α-Lithiation-electrophile trapping of N-thiopivaloylazetidin-3-ol: Stereoselective synthesis of 2-substituted 3-hydroxyazetidines

Article abstract of DOI:10.1021/jo3025225

α-Lithiation of N-thiopivaloylazetidin-3-ol and subsequent electrophile trapping provides access to a range of 2-substituted 3-hydroxyazetidines with generally good trans-diastereoselectivity, aside from deuteration, which gives the cis-diastereoisomer. Deuterium labeling studies indicate that the initial α-deprotonation occurs preferentially, but not exclusively, in a trans-selective manner. These studies also suggest that the stereochemical outcome of the electrophile trapping depends on the electrophile used but is independent of which α-proton (cis or trans to the hydroxyl group) is initially removed.

Full text of DOI:10.1021/jo3025225

Article
pubs.acs.org/joc
α‑Lithiation−Electrophile Trapping of N‑Thiopivaloylazetidin-3-ol:
Stereoselective Synthesis of 2‑Substituted 3‑Hydroxyazetidines
David M. Hodgson,* Christopher I. Pearson, and Amber L. Thompson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: α-Lithiation of N-thiopivaloylazetidin-3-ol and
subsequent electrophile trapping provides access to a range of
2-substituted 3-hydroxyazetidines with generally good trans-
diastereoselectivity, aside from deuteration, which gives the cis-
diastereoisomer. Deuterium labeling studies indicate that the
initial α-deprotonation occurs preferentially, but not exclu-
sively, in a trans-selective manner. These studies also suggest
that the stereochemical outcome of the electrophile trapping
depends on the electrophile used but is independent of which
α-proton (cis or trans to the hydroxyl group) is initially removed.
Scheme 1. α-Deprotonation and Electrophile Trapping of N-
Thiopivaloylazetidine
INTRODUCTION
■
Azetidines have received significantly less attention from the
synthesis community in comparison with the larger and smaller
azacycles.1 However, azetidines are being increasingly incorpo-
rated into drug candidates2 and are also finding utility as ligands
in metal-catalyzed transformations.3 In particular, the 3-
hydroxy- or 3-alkoxyazetidine motif is present in a number of
drug leads4 and in natural products5 (Figure 1).
medicinal chemistry programs prompted the present inves-
tigations of the 3-oxygenated system 1 (Scheme 1, X = OR).
Despite the potential issues of β-elimination from the α-
lithiated intermediate 2 and controlling diastereoselectivity in
the electrophile trapping, this work has resulted in a promising
entry to 2,3-disubstituted azetidines 3 (X = OR).
RESULTS AND DISCUSSION
■
We initially attempted lithiation−deuteration (as well as in situ
silylation) of silyloxythioamide 7 (Scheme 2). Silyloxythioa-
mide 7 was prepared in four steps from N-benzhydrylazetidin-
3-ol (4), by silylation to give silyl ether 5 (quant),
hydrogenolytic N-deprotection and N-pivaloylation to give
silyloxyamide 6 (90% over two steps), and finally, amide
thionation using P2S5 (93%). However, only starting thioamide
7 and/or azetine 9 (up to 98% yield) were obtained from the
lithiation experiments. Azetine 9 is likely formed by rapid β-
elimination of silyloxide from the transient α-lithiated
intermediate 8.9
Figure 1. Examples of 3-oxygenated azetidine-containing drug leads4
and natural products.5
With the aim of avoiding the undesired elimination pathway,
we examined C,O-dilithiation of the unprotected azetidinol
12.10 This azetidinol 12 could be conveniently prepared in two
steps from commercially available azetidin-3-ol hydrochloride
In most strategies to substituted azetidines, the substituents
are required to be present on a precursor or precursors, prior to
ring formation.1,6 We recently reported a method for α-
electrophile incorporation on azetidine 1 (Scheme 1, X = H), in
which the rarely studied N-thiopivaloyl group plays a crucial
role.7 The ready availability of the 3-hydroxyazetidine system
(from epichlorohydrin and benzhydrylamine)8 and its value in
Received: November 19, 2012
Published: January 10, 2013
© 2013 American Chemical Society
1098
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
Scheme 2. Synthesis and Lithiation−Elimination of Silyloxythioamide 7
(10) (Scheme 3), by diacylation and amide thionation (93%),
followed by de-esterification (95%) of the resulting thioamide
ester 11.
Table 1. Scope of Electrophile Incorporation into Azetidinol
12
Scheme 3. Synthesis and Lithiation of Azetidinol 12
In the event, azetidinol 12 underwent partial lithiation−
deuteration (92% recovery, 48% D, 90:10 dr) under the
conditions originally used with azetidine 1 (X = H) but using
twice the quantity of s-BuLi (2.4 equiv) to take account of the
free hydroxyl. Further experimentation in THF established that
complete deuterium incorporation to give 13a (E = D) could
be obtained by increasing the concentration (from 0.1 to 0.3
M), with the optimal yield (91%, 90:10 dr) being obtained
using the conditions indicated in Scheme 3. Lithiation above
−78 °C led to reduced dr values (73:26 at −46 °C), whereas no
significant improvement was observed at −98 °C. Using no, or
decreased equivalents, of TMEDA did give product but in
slightly suppressed yields. Experiments carried out in Et2O did
not give higher than 33% deuterium incorporation, with poor
solubility of the deprotonated species likely being a
contributory factor. Application of the optimized conditions
in THF to a range of other electrophiles gave the results shown
in Table 1.
Alkylation (entries 1−4), including benzylation and allylation
(entries 3 and 4), as well stannylation (entry 5), and reaction
with aromatic aldehydes (entries 6 and 7) and with Mander’s
reagent (entry 8) all proceeded to give the corresponding 2,3-
disubstituted azetidine 13 in good yield. Aside from
methylation (entry 1),11 high trans-2,3-diastereoselectivity was
observed with the electrophiles in Table 1. With azetidine 1 (X
= H), benzaldehyde and para-chlorobenzaldehyde had
previously given the adduct alcohols as single diastereomers;7
for azetidinol 12, these prochiral electrophiles led to the same
relative stereochemistry between C-2 and the side-chain
carbinol but at a reduced level (entries 6 and 7). The reaction
with methyl cyanoformate gave C- and O-methoxycarbonylated
azetidine 13i (entry 8), which provides potential access to
azetidine amino acids and mugineic acid-type natural products
a
Ratio of trans/cis 69:31 (entry 1), 93:7 (entry 8); major
b
diastereoisomer shown. Ratio of 75:25 (entry 6) and 57:43 (entry
7) mixture of epimers at side-chain carbinol; major diastereoisomer
shown.
(Figure 1). The above stereochemical assignments are based on
X-ray crystallographic analysis of the minor epimer epi-13g
(epimeric to 13g at the side-chain benzylic position) derived
from benzaldehyde12 and proton coupling constant analysis.13
The vicinal coupling constant between the ring protons at C-2
and C-3 was 3.3 Hz for both 13g and epi-13g and was similar
(2−4 Hz) for all other adducts in Table 1.14 In contrast, J for
3
1099
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
the corresponding minor cis-methylated diastereoisomer of 13b
was 6.6 Hz.
Scheme 6. Lithiation−Deuteration of cis-13a and of trans-
13a
Effective deprotection of an α-substituted azetidinol 13 can
be achieved using MeLi in THF with TMEDA at 0 °C (92%
from 13d, isolated as the hydrochloride salt 14, Scheme 4).
Conversion to the corresponding pivalamide 15, in 81% yield
from 13d, was facilitated using MeCO3H.
Scheme 4. Deprotection and Thioamide to Amide
Conversion
should lead to small amounts 18-2,4Dtc and 18-2,4Dcc,
respectivelyalthough not detectable/analyzable by NMR)
does not negate these conclusions.
Lithiation−protonation of cis-13a and of trans-13a resulted
in a cis/trans dr change from 90:10 to 64:36 (quant) and no
change in dr (86% yield), respectively (Scheme 7).13 These
In contrast to the results shown in Table 1, deuterium
trapping of lithiated azetidinol 12 occurs predominantly cis to
the hydroxyl group (cis-13a, 90:10 cis/trans). This cis
configuration was assigned from 1H NMR analysis.13 On
deuteration, the appearance of the multiplet due to H-3 at the
carbinol carbon changed from a triplet of triplets (3J = 6.6 and
3.9 Hz) for 12 to a triplet of doublets (3J = 6.6 and 3.9 Hz) for
cis-13a, indicating the loss of a 3.9 Hz coupling, corresponding
to loss of a proton cis to the alcohol. These observations
prompted an investigation into the stereoselectivity of the
lithiation and electrophile trapping steps,15 using cis-13a and
the inverted deuterium adduct trans-13a. The latter was
synthesized by inversion of the alcohol in cis-13a through
acetate displacement of the derived triflate 16 to give acetate
17, followed by deacetylation (Scheme 5). In contrast to cis-
13a, H-3 for the inverted deuterium adduct trans-13a appeared
as a doublet of triplets (3J = 6.6 and 3.9 Hz).
Scheme 7. Lithiation−Protonation of cis-13a and of trans-
13a
Scheme 5. Synthesis of trans-13a
results can be rationalized as follows. The earlier dideuteration
results with cis-13a and trans-13a (Scheme 6) indicate that the
regioselectivity of the deprotonation between the 4- and 2-
positions is ∼6:4 and 8:2, respectively, in favor of the 4-
position. On lithiation−protonation of cis-13a (Scheme 7), the
4-lithiated intermediate (comprising ∼60% of the total lithiated
azetidinol) will regenerate cis-13a, whereas the 2-lithiated
species (∼40%) will give trans-13a. However, for lithiation−
protonation of trans-13a, both the 4-lithiated and the 2-lithiated
species regenerate trans-13a. These results therefore suggest
that there is a strong bias for cis-protonation (deuteration),
regardless of whether a cis or trans proton is originally removed.
Lithiation−benzylation of cis-13a and of trans-13a both result
in a mixture of the two possible regioisomers: the cis- and trans-
2-deuterated 4-benzylated derivatives (19-2Dc-4Bnt and 19-
2Dt-4Bnt) and the 2,2-derivative (19-2Dc-2Bnt) (Scheme 8).
