Organocatalytic asymmetric domino aza-michael - Mannich reaction: Synthesis of tetrahydroimidazopyrimidine derivatives

Article abstract of DOI:10.1021/jo201301p

Highly substituted tetrahydroimidazopyrimidine derivatives with three chiral centers have been synthesized for the first time using an organocatalytic asymmetric domino aza-Michael - Mannich reaction of α,β-unsaturated aldehydes and N-arylidene-1H-imidazo

Full text of DOI:10.1021/jo201301p

NOTE
pubs.acs.org/joc
Organocatalytic Asymmetric Domino Aza-MichaelÀMannich
Reaction: Synthesis of Tetrahydroimidazopyrimidine Derivatives
Hong Li,† Junling Zhao,*,† Lili Zeng,† and Wenhui Hu*,†,‡
†Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Science Park, Guangdong 510530,
People’s Republic of China
‡State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong 510120, People’s Republic of China
S Supporting Information
b
ABSTRACT: Highly substituted tetrahydroimidazopyrimidine
derivatives with three chiral centers have been synthesized for
the first time using an organocatalytic asymmetric domino aza-
MichaelÀMannich reaction of R,β-unsaturated aldehydes and
N-arylidene-1H-imidazol-2-amines. This efficient approach fur-
nishes the products in good yields (42À87%) with excellent
stereoselectivities (>20:1 dr, up to >99% ee).
Scheme 1. Domino Aza-MichaelÀMannich Reaction of r,β-
he tetrahydroimidazopyrimidine ring system is found in
many naturally occurring products that have attracted
Unsaturated Aldehyde and N-Arylidene-1H-imidazol-2-
T
attention due to the broad scope of their biological activities.1,2
Different classes of tetrahydroimidazopyrimidine compounds
have shown antidepressant2a,b and antihypertonia2c activities
that have been put to pharmaceutical uses. However, syntheses
of tetrahydroimidazopyrimidine derivatives are not very well
documented in the literature.2b,3 The traditional methods for
their synthesis often require many synthetic manipulations and
purifications, which result in low overall yields. Thus the devel-
opment of novel, concise methodologies that allow the rapid
construction of these tetrahydroimidazopyrimidine skeletons,
preferably in a single operation, is highly desired.
amine
group of imidazole is not acidic enough to participate in N-
alkyaltion reactions. The introduction of electron-withdrawing
groups, such as carbonyl or cyano, can reduce the pKa value of this
NÀH group, making it possible for N-alkylation reactions13,14,15b
to occur. The iminic group is a weak electron-withdrawing group
and enables many further transformations. We envisaged that the
N-arylidene-1H-imidazol-2-amines (1) and the R,β-unsaturated
aldehydes (2) might be suitable substrates for the domino aza-
MichaelÀMannich reaction and that they would generate the
highly substituted tetrahydroimidazopyrimidine derivatives (3).
To test our hypothesis, the readily available L-proline-derived
secondary amines (IÀIV), which are capable of both iminium16
and enamine17 catalysis, were explored as catalysts for this
domino reaction.
The reaction of N-benzylidene-1H-imidazol-2-amine (1a)
and cinnamaldehyde (2a) was selected as a model reaction.
We first studied catalysis of the domino reaction with diphenyl
prolinol silyl ether (I) in dichloromethane. The reaction pro-
ceeded with high stereoselectivity (97% ee, >20:1 dr) but in low
yield (30%, Table 1, entry 1). There was no significant improve-
ment in yield when using a variety of different solvents, most
Organocatalytic domino reactions4À6 allow the sequential
formation of several new bonds and chiral centers in just one
operation. They have been proven to be powerful tools for the
efficient and stereoselective synthesis of complex molecules7 that
are difficult to access by traditional methods. The aza-Michael
addition8 participated domino reaction provides a simple and
direct way for the synthesis of nitrogen-containing heterocycles.
For example, the asymmetric syntheses of 1,2-dihydroquin-
olines,9 pyrrolidines,10 tetrahydro-1,2-oxazines,11 and iso-
indolines12 have been realized. Herein, we report the first
asymmetric synthesis of enantioenriched tetrahydroimidazopyr-
imidine derivatives through an organocatalytic domino strategy
using R,β-unsaturated aldehydes and N-arylidene-1H-imidazol-
2-amines as starting materials (Scheme 1).
