A Cascade Suzuki-Miyaura/Diels-Alder Protocol: Exploring the Bifunctional Utility of Vinyl Bpin

Article abstract of DOI:10.1055/s-0037-1611228

Cascade reactions are an important strategy in reaction design, allowing streamlining of chemical synthesis. Here we report a cascade Suzuki-Miyaura/Diels-Alder reaction, employing vinyl Bpin as a bifunctional reagent in two distinct roles: as an organoboron nucleo phile for cross-coupling and as a Diels-Alder dienophile. Merging these two reactions enables a rapid and operationally simple synthesis of functionalized carbocycles in good yield. The effect of the organoboron subtype on Diels-Alder regioselectivity was investigated and postsynthetic modifications were carried out on a model substrate. The potential for a complementary Heck/Diels-Alder process was also assessed.

Full text of DOI:10.1055/s-0037-1611228

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
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D. L. Cain et al.
Letter
Synlett
A Cascade Suzuki–Miyaura/Diels–Alder Protocol:
Exploring the Bifunctional Utility of Vinyl Bpin
David L. Caina
Calum McLaughlinb
John J. Molloyb
Cameron Carpenter-Warrena
Niall A. Andersonc
X
Bpin
Pd cat., Δ
17 examples
up to 88% yield
R1
Bpin
R1
R2
R2
• Vinyl Bpin as a bifunctional reagent
• Tandem Suzuki–Miyaura/Diels–Alder reaction
• Rapid access to borylated cyclohexenes
Allan J. B. Watson*a
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2-1
5
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2-4
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a EaStCHEM, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, KY16 9ST, UK
aw260@st-andrews.ac.uk
b WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
c GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road
Stevenage, Hertfordshire, SG1 2NY, UK
Received: 07.09.2018
Accepted: 30.09.2018
Published online: 24.10.2018
DOI: 10.1055/s-0037-1611228; Art ID: st-2018-d0578-l
form complex tetracyclic fused ring systems (Scheme 1,
a).16 Lee employed a cascade DA/cross-coupling protocol,
generating an organoindium reagent in situ, to enable a
subsequent Pd-catalyzed cross-coupling (Scheme 1, b).17
Welker reported a three-component tandem Suzuki–
Miyaura/DA cascade involving an initial cycloaddition be-
tween a borylated diene and electron-deficient dienophile
followed by a subsequent cross-coupling with an aryl
iodide (Scheme 1, c).18 In all previously reported methods
the DA is performed with a highly activated, electron-
deficient dienophile. We recently disclosed a tandem cross-
coupling/DA reaction, to generate molecular complexity.19
Again, these reactions required highly activated dienophiles
to promote reactivity.
Abstract Cascade reactions are an important strategy in reaction
design, allowing streamlining of chemical synthesis. Here we report a
cascade Suzuki–Miyaura/Diels–Alder reaction, employing vinyl Bpin as a
bifunctional reagent in two distinct roles: as an organoboron nucleo-
phile for cross-coupling and as a Diels–Alder dienophile. Merging these
two reactions enables a rapid and operationally simple synthesis of
functionalized carbocycles in good yield. The effect of the organoboron
subtype on Diels–Alder regioselectivity was investigated and postsyn-
thetic modifications were carried out on a model substrate. The poten-
tial for a complementary Heck/Diels–Alder process was also assessed.
Key words Bpin, cascade, cross-coupling, Diels–Alder, Suzuki–Miyaura
Here we explore the utility of vinyl Bpin as both cross-
coupling nucleophile and dienophile for the cascade syn-
thesis of borylated carbocycles (Scheme 1, d). While vinyl
Bpin is a competent cross-coupling nucleophile, its utility
as a dienophile is underdeveloped.19,20 However, a cross-
coupling/DA cascade utilizing vinyl Bpin as both nucleo-
phile and dienophile would construct borylated cyclo-
hexenes, capable of an array of further transformations.
We initiated the optimization study (Table 1) using tri-
flate 1a with excess vinyl BPin. Employing conditions previ-
ously established in our group,21–25 the Suzuki–Miyaura
event proceeded rapidly and quantitatively, delivering
Dane’s diene (2a) as an intermediate.26,27 We believed ther-
mal promotion would enable cyclization, and a tempera-
ture screen indicated that a minimum of 150 °C (Table 1,
entries 1–4) was necessary to drive the DA reaction to com-
pletion; 5 equivalents of vinyl BPin were required to over-
come organoboron degradation and offset a competing
homo DA consuming diene intermediate 2a (Table 1, entries
6–8). A time study indicated that the reaction was complete
in 6 h (Table 1, entries 9 and 10). Given the electron-rich,
Cascade methodologies are recognized as an enabling
approach to chemical synthesis.1–4 The modularity with
which complex molecules can be created from embedding
downstream reactivity into small precursors is an appeal-
ing strategy for synthetic chemists, allowing the use of
highly reactive, nonisolable intermediates, reducing step
count, and leading to overall improvements in chemical
efficiency.
The Diels–Alder (DA) reaction is one of the most widely
explored reactions within cascade sequences.1–4 This popu-
larity stems from variety of methods to prepare dienes, in
combination with the ability to effectively generate stereo-
chemically enriched six-membered rings with relative ease.
The diene component of the DA reaction can often be chal-
lenging to handle since particular dienes are prone to rapid
decomposition or polymerization upon isolation.5 As a re-
sult, considerable research has been focused on the genera-
tion and in situ applications of specific dienes.6–15
Cross-coupling reactions are effective methods for the
preparation of dienes for in situ DA reactions.13–15 For exam-
ple, Padwa reported a cascade Stille/intramolecular DA to
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
D. L. Cain et al.
Letter
Synlett
reactive nature of the intermediate diene 2a, we were con-
cerned that these reaction conditions would not be broadly
transferrable. A control experiment using des-methoxy tri-
flate 1b, via diene 2b, indicated that longer reactions times
would potentially be necessary for less electron-rich sub-
strates (Table 1, entries 11 and 12).
a) Tandem Stille/intramolecular Diels–Alder (Padwa, 2006)
O
O
MeO2C
I
O
Pd(PPh3)4, CuCl, LiCl, 60 °C
O
O
N
O
N
PMB
PMB
O
MeO2C
SnBu3
O
b) Tandem Diels–Alder/cross-coupling reaction (Lee, 2010)
The scope of the reaction was subsequently investigated
(Scheme 2). All substrates were isolated as the correspond-
ing alcohol to aid characterization and separation of the
regioisomers generated from the cycloaddition. The tetra-
lone-derived scaffolds (4a–g) displayed good yields in all
examples, with both electron-donating (4a,4d,e) and electron-
withdrawing groups (4f) tolerated, in addition to a chro-
mane example (4g). The position and nature of the substit-
uent on the aromatic ring had little effect on the regioselec-
tivity of the cycloaddition, with a moderate (ca. 3:1) ratio of
regioisomers observed throughout. However, a single dia-
stereomer was produced, which following X-ray crystallo-
graphic analysis confirmed an endo DA adduct (vide infra).
Use of styrenyl and alkenyl electrophiles (4h–q) allowed
the formation of cyclohexenyl products (Scheme 2). Homo
DA was found to be significantly more problematic in these
cases. However, this could be circumvented using 7 equiva-
lents of vinyl Bpin to deliver a range of products in good
yield and with comparable levels of regiochemical control.
Br
EWG
R
EWG
EWG
i) In, DMF, 80 °C
•
ii) Pd2dba3·CHCl3, P(p-CF3-C6H4)3
R–X, LiCl, 100 °C
EWG
c) Tandem Diels–Alder/cross-coupling protocol (Welker, 2012)
I
EWG
Pd2dba3, K2CO3
EWG
MeCN:EtOH, 5:1, Δ
(RO)2B
d) This work: Exploring the bifunctional utility of vinyl Bpin
X
i) Pd(OAc)2, SPhos, Dioxane, 50 °C, 1 h
Bpin
R1
R1
Bpin
ii) 150 °C, 23 h
R2
R2
Scheme 1 Cross-coupling/DA in cascade methodologies; DMF = N,N-
dimethylformamide; EWG = electron-withdrawing group; pin = pinaco-
lato; PMB = para-methoxybenzyl.
Table 1 Optimization of SM/DA Cascade Reaction
Bpin
OTf
Time (h)
Pd(OAc)2 (4 mol%), SPhos (8 mol%)
H
H
+
Bpin
Bpin
Temp. (°C)
K3PO4 (3 equiv), Dioxane (x M)
H2O (5 equiv), 50 °C, 1 h
R
R
R
R
(1 equiv)
(x equiv)
R = OMe (1a)
R = OMe (2a)
R = OMe (3a)
R = OMe (3a')
R = H
(1b)
R = H
(2b)
R = H
(3b)
R = H
(3b')
Entry
Time (h)
Temp (°C)
Vinyl Bpin (equiv)
Concentration (M)
Conv. (%)a
r.r.b
c
1
2
23
23
23
23
23
23
23
23
4
75
100
125
150
150
150
150
150
150
150
150
150
5
5
5
5
5
2
3
4
5
5
5
5
0.125
0.125
0.125
0.125
0.25
24
33
66
98
85
62
84
93
88
99
88d
96d
–
c
–
c
3
–
4
3:1
5
3.1:1
6
0.125
0.125
0.125
0.125
0.125
0.125
0.125
3.1:1
3.2:1
3.2:1
3.1:1
3.5:1
3.1:1
3.1:1
7
8
9
10
11
12
6
6
23
a Conversion determined by 1H NMR spectroscopy using an internal standard.
b r.r. = regioisomeric ratio of 3a/3a′ or 3b/3b′. Determined by 1H NMR spectroscopy after oxidation.
c Unable to be determined due to impurity profile.
d Reactions using 1b.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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D. L. Cain et al.
Letter
Synlett
Table 2 Diels–Alder Regioselectivity: Variation of Vinyl Boron Species
i) Pd(OAc)2 (4 mol%), SPhos (8 mol%)
K3PO4 (3 equiv), Dioxane (0.125 M)
H2O (5 equiv), 50 °C, 1 h
X
OH
i) Dioxane (0.125 M)
150 °C, 23 h
R1
OH
Bpin
R1
ii) 150 °C, 23 h
R2
X = Br, OTf
(1 equiv)
(5 equiv)
BX
R2
iii) H2O2 (20 equiv), NaOH (4 equiv)
THF, 0 °C to r.t.
+
OH
ii) Oxidation (see table)
F
(5–7 equiv)
F
F
(1 equiv)
OH
OH
OH
2q
4q
4q'
H
H
H
F
Entry
Vinyl boron species (BX)
Ratio (4q/4q′)a
MeO
4a, 72% (3:1)a
4b, 88% (3.1:1)a
4c, 74% (3.2:1)a,c
1
2
3
4
5
Bpin
3.7:1b
3.5:1c
3.5:1d
2.8:1e
3.6:1b
OH
BF3K
OH
O2N
OH
H
Bdan
H
H
MeO
BMIDA
boroxine
OMe
4d, 75% (3.3:1)a,c
a Determined after oxidation to the corresponding alcohol.
b Oxidation conditions: H2O2 (20 equiv), 2 M NaOH (4 equiv), THF, 0 °C to
r.t., 1 h.
4e, 81% (3.3:1)a,c
4f, 72% (3.3:1)a,c
OH
OH
OH
c Oxidation conditions: Oxone® (1.1 equiv), acetone/H2O (1:1), r.t., 2 h.
d (i) 2 M HCl (6 equiv), THF, r.t., 23 h; (ii) H2O2 (20 equiv), 2 M NaOH
(4 equiv), THF, 0 °C to r.t., 1 h.
H
e (i) K3PO4 (3 equiv), H2O (5 equiv), CPME, 80 °C, 10 min; (ii) Oxone®
(2.5 equiv), CPME/H2O (4:1), 70 °C, 1 h; dan = 1,8-diaminonaphthalenate;
MIDA = N-methyliminodiacetate; pin = pinacolato.
O
F
F
4g, 50% (1.9:1)a,c
OH
4h, 69% (3.4:1)b,c
4i, 69% (3.7:1)b,c
OH
OH
Me
N
Under the aqueous basic conditions used for the initial
Suzuki–Miyaura cross-coupling of the tandem process the
vinyl BPin could conceivably exist as its boronate deriva-
tive,28 which exhibits significantly different electronic
properties to the parent neutral boronic ester. Since alter-
ing the electronics of the dienophile may have a direct in-
fluence on the regioselectivity of the cycloaddition, we as-
sessed several different organoboron species (Bpin, BMIDA,
boroxine, BF3K, Bdan) to determine any influence on regio-
selectivity (Table 2). However, no noticeable trends were
observed, with all reactions producing a similar regioiso-
meric ratio. The cycloaddition requires significant thermal
promotion and it is possible that these observations could
be explained by the high temperatures required for reactiv-
ity overriding any potentially subtler electronically induced
kinetic effects.
In order to demonstrate potential synthetic application
of this method, we carried out postsynthetic modifications
of a benchmark substrate (4a; major regioisomer). Di-
hydroxylation, alkene migration, hydrogenation, oxidation,
acylation, and alcohol protection were all shown to be fea-
sible, giving compounds 5a–f and illustrating the potential
of diversification capabilities (Scheme 3). Compound 5e
was characterized by X-ray diffraction, confirming relative
stereochemistry and providing evidence that the cycloaddi-
tion proceeds via the endo transition state.
N
Ph
Me
4j, 39% (4.5:1)b,c
4k, 46% (2.9:1)b
4l, 64% (4:1)b,c
OH
OH
OH
MeO2C
4m, 64% (4.5:1)b,c
4n, 57% (2.6:1)b,d
4o, 62% (4:1)b,c
OH
OH
Me
4p, 63% (2:1)b,c,e
F
4q, 72% (3.7:1)b
Scheme 2 Substrate scope of the cascade reaction. Major regioisomer
displayed. Isolated yields of regioisomeric products. Numbers in brack-
ets are the r.r. a Using 5 equiv vinyl Bpin. b Using 7 equiv vinyl Bpin.
c[n = 2]. d[n = 3]. e d.r. of both regioisomers = 2:1.
Lastly, use of β-methyl styrene resulted in the formation
of the product 4p in moderate yield. Interestingly, a change
in regioselectivity was observed with this substrate, now
favoring what was the minor regioisomer for all previous
examples.
Based on the moderate regioselectivity observed
throughout as well as the reversal of regioselectivity in ex-
ample 4p, we were interested to assess what, if any, impact
the nature of the organoboron substituent had on the regio-
selectivity of the cycloaddition (Table 2).
Lastly, we explored the feasibility of performing a
Heck/DA cascade reaction using vinyl Bpin (Scheme 4, a),
given the recent successful methodology implementing a
variety of dienophiles,19 as this would provide expedient
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
D. L. Cain et al.
Letter
Synlett
HO
HO
OH
OH
OH
a) Approach to vicinal Bpin products via Heck/Diels-Alder using vinyl Bpin
H2, Pd/C
H
H
Bpin
Bpin
Bpin
Bpin
Pd cat.
X
EtOH, r.t.
MeO
H
Bpin
MeO
MeO
R1
Heck
Diels-Alder
R1
R1
5a, 64% (5:1)
OsO4,
acetone
NMO, r.t.
5b, 90%
5c, 69% (7:3)
b) Attempts towards the sequential process
Bpin
HCl, MeOH/CH2Cl2
r.t.
Pd(OAc)2 (4 mol%)
SPhos (8 mol%)
OTf
Bpin
OH
Et3N (3 equiv)
AgOAc (2 equiv)
Dioxane (0.25 M)
40 °C, 24 h
H
MeO
(2 equiv)
(1 equiv)
MeO
4a
1a
6a, 32%
MeO
Bpin
TBSCl, CH2Cl2
imid, 0 °C to r.t.
DMP,
CH2Cl2
0 °C to r.t.
PNBCl, CH2Cl2
DMAP, r.t.
Bpin
(5 equiv)
Bpin
O
OTBS
150 °C, 24 h
OPNB
8
MeO
H
H
7a
6
Scheme 4 a) Proposed one-pot cascade Heck/DA reaction; b) stepwise
MeO
MeO
MeO
approach to elucidating feasibility of reaction.
5d, 92%
5e, 72%
5f, 51%
was assessed and found to have little impact on the out-
come of the process, suggesting the thermal activation
required erodes any potential stereoelectronically induced
regioselectivity. In addition, a set of derivatization reactions
was carried out to demonstrate synthetic versatility of
these building blocks as intermediates. Finally, the possibil-
ity of a cascade Heck/Diels–Alder reaction was investigated
through a stepwise approach, however, the reaction could
not be driven to the desired product.
Scheme 3 Illustrative synthetic modifications of 4a; DMAP = 4-di-
methylaminopyridine; DMP = Dess–Martin periodinane; imid = imidaz-
ole; NMO = N-methylmorphonline N-oxide; PNB = para-nitrobenzoyl
chloride; TBS = tert-butyldimethylsilyl.
Funding Information
access to vicinyl Bpin systems. Initial efforts in performing
the reaction in a one-pot process proved unsuccessful; as a
result, a stepwise approach was adopted for proof of con-
cept. The Bpin diene intermediate 6a was successfully iso-
lated, albeit in low yield (Scheme 4b): this reaction deliv-
ered complex mixtures of products, likely via homo-Diels–
Alder as well as protodeboronation. Despite our best efforts,
and our acquired knowledge on this DA reaction, we were
unable to obtain the DA adduct 7a upon exposing the diene
6a to excess vinyl Bpin at elevated temperatures. The reac-
tion yielded a complex mixture of unknown products, this
could be due to the noted poor stability/high reactivity of
intermediate 6a and exacerbated by the requirement for
high temperatures.
Industrial CASE studentship awarded from EPSRC and GlaxoSmith-
Kline.()
Acknowledgment
We thank the EPSRC, GlaxoSmithKline, and the University of
St Andrews for studentship funding (DLC), and the University of
St Andrews and the EPSRC UK National Mass Spectrometry Facility at
Swansea University for analyses.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611228.
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In summary, we have developed a cascade Suzuki–
Miyaura/Diels–Alder protocol enabling expedient access to
borylated carbogenic frameworks, exploiting the unique re-
activity of vinyl Bpin as both cross-coupling partner and
dienophile.29 The process tolerates a variety of functional
groups, producing cycloadducts in moderate to good yields
and with moderate regioselectivity. The effect of the orga-
noboron substituent on the Diels–Alder regioselectivity
References and Notes
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D. L. Cain et al.
Letter
Synlett
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weighed into an oven-dried microwave vial. The reaction vessel
was then capped and purged with N2 before the addition of 1,4-
dioxane (0.125 M) and H2O (5 equiv). The reaction mixture was
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equiv) and 2 M NaOH (4 equiv) sequentially. After 5 min the
reaction mixture was allowed to warm to room temperature
and was stirred for 1 h. The mixture was quenched with
Na2S2O3 at 0 °C until effervescence ceases and diluted with sat.
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(29) General Experimental Procedure for the Tandem Suzuki–
Miyaura/Diels–Alder Reaction
Compound 4a
Prepared according to General Procedure using 6-methoxy-3,4-
dihydronaphthalen-1-yl trifluoromethanesulfonate (77.0 mg,
0.25 mmol, 1 equiv), Pd(OAc)2 (2.2 mg, 0.01 mmol, 4 mol%),
SPhos (8.2 mg, 0.02 mmol, 8 mol%), vinyl Bpin (192 mg, 1.25
mmol, 5 equiv), K3PO4 (159 mg, 0.75 mmol, 3 equiv), 1,4-
dioxane (2 mL, 0.125 M) and H2O (22.5 μL, 1.25 mmol, 5 equiv),
then aqueous H2O2 (30% w/v, 500 μL, 5 mmol, 20 equiv), 2 M
NaOH (500 μL, 1 mmol, 4 equiv), and THF (1 mL). After the reac-
tion was complete, the reaction mixture was subjected to the
purification method outlined in the General Procedure (silica
gel, 0–60% EtOAc in PE 40–60°) to afford the desired mixture of
products as a yellow oil (41.3 mg, 72%, 3:1 r.r.). The major regio-
isomer was separated by column chromatography (ca. 95%
purity).
Data for the Major Regioisomer
IR (film): νmax = 3364 (br), 2914, 2847, 2830, 1605, 1493, 1456,
1279, 1253, 1231, 1034 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
7.51 (dd, J = 8.8, 6.0 Hz, 1 H), 6.71 (dd, J = 8.8, 2.5 Hz, 1 H), 6.60
(d, J = 2.6 Hz, 1 H), 6.07–6.02 (m, 1 H), 4.04–3.95 (m, 1 H), 3.79
(s, 3 H), 2.95–2.75 (m, 2 H), 2.61–2.54 (m, 1 H), 2.52–2.39 (m, 1
H), 2.23–2.10 (m, 2 H), 2.02–1.94 (m, 1 H), 1.54–1.49 (m, 1 H),
1.46–1.36 (m, 1 H). 13C NMR (101 MHz, CDCl3): δ = 158.7, 138.0,
135.7, 127.1, 125.1, 115.5, 113.4, 112.9, 67.7, 55.4, 40.7, 36.7,
36.1, 31.2, 30.5. HRMS: m/z calcd for [M + H]+ (C15H19O2):
231.1380; found: 231.1378.
Pd(OAc)2(4 mol%), SPhos (8 mol%), vinyl (pseudo)halide
(1 equiv), vinyl Bpin (5–7 equiv), and K3PO4(3 equiv) were
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E