Synthesis of Aryldihalomethanes by Denitrogenative Dihalogenation of Benzaldehyde Hydrazones

Article abstract of DOI:10.1002/adsc.201700393

We report a denitrogenative dihalogenation reaction of phenyldiazomethanes in which the hypervalent iodine reagents PhICl₂ and TolIF₂ act as surrogates for elemental chlorine and fluorine. Halogen transfer from iodane to aryldiazomethane is described, as is a tandem oxidative dihalogenation reaction between iodane and hydrazone. This is the first use of non-α-stabilized diazo compounds in this reaction, which provided an efficient synthesis of aryldifluoromethane (ArCHF₂) and aryldichloromethane (ArCHCl₂) derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201700393

Title: Synthesis of Aryldihalomethanes by Denitrogenative
Dihalogenation of Benzaldehyde Hydrazones
Authors: Zhensheng Zhao, Kaivallya Kulkarni, and Graham Murphy
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Aryldihalomethanes by Denitrogenative Dihalogen-
ation of Benzaldehyde Hydrazones
Zhensheng Zhao,a Kaivalya G. Kulkarni,a and Graham K. Murphya,*
a
Department of Chemistry, University of Waterloo, 200 University Ave W, Waterloo, ON, Canada, N2L3G1
phone: 1-519-888-4567; fax: 1-519-746-0435; email: graham.murphy@uwaterloo.ca
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
N-H and O-H functional groups.[15] We wished to de-
Abstract. We report a denitrogenative dihalogenation re-
action of phenyldiazomethanes in which the hypervalent
iodine reagetns PhICl2 (1) and TolIF2 (2) act as surrogates
for elemental Cl2 and F2. Halogen transfer from iodane to
aryldiazomethane (3) is described, as is a tandem oxida-
tive dihalogenation reaction between iodane and hydra-
zone. This is the first use of non--stabilized diazo com-
pounds in this reaction, which proved an efficient synthe-
sis of ArCHF2 (5) and ArCHCl2 (6) derivatives.
velop a strategy to access the ArCHF2 and ArCHCl2
groups by reacting iodanes and diazo compounds,
though we found very few examples of such reactivity
in the literature. Iodine has only twice been shown to
oxidize a benzaldehyde hydrazone to the correspond-
ing gem-diiodide (Scheme 1, a),[16] and similar reac-
tions with other elemental halogens failed.[17] Two
strategies have emerged for gem-dichloride and gem-
difluoride synthesis from benzaldehyde hydrazones,
consisting of three substrates: one example using 6
equiv of CuCl2 (Scheme 1, b)[18] and two examples us-
ing 4 equiv of the violently-reactive iodinemonofluo-
ride (Scheme 1, c).[19] The potential to replace excess
quantities of transition metal salts or fluorine gas-de-
rived reagents with stable, easily prepared, and poten-
tially recyclable hypervalent iodine reagents in this
transformation is appealing. Reported here is the first
systematic investigation the denitrogenative dihalo-
genation reaction of benzaldehyde hydrazones using
iodanes 1 and 2 as surrogates for elemental chlorine
and fluorine, respectively. Two options for achieving
Keywords: Diazo compounds; Halogenation; Hydra-
zones; Hypervalent compounds; Synthetic methods
(Dichloroiodo)benzene[1] (1) and (difluoroiodo)tolu-
ene[2] (2) are highly selective oxidants whose reactivity
is driven by the concomitant reduction of iodine(III) to
iodine(I).[3,4] An exploitable by-product of these reac-
tions is transfer of the iodane’s ligand(s) to their reac-
tion partners. For example, attack of the electrophilic
iodane by enol ethers, enamines, and related electron-
rich functionalities will generate -functionalized
products.[5] In reactions with alkenes, iodanes produce
1,1- or 1,2-difunctionalized products,[6] and in recent
reactions with diazo compounds, they have been
shown to give gem-dichloride,[7] gem-difluoride,[8]
gem-oxyfluoride[9] and gem-oxyacetylide[10] products.
