Catalytic enantioselective synthesis of azacycloalkenes via intermolecular rhodium carbenoid C-H insertion/ring-closing metathesis sequence

Article abstract of DOI:10.1016/j.tetlet.2011.12.019

Enantiomerically enriched cyclopropanes and products of C-H insertion reactions were obtained in excellent combined yields and enantioselectivities as a consequence of rhodium-catalyzed decomposition of vinyl diazoacetate in the presence of tert-butoxycarbonyl-(Boc)-protected amines as trapping agents. A series of enantiomerically enriched six- to eight-membered nitrogen-containing heterocycles were subsequently prepared via ring-closing metathesis of the dienes catalyzed by ruthenium benzylidene complex.

Full text of DOI:10.1016/j.tetlet.2011.12.019

Tetrahedron Letters 53 (2012) 849–851
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Tetrahedron Letters
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Catalytic enantioselective synthesis of azacycloalkenes via intermolecular
rhodium carbenoid C–H insertion/ring-closing metathesis sequence
⇑
Mark C. McMills, Ross J. Humes, Oksana M. Pavlyuk
Department of Chemistry and Biochemistry, 377 Clippinger Laboratories, Ohio University, Athens, OH 45701, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically enriched cyclopropanes and products of C–H insertion reactions were obtained in excel-
lent combined yields and enantioselectivities as a consequence of rhodium-catalyzed decomposition of
vinyl diazoacetate in the presence of tert-butoxycarbonyl-(Boc)-protected amines as trapping agents. A
series of enantiomerically enriched six- to eight-membered nitrogen-containing heterocycles were sub-
sequently prepared via ring-closing metathesis of the dienes catalyzed by ruthenium benzylidene
complex.
Received 11 November 2011
Revised 2 December 2011
Accepted 5 December 2011
Available online 13 December 2011
Keywords:
Diazo
Published by Elsevier Ltd.
Azacycle
Metathesis
C–H insertion
Development of new methods for the synthesis of structurally
advanced intermediates of the general type A and B (Fig. 1) is sig-
nificant to synthetic organic chemists since such heterocyclic scaf-
folds are present in a variety of alkaloids and biologically active
overall yields and excellent enantioselectivities. Regioselective C–
H activation next to the nitrogen atom was first reported by Davies
and Venkataramani, where the authors described an unprece-
dented, selective carbenoid insertion into a methyl C–H bond in
deference to the electronically favorable allylic C–H bond. Based
on this seminal study, we decided to test the chemo- and regiose-
lectivity of the acceptor/donor carbenoid derived from vinyldia-
zoacetate with a series of simple N-Boc-protected ethyl amines.
Specifically, we wanted to determine which of the two methylenes
6
1
molecules. Ring-closing metathesis (RCM) is considered one of
the key reactions for the construction of carbo- and heterocyclic
2
compounds of various ring sizes. In combination with other reac-
3
4
tion processes, such as C–H or X–H (X = N, O) insertion, RCM has
become one the most powerful techniques available for the con-
struction of highly functionalized heterocyclic rings.
a
to the nitrogen would be prone to C–H activation. For this pur-
pose, we prepared a series of alkenyl amines 1a–d (Scheme 1) using
a straightforward two-step synthetic sequence involving Boc-
protection of the commercially available allyl- and butenylamines
followed by alkylation with iodoethane in the presence of NaH.7
Pentenyl- and hexenylamines were prepared from the correspond-
8
ing nitriles by reduction with LAH. The choice of nitrogen protect-
ing group was influenced by the findings of Davies and
6
Venkataramani, where it has been determined that changing the
nitrogen protecting group from Boc to Cbz does not alter the yields
or the regioselectivity of the C–H insertion. However, in the same
study it has been demonstrated that changing the nitrogen protect-
ing group from Boc to Fmoc or Teoc results in the significantly lower
reaction yields. For these reasons, we have decided to protect the
nitrogen as a tert-butyl carbamate in our study.
Figure 1. Nitrogen-containing heterocyclic scaffolds.
In our previous Letter we reported racemic synthesis of a series
of five- to eight-membered heterocycles of type A via a tandem N–H
insertion/RCM sequence.5 Based on those preliminary results, we
have expanded this methodology to include a similar carbenoid
The electron acceptor/electron donor a-diazocarbonyl 2 developed
insertion into the C–H bond of a methylene carbon
followed by RCM to afford azacycloalkenes of the type B in good
a
to the nitrogen
by Davies et al. was prepared in two steps from the commercially avail-
able trans-styryl acetic acid through Fischer esterification followed by
diazo transfer with p-acetamidobenzenes ulfonyl azide (p-ABSA), and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Excellent yields of the
methylstyryldiazoacetate were obtained provided the crude reaction
9
⇑
Corresponding author.
E-mail address: op387905@ohio.edu (O.M. Pavlyuk).
0
040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.12.019

