Chemoselective amination of propargylic C(sp3)-H bonds by cobalt(II)-based metalloradical catalysis

Article abstract of DOI:10.1002/anie.201400557

Highly chemoselective intramolecular amination of propargylic C(sp ³)-H bonds has been demonstrated for N-bishomopropargylic sulfamoyl azides through cobalt(II)-based metalloradical catalysis. Supported by D _2h-symmetric amidoporphyrin ligand 3,5-Di^tBu-IbuPhyrin, the cobalt(II)-catalyzed C-H amination proceeds effectively under neutral and nonoxidative conditions without the need of any additives, and generates N ₂ as the only byproduct. The metalloradical amination is suitable for both secondary and tertiary propargylic C-H substrates with an unusually high degree of functional-group tolerance, thus providing a direct method for high-yielding synthesis of functionalized propargylamine derivatives. Make a ring of it: Highly chemoselective intramolecular amination of propargylic C(sp³)-H bonds has been achieved with a high degree of functional-group tolerance through the title reaction. The [Co(P1)]-catalyzed C-H amination proceeds under neutral and nonoxidative conditions without the need of any additives, thus providing a direct method for efficient synthesis of functionalized propargylamine derivatives with N₂ as the only by-product.

Full text of DOI:10.1002/anie.201400557

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Angewandte
Communications
DOI: 10.1002/anie.201400557
Cyclization
3
À
Chemoselective Amination of Propargylic C(sp ) H Bonds by
Cobalt(II)-Based Metalloradical Catalysis**
Hongjian Lu,* Chaoqun Li, Huiling Jiang, Christopher L. Lizardi, and X. Peter Zhang*
Abstract: Highly chemoselective intramolecular amination of
its application has been limited to the preparation of
propargylamines bearing a tertiary carbon center at the
propargylic position.[6]
3
À
propargylic C(sp ) H bonds has been demonstrated for N-
bishomopropargylic sulfamoyl azides through cobalt(II)-
based metalloradical catalysis. Supported by D2h-symmetric
amidoporphyrin ligand 3,5-DitBu-IbuPhyrin, the cobalt(II)-
À
Selective amination of omnipresent C H bonds by metal-
mediated nitrene insertion represents a powerful approach
for direct introduction of valuable amino functionalities into
molecules.[7] This direct transformation has the potential to
serve as an efficient alternative to traditional approaches for
amine syntheses, which are based on functional-group trans-
formations. Its realization may have far-reaching impact for
amine synthesis and their practical applications in different
fields. Accordingly, the direct synthesis of propargylamines
À
catalyzed C H amination proceeds effectively under neutral
and nonoxidative conditions without the need of any additives,
and generates N2 as the only byproduct. The metalloradical
amination is suitable for both secondary and tertiary prop-
À
argylic C H substrates with an unusually high degree of
functional-group tolerance, thus providing a direct method for
high-yielding synthesis of functionalized propargylamine
derivatives.
À
based on metal-catalyzed amination of propargylic C H
bonds could become an alternative approach to traditional
methods. In addition to propargylamines containing tertiary
Significant effort has been devoted to developing synthetic
À
methods for accessing propargylamines as they serve as
versatile intermediates in organic synthesis,[1] as well as
important structural elements in natural and synthetic
products having interesting biological activities.[2] Tradition-
ally, propargylamines have been prepared through the
addition of metal alkynylides to imines. Since this traditional
method typically requires stoichiometric amounts of metal
alkynylides, which are known to be moisture sensitive,[3] it
reduces the degree of functional-group tolerance and has
largely restricted the applications. Consequently, there has
been continued interest in developing new methods for the
synthesis of propargylamines under mild reaction conditions
with a high degree of functional-group tolerance. Among the
different approaches that have been developed recently, the
transition-metal-catalyzed three-component one-pot cou-
pling of an aldehyde, an alkyne, and an amine represents
one of the most general and atom-economic methods. This so-
called A3-coupling provides a catalytic method for efficient
synthesis of propargylamines under mild reaction conditions
with H2O as the only byproduct.[4,5] Since A3-coupling is
mainly suitable for aldehydes as one of the coupling partners,
carbon atoms, catalytic propargylic C H amination would
also allow preparation of propargylamines bearing a quater-
nary carbon center at the propargylic position. While metal-
catalyzed amination has been successfully demonstrated with
[7]
À
several different types of C H substrates, few catalytic
systems are known for chemoselective amination of prop-
Because of the electrophilic
nature of the key metallonitrene intermediates, its addition to
3
[8a,9]
À
argylic C(sp ) H bonds.