The breadth of differently-substituted iodanes and di-
azo compounds available, coupled with their mild, en-
vironmentally benign reaction conditions, develop-
ment of this strategy holds significant potential for the
discovery of valuable new chemical reactivity.
a) gem-Diiodides:
Barton, Sternhell, Pross
b) gem-Dichloride:
Myers
c) gem-Difluorides:
Rozen
NNH2
NNH2
NNHTBS
H
H
H
BzO
R
R = CN, NO2
OMe
OPh
6 equiv CuCl2
6 equiv Et3N
-10 °C to rt
6 equiv I2
6 equiv Et3N
4 equiv IF
CHCl3, -78 °C
Cl
Cl
I
I
F F
Cl Cl
I
H
H
H
Recently, we have been investigating new chlorin-
ating and fluorinating reactions mediated by iodanes 1
and 2.[11,12] Because organofluorine compounds play
important roles in the fields of medicinal- and agro-
chemistry, materials science, and medical imaging, de-
veloping innovative strategies for incorporating fluo-
rine into organic scaffolds is economically and socie-
tally important.[13,14] One such fluorine-containing tar-
get is the difluoromethyl (-CHF2) group, which is
known to act as a surrogate hydrogen bond donor for
BzO
R
1
OMe
OPh
F
F
d) This work: aryldichloromethanes and aryldifluoromethanes:
N2
I
NNH2
X
X
1 equiv
2 equiv
H
H
H
1 or 2
1 or 2
3
4
5 X = F
6 X = Cl
2
R
R
R
Scheme 1. Synthesis of aryldihalomethanes from benzalde-
hyde hydrazones via tandem oxidation/dihalogenation.
1
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
this reactivity were discovered: the reaction of stabi-
lized phenyl diazomethanes 3 with one equivalent of
iodanes 1 and 2, or a tandem oxidation/dihalogenation
reaction of hydrazones 4 mediated by two equivalents
of iodane (Scheme 1, d).
substrate scope was investigated using mono-substi-
tuted hydrazones (4a-n), and to correlate the electron
withdrawing ability of the substituent (and thus the sta-
bility of the diazo intermediate) with reaction efficacy
the hydrazones are arranged from most to least stabi-
lized.[26] Electron-poor substrates 4a-i underwent the,
We began this investigation using (p-nitrophenyl)-
diazomethane 3a, prepared via a Bamford-Stevens re-
action of 8a (Scheme 2). Diazo 3a was treated with
TolIF2 under BF3OEt2 catalysis[8a] but the reaction
failed, presumably due to diazo decomposition by
strong Lewis acid and high temperature.[20] Effective
reaction conditions were eventually discovered by var-
ying the solvent, temperature, Lewis acid[21] and the
order and rate of diazo and iodane addition. Under 25
mol% TiF3 catalysis in CH2Cl2 at reflux, the gem-
difluoride 5a was recovered in 70% yield, along with
minor quantities of oxidation by-product 7a and mon-
ofluoride 9a. An analogous chlorination reaction em-
ploying 5 mol% pyridine for iodane activation gave
gem-dichloride 6a in 70% yield, with only a trace of
by-product 7a. These results demonstrated for the first
time the use of non--stabilized diazo compounds in
the geminal ligand transfer reaction with iodanes.
