Effect of microwave heating in the asymmetric addition of dimethylzinc to aldehydes

Article abstract of DOI:10.1016/j.jorganchem.2008.03.003

Microwave-heated enantioselective additions of dimethylzinc to various aldehydes are reported. Dramatically reduced reaction times and lower catalyst loadings (5%), compared with conventionally used conditions, can be achieved, with excellent yields and just small loss of enantioselectivity (up to 83% enantioselectivity is achieved). In the reaction with aliphatic aldehydes the same enantioselectivity has been achieved for microwave-heated and conventional room temperature conditions.

Full text of DOI:10.1016/j.jorganchem.2008.03.003

Journal of Organometallic Chemistry 693 (2008) 2017–2020
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Effect of microwave heating in the asymmetric addition of dimethylzinc
to aldehydes
*
Miroslav Genov, Gorka Salas, Pablo Espinet
IU CINQUIMA/Química Inorgánica, Facultad de Ciencias, Universidad de Valladolid, 47071 Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-heated enantioselective additions of dimethylzinc to various aldehydes are reported. Dramat-
ically reduced reaction times and lower catalyst loadings (5%), compared with conventionally used con-
ditions, can be achieved, with excellent yields and just small loss of enantioselectivity (up to 83%
enantioselectivity is achieved). In the reaction with aliphatic aldehydes the same enantioselectivity has
been achieved for microwave-heated and conventional room temperature conditions.
Ó 2008 Elsevier B.V. All rights reserved.
Received 13 February 2008
Received in revised form 3 March 2008
Accepted 3 March 2008
Available online 10 March 2008
Keywords:
Addition reactions
Asymmetric synthesis
Aminoalcohols
Microwave
Zinc
1. Introduction
Microwave irradiation has become recently a possibility for
improving reaction yields and shortening the reaction times
The asymmetric addition of dialkylzinc compounds to alde-
hydes is today one of the most powerful methodologies to access
to optically active secondary alcohols, which are important struc-
tural fragments of many natural products and drug compounds
[1–3]. Since the initial report of Oguni and Omi in 1983 on the
reaction of diethylzinc with benzaldehyde, with 49% enantioselec-
tivity [4], and the synthetic breakthrough of Noyori and coworkers
raising the enantioselectivity to 95% (using (À)-3-exo-dimethyla-
minoisoborneol as ligand) [5], the research on asymmetric organo-
zinc additions to carbonyl compounds has continued receiving
attention [6]. In spite of that, there are only very few examples
reporting highly enantioselective asymmetric additions of dialkyl-
zincs to aldehydes proceeding rapidly (20–30 min) [7,8]. Most of
the published cases require longer reaction times, ranging from
several hours to several days [1,9–11]. There are two main ap-
proaches to catalyze the reactions of benzaldehyde with diethyl-
zinc and dimethylzinc:1,6 by chiral aminoalcohols, and by chiral
diols in combination with Ti(O-iPr)4. The second approach seems
to be less efficient, according to the higher catalyst loadings. Partic-
ularly slow and difficult are the reactions with the less reactive
dimethylzinc. Therefore, methods to accelerate these reactions
should be very welcome, provided that a sensible compromise
between reaction rate, yield and enantioselectivity can be reached.
[12,13]. Possibly due to the concern that higher reaction tempera-
tures typically lead to reduced enantioselectivities, there are com-
paratively few reports in the literature involving microwave-
heated asymmetric reactions [14–17]. Amongst them, we have re-
ported recently the successful application of microwave heating to
asymmetric Pd-catalyzed Suzuki and Negishi reactions [18].
In the lack of precedents of application of microwave irradiation
to the enantioselective asymmetric additions of dialkylzincs to
aldehydes, we decided to study the reaction system with the slug-
gish Me2Zn at higher temperatures induced by a microwave reac-
tor, and compare them with reference reactions with conventional
methods, in order to check whether the reactions could be acceler-
ated at a reasonable enantioselectivity cost. Due to the very much
lower reactivity of Me2Zn compared to its higher homologues the
development of efficient methodologies for addition of a methyl
group to a carbonyl group in short times still remains a challenge.
2. Results and discussion
The synthetic procedure chosen to study representative reac-
tions under microwave heating was the chiral aminoalcohol-cata-
lyzed version (Scheme 1), which is usually more efficient. As chiral
catalysts we selected the easily available aminoalcohols 1 and 2.
