Synthesis of 1,3-disubstituted azetidines via a tandem ring-opening ring-closing procedure

Article abstract of DOI:10.1055/s-0031-1291014

The synthesis of N-substituted symmetrical azetidines has been achieved in high yields via the reaction of primary amines undergoing an epoxide ring-opening reaction followed by an in situ ring-closing step. Georg Thieme Verlag Stuttgart · New Yorkv.

Full text of DOI:10.1055/s-0031-1291014

LETTER
▌1511
lSetyternthesis of 1,3-Disubstituted Azetidines via a Tandem Ring-Opening
Ring-Closing Procedure
1,3-Disubstituted Azetidines
Andrea March-Cortijos,a Timothy J. Snape,*b Nicholas J. Turnera
a
School of Chemistry, University of Manchester, Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK
b
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, Lancashire, PR1 2HE, UK
Fax +44(1772)892929; E-mail: tjsnape@uclan.ac.uk
Received: 16.01.2012; Accepted after revision: 23.03.2012
enantiomerically pure β-amino tertiary alcohols,2,3 we are
interested in exploiting the synthetic flexibility and utility
of our recent work with the goal of accessing new molec-
ular building blocks and biologically active products. In
particular, we hoped that we could apply our recent work
towards the development of a new synthetic route to azeti-
dines possessing a tertiary alcohol moiety.
Abstract: The synthesis of N-substituted symmetrical azetidines
has been achieved in high yields via the reaction of primary amines
undergoing an epoxide ring-opening reaction followed by an in situ
ring-closing step.
Key words: azetidines, tertiary alcohols, azo compounds, cycliza-
tion, tandem reaction
Upon examination of the possible competing reactions
that could occur between amines and a suitably function-
alised biselectrophilic reactant such as 14 (Scheme 1) it
became clear that a number of potential products could be
formed, all of which may be of use for the synthesis of β-
amino tertiary alcohols and derivatives, but more impor-
tantly, that they might also be of use to access azetidines
(i.e., if route b was preferred).
Azetidines constitute an extremely useful motif in organic
chemistry due to their propensity to undergo a range of re-
actions in both the neutral and charged state.1 Azetidines
and their derivatives also occur in a number of biological-
ly active compounds which adds to their utility. However,
in comparison to other three-, five-, and six-membered-
ring nitrogen heterocycles, the chemistry of azetidines is
less well developed, and it has been suggested that this
lack of development could be due to their limited avail-
ability.1
We anticipated that due to the neopentyl nature of tosylate
1 we could rule out a direct SN2 nucleophilic displacement
of the tosyl group by the amine, presuming that any reac-
tion would proceed via intermediate 2, the product of an
epoxide ring-opening reaction, as reported previously.3
The question was what route would the subsequent reac-
As part of an on-going research programme into the de-
velopment of generic and flexible routes to tertiary alco-
hols, and in particular the synthesis and application of
O
O
primary
amine
TBSO
OTs
route a
TBSO
TBSO
OTs
O
3 equiv
NH2R1
– TsOH
NHR1
1
3
2, intermediate
not isolated
4-endo-tet
cyclisation
proton
transfer
disfavoured
route b
primary
amine
HO
4-exo-tet
cyclisation
OH
OH
NHR1
TBSO
TBSO
OTs
TBSO
N
favoured
R1
NHR1
NHR1
6
4
5
not isolated
Scheme 1 Potential Route to Symmetrical Azetidines
SYNLETT 2012, 23, 1511–1515
Advanced online publication: 25.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291014; Art ID: ST-2012-D0041-L
© Georg Thieme Verlag Stuttgart · New York

1512
A. March-Cortijos et al.
LETTER
Table 1 Results of the Ring Opening of 1 with Primary Amines to
tion take based on the possibilities available? As shown in
Scheme 1, subsequent reaction steps via route a would
proceed via an established5 ring-forming reaction to cre-
ate a second epoxide (3). This could subsequently react
and undergo either a second epoxide ring-opening reac-
tion with another equivalent of the amine in situ, thus giv-
ing symmetrical tertiary alcohols such as 4, or, if epoxide
3 could be isolated, this route could provide a useful
building block for the synthesis of a range of different
products through attack of the epoxide in separate reac-
tions with a range of nucleophiles.