NH2
F
F
Cl Cl
N
2.3 equiv TolIF2
2.5 equiv PhICl2
H
H
H
25 mol% TiF3
CH2Cl2, reflux
10 mol% pyridine
DCE, reflux
R
R
6
R
5
4
yield[a,b]
yield[a,b]
product
substrate
product
F
F
Cl Cl
H
H
5a, 70%
4a
6a, 80%
6b, 68%
6c, 69%
6d, 58%
6e, 77%
O2N
O2N
O2N
O2N
F
F
Cl Cl
5b, 63%
5c, 69%
5d, 62%
4b
4c
4d
4e
H
H
F
F
Cl Cl
H
H
NC
NC
NC
NC
F
F
Cl Cl
H
H
F
F
Cl Cl
5e, 66%[c]
5f, 60%
H
H
NHR
O
N2
N
KOH
RNHNH2
F3C
MeO2C
Br
F3C
MeO2C
Br
H
H
F
F
Cl Cl
H
(R = Ts)
H
H
O2N
O2N
O2N
O2N
4f
6f, 91%
6g, 91%
O2N
7a
8a R = Ts
4a R = H
3a
F
F
Cl Cl
O
F
F
F
H
5g, 68%[c]
4g
H
H
1.1 equiv TolIF2
3a
H
H
H
F
F
Cl Cl
25 mol% TiF3
CH2Cl2, 40 °C
O2N
O2N
5h, 55%
5i, 45%
H
4h
4i
H
6h, 64%
5a
9a
10% yield
7a
70% yield
10% yield
TsO
TsO
F
F
Cl Cl
BnO
BnO
O
H
Cl Cl
Cl
H
6i, 41%[c]
H
H
1.1 equiv PhICl2
3a
H
H
5 mol% pyridine
DCE, rt
F
F
Cl Cl
O2N
O2N
5j, 66%[c]
5k, 63%
4j
6j, 69%
6k, 85%
H
H
6a
10a
7a
70% yield
N/A
trace
F
F
Cl Cl
H
4k
H
Scheme 2. Synthesis and gem-dihalogenation of 3a.
Ph
Me
Ph
Me
F
F
Cl Cl
5l, 66%[c]
H
4l
H
6l, 52%
6m, 6%[c]
6n, 0%
Phenyldiazomethanes are both shock- and thermally
sensitive when substituted with groups less electron-
withdrawing than nitro, so to develop a method more
tolerant to less stabilized substrates, the diazo com-
pounds necessitated in situ generation.[22] Since
iodanes can oxidize hydrazones (eg 4),[23] we hypoth-
esized that a tandem oxidation/gem-dihalogenation se-
quence might be effected with two equivalents of
iodane. The additional step required over the conver-
sion of aldehydes to gem-difluorides using deoxyfluor-
ination agents DAST and Deoxo-fluor[24] is mitigated
by the ease of benzaldehyde hydrazone preparation,
and the benefit of replacing thermally unstable, fuming
liquids with a stable, easily-manipulated solid fluori-
nating agent. Subjecting hydrazone 4a to a variety of
reaction conditions of changing solvent, temperature,
or catalyst and iodane loading, led us to discover that
at 40 °C with 2.3 equiv of 2 and 25 mol% TiF3, 4a is
converted to 5a in 70% yield, again with minor
amounts of by-products 7a and 9a (Scheme 3).[25] The
F
F
Cl Cl
5m, 13%[c]
5n, 0%
H
4m[d]
4n
H
MeO
MeO
F
F
Cl Cl
H
H
Me2N
O2N
Me2N
O2N
F
F
F
F
Cl Cl
5o, 53%
5p, 69%
5q, 63%
H
4o
6o, 79%
6p, 68%
6q, 80%
H
Br
Br
F
Cl Cl
O2N
O2N
H
4p
H
Me
Me
F
Cl Cl
O2N
O2N
H
4q
H
MeO
MeO
Scheme 3. Denitrogenative dihalogenation of benzaldehyde
hydrazone derivatives. [a]Isolated yield. [b]0-10% yield of 7
and 9. [c]1H NMR yield. [d]With 2, 46% yield of 7m; with 1,
60% yield of 7m.
