N-Pyridylmethylephedrine derivatives in the catalytic asymmetric addition of diethylzinc to aldehydes and diphenylphosphinoylimines

Article abstract of DOI:10.1016/j.tetasy.2009.08.014

N-Pyridylmethyl-substituted Ephedra derivatives were synthesized by either direct alkylation or reductive alkylation of (1R,2S)-norephedrine, (1S,2S)-pseudo norephedrine, and (1R,2S)-ephedrine. These derivatives were then employed in asymmetric addition reactions with diethylzinc and aldehydes and diphenylphosphinoylimines. The use of the diastereomers from the Ephedra family allowed for a systematic evaluation of the contribution of the N-pyridylmethyl.

Full text of DOI:10.1016/j.tetasy.2009.08.014

Tetrahedron: Asymmetry 20 (2009) 2154–2161
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
N-Pyridylmethylephedrine derivatives in the catalytic asymmetric addition
of diethylzinc to aldehydes and diphenylphosphinoylimines
*
*
Sucharita Banerjee, Jonathan A. Groeper, Jean M. Standard , Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2009
Accepted 18 August 2009
Available online 12 September 2009
N-Pyridylmethyl-substituted Ephedra derivatives were synthesized by either direct alkylation or reductive
alkylation of (1R,2S)-norephedrine, (1S,2S)-pseudo norephedrine, and (1R,2S)-ephedrine. These derivatives
were then employed in asymmetric addition reactions with diethylzinc and aldehydes and diph-
enylphosphinoylimines. The use of the diastereomers from the Ephedra family allowed for a systematic
evaluation of the contribution of the N-pyridylmethyl.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
hanced the level of enantioselection of the reaction over that of
the N-benzyl substituent (cf. catalysis with 6 and 7). Wu et al. spec-
Since the pioneering efforts of Oguni and Omi in 1984 in the
development of the catalytic asymmetric addition of diorganozinc
compounds to aldehydes, there have been many research groups
that have explored the preparation and application of structurally
diverse ligands.1,2 Among the ligands that have shown great prom-
ise in this field, the Ephedra alkaloids ephedrine and norephedrine
have been remarkably successful as chiral, non-racemic templates
for building a diverse array of ligands (Fig. 1). Soai et al.2b,3 were
instrumental in demonstrating the effectiveness of the Ephedra
alkaloids by the synthesis and application of a variety of symmet-
rically substituted N,N-dialkylnorephedrine derivatives, for exam-
ple, 1a–c. Mono N-alkylnorephedrine derivatives 2a–c have also
been prepared and studied,4,5 although the N,N-dialkyl derivatives
are usually more effective in generating higher enantiomeric ratios
when applied in the catalytic asymmetric addition of diorganozinc
reagents to carbonyl compounds. Of particular interest were the
N,N-disubstituted ephedrine-derived systems, such as 3a–c, where
the two N-alkyl substituents are of different constitutions, one
being a methyl group and the other being a benzyl or substituted
benzyl moiety. Despite the dissymmetry of the substituents, these
ligands still provide very good enantioselectivities.6–9
ulated that the level of substitution on the b-amino alcohol frame-
work was responsible for the high enantioselectivity observed with
the application of ligand 7. It was also proposed that the N-pyridyl-
methyl group only had a limited supporting role in the overall pro-
cess.10 There is the possibility that the N-pyridylmethyl ligand is
more involved in the overall catalysis than originally proposed.
Herein, we report on our efforts to study the impact of the N-pyr-
idylmethyl group in Ephedra ligands in the catalytic asymmetric
addition of diethylzinc to aldehydes and the ligand promoted addi-
tion of diethylzinc to N-(P,P-diphenylphosphinoyl) imines.
2. Results and discussion
(1R,2S)-Norephedrine 10 and (1S,2S)-pseudonorephedrine 11
were reductively alkylated by the reaction with either benzalde-
hyde, pyridine-2-carboxaldehyde, 5-methylpyridine carboxaldeh-
dye, or quinoline-2-carboxaldehyde followed by treatment with
sodium borohydride to afford derivatives 12–18 (Scheme 2). These
compounds were used as ligands in the catalytic asymmetric addi-
tion of diethylzinc to benzaldehyde as a test reaction (Table 1). Li-
gand 12 is a known compound that has been employed in the
asymmetric addition reaction.5 This ligand is described here for
the sake of comparison. The comparative product enantioselectiv-
ities generated by ligands 12 and 13 [12 (84.5:15.5 favoring the
(R)-enantiomer); 13 (45:55 favoring the (S)-enantiomer)] illus-
trated the different capacity for asymmetric induction exhibited
by these diastereomeric derivatives. The opposite configurations
observed in the products are believed to be due to the change in
configuration at the benzylic position.
In the context of these substituted Ephedra compounds, Wu
et al.10 have demonstrated that the introduction of a pyridylmethyl
substituent, a group that is effectively isosteric with the benzyl
substituent, could have a detrimental effect on the enantiomeric
ratio observed for the asymmetric addition of diethylzinc to alde-
hydes (Scheme 1, cf. catalysis with 45 and 5). In contrast, the use
of a highly substituted b-amino alcohol template derived from L-
valine demonstrated that the N-pyridylmethyl substituent en-
Interestingly, when the N-benzyl substituent was replaced
with an N-pyridylmethyl group to afford derivatives 5 and 14,
* Corresponding authors. Tel.: +1 309 438 7854; fax: +1 309 438 5538.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.014

S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
2155
R
H3C
HO
Ph
NR2
CH3
HO
Ph
NHR
CH3
HO
Ph
N
CH3
1a: R = -CH3
2a: R = -CH3
3a: R = -H (benzyl)
3b: R = -(CHPhCH2)n- (polymer bound)
3c: R = -C(CH2CH2C6F13 3
1b: R = -n-C4H9
1c: R = -CH2C6H5
2b: R = -CH2CH3
2c: R = -CH(CH3)2
)
Figure 1. Ephedra derived ligands for asymmetric synthesis.