Both have been reported to give excellent enantioselectivities
although in different reaction times. The a-
noalcohol 2-O-isopropylidene-5-deoxy-5-morpholino-a-
uranose (1) was synthesized according to the literature
D
-xylose derived c-ami-
D-xylof-
* Corresponding author.
E-mail address: espinet@qi.uva.es (P. Espinet).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.03.003

2018
M. Genov et al. / Journal of Organometallic Chemistry 693 (2008) 2017–2020
benzaldehyde with dimethylzinc catalyzed by 1 or 2, along with
some conventional reactions for comparison. Hexane, toluene, or
mixtures of both, are known to give the best results in conven-
tional conditions. Thus, the reactions were carried out in toluene
with 0.5 mmol/ml concentration of PhCHO, or in a hexane/toluene
mixture with 0.2 mmol/ml of PhCHO, using a twofold excess of
Me2Zn, at 75 °C. In all the reactions the formation of reduction
byproduct 5 was insignificant.
For the slow ligand 1, the conventional reaction with benzalde-
hyde 3a at room temperature catalyzed by 1 (10 mol%) gives, after
1 week, the product 4a in 98% yield and 87% ee (Table 1, entry 1).
Using ligand 1 in 10 mol% and 20 min irradiation time resulted in a
considerable drop in yield (55%) but with a reasonable enantio-
meric excess (83%) (Table 1, entry 2). Increasing the reaction time
to 1 h improved the yield to 75% without loss of enantioselectivity
(Table 1, entry 3). The 2 h reaction resulted in further improved
yield of 88%, still with 82% ee (Table 1, entry 4). Finally, for 5 h irra-
diation time nearly quantitative yield of 5 was reached with 82%
enantiomeric excess (Table 1, entry 5). Thus, although there is a
reduction of ee from 87% to 82%, the reaction time is dramatically
shortened in a ratio 33:1, which may be a reasonable trade-off for
particularly difficult reagents.
For the catalysis with ligand 2 at low temperature, the results
by Pericàs and coworkers producing 4a in 87% yield and 94% ee
in 24 h, in hexanes/toluene at 0 °C, are almost unbeatable [8,22].
Aimed at testing the microwave-heating methodology we carried
out conventional room temperature reactions in 1 h, to compare
them with the microwave results in the same time at moderate
temperature (75 °C) (Table 1, entries 6–19). In some preliminary
tests with benzaldehyde (3a), we noted that the use of only toluene
as solvent improved the yields compared to the use of hexanes/tol-
uene, so the reactions were made in toluene.
2
p
m
p
n
6
4
Scheme 1.
procedure [19]. It has been shown to be a very efficient catalyst for
the reaction of diethyl- and diisopropylzinc with benzaldehyde
(reaction times in the range 10–16 h) [20,21]. The commercially
available b-aminoalcohol 2-piperidino-1,1,2-triphenylethanol (2)
also provides excellent enantioselectivity in the reactions of benz-
aldehyde with diethyl- and dimethylzinc [8,22].
In order to compare the performance under microwave heated
reactions with the original conventional low temperature reactions
reported by Cho and Kim, and Pericàs and coworkers, respectively,
reactions were carried out setting the other reaction conditions
(concentration, solvent amounts and catalyst loadings) exactly
according to the original reports [8,20–22]. Moreover, we repro-
duced some reported reactions in order to make sure that our
experimental handling matched the reported work, and also to ob-
tain reference values for unreported reagent concentrations used
in our Mw experiments. The active intermediate (presumably a
complex of Me2Zn with 1 or 2) was formed in situ by mixing the
corresponding amount of Me2Zn and 1 or 2, and stirring for
30 min at room temperature. Then, the aldehyde was added and
the reaction was irradiated for the time specified in Table 1, which
summarizes the results of the microwave-heated reactions of
The conventional room temperature reaction of benzaldehyde
(3a) (Table 1, entry 6) gave only 39% yield and 90% ee in 1 h in tol-
uene. Under 75 °C microwave heating the reaction delivered the
product in 98% yield and 82% ee (Table 1, entry 7). The conven-
tional oil bath heated reaction at 75 °C for 1 h produced 4a with
94% yield and 82% ee (Table 1, entry 8). This result clearly indicates
that the acceleration observed is a matter of the higher tempera-
ture and not of any special non-thermal microwave effect. The
Table 1
Enantioselective addition of Me2Zn to aldehydesa
Entry
Aldehyde 3b
Ligand (mol%)
Time
Temperature (°C)
Product yield 4c (%)
Reduction product 5 (%)
Ee (%)d
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
2 (10)
2 (10)
2 (10)
2 (5)
2 (10)
2 (5)
2 (10)
2 (5)
2 (10)
2 (5)
2 (10)
2 (5)
2 (10)
2 (5)
7 days
20 min
1 h
2 h
5 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
r.t.
