Rapid synthesis of 4-benzyl-4-aminopiperidines by addition of Grignard reagents to N-(1-Boc-piperidin-4-ylidene)-tert-butanesulfinyl imine

Article abstract of DOI:10.1055/s-2006-950442

Two concise methods for the synthesis of aryl-substituted 4-benzyl-4-aminopiperidines by the addition of benzyl Grignard reagents to sulfinyl imines were developed. The hydration-prone tert-butanesulfinyl imine derived from N-Boc-piperidin-4-one was trapp

Full text of DOI:10.1055/s-2006-950442

LETTER
2565
Rapid Synthesis of 4-Benzyl-4-aminopiperidines by Addition of Grignard
Reagents to N-(1-Boc-Piperidin-4-ylidene)-tert-butanesulfinyl Imine
R
apid Syn
o
thesis of 4-B
h
e
nzyl-4-amin
n
opiperidines J. Caldwell, Ian Collins*
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont,
Surrey, SM2 5NG, UK
Fax +44(20)87224205; E-mail: ian.collins@icr.ac.uk
Received 22 May 2006
group at an early stage in this multi-step synthesis made it
less suitable for the rapid preparation5,6b,d of a wide range
of substituted 4-benzyl-4-aminopiperidines, and we there-
fore sought a more direct route.
Abstract: Two concise methods for the synthesis of aryl-substitut-
ed 4-benzyl-4-aminopiperidines by the addition of benzyl Grignard
reagents to sulfinyl imines were developed. The hydration-prone
tert-butanesulfinyl imine derived from N-Boc-piperidin-4-one was
trapped as a stable a-(N-sulfinyl)aminonitrile, which underwent
displacement of the nitrile on treatment with Grignard reagents. Al-
ternatively, benzyl and allyl Grignards added to the sulfinyl imine
in situ in a one-pot procedure. Acid deprotection provided various
substituted 4-benzyl-4-aminopiperidines.
The development of organometallic additions to N-(tert-
butanesulfinyl)imines by the groups of Ellman and others
is well known,6 with the examples based on N-cyclo-
hexylidene sulfinamides of particular relevance to this
work.6c Here, we describe the application of the sulfinyl
imine addition methodology to the synthesis of 4-benzyl-
4-aminopiperidines 3 from N-Boc-piperidin-4-one 1
(Scheme 2). This starting material was chosen since both
the N-Boc and N-sulfinamide protecting groups were
anticipated to be easily removed by treatment with acid in
a single final synthetic step.
Key words: heterocycles, piperidines, imines, Grignard reactions,
tandem reactions
The utility of 4-aminopiperidines as scaffolds in biologi-
cally active synthetic compounds has long been apparent.1
Our particular need for 4-benzyl-4-aminopiperidines with
various aryl substitution patterns prompted a search for
suitable synthetic approaches, and showed that relatively
few literature methods currently exist for the synthesis of
such species. Of these, the most versatile employs a
Curtius rearrangement as the key transformation.1c Other
procedures involve the Ritter reaction of 4-substituted
piperidin-4-ols2 or the addition of organometallic reagents
to the imines formed from the condensation of piperidin-
4-ones with anilines3 or benzylamines.4
O
S
O
N
R
NH2
N
N
N
H
Boc
Boc
1
2
3
Scheme 2
CN
CN
CO2H
NH2
Our initial strategy was to follow the procedure reported
by Ellman, whereby N-cyclohexylidene sulfinamide in-
termediates were first prepared.6c Although observed to be
susceptible to hydrolysis on silica gel, these sulfinyl
imines could nonetheless be isolated and purified in good
yield. In the case of sulfinyl imine 2, immediate use of a
crude sample of the worked-up reaction did lead to reac-
tion with benzyl Grignard reagents. However, attempts to
isolate 2 gave predominantly the hydrate 47 as a white sol-
id following aqueous workup and trituration with hexane
(Scheme 3). The identity of 4 was assigned by mass spec-
trometry and NMR, in particular the presence of a charac-
teristic quaternary carbon resonance at ca. d = 80 ppm
(piperidine C-4) and the presence of a readily exchange-
able proton (d = 5.52 ppm; OH) in the 1H spectrum deter-
mined in DMSO-d6. The facile hydration of 2 parallels the
known propensity of piperidin-4-ones to form hydrates.8
Ar
Ar
Ar
b,c
a
d–h
N
N
N
N
Boc
Boc
Boc
H
Scheme 1 Reagents and conditions: (a) LDA, ArCH2Br; (b) 6 M
HCl, reflux; (c) Boc2O, Et3N, CH2Cl2, r.t.; (d) i-BuOCOCl, Et3N,
THF, –15 °C; (e) NaN3, THF–H2O, r.t.; (f) 90 °C, toluene, then HCl
(g) Boc2O, 2 M NaOH, r.t.; (h) 4 M HCl in dioxane, MeOH, r.t.
