Dialkylzinc-Assisted Alkynylation of Nitrones

Article abstract of DOI:10.1021/ol025618n

(matrix presented) Reaction of nitrones with terminal alkynes takes place readily in the presence of a substoichiometric amount of diethylzinc in toluene, affording N-propargyl-hydroxylamines in excellent yields and purity.

Full text of DOI:10.1021/ol025618n

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1463-1466
Dialkylzinc-Assisted Alkynylation of
Nitrones
Sandra Pinet, Shashi Urvish Pandya, Pierre Yves Chavant, Alexander Ayling, and
Yannick Vallee*
LEDSS, UMR 5616, UniVersite´ J.Fourier, BP53, F-38041 Grenoble Cedex 9, France
yannick.Vallee@ujf-grenoble.fr
Received January 25, 2002
ABSTRACT
Reaction of nitrones with terminal alkynes takes place readily in the presence of a substoichiometric amount of diethylzinc in toluene, affording
N-propargyl-hydroxylamines in excellent yields and purity.
We recently published1 a study of the vinylation of nitrones
by vinylzinc reagents. The latter were prepared by hydro-
zirconation of terminal alkynes followed by zirconium-to-
zinc exchange according to the procedures of Wipf.2 In some
of our runs, we found that the desired N-allyl-hydroxylamine
was contaminated by N-propargyl-hydroxylamine, issued
from unreacted alkyne. Checking the outcome of this side
reaction led us to the present communication of a new
reaction of terminal alkynes with nitrones, in the presence
of substoichiometric amounts of diethylzinc.
reagents is concerned, the reports are few compared to the
related reactions of aldehydes and 1-alkynylzinc (separately
prepared by action of dialkylzinc to terminal alkynes). These
additions to aldehydes are catalyzed by several types of
ligands, allowing enantioselective versions.6
Another interesting trend of these additions to aldehydes
is the feasibility of the nucleophilic addition of terminal
alkynes in the presence of weak bases and/or substoichio-
metric amounts of bases.7 The recent Meerwein-Ponndorf-
Verley alkynylation of aldehydes should also be quoted.8
The versatility of propargylic amines has been widely
exemplified.3 One of the ways to these reagents is the
addition of an acetylide onto a CdN double bond. Usually
the acetylides are prepared by the action of a stoichiometric
base on terminal alkynes; asymmetric versions have been
developed.4,5 However, as far as the use of organozinc
Carreira et al. recently found9 that the combined action of
small amounts of a zinc salt and a tertiary amine onto a
(4) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-
1946. Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094. Umeno,
M.; Suzuki, A. Chem. Ind. 1996, 64, 645-666. Zweifel, G.; Miller, J. A.
Org. React. 1984, 32, 375-517. Merino, P.; Anoro, S.; Castillo, E.;
Merchan, F.; Tejero, T. Tetrahedron: Asymmetry 1996, 7, 1887-1890.
Dagoneau, C.; Denis, J.-N.; Vallee, Y. Synlett 1999, 602-604. Dagoneau,
C.; Tomassini, A.; Denis, J.-N.; Vallee, Y. Synthesis 2001, 150-154.
Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H. P. J. Org. Chem. 2000,
65, 6423-6426. Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970-
8972. Ahn, J. H.; Joung, M. J.; Yoon, N. M.; Oniciu, D. C.; Katritzky, A.
R. J. Org. Chem. 1999, 64, 488-492. Rae, A.; Ker, J.; Tabor, A. B.; Castro,
J. L.; Parsons, S. Tetrahedron Lett. 1998, 39, 6561-6564. Corey, E. J.;
Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151-3152. Enders, D.;
Schankat, J. HelV. Chim. Acta 1993, 76, 402-6. Williams, R. M.; Aldous,
D. J.; Aldous, S. C. J. Chem. Soc., Perkin Trans. 1 1990, 171-172.
(5) Denis, J.-N.; Tchertchian, S.; Tomassini, A.; Vallee, Y. Tetrahedron
Lett. 1997, 38, 5503-5506.
(1) Pandya, S. U.; Garcon, C.; Chavant, P. Y.; Py, S.; Vallee, Y. Chem.
Commun. 2001, 1806-1807.
(2) Wipf, P.; Phillips, A. J. Angew. Chem., Int. Ed. 2001, 40, 463. Wipf,
P.; Takahashi, H.; Zhuang, N. Pure Appl. Chem. 1998, 70, 1077-1082.
Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454-6455. Wipf, P.. Xu, W.;
Takahashi, H.; Jahn, H.; Coish, P. D. G. Pure Appl. Chem. 1997, 69, 639-
644.
(3) Wright, J. L.; Gregory, T. F.; Kesten, S. R.; Boxer, P. A.; Serpa, K.
A.; Meltzer, L. T.; Wise, L. D.; Espitia, S. A.; Konkoy, C. S.; Whittemore,
E. R.; Woodward, R. M. J. Med. Chem. 2000, 43, 3408-3419. Hoepping,
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10.1021/ol025618n CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/28/2002

