Solvent-free synthesis of a secondary N -benzhydrylamine as a chiral reagent for asymmetric deprotonation of bicyclic N -benzylamino ketones

Article abstract of DOI:10.1055/s-0033-1340955

Several chiral secondary N-benzhydrylamines were synthesized in good yields (68-92%) without racemization by the direct alkylation of amines with benzhydryl chloride under solvent-free conditions. Using the solvent-free conditions (R)-N-benzhydryl-1-phenylethylamine was obtained with the highest yield (92%), purified on ion-exchange resin, and converted to its hydrochloride salt. The resulting chiral amine hydrochloride was transformed into lithium amide/lithium chloride mixture used in asymmetric deprotonations of N-benzyl analogues of tropinone and granatanone followed by aldol reactions giving products in high diastereomeric purities (up to 96%) and enantiomeric excesses of 77 to 96%. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340955

PAPER
▌1475
paper
Solvent-Free Synthesis of a Secondary N-Benzhydrylamine as a Chiral
Reagent for Asymmetric Deprotonation of Bicyclic N-Benzylamino Ketones
Asymmetric Deprotonation with a Chiral Secondary N-Benzhydrylamine
Aneta Nodzewska,* Katarzyna Sidorowicz, Michal Sienkiewicz
Institute of Chemistry, University of Bialystok, Hurtowa 1, 15-399 Bialystok, Poland
Fax +48(85)7470113; E-mail: annodz@uwb.edu.pl
Received: 20.12.2013; Accepted after revision: 17.02.2014
In search of selective deprotonating reagents, a decision
Abstract: Several chiral secondary N-benzhydrylamines were syn-
was made to employ another known chiral lithium amide
thesized in good yields (68–92%) without racemization by the di-
Li-3,6 derivative from N-benzhydryl-1-phenylethylamine.
Until now, the enantiomerically pure amine 3 has been
rect alkylation of amines with benzhydryl chloride under solvent-
free conditions. Using the solvent-free conditions (R)-N-benzhy-
dryl-1-phenylethylamine was obtained with the highest yield prepared by a two-step low-yielding (up to 42%) proce-
(92%), purified on ion-exchange resin, and converted to its hydro-
chloride salt. The resulting chiral amine hydrochloride was trans-
formed into lithium amide/lithium chloride mixture used in
or in moderate yield (70–75%) by the reaction of α-meth-
asymmetric deprotonations of N-benzyl analogues of tropinone and
granatanone followed by aldol reactions giving products in high
dure: (i) imine synthesis and (ii) reduction of imine to sec-
ondary amine (LiAlH4,10 H2, Pd/C,11 or catecholborane12)
ylbenzylamine (6) with N-benzhydryl bromide in
DMPU.13 Although N-alkylation of primary amines using
diastereomeric purities (up to 96%) and enantiomeric excesses of 77
benzhydryl halide is a well-known transformation, the
typical reaction conditions involve the use of solvent such
as DMF,14 DCE,15 CHCl3,16 MeCN,17 or DMPU13,18 and
purification of products by column chromatography.
to 96%.
Key words: aldol reaction, N-alkylation, asymmetric synthesis,
amines, enantioselectivity
Herein, we wish to report a one-step, solvent-free, and
chromatography-free synthesis of a chiral amine hydro-
chloride, the precursor of lithium amide Li-3, via direct N-
benzhydrylation of 1-phenylethylamine (6). In this more
environmentally benign process, other chiral primary
amines can also be converted into corresponding N-benz-
hydryl derivatives.
The use of chiral lithium amides in asymmetric
deprotonation1 followed by aldol reaction is a successful
method for C–C bond construction in enantioselective
synthesis.2 Koga’s bidentate lithium amide Li-1 (Figure
1)3 and lithium bis(1-phenylethyl)amide (Li-2) (popular-
ized by Simpkins)4 are the most typical and effective chi-
ral amide bases used in the deprotonation–aldol reaction
of bicyclic bridged N-methyl β-amino ketones such as tro-
pinone (4)5 and granatanone (pseudopelletierine, 5).6
Synthesis of Chiral N-Benzhydrylamines
Chiral secondary amines were obtained by the reaction of
selected primary amines 6–8 (Figure 2, Table 1) with
benzhydryl chloride in the absence of organic solvent at
high temperature in good to excellent yields (68–92%).
The product 3 was synthesized with the highest yield
(92%) in 18 hours at 140 °C without racemization. The
optical purity was checked by measuring the specific op-
Ph
NLi
Ph
N
Li
Ph
N
Ph
N
Li
Ph
Ph
Li-1
Li-2
Li-3
20
Figure 1 Chiral lithium amides used in the deprotonation of ketones
tical rotation of pure, free amine 3 ([α]D +43.2, c 1.0,
25
CHCl3) and comparing it with the literature values ([α]D
+44.7, c 1.5, CHCl3;13 [α]D20 +43.7, c 1.6, CH2Cl219).
