Directed ortho-Metalation of Aryl Amides, O-Carbamates, and Methoxymethoxy Systems: Directed Metalation Group Competition and Cooperation

Article abstract of DOI:10.1002/ejoc.201701143

A systematic study on the competitive metalation of derivatives containing four directed metalation groups (DMGs), namely, Cl, OMe, methoxymethoxy (OMOM), and CONEt₂, in comparison with the OCONEt₂ DMG is described. In addition, the

Full text of DOI:10.1002/ejoc.201701143

A Journal of
Accepted Article
Title: Directed ortho Metalation of Aryl Amides, O-Carbamates, and
OMOM Systems. Directed Metalation Group Competition and
Cooperation
Authors: Victor Snieckus, Jalil Miah, Mukund Sibi, S. Chattopadhyay,
and Wole Familioni
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701143
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10.1002/ejoc.201701143
European Journal of Organic Chemistry
Directed ortho Metalation of Aryl Amides, O-Carbamates, and
OMOM Systems. Directed Metalation Group Competition and
Cooperation
M. A. Jalil Miah,*[a, b] M. P. Sibi,[c] S. Chattopadhyay, [d] O. B. Familoni[e] and V. Snieckus*[a]
[a] Prof. Dr. M. A. Jalil Miah, Prof. Dr. V. Snieckus
Department of Chemistry, Queen’s University, Kingston, ON K7L 3N6, Canada
Email: snieckus@chem.queensu.ca, jalilmiah@gmail.com
[b] Prof. Dr. M. A. Jalil Miah
Department of Chemistry, Rajshahi University, Rajshahi University, 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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10.1002/ejoc.201701143
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Abstract:
A systematic study on the competitive metalation of four directed
metalation group (DMG)-bearing derivatives (DMG = Cl, OMe, OMOM, and CONEt2)
in comparison with the OCONEt2 DMG is described (Table 2). In addition, anionic
ortho Fries (AoF) rearrangement (Table 3), the double metalation-electrophile quench
of 1,2- and 1,4-O-carbamates (Scheme 2) and iterative metalation procedures
(Scheme 3) is presented. The results provide new methodology for the synthesis of
functionalized contiguously 1,2,3- and 1,2,3,4-substituted aromatic derivatives of
difficult accessibility and potential broad utility. A comparison of the present
methodology with previously developed routes is given in selected examples with
emphasis on such substituted compounds (Table 5).
OAm
OH
Am
OAm
E
AoF condition
DoM
s-BuLi/TMEDA/
THF/ 78oC to rt
1. s-BuLi/TMEDA/
H
THF/ 78oC
DMG
DMG
DMG
2. E+/ 78 C to rt
23 examples
24 96% yields
10 examples
16 93% yields
Am = CONEt2
Et2N
O
OAm
R
R
O
O
OAm
OAm
R
OAm
6 examples
63 89% yields
R
Et2N
O
8 examples
40 84% yields
double AoF
DoM = Directed ortho Metalation. AoF = Anionic ortho Fries
The Directed ortho Metalation (DoM) strategy has attained a prominent position,
in concept and practice, for the construction of polysubstituted aromatics and
̶
[7]
heteroaromatics in both academic and industrial laboratories.[1]
Among the
extensive list of carbon- and heteroatom-based Directed Metalation Groups (DMGs)
̶
which have been developed,[1] [4] a number may be considered to be adequately tested
[1] [2]
for reproducibility and widely adapted in synthesis.
,
A hierarchal order of
representative DMGs is shown in Table 1. The given order of ranking is based on the
[1]
̶
[3,],[8] [18]
studies of numerous groups
using both inter- and intra-molecular
competition experiments in which two DMG substrates and two DMGs on the same
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10.1002/ejoc.201701143
European Journal of Organic Chemistry
substrate respectively are allowed to compete for one equivalent of base, followed by
quench with a deuterium source (usually MeOD). While establishment of kinetic
conditions (-78oC, short reaction times) for the deprotonation is always sought,
consideration of exothermicity of reaction and, significantly for the intramolecular
experiments, resonance and inductive effects of one DMG on the other of metalation,
give only qualitative character to these experiments. Nevertheless, the established
̶
36]
hierarchy[19
has considerable value in allowing planning towards the synthesis of
chosen substituted aromatics in context of ortho-, meta- and para-related DMG
frameworks (Scheme 1). Thus, systems 1 and 3 are unexceptional in giving products
of metalation as indicated by the arrows; meta-DMG system 2 has the beneficial but
not completely invariable quality, observed for a number of DMGs, of metalation
occurring synergistically in between the two DMGs.
