Directed Ortho and Remote Metalation of Naphthalene 1,8-Diamide: Complementing SEAr Reactivity for the Synthesis of Substituted Naphthalenes

Article abstract of DOI:10.1021/acs.orglett.1c00521

Mono- and dianion species of 1,8-naphthalene diamide 2 were generated under sec-BuLi/TMEDA conditions and trapped with a variety of electrophiles to give 2- and 2,7- substituted products 3 and 4. Using Suzuki-Miyaura cross-coupling, mono- and di-iodinated products were converted into the corresponding 2-aryl (5) and 2,7-diaryl (6) products, respectively. The amide-amide rotation barrier of 2 was established by VT NMR, and the structure of fluorenone structure 9, obtained by remote metalation, was secured.

Full text of DOI:10.1021/acs.orglett.1c00521

pubs.acs.org/OrgLett
Letter
Directed Ortho and Remote Metalation of Naphthalene 1,8-Diamide:
Complementing SEAr Reactivity for the Synthesis of Substituted
Naphthalenes
Christopher C. V. Jones, Jignesh J. Patel, Ross D. Jansen-van Vuuren, Gregory M. Ross, Bernd O. Keller,
Francoise Sauriol, Gabriele Schatte, Erin R. Johnson,* and Victor Snieckus
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ABSTRACT: Mono- and dianion species of 1,8-naphthalene diamide 2 were generated under sec-BuLi/TMEDA conditions and
trapped with a variety of electrophiles to give 2- and 2,7- substituted products 3 and 4. Using Suzuki−Miyaura cross-coupling, mono-
and di-iodinated products were converted into the corresponding 2-aryl (5) and 2,7-diaryl (6) products, respectively. The amide−
amide rotation barrier of 2 was established by VT NMR, and the structure of fluorenone structure 9, obtained by remote metalation,
was secured.
Although the DoM reaction of simple 1- and 2-Directed
Metalating Group (DMG)-substituted naphthalenes has been
investigated,18a disubstituted mono- and di-DMGs systems
have received scant attention. Further, dimetalated aromatics
are relatively unrecognized and synthetically underdeveloped
species and intermediates, based on previous reports from our
and other laboratories (1a−g, Figure 1).20 In the context of the
1,8-substituted naphthalene containing the powerful N,N-
diethyl carboxamide DMG, and by extension the N,N diethyl
O-carbamate, Wuest et al. synthesized 2,7-derivatives of 1,8-
naphthalenediol (using the carbamate as the precursor) as
novel ligands for titanium catalysts,20e Snieckus et al.
synthesized 3,6-derivatives of N,N-diethylnaphthalene-1,8-
dicarboxamide,21 and Clayden et al. prepared a 2-formyl 8-
substituted-1-naphthamide.22 Thus, this work represents the
first study involving the preparation of 2- and 2,7-derivatives of
o organic chemists, the naphthalene ring, initially part of
1,2
Tisolates obtained from coal tar distillates,
has attained
considerable representation as a substructure in natural
products,3,4 bioactive molecules and drugs,5 nanomaterials,6
transition metal coordinated ligands,7 and other materials with
useful properties.8,9 The 1,8-disubstituted naphthalenes are of
special and long-standing interest due to their properties of
atropisomerism,10 as structural components in natural
products,11 use as proton sponges,12 nerve growth factor
(NGF) inhibitors,13 models of biological receptors,14 light-
energized compounds,15 and ligands for catalysis. The
synthesis of substituted naphthalenes encompasses a vast
number of methods.16,17 However, as a cursory perusal of the
literature will indicate, a need exists for systematic, wide-
ranging methodologies for the regioselective construction of
naphthalenes with three or more substituents.18
In the context of contributions toward providing new,
unusually substituted 1,8-naphthal-imides and -diamides, we
envisaged the advantage of Directed ortho Metalation (DoM)
derived routes19 based on N,N-diethyl naphthalene 1,8-
dicarboxamide 2, for establishing convenient syntheses of
1,2,8- and 1,2,7,8-substituted derivatives 3 and 4.
