10.1002/chem.201904288
Chemistry - A European Journal
COMMUNICATION
mL, 8 equiv) in a 9:1 tetrahydrofuran:water mixture (20 mL) was added.
The reaction mixture was allowed to stir for 1 h before transferring to a
separatory funnel, washed once with 1M aqueous HCl, dried over Na2SO4,
and concentrated under reduced pressure. The crude hydroxamic acid
was then recrystallized from hexanes to give 1a (1.01 g, quantitative yield)
which was used immediately in Step 3: To a 100 mL round-bottomed flask
equipped with a reflux condenser and charged with a magnetic stir bar was
added 1a (1.01 g, 1 equiv), di-tert-butyl peroxide (3.7 mL, 5 equiv), triethyl
phosphite (1.0 mL, 1.5 equiv), and 1,2-dichloroethane (25 mL). The flask
was heated to 90 °C under an air atmosphere for 24 h. Upon consumption
of 1a as determined by TLC (25% ethyl acetate in hexanes), the reaction
mixture was concentrated under reduced pressure before the addition of
6M aqueous HCl (7 mL) and dioxane (7 mL). The mixture was then heated
to 100 °C for 48 h before cooling to ambient temperature, extracted 3 times
with ethyl acetate to remove salicylic acid. The remaining fraction was
concentrated to provide N-methylaniline hydrochloride as an off-white
crystalline solid (447 mg, 77% yield).
P(OEt)3
OP(OEt)3
deoxygenation
NR
O
NR
O
O
N-O, ~65 kcal/mol
P=O, 148 kcal/mol
R
OH
N
O
NO-H, ~88 kcal/mol
CO-H, 85-95 kcal/mol
addition
HAT
R
N
HO
NR
NR
O
O
elimination
R
H
N
then, H+
C-O, 79 kcal/mol
C-N, 90-100 kcal/mol
hydrolysis
Acknowledgements
+ salicylic acid
Scheme 5. Mechanistic proposal. See ref. 23 for bond dissociation energies.
This work was supported by start-up funds provided by the
University of California San Diego.
Anilines are essential motifs found in a variety of organic
compounds and synthesizing them from phenols is a particularly
promising pursuit due to the push to use biorenewable
compounds such as aryl ethers as chemical feedstocks. The
application of our mild, deoxygenative approach allows for phenol
to aniline conversion in only 3 synthetic steps without the need for
intermediate purifications using inexpensive triethyl phosphite
reagent. The use of N-centered radicalophiles allows for a broad
range of sterically and electronically varied phenols to participate
in this process.
Keywords: aniline • phenol • radicals • deoxygenation •
phosphite
[1]
[2]
R. Rappoport in The Chemistry of Anilines, Wiley, 2007.
M. B. Smith in March's Advanced Organic Chemistry (7 ed), Wiley-VCH,
2015.
[3]
(a) C. Sambiagio, S. P. Marsden, A. J. Blacker, P. C. McGowan, Chem.
Soc. Rev. 2014, 43, 3525 – 3550. (b) S. E. Creutz, K. J. Lotito, G. C. Fu,
J. C. Peters, Science 2012, 338, 647 – 651.
[4]
[5]
P. Ryuiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564 – 12564.
(a) Q. Shen, S. Shekhar, J. P. Stambuli, J. F. Hartwig, Angew. Chem. Int.
Ed. 2005, 44, 1371−1375; Angew. Chem. 2005, 117, 1395-1399. (b) Q.
Shen, T. Ogata, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 6586−6596.
D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters, Tetrahedron
Lett. 1998, 39, 2933 – 2936.
Experimental Section
[6]
[7]
[8]
P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T.
Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944.
(a) J. F. Hartwig, S. Shekhar, Q. Shen, F. Barrios-Landeros, in PATAI′S
Chemistry of Functional Groups, Wiley-VCH, 2009. (b) I. P. Beletskaya,
A. V. Cheprakov, Coor. Chem. Rev. 2004, 248, 2337-2364. (c) J. Bariwal,
E. Van der Eycken, Chem. Soc. Rev. 2013, 42, 9283-9303. (d) I, P.
Beletskaya, A, V. Cheprakov, Organometallics 2012, 31, 7753-7808. (e)
J. A. Joseph, S. Pritadarshini, Org. Process Res. Dev. 2017, 21, 1889-
1924.
