Accessing alternative reaction pathways of the intermolecular condensation between homo-propargyl alcohols and terminal alkynes through divergent gold catalysis

Article abstract of DOI:10.1039/c6cc09794d

An intermolecular condensation of alkynols and terminal alkynes is reported. Using IPrAuNTf₂, an efficient Au-catalyzed cyclization-alkynylation strategy furnishes (2-arylalkynyl) cyclic ethers in moderate to excellent yields (up to 94%). This strategy is extended to the synthesis of functionalized 2,3-dihydrooxepines via the sequential Au-catalyzed ring expansion of the cyclic ether substrates.

Full text of DOI:10.1039/c6cc09794d

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Accessing Alternative Reaction Pathways of the Intermolecular
Condensation between Homo-Propargyl Alcohols and Terminal
Alkynes through Divergent Gold Catalysis
Cite this: DOI: 10.1039/x0xx00000x
Courtney A. Smith, Stephen E. Motika, Lukasz Wojtas, Xiaodong Shi*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An intermolecular condensation of alkynols and terminal
alkynes is reported. Using IPrAuNTf2, an efficient Au-catalyzed
cyclization-alkynylation strategy furnishes (2-arylalkynyl) cyclic
ethers in moderate to excellent yields (up to 94%). This
strategy is extended to the synthesis of functionalized 2,3-
dihydrooxepines via the sequential Au-catalyzed ring
expansion of the cyclic ether substrates.
Gold(I) catalysis has developed rapidly in recent years and
the resulting methodologies have proved useful for the facile
installation of molecular complexity.1 Gold’s intrinsic
π-acid
mode of activation has rendered it synthetically valuable in
promoting reactions involving substrates bearing unsaturated
C-C moieties (alkyne, allene, and alkene; Scheme 1A).
Consequently, the design of selective catalytic systems is often
problematic when multiple reactive functional groups are
present. 2 Furthermore, additional challenges in attaining
selectivity arise if these catalytic systems are a composite of
intra- and inter- molecular reactions.3
Scheme 1. Gold-catalyzed C-C multiple bond activation
Despite these recent advances, certain concerns regarding
the mechanisms of the reactions have not been completely
addressed. First, the enyne cycloisomerization reaction
between homo-propargyl alcohol
tolerated only by aliphatic alkynes (Scheme 1B). This result was
unexpected considering that gold -acid activation of aryl-
1 and terminal alkyne 2 was
Over the past several years, our group has demonstrated
the application of 1,2,3-triazole gold(I) (TA-Au) catalysts in
promoting these challenging transformations.4 One relevant
example is the intermolecular condensation between homo-
propargyl alcohols and terminal aliphatic alkynes to afford 2,3-
dihydrooxepines (Scheme 1B).5 Within this reaction pathway, a
vinyl ether intermediate is selectively formed via the
intermolecular gold-catalyzed hydroalkoxylation of the
terminal alkyne. Moreover, in exploring the reactivity of vinyl
ethers with terminal alkynes under triazole gold-catalytic
conditions, we later developed an intermolecular alkynylation
of vinyl ethers.6
π
substituted terminal alkynes is extensively documented.7 A
messy reaction mixture was obtained when aryl-substituted
terminal alkynes such as phenylacetylene were used. Second,
for the alkynylation of vinyl ether 4, aliphatic alkynes such as 1-
hexyne resulted in slightly lower yields in comparison with
aromatic alkynes (Scheme 1C). Based on these observations,
changing the substrate of either reaction has the potential to
dramatically alter the reaction pathway, and this phenomenon
warrants further investigation.
Our strategy in exploring this unique catalytic system was
focused on: 1) extending the reaction scope of the 2,3-
dihydrooxepine synthesis to include aryl-substituted terminal
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
* E-mail: xmshi@usf.edu
Electronic Supplementary Information (ESI) available: Experimental procedures and
spectroscopic data of new compounds. CCDC 1521359, 1521360, and 1521361. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/c000000x/
This journal is © The Royal Society of Chemistry 20xx
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alkynes and, 2) exploring the possibility of a cascade process tolerated without significant decomposition of the product.
-
for the alkynylation of vinyl ether
B
(Scheme 2).8 9
The amino acid derivative 6q and estrone derivative 6r were
also prepared, demonstrating the tolerance of the reaction
conditions to a variety of functional groups. Conversely, non-
aromatic terminal alkynes such as cyclopentyl acetylene, 1-
hexyne, and TMS acetylene, did not form the desired
alkynylation product.
