Regio- and stereocontrolled access to ?-boronated unsaturated amino esters and derivatives from (z)-alkenyl 1,2-bis(boronates)

Article abstract of DOI:10.1021/jo402237t

The Borono-Mannich reaction of (Z)-1-alkene-1,2-diboronic esters proceeded regioselectively at the terminal C-B bond to afford (E)-?-boronated unsaturated amino esters in good yields. These compounds were then subjected to Suzuki couplings for the creatio

Full text of DOI:10.1021/jo402237t

Note
pubs.acs.org/joc
Regio- and Stereocontrolled Access to γ‑Boronated Unsaturated
Amino Esters and Derivatives from (Z)‑Alkenyl 1,2-Bis(boronates)
Tailor Sridhar,†,‡ Fabienne Berree,† Gangavaram V. M. Sharma,*,‡ and Bertrand Carboni*,†
́
†Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS−Universite
́
de Rennes 1, 263 Avenue du Gen
́
er
́
al Leclerc, Campus de
̂
Beaulieu, Batiment 10A, 35042 Rennes Cedex, France
‡Organic and Biomolecular Chemistry Division, CSIR−Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
S
* Supporting Information
ABSTRACT: The Borono−Mannich reaction of (Z)-1-alkene-1,2-diboronic esters proceeded regioselectively at the terminal
C−B bond to afford (E)-γ-boronated unsaturated amino esters in good yields. These compounds were then subjected to Suzuki
couplings for the creation of diversely substituted olefinic amino acid systems. Several other functional transformations were also
carried out to illustrate the synthetic utility of the Petasis products.
Scheme 1. Some Representative Examples of the Reactivity of
1-Alkene-1,2-diboronic Esters 1
lkenyl boronates constitute an important family of
Aorganoboron compounds whose utility in organic synthesis
has been repeatedly illustrated.1 Among this class of versatile
intermediates, 1-alkene-1,2-diboronic esters 1 have been
relatively poorly studied. Since the discovery of an efficient cis-
selective route to these species by platinum-catalyzed diboration
of alkynes in 1993, most of the work related to these compounds
has been focused on their metal-catalyzed cross-coupling
reactions.2 Regioselective palladium Suzuki coupling at the
terminal C−B bond can be followed by the introduction of a
second aryl or heteroaryl moiety to afford unsymmetrical
tetrasubstituted alkenes (Scheme 1).3,4 By contrast, the use of
a differently protected diboron, instead of the classical bis-
(pinacolato)diboron, allowed internal selective cross coupling.5
Other convincing examples of the interest of compounds 1 were
provided by couplings with 2 equiv of the same electrophile2a,3 6
e,
and annulation reactions with aromatic dihalides.7 Much less has
been reported about other aspects of their reactivity. Double
carbomethoxylation,8 enantioselective hydrogenation,9 fluoro-
deboronation,10 and Diels−Alder cycloaddition11 were recently
described (Scheme 1), whereas, to the best our knowledge, no
Borono−Mannich reactions have been hitherto carried out with
the 1,2-diboronic esters as substrates.
This transformation, now referred to as the Petasis reaction,
involving aldehyde or ketone, unsaturated organoborane, and
amine partners, enables the preparation of a wide variety of
molecules with high levels of structural diversity.12,13 In the
course of our research programs devoted to the synthesis of
amino acids14 and multicomponent assembly processes involv-
ing boronic acids or their derivatives,15 in this article, we have
investigated a new route to γ-boronated unsaturated amino esters
2 from bis(boronates) 1 (Scheme 2). These compounds may
have interesting biological properties, by themselves or by their
derivatives;16 the presence of a boronate group also allows access
through diverse functionalizations, for example, cross coupling,
oxidation, or azidation,1 to a number of diversely substituted
amino acids or heterocycles.
Received: October 8, 2013
© XXXX American Chemical Society
A
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Note
perborate in THF/water afforded γ-oxo α-aminoester 4 in 74%
yield, whereas the copper-catalyzed reaction with sodium azide in
methanol gave alkenylazide 5.19 In addition, a one-pot
procedure, which avoided the need to isolate this potentially
unstable species, was employed to synthesize 4-aryl-1,2,3-triazole
6 directly from 2a and phenylacetylene in an overall yield of
36%.19,20
Scheme 2. Access to Diversely Substituted Amino Esters from
1,2-Bis Boronates
In conclusion, a regioselective Petasis reaction has been
performed for the first time at the terminal C−B bond of (Z)-
1-alkene-1,2-diboronic esters. The resulting amino esters were
then subjected to Suzuki coupling with the second boronate
moiety to give the corresponding amino esters. This protocol
provides an opportunity not only for the conversion of bis-
boronates into Petasis/Suzuki products but also to other
functionalized amino esters derivatives by exploiting the
versatility of the boronic ester group.
