General method for the expedient synthesis of salt-free diorganozinc reagents using zinc methoxide

Article abstract of DOI:10.1021/ja710864p

The effect of counterions has a great impact on the solubility of magnesium salts in Et2O. By reacting Zn(OMe)2 with readily available Grignard reagents, it was possible to induce the complete precipitation of magnesium salts and then obtain salt-free dio

Full text of DOI:10.1021/ja710864p

Published on Web 02/12/2008
General Method for the Expedient Synthesis of Salt-Free Diorganozinc
Reagents Using Zinc Methoxide
Alexandre Coˆte´ and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, QC H3C 3J7 Canada
Received December 5, 2007; E-mail: andre.charette@umontreal.ca
Table 1. Zinc Salts Screening
Finding the right balance between reactivity and selectivity is
one of the greatest challenges in synthetic chemistry. In this context,
diorganozinc reagents have proven effective, particularly in asym-
metric catalysis.1 The first diorganozinc reagents were prepared over
a century ago.2 However, only recently has progress been made in
the synthesis of functionalized reagents, beginning with the seminal
work of Knochel and co-workers.3 Furthermore, a quick overview
of the literature clearly indicates that functionalized diorganozinc
reagents are underused in asymmetric catalysis, especially outside
academic laboratories. One possible explanation for this is that
current methods for preparing them are somewhat troublesome (eqs
1-3). One must deal with (1) the potential hazards caused by the
handling of highly pyrophoric chemicals and/or (2) the presence
of byproducts, which may be present in stoichiometric amounts
and be incompatible with catalytic reactions.4 Depending on the
synthetic method used, the main byproducts are salts,5 residual
organometallic species such as boranes,6 or simply an excess of
reagent. Although some diorganozinc compounds can be purified
by distillation or sublimation, the approach remains tedious and
limited to volatile and relatively non-functionalized compounds.
Herein we report an efficient, safe, and general method for preparing
diorganozinc reagents while eliminating byproducts.
yielda
(%)
eeb
(%)
entry
X
1
2
nonec
Cl
>95
51
>95
>95
95
0
27
0
0
0
3
F
4
CN
5
TfO
6
7
8
9
CO3
MeO
CF3CH2O
i-PrO
93
0
95
46
83
97
10
0
10
11
12
13
14
15
16
17
18
19d
20e
21e
CH3OCH2CH2O
CH3OCH2CH2OCH2CH2O
(CH3)2NCH2CH2O
n-C5H11O
Acac
AcO
BzO
CH2CH(CO)O
OCH2CH2O
MeO
88
65
78
97
88
2
45
44
94
57
45
59
41
55
97
27
89
0
R-Metal + ZnX2
98 R2Zn + Metal-X
(1)
(2)
(3)
R1-Metal + R2 Zn
9
8 R1 Zn + Metal-R2
21
>95
90
35
97
13
2
2
AcO
MeO
R1-X + R2 Zn
9
8 R1 Zn + R2-X
2
2
a NMR yields were determined using an internal standard. b Enantiomeric
excesses were determined by SFC on chiral stationary phase. c No zinc salt
was used. d EtMgBr (3.95 equiv) in Et2O was used. e EtMgCl (4.5 equiv)
was used.
Advantages such as the high reactivity of organomagnesium
reagents, their readily commercial availability, and their ease of
preparation and handling all justified our choice to employ them
as precursors for diorganozinc reagent synthesis.7 As well, recent
work from Knochel shows that Grignard reagents can tolerate many
functionalities.8 However, this approach inevitably leads to the
formation of undesired magnesium salts (eq 1). To overcome this
drawback, it is possible to add complexing agents, such as 1,4-
dioxane9 or 15-crown-5,10 in order to initiate their precipitation as
an insoluble complex, thereby eliminating the precipitate by
filtration or centrifugation. Yet, even if this method is compatible
with some catalytic systems,11 both the [R2Zn•dioxane] complex
produced and/or the excess of 1,4-dioxane required for this step
remain problematic in other cases.12
To avoid such excess of additive, we studied the effect of
counterions on the reactivity of zinc salts, and we hoped to control
the solubility of the magnesium salts so they could be removed by
filtration/centrifugation without the need to add any additive. Since
it is difficult to accurately quantify organometallic and inorganic
impurities remaining in diorganozinc solutions,13 we decided to
identify the optimal conditions by using the prepared R2Zn solution
in the catalytic enantioselective addition to imines.14 We chose a
reaction developed in our laboratories employing Me-BozPHOS,
which is known to be very sensitive to the presence of salts.
