Rhodium(I)-Catalyzed 1,4-Addition of Arylboronic Acids to Acrylic Acid in Water: One-Step Preparation of 3-Arylpropionic Acids

Abstract

A practical method for the one-step preparation of 3-arylpropionic acids through rhodium-catalyzed 1,4-addition of arylboronic acids to acrylic acid is reported. The method is applicable to a broad scope of aryl boronic acids and displays a wide functional group tolerance operating in water as the optimal reaction medium.

Formation of C-C bonds via rhodium catalysis has become a powerful emergent tool in organic synthesis. [¹] Of particular value is the rhodium-catalyzed conjugate addition of arylboronic acids to activated and unactivated al­kenic substrates (Miyaura-Hayashi reaction) such as enones, [²] unsaturated esters, [³] aldehydes, [4] amides, [5] phosphonates, [6] sulfones, [7] allyl amines, [8] allyl sulfones, [9] boryl­alkenes, [¹0] bicyclic alkenes [¹¹] and vinyl- [¹²] and alkynylarenes. [¹³] However, to the best of our knowledge, the use of α,β-unsaturated carboxylic acids as Michael acceptors in such a transformation is unknown. [¹4] This is surprising since the resulting 3-arylpropionic acids are highly selective agonists of the sphingosine-1-phosphate receptor (S1P1) and therefore of significant interest to medicinal chemistry. [¹5] Herein, we disclose a one-step protocol for the preparation of 3-arylpropionic acids employing the first rhodium-catalyzed 1,4-addition of arylboronic acids to acrylic acid [¹6] yielding valuable 3-arylpropionic acids employing water as the optimal reaction medium (Scheme  [¹] ).

As a model system, we studied the reaction of phenylboronic acid with acrylic acid employing standard conditions used for the Miyaura-Hayashi reaction (Table  [¹] ) and first looked at the influence of the nature of the organoboron reagent.

Table 1 Reaction Conditions for the 1,4-Addition of Phenylboron Reagents to Acrylic Acid^a

Entry	Catalystb	PhBX2 c	Solvent	Yield (%)d
1	[Rh(cod)OH]2	PhB(pin)	H2O	31
2	[Rh(cod)OH]2	PhBF3K	H2O	52
3	[Rh(cod)OH]2	Ph4BNa	H2O	0
4	[Rh(cod)OH]2	(PhBO)3	H2O	93
5	[Rh(cod)OH]2	PhB(OH)2	H2O	96
6	[Rh(cod)Cl]2	PhB(OH)2	H2O	93
7	[Rh(cod)2BF4]	PhB(OH)2	H2O	12
8	[RhCl3˙3H2O]	PhB(OH)2	H2O	0
9	[Ir(cod)Cl]2	PhB(OH)2	H2O	<10
10	[Ru(cod)Cl2]n	PhB(OH)2	H2O	0
11	[Rh(cod)OH]2	PhB(OH)2	t-BuOH	64
12	[Rh(cod)OH]2	PhB(OH)2	acetone	54
13	[Rh(cod)OH]2	PhB(OH)2	dioxane	0
a Reaction conditions: [Rh(cod)OH]2 (0.005 mmol), acrylic acid (0.2 mmol) and PhBX2 (0.5 mmol) in degassed solvent (1.8 mL) were heated in a closed Schlenk vessel at 75 ˚C for 16 h under argon.¹7 b cod: 1,5-cyclooctadiene. c pin: pinacol. d Isolated yields.

