Directed ortho metalation strategies. Effective regioselective routes to 1,2-, 2,3-, and 1,2,3-substituted naphthalenes

Article abstract of DOI:10.1021/ol500707w

The regioselective synthesis of 2,3-di- and 1,2,3-trisubstituted naphthalenes via Directed ortho Metalation (DoM) strategies of N,N-diethyl-O-naphthyl-2-carbamate (1) is presented. Sequential LiTMP metalation-electrophile quench and s-BuLi/TMEDA (or t-BuLi)-electrophile quench of naphthyl-2-carbamate 1 provides a general route to contiguously substituted naphthalenes (6) with full regioselectivity. Further derivatization via ipso-halodesilylation and Suzuki-Miyaura cross-coupling leads ultimately to substituted halonaphthalenes and benzonaphthopyranones (9).

Full text of DOI:10.1021/ol500707w

Letter
pubs.acs.org/OrgLett
Directed ortho Metalation Strategies. Effective Regioselective Routes
to 1,2‑, 2,3‑, and 1,2,3-Substituted Naphthalenes
Katherine Groom,#,† S. M. Shakil Hussain,#,‡ Justin Morin,# Christian Nilewski,#,§ Toni Rantanen,⊥
and Victor Snieckus*,#
⊥Snieckus Innovations, 945 Princess Street, Kingston, Ontario K7L 3N6, Canada
#Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
ABSTRACT: The regioselective synthesis of 2,3-di- and 1,2,3-
trisubstituted naphthalenes via Directed ortho Metalation
(DoM) strategies of N,N-diethyl-O-naphthyl-2-carbamate (1)
is presented. Sequential LiTMP metalation−electrophile
quench and s-BuLi/TMEDA (or t-BuLi)-electrophile quench
of naphthyl-2-carbamate 1 provides a general route to
contiguously substituted naphthalenes (6) with full regiose-
lectivity. Further derivatization via ipso-halodesilylation and
Suzuki−Miyaura cross-coupling leads ultimately to substituted halonaphthalenes and benzonaphthopyranones (9).
he significance of the naphthalene nucleus is manifested in
regioselective ipso-halodesilylation reactions,10 leading to the
synthesis of rare prototype halonaphthols. In addition, we report
on Suzuki−Miyaura cross-couplings and directed remote
metalation (DreM)-induced anionic Fries rearrangement−
cyclizations which provides a route to aromatic polycyclic
lactones. The recently disclosed mild, Schwartz reagent-
mediated O-carbamate to naphthol deprotection11 and Ni-
catalyzed cross-couplings of aryl O-carbamates with aryl and
heteroaryl boronic acids12 are additional features through which
the utility of the reported chemistry may be anticipated.
T
important classes of pharmaceutical core structures,1
natural products,2 agrochemicals,3 materials,4 and powerful
ligands for asymmetric catalysis5 (Figure 1). In part as a
Some 2-DMG bearing naphthalenes have been shown to
undergo C-3 metalation mostly utilizing t-BuLi in Et2O.13
Previous work in our laboratories has shown that DoM reactions
of O-naphthyl 2-carbamates using s-BuLi/TMEDA combina-
tions lead to low yields of products and poor C1/C3
regioselectivity.8d Therefore, to surmount this difficulty we
tested the regioselective discrimination behavior of the sterically
demanding lithium 2,2,6,6-tetramethylpiperidide (LiTMP) base.
As a trial experiment, the naphthyl-2-carbamate 1 (Scheme 1)
was subjected to treatment with LiTMP (1.2 equiv/THF/−78
°C/1 h−warm to rt) in the expectation of observing one or both
possible anionic ortho Fries rearrangement products.14 Encour-
agingly, N,N-diethyl-3-carboxamido 2-naphthol 2 was obtained
Figure 1. Selected examples of natural products, biologically active
molecules, and chiral ligands exhibiting polysubstituted naphthalene
scaffolds.
consequence, the 1,2-di-, 2,3-di-, and 1,2,3-trisubstitution
patterns have received considerable attention in medicinal
chemistry. Although a number of substituted naphthalenes are
commercially available, there continues to be a lack of general
and flexible methods for the preparation of contiguously
substituted, e.g. 2,3-di- and 1,2,3-trisubstituted, naphthalenes.6
As part of improving the positional strength of the Directed
ortho Metalation (DoM) strategy in aromatic and heteroaromatic
synthesis,7 efforts in our laboratories have aimed to enhance
available methodologies for the construction of substituted
naphthalenes.8 In continuation of these goals, herein we report
results on the regioselective metalation chemistry of the N,N-
diethyl-O-naphthyl-2-carbamate (1), featuring one of the most
powerful directed metalation groups (DMGs),9 and provide
general methods for the construction of 2,3-di- and 1,2,3-
trisubstituted naphthalenes. Furthermore, we demonstrate
Scheme 1. Regioselective Anionic ortho Fries Rearrangement
Received: March 6, 2014
Published: April 24, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
in 80% yield with no evidence for the formation of the analogous
1-carboxamido product. Replacement of LiTMP with LDA
under identical conditions afforded 2 in comparable (69%) yield.
With these results in hand, we carried out systematic LDA and
LiTMP metalation/TMSCl or TESCl quench experiments
(Table 1). Adding the LDA (1.2 equiv)/TMSCl (2.4 equiv)
5 (26%), the result of CIPE-induced7c α-silyl methyl
deprotonation−carbamoyl migration. Assignment of the struc-
ture of 5 was further secured by CsF-mediated desilylation to 2-
naphthol. The greater acidity of the α-methyl hydrogens of TMS
vs TES groups possibly combined with a steric effect may be the
rationale for the observed difference in reactivity.16
With the optimum conditions established, the reaction was
generalized for a series of electrophiles to give diverse 2,3-
disubstituted naphthalenes in good to excellent yields (Table 2).
Table 1. Optimization of the DoM Reaction on N,N-Diethyl-
O-naphthyl-2-carbamate (1)
Table 2. Scope of the DoM Reaction on N,N-Diethyl-O-
naphthyl-2-carbamate (1)
a
entry
base (equiv)
E1+ (equiv)
product (E1)
yield (%)
c
1
2
3
4
5
6
7
LDA (1.2)
TMSCl (2.4)
TMSCl (2.4)
TMSCl (2.2)
TMSCl (2.4)
TMSCl (2.4)
TMSCl (3.0)
TESCl (3.0)
TMSCl (3.0)
3a (TMS)
3a (TMS)
3a (TMS)
3a (TMS)
3a (TMS)
3a (TMS)
3b (TES)
3a (TMS)
39
LDA (1.2)
44
cd
,
a
entry
E1+ (3 equiv)
product (E1)
yield (%)
LDA (2.0)
N/A
c
LiTMP (1.2)
LiTMP (1.2)
LiTMP (3.0)
LiTMP (3.0)
LiTMP (3.0)
51
b
1
2
3
4
5
6
7
8
MeI
3c/3d (Me/Et)
3e (Br)
60/21
47
85
87
85
Br2
65
94
91
63
79
65
72
I2
3f (I)
C2Cl6
PhCHO
ClCONEt2
MeOBpin
BzCl
3g (Cl)
b
8
3h (PhC(OH))
3i (CONEt2)
3j (Bpin)
a
A mixture of base and electrophile were added to starting material at
b
either 0 or −78 °C. Base was added to starting material, the mixture
was metalated for 1.5 h, and the electrophile was added. Reactions
were performed at 0 °C instead of −78 °C. Mixture of products: 1-
TMS/3-TMS (3a)/bis-TMS (6a) = 1.8:0.2:2.2 as determined by GC-
c
3k (PhCO)
d
a
LiTMP (3.0 equiv) was added dropwise to a solution of starting
material (1.0 equiv) in THF at −78 °C, metalated for 1.5 h, and
MS analysis.
b
quenched with the electrophile (3.0 equiv). The 3-ethyl derivative
(3d) is a result of the slow addition of electrophile. Adding MeI all at
once may eradicate it completely. See SI for details.
combination to starting material (Martin conditions)15 at 0 °C
led to low yields of the desired product (3a) (Table 1, entry 1).
Decreasing the temperature was not helpful (entry 2), and when
the amount of base was increased, mixtures of mono and bis-
silylated products were observed (entry 3). Similar results were
obtained with LiTMP (entries 4 and 5). However, under excess
LiTMP/TMSCl and LiTMP/TESCl conditions, monosilylated
products 3a and 3b were obtained in excellent yields (entries 6
and 7). Because not all electrophiles are compatible with the base
under Martin conditions, the metalation was also established
with the addition order of base to starting material, followed by
quenching with an electrophile (entry 8).
In an observation of promising synthetic interest, when,
instead of 3.0 equiv of TESCl, only 1.2 equiv were used under
identical conditions, product 4b was obtained in 64% yield,
resulting from what appears to be sequential C3-deprotonation−
silylation, C1-deprotonation−anionic ortho Fries rearrangement
(Scheme 2). For comparison purposes, the same reaction was
carried out with TMSCl and gave, in addition to the analogous
product 4a (28%), the desired product 3a (31%) and compound
It is interesting to note that treatment of naphthyl-2-carbamate 1
with 2.4 equiv of sec-BuLi/TMEDA at −78 °C followed by the
addition of 2.4 equiv of TMSCl provided direct access to 1,3-bis-
trimethylsilyl substituted naphthyl-2-carbamate (6a; see Sup-
porting Information (SI) for details) in 72% yield.
Justifiably, the availability of the regiochemically pure C3-
substituted naphthalenes 3a−k prompted exploration of second
C1-DoM reactions. Of special interest were syntheses of silylated
and halogenated C1-derivatives for the purpose of further ipso-
halodesilylation and cross-coupling reactions, respectively. Using
O-carbamates 3a, 3b, 3e, and 3g metalation followed by
quenching with a variety of electrophiles gave a series of 1,3-
functionalized O-naphthyl 2-carbamates 6b−j in synthetically
useful yields (Table 3). In all cases, temperature control was
essential to avoid lower yields due to the ease of competing
anionic ortho-Fries rearrangement. This control was achieved via
a syringe pump or by changing the metalation system to t-BuLi/
Et2O (see SI for details). Furthermore, in order to avoid
complications of potential alkyllithium-mediated metal−halogen
exchange, the C3-bromo derivative 3e was subjected to LDA
metalation conditions. Following iodine and TESCl quench,
products 6i and 6j, respectively, were obtained in good yields.
Noteworthy is the undoubtedly facile conversion of compounds
6b−g into 1-substituted 2-naphthols by acid- or fluoride-
mediated desilylation and Schwartz reduction.11
Scheme 2. Anionic ortho-Fries Rearrangement Results
The availability of bis-silylated carbamate 6a and monosily-
lated derivatives 3a, 6b, and 6g encouraged the pursuit of
electrophile-induced ipso-desilylation studies for the construc-
tion of differentially functionalized naphthalenes (Table 4).
Thus, treatment of 3a with pyridinium tribromide cleanly
afforded the corresponding 3-bromo derivative 3e in high yield
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Organic Letters
Letter
scopic data with the materials obtained from DoM chemistry. To
affect a second bromo-induced ipso-desilylation on 6b, pyHBr3
was found to be ineffectual. However, when Br2 in CH2Cl2 at 80
°C under microwave heating was used, the reaction proceeded
smoothly in 10 min to furnish the 3-bromo-1-iodo O-carbamate
6i in quantitative yield (entry 4). Interestingly and in contrast, 6g
was found to be reactive and excess ICl at −20 °C furnished the
inverted 1-bromo-3-iodo isomer 6k (entry 5).
The availability of regioselectively iodinated naphthyl 2-
carbamates 6b and 6c prompted the rational step to achieve
greater structural complexity by effecting Suzuki−Miyaura cross-
coupling−directed remote metalation (DreM) chemistry. Thus,
biaryls 7a and 7b were efficiently prepared using conventional
Suzuki−Miyaura Pd-catalyzed conditions on 6b and 6c with
phenyl boronic acid respectively (Scheme 3).
