Stereodivergent Intramolecular C(sp3)-H Functionalization of Azavinyl Carbenes: Synthesis of Saturated Heterocycles and Fused N -Heterotricycles

Article abstract of DOI:10.1021/jacs.5b04295

A general approach for the formation of five-membered saturated heterocycles by intramolecular C(sp³)-H functionalization is reported. Using N-sulfonyltriazoles as Rh(II) azavinyl carbene equivalents, a wide variety of stereodefined cis-2,3-dis

Full text of DOI:10.1021/jacs.5b04295

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Stereodivergent Intramolecular C(sp3)-H Functionalization of Azavinyl
Carbenes: Synthesis of Saturated Heterocycles and Fused N-Heterotricycles
Vincent N. G. Lindsay, Heléné M.-F Viart, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Jun 2015
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Stereodivergent Intramolecular C(sp )H Functionalization of
Azavinyl Carbenes: Synthesis of Saturated Heterocycles and
Fused N-Heterotricycles
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Vincent N. G. Lindsay, Hélène M.-F. Viart, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder
ABSTRACT: A general approach for the formation of five-
Scheme 1. Synthesis of tetrahydrofurans and N-
heterocycles via metal-catalyzed CH insertion
3
membered saturated heterocycles by intramolecular C(sp )-
H functionalization is reported. Using N-sulfonyltriazoles as
Rh(II) azavinyl carbene equivalents, a wide variety of ste-
reodefined cis-2,3-disubstituted tetrahydrofurans were ob-
tained in good to excellent diastereoselectivity from acyclic,
readily available precursors. The reaction is shown to be
amenable to gram-scale, and judicious choice of reaction
conditions allowed for stereodivergence, providing selective
access to the trans diastereomer, in good yield. The result-
ing products were shown to be valuable intermediates for
the direct preparation of fused N-heterotricycles in one step
by intramolecular CH amination or Pictet-Spengler cycliza-
tion.
Saturated five-membered heterocycles such as tetrahy-
drofurans are ubiquitous structural motifs found in an array
of natural products and other biologically relevant mole-
In the last few years, 1-sulfonyl-1,2,3-triazoles have prov-
en to be extremely versatile Rh(II) azavinyl carbene equiva-
lents in numerous carbene transfer processes. In contrast
with α-diazocarbonyl compounds or dialkyldiazomethanes,
the use of N-sulfonyltriazoles as carbenoid precursors can
lead to the rapid elaboration of substituted N-heterocycles,
by cyclization of the resulting imino group after the carbene
transfer has occurred (Scheme 1b). When these transfor-
mations are applied in an intramolecular sense, ring-fused
N-heterocycles are directly obtained from acyclic precursors
in a particularly efficient manner. In our continuing efforts to
utilize such intramolecular azavinyl carbene transfer reac-
tions for the expedient synthesis of fused N-heterocycles,
we envisioned that the corresponding intramolecular CH
insertion into an ethereal CH bond would lead to a ste-
reodefined 3-imino tetrahydrofuran, which could be elabo-
rated into fused N-heterocycles by engaging the resulting N-
sulfonylamino moiety of the product (Scheme 1c). In this
work, we report a general approach to the synthesis of
saturated heterocycles using a stereodivergent intramolecu-
1
6
cules. For the synthesis of polysubstituted and ring-fused
analogues of these compounds, efficient access to ste-
2
reodefined products remains a formidable challenge. The
preparation of substituted tetrahydrofurans often proceeds
by CO bond formation, via cyclization of linear substrates
with predefined stereochemistry. A strategically powerful
alternative to this approach involves intramolecular CC
bond formation from an acyclic aliphatic ether, where both
the cyclization and the generation of stereocenters occur in
the same step, ideally from an unactivated substrate. In
recent years, metal-catalyzed carbenoid CH insertion
reactions have been shown to be robust processes for
stereoselective CC bond formation from ethereal CH
6a
7
7
c-
d
3
bonds. While such a stategy has been widely utilized for
the intramolecular formation of stereodefined dihydrobenzo-
furans from aryl ethers, only scarce and specific examples
8
4
have been reported for the analogous formation of polysub-
4
b,5
stituted tetrahydrofurans.
