Highly diastereoselective synthesis of 2,6-di[1-(2-alkylaziridin-1-yl) alkyl]pyridines, useful ligands in palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1002/adsc.200606109

C₂-Symmetrical, enantiopure 2,6-di[1-(1-aziridinyl)alkyl] pyridines (DIAZAPs) were prepared by a high-yielding, three-step sequence starting from 2,6-pyridinedicarbaldehyde and (S)-valinol or (S)-phenylglycinol. The new compounds were tested as

Full text of DOI:10.1002/adsc.200606109

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DOI: 10.1002/adsc.200606109
Highly Diastereoselective Synthesis of 2,6-Di[1-(2-alkylaziridin-1-
yl)alkyl]pyridines, Useful Ligands in Palladium-Catalyzed Asym-
metric Allylic Alkylation
Diego Savoia,a,* Giuseppe Alvaro,b Romano Di Fabio,b Claudio Fiorelli,a
Andrea Gualandi,a Magda Monari,a and Fabio Piccinellia
a
Dipartimento di Chimica “G. Ciamician”, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax: (+39)-051-209-9456; e-mail: diego.savoia@unibo.it
Medicines Research Centre, GlaxoSmithKline S.p.A., via Fleming 4, 37135 Verona, Italy
b
Received: March 15, 2006; Accepted: June 14, 2006
Dedicated to Professor Achille Umani-Ronchi on the occasion of his 70th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: C2-Symmetrical, enantiopure 2,6-di[1-(1- and up to 99% enantiomeric excess were obtained in
aziridinyl)alkyl]pyridines (DIAZAPs) were prepared the reactions of the enolates derived from malonate,
by a high-yielding, three-step sequence starting from phenyl- and benzylmalonate dimethyl esters with
2,6-pyridinedicarbaldehyde and (S)-valinol or (S)- 1,3-diphenyl-2-propenyl ethyl carbonate.
phenylglycinol. The new compounds were tested as
ligands in palladium-catalyzed allylation of carban- Keywords: allylation; amines; asymmetric catalysis;
ions in different solvents. Almost quantitative yield palladium; substituent effects
Introduction
dine-bis(oxazolines) 1 (Pyboxs)[2] as well as the more
recently developed pyridine-bis(oxazines) (Pyboxa-
AHCTREUNG
Nitrogen-containing ligands are being increasingly ap- zines) ligands 2[3] and pyridine-bis(imidazolidines) 3.[4]
plied in asymmetric catalysis,[1] since they present sev- Both ligands 1 and 2 are readily prepared from 2,6-
eral advantages with respect to the more conventional pyridinedicarboxylic acids and enantiopure b- and g-
phosphorus-containing ligands, even in transition amino alcohols, respectively, without the need to con-
metal-catalyzed reactions. Indeed, the amine function- struct new stereocenters.
ality can coordinate any metal species, ranging from
Pyridinediimines 4, which are similarly prepared
lithium and magnesium to zinc, copper, early transi- from 2,6-pyridinedicarbaldehyde, have been also used
tion metal complexes and also precious metals. More- as ligands in metal-catalyzed asymmetric reactions.[5]
over, the amine group can be converted to other ni- Moreover, N,N’,N’’-terdentate ligands 5[6] bearing two
trogen-containing functional groups with different chiral amine functions in the lateral chains of the pyr-
electronic and chemical (acid, base) properties, e.g., idine ring were prepared from 2,6-di(chloromethyl)-
amides and imines. The availability of optically active pyridine, then used in transamination reactions with
amines from the chiral pool, by resolution processes moderate enantioselectivities. However, only a few
and in part by stereoselective syntheses makes the use compounds with stereocenters at the benzylic posi-
of nitrogen-containing ligands convenient as bases tions have been described. The (R,R)- and (S,S)-enan-
and auxiliaries in asymmetric syntheses, or as ligands tiomers of the ligands 6[6a] and 7[7] were obtained after
of metal species in catalytic reactions. A significant separation from the meso-compounds and resolution
niche in the domain of nitrogen ligands is held by of the racemic mixture or copper complex, but no ap-
N,N’,N’’-terdentate ligands, especially those having plication of these ligands in asymmetric syntheses has
C2-symmetry. The pyridine ring is present in most been hitherto described. Also, chiral C2-symmetric,
compounds of this type (Figure 1), where it has the substituted bipyridines and terpyridines have been ex-
role of a spacer between two identical N-containing ploited as metal ligands for asymmetric synthesis.[1c]
moieties, e.g., the widely used, high-performing pyri-
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Diego Savoia et al.
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ates 9 can also be used for the preparation of 2,6-
di(1-aminoalkyl)pyridines (DIAMAPs) 11, by oxida-
tive cleavage of the chiral auxiliaries, and their N-sub-
stituted derivatives, of potential interest as ligands or
auxiliaries in asymmetric reactions. The results of on-
going studies on this theme will be reported in due
course.
Results and Discussion
Preparation of the Ligands
The sequence of steps described in Scheme 1 was fol-
lowed to prepare the DIAZAP ligands 10a and b.
The starting O-silylated diimines 8a and b were pre-
pared in almost quantitative yields from the corre-
sponding diimines bearing unprotected OH groups by
the protocol previously described for the analogous
monoimines,[8,9] and then used directly in the follow-
ing step without purification. Organolithium com-
pounds were found to be the reagents of choice to
achieve a highly efficient, regio- and diastereoselec-
tive double addition to the azomethine groups in an-
hydrous tetrahydrofuran (THF) at À788C under an
inert atmosphere. The outcomes of such reactions
Figure 1. C2-Symmetrical, pyridine-based N,N,N-terdentate
ligands.