The cis- and trans-2,4-derivatives (where cis and trans refer to
stereochemistry relative to the alcohol) likely derive directly
from 4-lithiation of the major and minor diastereoisomeric
azetidinols which comprise the starting material, as the ratios
match. Both stereoisomers can be observed in these cases, as
the position of the deuterium can now be established relative to
the newly installed benzyl group. 2-Lithiation−benzylation
from either cis-13a or trans-13a gave only the trans-2-
The preference for proton removal (cis or trans to OLi under
the reaction conditions) was examined by lithiation−deutera-
tion of cis-13a and of trans-13a, which gave dideuterated
adducts 18 (Scheme 6). 2,4-Dideuterated adduct is present in a
greater proportion from trans-13a (2,4-:2,2-, 82:18) than from
cis-13a (2,4-:2,2-, 62:38), indicating a preference for trans-
deprotonation, which in the case of trans-13a is blocked at C-2
by the presence of the trans-deuterium (primary kinetic isotope
effect). While less preferable to trans-deprotonation, cis-
deprotonation does occur competitively, as evidenced by the
formation of the 2,2-dideuterated adduct 18-2,2D from trans-
13a and the unequal ratio of dideuterated adducts from cis-13a
(assuming no significant secondary kinetic isotope effect). The
presence of ∼10% of trans-13a in cis-13a and visa versa (which
1100
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
1-(3-((tert-Butyldimethylsilyl)oxy)azetidin-1-yl)-2,2-dime-
thylpropan-1-one (6). To a stirred solution of silyl ether 5 (5.30 g,
15.0 mmol) in MeOH (100 mL) at rt were added ammonium formate
(4.73 g, 75.0 mmol) and 10 wt % Pd/C (530 mg) under nitrogen. The
reaction mixture was heated to reflux, and after 2 h, upon cooling to rt,
the reaction mixture was filtered through a pad of Celite, then
concentrated to dryness under reduced pressure. The crude residue
was dissolved in CH2Cl2 (75 mL). To the resulting solution were
added DMAP (670 mg, 5.5 mmol) and Et3N (4.2 mL, 30.1 mmol).
The reaction mixture was cooled to 0 °C, and pivCl (2.2 mL, 17.9
mmol) was added dropwise over 5 min. The reaction mixture was
warmed slowly to rt and stirred overnight. After quenching with aq
HCl (1 M, 75 mL) the aqueous layer was extracted with CH2Cl2 (2 ×
50 mL). The combined organic layers were washed with H2O (75 mL)
then brine (75 mL), dried (Na2SO4), and concentrated to dryness
under reduced pressure. Purification (Si gel, pet ether/EtOAc 19:1→
4:1) gave silyloxyamide 6 as a white solid (3.65 g, 90%): Rf 0.36 (pet
ether/Et2O 3:2); mp 32−34 °C; IR (neat/cm−1) 2956 m, 2931 m,
Scheme 8. Lithiation−Benzylation of cis-13a and of trans-13a
benzylated adduct 19-2Dc-2Bnt.16 These observations indicate
that there is a strong bias for electrophile trapping (apart from
protonation/deuteration) to occur trans to the C-3 lithium
alkoxide, regardless of whether a cis or trans proton is initially
removed at C-2. However, further conclusions concerning
configurational (in)stability of the intermediate organolithiums
and whether the electrophile trapping step occurs with
retention/inversion/SET pathways cannot be made from the
results obtained.
1
2858 w, 1628 s, 1415 m, 1131 m, 988 m, 836 m, 777 m; H NMR
(500 MHz, T = 363 K, toluene-d8) δ 4.21 (1H, m, CHO), 4.05 (2H,
dd, J = 9.1, 6.9 Hz, NCHH), 3.84 (2H, dd, J = 9.1, 4.1 Hz, NCHH),
1.08 (9H, s, C(O)C(CH3)3), 0.84 (9H, s, Si(CH3)2C(CH3)3), −0.07
(6H, s, Si(CH3)2C(CH3)3); 13C NMR (125 MHz, T = 363 K, toluene-
d8) δ 177.1 (CO), 62.7 (CHO), 61.4 (N−CH2), 38.9 (C(O)
C(CH3)3), 27.7 (C(CH3)3), 26.0 (C(CH3)3), 18.2 (Si(CH3)2C-
(CH3)3), −4.8 (Si(CH3)2C(CH3)3); LRMS (ESI+) 272.2 ([M + H]+,
100%); HRMS (ESI+) calcd for C14H30NO2Si 272.2040, found
272.2039.
CONCLUSIONS
1-(3-(tert-Butyldimethylsilyloxy)azetidin-1-yl)-2,2-dimethyl-
propane-1-thione (7). To a stirred solution of silyloxyamide 6 (3.65
g, 13.4 mmol) in pyridine (40 mL) at rt was added P2S5 (3.70 g, 16.6
mmol). The reaction mixture was heated to 75 °C for 2 h, then after
cooling to rt was concentrated under reduced pressure to ∼20 mL.
The partially concentrated reaction mixture was poured onto aq HCl
(1 M, 100 mL) and stirred vigorously for 10 min. The aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with aq HCl (1 M, 100 mL), H2O (100 mL), then brine
(100 mL), dried (Na2SO4), and concentrated to dryness under
reduced pressure. Purification (Si gel, pet ether/Et2O 1:0→9:1) gave
silyloxythioamide 7 as a white solid (3.60 g, 93%): Rf 0.57 (pet ether/
Et2O 9:1); mp 56−58 °C; IR (neat/cm−1) 2960 m, 2929 m, 2858 m,
1487 m, 1470 m, 1128 s, 841 s, 775 m; 1H NMR (400 MHz, CDCl3) δ
4.67 (1H, ddd, J = 10.6, 6.6, 2.0, Hz, NCHH), 4.58 (1H, tt, J = 6.6, 4.3
Hz, OCH), 4.48 (1H, ddd, J = 12.4, 6.6, 2.0 Hz, NCHH), 4.24 (1H,
ddd, J = 10.6, 4.3, 2.0 Hz, NCHH), 4.07 (1H, ddd, J = 12.4, 4.3, 2.0
Hz, NCHH), 1.34 (9H, s, C(S)C(CH3)3), 0.89 (9H, s, Si(CH3)2C-
(CH3)3), 0.07 (3H, s, Si(CH3)2C(CH3)3), 0.07 (3H, s, Si(CH3)2C-
(CH3)3); 13C NMR (100 MHz, CDCl3) δ 209.9 (CS), 66.2
(NCH2), 66.0 (NCH2), 60.3 (CHO), 43.2 (C(S)C(CH3)3), 29.7
(C(CH3)3), 25.6 (C(CH3)3), 17.9 (Si(CH3)2C(CH3)3), −5.0 (Si-
(CH3)2C(CH3)3), −5.1 (Si(CH3)2C(CH3)3); LRMS (FI+) 287.17
([M]+, 100%); HRMS (FI+) calcd for C14H29NOSSi 287.1739, found
287.1737.
■
In summary, readily available N-thiopivaloylazetidin-3-ol (12)
has been shown to undergo α-lithiation−electrophile trapping
with a range of electrophiles, providing 2-substituted 2-
hydroxyazetidines 13. Deuterium labeling studies indicate that
the α-deprotonation step is preferentially, but not exclusively,
trans-stereoselective. Nevertheless, high trans-diastereoselectiv-
ity is observed on incorporation of most electrophiles. A
notable exception is protonation, where the alkoxide may be
involved in directing the protonation cis to itself.17 Our work
indicates that the stereochemical outcome of the lithiated
azetidinol trapping depends on the electrophile used but is
independent of which α-proton (cis or trans to the hydroxyl
group) is initially removed. These studies demonstrate that
electrophile incorporation with high levels of diastereocontrol is
possible on a simple azetidine and suggest that further
opportunities exist for azetidine diversity generation using
this strategy.
EXPERIMENTAL SECTION
■
3-((tert-Butyldimethylsilyl)oxy)-1-(diphenylmethyl)azetidine
(5). To a stirred solution of N-benzhydrylazetidin-3-ol (4) (3.60 g,
15.0 mmol) and TBSCl (2.73 g, 18.1 mmol) in CH2Cl2 (30 mL) at rt
was added imidazole (1.23 g, 18.1 mmol). After 30 min, the reaction
mixture was filtered, and the filter cake washed with CH2Cl2 (10 mL).
The filtrate was concentrated to dryness under reduced pressure.
Purification (Si gel, pet ether/Et2O 1:0→9:1) gave silyl ether 518 as an
off-white solid (5.30 g, quant): Rf 0.83 (pet ether/EtOAc 3:2); mp
45−47 °C; IR (neat/cm−1) 2929 w, 2854 w, 2832 w, 1451 w, 1307 w,
1-(2-Azetinyl)-2,2-dimethylpropane-1-thione (9). To a stirred
solution of silyloxythioamide 7 (100 mg, 0.35 mmol) in THF (1 mL)
at −78 °C was added TMEDA (315 μL, 2.10 mmol). s-BuLi (777 μL,
1.35 M in cyclohexane/hexane (92/8), 1.05 mmol) was added
dropwise to the reaction mixture over 5 min, resulting in a
characteristic deep yellow color. After 30 min, MeOH (71 μL, 1.75
mmol) was added, and the reaction mixture was stirred for 10 min.
The cooling bath was removed, and the reaction mixture was stirred
for another 10 min, quenched with aq HCl (1 M, 5 mL), and extracted
with EtOAc (3 × 5 mL). The combined organic layers were washed
with H2O (5 mL) then brine (5 mL), dried (Na2SO4), and
concentrated to dryness under reduced pressure. Purification (Si gel,
pet ether/Et2O 9:1) gave azetine 9 as a yellow syrup (53 mg, 98%): Rf
0.30 (pet ether/Et2O 9:1); IR (neat/cm−1) 2968 w, 1456 s, 1364 w,
1
1204 m, 1204 m, 1182 m, 1160 w, 880 m, 836 m, 780 m, 703 m; H
NMR (400 MHz, CDCl3) δ 7.42−7.18 (10H, m, Ar), 4.47 (1H, quint,
J = 6.1 Hz, CHO), 4.37 (1H, s, CHPh2), 3.55 (1H, dd, J = 6.1, 2.0 Hz,
NCHH), 3.53 (1H, dd, J = 6.1, 2.0 Hz, NCHH), 2.84 (1H, dd, J = 6.3,
2.0 Hz, NCHH), 2.82 (1H, dd, J = 6.3, 2.0 Hz, NCHH), 0.87 (9H, s,
Si(CH3)2C(CH3)3), 0.03 (6H, s, Si(CH3)2C(CH3)3); 13C NMR (100
MHz, CDCl3) δ 142.3 (Ar), 128.4 (Ar), 127.4 (Ar), 127.0 (Ar), 78.6
(NCHPh2), 63.8 (NCH2), 61.8 (CHO), 25.8 (Si(CH3)2C(CH3)3),
18.0 (Si(CH3)2C(CH3)3), −5.0 (Si(CH3)2C(CH3)3); LRMS (ESI+)
354.20 ([M + H]+, 80%); HRMS (ESI+) calcd for C22H32NOSi
354.2248, found 354.2236.