A common challenge in these
3
lar Rh-catalyzed azavinyl carbenoid C(sp )H insertion
reactions, typically using Rh(II) carbenoids derived from -
diazocarbonyl compounds, lies in the diastereocontrol of the
intramolecular CH insertion step when flexible aliphatic
ethers are employed as substrates. Very recently, Che et al.
demonstrated that Ru-porphyrin catalysts are particularly
efficient in such a process with dialkyldiazomethanes
formed in situ from N-sulfonylhydrazones, leading to a va-
riety of stereodefined saturated heterocycles via a Ru dial-
reaction. Moreover, the resulting products were directly
utilized for the synthesis of ring-fused N-heterotricycles
such as a tetrahydroquinoline and a tetrahydrobenzazepine,
through the use of an intramolecular CH amination or
Pictet-Spengler cyclization, respectively. Considering the
ubiquity of polysubstituted and ring-fused tetrahydrofurans
and the lack of a unified route for their stereoselective for-
mation, this work should find broad applicability in the elab-
oration of complex molecules.
5g
kylcarbene (Scheme 1a).
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a
In order to evaluate the viability of our approach, we first
synthesized N-sulfonyltriazole 1a in two simple steps from
commercially available 3-butyn-1-ol, and subjected it to
standard conditions for Rh(II)-catalyzed azavinyl carbene
2).
Under the optimized conditions, the resulting N-
1
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6
7
8
9
1
1
1
1
1
1
1
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1
1
2
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2
2
2
2
2
2
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5
6
sulfonyl amide 2a was isolated in 93% yield and 96:4 dr,
and the procedure could be conducted on gram-scale with
similar efficiency.
6
a
transfer reactions (eq 1).
While the desired 3-
iminotetrahydrofuran 2aa was cleanly formed in good NMR
yield (83%), only very poor diastereoselectivity was ob-
tained (47:53). Interestingly, no 1,2-hydride shift side-
product was observed, a common problem with alkyl-
7
e,9
substituted carbenoid precursors.
With these conditions in hand, a variety of stereodefined
saturated five-membered heterocycles were efficiently pre-
pared (Table 2). Various substituted benzyl ethers were well
tolerated as substrates, as well as an electron rich hetero-
0
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0
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9
0
3
cyclic variant (entries 1-7). C(sp )H insertion into an allylic
A survey of various Rh(II) catalysts revealed that the na-
ture of the carboxylate ligands had an enormous impact on
the diastereoselectivity of the reaction, with the most hin-
dered complexes affording the highest cis:trans ratio of 2aa
ethereal position is also possible, with a minimal amount of
competitive cyclopropanation observed on the proximal
double bond (entry 8). Gratifyingly, substrates bearing an
aliphatic R group, though less activated towards CH inser-
tion, afford a high yield of the corresponding tetrahydrofuran
(
Table 1, entries 1-8). Commercially available catalyst
Rh (tpa) gave optimal diastereoselectivity, though it proved
2
4
(entry 9). Insertion into methine CH bonds, leading to
to be significantly less reactive and the reaction time had to
be increased to 4 h in order to achieve complete conversion
highly substituted analogues 2j and 2k, was found to also
proceed, in good yields (entries 10-11). In addition to tetra-
hydrofurans, the formation of products such as 2l and 2m
demonstrate that pyrrolidines and cyclopentanes can be
accessed by this method in excellent diastereoselectivity
(entries 12-13). The use of a homologated substrate such
as 1n afforded tetrahydrofuran 2n instead of the expected
tetrahydropyran, presumably by a Rh(II)-catalyzed oxonium
(entries 8-9). Most non-coordinating solvents were tolerat-
ed, however the use of CH Cl led to an increase in both
2
2
10
the yield and the diastereoselectivity (entry 10).
Table 1. Optimization of the intramolecular Rh(II)-
catalyzed azavinyl carbene CH insertion
12
ylide formation / [1,2]-alkyl shift sequence (Scheme 2).