The enantiomerically pure enolates and aldols of tropi-
none obtained in this way have been used as key interme-
diates in stereoselective synthesis of tropane-based
alkaloids.7 Unfortunately, the substituted aldols of N-Bn,
N-Cbz, and N-triazene analogues are generally formed
with lower enantioselectivities (ee below 86%) by using
Li-1 and Li-2.8 Efficient enantioselective synthesis of N-
benzylnortropinone and N-benzylnorgranatanone aldols
followed by hydrogenolysis of benzyl group may be vital
for accessing nor-analogues of aldols and related synthet-
ic intermediates for possible tropane or granatane based
pharmaceutical agent.9
The amine 3 was isolated and purified on ion-exchange
resin (Dowex 50WX2) by scavenging and subsequent re-
leasing of the amine product. Thus, instead of using harm-
ful organic solvents and time-consuming, hard-to-scale-
up column chromatography on silica gel, we used more
environmentally friendly solvents, that is, water, metha-
nol, and aqueous ammonia in faster ion-exchange extrac-
tion, in order to remove the unreacted benzhydryl chloride
Me
COOMe
NH2
NH2
N
N
N
Ph
NH2
Ph
NH2
Ph
Ph
6
7
8
9
SYNTHESIS 2014, 46, 1475–1480
Advanced online publication: 24.03.2014
DOI: 10.1055/s-0033-1340955; Art ID: SS-2013-T0827-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Figure 2 Substrates subjected to N-benzhydrylation under neat con-
ditions

1476
A. Nodzewska et al.
PAPER
and side products (benzhydryl alcohol) from the amine. In of conditions for the efficient, highly enantioselective,
this case, the use of an acid–base extraction during the and easy to carry out deprotonation of N-benzyl analogues
workup was inadvisable due to poor dissolution and for- of tropinone 13 and granatanone 14 are described. During
mation of emulsions. The resulting final amine product our earlier8 and current research we have noticed that lith-
(methanol solution) was converted into hydrochloride salt ium N-benzhydryl-1-phenylethylamide (Li-3, 92% ee,
by addition of aqueous hydrochloric acid and crystallized Table 2, entry 3) was the most effective chiral deprotonat-
from a mixture of ethanol and ethyl acetate. The dried hy- ing reagent of the three lithium amides (Li-1, Li-2, Li-3)
drochloride salt was a convenient form to use in the depro- tested in the aldol reactions of N-benzylnortropinone (13)
tonation reaction. Use of hydrochloride salt of N- with benzaldehyde.
benzhydryl-1-phenylethylamine contrary to free amine
(sticky oil) offers many advantages. The solid salt is easy
to dry, can be weighed accurately, and is easy to manipu-
late without a protective gas atmosphere. Unlike the free
amine, the hydrochloride salt does not absorb carbon di-
oxide and water from the air during storage. Besides that,
the reaction of amine hydrochloride salt with two equiva-
lents of n-butyllithium generates a 1:1 mixture of lithium
Herein, we present the applications of this chiral lithium
amide Li-3 and other N-benzhydryl base amides for enan-
tioselective aldol reactions of N-benzyl bicyclic amino ke-
tones 13 and 14, and the comparison of two typical
procedures of asymmetric deprotonation. In the first pro-
cedure, free amine 3, n-butyllithium (1.1 equiv), and lith-
ium chloride additive were employed in an optimal5c
amount range of 0.5–1 equivalent (per amide). In the sec-
ond procedure, 1 equivalent of amine hydrochloride salt
amide and lithium chloride, which often gives superior
enantioselectivity in deprotonations of ketones.5c There is
3·HCl and 2 equivalents of n-butyllithium were used. In
no need for addition of inorganic salts to improve selectiv-
all reactions, the lithium amide21 was generated at 0 °C in
ity, for example, lithium chloride, which may be hard to
THF solution, and cooled to –78 °C before the slow addi-
dry and dissolve in tetrahydrofuran, simplifies the reac-
tion of a dissolved ketone. For the aldol reaction of N-ben-
tion procedures significantly.
zylnortropinone with
a representative aldehyde –
benzaldehyde – the best results were obtained with the ad-
dition of a half equivalent of lithium chloride (92% ee, Ta-
ble 2, entry 3). However, we observed that differences in
achieved enantioselectivities with an amount of lithium
chloride ranging from 0.5 to 1 equivalent were practically
insignificant (within experimental error, Table 2, entries
2–6). Therefore, in the rest aldol reaction with N-benzyl-
amino ketones, the easier and simpler procedure using
amine hydrochloride salt was applied. In the asymmetric
aldol reactions of N-benzylnortropinone and norgranata-
none four aldehydes were employed: benzaldehyde, 4-
bromobenzaldehyde, 4-fluorobenzaldehyde, and 4-tri-
fluoromethylbenzaldehyde. The exo,anti-aldols were the
only detectable products and were obtained in good yields
(up to 88%) and with high enantiomeric excesses 77–96%
(Table 2). Preparation of the lithium amide/lithium chlo-
ride mixture from amine hydrochloride gave good results
by adding lithium chloride to lithium amide before depro-
tonation (Table 2, entries 5, 6, 9, 10, 14, 15).