(Z)-Alkenyl 1,2-bis(boronates) 1 were prepared in good yields
according to a known protocol2 from the corresponding alkynes,
1-hexyne, 3-hexyne, propargyl trimethylsilane, and phenyl-
acetylene, independently on reaction with bis(pinacolato)-
diboron in the presence of tetrakis(triphenylphosphine)-
platinum as catalyst in DMF/toluene at 80 °C for 18 h. These
boronic esters 1a−d were then subjected to regioselective Petasis
reaction at the terminal C−B bond using different amines and
glyoxylic acid in HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol) at
room temperature for 8 h to give the corresponding γ-boronated
unsaturated amino acids. Poor results were obtained with other
solvents, such as methanol or THF, as previously reported,17
which was attributed to the positive effect of HFIP on the
formation of ionic intermediates and stabilization of polarized
transition states. Thus, prepared amino acids were directly
subjected to esterification with an ethereal solution of CH2N2 to
afford corresponding γ-boronated esters 2 with diversity (Table
1). A single isomer was present with an E stereochemistry, as
evidenced from NOESY experiments; no product resulting from
a double Petasis condensation was detected under these
experimental conditions. Yields are moderate to good (50−
69% over two steps), with the best results being generally
obtained with morpholine or N-substituted piperazines (entries
1, 3, 4, and 7). The reaction also took place with (S)-(−)-N-
benzyl-α-methylbenzylamine, a more sterically demanding
amine than dibenzylamine, but with poor diastereoselectivity
(dr 58:42) (entry 5). In addition, it should also be noted that no
reaction occurred at room temperature with the primary amine,
PhCH2NH2, and 1a (entry 6) as with the tetrasubstituted
bisboronate 1d and morpholine (entry 11), whereas complex,
inseparable mixtures are produced upon heating at 50 °C in
HFIP for 2 h.
The thus obtained esters 2 were engaged in Suzuki−Miyaura
cross-coupling reactions with different aromatic halides in the
presence of [1,1′-bis(diphenylphosphino)ferrocene]-
dichloropalladium(II) and potassium phosphate tribasic mono-
hydrate in THF/H2O at reflux.18 The corresponding esters 3
were obtained in good (60−89%) yields (Table 2), with no
significant influence being noticed on the basis of the nature of
the aromatic ring substituent (entries 5 and 6, 8 and 9).
Heteroaromatic halide can be used with similar efficiency (entry
3). The coupling reactions proceeded with retention of
configuration to afford the Z isomers as single products except
in the case of 2-bromo toluene, which gave a 58:42 mixture of
geometrical isomers.
EXPERIMENTAL SECTION
■
General Information and Materials. All commercially available
chemicals were used without further purification. Tetrahydrofuran
(THF), diethylether, and 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP)
were used as received. Analytical thin-layer chromatography was
performed on silica gel 60 F254 plates. The compounds were
characterized by 1H, 13C, and 11B NMR techniques. 1H and 13C spectra
were recorded in CDCl3 (internal standard: 7.26 ppm, 1H; 77.00 ppm,
13C) and 11B NMR chemical shifts to external BF3·OEt2 (0.0 ppm).
High-resolution mass spectra (HMRS) were recorded on a micro-TOF-
Q II mass analyzer or Q-TOF 2 using positive ion electrospray.
Compounds 1a,10 1b,3d 1c,2b and 1d3b were prepared according to a
known protocol.2 The ethereal solution of CH2N2 was generated from
N-nitroso-N-methylurea according to the literature.21
General Procedure for Petasis Reaction. Glyoxylic acid
monohydrate (0.33 mmol) and amine (0.33 mmol) were added to a
stirred solution of bispinacolate ester 1 (0.3 mmol) in hexafluor-
opropan-2-ol (2 mL) under an argon atmosphere at room temperature.
The reaction mixture was stirred for 8 h. The solvent was removed under
reduced pressure to give a residue that was directly used for the further
esterification reaction. To a solution of the crude acid in diethylether (5
mL) at 0 °C was added a solution of CH2N2 in ether21 until the
persistence of yellow color. After 2 h, the solvent was evaporated, and
the resulting residue was purified by column chromatography (230−400
mesh silica gel, EtOAc in cyclohexane) to afford γ-boronated
unsaturated amino esters 2 in 50−69% yield (over two steps) (Table 1).
Methyl 4-(4,4,4,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(mor-
pholino)-oct-3-enoate 2a. Seventy six milligrams (69%). Colorless
oil, Rf = 0.25 (EtOAc/cyclohexane 20:80). 1H NMR (300 MHz,
CDCl3): δ 5.96 (d, J = 9.8 Hz, 1H), 4.32 (d, J = 9.8 Hz, 1H), 3.73 (t, J =
4.3 Hz, 4H), 3.69 (s, 3H), 2.59−2.48 (m, 4H), 2.24−2.07 (m, 2H,),
1.41−1.21 (m, 4H), 1.27 (s, 12H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 171.8, 140.4 (br), 136.7, 83.4, 69.1, 66.7, 51.9,
51.0, 36.4, 31.7, 24.8, 24.7, 22.2, 13.9. 11B NMR (96 MHz, CDCl3): δ
30.0 (br s). HRMS (ESI+): m/z (M + H)+ calcd for C19H35NO511B,
368.26083; found, 368.2608.