Table 1
OH
Ph
OH
H
N
H
N
Catalytic asymmetric addition of diethylzinc with ligands 4 and 12–18
Ph
X
Ph
X
O
OH
H
Et
Ph
Ephedra ligands 4, 12-18
CH3
Ph
H
Et2Zn, toluene
4: X = CH (ref. 5)
5: X = N
6: X = CH
7: X = N
8a
9a
Entry
Liganda
Enantiomeric ratiob
% eec
ligand 4: 69%ee (R)
ligand 5: 3.3%ee (S)
ligand 6: 34.5%ee (R)
ligand 7: 91.8%ee (R)
O
OH
ligand 4-7, Et2Zn
1
2
3
4
5
6
7
8
12
13
510
14
15
16
17
18
84.5 (R):15.5 (S)
45.0 (R):55.0 (S)
48.4 (R):51.6 (S)
47.9 (R):52.1 (S)
42.9 (R):57.1 (S)
34.3 (R):65.7 (S)
62.3 (R):37.7 (S)
59.5 (R):40.5 (S)
69 (R)
10 (S)
toluene
Ph
H
Ph
3.3 (S)
4.2 (S)
14.3 (S)
31.5 (S)
24.6 (R)
19.0 (R)
8a
9a
Scheme 1. N-Pyridyl ligands and asymmetric addition.
the diastereoselectivities of the reaction underwent a drastic
change. The Ephedra-based ligands 5 and 14 afforded the product
alcohol in very low enantioselectivies, and in each case, the same
(S)-configuration was obtained. The N-benzyl analogue of 5, that
is, 12, afforded the (R)-configured product as the dominant enan-
tiomer in the asymmetric addition process. This change in config-
uration suggested that the presence of the N-pyridylmethyl
substituent is indeed involved in a significant way which dimin-
ishes the impact of the benzylic position on the Ephedra ligand.
Mechanistically, it is proposed that there are equilibria involving
multiple species that are capable of yielding the addition product
either through coordination in the commonly accepted transition
state model11 TS-1 or in a transition state that involves the N-
methylpyridyl ligand TS-2 (Fig. 2). As depicted in TS-2, the interac-
tion with the nitrogen of the pyridyl ring with diethylzinc leads to
a transition state in which an eight-membered ring with significant
flexibility forms.
a
b
c
All reactions reached completion as determined by 1H NMR spectroscopy.
Enantiomeric ratios were determined by chiral stationary phase HPLC.
Absolute configuration was determined by comparison of HPLC data with the
literature values (see Ref. 3).
Presumably, the presence of the a-methyl ring substituent dimin-
ishes the ability of the pyridyl nitrogen to coordinate to the dieth-
ylzinc thereby allowing the TS-1 to make a greater contribution to
the stereochemical outcome of the reaction. Finally, the use of the
N-quinolylmethyl derivatives 17 and 18 afforded the (R)-enantio-
mer as the dominant product. This would suggest that the N-quin-
olylmethyl substituent is even more efficient in diminishing the
contribution of the alternate coordinating form TS-2.
The collected results from the use of Ephedra ligands 5 and 12–
19 clearly suggest that the introduction of an additional mode of
coordination can be detrimental to obtaining good levels of enan-
tioselection in the catalytic asymmetric addition of diethylzinc to
The use of N-pyridylmethyl derivatives 15 and 16 yielded
marginally improved enantioselectivities in the observed products.
R
1a.
X
CHO
X = CH or N
OH
R2
EtOH, MgSO4
1b. NaBH4, EtOH
NH2
R1
CH3
10: R1 = -Ph; R2 = -H
11: R1 = -H; R2 = -Ph
OH
R2
H
N
OH
R2
H
N
OH
H
N
OH
R2
H
N
R1
R1
R1
R2
R1
N
N
CH3
N
CH3
CH3
CH3
CH3
12: R1 = -Ph; R2 = -H (ref. 5)
13: R1 = -H; R2 = -Ph (81%)
5: R1 = -Ph; R2 = -H (ref. 10)
14: R1 = -H; R2 = -Ph (79%)
15: R1 = -Ph; R2 = -H (82%)
16: R1 = -H; R2 = -Ph (66%)
17: R1 = -Ph; R2 = -H (84%)
18: R1 = -H; R2 = -Ph (63%)
Scheme 2. Ligand synthesis.

2156
S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
Et
R
Et
O
H
Zn
Zn
R1
R2
R1
R2
H3C
R1
R2
H
O
O
N
R
OH
N
O
N
Et
Et2Zn, RCHO
Zn
Et
Zn
Et
H3C
H3C
H
Et
H
H
N
X
R3
X
R3
R3
5, 12-18
X = -CH, N
TS-1
good enantioselectivity
TS-2
compromised enantioselectivity
Figure 2. Proposed transition states.
benzaldehyde. There was also an interest in determining if the use
of b-tertiary amino alcohols derived from (1R,2S)-ephedrine 19 and
(1S,2S)-pseudoephedrine 20 might offer improved enantioselec-
tion in the asymmetric process and provide greater insight into
the contribution of the N-pyridylmethyl group. To this end, 19
Table 2
Catalytic asymmetric addition of diethylzinc with 3a and 21–24
O
OH
H
Et
3a, 21-24
Ephedra ligand
Ph
H
Et2Zn, toluene
Ph
and 20 were alkylated with either benzyl bromide or with a-bro-
8a
9a
momethylpyridinium hydrobromide to afford ligands 3a and
21–24 (Scheme 3). For the sake of carrying out a more complete
structural comparison, (1R,2S)-norephedrine 10 was reacted with
two equivalents of benzyl bromide to afford the known N,N-diben-
zylnorephedrine derivative 243a,12 in 48% yield after chromatogra-
phy. With these ligands in hand, we pursued a preliminary study
on the asymmetric addition reactions with diethylzinc and benzal-
dehyde (Table 2).
In contrast to the secondary b-amino alcohols derived from
(1R,2S)-norephedrine, the tertiary systems, with the exception of
ligands 23 and 24, exhibited significantly higher enantiomeric ra-
tios. The ephedrine-based ligand 3a yielded an enantiomeric ratio
of 88:12 (76% ee) favoring the (R)-enantiomer. The N-pyridyl-
methyl ephedrine-based analogue 21 afforded an enantiomeric ra-
tio of 84.5:15.5 (69% ee) favoring the (R)-enantiomer as well. This
was a considerable change from the results obtained from the use
of the N-benzyl- and N-pyridylmethylnorephedrine derivatives 12
and 5 which yielded the addition products in ratios of 84.5 (R):15.5
(S) (69% ee) and 48.4 (R):51.6 (S) (3.3% ee), respectively. In the case
of the norephedrine ligand 5 where the nitrogen is secondary, it is
presumed that the N-pyridylmethyl can readily coordinate with
diethylzinc, leading to lower selectivity.
