Air-Stable Pd Catalytic Systems for Sequential One-Pot Synthesis of Challenging Unsymmetrical Aminoaromatics

Article abstract of DOI:10.1021/acs.joc.6b01248

The selective functionalization of dibromoaromatic scaffolds using air-stable palladium catalytic systems was carried out. This methodology involved rapid mono and diselective Buchwald-Hartwig aminations via microwave irradiation. The conditions were optimized to couple sequentially different moieties in one pot. Couplings with a wide scope of amines allowed accessing a new library of symmetrical and unsymmetrical derivatives (35 examples). Using this versatile method, a near-IR push-pull sensor was prepared installing the electron-donating and -withdrawing groups through a multicomponent reaction. These conditions revealed to be gram-scalable and adaptable to various groups; hence, promoting facile use in synthetic chemistry.

Full text of DOI:10.1021/acs.joc.6b01248

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Article
Air-stable Pd catalytic systems for sequential one-pot
synthesis of challenging unsymmetrical aminoaromatics
Janah Shaya, Marie-Angélique Deschamps, Benoît Y. Michel, and Alain Burger
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Jul 2016
Downloaded from http://pubs.acs.org on July 27, 2016
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The Journal of Organic Chemistry
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Air-stable Pd catalytic systems for sequential one-pot synthesis of
challenging unsymmetrical aminoaromatics
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Janah Shaya, MarieꢀAngélique Deschamps, Benoît Y. Michel, and Alain Burger*
Institut de Chimie de Nice, UMR 7272, Université de Nice Sophia Antipolis, CNRS, Parc Valrose, 06108 Nice
Cedex 2, France.
Pd catalysis, Buchwald-Hartwig amination, C-N cross-coupling, fluorene, desymmetrization, diamination
ABSTRACT: The selective functionalization of dibromoaromatic scaffolds using airꢀstable palladium catalytic
systems was carried out. This methodology involved rapid monoꢀ and diꢀselective BuchwaldꢀHartwig aminations
via microwave irradiation. The conditions were optimized to couple sequentially different moieties in one pot.
Couplings with a wide scope of amines allowed accessing a new library of symmetrical and unsymmetrical deꢀ
rivatives (35 examples). Using this versatile method, a nearꢀIR pushꢀpull sensor was prepared installing the elecꢀ
tronꢀdonating and withdrawing groups through a multiꢀcomponent reaction. These conditions revealed to be
gramꢀscalable and adaptable to various groups; hence, promoting facile use in synthetic chemistry.
INTRODUCTION
Paralleled by the growing number of applications in material sciences (electronics, photonics) and therapeutics
1
(
natural products, pharmaceuticals), selective functionalization of aromatic compounds has received broad conꢀ
siderations. Numerous palladiumꢀcatalyzed methodologies have emerged as reliable avenues to generate such
2
aromatic products. However, controlled couplings have been limited to a narrow array of substrates based on the
3
halogen selectivities (Br/Cl or I/Br). Indeed, selective couplings of simple dihalogenated aromatic scaffolds are
4
seldom reported in the literature.
1a
Considering fluorene in particular for its significant applications, Pdꢀcatalyzed monoꢀamination of 2,7ꢀ
5
dibromofluorenes was limited to aryl amines (Scheme 1). Long routes engaging harsh conditions as nitrations
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6
and Ullmannꢀtype couplings are hitherto used to synthesize aminofluorene derivatives. Such conventional routes
might still be preferred due to the overestimation of the role of glove box in BuchwaldꢀHartwig CꢀN couplings. The
endless list of costly palladium sources, ligands, and bases also complicates the choice of suitable catalytic sysꢀ
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tems for synthetic chemists. Hence, we were encouraged to investigate the development of robust catalytic conꢀ
ditions to generate diverse aminoꢀaromatic libraries and synthesize products inaccessible by classical aminations.
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Our group recently reported a library of fluorescent fluorene probes. During our initial study, we developed a
convenient Pdꢀcatalyzed methodology for the preparation of pushꢀpull dyes starting from 7ꢀbromoꢀ9,9ꢀ
2c,3d,9
dimethylfluoreneꢀ2ꢀcarbaldehyde. We now wish to report an appendage DiversityꢀOriented Synthesis (DOS)
of functionalized aromatic compounds using airꢀstable palladium catalytic systems (Scheme 1).
Scheme 1. State-of-the-art on selective functionalization of bromofluorenes
a) Previous works:
- Literature
Pd-catalyzed
monoamination
Br
Br
Br
O
NHR
1
ref. 5
R = aryl
-
Our group
Pd-catalyzed
amination
R
O
N
R
Br
ref. 8
R = aryl and
aliphatic
b) This works: One-step selective amination
selective
monoamination
Push-Pull probe (PP)
R1
N
Br
N
PhHN
R -R = H, aryl
aliphatic
R2
S
1
4
N
&
Br
Br
one-pot C-N
unsymmetrized
diaminofluorenes
&
Stille couplings
R1
R3
N
R4
R1
N
N
R2
R2
Extension to other
dibromoaromatic
scaffolds
This methodology involves MWꢀassisted monoꢀ and diꢀamination of easilyꢀaccessible dibromoaromatic scafꢀ
folds. An extent of the latter provides sequential oneꢀpot CꢀN/CꢀN and CꢀN/Stille couplings. Scope and limitations
have been tested with dibrominated 2,7-fluorenes, 2,7ꢀnaphthalenes, 2,6ꢀpyridines and 2,5ꢀthiophenes. This work
permits the access to a variety of useful symmetrical and unsymmetrical aromatic compounds. For example, 2ꢀ
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aminoꢀ7ꢀvinylfluorenes are important intermediates for numerous applications. The vinyl group is amenable to
polymerization in lightꢀharvesting materials, metathesis, MizorokiꢀHeck crossꢀcoupling, and oxidative cleavage to
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form pushꢀpull sensors. The amino moiety is beneficial for biomedical research and nanoparticles functionalizaꢀ
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tion. Using these conditions, a nearꢀIR probe PP (Scheme 1) was prepared by a multiꢀcomponent reaction
comprising one CꢀN and two Stille couplings.
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RESULTS AND DISCUSSION
Figure 1. Optimization of the reaction conditions.
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2 3 4 5 6 7 8 9 101112131415161718
Entry
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Deviation from
standard conditions
b
Entry
Screened Ligands
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PPh3
P(oꢀTol)3
PCy3
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P(tꢀBu)3
DavePhos
BrettPhos
RuPhos
JohnPhos
XantPhos
ꢀ
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Ligand
Screening
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Cs
CO
Base
Base
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3
KOtBu
Pd(dba)
Catalyst
Solvent
Temp
Activation
Ligand
Loading
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Dioxane
rt
MW (45 min)
8 mol%
Doubled
Results were depicted as bar graphs displaying the GCMS conversion and the selectivity of mono/di aminated products
2a/3a). The corresponding entries were summarized in table by displaying the changed parameter.
(
We started our investigations using a stoichiometric mixture of 2,7ꢀdibromofluorene and Nꢀmethylaniline. This
amine was chosen as an acyclic aliphaticꢀaromatic substrate. Different catalytic conditions were examined and
their corresponding selectivities of monoꢀ versus diꢀaminated products were outlined in Figure 1. Monodentate
triarylphosphines, such as PPh and P(oꢀTol) were tested with low success (Entries 1ꢀ2). PPh exhibited a poor
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3
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conversion (5%) whereas P(oꢀTol) favored diamination (25 %) with dehalogenation side reactions. Reductive
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dehalogenation was also observed with first generation ligand PCy (Entry 3). Almost all the other ligands affordꢀ
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ed the aminated products (2a and 3a) in complete mass balance relative to the amine starting materials (Entries
3
ꢀ10). The monodentate ligands (L4-8) mainly led to the diaminofluorene (3a) (Entries 3ꢀ8). The chelating bidenꢀ
tate ligands (XantPhos and BINAP) resulted in the monoꢀaminated fluorene (2a) as the major product in line with
4i,j,12
previous studies conducted on dibromobenzene (Entries 9ꢀ10).
Cs CO as a representative of carbonate base demonstrated a moderate conversion (Entry 11). tꢀBuOK and tꢀ
2
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BuONa almost gave the same efficient results (Entries 10 vs 12). Pd(dba) was monoꢀselective; however, the
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reaction did not reach to completion after 18 h (Entry 13). The observed slower kinetics is consistent with the
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more stericallyꢀhindered Pd(dba)L species. The crossꢀcoupling did not work at room temperature (Entry 15).
