Synthesis of Hydrazines via Radical Generation and Addition of Azocarboxylic tert -Butyl Esters

Article abstract of DOI:10.1021/acs.orglett.8b00448

A new chemistry of azo compounds that is a radical generation and addition in situ of azocarboxylic tert-butyl esters to synthesize hydrazines has been described. The protocol provides a novel strategy for the synthesis of various hydrazines. The advantag

Full text of DOI:10.1021/acs.orglett.8b00448

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Hydrazines via Radical Generation and Addition of
Azocarboxylic tert-Butyl Esters
Chen-Hao Ru, Shi-Huan Guo, Gao-Fei Pan, Xue-Qing Zhu, Ya-Ru Gao, and Yong-Qiang Wang*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
ABSTRACT: A new chemistry of azo compounds that is a radical
generation and addition in situ of azocarboxylic tert-butyl esters to
synthesize hydrazines has been described. The protocol provides a novel
strategy for the synthesis of various hydrazines. The advantages of the
transformation include broad substrate scope, benign conditions, and
convenient operation.
ince Griess first discovered the diazo compounds in 1858,1
and in the following year Martius and Griess prepared
ylic tert-butyl ester 1a as a model substrate to seek the optimal
reaction conditions for the development of a new chemistry of
azo compounds to synthesize hydrazines (Table 1). First, we
S
commercial azo dyes,2 azo compounds have attracted intense
attention due to their interesting physical and chemical
properties.3 Besides being the most important and versatile
class of colored organic compounds used as dyes and
pigments,4 azo compounds (e. g., methyl orange) can be
employed as acid−base indicators. Azo compounds [e.g.,
azobis(isobutyronitrile) (AIBN)] are also widely utilized as
initiators in free-radical polymerizations and other radical-
induced reactions.5 Recently, azo-based molecules were found
to be powerful tools for the fabrication of multi-stimuli-
responsive degradable materials.6 Herein, we disclose a new
chemistry of azo compounds, the first radical generation, and
addition in situ to synthesize various hydrazines.
a
Table 1. Optimization of the Reaction Conditions
b
entry
solvent
HFIP
temp (°C) time (h) conv (%) yield (%)
1
2
3
4
5
6
7
8
9
25
25
24
24
24
24
28
4
30
9
26
5
CF3CH2OH
It is well-known that hydrazines are a kind of valuable
organic compounds.7 Many hydrazines show remarkable
biological activities.8 Several similar molecules to hydrazines
are effective for treatment of tuberculosis, hypertension, and
Parkinson’s disease.7b Hydrazine-based petidomimetics are
found to be potent agents against diseases such as SARS,
AIDS, and hepatitis.9 Additionally, in the field of organic
synthesis, hydrazines are essential amino acid precursors10 and
versatile synthetic building blocks for heterocycle syntheses.11
In the hydrazine family, N-Boc-protected N,N′-disbstituted
hydrazines are interesting molecules. Typically, they can be
synthesized via transition-metal-catalyzed (e.g., Pd and Cu)12 or
base-promoted (e.g., n-BuLi)13 amination reactions of
hydrazines with haides or boronic acids. In this paper, we
reported a novel synthetic method for such hydrazines.
The research originated from the reaction where phenyl-
azocarboxylic tert-butyl ester 1a was in the presence of
hexafluoroisopropanol (HFIP) at room temperature for 24 h
to afford the intriguing hydrazine compound 2a (the structure
was confirmed by single-crystal X-ray analysis) in 26% yield.
We realized this would be a new chemistry for azo compounds,
and if the reaction conditions had been optimized, a novel
strategy for the synthesis of hydrazines from azo compounds
would be developed. Accordingly, we chose phenylazocarbox-
c
other solvents
0
0
d
solvent
25
35
40
45
50
58
<5
80
<5
64
93
93
93
93
HFIP
HFIP
HFIP
HFIP
HFIP
100
100
100
100
1.5
1
1
a
b
c
1a (0.5 mmol) reacted in solvent (0.5 mL). Isolated yield. Other
solvents: MeOH, EtOH, 2-propanol, H2O, acetic acid, DMSO,
CH3CN, THF, ClCH2CH2Cl, 1,4-dioxane, toluene, xylene, acetone,
d
pyridine, benzene, formamide, DMF, EtOAc, CH2Cl2. Added 5% of
THF/DCM (1:1) into HFIP (0.5 mL).
