A short synthesis of a trifold orthogonally protected, novel aminoazepanol building block

Article abstract of DOI:10.1055/s-0031-1289564

Orthogonally protected cis-5-aminoazepan-3-ol derivatives were prepared in three steps from N-Boc allylic amine, acrolein, and N-benzylhydroxylamine with an intramolecular 1,3-dipolar cycloaddition as the key reaction. Georg Thieme Verlag Stuttgart · New

Full text of DOI:10.1055/s-0031-1289564

LETTER
2841
A Short Synthesis of a Trifold Orthogonally Protected, Novel Aminoazepanol
Building Block
Synthesis of
a
Novel
A
a
minoazepa
r
nol Buil
t
iock na Würdemann, Jens Christoffers*
Institut für Reine und Angewandte Chemie, Carl von Ossietzky Universität Oldenburg, 26111 Oldenburg, Germany
Fax +49(441)7983873; E-mail: jens.christoffers@uni-oldenburg.de
Received 25 August 2011
Aminoaldehyde 6 is the starting material for the synthesis
Abstract: Orthogonally protected cis-5-aminoazepan-3-ol deriva-
tives were prepared in three steps from N-Boc allylic amine, ac-
rolein, and N-benzylhydroxylamine with an intramolecular 1,3-
dipolar cycloaddition as the key reaction.
of the nitrone 7, which seemed to be a suitable precursor
for an intramolecular 1,3-dipolar cycloaddition with the
allyl group (Scheme 1). Therefore, we initially prepared
aldehyde 6 in two steps by alkylation of deprotonated
(NaH in DMSO) carbamate 58 with 2-(2-bromoethyl)di-
oxolane (49% yield) and subsequent hydrolysis of the ac-
etal (TsOH, acetone, H2O, 66% yield). Product 6 was,
however, very hard to separate from remaining starting
material (28%) and could therefore not be obtained in
pure form. Fortunately, aldehyde 6 could be obtained in
one step by conjugate addition of carbamate 5 to acrolein,
when camphorsulfonic acid9 was applied as a substoichio-
metric additive.10 Conversion of compound 6 with
BnNHOH11 under ambient conditions indeed yielded ni-
trone 7, which could be detected by NMR, but not isolat-
ed. Upon heating, the intermediate 7 underwent 1,3-
dipolar nitrone–alkene cycloaddition.12 In contrast to our
expectations as well as to literature reports on products
with similar ring size,13 no annulated isoxazolidine was
detectable, which could have been further transformed to
a 4-amino-3-(hydroxymethyl)piperidine derivative. In-
stead, the bridged compound 9 was obtained.14 The latter
resulted from a Markovnikov-type regiochemistry of a not
fully concerted, initial addition of the iminium-type car-
bon atom to the allylic C–C double bond generating posi-
tive charge on the secondary olefinic carbon atom. The
product 9 was gratefully obtained with good yield and its
constitution was established by 2D NMR experiments.
The N–O bond of compound 9 could be reductively
cleaved with Zn in an acidic milieu to yield the Boc-pro-
tected N-benzylamino azepanol 8 in moderate yield.
Transfer hydrogenolysis of the benzyl group with
HCO2NH4 and Pd/C led with almost quantitative yield to
the primary amine 11. The latter product could also be
directly obtained from isoxazolidine 9 by transfer hydro-
genation (almost quantitative yield). Furthermore, hydro-
genation of compound 9 and introduction of a Cbz group
at the primary amine could be performed in a sequential
one-pot operation yielding the orthogonally double-car-
bamate-protected building block 1015 in reasonable yield.
Finally, the triple-protected aminoazepanol 1216 was ob-
tained by acetylation of compound 10 (89%).
Key words: azepanes, amines, 1,3-dipolar cycloaddition, N-het-
erocycles, nitrones
The azepane ring is an important structural motif in phar-
maceutically active compounds. Prominent examples are
antihistaminic azelastine (1),1 the cyclin-dependent ki-
nase inhibitor paullone (2),2 and the alkaloid ibugaine (3),
which is a psychoactive, traditional African drug
(Figure 1) that has recently come into focus for treatment
of opiate addiction.3 Zilpaterol (4) is marketed as a feed
additive for beef cattle.4 Monocyclic aminoazepanes with
several additional hydroxy groups were reported to be po-
tent glycosidase inhibitors.5 Aminoazepan-2-ones, that is,
caprolactam derivatives, were reported as peptidomimet-
ics.6 In the course of our investigations in piperidine de-
rivatives as scaffolds for medicinal chemistry,7 we found
a straightforward and extraordinarily short access to or-
thogonally protected, new 5-amino-3-hydroxyazepane
derivatives, which we wish to report herein.