2
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
difluorination reaction in moderate to good yield, as
did the electron neutral hydrazones 4j and 4k, which
proceeded in 66% and 63% yield, respectively. The
moderately electron-rich p-methyl derivative 4l under-
went difluorination in 66% yield; however, substrates
bearing stronger p- OMe (4m) and p-NMe2 (4n) elec-
tron-donating groups generally failed. For 4m, only
13% yield of 5m was observed by 1H NMR, with al-
dehyde 7m recovered in 46% yield. Complete decom-
position of hydrazone was observed for 4n, with only
a trace of 7n observed. Di-substituted hydrazones 4o-
q were studied, and because the difluorination reac-
tions proceeded as well (53-69% yield) as the mono-
substituted hydrazones, the net electron-withdrawing
ability of the substrates appears to override the desta-
bilizing effect of the para-substituent. Overall, the re-
action was suitable for stabilized, neutral and even
moderately destabilized diazos, and only for the elec-
tron-rich substrates did the reaction fail.[27]
Owing to the importance of gem-dichlorides in nu-
merous synthetic transformation, and as functional
groups in biologically-relevant natural products, we
investigated the gem-dichlorination reactions.[28]
Again, the use of a moisture-stable, solid hypervalent
iodine reagent in place of the highly sensitive BCl3,
PCl5, (COCl)2 or Ph3PCl2, etc, would compensate for
the additional step involved.[29] Hydrazone 4a was
converted to 6a in high yield, as did the electron-poor
hydrazones 4b-i, except for m-OBn substrate 4i, which
was similarly low yielding in the fluorination reaction.
Hydrazones 4j-l, with electron-neutral or moderately
electron-rich substituents, performed well, but hydra-
zones 4m and 4n failed. The reaction of 4m was again
dominated by the oxidation pathway (7m, 60% yield),
whereas 4n underwent rapid decomposition and failed
to provide any of 6n or 7n. However, the destabilizing
effect of para- electron donating groups could again
be overridden by a strong electron withdrawing (6o-q).
It is noteworthy that the yields of the fluorination re-
actions beginning with either 4a or 3a were equal, but
the tandem process significantly (10%) higher for the
chlorination reactions, and that very little of 10 was
ever encountered, though by-product 9 was consist-
ently observed.
mixture aliquots clearly indicated the presence of the
diazo compound (Figure 1, b).
a)
3a
b)
TolIF2 (1.0 eq)
TiF3 (25%)
4a
DCM, -78 oC , 3h
c)
4a
+ 2
Figure 1. 1H NMR identification of diazo 3a from the reac-
tion mixture of 4a with 2. a) Reference diazo compound 3a;
b) reaction mixture after 3 hrs at -78 °C; and c) initial rea-
gent mixture of 4a and 2.
The origin of the hydrofluorination byproducts were
also investigated.[25] Partial deuterium exchange was
accomplished by stirring hydrazone 4a in CDCl3 with
20 equiv of D2O, providing a mixture of deuterated
products in 1.8:1 ratio (Scheme 4). Subjecting this hy-
drazone mixture to TolIF2 in the absence of TiF3 gave
a 1.7:1 mixture of deuterated and non-deuterated ben-
zylic fluorides 9a.
NH2
H
NH2
ND2
NHD
H
N
N
N
N
CDCl3
D2O
H
H
O2N
O2N
O2N
O2N
4a
1.8
1
1.7 equiv TolIF2
DCM, reflux
F
H
F
D
H
H
O2N
O2N
1.7
9a
D-9a
1
:
Because of the differences in electrophilicity for
iodanes 1 and 2, the increased basicity of fluoride over
chloride, and the differing product distributions ob-
served for the chlorination and fluorination reactions,
we believe the mechanisms of these reactions are dif-
ferent. Control experiments performed during the di-
chlorination of substituted oxindole-3-hydrazones in-
dicated that the reactions likely did not proceed via di-
azo intermediates,[23e] and the lack of products 10 in
this current work further supports this. To determine
whether diazo intermediate 3a was possibly forming
during the fluorination reactions, we treated hydrazone
4a with TolIF2 at low temperature, and maintained the
reaction -78 °C over several hours (Figure 1).[25] Com-
parison of the 1H NMR spectra of the reference diazo
compound 3a (Figure 1, a), and the initial 4a and 2
mixture (Figure 1, c), with spectra recorded of reaction
Scheme 4. Deuterium labelling to elucidate the origin of 9a.
