Copper-catalyzed intermolecular trifluoromethylazidation of alkenes: Convenient access to CF3-containing alkyl azides

Article abstract of DOI:10.1002/anie.201309991

A novel copper-catalyzed intermolecular trifluoromethylazidation of alkenes has been developed under mild reaction conditions. A variety of CF ₃-containing organoazides were directly synthesized from a wide range of olefins, including activated and unactivated alkenes, and the resulting products can be easily transformed into the corresponding CF₃- containing amine derivatives. The title reaction proceeds with a CF ₃⁺ reagent under mild reaction conditions. This transformation presents a broad substrate scope and good functional-group tolerance. A variety of CF₃-containing organoazides are directly synthesized from a wide range of olefins, including activated and unactivated alkenes. The resulting products are easily transformed into the corresponding amine derivatives. Copyright

Full text of DOI:10.1002/anie.201309991

Angewandte
Chemie
DOI: 10.1002/anie.201309991
Synthetic Methods
Copper-Catalyzed Intermolecular Trifluoromethylazidation of
Alkenes: Convenient Access to CF3-Containing Alkyl Azides**
Fei Wang, Xiaoxu Qi, Zhaoli Liang, Pinhong Chen, and Guosheng Liu*
Dedicated to Professor Huilin Chen on the occasion of his 75th birthday
Abstract: A novel copper-catalyzed intermolecular trifluoro-
methylazidation of alkenes has been developed under mild
reaction conditions. A variety of CF3-containing organoazides
were directly synthesized from a wide range of olefins,
including activated and unactivated alkenes, and the resulting
products can be easily transformed into the corresponding
CF3-containing amine derivatives.
groups can be simultaneously introduced into organic com-
pounds, efficient synthesis of trifluoromethylated organo-
azides and related amine derivatives might be expected, and
might provide an opportunity to introduce CF3 into the
original lead compounds or drugs to adjust their bioactivity.
However, the efficient synthesis of CF3-containing organo-
azides is quite rare.[7] Herein, we report a novel copper-
catalyzed intermolecular trifluoromethylazidation of alkenes
to deliver vicinal CF3-substituted alkyl azides in one step,
where the less reactive Togni reagent II is employed as a CF3
source (Scheme 1). Importantly, broad substrate scope with
respect to the olefins was observed, and a wide range of
functional groups were tolerated under these reaction con-
ditions. These CF3-containing organoazides can be easily
transformed into related amine derivatives.
Orangoazides have been recognized as important organic
compounds and are widely applied in organic synthesis as
valuable intermediates and building blocks because of their
versatile chemical reactivities and bioactivities.[1] For instance,
elegant methodologies have been developed for the trans-
formation of organoazides into nitrogen-containing hetero-
cycles which have extensively been used in pharmaceuticals
and agricultral chemicals.[1a,b,f] Its unique reactivity permits
their use in bioconjugation with click chemistry.[2] In addition,
the azide moiety has been used to design lead compounds for
drug discovery. Representative compounds (A–C) exhibited
some bioactivity, such as enzyme inhibition or antiviral and
disrafting activity (Figure 1).[3] Therefore, the introduction of
an azide group into organic molecules has attracted much
attention.[1a,b,4,5] As we know, the trifluoromethyl group is
prevalent in pharmaceuticals and agrochemicals owing to its
unique properties.[6] We speculated that, if both CF3 and azide
Recently, the groups of Buchwald, Liu, Wang and,
Sodeoka reported copper-catalyzed allylic trifluoromethyla-
tion.[8] Meanwhile, our group reported the first difunctional-
ization of alkenes involving trifluoromethylation using a pal-
ladium catalyst.[9] Since then, a variety of trifluoromethylation
reactions of terminal alkenes have been published.[10] Among
these studies, most of reactions were focused on terminal
electron-rich olefins with limited substrate scope, and
+
employed the very reactive Togni Reagent I as a CF3
source. In addition, a carbon radical or carbon cation
intermediate was proposed to be involved in these reactions
(Scheme 1). Thus, we envisioned that, if this intermediate
could be trapped by an azide reagent, a highly efficient
synthesis of CF3-containing organoazides might be expected.
To test the above hypothesis, initial studies were focused on
the model reaction of styrene (1a) with azidotrimethylsilane
(TMSN3) and a trifluoromethylating reagent in the presence
of a copper catalyst.
As shown in Table 1, screening for the CF3 source implied
that the combination of PhI(OAc)2 with trimethyl(trifluor-
omethyl)silane (TMSCF3) did not deliver the desired trifluor-
Figure 1. Representative bioactive organic azides.
