Rearrangement of 1-Phenylbutane-1,3-diamines via an azetidinium cation intermediate

Article abstract of DOI:10.1055/s-0030-1259957

Treatment of 4-amino-4-phenyl-butan-2-ol with mesyl chloride, followed by displacement with amine nucleophiles resulted in a 1,3 rearrangement via an azetidinium cation intermediate. This rearrangement has been proven to proceed via a double inversion of stereocentres at positions 1 and 3. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259957

LETTER
1101
Rearrangement of 1-Phenylbutane-1,3-diamines via an Azetidinium Cation
Intermediate
R
earrangement via
a
anAzetidi
v
nium
C
ation
i
Interm
d
ediate C. Blakemore, Jean-Yves Chiva,* Iain Thistlethwaite
Sandwich Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
E-mail: Jean-Yves.Chiva@Pfizer.com
Received 8 March 2011
F
F
Abstract: Treatment of 4-amino-4-phenyl-butan-2-ol with mesyl
chloride, followed by displacement with amine nucleophiles result-
ed in a 1,3 rearrangement via an azetidinium cation intermediate.
This rearrangement has been proven to proceed via a double inver-
O
sion of stereocentres at positions 1 and 3.
NH
N
Key words: amines, azetidinium cation, double inversion, nucleo-
philes, rearrangement
N
N
N
maraviroc (1)
HIV is a global health problem which is estimated to have
already caused the deaths of more than 25 million people1
worldwide. Maraviroc (1) is the first of a number of CCR5
antagonists that have been developed to block viral entry
into cells. As a follow-up to maraviroc, we were interested
in replacing the central tropane core with alternative
amines. This strategy led us to the synthesis of 1-amido-
1-phenyl-3-piperidinylbutanes2 exemplified by com-
pound 2 (Figure 1).
O
NH
N
N
N
N
2
In this letter we wish to describe an unusual rearrange-
ment occurring via a four-membered-ring cationic inter-
mediate observed during these syntheses.
Figure 1 Maraviroc and follow-up series
To circumvent these issues, we designed an alternative
route where the key step was a nucleophilic substitution
(Scheme 2). The SN2 reaction of the nucleophilic piperi-
dine with the appropriate diastereomerically pure mesy-
late 7 should afford the desired a-methyl piperidine 6.
Initially, the a-methyl piperidine skeleton was formed us-
ing a reductive amination protocol (Scheme 1). For exam-
ple, for the synthesis of 2, enantiopure Boc-protected
ketone 3 and 4-substituted triazole piperidine 4 were re-
acted in the presence of a Lewis acid to form an interme-
diate imine; this imine was subsequently reduced using There are several potential issues with this strategy. First-
sodium cyanoborohydride leading to 5 as a 2:1 mixture of ly, the nucleophilicity of the piperidine nitrogen is influ-
diastereomers, and the active isomer was isolated by col- enced by the nature of the heterocycle and this could
umn chromatography.
potentially make the displacement more challenging.
There is also not much precedent for this type of second-
ary mesylate displacement with piperidine derivatives. Fi-
nally, the mesylate group is in a 1,3 relationship with the
Boc-protected amine and there is potential for intramolec-
ular ring-closure reactions.
There is, however, scope to improve this process: the sep-
aration proved very challenging in some instances, and a
significant amount of valuable piperidine nucleophile was
wasted in the synthesis of the inactive and undesired dia-
stereomer.
O
O
O
NH
N
O
NH
O
N
1. Ti(Oi-Pr)4, EtOH, r.t.
2. NaCNBH3
59%
+
HN
N
N
N
N
N
3
4
5
Scheme 1 Reductive amination
SYNLETT 2011, No. 8, pp 1101–1104
x
x.
x
x.
2
0
1
1
Advanced online publication: 18.04.2011
DOI: 10.1055/s-0030-1259957; Art ID: D33010ST
© Georg Thieme Verlag Stuttgart · New York