1
1137 m, 935 m, 689 m; H NMR (400 MHz, CDCl3, 3:1 mixture of
rotamers) (major rotamer) δ 6.98 (1H, s, NCH), 6.04 (1H, s, NCH
CH), 4.67 (2H, s, NCH2), 1.38 (9H, s, C(CH3)3); (minor rotamer) δ
1101
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
7.35 (1H, s, NCH), 6.14 (1H, s, NCHCH), 4.86 (2H, s, NCH2),
1.42 (3H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) (major
rotamer) δ 203.8 (CS), 139.4 (NCH), 118.0 (NCHCH), 62.0
(NCH2), 43.0 (C(CH3)3), 30.3 (C(CH3)3); (minor rotamer) δ 203.8
(CS), 141.7 (NCH), 118.7 (NCHCH), 63.9 (NCH2), 43.0
(C(CH3)3), 31.0 (C(CH3)3); LRMS (FI+) 155.08 ([M]+,100%);
HRMS (FI+) calcd for C8H13NS 155.0769, found 155.0767.
3.9 Hz, CHOH), 4.42 (0.95H, dd, J = 13.1, 6.6 Hz, NCHcisHtrans), 4.28
(0.53H, ddd, J = 11.0, 3.9, 2.3 Hz, NCHcisHtrans), 4.04 (0.57H, ddd, J =
13.1, 3.9, 2.3 Hz, NCHcisHtrans), 3.75 (1H, br, OH), 1.29 (9H, s,
C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 209.9 (CS), 65.8
(NCH2), 65.5 (t, J = 23 Hz, NCHD), 65.4 (NCH2), 65.1 (t, J = 23 Hz,
NCHD), 59.6 (CHOH), 59.6 (t, J = 7 Hz, CHOH), 43.1 (C(CH3)3),
29.5 (C(CH3)3); LRMS (ESI+) 175.11 ([M + H]+, 85%); HRMS
(ESI+) calcd for C8H15DNOS 175.1010, found 175.1011.
1-(2,2-Dimethylpropanethioyl)azetidin-3-yl pivalate (11). A
suspension of azetidin-3-ol hydrochloride (10) (8.0 g, 73 mmol) in py
(80 mL) was heated to 50 °C for 5 min, then cooled to rt. DMAP (1.8
g, 15 mmol) and pivCl (22 mL, 179 mmol) were added, and after 1 h,
P2S5 (19 g, 85 mmol) and py (50 mL) were added and the reaction
mixture was heated to 75 °C. After 1 h, the reaction mixture was
cooled, concentrated to half volume under reduced pressure, diluted
with EtOAc (200 mL), and washed with aq HCl (2 M, 500 mL). The
organic layer was washed successively with H2O (200 mL) and brine
(200 mL), dried (Na2SO4), filtered, and concentrated to dryness under
reduced pressure. Purification (Si gel, heptane/EtOAc 1:0→4:1) gave
thioamide ester 11 as a colorless syrup which solidified on standing
(17.4 g, 93%): Rf 0.45 (heptane/EtOAc 4:1); mp 50−52 °C; IR (neat/
cm−1) 2965 w, 2872 w, 1781 s, 1484 m, 1465 m, 1321 m, 1139 s, 1004
w, 890 m; 1H NMR (400 MHz, CDCl3) δ 5.12 (1H, tt, J = 6.8, 4.2 Hz,
CHO), 4.80 (1H, ddd, J = 11.6, 6.8, 2.1 Hz, NCHH), 4.54 (1H, ddd, J
= 13.3, 6.8, 2.1 Hz, NCHH), 4.27 (1H, ddd, J = 11.6, 4.2, 2.1 Hz,
NCHH), 4.19 (1H, ddd, J = 13.3, 4.2, 2.1 Hz, NCHH), 1.33 (9H, s,
C(CH3)3), 1.21 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ
210.6 (CS), 178.0 (C(O)), 63.3 (NCH2), 62.0 (CHO), 61.9
(NCH2), 43.2 (C(S)C(CH3)3), 38.5 (C(O)C(CH3)3), 29.7 (C(S)C-
(CH3)3), 26.9 (C(O)C(CH3)3); LRMS (ESI+) 280.12 ([M + Na]+
100%); HRMS (ESI+) calcd for C13H23NNaO2S 280.1342, found
280.1339.
1-(3-Hydroxy-2-methyl-azetidin-1-yl)-2,2-dimethylpropane-
1-thione (13b). MeI (180 μL, 2.9 mmol) was used following General
Procedure A, but on half the scale. Purification (Si gel, pet ether/
EtOAc 4:1) gave methylated azetidinol 13b as a pale yellow syrup (39
mg, 72%, 69:31 trans/cis,13 dr determined by integration at δH 1.32
and 1.30): Rf 0.38 (pet ether/EtOAc 3:2); IR (neat/cm−1) 3364 br,
2965 w, 2929 w, 1461 s, 1434 s, 1364 w, 1135 m; LRMS (ESI+) 188.12
([M + H]+, 40%); HRMS (ESI+) calcd for C9H18NOS 188.1104,
found 188.1105. Major diastereoisomer: 1H NMR (400 MHz,
CDCl3) δ 4.74 (1H, ddd, J = 11.4, 6.1, 2.4 Hz, NCHcisHtrans), 4.59
(1H, qdd, J = 6.6, 3.0, 2.4 Hz, NCH), 4.23 (1H, dd, J = 11.4, 3.0 Hz,
NCHcisHtrans), 4.14 (1H, dt, J = 6.1, 3.0 Hz, CHOH), 3.18 (1H, br,
OH), 1.56 (3H, d, J = 6.6 Hz, CH3), 1.32 (9H, s, C(CH3)3); 13C NMR
(100 MHz, CDCl3) δ 211.2 (CS), 74.0 (NCH), 67.9 (CHOH),
64.6 (NCH2), 43.5 (C(CH3)3), 29.6 (C(CH3)3), 16.0 (CHCH3).
Minor diastereoisomer: 1H NMR (400 MHz, CDCl3) δ 4.97 (1H, qd,
J = 6.6, 6.6 Hz, NCH), 4.74 (1H, m, CHOH), 4.67 (1H, ddd, J = 10.9,
7.3, 1.0 Hz, NCHcisHtrans), 4.33 (1H, ddd, J = 10.9, 5.3, 2.0 Hz,
NCHcisHtrans), 2.82 (1H, br, OH), 1.55 (3H, d, J = 6.6 Hz, CH3), 1.30
(9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 209.3 (CS),
70.6 (NCH), 64.6 (NCH2), 61.7 (CHOH), 43.3 (C(CH3)3), 29.5
(C(CH3)3), 10.3 (CHCH3).
1-(3-Hydroxy-2-butyl-azetidin-1-yl)-2,2-dimethylpropane-1-
thione (13c). BuI (986 μL, 8.66 mmol) was used following General
Procedure A, but on five times the scale. Purification (Si gel, pet ether/
EtOAc 19:1→4:1) gave butylated azetidinol 13c as a pale yellow syrup
(451 mg, 68%): Rf 0.64 (pet ether/EtOAc 3:2); IR (neat/cm−1) 3372
br, 2958 w, 2923 m, 2854 m, 1461 s, 1435 m, 1363 w, 1134 m, 737 m;
1H NMR (400 MHz, CDCl3) δ 4.68 (1H, ddd, J = 12.6, 7.5, 1.8 Hz,
NCHcisHtrans), 4.52 (1H, m, NCH), 4.24−4.19 (2H, m, CHOH and
NCHcisHtrans), 2.90 (1H, br s, OH), 2.41−2.33 (1H, m,
CHHCH2CH2CH3), 1.67 (1H, ddt, J = 14.7, 7.3, 7.1 Hz,
CHHCH2CH2CH3), 1.38−1.24 (4H, m, CH2CH2CH2CH3), 1.33
(9H, s, C(CH3)3), 0.91 (3H, t, J = 7.1 Hz, CH2CH2CH2CH3); 13C
NMR (100 MHz, CDCl3) δ 211.3 (CS), 78.0 (NCH), 66.6
(CHOH), 64.9 (NCH2), 43.5 (C(CH3)3), 29.7 (C(CH3)3), 28.3
(CH2 CH2 CH2 CH3 ), 25. 9 (CH2 CH2 CH2 CH3 ), 22. 5
(CH2CH2CH2CH3), 14.0 (CH2CH2CH2CH3); LRMS (ESI+) 230.17
([M + H]+, 55%); HRMS (ESI+) calcd for C12H24NOS 230.1573,
found 230.1569.
1-(3-Hydroxyazetidin-1-yl)-2,2-dimethylpropane-1-thione
(12). To a solution of thioamide ester 11 (15.0 g, 58 mmol) in MeOH
(20 mL) was added NaOMe (26 mL, 25 wt % in MeOH, 117 mmol).