The reactions of 2-carbonyl-substituted indoles13 and
pyrroles14 with enals have been realized for the syntheses of
pyrrolidine-fused heterocycles. However, the asymmetric synth-
esis of six-membered ring-fused heterocycles, such as biologically
interesting tetrahydroimidazopyrimidines, through aza-Michael
reaction of nitrogen heterocycles has not been reported. We
would like to focus our research on this challenging task. Unlike
tetrazole, triazole, and other nitrogen heterocycles,15 the NÀH
Received: June 22, 2011
Published: August 10, 2011
r
2011 American Chemical Society
8064
dx.doi.org/10.1021/jo201301p J. Org. Chem. 2011, 76, 8064–8069
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimizing of the Reaction Conditionsa
Table 2. Substrate Scope of the Domino Aza-MichaelÀ
Mannich Reactiona
entry
R1
R2
Ph (2a)
yieldb (%) drc eed (%)
1
2
3
4
5
6
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
80 3a
71 3b
50 3c
60 3d
68 3e
70 3f
58 3g
>20:1 >99
>20:1 99
>20:1 >99
>20:1 99
>20:1 >99
3-MeC6H4 (2b)
3-OMeC6H4 (2c)
3-ClC6H4 (2d)
3-BrC6H4 (2e)
3-NO2C6H4 (2f)
4-MeC6H4 (2g)
entry catalyst
solvent
time (h) yieldb (%) drc eed (%)
1
2
I
DCM
THF
24
24
24
24
24
6
30
>20:1 97
>20:1 95
>20:1
>20:1
99
99
I
30
7e Ph (1a)
3
I
toluene
trace
trace
20
ND
ND
ND
ND
8
Ph (1a)
4-MeOC6H4 (2h) 54 3h
>20:1 >99
4
I
ether
9e Ph (1a)
10e Ph (1a)
11e Ph (1a)
12 Ph (1a)
13 Ph (1a)
14 Ph (1a)
4-ClC6H4 (2i)
4-BrC6H4 (2j)
4-NO2C6H4 (2k)
piperonyl (2l)
2-furyl (2m)
76 3i
72 3j
76 3k
66 3l
>20:1
>20:1
98
98
5
I
CHCl3
>20:1 98
>20:1 96
>20:1 99
>20:1 98
>20:1 >99
>20:1 98
>20:1 99
6
I
MeOH
55
>20:1 >99
7
I
DCM/MeOH (9:1)
DCM/MeOH (1:1)
DCM/MeOH (9:1)
DCM/MeOH (9:1)
DCM/MeOH (9:1)
DCM/MeOH (9:1)
DCM/MeOH (9:1)
16
12
16
12
24
24
24
73
>20:1
99
99
99
98
97
99
99
99
8
I
77
9e
10f
11e
12e
13e
I
80
49 3m >20:1
2-thiophene (2n)
42 3n
60 3o
62 3p
85 3q
87 3r
75 3s
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
I
73
15 4-OMeC6H4 (1b) 4-ClC6H4 (2i)
16 4-OMeC6H4 (1b) 4-NO2C6H4 (2k)
17e 4-CF3C6H4 (1c) Ph (2a)
II
III
IV
42
NR
trace
ND
ND
a Reactions was performed with N-benzylidene-1H-imidazol-2-amine
(0.13 mmol), cinnamaldehyde (0.1 mmol), and secondary amine
(0.02 mmol) in solvent (0.5 mL) at room temperature. b Isolated yield.
18 4-CF3C6H4 (1c) 4-ClC6H4 (2i)
19e 4-CF3C6H4 (1c) 4-NO2C6H4 (2k)
a Reactions was performed with N-arylidene-1H-imidazol-2-amine (0.13
mmol), R,β-unsaturated aldehyde (0.1 mmol), I (0.02 mmol), and
PhCOOH (20 mol %) in DCM/MeOH (9:1, 0.3 mL) at room
temperature. b Isolated yield. c Determined by 1H NMR of the products.
d Determined by HPLC analysis with the corresponding alcohol.
e DCM/MeOH (1:1) as solvent.
1
c Determined by H NMR of the products. d Determined by HPLC
analysis with the corresponding alcohol. e With 20% PhCOOH as
additive. f With 20% NaOAc as additive.
likely due to the poor solubility of 1a in these solvents. However,
high stereoselectivities were retained (Table 1, entries 2À5).
When methanol was used as solvent, the starting material 1a was
completely consumed in just 6 h to provide the product 3a in
55% yield and 96% ee (Table 1, entry 6). The arylaldehyde and
2-aminoimidazole derived from the decomposition of 1a also
were detected. Those results suggested that 1a was more active in
methanol and that the use of a mixture of dichloromethane and
methanol might improve the efficiency of the reaction. Experi-
ments indicated that this was the case. After extensive screening,
the best results in terms of yield (73%) and enantioselectivity
(99%) were obtained using a 9:1 ratio of dichloromethane and
methanol (Table 1, entry 7). The yield was improved to 80% by
the addition of benzoic acid while retaining high enantioselec-
tivity (>99% ee, Table 1, entry 9). In contrast, the addition of
sodium acetate had almost no influence on the reaction (Table 1,
entry 11). Other secondary amine catalysts also were examined
as catalysts: the reaction proceeded in 42% yield and 99% ee
when catalyst II (Table 1, entry 12) was used, and there were no
domino reaction product detected in 24 h when catalysts III and
IV were employed (Table 1, entries 13 and 14).
tolerated, yielding the expected products in moderate to high
yields (54À80%) and excellent stereoselectivities (>97% ee,
>20:1 dr, Table 2, entries 1À12). The reaction of 2-furyl and
2-thiophene enal led to the formation of 3m and 3n in 49 and 42%
yields, respectively, both in 99% ee (Table 2, entries 13 and 14).
The electronic nature of the substituent on the aromatic ring of
1 had little influence on the reaction. Extensions of this strategy
to use the less reactive aliphatic enals were unsuccessful; no
reaction occurred when crotonaldehyde was used.
The absolute configuration of the three new chiral centers of
3n was assigned as 5S, 6S, and 7R by X-ray crystallographic
analysis of 4n (the alcohol corresponding to 3n, Figure 1). On
the basis of this observation, a plausible catalytic cycle for the
reaction is proposed in Scheme 2. The reaction starts with the
iminium activation of 2 by I, followed by aza-Michael addition of
1 to the iminium ion to give intermediate A. The enamine of A
undergoes an intramolecular Mannich reaction to give B. The
catalyst is regenerated for the next catalytic cycle through
hydrolysis of B: B then hydrolyzes to give tetrahydroimidazo-
pyrimidine 3.
With the optimal reaction conditions in hand, the substrate
scope of this domino aza-MichaelÀMannich reaction was ex-
plored, and the results are summarized in Table 2. Various
substituted aromatic enals were examined. Both electron-with-
drawing and electron-donating groups on the aromatic ring were
In summary, we have developed a novel organocatalytic
domino aza-MichaelÀMannich reaction of N-arylidene-1H-imi-
dazol-2-amines and R,β-unsaturated aldehydes for use in the
synthesis of highly substituted tetrahydroimidazopyrimidine
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NOTE
(br s, 2H), 3.83 (s, 3H); 13C NMR (125 MHz, DMSO-d6, ppm) δ 162.6,
159.2, 151.4, 130.9, 128.9, 114.9, 55.9; HR-MS (ESI) m/z 202.0979 [M +
H]+, calcd for C11H12N3O, 202.0980.