Produce Azetidinesa (continued)
Entry Amine
Product
Com- Yield
pound (%)b
HO
NH2
TBSO
N
9
15
78
HO
Table 1 Results of the Ring Opening of 1 with Primary Amines to
Produce Azetidinesa
TBSO
NH2
N
Entry Amine
Product
Com- Yield
pound (%)b
10
16
97
HO
1
7
50
H2N
TBSO
N
a Reaction conditions: Epoxide 1 was dissolved in EtOH (0.1 M), the
amine added (3 equiv), and the reaction heated to reflux for 8 h.
b Isolated yields.
HO
HO
c n.r. = no reaction.
2
3
8
9
88
84
H2N
H2N
TBSO
TBSO
N
N
HO
TBSO
N
F
NH2
4
10
43
F
OMe
NH2
5
6
n.r.c
11
12
n.r.c
80
HO
Figure 1 X-ray crystal structures of 7 and 8 (hydrogens omitted for
TBSO
NH2
N
clarity)13
Alternatively, route b in Scheme 1, indicates that interme-
diate 2 could undergo a proton-transfer step, prior to a fa-
voured 4-exo-tet ring closure to give N-substituted
azetidines such as 6; similar compounds are known to
possess potent biological activity.6,7 This azetidine prod-
uct is presumably not achievable via route a due to a rela-
tively unfavoured 4-endo-tet cyclisation being required
for its preparation.8
HO
HO
NH2
7
8
TBSO
TBSO
13
14
92
88
N
N
NH2
To test this hypothesis, and to determine what the major
products formed would be, we prepared compound 1 in an
efficient three-step sequence, from the known compound
[2-(hydroxymethyl)oxiran-2-yl]methyl acetate,2,3 which
included TBS protection of the primary alcohol (82%),
methanolysis of the acetate (91%), and subsequent tosyl-
Synlett 2012, 23, 1511–1515
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3-Disubstituted Azetidines
1513
O
O
secondary
amine
TBSO
OTs
route a'
– TsOH
TBSO
TBSO
OTs
O
NHR1R2
NR1R2
1
18
17, intermediate
proton
transfer
secondary
amine
route b'
HO
secondary
amine
OH
OH
cyclisation
NR1R2
TBSO
R2
TBSO
OTs
TBSO
N
R1
21, azetidinium ion
NR1R2
NR1R2
20
19
Scheme 2 Proposed mechanism for the synthesis of symmetrical diamines 19
ation of the newly exposed primary alcohol (90%), to here may be accelerated by the gem-dialkyl effect reduc-
yield 1 in sufficient quantities for further study.
ing the rotational degrees of freedom and placing the re-
acting centres closer together.12 Figure 1 shows the X-ray
crystal structures of compounds 7 and 8.13
Following its synthesis, the reaction of 1 with a range of
primary amines (3 equiv) as outlined in Table 1, was stud-
ied. Purification and isolation of the reaction products oc- Having identified that the major products formed from the
curred in good to excellent yields (Table 1), except in the reaction of 1 with primary amines were the symmetrical
case of entries 4 and 5, where we assume the poor nucleo- azetidines (presumably via route b), we sought to discover
philicity of 4-fluoroaniline is responsible for the low yield if the reaction pathways would change if secondary
in that case and the sterically hindered nature of the react- amines were used instead, not least because the analogous
ing centre in 2-anisidine is possibly responsible for the reaction product 21 (Scheme 2) would be an azetidinium
lack of reactivity in the attempted production of 11. After ion which is potentially capable of further reaction in si-
heating the reaction mixture at reflux for eight hours we tu.1 It was also possible that a number of other scenarios
isolated the symmetrical azetidines 7–16 as the only de- could occur; either the synthetically useful tertiary amines
tectable reaction products in all cases. However, since we 18 or 20 would be isolated, unlike before, where the in-
did not observe, and were not able to isolate proposed in- creased steric bulk of the amines would restrict subse-
termediates 3 or 5 (even when using 1 equiv of the amine), quent reaction, or, if the amine was not found to be too
we were unable to prove that these were formed. Howev- sterically demanding, then a double addition product 19
er, this mechanism does share with other known methods may be isolated, the result of the attack of a second equiv-
of azetidine synthesis a common ring-closing step which alent of amine with either 18 or 21 (Scheme 2).
