Trichloromethyl ketones as synthetically versatile donors: Application in direct catalytic mannich-type reactions and the stereoselective synthesis of azetidines

Article abstract of DOI:10.1002/anie.200600227

Chemical transformers! Catalytic nucleophilic activation of trichloromethyl ketones allows applications in intermolecular carbon-carbon bond-forming reactions. Mannich adducts such as azetidines can be obtained from the primary products in high yield and syn selectivity. PG = protecting group. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200600227

Communications
Nucleophilic Reactions
DOI: 10.1002/anie.200600227
Trichloromethyl Ketones as Synthetically
Versatile Donors: Application in Direct Catalytic
Mannich-Type Reactions and the Stereoselective
Synthesis of Azetidines**
Hiroyuki Morimoto, Sean H. Wiedemann,
Akitake Yamaguchi, Shinji Harada, Zhihua Chen,
Shigeki Matsunaga,* and Masakatsu Shibasaki*
The catalytic generation of metal enolates in situ and their use
in stereoselective carbon–carbon bond-forming reactions are
subjects of vigorous current research.[1] This strategy is
superior in terms of atom economy to conventional methods
that employ stoichiometric amounts of strong base.[2]
Although various metal catalysts have proven effective in
this regard, and enantioselective variants have been reported
during the last decade, nucleophiles have been mostly limited
to ketones.[3] Catalytic generation in situ of metal enolates
derived from carboxylic acid derivatives is still a formidable
taskowing to the high p Ka value of the a protons. The
development of a suitably activated carboxylic acid derivative
and/or a new catalyst capable of promoting catalytic ester
enolate formation in situ would thus be of considerable
significance. Recently, Evans et al. reported highly diastereo-
[*] H. Morimoto, Dr. S. H. Wiedemann, A. Yamaguchi, S. Harada,
Z. Chen, Dr. S. Matsunaga, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
[**] We thank Prof. S. Kobayashi, H. Kiyohara, and T. Ogino at the
University of Tokyo for their kind help in X-ray crystallographic
analysis. This work was supported by Grant-in-Aid for Specially
Promoted Research and Grant-in-Aid for Encouragements for Young
Scientists (B) (for SM) from JSPS and MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
and enantioselective catalytic aldol reactions by using N-
acyloxazolidinones and N-acylthiazolidinethiones as
age[10] b). It is well-known that Favorskii rearrangements of
trichloromethyl ketones readily proceed under basic condi-
tions.[13] Therefore, the desired intermolecular reaction with
electrophiles c) must proceed faster than intramolecular
Favorskii rearrangement d). We hypothesized that, in the
presence of a suitably activated electrophile, the intermolec-
ular path c) could be favored because the Favorskii rear-
rangement generates a strained cyclopropanone intermedi-
ate.
We investigated Mannich-type reactions of trichloro-
methyl ketone 1a[14] with imines 2a–d bearing different
protecting groups (Table 1, entries 1–4) at ꢀ408C in the
donors.[4] Shair and co-workers have also developed remark-
able diastereo- and enantioselective aldol reactions with
malonic acid half-thioesters.[5] We have in turn contributed an
aldol reaction with nitriles.[6] On the other hand, methods
applicable to the direct Mannich-type reaction[1b] of ester-
equivalent donors are rare. We previously reported the use of
an N-acylpyrrole as an ester-equivalent donor in Mannich-
type reactions;[7] however, the reaction was limited to an a-
hydroxy-substituted nucleophile. A direct catalytic Mannich-
type reaction with an alkyl-substituted ester-equivalent donor
has not been reported.[8] Herein we inves-
tigate the utility of trichloromethyl ketones
1 (Scheme 1) as Mannich donors. A cata-
lytic amount of p-MeO-C6H4OLi promotes
the direct Mannich-type reaction of 1 with
high diastereoselectivity (syn/anti = 6:1– >
20:1) and in good yield (up to 96%).
Trichloromethyl ketones not only serve as
ester and amide synthetic equivalents, but
also enable unique transformations. Con-
versions of Mannich adducts, including the
stereoselective synthesis of trisubstituted
azetidine-2-carboxylates, are demonstrated
herein.
Table 1: Optimization of reaction conditions.
