A domino Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines and application to the synthesis of the ceramide transport inhibitor (±)-HPA-12

Article abstract of DOI:10.1016/j.tet.2017.11.010

A Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines with primary and secondary amines has been developed which affords 4-hydroxy-3-aminoketones. The aza-Michael products were reduced using non-selective NaBH₄/MeOH or diastereoselective (up to 92:8) SnCl₄/NaBH₄ conditions yielding (1R^?,3S^?)-3-amino-1,4-diols in up to 97% and 70% yield respectively. The major reduction product was converted in two steps to (±)-HPA-12, which is an inhibitor of the cytosolic ceramide transporting protein.

Full text of DOI:10.1016/j.tet.2017.11.010

Accepted Manuscript
A domino Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines and
application to the synthesis of the ceramide transport inhibitor (±)-HPA-12
Sarah V.A.-M. Legendre, Martyn Jevric, Julian Klepp, Christopher J. Sumby, Ben W.
Greatrex
PII:
S0040-4020(17)31146-8
10.1016/j.tet.2017.11.010
TET 29090
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 September 2017
Revised Date: 30 October 2017
Accepted Date: 3 November 2017
Please cite this article as: Legendre SVA-M, Jevric M, Klepp J, Sumby CJ, Greatrex BW, A domino
Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines and application to the synthesis of
the ceramide transport inhibitor (±)-HPA-12, Tetrahedron (2017), doi: 10.1016/j.tet.2017.11.010.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A domino Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines and
application to the synthesis of the ceramide transport inhibitor (±)-HPA-12
Sarah V. A.-M. Legendre,1 Martyn Jevric,1 Julian Klepp,1 Christopher J. Sumby2 and Ben
W. Greatrex1*
1School of Science and Technology, University of New England, Armidale, Australia, 2351.
2School of Chemical and Physical Sciences, University of Adelaide, Adelaide, Australia,
5005.
* Corresponding author
ben.greatrex@une.edu.au
1

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Abstract
A Kornblum-DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines with primary and
secondary amines has been developed which affords 4-hydroxy-3-aminoketones. The aza-
Michael products were reduced using non-selective NaBH4/MeOH or diastereoselective (up
to 92:8) SnCl4/NaBH4 conditions yielding (1R*,3S*)-3-amino-1,4-diols in up to 97% and 70%
yield respectively. The major reduction product was converted in two steps to (±)-HPA-12,
which is an inhibitor of the cytosolic ceramide transporting protein.
Keywords
Kornblum-DeLaMare rearrangement; Conjugate addition; Endoperoxide; Domino reaction
2

