Ligand-free suzuki coupling of arylboronic acids with methyl (E)-4-bromobut-2-enoate: Synthesis of unconventional cores of HIV-1 protease inhibitors

Article abstract of DOI:10.1021/ol3016786

An effective ligand-free Suzuki coupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids has been accomplished. Thus, a number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent yields under mild conditions. This method enables the preparation of diverse aryl-substituted cores of HIV-1 protease inhibitors.

Full text of DOI:10.1021/ol3016786

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3928–3931
Ligand-Free Suzuki Coupling
of Arylboronic Acids with Methyl
(E)-4-Bromobut-2-enoate: Synthesis
of Unconventional Cores of HIV-1
Protease Inhibitors
Lucia Chiummiento, Maria Funicello,* Paolo Lupattelli, and Francesco Tramutola
ꢀ
Dipartimento di Chimica “Antonio Mario Tamburro”, Universita Degli Studi della Basilicata,
Viale dell’Ateneo Lucano 10, 85100, Potenza, Italy
maria.funicello@unibas.it
Received June 19, 2012
ABSTRACT
An effective ligand-free Suzuki coupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids has been accomplished.
Thus, a number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent yields under mild conditions.
This method enables the preparation of diverse aryl-substituted cores of HIV-1 protease inhibitors.
Metal-catalyzed cross-couplings are powerful tools for
organic chemists to form new CÀC bonds.1 Among these
cross-coupling processes, the Suzuki reaction2 is one of
the most attractive because of the ready availability of
organoboron compounds, their high compatibility toward
numerous functional groups, air-stability, and lower toxicity
than other organometallic species. Over the past decade,
impressive enhancements have been achieved through the
potential to unite different electrophiles with organoboron
reagents as the nucleophilic component. Palladium-catalyzed
couplings of alkynyl, aryl, alkenyl, and alkyl electrophiles
with boronic acids have been widely described in the litera-
ture. Nevertheless, protocols involving allylic halides have
not been extensively explored,3 although these are extremely
useful for the concomitant formation of new CÀC bonds and
the introduction of allylic moieties to target compounds.
In our continuous pursuit of new HIV-1 protease inhi-
bitors (PIs) bearing unconventional P1-ligands,4 we have
speculated a convenient synthetic route to introduce
diversity into the common hydroxyethylamino core5 pre-
sent in several approved PIs (e.g., darunavir6) (Scheme 1).
In a simple retrosynthetic approach, variously functiona-
lized aromatic groups can be incorporated by Suzuki
coupling between an activated C(sp3) bromide (allylic
electrophile) and an array of arylboronic acids to furnish
methyl 4-arylcrotonates (2).
Some strategies to prepare (E)-4-arylbut-2-enoates in
moderate to good yield imply a new CdC bond formation
(4) (a) Chiummiento, L.; Funicello, M.; Lupattelli, P.; Tramutola,
F.; Campaner, P. Tetrahedron 2009, 65, 5984–5989. (b) Bonini, C.;
Chiummiento, L.; De Bonis, M.; Di Blasio, N.; Funicello, M.;
Lupattelli, P.; Pandolfo, R.; Tramutola, F.; Berti, F. J. Med. Chem.
2010, 53, 1451–1457. (c) Chiummiento, L.; Funicello, M.; Lupattelli, P.;
Tramutola, F.; Berti, F.; Marino-Merlo, F. Bioorg. Med. Chem. Lett.
2012, 22, 2948–2950.
(1) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: New York, 2004.
(2) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457–2483. (b) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723–6737.
(3) (a) Moreno-Manas, M.; Pajuelo, F.; Pleixats, R. J. Org. Chem.
1995, 60, 2396–2397. (b) Singh, R.; Viciu, M. S.; Kramareva, N.;
Navarro, O.; Nolan, S. P. Org. Lett. 2005, 7, 1829–1832. (c) Alacid,
(5) Although (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane, a
common key intermediate in the synthesis of several PIs, is commercially
available, this is expensive and limited only to the incorporation of a
phenyl as the P1 ligand.
(6) Ghosh, A. K.; Anderson, D. D.; Weber, I. T.; Mitsuya, H. Angew.
Chem., Int. Ed. 2012, 51, 1778–1802.
ꢁ
E.; Najera, C. J. Organomet. Chem. 2009, 694, 1658–1665.
r
10.1021/ol3016786
Published on Web 07/17/2012
2012 American Chemical Society

