Switchable [3+2] and [4+2] Heteroannulation of Primary Propargylamines with Isonitriles to Imidazoles and 1,6-Dihydropyrimidines: Catalyst Loading Enabled Reaction Divergence

Article abstract of DOI:10.1002/chem.201601560

Isonitrile 1 due to its carbene-like reactivity serves generally as a one-carbon synthon in a diverse set of organic transformations. We report in this article that the isocyano group can also act as a polarized triple bond to undergo, as a two-atom synthon, heteroannulation with primary propargylamines 15. In addition, we serendipitously discovered that the reaction pathways can be modulated by simply changing the catalyst loading. In the presence of 0.1?equiv of Yb(OTf)₃or TfOH, the reaction between 1 and 15 afforded exclusively imidazoles 16 by a formal [3+2] cycloaddition. At a higher catalyst loading (Yb(OTf)₃(0.4?equiv) or TfOH (0.5?equiv)) under otherwise identical conditions, the same reaction furnished 1,6-dihydropyrimidines 17 in good to excellent yields by way of a formal [4+2] cycloaddition process. Mechanistic investigations indicated that both annulations went through an amidine intermediate resulting from the insertion of the isocyano group to the NH bond of the primary amine. Subsequent catalyst-loading-dependent 5-exo-dig or 6-endo-dig cyclization provided selectively the two heterocycles, respectively.

Full text of DOI:10.1002/chem.201601560

DOI: 10.1002/chem.201601560
Full Paper
&
Organic Synthesis
Switchable [3+2] and [4+2] Heteroannulation of Primary
Propargylamines with Isonitriles to Imidazoles and 1,6-
Dihydropyrimidines: Catalyst Loading Enabled Reaction
Divergence
Shuo Tong,[a] Qian Wang,[a] Mei-Xiang Wang,[b] and Jieping Zhu*[a]
Abstract: Isonitrile 1 due to its carbene-like reactivity serves
generally as a one-carbon synthon in a diverse set of organic
transformations. We report in this article that the isocyano
group can also act as a polarized triple bond to undergo, as
a two-atom synthon, heteroannulation with primary propar-
gylamines 15. In addition, we serendipitously discovered
that the reaction pathways can be modulated by simply
changing the catalyst loading. In the presence of 0.1 equiv
of Yb(OTf)3 or TfOH, the reaction between 1 and 15 afforded
exclusively imidazoles 16 by a formal [3+2] cycloaddition. At
a higher catalyst loading (Yb(OTf)3 (0.4 equiv) or TfOH
(0.5 equiv)) under otherwise identical conditions, the same
reaction furnished 1,6-dihydropyrimidines 17 in good to ex-
cellent yields by way of a formal [4+2] cycloaddition pro-
cess. Mechanistic investigations indicated that both annula-
tions went through an amidine intermediate resulting from
the insertion of the isocyano group to the NH bond of the
primary amine. Subsequent catalyst-loading-dependent 5-
exo-dig or 6-endo-dig cyclization provided selectively the
two heterocycles, respectively.
Introduction
The chemistry of isonitriles 1 has been dominated by the nu-
cleophilic carbene-like reactivity of its divalent isocyano
carbon. Indeed, it adds readily to an electrophile (e.g. carbonyl,
imine, electron-deficient double bond, etc) to form a nitrilium
intermediate 2 that can be trapped by a nucleophile to form
an a-adduct 3 (Eq. (1), Scheme 1). The capacity of isonitrile to
undergo an a-addition with both an electrophile and a nucleo-
phile has been extensively exploited in the development of
novel multicomponent reactions[1] ever since the discovery of
the classic Passerini-3CR[2] and Ugi-4CR.[3] For the very same
reason, the isocyano group acts generally as a one-carbon syn-
thon in a broad range of [4+1],[4] [3+1],[5] [5+1],[6] and
[2+2+1][7] cycloaddition reactions (Eq. (2), Scheme 1)[8] and rad-
ical-addition processes.[9]On the other hand, the isocyano
group is also a strong two-electron donor ligand capable of
forming complexes with a range of transition metals and its re-
[a] Dr. S. Tong, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique FØdØrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Scheme 1. Modulable reactivity of the isocyano group.
activity can be subsequently modulated by the nature of the
metals. The coordination of isonitrile to electron-rich low-
valent Group 6 and 7 elements with high p-electron releasing
ability renders the isocyano nitrogen nucleophilic. In the pres-
ence of an electrophile, the N-alkylation occurs to provide ami-
nocarbyne species 4 (M=Mo, W, Re, etc, Eq (3), Scheme 1).[10]
When the coordination center is not a good p-electron donor
and behaves as a good s-electron acceptor (Lewis acid), the di-
Homepage: http://lspn.epfl.ch
[b] Prof. Dr. M.-X. Wang
Laboratory of Bioorganic Phosphorous Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601560.
