An approach to azabicyclo[ n.3.1]alkanes by double mannich reaction

Article abstract of DOI:10.1055/s-0029-1217137

Chlorotrimethylsilane-promoted double Mannich annulation of ketones using N,N-bis(methoxymethyl)benzylamine has been explored. It has been shown that the structure of the substrate drastically influenced the outcome of the reaction. The method allows azabicyclo[n.3.1]alkane derivatives (n=2-5) to be obtained in good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1217137

PAPER
493
An Approach to Azabicyclo[n.3.1]alkanes by Double Mannich Reaction
Double
Mannich
An
nnulation drey P. Mityuk,a Aleksandr V. Denisenko,a Oleksandr P. Dacenko,a Oleksandr O. Grygorenko,*a,b
Pavel K. Mykhailiuk,a,b Dmitriy M. Volochnyuk,a,c Oleg V. Shishkin,d Andrey A. Tolmacheva,b
a
Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine
b
Fax +380(44)5024832; E-mail: gregor@univ.kiev.ua
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
STC ‘Institute for Single Crystals’, National Academy of Science of Ukraine, 60 Lenina ave., Kharkiv 61001, Ukraine
c
d
Received 29 September 2009; revised 19 October 2009
NMe
Abstract: Chlorotrimethylsilane-promoted double Mannich annu-
lation of ketones using N,N-bis(methoxymethyl)benzylamine has
been explored. It has been shown that the structure of the substrate
drastically influenced the outcome of the reaction. The method al-
NH
OH
lows azabicyclo[n.3.1]alkane derivatives (n = 2–5) to be obtained
in good yields.
O
HN
Ph
O
Key words: annulation, Mannich bases, molecular rigidity, bicy-
clic compounds, chlorotrimethylsilane
1
2
NMe
N
N
N
Fragment-based drug design, which became a novel para-
digm for drug discovery in the last decade,1 appeared to
require even more demanding and novel diverse building
blocks than high-throughput screening; this has represent-
ed an ongoing challenge to synthetic chemists. Conforma-
tionally restricted and rigid building blocks exhibit some
advantages in the design of drug candidates when com-
pared to their flexible analogs, mainly due to the decrease
in entropy of binding of the potential drug candidate with
its biological target.2 This concept is embodied in aza-
substituted bicyclic scaffolds (Figure 1), which are wide-
spread both in natural compounds [e.g. (+)-makomakine
(1)3 or atropine (2)] and in synthetic drugs [e.g. anti-HIV
Maraviroc (3)4 or 5-HT3 receptor antagonist Granisetron
(4)5].
N
O
HN
O
F
F
HN
N
NMe
3
4
Figure 1
O
n
O
R1
OMe
OMe
R1
R2
N
+
n
R2
Over the last few years, several examples of double
Mannich annulation of cyclic ketones using N,N-bis(alk-
oxymethyl)alkylamines have been reported (Scheme 1).6
Most of these referred to cyclic b-keto esters; Mannich
annulations of other cyclic ketones appeared to be more
sensitive to the nature of the substrate.6c
N
Scheme 1
O
O
O
O
CN
Recently, we started a project on the design and the syn-
thesis of conformationally constrained and rigid bicyclic
diamines as potential building blocks for drug design.7 As
a part of this project, we were interested in chlorotrimeth-
ylsilane-promoted double Mannich annulations of the
substrates 5–11 using N,N-bis(alkoxymethyl)alkylamines
(Figure 2). N,N-Bis(methoxymethyl)benzylamine (12)
was used in all the annulations reported below in order to
make further N-deprotection of azabicyclo[n.3.1]alkane
derivatives possible.
