Selective formation of 2-imidazolines and 2-substituted oxazoles by using a three-component reaction

Article abstract of DOI:10.1002/chem.200800271

Selective formation of 2H-2-imidazolines and 2-substituted oxazoles by using a multicomponent reaction of amines, either aldehydes or ketones, and a-acidic isocyano amides or esters is described. By selecting the appropriate solvent, Ag^I or Cu^I catalyst, or by employing a weak Bronsted acid, the product formation can be fully controlled and directed quantitatively to the desired heterocyclic scaffold. The described experimental procedures not only significantly increase the scope of compatible inputs for this complexitygenerating three-component reaction, but also allow for considerable chemical diversity: At least four diversity points in two distinct scaffolds can be exploited in this way.

Full text of DOI:10.1002/chem.200800271

FULL PAPER
DOI: 10.1002/chem.200800271
Selective Formation of 2-Imidazolines and 2-Substituted Oxazoles by Using a
Three-Component Reaction
Niels Elders, Eelco Ruijter, Frans J. J. de Kanter, Marinus B. Groen, and
Romano V. A. Orru*[a]
Abstract: Selective formation of 2H-2-
imidazolines and 2-substituted oxazoles
by using a multicomponent reaction of
amines, either aldehydes or ketones,
and a-acidic isocyano amides or esters
is described. By selecting the appropri-
ate solvent, AgI or CuI catalyst, or by
employing a weak Brønsted acid, the
product formation can be fully con-
trolled and directed quantitatively to
the desired heterocyclic scaffold. The
described experimental procedures not
only significantly increase the scope of
compatible inputs for this complexity-
generating three-component reaction,
but also allow for considerable chemi-
cal diversity: At least four diversity
points in two distinct scaffolds can be
exploited in this way.
Keywords: heterocycles · imidazo-
lines · multicomponent reactions ·
oxazoles · selectivity
Introduction
products (I1, I2, …, IN) and the final reaction product (P) are
reversible (Scheme 1).
Multicomponent reactions (MCRs) combine at least three
different substrates in one reaction flask.[1] As such, MCRs
have emerged as useful and atom-efficient strategies for the
rapid introduction of molecular complexity and diversity
starting from rather simple building blocks.[2] Developments
are fast in this area and several
As already suggested by Ugi et al.,[1a] distinction can be
made between three categories of MCRs. Type I MCRs are
sequences of reversible reactions, whereas type II MCRs are
sequences of reversible reactions that are terminated by an
irreversible reaction step. Finally, type III MCRs are se-
classes of interesting heterocy-
cles with potential biological ac-
tivities are now accessible
through using MCRs.[1]
MCRs are
a subclass of
domino or tandem reactions
and hence are one-pot sequen-
ces of two or more reactions.[3]
Clearly, much of the success of
such processes depends on to
which extent the reactions lead-
ing to intermediate reaction
Scheme 1. Type I, II, and III multicomponent reactions.[1a]
quences of irreversible elementary reactions. Type I MCRs
are only rarely successful, because the yield of the final
product (P) strongly depends on thermodynamics. However,
with type II and III MCRs thermodynamics at least favor
the final reaction step and efficient product formation is
possible. Most of the reported MCRs to date are of type II.
It should, however, be realized that an irreversible last reac-
tion step does not exclude the formation of side products,
because all preceding reactions are equilibria and more than
[a] N. Elders, Dr. E. Ruijter, Dr. F. J. J. de Kanter, Prof. Dr. M. B. Groen,
Prof. Dr. R. V. A. Orru
Department of Chemistry and Pharmaceutical Sciences
Vrije Universiteit Amsterdam
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
Fax : (+31)2-59-87488
E-mail: rva.orru@few.vu.nl
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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4961

one reactive species may be present at the same time. The
reactivity of the starting materials and in situ-generated in-
termediates may result in competitive reaction paths, and
consequently, in (uncontrolled) formation of (side) prod-
ucts.[4] Careful optimization of the reaction conditions of
type II MCRs is therefore often crucial for useful synthetic
application.
In addition to the formation of 2-imidazolines (4), a
second MCR yielding 2-substituted oxazoles[8] (5) and in-
volving essentially the same components has been report-
ed.[9] The reaction has been well studied for the use of iso-
cyano amides, in which morpholine is typically chosen as the
R1 substituent, although other dialkylamino substituents can
be used as well.[9a,d,f,j] The mechanism of this reaction pre-
sumably starts with attack of the terminal isonitrile carbon
atom to the (pre-formed) imine leading to intermediate B
followed by proton abstraction and ring closure (Scheme 2,
path III).[9c,d,g,i,k] However, initial (base-promoted) ring clo-
sure (reported for the formation of 2H-oxazoles[10i]) followed
by attack of the oxazolide anion C to the (protonated)
imine cannot be excluded (path IV). The R2 substituent of
the isocyanide can be varied to a considerable extent (Ph,
H, Me, Bn, iPr) and either aldehydes or ketones can be
used as the carbonyl input. In addition, the MCR tolerates
both primary and secondary amines, although in the case of
primary amines the isolated yields are typically somewhat
lower. Again, optimization of reaction conditions appeared
crucial for optimal performance. Toluene and MeOH were
found to be excellent solvents, and the MCR can be acceler-
Recently, we reported a flexible and easy to perform type
II MCR for the formation of 2H-2-imidazolines[5] (4) start-
ing from a-acidic isocyanides (1), aldehydes or ketones (2),
and primary amines (3) (Scheme 2).[6] A wide variety of al-
dehydes and amines can be used in this MCR. Careful opti-
mization of the reaction conditions showed that the scope of
compatible isocyanides could be expanded considerably by
selecting MeOH as the solvent.[5] The reaction mechanism
probably involves a Mannich-type addition of deprotonated
isocyanide intermediate A to a (protonated) imine, followed
by ring closure to the heterocyclic product, and a proton
shift (Scheme 2, path I). However, a concerted [2+3] cyclo-
addition of A to the imine, followed by protonation of the
resulting anion (path II) cannot be excluded. The reaction
rates and the scope of compatible isocyanides can be in-
creased even further by employing a catalytic amount of
AgOAc.[7] The reactions can be run at high concentration
(2.0m) without special solvent/reagent handling. The re-
agents can be mixed in equimolar amounts without pre-for-
mation of the imine, which simplifies the experimental and
work-up procedure. Consequently, this MCR is easily scalea-
ble but also applicable in a combinatorial setup for the easy
generation of libraries of 2H-2-imidazolines (4).[5]
ated by using weak Brønsted acids like NH4Cl, pyri
A
AHCTREUNG
be mixed in equimolar amounts to simplify the work-up pro-
cedure.[9b]
Recently, Zhu and co-workers reported that the MCR to-
wards formation of oxazoles (5) can also be performed by
using an isocyano ester with a strongly electron-withdrawing
1
2
À
group at the a position (Scheme 2; R =OMe, R =p-NO2
Scheme 2. Possible reaction paths for the MCR between amines, either aldehydes or ketones, and a-acidic isocyanides, which leads to either 2-imidazo-
lines or oxazoles.
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Formation of Imidazolines and Oxazoles
FULL PAPER
Ph).[9k] Although isocyano esters are substrates that typically
yield 2-imidazolines (4),[5,6] a wide variety of aldehydes and
amines were used in this MCR to afford the corresponding
5-methoxyoxazoles in moderate to excellent yields.
The results reported by Zhu, as well as those reported by
us, clearly indicate that several reaction pathways are avail-
able for the same type of substrates and that the reaction
path that is followed cannot be correlated to the class of iso-
cyanide used. This observation
The 3-CR employing isocyano amides: All reactions were
performed in MeOH at room temperature with the isocyano
amide (1a–c; 0.2m concentration), compounds 2a and 3a,
and in the presence of MgSO4 (Scheme 3). The first experi-
ment, in which the glycine-derived isocyano amide 1a (R=
H) was employed, already showed formation of a nearly 1:1
mixture of 2-imidazoline 4a and oxazole 5a (Table 1,
entry 1), which indicated that oxazole and 2-imidazoline for-
led us to believe that it is possi-
ble to control and direct the
outcome of the MCR between
a-acidic isocyanides, (primary)
amines, and either aldehydes or
ketones. We envisioned that by
carefully tuning the reaction
conditions, either the 2H-2-imi-
dazolines (4) or 2-substituted
oxazoles (5) could be formed
Scheme 3. Course of the MCR using AgOAc or a Brønsted acid.
selectively and in good yields.
Here, we describe in detail our efforts to control and direct
the three-component reaction (3-CR). The tuning of condi-
tions is based on the mechanistic considerations as summar-
ized in Scheme 2, which evolves from all the available exper-
imental data for both imidazoline and oxazole formation by
means of this 3-CR. In addition, the following considera-
tions and observations are also crucial for understanding the
setup of the studies reported in this paper: 1) 2-Imidazoline
formation is stimulated by the addition of an AgI salt, such
as AgOAc, because the MCR is accelerated due to an in-
creased concentration of the (silver-coordinated) isocyanide
anion A (Scheme 2, paths I and II).[7] Furthermore, when
path III is considered, AgOAc may block oxazole formation
by coordination of the isocyanide carbon atom to AgI, thus
reducing its nucleophilicity.[11] 2) Oxazole formation is accel-
erated by addition of a weak Brønsted acid, which activates
the imine.[9b] In addition, the slight decrease in pH of the re-
action medium will probably lower the concentration of de-
protonated isocyanide anion A, which may favor reaction
path III (Scheme 2).
mation occur simultaneously. The conversion was increased
when the reaction was run at 608C (entry 2), without affect-
ing the product ratio. In agreement with our concept, addi-
tion of a catalytic amount (2 mol%) of AgOAc resulted in a
significantly increased product ratio in favor of 2-imidazo-
line (97:3, entry 3). By increasing the catalyst loading to
5 mol%, 2-imidazoline 4a was formed nearly quantitatively
after 4 h (entry 4). Formation of oxazole 5a was not ob-
served at all upon slow addition of isocyanide 1a over 21 h,
thus allowing the isolation of 4a in 91% yield (entry 5).
As discussed above, running the 3-CR in the presence of
a weak Brønsted acid should favor oxazole formation.
Indeed, when the condensation between 1a, 2a, and 3a was
performed in the presence of two equivalents of NH4Cl,
quantitative conversion of isocyanide 1a was observed after
22 h (entry 6) and no traces of 2-imidazoline 4a were detect-
ed in the crude reaction mixture. Although the formation of
1
4a was not observed, the H NMR spectrum of the crude
mixture did indicate the presence of many (unidentified)
Table 1. Optimization of conditions to direct the MCR of either isocyanide 1a or 1b with 2a and 3a.[a]
Results and Discussion
Entry
1
Promoter
T [8C]/Time
Conversion [%]
A
Isolated yield [%]
1
2
3
4
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
none
none
RT/3 d
60/22 h
RT/22 h
RT/4 h
RT/22 h
RT/22 h
60/2 h
60/22 h
60/5 h
RT/2 d
RT/4 d
60/24 h
60/5 h
54
100
100
100
100
ACHTREUNG
To obtain comparable data for
our studies to control and
direct the 3-CR towards selec-
tive formation of either the 2-
imidazoline or the 2-substituted
oxazole, test systems were se-
lected in which only the type of
isocyanide (1) was varied. The
oxo and amine components
(acetone (2a) and benzylamine
(3a), respectively) were kept
the same in all reactions.
ACHTREUNG
AgOAc (2 mol%)
AgOAc (5 mol%)
AgOAc (2 mol%)
NH4Cl (2.0 equiv)
NH4Cl (2.0 equiv)
NH4Cl (2.0 equiv)
Et3N·HCl (2.0 equiv)
none
ACHTREUNG
ACHTREUNG
5[b]
6
A
91 (4a)
100[c]
100[c]
48
ACHTREUNG
7
ACHTREUNG
8[d]
9
ACHTREUNG
100[c]
n.d.[c]
0
ACHTREUNG
10
11
12
13
ACHTREUNG
AgOAc (2 mol%)
AgOAc (2 mol%)
Et3N·HCl (1.0 equiv)
n.d.[c]
100[c]
ACHTREUNG
A
49 (5b)
[a] Reactions were performed in MeOH at RT on a 1.0 mmol scale (0.2m of 1a or 1b). Conversions and prod-
uct ratios were determined by H NMR spectroscopy. [b] The isocyanide was added over 21 h, followed by 1 h
1
additional reaction time. [c] Unidentified side products detected. [d] Reaction performed in toluene.
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4963

R. V. A. Orru et al.
side products. Performing the same reaction at 608C in-
creased the reaction rate (entry 7), but did not result in a
cleaner reaction. When toluene was used as the solvent in-
stead of MeOH, the side products were not detected. How-
ever, the slow conversion (48% after 22 h) and, more impor-
tantly, the detection of imidazoline 4a, indicated that we
were not tuning the conditions in the desired direction
(entry 8). In this reaction NH3 may react as the amine com-
ponent instead of 3a and in this way interfere with the
MCR.[12] To exclude this possibility we decided to follow the
conditions described earlier by Zhu, by employing Et3N·HCl
as the Brønsted acid.[9] In this case, again, the product for-
mation was found to be entirely in favor of the oxazole
(entry 9). However, the MCR suffered from another side
product, that is, oxazole 6 (11% isolated yield, Table 2). Ap-
parently, morpholine was partially liberated, most likely
through transamidation of the isocyanide,[13] and reacted in
the 3-CR instead of benzylamine (3a). The overall conver-
sion of 1a is independent of the amount of Brønsted acid
used (Table 2), but the amount of 6 relative to 5a decreases
when less of the Brønsted acid is used. However, by using
substoichiometric amounts of Et3N·HCl, 2-imidazoline 4a
can be detected in the crude reaction mixture (Table 2, en-
tries 3 and 4). Under optimized conditions, that is, heating
the substrates at 608C for 5 h in the presence of one equiva-
lent of Et3N·HCl, the desired oxazole 5a could be isolated
in a very respectable 73% yield (Table 2, entry 2). In con-
clusion, with this set of inputs it is possible to control and
direct the 3-CR to an acceptable extent and selectively
access either 2-imidazoline 4a or oxazole 5a.
with an electron-donating group (R=Et) was studied. When
1b was stirred with 2a and 3a in the absence of a promoter
(AgOAc or Et3N·HCl) only the corresponding oxazole 5b
could be identified while considerable amounts of unidenti-
fied (side) products were detected as well (Table 1,
entry 10). When the same reaction was performed in the
presence of AgOAc (2 mol%), no reaction could be ob-
served at all after stirring for four days (entry 11). Only the
corresponding imine and unreacted 1b were detected, which
suggests that indeed reaction path III (Scheme 2) is fol-
lowed. Heating the reaction mixture at 608C immediately
resulted in the formation of a black metallic precipitate
most likely originating from AgOAc. Consequently, the
same results were obtained as those for the reaction run in
the absence of promoter (entries 12 and 10, respectively).