The pseudoephedrine ligands 22 and 23 predominantly affor-
ded the (S)-enantiomer of the addition product when employed
in the asymmetric addition reaction. The N-benzylpseudoephe-
drine derivative 22 had a moderate enantiomeric ratio of 20:80
(60% ee) favoring the (S)-enantiomer. However, the corresponding
N-pyridylmethyl derivative 23 yielded the product with an enanti-
oselectivity of 45:55 (10% ee) favoring the (S)-enantiomer.
For the sake of further comparison, the N,N-dibenzylnorephe-
drine ligand 24 was also employed in the asymmetric reaction. It
Entry
Liganda
Enantiomeric ratiob
% eec
1
2
3
4
5
3ad
21
22
23
24
88.0 (R):12.0 (S)
84.5 (R):15.5 (S)
20.0 (R):80.0 (S)
45.0 (R):55.0 (S)
53.0 (R):47.0 (S)
76 (R)
69 (R)
60 (S)
10 (S)
6 (R)
All reactions reached completion as determined by 1H NMR spectroscopy.
Enantiomeric ratio was determined by chiral stationary phase HPLC.
Absolute configuration was determined by comparison of HPLC data with the
a
b
c
literature values (see Ref. 3).
d
See Ref. 6.
was determined that the system was not effective in inducing
asymmetry [53:47 (6% ee) favoring the (R)-enantiomer] and that
reduction of the aldehyde substrate was a major reaction pathway
(>40%). The presence of the reduction product is suggestive of the
failure of the catalyst system to properly interact with the sub-
strate. With these results in hand, a tentative model for the cata-
lytic asymmetric addition of diethylzinc to these ligands was
developed (Fig. 3).
The enantioselectivity was moderate (60% ee) in the case of the
ephedrine derived 3a, but this was in contrast to the very low
enantioselectivity observed for the related N,N-dibenzylnorephe-
drine ligand 24. This ligand differed from 3a only by the substitu-
tion at nitrogen (–CH2Ph vs –CH3) but afforded a significantly
lower enantiomeric excess when used in the asymmetric addition
process. The origin of the lower enantioselectivity is believed to be
rooted in the presence of transition states of an acyclic nature (TS–
Et2Zn–24B) that diminish the capacity of the norephedrine scaffold
to influence the stereochemical outcome of the reaction (Fig. 3).
OH
OH
R2
X
X
CH2Br
NHR3
R1
N
R2
K2CO3, THF, 48 hrs
R3
R1
CH3
CH3
10: R1 = -Ph; R2 = R3 = -H
3a: R1 = -Ph; R2 = -H; R3 = -CH3; X = -H (82%)
19:
20:
R
1 = -Ph; R2 = -H; R3 = -CH3
21:
22:
R
R
1 = -Ph; R2 = -H; R3 = -CH3; X = -N (51%)
1 = -H; R2 = -Ph; R3 = -CH3; X = -H (78%)
R = -H; R2 = -Ph; R3 = -CH3
1
23: R1 = -H; R2 = -Ph; R3 = -CH3; X = -N (41%)
24: R1 = - h; R2 = -H; R3 = -CH2Ph; X = -H (48%)
P
Scheme 3. Ligand synthesis.

S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
2157
H
H
H
H
H
CH3
Et
H
Ph
Ph
Ph
OH
CH3
N
CH3
CH3
Zn
N
N
Et
O
O
O
Zn
Zn
Et
Ph
H
Zn
Et
Zn
Et
ZnEt
Et
Et
Et
O
O
(R)-9a
O
Ph
Ph
Et
Ph
H
H
H
TS-Et2Zn-3a
Moderate enantioselectivity
TS-Et2Zn-24A
TS-Et2Zn-24B
Poor reactivity and low enantioselectivity
Potential for open ring intermediates
Figure 3. Proposed transition states for the asymmetric addition with 3a and 24.
There was an interest in a computational evaluation of the poten-
tial intermediates and transition states that might be involved in the
overall process. The use of a Semi-empirical PM3 methodological
approach was pursued for the study of the interaction of the Ephedra
ligand 3a with diethylzinc and benzaldehyde to address the concern
of the facial preference (Re- or Si-face) for the addition reaction
(Fig. 4). The transition state shown in Figure 4 correctly predicted that
the stereochemical formation of the (R)-enantiomer of the addition
product would require less energy to form than the (S)-enantiomer
where the aldehyde would be arranged in the opposite orientation
Based on the fact that ligand 3a catalyzed the asymmetric addi-
tion of diethylzinc to benzaldehyde with a ratio of 88.0 (R):12.0 (S)
and that ligand 21 catalyzed the same reaction to a similar degree,
it is possible that both ligands might be undergoing similar reac-
tion pathways. The slightly lower enantioselectivity observed in
the application of 21 might be due to the competitive pathways
wherein the pyridyl nitrogen becomes an active participant.
At this stage, the more successful ligands derived from (1R,2S)-
norephedrine and (1R,2S)-ephedrine were reacted with a variety of
aldehyde substrates to determine if the reactivity trends would re-
main the same (Table 3). Thus, the application of the N-benzyl-
ephedrine in the asymmetric addition reaction afforded the
product in an enantiomeric ratio of 91:9 (82% ee) with the (R)-con-
figuration dominating. More importantly, we learnt that the N-pyr-
idylmethylephedrine ligand 21 yielded a comparable level of enan-
tioselection when employed in the addition reaction [87.7:12.2
favoring the (R)-enantiomer]. This suggested that the N-pyridyl-
methyl substituent did not have a detrimental effect on the
reaction as was the case with the N-pyridylmethylnorephedrine
ligand 5 (Scheme 1). The application of the N,N-dibenzylnorephe-
drine ligand 21 afforded the target product in addition to a signif-
icant reduction of the 2-naphthaldehyde substrate. The asym-
metric addition reaction with trans-cinnamaldehyde exhibited a
more pronounced difference in the enantioselection when compar-
ing the products of the reactions employing 3a and 21 as catalysts.