Table 1 Benzhydrylation of Primary Amines under Solvent-Free
Conditions
Ph
Ph
Ph
Ph2CHCl
R1
N
Ph
R1
NH2
H
Primary amine
N-Benzhydrylamine
Yield (%)
(R)-6
(R)-7
(S)-7
(R)-8
(S)-8
(R)-9
(R)-3
92
80
68
81
72
52
(R)-10
(S)-10
(R)-11
(S)-11
rac-12
Unfortunately, the solvent-free method of direct benzhy-
drylation has limitations: under neat N-alkylation condi-
tions neither amino acid ester 9 nor amino alcohol (2-
phenylglycinol obtained by the reduction of 9) reacted se-
lectively. In the reaction of 9 with N-benzhydryl chloride
at 140 °C racemization of product occurred, whereas the
corresponding amino alcohol did not react chemoselec-
tively. The reaction gave a mixture of N-benzhydryl and
O-benzhydryl products in a ratio of 1:4.
These results demonstrate that amide Li-3 was an effec-
tive enantiodifferentiating reagent, especially in asym-
metric deprotonation of N-benzylnortropinone followed
by reaction with 4-fluorobenzaldehyde (96% ee, entries 9,
10). Our earlier work8 showed that reactions of N-substi-
tuted bicyclic amino ketones (13, 14, and N-Cbz, N-tri-
azene analogues of tropinone) using lithium amide bases
(Li-1 and Li-2) gave the aldols 16, 18 with low to moder-
ate enantiomeric excesses (8–86%). Using the reagent
(R)-3 for deprotonation–aldol reaction of N-benzylnortro-
pinone and N-benzylnorgranatanone gave notably better
results (72–96% ee).
Application of Chiral N-Benzhydrylamines 3, 10, and
11 in Aldol Reactions
Tropinone and pseudopelletierine (granatanone) are stere-
oselectively deprotonated with chiral amide bases (under
optimized condition) in the presence of lithium chloride,
which is known to increase the enantioselectivity.6,7b,20 In
all cases the products are formed with excellent exo,anti-
diastereoselectivity, up to 96%. Below, the optimization
The amide bases (R)-Li-10 and (R)-Li-11 were also tested
in the deprotonation–aldol reactions of tropinone and N-
benzylnortropinone with benzaldehyde. However, these
reactions gave unsatisfactory conversions and yields. Un-
Synthesis 2014, 46, 1475–1480
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Deprotonation with a Chiral Secondary N-Benzhydrylamine
1477
mined by X-ray crystal structure analysis. Based on previ-
ous experience with this type of aldols23 the relative
configurations of the new products 16c,d and 18b–d were
defined as exo,anti by analogy to the known exo,anti-16b
using relevant coupling constants of the characteristic
doublets of the carbinol hydrogen CH(OH)–R (for all the
exo,anti-isomers, J ranged from 2.5 to 3.6 Hz).24
Table 2 Application of Amine (R)-3 in Deprotonations of Bicyclic
Amino Ketones
1. chiral amine (R)-3
n-BuLi, (LiCl)
2. R2CHO
O
N
O
HO
H
R2
N
R2 = Ph, 4-BrC6H4,
4-FC6H4, 4-F3CC6H4
n
n
R1
R1
4 n = 1, R1 = Me
13 n = 1, R1 = Bn
5 n = 2, R1 = Me
14 n = 2, R1 = Bn
15 n = 1, R1 = Me
16 n = 1, R1 = Bn
17 n = 2, R1 = Me
18 n = 2, R1 = Bn
The enantiomeric excesses of all the prepared exo,anti-al-
dols were measured by 1H NMR spectroscopy in the pres-
ence of (R)-(–)-1-(9-anthryl)-2,2,2-trifluoroethanol [(R)-
TFAE]. Under these conditions, the doublet of carbinol
hydrogen CH(OH)–R was separated into two doublets al-
lowing for quick calculation of enantiomeric excesses.
The characteristic doublet of the predominantly formed,
known 1R,2S,5S,9R-enantiomer 16b25 was easily distin-
guishable because the signal for this enantiomer was
downfield (4.96 ppm) relative to the doublet of the minor
enantiomer (4.93 ppm). The absolute configuration of the
major 1R,2S,5S,9R-enantiomer 16b25 formed in the de-
protonation–aldol reaction with chiral amide (R)-Li-3 was
determined from crystal structure. The absolute configu-
ration of all major enantiomers of aldols formed in the
tested reactions were determined from the relative posi-
tion of signals corresponding to the carbinol hydrogen
CH(OH)–R in 1H NMR spectra recorded in the presence
of (R)-TFAE (as shown in Table 2).
Entry
Ketone Aldola
LiCl
Yield
ee
(R2)
(equiv)b (%)
(%)c
1
2
4
13
13
13
13
13
13
13
13
13
13
5
15aa (Ph)
0.7
0
78
88
87
85
87
81
76
80
89
88
90
78
82
70
72
75
65
70
77
85
92
90
91
90
75
75
96
96
80
83
82
76
77
72
85
78
16aa (Ph)
3
16a (Ph)
0.5
0.7
1
4
16a (Ph)
5
16a (Ph)
6
16a (Ph)
1d
0.5
1d
1
7
16ba (4-BrC6H4)
16ba (4-BrC6H4)
16c (4-FC6H4)
16c (4-FC6H4)
16d (4-F3CC6H4)
17aa (Ph)
8
9
In summary, an efficient (92% yield), solvent-free synthe-
sis of chiral N-benzhydryl-1-phenylethylamine (3) via di-
rect N-alkylation reaction of α-methylbenzylamine (6)
was developed. Product isolation using ion-exchange res-
in and crystallization provided chiral amine hydrochloride
salt, which was an effective and convenient reagent to use
for the asymmetric deprotonations of N-benzylnortropi-
none and N-benzylnorgranatanone. The reagent provided
the highest, so far observed, enantioselectivity in deprot-
onation the N-benzyl analogues of tropinone and granata-
none. Use of Li-3/LiCl mixture, generated from 3·HCl,
allowed to reach enantioselectivity up to 96% in the reac-
tion of N-benzylnortropinone with 4-fluorobenzaldehyde.
