ZrCl4-catalyzed X-C/C-C bond formation for the geometric selective synthesis of (E)-β-iodo aza Morita-Baylis-Hillman (MBH) adducts

Article abstract of DOI:10.1016/j.tetlet.2006.08.128

A geometric selective synthesis of (E)-β-iodo and β-alkyl vinyl ketones (MBH amino adducts) has been developed through a three-component Mannich-type reaction. The reaction was conveniently conducted by generating 3-iodo allenolate intermediates via the α

Full text of DOI:10.1016/j.tetlet.2006.08.128

Tetrahedron Letters 47 (2006) 7699–7702
ZrCl4-catalyzed X–C/C–C bond formation
for the geometric selective synthesis of (E)-b-iodo
aza Morita–Baylis–Hillman (MBH) adducts
Qingjiang Li,a Min Shi,a,* Joshua M. Lyteb and Guigen Lib,*
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 354 Fenglin Lu,
Shanghai 200032, China
bDepartment of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
Received 31 July 2006; revised 26 August 2006; accepted 30 August 2006
Available online 18 September 2006
Abstract—A geometric selective synthesis of (E)-b-iodo and b-alkyl vinyl ketones (MBH amino adducts) has been developed
through a three-component Mannich-type reaction. The reaction was conveniently conducted by generating 3-iodo allenolate inter-
mediates via the a,b-unsaturated addition of TMS-I to 3-butyn-2-one followed by a carbonyl addition onto N-aryl imines in the
presence of ZrCl4 catalyst. The resulting b-iodo allylic amines can be readily converted into b-alkyl Morita–Baylis–Hillman adducts
by performing Suzuki and Kumada cross-couplings.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In the past decade, the Morita–Baylis–Hillman (MBH)
and related reactions have received considerable atten-
tion among the organic and medicinal communities.1–3
The MBH amino and hydroxyl adducts resulting from
these reactions can be extensively utilized for the synthe-
sis of numerous chemically and biologically important
targets.4
mation of b-iodo MBH amino adducts with dominant
(E)-geometry without much success. In this paper, we
are pleased to report our initial study for this purpose
by using unactivated imines as electrophilic acceptors
and softer Lewis acids. To the best of our knowledge,
this could be the first example of using unactivated imi-
nes as electrophiles for the synthesis of b-halo MBH
amino adducts.7 This reaction can be readily performed
by reacting 3-butyn-2-one and iodotrimethylsilane to
generate b-iodo TMS-allenolate followed by its carbonyl
addition onto imines in the presence of ZrCl4 as the cat-
alyst (Scheme 2). In addition, the subsequent cross-cou-
plings using the b-iodo MBH amino adducts are also
presented (Scheme 3).
Recently, our laboratories have been actively involved in
the development of synthetic approaches to (Z)-b-halo
MBH adducts, which cannot be obtained from classical
Morita–Baylis–Hillman catalysis.5,6 These methods are
mainly based on the multicomponent couplings of a,b-
acetylenic ketones or esters with aldehydes or activated
imines in the presence of metal halides (Et2AlI, MgI2,
etc.), which act as both Lewis acid promoters and halo-
gen sources (Scheme 1). The presence of an extra halo-
gen in the resulting MBH adducts enables a number of
further synthetic transformations.
The initial attempt at this reaction utilized the phenyl
protected imine of benzaldehyde as the electrophile to
react with b-iodo TMS-allenolate. Interestingly, in the
absence of any catalyst the aza MBH product (1a) was
obtained in a good chemical yield of 65% (Table 1, entry
1) under standard conditions.8 Interestingly, the use of
several typical Lewis acids, such as SnCl4, TiCl4, and
BF3ÆOEt2, diminished the reaction and resulted in a
small amount of the desired product (Table 1, entries
2–4). However, after the Lewis acid catalyst was chan-
ged to ZrCl4, which is a slightly softer Lewis acid, the
reaction proceeded smoothly to give the desired aza
To extend the scope of our previous methods, we have
been attempting to control the reaction toward the for-
Keywords: b-Iodovinyl ketone; Mannich-type reaction; Morita–Baylis–
Hillman adduct.
*
Corresponding authors. E-mail addresses: mshi@mail.sioc.ac.cn;
guigen.li@ttu.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.128

