Germanium(II)-mediated reductive Mannich-type reaction of α-bromoketones to N-alkylimines

Article abstract of DOI:10.1002/anie.200800194

(Chemical Equation Presented) A versatile metal: Germanium was effectively used in a novel and efficient method for the Mannich-type reaction between α-bromoketones and simple N-alkyl imines (see scheme). Germanium(II) acts as a reducing agent, forming a

Full text of DOI:10.1002/anie.200800194

Communications
DOI: 10.1002/anie.200800194
Synthetic Methods
Germanium(II)-Mediated Reductive Mannich-Type Reaction of
a-Bromoketones to N-Alkylimines**
Shin-ya Tanaka, Nobuo Tagashira, Kouji Chiba, Makoto Yasuda, and Akio Baba*
The b-aminoketone is an important structural intermediate in
the synthesis of many biologically active compounds.[1,2]
Mannich-type reactions provide one of the most efficient
approaches to the synthesis of the b-aminoketone skeleton
and considerable efforts have been devoted to the improve-
ment of this methodology.[3,4] In particular, Lewis acid
catalyzed addition of silicon enolates to imines has been
Scheme 1. Mannich-type reactions of the lithium enolate (energy
values are calculated values).
extensively studied and the method is well-established.[5] In
addition, direct organocatalyst-promoted Mannich-type reac-
tions have recently received increasing attention.[6] Generally,
imines bearing aryl groups or electron-withdrawing groups,
such as sulfonyl, carbonyl (Boc, Cbz, etc.), or phosphine oxide
groups, on the nitrogen atom have been employed. However,
no general method that uses an N-alkylimine in a Mannich-
type reaction with a ketone-derived enolate has been
reported because of the poor electrophilicity of N-alkyli-
mines.[7] In addition, Mannich-type reactions between metal
enolates and N-alkylimines would be less thermodynamically
favorable because of the increased basicity of the product
(metal amide). In fact, theoretical calculations for the
Mannich-type reaction involving ketone-derived lithium
enolate 2a show that the addition to N-benzylidenemethyl-
amine (1b, DE = 14kcalmol À1) is less favorable than addition
These results strongly suggest that addition of the ketone-
derived enolate to N-alkylimines remains a challenge to
researchers in the field. Herein, we report the first general
and practical reaction system for Mannich-type reactions that
employ germanium-enolate species.
First, we tested several low-valent metals in the reductive
Mannich-type reaction between a-bromoketone 4a and
N-benzylidenemethylamine (1b; Table 1). Zn and SnCl2
were ineffective (Table 1, entries 1 and 2), and SmI2, which
is known to be an effective reductant,[10] resulted in poor
yields (Table 1, entries 3 and 4). In contrast, GeCl2/dioxane
markedly raised the yield of b-aminoketone 5ba to 32%
(Table 1, entry 5).[11] To increase the yield, we screened
various Lewis acids for their catalytic activity in the germa-
nium-mediated system. Addition of TiCl4 lowered the yield to
6% (Table 1, entry 6), and BF3·OEt2, Zn(OTf)2, and
of 2a to N-benzylideneaniline (1a, DE = 0 kcalmolÀ1
;
Scheme 1).[8] Similar results were calculated for Mannich-
type reactions by using ester-derived lithium enolate 2b. Use
of the ester-derived enolate in the Mannich-type reaction,
however, is more favorable than use of the corresponding
ketone-derived enolate because of the higher reactivity of the
ester-derived enolate.[9] Formation of N-methyl adduct 3d is
unfavorable (DE = 7 kcalmolÀ1) compared with the exother-
mic formation of N-phenyl adduct 3c (DE = À7 kcalmolÀ1).
Table 1: Optimizingthe reaction with N-methylimine 1b.[a]
Entry Reductant
1[c] Zn
X (equiv) Conditions
Catalyst Yield[b]
[%]
[*] S.-y. Tanaka, N. Tagashira, K. Chiba, Dr. M. Yasuda, Prof. Dr. A. Baba
Department of Applied Chemistry
1.5
1.5
3.0
3.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
688C, 2 h
RT, 2 h
none
none
none
<1
<1
14
<1
32
6
Center for Atomic and Molecular Technologies (CAMT)
Graduate School of Engineering, Osaka University
2-1, Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7387
2
SnCl2
3[c] SmI2
À788C, 2 h
4[c] SmI2
À788C to RT, 2 h none
5
6
7
8
9
10
11
12
13
14
GeCl2/dioxane
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
RT, 2 h
none
TiCl4
E-mail: baba@chem.eng.osaka-u.ac.jp
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
GeCl2/dioxane
BF3·OEt2
Zn(OTf)2
33
34
K. Chiba
Science and Technology System Division
Ryoka Systems Inc., 1-28-38 Shinkawa
Chuo-ku, Tokyo 104-0033 (Japan)
Me3SiOTf 34
Bi(OTf)3
In(OTf)3
Y(OTf)3
Sc(OTf)3
Yb(OTf)3
45
52
71
84
93
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology of the Japanese Government. S.T. expresses his special
thanks for Research Fellowships of the Japan Society for JSPS
Research Fellowships for YoungScientists.