The aldol reactions of the bicyclic ketones mediated by
the synthesized reagent provided products in good yields
(65–89%) and with good enantiomeric excesses (77–
96%).
10
11
12
13
14
15
16
17
18
1d
1d
0.5
1
5
17aa (Ph)
14
14
14
14
14
18aa (Ph)
1
18aa (Ph)
1d
1d
1d
1d
18b (4-BrC6H4)
18c (4-FC6H4)
18d (4-F3CC6H4)
a Syntheses and characterizations of compounds 15a,7c 16a,22a 16b,25
17a,6 and 18a22b are described in the literature.
b The amount of LiCl used in the reaction (per amide).
c The enantiomeric excesses of the crude products were measured by
1H NMR in the presence of (R)-(–)-1-(9-anthryl)-2,2,2-trifluoroetha-
nol [(R)-TFAE].
Granatanone (5, pseudopelletierine), N-benzylnortropinone (13),
and N-benzylnorgranatanone (14) were synthesized by an adapted
literature procedure.26 All air sensitive reactions were carried out
under argon. THF was distilled under argon from sodium/benzo-
phenone. TLC was performed on precoated plates (silica gel 60,
F254). The spots were detected using UV light (254 nm), and phos-
phomolybdic acid. 1H and 13C NMR spectra were recorded at r.t. in
CDCl3 at 200 or 400 MHz and 50 or 100 MHz, respectively. The
chemical shifts are reported relative to TMS. IR spectra were re-
corded on a FTIR spectrophotometer in CHCl3. High-resolution
mass spectra were recorded on a TOF spectrometer in ESI mode.
The enantiomeric purities of aldols were determined by 1H NMR in
the presence of (R)-(–)-1-(9-anthryl)-2,2,2-trifluoroethanol [(R)-
TFAE].
d
One equivalent of amine hydrochloride and two equivalents of
n-BuLi were used.
der optimized conditions, the corresponding aldols 15a
and 16a were formed with 23% and 10% conversion and
enantiomeric excess of 70% and 49%, respectively, clear-
ly indicating that sterically hindered reagents were unsuit-
able. Therefore, we abandoned further testing of these
amide bases in asymmetric deprotonation of ketones 4, 5,
13, and 14.
In our earlier work, the relative configurations of exo,anti-
aldols22 16b, 18a and exo,syn-16b were positively deter-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1475–1480

1478
A. Nodzewska et al.
PAPER
N-Alkylation of Secondary Amines: (R)-N-Benzhydryl-1-
phenylethylamine Hydrochloride [(R)-3·HCl);27 Typical Proce-
dure
13C NMR (50 MHz, CDCl3): δ = 173.4, 143.03, 143.02, 138.0,
128.6, 128.5, 128.4, 128.0, 127.44, 127.37, 127.31, 127.2, 127.1,
64.2, 62.7, 52.0.
Anhydrous K2CO3 (3.04 g, 22.0 mmol) was added to a mixture of
(R)-(+)-α-methylbenzylamine (6; 6.45 mL, 6.06 g, 50.0 mmol) and
benzhydryl chloride (11.6 mL, 13.2 g, 65.0 mmol). The suspension
was heated at 140 °C for 18 h, and then poured into EtOH (1 L) and
H2O (150 mL). The mixture was loaded on activated Dowex-
50WX2 (ion-exchange resin), washed with MeOH (300 mL) and
EtOAc (100 mL), and then eluted with MeOH–NH3·H2O (9:1) until
no product was observable by TLC (eluent: MeOH–CH2Cl2 sat.
with NH3, 5.95). Collected ammonia solutions were concentrated.
Then 10% aq HCl (4.5 mL) was added to the crude product, and
H2O was evaporated in vacuo. The product was crystallized from a
mixture of EtOH and EtOAc to give (R)-3·HCl as a white solid;
yield: 12.6 g (78%); mp 203–204 °C; [α]D20 –99.0 (c 1.10, CHCl3).
Enantioselective Deprotonation Using Amine Hydrochloride
Followed by Aldol Reaction; (–)-(1R,2S,5S)-8-Benzyl-2-[(R)-(4-
fluorophenyl)(hydroxy)methyl]-8-azabicyclo[3.2.1]octan-3-one
[(–)-exo,anti-16c]; Typical Procedure
To a cooled (0 °C) solution of chiral (R)-3·HCl (0.517 g, 1.60
mmol, 1.05 equiv) in THF (4 mL) was added a solution of n-BuLi
in hexane (1.28 mL, 2.50 M, 3.19 mmol, 2.1 equiv) in THF (2 mL).