̶
36]
Table 1. Hierarchal Order of DMGs and Conditions for DoM [19
DMG
DMG
Discovery [ref]
Conditions, temp
Power,
Decreasing
Order
OP(O)(NR2)2 Nasman 1986[19]
s-BuLi/TMEDA/THF/-103 to -
93 oC
≥ OCONR2
Snieckus 1983[20]
s-BuLi /THF/TMEDA /-78 oC
SO(1,2)t-Bu
Stoyanovich1966[21] n-BuLi/THF/none/-78 oC
Snieckus 1989[10]
Snieckus 1992[22]
Beak 1977[23]
n-BuLi/THF/-78 oC
CONR2
s-BuLi/THF/TMEDA /-78 oC
CONHR
Hauser 1964[24]
n-BuLi/THF, Et2O/TMEDA or
none/-78 oC
SO2NR2
Hauser 1969[25]
s-BuLi /THF/none /-78 to 0 oC
n- SO2NHR Hauser 1968[26]
n-BuLi /THF/none/-10 to 25 oC
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Meyers 1975 [27]
n-BuLi or s-BuLi/THF or
N
Gschwend 1975[28] Et2O/none/
-45 to 0 oC
O
CO2H
Mortier 1994[29]
s-BuLi /THF/ TMEDA /-90 oC
OMOM ≈
OMEM
Christensen
n-BuLi or t-BuLi/Et2O/none/-
1975[30]
20 to 25 oC
Townsend 1981[31]
Ronald 1982[32]
Ellison 1973[33]
n-BuLi/Et2O/none/rt
NH(BOC)
Gschwend 1979[34] t-BuLi/ THF/none/-50 to -20
oC
NH(Piv)
F
Muchoswki[35]
n-BuLi/ THF/none/-40 oC
Gilman 1957[36]
n-BuLi/THF/none/ -50 oC
As part of a comprehensive study of the N,N-dialkyl O-carbamate DMG, we
reported on its DoM chemistry for the general synthesis of ortho-disubstituted
derivatives as well as its anionic ortho-Fries rearrangement to obtain salicylamides. [37]
In that work, we restricted the study to the bare O-phenyl carbamate, methyl
substituted derivatives, and naphthyl O-carbamates. Herein we describe results of a
systematic study on the competitive metalation of four DMG-bearing derivatives (DMG
= Cl, OMe, OMOM, and CONEt2) in comparison with the OCONEt2 DMG. In addition,
we report results on the double metalation-electrophile quench of 1,2- and 1,4-O-
carbamates for the synthesis of contiguously tetrasubstituted derivatives and iterative
metalation procedures of potential value in synthesis of aromatic molecules.
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The studies on the four DMG-substituted O-carbamates are depicted in (Table
2). The variable conditions that can affect the reaction were brought under control by
carrying out the reaction in the same flask and under the same temperature and solvent
conditions for easy comparison. The structures of the products were assigned by
analysis of their 13C NMR spectra based on reduction of intensities of the signals for the
substituted carbons compared to the corresponding signals in the starting materials (for
details, see SI).[38]
Table 2. DoM Reactions of DMG-substituted Aryl O-Carbamates 4
Entry Compd DMG
E+
Product
DMG
6-Cl
2-Cl
2-Cl
3-Cl
3-Cl
3-Cl
4-Cl
E
Yield,%
1
2
3
4
5
6
7
4a
4a
4a
4b
4b
4b
4c
2-Cl
2-Cl
2-Cl
3-Cl
3-Cl
3-Cl
4-Cl
ClCONEt2 5a
2-Am
6-TMS
6-I
78
TMSCl
I2
5b
5c
5d
5e
5f
79
93
MeOD
PhCHO
TMSCl
2-D
85 (80% d1)
2-PhCH(OH) 81
2-TMS
2-Am
89
77
ClCONEt2 5g
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European Journal of Organic Chemistry
8
4d
4d
4d
4e
4e
4e
2-OMe
2-OMe
2-OMe
3-OMe
3-OMe
3-OMe
MeI
5h
2-OMe
6-OMe
2-OMe
3-OMe
3-OMe
3-OMe
6-Me
92
9
ClCONEt2 5i
2-Am
90
10
11
12
13
TMSCl
MeOD
MeI
5j
6-TMS
2-D
68
5k
5l
93, 97% d1
90[b] (70:30)
83[c] (76:24)
2-Me: 6-Me
2-CO2H
6-CO2H
2-I
CO2
5m
14
4e
3-OMe
I2
5n
3-OMe,
5-OMe
75[d] (92:8)
2-I
15
16
17
18
19
20
21
22
4f
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
MeI
5o
5p
5q
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
2-Me
72
4f
DMF
CO2
2-CHO
2- CO2H
2-Am
42[e]
4f
69
4f
ClCONEt2 5r
