Linear-selective rhodium(I)-catalyzed addition of arylboronic acids to allyl sulfones

Article abstract of DOI:10.1002/anie.201004345

One step further: The rhodium(I)-catalyzed addition of readily available arylboronic acids to allyl sulfones affords the linear (formal) hydroarylated products in good yields and excellent regioselectivities. The reaction broadens the scope of unactivated

Full text of DOI:10.1002/anie.201004345

Communications
DOI: 10.1002/anie.201004345
Rhodium Catalysis
Linear-Selective Rhodium(I)-Catalyzed Addition of Arylboronic Acids
to Allyl Sulfones**
Gavin C. Tsui and Mark Lautens*
À
Rhodium-catalyzed C C bond formation has become one of
include rhodium-catalyzed addition of arylboronic acids to
strained bicyclic alkenes and vinylarenes.[4,5] We reported that
simple protected allylic amines will also participate in
rhodium-catalyzed addition reactions to afford linear and
branched (formal) hydroarylated products.[6] The regioselec-
tivity was found to be highly dependent on the protecting
group.
the most studied and widely used synthetic methods.[1]
A
particularly powerful transformation is the rhodium-cata-
lyzed 1,4-addition of arylboronic acids to activated alkenes
developed by Miyaura and Hayashi (Scheme 1).[2] Since the
To broaden the scope of unactivated alkenes in the
rhodium-catalyzed addition reactions, we decided to employ
readily available allyl sulfones 1 (Scheme 1). Sulfones have
displayed great utility and versatility in synthetic applica-
tions.[7] The linear addition products 2 have been used as
precursors for further transformations.[8] Rhodium-catalyzed
addition of arylboronic acids and aryltitanium reagents to a,b-
unsaturated sulfones are known.[3f,9] To the best of our
knowledge, no example of addition to allyl sulfones has
been reported. There is evidence supporting the directing
effect of sulfone in rhodium-catalyzed hydroboration of
allylic substrates.[10] We envisioned that the directing/coordi-
nating ability of the sulfone group may enhance the reactivity
of the otherwise unreactive alkene component and potentially
lead to regioselective product formation in the rhodium-
catalyzed addition of arylboronic acids to allyl sulfones.
We began our investigations by using commercially
available allyl phenyl sulfone 1a as the substrate. When
reacting 1a with 2.5 equivalents of phenylboronic acid in the
presence of 2 mol% [{Rh(cod)OH}2] (cod = 1,5-cycloocta-
diene) and 6 mol% binap (2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl) in dioxane/H2O (100:1) at 758C for 12 hours, the
linear addition product 2a was obtained exclusively in 90%
yield (Table 1, entry 1).
The branched product 3 and “Heck” product 4 (through
addition/elimination) were not observed under these condi-
tions. Isomerization of the double bond, which is a known
process in rhodium catalysis of allylic substrates,[1c] also did
not take place. This result was particularly encouraging
because it showed both high reactivity and excellent regio-
selectivity of the allyl sulfone substrate in the rhodium-
catalyzed addition process. The amount of added water
affected the reaction yield. Reaction without added water and
reaction with a larger amount of water (dioxane/H2O = 10:1)
both led to incomplete conversion. The use of excess
arylboronic acid was necessary because of the competing
hydrolytic deboronation process under the reaction condi-
tions.[1a] Using [[{Rh(cod)OH}2] without added ligand or
[{Rh(cod)Cl}2] as the catalyst source gave very poor con-
versions (Table 1, entries 2 and 3, respectively). The use of
tol-binap or biphep (2,2’-bis(diphenylphosphino)-1,1’-
biphenyl) as ligands was also effective (Table 1, entries 4
and 5, respectively), but the use of dppb (1,4-bis(diphenyl-
Scheme 1. Rhodium-catalyzed addition of arylboronic acids to
activated and unactivated alkenes.
initial application to the enone systems, this strategy has been
successfully extended to other activated alkenes such as a,b-
unsaturated esters, aldehydes, amides, phosphonates, sul-
fones, and nitro compounds.[3] However, the substrates for
these transformations are limited to alkenes that are activated
by electron-withdrawing groups. The addition to unactivated
alkenes remains a challenge. Recent advances on this front
[*] G. C. Tsui, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
Fax: (+1)416-946-8185
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML/
[**] This research was supported by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the Merck Frosst
Centre for Therapeutic Research, and the University of Toronto. We
thank Dr. Timothy Burrow for assistance with NMR experiments. We
acknowledge L. Edgar for the preparation of some substrates.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004345.
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Chemie
Table 1: Rhodium-catalyzed addition of organoboron reagents to allyl
phenyl sulfone (1a): Optimization.
Table 2: Rhodium-catalyzed addition of arylboronic acids to allyl phenyl
sulfone (1a): Scope of arylboronic acids.
Entry
R
Product
Yield
[%][a]
1[b]
4-Ac
4-OMe
4-CF3
4-CO2Me
4-NHBoc
4-NHCbz
4-SMe
4-Cl
3-Ac
3-OMe
3-CF3
2-Me
2-OMe
2-naphthyl
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
2aj
2ak
2al
2am
2an
91
85
84
65
84
81
78
67
82
92
75
87
50
95[d]
2[b]
3[b]
Entry
[Rh] catalyst
Ph-[B]
Yield of
2a:3[b]
4[b]
5[b]
2a [%]
6[b]
1
2
3
4
5
6
7
8
9
10
[{Rh(binap)OH}2]
[{Rh(cod)OH}2]
[{Rh(binap)Cl}2]
[{Rh(tol-binap)OH}2]
[{Rh(biphep)OH}2]
[{Rh(dppb)OH}2]
[{Rh(binap)OH}2]
[{Rh(binap)OH}2]
[{Rh(binap)OH}2]
[{Rh(binap)OH}2]
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
Ph4BNa
90[a,c]
5[b]
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
7[b]
8[c]
26[b]
76[b]
78[b]
9[b,d]
<5[b]
37[b]
45[b]
89[a]
9[b]
10[b]
11[c]
12[b]
13[b]
14[c]
[e]
–
PhBF3K
>99:1
>99:1
>99:1
PhBPin[f]
(PhBO)3
[a] Yield of isolated product. [b] Dioxane. [c] Dioxane/H2O (100:1).
[d] 52% Yield without added water. Boc=tert-butoxycarbonyl, Cbz=
benzyloxycarbonyl.
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy of
the crude material. [c] Using dioxane gave 72% of 2a and 13% of
unreacted starting material; using dioxane/H2O (10:1) gave 67% of 2a
and 13% of unreacted starting material. [d] 45% of unreacted starting
material and 21% of 4 were observed. [e] Not determined. [f] PhBPin=
phenylboronic acid pinacol ester.
The effect of the substituent on the sulfonyl group was
also studied (Table 3). Linear addition products 2b–2j were
obtained with excellent regioselectivities. Electron-rich and
electron-poor aromatic groups gave good yields (Table 3,
entries 1–4). More sensitive functional groups such as bro-
mide and acetamide and a sterically hindered 2-methyl group
required double the catalyst loading to achieve higher yields
(Table 3, entries 5–7). Non-aromatic allyl methyl sulfone (1i)
participated in the reaction albeit a lower yield was obtained
(Table 3, entry 8). The synthetically useful benzothiazolyl
sulfone (1j) gave a poor yield (Table 3, entry 9).[12]
phosphino)butane) gave poor conversion and an increased
amount of “Heck” product 4 (Table 1, entry 6). We next
investigated the effect of the organoboron reagent. Sodium
tetraphenylborate was ineffective and led to no conversion
(Table 1, entry 7). Potassium phenyltrifluoroborate and phe-
nylboronic acid pinacol ester only gave modest yields and an
increased amount of 4 (Table 1, entries 8 and 9, 8% and 7%
of 4, respectively). Phenylboroxine, an alternative reagent for
phenylboronic acid, gave comparable yield of the linear
product 2a (Table 1, entry 10). In all of the above cases, the
branched product 3 was not observed.
Table 3: Rhodium-catalyzed addition of arylboronic acids to functional-
ized allyl sulfones (1b–j): Scope of sulfonyl substituent groups.
The scope of arylboronic acids was subsequently studied
using allyl phenyl sulfone 1a as the substrate under the
optimized conditions (Table 2). A wide range of functional-
ized arylboronic acids were employed to afford the linear
products 2aa–2an in moderate to high yields and excellent
regioselectivities. Electron-rich and electron-poor groups at
the 4 and 3 positions gave good yields (Table 2, entries 1–3, 9–
11). Functional groups such as ester, carbamate, sulfide, and
chloride were tolerated (Table 2, entries 4–8). A methyl
group at the 2-position did not hinder the reaction, but a
methoxy group at the same position significantly decreased
the yield (Table 2, entries 12 and 13, respectively). The 2-
naphthylboronic acid gave very high yield of the product
(Table 2, entry 14). In most cases, the reaction did not require
additional water, presumably the water content in the
commercial arylboronic acids facilitates protodemetala-
tion.[11] In some cases, adding water increased the yield
significantly (Table 2, entries 8, 11, and 14).
Entry
R
Yield
[%][a]
1
2
3
4
4-OMeC6H4 (1b)
4-MeC6H4 (1c)
4-FC6H4 (1d)
4-ClC6H4 (1e)
4-BrC6H4 (1 f)
4-NHAcC6H4 (1g)
2-MeC6H4 (1h)
Me (1i)
89
87
92
90
49
71
88
60
23[c]
5[b]
6[b]
7[b]
8
9
benzothiazolyl (1j)
[a] Yield of isolated product. [b] [{Rh(cod)OH}2] (4 mol%), binap
(12 mol%). [c] No improvement with double catalyst loading.
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Communications
To investigate the effect of carbon-chain length, the
homoallyl substrate 5 was employed under the standard
conditions [Eq. (1)]. A mixture of linear and branched
products (1.7:1) was obtained in 61% yield. The increase of
2 from the protonolysis of intermediate B, but suggested an
alternative b-hydride elimination/re-insertion pathway which
generates intermediate D. The protonolysis of D leads to
product 2 formation and catalyst regeneration.
The directing effect of the sulfone group was also shown in
the reactions with propargyl sulfone 8, an unsymmetrical and
unactivated alkyne [Eq. (3)]. High regisoelectivities favoring
carbon-chain length by one carbon atom caused a substantial
decrease in yield and loss of regioselectivity (cf. Table 2,
entry 1). On the other hand, no reaction occured with vinyl
phenyl sulfone under the same conditions, in accordance with
literature reports.[3f,9] We also tested substrates which contain
internal alkenes such as cinnamyl phenyl sulfone, crotyl p-
tolyl sulfone and 3-(phenylsulfonyl)cyclohex-1-ene, as well as
a substrate with substituents at the a position (a,a-dimethyl-
allyl phenyl sulfone). No reaction occurred with these more
sterically hindered alkenes. The sulfone group was essential
for the reactivity since allyl phenyl sulfide and sulfoxide did
not react under the same conditions.
The proposed catalytic cycle is shown in Scheme 2.
Presumably the sulfone group of substrate 1 plays two roles:
1) enhancing the reactivity of the alkene component by
product 9 were obtained, presumably resulting from the
analogous five-membered rhodacycle intermediate as pro-
posed in Scheme 1. When 2-formylphenylboronic acid was
used, the indenol product 11 was obtained as a single
regioisomer (determined by NOE experiments) in high
yield through
a
domino addition/annulation process
[Eq. (4)].[13c,d] Regioselective rhodium-catalyzed addition of
Scheme 2. Proposed catalytic cycle of rhodium(I)-catalyzed addition of
arylboronic acids to allyl sulfones (1).
arylboronic acids to unsymmetrical alkynes are usually
limited to alkynes substituted with electron-withdrawing,
aromatic/heteroaromatic, and sterically encumbering
groups.[1a,e,5b–d,13] To the best of our knowledge, this is one of
the few examples of highly regioselective rhodium-catalyzed
addition to unactivated alkynes. The multisubstituted alkenyl
products 9 and 11 are useful precursors for further trans-
formations such as Julia olefinations.
In conclusion, we have developed a highly linear-selective
rhodium(I)-catalyzed addition of arylboronic acid to allyl
sulfones. These studies have extended the scope of unacti-
vated alkenes that can participate in the rhodium-catalyzed
coordinating to the rhodium–aryl species A prior to insertion;
2) controlling the regioselectivity of the alkene insertion by
forming a stabilized five-membered rhodacycle intermediate
B. Protonolysis of B would furnish product 2 and regenerate
the catalyst. However, deuterium-quenching experiments
using D2O gave the deuterated product [D]-2an with 60%
deuterium incorporation exclusively at the benzylic position
[Eq. (2)]. This result ruled out the direct formation of product
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unactivated alkynes such as propargyl sulfones to afford
substituted alkenyl products in high regioselectivities. Further
studies on mechanism, branched product formation, and
utilization of the addition products are currently in progress.
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Received: July 16, 2010
Revised: September 1, 2010
Published online: October 12, 2010
Keywords: allylic compounds · hydroarylation · regioselectivity ·
.
rhodium · sulfones
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