The results in Table 1 indicate that, when Et2Zn was prepared
from EtMgCl and ZnCl2 (entry 2), a decrease in reactivity and
enantioselectivity was observed. Even if the exact nature of the
interference is unknown, we established that species such as
halogenated ions, MgX2 and EtZnX, greatly altered the efficiency
of the reaction.4b,15 When zinc salts with counterions corresponding
to F-, CN-, OTf-, CO32-, and (OCH2CH2O)2- ions were used
(entries 3-6 and 18), the latter were too insoluble in Et2O to react.
Therefore, results clearly illustrated the uncatalyzed addition of
Grignard reagents to imines.
Although zinc alkoxides appeared to be visually insoluble (with
the exception of isopropoxide), they reacted with Grignard reagents
in an exothermic fashion (entries 7-13). However, the solubility
of the resulting magnesium salts greatly depended on the nature of
the alkoxide, but outstanding yields and enantioselectivities were
observed with zinc methoxide and methoxyethoxide.16 Zinc acetate
could also be used (entry 15), and it showed similar results as with
9
10.1021/ja710864p CCC: $40.75 © 2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 2771-2773
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C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Addition to Imines
Table 3. Catalytic Enantioselective Conjugated Addition
yielda
eeb
(%)
yielda
eeb
(%)
entry
R
(%)
entry
R
(%)
1
Et
95 (2)
90 (2)
96 (2)
57 (3)
96 (4)
73 (5)
98
98
98
95
96
97
2
Etc
Etd
i-Pr
1
Et
89 (8)
>98
>98
>98
94
2
Etc
88 (8)
3
3
Etd
i-Pr
n-Bu
i-Bu
86 (8)
4
4e
5
93 (9)
5
n-Bu
n-C10H21
6e
94 (10)
95 (11)
94 (12)
97 (13)
97 (14)
>95
6
97
7e
8
c-Hex
n-C10H21
PhCH2CH2
94
a Isolated yields. b Enantiomeric excesses were determined by SFC on
chiral stationary phase. c Zn(OMe)2 (2 equiv) was formed in situ from ZnCl2
(2 equiv) and NaOMe (4.2 equiv). d Neat Et2Zn was dissolved in Et2O.
e The reaction was run for 48 h.
>98
9
>98
a Isolated yield. b Enantiomeric excesses were determined by SFC on
chiral stationary phase or by 13C NMR spectroscopy after derivatization
with 1,2-diphenylethylenediamine. c Zn(OMe)2 (2 equiv) was formed in situ
from ZnCl2 (2 equiv) and NaOMe (4.2 equiv). d Neat R2Zn was dissolved
in Et2O. e Styrene (1 equiv) was added according to ref 22.
zinc methoxide or neat Et2Zn. Furthermore, zinc carboxylates were
usually less soluble and less reactive than alkoxides. When an excess
of Grignard reagent was used with Zn(OAc)2 specifically, the
reaction proceeded as well as with a stoichiometric quantity (entry
20). We believed that the carboxylate ions have the potential to
act as a scavenger for Grignard reagents used in excess. A more
detailed study led us to establish that there are reactivity issues
between Zn(OAc)2 and long alkyl chains. This prompted us to favor
Zn(OMe)2 for the rest of our investigation. The use of organomag-
nesium bromide was also tested, but it turned out to be problematic
under these conditions (entry 19). Since the insolubility of the
magnesium salts are strongly dependent on the solvent used,
Grignard reagents have to be consistently dissolved in Et2O, and
not in THF. Chlorinated Grignard reagents and Et2O were a crucial
combination when it comes to controlling salt precipitation.