The mixture was stirred for 50 min, cooled to –78 °C and a solution
of N-benzylnortropinone (13; 0.327 g, 1.52 mmol, 1 equiv) in THF
(2 mL) was added dropwise. After stirring for 1 h, 4-fluorobenzal-
dehyde (0.208 g, 1.67 mmol, 1.1 equiv) was added. The mixture
was stirred for another 10 min, and then the reaction was quenched
with aq NH4Cl (10 mL), and extracted with CH2Cl2 (3 × 12 mL).
The combined extracts were dried (Na2SO4) and concentrated under
vacuum. Precipitation from a mixture of CH2Cl2–hexane gave
exo,anti-16c; yield: 0.454 g (88%); 96% ee [1H NMR in the pres-
ence of (R)-TFAE]; white solid; mp 110–111 °C; 99% ee after re-
IR (KBr): 3375, 2937, 2784, 1577, 1457 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.66 (t, J = 11.0 Hz, 1 H,
NH·HCl), 10.43 (t, J = 11.0 Hz, 1 H, NH·HCl), 7.72–7.05 (m, 15 H,
ArH), 4.73 [d, J = 9.4 Hz, 1 H, CH(Ph)2], 4.07–3.96 (m, 1 H,
CHMe), 1.36 (d, J = 6.9 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 136.2, 134.6, 133.8, 133.0, 129.2,
129.1, 129.0, 128.7, 128.64, 128.59, 128.5, 128.4, 64.6, 58.6, 20.0.
20
crystallization; [α]D –33.8 (c 0.65, MeOH); Rf = 0.5 (hexanes–
EtOAc–Et3N, 72:18:10).
IR (CHCl3): 3011, 2962, 1712, 1607, 1511, 1069 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.48–7.32 (m, 5 H, ArH), 7.20–
7.11 (m, 2 H, ArH), 6.90–6.70 (m, 2 H, ArH), 5.07 [d, J = 2.9 Hz, 1
H, CH(OH)Ph], 3.75–3.66 (m, 3 H, NCH2Ph, NCH, C1), 3.63–3.55
(m, 1 H, NCH, C5), 2.79 [ddd, J = 15.9, 4.7, 1.8 Hz, 1 H, ax-
CH(H)CO], 2.40 [d, J = 2.2 Hz, 1 H, CHCH(OH)Ar], 2.38–2.15 [m,
3 H, eq-CH(H)CO, CH(H) (C6, C7)], 1.75–1.52 [m, 2 H, CH(H)
(C6, C7)].
(R)-N-Benzhydryl-1-phenyl-2-(piperidin-1-yl)ethanamine
[(R)-10]
Isolated from 10·HCl solution by extraction; yield: 1.48 g (80%,
20
5 mmol scale); yellow oil; [α]D –76.6 (c 0.70, CHCl3); Rf = 0.7
(MeOH–CH2Cl2, 1:9).
IR (CHCl3): 3291, 2938, 1493, 1453, 909 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.48–7.11 (m, 15 H, ArH), 4.62
[s, 1 H, CH(Ph)2], 3.66 (dd, J = 11.2, 3.2 Hz, 1 H, NHCHCH2), 2.52
[t, J = 11.7 Hz, 1 H, PhCHCH(H)N], 2.35–2.22 (m, 2 H, CH of pi-
peridine ring), 2.22–2.18 [m, 3 H, PhCHCH(H)N, CH of piperidine
ring], 1.64–1.48 (m, 4 H, piperidine CH2), 1.48–1.32 (m, 2 H, piper-
idine CH2).
13C NMR (100 MHz, CDCl3): δ = 144.8, 143.9, 143.1, 128.3, 128.2,
128.0, 127.9, 127.7, 127.5, 127.1, 126.8, 126.4, 66.4, 62.7, 56.5,
54.5, 26.1, 24.4.
13C NMR (100 MHz, CDCl3): δ = 208.2, 161.9 (d, 1JC,F = 243 Hz),
4
137.5, 137.4 (d, JC,F = 3 Hz), 129.0, 128.8, 127.8, 127.1 (d,
3JC,F = 8 Hz), 114.8 (d, 2JC,F = 21 Hz), 75.9, 65.0, 64.4, 58.9, 57.0,
51.6, 26.8, 26.4.
HRMS-ESI: m/z [M + H]+ calcd for C21H23FNO2: 340.1713; found:
340.1708.
(+)-(1R,2S,5S)-8-Benzyl-2-{(R)-hydroxy[4-(trifluorometh-
yl)phenyl]methyl}-8-azabicyclo[3.2.1]octan-3-one [(+)-exo,anti-
16d]
HRMS-ESI: m/z [M + H]+ calcd for C26H31N2: 371.2487; found:
371.2473.
20
Yield: 0.526 g (90%); white solid; mp 120–122 °C; 80% ee; [α]D
+1.8 (c 1.15, CHCl3); Rf = 0.5 (hexanes–EtOAc–Et3N, 72:18:10).