We envisioned a three-step route to enantiopure
C2-symmetrical N,N’,N’’-terdentate ligands mimicking
our previously described synthesis of pyridine-aziri-
dine ligands[8] and involving the addition of organo-
metallic reagents to a chiral diimine derived from 2,6-
pyridinedicarbaldehyde. Taking advantage from our
experience in the asymmetric synthesis of amines
from imines,[9] particularly concerning the addition of
organometallic reagents to chiral pyridineimines,[10]
we have investigated the addition of allylic zinc re-
agents and organolithium compounds to the diimines
8a and 8b derived from (S)-valinol and (S)-phenylgly-
cinol, respectively. As a matter of fact, preliminary
experiments showed that Grignard reagents were less
effective. While the reactions with allylic zinc reagents
will be described elsewhere, we report here the reac-
tions of these imines with organolithium compounds
and the subsequent conversion of the b-amino alcohol
products
9 to 2,6-di[1-(1-aziridinyl)alkyl]pyridines
(DIAZAPs) 10 following Mitsunobu cyclization. By
this strategy, the carbon skeleton of the starting chiral
amino alcohol and the absolute configuration of the
inherent stereocenters are retained in the final mole-
cule. The new ligands are then used in the palladium-
catalyzed asymmetric allylic alkylation (AAA) of sta-
bilized carbanions, providing higher enantioselectivity
with respect to the analogous, previously described,
bidentate pyridine-aziridine ligands.[8] The intermedi- Scheme 1.
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Diastereoselective Synthesis of 2,6-Di[1-(2-alkylaziridin-1-yl)alkyl]pyridines
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using methyl-, n-butyl-, tert-butyl- (in Et2O), 3,3-dime- The S,S configuration of the two newly formed stereo-
thylbutyl-, and phenyllithium together with the subse- centers at the benzylic positions was at first assumed
quent transformations of the products 9a and b to the considering the sense of asymmetric induction previ-
DIAZAPs 10, are reported in Table 1. Of particular ously observed in the addition of organolithium re-
note, 3,3-dimethylbutyllithium was easily and effec- agents to the analogous 2-pyridine monoimine,[8] and
tively prepared by the reaction of tert-butyllithium (2 then was confirmed by the X-ray structure obtained
equivalents) with THF (solvent) at room temperature, for one palladium complex derived from one of these
involving the addition of tert-butyllithium to ethylene, ligands (see below). Column chromatography of the
which is formed together with the lithium enolate of crude reaction products often allowed isolation of the
acetaldehyde, following the initial cleavage of THF main diastereomer only, however, enriched chromato-
by tert-butyllithium.[10] It is noteworthy that almost all graphic fractions of the minor diastereomer were ob-
the reactions gave the expected products 9a and b in tained, allowing its C1 symmetry to be determined. In
high yields and with very high diastereoselectivities. particular, the separation of the diastereomers was
As a matter of fact, apart from the addition of tert-bu- difficult for 9aa’ and 9ac’, and low yields of the pure
tyllithium to both imines (entries 3 and 8), which pro- main (S,S)-diastereomer were obtained. In these
vided the corresponding amino alcohols with low dia- cases, it was preferable to merely filter the crude reac-
stereomeric ratios (dr), the reactions of organolithium tion mixtures through a small pad of silica and use
reagents with the valinol-derived imine 8a occurred in the diastereomeric mixtures in the subsequent step,
most cases with higher diastereoselectivities (dr of 9a that is the cyclization to DIAZAPs 10aa’ and 10ac’,
94:6) with respect to the phenylglycinol-derived imine since the diastereomers of the latter compounds were
8b (dr of 9b 91:9). For the imine 8a, the best result more readily separated by chromatography. The aziri-
was obtained with phenyllithium, which afforded the dine ring was built from the intermediate compounds
amino alcohol 9ae’ in 95% yield and dr 98:2. Howev- 9a and b by applying the Mitsunobu methodology,
er, the addition of methyllithium to 8b (entry 6) was i.e., by reaction with diethyl azadicarboxylate
even more diastereoselective, as the pure diastereo- (DEAD) and triphenylphosphine in THF at room
mer (S,S)-9ba’ was obtained in 94% yield after temperature. In fact, the DIAZAPs 10a and b were
column chromatography of the crude reaction prod- obtained with high yields, as the coproducts could
uct, where no other diastereomer was detected by often be separated by column chromatography. In the
1H NMR spectroscopy.
case of phenylglycinol derivatives, the diastereomers
It should be observed that all the organometallic of both the amino alcohols 9bb’, 9bc’ and 9be’ and the
additions produced only two of three possible diaste- corresponding aziridines 10bb’, 10bc’and 10be’ could
reomers of the compounds 9: the prevalent one had not be separated. Other methods to achieve the cycli-
1
C2 symmetry, as observed by H NMR spectroscopy. zation of the b-amino alcohol moieties to aziridines
Table 1. Addition of organolithium reagents (3 equivalents) to the imines 8a and 8b dissolved in THF at À788C.
Entry
Imine (R1)
R2 Li
Product
dr[a]
Yield [%]
9[b]
10[c]
1
2
3
4
5
6
7
8
9
8a (i-Pr)
“
“
“
MeLi
9aa’
9ab’
9ac’
9ad’
9ae’
9ba’
9bb’
9bc’
9be’
95:5
95:5
84:16
94:6
98:2
>99:1
91:9
86:14
92:8
95
10aa’ (85)
10ab’ (87)
10ac’ (84)[e]
10ad’ (86)
10ae’ (90)
10ba’ (85)
10bb’ (90)[h]
10bc’ (86)[i]
10be’ (89)[j]
n-BuLi
t-BuLi[d]
t-BuCH2CH2Li[f]
PhLi
95 (79)[c]
95 (54)[c]
84 (70)[c]
95
“
8b (Ph)
MeLi
94[g]
93 (76)
94(59)
98 (84)
“
“
“
n-BuLi
t-Bu[d]
PhLi
[a]
Determined by 1H NMR spectroscopy of the crude reaction products.