[a] Reaction conditions: 1a (0.6 mmol), reductant (X equiv), 4a
(0.9 mmol), catalyst (0.06 mmol), and CH2Cl2 (2 mL). [b] Yield deter-
mined from 1HNMR spectrum. [c] Run in THF.
Supportinginformation for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200800194.
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Me3SiOTf were also found to be poor catalysts (Table 1,
entries 7–9). In contrast to these representative Lewis acids,
Bi(OTf)3 and In(OTf)3 both increased the yield to approx-
imately 50% (Table 1, entries 10 and 11). The group three
metal triflates, Y(OTf)3 and Sc(OTf)3, also increased the
product yield (Table 1, entries 12 and 13); Yb(OTf)3 was the
most effective catalyst among the Lewis acids screened,
producing 5ba in excellent yield (Table 1, entry 14).[12]
dibromide 4d and imine 1f. Subsequent treatment with
aqueous NaHCO3 afforded the substituted piperidine 5 fd in
good yield [Eq. (1)]. The 2-arylpiperidine unit is an important
Because of the effective optimization of the reaction
(Table 1), the generality of the method was investigated under
optimized conditions (Table 2). High yields were obtained
from N-methylimines derived from aromatic aldehydes bear-
ing electron-withdrawing or electron-donating groups
(Table 2, entries 1–4). N-Benzylimine 1 f, N-allylimine 1g,
and N-phenylimine 1a also gave their respective products in
excellent yields (Table 2, entries 5–7). Even enolizable imines
1h–i effectively afforded the desired b-aminoketones
(Table 2, entries 8–9). Both aliphatic and aromatic secondary
a-bromoketones 4b–c furnished the desired products in
modest to high yields. The diastereoselectivities were sub-
strate dependent, ranging from 55 to 83% (Table 2,
entries 10–12). The use of a mild catalyst, Bi(OTf)3, in the
reaction with formaldimine 1j gave higher yields than those
obtained with Yb(OTf)3 (Table 2, entries 13–16).
structure found in a number of biologically active com-
pounds.[13] Next, we synthesized the antihypertensive agent,
Be-2254, in just a few reaction steps (Scheme 2).[1c] Formald-
imine 1k was prepared in two steps from commercially
available tyramine hydrogen chloride 6. The germanium-
mediated Mannich-type reaction of 1k and subsequent
treatment with 5n HCl afforded Be-2254( 8ke) in 15%
overall yield.
The mild and selective reducing ability of GeCl2/dioxane
was demonstrated in the Mannich-type reaction by using
To complement the experimental studies, the thermody-
namic parameters of the reaction involving trichlorogerma-
nium enolate 2c[14] were evaluated
Table 2: Reaction of various imines 1 with a-bromoketones 4.[a]
(Scheme 3).[8] Notably, results of
the theoretical calculations show
that the reactions of N-phenyl 1a
and N-methylimine 1b are equally
Entry
Imine
1b R=H
a-Bromoketone
Product
Yield[b] [%]
exothermic (DE = À24kcalmol À1).
This result differs considerably
from those obtained for the lith-
ium-enolate reactions. The results
of the calculations were consistent
with the experimental results,
which demonstrated that both N-
aromatic and N-alkylimines could
be successfully used.
1
4a
4a
4a
4a
4a
4a
4a
5ba
5ca
5da
5ea
5 fa
5ga
5aa
93 (84)
86 (79)
97 (83)
89 (84)
96 (83)
91 (82)
93 (81)
2[c]
3
1c R=NO2
1d R=OMe
1e R=Br
1 f R=Bn
1g R=allyl
1a R=Ph
4[d]
5
6
7
8[d]
1h
1i
4a
4a
5ha
66 (40)
Our next objective was to
determine the structural features
that contribute to the germanium-
mediated Mannich-type reaction.
To achieve this goal, we investi-
gated optimized structures of the
Mannich adducts by using the lith-
ium enolate and the trichloroger-
manium enolate.
