Metal-free iodine(III)-promoted direct intermolecular C-H amination reactions of acetylenes

Article abstract of DOI:10.1021/ja306211q

A direct metal-free amination of arylalkynes has been developed, which proceeds by reaction of the terminal alkyne with the hypervalent iodine reagent PhI(OAc)NTs₂ within a single-step operation. This unprecedented intermolecular C-H to C-N bond conversion provides rapid access to the important class of ynamides. In addition to the title reaction, the related transformation between alkylated alkynes and the iodine(III) reagent is also discussed.

Full text of DOI:10.1021/ja306211q

Article
pubs.acs.org/JACS
Metal-Free Iodine(III)-Promoted Direct Intermolecular C−H
Amination Reactions of Acetylenes
,‡
́
Jose A. Souto, Peter Becker, Alvaro Iglesias, and Kilian Muniz*
́
̃
†Institute of Chemical Research of Catalonia (ICIQ), Avgda Països Catalans 16, 43007 Tarragona, Spain
‡Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluïs Companys, 23, 08010 Barcelona, Spain
S
* Supporting Information
ABSTRACT: A direct metal-free amination of arylalkynes has
been developed, which proceeds by reaction of the terminal
alkyne with the hypervalent iodine reagent PhI(OAc)NTs2
within a single-step operation. This unprecedented intermo-
lecular C−H to C−N bond conversion provides rapid access to the important class of ynamides. In addition to the title reaction,
the related transformation between alkylated alkynes and the iodine(III) reagent is also discussed.
Michael-type addition followed by aryl migration to give the
corresponding ynamide product.9 Although this reaction has
received extensive application,11 it requires the individual
preformation of both the metalated amides and the required
reagent 1 incorporating the acetylene for posterior amination.
As a consequence, construction of the corresponding reagent 1
is required for each acetylene, which may be less convenient,
particularly in the cases of accessing a larger series of ynamides.
We considered the development of an alternative direct
metal-free oxidative Csp−N bond formation using free
acetylenes as an economically interesting addition to the
above-mentioned protocols. This idea originates from our
recent interest in the use of hypervalent iodine(III) reagents12
for metal-free amination reactions including diamination of
alkenes13 and 1,3-dienes,14 and allylic amination reactions,15
respectively. Isolation of a new class of hypervalent iodine(III)
reagents13a ArI(OAc)N(SO2R)2, 2, with a defined iodine−
nitrogen bond has set the basis for development of new metal-
free amination.16−19 In an ongoing effort to explore the
chemistry of 2, its direct reaction with terminal alkynes was
investigated with the aim to develop a direct metal-free Csp
amination.
INTRODUCTION
■
Ynamides represent a unique building block for organic
synthesis, and they have recently been referred to as a modern
functional group for the new millennium.1,2 Obviously, their
synthesis from amides and acetylenes through a direct C−N
bond formation is the most appreciable way of preparation.
Despite certain efforts, such an approach remains largely
unrealized. As to a noteworthy exception, Stahl,3 Evano,4 and
Jiao5 reported elegant copper-catalyzed aerobic coupling
reactions, and useful protocols using stoichiometric amounts
of copper were also reported.6,7
A particularly interesting entry to ynamides consists of an
approach originally described by Stang,8 who introduced
acetylene−nitrogen bond-forming reactions using preformed
acetylenyl iodonium(III) salts 1 (Scheme 1, top).9,10 The
reaction requires addition of a nitrogen nucleophile, usually in
its metalated form, which reacts with the triple bond in 1 in a
Scheme 1. Formation of Ynamides: Classic Multistep
Approach Involving Preformed Acetylenyliodonium Salts
(Top) and New Single Sequence Using Preformed 2 and
Free Acetylene (Bottom)
We here report a simple, rapid, and robust protocol for such
a metal-free synthesis of ynamides from acetylenes involving an
unprecedented C−H to C−N bond conversion (Scheme 1,
bottom).
