A Mannich-cyclization approach for the asymmetric synthesis of saturated N-heterocycles

Article abstract of DOI:10.1055/s-2004-835622

A concise asymmetric synthesis of disubstituted N-heterocycles is reported. Our approach utilizes an optimized Mannich reaction of functionalized aldehydes, followed by a novel dehydrative cyclization mediated by the Staab reagent (1,1′-carbonyldiimidazol

Full text of DOI:10.1055/s-2004-835622

LETTER
2751
A Mannich–Cyclization Approach for the Asymmetric Synthesis of Saturated
N-Heterocycles
A
symmetric Synth
l
esis of
e
Saturated
N
x
-Heterocycl
a
e
s
nder Münch, Bianca Wendt, Mathias Christmann*
Institut für Organische Chemie, RWTH Aachen, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: christmann@oc.rwth-aachen.de
Received 20 August 2004
Mannich
H
Abstract: A concise asymmetric synthesis of disubstituted N-het-
erocycles is reported. Our approach utilizes an optimized Mannich
reaction of functionalized aldehydes, followed by a novel dehydra-
tive cyclization mediated by the Staab reagent (1,1¢-carbonyldiimi-
dazole, CDI). The method was applied to the synthesis of
azetidines, piperidines and pyrrolidines.
H
O
X
N
H
H
H2N
H
N
Ph
HO
X
1
Key words: stereoselective synthesis, heterocycles, cyclizations,
azetidines, organocatalysis
(+)-astrophylline
X
X
N
NH2
Saturated nitrogen heterocycles1 are privileged structural
motifs2 in natural and synthetic bioactive compounds (e.g.
1–3, Scheme 1).3–5 When looking at their connectivity, we
envisioned that many of the structures could be assembled
in a straightforward fashion by Mannich reactions of ap-
propriately functionalized aldehydes, followed by one or
two nucleophilic displacements with the amino group.
Herein, we report an efficient protocol for a proline-cata-
lyzed Mannich dimerization of four-carbon building
blocks. In addition, we will present a novel cyclization
reaction allowing for the rapid synthesis of four- to six-
membered N-heterocycles.6 After the renaissance of the
asymmetric Robinson annulation7 and its extension to
intermolecular C–C bond forming reactions,8 List9 de-
scribed the first proline-catalyzed direct Mannich reac-
tion.10,11
H
H
HO
HO
2
Mannich
(+)-trachelanthamidine
Mannich
OH
OH
N
O
F
3
F
ezetimibe (zetia)
Scheme 1 Mannich disconnection of biologically relevant targets.
Changing the protecting group to acetate (9b)16 improved
the enantioselectivity to 87% (Table 1, entry 7). A survey
of different solvents revealed acetonitrile to be superior to
DMF.
In this reaction (Scheme 2), the proline catalyst and an
enolizable carbonyl compound 4 form an enamine 6
(Mannich donor), which reacts with an imine 7 (Mannich
acceptor). If donor (4) and acceptor aldehyde (5) are
identical, the reaction is called self-Mannich reaction or
Mannich dimerization. In 2003, the Barbas group12 and
others13 reported, that the proline-catalyzed Mannich
dimerization of p-anisidine and several aliphatic alde-
hydes afforded – after reduction with sodium borohydride
– the corresponding g-amino alcohols 8 in good yield and
stereoselectivity.
Not only did it improve the ee and the de, but also the re-
action occurred with reasonable rates at lower tempera-
tures, while in DMF, the reaction practically ceases below
–20 °C. We were pleased to find that even at –40 °C the
reaction was complete within 12 hours, giving the desired
amino alcohol in 85% and 98% ee (Table 1, entry 5).17
This represents a remarkable finding, since proline-cata-
lyzed reactions generally have been reported in a temper-
ature range between 25 °C and –20 °C, in some cases
limited by the solvents’ freezing point. While the influ-
ence of the remote protecting groups remains speculative
We wanted to extend this reaction to functionalized
substrates and improve the stereoselectivity. Initially un-
der conditions employed by Barbas et al. (DMF, –15 °C)
with 4-tert-butyldimethylsilyloxybutanal (9a)14 as the
substrate, we were able to obtain the desired amino alco-
hol 10a in 80% yield and 63% ee (Table 1, entry 2).15
O
OH
R
CO2H
6
N
L-proline (cat.)
PMP
R´
N
4
R
O
p-anisidine
R´
HN
7
SYNLETT 2004, No. 15, pp 2751–2755
Advanced online publication: 22.10.2004
0
7
.1
2
.2
0
0
4
R
5
PMP
R´
8
DOI: 10.1055/s-2004-835622; Art ID: G32704ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Mechanism of the Mannich reaction.