The optimized structures of the
lithium–adducts (3a and 3b) are
depicted in Figure 1a–b. The main
difference between the structures
is the negative charge on the nitro-
gen atoms (3a À0.84498, 3b
À1.00322). In 3a, a lone pair on
the nitrogen atom is in same plane
as the phenyl ring (Li-N-C1’-C2’
dihedral angle = 174.88), effec-
9[e]
5ia
65 (44)
10
11
1b
1g
4b
4b
5bb (R=Me) 71[f] (51)
5gb (R=allyl) 80[g] (60)
12
1b
4c
5bc
97[h] (97)
13[i]
1j
1j
4a
4a
5ja
5ja
60
67 (58)
14[I,j]
15[i]
1j
1j
4b
4b
5jb
5jb
27
52 (44)
16[i,j]
[a] Reaction conditions: 1 (0.6 mmol), GeCl3/dioxane (0.9 mmol), 4 (0.9 mmol), Yb(OTf)3 (0.06 mmol),
and CH2Cl2 (2 mL), unless otherwise stated. [b] Yield determined from 1HNMR spectrum and values in
parentheses are yields of the isolated products. [c] RT, 15 min. [d] RT, 1 h. [e] Used 5 mol% Yb(OTf)3.
[f] anti/syn=73:27. [g] anti/syn=83:17. [h] d.r.=55:45. [i] RT, 30 min. [j] Bi(OTf)3 was used instead of
Yb(OTf)3.
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As a result, the reaction pathway for the N-alkyl Mannich
adduct would be unfavorable, as noted in Scheme 1.
Unlike 3a–b, the nitrogen atoms of germanium–adducts
3e–f have similar negative charges (3e À0.92023, 3 f
À0.93238; Figure 1c–d). In addition, the phenyl ring of 3e is
almost perpendicular to the plane of N, Ge, and C1’ (Ge-N-
C1’-C2’ dihedral angle = 108.78). Conjugation of the phenyl
ring with a lone pair on the nitrogen atom is likely to be
sterically unfavorable, thus explaining the difference in the
charge. The adducts (3e–f) have germanium centers that
exhibit a distorted trigonal bipyramidal structure with the
À
nitrogen center in an equatorial position. The Ge N bond
distances are much shorter (3e 1.796 Š, 3 f 1.788 Š) than the
sum of the covalent radii (1.96 Š)[15]—possibly because of the
effective d or p orbital interaction between germanium and
the nitrogen atoms.[16] The strong bond contributes to the
stabilization of adducts 3e and 3 f, although conjugation with
the phenyl group is disturbed. These results strongly suggest
that the germanium-mediated reaction takes place regardless
of the substituents on the nitrogen atom. The difference in the
thermodynamic values between Schemes 1 and 3 provides
Scheme 2. Facile synthesis of Be-2254. Reagents and conditions:
a) tBuMe2SiCl, imidazole, CH2Cl2, RT, 84%; b) (CH2O)n, MgSO4,
CH2Cl2, RT, 96%; c) GeCl2/dioxane, Bi(OTf)3, CH2Cl2, RT, 53% NMR
yield, 30% yield of isolated product (not optimized); d) 5n HCl,
1008C, 64%.
À
strong evidence that the pp dp bond in the germanium amide
effectively stabilizes the adducts.
In summary, an efficient method for the Mannich-type
reaction of a-bromoketones with simple N-alkylimines was
demonstrated. Germanium is a novel promoter with three
Scheme 3. Mannich-type reactions of trichlorogermanium enolate
(energy values are calculated values).
À
roles: 1) reduction of the a-bromoketones, 2) C C bond
formation, and 3) stabilization of the Mannich adducts.
Detailed mechanistic studies and additional applications of
the system are ongoing.
Experimental Section
3-Bromo-3-methyl-2-butanone (4a, 0.9 mmol) was added to a stirred
suspension of N-benzylidenemethylamine (1b, 0.6 mmol), Yb(OTf)3
(0.06 mmol), and GeCl2/dioxane (0.9 mmol) in CH2Cl2 (2 mL) at
room temperature. The mixture was then stirred for 2 h at room
temperature, and saturated aq. NaHCO3 (20 mL) was added. The
mixture was extracted with Et2O (10 mL ” 3), dried (MgSO4), and
evaporated. The crude product was purified by silica gel chromatog-
raphy to afford aminoketone 5ba as a colorless solid.
Received: January 15, 2008
Revised: May 22, 2008
Published online: July 22, 2008
Keywords: amino ketones · germanium · imines · Lewis acids ·
.
Mannich reaction
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