Synthesis of bridged 1,4-diazepane derivatives via Schmidt reactions

Article abstract of DOI:10.1016/j.tetlet.2010.01.121

A series of bridged 1,4-diazepanes (i.e., diazabicyclo[n.3.2]alkanes, n = 3-5) selectively protected at one of the nitrogen atoms was prepared, for possible application in drug design, via Schmidt rearrangement of the corresponding ketones.

Full text of DOI:10.1016/j.tetlet.2010.01.121

Tetrahedron Letters 51 (2010) 1790–1792
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Tetrahedron Letters
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Synthesis of bridged 1,4-diazepane derivatives via Schmidt reactions
Andrey P. Mityuk a, Aleksandr V. Denisenko a, Oleksandr P. Dacenko a, Oleksandr O. Grygorenko a,b,
,
*
a
a,b
Pavel K. Mykhailiuk a,b, , Dmitriy M. Volochnyuk , Andrey A. Tolmachev
*
a Enamine Ltd, Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
b Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of bridged 1,4-diazepanes (i.e., diazabicyclo[n.3.2]alkanes, n = 3–5) selectively protected at one of
the nitrogen atoms was prepared, for possible application in drug design, via Schmidt rearrangement of
the corresponding ketones.
Received 2 December 2009
Revised 12 January 2010
Accepted 29 January 2010
Available online 4 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Though combinatorial chemistry remains an essential part of
drug discovery, so far this approach has demonstrated a poor suc-
cess rate, presumably due to the rather limited chemical space cov-
ered by the products obtained. This is partially due to classical
combinatorial libraries suffering from lack of molecular rigidity.1
Fragment-based drug design which became a novel paradigm for
drug discovery in the last decade2 also appeared to require con-
formationally restricted and rigid building blocks. Due to a prede-
fined spatial orientation of the molecular fragments located on a
conformationally rigid scaffold, a decrease in entropy of binding
of the molecule with its biological target might be expected, thus
leading to higher affinity of the potential drug candidate.3
Aliphatic diamines exemplify privileged structures among other
small molecules of importance to drug discovery.4 Conformational-
ly restricted diamines have been widely used in drug design; in
particular, piperazine 1 and 1,4-diazepane 2 scaffolds are constitu-
ents of Sildenafil 35 and Fasudil 4,6 and compounds with antibac-
terial 5,7 nootropic and antiamyloidogenic 68 activities (Fig. 1).
In this Letter, we report our results on the synthesis of bridged
1,4-diazepanes 7–10 (Scheme 1). Retrosynthetic analysis of 7–10
leads to N-benzyl azabicyclo[n.3.1]alkanones 11–14 as convenient
starting materials which are readily prepared by double Mannich
annelation of the corresponding cycloalkanones.9 It should be
noted that the synthetic approach should consider the possibility
of generating diamines 7–10 monoprotected at one of the nitrogen
atoms; this feature is essential for further selective modification.
To achieve ring expansion of the bicyclic cores of 11–14, we
decided to use classical Schmidt reaction conditions (sodium
azide–sulfuric acid).10 It emerged that the bridge length in mole-
cules of 11–14 is a crucial factor that determines the reaction out-
come. In particular, in the case of azabicyclo[3.2.1]octane
derivative 11, fragmentation occurred instead of rearrangement
leading to the formation of tetrahydro-1H-azepine 15 in 71%
yield.11 When ketone 12 was submitted to the Schmidt reaction,
a
mixture of hexahydroazocine 1612 (23%) and diazabicy-
clo[3.3.2]decane 1713 (40%) was obtained. Finally, rearrangement
OEt
H
N
H
N
O
N
S
N
N
N
H
O
HN
N
H
N
O
N
O
N
1
2
3
N
OH
O
NH
F
O
O
S
N
O
N
N
O
Br
N
N
H
4
5
6
Figure 1.
O
n
H
N
n
NH
N
Ph
7, n = 1
8, n = 2
9, n = 3
10, n = 4
11, n = 1
12, n = 2
13, n = 3
14, n = 4
* Corresponding authors. Tel.: +38 044 239 33 15; fax: +38 044 502 48 32.
