High chemoselectivity in the phenol synthesis

Article abstract of DOI:10.3762/bjoc.7.90

Efforts to trap early intermediates of the gold-catalyzed phenol synthesis failed. Neither inter- nor intramolecularly offered vinyl groups, ketones or alcohols were able to intercept the gold carbenoid species. This indicates that the competing steps of

Full text of DOI:10.3762/bjoc.7.90

High chemoselectivity in the phenol synthesis
Matthias Rudolph1, Melissa Q. McCreery2, Wolfgang Frey2
and A. Stephen K. Hashmi*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 794–801.
1Organisch-Chemisches Institut, Ruprecht-Karls-Universität
Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
and 2Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
doi:10.3762/bjoc.7.90
Received: 01 April 2011
Accepted: 23 May 2011
Published: 10 June 2011
Email:
A. Stephen K. Hashmi* - hashmi@hashmi.de
Guest Editor: F. D. Toste
* Corresponding author
© 2011 Rudolph et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alcohols; alkenes; alkynes; furans; gold; ketones
Abstract
Efforts to trap early intermediates of the gold-catalyzed phenol synthesis failed. Neither inter- nor intramolecularly offered vinyl
groups, ketones or alcohols were able to intercept the gold carbenoid species. This indicates that the competing steps of the gold-
catalyzed phenol synthesis are much faster than the steps of the interception reaction. In the latter the barrier of activation is higher.
At the same time this explains the high tolerance of this very efficient and general reaction towards functional groups.
Introduction
As documented in numerous reviews [1-10], over the last oxides D [19] and oxepines C [20] could be detected as inter-
eleven years homogeneous gold catalysis has emerged from mediates, and these could even be trapped by Diels–Alder reac-
early examples [11,12] which documented its potential for tions. In addition, labelling studies were carried out and the
organic synthesis of even complex molecules to an established electronic influence of substituents was investigated [21].
tool in preparative organic chemistry [13,14]. One of these early Computational studies as well as side-products produced in the
examples is the gold-catalyzed phenol synthesis [12] in which reaction pointed towards intermediates A and B (Scheme 1)
the furan-ynes 1 used as substrates represent the first ene–yne- [22-25]. Moreover, interesting new pathways were opened
type compounds ever used in gold catalysis. While many when ynamides and alkynyl ether substrates were employed:
investigations in the field focused on methodology, mecha- Here A is also a possible intermediate along these pathways
nistic research was much less widespread [2,3,15]. The gold- [25].
catalyzed ene–yne cycloisomerization reactions are, mechanisti-
cally, very complex reactions [16-18], and the furan–yne cycloi- Since direct experimental evidence existed only for C and D,
somerization is no exception. For the latter reaction arene we intended to intercept the postulated carbenoid intermediates
794

Beilstein J. Org. Chem. 2011, 7, 794–801.
Scheme 2: Efforts for intermolecular trapping with olefins failed.
Experiments with a competing carbonyl group (competing with
the carbonyl group in intermediate B) were also unsuccessful.
Ketone 5 [37], prepared by the addition of methyllithium to
commercially available hex-5-enoic acid, was used as an
external carbonyl group. Reaction with both tosylamide 3 and
Scheme 1: Mechanism of the furan–yne reaction.
A or B. Apart from intermolecular trapping [26-33], intramolec- ether 6 always delivered the phenolic products 4 or 7, respect-
ular trapping of such carbenoids has also been reported [34]. ively (Scheme 3). The same result was obtained when PtCl2
One option would be to offer a competing carbonyl group, to was used as the catalyst for the conversion of 3.
produce a carbonyl ylide, which could then undergo a 1,3-
dipolar cycloaddition [35]. The second option would be a clas- Intramolecular olefinic trapping reagents
sical cyclopropanation of an olefin. A third option would be The next step was to offer the styrene unit in an intramolecular
trapping of intermediate A with an intramolecular hydroxy manner. Substrate 8 could potentially undergo three different
nucleophile [36]. Here we report our observations when trying modes of reaction (Scheme 4). After the initial step, the inter-
to apply these principles to intermediates of type A or B.
mediate E would be produced (analogous to A). Cyclopropana-
tion of the styrene subunit by the cyclopropyl carbenoid would
deliver 9. If E rearranged to the vinylcarbenoid F, the two
competing reactions would be the formation of the phenol 10
Results and Discussion
Intermolecular olefinic trapping reagents
We started with the simplest experiments, namely the intermol- and cyclopropanation to form 11.
ecular trapping of the gold carbenoid intermediates. When 3
was reacted in the presence of an activated olefin, such as The synthesis of 8 was possible by a short route (Scheme 5).
norbornene or styrene, phenol 4 was formed exclusively in Starting from the commercially available 2-bromostyrene (12),
essentially quantitative yield, no other products could be a halogen–metal exchange and subsequent formylation
detected (Scheme 2).
according to a procedure of Fukumoto et al. [38] gave 13. Add-
Scheme 3: Efforts for intermolecular trapping with ketones failed.
795

