A one-pot asymmetric sequential animation-alkylation of aldehydes: Expedient synthesis of aliphatic chiral amines

Article abstract of DOI:10.1002/ejoc.200600781

A one-pot asymmetric sequential amination-alkylation method has been developed for the synthesis of alkyl-alkyl′ α-chiral primary amines (aliphatic primary amines with a chiral center adjacent to the nitrogen atom) from aldehydes. In situ aldimine formati

Full text of DOI:10.1002/ejoc.200600781

FULL PAPER
DOI: 10.1002/ejoc.200600781
A One-Pot Asymmetric Sequential Amination-Alkylation of Aldehydes:
Expedient Synthesis of Aliphatic Chiral Amines
Vijay N. Wakchaure,[a] Rashmi R. Mohanty,[a] Ahson J. Shaikh,[a] and Thomas C. Nugent*[a]
Keywords: Amines / Enantioenriched amines / In situ aldimine formation / Cuprates / (R)- or (S)-α-(methylbenzyl)amine
A
one-pot asymmetric sequential amination-alkylation
provides good yield (77–88%) and diastereomeric excess
(77–92%) for amines 2 or 5. To further demonstrate the use-
fulness of this method, several of the secondary amine prod-
ucts (2d, 2e, and 5) were hydrogenolyzed, providing the cor-
responding enantioenriched alkyl-alkylЈ α-chiral primary
amines 3d, 3e, and 6 (86–96% yield).
method has been developed for the synthesis of alkyl-alkylЈ
α-chiral primary amines (aliphatic primary amines with a chi-
ral center adjacent to the nitrogen atom) from aldehydes. In
situ aldimine formation from non-branched, α-branched, and
β-branched aliphatic aldehydes with (R)- or (S)-α-(meth-
ylbenzyl)amine [catalyzed by 5 mol-% Ti(OiPr)4] followed by
reaction with a methyl, ethyl, or n-butyl cuprate complex in
the presence of boron trifluoride or an allyl Grignard reagent
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
tion steps starting from aliphatic aldehydes. Highly dia-
stereoselective allyl anion additions to the chiral aldimines
of (R)-phenylglycine amide have been achieved by Kellogg,
Broxterman, and co-workers, again three reaction steps are
required from aldehydes to produce the primary amine.[12e]
More recently, the groups of Charette[8] and Hoveyda and
Snapper[9] have independently developed enantioselective
carbanion methods relying on in situ aldimine formation
(enantioselective sequential amination-alkylation of alde-
hydes), thus decreasing the number of reaction steps start-
ing from aliphatic aldehydes to two.
Introduction
α-Chiral amine moieties are found in agrochemicals, nat-
ural products, and pharmaceutical drugs.[1] Despite their
importance, asymmetric methods for their efficient synthe-
sis have only recently begun to appear. For the synthesis of
aliphatic amines, two main strategies have had significant
impact: one employing “hydrogen” chemistry (molecular
hydrogen,[2] transfer hydrogen,[3] hydrides,[4] or hydro-
silylation[5]) and another based on carbanion[6–12] chemis-
try. Comparison of the literature pertaining to these two
different approaches shows them to be generally comple-
mentary. For example, the carbanion methods are particu-
larly good for the synthesis of α-chiral amines with two
similarly sized aliphatic substituents at the α-chiral carbon
Results and Discussion
atom in high de or ee. Presently, this is not possible when Two-Step Strategy Leading to Aliphatic α-Chiral Primary
using the “hydrogen” based methods.
Amines
The aforementioned methods all rely on carbonyl com-
pounds and amine starting materials, but flexibility regard-
ing the amine is not possible yet.[13] Instead, specific sources
of nitrogen (e.g. tert-butanesulfinamide, α-(methylbenzyl)
amine, anisidine, and diphenylphosphinoylamide) are used
and the supporting amine functionality is removed during
the last step to provide an α-chiral aliphatic primary amine.