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1. Introduction
The 3,6-dihydro-1,2-dioxine moiety (1,2-dioxine) is a surprisingly versatile functional group
in organic synthesis.1-4 Readily prepared from 1,3-butadienes via the photochemical addition
of singlet oxygen,5-7 1,2-dioxines can react at either the peroxide bond or through the alkene,
disrupting the weak peroxide bond or keeping it intact respectively. A common reaction seen
with peroxides under basic conditions is the Kornblum-DeLaMare reaction, a process which
yields 4-hydroxyenones from 1,2-dioxines after removal of the proton α to the peroxide
linkage (Scheme 1).8,9 Homolytic cleavage of the peroxide bond can be accomplished using
transition metal catalysis and also affords 4-hydroxyenones in high yield along with some
bisepoxide products from radical cyclisation onto the alkene.10 Stereoselective examples of
both processes have been reported allowing the desymmetrisation of meso-endoperoxides
using cinchona alkaloid derivatives11,12 or chiral Co(II)salen complexes13 with good to
excellent enantioselectivity.
A common rearrangement product, if the Kornblum-DeLaMare reaction is carried out with
monocyclic 1,2-dioxines and tertiary amines, is the 1,4-dicarbonyl derivative.14,15 The
reaction sequence for 3,6-diphenyl-3,6-dihydro-1,2-dioxine (1) is shown in Scheme 1.
Mechanistically, the rearrangement yielding diketone 4 either proceeds through the bis-enol
intermediate 3a generated by the allylic deprotonation which then tautomerises to 4, or
possibly through a 1,2-sigmatropic shift affording 3b. During a recent attempt to use these
1,4-dicarbonyl derivatives in synthesis, we discovered that primary and secondary amines do
not promote the 1,4-dicarbonyl rearrangement, but instead undergo reversible aza-Michael
addition as nucleophiles (Scheme 1). The observed domino sequence was surprising as
heating benzylamine with 1,2-dioxine 1 affords substituted pyrrole 7 through a Paal-Knorr
process via the 1,4-diketone 4.14 This observation inspired us to examine the 1,4-addition
more closely as the intermediates formed could potentially be useful in synthesis.
A potential target identified for this chemistry is the ceramide analogue HPA-12, which is an
inhibitor of the cytosolic ceramide transporting protein (CERT).16,17 The CERT protein is
responsible for the cytosolic transport of ceramide from the endoplasmic reticulum to the
golgi apparatus where it is converted to sphingomyelin.18,19 Ceramide itself is an important
intracellular messenger and inhibition of sphingomyelin synthesis could potentially affect
ceramide levels in the cell. HPA-12 has been shown to sensitise cancer cells to
chemotherapy,20 interferes with sphingolipid uptake by Chlamydia psittaci and inhibits the
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growth of C. trachomatis.21,22 Since its discovery, multiple syntheses of HPA-12 and its
isomers have been reported as well as some derivatives.23-26,17,27-33
NEt3, Co(II)
or BnNH2
OH
OH
OH
OH
O
O
O
NEt3
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
Ph
[1,2]-shift
NEt3
1
2
3a
BnNH2
25°C
O
O
NHBn
OH
NHBn
OH
3b
Ph
Ph
Ph
Ph
6a
5a
O
O
Ph
Ph
4
BnNH2
80°C
Bn
BnNH2
80°C
N
Ph
Ph
1
7
Scheme 1. Reactions of 1,2-dioxines with triethylamine and benzylamine.
2. Results and discussion
We have investigated the effects of solvent and temperature on the yields and the
stereoselectivity of the reaction of amine and 1,2-dioxine 1 (Table 1). The reaction outcome
for 1,2-dioxine 1 was not strongly dependant on temperature or solvent yielding mixtures of
both 5a and 6a and only moderate selectivity was seen at low temperatures (entries 2 and 3).
Furthermore, lower temperatures significantly slowed the ring-opening by amine although
these reactions could be catalysed using Co(II)salen which reduced the time required for
completion (entries 4 and 5). The stereoselectivity of the reaction starting with 1,2-dioxine 1
was not significantly changed in protic or aprotic reaction mediums and so the low
temperature reaction in methanol was not examined further (entry 5). The use of the sterically
hindered tert-butylamine gave greater selectivity in the addition, however, the competitive
rearrangement to 1,4-diketone 4 lowered the yield of addition product (entry 6).
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Table 1. Reactions of 1 with primary amines.
Entrya
Amine
Time
(h)
Temp
(°C)
Solvent
Yield
(%)
5:6
1
2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
t-BuNH2
0.5
72
72
3
25
-15
-15
-60
-50
25
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
100
84b
64b
74
54:46
45:55
65:35
66:34
43:57
83:17
3
4c
5c
3
n.d.
57b
6
2.5
a
Reactions were performed on a 50-250 mg scale using 1.2 equivalents of amine.
b Conversion to product determined using benzhydrol as an internal standard in the reaction
mixture. Remaining material was diketone 4. c Reaction was catalysed using 1% Co(II)salen.
n.d. = not determined.
The 3-aminocarbonyl products 5 and 6 were found to be unstable at room temperature both
neat and in solution. The isomers 5a and 6a could be separated by chromatography, however,
the isomers underwent interconversion via the 4-hydroxyenone in CDCl3. If the mixture was
stored neat at 25°C for 7 days, quantitative transformation into the diketone 4 was seen.
These observations are consistent with the reaction of 3,6-dihydro-1,2-dioxines and primary
amines affording pyrroles at elevated temperatures which involves the 1,4-dicarbonyl.14
Our inability to greatly affect the stereoselectivity of the addition as well as the
interconversion of diastereomers led us to examine the simpler 3-aryl-3,6-dihydro-1,2-
dioxines (Table 2). The reaction of phenyl-substituted dioxine 8 with benzylamine gave an
excellent yield of ring-opening/addition product 10a after removal of volatile components.
The reaction was general for primary amines affording 10b-d, and the secondary amines
morpholine and pyrrolidine also yielded the 3-amino-4-hydroxyketone products 10e and 10f.
The lower basicity of aniline meant that ring-opening occurred very slowly, however the
reaction furnished the amino ketone 10g in good yield when catalytic triethylamine was
added. The reactions were highly selective and isolation of the product using these volatile
amines consisted of simple evaporation of the volatiles under reduced pressure giving the 4-
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hydroxy-3-aminoketones which were stable for up to a day at room temperature. The reaction
of non-volatile secondary amines posed a challenge as silica gel purification of adducts
prepared using secondary amines led to the formation of trans-enone 14 due to the retro-aza-
Michael reaction. The elimination product 14 was also observed when a substoichiometric
quantity of amine was used in the reaction.
The reaction of hydrazine and acyclic α,β-unsaturated ketones is known to lead to
dihydropyrazoles by a 1,4-addition/dehydration sequence and a number of biological
activities for this class of derivative are known.34-36 The reaction of 1,2-dioxine 8 and
hydrazine hydrate catalysed by triethylamine led to a quantitative yield of dihydropyrazole
12. The reaction of o-phenylenediamine and 8 at 20 °C similarly led to imine 13 as the sole
product, however, separation of residual o-phenylenediamine by flash chromatography was
not possible.
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Table 2. Domino reactions of primary and secondary amines (NHR1R2) with 3-aryl-3,6-
dihydro-1,2-dioxines 8 and 9.
a
Reactions were performed on 0.24-1.7 mmol of 1,2-dioxine at 20 °C. Reactions were
catalysed using triethylamine. b Diazepane 13 contained residual o-phenylenediamine.
The amine addition products 10a,c-f and 13 formed from primary amines existed in
equilibrium with up to 10% of the furanol 15 (or hemiaminal) formed by cyclisation of the 4-
hydroxy group onto the aromatic ketone (Scheme 2). Evidence for this cyclisation was seen
in the NMR spectra of the aminoketones with resonances around δ 105 ppm in the 13C NMR
spectra and an upfield shift for the methylene adjacent to the ketone in the 1H NMR spectra.
The furanols from the secondary amine addition products were more prevalent in solution,
and 10e and 10f existed as the furanols 15e and 15f respectively when crystalline. Evidence
for the furanols 15e and 15f was seen in the IR spectra as the solids lacked the IR absorptions
1
at 1681-1682 cm-1. Furthermore, when a H NMR was obtained immediately upon
dissolution, the majority of the mixture corresponded to the furanol. Monitoring the mixture
by 1H NMR demonstrated that after 10 minutes equilibrium had been reached and the open-
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chain aminoketone dominated. Although there was a clear preference for one furanol
diastereomer, both were present and no attempt was made to assign the stereochemistry of the
hemiketal centre.
Scheme 2. Formation of furanol 15 from aminoketone 10.
The reduction of the ketone was examined as a way of eliminating the retro-aza-Michael
reaction and would also lead to the 3-amino-1,4-diol motif which was required for the
synthesis of HPA-12 (Table 3). Due to the low stability of the aminoketones, a one-pot
Kornblum-DeLaMare/aza-Michael/reduction approach to the products was used and reaction
optimisation was focussed on the benzylic amine 10a as the benzyl group could be readily
removed exposing the primary amine. Reduction of the acyclic ketone with NaBH4/MeOH
gave virtually no selectivity between the reduction products 17 and 18 although separation of
the isomers was straightforward using flash chromatography and usually only a single
column chromatographic separation was required to obtain pure fractions of each isomer.
Moderate selectivity for the syn-product (74:26 17a/18a), matching HPA-12 stereochemistry,
was obtained using Zn(BH4)2 at −60 °C (entry 2), however, yields were reduced compared to
using the non-selective NaBH4/MeOH conditions (entry 1). The best selectivity was obtained
for the reduction of the ketone using a catalytic amount of SnCl4 combined with NaBH4
which provided a 92:8 ratio of 17a/18a in 70% yield (entry 3). The yield was reduced when a
stoichiometric quantity of SnCl4 was used for the reduction (entry 5) and CeCl3/NaBH4,
which has been previously used for diastereoselective reductions,37 reversed the selectivity of
the reduction (entry 6). The conditions were not selective for all of the aminoketones and in
some cases only decomposition products were observed due to the presence of even catalytic
quantities of Lewis acid. The potential for bioactivity in these 3-amino-1,4-diols made both
diastereomers desirable and therefore the non-selective NaBH4/MeOH reduction was used for
the reduction of all of the addition products. The diols were obtained in good to excellent
yields and samples of each diastereomer were obtained by chromatography.
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Table 3. Two-step one-flask preparation of 1-aryl-3-amino-1,4-diols from 1,2-dioxines.
Entry
Dioxine
Amine
Reducing agent
(equiv)
Additive
Solvent Temp
(°C)
Products
Conversion
Ratio
Yield
(%)
1
8
8
8
8
8
8
8
8
8
8
8
8
8
BnNH2
NaBH4 (1.0)
Zn(BH4)2 (1.0)
NaBH4 (0.8)
NaBH4 (1.2)
NaBH4 (4.0)
NaBH4 (3.0)
NaBH4 (1.0)
NaBH4 (0.4)
NaBH4 (1.0)
NaBH4 (0.4)
NaBH4 (1.0)
NaBH4 (0.4)
NaBH4 (1.0)
-
MeOH
THF
25
17a/18a
17a/18a
17a/18a
17a/18a
17a/18a
17a/18a
17b/18b
17b/18b
17c/18c
17c/18c
17d/18d
17d/18d
17e/18e
100
100
95
56:44
74:26
92:8
91:9
92:8
31:69
60:40
-
96
63
70
41
38
49
75
2
BnNH2
-
−60
3
BnNH2
SnCl4 (0.2)
THF
0 to 20
0 to 20
0 to 20
0 to 20
20
4
BnNH2
SnCl4 (0.3)
EtOH
THF
76
5
BnNH2
SnCl4 (1.0)
85
6
BnNH2
CeCl3 (1.0)
THF
100
100
100
100
100
100
76
7
t-BuNH2
t-BuNH2
AllylNH2
AllylNH2
n-BuNH2
n-BuNH2
-
MeOH
THF
a
8
SnCl4 (0.1)
0 to 20
20
-
9
-
MeOH
THF
59:41
-
85
a
10
11
12
13
SnCl4 (0.1)
0 to 20
20
-
-
MeOH
THF
55:45
90:10
54:46
96
25
97
SnCl4 (0.1)
-
0 to 20
20
MeOH
100
14
8
NaBH4 (0.4)
SnCl4 (0.1)
THF
0 to 20
17e/18e
71
92:8
60
73
15
16
8
8
NaBH4 (1.0)
NaBH4 (0.4)
-
MeOH
THF
20
17f/18f
17f/18f
100
100
62:38
-
a
SnCl4 (0.1)
0 to 20
-
17
18
19
20
8
PhNH2
PhNH2
BnNH2
BnNH2
NaBH4 (1.0)
NaBH4 (0.4)
NaBH4 (1.0)
NaBH4 (1.0)
-
MeOH
THF
20
17g/18g
17g/18g
19a/20a
21a/22a
100
100
100
100
50:50
-
100
a
8
SnCl4 (0.1)
0 to 20
20
-
9
-
-
MeOH
MeOH
64:36
50:50
59
69
16
20
a Only decomposition products were observed.
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The assignment of stereochemistry in the diol series was made on the basis of a conserved
coupling pattern between H1 and the adjacent methylene seen in each of the diastereomers. A
discussion for the two diols 17a and 18a is given highlighting the preferred conformation for
each diastereomer. The syn-diastereomer 17a had a JH1-H2α of 10.0 Hz and JH1-H2β of 2.7 Hz
consistent with the conformation where H1 has one anti and one gauche coupling partner
(Figure 1). The anti-diastereomer 18a had a JH1-H2α of 6.0 Hz and JH1-H2β of 5.3 Hz consistent
with a preference for two gauche interactions. The lack of free rotation in these acyclic
compounds along the C1-C2 bond was attributed to an intramolecular hydrogen bond
between the C1-OH and the C3-N which was also seen in the X-ray crystal structure of 17b.
The conserved coupling pattern combined with the X-ray structure of 17b was used to assign
the relative stereochemistry of all diols. On the basis of coupling constants at H1, the
conformation of 18b differed to the other anti-diols presumably due to the influence of the
bulky tert-butyl group. With the exception of 17f/18f, the syn-substituted product eluted prior
to the anti-product when purified by flash chromatography. The products 17g and 18g
derived from the addition of aniline were more difficult to separate although still
demonstrated the coupling pattern which was used to assign the relative stereochemistry.
Bn
Bn
HN
HOH2C
H
HOH2C
H
HN
H
H
H
O
H
Ph
O
H
H
H
Ph
17a
H
18a
17b
Figure 1. Newman projections for 17a and 18a showing preferred conformations and the X-
ray structure for 17b. The perspective view of 17b is given with ellipsoids at the 50%
probability level and selected atom labelling. The hydrogen bond O-H···N (DO-N = 2.713(1)
Å; angleOH-N = 145.53(7)°) is shown with a red dashed cylinder. Carbon, grey; hydrogen,
white; nitrogen, blue; and oxygen, red.
To demonstrate the utility of the domino reaction chemistry, the synthesis of (±)-HPA-12
(27) was attempted and the results are shown in Scheme 3. The sequence to the target from
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17a first required the removal of the benzyl group by hydrogenolysis which was achieved
using fresh Pd/C in EtOH affording 23. The results of the hydrogenolysis depended on the
batch of Pd/C used; in some reactions deoxygenation giving 24 and 25 were observed and
these were the major products when PdCl2 was used as catalyst. The reaction of the free
amine with p-nitrophenyl dodecanoate afforded 27 in good yield although the reaction took 7
days to reach completion. The stereochemistry of the product 27 was confirmed by matching
the reported NMR data to the revised structure of HPA-12 which confirmed the relative
stereochemical assignment in 17a.16 The synthesis of enantiopure HPA-12 has been reported
using α-methylbenzylamine as a chiral auxiliary for the separation of enantiomers.17
A
similar approach might be possible starting with 1,2-dioxine, however, this was beyond the
scope of the current work.
1. H2, Pd/C
NHBn
OH NH2
OH NHBn
OH
EtOH
OH
OH
Ph
Ph
Ph
64%
24
25
(±)-17a
23
NH2
OH
O
Ph
CH2Cl2
PNPO
(CH2)10CH3
75%
26
O
OH HN
(CH2)10CH3
OH
1'
3'
Ph
(±)-27, (HPA-12)
Scheme 3. Synthesis of (±)-HPA-12 from 17a. PNP = para-nitrophenyl.
3. Conclusions
This work has demonstrated a useful and interesting domino reaction involving 1,2-dioxines
and primary and secondary amines. Both aryl and alkyl amines can promote the ring-opening
and add via an aza-Michael reaction to give 3-amino-4-hydroxyketones. These aminoketones
are also transiently formed during the production of pyrroles from 1,2-dioxines as the 1,4-
addition is much faster than rearrangement to 1,4-dicarbonyl. A selective reduction using
SnCl4/NaBH4 was developed to provide the correct (1S*,3R*)-diastereomer of the 1,4-diol
which was then used to synthesise the ceramide transport inhibitor (±)-HPA-12 in an
additional two-steps. The preparation of analogues of HPA-12 is underway and will be
reported in due course.
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4. Experimental
General experimental
1
Solvents were dried using literature procedures. H NMR spectra recorded in CDCl3 were
recorded at 298 K referenced to TMS (0 ppm) and 13C NMR spectra were referenced to
residual solvent (77.16 ppm). MS were recorded using an Agilent 6120 Quadrupole detector.
Melting points are uncorrected. HRMS were recorded in positive ESI V mode (source
temperature 80 °C, desolvation temperature 150 °C, capillary 2.5 kV). 3,6-Diphenyl-3,6-
dihydro-1,2-dioxine (1),38 3-phenyl-3,6-dihydro-1,2-dioxine (8)38 and 3-(2-chlorophenyl)-
3,6-dihydro-1,2-dioxine (9)39 were prepared according to the general procedure and had
spectral data consistent with literature values. Other reagents were used as purchased.
General procedure for the preparation of 1,2-dioxines 1, 8, 9 and 16 via photooxidation.
Rose bengal bis(tetrabutylammonium) salt. To a well stirred rose bengal solution (500 mg,
0.49 mmol, 1.0 eq) in chloroform (60 mL), tetrabutylammonium bromide (320 mg,
0.99 mmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 19 h, then filtered to
remove NaBr (99 mg, 98% recovery) and the NaBr washed with chloroform (3 × 30 mL).
The pink filtrate was concentrated under reduced pressure giving rose bengal
1
tetrabutylammonium salt as a pink solid (701 mg, 98%); H NMR (500 MHz, CD3OD)
δ 7.97-7.86 (m, 2 H), 3.27-3.22 (m, 16 H), 1.70-1.63 (m, 16 H), 1.45-1.38 (m, 16 H), 1.07-
0.98 (m, 24 H); 13C NMR (125 MHz, CD3OD) δ 79.54, 79.47, 79.3, 59.6, 59.54, 59.52, 24.8,
20.73, 20.71, 13.9; FT-IR (neat) 2960, 2874, 1631, 1547, 1466, 1381, 1350, 1245, 1167,
1030, 950, 924, 881, 744, 658, 638 cm-1; UV-Vis (MeOH) λ(ε) 552 (12640).
Photooxidation reactions. A solution of substituted 1,3-butadiene (2.0 g) and the sensitiser
rose bengal bis(tetrabutylammonium) salt (0.85 mol%) in CH2Cl2 (100 mL) in a jacketed
tubular reactor cooled to 5 °C was bubbled with oxygen and irradiated with 2 × 55 W
compact fluorescent lamps for 1-5 days. If photobleaching occurred, an additional portion of
sensitiser was added during the course of the reaction. When complete, the solution was
concentrated under reduced pressure and the product purified by gradient flash
chromatography (petroleum ether to 4:1 petroleum ether/EtOAc) and unreacted starting
material was recycled.
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5-(3,6-Dihydro-1,2-dioxin-3-yl)benzo[d][1,3]dioxole (9). Potassium tert-butoxide (2.70 g,
24.1 mmol, 1.2 equiv) was added to a well stirred solution of allyltriphenylphosphonium
bromide (9.19 g, 24.0 mmol, 1.2 equiv) in freshly distilled diethyl ether (40 mL). After
30 min of stirring at 20 °C, piperonal (3.00 g, 20.0 mmol, 1.0 equiv) was added dropwise to
the mixture. The reaction was stirred for 2 h, then quenched with petroleum ether (50 mL).
The solution was filtered through Celite and washed with petroleum ether (3 × 50 mL). The
crude was concentrated under reduced pressure then purified by flash chromatography
(petroleum ether) giving an E/Z mixture of 5-(buta-1,3-dien-1-yl)benzo[d][1,3]dioxole as a
1
colourless oil (2.80 g, 81%, E/Z 51:49). (E)-Isomer. H NMR (500 MHz, CDCl3) δ 6.96 (d,
J = 1.7 Hz, 1 H), 6.84 (dd, J = 8.0, 1.7 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.64 (br dd,
J = 15.7, 10.3 Hz, 1 H), 6.49 (d, J = 15.7 Hz, 1 H), 6.48 (ddd, J = 16.7, 10.3, 10.3 Hz, 1 H),
13
5.95 (s, 2 H), 5.30 (dd, J = 16.7, 1.3 Hz, 1 H), 5.14 (dd, J = 10.3, 1.3 Hz, 1 H); C NMR
(125 MHz, CDCl3) δ 148.2, 147.4, 137.3, 132.6, 131.8, 128.2, 121.5, 117.0, 108.5, 105.6,
101.2; FT-IR (neat) 3009, 2889, 2777, 1805, 1605, 1501, 1486, 1441, 1350, 1234, 1190,
1115, 1084, 1037, 1001, 932, 902, 866, 820 cm-1; EIMS m/z 175 (10), 174 ([M]+, 81), 173
(16), 144 (18), 143 (14), 116 (67), 115 (100), 91 (28), 89 (12), 63 (11); (Z)-Isomer. 1H NMR
(500 MHz, CDCl3) δ 6.87 (dddd, J = 16.8, 11.0, 10.2, 1.0 Hz, 1 H), 6.84 (br s, 1 H), 6.80-
6.79 (m, 2 H), 6.35 (br d, J = 11.4 Hz, 1 H), 6.18 (br dd, J = 11.4, 11.0 Hz, 1 H), 5.96 (s,
2 H), 5.35 (dddd, J = 16.8, 1.8, 1.0, 1.0 Hz, 1 H), 5.21 (ddd, J = 10.2, 1.8, 1.0 Hz, 1 H);
13C NMR (125 MHz, CDCl3) δ 147.7, 146.8, 133.3, 131.6, 130.1, 129.9, 123.1, 119.4, 109.3,
108.3, 101.1; FT-IR (neat) 3010, 2888, 2778, 1802, 1605, 1501, 1485, 1442, 1351, 1249,
1236, 1192, 1157, 1122, 1100, 1037, 1000, 931, 900, 866, 820, 804, 787, 657 cm-1; EIMS m/z
175 (9), 174 ([M]+, 73), 173 (17), 144 (19), 143 (13), 117.1 (9), 116.1 (65), 115.1 (100), 89
(12), 63 (11). The photooxidation of 5-(buta-1,3-dien-1-yl)benzo[d][1,3]dioxole (2.0 g,
11.5 mmol, 1.0 equiv) according to the general procedure modified using meso-
tetraphenylporphine (100 mg, 0.16 mmol) then purification by flash chromatography (0:1 to
1
1:4 EtOAc/petroleum ether) afforded 9 as a colourless oil (484 mg, 20%); H NMR
(500 MHz, CDCl3) δ 6.88-6.86 (m, 2 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.17 (dddd, J = 10.4, 3.4,
2.4, 2.1 Hz, 1 H), 6.06 (dddd, J = 10.4, 2.1, 2.1, 2.1 Hz, 1 H), 5.96-5.95 (m, 2 H), 5.53 (dddd,
J = 2.4, 2.4, 2.1, 2.1 Hz, 1 H), 4.74 (dddd, J = 16.5, 2.4, 2.4, 2.4 Hz, 1 H), 4.56 (dddd,
13
J = 16.5, 3.4, 2.1, 2.1 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 148.3, 147.9, 131.0, 127.1,
13