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valent carbon atom of the ligated isonitrile becomes electro-
philic and is susceptible to nucleophilic attack. With a pronu-
cleophile NuH, insertion of isocyanide to NuÀH takes place to
afford product 5 (e.g. M=Cu, Zn, Ag, lanthanide, etc, Eq. (4),
Scheme 4).[11] With a nucleophile containing an electrophilic
center, a sequence of reactions involving nucleophilic addition
to the isocyano carbon followed by an intramolecular N-alkyla-
tion could occur to furnish a heterocyclic aminocarbene com-
plex 6 (Eq (5), Scheme 1).[12] Both b-halo ethylamines (M=Pd,
Pt, Au, etc)[13] and propargyl amines (M=Mn)[14] have been
used as bifunctional substrates for the synthesis of NHC–metal
complexes. In these transformations, both the terminal carbon
and the internal nitrogen atoms of the isocyano group partici-
pated in the reaction by acting as an electrophilic and nucleo-
philic center, respectively. Therefore, the isocyano group react-
ed formally as a polarized triple bond. Notably, this unusual re-
activity profile remained largely unexplored in organic synthe-
sis.[15]
In connection with our long-standing interest in isocyanide
chemistry,[16] we have recently initiated a research program
aimed at exploiting the new reactivity of the isocyano group[17]
and become particularly interested in the reaction of bifunc-
tional substrates of type 7 containing both an acidic proton
(XH) and an electrophilic center. Keto acids[18] and in situ
formed imino acids[19] are typical reactants that have been ex-
ploited in the development of Ugi-type reactions. These reac-
tions, initiated by nucleophilic addition of an isocyano carbon
atom to the electrophilic center, followed by the classic a-addi-
tion pathway leading to 9 via the isonitrilium intermediate 8
(Eq. (1), Scheme 2). We hypothesized that if, in the presence of
a suitable catalyst, the reaction of isonitriles 1 and substrates 7
can be initiated by insertion of isocyano group to the XÀH
bond leading to 10 and if the metal salt was chosen in such
a way that the resulting CÀM bond in 10 was prone to protoly-
sis, then the formation of intermediate 11 with the concurrent
regeneration of catalyst MXn might be expected. The final cyc-
lization of 11 assisted by the lone pair of the heteroatom
would produce heterocycle 12 (Eq (2), Scheme 2). Overall, the
isocyano group would serve as a two-atom synthon in this het-
eroannulation process.
Scheme 2. Isocyanide as a polarized triple bond in heteroannulation reac-
tions.
to examine the reaction between isonitriles 1 and primary
propargylamines 15. We serendipitously discovered that the
reaction between 1 and 15 can be channeled towards the for-
mation of either imidazoles 16 or 1,6-dihydropyrimidines 17 by
simply adjusting the catalyst loading (Eq. (4), Scheme 2). In the
presence of Yb(OTf)3 or TfOH (0.1 equiv), the reaction of 1 with
15 afforded imidazoles 16 by way of a formal [3+2] heteroan-
nulation process. By simply increasing the catalyst loading
(Yb(OTf)3 (0.4 equiv) or TfOH (0.5 equiv)), the same reaction
provided 1,6-dihydropyrimidines 17 by a formal [4+2] cycload-
dition. Mechanistic investigations indicated that both hetero-
annulations went through an amidine intermediate resulting
from the insertion of isocyanide to the NÀH bond of primary
amines 15. Subsequent 5-exo-dig or 6-endo-dig cyclization pro-
vided selectively the two different heterocycles.