Methyl 2-Dibenzylamino-4-(4,4,4,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)-oct-3-enoate 2b. Seventy two milligrams (50%). Colorless
oil, Rf = 0.40 (EtOAc/cyclohexane 30:70). 1H NMR (300 MHz,
CDCl3): δ 7.39−7.40 (m, 4H), 7.29−7.26 (m, 4H), 7.20−7.19 (m, 2H),
6.16 (d, J = 9.3 Hz, 1H), 4.74 (d, J = 9.3 Hz, 1H), 3.76 (s, 4H), 3.69 (s,
3H), 2.26−2.11 (m, 2H), 1.42−1.29 (m, 4H), 1.09 (s, 6H), 1.05 (s, 6H),
0.91 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 173.2, 139.8,
137.7, 128.7, 128.0, 126.6, 83.0, 63.2, 54.9, 51.4, 36.5, 31.9, 26.9, 24.6,
24.4, 22.3, 14.0 (C α to boron not visible). 11B NMR (96 MHz, CDCl3):
δ 30.4 (br s). HRMS (ESI+): m/z (M + H)+ calcd for C29H41NO411B,
478.31286; found, 478.3129.
Methyl 4-(4,4,4,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(pyri-
The synthetic utility of the amino esters 2 was also
demonstrated by several transformations of the boronic ester
group (Scheme 3). For example, oxidation of 2a with sodium
din-4-yl)piperazino-oct-3-enoate 2c. Seventy six milligrams (57%).
1
Colorless oil, Rf = 0.30 (EtOAc/cyclohexane 30:70). H NMR (300
MHz, CDCl3): δ 8.18 (d, J = 3.9 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 6.64−
B
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Note
Table 1. Borono−Mannich Route to γ-Boronated Unsaturated Amino Esters 2
a
b
Yields are calculated over two steps after purification by column chromatography. Mixtures of two diastereomers (58:42).
6.59 (m, 2H), 5.99 (d, J = 9.8 Hz, 1H), 4.40 (d, J = 9.8 Hz, 1H), 3.72 (s,
3H,), 3.57 (t, J = 4.9 Hz, 4H), 2.66−2.53 (m, 4H), 2.18−2.02 (m, 2H),
1.41−1.26 (m, 4H), 1.26 (s, 12H), 0.87 (t, J = 7.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 172.2, 147.8, 137.5, 137.2, 113.2, 107.0, 83.4, 68.9,
51.9, 50.4, 45.1, 36.5, 31.8, 24.8, 24.7, 22.3, 13.9. 11B NMR (96 MHz,
CDCl3): δ 29.8 (br s). HRMS (ESI+): m/z (M + H)+ calcd for
C24H39N3O411B, 444.30336; found, 444.3037.
Methyl 4-(4,4,4,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(1,1-
dimethylethoxy)carbonyl]piperazino-oct-3-enoate 2d. Eighty eight
milligrams (63%). Colorless oil, Rf = 0.30 (EtOAc/cyclohexane 30:70).
C
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Note
(58%). Colorless oil, Rf = 0.29 (EtOAc/cyclohexane 8:92). Mixture of 2
diastereomers (55:45). 1H NMR (400 MHz, CDCl3): δ 7.45−7.43 (m,
3H), 7.36−7.15 (m, 7H), 6.16 (d, J = 9.3 Hz, 0.55H), 6.00 (d, J = 9.1 Hz,
0.45H), 4.93 (d, J = 9.2 Hz, 0.45H), 4.86 (d, J = 9.4 Hz, 0.55H), 4.12−
4.06 (m, 1H), 3.98 (d, J = 15.2 Hz, 0.55H), 3.93 (d, J = 15.4 Hz, 0.55H),
3.89 (d, J = 15.4 Hz, 0.45H), 3.81 (d, J = 15.2 Hz, 0.45H), 3.65 (s, 3 ×
0.45H), 3.47 (s, 3 × 0.55H), 2.20−2.04 (m, 2H), 1.40 (d, J = 7.2 Hz, 3 ×
0.45H), 1.38 (d, J = 7.4 Hz, 3 × 0.55H), 1.34−1.25 (m, 4H), 1.19 (s, 12
× 0.45H), 1.16 (s, 12 × 0.55H), 0.89 (t, J = 7.1 Hz, 3 × 0.45H), 0.88 (t, J
= 7.0 Hz, 3 × 0.55H). 13C NMR (100 MHz, CDCl3): δ 174.1, 173,6,
144.35, 143.8, 141.9, 141.7, 139.7, 139.2, 136.6 (br), 128.2, 128.1,
127.95, 127.9, 127.85, 127.8, 126.55, 126.5, 126.3, 126.1, 83.0, 83.0, 62.8,
62.5, 59.0, 58.35, 51.7, 51.6, 51.4, 51.2, 36.4, 36.2, 31.8, 31.6, 24.7, 24.5,
24.4, 22.3, 22.2, 16.9, 14.0. 11B NMR (96 MHz, CDCl3): δ 30.0 (br s).
HRMS (ESI+): m/z (M + H)+ calcd for C30H43NO411B, 492.3285;
found, 492.3279.
Table 2. Suzuki Couplings with γ-Boronated Unsaturated
Amino Esters 2
Methyl 4-(4,4,4,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(mor-
pholino)-5-(trimethylsilyl)-pent-3-enoate 2g. Seventy one milligrams
(60%). Colorless oil, Rf = 0.25 (EtOAc/cyclohexane 10:90). 1H NMR
(300 MHz, CDCl3): δ 5.80 (d, J = 9.9 Hz, 1H), 4.47 (d, J = 9.9 Hz, 1H),
3.74 (t, J = 4.0 Hz, 4H), 3.68 (s, 3H), 2.60−2.46 (m, 4H), 1.67 (s, 2H),
1.25 (s, 6H), 1.24 (s, 6H), −0.05 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 171.9, 137.2 (br),135.1, 83.5, 69.0, 66.7, 51.8, 51.0, 26.6, 24.9, −1.5.