checked the solvent of the reaction. To our great surprise, the
solvents, except HFIP and trifluoroethanol, could not provide
any desired product 2a, and HFIP was the best one (Table 1,
entries 1−3). Furthermore, the addition of THF/DCM (5%)
into HFIP also obviously inhibited the reaction (Table 1, entry
4). Then, with HFIP as the solvent, the reaction temperature
was investigated (Table 1, entries 5−9). At 40 °C, the reaction
Received: February 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00448
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
provided complete conversion and 93% yield after 4 h (Table 1,
entry 6). Higher temperature only accelerated the reaction rate
without an increase in yield. Thus, the optimized reaction
conditions for the synthesis of 2a were identified as follows: 1a
(0.5 mmol) in HFIP (0.5 mL) at 50 °C for 1 h (Table 1, entry
8).
procedure and could be versatile handles for further trans-
formations. Disubstituted phenylazocarboxylic tert-butyl esters
were also effective substrates for the reaction to give the
corresponding products 2q−u in good yields. Interestingly, a
heteroarene substrate, for example, pyridine azocarboxylic tert-
butyl ester, was subjected to the reaction conditions to provide
the corresponding product containing four nitrogen atoms in
good yield (2v) with no competitive radical addition to the
heterocyclic ring observed. Gratifyingly, alkyl azocarboxylic tert-
butyl ester was also a suitable substrate for the reaction.
Cyclohexylazocarboxylic tert-butyl ester 1w afforded the desired
product 2w in excellent yield. It should be mentioned that, in
all cases above, the addition reactions occurred on the nitrogen
atom linked to Boc group, and no product, reacted at another
nitrogen atom, could be detected upon analysis of the reaction
mixtures, showing that the method possesses great regiose-
lectivity.14 The structure of 2v was confirmed by single-crystal
X-ray diffraction analysis.
With the optimal reaction conditions in hand, the scope of
azo compounds was tested (Scheme 1). Phenylazocarboxylic
a,b
Scheme 1. Substrate Scope
Next, we investigated the possibility of cross reactions. We
put phenylazocarboxylic tert-butyl ester 1a and p-chloropheny-
lazocarboxylic tert-butyl ester 1i into one bottle and added
HFIP to react at 50 °C (Scheme 2). The reaction gave only a
Scheme 2. Reaction of 1a and 1i
small amount of self-addition products 2a (17%) and 2i (15%)
but cross-addition product 2ai (the structure was unambigu-
ously confirmed by single-crystal X-ray diffraction analysis) in
good yield (57%). The result demonstrated that the formation
of an aromatric radical with an electron-withdrawing group was
likely easier.
Then, other cross-addition reactions were exploited (Scheme
3). Pleasingly, they all underwent the additions of an aromatric
radical bearing a relatively stronger electron-withdrawing group
to another partner, providing the desired cross-addition
products in good yields, even with two partners possessing
slight differences in electron properties such as phenyl-
azocarboxylic tert-butyl ester 1a and m-tolueneazocarboxylic
tert-butyl ester 1c to produce 2ca in moderate yield. These
results verified that the outcome of the cross reaction was very
sensitive to the electronic properties of the substrates. This
distinguishable character leads the approach to broader
applications in the future. The structure of 2ip was also
confirmed by single-crystal X-ray diffraction analysis.
a
Reaction conditions: 1 (0.5 mmol) in HFIP (0.5 mL) reacted at 50
b
c
°C. Isolated yields. The substrate (10.0 mmol) was used.
tert-butyl esters bearing the substituents at the ortho-, meta-, or
para-positions of the aromatic ring smoothly underwent the
reactions to provide the products 2a−p in good yields. Both
electron-donating (1b−f) and electron-withdrawing substitu-
ents (1g−p) were well tolerated. A broad range of substituent
groups with diverse steric and electronic properties (Me, Et, t-
Bu, F, Cl, Br, I, CF3O, and CN) were compatible with this
To achieve insight into the reaction mechanism, we carried
out a series of experiments. First, when the reaction was in air,
oxygen, or argon atmosphere, the yield was not obviously
changed. Under the standard reaction conditions, a radical-
trapping reagent, 1,1-dephenylethylene (1.0 equiv), was
introduced into the reaction system of 1a. After 2 h at 50
°C, only 8% of 2a was obtained, and a main product, namely,
B
DOI: 10.1021/acs.orglett.8b00448
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
forms a nitrogen-centered radical that abstracts a hydrogen
atom from HFIP to give hydrazine product.