Table 2. Reaction scope of alkynylation cascadea,b,c
6b: R = H, 87%;
Scheme 2. Proposed reaction pathways
6h: R = m-F, 89%;
6c: R = p-OMe, 72%;
6d: R = p-CF3, 86%;
6e R = p-F, 82%;
6f: R = p-Br, 68%;
6g: R = m-CF3, 61%;
R
6i: R = m-Cl, 73%;
6j: R = m-CH3, 82%;
6k: R = o-CF3, 58%;
6l: R = o-CH3, 94%;
O
O
As shown in Table 1, the reaction of 1a with aromatic
alkyne 2b under our previously reported conditions resulted in
a messy reaction, with no formation of dihydrooxepine 3a
(entry 2). To explore the plausibility of a cascade process, we
screened various gold catalysts (see ESI†). Interestingly, when
5% RuPhosAuNTf2 was used as the catalyst, alkyne 6b was
observed, albeit in low yield (31%, entry 3). Since the
Ph
Ph
S
R
Fe
R:
6n: 93%
O
O
6m: 83%
O
6o: 56%
O
O
formation of 6b requires gold π-acid activation of the internal
NHBoc
X
H
6q: 86%
6r: 69%
6p: 66%
alkyne of 1a, we increased the reaction temperature with the
objective of promoting the intramolecular cyclization of 1a
over intermolecular hydroalkoxylation. Gratifyingly, the
reaction yield was improved to 61% (entry 4). Finally, ligand
screening revealed IPrAuNTf2 as the optimal catalyst, affording
the desired product 6b in excellent yield (5% loading, 91%
yield, entry 5; 4% loading, 87% yield, entry 6). Having
identified the optimal conditions, we turned our attention to
exploring the reaction scope (Table 2).
H
H
O
O
X-Ray of 6m
CCDC 1521359
6s: X = NMe, 79%;
6t: X = O, 95%
6aa: R = p-OMe, 67%;
6ab: R = p-tBu, 83%;
6ac: R = p-CF3, 74%;
6ad: R = p-F, 78%;
Ph
R
Ph
O
O
6ae: R = p-Br, 88%;
6af: R = m-CH3, 76%;
6ag: R = m-CF3, 81%;
6ak: 91%
Ph
Table 1. Optimization of reaction conditionsa,b
Ph
6ah: R = m-Cl, 84%[b]
6ai: R = o-CH3, 93%;
;
Ph
O
O
O
Ph
Ph
6al: 87%, exo:endo = 10:3[c]
6aj: 81%
Ph
yield (%)
convn
(%)
Ph
Entry
Conditions
2 (eq)
Ph
3
6
OH
O
O
O
5% [XPhosAu(TA)]OTf, 1% Cu(OTf)2,
toluene, rt, 24h
n
1
2
2a (3) 100 84% n.d.
2b (3) 100 <5% n.d.
Same conditions as entry 1,
messy reaction
6am: 84%
6an: 93%
6ao: 79%
Ph
Ph
3
4
5
6
7
8
5% RuPhosAuNTf2, CHCl3, rt, 12h
5% RuPhosAuNTf2, CHCl3, 40 oC, 4h
5% IPrAuNTf2, CHCl3, 40 oC, 4h
4% IPrAuNTf2, CHCl3, 40 oC, 4h
1% IPrAuNTf2, CHCl3, 40 oC, 4h
5% IPrAuNTf2, CHCl3, 40 oC, 4h
Other catalysts (5) including AuCl3, HOTf,
pTsOH•H2O, In(OTf)3, Pd(OAc)2, CuBr,
Cu(OTf)2, ZnBr2, AgOTf
2b (3) 100 n.d. 47%
2b (3) 100 n.d. 61%
2b (3) 100 n.d. 91%
2b (3) 100 n.d. 87%
2b (3) 100 n.d. 34%
2b (2) 100 56% 36%
O
O
Ph
6aq: 95%, dr=3:2[c]
Ph
6ap: 66%, dr=1:1[c]
a General conditions:
1
(0.2 mmol), 2 (3 eq), IPrAuNTf2 (3 mol %) in CHCl3 (0.8 mL)
under Ar at 40 oC. Yields of isolated products are given. Reference the ESI for
detailed conditions. b Reaction heated at 60 oC c Ratio determined via 1H-NMR.
9
2b (3) <30% n.d. <5%
a
General conditions: 1 (0.2 mmol), 2 (eq), and gold catalyst (mol %) in CHCl3 (0.8 mL)
under Ar; b The yield was determined by 1H-NMR using 1,3,5-trimethoxybenzene as the
internal standard.