Yield of the crude reaction product. Unless otherwise indicated, the diastereomers were not separated.
Yield of pure (S,S)-9 isolated after column chromatography.
[b]
[c]
[d]
[e]
[f]
The reaction was performed in diethyl ether.
The product was obtained after column chromatography as a 89:11 mixture of diastereomers.
The reagent was prepared in situ by adding t-BuLi to THF (solvent) at 08C.
The crude product was apparently pure by 1H NMR spectroscopy.
The product was obtained after column chromatography as a 91:9 mixture of diastereomers.
The product was obtained after column chromatography as an 86:14 mixture of diastereomers.
The product was obtained after column chromatography as a 92:8 mixture of diastereomers.
[g]
[h]
[i]
[j]
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Diego Savoia et al.
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were less satisfactory in our hands, affording lower Major drawbacks of said bisdentate ligands were their
yields and causing a more difficult purification of the low reaction rates, even with the more reactive car-
products.
bonate 14b, and their incapability to adequately stabi-
lize zerovalent palladium emanating from nucleophil-
ic attack on the intermediate h3-allylic complexes,
leading to precipitation of Pd black and consequently
a low to moderate yield of product 15.
Palladium-Catalyzed AAA Reactions in the Presence
of DIAZAP Ligands
In fact, we have designed the structure of the
We have previously described the synthesis of enan- N,N’,N’’-terdentate DIAZAP ligands to overcome
tiopure (N,N’)-bidentate ligands, i.e., 2-[1-(1-aziridin- those problems. Our idea was also based on the
yl)alkyl]pyridines, 12a–c,[8] which have only one arm report that a higher reaction rate was obtained using
attached to the pyridine ring, as compared to the a P,N,N-terdentate ligand instead of a bidentate P,N-
(N,N’,N’’)*-terdentate DIAZAP ligands 10 described ligand in Pd-catalyzed AAA reactions;[11] a result that
in this work. The crystalline complexes [(N,N’)
G
allyl)Pd][SbF6] 13 prepared from those ligands were the terdentate ligand to effectively stabilize either
G
used as catalysts in the AAA of sodium dimethylmal- Pd(0) or (allylic)Pd(II)+ complexes involved in the
onate with 1,3-diphenyl-2-propenyl acetate 14a and catalytic cycle. However, in the case of our terdentate
1,3-diphenyl-2-propenyl ethyl carbonate 14b to give ligands, taking into account the effects of substituents
the substitution product 15 (Scheme 2).
in the bidentate ligands on enantioselectivity, it was
difficult to foresee the importance of the C6 pyridine
substituent (aziridine-alkyl group) in 10, which could
potentially oppose the asymmetric induction of the
aziridine substituent.
A number of reactions were carried out on the al-
lylic carbonate 14b with the anion of dimethyl malo-
nate, generated by treatment of dimethyl malonate
with either sodium hydride or bis(trimethylsilyl)amide
(BSA) and a catalytic amount of potassium acetate in
different solvents (Table 2). Allylpalladium chloride
dimer and the terdentate ligands 10a and b were used
as precursors of the effective enantioselective catalyst.
The ligands derived from (S)-valinol were examined
first. The carbonate 14b was treated with the pre-
formed sodium salt of dimethyl malonate (1.5 molar
equivalents) and catalytic amounts of allylpalladium
chloride dimer (5 mol%) and ligand 10aa’ (10 mol%)
in tetrahydrofuran at room temperature. The course
of the reaction was monitored by GC and TLC analy-
sis and an almost complete conversion of the starting
compounds was observed after 24 h. The product 15
was isolated in high yield and 76% ee in favour of the
R enantiomer (Table 2, entry 1). It should be ob-
served that the prior preparation of the palladium salt
[(h3-allyl)
N
N
smooth reaction occurred and the formation of black
palladium was observed only when the reaction was
almost complete. In a second run (entry 2) at À208C,
with all the other experimental conditions being un-
Scheme 2.
By comparing the performances of two homochiral changed, we observed that the same ee was obtained,
N,N’-bidentate complexes bearing the same skeleton but a longer reaction time was required to obtain a
but a different C2-aziridine substituent (Ph vs. i-Pr), a satisfactory yield of product. Hence, all the successive
better enantioselectivity was obtained with the Ph- reactions were carried out at 258C.
substituted ligand (ee 90% vs. 41%), in both cases fa-
The role of the solvent was then examined and it
vouring the formation of the product (S)-15. On the was found that the reaction takes place also in di-
other hand, the complex 13c with the C6-pyridine chloromethane, despite the poor solubility of sodium
benzyl substituent gave the opposite enantioselectivi- dimethyl malonate and the consequent lower reaction
ty, as (R)-15 was obtained with moderate ee (47%). rate, but a slightly lower ee was obtained (entry 3).