On the other hand, when the 3-CR between 1b, 2a, and 3a
was performed in the presence of one equivalent of
Et3N·HCl as reported above, formation of 5b was relatively
clean (entry 13, isolated yield 49%).
These results suggest that the 3-CR of isocyano amides
with an electron-donating group at the a-carbon atom, ben-
zylamine (3a), and acetone (2a) can be directed towards ox-
azoles in a straightforward procedure but not to 2-imidazo-
lines. Next, we investigated the use of isocyanide 1c, which
has an electron-withdrawing phenyl group at the a position.
Stirring the components (1c, 2a, and 3a) for two days under
the standard conditions resulted in a 10:90 product mixture
in favor of oxazole 5c (Table 3, entry 1). When this reaction
was performed under the optimized conditions as described
for the 3-CR of 1a, 2a, and 3a (1 equiv Et3N·HCl; see
above), product formation was complete within 5 h and ox-
Encouraged by these initial results we decided to investi-
gate the influence of electron-donating versus electron-with-
drawing a substituents (R) in the isocyanide input on the
outcome of the 3-CR. First, the behavior of isocyanide 1b
A
isolation in 56% yield (entry 2). On the other hand, when
the same reaction was performed in the presence of 2 mol%
AgOAc, formation of 2-imidazoline increased to 19%.
However, the major product formed was not 5c but rather
2H-oxazole 7 (entry 3). This product is most likely formed
by coordination of 1c to AgI followed by loss of the a
proton and intramolecular attack of the carbonyl oxygen to
Table 2. Influence of the amount of Et3N·HCl on the ratio of products
formed from the 3-CR between isocyanide 1a with 2a and 3a.[a]
the
(silver-coordinated)
isocyanide
carbon
atom
(Scheme 4).[7] This reaction path is clearly catalyst con-
trolled, since increasing the amount of AgOAc had a nega-
tive effect on the 2-imidazoline formation (4c/7 8:92,
Table 3. Optimization of conditions to direct the MCR using isocyanide
1c with 2a and 3a.[a]
Entry
Promoter
Time
Conv.
[%]
[7/4c/5c]
Isolated
yield [%]
Entry Et3N·HCl
[equiv]
t=6.5h
[4a/5a/6] Conv.
[%]
t=20h
[4a/5a/6] yield
[%]
Isolated
N
Conv.
[%]
1
none
2 d
5 h
21 h
21 h
6.5 h
4 d
63
100
100
100
100
100
ACHTREUNG
2[b]
3
Et3N·HCl (1 equiv)
AgOAc (2 mol%)
AgOAc (10 mol%)
AgOAc (1 mol%)
CuI (2 mol%)
A
56 (5c)
65 (7)
1
2
2.0
1.0
66
63
A
A
ACHTREUNG
C
G
4
ACHTREUNG
5[c]
6[c]
ACHTREUNG
3
4
0.5
0.25
63
60
N
A
A
60 (4c)
N
ACHTREUNG
[a] Reactions were performed in MeOH at RT on a 1.0 mmol scale (0.2m
of 1c). Conversions and product ratios were determined by 1H NMR
spectroscopy. [b] Reaction performed at 608C. [c] Reaction performed at
2.0m concentration.
[a] Reactions were performed in MeOH at RT in equimolar substrate
ratios on a 1.0 mmol scale (0.2m). Conversions (Conv.) and product
ratios were determined by H NMR spectroscopy.
1
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Formation of Imidazolines and Oxazoles
FULL PAPER
formed at all. For example, performing the reaction in the
presence of 2 mol% AuCl·THT (THT: tetrahydrothio-
phene) or AuCl·SMe2 resulted in the rather slow formation
of a 1:1 mixture of 4c and 5c (Figure 1, 63 and 74% after
3 d, respectively). When the amount of AuI catalyst was in-
creased to 10 mol%, quantitative conversion of 1c was ob-
served in 21 h. However, oxazole 5c was the major product
(4c/5c 30:70), which indicated that the MCR towards for-
mation of oxazoles might also be facilitated by this AuI
salt.[14a] On the other hand, the relative amount of 2-imida-
zoline 4c increased when CuI salts were used as the cata-
lyst.[14b] Again, the size of the anion is important for the
ratio in which 4c is formed. On the basis of these conditions
we were able to isolate 4c in 60% yield by increasing the
overall reaction concentration to 2.0m and stirring the reac-
tion mixture for four days in the presence of 2 mol% CuI
(Table 3, entry 6).
Scheme 4. AgI-catalyzed formation of 2H-oxazole 7 in an MCR between
1c, 2a, and 3a.
entry 4). On the other hand, increasing the overall concen-
tration of the reaction mixture to 2.0m in combination with
decreasing the catalyst loading to 1 mol% facilitated imida-
zoline formation (entry 5), although oxazole 7 remained the
major product.
The 3-CR employing a-aryl isocyano esters: Although the
above results demonstrate that careful tuning of the reaction
conditions allows control over the course of the 3-CR when
isocyano amides 1a–c are used, the frequent formation of
side products hampers straightforward application towards
selective formation of either 2-imidazolines (4) or 2-substi-
tuted oxazoles (5). We turned our attention to the use of a-
aryl-substituted isocyano esters 1d–j in the 3-CR
(Scheme 5). As mentioned in the introduction, so far isocya-
no esters have been reported to selectively produce 2-imida-
zolines (4),[5,6] the only notable exception being a-(p-nitro-
phenyl)-a-isocyanoacetate (1e), which was found to undergo
the MCR leading to the corresponding 5-methoxyoxazo-
les.[9k] Stirring isocyanide 1d (R=H) with acetone (2a) and
benzylamine (3a) in the absence of promoter and under the
same general conditions as described for 1a–c resulted in
the formation of a 14:86 mixture of 2-imidazoline 4d and
oxazole 5d, respectively (Table 4, entry 1). Encouraged by
this initial result, which indicates that the scope for the
3-CR towards 5-methoxyoxazole formation can be expanded
with respect to the isocyanide and carbonyl inputs,[15] we fur-
ther optimized the conditions towards selective formation of
the oxazoles. However, no major influence on either the
product ratio or the reaction rate could be observed in the
presence of one equivalent of Et3N·HCl (Table 4, entry 2).
The use of counterions other than ÀOAc for the AgI cata-
lyst generally had only a minor influence on the product
ratio between 4c, 5c, and 7 (Figure 1). With PF6 , BrÀ, ClÀ,
À
À
BPh4 , and IÀ as counterions for AgI, 2-imidazoline 4c (gray
bars) could be detected in higher relative amounts than that
found when using ÀOAc, although the overall reaction time
to reach completion increased in some cases (AgI: 64%
conversion after 21 h). The only trend that could be ob-
À
served is that larger anions like BPh4 and IÀ tend to give
less of the undesired oxazole 7 (black bars). A possible ra-
tionalization for this observation is that larger anions in-
crease the steric bulk around the terminal isocyanide carbon
atom, thus leading to less facile intramolecular ring closure
through attack of the carbonyl oxygen atom. Consequently,
oxazole formation is less favored. When other Group 14
metal salts were used in the 3-CR, 2H-oxazole 7 was not
Figure 1. Metal salt versus product ratio and conversion (after 21 h, num-
bers in italics [%]) for the MCR between acetone (2a), benzylamine
(3a), and isocyanide 1c. The white bars show data for oxazole 5c, gray
bars show data for imidazole 4c, and black bars show data for oxazole 7.
Scheme 5. MCRs using a-phenyl isocyano esters 1d–j.
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4965

R. V. A. Orru et al.
Table 4. Screening for optimal solvents for the MCR of isocyanide 1d
(R=H) with 2a and 3a.[a]
Entry
Solvent
t [h]
Conv. [%]
A
Isolated yield [%]
1
MeOH
MeOH
CH2Cl2
toluene
MeCN
DMF
24
24
20
20
20
4
100
100
60
ACHTREUNG
2[b]
3
ACHTREUNG
AHCTREUNG
4
5
83
ACHTREUNG
100
100
100
ACHTREUNG
6
A
59 (5d)
65 (4d)
7[c]
MeOH
22
ACHTREUNG
[a] Reactions were performed at RT on 1.0 mmol scale (0.2m of 1d).
1
Conversions and product ratios were determined by H NMR spectrosco-
py. [b] 1 equiv Et3N·HCl added. [c] 2 mol% AgOAc used as catalyst; iso-
cyanide 1d added as a 1m solution over 21 h, followed by 1 h additional
reaction time.
Figure 2. Reaction time and product ratio 4d–j/5d–j (black and white
bars, respectively), influenced by the pKa of the a proton in the a-phenyl
isocyano esters (1d–j) using reaction method A (MeOH, in the absence
of a promoter).
From our earlier work it became clear that the 2-imidazo-
line 3-CR is relatively fast in protic polar solvents.[5] Thus,
changing the reaction medium from MeOH to any aprotic
solvent would retard the 2-imidazoline formation, and may
favor formation of 5-methoxyoxazoles. This approach
indeed proved successful. When the reaction between 1d,
2a, and 3a was run in either polar (MeCN and DMF) or
apolar (CH2Cl2 and toluene) aprotic solvents instead of
MeOH, the corresponding oxazole 5d was the sole product
detected (Table 4, entries 3–6). The reaction rate was strong-
ly dependent on the solvent used. For example, when
CH2Cl2 or toluene was used, the isocyanide substrate 1d
could still be detected in the reaction mixture after 20 h (60
and 83% conversion, respectively, entries 3 and 4), whereas
in MeCN full conversion was observed (entry 5). DMF
proved to be the solvent of choice, and led to the complete
conversion of 1d to oxazole 5d within four hours (entry 6,
59% isolated yield). As reported by us earlier,[6b] 2-imidazo-
line 4d is formed selectively by performing the reaction in
the presence of AgOAc (Table 4, entry 7, 65% isolated
yield). In conclusion, the course of the 3-CR depends criti-
cally on the solvent used. By carefully selecting the right sol-
vent and promoter, complete control towards either 2-imida-
zoline or 5-methoxyoxazole formation can be achieved.
The pKa of the a proton in the isocyanide inputs is be-
lieved to be of critical importance[6b] and, most likely, gov-
erns the reaction path of the 3-CR and, consequently, the
ratio in which the products are formed. To investigate the
extent to which the electronic properties of the R group in
the a-aryl isocyano esters determines the course of the 3-
CR, six additional a-aryl isocyano esters (1e–j, Scheme 5)
were studied. For each isocyanide the 3-CR was performed
under three different reaction conditions. First, the standard
conditions in the absence of promoter (method A, Figure 2)
were employed, which usually give mixtures of the corre-
sponding 2-imidazolines (4d–j) and oxazoles (5d–j). Then,
conditions for each isocyanide were selected that should se-
lectively produce either the 2-imidazoline or the oxazole
(methods B and C, respectively, Table 5).
Table 5. Applying optimal conditions for directing the 3-CR to either 2-
imidazoline (method B) or oxazole (method C) formation using a-aryl
isocyano esters 1e–j.[a]
Entry
1
Method B[b]
Isolated
Method C[c]
[4/5] Isolated
A
Time
ACHTREUNG
yield [%]
yield [%]
1[d]
2[d,e]
3
1e
1e
1 f
1 f
1g
1h
1i
C
0.5 h
11 h
N
62 (5e)
72 (4e)
59 (5 f)
4[e]
5
25 (4 f)
n.d.
67 (4h)
75 (4i)
87 (4j)
2 h
2 h
8 h
7 d
48 (5g)
57 (5h)
64 (5i)
6
7
8
1j
[a] Reactions were performed on a 1.0 mmol scale (0.2m of 1e–j). Con-
versions and product ratios were determined by 1H NMR spectroscopy.