Overall, our developed protocol is technically simple, easy, and
expedient. Filtration/centrifugation is a vital step in diorganozinc
reagents synthesis. Although similar results can be obtained using
either technique, each offers certain advantages. While centrifuga-
tion is quick and allows the simultaneous treatment of several
samples, filtration allows a better recovery of the solution and works
well on a large scale.
Table 4. Catalytic Enantioselective Addition to Aldehydes
yielda
(%)
eeb
(%)
entry
R
1
2
3
4
Et (16)
93
95
96
63e
98
98
97
97
Etc (16)
Etd (16)
n-C10H21 (17)
a Isolated yields. b Enantiomeric excesses were determined by SFC on
chiral stationary phase. c Zn(OMe)2 (2 equiv) was formed in situ from ZnCl2
(2 equiv) and NaOMe (4.2 equiv). d Neat Et2Zn was dissolved in Et2O.
e The low yield is explained by the formation of the reduction product.
catalytic addition to cyclohexenone21 also proceeded smoothly with
excellent reactivity. As the data indicate in Table 3, the synthesis
of dialkylzinc reagents from Zn(OMe)2 tolerated primary, second-
ary, branched, linear, or long chains.
Zn(OMe)2 is not commercially available and may be prepared
from Et2Zn and MeOH.17 An alternate convenient protocol was
developed to generate this salt in situ (eq 4) from ZnCl2 and
NaOMe.18 The resulting mixture19 can be used as a surrogate to
pure Zn(OMe)2 and is suitable for the diorganozinc reagent
preparation. Excess NaOMe, required for complete conversion of
ZnCl2, was removed along with the other salts during centrifugation
or filtration.13b,20
The addition to an aldehyde catalyzed with a chiral amino alcohol
(Table 4)23 also turned out to give high yields and enantiocontrol.
Due to the difficulty in forming aryl- or vinylmagnesium
chlorides in Et2O, we developed a modification to accommodate
arylmagnesium bromides by adding NaOMe to the reaction. Mg-
(OMe)2 and NaBr are then formed, which are insoluble in Et2O.24
This derived procedure gave comparable results to those obtained
with the Walsh method25 or with pure commercial reagents for the
addition of a phenyl group to 2-naphthaldehyde (Table 5, entries
1-3). Notably, this reaction is a good example of why an excess
of 1,4-dioxane can be detrimental to catalysis (entry 3). As well,
the synthesis of mixed diorganozinc reagents is very simple: two
different Grignard reagents must be added to Zn(OMe)2 (entry 4).26
Since a slight excess of Zn(OMe)2 is used in proportion to the
Grignard reagent, traces of RZnOMe still remain in the solution.
However, such species are known to generate a stable tetramer,27
which has little or no interaction with catalytic systems, as illustrated
The use of Zn(OMe)2, either preformed (from diethylzinc and
methanol) or generated in situ, produced excellent yields and
selectivities (Table 2, entries 1-3), comparable to those obtained
with neat Et2Zn. The addition of other alkyl chains also gave
excellent enantioselectivities (entries 4-6).
The dialkylzinc solutions prepared by this method were then
tested in other catalytic asymmetric reactions. The conjugated
9
2772 J. AM. CHEM. SOC. VOL. 130, NO. 9, 2008

C O M M U N I C A T I O N S
Table 5. Modification Using Brominated Grignard Reagents
(b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824. (c) Bercot, E. A.;
Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248-10249.
(2) Frankland, E. Liebigs Ann. Chem. 1849, 71, 171-213.
(3) (a) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188. (b)
Knochel, P.; Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F. In The
Chemistry of Organozinc Compounds; Rappoport, Z., Marek, I., Eds.;
Wiley: Chichester, 2006; pp 287-393. (c) Knochel, P.; Millot, N.;
Rodriguez, A.; Tucker, C. E. Org. React. 2001, 58, 417-731 and
references therein.
