Directed ortho-Metalation of O-Aryl N,N-Dialkylcarbamates: Methodology, Anionic ortho-Fries Rearrangement, and Lateral Metalation

Article abstract of DOI:10.1002/ejoc.201701142

The directed ortho-lithiation reactions of O-aryl N,N-dialkylcarbamates as well as O-1-naphthyl and O-2-naphthyl N,N-dialkylcarbamates with sec-butyllithium/tetramethylethylenediamine (sBuLi/TMEDA) followed by quenching with various electrophiles afford a range of polysubstituted aromatic compounds. If the solutions of the ortho-lithiated carbamates are warmed to room temperature without the addition of external electrophiles, salicylamide and 1- and 2-hydroxynaphthamide derivatives are formed through anionic ortho-Fries rearrangements. The relative stabilities and reactivities of different O-aryl N,N-dialkylcarbamates were investigated. The lateral metalation of 2-tolyl carbamates with lithium diisopropylamide (LDA) provides a route to benzo[b]furan-2(3H)-ones. Previously reported results are used in a comparison of seven O-based directed metalation groups in reactions with several electrophiles. The described methodology is useful for the preparation of 1,2,3-substituted aromatic compounds.

Full text of DOI:10.1002/ejoc.201701142

A Journal of
Accepted Article
Title: Directed ortho-Metalation of N,N-Dialkyl O-Aryl Carbamates.
Methodology, Anionic ortho Fries Rearrangement, and Lateral
Metalation
Authors: Victor Snieckus, Jalil Miah, Mukund Sibi, S. Chattopadhyay,
and O.B. Familoni
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701142
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701142
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
Directed ortho-Metalation of N,N-Dialkyl O-Aryl Carbamates. Methodology,
Anionic ortho Fries Rearrangement, and Lateral Metalation
M. A. Jalil Miah,*[b] M. P. Sibi,[c] S. Chattopadhyay,[d] O. B. Familoni[e] and V.
Snieckus*[a]
Dedicated to the Bangladesh nation with ardent hope for rising to the challenges of
an improved state in the global village.
*[a] Prof. Dr. V. Snieckus
Department of Chemistry, Queen’s University, Kingston, ON K7L 3N6, Canada
Email: snieckus@chem.queensu.ca
*[b] Prof. Dr. M. A. Jalil Miah
Department of Chemistry, Rajshahi University, Rajshahi 6205, Bangladesh.
Email: jalilmiah@gmail.com
[c] Prof. Dr. M. P. Sibi
Department of Chemistry, North Dakota State University, Fargo ND 58105-5516,
USA
Email: Mukund.sibi@ndsu.edu
[d] Prof. Dr. S. Chattopadhyay
Department of Chemistry, Jadavpur University, Kolkata 700032, India.
Email: schattopadhyay@chemistry.jdvu.ac.in
[e] Prof Dr. O. B. Familoni
Department of Chemistry, University of Lagos, Akoba-Yaba, Lagos, Nigeria
Email: familonio@yahoo.com
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Abstract
Described is the directed ortho-lithiation reaction of N,N-dialkyl O-aryl carbamates,
N,N-dialkyl O-naphthyl-1 and N,N-dialkyl O-naphthyl-2 carbamates with sec-
butyllithium/TMEDA followed by quenching with various electrophiles to afford a
range of polysubstituted aromatic compounds (Tables 1 and 2, Schemes 2 and 3).
Warming solutions of the ortho-lithiated O-carbamates to room temperature without
external quench with electrophiles leads to the formation of salicylamide and 1- and
2-hydroxynaphthamide derivatives by anionic ortho-Fries rearrangements (Scheme
4). The relative stability and reactivity of different N,N-dialkyl O-carbamates has
been investigated. Lateral metalation of 2-tolyl O-carbamate with LDA provides a
synthesis of benzo[b]furan-2(3H)-ones (Scheme 2). Using reported results, a
comparison of seven O-based directed metalation groups in reaction with several
electrophiles is made. The described methodology is useful for the preparation of
highly, 1,2,3-substituted, aromatic compounds.
̶
The directed ortho metalation (DoM) [1 2] constitutes a synthetic strategy which
has witnessed considerable utility for the efficient and regioselective construction of
polysubstituted aromatic and heteroaromatic molecules of biological and
̶
agrochemical interest. [3 4] Among the considerable number of carbon- and
heteroatom-based directed metalation groups (DMGs), oxygen atom-based DMGs
hold a prominent position due to the original, almost concurrent, discovery by Wittig[5]
and Gilman[6] of the ortho-metalation of anisole. These original findings spawned,
over 70 years, numerous oxygen-based DMGs whose value is manifested especially
in their conversion into phenol derivatives (Scheme 1). The OMe and OMOM DMGs
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
[7
̶
have received considerable use in synthesis and the O-carbamate OCONR2 11] is
now recognized as the most powerful DMG, challenged only recently by the O-
phosphodiamidate OP(O)(NR2)2 group,[12] Since its discovery,[7] the OCONR2 DMG
has witnessed new methods of preparation, deprotection,[38, 43] and considerable
synthetic use.[44] Recently, Sanz and coworkers.[44a] have reported a thorough study
of the DoM and AoF rearrangement of dihalo (chloro--, bromo- and -fluoro) O-
carbamates which nicely extend the studies reported herein. The OCONR2 group
also participates in the directed remote metalation reactions, [45] has been discovered
to be a partner in Ni-catalyzed Suzuki-Miyaura[46] and Kumada-Corriu[47] cross
coupling reactions, and has been the subject of mechanistic studies.[48]
DMG
Relative
DMG
Discovery, year
Recent Examples
Power[a]
OMe[b]
5
Wittig 1938, 1940[5]
Gilman 1939, [6]
Smith 2009[13]
Meskova 2013[14]
Tietze 2014[15]
Snieckus 2007[19]
OMOM
2
Christensen 1975[16]
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
Townsend 1981[17]
Ronald 1982[18]
Xiang 2007[20]
Snider 2007[21]
OTHP
4
1
Parham 1948[22]
Cassidy 1957[23]
Geneste 2001[24]
Azzouz 2006[25]
OCONR2
Snieckus 1983,[7]
Snieckus 1992[26]
Snieckus 2008[27]
Garg, Snieckus
2011[28]
OCH2CH2OMe[b]
3
Ellison 1973[29]
Wada 1985[30]
Wada 1985[30]
OCH2CH2NMe2 Unknown
-
OP(O)(NR2)2
≥ OCONR2 Nasman 1986[31]
Watanabe1989[32]
Snieckus 2008 [12]
OSEM
Unknown
Unknown
Snieckus 1990[33]
Snieckus 1999[34]
-
-
OCON(Me)C-
(Me)2Ph
OSO2NR2
Unknown
Snieckus, 2005[35]
Hoppe 2001[36]
Garg, Snieckus
2011[28]
OCON(TMS)iPr Unknown
Snieckus 2005[37]
Hoppe 2006[38]
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
OP(O)(OR)2
Unknown
Melvin 1981[39]
Cambie 1982[40]
Dhawan1986[41]
Watanabe1989[32]
Snieckus 2008 [12]
[a] Estimated from qualitative competitive experiments, see ref [1b]; [b] The ratio of (2-methoxyethoxy) benzene to anisole metalation ≈ 14:1 (d-
experiment, see ref [29].
Herein we report 1) an extensive methodological investigation of the DoM
reactions of aryl and naphthyl O-carbamates, 2) their anionic ortho-Fries (AoF)
rearrangement in both series, 3) the effect of carbamate N-alkyl group variation on
the efficiency of DoM and the AoF, and 4) the competitive DoM and lateral
metalation of ortho-tolyl O-carbamates, including, in case of the latter, conversion to
benzofuranones. In the sequel, we present intramolecular competition studies of the
O-carbamate with several other prominent DMGs and illustrative iterative DoM
chemistry. [49] These studies, combined, extend substantially the preliminary
results[7] in all aspects above and provide new avenues for diverse utility of DMG =
OCONR2 DoM reactions of potential synthetic value and application.
Methodological Studies
N,N-Diethyl O-phenyl carbamate 4, readily obtained by treatment of phenol
with N,N-diethyl carbamoyl chloride in pyridine (see SI), upon metalation under the
originally established optimized conditions (s-BuLi/TMEDA/THF/-78 °C)[7]
followed by deuteration (MeOD) afforded deuterated product 5 in almost quantitative
yield (95%) and high d-incorporation (96 d1 %) (Table 1).
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Table 1. Synthesis of N,N-Diethyl 2-Substituted O-Aryl Carbamates
Product
E
E+
Yield [%][a]
MeOD
MeI
5
6
7
D
95[b]
Me
80
75
DMF
8[c]
9
CHO
73
73
86
80
22
86
90
22
79
79
87
86
86
78
98[e]
CO2
CO2H
CONEt2
CONHPh
COMe
CH(OH)Pr-n
CH(OH)Ph
C(OH)Ph2
TMS
ClCONEt2
PhNCO
Ac2O
10[d]
11
12
13
14
15
16
17
18
19
20
21
22
n-PrCHO
PhCHO
Ph2CO
TMSCl
(MeS)2
(PhS)2
SMe
SPh
Cl3CCCl3
BrCH2CH2Br
I2
Cl
Br
I
B(OMe)3/H2O2,
HOAc
OH
[a] Based on purified (crystallized or distilled) materials. [b] 96% d1 (by MS). [c] 42% of the product was isolated
as salicylaldehyde. [d] Identical to product prepared by treatment of N,N-diethyl 2-hydroxybenzamide with
CONEt2. [e] Isolated as product of hydrolysis (see SI).
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From the synthetic perspective, quantitative d-incorporation indicates the
formation of a high concentration of anion under the given conditions. With this
anticipation, but based on relative reactivity, a variety of electrophiles were
introduced to give products 6-22 in good to excellent yields, the exceptions being
compounds 12 and 15 possibly due to presence of acidic C-H bonds in the
electrophile and SET reactions respectively. Thus, aside from alkylaton and allylation
(6, 7), diverse carbon electrophiles at carboxaldehyde (8), carboxylic acid (9
carbinol (13, 14) oxidation states were obtained. Products with ortho-sulfur (17, 18), -
halo (19 21), and -hydroxy (22) substituents, the latter a result which shows ability to
differentiate catechol hydroxyls, were also cleanly obtained. Compounds 10 and 11
̶ 11) and
̶
are poised for further DoM reactions[49] while products 16, 17, 19
̶ 21, and 22 are
basic substrates for further modern synthetic manipulation.
In view of the ready availability of the N,N-dimethyl O-phenyl carbamate 23
and with the intent to make a parallel comparison and contrast with the N,N-diethyl
vs the N,N-dimethyl benzamide DoM reactivity,[50] we tested compound 23 under
several different conditions and electrophile quench experiments (Table 2). Thus,
when 23 was subjected to lithiation under the standard conditions (s-
Buli/TMEDA/THF/-78°C) for 45 min, quenched with MeI, and the reaction mixture
was allowed to warm to room temperature, the salicylamide derivative 25, resulting
from an anionic ortho-Fries rearrangement (see below), was obtained exclusively in
75% yield rather than the ortho-methylated carbamate 24a (entry 1, Table 2). This
result indicates that the rate of the anionic ortho-Fries rearrangement for 23 is very
fast compared with the corresponding reaction on the N,N-diethyl analogue 4.
However, under these conditions but a short lithiation time (10 min) and quenching
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10.1002/ejoc.201701142
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with MeI, the ortho-methyl derivative 24a was obtained as the major product (60%
yield) with minor amounts of the rearrangement product 25 (20% yield) (entry 2). At
-95 oC and 10 min lithiation time, only compound 24a was isolated in high yield
(90%) with no detectable amount of 25 (entry 3). These conditions were adopted to
quenching with two other electrophiles furnishing products 24b and 24c in good
yields (entries 4 and 5).
Table 2. Metalation Studies of N,N-Dimethyl O-Phenyl Carbamate 23.
Entry
Temp oC
Time
(min)
E+
Product, yield [%][a]
24 (E)
25
1
2
3
4
5
̶
̶
̶
̶
̶
78
78
95
95
95
45
10
10
10
10
MeI
-
75
20
MeI
24a: 60 (Me)
24a: 90 (Me)
MeI
-
Et2NCOCl
TMSCl
24b: 70 (CONEt2) -
24c: 88 (TMS)
-
[a] Yields of isolated products.
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To further define the scope of the DoM chemistry of aryl O-carbamates,
systems bearing additional DMGs were investigated and are reported separately, [49]
while the metalation of the three isomeric ortho-tolyl O-carbamates 26a-b and 6 are
presented in Scheme 2. The 3-methyl isomer 26a leads to the formation of silylated
product 27a, paralleling the behavior of the corresponding benzamide[50] which also
undergoes reaction at the less hindered C2-site. The 4-methyl derivative 26b
underwent clean metalation and silylation to give 27b as the only detected (NMR)
and isolated product thus confirming the expected inconsequential and relatively
weak acidity of the 4-methyl hydrogens under these conditions. [50]
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The 2-methyl O-carbamate 6 behaved uniquely to give a mixture of DoM (28) and
lateral metalation (29) [7, 51] products using a TMSCl quench experiment (28:29 = 2:1
from 1H NMR, by integration of Me and CH2 signals) (Scheme 2).
On the other hand, LDA metalation and warming to room temperature resulted in the
formation of products 30 (60% yield) and 31 (8% yield) indicating exclusive
metalation at the benzylic position. In context of the complex induced proximity
effect (CIPE), [45c] the strongly basic s-BuLi/TMEDA conditions are responsible for the
predominant formation of the ortho metalation product 28 over the lateral metalation
product 29 while the LDA conditions, without an electrophile quench, allows
formation of equilibrium concentration of the ortho-tolyl anion which is driven to
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
carbamoyl migration to form 30 by a substantial phenolate leaving group effect. The
formation of 31 may be rationalized by intermolecular carbamoyl migration from 6
facilitated by the higher acidity of the resulting α-acetamide anion in spite of its
phenolate deactivation. Treatment of 30 under acid-catalyzed conditions (1M HCl or
p-TsOH/C6H6) led to 2(3H)-benzofuranone 33 (72-94% yields) while compound 31
was found to undergo facile hydrolysis and decarboxylation (1M HCl) to give 2-
hydroxy-phenylacetic acid 32 (69% yield) which, without isolation also underwent
cyclization to 33. This methodology has found use for the synthesis of
benzofuranone derivatives with substituent patterns difficult to obtain by other
means. For instance, 7-chloro-, 7-methoxy-, and 6-methyl-2(3H)-benzofuranones as
well as an unnamed metabolite from a Helenium species bearing the 2(3H) -
[44g]
benzofuranone system have been prepared by this sequence.
The DoM reaction was then extended to O-naphthyl carbamates. N,N-Diethyl
O-1-naphthyl carbamate 34 was found to undergo smooth lithiation under the
standard conditions (s-BuLi/TMEDA/THF/-78 °C) and, following quench with MeI,
Et2NCOCl and TMSCl, gave products 35a, 35b, and 35c respectively in high yields
(Scheme 3).[52]
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On the other hand, N,N-diethyl O-2-naphthyl carbamate 36a, was found to
afford isomeric 1- and 3-substituted naphthyl carbamates 37a (17% yield) and 38a
(45% yield) for TMSCl and 38b (51% yield) for Et2NCOCl quenching experiments,
respectively (Scheme 3). In addition, the AoF rearrangement product, 3-hydroxy-2-
naphthamide 39 was obtained in 20–26% yields in both series. Although purification
of 37a was difficult (see SI), it was cleanly obtained in 81% yield by the metal-
halogen exchange/TMSCl quench procedure of 1-bromo-2-naphthyl carbamate 36b
under the preferred metal-halogen exchange conditions. [53]. This result and the
analogous quench experiment with Et2NCOCl to give 37b (39% yield)
unambiguously defines that C1-regioselective metalation had occurred. It also allows
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the conclusion that the 1-lithiated 2-carbamoyloxy species is stable under these
conditions with respect to equilibration to the corresponding 3-lithiated species.
Stability of the 1-lithio intermediate was established for an extended time (6 h) at -
78°C before treatment with TMSCl to furnish only 37a (85% yield) and no other
identifiable products (see SI). Also 2-hydroxy-1-naphthamide 40 (77% yield) was
obtained cleanly from 36b under metal-halogen exchange conditions via the AoF
rearrangement. Conditions for greater C1- vs C3-regioselectivity in context of the
synthesis of multisubstituted naphthalene derivatives using LiTMP and LDA bases
have been recently reported from our laboratories.[2d] To note a different DMG, we
have also previously reported that the 2-(trimethylsilyl)ethoxymethoxy (OSEM)
derivative of 2-naphthol shows preference for C3-DoM chemistry..[33]
The Anionic ortho-Fries Rearrangement
As originally observed,[7] in the absence of any external electrophile, the
intermediate lithiated species, formed under standard conditions (s-
BuLi/TMEDA/THF/-78 ° C) from 4, upon slow warming to room temperature,
undergoes rearrangement to give salicylamide derivatives 41a (Scheme 4) by a
process which is the equivalent of the well known Lewis acid-catalyzed
transformation,[54] and may be formally termed the anionic ortho-Fries (AoF)
rearrangement. In the anionic ortho-Fries rearrangement, the O-carbamate
effectively serves as a “carrier” of the amide group, a powerful DMG,[1b] into the ortho
position for enticement of further DoM chemistry.
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The AoF reaction was extended to the synthesis of methyl substituted
salicylamide derivatives 41b-d from readily available starting materials 6a and 26a
̶
b
(Scheme 4) and has been applied to systems bearing other DMGs in work described
separately. [49] Not surprisingly, based on the DoM chemistry of 26b where methyl
group deprotonation is not observed (see Table 1), its anionic ortho-Fries
rearrangement leads to the 5-methyl-2-hydroxybenzamide derivative 41d in good
yield. On the other hand, the 3-methyl (26a) and 2-methyl (6a) O-carbamates lead
solely to the 4-methyl (41c) and 3-methyl (41b) derivatives respectively,
regioselective processes which differ from their behavior in the kinetic electrophile
quench experiments (see Table 1). The thermodynamic control conditions of the
rearrangements may imply that methyl group deprotonation occurs but the reactions
are driven to their end products by the leaving group stability of the respective
phenolate anions. Interestingly, metalation of the N,N-dimethyl O-carbamate 24
corresponding to 6a afforded a mixture of rearrangement product 43 (56% yield) and
the lateral metalation carbamoyl migration product 44 (25% yield) (see SI).
Furthermore, notable contrasting results are observed in the excess LDA and s-
BuLi/TMEDA mediated reactions of 6a and the corresponding dimethylamide of 24
(see SI). While further rationalization is presently inappropriate owing to lack of
structural and theoretical evidence, the synthetic value of the rapid access to
salicylamides 41b-d, in particular the 1,2,3-contiguously substituted 41b, may be
appreciated, for example, in view of the recent establishment of mild conditions for
the benzamide to benzaldehyde conversion using the Schwartz reagent. [43c]
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In a comparative study, metalation of N,N- dimethyl O-phenyl carbamate 23
(Table 2) under s-BuLi/TMEDA/THF/-95 oC/5.5 h conditions followed by quenching
with NH4Cl at this temperature and warming to room temperature afforded the AoF
rearrangement product 25 in 86% yield while application of the identical conditions
on N,N-diethyl O-phenyl carbamate 4 but maintaining the metalation time at -78oC
for 5.5 h, quenching at -78 oC and warming to room temperature over 8 h gave a
mixture of 4 and 41a in a 92.5:7.5 ratio in 90% yield, indicating the relative greater
stability of the lithiated species of 4 over that of 23.
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In a concurrent study, the 1- and 2-naphthyl O-carbamates 34 and 36a were
subjected to the AoF rearrangement conditions to furnish amides 42 and a mixture of
amides 39 and 40 respectively paralleling the results of the electrophile quench
experiments (Scheme 3). Compound 39 is known while product 40 was identified by
comparison of spectral and physical properties with material prepared from bromo
derivative 36b by metal-halogen exchange followed by anionic rearrangement (see
SI).
In order to distinguish between an intra- and inter-molecular anionic 1,3-
carbamoyl migration, a mixture of one equivalent each of N,N-dimethyl O-phenyl
carbamate 23 and N,N-diethyl O-4-tolyl carbamate 26b was lithiated with two
equivalent of base, (-95° C, 8 h, warming to rt); the corresponding salicylamide
derivatives 25 (75% yield) and 41d (7% yield) were obtained with no evidence for
cross over products thus suggesting an intramolecular anionic O to C-carbamoyl
migration (AoF rearrangement).
The high yields of the anionic ortho-Fries rearrangement products which are
usually obtained (Scheme 4) also suggest that the reaction proceeds via an
intramolecular mechanism with the formation of the tetrahedral intermediate 45,
analogous to the intermediate 47 formulated for the anionic rearrangement of ketone
46 to product 48 (Scheme 5).[55]
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Comparison of O-based DMGs and Conclusions
We have demonstrated that the N,N-diethyl O-carbamate is an excellent directed
metalation group (DMG) for the regioselective construction of substituted aromatics
by DoM chemistry, shown the reaction to have generality for aryl (Table 1) and
naphthyl (Scheme 3) O-carbamates, and found application in methyl-substituted O-
carbamates to afford highly substituted products as well as potential for the synthesis
of benzofuranones (Scheme 2). Together with the facile and practical anionic ortho-
Fries rearrangement, these protocols furnish products not readily available by other
methodologies (Scheme 4). The hierarchical position of the O-carbamate (Scheme
1) and its conversion into phenol under mild reductive conditions[56] places it in a
compelling position as a DMG of choice (Table 3) for synthetic aromatic chemistry.
Bearing in mind the caveat for the required reproduction of synthetic experiments,
several useful points may be perceived from the presented data: a) for the seminal
DMG = OMe (entry 1), the use of t-BuLi appears to be commonly adopted (entries 2-
5) but perhaps not required; b) DMG = OMOM survives metalation at 0oC and rt to
provide reasonably efficient reactions (entries 6-11) ; c) the acid-labile OMEM is an
inadequately investigated DMG (entries 12-16); n-BuLi/THF/TMEDA/–20 10 OC
conditions provide high yields of products for the insufficiently appreciated, mildly
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10.1002/ejoc.201701142
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deprotectable OTHP DMG (entries 17-19); d) DMG = OSO2NR2 and OP(O)(NR2)2
are perhaps non-competitive for broad synthetic use in view of the low temperatures
required for the deprotonation (entries 20-28); e) the OCONR2 fares well in
comparison with other O-based DMGs in, for example, DMF and CO2 quench
experiments (entries 30 and 31). To conclude, for requirements of mild acid
sensitive DMGs, OMOM is a primary choice with the proviso that OTHP deserves
further test. For Lewis-acid stability, the OCONR2 is a constructive choice. The fact
that all comparisons are made on unsubstituted DMG systems represents the final
caveat.
In the sequel, [49] the comparative and synergistic effects in DoM reactivity of
the O-carbamate with respect to several other DMGs is presented.
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Table 3. Comparison of Reaction Efficiencies of Selective O-Based DMGs
DMG
OMe
Entry
E+
E
Yield
%
[ref]
Conditions
1
2
3
4
5
[a]
[b]
[c]
[b]
[d]
DMF
CHO
60
75
[57]
[13]
PhCHO
CO2
Ph(CH)OH
COOH
CO2H
54
̶
60 [6]
CO2
80
70
[13]
[18]
CO2/CH2N2 CO2Me
OMOM
6
7
[e]
[f]
MeI
DMF
DMF
DMF
CO2
I2
Me
59
[59]
CHOc
CHO
CHO
CO2H
I
80
̶
85 [16]
8
[g]
[h]
[h]
[h]
89
95