ꢀ
more-electron-rich C C bonds would be typically preferred
[8]
À
over amination of the propargylic C H s bonds. By
decreasing the electrophilicity of the corresponding Rh2/
nitrene intermediates through replacement of the sulfamates
with carbamates, Schomaker and co-workers reported that
À
intramolecular propargylic C H amination of homopropar-
gylic carbamates could be successfully catalyzed by [Rh2-
(esp)2] in combination with PhI(OAc)2 and MgO, thus
generating five-membered propargylamine derivatives in
good yields.[9a] However, because of the competitive electro-
philic addition of Rh2/nitrene intermediates to the electron-
[8a]
ꢀ
rich C C bonds under these catalytic conditions,
the
À
intramolecular propargylic C H amination of sulfamates
gave the corresponding six-membered propargylamines in
only moderate yields.[8a,9a] It should be noted that the ring size
[*] Prof. Dr. H. J. Lu, Dr. C. Li, Dr. H. Jiang, C. L. Lizardi,
Prof. Dr. X. P. Zhang
À
of the resulting heterocycles from intramolecular C H
Department of Chemistry, University of South Florida
Tampa, FL 33620-5250 (USA)
E-mail: xpzhang@usf.edu
amination is typically governed by the substrate geometry
and lengths of the tethers.[7a]
Cobalt(II) complexes of porphyrins, [Co(Por)], which
exist as stable metalloradicals, have emerged as a new class of
catalysts which have proven to be effective for activating
azides as nitrene sources for amination of various types of
Prof. Dr. H. J. Lu
Institute of Chemistry and BioMedical Sciences
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210093 (China)
E-mail: hongjianlu@nju.edu.cn
À
C H bonds, including challenging primary and electron-
deficient C H bonds.[10,11] Different from electrophilic metal-
À
[**] We are grateful for financial support from the NSF (CHE-1152767)
and NIH (R01-GM098777).
lonitrene intermediates associated with Rh2-catalyzed sys-
tems, the cobalt(II)-based metalloradical amination has been
demonstrated to proceed through a stepwise radical mecha-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400557.
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nism.[12] Consequently, it has been shown that the reactivity
and selectivity profile of the cobalt(II)-based amination
acceleration in a cobalt(II)-based MRC.[11a–e] It is worth
emphasizing the operational simplicity and cleanness of the
cobalt(II)/azide-based system, which gave rise to a catalytic
process where the desired product 2a existed as the sole
compound after completion of the reaction.
system is governed by the bond dissociation energy (BDE)
[11a–c]
À
rather than electron density of the reacting C H bonds.
This concept of metalloradical catalysis (MRC) has been
successfully applied to address chemoselectivity issues in
Under the optimized reaction conditions (2 mol% of
[Co(P1)] in benzene at 408C for 20 h), the intramolecular
propargylic amination was shown to be applicable to the
sulfamoyl azides 1 having various N substitutions (Table 1).
For example, the substrates containing electron-donating N-
alkyl substituents, whose corresponding sulfamides would be
degraded under the [Rh2(esp)2]/PhI(OAc)2/MgO catalytic
system,[17] were suitable substrates for the cobalt(II)-based
À
intramolecular allylic C H amination versus competitive
[11b]
=
C C aziridination.
