Lewis acid-catalyzed formation of Ugi four-component reaction product from Passerini three-component reaction system without an added amine

Article abstract of DOI:10.1016/j.tet.2007.10.050

In the presence of a Lewis acid the phenol-Passerini three-component reaction (phenol-P-3CR) system is found to deliver a product of the phenol-Ugi four-component reaction (phenol-U-4CR). It is the first demonstration of an isocyanide as an amine equivale

Full text of DOI:10.1016/j.tet.2007.10.050

Available online at www.sciencedirect.com
Tetrahedron 63 (2007) 12866–12876
Lewis acid-catalyzed formation of Ugi four-component
reaction product from Passerini three-component
reaction system without an added amine
a
Wei-Min Daia,b, and Huoming Li
*
aLaboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
bDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
Received 14 August 2007; revised 9 October 2007; accepted 12 October 2007
Available online 16 October 2007
Abstract—In the presence of a Lewis acid the phenol-Passerini three-component reaction (phenol-P-3CR) system is found to deliver a product
of the phenol-Ugi four-component reaction (phenol-U-4CR). It is the first demonstration of an isocyanide as an amine equivalent in iso-
cyanide-based multicomponent reactions (IMCRs). In general, by using Ti(O-i-Pr)4 in MeOH both phenol-U-4CR and U-4CR products
are synthesized from an aromatic aldehyde, a phenolic or carboxylic acid, and an isocyanide. Moreover, by using MeCN as the solvent,
the phenol-P-3CR products can be obtained in good yields without contamination of the phenol-U-4CR products.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
6,7-diaminobenzo[b]furans from the reactions of 2 with
enones.13a–d Lewis acid-catalyzed reaction of ketones with
2 equiv of 2 was reported to afford b,g-unsaturated a-oxo-
carboxamides whose a-carbon originates from 2.14 Mono-
addition of isocyanides with ketones, epoxides, cyclic
ketals, and an aziridine mediated by a Lewis acid has been
disclosed, yielding various heterocycles15a–c and homo
U-4CR products.15d Insertion of isocyanides into aromatic
C–H was promoted by Lewis acids such as AlCl3 to furnish
aryl imines.13e Formation of byproducts was also noted for
Lewis acid-catalyzed P-3CR but the detail was not exami-
ned.8g We report here on Lewis acid-catalyzed formation
of U-4CR and phenol-U-4CR products from an aromatic
aldehyde, a carboxylic or phenolic acid, and an isocyanide
in the absence of an added amine. It offers the first demon-
stration of an isocyanide as an amine equivalent in IMCRs.
We also report on high-yielding phenol-P-3CR in MeCN
with 10 mol % i-Pr2NEt without contamination of the
phenol-U-4CR product.
The Passerini three-component reaction (P-3CR)1 and the
Ugi four-component reaction (U-4CR)2 are the known iso-
cyanide-based multicomponent reactions (IMCRs) useful
for generation of molecular diversity.3,4 In P-3CR (Eq. 1 in
Chart 1) an oxo compound 1, an isocyanide 2, and a carboxy-
lic acid 3 are coupled to produce an a-acyloxy carboxamide
6 while in U-4CR (Eq. 3 in Chart 1) an a-amido carbox-
amide 8 is formed from the reaction of an isocyanide 2, a
carboxylic acid 3, and an imine, which is normally formed
in situ from an oxo compound 1 and an amine 5. When the
carboxylic acid 3 is replaced by an electron-deficient pheno-
lic acid 4 a Smiles rearrangement5 is proposed as the
irreversible step in the phenol-Passerini three-component re-
action (phenol-P-3CR)6 and the phenol-Ugi four-component
reaction (phenol-U-4CR)7 as shown in Eqs. 2 and 4 of Chart
1. Lewis acid catalysis, although it is not required for major-
ity of the reported IMCRs, has been demonstrated for both
P-3CR and U-4CR.8–10 Moreover, under Lewis acid cataly-
sis, incorporation of two isocyanide molecules into the end
product (double insertion) has been observed, providing
many variants of the Passerini-type reaction. These include
formation of (a) 2,3-bis(alkylimino)oxetane from the re-
action of 2 with acetone at ꢀ78 ꢁC;11 (b) 2,3-diiminotetra-
hydrofurans and a-arylamino arylimino-g-butenolides from
the reactions of 2 with epoxides;12 and (c) 2,3-bis(aryl-
imino)pyrane derivatives, unsaturated iminolactones, and
2. Results and discussion
In connection with our work on synthesis of 3,4-dihydro-
3-oxo-2H-1,4-benzoxazines from 2-aminophenols,16 we
€
were interested in the phenol-U-4CR reported by El Kaım
and Grimaud in 2005.7a During our study on the U-4CR of
nitrophenols, aromatic aldehydes, glycine methyl ester
hydrochloride, and isocyanides we discovered that a phenol-
P-3CR took place without incorporation of the amine into
the products.17 Moreover, from the reaction of 1a, 2a, and
4a (1a/2a/4a¼1.3:1.5:1.0) carried out in MeOH at 60 ꢁC
Keywords: Lewis acid; Phenols; P-3CR; Smiles rearrangement; U-4CR.
* Corresponding author. Tel.: +852 23587365; fax: +852 23581594; e-mail
addresses: chdai@ust.hk; chdai@zju.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.050

W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
12867
O
O
R3
O
R4
NC
R3
CO2H
R4
P-3CR
+
+
+
+
N
H
R1
R2
R1 R2
6
O
1
2
3
O
O
O
R3
NC
R3
OH
Ar
phenol-P-3CR
N
H
Ar
R1
R2
R1 R2
7
1
2
4
O
R5
N
O
NH2
R5
R3
R4
NC
R3
CO2H
R4
U-4CR
+
+
+
+
+
N
H
R1
R2
R1 R2
8
O
1
2
3
5
O
R5
N
O
NH2
R5
R3
NC
R3
OH
Ar
phenol-U-4CR
+
N
H
Ar
R1
R2
R1 R2
9
1
2
4
5
Chart 1. General description of IMCRs. P-3CR and U-4CR involve a Mumm-type rearrangement and phenol-P-3CR and phenol-U-4CR involve a Smiles
rearrangement as the irreversible step, respectively.
(Scheme 1 and Fig. 1a) we obtained an inseparable mixture
of the phenol-P-3CR product 7a with a minor byproduct 9a.
The ratio of 7a/9a is 67:33 and the combined yield is 90%. It
was proved that the minor byproduct was generally pro-
duced, although to a different extent, for the reactions of
aromatic aldehydes without an electron-withdrawing group
such as benzaldehyde 1a, 4-methoxybenzaldehyde, and
2-furaldehyde. Fortunately, upon treating the mixture of 7a
and 9a with AcCl–H2O in refluxing CH2Cl2, compound 9a
could be selectively decomposed, providing the pure product
7a in 54% isolated yield (Fig. 1b). Compound 7a was also
obtained from the same reaction of 1a, 2a, and 4a performed
in MeCN (vide infra). As shown in Figure 1a and c, com-
pound 9a has a characteristic proton signal at 2.85 ppm
(t, J¼12.0 Hz). Because pure 9a was not available at the
time, its structure and the acid-promoted decomposition
products 10 and 11 (Scheme 1) could not be firmly
determined.
NO2
HO
CHO
Ph
NC
Cy
MeOH
+
+
60 °C, 36 h
(90%; 7a:9a = 67:33)
CO2Me
O
1a
2a
4a
Cy
O
NO2
NO2
Cy
O
Cy
N
N
+
N
H
H
Ph
Ph
9a
CO2Me
CO2Me
7a
AcCl, H2O
CH2Cl2, refluxing
Cy
HN
O
NO2
O
Cy
Cl
Cy
OH
Ph
+
N
N
H
H
Ph
CO2Me
10
11
12
1
Figure 1. Partial H NMR charts of (a) a 67:33 inseparable mixture of 7a
and 9a; (b) pure 7a; and (c) pure 9a.
