A site-selective and stereospecific cascade Suzuki-Miyaura annulation of alkyl 1,2-bisboronic esters and 2,2′-dihalo 1,1′-biaryls

Article abstract of DOI:10.1039/d1cc00648g

A cascade Suzuki-Miyaura cross-coupling giving rise to 9,10-dihydrophenanthrenes has been developed. Using biaryls with unsymmetrical substitution-pattern full site-selectivity was observed. Furthermore, this cross-coupling of an alkyl 1,2-bisboronic pinacol ester proceeds through the challenging coupling of a secondary boronate with complete stereoretention.

Full text of DOI:10.1039/d1cc00648g

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A site-selective and stereospecific cascade
Suzuki–Miyaura annulation of alkyl 1,2-bisboronic
Cite this: Chem. Commun., 2021,
57, 3909
esters and 2,20-dihalo 1,10-biaryls†
Received 6th February 2021,
Accepted 9th March 2021
b
Suzanne Willems,a Georgios Toupalas,
Julia C. Reisenbauerb and
ab
Bill Morandi
*
DOI: 10.1039/d1cc00648g
rsc.li/chemcomm
A cascade Suzuki–Miyaura cross-coupling giving rise to 9,10-dihydro- whether these reagents could be successfully employed in site-
phenanthrenes has been developed. Using biaryls with unsymmetrical selective annulation reactions. We reasoned that the direct,
substitution-pattern full site-selectivity was observed. Furthermore, modular synthesis of tricyclic 9,10-dihydrophenanthrenes,
this cross-coupling of an alkyl 1,2-bisboronic pinacol ester proceeds could be achieved using a tailored annulation reaction that
through the challenging coupling of a secondary boronate with com- takes advantage of these reagents. Key to the development of
plete stereoretention.
this reaction would be the high site-selectivity of both cross-
coupling events (Fig. 1) that would, crucially, take advantage of
The Suzuki–Miyaura cross-coupling has found broad use in the matching reaction rates between the two different nucleo-
the synthesis of drugs, agrochemicals, fine chemicals, and philic (11 vs. 21 C–Bpin) and electrophilic (C–Br vs. C–Cl) sites
polymers.1–3 In combination with cascade annulations, in present on the two reagents.
which multiple bonds are formed in a single reaction vessel,
Herein we report the development of a Pd-catalyzed site-
it offers the possibility to rapidly build up molecular complexity, selective and stereospecific cascade annulation of alkyl 1,
limit chemical waste, and improve step-economy.4
2-bisboronic pinacol esters and 2-bromo-20-chloro biaryls.
We entered our studies by identifying a suitable model alkyl
Selected examples of cascade Suzuki–Miyaura cross-coupling
reactions with alkenyl 1,2-bisboronic pinacol esters have been 1,2-bisboronic pinacol ester (Scheme 1). Initial exploration
previously reported for the synthesis of polycyclic aromatic hydro- focused on the use of symmetrical 2,20-dibromobiphenyl 2b, as
carbons (PAH) by Shimizu and Hiyama (Fig. 1).5,6 In addition, this would simplify reaction monitoring and allow rapid identifi-
Wang has reported a cascade annulation with alkyl 1,1-bisboronic cation of promising conditions for this highly challenging annu-
pinacol esters in the synthesis of 9H-fluorenes.7
lation reaction. Using previously reported reaction conditions,19
Alkyl 1,2-bisboronic pinacol esters can be readily accessed in
racemic and stereoselective fashion using transition metal-
catalyzed and organocatalytic approaches.8–17 The Morken
group has reported a Suzuki–Miyaura cross-coupling of the
alkyl 1,2-bisboronic pinacol esters in which either the primary
or secondary position can be selectively functionalized (Fig. 1).18,19
However, despite their facile synthesis and intriguing site-selective
reactivity, these reagents have not yet been evaluated in cascade
annulation reactions.
Given the straightforward access and site-selective reactivity
of the stable alkyl 1,2-bisboronic pinacol esters, we questioned
a
¨
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1,
¨
Mulheim an der Ruhr 45470, Germany
b
¨
¨
Laboratorium fur Organische Chemie ETH Zurich, Vladimir-Prelog-Weg 3,
¨
HCI, Zurich 8093, Switzerland. E-mail: morandib@ethz.ch
† Electronic supplementary information (ESI) available. CCDC 2054485. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1cc00648g
Fig. 1 Reaction design of
based on alkyl 1,2-bisboronic pinacol esters.
a cascade Suzuki–Miyaura cross-coupling
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might release hydroxide ions more gradually as compared to
potassium hydroxide due to its lower solubility.26
Having optimized the reaction conditions, we next investi-
gated whether we could verify the central hypothesis of this
work, namely that the two unsymmetrically substituted
reagents can undergo a site-selective cross-coupling reaction.