To fully investigate the scope of this alkynylation reaction,
different alkynols were also assessed. Substitution at the para
A variety of phenylacetylene derivatives were subjected to
the optimized reaction conditions and subsequently afforded
the desired products in good yield (6b-6l). Other aromatic
alkynes such as ferrocenyl (6m, structure confirmed by X-ray),
thiophenyl (6n), and pyrenyl (6o) derivatives could also be
utilized in the reaction. Additionally, alkynes bearing
adamantyl (6p), indole (6s), and benzofuran (6t) moieties were
(
6aa-6ae), meta (6af-6ah), and ortho (6ai) position of the
benzene ring on the homopropargyl alcohol afforded good
yields. Additionally, the naphthyl derivative 6aj could be
furnished in good yield (81%). To probe the endo/exo
selectivity of the cyclization step, we used a series of
extended-chain internal alkynols bearing aliphatic or phenyl
substitution. Aliphatic substitution selectively yielded the exo
2 | J. Name., 20xx, 00, 1-3
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DOI: 10.1039/C6CC09794D
product (6ak), while phenyl substitution resulted in a 10:3 corresponding ketone 1a’ via gold-catalyzed hydrolysis.11 Thus,
mixture of exo:endo isomers (6al). Terminal alkynes were 1a’ serves as a viable intermediate in the formation of 6b
tolerated under the reaction conditions, yielding the 5-exo After the full conversion of 1a’ to 6b, a slow conversion of 6b
6am), 6-exo (6an), and 7-exo (6ao) products. In contrast, the occurs with concomitant formation of 3b Monitoring the
.
(
.
terminal alkyne substrate for 8-exo cyclization gave trace analogous reaction in the presence of 3 equivalents of
formation of the desired product. To determine the phenylacetylene indicated low yield of 3b (<30%) after 48
diastereoselectivity of the alkynylation reaction, we utilized hours (Figure 1).
enantiomerically pure alkynols. However, when an α-methyl
Ph
Ph
homopropargyl alcohol is used (6aq, dr = 3:2) or an α,β-di-
O
OH
5% IPrAuNTf2
O
Ph
+
substituted homopropargyl alcohol (6ap, dr = 1:1), low
diastereoselectivity was exhibited. Next, we diverted our focus
to the development of a strategy for the synthesis of the
(1.1 eq, 2b)
Ph
6b
CHCl3, 40 o
C
Ph
Ph
1a
3b
corresponding 2,3-dihydrooxepine 3b
.
During optimization of the reaction conditions (Table 1),
we observed that if 2 equivalents of terminal alkyne 2b were
used, the yield of the desired product 6b was reduced.
1
Monitoring the reaction using H-NMR revealed the formation
of dihydrooxepine 3b as the major by-product (see ESI†).
Reducing the amount of phenylacetylene to 1.1 equivalents
resulted in the formation of 3b as the major product in 74%
yield. Notably, 3b was unstable upon chromatographic
isolation. Therefore, the dienophile tetracyanoethylene was
used to trap the product via a Diels Alder cycloaddition10 and
the adduct 7b was obtained in 71% isolated yield over two
steps. The structure of 7b was unambiguously characterized
by X-ray crystallography (see ESI†). With these new optimized
conditions for the synthesis of 2,3-dihydrooxepines, various
aromatic alkynes were subjected to the reaction and moderate
yields of the derivatives were obtained (Table 2).
Figure 1. Reaction kinetic profile
Therefore, this kinetic profile and the intermediary nature
of 6b suggest that, unlike the analogous reaction involving
aliphatic terminal alkynes, oxepine 3b was formed via
rearrangement of alkyne 6b.
12 To confirm this hypothesis, 6b
was isolated and subjected to the reaction conditions (5%
o
IPrAuNTf2, 40 C). Within 6 hours, full conversion of 6b was
Table 2. Reaction scope of oxepine adductsa
attained, with oxepine 3b formed in 63% yield (Figure 2A).
Notably, treating 6b with a catalytic amount of HNTf2 (5%) led
to decomposition of the substrate with no observation of
oxepine (Figure 2A). These results confirmed that this ring-
expansion rearrangement is a gold-catalyzed process.
