1 H total), 3.70 (dd, J = 12.3, 6.6 Hz) and
3.44 (dd, J = 12.2, 6.6 Hz, 1 H total), 3.09 (quint, J = 7.2 Hz) and
3.03 (quint, J = 7.0 Hz, 1 H total), 1.34 (d, J = 7.0 Hz) and 1.25 (d,
J = 7.2 Hz, 3 H total).
13C NMR (75 MHz, CDCl3): d = 162.0 (d, C, JC,F = 244 Hz), 161.9
(d, C, JC,F = 243 Hz), 138.0 (d, C, JC,F = 3.0 Hz), 137.7 (d, C,
JC,F = 3.0 Hz), 129.3 (d, CH, JC,F = 7.5 Hz), 129.2 (d, CH, JC,F = 7.5
Hz), 115.8 (d, CH, JC,F = 22 Hz), 115.4 (d, CH, JC,F = 21 Hz), 83.2
(CH), 82.7 (CH), 61.44 (CH2), 61.37 (CH2), 40.05 (CH), 39.99
(CH), 18.5 (CH3), 17.7 (CH3).
Hydroperoxides 14, 18, and 22 were also reduced by the same pro-
cedure to furnish diols 15, 19, and 23 as inseparable diastereomeric
mixtures in 87, 81, and 85% yields, respectively.
Catalytic Hydrogenation of b-Hydroxyhydroperoxide 9
A solution of b-hydroxyhydroperoxide 9 (0.200 g, 0.869 mmol) in
EtOAc (15 mL) was hydrogenated in the presence of Adam’s cata-
lyst (PtO2, 0.003 g) using a Parr shaker assembly at r.t. and pressure
for 1 h. The reaction mixture was filtered over Celite, concentrated,
and the crude product was purified by column chromatography over
silica gel to furnish the saturated diol 11 (96%) as a colorless oil.
ESI-MS: m/z = 223 [M + Na+].
3-Naphthalen-2-ylbutane-1,2-diol (11)
Oil.
3-Hydroperoxy-4-phenylpentan-1-ol (18)
FT-IR (neat): 751, 1068, 1109, 1623, 2929, 3282 cm–1.
Oil.
FT-IR (neat): 836, 1038, 1601, 2926, 3396 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.67–7.28 (m, 7 H), 3.81 (dt,
J = 7.4, 2.6, 1 H), 3.73 (dd, J = 11.4, 2.8 Hz) and 3.39 (dd, J = 11.3,
2.9 Hz, 1 H total), 3.49 (dd, J = 11.4, 7.2 Hz) and 3.29 (dd, J = 11.3,
7.5 Hz, 1 H total), 2.98 (quint, J = 7.0 Hz) and 2.89 (quint, J = 7.0
Hz, 1 H total), 3.02–2.84 (br m, 2 H, 2 OH), 1.41 (d, J = 7.0 Hz) and
1.32 (d, J = 7.0 Hz, 3 H total).
13C NMR (75 MHz, CDCl3): d = 140.9 (C), 133.7 (C), 133.6 (C),
132.6 (C), 132.5 (C), 128.4 (CH), 128.3 (CH), 127.79 (H), 127.76
(CH), 126.8 (CH), 126.30 (CH), 126.27 (CH), 126.21 (CH), 126.17
(CH), 125.7 (CH), 125.6 (CH), 76.7 (CH), 76.3 (CH), 65.2 (CH2),
64.8 (CH2), 43.1 (CH), 43.0 (CH), 18.0 (CH3), 17.7 (CH3).
1H NMR (300 MHz, CDCl3): d = 10.49 (br m, 1 H, OOH), 7.39–
7.15 (m, 5 H), 4.16–3.54 (m, 3 H), 3.27 (quint, J = 6.7 Hz) and 3.08
(quint, J = 7.4 Hz, 1 H total), 1.79–1.49 (m, 2 H), 1.35 (d, J = 6.9
Hz) and 1.27 (d, J = 6.9 Hz, 3 H total).
13C NMR (50 MHz, CDCl3): d = 144.2 (C), 143.6 (C), 128.9 (CH),
128.8 (CH), 128.4 (CH), 128.3 (CH), 126.9 (CH), 126.8 (CH), 88.8
(CH), 88.7 (CH), 60.6 (CH2), 42.9 (CH), 41.9 (CH), 33.2 (CH2),
31.9 (CH2), 18.7 (CH3), 15.8 (CH3).
ESI-MS: m/z = 197 [M + H+].
ESI-MS: m/z = 239 [M + Na+].
4-Biphenyl-4-yl-3-hydroperoxypentan-1-ol (22)
EI-HRMS: m/z calcd for C14H16O2 [M+]: 216.1150; found:
216.1148.
Oil.
FT-IR (neat): 821, 1042, 1600, 2949, 3401 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59–7.23 (m, 9 H), 4.27–4.01 (m,
1 H), 3.88–3.64 (m, 2 H), 3.34–3.05 (m, 2 H), 1.82–1.62 (m, 2 H),
1.41 (d, J = 7.0 Hz) and 1.33 (d, J = 7.2 Hz, 3 H total).