(R)-N-Benzhydryl-2-(4-methylpiperazin-1-yl)-1-phenylethan-
amine [(R)-11]
1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 8.3 Hz, 2 H, ArH),
7.48–7.32 (m, 5 H, ArH), 7.31 (d, J = 8.4 Hz, 2 H, ArH), 5.13 [d,
J = 2.5 Hz, 1 H, CH(OH)Ph], 3.77–3.66 (m, 3 H, NCH2Ph, NCH,
C1), 3.63–3.57 (m, 1 H, NCH, C5), 2.79 [ddd, J = 16.0, 4.7, 1.9 Hz,
1 H, ax-CH(H)CO], 2.45 [d, J = 2.0 Hz, 1 H, CHCH(OH)Ar], 2.40–
2.18 [m, 3 H, eq-CH(H)CO, CH(H) (C6, C7)], 1.76–1.59 [m, 2 H,
CH(H) (C6, C7)].
Isolated from 11·HCl solution by extraction; yield: 1.56 g (81%,
20
5 mmol scale); yellow oil; [α]D –80.2 (c 0.85, CHCl3); Rf = 0.5
(MeOH–CH2Cl2, 1:9).
IR (CHCl3): 3294, 2943, 2804, 1455, 1165, 909 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.42 (m, 2 H, ArH), 7.41–
7.17 (m, 13 H, ArH), 4.62 [s, 1 H, CH(Ph)2], 3.65 (dd, J = 11.2, 3.2
Hz, 1 H, NHCHCH2), 3.28 (br s, 1 H, NH), 2.52 [t, J = 11.9 Hz, 1
H, PhCHCH(H)N], 2.65–2.15 (m, 8 H, CH of piperazine ring), 2.33
(s, 3 H, CH3), 2.65 [dd, J = 12.3 Hz, 3.3 Hz, 1 H, PhCHCH(H)N].
13C NMR (100 MHz, CDCl3): δ = 207.8, 145.6, 137.4, 129.3 (q,
3
2JC,F = 32 Hz), 129.1, 128.9, 127.9, 125.9, 125.0 (q, JC,F = 4 Hz),
1
124.2 (q, JC,F = 272 Hz), 76.0, 65.1, 63.9, 59.0, 57.0, 51.6, 26.9,
26.5.
HRMS-ESI: m/z [M + H]+ calcd for C22H23F3NO2: 390.1681; found:
390.1684.
13C NMR (100 MHz, CDCl3): δ = 144.5, 143.9, 142.6, 128.33,
128.25, 128.0, 127.9, 127.6, 127.4, 127.1, 126.9, 126.4.
HRMS-ESI: m/z [M + H]+ calcd for C26H32N3: 386.2596; found:
386.2589.
(+)-(1R,2S,5S)-9-Benzyl-2-[(R)-(4-bromophenyl)(hy-
droxy)methyl]-9-azabicyclo[3.3.1]nonan-3-one [(+)-exo,anti-
18b]
Methyl rac-2-(Benzhydrylamino)-2-phenylacetate (12)28
Isolated from 12·HCl solution by extraction; yield: 0.862 g (52%,
5 mmol scale); yellow oil; Rf = 0.43 (hexanes–EtOAc, 85:15).
IR (CHCl3): 3339, 3065, 1735, 1494, 1454, 1173 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.46–7.18 (m, 15 H, ArH), 4.75
[s, 1 H, CH(Ph)2], 4.36 (s, 1 H, CHCO2Me), 3.68 (s, 3 H, CH3).
20
Yield: 0.466 g (75%); white solid; mp 124–125 °C; 72% ee; [α]D
+7.1 (c 0.60, CHCl3); Rf = 0.37 (hexanes–EtOAc–Et3N, 72:18:10).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.48 (m, 7 H, ArH), 7.07 (d,
J = 8.4 Hz, 2 H, ArH), 6.98 (br s, 1 H, OH), 5.10 [d, J = 3.6 Hz, 1
H, CH(OH)Ph], 4.08 (d, J = 12.8 Hz, 1 H, NCH2Ph), 4.04 (d,
J = 12.8 Hz, 1 H, NCH2Ph), 3.43 (d, J = 3.5 Hz, 1 H, NCH, C1),
3.37 (br s, 1 H, NCH, C5), 2.87 [dd, J = 16.4 Hz, J = 7.0 Hz, 1 H,
Synthesis 2014, 46, 1475–1480
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PAPER
Asymmetric Deprotonation with a Chiral Secondary N-Benzhydrylamine
1479
ax-CH(H)CO], 2.51 [d, J = 3.5 Hz, 1 H, CHCH(OH)Ar], 2.43 [d,
J = 16.4 Hz, 1 H, eq-CH(H)CO], 2.21–2.09 [m, 2 H, CH(H) (C6,
C8)], 1.68–1.59 [m, 2 H, CH(H) (C6, C8)], 1.42–1.30 [m, 2 H, CH2
(C7)].
13C NMR (100 MHz, CDCl3): δ = 209.2, 140.5, 137.2, 131.1, 129.1,
128.9, 127.9, 127.3, 121.1, 77.03, 61.1, 58.6, 56.0, 51.2, 48.5, 23.3,
22.8, 16.5.
References
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Deprotonations using Chiral Lithium Amide Bases, In
Topics in Current Stereochemistry; Vol. 26; Gawley, R. E.,
Ed.; Wiley-VCH: Weinheim, 2010.
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Moriyama, M.; Fukuyama, Y. J. Org. Chem. 2007, 72, 3065.