O
7
5
O
6
8
O
O
MeO
9
10
11
Figure 2
The structure of the substrate appeared to influence dras-
tically the outcome of the double Mannich annulations of
cyclic ketones using amine 12. In particular, reaction of
12 with cyclopentanone 5 and cyclohexanone 6 resulted in
the formation of ketals 15 (18%) and 16 (80%), respec-
SYNTHESIS 2010, No. 3, pp 0493–0497
x
x
.
x
x
.2
0
0
9
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217137; Art ID: P13409SS
© Georg Thieme Verlag Stuttgart · New York

494
A. P. Mityuk et al.
PAPER
tively. In the case of ketone 5, N-benzylidenebenzylamine benzoxazine derivative 22 was isolated in 66% yield
(17) was also isolated in 23% yield (Scheme 2). The (Scheme 5). The structure of compound 22 was confirmed
mechanism of the formation of 17 is unclear; however it by 2D NMR (HMBC) spectroscopy and X-ray crystal
is certain that partial oxidation of benzylamine to benzal- structure analysis (Figure 3). Formation of compounds
dehyde is one of the steps of the reaction. Compounds 15 with a related tricyclic core in Mannich-type reactions has
and 16 were transformed into the corresponding amino been reported previously.8 It is interesting to note that the
ketones 18 and 19, respectively, by treatment with tri- cis-isomer of 22, which is expected to be thermodynami-
fluoroacetic acid. We believe that ring constraints in the cally less stable, was also formed in the reaction. Com-
bicyclic systems of ketones 18 and 19 lead to the en- pound 22 was transformed into the target
hanced reactivity of their carbonyl group, thus resulting in bicyclo[3.3.1]nonane 23 in 95% yield by treatment with
acid-catalysed formation of ketals 15 and 16 under the an- trifluoroacetic acid (Scheme 5).
hydrous conditions of the double Mannich condensation.
O
OMe
O
8a
O
O
MeO
OMe
8
12
TFA
CN
2
O
4a
12
TFA
Ph
Me3SiCl
4
N
Ph
NC
23, 95%
N
Me3SiCl
CN
22, 66%
n
n
Ph
N
8
n
N
Ph
Scheme 5
5
6
, n = 1
, n = 2
18, n = 1, 95%
19, n = 2, 96%
15, n = 1, 18%
16, n = 2, 80%
N
17
Scheme 2
This effect appeared to be very sensitive to the structure
of the substrate, for example, reaction of 12 and g-pyra-
none (7) resulted in the direct formation of ketone 20; no
ketal product 21 was isolated (Scheme 3). Analogously, in
the case of cycloheptanone (9) and cyclooctanone (10),
the corresponding amino ketones 13 and 14 were obtained
in 45 and 46% yields, respectively (Scheme 4). These re-
sults are in accordance with literature data reported for
other N,N-bis(alkoxymethyl)alkylamines.6c
Figure 3 Molecular structure of compound 22
An analogous reaction of 12 with (4-methoxyphenyl)ace-
tone (11) led to the formation of 1,3-oxazinane derivative
24 (51%; Scheme 6). As in the case of 22, compound 24
was transformed into piperidone 25 in 35% yield by treat-
ment with trifluoroacetic acid.
When benzylamine derivative 12 was allowed to react
with 2-cyanocyclohexanone (8), the octahydro-2H-1,3-
O
MeO
O
OMe
O
12
MeO
O
Me3SiCl
N
N
O
12
TFA
O
N
N
Me3SiCl
Ph
O
Ph
7
20, 68%
21
OMe
O
MeO
MeO
Scheme 3
11
24, 51%
25, 35%
O
Scheme 6
O
Ph
+
N
OMe
Me3SiCl
To conclude, chlorotrimethylsilane-promoted double
Mannich annulation of ketones using N,N-bis(methoxy-
methyl)benzylamine is an efficient method for the con-
struction of azabicyclo[n.3.1]alkane systems (n = 2–5).
The structure of the substrate is crucial for the outcome of
the process: whereas classical Mannich bases are formed
n
OMe
N
n
Ph
09, n = 1
10, n = 2
12
13, n = 1, 45%
14, n = 2, 46%
Scheme 4
Synthesis 2010, No. 3, 493–497 © Thieme Stuttgart · New York

PAPER
Double Mannich Annulation
495
3-Benzyl-8a-methoxyoctahydro-1,3-benzoxazine-4a-carbo-
nitrile (22)
Yield: 9 g (66%); white powder; mp 81–82 °C.
in the case of higher cycloalkanones and g-pyranone, the
reaction of cyclopentanone, cyclohexanone and 4-meth-
oxyphenylacetone is complicated by ketal or 1,3-oxazi-
nane formation.