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Dioxane (Entry 14) mostly afforded the monoꢀproduct, nonetheless the reaction was cleaner in toluene. MW actiꢀ
vation gave the shortest reaction time (Entries 10 vs 16). The best molar ratio of the [Pd]:ligand was optimized as
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:3 with a loading of 4 mol% (Entries 10 vs 17). A lowering to 1 mol% inevitably slowed down the reaction rate.
Premixing the catalytic system significantly accelerated the kinetics presuming an efficient activation of Pd(0)
The Journal of Organic Chemistry
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complex. It is noteworthy that premixing becomes a prerequisite in the case of BINAP. The monoꢀamination
conditions were established as follows: Pd(OAc) (4 mol%), BINAP (12 mol%), NaOtBu (1.1 eq), amine (1.2 eq),
2
toluene MW irradiations for 45 min (Entry 16). Doubling the catalytic loading along with excess of amine (Entry
18) led to complete diamination.
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Scheme 2. Scope and limitation pattern of the selective mono-amination of 1.
[a]
[b]
[c]
Yields in parenthesis. Under thermal heating conditions; Reaction performed at 1ꢀgram scale; GCMS converꢀ
sion to the product.
The scope and limitations of this methodology were investigated (Schemes 2&3). The chosen monoꢀamination
conditions were applied to introduce a variety of amines (Scheme 2). The selective mono crossꢀcoupling was
efficient on pyrrole (2b, 80 %), cyclic secondary amines (2d-h, 50ꢀ81 %), and primary amines (2j-k, 67ꢀ82 %). To
our delight, the diethylamine was also coupled efficiently (2i, 62 %). Most reactions proceeded to completion in 45
mins under MW irradiation. Piperidine 2e and azetidine 2g were irradiated twice for 45 mins, their yields remained
moderate (50ꢀ62 %). The reaction was efficiently scaledꢀup to one gram (2e, 2i-j). Considering the unprotected
piperazine 2l, low conversion of starting material was obtained. Surprisingly, no dimerization was observed. This
might open up new prospects for conjugation avoiding the additional steps of protectionꢀdeprotection of piperaꢀ
zine. The reaction conditions were limited on imidazole 2c. Regarding carbamate coupling (2m-n), it required
higher palladium catalytic loadings, which yielded the debrominated monoꢀcoupled derivative as the major prodꢀ
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uct. Since carbamates present a different reactivity: tꢀBuOH, NMP and THF were likewise screened without sucꢀ
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cess.
Scheme 3. Diamination reaction of 1.
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Minor modification of the catalytic system allows for the preparation of diaminofluorenes (Scheme 3). A conꢀ
trol reaction by using a large excess of amine (5 eq.) evidenced no inhibition of the process. A range of diaminoꢀ
fluorenes (3a-e) was prepared in good to excellent yields (61ꢀ89 %). The employed conditions revealed to be
effective and tolerant towards various model aliphatic and aromatic amines.
Scheme 4. Sequential couplings of 1.
[
a]
GCMS conversion.
Next, we examined the synthesis of unsymmetrical fluorenes using a oneꢀpot 2ꢀstep protocol (Scheme 4). In
this case, MW conditions were too demanding and generated inseparable mixtures. On the other side, thermal
heating proved to be promising. Products 4a-e (46ꢀ76 %) were obtained by the sequential CꢀN/Stille couplings
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using the optimized conditions of entry 8. Specifically, once the monoꢀaminated product was formed, tributylvinylꢀ
tin and a subsequent catalytic loading were concomitantly added. The synthesis of products bearing two distinct
amines (4f-g) was also achieved (43ꢀ60 %) by sequential oneꢀpot CꢀN/CꢀN couplings. The limitations of this type
of desymmetrization are reflective of those of selective monoꢀamination (compare 4d and 2c). The choice of
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amines that worked efficiently for monoꢀamination (Scheme 1) would lead to an efficient sequential oneꢀpot
coupling. Regarding the second catalytic loading, the reaction showed poor yields when it was not followed by a
subsequent addition of the catalytic system. The addition of a second stoichiometric base is mandatory. We
chose to focus on the double catalytic addition in this work to obtain good yields, as many factors can directly
deactivate the palladium catalyst outside the glove box and this challenging reaction aims to synthesize useful
materials. The highest yield of this series was observed for the pyrryl 4c (76 %).
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Scheme 5 compares the oneꢀpot approach (69 %) to the classical twoꢀstep synthesis (76 %) of compound 4e.
The good yield demonstrates that the developed procedure is costꢀ and timeꢀefficient in synthesizing interesting
products.
Scheme 5. Sequential one-pot versus classical two-step synthesis of 4e.
To further scope this method, different dibromo coupling partners with electronic diversity was tested. The reꢀ
sults were illustrated in Chart 1. Regarding the electronꢀneutral naphthalene moiety, all the optimized catalytic
systems worked as adequately as on fluorenes. Aromatic and aliphatic amines were introduced with monoꢀ or diꢀ
selectivity as desired furnishing 5a-d (65ꢀ83 %). The sequential synthesis of naphthalenes bearing varied combiꢀ
nations of amines was fruitful and generated compound 5e in appreciable yields (64%). The electronꢀdeficient
pyridine reacted in higher yields (6a-f, 71ꢀ94%). 6e was prepared as an example of the sequential addition in
significant yield (71%). It is worth noting that 2,5ꢀdibromopyridine underwent monoꢀamination with 0,5 mol%
Pd(OAc) catalytic system or even with excess amine (5 eq.) in the absence of palladium catalyst. Nevertheless,
2
diꢀ or sequentialꢀamination of this heteroaryl compound undoubtedly requested the developed catalytic condiꢀ
tions. Arylaminothiophenes were obtained successfully and were stable to isolate (7a-b, 42ꢀ54 %). Amination was
still selective on such electronꢀrich aromatic scaffold. Considering saturated cyclic amines (7c-e), the mono/di
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conditions were selective with acceptable conversions (47ꢀ72 %). However, these electronꢀrich products proved
to be unstable upon isolation and appeared as a scope limitation.
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Chart 1. Scope and limitations of different dibromoaromatic scaffolds.
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The strength of this method permitted to access the nearꢀIR probe 8 (λAbs = 395 nm and λEm = 640 nm in chloꢀ
roform, Figure S1) in a 3ꢀstep simple protocol (Scheme 6). This multiꢀcomponent reaction clearly asserts the verꢀ
satility of our synthetic approach. The synthesis was concise and good yielding. It resulted in synthesis of an adꢀ
vanced dye without the tedious isolation of two intermediates.
Scheme 6. Construction of push-pull sensor 8.
CONCLUSION
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In sum, an appendage DOS was realized starting from simple dibromoaromatic compounds, and based on a
platform of versatile palladium crossꢀcouplings. The atomꢀ and stepꢀefficient methodology has allowed the synꢀ
thesis of 35 examples including most challenging unsymmetrical substrates. We believe this catalytic route conꢀ
stitutes a more viable alternative to other long synthetic routes. The obtained vinylamino products are valuable
intermediates that could be further employed to deliver a variety of light harvestingꢀmaterials and polymers. Using
the same conditions, synthesis of nearꢀIR probe was achieved via a versatile 3ꢀstep reaction involving a CꢀN and
two Stille couplings.
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EXPERIMENTAL SECTION
All reactions involving waterꢀ or airꢀsensitive material were performed in ovenꢀdried glassware under an argon
or nitrogen atmosphere by using Schlenk techniques employing doubleꢀline argonꢀvacuum lines and dry solvents.
The reactions were monitored simultaneously by gas chromatography (GC/MS) and by thinꢀlayer chromatography
and visualized both by UV radiation (254 & 365 nm) and by spraying with relevant staining agent (KMnO or Ninꢀ
4
1
13
1
hydrin). Chemical shifts (δ) are given in ppm to the nearest 0.01 ( H) or 0.1 ppm ( C{ H}NMR) (recorded with
13
complete proton decoupling and written as C in the experimental part for simplicity. The coupling constants (J)
are given in Hertz (Hz). The signals are reported as follows: (s=singlet, d=doublet, t=triplet, quint=quintet,
sext=sextet, m=multiplet, br=broad). GCMS mass spectra were recorded using an ion trap mass spectrometer
with EI source (70eV). LCMS mass spectra were recorded using an ion trap mass spectrometer equipped with an
ESI source. HRMS were recorded on a hybrid ion trap−Orbitrap mass spectrometer using ESI. Microwave reacꢀ
tions were conducted using a monowave focused heating model with an internal probe.
