Gold(I)-catalyzed cyclization of alkynyl hydrogen phosphates

Article abstract of DOI:10.1002/asia.201100147

Functionalization of alkynols: An efficient gold(I)-catalyzed intramolecular hydrophosphoryloxylation of alkynyl hydrogen phosphates has been developed and provides structurally interesting cyclic vinyl phosphates through 6-endo-dig, 6-exo-dig, or 7-exo-d

Full text of DOI:10.1002/asia.201100147

COMMUNICATION
DOI: 10.1002/asia.201100147
Gold(I)-Catalyzed Cyclization of Alkynyl Hydrogen Phosphates
Bathoju Chandra Chary,[a] Wee Suan Low,[a] Sunggak Kim,*[a] Hyunseok Kim,[b] and
Phil Ho Lee*[b]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Gold-catalyzed nucleophilic additions to alkynes have at-
tracted a great deal of attention in recent years. These nu-
cleophilic additions include hydroamination, hydration, hy-
droalkoxylation, hydrocarboxylation[1] as well as the use of
other oxygen-[2] or nitrogen-containing nucleophiles[3] such
gold catalyst, the hydroxy moiety of the phosphoryl func-
tional group could initiate an intramolecular attack on the
gold-activated alkyne to give a cyclized product. The mode
of cyclization is important as it determines the size of the
ring formed and thus the functional group of the compound.
In the case of the gold-catalyzed hydrocarboxylation of w-
acetylenic acids, the cyclization proceeded by a 5-exo-dig
and 6-exo-dig ring closure (Scheme 2).[9]
as ketones and imines or even carbon nucleophiles such as
[4]
C C double bonds in enols or arenes.[5] Recently, we re-
À
ported the gold-catalyzed addition of diphenyl phosphate to
alkynes to yield vinyl phosphates through the Markovnikov
addition.[6] Although the Markovnikov addition is usually
observed for terminal alkynes, for unsymmetrical alkynes,
there is a regioselectivity issue, which is difficult to resolve.
In this regard, we have been interested in utilizing alkynyl
hydrogen phosphates as temporary phosphate tethers,[7] not
only to control the regioselectivity of the cyclization but
also to utilize the cyclic phosphate products as coupling
partners in transition-metal-catalyzed cross coupling reac-
tions.[8] As shown in Scheme 1, we envisaged that upon the
activation of the alkyne triple bond using an appropriate
Scheme 2. Preparation of alkynyl hydrogen phosphate.
Alkynyl hydrogen phosphates could be prepared readily
by treatment of alkynols with phosphorodichloridate and
triethylamine in tetrahyrdrofuran and subsequent hydrolysis
of 3. Although such phosphoryl transfer reactions are often
carried out in the presence of Lewis acid catalysts, in partic-
ular TiCl4,[10] we began our study in the absence of TiCl4
using propargyl alcohol. Treatment of propargyl alcohol
with phenyl phosphorodichloridate (1.2 equiv) and triethyla-
mine (1.2 equiv) at 08C for 3 hours followed by the addition
of water for 3 hours afforded the desired product 4a in 66%
yield together with dialkylated product 5 (n=1; 20%). The
optimum conditions to minimize the formation of 5: (1) add
a slight excess of phosphorodichloridate (1.05 equiv) drop-
wise to a solution of propargyl alcohol and triethylamine
(1.2 equiv) in tetrahydrofuran at 08C for 30 min and subse-
quent stirring at 08C for 3 h, (2) followed by treatment with
an excess of water at room temperature for 3 hours to
Scheme 1. AuI-catalyzed cyclization of alkynyl hydrogen phosphates.
[a] B. C. Chary, W. S. Low, Prof. Dr. S. Kim
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
Fax : (+65)6791-7765
E-mail: sgkim@ntu.edu.sg
[b] Dr. H. Kim, Prof. Dr. P. H. Lee
Department of Chemistry
Institute of Molecular Science and Fusion Technology
Kangwon National University
Chuncheon 200-701 (Republic Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100147.