11B NMR (96 MHz, CDCl3): δ 29.7 (br s). HRMS (ESI+): m/z (M +
Na)+ calcd for C19H36NO511BNaSi, 420.23535; found, 420.2351.
Methyl 2-Benzyl(methy)amino-4-(4,4,4,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)-5-(trimethylsilyl)-pent-3-enoate 2h. Sixty nine milli-
1
grams (53%). Colorless oil, Rf = 0.15 (EtOAc/cyclohexane 3:97). H
NMR (400 MHz, CDCl3): δ 7.40−7.19 (m, 5H), 5.97 (d, J = 9.6 Hz,
1H), 4.73 (d, J = 9.6 Hz, 1H), 3.76−3.54 (m, 2H), 3.73 (s, 3H), 2.21 (s,
3H), 1.73 (s, 2H), 1.23 (s, 6H), 1.21 (s, 6H), 0.00 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 173.1, 139.2 (br), 136.1, 129.2, 128.1, 126.9, 83.3,
67.0, 58.5, 51.6, 38.7, 26.6, 24.9, 24.8, −1.5 (C α to boron not visible).
11B NMR (96 MHz, CDCl3): δ 29.6 (br s). HRMS (ESI+): m/z (M +
H)+ calcd for C23H3911BNO4Si, 432.27414; found, 432.2738.
Methyl 4-(4,4,4,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(mor-
pholino)-4-phenyl-but-3-enoate 2i. Sixty two milligrams (53%).
1
Colorless oil, Rf = 0.30 (EtOAc/cyclohexane 20:80). H NMR (400
MHz, CDCl3): δ 7.42−7.22 (m, 5H), 6.40 (d, J = 9.9 Hz, 1H), 4.32 (d, J
= 9.9 Hz, 1H), 3.78−3.74 (m, 4H), 3.74 (s, 3H), 2.67−2.54 (m, 4H),
1.35 (s, 6H), 1.34 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 171.3, 141.3,
138.2, 128.7, 128.3, 127.3, 126.6, 84.1, 70.0, 66.8, 52.1, 51.3, 24.9, 24.7.
11B NMR (96 MHz, CDCl3): δ 30.3 (br s). HRMS (ESI+): m/z (M +
Na)+ calcd for C21H3011BNO5Na, 410.21147; found, 410.2112.
Methyl 2-Dibenzylamino-4-(4,4,4,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)-4-phenyl-but-3-enoate 2j. Eighty one milligrams (54%).
1
Colorless oil, Rf = 0.15 (EtOAc/cyclohexane 3:97). H NMR (400
MHz, CDCl3): δ 7.39 (d, J = 7.8 Hz, 4H), 7.33−7.24 (m, 8H,), 7.21−
7.15 (m, 3H), 6.53 (d, J = 9.3 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H), 3.81 (s,
4H), 3.69 (s, 3H), 1.09 (s, 6H), 1.06 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 172.4, 142.2, 139.9, 139.5, 137.1 (br), 128.7, 128.15, 128.10,
127.4, 126.8, 126.7, 83.7, 63.7, 55.0, 51.6, 24.6, 24.5. 11B NMR (96 MHz,
CDCl3): δ 30.3 (br s). HRMS (ESI+): m/z (M + H)+ calcd for
C31H37NO411B, 498.28156; found, 498.2809.
General Procedure for Suzuki Coupling. To a solution of ester 2
(0.14 mmol) in THF (1.2 mL) and water (30 μL) under an argon
atmosphere were added [1,1′-bis (diphenyl phosphino)ferrocene]-
dichloropalladium(II) (0.0028 mmol), potassium phosphate tribasic
monohydrate (0.42 mmol), and arylbromide (0.28 mmol) at room
temperature. The reaction mixture was heated at reflux for 8 h, cooled to
room temperature, and diluted with water. The aqueous layer was
extracted with Et2O (2 × 15 mL). The combined organic extracts were
dried over MgSO4 and evaporated under vacuum. The residue was
purified by column chromatography (230−400 mesh silica gel, EtOAc in
cyclohexane) to give ester 3 in 69−89% yield (Table 2).
a
Yields are calculated after purification by column chromatography.
1H NMR (300 MHz, CDCl3): δ 5.90 (d, J = 9.7 Hz, 1H), 4.29 (d, J = 9.7
Hz, 1H), 3.65 (s, 3H), 3.41−3.39 (m, 4H), 2.56−2.40 (m, 4H), 2.23−
207 (m, 2H), 1.40 (s, 9H), 1.34−1.22 (m, 4H), 1.22 (s, 12H), 0.93 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.0, 154.6, 139.8 (br),
137.1, 83.3, 79.4, 68.5, 51.7, 50.2, 43.0 (br), 36.4, 31.7, 28.3, 24.7, 24.6,
22.2, 13.8. 11B NMR (96 MHz, CDCl3): δ 30.2 (br s). HRMS (ESI+):
m/z (M + Na)+ calcd for C24H43N2O611BNa, 489.31119; found,
489.3112.