Phenylboronic pinacol ester and potassium phenyltrifluoroborate showed modest activity in the presence of [Rh(cod)OH]₂ in water (31% and 52% respectively, entries 1 and 2). While sodium tetraphenylborate was completely ineffective (entry 3), phenylboroxine, an alternative reagent for phenylboronic acid, gave high yields in this 1,4-addition process (93%, entry 4), comparable to its parent compound (96%, entry 5). [Rh(cod)Cl]₂ was also shown to be effective in such a transformation (93%, entry 6). [¹8] Notably, the reaction between phenylboronic acid and acrylic acid was run on a 2.5-mmol scale and furnished slightly lower yield (82%; see Supplementary Information). An excess of boronic acid proved necessary due to competing protodeborylation. [¹a] Using cationic rhodium or Rh(III) precursors (entries 7 and 8) or changing the metal catalyst from iridium (entry 9) to ruthenium (entry 10) were deleterious. A screening of suitable reaction media revealed water to be the optimal medium in terms of catalyst activity (entries 5 and 11-13). It is worth noting that the aqueous medium turns the process heterogeneous, allowing for facile product separation by simple EtOAc extraction. With the optimal, highly active catalyst system in hand (Table  [¹] , entry 5), we explored the substrate scope of the reaction (Table  [²] ).

Table 2 Scope of the Rhodium-Catalyzed 1,4-Addition of Arylboronic Acids to Acrylic Acid^a (continued)

Entry	Product	Yield (%)b
1		96
2		80
3		90
4c		83
5		91
6		87
7		83
8		94
9		90
10		76
11		72
12		71
13		95
a Reaction conditions: [Rh(cod)OH]2 (0.005 mmol), acrylic acid (0.2 mmol) and arylboronic acid (0.5 mmol) in degassed H2O (1.8 mL) were heated in a closed Schlenk vessel at 75 ˚C for 16 h under argon.¹7 b Isolated yields. c T = 100 ˚C.

Good yields were obtained for the addition of phenylboronic acid and p-tolylboronic acid to acrylic acid (entries 1 and 2, 96% and 80% yield, respectively). Sterical hindrance is tolerated at the boronic acid reaction partner as exemplified by the formation of 3-(2′-methylphenyl)propionic acid (entry 3) and 3-(2′,6′-dimethylphenyl)propionic acid (entry 4) in high yields (90% and 83%, respectively). It is noteworthy that known alternative accesses to these compounds require multistep synthesis. [¹9] Both electron-donating as well as electron-withdrawing substituents in the arylboronic acid system were well tolerated (entries 5-9). Furthermore, aryl bromides are inert under these reaction conditions, and allow further functionalization via palladium-based cross-coupling methodology. Moreover, heteroaromatic boronic acids as well as styryl boronic acids were efficient reaction partners (entries 10-12), thus highlighting the wide functional group tolerance of this catalyst system. Again, a previously reported multistep-demanding synthesis of 3-(3′-thienyl)propionic acid could be replaced by our simple one-step protocol (entry 10). [²0] Even though certain rhodium catalysts are known to promote the addition of arylboronic acids to aldehydes, an unprotected aldehyde function proved compatible with the reaction conditions (entry 13).

Taking into account that α-deuterated 3-phenylpropionic acid (100% deuteration in α-position, Scheme  [²] ) is obtained when benzene boronic acid reacts with acrylic acid in D₂O, the following mechanism could be proposed (Scheme  [³] ): transmetallation of arylboronic acid to [Rh(I)]OH furnishes an arylrhodium(I) complex, [¹²] which after coordination of acrylic acid followed by insertion into the Rh-Ar bond would provide the rhodium enolate, which may be either O- or C-bound. Hydrolysis of this rhodium enolate with water would release the desired 3-arylpropionic acid and explains the α-deuterium incorporation upon use of D₂O. The fact that we observed high yield of the 1,4-addition product compared to a competing protodeborylation of the arylboronic acid under the experimental conditions applied, suggests that the insertion of acrylic acid into the Rh-Ar bond is faster than the oxidative addition of the carboxylic acid to the rhodium center followed by the protolytic cleavage of the rhodium-aryl bond.

In summary, we have developed the first rhodium-catalyzed 1,4-addition of arylboronic acids to acrylic acid furnishing valuable 3-arylpropionic acids in good to high yields operating in water as the reaction medium. This methodology is applicable to a variety of substrates, displays a wide functional group tolerance and expands the scope of rhodium-catalyzed C-C bond-forming reactions.

Supporting Information including experimental details and spectroscopic data of all new compounds is available online at ­http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

This work was supported by the DFG, the International Research Training Group ‘Catalysts and Catalytic Reactions for Organic Synthesis’ (IRTG 1038), the Fonds der Chemischen Industrie, the Krupp Foundation and the Humboldt Foundation (postdoctoral fellowship to N.R.V.). We thank Umicore, BASF and Wacker for generous gifts of chemicals.