Scheme 1. Phenol-Passerini-3CR reaction carried out in MeOH.

12868
W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
Table 1. Effect of Lewis acid-catalysis on phenol-U-4CRa
Lewis acid
MeOH, 60 °C
7a
+
9a
1a + 2a
+
4a
Entry
Lewis acid
t (h)
Conversionb (%)
7a/9ac
1
2
3
4
5
6
7
8
Noned
None
ZnBr2
Mg(ClO4)2
AgOTf
Zn(OTf)2
Cu(OTf)2
Sn(OTf)2
Sm(OTf)3
Yb(OTf)3
Ti(O-i-Pr)4f
Ti(O-i-Pr)4g
Ti(O-i-Pr)4g
Ti(O-i-Pr)4g,j
Ti(O-i-Pr)4g,k
Ti(O-i-Pr)4
36
36
72
36
72
72
72
72
24
72
72
72
24
40i
48i
48i
100
100
88
65
100
47
49
28
37
67:33
53:47
36:64
32:68
51:49
21:79
21:79
15:85
12:88
0:100
0:100
0:100
0:100h
0:100
77:23
0:100
9
10
11
12
13
14
15
16
30e
46e
23e
77e
70e
55
Figure 2. X-ray crystal structure of 9b.
acid-catalyzed reaction of benzyl isocyanide as shown in en-
try 2 of Table 2. From pure 9a, compounds 10 and 11 were
obtained in 77% and 86% yields after the acidic decomposi-
tion (Scheme 1). It should be mentioned that a minor product
12 (10%) was obtained from the Lewis acid-catalyzed reac-
tion of 1a, 2a, and 4a but it did not formed during the acidic
decomposition of 9a. The results imply that chloride anion
preferentially attacks at the protonated 9a, instead of water,
to form the product 10.
58e
a
All reactions were carried out in the presence of 20 mol % of Lewis acid
unless otherwise stated. 1a/2a/4a¼1.3:3.0:1.0.
Estimated for 4a.
b
c
d
e
f
Determined by 1H NMR analysis.
Data taken from Scheme 1. 1a/2a/4a¼1.3:1.5:1.0.
Isolated yield of pure 9a.
Ti(O-i-Pr)4 of 50 mol % was used.
Ti(O-i-Pr)4 of 5 mol % was used.
g
h
i
Compound 12 (Scheme 1) was isolated in 10% yield.
Carried out at room temperature.
No solvent used.
j
With the above established Ti(O-i-Pr)4-catalyzed con-
ditions, we selectively screened formation of the phenol-
U-4CR products 9 (Chart 1, Eq. 4; R1¼H and R5¼R3; 5 is
replaced by 2) by using four aldehydes, four phenols, and
two isocyanides in MeOH at 60 ꢁC in the presence of
5 mol % Ti(O-i-Pr)4 (Table 2). The products 9a–g were ob-
tained in 43–77% isolated yields without contamination of
the phenol-P-3CR products 7a–f. However, minor products
structurally similar to 12 were detected in these reactions.
k
Two equivalents of MeOH used.
In searching for conditions for selective formation of 9a we
systematically examined Lewis acid catalysis for the re-
action of 1a, 2a, and 4a, and the results are summarized in
Table 1. By using 3 equiv of cyclohexyl isocyanide 2a, the
ratio of 7a/9a changed from 67:33 to 53:47 (entry 2 vs entry
1). ZnBr2 and Mg(ClO4)2 were found to promote the for-
mation of 9a (entries 3 and 4). By using a series of metal tri-
flates, the ratio of 7a/9a increases from 51:49 to 0:100 in the
order of Ag+<Zn2+<Cu2+<Sn2+<Sm3+<Yb3+ (entries 5–
10, Table 1). However, the product 9a was isolated only in
30% yield after 72 h at 60 ꢁC under Yb(OTf)3 catalysis.
When 20 mol % Ti(O-i-Pr)4 was used the yield of 9a was im-
proved to 46% (entry 11). Further increase of the Lewis acid
to 50 mol %, the yield of 9a decreased to 23% (entry 12).
Finally, we were pleased to find that 9a could be prepared
in 77% yield in a pure form using 5 mol % Ti(O-i-Pr)4 at
60 ꢁC for 24 h (entry 13 and Fig. 1c). Moreover, the same re-
action took place at room temperature for 40 h, furnishing 9a
in 70% yield (entry 14). We observed a significant solvent
effect on the Lewis acid-catalyzed reaction. In the absence
of a solvent, the reaction became sluggish to produce
a 77:23 mixture of 7a and 9a (Table 1, entry 15 vs entry
14). When 2 equiv of MeOH was added, the reaction only
afforded 9a in a slightly lower yield of 58% (Table 1, entry
16 vs entry 14). The solvent effect clearly supports involve-
ment of the solvent molecules in the formation of the phenol-
U-4CR product 9a (vide infra).
€
In El Kaım and Grimaud’s work, 2-furaldehyde fails to
form phenol-U-4CR product with 4-chlorobenzylamine in
MeOH at 60 ꢁC.6b Under our Lewis acid-catalyzed con-
ditions, the furan-containing compound 9c was produced
in 64% yield even at room temperature (Table 2, entry 3).
Cinnamaldehyde did not form either phenol-U-4CR product
nor phenol-P-3CR product in MeOH.6b We discovered that
by using MeCN as the solvent the cinnamaldehyde-derived
phenol-P-3CR product 7h was formed at 80 ꢁC in the pres-
ence of 10 mol % i-Pr2NEt (Table 2, entry 8).19 We were
pleased to find out that the reaction of 1a, 2a, and 4a took
place by using 10 mol % i-Pr2NEt in MeCN at 80 ꢁC for
20 h to furnish 7a as the sole product in 91% isolated yield
(Table 2, entry 1). It differs from formation of the mixed
products in MeOH as given in Scheme 1. The effect of
MeCN on the phenol-P-3CR was confirmed for other related
reactions and 7b–g were synthesized in a pure form in 62–
87% yields (Table 2, entries 2–7). Our method provides an
improved synthesis of the known 7g in 73% yield as com-
pared to 57% yield obtained from the same reaction carried
out in MeOH at 45 ꢁC for 72 h.6b From the same set of aro-
matic aldehydes 1a–d, isocyanides 2a,b, and phenolic acids
4a–d, the phenol-P-3CR products 7a–g and the phenol-
U-4CR products 9a–g can be selectively synthesized by
employing the polar, aprotic solvent, MeCN and catalytic
i-Pr2NEt, and by applying Ti(O-i-Pr)4 catalysis in a protic
solvent, MeOH, respectively.
With pure 9a in hand, we finally characterized its structure
with reference to a related compound 9b, whose structure
was established by X-ray crystal structural analysis as shown
in Figure 2.18 Compound 9b was prepared from the Lewis

W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
12869
Table 2. Selective formation of phenol-P-3CR products 7a–h and phenol-U-4CR products 9a–g controlled by different solvents and catalytic Ti(O-i-Pr)4
R3
N
O
O
NC
R3
OH
Ar
O
phenol-U-4CR
phenol-P-3CR
+
+
R3
O
R3
H
R2
N
H
Ar
N
H
Ar
10 mol % i-Pr2NEt
MeCN, 80 °C
5 mol % Ti(Oi-Pr)4
MeOH, 60 °C
R2
7a-h
R2
9a-g
1a-e
2a,b
4a-d
Entry
1
Phenol-P-3CR product 7a
t (h)
Yield (%)
91
Phenol-U-4CR product 9b
t (h)
Yield (%)
Cy
O
O
O
NO2
NO2
NO2
O
NO2
Cy
Bn
Cy
O
Cy
N
20
24
24
77 (plus 10% 12)c
N
H
N
H
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
7a
9a
Bn
N
O
NO2
Bn
O
N
H
N
H
2
3
72
72
86
87
66
64
Ph
Ph
7b
9b
Cy
N
O
NO2
NO2
O
Cy
Bn
N
H
N
H
72d
CO2Me
CO2Me
O
O
7c
9c
Bn
N
O
NO2
O
Bn
O
N
H
N
H
CO2Me
4
72
66
48
51
OMe
OMe
9d
7d
Bn
N
O
CO2Me
O
CO2Me
Bn
O
Bn
N
N
5
6
72
72
62
72
48
48
43
45
H
H
Ph
7e
Ph
9e
NO2
NO2
NO2
O
Bn
N
O
NO2
Bn
O
Bn
N
N
H
H
Ph
7f
Ph
9f
CO2Me
NO2
CO2Me
NO2
Cy
N
O
O
O
Cy
O
Cy
N
N
H
H
7
48e
73
48
53
Cl
7g
Cl
9g
NO2
Cy
O
N
H
8
72
33
Ph
7h
a
Carried out in MeCN at 80 ꢁC in the presence of 10 mol % i-Pr2NEt. 1/2/4¼1.3:1.5:1.0.
b
c
d
e
Carried out in MeOH at 60 ꢁC in the presence of 5 mol % Ti(O-i-Pr)4. 1/2/4¼1.3:3.0:1.0.
