Pd-catalyzed sp-sp3cross-coupling of benzyl bromides using lithium acetylides

Article abstract of DOI:10.1039/d1cc02762j

Organolithium-based cross-coupling reactions have emerged as an indispensable method to construct C-C bonds. These transformations have proven particularly useful for the direct and fast coupling of various organolithium reagents (sp, sp², and sp³) with aromatic (pseudo) halides (sp²). Here we present an efficient method for the cross-coupling of benzyl bromides (sp³) with lithium acetylides (sp). The reaction proceeds within 10 min at room temperature and can be performed in the presence of organolithium-sensitive functional groups such as esters, nitriles, amides and boronic esters. The potential application of the methodology is demonstrated in the preparation of key intermediates used in pharmaceuticals, chemical biology and natural products.

Full text of DOI:10.1039/d1cc02762j

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Pd-catalyzed sp–sp3 cross-coupling of benzyl
bromides using lithium acetylides†
Cite this: Chem. Commun., 2021,
57, 7529
Anirban Mondal,
Ben L. Feringa
Paco Visser,
Anna M. Doze, Jeffrey Buter * and
Received 26th May 2021,
Accepted 28th June 2021
*
DOI: 10.1039/d1cc02762j
rsc.li/chemcomm
Organolithium-based cross-coupling reactions have emerged as an to e.g. organozinc, –boron, –silicon, or –tin reagents. Having success-
indispensable method to construct C–C bonds. These transformations fully tamed the extreme reactivity of organolithium compounds12 in
have proven particularly useful for the direct and fast coupling of various batch reactions, these palladium-catalyzed C–C bond formation reac-
organolithium reagents (sp, sp2, and sp3) with aromatic (pseudo) halides tions proceed fast (5–60 min) with high conversion and selectivity,13
(sp2). Here we present an efficient method for the cross-coupling of and can be performed at room temperature,14 with a nickel catalyst,15
benzyl bromides (sp3) with lithium acetylides (sp). The reaction proceeds without solvent,16 under air,16 on ‘water’,17 at low temperature18 and
within 10 min at room temperature and can be performed in the have found application in stereoselective natural product synthesis.19
presence of organolithium-sensitive functional groups such as esters, Recently, we reported a Sonogashira coupling employing lithium
nitriles, amides and boronic esters. The potential application of the acetylides.20 These reactions proceed at room temperature within
methodology is demonstrated in the preparation of key intermediates 45 min, and display a remarkable functional group tolerance, includ-
used in pharmaceuticals, chemical biology and natural products.
ing organolithium-sensitive functional groups such as esters, nitriles
and boronic esters. Having demonstrated the cross-coupling of
Benzyl alkynes are versatile synthetic intermediates,1 which are lithium acetylides with aryl bromides, we envisioned the development
also found in several natural products,2 pharmaceuticals, poly- of fast and selective methodology for the functionalization of benzyl
meric materials3 and applied in click chemistry.4 Although, at bromides (Scheme 1). Herein, we describe the cross-coupling of a
first sight, alkynylation at the benzylic position appears trivial, variety of benzyl bromides with lithium acetylides, proceeding at
this transformation has proven to be surprisingly challenging room temperature in only ten minutes. Notably, the protocol shows
as exemplified in previous reports showing the necessity of high selectivity and an impressive tolerance towards functional
(i) transition metal-catalyzed cross-coupling of metal-alkynyls;5 groups such as esters, amides, nitriles, and a boronic ester. Further-
(ii) Sonogashira-type coupling using terminal alkynes;6 and more, the versatility of the benzylic alkynes was displayed in the
(iii) direct substitution of benzyl halides with an alkynyl lithium in construction of key intermediates applied in the synthesis of phar-
the presence of the deaggregation agent N,N0-dimethylpropyleneurea maceuticals and natural products.
(DMPU).7 Despite the intrinsic reactivity of both the nucleophile
and electrophile in the latter example, this ‘textbook’ SN2 reaction
required DMPU to proceed.8 This method can therefore not be
applied in the presence of organolithium-sensitive functional
groups due to the enhanced reactivity of organolithium reagents
in the presence of e.g. DMPU, HMPA, TMEDA.9 Following pio-
neering work by Murahashi, on the early development of
organolithium-based cross-coupling reactions,9,10 our group intro-
duced a general methodology for the direct palladium-catalyzed
cross-coupling of organolithium reagents with aryl- and alkenyl
bromides to construct C–C bonds,11 thereby avoiding transmetalation
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
Groningen 9747 AG, The Netherlands. E-mail: j.buter@rug.nl, b.l.feringa@rug.nl
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 (a) Previous approaches towards the transition metal-catalyzed
d1cc02762j
cross-coupling of organometallic acetylenes with benzyl bromides. (b) This work.
