Unanticipated participation of HCl in nucleophilic chlorination reaction: Expedient route to meta chlorophenols

Article abstract of DOI:10.1016/j.tetlet.2015.11.012

o-Quinone monoketals participated in a 1,4-addition reaction with HCl furnishing m-chlorophenols in high yields. Several readily available o-quinone monoketals were selected to display the generality of this serendipitous and unprecedented reaction and the results are presented herein.

Full text of DOI:10.1016/j.tetlet.2015.11.012

Tetrahedron Letters 57 (2016) 15–19
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unanticipated participation of HCl in nucleophilic chlorination
reaction: expedient route to meta chlorophenols
⇑
Santhosh Kumar Chittimalla , Chennakesavulu Bandi
Medicinal Chemistry Department, AMRI Singapore Research Centre, 61 Science Park Road, #05-01, The Galen, Science Park II, Singapore 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2015
Revised 10 October 2015
Accepted 4 November 2015
Available online 5 November 2015
o-Quinone monoketals participated in a 1,4-addition reaction with HCl furnishing m-chlorophenols in
high yields. Several readily available o-quinone monoketals were selected to display the generality of this
serendipitous and unprecedented reaction and the results are presented herein.
Ó 2015 Elsevier Ltd. All rights reserved.
This communication is dedicated to Dr.
Hsing-Pang Hsieh on the occasion of his
53rd birthday
Keywords:
Quinone monoketals
Chlorophenols
1,4-Addition
Halogen effect
Tandem reactions
For the past few years our research group has been involved in
expanding the scope of masked o-benzoquinones (MOBs, o-qui-
none monoketals)1,2 in organic synthesis.3 During the course of
our research programme employing MOBs as substrates, a variety
of meta functionalized phenols have been synthesized.2d,4
Interestingly, during the optimization process for the preparation
dearomatization–1,4-addition reaction–rearomatization sequence.
As a result of this unprecedented outcome coupled with a novel
procedure for meta chlorination of phenols in hand, it was contem-
plated that this serendipitous observation was worth pursuing
further.
Our investigations for the envisaged protocol commenced by
verifying the conversion of MOB 2a to product 3a-m. To begin with,
phenol 1a was converted to MOB 2a via oxidative dearomatization
using PhI(OAc)2 in methanol (Scheme 1).2–4 The obtained MOB 2a
was subsequently treated with 4 N HCl in 1,4-dioxane (5 equiv) at
room temperature. Almost instantaneous disappearance of the yel-
low colour of the reaction mixture indicated the complete con-
sumption of MOB 2a. However, the reaction was run for 2–3 min
to ascertain that MOB 2a was completely consumed. Simple aque-
ous work-up (saturated aqueous NaHCO3/ethyl acetate) provided
clean product in 95% yield (Table 1, entry 1) without the need for
column chromatographic purification.6 The coupling constants
(JH4–H6 = JH6–H4 = 2.4 Hz) from the 1H NMR spectra indicated the
meta relationship of protons H4 and H6 in 3a-m confirming the
assigned regiochemistry. After some experimentation it was found
that the reaction was high yielding and instantaneous even when
2.0 equiv of HCl was used, which represented the optimal condi-
tions for subsequent reactions. Encouraged by this result several
o-quinone monoketals 2b–j (Scheme 1) were prepared from
readily available 2-methoxyphenols.2–4,7c To our satisfaction MOBs
of aryl glycine derivative
I and C-aryl acetophenone II, we
observed the formation of small quantities of m-chlorophenol
derivative 3a-m (Fig. 1). However, this was only noticed when
MOB 2a was not completely consumed in the first step (Michael
addition). Therefore, we attributed the unexpected formation of
2,3-dimethoxy-5-chloro phenol (3a-m) to the nucleophilic 1,4-
addition of ‘chloride’ from HCl (utilized in the second step) to
MOB 2a followed by aromatization. We were intrigued by the
fact that ‘chloride’ was able to undergo
a smooth Michael
addition to MOB 2a. To the best of our knowledge, such an
observation is unknown in o-quinone monoketal chemistry.5 In
general, phenols undergo electrophilic substitution producing
ortho or para derivatized products. In the present reaction, starting
from 2,3-dimethoxyphenol (1a, the precursor of MOB 2a, Fig. 1),
we ended-up with
a m-chlorophenol derivative 3a-m via a
⇑
Corresponding author.