General rearrangement procedure: To a 1-dram vial charged with a
magnetic stir bar was added hydroxamic acid (20 mg, 1 equiv), di-tert-butyl
peroxide (5 equiv), triethyl phosphite (1.5 equiv), and 1,2-dichloroethane
(0.5 mL). The reaction mixture was heated to 90 °C for 24 h or until
consumption of starting material as determined by thin layer
chromatography (5% ethyl acetate in hexanes). The crude reaction
mixture was concentrated under reduced pressure and purified by flash
chromatography (5-10% ethyl acetate in hexanes).
[9]
(a) S. Voth, J. W. Hollett, J. A. McCubbin, J. Org. Chem. 2015, 80, 2545-
2553. (b) N. Chatterjee, A. Goswami, Org. Biomol. Chem. 2015, 13,
7940-7945. (c) A. Llangovan, P. Sakthivel, P. Sakthivel, Org. Chem.
Front. 2016, 3, 1680-1685. (d) G. K. S. Prakash, L. Gurung, E. R. Marinez,
T. Mathew, G. A. Olah, Tetrahedron Lett. 2016, 57, 288-291. (e) H.-B.
Sun, L. Gong, Y.-B. Tian, J.-G. Wu, X. Zhang, J. Liu, Z. Fu, D. Niu, Angew.
Chem. Int. Ed. 2018, 57, 9456-9460; Angew. Chem. 2018, 130, 9600-
9604.
3-Step sequence of N-methylaniline hydrochloride: Step 1: To a 100 mL
round-bottomed flask charged with
a magnetic stir bar and N,N-
dimethylformamide (50 mL) was added 2-iodobenzoic acid (1.00 g, 1
equiv), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.8 mL, 3 equiv), phenol
(0.76 g, 2 equiv), pyridine (63 µL, 0.20 equiv), Cu powder (11 mg, 0.04
equiv), and CuI (32 mg, 0.04 equiv). The reaction mixture was sparged
with N2 for 10 mins prior to heating to 140 °C for 12 h. The mixture was
cooled to ambient temperature and then poured into 200 mL of ice cold 1M
HCl solution. The mixture was then filtered to furnish the crude diaryl ether
(0.85 g, quantitative yield). Crude carboxylic acid from Step 1 was
immediately carried forward to Step 2: In a 100 mL round-bottomed flask
charged with the carboxylic acid from Step 1 (0.85 g, 1 equiv) with
dichloromethane (20 mL) and N,N-dimethylformamide (310 µL). Oxalyl
chloride (1.8 mL, 5 equiv) was added and the reaction mixture was stirred
[10] For examples of intermolecular radical, C-H aryl amination, see: (a) F.
Minisci, R. Galli, Tetrahedron Lett. 1965, 6, 1679 – 1684. (b) F. Minisci,
Synthesis 1973, 1973, 1 – 24. (c) N. A. Romero, K. A. Margrey, N. E. Tay,
D. A. Nicewicz, Science 2015, 349, 1326 – 1330. (d) J. Davies, T. D.
Svejstrup, D. F. Reina, N. S. Sheikh, D. Leonori, J. Am. Chem. Soc. 2016,
138, 8092 – 8095. (e) T. D. Svejstrup, A. Ruffoni, F. Juliá, V. M. Aubert,
D. Leonori, Angew. Chem. Int. Ed. 2017, 56, 14948 – 14952; Angew.
Chem. 2017, 129, 15144-15148. (f) X.-D. An, S. Yu, Tetrahedron Lett.
at ambient temperature for
1 h after which a solution of N-
methylhydroxylamine hydrochloride (2.0 g, 6 equiv) and triethylamine (4.5
This article is protected by copyright. All rights reserved.