Our working hypothesis for the fluorination reac-
tion, including our proposal for the occurrence of the
by-products 7 and 9, is depicted in Figure 2. Rapid and
facile oxidation of hydrazone 4, possibly via fluoride-
mediated -elimination of iodotoluene from an adduct
such as A, would provide diazo 3. Diazo 3 can react
via two competing pathways: with the TiF3- activated
iodane or with the HF by-product of the preceding ox-
idation. Since TolIF2 is not a competitive electrophilic
partner for diazos 3 without Lewis acid activa-
tion,[18b,30] product 9 dominates in the absence of TiF3.
In the presence of TiF3 the iodane 2 sufficiently elec-
trophilic to be attacked by 3, giving adduct B, which
can undergo successive, rapid fluorination events to
3
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
give 5.[31] An alternate, competing oxidation pathway
that gives aldehyde 7 is also operative in the reaction,
though it 7 was predominantly observed with electron
rich substrates that would seek to avoid formation of
an unstable diazo.
Acknowledgements
This work was supported by the Natural Sciences and Engineering
Research Council (NSERC) of Canada and the University of Wa-
terloo.
References
H
NH2
N
H
Tol
N
N2
N
I
TolIF2
-HF
-HF
[1] C. Willgerodt, J. Prakt. Chem. 1886, 33, 154.
F
H
H
-TolI
[2] R. F. Weinland, W. Stille, Liebigs Ann Chem 1903, 328,
4
A
3
R
R
R
132-139.
TolIF2
TiF3
HF
TolIF2
[3] For leading books on the structure and reactivity of
hypervalent iodine reagents see a) V. Zhdankin,
Hypervalent Iodine Chemistry: Preparation, Structure,
and Synthetic Applications of Polyvalent Iodine
Compounds, John Wiley & Sons, 2013, pp. 468; b) A.
Varvoglis, The Organic Chemistry of Polycoordinated
Iodine, VCH, New York, N.Y., 1992, pp. 414; c) T.
Wirth, Hypervalent Iodine Chemistry: Modern
Developments in Organic Synthesis, Springer Berlin
Heidelberg, Berlin, 2003; d) T. Kaiho, Iodine chemistry
and applications, Wiley, Hoboken, New Jersey, 2015,
pp. 636.
F
H
F
7
F
F
Tol
I
N2
H
F
H
-N2
H
9
-TolI
R
5
B
R
R
Figure 2. Plausible reaction pathway for the oxidation/gem-
difluorination reaction.
In conclusion, we have developed an effective syn-
thesis of aryldihalomethanes from benzaldehyde hy-
drazones and the stable, easily-prepared iodanes
PhICl2 and TolIF2. A non--stabilized diazo com-
pound proved a viable substrate, with the chlorination
and fluorination reactions bring rapid and good yield-
ing. An inherently safer, general approach to aryldi-
chloro- and aryldifluoromethanes was achieved start-
ing from readily-available hydrazones, which enabled
us employ electron-neutral and modestly electon-do-
nating substrates in this reaction. Use of Lewis acid or
Lewis base activating agents accelerated the ligand
transfer process, and generated the desired products in
moderate to excellent yield for all but the most elec-
tron-rich substrates. Our mechanistic hypothesis is
supported by the observation of diazo formation by 1H
NMR, and by the deuterium transfer observed from the
deuterated hydrazone. This was the first systematic in-
vestigation of benzaldehyde hydrazones in oxidative
dihalogenation reactions, and is the first use of diazo
substrates not possessing an -diazo stabilizing group
in reactions with iodanes. Further reactions of unstabi-
lized diazo or hydrazone-containing compounds with
iodanes will be disclosed in due course.
[4] For comprehensive reviews on the chemistry of
hypervalent iodine reagents see a) A. Yoshimura, V. V.
Zhdankin, Chem. Rev. 2016, 116, 3328-3435; b) V. V.
Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299-
5358; c) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002,
102, 2523-2584.
[5] For recent reviews see a) E. A. Merritt, B. Olofsson,
Synthesis 2011, 517-538; b) A. Jobin-Des Lauriers, C. Y.