ACCEPTED MANUSCRIPT
125.1, 122.9, 109.1, 108.4, 101.3, 80.5, 70.0; FT-IR (neat) 2886, 1732 (weak), 1608, 1486,
1441, 1237, 1034, 933, 795, 609 cm-1; ESIMS m/z 207.1 [M + H]+.
General procedure for the reaction of 1,2-dioxines with primary and secondary amines.
To a stirred solution of 3,6-dihydro-1,2-dioxine (1 mmol) in CH2Cl2 (5 mL) was added the
amine (1.3-3.9 mmol) and the reaction stirred for 30 min or until no starting material
remained by TLC. The volatiles were removed under reduced pressure and higher boiling
amines were removed by the addition and evaporation of toluene.
3-(Benzylamino)-4-hydroxy-1,4-diphenylbutan-1-one (5a/6a). The reaction of 1,2-dioxine
1 (106 mg, 0.44 mmol, 1.0 equiv) and benzylamine (63 µL, 0.58 mmol, 1.3 equiv) according
to the general procedure afforded 5a/6a as a colourless oil (154 mg, 100% yield, 5a/6a
54:46). The diastereomers were partially separated by flash chromatography (1:4
1
EtOAc/petroleum ether); Major isomer (5a). H NMR (500 MHz, CDCl3) δ 7.81-7.79 (m,
2 H), 7.57-7.54 (m, 1 H), 7.44-7.23 (m, 12 H), 4.60 (d, J = 7.2 Hz, 1 H), 3.78 (d, J = 12.7 Hz,
1 H), 3.63 (d, J = 12.7 Hz, 1 H), 3.39 (ddd, J = 7.2, 7.2, 4.5 Hz, 1 H), 3.13 (dd, J = 17.1,
4.5 Hz, 1 H), 3.00 (dd, J = 17.1, 7.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 199.4, 142.0,
139.8, 136.9, 133.5, 128.8, 128.63, 128.62, 128.3, 128.2, 128.0, 127.4, 127.1, 74.7, 61.0,
51.1, 38.6; FT-IR (neat) 3060, 3027, 2890, 1678, 1597, 1580, 1494, 1448, 1276, 1212, 1180,
1046, 1026, 1001, 915, 742, 696 cm-1; ESIMS m/z 346.2 [M + H]+; Minor isomer (6a).
1H NMR (500 MHz, CDCl3) δ 7.72-7.70 (m, 2 H), 7.52-7.49 (m, 1 H), 7.43-7.22 (m, 12 H),
5.03 (d, J = 3.6 Hz, 1 H), 3.98 (d, J = 12.8 Hz, 1 H), 3.91 (d, J = 12.8 Hz, 1 H), 3.39 (ddd,
J = 6.3, 6.3, 3.6 Hz, 1 H), 2.93-2.84 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 200.1, 140.8,
139.9, 136.8, 133.4, 128.7 (×2), 128.5, 128.4, 128.2, 127.4, 126.0, 125.9, 71.6, 59.9, 51.8,
37.6; FT-IR (neat) 3060, 3027, 2890, 1678, 1597, 1580, 1494, 1448, 1276, 1212, 1180, 1046,
1026, 1001, 915, 742, 696 cm-1; ESIMS m/z 346.2 [M + H]+.
3-(tert-Butylamino)-4-hydroxy-1,4-diphenylbutan-1-one (5b/6b). The reaction of 1,2-
dioxine 1 (296 mg, 1.24 mmol, 1.0 equiv) and tert-butylamine (260 µL, 2.49 mmol,
2.0 equiv) for 2.5 h according to the general procedure afforded after flash chromatography
14

ACCEPTED MANUSCRIPT
(1:49 to 1:19 MeOH/CH2Cl2) 5b/6b as a colourless oil (221 mg, 57% yield, 5b/6b 83:17);
Major isomer (5b). 1H NMR (500 MHz, CDCl3) δ 7.62-7.60 (m, 2 H), 7.51-7.47 (m, 1 H),
7.38-7.26 (m, 7 H), 4.84 (d, J = 3.9 Hz, 1 H), 3.54 (ddd, J = 9.1, 3.9, 3.9 Hz, 1 H), 2.91 (dd,
J = 15.1, 3.9 Hz, 1 H), 2.53 (dd, J = 15.1, 9.1 Hz, 1 H), 1.08 (s, 9 H); 13C NMR (125 MHz,
CDCl3) δ 200.1, 141.2, 136.6, 133.2, 128.6, 128.4, 128.2, 127.3, 125.8, 74.4, 55.0, 51.1, 39.2,
30.0; FT-IR (in CDCl3) 3344, 3069, 3031, 2963, 1673, 1598, 1580, 1493, 1448, 1364, 1227,
1209, 1022, 964, 909, 731, 699, 647 cm-1; ESIMS m/z 312.2 [M + H]+. Minor isomer (6b).
1H NMR (500 MHz, CDCl3) δ 7.62-7.60 (m, 2 H), 7.51-7.47 (m, 1 H), 7.38-7.26 (m, 7 H),
4.36 (d, J = 7.8 Hz, 1 H), 3.56-3.52 (m, 1 H), 2.34 (dd, J = 13.1, 6.2 Hz, 1 H), 2.27 (dd,
13
J = 13.1, 2.2 Hz, 1 H), 1.07 (s, 9 H); C NMR (125 MHz, CDCl3) δ 199.7, 141.4, 137.1,
133.3, 128.6, 128.3, 128.0, 127.2, 125.7, 74.8, 56.4, 51.0, 40.7, 30.3; FT-IR (in CDCl3) 3344,
3069, 3031, 2963, 1673, 1598, 1580, 1493, 1448, 1364, 1227, 1209, 1022, 964, 909, 731,
699, 647 cm-1; ESIMS m/z 312.2 [M + H]+;
3-(Benzylamino)-4-hydroxy-1-phenylbutan-1-one (10a). The reaction of 1,2-dioxine 8
(154 mg, 0.95 mmol, 1.0 equiv) and benzylamine (168 µL, 1.54 mmol, 1.6 equiv) according
to the general procedure afforded 10a as a colourless oil (244 mg, 96%). Aminoketone 10a
1
was in equilibrium with hemiketal 15a in CDCl3 solution (10a/15a 96:4); H NMR
(500 MHz, CDCl3) δ 7.92-7.91 (m, 2 H), 7.54-7.51 (m, 1 H), 7.43-7.40 (m, 2 H), 7.32-7.19
(m, 5 H), 3.80-3.76 (m, 2 H), 3.70 (dd, J = 11.0, 4.2 Hz, 1 H), 3.46 (dd, J = 11.0, 4.8 Hz,
1 H), 3.33 (dddd, J = 6.1, 6.1, 4.8, 4.2 Hz, 1 H), 3.18-3.09 (m, 2 H), 2.63 (br s, 2 H);
13C NMR (125 MHz, CDCl3) δ 199.5, 140.0, 136.9, 133.4, 128.7, 128.6, 128.21, 128.17,
127.2, 63.1, 55.2, 51.3, 40.6; FT-IR (neat) 3028, 2872, 1734, 1679, 1597, 1580, 1494, 1448,
1372, 1241, 1212, 1180, 1111, 1044, 1001, 911, 846, 751, 732, 690 cm-1; ESIMS m/z 270.1
[M + H]+. 4-Benzylamino-2-phenyltetrahydrofuran-2-ol (15a). 1H NMR (500 MHz,
CDCl3, partial) δ 4.19 (dd, J = 9.5, 5.1 Hz, 1 H), 4.11 (br d, J = 9.5 Hz, 1 H), 3.60 (dddd,
J = 5.5, 5.1, 4.6, 4.6 Hz, 1 H), 2.34 (br d, J = 13.2 Hz, 1 H), 2.03 (dd, J = 13.2, 5.5 Hz, 1 H);
13C NMR (125 MHz, CDCl3, partial, 2 isomers) δ 143.1, 128.6, 128.4, 128.31, 128.27, 128.1,
128.0, 127.5, 127.2, 126.9, 125.7, 106.4, 101.8, 73.9, 72.6, 66.8, 60.5, 58.0, 51.8, 45.3.
15