Entry
PG (imine)
Catalyst
[mol%]
1a
[equiv]
Additive
t
[h]
Yield
[%][a]
Product
syn/anti[b]
1
2
3
4
5
6
7
Bn (2a)
p-MeOC6H4 (2b)
p-Ts (2c)
Ph2P(O) (2d)
Ph2P(O) (2d)
Ph2P(O) (2d)
Ph2P(O) (2d)
10
10
10
10
10
10
5
5
5
5
5
2
2
2
–
–
–
–
24
24
12
1
0
0
3aa
3ba
3ca
3da
3da
3da
3da
–
–
14:1
>20:1
>20:1
>20:1
>20:1
95
88
84
96
95
–
3
3
3
M.S. 3A[c]
M.S. 3A[c]
Trichloromethyl carbinols[9] and tri-
chloromethyl ketones[10] are versatile build-
ing blocks in synthesis. The trichloromethyl
group is a good leaving group;[11] thus,
trichloromethyl ketones can be readily
[a] Yield of isolated product. [b] Determined by H NMR spectroscopic analysis. [c] 200 mgmmolꢀ1 of
2d was used. M.S. 3A=3-Š molecular sieves, PG=protecting group.
1
presence of p-MeO-C6H4OLi (10 mol%) as a base.[15] With 2a
and 2b, no Mannich adduct was observed (Table 1, entries 1
and 2). Imines 2c and 2d, which bear electron-withdrawing
substituents, produced the desired Mannich adducts in good
yield and with high syn selectivity (Table 1, entry 3: 12 h, 95%
yield, syn/anti = 14:1; entry 4: 1 h, 88% yield, syn/anti > 20:1).
Because the N-diphenylphosphinoyl (N-Dpp) imine 2d had
the best reactivity and syn selectivity,[16] it was used for further
optimization. As shown in Table 1, entries 5 and 6, 3-Š
molecular sieves were effective in allowing the molar excess
of 1a to be decreased while maintaining high reaction yield.
The reaction of 1a (2 equiv) proceeded smoothly in the
Scheme 1. Possible reaction pathways of trichloromethyl ketones under
presence of 3-Š molecular sieves, affording the Mannich
adduct 3da after 3 h in 96% yield with an excellent d.r.
(> 20:1). The reaction proceeded equally well with only
5 mol% of base (Table 1, entry 7). The success of the
Mannich reaction with 5–10 mol% catalyst loading implies
that side reactions such as the Favorskii rearrangement, which
quenches catalytic base by production of HCl, are negligible.
As summarized in Table 2, Mannich-type reactions pro-
ceeded well using various aryl (Table 2, entries 1–4), hetero-
aryl (Table 2, entries 5–6), alkenyl (Table 2, entry 7), and
alkyl[17] N-Dpp imines (Table 2, entries 8–10). In all examples,
the reactions were complete within 1–6 h, and good to
excellent diastereoselectivity (syn/anti = 6:1– > 20:1)[18] was
obtained. Notably, the reaction proceeded in good yield when
using readily isomerizable aliphatic N-Dpp imines. The low
pKa value of 1a, ascribed to the inductive effects of the
basic conditions.
converted into carboxylic acids,[10a] esters,[10b] and amides.[10c]
Furthermore, the strong inductive effect of the trichloro-
methyl group lowers the pKa value of the a protons of
trichloromethyl ketones sufficiently to allow catalytic depro-
tonation. These properties make 1 a promising ester-equiv-
alent donor. Nonetheless, to our knowledge, there are no
reports of 1 being used for stereoselective intermolecular
carbon–carbon bond-forming reactions, probably owing to
stability problems under basic conditions.[12] The requisite
selectivities for utilizing enolates of 1 are summarized in
Scheme 1. Careful selection of base and reaction conditions is
important to promote the desired catalytic enolate formation
ꢀ
a) while preventing undesired haloform C C bond cleav-
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Table 2: Catalytic direct syn-selective Mannich-type reactions of trichlo-
romethyl ketones 1a–1d with N-Dpp imines 2d–2m.[a]
Entry R1 (Imine)
R2 (1)
t
Yield
3
syn/
[h] [%][b]
anti[c]
1
2
3
4
5
6
7
Ph (2d)
p-Cl-C6H4 (2e)
p-Me-C6H4 (2 f)
p-MeOC6H4 (2g) CH3 (1a)
2-furyl (2h)
CH3 (1a)
CH3 (1a)
CH3 (1a)
3
4
6
5
1
2
1
96
93
89
68
88
89
81
3da >20:1
3ea >20:1
3 fa >20:1[d]
3ga >20:1[d]
Scheme 2. Postulated catalytic cycle and transition-state model for syn
selectivity.