3-(4-Fluorophenyl)butane-1,2-diol (15)
Oil.
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

PAPER
Double Bond Reduction with Hydrazinium Carbazate–H2O2
1021
FT-IR (neat): 1035, 1066, 1605, 2929, 3322 cm–1.
132.6 (C), 132.7 (C), 128.7 (CH), 128.2 (CH), 127.9 (CH), 127.8
(CH), 127.8 (CH), 126.7 (CH), 126.5 (CH), 126.4 (CH), 126.2
(CH), 125.9 (CH), 125.8 (CH), 75.4 (CH), 74.9 (CH), 64.3 (CH2),
64.1 (CH2), 41.4 (CH), 41.1 (CH), 21.2 (CH3), 21.0 (CH3), 20.9
(CH3), 20.9 (CH3), 18.2 (CH3), 17.5 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.21–6.95 (m, 4 H), 3.72–3.64 (m,
2 H), 3.45 (dd, J = 11.8, 7.7 ) and 3.27 (dd, J = 11.1, 7.6 Hz, 1 H to-
tal), 2.82 (quint, J = 7.0 Hz) and 2.75 (quint, J = 7.1 Hz, 1 H total),
2.86–2.70 (br m, 2 H, 2 OH), 1.30 (d, J = 7.0 Hz) and 1.24 (d,
J = 7.1 Hz, 3 H total).
FAB-MS: m/z = 301 [M + H+].
13C NMR (75 MHz, CDCl3): d = 161.9 (C, d, JC,F = 243 Hz) 161.8
(C, d, JC,F = 244 Hz), 139.6 (C, d, JC,F = 3.0 Hz), 139.0 (C, d,
JC,F = 3.0 Hz), 129.6 (CH, d, JC,F = 8.0 Hz), 129.1 (d, CH, JC,F = 7.5
Hz), 115.5 (d, CH, JC,F = 21 Hz), 76.8 (CH), 76.4 (CH), 65.1 (CH2),
64.8 (CH2), 42.3 (CH), 42.2 (CH), 18.2 (CH3), 17.7 (CH3).
EI-HRMS: m/z calcd for C18H20O4 [M+]: 300.1362; found:
300.1360.
Anal. Calcd for C18H20O4: C, 71.98; H, 6.71. Found: C, 72.25; H,
6.50.
ESI-MS: m/z = 185 [M + H+].
Acetic Acid 1-Acetoxymethyl-2-(4-fluorophenyl)propyl Ester
(16)
Oil.
4-Phenylpentane-1,3-diol (19)
Oil.
FT-IR (neat): 1049, 1604, 1743, 2973 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.35–7.17 (m, 5 H), 3.94–3.70 (m,
3 H), 2.84–2.70 (m, 3 H), 1.70–1.51 (m, 2 H), 1.32 (d, J = 7.1 Hz)
and 1.26 (d, J = 7.0 Hz, 3 H total).
13C NMR (50 MHz, CDCl3): d = 146.4 (C), 129.0 (CH), 128.9 (CH),
128.7 (CH), 128.5 (CH), 128.2 (CH), 127.2 (CH), 126.9 (CH),
125.3 (CH), 124.9 (CH), 76.8 (CH), 65.4 (CH2), 46.9 (CH), 46.7
(CH), 36.4 (CH2), 35.9 (CH2), 17.9 (CH3), 16.8 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.22–6.95 (m, 4 H), 5.27–5.20 (m,
1 H), 4.23 (dd, J = 12.0, 3.3 Hz) and 4.13 (dd, J = 12.0, 2.9 Hz, 1 H
total), 4.00 (dd, J = 12.0, 6.8 Hz) and 3.78 (dd, J = 12.0, 6.5 Hz, 1
H total), 3.08 (quint, J = 7.1 Hz) and 3.04 (quint, J = 6.8 Hz, 1 H
total), 2.01 (s) and 1.94 (s, 3 H total), 2.09 (s) and 2.04 (s, 3 H total),
1.30 (d, J = 7.1 Hz) and 1.28 (d, J = 6.8 Hz, 3 H total).
13C NMR (75 MHz, CDCl3): d = 170.8 (C), 170.7 (C), 170.65 (C),
170.4 (C), 162.0 (d, C, JC,F = 244 Hz), 161.9 (d, C, JC,F = 243 Hz),
138.0 (d, C, JC,F = 3.0 Hz), 137.8 (d, C, JC,F = 3.0 Hz), 129.5 (d, CH,
JC,F = 8.0 Hz), 129.2 (d, CH, JC,F = 8.0 Hz), 115.7 (d, CH, JC,F = 22
Hz), 115.3 (d, CH, JC,F = 21 Hz), 75.3 (CH), 74.8 (CH), 63.9 (CH2),
63.9 (CH2), 40.4 (CH), 40.2 (CH), 21.1 (CH3), 20.9 (CH3), 17.9
(CH3), 17.6 (CH3).
+
ESI-MS: m/z = 198.4 [M + NH4 ].
4-Biphenyl-4-ylpentane-1,3-diol (23)
Oil.
