Copper-catalyzed hydroamination of propargyl imidates

Article abstract of DOI:10.1016/j.tetlet.2017.10.043

Propargyl imidates derived from aromatic and aliphatic nitriles cyclize at room temperature in high yields when treated with a catalytic amount of copper (I) iodide. This 5-exo-dig process affords dihydrooxazoles which do not aromatize under the reaction

Full text of DOI:10.1016/j.tetlet.2017.10.043

Accepted Manuscript
Copper-catalyzed hydroamination of propargyl imidates
Patrick J. Fricke, Jenna L. Stasko, Dylan T. Robbins, Alexander C. Gardner,
Jacqueline Stash, Mark J. Ferraro, Michael W. Fennie
PII:
S0040-4039(17)31335-7
https://doi.org/10.1016/j.tetlet.2017.10.043
TETL 49405
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
30 August 2017
10 October 2017
16 October 2017
Please cite this article as: Fricke, P.J., Stasko, J.L., Robbins, D.T., Gardner, A.C., Stash, J., Ferraro, M.J., Fennie,
M.W., Copper-catalyzed hydroamination of propargyl imidates, Tetrahedron Letters (2017), doi: https://doi.org/
10.1016/j.tetlet.2017.10.043
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Copper-catalyzed hydroamination of
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Patrick J. Fricke, Jenna L. Stasko, Dylan T. Robbins, Alexander C. Gardner, Jacqueline Stash, Mark J. Ferraro,
and Michael W. Fennie*

1
Tetrahedron Letters
Copper-catalyzed hydroamination of propargyl imidates
Patrick J. Fricke, Jenna L. Stasko, Dylan T. Robbins, Alexander C. Gardner, Jacqueline Stash, Mark J.
Ferraro, and Michael W. Fennie*
Department of Chemistry, The University of Scranton, 800 Linden Street, Scranton, Pennsylvania 18509, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Propargyl imidates derived from aromatic and aliphatic nitriles cyclize at room temperature in
high yields when treated with a catalytic amount of copper (I) iodide. This 5-exo-dig process
affords dihydrooxazoles which do not aromatize under the reaction conditions, and which are
isolated without chromatography. Investigations of the reaction scope, subsequent
Available online
functionalization of the reaction products, and preliminary mechanistic data are presented.
2017 Elsevier Ltd. All rights reserved.
Keywords:
Hydroamination
Copper Catalysis
Heterocycles
Alkynes
Imidates
Introduction
Oxazoles and related heterocycles are important components of
many biologically active natural products and pharmaceuticals.1,2
In addition to the Robinson-Gabriel oxazole synthesis and its
variants,3 catalytic methods for the synthesis of oxazoles have
been developed,4 notably the cycloisomerization of propargyl
amides using transition metal catalysts such as AuCl3 or FeCl3
(A, Figure 1).5,6 An intermediate in these catalytic examples is a
non-aromatic 5-methylene-4,5-dihydrooxazole resulting from a
5-exo-dig cyclization. Interestingly, other metal catalysts have
been discovered that chemoselectively convert propargyl amides
to dihydrooxazoles without concomitant aromatization to the
oxazoles.7–13 The exocyclic double bond of these compounds
represents a handle which has been used to access several classes
of functionalized oxazoles.14,15
Figure 1. Oxazole and dihydrooxazole syntheses. M: Au(I),
Ag(I), Pd(II), Zn(II), Cu(I) if R2 ≠ H.