Table 3. Synthesis of 1,3-Disubstituted O-Naphthyl-2-
carbamates 6b−j
compd
(E1)
product
(E2)
yield
(%)
a
+
entry
base
E2
1
s-BuLi/TMEDA 3a (TMS)
I2
I2
I2
I2
6b (I)
69
61
57
73
b
2
t-BuLi
3a (TMS)
6b (I)
3
s-BuLi/TMEDA 3b (TES)
6c (I)
b
4
t-BuLi
3b (TES)
6c (I)
c
5
s-BuLi/TMEDA 3a (TMS)
s-BuLi/TMEDA 3a (TMS)
DMF
C2Cl6
MeI
6d (CHO)
6e (Cl)
6f (Me)
6g (Br)
6h (TMS)
6i (I)
51
6
81
77
64
83
68
63
7
s-BuLi/TMEDA 3a (TMS)
Scheme 3. Suzuki−Miyaura Cross-Coupling and Synthesis of
Benzonaphthopyranones
b
8
t-BuLi
3a (TMS)
Br2
9
s-BuLi/TMEDA 3g (Cl)
TMSCl
I2
10
11
LDA
LDA
3e (Br)
3e (Br)
TESCl
6j (TES)
a
Base (1.2 equiv) is added to a solution of starting material at −78 °C;
b
after metalating for 1 h, the electrophile was added slowly. Et2O is
used, and the metalation time was 20 min. Under the reaction
c
conditions, the carbamoyl group is cleaved affording the 2-hydroxy-3-
trimethylsilyl-1-naphthaldehyde 6d as the product.
Table 4. Halo-ipso-desilylation Reactions
By treatment of 7a with an excess of LDA in refluxing THF, the
anionic remote Fries rearrangement product 8a was obtained in
low yield together with 23% of byproduct 10a (analogous to 5, cf.
Scheme 2). In an attempt to increase the yields and to eliminate
product 10a, the TES derivative 7b, with less acidic and more
sterically hindered α-silyl hydrogens, was subjected to the same
LDA conditions. The analogous product 10b was not obtained
although the reaction did not proceed to completion.
Introduction of a synergistic OMe DMG ortho to the desired
remote metalation site (Scheme 3, compounds 7c and 7d) clearly
improved the yield of the migration product (60% and 84%,
respectively). When briefly subjected to heating in acetic acid,
8a−8d afforded the benzonaphthopyranones 9a−9d in good
yields, compounds known in the context of synthesis of axially
chiral natural products.17
In summary, we have developed a new convenient method-
ology for the synthesis of 2,3-disubstituted (3) and 1,2,3-
trisubstituted naphthalenes (6), the latter class being readily
achieved by two routes: (i) via the regioselective metalations of 3,
and (ii) via a regioselective halo-ipso-desilylation of 6a, 6b, and
6g. This methodology provides routes for the preparation of
naphthalenes which are difficult to obtain by conventional
chemistry, are commercially inaccessible, and/or are seemingly
simple but unavailable or require expensive derivatives.
Furthermore, observations of potential general synthetic value
of sequential reactivity, which provide trisubstituted naphtha-
lenes from a monosubstituted O-carbamate (Scheme 2), have
been presented. Finally, the methodology has been applied to the
synthesis of benzonaphthopyranones 9a−9d which represent
(Table 4, entry 1). At room temperature and with less pyHBr3,
the 1,3-disilylated carbamate 6a gave the derivative 6g in high
yield (entry 2). This regioselective 1-bromo ipso-desilylation may
be rationalized by the extended conjugation and hence greater
stabilization of the incipient β-arenium intermediate than that
arising from C3-bromonium ion attack. The same regioselectivity
was observed upon iodination of 6a with ICl to give the
corresponding 1-iodo derivative 6b in 81% yield (entry 3). The
regiochemical outcome was verified by comparison of spectro-
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data for new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: snieckus@chem.queensu.ca.
Present Addresses
†GL Chemtec, 1456 Wallace Road, L6L 2Y2, Oakville, Canada.
‡Center for Petroleum and Minerals, King Fahd University of
Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi
Arabia.
§Department of Chemistry, BioScience Research Collaborative
(BRC), Rice University, 6100 Main Street, Houston, TX 77005,
USA.
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̈
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́
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NSERC Canada is gratefully acknowledged for continuing
funding via the Discovery Grant (DG) Program. We thank Dr.
Bert Nolte for discussions and Karen Puumala and Prof. Jalil
Miah for preliminary observations.
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catalysis: Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155.
(c) BINOL derived ligands in asymmetric olefin metathesis: Hoveyda,
A. H.; Schrock, R. R. Chem.Eur. J. 2001, 7, 945 and references therein.
(17) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem.
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