Initially we found that a synthesis based on the Curtius re-
arrangement, related to a recently published procedure,1c
was an effective route to 4-benzyl-4-aminopiperidines
(Scheme 1). Typical yields for the sequence were 28–
39%, with the Curtius rearrangement itself being the least
efficient step (50–53%). Although amenable to multi-
gram scale up, the introduction of the substituted aryl
To avoid this unproductive transformation we attempted
to trap the sulfinyl imine 2 through a Strecker reaction
with trimethylsilylcyanide before workup.9 A stable
SYNLETT 2006, No. 16, pp 2565–2568
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-950442; Art ID: D14806ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
6

2566
J. J. Caldwell, I. Collins
LETTER
Table 1 In situ Reaction of Sulfinimine 2 with Benzyl Grignards
O
O
S
H
O
N
S
HO
N
S
O
HN
R
R
NH2
a
b
O
a
b
N
N
N
Boc
Boc
Boc
N
N
N
Boc
1
2
4
Boc
6a–k
H
1
3a–k
c
57%
Entrya
R
Yield of 6 (%)b Yield of 3 (%)b
Ph
Ph
H
H
NC
N
N
NH2
a
b
c
d
e
f
H
39
42
48
35
57
32
66
39
59
55
57
80
88
88
89
77
86
76
80
84
88
60
S
S
O
O
d
e
2-Cl
80%
49%
N
Boc
N
N
H
Boc
3-OMe
3-OCF3
2,4-Cl
2-Cl-4-F
2,6-Cl
2-OCF3
2,5-Cl
2,3-Cl
4-Ph
5
6a
3a
Scheme 3 Reagents and conditions: (a) tert-butanesulfinamide,
Ti(OEt)4, THF, reflux; (b) aqueous workup; c) TMSCN, THF, reflux;
(d) BnMgCl, THF, reflux; (e) 4 M HCl in dioxane, MeOH, r.t.
a-(N-sulfinyl)aminonitrile 5 was formed in 57% yield
(Scheme 3),13 which could be stored indefinitely at room
temperature.
g
h
i
The reactions of N-aryl and N-alkyl a-aminonitriles with
organomagnesium or organolithium species leading to
displacement of the nitrile group through in situ formation
of reactive imines have been described.10 By analogy, re-
action of a-(N-sulfinyl)aminonitrile 5 with Grignard re-
agents was expected to give the required 4-substituted-4-
(tert-butanesulfinamido)piperidines. Indeed, treatment of
5 with two equivalents of benzylmagnesium chloride in
refluxing tetrahydrofuran afforded the adduct 6a in 49%
yield. To our knowledge, this is the first time this transfor-
mation has been demonstrated for a-(N-sulfinyl)aminoni-
triles. The sulfinamide 6a was deprotected by treatment
with acid to give 4-benzyl-4-aminopiperidine (3a; 80%).
j
k
a Reagents and conditions: (a) tert-butylsulfinamide, Ti(OEt)4
(2 equiv), THF, reflux; then Grignard reagent (5 equiv), THF, r.t.;
(b) 4 M HCl in dioxane, MeOH, r.t.
b Yields are unoptimised and refer to isolated materials, homogeneous
by NMR analysis, TLC and/or HPLC, and characterised by NMR and
MS.
The 4-benzyl-4-(tert-butanesulfinamido)piperidines 6a–k
thus prepared were deprotected under acidic conditions as
anticipated to provide the required diamines 3a–k in a
simple two-pot procedure from readily available N-Boc-
piperidin-4-one. The overall yields of the diamines were
moderate (28–50%) but compared well with typical yields
(29–39%) from the Curtius route (Scheme 1). Additional-
ly, the considerable reduction in the number of synthetic
transformations made this route preferable for the con-
struction of a diverse range of 4-benzyl-4-aminopiperi-
dine scaffolds.
Although an effective means of overcoming the unwanted
hydration, an extra step had been added to the process.