The structure of 12 is found in Scheme 1. Formation of similar compounds with 12 was observed in other entries.
Carried out at room temperature in dark.
Known compound, see Ref. 19.
Lewis acid-catalyzed P-3CR using carboxylic acids as the
acid component has been reported in the literature.8 How-
ever, to the best of our knowledge there is no prior report
on formation of the carboxylic acid-derived U-4CR products
8 (Chart 1, Eq. 3; R1¼H and R5¼R3; 5 is replaced by 2) from
the P-3CR system without an added amine. We conducted
the reaction of 1a, 2b, and 3a (1a/2b/3a¼1.3:3.0:1.0) in
MeOH at 40 ꢁC in the presence of 5 mol % Ti(O-i-Pr)4 and

12870
W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
CO2H
NO2
spectra, the P-3CR product 6a and mandelic acid methyl
CHO
Ph
NC
Bn
ester 13 were likely formed. It should be emphasized that
aromatic carboxylic acids such as 3a,b are essential for for-
mation of the U-4CR products 8. Reactions using aliphatic
carboxylic acids gave much more complex mixtures.
5 mol % Ti(Oi-Pr)4
+
+
MeOH, 40 °C, 24 h
1a
2b
3a: X = 4-NO2
3b: X = 2-NO2
We propose a mechanism for the Lewis acid-catalyzed for-
mation of U-4CR and phenol-U-4CR products 8 and 9 as
shown in Scheme 3. In contrast to P-3CR the mechanism
of U-4CR is generally accepted to involve addition of an
isocyanide to an iminium species 24 and an irreversible
intramolecular rearrangement within a-adduct 26.3a,20 In
formulating our reaction mechanism, the first consideration
focuses on whether an isocyanide molecule can be trans-
formed into a primary amine or an imine species in the pres-
ence of a Lewis acid. There are several known possibilities
of formation of imine derivatives via insertion of isocyanides
into X–H bonds (X¼O, C, P). Hydrolysis (insertion of wa-
ter) of isocyanides has been used in organic synthesis21a,b
and it is also a competing side reaction in IMCRs,10c,20,21c,22
leading to mono N-substituted formamides. The latter could
be converted into primary amines but only in the presence of
mineral acids such as hydrochloric acid with heating at
O2N
O2N
Bn
N
O
O
O
Bn
Bn
O
OH
Ph
N
N
H
MeO
H
Ph
O
Ph
O
8a: X = 4-NO2 (65%)
8b: X = 2-NO2 (60%)
6a: X = 4-NO2
6b: X = 2-NO2
13
Scheme 2. Lewis acid-catalyzed U-4CR without an added amine.
obtained the U-4CR product 8a in 65% yield (Scheme 2).
Similarly, 8b was formed in 60% yield. The results clearly
demonstrate that 1 equiv of isocyanide serves as the amine
component required for formation of the U-4CR products.
An inseparable mixture of two minor products was obtained
1
together with 8a. According to analysis of the H NMR
TiIV
TiIV
OH
OH
O
O
+H2O; - R3NH2
OMe
O
OH
H
OMe
H
R2
R2
R2
R2
O
N
HN
N
R3
R3
R3
12: R2 = Ph, R3 = Cy
15b
13: R2 = Ph
15a
G-OH = H2O
H
H
G
OH
TiIV
R2
TiIV
O
R2
TiIV
O R
G-OH =
O
O-R
O
3 or 4
C
O
R2
N
G
O
G
R3
R2
N
N
H
R3
N
R3
R3
H
15c
2
14
1
16
TiIVOH
ROH
H
H O
R2
R3
R2
N
TiIVOR
H2O
+
N
O-R
+
G
R
R
O
O
R3
O
G
17
18
19
G OH
R3
R3
O
N
N
H
R2
G
R2
H
R2
R3
O
C=NR3
O
O
G
O
G
H
N
O
O
N
H
O
G
R3
R2
G
N
R3
H
H
N
R3
22
25
24
26
20
-GOH
Ti(IV)
R2
O
O
R3
N
R3
N
TiIV
O
R3
N
H
R3
N
RO
H
G
N
R3
H
O
G
R2
R2
21
23a: R = Me
23b: R = Bn
8: G = C(O)R4
9: G = Ar
27
Scheme 3. Proposed mechanism of Lewis acid-catalyzed U-4CR and phenol-U-4CR without an added amine. Ligands to Ti(IV) are omitted for clarity.

W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
12871
50 ꢁC.21a,b In an analogous manner, insertion of carboxylic
acids with isocyanides was proposed to afford either mono
N-substituted formamides or diacyl imides.23 Insertion of
alcoholic O–H into isocyanides normally does not take place
but it can be promoted by transition metals such as
Ni(0)24a and Cu(I),24b affording polymeric compounds and
N,N0-disubstituted formamidines, respectively. Rare-earth
silylamides, Ln[N(SiMe3)2]3 (Ln¼Y, La, Sm, Yb),25a and
actinide complexes, [(Et2N)3U][BPh4] and Cp2*AnMe2
(Cp*¼C5Me5, An¼U and Th),25b are effective for catalyz-
ing insertion of terminal alkyne C–H with isocyanides to
furnish 1-aza-1,3-enynes. AlCl3-catalyzed insertion of iso-
cyanides into electron-rich aromatic C–H is reported to pro-
duce arylimines.13e,26 This include insertion reactions at the
C3 position of indoles, and the C2 positions of pyrroles, thio-
phenes, and 1,3,5-trimethoxybenzene. Finally, Pd-catalyzed
insertion of isocyanides into P(O)–H furnished phosphinoyl
imines.27
metal-free species 20, the Ti(IV)-coordinated alkoxide in
the complex 15c becomes considerably inert toward a
Mumm or Smiles rearrangement for the formation of
P-3CR or phenol-P-3CR products. Alternatively, the oxygen
at the benzylic carbon in TiIVO–CH(R2) (R2 is an aromatic
ring) is readily cleaved for cyclization toward formation of
aziridine once the iminium double bond is removed by addi-
tion of a solvent molecule, ROH.24b Our experimental obser-
vations are consistent with formation of 16 from 15c.
Oxophilic Lewis acids such as Ti(IV), Ln(III), and Sn(II)
facilitate dissociation of TiIVOdꢀ/Cd+H(R2), giving higher
ratio for the product 9a (Table 1, entries 8–11). The develop-
ing benzylic carbocation should be stabilized by an electron-
rich substituent R2 as we observed for the aldehydes used in
Table 2. The observed solvent effect (Table 1, entries 15 and
16) reinforces the notion that the alcoholic solvent, MeOH,
participates in the formation of 16 from 15c. In addition,
conformational preference around the TiIVO(R2)HC–
C(OG)¼N+HR3 single bond may disfavor the intramolecu-
lar rearrangement in the reactions using ortho-substituted
nitrophenols and aromatic carboxylic acids. Decomposition
of 16 gives the iminium ion 17, which cleaves the oxonium
fragment 18 with formation of the imine 19. The sequence of
16/17/18+19 is supported by detection of benzyl for-
mate 23b by GC–MS analysis of the reaction mixture of
1a, 2a, and 4a with benzyl alcohol used as the solvent.
