A new synthesis of γ-butyrolactones via AuCl3- or Hg(II)-catalyzed intramolecular hydroalkoxylation of 4-bromo-3-yn-1-ols

Article abstract of DOI:10.1021/ol2033493

An efficient conversion of 4-bromo-3-yn-1-ols to γ-butyrolactones via AuCl₃-catalyzed electrophilic cyclization (hydroxyl-assisted regioselective hydration) in wet toluene is described. Various secondary and tertiary alcohols including benzylic systems were found to be equally reactive with moderate to excellent yields obtained in all cases.

Full text of DOI:10.1021/ol2033493

ORGANIC
LETTERS
2012
Vol. 14, No. 3
824–827
A New Synthesis of γ-Butyrolactones via
AuCl3- or Hg(II)-Catalyzed Intramolecular
Hydroalkoxylation of 4-Bromo-3-yn-1-ols†
Maddi Sridhar Reddy,* Yalla Kiran Kumar, and Nuligonda Thirupathi
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,
Lucknow 226 001, India
msreddy@cdri.res.in; sridharreddymaddi@yahoo.com
Received December 15, 2011
ABSTRACT
An efficient conversion of 4-bromo-3-yn-1-ols to γ-butyrolactones via AuCl3-catalyzed electrophilic cyclization (hydroxyl-assisted regioselective
hydration) in wet toluene is described. Various secondary and tertiary alcohols including benzylic systems were found to be equally reactive with
moderate to excellent yields obtained in all cases.
Cycloisomerization via intramolecular hydroalkoxyla-
tion and hydroamination of alkynes with tethered hydro-
xyl or amino groups is currently an emerging method for
the synthesis of various heterocycles such as pyrroles,
furans, quinolines, spiroketals, and many new frameworks
whicharenot otherwise readily accessible.1,2 Variousmetal
ions including Au(I), Au(III), Hg(II), Fe(III), Zn(II), Ag-
(I), Pd(0), Pd(II), Cu(II), Ni, Co, and Ir have been em-
ployed to functionalize alkynes.1,2 In particular, the recent
explosion of interest in gold catalysis has not only made the
several existing methods easier but also led to the synthesis
of a variety of novel heterocyclic architectures.1 The
popularity of such chemistry stems from the easy access
to alkyne intermediates and the brevity of approach and
because the alkyne intermediates are inert to various
reagents and reaction conditions and, hence, can be used
to conceal the required subunit until an appropriate point
is reached in a long total synthesis. We herein report for the
first time the conversion of 4-bromo-3-yn-1-ols to butyr-
olactones using AuCl3 in aqueoustoluene (Scheme 1, eq3).
The starting substrates, bromoalkynols, can be easily
accessed from alkynes, alkynylsilanes, and dibromoolefins
(3) (a) Gallagher, P. W.; Terstiege, I.; Maleczka, R. E. J. Am. Chem.
Soc. 2001, 123, 3194–3204. (b) Boden, C. D. J.; Pattenden, G.; Ye, T.
J. Chem. Soc., Perkin Trans. 1 1996, 2417–2419. (c) Gonzalez, I. Cl.;
Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099–9108. (d) Lu, W.;
Zheng, G.; Cai, J. Tetrahedron 1999, 55, 7157–7168.
(4) (a) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem. 2005,
243, 43–72. (b) Miyabe, H.; Fujji, K.; Goto, T.; Naito, T. Org. Lett. 2000,
2, 4071–4074. (c) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675–
678. (d) Koch, S. S. C.; Chamberlin, A. R. Enantiomerically Pure γ-
Butyrolactones; Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 1995;
pp 687À725. (d) Fernandez, A.-M.; Plaquevent, J.-C.; Duhamel, L.
J. Org. Chem. 1997, 62, 4007–4014. (e) Collins, I. J. Chem. Soc., Perkin
Trans. 1 1998, 1869–1888.
(5) For a few examples of synthesis of lactones, see: (a) Huang, L.;
Jiang, H.; Qi, C.; Liu, X. J. Am. Chem. Soc. 2010, 132, 17652–17654. (b)
Dohi, T.; Takenaga, N.; Goto, A.; Maruyama, A.; Kita, Y. Org. Lett.
2007, 9, 3129–3132. (c) Schomaker, M. M.; Travis, B. R.; Borhan, B.
Org. Lett. 2003, 5, 3089–3092. (d) Seitz, M.; Reiser, O. Curr. Opin. Chem.
Biol. 2005, 9, 285–292. (e) Ogliaruso, M. A.; Wolfe, J. F. In Synthesis of
Lactones and Lactams; John Wiley & sons: New York, 1993. (f) Trost,
B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680–11683. (g) Nosse,
B.; Chhor, R. B.; Jeong, W. B.; Bohm, C.; Reiser, O. Org. Lett. 2003, 5,
941–944. (h) Compain, P.; Gore, J.; Vatele, J. ÀM. Tetrahedron 1996, 52,
10405–10416. (I) Gutierrez, J. L. G.; Jimenez-Cruz, F.; Espinosa, N. R.
Tetrahedron Lett. 2005, 46, 803–803.
(1) For some recent examples, see: (a) Yao, T.; Zhang, X.; Larock,
R. C. J. Am. Chem. Soc. 2004, 126, 11164–11165. (b) Kothandaraman,
P.; Rao, W.; Foo, S. J.; Chan, P. W. H. Angew. Chem., Int. Ed. 2010, 49,
4619–4623. (c) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489–4492. (d)
Patil, N. T.; Kavthe, R. D.; Shinde, V. S.; Sridhar, B. J. Org. Chem. 2010,
75, 3371–3380. (e) Fang, C.; Pang, Y.; Forsyth, C. J. Org. Lett. 2010, 12,
4528–4531. (f) Nishizawa, M.; Imagawa, H.; Yamamoto, H. Org.
Biomol. Chem. 2010, 8, 511–521. (g) Carney, M. M.; Donoghue, P. J.;
Wuest, W. M.; Wiest, O.; Helquist, P. Org. Lett. 2008, 10, 3903–3906. (h)
Sandelier, M. J.; DeShong, P. Org. Lett. 2007, 9, 3209–3212 and the
references therein.
(2) (a) Ravindar, K.; Reddy, M. S.; Deslongchamps, P. Org. Lett.
2011, 13, 3178–3181. (b) Ravindar, K.; Reddy, M. S.; Lindqvist, L.;
Pelletier, J.; Deslongchamps, P. J. Org. Chem. 2011, 76, 1269–1284. (c)
Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.; Deslongchamps,
P. Org. Lett. 2010, 12, 4420–4423.
r
10.1021/ol2033493
Published on Web 01/25/2012
2012 American Chemical Society