Beilstein J. Org. Chem. 2011, 7, 794–801.
Scheme 4: Potential products of an intramolecular trapping experiment with substrate 8.
Scheme 6: With substrate 8 the product of the phenol synthesis was
exclusively obtained.
Scheme 5: Synthesis of the substrate 8.
ition of ethynylmagnesium bromide to 13 led to 14, which
reacted with furan 15 [40] under Mitsunobu conditions [39] to
afford 8. While the yields were good for the first two steps of
the reaction sequence, the yield of the last step was only 32%.
With AuCl3 the phenol 10 was formed exclusively (Scheme 6).
The structure was unambiguously confirmed by X-ray crystal
structure analysis (Figure 1). It shows an interesting hydrogen
bond-like interaction of the phenolic hydroxy group and the
Figure 1: Solid-state molecular structure of 10.
Intramolecular ketone as potential trapping
alkene unit. After changing the solvent from acetonitrile to reagent
CDCl3, and the gold(I) catalyst to [Mes3PAu]NTf2 [41], only Next we decided to use a carbonyl group as the competing unit.
10 was again observed. Thus, neither of the two oxidation states The intermediate G, formed from substrate 16, would offer the
of the gold catalyst gave any product derived from the inter- option of competition of the phenol synthesis (Scheme 7,
cepted intermediate (the solvent was changed to CDCl3 since pathway a) to yield 18, and reaction with the second carbonyl
the activity of gold(I) is significantly reduced by MeCN).
group (Scheme 7, pathway b). The latter would form intermedi-
796

