Synthesis of halogenated phenols by directed ortho-lithiation and ipso-iododesilylation reactions of O-aryl N-isopropylcarbamates

Article abstract of DOI:10.1055/s-2006-926462

The regioselective synthesis of halogenated phenols via directed ortho-lithiation reactions of in situ N-silylated O-aryl N-isopropylcarbamates is reported. This protocol is complemented by ipso-iododesilylation reactions of C-silylated carbamates and iodine-magnesium exchange reactions, which are facilitated by the adjacent carbamoyl group. These methods provide an entry into a series of o-fluoro-, o-iodo-, and o,o′-diiodophenols in high yields which are otherwise difficult to obtain. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926462

1578
PAPER
Synthesis of Halogenated Phenols by Directed ortho-Lithiation and
ipso-Iododesilylation Reactions of O-Aryl N-Isopropylcarbamates
HalogenatedPhenols
b
a
yLithiation
t
a
ndIo
t
dodesi
h
lylation
R
eac
i
tions as Kauch, Dieter Hoppe*
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8336531; E-mail: dhoppe@uni-muenster.de
Received 23 December 2005
(b)
(a)
O
Abstract: The regioselective synthesis of halogenated phenols via
directed ortho-lithiation reactions of in situ N-silylated O-aryl N-
isopropylcarbamates is reported. This protocol is complemented by
ipso-iododesilylation reactions of C-silylated carbamates and io-
dine–magnesium exchange reactions, which are facilitated by the
adjacent carbamoyl group. These methods provide an entry into a
series of o-fluoro-, o-iodo-, and o,o¢-diiodophenols in high yields
which are otherwise difficult to obtain.
R
R
R
R
OCbH
O
N
1
2
SiMe2R'
Li
O
E
(c)
(d)
O
R
O
N
O
N
3
4
SiMe2R'
SiMe2R'
Key words: electrophilic aromatic substitution, Grignard reactions,
halides, lithiation, phenols
E
E
(e)
R
CbH = C(O)NHi-Pr
R' = Me or t-Bu
OH
OCbH
6
5
Haloarenes are compounds of high practical utility for the
synthesis of complex target molecules. Iodo-, bromo-, or
chloro-substituted arenes are widely used to form carbon–
carbon and carbon–heteroatom bonds in transition metal
catalyzed processes.1 Organofluorine compounds, on the
other hand, play an important role in recent pharmaceuti-
cal, agrochemical, and materials science.2 Although di-
verse methods have been developed to introduce halogens
into aromatic rings,3 the selective preparation of function-
alized aryl halides with a requisite substitution pattern
may still be a difficult task. In addition, methods for the
selective formation of C–F bonds are rare and often incon-
venient,4 so that the synthesis of fluorine-containing
arenes is best carried out by modification of readily avail-
able aryl fluorides.
Scheme 1 Directed ortho-lithiation of O-aryl N-isopropylcarba-
mates. Reagents and conditions: (a) TMSOTf or TBSOTf, TMEDA,
Et2O, r.t., 30 min; (b) n- or s-BuLi/TMEDA, –78 °C, 1 h; (c) EX,
–78 °C, 1 h; (d) 2 M HCl, –78 °C to r.t.; (e) 2 M NaOH, EtOH, r.t., 2 h.
TBAF, THF, r.t.) with complete retention of sensitive sub-
stituents.
This new directed metalation group (DMG) combines
several advantages of the classical methoxymethyl-
(MOM)7 and N,N-diethylcarbamoyl group:8 a strong di-
recting ability for the DoM reaction, mild conditions for
the deprotection of the phenol function, and high yields
within each synthetic step.
The starting O-aryl N-isopropylcarbamates (Figure 1) are
conveniently prepared by reaction of the corresponding
phenols with isopropyl isocyanate. Herein, we report the
utilization of this new directed ortho-lithiation protocol in
combination with ipso-iododesilylation reactions for the
regioselective synthesis of a series of fluorinated phenols,
o-iodophenols, and o,o¢-diiodophenols which are other-
wise difficult to prepare.
The directed ortho-metalation (DoM) reaction represents
one of the core techniques for the regioselective assembly
of polysubstituted aromatic compounds.5 In cooperation
with Snieckus, we uncovered recently a new phenol acti-
vation group for this reaction (Scheme 1).6 O-Aryl N-iso-
propylcarbamates 1 are temporarily and in situ N-
protected by means of trimethylsilyl or tert-butyldi-
methylsilyl triflate to form stable intermediates 2 for the
following ortho-lithiation with n- or sec-butyllithium/
TMEDA at –78 °C in diethyl ether. The formed aryllithi-
ums 3 can be trapped with a wide variety of electrophilic
reagents. The N-silyl group of the initial substitution prod-
uct 4 is completely removed upon aqueous workup.
Deprotection of the ortho-substituted carbamates 5 to the
corresponding phenols 6 may readily be achieved under
mild basic conditions (e.g., 2 M NaOH, EtOH, r.t. or
OCbH
OCbH
7a: R = F
8a: R = OMe
8b: R = F
8c: R = H
7b: R = SiMe3
7c: R = t-Bu
7d: R = I
R
R
R
Figure 1 O-Aryl N-isopropylcarbamates used in this study
The substitution of 2-chlorophenol via directed ortho-
lithiation and subsequent substitution of the correspond-
ing N-isopropylcarbamate has been reported previously to
proceed smoothly in high yield.6a In continuation of this
study, we examined the lithiation of 2-fluorophenyl car-
bamate 7a as an example for a fluorine-containing sub-
strate (Table 1). As shown by Schlosser and co-workers,
SYNTHESIS 2006, No. 10, pp 1578–1589
x
x.
x
x
.
2
0
0
6
Advanced online publication: 08.05.2006
DOI: 10.1055/s-2006-926462; Art ID: Z24705SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Halogenated Phenols by Lithiation and Iododesilylation Reactions
1579
Table 1 Substitution of 2-Fluorophenol via Directed ortho-Lithiationa
OCbH
SiMe3
OCbH
E
OH
F
F
F
E
(a)
(b)
7a
Me3Si
11
Entry
EX
E
Carbamate
Yield (%)
Phenol
Yield (%)
1
2
3
4
5
6
7
8
Me3SiCl
SiMe3
SnBu3
I
9a
9b
9c
9d
9e
9f
97b
93
87
90
91
95
83
87
10a
96
–
c
Bu3SnCl
I2
–
10bd
10cd
10dd
97
98
98
–
(BrCH2)2
C2Cl6
Br
Cl
c
MeI
Me
–
c
PhCHO
Ph2CO
CH(OH)Ph
C(OH)Ph2
9g
9h
–
–
10e
99
a Conditions: (a) (i) TMSOTf, TMEDA, Et2O, r.t., (ii) n-BuLi/TMEDA, –78 °C, (iii) EX, –78 °C; (b) 2 M NaOH, EtOH, r.t.
b With s-BuLi/TMEDA: 59%; compound 11 was also isolated in 17% yield.
c Reaction not carried out.
d Known compounds.10
the position adjacent fluorine in these kinds of arenes may methanol (97%, Scheme 2) or with elemental bromine in
also be regioselectively metalated if an appropriate base is dichloromethane (92%). In the latter case, trace amounts
chosen.9 A first attempt, using s-BuLi/TMEDA followed of the protodesilylation product were also found. Products
by reaction with trimethylsilyl chloride, furnished the ex- with halogen incorporated in the 5-position were not
pected silane 9a in 59% yield (entry 1). However, 17% of formed.
the 3,6-bis-silylated product 11 were also formed, pre-
sumably due to the in situ quench ability of TMSCl and
OH
OH
E
CHO
Me3Si
CHO
(ref. 12)
(a or b)
the DMG function of the fluoro-substituent. After having
exchanged s-BuLi for the weaker n-BuLi, the reactions
with several electrophiles gave the ortho-substituted car-
bamates 9 as sole products and the usual high yields (83–
97%) were achieved. Subsequent carbamate ester cleav-
age, using standard conditions (2 M NaOH, EtOH, r.t., 2
h) gave the free phenols 10 in nearly quantitative yields. It
is quite likely, that other fluorinated phenols may also be
substituted by our method with similar efficiency. Some
examples for the substitution of 3,5-difluorophenol are
discussed below.
7b
12 (87%)
13a: E = I (97%)
13b: E = Br (92%)
Scheme 2 Synthesis of 3-iodo- and 3-bromosalicylaldehyde (13a)
and (13b). Reagents and conditions: (a) ICl, MeOH, r.t.; (b) Br2,
CH2Cl2, 0 °C to r.t.
However, phenols are in general poor substrates for these
reactions if no other electron-withdrawing groups are
attached to the aromatic ring. Competing electrophilic
substitution of hydrogen occurs within these strongly ac-
tivated arenes. Fortunately, we found that this drawback
can be avoided if phenols protected with the N-isopropyl-
carbamoyl group are employed. This suggested that the
ipso-substitution of arylsilanes could be used as comple-
mentary method to our DoM protocol.14
Arylsilanes are particular useful intermediates in organic
synthesis since the silyl group can easily be converted into
a variety of functional groups via electrophilic aromatic
ipso-substitution.11 This method offers a couple of inter-
esting features. The C-silyl group is stable to most stan-
dard organic transformations including directed
metalation reactions, ipso-substitution always gives a sin-
gle isomer and can be carried out under mild conditions
even with deactivated systems.
At first, we examined several ipso-substitution reactions
of o-(trimethylsilyl)biphenyl-2-yl carbamate 14 since the
employed arylsilane as well as the resulting products 15a–
d are known compounds from previous directed metala-
tion studies.6 Proto-, iodo-, and borodesilylation proceed-
ed without side product formation (Table 2). Although the
bromodesilylation reaction furnished a good yield as well
(entry 3), some trace amounts (< 4%) of a hydrogen sub-
In the accompanying paper,12 we describe the one-pot
synthesis of salicylaldehydes via lithiation of the corre-
sponding carbamates. The 3-iodo and 3-bromo analogue
13a and 13b13 can not be obtained directly by the DoM re-
action, but we found that 3-(trimethylsilyl)salicylalde-
hyde (12) underwent clean halodesilylation with ICl in
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

1580
M. Kauch, D. Hoppe
PAPER
Table 2 Substitution Reactions of o-Silylbiphenylyl Carbamate 14
and O-TBS protected alcohols 18 were synthesized and
subjected to iododesilylation (Scheme 4). Carbamate 19a
was obtained in moderate yield (64%), whereas complete
benzylic chlorination was observed with the O-TBS pro-
tected alcohol 18b. After some experimentation, we found
that the benzylic substitution could be efficiently sup-
pressed by adding an excess of potassium acetate to the re-
action mixture. Hence, carbamate 19b was isolated in
87% yield together with 8% of remaining starting material
18b. Remarkably, the O-acetyl group in 19a can be re-
moved by treatment with DIBAL-H without touching the
carbamoyl moiety (94%).
