Alkane C-H insertion by aryne intermediates with a silver catalyst

Article abstract of DOI:10.1021/ja400477r

Arynes generated directly from alkyne building blocks in the presence of silver catalysts effectively activate primary, secondary, and tertiary alkane C-H bonds. This C-H insertion requires only a catalytic amount of silver complex and modest heating compared to harsh conditions and extra promoters including directing groups, oxidants, and bases in typical transition-metal-based C-H bond functionalizations. Preliminary mechanistic studies suggest that the C-H bond-breaking and new bond-forming events take place in a concerted manner, rendering a formal 1,2-addition of C-H bond across the π-bond of arynes.

Full text of DOI:10.1021/ja400477r

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Communication
Alkane C–H Insertion by Aryne Intermediates with a Silver Catalyst
Sang Young Yun, Kung-Pern Wang, Nam-Kyu Lee, Phani Mamidipalli, and Daesung Lee
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja400477r • Publication Date (Web): 11 Mar 2013
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Alkane C–H Insertion by Aryne Intermediates with a Silver Catalyst
Sang Young Yun, KungꢀPern Wang, NamꢀKyu Lee, Phani Mamidipalli and Daesung Lee*
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Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607ꢀ7061
Supporting Information
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Previously we reported an unusual reactivity of multynes6
with Grubbs ruthenium alkylidene complexe7 under an ethꢀ
ABSTRACT: Arynes generated directly from alkyne
building blocks in the presence of silver catalyst effectiveꢀ
ly activate primary, secondary and tertiary alkane C–H
bonds. This C–H insertion requires only a catalytic
amount of silver complex and modest heating compared
to harsh conditions and extra promoters including diꢀ
recting groups, oxidants, and bases in typical transition
metalꢀbased C–H bond functionalizations. Preliminary
mechanistic studies suggest that the C–H bondꢀbreaking
and new bondꢀforming events take place in a concerted
manner, rendering a formal 1,2ꢀaddition of C–H bond
across the πꢀbond of arynes.
ylene atmosphere whereby a 1,4ꢀhydrovinylative cyclization was
effectively promoted (Scheme 1).8,9 While expanding the synꢀ
thetic utilities of this hydrovinylation process,10 we found that
in the presence of other metal complexes such as AgOTf,
tetrayne 1 was converted into a tricyclic compound, which
could be rationalized by the formation of an aryne intermediꢀ
ate11,12 followed by its alkane C–H bond insertion. Even though
arynes have been employed in organic synthesis for more than
a century,13,14 alkane C–H bond functionalization by aryne speꢀ
cies has not been reported in the literature except for electronꢀ
rich aromatic C–H bonds,15 We surmised that the effective C–H
bond functionalization should be the consequence of the
presence of a suitable metal catalyst that would generate an
Alkane C–H bonds exist ubiquitously in organic compounds,
but due to their inert nature, they are reluctant to be engaged in
chemical processes forming new bonds. The functionalization
of these inert C–H bonds, although challenging and thus a
longꢀstanding research objective in academia and industry,
would allow the most abundant natural saturated hydrocarbon
feedstock to be processed to more valuable products.1ꢀ3 From
the perspective of developing environmentally benign and atꢀ
omꢀeconomical methods, the direct catalytic C–H bond funcꢀ
tionalization would have a significant merit because in princiꢀ
ple, this technology will allow production of valuable chemical
entities with the formation of a lesser amount of harmful byꢀ
products in more costꢀ and energyꢀeffective manners. In recent
years, a rapid evolution of directing groupꢀassisted metalꢀ
catalyzed C–H bond functionalization processes has been witꢀ
nessed.4 Despite their benefits in facilitating the functionalizaꢀ
tion of inert C–H bonds in these approaches, the directing
group needs to be removed after all when it is not a part of the
target molecules, which is a significant limitation of this apꢀ
proach. In addition, the necessity of stoichiometric amounts of
activators such as oxidants and bases or other additives signifiꢀ
cantly compromise the practicality of the current metalꢀ
catalyzed C–H functionalization approaches.5
intermediate viewed as a metalꢀstabilized aryl cation (A in eq 1)
or a 1,2ꢀbisꢀcarbeneꢀcarbenoid canonical form (B in eq. 1). Difꢀ
ferent from free arynes, these metalꢀcomplexed arynes16 have a
subtle balance for its stability and reactivity such that even the
least nucleophilic C–H bonds can be activated. Here we report
a new C–H bond functionalization by arynes in the presence of
silver catalyst, where unactivated 1°, 2° and 3 ° C–H bonds are
effectively added across the πꢀbond of arynes.
Table 1. Screening of Catalysts and Reaction Conditions
R
R
Catalyst (10 mol%)
TsN
toluene, 90 oC, 5 h
N
Ts
H
Et
Ph
R =
H
1
2
Et
entry
catalyst
yield (%)a
entry
catalyst
yield (%)a
AgOTf
AgSbF6
AgNO3
AgOAc
AgO
Sm(OTf)3
In(OTf)3
Sc(OTf)3
Ru3(CO)12
PPh3AuCl
PtCl2
1
2
3
4
5
6
7
91b
88
82
85
23
86
73
8
9
62
78
63
53c,d
0
10
11
12
13
14
Scheme 1.