utilise the reaction of amines with 1,3-disubstituted al-
Under the same reaction conditions to those used with the
primary amines, we subjected 1 to a series of secondary
kyls.9–11 It is also possible that the formation of azetidines
Table 2 Results of the Ring Opening of 1 with Secondary Amines to Produce Symmetrical Diaminesa
Entry
Amine
Product
Compound
Yield (%)b
81
OTBS
N
1
22
N
H
N
N
OH
OTBS
N
N
H
2
3
23
24
78
83
OH
OTBS
N
N
H
N
OH
a Reaction conditions: Epoxide 1 was dissolved in EtOH (0.1 M), the amine added (3 equiv), and the reaction heated to reflux for 8 h.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1511–1515

1514
A. March-Cortijos et al.
LETTER
ddt, J = 1.2, 1.6, 10.4 Hz, CH), 5.17 (1 H, ddt, J = 1.6, 3.2, 17.2 Hz,
CH), 5.76 (1 H, ddt, J = 6.2, 10.4, 17.2 Hz, CH). 13C NMR (100
MHz): δ = –5.4 (CH3), 18.3 (C), 25.8 (CH3), 61.9, 63.3, 67.9 (CH2),
69.9 (C), 117.4 (CH2), 134.3 (CH). MS (ES, +ve): m/z (%) = 258.0
(100) [M + H]+. HRMS–FAB: m/z calcd for C13H27NO2Si + H+:
258.1811 [M + H]+; found: 258.1897. IR: νmax = 3395 cm–1.
amines (Table 2). In the event, product 19 was isolated in
excellent yields with the three secondary amines used.
Whether the formation of 19 proceeds by route a′ or route
b′ (Scheme 2) remains to be seen. Since an azetidinium
ion cannot be formed in the primary amine case the reac-
tion stops at the azetidine (Scheme 1); no double addition
is observed with primary amines. Conversely, double ad-
dition is the exclusive product when secondary amines are
used, therefore it is likely that the double addition product
forms as a result of addition to azetidinium ion 21, for if
these reactions did proceed via epoxide ring opening (18
→ 19) to give the double addition products, it would have
3-[(tert-Butyldimethylsilyloxy)methyl]-1-(prop-2-ynyl)azetidin-
3-ol (8)
Yield 88%, yellow solid; mp 70–73 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.09 (6 H, s, CH3), 0.90 (9 H, s, t-Bu), 2.27 (1 H, t, J =
2.0 Hz, CH), 3.19 (1 H, d, J = 2.0 Hz, HaHb), 3.21 (1 H, d, J = 2.0
Hz, HaHb), 3.33 (4 H, m, 2 × CH2), 3.81 (2 H, s, CH2). 13C NMR
(100 MHz): δ = –5.4 (CH3), 18.3 (C), 25.8 (CH3), 45.3, 61.4, 68.0
(CH2), 69.5 (C), 73.1 (CH), 78.6 (C). MS (ES, +ve): m/z (%) = 256.1
been expected to be observed with primary amines (3 → (100) [M + H]+. HRMS–FAB: m/z calcd for C13H25NO2Si + H+:
256.1733 [M + H]+; found: 256.1733. IR: νmax = 3391 cm–1.
4). These results suggest that routes b and b′ are followed
in these reactions.
1-Benzyl-3-[(tert-Butyldimethylsilyloxy)methyl]azetidin-3-ol
(9)
These additional results suggest that this method could
potentially be exploited further towards the synthesis of
highly functionalised β-amino tertiary alcohols by the
careful manipulation of azetidinium ring-opening reac-
tions.
Yield 84%, oil. 1H NMR (400 MHz, CDCl3): δ = 0.09 (6 H, s, CH3),
0.90 (9 H, s, t-Bu), 3.01 (2 H, d, J = 2.0 Hz, 2 × HaHb), 3.35 (2 H,
d, J = 2.0 Hz, 2 × HaHb), 3.67 (2 H, s, CH2), 3.80 (2 H, s, CH2), 7.28
(5 H, m, Ar). 13C NMR (100 MHz): δ = –5.4 (CH3), 18.3 (C), 25.8
(CH3), 2 × 63.5, 68.1 (CH2), 70.0 (C), 127.0, 128.3, 128.4 (CH),
138.1 (C). MS (ES, +ve): m/z (%) = 308.1 (100) [M + H]+. HRMS–
FAB: m/z calcd for C17H29NO2Si + H+: 308.2046 [M + H]+; found:
308.2053. IR: νmax = 3388 cm–1.
In conclusion, we have developed a new method for the
synthesis of 1,3-disubstituted azetidines from primary
amines via an in situ two-step process in high yields. We
have also shown that secondary amines give different
products under the same reaction conditions, posing inter-
esting questions about the mechanism taking place and the
synthetic utility of the products and intermediates ob-
tained.