E-mail addresses: gregor@univ.kiev.ua (O.O. Grygorenko), pashamk@gmx.de
(P.K. Mykhailiuk).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.121

A. P. Mityuk et al. / Tetrahedron Letters 51 (2010) 1790–1792
1791
References and notes
O
H
N
H2N
n
1. Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003, 43, 218–227.
O
NaN3
2. (a) Erlanson, D. A.; McDowell, R.; O’Brien, T. J. Med. Chem. 2004, 47, 3463–3482;
(b) Alex, A. A.; Flocco, M. M. Curr. Topic Med. Chem. 2007, 7, 1544–1567; (c)
Hajhuk, P. J.; Greer, J. Nat. Rev. Drug Disc. 2007, 6, 211–219.
3. (a) Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University Press:
New York, 2005. pp 210–213; (b) Komarov, I. V.; Grygorenko, O. O.; Turov, A.
V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73, 785–810.
4. (a) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101–114;
(b) Shivanyuk, A. N.; Volochnyuk, D. M.; Komarov, I. V.; Nazarenko, K. G.;
Radchenko, D. S.; Kostyuk, A.; Tolmachev, A. A. Chem. Today 2007, 25, 12–13.
5. Terrett, N. K.; Bell, S. A.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6,
1819–1824.
O
+
H2SO4
N
n
n
N
N
Ph
Ph
Ph
11, n = 1
12, n = 2
13, n = 3
14, n = 4
15, n = 1, 71%
16, n = 2, 23%
17, n = 2, 40%
18, n = 3, 65%
19, n = 4, 60%
Scheme 2.
6. Sielecki, T. M.; Boylan, J. F.; Benfield, P. A.; Trainor, J. L. J. Med. Chem. 2000, 43,
1–18.
7. Kleinman, E. F. Eur. Patent EP 297858, 1989; Chem. Abstr. 1989, 110, 173112.
8. Hammond, P. S.; Mazurov, A. A.; Miao, L.; Xiao, Y.-D.; Bhatti, B.; Strachan, J.-P.;
Murthy, V. S.; Kombo, D. C.; Akireddy, S. R. PCT Int. Pat. WO 2008112734, 2008;
Chem. Abstr. 2008, 149, 378709.
9. Mityuk, A. P.; Denisenko, A. V.; Dacenko, O. P.; Grygorenko, O. O.; Mykhailiuk, P. K.;
Volochnyuk, D. M.; Shishkin, O. V.; Tolmachev, A. A. Synthesis 2010, 493–497.
10. (a) Schmidt, K. F. Ber. 1924, 57, 704; (b) Wolff, H.. In Organic Reactions; Adams,
R., Ed.; Wiley-VCH: New York, 1946; Vol. 3, p 307.
11. Schmidt reaction of ketones 11–14 (general procedure, the reaction of 3-benzyl-3-
aza-bicyclo[3.2.1]octan-8-one (11) is given as an example): To a mixture of CHCl3
(66 mL) and H2SO4 (40 g), ketone 11 (9.4 g, 44 mmol) was added slowly
followed by NaN3 (3.4 g) at 10–20 °C with stirring (Caution: External cooling
should be used). The resulting mixture was stirred overnight, then slowly
added to an excess of saturated aqueous NaHCO3 (700 mL) and extracted with
CH2Cl2 (3 Â 150 mL). The combined organic extracts were dried over Na2SO4
and then evaporated to dryness. The residue was recrystallized from benzene–
hexanes to give 7.1 g (31 mmol, 71%) of 1-benzyl-2,3,4,7-tetrahydro-1H-
azepine-3-carboxamide (15) as a white solid. Mp 109 °C. MS (m/z, CI): 231
(MH+). Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 73.37;
H, 8.03; N, 11.96. 1H NMR (CDCl3), d: 7.61 (br s, 1H, CONHH), 7.35 (t, J = 7.0 Hz,
2H, C6H5), 7.30 (m, 3H, C6H5), 5.88 (m, 1H, 5- or 6-CH), 5.77 (m, 1H, 5- or 6-CH),
5.75 (br s, 1H, CONHH), 3.66 (d, J = 13.1 Hz, 1H, CHHC6H5), 3.62 (d, J = 13.1 Hz,
1H, CHHC6H5), 3.28 (m, 2H), 3.01 (dd, J = 15.2 and 4.4 Hz, 1H), 2.80 (dd, J = 13.0
and 2.2 Hz, 1H, CHH), 2.69 (m, 1H), 2.63 (m, 1H), 2.46 (d, J = 15.2 Hz, 1H). 13C
NMR (CDCl3), d: 177.1 (C@O), 138.1 (1-C of C6H5), 131.2 (CH), 129.5 (CH), 129.0
(CH), 128.5 (CH), 127.5 (CH), 63.1 (CH2), 60.6 (CH2), 54.3 (CH2), 43.4 (3-CH),
30.7 (4-CH2).