Considering the fact that the BDE of
À
secondary propargylic C H bonds is similar to that of
À1 [13]
À
secondary allylic C H bonds ( ꢁ 83 kcalmol ), we antici-
pated the possibility of chemoselective amination of prop-
À
argylic C H bonds through cobalt(II)-based MRC if the
ꢀ
radical addition of the cobalt(II)/nitrene radical to C C
À
bonds could be disfavored. Herein, we report that [Co(Por)]
catalysts are effective for intramolecular amination of sulfa-
moyl azides with complete control of the chemoselectivity for
metalloradical system, as shown by the chemoselective C H
amination reactions of sulfamoyl azides with N-benzyl (2a),
N-methyl (2b), N-ethyl (2c), N-isopropyl (2d), N-allyl (2n),
and N-butyl (2p) substituents. Additionally, the propargylic
À
ꢀ
propargylic C H bonds without direct reaction at the C C
À
À
bond or other common C H bonds (Scheme 1).
C H bonds in sulfamoyl azides with electron-withdrawing
N substituents were also successfully aminated with complete
chemoselectivity, as exemplified by the high-yielding forma-
Table 1: Synthesis of functionalized propargylamine derivatives from
À
Scheme 1. Synthesis of propargylamines by catalytic C H amination.
À
chemoselective propargylic C H amination of sulfamoyl azides cata-
lyzed by [Co(P1)].[a,b]
At the onset of our study, the N-bishomopropargylic
sulfamoyl azide 1a[14,15] was used as the initial substrate for
À
intramolecular C H amination by [Co(Por)] (Scheme 2). We
were delighted to find that intramolecular amination of the
À
secondary propargylic C H a to the unprotected terminal
alkyne in 1a was catalyzed by [Co(TPP)] (2 mol% at 408C),
thus forming the corresponding propargylamine 2a in a mod-
erate yield (42%). The catalytic reaction exhibited complete
À
chemoselectivity toward propargylic C H amination, without
À
competitive homopropargylic C H amination and addition to
ꢀ
the C C bond. When [Co(P1)], in which the D2h-symmetric
porphyrin ligand 3,5-DitBu-IbuPhyrin P1 is functionalized
with amide functionalities, as hydrogen-bonding donors, at
the ortho-positions of the meso-phenyl groups,[16] was used as
the catalyst, the yield for chemoselective formation of 2a was
dramatically improved to near quantitative. This result
represents another demonstration of hydrogen-bonding
[a] Performed in C6H6 at 408C for 20 h using 2 mol% [Co(P1)] under N2
in the presence of 4 ꢀ M.S.; [azide 1]=0.10m. [b] Yield of isolated
products. [c] 5 mol% [Co(P1)], azide 1e=1.0 mmol. [d] 808C for 3 h.
[e] Yield of isolated products after repeating the reaction three times
without isolating the catalyst. [f] d.r.=68:32. Boc=tert-butoxycarbonyl,
TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
Scheme 2. Ligand effects on the [Co(Por)]-catalyzed intramolecular
À
propargylic C H amination of sulfamoyl azide. M.S.=molecular
sieves.
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tion of the six-membered propargylamine 2e from the
corresponding N-Boc-protected azide on a 1.0 mmol scale.
This result indicates that the radical reactivity of the
corresponding cobalt(III)/nitrene radical intermediate
remained the dominant factor despite its increased electro-
philicity owing to the presence of the electron-withdrawing
N substituent.
The BDEs were recognized as a fundamentally important
factor in metalloradical amination for controlling and differ-
[11]
À
entiating reactivity and selectivity of various C H bonds.