2752
A. Münch et al.
LETTER
Table 1 Reaction Optimization on the Mannich Reaction of Substituted Butyraldehydesa
PMP
30 mol% (L)-proline
p-anisidine
HN
OR
OR
O
HO
conditions
9a: R = TBS
9b: R = Ac
OR
10a,b
Entry
R
Solvent
DMF
Temp (°C)
Yield (%)
de (%)
28
ee (%)b
67 (31)
63 (34)
87 (38)
95 (50)
98 (61)
56 (43)
87 (83)
80 (33)
86 (51)
1
2
3
4
5
6
7
8
9
TBS
TBS
TBS
TBS
TBS
Ac
4
–15
4
46
80
68
86
85
56
73
58
79
DMF
36
MeCN
MeCN
MeCN
DMF
44
–23
–40
4
64
80
22
Ac
DMF
–15
4
38
Ac
MeCN
MeCN
14
Ac
–23
36
a Conditions: (1) 4 equiv of aldehyde, 1 equiv of p-anisidine, 30 mol% (L)-proline; (2) NaBH4.
b The numbers in parentheses refer to the minor diastereomer.
at this point, these subtle effects may become important in that require tedious separation. To this end, we have de-
achieving our long term goal of controlling a substrate’s veloped a mild protocol that is applicable to different ring
capacity to act selectively either as Mannich donor or ac- sizes and tolerant of several functional groups. As out-
ceptor. With the amino alcohols in hand, we then turned lined in Scheme 3, the readily available 1,1¢-carbonyl-
our attention to the crucial cyclization. This reaction is diimidazole (CDI)21 was utilized as a dehydrating agent,
generally performed by activation of the hydroxyl group whereby the resulting by-products are simply imidazole
towards nucleophilic displacement by the amino group. and carbon dioxide (Scheme 3, equation 1). In fact, when
Traditional protocols involve conversion of the hydroxy the amino alcohols 11 were refluxed with CDI in acetoni-
group to the mesylate followed by base-mediated cycliza- trile, formation of the more polar carbamate 12 was ob-
tion (MsCl, Et3N),18 Appel-type reactions (CBr4, Ph3P)19 served. These intermediates could be isolated or heated
or Mitsunobu activation (DEAD, Ph3P).20 The drawback further to form the corresponding heterocycles 13. Al-
of the above mentioned methods are the use of toxic (T+) though we have not found any precedent for this reaction,
or expensive reagents and/or the formation of by-products it was shown that benzylic hydroxy groups bearing a
This work:
R1
R1
R1
R2
R2
R2
– ImH, – CO2
CDI
O
n
n
n
(1)
– ImH
HN
HN
N
HO
N
O
N
13
OMe
OMe
OMe
n = 0–2
R1 = alkyl
11
12
R2 = alkyl, aryl
Mulvihill and Szmuszkovicz:
N
N
R1
N
R2
OH
N
N
R3
O
O
N
R3
R2
CDI
- CO2
R3
(2)
N
R3
– ImH
N
R2
R1
14
N
R1
N
15
cis-aziridinium intermediate
R1
R2
16
R1–R3 = alkyl
Scheme 3 Mechanism of the heterocycle formation (equation 1) and use of CDI as leaving group/nucleophile (equation 2).
Synlett 2004, No. 15, 2751–2755 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Saturated N-Heterocycles
2753
tertiary b-amino group can be substituted with imidazole (Table 2, entries 1, 2) as well as aliphatic PMP-protected
(14 → 16) using CDI.22 The observed retention of config- amines (Table 2, entries 3, 4) were used in the reaction.
uration was explained with an aziridinium-intermediate
15 (Scheme 3, equation 2), which indicates a concerted
C–N bond formation–decarboxylation rather than an SN1-
pathway.
Gratifyingly, TBS and acetate protecting groups were sta-
ble under the conditions (Table 2, entries 1, 5–8), which
allowed for further functionalization of the products. The
method is not limited to 2,3-cis-azetidines (entry 6),
For the synthesis of pyrrolidine 18, the primary alcohol of though we mainly examined syn-amino alcohols due to
10a was protected as TBDPS ether and the more labile their preferential formation in the proline-catalyzed Man-
TBS groups were removed with p-toluenesulfonic acid in nich process. Since the diastereomeric azetidines show
methanol (Scheme 4). When diol 17 was heated with three distinctive differences in their 1H NMR spectra, this meth-
equivalents of CDI in acetonitrile, the cyclization oc- od also facilitates the assignment of the relative configu-
curred smoothly. In order to cleave the remaining carbam- ration of the amino alcohols 21. As shown in Scheme 5,
ate, the reaction mixture was treated with 2 N NaOH– the PMP group of 22c was removed easily by oxidation
THF. Interestingly, the disubstituted pyrrolidine 18 was with ceric ammonium nitrate (CAN). In order to facilitate
observed almost exclusively.