N-(4-(Trifluoromethyl)benzylidene)-1H-imidazol-2-amine
(1c). The title compound was obtained according to general procedure
described above in 70% yield: 1H NMR (400 MHz, DMSO-d6, ppm) δ
12.49 (s, 1H), 9.24 (s, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz,
2H), 7.19 (br s, 1H), 6.99 (br s, 1H); 13C NMR (125 MHz, DMSO-d6,
ppm) δ 157.9, 150.5, 139.7, 131.4 (q, JCÀF = 31.6 Hz), 129.5, 126.2,
126.1, 124.4 (q, JCÀF = 270.8 Hz); HR-MS (ESI) m/z 240.0743 [M + H]+,
calcd for C11H9N3F3, 240.0749.
General Procedure for Organocatalytic Asymmetric Aza-
MichaelÀMannich Reaction. To a solution of catalyst I (0.02
mmol), benzoic acid (0.02 mmol), and R,β-unsaturated aldehyde 2
(0.1 mmol) in 0.3 mL of DCM/MeOH (9/1) was added N-arylidene-
1H-imidazol-2-amine 1 (0.13 mmol) at room temperature. After
completion of the reaction as analyzed by TLC, the reaction mixture
was directly purified by silica gel column chromatography to give the
desired product 3. 3was dissolved in 2 mL of EtOH, and NaBH4 (1.0equiv)
in EtOH (0.1 M) was added. The mixture was stirred under room
temperature for 30 min. The volatile was evaporated under vacuum, and
the residue was purified by silica gel column chromatography to give the
corresponding alcohol 4 in almost quantitative yield.
Figure 1. X-ray structure of 4n.
Scheme 2. Proposed Catalytic Cycle of the Domino Aza-
MichaelÀMannich Reaction
(5S,6S,7R)-5,7-Diphenyl-5,6,7,8-tetrahydroimidazo[1,2-a]
pyrimidine-6-carbaldehyde (3a). The title compound was ob-
tained using the general procedure described above, in 80% yield and
>99% ee: [R]20D = +34.9 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3, ppm) δ 9.22 (s, 1H), 7.49À7.46 (m, 2H), 7.38À7.26 (m, 6H),
7.20À7.15 (m, 2H), 6.26 (s, 1H), 6.01 (s,1H), 5.41 (d, J = 10.0 Hz, 1H),
4.62 (d, J = 10.0 Hz, 1H), 3.54À3.49 (m, 1H); 13C NMR (125 MHz,
CDCl3, ppm) δ 200.1, 148.3, 138.0, 137.4, 129.0, 128.9, 128.85, 128.7,
127.7, 127.5, 123.6, 112.6, 60.4, 57.9, 57.3; HR-MS (ESI) m/z 336.1708
[M + MeOH + H]+, calcd for C20H22N3O2, 336.1712. The enantio-
meric excess was determined by HPLC analysis of the corresponding
alcohol (after treatment with NaBH4) using a Daicel Chiralpak OD-H
column, hexane (0.1% TEA)/i-PrOH = 9:1, flow rate = 1.0 mL/min: tr =
10.6 min (major) and tr = 32.5 min (minor).
derivatives bearing three chiral centers. The reaction is catalyzed
efficiently by readily available diphenylprolinol silyl ethers with
moderate to good yield (42À87%) and high stereoselectivities
(>97% ee, >20:1 dr). This strategy described could be extended
to the asymmetric synthesis of biologically important tetrahy-
dropyrazolopyrimidine derivatives18 and other tetrahydropyri-
midine-fused heterocycles.
(5S,6S,7R)-7-phenyl-5-m-tolyl-5,6,7,8-tetrahydroimidazo-
[1,2-a]pyrimidine-6-carbaldehyde (3b). The title compound was
obtained using the general procedure described above, in 71% yield and
1
99% ee: [R]20 = +38.3 (c = 1.00 in CH2Cl2); H NMR (400 MHz,
D
CDCl3, ppm) δ 9.24 (d, J = 1.2 Hz, 1H), 7.50À7.48 (m, 2H), 7.40À7.26
(m, 3H), 7.22 (dd, J = 7.6, J = 8.0 Hz 1H), 7.11 (d, J = 7.6 Hz, 1H),
7.05À6.95 (m, 2H), 6.35 (s, 1H), 6.06 (s, 1H), 5.38 (d, J = 10.4 Hz, 1H),
4.62 (d, J = 10.4 Hz, 1H), 3.54 (ddd, J = 1.2 Hz, J = 10.4 Hz, J =
10.4 Hz, 1H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3, ppm) δ 200.3,
148.4, 138.7, 138.1,137.6, 129.5, 129.1, 129.0, 128.8, 128.3, 127.6, 124.9,
124.6, 112.8, 60.6, 58.1, 57.6, 21.4; HR-MS (ESI) m/z 350.1866
[M + MeOH + H]+, calcd for C21H24N3O2, 350.1869. The enantio-
meric excess was determined by HPLC analysis of the corresponding
alcohol (after treatment with NaBH4) using a Daicel Chiralpak OD-H
column, hexane (0.1% TEA)/i-PrOH = 9:1, flow rate = 1.0 mL/min: tr =
8.5 min (major) and tr = 19.8 min (minor).