RESULTS AND DISCUSSION
■
Our efforts to accomplish such a transformation are
summarized in Table 1. An initial approach followed earlier
work13,14 and employed a reagent combination of iodosoben-
zene diacetate and 2 equiv of bistosylimide for the amination of
phenylacetylene 3a as standard substrate. The desired ynamide
4a formed but was isolated only in a low yield of 10% (Table 1,
entry 1). An excess of an equimolar mixture15 of the preformed
Received: June 26, 2012
Published: August 21, 2012
© 2012 American Chemical Society
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Table 1. Discovery and Optimization of Metal-Free
Amination of Phenylacetylene (0.2 mmol scale)
Table 2. Variation of Nitrogen Source in Metal-Free
Amination of Phenylacetylene (0.2 mmol scale)
yield
a
entry
1
conditions
(%)
PhI(OAc)2 (1.2 equiv), HNTs2 (2.4 equiv), DCM, 50 °C,
10
16
10
12
0
15 h
2
3
4
5
6
7
PhI(OAc)(NTs2), 2a (1.4 equiv), HNTs2 (1.5 equiv), DCM,
50 °C, 15 h
PhI(OAc)(NTs2), 2a (1.4 equiv), HNTs2, (1.5 equiv), I2 (0.1
equiv), DCM, 50 °C, 15 h
PhI(OAc)(NTs2), 2a (1.4 equiv), HNTs2 (1.5 equiv), Bu4NI
(0.2 equiv), DCM, 50 °C, 15 h
PhI(OAc)(NTs2), 2a (1.4 equiv), HNTs2 (1.5 equiv), Bu4NI
(1 equiv), DCM, 50 °C, 15 h
PhI(OAc)(NTs2), 2a (1.4 equiv), HNTs2 (1.5 equiv), DCE,
70 °C, 15 h
PhI(OAc)(NTs2), 2a (1.4 equiv), HNTs2 (0.1 equiv), DCM,
50 °C, 15 h
31
32
8
PhI(OAc)(NTs2), 2a (1.4 equiv), DCE, 80 °C, 15 h
PhI(OAc)(NTs2), 2a (0.9 equiv), DCE, 80 °C, 15 h
PhI(OAc)(NTs2), 2a (0.8 equiv), DCE, 80 °C, 15 h
PhI(OAc)(NTs2), 2a (1.0 equiv), PhCl, 80 °C, 15 h
PhI(OAc)(NTs2), 2a (1.0 equiv), DCE, 80 °C, 30 min
56
68
61
59
61
9
10
11
12
13
b
PhI(OAc)(NTs2), 2a (0.98 equiv), DCE, 80 °C, 20 min
84
a
b
Isolated yield after purification. Aqueous workup.
reagent PhI(OAc)NTs2, 2a, and free bistosylimide led to only a
minor increase in yield (entry 2). Addition of iodine or iodide
had been successful in recent metal-free alkene diamination
reactions;20 however, it was entirely unsuccessful for the
present case (entries 3−5). Changing the solvent from
dichloromethane to dichloroethane allowed for working at
higher temperature, which increased the yield to 31% (entry 6).
A similar result was obtained in the presence of a catalytic
amount of free imide (entry 7), while reagent 2a alone
increased the yield to 56% (entry 8). Using reagent 2a as
limiting component further increased the yield (entries 9 and
10). Experiments with other chlorinated solvents such as
chlorobenzene had no beneficial consequences (entry 11). The
observations from entries 1−10 suggested that an excess of 2a
and/or presence of acids or additives affect the yield of 4a.
Indeed, employing a shorter reaction time of 30 min resulted in
an isolated yield of 61% (entry 12). Optimum conditions were
obtained for a reaction with 0.98 equiv of 2a and a short
reaction time of 20 min. Upon rapid aqueous quench, the
desired product 4a was obtained analytically pure in 84% yield
(entry 13).
The advantage of the present one-step methodology is
further demonstrated by its ease of application in the synthesis
of labeled products. To this end, reagent 2a bearing a 15N-
labeled bistosylimido group was prepared and upon reaction
with 3a gave the ynamide 4a-15N in a comparable yield (Table
2, entry 2). This new reaction of ynamide formation is not
limited to bistosylimide but proceeds with related nitrogen
sources as well. Using alternative bissulfonimides bis-
(phenylsulfoyl)imide, mesyltosylimide, and bismesylimide, the
corresponding products PhCCN(SO2Ph)2 4aa, PhCCNMsTs
4ab, and PhCCNMs2 4ac were obtained in 48−83% yield,
respectively (entries 3−5). In contrast, other nitrogen sources
such as saccharine and phthalimide did not engage in carbon−
a
b
Isolated yield after purification. Without isolation of preformed 2.
c
No reaction.
nitrogen bond formation under these conditions (entries 6 and
7).
This outcome is readily explained by our earlier observation
that formation of reagents 2 is a pKa-driven process, based on
the high acidity of the bissulfonimides (Scheme 2).13a It
Scheme 2. Formation of Mixed Iodine(III) Reagents 2
proceeds through irreversible displacement of acetic acid and
leads to a compound with an activated I−N bond. In contrast,
the combination of iodosobenzene diacetate and saccharine or
phthalimide16 is entirely inefficient for the present trans-
formation. Such a reagent combination would not provide a
suitably electrophilic iodine(III) reagent as these two nitrogen
sources do not display sufficient acidity.