OCbH
SiMe3
OCbH
E
Ph
Ph
EX
Entry
EX, Conditions
TFA, reflux
E
H
I
Product
15a
Yield (%)
97
1
2
3
4
ICl, CH2Cl2, r.t.
Br2, CH2Cl2, r.t.
BBr3, CH2Cl2, r.t.a
15b
ca. 100
91
Br
15c
15d
84
O
O
B
OPG
Ph
OPG
Ph
a Followed by esterification: pinacol, MgSO4, CH2Cl2, r.t.
(a)
(b)
16c
OCbH
OCbH
SiMe3
I
PG = Ac:
PG = TBS:
PG = H:
18a (96%)
18b (83%)
19a (64%)
19b (87%)
19c (94%)
(c)
stitution product bearing the TMS group together with one
bromine atom was obtained.
Scheme 4 Synthesis of o-iodoaryl carbamates 19. Reagents and
conditions: For PG = Ac: (a) AcCl, pyridine, CH2Cl2, r.t.; (b) ICl,
CH2Cl2, r.t.; (c) DIBAL-H, CH2Cl2, 0 °C. For PG = TBS: (a) TBS-
OTf, DIPEA, CH2Cl2, 0 °C; (b) ICl, KOAc, CH2Cl2, r.t.
Remarkably, no free phenols resulting from carbamate es-
ter cleavage are observed in these reactions indicating a
certain stability of the N-isopropylcarbamoyl group to-
wards strong proton and Lewis acids. Since other com-
mon phenol protecting groups like alkyl- (e.g., Me, i-Pr)
or alkoxyalkylethers (e.g., MOM, THP) are cleaved under
these conditions,15 the carbamoyl group may be used as an
orthogonal protecting group.
The substitution of 2-tert-butylphenyl carbamate 7c by
the DoM reaction proved to be a difficult task (Scheme 5,
Table 3). Competing carbamoyl migration in the lithiated
intermediate (anionic ortho-Fries rearrangement)8 com-
plicates the substitution with external electrophiles. Reac-
tion with TMSCl under standard conditions (entry 1) gave
the expected substitution product 20 in low yield and
carboxamide 21 as main product. Fortunately, a low tem-
perature in situ quench (inverse addition of electrophile
and base) furnished silane 20 as sole product (entry 2),
However, the combination of our ortho-lithiation protocol
with the shown ipso-substitution reactions can be advan-
tageously used to introduce two functional groups into
phenols, which are not stable to further metalation chem-
istry. Herein, we demonstrate the usefulness of this strat-
egy to synthesize o-iodo- and o,o¢-diiodophenols.
The o-silylphenyl carbamate 7b was chosen as represen- whereas the migration product 21 could be obtained selec-
tative example (Scheme 3). Thus, ortho-lithiation and tively by reaction with LDA between 0 °C and room tem-
electrophile quench furnished the substituted carbamates perature (entry 3). Iododesilylation of 20 afforded then
carbamate 22 in which the o-iodo substituent may be fur-
ther utilized for cross-coupling6b or iodine–magnesium
exchange reactions (vide infra).
16a–c in high yields. Subsequent application of the stan-
dard conditions for ipso-iododesilylation (ICl, CH2Cl2,
r.t.) gave the bromo- and benzoyl-substituted o-iodoaryl
carbamates 17a and 17b, which cannot be obtained by two
consecutive DoM reactions.
OCbH
E
OH O
t-Bu
t-Bu
(a)
N
H
7c
+
OCbH
E
OCbH
E
Me3Si
I
(a)
(b)
20: E = SiMe3
22: E = I (97%)
21
(b)
7b
16a (89%)
16b (81%)
16c (88%)
17a (97%)
17b (93%)
E = Br:
E = C(O)Ph:
E = CH(OH)Ph:
Scheme 5 Synthesis of o-iodoaryl carbamate 22. Reagents and con-
ditions: (a) See: Table 3; (b) ICl, CH2Cl2, r.t.
Scheme 3 Synthesis of o-iodoaryl carbamates 17. Reagents and
conditions: (a) (i) TBSOTf, TMEDA, Et2O, r.t., (ii) s-BuLi/TMEDA,
–78 °C, (iii) BrCH2CH2Br, ClC(O)Ph, or PhCHO, –78 °C; (b) ICl,
CH2Cl2, r.t.
The synthesized o-iodoaryl carbamates were deprotected
to yield o-iodophenols 23 without incident (Table 4). As
we have shown previously, tetrabutylammonium fluoride
is a suitable reagent,6b leading to decarbamoylation and O-
TBS deprotection in 19b within one step (entry 4).
The a-hydroxyalkylated carbamate 16c underwent iodo-
desilylation as well, but the benzylic hydroxyl group
proved to be unstable under the reaction conditions and
was substituted by chlorine.16 Consequently, the O-acetyl
The ipso-iododesilylation method employed in the
present study offers also a route to o,o¢-diiodophenols as
exemplified for carbamates 8a–c (Scheme 6). Due to the
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

PAPER
Halogenated Phenols by Lithiation and Iododesilylation Reactions
1581
Complementary to this strategy, the directed ortho-lithia-
tion of carbamates 8a and 8b by our method, followed by
an iodine quench of the lithium intermediates, furnished
the o-iodoaryl carbamates 27a and 27b with 90 and 92%
yield (Scheme 7). Basic hydrolysis afforded then the cor-
responding mono-iodinated phenols 28.18 Noteworthy, all
metalations of 8a and 8b with n-butyllithium/TMEDA in
diethyl ether occurred exclusively ortho to the carba-
moyloxy group. By-products resulting from competing
metalation of the 4-position were not detected.
Table 3 Directed ortho-Lithiation of tert-Butylphenyl Carbamate
7c
Entry
Conditionsa
Yield (%) Yield (%)
of 20
of 21
1
2
3
s-BuLi/TMEDA, –78 °C, 1 h,
then TMSCl, –78 °C, 1 h
25
67
TMSCl, then s-BuLi/TMEDA,
–78 °C, 2 h
99
–
LDA, 0 °C, 4 h, then r.t., 2 h
–
95
a After N-TMS protection: TMSOTf, TMEDA, Et2O, r.t.
OCbH
I
OH
I
(b)
(a)
8a,b
R
R
R
R
OCbH
OCbH
I
R = OMe:
R = F:
27a (90%)
27b (92%)
28a (95%)
28b (94%)
Me3Si
SiMe3
I
(a)
(b)
8a–c
R
R
R
R
Scheme 7 Synthesis of o-iodophenols 28. Reagents and conditions:
(a) (i) TMSOTf, TMEDA, Et2O, r.t., (ii) n-BuLi/TMEDA, –78 °C,
(iii) I2, –78 °C; (b) 2 M NaOH, EtOH, THF, r.t.
24a (96%)
24b (98%)
24c (98%)
25a (100%)
25b (93%)
25c (96%)
R = OMe:
R = F:
R = H:
OH
Besides transition metal–catalyzed cross–coupling reac-
tions, the halogen–magnesium exchange developed by
Knochel et al. has been proven to be a valuable tool for
further transformations of aryl halides.19 The reaction of
isopropylmagnesium chloride or bromide with iodoarenes
in THF allows the preparation of aryl Grignard reagents
bearing sensitive functional groups at temperatures below
0 °C. The rate of the exchange is significantly influenced
by the electronic nature of the aromatic ring. In general,
electron-withdrawing groups enhance the exchange rate
and lower reaction temperatures can be applied in these
cases.
I
I
(c)
R
R
R = OMe:
R = F:
R = H:
26a (94%)
26b (96%)
26c (97%)
Scheme 6 Synthesis of o,o¢-diiodophenols 26. Reagents and condi-
tions: (a) (i) TMSOTf, TMEDA, Et2O, r.t., (ii) n- or s-BuLi/TMEDA,
TMSCl, –78 °C; (b) ICl, CH2Cl2, 0 °C to r.t.; (c) 2 M NaOH, EtOH,
THF, r.t.
in situ quench ability of silyl chlorides, the DoM reaction
of these substrates using an excess of n- or s-BuLi/
TMEDA and TMSCl afforded o,o¢-bis-silylated carbam-
ates 24 in high yields (96–98%). Subsequent iododesily-
lation proceeded smoothly even with 24b bearing two
deactivating fluoro-substituents. Removal of the O-car-
bamoyl group in the usual manner gave the o,o¢-di-
iodophenols 26a–c17 in excellent overall yields.
We investigated the iodine–magnesium exchange with
the simple o-iodophenyl carbamate 7d (Table 5, entries 1
and 2). After in situ N-TBS protection, the reaction with i-
PrMgCl in THF proceeded rapidly even at –30 °C. This
finding is in accordance with observations that chelating
groups ortho to the carbon–halogen bond facilitate the ex-
change to take place under milder conditions than usual.
The intermediate organomagnesium derivative was
trapped after 45 minutes with benzaldehyde or with ethyl
(2-bromomethyl)acrylate in the presence of CuCN·2LiCl
to furnish 29a6a and 29b, respectively, in 88 and 82%
yield. o,o¢-Diiodophenyl carbamate 25c underwent clean
mono-iodine–magnesium exchange (entries 3 and 4),
whereas early attempts to perform a mono-iodine–lithium
exchange using n-butyllithium failed under several condi-
tions.
Table 4 Deprotection of o-Iodoaryl N-Isopropylcarbamatesa
OCbH
I
OH
R
R
I
(a)
Entry
R
Substrate
17a
Product
23ab
23b
Yield (%)
ca. 100
98
1
2
3
4
5
Br
C(O)Ph
17b
Remarkably, the Grignard reagent derived from 22, which
undergoes readily the anionic ortho-Fries rearrangement
at room temperature, can be substituted at –30 °C (entries
5 and 6). The corresponding allylation product 29e and
addition product 29d to benzaldehyde are obtained in sat-
isfactory yields (74 and 76%). Only trace amounts of the
undesired migration product 21 were observed. In sharp
contrast, the corresponding lithium intermediate under-
goes the rearrangement rapidly even at –78 °C and good
CH(OH)Ph
19c
23c
92
CH(OTBS)Ph
19b
23cc
23d
93
t-Bu
22
ca. 100
a Conditions: (a) 2 M NaOH, EtOH, r.t.; for entry 4: TBAF, THF, r.t.
b Known compound.10
c R = CH(OH)Ph.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

1582
M. Kauch, D. Hoppe
PAPER
Table 5 Substitution of o-Iodoaryl Carbamates via Iodine–Magnesium Exchangea
MgBr
O
I
E
(a)
OCbH
O
N
OCbH
R
R
R
SiMe2t-Bu
Entry
Substrate
R
H
H
EX
E
Product
29a
Yield (%)
1
2
7d
7d
PhCHO
CH(OH)Ph
88
82
29b
Br
CO2Et
CO2Et
3
4
25c
25c
I
I
PhCHO
CH(OH)Ph
19c
29c
87
74
Br
CO2Et
CO2Et
5
6
22
22
t-Bu
t-Bu
PhCHO
CH(OH)Ph
29d
29e
76
74
Br
a Conditions: (a) (i) TBSOTf, TMEDA, Et2O, r.t., (ii) i-PrMgCl, THF, –30 °C, (iii) For entries 2, 4, 6: CuCN·2LiCl, –30 °C, (iv) EX, –30 °C.
1H NMR (300 MHz): d = 1.23 (d, J = 6.6 Hz, 6 H), 3.89 (m, 1 H),
4.96 (br s, 1 H, NH), 7.04–7.24 (m, 4 H).
yields of substitution product could only be obtained us-
ing an in situ quench (vide supra). Thus, this route, ipso-
iododesilylation followed by iodine–magnesium ex- 13C NMR (75 MHz): d = 22.6, 43.6, 116.5 (d, J = 19 Hz), 124.2,
124.2, 126.3 (d, J = 7 Hz), 138.6 (d, J = 12 Hz), 152.7, 154.6 (d,
J = 249 Hz).
change and electrophile quench may be advantageously
used in difficult cases or to functionalize the arene at a
later stage of the synthesis.
Anal. Calcd for C10H12FNO2 (197.21): C, 60.90; H, 6.13; N, 7.10.
Found: C, 60.86; H, 6.11; N, 6.99.
In conclusion, we have demonstrated the efficient synthe-
sis of o-iodo- and o,o¢-diiodophenols by a combination of
directed ortho-lithiation and ipso-iododesilylation reac-
tions of O-aryl N-isopropylcarbamates. The o-iodoaryl
carbamates were subjected to iodine–magnesium ex-
change reactions which proved to complement the io-
dodesilylation method for further functionalization. This
strategy may advantageously be used to introduce two (or
more) substituents into phenols, which are not stable to
further DoM reactions. The ipso-substitution of silyl
groups may also be extended to other positions at the aro-
matic ring and functional groups other than iodine. Fur-
thermore, DoM reactions of two fluoro-substituted
carbamates afforded high yields and showed complete re-
gioselectivity for the ortho-position adjacent the carba-
moyloxy group. These results confirm the high directing
ability of the new N-isopropyl-N-silyl-carbamoyloxy
DMG and the high practical utility of our method for the
synthesis of polysubstituted arenes.
2-Iodophenyl Isopropylcarbamate (7d)
Prepared from 2-iodophenol (8.80 g, 40 mmol) as described for 7a;
yield: 12.07 g (99%); colorless solid; mp 72 °C.
IR (KBr): 3321, 2975, 1709, 1224, 1051, 731 cm–1.
1H NMR (400 MHz): d = 1.25 (d, J = 6.5 Hz, 6 H), 3.90 (m, 1 H),
5.01 (br s, 1 H, NH), 6.93 (td, J = 7.8, 1.2 Hz, 1 H), 7.18 (dd, J = 7.9,
1.2 Hz, 1 H), 7.34 (td, J = 7.8, 1.2 Hz, 1 H), 7.79 (dd, J = 7.9, 1.2
Hz, 1 H).
13C NMR (100 MHz): d = 22.8, 43.6, 90.9, 123.4, 127.1, 129.3,
139.2, 151.2, 152.5.
Anal. Calcd for C10H12INO2 (305.11): C, 39.36; H, 3.96; N, 4.59.
Found: C, 39.42; H, 3.77; N, 4.54.
2-tert-Butylphenyl Isopropylcarbamate (7c)
Prepared from 2-tert-butylphenol (6.01 g) as described for 7d;
yield: 9.41 g (100%); colorless solid; mp 98 °C.
IR (KBr): 3316, 3052, 2967, 1716, 1532, 755 cm–1.
1H NMR (300 MHz): d = 1.24 (d, J = 6.5 Hz, 6 H), 1.36 (s, 9 H),
3.93 (m, 1 H), 4.84 (br s, 1 H, NH), 7.04 (dd, J = 7.8, 1.5 Hz, 1 H),
7.08–7.23 (m, 2 H), 7.35 (dd, J = 7.8, 1.6 Hz, 1 H).
Details concerning standard operations and purification of solvents
and reagents can be found in previous publications.6 NMR spectra
were recorded in CDCl3 with TMS as reference. Melting points are
uncorrected. Flash column chromatography (FCC) was performed
on Merck silica gel 60 (40–63 mm) using Et2O–pentane mixtures.
13C NMR (100 MHz): d = 22.9, 30.2, 34.5, 43.4, 124.2, 125.1,
126.7, 126.9, 141.3, 149.5, 153.7.
Anal. Calcd for C14H21NO2 (235.33): C, 71.46; H, 8.99; N, 5.95.
Found: C, 71.68; H, 9.02; N, 6.04.
2-Fluorophenyl Isopropylcarbamate (7a)
Prepared from 2-fluorophenol (3.32 g, 29.6 mmol) according to our
standard procedure;6a yield: 5.51 g (94%); colorless solid; mp
57 °C.
3,5-Dimethoxyphenyl Isopropylcarbamate (8a)
Prepared from 3,5-dimethoxyphenol (4.63 g, 30 mmol) as described
for 7a; yield: 6.78 g (95%); colorless solid; mp 95 °C.
IR (KBr): 3403, 2971, 1749, 1608, 1124, 1058 cm–1.
IR (KBr): 3327, 2987, 1711, 1258, 1039, 746 cm–1.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

PAPER
Halogenated Phenols by Lithiation and Iododesilylation Reactions
1583
1H NMR (400 MHz): d = 1.22 (d, J = 6.5 Hz, 6 H), 3.76 (s, 6 H),
3.88 (m, 1 H), 4.88 (br s, 1 H, NH), 6.32 (br s, 3 H).
2-Fluoro-6-iodophenyl Isopropylcarbamate (9c)
Prepared from 7a (0.197 g, 1.0 mmol) as described for 9a (EX = I2);
yield: 0.281 g (87%); colorless solid; mp 72 °C.
13C NMR (100 MHz): d = 22.8, 43.4, 55.4, 97.8, 100.2, 152.6,
153.4, 161.0.
IR (KBr): 3328, 2975, 1724, 1268, 1025, 766 cm–1.
Anal. Calcd for C12H17NO4 (239.27): C, 60.24; H, 7.16; N, 5.85.
Found: C, 60.25; H, 7.03; N, 6.08.
1H NMR (300 MHz): d = 1.26 (d, J = 6.5 Hz, 6 H), 3.91 (m, 1 H),
5.06 (br s, 1 H, NH), 6.87–6.98 (m, 1 H), 7.12 (m, 1 H), 7.56 (d,
J = 8.0 Hz, 1 H).
3,5-Difluorophenyl Isopropylcarbamate (8b)
Prepared from 3,5-difluorophenol (3.90 g) as described for 8a;
yield: 6.08 g (94%); colorless solid; mp 67 °C.
13C NMR (75 MHz): d = 22.8, 43.9, 92.7, 116.8 (d, J = 19 Hz),
127.9 (d, J = 8 Hz), 134.0 (d, J = 4 Hz), 147.5 (d, J = 19 Hz), 151.4,
154.9 (d, J = 254 Hz).
IR (KBr): 3336, 2980, 1716, 1532, 1246, 1128 cm–1.
Anal. Calcd for C10H11FINO2 (323.10): C, 37.17; H, 3.43; N, 4.34.
Found: C, 37.19; H, 3.30; N, 4.19.
1H NMR (400 MHz): d = 1.23 (d, J = 6.6 Hz, 6 H), 3.88 (m, 1 H),
4.96 (br s, 1 H, NH), 6.65 (tt, J = 8.9, 2.2 Hz, 1 H), 6.65 (dd, J = 7.9,
2.2 Hz, 2 H).
2-Bromo-6-fluorophenyl Isopropylcarbamate (9d)
Prepared as described for 9c (EX = BrCH2CH2Br); yield: 0.248 g
(90%); colorless solid; mp 100 °C.
13C NMR (100 MHz): d = 22.7, 43.6, 100.7 (t, J = 26 Hz), 105.5 (d,
J = 28 Hz), 152.4, 152.5 (t, J = 14 Hz), 162.9 (dd, J = 248, 15 Hz).
IR (KBr): 3281, 3053, 2974, 1714, 1251, 764 cm–1.
Anal. Calcd for C10H11F2NO2 (215.20): C, 55.81; H, 5.15; N, 6.51.
Found: C, 55.77; H, 4.97; N, 6.43.
1H NMR (300 MHz): d = 1.26 (d, J = 6.5 Hz, 6 H), 3.90 (m, 1 H),
5.02 (br s, 1 H, NH), 7.01–7.15 (m, 2 H), 7.35 (m, 1 H).
Directed ortho-Lithiation; General Procedure 1 (GP 1)
A stirred solution of the carbamate (1.0 mmol) and TMEDA (0.128
g, 1.1 mmol) in Et2O (10 mL) at r.t. was treated dropwise with
TMSOTf or TBSOTf (1.05 mmol, 1.1–1.4 M in pentane). After 30
min, the resulting mixture was cooled to –78 °C, and TMEDA
(0.233 g, 2.0 mmol) and n-BuLi or s-BuLi (2.0 mmol) were added
consecutively. The mixture was stirred for 1 h and treated with the
given electrophile (EX, 2.5 mmol, dissolved in a minimum amount
of Et2O). After 1 h, MeOH (0.1 mL) and aq 2 M HCl (6 mL) were
added, and the mixture was allowed to warm to r.t. The aqueous lay-
er was extracted with Et2O (3 × 20 mL) and the combined organic
extracts were washed with aq sat. NaHCO3 solution (10 mL) and
dried (MgSO4). The crude product was purified by FCC (Et2O–pen-
tane mixtures).
13C NMR (75 MHz): d = 22.7, 43.9, 115.7 (d, J = 19 Hz), 118.5,
127.0 (d, J = 8 Hz), 128.2 (d, J = 3 Hz), 137.2 (d, J = 15 Hz), 151.5,
155.9 (d, J = 252 Hz).
Anal. Calcd for C10H11BrFNO2 (276.10): C, 43.50; H, 4.02; N, 5.07.
Found: C, 43.26; H, 4.17; N, 4.95.
2-Chloro-6-fluorophenyl Isopropylcarbamate (9e)
Prepared as described for 9c (EX = C2Cl6); yield: 0.210 g (91%);
colorless solid; mp 106 °C.
IR (KBr): 3278, 2977, 1717, 1251, 1023, 905, 766 cm–1.
1H NMR (300 MHz): d = 1.23 (d, J = 6.5 Hz, 6 H), 3.88 (m, 1 H),
5.14 (br s, 1 H, NH), 7.00–7.15 (m, 2 H), 7.16–7.23 (m, 1 H).
13C NMR (75 MHz): d = 22.6, 43.9, 115.0 (d, J = 19 Hz), 125.2 (d,
J = 3 Hz), 126.3 (d, J = 9 Hz), 129.4, 136.0 (d, J = 15 Hz), 151.5,
156.0 (d, J = 252 Hz).
2-Fluoro-6-(trimethylsilyl)phenyl Isopropylcarbamate (9a)
Prepared according to GP 1 (TMSOTf, n-BuLi, EX = TMSCl) from
carbamate 7a (0.099 g, 0.5 mmol); yield: 0.131 g (97%); colorless
solid; mp 61 °C.
Anal. Calcd for C10H11ClFNO2 (231.65): C, 51.85; H, 4.79; N, 6.05.
Found: C, 51.90; H, 4.69; N, 5.90.
IR (KBr): 3331, 3069, 2974, 1714, 1023, 838, 751 cm–1.
2-Fluoro-6-methylphenyl Isopropylcarbamate (9f)
Prepared as described for 9c (EX = MeI); yield: 0.200 g (95%);
colorless solid; mp 66 °C.
1H NMR (300 MHz): d = 0.29 (s, 9 H), 1.24 (d, J = 6.6 Hz, 6 H),
3.91 (m, 1 H), 4.87 (br s, 1 H, NH), 7.06–7.24 (m, 3 H).
13C NMR (75 MHz): d = –1.0, 22.8, 43.7, 117.4 (d, J = 19 Hz),
126.4 (d, J = 6 Hz), 129.5 (d, J = 4 Hz), 135.5, 142.7 (d, J = 12 Hz),
152.6, 154.7 (d, J = 252 Hz).
IR (KBr): 3287, 3051, 2975, 1706, 1254, 771 cm–1.
1H NMR (300 MHz): d = 1.24 (d, J = 6.6 Hz, 6 H), 2.23 (s, 3 H),
3.89 (m, 1 H), 4.96 (br s, 1 H, NH), 6.84–7.16 (m, 3 H).
Anal. Calcd for C13H20FNO2Si (269.39): C, 57.96; H, 7.48; N, 5.20.
Found: C, 57.93; H, 7.65; N, 5.07.
13C NMR (75 MHz): d = 15.8, 22.8, 43.7, 113.8 (d, J = 19 Hz),
125.8 (d, J = 9 Hz), 133.6, 137.2 (d, J = 13 Hz), 152.5, 155.2 (d,
J = 247 Hz).
2-Fluoro-6-(tributylstannyl)phenyl Isopropylcarbamate (9b)
Prepared as described for 9a (EX = Bu3SnCl); yield: 0.255 g (93%);
colorless oil.
Anal. Calcd for C11H14FNO2 (211.32): C, 62.55; H, 6.68; N, 6.63.
Found: C, 62.43; H, 6.75; N, 6.50.
IR (film): 3331, 2959, 2935, 1260, 1725, 776 cm–1.
2-Fluoro-6-(hydroxyphenylmethyl)phenyl Isopropylcarbamate
(9g)
Prepared as described for 9a (EX = PhCHO); yield: 0.126 g (83%);
colorless solid; mp 103 °C.
1H NMR (300 MHz): d = 0.89 (t, J = 7.3 Hz, 9 H), 1.04–1.13 (m, 6
H), 1.25 (d, J = 6.6 Hz, 6 H), 1.26–1.39 (m, 6 H), 1.45–1.60 (m, 6
H), 3.90 (m, 1 H), 4.77 (br d, 1 H, NH), 7.00–7.23 (m, 3 H).
13C NMR (75 MHz): d = 10.0, 13.6, 22.9, 27.3, 29.0, 43.6, 116.6 (d,
J = 19 Hz), 126.6 (d, J = 5 Hz), 131.5 (d, J = 4 Hz), 137.9 (d, J = 4
Hz), 143.0 (d, J = 19 Hz), 152.7, 154.6 (d, J = 253 Hz).
IR (KBr): 3361, 3035, 2875, 1726, 782, 743, 700 cm–1.
1H NMR (300 MHz): d = 1.18/1.20 (d, J = 6.6 Hz, 6 H), 2.99 (br s,
1 H, OH), 3.81 (m, 1 H), 4.98 (br d, 1 H, NH), 5.97 (s, 1 H), 7.00–
7.19 (m, 3 H), 7.20–7.43 (m, 5 H).
Anal. Calcd for C22H38FNO2Sn (486.25): C, 54.34; H, 7.88; N, 2.88.
Found: C, 54.45; H, 7.92; N, 2.74.
13C NMR (75 MHz): d = 22.7, 43.8, 70.4, 115.7 (d, J = 19 Hz),
123.4 (d, J = 3 Hz), 126.3, 126.6 (d, J = 8 Hz), 127.4, 128.3, 136.3
(d, J = 14 Hz), 139.4, 142.2, 152.8, 155.0 (d, J = 249 Hz).
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

1584
M. Kauch, D. Hoppe
PAPER
Anal. Calcd for C17H18FNO3 (303.33): C, 67.31; H, 5.98; N, 4.62.
Found: C, 67.20; H, 5.79; N, 4.40.
M in pentane). After 1 h at 0 °C and 1 h at r.t., aq 2 M HCl (4 mL)
was added. Workup and FCC were performed according to GP 1 to
yield 18b; yield: 0.513 g (83%); colorless solid; mp 115 °C.
2-Fluoro-6-(hydroxydiphenylmethyl)phenyl Isopropylcarba-
mate (9h)
Prepared as described for 9c (EX = Ph2CO); yield: 0.329 g (87%);
colorless solid; mp 141 °C (dec.).
IR (KBr): 3354, 3063, 2955, 1706, 836, 778, 702 cm–1.
1H NMR (400 MHz): d = –0.07/–0.02 (s, 6 H), 0.23 (s, 9 H), 0.88
(s, 9 H), 1.21/1.25 (d, J = 6.6 Hz, 6 H), 3.89 (m, 1 H), 4.76 (br d, 1
H, NH), 5.84 (s, 1 H), 7.13–7.28 (m, 3 H), 7.30–7.41 (m, 5 H).
IR (KBr): 3344, 3056, 2970, 1735, 777, 750, 702 cm–1.
13C NMR (100 MHz): d = –5.1/–4.9, –0.7, 23.0/23.1, 25.9, 43.5,
70.7, 125.8, 126.5, 126.8, 127.9, 129.5, 132.8, 134.0, 137.8, 144.6,
151.9, 153.5.
1H NMR (300 MHz): d = 0.98 (d, J = 6.5 Hz, 6 H), 3.54 (m, 1 H),
4.14 (br s, 1 H, OH), 4.50 (br d, 1 H, NH), 6.53 (br d, J = 7.8 Hz, 1
H), 6.95–7.06 (m, 1 H), 7.06–7.16 (m, 1 H), 7.20–7.39 (m, 10 H).
Anal. Calcd for C26H41NO3Si (471.78): C, 66.19; H, 8.76; N, 2.97.
Found: C, 66.04; H, 8.72; N, 2.83.
13C NMR (75 MHz): d = 22.5, 43.6, 81.0, 116.3 (d, J = 19 Hz),
125.3, 125.4 (d, J = 9 Hz), 127.2, 127.4, 127.9, 137.0 (d, J = 14 Hz),
142.1, 145.5, 151.2, 156.0 (d, J = 251 Hz).
2-tert-Butyl-6-(trimethylsilyl)phenyl Isopropylcarbamate (20)
Prepared according to GP 1 (TMSOTf) from 7c (0.235 g) but adding
first TMSCl and then s-BuLi/TMEDA; yield: 0.304 g (99%); color-
less solid; mp 214 °C.
Anal. Calcd for C23H22FNO3 (379.42): C, 72.81; H, 5.84; N, 3.69.
Found: C, 72.80; H, 5.91; N, 3.43.
2-Bromo-6-(trimethylsilyl)phenyl Isopropylcarbamate (16a)
Prepared according to GP 1 (TBSOTf, s-BuLi, EX = BrCH2CH2Br)
from carbamate 7b6a (0.251 g); yield: 0.294 g (89%); colorless sol-
id; mp 109 °C.
IR (KBr): 3316, 3059, 2980, 1703, 1256, 834, 755 cm–1.
1H NMR (300 MHz): d = 0.28 (s, 9 H), 1.23 (d, J = 6.6 Hz, 6 H),
1.35 (s, 9 H), 3.90 (m, 1 H), 4.80 (br d, 1 H, NH), 7.16 (t, J = 7.5
Hz, 1 H), 7.34 (dd, J = 7.3, 1.6 Hz, 1 H), 7.42 (dd, J = 7.8, 1.6 Hz,
1 H).
IR (KBr): 3307, 3060, 2974, 1708, 1207, 840, 748 cm–1.
1H NMR (400 MHz): d = 0.28 (s, 9 H), 1.25 (d, J = 6.6 Hz, 6 H),
3.92 (m, 1 H), 4.95 (br d, 1 H, NH), 7.07 (t, J = 7.6 Hz, 1 H), 7.38
(dd, J = 7.3, 1.5 Hz, 1 H), 7.58 (dd, J = 7.9, 1.5 Hz, 1 H).
13C NMR (75 MHz): d = –0.1, 23.1, 30.9, 35.0, 43.4, 125.5, 129.1,
133.5, 134.9, 141.8, 153.8, 154.3.
Anal. Calcd for C17H29NO2Si (307.51): C, 66.40; H, 9.51; N, 4.45.
Found: C, 66.55; H, 9.52; N, 4.57.
13C NMR (100 MHz): d = –0.9, 22.9, 43.6, 118.0, 126.8, 133.9,
134.3, 135.6, 152.3, 152.4.
Anal. Calcd for C13H20BrNO2Si (330.29): C, 47.27; H, 6.10; N,
4.24. Found: C, 47.34; H, 5.92; N, 4.25.
3-tert-Butyl-2-hydroxy-N-isopropylbenzamide (21)
Prepared according to GP 1 (TMSOTf) from 7c (0.235 g) using
LDA [2.5 mmol in Et2O (2 mL), 0 °C, 4 h, r.t., 2 h] without EX;
yield: 0.224 g (95%); colorless solid; mp 71 °C.
2-Benzoyl-6-(trimethylsilyl)phenyl Isopropylcarbamate (16b)
Prepared as described for 16a [EX = PhC(O)Cl, 6.0 mmol]; yield:
0.287 g (81%); colorless solid; mp 136 °C.
IR (KBr): 3380, 2974, 1623, 1540, 1429, 806, 747 cm–1.
1H NMR (400 MHz): d = 1.27 (d, J = 6.6 Hz, 6 H), 1.42 (s, 9 H),
4.28 (m, 1 H), 6.07 (br s, 1 H, NH), 6.75 (t, J = 7.8 Hz, 1 H), 7.19
(dd, J = 7.9, 1.5 Hz, 1 H), 7.38 (dd, J = 7.7, 1.5 Hz, 1 H), 13.01 (s,
1 H, OH).
IR (KBr): 3318, 3056, 2973, 1736, 1656, 841, 703 cm–1.
1H NMR (400 MHz): d = 0.31 (s, 9 H), 1.06 (d, J = 6.6 Hz, 6 H),
3.65 (m, 1 H), 4.68 (br d, 1 H, NH), 7.25 (t, J = 7.4 Hz, 1 H), 7.40–
7.47 (m, 3 H), 7.52–7.57 (m, 1 H), 7.61 (dd, J = 7.4, 1.7 Hz, 1 H),
7.81–7.85 (m, 2 H).
13C NMR (75 MHz): d = 22.7, 29.3, 35.0, 41.8, 114.2, 117.5, 123.1,
130.9, 139.0, 161.1, 170.2.
13C NMR (100 MHz): d = –0.9, 22.7, 43.3, 124.3, 128.1, 130.3,
131.7, 131.8, 132.6, 133.9, 137.5, 137.7, 153.1, 153.4, 195.2.
Anal. Calcd for C14H21NO2 (235.33): C, 71.46; H, 8.99; N, 5.95.
Found: C, 71.36; H, 9.00; N, 5.82.
Anal. Calcd for C20H25NO3Si (355.50): C, 67.57; H, 7.09; N, 3.94.
Found: C, 67.37; H, 7.01; N, 3.84.
3,5-Dimethoxy-2,6-bis(trimethylsilyl)phenyl Isopropylcarba-
mate (24a)
2-Hydroxyphenylmethyl-6-(trimethylsilyl)phenyl Isopropyl-
carbamate (16c)
Prepared as described for 16a from 7b6a (0.377 g, 1.5 mmol) using
s-BuLi/TMEDA (3.75 mmol) and PhCHO (4.5 mmol); yield: 0.470
g (88%); colorless solid; mp 131 °C.
Prepared from 8a (120 g, 0.5 mmol) according to GP 1 (TMSOTf),
but adding first TMSCl (2.0 mmol) and then s-BuLi/TMEDA (1.75
mmol, 2 h); yield: 0.184 g (96%); colorless solid; mp 177 °C.
IR (KBr): 3314, 2973, 1701, 1240, 1089, 840 cm–1.
1H NMR (300 MHz): d = 0.24 (s, 18 H), 1.20 (d, J = 6.6 Hz, 6 H),
3.78 (s, 6 H), 3.87 (m, 1 H), 4.53 (br d, 1 H, NH), 6.27 (s, 1 H).
IR (KBr): 3335, 3059, 2962, 1682, 843, 756, 701 cm–1.
1H NMR (300 MHz): d = 0.28 (s, 9 H), 1.23/1.24 (d, J = 6.5 Hz, 6
H), 3.41 (br s, 1 H, OH), 3.89 (m, 1 H), 4.91 (br d, 1 H, NH), 5.93
(s, 1 H), 7.12–7.44 (m, 8 H).
13C NMR (75 MHz): d = 1.1, 22.6, 43.3, 55.0, 92.1, 112.5, 154.2,
160.9, 167.5.
Anal. Calcd for C18H33NO4Si2 (383.63): C, 56.35; H, 8.67; N, 3.65.
Found: C, 56.04; H, 8.66; N, 3.51.
13C NMR (75 MHz): d = –0.8, 22.8, 43.7, 69.7, 126.3, 126.3, 126.9,
128.0, 131.2, 132.8, 134.8, 136.9, 142.7, 152.9.
Anal. Calcd for C20H27NO3Si (357.52): C, 67.19; H, 7.61; N, 3.92.
Found: C, 67.09; H, 7.43; N, 3.74.
3,5-Difluoro-2,6-bis(trimethylsilyl)phenyl Isopropylcarbamate
(24b)
Prepared from 8b (215 g, 1.0 mmol) as described for 24a, but using
n-BuLi/TMEDA; yield: 0.352 g (98%); colorless solid; mp 185 °C.
2-(tert-Butyldimethylsilyloxy)phenylmethyl-6-(trimethylsilyl)-
phenyl Isopropylcarbamate (18b)
To a solution of 16c (0.470 g, 1.32 mmol) and DIPEA (0.51 g, 3.95
mmol) in CH2Cl2 (14 mL) at 0 °C was added TBSOTf (5.0 mL, 0.66
IR (KBr): 3328, 2974, 1706, 1232, 1058, 846 cm–1.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

PAPER
Halogenated Phenols by Lithiation and Iododesilylation Reactions
1585
1H NMR (300 MHz): d = 0.31 (s, 18 H), 1.23 (d, J = 6.6 Hz, 6 H),
3.87 (m, 1 H), 4.87 (br d, 1 H, NH), 6.58 (t, J = 9.3 Hz, 1 H).
1H NMR (400 MHz): d = 1.27 (d, J = 6.6 Hz, 6 H), 3.92 (m, 1 H),
5.06 (br d, 1 H, NH), 6.81 (t, J = 8.0 Hz, 1 H), 7.55 (dd, J = 8.0, 1.2
Hz, 1 H), 7.74 (dd, J = 8.0, 1.2 Hz, 1 H).
13C NMR (75 MHz): d = 0.4, 22.8, 43.4, 101.2 (t, J = 31 Hz), 116.4
(d, J = 35 Hz), 153.7, 160.5 (d, J = 17 Hz), 168.7 (dd, J = 245, 16
Hz).
13C NMR (100 MHz): d = 22.8, 43.8, 92.8, 117.5, 128.4, 133.3,
138.3, 148.7, 151.1.
Anal. Calcd for C16H27F2NO2Si2 (359.56): C, 59.45; H, 7.57; N,
3.90. Found: C, 53.49; H, 7.68; N, 3.71.
Anal. Calcd for C10H11BrINO2 (384.01): C, 31.28; H, 2.89; N, 3.65.
Found: C, 31.29; H, 2.61; N, 3.65.
2,6-Bis(trimethylsilyl)phenyl Isopropylcarbamate (24c)
Prepared according to GP 1 (TMSOTf) from 8c6a (0.179 g) using s-
BuLi/TMEDA (3.5 mmol) and TMSCl (4.0 mmol); yield: 0.318 g
(98%); colorless solid; mp 206 °C.
2-Benzoyl-6-iodophenyl Isopropylcarbamate (17b)
Prepared from 16b (0.213 g) as described for 17a; yield: 0.228 g
(93%); colorless solid; mp 103 °C.
IR (KBr): 3325, 2972, 1736, 1660, 1213, 788, 716 cm–1.
IR (KBr): 3322, 3059, 2973, 1710, 1256, 841, 749 cm–1.
1H NMR (400 MHz): d = 1.08 (d, J = 6.6 Hz, 6 H), 3.68 (m, 1 H),
4.78 (br d, 1 H, NH), 7.03 (t, J = 7.7, 1 H), 7.39–7.47 (m, 3 H),
7.53–7.60 (m, 1 H), 7.78–7.83 (m, 2 H), 7.96 (d, J = 7.9 Hz, 1 H).
1H NMR (300 MHz): d = 0.27 (s, 18 H), 1.23 (d, J = 6.6 Hz, 6 H),
3.89 (m, 1 H), 4.74 (br d, 1 H, NH), 7.21 (t, J = 7.3 Hz, 1 H), 7.50
(d, J = 7.3 Hz, 2 H).
13C NMR (100 MHz): d = 22.6, 43.6, 93.2, 126.6, 128.3, 130.1,
130.1, 133.1, 133.9, 136.8, 141.7, 148.8, 151.6, 193.8.
13C NMR (75 MHz): d = –0.5, 23.1, 43.3, 125.2, 132.7, 136.7,
154.2, 160.1.
Anal. Calcd for C17H16INO3 (409.22): C, 49.90; H, 3.94; N, 3.42.
Found: C, 49.92; H, 3.67; N, 3.42.
Anal. Calcd for C16H29NO2Si2 (323.58): C, 59.39; H, 9.03; N, 4.33.
Found: C, 59.57; H, 9.16; N, 4.32.
2-(tert-Butyldimethylsilyloxy)phenylmethyl-6-iodophenyl Iso-
propylcarbamate (19b)
Prepared from 18b (0.283 g) according to GP 2 (12 h) but with ad-
dition of KOAc (0.236 g, 2.4 mmol); yield: 0.273 g (87%); colorless
solid; mp 105 °C.
2-Iodo-3,5-dimethoxyphenyl Isopropylcarbamate (27a)
Prepared as described for 9c from 8a (0.239 g); yield: 0.328 g
(90%); colorless solid; mp 96 °C (dec.).
IR (KBr): 3332, 2977, 1709, 1527, 1105, 821 cm–1.
IR (KBr): 3312, 2955, 1712, 1208, 867, 776, 703 cm–1.
1H NMR (400 MHz): d = 1.25 (d, J = 6.6 Hz, 6 H), 3.79 (s, 3 H),
3.85 (s, 3 H), 3.89 (m, 1 H), 5.00 (br d, 1 H, NH), 6.31 (d, J = 2.6
Hz, 1 H), 6.44 (d, J = 2.6 Hz, 1 H).
1H NMR (300 MHz): d = –0.03/–0.02 (s, 6 H), 0.90 (s, 9 H), 1.25/
1.27 (d, J = 6.6 Hz, 6 H), 3.89 (m, 1 H), 4.93 (br d, 1 H, NH), 5.89
(s, 1 H), 6.95 (t, J = 7.8 Hz, 1 H), 7.15–7.38 (m, 5 H), 7.60 (br d,
J = 7.8 Hz, 1 H), 7.66 (dd, J = 7.8, 1.3 Hz, 1 H).
13C NMR (100 MHz): d = 22.9, 43.6, 55.6, 56.5, 72.9, 96.6, 100.9,
152.4, 152.8, 159.5, 161.5.
13C NMR (75 MHz): d = –5.1/–4.9, 22.8/23.0, 25.8, 43.7, 71.6,
92.4, 126.4, 127.1, 127.6, 127.8, 128.1, 138.0, 140.2, 143.9, 147.5,
151.7.
Anal. Calcd for C12H16INO4 (365.16): C, 39.47; H, 4.42; N, 3.84.
Found: C, 39.36; H, 4.27; N, 3.84.
3,5-Difluoro-2-iodophenyl Isopropylcarbamate (27b)
Prepared as described for 9c from 8b (0.215 g); yield: 0.313 g
(92%); colorless solid; mp 97 °C.
Anal. Calcd for C23H32INO3Si (525.50): C, 52.57; H, 6.14; N, 2.67.
Found: C, 52.75; H, 6.11; N, 2.57.
2-tert-Butyl-6-iodophenyl Isopropylcarbamate (22)
Prepared from 20 (0.308 g, 1.0 mmol) according to GP 2 (2 h);
yield: 0.351 g (97%); colorless solid; mp 116 °C.
IR (KBr): 3322, 2982, 1708, 1246, 1070, 843 cm–1.
1H NMR (300 MHz): d = 1.26 (d, J = 6.5 Hz, 6 H), 3.90 (m, 1 H),
5.09 (br s, 1 H, NH), 6.74 (td, J = 8.2, 2.7 Hz, 1 H), 6.84–6.97 (m,
1 H).
IR (KBr): 3310, 2973, 1714, 1204, 1015, 774 cm–1.
1H NMR (400 MHz): d = 1.27 (d, J = 6.6 Hz, 6 H), 1.33 (s, 9 H),
3.94 (m, 1 H), 5.02 (br d, 1 H, NH), 6.86 (t, J = 7.9 Hz, 1 H), 7.35
(dd, J = 8.0, 1.4 Hz, 1 H), 7.68 (dd, J = 7.8, 1.4 Hz, 1 H).
13C NMR (75 MHz): d = 22.7, 43.9, 73.8 (dd, J = 28, 5 Hz), 101.4
(t, J = 27 Hz), 107.4 (dd, J = 25, 4 Hz), 151.6, 153.0 (dd, J = 15, 7
Hz), 163.3 (dd, J = 250, 14 Hz), 162.4 (dd, J = 247, 14 Hz).
13C NMR (100 MHz): d = 23.0, 30.4, 35.2, 43.6, 95.0, 127.0, 127.5,
137.6, 144.4, 149.4, 152.1.
Anal. Calcd for C10H10F2INO2 (341.09): C, 35.21; H, 2.96; N, 4.11.
Found: C, 35.44; H, 2.94; N, 3.98.
Anal. Calcd for C14H20INO2 (361.22): C, 46.55; H, 5.58; N, 3.88.
Found: C, 46.56; H, 5.46; N, 3.77.
ipso-Iododesilylation; General Procedure 2 (GP 2)
A solution of the silyl- or bis-silylarene (0.6 mmol) in CH2Cl2 (9
mL) at 0 °C was treated with ICl (0.66 or 1.26 mmol, 0.5–1.5 M in
CH2Cl2). After 30 min, the mixture was allowed to warm to r.t. and
stirred for the given time. Then, aq sat. Na2S2O3 solution (4 mL) was
added, the aqueous layer was extracted with Et2O (3 × 20 mL), and
the combined organic layers were washed with brine (10 mL) and
dried (MgSO4). The crude product was purified by FCC (Et2O–pen-
tane mixtures).
2,6-Diiodo-3,5-dimethoxyphenyl Isopropylcarbamate (25a)
Prepared from 24a (0.153 g, 0.4 mmol) according to GP 2 (0 °C, 3
h); yield: 0.196 g (100%); colorless solid; mp 162–172 °C (dec.).
IR (KBr): 3305, 2970, 1716, 1533, 1110, 821 cm–1.
1H NMR (300 MHz): d = 1.28 (d, J = 6.5 Hz, 6 H), 3.89 (s, 6 H),
3.79–3.99 (m, 1 H), 5.03 (br d, 1 H, NH), 6.29 (s, 1 H).
13C NMR (75 MHz): d = 22.9, 43.7, 56.8, 73.7, 93.0, 150.9, 152.5,
160.3.
2-Bromo-6-iodophenyl Isopropylcarbamate (17a)
Prepared from 16a (0.198 g) according to GP 2 (2.5 h); yield: 0.223
g (97%); colorless solid; mp 117 °C.
Anal. Calcd for C12H15I2NO4 (491.06): C, 29.35; H, 3.08; N, 2.85.
Found: C, 29.59; H, 2.99; N, 2.64.
IR (KBr): 3296, 2970, 1725, 1428, 1213, 772 cm–1.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

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M. Kauch, D. Hoppe
PAPER
3,5-Difluoro-2,6-diiodophenyl Isopropylcarbamate (25b)
Prepared from 24b (0.144 g, 0.4 mmol) according to GP 2 (24 h);
yield: 0.173 g (93%); colorless solid; mp 129 °C.
2-Fluoro-6-(trimethylsilyl)phenol (10a)
Prepared from 9a (0.162 g) according to GP 3; yield: 0.106 g (96%);
pale yellow oil.
IR (KBr): 3322, 2975, 1708, 1239, 1073, 841 cm–1.
IR (film): 3584, 2955, 1447, 1257, 842, 757 cm–1.
1H NMR (300 MHz): d = 1.29 (d, J = 6.6 Hz, 6 H), 3.93 (m, 1 H),
5.10 (br d, 1 H, NH), 6.82 (t, J = 7.7 Hz, 1 H).
1H NMR (400 MHz): d = 0.31 (s, 9 H), 5.22 (br d, 1 H, OH), 6.83
(ddd, J = 8.1, 7.4, 4.6 Hz, 1 H), 7.05 (ddd, J = 10.6, 8.1, 1.5 Hz, 1
H), 7.10 (br d, J = 7.4 Hz, 1 H).
13C NMR (75 MHz): d = 22.8, 44.0, 75.0 (d, J = 32 Hz), 101.5 (t,
J = 29 Hz), 150.3, 160.6 (d, J = 18 Hz), 162.8 (dd, J = 248, 14 Hz).
13C NMR (100 MHz): d = –1.1, 116.1 (d, J = 18 Hz), 120.5 (d, J = 6
Hz), 128.4, 129.9 (d, J = 4 Hz), 147.7 (d, J = 13 Hz), 150.6 (d,
J = 239 Hz).
Anal. Calcd for C10H9F2I2NO2 (466.99): C, 25.72; H, 1.94; N, 3.00.
Found: C, 25.84; H, 1.88; N, 2.81.
Anal. Calcd for C9H13FOSi (184.28): C, 58.66; H, 7.11. Found: C,
59.01; H, 7.38.
2,6-Diiodophenyl Isopropylcarbamate (25c)
Prepared from 24c (0.194 g) according to GP 2 (2.5 h); yield: 0.248
g (96%); colorless solid; mp 134 °C.
2-Fluoro-6-iodophenol (10b)
Prepared from 9c (0.194 g) according to GP 3; yield: 0.139 g (97%);
pale yellow oil.
IR (KBr): 3291, 3045, 2968, 1723, 1212, 765 cm–1.
1H NMR (300 MHz): d = 1.28 (d, J = 6.5 Hz, 6 H), 3.93 (m, 1 H),
5.05 (br s, 1 H, NH), 6.64 (t, J = 7.9 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 2
H).
IR (film): 3469, 1476, 1264, 1220, 860, 764 cm–1.
1H NMR (400 MHz): d = 5.51 (s, 1 H, OH), 6.64 (td, J = 8.2, 5.2
Hz, 1 H), 7.07 (ddd, J = 10.1, 8.2, 1.3 Hz, 1 H), 7.45 (dt, J = 8.2, 1.3
Hz, 1 H).
13C NMR (75 MHz): d = 22.9, 43.8, 91.5, 128.8, 139.4, 151.0,
151.2.
13C NMR (100 MHz): d = 84.6, 116.1 (d, J = 19 Hz), 122.2 (d, J = 7
Hz), 133.8 (d, J = 4 Hz), 143.9 (d, J = 15 Hz), 149.9 (d, J = 245 Hz).
Anal. Calcd for C10H11I2NO2 (431.01): C, 27.87; H, 2.57; N, 3.25.
Found: C, 27.99; H, 2.34; N, 3.10.
Anal. Calcd for C6H4FIO (238.00): C, 30.28; H, 1.69. Found: C,
30.53; H, 1.79.
2-Hydroxy-3-iodobenzaldehyde (13a)
Prepared from 1212 (0.117 g) according to GP 2 (12 h) but using
MeOH as solvent; yield: 0.144 g (97%); pale yellow solid; mp
77 °C (Lit.13c mp 69–71 °C).
2-Bromo-6-fluorophenol (10c)
Prepared from 9d (0.166 g) according to GP 3; yield: 0.112 g (98%);
colorless solid; mp 50 °C (Lit.10 mp 47–48 °C).
IR (KBr): 2843, 1639, 1433, 1215, 1118, 732 cm–1.
IR (KBr): 3400, 1487, 1268, 1220, 870, 764 cm–1.
1H NMR (400 MHz): d = 6.84 (t, J = 7.7 Hz, 1 H), 7.57 (dd, J = 7.7,
1.5 Hz, 1 H), 7.99 (dd, J = 7.8, 1.5 Hz, 1 H), 9.77 (s, 1 H), 11.81 (s,
1 H, OH).
1H NMR (400 MHz): d = 5.21 (br s, 1 H, OH), 6.76 (td, J = 8.3, 5.4
Hz, 1 H), 7.05 (ddd, J = 10.1, 8.3, 1.5 Hz, 1 H), 7.26 (dt, J = 8.3, 1.5
Hz, 1 H).
13C NMR (100 MHz): d = 85.4, 120.5, 121.6, 133.9, 146.1, 160.4,
195.9.
13C NMR (100 MHz): d = 110.8 (d, J = 2 Hz), 115.4 (d, J = 18 Hz),
121.1 (d, J = 8 Hz), 127.6 (d, J = 4 Hz), 141.5 (d, J = 15 Hz), 151.1
(d, J = 246 Hz).
Anal. Calcd for C7H5IO2 (248.02): C, 33.90; H, 2.03. Found: C,
33.95; H, 1.96.
Anal. Calcd for C6H4BrFO (191.00): C, 37.73; H, 2.11. Found: C,
37.69; H, 1.93.
2-Bromo-3-hydroxybenzaldehyde (13b)
Prepared from 1212 (0.097 g, 0.5 mmol) according to GP 2 (10 h)
but using Br2 as reagent; yield: 0.092 g (92%); pale yellow solid; mp
54–55 °C (Lit.13b mp 49–52 °C).
2-Chloro-6-fluorophenol (10d)
Prepared from 9e (0.139 g) according to GP 3; yield: 0.086 g (98%);
colorless solid; mp 65 °C (Lit.10 mp 63–64 °C).
IR (KBr): 2851, 1655, 1437, 1290, 1128, 733 cm–1.
IR (KBr): 3386, 1492, 1271, 1220, 886, 769 cm–1.
1H NMR (300 MHz): d = 6.95 (t, J = 7.8 Hz, 1 H), 7.55 (dd, J = 7.7,
1.6 Hz, 1 H), 7.78 (dd, J = 7.8, 1.5 Hz, 1 H), 9.86 (s, 1 H), 11.95 (s,
1 H, OH).
1H NMR (300 MHz): d = 5.17 (br s, 1 H, OH), 6.81 (td, J = 8.3, 5.5
Hz, 1 H), 7.01 (ddd, J = 10.1, 8.4, 1.4 Hz, 1 H), 7.11 (dt, J = 8.2, 1.5
Hz, 1 H).