In an attempt to observe a single regioisomer, we used
unsymmetrically substituted biaryls and performed an annula-
tion with alkyl 1,2-bisboronic pinacol esters (Scheme 2). Excitingly,
introduction of a Me- or F-substituent on the biaryl substrate
indeed led to a single regioisomer (3b–3i). Additionally, an
electron-poor mono CF3-substituted biaryl and an electron-rich
methoxy-substituted biaryl also gave the corresponding products
with high regioselectivity (3j, 3k). We rationalize this selectivity with
the different reaction rates of the reactive centers in both bifunc-
tional reagents (11 vs. 21 C–Bpin, C–Br vs. C–Cl). Initially, a C–C
bond between the primary C–Bpin and Ar–Br is formed, followed
by the intramolecular cyclization between the secondary C–Bpin
and Ar–Cl.
Biaryls with a symmetric substitution pattern (3l, 3m)
were also well tolerated. An attempt to cyclize 2,20-dibromo-1,
10-binaphtalene did not afford any annulated product. The ability
to rotate freely around the biaryl bond might therefore be crucial
to the efficiency of the second coupling step. Furthermore, an
extension to heterocyclic biaryls proved unsuccessful.
Turning our focus to the alkyl 1,2-bisboronic pinacol ester
scope, sterically more encumbered substituents showed good
compatibility with the annulation reaction (3n–s). A dinucleophile
containing a primary chloride (3s) and a eugenol-derivative (3t)
were efficiently converted to the annulated product. Unfortu-
nately, nitrile, ester or ketone functionalities were not tolerated.
Similarly, double secondary, ethane- or methane-derived dinu-
cleophiles did not yield cyclized products. Finally, the model
reaction could be scaled up to a 5 mmol scale yielding 57%
(0.76 g) of the annulated product 3a.
Intrigued by the high efficiency and selectivity of the trans-
formation, we monitored the model reaction more closely. The
chlorinated reaction intermediate 4 could be isolated when
stopping the reaction after three hours (Scheme 3A). In con-
trast, the corresponding brominated intermediate was not
observable. NMR studies showed that compound 4 exists as a
mixture of two atropoisomers that are interconvertible at
elevated temperature (see ESI,† for details). Using the inter-
mediate 4 as a starting material in our reaction, the annulated
product was observed in high yield (Scheme 3A). Interestingly,
using potassium hydroxide as a base gave a comparable con-
version (77%, see ESI†) to the cyclized product in this single-
step, intramolecular coupling reaction. The intramolecular
nature of the coupling between the secondary boronic pinacol
ester and the aryl chloride may be key to facilitate the challenging
secondary cross-coupling. To substantiate this hypothesis, an
intermolecular control reaction was performed. As expected, both
reactions using the corresponding homobenzylic boronic pinacol
ester and either bromobenzene or chlorobenzene did not yield
any of the cross-coupled product (see ESI,† for details). Usually,
the Pd-catalyzed Suzuki–Miyaura cross-coupling of aliphatic,
Scheme 1 Optimization of the annulation reaction using alkyl 1,2-bisboronic
pinacol ester 1a and biaryls 2 to yield 9,10-dihydrophananthrene 3a.
the octyl-1,2-bisboronic pinacol ester 1a only gave trace amounts
of the cyclized product, further highlighting the challenges in
developing such a process. A sequence of experiments allowed us
to find a promising Pd2(dba)3/IPr HCl (1 : 4) catalytic system in
THF which gave 35% of 9-hexyl-9,10-dihydrophenanthrene 3a in
the presence of KOH (Scheme 1 and Table 1, entry 1). We next
explored the reactivity of other electrophilic coupling partners in
the cyclization reaction. 2,20-Dichlorobiphenyl 2c gave a cleaner
reaction and a similar amount of annulated product compared to
the dibromide 2b (entry 1 and 2). In contrast, the diiodide 2d gave
a diminished product yield (entry 3). 2,20-Biphenol derived ditriflate
2e and dimesylate 2f were unreactive and starting materials were
recovered (entry 4 and 5). Combining these preliminary observa-
tions, we envisioned that optimizing conditions for 2-bromo-20-
chloro biphenyl 2a may set the stage for the subsequent develop-
ment of a fully site-selective annulation process.20,21
Excitingly, using 2-bromo-20-chloro biphenyl 2a, the yield
increased to 48% (entry 6). Further optimization showed that
the use of barium hydroxide as a base under more dilute
reaction conditions was crucial to increase the yield of the
double Suzuki–Miyaura to 76% (entry 12). The availability of
hydroxides plays a pivotal role in the efficiency of the Suzuki–
Miyaura cross-coupling as discussed by Amatore and Jutand,22
as well as Hartwig.23 Based on these studies, we postulate that
changing the counterion of the hydroxide-source may increase
the activity of the Pd-catalyst during transmetalation due to
a weaker binding affinity of the barium-compared to the
potassium-counterion.24,25 Furthermore, barium hydroxide
Table 1 Optimization of reaction conditionsa
Entry
Base (x equiv.)