Indeed, we have very recently reported a synthesis of imida-
zolium 14 in which the isocyano group acted formally as a po-
larized triple bond, hence as a two-atom synthon, to undergo
formal [3+2] cycloaddition with secondary propargylamines 13
(Eq. (3), Scheme 2).[20] In this multicatalytic process, three task-
specific metal salts acted cooperatively to channel the reaction Results and Discussion
towards the formation of 1,3,4,5-tetrasubstituted imidazolium
Switchable [3+2] and [4+2] heteroannulation between iso-
salts 14. Ytterbium triflate catalyzed the insertion of isocyanide
to the NH bond, silver triflate catalyzed the 5-exo-dig cycliza-
tion of the resulting propargyl amidines, and potassium triflate
underwent salt metathesis with the hypothetical vinyl silver
species to regenerate the catalytic species. Concurrently, Lavilla
and co-workers[21] independently reported a hydrochloride-pro-
moted heteroannulation between 1 and 13 to afford the same
product 14. In both cases, a secondary amine was used as a nu-
cleophile to initiate the heteroannulation sequence. To enlarge
the scope of this novel heteroannulation process, we set out
nitriles and primary propargylamines
Discovery and survey of reaction conditions: The imidazole
nucleus is a structural motif found in many bioactive natural
products, pharmaceuticals, and agrochemicals.[22] In spite of
the existence of a number of synthetic methodologies,[22–24]
the development of new and general methods of synthesis is
still highly demanding.[25] In our preliminary studies, we have
shown that the reaction between secondary propargylamines
13 and tert-butyl isonitrile (1a) in the presence of a catalytic
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was surprising since this compound was never observed in the
reaction of secondary propargylamines 13 with isonitriles 1. It
is nevertheless of high interest since dihydropyrimidines, aza-
analogues of dihydropyridines, are of significant medicinal im-
portance[27] and only a limited synthetic methodology has
been developed for their synthesis.[28] Therefore, we set out to
optimize conditions to drive the reaction towards the forma-
tion of either imidazole 16a or 1,6-dihydropyrimidine 17a.
It was quickly found that the ratio of 16a and 17a depend-
ed on the catalyst loading and reaction temperature (Table 1,
entries 4 to 8). Performing the reaction in the presence of
0.4 equivalents of Yb(OTf)3 at 1408C provided compound 17a
exclusively in 86% yield (entry 7). On the other hand, with
0.1 equivalents of Yb(OTf)3, the same reaction furnished 16a as
a major product in 63% isolated yield (entry 8). Further screen-
ing of catalysts indicated that TfOH was equally effective in
catalyzing the heteroannulation of 1a with 15a in two differ-
ent ways as Yb(OTf)3.[29] With lower loading of TfOH (0.1 equiv),
16a was isolated in 73% yield together with a trace amount of
17a (entry 9). Increasing the loading of TfOH to 0.5 equiv, 1,6-
dihydropyrimidine 17a was formed in 78% isolated yield
(entry 13).[30] It is worth noting that both Lavilla[21] and
Hulme[31] have previously demonstrated that acid-catalyzed iso-
cyanide insertion into the NH bond, while effective with ani-
lines, failed with aliphatic amines. Finally, tributylammonium
triflate (nBu3NH+TfOÀ), a white solid easily prepared from
nBu3N and TfOH, was also able to catalyze the [2+3] heteroan-
nulation between 1a and 15a (entry 14). On the other hand,
tetrabutylammonium triflate was devoid of catalytic activity
(entry 15).
Scheme 3. N-Dealkylative heteroannulation between tBuNC (1a) and secon-
dary propargylamine 13.
amount of Yb(OTf)3 (0.2 equiv) and AgOTf (0.1 equiv) afforded
1,4,5-trisubstituted imidazoles 18 resulting from the N-dealky-
lation of the initially formed imidazolium salt (Scheme 3). In
this domino process, tBuNC (1a) served formally as a synthetic
equivalent of “+C=NÀ”. Based on our mechanistic assumption,
we reasoned that the same reaction should afford directly the
imidazoles without involving an N-dealkylation step if primary
propargyl amines were used as reaction partners of isonitriles.
Although this reaction will also give a 1,4,5-trisubstituted imi-
dazoles 16, the connectivity of the substituents in 16 will be
different from that of 18.