Scheme 2. Rh(II)-catalyzed oxonium ylide formation /
[1,2]-alkyl shift with extended tethers
entry Rh
2
L
4
R
time yield
dr
(c:t)
a,b
a
(h)
(%)
1
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
2
2
2
2
2
2
2
2
2
2
2
(O
(OAc)
(Ooct)
(tfa)
(Adc)
(OPiv)
(esp)
2
CH)
4
H
1
23 (77)
72 (13)
83 (<5)
<5 (83)
83 (<5)
80 (<5)
79 (<5)
17 (71)
72 (5)
38:62
33:67
47:53
-
2
4
Me
n-C
1
3
4
7
H
15
1
4
4
CF
3
1
5
4
1-Ad
1
69:31
72:28
82:18
95:5
93:7
96:4
96:4
a
6 4
PMP: 4-MeO-C H
6
4
CMe
c
3
1
The crude imine intermediate obtained following CH in-
7
2
1
sertion can be directly used as an electrophile in a 1,2-
addition reaction, as exemplified by Grignard addition to
imine 2aa, affording tetrahydrofuran 3 possessing three
8
(tpa)
(tpa)
(tpa)
(tpa)
4
CPh
CPh
CPh
CPh
3
1
9
4
3
4
12b,13-14
contiguous stereocenters (eq 3).
d
10
4
4
3
3
4
81 (18)
96 (<5)
d,e
1
1
4.5
a
Determined by NMR analysis of the crude mixture using
b
1
,3,5-trimethoxybenzene as internal standard. Yield of
remaining
c
1a
in
parentheses.
2 2
Rh (esp) :
While sterically hindered Rh
in high diastereoselectivity, our initial investigations had
revealed that the use of other catalysts such as Rh (OAc)
2 4
(tpa) affords the cis product
Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic
d
e
acid)]. Using CH
2
Cl
2
as solvent. 2 mol% catalyst was
2
4
used.
can provide a trans-selective reaction, allowing the devel-
opment of a stereodivergent approach (see Table 1, entry
In view of developing a general method, the catalyst load-
ing was increased to 2 mol%, insuring complete conversion
in a timely fashion for most substrates (entry 11). It was
found that prolonged reaction times (>5 h) or higher reac-
tion temperatures led to partial decomposition of the product
2
). Such an effect on the diastereoselectivity might be due
to a difference in the degrees of freedom of the substituents
around the CC bond being formed, where small carbox-
ylates such as OAc allow these groups (here, Ph and
C=NTs) to be placed in a more stable trans configuration in
1
1
and were therefore avoided. While the resulting imine
product is somewhat unstable to silica gel chromatography,
isolation of the product was readily achieved after reduction
1
0
the transition state. After further optimization, performing
the Rh (OAc) -catalyzed reaction with substrate 1a in tolu-
ene in the presence of 2-picoline as an additive (5 mol%)
2
4
1
5
4
with LiAlH , directly added at 0 °C to the crude mixture (eq
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allowed access to the trans diastereomer, in good yield
(Scheme 3).
Scheme 3. Stereodivergence of the C(sp )H inser-
tion: access to the trans diastereomer
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. Substrate scope of the intramolecular Rh(II)-
catalyzed azavinyl carbene CH insertion
Finally, the 3-methylamino moiety of the products ob-
tained following imine reduction can be further utilized for
the rapid construction of N-heterotricycles by intramolecular
CN bond formation events (Scheme 4). As exemplified
with N-sulfonyl amide 2a, the use of commercially available
1,3-diiodo-5,5-dimethylhydantoin (DIH) allowed the direct
formation of 5-6-6 fused tetrahydroquinoline 4 by a metal-
entry substrate
product
yield dr
a
b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(%)
(c:t)
1
93
96:4
1
6
free CH amination process. Furthermore, modified Pictet-
Spengler conditions using paraformaldehyde, TFAA and
MsOH in DCE provided fused tetrahydrobenzazepine 5 in
good yield, without the need for an electron-donating aro-
2
89
93:7
17
matic ring. In both cases, X-ray crystal structures were
obtained to unambiguously confirm the structure of the N-
heterotricyclic products.