ACCEPTED MANUSCRIPT
3-(tert-Butylamino)-4-hydroxy-1-phenylbutan-1-one (10b). The reaction of 1,2-dioxine 8
(90 mg, 0.55 mmol, 1.0 equiv) and tert-butylamine (80 µL, 0.77 mmol, 1.4 equiv) according
1
to the general procedure afforded 10b as a light orange oil (125 mg, 96%); H NMR
(500 MHz, CDCl3) δ 7.97-7.93 (m, 2 H), 7.58-7.53 (m, 1 H), 7.47-7.44 (m, 2 H), 3.55 (dd,
J = 10.2, 4.8 Hz, 1 H), 3.42 (dddd, J = 6.7, 5.7, 5.1, 4.8 Hz, 1 H), 3.32 (dd, J = 10.2, 5.1 Hz,
1 H), 3.23 (dd, J = 16.2, 6.7 Hz, 1 H), 2.99 (dd, J = 16.2, 5.7 Hz, 1 H), 2.28 (br s, 2 H), 1.08
(s, 9 H); 13C NMR (125 MHz, CDCl3) δ 199.5, 137.0, 133.4, 128.8, 128.2, 65.2, 51.2, 50.0,
43.3, 29.9; FT-IR (in CDCl3) 2964, 1674, 1625, 1597, 1579, 1448, 1363, 1284, 1209, 1180,
1104, 1022, 1001, 908, 753, 730, 689, 660, 646 cm-1; ESIMS m/z 236.2 [M + H]+.
3-(Allylamino)-4-hydroxy-1-phenylbutan-1-one (10c). The reaction of 1,2-dioxine 8
(80 mg, 0.49 mmol, 1.0 equiv) and allylamine (50 µL, 0.67 mmol, 1.4 equiv) according to the
general procedure afforded 10c as a light yellow oil (105 mg, 98%). Aminoketone 10c was in
1
equilibrium with hemiketal 15c in CDCl3 solution (10c/15c 95:5); H NMR (500 MHz,
CDCl3) δ 7.94-7.93 (m, 2 H), 7.56-7.53 (m, 1 H), 7.45-7.42 (m, 2 H), 5.86 (dddd, J = 17.1,
10.4, 6.0, 6.0 Hz, 1 H), 5.16 (dddd, J = 17.1, 1.5, 1.5, 1.5 Hz, 1 H), 5.06 (dddd, J = 10.4, 1.5,
1.5, 1.5 Hz, 1 H), 3.70 (dd, J = 10.9, 4.1 Hz, 1 H), 3.46 (dd, J = 10.9, 5.1 Hz, 1 H), 3.34-3.29
13
(m, 1 H), 3.27-3.25 (m, 2 H), 3.15-3.13 (m, 2 H), 2.60 (br s, 2 H); C NMR (125 MHz,
CDCl3) δ 199.5, 136.9, 136.5, 133.4, 128.7, 128.2, 116.3, 63.1, 54.9, 49.6, 40.5; FT-IR (neat)
3309, 3065, 2877, 1678, 1596, 1580, 1448, 1416, 1366, 1283, 1212, 1181, 1106, 1045, 1000,
919, 752, 689 cm-1; ESIMS m/z 220.1 [M + H]+. 4-(Allylamino)-2-phenyltetrahydrofuran-
1
2-ol (15c). H NMR (500 MHz, CDCl3, partial) δ 5.21 (ddd, J = 1.5, 1.5, 1.5 Hz, 1 H), 5.12
(ddd, J = 1.5, 1.5, 1.5 Hz, 1 H), 4.21 (dd, J = 9.5, 5.3 Hz, 1 H), 4.09 (br d, J = 9.5 Hz, 1 H),
3.61 (dddd, J = 5.3, 5.3, 1.2, 1.2 Hz, 1 H), 2.29 (br d, J = 13.2 Hz, 1 H), 2.01 (dd, J = 13.2,
5.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 147.9, 135.7, 132.9, 125.6, 123.6, 116.8, 106.3,
73.9, 57.9, 50.1, 45.3.
3-(Butylamino)-4-hydroxy-1-phenylbutan-1-one (10d). The reaction of 1,2-dioxine 8
(103 mg, 0.64 mmol, 1.0 equiv) and n-butylamine (85 µL, 0.86 mmol, 1.3 equiv) according
to the general procedure afforded 10d as a colourless oil (149 mg, 98%). Aminoketone 10d
1
was in equilibrium with hemiketal 15d in CDCl3 solution (10d/15d 94:6); H NMR
16

ACCEPTED MANUSCRIPT
(500 MHz, CDCl3) δ 7.95-7.94 (m, 2 H), 7.57-7.54 (m, 1 H), 7.46-7.43 (m, 2 H), 3.71 (dd,
J = 10.9, 4.4 Hz, 1 H), 3.43 (dd, J = 10.9, 5.0 Hz, 1 H), 3.28 (dddd, J = 6.3, 6.3, 5.0, 4.4 Hz,
1 H), 3.14 (app d, J = 6.3 Hz, 2 H), 2.63 (ddd, J = 11.1, 7.1, 7.1 Hz, 1 H), 2.57 (ddd, J = 11.1,
7.1, 7.1 Hz, 1 H), 2.44 (br s, 2 H), 1.48-1.41 (m, 2 H), 1.37-1.29 (m, 2 H), 0.89 (t, J = 7.3 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 199.6, 137.0, 133.4, 128.8, 128.2, 63.1, 55.6, 46.7, 40.5,
32.5, 20.5, 14.0; FT-IR (neat) 2959, 2929, 2872, 1680, 1597, 1580, 1448, 1372, 1284, 1212,
1041, 1002, 754, 691 cm-1; ESIMS m/z 236.2 [M + H]+. 4-(Butylamino)-2-
1
phenyltetrahydrofuran-2-ol (15d). H NMR (500 MHz, CDCl3, partial) δ 4.20 (dd, J = 9.5,
4.9 Hz, 1 H), 4.09 (br d, J = 9.5 Hz, 1 H), 3.59 (dd, J = 4.9, 4.9 Hz, 1 H), 2.28 (br d,
13
J = 13.1 Hz, 1 H), 2.01 (dd, J = 13.1, 4.9 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 147.7,
133.0, 125.7, 123.7, 106.4, 74.0, 62.0, 58.8, 47.4, 45.3, 32.2, 29.8.
4-Hydroxy-3-morpholino-1-phenylbutan-1-one (10e). The reaction of 1,2-dioxine 8
(99 mg, 0.61 mmol, 1.0 equiv) and morpholine (76 µL, 0.88 mmol, 1.4 equiv) according to
the general procedure afforded 10e (150 mg, 98%) as a colourless oil. Upon standing, crystals
of 15e formed in the oil and these were collected by suspending the crystals in a minimal
amount of EtOAc cooled to −15 °C and collecting on a sintered glass funnel. Aminoketone
1
10e was in equilibrium with hemiketal 15e in CDCl3 solution (10e/15e 91:9); H NMR
(500 MHz, CDCl3) δ 7.96-7.94 (m, 2 H), 7.61-7.56 (m, 1 H), 7.50-7.47 (m, 2 H), 3.79-3.68
(m, 4 H), 3.61-3.57 (m, 1 H), 3.49-3.41 (m, 2 H), 3.29 (dd, J = 16.2, 4.1 Hz, 1 H), 3.11 (br s,
1 H), 2.77 (dd, J = 16.2, 8.0 Hz, 1 H), 2.71 (ddd, J = 10.6, 5.8, 3.0 Hz, 2 H), 2.53 (ddd,
J = 10.6, 5.8, 3.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 198.6, 136.9, 133.6, 128.9, 128.2,
67.4, 61.6, 60.9, 48.9, 34.5; FT-IR (in CDCl3) 3418, 2955, 2854, 1681, 1597, 1449, 1361,
1290, 1265, 1211, 1116, 1065, 1029, 1003, 948, 915, 857, 755, 692 cm-1; ESIMS m/z 250.1
1
[M + H]+. 4-Morpholino-2-phenyltetrahydrofuran-2-ol (15e). mp 95.9-96.2 °C; H NMR
(500 MHz, CDCl3) δ 7.58-7.56 (m, 2 H), 7.37-7.29 (m, 3 H), 4.34 (dd, J = 8.4, 7.6 Hz, 1 H),
4.05 (dd, J = 8.4, 6.6 Hz, 1 H), 3.76-3.67 (m, 4 H), 3.46-3.43 (m, 1 H), 2.65 (br s, 1 H), 2.50-
13
2.39 (m, 5 H), 1.90 (dd, J = 12.4, 9.2 Hz, 1 H); C NMR (125 MHz, CDCl3, 2 isomers)
δ 143.6, 142.4, 128.37, 128.35, 128.26, 128.1, 125.6, 125.4, 106.4, 105.8, 71.3, 69.4, 67.0,
66.9, 65.9, 65.1, 52.30, 52.26, 43.9, 43.0; FT-IR (neat) 2961, 1446, 1401, 1325, 1266, 1225,
1198, 1148, 1114, 1089, 1069, 1049, 1025, 971, 953, 918, 886, 868, 766, 703, 678 cm-1.
17