[b] MeOH used as solvent; 2 mol% AgOAc added as catalyst; isocya-
nides were added as a 1m solution in MeOH over 21 h, followed by 1 h
additional reaction time. [c] DMF used as solvent. [d] 1e was added as a
1m solution in CH2Cl2 due to its poor solubility in MeOH. [e] 5 mol%
AgOAc. [f] 55% conversion. [g] 79% conversion. [h] 52% conversion
after 22 h; 48 h total reaction time.
electronic nature of the R substituent(s) present on the a-
aryl group of 1. When 1e (R=p-NO2) was combined with
2a and 3a the product ratio was found to be entirely in
favor of oxazole 5e (Figure 2, [0:100]). The same conditions
but now using an isocyano ester with a chloro substituent at
the ortho, meta, or para position (1 f–h) still predominantly
gave the corresponding oxazoles (5 f–h), but minor amounts
of the 2-imidazolines (4 f–h) could be detected in the reac-
tion mixture as well (2–3%, black bars). As discussed
above, when 1d (R=H) was employed under identical con-
ditions, the corresponding oxazole was still the major prod-
uct formed (4d/5d 14:86). However, when the a-aryl group
was equipped with electron-donating R groups (1i, 1j) the
3-CR (in the absence of promoter) favored formation of 2-
imidazoline (Figure 2). Thus, one-pot reaction of 1i (R=p-
OMe), 2a, and 3a in MeOH gave a 52:48 mixture of 4i and
5i, respectively. This ratio completely turned in favor of the
corresponding 2-imidazoline (4j) when 1j (R=o,p-(OMe)2)
was employed as the isocyanide input. The electronic nature
As expected, the ratio in which 4d–j (Figure 2, black
bars) and 5d–j (Figure 2, white bars) are formed in the ab-
sence of promoter (method A) is clearly governed by the
4966
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4961 – 4973

Formation of Imidazolines and Oxazoles
FULL PAPER
of the R substituent in 1d–j not only has a profound influ-
ence on the observed product ratios, but also has a clear
effect on the reaction rates. By using method A, the MCR
with 1e (R=p-NO2) was complete within one hour, whereas
with 1j (R=o,p-(OMe)2) only 45% conversion was reached
after seven days (all other reactions reached completion
within the time shown). It should, however, be noted that
besides the pKa of the a proton, the extended reaction times
may also be attributed to steric congestion due to ortho sub-
stitution at the a-phenyl ring of some of the isocyanides
used. This is supported by the observation that the 3-CR of
1 f, 2a, and 3a proceeds much slower under the standard
conditions than the same reaction using 1g or 1h (Figure 2).
In most cases the course of the 3-CR could be directed
completely to 2-imidazoline (4e–j) by slow addition of the
a-aryl isocyano ester (1e–j) to a mixture of 2a and 3a in
MeOH in the presence of 2 mol% AgOAc (Table 5, method
B).[16] In some cases 5 mol% AgOAc was required to selec-
tively produce the 2-imidazoline (entry 2). A notable excep-
tion is the selective formation of 4 f, which could not be ach-
ieved. It appears that the relatively large o-Cl substituent in
1 f makes the nucleophilic attack of the deprotonated a-
carbon atom in 1 f more difficult (Scheme 2, paths I and II),
which hampers selective formation of 4 f. Even with the use
of 5 mol% AgOAc, imidazoline 4 f was only formed as the
minor product (entry 4). In most cases, however, the isolated
yields are typical for 2-imidazolines (67–87%).[5,6]
Influence of the imine on the course of the 3-CR: From the
experimental data presented in the previous sections, it is
clear that judicious selection of the reaction conditions
offers full control over the course of the 3-CR towards
either 2-imidazoline or oxazole products from the same
starting materials. For full control, the steric and electronic
properties of the isocyanide used are of major importance.
However a clear influence of the in situ-generated imine is
observed as well. For a number of different imines (gener-
ated from 2a–f and 3a–e, Table 6) in combination with iso-
cyano ester 1d we studied the outcome of the 3-CR under
optimal conditions as described above for 2-imidazoline for-
mation (method B) and for 5-methoxyoxazole formation
(method C). When 1d, benzylamine, and a series of carbon-
yl components with increasingly sterically demanding sub-
stituents R1 and R2 were allowed to react under the condi-
tions of method B (AgOAc, MeOH), formation of the cor-
responding 2-imidazolines (4d,k,l,m) decreased gradually
(Table 6, entries 1–4). However, when the same reactions
were performed in DMF (method C), 5-methoxyoxazole
(5d,k,l,m) formation increased with larger R1 and R2 sub-
stituents in the oxo component (Table 6, entries 1–4). The
same trend was observed when the steric constraints of the
amine component 3 were increased (entries 5–8). The reac-
tion of 1d, cyclohexanone (2e), and the smallest possible
amine, ammonia (3b), could be fully directed to either the
formation of 2-imidazoline 4n or oxazole 5n (using method
B and C, respectively; entry 5). However, under the condi-
When the reactions of 1e–i with 2a and 3a were per-
formed in DMF (Table 5,
method C) the corresponding
Table 6. Influence of the carbonyl and amine components on the 3-CR with isocyano ester 1d.[a]
oxazoles 5e–i were formed
quantitatively. Typically, the
conversion of the isocyanides
proceeds twice as fast in this
polar aprotic solvent than the
reactions performed in MeOH
(method A, Figure 2). The iso-
lated yields reported for 5e–i
(entries 1, 3, 5, 6 and 7) are typ-
ical and comparable to yields
reported by Zhu et al. for simi-
lar reactions employing primary
amines (48–62%).[9] It should
be noted that reaction of isocy-
anide 1j with 2a and 3a in
DMF did not take place at all.
Because formation of inter-
mediate B (Scheme 2, path III)
through nucleophilic attack of
the terminal NC carbon atom
on the imine should be easy in
the case of isocyanide 1j, this
result might indicate that
MeOH and/or AgI catalysis is
essential for abstraction of the
a proton.
Entry
R1
R2
R3
R4
Method B[b]
[4/5]
Method C[c]
[4/5]
G
Isolated yield [%]
N
Isolated yield [%]
1[d]
2
3
Me
Me
Me
Et
H
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
C
89 (4k)
65 (4d)
16 (4l)
0 (4m)
63 (4n)
0 (4o)
C
0 (5k)
59 (5d)
53 (5l)
49 (5m)
69 (5n)
63 (5o)
61 (5p)
Me
Et
Et
À
À
À
4
5[e]
6
G
À
À
(CH2)5
G
nPr
morpholino
À
7
A
0 (4p)
À
À
8
(CH2)5
tBu
H
[00:00][f]
G
9
iPr
H
tBu
H
[46:54]
26 (4q)
G
59 (5q)
[a] Reactions were performed on a 1.0 mmol scale (0.5m of 1d). Product ratios were determined by 1H NMR
spectroscopy. [b] MeOH used as solvent, 2 mol% AgOAc added as catalyst, and isocyanide added as a 1m so-
lution in MeOH over 21 h (0.33m), followed by 1 h additional reaction time. [c] DMF used as solvent.
[d] 2.0 equiv acetaldehyde used. [e] NH4Cl (2 mmol) used as amine component in combination with Et3N
(2.0 mmol). [f] 50% conversion.
Chem. Eur. J. 2008, 14, 4961 – 4973
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4967

R. V. A. Orru et al.
tions optimized for initial attack of the a-carbon atom of
the isocyanide to the imine (Scheme 2, paths I and II), only
oxazole formation was observed by using amine inputs that
were more sterically demanding. Thus, combination of 1d,
cyclohexanone (2e), and either n-propylamine (3c) or ben-
zylamine (3a) led to the sole formation of 5o and 5p (en-
tries 6 and 7, respectively). When the steric constraints were
further increased (t-butylamine, entry 8) even the corre-
sponding 5-methoxyoxazole product was not formed. In-
stead, as reported by Zhu et al.,[9k,17] 2-(hydroxyalkyl)-5-me-
thoxyoxazole (8) was obtained as the major product. Even
prolonged stirring of cyclohexanone and t-butylamine in the
presence of 3 Š molecular sieves before addition of the iso-
cyanide only resulted in the formation of 8 as judged by
1H NMR spectroscopic analysis of the crude reaction mix-
ture. However, application of t-butylamine as a bulky amine
input is tolerated in the 3-CR for both 2-imidazoline and ox-
azole formation when a less sterically demanding carbonyl
component is used (entry 9).[6b]
mation because of the higher nucleophilicity of the a anion
À
in the deprotonated isocyanide. Obviously, the C C bond
formation between two quaternary carbon atoms is strongly
influenced by steric bulk around the isocyanide and imine.
Consequently, preference for oxazole formation increases
with the application of inputs that are more sterically de-
manding. However, for a synthetically useful range of reac-
tant combinations, the 3-CR can be completely directed to-
wards either imidazoline or oxazole formation by selecting
the appropriate conditions. Thus, AgI (or CuI) catalysis pro-
duces 2-imidazolines, and application of a Brønsted acid
and/or use of an aprotic solvent selectively provides the cor-
responding oxazoles. The described experimental proce-
dures not only significantly increase the scope of compatible
inputs for this complexity-generating 3-CR, but also allows
considerable chemical diversity to be addressed: At least
four diversity points in two distinct scaffolds can be
exploited.
Clearly, imines with relatively small substituents give the
corresponding 2-imidazolines under the conditions of
method B, whereas imines that are more sterically demand-
ing tend to give the corresponding oxazoles under the condi-
tions of method C. This is in agreement with the reaction
pathways shown in Scheme 2. For 2-imidazoline formation,
the a-carbon atom of the isocyanide is most likely involved
in the initial reaction step (paths I and II), whereas for ox-
Experimental Section
General: Unless stated otherwise, all solvents and commercially available
reagents were used as purchased (without any further purification). Slow
additions were performed by using a New Era NE-1800 multisyringe
pump. Melting points were measured by using a Stuart Scientific SMP3
melting point apparatus and are uncorrected. Infrared (IR) spectra were
recorded with neat samples on KBr tablets by using a Matteson Instru-
ment 6030 Galaxy Series FTIR spectrophotometer. 1H and 13C (attached
A
proton test) NMR spectra were recorded on
a Bruker Avance 400
lieved to react first (path III). With imines that are more
sterically demanding the a-carbon atom of the isocyanide,
which is sterically less accessible, cannot effectively ap-
proach the imine sp2-carbon atom, which results in de-
creased formation of the imidazoline and favors oxazole for-
mation by means of direct attack of the terminal isocyanide
carbon atom.
(400.13 MHz for 1H and 100.62 MHz for 13C) or a Bruker Avance 250
(250.13 MHz for H and 62.90 MHz for 13C) spectrometer using CHCl3 as
1
the internal standard (1H: d=7.26 ppm; 13C{1H}: d=77.0 ppm). Fast atom
bombardment (FAB) mass spectrometry was carried out using a JEOL
JMS SX/SX 102A four-sector mass spectrometer, coupled to a JEOL
MS-MP9021D/UPD system program (samples were loaded in a matrix
solution (3-nitrobenzyl alcohol) onto a stainless-steel probe and bom-
barded with xenon atoms (3 KeV)). Electron impact (EI) mass spectrom-
etry was carried out using a Finnigan MAT900 spectrometer (electron
ionization voltage 70 eV). Chromatographic purification refers to flash
chromatography using the indicated solvent (mixture) and Merck 90
standardized Al2O3 (activity II–III, particle size 0.063–0.200 mm, 70–230
mesh ASTM) or Silicycle Silia-P flash silica gel (particle size 40–63 mm,
pore diameter 60 Š). Thin-layer chromatography was performed using
TLC plates from Merck (Al2O3, 60 F254 on aluminum with fluorescence
indicator or silica gel, Kieselgel 60 F254 neutral, on aluminum with fluo-
rescence indicator). Compounds on TLC were visualized by using UV
light. Isocyanides 1a,[18] 1b,[18b] 1c,[19] 1d,[6a] and 1e[9k] were synthesized
according to literature procedures.
Conclusion
Judicious selection of the reaction conditions for the 3-CR
between amines, either a-isocyano esters or amides, and
either aldehydes or ketones results in selective formation of
either 2-imidazolines or oxazoles. The range of compatible
isocyanides for the MCR that leads to imidazolines has been
expanded to include the use of isocyano amides, whereas
the range of compatible isocyanides for 5-methoxyoxazole
formation has been expanded to include a wider range of a-
aryl isocyano esters. Under standard reaction conditions
using MeOH (method A), competitive formation of 2-imida-
zolines and oxazoles is often observed. The reaction path
followed seems to be mainly governed by two factors: 1) the
relative ease of a-proton abstraction in the isocyanide input
and 2) the steric constraints of both the isocyanide and the
in situ-generated imine. a-Aryl isocyano esters bearing elec-
tron-withdrawing substituents favor oxazole formation due
to stabilization of the a-anionic species (A). On the other
hand, electron-donating substituents favor imidazoline for-
General procedure 1—Screening of reaction conditions: Unless stated
otherwise, a 10 mL reaction vial was charged with isocyanide 1a–d
(1.0 mmol), the appropriate solvent (5.0 mL), MgSO4 (100 mg), benzyl-
amine (3a; 162 mL, 160 mg, 1.5 mmol), acetone (2a; 150 mL, 118 mg,
2.0 mmol), and reported promoter. Reactions were performed at RT and
aliquots (100 mL) were taken, until the given time or full conversion of
the isocyanide. Samples were analyzed by using 1H NMR (CDCl3) spec-
troscopy after filtration and evaporation of the sample to dryness.
General procedure 2—Synthesis of the a-phenyl isocyano esters: Isocya-
no esters 1 f–j were synthesized from their corresponding amino acids in
three steps following our previously reported procedure.[5]
Methyl 2-(o-chlorophenyl)-2-isocyanoacetate (1 f): General procedure 2
was followed using (Æ)-2-chlorophenylglycine (10.0 g, 53.8 mmol) to give
1 f as a clear red oil (6.99 g, 33.4 mmol, 62%). Purification was per-
formed by means of column chromatography (silica gel, EtOAc/cyclohex-
4968
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Chem. Eur. J. 2008, 14, 4961 – 4973

Formation of Imidazolines and Oxazoles
FULL PAPER
1
ane 1:2, Rf =0.59). H NMR (400.13 MHz, CDCl3): d=7.59–7.57 (m, 1H),
and concentrated, and the resulting 2-imidazoline was purified by means
of column chromatography.
7.46–7.44 (m, 1H), 7.39–7.36 (m, 2H), 5.85 (s, 1H), 3.82 ppm (s, 3H);
13C{1H} NMR (100.62 MHz, CDCl3): d=165.4 (C), 161.6 (C), 133.1 (C),
130.9 (CH), 130.3 (C), 130.1 (CH), 128.6 (CH), 127.8 (CH), 57.1 (CH),
53.9 ppm (CH3); IR (KBr): n˜ =2146 (s), 1759 (s), 1477 (m), 1437 (m),
1433 (m), 1223 (s), 1033 cmÀ1 (m); MS (FAB, 3 KeV): m/z (%): 210 (18)
[M+H]+, 183 (100) [MÀNC]+; HRMS (FAB, 3 KeV): m/z calcd for
C10H9ClNO2 [M+H]+: 210.0322; found: 210.0318.