O
H
N
NaN3
H2SO4
O
O
O
N
N
Ph
Ph
20
21
Scheme 3.
H
N
H
N
O
LiAlH4
n
n
N
N
Ph
Ph
17, n = 2
18, n = 3
19, n = 4
22, n = 2, 96%
23, n = 3, 95%
24, n = 4, 85%
Scheme 4.
12. 1-Benzyl-1,2,3,4,5,8-hexahydro-azocine-3-carboxamide (16) was obtained
from 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (12) in 23% (1.8 g) yield after
purification by flash chromatography of the mother liquor obtained by
recrystallization of 17 [hexanes–2-propanol (3:1)]. Mp 88–89 °C (benzene–
hexanes). MS (m/z, CI): 245 (MH+). Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25;
N, 11.46. Found: C, 73.99; H, 8.51; N, 11.09. 1H NMR (CDCl3), d: 7.33 (m, 4H,
C6H5), 7.29 (m, 1H, 4-CH of C6H5), 6.69 (br s, 1H, NH), 5.89 (m, 1H, CH@CH),
5.60 (br s, 1H, NHH), 5.56 (m, 1H, CH@CH), 3.67 (d, J = 13.2 Hz, 1H, CHHC6H5),
3.61 (d, J = 13.2 Hz, 1H, CHHC6H5), 3.41 (dd, J = 15.4 and 6.5 Hz, 1H, 8-CHH),
3.11 (dd, J = 15.4 and 6.3 Hz, 1H, 8-CHH), 3.00 (dd, J = 13.2 and 7.8 Hz, 1H, 2-
CHH), 2.82 (d, J = 13.2 Hz, 1H, 2-CHH), 2.79 (m, 1H), 2.66 (m, 1H), 2.27 (m, 1H),
1.99 (m, 1H), 1.88 (m, 1H). 13C NMR (CDCl3), d: 178.1 (C@O), 138.8, 132.6,
129.1, 128.6, 127.4, 125.5, 61.6 (CH2C6H5), 55.5, 50.6, 43.3, 30.2, 25.3.
13. 3-Benzyl-3,9-diaza-bicyclo[3.3.2]decan-10-one (17) was obtained from 3-
benzyl-3-azabicyclo[3.3.1]nonan-9-one (12) in 40% (3.1 g) yield. Mp 158 °C
(benzene). MS (m/z, CI): 245 (MH+). Anal. Calcd for C15H20N2O: C, 73.74; H,
8.25; N, 11.46. Found: C, 73.52; H, 8.09; N, 11.70. 1H NMR (CDCl3), d: 7.35 (m,
4H, C6H5), 7.27 (m, 1H, 4-CH of C6H5), 7.21 (br d, J = 6.2 Hz, 1H, NH), 3.57 (d,
J = 13.1 Hz, 1H, CHHC6H5), 3.51 (d, J = 13.1 Hz, 1H, CHHC6H5), 3.39 (q, J = 6.6 Hz,
1H, 1-CH), 2.84 (dd, J = 12.4 and 5.0 Hz, 1H), 2.76 (m, 2H), 2.45 (d, J = 11.7 Hz,
1H), 2.37 (d, J = 13.1 Hz, 1H), 2.11 (m, 1H), 1.76–1.97 (m, 4H), 1.52 (m, 1H). 13C
NMR (CDCl3), d: 179.4 (C@O), 138.9 (1-C6H5), 129.0 (CH), 128.4 (CH), 127.2
(CH), 63.6 (CH2), 61.5 (CH2), 55.6 (CH2), 48.5 (CH), 45.7 (CH), 27.9 (CH2), 23.8
(CH), 22.8 (CH).