Under the optimized conditions from Table 1, entry 10, a
series of different acetylenes 3 was submitted to provide the
corresponding ynamide products 4 in good to excellent yields
(Table 3).
All reactions proceed readily within minutes by warming a
mixture of 3 and the preformed reagent 2a. To exemplify the
ease of performance, reaction of 3a was successfully conducted
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of the arene group, common functional groups and substituents
are all tolerated and include para substitution (entries 2−5),
meta substitution (entries 6 and 7), and ortho substitution
(entry 8). The latter required a longer reaction time, probably
due to steric hindrance in the initial step of acetylene
functionalization. A 2,4-disubstitution and naphthyl derivative
were equally reactive (entries 9 and 10). Finally, the
bisacetylene 3k underwent selective mono- and bisamination,
depending on the relative ratio 3k:2a (entries 11 and 12). In all
cases, the obtained products 4 are stable compounds, which
display high crystallinity due to the bissulfonimide group. Their
structures are in agreement with spectroscopic data and for the
two products 4a and 4d were unambiguously assured from X-
ray analysis.21
Table 3. Metal-Free Amination of 1-Aryl Acetylenes:
Substrate Scope (0.2 mmol scale)
With the development of this new direct Csp−N bond
formation, interesting new ynamides are now accessible from
reaction between a stable iodine(III) reagent 2a and standard 1-
aryl acetylenes 3, which represent common bulk materials.22 It
is also the first amination process with reagents 2a that
proceeds readily without additional activation through a second
bissulfonylimide.
For the present transformation, we propose a mechanism
based on literature precedence that starts from dissociation of
reagent 2a followed by reversible coordination of the
electrophilic iodine(III) to the aryl acetylene. The resulting
complex A further acidifies the alkyne C−H bond, leading to
internal deprotonation23 and loss of acetic acid to form a σ-
alkynyl iodine(III) B (Figure 1).
Figure 1. Mechanistic proposal.
A competition experiment for 3f and its terminally
deuterated derivative 3f-d1 resulted in an isotope effect kH/kD
of 4.4, suggesting a rate-limiting carbon−iodine bond formation
step (Scheme 3).21 Interestingly, terminally silylated acetylenes
such as PhCCSiMe3 did not undergo the amination reaction.
While this is in contrast to their successful role in
stoichiometric formation of acetylenyl iodonium(III) salts,24
direct applicability of terminal acetylenes under our conditions
must be considered superior from a synthetic standpoint.
Subsequent to formation of B, Michael addition8,9,11 of the free
Scheme 3. Kinetic Isotope Effect in the Amination of 3f
a
b
c
Isolated yield after purification. A 10 mmol reaction. Yield in
d
brackets is based on recovered starting material. Two equivalents of
alkyne. Two equivalents of PhI(OAc)NTs2.
e
on a 10 mmol scale, where the product was obtained from a
single crystallization in 78% yield (entry 1). Regarding variation
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bistosylimide nucleophile forms an alkylidenecarbene C upon
loss of iodobenzene.25 Subsequent rearrangement provides the
ynamide product 4. A stoichiometric control experiment
between the preformed known σ-alkynyl iodine(III) 526 and
bistosylimide gave 4a in 76% isolated yield (Scheme 4),
Scheme 5. Isolation of Ferrocenyl Enimide 6a
Scheme 4. Stoichiometric Control Experiment
indicating the intermediacy of B. Interestingly, this reaction
could be carried out at room temperature, suggesting that all
steps from B to 4a do not require high temperature and thereby
verify that C−H cleavage is rate determining.
A reaction profile for amination of 3g to 4g is in agreement
with the described results.21 Only the terminal acetylene 3g and
ynamide 4g were detected throughout the reaction, which
suggests that states B and C are rather short-living
intermediates.
Scheme 6. Domino Ynamide Formation/Condensation
Reaction
Electronic influences are negligible in the amination reactions
of acetylenes 3a−d. The corresponding competition experi-
ments all show closely related reaction rates resulting in values
between 0.95 and 1.05 for kH/kX for these arenes with σp‑Hammett
values in the range from −0.27 to −0.17. This is different for 4-
bromophenyl acetylene 3e (σp‑Hammett = 0.39), which in
competition with 3a gives a 1:3.8 ratio of 4e:4a. In a more
pronounced manner, 4-nitrophenyl acetylene does not engage
in ynamide formation at all and is reisolated unchanged after 4
h in the presence of 2a. These observations suggest the
individual reactivity pattern change for electron-withdrawing
substituents and that in these cases the importance of an initial
interaction between the acetylene in 3 and the reagent 2a is
dominating. This step also underlines the superiority of
reagents 2 with a labile iodine−nitrogen bond (Scheme 2),
enabling rapid dissociation and alkyne coordination. Release of
acetic acid throughout the reaction requires timely workup as
products 4 were found unstable in the presence of acid.
