Dirhodium caprolactamate catalyzed alkoxyalkylation of terminal alkynes

Article abstract of DOI:10.1055/s-0033-1339290

Dirhodium caprolactamate [Rh₂(cap)₄] effectively catalyzes alkoxyalkylation of terminal alkynes in the presence of tert-butyl hydroperoxide (TBHP) under mild conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339290

LETTER
▌1693
lDettierrhodium Caprolactamate Catalyzed Alkoxyalkylation of Terminal Alkynes
Rh2(cap)4-Catalyzed α-Functionalization of Ethers
Xiarepati Tusun,a,b Chong-Dao Lu*a
a
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, P. R. of China
Fax +86(991)3838708; E-mail: clu@ms.xjb.ac.cn
b
University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received: 23.04.2013; Accepted after revision: 27.05.2013
bon adjacent to the oxygen of ethers, given that ethers are
Abstract: Dirhodium caprolactamate [Rh2(cap)4] effectively cata-
potential precursors of α-alkoxyalkyl radicals.6 Here we
lyzes alkoxyalkylation of terminal alkynes in the presence of tert-
continue our research into dirhodium complexes and their
butyl hydroperoxide (TBHP) under mild conditions.
catalytic applications7 by reporting the direct addition of
Key words: alkoxyalkylation, alkynes, catalysis, dirhodium(II)
ethers to terminal alkynes in the presence of Rh2(cap)4 cat-
alyst and TBHP. Using this approach, we have synthe-
sized a variety of allyl ether derivatives (Scheme 1, eq 3).
Pioneering work by Doyle and coworkers has demonstrat-
We began our studies by testing the reaction of phenyl-
ed that dirhodium caprolactamate [Rh2(cap)4] is an effec-
acetylene (1a) and tetrahydrofuran (THF, 2a) in the pres-
tive catalyst when used in conjunction with tert-butyl
ence of Rh2(cap)4 catalyst and t-BuOOH. With 0.1 mol%
hydroperoxide (TBHP) for allylic, benzylic, and propar-
gylic oxidations (Scheme 1, eq 1).1–3 This catalytic oxida-
tive approach has been extended to the functionalization
of the carbon adjacent to the nitrogen in tertiary amines
(Scheme 1, eq 2).4
catalyst loading, the reaction conducted at room tempera-
ture for 12 hours gave the allyl ether 3a in 59% yield with
an E/Z ratio of 1:1.7 (Table 1, entry 1). Higher yield (76%)
was obtained when 0.5 mol% Rh2(cap)4 were used (Table
1, entry 2). The reaction was further improved by elevat-
ing the reaction temperature to 50 °C, affording the de-
sired product 3a in 84% yield in three hours (Table 1,
entry 3). Comparable yield (82%) was obtained when the
reaction was carried out on a 1 g scale (Table 1, entry 4).
The yields obtained using our protocol is higher than
yields reported in the literature.8–10 For example, a micro-
wave-assisted protocol for this reaction gave 60% yield;8
a TBHP-promoted protocol, 51% yield at 50 °C9a and
61% yield9b at 120 °C; a CuBr/TBHP-promoted protocol,
62% yield;9a and an Me2Zn/O2-initiated protocol, 28%
yield with high E-selectivity.10
Rh2(cap)4
t-BuOOH
H
H
O
(1)
refs. 1–3
R
AG
R
AG
AG = activating group =
allyl, propargyl, benzyl
N
O
Rh
Rh
Rh2(cap)4
Rh2(cap)4
t-BuOOH
R2
N
R2
N
R1
R1
R3
ref. 4
(2)
(3)
R3
Table 1 Optimization of Reaction Conditionsa
Nu
nucleophile
H
H
Rh2(cap)4
Rh2(cap)4
t-BuOOH
R1
O
t-BuOOH
O
R2
+
R1
O
H
O
R2
this work
1a
2a
3a
R3
H
R3
Entry
Catalyst loading Temp
Time
(h)
Yield (%)b
(E/Z)c
Scheme 1 Rh2(cap)4-catalyzed functionalization of the carbon adja-
cent to the ether oxygen
(mol%)
(°C)
1
0.1
0.5
0.5
0.5
r.t.
r.t.