87
4f
TMSCl
5s
5t
2-TMS
62
4g
4g
4h
2-OMOM MeOD
2-OMOM 6-D/3-D
6-OMOM 2-Am
3-OMOM 2-D
88 (63% d1)
48
2-OMOM ClCONEt2 5u
3-OMOM MeOD 5v
96
(55% d1)
24[f]
23
24
4h
4i
3-OMOM ClCONEt2 5w
4-OMOM MeOD 5x
3-OMOM 2-Am
4-OMOM 2-D
83
(66% d1)
70
25
26
4i
4-OMOM ClCONEt2 5y
4-OMOM 2-Am
4j
3-OAm
2-Am
MeOD
MeOD
5z
3-OAm
2-Am
2-D
6-D
76 (64% d1)
27
4k
5aa
86
(55% d1)
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28
29
4k
4l
2-Am
3-Am
ClCONEt2 5ab
2-Am
3-Am
6-Am
3-Am
2-D
80 (82:18)
MeOD
5ac
85
(33% d1)
7[g]
30
31
32
4l
3-Am
4-Am
4-Am
ClCONEt2 5ad
MeOD 5ae
ClCONEt2 5af
3-Am
4-Am
4-Am
2-Am
2-D
4m
4m
85 (66 %d1)
2,4- di-Am: 3,4 69 (3:2)
di-Am
[a] Yields of isolated products; [b] N,N-diethyl O-(2-methyl -3-methoxy)phenylcarbamate, (70%) and N,N-diethyl O-(6-methyl-3-
methoxy)phenylcarbamate, (30%); [c] N,N-diethyl O-(2-carboxy-3-methoxy)phenyl-carbamate (76%, converted into 2-hydroxy-6-methoxybenzoic
acid) and N,N-diethyl O-(2-carboxy-5-methoxy) phenylcarbamate (24%, converted to 2-hydroxy-5-methoxybenzoic acid) see SI; [d] N,N-diethyl O-
(2-iodo-3-methoxy) phenylcarbamate, and N,N-diethyl O-(2-iodo-5-methoxy) phenylcarbamate, see SI; [e] Salicyldehyde, 58%; [f] N,N-Diethyl-2-
hydroxy-6-methoxymethoxybenzamide was isolated (50%); [g] In addition, 1, 2-bis-N,N-diethyl-3-hydroxyphthalamide was obtained in 16% yield.
[1] [2]
The chloro group is a very poor DMG on its own
,
but contributes to
regioselective 2-deprotonation when in a 1,3-relationship with a more powerful DMG.
Thus, both 2- and 4-chloro O-carbamates 4a and 4c afford products 5a-c and 5g
respectively while the 3-chloro derivative 4b leads to 2-substituted products 5d-f with
selected electrophiles (entries 1
̶
7). Similarly, the OMe DMG, originating with the
̶
discovery of the DoM reaction by Wittig and Gilman,[39] [41] which has been widely and
̶
dependably used, [1], [42] [44] does not interfere with clean deprotonation ortho to the O-
carbamate as is seen in the conversion of 2- and 4-methoxy derivatives 4d and 4f into
the corresponding products 5h-j (entries 8-10) and 5o-s (entries 15-19) while the 3-
methoxy compound 4e affords 2-substituted products 5k-n (entries 11-14) albeit with
less selectivity than the 3-chloro analogue 4b (entries 5-6). The 2-, 3-, and 4-OMOM
derivatives, 4g, 4h, and 4i led to results showing less desirable regioselectivity. Thus,
while 4g, 4h and 4i all underwent highly regioselective deuteration to give compounds
5t, 5v, and 5x respectively (entries 20, 22 and 24), carbamoylation of these substrates
gave variant observations. Good yield in the regioselective conversion of 4g into 5u
(entry 21) was observed; however, treatment of 4h with diethyl carbamoyl chloride
afforded a mixture of 2-substituted product 5w in addition to 2-hydroxy-6-OMOM
benzamide (entry, 23, see footnote f, Table 2) which may have arisen by either AoF
rearrangement or, perhaps less likely, by 2-carbamoylation followed by a de O-
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10.1002/ejoc.201701143
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carbamoylation reaction. The 4-OMOM derivative 4i, on the other hand, gave 5y
(70%) (entry 25) as the major product, indicative of the greater DMG power of
OCONEt2 over OMOM. The 1,3-O-carbamoyl derivative 4j was subjected to a
metalation-deuteration experiment to cleanly afford the 2-deuterio product 5z (76%,
66% d1) (entry 26).
