Transition metal-free intermolecular a-C-H amination of ethers at room temperature

Article abstract of DOI:10.1002/adsc.201400646

We describe a new method for the intermolecular amination of the α-C-H bonds of ethers. A hypervalent iodine reagent was used as oxidant to enable the amination of cyclic and acyclic alkyl ethers with a wide range of amides, imides, and amines. The amination occurred at room temperature and without a transition metal catalyst. The method could be used to synthesize the anti-cancer prodrug Tegafur and its analogues.

Full text of DOI:10.1002/adsc.201400646

COMMUNICATIONS
DOI: 10.1002/adsc.201400646
À
Transition Metal-Free Intermolecular a-C H Amination of
Ethers at Room Temperature
Ivan Buslova and Xile Hua,*
a
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fꢀdꢀrale de Lausanne (EPFL), SB-ISIC-LSCI, BCH 3305, CH-1015 Lausanne, Switzerland
Fax : (+41)-(0)21-693-9305; phone: (+41)-(0)21-693-9781; e-mail: xile.hu@epfl.ch
Received: July 3, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400646.
Abstract: We describe a new method for the inter-
molecular amination of the a-C H bonds of ethers.
(THF) and ethers, but the reactions required illumina-
tion and heating at 708C and only purines were alky-
lated.[17] Ochiai and co-workers reported metal-free
À
A hypervalent iodine reagent was used as oxidant
to enable the amination of cyclic and acyclic alkyl
ethers with a wide range of amides, imides, and
amines. The amination occurred at room tempera-
ture and without a transition metal catalyst. The
method could be used to synthesize the anti-cancer
prodrug Tegafur and its analogues.
À
a-C H amination of ethers, but only the triflylamino
group could be transferred.[18] Herein, we report
a mild and general method for the transition metal-
À
free direct C H amination of ethers using a hyperva-
lent iodine reagent[19] as the sole oxidant at room tem-
perature (Scheme 1). The protocol has a wide sub-
strate scope, especially on the nitrogen-containing re-
action partners. The resulting aminated ethers can
serve as valuable synthetic intermediates to a,w-
amino alcohols[20] and modified THF-containing natu-
ral products.[21,22] The introduction of an alkyl ether
moiety on a biologically active amine molecule may
enhance the latter compoundꢁs lipophilicity. Thus, the
À
Keywords: amination; C H functionalization; hy-
pervalent iodine; nucleosides; radicals
Nitrogen is ubiquitous in pharmaceuticals, natural current amination method can be a useful tool in me-
products and materials. The preparation of nitrogen- dicinal chemistry. Indeed, a number of aminated THF
containing molecules is therefore a major task in syn- derivatives are anti-viral and anti-tumor agents
thetic chemistry. In recent years, direct C H amina- (Scheme 2).[23–26] Fuchigami et al. reported several ex-
À
tion has emerged as an attractive method for the con- amples of amination of THF with alkylamines using
[1–6]
À
struction of new C N bonds.
Compared with con- electrochemical oxidation; however, the conversions
ventional amination methods, C H amination avoids and yields were low.[27] Feldman et al. reported
the pre-installation of transformable functional a single example of amination of THF with cyclohex-
groups so that it is potentially more efficient and envi- yltosylamide in a 45% yield using an alkynyliodonium
ronmentally more friendly. Transition metal catalysis triflate as oxidant.[28] Yu and co-workers reported to-
plays a dominant role in this area, however, transition sylamination of cyclic ethers using a Cu catalyst and
À
À
metal-free C H amination methods are desirable al- PhIACTHNUTRGNEUNG
(OAc)2 as oxidant.[20] Compared with these prece-
ternatives because they do not require expensive or dents, our method is much more convenient, general,
toxic metal in the synthesis.[7] Although a number of and synthetically useful.
À
À
transition metal-free intermolecular C H amination
The direct a-C H amination of THF (1a) with N-
reactions have been reported,[7–16] the scope of these benzylmethanesulfonamide (2a) was used as the test
transformations is still narrow. For example, the nitro- reaction (Table 1). This formal oxidative coupling[29]
gen sources were limited to N-haloamines, phthali- requires both an oxidant and a hydrogen acceptor.