(4) (a) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull. Chem. Soc. Jpn
2000, 73, 999-1014. (b) Rudolph, J.; Lormann, M.; Bolm, C.; Dahmen,
S. AdV. Synth. Catal. 2005, 347, 1361-1368. (c) Jeon, S.-J.; Li, H.; Garc´ıa,
C.; LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70, 448-455.
(5) Even if MgCl2 and LiCl are hardly soluble in Et2O, they may affect
catalytic reactions. See ref 12.
yielda
eeb
(%)
entry
R
(%)
(6) (a) Boron residues significantly decreased yields when used in catalytic
addition to imines (unpublished results). (b) For an example of the
detrimental effect of boron residues on selectivities, see: Powell, N. A.;
Rychnovsky, S. D. J. Org. Chem. 1999, 64, 2026-2037.
(7) (a) Richey, H. G., Jr. Grignard Reagents: New DeVelopments; Wiley:
Chichester, 2000; p 418. (b) Wakefield, B. J. Organomagnesium Methods
in Organic Synthesis; Academic Press: London, 1995; p 249.
(8) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.;
Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302-4320 and references therein. (b) Vu, V. A.; Marek, I.; Polborn,
K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 351-352. (c)
Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333-
3336.
1
Ph
Ph
Ph
Et
90 (18)
98 (18)
63 (18)
96 (16)
92 (16)
70 (19)
98
98
93
98
98
98
2c,d
3c,e
4
5f
6
Et
TBDMSO(CH2)4
a Isolated yield. b Enantiomeric excesses were determined by SFC on
chiral stationary phase. c Mixed diorganozinc was used. d EtZnPh was
generated from Et2Zn (0.75 equiv) and Ph2Zn (0.75 equiv). e EtZnPh was
generated from EtMgBr (1.5 equiv), PhMgBr (1.45 equiv), ZnCl2 (1.5
equiv), and 1,4-dioxane (10.5 equiv) (see ref 11). f EtMgBr (3.3 equiv) was
used in combination with NaOMe (3.6 equiv) and NaOBz (0.6 equiv).
(9) (a) Schlenk, W.; Schlenk, W., Jr. Ber. Dtsch. Chem. Ges. B 1929, 62,
920-924. (b) Noller, C. R.; White, W. R. J. Am. Chem. Soc. 1937, 59,
1354-1359.
(10) (a) Pajerski, A. D.; Chubb, J. E.; Fabicon, R. M.; Richey, H. G., Jr. J.
Org. Chem. 2000, 65, 2231-2235. (b) Krasovskiy, A.; Straub, B. F.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 159-162.
herein.28 When necessary, the use of an excess of Grignard reagent
in combination with an insoluble and slow-to-react scavenger, such
as NaOBz,29 will eliminate the presence of organozinc alkoxide
(Table 5, entry 5).
Finally, these conditions were also applied to the addition to
â-nitrostyrene17 catalyzed with a copper•Me-BozPHOS complex
(eq 5).30
(11) (a) Seebach, D.; Behrendt, L.; Felix, D. Angew. Chem., Int. Ed. Engl.
1991, 30, 1008-1009. (b) von dem Bussche-Hu¨nnefeld, J. L.; Seebach,
D. Tetrahedron 1992, 48, 5719-5730.
(12) (a) Harutyunyan, S. R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.;
Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2006, 128, 9103-9118. (b) van der Worp, H. Ph.D. Thesis, University
of Groningen, The Netherlands, 1997, and references therein. (c) See Table
5, entry 5.
(13) The addition to a Grignard reagent on a zinc salt potentially generates
several organic, organometallic, and inorganic species, some of which
are actually in equilibrium with each other: (a) Guijarro, A. The Chemistry
of Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; Wiley:
Chichester, 2006; pp 193-236. (b) Fabicon, R. M.; Richey, H. G., Jr. J.
Chem. Soc., Dalton Trans. 2001, 783-788.
(14) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B. J. Am. Chem.
Soc. 2003, 125, 14260-14261.
(15) Goldsmith, P. J.; Teat, S. J.; Woodward, S. Angew. Chem., Int. Ed. 2005,
44, 2235-2237.