2
Tetrahedron
The cycloisomerization, or hydroamination, of the isomeric
propargyl imidates to the corresponding 4-methylene-4,5-
dihydrooxazoles, however, has been less-extensively studied.16
Overman and coworkers reported both the thermal and the
stoichiometric DBU-promoted hydroamination of two
benzimidates (A, Figure 2), and provided examples of their
subsequent functionalization.17 Isolation of these dihydrooxazoles
from the DBU procedure was complicated by the instability of
the products to chromatography, and the thermal procedure was
limited to dilute solutions. The groups of Hashmi,18 Shin,19 and
Hii20 have reported catalytic gold and silver hydroaminations
restricted to propargyl trichloroacetimidates (B, Figure 2).
Although these methods afford trichloromethyl-substituted
products, a robust and catalytic route to the electron-rich, non-
trichloromethyl-substituted, aryl- and alkyl-substituted 4-
methylene-4,5-dihydrooxazoles remains unexplored. Herein we
report the catalytic hydroamination of both aryl- and alkyl-
substituted propargyl imidates using a copper catalyst that
produces 4-methylene-4,5-dihydrooxazoles, which are isolated in
good to near-quantitative yields and high purity without
chromatography (C, Figure 2).
Other catalysts were then tested in this reaction to determine if
chemoselectivity for 4a could be obtained. Table 1 summarizes
the results of reactions of 3a with a metal salt (5 mol% loading)
in CDCl3 at room temperature for 24 h. Precious metal gold,
palladium, and silver compounds promoted hydroamination (as
measured by 1H NMR spectroscopy), but none provided desired
levels of reactivity and chemoselectivity. KAuCl4 exhibited rapid
reactivity similar to AuCl3 (entry 1). Pd(PhCN)2Cl2 and
Pd(OAc)2 afforded conversion to both dihydrooxazole 4a and
oxazole 5a (entries 2 and 3), whereas Pd(PPh3)Cl2 afforded
partial conversion to 4a with no oxazole formation (entry 4).
AgOTf (entry 5) was more reactive than both Ag2SO4 and AgI
(entries 6 and 7), with the latter two showing chemoselectivity
for dihydrooxazole 4a. Non-precious metals also promoted
hydroamination at room temperature. ZnCl2 was an effective
catalyst, affording almost complete conversion to 4a with
minimal formation of 5a (entry 8). FeCl3 favored formation of 5a
over 4a, but in low conversion. CuCl2 was not an effective
catalyst (entry 10), but the Cu(I) compounds CuCl, CuBr, and
CuI (entries 11, 12, and 13), however, provided complete
conversion of 3a to 4a with only trace formation of oxazole 5a.
Table 1. Conversion of 3a to 4a and/or 5a.
Figure 2. Hydroamination of Propargyl Imidates
Results and Discussion
Entry
1
Catalysta
KAuCl4
Pd(PhCN)2Cl2
Pd(OAc)2
Pd(PPh3)2Cl2
AgOTf
Ag2SO4
AgI
% 3ab
0
% 4ab
0
% 5ab
100
42
To begin, model substrate 3a was synthesized via a Pinner
reaction of 4-chlorobenzonitrile and propargyl alcohol saturated
with gaseous HCl (Scheme 1).21 The resultant HCl salt was
collected by filtration, and subsequent neutralization afforded the
free base as a stable solid.
2
0
59
73
16
90
12
7
3
0
27
4
84
0
0
5
10
Scheme 1. Synthesis of substrate 3a
6
88
93
6
0
7
0
8
ZnCl2
92
6
2
9
FeCl3
72
94
0
22
10
11
12
13
CuCl2
6
0
CuCl
>99
>99
>99
trace
trace
trace
Upon exposure of 3a to 5 mol% AuCl3 in CDCl3 at room
temperature for 10 min, both dihydrooxazole 4a and oxazole 5a
were observed by 1H NMR spectroscopy in a 90:10 ratio, with no
starting material remaining (Scheme 2). After 2 h, 4a was
converted to 5a quantitatively. Unlike the reactions of propargyl
trichloroacetimidates described by Hashmi, the reaction of this
aromatic propargyl imidate with AuCl3 was not chemoselective
for the dihydrooxazole at short reactions times.
CuBr
0
CuI
0
aConditions: catalyst (5 mol%), CDCl3 (0.25 M), room
temperature, 24 h. bDetermined by 1H NMR spectroscopy.
CuI was recognized as an ideal catalyst not only because it is an
easily-handled, stable solid, but moreover, the heterogeneous
reaction conditions afforded by this insoluble catalyst obviates
the need for flash chromatography, to which these products have
limited stability. Once the reactions in CHCl3 completed, the
insoluble CuI was removed by filtration, affording products in
high purity after solvent removal (see the Supplemental Data).
Scheme 2. Hydroamination of 3a with AuCl3