Boc
N
H
N
1. Boc2O
2. H2, Pd-C
N
NH
Ph
23
25, 68%
Scheme 5.
of compounds 13 and 14 resulted in exclusive formation of amides
1814 (65%) and 1915 (60%), respectively (Scheme 2). This effect ap-
pears to be very sensitive to modification of the bicyclic core, in
particular, compound 20 gives only the usual bicyclic Schmidt
rearrangement product 21 under these reaction conditions
(Scheme 3).16
14. 8-Benzyl-8,10-diaza-bicyclo[4.3.2]undecan-11-one (18) was obtained from 8-
benzyl-8-azabicyclo[4.3.1]decan-10-one (13) in 65% (6.2 g) yield. Mp 126 °C
(benzene). MS (m/z, CI): 259 (MH+). Anal. Calcd for C16H22N2O: C, 74.38; H,
8.58; N, 10.84. Found: C, 74.02; H, 8.85; N, 11.07. 1H NMR (DMSO-d6), d: 7.51
(br d, J = 6.8 Hz, 1H, NH), 7.35 (m, 4H, C6H5), 7.27 (m, 1H, 4-CH of C6H5), 3.49
(m, 2H, CH2C6H5), 3.28 (m, 1H), 2.92 (d, J = 11.9 Hz, 1H), 2.64 (d, J = 11.9 Hz,
1H), 2.51 (m, 1H), 2.25 (d, J = 11.9 Hz, 2H), 2.09 (m, 2H), 1.92 (m, 1H), 1.73 (m,
1H), 1.61 (m, 2H), 1.43 (m, 2H). 13C NMR (CDCl3), d: 180.6 (C@O), 138.8 (1-C of
C6H5), 129.4 (CH), 128.5 (CH), 127.4 (CH), 64.9 (CH2), 62.5 (CH2), 57.7 (CH2),
51.5 (CH), 47.2 (CH), 36.6 (CH2), 33.4 (CH2), 26.1 (CH2), 24.9 (CH2).
15. 9-Benzyl-9,11-diaza-bicyclo[5.3.2]dodecan-12-one 19 was obtained from 9-
benzyl-9-azabicyclo[5.3.1]undecan-11-one 14 in 60% (5.8 g) yield. Mp 180 °C
(benzene). MS (m/z, CI): 273 (MH+). Anal. Calcd for C17H24N2O: C, 74.96; H,
8.88; N, 10.28. Found: C, 75.37; H, 9.13; N, 10.01. 1H NMR (CDCl3), d: 7.34 (m,
4H, C6H5), 7.26 (m, 1H, 4-CH of C6H5), 6.39 (br s, 1H, NH), 3.63 (d, J = 13.1 Hz,
1H, CHHC6H5), 3.57 (d, J = 13.1 Hz, 1H, CHHC6H5), 3.20 (m, 1H), 2.80 (m, 2H),
2.66 (m, 1H), 2.45 (m, 2H), 2.34 (m, 1H), 1.91 (m, 1H), 1.68–1.85 (m, 5H), 1.36
(m, 3H). 13C NMR (CDCl3), d: 179.3 (C@O), 139.2 (1-C of C6H5), 129.1 (CH), 128.5
Compounds 17–19 were reduced with lithium aluminium hy-
dride to afford monoprotected diamine derivatives 22–24 suitable
for further selective modification (Scheme 4).17–19
An ability to obtain orthogonally monoprotected dia-
zabicycloalkane derivatives (i.e., 25) was also demonstrated in
the case of the diamine 8 (Scheme 5).20
In conclusion, an expedient approach to selectively monopro-
tected derivatives of diamines 8–10 (compounds 22–25) which
are of interest for drug design has been developed.
Acknowledgement
The authors are thankful to Olga V. Manoylenko for her invalu-
able help with chromatographic separations.

1792
A. P. Mityuk et al. / Tetrahedron Letters 51 (2010) 1790–1792
(CH), 127.3 (CH), 64.2 (CH2), 60.4 (CH2), 55.4 (CH2), 50.6 (CH), 47.8 (CH), 31.7
(CH2), 29.4 (CH2), 25.0 (CH2), 24.5 (CH2), 23.5 (CH2).