Methyl 4-(4-Methylphenyl)-2-(morpholino)-oct-3-enoate 3a.
Thirty five milligrams (75%). Colorless oil, Rf = 0.40 (EtOAc/
1
cyclohexane 10:90). H NMR (300 MHz, CDCl3): δ 7.14 (d, J = 7.9
Hz, 2H), 7.02 (d, J = 7.9 Hz, 2H), 5.48 (d, J = 9.9 Hz, 1H), 3.73 (s, 3H),
3.69 (t, J = 4.5 Hz, 4H), 3.52 (d, J = 9.9 Hz, 1H), 2.58−2.45 (m, 2H),
Methyl 2-(S)-Benzyl-α-methylbenzylamino-4-(4,4,4,5-tetrameth-
yl-1,3,2-dioxaborolan-2-yl)-oct-3-enoate 2e. Eighty five milligrams
D
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Scheme 3. Synthetic Transformations of γ-Boronated Unsaturated Amino Ester 2a
2.38−2.26 (m, 4H), 2.36 (s, 3H), 1.33−1.22 (m, 4H), 0.84 (t, J = 7.0 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 171.8, 149.3, 136.9, 136.8, 128.9,
128.0, 120.0, 67.9, 66.7, 52.0, 50.9, 39.4, 29.8, 22.2, 21.2, 13.8. HRMS
(ESI+): m/z (M + Na)+ calcd for C20H29NO3Na, 354.20451; found,
354.2042.
1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.56 (d, J = 9.9 Hz, 1H), 3.40 (t, J = 4.5
Hz, 4H), 2.49−2.39 (m, 2H), 2.39−2.29 (m, 2H), 2.29−2.19 (m, 2H),
1.42 (s, 9H), 1.34−1.21 (m, 4H), 0.84 (t, J = 7.0 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 172.1, 158.7, 154.6, 148.5, 132.2, 129.3, 120.5, 113.5,
79.6, 67.6, 55.2, 51.9, 50.3, 43.0 (br), 39.4, 29.8, 28.4, 22.1, 13.8. HRMS
(ESI+): m/z (M + H)+ calcd for C25H39N2O5, 447.2859; found,
447.2858.
Methyl 2-(Morpholino)-4-(4-methoxyphenyl)-5-(trimethylsilyl)-
pent-3-enoate 3g. Forty two milligrams (80%). Colorless oil, Rf =
0.39 (EtOAc/cyclohexane 10:90). 1H NMR (300 MHz, CDCl3): δ 7.17
(d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.29 (d, J = 10.1 Hz, 1H),
3.82 (s, 3H), 3.74 (s, 3H), 3.70−3.67 (m, 4H), 3.62 (d, J = 10.1 Hz, 1H),
2.55−2.45 (m, 2H), 2.33−2.23 (m, 2H), 1.91 (s, 2H), −0.17 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 172.2, 158.8, 146.2, 133.3, 129.6, 118.1,
Methyl 4-(2-Methylphenyl)-2-(morpholino)-oct-3-enoate 3b.
Twenty milligrams (60%). Colorless oil, Rf = 0.40 (EtOAc/cyclohexane
1
30:70). Mixture of 2 diastereomers (58:42). H NMR (300 MHz,
CDCl3): δ 7.22−7.12 (m, 3H), 6.93 (d, J = 6.9 Hz, 0.4H), 6.92 (d, J = 6.6
Hz, 0.6H), 5.58 (d, J = 9.6 Hz, 0.4H), 5.56 (d, J = 10 Hz, 0.6H), 3.73−
3.68 (m, 4H), 3.71 (s, 3 × 0.4H), 3.68 (s, 3 × 0.6H), 3.28 (d, J = 9.6 Hz,
0.4H), 3.23 (d, J = 9.9 Hz, 0.6H), 2.56−2.47 (m, 2H), 2.33−2.23 (m,
4H), 2.23 (s, 3 × 0.4), 2.15 (s, 3 × 0.6H), 1.43−1.29 (m, 4H), 0.88 (t, J =
7.0 Hz, 3 × 0.6H), 0.86 (t J = 7.1 Hz, 3 × 0.4). 13C NMR (75 MHz,
CDCl3): δ 171.7, 171.6, 148.6, 148.6, 139.4, 139.0, 135.5, 134.1, 130.0,
129.5, 128.0, 127.1, 127.0, 125.2, 125.1, 121.2, 120.8, 68.4, 68.3, 66.7,
51.7, 51.7, 51.1, 51.05, 38.6, 38.2, 29.6, 29.4, 22.4, 22.2, 19.2, 18.9, 13.8.
HRMS (ESI+): m/z (M + Na)+ calcd for C20H29NO3Na, 354.20451;
found, 354.2047.
113.4, 68.0, 66.9, 55.2, 51.8, 50.9, 31.0, −1.5. HRMS (ESI+): m/z (M +
Na)+ calcd for C20H31NO4SiNa, 400.19201; found, 400.1913.