O
N
Me
N
N
O
NH
N
H
Cl
1
2
O
NH
MeO
N
N
Et
N
i-PrHN
H
OH
3
4
Figure 1 Examples of biologically active 4-aminoazepanes
In summary, cis-5-aminoazepan-3-ol derivatives 8, 10,
and 11 with orthogonal nitrogen-protective groups were
obtained in three steps from N-Boc allylic amine 5. The
first step was the sulfonic acid catalyzed conjugate addi-
tion of carbamate 5 to acrolein, which was followed by in
SYNLETT 2011, No. 19, pp 2841–2843
Advanced online publication: 31.10.2011
DOI: 10.1055/s-0031-1289564; Art ID: B16411ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2842
M. Würdemann, J. Christoffers
LETTER
Boc
N
CHO
(a)
NHBoc
CHO
5
6, 67%
(b)
BnNHOH
Boc
N
N
O
Bn
7
Boc
N
Boc
N
(c)
(d), (e)
Bn
N
N
HO
HO
Boc
O
NHBn
NHCbz
10, 66%
8, 64%
9, 80%
(d)
(f)
96%
89%
Boc
Boc
N
N
(d)
HO
AcO
96%
NH2
NHCbz
11
12
Scheme 1 Synthesis of aminoazepanols. Reagents and conditions: (a) camphorsulfonic acid (0.2 equiv), CH2Cl2, 0–23 °C, 1 h; (b) MeCN,
23 °C, 0.5 h; 85 °C, 16 h; (c) Zn (4 equiv), THF–AcOH–H2O (1:1:2), 60 °C, 16 h; (d) cat. Pd/C, HCO2NH4 (5 equiv), MeOH, 65 °C, 3 h; (e)
CbzCl (1.4 equiv), Et3N (1.4 equiv), MeOH, 23 °C, 16 h; (f) Ac2O (1.5 equiv), pyridine (1.5 equiv), CH2Cl2, 23 °C, 16 h.
K.; Huber, E. W.; Peet, N. P.; Weintraub, P. M. Tetrahedron
1994, 50, 1033.
(6) Tanaka, K.-i.; Nemoto, H.; Sawanishi, H. Tetrahedron:
situ nitrone formation with N-benzyl hydroxyl amine.
Heating of this adduct led to a bridged oxazolidine 9 with
unexpected regiochemistry. The latter could be reductive-
ly transformed to the above-mentioned azepane-deriva-
tives, which are considered to be very valuable building
blocks and scaffolds for combinatorial chemistry.
Asymmetry 2005, 16, 1989.
(7) (a) Schramm, H.; Saak, W.; Hoenke, C.; Christoffers, J.
Eur. J. Org. Chem. 2010, 1745. (b) Rosiak, A.; Hoenke, C.;
Christoffers, J. Eur. J. Org. Chem. 2007, 4376.
(8) De Amici, M.; De Micheli, C.; Misani, V. Tetrahedron
1990, 46, 1975.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(9) Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.;
Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem.
Soc. 2002, 124, 8584.
(10) tert-Butyl N-Allyl-N-(3-oxopropyl)carbamate (6)
Acrolein (16.9 g, 302 mmol) and camphorsulfonic acid (1.40
g, 6.04 mmol) were added to an ice-cooled solution of N-Boc
allylamine (5, 4.75 g, 30.2 mmol) in CH2Cl2 (75 mL). The
resulting solution was stirred at 0 °C for 15 min and at 23 °C
for 30 min. The mixture was then washed with sat. NaHCO3
solution (75 mL), and the organic layer was dried (MgSO4).