(5S,6S,7R)-5-(3-Methoxyphenyl)-7-phenyl-5,6,7,8-tetra-
hydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3c). The ti-
tle compound was obtained using the general procedure described
above, in 50% yield and >99% ee: [R]20D = +35.6 (c = 1.00 in CH2Cl2);
1H NMR (400 MHz, CDCl3, ppm) δ 9.22 (d, J = 1.6 Hz, 1H), 7.55À
7.48 (m, 2H), 7.46À7.30 (m, 3H), 7.26À7.20 (m, 2H), 6.85À6.78 (m,
2H), 6.72 (s, 1H), 6.29 (s, 1H), 6.07 (d, J = 0.8 Hz, 1H), 5.39 (d, J = 10.0
Hz, 1H), 4.61 (d, J = 10.0 Hz, 1H), 3.76 (s, 3H), 3.52 (ddd, J = 1.6 Hz, J =
10.0 Hz, J = 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ 200.2,
159.9, 148.4, 139.7, 137.6, 129.9, 129.03, 129.0, 127.5, 124.6, 120.0,
114.1, 113.2, 112.7, 60.5, 58.0, 57.6, 55.3; HR-MS (ESI) m/z 366.1816
’ EXPERIMENTAL SECTION
General Procedure for the Preparation of 1aÀ1c. To a
solution of benzaldehyde (1.92 mL, 18.8 mmol) in dichloromethane
(15 mL) were added sequentially 2-aminoimidazole sulfate (3.7 g,
14.3 mmol), tetraisopropyl orthotitanate (6.83 mL, 23.3 mmol), and
triethylamine (3.9 mL, 28.1 mmol). The reaction mixture was stirred at
room temperature for 24 h and then concentrated in vacuo. The residue
was taken up in ethyl acetate and water and filtered. The filtrate was
separated, and the organic phase was dried over anhydrous sodium
sulfate and concentrated. The crude product was recrystallized from
ethyl acetate/hexane to afford 1a19 in 60% yield: 1H NMR (400 MHz,
DMSO-d6, ppm) δ 12.23 (s, 1H), 9.15 (s, 1H), 7.95 (m, 2H), 7.58À7.50
(m, 3H), 7.15 (br s, 1H), 6.93 (br s, 1H).
N-(4-Methoxybenzylidene)-1H-imidazol-2-amine (1b). The
title compound was obtained according to general procedure described
above in 50% yield: 1H NMR (400 MHz, DMSO-d6, ppm) δ 12.17 (s,
1H), 9.08 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.0
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NOTE
[M + MeOH + H]+, calcd for C21H24N3O3, 366.1818. The enantio-
meric excess was determined by HPLC analysis of the corresponding
alcohol (after treatment with NaBH4) using a Daicel Chiralpak OD-H
column, hexane (0.1% TEA)/i-PrOH = 9:1, flow rate =1.0 mL/min: tr =
12.3 min (major) and tr = 28.3 min (minor).
Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH = 9:1, flow rate =
1.0 mL/min: tr = 9.7 min (major) and tr = 20.3 min (minor).
(5S,6S,7R)-5-(4-Methoxyphenyl)-7-phenyl-5,6,7,8-tetra-
hydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3h). The
title compound was obtained using the general procedure described
above, in 54% yield and >99% ee: [R]20D = +50.0 (c = 1.00 in CH2Cl2);
1H NMR (400 MHz, CDCl3, ppm) δ 9.23 (d, J = 1.2 Hz, 1H),
7.51À7.48 (m, 2H), 7.40À7.30 (m, 3H), 7.13 (d, J = 8.4, Hz, 2H),
6.84 (d, J = 8.4, Hz, 2H), 6.24 (s, 1H), 6.02 (s, 1H), 5.35 (d, J = 10.4 Hz,
1H), 4.60 (d, J = 10.0 Hz, 1H), 3.78 (s, 3H), 3.49 (ddd, J = 1.2 Hz, J =
10.0 Hz, J = 10.4 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ 200.4,
159.7,148.5, 137.7, 130.0, 129.0, 128.9, 127.6, 124.4, 114.2, 112.4, 60.7,
57.6, 55.2; HR-MS (ESI) m/z 366.1806 [M + MeOH + H]+, calcd for
C21H24N3O3, 366.1818. The enantiomeric excess was determined by
HPLC analysis of the corresponding alcohol (after treatment with
NaBH4) using a Daicel Chiralpak OD-H column, hexane (0.1%
TEA)/i-PrOH = 9:1, flow rate = 1.0 mL/min: tr =16.6 min (major)
and tr = 33.5 min (minor).
(5S,6S,7R)-5-(4-Chlorophenyl)-7-phenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3i). The title com-
pound was obtained according to general procedure described above, in
76% yield and 98% ee: [R]20D = +47.8 (c = 1.00 in CH2Cl2); 1H NMR
(400 MHz, CDCl3, ppm) δ 9.21 (d, J = 0.8 Hz, 1H), 7.48À7.45 (m, 2H),
7.40À7.33 (m, 3H), 7.29 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.38
(s, 1H), 6.04 (s, 1H), 5.44 (d, J = 10.0 Hz, 1H), 4.62 (d, J = 10.0 Hz, 1H),
3.49À3.44 (m, 1H); NMR (125 MHz, CDCl3, ppm) δ199.7, 148.1, 137.0,
136.5, 134.7, 129.18, 129.15, 129.1, 128.7, 127.4, 123.9, 112.6, 60.3, 57.4,
57.1; HR-MS (ESI) m/z 370.1316 [M + MeOH + H]+, calcd for
C20H21N3O2Cl, 370.1322. The enantiomeric excess was determined by
HPLC analysis of the corresponding alcohol (after treatment with NaBH4)
using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH =
9:1, flow rate = 1.0 mL/min: tr = 11.0 min (major) and tr = 31.3 min
(minor).