Table 1. Effect of Various Reaction Parameters on the
Efficiency of a Suzuki Cross-Coupling
Scheme 1. Retrosynthesis of PIs Bearing Disparate Ar Groups
as P1 Ligands
Pd(OAc)2
(mol %)
P(t-Bu)2Me temp
ratio
2a:4:5a
yield of
2aa (%)
entry
(mol %)
(°C)
1
2
5
5
20
15
10
5
70
70
70
70
70
50
rt
74:23:3
74:23:3
74:23:3
95:5:0
95:5:0
97:3:0
98:2:0
À
74
74
74
95
95
97
98
À
3
5
4
5
5
5
À
6
5
À
7
5
À
8
5
10
À
rt
9
2.5
1
rt
98:2:0
98:2:0
À
98 b
75
À
10
11
12 c
13 d
À
rt
À
2.5
2.5
À
rt
À
rt
98:2:0
À
80
À
À
rt
a Determined by GC analysis versus a calibrated internal standard
(average of two experiments). b Isolated yield (average of two
experiments). c 1.1 equiv of phenylboronic acid was employed. d No KF.
by Wittig-like reaction,7 modified Julia olefination,8 or alkene
cross-metathesis.9 However, some limitations remain:
(1) required starting materials are not readily accessible and
(2) some functional groups are not tolerated. Furthermore, to
date, only very few examples of cross-coupling based syn-
thesis of (E)-4-arylbut-2-enoates have been described. Besides
the Heck reaction, which in this case does not afford high
regio- and sometimes stereoselectivity,10 only one effective
example has been accomplished: a low-valent iron complex
catalyzed reaction of phenylmagnesium bromide with methyl
4-bromocrotonate.11 A palladium-catalyzed Stille coupling
of (Z)-vinylstannyl carboxylate with benzyl bromide has
been reported as well, providing the product with cis
stereochemistry.12
Thus, we first considered the Suzuki cross-coupling
between methyl 4-bromocrotonate and phenylboronic
acid, and the effect of different parameters was studied
(Table 1). This reaction could, in principle, proceed toward
the formation of three isomers: the desired coupling pro-
duct 2a, its cis-stereoisomer 4, and its regioisomer 5 where-
by the double bond rearranges to the styryl position.14
As shown in Table 1, this method was significantly
sensitive to the relative amount of palladium source and
ligand employed in the reaction.15 On the basis of reported
data on alkyl bromides,16 we first began by using a 2- to
4-fold excess of P(t-Bu)2Me with respect to Pd source:
the three isomers 2a, 4, and 5 were always generated in
the same ratio (74:23:3, entries 1À3). In contrast, when the
metal/ligand ratio was decreased to 1:1 or, even, in the
absence of phosphine, this reaction afforded the desired
trans-product 2a with high selectivity (entries 4 and 5).
The latter result was delightfully interesting and rather
unexpected. Indeed, although the acceleration observed in
phosphine-free palladium-catalyzed Suzuki cross-couplings
is well-known,17 the positive effect on stereoselectivity
Considering the synthetic potential of the arylation of
4-bromocrotonates and the lack of systematic studies on
these electrophiles, we have been motivated to investigate
this specific process to accomplish a general high-yield
Suzuki protocol that furnishes (E)-4-arylbut-2-enoates.13
(7) Cannon, J. G.; True, C. D.; Long, J. P.; Bhatnagar, R. K.;
Leonard, P.; Flynn, J. R. J. Med. Chem. 1989, 32, 2210–2214.
(8) Blakemore, P. R.; Ho, D. K. H.; Nap, D. M. Org. Biomol. Chem.
2005, 3, 1365–1368.
(9) (a) Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K.
Org. Lett. 2008, 10, 1325–1328. (b) Voigtritter, K.; Ghorai, S.; Lipshutz,
B. H. J. Org. Chem. 2011, 76, 4697–4702.
(10) Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc.
2008, 130, 11270–11271.
(14) Narahashi, H.; Shimizu, I.; Yamamoto, A. J. Organomet. Chem.
2008, 693, 283–296.
€
(11) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773–8787.
(12) Serrano, J. L.; Fairlamb, I. J. S.; Sanchez, G.; Garcıa, L.; Perez,
J.; Vives, J.; Lopez, G.; Crawforth, C. M.; Taylor, R. J. K. Eur. J. Inorg.
Chem. 2004, 2706–2715.
(13) A first attempt of Suzuki reaction between ethyl 4-bromo-
crotonate and thienylboronic acids has been described in: Bonini, C.;
Chiummiento, L.; De Bonis, M.; Funicello, M.; Lupattelli, P.; Pandolfo,
R. Tetrahedron: Asymmetry 2006, 17, 2919–2924.
(15) For examples of cross-coupling reactions affected by the ratio of
phosphine to palladium, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2000, 122, 4020–4028. (b) Tsukamoto, H.; Uchiyama, T.;
Suzuki, T.; Kondo, Y. Org. Biomol. Chem. 2008, 6, 3005–3013.
(c) Nishikata, T.; Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 12103–
12105.
(16) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662–13663.
Org. Lett., Vol. 14, No. 15, 2012
3929