[*] F. Wang, X. Qi, Z. Liang, Dr. P. Chen, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn
[**] We are grateful for financial support from the National Natural
Science Foundation of China (21225210, 21121062, and 20923005),
the National Basic Research Program of China (973-
2011CB808700), the Science Technology Commission of the
Shanghai Municipality (11JC1415000), and the CAS/SAFEA Inter-
national Partnership Program for Creative Research Teams.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309991.
Scheme 1. Trifluoromethylazidation of alkenes.
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Table 1: Optimization of the reaction conditions.[a,b]
Table 2: Substrate scope of the styrenes.[a,b]
Entry
[CF3]
[N3]
Yield [%]
1
2
3
4
5
PhI(OAc)2 + TMSCF3
Umemoto reagent
Togni reagent I
Togni reagent II
Togni reagent II
Togni reagent II
Togni reagent II
Togni reagent II
Togni reagent II
TMSN3
TMSN3
TMSN3
TMSN3
TsN3
0
38
65
88
0
6
NaN3
0
7[c]
8[d]
9[e]
TMSN3
TMSN3
TMSN3
89
77
0
[a] Reaction conditions: 1a (0.1 mmol), Cu catalyst (10 mol%), [N3]
(0.2 mmol), [CF3+] reagent (0.15 mmol) in N,N-dimethylacetamide
(DMA, 0.5 mL) at room temperature. [b] Yield determined by 19F NMR
spectroscopy. [c] Copper(I) catalyst (5 mol%). [d] Copper(I) catalyst
(2 mol%). [e] Without copper catalyst. TMS=trimethylsilyl, TsN3 =4-
methylbenzenesulfonyl azide.
[a] All the reactions were conducted in 0.2 mmol scale. [b] Yield of
isolated product. [c] 3.0 mmol scale. [d] (E)-b-methyl styrene as sub-
strate. [e] (Z)-b-methyl styrene. [f] d.r.=8:1; [g] d.r.=12:1.
omethylazidation product (entry 1).[11] Gratifyingly, the com-
monly used CF3+ reagent, such as the Umemoto reagent and
Togni reagent I, could be used to achieve the intermolecular
trifluoromethylazidation of alkenes (entries 2 and 3). And the
reaction did afford the desired product 2a in 65% yield in the
presence of the Togni reagent I. Unfortunately, a significant
amount of a trifluoromethyl esterification product was also
obtained as a side product, wherein o-iodobenzoic acid,
released from Togni reagent I, was involved in the reac-
tion.[10c] And this side reaction could not be suppressed by
further optimization of the reaction conditions. To address
this issue, the less reactive Togni reagent II was applied and
the reaction afforded 2a in excellent yield (88%, entry 4).
Next, some azide reagents were investigated. Only TMSN3
was proven to be an efficient nitrogen source, and other
reagents, such as TsN3 and NaN3, were ineffective (entries 4–
6). Finally, a survey on metal catalysts demonstrated that
copper salts were active catalysts, and [Cu(CH3CN)4]PF6 was
the best one. There is no significant drop in the yield when the
catalyst loading is lowered to 5 mol%, and good yield (77%)
could be also obtained with only 2 mol% catalyst. No
reaction occurred in the absence of a copper catalyst
(entries 7–9).[12]
With the optimized reaction conditions in hand, the
substrate scope of the styrenes was examined in the presence
of 5 mol% of the copper catalyst and the results are
summarized in Table 2. Substrates 1a–q, having various
substituents (R) on the aromatic ring, including electron-
donating and electron-withdrawing groups, were compatible
with the current transformation. And a series of functional
groups, such as halogen, ester, phenol, nitro, nitrile, carboxylic
acid, aldehyde, were tolerated under the reaction conditions
to give the desired products 2a–q in good yields. In particular,
the substrate 1n, bearing an o-carboxylic acid, delivered the
product 2n in good yield without any of the cyclization
product.[13] In addition, 2-chloro-3-vinylquinoline (1r) was
also suitable for this transformation, thus giving the product
2r in 65% yield. The substrate 1s, with a triazole group,
provided the corresponding product 2s in 95% yield. For the
1,1-disubstituted substrate 1t, the reaction proceeded very
well to give the b-CF3-substituted tertiary alkyl azide 2t in
93% yield. Compared to terminal alkenes, internal alkenes
exhibited slightly lower reactivity. For instance, reactions of
both (E)-1u and (Z)-1u afforded 2u with the same diaste-
reoisomeric ratio (8:1), but in low yield (40 and 33%,
respectively). For the electron-deficient styrene tert-butyl
cinnamate (1v), the reaction also provided the desired
product 2v in moderate yield (45%) and good diastereose-
lectivity (12:1), and it can be further transformed into a CF3-
substituted b-amino acid.