Regarding the carbanion approaches to alkyl-alkylЈ α-chiral
amines, the methods of Ellman[6] are precedent-setting, be-
cause they result in high overall yields and ee in three reac-
Noting the beneficial qualities of the aforementioned
methods, we developed an alternative approach by using
the chiral ammonia equivalents (R)- or (S)-α-(methylben-
zyl)amine (α-MBA) to achieve alkyl-alkylЈ α-chiral primary
amine synthesis in two reaction steps from aliphatic alde-
hydes (Scheme 1). The first step in this one-pot sequence is
the reaction of aliphatic aldehydes 1 with (R)- or (S)-α-
MBA in the presence of 5 mol-% Ti(OiPr)4 for 30 min at
room temperature. Addition of this mixture to a dialkyl
cuprate complex in the presence of boron trifluoride at
–78 °C provides α-chiral amines 2 as the major dia-
stereomeric products. Previous approaches based on α-
MBA[11] have always relied on forming and isolating the
corresponding (R)- or (S)-N-α-(methylbenzyl) aldimine be-
fore adding the carbanion. Our method reduces this two-
step procedure to a one-pot procedure. Finally, to show the
[a] Department of Chemistry, School of Engineering and Science,
International University Bremen,
Campus Ring 1, 28759 Bremen, Germany
Fax: +49-421-200-3229
E-mail: t.nugent@iu-bremen.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 959–964
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
959

V. N. Wakchaure, R. R. Mohanty, A. J. Shaikh, T. C. Nugent
FULL PAPER
full potential of this method, we removed the chiral auxil- MBA, and Ti(OiPr)4 (5 mol-%), prior to carbanion ad-
iary from amines 2 to obtain the enantioenriched α-chiral dition, showed the expected aldimine (Ͼ97 area%) before
primary amines 3 in high yield and unaffected ee.
30 min. After carbanion addition, Ͼ95 area% of 1a and
the corresponding aldimine was consumed. Failure to use
Ti(OiPr)4 resulted in significantly lower product yields
(compound 2a) due to unreacted starting materials and by-
product formation.
After establishing that in situ aldimine formation was
possible, the feasibility of efficient n-butyl carbanion ad-
dition had to be assessed. Addition to a Grignard reagent
(nBuMgCl) alone or in the presence of stoichiometric quan-
tities of a copper salt (CuI, CuBr, CuBr·SMe2, or CuCN)
[16]
Scheme 1. Two-step procedure for the synthesis of enantioenriched
aliphatic primary amines.
did not provide the desired amine product 2a (Table 1,
entries 1 and 3–6). The use of BF3·OEt2 has been previously
reported to improve the yield and diastereoselectivity of
cuprate additions.[11a,11c,17] Upon addition of the in situ
formed aldimine to nBuMgCl in the presence BF3·OEt2 and
a catalytic amount of CuBr, we clearly observed amine 2a
as the major product, but in low diastereoselectivity
(Table 1, entries 7 and 8).
Proof of Concept
To investigate the feasibility of a one-pot sequential am-
ination-alkylation reaction, we first had to establish that ali-
phatic aldehydes could be reliably and completely converted
to aldimines. Isovaleraldehyde (1a) was chosen for this pur-
The best results (yield and diastereoselectivity) were ob-
pose and was used as the limiting reagent (5 mmol). The tained when using nBuMgCl with stoichiometric amounts
chiral ammonia equivalents (R)- or (S)-α-MBA of CuBr, which was preferred over CuI, which, in turn, was
(1.05 equiv.) were chosen, because they offer flexibility in preferred over CuBr·SMe2 or CuCN (Table 1, compare en-
producing either enantiomeric series of the desired amine tries 11, 13, 16, and 17). For example, when CuI was the
product, are the least expensive amine auxiliaries available, source of copper, only 2.0 equiv. of cuprate was required,
and are routinely used in the pharmaceutical industry.[14] and amine 2a was obtained in 77% yield and 89% dia-
The choice of Ti(OiPr)4 to catalyze aldimine formation was stereoselectivity (Table 1, entry 16). Adding more than
based on our experience with its use for ketimine forma- 2.0 equiv. of a CuI based cuprate did not improve the yield
tion.[15] GC analysis of a mixture of aldehyde 1a, (S)-α- or de. Slightly improved results (85% yield and 90% dia-
Table 1. Reaction parameter optimization for the one-pot asymmetric sequential amination-alkylation of isovaleraldehyde.[a]
Entry Cu salt
nBuMgCl (equiv.)
nBuLi (equiv.)
BF3·OEt2 (equiv.)