1H NMR (CDCl3): d = 7.22 (m, 5 H, PhH), 4.06 (d, J = 7.6 Hz, 1 H,
2-CHH), 4.00 (d, J = 7.6 Hz, 1 H, 2-CHH), 3.52 (d, J = 13.1 Hz,
1 H, CHHPh), 3.34 (d, J = 13.1 Hz, 1 H, CHHPh), 3.20 (s, 3 H,
OCH3), 2.97 (d, J = 12.0 Hz, 1 H, 4-CHH), 2.56 (m, 2 H, 8-CH2),
2.13 (d, J = 12.0 Hz, 1 H, 4-CHH), 1.58–1.69 (m, 3 H), 1.49–1.58
(m, 2 H), 1.38–1.48 (m, 1 H).
13C NMR (CDCl3): d = 131.2 (ipso-PhC), 128.6 (CH), 127.6 (CH),
127.5 (CH), 121.5 (CN), 96.9 (8a-C), 78.0 (2-CH2), 57.0 (CH2Ph),
54.3 (4-CH2), 47.8 (OCH3), 42.3 (4a-C), 31.6 (CH2), 31.1 (CH2),
22.5 (CH2), 21.9 (CH2).
Solvents were purified according to standard procedures. All start-
ing materials were purchased from Acros, Merck or Fluka. Analyt-
ical TLC was performed using Polychrom SI F254 plates. Column
chromatography was performed using Kieselgel Merck 60 (230–
400 mesh) as the stationary phase. 1H, 13C NMR, and all 2D NMR
spectra were recorded on a Bruker 170 Avance 500 spectrometer
(499.9 MHz for 1H, 124.9 MHz for 13C). Chemical shifts (d) are re-
ported in ppm downfield from TMS (1H, 13C) as an internal stan-
dard. Mass spectra were recorded on an Agilent 1100 LCMSD SL
instrument (CI) and Agilent 5890 Series II 5972 GCMS instrument
(EI). Elemental analyses were performed on an Elementar Vario
MICRO Cube CHNS/O analyzer. Flash chromatography was per-
formed using a Buchi Fraction Collector C-660 (5–6 bar, 460 × 36
mm column, silica gel).
MS: m/z = 254 [M+], 163, 91 [C7H7 ].
+
Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C,
71.76; H, 7.63; N, 10.01.
8-Benzyl-8-azabicyclo[4.3.1]decan-10-one (13)
Prepared from cycloheptanone 9 and purified by flash chromatog-
raphy (CHCl3–EtOAc, 9:1).
2-Cyanocyclohexanone (8)
Yield: 15.6 g (46%); mp 66 °C (hexane).
Heptanedinitrile (70 g) was added to a suspension of NaH (25 g) in
anhydrous THF (1.2 L). The resulting mixture was refluxed for 10
h (reaction monitored by TLC), cooled to r.t., quenched with MeOH
(60 mL), stirred for 30 min, and evaporated in vacuo. The residue
was dissolved in a mixture of H2SO4 (90 g) and H2O (550 mL) and
the solution was stirred at r.t. for 30 min, then extracted with Et2O
(3 × 350 mL). The combined organic extracts were evaporated un-
der reduced pressure and the residue was distilled in vacuo (81–
83 °C/1 mmHg) to give 2-cyanocyclohexanone (8; 51.5 g, 73%) as
a pale-yellow oil. The spectral and physical data were in agreement
with those previously reported.9
1H NMR (CDCl3): d = 7.34 (m, 4 H, o-PhH and m-PhH), 7.25 (t,
J = 6.8 Hz, 1 H, p-PhH), 3.49 (s, 2 H, NCH2Ph), 2.82 [d,
J = 11.2 Hz, 2 H, endo-7(9)-CHH], 2.60 (t, J = 3.4 Hz, 2 H, 1- and
6-CH), 2.41 [dd, J = 11.2, 3.4 Hz, 2 H, exo-7(9)-CHH], 2.05 (m,
2 H), 1.77 (m, 2 H), 1.58 (m, 2 H), 1.42 (m, 2 H).
13C NMR (CDCl3): d = 212.9 (C=O), 138.4 (PhC-1), 128.9 (CH),
128.2 (CH), 127.0 (CH), 62.7 (CH2), 59.5 (CH2), 48.6 (1-CH and 6-
CH), 31.2 (CH2), 26.7 (CH2).