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Diastereoselective Synthesis of 2,6-Di[1-(2-alkylaziridin-1-yl)alkyl]pyridines
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Table 2. Enantioselective alkylation of dimethyl malonate with 1,3-diphenyl-2-propen-1-yl acetate 14a and ethyl carbonate
14b.[a]
Entry
Ligand (mol%)
Base
Solvent
Time [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
10aa’ (10)
NaH
“
“
“
THF
THF
24
96
48
24
48
48
48
16
24
18
15
24
24
72
3
2
8
5
48
16
48
16
24
79
69
85
81
86
84
86
90
85
89
90
89
87
82
90
92
87
90
77
89
64
88
92
76
76
73
63
60
69
70
62
76
86
82
88
13
82
98
98
98
98
80
81
70
83
76
10aa’ (10)[b]
10aa’ (10)
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
10ab’ (10)
10ab’ (10)
10ac’ (10, dr 89:11)
10ad’ (10)
10ad’ (10)
10ae’ (10)
10ae’ (10)
10ae’ (10)
10ae’ (10)
10af’ (10)
10ba’ (10)
10ba’ (10)
10ba’ (10)
10ba’ (3)
10ba’ (3)
10bb’ (10, dr 91:9)
10bb’ (10, dr 91:9)
10bc’ (10, dr 86:14)
10be’ (10, dr 92:8)
10bf’ (10)
“
BSA/AcOK
NaH
BSA/AcOK
NaH
CH2Cl2
THF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NaH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
BSA/AcOK
BSA/AcOLi
BSA/AcOK
NaH
NaH
BSA/AcOK
BSA/AcOK
BSA/AcOLi
NaH
BSA/AcOK
BSA/AcOK
BSA/AcOK
BSA/AcOK
[a]
The reactions were performed on the carbonate 14b at 258C generating the nucleophile by two protocols: A) dimethyl
malonate (1.5 equivs.) and NaH (1.5 equivs.), or B) dimethyl malonate (2.5 equivs.), bis(trimethylsilyl)acetamide (BSA, 3
equivs.) and KOAc or LiOAc (0.1 equiv).
The reaction was carried out at À208C.
[b]
The same trend was observed when the n-butyl substi- 9a,f’, followed by the usual cyclization step
tuted ligand 10ab’ was used in both solvents, but the (Scheme 1). The correctness of our hypothesis was
ees (60–63%) were lower (entries 4, 5). Similar results demonstrated by the observation that the typical allyl-
were obtained with the tert-butyl substituted ligand ic alkylation of sodium dimethyl malonate with the al-
10ac’ (used as a 84:16 mixture of inseparable diaste- lylic carbonate 14a in THF at 258C in the presence of
reomers) and the ligand 10ad’ (R2 =t-BuCH2CH2) in 10 mol% of ligand 10af’ occurred with very low enan-
different experimental conditions. Finally, the phenyl tioselectivity (13% ee, entry 13).
substituted ligand 10ae’ provided high levels of enan-
tioselectivity (ee up to 88% in entry 12).
The terdentate ligands 10b, derived from (S)-phe-
nylglycinol and hence carrying phenyl substituents on
At this point, we wanted to demonstrate the need the aziridine rings, were then examined in the same
or usefulness of a substituent, and hence a stereocen- typical AAA reaction. (R)-15 was formed in all cases
ter, at the benzylic positions. In our opinion, this with ees definitely superior to those obtained with the
would induce the stereoselective formation of the N- corresponding (S)-valinol-derived ligands 10a. For ex-
aziridine stereocenter in the cationic palladium com- ample, using sodium hydride as the base in THF in
plex. It should be observed that N-alkylaziridines are the presence of allylpalladium chloride dimer (5
not pyramidally stable at room temperature, and the mol%) and the ligand 10ba’ (10 mol%) the product
bulkiness of the substituent decreases the barrier of (R)-15 was obtained with 82% yield and 82% ee
inversion.[12] As a matter of fact, all the previously after 72 h (entry 14). Then, we observed that in di-
prepared h3-allylic palladium complexes carrying bi- chloromethane, despite the very low solubility of
dentate (N,N)*-ligands displayed a unique configura- sodium dimethyl malonate, the reaction with the
tion of the aziridine nitrogen atoms, that is dictated ligand 10ba’ was almost complete after only 3 h and
by the configuration of the benzylic carbon stereocen- the product was obtained with excellent yield and
ters and minimizes the steric interactions between the 98% ee (entry 15). The same level of enantioselectivi-
benzylic (R2) and aziridine (R1) substituents. To that ty was obtained by performing the reaction with the
purpose, we synthesized the ligand 10af’ by reduction same ligand and generating the nucleophile by the al-
of the diimine 8a to give the intermediate diaminediol ternative protocol (BSA-AcOK in CH2Cl2, entry 16),
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Diego Savoia et al.
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even with reduced amounts of ligand (3 mol%, en-
tries 17 and 18).
It was apparent that an increase in the bulkiness of
the R2 substituents in the ligands 10b caused a de-
crease of the reaction rate. The n-butyl- and phenyl-
substituted ligands 10bb’, 10bc’ and 10be’ were used
as an inseparable mixture of diastereomers, with the
(S,S) and (S,R) configurations of the two benzylic ste-
reocenters (dr 91:9, 86:14 and 92:8, respectively); nev-
ertheless high ees were obtained (ees 80, 81, 70 and
83% in entries 19 to 22). Finally, we were surprised to
find that the ligand 10bf’ (R2 =H, Scheme 1), in con-
trast to the analogous (S)-valinol-derived 10af’ (13%
ee, entry 13), provided a moderate enantioselectivity
(76% ee, entry 23).