Methyl 4-(4-Methylphenyl)-2-(morpholino)-4-phenyl-but-3-
enoate 3h. Thirty nine milligrams (80%). Colorless oil, Rf = 0.40
1
(EtOAc/cyclohexane 10:90). H NMR (300 MHz, CDCl3): δ 7.30−
7.25 (m, 5H), 7.21 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 6.15 (d, J
= 10.1 Hz, 1H), 3.77−3.72 (m, 5H), 3.76 (s, 3H), 2.65−2.58 (m, 2H),
2.44−2.38 (m, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
171.4, 148.0, 141.5, 137.5, 135.7, 129.7, 129.0, 128.2, 128.0, 127.5, 122.2,
68.3, 66.8, 52.1, 51.1, 21.3. HRMS (ESI+): m/z (M + Na)+ calcd for
C22H25NO3Na, 374.17321; found, 374.1736.
Methyl 2-Dibenzylamino-4-(4-nitrophenyl)-4-phenyl-but-3-
enoate 3i. Fifty four milligrams (78%). Colorless oil, Rf = 0.35
(EtOAc/cyclohexane 7:93). 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J =
8.7 Hz, 2H), 7.35−7.17 (m, 17H), 6.43 (d, J = 9.8 Hz, 1H), 4.10 (d, J =
9.8 Hz, 1H), 3.86 (d, J = 13.7 Hz, 2H), 3.83 (s, 3H), 3.72 (d, J = 13.7 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 172.2, 147.0, 145.6, 144.8, 140.7,
139.0, 130.4, 128.7, 128.4, 128.3, 128.2, 127.6, 127.0, 124.6, 123.4, 60.4,
55.0, 51.8. HRMS (ESI+): m/z (M + Na)+ calcd for C31H28N2O4Na,
515.19468; found, 515.1948.
Methyl 4-(Pyridin-3-yl)-2-(morpholino)-oct-3-enoate 3c. Thirty
seven milligrams (82%). Colorless oil, Rf = 0.15 (EtOAc/cyclohexane
40:60). 1H NMR (300 MHz, CDCl3): δ 8.54 (d, J = 3.6 Hz, 1H), 8.50 (s,
1H), 7.49 (dt, J = 1.9, 7.8 Hz, 1H), 7.30 (dd, J = 4.9, 7.5 Hz, 1H), 5.65 (d,
1H, J = 10 Hz), 3.72 (s, 3H), 3.68 (t, J = 4.6 Hz, 4H), 3.42 (d, J = 10 Hz,
1H), 2.49 (dt, J = 4.9, 9.5 Hz, 2H), 2.41−2.26 (m, 4H), 1.36−1.22 (m,
4H), 0.85 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.4,
149.0, 148.5,145.2, 135.7, 135.5, 123.1, 122.7, 67.7, 66.7, 52.0, 50.8, 39.0,
29.6, 22.0, 13.7. HRMS (ESI+): m/z (M + H)+ calcd for C18H27N2O3,
319.20162; found, 319.2017.
Methyl 2-Dibenzylamino-4-(4-methylphenyl)-oct-3-enoate 3d.
Fifty three milligrams (86%). Colorless oil, Rf = 0.25 (EtOAc/
1
cyclohexane 1:99). H NMR (400 MHz, CDCl3): δ 7.19−7.16 (m,
10H), 7.0 (s, 4H), 5.69 (d, J = 9.8 Hz, 1H), 4.07 (d, J = 9.8 Hz, 1H), 3.69
(s, 3H), 3.66 (s, 4H), 2.45−2.40 (m, 2H), 2.33 (s, 3H,), 1.31−1.28 (m,
4H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.4,
147.6, 139.6, 136.9, 136.4, 128.7, 128.0, 127.9, 126.6, 120.1, 60.6, 54.9,
51.4, 39.3, 30.1, 22.2, 21.1, 13.9. HRMS (ESI+): m/z (M + H)+ calcd for
C30H36NO2, 442.2746; found, 442.2742.
Oxidation of Boronate 2a. Sodium perborate monohydrate (45
mg, 0.45 mmol) was added to a stirred solution of ester 2a (50 mg, 0.14
mmol) in THF (2 mL) and water (2 mL) at room temperature. The
reaction mixture was stirred during 12 h and then diluted with water.
The aqueous layer was extracted with Et2O (2 × 5 mL). The combined
organic extracts were dried over MgSO4 and evaporated under vacuum.
The resulting residue was purified by column chromatography (230−
400 mesh silica gel, EtOAc/cyclohexane, 1:9 to 1:2) to afford γ-keto
amino ester 4 (26 mg) in 74% yield as a colorless oil.
Methyl 4-(4-Nitrophenyl)-2-(pyridin-4-yl)piperazino-oct-3-enoate
3e. Fifty milligrams (82%). Colorless oil, Rf = 0.25 (EtOAc/cyclohexane
20:80). 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 8.7 Hz, 2H), 8.17−
8.15 (m, 1H), 7.49−7.42 (m, 1H,), 7.36 (d, J = 8.7 Hz, 2H), 6.65−6.58
(m, 2H), 5.72 (d, J = 10.0 Hz, 1H), 3.75 (s, 3H), 3.56−3.49 (m, 4H),
3.47 (d, J = 10.0 Hz, 1H), 2.64−2.57 (m, 2H), 2.47−2.40 (m, 4H),
1.35−1.25 (m, 4H), 0.87 (t, J = 6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 171.4, 159.2, 147.9, 147.1, 146.6, 137.5, 129.2, 123.5, 122.9,
113.4, 107.0, 67.6, 52.1, 50.3, 45.1, 38.9, 29.7, 22.1, 13.8. HRMS (ESI+):
m/z (M + H) + calcd for C24H31N4O4, 439.23453; found, 439.2342.