This governing principle was also well demonstrated in the
current catalytic system, [Co(P1)], for regioselective amina-
À
tion of the propargylic C H bonds of sulfamoyl azides
(Table 1). Previous reports indicated that the normal aliphatic
À
À
Moreover, the cobalt(II)-catalyzed chemoselective C H
C H bonds, including primary, secondary, and tertiary
3
À
amination could be applied to a wide range of sulfamoyl
azides bearing different alkyne elements (Table 1). In addi-
tion to the azides with terminal alkynes (2a, 2e, 2n, and 2p–
s), the catalytic system was also suitable for azides derived
from internal alkynes with various substituents, as demon-
strated by the high-yielding amination reactions of alkynes
substituted with aryl (2b–d and 2h–j), alkyl (2 f and 2l), and
silyl (2g and 2o) groups. It should be noted that the sulfide
group in the azide 1i was well tolerated because of the non-
oxidative conditions. Furthermore, intramolecular propar-
C(sp ) H bonds, could also be effectively aminated by
[Co(P1)] under similar reaction conditions.[11a] As a result of
the lower BDE of propargylic C H bonds (BDE of prop-
À
À1
À
À
argylic C H bonds: ca. 85 kcalmol ; BDE of aliphatic C H
bonds: ca. 98 kcalmolÀ1),[13] we showed that the intramolec-
À
ular amination of propargylic C H bonds could be selectively
catalyzed by [Co(P1)] in the presence of different types of
aliphatic C H bonds (Table 1). Using the N-benzyl-N-bis-
homopropargylic sulfamoyl azide 1o as an example, the co-
À
balt(II)-based metalloradical system achieved the highly
À
À
gylic C H amination of the enyne-based sulfamoyl azide 1k
selective 1,6-amination of the propargylic C H bonds in 1o
3
À
could also be chemoselectively catalyzed by [Co(P1)], thus
forming the propargylamine 2k without affecting the con-
jugated enyne functionality. The high degree of functional-
group tolerance and chemoselectivity of the cobalt(II)-based
metalloradical system was further demonstrated with the
amination of the sulfamoyl azide 1l containing an unpro-
tected propargylic secondary alcohol; remarkably, the cata-
lytic reaction afforded the desired propargylic amine 2l in
excellent yield without any side reactions from the propar-
without amination of the much stronger primary C(sp ) H
2
À
bonds and aromatic C(sp ) H bonds located the same
number of carbon atoms away. Similarly, highly regioselective
propargylic amination was accomplished in the presence of
acyclic and cyclic secondary C(sp ) H bonds, as shown with
the catalytic reactions of 1p and 1q, respectively.
In addition to the above examples of various sulfamoyl
azides with secondary propargylic C H bonds for formation
3
À
À
of propargylamines containing a tertiary carbon atom, the
À
À
gylic alcohol unit. It is noted that the intramolecular C H
cobalt(II)-catalyzed 1,6-C H amination process worked
À
amination of the corresponding carbamate with the similar
propargylic alcohol unit was shown to be problematic for the
Rh2-based catalytic system.[9] Surprisingly, the cobalt(II)-
catalyzed system could be extended to the 1-bromoalkyne-
derived sulfamoyl azide 1m, thus forming the corresponding
amination product 2m in a high yield with no complication
from the bromoethynyl functional group. The outstanding
equally well with tertiary propargylic C H substrates, as
illustrated by the effective amination reaction of the sulfa-
moyl azide 1s, which gave the corresponding propargylamine
2s containing a synthetically challenging quaternary carbon
center in 92% yield (Table 1).[19]
This cobalt(II)-based MRC intramolecular propargylic
C H amination presents a practical route to access various
À
À
chemoselectivity toward propargylic C H amination was
unsymmetric cyclic sulfamide derivatives (2). In view of the
impressively diverse array of biological activities of cyclic
sulfamide-containing compounds reported in numerous
recent patents,[20] the products 2, bearing other functionalities
in addition to the highly versatile alkyne functional groups,
may serve as valuable synthetic intermediates for applications
in biology and medicine. Furthermore, the neutral and non-
oxidative reaction conditions of the cobalt(II)-based catalytic
system may allow direct use of substrates which have
pharmaceutical relevance and often contain various function-
alities. For example, the [Co(P1)] catalyst could be success-
fully utilized for intramolecular amination of the deoxyur-
idine-based substrate 1t, thus providing the new deoxyuridine
derivative containing the cyclic sulfamide 2t in 90% yield
(Scheme 3). When the reaction was scaled up to 0.65 mmol
and with a lower catalyst loading (0.5 mol%), a similarly high
yield (88%) was obtained in 70 hours. Given that the variants
of deoxyuridine, such as idoxuridine and trifluridine, have
been used as antiviral drugs,[21] this type of modification of
deoxyuridine may offer an attractive opportunity for obtain-
ing new compounds having interesting biological activities.