After filtration, the solvent was removed, and the residue
was purified by chromatography on SiO2 (hexane–MTBE,
1:1; Rf = 0.33) to yield the title compound 6 (4.34 g, 20.4
mmol, 67%) as a colorless liquid. 1H NMR (500 MHz,
CDCl3): d = 1.42 (s, 9 H), 2.61–2.69 (m, 2 H), 3.45–3.53 (m,
2 H), 3.76–3.85 (m, 2 H), 5.05–5.15 (m, 2 H), 5.67–5.80 (m,
1 H), 9.76 (t, J = 1.6 Hz, 1 H) ppm. 13C{1H} NMR (125
MHz, CDCl3): d = 28.29 (3 × CH3), 40.64 (CH2), 43.34
(CH2), 50.42 (CH2), 79.97 (C), 116.36 (CH2), 133.95 (CH),
155.16 (C), 200.85 (CH) ppm. IR (ATR): 3084 (w), 2976
(w), 2932 (w), 2725 (w), 1723 (m), 1687 (vs), 1463 (m),
1407 (s), 1366 (s), 1247 (s), 1168 (vs), 1145 (vs), 920 (m),
864 (m), 774 (m) cm–1. MS (CI, isobutane): m/z (%) = 214
References and Notes
(1) (a) Horbal, J. M.; Bernstein, J. A. Clin. Med. Insights
Therapeut. 2010, 2, 427. (b) Bernstein, J. A. Curr. Med.
Res. Opin. 2007, 23, 2441.
(2) Tolle, N.; Kunick, C. Curr. Top. Med. Chem. 2011, 11, 1320.
(3) Gallo, C.; Renzi, P.; Loizzo, S.; Loizzo, A.; Capasso, A.
Pharmacologyonline 2009, 3, 906.
(4) Delmore, R. J.; Hodgen, J. M.; Johnson, B. J. J. Anim. Sci.
2010, 88, 2825.
(5) (a) Marcelo, F.; He, Y.; Yuzwa, S. A.; Nieto, L.; Jimenez-
Barbero, J.; Sollogoub, M.; Vocadlo, D. J.; Davies, G. D.;
Bleriot, Y. J. Am. Chem. Soc. 2009, 131, 5390. (b) Li, H.;
Marcelo, F.; Bello, C.; Vogel, P.; Butters, T. D.; Rauter,
A. P.; Zhang, Y.; Sollogoub, M.; Bleriot, Y. Bioorg. Med.
Chem. 2009, 17, 5598. (c) Li, H.; Bleriot, Y.; Mallet, J.-M.;
Rodriguez-Garcia, E.; Vogel, P.; Zhang, Y.; Sinay, P.
Tetrahedron: Asymmetry 2005, 16, 313. (d) Winkler, D. A.
J. Med. Chem. 1996, 39, 4332. (e) Farr, R. A.; Holland, A.
Synlett 2011, No. 19, 2841–2843 © Thieme Stuttgart · New York

LETTER
Synthesis of a Novel Aminoazepanol Building Block
under reduced pressure the residue was purified by
2843
(49) [M + H+], 158 (100). HRMS: m/z calcd for C11H20NO3:
214.1443; found: 214.1437 [M + H+]; C11H19NO3 (213.27).
(11) Maskill, H.; Jencks, W. P. J. Am. Chem. Soc. 1987, 109,
2062.
chromatography on SiO2 (hexane–MTBE, 10: 1; Rf = 0.27)
to give the title compound 10 (240 mg, 0.659 mmol, 66%) as
a colorless resin. Due to the carbamate group, NMR spectra
show a partially doubled signal set, ratio ca. 2:1. 1H NMR
(500 MHz, CDCl3): d = 1.42 (s, 18/3 H), 1.46 (s, 9/3 H),
1.74–1.85 (m, 2 H), 1.87–1.96 (m, 1 H), 2.01–2.10 (m, 1 H),
3.14 (dt, J = 14.1, 5.6 Hz, 1 H), 3.23 (dd, J = 15.0, 2.7 Hz, 1
H), 3.28–3.41 (m, 1 H), 3.49–3.61 (m, 2/3 H), 3.64–3.71 (m,
2/3 H), 3.74–3.80 (m, 1/3 H), 3.84 (dd, J = 14.9, 4.6 Hz, 2/3
H), 3.88–3.94 (m, 2/3 H), 4.02–4.09 (m, 1/3 H), 4.11–4.17
(m, 2/3 H), 5.08 (s, 2 H), 5.55 (d, J = 7.2 Hz, 1/3 H), 5.88 (d,
J = 6.7 Hz, 2/3 H), 7.28–7.33 (m, 1 H), 7.33–7.37 (m, 4 H)
ppm. 13C{1H} NMR (125 MHz, CDCl3): d = 28.17 (6/3
CH3), 28.31 (3/3 CH3), 32.37 (1/2 CH2), 33.62 (1/2 CH2),