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Our investigations started by reacting benzyl bromide, as well addition time of 10 min of the lithium acetylide (see ESI†
as its p-OMe and p-CF3 derivatives, with trimethylsilyl- and Table S1). With a growing incentive to develop more sustain-
tri(isopropyl)-silyl lithium acetylide, using different solvents, which able chemical reactions, in which the amount of waste gener-
in the absence of a transition-metal catalysts were affording only ated is minimized,22 we were also keen to explore whether this
mediocre conversion to 3 (16%, THF after 2 h, see ESI† Table S1). reaction could be performed without the use of additional
Moreover, performing the reaction in N-methyl-2-pyrrolidone solvents. Diminished solvent use could result in a transforma-
(NMP), DMPU, or toluene also did not result in a productive tion with a decreased E-factor.23 Addition of 2a to a mixture of
reaction. These initial observations clearly demonstrated the 1 and Pd[P(tBu)3]2 over 5 min under open-flask conditions
necessity for the development of a catalytic method. Next the provided the desired product 3 with 74% conversion (entry 8).
screening of a series of different Pd-catalysts and varying Increasing the catalyst loading from 5 to 7.5% greatly improved
the addition time of the lithium acetylide 2a (Table 1) was both conversion and selectivity (entry 9).
pursued. Satisfyingly, the use of 5 mol% of oxygen-activated
Although promising in terms of low E-factor, further screening
Pd[P(tBu3)]2,14 a catalyst we previously disclosed to be effective showed that the general applicability was more troublesome,
for the Sonogashira-type cross-coupling of lithium acetylides presumably due to the heterogenic nature of the reaction. With
with aryl bromides,20 resulted in 98% conversion into the the optimized conditions obtained, using [Pd(m-I)PtBu3]2 (3 mol%)
desired product 3 (entry 1). Lowering the addition time from as the catalyst (see ESI† Fig. S1 for the proposed mechanism), we
30 to 15 min retained quantitative conversion, albeit with continued to investigate the general nature of the transformation
slightly lower selectivity (95%, entry 2). Moderate conversion by reacting benzyl bromides bearing different arene substituents
of 44%, paired with a decreased selectivity, was observed when (Scheme 2). During our initial studies, we found that chromato-
we lowered the addition time from 15 to 5 min (entries 2 vs. 3). graphic separation of the desired products from minor amounts of
Next, we investigated the use of [Pd(m-I)PtBu3]2, previously homo-coupling side-products proved to be challenging. However,
reported as an effective catalyst in Kumada-type cross- we discovered that simply switching from lithium (trimethylsilyl)
couplings by Schoenebeck and co-workers.21 Addition of the acetylide 2a to lithium(triisopropylsilyl) acetylide 2b circumvented
lithium acetylide over either 10 or 5 min in the presence of this issue. Hence, we evaluated the generality of the reaction mainly
5 mol% catalyst resulted in near-quantitative conversion with using 2b. Benzyl bromides with various arene substituents reacted
excellent selectivity (entries 4 and 5). Decreasing the catalyst smoothly towards the corresponding coupling products. Unsubsti-
loading to 2.5 mol% with an addition time of 5 min, however tuted benzyl bromide was converted with both 2a and 2b to form 3
resulted in moderate conversion with decreased selectivity and 5 in excellent yield. Performing the synthesis of 5 on gram-
(entry 6). After optimizing the addition time, as well as the scale afforded the desired product in similar yield (82%). The
reaction conditions and organolithium-concentration, we reaction of 2-(bromomethyl)-naphthalene also proceeded, provid-
found that optimal results were obtained using 3 mol% of ing 6 in 62% yield. Substrates bearing p-alkyl substituents readily
the Pd–I dimer complex with toluene as solvent, and an underwent the cross-coupling reaction, to give 7 and 8 in 91% and
70% yield, respectively. The presence of electron-donating
para-substituents was also tolerated i.e. p-thioanisole 9 (81%).