2a–f X1, X2
Solvent/H2O (y : z)
3ab [%]
1
2
3
4
5
6
7
8
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
KOH (3)
Ba(OH)2 (2)
Ba(OH)2 (2)
Ba(OH)2 (2)
Ba(OH)2 (2)
—
Br, Br
Cl, Cl
I, I
THF (10 : 1)
THF (10 : 1)
THF (10 : 1)
THF (10 : 1)
THF (10 : 1)
THF (10 : 1)
THF (1 : 1)
Dioxane (1 : 1)
H2O
35
33
6
4
0
48
70
31
53
76
0
OTf, OTf
OMs, OMs
Br, Cl
Br, Cl
Br, Cl
Br, Cl
Br, Cl
Br, Cl
Br, Cl
9
10c
11c
12cd
THF (4 : 1)
THF (4 : 1)
THF (4 : 1)
Ba(OH)2 (2)
0
a
Reaction conditions: 1a (0.1 mmol),
2 (0.1 mmol), Pd2(dba)3
(0.005 mmol), IPr HCl (0.02 mmol), base (0.2–0.3 mmol), THF/H2O
b
(0.1 mol Lꢀ1), 100 1C, 24 h. GC yield using n-tetradecane as internal
c
d
standard. THF/H2O (0.04 mol Lꢀ1). Without Pd2(dba)3 and IPr HCl.
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Scheme 2 Scope of the double Suzuki–Miyaura cross coupling of alkyl 1,2-bisboronic pinacol esters 1 with 2-bromo-20-chloro biaryls 2 to afford
9,10-dihydrophenanthrenes 3. Yields are for isolated products. See ESI,† for further information.
Scheme 3 Mechanistic studies of the Suzuki–Miyaura annulation reaction. (A) Isolation of the key reaction intermediate 4 and a mono-coupling to the
annulated 9,10-dihydrophenanthrene 3a. (B) Cascade cross-coupling of the enantioenriched alkyl 1,2-bisboronic pinacol ester (S)-1b and
the derivatization to crystallize (S)-5 (CCDC #2054485†): (a) TBAF (2 equiv.), THF, r.t., 3 h, (b) DMP (1.25 equiv.), DCM, 0 1C to r.t., 1.5 h, (c) DNP
(1.2 equiv.), HCl (35% in H2O, 2 equiv.), MeOH, r.t., 24.
chiral coupling reagents is stereospecific.27 Thus, using the 9,10-dihydrophenanthrenes. We have shown that a notoriously
Pt(dba)3/TADDOL-protocol developed by Morken et al. for the challenging cross-coupling of a secondary pinacol boronic ester
enantioselective diborylation of terminal alkenes, we synthesized and the aryl chloride is enabled by the proximity of the reactive
an enantioenriched dinucleophile (S)-1b and performed the sites which plays a key role to the success of this annulation.
annulation reaction (Scheme 3B).9 The product was obtained with Thus, this cascade reaction also suggests a new avenue to
complete enantiospecificity.28 Derivatization and crystallization facilitate the otherwise challenging cross-coupling of secondary
of the major enantiomer after preparative HPLC revealed the aliphatic boron nucleophiles.30
absolute configuration of enantiomer (S)-3n, showing that the
Financial support from the Max-Planck-Gesellschaft and
configuration is retained during the annulation reaction. This Max-Planck-Institut fu¨r Kohlenforschung and ETH Zu¨rich.
result is in accordance with literature precedent showing that Prof. List is acknowledged for sharing analytical equipment
stereoretentive transmetalation is the predominant pathway in and the technical departments of MPI KOFO are acknowledged
this type of cross-coupling reactions.27
for assistance and the ETH D-CHAB small molecule crystal-
In summary, we have reported a site-selective double lography center for single-crystal analysis. G. T. acknowledges a
Suzuki–Miyaura cross-coupling using non-symmetric bifunc- fellowship of the Studienstiftung des deutschen Volkes. J. C. R.
tional reagents. This reaction allows for easy access to twenty acknowledges a fellowship of the Stipendienfonds Schweizer-
different 9,10-dihydrophenanthrenes, a biologically-relevant ische Chemische Industrie (SSCI). We thank the Morandi group
scaffold.29 The high stereospecificity of our annulation reaction members for proof reading of the manuscript. Open Access
shows that it offers a direct access to enantiomerically enriched funding provided by the Max Planck Society.
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