3-[(tert-Butyldimethylsilyloxy)methyl]-1-(4-fluorophenyl)azeti-
din-3-ol (10)
Yield 43%, yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.12 (6 H,
s), 0.92 (9 H, s), 3.65 (2H, d, J = 8.0 Hz, HaHb), 2.81 (2 H, d, J = 8.0
Hz, HaHb), 3.86 (2 H, s, CH2), 6.41 (2 H, m, Ar), 6.92 (2 H, m, Ar).
13C NMR (100 MHz): δ = –5.3 (CH3), 18.3 (C), 25.9 (CH3), 61.9,
68.2 (CH2), 70.1 (C), 112.8 (JC–F = 40 Hz), 115.4 (JC–F = 80 Hz,
CH), 148.2, 157.3 (C). MS (ES, +ve): m/z (%) = 312.1 (100) [M +
H]+. HRMS–FAB: m/z calcd for C16H26FNO2Si + H+: 312.1750
[M + H]+; found: 312.1565. IR: νmax = 3388 cm–1.
Commercially available reagents were used as received without pu-
rification. Analytical TLC was performed with Kieselgel 60 F254, in
a variety of solvents on plastic-backed plates. The plates were visu-
alised by UV light (254 nm) and KMnO4 solutions. Flash column
chromatography was conducted with Merck silica gel 60H (40–60
μm, 230–400 mesh) under bellows pressure. Nominal mass spectra
were recorded on an a Waters LCT mass spectrometer connected to
a Waters Alliance 1100 LC autosampler and controlled by Waters
Masslynx 4.1 and OpenAccess software using electrospray (ES)
3-[(tert-Butyldimethylsilyloxy)methyl]-1-cyclopentylazetidin-3-
ol (12)
Yield 80%, white solid. 1H NMR (400 MHz, CDCl3): δ = 0.09 (6 H,
s, CH3), 0.90 (9 H, s, t-Bu), 1.48 (4 H, m, 2 × CH2), 1.71 (4 H, m, 2
× CH2), 2.88 (1 H, m, CH), 3.16 (2 H, d, J = 8.0 Hz, 2 × HaHb), 3.45
(2 H, d, J = 8.0 Hz, 2 × HaHb), 3.73 (2 H, s). 13C NMR (100 MHz):
δ = –5.4 (CH3), 18.2 (C), 24.4 (CH2), 25.8 (CH3), 30.0, 62.3, 67.4
(CH2), 69.1 (CH), 69.5 (C). MS (ES, +ve): m/z (%) = 287.4 (100)
[M + 2H]+. HRMS–FAB: m/z calcd for C15H31NO2Si + H+:
286.2202 [M + H]+; found: 286.2205. IR: νmax = 3355 cm–1.
1
ionisation. H NMR and 13C NMR spectra were recorded on a
Bruker Avance 300 (300 MHz) or a Bruker DPX 400 (400 MHz)
spectrometer. All chemical shifts (δ) are quoted in parts per million
(ppm) relative to a calibration reference of the residual protic
solvent; CHCl3 (δ = 7.26, s) was used as the internal standard in
1H NMR spectra, and 13C NMR shifts were referenced using CDCl3
(δ = 77.0, t) with broad-band decoupling. The following abbrevia-
tions were used to define the multiplicities: d, doublet; m, multiplet;
s, singlet; t, triplet.