mides, sulfonamides and some specific nitrogen het-
erocycles. Moreover, amination mostly worked on ac-
À
tivated aryl, benzylic, and allylic C H bonds. Amina-
3
À
tion of other C
N
Guo and co-workers developed the metal-free
À
direct alkylation of purines with tetrahydrofuran Scheme 1. Intermolecular a-C H amination of ethers.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Ivan Buslov and Xile Hu
We found that the amination product could be ob-
tained by applying a one-pot, two-step reaction proce-
dure. For example, deprotonation of N-benzylmeth-
AHCTUNGTREGaNNUN nesulfonamide by NaH followed by oxidation by (di-
acetoxyiodo)benzene (DIB), both in THF and at
room termperature, gave 3a in a 43% yield (entry 1,
Table 1). Other oxidants such as O2, K2S2O8 and I2
were ineffective (entries 2–5, Table 1). The yield
could be improved to 85% and 87%, using Ph2IOTf
and Ph2IPF6 as the oxidant, respectively (entries 6 and
7, Table 1). NaH was the optimal base; replacement
of NaH with Cs2CO3, KO-t-Bu, or NaOH led to di-
minished yields (entries 8–10, Table 1). THF was the
best solvent; reactions carried out in dichlorome-
thane, dichloroethane, ethyl acetate and toluene using
10 equiv. of THF as the reagent were inefficient (en-
tries 11–14, Table 1). However, an encouraging yield
of 66% was obtained when the amination reaction
was carried out in acetonitrile (MeCN) using
10 equiv. of THF at 408C (entries 15–17, Table 1).
Without the base, no product was formed (entry 18,
Table 1).
Scheme 2. Selected examples of aminated THF derivatives
that exhibit biological activity.
The optimized reaction protocol (entry 7, Table 1)
was then applied for the amination of THF (1a) with
a wide range of sulfonamides (Table 2). To our de-
light, aryl-, benzyl-, allyl-, and alkyl-substituted mesyl-
amines all could be alkylated (3a–3h, Table 2). Both
Table 1. Optimization of reaction conditions.[a]
primary and secondary alkylACTHNUGRTNEUNG(mesyl)amines were effi-
cient reaction partners, giving high yields of amina-
tion products (3b and 3d, Table 2). An alkyl group
containing a terminal double bond was tolerated with-
out isomerization (3d, Table 2). A tert-butyl-substitut-
ed mesylamine was coupled in a modest yield of 39%
(3c, Table 2), probably due to the steric encumbrance
of the tertiary alkyl group. A similar scope was found
for the coupling of tosyl amines (3i–3n, Table 2).
Alkyl-, benzyl-, allyl-substituted tosylamines could be
used. Nosylamines, however, could not be alkylated,
and the starting sulfonamides could be recovered at
the end of the reactions. The unreactivity of nosyla-
Entry
Base
Oxidant
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
NaH
NaH
NaH
NaH
NaH
NaH
NaH
KO-t-Bu
Cs2CO3
NaOH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
–
DIB
I2
I2/DIB
K2S2O8
O2
THF
THF
THF
THF
THF
THF
THF
THF
43
–
36
–
–
85
87
38
Ph2IOTf
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IPF6
Ph2IOTf
9
THF
THF
25
18
10
11
12
13
14
15
16
17
18
5[c]
<1[c]
12[c]
4[c]
66[e]
40[c]
37[d]
–
À
CH2Cl2
ClC2H4Cl
EtOAC
toluene
MeCN
MeCN
MeCN
THF
mines suggests that the acidity of the amine N H
bond is not the only determining factor in this type of
direct amination reaction.
The scope of the amine partner was then expanded
to include acetamides and trifluoroacetamides. Grati-
fyingly, the reaction protocol was efficient for the
direct amination of THF using these amides
(Table 3). Increasing the amount of Ph2IPF6 to
1.5 equiv, was beneficial. Alkyl-, allyl-, benzyl- and
aryl-substituted amides could be coupled in good
yields (5a–5h, Table 3). The functional group toler-
ance was demonstrated with arylacetamides. Ester, ni-
trile, CF3, aryl-I, aryl-Br, and ether groups were all
compatible (5i–5n, Table 3). N-(6-Methylpyridin-2-
yl)acetamide was also successfully alkylated (5o,
Table 3). The phenol group was not tolerated due to
competitive O-arylation. Significantly, the bulky tert-
[a]
Reaction conditions: under N2, deprotonation of 2a
(0.25 mmol) with base (0.25 mmol) in THF (1 mL) at
room tempeature for 1 h, then addition of oxidant
(0.3 mmol) and reaction at room temperature for 10 h.
Calibrated GC yield using n-dodecane as an internal
standard.
THF (2.5 mmol) in 1 mL of solvent, room temperature,
12 h.
THF (1.25 mmol) in 1 mL of MeCN, 408C, 6 h.