50
50
12
12
3
59 (1:1.7)
76 (1:1.7)
84 (1:1.7)
82 (1:1.7)
These catalytic oxidations involving TBHP are initiated
by Rh2(cap)4-catalyzed cleavage of the peroxide bond of
TBHP, generating tert-butoxy radical. This radical then
abstracts a hydrogen atom from another TBHP to form
tert-butylperoxy radical, which acts as an oxidant in sub-
sequent transformations.5 We envisaged that this radical-
based protocol might be useful for functionalizing the car-
2
3
4d
4
a Reaction conditions: 1a (0.5 mmol), t-BuOOH (2.0 mmol), and a
catalytic amount of Rh2(cap)4 in THF (10 mL).
b Isolated yield.
c E/Z ratios were determined by 1H NMR analysis of crude reaction
mixtures.
SYNLETT 2013, 24, 1693–1696
d Reaction scale = 1 g.
Advanced online publication: 28.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339290; Art ID: ST-2013-W0378-L
© Georg Thieme Verlag Stuttgart · New York

1694
X. Tusun, C.-D. Lu
LETTER
With these promising preliminary results in hand, we ex- 3b–d. Terminal alkynes bearing aliphatic substitutions
amined the scope of the Rh2(cap)4-catalyzed alkoxyalkyl- appeared to be less reactive; longer reaction times were
ation of terminal alkynes by varying the alkynes and required to ensure alkyne consumption and give moderate
ethers used (Table 2). As shown in Table 2, electron-rich yields of the desired products 3e–i (Table 2, entries 5–9).
(entries 2 and 3) and mild electron-poor aryl acetylenes Functional groups such as silyl ether (Table 2, entry 6),
(entry 4) performed well in the reaction and provided hydroxyl (Table 2, entry 8), and amide (Table 2, entry 9)
ready access to functionalized 2-vinyl tetrahydrofurans were well tolerated under the reaction conditions.
Table 2 Substrate Scope for the Addition of Ethers to Alkynes
Rh2(cap)4 (0.5 mol%)
t-BuOOH (2 equiv), 50 °C
2-vinyl ether
alkyne
ether
+
1
2
3
Entry
1
Alkyne
Ether
Time (h)
Product
Yield (%)a (E/Z)b
O
3
84 (1:1.7)
O
2a
1a
1b
3a
3b
O
O
2
3
4
24
48
20
71 (1:1.7)
69 (1:1.7)
86 (1:1.7)
2a
O
O
MeO
MeO
2a
1c
3c
O
O
Br
Br
2a
1d
3d
H15C7
H15C7
55 (2.0:1)d
69 (1.5:1)
57 (2.6:1)d
72 (2.5:1)d
O
O
5
6
7
8
96
96
96
60
1e
2a
3e
Et3SiO
1f
Et3SiO
3f
O
O
2a
BnO
1g
BnO
3g
O
O
2a
HO
HO
O
O
1h
O
2a
3h
O
N
9c
72
74 (2.8:1)d
O
N
O
2a
3i
1i
Synlett 2013, 24, 1693–1696
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rh2(cap)4-Catalyzed α-Functionalization of Ethers
1695
Table 2 Substrate Scope for the Addition of Ethers to Alkynes (continued)
Rh2(cap)4 (0.5 mol%)
t-BuOOH (2 equiv), 50 °C
2-vinyl ether
alkyne
ether
+
1
2
3
Entry
10
Alkyne
Ether
Time (h)
14
Product
Yield (%)a (E/Z)b
O
44 (1:1.7)d
O
2b
1a
1a
3j
O
O
O
11
16
53 (1:1.6)d
O
2c
3k
3l
O
O
12
13
22
14
49 (1:1.3)d
42 (1:1.3)
2d
1a
1a
OMe
OMe
OMe
MeO
2e
3m
a Isolated yield.
b E/Z ratios were determined by 1H NMR analysis of crude reaction mixtures.
c Reaction conditions: 1e (0.5 mmol), t-BuOOH (4 equiv), and Rh2(cap)4 (1 mol%) in THF (10 mL) at 70 °C.
d Inseparable geometric isomers.