Therefore an attempt was made to react the sulfinyl imine
2 directly in situ with benzylmagnesium chloride. Al-
though alkyl Grignard reagents containing b-hydrogen
atoms react with titanium alkoxides to form low-valent
titanium reagents,11 this was not anticipated to be a prob-
lem for benzylic systems. The compatibility of Grignard
reagents with titanium alkoxides in the context of
intramolecular chelate-controlled additions has been
previously demonstrated.12 Gratifyingly, addition of five
equivalents of benzylmagnesium chloride to the reaction
mixture after formation of the sulfinylimine yielded the
sulfinamide 6a13 in 39% yield after chromatography. This
one-pot procedure compared favourably with the yield for
the two-step procedure via the nitrile 5 (28%). The use of
only 2.5 equivalents of Grignard reagent reduced the yield
(23%), while an improvement was seen when ten equiva-
lents were added (50%).
Having developed successful methodology for the con-
cise synthesis of 4-benzyl-4-aminopiperidines, the scope
of the reaction with other substrates and organometallics
was tested. The ring-expanded tert-butyl 4-oxoazepane-1-
carboxylate 7 gave protected amine 8 in 54% yield under
the standard reaction conditions and was deprotected to
the 4-benzyl-4-aminoazepane (9; Scheme 4). No desired
product could be detected when the sulfinyl imine 2 was
treated in situ with a range of other Grignard reagents.
This contrasts with the results of Ellman and colleagues,6c
where many organometallics were found to be effective
nucleophiles in reactions with the sulfinyl imines derived
from cyclohexanones. However, the procedure was suc-
cessful when allylmagnesium chloride was used, giving
The protocol was successfully extended to a range of
substituted benzylic Grignard reagents bearing both elec-
tron-donating and electron-withdrawing substituents
(Table 1).13
Synlett 2006, No. 16, 2565–2568 © Thieme Stuttgart · New York

LETTER
Rapid Synthesis of 4-Benzyl-4-aminopiperidines
2567
A.; Schmatz, D. M.; Ellman, J. A. Bioorg. Med. Chem. Lett.
2005, 15, 345. (c) Jiang, X.; Song, Y.; Long, Y. Bioorg.
Med. Chem. Lett. 2004, 14, 3675; and references therein.
(2) (a) Micovic, I.; Ivanovic, M. D.; Vuckovic, S. M.; Prostran,
M. S.; Dosen-Micovic, L.; Kiricojevic, V. D. Bioorg. Med.
Chem. Lett. 2000, 10, 2011. (b) Chen, H. G.; Chung, F.-Z.;
Goel, O. P.; Johnson, D.; Kesten, S.; Knobelsdorf, J.; Lee, H.
T.; Rubin, J. R. Bioorg. Med. Chem. Lett. 1997, 5, 555.
(3) (a) Cossy, J.; Poitevin, C.; Gomez Pardo, D.; Peglion, J. L.;
Dessinges, A. Synlett 1998, 251. (b) Cossy, J.; Poitevin, C.;
Gomez Pardo, D. J. Org. Chem. 1998, 63, 4554.
10 with similar efficiency (41%) to the benzylic examples
(Scheme 4). Variation of the N-protecting group was test-
ed using N-tosylpiperidin-4-one (12). A similar reactivity
profile was observed to that of 1 in that only benzyl Grig-
nards were found to be effective nucleophiles (Scheme 4).
H
O
NH2
N
Ph
Ph
S
a
b
O
54%
67%
(c) Kudzma, L. V.; Severnak, S. A. S.; Benvenga, M. J.;
Ezell, E. F.; Ossipov, M. H.; Knight, V. V.; Rudo, F. G.;
Spencer, H. K.; Spaulding, T. C. J. Med. Chem. 1989, 32,
2534.
NH
NBoc
NBoc
7
8
9
H
N
O
NH2
(4) Palmer, R. A.; Salas, S.; Kouznetsov, V.; Stashenko, E.;
Montenegro, N. G.; Fontela, A. G. J. Heterocycl. Chem.
2001, 38, 837.
S
a
b
O
41%
94%
N
N
N
H
(5) Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921.
(6) (a) Brinner, K. M.; Ellman, J. A. Org. Biomol. Chem. 2005,
3, 2109. (b) Jiang, W.; Chen, C.; Marinkovic, D.; Tran, J. A.;
Chen, C. W.; Arellano, L. M.; White, N. S.; Tucci, F. C. J.
Org. Chem. 2005, 70, 8924. (c) McMahon, J. P.; Ellman, J.