The water molecule involved in hydrolysis of 18 comes
from cyclization of 15c. By following the established mech-
anisms the U-4CR and phenol-U-4CR products 8 and 9 are
obtained from 19. We noted that high Ti(O-i-Pr)4 loading
decreased the yield of 9a (Table 1, entry 12). It can be
explained by formation of the Ti(IV) complex 27, which
prevents intramolecular rearrangement to the end products
8 and 9.
Apparently the above mentioned metal-catalyzed insertion
reactions of isocyanides with alcoholic O–H, C–H, and
P(O)–H bonds do not apply to our Lewis acid-catalyzed
U-4CR and phenol-U-4CR reactions. In order to rule out for-
mation of a primary amine from isocyanide hydrolysis by
moisture or phenols, we carried out the control experiment
by treating benzyl isocyanide 2b and the nitrophenol 4a
with 5 mol % Ti(O-i-Pr)4 in MeOH at 60 ꢁC for 24 h. The re-
action mixture was analyzed directly by GC–MS and after
condensation the residue was analyzed by 1H NMR spectros-
copy. The 1H NMR spectrum showed both 2b and 4a being
the major components along with a minor new species,
which was assigned as N-benzylformamide (21% compared
to 2b by integrations of the benzyl protons, see page S50 of
Supplementary data). GC–MS analysis gave the relative
abundance according to the peak areas for 4a (53.5%), 2b
(32.4%), N-benzylformamide (10.4%), and benzylamine
(0.6%). Since the boiling point of benzylamine is 184–
185 ꢁC, it should not be removed during condensation of
the reaction mixture. These results indicated that partial hy-
drolysis of 2b occurred but the resultant N-benzylformamide
did not further decompose into benzylamine in the presence
of Ti(O-i-Pr)4 in MeOH with heating. It is worthy mention-
ing that N-cyclohexylformamide was not detected by GC–
MS in the reaction mixture of 1a, 2a, and 4a carried out in
benzyl alcohol for trapping 23b (vide infra). The results
suggest that isocyanide hydrolysis is quite slower21c as
compared to other reactions of isocyanides.
We identified two side reaction products, the a-hydroxy
carboxamide 12 and mandelic acid methyl ester 13. Similar
products of the type 12 were reported for the BF3-catalyzed
reaction of oxo compounds, isocyanides, and water.14a It
should be formed by addition of water onto the nitrilium
ion 14 followed by isomerization of 15a. In a similar man-
ner, the solvent molecule, MeOH, reacts with 14 to form
the a-adduct 15b. Hydrolysis of 15b should produce 13.
An analogous procedure has been reported to occur under
basic conditions.10b Moreover, 15b can enter the same path-
way described for 15c as outlined in Scheme 3.
We attempted asymmetric U-4CR and phenol-U-4CR by
employing chiral ligands-modified Ti(OR)4 complexes.29
Unfortunately, no enantioselectivity was observed.30 The re-
sults are consistent with our proposed reaction mechanism in
Scheme 3 with the imine 19 as the key reactant. Up to date
there is no report on successful catalytic enantioselective
U-4CR without use of chiral auxiliaries.9
It has been reported that addition of an isocyanide to an oxo
compound in the presence of BF3$OEt2 forms an imino-ox-
irane species, which can be converted into an a-lactam 21
(Scheme 3).11 The latter is known to react with ‘weak protic
acids’ (carboxylic acids and hydrofluoric acid, pKa>0) to
produce P-3CR products while with ‘strong protic acids’
(sulfonic acids and hydrochloric acid, pKa<0) to furnish
an iminium salt with decarbonylation.28 It seems unlikely
that an iminium salt can be formed via an a-lactam 21 under
our phenol-U-4CR and U-4CR conditions in the absence of
a strong protic acid.
3. Conclusion
In summary, we have established the Ti(O-i-Pr)4-catalyzed
formation of U-4CR and phenol-U-4CR products in
MeOH from aromatic aldehydes, carboxylic or phenolic
acids, and isocyanides without added amines. By using
MeCN as the solvent, the phenol-P-3CR products are
As depicted in Scheme 3, we propose a new type of aziridine
derivative 16 formed from the known a-adduct 15c sug-
gested for Ti(OR)4-catalyzed P-3CR.8g As compared to the

12872
W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
prepared in the absence of Ti(O-i-Pr)4. A mechanism is pro-
posed for formation of the novel aziridine intermediate 16
from the initially formed a-adduct 15c. It is a novel reaction
pathway for IMCRs and is favored for the reactions with
combination of aromatic aldehydes, aromatic carboxylic
acid or phenols, and isocyanides in the presence of an oxo-
philic Lewis acid.
81.1, 52.6, 48.1, 32.6, 32.6, 25.4, 24.5, 24.5; MS (+ESI)
m/z (relative intensity) 435 (M+Na+, 100). Anal. Calcd for
C22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C, 64.30;
H, 6.05; N, 6.58.
4.2.2. N-Benzyl-2-(40-methoxycarbonyl-20-nitrophen-
oxy)-2-phenylacetamide (7b). Prepared in 86% yield
(Table 2, entry 2). Compound 7b: a yellow crystalline solid;
mp 149–150 ꢁC (EtOAc–hexane); Rf¼0.45 (33% EtOAc in
hexane); IR (film) 3407, 3321, 2952, 1727, 1683, 1618,
4. Experimental
4.1. General methods
1
1537, 1272 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.64 (d,
J¼2.4 Hz, 1H), 8.09 (dd, J¼8.8, 2.0 Hz, 1H), 7.72 (t, J¼
5.2 Hz, 1H), 7.54 (dd, J¼8.4, 2.0 Hz, 2H), 7.43–7.37 (m,
3H), 7.33–7.25 (m, 5H), 7.03 (d, J¼8.8 Hz, 1H), 5.84 (s,
1H), 4.55 and 4.46 (ABqd, J¼15.6, 6.8 Hz, 2H), 3.92 (s,
3H); 13C NMR (100 MHz, CDCl3) d 167.6, 164.4, 153.1,
138.8, 137.4, 135.8, 134.4, 129.2, 129.0 (ꢂ2), 128.6 (ꢂ2),
128.0, 127.5 (ꢂ2), 127.4, 126.3 (ꢂ2), 123.8, 115.7, 81.0,
52.5, 43.3; MS (+ESI) m/z (relative intensity) 443
(M+Na+, 100), 421 (M+H+, 27). Anal. Calcd for
C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C, 65.68;
H, 4.78; N, 6.70.
1H and 13C NMR spectra were recorded on a 400 or
1
300 MHz spectrometer in CDCl3 (400 or 300 MHz for H
and 100 or 75 MHz for 13C, respectively) with CHCl3 as
the internal reference. IR spectra were taken on Nicolet
Nexus FTIR 470 spectrophotometer. Mass spectra (MS)
were measured by the +ESI or ꢀESI method on HP5989B
at 70 eV. High-resolution mass spectra (HRMS) were mea-
sured by the +ESI on Bruker Apex III (7.0 Tesla) FTICRMS.
Silica gel pre-coated on glass was used for thin-layer chro-
matography using UV light or 7% ethanolic phosphomolyb-
dic acid and heating as the visualizing methods. Silica gel
and petroleum ether (PE; bp 60–90 ꢁC) were used for flash
column chromatography. Yields refer to chromatographi-
cally and spectroscopically (1H NMR) homogeneous mate-
rials. Anhydrous MeOH was freshly distilled from Mg
tunings. Anhydrous CH3CN was freshly distilled from
CaH2. Other reagents were obtained commercially and
used as received. Ambient temperature ranges from 10 to
30 ꢁC.