In the final series, the strong CONEt2 DMG was tested in all three positional
isomer variants (Table 2). The clear preference for a O-carbamate dominant DMG
effect is seen in deuteration experiments on all three systems 4k, 4l, and 4m to give
products 5aa, 5ac, and 5ae respectively (entries 27, 29, 31). Using the bulky
ClCONEt2 as the quenching reagent on 4k afforded a mixture which also highly
favored the ortho to O-carbamate substituted product 5ab (entry 28). However, the 3-
amide 4l led to non-regioselective reaction to mixtures of isomer 5ad (entry 30) and a
phenol (see footnote [g]),resulting from an AoF rearrangement. The 4-amide 4m gives
deuterated (5ae, entry 31) and carbamoylated (5af, entry 32) products favoring
regioselectivity for the O-carbamate DMG.
In order to extend and enhance the scope of the AoF rearrangement to DMG-
substituted aromatics, a selected group of substrates from the above competition
experiments was studied (Table 3). Thus, under the standard conditions (s-
BuLi/TMEDA/THF/ 78o) the 2-chloro and 2-methoxy O-carbamates 4a and 4d
furnished the contiguously 1,2,3-substituted salicylamides 6a and 6c respectively
(entries 1 and 3). The DoM (entry 7, Table 2) – AoF (entry 2, (Table 3), 4c to 6b)
combination, was a pivotal tactic in the synthesis of the fungal metabolite ochratoxin
B.[45]
Table 3. Competitive anionic ortho Fries Rearrangement of DMG-substituted Aryl O-Carbamates 4
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Entry Compd DMG
Product DMG
Yld,%[a]
1
2
3
4
4a
4c
4d
4e
2-Cl
6a
6b
6c
6d
3-Cl
75
4-Cl
5-Cl
65
2-OMe
3-OMe
3-OMe
6-OMe:
4-OMe
5-OMe
6-OMOM
6-OAm
3-Am
68
68
(70: 30)
60
5
4f
4-OMe
6e
6
4h
4j
3-OMOM 6f
68
7
3-OAm
2-Am
6g
6h
6i
86
8
4k
4l
30
9
3-Am
6-Am
16
10
6g
6-OAm
6j
3-Am,6-OH 93
[a] Yields of isolated products.
The 3- and 4-methoxy O-carbamates 4e and 4f led to the corresponding
isomers 6d and 6e (entries 4 and 5) with the former conversion lacking regioselectivity.
Analogous to the corresponding 3-OMe derivative 4e, the 3-OMOM 4h and, more
synthetically interesting, the 3-O-carbamate 4j, afforded the in-between AoF
rearrangement products 6f (68% yield, entry 6) and 6g (86% yield, entry 7)
respectively. To conclude this study, two isomeric amide aryl O-carbamates 4k and
4l were subjected to the anionic ortho-Fries to afford 6h (entry 8) and 6i (entry 9)
respectively, albeit both were obtained in low yields, the latter being a side product in
the carbamoylation experiment (Table 2, entry 30). The availability of the phenol 6g
allowed a test of the anionic Fries in the presence of an acidic phenol group and this
reaction, under 3 equiv s-BuLi/TMEDA conditions, led smoothly to the formation of the
resorcinol 6j in 93% yield.
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Our original results concerning the generation of dianions of mono- and di-DMG
[46]
[47]
containing derivatives
and thiophene 2-carboxamides
encouraged a more
detailed study on the dilithiation reaction [48]
of the 1,2-di- and 1,4-di- O-carbamates 7 and 8 (Table 4). Dilithiated aromatics,
̶
[53]
generally generated by metal-halogen exchange processes,[49]
unknown [54], [55] and underdeveloped species.[56]
are relatively
[a]
Table 4. Dilithiation of Aryl 1,2- and 1,4-di-O-carbamates
Compd E+
Product
R1
R2
Yld ,%
[b]
Entry
[c]
1
2
3
4
5
6
7
7
7
7
7
7
7
7
MeOD
9a
D
D
84
ClCONEt2
ClCONEt2
TMSCl
9b
9c
9d
9e
9f
Am
H
Am
40
61
58
78
44
55
Am
TMS
H
TMS
TMS
SMe
Am
TMSCl
(MeS)2
SMe
TMS
a) TMSCl;
b. ClCONEt2
a) TMSCl;
b) (MeS)2
9g
8
7
9h
TMS
SMe
62
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[d]
9
10
11
12
13
14
8
8
8
8
8
8
MeOD
ClCONEt2
TMSCl
TMSCl
(MeS)2
MeI
10a
10b
10c
10d
10e
10f
D
D
83
63
67
78
71
89
Am
TMS
H
Am
TMS
TMS
SMe
Me
SMe
Me
[a] Dilithiation of the aryl dicarbamates 7 and 8 was effected under standard conditions (2.2 equiv I-BuLi/2.2 equiv TMEDA/THF/-78°C). Subsequent
treatment with electrophiles led to 2,5-disubstitued products 9a-h and 10a-f; [b] Yields correspond to purified (chromatographed and/or distilled
and recrystallized) materials; [c] Entry 1: 57% d2 , 43% d1 ; [d] Entry 9: 64.2% d2 , 35.8% d1 .
Dicarbamates 7 and 8 (Table 4), readily obtained from catechol and
hydroquinone respectively (see SI) were studied under conditions of 2 equiv of s-
o
BuLi/TMEDA/THF/-78 C metalation conditions followed by quench with excess of
electrophile. Using these conditions, followed by deuteration, resulted in formation
of mono- and di-deuterated products in almost equal amounts (MS analysis) indicating
incomplete dianion formation and therefore forecasting inefficient reactions with other
electrophiles. Consistent with this observation, quenching with ClCONEt2 and TMSCl
respectively afforded disubstituted 1,2-di-O-carbamates 9b and 9d in modest yields.
In order to establish mono anion reactivity, treatment of 7 with 1 equiv of s-
BuLi/TMEDA under the same conditions followed by slightly more than 1 equiv of
electrophiles resulted in the formation of monosubstituted product 9c and 9e
respectively. The reasonably good yield of 9e may be due to the compatibility or slow
̶
[60]
rate of reactivity of TMSCl with alkyllithium reagents. [57]
The last cases of dilithiation and electrophile quench experiments on 7 involved
a (MeS)2 quench and provided product 9f (entry 6) in low yield. Sequential introduction
of two electrophiles was also successful. Thus, by treatment of 7 with TMSCl followed
by ClCONEt2 and TMSCl followed by (MeS)2 furnished the more diversely substituted
products 9g and 9h (entries 7 and 8) respectively. The dianionic ortho,ortho-Fries
rearrangement of 7, carried out by treatment with 2 equiv of base and warming the
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10.1002/ejoc.201701143
European Journal of Organic Chemistry
solution to room temperature gave, after standard methylation, the terephthalamide
11a (22% yield) in addition to the known benzamide 11b (9% yield). [61]
Similarly, the 1,4-di-O-carbamate 8 was subjected to the 2 equiv of s-
BuLi/TMEDA metalation conditions and electrophile quench reactions to afford a
series of symmertrically substituted products 10a-f (entries 9-14). In addition, whereas
1,2-di-O-carbamate 7 had given an inseparable and therefore uncharacterizable
mixture of methylated products, 8 afforded, upon treatment with MeI, dimethylated
derivative 10f in high yield (entry 14). Mono anion generation of 8 was accomplished
as shown by its treatment with TMSCl to furnish product 10d (entry 12). A double
anionic ortho Fries rearrangement of 8 was also achieved to give, after treatment with
methyl iodide, the paraphthalamide 12 in low yield.
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Iterative Metalation
Consideration of DoM reactions in context of iterative, multiple metalations
reveals an overabundance of possibilities. Thus, in the basic consideration (Scheme
2), sequential metalation-electrophile quench with two different or same electrophiles
can furnish, with the caveat that E1 must be stable to the strongly basic conditions or
a suitably protected group, a 1,2,3-substituted aromatic as conceptualized in 13. The
presence of an unreactive or protected group G as in 14 provides the opportunity to
introduce a second DMG2 (step a) by use of an appropriate electrophile (as has been
demonstrated for the ClCONEt2 DMG in examples collected in (Table 1). The thus
introduced DMG2, if relatively strong, [37] may serve for further DoM reaction (step b)
to introduce DMG3. The continuation of this first step of walk-around-the-ring anionic
chemistry may be envisaged. With regard to two DMGs, the ortho-, meta- and para-
relations may be envisaged, of which only the meta-DMG1-DMG2 isomer is considered
in 15. Thus, synergistic effects of DMG1 and DMG2 affect the introduction of E1 (step
a). Given that DMG1 > DMG2 in metalation power, a DMG3 may be introduced (step
b) and consideration of DMG3 > DMG2 will allow a further metalation and DMG4
introduction (step c). Conceptualization 15 has been previously achieved in our
laboratories. [62], [63]
In the present study, contemplation of the ortho and para two DMG isomer
systems leads to considerable numbers of combinations. Two cases, based on the O-
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10.1002/ejoc.201701143
European Journal of Organic Chemistry
carbamoyl DMG were tested in iterative protocols (Scheme 3). Thus, the original N,N-
diethyl phenyl O-carbamate 16, upon sequential metalation, silylation, metalation and
carbamoylation with equivalent amounts of base and electrophile and maintaining the
-78 oC, gave the trisubstituted substance 17 in reasonable yield. An attempt to carry
out a third metalation and quench with ClCONEt2 in the same pot to obtain 18 failed.
However, isolation and purification of 17 followed by use of the standard conditions for
deprotonation and treatment with ClCONEt2 gave the contiguously tetrasubstituted
aromatic molecule 18 in good yield.
In the second tested case for iterative DoM reactions, the 2-methoxy O-
carbamate 4d was subjected to the one pot, two metalation-electrophile quench
sequences using ClCONEt2 and MeI as quenching reagents to afford a further case of
a contiguously tetrasubstituted product 19 in acceptable yield. Both products may be
amenable to further DoM chemistry.
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10.1002/ejoc.201701143
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Summary, Comparative Analysis, and Conclusions
The predisposition for the formation of 1,2,3-substituted products by DoM and
AoF processes (to highlight at random, 5d-f, 5v-w, 5ad (Table 2) and 6a, 6c, 6g,
(Table 4) and their conversion into phenol [20, 64, 65] and benzaldehyde and benzoic acid
[20, 64, 65]
derivatives
presents methodology of considerable advantage over other
routes for the preparation of such contiguously substituted aromatics. In addition,
potential for the synthesis of more highly substituted products owing to the nature of
readily available starting materials may be gleaned from Tables 2 and 3 as well as
from the dilithiation reactions which lead to tetrasubstituted products, especially those
of contiguous 1,2,3,4-substitution (Table 4).
To provide an awareness of the O-carbamate DoM methodologies in
comparison to other synthetic procedures, a brief compilation of selected cases with
focus on 1,2,3-trisubstituted systems are depicted in Table 5.
Table 5. Competitive Methods for the Synthesis of Substituted Aromatics
Synthetic Method
DoM
Other
Starting
Material
(SM)
Starting
Material
(SM)
ArOAm
Steps to
Steps
to
Product [b] TMd
(oy)[c]
(oy)[c]
TM[e]
(oy)[c]
[ref]
Me
1
2
3
2, 36%
[66a]
OAm
Me
(50%)
[66b]
$10s/100 g
$100s/kg
$100s/kg
5h
(92 %)
3 (55%)
N/A[f]
$ 100s/g
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3
5i
(90 %)
3 (54%)
3 (42%)
N/A[f]
$10s/g
4
41b
(70 %)
4, 30%
[67]
$10s/100g
5
5c (93 %) 3 (56%)
5l (~70%) 3 (42%)
5,
[68][g]
$70s-
200s/100g
$10s-100s/g
6
4, 26%
[69]
$60s-
100s/100g
$10/g
7
5m
3 (45%)
N/A[f]
(~76%)
$100s/g
8
5ab
(~82%)
3 (~50%)
2, 46-
61%
[70]
$100s/g
$10s/100g
9
6i (16 %) 3 (10%)
5,
[71a];
6, 9%
[71b]
$40s-
60s/100g
$10s/100g
$100s/g
10
6j (93 %) 3 (52%)
N/A[f]
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11
9b (40 %) 2 (35%)
1, 35-
56%
[72]
$1000/kg
12
10b
(63%)
3 (37%)
1. 22-
93%
[73]
$10s-100s/g
[a] From various commercial sources (April, 2017 prices) given in factor of 10/g in USD. Two values indicate different suppliers; [b] Structure
number corresponds to the O-carbamate product obtained from the given obtained using SM; [c] oy = overall yield; [d] An approximate yield based
on carbamate to phenol conversion at 85% which represents average yield for the Schwartz reagent (see, ref: [64]; [e] Calculated from the most
efficient reported route. [f] No commercial source or reported synthesis. [g]oy not available; last step (deprotection) proceeds in 94% yield.
2,6-Dimethylphenol (entry 1), a relative simple an inexpensive molecule,
available by high pressure/temperature industrial chemistry from ortho-cresol in two
[66a]
steps and 36% yield
and is available from the same starting material in same
[66b]
number of steps and 50% yield
by the ortho-lithiation of N,N-diethyl O-(2-
tolylcarbamate (6, Scheme 2 [37]).
On the other hand, the expensive, commercially available but, to the best of our
knowledge, unreported 2-methoxy-6-methylphenol (entry 2) may be prepared from
commercially available 2-methoxyphenol via the corresponding O-carbamate
derivative 5h in 3 steps and estimated 55% overall yield. The commercially available
2-hydroxy-3-methoxybenzoic acid and its corresponding aldehyde (entry 3) have an
extensive history as natural products of biological and ecological significance.
Both compounds may be prepared by DoM chemistry from 2-methoxyphenol via 5i in
reasonable overall yield. The corresponding 2-hydroxy-3-methyl benzoic acid and
aldehydes (entry 4) are surprisingly inexpensive at least based on the reported [67]
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10.1002/ejoc.201701143
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synthesis which is carried out over four steps in atom-uneconomical fashion.
According to the carbamate DoM route via 41b, this molecule should be available in
three steps and 42% overall yield.
The synthesis of the expectedly expensive differentially halogenated phenol
(entry 5) is a good illustration of the value of DoM chemistry since it has been prepared
from 2-iodophenol (via 5c) in acceptable yield; [68a] it has been also prepared from the
less costly 2-chloro-phenol in unreported yield.[68b] The in-between two DMG facility
is a hallmark of the DoM approach as may be gleaned from the synthesis of 3-
methoxy-2-methyl- and 2-carboxy-phenol (entries 6 and 7). Starting from common 3-
methoxyphenol, target molecule 3-methoxy-2-methyl phenol is obtained either via the
carbamate (5l) (three steps, 42% overall yield) or 2,6-dihydroxytoluene (complicated
four steps, 26% overall yield).[69] The corresponding 2-carboxylic acid (entry 7) may
be obtained via O-carbamate 5m in modest 45% yield; its synthesis is not reported.
The expensive 2-hydroxyisophthalic diester (entry 8) maybe prepared by several
classical routes, [70a, 70b] the best and most recent of which requires the acceptably priced
3-methylsalicylic acid as starting material.[70a] Alternatively, it should be available in 3
steps and overall ~50% yield via DoM-AoF chemistry (5ab) followed by hydrolysis. 3-
Hydroxyphthalic acid (entry 9) and its anhydride are available by a route [71] based on
traditional aromatic chemistry from the modestly priced 3-nitrophthalic acid. The O-
carbamate route, via 6i does not promise an efficient route but it may also be prepared
relatively efficiently by DoM chemistry from 2-methoxybenzamide.[61]
Entries 10-12 give examples of contiguously tetrasubstituted aromatics which
may be prepared by O-carbamate DoM tactics. The routes follow starting with O-
dicarbamates prepared from corresponding diphenols which lead to DoM products 6j,
9b, and 10b and should provide, by reduction and hydrolysis reactions, the respective
isophthalic (entry 10) and terphthalic (entries 11 and 12) target molecules in
reasonably short routes and modest yields. Previous syntheses,[72,73] although
developed on scale for commercial production, require high temperatures, dangerous
materials, and corrosive reagents and proceed in variable yields.
The compilation of Table 5 places O-carbamate DoM methodology against
other reported reaction paths for the construction of polysubstituted aromatics. We
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10.1002/ejoc.201701143
European Journal of Organic Chemistry
emphasize selected groups of contiguously 1,2,3- and 1,2,3,4-substituted derivatives
in order to highlight the meagre availability of these structural classes from commercial
sources. Although yields via DoM chemistry are partially estimates based on average
yields expected by reduction and hydrolysis of phenol and amide functional groups,
these approximations should be sufficient for decisions made in a synthetic endeavors
of polysubstituted aromatic targets.
In conclusion, work presented in in this and the sequel report [37] demonstrates
the superiority of the O-carbamate function as an ortho director over the chloro,
methoxy, tertiary amide and methoxymethoxy groups in DoM chemistry and leads to
the conclusion that it is the functionality of paramount choice among the oxygen-based
DMGs. Routes the synthesis of a variety of substituted aryl O-carbamates have been
demonstrated by DoM and AoF rearrangement reactions. Especially valuable are
processes which lead to contiguously 1,2,3- and 1,2,3,4-substituted aromatic arrays
that are difficult to achieve or unavailable by alternative and traditional methods. The
competitive and advantageous nature of O-carbamates DoM reactions is illustrated in
selected examples of comparison with those previously reported (Table 5). Although
considerable results are already available, the further application of the described
methodology in synthesis may be anticipated.
OAm
OH
Am
OAm
E
AoF condition
DoM
s-BuLi/TMEDA/
THF/ 78oC to rt
1. s-BuLi/TMEDA/
H
THF/ 78oC
DMG
DMG
DMG
2. E+/ 78 C to rt
23 examples
24 96% yields
10 examples
16 93% yields
Am = CONEt2
Et2N
O
OAm
R
R
O
O
OAm
OAm
R
OAm
6 examples
63 89% yields
R
Et2N
O
8 examples
40 84% yields
double AoF
DoM = Directed ortho Metalation. AoF = Anionic ortho Fries
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Experimental
Standard Procedures
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 procedures 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.
Relative Directed Metalation Abilities of Chloro, Methoxy, Carbamoyloxy,
Tertiary Amide and Methoxymethoxy Groups by Intramolecular Competition
Experiments.
The intramolecular competition in metalation of methoxymethoxy (MOM)
and the tertiary amide (CONEt2) positioned ortho, meta and para with respect to a
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10.1002/ejoc.201701143
European Journal of Organic Chemistry
carbamoyloxy group (OCONEt2) was examined. The sites of lithiation were
determined by analysis of the 13C NMR spectra show a reduction in intensities of
the signals for the substituted carbons in the products compared to the
corresponding signal in the starting materials according to the method of Beak.[3]
The position of substitution was assigned by using established additivity of
individual 13C NMR substituent chemical shifts either from the literature [4], [5] or as
determined (Table 5). The shift value expresses the direction and magnitude of a
carbon’s chemical shift difference from δ 128.5 ppm, the shift of benzene. The
experimental chemical shift difference () of aromatic carbons of O-phenyl
carbamate were found to fit reasonably well with the chemical shift difference ()
of aromatic carbons of phenyl acetate. These findings were also confirmed by
comparing the 13C NMR spectrum of N, N-diethyl O-(N,N-diethyl carbamoyl)phenyl
carbamate following the method of Beak.[3] The method is exemplified by the
calculations of chemical shift values of aromatic carbons in compounds 5i and 5ab.
Directed ortho Metalation (DoM) Reactions
Standard Procedures
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 (60 ML) at -78°C
under nitrogen. After a reaction period 1h, the mixture was treated with a THF
solution of an electrophile. The resulting reaction mixture 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
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10.1002/ejoc.201701143
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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.
Anionic ortho-Fries Rearrangement: 1,3- or 1,4- 0 --> C Carbamoyl Migration
Lithiation of the appropriate carbamate was carried out with s-BuLi (Procedure 1):
or LDA (Procedure 2). Standard workup and column chromatography using 1:1
(v/v) EtOAc-hexane as eluent/distillation/recrystallization] and the resulting lithiated
carbamate, without being quenched with electrophiles, was allowed to warm to
room temperature over 8 h. Processing in usual manner as described in Procedure
1 or 2 gave the crude product.
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