A. Org. Lett. 2004, 6, 1645. (d) Mukade, T.; Dragoli, D. R.;
Ellman, J. A. J. Comb. Chem. 2003, 5, 590. (e) Shaw, A.
W.; deSolms, S. J. Tetrahedron Lett. 2001, 42, 7173.
(f) Ellman J. A., Owens T. D., Tang T. P.; Acc. Chem. Res.;
2002, 35: 984; and references therein.
Boc
Boc
1
10
11
O
S
O
S
O
N
N
HN
Ph
a
32%
N
N
Ts
Ts
Ts
(7) Compound 4: 1H NMR (500 MHz, DMSO): d = 1.11 (s, 9
H), 1.39 (s, 9 H), 1.66–1.69 (m, 4 H), 3.11–3.14 (m, 2 H),
3.45–3.50 (m, 2 H), 5.30 (s, 1 H), 5.52 (s, 1 H, signal
removed on addition of D2O). 13C NMR (125 MHz, DMSO):
d = 22.6, 28.1, 37.2, 38.0, 54.5, 78.5, 81.4, 153.8. MS (ES+):
m/z = 343 [M + Na+], 303 [M + H+ – H2O].
12
Scheme 4 Reagents and conditions: (a) tert-butylsulfinamide,
Ti(OEt)4, THF; then Grignard reagent, THF; (b) 4 M HCl in dioxane,
MeOH, r.t.
(8) (a) Conroy, J. L.; Sanders, T. C.; Seto, C. T. J. Am. Chem.
Soc. 1997, 119, 4285. (b) Burkey, T. J.; Fahey, R. C. J. Org.
Chem. 1985, 50, 1304.
(9) (a) Avenoza, A.; Busto, J. H.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. Synthesis 2005, 575.
(b) Mabic, S.; Cordi, A. A. Tetrahedron 2001, 57, 8861.
(10) (a) Kudzma, L. V.; Spencer, H. K.; Anaquest, S. A. S.
Tetrahedron Lett. 1988, 29, 6827. (b) Overman, L. E.;Burk,
R. M. Tetrahedron Lett. 1984, 25, 1635.
In summary, concise procedures for the synthesis of aryl
substituted 4-benzyl-4-aminopiperidines by the addition
of benzyl Grignard reagents to sulfinyl imines have been
developed, which show advantages over the more tradi-
tional Curtius approach in terms of the reduced number of
synthetic manipulations and are competitive in overall
yield. The hydration-prone tert-butanesulfinyl imine de-
rived from N-Boc-piperidin-4-one can be trapped as a
stable a-(N-sulfinyl)aminonitrile, which undergoes dis-
placement of the nitrile on treatment with Grignard re-
agents. Alternatively, benzyl and allyl Grignards will add
to the sulfinyl imine in situ in a one-pot procedure. Simple
acid deprotection provides various substituted 4-benzyl-
4-aminopiperidines which should prove useful scaffolds
for the synthesis of biologically active compounds.
(11) Kulinkovich, O. Eur. J. Org. Chem. 2004, 4517.
(12) Bartoli, G.; Bellucci, M.; Bosco, M.; Marcantoni, E.;
Sambri, L. Chem. Eur. J. 1998, 4, 2154.
(13) tert-Butyl 4-Cyano-4-(tert-butanesulfinamido)piper-
idine-1-carboxylate (5): A solution of N-Boc-piperidin-4-
one (1; 0.90 g, 4.52 mmol), tert-butanesulfinamide (0.58 g,
4.8 mmol) and Ti(OEt)4 (1.9 mL, 9 mmol) in anhyd THF (20
mL) was refluxed under N2 for 20 h. The red solution was
cooled, TMSCN (0.66 mL, 5 mmol) was added and the
solution was refluxed for 3 h. The cooled solution was
diluted with brine (20 mL) and EtOAc (20 mL). The
suspension was filtered through Celite, washing with further
EtOAc. The filtrate was separated and the organic layer was
dried (Na2SO4) and concentrated. Flash column
Acknowledgment
This work was supported by Cancer Research UK [CUK] grant
number C309/A2187. Additional funding was received from Astex
Therapeutics Ltd (JJC).