40.26 (1/2 CH2), 41.76 (1/2 CH2), 43.64 (1/2 CH2), 43.93 (1/
2 CH2), 47.90 (CH), 50.17 (1/2 CH2), 52.63 (1/2 CH2), 66.36
(1/2 CH2), 66.68 (1/2 CH2), 68.78 (1/2 CH), 69.96 (1/2 CH),
80.11 (1/2 C), 80.32 (1/2 C), 127.93 (2 CH), 128.02 (CH),
128.34 (2 × CH), 136.45 (C), 154.98 (1/2 C), 155.53 (1/2 C),
157.49 (C) ppm. IR (ATR): 3324 (m), 3065 (w), 3034 (w),
2975 (m), 2930 (m), 1689 (vs), 1668 (vs),1527 (m), 1479
(m), 1454 (m), 1416 (s), 1366 (s), 1248 (s), 1160 (vs),
1058 (s), 1027 (s), 865 (m), 736 (s), 697 (s) cm–1. MS (CI,
isobutane): m/z (%) = 365 (28) [M + H+], 309 (100). HRMS:
m/z calcd for C19H29N2O5: 365.2077; found: 365.2068 [M +
H+]; C19H28N2O5 (364.44).
(12) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.
(13) (a) LeBel, N. A.; Post, M. E.; Whang, J. J. J. Am. Chem. Soc.
1964, 86, 3759. (b) Oppolzer, W.; Keller, K. Tetrahedron
Lett. 1970, 1117.
(14) tert-Butyl 7-Benzyl-8-oxa-3,7-diazabicyclo[4.2.1]nonane-
3-carboxylate (9)
Benzylhydroxylamine (485 mg, 3.94 mmol) was added to a
solution of aldehyde 6 (800 mg, 3.75 mmol) in MeCN (16
mL), and the mixture was stirred for 30 min at 23 °C and for
16 h under reflux. The solvent was evaporated, and the
residue was chromatographed on SiO2 (hexane–EtOAc, 2:1;
Rf = 0.29) to yield the title compound 9 (964 mg, 3.03 mmol,
81%) as a colorless solid, mp 65–66 °C. Due to the
carbamate group, NMR spectra show a partially doubled
signal set. 1H NMR (500 MHz, CDCl3): d = 1.47 (s, 9 H),
1.55–1.70 (m, 2 H, 5-H), 1.83–1.89 (m, 1 H, 9-H), 2.49–2.57
(m, 1 H, 9-H), 2.94 (d, J = 14.6 Hz, 1/2 H, 2-H), 3.04 (d,
J = 14.7 Hz, 1/2 H, 2-H), 3.08–3.15 (m, 1/2 H, 4-H), 3.15–
3.23 (m, 1/2 H, 4-H), 3.43–3.47 (m, 1 H, 6-H), 3.73 (d,
J = 12.8 Hz, 1/2 H, BnCH2), 3.75 (d, J = 12.6 Hz, 1/2 H,
BnCH2), 3.77–3.83 (m, 1/2 H, 4-H), 3.83–3.86 (m, 1/2 H, 2-
H), 3.94–3.99 (m, 1/2 H, 4-H), 4.01–4.07 (m, 1/2 H, 2-H),
4.06 (d, J = 12.7 Hz, 1 H, BnCH2), 4.69 (dd, J = 8.8, 3.4 Hz,
1/2 H, 1-H), 4.72 (dd, J = 8.7, 3.6 Hz, 1/2 H, 1-H), 7.25–7.30
(m, 1 H), 7.31–7.39 (m, 4 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): d = 28.27 (3 × CH3), 32.10 (1/2 CH2, C-9), 32.23
(1/2 CH2, C-9), 32.95 (1/2 CH2, C-5), 33.57 (1/2 CH2, C-5),
42.00 (1/2 CH2, C-4), 42.58 (1/2 CH2, C-4), 49.72 (1/2 CH2,
C-2), 50.79 (1/2 CH2, C-2), 60.35 (1/2 CH, C-6), 60.48 (1/2
CH, C-6), 62.77 (CH2, Ph-CH2), 77.52 (1/2 CH, C-1), 77.70
(1/2 CH, C-1), 79.24 (1/2 C, BocC), 79.41 (1/2 C, BocC),
127.24 (CH), 128.27 (2 × CH), 128.80 (CH), 128.86 (CH),
137.37 (C), 154.87 (1/2 C), 155.48 (1/2 C) ppm. IR (ATR):
2975 (m), 2952 (m), 2910 (m), 1688 (vs), 1461 (s), 1413
(vs), 1364 (s), 1322 (s), 1172 (vs), 1125 (vs), 1063 (s), 984
(s), 878 (vs), 810 (m), 744 (vs), 698 (s) cm–1. MS (CI,
isobutane): m/z (%) = 319 (100) [M + H+], 263 (16). HRMS:
m/z calcd for C18H27N2O3: 319.2022; found: 319.2015 [M +
H+]; C18H26N2O3 (318.41).