E-mail addresses: santhosh.chittimalla@amriglobal.com, chemcsk@gmail.com
(S.K. Chittimalla).
http://dx.doi.org/10.1016/j.tetlet.2015.11.012
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

16
S. K. Chittimalla, C. Bandi / Tetrahedron Letters 57 (2016) 15–19
our previouswork: ref. 4a
step 1: Michael addition
(i) LDA, THF
then
2c–e, the C-4 position appeared to be the next preferred position
OH
for ‘chloride’ addition, subsequently providing 3c-p to 3e-p as
the minor isomer. Similar para selectivity was observed during
the synthesis of 3-arylindoles where MOBs were utilized as an aryl
source.2d
OMe
MeO2C
0 o
C
MeO2C
Me
O
OMe
CF3
F3C
N
OMe
OMe
Me
N
OMe
Table 1
rt
2a
I
or
Tandem 1,4/1,6-nucleophilic ‘chloride’ addition followed by aromatizationa
or
OH
step 2: Aromatization
O
OMe
OMe
Entry
Substrate
Product/isolated yield
OH
(ii)
4 N HCl in
1,4-dioxane, rt
O
Ph
Me
O
OCH3
1
1
Ph
OCH3
2
3
6
OCH3
II
2
1
2a
2b
3a-m: 95%
3b-m: 92%
6
unexpected side product:
observed only when MOB 1 was not
5
OCH3
Cl
OCH3
5
3
4
4
completely consumed in step 1.
Cl
OH
O
OH
Cl
O
OCH3
OCH3
OCH3
O
' ? '
' ? '
OCH3
OCH3
OCH3
2a
2
-
O
m-
Cl
'Cl ' from
OCH3
HCl
OCH3
3a-m (15 - 25 %)
O
O
O
OH
Figure 1. Unexpected formation of chlorophenol derivative 3a-m via ‘chloride’
Michael addition to MOB 2a.
OCH3
OCH3
OCH3
CH3
3c-m: 81% (m:
p = 90:10)a
3
4
5
2c
2d
2e
m-
Cl
CH3
p-
OH
2b–e provided the expected meta chlorophenols 3b-m to 3e-m as
major isomers along with small amounts of other regioisomers
as indicated in Table 1, entries 2–5. A unique feature of MOBs is
that all its carbon centres (C-1 to C-6) are potentially electrophilic
in nature (Fig. 2).7 As a consequence the possibility for the forma-
tion of other regioisomers is often inevitable. However, the exclu-
sive formation of, or unequal amounts of regioisomers in the
nucleophilic addition onto MOB can be attributed to (i) the nature
of nucleophile (ii) electronic factors (i.e., substituents dictating the
charge densities at the reaction centre) and (iii) sterically hindering
groups near to the reaction site. The cumulative effect of the above
factors influencing the regioselectivity also cannot be ruled-out.
Thus, in the present study the formation of small amounts of
regioisomers was not surprising. From the above results, it was evi-
dent that the carbonyl group strongly dictated ‘chloride’ addition
to C-3, resulting in the observed meta-selectivity. Moreover, activa-
tion by the dimethoxy ketal moiety (Fig. 2, B) in MOB 2 could in
principle provide 3-o (ortho) or 3-p (para) products. In MOBs
O
O
OCH3
OCH3
3d-mb: 82%
3d-p: 2% (m:p:
o = 91:6:3)a
OCH3
Br
o-
m-
Cl
Br
p-
OH
OCH3
OCH3
OCH3
3e-m: 82% (m:
p = 90:10)a
m-
o-
CO2CH3
Cl
CO2CH3
p-
OH
O
OCH3
OCH3
OCH3
m-
Cl
3f-m: 78% (m:
o = 87:13)a
6
2f
O
O
O
O
O
OH
OH
OCH3
OCH3
o-
OCH3
Cl
3g-m: 0%
3g-o: 90%
7
2g
2h
m-
CH3
CH3
CH3
CH3
4 N HCl
1,4-dioxane
(2 equiv)
OH
O
H3C
H3C
O
PhI(OAc)2
CH3OH
OCH3
OCH3
OCH3
R1
OCH3
OCH3
o-
OCH3
Cl
0 °C to rt
30 min
rt, 2 min
3h-m + 3h-
o = 90% (m:
o = 25:75)a
R1
8c
R2
R2
m-
1a−1j
2a (95%); 2b (93%); 2c (93%);
Br
O
Br
OH
2d (90%); 2e (94%); 2f (88%);
2g (95%); 2h (90%); 2i (93%); 2j (93%)
OCH3
OCH3
o-
OCH3
Cl
3i-m + 3i-
o = 90% (m:
o = 30:70)a
OH
OH
OH
9c
2i
2j
OCH3
R1
m-
OCH3
R1
Cl
OCH3
R1
Cl
Cl
Cl
R2
Cl
R2
3j-o: 90%d(m:
o = 0:100)d
10b
3a-m−3f-m;
3h-m−3j-m
3c-p−3e-p
3d-o; 3f-o−3j-o
a: R1 = OCH3; R2 = H b: R1 = ketal; R2 = H c: R1 = CH3; R2 = H
d: R1 = Br; R2 = H e: R1 = CO2CH3; R2 = H f: R1 = H; R2 = ketal
g: R1 = H; R2 = tBu h: R1 = H; R2 = Br i: R1 = H; R2 = Cl j: R1 = H; R2 = F
Ratio of isomers was obtained by 1H NMR integration of diagnostic peaks in the
a
crude reaction mixture.
b
Ref. 8.
c
Chromatographically inseparable mixture of isomers was obtained.
Small amount of an inseparable unknown impurity was also observed.
Scheme 1. Preparation of masked o-benzoquinones (MOBs) and nucleophilic
‘chloride’ addition to MOBs.
d

S. K. Chittimalla, C. Bandi / Tetrahedron Letters 57 (2016) 15–19
17
analysis of the crude reaction mixture), respectively. However, a
small role of sterics caused by halogens near to the reaction centre
cannot be ruled-out for the observed reversal of regioselectivity.
The assignment of regioselectivity was straightforward in most
cases. For example, in the cases of 3a-m to 3e-m both aromatic
protons had coupling constants of 2.4 Hz indicating the meta rela-
tionship of these protons; similarly 3f-o to 3j-o and 5 showed cou-
pling constants between 1.8 Hz and 2.8 Hz indicating the meta
relationship of the protons on the aromatic ring. Subsequently,
for products 3f-m, 3h-m, 3i-m, regioselectivity was assigned based
on the observed singlets in the aromatic region. The minor isomer
3e-p was assigned by comparing its 1H NMR d values with that of
starting phenol 1e as shown in Figure 3. In the cases of substrates
2c and 2d where the major isomers were unambiguously assigned
based on meta coupling constants, regioselectivity assignment of
the minor isomers seemed challenging. However, upon comparing
d values of the 1H NMR spectra of 3d-o and 3d-p the minor isomers
were tentatively assigned as shown in Figure 3.10 The difference in
d ppm values of the aromatic protons was very small in 3d-o indi-
cating that both protons were experiencing a similar environment.
In the case of 3g-o, meta coupling unambiguously supported the
assigned regioselectivity. Moreover, 2D-NOESY experiments also
indicated the same. In regioisomer 3c-p, the methyl group did
not show any cross peaks with aromatic protons in a 2D-NOESY
experiment indicating the assigned regioselectivity.10
I
Nu
Nu
Cl-
O
2
2
O
O
1
1
6
H
H
3
4
3
4
Nu
6
OCH3
OCH3
O CH3
H
5
5
OCH3
O
H3CO
CH3
Nu
Nu
Nu
A
B
C
II
X
Cl-
Cl-
O
O
H
OCH3
OCH3
H
OCH3
CH3
X
O
X = Br, Cl, F
Figure 2. (I) A and B: All carbon centres in a MOB are electrophilic in nature; C:
Rationale for the observed ortho selectivity in the case of p-quinone monoketals; (II)
possible reason for ortho preference of the ’chloride’ nucleophile for halogenated
MOBs 2h–2j.