Scheme 3. Cross Reactions
In summary, a new chemistry of azo compounds, namely, the
radical generation and addition in situ of azocarboxylic tert-
butyl esters to synthesize hydrazines, has been disclosed. The
transformation features broad substrate scope, benign con-
ditions, and convenient operation. The studies furnish
important complementary protocols for the synthesis of
important hydrazines. We anticipate this work will provide
insight into azo chemistry and should have broad applications.
Further investigations on detailed reaction mechanism and
extend the reaction are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00448.
a
Reaction conditions: 1 (0.5 mmol) and 1′ (0.6 mmol) in HFIP (1.0
b
mL) reacted at 50 °C. Isolated yields.
Experimental procedures and spectral data (PDF)
the adduct 3 of phenyl with 1,1-dephenylethylene, was isolated
in 85% yield (Scheme 4, eq 1), indicating the phenyl radical
Accession Codes
CCDC 1821853−1821854 and 1821860−1821861 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
Scheme 4. Studies on the Reaction Mechanism
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangyq@nwu.edu.cn.
ORCID
Yong-Qiang Wang: 0000-0002-2774-3248
Notes
existed in reaction system. In addition, we found that gas
collected from the reaction system made a clear lime-colored
aqueous solution cloudy. Thus, we confirmed that carbon
dioxide was generated from reaction system. We further
investigated the hydrogen atom source of hydrazine by
isotope-labeling experiments (Scheme 4, eq 2). When the
reaction of 1a was stirred in (CF3)2CHOD (2.0 mL) at 50 °C
for 2 h, the deuterium product 4 was obtained in 92% yield,
indicating the hydrogen atom of hydrazine was coming from
HFIP.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC-21572178 and NSFC-
21702162), the Natural Science Basic Research Plan in Shaanxi
Province of China (Program No. 2017JM2006), the Key
Science and Technology Innovation Team of Shaanxi Province
(2017KCT-37), and the Scientific Research Program Funded
by Shaanxi Provincial Education Department (Program No.
17JK0788).
On the basis of these results and the related literature,15
a
tentative mechanism was proposed in Scheme 5. The reaction
begins with the generation of phenyl radical (proven by the
radical-trapping experiment) through releasing nitrogen and
carbon dioxide from starting material. Then, the addition of
phenyl radical to another phenylazocarboxylic tert-butyl ester
REFERENCES
■
(1) (a) Griess, P. Liebigs Ann. Chem. 1858, 106, 123. (b) Griess, P.
Liebigs Ann. Chem. 1860, 113, 207.
(2) (a) Martius, C.; Griess, P. Z. Chem. 1862, 2 (132), 689.
(b) Griess, P. Liebigs Ann. Chem. 1862, 121, 262.
Scheme 5. Proposed Mechanism
(3) (a) Natansohn, A.; Rochon, P. Chem. Rev. 2002, 102, 4139.
(b) Sourisseau, C. Chem. Rev. 2004, 104, 3851. (c) Hofling, S. B.;
̈
Bartuschat, A. L.; Heinrich, M. R. Angew. Chem., Int. Ed. 2010, 49,
9769. (d) Chudasama, V.; Ahern, J. M.; Dhokia, D. V.; Fitzmaurice, R.
J.; Caddick, S. Chem. Commun. 2011, 47, 3269. (e) Beveridge, R. E.;
Batey, R. A. Org. Lett. 2012, 14, 540. (f) Wang, Y.; Li, Q. Adv. Mater.
2012, 24, 1926. (g) Bandara, H. M. D.; Burdette, S. C. Chem. Soc. Rev.