After 1 h, the reaction mixture was concentrated to dryness under
reduced pressure and the crude reaction mixture purified (Si gel,
heptane/EtOAc 1:0→2:3) to give azetidinol 12 as a colorless syrup
which solidified on standing (9.6 g, 95%): Rf 0.27 (pet ether/EtOAc
3:2); mp 54−56 °C; IR (neat/cm−1) 3363 br, 2968 w, 1471 s, 1447 s,
1
1137 m, 1007 m, 730 s; H NMR (400 MHz, CDCl3) δ 4.69 (1H,
ddd, J = 11.0, 6.6, 2.0 Hz, NCHH), 4.63 (1H, tt, J = 6.6, 3.9 Hz,
CHOH), 4.47 (1H, ddd, J = 13.1, 6.6, 2.3 Hz, NCHH), 4.31 (1H, ddd,
J = 11.0, 3.9, 2.3 Hz, NCHH), 4.09 (1H, ddd, J = 13.1, 3.9, 2.0 Hz,
NCHH), 3.26 (1H, br, OH), 1.32 (9H, s, C(CH3)3); 13C NMR (100
MHz, CDCl3) δ 210.0 (C(S)C(CH3)3), 65.8 (NCH2), 65.5 (NCH2),
59.9 (CHOH), 43.2 (C(CH3)3), 29.6 (C(CH3)3); LRMS (FI+) 173.09
([M]+, 100%); HRMS (FI+) calcd for C8H15NOS 173.0874, found
173.0879.
1-(3-Hydroxy-2-benzyl-azetidin-1-yl)-2,2-dimethylpropane-
1-thione (13d). BnBr (1.03 mL, 8.66 mmol) was used following
General Procedure A, but on five times the scale. Purification (Si gel,
heptane/EtOAc 9:1→8:2) gave benzylated azetidinol 13d as a pale
yellow syrup (559 mg, 74%): Rf 0.64 (pet ether/EtOAc 3:2); IR (neat/
cm−1) 3365 br, 2966 w, 2930 w, 1455 s, 1432 s, 1125 m, 995 m, 702 s;
1H NMR (400 MHz, CDCl3) δ 7.32−7.22 (5H, m, Ar), 4.83 (1H,
dddd, J = 7.8, 3.3, 3.0, 2.0 Hz, NCH), 4.28 (1H, dt, J = 6.1, 3.0 Hz,
CHOH), 4.22 (1H, ddd, J = 11.1, 6.1, 2.0 Hz, NCHcisHtrans), 4.10 (1H,
dd, J = 11.1, 3.0 Hz, NCHcisHtrans), 3.46 (1H, dd, J = 13.9, 3.3 Hz,
CHHPh), 3.36 (1H, dd, J = 13.9, 7.8 Hz, CHHPh), 1.86 (1H, br,
OH), 1.33 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 211.6
(CS), 136.4 (Ar), 129.7 (Ar), 128.4 (Ar), 126.7 (Ar), 77.5 (NCH),
65.2 (CHOH), 64.7 (NCH2), 43.6 (C(CH3)3), 33.8 (CH2Ph), 29.6
(C(CH3)3); LRMS (ESI+) 286.14 ([M + Na]+, 100%); HRMS (ESI+)
calcd for C15H22NOS 264.1417, found 264.1414.
General Procedure A: α-Deprotonation/Electrophile Trap-
ping of Azetidinol 12. To a stirred solution of azetidinol 12 (100
mg, 0.58 mmol) in THF (2 mL) at −78 °C under argon was added
TMEDA (519 μL, 3.46 mmol). s-BuLi (1.24 mL 1.40 M in
cyclohexane/hexane (92:8), 1.73 mmol) was added dropwise to the
reaction mixture over 5 min, resulting in a characteristic deep yellow
color. After 30 min, the electrophile was added and the reaction
mixture stirred for 30 min. The cooling bath was removed, and the
reaction mixture was stirred for another 30 min, quenched with aq
HCl (1 M, 5 mL), and extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with H2O (5 mL) then brine (5
mL), dried (Na2SO4), and concentrated to dryness under reduced
pressure.
1-(2-Deutero-3-(hydroxy)-azetidin-1-yl)-2,2-dimethylpro-
pane-1-thione (cis-13a). CD3OD (70 μL, 1.7 mmol) was used
following General Procedure A. Purification (Si gel, pet ether/EtOAc
3:2) gave the deuterated azetidinol 13a as a colorless syrup which
solidified on standing (92 mg, 91%, 100% D, 90:10 cis/trans,13 dr
determined by integration at δH 4.67 + 4.42 and 4.28 + 4.04): Rf 0.27
(pet ether/EtOAc 3:2); mp 54−56 °C; IR (neat/cm−1) 3361 br, 2966
1-(2-Allyl-3-hydroxyazetidin-1-yl)-2,2-dimethylpropane-1-
thione (13e). Allyl bromide (75 μL, 0.87 mmol) was used following
General Procedure A, but on half the scale. Purification (Si gel, pet
ether/EtOAc 9:1→1:1) gave allylated azetidinol 13e as a yellow syrup
(37 mg, 60%): Rf 0.23 (pet ether/EtOAc 4:1); IR (neat/cm−1) 3369
br, 2966 w, 2872 w, 1460 s, 1395 w, 1135 m, 1001 s, 918 m, 796 w,
1
m, 1467 s, 1395 w, 1134 s, 1006 m; H NMR (400 MHz, CDCl3) δ
4.67 (0.95H, dd, J = 11.0, 6.6 Hz, NCHcisHtrans), 4.59 (1H, td, J = 6.6,
1102
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
1
732 w; H NMR (400 MHz, CDCl3) δ 5.74 (1H, ddt, J = 17.2, 10.1,
1-(2-((4-Chlorophenyl)(hydroxy)methyl)-3-hydroxyazetidin-
1-yl)-2,2-dimethylpropane-1-thione (13h). p-Chlorobenzalde-
hyde (122 mg, 0.87 mmol) was used following General Procedure
A, but on half the scale. Purification (Si gel, pet ether/EtOAc 9:1→
4:1) gave both aldehyde azetidinol diastereoisomers: epi-13h as a pale
yellow syrup (31 mg, 34%) and 13h as a pale yellow syrup (43 mg,
47%). Minor diastereoisomer (epi-13h): Rf 0.54 (pet ether/EtOAc
3:2); IR (neat/cm−1) 3254 br, 2969 w, 1470 s, 1244 w, 1127 m, 1090
7.1 Hz, CH2CHCHcisHtrans), 5.18 (1H, d J = 17.2 Hz, CH2CH
CHcisHtrans), 5.16 (1H, d, J = 10.1 Hz, CH2CHCHcisHtrans), 4.65−
4.61 (2H, m, NCH and NCHcisHtrans), 4.27 (1H, dt, J = 6.5, 3.0 Hz,
CHOH), 4.22 (1H, dd, J = 11.0, 3.2 Hz, NCHcisHtrans), 2.92 (1H, ddd,
J = 14.5, 7.5, 2.5 Hz, CHHCHCH2), 2.76 (1H, ddd, J = 14.5, 7.5,
7.0 Hz, CHHCHCH2), 2.66 (1H, br, OH), 1.33 (9H, s, C(CH3)3);
13C NMR (100 MHz, CDCl3) δ 211.6 (CS), 131.9 (CHCH2),
1
m, 1007 m, 911 m, 854 w, 730 s; H NMR (400 MHz, CDCl3) δ
119.0 (CHCH2), 76.4 (NCH), 65.4 (CHOH), 64.9 (NCH2), 43.6
(C(CH3)3), 32.6 (CH2CHCH2), 29.7 (C(CH3)3); LRMS (ESI+)
214.13 ([M + H]+, 85%); HRMS (ESI+) calcd for C11H19NNaOS
236.1080, found 236.1082.
7.37−7.32 (4H, m, Ar), 5.65 (1H, s, p-ClPhCH(OH)), 4.91 (1H, dt, J
= 3.2, 2.0 Hz, NCH), 4.35 (1H, dt, J = 6.5, 3.2 Hz, CHOH), 4.26 (1H,
ddd, J = 11.0, 6.5, 2.0 Hz, NCHcisHtrans), 4.09 (1H, dd, J = 11.0, 3.2 Hz,
NCHcisHTrans), 1.32 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3)
δ 212.9 (CS), 137.7 (Ar), 133.6 (Ar), 128.6 (Ar), 127.8 (Ar), 82.2
(NCH), 70.5 (p-ClPhCH(OH)), 64.9 (NCH2), 62.3 (CHOH), 43.7
(C(CH3)3), 29.6 (C(CH3)3); LRMS (ESI+) 336.10 ([M + Na]+,
100%); HRMS (ESI+) calcd for C15H20ClNNaO2S 336.0795, found
336.0800. Major diastereoisomer (13h): Rf 0.37 (pet ether/EtOAc
3:2); IR (neat/cm−1) 3363 br, 2972 w, 1459 s, 1365 w, 1131 m, 1091
1-(3-Hydroxy-2-(tributylstannyl)azetidin-1-yl)-2,2-dimethyl-
propane-1-thione (13f). Bu3SnCl (2.3 mL, 8.48 mmol) was used
following General Procedure A, but on five times the scale. Purification
(Si gel, pet ether/EtOAc 39:1→4:1) gave stannylated azetidinol 13f as
a colorless syrup (1.1 g, 82%): Rf 0.33 (pet ether/EtOAc 9:1); IR
(neat/cm−1) 3361 br, 2923 w, 2854 w, 1465 s, 1364 w, 1124 w, 910 m,
732 s; 1H NMR (400 MHz, CDCl3) δ 4.72 (1H, ddd, J = 11.6, 5.8, 2.5
Hz, NCHcisHtrans), 4.58 (1H, ddt, J = 6.3, 5.8, 3.3 Hz, CHOH), 4.40−
4.38 (1H, m, NCH), 4.36 (1H, dd, J = 11.6, 3.3. Hz, NCHcisHtrans),
2.30 (1H d, J = 6.3 Hz, CHOH), 1.65−1.42 (6H, m,
CH2CH2CH2CH3), 1.35 (9H, s, C(CH3)3), 1.36−1.26 (6H, m,
CH2CH2CH2CH3), 0.97−0.92 (6H, m, CH2CH2CH2CH3), 0.90 (9H,
t, J = 7.3 Hz, CH2CH2CH2CH3); 13C NMR (100 MHz, CDCl3) δ
202.5 (CS), 71.6 (NCH), 66.0 (NCH2), 64.9 (CHOH), 42.7
(C(CH3)3), 30.0 (CH2CH2CH2CH3), 29.0 (CH2CH2CH2CH3), 27.5
(C(CH3)3), 13.7 (CH2CH2CH2CH3), 11.5 (CH2CH2CH2CH3);
LRMS (ESI+) 464.20 ([M + H]+, 68%); HRMS (ESI+) calcd for
C20H41NOSSn 464.2005, found 464.1991.