to completion overnight at 20 °C, leading to the propargylic
N-hydroxylamine. The addition is more sluggish if benzyl-
idene-arylamine-N-oxide or benzylidene-tert-butylamine-N-
oxide, or O-protected propargyl alcohols are used. In some
instances, on standing, a cyclization of the product propar-
gylic N-hydroxylamine into 2,3-dihydroisoxazole (see below)
was observed.
A dramatic improvement was brought by changing from
dichloromethane to toluene. In this solvent, not only is the
reaction much quicker, but it can be completed in the
presence of only 0.2 equiv of diethylzinc (use of 0.1 equiv
is possible, but the results are less reproducible) within 4 h
at 20 °C.
In such conditions, the reaction becomes highly efficient
and general, as exemplified in Figure 1 and Table 1.
Table 1. Reaction Time and Yields of the Additions
nitrone
alkyne
time (h)
yield (%)
notes
A
A
A
A
A
A
A
A
A
A
A
B
B
B
C
D
D
D
D
D
1
2
3
4
5
6
7
8
9
10
11
1
4
5
8
1
1
3
6
30
2
3
6
23
8
30
20
8
9
1.5
1.5
2
19
92
82
88
92
96
90
78
62
90
82
<42
72
56
61
quant
94
83
97
87
a
Figure 1. Reaction of nitrones and alkynes in the presence of 0.2
equiv of Et2Zn in toluene at 20 °C.
b
c
mixture of a terminal alkyne and an aldehyde9,10 or a nitrone11
leads smoothly and efficiently to the propargyl adduct. In
the case of nitrones the addition of alkynes is best run in the
presence of zinc trifluoromethanesulfonate and a tertiary
amine in dichloromethane or acetonitrile at 23 °C.11
Since our own study began with the identification of this
addition as a side reaction in dichloromethane, we first
worked in this solvent. We found that in dry dichloro-
methane, a slow reaction of benzylidene-benzylamine-N-
oxide, 1-hexyne, and diethylzinc in a 1:2:1 ratio12 proceeds
d
e
f
4.5
dr 78/22
dr 81/19
dr 74/26
dr 76/24
dr 77/23
24 (-10 °C)
3
4
3
6
8
91
a Nitrone (1 mmol), terminal alkyne (1.3 mmol), and diethyl zinc (1 M
solution in hexanes, 0.2 mmol) in anhydrous toluene (4 mL) were stirred
in a Schlenk tube under N2. b 0.3 equiv of diethylzinc was used. c Depro-
tected A8 was isolated as a side product (21% yield). d In one run, after 9
h, the crude mixture contained 42% product A11, 33% nitrone A, 7%
2-benzyl-3-phenyl-2,3-dihydro-isoxazole-5-carboxylic acid tert-butyl ester,
and 18% 2-benzyl-3-phenyl-2,3-dihydro-isoxazole-4-carboxylic acid tert-
butyl ester. e Product is obtained solely as 2,3-dihydroisoxazole (Figure 2).
f dr: diastereoisomeric ratio
(7) Chang, S.; Na, Y.; Choi, E.; Kim, S. Org. Lett. 2001, 3, 2089-2091.
Lee, S.; Kim, C. K.; Jung, Y. G.; Kang, Y. S.; Kim, T. K. In Eur. Pat.
Appl. (SK Corporation, S. Korea) Ep, 2000, p 24. Koradin, C.; Aisca, B. J.
J.; Henkelmann, J.; Preiss, T.; Knochel, P.; Tzelis, D. In Eur. Pat. Appl.
(Basf Aktiengesellschaft, Germany) Ep, 2000, p 8. Tzalis, D.; Knochel, P.
Angew. Chem., Int. Ed. 1999, 38, 1463-1465. Costa, M.; Chiusoli, G. P.;
Rizzardi, M. Chem. Commun. 1996, 1699-1700. Babler, J. H.; Liptak, V.
P.; Phan, N. J. Org. Chem. 1996, 61, 416-417. Nilsson, B. M.; Hacksell,
U. J. Heterocycl. Chem. 1989, 26, 269-275. Hayashi, M.; Inubushi, A.;
Mukaiyama, T. Chem. Lett. 1987, 1975-1978. Tan, L.; Chen, C.-y.; Tillyer,
R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. 1999, 38,
711-713.
In most cases, the propargylic N-hydroxylamines are
obtained pure after a simple washing of the crude material
in pentane. Contamination by a product that would be issued
from addition of an ethyl moiety1 onto the nitrone is never
observed (1H NMR). Carreira et al.13 observed that the
products are prone to cyclization to form 2,3-dihydroisox-
azoles. In our conditions, this side product remains beyond
NMR detection after workup. A curious exception is
observed when a tert-butyl substituent is on the nitrogen
atom: the reaction of C and 8 leads to complete cyclization
(8) Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.; Maruoka, K. Tetra-
hedron 2001, 57, 867-873. Ooi, T.; Takaya, K.; Miura, T.; Maruoka, K.
Synlett 2000, 69-70. Ooi, T.; Miura, T.; Maruoka, K. J. Am. Chem. Soc.
1998, 120, 10790-10791.
(9) Frantz, D. E.; Faessler, R.; Tomooka, C. S.; Carreira, E. M. Acc.
Chem. Res. 2000, 33, 373-381.
(10) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-
9688. Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org.
Lett. 2000, 2, 4233-4236. El-Sayed, E.; Anand, N. K.; Carreira, E. M.
Org. Lett. 2001, 3, 3017-3020. Frantz, D. E.; Faessler, R.; Carreira, E. M.
J. Am. Chem. Soc. 2000, 122, 1806-1807. Sasaki, H.; Boyall, D.; Carreira,
E. M. HelV. Chim. Acta 2001, 84, 964-971. Frantz, D. E.; Faessler, R.;
Carreira, E. M. Chemtracts 2000, 13, 427-430.
(11) Frantz, D. E.; Faessler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245-11246.
(12) 1-Hexyne has to be used in excess only because of its high volatility;
for all other alkynes, we used 1.3 equiv.
(13) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2,
2331-2333.
1464
Org. Lett., Vol. 4, No. 9, 2002