(1-Benzyl-5,5-dimethyl-4,5-dihydro-1H-imidazol-4-yl)(morpholino)meth-
A
1.0 mmol) to give 4a as a pale brown oil (274 mg, 0.91 mmol, 91%). Rf =
0.33 (Al2O3, EtOAc/MeOH (10%)); 1H NMR (250.13 MHz, CDCl3): d=
7.38–7.27 (m, 5H), 6.90 (d, 4J=1.4 Hz, 1H), 4.70 (d, 4J=1.4 Hz, 1H),
4.24 (d, 2J=15.2 Hz, 1H), 4.21 (d, 2J=15.2 Hz, 1H), 3.72–3.69 (m, 8H),
1.33 (s, 3H), 1.18 ppm (s, 3H); 13C{1H} NMR (62.90 MHz, CDCl3): d=
168.8 (C), 156.2 (CH), 138.0 (C), 128.7 (2CH), 127.7 (2CH), 127.7 (CH),
76.3 (CH), 67.1 (CH2), 66.8 (CH2), 64.5 (C), 46.4 (CH2), 45.9 (CH2), 42.5
(CH2), 27.4 (CH3), 20.9 ppm (CH3); IR (KBr): n˜ =2860 (w), 1648 (s),
1602 (s), 1454 (m), 1229 (m), 1003 cmÀ1 (w); MS (EI, 70 eV): m/z (%):
301 (8) [M]+, 286 (6) [MÀCH3]+, 187 (100) [MÀC5H8NO2]+, 91 (91)
[C7H7]+; HRMS (EI, 70 eV): m/z calcd for C17H23N3O2 [M]+: 301.17903;
found: 301.17772.
Methyl 2-(m-chlorophenyl)-2-isocyanoacetate (1g): General procedure 2
was followed using (Æ)-3-chlorophenylglycine[20] (4.85 g, 21.2 mmol) to
give 1g, after 1 h of stirring at 08C, as a dark red oil (0.76 g, 3.6 mmol,
17%). Purification was performed by means of two column chromatogra-
phy steps (silica gel, EtOAc/cyclohexane 1:1, Rf =0.80; silica gel, EtOAc/
cyclohexane 1:2, Rf =0.59). The isolated product was sufficiently pure for
follow-up reactions. 1H NMR (250.13 MHz, CDCl3): d=7.49–7.31 (m,
4H), 5.34 (s, 1H), 3.81 ppm (s, 3H); 13C{1H} NMR (62.90 MHz,
CDCl3):[21] d=165.5 (C), 135.2 (C), 133.4 (C), 130.5 (CH), 129.9 (CH),
126.9 (CH), 124.9 (CH), 59.6 (CH), 54.0 ppm (CH3); IR (KBr): n˜ =2149
(s), 1859 (w), 1758 (s), 1637 (m), 1597 (m), 1433 (m), 1251 (s), 1031 cmÀ1
(m); MS (EI, 70 eV): m/z (%): 209 (88) [M]+, 150 (100) [MÀC2H3O2]+;
HRMS (EI, 70 eV): m/z calcd for C10H8ClNO2 [M]+: 209.02436; found:
209.02520.
(1-Benzyl-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazol-4-yl)(morpholi-
no)methanone (4c): General procedure 3 was followed using 1c (230 mg,
1.0 mmol) to give 4c as a yellow oil (266 mg, 0.60 mmol, 60%). Rf =0.50
(silica gel, EtOAc); 1H NMR (250.13 MHz, CDCl3): d=7.35–7.15 (m,
10H), 7.11 (s, 1H), 4.19 (d, 2J=15.0 Hz, 1H), 4.03 (d, 2J=15.0 Hz, 1H),
3.85–3.65 (m, 5H), 3.58–3.50 (m, 2H), 2.81–2.75 (m, 1H), 1.52 (s, 3H),
0.89 ppm (s, 3H); 13C{1H} NMR (100.62 MHz, CDCl3): d=170.2 (C),
156.4 (CH), 138.0 (C), 136.9 (C), 128.6 (2CH), 128.1 (2CH), 127.6
(2CH), 127.6 (CH), 127.5 (CH), 126.9 (2CH), 83.9 (C), 71.4, 66.6 and
66.2 (2CH2 and C), 47.8 (CH2), 45.5 (CH2), 43.2 (CH2), 22.5 (CH3),
21.2 ppm (CH3); IR (KBr): n˜ =3026 (w), 2963 (w), 2854 (w), 1951 (w),
1634 (s), 1598 (s), 1456 (m), 1251 (s), 1113 cmÀ1 (s); MS (EI, 70 eV): m/z
(%): 377 (10) [M]+, 376 (20) [MÀH]+, 362 (100) [MÀCH3]+, 286 (25)
[MÀC7H7]+; HRMS (EI, 70 eV): m/z calcd for C23H27N3O2 [M]+:
377.21033; found: 377.20942.
Methyl 2-(p-chlorophenyl)-2-isocyanoacetate (1h): General procedure 2
was followed using (Æ)-4-chlorophenylglycine (15.4 g, 67.4 mmol) to give
1h, after 1 h of stirring at 08C, as a dark red oil (5.65 g, 26.8 mmol,
40%). Purification was performed by means of column chromatography
(silica gel, EtOAc/cyclohexane 1:4, Rf =0.25). 1H NMR (250.13 MHz,
CDCl3): d=7.42 (s, 4H), 5.35 (s, 1H), 3.80 ppm (s, 3H); 13C{1H} NMR
(100.62 MHz, CDCl3): d=165.6 (C), 162.2 (C), 135.8 (C), 130.2 (C), 129.4
(2CH), 128.0 (2CH), 59.6 (CH), 53.9 ppm (CH3); IR (KBr): n˜ =2149 (s),
1758 (s), 1637 (m), 1495 (m), 1436 (w), 1252 (s), 1093 cmÀ1 (m); MS (EI,
70 eV): m/z (%): 209 (54) [M]+, 177 (54) [MÀCH4O]+, 150 (100)
[MÀC2H3O2]+, 124 (37) [C7H5Cl]+, 111 (10) [C6H4Cl]+; HRMS (EI,
70 eV): m/z calcd for C10H8ClNO2 [M]+: 209.02436; found: 209.02431.
Methyl 1-benzyl-5,5-dimethyl-4-(4-nitrophenyl)-4,5-dihydro-1H-imidazole-
4-carboxylate (4e): General procedure 3 was followed using 1e (220 mg,
1.0 mmol) to give 4e as a red oil (264 mg, 0.72 mmol, 72%). Due to poor
solubility of the isocyanide in MeOH, 1e was added as a 1m solution in
CH2Cl2, with 5 mol% AgOAc used as catalyst. Rf =0.40 (silica gel,
EtOAc); 1H NMR (250.13 MHz, CDCl3): d=8.19 (d, 3J=9.3 Hz, 2H),
7.88 (d, 3J=9.3 Hz, 2H), 7.39–7.24 (m, 5H), 7.15 (s, 1H), 4.22 (s, 2H),
3.77 (s, 3H), 1.41 (s, 3H), 0.80 ppm (s, 3H); 13C{1H} NMR (62.90 MHz,
CDCl3): d=171.3 (C), 156.8 (CH), 147.4 (C), 145.0 (C), 137.5 (C), 129.1
(2CH), 128.8 (2CH), 127.8 (CH), 127.5 (2CH), 122.7 (2CH), 84.4 (C),
69.2 (C), 52.6 (CH3), 46.1 (CH2), 23.0 (CH3), 22.5 ppm (CH3); IR (KBr):
n˜ =2989 (w), 2947 (w), 1728 (s), 1607 (m), 1592 (s), 1517 (s), 1348 (s),
1227 (m), 1042 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 308 (51)
[MÀC2H3O2]+, 91 (100) [C7H7]+; MS (FAB, 3 KeV): m/z (%): 368 (100)
[M+H]+, 308 (20) [MÀC2H3O2]+, 91 (100) [C7H7]+; HRMS (FAB,
3 KeV): m/z calcd for C20H22N3O4 [M+H]+: 368.1610; found: 368.1614.
Methyl 2-(p-methoxyphenyl)-2-isocyanoacetate (1i): General procedure 2
was followed using (Æ)-4-methoxyphenylglycine[20] (3.86 g, 17.3 mmol) to
give 1i as a dark red oil (1.76 g, 8.58 mmol, 50%). Purification was per-
formed by means of column chromatography (silica gel, EtOAc/cyclohex-
1
ane 1:1, Rf =0.66). H NMR (250.13 MHz, CDCl3): d=7.38 (m, 2H), 6.93
(m, 2H), 5.31 (s, 1H), 3.82 (s, 3H), 3.78 ppm (s, 3H); 13C{1H} NMR
(100.62 MHz, CDCl3): d=166.3 (C), 161.0 (C), 160.5 (C), 128.0 (2CH),
123.9 (C), 114.5 (2CH), 59.7 (CH), 55.4 (CH3), 53.6 ppm (CH3); IR
(KBr): n˜ =2957 (w), 2149 (s), 1757 (s), 1611 (m), 1512 (s), 1438 (m), 1254
(s), 1178 (m), 1031 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 205 (23) [M]+,
173 (3) [MÀCH4O]+, 146 (100) [MÀC2H3O2]+; HRMS (EI, 70 eV): m/z
calcd for C11H11NO3 [M]+: 205.07389; found: 205.07333.
Methyl 2-(o,p-dimethoxyphenyl)-2-isocyanoacetate (1j): General proce-
dure 2 was followed using (Æ)-2,4-dimethoxyphenylglycine[20] (2.87 g,
11.3 mmol) to give 1j as an orange oil (1.34 g, 5.70 mmol, 50%). Purifica-
tion was performed by means of column chromatography (silica gel,
EtOAc/cyclohexane 1:1, Rf =0.66). 1H NMR (400.13 MHz, CDCl3): d=
7.31 (d, 3J=8.4 Hz, 1H), 6.53 (dd, 3J=8.4 Hz, 4J=2.4 Hz, 1H), 6.48 (d,
4J=2.4 Hz, 1H), 5.65 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.78 ppm (s,
3H); 13C{1H} NMR (62.90 MHz, CDCl3): d=166.6 (C), 162.0 (C), 159.3
(C), 157.3 (C), 129.0 (CH), 113.7 (C), 105.0 (CH), 98.8 (CH), 55.8 (CH3),
55.4 (CH3), 54.3 (CH), 53.4 ppm (CH3); IR (KBr): n˜ =2961 (w), 2840
(w), 2148 (s), 1757 (s), 1614 (s), 1590 (m), 1509 (m), 1212 (s), 1031 cmÀ1
(s); MS (EI, 70 eV): m/z (%): 235 (19) [M]+, 176 (100) [MÀC2H3O2]+;
HRMS (EI, 70 eV): m/z calcd for C12H13NO4 [M]+: 235.08446; found:
235.08525.
Methyl 1-benzyl-4-(2-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1H-imida-
zole-4-carboxylate (4 f): General procedure 3 was followed using 1 f
(210 mg, 1.0 mmol) to give 4 f as an orange oil (89 mg, 0.25 mmol, 25%).
AgOAc (5 mol%) was used as catalyst. Rf =0.32 (silica gel, EtOAc/cyclo-
hexane 1:1); 1H NMR (250.13 MHz, CDCl3): d=7.90 (dd, 3J=7.5 Hz,
4J=2.0 Hz, 1H), 7.42–7.19 (m, 8H), 6.99 (s, 1H), 4.29 (s, 2H), 3.65 (s,
3H), 1.94 (s, 3H), 0.66 ppm (s, 3H); 13C{1H} NMR (62.90 MHz, CDCl3):
d=170.4 (C), 156.3 (CH), 138.1 (C), 137.9 (C), 132.9 (C), 131.1 (CH),
129.6 (CH), 128.8 (2CH), 128.6 (CH), 127.6 (CH), 127.5 (2CH), 126.4
(CH), 84.2 (C), 68.4 (C), 52.2 (CH3), 45.9 (CH2), 25.6 (CH3), 21.6 ppm
(CH3); IR (KBr): n˜ =3031 (w), 2943 (w), 1733 (s), 1597 (s), 1467 (m),
1225 (s), 1167 (m), 1051 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 356 (6)
[M]+, 297 (100) [MÀC2H3O2]+, 265 (10) [MÀC7H7]+, 91 (64) [C7H7]+;
HRMS (EI, 70 eV): m/z calcd for C20H21ClN2O2 [M+]: 356.12916; found:
356.12879.
General procedure 3—Synthesis of 2-imidazolines 4a,c–j: Isocyanide
(4a,c–j; 1 mL of a 1m solution, 1.0 mmol) in MeOH was added over 21 h
to a stirred solution of 3a (162 mL, 160 mg, 1.5 mmol), 2a (150 mL,
118 mg, 2.0 mmol), MgSO4 (100 mg), and 2.0 mol% AgOAc (3.3 mg,
0.020 mmol) in MeOH (4 mL). After 1 h of additional stirring, water
(15 mL) was added, and the resulting mixture was extracted with CH2Cl2
(3”10 mL). The organic layers were combined, dried (MgSO4), filtered,
Methyl 1-benzyl-4-(3-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1H-imida-
zole-4-carboxylate (4g): General procedure 3 was followed using 1g
(210 mg, 1.0 mmol) to give 4g as a yellow oil (46 mg, 0.13 mmol, 13%).