Table 2 Synthesis of Substituted Azetidinesa
Piperidine 20 was synthesized in two steps from 19, which
was obtained from a three-component Mannich reaction
of 5-tert-butyldimethylsilyloxypentanal and benzalde-
hyde as a non-enolizable Mannich acceptor. The TBS
group was cleaved (TBAF) and the resulting diol was re-
fluxed with CDI in acetonitrile for 2 hours. After removal
of the solvent, the reaction mixture was heated to 150 °C
under high vacuum in a Kugelrohr apparatus to facilitate
the decarboxylative cyclization. Hydrolysis of the remain-
ing carbamate afforded piperidine 20 in 62% yield.
O
O
PMP
R1
PMP
PMP
R1
HN
O
N
Im
Im
N
R1
conditions
HO
R2
R2
R2
21
22
23
not observed
Entry
1
22
Yield (%) Compound
74
22a
OMe
PMP
HN
N
PMP
N
HO
OH
TBSO
c
a,b
OH
10a
17
OTBDPS
PMP
TBDPSO
18
2
22b
82
PMP
N
HN
OH
d,e
TBSO
N
HO
3
4
5
22c
22d
22e
75
71
82
PMP
PMP
20
N
19
Scheme 4 Reagents and conditions: a) TBDPSCl, imidazole, DMF,
92%; b) p-TsOH, MeOH, 91%; c) CDI, MeCN, reflux, then 2 N
NaOH, THF, 69%; d) TBAF, THF, 96%; e) CDI, MeCN, reflux, then
remove solvent; 150 °C, 0.05 mbar; 2 N NaOH, THF, 62%.
PMP
N
PMP
PMP
N
N
Among N-heterocycles, the four-membered azetidines
possess orphan status.23 This may be explained by lack of
general methods for their asymmetric synthesis.24 When
applying the above mentioned conditions to the g-amino
alcohols 21,25 one would rather expect the formation of
cyclic carbamates (23) than the 4-exo ring-closure to the
azetidines 22, as witnessed for other N-protecting groups
like methyl or benzyl.26 However, in none of the examined
cases was any carbamate formation observed. Table 2
summarizes the scope of the different azetidines that can
be accessed.27 All reactions were carried out in a Kugel-
rohr apparatus. The imidazole formed in the reaction can
be easily removed by filtration through silica gel. Prod-
ucts of lower molecular weight (Table 2, entries 2–4)
could be collected in the receiving flask. Benzylic
OAc
OAc
AcO
AcO
6b
7
22f
22g
22h
84
73
71
PMP
N
OTBS
TBSO
TBSO
8
PMP
N
OTB
a Conditions: 1.0 equiv amino alcohol, 2 equiv CDI, MeCN, reflux;
remove solvent, then 150 °C, 0.05 mbar, 2–4 h.
b Prepared from the anti-diastereomer obtained in the Mannich
reaction.
Synlett 2004, No. 15, 2751–2755 © Thieme Stuttgart · New York

2754
A. Münch et al.
LETTER
(12) Notz, W.; Tanaka, F.; Watanabe, S.-i.; Chowdari, N. S.;
PMP
a, b
Boc
N
N
Turner, J. M.; Thayumanavan, R.; Barbas, C. F. III J. Org.
Chem. 2003, 68, 9624.
(13) (a) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.;
Shoji, M.; Sakai, K. Angew. Chem. Int. Ed. 2003, 42, 3677.
(b) Cordova, A. Chem.–Eur. J. 2004, 10, 1987.
(14) Mann, S.; Carillon, S.; Breyne, O.; Marquet, A. Chem.–Eur.
J. 2002, 2, 439.
22c
24
Scheme 5 Reagents and conditions: a) CAN, MeCN–H2O;
b) Boc2O, PhMe, 25% aq NaOH, 72%.
(15) To a cooled (–40 °C) solution of (L)-proline (17.3 mg, 0.15
mmol) and p-anisidine (61.6 mg, 0.5 mmol) in MeCN (5
mL) was added 4-OTBS-butanal (809 mg, 4 mmol). The
reaction mixture was stirred for 4 h at this temperature and
then put into a freezer (–30 °C) overnight. The mixture was
diluted with Et2O (2 mL) and allowed to reach 0 °C. After
the addition of NaBH4 (500 mg), the reaction was stirred for
15 min at this temperature and allowed to reach r.t. The
mixture was poured into half sat. aq NH4Cl (50 mL). After
30 min, the aqueous layer was extracted with Et2O (3 × 50
mL) and the combined organic layers are dried with Na2SO4.