(DHf (R-ent) = ꢀ143.2 kcal/mol,
DHf (S-ent) = ꢀ138.2 kcal/mol).
H
H
Ph
CH3
CH3
N
O
Zn
(R)-9a
Et
Zn
O
Et
H
C
H
H
Ph
CH3
Transition state A-Et2Zn-3a
Figure 4. Putative transition state for ligand 3a and Et2Zn (PM3 semi-empirical
calculations: red = oxygen; blue = nitrogen; and green = zinc).
Table 3
Catalytic asymmetric 1,2-addition of diethylzinc with 3a and 21–24
O
OH
H
Et
3a, 21-24
Ephedra ligand
R
H
Et2Zn, toluene
R
9b: R = -2-(C8H7)
8b: R = -2-(C8H7)
9c: R = -CH=CHPh
9d: R = -CH2OCH2Ph
8c: R = -CH=CHPh
8d: R = -CH2OCH2Ph
Entry
RCHO
Ligand
Yielda
Enantiomeric ratio (R:S), (ee)
Config.d
1
2
3
4
5
6
7
8
9
2-C10H7–
2-C10H7–
2-C10H7–
trans-PhCH@CH–
trans-PhCH@CH–
trans-PhCH@CH–
BnOCH2–
BnOCH2–
BnOCH2–
3a
21
24
3a
21
24
3a
21
24
88
79
82
82
60
72
73
96
35
91.1:8.9 (82)b
87.7:12.2 (76)b
Reductionc
(R)
(R)
nde
(R)
(R)
(R)
nde
nde
nde
84.9:15.1 (70)b
74.4:25.6 (49)b
60.8:39.2 (22)b
52.9:47.1 (5)
39.6:60.4 (21)
46.9:53.1 (6)
a
b
c
Isolated yield after flash chromatography.
Enantiomeric ratio was determined by CSP HPLC with a chiralcel OD column.
1H NMR spectrum indicated the formation of 2-naphthylmethyl alcohol.
d
e
The absolute configuration was determined by comparison with order of elution values from the literature (see Ref. 3).
The absolute configuration was not determined.

2158
S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
This may be due to the difference in the steric demands of the
trans-cinnamaldehyde and 2-naphthaldehyde. Finally, the use of
the benzyloxyacetaldehyde in the asymmetric process afforded
poor enantioselectivities with all ligands presumably due to the
coordination of the aldehyde with diethylzinc to create multiple
species with stereochemically divergent pathways. Surprisingly,
the N-pyridylmethyl ligand 21 gave the best result; the origin for
this result is unknown but speculation is focused on the N-pyridyl-
methyl substituent.
These collected results proved to be interesting but there was
also an interest in employing these systems in the asymmetric
addition of diethylzinc to N-(P,P-diphenylphosphinoyl)imines13 to
further attempt to understand the contribution of the N-pyridyl-
methyl group. This work began with the synthesis of a series of
phosphinoylimines using the method of Jennings and Lovely
(Scheme 4).14 With the requisite imines 25a–d in hand, the ephed-
rine-based ligands 3a, 21, and 24 were employed in the addition
reaction (Table 4).
Pathway B
Pathway A
H
H
CH3
CH3
Ph
CH3
H
O
H
Ph
CH3
N
Zn
O
O
N
Et
Et
Zn
Et
Et
N
Zn
O
Zn
Ph
N
P
P
Ph
Ph
N
Ph
Et
H
Ph
Et
Ph
H
Transition state B-Et2Zn-21-imine
Transition state A-Et2Zn-3a-imine
Figure 5. Putative transition states for ligand 3a and 21 with Et2Zn (PM3 semi-
empirical calculations).
both pathways illustrated in Figure 5 were possible. This does
not preclude the existence of other transition states not depicted
here. The low enantiomeric excess observed from the use of 21
makes a reasonable determination of a proposed comprehensive
mechanism not viable.
PO(Ph)2
O
N
H
Ph2PONH2, TiCl4, TEA
CH2Cl2
H
R
R
3. Conclusion
8a:
8b:
R = -H
R = -F
25a:
R = -H (43%)
R = -F (54%)
R = -Cl (43%)
R = -OMe (85%)
25b:
25c:
25d:
8c: R = -Cl
The ligands prepared in this work strongly suggest that the
presence of the N-pyridylmethyl on the Ephedra scaffold leads to
diminished levels of enantioselection in the asymmetric addition
of diethylzinc to aldehydes. The effect is even more pronounced
in the case of the asymmetric reaction with diethylzinc and diph-
enylphosphinoylimines. It is proposed that the nitrogen of the N-
pyridylmethyl group allows for alternate transition states that
compromise the capacity of the Ephedra component of the ligand
to transmit asymmetry.
8d: R = -OMe
Scheme 4. Diphenylphoshinoylimine synthesis.
Table 4
Asymmetric 1,2-addition of diethylzinc to diphenylphosphinoylimines 25a–d
NHP(O)NH2
3a, 21, 24
Ephedra ligands
25a-d
Et2Zn, toluene
R
4. Experimental section
4.1. General remarks
26a-d
Entry
Imine
Ligand
Yielda
Enantiomeric ratio, (|R–S|)
Config.
1
2
3
4
5
6
7
8
9
25a
25a
25a
25b
25b
25b
25c
25c
25c
25d
25d
25d
3a
21
24
3a
21
24
3a
21
24
3a
21
24
92
68
67
89
77
58
46
48
67
42
Inc.d
48
94.2:5.8 (88)b
45.3:54.7 (9)b
74.4:25.7 (49)b
95.9:4.1 (92)c
38.0:62.0 (24)c
90.7:9.3 (81)c
95.0:5.0 (90)c
44.9:55.2 (10)c
86.3:13.7 (73)c
97.2:2.8 (94)b
nde
(R)
(S)
(R)
(R)
(S)
(R)
(R)
(S)
(R)
(R)
(S)
(R)
Diethylzinc solutions (1 M in hexanes), dry toluene, and
(1R,2S) norephedrine were purchased from Sigma–Aldrich. Pyri-
dine-2-carboxaldehyde, 6-methyl pyridine-2-carboxaldehyde, and
quinoline-2-carboxaldehyde were purchased from Alfa Aesar.
