Catalytic enantioselective addition of dialkylzinc reagents to N-acylpyridinium salts

Article abstract of DOI:10.1002/anie.200904981

(Chemical equation presented) A pinch of salt: The first catalytic addition of dialkylzinc reagents to N-acylpyridinium salts with good yields and excellent enantioselectivities uses a copper-(S)-L complex as the catalyst. The versatility of the method is

Full text of DOI:10.1002/anie.200904981

Angewandte
Chemie
DOI: 10.1002/anie.200904981
Asymmetric Catalysis
Catalytic Enantioselective Addition of Dialkylzinc Reagents to
N-Acylpyridinium Salts**
M. ꢀngeles Fernꢁndez-Ibꢁꢂez, Beatriz Maciꢁ, Maria Gabriella Pizzuti, Adriaan J. Minnaard,*
and Ben L. Feringa*
Table 1: Screening of copper salts, solvents, chloroformates, and ligands
for the addition of Et2Zn to N-acylpyridinium salts.[a]
Chiral, substituted piperidinones are key units in medicinal
chemistry and highly versatile intermediates in organic syn-
thesis.[1] A number of synthetic methodologies have been
developed to access these useful heterocyclic compounds.[2]
An important strategy for their construction is the direct
asymmetric addition of nucleophiles to N-acylpyridinium
salts. Although significant progress has been achieved in this
area,[3] most studies have focused on the use of chiral pyridine
substrates. Only two examples have been described for the
catalytic enantioselective nucleophilic addition to N-acylpyr-
idinium salts (using TMSCN[4] and alkynes[5] as nucleophiles).
To the best of our knowledge, there have been no reports on a
catalytic enantioselective addition of organometallic reagents
to N-acylpyridinium salts. Herein, we disclose the first highly
enantioselective addition of dialkylzinc reagents to N-acyl-
pyridinium salts using copper/phosphoramidite catalysts.
As summarized in Table 1, we initially studied the
reaction of 4-methoxypyridine with various chloroformates,
solvents, copper salts, and phosphoramidites (Figure 1). A
typical procedure consists of the reaction of 4-methoxypyr-
idine with the corresponding chloroformate (1 equiv) at
À788C for 30 minutes and subsequent addition of a solution
of freshly prepared catalyst, derived from the appropriate
copper salt and (S,R,R)-L1, and then addition of Et2Zn.
Under these conditions, using Cu(OTf)2, (S,R,R)-L1, and
benzyl chloroformate, several solvents were tested (Table 1,
entries 1–4). The reaction in THF gave the desired product
with 34% ee (Table 1, entry 4), and the screening of different
chloroformates (Table 1, entries 5–7) did not provide better
enantioselectivities. The use of phosphoramidite ligand (S,R)-
L2, which gives excellent results in the 1,4-addition of
dialkylzinc reagents to N-protected 2,3-dehydro-4-piperi-
dones,[6] led to an increase in the ee value to 59% (Table 1,
entry 8). We also studied the effect of the copper salt upon the
reaction, but lower enantioselectivities compared to those
obtained using Cu(OTf)2 were achieved in all the cases
Entry
R
Ligand Solvent Cu salt
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Me L1
Et
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
L1
L1
L1
L1
toluene Cu(OTf)2
30
30
26
26
25
18
25
n.d.
n.d.
8
12
5
34
5
10
0
59
46
40
55
29
74
41
CH2Cl2
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
L1
L1
L2
L2
L2
L2
L2
L3
L3
9
10
11
12
13
14[e]
CuBr·SMe2 n.d.
CuTC[d]
n.d.
n.d.
26
CuCN
Cu(OTf)2
Cu(OTf)2
20
[a] Reaction conditions: 4-Methoxypyridine (1 equiv, 0.12m), ClCO2Bn
(1 equiv), Cu(OTf)2 (5 mol%), L (10 mol%), R2Zn (2 equiv). [b] Overall
yield of isolated product from 4-methoxypyridine. [c] Determined by
=
HPLC analysis on a chiral stationary phase (Chiralpak AS). [d] CuTC
Copper(I) thiophene-2-carboxylate. [e] Reaction was carried out at
À458C. Bn=benzyl, THF=tetrahydrofuran, Tf=trifluoromethanesul-
fonyl, n.d.=not determined.
[*] Dr. M. ꢀ. Fernꢁndez-Ibꢁꢂez, Dr. B. Maciꢁ, Dr. M. G. Pizzuti,
Prof. Dr. A. J. Minnaard, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4296
Figure 1. Phosphoramidite ligands used in this study.
E-mail: a.j.minnaard@rug.nl
(Table 1, entries 9–12). The screening of more than 40 differ-
ent phosphoramidite ligands[7] concluded with ligand (S)-L3
being the most suitable in terms of enantioselectivity
(74% ee), despite the relatively low yield (Table 1,
entry 13). To improve the yield, the reaction was carried out
at À458C; however, a similar yield and lower enantioselec-
tivity (41% ee) were obtained (Table 1, entry 14).
b.l.feringa@rug.nl
[**] This research was financially supported by the Dutch Ministry of
Economic Affairs. M.A.F.-I. is grateful to the Spanish Ministry of
Education and Science for a postdoctoral fellowship. Dr. S. R.
Harutyunyan is thanked for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904981.
Angew. Chem. Int. Ed. 2009, 48, 9339 –9341
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9339