With this idea in mind, propargylamine 15a and tert-butyli-
sonitrile (1a) were chosen as test substrates for the survey of
reaction conditions (Table 1). While no reaction occurred under
thermal conditions (Table 1, entry 1), heating a solution of 1a
and 15a in xylenes at 908C in the presence of ytterbium tri-
flate (Yb(OTf)3, (0.2 equiv)) afforded the NH insertion product
19a (entry 2).[20,26] Increasing the reaction temperature to
1208C provided cleanly imidazole 16a and 1,6-dihydropyrimi-
dine 17a in a one-to-one ratio (entry 3). The formation of 17a
Scope of catalyst loading-dependent [3+2] and [4+2] cyclo-
additions between primary propargylamines 15 and isoni-
triles 1
Table 1. Survey of conditions for heteroannulation between 1a and 15a:
Catalyst-loading-dependent reaction divergence.
With the optimum conditions in hand, the generality of this
catalyst loading controlled heteroannulation processes was in-
vestigated. For the sake of convenience, nBu3NH+TfOÀ
(0.2 equiv) was used instead of TfOH for the synthesis of imida-
zole. As it is shown, imidazoles 16 and 1,6-dihydropyrimidines
17 (Scheme 4) with different substituents were easily accessi-
ble from the same starting materials by simply varying the cat-
alyst loading. The reaction is not sensitive to the electronic
properties of the R1 and R2 groups and most importantly, pri-
mary, secondary, tertiary alkyl, and aryl isocyanides were all ac-
cepted substrates. Both (S)- and (R)-a-methyl benzyl isocya-
nides participated in the reaction to afford imidazoles (16o,
16p) or 1,6-dihydropyrimidines (17o, 17p, d.r.=2:1). For the
[2+3] heteroannulation of 1 with 15, the reaction catalyzed by
nBu3NH+OTfÀ (0.2 equiv) afforded in general better yields of
imidazoles than those catalyzed by Yb(OTf)3 (0.1 equiv), where-
as for the [2+4] heteroannulation of 1 with 15, higher yields of
1,6-dihydropyrimidines were obtained using Yb(OTf)3
(0.4 equiv) as a catalyst. The structures of compounds 16a,
16c, and 17k were confirmed by X-ray crystallographic analy-
sis.[32]
Entry
Cat. (equiv)
T [8C]
t [h]
16a [%][b]
17a [%][b]
1
2
3
4
5
6
7
8
–
120
90
12
8
2
2
1
0
trace
50
40
35
0
trace
50
60
65
Yb(OTf)3 (0.2)[c]
Yb(OTf)3 (0.2)
Yb(OTf)3 (0.2)
Yb(OTf)3 (0.2)
Yb(OTf)3 (0.3)
Yb(OTf)3 (0.4)
Yb(OTf)3 (0.1)
TfOH (0.1)
120
130
140
140
140
140
140
140
140
140
140
140
140
1
2
17
83
trace
63[d]
73[d]
70
55
34
trace
70[d]
0
86[d]
trace
trace
15
1.5
0.5
0.5
0.5
0.5
0.5
2.5
2.5
9
10
11
12
13
14
15
TfOH (0.2)
TfOH (0.3)
TfOH (0.4)
TfOH (0.5)
nBu3NH+OTfÀ (0.2)
nBu4N+OTfÀ (0.2)
31
56[d]
78[d]
0
0
[a] Reaction conditions: 15a (0.2 mmol), 1a (0.4 mmol), catalyst, xylenes
(c=0.1m). [b] NMR yield unless otherwise specified. [c] Only insertion
product 19a was formed. [d] Isolated yield.
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Scheme 4. Catalyst-loading-dependent heteroannulation of primary propargylamines with isonitriles: Scope of [3+2] and [4+2] cycloadditions.
Mechanistic studies
plained by the N-acylation of amines 15 by the in situ generat-
ed formimidate carboxylate mixed anhydride (FCMA) 21
(Eq. (2), Scheme 5),[33] the triflic acid-catalyzed NH-insertion of
amine to isocyanide, to the best of knowledge, is unknown.