13C NMR (75 MHz): d = 111.2, 120.7, 121.3, 132.8, 139.9, 158.1,
195.9.
13C NMR (75 MHz): d = 114.8 (d, J = 19 Hz), 120.3 (d, J = 8 Hz),
121.6 (d, J = 3 Hz), 124.7 (d, J = 4 Hz), 140.7 (d, J = 15 Hz), 151.4
(d, J = 245 Hz).
Anal. Calcd for C7H5BrO2 (201.02): C, 41.82; H, 2.51. Found: C,
42.20; H, 2.45.
Anal. Calcd for C6H4ClFO (146.55): C, 49.17; H, 2.75. Found: C,
49.19; H, 2.69.
Phenol-Deprotection; General Procedure 3 (GP 3)
To a solution of the carbamate (0.6 mmol) in EtOH (10 mL) and
THF (2 mL, in case of inhomogeneous mixtures) at r.t. was added
aq 2 M NaOH (0.75 mL, 1.5 mmol) and the resulting mixture was
stirred for 2 h. Then, aq 2 M HCl (2 mL) and Et2O (10 mL) were
added, the aqueous layer was extracted with Et2O (3 × 10 mL), and
the combined organic phases were washed with brine (10 mL) and
dried (MgSO4). The crude product was purified by FCC (Et2O–pen-
tane mixtures).
2-Fluoro-6-(hydroxydiphenylmethyl)phenol (10e)
Prepared from 9h (0.152 g, 0.4 mmol) according to GP 3; yield:
0.117 g (99%); colorless solid; mp 150–155 °C (dec.).
IR (KBr): 3455, 1466, 1260, 789, 765, 750, 700 cm–1.
1H NMR (400 MHz): d = 3.95 (s, 1 H, OH), 6.32 (dt, J = 8.0, 1.4
Hz, 1 H), 6.68 (td, J = 8.0, 5.2 Hz, 1 H), 7.05 (ddd, J = 10.4, 8.1, 1.4
Hz, 1 H), 7.20–7.25 (m, 4 H), 7.31–7.37 (m, 6 H), 7.52 (br s, 1 H,
OH).
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Halogenated Phenols by Lithiation and Iododesilylation Reactions
1587
13C NMR (75 MHz): d = 83.3, 115.3 (d, J = 18 Hz), 118.3 (d, J = 8
Hz), 125.0 (d, J = 3 Hz), 127.5, 127.8, 127.8, 134.0, 143.6 (d, J = 14
Hz), 145.2, 152.1 (d, J = 243 Hz).
1H NMR (300 MHz): d = 3.90 (s, 6 H), 5.98 (br s, 1 H, OH), 6.08
(s, 1 H).
13C NMR (75 MHz): d = 56.7, 64.7, 88.4, 154.9, 160.1.
Anal. Calcd for C19H15FO2 (294.32): C, 77.54; H, 5.14. Found: C,
77.32; H, 4.98.
Anal. Calcd for C8H8I2O3 (405.96): C, 23.67; H, 1.99. Found: C,
23.86; H, 1.83.
2-Bromo-6-iodophenol (23a)
Prepared from 17a (0.154 g, 0.5 mmol) according to GP 3; yield:
0.119 g (ca. 100%); colorless solid; mp 63 °C (Lit.10 mp 60–61 °C).
3,5-Difluoro-2,6-diiodophenol (26b)
Prepared from 25b (0.117 g, 0.25 mmol) according to GP 3; yield:
0.092 g (96%); colorless solid; mp 114 °C.
IR (KBr): 3422, 1441, 1323, 755, 703 cm–1.
IR (KBr): 3436, 1579, 1410, 1132, 1027, 812 cm–1.
1H NMR (400 MHz): d = 5.90 (s, 1 H, OH), 6.55 (t, J = 7.9 Hz, 1
H), 7.45 (dd, J = 7.9, 1.4 Hz, 1 H), 7.65 (dd, J = 7.9, 1.4 Hz, 1 H).
1H NMR (400 MHz): d = 6.11 (br s, 1 H, OH), 6.59 (t, J = 7.9 Hz,
1 H).
13C NMR (100 MHz): d = 83.2, 108.7, 123.4, 132.7, 138.5, 151.5.
13C NMR (75 MHz): d = 65.4 (d, J = 33 Hz), 96.5 (t, J = 29 Hz),
156.2, 162.9 (dd, J = 247, 15 Hz).
Anal. Calcd for C6H4BrIO (298.90): C, 24.11; H, 1.35. Found: C,
24.49; H, 1.35.
Anal. Calcd for C6H2F2I2O (381.89): C, 18.87; H, 0.53. Found: C,
19.14; H, 0.65.
2-Benzoyl-6-iodophenol (23b)
Prepared from 17b (0.107 g, 0.26 mmol) according to GP 3; yield:
0.083 g (98%); yellow solid; mp 97 °C.
2,6-Diiodophenol (26c)
Prepared from 25c (0.129 g, 0.3 mmol) according to GP 3; yield:
0.101 g (97%); colorless solid; mp 68 °C (Lit.17b mp 65.5–67.5 °C).
IR (KBr): 3459, 1609, 1324, 792, 746, 704 cm–1.
1H NMR (400 MHz): d = 6.68 (t, J = 7.9 Hz, 1 H), 7.48–7.54 (m, 2
H), 7.58–7.64 (m, 2 H), 7.65–7.69 (m, 2 H), 7.98 (dd, J = 7.7, 1.4
Hz, 1 H), 12.89 (s, 1 H, OH).
IR (KBr): 3462, 1552, 1433, 1312, 1125, 828, 752 cm–1.
1H NMR (300 MHz): d = 5.74 (s, 1 H, OH), 6.39 (t, J = 7.9 Hz, 1
H), 7.66 (d, J = 7.9 Hz, 2 H).
13C NMR (100 MHz): d = 86.4, 119.2, 120.3, 128.4, 129.2, 132.3,
133.8, 137.2, 145.6, 161.8, 201.1.
13C NMR (75 MHz): d = 82.4, 124.1, 139.3, 153.5.
Anal. Calcd for C6H4I2O (345.90): C, 20.83; H, 1.17. Found: C,
20.99; H, 1.17.
Anal. Calcd for C13H9IO2 (324.11): C, 48.17; H, 2.80. Found: C,
48.19; H, 2.81.
2-Iodo-3,5-dimethoxyphenol (28a)
Prepared from 27a (0.219 g) according to GP 3; yield: 0.159 g
(95%); colorless solid; mp 72 °C (Lit.18 mp 73 °C).
2-Hydroxyphenylmethyl-6-iodophenol (23c)
To a solution of 19b (0.137 g, 0.26 mmol) in THF (3 mL) at r.t. was
added TBAF (0.78 mL, 1.0 M in THF). After 4 h, aq sat. NH4Cl so-
lution was added. Workup and FCC were performed as described in
GP 3 to afford 23c; yield: 0.079 g (93%); colorless solid; mp 88 °C.
IR (KBr): 3460, 2940, 1581, 1206, 1148, 1089, 809 cm–1.
1H NMR (400 MHz): d = 3.78 (s, 3 H), 3.83 (s, 3 H), 5.57 (s, 1 H,
OH), 6.07 (d, J = 2.6 Hz, 1 H), 6.28 (d, J = 2.6 Hz, 1 H).
IR (KBr): 3243, 3051, 1448, 1010, 772, 735, 698 cm–1.
13C NMR (100 MHz): d = 55.5, 56.4, 67.1, 92.0, 92.8, 156.5, 159.0,
162.3.
1H NMR (300 MHz): d = 2.96 (br s, 1 H, OH), 5.99 (s, 1 H), 6.60 (t,
J = 7.8 Hz, 1 H), 6.97 (dd, J = 7.6, 1.4 Hz, 1 H), 7.25–7.46 (m, 5 H),
7.63 (dd, J = 7.9, 1.4 Hz, 1 H), 7.74 (br s, 1 H, OH).
Anal. Calcd for C8H9IO3 (280.06): C, 34.31; H, 3.24. Found: C,
33.97; H, 3.04.
13C NMR (75 MHz): d = 75.7, 86.4, 121.9, 126.7, 128.1, 128.2,
128.5, 128.7, 138.3, 141.6, 153.6.
3,5-Difluoro-2-iodophenol (28b)
Prepared from 27b (0.205 g) according to GP 3; yield: 0.144 g
(94%); colorless oil.
Anal. Calcd for C13H11IO2 (326.13): C, 47.88; H, 3.40. Found: C,
47.89; H, 3.39.
IR (film): 3480, 3095, 1594, 1438, 1033, 835 cm–1.
2-tert-Butyl-6-iodophenol (23d)
Prepared from 22 (0.181 g, 0.5 mmol) according to GP 3; yield:
0.138 g (ca. 100%); colorless oil.
1H NMR (400 MHz): d = 5.68 (br s, 1 H, OH), 6.49 (td, J = 8.4, 2.7
Hz, 1 H), 6.58–6.63 (m, 1 H).
IR (film): 3477, 2996, 1427, 1238, 1184, 770, 739 cm–1.
13C NMR (100 MHz): d = 68.1 (dd, J = 29, 4 Hz), 96.8 (t, J = 28
Hz), 98.8 (dd, J = 26, 4 Hz), 157.0 (dd, J = 15, 7 Hz), 164.4 (dd,
J = 248, 15 Hz), 162.1 (dd, J = 246, 15 Hz).
1H NMR (300 MHz): d = 1.39 (s, 9 H), 5.47 (br d, 1 H, OH), 6.60
(t, J = 7.9 Hz, 1 H), 7.23 (dd, J = 7.9, 1.6 Hz, 1 H), 7.52 (dd, J = 7.9,
1.6 Hz, 1 H).
Anal. Calcd for C6H3F2IO (255.99): C, 28.15; H, 1.18. Found: C,
28.12; H, 1.26.
13C NMR (75 MHz): d = 29.4, 35.5, 89.3, 122.0, 127.7, 136.0,
137.1, 152.7.
I/Mg Exchange; General Procedure 4 (GP 4)
Anal. Calcd for C10H13IO (276.11): C, 43.50; H, 4.75. Found: C,
43.90; H, 4.83.
Following GP 1, the carbamate (0.5 mmol) in Et2O (3 mL) was N-
TBS protected. Then, the mixture was filtered through a short plug
of neutral alumina. The solvent was removed in vacuo, the residue
was redissolved in THF (5 mL), and i-PrMgCl (0.33 mL, 2 M in
THF, 0.65 mmol) was added at –30 °C. After 45 min, the electro-
phile (EX, 1.25 mmol) was added, the mixture was stirred for the
given time, allowed to warm to r.t., and quenched with aq 2 M HCl
(4 mL). Workup and FCC were performed as described in GP 1.