ACCEPTED MANUSCRIPT
4-Hydroxy-1-phenyl-3-(pyrrolidin-1-yl)butan-1-one (10f). The reaction of 1,2-dioxine 8
(81 mg, 0.50 mmol, 1.0 equiv) and pyrrolidine (60 µL, 0.73 mmol, 1.5 equiv) according to
the general procedure afforded 10f as a colourless oil. When left to stand for 3 hours,
crystallisation into hemiketal 15f occurred yielding a white solid (115 mg, 98%).
Aminoketone 10f was in equilibrium with hemiketal 15f in CDCl3 solution (10f/15f 69:31);
1H NMR (500 MHz, CDCl3) δ 7.98-7.96 (m, 2 H), 7.60-7.56 (m, 1 H), 7.49-7.46 (m, 2 H),
3.73 (dd, J = 10.8, 4.3 Hz, 1 H), 3.50 (dd, J = 10.8, 6.2 Hz, 1 H), 3.42 (dddd, J = 8.2, 6.2, 4.3,
4.3 Hz, 1 H), 3.25 (dd, J = 16.5, 4.3 Hz, 1 H), 3.11 (dd, J = 16.5, 8.2 Hz, 1 H), 2.70-2.68 (m,
4 H), 1.81-1.79 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 199.2, 137.1, 133.4, 128.8, 128.3,
63.0, 59.1, 49.7, 36.7, 23.6; FT-IR (in CDCl3) 3347, 2962, 2817, 1682, 1599, 1448, 1286,
1214, 1042, 1003, 755, 692 cm-1; ESIMS m/z 256.2 [M + Na]+. 2-Phenyl-4-(pyrrolidin-1-
1
yl)tetrahydrofuran-2-ol (15f). mp 81.1-82.3 °C; H NMR (500 MHz, CDCl3) δ 7.60-7.59
(m, 2 H), 7.37-7.33 (m, 2 H), 7.31-7.29 (m, 1 H), 4.40 (ddd, J = 9.6, 1.0, 1.0 Hz, 1 H), 4.07
(dd, J = 9.6, 4.6 Hz, 1 H), 3.09-3.08 (m, 1 H), 2.73-2.71 (m, 4 H), 2.50 (d, J = 13.1 Hz, 1 H),
2.05 (dd, J = 13.1, 4.9 Hz, 1 H), 1.85-1.82 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 142.2,
128.2, 128.0, 125.8, 106.1, 72.1, 65.8, 52.9, 45.1, 24.9; FT-IR (neat) 2956, 2802, 1610, 1446,
1385, 1327, 1289, 1237, 1194, 1156, 1119, 1065, 1040, 1030, 982, 955, 917, 874, 798, 760,
696, 674 cm-1.
4-Hydroxy-1-phenyl-3-(phenylamino)butan-1-one (10g). The reaction of 1,2-dioxine 8
(107 mg, 0.66 mmol, 1.0 equiv), triethylamine (6 drops) and aniline (72 µL, 0.79 mmol,
1.2 equiv) according to the general procedure afforded after flash chromatography (1:4
1
EtOAc/petroleum ether) 10g as a colourless oil (165 mg, 98%); H NMR (500 MHz, CDCl3)
δ 7.94-7.92 (m, 2 H), 7.58-7.55 (m, 1 H), 7.46-7.42 (m, 2 H), 7.19-7.16 (m, 2 H), 6.76-7.73
(m, 1 H), 6.69-6.67 (m, 2 H), 4.16 (dddd, J = 7.2, 4.4, 4.4, 4.4 Hz, 1 H), 4.01 (br s, 1 H), 3.81
(dd, J = 10.9, 4.4 Hz, 1 H), 3.75 (dd, J = 10.9, 4.4 Hz, 1 H), 3.31 (dd, J = 16.8, 7.2 Hz, 1 H),
3.23 (dd, J = 16.8, 4.4 Hz, 1 H), 3.05 (br s, 1 H); 13C NMR (125 MHz, CDCl3) δ 199.7, 146.8,
136.8, 133.4, 129.5, 128.7, 128.2, 118.2, 114.0, 63.8, 51.4, 39.4; FT-IR (in ACN) 3617, 3002,
2948, 2293, 2253, 1634, 1442, 1375, 1038, 918, 754 cm-1; ESIMS m/z 256.1 [M + H]+.
18

ACCEPTED MANUSCRIPT
1-(Benzo[d][1,3]dioxol-5-yl)-3-(benzylamino)-4-hydroxybutan-1-one (11a). The reaction
of 1,2-dioxine 9 (50 mg, 0.24 mmol, 1.0 equiv) and benzylamine (54 µL, 0.49 mmol,
2.0 equiv) according to the general procedure afforded after flash chromatography (0:1 to
1
1:19 MeOH/CHCl3 + 2% NH4OH) 11a as a colourless oil (54 mg, 71%); H NMR
(500 MHz, CDCl3) δ 7.55 (dd, J = 8.2, 1.8 Hz, 1 H), 7.42 (d, J = 1.8 Hz, 1 H), 7.32-7.30 (m,
4 H), 7.25-7.22 (m, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.04 (s, 2 H), 3.83 (d, J = 13.0 Hz, 1 H),
3.81 (d, J = 13.0 Hz, 1 H), 3.75 (dd, J = 10.9, 4.1 Hz, 1 H), 3.46 (dd, J = 10.9, 4.6 Hz, 1 H),
13
3.35 (dddd, J = 6.3, 6.0, 4.6, 4.1 Hz, 1 H), 3.15-3.06 (m, 2 H), 2.20 (br s, 2 H); C NMR
(125 MHz, CDCl3) δ 197.5, 152.2, 148.4, 140.1, 131.9, 128.7, 128.3, 127.3, 124.7, 108.1,
108.0, 102.1, 63.2, 55.4, 51.3, 40.5; FT-IR (neat) 3399, 2900, 1665, 1601, 1487, 1440, 1354,
1243, 1097, 1033, 931, 805, 699 cm-1; ESIMS m/z 314.1 [M + H]+.
1-(Benzo[d][1,3]dioxol-5-yl)-3-(tert-butylamino)-4-hydroxybutan-1-one
(11b).
The
reaction of 1,2-dioxine 9 (350 mg, 1.70 mmol, 1.0 equiv) and tert-butylamine (0.7 mL,
6.70 mmol, 3.9 equiv) according to the general procedure afforded after flash
chromatography (1:19 MeOH/CH2Cl2 + 2% NH4OH) 11b as a yellow oil (430 mg, 91%);
1H NMR (500 MHz, CDCl3) δ 7.55 (dd, J = 8.2, 1.8 Hz, 1 H), 7.42 (d, J = 1.8 Hz, 1 H), 6.85
(d, J = 8.2 Hz, 1 H), 6.05 (s, 2 H), 3.54 (dd, J = 10.3, 4.8 Hz, 1 H), 3.41 (dddd, J = 6.8, 5.8,
4.8, 4.8 Hz, 1 H), 3.31 (dd, J = 10.2, 4.8 Hz, 1 H), 3.16 (dd, J = 15.9, 6.8 Hz, 1 H), 2.92 (dd,
J = 15.9, 5.8 Hz, 1 H), 2.24 (br s, 2 H), 1.10 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ 197.4,
152.1, 148.5, 132.1, 124.7, 108.1, 108.0, 102.1, 65.2, 51.3, 50.2, 43.1, 30.0; FT-IR (neat)
2962, 1667, 1602, 1503, 1488, 1440, 1360, 1247, 1111, 1036, 933, 892, 808, 621 cm-1;
ESIMS m/z 280.2 [M + H]+.
3-Phenyl-4,5-dihydro-1H-pyrazol-5-yl)methanol (12). To a solution of 1,2-dioxine 8
(21 mg, 0.13 mmol, 1.0 equiv) in CDCl3/CD3OD (1:2) was added hydrazine monohydrate
(20 µL, 0.41 mmol, 3.2 equiv) and the mixture left to stir for 3.5 h at 20 °C. The volatiles
were then removed under reduced pressure and the residue dried under high vacuum to afford
12 as a yellow oil (22.5 mg, 100%). 1H NMR (500 MHz, CDCl3) δ 7.66-7.63 (m, 2 H), 7.39-
7.32 (m, 3 H), 4.05 (dddd, J = 10.6, 8.8, 6.0, 3.9 Hz, 1 H), 3.73 (dd, J = 11.1, 3.9 Hz, 1 H),
3.62 (dd, J = 11.1, 6.0 Hz, 1 H), 3.13 (dd, J = 16.4, 10.6 Hz, 1 H), 2.91 (dd, J = 16.4, 8.8 Hz,
19

ACCEPTED MANUSCRIPT
1 H); 13C NMR (125 MHz, CDCl3) δ 153.4, 132.8, 129.1, 128.7, 126.2, 63.6, 61.2, 34.7; FT-
IR (neat) 3315, 2920, 1684, 1449, 1266, 1035, 756, 693 cm-1; ESIMS m/z 177.1 [M + H]+.
(4-Phenyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-2-yl)methanol (13). The reaction of 1,2-
dioxine 8 (57 mg, 0.35 mmol, 1.0 equiv) and o-phenylenediamine (114 mg, 1.09 mmol,
3.0 equiv) according to the general procedure afforded, after 10 days and purification by flash
chromatography (1:19 MeOH/CH2Cl2), 13 as a brown oil containing residual o-
phenylenediamine (88 mg, 100%, adjusted yield). Imine 13 was in equilibrium with the
cyclic hemiaminal 2-phenyl-2,4,5,6-tetrahydro-1H-2,5-methanobenzo[d][1,3,6]oxadiazocine
1
in CDCl3 solution (85:15); H NMR (500 MHz, CDCl3) δ 7.98-7.95 (m, 2 H), 7.47-7.43 (m,
3 H), 7.33-7.30 (m, 1 H), 7.04-7.00 (m, 2 H), 6.77-6.75 (m, 1 H), 4.07-3.99 (m, 1 H), 3.49
(dd, J = 10.6, 4.7 Hz, 1 H), 3.45 (dd, J = 10.6, 7.9 Hz, 1 H), 3.45 (br s, 2 H), 2.82 (dd,
J = 13.6, 4.4 Hz, 1 H), 2.66 (dd, J = 13.6, 7.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 168.3,
139.9, 139.4, 137.9, 130.4, 128.6, 128.3, 127.0, 126.3, 121.7, 121.3, 68.0, 66.0, 31.4; FT-IR
(neat) 3384, 3363, 3289, 3185, 3053, 1621, 1592, 1501, 1472, 1266, 1030, 926, 796, 732,
694 cm-1; ESIMS m/z 253.1 [M + H]+; HRMS (ESI) calcd for C16H17N2O+ [ M + H]+
253.1341,
found
253.1337.
2-Phenyl-2,4,5,6-tetrahydro-1H-2,5-
1
methanobenzo[d][1,3,6]oxadiazocine. H NMR (500 MHz, CDCl3, partial) δ 7.71-7.70 (m,
2 H), 4.76 (br s, 1 H), 4.07-4.04 (m, 1 H), 3.85-3.74 (m, 2 H), 3.45 (br s, 2 H), 2.37 (d,
13
J = 12.3 Hz, 1 H), 2.66 (dd, J = 12.3, 5.7 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 144.9,
133.5, 132.3, 128.5, 128.0, 125.2, 120.61, 120.56, 119.92, 119.88, 94.9, 73.2, 53.9, 50.0.
General procedure for the preparation of 3-amino-1,4-diols from 1,2-dioxine using
NaBH4/SnCl4. A stock solution of reducing agent was prepared by dissolving NaBH4
(93.8 mg, 2.48 mmol, 4.0 equiv) in THF (2.0 mL), cooling to 0 °C and then adding a 1.0 M
solution of SnCl4 (620 µL, 0.62 mmol, 1.0 equiv). The solution was stirred for 24 hours at 0-
15 °C before use. In a separate flask 3,6-dihydro-1,2-dioxine (1.0 equiv) was dissolved in
CH2Cl2 (200 µL) and the primary or secondary amine (1.5 equiv) was added. After 30 min of
stirring at 20 °C, the mixture was concentrated under reduced pressure and the residue
dissolved in the solvent listed in Table 3. The mixture was cooled to 0 °C and a volume of
20