THF (2.5 mmol) in 1 mL of MeCN, 408C, 6 h.
[b]
[c]
[d]
[e]
2
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

À
COMMUNICATIONS
Transition Metal-Free Intermolecular a-C H Amination of Ethers
Table 2. Amination of THF with sulfonamides.[a]
Table 3. Amination of THF with acetamides and trifluoro-
AHCTUNGTRENNUNG
acetamides.[a]
[a]
Reaction conditions: under N2, deprotonation of a sulfon-
ACHTUNGTRENNUNGamide (0.5 mmol) with NaH (0.5 mmol) in 1 mL of THF
at room temperature for 1 h, then addition of Ph2IPF6
(0.6 mmol) in 1 mL of THF and reaction at room temper-
ature for 6 h, yields are of isolated products.
[b]
Yield of two diastereomers (3f and 3g).
[a]
[b]
Reaction conditions: under N2, deprotonation of an
amide (0.5 mmol) with NaH (0.5 mmol) in 1 mL of THF
at room temperature for 3 h, addition of Ph2IPF6
(0.75 mmol) in 1 mL of THF and reaction at room tem-
perature for 6 h, the yields are of isolated products.
Ph2IPF6 (0.6 mmol) was added to potassium phthalimide
(0.5 mmol) in 2 mL of THF and reaction at 408C for
12 h.
butyl-trifluoroacetamide was coupled to afford a good
yield of 58% (5f, Table 3). The reaction with N-
benzyl-trifluoroacetamide (4h) was repeated in
a 5 mmol scale leading to an 80% isolated yield of the
desired
acetamide (5h). It is noted that aryl-substituted
amides were coupled in very high yields, i.e., in the
N-benzyl-N-(tetrahydrofuran-2-yl)trifluoro-
ACHTUNGTRENNUNG
range of 90%. Finally, the commercially available po- 2-Methyltetrahydrofuran presented an interesting test
tassium phthalimide could be coupled in a 75% yield for chemoselectivity. An amination occurred with 4:1
À
in a modified procedure (without the base) (5p, selectivity favoring the sterically less encumbered C
Table 3).
H bond at the 4 position (8e, Table 5). No diastereo-
À
The a-C H amination method could be applied on selectivity was observed.
free secondary amines without a sulfonyl or acyl The direct amination also worked on acyclic ethers
groups (Table 4). Imidazole, benzimidazole, indole, such as dimethoxyethane (DME). The internal C H
and carbazole could be alkylated in good to excellent bonds were preferentially aminated (8f–8h, Table 5).
yields. Aromatic amines worked better in these reac- Unfortunately diethyl ether and methyl tert-butyl
À
tions.
ether could not be aminated in reasonable yields
Alkyl ethers other than THF were then tested for using this protocol, probably due to the low solubility
the direct amination reactions (Table 5). 1,4-Dioxane of the other reagents in these solvents.
À
could be aminated in good yields (8a–8b, Table 5).
Tetrahydropyran was also aminated (8c–8d, Table 5). for the synthesis of biologically active molecules in-
The new a-C H amination protocol was applied
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Ivan Buslov and Xile Hu
Table 4. Amination of THF with secondary amines.[a]
first tested (Table 6). The corresponding nucleoside
analogue was obtained in 85% yield. The PMB group
on the thymine was difficult to remove.
The more labile Boc group was used as the protect-
ing group for the nucleobases. N3-Boc-5-fluorouracil
was synthesized in two steps and was then reacted
with different alkyl ethers (Table 6). Reaction with
THF provided 10b in a yield of 81%; 10b was then
converted quantitatively to N1-(tetrahydrofuran-2-yl)-
5-fluorouracil, Tegafur, by heating at 758C in isopro-
pyl alcohol. Alkylation with tetrahydropyran, dioxane,
and DME also worked, albeit with lower yields.
Therefore, this amination method might be useful for
the rapid derivatization of biologically active com-
pounds.
[a]
Reaction conditions: under N2, deprotonation of an aro-
matic N-heterocycle (0.5 mmol) with NaH (0.5 mmol) in
1 mL of THF at room temperature for 1 h, then addition
of Ph2IPF6 (0.75 mmol) in 1 mL of THF and reaction at
room temperature for 6 h, the yields are of isolated prod-
ucts.