3-[(tert-Butyldimethylsilyloxy)methyl]-1-isopropylazetidin-3-ol
(13)
Yield 92%, colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.07 (6
H, s, CH3), 0.88 (9 H, s, t-Bu), 0.94 (6 H, d, J = 6.4 Hz, 2 × CH2),
2.38 (1 H, hept, J = 6.4 Hz, CH), 2.99 (2 Hz H, d, J = 9.6 Hz, 2 ×
HaHb), 3.36 (2 H, d, J = 9.6 Hz, 2 × HaHb), 3.72 (2 H, s, CH2). 13
C
Preparation of Compounds in Table 1
NMR (100 MHz): δ = –5.4, 18.2 (CH3), 19.5 (C), 25.8 (CH3), 58.6
(CH), 62.1, 67.7 (CH2), 68.6 (C). MS (ES, +ve): m/z (%) = 260.1
(100) [M + H]+. HRMS–FAB: m/z calcd for C13H29NO2Si + H+:
260.2046 [M + H]+; found: 260.2043. IR: νmax = 3371 cm–1.
To a solution of {2-[(tert-butyldimethylsilyloxy)methyl]oxiran-2-
yl}methyl 4-methylbenzenesulfonate (1, 100 mg, 0.27 mmol) in
EtOH (2.7 mL, 0.1 M) was added the corresponding amine (3 equiv,
Table 1). The solution was heated at reflux for 8 h and allowed to
cool slowly to r.t. The mixture was evaporated in vacuo, and the
crude material was purified by column chromatography (SiO2; EtO-
Ac in PE).
(R)-3-[(tert-Butyldimethylsilyloxy)methyl]-1-(1-phenyle-
thyl)azetidin-3-ol (14)
Yield 88%, colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.08 (3
H, s), 0.10 (3 H, s) 0.90 (9 H, s, tBu), 1.21 (3 H, d, J = 6.8 Hz, CH3),
2.84 (1 H, d, J = 7.8 Hz, HaHb), 2.99 (1 H, d, J = 7.8 Hz, HaHb), 3.09
(1 H, d, J = 7.6 Hz, HcHd), 3.34 (1 H, q, J = 6.8 Hz, CH), 3.42 (1 H,
d, J = 7.6 Hz, HcHd), 3.79 (1 H, d, J = 10.0 Hz, HeHf), 3.81 (1 H, d,
J = 10.0 Hz, HeHf), 7.27 (5 H, m, Ar). 13C NMR (100 MHz): δ =
–5.3 (CH3), 18.3 (C), 21.5, 25.9 (CH3), 62.4, 62.5, 68.3 (CH2), 68.7
1-Allyl-3-[(tert-Butyldimethylsilyloxy)methyl]azetidin-3-ol (7)
Yield 50%, yellow solid; mp 65–67 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.09 (6 H, s, CH3), 0.90 (9 H, s, t-Bu), 2.96 (1 H, d, J =
1.6 Hz, HaHb), 2.98 (1 H, d, J = 1.6 Hz, HaHb), 3.12 (1 H, t, J = 1.2
Hz, HcHd), 3.13 (1 H, t, J = 1.2 Hz, HcHd), 3.36 (1 H, d, J = 1.8 Hz,
HeHf), 3.38 (1 H, d, J = 1.8 Hz, HeHf), 3.79 (2 H, s, CH2), 5.10 (1 H,
Synlett 2012, 23, 1511–1515
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3-Disubstituted Azetidines
1515
(CH), 69.0 (C), 127.0, 127.1, 128.3 (CH), 143.4 (C). MS (ES, +ve):
m/z (%) = 322.1 (100) [M + H]+. HRMS–FAB: m/z calcd for
C18H31NO2Si + H+: 322.2202 [M + H]+; found: 322.2204. IR: νmax
= 3397 cm–1. [α]D –29.4 (c 0.034, EtOH).
2.39 (2 H, d, J = 15.6 Hz, 2 × HaHb), 2.40 (6 H, s, 2 × CH3), 2.56 (2
H, d, J = 15.6 Hz, 2 × HaHb), 3.41 (4 H, d, J = 2.0 Hz, 2 × CH2), 3.43
(2 H, s, CH2). 13C NMR (100 MHz) δ = –5.5 (CH3), 18.1 (C), 25.8,
44.2 (CH3), 47.6, 58.4, 65.0 (CH2), 72.5 (CH), 73.8, 79.6 (C). MS
(ES, +ve): m/z (%) = 339.2 (100) [M + H]+. HRMS–FAB: m/z calcd
for C18H34N2O2Si + H+: 339.2423 [M + H]+; found: 339.2420. IR:
(R)-3-[(tert-Butyldimethylsilyloxy)methyl]-1-(1-phenylpro-
pyl)azetidin-3-ol (15)
ν
max = 3371 cm–1.