(16) As alkoxide chains became more hydrophobic, the solubility of magnesium
salts increased and, consequently, the catalysis was compromised.
(17) See Supporting Information for more details.
(18) (a) Shiner, V. J., Jr.; Beg, M. A. Inorg. Chem. 1975, 14, 157-158. (b)
Gut, R. HelV. Chim. Acta 1964, 47, 2262-2278.
In summary, we have exploited the weak solubility of magnesium
methoxide in order to synthesize diorganozinc reagents dissolved
in Et2O without undesired reaction byproducts. It represents an
attractive method to access both functionalized dialkylzinc and
diarylzinc reagents.31 Finally, the reagents produced show no change
in the efficiency of all tested asymmetric catalytic reactions in
comparison to purified reagents. The work presented herein is a
good complement to other methods since it focuses on asymmetric
catalysis and potentially improves the scope of already known
enantioselective reactions.
(19) The formation of a Na2[Zn2Cl2(OMe)4] or a [Zn2(Ome)3]Cl complex is
also possible. See ref 18.
(20) Kamienski, C. W.; Lewis, D. H. J. Org. Chem. 1965, 30, 3498-3504.
(21) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H.
M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2623.
(22) Li, K.; Alexakis, A. Angew. Chem., Int. Ed. 2006, 45, 7600-7603.
(23) Nugent, W. A. Chem. Commun. 1999, 1369-1370.
(24) (a) Kapoor, P. N.; Bhagi, A. K.; Sharma, H. K.; Kapoor, R. N. J.
Organomet. Chem. 1989, 369, 281-284. (b) Gupta, S.; Sharma, S.; Narula,
A. K. J. Organomet. Chem. 1993, 452, 1-4.
(25) Kim, J. G.; Walsh, P. J. Angew. Chem., Int. Ed. 2006, 45, 4175-4178.
(26) Dialkylzinc: (a) Lutz, C.; Jones, P.; Knochel, P. Synthesis 1999, 312-
316. (b) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.;
Reddy, C. K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1496-1498. (c)
Lipshutz, B. H.; Wood, M. R.; Tirado, R. J. Am. Chem. Soc. 1995, 117,
6126-6127. (d) Rimkus, A.; Sewald, N. Org. Lett. 2002, 4, 3289-3291.
Alkylalkenylzinc: (e) Dahmen, S.; Bra¨se, S. Org. Lett. 2001, 3, 4119-
4122. (f) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197-5200. (g)
Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729-1732.
Alkylarylzinc: (h) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K.
Angew. Chem., Int. Ed. 2000, 39, 3465-3467. Alkylakynylzinc: (i) Niwa,
S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937-943.
(27) The coordinate bonds of organozinc halide tetramers are weaker than those
of organozinc alkoxides.
Acknowledgment. This work was supported by NSERC
(Canada), Merck Frosst Canada Ltd., Boehringer Ingelheim (Canada)
Ltd., the Canada Research Chairs Program, the Canadian Founda-
tion for Innovation and the Universite´ de Montre´al. A.C. is grateful
to NSERC (ES D) for postgraduate fellowship, and to TD Bank
Financial Group.
(28) (a) Kitamura, M.; Okada, S.; Suga. S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028-4036. (b) Boersma, J.; Noltes, J. G. Tetrahedron Lett.
1966, 14, 1521-1525.
(29) In most cases, CH3CO2Na and CF3CO2Na also afford good results.
(30) Coˆte´, A.; Lindsay, V. N. G.; Charette, A. B. Org. Lett. 2007, 9, 85-87.
(31) Most methods to prepare highly functionalized Grignard reagents either
generate partially soluble salts and/or need salts as additive and/or use
complexing solvents. For any of these reasons, they are not compatible
with our new protocol to generate salt-free diorganozinc reagents.
Supporting Information Available: Additional results, tables,
experimental procedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
References
(1) (a) Soai, K.; Kawasaki, T. In The Chemistry of Organozinc Compounds;
Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, 2006; pp 555-593.
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