R
1) 5% IPrAuNTf2,
40 oC, CHCl3 (0.25M)
Ar
CN
CN
O
(1.1 eq, 2)
one-pot,
isolated yield
of two steps
OH
+
NC
NC
CN
CN
CN
CN
2)
75 o
C
R
Ar
1
7
8
Ph
CN
7b: R = H, 71%;
7h: R = m-CH3, 61%;
7i: R = m-F, 68%;
7j: R = m-Cl, 59%;
7k: R = p-tBu, 64%;
7l: R = p-Br, 54%;
R
7c: R = o-CH3, 73%;
7d: R = m-CH3, 61%;
7e: R = p-tBu, 65%;
7f: R = p-Br, 67%;
7g: R = p-CF3, 59%;
O
CN
CN
CN
CN
CN
O
CN
R
CN
Ph
Ph
CN
Ph
CN
O
CN
O
CN
CN
CN
CN
CN
Ph
S
7n: 74%
single isomer
X-Ray of 7b
CCDC 1521360
X-Ray of 7g
CCDC 1521361
7m: 81%
a
General conditions:
1 (0.4 mmol), 2 (1.1 eq), and IPrAuNTf2 (5 mol %) in dry
CHCl3 (1.6 mL) under Ar atmosphere at 40 oC. The crude was passed through
silica,
(1.5 eq) was added, and the reaction was heated at 75 oC. Yields of
isolated products are given.
8
Accordingly, to explore the progression of this process, we
monitored the kinetics of the reaction with 1H-NMR.
Interestingly, within approximately 15 minutes, homo-
propargyl alcohol 1a was completely converted to the
Figure 2. Exploration of reaction mechanism
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An additional mechanistic concern is the reactivity
difference between aliphatic and aryl-substituted terminal
alkynes. As shown in Figure 2B, treating either alkyne 1a
(Figure 2C) or ketone 1a’ (Figure 2D) with an equimolar ratio of
aliphatic and aromatic alkyne afforded alkyne 6b as the major
product, with no aliphatic oxepine or alkynylation observed.
This data suggests that gold-acetylides formed from either
aliphatic or aryl-substituted terminal alkynes exhibit divergent
reactivity within the catalytic system based on alkyne
substitution. Therefore, the intramolecular cyclization of
homo-propargyl alcohol 1a efficiently out-competes the
intermolecular hydroxylation of the terminal alkyne,
selectively forming the alkynylation product 6b.
Chem. Commun., 2013, 49, 1282; (e) R. Meiss, K. Kumar, and H.
Waldmann, Chem. Eur. J., 2015, 21, 13526; (f) J. Miró, M. Sánchez-
Roselló, J. González, C. del Pozo and S. Fustero, Chem. Eur. J., 2015,
21, 5459; (g) W. D. Rao, M. J. Koh, P. Kothandaraman and P. W. H.
Chan, J. Am. Chem. Soc., 2012, 134, 10811; (h) P. B. Brady, E. M.
Carreira, Org. Lett., 2015, 17, 3350.
3
4
.
.
Y. Wei and M. Shi, ACS Catal., 2016, 6, 2515.
(a) S. E. Motika, Q. Wang, N. G. Akhmedov, L. Wojtas and X. Shi,
Angew. Chem., Int. Ed., 2016, 55, 11582; (b) Y. Yang, A. Qin, K. Zhao,
D. Wang and X. Shi, Adv. Synth. Catal., 2016, 358, 1433. (c) Q. Wang,
S. E. Motika, N. G. Akhmedov, J. L. Petersen and X. Shi, Angew.
This result contrasts with our previously reported system in Chem., Int. Ed., 2014, 53, 5418; (d) H. Duan, S. Sengupta, J. L.
which intermolecular hydroalkoxylation was preferred.
Furthermore, by utilizing the N-heterocyclic carbene gold
catalyst IPrAuNTf2, 13 the internal alkyne functionality of
Petersen, N. G. Akhmedov and X. Shi, J. Am. Chem. Soc., 2009, 131,
12100.
5 (a) S. Hosseyni, L. Wojtas, M. Li and X. Shi, J. Am. Chem. Soc.,
.
compound
6 can be activated to form oxepine 3 through a
2016, 138, 3994; (b) V. Snieckus and L. C. Frota, Synfacts, 2016, 12,
ring-expansion rearrangement (a detailed mechanistic study is
currently under investigation). Consequently, aryl-substituted
terminal alkynes are successfully implemented into a highly
efficient gold-catalyzed synthesis of 2,3-dihydrooxepines for
the first time.
573.
6
.
S. Hosseyni, C. A. Smith and X. Shi, Org. Lett., 2016, ASAP.
7
.
(a) W. Wang, G. B. Hammond and B. Xu, J. Am. Chem. Soc., 2012,
134, 5697; (b) D. J. Gorin and F. D. Toste, Nature, 2007, 446, 395.