1102
D. C. Blakemore et al.
LETTER
O
O
O
NH
O
NH
O
S
+
HN
N
Het
Het
O
O
6
7
8
N
N
N
N
Het =
N
N
Scheme 2 Retrosynthetic approach
In order to validate our approach, we first needed to syn- found, following the deprotection of the allyl group, that
thesise mesylate 7 as a single diastereomer. Reduction of the expected product 17 was not obtained. To our surprise,
enantiomerically pure ketone 3 with sodium borohydride 16 was obtained where the piperidine was incorporated at
gave the two diastereomeric alcohols 9 and 10 as a 3:2 the benzylic position. To rationalise this unexpected find-
mixture (Scheme 3).
ing, we propose that an intramolecular attack of the nu-
cleophilic amine onto the mesylate occurs first. This
would result in the formation of an azetidinium cation in-
termediate which would then be attacked preferentially at
its more activated benzylic position (Scheme 6).
O
O
NH OH
O
Since both reactions are SN2 displacements the net result
should be an inversion in chirality at both stereogenic cen-
tres.
O
NH
O
9
NaBH4, EtOH
r.t., 70%
+
Such anchimeric assistance from an amine, when involv-
ing three-membered aziridines, is well precedented in the
literature. However, it is less common for entropically dis-
favoured four-membered azetidines.
O
3
O
NH OH
In fact, a thorough investigation of the literature revealed
that the formation and re-opening of an azetidinium ion
intermediate has only been reported by O’Brien3 using
phenol nucleophiles. However, it is interesting to note that
some stereochemical leakage was observed in these reac-
tions.
10
Scheme 3 Ketone reduction
Separation of the alcohols by flash chromatography on sil-
ica was straightforward and could be accomplished easily
on multigram scale.
Based on these preliminary findings, we were very keen
to investigate both the regioselectivity and the stereospec-
ificity of our rearrangement in more detail. To do so, we
elected to work with diastereomers 18 and 21 as our pre-
A key issue in the mesylate formation was the potential
formation of chloride side product (via the chloride ion
generated from reaction with mesyl chloride). Such a re-
action would lead to some scrambling of stereogenic in-
tegrity. To avoid this issue, we found that mesylate
formation was best carried out at –40 °C with the base
added to the alcohol after the mesyl chloride. Reversing
the order of addition gave a mixture of desired mesylate
and chloride.
O
O
O
NH OMs
O
NH OH
MsCl, Et3N
CH2Cl2, –40 °C
9 or 10
11
Reaction of mesylate 11 with amine 12 took place under
standard displacement conditions (Scheme 4) but did not
provide the expected product. Instead, the major reaction
was postulated to be an intramolecular attack of the oxy-
gen of the Boc group on the mesylate (followed by loss of
the tert-butyl group) resulting in low yields of 13.
N
NH
N
N
O
HN
O
12
K2CO3, MeCN
reflux
To avoid this issue, we elected to swap the Boc protecting
group for a diallyl group (Scheme 5).
13
Although reaction of diallyl-protected mesylate 14 with
amine 4 proceeded in high yield, it was subsequently
Scheme 4 Mesylate displacement of Boc-protected intermediate
Synlett 2011, No. 8, 1101–1104 © Thieme Stuttgart · New York

LETTER
Rearrangement via an Azetidinium Cation Intermediate
1103
N
HN
N
N
N
N
N
N
N
N
N
N
RhCl(PPh3)3
4
N
OMs
MeCN–H2O
50%
K2CO3, MeCN
reflux
NH2
74%
N
14
16
15
O
NH2
O
NH
N
N
HCl (g)
N
N
N
N
N
N
Et2O, MeOH
5
17
Scheme 5 Rearrangement
Het
N
N
N
OMs
N+
Het
NH
Scheme 6 Mechanism of the rearrangement
ferred mesylate and to use piperidine 19 as our nucleo-
Table 1 Result of Rearrangement Using a Range of Amines
philic amine (Scheme 7).
R1
R2
In both cases, reaction proceeded in good yields with only
one diastereomeric product observable by HPLC and
NMR. We were encouraged by this result as it seems in-
dicative of high level of stereospecificity in the reaction.
N
N
R1
R2
N
N
H
OMs
K2CO3
MeCN
reflux
The relative stereochemistry of the substituents was prov-
en in each case via NOE analysis. The relative stereo-
chemistry of the product observed in each case was
consistent with our proposal that double inversion had oc-
curred (although only relative stereochemistry was deter-
mined).
F
F
24
23
Entry
Amine
Yield (%)
1
2
3
4
5
6
7
8
methylamine
diisopropylamine
n-butylamine
tert-butylamine
benzylamine
N-methylpiperazine
morpholine
33
decomp.
71
A range of nucleophile amines were then investigated to
assess the scope of the rearrangement using mesylate 23
as the coupling partner. Results are summarized in
Table 1.
54
63
Although there are limitations to this reaction, notably
with sterically hindered amine as illustrated with entry 2,
most reactions proceeded in good yields across a range of
amine nucleophiles, for example, primary, secondary,
benzylic, and heterocyclic amines all worked well. The
poor yield with methylamine (entry 1) is probably due to
the volatile nature of this nucleophile. In each case, only
one isomer was observed suggesting that stereochemical
leakage was kept to a minimum.
78
77
aniline
61
In order to get a closer comparison of our results with
those described in O’Brien’s work, we examined the reac-
tion using phenol 25 as the nucleophile (Scheme 8). We
Synlett 2011, No. 8, 1101–1104 © Thieme Stuttgart · New York