1H NMR (200 MHz, CDCl3): d = 7.65–7.30 (m, 9 H), 4.02–3.78 (m,
3 H), 2.91–2.85 (m, 1 H), 1.89–1.64 (m, 3 H), 1.39 (d, J = 7.0 Hz)
and 1.36 (d, J = 7.0 Hz, 3 H total).
+
ESI-MS: m/z = 286 [M + NH4 ].
13C NMR (50 MHz, CDCl3): d = 143.7 (C), 142.7 (C), 141.2 (C),
140.1 (C), 139.8 (C), 129.2 (CH), 128.9 (CH), 128.7 (CH), 127.6
(CH), 127.4 (CH), 77.0 (CH), 76.8 (CH), 62.3 (CH2), 62.0 (CH2),
46.6 (CH), 46.4 (CH), 36.4 (CH2), 35.9 (CH2), 17.9 (CH3), 16.9
(CH3).
Acetic Acid 1-(2-Acetoxyethyl)-2-phenylpropyl Ester (20)
Oil.
FT-IR (neat): 1741 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.64–7.21 (m, 5 H), 4.10–3.95 (m,
3 H), 3.00–2.97 (m, 1 H), 2.31–2.16 (m, 2 H), 2.07 (s) and 1.95 (s,
3 H total), 2.00 (s) and 1.88 (s, 3 H total), 1.30–1.25 (m, 3 H).
ESI-MS: m/z = 257.2 [M + H+].
Acetylation of Saturated Diols; Typical Procedure
+
ESI-MS: m/z = 282.4 [M + NH4 ].
To a stirred solution of diol 11 (0.100 g, 0.463 mmol) in CH2Cl2 (5
mL) were added Ac2O (0.23 mL, 5 equiv), Et3N (0.23 mL, 5 equiv),
and a catalytic amount of DMAP (2 mg) in succession and the reac-
tion mixture was allowed to stir for 2 h. The mixture was concen-
trated under vacuum and the crude product was purified by column
chromatography over silica gel to furnish the diacetate 12 (0.125 g,
91%) as an oil.
Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 67.82; H,
7.29.
Acetic Acid 1-(2-Acetoxyethyl)-2-biphenyl-4-ylpropyl Ester
(24)
Oil.
FT-IR (neat): 1741 cm–1.
Saturated diols 15, 19 and 23 were also acetylated by the same pro-
cedure to furnish corresponding diacetates 16, 20 and 24 as insepa-
rable diastereomeric mixtures in 93, 91, and 89% yields,
respectively.
1H NMR (200 MHz, CDCl3): d = 7.62–7.23 (m, 9 H), 5.29–5.23 (m,
1 H), 4.10–4.02 (m, 2 H), 3.08 (quint, J = 7.1 Hz) and 3.00 (quint,
J = 7.1 Hz, 1 H total), 2.12 (s) and 2.03 (s, 3 H total), 2.04 (s) and
2.01 (s, 3 H total), 1.67–1.52 (m, 2 H), 1.36–1.31 (m, 3 H).
Acetic Acid 1-Acetoxymethyl-2-naphthalen-2-ylpropyl Ester
(12)
Oil.
+
ESI-MS: m/z = 358.4 [M + NH4 ].
EI-HRMS: m/z calcd for C21H24O4: 340.1675; found: 340.1678.
FT-IR (neat): 1047, 1650, 1744, 2971 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.85–7.38 (m, 7 H), 5.44–5.37 (m, Acknowledgment
1 H), 4.32 (dd, J = 12.0, 3.0 Hz) and 4.17 (dd, J = 12.0, 2.8 Hz, 1 H
A.S.S., N.K.N., V.P.V., M.H., N.G., and S.P. are thankful to
total), 4.08 (dd, J = 12.0, 7.1 Hz) and 3.85 (dd, J = 12.0, 6.6 Hz, 1
H total), 2.15 (s) and 2.06 (s, 3 H total), 3.30 (br quint, J = 7.1 Hz)
and 3.22 (quint, J = 7.1 Hz, 1 H total), 1.42 (merged d) and 1.40 (d,
J = 7.1 Hz, 3 H total), 2.03 (s) and 1.95 (s, 3 H total).
13C NMR (75 MHz, CDCl3): d = 170.9 (C), 170.82 (C), 170.78 (C),
170.5 (C), 139.8 (C), 139.6 (C), 133.8 (C), 133.6 (C), 132.8 (C),
Council for Scientific and Industrial Research (CSIR), New Delhi
and University Grant Commission (UGC) for the award of Senior
Research Fellowships. We thank SAIF, Lucknow for providing
spectral and analytical data.
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York

1022
C. Singh et al.
PAPER
(7) (a) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg.
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multiplicity pattern in 1H NMR spectra.
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(19) Diimide reduction of ascaridole using dipotassium
azodicarboxylate is known to furnish dihydroascaridole in
~40% yield: see reference 10a.
(20) In our hands all these peroxides have behaved well, but the
usual precautions for handling of peroxides are
recommended.
Synthesis 2010, No. 6, 1014–1022 © Thieme Stuttgart · New York