represents a novelty, particularly with allyl bromides as the
electrophiles. The higher efficiency of such a ligand-free
protocol was confirmed by the data obtained at lower
temperatures (entries 6À8) and with lower catalyst load-
ing, finally leading to the best conditions (entry 9).
For the Suzuki reaction illustrated in entry 9, different
conditions were tested: (1) the use of toluene, DME, THF,
and DMF rather than 1,4-dioxane as the solvent, resulted
in formation of the product in somewhat diminished yield
(75À90%); (2) on a gram scale, the reaction proceeded
in 98% yield; (3) a first attempt of a ligandless nickel-
catalyzed reaction by using NiI2 (5 mol %) rather than
the palladium source, essentially generated no coupling
product.
Table 2. Cross-Coupling of Methyl 4-Bromocrotonate with
Arylboronic Acids
Lower catalyst loading or amount of boronic acid
resulted in identical selectivity but lower yield (entries 10
and 12). In the absence of either Pd catalyst or base (KF),
essentially no product was observed (entries 11 and 13).
To explore the scope and limitation of this method,
coupling reactions between a variety of arylboronic acids
and methyl 4-bromocrotonate were investigated under the
optimized conditions (Table 2). Gratifyingly, this protocol
tolerated a variety of common functional groups such as
alkyl, ether, thioether, hydroxyl, aryl, halogen, trifluoro-
methyl, nitro, and aldehyde, regardlessofthe ortho-, meta-,
or para-position. The intrinsic reactivity of the employed
nucleophile determined the ease of this cross-coupling.
Particularly, electron-rich arylboronic acids (activated
nucleophiles) displayed higher reactivity than electron-
deficient ones (deactivated nucleophiles). Either activated
or weakly deactivated nucleophiles were shown to react
successfully with methyl 4-bromocrotonate under the
standard conditions (entries 2À8). The use of hindered
(entry 1) and electron-deficient (entries 9À11) arylboronic
acids required longer reaction times.18
More challenging deactivated nucleophiles only
reacted at higher temperature but afforded the styryl regio-
isomers (eq 1).
a Isolated yield (average of two experiments). b Run for 6 h. c Run for 10 h.
product in excellent or somewhat good yield, respectively
(eqs 2 and 3).
Other organoboron compounds can be utilized in this
cross-coupling as well;indeed, the reaction witha boronate
ester or a potassium trifluoroborate provided the coupling
(17) (a) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034–
5037. (b) See reference 3a. (c) Gerbino, D. C.; Mandolesi, S. D.; Schmalz,
ꢀ
H.-G.; Podesta, J. C. Eur. J. Org. Chem. 2009, 3964–3972.
(18) Coupling products bearing electron-deficient aryl groups are
more prone to isomerize to the corresponding styrene-like compounds.
In this regard, reaction time was of paramount importance. Indeed,
when these cross-couplings were conducted for longer than the necessary
reaction time or at higher temperature, total conversion of allylbenzene
products to styryl compounds occurred.
Finally, we could exploit the ability to obtain an array of
4-arylcrotonates in our synthesis of the core of PIs. As an
3930
Org. Lett., Vol. 14, No. 15, 2012

and NBS in CH2Cl2 in 92% yield over the two steps.19
At this stage, we introduced the two stereocenters by
Sharpless asymmetric dihydroxylation of compound 8,
using (DHQD)2AQN under reported conditions,20 to
furnish the corresponding syn-bromo diol. The latter
intermediate was cyclized with K2CO3 in MeOH to chiral
hydroxy epoxide 9 in 72% yield and 90% ee.21 Next, the
oxiranyl ring-opening reaction on 9 with i-BuNH2 in
i-PrOH at reflux afforded product 10 in quantitative yield.
The resulting amino diol was first protected at the amino
function with Boc2O, Et3N in CH2Cl2 and then, without
any purification, was cyclized with NaH in THF to render
the respective oxazolidin-2-one 11 in 94% yield.22 It is
noteworthy that the process of cyclization only affords the
five-membered ring rather than the six-membered one,
which indicates that the formation of the oxazolidin-
2-one ring is highly preferred.23 Therefore, we had the
regioselective protection of the vicinal amino alcohol,
whereas the adjacent free hydroxy group was prone to be
activated by MsCl, Et3N in CH2Cl2 and then displaced by
NaN3 in DMF to furnish product 12 in 78% yield over the
two steps. The latter compound represents a very attrac-
tive, highly functionalized synthon which can be used as a
versatile building block. At last, deprotection of the amino
alcohol moiety mediated by basic hydrolysis furnished the
desired compound 13 in 90% yield.24
Scheme 2. Synthesis of the Hydroxyethylamino Core of PIs
Starting from 4-Arylcrotonate 2j
In conclusion, we have described effective, ligand-free,
palladium-catalyzed Suzuki cross-couplings of methyl
4-bromocrotonate with arylboronic acids. It is noteworthy
that this protocol is not air-sensitive and does not require
special handling. Studies on the potential to drive this
reaction toward the stereoselective formation of cis-products
are ongoing in our laboratory.
Furthermore, we have shown how this reaction can be
efficiently used as the first step in a high-yield enantio-
selective synthesis of the core of PIs incorporating diverse
aromatic groups as unconventional P1-ligands.
Acknowledgment. Support has been provided by MIUR
example, we report in Scheme 2 this approach starting
from cross-coupling product 2j.
ꢀ
(Italian Ministry of University) - PRIN 2008 and Universita
degli Studi della Basilicata.
Thus R,β-unsaturated ester 2j was reduced by DIBALH
in CH2Cl2 to the corresponding allyl alcohol, which was
subsequently transformed to allyl bromide 8 by using PPh3
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via Internet at http://pubs.acs.org
(19) For an alternative synthesis of allyl bromides via cross-metathesis,
see: Blanco, O. M.; Castedo, L. Synlett 1999, 5, 557–558.
(20) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35,
448–451.
(21) The preparation of a chiral hydroxy epoxide similar to com-
pound 9 was previously reported in: Fernandes, R. A. Tetrahedron:
Asymmetry 2008, 19, 15–18. However, therein, (DHQD)2PHAL was
used as the chiral ligand in the AD. In our case, those conditions
afforded the desired product in only 54% yield and 80% ee.
(22) Coe, D. M.; Perciaccante, R.; Procopiou, P. A. Org. Biomol.
Chem. 2003, 1, 1106–1111.
(23) Chiummiento, L.; Funicello, M.; Tramutola, F. Chirality 2012,
24, 345–348.
(24) Wang, H; Rizzo, C. J. Org. Lett. 2001, 3, 3603–3605.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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