Methyl 4-(4-Methoxyphenyl)-2-[4-(1,1-dimethylethoxy)carbonyl]-
piperazino-oct-3-enoate 3f. Fifty six milligrams (89%). Colorless oil Rf
1
Methyl 2-(Morpholino)-4-oxo-octanoate 4. H NMR (400 MHz,
CDCl3): δ 3.77−3.73 (m, 1H), 3.67 (s, 3H), 3.67−3.61 (m, 4H), 2.99
(dd, J = 17.0, 9.2 Hz, 1H), 2.75−2.64 (m, 2H), 2.56−2.47 (m, 2H), 0.86
(t, J = 7.4 Hz, 2H), 1.49 (quint, J = 7.4 Hz, 2H), 1.24 (hex, J = 7.4 Hz,
2H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 207.3,
169.8, 65.9, 61.9, 50.7, 49.2, 41.8, 40.6, 24.7, 21.25, 12.8. HRMS (ESI+):
m/z (M + Na)+ calcd for C13H23NO4Na, 280.1525; found, 280.1523.
Azidation of Boronate 2a. Sodium azide (12 mg, 0.18 mmol) and
copper sulfate (15 mg, 0.095 mmol) were added to a stirred solution of
1
= 0.15 (EtOAc/cyclohexane 10:90). H NMR (300 MHz, CDCl3): δ
7.08 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.49 (d, J = 10.0 Hz,
E
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Note
boronic ester 2a (56 mg, 0.15 mmol) in MeOH (2 mL) at room
temperature. The reaction mixture was stirred during 24 h and then
diluted with water. The aqueous layer was extracted with CH2Cl2 (2 × 5
mL). The combined organic extracts were dried over MgSO4 and
evaporated under vacuum. The resulting residue was purified by column
chromatography (230−400 mesh silica gel, EtOAc/cyclohexane, 1:9 to
1:4) to afford γ-azido amino ester 5 (30 mg) in 71% yield as a colorless
oil.
(c) Yavari, K.; Moussa, S.; Ben Hassine, B.; Retailleau, P.; Voituriez, A.;
Marinetti, A. Angew. Chem., Int. Ed. 2012, 51, 6748. (d) Mace, A.;
Tripoteau, F.; Zhao, Q.; Gayon, E.; Vrancken, E.; Campagne, J.-M.;
Carboni, B. Org. Lett. 2013, 15, 906.
(4) For intramolecular versions, see: (a) Carson, M. W.; Giese, M. W.;
Coghlan, M. J. Org. Lett. 2008, 10, 2701. (b) Yoshida, H.; Asatsu, Y.;
Mimura, Y.; Ito, Y.; Oshita, J.; Takaki, K. Angew. Chem., Int. Ed. 2011, 50,
9676.
(5) Iwadate, N.; Sugimone, M. J. Am. Chem. Soc. 2010, 132, 2548.
(6) Baldoli, C.; Bossi, A.; Giannini, C.; Licandro, E.; Maiorana, S.;
Perdicchia, D.; Schiavo, M. Synlett 2005, 1137.
(7) (a) Shimizu, M.; Tomioka, Y.; Nagao, I.; Kadowaki, T.; Hiyama, T.
Chem.Asian J. 2012, 7, 1644 and references therein. (b) Lin, Q. X.;
Ho, T. L. Tetrahedron 2013, 69, 2996.
Methyl 2-(Morpholino)-4-azido-oct-3-enoate 5. 1H NMR (400
MHz, CDCl3): δ 4.74 (d, J = 9.5 Hz, 1H), 3.95 (d, J = 9.5 Hz, 1H), 3.67
(t, J = 4.6 Hz, 4H), 3.66 (s, 3H), 2.56−2.49 (m, 2H), 2.45−2.38 (m,
2H), 2.26 (t, J = 7.5 Hz, 2H), 1.47 (quint, J = 7.5 Hz, 2H), 1.32 (hex, J =
7.5 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
171.3, 141.2, 109.2, 66.8, 65.35, 52.0, 50.9, 32.2, 29.4, 21.9, 13.7. HRMS
(ESI+): m/z (M-N2 + Na)+ calcd for C13H22N2O3Na, 277.1528; found,
277.1530.
One-Pot Access to Triazole 6. Sodium azide (9 mg, 0.13 mmol)
and copper sulfate (11 mg, 0.07 mmol) were added to a stirred solution
of ester 2a (40 mg, 0.11 mmol) in MeOH (2 mL) at room temperature.
The reaction mixture was stirred during 24 h. Sodium ascorbate (11 mg,
0.05 mmol) and phenylacetylene (12 mg, 0.12 mmol) were added, and
the reaction mixture was stirred for 24 h and then diluted with water.
The aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The
combined organic extracts were dried over MgSO4 and evaporated
under vacuum. The resulting residue was purified by column
chromatography (230−400 mesh silica gel, EtOAc/cyclohexane, 1:9
to 1:2) to afford γ-triazolyl amino ester 6 (15 mg) in 36% yield (two
steps) as a colorless oil.
