Remote C-H functionalization: Using the N-O moiety as an atom-economical tether to obtain 1,5- and the rare 1,7-C-H insertions

Article abstract of DOI:10.1002/anie.201000160

(Chemical Equotion Present) Dr. N-O: Rhodium-catalyzed intramolecular C-H insertion with diazocompounds, which are tethered by alkoxyamines, afforded 1,5- and the rare 1,7-insertion products (see scheme; Bn = benzyl). The resulting N-O tether is unaffected under the C-H insertion reaction conditions and it can be readily cleaved or transformed into various functionalities. The reduction of the N-O moiety controls acyclic stereochemistry.

Full text of DOI:10.1002/anie.201000160

Communications
DOI: 10.1002/anie.201000160
À
C H Insertion
À
À
Remote C H Functionalization: Using the N O Moiety as an Atom-
Economical Tether to Obtain 1,5- and the Rare 1,7-C H Insertions**
À
Jingxin Wang, Bogdan Stefane, Deana Jaber, Jacqueline A. I. Smith, Christopher Vickery,
Mouhamed Diop, and Herman O. Sintim*
Contemporary organic synthesis faces the demands of
improving its efficiency[1] by redox and atom economy,
including achieving superior chemo-, regio-, and stereoselec-
tivity.[2] Consequently, there has been great interest in the
The use of the nitro group to introduce amino-hydroxy
groups into complex molecules through different stereose-
lective strategies has been elegantly demonstrated by the
Denmark group and others.[13] Along this line, we reasoned
À
À
À
transformations of inert C H bonds, as these open up new
avenues in synthesis. Significant progress has been made
that C H-insertion reactions using an N O tether that is
obtained from the transformation of a chiral heteroatom
could be a simple way to stereoselectively introduce amino-
towards site-selective C H-insertion reactions,[3] but this field
À
still presents major challenges[4] owing to the ubiquitous
alcohol functionality into complex molecules.[14] The N O
moiety is a perfect atom-economical tether because several
mild methods are available for the facile cleavage of the N O
bond with complete retention of the atoms that constitute the
À
À
nature of C H bonds in organic molecules. The regioselec-
À
À
tivity of C H insertions is governed by electronic, steric, and
conformational factors.[5] In non-constrained systems, intra-
À
À
À
molecular C H-insertion reactions predominately afford
five-membered rings. Three, four, six, and rarely higher-
tether. Thus far, the use of an N O tether to direct C C bond
formation through carbenoid insertion is under-developed.[15]
membered rings[6] can only be obtained by intramolecular
N O-tethered intramolecular C H insertion via an entropi-
cally favorable six-membered transition state (TS) would
enable insertion alpha to the oxygen atom to give compound
B whereas compound C would be obtained by insertion into
À
À
[7]
À
C H insertion if the system is specially constrained,
contains special moieties,[8,9] or if the C H bond is activated
À
by a heteroatom.[6a,10] Thus far, not many systems have been
shown to afford rings larger than five-membered rings
without the need to bias the system. The discovery of new
rules and tethers that facilitate the construction of bigger ring
À
the C H bond, which is beta to the oxygen atom in diazo
substrate A (Scheme 1).[6a] Because enantiopure secondary
alcohols can be readily obtained using a myriad of methods,
such as the asymmetric reduction of ketones,[16] difficult-to-
obtain enantiopure tertiary alcohols can be accessed after
À
sizes by C H insertion will enable the remote functionaliza-
tion of complex molecules.
À
Tethering reacting partners together can lead to better
regio- and stereoselectivities, but this selectivity can be
negated if the tether is difficult to remove or transform into
other moieties. New tethers that can either be readily
N O cleavage.
À
À
Conversely, N O-tethered intramolecular C H insertion
via an eight-membered TS to give seven-membered ring
products would enable the functionalization of a remote
center using an existing heteroatom moiety (compound D,
À
transformed into other functionalities or do not limit C H
À
insertion to specific ring sizes are highly desirable. Herein, we
identify N-alkoxy-N-alkyl amides as atom-economical tethers
Scheme 1). A challenge in using amide tethers in C H-
insertion reactions to obtain remote functionalized products
is to design strategies that can bias the conformer equilibrium
to achieve site-specific functionalization (A1 or A2;
Scheme 2). For N-alkoxy-N-alkyl diazo compounds, the
conformation whereby the alkoxy moiety is positioned trans
to the carbonyl functionality (A1; Scheme 2) is at least
À
for C H-insertion reactions to give amino-hydroxy function-
alized systems.[11,12] We demonstrate, using both computa-
tional and experimental methods, that this tether facilitates
À
À
remote C H functionalization reactions, and that the C H
insertion site selectivity using this particular tether can be
modulated by the reaction conditions and/or the electronics
of the ligand of the dirhodium catalyst.