9,9-dimethyl-9H-fluorene: To a stirred solution of 9Hꢀfluorene (3.00 g, 18.1 mmol, 1 eq.) in DMSO (35 mL) at
60 °C, were sequentially added potassium iodide (300 mg, 1.8 mmol, 0.1 eq.), iodomethane (5.76 g, 40.6 mmol,
2.25 eq.), and very cautiously powdered potassium hydroxide (8.30 g, 146.8 mmol, 4 eq.). The resulting reaction
mixture was stirred at room temperature overnight before being poured into 200 mL of water. A light yellow preꢀ
cipitate was formed, then filtered out, washed with cold water, and dried under vacuum. The light yellow solid was
purified by crystallization from methanol to provide the 9,9ꢀdimethylated fluorene (2.94 g, 84 %) as white crystals.
1
13
HꢀNMR (200 MHz, CDCl , δ): 7.77ꢀ7.73 (m, 2H), 7.48ꢀ7.42 (m, 2H), 7.41ꢀ7.33 (m, 4H), 1.51 (s, 6H). CꢀNMR
3
(50 MHz, CDCl , δ): 153.7 (2C), 139.3 (2C), 127.4 (2C), 126.9 (2C), 122.7 (2C), 120.1 (2C), 47.4, 27.3 (2C). GCꢀ
3
+
.
MS (m/z): 194.2 [M] . Mp: 96ꢀ98 °C.
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Page 10 of 21
2
,7-dibromo-9,9-dimethyl-9H-fluorene (1): To a solution of 9,9ꢀdimethylꢀ9Hꢀfluorene (2.18 g, 11.2 mmol, 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
eq.) in CHCl (25 mL) in a reaction vessel suspended in ice bath, liquid bromine (1.40 mL, 25.8 mmol, 2.3 eq.)
3
was carefully added dropwise. The reaction mixture was stirred for 4 h, quenched with sat. aq. Na S O (15 mL),
2
2
3
and extracted with CHCl (3*15 mL). The separated organic layer was washed with brine, dried over anhydrous
3
MgSO , and concentrated in vacuo. The crude product was purified by crystallization from DCM/MeOH to give 1
4
1
3
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2.85 g, 76 %) as white crystals. HꢀNMR (200 MHz, CDCl , δ): 7.55 (d, J=8.0 Hz, 2H, H4,5), 7.54 (d, J=1.5 Hz,
3
4
3
13
2H, H1,8), 7.45 (dd, J=1.5 Hz, J=8.0 Hz, 2H, H3,6), 1.46 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.4 (2C),
3
+
.
137.3 (2C), 130.5 (2C), 126.3 (2C), 121.6 (4C), 47.5, 27.0 (2C). MS (m/z): 352.0 [M] . Mp: 179ꢀ181 °C.
Synthesis of 2a-l: General procedure for the Buchwald-Hartwig selective mono-amination (GP-A).
Pd(OAc) (4 mol%), tꢀBuONa (1.1 eq.), and BINAP (12 mol%) were added to a previouslyꢀdried reaction tube
2
containing a magnetic bar. The tube was purged with argon for 3 cycles using Schlenk technique. The mixture
was dissolved in toluene (0.1 M) and stirred for 15 min under argon at rt. Then, the dibromo aryl reagent (1 eq.)
was added, followed by 15 min of further stirring (at rt or 100 °C for better). Finally, the amine (liquid or dissolved
in toluene) (1.1 eq.) was added, and the reaction mixture was irradiated in the microwave oven at 300 W/ 180 °C
for 45 minutes (or classically heated at 100 °C in an oil bath overnight for thermal activation). The reaction was
concomitantly monitored by TLC and GCMS until complete conversion. The resulting mixture was cooled down to
®
room temperature, diluted by CH Cl , and filtered over a pad of Celite . The volatiles were removed under reꢀ
2
2
duced pressure, and the residue was purified by silica gel column chromatography using a slow gradient to give
the desired product. 2aꢀk series of products was prepared on 100 mg scale (0.28 mmol) except when otherwise
indicated.
7
-bromo-N,9,9-trimethyl-N-phenyl-9H-fluoren-2-amine (2a): Eluent for flash chromatography (PE/Et O =
2
gradient up to 98:2, R = 0.45) providing 2a as a yellow solid (89 mg, 0.24 mmol, 86 %). Thermal heating: (80 mg,
f
1
0.21 mmol, 76 %). HꢀNMR (200 MHz, CDCl , δ): 7.49ꢀ7.16 (m, 6H), 7.02ꢀ6.86 (m, 5H), 3.29 (s, 3H), 1.34 (s, 6H).
3
13
CꢀNMR (50 MHz, CDCl , δ): 155.5, 154.9, 149.1 (2C), 138.4, 131.5, 130.1, 129.4 (2C), 126.1, 121.6, 120.8
3
+
+
(
3C), 120.6, 119.8, 119.4, 114.4, 47.2, 40.7, 27.7 (2C). HRMS (ESI ): m/z calcd for C H NBr: 378.0852 [M+H] ;
22 21
found 378.0855.
1
-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)-1H-pyrrole (2b): Eluent for flash chromatography (PE/Et O = graꢀ
2
1
dient up to 98:2, R = 0.45) providing 2b as a yellow solid (74 mg, 0.22 mmol, 80 %). HꢀNMR (200 MHz, CDCl ,
f
3
3
13
δ): 7.72 (d, J=8.0 Hz, 1H), 7.60ꢀ7.36 (m, 5H), 7.16 (t, J=2.0 Hz, 2H), 6.40 (t, J=2.0 Hz, 2H), 1.52 (s, 6H). Cꢀ
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NMR (50 MHz, CDCl , δ): 155.7, 155.0, 140.6, 137.6, 135.9, 130.4, 126.3, 121.4, 121.1, 121.1, 120.0, 119.7 (2C),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
1
15.4, 110.6 (2C), 47.7, 27.1 (2C). HRMS (ESI ): m/z calcd for C H NBr: 338.0539 [M+H] ; found 338.0540.
19 17
1
-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)-1H-imidazole (2c): Eluent for flash chromatography (PE/Et O =
2
1
gradient up to 98:2) providing 2c as a yellow solid (24 mg, 0.07 mmol, 28 %) HꢀNMR (200 MHz, CDCl , δ): 7.90
3
3
3
3
4
(
s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.47 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.40ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
7
.32 (m, 3H), 7.23 (s, 1H), 1.51 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.7, 155.3, 137.7, 137.0, 136.9, 135.8,
3
+
1
30.6 (2C), 126.4, 121.8, 121.7, 121.3, 121.0, 118.6, 116.4, 47.5, 27.1 (2C). HRMS (ESI ): m/z calcd for
+
C H N Br: 339.0491 [M+H] ; found 339.0494. Mp: 172ꢀ174 °C.
18
16
2
1-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)azepane (2d): Eluent for flash chromatography (PE/Et O = gradient
2
1
up to 98:2, R = 0.5) providing 2d as a yellow solid (83 mg, 0.23 mmol, 81 %). HꢀNMR (200 MHz, CDCl , δ): 7.51
f
3
3
3
(br d, J=8.0 Hz, 1H, H4’), 7.46 (br s, 1H, H8’), 7.43ꢀ7.34 (m, 2H, H5’,6’), 6.70 (br s, 1H, H1’), 6.68 (br d, J=8.0
3
Hz, 1H, H3’), 3.53 (t, J=6.0 Hz, 4H, CH 2,7), 1.84 (br m, 4H, CH 3,6), 1.59 (br m, 4H, CH 4,5), 1.45 (s, 6H,
2
2
2
13
2CH3). CꢀNMR (50 MHz, CDCl , δ): 155.3, 154.9, 149.4, 139.2, 129.9, 129.4, 125.8, 121.1, 119.7, 118.4, 110.5,
3
+
+
105.1, 49.6 (2C), 47.0, 27.9 (2C), 27.5 (2C), 27.3 (2C). HRMS (ESI ): m/z calcd for C H NBr: 370.1165 [M+H] ;
21
25
found 370.1166. Mp: 140ꢀ142 °C.