using well-established literature precedents (Scheme 1,
eq 3).3
Table 1. Optimization Studies for the synthesis of butyrolactone
3a from 2a
γ-Butyrolactones are very common structural units in
many biologically active compounds and natural pro-
ducts.4 Consequently, the development of efficient synthe-
ses of lactone rings has been an important objective.5 In
continuation of our interest in the electrophile-initiated
cycloisomerization of alkynols via hydroalkoxylation,2 we
were curious to know the reactivity of bromoalkynes.
Based on previous mechanistic work,1c,f,2a we conceived
Scheme 1. Concept for the Synthesis of γ-Butyrolactones Based
on the Previous Mechanistic Studies
a new synthesis of γ-butyrolactones from 4-bromo-3-yn-1-
ols as described in the Scheme 1 (eq 3 based on eqs 1 and 2).
Thus, we initiated our study (Table 1) on 2a, which was
obtained from cycloheptanone via propargylation6 and
bromination3 using literature precedents (eq 4). Bromina-
tion of 1a to give 2a was not adversely affected by the
presence of the free hydroxyl group, and hence its protec-
tion was not necessary. Various secondary and tertiary
unprotected 3-alkyn-1-ols were converted to the corre-
sponding terminal bromides in high yield (vide infra,
Table 2). The reason for emphasizing the bromination of
unprotected 3-alkyn-1-ols7 is that a similar process on
4-alkyn-1-ols leads to the formation of a mixture of products
and decomposition of the substrates (Table 1, eq 5).
Initially, we treated 2a with 0.1 equiv of HgCl2 (entries 1
and 2) in CH3CN/H2O (9/1). After 30 h at 50 °C, the
expected product 3a was obtained in only 5% yield while
most of the starting material remained unaffected. No
significant improvement was observed either in yield of
product or in reaction speed with increased catalyst load-
ing and with extended reaction times. Hg(OAc)2 and Hg-
(OTFA)2 were found to be ineffective, with most of the
a All reactions were conducted with 1 mmol of substrate in 0.25 M
concentration. b Most of the starting material was recovered. c Uniden-
tified mixture of products obtained. d Rest of the starting material
decomposed.
starting material being recovered after several hours of
reaction (entries 3 and 4). Use of CH2Cl2, THF, acetone,
and toluene with any of the above catalysts did not change
the outcome.
Employment of Hg(OTf)2, however, produced better
results (entries 5, 6, and 7). Initially, when 10 mol % of
catalyst was used in wet acetonitrile at 60 °C, the reaction
proceeded over 6 h until ∼20% of starting material was
consumed, but thereafter it became sluggish, remaining
incomplete even after 2 days giving 3a in 25% yield, with
55% of the recovered starting material. Increased catalyst
loading to 25 mol % led to consumption of approximately
half of the starting material (TLC) to afford 37% of 3a.
Use of 50 mol % of Hg(OTf)2, although an unacceptable
loading of a catalyst, led to complete reaction in 0.5 h at
40 °C to produce 3a in 62% yield. Overall, it appears that
each equivalent of Hg(OTf)2 is reacting with ∼2 equiv of
the substrate. Based on this observation, we propose the
reaction pathway shown in Figure 1.
(6) Njardarson, J. T.; Wood, J. L. Org. Lett. 2001, 3, 2431–2434.
(7) One example of conversion of unprotected homopropargyl alco-
hol to corresponding bromoalkyne was reported in ref 3a.
Org. Lett., Vol. 14, No. 3, 2012
825

Table 2. Synthesis of γ-Butyrolactones 3 from 2 via Au(III) or
Hg(II) Catalyzed Cycloisomerization
Figure 1. Proposed pathway for the synthesis of lactones using
Hg(OTf)2 as catalyst.
Accordingly, the Hg(II) species expelled in the first
catalytic cycle was HgBrOTf which, in the second catalytic
cycle, converted to HgBr2, probably because the bromide
ion is a stronger nucleophile and the triflate ion is a better
leaving group. HgBr2 might be less efficient, and hence the
reaction became very slow after all of the Hg(OTf)2 and
HgBrOTf were converted to HgBr2.
In support of this, when we employed HgBr2 as the
catalyst for the conversion of 2a to 3a, the reaction was
observed to be sluggish and far less productive, irrespective
of catalyst loading and reaction temperature (entry 8).
Further support for the postulated mechanism came when
we used AgOTf as a cocatalyst, which could trap the
bromide counterion and increase the triflate ion concen-
tration. The reaction was faster and was complete at room
temperature affording 3a in 66% yield (entry 9). AgOTf
alone was not reactive (entry 10). CH3CN was found to be
the better choice of solvent compared to CH2Cl2, THF,
acetone, and toluene.
Next, we examined other alkynophilic catalysts, e.g.
FeCl3 and Bi(OTf)3, and Brønsted acids, e.g. TfOH and
PPTS, but none of them were fruitful giving back mostly
starting material or a mixture of unidentified products
(entries 11À14). Pd(CH3CN)2/CuCl2 and Pd(OAc)2,
which were earlier used to convert 4-(trimethylsilyl)-3-yn-
1-ols to corresponding lactones,3d also proved ineffective.8
Finally, we were delighted to identify an exciting lead in the
form of AuCl3 (10 mol %) in wet toluene (a better choice of
solvent compared to CH3CN), which led to the clean
a Isolated yields. b All reactions were conducted with 1 mmol of
substrate in 0.25 M concentration. c Starting material decomposed.
(8) Starting material decomposed from the beginning of the reaction.
826
Org. Lett., Vol. 14, No. 3, 2012