Next, MOB 2f (4-ketal substitution, Table 1, entry 6) was sub-
jected to the optimized reaction conditions. As usual MOB 2f pro-
vided 3f-m as the major isomer (78% isolated yield) along with 13%
of isomer 3f-o as indicated by 1H NMR analysis of the crude
reaction mixture. Interestingly, the ketal group in the minor isomer
3f-o was hydrolysed during column chromatography to give ben-
zaldehyde derivative 5. Alternatively, when the reaction mixture
3f-m + 3f-o was further treated with 15.0 equiv of 4 N aq HCl
and heated to 50 °C for 6 h, the ketal groups of both isomers were
hydrolysed providing separable benzaldehyde derivatives 4 and 5
in acceptable yields (Scheme 2).
To further evaluate the scope of the reaction we then subjected
o-naphthoquinone monoketals 811 and 911 to the general reaction
conditions. Both substrates underwent the tandem Michael-addi-
tion followed by the aromatization reaction sequence providing
the expected m-chloronaphthol derivatives 1012 and 11 in high
yields (Scheme 3).
OH
OH
OH
To test the effect of steric hindrance near the reaction site on
the regioisomeric ratio MOB 2g was utilized which exclusively fur-
nished isomer 3g-o (Table 1, entry 7). This suggested that the bulky
t-butyl group indeed completely blocked the b-position of the
Hd
Cl
OCH3
R1
Cl
OCH3
Ha
Hd
Cl
OCH3
Ha
Hc
a,b-unsaturated ketone from ‘chloride’ attack. Subsequently, 4-
Hb
R2
R2
halogenated MOBs 2h–j were tested in the reaction. 4-Bromo
(2h) and 4-chloro (2i), substituted MOBs provided inseparable
mixtures of chlorophenol derivatives 3h/i-m and 3h/i-o, where
meta regioselectivity was the minor reaction pathway (Table 1,
entries 8 and 9). The reversal of the regioselectivity in these cases
could be due to halogens’ ability to participate in mesomeric effect,
thus changing the selectivity (Fig. 2-II). To further ascertain the
presence of the halogen effect, we utilized MOB 2j (with a fluoro
substitution) in the reaction. On the basis that fluorine participates
in strong electron-donating resonance9 compared to chloro and
bromo,9 we anticipated a profound halogen effect in MOB 2j. As
expected, in the case of MOB 2j the only product observed was
2j-o (Table 1, entry 10) compared to ortho/meta products in ratio
of 75:25 and 70:30 for MOBs 2h and 2i (as indicated by 1H NMR
meta coupling
JHb-Hd = 2.4 Hz
3a-m to 3e-m
meta coupling
JHa-Hc = 2.0 - 2.8 Hz
3f-o to 3j-o
Ha& Hd observed
as singlets
3f-m, 3h-m, 3i-m
comparison of δ values in phenol '1e' and '3e-p'
OH
OH
7.14
Hd
6.94
Hd
OCH3
OCH3
7.04
CO2CH3 Hc
7.04
Hc
CO2CH3
H
1ae
Cl
3e-p
7.38
OH
OH
6.88
Hd
Cl
OCH3
Br
OCH3
Br
7.15
Hc
Hc
6.99
Hb
7.03
Cl
4 N HCl
4 N HCl
1,4-dioxane/H2O
50 °C
OH
2f
3f-m + 3f-o
3d-o
3d-p
1,4-dioxane
OH
OH
Cl
OH
Cl
OCH3
Ha
Hd
OCH3
CH3
OCH3 Cl
OCH3
Hc
Hc
CH3
CH3
Cl
H3C
CHO
4 (65%)
CHO
5 (5%)
In 2D-NOESY spectra no cross peaks
2D-NOESY cross peaks with aromatic protons observed
3g-o 3c-p
Scheme 2. One pot tandem nucleophilic ‘chloride’ addition–aromatization–ketal
deprotection sequence.
Figure 3. Regioselectivity assignment for the obtained products.