Received: December 16, 2020
Published: March 5, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00521
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1966−1973
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Scheme 1. Suzuki−Miyaura Cross-Coupling of Mono- and
Di-iodo Naphthalene Diamides 3b and 4f
Figure 1. Aromatic dilithiated species.20
N,N-diethylnaphthalene-1,8-dicarboxamide, which is an attrac-
tive pursuit considering the utility of naphthalene derivatives in
the design of chiral catalysts,23 medicinal compounds,24 and
functional materials such as photoswitches25 and liquid
crystals.26 Furthermore, the novel ortho-substituted bis-amides
can be transformed to other functional groups, e.g., esters,27 or
cross-coupled with other moieties,28 opening up a new family
of compounds for exploration.
Scheme 2. Directed Remote Metalation of N,N-Diethyl-2,7-
diphenylnaphthalene-1,8-dicarboxamide 6a
Herein we report studies on the mono- and dianion (1g)29
DoM chemistry of N,N-diethylnaphthalene-1,8-dicarboxamide
(2). The Suzuki−Miyaura cross-coupling reactions of the
derived halo derivatives 3b and 4f (Table 1, Scheme 1), a
Table 1. DoM and Electrophilic Quench of Naphthalene
Bis-amide 2
% yield of
products
electrophile quench
To initiate our study, previous experience with phthalamide
metalation,20c awareness of accumulated evidence to the nature
of lithiated aromatic amide structures,33 and some appreciation
of the profound effects of complexation30,34 and, hence,
reactivity of intermediates as a function of stoichiometry,35
guided our initial deuteration-quench study (Table 1). In order
to determine the relative amounts of deuterated species formed
as a function of base concentration, metalation (1.1 equiv of
sec-BuLi/TMEDA/−78 °C/30 min) of N,N-diethyl naphtha-
lene-1,8-dicarboxamide (2), prepared from the commercially
available 1,8-naphthalic anhydride,36 followed by quenching
with excess CD3OD and warming to rt provided product 4a in
>90% yield. HRMS analysis37 showed a d1/d2 = 33:67 ratio (d1
= mono incorporation, d2 = bis incorporation). Maximization
of d2 species (d1/d2 = 18:82) was achieved using 2.2 equiv of
the sec-BuLi/TMEDA complex (entry 1, Table 1), and there
was no further substantial change of this ratio when 3 equiv
and 4 equiv of base were used (see Supporting Information
(SI)). The requirement for an excess of 2 equiv of alkyllithium
reagent for a double DoM reaction was previously established
for bis-N,N-diethyl phthalimide.20c These results indicate that,
whatever the nature of the aggregated species produced, excess
equivalents of base result in a higher concentration of the 2,7-
dianion 1g under the equilibrating metalation reaction
conditions.
sec-BuLi/TMEDA
3a−b and/or
4a−f
entry
(equiv)
E+
E
1
2
3
4
5
6
7
8
2.2/2.2
1.1/1.1
4.4/4.4
2.2/2.2
2.2/2.2
ipso
CD3OD
TMSCl
TMSCl
DMF
(SMe)2
Br2
D
4a, 90 (d1 82%)
a
TMS
TMS
CHO
SMe
Br
3a, 15 + 4b, 25
b
4b, 50
4c, 40
4d, 75
c
4e, 77
d
1.1/1.1
2.2/2.2
CF3CH2I
CF3CH2I
I
I
3b, 24 + 4f, 35
b
4f, 87
a
b
c
38% of 2 was recovered. 5.0 equiv of E+ were used. Achieved by an
ipso-desilylation−bromination of 4b (TMS) in 77% yield with Br2
(see Supporting Information). 18% of 2 was recovered.