References and Notes

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• 19a Zhang X. De Los Angeles JE. He M.-Y. Dalton JT. Shams G. Lei L. Patil PN. Feller DR. Miller DD. Hsu F.-L. J. Med. Chem.  1997,  40:  3014 
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Slightly lower yields were obtained when non-degassed H₂O was used.

Frost and co-workers reported the failure of the reaction between 1-naphthalene boronic acid and free α,β-unsaturated carboxylic acid with [Rh(COD)Cl]₂ (see ref 3b). In our hands, the use of 2-naphthalene boronic acid in the presence of acrylic acid did not work with [Rh(COD)OH]₂ either, which tends to prove the poor reactivity of naphthalene boronic acid derivatives when mixed together with free carboxylic acid under such conditions.

References and Notes

• 1a Fagnou K. Lautens M. Chem. Rev.  2003,  103:  169 
  Search in Google Scholar
• 1b Hayashi K. Yamasaki K. Chem. Rev.  2003,  103:  2829 
  Search in Google Scholar
• 1c Evans PA. Modern Rhodium-Catalyzed Organic Reactions   Wiley-VCH; Weinheim: 2005. 
• 1d Skucas E. Ngai M.-Y. Komanduri V. Krische MJ. Acc. Chem. Res.  2007,  40:  1394 
  Search in Google Scholar
• 1e Miura T. Murakami M. Chem. Commun.  2007,  217 
• 1f Lewis JC. Bergman RG. Ellman JA. Acc. Chem. Res.  2008,  41:  1013 
  Search in Google Scholar
• 1g Colby DA. Bergman RG. Ellman JA. Chem. Rev.  2010,  110:  624 
  Search in Google Scholar
• 1h Edwards HJ. Hargrave JD. Penrose SD. Frost CG. Chem. Soc. Rev.  2010,  39:  2093 
  Search in Google Scholar
• 2a Sakai M. Hayashi M. Miyaura N. Organometallics  1997,  16:  4229 
  Search in Google Scholar
• 2b Takaya Y. Ogasawara M. Hayashi T. Sakai M. Miyaura N. J. Am. Chem. Soc.  1998,  120:  5579 
  Search in Google Scholar
• 2c Ghosh AK. Bilcer G. Schiltz G. Synthesis  2001,  2203 
• 2d List B. Castello C. Synlett  2001,  1687 
• 2e Reetz MT. Moulin D. Gosberg A. Org. Lett.  2001,  3:  4083 
  Search in Google Scholar
• 3a Sakuma S. Sakai M. Itooka N. Miyaura N. J. Org. Chem.  2000,  65:  5951 
  Search in Google Scholar
• 3b Chapman CJ. Frost CG. Adv. Synth. Catal.  2003,  345:  353 
  Search in Google Scholar
• 4 Paquin J.-F. Defieber C. Stephenson CRJ. Carreira EM. J. Am. Chem. Soc.  2005,  127:  10850 
  CrossrefSearch in Google Scholar
• 5a Senda T. Ogasawara M. Hayashi T. J. Org. Chem.  2001,  66:  6852 
  Search in Google Scholar
• 5b Sakuma S. Miyaura N. J. Org. Chem.  2001,  66:  8944 
  Search in Google Scholar
• 6 Hayashi T. Senda T. Takaya M. Ogasawara M. J. Am. Chem. Soc.  1999,  121:  11591 
  CrossrefSearch in Google Scholar
• 7 Mauleon P. Carretero JC. Org. Lett.  2004,  6:  3195 
  CrossrefSearch in Google Scholar
• 8 Tsui GC. Menard F. Lautens M. Org. Lett.  2010,  12:  2456 
  CrossrefSearch in Google Scholar
• 9 Tsui GC. Lautens M. Angew. Chem. Int. Ed.  2010,  49:  8939 
  Search in Google Scholar
• 10 Sasaki K. Hayashi T. Angew. Chem. Int. Ed.  2010,  49:  8145 
  CrossrefSearch in Google Scholar