+
MS: m/z = 243 [M+], 152, 120, 106, 91 [C7H7 ].
Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C,
79.35; H, 8.38; N, 6.01.
N,N-Bis(methoxymethyl)benzylamine (12)
The procedure used was essentially the same as that reported for the
synthesis of N,N-bis(ethoxymethyl)benzylamine.6b Anhydrous
K2CO3 (387 g) was added to a mixture of anhydrous MeOH (675 g)
and paraformaldehyde (273 g). Then benzylamine (300 g) was add-
ed over a period of 1.5 h, and the resulting mixture was stirred for
48 h. The crude reaction mixture was filtered to remove all the sol-
ids and evaporated in vacuo. The residue was suspended in anhy-
drous CH2Cl2 (1 L) and filtered. The combined filtrates were
evaporated, and the residue was distilled in vacuo (102–103 °C/
1 mmHg) to give amine 12.
9-Benzyl-9-azabicyclo[5.3.1]undecan-11-one (14)
Prepared from cyclooctanone 10 and purified by flash chromatog-
raphy (hexane–EtOAc, 9:1).
Yield: 11.2 g (45%); oil.
1H NMR (CDCl3): d = 7.39 (d, J = 7.3 Hz, 2 H, o-PhH), 7.35 (t,
J = 7.3 Hz, 2 H, m-PhH), 7.28 (t, J = 7.3 Hz, 1 H, p-PhH), 3.58 (s,
2 H, NCH2Ph), 2.84 (d, J = 11.2 Hz, 2 H, 8- and 10-CHH), 2.44 (d,
J = 11.2 Hz, 2 H, 8- and 10-CHH), 2.35 (m, 4 H), 1.89 (m, 2 H),
1.80 (m, 2 H), 1.67 (m, 1 H, 4-CHH), 1.33 (m, 1 H, 4-CHH), 1.25
(m, 2 H).
13C NMR (CDCl3): d = 217.6 (C=O), 138.9 (PhC-1), 128.9, 128.3,
127.2, 62.2 (NCH2Ph), 58.5 (8- and 10-CH2), 50.6 (1- and 7-CH),
31.3 (CH2), 24.6 (CH2).
Yield: 339 g (62%).
1H NMR (CDCl3): d = 7.36 (m, 4 H, o-PhH and m-PhH), 7.28 (m,
1 H, p-PhH), 4.26 (s, 4 H, NCH2OCH3), 4.03 (s, 2 H, PhCH2), 3.30
(s, 6 H, OCH3).
13C NMR (CDCl3): d = 138.6 (PhC-1), 128.6 (CH), 128.0 (CH),
126.8 (CH), 85.5 (NCH2OCH3), 54.6 (OCH3), 52.4 (PhCH2N).
+
MS: m/z = 257 [M+], 166, 120, 106, 91 [C7H7 ].
Anal. Calcd for C17H23NO: C, 79.33; H, 9.01; N, 5.44. Found: C,
79.61; H, 8.77; N, 5.50.
+
MS: m/z = 195 [M+], 164, 91 [C7H7 ].
Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C,
67.95; H, 8.41; N, 6.92.
3-Benzyl-8,8-dimethoxy-3-azabicyclo[3.2.1]octane (15)
Prepared from cyclopentanone 5.
Reaction of N,N-Bis(methoxymethyl)benzylamine (12) with
Ketones 5–11; Typical Procedure
Yield: 4.8 g (18%); mp 58 °C (hexane).