Cu(OTf)2
Zn(OTf)2
0
none
0
aDetermined by 1H NMR. bNo conversion at 60 oC.
.
.
cHBF4 OEt2 (15 mol%) was used. dNo conversion without HBF4 OEt2
First we examined the effectiveness of various catalysts for
C–H bond activation with bisꢀ1,3ꢀdiyne substrate 1 containing
ynamide tether (Table 1).17 When a catalytic amount (10 mol%)
of silver trifluoromethanesulfonate (AgOTf) was employed in
toluene at 90 °C, complete conversion was observed within 5 h
of reaction time, and the isolated product was unambiguously
identified as the expected C–H insertion product 2 (entry 1).
Various silver salts including AgSbF6, AgNO3, AgOAc exhibited
similar level of catalytic activity, affording 82–88% yields of 2
but AgO gave only 23% yield of the product (entries 2 to 5).
Other metal triflates such as Cu(OTf)2, Zn(OTf)2, Sm(OTf)3,
In(OTf)3, and Sc(OTf)3 were found to promote the C–H activaꢀ
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tion in only slightly lower (86–62%) yields (entries 6 to 10). A
methyl group at the propargylic carbon afforded 4b in markedꢀ
cationic ruthenium carbonyl complex, known for hydroaminaꢀ
tion and C–H bond activation generated from Ru3(CO)12 and
HBF4—OEt2 also promoted the reaction smoothly, providing
ly improved yield (92%) even under standard conditions
(AgOTf, toluene), probably due to the known beneficial effect of
the geminal dialkyl group on ring closure reactions.20 The reacꢀ
tions of 3c and 3d were also performed with AgSbF6 in iodoꢀ
benzene, providing 2° C–H bond insertion products 4c and 4d
in 78% and 75% yields, respectively. Nearly quantitative yields
of 2o and 3° C–H bond insertion products 4e and 4f were obꢀ
tained from substrates 3e and 3f. While the C–H insertion
onto a pendant cyclopentyl moiety provided a single diastereꢀ
omer 4g in 72% yield, substrates containing the corresponding
cyclohexyl and cycloheptyl moieties generated diastereomeric
mixtures of 4h and 4i.21 Interestingly, bridged bicycle frameꢀ
works, such as bicyclo[2,2,1]heptanes 4j and 4k as well as bicyꢀ
clo[3,2,1]octane 4l, were created in high yields via the insertion
into a remote C–H bond on the pendant cycloalkyl groups.
Substrates 4m–o containing a silyl ether moiety, alkene and
alkyne functionalities were tolerant if these functional groups
are not directly attached to the carbon center where the C–H
insertion occurs.22 The existing stereogenic center like in (S)ꢀ
citronellyl substituted bisꢀ1,3ꢀdiyne 3p did not impose any
stereochemical bias for the diastereotopic C–H insertion
events, affording 4p as a 1:1 diastereomeric mixture in 85%
yield. Next, we briefly examined the chemoselectivity of the
insertion using substrates 3q and 3r that possess two different
kinds of available C–H bonds for insertion environment of
which is biased by both electronic and steric factors. It was
found that the 2° C–H bond in substrate 3q was significantly
more reactive than its 1° C–H bond, affording a mixture of 4q
and 4q' in 80% yield with a 13:1 ratio (eq. 2). The C–H inserꢀ
tion in substrate 3r occurred at the indicated cyclic secondary
C–H bond with significant preference over the primary C–H
bond, generating a 10:1 mixture of 4r and 4r' in 88% yield (eq.
3).
1
2
3
4
5
6
7
8
18
53% yield of the C–H insertion product (entry 11), but
Ru3(CO)12 alone was ineffective, and the starting material deꢀ
composed. On the contrary, other metal complexes known for
19
their high affinity for alkynes such as PPh3AuCl and PtCl2
generated only intractable material (entries 12 and 13). Without
catalysts13 under otherwise identical conditions, the substrate
decomposed with no vestige of the product (entry 14).
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Table 2. Reaction Scope of Primary, Secondary and Tertiary
C–H Bond Insertion
R
R
AgOTf (10 mol%)
toluene, 90 oC, 5 h
X
X
Y
Y
R'
R2
R1
3a–p
4a–p
H
R
R
R
TsN
N
Ts
N
Ts
4a
4b
Ph-(4-OMe) 4c 78%
Ph-(4-Cl) 4d 75%
R =
92%
62%*
R
R
R
H
TsN
TsN
R =
N
Ts
H
4g
4f
4e
Ph-(4-Cl)
72%
95%
96%
R
R
R
R
R
AgOTf (10 mol%)
(2)
TsN
H
toluene, 90 oC, 5 h
2:1
N
N
Ts
Ts
N
Ts
80%
H
N
Ts
4q
3q
H
+
4q : 4q' = 13 : 1
4h
4i
R
nBu 4j 92%
R =
CH2OBn
Ph-(4-OMe)
79%
R =
OMe
82%
R
CH2OPMB 4k 88%
N
R
R
Ts
4q'
H
TsN
TsN
R
N
Ts
OTBS
R
4n
AgOTf (10 mol%)
4m
(3)
4l
TsN
TsN
toluene, 90 oC, 5 h
88%
H
Ph-(4-OMe)
R
R =
OTBS
H
4r
93%
96%
90%
3r
H
4r : 4r' = 10 : 1
R
R
R =
+ TsN
TsN
H 1:1
N
Ts
4r'
H
4p
4o
TBS
To gain mechanistic insights into the C–H activation proꢀ
Ph
R =
85%
cess, a deuteriumꢀlabeled substrate 3s was employed (eq. 4).