Yield 78%, white solid; mp 59–61 °C. 1H NMR (400 MHz, CDCl3):
δ = 0.06 (3 H, s, CH3), 0.08 (3 H, s. CH3), 0.66 (3 H, t, J = 7.6 Hz,
CH3), 0.88 (9 H, s, t-Bu), 1.45 (1 H, dqd, J = 13.4, 9.6, 7.6 Hz,
HaHb), 1.69 (1 H, dqd, J = 13.4, 7.6, 3.6 Hz, HaHb), 2.82 (1 H, d,
J = 8.0 Hz, HcHd), 2.95 (1 H, d, J = 8.0 Hz, HcHd), 3.03 (1 H, ddd,
J = 7.8, 2.0, 0.8 Hz, HeHf), 3.07 (1 H, dd, J = 3.6, 9.6 Hz, CH), 3.40
(1 H, ddd, J = 7.8, 2.0, 0.8 Hz, HeHf), 3.73 (1 H, d, J = 10.4 Hz,
HgHh), 3.77 (1 H, d, J = 10.4 Hz, HgHh), 7.24 (5 H, m, Ar). 13C NMR
(100 MHz): δ = –5.4 (CH3), 10.0 (CH3), 18.3 (C), 25.8 (CH3), 27.3,
62.3, 62.5, 68.2 (CH2), 69.3 (C), 75.5 (CH), 127.0, 128.0, 128.1
(CH), 141.3 (C). MS (ES, +ve): m/z (%) = 336.1 (100) [M + H]+.
HRMS–FAB: m/z calcd for C19H33NO2Si + H+: 336.2359 [M + H]+;
found: 336.2356. IR: νmax = 3375 cm–1. [α]D +40.3 (c 0.30, EtOH).
1,3-Bis[benzyl(methyl)amino]-2-[(tert-butyldimethylsilyl-
oxy)methyl]propan-2-ol (24)
Yield 83%, yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.04 (6 H,
s, 2 × CH3), 0.80 (9 H, s, t-Bu), 2.22 (6 H, s, 2 × CH3), 2.52 (4 H, s,
2 × CH2), 3.44 (2 H, s, CH2), 3.54 (2 H, d, J = 13.6 Hz, HaHb), 2.65
(2 H, d, J = 13.6 Hz, HaHb), 7.23 (10 H, m). 13C NMR (100 MHz):
δ = –5.6 (CH3), 18.0 (C), 25.8, 44.4 (CH3), 60.2, 63.9, 65.6 (CH2),
74.2 (C), 126.9, 128.2, 128.8 (CH), 139.6 (C). MS (ES, +ve): m/z
(%) = 443.3 (100) [M + H]+. HRMS–FAB: m/z calcd for
C26H42N2O2Si + H+: 443.3094 [M + H]+; found: 443.3091. IR:
ν
max = 3329 cm–1.
(R)-3-[(tert-Butyldimethylsilyloxy)methyl]-1-[1-(naphthalen-2-
yl)ethyl]azetidin-3-ol (16)
Acknowledgment
Yield 97%, colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.11 (3
H, s, CH3), 0.12 (3 H, s, CH3), 0.92 (9 H, s, t-Bu), 1.31 (3 H, d, J =
6.4 Hz, CH3), 2.96 (1 H, d, J = 8.0 Hz, HaHb), 3.06 (1 H, d, J = 8.0
Hz, HaHb), 3.16 (1 H, d, J = 8.4 Hz, HcHd), 3.49 (1 H, d, J = 8.4 Hz,
HcHd), 3.54 (1 H, q, J = 6.4 Hz, CH), 3.80 (1 H, d, J = 10.0 Hz, He-
Hf), 3.84 (1 H, d, J = 10.0 Hz, HeHf), 7.46 (3 H, m, Ar), 7.79 (4 H,
m, Ar). 13C NMR (100 MHz): δ = –5.4 (CH3), 18.3 (C), 21.3, 25.9
(CH3), 62.5, 62.6, 68.1 (CH2), 68.8 (CH), 69.0 (C), 125.4, 125.5,
125.7, 125.8, 127.6, 127.7, 128.0 (CH), 132.8, 133.3, 141.0 (C). MS
(ES, +ve): m/z (%) = 372.2 (100) [M + H]+. HRMS–FAB: m/z calcd
for C22H33NO2Si + H+: 372.2314 [M + H]+: found: 372.2280. IR:
The authors would like to thank CoEBio3 for financial support.
