Three-component reactions of CF3-substituted boranes, ethyl diazoacetate and imines

Article abstract of DOI:10.1016/j.tetlet.2012.08.153

Aryl(methoxy)(trifluoromethyl)boranes, generated in situ, readily react with ethyl diazoacetate and N-(4- methoxyphenyl)imines to give derivatives of β-amino acids. In this process, the electron-deficient borane reacts with the diazo compound followed by trapping of the intermediate boron enolate by the imine. The final products are predominantly produced as syn isomers.

Full text of DOI:10.1016/j.tetlet.2012.08.153

Tetrahedron Letters 53 (2012) 6216–6218
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component reactions of CF3-substituted boranes, ethyl diazoacetate
and imines
Pavel K. Elkin a, Vitalij V. Levin a, Alexander D. Dilman a, , Marina I. Struchkova a, Dmitry E. Arkhipov b,
⇑
Alexander A. Korlyukov b
a N.D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
b A.N. Nesmeyanov Institute of Organoelement Compounds, 119991 Moscow, Vavilov Str. 28, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Aryl(methoxy)(trifluoromethyl)boranes, generated in situ, readily react with ethyl diazoacetate and N-(4-
methoxyphenyl)imines to give derivatives of b-amino acids. In this process, the electron-deficient borane
reacts with the diazo compound followed by trapping of the intermediate boron enolate by the imine. The
final products are predominantly produced as syn isomers.
Received 20 July 2012
Revised 15 August 2012
Accepted 31 August 2012
Available online 7 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Boranes
Boronic esters
Diazocarbonyl compounds
Trifluoromethylation
Multicomponent reaction
Imines
Multicomponent reactions constitute an efficient method for
assembling organic compounds.1 While isonitriles have dominated
this field, another direction has come to the fore with the advent of
the boronic Mannich reaction.2 As an alternative strategy for three-
component couplings using organoboron compounds, the reaction
R1 BX2
O
H
O
Y
Y
R3
MeO
R3
R2
R1 R2
MeO
of boranes with a-diazoesters and a suitable electrophile (aldehyde
N2
Y
or imine) could be envisaged (Scheme 1). This reaction results in
the formation of two C–C bonds and affords important aldol-type
or Mannich-type products.
R3
BX2
O
The process is limited to the reactions of boranes with a-diazo-
O
O
R2
R1
esters and is best performed using trialkylboranes.3–5 While the
use of trialkylboranes together with aldehydes was reported by
Mukaiyama,6 the loss of two alkyl groups significantly narrows
the scope of the method. To overcome this problem, Schaus em-
ployed aryl-substituted BBN derivatives (Ar-BBN) in combination
with N-methoxycarbonylimines in the presence of a copper(II) cat-
alyst.7 However, the required boryl reagents were not readily avail-
able and the reaction was not applicable to conventional
diazoacetate esters.7 Recently, we reported that CF3-substituted
boranes, which can be easily generated starting from simple boro-
nic acids or their esters, react smoothly with ethyl diazoacetate.8 In
the latter process, the CF3-group plays a key activating effect by
increasing the Lewis acidity of boron thereby allowing for the facile
R2
R1
R2
MeO
MeO
MeO
N2 B
X2
R1
X2B
reagents:
Alk3B, Y = O
Ar-BBN, Y = NC(O)OMe
Mukaiyama, 1973
Schaus, 2011
this work
ArB(CF3)OMe, Y = N-PMP
Scheme 1.
interaction of the borane with the diazo group. Herein, we report
the application of CF3-substituted boranes in a three-component
coupling with ethyl diazoacetate (EDA) and imines.
⇑
Methyl boronic ester 1a was converted into borate salt 2a by
nucleophilic trifluoromethylation according to the reported
Corresponding author. Fax: +7 499 1355328.
E-mail address: adil25@mail.ru (A.D. Dilman).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.153