ppm.15 On addition of 160 µmol of alkyne 10, this signal
does not shift, but its intensity immediately decreases 16%
(loss of 25 µmol dimethylzinc). Comparison of the integral
of the acetylenic proton (1.92 ppm) and the integrals of other
signals of the alkyne show an apparent lack of terminal H
(33%, ∼60 µmol H). The remainder of the dimethylzinc is
then very slowly consumed (more than 6 h for completion).
Our best explanation is that the first rapid incomplete reaction
is assisted by some impurity (moisture?) that is present at
the start but is rapidly consumed. Then, the observation of
a single set of signals hints for a rapid exchange of the
acetylenic protons, as already proposed by others.9
When increasing amounts of nitrone A are added to a
solution of dimethylzinc in d8-toluene, nucleophilic addition
is not observed after 15 min. The intensity of the methyl
signal does not change, but a downfield shift is observed
for both the methylzinc signal and the nitrone benzylic
methylene (0.2 and 0.1 ppm, respectively)
Another reaction was run with a 1.8:1:0.1 ratio of alkyne
10, nitrone A, and dimethylzinc in d8-toluene. On addition
of the alkyne to the dimethylzinc solution at 23 °C, the
dimethylzinc signal decreases by 40%, without shift. The
acetylenic H is at 1.98 ppm. On addition of the nitrone, the
dimethylzinc signal disappears within 2 min, and the
acetylenic H shifts to 2.10 ppm. Such a shift again indicates
that a rapid exchange of the corresponding proton is taking
place. The reaction proceeds slowly (12% after 1 h). As the
amount of product increases, the basicity of the medium
changes. Remarkably, this causes not only shifts of the
acetylenic H resonance (from 2.10 to 2.01 ppm) but also of
the nitrone signals (benzylic singlet of A, from 4.58 to 4.43
ppm).
Figure 2. Cyclization of the primary adduct of a N-tert-butyl-
nitrone.
after 19 h (Figure 2). In the case of N-aryl-hydroxylamines,
we observed that the product is particularly unstable, even
after purification. Although the nitrone B is fully consumed,
isolated yields of products B1, B4, and B5 are lower.
In the case of the tert-butyl propiolate (run A11), the
reaction is very sluggish; the transformation of the nitrone
cannot be completed, and the expected hydroxylamine A11
is contaminated with side products (in variable propor-
1
tions) that we suppose (on H NMR basis) to be 2-benzyl-
3-phenyl-2,3-dihydro-isoxazole-5-carboxylic acid tert-butyl
ester (issued from cyclization of A11) and its isomer
2-benzyl-3-phenyl-2,3-dihydro-isoxazole-4-carboxylic acid
tert-butyl ester (issued from thermal 1,3-dipolar cyclo-
addition).
The propargylic N-hydroxylamines can be easily reduced5
to provide the expected N-propargylamines in good yields,
as shown in Figure 3.
Finally, the fate of dimethylzinc was more closely exami-
nated. A mixture of 200 µmol of dimethylzinc and 290 µmol
of alkyne 10 shows a methyl signal at -0.71 ppm. On
addition of 200 µmol of nitrone A, it shifts to -0.60 ppm
and broadens. Then, all three reagents are consumed in about
1 h, and noticeably, the methylzinc and nitrone signals
decrease in the same proportions (Figure 4). At this stage,
Figure 3. Reduction of the hydroxylamines.
Thus, the conditions are compatible with a large array of
functional groups. Versatile acetylenic moieties, including
propargylic ethers, acetates, and acetals, can be introduced.
The addition of trimethylsilylacetylene (A6) followed by
desilylation,14 provides an easy way to the formal addition
of acetylene.
Discussion of the Mechanism. To get insight into the
mechanism, we first checked that in our conditions zinc
triflate alone does not catalyze the reaction (20 °C, 24 h, no
reaction). It could also be supposed that the hydroxylamine
produced in the reaction could replace the tertiary amine used
in Carreira’s system. However, a mixture of alkyne 1, nitrone
A, zinc triflate (0.2 mole equiv) and 0.2 mole equiv of
product A1 (from a previous run) does not show any change
in toluene at 20 °C for 24 h.
The reactions were then followed by NMR in d8-toluene.
Dimethylzinc was used instead of diethylzinc. A solution of
80 µmol of dimethylzinc shows a sharp singlet at -0.75
Figure 4. Plot of amounts/time in a NMR-tube experiment.
(14) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319-4321.
Org. Lett., Vol. 4, No. 9, 2002
1465