4.2.3. N-Cyclohexyl-2-(40-methoxycarbonyl-20-nitrophen-
oxy)-2-(furan-200-yl)acetamide (7c). Prepared in 87%
yield (Table 2, entry 3). Compound 7c: a white crystalline
solid; mp 128–130 ꢁC (EtOAc–hexane); Rf¼0.44 (33%
EtOAc in hexane); IR (film) 3397, 2933, 2855, 1728,
;
1686, 1617, 1533, 1271 cmꢀ1 1H NMR (400 MHz,
CDCl3) d 8.62 (d, J¼2.4 Hz, 1H), 8.19 (dd, J¼8.8, 1.6 Hz,
1H), 7.43 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼1.2 Hz, 1H), 7.29
(d, J¼8.8 Hz, 1H), 6.54 (d, J¼3.2 Hz, 1H), 6.37–6.35 (m,
1H), 5.83 (s, 1H), 3.91 (s, 3H), 3.87–3.80 (m, 1H), 1.99–
1.22 (m, 10H); 13C NMR (100 MHz, DMSO-d6) d 164.7,
164.5, 153.5, 148.4, 144.8, 139.7, 135.5, 127.1, 123.3,
116.7, 112.2, 111.3, 74.3, 53.0, 48.3, 32.5, 32.4, 25.6,
24.8, 24.7; MS (+ESI) m/z (relative intensity) 425 (M+Na+,
100), 403 (M+H+, 32). Anal. Calcd for C20H22N2O7:
C, 59.70; H, 5.51; N, 6.96. Found: C, 59.70; H, 5.63;
N, 6.95.
4.2. General procedure for phenol-Passerini-3CR
in MeCN with 10 mol % i-Pr2NEt: synthesis
of a-acyloxy carboxamides 7a–h
To a solution of phenol (0.20 mmol) in anhydrous MeCN
(0.2 mL, 1.0 M) were added aldehyde (0.26 mmol,
1.3 equiv), N,N-diisopropylethylamine (4 mL, 0.02 mmol,
10 mol %), and isocyanide (0.30 mmol, 1.5 equiv). The re-
sultant mixture was stirred at 80 ꢁC under a nitrogen atmo-
sphere for 20–72 h as specified in Table 2. The reaction
mixture was concentrated under reduced pressure and the
crude product was then purified by flash column chromato-
graphy (silica gel, eluted with 20% EtOAc in PE) to provide
the products 7a–h. The structures and yields of 7a–h are
listed in Table 2.
4.2.4. N-Benzyl-2-(40-methoxycarbonyl-20-nitrophen-
oxy)-2-(400-methoxyphenyl)acetamide (7d). Prepared in
66% yield (Table 2, entry 4). Compound 7d: a yellow crys-
talline solid; mp 139–141 ꢁC (EtOAc–hexane); Rf¼0.40
(33% EtOAc in hexane); IR (film) 3407, 3303, 2953, 1727,
;
1683, 1616, 1537, 1270 cmꢀ1 1H NMR (400 MHz,
CDCl3) d 8.62 (d, J¼2.0 Hz, 1H), 8.08 (dd, J¼8.8, 2.0 Hz,
1H), 7.68 (t, J¼6.4 Hz, 1H), 7.45–7.40 (m, 2H), 7.32–7.23
(m, 5H), 7.02 (d, J¼8.8 Hz, 1H), 6.92–6.87 (m, 2H), 5.76
(s, 1H), 4.53 and 4.48 (ABqd, J¼14.8, 6.0 Hz, 2H), 3.90 (s,
3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.9,
164.4, 160.3, 153.2, 138.8, 137.5, 135.8, 128.6 (ꢂ2),
128.0, 127.8 (ꢂ2), 127.5 (ꢂ2), 127.5, 126.4, 123.7, 115.8,
114.5 (ꢂ2), 80.9, 55.2, 52.5, 43.3; MS (+ESI) m/z (relative
intensity) 473 (M+Na+, 100), 451 (M+H+, 10). Anal. Calcd
for C24H22N2O7: C, 63.99; H, 4.92; N, 6.22. Found: C,
64.02; H, 4.95; N, 6.25.
4.2.1. N-Cyclohexyl-2-(40-methoxycarbonyl-20-nitrophen-
oxy)-2-phenylacetamide (7a). Prepared in 91% yield
(Table 2, entry 1). Compound 7a: a pale yellow crystalline
solid; mp 132–134 ꢁC (EtOAc–hexane); Rf¼0.30 (33%
EtOAc in hexane); IR (KBr) 3397, 3314, 2933, 2855,
1728, 1678, 1618, 1534, 1275, 1124 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 8.66 (d, J¼1.6 Hz, 1H), 8.08 (dd, J¼
8.8, 2.4 Hz, 1H), 7.51–7.47 (m, 2H), 7.38–7.30 (m, 4H),
7.00 (d, J¼9.2 Hz, 1H), 5.73 (s, 1H), 3.89 (s, 3H), 3.78–
3.75 (m, 1H), 1.90–1.83 (m, 2H), 1.72–1.68 (m, 2H),
1.59–1.55 (m, 1H), 1.31–1.21 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 166.6, 164.5, 153.3, 138.8, 135.9,
134.7, 129.2, 129.1 (ꢂ2), 128.1, 126.4 (ꢂ2), 123.8, 115.7,
4.2.5. N-Benzyl-2-(20-methoxycarbonyl-40-nitrophen-
oxy)-2-phenylacetamide (7e). Prepared in 62% yield
(Table 2, entry 5). Compound 7e: a white crystalline solid;
mp 120–122 ꢁC (EtOAc–hexane); Rf¼0.53 (33% EtOAc in

W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
12873
hexane); IR (film) 3350, 2953, 1722, 1682, 1524, 1346,
4.3. Representative procedure for Ti(O-i-Pr)4-catalyzed
phenol-U-4CR: synthesis of acetamide 8a,b
1
1258 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.81 (d, J¼
2.0 Hz, 1H), 8.61 (t, J¼5.2 Hz, 1H), 8.19 (dd, J¼9.2,
2.8 Hz, 1H), 7.54–7.52 (m, 2H), 7.41–7.25 (m, 8H), 6.89
(d, J¼9.6 Hz, 1H), 5.74 (s, 1H), 4.57 and 4.49 (ABqd, J¼
15.2, 6.4 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 168.0, 163.8, 160.9, 141.2, 137.8, 134.8, 129.3,
129.1, 129.0 (ꢂ2), 128.5 (ꢂ2), 128.2, 127.8 (ꢂ2), 127.3,
126.4 (ꢂ2), 119.5, 114.9, 81.0, 52.5, 43.4; HRMS (+ESI)
calcd for C23H20N2O6Na+ (M+Na+), 443.1214; found:
443.1199.
To a solution of p-nitrobenzoic acid (33.0 mg, 0.20 mmol) in
anhydrous MeOH (0.2 mL, 1.0 M) were added benzalde-
hyde (27 mL, 0.26 mmol, 1.3 equiv), Ti(O-i-Pr)4 (3 mL,
0.01 mmol, 5 mol %), and benzyl isocyanide (75 mL,
0.60 mmol, 3.0 equiv). The resultant mixture was stirred at
40 ꢁC under a nitrogen atmosphere for 24 h. The reaction
mixture was concentrated under reduced pressure and the
crude product was then purified by flash column chromato-
graphy (silica gel, eluted with EtOAc/CH2Cl2/PE¼1:2:2)
to provide the product 8a (65.0 mg, 65%).
4.2.6. N-Benzyl-2-(50-methoxycarbonyl-20-nitrophen-
oxy)-2-phenylacetamide (7f). Prepared in 72% yield (Table
2, entry 6). Compound 7f: a yellow crystalline solid; mp
134–136 ꢁC (EtOAc–hexane); Rf¼0.49 (33% EtOAc in hex-
ane); IR (film) 3408, 3315, 2953, 1729, 1683, 1526, 1293,
4.3.1. Synthesis of N-benzyl-2-(N0-benzyl-40-nitrobenz-
amido)-2-phenylacetamide (8a). Prepared in 65% yield.