We reasoned that the same type of intermediate 24, reminis-
cent of FCMA 21 (Eq. (3), Scheme 5) is also formed and that
the primary amine, being a soft nucleophile, would attack pref-
erentially the imidate carbon atom leading to amidine 19.[34]
Being one of the strongest organic acids (pKa (H2O)=À14),
TfOH will protonate the primary amines 15, upon mixing, lead-
ing to ammonium salts. Therefore, the reaction mixture would
be only weakly acidic. Indeed in the absence of amine, tBuNC
polymerized rapidly upon addition of TfOH (0.5 equiv) at room
temperature. The fact that nBu3NH+OTfÀ was also capable of
catalyzing the same transformation led us to hypothesize that
the true catalyst might be in fact the ammonium salt formed
in situ from propargylamines and TfOH. Indeed, the triflate salt
25 derived from propargylamine 15a can catalyze the reaction
of 15a with 1a to afford 16a in 81% yield (Eq. (4), Scheme 5).
Since we have shown that amidine 19a is a common inter-
mediate for both heterocycles 16a and 17a, it is reasonable to
assume that these two heterocycles are formed by 5-exo-dig
and 6-endo-dig cyclizations of 19a, respectively. While both
processes are in principle allowed according to Baldwin’s
rule,[35] the formation of a five-membered ring is generally pre-
ferred kinetically, although it is known that both the substrate
structures and the reaction conditions can alter the regioselec-
tivity.[36] As a matter of fact, regioselective cyclization of struc-
turally related substrates such as 2-alkynyl benzoic acid 26,[37]
2-alkynyl benzamides 27,[38] propargyl ureas 28,[39] and prop-
Control experiments were performed to gain insights into the
reaction mechanism. Reaction of 1a and 15a in the presence
of formic acid or acetic acid (0.5 equiv) under otherwise identi-
cal conditions afforded as major products the N-acylated prod-
ucts 20a (R=H) and 20b (R=Me), respectively (Eq. (1),
Scheme 5). Neither imidazole 16a nor 1,6-dihydropyrimidi-
ne17a was formed under these conditions. While the transfor-
mation depicted in Equation (1) is known and can be ex-
Scheme 5. Results of control experiments. [a] Yield was not determined.
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Scheme 7. Isolation of 1,4-dihydropyrimidine and its isomerization to 1,6-di-
hydropyrimidine. Conditions: a) Yb(OTf)3 (0.4 equiv), xylenes, 1408C; b) Satu-
rated aqueous NaHCO3, RT, 5 min.
Figure 1. Amidines and related substrates.
argyl guanidines 29[40] has been extensively studied and condi-
tions have been established for performing either a 5-exo-dig
or a 6-endo-dig cyclization (Figure 1). However, the cyclization
of amidine 19 has been far less investigated and to the best of
our knowledge, only 5-exo-dig cyclization leading to imidazole
is known.[20,21,24d,e] Indeed, in this case, the 5-exo-dig cyclization
furnishes an aromatic compound 16 after facile double-bond
isomerization of the primary cyclization product 30, providing,
therefore, additional thermodynamic driving force (pathway a,
Scheme 6).[41]
at the present stage, we do not have a clear-cut explanation
on how the catalyst loading switched the reaction pathways.
Conclusion
In summary, we have developed a novel synthesis of two im-
portant heterocycles from the same propargylamines and iso-
nitriles. In these heteroannulation reactions, the isocyano
group served formally as a polarized multiple bond, hence
a two-atom synthon, while the primary propargylamine acted
either as a three or four-atom synthon to undergo the [3+2]
or [4+2] heteroannulation with isonitrile. While the switchable
catalyst-controlled selective generation of different products
from the same starting materials has attracted attention of
chemists for years, the intriguing catalyst loading enabled reac-
tion divergence reported here added yet another dimension to
the field of diversity-oriented synthesis.[45]
Experimental Section
For details of the synthetic procedures, physical and spectroscopic
data, copies of 1H, 13C NMR spectra of compounds, see the Sup-
porting Information.
Scheme 6. Possible reaction pathways to imidazoles 16 and 1,6-dihydropyri-
midine 17.
