Synthesis of o-chlorophenols via an unexpected nucleophilic chlorination of quinone monoketals mediated by N,N′-dimethylhydrazine dihydrochloride

Article abstract of DOI:10.1039/c4ob00391h

An unexpected nucleophilic chlorination of a quinone monoketal while carrying out a pyrazolidine synthesis has led to a general preparation of multisubstituted phenols. The products are obtained in good to high yields under mild conditions. The bridged pyrazolidines that were the original targets are obtained in the presence of a protic solvent. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00391h

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Synthesis of o-chlorophenols via an unexpected
nucleophilic chlorination of quinone monoketals
mediated by N,N’-dimethylhydrazine
dihydrochloride†
Cite this: Org. Biomol. Chem., 2014,
12, 2854
Received 20th February 2014,
Accepted 21st March 2014
Zhiwei Yin,a,b Jinzhu Zhang,a,b Jing Wu,a,b Riana Green,a Sihan Lia,b and
DOI: 10.1039/c4ob00391h
www.rsc.org/obc
Shengping Zheng*a,b
An unexpected nucleophilic chlorination of a quinone monoketal monoketals and monosubstituted aliphatic hydrazines
while carrying out a pyrazolidine synthesis has led to a general through a 1,2-addition, aromatization, isomerization and cycli-
preparation of multisubstituted phenols. The products are zation process.2a We also have demonstrated a synthesis of
obtained in good to high yields under mild conditions. The bridged bridged isoxazolidines via a double hetero-Michael addition
pyrazolidines that were the original targets are obtained in the between N-substituted hydroxylamines and quinone mono-
presence of a protic solvent.
ketals.2b To our surprise, when we extended the nucleophile to
commercially available N,N′-dimethylhydrazine dihydrochlo-
ride, under the same conditions (DBU, CH3CN, room tempera-
ture), the expected pyrazolidine was not obtained. Aside from
the recovered starting material, a product was isolated in 2%
yield. This product was shown to be a chlorophenol from MS
and NMR spectra (Scheme 1). After comparison of the spectra
with those of an authentic sample, the product was character-
Quinone monoketals are quinone equivalents with both carbo-
nyls and double bonds being differentiated. They are impor-
tant building blocks in the synthesis of structurally complex
molecules.1 Recently we were interested in heterocycle syn-
thesis from nucleophilic addition to quinonoids.2 We have
developed a Fischer indole synthesis via coupling of quinone
Table 1 Screening of the chloride source
Entry
Chloride
Temperature (°C)
Time
Yielda (%)
1
2
3
4
5
6
7
8
1a
25
25
25
25
1 h
1 h
1 h
1 h
1 h
20 min
1 h
1 h
1 h
82
80
62
56
55
99
83
32
0
1bb
1c
1d
Scheme 1 Unexpected formation of chlorophenols.
HCl (1 M)
1a
25
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Pyr·HClb
TMSCl
Et3N·HCl
TBACc
ZnCl2
aDepartment of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10065,
USA
9
10
11
1 h
1 h
0
0
bThe Graduate Center, The City University of New York, 365 5th Avenue, New York,
New York 10016, USA. E-mail: szh0007@hunter.cuny.edu; Fax: +1 212-772-5332;
a Isolated yield. b Much lower yields for substituted quinone
monoketals. c Tetrabutylammonium chloride.
Tel: +1 212-396-6322
†Electronic supplementary information (ESI) available. CCDC 921686 and
971456. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob00391h
MeNHNHMeÁ2HCl MeONHMeÁHCl H2NNH2 ÁHCl sec-BuNHNH2 Á2HCl
1a
1b
1c
1d
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ized unambiguously as 2-chloro-4-methoxy-phenol 3a,3 pre- for this transformation (Table 1). Although different chloride
sumably via a formal SN2′ substitution by chloride at the sources can effect this nucleophilic chlorination, it was found
α-position of the carbonyl group and an ensuing aromatiza- that N,N′-dimethylhydrazine dihydrochloride gave the best
tion. When the reaction was run in the absence of DBU at result under reflux conditions (CH3CN as the solvent).
room temperature, 3a was obtained in 82% yield, and
With optimized conditions identified, we then explored the
upgraded to 99% yield under refluxing conditions (cf. Table 1). scope of quinone monoketals. All quinone monoketals are pre-
It is well known that quinone monoketals can undergo acid- pared in one step from commercial phenols by PIDA oxidation
catalyzed allylic substitution with carbon nucleophiles such as according to Tamura–Kita–Pelter protocol.6 As shown in
electron-rich arenes.4 To the best of our knowledge, there are Table 2, quinone monoketals with at least one unsubstituted
few precedents where halide is reported to undergo nucleophi- alpha carbon to the keto group are good substrates for this