The role of different palladium sources was briefly
investigated carrying out the allylation of the malo-
nate anion (BSA, AcOK) with the carbonate 14b in
the presence of the ligand 10ba’ in dichloromethane
at 258C (Table 3). In comparison with the reaction
Table 3. Different palladium sources for the enantioselective
alkylation of dimethyl malonate with 1,3-diphenyl-2-propen-
1-yl ethyl carbonate 14b in the presence of ligand 10ba’.[a]
Entry Pd catalyst (3
mol%)
Time
[h]
Yield [%] of
(S)-15
ee
[%]
1
2
3
4
(allylPdCl)2
Pd(OAc)2
PdCl2
Pd(dba)2CHCl3
3
87[b]
76
81
98
87
94
96
G
24
24
24
G
85
[a]
The reactions were performed on the carbonate 14b in
dichloromethane at 258C using dimethyl malonate (2.5
equivs.), bis(trimethylsilyl)acetamide (BSA, 3 equivs.),
KOAc (0.1 equiv.) and ligand 10ba’ (3 mol%).
Scheme 3.
catalyzed by allylpalladium chloride dimer (entry 1),
which was almost complete after only 3 h, the reac-
tions catalyzed by palladium acetate, palladium chlo-
ride and the dibenzylideneacetonate complex re- 17a was assigned on the basis of the optical rotation
quired 24 h to give comparable yields and slightly (À).[13e] Since the previously unknown compound 17b
lower ees; up to 85% yield and 96% ee were obtained has the same sense of optical rotation of 17a, the
with the latter catalyst (entry 4).
same configuration is assumed.
Then, to extend the scope of our catalytic system,
The cyclohexenyl carbonate 18 was poorly reactive
we investigated the AAA reactions of other stabilized in the usual experimental conditions and the ee of the
enolates as well as diversely substituted allylic carbo- derived product 19[14] was low. For example, using
nates (Scheme 3). The enolates derived from substi- ligand 10ba’, a 40% yield and 6% ee were achieved,
tuted malonates have been relatively less employed as whereas a 68% yield and 37% ee were obtained with
nucleophiles, and chiral P,P, P,N and N,P,N ligands the ligand 10ae’, in both cases after 3 days. The reac-
have been used.[13] We were pleased to find that the tion rate could be slightly increased in the presence of
alkylations of the benzyl- and phenyl-substituted mal- silver tetrafluoroborate, and good yields of the cyclo-
onate esters 16a and b, respectively, proceeded hexenyl-substituted malonate 19 were obtained after
smoothly in the presence of the ligand 10ba’ to give 2 days using either ligand 10ad’ or 10ae’, but the ee
the products 17a and b in high yields and with 97– did not exceed 38%. Surprisingly, the use of ligand
99% ees. The S configuration of the stereocenter in 10ba’ resulted in a low yield of 19 (40%) and very
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Diastereoselective Synthesis of 2,6-Di[1-(2-alkylaziridin-1-yl)alkyl]pyridines
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low ee (6%). Similarly, the reaction of dimethyl malo- Tentative Explanation of Mechanism and
nate anion with ethyl 3-penten-2-yl carbonate 20 in Enantioselectivity
the presence of the ligands 10ae’ and 10ba’ afforded
the substitution product 21 in good yields in the pres- Different (allyl)- and (1,3-diphenylallyl)Pd+ salts
ence of AgBF4 but with low ees (up to 28%). Utiliz- bearing the (S)-valinol- and (S)-phenylglycinol-de-
ing the unsymmetrically disubstituted allylic carbon- rived ligands, 10ae’ and 10ba’, with PF6, SbF6 or BF4
ate 22, a mixture of products (ratio 95:5) was ob- counterions, were prepared by standard methodology.
tained, as usually found with other ligands:[15] the These salts were generally obtained as white or yel-
prevalent product 23 was formed by reaction at the lowish powders, and some of them appeared impure
1
methyl-substituted allylic terminus with low enantio- by H NMR analysis. Up till now, we have been able
selectivity (ee 14%), whereas the minor regioisomer to obtain crystals suitable for X-ray crystallographic
24 was obtained with 95% ee (Scheme 3).
structure determinations only in the case of the salt
(allyl)Pd][PF6]. The crystal structure
Finally, we turned our attention to the capability of [(10ae’)
A
ACHTREUNG
our catalytic system to induce enantioselectivity in (Figure 2) is quite similar to those of the previously
the formation of a quaternary stereogenic center at
the nucleophilic carbon. This goal should be achieved
by the discrimination of the two diastereotopic faces
of a fully substituted planar enolate attacking the h3-
allylic ligand. This is difficult to realize because the
chiral N,N,N-ligand does not interfere in any way with
the incoming nucleophile, and the newly formed ste-
reocenter is more remote from the inducing stereo-
center(s) than in previous experiments. Hence, we in-
vestigated the reaction of (E)-cinnamyl ethyl carbon-
ate 25 with the anion derived from 2-ethoxycarbonyl-
cyclohexanone 26 under the usual reaction conditions
(BSA, AcOK, CH2Cl2) (Scheme 4). The reaction pro-
Figure 2. X-ray structure of the [(10ae’)
(allyl)Pd]+ cation.
G
Only the dominant orientation (84%) of the allyl ligand is
À
shown. Selected bond lengths (Å): N(1) Pd(1) 2.158(3),
N(2) Pd(1) 2.109(3), C(30) Pd(1) 2.178(4), C(31) Pd(1)
À
À
À
À
À
À
2.138(4), C(32) Pd(1) 2.126(4). Bite angle N(2) Pd(1)
N(1): 78.06(11)8.
reported allylic palladium salts with pyridine-aziridine
ligands,[8] featuring the bidentate coordination of the
ligand to palladium cation and the h3 hapticity of the
endo/exo allyl ligand. The palladium-aziridine bond is
shorter than the palladium-pyridine bond [2.109(3) vs.