Legault, Asian J. Org. Chem. 2016, 5, 1078-1099; c) D.-
Q. Dong, S.-H. Hao, Z.-L. Wang, C. Chen, Org. Biomol.
Chem. 2014, 12, 4278-4289.
[6] For recent reviews see a) S. V. Kohlhepp, T. Gulder,
Chem. Soc. Rev. 2016, 45, 6270-6288; b) R. M. Romero,
T. H. Wöste, K. Muñiz, Chem. Asian J. 2014, 9, 972-983.
[7]a) A. Roedig, H. Aman, E. Fahr, Liebigs Ann Chem 1964,
675, 47-59; b) G. K. Murphy, F. Z. Abbas, A. V. Poulton,
Adv. Synth. Catal. 2014, 356, 2919-2923; c) K. E.
Coffey, G. K. Murphy, Synlett 2015, 26, 1003-1007; d)
J. Tao, T. N. Tuck, G. K. Murphy, Synthesis 2016, 48,
772-782.
[8] a) J. Tao, R. Tran, G. K. Murphy, J. Am. Chem. Soc.
2013, 135, 16312-16315; b) E. Emer, J. Twilton, M.
Tredwell, S. Calderwood, T. L. Collier, B. Liegault, M.
Taillefer, V. Gouverneur, Org. Lett. 2014, 16, 6004-
6007; c) Y. Zhou, Y. Zhang, J. Wang, Org. Biomol.
Chem. 2016, 14, 10444-10453.
Experimental Section
To a PFA vial equipped with a magnetic stir bar was charged
(difluoroiodo)toluene (178 mg, 0.69mmol, 2.3 equiv) and
anhydrous CH2Cl2 (3 mL), and the resulting solution was
placed under a nitrogen atmosphere. The reaction vial was
immersed in a preheated 40 °C oil bath, and stirred while
TiF3 (7.8 mg, 25 mol%) was added. To this, a solution of
hydrazone 4 (0.3 mmol, 1 equiv) in CH2Cl2 (1.2 mL) was
added dropwise over 8 minutes using a syringe pump. The
reaction was monitored by TLC analysis, and upon con-
sumption of the hydrazone (5-30 min), the reaction mixture
was cooled to room temperature, transferred to a round bot-
tom flask and concentrated by under vacuum by rotary evap-
oration. The resulting crude product mixture was purified by
flash silica gel chromatography to provide gem-difluorome-
thyl arenes 5.
[9] W. M. Yuan, L. Eriksson, K. J. Szabo, Angew. Chem.,
Int. Ed. 2016, 55, 8410-8415; Angew. Chem. 2016, 128,
8550-8555.
[10] D. P. Hari, J. Waser, J. Am. Chem. Soc. 2016, 138,
2190-2193.
[11] For the synthesis and reactivity of 1 see a) J. Yu, C.
Zhang, Synthesis 2009, 2324-2328; b) X. Duan, H. Zhou,
X. Tian, J. Liu, J. Ma, Synthesis 2015, 47, 777-782; c) L.
4
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
K. B. Garve, P. Barkawitz, P. G. Jones, D. B. Werz, Org.
Champagne, J. Desroches, J. F. Paquin, J. Fluorine
Chem. 2016, 190, 1-6.
Lett. 2014, 16, 5804-5807; d) L. L. Tang, D. Zhang-
Negrerie, Y. F. Du, K. Zhao, Synthesis 2014, 46, 1621-
1629; e) M. S. Carle, G. K. Shimokura, G. K. Murphy,
Eur. J. Org. Chem. 2016, 3930-3933. For solid
supported, catalytic or recyclable applications see e) J.
M. Chen, X. M. Zeng, K. Middleton, V. V. Zhdankin,
Tetrahedron Lett. 2011, 52, 1952-1955; f) A. Podgorsek,
M. Jurisch, S. Stavber, M. Zupan, J. Iskra, J. A. Gladysz,
J. Org. Chem. 2009, 74, 3133-3140; g) M. Ochiai, K.
Miyamoto, Eur. J. Org. Chem. 2008, 4229-4239.
