Metal-free tetrahydrofuranylation of alcohols with tertbutyl nitrite

Article abstract of DOI:10.1016/j.tetlet.2020.152251

Metal-free tetrahydrofuranylation of alcohols in the presence of tertbutyl nitrite is described, providing a facile and green route for the protection of hydroxy groups. Mechanistic studies demonstrate that this transformation proceeds in a radical way, and involves alkyl nitrite of corresponding alcohol as the key intermediate.

Full text of DOI:10.1016/j.tetlet.2020.152251

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Metal-free tetrahydrofuranylation of alcohols with tertbutyl nitrite
Kang Bi, Yue-Ming Cai, Yun-Bing Zhou, Junyue Lin, Miao-Chang Liu
PII:
S0040-4039(20)30718-8
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152251
TETL 152251
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 March 2020
6 July 2020
10 July 2020
Please cite this article as: Bi, K., Cai, Y-M., Zhou, Y-B., Lin, J., Liu, M-C., Metal-free tetrahydrofuranylation of
alcohols with tertbutyl nitrite, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152251
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Metal-Free Tetrahydrofuranylation of
Alcohols with Tertbutyl Nitrite
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Kang Bia , Yue-Ming Caia , Yun-Bing Zhoua , Junyue Linb, * and Miao-Chang Liua, *

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Metal-Free Tetrahydrofuranylation of Alcohols with Tertbutyl Nitrite
Kang Bia, Yue-Ming Caia, Yun-Bing Zhoua, Junyue Linb, * and Miao-Chang Liua, *
aCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325035, P. R. of China
bCollege of Chemistry & Chemical Engineering, Jinggangshan University, Jinggangshan, 343600, P. R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Metal-free tetrahydrofuranylation of alcohols in the presence of tertbutyl nitrite is described,
providing a facile and green route for the protection of hydroxy groups. Mechanistic studies
demonstrate that this transformation proceeds in a radical way, and involves alkyl nitrite of
corresponding alcohol as the key intermediate.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Tertbutyl nitrite
Alkoxyl radical
Protection of alcohols
Metal-Free
Tetrahydrofuran
Alcohols have always been a class of important synthetic
precursors in organic synthesis on account of their availability,
variety and abundance on earth. Considering their instability
under harsh reaction conditions, hydroxy groups usually need to
be protected in advance. Among currently existed approaches to
protecting hydroxy groups, tetrahydrofuranylation of alcohols is
getting more attention from organic chemists, since hydrolysis of
THF-ether can proceed under milder conditions in shorter time
compared with well researched THP-group.[1] In 1976, Professor
Gen and coworkers disclosed the first tetrahydrofuranylation of
alcohols in the presence of SOCl2.[2] Then, lots of reaction
conditions applied in tetrahydrofuranylation of alcohols such as
CrCl2,[3] alkylperoxy-λ3-iodane,[4] Mn(0) powder,[5] and VCl3[6] in
the presence of CCl4 were established successively by Falck,
Sueda, Mioskowski and Laxminarayana. In 2013, Deng’s group
developed a CuBr2-promoted alcohol tetrahydrofuranylation,[7]
but it suffered from relatively low yields. Recently, a light-
promoted metal-free cross dehydrogenative coupling between
ethers and alcohols was described by Vincent’ group.[8] The use
nitrogen, the reaction delivered lower yields of 72% and 52%
(Table 1, entry 4 and 5). Raising temperature to 90°C was
beneficial to the yield of 2a (Table 1, entry 6), whereas a further
lift of temperature to 100°C showed no improvement (Table 1,
entry 7). Furthermore, a lower temperature of 60°C resulted in a
sharp decrease in the yield of the desired product (Table 1, entry
8), indicating that the temperature is crucial to the efficiency of
this transformation. Remarkably, the use of 2.5 equivlents of
tBuONO led to an excellent yield of 2a (Table 1, entry 12).
Further screening of oxidants (Table 1, entries 14-17) showed
that tBuONO was identified as the most efficient oxidant.
Therefore, the optimal conditions entailed the use of tBuONO
(2.5 equiv) as an oxidant in THF at 90 °C.
With the optimal reaction conditions in hand, we further
explored the possibility to extend the methodology to a variety of
alkyl alcohols (Table 2). 1-Phenyl-2-propanol (1b) was subjected
to the optimal reaction conditions, and delivered the
diastereoisomers 2b with a low yield compared to that of 2a,
indicating that steric effect showed negative influence on the
efficiency of this transformation. Changing the phenyl moiety to
fluorenyl or naphthyl moiety afforded the desired products in
75% (1c) and 91% (1d) yields respectively. A series of alicyclic
alcohols with different sizes were successfully reacted to afford
corresponding products in moderate to good yields (50-86%,2e-
2k). In the case of macrocyclic alcohol (1h), an obvious decrease
in yield was observed. Liner alcohols (1l and 1m) also worked
efficiently with excellent yields. The halogen substituents such as
Br and Cl (1m-1o) were well tolerated under standard conditions.
Alcohols containing a heterocyclic ring (1p-1r) or an alkyne
moiety proved to be a suitable substrate and provided the desired
products (2p-2r) in 25-89% yields. Due to the formation of
aldehydes as major byproducts, allyl and propargyl alcohols
afforded inferior yields (1p vs 1q, 1s vs 1t). It is worthy to note
that this method was successfully applied to the hydroxy group
of other reagents including ceric ammonium nitrate,[9] p-TsCl[10]
[11]
and
(Bu4N)2S2O8
also
successfully
enabled
tetrahydrofuranylation of alcohols. Despite these advances, the
development of a facile and green procedure for the preparation
of tetrahydrofuranether is still desired. Herein, we report a metal-
free method for tetrahydrofuranylation of alcohols with tertbutyl
nitrite.
To commence our investigation, the reaction of 2-
phenylethanol in THF at 80°C was chosen as a model reaction
system in the presence of tBuONO. Gratifyingly, we found that
the reaction afforded the desired product (2a) in 74% yield in the
presence of two equivalents of tBuONO (Table 1, entry 1).
Prolonging the reaction time led to an increased yield (Table 1,
entry 2). Notably, when the atmosphere was replaced by air or