(5S,6S,7R)-5-(4-Bromophenyl)-7-phenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3j). The title com-
pound was obtained using the general procedure described above, in
72% yield and 98% ee: [R]20D = +64.4 (c = 1.00 in CH2Cl2); 1H NMR
(400 MHz, CDCl3, ppm) δ 9.21 (d, J = 1.6 Hz, 1H), 7.49À7.30 (m, 7H),
7.08 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 1.2 Hz, 1H), 6.04 (d, J = 1.6 Hz, 1H),
5.43 (d, J = 10.0 Hz, 1H), 4.59 (d, J = 10.0 Hz, 1H), 3.47 (ddd, J = 1.6 Hz,
J = 10.0 Hz, J = 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ
199.8, 148.4, 137.5, 137.2, 132.1, 129.4, 129.2, 127.4, 125.0, 122.8, 112.6,
60.7, 57.6, 57.2; HR-MS (ESI) m/z414.0809 [M + MeOH + H]+, calcd for
C20H21N3O2Br, 414.0817. The enantiomeric excess was determined by
HPLC analysis of the corresponding alcohol (after treatment with NaBH4)
using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH =
9:1, flow rate = 1.0 mL/min: tr = 12.1 min (major) and tr = 35.2 min
(minor).
(5S,6S,7R)-5-(3-Chlorophenyl)-7-phenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3d). The title com-
pound was obtained using the general procedure described above, in 60%
yield and 99% ee: [R]20D = +36.3 (c = 1.00 in CH2Cl2); 1H NMR (400
MHz, CDCl3, ppm) δ 9.23 (d, J = 1.6 Hz, 1H), 7.50À7.47(m, 2H),
7.46À7.30 (m, 3H), 7.30À7.20 (m, 2H), 7.19 (s, 1H), 7.12À7.08(m, 1H),
6.50 (d, J = 1.6 Hz, 1H), 6.10 (d, J = 1.6 Hz, 1H), 5.89 (br s, 1H), 5.46 (d,
J = 10.0 Hz, 1H), 4.61 (d, J = 10.0 Hz, 1H), 3.50 (ddd, J = 1.6 Hz, J = 10.0
Hz, J = 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ 199.6, 148.2,
140.2, 137.1,134.8, 130.1, 129.09, 129.07, 129.0, 127.7, 127.4, 125.0, 124.0,
112.6, 60.1, 57.2, 57.0; HR-MS (ESI) m/z 370.1323 [M + MeOH + H]+,
calcd for C20H21N3O2Cl, 370.1322. The enantiomeric excess was deter-
mined by HPLC analysis of the corresponding alcohol (after treatment with
NaBH4) using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/
i-PrOH = 9:1, flow rate =1.0 mL/min: tr = 9.6 min (major) and tr = 37.8
min (minor).
(5S,6S,7R)-5-(3-Bromophenyl)-7-phenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3e). The title com-
pound was obtained using the general procedure described above, in
68% yield and >99% ee: [R]20D = +36.2 (c = 1.00 in CH2Cl2); 1H NMR
(400 MHz, CDCl3, ppm) δ 9.23 (d, J = 1.2 Hz, 1H), 7.50À7.45 (m, 2H),
7.42À7.26 (m, 5H), 7.20À7.10 (m, 2H), 6.21 (s, 1H), 6.01(d, J = 1.6 Hz,
1H), 5.42 (d, J = 9.6 Hz, 1H), 4.58 (d, J = 10.0 Hz, 1H), 3.48 (ddd, J = 1.2
Hz, J = 9.6 Hz, J = 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ
199.8, 148.6, 140.9, 137.4, 131.8, 130.6, 130.4, 129.1, 129.0, 127.5, 126.4,
124.9, 122.9, 112.4, 60.5, 57.4, 57.0; HR-MS (ESI) m/z 414.0822 [M +
MeOH + H]+, calcd for C20H21N3O2Br, 414.0817. The enantiomeric
excess was determined by HPLC analysis of the corresponding alcohol
(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,
hexane (0.1% TEA)/i-PrOH = 9:1, flow rate = 1.0 mL/min: tr = 10.2 min
(major) and tr = 37.5 min (minor).
(5S,6S,7R)-5-(3-Nitrophenyl)-7-phenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3f). The title com-
pound was obtained using the general procedure described above,
1
in 70% yield and 99% ee: [R]20 = +9 (c = 1.00 in CH2Cl2); H
D
NMR (400 MHz, CDCl3, ppm) δ 9.27 (d, J = 0.8 Hz, 1H), 8.13À8.11
(m, 1H), 8.01 (s, 1H), 7.52À7.38 (m, 4H), 7.38À7.26 (m, 3H), 6.28
(d, J = 1.2 Hz, 1H), 6.00 (d, J = 1.6 Hz, 1H), 5.64 (d, J = 8.8 Hz, 1H), 4.68
(d, J = 8.8 Hz, 1H), 3.53À3.48 (m, 1H); 13C NMR (125 MHz, CDCl3,
ppm) δ 199.2, 148.6, 148.4, 141.1, 137.2, 133.6, 129.2, 129.0, 127.3,
125.3, 123.5, 122.5, 112.2, 60.1, 57.0, 56.4; HR-MS (ESI) m/z 381.1559
[M + MeOH + H]+, calcd for C20H21N4O4, 381.1563. The enantio-
meric excess was determined by HPLC analysis of the corresponding
alcohol (after treatment with NaBH4) using a Daicel Chiralpak OD-H
column, hexane (0.1% TEA)/i-PrOH = 85:15, flow rate = 0.8 mL/min:
tr = 15.8 min (major) and tr = 44.7 min (minor).