75
75
75
75
r.t.
75
98 (4a)
55 (4a)
75 (4a)
88 (4a)
97 (4a)
39 (4a)
98 (4a)
94 (4a)
95 (4a)
36 (4b)
82 (4b)
45 (4c)
89 (4c)
55 (4d)
82 (4d)
55 (4e)
96 (4e)
62 (4f)
93 (4f)
1
1
87 (R)
83 (R)
83 (R)
82 (R)
82 (R)
90 (S)
81 (S)
82 (S)
80 (S)
90 (S)
81 (S)
90 (S)
80 (S)
89 (S)
80 (S)
75 (S)
66 (S)
65 (S)
65 (S)
1
1
61
61
Traces
0.7
1.3
75 (oil bath)
9
75
r.t.
75
r.t.
75
r.t.
75
r.t.
75
r.t.
75
10
11
12
13
14
15
16
17
18
19
0.5
1.6
1 h
1 h
1
1.5
3f
a
Ratio aldehyde: Me2Zn = 1:2. Reactions carried out in toluene.
Concentrations: 1 mmol aldehyde in 2 ml of solvent.
Determined by GC analysis.
b
c
d
Determined by GC analysis of the product or of its acetate for 4f.

M. Genov et al. / Journal of Organometallic Chemistry 693 (2008) 2017–2020
2019
somewhat lower yield (94%) of the classic heating compared to the
microwave heating (Table 1, entry 7) could be explained with the
higher efficiency and the ‘‘bulk heating” ability of the microwaves
[23]. It is very important to note that reducing the catalyst loading
of 2 to 5% still produced 4a in 95% yield and 80% ee in 1 h (Table 1,
entry 9), while the corresponding room temperature reactions al-
ways required 10 mol% of catalyst in order to achieve the maxi-
mum product yield of 4a. At the same time the reduction of the
catalyst loading from 10 to 5 mol% never caused a drop of enanti-
oselectivity in our reactions. Obviously, the gain in shortening the
time to get a high yield of the reaction is to be weighed against the
reduction in selectivity, but still high ee’s are obtained an the pro-
cedure can be synthetically interesting in particular cases.
In view of the high efficiency achieved with 2 for Me2Zn addi-
tion we decided to study the microwave heated reaction with other
aldehydes (3b–f). In order to better illustrate the microwave accel-
eration effect we report the reaction results achieved in 1 h at
room temperature with 10% ligand, compared with the results ob-
tained in 1 h at 75 °C with only 5% ligand. It should be noted that,
in all the cases with the ligand 2 reported in the literature at room
temperature, to obtain reaction yields comparable to the values re-
ported here under microwave heating in 1 h, 24 h or higher reac-
tion times are required.
The room temperature reaction of 4-methylbenzaldehyde (3b)
(Table 1, entry 10) resulted in 36% yield and 90% ee in 1 h with
10 mol% of 2. Under microwave heating at 75 °C the desired prod-
uct was obtained in 82% yield and 81% ee (Table 1, entry 11) but
with only 5 mol% of the catalyst. With 3-methylbenzaldehyde
(3c) we obtained similar results: The conventional reaction gives
after 1 h 4c in only 45% yield and 90% ee (Table 1, entry 12) while
the microwave version with 5 mol% of 2 for the same time results
in 89% product yield and 80% ee (Table 1, entry 13).
The same trend has been demonstrated with the next two alde-
hydes, 4-chlorobenzaldehyde (3d) (Table 1, entry 14 vs. entry 15)
and cinnamaldehyde (3e) (Table 1, entry 16 vs. entry 17). Gener-
ally, in all these cases the enantioselectivity decreases no more
than 10% while reaction rate increases dramatically.
tanal 3f remains intact compared with the room temperature
version.
Additionally, it is worth noting that microwave-heated reac-
tions can be very useful, even in cases when the enantioselectivity
achieved was nor satisfactory, for rapid screening to find out reac-
tion conditions for slow reactions. In effect our results suggest that,
once the results of the microwave screening are available, moder-
ate (5–10%) but not extraordinary improvement in enantioselectiv-
ity should be expected in general for reactions carried out in
slower, non-irradiated conditions.