7700
Q. Li et al. / Tetrahedron Letters 47 (2006) 7699–7702
OH
COR
I
R'
R'CHO
TMSI or Et2AlI
or TiCl4 /(n-Bu)4NI
or MgI2
COR
MO
I
R
C
Pg
HN
R = CH3 or OCH3
R'
N
Pg
COR
I
R'
Scheme 1. Selective synthesis of (Z)-b-halo MBH adducts.
For each of the cases listed in Table 2, (E)-geometry was
controlled very well. In fact, only (E)-isomer was ob-
served as revealed by NMR analysis. (E)-Geometry of
the b-iodo Morita–Baylis–Hillman product was unam-
biguously confirmed by NOESY spectroscopic analysis,
and was proven to be opposite to that observed in our
previous processes.6a,b Obviously, in the present system
the exclusive E-selectivity of b-iodo MBH amino ad-
ducts is directed by the thermodynamic control and
the room temperature condition accounts for this
observation.
C6H5
C6H5
NH
I
O
O
ZrCl4, CH2Cl2
-78 oC-r.t.
C6H5
N
+ TMSI +
C6H5
1a
Scheme 2.
MBH product (1a) in an excellent chemical yield (97%,
entry 5, Table 1). This excellent result can be explained
by the fundamental principle of hard/soft interactions of
acid and base in which the N atom can coordinate onto
the Zr center more effectively than onto the Ti center.12
To further extend the application of the resulting aza
MBH adducts, we also performed the cross-coupling
reactions to generate (E)-b-alkyl and aryl MBH amino
adducts,9,10 which have not been documented well.
Under optimized conditions, we next attempted to
extend the scope of substrates for this reaction. As sum-
marized in Table 2, the carbonyl addition of b-iodo
TMS-allenolate to those imines bearing electron-with-
drawing groups on the aromatic ring proceeded
smoothly to give the corresponding b-iodo Morita–Bay-
lis–Hillman adducts (1b–f) in good to excellent yields
(76–95%, entries 1–6, Table 2). However, when an elec-
tron-donating group attached aryl imine was subjected
to the reaction under standard conditions, there was
only a trace amount of the desired adduct formed. Con-
sidering the versatile utility of a-amino acid, the imine
derived from ethyl glyoxylate was thus studied for this
reaction. Unfortunately, the b-iodo MBH adduct (1g)
was obtained in a poor chemical yield of 38% (entry 7,
Table 2).
Table 1. Results of screening catalysts for the aza MBH synthesis8
Entry
Catalyst
Yielda,b (%)
1a
1
2
3
4
5
No cat.
SnCl4
TiCl4
BF3ÆOEt2
ZrCl4
65
Trace
16
Trace
97
a Isolated yields.
b The reaction mixture was maintained at À78 ꢁC for 2 h before the
imine and catalysts were added, then warmed to room temperature
for an additional 2 h.
Ph
C6H5
N
O
PhB(OH)2, Pd(PPh3)4
C6H5
NaHCO3, H2O/DCE, reflux
Ph
Ph
C6H5
C6H5
C6H5
C6H5
3, 69%
NH
I
PhCH2Br, K2CO3
THF, reflux
N
I
O
O
Ph
O
C6H5
C6H5
N
MeMgBr, CuI
THF, 0 oC-r.t.
2
Me
4, 82%
Scheme 3. Protection of the Mannich-type adduct and the subsequent cross-coupling reactions.

Q. Li et al. / Tetrahedron Letters 47 (2006) 7699–7702
7701
Table 2. Results of the three-component Mannich-type reaction
J. D.; Wei, H.-X. In Recent Research Developments in
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R2
NH
O
O
ZrCl4, CH2Cl2
-78 oC-r.t.
R1
N
R1
+
+
TMSI
R2
I
1
Entry
R1
R2
C6H5
4-BrC6H4
3-CF3C6H4
C6H5
C6H5
C6H5
C6H5
Product
Yielda,b (%)
1
1
2
3
4
5
6
7
C6H5
C6H5
C6H5
4-ClC6H4
2,4-Cl2C6H3
4-NO2C6H4
EtO2C
1a
1b
1c
1d
1e
1f
97
95
88
84
82
76
38
1g
a Isolated yields.
b The reaction mixture was maintained at À78 ꢁC for 2 h before the
imine and catalysts were added, then warmed to room temperature
for an additional 2 h.
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8. Typical reaction procedures for the synthesis of E-b-
iodovinyl ketone 1a: In a dry vial, under argon protection,
iodotrimethylsilane (85 lL, 0.6 mmol) was added slowly to
a solution of 3-butyn-2-one (47 lL, 0.6 mmol) in 2.0 mL
of dichloromethane at À78 ꢁC. The resulting solution was
stirred for 2 h before 0.1 mmol of catalyst and imine
(91 mg, 0.5 mmol) were charged. The reaction mixture was
maintained at À78 ꢁC for 2.0 h with stirring and allowed
to warmup to room temperature for another 2 h. After
quenching by 1.0 M of aqueous HCl solution (1.0 mL), the
aqueous layer was extracted with EtOAc (3 · 5.0 mL). The
combined organic layers were washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by
flash chromatography (neutral Al2O3 column, eluent:
CH2Cl2/petroleum ether = 1/2) to provide the pure
product.
The first attempt to perform the Suzuki and Kumada
couplings11,12 were proven unsuccessful, which could
be due to the active NH functional group. This func-
tional group was next protected by treating with benzyl
bromide in refluxing THF in the presence of potassium
carbonate (Scheme 2). After it was protected, these two
cross-couplings proceeded smoothly with phenylboronic
acid and methylmagnesium bromide under the known
conditions as reported by Rault11 and Richards,12 re-
spectively. The corresponding products 3 and 4 were ob-
tained in good yields of 69% and 82%, respectively
(Scheme 3).
In conclusion, a stereoselective three-component Man-
nich-type reaction of imines, 3-butyn-2-one, and TMS-I
using ZrCl4 as the catalyst has been developed. This
reaction provided an easy access to b-branched
Morita–Baylis–Hillman (MBH) amino adducts. The
reaction can be conveniently conducted under concise
conditions. These products can be further subjected to
the metal catalyzed cross-coupling reactions to afford
novel b-alkyl and aryl MBH amino adducts in an
exclusive E-geometric configuration.
Acknowledgements
We thank the State Key Project of Basic Research (Pro-
ject 973) (No. G2000048007), the Robert Welch founda-
tion (US, D-1361), Shanghai Municipal Committee of
Science and Technology (04JC14083), Chinese Academy
of Sciences (KGCX2-210-01), and the National Natural
Science Foundation of China for financial support
(20472096, 203900502, and 20272069).
References and notes
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