Inspired by the reaction of styrenes, we turned our
attention to expanding the substrate scope to alkyl-substi-
tuted alkenes. First, 1,1-dialkyl substituted alkenes were
surveyed under standard reaction conditions. As shown in
Table 3, to our great delight, a range of 1,1-dialkyl-substituted
alkenes (3a–h) were suitable for this trifluoromethylazidation
reaction and gave the tertiary alkyl azides 4a–h in good yields.
Similar to styrenes, a series of functional groups, such as ester,
ether, imide, and good leaving groups (OTs), were tolerated
under these reaction conditions. However, following a survey
of monoalkyl-substituted alkenes, the desired product was
obtained in low yield. After additional optimization of the
reaction conditions, we were delighted to find that the
reaction yield could be improved by switching the solvent
from DMA to CH3CN (see the Supporting Information). As
shown in Table 3, a number of monoalkyl-substituted alkenes
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Table 3: Substrate scope for acyclic alkenes.[a,b]
Table 4: Substrate scope of the cyclic alkenes.[a,b]
[a] All the reactions were conducted on a 0.2 mmol scale. [b] Yield of
isolated product. [c] CH3OH as solvent. [d] Yield determined by 19F NMR
spectroscopy. [e] Yield of the isolated amine derivatives RNHCbz (one-
pot reaction). [f] Yield of the isolated RNHCOC6H4NO2-p (one-pot
reaction).
4y as the major product in 62% yield and 10:1 regioselec-
tivity.
As mentioned above, the acyclic internal alkenes exhib-
ited slightly poor reactivity. Thus, we turned to cyclic alkenes.
As shown in Table 4, the reactions of cyclic substrates from
five- to eight-membered rings proceeded smoothly to produce
the trifluoromethylated cyclic organoazides 6a–e in good
yields. Importantly, most of these reactions (5a–d) exhibited
excellent diastereoselectivity. In contrast, reaction of the
eight-membered-ring substrate 5e had moderate diastereo-
selectivity (5:1). Notably, as a result of the highly volatile
nature of 6a,b and 6d,e, these products were directly trans-
formed in situ into their amine derivatives for character-
ization. The structure of 6c was determined by X-ray analysis.
For the substrates 5 f,g, the reactions led to the products 6 f,g
in moderate yields with excellent diastereomeric ratios
(> 20:1).
Next, several complex molecules containing an alkenyl
group were selected as candidates for this transformation. As
listed in Table 5, the steroid substrates 7a and 7b, bearing
a cyclic alkenyl group, were compatible under these reaction
conditions and yielded the desired trans-products 8a and 8b,
respectively, in satisfactory yields with excellent regio- and
diastereoselectivity. The structure of 8a was confirmed by X-
ray analysis. The cinchonine derivatives 7c and 7d were also
good candidates for this transformation, thus giving 8c and
8d, respectively, in 50–54% yield with good diastereoselec-
tivity (10:1). However, detailed configurations for 8c and 8d
have not yet been determined. Finally, the alkene substrate 7e
with a sugar moiety and the estrone derivative 7 f afforded the
corresponding organoazide products 8e and 8 f in 45% and
81% yields, respectively, but with low diastereoselectivity
(1:1). All those products could be potentially utilized in
medicinal chemistry.
[a] All the reactions were conducted on a 0.2 mmol scale. [b] Yield of
isolated product. [c] Ratio of regioisomer.
could be transformed into the desired products 4i–q in
moderate to good yields. Again, good functional-group
compatibility was also observed. Furthermore, we postulated
that, if a,b-unsaturated carboxylates were good candidates for
this transformation, a highly efficient method for the synthesis
of CF3-containing a-amino acids might be achieved because
of the easy conversion of an organoazide into an amine. Thus,
several a,b-unsaturated substrates were tested. As shown in
Table 3, all of those substrates were well tolerated under the
reaction conditions and gave the corresponding products 4r–v
in satisfactory yields. Interestingly, the vinyl phosphonic ester
3w delivered the desired product 4w, albeit in aslightly lower
yield (30%). Finally, two conjugated dienes, 3x and 3y, were
treated under the standard reaction conditions, and the
substrate-controlled regioselectivities were observed to pro-
vide either 1,2- or 1,4-addition products. For instance, the
reaction of 3x, bearing an aryl-substituted diene, afforded the
1,2-addition product 4x as the major product in 52% yield
with 7:1 regioselectivity. In contrast, the reaction of 3y with
the alkyl-substituted diene delivered the 1,4-addition product
Sodeoka and co-workers have reported that the reaction
of 9 could yield the CF3-containing oxindole 11 in the
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Table 5: Substrate scope with respect to complex molecules.[a,b]
respectively, by hydrogenation. To achieve the synthesis of
chiral CF3 amino acids, a chiral sulfonylamide (NR*) was
introduced into the substrates. As shown in Equation (5), the
reaction of 15a afforded 16a in 68% yield with a 4:1
diastereomeric ratio. In contrast, reaction of 15b delivered
16b in 59% yield with good diastereomeric ratio (9:1). After
recystallization, the chiral products 16b (d.r. = 13:1) were
further transformed into the related chiral CF3 amino acids
14b in good yields.