-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)piperidine (2e): Reaction performed on 1 gram scale (2.84
mmol). Eluent for flash chromatography (PE/EA = gradient up to 95:5, R = 0.6) providing 2e as a yellow solid
1
f
1
3
4
(
625 mg, 1.76 mmol, 62 %). HꢀNMR (200 MHz, CDCl , δ): 7.55 (d, J=8.0 Hz, 1H, H4’), 7.49 (d, J=2.0 Hz, 1H,
3
3
3
4
3
H8’), 7.42 (d, J=8.0 Hz, 1H, H5’), 7.39 (dd, J=8.0 Hz, J=2.0 Hz, 1H, H6’), 7.00 (br s, 1H, H1’), 6.94 (dd, J=8.0
4
3
Hz, J=2.0 Hz, 1H, H3’), 3.23 (t, J=6.0 Hz, 4H, CH 2,6), 1.77 (br m, 4H, CH 3,5), 1.62 (br m, 2H, CH 4), 1.45 (s,
2
2
2
13
6
H, 2CH3). CꢀNMR (50 MHz, CDCl , δ): 155.3, 154.7, 152.6, 138.7, 130.0, 129.6, 125.9, 120.7, 120.4, 119.3,
3
+
1
15.5, 110.8, 51.1 (2C), 47.1, 27.3 (2C), 26.0 (2C), 24.4. HRMS (ESI ): m/z calcd for C H NBr: 356.1008
20
23
+
[
M+H] ; found 356.1008. Mp: 133ꢀ135 °C.
1
-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)pyrrolidine (2f): Eluent for flash chromatography (PE/Et O = gradiꢀ
2
1
ent up to 97:3, R = 0.32) providing 2f as a yellow solid (79 mg, 0.23 mmol, 83 %). HꢀNMR (200 MHz, CDCl , δ):
f
3
3
4
7
.41 (d, J=8.0 Hz, 1H, H4’), 7.36 (br d, J=2.0 Hz, 1H, H8’), 7.27 (m, 2H, H5’,6’), 6.45 (br s, 1H, H1’), 6.42 (dd,
3
4
3
13
J=8.0 Hz, J=2.0 Hz, 1H, H3’), 3.24 (t, J=7.0 Hz, 4H, CH 2,5), 1.91 (m, 4H, CH 3,4), 1.34 (s, 6H, 2CH ). Cꢀ
2
2
3
NMR (50 MHz, CDCl , δ): 155.2, 154.9, 148.2, 139.3, 129.9 (2C), 125.8, 121.1, 119.7, 118.3, 110.9, 105.5, 48.0
3
+
+
(
2C), 47.0, 27.5 (2C), 25.6 (2C). HRMS (ESI ): m/z calcd for C H NBr: 342.0852 [M+H] ; found 342.0852.
19 21
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1
-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)azetidine (2g): Eluent for flash chromatography (PE/Et O = gradient
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
up to 98/2, R = 0.18) providing 2g as a yellow solid (45 mg, 0.14 mmol, 50 %). HꢀNMR (200 MHz, CDCl , δ):
f
3
3
4
7
.43 (d, J=8.0 Hz, 1H , H4’), 7.39 (br s, 1H, H8’), 7.33ꢀ7.27 (m, 2H, H5’,6’), 6.37 (br d, J=2.0 Hz, 1H, H1’), 6.33
3
4
3
3
(
dd, J=8.0 Hz, J=2.0 Hz, 1H, H3’), 3.87 (t, J=7.0 Hz, 4H, CH 2,4), 2.32 (q, J=7.0 Hz, 2H, CH 3), 1.35 (s, 6H,
2 2
13
2
1
3
CH3). CꢀNMR (50 MHz, CDCl , δ): 155.0 (2C), 152.4, 139.1, 130.0 (2C), 125.9, 120.8, 120.0, 118.9, 110.4,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
05.3, 52.7 (2C), 47.0, 27.4 (2C), 17.0. HRMS (ESI ): m/z calcd for C H NBr: 328.0695 [M+H] ; found
18
19
28.0696.
4-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)morpholine (2h): Eluent for flash chromatography (PE/EA = gradiꢀ
1
ent up to 95:5, R =0.15) providing 2h as a yellow solid (71 mg, 0.20 mmol, 72 %). HꢀNMR (200 MHz, CDCl , δ):
f
3
3
4
4
3
4
7
1
1
.40ꢀ7.31 (m, 3H), 7.21 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.69 (dd, J=8.0 Hz, J=2.0 Hz,
3
3
13
H), 3.71 (t, J=5.0 Hz, 4H), 3.05 (t, J=5.0 Hz, 4H), 1.26 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.4, 154.9,
3
51.6, 138.4, 130.6, 130.1, 126.0, 120.9, 120.6, 119.7, 114.8, 110.1, 67.0 (2C), 49.8 (2C), 47.2, 27.4 (2C). HRMS
+
+
(
ESI ): m/z calcd for C H NOBr: 358.0801 [M+H] ; found 358.0804. Mp: 165ꢀ167 °C.
19 21
6d
7-bromo-N,N-diethyl-9,9-dimethyl-9H-fluoren-2-amine (2i): Reaction performed on 1 gram scale (2.84
mmol). Eluent for flash chromatography (PE/Et O = gradient up to 98/2, R = 0.35) providing 2i as a yellow solid
2
f
1
3
(606 mg, 1.76 mmol, 62 %). HꢀNMR (200 MHz, CDCl , δ): 7.54ꢀ7.40 (m, 4H), 6.69ꢀ6.65 (m, 2H), 3.43 (q, J=7.0
3
3
13
Hz, 4H), 1.45 (s, 6H), 1.22 (t, J=7.0 Hz, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.3, 154.9, 148.1, 139.1, 129.9,
3
+
.
125.8, 121.2, 119.8, 118.4, 111.0, 105.7, 47.0, 44.9 (2C), 27.5 (2C), 12.7 (2C). GCꢀMS (m/z): 343.1 [M] . Mp:
142ꢀ144 °C.
7-bromo-9,9-dimethyl-N-phenyl-9H-fluoren-2-amine (2j): Reaction performed on 1 gram scale (2.84
mmol). Eluent for flash chromatography (PE/DCM = gradient up to 9/1, R = 0.13) providing 2j as a yellow solid
f
1
(
848 mg, 2.33 mmol, 82 %). HꢀNMR (200 MHz, CDCl , δ): 7.62ꢀ7.41 (m, 4H), 7.37ꢀ7.22 (m, 2H), 7.16ꢀ6.95 (m,
3
13
5
1
3
H), 1.47 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.3, 155.1, 143.1 (2C), 138.4, 131.4, 130.1, 129.5 (2C), 126.0,
3
+
21.3, 121.1, 120.5, 119.7, 118.0 (2C), 116.9, 112.0, 47.1, 27.2 (2C). HRMS (ESI ): m/z calcd for C H NBr:
21
19
+
64.0695 [M+H] ; found 364.0698.
7-bromo-N-butyl-9,9-dimethyl-9H-fluoren-2-amine (2k): Eluent for flash chromatography (PE/Et O = gradient
2
1
up to 99/1, R = 0.11) providing 2k as an amorphous yellow solid (64 mg, 0.18 mol, 67 %). HꢀNMR (200 MHz,
f
3
3
CDCl , δ): 7.56ꢀ7.27 (m, 4H), 6.71ꢀ6.56 (m, 2H), 3.18 (t, J=7.0 Hz, 2H), 1.66 (q, J=7.0 Hz, 2H), 1.52ꢀ1.26 (m,
3
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The Journal of Organic Chemistry
3
13
2
H), 1.43 (s, 6H), 0.98 (t, J=7.0 Hz, 2H). CꢀNMR (50 MHz, CDCl , δ): 155.3, 154.9, 148.7, 140.0, 139.1, 130.0,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+.
1
25.9, 121.2, 119.9, 118.8, 112.0, 106.9, 47.0, 44.2, 31.8, 27.4 (2C), 20.5, 14.1. GCꢀMS (m/z): 343.1 [M] .
Synthesis of 3a-e: General procedure for the Buchwald-Hartwig diamination (GP-B): Pd(OAc) (8 mol%),
2
tꢀBuONa (2.2 eq.), and JohnPhos (24 mol%) were added to a previouslyꢀdried reaction tube containing a magnetꢀ
ic bar. The tube was purged with argon for 3 cycles using Schlenk technique. The mixture was dissolved in toluꢀ
ene (0.1 M) and stirred for 15 min at rt under argon. Then, the dibromo aryl reagent (1 eq.) was added and folꢀ
lowed by 15 mins further stirred for 15 mins (at rt or 100 °C for better activation). Finally, the amine (liquid or disꢀ
solved in toluene) (2.2 eq.) was added, and the reaction mixture was irradiated in the microwave oven at 300 W/
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
80 °C for 1 h (or classically heated at 100 °C in an oil bath overnight for thermal activation). The reaction was
monitored by TLC and GCMS until complete conversion. The resulting mixture was cooled down to room temperꢀ
®
ature, diluted by CH Cl , and filtered over a pad of Celite . The volatiles were removed under reduced pressure,
2
2
and the residue was purified by silica gel column chromatography to give the desired product. 3aꢀe series of
products was prepared on 100 mg scale (0.28 mmol).