Solvent
Yield (%)[b]
de (%)[c]
1
2
3
4
5
6
none
none
CuI
5
5
4
6
6
–
5
6
–
6
6
6
6
–
4
4
6
–
–
–
–
–
–
9
–
–
6
–
–
–
–
6
–
–
–
10
–
2
–
–
–
–
2
2
3
2
2
2
2
3
2
2
3
5
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
CH2Cl2
THF
THF
THF
Et2O
THF
THF
0
0
0
0
0
0
–
–
–
–
–
–
44
52
80
88
90
85
88
65
85
89
71
84
CuBr
CuBr·SMe2
CuCN
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr·SMe2
CuI
7[d]
8[e]
9[f]
10
11
12
13
14
15
16
17[f]
18
–
[g]
[g]
–
[g]
–
88
85
80
[g]
–
[g]
–
CuI
CuI
CuCN
CuCN
78
77
[g]
–
81
[a] Isovaleraldehyde (5.0 mmol, 1 equiv.), (S)-α-MBA (1.05 equiv.), Ti(OiPr)4 (5 mol-%), solvent (0.08–0.10 ). [b] Isolated yield of both
diastereomers after flash chromatography. [c] Determined by GC analysis; the major diastereomer is (S,S)-2a. [d] 5 mol-% CuBr was used.
[e] 25 mol-% CuBr was used. [f] 25% of the starting material remained unreacted (GC area%). [g] The isolated yield was not recorded,
because of the low de and/or the presence of unreacted starting material (Ͼ15% by GC).
960
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Eur. J. Org. Chem. 2007, 959–964

One-Pot Asymmetric Sequential Amination-Alkylation of Aldehydes
FULL PAPER
stereoselectivity) were observed when using CuBr, albeit Table 2. Scope of aliphatic aldehyde and carbanion substrates.[a]
3.0 equiv. of cuprate were required (Table 1, entry 11). As
we examined more aldehyde substrates, higher yields and
diastereoselectivity were observed for CuBr cuprates than
for CuI cuprates. The counterion of the Grignard reagent
had no effect on reactivity or diastereoselectivity when com-
paring nBuMgCl to its analogous bromide. Finally, the dia-
stereoselectivity was found to be higher in Et2O than in
THF or CH2Cl2 (Table 1, entries 10–12, 15, and 16).
Satisfactory results were also observed when nBuMgCl
was replaced with nBuLi (Table 1, entry 18); however, un-
like a Grignard reagent, nBuLi required CuCN (preferred
over CuBr or CuI) in the presence of BF3·OEt2 (Table 1,
entries 9 and 14). This method could not be extended to the
use of other Gilman reagents (e.g. methyl- or ethyllithium in
THF or Et2O).
Compared with other in situ methods,[8,9] which require
a minimum of 5 or 6 equiv. of ZnEt2 (the standard source
of carbanion in these studies), our method requires 2 or
3 equiv. of nBu2CuX. Compared to methods based on pre-
formed (R)- or (S)-N-α-(methylbenzyl) aldimines, our
method requires the same number of equivalents of
nBu2Cu·MgI,
or one additional equivalent
of
nBu2Cu·MgBr.[11c]
Examination of Various Normal and Branched Aliphatic
Aldehydes with Methyl, Ethyl, and n-Butyl Carbanions
After determination of the basic reaction parameters, we
turned our attention to diversifying the starting aliphatic
aldehyde and investigating the effect of adding carbanions
with different chain lengths to those aldehydes. Addition of
n-butyl cuprate to isobutyraldehyde or heptaldehyde pro-
ceeded in good yield and diastereoselectivity (Table 2, en-
tries 3 and 6). It is significant to note the high de (86%) of
2f, which has two very similarly sized α-substituents (n-
hexyl and n-butyl). In the case of methyl and ethyl cuprates,
THF was not only preferred over Et2O, but essential for
allowing complete reaction to occur. This was readily ex-
[a] Aldehyde (5.0 mmol, 1 equiv.), (S)-α-MBA (1.05 equiv.),
Ti(OiPr)4 (5 mol-%), solvent (0.08–0.10 ), CuBr (3 equiv.),
MeMgCl, EtMgCl, or nBuMgCl (6 equiv.), and BF3·OEt2
(2 equiv.). [b] Isolated yield of both diastereomers after chromatog-
plained by the low observed solubility of both methyl and raphy. [c] Determined by GC analysis. [d] CuBr (4 equiv.), EtMgCl
(8 equiv.), BF3·OEt2 (4 equiv.). [e] 15% starting material remained
ethyl cuprates in Et2O, whereas the more lipophilic n-butyl
unreacted (GC area%). [f] The isolated yield was not recorded.
cuprate was readily soluble in Et2O.