ACCEPTED MANUSCRIPT
reducing agent in solution corresponding to SnCl4 (0.1 equiv) and NaBH4 (0.4 equiv) was
added. The mixture was stirred at 0 °C for 6 h and then a second portion of reducing agent
mixture corresponding to SnCl4 (0.1 equiv) and NaBH4 (0.4 equiv) was added. After a further
18 h of stirring at 0 °C, the product was washed with a saturated solution of Na2CO3 (10 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated under reduced pressure and the residue purified by flash
chromatography.
General procedure for the preparation of 3-amino-1,4-diols from 1,2-dioxine using
NaBH4/MeOH. To a stirred solution of 3,6-dihydro-1,2-dioxine (1.0 equiv) in methanol
(0.50 mL) was added the primary or secondary amine (1.5 equiv). After 30 min of stirring at
20 °C, sodium borohydride (2.0 equiv) was added and the resulting mixture stirred for 1 h.
The mixture was diluted with a saturated solution of Na2CO3 and extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4) then concentrated under reduced pressure and
the residue purified by flash chromatography.
(1S*,3R*)-(Benzylamino)-1-phenylbutane-1,4-diol (17a). The reaction of 1,2-dioxine 8
(10.8 mg, 67 µmol, 1.0 equiv), benzylamine (8 µL, 73 µmol, 1.1 equiv) and a solution of
0.25:1 SnCl4/NaBH4 (1.24 M, 2 × 20 µL, 0.74 equiv NaBH4) according to the general
procedure afforded a colourless oil (12.7 mg, 70% yield, 17a/18a 92:8). The diastereomers
were separated by flash chromatography (0:1 to 1:19 MeOH/CHCl3 + 2% NH4OH) to give
1
17a as a colourless oil; H NMR (500 MHz, CDCl3) δ 7.36-7.22 (m, 10 H), 4.98 (dd,
J = 10.3, 2.6 Hz, 1 H), 3.92 (d, J = 12.6 Hz, 1 H), 3.77 (d, J = 12.6 Hz, 1 H), 3.76 (dd,
J = 11.0, 3.8 Hz, 1 H), 3.59 (br s, 1 H), 3.51 (dd, J = 11.0, 3.6 Hz, 1 H), 3.01 (dddd, J = 10.3,
3.8, 3.6, 3.6 Hz, 1 H), 2.33 (br s, 2 H), 1.78 (ddd, J = 14.4, 10.3, 10.3 Hz, 1 H), 1.69 (ddd,
J = 14.4, 3.6, 2.6 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 145.2, 139.5, 128.7, 128.5, 128.4,
127.5, 127.3, 125.7, 74.7, 62.8, 58.8, 50.8, 40.8; FT-IR (in CDCl3) 3000, 2916, 2245, 1452,
1361, 1206, 1047, 1027, 985, 906, 725 cm-1; ESIMS m/z 272.1 [M + H]+; HRMS (ESI) calcd
+
for C17H22NO2 [ M + H]+ 272.1651, found 272.1657.
21

ACCEPTED MANUSCRIPT
(1R*,3R*)-(Benzylamino)-1-phenylbutane-1,4-diol (18a). Colourless oil; 1H NMR
(500 MHz, CDCl3) δ 7.36-7.22 (m, 10 H), 4.98 (dd, J = 7.1, 4.2 Hz, 1 H), 3.84 (d,
J = 12.8 Hz, 1 H), 3.77 (d, J = 12.8 Hz, 1 H), 3.76 (dd, J = 10.8, 4.1 Hz, 1 H), 3.60 (dd,
J = 10.8, 6.2 Hz, 1 H), 2.90 (dddd, J = 6.2, 6.2, 4.2, 4.1 Hz, 1 H), 1.97-1.87 (m, 2 H);
13C NMR (125 MHz, CDCl3) δ 145.1, 139.6, 128.8, 128.5, 128.4, 127.5, 127.1, 125.7, 72.5,
63.5, 56.4, 51.2, 38.3; FT-IR (in CDCl3) 3302, 3027, 2858, 1603, 1493, 1451, 1344, 1205,
+
1107, 1028 cm-1; ESIMS m/z 272.1 [M + H]+; HRMS (ESI) calcd for C17H22NO2 [ M + H]+
272.1651, found 272.1653.
(1S*,3R*)-3-(tert-Butylamino)-1-phenylbutane-1,4-diol (17b). The reaction of 1,2-dioxine 8
(59 mg, 0.36 mmol, 1.0 equiv), tert-butylamine (46 µL, 0.44 mmol, 1.2 equiv) and sodium
borohydride (28 mg, 0.74 mmol, 2.1 equiv) according to the general procedure afforded a
colourless solid (65 mg, 75% yield, 17b/18b 60:40). Flash chromatography (0:1 to 1:19
MeOH/CH2Cl2 + 2% NH4OH) gave 17b as colourless crystals; mp 105-107 °C
1
(CHCl3/petroleum ether); H NMR (500 MHz, CDCl3) δ 7.38-7.31 (m, 4 H), 7.25-7.22 (m,
1 H), 4.87 (dd, J = 10.2, 2.2 Hz, 1 H), 3.60 (dd, J = 10.7, 4.9 Hz, 1 H), 3.55 (dd, J = 10.7,
2.9 Hz, 1 H), 3.19 (dddd, J = 10.2, 4.6, 4.5, 2.9 Hz,1 H), 1.78 (ddd, J = 14.2, 10.2, 10.2 Hz,
13
1 H), 1.71 (ddd, J = 14.2, 4.5, 2.2 Hz, 1 H), 1.21 (s, 9 H); C NMR (125 MHz, CDCl3)
δ 145.3, 128.3, 127.1, 125.6, 74.0, 66.0, 53.2, 51.4, 42.4, 30.0; FT-IR (neat) 3300, 2961,
1455, 1392, 1362, 1207, 1121, 1082, 1054, 1024, 985, 963, 916, 835, 757, 720 cm-1; ESIMS
+
m/z 238.1 [M + H]+; HRMS (ESI) calcd for C14H24NO2 [ M + H]+ 238.1807, found
238.1799.
(1R*,3R*)-3-(tert-Butylamino)-1-phenylbutane-1,4-diol (18b). Colourless crystals; mp 97-
98 °C (CHCl3/petroleum ether); 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 4 H), 7.26-7.22
(m, 1 H), 4.93 (dd, J = 9.6, 3.2 Hz, 1 H), 3.71 (dd, J = 10.5, 5.2 Hz, 1 H), 3.63 (dd, J = 10.5,
7.0 Hz, 1 H), 3.09 (dddd, J = 7.0, 5.2, 5.1, 4.2 Hz, 1 H), 1.93 (ddd, J = 14.6, 9.6, 5.1 Hz, 1 H),
13
1.76 (ddd, J = 14.6, 4.2, 3.2 Hz, 1 H), 1.14 (s, 9 H); C NMR (125 MHz, CDCl3) δ 145.4,
128.4, 127.2, 125.9, 72.2, 65.2, 52.1, 51.5, 41.1, 29.9; FT-IR (in CDCl3) 3263, 2966, 2930,
2863, 1452, 1391, 1365, 1342, 1230, 1207, 1098, 1075, 1057, 972, 927, 814, 755, 739,
22

ACCEPTED MANUSCRIPT
+
697 cm-1; ESIMS m/z 238.2 [M + H]+; HRMS (ESI) calcd for C14H24NO2 [ M + H]+
238.1807, found 238.1799.
(1S*,3R*)-3-(Allylamino)-1-phenylbutane-1,4-diol (17c). The reaction of 1,2-dioxine 8
(55 mg, 0.34 mmol, 1.0 equiv), allylamine (31 µL, 0.41 mmol, 1.2 equiv) and sodium
borohydride (29 mg, 0.77 mmol, 2.3 equiv) gave a colourless oil as a mixture of
diastereomers (65 mg, 85% yield, 17c/18c 59:41). The diastereomers were separated after
flash chromatography (0:1 to 1:9 MeOH/CHCl3 + 2% NH4OH) to give 17c as a colourless
oil; 1H NMR (500 MHz, CDCl3) δ 7.37-7.22 (m, 5 H), 5.92 (dddd, J = 17.1, 10.3, 6.2, 5.8 Hz,
1 H), 5.22 (dddd, J = 17.1, 1.5, 1.5, 1.5 Hz, 1 H), 5.13 (dddd, J = 10.3, 1.5, 1.5, 1.5 Hz, 1 H),
4.90 (dd, J = 10.0, 2.8 Hz, 1 H), 3.72 (dd, J = 11.0, 4.2 Hz, 1 H), 3.51 (dd, J = 11.0, 3.6 Hz,
1 H), 3.41 (dddd, J = 13.8, 5.8, 1.5, 1.5 Hz, 1 H), 3.25 (dddd, J = 13.8, 6.2, 1.5, 1.5 Hz, 1 H),
3.21 (br s, 3 H), 3.00 (dddd, J = 9.8, 4.2, 3.8, 3.6 Hz, 1 H), 1.78 (dd, J = 14.3, 10.0 Hz, 1 H),
1.71 (ddd, J = 14.3, 3.8, 2.8 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 145.2, 136.3, 128.5,
127.3, 125.7, 116.8, 74.7, 62.9, 58.6, 49.1, 40.7; FT-IR (in CH2Cl2) 3298, 2917, 1644, 1452,
1420, 1344, 1265, 1044, 994, 922, 733, 700 cm-1; ESIMS m/z 222.1 [M + H]+; HRMS (ESI)
calcd for C13H20NO2 [ M + H]+ 222.1494, found 222.1497.
+
(1R*,3R*)-3-(Allylamino)-1-phenylbutane-1,4-diol (18c). Colourless oil; 1H NMR
(500 MHz, CDCl3) δ 7.38-7.31 (m, 4 H), 7.26-7.23 (m, 1 H), 5.90 (dddd, J = 17.4, 10.2, 6.1,
6.1 Hz, 1 H), 5.21 (dddd, J = 17.4, 1.5, 1.5, 1.5 Hz, 1 H), 5.14 (dddd, J = 10.2, 1.5, 1.4,
1.3 Hz, 1 H), 4.99 (dd, J = 7.4, 3.9 Hz, 1 H), 3.79 (br s, 3 H), 3.74 (dd, J = 11.0, 4.2 Hz, 1 H),
3.62 (dd, J = 11.0, 6.4 Hz, 1 H), 3.35-3.26 (m, 2 H), 2.89 (dddd, J = 6.4, 6.4, 4.2, 4.2 Hz,
1 H), 1.93 (ddd, J = 14.7, 6.4, 3.9 Hz, 1 H), 1.88 (ddd, J = 14.7, 7.4, 4.2 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 144.9, 135.4, 128.5, 127.2, 125.7, 117.3, 72.2, 63.3, 56.6, 49.3, 38.0;
FT-IR (in CH2Cl2) 3292, 2921, 2848, 1644, 1452, 1418, 1343, 1203, 1044, 995, 920, 756,
+
701 cm-1; ESIMS m/z 222.1 [M + H]+; HRMS (ESI) calcd for C13H20NO2 [ M + H]+
222.1494, found 222.1500.
23