Such a high degree of functional-group tolerance exhibited by
further highlighted by the catalytic reactions of the sulfamoyl
azide 1n with an N-allyl substituent. Despite the existence of
both alkene and alkyne functionalities, which are normally
prone to electrophilic addition, [Co(P1)] chemoselectively
À
aminated the propargylic C H bond without affecting the
=
ꢀ
potentially reactive C C and C C bonds. The multifunctional
propargylic amine products such as 2k–n may serve as
intermediates for the synthesis of other useful amine deriv-
atives. For example, 2l may allow access to the corresponding
allenic amine, which is difficult to prepare.[9a] In addition to
chemoselectivity, our preliminary results also demonstrated
À
the possibility of controlling the enantioselectivity of the C H
amination process through the employment of cobalt(II)
complexes of D2-symmetric chiral amidoporphyrins [Co(D2-
Por*)] as chiral metalloradical catalysts (see Table S1 in the
Supporting Information).[18] Furthermore, to enhance the
practicality of the catalytic system, the amination reaction of
azide 1j was successfully repeated three times without
isolating the catalyst [Co(P1)], thus affording the desired
product 2j in similarly high yields (see Table S2 in the
Supporting Information).
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À
Scheme 3. Application of catalytic propargylic C H amination for
deoxyuridine-based sulfamoyl azide. Bz=benzoyl.
cobalt(II)-based MRC should increases the potential of this
catalytic system for synthetic applications.
As another exploration of their synthetic applications, the
products 2 could serve as convenient precursors for the
synthetically valuable 1,3-diamines. For example, the -SO2-
bridging unit in 2e could be conveniently opened on
a 0.9 mmol scale by alcohols such as 2,2,2-trichloroethanol
in the presence of DMAP,[17] thus providing the corresponding
alkyne-containing 1,3-diamine 3e in a high yield (Scheme 4).
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diamine with different protecting groups. DMAP=4-(N,N-dimethyl-
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Since the two amine units in 3e are differentially protected by
Boc and Tces groups, it should be easily transformed into
various 1,3-diamine derivatives by utilizing known trans-
formations for alkynes.
In summary, we have demonstrated for the first time
a chemoselective catalytic system using cobalt(II)-based
À
[5] For synthesis of propargylamines through alkynylation of C H
metalloradical catalysis for intramolecular amination of
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3
À
propargylic C(sp ) H bonds of N-bishomopropargylic sulfa-
moyl azides. The metalloradical catalyst [Co(P1)] is highly
effective for chemoselective amination of different types of
À
propargylic C H bonds with excellent regioselectivity, thus
affording six-membered cyclic sulfamides, with unaffected
alkyne substituents, in excellent yields.[22] In addition to the
alkyne functionality, the cobalt(II)-based metalloradical ami-
nation, which operates under neutral and non-oxidative
conditions, has been shown to tolerate a range of other
functional groups, including alkenes and unprotected alco-
hols. The resulting tertiary and quaternary carbon-containing
propargylamine products from this new catalytic process may
find a myriad of synthetic applications.
[6] For examples of A3-coupling using activated acyclic ketones as
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Received: January 18, 2014
Revised: March 16, 2014
Published online: May 19, 2014
Keywords: alkynes · chemoselectivity · cobalt · heterocycles ·
.
homogeneous catalysis
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