16. Garrison, G. L.; Berlin, K. D.; Scherlag, B. J.; Lazzara, R.; Patterson, E.; Sangiah, S.;
Chen, C.-L.; Schubot, F.; Siripitayananon, J.; Hossain, M. B.; van der HeIm, D. J.
Org. Chem. 1993, 58, 7670–7678.
be performed by flash chromatography [Et2O–MeOH (2:1) as eluent]. MS (m/
z, EI): 258 (M+), 191 (M+–C7H7), 134, 91 (C7H7+). Anal. Calcd for C17H26N2: C,
79.02; H, 10.14; N, 10.84. Found: C, 78.77; H, 10.45; N, 10.49. 1H NMR
(CDCl3), d: 7.36 (m, 4H, C6H5), 7.30 (m, 1H, 4-CH of C6H5), 3.78 (s, 1H), 3.67
(s, 1H), 3.65 (d, J = 13.0 Hz, 1H, CHHC6H5), 3.58 (d, J = 13.0 Hz, 1H, CHHC6H5),
3.20 (s, 1H), 3.00 (d, J = 14.3 Hz, 1H), 2.88 (dd, J = 14.4 and 5.1 Hz, 1H), 2.80
(m, 2H), 2.66 (d, J = 14.0 Hz, 1H), 1.83–2.19 (m, 5H), 1.70 (m, 3H), 1.57 (m,
1H), 1.45 (m, 2H). 13C NMR (CDCl3), d: 138.8 (1-C of C6H5), 129.9 (CH), 128.1
(CH), 127.0 (CH), 65.2 (CH2), 60.9 (CH2), 59.0 (CH2), 54.8 (1-CH), 49.8 (CH2),
38.7 (6-CH), 35.0 (CH2), 32.0 (CH2), 31.8 (CH2), 26.1 (CH2), 26.0 (CH2).
20. Procedure for the synthesis of 25: To a solution of amine 23 (8.6 g, 37 mmol) in
Et2O (100 mL), a solution of NaOH (6 g, 0.150 mol) in H2O (30 mL) was added.
To the resulting mixture, a solution of Boc2O (9.8 g, 45 mmol) in Et2O (30 mL)
was added dropwise. The reaction mixture was stirred overnight, then the
aqueous phase was separated and washed with Et2O (2 Â 30 mL). The
combined organic extracts were dried over MgSO4 and evaporated to
dryness. The residue was dissolved in MeOH (80 mL) and hydrogenated over
20% Pd(OH)2 on charcoal at 50 bar and at 40 °C for 5 h. The catalyst was filtered
off, and the solvent was removed in vacuo. The residue was purified by flash
chromatography [hexane–2-propanol (gradient 9:1 to 1:1) as eluent] to give
tert-butyl 3,9-diazabicyclo[3.3.2]decane-9-carboxylate (25) (6.1 g, 25 mmol,
68%). Anal. Calcd for C13H24N2O2: C, 64.97; H, 10.07; N, 11.66. Found: C, 65.19;
H, 10.25; N, 11.31. MS (m/z, EI): 240 (M+), 184 (M+À(CH3)2C@CH2), 167
(M+À(CH3)3CO), 139, 110, 96, 82, 68, 57. The product was obtained as a
mixture of E/Z rotamers at the amide bond. 1H NMR (CDCl3): 4.71 (s, 0.6H, 1-
CH), 4.48 (s, 0.4H, 1-CH), 3.77 (d, J = 12.8 Hz, 0.4H, 10-CHH), 3.66 (d, J = 12.8 Hz,
0.6H, 10-CHH), 3.43 (d, J = 12.8 Hz, 0.6H, 10-CHH), 3.41 (d, J = 12.8 Hz, 0.4H, 10-
CHH), 3.06 (m, 2H), 2.79 (m, 2H), 2.16 (s, 0.4H, 5-CH), 2.11 (s, 0.6H, 5-CH), 1.94
(m, 1H), 1.85 (m, 2H), 2.57 (m, 2H), 1.55 (m, 1H), 1.47 (m, 1H), 1.46 (s, 9H). 13C
NMR (CDCl3): 155.7 and 155.4 (C@O), 79.2 ((CH3)3C), 54.9, 54.8, 54.7, 53.8,
53.4, 52.8, 51.9, 51.4, 34.9, 34.7, 29.1, 29.0, 28.7 and 28.6 ((CH3)3C), 28.2, 27.9,
22.7 and 22.6.