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(4) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins,
N. S. Tetrahedron 1990, 46, 523.
HRMS-ESI: m/z [M + H]+ calcd for C22H25BrNO2: 414.1069;
found: 414.1065.
(–)-(1R,2S,5S)-9-Benzyl-2-[(R)-(4-fluorophenyl)(hy-
droxy)methyl]-9-azabicyclo[3.3.1]nonan-3-one [(+)-exo,anti-
18c]
20
Yield: 0.345 g (65%); white solid; mp 68–69 °C; 85% ee; [α]D
(5) (a) Pollini, G. P.; Benetti, S.; De Risi, C.; Zanirato, V. Chem.
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Lett. 2009, 50, 7196. (c) Lazny, R.; Sienkiewicz, M.;
Olenski, T.; Urbanczyk-Lipkowska, Z.; Kalicki, P.
Tetrahedron 2012, 68, 8236. (d) Majewski, M.; Lazny, R.;
Ulaczyk, A. Can. J. Chem. 1997, 75, 754. (e) Majewski, M.;
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Nodzewska, A.; Sienkiewicz, M. Pol. J. Chem. 2006, 80,
659; Chem. Abstr. 2007, 146, 338050.
–11.8 (c 0.75, CHCl3); Rf = 0.5 (hexanes–EtOAc–Et3N, 72:18:10).
1H NMR (400 MHz, CDCl3): δ = 7.50–7.27 (m, 5 H, ArH), 7.21–
7.13 (m, 2 H, ArH), 6.98 (t, J = 8.7 Hz, 2 H, ArH), 5.12 [d, J = 3.6
Hz, 1 H, CH(OH)Ph], 4.09 (d, J = 12.8 Hz, 1 H, NCH2Ph), 4.04 (d,
J = 12.8 Hz, 1 H, NCH2Ph), 3.43 (d, J = 3.2 Hz, 1 H, NCH, C1),
3.37 (br s, 1 H, NCH, C5), 2.89 [dd, J = 16.3, 7.0 Hz, 1 H, ax-
CH(H)-CO], 2.51 [d, J = 3.2 Hz, 1 H, CHCH(OH)Ar], 2.43 [d,
J = 16.3 Hz, 1 H, eq-CH(H)CO], 2.25–2.08 [m, 2 H, CH(H) (C6,
C8)], 1.70–1.52 [m, 2 H, CH(H) (C6, C8)], 1.43–1.30 [m, 2 H, CH2
(C7)].
13C NMR (100 MHz, CDCl3): δ = 209.4, 162.0 (d, 1JC,F = 243 Hz),
4
137.4, 137.2 (d, JC,F = 3 Hz), 129.1, 128.9, 127.9, 127.2 (d,
3JC,F = 8 Hz), 114.9 (d, 2JC,F = 21 Hz), 77.1, 61.5, 58.6, 56.1, 51.4,
48.6, 23.3, 22.8, 16.6.
HRMS-ESI: m/z [M + H]+ calcd for C22H25FNO2: 354.1869; found:
354.1875.
(8) Lazny, R.; Nodzewska, A.; Sienkiewicz, M. Lett. Org.
Chem. 2010, 7, 21.
(9) Kusano, G.; Orihara, S.; Tsukamoto, D.; Shibano, M.;
Coskun, M.; Guvenc, A.; Erdurak, C. S. Chem. Pharm. Bull.
2002, 50, 185.
(10) Duhamel, L.; Ravard, A.; Plaquevent, J. C.; Ple, G.;
Davoust, D. Bull. Soc. Chim. Fr. 1990, 787.
(11) Nowak, P. Ph.D. Disssertation; University of
Saskatchewan: Canada, 1998,
http://library.usask.ca/theses/available/etd-10212004-
001009/unrestricted/NQ32795.pdf (30.08.2012).
(12) Enders, D.; Rembiak, A.; Seppelt, M. Tetrahedron Lett.
2013, 54, 470.
(13) Juaristi, E.; Murer, P.; Seebach, D. Synthesis 1993, 1243.
(14) Lovick, H. M.; An, D. K.; Livinghouse, T. S. Dalton Trans.
2011, 40, 7697.
(15) Kirincich, S. J.; Xiang, J.; Green, N.; Tam, S.; Yang, H. Y.;
Shim, J.; Shen, M. W. H.; Clark, J. D.; McKew, J. C. Bioorg.
Med. Chem. 2009, 17, 4383.
(16) Page, P. C. B.; Allin, S. M.; Dilly, S. J.; Buckley, B. R.
Synth. Commun. 2007, 37, 2019.
(–)-(1R,2S,5S)-9-Benzyl-2-{(R)-hydroxy[4-(trifluorometh-
yl)phenyl]methyl}-9-azabicyclo[3.3.1]nonan-3-one [(+)-exo,an-
ti-18d]
Yield: 0.424 g (70%); white solid; mp 132–134 °C; 90% ee after re-
20
crystallization; [α]D –3.7 (c 0.90, CHCl3); Rf = 0.5 (hexanes–
EtOAc–Et3N, 72:18:10).