[*] J. Wang, Dr. B. Stefane, D. Jaber, J. A. I. Smith, C. Vickery, M. Diop,
Prof. Dr. H. O. Sintim
Department of Chemistry and Biochemistry, University of Maryland
College Park, MD 20742 (USA)
Fax: (+1)301-314-9121
E-mail: hsintim@umd.edu
Homepage: http://www2.chem.umd.edu/Groups/sintim/
index.php
[**] This work was supported by the University of Maryland, Fulbright
(to B.S.), Beckman (to M.D.), and GANN (to J.A.I.S.) fellowships.
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000160.
Scheme 1. Remote C H functionalization using an atom-economical
tether.
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Angewandte
Chemie
À
Supporting Information). Together, these factors favor C H
insertion at the position a to the oxygen atom (S6) over the
alternative product (S15, Figure 1; for detailed analysis, see
the Supporting Information). The preparation of diazoalkoxy-
À
amide substrates 4a–l for regioselective C H insertion was
straightforward (Scheme 3). With a range of N-alkoxy-N-
alkyl diazoamides in hand (4a–4l), we proceeded to inves-
À
tigate their intramolecular C H-insertion reactions
Scheme 2. Conformational equilibrium in acyldiazo systems.
5 kcalmolÀ1 more stable than the conformer which has both
the carbonyl and alkoxy moieties cis to each other (A2;
Scheme 2 and Figure 1).[17] Increasing the steric bulk of the N-
alkyl group does not change the conformational ratio of A1 to
A2, in contrast to the well-studied diazoamides in which more
bulky N-alkyl substituents prefer to be cis to the carbonyl
moiety to avoid unfavorable 1,3-allylic strain.[18]
Two unfavorable factors, lone pair–lone pair repulsion
and re-enforcing dipole moments (A2; Scheme 2), probably
account for the lower stability of the cis conformer (compare
the energy levels of S10 + X and S1 + X, Figure 1). The rate-
Scheme 3. Synthesis of N-alkoxy-N-alkyl diazoamides 4a–4l: a) Phtha-
lylglycyl chloride, Et3N, CH2Cl2, 08C, 5 h; b) hydrazine, ethanol, 408C,
4 h; then NaNO2, H2O, CH2Cl2, HCl or HOAc (pH 2–4), 08C, 2 h.
À
determining step for the C H insertion depends upon nitro-
gen extrusion (Figure 1 and Ref. [5d]). Calculations at the
B3LYP/631GLAN level reveal that nitrogen extrusion from
the complex of the rhodium catalyst and the N-alkoxy
diazoamide is more facile (by 3.4 kcalmolÀ1) when the
N-alkoxy moiety is trans to the carbonyl group than when
the group is cis to the carbonyl group (Figure 1 and the
Scheme 4. [{Rh(OAc)2}2]-catalyzed reaction of substrates 4a–4l.
(Scheme 4). Preliminary
results using 4c as
a
model substrate showed
À
that the 1,5-C H insertion
product was the major
À
product with the 1,7-C H
insertion product as
a
minor product (Table 1,
entry 1). Interestingly, the
À
1,6-C H insertion product
was not observed at all.
Obtaining the unusual 1,7-
À
C H insertion product,
albeit as a minor product,
prompted us to investigate
different reaction condi-
tions and substrate substi-
tution patterns that might
increase the ratio of the
À
1,7-C H insertion product
(7c). Temperature seems
to only have
a minor
effect on the product dis-
tribution of N-alkoxy-N-
À
alkyl diazoamide C H-
insertion
reactions;
higher temperatures mar-
À
Figure 1. Reaction pathways and the potential surface of the C H insertion model reaction at the B3LYP/
631GLAN level. The simpler dirhodium catalyst X and substrate S1 were used instead of dirhodium tetraacetate
À
ginally favor the 1,5-C H
and more complex substrates to make the computation more manageable.
insertion product (cf.
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3965

Communications
Table 1: Screening of the RhII-catalyzed reaction of 4c.
Table 2: [{Rh(AcO)2}2]-catalyzed reactions of 4a–4l.