Substituents in the meta-position also posed no problem since
m-methoxy- and m-methyl-substituted benzyl bromides were effi-
Table 1 Screening of conditionsa for the direct cross-coupling using
lithium acetylides
ciently converted to the corresponding products 10 (84%) and 11
(86%), respectively. Sterically demanding o-substituted methyl- and
phenyl benzyl bromides remained challenging, resulting in non-
productive reactions with lithium(triisopropylsilyl) acetylide 2b.
Reducing the steric bulk of the acetylide by using lithium (tri-
Time Conversion of 1 3 : 4b
methylsilyl) acetylide (2a) proved crucial, and smoothly provided 12
and 13 (see ESI† Fig. S1 for detailed explanation). Next, we moved
our attention towards electron-poor benzyl bromides. The reaction
of both m and p-CF3 benzyl bromide provided the desired product
14 and 15 in 61% and 75% yield, respectively. A significant
difference in reactivity, however, was observed in the reactions of
p- and m-nitrobenzyl bromide. The attempted cross-coupling with
p-nitrobenzyl bromide proceeded with full conversion towards the
homo-coupled 1,2-biarylethane. Due to the high acidity of the benzylic
position (pKa p-nitrotoluene = 20.4 vs. pKa acetylene = 25),24 lithium–
halogen exchange results in the formation of a more stable
p-nitrobenzyl anion, subsequently forming the 1,2-biarylethane side-
product.25 As expected, the homo-coupling product was not observed
when we moved the nitro-substituent out of conjugation with respect
to the benzylic position, which provided us with the desired product
Entry [Pd]
Mol% (min) (%)
(%)
1
2
3
4
5
6
7
8
9
Pd(PtBu3)2/O2
5
30
15
5
499
499
44
98 : 2
95 : 5
82 : 18
97 : 3
96 : 4
88 : 12
96 : 4
86 : 14
94 : 6
[Pd(m-I)PtBu3]2
5
10
5
98
99
[Pd(m-I)PtBu3]2c
2.5
3
5
5
10
5
59
499
87
[Pd(l-I)PtBu3]2
Pd(PtBu3)2/under aird
Pd(PtBu3)2/under aird 7.5
5
499
a
Reaction conditions. RLi prepared from trimethylsilyl acetylene
(0.65 mmol) and nBuLi (1.6 M in hexanes; 1 equiv.) in THF (0.5 M)
was added dropwise to a solution of [Pd] and 1 (0.5 mmol) in toluene
b
c
(4 mL). Conversion determined by GC–MS analysis. RLi was pre-
pared from trimethylsilyl acetylene (0.65 mmol) and nBuLi (1.6 M in
hexanes; 1 equiv.) in THF (0.6 M), and diluted with toluene (final
d
concentration: 0.35 M). The reaction was performed under air in the
absence of additional solvent.
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acidic position (pKa of phenylacetonitrile B22).24 Despite bearing
these two reactive sites, our procedure afforded 23 in 47% yield. The
use of the azobenzene moiety in photopharmacology28 is of great
interest due to its easy access and photo-switching behavior. The
introduction of the benzylic alkyne functionality allows for facile
attachment of the pharmacophore by means of Cu-catalyzed click-
chemistry.4,29 Using our method, we successfully attached the ‘click
handle’ to the azobenzene core in 67% yield (24). We also examined
the reactions of benzyl bromides bearing both C(sp2)- and C(sp3)-
bromides, as we previously observed that [Pd(m-I)PtBu3]2 is also an
effective catalyst for the cross-coupling of lithium acetylides with aryl
bromides.20 We were pleased to obtain the double coupling products
25–27 in 48–52% yield. These products are highly versatile synthons
due to their application in various cycloaddition and cyclisation
reactions.30 Moreover, we were also able to synthesize di-(28) and
tri-(29) substituted benzyl acetylenes in a one-pot procedure providing
excellent yields of multiple coupled products. These compounds can
fulfill roles as bridging/spacer units and dendrimer building blocks
(core and branching point), respectively.31 Finally, we also performed
the cross-coupling reactions by reacting two other substituted lithium
acetylides with m-ester substituted benzyl bromide. As expected,
the lithium acetylenes generated from both phenylacetylene and
9-ethynylphenanthrene reacted smoothly and afforded 30–31 in
46% and 52% yield. In order to demonstrate the potential synthetic
application of the methodology, we envisioned benzylic alkynes as
versatile precursors for a wide array of products.3 There are numerous
applications of the terminal alkynes3 which are directly accessible via
our cross-coupling product using a TBAF-mediated deprotection.32 It
should be noted that benzylic alkynes can undergo alkyne-allene
isomerization under basic deprotection conditions. This can however
be circumvented by carrying out the reaction with AgNO3/KI.33
Importantly however, allenes can also be very useful functional groups
in view of their reactivity towards cycloaddition and cyclisation
reaction.34 We compared the use our new acetylene coupling reaction
to previously reported syntheses of important benzylic alkynes
(Scheme 3). Fluorobenzyl alkyne 32 was used for the synthesis of
Scheme 2 Scope of the benzyl alkyne synthesis. Reaction conditions.
