Intercepting the Breslow intermediate via Claisen rearrangement: Synthesis of complex tertiary alcohols without organometallic reagents

Article abstract of DOI:10.1021/ol303053c

A novel Claisen rearrangement in which the Breslow intermediate is engaged as a hydroxy-substituted N,S-ketene acetal to provide complex 3° alcohols without the use of organometallic reagents is reported. The reaction constitutes an unprecedented reactivi

Full text of DOI:10.1021/ol303053c

ORGANIC
LETTERS
2013
Vol. 15, No. 1
3–5
Intercepting the Breslow Intermediate via
Claisen Rearrangement: Synthesis of
Complex Tertiary Alcohols without
Organometallic Reagents
Sefat Alwarsh,† Kolawole Ayinuola,† Silvana S. Dormi, and Matthias C. McIntosh*
119 Chemistry Building, University of Arkansas, Fayetteville, Arkansas 72701,
United States
mcintosh@uark.edu
Received November 6, 2012
ABSTRACT
A novel Claisen rearrangement in which the Breslow intermediate is engaged as a hydroxy-substituted N,S-ketene acetal to provide complex 3° alcohols
without the use of organometallic reagents is reported. The reaction constitutes an unprecedented reactivity mode for the Breslow intermediate.
Thiamine diphosphate (1) is an essential cofactor for
several enzymes, including transketolase, acetolactate
synthase, and pyruvate oxidase, decarboxylase, and oxidore-
ductases (Figure 1).1 In 1958, as a part of an investigation
of the mechanism of thiamine action, Breslow proposed
carbene 2 and enol 3 as transient intermediates in the
N-methylthiazolium-catalyzed benzoin condensation of
benzaldehyde.2 The so-called Breslow intermediate 3,
and other azole-based variants, has been implicated in a
variety of N-heterocyclic carbene (NHC) catalyzed pro-
cesses involving aldehydes.3 While a stable thiazolyl
carbene analogous to 2 has been characterized,4,5 the
corresponding Breslow intermediate 3 has thus far eluded
even spectroscopic detection.6À8
† These authors contributed equally.
(1) Jordan, F.; Patel, M. S. Thiamine - Catalytic Mechanisms in
Normal and Disease States; Marcel Dekker, Inc.: New York, 2004; p 588.
(2) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
(3) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606–5655. Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37,
2691–2698. Vora, H. U.; Rovis, T. Aldrichimica Acta 2011, 44, 3–11.
Biju, A. T.; Kuhl, N.; Glorius, F. Angew. Chem., Int. Ed. 2011, 44, 1182–
1195. Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522.
(4) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liebigs Ann.
1997, 365–374.
Figure 1. Thiamine diphosphate and Breslow intermediate 3.
Most NHC-catalyzed reactions involving aldehydes are
thought to proceed via mechanisms in which intermediates
such as 3 behave as nucleophilic enamines.3 However, one
(5) Vignolle, J.; Cattoen, X.; Bourissou, D. Chem. Rev. 2009, 109,
3333–3384.
(6) DiRocco, D. A.; Oberg, K. M.; Rovis, T. J. Am. Chem. Soc. 2012,
134, 6143–6145.
r
10.1021/ol303053c
2012 American Chemical Society
Published on Web 12/05/2012