conversion of 2a to 3a at room temperature in 87% yield.
Elevating the reaction temperature to 60 °C reduced the
reaction time from 12 to 4 h but with a drop in yield to
68%. Use of 5 mol % of the catalyst caused the reaction to
slow (28 h) and be lower yielding (74%).
counterparts. Hg(OTf)2 along with the AgOTf cocatalyst
was also tested with a few of the substrates (2b, 2d, 2i, 2nÀo)
in Table 2. Somewhat lower yields were obtained with
Hg(OTf)2 compared to AuCl3 (entries 1, 3, 8, 13, and 14).
Lastly, we propose that AuCl3 catalysis follows a similar
pathway to that explained in Figure 1. Of course the
bromide counterion interference, in this case, does not
slow the reaction, as bromide is a better leaving group and
a better nucleophile than chloride.
In conclusion, we have demonstrated that 4-bromo-3-
alkyn-1-ols can be cyclized to butyrolactones under ex-
tremely mild conditions in the presence of AuCl3. The
reactions were carried out under aqueous and open air
conditions, and no supportive catalysts or additives were
required. The corresponding lactones were isolated in high
yield. Theprocessconstitutes aneasyand efficientaccessto
highly valuable building blocks of natural products or
biologically active compounds. Our next aim is to extend
the method to γ-lactams and higher lactones.
With this exciting result, we set out to investigate the
scope of the transformation. Thus, several secondary and
tertiary 4-bromo-3-alkyn-1-ols along with benzylic hydro-
xyl systems were subjected to AuCl3- and Hg(OTf)2-cata-
lyzed cascade cycloisomerizations, and the results are
summarized in Table 2. As is apparent from the table,
secondary alcohols 2bÀg, which include benzylic systems
2dÀg, consistently produced the corresponding lactones in
75À92% yields. A significant effect of electron density in
the phenyl ring attached to the carbinol was observed on
the reaction speed and yield (affecting the nucleophilicity
of the hydroxyl group). Thus, o-chlorophenyl substrate 2h
reacted in a lower yield compared with 2d and 2e due to a
negative inductive effect and steric hindrance created by
the proximity of chlorine to the carbinol carbon. Similarly,
p-nitrophenylsubstrate2f, which hasa strong withdrawing
effecton carbinol attachedtothe phenylcarbon, requireda
higher temperature (65 °C) to ensure the completion of the
reaction and reacted in a lower yield compared with its
meta-counterpart 2g (75% compared to 92%). Surpris-
ingly, p-OMe-substituted benzylalcohol 2i decomposed
with both Hg(II) and AuCl3 catalysts and no product
was isolated. That was probably due to benzylic oxygen
cleavage, with the help of the extended conjugation from
the methoxy group in one of the intermediates involved
that had a positive charge on the oxygen. Tertiary alcohols
2lÀn also reacted smoothly to give the required products in
85À92% yield. Notably, methyl tertiary carbinols 2jÀk
and 2oÀp reacted in lower yields compared with their other
Acknowledgment. We thank Prof. Pierre Deslong-
champs, University of Sherbrooke, Canada and Dr. Tush-
ar K. Chakraborty, Director, CSIR-CDRI, India for their
constant encouragement. Y.K.K. and N.T. thank CSIR
for the award of fellowships. We thank the SAIF division,
CDRI for analytical support (NMR, IR, Mass).
Supporting Information Available. Experimental pro-
1
cedures and copies of H and 13C NMR spectra of all
compounds (2aÀp, 3aÀp). This material is available free
of charge via the Internet at http://pubs.acs.org.
† CDRI Communication number: 8192.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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