lic addition to quinone monoketals possibly via allylic substi- nucleophilic chlorination. Quinone ethylene monoketal and
tution5a or 1,4-addition.5b,c Herein, we report our results on quinone trimethylene monoketal both afforded chloroalcohols
the regioselective synthesis of chlorophenols via a nucleophilic in good yields (3b & 3c). Their structures were characterized
chlorination of quinone monoketals.
unambiguously by X-ray crystallography.7 Generally, monosub-
We first investigated a variety of hydrochloride salts of stituted quinone dimethyl monoketals gave chlorophenols as
organic bases and inorganic chlorides for their effectiveness one regioisomer (3d–3k), except in the cases of 3l–3n, where
Table 2 Scope of quinone monoketalsa
a Yields in parentheses are isolated yields. b Quinone imine ketal as starting material. c TMSBr as bromide source (MeNHNHMe·2HBr gave lower
yield). d PhSH + NH2NH2·H2SO4. e Styrene as nucleophile.
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Table 3 Substitution of mixed quinone monoketals
2t (R = Me, R′ = Et)
2u (R = Me, R′ = iPr)
3a (R = Me): 3t (R′ = Et)
85% (1 : 3.5)a
3a (R = Me): 3u (R′ = iPr)
85% (1 : 7.5)a
2v (R = Me, R′ = propargyl)
2w (R = Me, R′ = TBS)c
81%b (3a as sole product)
3a (R = Me) 25%b
3w (R′ = TBS) 46%b
Scheme 2 Expected bridged pyrazolidine synthesis.
a NMR ratio of an inseparable mixture. b Isolated yield. c The crude
NMR ratio of 3a/3w is 1 : 1.6.
two regioisomers were obtained. Quinone monoketal with an
electron-withdrawing methoxycarbonyl group still led to ortho-
chlorophenol 3g, instead of a meta-phenol through 1,4-
addition to the β-carbon of the unsaturated ester, which attests
to the generality of this method. Multisubstituted chlorofluoro-
phenols were synthesized in high yields, as demonstrated in
3o–3s, which otherwise would be obtained with difficulty.8
Quinone imine ketal 4′9 is a good substrate for our nucleo-
philic chlorination to afford ortho-chloroanilide 4 as the sole
product. Other nucleophiles, such as bromide, thiophenol10
and styrene,10,11 can also undergo this allylic substitution
(5–7).
Scheme 3 Possible mechanisms.
Mixed quinone monoketals gave a mixture of inseparable
products. The major products are those where methanol acted
as a better leaving group12 (Table 3, 2t–2u). On the other hand,
for methyl propargyl mixed quinone monoketal 2v, the sole
product is 3a due to propargyl alcohol acting as a better
leaving group. Mixed quinone monoketal 2w13 may offer an
evidence for the relative leaving ability of methanol and tert-
butyldimethylsilanol in the quinone monoketal setting. The
ratio of 3a to 3w is ca. 1 : 1.6 from proton NMR of the crude
products, while 1 : 1.8 for isolated products, which implies
methanol is
a slightly better leaving group than tert-
butyldimethylsilanol.14
Scheme 4 Experiments favoring mechanism b.
After screening the solvents, it was found that the expected
bridged pyrazolidine could be obtained under basic conditions
when a protic solvent was used. 2-Methyl and 3-methyl
quinone monoketals also gave pyrazolidines in moderate
yields (Scheme 2).
For the mechanistic speculation, this chlorination can be
rationalized by either a direct SN2′-type substitution (mechan-
ism a) or a regioselective 1,4-addition to the preformed more
electron-withdrawing oxocarbenium cation15 (mechanism b),
which is reminiscent of the mechanism of the Thiele reaction
(Scheme 3).16
quinol ether 13 gave the expected substitution while 15 did
not (Scheme 4).
Conclusions
In summary, we have demonstrated an unexpected nucleophi-
lic chlorination of quinone monoketals mediated by N,N′-
dimethylhydrazine dihydrochloride. It provides a simple way
to make multisubstituted phenols regioselectively. Moreover,
Circumstantial evidence favoring cation mechanism
b
includes: (1) scrambling experiments which incorporated
solvent; (2) fast 1,4-addition of HCl to benzoquinone;17 and (3)
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the relative ability of methoxy and siloxy as leaving group
was also studied using mixed quinone monoketals as the
substrates.
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Acknowledgements
We are grateful to Professors Richard Franck, Randy Mootoo
and Klaus Grohmann at Hunter College for helpful discus-
sions. We thank Dr Lijia Yang (CCNY), Ms Rong Wang
(MSKCC) and Dr Chunhua Hu (NYU) for mass spectrometric
and X-ray crystallographic assistance respectively. Financial
support from the Bertha and Louis Weinstein Research Grant
and NIH (SC2GM100783) is also acknowledged.
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