[22] a) M. I. Javed, M. Brewer, Org. Lett. 2007, 9, 1789-
1792; b) V. L. Rendina, D. C. Moebius, J. S. Kingsbury,
Org. Lett. 2011, 13, 2004-2007. For additional
information on diazocarbonyl reactivity see c) M. P.
Doyle, M. A. Mckervey, T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds:
From Cycloproapanes to Ylides. Wiley-Interscience:
1998; p 652; d) T. Ye, M. A. Mckervey, Chem. Rev.
1994, 94, 1091-1160; e) Z. H. Zhang, J. B. Wang,
Tetrahedron 2008, 64, 6577-6605.
[12] For the synthesis and reactivity of 2 see a) M. A. Arrica,
T. Wirth, Eur. J. Org. Chem. 2005, 2005, 395-403; b) J.
Yu, J. Tian, C. Zhang, Adv. Synth. Catal. 2010, 352, 531-
546; c) P. Conte, B. Panunzi, M. Tingoli, Tetrahedron
Lett. 2006, 47, 273-276; d) T. Inagaki, Y. Nakamura, M.
Sawaguchi, N. Yoneda, S. Ayuba, S. Hara, Tetrahedron
Lett. 2003, 44, 4117-4119; e) W. B. Motherwell, M. F.
Greaney, D. A. Tocher, J. Chem. Soc., Perkin Trans. 1
2002, 2809-2815; f) M. Yoshida, K. Fujikawa, S. Sato,
S. Hara, Arkivoc 2003, 36-42. For solid supported or
catalytic applications see g) I. G. Molnar, R. Gilmour,
J. Am. Chem. Soc. 2016, 138, 5004-5007; h) H. Togo, K.
Sakuratani, Synlett 2002, 1966-1975; i) T. Kitamura, K.
Muta, J. Oyamada, J. Org. Chem. 2015, 80, 10431-
10436.
[23] a) D. H. R. Barton, J. C. Jaszberenyi, W. S. Liu, T.
Shinada, Tetrahedron 1996, 52, 14673-14688; b) P. A.
S. Smith, E. M. Bruckmann, J. Org. Chem. 1974, 39,
1047-1054; c) A. Cnossen, J. C. M. Kistemaker, T.
Kojima, B. L. Feringa, J. Org. Chem. 2014, 79, 927-935;
d) L. Lapatsanis, G. Milias, S. Paraskewas, Synthesis
1985, 1985, 513-515; e) K. E. Coffey, R. Moreira, F. Z.
Abbas, G. K. Murphy, Org. Biomol. Chem. 2015, 13,
682-685.
[24] For examples of the conversion of benzaldehydes to
benzal fluorides see a) G. S. Lal, G. P. Pez, R. J. Pesaresi,
F. M. Prozonic, H. S. Cheng, J. Org. Chem., 1999, 64,
7048-7054; b) T. Gustafsson, R. Gilmour, P. H.
Seeberger, Chem. Commun., 2008, 3022-3024; c) S.
Verhoog, L. Pfeifer, T. Khotavivattana, S. Calderwood,
T. L. Collier, K. Wheelhouse, M. Tredwell, V.
Gouverneur, Synlett, 2016, 27, 25-28.
[13] J.-P. Bégué, D. Bonnet-Delpon, Bioorganic and
medicinal chemistry of fluorine, John Wiley & Sons,
Hoboken, N.J., 2008, pp. 365.
[14] a) E. Lee, A. S. Kamlet, D. C. Powers, C. N. Neumann,
G. B. Boursalian, T. Furuya, D. C. Choi, J. M. Hooker,
T. Ritter, Science 2011, 334, 639-642; b) V. Gouverneur,
Nat. Chem. 2012, 4, 152-154.
[25] See the supporting information for reaction
optimization details, mechanistic studies and related
discussion.
[26] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91,
[15] J. A. Erickson, J. I. McLoughlin, J. Org. Chem. 1995,
60, 1626-1631.