90:1
0
3
4
5
6
89
80
77
78
Scheme 4. Synthesis of N-Heterotricycles via intra-
a
molecular CH amination and Pictet-Spengler
98:2
95:5
89:1
1
7
81
97:3
c
82:1
8
8
71
88
In summary, a general and stereodivergent intramolecular
3
Rh(II)-catalyzed azavinyl carbene C(sp )H insertion reac-
tion was developed, providing access to an array of ste-
reodefined cis-2,3-disubstituted saturated heterocycles. The
reaction proceeds on gram-scale with similar efficiency, and
the use of an alternative set of conditions is shown to pro-
vide access to the trans diastereomer of these compounds,
in good yield. The resulting products were utilized for the
rapid formation of fused N-heterotricycles through different
intramolecular CN bond forming processes. Cognizant of
the ubiquity of polysubstituted and ring-fused tetrahydrofu-
rans, this work should find broad applicability in the synthe-
sis of biologically relevant molecules. Future studies in the
field of intramolecular azavinyl carbene insertion reactions
8
3
7:1
9
1
1
0
1
82
97
58
67
-
-
d
e
1
1
will seek to render these transformations enantioselective.
>98:
2
12
ASSOCIATED CONTENT
Supporting Information
>98:
2
1
3
Experimental details and spectroscopic data. This material
is available free of charge via the Internet at
http://pubs.acs.org.
a
b
Isolated yield. Determined by NMR analysis of the
c
crude mixture. Rh
lyst. Rh
mol% of Rh
2
(S-PTAD)
(3 mol%) was used as catalyst. Using 3
(tpa)
4
(2 mol%) was used as cata-
AUTHOR INFORMATION
d
e
2 4
(Adc)
2
4
.
Corresponding Author
rsarpong@berkeley.edu
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Notes
Brown, R. Chem. Commun. 1998, 1895. (g) Reddy, A. R.; Zhou, C.-
Y.; Guo, Z.; Wei, J.; Che, C.-M. Angew. Chem. Int. Ed. 2014, 53,
The authors declare no competing financial interests.
14175.
ACKNOWLEDGMENT
(6) For reviews and seminal examples on the use of N-
sulfonyltriazoles as Rh-azavinyl carbene equivalents, see: (a)
Davies, H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 43, 5151. (b)
Anbarasan, P.; Yadagiri, D.; Rajasekar, S. Synthesis 2014, 46,
This work was supported by the NSF (CAREER 0643264 to
R.S., and under the CCI Center for Selective CH Func-
tionalization, CHE-1205646). We are grateful to the FRQNT
(B3) for a postdoctoral scholarship to V.N.G.L., to the
Carlsberg Foundation for a postdoctoral scholarship to
H.M.-F.V., and to Abbott, Eli Lilly, and Roche for financial
support. We thank A. DiPasquale for solving the crystal
structures of 2a, 4 and 5 (displayed with CYLView), sup-
ported by NIH Shared Instrumentation Grant (S10-
RR027172).
3004. (c) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem. Int. Ed.
2012, 51, 862. (d) Gulevich, A. V.; Gevorgyan, V. Angew. Chem.
Int. Ed. 2013, 52, 1371. (e) Horneff, T.; Chuprakov, S.; Chernyak,
N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130,
14972. (f) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.;
Fokin, V. V. J. Am. Chem. Soc. 2009, 131, 18034.
(7) For examples of the synthesis of fused N-heterocycles via an
intramolecular azavinyl carbene transfer, see: (a) Miura, T.; Fu-
nakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 2272. (b)
Alford, J. S.; Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc.
0
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(13) Rh(I)-catalyzed addition of PhB(OH)
2
and Cu(I)-catalyzed
addition of Et Zn only led to very low yields of the corresponding
2
adducts in this case due to various side-reactions.
(14) For recent reviews on the addition of nonstabilized carbani-
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6
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2
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