Communications
To check if the low yield was a result of problems in the
good yield (69%) and excellent enantioselectivity (95% ee)
(Table 2, entry 7).
formation of the N-acylpyridinium salt 1, we increased the
temperature to room temperature for the preparation of the
salt 1 . Much to our delight, under these reaction conditions,
the yield increased to 37% and the enantioselectivity
increased significantly to reach 89% ee (Table 2, entry 1).
To prove the synthetic utility of the method, different
dialkylzinc reagents were tested. Noncommercial dialkylzinc
reagents were prepared by using the new methodology
introduced by Cꢀtꢁ and Charette.[8] The addition of nBu2Zn
and (PhCH2CH2)2Zn gave the corresponding 2,3-dihydro-4-
pyridones 2e,f with good yields and excellent enantioselec-
tivities (Table 3, entries 2 and 3). In the case of the bulky
Table 2: Optimization of the addition of Et2Zn to N-acylpyridinium
salts.[a]
Table 3: Addition of R2Zn to N-acylpyridinium salts.[a]
Entry
Equiv of ClCO2Bn
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
1.2
2
2
2
1.2
4
RT
RT
RT
RT
–
0.5
0.5
4
37
37
34
0
16
45
69
89
90
81
–
66
89
95
Entry
R
Product[b]
Yield [%][c]
ee [%][d]
1
2
3
4
Et
Bu
CH2CH2Ph
iPr
2a
2e
2 f
2g
69
63
50
65
95 (À)
93 (À)
97 (À)
56 (À)
4[d]
5[e]
6
4
0
0
0.5
0.5
7[f]
4
[a] Reaction conditions: 4-Methoxypyridine (1 equiv, 0.08m), ClCO2Bn
(4 equiv), Cu(OTf)2 (5 mol%), L3 (10 mol%), R2Zn (2.5 equiv). [b] Abso-
lute configuration was deduced by analogy to the literature data for 2h
(see reference [11]). [c] Overall yield of isolated product from 4-
methoxypyridine. [d] Determined by HPLC analysis on a chiral stationary
phase. The sign in parentheses indicates the sign of the optical rotation
(see the Supporting Information for further details).
[a] Reaction conditions: 4-Methoxypyridine (1 equiv, 0.12m), ClCO2Bn
(x equiv), Cu(OTf)2 (5 mol%), L3 (10 mol%), R2Zn (2.5 equiv). [b] Over-
all yield of product isolated from 4-methoxypyridine. [c] Determined by
HPLC analysis on a chiral stationary phase (Chiralpak AS). [d] Slow
addition of Et2Zn. [e] ClCO2Bn was added after Et2Zn. [f] 1a was added
dropwise to the reaction mixture.
The use of two equivalents of benzyl chloroformate provided
similar results (Table 2, entry 2), but a longer reaction time
for the formation of the salt 1a gave a lower yield and
enantioselectivity, perhaps because of the instability of the
salt (Table 2, entry 3). Other experimental modifications,
such as the slow addition of Et2Zn to the reaction mixture
(Table 2, entry 4) or the addition of benzyl chloroformate as
the final reagent (Table 2, entry 5), gave no conversion and
lower enantioselectivity and yield, respectively.
iPr2Zn, the enantioselectivity of the product 2g was lower
(Table 3, entry 4), which was not entirely unexpected in view
of previous work.[9] The less reactive Me2Zn did not provide
the desired product at À788C or À558C, and starting material
was recovered.[10]
To additionally demonstrate the synthetic potential of this
new methodology, the formal synthesis of the alkaloid (À)-
coniine is presented (Scheme 1). The addition of the non-
In the reaction of 4-methoxypyridine with 1.2 equivalents
of benzyl chloroformate in THF, a white solid was formed (we
1
assumed this to be the salt 1a); nevertheless, the H NMR
analysis of the reaction mixture showed the presence of
approximately 50% of remaining 4-methoxypyridine. To shift
the equilibrium towards the formation of the salt, we tried
different additives (AgNO3, AgBF4, NaBPh4, MgBr2·OEt2,
etc.); however, lower yields and enantioselectivities were