Compound 8a: a white crystalline solid; mp 198–200 ꢁC
(EtOAc–hexane); Rf¼0.50 (33% EtOAc in hexane); IR
(KBr) 3407, 3284, 1653, 1633, 1524, 1350 cmꢀ1; 1H NMR
(400 MHz, CDCl3) (signal broadening is observed arising
from atropisomerism) d 8.10 (br d, J¼8.0 Hz, 2H), 7.52 (br
d, J¼8.8 Hz, 2H), 7.43 (br s, 1H), 7.34–7.19 (m, 9H),
7.15–7.09 (m, 3H), 6.90 (br s, 2H), 6.17 (br s, 1H), 5.80
(br s, 1H), 4.66–4.46 (m, 4H); 13C NMR (100 MHz,
CDCl3) (signal broadening is observed arising from atropi-
somerism) d 171.0, 168.8, 148.1 (ꢂ2), 142.3, 137.7, 136.7
(br), 136.5 (br), 134.1 (br), 129.9 (br, ꢂ2), 129.0 (ꢂ2),
129.0 (ꢂ2), 128.6 (ꢂ2), 128.3 (br, ꢂ2), 127.5 (ꢂ2), 127.4
(br), 127.1 (br), 126.6 (br), 123.5 (ꢂ2), 64.1 (br), 52.1
(br), 43.7; MS (ꢀESI) m/z (relative intensity) 478 (MꢀH+,
100). Anal. Calcd for C29H25N3O4: C, 72.64; H, 5.25; N,
8.76. Found: C, 72.67; H, 5.26; N, 8.72.
1
1236 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.97 (d, J¼
8.4 Hz, 1H), 7.71 (dd, J¼8.8, 1.2 Hz, 1H), 7.70–7.30 (m,
2H), 7.56 (d, J¼6.4 Hz, 2H), 7.43–7.35 (m, 3H), 7.32–
7.24 (m, 5H), 5.85 (s, 1H), 4.56 and 4.46 (ABqd, J¼14.8,
6.0 Hz, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 167.8, 164.5, 149.6, 141.8, 137.6, 135.6, 134.6, 129.2,
129.0 (ꢂ2), 128.6 (ꢂ2), 127.5 (ꢂ2), 127.4, 126.6 (ꢂ2),
126.3, 122.6, 116.9, 80.9, 52.9, 43.3; MS (+ESI) m/z (rela-
tive intensity) 443 (M+Na+, 100), 421 (M+H+, 18). Anal.
Calcd for C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found:
C, 66.19; H, 4.83; N, 6.71.
4.2.7. N-Cyclohexyl-2-(40-chlorophenyl)-2-(20-nitrophen-
oxy)acetamide (7g).6b Prepared in 73% yield (Table 2, en-
try 7). Compound 7g: a white crystalline solid; mp 158–
159 ꢁC (EtOAc–hexane); lit.6b mp 142 ꢁC; Rf¼0.45 (33%
EtOAc in hexane); IR (KBr) 3391, 3268, 3081, 2931,
4.3.2. N-Benzyl-2-(N0-benzyl-20-nitrobenzamido)-2-phe-
nylacetamide (8b). Prepared in 60% yield. Compound 8b:
a white crystalline solid; mp 148–150 ꢁC (EtOAc–hexane);
Rf¼0.55 (50% EtOAc in hexane); IR (KBr) 3310, 1646,
2854, 1655, 1525 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d 8.02 (dd, J¼8.0, 1.2 Hz, 1H), 7.48–7.43 (m, 3H), 7.38
(br d, J¼8.0 Hz, 1H), 7.34 (d, J¼8.4 Hz, 2H), 7.09 (dd,
J¼8.0, 8.0 Hz, 1H), 6.89 (d, J¼8.4 Hz, 1H), 5.62 (s, 1H),
3.80–3.70 (m, 1H), 1.90–1.83 (m, 2H), 1.73–1.69 (m, 2H),
1.60–1.57 (m, 1H), 1.37–1.21 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 166.7, 150.1, 139.1, 135.1, 134.9,
133.8, 129.1 (ꢂ2), 127.7 (ꢂ2), 126.6, 121.8, 115.7, 80.0,
48.1, 32.6 (ꢂ2), 25.4, 24.5 (ꢂ2); MS (+ESI) m/z (relative in-
tensity) 413 (M+2+Na+, 37), 411 (M+Na+, 100). Anal.
Calcd for C20H21ClN2O4: C, 61.78; H, 5.44; N, 7.20. Found:
C, 61.78; H, 5.44; N, 7.21.
1
1635, 1530, 1347 cmꢀ1; H NMR (300 MHz, CDCl3) (sig-
nal broadening is observed arising from atropisomerism)
d 8.20–8.10 (m, 1H), 7.63–7.46 (m, 5H), 7.40–7.00 (m,
14H), 6.16 (br s, 1H), 4.57 and 4.52 (ABqd, J¼14.7,
6.0 Hz, 2H), 4.46 and 4.37 (ABq, J¼16.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) (signal broadening is observed
arising from atropisomerism) d 168.4 (ꢂ2), 144.2, 137.3,
135.0, 134.0, 133.7, 132.2, 129.4 (ꢂ2), 129.2, 128.5 (ꢂ2),
128.4, 128.1, 128.0 (ꢂ2), 127.9, 127.9 (ꢂ2), 127.5, 126.9
(ꢂ2), 126.7, 123.9 (ꢂ2), 63.7, 51.9, 43.2; MS (+ESI) m/z
(relative intensity) 502 (M+Na+, 100); HRMS (+ESI) calcd
for C29H26N3O+4 (M+H+), 480.1923; found: 480.1924.
4.2.8. N-Cyclohexyl-2-(20-nitrophenoxy)-4-phenyl-but-3-
enamide (7h). Prepared in 33% yield (Table 2, entry 8).
Compound 7h: a pale yellow oil; Rf¼0.47 (33% EtOAc in
hexane); IR (film) 3388, 2932, 2854, 1676, 1606,
4.4. General procedure for Ti(O-i-Pr)4-catalyzed phe-
nol-Ugi-4CR: synthesis of a-amido carboxamides 9a–g
1524 cmꢀ1 1H NMR (400 MHz, CDCl3) d 8.02 (dd,
;
J¼8.0, 1.6 Hz, 1H), 7.54 (td, J¼8.0, 1.6 Hz, 1H), 7.41–
7.25 (m, 6H), 7.13–7.09 (m, 2H), 6.75 (br d, J¼16.4 Hz,
1H), 6.44 (dd, J¼16.4, 5.6 Hz, 1H), 5.35 (dd, J¼5.6,
1.6 Hz, 1H), 3.82–3.78 (m, 1H), 1.95–1.87 (m, 2H), 1.86–
1.69 (m, 2H), 1.62–1.55 (m, 1H), 1.41–1.20 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 166.8, 150.7, 139.2, 135.4,
135.1, 133.3, 128.6 (ꢂ2), 128.3, 126.8 (ꢂ2), 126.5, 122.8,
121.7, 115.9, 80.1, 48.2, 32.7 (ꢂ2), 25.4, 24.6 (ꢂ2); MS
(+ESI) m/z (relative intensity) 403 (M+Na+, 100); HRMS
(+ESI) calcd for C22H24N2O4Na+ (M+Na+), 403.1620;
found: 403.1610.
To a solution of phenol (0.20 mmol) in anhydrous MeOH
(0.2 mL, 1.0 M) were added aldehyde (0.26 mmol,
1.3 equiv), Ti(O-i-Pr)4 (3 mL, 0.01 mmol, 5 mol %), and iso-
cyanide (0.60 mmol, 3.0 equiv). The resultant mixture was
stirred at 60 ꢁC under a nitrogen atmosphere for 24–48 h.