P. K. Elkin et al. / Tetrahedron Letters 53 (2012) 6216–6218
6217
Table 2
Three-component reaction
Me3SiCF3, KF
DME
OMe
OMe
OMe
OMe
Ph
1a
B
Ph
B
O
CF3
N2
K
2a, 97%
OEt
R
PMP
R
OMe
OMe
O
HN
i
Ar
B
Scheme 2.
PMP
DME
EtO
1
N
Ar
5
4
Table 1
Reaction of borate salt 2a with EDA and imine 4aa
i:
Me3SiCF3, KF;
Me3SiCl, PhNMe2, 20 → 0 °C, 10 min;
EDA, 3, 40 °C, 1 h, then 40 °C → rt, 1.5 h
OMe
OMe
B
CF3
L
Me3SiCl
OMe
Ph
2a
Ph
3a
B
solvent,
additive
CF3
K
Entry
Ar
R
Product
Yielda (%)
drb
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
Ph
4-NO2C6H4
4-MeOC6H4
(E)-PhCH@CH
i-Pr
2-Thienyl
2-Furyl
Ph
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
81
75
68
74
84
75
87
80
63
75
65
78
80
>95:5
>95:5
>95:5
79:21
58:42
85:15
81:19
>95:5
87:13
>95:5
64:36
84:16
83:17
PMP
N
O
PMP
+
O
HN
O
N2
4a
C6H4F
OEt
+
EtO
EtO
40 °C, 1 h,
then 40 °C → rt, 1.5 h
Ph
Ph
F
5a, dr > 95 : 5
6
9
1-Naphthyl
1-Naphthyl
2-Thienyl
4-MeOC6H4
3-CF3C6H4
10
11
12
13
5j
5k
5l
Entry
Solvent
Additive
Yield of 5ab (%)
Yield of 6b (%)
1
2
DME
CH2Cl2
THF
DME
DME
DME
DME
DME
DME
DME
—
—
—
44
21
14
<5
14
23
54
27
55
84d
18
48
52
52
40
32
37
33
37
<5
5m
3c
4
a
BF3ÁEt2O
Isolated yield.
b
5
6
7
8
Pyridine
Determined by NMR spectroscopy of the crude product.
4-Methylpyridine
2,6-Lutidine
Et3N
N-Methylmorpholine
PhNMe2
9
O
10
Cl
Cl
O
N
N
a
b
c
Ratio 2a: Me3SiCl: additive: EDA: 4a = 1.34: 1.34: 1.34: 1.2: 1.
Determined by NMR spectroscopy using CH2Br2 as an internal standard.
EDA and imine were added at À20 °C.
Isolated yield.
O
N
PMP
Ar
, H2SO4
O
NH2
Ar
O
HN
d
Cl
EtO
7, 75%
EtO
procedure using 1,2-dimethoxyethane (DME) as the solvent8
(Scheme 2). The salt 2a was treated with chlorotrimethylsilane to
generate borane 3a, which was treated with EDA and N-(4-
methoxyphenyl)-substituted imine 4a at À40 °C followed by slow
warming to room temperature (Table 1). After aqueous work-up
the crude product was analyzed by 1H and 19F NMR spectroscopy.
The reaction performed in DME afforded the desired product 5a as
single diastereoisomer in modest yield along with ester 6 (entry 1).
Earlier, we observed that the boryl enol ether, which is formed
after reaction of borane 3a with EDA, was not stable.8 We proposed
that addition of a stoichiometric amount of a Lewis base might
reversibly bind to the Lewis acidic boryl species leading to an in-
crease of its stability. Using pyridine as an additive the reaction
was inefficient, presumably due to strong coordination to boron.
With more sterically hindered 2,6-lutidine the combined yield of
5a and 6 was increased notably (entries 5–7). Finally, the optimum
result was achieved with the use of N,N-dimethylaniline as the
additive leading to an 84% isolated yield of 5a, while by-product
6 was formed in a trace amount.
Ph
Ph
5a
Ar = 4-FC6H4
Scheme 3.
analogy. In two examples poor selectivity was observed (entries
5 and 11).
The 4-methoxyphenyl substituent can be removed from prod-
ucts 5 by treatment with trichloroisocyanuric acid in the presence
of sulfuric acid,11 as was exemplified by the conversion of com-
pound 5a into amine 7 (Scheme 3).
In summary, we have developed a three-component reaction
using organoboron derivatives, ethyl diazoacetate, and imines
which furnishes b-amino acid derivatives in good yields and in good
syn stereosoelectivities.12 The key CF3-substituted borane species
can be readily generated in situ starting from boronic acid esters.
The presence of N,N-dimethylaniline which coordinates reversibly
with the Lewis acidic boron is important for reaction efficiency.
The X-ray diffraction analysis of compound 5a9 demonstrated
that it had a syn relationship between the Ph and NH-PMP substit-
uents, which suggests the cis arrangement of boryl and phenyl
fragments in the intermediate boryl enolate and a concerted Zim-
merman–Traxler transition state during reaction with the imine.10
Under the optimized conditions various CF3-substituted bor-
anes, generated in situ from esters of boronic acids 1, were reacted
with EDA and several imines (Table 2). The reactions of imines de-
Acknowledgments
This work was supported by the Russian Foundation for Basic
Research (project 11-03-00362) and the Ministry of Science (pro-
ject MD-1151.2011.3).
Supplementary data
rived from aromatic,
hydes gave products 5 in good isolated yields and, as a rule, good
diastereoselectivity. The major isomer was assigned to be syn by
a
,b-unsaturated, and branched aliphatic alde-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
153.