18
S. K. Chittimalla, C. Bandi / Tetrahedron Letters 57 (2016) 15–19
OH
4 N HCl
1,4-dioxane
(2 equiv)
OH
O
OCH3
R1
R2
R1
R2
PhI(OAc)2
CH3OH
rt, 2 min
0 °C to rt
30 min
PhI(OAc)2
Cl
OH
O
4 N HCl
1,4-dioxane
(2 equiv)
2.2 equiv in
2 portions at
2 h interval
OCH3
OCH3
H3CO OCH3
OCH3
12: R1 = R2 = H
15: R1 = R2 = H (93%)
R = H; 10 (94%)
16: R1 = H; R2 = OCH3 (90%)
17: R1 = t-Bu; R2 = H (94%)
CH3OH
rt, 16 h
rt, 2 min
13: R1 = H; R2 = OCH3
14: R1 = t-Bu; R2 = H
OH
OCH3
OH
OH
OH
R
R
Cl
Cl
Cl
Cl
R = H; 6
R = Br; 7
R = H; 8 (76%)
R = Br; 9 (73%)
OCH3
Br
OCH3
18 (94%)
OCH3
OCH3
20 (94%)
R = Br; 11 (93%)
19 (90%)
Scheme 3. o-Naphthoquinone monoketals 8, 9 as substrates in a tandem ‘chloride’
Michael addition–aromatization sequence.
Scheme 4. p-Quinone monoketals as substrates in the nucleophilic ‘chloride’
addition–aromatization sequence.
Recently it was reported that p-quinone monoketals, upon
reaction with N,N0-dimethylhydrazine dihydrochloride, provided
o-chlorophenols.5 It was also reported that 1 N HCl was successful
in providing o-chlorophenol 15 in good yield, however substituted
p-quinone monoketals provided lower yields under these condi-
tions. To our delight, using our reaction procedure not only unsub-
stituted p-quinone monoketal 15, but even substituted p-quinone
monoketals 16 and 17 provided high yields of the o-chlorophenol
products 19 and 20, respectively (Scheme 4). In all cases the reac-
tion was complete within 2 min and a simple aqueous work-up
provided the clean product without the need for further purifica-
tion. It appears that preferential activation of the methoxy group
over the ketone moiety in p-quinone monoketals (15–17, Fig. 2C)
by HCl results in the observed reversal of regioselectivity in the
nucleophilic chloride addition. It should also be noted that acid
mediated displacement of an allylic methoxy group in p-quinone
monoketals was observed in several instances.13
General procedure for the preparation of m-chlorophenols: To
MOB 2a (1.0 mmol) in a reaction vessel was added 4 N HCl in
1,4-dioxane (0.5 mL, 2 mmol) drop-wise. Disappearance of the yel-
low colour of MOB 2a was instantaneous. The solvent was evapo-
rated in vacuo. The residue was diluted with ethyl acetate (10 mL)
and washed with saturated aqueous NaHCO3 (5 mL). The organic
fractions were dried over Na2SO4, filtered and concentrated to give
m-chlorophenol 3a in 95% yield. Whenever required column chro-
matographic purification was performed using ethyl acetate/hex-
anes gradient as eluent.
Acknowledgments
The authors sincerely thank Dr. Takeshi Yura and Dr. Anjan
Chakrabarti for encouragement. Financial support from AMRI
Singapore is gratefully acknowledged.
In conclusion, a convenient and efficient method for the meta-
chlorination of certain phenols has been developed. The reaction
protocol relied on an arene oxidation–‘chloride’ Michael addi-
tion–aromatization sequence. It should be noted that the reaction
conditions tolerated ester and ketal functionalities in substrates
2e, 2b and 2f respectively. Moreover, this strategy could be
extended to o-naphthoquinone derivatives which provided the
corresponding chloronaphthols in high yields. In addition, it is evi-
dent from our study that commercial 4 N HCl in 1,4-dioxane is a
highly reliable source of ‘chloride’ in the reaction and is distinct
from that of a recent study which relied on N,N0-dimethylhy-
drazine dihydrochloride to furnish o-chlorophenols. Although
regioisomers were obtained with several substrates, the observed
regioselectivity was high and the isomers could be separated in
some cases.
Supplementary data
Supplementary data (copies of 1H and 13C NMR spectral data
along with hydroxyl group 1H NMR chemical shift trend table)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.11.012.
References and notes
1. For reviews on quinone monoketals see, (a) Pouysegu, L.; Deffieux, D.; Quideau,
S. Tetrahedron 2010, 66, 2235–2261; (b) Quideau, S.; Pouysegu, L.; Deffieux, D.
Synlett 2008, 467–495; (c) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev.
2004, 104, 1383–1430; (d) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35,
856–866.