The reaction mixture was concentrated under reduced pres-
sure and the crude product was then purified by flash column
chromatography (silica gel, eluted with 20% EtOAc in PE)
to provide the products 9a–g. The structures and yields of
9a–g are listed in Table 2.

12874
W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
4.4.1. N-Cyclohexyl-2-[N0-cyclohexyl-(40-methoxycar-
bonyl-20-nitrophenyl)amino]-2-phenylacetamid (9a) and
N-cyclohexyl-2-hydroxy-2-phenylacetamide (12). Com-
pounds 9a and 12 were prepared in 77% and 10% yields, re-
spectively (Table 2, entry 1). Compound 9a: a yellow oil;
Rf¼0.30 (33% EtOAc in hexane); IR (film) 3361, 2933,
(M+Na+, 100); HRMS (+ESI) calcd for C26H33N3O6Na+
(M+Na+), 505.2262; found: 506.2241.
4.4.4. N-Benzyl-2-[N0-benzyl-(40-methoxycarbonyl-20-
nitrophenyl)amino]-2-(400-methoxyphenyl)acetamide
(9d). Prepared in 51% yield (Table 2, entry 4). Compound
9d: a yellow crystalline solid; mp 153–155 ꢁC (EtOAc–
hexane); Rf¼0.50 (33% EtOAc in hexane); IR (film)
3363, 3312, 1724, 1667, 1612, 1530, 1512, 1251 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d 8.16 (d, J¼1.6 Hz, 1H), 7.88
(dd, J¼8.4, 1.6 Hz, 1H), 7.37 (br d, J¼9.2 Hz, 2H), 7.30
(t, J¼6.0 Hz, 1H, –NH), 7.20–7.08 (m, 6H), 6.99 (d,
J¼8.4 Hz, 1H), 6.93–6.87 (m, 4H), 6.69 (br d, J¼6.8 Hz,
2H), 4.94 (s, 1H), 4.42 and 4.11 (ABqd, J¼14.4,
7.2 Hz, 2H), 4.09 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H); 13C
2855, 1731, 1673, 1532, 1290, 1249 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 8.31 (d, J¼2.0 Hz, 1H), 7.94 (dd, J¼
8.4, 1.6 Hz, 1H), 7.66 (d, J¼8.8 Hz, 1H), 7.47 (d, J¼
6.8 Hz, 2H), 7.23–7.17 (m, 4H), 5.01 (s, 1H), 3.90 (s, 3H),
3.56–3.53 (m, 1H), 2.85 (t, J¼11.6 Hz, 1H), 1.87–0.73 (m,
20H); 13C NMR (100 MHz, CDCl3) d 170.2, 164.6, 149.3,
143.6, 136.9, 132.1, 131.5, 128.7 (ꢂ2), 128.2 (ꢂ2), 127.9,
126.7, 125.7, 71.6, 62.9, 52.6, 47.6, 32.5, 32.3, 29.3, 29.2,
25.8, 25.8, 25.3 (ꢂ2), 24.6 (ꢂ2); HRMS (+ESI) calcd for
C28H35N3O5Na+ (M+Na+), 516.2469; found: 516.2465.
NMR (100 MHz, CDCl3)
d
169.9, 164.7, 159.9,
146.2, 145.6, 137.6, 134.3, 133.1, 129.9 (ꢂ2), 129.0
(ꢂ2), 128.4, (ꢂ2), 128.3 (ꢂ2), 127.8, 127.6 (ꢂ2), 127.2,
127.2, 126.3, 126.2, 125.9, 114.3 (ꢂ2), 70.1, 56.2, 55.3,
52.5, 43.3; MS (+ESI) m/z (relative intensity) 562
(M+Na+, 100), 540 (M+H+, 24). Anal. Calcd for
C31H29N3O6: C, 69.00; H, 5.42; N, 7.79. Found: C, 69.03;
H, 5.41; N, 7.79.
Compound 12: a colorless oil; Rf¼0.30 (20% EtOAc in hex-
ane); IR (KBr) 3342, 3264, 2934, 2853, 1642, 1060 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.37–7.32 (m, 5H), 6.00 (d,
J¼6.4 Hz, 1H), 4.96 (d, J¼3.2 Hz, 1H), 3.75–3.73 (m,
2H), 1.84 (t, J¼12.4 Hz, 2H), 1.75–1.51 (m, 3H), 1.04–
1.03 (m, 2H), 1.03–1.00 (m, 3H); 13C NMR (100 MHz,
CDCl3) d 171.1, 139.7, 128.8 (ꢂ2), 128.5, 126.8 (ꢂ2),
74.0, 48.4, 32.9, 32.8, 25.4, 24.7, 24.6; HRMS (+ESI) calcd
for C14H19NO2Na+ (M+Na+), 256.1308; found: 256.1305.
4.4.5. N-Benzyl-2-[N0-benzyl-(20-methoxycarbonyl-40-
nitrophenyl)amino]-2-phenylacetamide (9e). Prepared in
43% yield (Table 2, entry 5). Compound 9e: a yellow crys-
talline solid; mp 146–148 ꢁC (EtOAc–hexane); Rf¼0.60
(33% EtOAc in hexane); IR (film) 3308, 1721, 1667, 1521,
4.4.2. N-Benzyl-2-[N0-benzyl-(40-methoxycarbonyl-20-
nitrophenyl)amino]-2-phenylacetamide (9b). Prepared in
66% yield (Table 2, entry 2). Compound 9b: a yellow crys-
talline solid; mp 117–119 ꢁC (EtOAc–hexane); Rf¼0.60
(33% EtOAc in hexane); IR (film) 3363, 1727, 1673, 1531,
1
1339, 1266 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.33 (d,
J¼2.4 Hz, 1H), 8.02 (dd, J¼8.8, 2.4 Hz, 1H), 8.03–7.98
(br s, 1H, –NH), 7.47–7.44 (m, 2H), 7.39–7.30 (m, 3H),
7.20–7.09 (m, 6H), 7.00 (d, J¼9.2 Hz, 1H), 6.95 (dd,
J¼8.0, 1.2 Hz, 2H), 6.68 (d, J¼7.2 Hz, 2H), 5.03 (s, 1H),
4.47 and 4.09 (ABqd, J¼14.4, 6.8 Hz, 2H), 416 and 4.06
(ABq, J¼14.4 Hz, 2H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 169.9, 166.4, 155.0, 142.8, 137.9, 135.6, 134.8,
128.9 (ꢂ2), 128.8 (ꢂ2), 128.8 (ꢂ2), 128.6, 128.3 (ꢂ4),
127.9 (ꢂ2), 127.7, 127.4, 127.2, 126.8, 126.5, 125.0, 71.8,
57.5, 52.8, 43.3; MS (+ESI) m/z (relative intensity) 548
(M+K+, 100), 532 (M+Na+, 73), 510 (M+H+, 15). Anal.
Calcd for C30H27N3O5: C, 70.71; H, 5.34; N, 8.25. Found:
C, 70.74; H, 5.33; N, 8.25.
1
1291 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.16 (d, J¼
2.0 Hz, 1H), 7.88 (dd, J¼8.4, 1.6 Hz, 1H), 7.48 (d,
J¼6.4 Hz, 2H), 7.38–7.34 (m, 4H), 7.20–7.07 (m, 6H),
7.01 (d, J¼8.8 Hz, 1H), 6.89–6.87 (m, 2H), 6.69 (d, J¼
7.2 Hz, 2H), 5.00 (s, 1H), 4.41 and 4.07 (ABqd, J¼14.4,
7.2 Hz, 2H), 4.09 (s, 2H), 3.93 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 169.6, 164.6, 146.1, 145.6, 137.5,
135.3, 134.1, 133.2, 129.0 (ꢂ2), 128.9 (ꢂ2), 128.7, 128.6
(ꢂ2), 128.4 (ꢂ2), 128.3 (ꢂ2), 127.9, 127.6 (ꢂ2), 127.1,
126.3, 126.2, 125.8, 70.7, 56.3, 52.5, 43.2; HRMS (+ESI)
calcd for C30H27N3O5Na+ (M+Na+), 532.1843; found:
532.1817.