À
The mechanism of the direct C H amination re-
ported here remains speculative. A radical process is
consistent with some experimental observations. The
amination is completely quenched in the presence of
10 mol% of TEMPO, a radical inhibitor. Lithiated al-
cluding the anti-cancer prodrug Tegafur using nucleo- kylamides failed to undergo amination, likely because
bases as the nitrogen sources. The reaction of para- alkylaminyl radicals are too difficult to generate
methoxybenzoyl-protected thymine with THF was under the reaction conditions. The deuterium kinetic
isotope effect (KIE) was measured in the reaction of
acetanilide (4d) with THF and THF-d8 at room tem-
perature. A primary deuterium KIE of 4.6 was ob-
À
Table 5. Amination of a-C H bonds of various alkyl
ethers.[a]
Table 6. Amination of alkyl ethers with protected 5-methyl-
uracil and 5-fluorouracil.[a]
[a]
Reaction conditions: under N2, deprotonation of sulfon-
amide or amide (0.5 mmol) with NaH (0.5 mmol) in
ACHTUNGTRENNUNG
2 mL of the corresponding ether at room temperature
for 3 h, then addition of Ph2IPF6 (0.75 mmol) and reac-
tion at room temperature for 6 h, the yields are of isolat-
ed products.
Ph2IPF6 (0.6 mmol) was added to potassium phthalimide
(0.5 mmol) in 2 mL of dioxane, 10 h, 608C.
Combined yield of diastereomers.
[a]
Reaction conditions: under N2, deprotonation of protect-
ed uracil derivative (0.5 mmol) with NaH (0.5 mmol) in
2 mL of the corresponding ether at room temperature for
3 h, then addition of Ph2IPF6 (0.85 mmol) and reaction at
room temperature for 6 h, the yields are of isolated prod-
ucts.
[b]
[c]
[d]
Yield of major regioisomer.
4
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

À
COMMUNICATIONS
Transition Metal-Free Intermolecular a-C H Amination of Ethers
served. This significant value of KIE suggests that the may be operating. In route I, D reacts with amidyl
rate-determining step involves the breaking of a-C H anion to form the corresponding anion-radical (E)[31]
À
bond. Given previously proposed mechanisms for the which is easily oxidized by diphenyliodonium cation
[20,27,28]
À
a-C H amination of ethers
and the specific re- to the amination product generating the diphenyl
action conditions described here, we considered sever- iodide radical (C) again and propagating the radical
al possible reaction pathways shown in Figure 1. The chain process [Eq. (4) and Eq. (5), Figure 1]. In route
salt metathesis reaction between Ph2IPF6 and sodium II, the THF radical D is oxidized by diphenyliodoni-
amide gives an ionic complex of diphenyliodonium um cation to give an oxonium ion (F) and radical C
and amide (A). Oxidation of the amide by the diphe- which also propagates the radical chain process [Eq.
nyliodonium oxidant via single electron transfer (6), Figure 1]. Reaction of F with amide then gives
(SET) then yields an aminyl radical (B) and a diphen- the amination product [Eq. (7), Figure 1].
yl iodide radical (C) [Eq, (1), Figure 1]. Radical C de-
In summary, we have developed a mild and effi-
À
composes to give PhI and Ph radical [Eq. (2), cient method for the intermolecular a-C H amination
Figure 1]. It is known that aminyl radicals are poor of cyclic and acyclic alkyl ethers. The method allows
hydrogen atom abstractors[30] so abstraction of hydro- direct amination with a wide range of sulfonamides,
gen atom from THF by B is unlikely. Instead, the amides, imide, and secondary amines with alkyl, aryl,
phenyl radical should react with THF to give the allyl, and benzyl substituents. The utility of this
THF radical D [Eq. (3), Figure 1]. Although combina- method was demonstrated in the synthesis of Tegafur
tion of the two radicals, B and D, can lead to the for- and its analogues. This transition metal-free method
mation of the amination product, due to the low con- provides a rapid access to a large number of nitrogen-
centration of both radical species, this pathway plays containing organic molecules that may serve as useful
no major role here. Instead, two alternative pathways synthetic intermediates or biologically active mole-
cules.
Experimental Section
À
General Procedure for the a-C H Bond Amination
of Alkyl Ethers
To a suspension of sodium hydride (60% dispersion in min-
eral oil, 20 mg, 0.5 mmol) in 2 mL of dry alkyl ether an
amide or sulfonamide (0.5 mmol) was added at room tem-
perature under nitrogen. After stirring for 3 h at room tem-
perature Ph2IPF6 (319 mg, 0.75 mmol) was added and the re-
action mixture was stirred for 6 h. The solvent was removed
under reduced pressure and resulting solid was subjected to
the column chromatography (silica gel) to afford the prod-
uct.
Acknowledgements
This work is supported by the EPFL.