• 11a Oguma K. Miura M. Satoh T. Nomura M. J. Am. Chem. Soc.  2000,  122:  10464 
  Search in Google Scholar
• 11b Lautens M. Dockendorff C. Fagnou K. Malicki A. Org. Lett.  2002,  4:  1311 
  Search in Google Scholar
• 11c Murakami M. Igawa H. Chem. Commun.  2002,  390 
• 11d Menard F. Lautens M. Angew. Chem. Int. Ed.  2008,  47:  2085 
  Search in Google Scholar
• 11e Panteleev J. Menard F. Lautens M. Adv. Synth. Catal.  2008,  350:  2893 
  Search in Google Scholar
• 12a Lautens M. Roy A. Fukuoka K. Fagnou K. Martin-Matute B. J. Am. Chem. Soc.  2001,  123:  5358 
  Search in Google Scholar
• 12b Pattison G. Piraux G. Lam HW. J. Am. Chem. Soc.  2010,  132:  14373 
  Search in Google Scholar
• 13a Amengual R. Michelet V. Genet J.-P. Tetrahedron Lett.  2002,  43:  5905 
  Search in Google Scholar
• 13b Lautens M. Yoshida M. Org. Lett.  2002,  4:  123 
  Search in Google Scholar
• 13c Lautens M. Yoshida M. J. Org. Chem.  2003,  68:  762 
  Search in Google Scholar
• 13d Genin E. Michelet V. Genet JP. J. Organomet. Chem.  2004,  689:  3820 
  Search in Google Scholar
• For non-rhodium-catalyzed use of α,β-unsaturated carboxylic acids as Michael acceptors, see:
• 14a Cooke MP. J. Org. Chem.  1987,  52:  5729 
  Search in Google Scholar
• 14b Aurell MJ. Domingo LR. Mestres R. Munoz E. Zaragoza R J. Tetrahedron  1999,  55:  815 
  Search in Google Scholar
• 14c Li Z. Shi Z. He C. J. Organomet. Chem.  2005,  690:  5049 
  Search in Google Scholar
• 15 Yan L. Huo P. Doherty G. Toth L. Hale JJ. Mills SG. Hajdu R. Keohane CA. Rosenbach MJ. Milligan JA. Shei GJ. Chrebet G. Bergstrom J. Card D. Quackenbush E. Wickham A. Mandala SM. Bioorg. Med. Chem. Lett.  2006,  14:  3679 
  Search in Google Scholar
• 16 α- and β-Substituted α,β-unsaturated carboxylic acids did not react under the conditions developed herein. Neither did alkylboronic acids (methyl and butylboronic acids) nor alkenylboronic acids (potassium vinyltrifluoroborate and vinylboronic acid pinacol ester)
• 19a Zhang X. De Los Angeles JE. He M.-Y. Dalton JT. Shams G. Lei L. Patil PN. Feller DR. Miller DD. Hsu F.-L. J. Med. Chem.  1997,  40:  3014 
  Search in Google Scholar
• 19b Beaulieu PL. Anderson PC. Cameron DR. Croteau G. Gorys VC. Grand-Maitre C. Lamarre D. Liard F. Paris W. Plamandon L. Soucy F. Thibeault D. Wernic D. Yoakim C. J. Med. Chem.  2000,  43:  1094 
  Search in Google Scholar
• 20 Hauze DB. Joullie MM. Tetrahedron  1997,  53:  4239 
  CrossrefSearch in Google Scholar

Slightly lower yields were obtained when non-degassed H₂O was used.

Frost and co-workers reported the failure of the reaction between 1-naphthalene boronic acid and free α,β-unsaturated carboxylic acid with [Rh(COD)Cl]₂ (see ref 3b). In our hands, the use of 2-naphthalene boronic acid in the presence of acrylic acid did not work with [Rh(COD)OH]₂ either, which tends to prove the poor reactivity of naphthalene boronic acid derivatives when mixed together with free carboxylic acid under such conditions.

• Supplementary Material