(1S,2S)-Pseudonorephedrine was synthesized by established proce-
dures. Calculations of intermediate and transition state optimized
geometries and energies were carried out by the Semi-empirical
PM3 methodology using the Spartan’02 for Linux molecular model-
ing software package. Optimized structures were confirmed as
minima or transition states by vibrational frequency analysis. All
reactions were performed under an inert nitrogen atmosphere. All
NMR spectra were collected using either a 500 MHz Bruker
NMR (125 MHz for13C {1H} spectroscopy), 400 MHz Varian NMR
(100 MHz for 13C {1H} spectroscopy) or 300 MHz Oxford
NMR (75 MHz for 13C {1H} spectroscopy) spectrometer with all spec-
tra recorded in CDCl3 (d = 77.0 ppm 13C) and reported in parts per
million (d scale) with tetramethylsilane as an internal standard
(d = 0 ppm 1H) and was used for 1H and 13C spectroscopy unless
otherwise stated. On some 1H NMR spectra, the OH and NH peaks
on the spectrum were not observed due to broadening. Infrared data
were acquired using a PerkinElmer Spectrum BX FT-IR spectropho-
tometer on KBr plates and reported in reciprocal centimeters
(cmꢀ1). Optical rotation data were gathered on a Jasco P-2000 polar-
imeter operating at 589 nm in an 8 ꢁ 100 mm cylindrical cell. HPLC
information was gathered on a Shimadzu HPLC SCL-10AVP instru-
ment with a UV–vis detector operating at 254 nm. Melting points
10
11
12
96.5:3.5 (93)b
a
b
c
Isolated Yield after flash chromatography.
Enantiomeric excess was determined by CSP HPLC with a chiralcel AD column.
Enantiomeric excess was determined by CSP HPLC (AS column).
d
The absolute configuration was determined by comparison with order of elu-
tion values from the literature (see Ref. 3).
e
The absolute configuration was not determined.
The N-benzylephedrine ligand 3a performed well in these trial
experiments as described in earlier literature and afforded prod-
ucts 26a–d in very good enantiomeric excess.6 In contrast, the
addition of diethylzinc mediated by the N-pyridylmethyl ligand
21 to the phosphinoylimines yielded the corresponding amine
products 26a–d in very low enantiomeric excess. It is proposed
that the two ligands, 3a and 21, potentially catalyze the addition
reaction through dissimilar transition states (Fig. 5). The use of
the PM3 Semi-empirical computational method suggested that

S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
2159
were determined using a Laboratory Devices Mel-Temp apparatus
4.2.4. (1S,2S)-2-((6-Methyl-2-pyridyl)methylamino)-1-phenyl-
1-propanol 16
and are uncorrected. Compound 5 was previously prepared by Wu
et al.10 Compounds 9a–c and 12 were previously prepared by Parrott
and Hitchcock.5 Diphenylphosphinoylimines 25a, 25c, and 25d have
been prepared and characterized by Jennings and Lovely.14 The
amine products 26a, 26c, and 26d have been prepared and charac-
terized by Gong, Mi, et al.15
The compound was obtained from the reductive alkylation of
(1S,2S)-pseudonorephedrine with 6-methyl-2-pyridinecarboxalde-
hyde as a white solid in 66% yield after trituration with diethyl
ether. 1H NMR (300 MHz, CDCl3) d 0.97 (3H, d, J = 6.6 Hz), 2.55
(3H, s), 2.82 (1H, dq, J = 6.6 Hz, J = 8.2 Hz), 3.84 (1H, d, J =
14.3 Hz), 4.02 (1H, d, J = 14.3 Hz), 4.55 (1H, d, J = 8.2 Hz), 7.03
(1H, d, J = 7.7 Hz), 7.08 (1H, d, J = 7.7 Hz), 7.25–7.36 (5H, m), 7.54
(1H, t, J = 7.7 Hz). 13C {1H} NMR (75 MHz, CDCl3) d 16.6, 24.1,
51.8, 59.6, 77.6, 118.9, 121.3, 126.8, 127.3, 127.9, 136.6, 142.5,
157.6, 158.9. FT-IR (Nujol) 3070, 1593, 1578, 1226, 1045, 784,
4.2. General procedure for alkylation
In a flame-dried, nitrogen-purged flask 1.0 g of (1S,2S)-pseudo-
norephedrine or (1R,2S)-norephedrine was dissolved in 20 mL of
absolute ethanol. To this solution was added a portion of anhy-
drous MgSO4 followed by the addition of 1.05 equiv of the alde-
hyde. The reaction mixture was allowed to react for 14–18 h at
which time the reaction vessel was cooled in an ice bath and
the Schiff’s base was reduced with the addition of 1.5 equiv of
NaBH4. The subsequent reduction was allowed to progress for
2 h after which the reaction was quenched by the addition of a
1 M NaOH solution. The ethanol was removed under vacuum
and the product was extracted with ethyl acetate and washed
with brine.
767, 706. Mp 107–109 °C. ½a D25
¼ þ112:5 (c 1, CH2Cl2). HRMS
ꢂ
(M+1) calcd for C16H21N2O: 257.1654, found: 257.1653.
4.2.5. (1R,2S)-1-Phenyl-2-(2-quinolylmethylamino)-1-propanol
17
The compound was obtained from the reductive alkylation of
(1R,2S) norephedrine with quinoline-2-carboxaldehyde as a yellow
solid in 84% yield after flash chromatography. 1H NMR (400 MHz,
CDCl3) d 0.95 (3H, d, J = 6.3 Hz), 3.01 (1H, dq, J = 3.5 Hz, J = 6.3 Hz),
4.14 (1H, d, J = 15.6 Hz), 4.23 (1H, d, J = 15.6 Hz), 4.8 (1H, d, J =
3.5 Hz), 7.22 (1H, d, J = 7.0 Hz), 7.28–7.35 (6H, m), 7.48 (1H, t,
J = 7.0 Hz), 7.66 (1H, dt, J = 7.0, 8.2 Hz), 7.75 (1H, d, J = 8.2 Hz), 8.05
(1H, d, J = 8.6 Hz) 13C {1H} NMR (100 MHz, CDCl3, due to coincidental
overlap, some peaks in the aromatic region are missing) d 14.5, 52.7,
59.0, 73.3, 120.2, 126.0, 126.1, 126.7, 127.4, 127.8, 128.6, 129.5,
136.5, 141.5, 147.3, 160.0. FT-IR (Nujol) 3100, 1617, 1598, 1267,
4.2.1. (1S,2S)-2-(Benzylamino)-1-phenyl-1-propanol 13
The compound was obtained from the reductive alkylation of
(1S,2S) pseudonorephedrine with benzaldehyde as white crystals
in 81% yield after recrystallization with diethyl ether and hexanes.