CH3 (1a)
CH3 (1a)
CH3 (1a)
3ha
3ia
3ja
6:1
8:1
7:1
2-thienyl (2i)
(E)-PhCH CH
=
(2j)
8[e] cyclohexyl (2k)
CH3 (1a)
2
3
3
78
71
73
3ka >20:1[d]
3la
>20:1[d]
3ma >20:1[d]
9[e] (CH3)CHCH2 (2l) CH3 (1a)
10[e] n-Bu( 2m)
CH3 (1a)
(61)[f]
87
11[g] Ph (2d)
12[h] Ph (2d)
CH3CH2 (1b)
PhCH2 (1c)
BnO(CH2)2
(1d)
2
6
1
3db
3dc >20:1
3dd 11:1
14:1
90
89
13
Ph (2d)
[a] 2 equivalents of 1 was used unless otherwise noted. [b] Yield of
isolated product after column chromatography unless otherwise noted.
[c] Determined by 1H NMR spectroscopic analysis of the crude mixture.
[d] Minor isomer was not detected. [e] Reaction was performed in the
absence of 3-Š molecular sieves using 1a (5 equiv). [f] Product was
isolated by crystallization (CHCl3/hexane) without chromatography.
[g] 3 equivalents of 1b was used. [h] Reaction was performed at ꢀ608C.
trichloromethyl group, allowed chemoselective nucleophilic
activation. Furthermore, Mannich adducts are quite crystal-
line and can be isolated without chromatography after
extractive workup. For example, diastereomerically pure
3ma was isolated in 61% yield by crystallization of a crude
mixture from CHCl3/hexane (Table 2, entry 10). Besides 1a,
trichloromethyl ketones with longer side chains (1b and 1c)
and oxygen functionality (1d) were applied (Table 2,
entries 11–13); they afforded Mannich adducts in 87–90%
yield with good diastereoselectivity (11:1– > 20:1). The Man-
nich-type reaction of 1c was performed at ꢀ608C to prevent
side reactions.
Scheme 3. Transformations of the trichloromethyl ketone moiety.
Reagents and conditions: a) NaOMe, MeOH, 0!258C, 15 min;
b) 1. NaOH, THF/H2O, 08C, 20 min; 2. Gly-OtBu·HCl, HOAt,
EDC·HCl, Et3N, 08C!RT, 14 h; c) EtSLi, EtSH, THF, 08C, 15 min;
d) LiAl(OtBu)3H, THF/CH2Cl2, ꢀ408C, 5 h; e) Zn(BH4)2, THF/Et2O,
ꢀ78 to ꢀ408C, 16 h. EDC=1-ethyl-3(3-dimethylaminopropyl)carbodi-
imide.
A postulated catalytic cycle and a transition-state model
that explains the observed syn selectivity are illustrated in
Scheme 2. p-MeO-C6H4OLi first deprotonates the a proton of
1. Trichloromethyl ketones favor the formation of Z enolate
II because of steric pressure from the bulky trichloromethyl
group.[19] The observed high syn selectivity is accounted for by
the Z-enolate transition state III. Protonation of IV by p-
MeO-C6H4OH regenerates the catalyst and affords 3.
The synthetic utility of the trichloromethyl ketone moiety
was demonstrated by the transformations shown in Scheme 3.
Mannich adducts 3da and 3la were readily converted into
esters 4da and 4la in 100% and 94% yield, respectively, by
treatment with NaOMe in MeOH for 15 min, during which no
epimerization was observed. Treatment of 3da with NaOH
followed by coupling with Gly-OtBu gave amide 5da in 84%
yield (two steps). The trichloromethyl ketone unit functions
not only as a synthetic equivalent for esters and amides, but
also as a unique template for further transformations. Treat-
ment of 3da and 3ka with basic ethanethiol for 15 min
afforded dithianes 6da and 6ka in 96% and 93% yield,
respectively.[10d] In this case, the thiol acts as both a
nucleophile and a reductant to give synthetically useful
protected aldehydes. syn-Selective reduction of the Mannich
adducts with LiAl(O-tBu)3H afforded the N-protected amino
alcohols 7da and 7ma, whereas anti-selective reduction with
Zn(BH4)2 afforded the N-protected amino alcohol 8da.[20]
The synthetic versatility of 7 and 8 can potentially be utilized
in stereoselective transformations as reported by Corey and
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Link.[9a,b] Furthermore, we also succeeded in the highly
stereocontrolled synthesis of azetidines (Scheme 4). By
treating 7da with aqueous NaOH in 1,2-dimethoxyethane
(DME), we obtained the azetidine-2-carboxylic acid 9da. The
amounts of a weakBrønsted base proceeded in good yield
and high syn selectivity (62–96%, syn/anti = 6:1– > 20:1).
Transformations of the Mannich adducts formed were
demonstrated, including a highly stereoselective synthesis of
azetidines. Efforts toward the use of trichloromethyl ketones
in conjunction with chiral catalysts in Mannich and other
addition reactions are ongoing.