References
[1] H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417–
424.
[2] M. Dꢃaz-Requejo, P. Pꢀrez, Chem. Rev. 2008, 108,
3379–3394.
[3] F. Collet, R. Dodd, P. Dauban, Chem. Commun. 2009,
5061–5074.
[4] D. Zalatan, J. Du Bois, Top. Curr. Chem. 2010, 292,
347–378.
[5] J. Du Bois, Org. Process Res. Dev. 2011, 15, 758–762.
[6] R. T. Gephart, T. H. Warren, Organometallics 2012, 31,
Figure 1. Proposed reaction pathways for the direct amina-
tion of alkyl ethers.
7728–7752.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Ivan Buslov and Xile Hu
[7] R. Samanta, K. Matcha, A. P. Antonchick, Eur. J. Org.
Cherm. 2013, 2013, 5769–5804.
[8] R. Fan, W. Li, D. Pu, L. Zhang, Org. Lett. 2009, 11,
1425–1428.
[19] V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299–
5358.
[20] L. He, J. Yu, J. Zhang, X.-Q. Yu, Org. Lett. 2007, 9,
2277–2280.
[9] H. Kim, J. Kim, S. Cho, S. Chang, J. Am. Chem. Soc.
2011, 133, 16382–16385.
[10] Y. Yan, Y. Zhang, C. Feng, Z. Zha, Z. Wang, Angew.
Chem. 2012, 124, 8201–8205; Angew. Chem. Int. Ed.
2012, 51, 8077–8081.
[21] A. Lorente, J. Lamariano-Merketegi, F. Albericio, M.
Alvarez, Chem. Rev. 2013, 113, 4567–4610.
[22] D. Liu, C. Liu, H. Li, A. W. Lei, Angew. Chem. 2013,
125, 4549–4552; Angew. Chem. Int. Ed. 2013, 52, 4453–
4456.
[11] T. Youhei, H. Junpei, Y. Kazuki, M. Satoshi, Chem.
[23] R. J. Haslam, M. M. L. Davidson, J. V. Desjardins, Bio-
chem. J. 1978, 176, 83–95.
Lett. 2012, 41, 1672–1674.
[12] J. Souto, D. Zian, K. MuÇiz, J. Am. Chem. Soc. 2012,
134, 7242–7245.
[24] T. A. Rich, R. C. Shepard, S. T. Mosley, J. Clin. Oncol.
2004, 22, 2214–2232.
[13] Q. Xue, J. Xie, H. Li, Y. Cheng, C. Zhu, Chem.
Commun. 2013, 49, 3700–3702.
[14] A. P. Antonchick, R. Samanta, K. Kulikov, J. Lategahn,
Angew. Chem. 2011, 123, 8764–8767; Angew. Chem. Int.
Ed. 2011, 50, 8605–8608.
[25] J. C. Martin, M. J. M. Hitchcock, E. De Clercq, W. H.
Prusoff, Antiviral Res. 2010, 85, 34–38.
[26] E. De Clercq, Rev. Med. Virol. 2009, 19, 287–299.
[27] T. Fuchigami, T. Sato, T. Nonaka, J. Org. Chem. 1986,
51, 366–369.
[15] R. Samanta, J. Bauer, C. Strohmann, A. Antonchick,
[28] K. S. Feldman, M. M. Bruendl, K. Schildknegt, A. C.
Bohnstedt, J. Org. Chem. 1996, 61, 5440–5452.
[29] C. Liu, H. Zhang, W. Shi, A. W. Lei, Chem. Rev. 2011,
111, 1780–1824.
Org. Lett. 2012, 14, 5518–5521.
[16] M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi, W.
Nakanishi, Science 2011, 332, 448–451.
[17] H.-M. Guo, C. Xia, H.-Y. Niu, X.-T. Zhang, S.-N. Kong,
D.-C. Wang, G.-R. Qu, Adv. Synth. Catal. 2011, 353,
53–56.
[30] M. Newcomb, in: Encyclopedia of Radicals in Chemis-
try, Biology and Materials, John Wiley, Chichester,
2012, pp 1–18.
[18] M. Ochiai, S. Yamane, M. Hoque, M. Saito, K. Miya-
moto, Chem. Commun. 2012, 48, 5280–5282.
[31] R. A. Rossi, A. B. Pierini, A. B. Penenory, Chem. Rev.
2003, 103, 71–167.
6
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
À
Transition Metal-Free Intermolecular a-C H Amination of
Ethers at Room Temperature
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Ivan Buslov, Xile Hu*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!