8. For selected examples of metal-catalyzed oxonium alkynylation,
Herein, we report the gold-catalyzed intermolecular
condensation of alkynols and aromatic terminal alkynes. It
was discovered that the initial alkynylated substrates undergo
a subsequent gold-catalyzed ring expansion to afford the
corresponding 2,3-dihydrooxepines. This reaction represents a
complementary synthesis to our previously reported enyne
cycloisomerization. Additionally, the transformation is an
illustration of reaction divergence that is tuned by altering the
structure of the substrate. As a result of the mild reaction
conditions, expedient functional group modification, and
mechanistic insight gained, this study holds significant value in
the advancement of gold-catalysis for the synthesis of complex
molecules.
see: (a) X-Q. Yao and C-J. Li, Org. Lett., 2006, 8, 1953; (b) C.
Obradors and A. M. Echavarren, Chem. Eur. J., 2013, 19, 3547; (c) M.
Michalska, O. Songis, C. Taillier, S. P. Bew and V. Dalla, Adv. Synth.
Catal., 2014, 356, 2040; (d) H. Ueda, M. Yamaguchi, H. Kameya, K.
Sugimoto and H. Tokuyama, Org. Lett., 2014, 16, 4948; (e) H. Ueda,
M. Yamaguchi and H. Tokuyama, Chem. Pharm. Bull., 2016, 64, 824.
9. For selected examples of metal-catalyzed iminium alkynylation,
see: (a) C. Koradin, K. Polborn and P. Knochel, Angew. Chem., Int.
Ed., 2002, 41, 2535; (b) T. F. Knöpfel, P. Zarotti, T. Ichikawa and E. M.
Carreira, J. Am. Chem. Soc., 2005, 127, 9682. (c) J. Han, B. Xu and G.
B. Hammond, J. Am. Chem. Soc., 2010, 132, 916.
10. (a) J. Yan, G. L. Tay, C. Neo, B. R. Lee and P. W. H. Chan, Org.
Lett., 2015, 17, 4176; (b) N. V. Borrero, L. G. DeRatt, L. F. Barbosa, K.
A. Abboud and A. Aponick, Org. Lett., 2015, 17, 1754; (c) A. Z.
Gonzalez and D. F. Toste, Org. Lett., 2010, 12, 200.
We thank the NIH (1R01GM120240-01), NSF (CHE-1362057)
and NSFC (21629201) for financial support. CAS thanks NSF (HRD-
1400837) for financial support.
11. T. X. M. Nguyen, B. Son-Meniel, J-C. Jullian and B. Figadere. Lett.
Org. Chem., 6, 630.
12. For recent examples of gold-catalyzed ring expansions, see: (a)
Notes and references
L-L. Zhu, X-X. Li, W. Zhou, X. Li and Z. Chen, J. Org. Chem., 2011, 76,
8814; (b) B. Bolte and F. Gagosz, J. Am. Chem. Soc., 2011, 133, 7696;
(c) K-D. Kim, H-S. Yeom, S. Shin, and S. Shin, Tetrahedron, 2012, 68,
5241; (d) W. Yuan, X. Dong, Y. Wei and M. Shi, Chem. Eur. J., 2012,
18, 10501; (e) J-H. An, H. Yun, S. Shin and S. Shin, Adv. Synth. Catal.,
2014, 356, 3749; (f) J. Zhao, J. Liu, X. Xie, S. Li and Y. Liu, Org. Lett.,
2015, 17, 5926; (g) M. Chen, N. Sun, W. Xu, J. Zhao, G. Wang and Y.
Liu, Chem. Eur. J., 2015, 21, 18571.
1 For a collection of recent reviews, see: (a) S. Pflasterer and A. S.
.
K. Hashmi, Chem. Soc. Rev., 2016, 45, 1331−1367; (b) R. Dorel and A.
M. Echavarren, Chem. Rev., 2015, 115, 9028; (c) M. Rudolph and A.
S. K. Hashmi, Chem. Soc. Rev., 2012, 41, 2448; (d) N. Krause and C.
Winter, Chem. Rev., 2011, 111, 1994; (e) A. Fürstner, Chem. Soc.
Rev., 2009, 38, 3208.
2. (a) G-Q. Chen, W. Fang, Y. Wei, X-Y. Tang and M. Shi, Chem. Sci.,
13
.
S. Díez-González, N. Marion and S. P. Nolan, Chem. Rev., 2009,
2016, 7, 4318; (b) W. Fang, X-Y. Tang and M. Shi, RSC Adv., 2016, 6,
4047; (c) E. Tomás-Mendivil, P. Y. Toullec, J. Díez, S. Conejero, V.
Michelet and V. Cadierno, Org. Lett., 2012, 14, 2520; (d) B. Alcaide,
P. Almendros, S. Cembellín, T. M. del Campo and I. Fernández,
109, 3612.
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