(16) cis-3-Acetoxy-5-(benzyloxycarbonylamino)-1-(tert-butyl-
oxycarbonyl)azepane (12)
Pyridine (316 mg, 3.99 mmol) and Ac2O (407 mg, 3.99
mmol) were added to a solution of azepanol 10 (969 mg,
2.66 mmol) in CH2Cl2 (10 mL). The solution was stirred at
23 °C for 24 h, and then the solvent was removed in vacuum.
The residue was chromatographed on SiO2 (hexane–MTBE,
1:2; Rf = 0.26) to yield ester 12 as a colorless oil (960 mg,
2.36 mmol, 89%). Due to the carbamate groups NMR
spectra show a partially doubled signal set. 1H NMR (500
MHz, CDCl3): d = 1.45 (s, 1/2 × 9 H), 1.47 (s, 1/2 × 9 H),
1.74–1.94 (m, 2 H), 1.96–2.01 (m, 1 H), 2.02 (s, 1/2 × 3 H),
2.05 (s, 1/2 × 3 H), 2.07–2.12 (m, 1 H), 3.14–3.26 (m, 1 H),
3.38–3.46 (m, 1/2 H), 3.50–3.66 (m, 2 H), 3.72–3.85 (m, 1
H), 3.88–3.96 (m, 1/2 H), 5.00–5.15 (m, 7/2 H), 5.22 (d,
J = 7.4 Hz, 1/2 H), 7.30–7.39 (m, 5 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): d = 21.06 (CH3), 28.23 (3 CH3), 33.25
(1/2 CH2), 33.94 (1/2 CH2), 38.28 (1/2 CH2), 38.77 (1/2
CH2), 43.58 (1/2 CH2), 44.12 (1/2 CH2), 47.62 (1/2 CH),
47.93 (1/2 CH), 49.94 (CH2), 66.51 (CH2), 70.51 (CH),
79.81 (1/2 C), 79.98 (1/2 C), 127.97 (2 CH), 128.02 (CH),
128.40 (2 CH), 136.35 (C), 155.04 (C), 155.27 (C), 169.67
(C) ppm. IR (ATR): 3327 (w), 2975 (w), 2936 (w), 1690
(vs), 1525 (m), 1455 (m), 1415 (m), 1366 (m), 1231 (vs),
1157 (s), 1030 (s), 699 (m), 646 (m), 624 (m) cm–1. MS (CI,
isobutane): m/z (%) = 407 (16) [M + H+], 351 (100), 307
(17). HRMS: m/z calcd for C21H31N2O6: 407.2182; found:
407.2180 [M + H+]; C21H30N2O6 (406.47).
(15) cis-5-(Benzyloxycarbonylamino)-1-(tert-butyloxy-
carbonyl)-3-hydroxyazepane (10)
Pd/C (100 mg, 10% w/w Pd) and ammonium formate (315
mg, 5.00 mmol) were added to a solution of isoxazolidine 9
(318 mg, 1.00 mmol) in MeOH (8 mL), and the mixture was
heated under reflux for 3 h. After cooling, the mixture was
filtered through Celite, the residue was rinsed with CH2Cl2
(ca. 15 mL), and the filtrate was evaporated. The residue was
dissolved in MeOH (3 mL) and the solution cooled in an ice
bath. CbzCl (239 mg, 1.40 mmol) and Et3N (142 mg, 1.40
mmol) were added, the ice bath was removed, and the
mixture stirred at 23 °C for 16 h. After removing the solvents
Synlett 2011, No. 19, 2841–2843 © Thieme Stuttgart · New York

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