1
Rf =0.13 (silica gel, EtOAc); H NMR (400.13 MHz, CDCl3): d=7.66 (m,
1H), 7.54–7.51 (m, 1H), 7.36–7.23 (m, 7H), 7.12 (s, 1H), 4.20 (d, 2J=
16.0 Hz, 1H), 4.18 (d, 2J=16.0 Hz, 1H), 3.76 (s, 3H), 1.37 (s, 3H),
Chem. Eur. J. 2008, 14, 4961 – 4973
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4969

R. V. A. Orru et al.
0.82 ppm (s, 3H); 13C{1H} NMR (62.90 MHz, CDCl3): d=171.6 (C), 156.5
(CH), 139.3 (C), 137.8 (C), 134.0 (C), 128.9 (CH), 128.8 (2CH), 128.0
(CH), 127.8 (CH), 127.7 (CH), 127.5 (2CH), 126.0 (CH), 84.2 (C), 69.1
(C), 52.4 (CH3), 46.0 (CH2), 22.9 (CH3), 22.3 ppm (CH3); IR (KBr): n˜ =
2971 (w), 1727 (s), 1602 (s), 1458 (w), 1397 (w), 1230 (s), 1164 (m),
1037 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 356 (1) [M]+, 297 (100)
[MÀC2H3O2]+, 91 (100) [C7H7]+; HRMS (EI, 70 eV): m/z calcd for
C20H21ClN2O2 [M+]: 356.12916; found: 356.12875.
7.40–7.11 (m, 10H), 7.17 (s, 1H), 4.45 (d, 2J=15.4 Hz, 1H), 4.36 (q, 3J=
6.5 Hz, 1H), 4.19 (d, 2J=15.4 Hz, 1H), 3.74 (s, 3H), 0.66 ppm (d, 3J=
6.5 Hz, 3H); minor isomer: d=7.56–7.52 (m, 2H), 7.40–7.11 (m, 8H),
2
2
7.14 (s, 1H), 4.42 (d, J=15.4 Hz, 1H), 4.21 (d, J=15.4 Hz, 1H), 3.85 (q,
3J=6.6 Hz, 1H), 3.71 (s, 3H), 1.34 ppm (d, 3J=6.6 Hz, 3H); 13C{1H}
NMR (100.62 MHz, CDCl3): major isomer: d=174.0 (C), 156.3 (CH),
137.3 (C), 136.2 (C), 128.8 (2CH), 128.1 (2CH), 127.8 (CH), 127.6
(2CH), 127.4 (CH), 126.7 (2CH), 83.0 (C), 59.7 (CH), 52.7 (CH3), 48.7
(CH2), 14.5 ppm (CH3); minor isomer: d=171.9 (C), 156.2 (CH), 143.0
(C), 136.2 (C), 128.7 (2CH), 128.1 (2CH), 127.7 (CH), 127.5 (2CH),
127.4 (CH), 126.2 (2CH), 82.5 (C), 63.9 (CH), 52.2 (CH3), 48.6 (CH2),
14.7 ppm (CH3); IR (KBr): n˜ =3027 (w), 2948 (w), 1726 (s), 1595 (s),
1493 (w), 1454 (m), 1240 (s), 1178 (m), 731 (m), 700 cmÀ1 (m); MS (FAB,
3 KeV): m/z (%): 309 (100) [M+H]+, 249 (33) [MÀC2H3O2]+, 91 (60)
[C7H7]+; HRMS (FAB, 3 KeV): m/z calcd for C19H21N2O2 [M+H]+:
309.1603; found: 309.1606.
Methyl 1-benzyl-4-(4-chlorophenyl)-5,5-dimethyl-4,5-dihydro-1H-imida-
zole-4-carboxylate (4h): General procedure 3 was followed using 1h
(210 mg, 1.0 mmol) to give 4h as an orange oil (239 mg, 0.67 mmol,
67%). Rf =0.43 (Al2O3, EtOAc/cyclohexane 1:2); 1H NMR (250.13 MHz,
CDCl3): d=7.62–7.56 (m, 2H), 7.38–7.23 (m, 7H), 7.11 (s, 1H), 4.18 (s,
2H), 3.75 (s, 3H), 1.36 (s, 3H), 0.82 ppm (s, 3H); 13C{1H} NMR
(100.62 MHz, CDCl3): d=171.9 (C), 156.4 (CH), 137.9 (C), 135.8 (C),
133.6 (C), 129.3 (2CH), 128.8 (2CH), 127.9 (2CH), 127.7 (CH), 127.5
(2CH), 84.1 (C), 69.0 (C), 52.4 (CH3), 46.0 (CH2), 22.9 (CH3), 22.3 ppm
(CH3); IR (KBr): n˜ =2972 (w), 1901 (w), 1727 (s), 1603 (s), 1490 (m),
1230 (s), 1165 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 356 (1) [M]+, 297 (86)
[MÀC2H3O2]+, 265 (6) [MÀC7H7]+, 168 (7) [MÀC12H9Cl]+, 91 (100)
[C7H7]+; HRMS (EI, 70 eV): m/z calcd for C20H21ClN2O2 [M+]:
356.12916; found: 356.13038.
Methyl
1-benzyl-5-ethyl-5-methyl-4-phenyl-4,5-dihydro-1H-imidazole-4-
carboxylate (4l): General procedure 6 was followed using 1d (175 mg,
1.0 mmol), 2-butanone (2c; 107 mL, 87 mg, 1.2 mmol), and 3a (131 mL,
128 mg, 1.2 mmol) to give 4l as a colorless oil (54 mg, 0.16 mmol, 16%).
Rf =0.20 (silica gel, EtOAc/cyclohexane 1:3); isolated as a 53:47 mixture
of diastereomers; 1H NMR (250.13 MHz, CDCl3): d=7.69 (dd, 3J=
7.7 Hz, 4J=2.0 Hz, 2H), 7.49 (dd, 3J=8.3 Hz, 4J=1.5 Hz, 2H), 7.39–7.19
(m, 16H), 7.17 (s, 1H), 7.16 (s, 1H), 4.29 (d, 2J=15.5 Hz, 1H), 4.22 (d,
2J=15.3 Hz, 1H), 4.17 (d, 2J=15.5, 1H), 4.05 (d, 2J=15.3 Hz, 1H), 3.77
(s, 3H), 3.72 (s, 3H), 2.30–2.15 (m, 1H), 1.74–1.59 (m, 1H), 1.54–1.26 (m,
Methyl 1-benzyl-4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1H-imida-
zole-4-carboxylate (4i): General procedure
3 was followed using 1i
(205 mg, 1.0 mmol) to give 4i as a yellow oil (264 mg, 0.75 mmol, 75%).
Rf =0.29 (silica gel, EtOAc/MeOH (5%)); 1H NMR (250.13 MHz,
CDCl3): d=7.54 (d, 3J=8.8 Hz, 2H), 7.36–7.23 (m, 5H), 7.11 (s, 1H),
6.86 (d, 3J=8.8 Hz, 2H), 4.19 (d, 2J=15.8 Hz, 1H), 4.16 (d, 2J=15.8 Hz,
1H), 3.81 (s, 3H), 3.75 (s, 3H), 1.36 (s, 3H), 0.84 ppm (s, 3H); 13C{1H}
NMR (100.62 MHz, CDCl3): d=172.2 (C), 159.0 (C), 156.1 (CH), 138.1
(C), 129.1 (C), 128.8 (2CH), 128.7 (2CH), 127.6 (2CH), 127.5 (2CH),
113.1 (2CH), 84.0 (C), 69.0 (C), 55.2 (CH3), 52.3 (CH3), 46.0 (CH2), 22.8
(CH3), 22.2 ppm (CH3); IR (KBr): n˜ =2945 (m), 2835 (w), 1725 (s), 1605
(s), 1510 (m), 1454 (m), 1248 (s), 1175 (m), 1038 cmÀ1 (m); MS (EI,
70 eV): m/z (%): 352 (6) [M]+, 293 (100) [MÀC2H3O2]+, 261 (6)
[MÀC7H7]+, 91 (80) [C7H7]+; HRMS (EI, 70 eV): m/z calcd for
C21H24N2O3 [M+]: 352.17869; found: 352.17799.
3
2H), 1.37 (s, 3H), 0.86 (t, J=7.5 Hz, 3H), 0.83 (s, 3H), 0.50 ppm (t, 3J=
7.3 Hz, 3H); 13C{1H} NMR (100.62 MHz, CDCl3): d=172.0 (C), 171.9
(C), 156.5 (CH), 155.9 (CH), 138.1 (C), 137.8 (C), 137.1 (C), 136.9 (C),
128.6 (4CH), 128.1 (2CH), 127.8 (2CH), 127.50 (4CH), 127.47 (2CH),
127.31 (2CH), 127.28 (2CH), 127.2 (2CH), 84.8 (C), 83.2 (C), 71.7 (C),
71.6 (C), 52.2 (2CH3), 46.3 (CH2), 45.9 (CH2), 29.4 (CH2), 29.2 (CH2),
23.4 (CH3), 22.0 (CH3), 9.4 (CH3), 8.5 ppm (CH3); IR (KBr): n˜ =2947
(m), 2837 (w), 1725 (s), 1606 (s), 1455 (m), 1261 (s), 1052 cmÀ1 (m); MS
(FAB, 3 KeV): m/z (%): 337 (100) [M+H]+, 277 (27) [MÀC2H3O2]+, 91
(66) [C7H7]+; HRMS (FAB, 3 KeV): m/z calcd for C21H25N2O2 [M+H]+:
337.1916; found: 337.1920.
Methyl 4-phenyl-1,3-diazaspiro[4.5]dec-2-ene-4-carboxylate (4n): General
A
Methyl
1-benzyl-4-(2,4-dimethoxyphenyl)-5,5-dimethyl-4,5-dihydro-1H-
procedure 6 was followed using 1d (175 mg, 1.0 mmol), cyclohexanone
(2e; 124 mL, 118 mg, 1.2 mmol), NH4Cl (107 mg, 2.0 mmol), and Et3N
(278 mL, 202 mg, 2.0 mmol) to give 4n (171 mg, 0.63 mmol, 63%) as a
sticky brown solid. (Chromatography: silica gel, EtOAc/methanol gradi-
ent.) H NMR (250.13 MHz, CDCl3): d=7.67 (dd, J=8.5 Hz, J=2.0 Hz,
2H), 7.36–7.27 (m, 4H), 4.65 (brs, 1H), 3.71 (s, 3H), 1.90–0.91 ppm (m,
10H); 13C{1H} NMR (100.62 MHz, CDCl3): d=172.2 (C), 152.4 (CH),
136.6 (C), 127.5 (2CH), 127.44 (2CH), 127.36 (CH), 80.3 (C), 72.9 (C),
52.1 (CH3), 34.5 (CH2), 34.3 (CH2), 25.2 (CH2), 23.3 (CH2), 22.7 ppm
(CH2); IR (KBr): n˜ =3432 (brs), 2929 (m), 2848 (w), 1731 (s), 1615 (s),
1445 (s), 1208 (s), 1016 cmÀ1 (w); MS (FAB, 3 KeV): m/z (%): 273 (100)
[M+H]+, 213 (33) [MÀC2H3O2]+; HRMS (FAB, 3 KeV): m/z calcd for
C16H21N2O2 [M+H]+: 273.1603; found: 273.1602.
imidazole-4-carboxylate (4j): General procedure 3 was followed using 1j
(235 mg, 1.0 mmol) to give 4j as a pale orange oil (333 mg, 0.87 mmol,
87%). The total reaction time was 48 h. Rf =0.40 (silica gel, EtOAc);
1H NMR (250.13 MHz, CDCl3): d=7.65 (d, 3J=8.5 Hz, 1H), 7.44–7.28
(m, 5H), 6.50 (dd, 3J=8.5 Hz, 4J=2.3 Hz, 1H), 6.43 (d, 4J=2.3 Hz, 1H),
4.31 (d, J=15.8 Hz, 1H), 4.26 (d, J=15.8 Hz, 1H), 3.82 (s, 3H), 3.74 (s,
3H), 3.60 (s, 3H), 1.74 (s, 3H), 0.62 ppm (s, 3H); 13C{1H} NMR
(62.90 MHz, CDCl3): d=171.4 (C), 159.9 (C), 157.6 (C), 156.1 (CH),
138.2 (C), 129.8 (CH), 128.5 (2CH), 127.3 (2CH), 127.2 (CH), 121.4 (C),
103.5 (CH), 98.7 (CH), 82.7 (C), 68.1 (C), 55.0 (CH3), 54.7 (CH3), 51.6
(CH3), 45.8 (CH2), 24.7 (CH3), 20.7 ppm (CH3); IR (KBr): n˜ =2940 (m),
2837 (w), 1731 (s), 1614 (s), 1579 (s), 1505 (m), 1456 (m), 1244 (w), 1207
(s), 1048 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 382 (2) [M]+, 323 (42)
[MÀC2H3O2]+, 106 (34) [C7H6O]+; HRMS (EI, 70 eV): m/z calcd for
C22H26N2O4 [M+]: 382.18926; found: 382.18875.
1
3
4
2
2
General procedure 4—Synthesis of oxazoles 5a–c: An isocyanide (1a–c;
1.0 mmol), 3a (162 mL, 160 mg, 1.5 mmol), 2a (150 mL, 118 mg,
2.0 mmol), Et3N·HCl (138 mg, 1.0 mmol), and MgSO4 (100 mg) were
stirred in MeOH (5 mL) for 5 h at 608C. Water (15 mL) was added, and
the resulting mixture was extracted with CH2Cl2 (3”10 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated, and
the resulting 2-imidazoline was purified by means of column chromatog-
raphy (Al2O3, EtOAc/cyclohexane 1:4).
General procedure 6—Synthesis of 2-imidazolines 4k,l,n: Unless stated
otherwise: A 1m solution of isocyanide 1d (1 mL, 175 mg, 1.0 mmol) in
MeOH was added over 21 h to a stirred solution of either aldehyde or
ketone (1.2 mmol), amine (1.2 mmol), MgSO4 (100 mg), and AgOAc
(3.3 mg, 0.020 mmol, 2.0 mol%) in MeOH (2 mL). After 1 h of additional
stirring, water (15 mL) was added, and the resulting mixture was extract-
ed with CH2Cl2 (3”10 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated, and the resulting 2-imidazoline was
purified by means of column chromatography.