2,6-Diiodo-3,5-dimethoxyphenol (26a)
Prepared from 25a (0.147 g, 0.3 mmol) according to GP 3; yield:
0.114 g (94%); colorless solid; mp 168–171 °C (dec.).
IR (KBr): 2933, 1560, 1341, 1212, 1103, 791 cm–1.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

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M. Kauch, D. Hoppe
PAPER
2-Hydroxyphenylmethyl-6-iodophenyl Isopropylcarbamate
(19c)
Prepared from 25c (0.216 g) according to GP 4 (EX = PhCHO, 2 h);
yield: 0.179 g (87%); colorless solid; mp 121 °C.
1H NMR (400 MHz): d = 1.24 (d, J = 6.5 Hz, 6 H), 1.35 (s, 9 H),
3.28 (d, J = 6.7 Hz, 2 H), 3.91 (m, 1 H), 4.90 (br d, 1 H, NH), 5.05–
5.14 (m, 2 H), 5.88–5.99 (m, 1 H), 7.08–7.11 (m, 2 H), 7.23–7.26
(m, 1 H).
IR (KBr): 3321, 3059, 2966, 1722, 1219, 784, 702 cm–1.
13C NMR (100 MHz): d = 23.0, 30.6, 34.6, 34.8, 43.4, 116.0, 125.3,
125.5, 128.0, 134.3, 136.5, 142.2, 147.7, 153.3.
1H NMR (300 MHz): d = 1.25 (d, J = 6.5 Hz, 6 H), 3.20 (br s, 1 H,
OH), 3.88 (m, 1 H), 5.09 (br s, 1 H, NH), 5.97 (s, 1 H), 6.93 (t,
J = 7.8 Hz, 1 H), 7.21–7.41 (m, 6 H), 7.72 (dd, J = 7.9, 1.5 Hz, 1 H).
Anal. Calcd for C17H25NO2 (275.39): C, 74.14; H, 9.15; N, 5.09.
Found: C, 73.93; H, 9.16; N, 4.89.
13C NMR (75 MHz): d = 22.8/22.8, 43.9, 70.8, 92.5, 126.3, 127.3,
128.0, 128.2, 129.2, 138.7, 139.2, 142.1, 148.5, 153.0.
Acknowledgment
Anal. Calcd for C17H18INO3 (411.23): C, 49.65; H, 4.41; N, 3.41.
Found: C, 49.66; H, 4.23; N, 3.27.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie (fellowship for M.K.).
2-tert-Butyl-6-(hydroxyphenylmethyl)phenyl Isopropylcarba-
mate (29d)
Prepared from 22 (0.108 g, 0.3 mmol) according to GP 4
(EX = PhCHO, 2 h); yield: 0.078 g (76%); colorless solid; mp
151 °C.
References
(1) Reviews: (a) Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004. (b) Volume on Cross-coupling Reactions,
Top. Curr. Chem. 2002, 219, 1–241.
(2) (a) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005,
44, 214. (b) Special issue on Fluorine in the Life Sciences,
ChemBioChem 2004, 5, 557–726.
(3) Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley: New York, 1999, 607.
(4) (a) Nyffeler, P. T.; Durón, S. G.; Burkart, M. D.; Vincent, S.
P.; Wong, C.-H. Angew. Chem. Int. Ed. 2005, 44, 192.
(b) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
1737.
IR (KBr): 3343, 2970, 1686, 1529, 1249, 703 cm–1.
1H NMR (400 MHz): d = 1.23/1.25 (d, J = 6.6 Hz, 6 H), 1.36 (s, 9
H), 3.51 (br s, 1 H, OH), 3.92 (m, 1 H), 5.06 (br d, 1 H, NH), 5.93
(s, 1 H), 7.04–7.13 (m, 2 H), 7.20–7.26 (m, 1 H), 7.28–7.35 (m, 3
H), 7.36–7.41 (m, 2 H).
13C NMR (100 MHz): d = 22.8/22.9, 30.5, 34.8, 43.8, 68.9, 126.1,
126.2, 126.8, 126.8, 127.9, 128.0, 138.5, 141.9, 143.0, 147.1, 155.0.
Anal. Calcd for C21H27NO3 (341.44): C, 73.87; H, 7.97; N, 4.10.
Found: C, 73.69; H, 8.05; N, 3.88.
(5) For reviews, see: (a) Snieckus, V. Chem. Rev. 1990, 90,
879. (b) Hartung, C. G.; Snieckus, V. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002,
330. (c) Clayden, J. In The Chemistry of Organolithium
Compounds; Rappoport, Z.; Marek, I., Eds.; Wiley:
Chichester, 2004, 495. (d) Gribble, G. W. In Science of
Synthesis, Vol. 8a; Majewski, M.; Snieckus, V., Eds.;
Thieme: Stuttgart, 2006, 357.
(6) (a) Kauch, M.; Hoppe, D. Can. J. Chem. 2001, 79, 1736.
(b) Kauch, M.; Snieckus, V.; Hoppe, D. J. Org. Chem. 2005,
70, 7149.
(7) Christensen, H. Synth. Commun. 1975, 5, 65.
(8) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
(9) For metalation studies of MOM protected mono- and
difluorophenols, see: (a) Marzi, E.; Mongin, F.; Spitaleri,
A.; Schlosser, M. Eur. J. Org. Chem. 2001, 2911.
(b) Marzi, E.; Gorecka, J.; Schlosser, M. Synthesis 2004,
1609.
2-[2-(Isopropylcarbamoyloxy)benzyl]acrylic Acid Ethyl Ester
(29b)
Prepared from 7d (0.153 g) according to GP 4 using CuCN·2LiCl
[0.7 mmol in THF (1.5 mL), 15 min] and BrCH2C(=CH2)CO2Et
(2.0 mmol, 12 h); yield: 0.119 g (82%); colorless oil.
IR (film): 3341, 2975, 1716, 1219, 1025, 764 cm–1.
1H NMR (300 MHz): d = 1.21 (d, J = 6.5 Hz, 6 H), 1.27 (t, J = 7.1
Hz, 3 H), 3.60 (s, 2 H), 3.86 (m, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.90
(br s, 1 H, NH), 5.35 (br s, 1 H), 6.22 (br s, 1 H), 7.10–7.29 (m, 4 H).
13C NMR (75 MHz): d = 14.1, 22.8, 32.3, 43.4, 60.7, 122.8, 125.4,
126.0, 127.6, 130.7, 131.1, 139.0, 149.4, 153.4, 166.9.
Anal. Calcd for C16H21NO4 (291.34): C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.58; H, 7.37; N, 4.71.
2-[3-Iodo-2-(isopropylcarbamoyloxy)benzyl]acrylic Acid Ethyl
Ester (29c)
(10) Baker, A. W.; Shulgin, A. T. Can. J. Chem. 1965, 43, 650.
(11) General reviews on arylsilanes and their application in
organic synthesis: (a) Keay, B. A. In Science of Synthesis,
Vol. 4; Fleming, I., Ed.; Thieme: Stuttgart, 2002, 685.
(b) Bassindale, A. R.; Glynn, S. J.; Taylor, P. G. In The
Chemistry of Organic Silicon Compounds, Vol. 2;
Rappoport, Z.; Apeloig, Y., Eds.; Wiley: Chichester, 1998,
355.
Prepared from 25c (0.216 g) as described for 29b; yield: 0.154 g
(74%); colorless oil.
IR (film): 3341, 2975, 1717, 1290, 1022, 776 cm–1.
1H NMR (300 MHz): d = 1.22–1.28 (m, 9 H), 3.63 (s, 2 H), 3.89 (m,
1 H), 4.18 (q, J = 7.1 Hz, 2 H), 5.00 (br d, 1 H, NH), 5.43 (s, 1 H),
6.25 (s, 1 H), 6.89 (t, J = 7.8 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 1 H), 7.68
(d, J = 7.9 Hz, 1 H).
13C NMR (75 MHz): d = 14.1, 22.8, 33.3, 43.6, 60.8, 92.7, 126.7,
127.4, 130.8, 133.9, 137.6, 138.4, 149.6, 152.0, 166.6.
(12) Kauch, M.; Hoppe, D. Synthesis 2006, xxx.
(13) Compounds 13a and 13b have been synthesized previously
in low yields by direct formylation of the 2-halophenols:
(a) Feldman, K. S.; Eastman, K. J.; Lessene, G. Org. Lett.
2002, 4, 3525. (b) Mcgarrigle, E. M.; Murphy, D. M.;
Gilheany, D. G. Tetrahedron: Asymmetry 2004, 15, 1343.
For alternative routes via ozonolysis of benzofurans, see:
(c) Crich, D.; Grant, D. J. Org. Chem. 2005, 70, 2384.
(d) Ishii, H.; Ohta, S.; Nishioka, H.; Hayashida, N.;
Harayama, T. Chem. Pharm. Bull. 1993, 41, 1166.
Anal. Calcd for C16H20INO4 (417.24): C, 46.06; H, 4.83; N, 3.36.
Found: C, 46.43; H, 4.89; N, 3.24.
2-Allyl-6-tert-butylphenyl Isopropylcarbamate (29e)
Prepared from 22 (0.108 g, 0.3 mmol) according to GP 4 using
CuCN·2LiCl [0.06 mmol in THF (0.5 mL)] and BrCH2CH=CH2 (4
h); yield: 0.061 g (74%); colorless solid; mp 105 °C.
IR (KBr): 3311, 2968, 1704, 1534, 1252, 773 cm–1.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York

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(14) For ipso-substitutions of DoM-derived arylsilanes including
O-aryl N,N-diethylcarbamates, see: Zhao, Z.; Snieckus, V.
Org. Lett. 2005, 7, 2523; and references cited therein.
(15) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999, 249.
(16) Similar results were reported for a related system:
Takahashi, M.; Hatano, K.; Kimura, M.; Watanabe, T.;
Oriyama, T. Tetrahedron Lett. 1994, 35, 579.
(17) For 26a, see: (a) Weeratunga, G.; Horne, S.; Rodrigo, R. J.
Chem. Soc., Chem. Commun. 1988, 721. For 26c, see:
(b) Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.;
Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1976, 1161.
(18) For 28a, see: Vasil’ev, A. A.; Engman, L. J. Org. Chem.
1998, 63, 3911.
(19) (a) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P.
Angew. Chem. Int. Ed. 1998, 37, 1701. For reviews, see:
(b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.
F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew.
Chem. Int. Ed. 2003, 42, 4302. (c) Jensen, A. E.; Dohle, W.;
Sapountzis, I.; Lindsay, D. M.; Vu, V. A.; Knochel, P.
Synthesis 2002, 565.
Synthesis 2006, No. 10, 1578–1589 © Thieme Stuttgart · New York