1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 8.2 Hz, 2 H, ArH),
7.48–7.30 (m, 5 H, ArH), 7.33 (d, J = 8.2 Hz, 2 H, ArH), 7.17 (br s,
1 H), 5.18 [d, J = 3.3 Hz, 1 H, CH(OH)Ph], 4.10 (d, J = 12.8 Hz, 1
H, NCH2Ph), 4.06 (d, J = 12.8 Hz, 1 H, NCH2Ph), 3.49 (d, J = 3.9
Hz, 1 H, NCH, C1), 3.39 (br s, 1 H, NCH, C5), 2.88 [dd, J = 16.4,
7.0 Hz, 1 H, ax-CH(H)CO], 2.59–2.55 [m, 1 H, CHCH(OH)Ar],
2.44 [d, J = 16.4 Hz, 1 H, eq-CH(H)CO], 2.27–2.12 [m, 2 H, CH2
(C6, C8)], 1.70–1.50 [m, 2 H, CH(H) (C6, C8)], 1.48–1.32 [m, 2 H,
CH(H) (C7)].
13C NMR (100 MHz, CDCl3): δ = 208.9, 145.4, 137.2, 129.4 (q,
3
2JC,F = 32 Hz), 129.1, 128.9, 128.0, 125.9, 125.0 (q, JC,F = 4 Hz),
1
124.2 (q, JC,F = 272 Hz), 77.2, 60.9, 58.8, 56.1, 51.3, 48.4, 23.3,
22.8, 16.5.
HRMS-ESI: m/z [M + H]+ calcd for C23H25F3NO2: 404.1837 found:
404.1841.
(17) Miyake, A.; Itoh, K.; Tada, N.; Tanabe, M.; Hirata, M.; Oka,
Y. Chem. Pharm. Bull. 1983, 31, 2329.
(18) Selim, K. B.; Matsumoto, Y.; Yamada, K.-I.; Tomioka, K.
Angew. Chem. Int. Ed. 2009, 48, 8733.
(19) Sciebura, J.; Gawronski, J. Tetrahedron: Asymmetry 2013,
24, 683.
Acknowledgment
We are grateful for the support from the University of Bialystok
(BST-125, BMN-172) and the National Science Centre of Poland
(Grant No. N N204 546939). We also thank Prof. R. Lazny for hel-
pful discussion.
(20) Majewski, M.; Wang, F. Tetrahedron 2002, 58, 4567.
(21) In the reaction of N-benzhydrylamine with n-BuLi, the
secondary amine hydrogen is removed, not the benzhydryl
proton. Although the pKa of diphenylmethane (PhCH2Ph) is
lower than that of the secondary amine, the rate of
abstraction of the CH proton by n-BuLi is much slower than
the rate of abstraction of proton from the heteroatom, that is,
the kinetic acidity, not the thermodynamic acidity
determines the deprotonation selectivity. The faster rate of
proton abstraction can be observed experimentally. In the
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1475–1480

1480
A. Nodzewska et al.
PAPER
presence of deuterated solvent, for example, MeOD, only the
NH hydrogen is substituted by deuterium and is invisible in
the NMR spectrum in contrast to Ph2CH {1H NMR (400
MHz, MeOD): δ = 7.45–7.08 (m, 15 H, ArH), 4.56 [s, 1 H,
CH(Ph)2], 3.64 (q, J = 6.7 Hz, 1 H, CHMe), 1.36 (d, J = 6.7
Hz, 3 H, CH3)}. Signal from Ph2CH is observed in the NMR
spectrum of Li-3, obtained in the reaction of amine 3 with
n-BuLi in THF-d8 under typical reaction condition (0 °C, 30
min) in NMR tube {1H NMR (400 MHz, THF-d8): δ = 7.38–
6.92 (m, 15 H, ArH), 4.81 [s, 1 H, CH(Ph)2], 3.74 (q, J = 6.4
Hz, 1 H, CHMe), 0.95 (d, J = 6.6 Hz, 3 H, CH3)}.
(23) (a) Lazny, R.; Nodzewska, A.; Sidorowicz, K.; Kalicki, P.
Beilstein J. Org. Chem. 2012, 8, 1877. (b) Lazny, R.;
Wolosewicz, K. Tetrahedron Lett. 2013, 54, 1103.
(24) In many cases, heating during crystallization caused the anti-
syn isomerization and the formation of exo,syn-products.
The characteristic doublet of the carbinol hydrogen in the
exo,syn-isomer was shifted upfield (about 0.1–0.2 ppm) and
had a lower coupling constant (up to 2.2 Hz).
(25) Brzezinski, K.; Lazny, R.; Nodzewska, A.; Sidorowicz, K.
Acta Crystallogr., Sect. C 2013, 69, 303.
(26) Momose, T.; Toshima, M.; Toyooka, N.; Hirai, Y.; Hans
Eugster, C. J. Chem. Soc., Perkin Trans. 1 1997, 1307.
(27) Collino, F. Boll. Chim. Farm. 1969, 108, 355; Chem. Abstr.
1969, 71, 101431.
(22) (a) Brzezinski, K.; Lazny, R.; Sienkiewicz, M.;
Wojtulewski, S.; Dauter, Z. Acta Crystallogr., Sect. E 2012,
68, o149. (b) Lazny, R.; Wolosewicz, K.; Dauter, Z.;
Brzezinski, K. Acta Crystallogr., Sect. E 2012, 68, o1367.
(28) Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46,
2025.
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© Georg Thieme Verlag Stuttgart · New York