2
Tetrahedron
Table 1. Optimization of reaction conditions.a
Table 2. Tetrahydrofuranylation of alcohols. a
Entry
1
Oxidant
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
n-BuONO
i-BuONO
t-BuOOH
(t-BuO)2
Temperature (°C)
t (h)
12
20
24
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Yield (%)b
80
80
80
80
80
90
100
60
70
90
90
90
90
90
90
90
90
74
81
82
72
52
87
73
39
79
58
79
93
89
79
82
12
17
2
3
4c
5d
6
7
8
9
10e
11f
12g
13h
14g
15g
16g
17g
a Reaction conditions: 1a (0.5 mmol), tBuONO (1 mmol), solvent (2 mL),
under an oxygen atmosphere.
b Isolated yields.
c Under air atmosphere.
d Under N2 atmosphere.
e t-BuONO (1.0 equiv).
f t-BuONO (1.5 equiv).
g Oxidant (2.5 equiv).
h t-BuONO (3.0 equiv).
a Reaction conditions: 1 (0.5 mmol), tBuONO (1.25 mmol), solvent (2 mL),
under oxygen atmosphere, isolated yields.
b Recovered starting material.
protection of natural compounds including Testosterone (1u) and
Epiandrosterone (1v). Interestingly, it was found that tBuONO
also enabled the reaction of tetrahydropyran and 2-phenylethanol
to provide desired product (2w). The low yields of products 2t-
2w were mainly attributed to the poor conversions.
In order to investigate the practicality of this reaction, we
carried out a gram-scale reaction using 1l as a substrate (Scheme
1a). After 30 h, the reaction successfully delivered the desired
product 2l in 74% yield with 20% of 1l to be recovered.
Some control experiments were conducted to shed light on the
mechanism of this procedure. The presence of 5 equivalents of
TEMPO led to only trace of product, supporting a radical way
(Scheme 1b). The reaction between 2-phenylethanol and
tBuONO under O2 or N2 atmosphere gave 20% and 37% yields
of intermediate 1aa respectively (Scheme 1c). In the absence of
tBuONO, the resulting intermediate 1aa could react with THF to
give the desired product 2a (Scheme 1d). The employment of O2
atmosphere delivered a better yield of 2a because oxygen could
abstract a hydrogen atom from THF to afford a radical
intermediate.[7] We also detected the formation of 2-
nitrosotetrahydrofuran (B) during the reaction (Scheme 1e). The
presence of O2 brought a negative impact on the reaction
efficiency probably due to the instability of B under O2
atmosphere. The intermediate B could react well with 1a to
produce the desired product 2a (Scheme 1f). These results
Scheme 1. Gram-Scale synthesis and some control experiments.
indicated that both 1aa and
B served as the reaction
intermediates.