(8) Yamamoto, Y. Adv. Synth. Catal. 2010, 352, 478.
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M. J. Am. Chem. Soc. 2011, 133, 13634.
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(12) For recent reviews on the Petasis three-component coupling
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P. M. P. Chem. Rev. 2010, 110, 6169. (b) Batey, R. A. In Boronic Acids:
Preparation and Applications in Organic Synthesis, Medicine and Materials,
2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2011; pp
427−477. (c) Carboni, B.; Berree
́
, F. In Science of Synthesis:
Multicomponent Reactions; Muller, T. J. G., Ed; Thieme: New York,
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2013; Vol 5, pp 219−259.
(13) For recent selected examples, see: (a) Norsikian, S.; Soule, J. F.;
Cannillo, A.; Guillot, R.; Tran Huu Dau, M. E.; Beau, J. M. Org. Lett.
2012, 14, 544. (b) Le Quement, S. T.; Flagstad, T.; Mikkelsen, R. J.;
Hansen, M. R.; Givskov, M. C.; Nielsen, T. E. Org. Lett. 2012, 14, 640.
(c) Li, Y.; Xu, M. H. Org. Lett. 2012, 14, 2062. (d) Han, W. Y.; Wu, Z. J.;
Zhang, X. M.; Yuan, W. C. Org. Lett. 2012, 14, 976. (e) Mizuta, S.;
Onomura, O. RSC Adv. 2012, 2, 2266. (f) Ascic, E.; Le Quement, S. T.;
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(g) Frauenlob, R.; Garcia, C.; Bradshaw, G. A.; Burke, H. M.; Bergin, E. J.
Org. Chem. 2012, 77, 4445. (h) Chrzanowska, M.; Grajewska, A.;
Meissner, Z.; Rozwadowska, M.; Wiatrowska, I. Tetrahedron 2012, 68,
3092. (i) Ghosal, P.; Shaw, A. K. J. Org. Chem. 2012, 77, 7627.
(j) Cannillo, A.; Norsikian, S.; Retailleau, P.; Dau Tran Huu, M. E.;
Iorga, B. I.; Beau, J. M. Chem.Eur. J. 2013, 19, 9127. (k) Han, W. Y.;
Zuo, J.; Zhan, X. M.; Yuan, W. C. Tetrahedron 2013, 69, 537.
(14) (a) Sharma, G. V. M; Reddy, N. Y.; Ravi, R.; Sreenivas, B.; Sridhar,
G.; Chatterjee, D.; Kunwar, A. C.; Hofmann, H. J. Org. Biomol. Chem
2012, 10, 9191. (b) Sharma, G. V. M; Kodeti, S. R.; Dutta, S. K.;
Velaparthi, S.; Narsimulu, K.; Anjaiah, G.; Basha, S. J.; Kunwar, A. C.
Chem.Eur. J. 2012, 18, 16046. (c) Sharma, G. V. M; Yadav, T. A.;
Choudhary, M.; Kunwar, A. C. J. Org. Chem. 2012, 77, 6834. (d) Sharma,
G. V. M; Sridhar, T.; Reddy, P. P.; Kunwar, A. C. Eur. J. Org. Chem. 2013,
3543.
Methyl 2-Morpholino)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-oct-3-
1
enoate 6. H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.80 (d, J =
7.1 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 5.71 (d, J =
9.4 Hz, 1H), 3.75−3.70 (m, 1H), 3.69 (s, 3H), 3.65 (t, J = 4.4 Hz, 4H),
2.63 (t, J = 7.3 Hz, 2H), 2.70−2.43 (m, 4H), 1.37−1.26 (m, 4H), 0.83 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.9, 147.3, 141.9,
130.1, 129.0, 128.4, 125.7, 120.7, 66.6, 65.4, 52.0, 50.6, 35.9, 28.8, 21.9,
13.7. HRMS (ESI+): m/z (M + H)+ calcd for C21H28N4O3Na,
407.2059; found, 407.2054.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 11B NMR spectra of compounds 2a−i. NOESY
NMR spectrum of compound 2b. 1H and 13C spectra of
compounds 3−6. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: esmvee@iict.res.in (G.V.M.S.).
*E-mail: bertrand.carboni@univ-rennes1.fr (B.C.).
■
Notes
́
(15) (a) Berree, F.; Gernigon, N.; Hercouet, A.; Lin, C. H.; Carboni, B.
The authors declare no competing financial interest.
Eur. J. Org. Chem. 2009, 329. (b) Tripoteau, F.; Verdelet, T.; Hercouet,
A.; Carreaux, F.; Carboni, B. Chem.Eur. J. 2011, 17, 13670.
́ ́
(c) Vovard-Le Bray, C.; Klein, H.; Dixneuf, P. H.; Mace, A.; Berree,
ACKNOWLEDGMENTS
■
This research has been performed as part of the Indo-French
“Joint Laboratory for Sustainable Chemistry at Interfaces”. We
thank CNRS, CSIR, and University of Rennes 1 for support of
this research. T.S. thanks CSIR for financial assistance.
F.; Carboni, B.; Derien, S. Adv. Synth. Catal. 2012, 354, 1919.
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G
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