Beilstein J. Org. Chem. 2011, 7, 794–801.
Scheme 7: Potential products of an intramolecular trapping experiment with substrate 16.
ate H, which could then either afford product 17 via intramolec- oxidized, followed by removal of the trimethylsilyl group from
ular 1,3-dipolar cycloaddition with the olefin, or could form the the alkyne also failed. Thus treatment of 27 with acetic acid in
diene 19 by proton migration.
aqueous THF gave the desired alcohol 31in quantitative yield.
However, whilst Ley oxidation [42] on the small-scale deliv-
The synthesis of 16 was only possible by a 9-step sequence ered ketone 32 in yields of up to 80%, on a larger scale the yield
(Scheme 8). The starting point was a Claisen condensation of of 32 dropped dramatically to 28% and was accompanied by
ester 20 and tert-butyl acetate (21) in the presence of lithium two side-products, 33 and 5. The latter are formed by an elimi-
hexamethyldisilazide as the base. Ketoester 22 was obtained in nation reaction of the amide in 32. Furthermore, it was not
56% yield, however, the two-fold addition of 21 could not be possible to deprotect ketone 32 due to rapid decomposition.
suppressed completely and 14% of the corresponding tertiary
alcohol 30 was also obtained. Reduction of the ketone 22 with One of the diastereoisomers of 28 was identified as the anti-pro-
sodium borohydride and protection of the alcohol 23 with tert- duct 28a by an X-ray crystal structure analysis (Figure 2).
butyldimethylsilylchloride delivered 24 in excellent yield.
Reduction of the ester group with diisobutylaluminiumhydride The conversion of 16 with 5 mol % AuCl3 proceeded fast and
gave aldehyde 25. The addition of lithiated trimethylsilylacety- gave exclusively phenol 18. No other products could be
lene provided the propargylic alcohol 26 and reaction with 15 detected (Scheme 9).
under Mitsunobu conditions yielded 27. Deprotection of the
alkyne 27 and the silyl ether 28, followed by the oxidation of The two gold(III) complexes 34 [43] and 35 [37] as well as the
the resulting alcohol 29 finally led to 16. It was not possible to dinuclear gold(I) complex 36 [44] gave the same result
remove both silyl groups simultaneously with TBAF, longer (Figure 3). When the catalyst was changed to platinum(II) chlo-
reaction times which would be necessary for the deprotection of ride in acetone, a complex mixture of inseparable products was
the hydroxy group led to decomposition of the substrate. At obtained.
0 °C and with a very short reaction time, the alkyne was depro-
tected selectively. Selective deprotection of the alcohol was Since the two diastereoisomers 28a and 28b with the propar-
then possible with a mixture of acetic acid/water/THF. Another gylic stereocenters were separable, we investigated the gold-
route, in which the alcohol function was deprotected first, then catalyzed conversion of the pure isomers. From the NMR
797

Beilstein J. Org. Chem. 2011, 7, 794–801.
Scheme 8: Synthesis of the substrate 16.
Figure 2: Solid-state molecular structure of 28a.
798

Beilstein J. Org. Chem. 2011, 7, 794–801.
Scheme 9: With substrate 16 the product of the phenol synthesis is obtained exclusively.
Figure 3: Catalysts 34, 35 and 36.
Figure 5: Structure of the desilylation product 38.
spectra taken during the conversion (Figure 4), it could be
clearly seen that no epimerization of the propargylic position thesis to yield 40, an intramolecular nucleophilic attack at the
occurred. In addition to the selective transformation to the activated three-membered ring could form intermediate J,
phenols 37a and 37b as the main reaction products, partial which, after protodeauration, would provide ketal 41.
removal of the TBS group was observed (38, Figure 5).
The synthesis of 39 was readily accomplished by the addition of
Intramolecular alcohol as potential trapping
reagent
lithiated sylvan 42 to the PMB-protected aldehyde 43
(Scheme 11) [45]. The resulting furfuryl alcohol 44 was then
For the interception of intermediate A we also considered the propargylated to give 45. The deprotection was however, prob-
option of an intramolecular hydroxy nucleophile, compound 39 lematic. Treatment of the latter with cerium ammonium nitrate
(Scheme 10) would represent this type of substrate. The inter- led to decomposition. Only with DDQ was the desired alcohol
mediate I would be an analogue of A. Instead of the phenol syn- 39 obtained in moderate yield.
Figure 4: 1H NMR spectra of the separated diastereoisomers of the substrates for catalysis 28 (left) and of the products 37 (right, the small signals
are due to the deprotected compounds 38).
799