1970
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Chem. Asian J. 2011, 6, 1970 – 1973

afford 4a in 75% yield. As shown in Table 1, primary alkyn-
yl alcohols were converted into the corresponding alkynyl
hydrogen phosphates in high yields (75%–86%). Similarly,
FeCl3, and PtCl2 and protic acids such as triflic acid and p-
toluenesulfonic acid were totally ineffective. However, iron
triflate derived from FeCl3 and AgOTf was also effective to
some extent in refluxing dichloroethane (Table 2, entry 7).
Table 3 illustrates the scope and limitations of the present
method. Using the standard reaction conditions, 4b and 4d
underwent the 6-endo-dig ring closure (Table 3, entries 1
and 3). Actually, concerning the mode of the cyclization, the
6-endo-dig was favored over the 5-exo-dig ring closure.
However, in related carboxylative cyclizations of propargyl
alcohols, several different observations were reported. First,
silver salt catalysts were effective for the cyclization.[12]
Second, the 5-exo-dig ring closure was favored over the 6-
endo-dig closure.[13,14] Similar trends were also observed with
propargyl amine derivatives.[15] Alkynyl hydrogen phosphate
4e that possesses two carbon atoms between the alkyne and
the phosphoryl functional groups also underwent the 6-exo-
Table 1. Preparation of alkynyl hydrogen phosphates.
4a (75%)
4b (84%)
4c (78%)
4d (86%)
4g (82%)
4e (85%)
4h (80%)
4 f (85%)
4i (76%)
Table 3. AuI-catalyzed cyclization of alkynyl hydrogen phosphates.
secondary alkynyl alcohols worked equally well, albeit with
slightly lower yields. However, a tertiary alknyl alcohol such
as 2-methylbut-3-yn-2-ol failed to give the corresponding al-
kynyl hydrogen phosphate under several conditions.[11]
Entry Alkynyl Phosphate
T
t
Product
Yield
[%][a]
[8C] [h]
To find out the most effective catalyst for the cyclization,
an initial study was carried out with 4a in dichloromethane.
Based on our previous results,[6,12] various gold catalysts as
well as other metal salts and protic acids were employed in
the cyclization reactions. As shown in Table 2, the
Ph3PAuCl/AgOTf catalytic system turned out to be most ef-
fective and provided 6-endo addition product 6a without
any indication of formation of the 5-exo addition product
(Table 2, entry 5). Also, it is noteworthy that Ph3PAuCl/
AgPF6 was totally ineffective for the cyclization (Table 2,
entry 4), although it was effective for intermolecular addi-
tion of diphenyl phosphate to alkynes.[6] Furthermore,
Ph3PAuCl/AgBF4 was effective to some extent (Table 2,
entry 3) but other transition-metal catalysts such as AgOTf,
1
RT
35
4
12
4
78
0
4b
6b
6c
6d
2
4c
3
RT
86
4d
4
RT
RT
0.5
90
85
4e
6e
5
4
Table 2. Reaction optimization of Au-catalyzed cyclization.
4 f
6 f
6g
6h
6i
6
RT
RT
RT
8
82
78
80
4g
Entry
Catalyst
T [8C]
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
AgOTf
AgBF4
RT
RT
RT
RT
12
12
1
0
<5
62
<5
94
0
63
0
0
7
8
Ph3PAuCl/AgBF4
Ph3PAuCl/AgPF6
Ph3PAuCl/AgOTf
FeCl3
FeCl3/AgOTf
PtCl2
4h
1
RT
0.1
12
2
12
12
12
12
12
8
0.5
reflux
reflux
RT
RT
RT
ACHTUNGTRENNUNG
(1:1.7)[b]
4i
9
InBr3
[a] Yield of isolated product. [b] Diastereomeric ratio.
10
11
12
Sc
N
0
0
0
p-TsOH
TfOH
RT
RT
[a] Yield of isolated product.