1H NMR (300 MHz, CDCl3) d 0.97 (3H, d, J = 6.3 Hz), 2.76 (1H, dq,
J = 6.3 Hz, J = 7.8 Hz), 3.67 (1H, d, J = 13.3 Hz), 3.88 (1H, d,
J = 13.3 Hz), 4.18 (1H, d, J = 7.8 Hz), 7.23–7.35 (10H, m). 13C {1H}
NMR (75 MHz, CDCl3, due to coincidental overlap, some peaks in
the aromatic region are missing) d 16.3, 51.0, 59.1, 77.5, 126.9,
127.0, 127.5, 128.0, 128.1, 139.9, 142.2. FT-IR (Nujol) 3100, 1600,
1152, 1083, 989,830,761, 696.Mp87–89 °C. ½a D25
þ 34:9 (c1,CH2Cl2).
ꢂ
HRMS (M+H)+ calcd for C19H21N2O: 293.1654, found: 293.1647.
4.2.6. (1S,2S)-1-Phenyl-2-(2-quinolylmethylamino)-1-propanol
18
The compound was obtained from the reductive alkylation of
(1S,2S)-pseudonorephedrine with quinoline-2-carboxaldehyde as
white crystals in 63% yield after trituration with diethyl ether. 1H
NMR (400 MHz, CDCl3) d 1.00 (3H, d, J = 6.6 Hz), 2.89 (1H, dq,
J = 6.6 Hz, J = 8.2 Hz), 4.08 (1H, d, J = 15.2 Hz), 4.23 (1H, d, J =
15.2 Hz), 4.33 (1H, d, J = 8.2 Hz), 7.24–7.38 (7H, m), 7.51 (1H, t,
J = 7.0 Hz), 7.69 (1H, dt, J = 7.0 Hz, J = 8.6 Hz), 7.79 (1H, d, J = 7.8 Hz),
8.09 (1H, t, J = 8.6 Hz). 13C {1H} NMR (100 MHz, CDCl3, due to coinci-
dental overlap, some peaks in the aromatic region are missing)
d 17.0, 52.5, 60.0, 77.9, 120.3, 126.2, 126.9, 127.4, 127.5, 128.2,
128.7, 129.6, 136.6, 142.5, 147.4, 160.1. FT-IR (Nujol) 3060, 1604,
1584, 1041, 1025, 759, 698. Mp. 66–68 °C. ½a D24
¼ þ128:9 (c 1,
ꢂ
CH2Cl2). HRMS (M+H+) calcd for C16H20NO: 242.1545, found:
242.1551.
4.2.2. (1S,2S)-1-Phenyl-2-(2-pyridylmethylamino)-1-propanol
14
The compound was obtained from the reductive alkylation of
(1S,2S)-pseudonorephedrine with 2-pyridine carboxaldehyde as a
light yellow oil in 79% yield after flash chromatography. 1H NMR
(400 MHz, CDCl3) d 0.98 (3H, d, J = 6.6 Hz), 2.84 (1H, dq, J = 6.6 Hz,
J = 8.2 Hz), 3.81 (1H, d, J = 14.3 Hz), 3.87 (1H, br s), 4.05 (1H, d,
J = 14.3 Hz), 4.30 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 5.1 Hz,
J = 7.4 Hz), 7.25–7.35 (6H, m), 7.63 (1H, t, J = 7.4 Hz, 8.49 (1H, d,
J = 5.1 Hz). 13C {1H} NMR (100 MHz, CDCl3) d 16.5, 52.0, 59.6, 77.6,
122.0, 122.2, 126.9, 127.5, 128.1, 136.5, 142.3, 148.9, 159.2. FT-IR
1222, 1045, 833, 742, 695. Mp 137–139 °C. ½a D25
¼ þ132:5 (c 1,
ꢂ
CH2Cl2). HRMS (M+1) calcd for C19H21N2O: 293.1654, found:
293.1646.
4.2.7. (1R,2S)-2-(Methyl(2-pyridylmethyl)amino)-1-
phenylpropan-1-ol 21
(neat) 702, 757, 1045, 1149, 1592, 3298. ½a D25
¼ þ92:1 (c 1, CH2Cl2).
ꢂ
In a 250 mL round-bottomed flask were added (1R,2S)-ephed-
rine (2.0 g, 12 mmol), THF (40 mL), K2CO3 (5.00 g, 36.3 mmol),
and 2-bromoethylpyridine.HBr (3.06 g, 12.1 mmol). The tempera-
ture of the reaction mixture was raised to reflux and was allowed
to run overnight (18 h). The reaction mixture was cooled to room
temperature. Next, NaOH (1 M, 100 mL) was added to the reaction
mixture, after which THF was evaporated from the reaction mix-
ture via rotary evaporation. The residue was extracted with NaOH
solution (1 M, 50 mL ꢁ 2) and EtOAc (50 mL ꢁ 2). The organic layer
was washed with brine (100 mL) and dried over MgSO4. The sol-
vent was evaporated via rotary evaporation. The resultant residue
was purified by flash chromatography using hexanes/EtOAc
(55:45) and triethylamine and the product was recovered as a col-
orless oil (51%). 1H NMR (400 MHz, CDCl3) d 1.00 (3H, d, J = 7.1 Hz),
2.28 (3H, s), 2.95 (1H, dq, J = 4.4 Hz, J = 7.1 Hz), 3.73 (1H,
d, J = 14.8 Hz), 3.89 (1H, d, J = 14.8 Hz), 4.89 (1H, d, J = 4.4 Hz),
HRMS (M+1) calcd for C15H19N2O: 243.1497, found: 243.1498.