ACCEPTED MANUSCRIPT
(1S*,3R*)-3-(Butylamino)-1-phenylbutane-1,4-diol (17d). The reaction of 1,2-dioxine 8
(12.3 mg, 76 µmol, 1.0 equiv), n-butylamine (8 µL, 81 µmol, 1.1 equiv) and a solution of
0.25:1 SnCl4/NaBH4 (0.62 M, 2 × 50 µL, 0.8 equiv NaBH4) according to the general
procedure afforded a mixture of diastereomers (4.6 mg, 25% yield, 17d/18d 90:10).
Separation of the diastereomers by flash chromatography (0:1 to 1:19 MeOH/CH2Cl2 +
1
2% NH4OH) afforded 17d as a colourless oil; H NMR (500 MHz, CDCl3) δ 7.34-7.28 (m,
4 H), 7.23-7.20 (m, 1 H), 4.85 (dd, J = 9.4, 3.5 Hz, 1 H), 3.76 (br s, 3 H), 3.60 (dd, J = 10.9,
4.0 Hz, 1 H), 3.40 (dd, J = 10.9, 3.7 Hz, 1 H), 2.86 (dddd, J = 9.4, 4.0, 4.0, 3.7 Hz, 1 H), 2.73
(ddd, J = 11.2, 7.5, 6.4 Hz, 1 H), 2.50 (ddd, J = 11.2, 7.5, 6.4 Hz, 1 H), 1.70-1.61 (m, 2 H),
1.49-1.40 (m, 2 H), 1.40-1.31 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 145.2, 128.3, 127.2, 125.7, 74.9, 62.6, 59.6, 46.1, 40.3, 32.6, 20.5, 14.0; FT-IR
(neat oil) 1451, 1195, 1118, 1027, 983, 909, 759, 730 cm-1; ESIMS m/z 238.1 [M + H]+;
+
HRMS (ESI) calcd for C14H24NO2 [ M + H]+ 238.1807, found 238.1809.
(1R*,3R*)-3-(Butylamino)-1-phenylbutane-1,4-diol (18d). Colourless oil; 1H NMR
(500 MHz, CDCl3) δ 7.38-7.32 (m, 4 H), 7.26-7.23 (m, 1 H), 5.01 (dd, J = 7.1, 3.9 Hz, 1 H),
3.75 (dd, J = 10.7, 4.2 Hz, 1 H), 3.61 (dd, J = 10.7, 6.1 Hz, 1 H), 3.19 (br s, 3H), 2.81 (dddd,
J = 6.9, 6.1, 4.2, 3.9 Hz, 1 H), 2.62-2.54 (m, 2 H), 1.93 (ddd, J = 14.5, 6.9, 3.9 Hz, 1 H), 1.87
(ddd, J = 14.5, 7.1, 3.9 Hz, 1 H), 1.54-1.44 (m, 2 H), 1.43-1.35 (m, 2 H), 0.94 (t, J = 7.2 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 145.3, 128.4, 127.1, 125.68, 72.5, 63.6, 57.3, 46.7, 37.9,
32.5, 20.6, 14.1; FT-IR (neat) 1451, 1344, 1030, 978, 909, 759, 730 cm-1; ESIMS m/z 238.1
+
[M + H]+; HRMS (ESI) calcd for C14H24NO2 [ M + H]+ 238.1807, found 238.1801.
(1S*,3R*)-3-Morpholino-1-phenylbutane-1,4-diol (17e). The reaction of 1,2-dioxine 8
(15.2 mg, 94 µmol, 1.0 equiv), morpholine (9 µL, 0.10 mmol, 1.1 equiv) and a solution of
0.25:1 SnCl4/NaBH4 (0.62 M, 2 × 60 µL, 0.8 equiv NaBH4) afforded a mixture of
diastereomers (14.0 mg, 60% yield, 17e/18e 92:8). Flash chromatography (0:1 to 1:19
MeOH/CH2Cl2 + 2% NH4OH) afforded 17e as colourless crystals; mp 113-115 °C; 1H NMR
(300 MHz, CDCl3) δ 7.38-7.22 (m, 5 H), 5.74 (br s, 1 H), 4.87 (dd, J = 9.7, 2.8 Hz, 1 H),
3.74-3.68 (m, 5 H), 3.60 (dd, J = 10.9, 5.6 Hz, 1 H), 2.99 (m, 1 H), 2.86 (ddd, J = 11.6, 4.6,
24

ACCEPTED MANUSCRIPT
4.6 Hz, 2 H), 2.66 (ddd, J = 11.6, 4.6, 4.6 Hz, 2 H), 2.17 (br s, 1 H), 1.86 (ddd, J = 14.5, 9.7,
13
9.7 Hz, 1 H), 1.62 (ddd, J = 14.5, 4.4, 2.8 Hz, 1 H); C NMR (75 MHz, CDCl3) δ 144.9,
128.5, 127.5, 125.7, 74.6, 67.6, 65.7, 61.3, 49.3, 35.5; FT-IR (in CDCl3) 3419, 2857, 2249,
1681, 1452, 1115, 1026, 905 cm-1; ESIMS m/z 252.1 [M + H]+; HRMS (ESI) calcd for
+
C14H22NO3 [ M + H]+ 252.1600, found 252.1605.
(1R*,3R*)-3-Morpholino-1-phenylbutane-1,4-diol (18e). Colourless oil; 1H NMR
(500 MHz, CDCl3) δ 7.37-7.35 (m, 4 H), 7.30-7.27 (m, 1 H), 4.93 (dd, J = 5.6, 4.9 Hz, 1 H),
4.67 (br s, 2H), 3.76-3.71 (m, 4 H), 3.62-3.57 (m, 2 H), 2.72-2.67 (m, 3 H), 2.63 (ddd,
J = 11.5, 4.6, 4.6 Hz, 2 H), 2.15 (ddd, J = 14.4, 7.8, 4.9 Hz, 1 H), 1.82 (ddd, J = 14.4, 5.6,
13
5.6 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 144.8, 128.7, 127.5, 125.6, 73.1, 67.7, 62.7,
61.6, 49.2, 34.4; FT-IR (in CDCl3) 3378, 2934, 2853, 2245, 1730, 1453, 1115, 1043, 1026,
+
907, 726, 701, 646 cm-1; ESIMS m/z 252.1 [M + H]+; HRMS (ESI) calcd for C14H22NO3 [ M
+ H]+ 252.1600, found 252.1608.
(1S*,3R*)-1-Phenyl-3-(pyrrolidin-1-yl)butane-1,4-diol (17f). The reaction of 1,2-dioxine 8
(54 mg, 0.33 mmol, 1.0 equiv), pyrrolidine (34 µL, 0.41 mmol, 1.2 equiv) and sodium
borohydride (26 mg, 0.69 mmol, 2.1 equiv) according to the general procedure afforded a
17f/18f as a mixture of diastereomers (57 mg, 73% yield, 17f/18f 62:38). Purification by
flash chromatography (0:1 to 1:19 MeOH/CHCl3 + 2% NH4OH) afforded 17f as a colourless
1
oil; H NMR (500 MHz, CDCl3) δ 7.40-7.32 (m, 4 H), 7.26-7.24 (m, 1 H), 4.92 (dd, J = 9.6,
3.4 Hz, 1 H), 3.76 (dd, J = 10.9, 5.5 Hz, 1 H), 3.69 (dd, J = 10.9, 5.8 Hz, 1 H), 3.01 (dddd,
J = 7.8, 5.8, 5.5, 5.5 Hz, 1 H), 2.89-2.82 (m, 2 H), 2.76-2.71 (m, 2 H), 1.85-1.76 (m, 6 H);
13C NMR (125 MHz, CDCl3) δ 145.4, 128.5, 127.4, 125.7, 74.1, 62.0, 61.4, 48.8, 37.9, 23.7;
FT-IR (in CH2Cl2) 3336, 2932, 2875, 1452, 1265, 1202, 1129, 1048, 904, 875, 735 cm-1;
+
ESIMS m/z 236.2 [M + H]+; HRMS (ESI) calcd for C14H22NO2 [ M + H]+ 236.1651, found
236.1655.
25