3
A solvent screen showed that other polar aprotic solvents
(MeCN, acetone, EtOAc) and non-polar solvents (benzene,
cyclohexane) could be utilized for the hydroamination, providing
high levels of chemoselectivity. Alcohols such as MeOH and
EtOH could be used, but small amounts of imidate solvolysis
products were detected over time. Solvolysis was not detected in
runs in t-BuOH. More acidic solvents such as AcOH and
CF3CH2OH were the only solvents tested that showed oxazole
formation to any great extent, likely because acids promote
isomerization of these dihydrooxazoles to oxazoles. CHCl3 was
used for subsequent reactions, however, because it easily
solubilized the range of substrates tested (vide infra).
Table 2. Solvent screen
Chemoselectivity for 4a,b
>95%
95-80%
<80%
MeCN, acetone, EtOAc,
benzene, cyclohexane, t-BuOH
MeOH,
EtOH
AcOH,
CF3CH2OH
aConditions: CuI (5 mol%), solvent (0.25 M), room temperature,
24 h. bDetermined by 1H NMR spectroscopy.
A series of imidates was synthesized using Pinner conditions,
which proved successful for a variety of aryl- and alkyl- nitrile
substrates (see Supplemental Data). The in situ generation of HCl
using acetyl chloride and propargyl alcohol was also effective,
providing imidates in comparable yields.22 The scope of the
hydroamination was then investigated using these imidates, as
shown in Table 3. Electron-rich benzimidates cyclized in
complete conversion and in good to excellent isolated yields (4b-
4g). The presence of an ortho-substituent on the aromatic ring
did not adversely affect the reaction (4h). Electron deficient
substrates generally took the full 24 h to reach completion
(compounds 4a, 4i, and 4j). Aliphatic dihydrooxazoles, even the
bulky adamantyl-substituted 4l, were obtained in excellent yields.
Likewise, the alkenyl imidate cyclized to afford the unsaturated
dihydrooxazole 4n. The reaction has been scaled up to 5 and 10
mmol (4i and 4d, respectively) with no loss of chemoselectivity
or purification complications. At the 10 mmol scale, the reaction
was conducted with a 2.5 mol% catalyst loading and was still
complete within 24 h (4d). Additionally, no special precautions
were taken to exclude air or moisture from these reactions.
aConditions: 0.30 mmol 3, 0.25 M CHCl3, 5 mol% CuI, 24 h.
bIsolated yield. c10 mmol scale. d2.5 mol% CuI used. e5 mmol scale.
This hydroamination protocol was then applied to the propargyl
trichloroacetimidate substrate used by the Hashmi, Shin, and Hii
groups. After 24 h, however, no reaction was observed for this
substrate (Scheme 3). This lack of reactivity may be due to the
extreme electron withdrawing nature of the trichloromethyl
group, which would be expected based on the slower reaction
rates observed for the electron deficient benzimidates.
Table 3. Hydroamination scope.a
Scheme 3. Reaction of a propargyl trichloroacetimidate
This result prompted further examination of the structural
constraints on these substrates, specifically, whether substitution
of the propargyl component was permitted (Scheme 4). The
Pinner reaction was used to synthesize benzimidates from 2-
butyn-1-ol (6a, 6b). Upon exposure to the standard reaction
conditions (5 mol% CuI, CHCl3, rt, 24 h) both 6a and 6b failed to
cyclize (A, Scheme 4), in contrast to the reactivity of the
corresponding propargyl imidates 3b (R = Ph) and 3e (R = 4-
MeO-C6H4). Only starting material was recovered in each
instance. In order to probe whether the increased sterics around
the alkyne were responsible for the lack of reactivity, the imidate