Beilstein J. Org. Chem. 2011, 7, 794–801.
Scheme 12: With substrate 39 and 45 exclusively the product of the
phenol synthesis is obtained.
Supporting Information
Scheme 10: Potential products of an intramolecular trapping experi-
ment with substrate 39.
Supporting Information File 1
Experimental details and characterization data of
synthesized compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-90-S1.pdf]
Acknowledgements
This work was generously supported by the Deutsche For-
schungsgemeinschaft (SFB 623) and by Umicore AG & Co.
KG.
References
1. Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. 2006, 118,
8064–8105. doi:10.1002/ange.200602454
Angew. Chem., Int. Ed. 2006, 45, 7896–7936.
doi:10.1002/anie.200602454
2. Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403.
doi:10.1038/nature05592
3. Fürstner, A.; Davies, P. W. Angew. Chem. 2007, 119, 3478–3519.
doi:10.1002/ange.200604335
Scheme 11: Synthesis of the substrate 39.
Angew. Chem., Int. Ed. 2007, 46, 3410–3449.
doi:10.1002/anie.200604335
The conversion of 39, catalyzed by AuCl3 in CDCl3, again only
produced the expected phenol 40 (Scheme 12). Not unexpect-
edly, the PMB-protected alcohol 45 was similarly converted to
46. PtCl2 did not lead to a change in selectivity.
4. Jiménez-Núñez, E.; Echavarren, A. M. Chem. Commun. 2007,
333–346. doi:10.1039/b612008c
5. Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265.
doi:10.1021/cr068434l
6. Arcadi, A. Chem. Rev. 2008, 108, 3266–3325. doi:10.1021/cr068435d
7. Muzart, J. Tetrahedron 2008, 64, 5815–5849.
doi:10.1016/j.tet.2008.04.018
Conclusion
The complete failure of both the inter- and the intramolecular
trapping experiments shows that the gold-catalyzed phenol syn-
thesis follows a reaction pathway low in energy. These observa-
tions also nicely explain the high functional group tolerance, for
example, towards olefins and alcohols.
8. Shen, H. C. Tetrahedron 2008, 64, 7847–7870.
doi:10.1016/j.tet.2008.05.082
9. Hashmi, A. S. K.; Bührle, M. Aldrichimica Acta 2010, 43, 27–33.
10.Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994–2009.
doi:10.1021/cr1004088
800

Beilstein J. Org. Chem. 2011, 7, 794–801.
11.Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem.
2000, 112, 2382–2385.
32.Fehr, C.; Galindo, J. Angew. Chem. 2006, 118, 2967–2970.
doi:10.1002/ange.200504543
doi:10.1002/1521-3757(20000703)112:13<2382::AID-ANGE2382>3.0.
CO;2-R
Angew. Chem., Int. Ed. 2006, 45, 2901–2904.
doi:10.1002/anie.200504543
Angew. Chem., Int. Ed. 2000, 39, 2285–2288.
doi:10.1002/1521-3773(20000703)39:13<2285::AID-ANIE2285>3.0.CO
;2-F
33.Nieto-Oberhuber, C.; López, S.; Muňoz, M. P.; Jiménez-Núñez, E.;
Buñuel, E.; Cárdenas, D. J.; Echavarren, A. M. Chem.–Eur. J. 2006,
12, 1694–1702. doi:10.1002/chem.200501089
34.López, S.; Herrero-Gómez, E.; Pérez-Galán, P.; Nieto-Oberhuber, C.;
Echavarren, A. M. Angew. Chem. 2006, 118, 6175–6178.
doi:10.1002/ange.200602448
12.Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000,
122, 11553–11554. doi:10.1021/ja005570d
13.Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766–1775.
doi:10.1039/b615629k
Angew. Chem., Int. Ed. 2006, 45, 6029–6032.
doi:10.1002/anie.200602448
14.Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208–3221.
doi:10.1039/b816696j
35.Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1996, 61,
73–81. doi:10.1021/jo951371e
15.Hashmi, A. S. K. Angew. Chem. 2010, 122, 5360–5369.
doi:10.1002/ange.200907078
36.Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962–6963.
doi:10.1021/ja051110e
Angew. Chem., Int. Ed. 2010, 49, 5232–5241.
doi:10.1002/anie.200907078
37.Rubottom, G. M.; Kim, C. J. Org. Chem. 1983, 48, 1550–1552.
doi:10.1021/jo00157a038
16.Nieto-Oberhuber, C.; López, S.; Jiménez-Núñez, E.; Echavarren, A. M.
Chem.–Eur. J. 2006, 12, 5916–5923. doi:10.1002/chem.200600174
17.Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Aldrichimica Acta 2010, 43,
37–46.
38.Hibino, S.; Sugino, E.; Adachi, Y.; Nomi, K.; Sato, K.; Fukumoto, K.
Heterocycles 1989, 28, 275–282. doi:10.3987/COM-88-S12
39.Mitsunobu, O.; Kato, K.; Tomari, M. Tetrahedron 1970, 26, 5731–5736.
doi:10.1016/0040-4020(70)80009-6
18.Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075–6089.
doi:10.1002/ejoc.200900790
40.Carrettin, S.; Blanco, M. C.; Corma, A.; Hashmi, A. S. K.
Adv. Synth. Catal. 2006, 348, 1283–1288.
19.Hashmi, A. S. K.; Rudolph, M.; Weyrauch, J. P.; Wölfle, M.; Frey, W.;
Bats, J. W. Angew. Chem. 2005, 117, 2858–2861.
doi:10.1002/ange.200462672
doi:10.1002/adsc.200606099
41.Blanco, M. C. AURICAT EU-RTN final report, Universität Stuttgart,
2006.
Angew. Chem., Int. Ed. 2005, 44, 2798–2801.
doi:10.1002/anie.200462672
42.Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639–666. doi:10.1055/s-1994-25538
20.Hashmi, A. S. K.; Kurpejović, E.; Wölfle, M.; Frey, W.; Bats, J. W.
Adv. Synth. Catal. 2007, 349, 1743–1750.
43.Canovese, L.; Cattalini, L.; Marangoni, G.; Tobe, M. L.
J. Chem. Soc., Dalton Trans. 1985, 731–735.
doi:10.1039/DT9850000731
doi:10.1002/adsc.200600653
21.Hashmi, A. S. K.; Rudolph, M.; Siehl, H.-U.; Tanaka, M.; Bats, J. W.;
Frey, W. Chem.–Eur. J. 2008, 14, 3703–3708.
doi:10.1002/chem.200701795
44.Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic, E.; Frey, W.; Bats, J. W.
Adv. Synth. Catal. 2006, 348, 709–713. doi:10.1002/adsc.200606012
45.Herb, C.; Maier, M. E. J. Org. Chem. 2003, 68, 8129–8135.
doi:10.1021/jo035054g
22.Martín-Matute, B.; Cárdenas, D. J.; Echavarren, A. M. Angew. Chem.
2001, 113, 4890–4893.
doi:10.1002/1521-3757(20011217)113:24<4890::AID-ANGE4890>3.0.
CO;2-V
Angew. Chem., Int. Ed. 2001, 40, 4754–4757.
doi:10.1002/1521-3773(20011217)40:24<4754::AID-ANIE4754>3.0.CO
;2-9
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
23.Martín-Matute, B.; Nevado, C.; Cárdenas, D. J.; Echavarren, A. M.
J. Am. Chem. Soc. 2003, 125, 5757–5766. doi:10.1021/ja029125p
24.Hashmi, A. S. K.; Wölfle, M.; Ata, F.; Hamzic, M.; Salathé, R.; Frey, W.
Adv. Synth. Catal. 2006, 348, 2501–2508.
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
doi:10.1002/adsc.200600367
25.Hashmi, A. S. K. Pure Appl. Chem. 2010, 82, 1517–1528.
doi:10.1351/PAC-CON-09-10-34
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
26.Miki, K.; Ohe, K.; Uemura, S. Tetrahedron Lett. 2003, 44, 2019–2022.
doi:10.1016/S0040-4039(03)00219-3
27.Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68, 8505–8513.
doi:10.1021/jo034841a
(http://www.beilstein-journals.org/bjoc)
28.Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 18002–18003. doi:10.1021/ja0552500
29.Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc.
2004, 126, 8654–8655. doi:10.1021/ja048094q
30.Fürstner, A.; Hannen, P. Chem. Commun. 2004, 2546–2547.
doi:10.1039/b412354a
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.90
31.Fürstner, A.; Hannen, P. Chem.–Eur. J. 2006, 12, 3006–3019.
doi:10.1002/chem.200501299
801