2.158(3) Å], and the terminal allylic carbon anti to
Scheme 4.
the aziridine forms
a
bond with palladium
[2.178(4) Å] longer than the allylic terminus anti to
ceeded smoothly to give the linear alkylation product the pyridine ring [2.126(4) Å]. This observation sup-
27 with high yield but only 27% ee. This result can be ports the hypothesis that the allylic terminus anti to
compared with the reported Pd-catalyzed enantiose- the aziridine has a more electrophilic character. The
lective synthesis of 27 using a P-chirogenic diamino- 1H NMR spectra of the CD2Cl2 solutions of this salt
phosphine oxide as the ligand, where 92% ee was ob- and all the other [(allyl)- or (À1,3-diphenylallyl)
C
À
À
major enantiomer of 27 by comparison with the au- were complex with broad absorptions, indicating the
thentic enantiomer.[16b]
presence of several species, although the endo- and
Adv. Synth. Catal. 2006, 348, 1883 – 1893
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1889

Diego Savoia et al.
FULL PAPERS
exo-(h3-allyl) (N,N)Pd+ species were predominant. ophile on the more electrophilic allylic terminus anti
Most importantly, in the case of the 1,3-diphenylallyl to the aziridine nitrogen of the intermediate 28 to
complexes, a higher ratio of rotamers (>3:1) was ob- give the (h2-alkene)Pd(0) complex h2-(N,N)-29
served for the complex derived from the ligand 10ba’, (Scheme 5). The regioselectivity of the nucleophilic
which afforded the highest enantioselectivity. More-
over, the spectra were complicated by the lack of C2-
symmetry of the ligand complex, demonstrating that
only one aziridine nitrogen was involved in Pd coordi-
nation. For example, for each rotamer, distinct ab-
sorptions were observed for the two benzylic protons.
In the absence of information on the reactive inter-
mediate involved in the enantioselective step, we can
only speculate on the origin of the enantioselectivity.
We take into account the available structural informa-
tion of the bidentate complex 13 and the mechanistic
Scheme 5.
hypothesis that has been suggested to explain the
sense of asymmetric induction provided by such li- attack is also favoured by the preferential clock-wise
gands.[8] Moreover, several studies on the binding rotation of the hydrocarbon ligand occurring during
properties of potentially terdentate ligands towards the formation of the most stable (h2-alkene)Pd com-
(allyl)Pd(II) cations have been reported.[17–19] For ex- plex 29, as the steric interactions between the alkene
ample, the X-ray crystal structure of a (terpyridine)- and the nitrogen ligand are reduced concurrently.
G
dynamic behaviour in solution has been studied by H
and 13C NMR spectroscopy.[17] It was therein shown Conclusions
that terpyridine binds the (h1-allyl)Pd+ fragment in
the terdentate fashion and (h3-allyl)Pd+ as a bidentate C2-Symmetrical N,N’,N“-terdentate ligands featuring
ligand. In fact, the two species are present both in the two aziridine rings in the lateral arms of a pyridine
crystal and in a CD2Cl2 solution in a dynamic equilib- ring are constructed by a short and efficient route
rium, which is strongly displaced towards the h3-allyl starting from commercially available building blocks:
form at low temperature. On the other hand, the 2,6- 2,6-pyridinedicarbaldehyde, optically pure b-amino al-
bis(diphenylphosphanylmethyl)pyridine (PNP) ligand cohols and organolithium reagents. These ligands (DI-
in the complex [(PNP)
N
N
dentate coordination mode both in the crystal and in up to 99%) in the allylic alkylation of dimethyl malo-
solution, where the complex is fluxional through h1–h3 nate anion and analogous C2-substituted anions. Con-
equilibrium processes.[18,19] This is in contrast to the trary to the corresponding bidentate ligands derived
behaviour of (N,P,N) ligands which act as (P,N)-biden- from 2-pyridinecarbaldehyde, the DIAZAP ligands
tate ligands in (h3-dimethylallyl)Pd+ complexes.[20] are capable of stabilizing both cationic and zerovalent
Similarly, the presence of the pyridine ring in a chiral palladium, thus avoiding the ready interruption of the
(P,N,N) ligand was unnecessary for high selectivity in catalytic cycle by deposition of Pd black. Unfortu-
the AAA reaction, suggesting that the ligand acts in a nately, application of these ligands in the allylic alky-
(P,N)-bidentate fashion.[21]
lation of different nucleophiles has met with low
On the basis of the precedent studies, we believe enantioselectivity or no success. However, it is expect-
that the prevalent rotamer of the reactive (h3-1,3- ed that they can be used in other transition metal cat-
diphenylallyl)
(N,N,N)Pd+ complex is 28, featuring the alyzed reactions.
A
syn,syn-configuration of the allylic ligand and reduced
interactions of the allylic phenyl groups and the aziri-
dine substituent. Moreover, in solution the chiral azir-
idinylalkyl substituent not involved in palladium che-
lation should take the same spatial arrangement as
observed in the crystal structure, with the methine hy-
drogen oriented towards the allylic ligand in order to
reduce the steric interactions. Obviously, owing to the
C2 symmetry of the nitrogen ligand, identical h3-(N,N)
complexes are formed when one or the other aziri-
dine nitrogen is involved in Pd coordination.
Experimental Section
General Protocol for the Preparation of Imines
To a solution of (S)-valinol (6 mmol, 0.618 g) or (S)-phenyl-
glycinol (6 mmol, 0.823 g) in THF (50 mL) was added anhy-
drous MgS04 (5 g), the aldehyde (3 mmol, 0.405 g) and the
mixture was stirred overnight. The solid phase was filtered
off on a pad of Celite and the organic solvent was evaporat-
ed under reduced pressure. The residue was dissolved in
CH2Cl2 (20 mL) and triethylamine (7 mmol, 0.708 g) and
If this assumption is correct, the sense of enantiose-
lectivity is easily explained by the attack of the nucle- chlorotrimethylsilane (7 mmol, 0.97 mL. 0.760 g) were added
1890
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1883 – 1893

Diastereoselective Synthesis of 2,6-Di[1-(2-alkylaziridin-1-yl)alkyl]pyridines
FULL PAPERS
at 08C. After 3 h the solvent was removed under vacuum. A
solution of cyclohexane/diethyl ether (1:1) was added and
the solid phase was filtered off on a pad of Celite. The or-
ganic solvent was evaporated under reduced pressure to
leave the imine in almost quantitative yield; this was used in
the following step without further purification.