1H NMR (CDCl3): d = 7.25 (d, J = 7.2 Hz, 2 H, o-PhH), 7.20 (t,
J = 7.2 Hz, 2 H, m-PhH), 7.13 (t, J = 7.2 Hz, 1 H, p-PhH), 3.45 (s,
2 H, NCH2Ph), 3.16 (s, 3 H, OCH3), 3.10 (s, 3 H, OCH3), 2.44 [dd,
J = 10.4, 2.7 Hz, 2 H, endo-2(4)CHH], 2.35 [d, J = 10.4 Hz, 2 H,
exo-2(4)CHH], 1.98 (s, 2 H, 1- and 5-CH), 1.63 (m, 4 H, 6- and 7-
CH2).
Chlorotrimethylsilane (91 g, 0.83 mol) was added to a mixture of 2-
cyanocyclohexanone (8; 51.5 g, 0.42 mol) and N,N-bis(methoxy-
methyl)benzylamine (12; 163g, 0.83 mol) in MeCN (660 mL). The
mixture was stirred under an atmosphere of nitrogen at r.t. for 96 h,
then quenched with sat. aq NaHCO3 (450 mL). The aqueous layer
was extracted with EtOAc (3 × 450 mL) and the combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. The crude
product (145 g) was recrystallized twice from hexane to obtain 22.
Synthesis 2010, No. 3, 493–497 © Thieme Stuttgart · New York

496
A. P. Mityuk et al.
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13C NMR (CDCl3): d = 140.0 (PhC-1), 128.6 (CH), 128.1 (CH),
126.7 (CH), 108.2 (C-8), 61.6 (CH2), 55.2 (CH2), 49.2 (OCH3), 47.4
(OCH3), 38.2 (CH), 25.8 (CH2).
3.33 (d, J = 11.4 Hz, 1 H, 2-CHH), 3.09 (d, J = 11.6 Hz, 1 H, 4-
CHH), 2.92 (m, 1 H, 7-CHH), 2.71 (d, J = 11.4 Hz, 1 H, 2-CHH),
2.56 (d, J = 11.6 Hz, 1 H, 4-CHH), 2.45 (m, 2 H, 5-CH and 8-
CHH), 2.23 (m, 1 H, 8-CHH), 2.08 (m, 1 H, 6-CHH), 1.99 (m, 1 H,
6-CHH), 1.55 (m, 1 H, 7-CHH).
13C NMR (CDCl3): d = 206.4 (C=O), 137.2 (PhC-1), 128.8, 128.7,
127.7, 118.2 (C≡N), 62.2 (2-CH2), 61.5 (CH2Ph), 59.5 (4-CH2),
49.8 (1-CH), 46.2 (5-CH), 38.8 (8-CH2), 33.6 (6-CH2), 20.8 (7-
CH2).
MS: m/z = 261 [M+], 230 [M+ – OCH3], 215, 198, 170, 134, 101, 91
+
[C7H7 ].
Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C,
73.82; H, 8.69; N, 5.16.
3-Benzyl-9,9-dimethoxy-3-azabicyclo[3.3.1]nonane (16)
Prepared from cyclohexanone 6.
MS: m/z = 254 [M+], 163, 91 [C7H7 ].
+
Yield: 20.4 g (80%); mp 88 °C (hexane).
Anal. Calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found: C,
75.69; H, 7.33; N, 10.78.
1H NMR (CDCl3): d = 7.36 (m, 4 H, o-PhH and m-PhH), 7.27 (m,
1 H, p-PhH), 3.45 (s, 2 H, NCH2Ph), 3.22 (s, 3 H, OCH3), 3.21 (s,
3 H, OCH3), 2.79 (d, J = 10.4 Hz, 2 H, 2- and 4-CHH), 2.74 (m,
1 H, 7-CHH), 2.55 (d, J = 10.4 Hz, 2 H, 2- and 4-CHH), 1.99 (s,
2 H, 1- and 5-CH), 1.92 (m, 2 H, 6- and 8-CHH), 1.70 (m, 2 H, 6-
and 8-CHH), 1.50 (m, 1 H, 7-CHH).