(5S,6S,7R)-7-Phenyl-5-p-tolyl-5,6,7,8-tetrahydroimidazo-
[1,2-a]pyrimidine-6-carbaldehyde (3g). The title compound was
obtained according to general procedure described above, in 58% yield
and 99% ee: [R]20D = +44.8 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3, ppm) δ 9.22 (d, J = 1.6 Hz, 1H), 7.50À7.49 (m, 2H), 7.48À7.26
(m, 3H), 7.20À7.05 (m, 4H), 6.35 (d, J = 0.8 Hz, 1H), 6.05 (d, J = 1.6
Hz, 1H), 5.38 (d, J = 10.0 Hz, 1H), 4.61 (d, J = 10.4 Hz, 1H), 3.52 (ddd,
J = 1.6 Hz, J = 10.0 Hz, J = 10.4 Hz, 1H), 2.32 (s, 3H); 13C NMR (125
MHz, CDCl3, ppm) δ 200.3, 148.3, 138.7, 137.7,135.1, 129.6, 129.1,
129.0, 127.7, 127.6, 124.6, 112.7, 60.7, 57.9, 57.7, 21.1; HR-MS (ESI)
m/z 350.1869 [M + MeOH + H]+, calcd for C21H24N3O2, 350.1869.
The enantiomeric excess was determined by HPLC analysis of the
corresponding alcohol (after treatment with NaBH4) using a Daicel
(5S,6S,7R)-5-(4-Nitrophenyl)-7-phenyl-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3k). The title com-
pound was obtained using the general procedure described above, in
1
76% yield and >99% ee: [R]20 = +58.0 (c = 1.00 in CH2Cl2); H
D
NMR (400 MHz, CDCl3, ppm) δ 9.25 (d, J = 0.8 Hz, 1H), 8.11 (d, J =
8.8 Hz, 1H), 7.48À7.45 (m, 2H), 7.39À7.26 (m, 5H), 6.24 (d, J =
1.6 Hz, 1H), 5.99 (d, J = 1.6 Hz, 1H), 5.63 (d, J = 9.2 Hz, 1H), 4.63 (d,
J = 9.2 Hz, 1H), 3.45 (ddd, J = 0.8 Hz, J = 9.2 Hz, J = 9.2 Hz, 1H); 13C
NMR (125 MHz, CDCl3, ppm) δ 199.2, 148.7, 147.8, 146.1, 137.1,
129.2, 129.1, 128.6, 127.3, 125.3, 124.0, 112.3, 60.3, 57.4, 56.5; HR-
MS (ESI) m/z 381.1554 [M + MeOH + H]+, calcd for C20H21N4O4,
381.1563. The enantiomeric excess was determined by HPLC
analysis of the corresponding alcohol (after treatment with NaBH4)
using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH =
80:20, flow rate = 0.8 mL/min: tr = 14.3 min (major) and tr = 33.7 min
(minor).
8067
dx.doi.org/10.1021/jo201301p |J. Org. Chem. 2011, 76, 8064–8069

The Journal of Organic Chemistry
NOTE
(5S,6S,7R)-5-(Benzo[d][1,3]dioxol-5-yl)-7-phenyl-5,6,7,8-
tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3l). The
title compound was obtained using the general procedure described
above, in 66% yield and 99% ee: [R]20D = +66.8 (c = 1.00 in CH2Cl2);
1H NMR (400 MHz, CDCl3, ppm) δ 9.24 (d, J = 1.6 Hz, 1H), 7.50À7.48
(m, 2H), 7.42À7.28 (m, 3H), 6.75À6.70 (m, 2H), 6.65 (s, 1H), 6.28 (d, J=
1.2 Hz, 1H), 6.07 (d, J = 1.6 Hz, 1H), 5.94 (d, J = 1.2 Hz, 2H), 5.32 (d, J =
10.0 Hz, 1H), 4.59 (d, J = 10.4 Hz, 1H), 3.48 (ddd, J = 1.6 Hz, J = 10.0 Hz,
J= 10.4 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ200.2, 148.4, 148.2,
147.9, 137.6, 131.89, 129.1, 129.0, 127.6, 124.7, 112.5, 108.3, 107.6, 101.3,
60.7, 57.9, 57.6; HR-MS (ESI) m/z 380.1597 [M + MeOH + H]+, calcd for
C21H22N3O4, 380.1610. The enantiomeric excess was determined by
HPLC analysis of the corresponding alcohol (after treatment with NaBH4)
using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH =
9:1, flow rate = 1.0 mL/min: tr = 19.8 min (major) and tr = 33.9 min
(minor).
(5S,6S,7R)-7-(4-Methoxyphenyl)-5-(4-nitrophenyl)-5,6,7,
8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3p).
The title compound was obtained using the general procedure described
above, in 62% yield and 97% ee: [R]20D = +57.4 (c = 1.00 in CH2Cl2); 1H
NMR(400 MHz, CDCl3, ppm) δ 9.23(d, J = 0.8Hz, 1H), 8.15 (d, J = 8.8
Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8
Hz, 2H), 6.31 (d, J = 1.6 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.62 (d, J = 9.6
Hz, 1H), 4.57 (d, J = 9.6 Hz, 1H), 3.79 (s, 3H), 3.44 (ddd, J = 0.8 Hz, J =
9.6 Hz, J = 9.6 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ 199.4,
160.2, 148.8, 146.1, 128.8, 128.7, 128.5, 125.4, 124.0, 114.5, 112.3, 60.7,
56.8, 56.6, 55.3; HR-MS (ESI) m/z 411.1656 [M + MeOH + H]+, calcd
for C21H23N4O5, 411.1668. The enantiomeric excess was determined by
HPLC analysis of the corresponding alcohol (after treatment with
NaBH4) using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/
i-PrOH = 80:20, flow rate = 0.8 mL/min: tr = 19.7 min (major) and tr =
40.0 min (minor).