̶
[58]
[60]
[60]
[60]
9
78
76
73
68
10
11
OMEM
12
13
14
15
16
[i]
[i]
[i]
[i]
[i]
MeI
Me
[30]
[30]
[30]
[30]
[30]
DMF
CHO
62
29
70
43
PhCHO
CO2
CH(OH)Ph
CO2H
TMS
TMSCl
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OTHP
17
18
19
[j], [k]
[j]
TMSCl
(PhS)2
C2Cl6
TMS
PhS
Cl
90
83
89
[22],
[24]
[22]
[j]
[22]
OSO-
NR2
20
21
22
23
24
[l]
[l]
[l]
[l]
[l]
DMF
CHO
CH(OH)Ph
TMS
MeS
63
80
96
88
78
[35]
[35]
[35]
[35]
[35]
PhCHO
TMSCl
(MeS)2
I2
I
OP(O)-
(NR2)2
25
[m,n]
MeI
Me
87
[32]
[12]
[32]
[32]
[32]
26
27
28
[m]
[m]
[m]
PhCOMe
TMSCl
PhC(OH)Me
TMS
64
79
64
(PhS)2
PhS
OCO-
NR2
29
30
31
32
33
34
[o]
[o]
[o]
[o]
[o]
[o]
MeI
Me
80
73
86
73
79
78
[7]
[7]
[7]
[7]
[7]
[7]
DMF
PhCHO
CO2
CHO
CH(OH)Ph
CO2H
TMS
I
TMSCl
I2
[a] n-BuLi/TMEDA/rt; [b] t-BuLi /THF / –78 OC; [c] n-BuLi/Et2O/reflux ; [d] t-BuLi/pet. ether/ 0oC ; [e] n-BuLi/hexane/rt; [f] n-BuLi/TMEDA/hexane/0
 5oC ; [g] n-BuLi/Et2O/rt ; [h] n-BuLi/Et2O/rt ; [i] n-BuLi/Et2O/rt; [j] n-BuLi/THF/ TMEDA/–20 to -10 OC/E+  rt; [k] n-BuLi/THF/–70/ E+ rt; [l] s-
BuLi/TMEDA/THF/-93 OC  rt; [m] s-BuLi/THF/-105 OC  -78 OC  0OC- rt (R = Me, Et); [n] s-BuLi/THF/-105 OC 78 OC  0OC  rt (R = Me,
Et) ; [o] s-BuLi/TMEDA/THF/-78 OC  0 OC.
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
Acknowledgements. We are grateful to NSERC Canada for Discovery Grants in
support of our synthetic programs. We thank Snieckus Innovations for additional
support. M. A. J. Miah is grateful to Rajshahi University, Bangladesh for sabbatical
leave, and Queens University, Kingston, ON, Canada for a Visiting Professorship.
Preliminary work was carried out by B. Beattie, B. Byron and J. Lee to whom we are
grateful.
Experimental Section
Procedure 1. Lithiation of O-Aryl Carbamates with s-BuLi/TMEDA. A solution of
the carbamate in dry THF (5-10 mL) was added dropwise by syringe injection to a
stirred solution of a 1:1 s-BuLi-TMEDA complex in dry THF at -78°C (or -90°C as
indicated) under nitrogen. After a reaction period (5 min to 1h as indicated), the mixture
was treated with an electrophile. The resulting solution was then allowed to warm to rt
over 8 h after which a few mL of aqueous NH4Cl solution was added and the THF was
removed in vacuo. Subsequent standard workup gave the crude product. The details
of the lithiation procedure which follow the above standard procedure are summarized
in the order as follows: name and number of molar equivalents of alkyllithium reagent
used, reaction temperature, lithiation time, and name and number of molar equivalents
of electrophile used.
Procedure 2. Lithiation of O-Aryl Carbamates with LDA. To a THF solution of
freshly distilled diisopropylamine (1.1 equiv) was added n-BuLi (1.1 equiv) at 0°C
under nitrogen and the solution was stirred for 30 min. The resulting solution of
lithium diisopropylamide was cooled to -78° C and the required carbamate (1.0
equiv) in THF (5 mL) was added by syringe injection. After 1 h, an electrophile was
added and the resulting solution was allowed to warm to rt over 8 h and processed in
the normal manner (as described in Procedure 1) to give the crude product.
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10.1002/ejoc.201701142
European Journal of Organic Chemistry
Procedure 3. Lithiation of the appropriate carbamate was carried out with s-
BuLi/TMEDA (Procedure 1) or LDA (Procedure 2) and the resulting lithiated
carbamate was allowed to warm to rt over 8 h. Processing in usual manner as
described in Procedure 1 gave the crude product.
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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Graphical Abstract
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