1-(3-Hydroxy-2-(hydroxy(phenyl)methyl)azetidin-1-yl)-2,2-
dimethylpropane-1-thione (13g). Benzaldehyde (352 μL, 3.46
mmol) was used following General Procedure A, but on twice the
scale. By TLC, both diastereoisomers appeared to have the same Rf,
with residual starting azetidinol 12 also falling at the same Rf.
Purification (Si gel, heptane/EtOAc 4:1) was achieved using UV trace
of eluting products. By TLC analysis of fractions, no difference could
be determined between the products. However, UV analysis of the
product-containing fractions showed two distinct products and traces
of starting material, collected individually, to give both benzaldehyde
azetidinol diastereoisomers: epi-13g as a clear crystalline solid (60 mg,
19%) and 13g as a pale yellow syrup (171 mg, 53%). A crystal of epi-
13g for X-ray crystallographic analysis was obtained by slow
evaporation from CDCl3. Minor diastereoisomer (epi-13g): Rf 0.45
(pet ether/EtOAc 3:2); mp 145−148 °C; IR (neat/cm−1) 3444 w,
2964 w, 2928 w, 1486 s, 1362 w, 1180 w, 1106 m, 1008 m, 703 m; 1H
NMR (400 MHz, CDCl3) δ 7.45−7.28 (5H, m, Ar), 5.76 (1H, d, J =
1.8 Hz, PhCH(OH)), 4.95 (1H, ddd, J = 3.3, 1.9, 1.8 Hz, NCH), 4.44
(1H, dt, J = 6.6, 3.3 Hz, CHOH), 4.29 (1H, ddd, J = 11.0, 6.6, 1.8 Hz,
NCHcisHtrans), 4.09 (1H, dd, J = 11.0, 3.3 Hz, NCHcisHtrans), 3.48 (1H,
s, OH), 1.34 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 212.8
(CS), 139.3 (Ar), 128.5 Ar), 127.8 (Ar), 126.3 (Ar), 82.5 (NCH),
70.8 (PhCH(OH)), 64.9 (NCH2), 62.4 (CHOH), 43.7 (C(CH3)3),
29.7 (C(CH3)3); LRMS (ESI+) 302.10 ([M + Na]+ 85%); HRMS
(ESI+) calcd for C15H21NNaO2S 302.1185, found 302.1181; for X-ray
data, see Supporting Information. Major diastereoisomer (13g): Rf
0.45 (pet ether/EtOAc 3:2); IR (neat/cm−1) 3354 br, 2966 w, 2924
1
m, 906 s, 791 m, 727 s; H NMR (400 MHz, CDCl3) δ 7.33 (4H, s,
Ar), 5.47 (1H, d, J = 6.8 Hz, p-ClPhCH(OH), 4.87 (1H, dd, J = 6.8,
1.8 Hz, NCH), 4.14−4.06 (3H, m, CHOH and NCHcisHtrans), 1.30
(9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 213.5 (CS),
137.6 (Ar), 134.0 (Ar), 128.6 (Ar), 128.3 (Ar), 81.5 (NCH), 71.0 (p-
ClPhCH(OH)), 64.4 (NCH2), 62.4 (CHOH), 43.8 (C(CH3)3), 29.7
(C(CH3)3); LRMS (ESI+) 336.10 ([M + Na]+, 82%); HRMS (ESI+)
calcd for C15H20ClNNaO2S 336.0795, found 336.0800.
Methyl 1-(2,2-dimethylpropanethioyl)-3-[(methoxy-
carbonyl)oxy]azetidine-2-carboxylate (13i). Methyl cyanofor-
mate (276 μL, 3.46 mmol) was used following General Procedure
A. Purification (Si gel, pet ether/EtOAc 9:1→4:1) gave azetidine
diester 13i as a pale yellow syrup which solidified on standing (115
mg, 68% 93:7 trans/cis,13 dr determined by integration of δH 5.01 and
4.56): Rf 0.70 (pet ether/EtOAc 3:2); mp 85−87 °C; IR (neat/cm−1)
2960 w, 1739 s, 1430 s, 1295 m, 1272 m, 1199 m, 1158 m, 992 m, 931
1
m, 790 m; H NMR (400 MHz, CDCl3) δ 5.01 (1H, dt, J = 6.7, 3.4
Hz, CHO), 4.96 (1H, m, NCH), 4.89 (1H, ddd, J = 11.1, 6.7, 1.9 Hz,
NCHcisHtrans), 4.44 (1H, dd, J = 11.1, 3.4 Hz, NCHcisHtrans), 3.83 (3H,
s, OCH3), 3.78 (3H, s, OCH3), 1.34 (9H, s, C(CH3)3); 13C NMR
(100 MHz, CDCl3) δ 212.3 (CS), 167.0 (NCHC(O)), 154.3
(CHOC(O)), 72.0, (NCH), 66.5 (CHO), 61.9 (NCH2), 55.5
(OCH3), 52.6 (OCH3), 43.2 (C(CH3)3), 29.5 (C(CH3)3); LRMS
(ESI+) 312.1 ([M + Na]+, 100%); HRMS (ESI+) calcd for
C12H19NNaO5S 312.0876, found 312.0868.
2-Benzylazetidin-3-ol hydrochloride (14). To a solution of
benzylated azetidinol 13d (69 mg, 0.26 mmol) in THF at 0 °C were
added TMEDA (196 μL, 1.31 mmol) and MeLi (873 μL, 1.50 M in
Et2O, 1.31 mmol). After 4 h, the reaction mixture was quenched with
MeOH (few drops) and concentrated to dryness under reduced
pressure. The crude reaction mixture was dissolved in a minimum of
MeOH and loaded onto a SCX-2 ion exchange column. The column
was washed through with CH2Cl2 (20 mL) and collected. The amine
product was released with NH3 (10 mL, 7 M in MeOH) followed by
CH2Cl2 (20 mL) and collected. The basic fractions were concentrated
to dryness under reduced pressure, redissolved in MeOH (2 mL), and
treated with HCl (2 M in Et2O, 2 mL), followed by concentrating to
dryness under reduced pressure to isolate the crude hydrochloride salt.
The crude product was suspended in acetone (2 mL) and decanted to
remove organic impurities, giving azetidine hydrochloride salt 14 as a
pale yellow solid (48 mg, 92%): mp 127−131 °C; IR (neat/cm−1)
3306 br, 2956 w, 2938 w, 2458 m, 2184 br, 1454 w, 1173 m, 1117 m,
1031 w, 977 w, 747 m, 702 s; 1H NMR (400 MHz, CD3OD) δ 7.38−
7.25 (5H, m, Ar), 4.53 (1H, q, J = 7.4 Hz, CHOH), 4.40 (1H, ddd, J =
8.9, 7.4, 6.8 Hz, NCH), 4.07 (1H, dd, J = 10.5, 7.4 Hz, NCHH), 3.74
(1H, dd, J = 10.5, 7.4 Hz, NCHH), 3.24 (1H, dd, J = 14.4, 6.8 Hz,
CHHPh), 3.17 (1H, dd, J = 14.4 8.9 Hz, CHHPh); 13C NMR (100
MHz, CD3OD) δ 136.5 (Ar), 130.2 (Ar), 130.1 (Ar), 128.5 (Ar), 73.0
(NCH), 68.4 (CHOH), 53.1, (NCH2), 38.1 (CH2Ph); LRMS (ESI+)
164.09 ([M − HCl + H)]+, 40%); HRMS (ESI+) calcd for C10H14NO
164.1070, found 164.1070.
1
wm 1455 s, 1433 m, 1364 w, 1244 w, 1130 w, 1041 w, 704 m; H
NMR (400 MHz, DMSO-d6) δ 7.35−7.26 (5H, m, Ar), 5.80 (1H, d, J
= 5.8 Hz, CHOH), 5.73 (1H, d, J = 4.3 Hz, PhCH(OH)), 5.72 (1H,
dd, J = 4.9, 4.3 Hz, PhCH(OH), 4.62 (1H, ddd, J = 4.9, 2.6, 2.0 Hz,
NCH), 4.03 (1H, ddt, J = 6.3, 5.8, 2.6 Hz, CHOH), 3.84 (1H, dd, J =
11.3, 2.6 Hz, NCHcisHtrans), 3.36 (1H, ddd, J = 11.3, 6.3, 2.0 Hz,
NCHcisHtrans), 1.15 (9H, s, (C(CH3)3); 13C NMR (100 MHz, DMSO-
d6) δ 209.6 (CS), 140.8 (Ar), 127.5 (Ar), 127.1 (Ar), 126.3 (Ar),
80.0 (NCH), 65.5 (NCH2), 65.2 (PhCH(OH), 60.8 (CHOH), 42.7
(C(CH3)3), 29.2 (C(CH3)3); LRMS (ESI+) 302.10 ([M + Na)+]
70%); HRMS (ESI+) calcd for C15H21NNaO2S 302.1185, found
302.1186.