4.2.3. (1R,2S)-2-((6-Methyl-2-pyridyl)methylamino)-1-phenyl-
1-propanol 15
The compound was obtained from the reductive alkylation of
(1R,2S)-norephedrine with 6-methyl-2-pyridinecarboxaldehyde as
a light yellow oil in 82% yield after flash chromatography. 1H NMR
(300 MHz, CDCl3) d 0.88 (3H, d, J = 6.6 Hz), 2.55 (3H, s), 2.98 (1H,
dq, J = 3.8, 6.6 Hz), 3.97 (1H, d, J = 14.6 Hz), 4.05 (1H, d, J = 14.6 Hz),
4.80 (1H, d, J = 3.8 Hz), 7.04 (1H, d, J = 7.7 Hz), 7.07 (1H, d,
J = 7.7 Hz), 7.23–7.36 (5H, m), 7.54 (1H, t, J = 7.7 Hz). 13C {1H} NMR
(75 MHz, CDCl3) d 14.5, 24.2, 52.1, 58.6, 73.0, 118.9, 121.4, 125.9,
126.6, 127.7, 136.6, 141.6, 157.7, 158.7. FT-IR (neat) 3303, 3062,
1594, 1578, 1118, 1028, 749, 701. ½a D25
¼ þ12:8 (c 1, CH2Cl2). HRMS
ꢂ
(M+1) calcd for C16H21N2O: 257.1654, found: 257.1645.

2160
S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
7.10–7.35 (7H, m), 7.58 (1H, dt, J = 6.1 Hz, J = 7.7 Hz), 8.46 (1H, d,
J = 4.9 Hz). 13C {1H} NMR (100 MHz, CDCl3) d 9.3, 39.1, 59.3, 64.1,
73.7, 121.6, 122.4, 126.0, 126.4, 127.6, 136.3, 143.4, 148.3, 160.0.
was added and allowed to react for 18–20 h. The reaction was
quenched with the dropwise addition of ammonium chloride.
Extraction consisted of treatment of the reaction mixture with
30 mL of ethyl acetate and washing the organic portion with 1 M
HCl and brine solutions followed by drying with anhydrous mag-
nesium sulfate and solvent removal.
FT-IR (neat) 3227, 1594, 1569, 1045, 159, 701. ½a D25
¼ ꢀ40:9 (c 1,
ꢂ
CH2Cl2). HRMS (M+1) calcd for C16H21N2O: 257.1654, found:
257.1665.
4.2.8. (1S,2S)-2-(Benzyl(methyl)amino)-1-phenyl-1-propanol 22
The compound was obtained from the alkylation of (1S,2S)-
pseudoephedrine with benzyl bromide (1.1 equiv) dissolved in
refluxing anhydrous THF and potassium carbonate (3 equiv) in
78% yield as a colorless oil after flash chromatography. 1H NMR
(400 MHz, CDCl3) d 0.80 (3H, d, J = 6.6 Hz), 2.21 (3H, s), 2.73 (1H,
dq, J = 6.6 Hz, J = 9.7 Hz), 3.48 (1H, d, J = 12.9 Hz), 3.73 (1H, d,
J = 12.9 Hz), 4.30 (1H, d, J = 9.7 Hz), 4.86 (1H, br s), 7.24–7.34
(10H, m). 13C {1H} NMR (100 MHz, CDCl3, due to coincidental over-
lap, some peaks in the aromatic region are missing) d 7.0, 35.4,
57.8, 64.6, 74.4, 127.0, 127.1, 127.4, 127.9, 128.2, 128.6, 138.4,
141.8. FT-IR (neat) 3334, 1601, 1585, 1093, 1024, 944, 759, 702.
4.3.1. (R)-1-(Benzyloxy)butan-2-ol 9d
In a 100 mL round-bottomed flask were added the ligand
(0.085 g, 0.332 mmol), toluene (17 mL), and Et2Zn (10.0 mL,
10.0 mmol). The reaction mixture was stirred for 30 min at room
temperature. To the reaction mixture was added benzyloxyacetalde-
hyde (0.5 g, 3.32 mmol). The reaction mixture was allowed to run
for 18 h at room temperature and the reaction was quenched with
HCl (1 M, 50 mL). The reaction mixture was extracted with EtOAc
(50 mL). The organic layer was washed with brine (50 mL) and dried
over MgSO4. The solvent was evaporated via rotary evaporation and
the product was purified by flash chromatography (hexanes/EtOAc,
99:1). Colorless oil (73%). ½a D25:0
¼ þ0:3 (c 1.7, CHCl3). IR (Nujol):
ꢂ
½
a 2D3
ꢂ
¼ þ110:7 (c 1, CH2Cl2). HRMS (M+1) calcd for C17H22NO:
3435, 2964, 1098, 738, 698. 1H NMR (400 MHz, CDCl3) d (ppm):
0.91 (t, J = 7.5 Hz, 3H), 1.44 (p, J = 7.5, 2H), 3.03 (s, 1H), 3.29 (dd,
J = 9.0 Hz, J = 2.7 Hz, 1H), 3.42 (dd, J = 9.0 Hz, J = 2.7 Hz, 1H), 3.65–
3.70 (m, 1H), 4.48 (s, 2H), 7.28–7.30 (m, 5H). 13C NMR (100 MHz,
CDCl3): 9.6, 25.9, 71.3, 72.9, 74.1, 127.3, 127.4, 128.0, 137.8. ESI-
HRMS calcd for C11H16O2Na (M+H+): 203.1048, found: 203.1046.
256.3627, found: 256.3633.
4.2.9. (1S,2S)-2-(Methyl(2-pyridylmethyl)amino)-1-phenyl-1-
propanol 23
The compound was obtained from the alkylation of (1S,2S) pseu-
doephedrine with 2-(bromomethyl) pyridinium hydrobromide
(1.1 equiv) dissolved in refluxing anhydrous THF and potassium car-
bonate (3 equiv) in 41% yield as a colorless oil after flash chromatog-
raphy. 1H NMR (300 MHz, CDCl3) d 0.82(3H, d, J = 6.6 Hz), 2.33 (3H, s),
2.77 (1H, dq, J = 6.6 Hz, J = 9.3 Hz), 3.65(1H,d, J = 14.3 Hz), 3.93(1H,d,
J = 14.3 Hz), 4.34 (1H, d, J = 9.3 Hz), 7.19 (1H, dt, J = 4.9 Hz, J = 6.1 Hz),
7.25–7.35 (5H, m), 7.43 (1H, d, J = 7.7 Hz), 7.69 (1H, dt, J = 6.1 Hz,
J = 7.7 Hz), 8.57 (1H, d, J = 4.9 Hz). 13C {1H} NMR (75 MHz, CDCl3) d
7.5, 36.4, 58.8, 64.9, 74.7, 121.9, 122.5, 127.0, 127.3, 127.8, 136.3,
141.7, 148.9, 158.7. FT-IR (neat) 3357, 1590, 1570, 1073, 757, 702.