4. Experimental
All reactions were carried out under dry Ar. Hexanes and tolu-
ene were dried over sodium and distilled prior to use. Dimethyl-
zinc (2 M in toluene) were purchased from Aldrich. Analytical gas
chromatography was performed on a Hewlett Packard 5890 Series
II machine equipped with a CHIRASIL-DEX CB (25 m  0.25 mm Â
0.25 mm) capillary column. Microwave-promoted experiments
were carried out with a CEM Discover 300W single mode micro-
wave instrument, with simultaneous cooling with compressed
air. The reaction mixtures were prepared under dry Ar in 10 ml
special glass reaction tubes with self-sealing septa that control
the pressure with a pressure sensor on top of the vial. The temper-
ature was monitored through a non-contact infrared sensor cen-
trally located beneath the cavity floor. Magnetic stirring was
provided to ensure complete mixing of the reaction mixture. The
power applied was 300 W with a ramp time of 1 min.
4.1. General procedure for Me2Zn addition reaction at room
temperature (Table 1)
In a dry 50 ml Schlenk flask with a Young’s tap and Teflon stir-
ring bar was introduced the corresponding amount of 1 or 2 and
dissolved in 1 ml of toluene. At room temperature, 1 ml of a 2 M
toluene solution of Me2Zn was added. After stirring for 30 min at
room temperature, 1 mmol of the corresponding aldehyde 3 was
added and the reaction mixture. After 1 h stirring at room temper-
ature the mixture was carefully hydrolyzed with saturated NH4Cl
solution, extracted with Et2O, filtered trough a short pad of silica
and analyzed with GC.
The microwave acceleration of the addition of Me2Zn catalysed
by 2 was examined also with an aliphatic substrate. 1-Heptanal 3f
was chosen as a representative of linear chain aldehydes. The stan-
dard room temperature reaction gave the product 4f in 62% yield
and 65% ee (Table 1, entry 18), while somewhat more satisfactory
conversion of 85% yield and 65% ee took 36 h at room temperature
[22]. Remarkably our microwave-accelerated reaction afforded 4f
in 93% yield without any loss of enantioselectivity (65%) (Table 1,
entry 19) compared to the reference reaction. In this case the
microwave conditions are by all means better than the room
temperature conditions. This result may be of importance for
further optimization of organozinc addition reactions to aliphatic
aldehydes.
4.2. General procedure for Me2Zn addition reactions under microwave
heating (Table 1)
The corresponding amount of 1 or 2 was dissolved in 1 ml of tol-
uene. At room temperature, 1 ml of a 2 M toluene solution of
Me2Zn was added. After stirring for 30 min at room temperature,
1 mmol of the corresponding aldehyde 3 was added and the reac-
tion vessel was sealed and irradiated at the corresponding temper-
ature and for the time indicated in Table 1. After cooling down the
mixture was carefully hydrolyzed with saturated NH4Cl solution,
extracted with Et2O, filtered trough a short pad of silica and ana-
lyzed with GC.
In the case of 4f, the crude dry reaction mixture was redissolved
in Et3N and then 100 ml of acetyl chloride were added carefully.
The mixture was then extracted with diethyl ether, dried, filtered,
and analyzed by GC.
3. Conclusions
In summary, we have performed microwave-assisted additions
of Me2Zn to various aldehydes catalyzed by aminoalcohols and
have shown that the reactions can be carried out with considerable
retention of stereoselectivity in the process, provided that the tem-
peratures are moderate. Obviously this saving of time should be
particularly interesting for the slow reagent (Me2Zn) or for slow li-
gands (such as 1). In these cases the use of microwave for perform-
ing the enantioselective addition of Me2Zn to aldehydes is to be
considered as a serious alternative. Moreover, it was possible to re-
duce the ligand loading from 10 mol% to 5 mol% while preserving a
high reaction rate and a good enantioselectivity. Remarkably, the
enantioselectivity of the reaction with aliphatic aldehydes as hep-
4.3. Chiral gas chromatography
For 4d: isotherm at 120 °C. For all other: 15 min at 100 °C, then
at 120 °C with a ramp of 10 °C/min.

2020
M. Genov et al. / Journal of Organometallic Chemistry 693 (2008) 2017–2020
[4] N. Oguni, T. Omi, Y. Yamamoto, A. Nakamura, Chem. Lett. (1983) 841.
Retention times:
[5] M. Kitamura, S. Suga, K. Kawai, R. Noyori, J. Am. Chem. Soc. 108 (1986)
6071.
[6] V. Dimitrov, K. Kostova, Lett. Org. Chem. 3 (2006) 39. and references cited
herein.
[7] M. Ishizaki, K. Fujita, M. Shimamoto, O. Hoshino, Tetrahedron: Asymmetry 5
(1994) 411.