[a] All the reactions were conducted on a 0.2 mmol scale. [b] Yield of the
isolated product. [c] TMSN3 (4 equiv) and the Togni reagent II (4 equiv).
[d] Yield based on recovery of 7b and 7e. [e] CH3CN as solvent.
presence of the Togni reagent I [Eq. (1)]. However, no
reaction occurred by replacing the Togni reagent I with the
less reactive Togni reagent II. Interestingly, when 9 was
treated under our reaction conditions, the reaction only
afforded the product 10 in 74% yield. This observation
suggested that the Togni reagent II might be activated by
a TMS group, then reacted with copper(I) to give the CF3
radical species for the subsequent step.[14] In addition, the
alkene substrate 1w, having a cyclopropyl group, also
proceeded well to afford the ring-open product (E)-2w in
good yield and excellent stereoselectivity [Eq. (2)]. For the
alkene 3z, bearing a cyclobutane group, the reaction also
afforded the ring-open product 4z in 71% yield [Eq. (3)].
These experiments also indicate the involvement of a radical
Further transformation of the trifluoromethylazidation
products was investigated. As shown in Scheme 2, both 2a
and 4i reacted with phenyl acetylene by employing copper(I)
as a catalyst to give the CF3-containing triazoles 17a (75%)
and 17i (84%), respectively. In addition, those CF3-contain-
ing azides, such as 2a and 4b, could also be reduced and
protected to deliver trifluoroethyl-substituted amine deriva-
tives in excellent yields. Interestingly, 4p was directly
converted into 5-trifluoroethyl-2-pyrrolidone (18c). Finally,
the CF3-substituted amine of 18d was also obtained from the
reduction of 8b in 86% yield.
À
species in the catalytic process. For the final C N3 bond
formation, either a pathway involving a carbon radical species
trapped by an azide radical or a carbon cation intermediate
reacting with an azide anion, are possible, but it is hard to
differentiate at the moment.
Then, a,b-unsaturated carboxylic acids were subjected to
the standard reaction conditions for the efficient synthesis of
CF3-substituted amino acids. As shown in Equation (4), the
acrylic acids 12a and 12b could be directly converted into the
corresponding 13a and 13b in good yields, and they can be
readily transformed into the CF3-amino acids 14a and 14b,
In summary, we have developed a novel copper-catalyzed
intermolecular trifluoromethylazidation of alkenes, in which
the less reactive Togni reagent II was employed as an oxidant
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Scheme 2. Further transformation of CF3-containing organoazides.
Reaction conditions: 1) In/NH4Cl (2 equiv), MeOH, reflux; 2) CbzCl
(1.1 equiv), Na2CO3 (1.2 equiv), THF, RT; 3) Boc2O (2 equiv), EtOAc.
Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl, THF=tetrahydro-
furan.
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S. L. Buchwald, Angew. Chem. 2011, 123, 9286; Angew. Chem.
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as well as a CF3 source under mild reaction conditions. Both
activated and unactivated alkenes were suitable for this
transformation, and a wide range of functional groups were
tolerated under the reaction conditions. Those CF3-containing
organoazides can be easily converted into the corresponding
amine derivatives. In addition, this method provides an
efficient way to synthesize CF3 amino acids. Further applica-
tion of this reaction is in progress.
[9] X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. Liu, J. Am. Chem. Soc.
2012, 134, 878.
Received: November 18, 2013
Published online: January 13, 2014
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Keywords: alkenes · azides · copper · fluorine ·
synthetic methods
.
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no reaction occurred. See the Supporting Information
(Table S1).
[13] For copper-catalyzed trifluoroesterification of 2n to give the
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[14] Addition of TEMPO could significantly inhibit this trifluoro-
methyl azidation reaction and a CF3-TEMPO adduct was
observed. For more details, see the Supporting Information.
[12] To identify whether this process was triggered by a Lewis acid,
[Cu(CH3CN)4]+PF6À was replaced by Yb(OTf)3 or In(OTf)3, but
1886
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Angew. Chem. Int. Ed. 2014, 53, 1881 –1886