4.4.6. N-Benzyl-2-[N0-benzyl-(50-methoxycarbonyl-20-
nitrophenyl)amino]-2-phenylacetamide (9f). Prepared in
45% yield (Table 2, entry 6). Compound 9f: an orange crys-
talline solid; mp 137–139 ꢁC (EtOAc–hexane); Rf¼0.58
(33% EtOAc in hexane); IR (film) 3368, 1729, 1667, 1529,
The structure of 9b was confirmed by X-ray crystallographic
analysis. The structural drawing is found in Figure 2.18
4.4.3. N-Cyclohexyl-2-[N0-cyclohexyl-(40-methoxycar-
bonyl-20-nitrophenyl)amino]-2-(furan-200-yl)acetamide
(9c). Prepared in 64% yield at room temperature for 72 h in
dark (Table 2, entry 3). Compound 9c: a yellow oil; Rf¼0.30
(33% EtOAc in hexane); IR (film) 3364, 2933, 2855, 1731,
1282 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.75 (dd,
;
J¼8.4, 1.6 Hz, 1H), 7.68 (d, J¼1.2 Hz, 1H), 7.54–7.50 (m,
3H), 7.46 (d, J¼8.8 Hz, 1H), 7.40–7.32 (m, 3H), 7.21–
7.080 (m, 6H), 6.92 (dd, J¼7.6, 1.6 Hz, 2H), 6.67 (d,
J¼7.2 Hz, 2H), 5.00 (s, 1H), 4.43 and 4.14 (ABqd,
J¼14.4, 6.8 Hz, 2H), 4.06 and 4.00 (ABq, J¼13.6 Hz,
2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) d 169.8,
164.7, 149.8, 142.0, 137.7, 135.7, 134.1, 133.5, 129.4
(ꢂ2), 128.9 (ꢂ2), 128.7 (ꢂ2), 128.6, 128.4 (ꢂ2), 128.3
(ꢂ2), 128.1, 127.9, 127.6 (ꢂ2), 127.2, 126.5, 124.3, 71.5,
57.5, 52.7, 43.2; MS (+ESI) m/z (relative intensity) 548
(M+K+, 100), 532 (M+Na+, 80), 510 (M+H+, 22). Anal.
Calcd for C30H27N3O5: C, 70.71; H, 5.34; N, 8.25. Found:
C, 70.74; H, 5.34; N, 8.25.
1682, 1537, 1289, 1250 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 8.25 (d, J¼2.0 Hz, 1H), 7.98 (dd, J¼8.4, 1.6 Hz,
1H), 7.68–7.66 (br s, 1H, –NH), 7.28 (d, J¼8.8 Hz, 1H),
7.21 (br s, 1H), 6.33 (d, J¼2.8 Hz, 1H), 6.16 (d, J¼2.0 Hz,
1H), 5.08 (s, 1H), 3.89 (s, 3H), 3.75–3.60 (m, 1H), 2.78 (t,
J¼12.0 Hz, 1H), 1.90–0.75 (m, 20H); 13C NMR
(100 MHz, CDCl3) d 168.3, 164.6, 149.2, 149.1, 144.0,
142.4, 132.2, 130.7, 127.8, 125.5, 110.7, 110.6, 64.1, 63.7,
52.5, 48.0, 32.5, 32.5, 30.6, 29.0, 26.0, 25.7, 25.3, 25.2,
24.7 (ꢂ2); MS (+ESI) m/z (relative intensity) 506

W.-M. Dai, H. Li / Tetrahedron 63 (2007) 12866–12876
12875
4.4.7. N-Cyclohexyl-2-[N0-cyclohexyl-(50-methoxycarbo-
Acknowledgements
nyl-20-nitrophenyl)amino]-2-(400-chlorophenyl)acet-
amide (9g). Prepared in 53% yield together with 10% of
7g (Table 2, entry 7). Compound 9g: a yellow crystalline
solid; mp 165–167 ꢁC (EtOAc–hexane); Rf¼0.46 (33%
EtOAc in hexane); IR (film) 3361, 1731, 1674, 1533,
This work was supported in part by the research grants from
The National Natural Science Foundation of China (Grant
No. 20672092) and Zhejiang University. Mr. Jianming Gu
of the X-ray crystallography facility of Zhejiang University
is acknowledged for assistance in the crystal structural anal-
ysis. W.-M. Dai is the recipient of the Cheung Kong Scholars
Award of The Ministry of Education of China.
1
1290 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.32 (d, J¼
2.0 Hz, 1H), 7.96 (dd, J¼8.0, 1.6 Hz, 1H), 7.58 (d, J¼
8.8 Hz, 1H), 7.42 (d, J¼8.4 Hz, 2H), 7.20 (d, J¼8.4 Hz,
2H), 7.16 (d, J¼8.4 Hz, 1H), 5.00 (s, 1H), 3.91 (s, 3H),
3.54–3.52 (m, 1H), 2.84–2.78 (m, 1H), 1.83–0.72 (m,
20H); 13C NMR (100 MHz, CDCl3) d 170.0, 164.5,
149.4, 143.2, 135.6, 134.1, 132.3, 131.5, 129.5 (ꢂ2), 129.0
(ꢂ2), 128.2, 125.8, 71.0, 62.9, 52.7, 47.7, 32.5, 32.4, 29.3,
29.2, 25.8, 25.8, 25.3, 25.3, 24.6 (ꢂ2); MS (+ESI) m/z
(relative intensity) 552 (M+2+Na+, 29), 550 (M+Na+,
100), 530 (M+2+H+, 10), 528 (M+H+, 21). Anal. Calcd for
C28H34ClN3O5: C, 63.69; H, 6.49; N, 7.96. Found: C,
63.69; H, 6.50; N, 7.97.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.10.050.
References and notes
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4.5. Acidic hydrolysis of amide 9a: formation of
N-cyclohexyl-2-chloro-2-phenylacetamide (10) and
N-cyclohexyl-4-methoxycarbonyl-2-nitroaniline (11)
€
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H2O (72 mL, 4.00 mmol, 20 equiv) was added a solution of
compound 9a (99.0 mg, 0.20 mmol) in CH2Cl2 (2.0 mL).
The resulting mixture was then refluxed for 12 h. The
reaction mixture was concentrated under reduced pressure
and the residue was purified by flash column chromato-
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compound 10 (39.0 mg, 77%) and compound 11 (48.0 mg,
86%).
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Obtained in 77% yield from 9a as a white crystalline solid;
mp 124–125 ꢁC (CH2Cl2–hexane); Rf¼0.35 (20% EtOAc in
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1537 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.42–7.33 (m,
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5H), 6.66 (br s, 1H), 5.34 (s, 1H), 3.83–3.75 (m, 1H),
2.00–1.90 (m, 2H), 1.74–1.70 (m, 2H), 1.64–1.59 (m, 1H),
1.47–1.31 (m, 2H), 1.28–1.15 (m, 3H); 13C NMR
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127.7 (ꢂ2), 61.7, 48.8, 32.8, 32.6, 25.4, 24.6 (ꢂ2); MS
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1
1265, 1223 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.85 (t,
J¼2.0 Hz, 1H), 8.40 (br d, J¼6.8 Hz, 1H, –NH), 7.98 (d, J¼
8.8 Hz, 1H), 6.86 (d, J¼9.2 Hz, 1H), 3.88 (s, 3H), 3.60–3.50
(m, 1H), 2.10–2.00 (m, 2H), 1.80–1.77 (m, 2H), 1.75–1.65
(m, 1H), 1.50–1.20 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 165.7, 146.9, 136.1, 131.0, 129.8, 116.6, 113.8, 52.0,
51.3, 32.5 (ꢂ2), 25.4, 24.4 (ꢂ2); MS (+ESI) m/z (relative
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30. We thank Dr. Xinglong Xing for assistance on these experi-
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