Freshly prepared 2b (1.3 equiv.; 0.35 M) was added to a solution, of
[Pd(m-I)PtBu3]2 (3 mol%) and corresponding benzyl bromide (0.5 mmol)
in toluene (2 mL), over 10 min. [a] The reaction was also performed on
1 gram scale with 82% yield [b] Quantitative formation to corresponding
1,2-biarylethane [c] Freshly prepared 2b (2.6 equiv.) was added to a solution
of [Pd(m-I)PtBu3]2 (6 mol%) and 1 (0.5 mmol) in toluene (4 mL) over 20 min.
[d] 3.9 equiv. of 2b was used (also see ESI† for more information).
17 in 45% yield. Although organolithium reagents can be of great use, CRTH2 receptor antagonists 33.35 The reported approach required
their inherent reactivity generally might limit their effectiveness as stoichiometric amounts of CuI, and a reaction time of 24 h at 75 1C.36
cross-coupling reagents in the presence of functional groups. In the Our methodology provided 32 in merely 10 min at room temperature,
case of lithium acetylides, due to their lower pKa, and therefore in a comparable yield (75% vs. 78%). Furthermore, benzyl alkyne 34 is
diminished reactivity compared to alkyl- and alkenyllithium reagents, of particular interesting since it is a common precursor used in the
we anticipated that this transformation should be feasible in the synthesis of lignans. These are plant-based natural products well-
presence of organolithium-sensitive functionalities. A nitrile-bearing known for a wide variety of biological activities such as antitumor,
substrate, which is prone to mono- or double addition reactions with antimitotic, and antiviral properties.37 Interestingly, coupling product
organolithium reagents to form various imines and carbinamines,26 34 has been used as a building block for the synthesis of metabolically
could be efficiently transformed into coupled product 18 (75%). The stable steganacin analogue 35.38 This natural product derived com-
presence of amides and esters are well tolerated and furnish 19–21 in pound exhibited cytotoxic activity against neuroblastoma cells. The
high yields, despite their usual tendency to engage in undesired 1, reported procedure required a reaction time of 16 h at 66 1C,
2-addition reactions with organolithium reagents to form ketones and providing the desired product in 90% yield. Our method gave rise
alcohols. Furthermore, the presence of a boronic ester, a versatile to the product in slightly reduced yield (82%), albeit using much
functionality for Suzuki–Miyaura cross-coupling reactions, was well- milder (RT) and significantly more time-efficient (30 min) conditions.
tolerated, despite the fact that they easily react with organolithium
In summary, we have developed a mild, fast and highly
compounds to form boronates.27 Under our reaction conditions, selective approach for the catalytic cross-coupling of benzyl
bifunctional product 22 was readily synthesized (54%). A particularly bromides with lithium acetylides. The reaction proceeds in ten
challenging substrate is phenylacetonitrile-based benzyl bromide, minutes at room temperature, offering an efficient pathway to a
containing, in addition to the reactive nitrile functionality, also an range of protected benzylic acetylenes in generally high yields
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under mild conditions. Due to the remarkable functional group
tolerance of the transformation, the alkynylation of benzyl
bromides with lithium acetylides might likely find applications
in the late-stage functionalization of (photo-)pharmacophores,
natural products, materials and pharmaceuticals.
This work was financially supported by ERC (advanced grant
No. 694345) and the Dutch Ministry of Education, Culture and
Science (Gravitation program No. 024.001.035) to B. L. F and
N. W. O. (Grant Number: 718,015,004) to A. M. D. Kolarski is
acknowledged for providing (E)-1-(4-(bromomethyl)-phenyl)-2-
phenyldiazene. R. Sneep is acknowledged for performing the
high-resolution mass spectrometry.
Conflicts of interest
The authors declare no conflict of interest.
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