ACCEPTED MANUSCRIPT
(1R*,3R*)-1-Phenyl-3-(pyrrolidin-1-yl)butane-1,4-diol (18f). Colourless solid; mp 104-
1
105 °C; H NMR (500 MHz, CDCl3) δ 7.39-7.33 (m, 3 H), 7.28-7.25 (m, 2 H), 5.00 (dd,
J = 7.7, 4.5 Hz, 1 H), 3.84 (dd, J = 11.5, 5.4 Hz, 1 H), 3.80 (dd, J = 11.5, 5.7 Hz, 1 H), 2.89-
2.81 (m, 5 H), 2.84 (br s, 2 H), 2.08 (ddd, J = 14.5, 5.3, 4.5 Hz, 1 H), 2.01 (ddd, J = 14.4, 7.7,
5.7 Hz, 1 H), 1.91-1.80 (m, 4 H); 13C NMR (125 MHz, CDCl3) δ 144.8, 128.6, 127.5, 125.8,
72.3, 62.4, 62.0, 50.5, 36.8, 23.5; FT-IR (in CH2Cl2) 3346, 2967, 1492, 1452, 1264, 1203,
+
1128, 1046, 902, 733 cm-1; ESIMS m/z 236.2 [M + H]+; HRMS (ESI) calcd for C14H22NO2
[ M + H]+ 236.1651, found 236.1654.
(1S*,3R*)-1-Phenyl-3-(phenylamino)butane-1,4-diol (17g). The reaction of 1,2-dioxine 8
(23 mg, 0.14 mmol, 1.0 equiv), aniline (15 µL, 0.16 mmol, 1.1 equiv) catalysed by
triethylamine (6 drops) and sodium borohydride (12 mg, 0.32 mmol, 2.3 equiv) according to
the general procedure afforded a colourless oil as 17g/18g as a mixture of diastereomers
(36 mg, 100% yield, 17g/18g 50:50). The diastereomers were separable by flash
chromatography (3:7 to 7:3 EtOAc/petroleum ether) to give 17g as a colourless oil; 1H NMR
(300 MHz, CDCl3) δ 7.32-7.20 (m, 5 H), 7.15-7.09 (m, 2 H), 6.72-6.68 (m, 1 H), 6.60-6.54
(m, 2 H), 4.81 (dd, J = 8.2, 3.9 Hz, 1 H), 3.67-3.52 (m, 3 H), 3.31 (br s, 3 H), 1.99-1.82 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 147.3, 144.6, 129.5, 128.6, 127.6, 125.7, 118.2, 114.2,
72.0, 64.5, 52.9, 41.4; FT-IR (neat) 3332, 3028, 2921, 1600, 1496, 1453, 1430, 1314, 1257,
1179, 1028, 909, 749, 731, 693 cm-1; ESIMS m/z 258.1 [M + H]+; HRMS (ESI) calcd for
+
C16H20NO2 [ M + H]+ 258.1494, found 258.1495.
(1R*,3R*)-1-Phenyl-3-(phenylamino)butane-1,4-diol (18g). Colourless oil; 1H NMR
(300 MHz, CDCl3) δ 7.32-7.21 (m, 5 H), 7.19-7.12 (m, 2 H), 6.77-6.72 (m, 1 H), 6.67-6.65
(m, 2 H), 4.88 (dd, J = 6.3, 6.3 Hz, 1 H), 3.73-3.59 (m, 3 H), 3.19 (br s, 3 H), 2.03-1.96 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 147.0, 144.5, 129.6, 128.7, 127.8, 125.8, 118.8, 114.8,
72.6, 64.5, 54.0, 41.1; FT-IR (neat) 3332, 3028, 2921, 1600, 1496, 1453, 1430, 1314, 1257,
1179, 1028, 909, 749, 731, 693 cm-1; ESIMS m/z 258.1 [M + H]+; HRMS (ESI) calcd for
+
C16H20NO2 [ M + H]+ 258.1494, found 258.1500.
26

ACCEPTED MANUSCRIPT
(1S*,3R*)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(benzylamino)butane-1,4-diol (19a). The reaction
of aminoketone 11a (54 mg, 0.17 mmol, 1.0 equiv) and sodium borohydride (13 mg,
0.34 mmol, 2.0 equiv) according to the general procedure afforded 19a/20a as a mixture of
diastereomers (32 mg, 59% yield, 19a/20a 64:36). The diastereomers were separated by flash
chromatography (0:1 to 1:9 MeOH/CHCl3 + 2% NH4OH) to afford 19a as a colourless oil;
1H NMR (500 MHz, CDCl3) δ 7.39-7.27 (m, 5 H), 6.89 (d, J = 1.7 Hz, 1 H), 6.80 (ddd,
J = 8.0, 1.7, 0.5 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 5.92 (s, 2 H), 4.83 (dd, J = 10.3, 2.6 Hz,
1 H), 3.97 (d, J = 12.6 Hz, 1 H), 3.83 (dd, J = 10.9, 4.3 Hz, 1 H), 3.81 (d, J = 12.6 Hz, 1 H),
3.58 (dd, J = 10.9, 3.8 Hz, 1 H), 3.06 (dddd, J = 10.3, 4.3, 3.8, 3.2 Hz, 1 H), 1.80 (ddd,
13
J = 14.4, 10.3, 10.3 Hz, 1 H), 1.70 (ddd, J = 14.4, 3.2, 2.6 Hz, 1 H); C NMR (125 MHz,
CDCl3) δ 147.8, 146.7, 139.5, 139.4, 128.8, 128.5, 127.6, 119.0, 108.2, 106.5, 101.0, 74.6,
62.9, 58.7, 50.9, 40.9; FT-IR (neat) 2904, 1712, 1628, 1486, 1440, 1241, 1034, 930, 807,
+
730, 698 cm-1; ESIMS m/z 316.1 [M + H]+; HRMS (ESI) calcd for C18H22NO4 [ M + H]+
316.1549, found 316.1552.
(1R*,3R*)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(benzylamino)butane-1,4-diol (20a). Colourless
1
oil; H NMR (500 MHz, CDCl3) δ 7.34-7.24 (m, 5 H), 6.77 (s, 1 H), 6.70 (s, 2 H), 5.89 (s,
2 H), 4.81 (dd, J = 5.1, 5.1 Hz, 1 H), 4.01 (br s, 3 H), 3.79 (d, J = 12.8 Hz, 1 H), 3.73 (d,
J = 12.8 Hz, 1 H), 3.67 (br dd, J = 10.6, 3.8 Hz, 1 H), 3.53 (br dd, J = 10.6, 6.0 Hz, 1 H),
2.87-2.82 (m, 1 H), 1.85-1.76 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 147.7, 146.5, 139.0,
138.9, 128.7, 128.5, 127.5, 118.7, 108.1, 106.3, 101.0 72.1, 63.0, 56.5, 50.9, 38.0; FT-IR
(neat) 2904, 1712, 1628, 1486, 1440, 1241, 1034, 930, 807, 730, 698 cm-1; ESIMS m/z 316.1
+
[M + H]+; HRMS (ESI) calcd for C18H22NO4 [ M + H]+ 316.1549, found 316.1548.
(1S*,3R*)-3-(Benzylamino)-1-(3-chlorophenyl)butane-1,4-diol (21a). The reaction of 1,2-
dioxine 16 (120 mg, 0.61 mmol, 1.0 equiv), benzylamine (80 µL, 0.73 mmol, 1.2 equiv),
catalysed by triethylamine (6 drops) and sodium borohydride (45 mg, 1.19 mmol, 2.0 equiv)
according to the general procedure afforded 21a/22a as a mixture of diastereomers (128 mg,
69% yield, 21a/22a 50:50). The diastereomers were separable by flash chromatography (1:9
1
MeOH/CH2Cl2) to give 21a as colourless crystals; mp 115-116 °C; H NMR (500 MHz,
27

ACCEPTED MANUSCRIPT
CDCl3) δ 7.68-7.66 (m, 1 H), 7.39-7.34 (m, 4 H), 7.30-7.26 (m, 3 H), 7.19-7.15 (m, 1 H),
5.29 (dd, J = 10.3, 2.1 Hz, 1 H), 3.98 (d, J = 12.6 Hz, 1 H), 3.87 (dd, J = 11.1, 4.0 Hz, 1 H),
3.84 (d, J = 12.6 Hz, 1 H), 3.60 (dd, J = 11.1, 3.6 Hz, 1 H), 3.13 (dddd, J = 10.3, 4.0, 3.6, 2.9
Hz, 1 H), 1.89 (ddd, J = 14.4, 2.9, 2.1 Hz, 1 H), 1.62 (ddd, J = 14.4, 10.3, 10.3 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 142.4, 139.2, 131.4, 129.3, 128.8, 128.5, 128.3, 127.6,
127.29, 127.26, 71.2, 62.8, 59.0, 50.9, 38.8; FT-IR (neat) 3303, 1440, 1351, 1199, 1097,
1051, 843, 760, 744, 723, 695 cm-1; ESIMS m/z 306.1 [M + H]+; HRMS (ESI) calcd for
+
C17H21ClNO2 [ M + H]+ 306.1261, found 306.1251.
(1R*,3R*)-3-(Benzylamino)-1-(3-chlorophenyl)butane-1,4-diol (22a). Colourless oil;
1H NMR (300 MHz, CDCl3) δ 7.55 (dd, J = 7.7, 1.8 Hz, 1 H), 7.39-7.14 (m, 8 H), 5.34 (dd,
J = 7.5, 3.4 Hz, 1 H), 3.92 (d, J = 12.9 Hz, 1 H), 3.85 (dd, J = 10.9, 4.2 Hz, 1 H), 3.84 (d,
J = 12.9 Hz, 1 H), 3.69 (dd, J = 10.9, 6.3 Hz, 1 H), 3.11 (br s, 3 H), 2.96 (dddd, J = 6.9, 6.3,
4.2, 3.8 Hz, 1 H), 2.02 (ddd, J = 14.8, 6.9, 3.4 Hz, 1 H), 1.88 (ddd, J = 14.8, 7.5, 3.8 Hz,
1 H); 13C NMR (75 MHz, CDCl3) δ 142.3, 139.1, 131.3, 129.4, 128.8, 128.6, 128.2, 127.6,
127.5, 127.1, 69.5, 63.5, 56.7, 51.1, 35.6; FT-IR (neat) 3303, 1440, 1351, 1199, 1097, 1051,
843, 760, 744, 723, 695 cm-1; ESIMS m/z 306.1 [M + H]+; HRMS (ESI) calcd for
+
C17H21ClNO2 [ M + H]+ 306.1261, found 306.1259.
(1S*,3R*)-3-Amino-1-phenylbutane-1,4-diol (23). A stirred solution of aminodiol 17a
(243 mg, 0.90 mmol, 1.0 equiv) and freshly opened 10% Pd/C (34 mg, 14% w/w) in ethanol
(10 mL) was bubbled with H2 for 5 min, then stirred at 18 °C under H2 for 7 days. The
mixture was filtered on Celite and washed with ethanol then the filtrate evaporated and the
residue purified by flash chromatography (0:1 to 1:4 MeOH/CH2Cl2 + 2% NH4OH) to afford
1
23 as a colourless oil (105 mg, 64%); H NMR (500 MHz, CDCl3) δ 7.36-7.30 (m, 4 H),
7.25-7.22 (m, 1 H), 4.88 (dd, J = 10.2, 2.6 Hz, 1 H), 3.51 (dd, J = 10.8, 4.3 Hz, 1 H), 3.35
(dd, J = 10.8, 6.6 Hz, 1 H), 3.26 (br s, 4 H), 3.09 (br s, 1 H), 1.71 (ddd, J = 14.3, 2.6, 2.6 Hz,
1 H), 3.53 (ddd, J = 14.3, 10.2, 10.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 145.0, 128.5,
127.4, 125.8, 74.7, 68.0, 53.8, 41.5.
28