N-Benzyl-2-(5-morpholinooxazol-2-yl)propan-2-amine (5a): General pro-
cedure 4 was followed using 1a (154 mg, 1.0 mmol) to give 5a as a yellow
oil (220 mg, 0.73 mmol, 73%). Rf =0.43; 1H NMR (250.13 MHz, CDCl3):
d=7.30–7.20 (m, 5H), 6.00 (s, 1H), 3.85–3.81 (m, 4H), 3.57 (s, 2H), 3.10–
3.07 (m, 4H), 1.66 (brs, 1H), 1.53 ppm (s, 6H); 13C{1H} NMR
(62.90 MHz, CDCl3): d=161.5 (C), 157.0 (C), 140.6 (C), 128.4 (2CH),
128.2 (2CH), 126.9 (CH), 102.7 (CH), 66.0 (2CH2), 54.5 (C), 48.5
(2CH2), 48.4 (CH2), 26.6 ppm (2CH3); IR (KBr): n˜ =2976 (m), 2857 (m),
1611 (s), 1567 (w), 1453 (m), 1378 (m), 1243 (m), 1119 (s), 898 cmÀ1 (s);
Methyl 1-benzyl-5-methyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxyl-
ate (4k): General procedure 6 was followed using 1d (175 mg, 1.0 mmol),
acetaldehyde (2b; 112 mL, 88 mg, 2.0 mmol), and benzylamine (3a;
131 mL, 128 mg, 1.2 mmol) to give 4k as an orange oil (274 mg,
0.89 mmol, 89%). Rf =0.27 (silica gel, EtOAc); isolated as a 38:62 mix-
1
ture of diastereomers; H NMR (250.13 MHz, CDCl3): major isomer: d=
4970
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4961 – 4973

Formation of Imidazolines and Oxazoles
FULL PAPER
MS (EI, 70 eV): m/z (%): 301 (10) [M]+, 286 (507) [MÀCH3]+, 196 (60)
[MÀC7H7N]+, 195 (26) [MÀC7H8N]+, 148 (100) [C10H14N]+, 91 (75)
[C7H7]+; HRMS (EI, 70 eV): m/z calcd for C17H23N3O2 [M]+: 301.17903;
found: 301.17807.
[C7H7]+; HRMS (FAB, 3 KeV): m/z calcd for C20H22N3O4 [M+H]+:
368.1610; found: 368.1614.
N-Benzyl-2-[4-(2-chlorophenyl)-5-methoxyoxazol-2-yl]propan-2-amine
(5 f): General procedure 5 was followed using 1 f (210 mg, 1.0 mmol) to
give 5 f, after 11 h reaction time, as a yellow oil (210 mg, 0.59 mmol,
N-Benzyl-2-(4-ethyl-5-morpholinooxazol-2-yl)propan-2-amine (5b): Gen-
eral procedure 4 was followed using 1b (182 mg, 1.0 mmol) to give 5b as
1
3
59%). Rf =0.23; H NMR (400.13 MHz, CDCl3): d=7.53 (dd, J=7.2 Hz,
4J=1.6 Hz, 1H), 7.44 (dd, 3J=7.6 Hz, 4J=1.2 Hz, 1H), 7.34–7.22 (m,
7H), 3.94 (s, 3H), 3.68 (s, 2H), 1.81 (brs, 1H), 1.59 ppm (s, 6H); 13C{1H}
NMR (62.90 MHz, CDCl3): d=159.0 (C), 154.6 (C), 140.5 (C), 133.4 (C),
131.5 (CH), 130.4 (C), 129.9 (CH), 128.9 (CH), 128.4 (2CH), 128.3
(2CH), 126.9 (CH), 126.6 (CH), 112.0 (C), 59.9 (CH3), 54.7 (C), 48.5
(CH2), 26.5 ppm (2CH3); IR (KBr): n˜ =3405 (w), 2984 (m), 2136 (w),
1650 (s), 1463 (m), 1444 (m), 1362 (s), 1199 (m), 1112 (m), 1014 cmÀ1
(m); MS (EI, 70 eV): m/z (%): 356 (1) [M]+, 341 (1) [MÀCH3]+, 297 (1)
[MÀC6H5]+, 148 (100) [C10H14N]+, 91 (48) [C7H7]+; HRMS (EI, 70 eV):
m/z calcd for C20H21ClN2O2 [M]+: 356.12916; found: 356.12804.
a
colorless oil (161 mg, 0.49 mmol, 49%). Rf =0.55; 1H NMR
(250.13 MHz, CDCl3): d=7.35–7.18 (m, 5H), 3.81–3.78 (m, 4H), 3.54 (s,
2H), 3.04–3.00 (m, 4H), 2.48 (q, 3J=7.5 Hz, 2H), 1.80 (brs, 1H), 1.53 (s,
6H), 1.20 ppm (t, 3J=7.5 Hz, 3H); 13C{1H} NMR (62.90 MHz, CDCl3):
d=163.2 (C), 150.4 (C), 140.6 (C), 128.4 (2CH), 128.3 (2CH), 127.3 (C),
126.9 (CH), 67.0 (2CH2), 54.8 (C), 51.4 (2CH2), 48.6 (CH2), 26.5 (2CH3),
19.1 (CH2), 13.9 ppm (CH3); IR (KBr): n˜ =3393 (s), 2967 (s), 2856 (m),
1679 (s), 1496 (m), 1453 (s), 1378 (m), 1260 (s), 1201 (s), 1116 cmÀ1 (s);
MS (EI, 70 eV): m/z (%): 329 (12) [M]+, 314 (27) [MÀCH3]+, 224 (32)
[MÀC7H7N]+, 148 (100) [C10H14N]+, 91 (100) [C7H7]+ 70 (60) [C4H8N]+;
HRMS (EI, 70 eV): m/z calcd for C19H27N3O2 [M]+: 329.21033; found:
329.21115.
N-Benzyl-2-[4-(3-chlorophenyl)-5-methoxyoxazol-2-yl]propan-2-amine
(5g): General procedure 5 was followed using 1g (210 mg, 1.0 mmol) to
give 5g, after 2 h reaction time, as an orange oil (171 mg, 0.48 mmol,
48%). Rf =0.15; 1H NMR (400.13 MHz, CDCl3): d=7.83–7.82 (m, 1H),
7.71–7.69 (m, 1H), 7.32–7.17 (m, 7H), 4.06 (s, 3H), 3.65 (s, 2H), 1.83
(brs, 1H), 1.58 ppm (s, 6H); 13C{1H} NMR (100.62 MHz, CDCl3): d=
158.9 (C), 154.5 (C), 140.4 (C), 134.5 (C), 133.5 (C), 129.7 (CH), 128.4
(2CH), 128.3 (2CH), 127.0 (CH), 126.1 (CH), 124.9 (CH), 123.0 (CH),
112.8 (C), 59.8 (CH3), 54.8 (C), 48.8 (CH2), 26.5 ppm (2CH3); IR (KBr):
n˜ =3411 (w), 2984 (m), 1724 (w), 1642 (s), 1599 (m), 1368 (m), 1113 (m),
1033 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 356 (1) [M]+, 148 (100)
[C10H14N]+, 91 (56) [C7H7]+; HRMS (EI, 70 eV): m/z calcd for
C20H21ClN2O2 [M]+: 356.12916; found: 356.12864.
N-Benzyl-2-(5-morpholino-4-phenyloxazol-2-yl)propan-2-amine
(5c):
General procedure 4 was followed using 1c (230 mg, 1.0 mmol) to give
5c as a colorless solid (211 mg, 0.56 mmol, 56%). Rf =0.73; m.p. 93–
968C; 1H NMR (400.13 MHz, CDCl3): d=8.00 (d, 3J=8.0 Hz, 2H), 7.42
(t, 3J=8.0 Hz, 2H), 7.33–7.23 (m, 6H), 3.89–3.86 (m, 4H), 3.65 (s, 2H),
3.14–3.12 (m, 4H), 1.88 (brs, 1H), 1.60 ppm (s, 6H); 13C{1H} NMR
(62.90 MHz, CDCl3): d=163.2 (C), 150.5 (C), 140.5 (C), 132.1 (C), 128.44
(2CH), 128.39 (2CH), 128.3 (2CH), 126.9 (CH), 126.8 (CH), 126.0
(2CH), 123.6 (C), 66.9 (2CH2), 54.9 (C), 50.4 (2CH2), 48.6 (CH2),
26.5 ppm (2CH3); IR (KBr): n˜ =3317 (s), 2977 (s), 2846 (s), 2830 (m),
1649 (s), 1494 (m), 1446 (m), 1376 (s), 1193 (s), 1112 cmÀ1 (s); MS (EI,
70 eV): m/z (%): 377 (1) [M]+, 195 (43) [MÀC13H12N]+, 194 (30)
[MÀC13H13N]+, 148 (52) [C13H13N2O2]+; HRMS (EI, 70 eV): m/z calcd
for C23H27N3O2 [M]+: 377.21033; found: 377.20861.
N-Benzyl-2-[4-(3-chlorophenyl)-5-methoxyoxazol-2-yl]propan-2-amine
(5h): General procedure 5 was followed using 1h (210 mg, 1.0 mmol) to
give 5h, after 2 h reaction time, as a red oil (203 mg, 0.57 mmol, 57%).
Rf =0.15; 1H NMR (250.13 MHz, CDCl3): d=7.79–7.76 (m, 2H), 7.38–
7.27 (m, 7H), 4.05 (s, 3H), 3.67 (s, 2H), 1.90 (brs, 1H), 1.60 ppm (s, 6H);
13C{1H} NMR (62.90 MHz, CDCl3): d=158.8 (C), 154.2 (C), 140.4 (C),
131.6 (C), 130.2 (C), 128.5 (2CH), 128.4 (2CH), 128.2 (2CH), 126.9
(CH), 126.2 (2CH), 113.1 (C), 59.8 (CH3), 54.8 (C), 48.5 (CH2), 26.5 ppm
(2CH3); IR (KBr): n˜ =2967 (w), 2857 (w), 1901 (w), 1719 (s), 1644 (s),
1495 (m), 1371 (s), 1211 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 356 (1)
[M]+, 148 (100) [C10H14N]+, 91 (74) [C7H7]+; HRMS (EI, 70 eV): m/z
calcd for C20H21ClN2O2 [M]+: 356.12916; found: 356.13017.
General procedure 5—Synthesis of oxazoles 5d–i: An isocyanide (1d–i;
1.0 mmol), 3a (162 mL, 160 mg, 1.5 mmol), 2a (150 mL, 118 mg,
2.0 mmol), and MgSO4 (100 mg) were stirred in DMF (5 mL) until com-
plete consumption of the isocyanide (monitored by 1H NMR). Water
(15 mL) was added, and the resulting mixture was extracted with CH2Cl2
(3”10 mL). The organic layers were combined, dried (MgSO4), filtered,
and concentrated, and the resulting oxazoles were purified by means of
column chromatography (silica gel, EtOAc/cyclohexane 1:4, unless stated
otherwise).
N-Benzyl-2-[4-(3-chlorophenyl)-5-methoxyoxazol-2-yl]propan-2-amine
(5i): General procedure 5 was followed using 1i (205 mg, 1.0 mmol) to
give 5i, after 8 h reaction time, as a yellow oil (226 mg, 0.64 mmol, 64%).
Rf =0.18; 1H NMR (400.13 MHz, CDCl3): d=7.75 (d, 3J=9.2 Hz, 2H),
7.34–7.21 (m, 5H), 6.94 (d, 3J=9.2 Hz, 2H), 4.02 (s, 3H), 3.84 (s, 3H),
3.65 (s, 2H), 1.84 (brs, 1H), 1.58 ppm (s, 6H); 13C{1H} NMR
(100.62 MHz, CDCl3): d=158.9 (C), 158.2 (C), 153.4 (C), 140.5 (C), 128.4
(2CH), 128.3 (2CH), 126.9 (CH), 126.4 (2CH), 124.3 (C), 114.4 (C),
114.0 (2CH), 60.2 (CH3), 55.3 (CH3), 54.9 (C), 48.6 (CH2), 26.5 ppm
(2CH3); IR (KBr): n˜ =3465 (w), 2987 (m), 2834 (m), 1649 (s), 1610 (m),
1515 (s), 1368 (m), 1247 (s), 1112 (m), 1019 cmÀ1 (m); MS (EI, 70 eV):
m/z (%): 352 (1) [M]+, 148 (100) [C10H14N]+, 91 (49) [C7H7]+; HRMS
(EI, 70 eV): m/z calcd for C21H24N2O3 [M]+: 352.17869; found: 352.17832.
N-Benzyl-2-(5-methoxy-4-phenyloxazol-2-yl)propan-2-amine (5d): Gener-
al procedure 5 was followed using 1d (175 mg, 1.0 mmol). A 4 h reaction
time followed by column chromatography (Al2O3, EtOAc/pentane 2:1,
Rf =0.85) furnished 5d as an orange oil (190 mg, 0.59 mmol, 59%).
1H NMR (250.13 MHz, CDCl3): d=7.85–7.81 (m, 2H), 7.39–7.22 (m,
8H), 4.04 (s, 3H), 3.65 (s, 2H), 1.83 (brs, 1H), 1.59 ppm (s, 6H); 13C{1H}
NMR (100.62 MHz, CDCl3): d=158.9 (C), 154.2 (C), 140.5 (C), 131.5
(C), 128.5 (2CH), 128.4 (2CH), 128.3 (2CH), 126.8 (CH), 126.2 (CH),
124.9 (2CH), 114.3 (C), 60.0 (CH3), 54.8 (C), 48.6 (CH2), 26.5 ppm
(2CH3); IR (KBr): n˜ =3426 (brs), 2985 (w), 2940 (w), 1958 (w), 1644
(m), 1369 (m), 1110 (m), 696 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 322 (1)
[M]+, 307 (1) [MÀCH3]+, 148 (100) [C10H14N]+, 91 (44) [C7H7]+; HRMS
(EI, 70 eV): m/z calcd for C20H22O2N2 [M]+: 322.16813; found: 322.16848.