8
50
M. C. McMills et al. / Tetrahedron Letters 53 (2012) 849–851
by chiral HPLC analysis (Table 1). The relative stereochemistry of
1
1
the isolated products was determined by H– H NOESY. Since no
H–C–C–H correlation was observed for the methyl hydrogens
a
to the nitrogen and the styryl hydrogens in 4a, these substituents
were assigned to be trans to one another. Moreover, the crosspeak
between the methines
a to the nitrogen and a to the ester in 4a
indicated the cis relationship for these hydrogens. NOESY analysis
showed a direct correlation of the styryl hydrogens and the hydro-
gens of the methylene
a to the nitrogen in 3a, indicating a cis rela-
tionship between these two substituents. Most interesting,
however, was that no C–H insertion occurred at the methylene of
the alkenyl chain, resulting in highly regioselective C–H activation
of the ethyl methylene. Since the two methylenes
a to the nitrogen
are both electronically activated, the regioselective reactivity of the
ethyl methylene may be a result of the acceptor/donor rhodium
carbenoid’s steric demand as described by Davies and Venkatara-
6
mani. That is, vinylcarbenoid–rhodium tetraprolinate complex
adopts a very specific conformation, resulting in a restricted ap-
proach of the corresponding trapping agent and a highly specific
transition state characteristic of stereoselective transformations.
No C–H insertion was observed at the methyl position of the ethyl
substituent, likely a result of C–H bond b to the nitrogen not being
electronically activated.
2 4
Scheme 1. Rh (S-DOSP) -catalyzed decomposition of vinyldiazoacetate 2.
mixture was quickly filtered through a short plug of silica and avoid-
ing heating by removing the solvent under reduced pressure at
With dienes 4a–d in hand, the C–H insertion products were
then treated with second generation Hoveyda–Grubbs catalyst in
refluxing DCE, resulting in the rapid cyclization of the dienes to
produce the corresponding azacycloalkenes 5a–c (Scheme 2) as a
mixture of Boc-rotamers in 95–98% isolated yields and 92–95%
ee (Table 2). No nine-membered ring was isolated when 4d was
subjected to the RCM conditions described above. Alternate reac-
tion conditions (Grubbs I or Grubbs II catalysts, DCM, rt) did not
change the reaction outcome, with polymerized dienes obtained
in each case. Although five- to eight-membered rings can be easily
obtained via RCM, 9- and 10-membered rings are notoriously more
6
20 °C. Moreover, a freshly prepared solution (0.1 M in dichloroeth-
ane) of the -diazocarbonyl substrate was immediately added via
cannula to a solution of N-Boc ethyl alkenylamine and Rh (S- or R-
DOSP) in order to avoid the undesired electrocyclization of the
a
2
4
10
vinyldiazoacetate 2 to the 3H-pyrazole. Interestingly, the insertion
reaction provided mixtures of cyclopropanes 3a–d in addition to the
C–H insertion products 4a–d in a 2:1 ratio. This product distribution
was unaffected by the choice of the rhodium catalyst (Rh
2 4
(OAc) ,
Rh (pfb) , Rh (TFA) , Rh (TPA) ) or solvent variation (hexanes, ben-
2
4
2
4
2
4
2
zene). Observed chemoselectivity is in stark contrast to our previous
findings, where no stereoselective cyclopropanation or C–H inser-
tion took place with the same vinyldiazoacetate/chiral catalyst sys-
tem and using N-Boc alkenyl amines as trapping agents.5 Instead,
only racemic N–H insertion products were isolated, leading to a con-
clusion that N–H insertions are mechanistically different processes
from C–H insertions and cyclopropanations. N–H insertions can be
thought to proceed via ylide-like intermediates, where decomplex-
ation of the chiral catalyst from the active intermediates is likely.
Alternatively, this transformation may proceed through an early