[g] BF3·OEt2 (3 equiv.). [h] After removal of chiral auxiliary, the ee
Comparing the addition of ethyl cuprate to progressively
was determined by chiral GC analysis of the trifluoroacetyl deriva-
more hindered aldehydes (heptaldehyde, isovaleraldehyde,
and finally isobutyraldehyde), we noted that the re-
sulting amine products 2 showed very little difference in de:
81%, 83%, and 86%, respectively (Table 2, entries 7, 2, 4).
tive of the primary amine. [i] CuBr (5 equiv.), MeMgCl (10 equiv.),
BF3·OEt2 (5 equiv.). [j] CuBr (6 equiv.), MeMgCl (12 equiv.),
BF3·OEt2 (6 equiv.).
This strongly implies that the aliphatic chain of the alde- conditions, the addition of dimethyl cuprates to isobutyral-
hyde does not reside in the crucial diastereotopic space of dehyde or heptaldehyde resulted in less than 80% conver-
the transition state responsible for carbanion facial selectiv- sion. Only after addition of 5 and 6 equiv. of methyl cupr-
ity. It should be noted that ethyl cuprate addition to isobu- ate, respectively, was complete consumption of the starting
tyraldehyde and heptaldehyde required the presence of material possible (Table 2, entries 5 and 8). For the synthe-
3 equiv. of ethyl cuprate and BF3·OEt2 for complete reac- sis of methyl-alkyl α-chiral amines, e.g. 2e and 2h, the pre-
tion, while isovaleraldehyde required 4 equiv.
viously outlined hydrogen methods[2–4a,5] provide superior
Nucleophilic addition of dimethyl cuprates is known to results. For all of the cuprate nucleophilic additions, the
be slow in comparison with other simple types of dialkyl (S,S)-2 amine is the major diastereomer formed when (S)-
cuprates, e.g. n-butyl.[17,18] Even under optimal reaction α-MBA is used as the chiral ammonia equivalent.[19,20]
Eur. J. Org. Chem. 2007, 959–964
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961

V. N. Wakchaure, R. R. Mohanty, A. J. Shaikh, T. C. Nugent
FULL PAPER
The stepwise approach relying on α-MBA (chiral imine Table 3. Hydrogenolysis of secondary amines 2 and 5.
formation, isolation, and subsequent carbanion addition)
has been previously examined and can be compared to our
work in one instance. nBu2Cu(CN)Li2 (2 equiv.) was the
cuprate of choice for the addition of an n-butyl carbanion
to (S)-α-(methylbenzyl) aldimine 4 in the presence of
BF3·OEt2, and this provided a 50% overall yield of amine
2c (from 1c) in 80% de (Scheme 2).[11b,11c] Our one-pot
method eliminates the need for isolation of the aldimine
intermediate and provides amine 2c in higher yield (77%)
and diastereoselectivity (92%).
[a] Diastereomeric amine (2.0 mmol, 1 equiv.), Pd(OH)2/C (5 mol-
%), AcOH (2 equiv.), EtOH (0.4 ), H2 (60 psi), room temperature.
[b] Isolated yield of analytically pure material starting from the
aldehyde. [c] Determined by chiral GC analysis of the trifluoroace-
tyl derivative of primary amine 3 or 6 with the racemate (see Sup-
Scheme 2. Preformed imine vs. in situ method.
porting Information). [d] Homoallylic amine (2.0 mmol, 1 equiv.),
Pd/C (4 mol-%), MeOH (0.4 ), H2 (50 psi), room temperature.