13C NMR (CDCl3): d = 139.9 (PhC-1), 128.6 (CH), 128.2 (CH),
126.7 (CH), 100.2 (C-9), 63.2 (CH2), 56.3 (CH2), 46.7 (OCH3), 46.4
(OCH3), 34.8 (CH), 28.3 (CH2), 21.0 (CH2).
3-Benzyl-3-azabicyclo[3.2.1]octan-8-one (18)
Prepared from 15 analogously to 3-benzyl-9-oxo-3-azabicy-
clo[3.3.1]nonane-1-carbonitrile (23) and purified by flash chroma-
tography (hexane–EtOAc, 9:1). The spectral and physical data were
in agreement with those previously reported.11
Yield: 3.3 g (95%).
3-Benzyl-3-azabicyclo[3.3.1]nonan-9-one (19)
MS: m/z = 275 [M+], 244 [M+ – OCH3], 212, 91 [C7H7 ].
+
Prepared from 16 analogously to 3-benzyl-9-oxo-3-azabicy-
clo[3.3.1]nonane-1-carbonitrile (23) and purified by flash chroma-
tography (hexane–EtOAc, 9:1). The spectral and physical data were
in agreement with those previously reported.11
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C,
73.98; H, 9.23; N, 4.87.
N-Benzylidenebenzylamine (17)
Yield: 9.4 g (96%); mp 51 °C (hexane).
Isolated as a by-product in the synthesis of 15 (4.5 g, 23%) by flash
chromatography of the mother liquor obtained after recrystalliza-
tion (hexane–EtOAc, 9:1). The spectral and physical data were in
agreement with those previously reported.10
Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C,
78.64; H, 8.06; N, 6.13.
7-Benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one (20)
Prepared from 17 analogously to 3-benzyl-9-oxo-3-azabicy-
clo[3.3.1]nonane-1-carbonitrile (23) and purified by flash chroma-
tography (hexane–EtOAc, 7:3). The spectral and physical data were
in agreement with those previously reported.12
3-Benzyl-6-methoxy-5-(4-methoxyphenyl)-6-methyl[1,3]oxazi-
nane (24)
Prepared from 1-(4-methoxyphenyl)propan-2-one (11) using 12
(2.2 equiv) and chlorotrimethylsilane (2.2 equiv) and purified by
flash chromatography (CHCl3–EtOAc, 4:1).
Yield: 10.3 g (68%)
Yield: 16.4 g (51%); oil.
1-Benzyl-3-(4-methoxyphenyl)piperidin-4-one (25)
Prepared from 24 analogously to 3-benzyl-9-oxo-3-azabicy-
clo[3.3.1]nonane-1-carbonitrile (23) and purified by flash chroma-
tography (hexane–EtOAc, 4:1).
1H NMR (CDCl3): d = 7.43 (d, J = 7.2 Hz, 2 H, o-PhH), 7.37 (t,
J = 7.2 Hz, 2 H, m-PhH), 7.31 (m, 3 H), 6.88 (d, J = 8.6 Hz, 2 H, 3¢-
ArH and 5¢-ArH), 4.70 (d, J = 9.2 Hz, 1 H, 2-CHH), 4.25 (d,
J = 9.2 Hz, 1 H, 2-CHH), 4.05 (d, J = 13.2 Hz, 1 H, CHHPh), 3.72
(d, J = 13.2 Hz, 1 H, CHHPh), 3.82 (s, 3 H, ArOCH3), 3.51 (m,
1 H), 3.30 (s, 3 H, 6-OCH3), 3.27 (m, 1 H), 2.78 (dd, J = 11.7,
1.7 Hz, 1 H), 1.31 (s, 3 H, 6-CH3).
13C NMR (CDCl3): d = 158.6 (4¢-ArC), 138.7 (C), 131.7 (C), 130.6
(CH), 129.0 (CH), 128.4 (CH), 127.2 (CH), 113.4 (CH), 99.8 (C-6),
76.8 (2-CH2), 56.0 (CH2Ph), 55.2 (ArOCH3), 51.2 (4-CH2), 48.0 (6-
OCH3), 46.5 (5-CH), 21.8 (CH3).