(39 mg, 0.24 mmol) in THF (1 mL) was added. The solution
was stirred overnight, then filtered through an HPLC filter
(0.45 mm) and the solvent was removed under reduced pres-
sure to give a white solid: yield: 0.130 g (91%).
White crystals, suitable for X-ray diffraction analysis were
obtained from a double-layer of CH2Cl2 and pentane: white
crystals; mp 124–1268C (dec); [a]20: +21.1 (c 1.2, CHCl3);
IR (KBr): n=3052, 3030, 2882, 160D5, 1567, 1496, 1452, 1265,
Preparation of b-Amino Alcohols 9 by Addition of
Organolithium Reagents to Imines 8
1014, 840, 732, 701, 553 cmÀ1
.
1
The H NMR spectra of all the allyl and 1,3-diphenylallyl
cationic Pd complexes synthesized showed the presence of
different species, but the exo and endo rotamers were preva-
lent with variable ratios. Specifically, the spectrum of the
complex 10ae’(1,3-diphenylallyl)PdPF6 (600 MHz, CDCl3)
showed a 55:45 ratio of two rotamers, with the following ab-
sorptions of the allylic protons: major rotamer, d =5.98 (t,
J=11.4 Hz, 1H), 4.75 (d, J=11.4 Hz, 1H), 4.67 (d, J=
11.4 Hz, 1H) ppm; minor rotamer, d =6.13 (t, J=11.4 Hz,
1H), 5.0 (d, J=11.4 Hz, 1H), 4.40 (d, J=11.4 Hz, 1H) ppm.
On the other hand, the 1H NMR spectrum (300 MHz,
CDCl3) of 10ba’(1,3-diphenylallyl)PdPF6 showed the pres-
ence of a prevalent species (ca. 75%) with the syn,syn ge-
ometry of the allylic ligand, whose protons gave absorptions
at d =6.16 (t, J=11.4 Hz, 1H), 4.43 (d, J=11.4 Hz, 1H) and
3.80 (d, J=11.4 Hz, 1H).
The organolithium reagent (9 mmol) was added to a mag-
netically stirred solution of the imine 8 (3 mmol) in THF
(10 mL) cooled to À788C. After 30 min, the reaction mix-
ture was slowly warmed at 08C, and quenched after 3 h by
adding 1 N HCl (10 mL). After 2 h NaOH pellets were
added until the solution reached pH 11, and the organic
phase was extracted with diethyl ether (3 ×10 mL). The col-
lected ether phases were dried over Na2SO4 and concentrat-
ed to leave the crude products. The diastereomeric ratio was
1
determined by H NMR analysis. Flash column chromatog-
raphy (SiO2), eluting with cyclohexane/ethyl acetate mix-
tures, gave the product which was directly used in the subse-
quent step. In order to obtain a satisfactory elemental analy-
sis, further purification by chromatography or crystallization
was carried out.
Preparation of b-Amino Alcohols 9af’ and 9bf’ by
Reduction of Imines 8a and 8b
A
G
G
X-Ray details: Bruker APEX II CCD diffractometer (Mo-
Ka radiation l=0.71073 Å). Results: C32H40F6N3PPd, Mr =
718.04, monoclinic P21, a=11.0990(13), b=13.3802(16), c=
11.9282(14) Å, b=112.045(2), V=1641.9(3) Å3, Z=2, 1x =
To a solution of imine 8a or b (1 mmol) in methanol (5 mL),
NaBH4 (2 mmol, 0.076 g) was added in one portion. After
1 h the reaction was quenched with 1 N HCl (5 mL) and fur-
ther stirred for 2 h. Then NaOH pellets were added until
the solution reached pH 11, and the organic phase was ex-
tracted with diethyl ether (3×10 mL). The collected ether
phases were dried over Na2SO4 and concentrated to leave
the crude product in quantitative yield. Pure compounds
were obtained by column chromatography (SiO2) eluting
with cyclohexane/ethyl acetate mixtures.
1.452 MgmÀ3, m 0.674 mmÀ1, F
ACHTREUNG
q
R1=0.0347, wR2=0.0860, GOF=0.997, absolute structure
parameter=À0.04(2). Crystallographic data (excluding
structure factors) for the structure reported in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC
297723. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2
Preparation of Aziridines 10
1EZ, UK [Fax: int. code + 44(1223)336–033; E-mail: de-
posit@ccdc.cam.ac.uk].
N
To a solution of b-amino alcohol 9 (2.8 mmol) in THF
(20 mL) was added PPh3 (6.2 mmol, 1.6 g). To this solution
DEAD (6.2 mmol, 1.082 g) was added dropwise. After 4 h, a
solution of 2 N KOH (10 mL) was added to the mixture,
which was stirred for 3 h. Diethyl ether was added (30 mL)
and the organic phase was separated. The aqueous phase
was extracted with Et2O (3×20 mL), and the collected or-
ganic phase was washed with 2 N KOH (3×10 mL), then
with brine. The organic phase was dried over Na2SO4 and
concentrated under reduced pressure. The residue was flash-
chromatographed on a SiO2 column eluting with cyclohex-
ane/ethyl acetate mixtures. In order to obtain analytically
pure samples, further purification by chromatography or
crystallization was carried out.