Alkylidene carbene intermediates of type C in reactions of
alkynyl iodine(III) compounds have also remained elusive due
to their high reactivity, but their involvement has been
corroborated by analysis of the respective reaction products.9
In the reaction of ferrocenyl acetylene 3l, the expected ynamide
did not form. Instead, the enimide 6a could be isolated together
with acetylferrocene 6b (35%), its hydrolysis product.
Formation of 6a should proceed from the corresponding
alkylidenecarbene intermediate upon aqueous workup (Scheme
5).
An investigation on N-benzoyl 2-acetylenyl aniline 3m
showed low conversion within the initial hour of reaction.
This is in accord with the observed reduced reactivity of 2-
methyl derivative 3h from Table 2. Still, upon prolonged
reaction time between 3m and 2a, formation of a single
compound was observed. This was not the expected ynamide
but its bicyclic derivative 7 (Scheme 6). We suggest formation
of this product to occur through the expected ynamide product
4m, which in the presence of acetic acid undergoes a
subsequent proton-catalyzed 6-exo-dig cyclization to form 7
as a single alkene regioisomer. However, we cannot exclude an
alternative pathway, which would proceed through intra-
molecular Michael addition by the amide resonance followed
by addition of bistosylimide to the resulting vinyl iodonium
intermediate. In any case, this example suggests that interesting
additional product diversification is possible under the chosen
reaction conditions.
Finally, we engaged in a brief evaluation of the amination of
aliphatic alkynes. In this series, the corresponding alkylidene
carbene intermediate should promote a C−H insertion
reaction.11o−q,27 As expected, treatment of 1-octyne 8a with
2a resulted in clean formation of the expected enimide 9a
(Table 4, entry 1), the structure of which was unambiguously
confirmed by X-ray analysis.21 Due to the acid lability of the
product, short reaction times are required. However, the high
volatility of the starting material resulted in low conversion,
which was overcome by an excess of acetylene (entry 2).
Substrates 8b,c demonstrated that the carbene insertion
reactions proceed equally well for primary and tertiary carbon
centers (entries 3 and 4). The bisacetylene 8d provides mono-
or bisamination depending on the amount of iodine(III)
reagent (entries 5 and 7), while only monoamination was
observed for the longer homologue 8e (entry 6). These new
intermolecular amination/cyclization reactions underline the
impressively broad synthetic possibilities in acetylene oxidation
with 2a.
Figure 2 shows the relevant mechanistic context of this
cyclopentannelation. The reaction again starts from coordina-
tion of the electrophilic iodine(III) to the terminal acetylene
(D) followed by formation of an acetylenyl iodine complex E,
which undergoes a Michael addition with bistosylimide. Loss of
iodobenzene leads to the alkylidene carbene intermediate F,
which undergoes position-selective C−H insertion to arrive at
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(III) 2a as the only reagent. They proceed at a high rate, and a
range of substituents and functional groups are tolerated. The
presented examples demonstrate the broad reaction potential of
PhI(OAc)NTs2 with terminal acetylenes, which add to related
metal-free reactions of diamination of alkenes13,14 and
benzylic16b and allylic15 amination.
Table 4. Metal-Free Amination of 1-Alkynes: Cyclopentene
Formation (0.2 mmol scale)
EXPERIMENTAL SECTION
■
Representative Synthesis of Ynamides: Compound 4a.
Phenylacetylene, 3a (22 μL, 0.204 mmol), was added to a solution
of PhI(OAc)(NTs2), 2a (0.12 g, 0.200 mmol), in DCE (2.0 mL), and
the reaction mixture was stirred at 80 °C. After 20 min the solution
was quenched by addition of a 10% aqueous solution of sodium
thiosulfate. Aqueous phase was extracted with DCM (3×). The
combined organic layers were washed with brine (2×) and dried, and
solvents were removed under reduced pressure. The title compound
was obtained as a white solid.