obtained in all cases. In view of the stability of the salt 1a, we
decided to continue our studies using a reaction temperature
of 08C. When forming 1a at 08C with a larger excess of benzyl
chloroformate (4 equiv), a higher yield (45%) and the same
enantioselectivity (89% ee) were obtained (Table 2, entry 6).
Finally, we observed that if we inverted the order of addition
of the reagents, adding a solution of the preformed salt 1a
(prepared at 08C by mixing 4-methoxypyridine with 4 equiv-
alents of benzyl chloroformate in THF and stirring 30 min)
dropwise into the reaction mixture comprising the catalyst
and Et2Zn at À788C, the desired product was obtained with
Scheme 1. Formal synthesis of (R)-coniine.
commercially available reagent nPr2Zn provided 2h with
good yield and high enantioselectivity. In the previous
reported synthesis of (R)-coniine, described by Comins and
co-workers, five steps are necessary to provide the inter-
mediate 2h.[11]
In conclusion, we have developed the first catalytic
enantioselective addition of dialkylzinc reagents to N-acyl-
pyridinium salts with good yields and excellent enantioselec-
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1729; For a catalytic enantioselective aza Diels–Alder reaction
tivities using a copper/phosphoramidite complex as the
catalyst. The versatility of the method to make advanced
chiral heterocyclic building blocks in a single step from 4-
methoxypyridine is illustrated in the formal synthesis of the
alkaloid (R)-coniine. Currently, efforts are directed towards
expanding the scope of this new asymmetric transformation
regarding the addition of functionalized dialkylzinc reagents.
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Experimental Section
Benzyl chloroformate (1 mmol) was added to a solution of 4-
methoxypyridine (0.25 mmol) in THF (1 mL) at 08C, and stirred for
30 min at the same temperature (solution A). A solution of the
catalyst, freshly prepared at room temperature from Cu(OTf)2
(0.0125 mmol, 5 mol%) and (S)-L3 (0.025 mmol, 10 mol%) in THF
(1 mL), was cooled down to À788C and the corresponding dialkylzinc
reagent (2.5 equiv) was added. Subsequently, solution A was added
dropwise to the reagent mixture (to collect all the salt 1a in the
syringe, the flask was washed twice with 2 portions of THF (0.5 mL)
each). The resulting mixture was stirred for 16 h at À788C, quenched
with aq. HCl (1m), and stirred for 10 min at room temperature. The
organic phase was separated, and the aqueous phase was extracted
with EtOAc (3 ꢂ 3 mL). The combined organic phases were dried
over MgSO4, and the solvent was removed under reduced pressure.
The crude product was purified by distillation and subsequent by flash
chromatography on silica gel (EtOAc/n-hexane 1:3) (see the Sup-
porting Information for further details).
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[7] For the formation of ligand libraries taking advantage of the
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Received: September 4, 2009
Published online: November 7, 2009
Keywords: asymmetric catalysis · copper · heterocycles ·
.
nucleophilic addition · phosphane ligands
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[10] The reaction with Me2Zn at À208C gave the desired product in
34% yield and 26% ee. In addition, preliminary experiments
with Ph2Zn did not provide the corresponding piperidone
probably because of solubility issues.
[11] R. S. Al-awar, S. P. Joseph, D. L. Comins, J. Org. Chem. 1993, 58,
7732 – 7739. The configuration of 2h has been assigned by
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