may alsoviewthe intermediate as a hydroxy-substituted N,
S-ketene acetal. From that perspective, a conceptually
novel disconnection for a Claisen rearrangement precursor
emerges (Scheme 1).9À12
However, no rearrangement product was detected upon
extended heating. Further experimentation revealed that
useofDBU inplace of NEt3 providedketone 11atambient
temperature. More importantly, heating of the reaction
mixture to 60À65 °C provided Claisen rearrangement pro-
duct 13a in 75% yield.15À17 No benzoin was detected by
TLC analysis of the crude reaction mixture upon compar-
ison to an authentic sample.
Scheme 1. Novel Retrosynthetic Approach to Claisen
Rearrangement Precursor 6
We probed the steric and electronic influences on the
reaction by surveying a variety of aromatic and heteroaro-
matic aldehydes (Figure 2). The reaction tolerated ortho
substitution to the aldehyde (13b,dÀf,i), reacting even with
1-naphthaldehyde, albeit in somewhat diminished yield.
Both electron-rich (13f,i,j) and electron-poor (13cÀe) alde-
hydes participated in the reaction. However, 4-nitrobenzal-
dehyde gave only products of the Cannizarro reaction.18
Pyridine-2-carboxaldehyde and 2-furaldehyde also pro-
vided good yields of rearrangement products (13g,h). We
were pleased to find that even an unprotected phenol was
tolerated (13i).
Rearrangement of an N-allyl-hydroxy-N,S-ketene ace-
tal 6 would provide tertiary alcohol 7. Such an approach
would require that intermediate 6 undergo rearrangement
in preference to participating in benzoin condensation.
Since the rearrangement would be intramolecular, and the
benzoin condensation intermolecular, it seemed plausible
that rearrangement might be kinetically favored.
In 1964, Metzger reported the condensation of N-methyl
benzothiazolium salt 8 (X = OSO3Me) with benzaldehyde
inthe presence ofNEt3 in methanol under refluxtoprovide
ketone 10 in 75% yield (Scheme 2).13 Using the Metzger
conditions, we found that reaction of benzothiazolium salt
9 (X = Br)14 likewise afforded the analogous N-allyl
ketone 11 in comparable yield.
Scheme 2. Metzger Condensation and Claisen Rearrangement
Figure 2. Claisen rearrangement products and yields from 9.
There were notable differences in reactivity of electron-
poor and -rich aldehydes. Electron-poor aldehydes reacted
more rapidly in both the Metzger condensation and the
(11) For another Claisen rearrangement of an enol, see: Wood, J. L.;
Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A. A.; Dietrich,
H.-J. J. Am. Chem. Soc. 1999, 121, 1748–1749.
(12) For reviews, see: The Claisen Rearrangement À Methods and
Applications; Nubbemeyer, U., Hiersemann, M., Eds.; Wiley-VCH: Weinheim,
2007; p 591 and additional reviews cited therein.
(13) (a) Metzger, J.; Larive, H.; Dennilauler, R.; Baralle, R.; Gaurat,
C. Bull. Soc. Chim. Fr. 1964, 2857–2867. (b) Doughty, M. B.; Risinger,
G. E. Bioorg. Chem. 1987, 15, 1–14.
(14) Yen, S. K.; Koh, L. L.; Huynh, H. V.; Hor, T. S. A. Dalton Trans.
2007, 3952–3958.
(7) Berkessel has recently reported the spectroscopic characterization
of an analogous intermediate formed from a imidazolyl carbene and
several aromatic aldehydes: Berkessel, A.; Elfert, S.; Yatham, V. R.;
Neudoerfl, J.-M.; Schloerer, N. E.; Teles, J. H. Angew. Chem., Int. Ed.
2012, 51, 1–6.
(8) Mayr has recently reported the isolation of several O-methylated
Breslow intermediates: Maji, B.; Mayr, H. Angew. Chem., Int. Ed. 2012,
51, 10408–10412.
(15) (a) Troisi has previously prepared 13a via Wittig rearrangement:
Capriati, V.; Florio, S.; Ingrosso, G.; Granito, C.; Troisi, L. Eur. J. Org.
Chem. 2002, 478–484. (b) Troisi’s preparation of 13a employed organo-
lithium reagents and cryogenic temperatures in both steps.
(16) There has recently been a renaissance of interest in stoichiometric
reactions of NHCs: Arduengo, A. J.; Calabreseb, J. C.; Davidsonb, F.;
Dias, H. V. R.; Goerlich, J. R.; Krafczyk, R.; Marshall, W. J.; Tamm, M.;
Schmutzler, R. Helv. Chim. Acta 1999, 82, 2348–2364. Coady, D. J.;
Bielawski, C. W. Macromolecules 2006, 39, 8895–8897. Hudnall, T. W.;
Moorhead, E. J.; Gusev, D. G.; Bielawski, C. W. J. Org. Chem. 2010, 75,
2763–2763. Moerdyk, J. P.; Bielawski, C. W. J. Am. Chem. Soc. 2012, 134,
6116–6119.
ꢀ
ꢀ
(9) Holloczki, O.; Kelemen, Z.; Nyulaszi, L. J. Org. Chem. 2012, 77,
6014–6022.
(10) For other approaches to N-allyl-N,X-ketene acetals derived
from azoles or azolines, see: (a) Ireland, R. E.; Willard, A. K. J. Org.
Chem. 1974, 39, 421–424. (b) Baldwin, J. E.; Walker, J. A. J. Am. Chem.
Soc. 1974, 96, 596–597. (c) Kurth, M. J.; Decker, O. H. W.; Hope, H.;
Yanuck, M. D. J. Am. Chem. Soc. 1985, 107, 443–448. (d) Kurth, M. J.;
Decker, O. H. W. J. Org. Chem. 1986, 51, 1377–1383. (e) Waetzig, S. R.;
Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 4138–4139.
(17) The capture of thiazolyl intermediates 12 via Claisen rearrange-
ment is arguably the most direct structural evidence yet for the Breslow
intermediate’s existence, since all of the elements of the intermediate are
retained in the rearranged product.
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Org. Lett., Vol. 15, No. 1, 2013