2. Synthetic protocols for the preparation of cyclohexadienones, see (a) Tamura,
Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927–3930; (b) Deffieux,
D.; Fabre, I.; Titz, A.; Leger, J.-M.; Quideau, S. J. Org. Chem. 2004, 69, 8731–8738;
(c) Pelter, A.; Elgendy, S. M. A. J. Chem. Soc., Perkin Trans. 1 1993, 1891–1896; (d)
Chittimalla, S. K.; Bandi, C.; Putturu, S.; Kuppusamy, R.; Boellaard, K. C.; Tan, D.
C. T.; Lum, D. M. J. Eur. J. Org. Chem. 2014, 2565–2575.
3. (a) Chittimalla, S. K.; Laxmi, S.; Amerlyn, C. M. L.; Jerald, L. K. J.; Kuppusamy, R.;
Putturu, S.; Bandi, C. RSC Adv. 2015, 5, 29391–29396; (b) Chittimalla, S. K.;
Bandi, C.; Putturu, S. RSC Adv. 2015, 5, 8050–8055; (c) Chittimalla, S. K.; Bandi,
C. RSC Adv. 2013, 3, 13663–13667; (d) Chittimalla, S. K.; Kuppusamy, R.;
Thiayagarajan, K.; Bandi, C. Eur. J. Org. Chem. 2013, 2715–2723; (e) Chittimalla,
S. K.; Kuppusamy, R.; Chakrabarti, A. Synlett 2012, 1901–1906.
4. (a) Chittimalla, S. K.; Kuppusamy, R.; Bandi, C. Synlett 2014, 1991–1996; (b)
Chittimalla, S. K.; Kuppusamy, R.; Naresh, A. Synlett 2015, 613–618.
5. While our project was in progress, nucleophilic addition of ‘chloride’ (N,N0-
OCH3
OCH3
OCH3
OCH3
H3CO
O
4 N HCl
H3CO
in 1,4-dioxane
2a
OCH3
OCH3
CH3OH
rt, 5 min
OCH3
OCH3
H3CO
OCH3
OCH3
dimethylhydrazine dihydrochloride as
a ‘chloride’ source) to p-quinone
OCH3
21 (71%)
monoketals generating o-chlorophenol derivatives was reported: Yin, Z.;
Zhang, J.; Wu, J.; Green, R.; Li, S.; Zheng, S. Org. Biomol. Chem. 2014, 12,
2854–2858.
6. When a methanolic solution of MOB 2a was treated with 4 N HCl in 1,4-
dioxane (2.0 equiv), we were surprised to isolate 1,2,3,5-tetramethoxybenzene
Figure 4. One pot tandem nucleophilic ‘methoxy’ addition–dimethoxy ketal
formation–aromatization sequence.6

S. K. Chittimalla, C. Bandi / Tetrahedron Letters 57 (2016) 15–19
2p-orbitals [compared to 3p
19
(21, 71% isolated yield, Fig. 4). However under the above reaction conditions,
MOB 2g and masked p-benzoquinone (MPB) 15 provided the corresponding
chlorophenols 3g-o and 18, respectively. Currently, we are not sure what the
driving force for the formation of 21 from 2a might be. Work towards
understanding this phenomenon is in progress. For analytical data for
compound 21, see Deodhar, M.; Black, D. StC.; Kumar, NTetrahedron 2007, 63,
5227–5235.
p–2pp
(Cl–C) or 4p
p–2pp
(Br–C)] which
strengthens the electron-donating resonance interaction. (a) Uneyama, K.
Organofluorine Chemistry; Blackwell: Oxford, 2006. pp 10–11; (b) Bingham, R. C.
J. Am. Chem. Soc. 1976, 98, 535–540; (c) Polishchuk, V. R.; Mysov, E. I.;
Stankevitch, I. V.; Chistyakov, A. L.; Potechin, K. A.; Struchkov, Y. T. J. Fluorine
Chem. 1993, 65, 233–238; (d) Wiberg, K. B.; Rablen, P. R. J. Org. Chem. 1998, 63,
3722–3730; (e) Carroll, T. X.; Thomas, T. D.; Bergersen, H.; Børve, K. J.; Saethre,
L. J. J. Org. Chem. 2006, 71, 1961–1968; (f) O’Hagan, D. Chem. Soc. Rev. 2008, 37,
308–319.
7. Representative precedents for site–selective nucleophilic additions on MOBs,
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9. The strong electron-donating nature of fluorine can be attributed to the
effective overlap of 2p-orbital of the lone pair on the fluorine with the carbon