Mp = 127−129 °C. 1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 6H),
7.3−7.4 (m, 3H), 7.39 (d, J = 7.8 Hz, 4H), 7.4−7.5 (m, 2H), 7.96 (d, J
= 8.4 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ = 21.8, 75.6, 77.8,
121.9, 128.3, 128.7, 128.8, 129.8, 132.0, 135.1, 146.0. IR ν(cm−1):
3065, 2923, 1595, 1382, 1365, 1169, 1082, 848, 808, 765, 656, 530.
HRMS (ESI-MS): calcd for C22H19NO4NaS2, 448.0653; found,
448.0654.
Representative Cyclopentene Annulation: Compound 9a. 1-
Octyne 8a (30 μL, 0.204 mmol) was added to a solution of
PhI(OAc)(NTs2), 2a (0.12 g, 0.200 mmol), in DCE (2.0 mL), and the
reaction mixture was stirred at 80 °C. After 20 min the solution was
quenched by addition of a 10% aqueous solution of sodium thiosulfate.
Aqueous phase was extracted with DCM (3×). The combined organic
layers were washed with brine (2×) and dried, and solvents were
removed under reduced pressure. The crude reaction mixture was
purified by column chromatography (silica gel, hexanes/EtOAc, 9:1, v/
v), and the title compound was obtained as a white solid.
a
b
c
Isolated yield after purification. At 25 °C. Five equivalents of
d
e
alkyne. At 50 °C. Two equivalents of PhI(OAc)NTs2 2a.
Mp = 92−94 °C. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.9
Hz, 3H), 1.2−1.4 (m, 4H), 1.5−1.6 (m, 1H), 2.1−2.2 (m, 1H), 2.3−
2.4 (m, 2H), 2.44 (s, 6H), 2.6−2.7 (m, 1H), 5.50 (q, J = 1.9 Hz, 1H),
7.32 (d, J = 8.3 Hz, 4H), 7.86 (d, J = 8.3 Hz, 4H). 13C NMR (100
MHz, CDCl3): δ = 14.0, 20.5, 21.6, 28.9, 33.1, 37.3, 43.1, 128.4, 129.4,
135.2, 136.6, 140.8, 144.8. IR ν(cm−1): 3060, 2927, 1596, 1510, 1365,
1340, 1161, 1111, 856, 669, 546. HRMS (ESI-MS): calcd for
C22H27N2O6NaS2, 456.1279; found, 456.1274.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 2. Mechanistic proposal.
Complete experimental details and characterization data for
new compounds, including CIF files on the X-ray crystallo-
graphic analyses of compounds 4a, 4d, 6a, 7, and 9a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
product 9. This mechanistic proposal is in full agreement with
an earlier investigation on nucleophilic addition to alkynyl
iodinonium reagents followed by intramolecular C−H insertion
of an alkylidene carbene intermediate.9
Several reactions for nitrogen-based heterocycle formation
have been reported in this context.9 These reactions all require
preformation of the acetylenyl iodonium group and proceed
through the corresponding intramolecular Michael addition.
Although known for carbon- and oxygen-based nuceo-
philes,27,28 the present examples of an intermolecular
amination/carbene insertion sequence are rare. As to an
exception, Stang reported addition of sodium azide to a
preformed octynyliodonium reagent to generate the azido
derivative of 9a.29 Our examples from Table 4 now
demonstrate that such reactions can be carried out readily
through the use of preformed iodine(III) reagents such as 2a.
In summary, we described conditions for new metal-free
direct amination reactions of acetylenes. These reactions are
operationally simple and require defined hypervalent iodine-
AUTHOR INFORMATION
Corresponding Author
E-mail: kmuniz@iciq.es
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by ICIQ Foundation and by the
́
Spanish Ministerio de Economia y Competitividad (CTQ2011-
25027). P.B. is a visiting student from RWTH Aachen
(Germany) and acknowledges the German DAAD for a
fellowship. The authors thank Dr. J. Benet-Buchholz, Dr. E.
́
C. Escudero-Adan, Dr. M. Martınez-Belmonte, and Dr. E.
́
Martin for crystal structure analyses and Prof. K. Miyamoto,
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(n) Klein, M.; Konig, B. Tetrahedron 2004, 60, 1087. Intramolecular
̈
University of Tokushima, for suggesting the control experiment
from Scheme 4.
versions: (o) Feldmann, K. S.; Bruendl, M. M.; Schildknegt, K. J. Org.
Chem. 1995, 60, 7722. (p) Feldmann, K. S.; Bruendl, M. M.;
Schildknegt, K.; Bohnstedt, A. C. J. Org. Chem. 1996, 61, 5440.
(q) Schildknegt, K.; Bohnstedt, A. C.; Feldmann, K. S.; Sambandam,
A. J. Am. Chem. Soc. 1995, 117, 7544.
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