1103
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
1-(2-Benzyl-3-hydroxyazetidin-1-yl)-2,2-dimethylpropan-1-
one (15). To an ice-cold stirred solution of AcOH (3 mL) and H2O2
(4 mL, 35% in H2O) was added benzylated azetidinol 13d (59 mg,
0.24 mmol) in CH2Cl2 (1 mL). After 4 h at 0 °C, the reaction mixture
was poured onto saturated aq NaHCO3 (30 mL) and extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with
saturated aq NaHCO3 (10 mL), H2O (10 mL), then brine (10 mL),
dried (Na2SO4), filtered, and concentrated to dryness under reduced
pressure to give pivalamide 15 as a colorless syrup (45 mg, 81%): Rf
0.23 (pet ether/EtOAc 3:2); IR (neat/cm−1) 2359 br, 2963 w, 1595 s,
1412 m, 1364 w, 1232 w, 1129 w, 736 w, 702 m; 1H NMR (400 MHz,
CDCl3) δ 7.32−7.20 (5H, m, Ar), 4.44 (1H, ddd, J = 7.8, 3.7, 3.3 Hz,
NCH), 4.18 (1H, dt, J = 6.8, 3.7 Hz, CHOH), 4.10 (1H ddd, J = 9.3,
6.8, 1.0 Hz, NCHcisHtrans), 3.95 (1H, dd, J = 9.3, 3.7 Hz, NCHcisHtrans),
3.20, (1H, dd, J = 13.9, 3.3 Hz, CHHPh), 3.02 (1H, dd, J = 13.9, 7.8
Hz, CHHPh), 1.15 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3)
δ 179.1 (C(O)), 136.7 (Ar), 129.6 (Ar), 128.3 (Ar), 126.4 (Ar), 71.7
(NCH), 65.7 (CHOH), 60.1 (NCH2), 38.7 (C(CH3)3), 36.7
(CH2Ph), 27.0 (C(CH3)3); LRMS (ESI+) 270.12 ([M + Na]+,
78%); HRMS (ESI+) calcd for C15H21NNaO2 270.1465, found
270.1466.
azetidin-3-ol trans-13a as a colorless syrup which solidified on standing
(186 mg, 66%, 100% D, 88:12 trans/cis,13 dr determined by integration
of δH 4.70 + 4.48 and 4.32 + 4.10): Rf 0.27 (pet ether/EtOAc 3:2); mp
54−56 °C; IR (neat/cm−1) 3359 br, 2968 w, 1469 s, 1364 w, 1255 w,
1
1138, 1005 m, 951 w, 730 s; H NMR (400 MHz, CDCl3) δ 4.70
(0.56 H, ddd, J = 11.1, 6.6, 1.5 Hz, NCHcisHtrans), 4.65 (1H, dt, J = 6.6,
3.9 Hz, CHOH), 4.48 (0.56H, ddd, J = 12.9, 6.6, 1.5 Hz,
NCHcisHtrans), 4.32 (0.94H, dd, J = 11.1, 3.9 Hz, NCHcisHtrans), 4.10
(0.94H, dd, J = 12.9, 3.9 Hz, NCHcisHtrans), 3.14 (1H, br, OH), 1.33
(9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 210.0 (CS),
65.8 (NCH2), 65.5 (T, J = 23 Hz, NCHD), 65.5 (NCH2), 65.2 (T, J =
23 Hz, NCHD), 59.8 (CHOH), 59.8 (t, J = 10 Hz, CHOH), 43.2
(C(CH3)3), 29.6 (C(CH3)3); LRMS (ESI+) 175.2 ([M + H]+, 100%);
HRMS (ESI+) calcd for C8H14DNNaOS 197.0829, found 197.0825.
Lithiation−Deuteration of cis-13a: 1-(2,4-Dideutero-3-
hydroxyazetidin-1-yl)-2,2-dimethylpropane-1-thione (18-
2,4Dcc) and 1-(2,2-Dideutero-3-hydroxyazetidin-1-yl)-2,2-
dimethylpropane-1-thione (18-2,2D). To a stirred solution of
azetidinol cis-13a (50 mg, 0.29 mmol) in THF (1 mL) at −78 °C
under argon was added TMEDA (261 μL, 1.74 mmol). s-BuLi (614
μL, 1.40 M in cyclohexane/hexane (92/8), 0.86 mmol) was added
very slowly dropwise to the reaction mixture over 5 min. After 30 min,
CD3OD (52 μL, 1.45 mmol) was added, and the reaction mixture was
stirred for 10 min. The cold bath was removed, and the reaction
mixture was stirred for another 10 min, quenched with aq HCl (1 M, 5
mL), and extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with H2O (5 mL) then brine (5 mL), dried
(Na2SO4), and concentrated to dryness under reduced pressure to give
azetidinol 18 as a pale yellow syrup (50 mg, 95%, 99% 2D, 62:38
2,4-:2,2-,13 dr determined by integration of δH 4.66 + 4.42 and 4.29 +
4.04 in comparison to cis-13a):13 IR (neat/cm−1) 3365 br, 2967 w,
2932 w, 1465 s, 1364 w, 1134 s, 1007 m, 913 m, 730 s; 1H NMR (400
MHz, CDCl3) δ 4.66 (0.76H, dd, J = 11.1, 6.6 Hz, NCHcisHtrans), 4.59
(1H, t, J = 6.6 Hz, CHOH), 4.42 (0.76H, dd, J = 12.9, 6.6 Hz,
NCHcisHtrans), 4.29 (0.23H, dd, J = 11.1, 3.5 Hz, NCHcisHtrans), 4.04
(0.26H, dd, J = 12.9, 3.5 Hz, NCHcisHtrans), 3.76 (1H, br s, OH), 1.29
(9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 209.9 (CS),
65.8 (NCH2), 65.5 (T, J = 23 Hz, NCHD), 65.4 (NCH2), 65.1 (T, J =
23 Hz, NCHD), 59.5 (CHOH), 59.5 (t, J = 8 Hz, CHOH), 43.1
(C(CH3)3), 29.5 (C(CH3)3); LRMS (ESI+) 198.08 ([M + Na]+,
93%); HRMS (FI+) calcd for C8H13D2NOS 175.1000, found
175.1001.
Lithiation−Deuteration of trans-13a: 1-(2,4-Dideutero-3-
hydroxyazetidin-1-yl)-2,2-dimethylpropane-1-thione (18-
2,4Dtc) and 1-(2,2-Dideutero-3-hydroxyazetidin-1-yl)-2,2-
dimethylpropane-1-thione (18-2,2D). To a stirred solution of
azetidinol trans-13a (50 mg, 0.29 mmol) in THF (1 mL) at −78 °C
under argon was added TMEDA (261 μL, 1.74 mmol). s-BuLi (614
μL, 1.40 M in cyclohexane/hexane (92/8), 0.86 mmol) was added
very slowly dropwise to the reaction mixture over 5 min. After 30 min,
CD3OD (52 μL, 1.45 mmol) was added and the reaction mixture
stirred for 10 min. The cold bath was removed, and the reaction
mixture was stirred for another 10 min, quenched with aq HCl (1 M, 5
mL), and extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with H2O (5 mL) then brine (5 mL), dried
(Na2SO4), and concentrated to dryness under reduced pressure to give
azetidinol 18 as a pale yellow syrup (45 mg, 90%, 91% 2D, 82:18
2,4-:2,2-,13 dr determined by integration of δH 4.69 + 4.46 and 4.31 +
4.08 in comparison to trans-13a):13 IR (neat/cm−1) 2251 br, 2968 w,
1467 s, 1364 w, 1139 m, 1112 m, 1007 w, 912 w, 730 s; 1H NMR (400
MHz, CDCl3) δ 4.69 (0.47H, dd, J = 11.1, 6.6 Hz, NCHcisHtrans),
4.64−4.60 (1H, m, CHOH), 4.46 (0.49H, dd, J = 12.9, 6.6 Hz,
NCHcisHtrans), 4.31 (0.56H, dd, 11.1, 3.9 Hz, NCHcisHtrans), 4.08
(0.57H, dd, J = 12.9, 3.9 Hz, NCHcisHtrans), 3.46 (1H, br, OH), 1.32
(9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 210.0 (CS),
65.8 (NCH2), 65.5 (T, J = 23 Hz, NCHD), 65.5 (T, J = 23 Hz,
NCHD), 65.5 (NCH2), 65.2 (T, J = 23 Hz, NCHD), 65.1 (T, J = 23
Hz, NCHD), 59.7 (CHOH), 59.7 (t, J = 8 Hz, CHOH), 59.7 (t, J = 8
Hz, CHOH), 43.2 (C(CH3)3), 29.6 (C(CH3)3); LRMS (ESI+) 198.1
2-Deutero-1-(2,2-dimethylpropanethioyl)-azetidin-3-yl
trifluoromethanesulfonate (16). To a stirred solution of deuterated
adduct cis-13a (417 mg, 2.39 mmol) in CH2Cl2 (10 mL) at −78 °C
was added DIPEA (538 μL, 3.11 mmol) followed by dropwise addition
of Tf2O (482 μL, 2.87 mmol). After 30 min, MeOH (1 mL) was
added and the reaction mixture concentrated to dryness under reduced
pressure. Purification (Si gel, pet ether/EtOAc 19:5→9:1) gave triflate
16 as a pale yellow syrup which solidified on standing (601 mg, 82%):
Rf 0.27 (pet ether/EtOAc 3:2); mp 55−57 °C; IR (neat/cm−1) 2981
w, 2907 w, 1470 m, 1441 m, 1353 s, 1218 m, 1171 m, 986 m, 914 m,
1
849 m; H NMR (400 MHz, CDCl3) δ 5.49 (1H, td, J = 6.4, 3.8 Hz,
CHO), 4.91 (0.95 H, dd, J = 11.9, 6.9 Hz, NCHcisHtrans), 4.73−4.62
(1.51H, m, NCHcisHtrans), 4.46 (0.58H, ddd, J = 13.8, 3.8, 2.1 Hz,
NCHcisHtrans), 1.36 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3)
δ 211.7 (CS), 118.3 (Q, J = 320 Hz, CF3), 72.9 (CHO), 72.9 (t, J =
5 Hz, CHO), 62.7 (NCH2), 62.4 (T, J = 23 Hz, NCHD), 61.7
(NCH2), 61.4 (T, J = 23 Hz, NCHD), 43.6 (C(CH3)3), 29.7
(C(CH3)3); δF (377 MHz, CDCl3) −74.7 (CF3); LRMS (FI+) 306.04
([M]+, 100%); HRMS (FI+) calcd for C9H13DF3NO3S2 306.0430,
found 306.0432.