While 6-endo-dig cyclization of amidine 19 to 31 followed
by double-bond isomerization could explain the formation of
1,6-dihydropyrimidine 17 (pathway b, Scheme 6), there could
be an alternative pathway to account for the formation of 1,6-
dihydropyrimidine 17 (pathway c). Protonation of amidine 19
would afford amidinium 32 which could subsequently isomer-
ize to allene 33 due to the increased acidity of the propargylic
CH in 32.[42] Two further isomerization steps would convert 33
to triene 35 via intermediate 34. A 6p-azaelectrocyclization of
35 would then afford directly the 1,6-dihydropyrimidine 17
(pathway c, Scheme 6).[43,44]
General procedure for the synthesis of imidazole 16
Conditions A: Yb(OTf)3 (12.0 mg, 0.02 mmol, 0.1 equiv), propargyla-
mine 15 (0.2 mmol), isonitrile 1 (0.4 mmol), and xylenes (2.0 mL)
were loaded into a sealed tube. The resulting mixture was heated
to 1408C and stirred for 0.5 h. After completion of the reaction, the
solution was quenched with sat. aq. NaHCO3 solution and extract-
ed with EtOAc. The combined organic layers were washed with
brine and dried over Na2SO4. The solvents were removed in vacuo
and the residue was purified by flash column chromatography to
afford imidazole 16.
To differentiate pathways b and c, the reaction between 1a
and 15a leading to 17a was re-examined in detail. Gratefully,
we were able to isolate 1,4-dihydropyrimidine 31a in 87%
yield by rapidly extracting the aqueous work-up solution and
confirmed that 31a was readily isomerized to thermodynami-
cally more stable form 17a in the presence of a weak base
such as NaHCO3 (Scheme 7). This result clearly indicated that
17a was most probably formed by a 6-endo-dig cyclization
rather than the 6p-azaelectrocyclization pathway. Nevertheless,
Conditions B: nBu3HN+ÀOTf (13.0 mg, 0.04 mmol, 0.2 equiv), prop-
argylamine 15 (0.2 mmol), isonitrile 1 (0.4 mmol), and xylenes
(2.0 mL) were loaded into a sealed tube. The resulting mixture was
heated to 1408C and stirred for 2.5 h. After completion of the reac-
tion, the solution was quenched with sat. aqueous NaHCO3 solu-
tion and extracted with EtOAc. The combined organic layers were
washed with brine and dried over Na2SO4. The solvents were re-
moved in vacuo and the residue was purified by flash column
chromatography to afford imidazole 16.
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[5] Selected examples, see: a) J. Charrier, A. Foucaud, H. Person, E. Louka-
kou, J. Org. Chem. 1983, 48, 481–486; b) D. Moderhack, M. Lorke, D.
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General procedure for the synthesis of 1,6-dihydropyrimi-
dine 17
Conditions C: Yb(OTf)3 (50.0 mg, 0.08 mmol, 0.4 equiv), propargyla-
mine 15 (0.2 mmol), isonitrile 1 (0.4 mmol), and xylenes (2.0 mL)
were loaded into a sealed tube. The resulting mixture was heated
to 1408C and stirred for 2 h. After completion of the reaction, the
solution was quenched with sat. aq. NaHCO3 solution and extract-
ed with EtOAc. The combined organic layers were washed with
brine and dried over Na2SO4. The solvents were removed in vacuo
and the residue was purified by flash column chromatography to
afford dihydropyrimidine 17.
[7] Selected examples, see: a) J. Li, Y. Liu, C. Li, X. Jia, Adv. Synth. Catal.
2011, 353, 913–917; b) J. Li, N. Wang, C. Li, X. Jia, Chem. Eur. J. 2012,
18, 9645–9650.
Conditions D: TfOH (15.0 mg, 9.0 mL, 0.1 mmol, 0.5 equiv), propar-
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Tobisu, N. Chatani, Chem. Lett. 2011, 40, 330–340; c) G. Qiu, Q. Ding, J.
Wu, Chem. Soc. Rev. 2013, 42, 5257–5269; d) T. Vlaar, E. Ruijter, B. U. W.
Maes, R. V. A. Orru, Angew. Chem. Int. Ed. 2013, 52, 7084–7097; Angew.
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Acknowledgements
Financial support from EPFL (Switzerland), Swiss State Secretar-
iat for Education and Research (SER), the Swiss National Sci-
ence Foundation (SNSF), and National Natural Science Founda-
tion of China are gratefully acknowledged. We thank Dr. R. Sco-
pelliti for X-ray crystallographic analysis.
Keywords: dihydropyrimidine · heteroannulation · imidazoles ·
insertion · isonitriles · propargylamine
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Received: April 4, 2016
Published online on May 3, 2016
Chem. Eur. J. 2016, 22, 8332 – 8338
www.chemeurj.org
8338
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim