Regioselective rhodium(I)-catalyzed hydroarylation of protected allylic amines with arylboronic acids

Article abstract of DOI:10.1021/ol100974f

A novel regioselective rhodium(I)-catalyzed hydroarylation of unactivated alkenes with arylboronic acids is described. The catalytic system employs [Rh(COD)OH]₂ and BINAP to effect the addition of various arylboronic acids to protected allylic amines. The regioselectivity was found to be highly dependent on the protecting group, favoring the linear addition product with up to 92% yield and >20:1 regioselectivity.

Full text of DOI:10.1021/ol100974f

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2456-2459
Regioselective Rhodium(I)-Catalyzed
Hydroarylation of Protected Allylic
Amines with Arylboronic Acids
Gavin Chit Tsui, Frederic Menard, and Mark Lautens*
DaVenport Laboratories, Department of Chemistry, UniVersity of Toronto, Toronto,
Ontario, Canada M5H 3H6
mlautens@chem.utoronto.ca
Received February 9, 2010
ABSTRACT
A novel regioselective rhodium(I)-catalyzed hydroarylation of unactivated alkenes with arylboronic acids is described. The catalytic system
employs [Rh(COD)OH]2 and BINAP to effect the addition of various arylboronic acids to protected allylic amines. The regioselectivity was
found to be highly dependent on the protecting group, favoring the linear addition product with up to 92% yield and >20:1 regioselectivity.
Rhodium-catalyzed carbon-carbon bond formation has been
the subject of extensive studies in recent years.1 In particular,
significant advances have been made in rhodium(I)-catalyzed
addition of arylboronic acids to alkenes activated by con-
jugated electron-withdrawing groups (Miyaura-Hayashi
reaction).2 The net outcome of the process is the addition of
hydrogen and aryl groups across the double bond (hydroary-
lation).3 However, the addition to unactivated alkenes still
remains a major challenge in this area. Strained alkenes, such
as norbornene, have been reported to insert into a rhodium-
aryl bond as a key step for facilitating multiple alkylation
of aromatic rings.4,5 In an earlier communication, we reported
a rhodium-catalyzed cross-coupling of styrenes with aryl-
boronic acids.6 The method afforded trans-stilbene products
in good yield, which were formed via a Heck-type
addition-elimination process. In contrast, heteroaromatic
alkenes such as 2-vinylpyridine led to the addition products
exclusively via an addition-hydrolysis process. Although
these reports contributed to broaden the scope of alkenes
that can undergo rhodium-catalyzed addition reactions, to
the best of our knowledge, rhodium-catalyzed hydroarylation
of simple alkenes, e.g., alkenes that are not conjugated or
(3) For examples of transition-metal-catalyzed hydroarylation of alkenes,
see: (a) Jana, R.; Tunge, J. A. Org. Lett. 2009, 11, 971. (b) Harada, H.;
Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772.
(c) Bhalla, G.; Oxgaard, J.; Goddard, W. A., III; Periana, R. A. Organo-
metallics 2005, 24, 3229. (d) Oxgaard, J.; Periana, R. A.; Goddard, W. A.,
III J. Am. Chem. Soc. 2004, 126, 11658. (e) Han, X.; Widenhoefer, R. A.
Org. Lett. 2006, 8, 3801. (f) Chianese, A. R.; Lee, S. J.; Gagne´, M. R.
Angew. Chem., Int. Ed. 2007, 46, 4042. (g) McKeown, B. A.; Foley, N. A.;
Lee, J. P.; Gunnoe, T. B. Organometallics 2008, 27, 4031. (h) Youn, S. W.;
Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (i) Martinez, R.; Genet,
J.-P.; Darses, S. Chem. Commun. 2008, 3855. (j) Foley, N. A.; Lee, J. P.;
Ke, Z.; Gunnoe, T. B.; Cundari, T. R. Acc. Chem. Res. 2009, 42, 585. (k)
Bartoli, G.; Cacchi, S.; Fabrizi, G.; Goggiamani, A. Synlett 2008, 2508.
(4) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem. Soc.
2000, 122, 10464.
(1) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (c) Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
Germany, 2005. (d) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J.
Acc. Chem. Res. 2007, 40, 1394. (e) Miura, T.; Murakami, M. Chem.
Commun. 2007, 217.
(2) For additions to enones, see: (a) Sakai, M.; Hayashi, M.; Miyaura,
N. Organometallics 1997, 16, 4229. (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
For additions to R,ꢀ-unsaturated esters, see: (c) Sakuma, S.; Sakai, M.;
Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951. For additions to
vinyl phosphonates, see: (d) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara,
M. J. Am. Chem. Soc. 1999, 121, 11591. For additions to vinyl nitro
compounds, see: (e) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem.
Soc. 2000, 122, 10716. For additions to R,ꢀ-unsaturated aldehydes, see: (f)
Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am.
Chem. Soc. 2005, 127, 10850.
(5) For related hydroarylation of other [2.2.1]bicyclic alkenes, see: (a)
Menard, F.; Lautens, M. Angew. Chem., Int. Ed. 2008, 47, 2085. (b)
Panteleev, J.; Menard, F.; Lautens, M. AdV. Synth. Catal. 2008, 350, 2893.
(6) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B.
J. Am. Chem. Soc. 2001, 123, 5358.
10.1021/ol100974f  2010 American Chemical Society
Published on Web 05/10/2010

part of strained systems, has not been reported.
the protecting group. Substrates 1a-g, including phthalimide,
sulfonamides, carbamates, and amides, reacted successfully
with 4-acetylphenylboronic acids under the above optimal
conditions (Table 1).
We envisaged the use of simple protected allylic amines
1 as substrates for the hydroarylation reaction (eq 1).
Acylated allylic amines are widely used in medicinal
chemistry,7 and allyl groups can be utilized to install various
aryl groups at a late stage in SAR studies of drug discovery.
The alkene moiety of these allylic amines is not activated,
yet we speculated the protecting groups could potentially
coordinate to the rhodium catalyst to facilitate the reaction.
Two possible regioisomeric products, the linear 2 and
branched 3 products, can be formed upon arylrhodation.
Since both products are common motifs in biologically active
compounds,7 developing a regioselective method to access
either product would be valuable. Moreover, the branched
product 3 is amenable to enantioselective hydroarylation,
which could provide useful chiral amine building blocks.8
The chemoselectivity of the reaction also needs to be
addressed: addition followed by ꢀ-hydride elimination could
lead to a Heck-type product, or the substrate could isomerize
to an enamine in the presence of the rhodium catalyst.9
Table 1. Rh-Catalyzed Hydroarylation of Protected Allylic
Amines with 4-Acetylphenylboronic Acids
entry
NR1R2
yield (%)a
2:3b
product
1
2
3
4
5
6
7
N-phthalyl, 1a
NHSO2p-Tol, 1b
NHSO2Me, 1c
NHCOOtBu, 1d
NHCOOBn, 1e
NHCOOEt, 1f
NHC(O)Me,c 1g
91
92
83
92
86
65
50
7:1
6:1
4:1
2:1
2:1
2:1
2:1
2aa
2ba
2ca
2da
2ea
2fa
2ga
a Isolated yields. b Determined by crude 1H NMR (400 MHz).
c Allyl-NHC(O)tBu, -NHC(O)Ph, -NHPh, -NHBn, -NTs2, and -NTsBoc gave
<5% crude yield of desired products; allyl-NBoc2 gave 20% crude yield,
using phenylboronic acid.
The phthalyl and tosyl groups gave the highest regiose-
lectivities (entries 1 and 2), followed by the mesyl group
(entry 3). The carbamates and amide (entry 4-7) gave poor
regioselectivities. Good yields (up to 92%) of the hydroary-
lation products were obtained. Ethyl carbamate and methyl
amide gave moderate yields (entries 6 and 7). More sterically
hindered amides (pivaloyl and benzoyl groups), aniline,
benzylamine, and substrates with two protecting groups (-Ts2,
-TsBoc, -Boc2) did not provide the desired products in
satisfactory yields (0-20%).
The scope of arylboronic acids was studied using allylic
phthalimide 1a, sulfonamide 1b, and carbamate 1d as
substrates (Table 2). Excellent regioselectivities (up to >20:
1) were achieved in the phthalimide series (entries 1-7).
Moderate to good yields were obtained, though higher
catalyst loadings were required for some boronic acids
(entries 1, 4, 5, and 7). In the sulfonamide series (entries
8-14), although moderate yields or varying degrees of
regioselectivity were obtained, the majority of the cases gave
good regioselectivities (6:1 to 8:1). In the carbamate series
(entries 15-20), moderate yields and poor regioselectivities
(1:1 to 2:1) were obtained. Electron-withdrawing groups at
the para-position of the arylboronic acid (-Ac, -CF3,
-CO2Me) gave better yields than an electron-donating group
(-MeO) at the same position (compare entries 1/7, 8/13, and
15/19). Meta- and ortho-substituents (3-Ac, 3-MeO and
2-Me) were also tolerated, affording the products in moderate
yields. The 2-Me group in the sulfonamide series (entry 14)
led to poorer regioselectivity. It was found that adding a small
amount of water (dioxane/water ) 100:1 v/v) had a beneficial
effect on regioselectivity in some cases (entries 2, 11, and
13). For example, compared to the result without added
water, the regioselectivity in 2aa increased significantly from
We initially studied the reaction of Boc-protected allylic
amine 1d with phenylboronic acid in the presence of
[Rh(COD)OH]2 and BINAP. Linear and branched products
2-Boc and 3-Boc were obtained in 70% yield in a 1:1 ratio
(eq 2). No Heck-type products or isomerized starting material
was observed in these conditions. Optimization of the
reaction conditions was then undertaken to improve the yield
and regioselectivity. Various parameters were studied, in-
cluding the catalyst source, ligand, organoboron reagent,
solvent, temperature, reaction time, and additives (see
Supporting Information). The initial [Rh(COD)OH]2/BINAP
conditions gave the best yield of the desired products.
Preferential formation of the linear product 2 was observed
with allylic amines bearing different protecting groups. The
yield and regioselectivity were found to be dependent on
(7) (a) Huang, Y.-T.; Blagg, B. S. J. J. Org. Chem. 2007, 72, 3609. (b)
Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336. (c) Svenson, J.;
Brandsdal, B.-O.; Stensen, W.; Svendsen, J. S. J. Med. Chem. 2007, 50,
3334.
(8) For an enantioselective synthesis of branched amines, see: Czekelius,
C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793.
(9) (a) Akutagawa, S. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Chapter
23, 41.4. (b) Inoue, S.-I.; Takaya, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori,
R. J. Am. Chem. Soc. 1990, 112, 4897.
Org. Lett., Vol. 12, No. 11, 2010
2457

7:1 to 15:1 (entry 2; cf. Table 1, entry 1), with a slight
decrease in yield. This effect was not observed in the
carbamate series.
Table 3. Effects of Sulfonamide Substituent Groupsa
Table 2. Scope of Arylboronic Acid Using Allyl-N-phthalimide,
Allyl-NHTs, and Allyl-NHBoca
entry
R
yield (%)b
2:3c
6:1
7:1
8:1
product
1
2
3
4
4-MeOC6H4, 1h
2-MeC6H4, 1i
4-FC6H4, 1j
CF3, 1k
92
88
2h
2i
2j
86
43d
>20:1
2k
a Reaction conditions: [Rh(COD)OH]2 (2 mol %), BINAP (6 mol %),
entry
1d
NR1R2
R
yield (%)b 2:3c product
boronic acid (2.5 equiv), 1,4-dioxane (2.5 mL), 75 °C, 12 h. b Isolated yields.
Determined by crude H NMR (400 MHz). d Average yield of two runs.
c
1
N-phthalyl, 1a 4-CF3
N-phthalyl, 1a 4-Ac
N-phthalyl, 1a 3-Ac
N-phthalyl, 1a 4-CO2Me
N-phthalyl, 1a 3-MeO
76
84
66
67
55
65
35
79
79
56
62
65
36
65
69
68
50
71
30
40
20:1 2ab
15:1 2aa
>20:1 2ac
11:1 2ad
>20:1 2ae
>20:1 2af
>20:1 2ag
8:1 2bb
6:1 2bc
2e f
,
3
4d
5d
6
Table 4. Effect of Carbon Chain Length
N-phthalyl, 1a
N-phthalyl, 1a 4-MeO
H
7d
8
NHTs, 1b
NHTs, 1b
NHTs, 1b
NHTs, 1b
NHTs, 1b
NHTs, 1b
NHTs, 1b
NHBoc, 1d
NHBoc, 1d
NHBoc, 1d
NHBoc, 1d
NHBoc, 1d
NHBoc, 1d
4-CF3
3-Ac
4-CO2Me
3-MeO
H
4-MeO
2-Me
4-CF3
3-Ac
4-CO2Me
3-MeO
4-MeO
2-Me
9
10
11e
12
8:1 2bd
>20:1 2be
6:1 2bf
13e g
15:1 2bg
3:1 2bh
1:1 2db
1:1 2dc
2:1 2dd
1:1 2de
1:1 2df
,
14
15
16
17
18
19
20
entry
NR1R2
n
yield (%)a
5:6b
product
1
2
3
NHTs, 4a
NHTs, 4b
N-phthalyl, 4c
b
2
3
0
62
48
35
1
1:1
1:1
>20:1
5a
5b
5c
a Isolated yields. Determined by crude H NMR (400 MHz).
1:1 2dg
a General conditions: 2 mol % [Rh(COD)OH]2, 6 mol % BINAP, 2.5
equiv of arylboronic acid, 2.5 mL of 1,4-dioxane, 75 °C, 12 h. b Isolated
yields. c Determined by crude 1H NMR (400 MHz). d 4 mol
%
reactivity, and product 2l was obtained in a yield comparable
to that with the nonmethylated sulfonamide (cf. Table 2, entry
12). The methyl group had a significant effect on regiose-
lectivity, favoring the linear product 2l exclusively.
[Rh(COD)OH]2, 12 mol % BINAP. e 1,4-Dioxane/H2O (2.5 mL/25 µL).
f Adding more water (1,4-dioxane/H2O ) 2.5 mL:250 µL) increased the
2:3 ratio (>20:1) but decreased conversion significantly (26% isolated yield).
g No added water: 33% yield, 2:3 ) 11:1.
The effects of the sulfonyl substituent group of sulfona-
mides 1h-k were subsequently studied. The products were
obtained in high yields favoring linear product 2 (Table 3).
Electron-rich, electron-poor, and ortho-substituted aromatic
groups all gave good yields and regioselectivities (entries
1-3). On the other hand, a drastic increase in regioselectivity
(>20:1) was observed with the CF3 group directly attached
to sulfone (entry 4).
To investigate whether the reaction could be extended to
alkenes other than allylic amines, substrates with a differing
carbon chain length were tested (Table 4).
The yield decreased significantly as the carbon chain length
increased, and a complete loss of regioselectivity was
observed (entries 1-2, cf. Table 1, entry 2). Vinyl phthal-
imide 4c afforded the linear product 5c exclusively albeit in
a low yield (entry 3). Intriguingly, this result demonstrates
a polarity reversal of the reactants since enamides/enamines
usually act as nucleophiles.10
A proposed catalytic cycle for the general reaction is
shown in Scheme 1. Fast transmetalation between the
rhodium catalyst and arylboronic acid generates Rh-Ar
species A. Subsequent coordination and insertion of alkene
1 would lead to intermediates B and C; this step determines
the regiochemical outcome of the product. Presumably,
certain XdO groups such as phthalyl and tosyl groups are
better at coordinating rhodium and thus stabilize intermediate
B by forming a six-membered rhodacycle, whereas a less
stable seven-membered ring would be formed in C. As a
result, the linear products 2 are formed predominantly upon
protonolysis, and the catalyst is regenerated. The fact that
(10) For our earlier report on palladium-catalyzed regioselective hy-
drostannation of substrate 4d, see: Lautens, M.; Kumanovic, S.; Meyer, C.
Angew. Chem., Int. Ed. 1996, 35, 1329.
Methylated sulfonamide 1l was also submitted to the
reaction (eq 3). The N-Me group did not impede the
2458
Org. Lett., Vol. 12, No. 11, 2010

the homoallylic substrate gave no regioselectivity (Table 4,
entry 1) may also support this hypothesis since no stabilized
rhodacycles would be formed. However, it is also possible
that B could undergo ꢀ-hydride elimination to form a
transient styrene-type intermediate D and Rh-H, which may
be in equilibrium with B and E. Protonolysis would lead to
the same linear product 2. We also hypothesize that the
coordination of the XdO group to rhodium would also
component of the substrate prior to insertion. The fact that
substrates without an XdO group such as allyl-NHPh and
-NHBn gave no desired product may support this argument
(Table 1).
In summary, a novel regioselective Rh(I)-catalyzed hy-
droarylation of protected allylic amines with arylboronic
acids was developed. The regioselectivity was found to be
dependent on the nature of the protecting group. Linear
products can be obtained in good yields and excellent
regioselectivities despite other competing processes such as
addition-elimination or isomerization. This represents one
of the few examples of Rh(I)-catalyzed addition of arylbo-
ronic acids to unactivated alkenes. Notably, the method
reported herein is complementary to Pd-catalyzed reactions
where ꢀ-elimination is more facile and generally the
predominant pathway. It should be noted that arylpropy-
lamines 2 are synthetic equivalents to fully reduced hydro-
cinnamyl amides where variation of the aryl group would
not be straightforward. However, the method reported herein
allows easy modulation of the aryl group in the last step.
Further investigation into the reaction mechanism, N-
substituent effect, use of other allylic substrates, and forma-
tion of branched product is in progress.
Scheme 1. Proposed Catalytic Cycle for Rh(I)-Catalyzed
Hydroarylation of Protected Allylic Amines
Acknowledgment. We thank NSERC, Merck Frosst
Canada, and the University of Toronto for support of our
program.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
explain the reactivity of the otherwise unactivated alkene
substrate 1 by bringing the Rh-Ar species close to the alkene
OL100974F
Org. Lett., Vol. 12, No. 11, 2010
2459