Under the typical C–H insertion conditions, nearly complete
deuterium incorporation (>98%) at the C2 position of product
4s was observed. When a competition experiment was perꢀ
formed with an equimolar mixture of a deuteriumꢀlabeled subꢀ
strate 3s and the unlabeled substrate 3j, no crossover products
were detected (Scheme S1). These results taken together imply
that C(sp3)–H bondꢀbreaking and C(sp2)–H bondꢀforming
events take place in a concerted rather than a stepwise manner.
In addition, diastereomericallyꢀenriched substrate 3t (dr =
10:1 and 1.1:1) provided 4t with diasteromeric ratios identical
to that of starting material 3t (eq. 5). The conserved stereoꢀ
chemistry in these two experiments is more favorably in line
90%
Isolated yields are indicated below each entry. *Reactions were performed with
AgSbF6 (10 mol%) in iodobenzene and the reported yields were measured by
1H NMR with an internal standard.
The scope of this catalytic C–H insertion reaction was furꢀ
ther explored with various unsymmetrical and symmetrical bisꢀ
1,3ꢀdiyne substrates (Table 2). In general, 1°, 2° and 3° C–H
bonds were activated to afford 5ꢀmembered ring products, yet
the substituent pattern in the alkyl chain significantly affected
the reaction efficiency. While the insertion of the 1° C–H bond
of 3a was best achieved with AgSbF6 (10 mol%) in iodobenzene
to form 4a in 62% yield, substrate 3b containing geminal diꢀ
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with a concerted mechanism for the C–H activation step more
than a stepwise process via radical or cationic intermediate.
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ASSOCIATED CONTENT
R
Supporting Information Experimental details, characteriꢀ
.
R
R =
AgOTf
TsN
zation data, NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org
(4)
TsN
2
toluene, 90 o
93%
C
3
1
D
D
D
4s
D
3s
Ph
AUTHOR INFORMATION
Ph
98% D incorporation
R
Corresponding Author
R
AgOTf
9
dsunglee@uic.edu
(5)
TsN
toluene, 90 o
C
N
Ts
10
11
12
13
14
15
16
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Ph
Author Contributions
Present Addresses
Ph
Ph-(4-OMe)
R =
3t
4t
with dr = 10 : 1
with dr = 1.1 : 1
with dr = 10 : 1
with dr = 1.1 : 1
85% yield
83% yield
ACKNOWLEDGMENT
We are grateful to the University of Illinois at Chicago for fiꢀ
nancial support.
R
R
R =
AgOTf
TsN
TsN
4u
(6)
toluene, 90 o
91%
C
H
D
3u
H/D
Ph
kH/kD = 1.0 ± 0.1
Ph
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(Scheme 2). In this mechanistic scenario, a sequence of bondꢀ
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Scheme 2. Possible Mechanism for C–H Insertion
In conclusion, we have developed a new catalytic alkane C–
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generated directly from alkyne building blocks. The simplicity
of operation, broad substrate scope, and excellent siteꢀ
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inspire the synthesis of various molecular structures in green
and atomꢀeconomical manners.
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(18) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000.
(19) For overviews on gold and platinumꢀcatalyzed activation
of alkynes (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth.
Catal. 2006, 348, 2271. (b) Suhre, M. H.; Reif, M.; Kirsch, S. F.
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Chem., Int. Ed. 2005, 44, 2798. (d) Shi, X.; Gorin, D. J.; Toste,
F. D. J. Am. Chem. Soc. 2005, 127, 5802. (e) Hashmi, A. S. K.;
Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391.
(f) Oi, S.; Tsukamoto, I.; Miyano, S.; Inoue, Y. Organometallics
2001, 20, 3704. (g) Harrak, Y. et al. J. Am. Chem. Soc. 2004,
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(b) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224. (c)
Karaman, R. Tetrahedron Lett. 2009, 50, 6083.
(21) See Supporting Information for details.
(22) If the silylether exists at the γꢀcarbon from the alkyne,
O–Si bond rather than C–H bond insertion occurred. See supꢀ
porting Information (Scheme S2).
(23) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed.
2012, 51, 3066.
(24) For silver additive effects on benzyne chemistry, see: (a)
Friedman, L. J. Am. Chem. Soc. 1967, 89, 3071. (b) Crews, P.;
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R. A. Tetrahedron Lett. 1970, 11, 1863. A goldꢀcarbenoid simiꢀ
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