The combination of Rh2(cap)4 and TBHP has already been for adducts 3a–m in all reactions of Table 2. We also ex-
reported to efficiently promote the oxidation of benzylic, amined reactions of phenylacetylene (1a) with alcohols
allylic and propargylic C–H bonds (Scheme 1, eq 1).2–4 In instead of ethers in the presence of Rh2(cap)4/TBHP. The
the present study, however, addition of ethers to alkynes reaction of 1a and methanol at 50 °C led to a complex
occurred preferentially, giving the desired adducts with- mixture of products, while the reaction of 1a and ethanol
out any significant formation of propargylic oxidation led to only trace amounts of product even at elevated tem-
products derived from 1e–i (Table 2, entries 5–9), allylic perature (90 °C), with the alkyne 1a remaining largely in-
oxidation products derived from 3e–i (Table 2, entries 5– tact.9b These results indicate that the Rh2(cap)4/TBHP
9), or benzylic oxidation products derived from 1g and 3g system is not suitable for promoting the addition of alco-
(Table 2, entry 7). This reaction preference has been at- hols to phenylacetylene (1a).
tributed to the presence of a large excess of ethers that
To probe the impact of a radical scavenger on this radical-
serve as both solvents and reactants and that preferentially
based addition, we conducted a control reaction (Scheme
act as radical traps over other reactants and products con-
2). We added the radical inhibitor 2,6-di-tert-butyl-4-
methylphenol (BHT) to the reaction of 1a and 2a, and
taining the activated C–H bonds.8–10
In addition to THF, we tested several cyclic and acyclic managed to completely suppress formation of 3a; in this
substrates containing alkoxy groups in the alkoxyalkyl- reaction, 1a remained intact, and products 4 and 5 formed
ation of phenylacetylene (Table 2, entries 9–13). Tetra- from reactions involving BHT and THF. We speculate
hydropyran and 1,4-dioxane proved suitable addition that product 4 formed by radical combination between the
partners under our reaction conditions (Table 2, entries 10 α-ethereal radical6 of THF (2a) and the phenoxy radical5
and 11). Moreover, we were able to use linear ethers 2d 6 generated from radical-mediated abstraction of the phe-
and 2e in the addition reaction to phenylacetylene, a result nolic hydrogen of BHT. Product 5, for its part, may have
not reported for previous protocols;8–10 these ethers pro- formed through radical 1,6-Michael addition12 of the ethe-
duced adducts 3l and 3m, respectively, in low yields (Ta- real radical to BHT quinone methide (BHT-QM)13 inter-
ble 2, entries 12 and 13).11 Low E/Z ratios were obtained mediate 8.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1693–1696

1696
X. Tusun, C.-D. Lu
LETTER
M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128,
5648.
(5) Ratnikov, M. O.; Farkas, L. E.; McLaughlin, E. C.; Chiou,
G.; Choi, H.; El-Khalafy, S. H.; Doyle, M. P. J. Org. Chem.
2011, 76, 2585.
(6) (a) Wallace, T. J.; Gritter, R. J. J. Org. Chem. 1962, 27,
3067. (b) Wallace, T. J.; Gritter, R. J. J. Org. Chem. 1961,
26, 5256.
Rh2(cap)4 (0.5 mol%)
OH
O
t-BuOOH (2 equiv)
2,6-di-tert-4-butyl-4-
methylphenol
t-Bu
t-Bu
t-Bu
t-Bu
(2 equiv), 50 °C, 4 h
1a
O
solvent = THF (2a)
O
(7) (a) Tusun, X.; Lu, C.-D. Synlett 2012, 23, 1801.
(b) Wusiman, A.; Tusun, X.; Lu, C.-D. Eur. J. Org. Chem.
2012, 3088. (c) Wang, H.-T.; Lu, C.-D. Tetrahedron Lett.
2013, 54, 3015.
4 (20%)
5 (28%)
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
(8) Zhang, Y.; Li, C.-J. Tetrahedron Lett. 2004, 45, 7581.
(9) (a) Huang, L.; Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y.
Synthesis 2009, 3504. (b) Liu, Z.-Q.; Sun, L.; Wang, J.-G.;
Han, J.; Zhao, Y.-K.; Zhou, B. Org. Lett. 2009, 11, 1437.