2012, 41, 1809. (h) Iamsaard, S.; Aßhoff, S. J.; Matt, B.; Kudernac, T.;
Cornelissen, J. J. L. M.; Fletcher, S. P.; Katsonis, N. Nat. Chem. 2014,
6, 229. (i) Chen, H.; Ma, X.; Wu, S.; Tian, H. Angew. Chem., Int. Ed.
C
DOI: 10.1021/acs.orglett.8b00448
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2014, 53, 14149. (j) Soberats, B.; Uchida, E.; Yoshio, M.; Kagimoto, J.;
Ohno, H.; Kato, T. J. Am. Chem. Soc. 2014, 136, 9552. (k) Zhao, D.;
Vasquez-Cespedes, S.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54,
́ ́
1657. (l) Lasch, R.; Heinrich, M. R. J. Org. Chem. 2015, 80, 10412.
(m) Yang, L.; Bai, Y.; Tan, X.; Wang, Z.; Zhang, X. ACS Macro Lett.
2015, 4, 611. (n) Lasch, R.; Fehler, S. K.; Heinrich, M. R. Org. Lett.
2016, 18, 1586. (o) Zhao, H.; Sen, S.; Udayabhaskararao, T.; Sawczyk,
X. Chin. Chem. Lett. 2007, 18, 499. (g) Hou, S.; Li, X.; Xu, J. Org.
Biomol. Chem. 2014, 12, 4952. (h) Yang, Z.; Hou, S.; He, W.; Cheng,
B.; Jiao, P.; Xu, J. Tetrahedron 2016, 72, 2186.
(13) Bredihhin, A.; Groth, U. M.; Maeorg, U. Org. Lett. 2007, 9,
̈
1097.
(14) For Pd-catalyzed amination of N-Boc aryl hydrazines with aryl
halides (ref 12a−d), the reaction site is the nitrogen atom ortho to the
Boc group to give the same products:
̌ ́
M.; Kucanda, K.; Manna, D.; Kundu, P. K.; Lee, J.-W.; Kral, P.; Klajn,
R. Nat. Nanotechnol. 2016, 11, 82. (p) Koutoulogenis, G. S.; Kokotou,
M. G.; Voutyritsa, E.; Limnios, D.; Kokotos, C. G. Org. Lett. 2017, 19,
1760.
(4) (a) Kawata, S.; Kawata, Y. Chem. Rev. 2000, 100, 1777.
(b) Barrett, C. J.; Mamiya, J.-I.; Yager, K. G.; Ikeda, T. Soft Matter
2007, 3, 1249. (c) Ferris, D. P.; Zhao, Y.-L.; Khashab, N. M.; Khatib,
H. A.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2009, 131, 1686.
(d) Raimondo, C.; Crivillers, N.; Reinders, F.; Sander, F.; Mayor, M.;
Samorì, P. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 12375. (e) Liu, J.;
Bu, W.; Pan, L.; Shi, J. Angew. Chem., Int. Ed. 2013, 52, 4375. (f) Chi,
X.; Ji, X.; Xia, D.; Huang, F. J. Am. Chem. Soc. 2015, 137, 1440.
(5) (a) May, J. A., Jr; Smith, W. B. J. Phys. Chem. 1968, 72, 2993.
(b) Moad, G.; Solomon, D. H.; Johns, S. R.; Willing, R. I.
Macromolecules 1984, 17, 1094. (c) Liu, L.; Wang, Z.; Fu, X.; Yan,
C.-H. Org. Lett. 2012, 14, 5692. (d) Li, B.-j.; Zhong, H.; Yu, H.-t. J.
Phys. Chem. B 2016, 120, 12950. (e) Li, Y. J.; Wu, K.; Li, Y.; Zhang, Y.;
Liu, J. J.; Wang, X. Z. J. Chem. Eng. Data 2018, 63, 27.
(15) Huang, P.-K. C.; Kosower, E. M. J. Am. Chem. Soc. 1967, 89,
3910.
(6) Mutlu, H.; Geiselhart, C. M.; Barner-Kowollik, C. Mater. Horiz.
2018, 5, 162.
(7) (a) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen
Compounds; Oxford University: New York, 1994. (b) Ragnarsson, U.