4.4. N-Benzylidene-P,P-diphenylphosphinic amide
In a 250 mL round-bottomed flask were added diphenylphosph-
inamide (3.00 g, 13.8 mmol) and dichloromethane (56 mL) and
cooled to 0 °C. Then triethylamine (5.80 mL, 41.3 mmol), titanium
tetrachloride (0.90 mL, 8.3 mmol), and benzaldehyde (1.40 mL,
13.8 mmol) were added. The reaction mixture was allowed to warm
to ambient room temperature, stirred for 1.5 h, and then gravity fil-
tered to remove titanium dioxide. The filtrate was collected and the
solvent was removed by rotary evaporation. The residue was treated
with diethyl ether (40 mL) and filtered to remove triethylammo-
nium chloride. The filtrate from this process was collected and the
solvent was removed. The resultant yellow residue was recrystal-
lized using dichloromethane and hexanes.
½
a 2D4
ꢂ
¼ þ98:2 (c 1, CH2Cl2). HRMS (M+1) calcd for C16H21N2O:
257.1654, found: 257.1643.
4.2.10. (1R,2S)-2-(Dibenzylamino)-1-phenylpropan-1-ol 24
In a 250 mL round-bottomed flask were added (1R,2S)-norephe-
drine (2.00 g, 13.3 mmol), THF (45 mL), K2CO3 (7.3 g, 53.0 mmol),
and benzyl bromide (3.20 mL,26.5 mmol). The temperature of the
reaction mixture was raised to reflux and allowed to run overnight
(18 h). The reaction mixture was cooled to room temperature. NaOH
(100 mL) was added to the reaction mixture, after which THF was
evaporated from the reaction mixture via rotary evaporation. The
residue was extracted with aqueous NaOH solution (1 M,
50 mL ꢁ 2) and EtOAc (50 mL ꢁ 2). The organic layer was washed
with brine (100 mL) and dried over MgSO4. The solvent was evapo-
rated via rotary evaporation. The resultant residue was purified by
flash chromatography using hexanes/EtOAc (8:2). Colorless oil
4.4.1. P,P-Diphenylphosphinoylimine of 4-fluorobenzaldehyde
25b
White solid (54%). Mp: 110–112 °C. IR (Nujol): IR (Nujol): 1626,
1238, 729, 702 cmꢀ1. 1H NMR (500 MHz, CDCl3) d (ppm): 7.15–7.47
(m, 10H), 7.93–8.03 (m, 4H), 9.29 (d, J = 32 Hz, 1H). ESI-HRMS calcd
for C19H15NOPF (M+H+): 324.0954, found: 324.0952.
4.5. Diethylzinc reaction with diphenylphosphinoylimines
(48%). ½a 2D4:4
¼ ꢀ40:4 (c 1.38, CHCl3). IR (Nujol): 3421, 1602, 747.
ꢂ
In a 100 mL round-bottomed flask were placed toluene (13.0 mL),
(1R,2S)-N-benzylephedrine (0.167 g, 0.66 mmol), N-benzylidene-
P,P-diphenylphosphinic amide (0.20 g, 0.66 mmol), and diethylzinc
(3.3 mL, 3.3 mmol). The reaction mixture was stirred for 48 h and
then the reaction was quenched by the addition of an aqueous
solution of ammonium chloride (50 mL). The organic layer was di-
luted with ethyl acetate (50 mL), washed with brine (50 mL), and
dried (MgSO4). The solvents were removed via rotary evaporation
and the product was purified by flash chromatography (hexanes/
EtOAc, 4:6). Colorless oil (53%).
1H NMR (500 MHz, CDCl3) d (ppm): 1.10 (d, J = 6.7 Hz, 3H), 2.71
(br s, 1H), 3.08 (p, J = 6.6 Hz, 1H), 3.42 (d, J = 14.0 Hz, 2H), 3.64 (d,
J = 14.0 Hz, 2H), 4.62 (d, J = 6.6 Hz, 1H), 7.10–7.22 (m, 15H). 13C
NMR (125 MHz, CDCl3): 8.9, 54.5, 58.4, 75.6, 126.6, 126.7, 127.1,
127.8, 128.1, 128.6, 139.8, 143.2. ESI-HRMS calcd for C23H26NO
(M+H+): 332.2014, found: 332.2002.
4.3. General procedure for the addition of diethylzinc to
aldehyde
4.5.1. (R)-P,P-Diphenyl-N-(1(4-fluorophenylbutyl)phosphinic
In a flame-dried, nitrogen-purged flask 0.33 mmol of the ligand
was added and dissolved in 13 equiv of dry toluene. To this solu-
tion was added 3.0 equiv of diethylzinc followed by a 20–30 min
reaction time after which 1.0 equiv of redistilled benzaldehyde
amide 26b
Mp: 133–135 °C. ½a D24:0
ꢂ
¼ þ19:0 (c 1.0, CHCl3). IR (Nujol): 3161,
1H NMR (500 MHz, CDCl3) d (ppm):
1224, 1056, 760, 722 cmꢀ1
.

S. Banerjee et al. / Tetrahedron: Asymmetry 20 (2009) 2154–2161
2161
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(t, 1H), 4.09 (m, 1H), 6.93–6.97 (m, 2H) 7.10–7.13 (m, 2H), 7.30–
7.34 (m, 2H), 7.41–7.48 (m, 4H), 7.71–7.75 (m, 2H), 7.83–7.87
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Acknowledgments
The authors acknowledge the support for this work by the do-
nors of the Petroleum Research Fund as administered by the Amer-
ican Chemical Society (PRF 48367-B1). The authors also thank the
National Science Foundation (NSF CHE-644950) for support of this
research. The NMR data collected in this work is based, in part,
upon the work supported by the National Science Foundation un-
der major research instrumentation grant CHE-0722385.
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