Regarding the addition of allyl carbanions, allylmagne-
sium chloride was found to be optimal and required no
BF3·OEt2 when examining isobutyraldehyde. The reaction
was performed by using substoichiometric amounts of
Ti(OiPr)4 (5 mol-% to 50 mol-%) followed by the addition
of allylmagnesium chloride at –78 °C. Addition of diallyl
cuprates did not improve upon this result. This reaction,
which represents a reverse sense of addition[21] relative to
the methyl, ethyl, or butyl additions, provided the homoal-
lylic amine 5 (not shown). The hydrogenolysis of this amine
afforded primary amine 6 in very good overall yield (84%),
but with mediocre enantioselectivity (76%). The stereo-
chemistry of 5 was confirmed by chemical correlation with
the known compound 6.[20] In general, cleavage of the auxil-
iary compounds proceeded smoothly with a Pd-based hy-
drogenolysis catalyst (Table 3) and provided the enantioen-
riched aliphatic α-chiral primary amines 3d, 3e, and 6 in
good overall yield (67–84%) with ee (chiral GC analysis)
values that corresponded to the de values of the starting
material 2 (achiral GC analysis) (compare Table 2 and
Table 3).
the methods using preformed α-MBA aldimines. Hydro-
genolysis formed alkyl-alkylЈ α-chiral primary amines in
very good overall yield and in the corresponding ee.
Furthermore, the ease of preparation makes our new asym-
metric sequential amination-alkylation method a competi-
tive alternative to the existing methodologies and should
be applicable to aromatic aldehydes and aryl cuprates. We
focused on the synthesis of aliphatic chiral amines in this
paper, because in the past they have been difficult to achieve
in high yield and ee.
Experimental Section
Representative experimental procedures for the one-pot asymmet-
ric sequential amination-alkylation preparation of amine (S,S)-2a
by using di-nBu2CuX (Table 1).
Synthesis of 2a with CuCN in THF: A round-bottom flask contain-
ing anhydrous CuCN (2.24 g, 25.0 mmol, 5.0 equiv.) was gently
heated (Ͻ 80 °C) with a heat gun under high vacuum for 5 min,
flushed with nitrogen, and cooled to room temperature before the
addition of THF (30.0 mL, in a total volume of 39.0 mL, 0.08 ).
This solution was cooled to –78 °C and added to nBuLi in hexanes
(20.0 mL, 2.5 , 50.0 mmol, 10.0 equiv.) over 5 min. The mixture
was then warmed to –45 °C, stirred for 15 min, and cooled back to
–78 °C. BF3·OEt2 (3.13 mL, 25.0 mmol, 5.0 equiv.) was added over
2 min and the solution was stirred for another 5 min. A prestirred
(0.5 h at room temp.) solution of isovaleraldehyde (0.54 mL,
5.0 mmol, 1.0 equiv.), THF (7.0 mL), Ti(OiPr)4 (73 µL, 0.25 mmol,
0.05 equiv.) and (S)-α-MBA (0.68 mL, 5.25 mmol, 1.05 equiv.) was
then added by cannula over 20–25 min. Additional THF (2.0 mL)
was added to the residual imine, and the resulting solution was
added by cannula to the reaction flask. The reaction solution was
stirred at –78 °C for 2 h, then at –45 °C for 1 h. The reaction was
Conclusions
We have developed a one-pot two-step procedure for the
synthesis of enantioenriched alkyl-alkylЈ α-chiral primary
amines from aliphatic aldehydes. The usefulness of (S)-α-
MBA as a chiral ammonia equivalent during the nucleo-
philic addition of methyl, ethyl, allyl, and n-butyl carban-
ions to non-branched, α-branched, and β-branched ali-
phatic aldehydes has been demonstrated in good yield and
de. We have significantly reduced the amount of carbanion
required relative to current in situ methods and have shown
that one isolation step can be removed in comparison with quenched by the addition of a 7:3 mixture (total volume 30 mL) of
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One-Pot Asymmetric Sequential Amination-Alkylation of Aldehydes
FULL PAPER
saturated NH4Cl and NH4OH (25%) at –45 °C and was stirred for
5 min. The cooling bath was removed, and the stirring was contin-
ued for another 90 min at room temp. Et2O (20 mL) was added,
and the biphasic solution was stirred for 5 min. The reaction mix-
ture was then filtered through a bed of Celite, and the Celite sub-
sequently washed with Et2O (3ϫ25 mL). The aqueous phase was
extracted with Et2O (3ϫ15 mL). The combined organic extracts
were washed with saturated NH4Cl (2ϫ25 mL), then with brine
(2ϫ20 mL), dried with Na2SO4, filtered, and the solvents were
evaporated to dryness to obtain the crude product (85% de). Purifi-
cation by silica gel flash chromatography (hexanes/EtOAc/NH4OH,
93.5:3.5:3) gave the mixture of diastereomers as a colorless viscous
liquid, which was then treated with ethereal HCl to yield the hydro-
chloride salt (1.15 g, 81% yield). The major (S,S) diastereomer was
isolated in pure form after recrystallization (EtOAc/hexanes, 4:6)
of the HBr salt. GC (program A, see General Experimental Details
in the Supporting Information): retention time [min]: major (S,S)-
2a isomer, 30.28; minor (R,S)-2a isomer, 29.35.
for at least 24 h.]. The major (S,S) diastereomer was isolated in
pure form either through further flash chromatography or by the
recrystallization of the HBr or HCl salt.