(5S,6S,7R)-5-(Furan-2-yl)-7-phenyl-5,6,7,8-tetrahydroimi-
dazo[1,2-a]pyrimidine-6-carbaldehyde (3m). The title com-
pound was obtained using the general procedure described above, in
49% yield and 99% ee: [R]20D = +52.3 (c = 1.00 in CH2Cl2); 1H NMR
(400 MHz, CDCl3, ppm) δ 9.34 (d, J = 1.2 Hz, 1H), 7.49À7.45 (m, 2H),
7.40À7.26 (m, 4H), 6.33À6.28 (m, 3H), 6.24 (d, J = 1.6 Hz, 1H), 5.51
(d, J = 10.0 Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 3.77 (ddd, J = 1.2 Hz, J =
9.6 Hz, J = 10.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, ppm) δ 199.5,
149.2, 147.5, 143.2, 137.6, 129.0, 128.9, 127.4, 124.7, 112.1, 110.5, 110.0,
57.2, 55.9, 51.0; HR-MS (ESI) m/z 326.1499 [M + MeOH + H]+, calcd
for C18H20N3O3, 326.1505. The enantiomeric excess was determined by
HPLC analysis of the corresponding alcohol (after treatment with
NaBH4) using a Daicel Chiralpak OD-H column, hexane (0.1%
TEA)/i-PrOH = 9:1, flow rate = 1.0 mL/min: tr = 13.1 min (major)
and tr = 40.5 min (minor).
(5S,6S,7R)-7-Phenyl-5-(thiophen-2-yl)-5,6,7,8-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbaldehyde (3n). The title com-
pound was obtained using the general procedure described above, in
42% yield and 99% ee: [R]20D = +41.9 (c = 1.00 in CH2Cl2); 1H NMR
(400 MHz, CDCl3, ppm) δ 9.29 (d, J = 1.6 Hz, 1H), 7.52À7.45 (m, 2H),
7.42À7.32 (m, 3H), 7.32À7.26 (m, 1H), 7.05À7.04 (m, 1H),
6.95À6.92 (m, 1H), 6.30 (d, J = 1.6 Hz, 1H), 6.20 (d, J = 1.6 Hz,
1H), 5.72 (d, J = 10.4 Hz, 1H), 4.60 (d, J = 10.0 Hz, 1H), 3.61 (ddd, J =
1.2 Hz, J = 10.0 Hz, J = 10.4 Hz, 1H); 13C NMR (125 MHz, CDCl3,
ppm) δ 199.8, 147.8, 140.6, 137.4, 129.1, 127.9, 127.6, 126.8, 126.5,
124.7, 112.4, 60.7, 57.8, 53.6; HR-MS (ESI) m/z 342.1263 [M + MeOH
+ H]+, calcd for C18H20N3O2S, 342.1276. The enantiomeric excess was
determined by HPLC analysis of the corresponding alcohol (after
treatment with NaBH4) using a Daicel Chiralpak OD-H column, hexane
(0.1% TEA)/i-PrOH = 9:1, flow rate = 1.0 mL/min: tr = 12.7 min
(major) and tr = 27.0 min (minor).
(5S,6S,7R)-5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-5,6,
7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3o).
The title compound was obtained using the general procedure de-
scribed above, in 60% yield and 98% ee: [R]20D = +28.6 (c = 1.00 in
CH2Cl2); 1H NMR (400 MHz, CDCl3, ppm) δ 9.22 (d, J = 1.6 Hz,
1H), 7.39 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8
Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 1.6 Hz, 1H), 6.03 (d,
J = 1.2 Hz, 1H), 5.43 (d, J = 10 Hz, 1H), 4.54 (d, J = 10.0 Hz, 1H), 3.80
(s, 3H), 3.43 (ddd, J = 1.6 Hz, J = 10.0 Hz, J = 10.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3, ppm) δ 200.0, 160.1, 148.5, 137.0, 134.6, 129.1,
128.6, 125.1, 114.5, 112.6, 60.9, 57.2, 57.1, 55.3; HR-MS (ESI)
m/z 400.1422 [M + MeOH + H]+, calcd for C21H23N3O3Cl,
400.1428. The enantiomeric excess was determined by HPLC
analysis of the corresponding alcohol (after treatment with NaBH4)
using a Daicel Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH =
9:1, flow rate = 1.0 mL/min: tr = 20.3 min (major) and tr = 47.0 min
(minor).
(5S,6S,7R)-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,
8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3q).
The title compound was obtained using the general procedure described
above, in 85% yield and 99% ee: [R]20D = +13.7 (c = 1.00 in CH2Cl2); 1H
NMR (400 MHz, CDCl3, ppm) δ 9.29 (d, J = 1.6 Hz, 1H), 7.62À7.60
(m, 4H), 7.32À7.26 (m, 3H), 7.17À7.14 (m, 2H), 6.19 (d, J = 1.6 Hz,
1H), 6.05 (d, J = 1.2 Hz, 1H), 5.41 (d, J = 9.6 Hz, 1H), 4.77 (d, J = 9.6 Hz,
1H), 3.53 (ddd, J = 1.2 Hz, J = 9.6 Hz, J = 9.6 Hz, 1H); 13C NMR (125
MHz, CDCl3, ppm) δ 199.7, 148.2, 142.0, 137.7, 131.0 (q, JCÀF
=
32.5 Hz), 129.0, 128.9, 128.0, 127.5, 127.0, 125.9, 125.8, 124.4, 123.8
(q, JCÀF = 271.0 Hz), 112.7, 60.2, 58.0, 56.7; HR-MS (ESI) m/z
404.1569 [M + MeOH + H]+, calcd for C21H21F3N3O2, 404.1586.
The enantiomeric excess was determined by HPLC analysis of the
corresponding alcohol (after treatment with NaBH4) using a Daicel
Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH = 9:1, flow rate =
1.0 mL/min: tr = 8.00 min (major) and tr = 33.2 min (minor).
(5S,6S,7R)-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,
8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3r).