165-195.
[27] Azine or stilbene by-products, characteristic phenyldi-
azomethanes undergoing thermal decomposition, were
not observed in these reactions. See a) D. Bethell, D.
Whittaker, J. Chem. Soc. B 1966, 778-782; b) H. Nozaki,
R. Noyori, K. Sisido, Tetrahedron 1964, 20, 1125-1132.
[16] a) D. H. R. Barton, R. E. O'Brien, S. Sternhell, J. Chem.
Soc. 1962, 470-476; b) A. Pross, S. Sternhell, Aust. J.
Chem. 1970, 23, 989-1003.
[17] For the use of elemental chlorine and bromine with
other types of hydrazone see A. Pross, S. Sternhell, Aust.
J. Chem. 1971, 24, 1437-1447.
[28] For examples of reactions of gem-dichlorides see a) J.
R. Halpert, C. Balfour, N. E. Miller, L. S. Kaminsky,
Mol. Pharmacol., 1986, 30, 19-24; b) G. W. Kabalka,
N.-S. Li, S. Yu, J. Organomet. Chem., 1999, 572, 31-36;
c) Y. Ishino, M. Mihara, S. Nishihama, I. Nishiguchi,
Bull. Chem. Soc. Jpn., 1998, 71, 2669-2672; d) M.
Steiniger, H. J. Schafer, Angew. Chem., Int. Ed., 1982,
21, 79-80. For discussion of natural products containing
gem-dichlorides see e) D. K. Bedke, C. D. Vanderwal,
Natural Product Reports, 2011, 28, 15-25; f) G. W.
Gribble, Heterocycles, 2012, 84, 157-207.
[18] a) M. E. Furrow, A. G. Myers, J. Am. Chem. Soc. 2004,
126, 5436-5445; b) M. E. Furrow, A. G. Myers, J. Am.
Chem. Soc. 2004, 126, 12222-12223. For another
example of using CuCl2 and CuBr2 in gem-dihalide
synthesis see c) T. Takeda, R. Sasaki, S. Yamauchi, T.
Fujiwara, Tetrahedron 1997, 53, 557-566.
[19] S. Rozen, D. Zamir, J. Org. Chem. 1991, 56, 4695-
4700.
[20] C. D. Gutsche, D. Redmore, Carbocyclic ring
expansion reactions, Academic Press, New York, 1968,
pp. 243.
[29] For examples of the conversion of benzaldehydes to
benzal chlorides see a) D. E. Armstrong, D. H.
Richardson, J. Chem. Soc., 1933, 496-500; b) G. W.
Kabalka, Z. Wu, Tetrahedron Lett., 2000, 41, 579-581;
c) J. An, X. P. Tang, J. Moore, W. Lewis, R. M. Denton,
Tetrahedron, 2013, 69, 8769-8776.
[21] a) G. S. Sinclair, R. Tran, J. Tao, W. S. Hopkins, G. K.
Murphy, Eur. J. Org. Chem. 2016, 2016, 4603-4606. For
similar examples of Bronsted acid activation of 2 see b)
T. Kitamura, S. Kuriki, M. H. Morshed, Y. Hori, Org.
Lett. 2011, 13, 2392-2394; c) R. Hemelaere, P. A.
[30] The Lewis acid was essential to suppressing the com-
peting hydrofluorination reaction. See K. G. Kulkarni, B.
5
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
Miokovic, M. Sauder, G. K. Murphy, Org. Biomol.
Chem. 2016, 14, 9907-9911.
[31] An alternate mechanism proceeding through diimide
interemediates has also been proposed. See reference
[17] for relevant discussion.
6
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10.1002/adsc.201700393
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of Aryldihalomethanes by Denitrogena-
tive Dihalogenation of Benzaldehyde Hydrazones
Adv. Synth. Catal. Year, Volume, Page – Page
Zhensheng Zhao,a Kaivalya G. Kulkarni,a and
Graham K. Murphya,*
7
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