4
Tetrahedron
derived from isomeric 3-butyn-2-ol (7) was subjected to the
As expected, the exocyclic alkene of the dihydrooxazole products
standard conditions. This substrate, however, cyclized to the
desired dihydrooxazole (B, Scheme 4) in a yield comparable to
the cyclization of the corresponding propargyl imidate 3e (R = 4-
MeO-C6H4). These results suggest that the mechanism for the
CuI-catalyzed reaction may involve formation of a copper (I)
acetylide23 species from a terminal alkyne, rather than an alkyne
π-activation/cyclization that is operative in the
of these hydroamination reactions can be further modified in a
variety of reactions (Scheme 6). For example, oxazole 5e was
obtained upon treatment of dihydrooxazole 4e with catalytic
TFA. Additionally, reaction of dihydrooxazole 4d with NBS
rapidly produced the 4-bromomethyloxazole 12. The [3+2]
cycloaddition of 4a with bromonitrile oxide provided access to
spirocyclic compound 13.
trichloroacetimidate reactions promoted by gold and silver
catalysts (B, Figure 2). To support this conjecture, an imidate
deuterated at the alkyne terminus was synthesized24 and treated
with the standard conditions (C, 2H-3c, Scheme 4) (the
exchangeable NH was retained, see the Supplementary Data).
The product 2H-4c was isolated in high yield, but hydrogen was
incorporated at both positions of the terminus of the exocyclic
alkene, indicating that scission of the deuterium–carbon bond
occurred during the transformation.
Scheme 6. Modification of dihydrooxazoles
Scheme 4. Hydroamination of substituted propargyl imidates
Conclusion
CuI is a practical catalyst for the conversion of aromatic and
aliphatic propargyl imidates to 4-methylene-4,5-dihydrooxazoles,
which are isolated in high yield and purity without
chromatography. These relatively electron-rich products do not
aromatize to the oxazoles in the presence of CuI, in contrast to
reactions with AuCl3, which had been used to synthesize the very
electron-deficient trichloromethyl-substituted dihydrooxazoles.
Moreover, this is an attractive method because CuI is an
inexpensive and readily-available catalyst, it does not require the
use of inert or moisture-free atmospheres, the insoluble CuI is
easily separated from the product after the room temperature
reaction is completed, it has been scaled up to 10 mmol, and the
products are easily modified for further uses. Several experiments
suggest the intermediacy of a copper (I) acetylide. Ongoing
studies will further elucidate this mechanism, and explore new
carbon–carbon bond forming reactions involving the
In such a process (Scheme 5), the basic nitrogen of an imidate
(B:) could serve to dedeuterate a copper-coordinated alkyne to
form the copper (I) acetylide (2H-9→10). After 5-exo-dig
cyclization, demetalation of 11 can proceed using available
deuterium and hydrogen sources to produce 2H-4c. Taken
together, the deuterium-labeling result and the lack of reactivity
for imidates 6a and 6b support a copper (I) acetylide
intermediate. Such an intermediate would also explain why
CuCl2 was an inefficient catalyst (Table 1, entry 10).
Additionally, it is possible that propargyl trichloroacetimidate 3o
did not react because the electron-deficient nitrogen was not
basic enough to promote copper acetylide formation.
dihydrooxazole products (cross-couplings, radical additions).
Acknowledgments
Scheme 5. Plausible mechanism (X: I or acetylide)
We are grateful to the University of Scranton for support of this
research. P.J.F. thanks the University for a Presidential
Fellowship for Summer Research. We thank Emily C.
McLaughlin for helpful discussions, and Dmitro Martynowych
for NMR assistance. Mass spectrometry was performed using
instrumentation supported by funding from a National Science
Foundation MRI Grant (#1039659, Teresa A. Garrett, P. I.).
Supplementary Material
Supplementary Data associated with this article may be found, in
the online version, at:

5
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