(10) Chen, Z.; Zhang, Y.-X.; An, Y.; Song, X.-L.; Wang, Y.-H.;
Zhu, L.-L.; Guo, L. Eur. J. Org. Chem. 2009, 5146.
(11) General Experimental Procedure for the Preparation of
2-Vinyl Ethers
6
7
8
Scheme 2 Interception of the α-ethereal radical of THF by BHT
In summary, we have applied Rh2(cap)4/TBHP-based cat-
alytic oxidation to the functionalization of carbons adja-
cent to ether oxygens. Using this protocol, we have
synthesized a variety of 2-vinyl ethers via direct addition
of ethers to terminal alkynes under mild reaction condi-
tions.
Alkyne (0.50 mmol) and Rh2(cap)4·2MeCN (0.0025 mmol,
1.8 mg, 0.5 mol%) were mixed in Et2O (10 mL), and TBHP
(5–6 M in decane, 1.0 mmol) was added. After stirring at
50 °C for the indicated time (Table 2), the reaction mixture
was evaporated to give the crude product, which was
purified by silica gel column chromatography using
EtOAc–PE as eluent to obtain 2-vinyl ethers. This General
Experimental Procedure was carried out using 1a (51 mg,
0.50 mmol) and 2f (10 mL). The reaction mixture was stirred
for 14 h at 50 °C and purified by silica gel chromatography
using PE–EtOAc (10:1) as eluent to give products (E)-3m
and (Z)-3m.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (21172251), the Hightech R&D Program of Xinjiang
Uygur Autonomous Region (201110111), and the Chinese Acade-
my of Sciences.
Compound (E)-3m: colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.42 (d, J = 7.6 Hz, 2 H), 7.34 (t, J = 7.6 Hz, 2
H), 7.28 (s, 1 H), 6.65 (d, J = 16.0 Hz, 1 H), 6.11 (dd,
J = 16.0, 7.6 Hz, 1 H), 4.02–3.90 (m, 1 H), 3.56–3.48 (m, 2
H), 3.42 (s, 3 H), 3.40 (s, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 136.6, 133.8, 128.8, 128.1, 126.82, 126.80, 81.6, 75.9,
59.5, 56.9. ESI-HRMS: m/z calcd for C12H16NaO2 [M +
Na]+: 215.1043; found: 215.1042.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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References and Notes
Compound (Z)-3m: colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.28 (m, 5 H), 6.78 (d, J = 11.6 Hz, 1 H),
5.58 (dd, J = 11.6, 9.6 Hz, 1 H), 4.46–4.37 (m, 1 H), 3.57–
3.51 (m, 2 H), 3.43 (s, 3 H), 3.27 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 136.8, 134.2, 130.0, 128.9, 128.6, 127.6,
76.2, 75.5, 59.6, 56.6. ESI-HRMS: m/z calcd for
C12H16NaO2 [M + Na]+: 215.1043; found: 215.1044. See the
Supporting Information for experimental details and
characterization data for all new compounds.
(1) For Rh2(cap)4-catalyzed allylic oxidation, see: (a) Catino, A.
J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004,
126, 13622. (b) Choi, H.; Doyle, M. P. Org. Lett. 2007, 9,
5349. (c) McLaughlin, E. C.; Choi, H.; Wang, K.; Chiou, G.;
Doyle, M. P. J. Org. Chem. 2009, 74, 730.
(2) For Rh2(cap)4-catalyzed benzylic oxidation, see: Catino, A.
J.; Nichols, J. M.; Choi, H.; Gottipamula, S.; Doyle, M. P.
Org. Lett. 2005, 7, 5167.
(3) For Rh2(cap)4-catalyzed propargylic oxidation, see:
McLaughlin, E. C.; Doyle, M. P. J. Org. Chem. 2008, 73,
4317.
(4) For Rh2(cap)4-catalyzed oxidation of tertiary amines to
initiate the Mannich reaction, see: Catino, A. J.; Nichols, J.
(12) Clive, D. L. J.; Fletcher, S. P.; Zhu, M. Chem. Commun.
2003, 526.
(13) (a) Dyall, L. K.; Winstein, S. J. Am. Chem. Soc. 1972, 94,
2196. (b) Omura, K. J. Org. Chem. 1984, 49, 3046.
Synlett 2013, 24, 1693–1696
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