[8] L. Solà, K. Reddy, A. Vidal-Ferran, A. Moyano, M. Pericàs, A. Riera, A. Alvarez-
Larena, J.-F. Piniella, J. Org. Chem. 63 (1998) 7078.
[9] For example E. Rijnberg, J.T.B.H. Jastrzebski, M.D. Janssen, J. Boersma, G. van
Koten, Tetrahedron Lett. 35 (1994) 6521.
[10] For example E. Rijnberg, N.J. Hovestad, A.W. Kleij, J.T.B.H. Jastrzebski, J.
Boersma, M.D. Janssen, A.L. Spek, G. van Koten, Organometallics 16 (1997)
2847.
3a: tr = 5.5 min; (R)-4a: tr = 18.6 min, (S)-4a: tr = 19.8 min; 5a:
tr = 18.2 min.
3b: tr = 9.9 min; (+)-4b: tr = 22.6 min, (À)-4b: tr = 24.1 min; 5b:
tr = 21.6 min.
3c: tr = 9.4 min; (+)-4c: tr = 24.5 min, (À)-4c: tr = 25.4 min; 5c:
tr = 23.9 min.
3d: tr = 7.1 min; (+)-4d: tr = 30.5 min, (À)-4d: tr = 34.8 min; 5d:
tr = 27.6 min.
3e: tr = 27.2 min; (+)-4e: tr = 39.5 min, (À)-4e: tr = 40.0 min; 5e:
tr = 40.5 min.
[11] For example M. Genov, V. Dimitrov, V. Ivanova, Tetrahedron: Asymmetry 8
(1997) 3703.
3f: tr = 3.6 min; 4f: tr = 8.0; acetylated (S)-4f: tr = 8.4 min; acet-
ylated (R)-4f: tr = 10.4 min; 5f: tr = 7.6 min.
[12] M. Larhed, C. Moberg, A. Hallberg, Acc. Chem. Res. 35 (2002) 717.
[13] O. Kappe, Angew. Chem. Int. Ed. 43 (2004) 6250. and references cited herein.
[14] Example for asymmetric allylic alkylations B. Trost, N. Andersen, J. Am. Chem.
Soc. 124 (2002) 14320.
The absolute configuration of the products was determined by
comparison of the sign of the optical rotation with the literature
data [24,25].
[15] Asymmetric Heck reaction P. Nilsson, H. Gold, M. Larhed, A. Hallberg, Synthesis
(2002) 1611.
[16] Asymmetric transfer hydrogenation S. Lutsenko, C. Moberg, Tetrahedron:
Asymmetry 12 (2001) 2529.
[17] Asymmetric transfer hydrogenation A. Bøgevig, I. Pastor, H. Adolfsson, Chem.
Acknowledgement
Eur. J. 10 (2004) 294.
[18] Asymmetric Suzuki and Negishi reactions M. Genov, A. Almor´ın, P. Espinet,
Tetrahedron: Asymmetry 18 (2007) 625.
[19] B. Cho, N. Kim, J. Chem. Soc., Perkin Trans. 1 (1996) 2901.
[20] B. Cho, N. Kim, Tetrahedron Lett. 35 (1994) 4115.
[21] B. Cho, W. Yang, Tetrahedron: Asymmetry 11 (2000) 2947.
[22] N. Garc´ıa-Delgado, M. Fontes, M. Pericàs, A. Riera, X. Verdaguer, Tetrahedron:
Asymmetry 15 (2004) 2085.
Projects CTQ2007-67411/BQU and INTECAT Consolider Ingenio
2010 (CSD2006-0003) from the Ministerio de Educación y Ciencia
are gratefully acknowledged.
References
[23] This basically means that the microwave heating is instantaneous and
homogeneous for all the sample, see Ref. [13].
[1] For a comprehensive review, see L. Pu, H.-B. Yu, Chem. Rev. 101 (2001) 757.
and references cited herein.
[24] G. Blay, I. Fernádez, V. Hernández-Olmos, A. Marco-Aleixandre, J.R. Pedro,
Tetrahedron: Asymmetry 16 (2005) 1953.
[2] K. Soai, S. Niwa, Chem. Rev. 92 (1992) 833.
[3] M. Yus, D.J. Ramón, Recent Res. Devel. Org. Chem. 6 (2002) 297.
[25] Y. Sokeirik, H. Mori, M. Omote, K. Sato, A. Tarui, I. Kumadaki, A. Ando, Org. Lett.
9 (2007) 1927.