Chem. Asian J. 2011, 6, 1970 – 1973
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1971

S. Kim and P. Ho Lee et al.
COMMUNICATION
ing mixture was concentrated to remove the THF before extracting with
CH2Cl2 (3ꢁ20 mL). The combined organic extracts were dried over anhy-
drous MgSO4 and concentrated under reduced pressure to afford the
crude material, which was then purified by silica-gel chromatography
(MeOH/CH2Cl2, 1:9).
dig cyclization to give the exo-methylene cyclized product
without the 7-endo-dig cyclization (Table 3, entry 4). When
the reaction was carried out in toluene at room temperature,
the reaction slowed down and required 4 hours to afford 6e
in 81% yield. When 4g was treated with 5 mol% Ph3PAuCl/
AgOTf in dichloromethane at room temperature, the cycli-
zation proceeded efficiently by 7-exo-dig ring-closure; the
desired product 6g was isolated in 82% yield (Table 3,
entry 6).
General procedure for the cyclization of alkynyl hydrogen phosphates
Chlorotriphenylphosphine gold(I) (5 mol%) and silver trifluoromethane-
sulfonate (5 mol%) were stirred in CH2Cl2 (1 mL) at room temperature
under a nitrogen atmosphere. A solution of the alkynyl hydrogen phos-
phate (0.30 mmol) in CH2Cl2 (2 mL) was added. The reaction mixture
was then allowed to stir for 0.5 h before extracting with CH2Cl2 (3ꢁ
20 mL). The combined organic phases were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure to afford the
crude material, which was then purified by silica-gel chromatography
(EtOAc/hexane, 3:7).
When the cyclization was carried out with 4c in refluxing
dichloromethane for 12 hours, no cyclization occurred
(Table 3, entry 2).[16] The reason as to why the cyclization re-
action did not work might be due to the steric interaction
between the methyl group in the hydrogen phosphates and
the gold complex, Ph3PAuOTf. Due to steric interaction
with the adjacent methyl group, the gold complex might not
be able to approach 4c in close enough proximity to coordi-
nate to the alkynyl group and activate it, thus the vinyl gold
complex 7 could not be formed. Our hypothesis was proven
to some extent by performing cyclization of 4i. The cycliza-
tion proceeded cleanly at room temperature in dichlorome-
thane and was complete within 0.5 hours to afford a 1:1.7 di-
asteromeric mixture of the 6-membered cyclic phosphate
(80%) through the 6-exo-dig ring closure (Table 3, entry 8).
In addition, to further functionalize the vinylic bond of the
ring, when the cyclization of halosubsitituted alkynyl hydro-
gen phosphates was performed, the reaction proceeded
smoothly to afford the cyclized products (Table 3, entries 5
and 7). The cyclization was stereospecific to yield Z-iodo
vinyl phosphate 6 f and 6h, the stereochemistry of which
was determined by NOESY experiments. The stereochemi-
cal outcome obtained here is consistent with the mechanism
involving an intramolecular trans-addition of the hydrogen
phosphate to the gold–alkyne complex.[17]
Acknowledgements
S.K. acknowledges financial support from Nanyang Technological Uni-
versity and P.H.L. thanks the National Research Foundation of Korea
through the NRL Program, an NRF grant funded by the Korean govern-
ment (MEST 2009-0087013), and the 2nd phase BK21 program for finan-
cial support.
Keywords: alkynes
·
catalysis
·
cyclization
·
gold
·
nucleophilic addition
[1] See for reviews: a) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180;
b) W. A. Herrmann, B. Cornils, Angew. Chem. 1997, 109, 1074;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1048; c) Y. Yamamoto, J.
Org. Chem. 2007, 72, 7817; d) Y. Fukuda, K. Utimoto, J. Org. Chem.
1991, 56, 3729; e) A. S. K. Hashmi, L. Schwarz, J. H. Choi, T. M.
Frost, Angew. Chem. 2000, 112, 2382; Angew. Chem. Int. Ed. 2000,
39, 2285.