Chem. Soc. Rev. 2001, 30, 205. (c) Wolter, M.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2001, 3, 3803. (d) Kang, H.-M.; Lim, Y.-K.; Shin, I.-J.;
Kim, H.-Y.; Cho, C.-G. Org. Lett. 2006, 8, 2047. (e) Bredihhin, A.;
Groth, U. M.; Maeorg, U. Org. Lett. 2007, 9, 1097. (f) Tsu
̌
pova, S.;
̈
Maeorg, U. Org. Lett. 2013, 15, 3381. (g) Akhbar, A. R.; Chudasama,
̈
V.; Fitzmaurice, R. J.; Powell, L.; Caddick, S. Chem. Commun. 2014,
50, 743. (h) Shamsabadi, A.; Chudasama, V. Org. Biomol. Chem. 2017,
15, 17.
(8) (a) Zhang, R.; Durkin, J. P.; Windsor, W. T. Bioorg. Med. Chem.
Lett. 2002, 12, 1005. (b) Raja, A.; Lebbos, J.; Kirkpatrick, P. Nat. Rev.
Drug Discovery 2003, 2, 857.
(9) (a) Zhang, R.; Durkin, J. P.; Windsor, W. T. Bioorg. Med. Chem.
Lett. 2002, 12, 1005. (b) Lee, T.-W.; Cherney, M. M.; Huitema, C.;
Liu, J.; James, K. E.; Powers, J. C.; Eltis, L. D.; James, M. N. G. J. Mol.
Biol. 2005, 353, 1137.
(10) (a) Papadopoulos, G. N.; Kokotos, C. G. Chem. - Eur. J. 2016,
22, 6964. (b) Wei, Y.; Zhang, H.-X.; Zeng, J.-L.; Nie, J.; Ma, J.-A. Org.
Lett. 2017, 19, 2162. (c) Trost, B. M.; Tracy, J. S. Org. Lett. 2017, 19,
2630.
(11) (a) Ricci, A. Modern Amination Methods; Wiley-VCH:
Weinheim, 2000. (b) Carlin, R. B.; Moores, M. S. J. Am. Chem. Soc.
1962, 84, 4107. (c) Barnish, I. T.; Gibson, M. S. J. Chem. Soc. C 1970,
854. (d) Kulagowski, J. J.; Moody, C. J.; Rees, M. J. Chem. Soc., Perkin
Trans. 1 1985, 2725. (e) Tamura, Y.; Tsugoshi, T.; Mohri, S.-I.; Kita,
Y. J. Org. Chem. 1985, 50, 1542. (f) King, F. D. J. Chem. Soc., Perkin
Trans. 1 1988, 3381. (g) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25,
607. (h) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(i) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (j) Oliva,
A.; Ellis, M.; Fiocchi, L.; Menta, E.; Krapcho, A. P. J. Heterocycl. Chem.
2000, 37, 47. (k) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (l) Baran,
P. S.; Guerrero, C. A.; Corey, E. J. Org. Lett. 2003, 5, 1999. (m) Kim,
Y. J.; Lee, D. Org. Lett. 2004, 6, 4351.
(12) For Pd-catalyzed reaction: (a) Lim, Y.-K.; Lee, K. S.; Cho, C.-G.
Org. Lett. 2003, 5, 979. (b) Lim, Y.-K.; Jung, J.-W.; Lee, H.; Cho, C.-G.
J. Org. Chem. 2004, 69, 5778. (c) Kang, H.-M.; Lim, Y.-K.; Shin, I.-J.;
Kim, H.-Y.; Cho, C.-G. Org. Lett. 2006, 8, 2047. (d) Stoll, R. S.; Peters,
M. V.; Kuhn, A.; Heiles, S.; Goddard, R.; Buhl, M.; Thiele, C. M.;
̈
Hecht, S. J. Am. Chem. Soc. 2009, 131, 357. For Cu-catalyzed reaction:
(e) Kim, K.-Y.; Shin, J.-T.; Lee, K.-S.; Cho, C.-G. Tetrahedron Lett.
2004, 45, 117. (f) Wang, Y. F.; Zhou, Y.; Wang, J. R.; Liu, L.; Guo, Q.
D
DOI: 10.1021/acs.orglett.8b00448
Org. Lett. XXXX, XXX, XXX−XXX