2
7
2
7
N ,N ,9,9-tetramethyl-N ,N -diphenyl-9H-fluorene-2,7-diamine (3a): Eluent for flash chromatography
1
(
PE/Et O = gradient up to 98:2, R = 0.25) providing 3a as a yellow solid (101 mg, 0.25 mmol, 89 %). HꢀNMR
2
f
3
3
(
200 MHz, CDCl , δ): 7.49 (d, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 4H), 7.08 (br s, 2H), 6.99ꢀ6.95 (m, 6H), 6.90ꢀ
3
13
6
.83 (m, 2H), 3.32 (s, 6H), 1.37 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.0 (2C), 149.4 (2C), 147.8 (2C), 133.5
3
(
(
2C), 129.3 (4C), 120.8 (2C), 120.4 (2C), 120.1 (2C), 119.1 (4C), 116.2 (2C), 47.0, 40.8 (2C), 27.4 (2C). HRMS
+
+
ESI ): m/z calcd for C H N : 405.2325 [M+H] ; found 405.2321. Mp: 143ꢀ145 °C.
29
29
2
1
,1'-(9,9-dimethyl-9H-fluorene-2,7-diyl)di-1H-pyrrole (3b): Eluent for flash chromatography (PE/Et O = graꢀ
2
1
dient up to 98:2, R = 0.26) providing 3b as a yellow solid (70 mg, 0.22 mmol, 78 %). HꢀNMR (200 MHz, CDCl ,
f
3
3
4
3
4
δ): 7.73 (d, J=8.0 Hz, 2H, H4,5), 7.45 (d, J=2.0 Hz, 2H, H1,8), 7.39 (dd, J=8.0 Hz, J=2.0 Hz, 2H, H3,6), 7.16 (t,
3
3
13
J=2.0 Hz, 4H, NCHpyr), 6.39 (t, J=2.0 Hz, 4H, CHpyr), 1.55 (s, 6H, 2CH ). CꢀNMR (50 MHz, CDCl , δ): 155.3
3
3
(2C, Ca,b), 140.3 (2C, C2,7), 136.3 (2C, Cc,d), 120.9 (2C, C4,5), 120.1 (2C, C3,6), 119.8 (4C, N(CHpyr)), 115.5
+
+
(2C, C1,8), 110.5 (4C, CHpyr), 47.4 (C9), 27.3 (2CH ). HRMS (ESI ): m/z calcd for C H N : 325.1699 [M+H] ;
3
23 21
2
found 325.1700. Mp: 265ꢀ267 °C.
,1'-(9,9-dimethyl-9H-fluorene-2,7-diyl)dipyrrolidine (3c): Eluent for flash chromatography (PE/EA = gradient
1
1
1
up to 98:2, R = 0.38) providing 3c as a yellow solid (55 mg, 0.16 mmol, 59 %). HꢀNMR (200 MHz, TFAꢀd , δ):
f
3
4
3
4
8
.02 (d, J=8.5 Hz, 2H, H4,5), 7.88 (d, J=2.0 Hz, 2H, H1,8), 7.58 (dd, J=8.5 Hz, J=2.0 Hz, 2H, H3,6), 4.26 (br t,
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3
3
13
J=5.0 Hz, 4H, N(CH ) ), 3.79 (br t, J=5.0 Hz, 4H, N(CH ) ), 2.51 (m, 8H, 2N(CH CH ) ), 1.58 (s, 6H, 2CH ). Cꢀ
2
2
2 2
2
2 2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
NMR (50 MHz, TFA-d , δ): 159.5 (2C, Ca,b), 142.3 (2C, Cc,d), 141.8 (2C, C2,7), 124.9 (2C, C4,5), 122.2 (2C,
+
C3,6), 117.5 (2C, C1,8), 62.6 (4C, N(CH )), 50.5 (C9), 27.4 (2CH ), 25.7 (4C, N(CH CH )). HRMS (ESI ): m/z
2
3
2
2
+
calcd for C H N : 333.2321 [M+H] ; found 333.2325. Mp: 162ꢀ164 °C.
23
29
2
4,4'-(9,9-dimethyl-9H-fluorene-2,7-diyl)dimorpholine (3d): Eluent for flash chromatography (PE/EA= gradient
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
up to 9:1, R =0.16) providing 3d as a yellow solid (74 mg, 0.20 mmol, 73 %). HꢀNMR (200 MHz, CDCl , δ): 7.52
f
3
3
4
3
4
3
(
d, J=8.0 Hz, 2H, H4,5), 6.97 (d, J=2.0 Hz, 2H, H1,8), 6.87 (dd, J=8.0 Hz, J=2.0 Hz, 2H, H3,6), 3.90 (t, J=5.0
3
13
Hz, 8H, 2O(CH ) ), 3.21 (t, J=5.0 Hz, 8H, 2N(CH ) ), 1.45 (s, 6H, 2CH ). CꢀNMR (50 MHz, CDCl , δ): 154.7
2
2
2 2
3
3
(
(
2C), 150.5 (2C), 132.2 (2C), 119.8 (2C), 114.8 (2C), 110.7 (2C), 67.2 (4C), 50.3 (4C), 47.0, 27.8 (2C). HRMS
+
+
ESI ): m/z calcd for C H O N : 365.2224 [M+H] ; found 365.2226. Mp: 232ꢀ234 °C.
23
29
2
2
2
2
7
7
N ,N ,N ,N -tetraethyl-9,9-dimethyl-9H-fluorene-2,7-diamine (3e): Eluent for flash chromatography (PE/EA =
1
gradient up to 98:2, R = 0.34) providing 3e as a yellow solid (57 mg, 0.61 mmol, 61 %). HꢀNMR (500 MHz, TFAꢀ
f
1
3
3
d , δ): 8.14 (d, J=8.0 Hz, 2H, H4,5), 7.70 (s, 2H, H1,8), 7.58 (br d, J=8.0 Hz, 2H, H3,6), 3.92 (m, 4H, 2CH ), 3.81
2
3
13
1
(
(
(
m, 4H, 2CH ), 1.66 (s, 6H, 2CH ), 1.34 (t, 12H, J=8.0 Hz, (CH CH ) ). CꢀNMR (125 MHz, TFAꢀd , δ): 159.9
2
3
2
3 4
2C), 142.6 (2C), 138.5 (2C), 125.6 (2C), 123.5 (2C), 118.6 (2C), 58.2 (2C), 50.6, 27.9 (2C), 11.4 (2C). GCꢀMS
+
.
+
+
m/z): 336.3 [M] . HRMS (ESI ): m/z calcd for C H N : 337.2638 [M+H] ; found 337.2639. Mp: 130ꢀ132 °C.
23
33
2
Synthesis of 4a-h: General procedure for the sequential C-N/C-N and C-N/Stille unsymmetrical cou-
plings. General procedure GPꢀA was carried out, the monoꢀaminated bromoaromatic product was isolated. The
pure product was subjected to GPꢀA using another nucleophile (amine for a second BuchwaldꢀHartwig coupling
or tributylvinyl tin for subsequent Stille coupling).
Procedure for sequential one-pot (GP-C): Pd(OAc) (4 mol%), tꢀBuONa (1.1 eq.), and BINAP (12 mol%)
2
were added to a previouslyꢀdried reaction tube containing a magnetic bar. The tube was purged with argon for 3
cycles using Schlenk technique. The mixture was dissolved in toluene (0.1 M) and stirred for 15 min at rt under
argon. Then, the dibromo aryl reagent (1 eq.) was added followed by 15 min further stirring (at rt or 100 °C for
better activation). Finally, the amine (liquid or dissolved in toluene) (1.1 eq.) was added, and the reaction mixture
was heated at 100 °C in an oil bath. The reaction was monitored by TLC and GCMS until diaminated product
started to appear (between 12ꢀ16 h). Then, another loading of the catalytic system (4 mol% [Pd]/ 12 mol% L/ 1.1
eq. tꢀBuONa) was reꢀadded followed by excess of second nucleophile (2 eq.). The final mixture was stirred at 100
°
C overnight and monitored by TLC and GCMS until complete conversion. The reaction was cooled down to room
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temperature, diluted by CH Cl , and filtered over a pad of Celite . The volatiles were removed under reduced
2
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pressure, and the residue was purified by silica gel column chromatography to give the desired product.
1-(9,9-dimethyl-7-vinyl-9H-fluoren-2-yl)piperidine (4a): Eluent for flash chromatography (PE/EA = gradient up
1
to 95:5, R = 0.71) providing 4a as a yellow solid (52 mg, 0.17 mmol, 62 %). HꢀNMR (200 MHz, CDCl , δ): 7.59
f
3
3
3
3
4
4
(
d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.47 (br s, 1H), 7.36 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 7.04 (d, J=2.0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
3
3
3
Hz, 1H), 6.94 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 6.82 (dd, J =17.5 Hz, J =11.0 Hz, 1H), 5.80 (d, Jtrans=17.5 Hz,
trans
cis
3
3
13
1
H), 5.24 (d, J =11.0 Hz, 1H), 3.25 (t, J=5.5 Hz, 4H), 1.78 (br m, 4H), 1.65 (br m, 2H), 1.50 (s, 6H). CꢀNMR
cis
(
50 MHz, CDCl , δ): 155.4, 153.6, 152.4, 139.6, 137.5, 135.3, 130.6, 125.7, 120.7, 120.1, 119.1, 115.5, 112.4,
3
+
+
1
11.1, 51.3 (2C), 46.8, 27.6 (2C), 26.1 (2C), 24.4. HRMS (ESI ): m/z calcd for C H N: 304.2061 [M+H] ; found
22 26
304.2060.
1-(9,9-dimethyl-7-vinyl-9H-fluoren-2-yl)pyrrolidine (4b): Eluent for flash chromatography (PE/EA = gradient
1
up to 95:5, R = 0.7) providing 4b as a yellow solid (43 mg, 0.15 mmol, 54 %). HꢀNMR (200 MHz, CDCl , δ): 7.54
f
3
3
4
3
3
(
m, 2H), 7.43 (br s, 1H), 7.33 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 6.78 (dd, J =17.0 Hz, J =11.0 Hz, 1H), 6.60 (d,
trans cis
4
3
4
3
3
J=2.0 Hz, 1H), 6.56 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 5.75 (d, J =17.0 Hz, 1H), 5.20 (d, J =11.0 Hz, 1H), 3.38
trans
cis
3
13
(
t, J=6.5 Hz, 4H), 2.04 (m, 4H), 1.48 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 156.0, 153.1, 148.1, 140.3, 137.8,
3
134.5, 126.9, 125.7, 121.1, 119.9, 118.4, 112.0, 110.8, 105.6, 48.1 (2C), 46.7, 27.7 (2C), 25.7 (2C). HRMS
+
+
(
ESI ): m/z calcd for C H N: 290.1903 [M+H] ; found 290.1903.
21 24
1
1-(9,9-dimethyl-7-vinyl-9H-fluoren-2-yl)-1H-pyrrole (4c): yellow solid (60 mg, 0.21 mmol, 76 %). HꢀNMR
3
3
(200 MHz, CDCl , δ): 7.74 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.45ꢀ7.36 (m, 3H), 7.17 (t,
3
3
3
3
J=2.0 Hz, 2H), 6.83 (dd, Jtrans=17.0 Hz, J =11.0 Hz, 1H), 6.40 (t, J=2.0 Hz, 2H), 5.84 (d, Jtrans=17.0 Hz, 1H),
cis
3
13
5
.30 (d, J =11.0 Hz, 1H), 1.54 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.6, 154.1, 140.3, 138.4, 137.2, 136.9,
cis
3
+
136.8, 125.9, 121.0, 120.4, 120.1, 119.9, 119.8 (2C), 115.5, 113.5, 110.5 (2C), 47.0, 27.5 (2C). HRMS (ESI ):
+
m/z calcd for C H N: 286.1591 [M+H] ; found 286.1590. Mp: 175ꢀ177 °C.
21
20
9,9-dimethyl-N-phenyl-7-vinyl-9H-fluoren-2-amine (4e): Eluent for flash chromatography (PE/DCM = gradient
1
up to 9/1, R = 0.28) providing 4e as a yellow solid (60 mg, 0.19 mmol, 69 %). HꢀNMR (200 MHz, CDCl , δ): 7.48
f
3
3
(
d, J=8.0 Hz, 2H), 7.36 (s, 1H), 7.29ꢀ7.13 (m, 3H), 7.06ꢀ6.92 (m, 4H), 6.90ꢀ6.62 (m, 2H), 5.73 (br s, 1H, NH),
3
3
13
5
1
1
.69 (d, J =17.0 Hz, 1H), 5.15 (d, J =11.0 Hz, 1H), 1.38 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.8, 153.6,
trans
cis
3
43.4, 142.7, 139.3, 137.4, 135.7, 132.4, 129.6 (2C), 125.8, 121.1, 121.0, 120.2, 119.2, 117.8 (2C), 117.0, 112.8,
+
+
12.4, 46.8, 27.4 (2C). HRMS (ESI ): m/z calcd for C H N: 312.1747 [M+H] ; found 312.1747.
2
3
22
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N,N-diethyl-9,9-dimethyl-7-(piperidin-1-yl)-9H-fluoren-2-amine (4f): Eluent for flash chromatography
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
(
PE/Et O = 99:1, R =0.12) providing 4f as a yellow solid (41 mg, 0.12 mmol, 43 %). HꢀNMR (200 MHz, TFAꢀd ,
2
f
δ): 8.05ꢀ7.98 (m, 2H), 7.68ꢀ7.46 (m, 4H), 3.99ꢀ3.77 (m, 4H), 3.75ꢀ3.61 (m, 4H), 2.25ꢀ2.04 (m, 4H), 1.55 (s, 6H),
13
1
.28ꢀ1.25 (m, 8H). CꢀNMR (125 MHz, TFAꢀd, δ): 159.9, 159.4, 143.7, 142.6, 142.2, 138.3, 125.4, 125.2, 123.3,
+
1
22.1, 118.4, 117.2, 61.2 (2C), 57.7 (2C), 50.4, 27.3 (2C), 25.9 (2C), 22.9, 11.4 (2C). HRMS (ESI ): m/z calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
C H N : 349.2638 [M+H] ; found 349.2638.
24
33
2
9,9-dimethyl-7-morpholino-N-phenyl-9H-fluoren-2-amine (4g): Eluent for flash chromatography (PE/EA =
1
gradient up to 9:1, R =0.22) providing 4g as a yellow solid (62 mg, 0.18 mmol, 60 %). HꢀNMR (200 MHz, CDCl ,
f
3
3
3
3
3
δ): 7.49 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.28ꢀ6.82 (m, 9H), 3.87 (t, J=5.0 Hz, 4H), 3.18 (t, J=5.0 Hz,
13
4
H), 1.41 (s, 6H). CꢀNMR (50 MHz, CDCl , δ): 155.0, 154.7, 150.6, 143.9, 141.5, 133.2, 132.1, 129.5 (2C),
3
+
1
20.6, 120.0, 119.9, 117.6, 117.3 (2C), 114.8, 113.1, 110.7, 67.2 (2C), 50.2 (2C), 47.0, 27.6 (2C). HRMS (ESI ):
+
m/z calcd for C H ON : 371.2118 [M+H] ; found 371.2120. Mp: 160ꢀ162 °C.
25
27
2
Desymmetrization of dibromoaromatics. All the series of products (5a-f, 6a-f and 7a-b) were prepared on
100 mg scale.
7-bromo-N,N-diethylnaphthalen-2-amine (5a): Following GP-A. Eluent for flash chromatography (PE/Et O =
2
1
gradient up to 98:2, R =0.49) providing 5a as a yellow solid (70 mg, 0.25 mmol, 72 %). HꢀNMR (200 MHz,
f
3
3
3
4
CDCl , δ): 7.76 (br s, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5 Hz, J=2.0 Hz, 1H),
3
3
4
4
3
3
13
7
.08 (dd, J=9.0 J=2.5 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 3.45 (q, J=7.0 Hz, 4H), 1.22 (t, J=7.0 Hz, 6H). Cꢀ
NMR (50 MHz, CDCl , δ): 146.5, 136.8, 129.2, 129.0, 127.8, 124.7, 124.6, 120.4, 116.1, 104.2, 44.7 (2C), 12.8
3
+
+
(
2C). HRMS (ESI ): m/z calcd for C H NBr: 278.0539 [M+H] ; found 278.0542.