Yield: 3.7 g (35%); oil.
1H NMR (CDCl3): d = 7.29–7.52 (m, 5 H, PhH), 7.26 (d, J = 8.6 Hz,
2 H, ArH), 6.97 (d, J = 8.6 Hz, 2 H, ArH), 3.85 (m, 1 H), 3.83 (s,
3 H, OCH3), 3.73 (s, 2 H, NCH2Ph), 3.24 (m, 1 H), 3.11 (m, 1 H),
2.85 (m, 1 H), 2.72 (m, 2 H), 2.58 (m, 1 H).
13C NMR (CDCl3): d = 208.1 (C=O), 158.7 (4-ArCH), 138.2 (2 C),
130.0 (CH), 129.1 (CH), 128.6 (CH), 127.5 (CH), 114.0 (CH), 62.0
(CH2), 60.2 (CH2), 55.6 (3-CH), 55.3 (OCH3), 53.6 (CH2), 40.7 (5-
CH2).
MS: m/z = 296 [M+ – OCH3], 176, 133, 91 [C7H7 ].
+
Anal. Calcd for C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found: C,
73.11; H, 8.01; N, 4.47.
+
MS: m/z = 295 [M+], 134, 121, 91 [C7H7 ].
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C,
77.02; H, 6.98; N, 4.93.
3-Benzyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carbonitrile (23)
Nitrile 22 (53.7 g, 0.188 mol) was dissolved in TFA (160 g) and
stirred overnight. The excess acid was removed in vacuo, and the
residue was adjusted to pH 8 with sat. aq NaHCO3. The mixture was
extracted with CH2Cl2 (3 × 250 mL) and the combined extracts
were dried over Na2SO4 and evaporated in vacuo. The residue was
purified by flash chromatography (hexane–EtOAc, 9:1) to give ke-
tone 23.
X-ray Diffraction Data for 22
Crystals for X-ray diffraction studies were obtained by crystalliza-
tion from MeCN. Empirical formula: C17H22N2O; triclinic; 293 K;
cell
dimensions:
a = 6.4829(5) Å,
b = 10.9024(8) Å,
c = 11.5044(8) Å, a = 74.398(6)°, b = 84.750(6)°, g = 76.232(7)°;
V = 760.3(1) Å3; Mr = 286.37; Z = 2; space group P1;
D(calcd) = 1.251 g/cm3; m(MoKa) = 0.082 mm–1; F(000) = 308. In-
tensity of 7199 reflections (3478 independent, Rint = 0.017) were
measured on an automatic Xcalibur 3 diffractometer (graphite
Yield: 13.5 g (28%); mp 92–94 °C (hexane).
1H NMR (CDCl3): d = 7.28 (m, 2 H, PhH), 7.22 (m, 3 H, PhH), 3.48
(d, J = 12.3 Hz, 1 H, CHHPh), 3.41 (d, J = 12.3 Hz, 1 H, CHHPh),
Synthesis 2010, No. 3, 493–497 © Thieme Stuttgart · New York

PAPER
Double Mannich Annulation
(4) Levy, J. A. AIDS 2009, 23, 147.
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497
monochromated MoKa radiation, CCD-detector, w scanning,
2Qmax = 55°).
The structure was solved by direct methods using the SHELX97
package.13 Positions of hydrogen atoms were located from electron-
density difference maps and refined using the isotropic model. Full-
matrix least-squares refinement against F2 in anisotropic approxi-
mation for non-hydrogen atoms was converged to wR2 = 0.091 for
3430 reflections (R1 = 0.035 for 2203 reflections with I>4s(I),
S = 0.892). Final atomic coordinates, geometrical parameters and
crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, 11 Union Road, Cambridge, CB2 1EZ,
UK [fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk] and
are available on request quoting the deposition number CCDC
741371.
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Synthesis 2010, No. 3, 493–497 © Thieme Stuttgart · New York