Palladium-Catalyzed Allylic Alkylation
To a solution of DIAZAP 10ba’ (0.03 mmol, 10 mg) in
CH2Cl2 (2 mL) was added (allylPdCl)2 (0.014 mmol, 5 mg)
and the solution was degassed and stirred for 1 h. 1,3-Di-
phenyl-2-propenyl ethyl carbonate (14b) (0.27 mmol, 76 mg)
was then added followed by dimethyl malonate (0.67 mmol,
90 mg), BSA (0.81 mmol, 0.165 g) and KOAc (0.02 mmol,
2 mg) after 10 min. The reaction was monitored by TLC
analysis and, when complete, quenched with 1 N HCl solu-
tion (1 mL) and the organic phase was extracted with dieth-
yl ether (3 ×10 mL). The organic layer was dried over
Na2SO4 and the solvents were evaporated to dryness. The
crude product was purified by chromatography on a silica
gel column (hexane/AcOEt, 75:5) affording methyl (R)-(E)-
3,5-diphenyl-2-methoxycarbonyl-4-pentenoate (15); yield:
73 mg (84%). An ee of 99% was determined by chiral
Preparation of Allylic Palladium Complexes; Typical
Procedure: [10ae’
N
N
Allylpalladium chloride dimer (73 mg, 0.1 mmol) was added
to a solution of ligand 10ae’ (80 mg, 0.2 mmol) in CH2Cl2
(4 mL) in one portion. After one hour a solution of NH4PF6
HPLC (Chiralpak AD; 2-propanol/hexane1:9, 1.0 mLminÀ1
;
Adv. Synth. Catal. 2006, 348, 1883 – 1893
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1891

Diego Savoia et al.
FULL PAPERS
250 nm); retention times: 10.7 min (major enantiomer), References
14.9 min (minor enantiomer).
17a: yield: 88%, ee: 97%; [a]20: À38.7 (c 2.0, CHCl3). The
ee was determined by chiral HPDLC (Chiralpak AD; 2-prop-
anol/hexane 3:97; 1.0 mLminÀ1, 250 nm); retention times:
16.6 min (major enantiomer), 17.1 min (minor enantiomer).
The absolute configuration of the product was determined
by comparison of its optical rotation with that of the known
compound.[13e]
[1] a) A. Togni, L. M. Venanzi, Angew. Chem. Int. Ed.
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17b: yield: 89%, ee: 99%; [a]20: À48.4 (c 1.5, CHCl3). The
ee was determined by chiral HPDLC (Chiralpak AD; 2-prop-
anol/hexane 1:99, 0.8 mLminÀ1, 250 nm); retention times:
8.3 min (minor enantiomer), 10.9 min (major enantiomer).
The absolute configuration was assumed by analogy with
compound 17a.
19: yield: 40%, ee: 6%; [a]2D0: +5.0 (c 1.1, CHCl3). The ee
was determined by chiral GC: Megadex Chiral column
(25 m, flow rate: 15 mLminÀ1, 508C (2 min), then 38CminÀ1
up to 1908C, FID detection): retention times: 27.2 min
(minor enantiomer), 27.3 min (major enantiomer). The ab-
solute configuration of the product was determined by com-
parison of its optical rotation with that of the known com-
pound.[14]
21: yield: 85%, ee: 28%; [a]20: +6.5 (c 1.2, CHCl3). The
ee was determined by chiral GDC (Megadex Chiral column
(25 m, flow rate: 15 mLminÀ1, isotherm 658C, FID detec-
tion); retention times: 49.5 min (minor enantiomer),
51.6 min (major enantiomer). The absolute configuration of
the product was determined by comparison of its optical ro-
tation with that of the known compound.[15]
23 and 24: The ratio was determined by GC-MS analysis.
The ees of 23 and 24 were determined by chiral HPLC
(Chiralpak OD, 2-propanol/hexane 1:99, 0.5 mLminÀ1,
250 nm); retention times of 24: 14.2 min (major enantio-
mer), 15.1 min (minor enantiomer); retention times of 23:
17.9 (minor enantiomer), 18.8 (major enantiomer).
27: yield: 83%, ee 27%; [a]2D0: À23.5 (c 1.6, CHCl3). The
ee was determined by chiral HPLC (Chiralpak OD, 2-propa-
nol/hexane 5:95, 0.4 mLminÀ1, 250 nm); retention times:
13.7 min (minor enantiomer), 15.6 min (major enantiomer).
The absolute configuration of the product was determined
by comparison of its optical rotation with that of the known
compound.[16b]
[7] a) K. Bernauer, F. Gretillat, Helv. Chim. Acta 1989, 72,
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Supporting Information
Characterization data for compounds 8, 9 and 10. Table with
bond lengths and angles for the cation (10ae’)
(allyl)Pd+.
1
A
1H NMR of the salt [(10ae’)
COSY of the salts [(10ae’)(1,3-diphenylallyl)Pd]
[(10ba’)(1,3-diphenylallyl)Pd][PF6].
C
ACHTREUNG
1
AHCTREUNG
ˇ
ˇ
ˇ
ˇ
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Acknowledgements
This work was carried out in the field of the Prin Project
“Sintesi e stereocontrollo di molecole organiche per lo svilup-
po di metodologie innovative”. A. G. held a scholarship from
GSK (Verona). We also thank the University of Bologna for
financial support.
1892
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Diastereoselective Synthesis of 2,6-Di[1-(2-alkylaziridin-1-yl)alkyl]pyridines
FULL PAPERS
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