References and Notes
(1) Couty, F.; Evano, G. Synlett 2009, 3053.
(2) March-Cortijos, A.; Snape, T. J. Tetrahedron: Asymmetry
2008, 19, 1761.
(3) March-Cortijos, A.; Snape, T. J. Org. Biomol. Chem. 2009,
7, 5163.
(4) Compound 1 is prepared by the method mentioned above in
the text from a precursor synthesised in ref. 2 and 3.
(5) Corey, E. J.; Marfat, A.; Goto, G.; Brion, F. J. Am. Chem.
Soc. 1980, 102, 7984.
ν
max = 3348 cm–1. [α]D +225.0 (c 0.024, EtOH).
Preparation of Compounds in Table 2
To a solution of {2-[(tert-butyldimethylsilyloxy)methyl]oxiran-2-
yl}methyl 4-methylbenzenesulfonate (1, 100 mg, 0.27 mmol) in
EtOH (2.7 mL, 0.1 M) was added the corresponding amine (3 equiv,
Table 2). The solution was heated at reflux for 8 h and allowed to
cool slowly to r.t. The mixture was evaporated in vacuo, and the
crude material was purified by column chromatography (SiO2;
MeOH in EtOAc).
(6) Hart, T.; Macias, A. T.; Benwell, K.; Brooks, T.;
D’Alessandro, J.; Dokurno, P.; Francis, G.; Gibbons, B.;
Haymes, T.; Kennett, G.; Lightowler, S.; Mansell, H.;
Matassova, N.; Misra, A.; Padfield, A.; Parsons, R.; Pratt,
R.; Robertson, A.; Walls, S.; Wong, M.; Roughley, S.
Bioorg. Med. Chem. Lett. 2009, 19, 4241.
(7) Roughley, S. D.; Hart, T. Tetrahedron Lett. 2010, 51, 5191.
(8) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(9) Hillier, M. C.; Chen, C. Y. J. Org. Chem. 2006, 71, 7885.
(10) Ju, Y. H.; Varma, R. S. J. Org. Chem. 2006, 71, 135.
(11) Toda, T.; Karikomi, M.; Ohshima, M.; Yoshida, M.
Heterocycles 1992, 33, 511.
1,3-Bis[Allyl(methyl)amino]-2-[(tert-butyldimethylsilyl-
oxy)methyl]propan-2-ol (22)
Yield 81%, yellow oil. 1H NMR (400 MHz, CDCl3): δ = 0.03 (6 H,
s, 2 × CH3), 0.87 (9 H, s, t-Bu), 2.31 (6 H, s, 2 × CH3), 2.37 (2 H, d,
J = 13.6 Hz, 2 × HaHb), 2.48 (2 H, d, J = 13.6 Hz, 2 × HaHb), 3.05
(2 H, dd, J = 6.4, 14.0 Hz, 2 × HcHd), 3.14 (2 H, dd, J = 6.4, 14.0
(12) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
(13) CCDC 840439 (7) and CCDC 840438 (8) contain the
supplementary crystallographic data for this paper.
These data can be obtained free of charge via
Hz, 2 × HcHd), 3.40 (2 H, s, CH2), 5.11 (4 H, m), 5.83 (2 H, m). 13
C
NMR (100 MHz) δ = –5.5 (CH3), 18.1 (C), 25.8, 44.4 (CH3), 59.8,
62.6, 65.2 (CH2), 73.8 (C), 117.0 (CH2), 136.2 (CH). MS (ES, +ve):
m/z (%) = 343.2 (100) [M + H]+. HRMS–FAB: m/z calcd for
C18H38N2O2Si + H+: 343.2736[M + H]+; found: 343.2770. IR:
νmax = 3295 cm–1.
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033.
1-(tert-Butyldimethylsilyloxy)-3-[methyl(prop-2-ynyl)amino]-
2-{[methyl(prop-2-ynyl)amino]methyl}propan-2-ol (23)
Yield 78%, colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.05 (6
H, s, 2 × CH3), 0.88 (9 H, s, t-Bu), 2.20 (2 H, t, J = 2.0 Hz, 2 × CH),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1511–1515

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.