between the zinc salts of A10 and alkyne 10 is effective.
After 10 min, nitrone A (200 µmol) is added again; it is
consumed with a concomitant formation of free product A10.
Finally, the solution is treated with 0.2 mL of d4-methanol.
The broad bands disappear, and the amount of product A10
significantly rises.
Scheme 1. Postulated Mechanism16
From these observations, some hypotheses can be gathered
as shown in Scheme 1. In an initiation step, a MeZn-A10
specie (III) would be formed by the reaction of some
alkynyl-methylzinc (I) with A. Alternatively, the dimethyl-
zinc-nitrone complex could be a better metallation agent
than dimethylzinc and would produce IV, which would give
III. III would react with the alkyne to form VI or with free
hydroxylamine VII to give V. Then the reaction would
proceed through the bottom cycle.
Thus, the present work presents a very mild, high-yielding,
clean, and chemoselective access to secondary propargylic
N-hydroxylamines and amines, which is of obvious interest
in synthesis. Further studies about a possible autocatalysis
and its implications in asymmetric versions are currently
underway.
Supporting Information Available: Experimental pro-
cedures, descriptions of spectra of nitrones B and D, and all
adducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
the free hydroxylamine product A10 is not observed. Instead,
several very broad bands grow (1-1.4, 3.9-4.8, 7.1-7.8
ppm), which we attribute to oligomeric zinc salts of A10.
After completion of this first step, more (460 µmol) alkyne
10 is added. Immediately, the presence of free hydroxylamine
A10 is observed. This proves that an acido-basic reaction
OL025618N
(15) Substituents are omitted for clarity
(16) De Koning, A. J.; Van Rijn, P. E.; Boersma, J.; Van der Kerk, G.
J. M. J. Organomet. Chem. 1979, 174, 129-140.
1466
Org. Lett., Vol. 4, No. 9, 2002