Received: January 19, 2006
Published online: April 5, 2006
Keywords: asymmetric catalysis · azetidines ·
.
diastereoselectivity · Mannich reaction · trichloromethyl ketones
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[2] B. M. Trost, Science 1991, 254, 1471.
Scheme 4. Stereoselective synthesis of azetidines from trichloromethyl
carbinols. Reagents and conditions: a) aq. NaOH, DME, 258C, 24 h;
b) TMSCHN2, MeOH/hexane, 258C. TMS=trimethylsilyl.
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reaction is considered to proceed via a gem-dichlorooxirane
intermediate.[9a] Intramolecular ring opening affords the
azetidine ring. After conversion into the corresponding
methyl esters, methyl azetidine-2-carboxylate 10da was iso-
lated in 72% yield (two steps).[21] From 8da, all-syn-substi-
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albeit in moderate yield (57% in two steps). The relative
configuration of 12da was confirmed by single-crystal X-ray
crystallographic analysis (Figure 1).[21,22] Because stereoselec-
tive syntheses of 3,4-syn-substituted azetidine-2-carboxylic
acids, particularly sterically hindered all-syn-substituted aze-
tidines, are rare, the present stereoselective method should
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In summary, we successfully developed a chemoselective
catalytic nucleophilic activation of trichloromethyl ketones
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ꢀ
and applied this method to intermolecular C C bond-forming
reactions. Direct Mannich-type additions of trichloromethyl
ketones to various N-Dpp imines in the presence of catalytic
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Figure 1. X-ray crystallographic structure of azetidine 12da. Ellipsoids
drawn at the 50% probability level.
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Communications
Staring, Tetrahedron Lett. 1997, 38, 1593; d) Z. Wang, S.
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[20] The relative configuration of 8da was determined by X-ray
crystallographic analysis of the corresponding cyclic carbamate;
see Supporting Information.
Campagna, K. Yang, G. Xu, M. E. Pierce, J. M. Fortunak, P. N.
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[21] For the determination of the relative configurations of 10da and
12da, see Supporting Information.
[22] CCDC 295183–295185 (12da, 3 fa, cyclic carbamate derived
from 8da, respectively) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[23] For the synthesis of azetidine-2-carboxylic acids (L-aze ana-
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[12] For exceptional results with methyl trichloromethylacetoacetate
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[13] For recent reports of Favorskii rearrangements and related
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[14] For the synthesis of trichloromethyl ketones 1a–d, see: a) E. J.
Corey, J. O. Link, Y. Shao, Tetrahedron Lett. 1992, 33, 3435, and
references therein; although trichloromethyl carbinols were
oxidized mainly by using stoichiometric amounts of chro-
mium(vi) reagents in the original report, we utilized the catalytic
oxidation method reported by workers at Merck: b) M. Zhao, J.
Li, Z. Song, R. Desmond, D. M. Tschaen, E. J. J. Grabowski, P. J.
Reider, Tetrahedron Lett. 1998, 39, 5323; Swern oxidation is also
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[15] We selected a phenoxide base for its relevance to ongoing
studies of the development of catalytic asymmetric reactions
with chiral metal phenoxides such as 1,1’-bi-2-naphthol (binol)
derivatives. Other bases with low nucleophilicity, such as Li{N-
(SiMe3)2} (10 mol%), also promoted the Mannich reaction of
imine 2d with 1a (5 equiv) at ꢀ408C in comparable yield (conv.
89%), albeit with lower syn selectivity (syn/anti = 13:1) and
longer reaction time (13 h) than the corresponding reactions in
Table 1.
[16] The N-Dpp group is useful because it is readily removed; for a
review on the use of N-Dpp imines in organic synthesis, see:
S. M. Weinreb, R. K. Orr, Synthesis 2005, 1205.
[17] For the synthesis of enolizable alkyl N-Dpp imines 2k–2m, see:
a) A. CôtØ, A. A. Boezio, A. B. Charette, Proc. Natl. Acad. Sci.
USA 2004, 101, 5405; b) J.-N. Desrosiers, A. CôtØ, A. B.
Charette, Tetrahedron 2005, 61, 6186; for related enolizable
alkyl N-Ts (Ts = p-toluenesulfonyl) imines, see: c) F. Chemla, V.
Hebbe, J.-F. Normant, Synthesis 2000, 75.
[18] The relative configuration of 3 fa was unequivocally determined
by single-crystal X-ray crystallographic analysis;[22] the relative
configurations of 3da and 3la were determined after conversion
into known compounds; see Supporting Information.
[19] For discussions on steric effects of the trichloromethyl group,
see: M. B. Smith, J. March, Advanced Organic Chemistry, 5th
3150
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Angew. Chem. Int. Ed. 2006, 45, 3146 –3150