chromatography, eluting with EtOAc, gave 5 as a white
powder (0.851 g, 2.58 mmol, 57%). 1H NMR (500 MHz,
CDCl3): d = 1.26 (s, 9 H), 1.46 (s, 9 H), 1.70–1.78 (m, 1 H),
1.81–1.90 (m, 1 H), 2.20–2.30 (m, 2 H), 3.15–3.25 (m, 2 H),
3.65 (br s, 1 H), 3.95–4.15 (m, 2 H). 13C NMR (125 MHz,
CDCl3): d = 22.3, 28.4, 36.2, 37.5, 40.0, 56.9, 80.5, 119.6,
154.2. MS (ES+): m/z = 352 [M + Na+], 329 [M + H+].
tert-Butyl 4-Benzyl-4-(tert-butanesulfinamido)piper-
idine-1-carboxylate(6a); Via Nitrile 5: A solution of 5
(0.206 g, 0.625 mmol) and benzylmagnesium chloride (2 M
References and Notes
(1) For some recent examples of biologically active compounds
containing the 4-aminopiperidine motif, see: (a) Bamford,
M. J.; Bailey, N.; Davies, S.; Dean, D. K.; Francis, L.;
Panchal, T. A.; Parr, C. A.; Sehmi, S.; Steadman, J. G.;
Takle, A. K.; Townsend, J. T.; Wilson, D. M. Bioorg. Med.
Chem. Lett. 2005, 15, 3407. (b) Brinner, K. M.; Powles, M.
Synlett 2006, No. 16, 2565–2568 © Thieme Stuttgart · New York

2568
J. J. Caldwell, I. Collins
LETTER
in THF, 0.70 mL, 1.4 mmol) in anhyd THF (3 mL) was
refluxed under N2 for 3 h. The cooled reaction mixture was
diluted with sat. aq NH4Cl (10 mL) and extracted with
EtOAc (2 × 10 mL). The extracts were dried (Na2SO4) and
concentrated. Flash column chromatography, eluting with
EtOAc, gave 6a as a straw-coloured oil (0.122 g, 0.309
mmol, 49%). 1H NMR (500 MHz, CDCl3): d = 1.25 (s, 9 H),
1.25–1.32 (m, 1 H), 1.46 (s, 9 H), 1.52–1.60 (m, 1 H), 1.72–
1.80 (m, 1 H), 2.37–2.42 (m, 1 H), 2.71 (d, J = 13.0 Hz, 1 H),
2.94–3.15 (m, 2 H), 3.21 (d, J = 13.0 Hz, 1 H), 3.32 (s, 1 H),
3.72–3.95 (m, 2 H), 7.25–7.39 (m, 5 H). 13C NMR (125
MHz, CDCl3): d = 23.0, 24.2, 28.4, 33.7, 36.5, 39.0, 49.0,
55.6, 56.5, 79.6, 126.7, 128.2, 131.8, 135.6, 154.8. MS
(ES+): m/z = 416 [M + Na+], 395 [M + H+].
N2 for 14 h. The solution was cooled to 0 °C and a solution
of benzylmagnesium chloride (2 M in THF, 0.77 mL, 15.45
mmol) was added. After stirring for 20 h at r.t., the crude
reaction mixture was absorbed onto silica gel. Flash column
chromatography, eluting with EtOAc–hexane (2:1), gave 6a
(0.473 g, 1.20 mmol, 39%).
4-Benzylpiperidin-4-amine (3a): A solution of 6a (0.094 g,
0.238 mmol) in MeOH (5 mL) and 4 M HCl–dioxane (5 mL)
was stirred for 24 h. Concentration and purification by ion-
exchange on an SCX-2 Isolute column, eluting with MeOH
then 2 M NH3–MeOH, gave 3a as a yellow oil (0.036 g,
0.189 mmol, 80%). 1H NMR (500 MHz, MeOD): d = 1.38–
1.43 (m, 2 H), 1.60–1.66 (m, 2 H), 2.74 (s, 2 H), 2.84–2.92
(m, 4 H), 7.21–7.32 (m, 5 H). 13C NMR (125 MHz, MeOD):
d = 32.2, 38.5, 49.2, 50.8, 127.6, 129.2, 131.8, 138.2. MS
(ES+): m/z (ES+) = 191 [M + H+], 174 [M + H+ – NH3].
Direct Synthesis: A solution of 1 (0.615 g, 3.09 mmol), tert-
butylsulfinamide (0.390 g, 3.21 mmol) and Ti(OEt)4 (1.26
mL, 6.00 mmol) in anhyd THF (15 mL) was refluxed under
Synlett 2006, No. 16, 2565–2568 © Thieme Stuttgart · New York