General procedure 7—Synthesis of oxazoles 5l–q: Unless stated other-
wise: Isocyanide 1d (175 mg, 1.0 mmol), either aldehyde or ketone
(1.2 mmol), an amine (1.2 mmol), and MgSO4 (100 mg) were stirred in
DMF (2 mL) for 17 h. Water (15 mL) was added, and the resulting mix-
ture was extracted with CH2Cl2 (3”10 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated, and the resulting
oxazoles were purified by means of column chromatography (silica gel).
N-Benzyl-2-[5-methoxy-4-(4-nitrophenyl)oxazol-2-yl]propan-2-amine
(5e): General procedure 5 was followed using 1e (220 mg, 1.0 mmol). A
30 min reaction time followed by column chromatography (silica gel,
EtOAc/cyclohexane 1:2, Rf =0.26) furnished 5e as a red oil (228 mg,
1
3
0.62 mmol, 62%). H NMR (250.13 MHz, CDCl3): d=8.23 (d, J=9.0 Hz,
2H), 7.94 (d, 3J=9.0 Hz, 2H), 7.35–7.23 (m, 5H), 4.13 (s, 3H), 3.67 (s,
2H), 1.90 (brs, 1H), 1.60 ppm (s, 6H); 13C{1H} NMR (62.90 MHz,
CDCl3): d=159.0 (C), 155.9 (C), 145.4 (C), 140.3 (C), 138.4 (C), 128.4
(2CH), 128.2 (2CH), 127.0 (CH), 124.9 (2CH), 124.0 (2CH), 111.7 (C),
59.5 (CH3), 54.8 (C), 48.5 (CH2), 26.5 ppm (2CH3); IR (KBr): n˜ =3401
(w), 2985 (w), 2940 (w), 1635 (s), 1600 (m), 1508 (s), 1337 (s), 1108 (m),
1024 cmÀ1 (m); MS (FAB, 3 KeV): m/z (%): 368 (5) [M+H]+, 352 (11)
[MÀCH3]+, 261 (93) [MÀC7H8N]+, 148 (100) [C10H14N]+, 91 (82)
N-Benzyl-2-(5-methoxy-4-phenyloxazol-2-yl)butan-2-amine (5l): General
procedure 7 was followed using 1d (175 mg, 1.0 mmol), 2-butanone (2c;
107 mL, 87 mg, 1.2 mmol), and 3a (131 mL, 128 mg, 1.2 mmol) to give 5l
as a pale orange oil (179 mg, 0.53 mmol, 53%). Rf =0.44 (EtOAc/cyclo-
hexane 1:3); 1H NMR (250.13 MHz, CDCl3): d=7.87 (dd, 3J=8.5 Hz,
4J=1.5 Hz, 2H), 7.45–7.21 (m, 8H), 4.05 (s, 3H), 3.71 (d, 2J=12.0 Hz,
1H), 3.62 (d, 2J=12.0 Hz, 1H), 1.94 (q, 3J=7.5 Hz, 2H), 1.82 (brs, 1H),
Chem. Eur. J. 2008, 14, 4961 – 4973
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4971

R. V. A. Orru et al.
1.58 (s, 3H), 0.95 ppm (t, 3J=7.5 Hz, 1H); 13C{1H} NMR (62.90 MHz,
CDCl3): d=158.4 (C), 154.2 (C), 140.6 (C), 131.6 (C), 128.34 (2CH),
128.28 (2CH), 128.2 (2CH), 126.8 (CH), 126.1 (CH), 124.9 (2CH), 114.1
(C), 59.8 (CH3), 58.1 (C), 48.1 (CH2), 32.7 (CH2), 22.0 (CH3), 8.1 ppm
(CH3); IR (KBr): n˜ =2974 (s), 2878 (w), 1644 (s), 1602 (w), 1498 (m),
1450 (s), 1372 (s), 1168 (m), 1017 cmÀ1 (s); MS (FAB, 3 KeV): m/z (%):
337 (6) [M+H]+, 321 (5) [MÀCH3]+, 307 (9) [MÀC2H5]+, 230 (100)
[MÀC8H10]+, 162 (100) [C11H16N]+, 91 (82) [C7H7]+; HRMS (FAB,
3 KeV): m/z calcd for C21H25N2O2 [M+H]+: 337.1916; found: 337.1918.
[MÀC4H8NO]+, 168 (100) [C10H18NO]+; HRMS (FAB, 3 KeV): m/z
calcd for C20H27N2O3 [M+H]+: 343.2022; found: 343.2017.
N-tert-Butyl-1-(5-methoxy-4-phenyloxazol-2-yl)-2-methylpropan-1-amine
(5q): General procedure 7 was followed using 1d (175 mg, 1.0 mmol),
isobutyraldehyde (2 f; 110 mL, 87 mg, 1.2 mmol), and t-butylamine (3e;
126 mL, 88 mg, 1.2 mmol) to give 5q as a yellow oil (177 mg, 0.59 mmol,
59%). Rf =0.32 (EtOAc/cyclohexane 1:5); 1H NMR (250.13 MHz,
CDCl3): d=7.81 (dd, 3J=7.5 Hz, 4J=1.3 Hz, 2H), 7.38 (t, 3J=7.5 Hz,
2H), 7.21 (tt, 3J=7.5 Hz, 4J=1.3 Hz, 1H), 4.03 (s, 3H), 3.56 (d, 3J=
3
6.8 Hz, 1H), 1.98–1.84 (m, 1H), 1.48 (brs, 1H), 1.04 (s, 9H), 1.00 (d, J=
N-Benzyl-3-(5-methoxy-4-phenyloxazol-2-yl)pentan-3-amine (5m): Gen-
eral procedure 7 was followed using 1d (175 mg, 1.0 mmol), 3-pentanone
(2d; 127 mL, 104 mg, 1.2 mmol), and 3a (131 mL, 128 mg, 1.2 mmol) to
give 5m as a yellow oil (170 mg, 0.49 mmol, 49%). Rf =0.50 (EtOAc/cy-
clohexane 1:3); 1H NMR (250.13 MHz, CDCl3): d=7.90–7.86 (m, 2H),
7.45–7.21 (m, 8H), 4.06 (s, 3H), 3.61 (s, 2H), 2.03–1.90 (m, 4H), 1.73
(brs, 1H), 0.93 ppm (t, 3J=7.5 Hz, 1H); 13C{1H} NMR (62.90 MHz,
CDCl3): d=158.1 (C), 154.2 (C), 140.6 (C), 131.6 (C), 128.3 (2CH),
128.24 (2CH), 128.22 (2CH), 126.8 (CH), 126.1 (CH), 124.9 (2CH),
114.0 (C), 60.9 (C), 59.8 (CH3), 47.4 (CH2), 26.9 (2CH2), 7.4 ppm
(2CH3); IR (KBr): n˜ =2966 (m), 2579 (m), 2496 (m), 1644 (s), 1602 (w),
1454 (s), 1368 (s), 1017 (s), 697 cmÀ1 (s); MS (FAB, 3 KeV): m/z (%): 351
(8) [M+H]+, 321 (42) [MÀC2H5]+, 244 (98) [MÀC8H10]+, 176 (100)
[C12H18N]+, 91 (80) [C7H7]+; HRMS (FAB, 3 KeV): m/z calcd for
C22H27N2O2 [M+H]+: 351.2073; found: 351.2072.
6.8 Hz, 3H), 0.89 ppm (d, 3J=6.8 Hz, 3H); 13C{1H} NMR (62.90 MHz,
CDCl3): d=158.0 (C), 153.9 (C), 131.5 (C), 128.3 (2CH), 126.1 (CH),
125.0 (2CH), 114.3 (C), 60.1 (CH), 56.9 (CH3), 50.6 (C), 34.0 (CH), 29.5
(3CH3), 19.1 (CH3), 19.0 ppm (CH3); IR (KBr): n˜ =2960 (s), 1644 (s),
1448 (m), 1365 (s), 1229 (s), 1016 cmÀ1 (s); MS (FAB, 3 KeV): m/z (%):
303 (37) [M+H]+, 259 (19) [MÀC3H7]+, 230 (100) [MÀC4H10N]+, 128
(99) [C8H18N]+, 72 (77) [C4H10N]+; HRMS (FAB, 3 KeV): m/z calcd for
C18H27N2O2 [M+H]+: 303.2073; found: 303.2074.
4-(2-(5-Morpholinooxazol-2-yl)propan-2-yl)morpholine (6): General pro-
cedure 4 was followed using 1a (154 mg, 1.0 mmol) to give 6 (31 mg,
0.11 mmol, 11%) as a pale yellow solid. Product eluted from column by
flushing with EtOAc (silica gel, EtOAc, Rf =0.16). M.p. 74–788C;
1H NMR (250.13 MHz, CDCl3): d=5.98 (s, 1H), 3.82 (m, 4H), 3.69 (m,
4H), 3.08 (m, 4H), 2.51 (m, 4H), 1.49 ppm (s, 6H); 13C{1H} NMR
(62.90 MHz, CDCl3): d=159.4 (C), 157.1 (C), 102.4 (CH), 67.6 (2CH2),
66.0 (2CH2), 57.8 (C), 48.5 (2CH2), 47.3 (2CH2), 23.6 ppm (2CH3); IR
(KBr): n˜ =2968 (s), 2856 (s), 1655 (m), 1610 (s), 1452 (m), 1243 (m),
1117 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 281 (4) [M]+, 266 (7)
[MÀCH3]+, 195 (100) [C4H8NO]+, 128 (54) [C7H14NO]+; HRMS (EI,
70 eV): m/z calcd for C14H23N3O3 [M]+ 281.17394; found: 281.17272.
1-(5-Methoxy-4-phenyloxazol-2-yl)cyclohexanamine (5n): General proce-
dure 7 was followed using 1d (175 mg, 1.0 mmol), cyclohexanone (2e;
124 mL, 118 mg, 1.2 mmol), NH3·HCl (107 mg, 2.0 mmol), and Et3N
(278 mL, 202 mg, 2.0 mmol) to give 5n as a red-brown oil (189 mg,
0.69 mmol, 69%). Rf =0.14 (EtOAc/cyclohexane 1:1); 1H NMR
(250.13 MHz, CDCl3): d=7.80 (dd, 3J=8.3 Hz, 4J=1.3 Hz, 2H), 7.40–
7.34 (m, 2H), 7.23–7.16 (m, 1H), 4.04 (s, 3H), 2.20–2.12 (m, 2H), 1.80
(brs, 2H), 1.77–1.46 ppm (m, 8H); 13C{1H} NMR (62.90 MHz, CDCl3):
d=159.9 (C), 153.9 (C), 131.5 (C), 128.4 (2CH), 126.2 (CH), 124.9
(2CH), 114.2 (C), 59.9 (CH3), 53.0 (C), 36.8 (2CH2), 25.4 (CH2),
22.1 ppm (2CH2); IR (KBr): n˜ =3359 (m), 2932 (s), 2855 (s), 1644 (s),
1603 (w), 1448 (m), 1369 (m), 1209 (m), 1017 cmÀ1 (s); MS (FAB,
3 KeV): m/z (%): 273 (66) [M+H]+, 256 (100) [MÀNH2]+, 98 (87)
[C6H12N]+; HRMS (FAB, 3 KeV): m/z calcd for C16H21N2O2 [M+H]+:
273.1603; found: 273.1603.
4-(4-Phenyloxazol-5-yl)morpholine (7): Isocyanide 4c (1.0 mmol), 3a
(162 mL, 160 mg, 1.5 mmol), 2a (150 mL, 118 mg, 2.0 mmol), MgSO4
(100 mg), and AgOAc (3.3 mg, 0.020 mmol, 2.0 mol%) were stirred in
MeOH (5 mL) for 21 h. Water (15 mL) was added, and the resulting mix-
ture was extracted with CH2Cl2 (3”10 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated, and the resulting
mixture was purified by means of column chromatography (silica gel,
EtOAc/cyclohexane 1:3, Rf =0.31) to furnish 7 as a pale yellow solid
(150 mg, 0.65 mmol, 65%). M.p. 67–708C; 1H NMR (250.13 MHz,
CDCl3): d=7.97–7.94 (m, 2H), 7.66 (s, 1H), 7.44–7.24 (m, 3H), 3.88–3.85
(m, 4H), 3.15–3.11 ppm (m, 4H); 13C{1H} NMR (62.90 MHz, CDCl3): d=
151.2 (CH), 146.0 (C), 131.6 (C), 128.5 (2CH), 127.1 (CH), 125.9 (2CH),
123.3 (C), 66.9 (2CH2), 50.3 ppm (2CH2); IR (KBr): n˜ =3116 (w), 2852
(s), 1645 (s), 1515 (s), 1110 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 230 (100)
[M]+, 144 (3) [MÀC4H8NO]+, 77 (10) [C6H5]+; HRMS (EI, 70 eV): m/z
calcd for C13H14N2O2 [M]+: 230.10608; found: 230.10564.
1-(5-Methoxy-4-phenyloxazol-2-yl)-N-propylcyclohexanamine (5o): Gen-
eral procedure 7 was followed using 1d (175 mg, 1.0 mmol), cyclohexa-
none (2e; 124 mL, 118 mg, 1.2 mmol), and n-propylamine (3c; 99 mL,
71 mg, 1.2 mmol) to give 5o as a yellow oil (199 mg, 0.63 mmol, 63%).