CuBr with Et2O as a Solvent: Isovaleraldehyde (0.54 mL, 5.0 mmol,
1.0 equiv.), CuBr (2.15 g, 15.0 mmol, 3.0 equiv.), nBuMgCl in THF
(15.0 mL, 2.0 , 30.0 mmol, 6.0 equiv.), BF3·OEt2 (1.27 mL,
10.0 mmol, 2.0 equiv.), Et2O (44.0 mL, 0.08 ); 90% de. Purifica-
tion by silica gel flash chromatography (hexanes/EtOAc/NH4OH,
93.5:3.5:3) gave the mixture of diastereomers as a colorless viscous
liquid, which was then treated with ethereal HCl to obtain the hy-
drochloride salt (1.21 g, 85% yield).
CuBr with THF as a Solvent: Isovaleraldehyde (0.54 mL, 5.0 mmol,
1.0 equiv.), CuBr (2.15 g, 15.0 mmol, 3.0 equiv.), nBuMgCl in THF
(15.0 mL, 2.0 , 30.0 mmol, 6.0 equiv.), BF3·OEt2 (1.27 mL,
10.0 mmol, 2.0 equiv.), THF (39.0 mL, 0.09 ); 88% de. Purifica-
tion by silica gel flash chromatography (hexanes/EtOAc/NH4OH,
93.5:3.5:3) gave the mixture of diastereomers as a colorless viscous
liquid, which was then treated with ethereal HCl to obtain the hy-
drochloride salt (1.25 g, 88% yield).
(S,S)-2a major isomer (free base): Rf = 0.48 (hexanes/EtOAc/
NH4OH, 83:15:2). 1H NMR (400 MHz, CDCl3): δ = 7.33–7.19 (m,
5 H), 3.86 (q, J = 6.4 Hz, 1 H), 2.38–2.32 (m, 1 H), 1.63–1.55 (m,
1 H), 1.33–1.12 (m, 12 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.84 (t, J =
6.8 Hz, 3 H), 0.77 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.6, 128.2, 126.7, 126.6, 55.1, 52.4, 44.4, 34.8, 27.7,
24.9, 24.6, 23.5, 22.8, 22.6, 14.0 ppm. HRMS (70 eV): calcd. for
C17H29N [M+] 247.2300; found 247.2295. LRMS (EI): m/z (%): 247
(2) [M+], 232 (4), 190 (100), 106 (10), 105 (82), 86 (48). IR (KBr):
CuBr with CH2Cl2 as
a Solvent: Isovaleraldehyde (0.54 mL,
5.0 mmol, 1.0 equiv.), CuBr (2.15 g, 15.0 mmol, 3.0 equiv.),
nBuMgCl in THF (15.0 mL, 2.0 , 30.0 mmol, 6.0 equiv.),
BF3·OEt2 (1.27 mL, 10.0 mmol, 2.0 equiv.), CH2Cl2 (39.0 mL,
0.09 ); 85% de. Purification by silica gel flash chromatography
(hexanes/EtOAc/NH4OH, 93.5:3.5:3) gave the mixture of dia-
stereomers as a colorless viscous liquid, which was then treated
with ethereal HCl to obtain the hydrochloride salt (1.13 g, 80%
yield).
ν
= 3441, 3026, 2956, 2930, 2628, 1467, 1367, 1154, 1118, 700,
˜
max
558 cm–1.
Synthesis of 2a with CuBr or CuI in THF, Et2O, or CH2Cl2
(Table 1): A round-bottom flask containing anhydrous CuBr or
CuI (2.0–3.0 equiv.) was gently heated (Ͻ 80 °C) with a heat gun
under high vacuum for 5 min, flushed with nitrogen, and cooled to
room temperature before the addition of THF, Et2O, or CH2Cl2
(30.0–35.0 mL, in a total volume of 39.0–44.0 mL, 0.10–0.08 ).