The title compound was obtained using the general procedure described
above, in 87% yield and 99% ee: [R]20D = +21.1 (c = 1.00 in CH2Cl2);
1H NMR (400 MHz, CDCl3, ppm) δ 9.28 (d, J = 1.6 Hz, 1H), 7.62 (dd,
J = 8.4 Hz, J = 8.4 Hz, 4H), 7.28 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz,
2H), 6.25 (d, J = 1.6 Hz, 1H), 6.05 (d, J = 1.6 Hz, 1H), 5.44 (d, J = 9.6 Hz,
1H), 4.74 (d, J = 9.6 Hz, 1H), 3.47 (ddd, J = 1.6 Hz, J = 9.6 Hz, J = 9.6 Hz,
1H); 13C NMR (125 MHz, CDCl3, ppm) δ199.3, 148.1, 141.7, 136.3, 134.8,
131.2 (q, JCÀF = 36.3 Hz), 129.0, 128.9, 128.9, 127.9, 127.0, 124.8, 123.7
(q, JCÀF = 276.0 Hz), 112.6, 60.2, 57.2, 56.7; HR-MS (ESI) m/z
438.1192 [M + MeOH + H]+, calcd for C21H20ClF3N3O2, 438.1196.
The enantiomeric excess was determined by HPLC analysis of the
corresponding alcohol (after treatment with NaBH4) using a Daicel
Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH = 9:1, flow rate =
1.0 mL/min: tr = 9.00 min (major) and tr = 30.7 min (minor).
(5S,6S,7R)-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,
8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3s).
The title compound was obtained using the general procedure described
above, in 75% yield and 99% ee: [R]20D = +33.0 (c = 1.00 in CH2Cl2);1H
NMR (400 MHz, CDCl3, ppm) δ 9.29 (d, J = 1.2 Hz, 1H), 8.16 (d, J =
8.4 Hz, 2H), 7.62 (dd, J = 8.4 Hz, J = 8.4 Hz, 4H), 7.33 (d, J = 8.8 Hz,
2H), 6.53 (d, J = 1.6 Hz, 1H), 6.11 (d, J = 1.6 Hz, 1H), 5.68 (d, J = 9.2 Hz,
1H), 4.79 (d, J = 9.2 Hz, 1H), 3.50 (ddd, J = 1.2 Hz, J = 9.2 Hz, J = 9.2 Hz,
1H); 13C NMR (125 MHz, CDCl3, ppm) δ198.5, 148.2, 147.9, 145.4, 141.4,
131.3 (q, JCÀF = 32.5 Hz), 128.4, 127.8, 126.1, 126.0, 125.1, 124.7, 123.3
(q, JCÀF = 270.0 Hz), 112.5, 59.8, 56.4, 56.3; HR-MS (ESI) m/z
449.1422 [M + MeOH + H]+, calcd for C21H20F3N4O4, 449.1437.
The enantiomeric excess was determined by HPLC analysis of the
corresponding alcohol (after treatment with NaBH4) using a Daicel
Chiralpak OD-H column, hexane (0.1% TEA)/i-PrOH = 80:20, flow
rate = 0.8 mL/min: tr = 12.7 min (major) and tr = 26.1 min (minor).
8068
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The Journal of Organic Chemistry
NOTE
’ ASSOCIATED CONTENT
(9) (a) Li, H.; Wang, J.; Xie, H. X.; Zu, L. S.; Jiang, W.; Duesler, E. N.;
Wang, W. Org. Lett. 2007, 9, 965. (b) Sunden, H.; Rios, R.; Ibrahem, I.;
Zhao, G. L.; Eriksson, L.; Cordova, A. Adv. Synth. Catal. 2007, 349, 827.
(c) Yoshitomi, Y.; Arai, H.; Makino, K.; Hamada, Y. Tetrahedron 2008,
64, 11568.
S
Supporting Information. Copies of CSP-HPLC chro-
b
matograms, and 1H and 13C NMR spectra of the products, and
X-ray crystallographic data of 4n. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Li, H.; Zu, L. S.; Xie, H. X.; Wang, J.; Wang, W. Chem. Commun.
2008, 5636.
(11) (a) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan, B.; Zhong, G. Angew.
Chem., Int. Ed. 2008, 47, 10187. (b) Zhu, D.; Lu, M.; Chua, J.; Tan, B.;
Wang, F.; Yang, X.; Zhong, G. Org. Lett. 2008, 10, 4585.
(12) Enders, D.; Narine, A.; Toulgoat, F.; Bisschops, T. Angew.
Chem., Int. Ed. 2008, 47, 5661.
’ AUTHOR INFORMATION
Corresponding Authors
*E-mail: zhao_junling@gibh.ac.cn, hu_wenhui@gibh.ac.cn.
(13) (a) Enders, D.; Wang, C.; Raabe, G. Sythesis 2009, 4119.
(b) Hong, L.; Sun, W. S.; Liu, C. X.; Wang, L.; Wang, R. Chem.—Eur.
J. 2010, 16, 440.
’ ACKNOWLEDGMENT
(14) Bea, J.; Lee, H.; Youn, S.; Kwon, S.; Cho, C. Org. Lett. 2010,
12, 4352.
(15) For selected examples on aza-Michael addition of heteroaro-
matic compounds, see: (a) Diner, P.; Nielsen, M.; Marigo, M.; Jorgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 1983. (b) Uria, U.; Vicario, J. L.;
Badia, D.; Carrillo, L. Chem. Commun. 2007, 2509.
This work was supported by the Guangdong Natural Science
Foundation (10251066302000000). Prof. Jinsong Liu is grate-
fully acknowledged for X-ray structure determination. The
authors also wish to thank Prof. Ke Ding for his assistance with
HPLC analysis.
(16) (a) Ahrendt, K. A.; Borth, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243. (b) Northrup, A. B.; MacMillan, D.W. C.
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