Entry
Catalyst[a]
T [8C]
Ratio 5:7[b]
4
R1(R2)
R3
R4
Total yield [%][a]
Ratio 5/7[b]
1
2
3
4
5
6
7
8
9
[{Rh(AcO)2}2]
[{Rh(AcO)2}2]
[{Rh(AcO)2}2]
[{Rh(AcO)2}2]
À40
0
88:12
90:10
92:8
94:6
96:4
64:36
60:40
94:6
94:6
>99:1
>99:1
a
b
c
d
e
f
g
h
i
Ph(H)
Ph(H)
Ph(H)
Ph(H)
Ph(H)
Ph(H)
Ph(H)
Ph(H)
Ph(Me)
Me(H)
Ph(H)
Et(H)
Me
Me
Me
Me
Me
Me
Me
H
H
Me
Et
iPr
iBu
Bn
67
58
75
64
80
83
77
65
65
53
54
78
61
50:11[c]
41:12[d]
70:5
51:13
59:21
58:25
62:15
40:25
36:29
5:48
25
40
70[c]
40
40
40
40
40
40
[{Rh(AcO)2}2]
[{Rh(CF3CO2)2}2]
[(Rh{CF3(CF2)2CO2}2)2]
[{Rh(heptylCO2)2}2]THF
[Rh2(esp)2]
[Ru2(cymene)2Cl4]
[Rh2(cap)4(CH3CN)2]
Mes
4-MeOBn
4-MeOBn
4-MeOBn
Bn
10
11
j
CO2Et
CO2Et
Me
k
l
Bn
Bn
Bn
0:54
65:7[e]
37:14[g]
[a] Reactions were performed using 2 mol% of the catalyst, CH2Cl2,
2 hours. [b] Ratio based on HPLC and H NMR spectroscopic analysis.
l[f]
Et(H)
Me
1
[c] Reaction was performed in ClCH2CH2Cl. esp= rhodium (a, a, a’, a’-
tetramethyl-1,3-benzenedipropionic acid, cap=caprolactamate.
[a] Yield of isolated product. [b] Ratio based on the yields of pure isolated
products. [c] 6% of six-membered analogue 6a was isolated. [d] 5% of
6b was isolated. [e] 6% of 6l was isolated. [f] Catalyzed by 4 mol%
[{Rh(CF3CO2)2}2]. [g] 10% of 6l was isolated. Mes=mesityl.
Table 1, entries 1–5). Conversely, the electronics of the
rhodium ligand play a pivotal role in product distribution.
Electrophilic carbenoids, generated from the electron-defi-
cient [{Rh(CF3CO2)2}2] or [{Rh[CF3(CF2)2CO2]2}2] complexes,
increase the propensity of the reaction to be channeled
À
through the 1,7-C H insertion reaction pathway whereas
electron-rich [Rh2(cap)4][19] promotes the exclusive formation
of the 1,5-insertion product (see Table 1, entries 6, 7, and 11).
Ruthenium-based catalysts, such as [Ru2(cymene)2Cl4], also
À
afforded the 1,5-C H insertion product almost exclusively
(entry 10, Table 1).
Scheme 5. [{Rh(OAc)2}2]-catalyzed reaction of tetrahydro-2H-pyran-2-yl
(8a) and tetrahydro-2H-pyran-2-yl-oxy (8b) diazo analogues. The
reaction conditions are the same as those indicated in the Table 2. In
the case of 8a, a minor product that was derived from the Buchner
reaction was observed; Bn=benzyl.
We proceeded to investigate how the substitution pattern
in the substrate affected the ratio of the 1,5- to 1,7-C H
À
insertion products when [{Rh(OAc)2}2] was used as the
catalyst. Compounds 4a–g were designed to probe how the
N-substituent affected product ratio. For most of the N sub-
stituents, 1,5- and 1,7- but not 1,6-insertion products were
obtained. However, for smaller N-alkyl groups (methyl and
ethyl groups, 4a and 4b, respectively), approximately 5% of
the 1,6-insertion product was obtained. The amount of 1,7-
bond (B8, Figure 2). Also, favorable interaction between the
lone pairs of the endocyclic oxygen atom and the s* of the
À
C Hg bond in B8 would increase the hydridic character of Hg
À
insertion product increases when primary N O tethers are
used (compounds 4h and 4i), in line with the lower propensity
[20]
À
for C H insertion to occur at primary centers. Compound
À
4l, which lacks benzylic C H bonds, afforded more 1,7- than
1,6-insertion product (albeit modestly).[21]
[22]
À
C H insertions next to carbonyl groups are rare;
consequently, 1,7-insertion products can be predominately
obtained when electron-withdrawing groups, such as esters,
Figure 2. Formation of the 1,5- and 1,7-insertion products.