14 17
1
-(7-bromonaphthalen-2-yl)-1H-pyrrole (5b): Following GP-A. Eluent for flash chromatography (PE/Et O =
2
1
gradient up to 98:2, R =0.54) providing 5b as a yellow solid (79 mg, 0.29 mmol, 83 %). HꢀNMR (200 MHz,
f
3
3
3
CDCl , δ): 7.87 (br s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.56 (s, 1H), 7.47 (dd, J=8.5 Hz,
3
4
3
4
13
J=2.0 Hz, 1H), 7.42 (dd, J=8.5 J=2. Hz, 1H), 7.10 (t, J=2.0 Hz, 2H), 6.32 (t, J=2.0 Hz, 2H). CꢀNMR (50 MHz,
CDCl , δ): 139.1, 135.1, 129.8, 129.7 (2C), 129.5, 129.0, 121.3, 120.5, 119.5 (2C), 116.3, 111.1 (2C). HRMS
3
+
+
(
ESI ): m/z calcd for C H NBr: 272.0069 [M+H] ; found 272.0070.
14 11
2
2
7
7
N ,N ,N ,N -tetraethylnaphthalene-2,7-diamine (5c): Following GP-B. Eluent for flash chromatography (PE/EA
1
=
gradient up to 95:5, R =0.29) providing 5c as a yellow solid (62 mg, 0.23 mmol, 65 %). HꢀNMR (200 MHz,
f
1
3
3
3
TFAꢀd , δ): 8.30 (d, J=9.0 Hz, 2H, H4,5), 8.20 (s, 2H, H1,8), 7.73 (d, J=9.0 Hz, 2H, H3,6), 3.85 (q, J=6.5 Hz,
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3
13
1
8
1
2
H, 4CH ), 1.23 (t, J=6.5 Hz, 12H, 4CH ). CꢀNMR (50 MHz, TFAꢀ d , δ): 137.8 (2C), 136.5, 134.9 (2C), 134.8,
2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
25.3 (2C), 121.5 (2C), 57.4 (4C), 11.3 (4C). HRMS (ESI ): m/z calcd for C H N : 271.2169 [M+H] ; found
18
27
2
71.2170. Mp: 120ꢀ122 °C.
(
naphthalene-2,7-diyl)di-1H-pyrrole (5d): Following GP-B. Eluent for flash chromatography (PE/EA = gradient
1
up to 95:5, R =0.5) providing 5d as a yellow solid (73 mg, 0.28 mmol, 81 %). HꢀNMR (200 MHz, CDCl , δ): 7.81
f
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
4
(
d, J=9.0 Hz, 2H, H4,5), 7.68 (br s, 2H, H1,8), 7.47 (dd, J=9.0 Hz, J=2.0 Hz, 2H, H3,6), 7.15 (t, J=2.0 Hz, 4H,
13
NCHpyr), 6.33 (t, J=2.0 Hz, 4H, CHpyr). CꢀNMR (50 MHz, CDCl , δ): 139.3 (2C), 134.6, 129.6 (2C), 129.4,
3
+
.
1
19.9 (2C), 119.6 (4C), 117.0 (2C), 111.0 (4C). GCꢀMS (m/z): 258.1 [M] . Mp: 205ꢀ207 °C.
4-(7-(1H-pyrrol-1-yl)naphthalen-2-yl)morpholine (5e): Following GP-C. Eluent for flash chromatography
1
(
PE/EA = gradient up to 95:5, R =0.13) providing 5e as a yellow solid (62 mg, 0.22 mmol, 64 %). HꢀNMR (200
f
3
3
4
3
MHz, CDCl , δ): 7.79 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.5 Hz,
3
4
3
3
3
J=2.0 Hz, 1H), 7.26 (m, 1H), 7.23 (t, J=2.0 Hz, 2H), 7.13 (br s, 1H), 6.41 (t, J=2.0 Hz, 2H), 3.94 (t, J=5.0 Hz,
3
13
4H), 3.30 (t, J=5.0 Hz, 4H). CꢀNMR (50 MHz, CDCl , δ): 150.1, 138.9, 135.2, 129.2, 128.8, 126.6, 119.7 (2C),
3
+
118.5, 117.8, 116.5, 110.6 (2C), 109.7, 67.0 (2C), 49.6 (2C). HRMS (ESI ): m/z calcd for C H ON : 279.1492
18
19
2
+
[M+H] ; found 279.1494. Mp: 182ꢀ184 °C.
18
6
-bromo-N,N-dibutylpyridin-2-amine (6a): Following GP-A. Eluent for flash chromatography (CyHex, R =
f
1
0
.21) providing 6a as an amorphous yellow solid (98 mg, 0.34 mmol, 88 %). HꢀNMR (200 MHz, CDCl , δ): 7.18
3
3
3
3
3
(
t, J=8.0 Hz, 1H, H4), 6.58 (d, J=8.0 Hz, 1H, H5), 6.29 (d, J=8.0 Hz, 1H, H3), 3.39 (t, J=7.5 Hz, 4H, N(CH ) ),
2 2
3
3
13
1
.55 (quint, J=7.5 Hz, 4H, N(CH CH ) ), 1.43ꢀ1.25 (m, 4H, (CH CH ) ), 0.95 (t, J=7.0 Hz, 6H, 2CH ). CꢀNMR
2 2 2 3 2 2 3
(
50 MHz, CDCl , δ): 156.8, 140.4, 139.0, 113.5, 103.7, 48.4 (2C), 29.7 (2C), 20.3 (2C), 14.1 (2C). GCꢀMS (m/z):
3
+.
2
86.1 [M+2] .
19
6
-bromo-N,N-diethylpyridin-2-amine (6b): Following GP-A. Eluent for flash chromatography (PE/DCM =
1
gradient up to 9:1, R = 0.5) providing 6b as an amorphous yellow solid (84 mg, 0.36 mmol, 94 %). HꢀNMR (200
f
3
3
3
3
MHz, CDCl , δ): 7.10 (t, J=8.0 Hz, 1H, H4), 6.50 (d, J=8.0 Hz, H5), 6.23 (d, J=8.0 Hz, 1H, H3), 3.36 (q, J=7.0
3
3
13
Hz, 4H, 2CH ), 1.06 (t, J=7.0 Hz, 6H, 2CH ). CꢀNMR (50 MHz, CDCl , δ): 157.5, 140.4, 139.1, 113.6, 103.6,
2
3
3
+
.
4
2.5 (2C), 12.8 (2C). GCꢀMS (m/z): 230.1 [M+2] .
2
2
6
6
20
N ,N ,N ,N -tetraethylpyridine-2,6-diamine (6c): Following GP-B. Eluent for flash chromatography (PE/Et O
2
1
= gradient up to 98:2, R =0.67) providing 6c as an amorphous yellow solid (69 mg, 0.31 mmol, 80 %). HꢀNMR
f
3
3
3
(200 MHz, CDCl , δ): 7.23 (t, J=8.0 Hz, 1H, H4), 5.72 (d, J=8.0 Hz, 2H, H3,5), 3.47 (q, J=7.0 Hz, 8H, 4CH ),
3
2
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3
13
1
.16 (t, J=7.0 Hz, 12H, 4CH ). CꢀNMR (50 MHz, CDCl , δ): 156.8 (2C, C2,6), 138.4 (C4), 91.9 (2C, C3,5), 42.5
3
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+.
(
4C, NCH ), 13.4 (4C, 4CH ). GCꢀMS (m/z): 222.2 [M] .
2 3
7c
2
,6-di(pyrrolidin-1-yl)pyridine (6d): Following GP-B. Eluent for flash chromatography (PE/Et O = gradient
2
1
up to 95/5, R = 0.47) providing 6d as an amorphous yellow solid (70 mg, 0.32 mmol, 83 %). HꢀNMR (200 MHz,
f
3
3
3
CDCl , δ): 7.25 (t, J=8.0 Hz, 1H, H4), 5.64 (d, J=8.0 Hz, 2H, H3,5), 3.43 (t, J=6.5 Hz, 8H, 2N(CH ) ), 1.95 (q,
3
2 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
13
J=6.5 Hz, 8H, 2N(CH CH ) ). CꢀNMR (50 MHz, CDCl , δ): 157.0 (2C, C2,6), 138.1 (C4), 93.1 (2C, C3,5), 46.5
2
2 2
3
+
.
(
4C, NCH ), 25.7 (4C, CH ). GCꢀMS (m/z): 217.2 [M] .