Claisen rearrangement based on TLC analysis of the reac-
tion mixture. For example, ketone formation had begun
within 30 min for 2-Br benzaldehyde, while 2,4-dimethyl-
benzaldehyde required 24 h for the ketone to begin to
appear. Similarly, the electron-poor or -neutral aldehydes
were heated at ca. 60À65 °C for 16 h to effect the re-
arrangement step, while the 2,4-dimethylbenzaldehyde-
derived ketone 11j required 48 h and the 2-oxy substituted
ketones 11f,i required 72 h at ca. 80À85 °C.
There are several practical benefits to this Claisen-based
method for the synthesisofcomplex diaryl 3° alcohols such
as 13aÀj.19,20 First, benzothiazoles are very common
heteroaromatic motifs in medicinal chemistry.21 AC-265347
and analogs thereof, for example, have been reported to be
calcium sensing receptor agonists (Figure 3).22 They were
prepared in the traditional fashion by addition of 2-lithio-
benzothiazole to the corresponding ketones at À78 °C. By
contrast, we prepared allyl analog 13j in 50% yield over
two steps from benzothiazole using our all-organic Claisen
approach.15b
Second, 2-lithiothiazole and -benzothiazole have been em-
ployed extensively in synthesis as acyl anion equivalents.23
These organometal reagents are not compatible with a large
number of comparatively acidic and/or electrophilic func-
tional groups.24 This necessitates the deployment of protec-
tive groups, with the attendant decrease in step economy25
and process efficiency.26 The mildness of the Claisen-based
approach avoids the need for protective groups for hydroxyl
Figure 3. Calcium sensing AC-265347 and allyl analog 13j.
and phenoxy groups and will presumably tolerate many
other comparatively acidic functionalities.
Third, unlike organometal-based approaches that re-
quire ethereal solvents, the above transformations were
carried out in methanol. Methanol is generally considered
to be a green solvent,27 which is an important considera-
tion for process and/or production scale synthesis.
Finally, the conventional approach to 3° alcohol synthe-
sis employing highly reactive organo Li or Mg nucleophiles
generally requires cryogenic conditions. This can be proble-
matic on production scale and requires more expensive
reactor equipment and careful monitoring of reaction tem-
perature due to the danger of exotherms.28 By contrast, only
mild heating is necessary to effect the Metzger condensa-
tion/Claisen rearrangement sequence. Increasing the scale
of the reaction to 10 g of benzothiazolium salt 9 provided a
77% yield of 13a with no alteration of reaction conditions.
In conclusion, we have prepared a variety of benzothia-
zole-based complex 3° alcohols in two steps under mild
conditions without the use of any organometallic reagents.
We continue to investigate the scope of the reaction.
(18) (a) Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306–
1315. (b) Abaee has reported that Cannizzaro reactions can occur under
similar conditions catalyzed by LiBr: Mojtahedi, M. M.; Akbarzadeh,
E.; Sharifi, R.; Abaee, M. S. Org. Lett. 2007, 9, 2791–2793. However,
exchange of the bromide counterion of 9a for a tosylate resulted in no
significant change in the reaction outcome, suggesting the Cannizzaro
reaction is NHC catalyzed.
(19) For less conventional anionic approaches to related compounds,
see: Popov, I.; Do, H.-Q.; Daugulis, O. J. Org. Chem. 2009, 74, 8309–
8313. Hirono, Y.; Kobayashi, K.; Yonemoto, M.; Kondo, Y. Chem.
Commun. 2010, 7623–7624.
Acknowledgment. The authors thank the NSF (CHE-
0911638), the NIH (P30RR031154), and the Arkansas Bio-
sciences Institute for support of this work and the Ministry of
Education of Saudi Arabia for a graduate fellowship for S.A.
(20) For other nonmetallic approaches to similar compounds, see:
(a) Burns, N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson, I. A.; Leighton,
J. L. Angew. Chem., Int. Ed. 2006, 45, 3811–3813. (b) Khodakovskiy,
P. V.; Mykhailiuk, P. K.; Volochnyuk, D. M.; Tolmachev, A. A.
Synthesis 2010, 1633–1638.
Supporting Information Available. Experimental pro-
1
cedures, compound characterization data, and H and
13C NMR spectra of 13aÀj. This material is available free
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The authors declare no competing financial interest.
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