Rf =0.20 (EtOAc/cyclohexane 1:3); 1H NMR (250.13 MHz, CDCl3): d=
7.82 (d, 3J=7.3 Hz, 2H), 7.38 (t, 3J=7.3 Hz, 2H), 7.20 (t, 3J=7.3 Hz,
1H), 4.04 (s, 3H), 2.37 (t, 3J=7.3 Hz, 2H), 2.23–2.15 (m, 2H), 1.73–1.34
(m, 11H), 0.87 ppm (t, 3J=7.3 Hz, 3H); 13C{1H} NMR (62.90 MHz,
CDCl3): d=158.3 (C), 154.0 (C), 131.7 (C), 128.3 (2CH), 126.1 (CH),
124.9 (2CH), 114.0 (C), 59.9 (CH3), 57.1 (C), 44.6 (CH2), 34.6 (2CH2),
25.7 (CH2), 23.7 (CH2), 22.1 (2CH2), 11.8 ppm (CH3); IR (KBr): n˜ =2939
(s), 2858 (m), 2563 (m), 1644 (s), 1498 (w), 1448 (s), 1369 (s), 1018 (s),
696 cmÀ1 (s); MS (FAB, 3 KeV): m/z (%): 315 (16) [M+H]+, 256 (100)
[MÀC3H8N]+, 140 (98) [C9H18N]+, 125 (45) [C8H15N]+; HRMS (FAB,
3 KeV): m/z calcd for C19H27N2O2 [M+H]+: 315.2073; found: 315.2068.
1-(5-Methoxy-4-phenyloxazol-2-yl)cyclohexanol (8): General procedure 7
was followed using 1d (175 mg, 1.0 mmol), cyclohexanone (2e; 124 mL,
118 mg, 1.2 mmol), and t-butylamine (3e; 126 mL, 88 mg, 1.2 mmol) to
give 8 as a yellow oil (85 mg, 0.31 mmol, 31%). Rf =0.33 (EtOAc/cyclo-
1
3
hexane 1:3); H NMR (250.13 MHz, CDCl3): d=7.80 (d, J=7.8 Hz, 2H),
7.37 (t, 3J=7.8 Hz, 2H), 7.21 (t, 3J=7.8 Hz, 1H), 4.05 (s, 3H), 2.57 (s,
1H), 2.13–1.39 ppm (m, 10H); 13C{1H} NMR (62.90 MHz, CDCl3): d=
158.1 (C), 154.2 (C), 131.2 (C), 128.4 (2CH), 126.3 (CH), 125.0 (2CH),
114.3 (C), 70.7 (C), 59.9 (CH3), 36.2 (2CH2), 25.1 (CH2), 21.8 ppm
(2CH2); IR (KBr): n˜ =3406 (s), 2938 (s), 2859 (m), 1643 (s), 1448 (m),
1370 (m), 1213 (m), 1017 (m), 696 cmÀ1 (m); MS (FAB, 3 KeV): m/z (%):
274 (79) [M+H]+, 256 (75) [MÀHO]+, 175 (100) [MÀC6H10O]+, 77 (75)
[C6H5]+; HRMS (FAB, 3 KeV): m/z calcd for C16H20NO3 [M+H]+:
274.1443; found: 274.1454.
4-[1-(5-Methoxy-4-phenyloxazol-2-yl)cyclohexyl]morpholine (5p): Gener-
al procedure 7 was followed using 1d (175 mg, 1.0 mmol), cyclohexanone
(2e; 124 mL, 118 mg, 1.2 mmol), and morpholine (3d; 105 mL, 105 mg,
1.2 mmol) to give 5p as an orange oil (210 mg, 0.61 mmol, 61%). Rf =
0.13 (EtOAc/cyclohexane 1:5); 1H NMR (250.13 MHz, CDCl3): d=7.82
(dd, 3J=7.5 Hz, 4J=1.3 Hz, 2H), 7.38 (t, 3J=7.5 Hz, 2H), 7.21 (tt, 3J=
7.5 Hz, 4J=1.3 Hz, 1H), 4.05 (s, 3H), 3.71–3.67 (m, 4H), 2.60–2.57 (m,
4H), 2.30–2.21 (m, 2H), 1.89–1.36 ppm (m, 8H); 13C{1H} NMR
(62.90 MHz, CDCl3): d=155.1 (C), 154.0 (C), 131.6 (C), 128.3 (2CH),
126.1 (CH), 125.0 (2CH), 113.9 (C), 67.7 (2CH2), 60.0 (C), 59.9 (CH3),
46.6 (2CH2), 32.2 (2CH2), 25.6 (CH2), 22.0 ppm (2CH2); IR (KBr): n˜ =
2636 (s), 2815 (s), 1643 (s), 1448 (m), 1364 (m), 1116 (s), 1008 (m),
702 cmÀ1 (m); MS (FAB, 3 KeV): m/z (%): 343 (2) [M+H]+, 256 (55)
Acknowledgements
This work was performed with financial support from the Dutch Science
Foundation (NWO, VICI-grant). Dr. M. T. Smoluch (Vrije Universiteit
4972
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4961 – 4973

Formation of Imidazolines and Oxazoles
FULL PAPER
Amsterdam) and Dr. J. W. H. Peeters (University of Amsterdam) are
kindly acknowledged for conducting the HRMS measurements.
Zhu, Angew. Chem. 2007, 119, 2537–2540; Angew. Chem. Int. Ed.
2007, 46, 2485–2488.
[10] For intramolecular oxazole formation from a-acidic isocyanides, see:
a) I. Maeda, K. Togo, R. Yoshida, Bull. Chem. Soc. Jpn. 1971, 44,
1407–1410; b) U. Schçllkopf, K. Hantke, Liebigs Ann. Chem. 1973,
1571–1582; c) U. Schçllkopf, P.-H. Porsch, Chem. Ber. 1973, 106,
3382–3390; d) R. Schrçder, U. Schçllkopf, E. Blume, I. Hoppe, Lie-
bigs Ann. Chem. 1975, 533–546; e) J. P. Chupp, J. J. DꢁAmico, K. L.
Leschinsky, J. Org. Chem. 1978, 43, 3553–3559; f) J. P. Chupp, K. L.
Leschinsky, J. Heterocycl. Chem. 1980, 17, 705–709; g) J. P. Chupp,
K. L. Leschinsky, J. Heterocycl. Chem. 1980, 17, 711–715; h) J.
Rachón, U. Schçllkopf, Liebigs Ann. Chem. 1981, 1693–1698;
i) V. V. Mishchenko, Z. I. Itov, S. D. Lꢁvova, G. K. Shostakovskaya,
V. I. Gunar, Phar. Chem. J. 1988, 22, 568–572.
[1] For recent reviews, see: a) A. Dçmling, I. Ugi, Angew. Chem. 2000,
112, 3300–3344; b) C. Hulme, V. Gore, Curr. Med. Chem. 2003, 10,
51–80; c) R. V. A. Orru, M. De Greef, Synthesis 2003, 1471–1499;
d) A. Jacobi von Wangelin, H. Neumann, D. Gçrdes, S. Klaus, D.
Strübing, M. Beller, Chem. Eur. J. 2003, 9, 4286–4294; e) V. Nair, C.
Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen, L. Ba-
lagopal, Acc. Chem. Res. 2003, 36, 899–907; f) J. Zhu, Eur. J. Org.
Chem. 2003, 1133–1144; g) G. Balme, E. Bossharth, N. Monteiro,
Eur. J. Org. Chem. 2003, 4101–4111; h) C. Simon, T. Constantieux,
J. Rodriguez, Eur. J. Org. Chem. 2004, 4957–4980; i) D. J. Ramón,
M. Yus, Angew. Chem. 2005, 117, 1628–1661; Angew. Chem. Int. Ed.
2005, 44, 1602–1634; j) P. Tempest, Curr. Opin. Drug Discovery
Dev. 2005, 8, 776–788; k) A. Dçmling, Chem. Rev. 2006, 106, 17–89.
[2] a) M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48–60;
Angew. Chem. Int. Ed. 2004, 43, 46–58; b) M. A. Mironov, QSAR
Comb. Sci. 2006, 25, 423–431.
[11] Coordination of the isocyanide carbon to AgI makes the (free) elec-
tron pair less reactive towards reaction with the imine (Scheme 2,
path III).
[12] NH4Cl proved to be successful as the NH3 input (in combination
with Et3N) for the synthesis of 4n and 5n (Table 6, entry 5).
[13] Although no direct evidence for the formation of isocyanobenzyl-
A
[3] a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; b) S. E. Denmark, A.
Thorarensen, Chem. Rev. 1996, 96, 137–166.
ited (M. A. Kraus, Synthesis 1973, 361–362), fusion of ammonium
salts with amides has been reported before (A. Galat, G. Elion, J.
Am. Chem. Soc. 1943, 65, 1566–1567).
[4] L. Weber, K. Illgen, M. Almstetter, Synlett 1999, 366–374.
[5] For a recent overview of the synthesis and application of 2-imidazo-
lines, see: N. Elders, R. F. Schmitz, F. J. J. de Kanter, E. Ruijter,
M. B. Groen, R. V. A. Orru, J. Org. Chem. 2007, 72, 6135–6142.
[6] a) R. S. Bon, C. Hong, M. J. Bouma, R. F. Schmitz, F. J. J. de Kanter,
M. Lutz, A. L. Spek, R. V. A. Orru, Org. Lett. 2003, 5, 3759–3762;
b) R. S. Bon, B. van Vliet, N. E. Sprenkels, R. F. Schmitz, F. J. J.
de Kanter, C. V. Stevens, M. Swart, F. M. Bickelhaupt, M. B. Groen,
R. V. A. Orru, J. Org. Chem. 2005, 70, 3542–3553.
[14] a) Oxazole formation may be caused by AuI activation of the imine.
For a recent example of imine activation by AuI, see: C. Gonzµlez-
Arellano, A. Corma, M. Iglesias, F. Sµnchez, Chem. Commun. 2005,
3451–3453; b) For a recent report on imidazoline formation by CuI
´
catalysis, see: D. Benito-Garagorri, V. Bocokic, K. Kirchner, Tetra-
hedron Lett. 2006, 47, 8641–8644.
[15] Previously, ketones were found to yield the corresponding 2-(hy-
droxyalkyl)oxazoles, see ref. [9k].
[7] Coordination of the terminal isocyanide carbon to AgI increases the
a acidity and terminal C electrophilicity of the isocyanide (also see
ref. [6b]).
[8] For a recent overview of the synthesis and reactions of oxazoles as
well as oxazole-containing natural products, see: a) D. C. Palmer,
Oxazoles: Synthesis, Reactions, and Spectroscopy, part A, Wiley,
New Jersey (USA), 2003; b) D. C. Palmer, Oxazoles: Synthesis, Re-
actions, and Spectroscopy, part B, Wiley, New Jersey (USA), 2004;
c) V. S. C. Yeh, Tetrahedron 2004, 60, 11995–12042.
[9] a) V. LobrØgat, G. Alcaraz, H. BienaymØ, M. Vaultier, Chem.
Commun. 2001, 817–818; b) X. Sun, P. Janvier, G. Zhao, H. Bien-
aymØ, J. Zhu, Org. Lett. 2001, 3, 877–880; c) P. Janvier, X. Sun, H.
BienaymØ, J. Zhu, J. Am. Chem. Soc. 2002, 124, 2560–2567; d) A.
Fayol, J. Zhu, Angew. Chem. 2002, 114, 3785–3787; Angew. Chem.
Int. Ed. 2002, 41, 3633–3635; e) P. Janvier, H. BienaymØ, J. Zhu,
Angew. Chem. 2002, 114, 4467–4470; Angew. Chem. Int. Ed. 2002,
41, 4291–4294; f) Q. Wang, Q. Xia, B. Ganem, Tetrahedron Lett.
2003, 44, 6825–6827; g) A. Fayol, J. Zhu, Org. Lett. 2004, 6, 115–
118; h) G. Cuny, R. Gµmez-Montano, J. Zhu, Tetrahedron 2004, 60,
4879–4885; i) A. Fayol, C. Housseman, X. Sun, P. Janvier, H. Bien-
aymØ, J. Zhu, Synthesis 2005, 161–165; j) T. Pirali, G. C. Tron, J.
Zhu, Org. Lett. 2006, 8, 4145–4148; k) D. Bonne, M. Dekhane, J.
[16] It is important to note that the ester analogues of the 2H-oxazole 7
(Scheme 4) were never formed upon AgI catalysis, most likely be-
cause of the intrinsically lower nucleophilicity of the ester carbonyl
oxygen in 1d–j compared with the amide carbonyl oxygen in 1c.
[17] For similar (and enantioselective) examples of 2-(hydroxyalkyl)oxa-
zole formation, see: a) G. Cuny, R. Gamez-Montano, J. Zhu, Tetra-
hedron 2004, 60, 4879–4886; b) S. Wang, M.-X. Wang, D.-X. Wang,
J. Zhu, Eur. J. Org. Chem. 2007, 4076–4080; c) S.-X. Wang, M.-X.
Wang, D.-X. Wang, J. Zhu, Org. Lett. 2007, 9, 3615–3618.
[18] a) K. Matzumoto, M. Suzuki, N. Yoneda, M. Miyoshi, Synthesis
1977, 249–250; b) C. Housseman, J. Zhu, Synlett 2006, 1777–1779.
[19] A. Fayol, C. Housseman, X. Sun, P. Janvier, H. BienaymØ, J. Zhu,
Synlett 2005, 161–165.
[20] Synthesized according to the method reported: F. P. Doyle, G. R.
Fosker, J. H. C. Nayler, H. Smith, J. Chem. Soc. 1962, 1440–1444.
[21] The terminal NC carbon atom is often not observed in the 13C NMR
spectrum for these type of compounds, also see ref. [6a].
Received: February 13, 2008
Published online: April 22, 2008
Chem. Eur. J. 2008, 14, 4961 – 4973
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4973