2 2
N,N-dibutyl-6-morpholinopyridin-2-amine (6e): Following GP-C. Eluent for flash chromatography (PE/Et O =
2
1
gradient up to 9:1, R = 0.48) providing 6e as an amorphous yellow solid (108 mg, 0.27 mmol, 71 %). HꢀNMR
f
3
3
3
(200 MHz, CDCl , δ): 7.28 (t, J=8.0 Hz, 1H, H4), 5.86 (d, J=8.0 Hz, 2H, H3), 5.84 (d, J=8.0 Hz, 2H, H5), 3.81 (t,
3
3
3
3
J=5.0 Hz, 4H, (CH ) O), 3.44 (t, J=5.0 Hz, 4H, (CH ) N
), 3.38 (t, J=7.5 Hz, 4H, N(CH ) ), 1.57 (quint,
2
2
2 2 morph
2 2
3
3
13
J=7.5 Hz, 4H, N(CH CH ) ), 1.33 (m, 4H, (CH CH ) ), 0.94 (t, J=7.5 Hz, 6H, 2CH ). CꢀNMR (50 MHz, CDCl3,
2
2 2
3
2 2
3
+
δ): 158.7, 156.9, 138.7, 95.4, 92.9, 67.0 (2C), 48.7 (2C), 45.8 (2C), 30.1 (2C), 20.5 (2C), 14.2 (2C). HRMS (ESI ):
+
m/z calcd for C H ON : 292.2383 [M+H] ; found 292.2384.
17
30
3
5
-bromo-N,N-diphenylthiophen-2-amine (7a): Following GP-A. Eluent for flash chromatography (PE/Et O =
2
1
gradient up to 99/1, R = 0.55) providing 7a as an amorphous yellow solid (72 mg, 0.22 mmol, 54 %). HꢀNMR
f
13
(
200 MHz, CDCl , δ): 7.40ꢀ7.33 (m, 5H), 7.23ꢀ7.01 (m, 7H). CꢀNMR (50 MHz, CDCl , δ): 146.5, 129.4, 129.3,
3
3
+
.
1
23.6, 123.0, 121.9, 108.8. GCꢀMS (m/z): 330.2 [M+2] .
2
5
2
5
N ,N -dimethyl-N ,N -diphenylthiophene-2,5-diamine (7b): Following GP-B. 7b as an amorphous yellow solꢀ
1
3
4
id (50 mg, 0.17 mmol, 42 %). HꢀNMR (200 MHz, CDCl , δ): 7.20 (dd, J=7.5 Hz, J=2.0 Hz, 2H, Hphenyl), 6.95ꢀ
3
4
13
6
.82 (m, 8H, Hphenyl), 6.62 & 6.61 (d each, J=1.5 Hz, 2H, Hthiophene), 3.31 (s, 6H, 2CH ). CꢀNMR (50 MHz,
3
CDCl , δ): 153.7 (C2, C5), 149.4 (2CꢀiꢀPh), 129.1 (4CꢀmꢀPh), 125.9, 120.0 (CꢀpꢀPh), 119.6 (CꢀpꢀPh), 118.8,
3
+
.
1
16.4, 42.1 (2CH ). GCꢀMS (m/z): 294.1 [M+2] .
3
7-(benzo[c][1,2,5]thiadiazol-5-yl)-9,9-dimethyl-N-phenyl-9H-fluoren-2-amine (8):
This procedure requires the preparation of two reactions in two previously-dried tubes.
First tube: Pd(OAc) (3 mg, 0.011 mmol, 4 mol%), tꢀBuONa (30 mg, 0,32 mmol, 1.1 eq.), and BINAP (21 mg,
2
0
,034 mmol, 12 mol%) were added to a previouslyꢀdried reaction tube containing a magnetic bar. The tube was
purged with argon for 3 cycles using Schlenk technique. The mixture was dissolved in 3 mL of toluene (0.1 M)
and stirred for 15 min at rt under argon. Then, dibromofluorene 1 (100 mg, 0,287 mmol, 1.0 eq.) was added folꢀ
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lowed by 15 min further stirring at 100 °C. Finally, aniline (30 mg, 0,32 mmol, 1.1 eq.) was added, and the reacꢀ
tion mixture was heated at 100 °C in an oil bath. The reaction was monitored by TLC and GCMS until bisꢀ
aminated product started to appear (14 h).
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9
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Second tube: Pd(OAc) (4 mg, 0,017 mmol, 4 mol% relative to 1.5 eq. of 5ꢀbromoꢀ2,1,3ꢀbenzothiadiazole), tꢀ
2
BuONa (45 mg, 0,47 mmol, 1.1 eq.), and BINAP (32 mg, 0,051 mmol, 12 mol%) were added to a previouslyꢀdried
reaction tube containing a magnetic bar. The tube was purged with argon for 3 cycles using Schlenk technique.
The mixture was dissolved in 4 mL of toluene (0.1 M) and stirred for 15 min at rt under argon. Then, 5ꢀbromoꢀ
0
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2
3
4
5
6
7
8
9
0
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9
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0
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9
0
2,1,3ꢀbenzothiadiazole (92 mg, 0,43 mmol, 1.5 eq.) was added followed by 15 min further stirring at 100 °C. Finalꢀ
ly, bis(tributyltin) (249 mg, 0,43 mmol, 1.5 eq.) was added, and the reaction mixture was heated at 100 °C in an
oil bath for 4 h. Note: this second reaction tube was prepared around 10 h after the beginning of the first
reaction. Then, another loading of the catalytic system (4 mol% [Pd]/ 12 mol% L/ 1.1 eq. tꢀBuONa) was reꢀadded
to the first reaction tube followed by the content of the second tube (2 eq.). The final mixture was stirred at 100 °C
overnight. The reaction was cooled down to room temperature, quenched with NaOH (1N) and stirred for addiꢀ
tional 30 min. The organic layer was extracted with DCM (2x) and the combined extracts were washed with water
(3x), dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by
flash chromatography on silica gel eluted with CyHex/EA (4/1, v/v) to provide compound 8 (61 mg, 51 %) as a
bright yellow solid. Purification by RPꢀHPLC provided an analytical sample for photophysical characterization;
(apparatus: WatersTM 600 Controller with WatersTM 996 Photodiode Array Detector and Jasco LCꢀNet II / ADC,
®
®
semiꢀpreparative column: Clarity 5ꢁ OligoꢀRP column 250 x 10 mm Phenomenex , flow rate 2.5 mL/min, using
the following gradient system: 25 % A –(5min)→ 5 % A / 95 % B –(25 min)→ 100 % B –(10 min) with A= 0.25
®
1
4
CH CN: 0.75 MilliQ water and B= CH CN. HꢀNMR (500 MHz, CD Cl , δ): 8.24 (d, J=1.0 Hz, 1H), 8.07 (d,
3
3
2
2
3
3
4
4
3
J=8.0 Hz, 1H), 8.01 (dd, J=8.0 Hz, J=1.0 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.31 (t,
3
4
3
4
3
4
J=7.5 Hz, 2H), 7.22 (d, J=1.5 Hz, 1H), 7.15 (dd, J=7.5 Hz, J=1.0 Hz, 2H), 7.08 (dd, J=8.0 Hz, J=1.5 Hz, 1H),
3
13
6.96 (t, J=7.5 Hz, 1H), 1.54 (s, 6H). CꢀNMR (126 MHz, CD Cl , δ): 156.3, 156.1, 154.7, 154.6, 143.7, 143.5,
2
2
143.3, 140.2, 137.6, 131.9, 130.7, 129.8, 127.0, 122.0, 121.7, 121.6, 121.5, 119.9, 118.3, 118.3, 117.0, 112.2,
+
+
47.4, 27.5. HRMS (ESI ): m/z calcd for C H N S: 420.1529 [M+H] ; found 420.1530.
27
22
3
ASSOCIATED CONTENT
Supporting Information
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Page 20 of 21
General methods, characterization (mass and NMR spectra). This material is available free of charge via the Inꢀ
ternet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail for A.B.: burger@unice.fr
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ACKNOWLEDGMENT
This research was supported by the French Government through the Ph.D. grant of J.S., the ANR (ANRꢀ12ꢀ
BS08ꢀ0003ꢀ02), PACA région (DNAfixꢀ2014ꢀ02862 and 2014ꢀ07199), and the FRM (DCM20111223038). We
would like to acknowledge A. R. Martin for the fruitful discussions.
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(
(
(
8) Shaya, J.; FontaineꢀVive, F.; Michel, B. Y.; Burger A. Chem. Eur. J. 2016, DOI: 10.1002/chem.201600581.
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(
(
11) Stevens, A. L.; Kaeser, A.; Schenning, A. P. H. J.; Herz, L. M. ACS Nano 2012, 6, 4777.
12) For related mechanistic considerations, see SI. DFT calculations to explain the selelctivity of BINAP are highly demanding and
are currently taking place in our lab.
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(
(
14) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144.
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(
(
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(
(
19) Agarwal, P. K.; Saifuddin, M.; Kundu, B. Tetrahedron 2010, 66, 862.
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