This solution was cooled to –45 °C and added to n-BuMgCl in
THF (4.0–6.0 equiv.) over 5 min. The mixture was then further
stirred at –45 °C for 15 min, and then cooled to –78 °C. BF3·OEt2
(2.0 equiv.) was added over 2 min, and the solution was stirred for
5 min. A prestirred (0.5 h at room temp.) solution of isovaleral-
dehyde (0.54 mL, 5.0 mmol, 1.0 equiv.) in THF, Et2O, or CH2Cl2
(7.0 mL), with Ti(OiPr)4 (73 µL, 0.25 mmol, 0.05 equiv.) and (S)-
α-MBA (0.68 mL, 5.25 mmol, 1.05 equiv.) was added by cannula
over 20–25 min. Additional THF, Et2O, or CH2Cl2 (2.0 mL) was
added to the residual imine, and the resulting solution was added
by cannula to the reaction flask. The reaction solution was stirred
at –78 °C for 2 h, then at –45 °C for 1 h. The reaction was quenched
by the addition of a 7:3 mixture (total volume 30 mL) of saturated
NH4Cl and NH4OH (25%) at –45 °C and was stirred for 5 min.
The cooling bath was removed, and the stirring was continued for
another 90 min at room temp. Et2O (20 mL) was added, and the
biphasic solution was stirred for 5 min. The reaction mixture was
then filtered through a bed of Celite, and the Celite was sub-
sequently washed with Et2O (3ϫ25 mL). The aqueous phase was
extracted with Et2O (3ϫ15 mL). The combined organic extracts
were washed with saturated NH4Cl (2ϫ25 mL), then with brine
(2ϫ20 mL), dried with Na2SO4, filtered, and evaporated to dry-
ness to obtain the crude product (de was measured with unpurified
material). Purification by silica gel flash chromatography provided
the mixture of diastereomers as a colorless viscous liquid, which
was treated with ethereal HCl to obtain the hydrochloride salt [note
that amine products are considered semivolatile and converted into
the HCl salts, then kept under high vacuum (defined as 0.5 Torr)
CuI with Et2O as a Solvent: Isovaleraldehyde (0.54 mL, 5.0 mmol,
1.0 equiv.), CuI (1.9 g, 10.0 mmol, 2.0 equiv.), nBuMgCl in THF
(10.0 mL, 2.0 , 20.0 mmol, 4.0 equiv.), BF3·OEt2 (1.27 mL,
10.0 mmol, 2.0 equiv.), Et2O (44.0 mL, 0.09 ); 89% de. Purifica-
tion by silica gel flash chromatography (hexanes/EtOAc/NH4OH,
93.5:3.5:3) gave the mixture of diastereomers as a colorless viscous
liquid, which was then treated with ethereal HCl to obtain the hy-
drochloride salt (1.09 g, 77% yield).
CuI with THF as a Solvent: Isovaleraldehyde (0.54 mL, 5.0 mmol,
1.0 equiv.), CuI (1.9 g, 10.0 mmol, 2.0 equiv.), nBuMgCl in THF
(10.0 mL, 2.0 , 20.0 mmol, 4.0 equiv.), BF3·OEt2 (1.27 mL,
10.0 mmol, 2.0 equiv.), THF (39.0 mL, 0.10 ); 85% de. Purifica-
tion by silica gel flash chromatography (hexanes/EtOAc/NH4OH,
93.5:3.5:3) gave the mixture of diastereomers as a colorless viscous
liquid, which was then treated with ethereal HCl to obtain the hy-
drochloride salt (1.12 g, 78% yield).
Supporting Information (see footnote on the first page of this arti-
cle): A summary of general experimental practices and detailed
procedures for all remaining compounds (2b, 2c, 2d, 2e, 2f, 2g, 2h,
3d, 3e, 5, and 6) and all 1H and 13C NMR spectra and GC chroma-
tograms (de and ee) are provided for all new compounds.
Acknowledgments
The authors are grateful for financial support from the Inter-
national University Bremen.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
963

V. N. Wakchaure, R. R. Mohanty, A. J. Shaikh, T. C. Nugent
FULL PAPER
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Received: September 5, 2006
Published Online: January 4, 2007
964
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Eur. J. Org. Chem. 2007, 959–964