transition state, where bond formation between the reacting species
may occur at greater distances from each other, and little or no influ-
ence of the chiral catalyst is observed. This early transition state may
be a result of greater polarization of the N–H bond in comparison to
the C–H bond. Therefore, nitrogen is a better nucleophile and com-
peting processes such as cyclopropanation are suppressed resulting
in a highly chemoselective transformation. In contrast, C–H inser-
tion and cyclopropanation reactions can be viewed as concerted
difficult to make. A similar trend was observed in our case, where
six- to eight-membered nitrogen heterocycles were formed with
relative ease and in excellent yields and the nine-membered ring
did not form at all. Highly functionalized compounds 5a–c can lend
themselves to further structural elaboration.
One-pot protocol for the synthesis of azacycles of the general
5
type B described in our previous report was attempted; however,
only complex mixtures of products were obtained. This may be due
to the competing cyclopropanation reaction, which complicates
the subsequent metathesis step by allowing cross-metathesis to
take place in addition to the desired intramolecular process.
We have addressed the stereoselective synthesis of various aza-
cycloalkenes in a highly regio-, diastereo-, and enantioselective
fashion by employing
a-diazocarbonyl insertions into the acti-
vated C–H bonds followed by RCM. Additionally, interesting che-
moselectivity trends of the acceptor/donor rhodium carbenoid
were observed. In contrast to the N–H insertion, where no
3
-bond processes. As a result of lower bond polarity, C–H bonds
Table 1
and olefins are weaker nucleophiles, and the presence of the neigh-
boring electron-donating groups such as nitrogen is necessary to
stabilize the positive charge buildup at the site undergoing inser-
tion. However, this low bond polarity may result in a later transition
state allowing the chirality transfer from the catalyst to the newly
forming bond of the reacting species. This transfer of chiral informa-
tion is possible if the bond breaking and new bond formation with
the carbene carbon proceeds at the same time as the ligated rhodium
2 4
Rh (S-DOSP) -catalyzed decomposition of vinyl diazoacetate 2
Product
Yielda (%)
deb (%)
eec (%)
3a
64
61
59
55
32
30
28
27
95
98
98
98
90
94
98
98
96
92
95
92
92
90
85
83
3b
3c
3d
4a
4b
4c
1
1
catalyst dissociates.
4d
Complete consumption of vinyldiazoacetate 2 resulted in the
combined product yields of 82–96% and both the cyclopropanes
a
b
c
Isolated yield after chromatography.
Determined by 1H NMR of crude material.
3
a–d and the C–H insertion products 4a–d were formed essentially
Determined by chiral HPLC on a (R,R)-Whelk-O 1 column.
as single diastereomers with high enantioselectivity as determined

M. C. McMills et al. / Tetrahedron Letters 53 (2012) 849–851
851
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4
Table 2
RCM of the C–H insertion products 4a–d
Product
Yielda (%)
deb (%)
eec (%)
5
5
5
5
a
b
c
98
96
>98
>98
>98
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93
95
92
—
4
4
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d
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1
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Acknowledgments
(
The authors thank the Office of Research and Sponsored Pro-
grams, the BioMolecular Innovation and Technology group (BMIT),
and the Department of Chemistry and Biochemistry, Ohio Univer-
sity for financial support. O.M.P. thanks the BMIT for financial sup-
port in the form of a Research Fellowship.
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Supplementary data
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