3
We are grateful for financial support from the National
Natural Science Foundation of China (21372177 and 21901187).
References and notes
1. Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61,
4439–4449. (a) Miyashita, R.; Yoshikoshi, A.; Grieco, P. A. J.
Org. Chem. 1977, 42, 3772-3774; (b) Bongini, A.; Cardillo, G.;
Orena, M.; Sandri, S. Synthesis 1979, 618-620; (c) Morizawa, Y.;
Mori, I.; Hiyama, T.; Nozaki, H. Synthesis 1981, 899-901; (d)
Olah, G.; Husain, A.; Singh, B. P. Synthesis 1985, 703-704; (e)
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Lett. 1988, 29, 4583-4586; (f) Ranu, B. C.; Saha, M. J. Org.
Chem. 1994, 59, 8269-8270; (g) Bhalerao, U. T.; Davis, K.J.; Rao,
B. V. Synth. Commun. 1996, 26, 3081-3085; (h) Habibi, M.H.;
Tangestaninejad, S.; Mohammadpoor-Baltork, I.; Mirkhani, V.;
Yadollahi, B. Tetrahedron Lett. 2001, 42, 2851-2853; (i)
Stephens, J. R.; Butler, P. L.; Clow, C. H.; Oswald, M. C.; Smith,
R. C.; Mohan, R. Eur. J. Org. Chem. 2003, 19, 3827-3831.
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Lett. 1976, 20, 1725-1726.
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Org. Lett. 2000, 2, 485-487.
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Chim. Acta 2007, 90, 2163-2166.
Scheme 2. Proposed reaction mechanism.
7. Wang, M.; Zhou, Z.; Tang, R.; Zhang, X.; Deng, C. Synlett. 2013,
24, 737-740.
Based on the results of control experiments and previous
references,[12] a plausible mechanism was described in Scheme 2.
First, a tBuO radical and a NO radical are generated from
homolytic cleavage of tBuONO. The tBuO radical or oxygen
abstracts a hydrogen atom from tetrahydrofuran to form a
carbon-centred radical A. Moreover, radical A could be accessed
via hydrogen atom transform between THF and oxygen radicals
generated from substrates. [13] On the other hand, alcohol reacts
with tBuONO to give corresponding alkyl nitrite which
8. Beniazza, R.; Abadie, B.; Remisse, L.; Jardel, D.; Lastécouères,
D.; Vincent, J. Chem. Commun. 2017, 53, 12708-12711.
9. Maione, A. M.; Romeo, A. Synthesis 1987, 250-251.
10. Yu, B.; Hui, Y. Synth. Commun. 1995, 25, 2037.
11. Jung, J. C.; Choi, H. C.; Kim, Y. H. Tetrahedron Lett. 1993, 34,
3581-3584.
12. (a) L. Troisi, C. Granito, L. Ronzini, F. Rosato, V. Videtta,
Tetrahedron Lett. 2010, 51, 5980-5983; (b) Chen, L.; Shi, E.; Liu,
Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J.
2011, 17, 4085-4089; (c) Kabasakalian, P.; Townley, E.; Yudis,
M. J. Am. Chem. Soc. 1962, 84, 2716-2718; (d) Akhtar, M.;
Barton, D. H. R.; Sammes, P. G. J. Am. Chem. Soc. 1965, 87,
4601-4607.
fragments into an alkoxyl radical and
a NO radical.
Subsequently, alkoxyl radical is coupled with radical A to afford
tetrahydrofuranylation product. Alternatively, NO radical is
trapped by A to generate intermediate B which undergoes a
nucleophilic substitution reaction with alcohol to form target
product.
13. Zhang, S.-Y.; Zhang, F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40,
1937–1949.
Supplementary Material
In summary, we have disclosed a new method to synthesize
tetrahydrofuran ether via the oxidative coupling between THF
and alcohols in the presence of tBuONO. Mechanism exploration
shows that this reaction proceeds in a radical way. The
advantages of this protocol include no need for metal, easy
operation, simple conditions and excellent functional group
tolerance, enabling it to be an attracting alternative method for
the protection of alcohols.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
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Acknowledgments

4
Tetrahedron
1. The protection of alcohols.
2. Synthesizing asymmetric ethers via
tBuONO-promoted oxidative coupling
between tetrahydrofuran and alcohols.
3. Exploring the potential applications of
tertbutyl nitrite in the organic synthesis.