6218
P. K. Elkin et al. / Tetrahedron Letters 53 (2012) 6216–6218
Road, Cambridge CB2 1EZ, UK (Fax: +44 (0) 1223 336033 or e-mail:
References and notes
deposit@ccdc.cam.ca.uk).
10. (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–1923; (b)
Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120–6123.
11. Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Alsters, P. L.; van
Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006, 47, 8109–8113.
12. General procedure for the reaction of borate salt 2a with ethyl diazoacetate and
1. (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3169–3210; (b) Domling,
A. Chem. Rev. 2006, 106, 17–89; (c) Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
2. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586; (b) Batey,
R. A. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005; pp 279–
304; (c) Petasis, N. A. In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005; pp 199–223.
3. (a) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 5936–5937; (b) Hooz, J.; Linke,
S. J. Am. Chem. Soc. 1968, 90, 6891–6892; (c) Hooz, J.; Gunn, D. M. Tetrahedron
Lett. 1969, 10, 3455–3458; (d) Hooz, J.; Gunn, D. M. J. Am. Chem. Soc. 1969, 91,
6195–6196.
4. Dichloroboranes (RBCl2) were exploited, but competing transfer of chlorine
was observed, see: (a) Hooz, J.; Bridson, J. N.; Calzada, J. G.; Brown, H. C.;
Midland, M. M.; Levy, A. B. J. Org. Chem. 1973, 38, 2574–2576; (b) Brown, H. C.;
Midland, M. M.; Levy, A. B. J. Am. Chem. Soc. 1972, 94, 3662–3664.
5. For recent developments, see: (a) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.;
Valdes, C. Nat. Chem. 2009, 1, 494–499; (b) Peng, C.; Zhang, W.; Yan, G.; Wang, J.
Org. Lett. 2009, 11, 1667–1670.
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7. Luan, Y.; Schaus, S. E. Org. Lett. 2011, 13, 2510–2513.
8. Elkin, P. K.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.;
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5259–5263.
9. The Olex2 drawing of the molecular structure of 5a and crystal data are
given in the Supplementary data. Crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystallographic Data
Centre (CCDC 887620) and are available free of charge at CCDC, 12 Union
imines 4. Me3SiCl (84 lL, 0.67 mmol) and PhNMe2 (84 lL, 0.67 mmol) were
added to a solution of salt 2a (172 mg, 0.67 mmol) in 1,2-dimethoxyethane
(1.5 mL) at À20 °C, and the mixture was stirred at À20 °C for 10 min and then
at 0 °C for 10 min. The mixture was cooled to À40 °C followed by the addition
of ethyl diazoacetate (63 lL, 0.6 mmol) and imine 4 (0.5 mmol). The mixture
was stirred for 1 h at À40 °C, and then allowed to warm to room temperature
over 1.5 h. For the work-up, H2O (5 mL) was added, and the organic phase was
extracted with hexanes (3 Â 5 mL). The combined organic extracts were dried
over Na2SO4, concentrated, and the residue was flash chromatographed on
silica gel.
General procedure for one-pot reaction of esters 1 with ethyl diazoacetate and
imines 4. KF (19 mg, 0.67 mmol) and Me3SiCF3 (89 lL, 0.75 mmol) were added
to a solution of dimethyl boronate 1 (0.67 mmol) in 1,2-dimethoxyethane
(1.5 mL), and the mixture was stirred overnight at room temperature. The
mixture was cooled to À20 °C followed by addition of Me3SiCl (84
0.67 mmol) and PhNMe2 (84 L, 0.67 mmol). The resulting solution was
stirred at À20 °C for 10 min and then at 0 °C for 10 min, and then cooled to
L, 0.6 mmol) and imine 4 (0.5 mmol) were
lL,
l
À40 °C. Ethyl diazoacetate (63
l
added, the mixture was stirred for 1 h at À40 °C, and then allowed to warm to
room temperature over 1.5 h. For the work-up, H2O (5 mL) was added, and the
organic phase was extracted with hexanes (3 Â 5 mL). The combined organic
extracts were dried over Na2SO4, concentrated, and the residue was flash
chromatographed on silica gel.