Removal of the solvent on a rotatory evaporator afforded the
crude amino alcohol as a colorless oil. The main impurity, 4-
OTBS-butanol, was removed by distillation in a Kugelrohr.
The residue was purified by flash chromatography (Et2O–
pentane 1:1) on silica gel to afford 10a (218 mg, 0.426
mmol, 85%, 98% ee) as a colorless oil. Rf = 0.42 (Et2O–
pentane 1:1); HPLC [Chiracel OD (4.6 × 250 mm] n-
heptane–i-PrOH 95:5, 1.0 mL/min, l = 254 nm): major
isomer: tR = 13.3 min; minor isomer: tR = 5.9 min. 1H NMR
(300 MHz, CDCl3): d = 6.78 (d, J = 8.9 Hz, 2 H), 6.62 (d,
J = 8.9 Hz, 2 H), 3.80–3.55 (m, 9 H), 3.41 (m, 1 H), 2.01 (m,
1 H), 1.70–1.48 (m, 6 H), 0.91 (s, 9 H) 0.89 (s, 9 H), 0.08 (s,
6 H), 0.03 (s, 6 H). 13C NMR (75 MHz, CDCl3): d = 152.4,
141.7, 115.5 (2 C), 114.9 (2 C), 64.4, 62.7, 61.7, 58.0, 55.7,
40.1, 30.5, 29.8, 27.7, 25.9 (6 C), 18.2 (2 C), –5.5 (2 C), –5.4
(2 C). IR (CHCl3): 3378 (m), 2932 (s), 2891 (s), 2858 (s),
1513 (s), 1468 (m), 1251 (s), 1098 (s), 1043 (m), 836 (s), 776
(s) cm–1. MS (EI): m/z (%) = 511 (32) [M+], 308 (100), 176
(74). HRMS (EI): m/z calcd for C27H53NO4Si2 [M+]:
511.3515. Found: 511.3513. Anal. Calcd for C27H53NO4Si2:
C, 63.35; H, 10.44; N, 2.74. Found: C, 62.91; H, 10.26; N,
3.17. [a]D25 = –17.2 (c 0.98, CHCl3).
the isolation, the crude amine was treated with Boc2O to
afford the Boc-protected azetidine 24 in 72% yield for two
steps.28
In conclusion, we have developed a short and efficient
route to various saturated N-heterocycles. Our strategy is
highlighted by a highly selective Mannich dimerization
followed by an unprecedented dehydrative cyclization
reaction with the Staab reagent. The application of this
strategy to the synthesis of natural products is underway
and will be reported in due course.
Acknowledgment
We thank the Fonds der Chemischen Industrie for a Liebig Stipen-
dium (M.C.) and Prof. Dieter Enders for his encouragement and
support.
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Synlett 2004, No. 15, 2751–2755 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Saturated N-Heterocycles
2755
(25) The starting materials were prepared according to ref. 15 or
as described by Barbas et al. (ref. 12).
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Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed.
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(27) A solution of the corresponding amino alcohol (0.2 mmol)
and 1,1¢-carbonyldiimidazole (0.4 mmol) in MeCN (10 mL)
was refluxed for 2 h. The solvent was evaporated in vacuo
and the intermediate carbamates were heated (150 °C) in a
Kugelrohr oven under high vacuum (0.05 mbar) for 2 h. The
residue was purified by flash chromatography on silica gel to
afford the azetidines. Products of lower molecular weight
were collected in the receiving flask. Spectral data for 22d:
colorless oil; Rf = 0.29 (Et2O–pentane 1:10). 1H NMR (400
MHz, CDCl3): d = 6.80 (d, J = 8.9 Hz, 2 H), 6.51 (d, J = 8.9
Hz, 2 H), 3.77 (m, 1 H), 3.75 (s, 3 H), 3.62 (dd, J = 8.0, 6.8
Hz, 1 H), 3.48 (dd, J = 6.8, 3.2 Hz, 1 H), 2.65 (m, 1 H), 1.83
(m, 2 H), 1.30 (d, J = 7.2 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 152.2, 147.4, 114.5 (2 C),
113.5 (2 C), 67.9, 58.1, 55.7, 27.5, 23.8, 14.7, 10.2. IR
(capillary): 2961 (s), 2873 (m), 2834 (m), 1511 (s), 1465 (s),
1293 (m), 1240 (s), 1120 (m), 1041 (m), 819 (s) cm–1. MS
(EI): m/z (%) = 205 (100) [M+], 176 (58), 163 (52), 135 (45),
134 (54). HRMS (EI): m/z calcd for C13H19NO [M+]:
205.1467. Found: 205.1467. [a]D25 –146.5 (c 1.04, CHCl3).
(28) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11253.
Synlett 2004, No. 15, 2751–2755 © Thieme Stuttgart · New York