[2] a) M. Murai, J. Uenishi, M. Uemura, Org. Lett. 2010, 12, 4788; b) Y.
Liu, F. Song, Z. Song, M. Liu, B. Yan, Org. Lett. 2005, 7, 5409;
c) A. S. K. Hashmi, L. Schwarz, J. H. Choi, T. M. Frost, Angew.
Chem. 2000, 112, 2382; Angew. Chem. Int. Ed. 2000, 39, 2285;
d) A. S. K. Hashmi, P. Sinah, Adv. Synth. Catal. 2004, 346, 432; e) T.
Yao, X. Whang, R. Larock, J. Am. Chem. Soc. 2004, 126, 11164.
[3] a) A. L. Pꢂrez, J. R. Cabrero-Antonino, ꢃ. Cantꢄn, A. Corma, J.
Org. Chem. 2010, 75, 7769; b) N. T. Patil, P. G. V. Lakshmi, V. Singh,
Eur. J. Org. Chem. 2010, 4719; c) A. Leyya, A. Corma, Adv. Synth.
Catal. 2009, 351, 4137; d) E. Mizushima, T. Hayashi, M. Tanaka,
Org. Lett. 2003, 5, 3349; e) F. Gasparrini, M. Giovannoli, D. Misiti,
G. Natile, G. Palmieri, L. Maresca, J. Am. Chem. Soc. 1993, 115,
4401.
In conclusion, we have developed an efficient gold(I)-cat-
alyzed cyclization of alkynyl hydrogen phosphates. The cyc-
lization underwent 6-endo-dig, 6-exo-dig, or 7-exo-dig ring
closure, depending on the number of carbon atoms present
(n=1, 2, 3) between the alkyne and phosphoryl group. The
success in synthesizing the cyclic vinyl phosphates will allow
us to study the regiospecific and stereospecific carbon–
carbon bond formations using transition-metal-catalyzed
cross-coupling reactions, which will be our next investiga-
tion.
[4] a) H. Ito, Y. Makida, A. Ochida, H. Ohmiya, M. Sawamura, Org.
Lett. 2008, 10, 5051; b) J. J. Kennedy-Smith, S. T. Staben, F. D. Toste,
J. Am. Chem. Soc. 2004, 126, 4526.
[5] a) T. D. Haro, C. Nevado, J. Am. Chem. Soc. 2010, 132, 1512; b) Z.
Shi, C. He, J. Am. Chem. Soc. 2004, 126, 13596; c) M. T. Reetz, K.
Sommer, Eur. J. Org. Chem. 2003, 3485.
Experimental Section
General procedure for alkynyl hydrogen phosphates
Phenyl phosphorodichloridate (665 mg, 0.47 mL, 3.15 mmol) was stirred
in THF (2 mL) at 08C under nitrogen. A solution of alkynyl alcohol
(3.00 mmol) in THF (2 mL) was added dropwise by syringe over 0.5 h
and then a solution of triethylamine (364 mg, 0.50 mL, 3.60 mmol) in
THF (2 mL) was also added dropwise to the reaction mixture for another
0.5 h. The white reaction mixture was then stirred for an additional 3 h at
08C and then warmed to room temperature for 1 h. Water (1 mL) was
subsequently added dropwise over 10 min and the resultant reaction mix-
ture was left to stir for an additional 3 h at room temperature. The result-
[6] P. H. Lee, S. Kim, A. Park, B. C. Chary, S. Kim, Angew. Chem. 2010,
122, 6958; Angew. Chem. Int. Ed. 2010, 49, 6806.
[7] a) G. Rubinstenn, J. Esnault, J.-M. Mallet, P. Sinay, Tetrahedron:
Asymmetry 1997, 8, 1327; b) K. T. Sprott, M. D. McReynolds, P. R.
Hanson, Org. Lett. 2001, 3, 3939; c) A. Whitehead, M. D. McRey-
nolds, J. D. Moore, P. R. Hanson, Org. Lett. 2005, 7, 3375.
[8] a) J. Tsuji, Palladium Reagents and Catalysts, New Perspectives For
the 21 st Century, Wiley, Chichester, UK, 2004; b) A. F. Littke, G. F.
Fu, Angew. Chem. 2002, 114, 4350; Angew. Chem. Int. Ed. 2002, 41,
1972
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 1970 – 1973

Gold(I)-Catalyzed Cyclizations
4176; c) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100,
3009; d) D. Gauthier, S. Beckendorf, T. M. Gøgsig, A. T. Lindhardt,
T. Skrydstrup, J. Org. Chem. 2009, 74, 3536; e) A. L. Hansen, J. P.
Ebran, T. M. Gøgsig, T. Skrydstrup, J. Org. Chem. 2007, 72, 6464;
f) J. P. Ebran, A. L. Hansen, T. M. Gøgsig, T. Skrydstrup, J. Am.
Chem. Soc. 2007, 129, 6931; g) A. L. Hansen, J. P. Ebran, M. Ahl-
quist, P. Norrby, T. Skrydstrup, Angew. Chem. 2006, 118, 3427;
Angew. Chem. Int. Ed. 2006, 45, 3349; h) A. L. Hansen, J. P. Ebran,
T. M. Gøgsig, T. Skrydstrup, Chem. Commun. 2006, 4137; i) H.
Fuwa, M. Sasaki, Org. Lett. 2007, 9, 3347.
[13] a) Y. Sugawara, W. Yamada, S. Yoshida, T. Ikeno, T. Yamada, J.
Am. Chem. Soc. 2007, 129, 12902; b) W. Yamada, Y. Sugawara,
H. M. Cheng, T. Ikeno, T. Yamada, Eur. J. Org. Chem. 2007, 2604.
[14] a) M. Costa, G. P. Chiusoli, M. Rizzardi, Chem. Commun. 1996,
1699; b) Y. Kayaki, M. Yamamoto, T. Ikariya, J. Org. Chem. 2007,
72, 647.
[15] S. Yoshida, K. Fukui, S. Kikuchi, T. Yamada, Chem. Lett. 2009, 38,
786.
[16] Similarly, hydrogen phosphate of hex-4-yn-3-ol did not undergo cyc-
lization.
[9] a) E. Genin, P. Y. Toullec, S. Antoniotti, C. Brancour, J. P. GenÞt, V.
Michelet, J. Am. Chem. Soc. 2006, 128, 3112; b) H. Harkat, J.-M.
Weibel, P. Pale, Tetrahedron Lett. 2006, 47, 6273; c) P. Y. Toullec, E.
Genin, S. Antoniotti, J.-P. Genet, V. Michelet, Synlett 2008, 707.
[10] S. Jones, D. Selitsianos, Org. Lett. 2002, 4, 3671.
[17] a) O. A. Egorova, H. Seo, A. Chatterjee, K. H. Ahn, Org. Lett. 2010,
12, 401; b) I. D. G. Watson, S. Ritter, F. D. Toste, J. Am. Chem. Soc.
2009, 131, 2056; c) M. C. P. Yeh, H. F. Pai, C. Y. Hsiow, Y. R. Wang,
Organometallics 2010, 29, 160; d) B. D. Sherry, L. Maus, B. N. Lafor-
teza, F. D. Toste, J. Am. Chem. Soc. 2006, 128, 8132.
[11] a) C.-Y. Liu, V. D. Pawar, J.-Q. Kao, C.-T. Chen, Adv. Synth. Catal.
2010, 352, 188; b) A. Sato, H. Ito, T. Taguchi, J. Org. Chem. 2005,
70, 709.
Received: February 14, 2011
Published online: May 30, 2011
[12] B. C. Chary, S. Kim, J. Org. Chem. 2010, 75, 7928.
Chem. Asian J. 2011, 6, 1970 – 1973
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1973