1104
D. C. Blakemore et al.
LETTER
(141 mg, 0.575 mmol) in CH2Cl2 (12 mL) at –40 °C. After 10 min,
Et3N (0.161 mL, 1.15 mmol) was added, and the mixture was stirred
for 2 h before being allowed to warm to r.t. and then stirred for an-
other 2 h. The solvent was evaporated under reduced pressure, and
the crude was taken up in EtOAc, washed with H2O, and dried over
MgSO4. The solvent was evaporated under reduced pressure to give
186 mg of the mesylate compound 18.
N
OMs
N
18
Piperidine (0.069 mL, 0.690 mmol) and K2CO3 (159 mg, 1.15
mmol) were added to a stirring solution of compound 18 (186 mg,
0.575 mmol) in MeCN (12 mL), and the mixture was refluxed for
16 h, then allowed to cool down to r.t. The solvent was evaporated
under reduced pressure, and the crude purified by flash chromatog-
raphy on silica [CH2Cl2–NH3 (10%)–MeOH = 100:0 to 95:5] to
give 140 mg of a white solid.
+
N
K2CO3
MeCN
reflux
78%
N
H
19
20
Characterization Data
N
1H NMR (CD3OD, 400 MHz): d = 7.34–7.22 (5 H, m), 5.67–5.57 (2
H, m), 5.04–4.83 (4 H, m), 3.43–3.40 (1 H, dd, J = 3.9, 10.2 Hz),
2.99–2.98 (4 H, m), 2.60–2.51 (1 H, m), 2.46–2.33 (4 H, br m),
2.18–2.11 (1 H, m), 1.88–1.82 (1 H, m), 1.65–1.49 (4 h, m), 1.38–
1.33 (2 h, m), 1.00 (3 h, d, J = 6.6 Hz). ESI-MS: m/z = 313 [M +
H]+.
OMs
N
21
+
N
K2CO3
MeCN
reflux
Procedure for the Synthesis of Compound 22
Mesyl chloride (0.057 mL, 0.733 mmol) was added dropwise to a
stirring solution of (2S,4S)-4-diallylamino-4-phenylbutan-2-ol (150
mg, 0.611 mmol) in CH2Cl2 (12 mL) at –40 °C. After stirring for 10
min, Et3N (0.171 mL, 1.22 mmol) was added, and the mixture was
stirred for 2 h before being allowed to warm to r.t. and stirred for
another 2 h. The solvent was evaporated under reduced pressure,
and the crude was taken up in EtOAc, washed with H2O and dried
over MgSO4. The solvent was evaporated under reduced pressure to
give 198 mg of the mesylate compound 21.
N
H
19
72%
22
Scheme 7 Diastereomer comparison
were pleased to find that the rearranged product 26 was
isolated in 86% yield; again, we saw no evidence of any
other diastereomeric product.
Piperidine (0.073 mL, 0.734 mmol) and K2CO3 (169 mg, 1.22
mmol) were added to a stirring solution of compound 21 (198 mg,
0.611 mmol) in MeCN (12 mL), and the mixture was refluxed for
16 h, then allowed to cool down to r.t. The solvent was evaporated
under reduced pressure, and the crude purified by flash chromatog-
raphy on silica [CH2Cl2–NH3 (10%)–MeOH = 100:0 to 95:5] to
give 138 mg of a white solid.
N
OMs
Characterization Data
F
1H NMR (CD3OD, 400 MHz): d = 7.35–7.22 (5 H, m), 5.67–5.57 (2
H, m), 5.09–5.08 (1 H, m), 5.05–5.04 (1 H, m), 4.95–4.93 (1 H, m),
4.92–4.90 (1 H, m), 3.75 (1 H, dd, J = 4.7, 10.9 Hz), 3.25–3.23 (1
H, m), 3.21–3.19 (1 H, m), 2.79–2.74 (2 H, m), 2.65–2.56 (1 H, m),
2.39 (4 H, br s), 2.11 (1 H, ddd, J = 4.3, 9.7, 14.1 Hz), 1.83 (1 H,
ddd, J = 4.7, 10.5, 13.7 Hz), 1.63–1.49 (4 H, m), 1.37–1.31 (2 H, br
m), 0.83 (3 H, d, J = 6.6 Hz). ESI-MS: m/z = 313 [M + H]+.
O
23
+
K2CO3
MeCN
reflux
N
HO
F
25
26
Scheme 8 Rearrangement using phenol as a nucleophile
Acknowledgment
The authors would like to thank Florian Wakenhut and David Fox
for advice and helpful discussions.
In conclusion, we have demonstrated that a novel rear-
rangement can occur on some 1,3-amino mesylates, and
we postulate that this reaction is likely to occur via in-
tramolecular formation of an azetidinium cation interme-
diate which, in the presence of a nucleophile, can
subsequently undergo ring opening. This rearrangement is
tolerant of a broad range of nucleophilic amines.
References
(1) http://data.unaids.org/pub/FactSheet/2009/
20091124_FS_global_en.pdf
(2) (a) Barber, C. G.; Blakemore, D. C. Bioorg. Med. Chem.
Lett. 2009, 19, 1075. (b) Barber, C. G.; Blakemore, D. C.
Bioorg. Med. Chem. Lett. 2009, 19, 1499.
(3) O’Brien, P.; Phillips, D. W.; Towers, T. D. Tetrahedron Lett.
2002, 43, 7333.
Procedure for the Synthesis of Compound 20
Mesyl chloride (0.054 mL, 0.690 mmol) was added dropwise to a
stirring solution of (2R,4S)-4-diallylamino-4-phenylbutan-2-ol
Synlett 2011, No. 8, 1101–1104 © Thieme Stuttgart · New York

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