À
are positioned next to the N O tether (4j and 4k, Table 2).
À
With 4j and 4k, the C H insertions occurred next to methyl
À
À
and phenyl groups, respectively. Interestingly, the 1,7-C H
in B8 and promote the formation of the 1,7-C H insertion
insertion only occurred on the si face when R3 = Me and R2 =
Ph (see the Supporting Information, Scheme S3) but was not
stereoselective when R3 = CO2R and R2 = Me).
product. In contrast, the equatorial Ha in B8 cannot be
activated by the lone pairs on the endocyclic oxygen atom
because of poor orbital overlap. In fact, Ha is deactivated by
virtue of being next to an electron-withdrawing oxygen
atom.[23] The transition state for the 1,7-insertion pathway in
B8 is probably stabilized by three-center–two-electron-like
À
The use of conformational effects to direct remote C H
functionalization is illustrated with substrates 8a and 8b,
which afford exclusively 1,5- and 1,7-C H insertion products,
respectively (Scheme 5). In 8b, an axial anomeric N O tether
was expected to predominate over an equatorial N O tether
because of favorable interaction between the lone pairs of the
À
À
À
À
interactions (s*C O, p orbital, s*C Hg). The low propensity
À
À
to form six-membered rings with N O-tethered diazo com-
pounds is further demonstrated with compounds 11 and 14
À
À
endocyclic oxygen atom and the s* of the anomeric C O
(Scheme 6). In both compounds the b-C H bonds are
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À
À
N O-tethered C H-insertion reaction, starting from readily
available enantioenriched secondary alcohols could be an
alternative solution to solving the acetate-aldol problem in
asymmetric aldol methodologies. Also, the addition of a butyl
À
À
nucleophile to the N O-tethered C H-insertion product 5
(R = iPr) gave the hemi-aminal product 19, without over
addition to the keto functionality. Compound 19 can be
further elaborated into diverse molecules by leveraging on
the diverse transformations of the keto group.
À
In conclusion, we have demonstrated that the N O tether
is a versatile, atom-economical tether that facilitates remote
À
C H functionalization in organic molecules. Use of this tether
À
to make complex molecules,[27] and further mechanistic
Scheme 6. b-C H bond activated substrates still predominantly
afforded the a 1,5-insertion products.
studies[28] aimed at understanding N O-tether-promoted
regioselection are being pursued in our laboratory.
À
activated by the oxygen atom,[24] but five-membered rings are
predominantly obtained with both starting materials. Starting
with enantiopure diastereomer 11, single diastereomeric
Received: January 11, 2010
Revised: February 22, 2010
Published online: April 15, 2010
À
products 12 and 13 are obtained, which indicates that N O
Keywords: diazoacetamides · insertion · regioselectivity ·
rhodium · tertiary alcohols
À
tethered C H-insertion reactions are stereospecific, in line
.
with an earlier observation by Taber and co-workers.[25]
À
The N O tether is a value-added tether because of its
versatility in being transformed into several different func-
tionalities that can be elaborated into diverse moieties. For
example, treatment of compound 5 (R = iPr; Scheme 7) with
Red-Al in anhydrous tetrahydrofuran and toluene, and
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Scheme 7. Transformations of 5a and 5c; synthesis of the tertiary
alcohols: a) Raney-Ni, EtOH, 708C; b) Red-Al, THF/toluene (1:2), then
zinc, AcOH/H2O (9:2); c) nBuLi, toluene, À788C to 108C; d) (S)-(+)-
a-methoxy-a-(trifluoromethyl)phenylacetyl chloride, Et3N, CH2Cl2,
408C. Red-Al=sodium bis(2-methoxyethoxy)aluminumhydride.
subsequent treatment with zinc dust, afforded tertiary alcohol
18 in 70% yield. Importantly, the aminohydroxy moiety in 18,
in which the alcohol is tertiary, is common in several bioactive
À
molecules. Also, the N O moiety can be cleaved without
sacrificing the carbonyl group. Treatment of enantiopure 5a
(R = Me, > 99% ee) with Raney nickel gave enantiopure 17
(> 99% ee, a non-aldol aldol product); confirming that de-
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À
À
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À
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À
O moiety have been reported, but, in those cases, N O bonds
À
À
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À
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3968 www.angewandte.org
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