17. Reduction of amides 17–19 (general procedure, synthesis of 3-benzyl-3,9-
diaza-bicyclo[3.3.2]decane (22) is given as an example): to a suspension of
LiAlH4 (4.7 g) in dry THF (200 mL), a solution of amide 17 (10 g, 41 mmol) in
THF (100 mL) was added dropwise, and the resulting mixture was refluxed for
36 h with stirring. Then H2O (20 mL) was added carefully, and the mixture was
stirred for 15 min. The precipitate was filtered off and washed with THF
(5 Â 100 mL). The filtrate was evaporated and distilled (127 °C/0.5 mmHg) to
give 9.0 g (39 mmol, 96%) of diamine 22. MS (m/z): 231 (MH+). Anal. Calcd for
C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C, 78.02; H, 9.27; N, 12.38. 1H
NMR (CDCl3), d: 7.28 (m, 4H, C6H5), 7.18 (m, 1H, 4-CH of C6H5), 3.48 (d,
J = 13.3 Hz, 1H, CHHC6H5), 3.42 (d, J = 13.3 Hz, 1H, CHHC6H5), 3.25 (m, 1H, 1-
CH), 3.02 (m, 2H), 2.93 (m, 2H), 2.53 (br s, 1H, NH), 2.41 (m, 1H), 2.33 (d,
J = 12.0 Hz, 1H), 2.28 (d, J = 12.0 Hz, 1H), 2.01 (m, 1H, 5-CH), 1.93 (m, 2H), 1.60–
1.70 (m, 3H). 13C NMR (CDCl3), d: 139.7 (1-C6H5), 128.4 (CH), 127.9 (CH), 126.5
(CH), 63.6 (CH2), 61.6 (CH2), 61.2 (CH2), 54.0 (1-CH), 51.5 (CH2), 36.5 (5-CH),
32.8 (CH2), 30.6 (CH2), 23.2 (CH2).
18. 8-Benzyl-8,10-diaza-bicyclo[4.3.2]undecane (23) was obtained from amide 18
in 95% (5.4 g) yield. Bp 139 °C/0.5 mmHg. MS (m/z): 245 (MH+). Anal. Calcd for
C16H24N2: C, 78.64; H, 9.90; N, 11.46. Found: C, 78.94; H, 9.63; N, 11.48. 1H
NMR (CDCl3), d: 7.33 (m, 4H, C6H5), 7.24 (m, 1H, 4-CH of C6H5), 3.62 (d,
J = 12.7 Hz, 1H, CHHC6H5), 3.39 (d, J = 12.7 Hz, 1H, CHHC6H5), 3.35 (m, 1H), 3.16
(d, J = 14.2 Hz, 1H), 2.93 (dd, J = 14.2 and 5.2 Hz, 1H), 2.88 (ddd, J = 11.7, 3.2 and
1.8 Hz, 1H), 2.58 (ddd, J = 13.6, 5.2 and 1.8 Hz, 1H), 2.49 (d, J = 13.6 Hz, 1H),
2.28 (d, J = 11.7 Hz, 1H), 2.12 (m, 1H), 1.96 (m, 2H), 1.85 (m, 1H), 1.77 (br s, 1H,
NH), 1.56–1.70 (m, 3H), 1.43–1.52 (m, 2H). 13C NMR (CDCl3), d: 139.8 (1-C of
C6H5), 129.6 (CH), 128.2 (CH), 127.0 (CH), 64.9 (CH2), 62.8 (CH2), 58.3 (1-CH),
50.1 (CH2), 38.6 (6-CH), 33.9 (CH2), 32.8 (CH2), 25.4 (CH2), 25.2 (CH2).
19. 9-Benzyl-9,11-diaza-bicyclo[5.3.2]dodecane (24) was obtained from amide
19 in 85% (4.8 g) yield. Bp 151 °C/0.5 mmHg. Alternatively, purification could