2-Deutero-1-(2,2-dimethylpropanethioyl)azetidin-3-yl ace-
tate (17). To a stirred solution of triflate 16 (586 mg, 1.91 mmol)
in DMF (10 mL) was added NaOAc (5.3 g, 65 mmol), and the
reaction mixture was heated to 70 °C. After 16 h, the reaction mixture
was cooled to rt, washed with H2O (10 mL), and extracted with
EtOAc (3 × 10 mL), and the combined organic layers were dried
(Na2SO4), filtered, and concentrated to dryness under reduced
pressure. Purification (Si gel, pet ether/EtOAc 9:1→4:1) gave acetate
17 as a colorless syrup (355 mg, 86%): Rf 0.41 (pet ether/EtOAc 4:1);
IR (neat/cm−1) 2968 w, 1741 s, 1462 m, 1437 m, 1364 w, 1225 s,
1143 m, 731 m; 1H NMR (400 MHz, CDCl3) δ 5.15 (1H, dt, J = 6.8,
3.8 Hz, CHO), 4.81 (0.59H, ddd, J = 11.4, 6.8, 1.3 Hz, NCHcisHtrans),
4.55 (0.60H, ddd, J = 13.4, 6.8, 1.3 Hz, NCHcisHtrans), 4.35 (0.93H, dd,
J = 11.4, 3.8 Hz, NCHcisHtrans), 4.23 (0.91H, dd, J = 13.4, 3.8 Hz,
NCHcisHtrans), 2.12 (3H, s, OC(O)CH3), 1.34 (9H, s, C(CH3)3); 13C
NMR (100 MHz, CDCl3) δ 210.6 (CS), 170.4 (C(O)), 63.3
(NCH2), 63.0 (T, J = 23 Hz, NCHD), 62.0 (CHO), 62.0 (t, J = 9 Hz,
CHO), 61.8 (NCH2), 61.6 (T, J = 23 Hz, NCHD), 43.3 (C(CH3)3),
29.7 (C(CH3)3), 20.6 (CH3); LRMS (ESI+) 217.1 ([M + H]+, 100%);
HRMS (ESI+) calcd for C10H16DNNaO2S 239.0935, found 239.0928.
1-(2-Deutero-3-(hydroxy)-azetidin-1-yl)-2,2-dimethyl-
propane-1-thione (trans-13a). To a stirred solution of acetate 17
(350 mg, 1.62 mmol) in MeOH (10 mL) was added NaOMe (15
drops, 30% in MeOH). After 10 min, the reaction mixture was
concentrated to dryness under reduced pressure. The residue was
washed with aq HCl (1 M, 10 mL) and extracted with EtOAc (20
mL), and the organic layer was washed with H2O (10 mL), then brine
(10 mL), dried (Na2SO4), filtered, and concentrated to dryness under
reduced pressure. Purification (Si gel, pet ether/EtOAc 3:2→2:3) gave
1104
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
([M + Na]+, 100%); HRMS (ESI+) calcd for C8H13D2NNaOS
198.0892, found 198.0893.
(135 μL, 0.90 mmol). s-BuLi (333 μL, 0.45 mmol, 1.35 M in
cyclohexane/hexane (92/8)) was added very slowly dropwise to the
reaction mixture over 5 min. After 30 min, BnBr (54 μL, 0.45 mmol)
was added and the reaction mixture stirred for 30 min. The reaction
mixture was warmed to room temperature and stirred for another 30
min, quenched with aq HCl (1 M, 5 mL), and extracted with EtOAc
(3 × 5 mL). The combined organic layers were washed with H2O (5
mL) and brine (5 mL), dried (Na2SO4), and concentrated to dryness
under reduced pressure. Purification (Si gel, pet ether/EtOAc 4:1→
2:3) gave azetidinol 19 as a pale yellow syrup (19 mg, 48%, 100% D,
60:10:30 2Dt-4Bnt/2Dc-4-Bnt/2Dc-2Bnt,13 dr determined by integra-
tion of δH 4.81, 4.19 and 4.09): Rf 0.64 (pet ether/EtOAc 3:2); IR
(neat/cm−1) 3373 br, 2967 w, 1454 s, 1435 m, 1129 m, 1091 m, 997
Lithiation−Protonation of cis-13a: 1-(2-Deutero-3-hydroxy-
azetidin-1-yl)-2,2-dimethylpropane-1-thione (13a). To a stirred
solution of azetidinol cis-13a (50 mg, 0.29 mmol) in THF (1 mL) at
−78 °C under argon was added TMEDA (261 μL, 1.74 mmol). s-BuLi
(614 μL, 1.40 M in cyclohexane/hexane (92/8), 0.86 mmol) was
added very slowly dropwise to the reaction mixture over 5 min. After
30 min, MeOH (58 μL, 1.43 mmol) was added and the reaction
mixture stirred for 10 min. The cold bath was removed, and the
reaction mixture was stirred for another 10 min, quenched with aq
HCl (1 M, 5 mL), and extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with H2O (5 mL) then brine (5
mL), dried (Na2SO4), and concentrated to dryness under reduced
pressure to give azetidinol 13a as a pale yellow syrup (50 mg, quant,
100% D, 64:36 cis/trans,13 dr determined by integration of δH 4.67 +
4.42 and 4.28 + 4.04). Characterization data are the same as that of cis-
13a, with the exception of two additional peaks in the 13C NMR
spectrum: 65.5 (T, J = 23 Hz, NCHD), 65.2 (T, J = 23 Hz, NCHD).
Lithiation−Protonation of trans-13a: 1-(2-Deutero-3-
hydroxyazetidin-1-yl)-2,2-dimethylpropane-1-thione (trans-
13a). To a stirred solution of azetidinol trans-13a (50 mg, 0.29
mmol) in THF (1 mL) at −78 °C under argon was added TMEDA
(261 μL, 1.74 mmol). s-BuLi (614 μL, 1.40 M in cyclohexane/hexane
(92/8), 0.86 mmol) was added very slowly dropwise to the reaction
mixture over 5 min. After 30 min, MeOH (52 μL, 1.45 mmol) was
added and the reaction mixture stirred for 10 min. The cold bath was
removed, and the reaction mixture was stirred for another 10 min,
quenched with aq HCl (1 M, 5 mL), and extracted with EtOAc (3 × 5
mL). The combined organic layers were washed with H2O (5 mL)
then brine (5 mL), dried (Na2SO4), and concentrated to dryness
under reduced pressure to give azetidinol trans-13a as a pale yellow
syrup (43 mg, 86%, 100% D, 87:13 trans/cis,13 dr determined by
integration of δH 4.70 + 4.48 and 4.32 + 4.10). Characterization data
are the same as that of trans-13a.
Lithiation−Benzylation of cis-13a: 1-(4-Deutero-3-hydroxy-
2-phenylazetidin-1-yl)-2,2-dimethylpropane-1-thione (19-2Dc-
4Bnt, 19-2Dt-4Bnt) and 1-(4-Deutero-3-hydroxy-2-phenyl-
azetidin-1-yl)-2,2-dimethylpropane-1-thione (19-2Dc-2Bnt).
To a stirred solution of azetidinol cis-13a (50 mg, 0.29 mmol) in
THF (1 mL) at −78 °C under argon was added TMEDA (261 μL,
1.74 mmol). s-BuLi (614 μL, 1.4 M in cyclohexane/hexane (92/8),
0.86 mmol) was added very slowly dropwise to the reaction mixture
over 5 min. After 30 min, BnBr (102 μL, 0.86 mmol) was added and
the reaction mixture stirred for 30 min. The reaction mixture was
warmed to room temperature and stirred for another 30 min,
quenched with aq HCl (1 M, 5 mL), and extracted with EtOAc (3 × 5
mL). The combined organic layers were washed with H2O (5 mL) and
brine (5 mL), dried (Na2SO4), and concentrated to dryness under
reduced pressure. Purification (Si gel, heptane/EtOAc 1:0→2:3) gave
azetidinol 19 as a pale yellow syrup (52 mg, 69%, 100% D, 61:6:33
2Dc-4Bnt/2Dt-4-Bnt/2Dc-2Bnt,13 dr determined by integration of δH
4.80, 4.18 and 4.08): Rf 0.64 (pet ether/EtOAc 3:2); IR (neat/cm−1)
3364 br, 3027 w, 2967 w, 1454 s, 1434 m, 1395 w, 1135 m, 1096 m,
910 m, 730 s, 702 m; 1H NMR (400 MHz, CDCl3) δ 7.32−7.22 (5H,
m, Ar), 4.80 (0.67H, ddd, J = 7.6, 3.5, 2.9 Hz, NCH) 4.24 (1H, dd, J =
6.3, 2.9 Hz, CHOH), 4.18 (0.94H, dd, J = 11.1, 6.3 Hz, NCHCisHTrans),
4.08 (0.38H, dd, J = 11.1, 2.9 Hz, NCHCisHTrans), 3.43 (1H, dd, J =
13.9, 3.5 Hz, CHHPh), 3.35 (0.3H, d, J = 13.9 Hz, CDCHHPh), 3.36
(0.7H, dd, J = 13.9, 7.6 Hz, CHHPh), 2.63 (1H, br, OH), 1.31 (9H, s,
C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 211.8 (C(S)), 136.5 (Ar),
129.7 (Ar), 128.4 (Ar), 126.7 (Ar), 77.5 (NCH), 65.3 (CHOH), 64.7
(NCH2), 64.4 (T, J = 23 Hz, NCDH), 43.6 (C(CH3)3), 33.9
(CH2Ph), 29.7 (C(CH3)3); LRMS (ESI+) 287.12 ([M + Na]+, 100%);
HRMS (ESI+) calcd for C15H20DNNaOS 287.1299, found 287.1296.
Lithiation−Benzylation of trans-13a: 1-(4-Deutero-3-hy-
droxy-2-phenylazetidin-1-yl)-2,2-dimethylpropane-1-thione
(19-2Dt-4Bnt, 19-2Dc-4Bnt) and 1-(2-Deutero-3-hydroxy-2-
phenylazetidin-1-yl)-2,2-dimethylpropane-1-thione (19-2Dc-
2Bnt). To a stirred solution of azetidinol trans-13a (26 mg, 0.15
mmol) in THF (0.5 mL) at −78 °C under argon was added TMEDA
1
m, 910 m, 730 s, 702 m; H NMR (400 MHz, CDCl3) δ 7.32−7.23
(5H, m, Ar), 4.81 (0.70H, dt, J = 6.6, 2.8 Hz, NCH), 4.25 (1H, m,
CHOH), 4.19 (0.40H, dd, J = 11.1, 6.8 Hz, NCHCisHTrans), 4.09
(0.90H, dd, J = 11.1, 2.8 Hz, NCHCisHTrans), 3.43 (1H, dd, J = 13.9, 3.5
Hz, CHHPh), 3.35 (0.3H, d, J = 13.9 Hz, CDCHHPh), 3.36 (0.7H,
dd, J = 13.9, 7.6 Hz, CHHPh), 2.52 (1H, br, OH), 1.32 (9H, s,
C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 211.7 (C(S)), 136.5 (Ar),
129.7 (Ar), 128.4 (Ar), 126.8 (Ar), 77.5 (NCH), 65.3 (CHOH), 64.7
(NCH2), 64.4 (T, J = 23 Hz, NCDH), 43.6 (C(CH3)3), 33.9
(CH2)Ph), 29.7 (C(CH3)3); LRMS (ESI+) 265.1 ([M + H]+, 100%);
HRMS (ESI+) calcd for C15H20DNNaOS 287.1299, found 287.1290.