d
subsequent Directed remote Metalation (DreM) reaction30 to
give the fluorenone 9 (Scheme 2), and the assessment of amide
rotational barriers of two derivatives 2 and 4f are also
described.31 This work establishes new and convenient routes
toward highly substituted naphthalenes and, categorically, to 2-
monosubstituted (3) and 2,7-disubstituted (4) naphthalene
1,8-dicarboxamides (Table 1), whose utility in various
currently active areas of material science has not been
adequately tested due to the lack of their availability by
synthesis using classical chemistry.32
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With optimization conditions in hand, compound 2 was
subjected to 4.4 equiv of the sec-BuLi/TMEDA complex,
followed by 4.4 equiv of TMSCl,38 to afford the 2,7-disilylated
derivative 4b in 50% optimized yield (entry 3, Table 1). As
previously argued,39 successful generation of a dimetalated or
higher-order metalated aromatic species promoted by one or
more DMGs is dependent upon electrostatic repulsion,
additional complexity in aggregation, and solubility, among
other factors. The lower yields of the bis-silylated product 4b
compared to those of the deuteration product using the same
amounts of base are undoubtedly due to the greater steric
effects presented by the TMSCl electrophile. Using these
conditions, several other electrophiles were tested. Thus, in
addition to silylation (entry 2), thiomethylation (entry 5) and
formylation (entry 4) were achieved to give products in
moderate yields. Iodination was unsuccessful using elemental
I2, but was achieved using CF3CH2I40 to afford product 4f in
very good yield (entry 8). Attempts to obtain the
corresponding dibromo compound 4e by use of Br2 and
BrCH2CH2Br reagents were unsuccessful. However, the
application of the ipso-desilylation protocol41 to the readily
available bis-TMS 4b using excess bromine led to the
formation of the dibrominated product 4e in good yield
(entry 6). A number of other electrophiles led to formation of
mixtures of intractable products and/or decomposition (see
Supporting Information).
carbazolyl) ethylboronic acid pinacol ester was able to couple
successfully with the 2,7-diiodo-N,N-diethyl-naphthalene-1,8-
dicarboxyamide 4f. The incorporation of the carbazole moiety
presents utility in the ever expanding field of organic
electronics.46
The extensive studies of rotational barriers of congested peri-
substituted naphthalene derivatives,22,47 by Clayden, Fuchter,
and Okamoto, and the intriguing X-ray structure of 4b
prompted a VT NMR study48 of the prototype 1,8-
disubstituted naphthalene 2 (Figure 3). Although rotational
Figure 3. Comparison of rotational barriers of selected 1,8-
disubstituted naphthalenes 7,51 8,52 and 2.
barriers of peri-substituted naphthalenes have been compre-
hensively studied over the years,49,50 the results from the
Clayden and Staab laboratories for energy barriers of 1,8-
disubstituted naphthalenes are most pertinent. Studies of 7 and
8 are of greatest relevance to our case 2. As gleaned from
Figure 3, compound 2 shows the highest ΔG‡ of all listed
compounds, indicative of the great electronic-dipole effect
hampering free rotation about the aryl−CO bond that, as
Clayden suggested,47a is more significant than the steric
influence of the two substituents. Thus, the additional amide in
2 (anti conformation) raises the barrier by ca. 3.5 kcal/mol
compared to the mono amide 751 and by 4.5 kcal/mol over the
electronically less demanding diketone system 8.52 The
additional electronic, and most likely steric, requirements of
2,7-diiodo-N,N-diethyl-naphthalene-1,8-dicarboxyamide 4f
prevent observation of its high rotational barrier.
The X-ray crystal structure of 4b was obtained (Figure 2; for
data, see Supporting Information) and showed that the amides
Figure 2. ORTEP X-ray crystal structure of 4b. Hydrogens are
omitted for clarity. Thermal ellipsoids in the molecular plot are shown
at the 30% probability level.
The availability of the 2,7-diphenyl derivative 6a prompted a
test of the Directed remote Metalation (DreM) reaction,30
a
process that has been broadly demonstrated for the synthesis
of fluorenones from biaryl monoamides.53 After a brief
investigation (see Supporting Information), conditions re-
cently utilized for remote metalation on biaryl systems54 using
equal proportions of LDA and TMEDA in hexane/Et2O (4:1)
afforded the monocyclized product 9 in 40% yield as a bright
orange crystalline material (Scheme 2). The structure of 9,
obtained by single-crystal X-ray crystallography (Figure 4),
shows significant steric repulsion, resulting in the amide group
being nearly orthogonal to the plane of the naphthyl ring.
We then sought to understand the observation of a mono-
DreM reaction to fluorenone 9 and not a double-DreM process
to fluoreno[1,2-α]fluorenedione 12 under the excess LDA
conditions. DFT calculations using the B3LYP functional,55,56
the XDM dispersion correction,57,58 and the PCM continuum
solvent59 model as implemented in Gaussian 0960 were
performed (see Supporting Information for details) to predict
the thermochemistry of the putative sequential DreM reactions
of species 6a, 9, and 12. The computed free-energy changes for
each reaction, 6a → 9 (ΔG = 2.9 kcal/mol) and 9 → 12 (ΔG
= 6.7 kcal/mol), indicate a lower ΔG for the first reaction,
consistent with the observed formation of compound 9, but
not 12.
are perpendicular to the naphthalene ring and the carbonyls
are pointing in diametrically opposite directions. The peri
relationship of the amides pushes them outward,42,43 thus
creating a smaller bond angle (116.9°) from the norm (120°),
with the resulting orientation of the TMS groups at a large
(125.2°) angle.
The availability of the 2,7-dibromo and 2,7-diiodo
naphthalene dicarboxamides 4e and 4f, and the knowledge
of arylated naphthalene diamides as significant materials in
solar-cell research,15 compelled us to attempt bis Suzuki−
Miyaura cross-coupling chemistry.44 To start, the 2-iodo-N,N-
diethyl-naphthalene-1,8-dicarboxyamide 3b was subjected to
coupling with selected aryl boronic acids under optimized
conditions (10 mol % Pd(PPh3)4/K3PO4/anhyd DMF)45 to
afford products 5a−f in consistently higher yields (Scheme 1).
A broad set of catalysts and conditions were screened (see
Supporting Information) for the more reactive diiodo 4f
derivative, which afforded the products 6a−h in similar yields.
A number of available aryl/heteroaryl and aliphatic boronic
acids (see Supporting Information) did not furnish the
expected products when reacted with 3b and/or 4f. Of the
aliphatic boronate esters/boronic acids explored, only the 2-(9-
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suggested, also based on calculations, that a protonated form
(proton squeezed between the two carbonyls) is the
thermodynamically controlled product. Given the difference
in functional groups (6a and 10) and nature of transition states
for the formation of diketone 12 from diamide and diester,
further comment is unwarranted.
To further investigate the differences between our two
sequential DreM reactions of 6a and 9, computational studies
were performed for both reaction pathways. Here, the LDA
catalyst was modeled as lithium dimethyl amide for simplicity.
One molecule of THF solvent, coordinated to the lithium, was
included in the calculations, following our previous similar
mechanistic study.63 The results for the pathway are shown in
Figure 5. Here, both 6a and 9 form prereaction complexes 15
and 18, respectively, in which the LDA coordinates to the
amide oxygen (Complex-Induced Proximity Effect).30 Depro-
tonation leads to the coordinated aryl carbanions 16 and 19,
which undergo cyclization to the tetrahedral carbinolamine
alkoxides 17 and 20, respectively, and thence by loss of LDA to
the final products 9 and 12. The cyclization step is found to
have a significantly higher free-energy barrier for 9 than for 6a,
consistent with the experimental finding that the second
deprotonation−cyclization reaction fails. The higher free-
energy barrier can be attributed to geometry differences in
Figure 4. ORTEP X-ray crystal structure of 9. Hydrogens are omitted
for clarity. Thermal ellipsoids in the molecular plot are shown at the
30% probability level.
Recently, Frantz reported the synthesis of fluoreno[1,2-
α]fluorenedione (12), as well as the linear isomeric fluoreno-
[2,1-α]fluorenedione, using double intramolecular Friedel−
Crafts cyclization reactions.62 The fluorene-dione 12 (Scheme
2) was obtained in 89% yield using hot sulfuric acid. In THF
solvent, the reaction 11 → 12 has a corresponding B3LYP-
XDM free energy penalty of 7.7 kcal/mol, similar to that seen
for 9 → 12. Frantz argued that strong acid was needed to
stabilize compound 12 and the corresponding protonated
transition state interspersed in the sequence 10 → 12.
Calculations at the B3LYP/6-31G* level62 indicate that the
sterically hindered difluorenone 12 has a ground-state energy
that is 13.4 kcal/mol higher than the unhindered [2,3-b]
isomer.62 For comparison, our B3LYP-XDM calculations
predict this relative energy difference to be 12.0 kcal/mol,
which is in fairly close agreement with the previous theoretical
value. Franz proposed that compound 12 adopts a “twisted,
helical C2-symmetric structure to accommodate steric clashing,
and likely electrostatic repulsion, of the two oxygen atoms” and
̋
the cyclization transition state. Specifically, the Burgi−Dunitz
angles (the highlighted C−C−O angles in the ball-and-stick
figure) are 107.9° and 110.3° for the transition states to form
17 and 20, respectively. The latter value is considerably larger
than the ideal value of ∼107°, which destabilizes the transition
state. Analogous DFT calculations on different biaryl amide
systems have led to similar conclusions regarding the inability
64,65
̋
to achieve the required Burgi−Dunitz angle.
Figure 5. Comparative reaction profiles (relative free energies, in kcal/mol) for the DreM reactions of 6a and 9, obtained using B3LYP-XDM and a
̋
continuum model of THF solvent. Transition-state geometries are shown in ball-and-stick format with the Burgi−Dunitz angles highlighted in
green.61
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In conclusion, we have demonstrated a new route for the
synthesis of 2- and 2,7-substituted naphthalene 1,8-dicarbox-
amides 3 and 4 by the Directed ortho Metalation (DoM)
strategy. A useful and high-yielding route to the 2,7-dibromo
derivative 4e was established by the ipso bromodesilylation
reaction of the bis-TMS derivative 4b. The DoM-Suzuki
reaction nexus was demonstrated on both mono- and di-iodo
derivatives 3b and 4f by coupling with selected aryl boronic
acids to obtain 5 and 6. Additionally, we have uncovered a
Directed remote Metalation (DreM) reaction on 6a to afford
the fluorenone 9 in moderate yield. These preliminary results
establish the potential of the DoM reaction for the preparation
of unusually substituted 1,8-naphthamides and, by implication,
the corresponding naphthimides66 and other functionalizations
that may be obtained by transformation of the diethyl
amides.27,28 Such compounds are not available by classical
methods and are of considerable current interest for use in
solar energy devices,15 molecular motors,67 chemo sensors,68
DNA binders,69 transition-metal based catalysts,70 and novel
cross-coupling partners.71 Thus, this novel chemistry opens the
door to an untapped class of compounds with a plethora of
potential applications in the materials science sphere and
beyond.
Victor Snieckus − Department of Chemistry, Queen’s
University, Kingston, ON K7L 3N6, Canada; orcid.org/
0000-0002-6448-9832
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00521
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSERC for continuous support to our
Discovery Grant (DG) programs. We are grateful to Compute
Canada for computational resources and to Frontier Scientific
for donation of samples of several aryl boronic acids, gratis. We
are thankful to John Stephenson, a 4th year undergraduate
engineering chemistry student, Queen’s University, Kingston,
ON, Canada for performing several experiments.
DEDICATION
■
In memory of Prof. Victor A. Snieckus (August 1, 1937 to
December 18, 2020). May his legacy live on. This manuscript
is Prof. Victor A. Snieckus’ last submission to an academic
journal before his passing.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00521.
■
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1
Accession Codes
CCDC 2050790−2050791 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
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AUTHOR INFORMATION
Corresponding Author
■
Erin R. Johnson − Department of Chemistry, Dalhousie
University, Halifax, NS B3H 4R2, Canada; orcid.org/
0000-0002-5651-468X; Email: erin.johnson@dal.ca
Authors
Christopher C. V. Jones − Department of Chemistry, Queen’s
University, Kingston, ON K7L 3N6, Canada; orcid.org/
0000-0002-6975-6805
Jignesh J. Patel − Department of Chemistry, Queen’s
University, Kingston, ON K7L 3N6, Canada
Ross D. Jansen-van Vuuren − Department of Chemistry,
Queen’s University, Kingston, ON K7L 3N6, Canada;
orcid.org/0000-0002-2919-6962
Gregory M. Ross − Northern Ontario School of Medicine,
Laurentian University, Sudbury, ON P3E 2C6, Canada
Bernd O. Keller − Numinus Bioscience, Nanaimo, BC V9R
6Z8, Canada
Francoise Sauriol − Department of Chemistry, Queen’s
University, Kingston, ON K7L 3N6, Canada
Gabriele Schatte − Department of Chemistry, Queen’s
University, Kingston, ON K7L 3N6, Canada
̈
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