2-Benzyl-1-(2,2-dimethylpropanethioyl)azetidin-3-yl ace-
tate (20). To a stirred solution of benzyl adduct 13d (412 mg, 1.56
mmol) in CH2Cl2 (5 mL) at −78 °C was added DIPEA (351 μL, 2.02
mmol) followed by dropwise addition of Tf2O (289 μL, 1.72 mmol).
After 30 min, MeOH (1 mL) was added and the reaction mixture
concentrated to dryness under reduced pressure. The crude triflate was
dissolved in DMF (5 mL) and to it was added NaOAc (1.28 g, 16
mmol) and the reaction mixture was heated to 70 °C. After 2 h, the
reaction mixture was cooled to rt, washed with H2O (10 mL), and
extracted with EtOAc (3 × 10 mL), and the combined organic layers
were dried (Na2SO4), filtered, and concentrated to dryness under
reduced pressure. Purification (Si gel, pet ether/EtOAc 39:1→9:1)
gave inverted acetate 20 as a colorless syrup (245 mg, 51%): Rf 0.44
(pet ether/EtOAc 9:1); IR (neat/cm−1) 2968 w, 2872 w, 1742 s, 1455
m, 1431 m, 1364 w, 1224 s, 1155 w, 1111 m, 1007 w, 910 m, 729 s,
700 m; 1H NMR (400 MHz, CDCl3) δ 7.36−7.19 (5H, m, Ar), 5.36−
5.28 (2H, m, NCH and CHOH), 4.75 (1H, ddd, J = 10.9, 7.3, 1.0 Hz,
NCHtransHcis), 4.20 (1H, ddd, J = 10.9, 5.3, 1.5 Hz, NCHtransHcis), 3.78
(1H, dd, J = 13.8, 1.6 Hz, CHHPh), 3.30 (1H, dd, J = 13.8, 9.2 Hz,
CHHPh), 2.09 (3H, s, CH3), 1.32 (9H, s, C(CH3)3); 13C NMR (100
MHz, CDCl3) δ 210.7 (CS), 170.0 (CO), 137.3 (Ar), 129.5 (Ar),
128.1 (Ar), 126.4 (Ar), 72.4 (NCH), 63.6 (CHOH), 63.3 (NCH2),
43.6 (C(CH3)3), 30.4 (NCH2Ph), 29.6 (C(CH3)3), 20.6 (CH3);
LRMS (ESI+) 306.2 ([M + H]+, 100%); HRMS (ESI+) calcd for
C17H23NNaO2S 328.1342, found 328.1337.
1-(2-Benzyl-3-hydroxyazetidin-1-yl)-2,2-dimethylpropane-
1-thione (cis-13d). To a stirred solution of inverted acetate 20 (245
mg, 0.80 mmol) in MeOH (3 mL) was added NaOMe (10 drops, 30%
in MeOH). After 1 h, the reaction mixture was concentrated to
dryness under reduced pressure. The residue was washed with aq HCl
(1 M, 10 mL) and extracted with CH2Cl2 (10 mL), and the organic
layer was washed brine (10 mL), dried (Na2SO4), filtered, and
concentrated to dryness under reduced pressure gave cis-benzyl adduct
cis-13d as a pale orange syrup which solidified on standing (184 mg,
1
87%); diastereoselectivity determined by H NMR coupling constant
analysis: Rf 0.47 (pet ether/EtOAc 4:1); mp 101−103 °C; IR (neat/
cm−1) 3368 br, 2996 w, 2964 w, 2929 w, 1468 s, 1435 s, 1357 w, 1253
1
w, 1149 m, 1109 m, 1037 w, 984 w, 829 w, 746 m, 702 m; H NMR
(400 MHz, CDCl3) δ 7.42−7.21 (5H, m, Ar), 5.17 (1H, dddd, J =
10.4, 7.3, 2.4, 2.0 Hz, NCH), 4.77 (1H, td, J = 7.3, 5.6 Hz, CHOH),
4.65 (1H, dd, J = 10.8, 7.3 Hz, NCHtransHcis), 4.23 (1H, ddd, J = 10.8,
5.6, 2.0 Hz, NCHtransHcis), 3.83 (1H, dd, J = 13.7, 2.4 Hz, CHHPh),
3.31 (1H, dd, J = 13.4, 10.4 Hz, CHHPh), 2.03 (1H, br, OH), 1.34
(9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 210.2 (CS),
138.2 (Ar), 129.4 (Ar), 128.5 (Ar), 126.4 (Ar), 74.5 (NCH), 64.7
(NCH2), 62.5 (CHOH), 43.5 (C(CH3)3), 29.6 (C(CH3)3); LRMS
1105
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106

The Journal of Organic Chemistry
Article
(ESI+) 286.2 ([M + Na]+, 100%); HRMS (ESI+) calcd for
C15H21NNaOS 286.1236, found 286.1244.
(11) Use of Me2SO4 gave slightly reduced yield and dr (67%, 57:43
dr), whereas MeOTf gave a poor yield and no diastereoselectivity
(19%, 50:50 dr).
(12) See the Supporting Information for details.
ASSOCIATED CONTENT
(13) For related differences in cis/trans 3J azetidine values, see:
Doomes, E.; Cromwell, N. H. J. Org. Chem. 1969, 34, 310−317.
(14) For a tabular comparison, see the Supporting Information.
(15) Gawley, R. E. Top. Stereochem. 2010, 26, 93−133.
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds, H analysis of
1
deuterated adducts and X-ray data for epi-13g. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
(16) By H NMR comparison with 13d and cis-13d, the latter being
available from 13d through the corresponding inverted acetate 20 by
an identical alcohol inversion sequence to that used for trans-10a (see
Experimental Section).
(17) Meyers, A. I.; Dickman, D. A. J. Am. Chem. Soc. 1987, 109,
1263−1265.
(18) Hu, B.; Sum, F.-W.; Malamas, M. Cyclic Amine Phenyl β-3
Adrenergic Receptor Agonists. WIPO Patent WO 2002/06232 A1,
January 24, 2002; Chem. Abstr. 2002, 136, 134676.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.hodgson@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank AstraZeneca and the EPSRC for funding, and L.
Campbell and P. Schofield (AstraZeneca) for helpful
discussions.
REFERENCES
■
(1) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108,
3988−4035.
(2) (a) Ikee, Y.; Hashimoto, K.; Nakashima, M.; Hayashi, K.; Sano,
S.; Shiro, M.; Nagao, Y. Bioorg. Med. Chem. Lett. 2007, 17, 942−945.
(b) Slade, J.; Bajwa, J.; Liu, H.; Parker, D.; Vivelo, J.; Chen, G.-P.;
̌
Calienni, J.; Villhauer, E.; Prasad, K.; Repic, O.; Blacklock, T. J. Org.
Process Res. Dev. 2007, 11, 825−835. (c) Evans, G. B.; Furneaux, R. H.;
Greatrex, B.; Murkin, A. S.; Schramm, V. L.; Tyler, P. C. J. Med. Chem.
2008, 51, 948−956.
(3) (a) Rama Rao, A. V.; Gurjar, M. K.; Kaiwar, V. Tetrahedron:
Asymmetry 1992, 3, 859−862. (b) Keller, L.; Sanchez, M. V.; Prim, D.;
Couty, F.; Evano, G.; Marrot, J. J. Organomet. Chem. 2005, 690, 2306−
2311. (c) Wang, M.-C.; Zhang, Q.-J.; Zhao, W.-X.; Wang, X.-D.; Ding,
X.; Jing, T.-T.; Song, M.-P. J. Org. Chem. 2008, 73, 168−176.
(4) (a) 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, 4241−4244.
(b) Gerlach, K.; Priepke, H.; Weinen, W.; Schuler-Metz, A.; Nar, H.
Substituted Azetidines, Manufacturing and Use Thereof as Medica-
ments. WIPO Patent WO 2008/135525 A2, November 13, 2008;
Chem. Abstr. 2008, 149, 556457.
(5) (a) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron 1994, 50,
265−274. (b) Raghavan, S.; Krishnaiah, V. J. Org. Chem. 2010, 75,
748−861.
(6) Rousseau, G.; Robin, S. Four-Membered Heterocycles: Structure
and Reactivity. In Modern Heterocyclic Chemistry, 1st ed.; Alzerez-
Builla, J., Vaquero, J. J., Barluenga, J., Eds.; Wiley-VCH: Weinheim,
Germany, 2011; Vol. 1, pp 163−268.
(7) Hodgson, D. M.; Kloesges, J. Angew. Chem., Int. Ed. 2010, 49,
2900−2903.
(8) Reddy, V. V. R. M. K.; Babu, K. K.; Ganesh, A.; Srinivasulu, P.;
Madhusudhan, G.; Mukkanti, K. Org. Process Res. Dev. 2010, 14, 931−
935.
(9) For a related observation with an N-Boc-pyrrolidine, see:
Mordini, A.; Valacchi, V.; Epiroti, F.; Reginato, G.; Cicchi, S.; Goti, A.
Synlett 2011, 235−240.
(10) (a) For C-5 lithiation of N-Boc-3-hydroxypyrrolidine, see:
Sunose, M.; Peakman, T. M.; Charmant, J. P. H.; Gallagher, T.;
Macdonald, S. J. F. Chem. Commun. 1998, 1723−1724. (b) For
reductive lithiation of N-Boc-3-hydroxy-2-(phenylthio)piperidine, see:
Zheng, X.; Chen, G.; Ruan, Y.; Huang, P. Sci. China, Ser. B: Chem.
2009, 52, 1631−1638.
1106
dx.doi.org/10.1021/jo3025225 | J. Org. Chem. 2013, 78, 1098−1106