An efficient synthesis of nitrogen-containing heterocycles via a tandem carbenoid N-H insertion/ring-closing metathesis sequence

Article abstract of DOI:10.1016/j.tetlet.2009.03.085

A series of five- to eight-membered nitrogen-containing heterocycles were prepared via a general and efficient one-pot, two-component sequence featuring rhodium-catalyzed insertion of a vinyl-substituted α-diazocarbonyls into the N-H bond of a series of tert-butoxycarbonyl-(Boc)-protected amines, followed by ring-closing metathesis catalyzed by ruthenium benzylidene complexes. This methodology allows easy and convenient access to highly functionalized azacycloalkenes in moderate yields and excellent chemoselectivity in a single transformation.

Full text of DOI:10.1016/j.tetlet.2009.03.085

Tetrahedron Letters 50 (2009) 2716–2718
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of nitrogen-containing heterocycles via a tandem
carbenoid N–H insertion/ring-closing metathesis sequence
Oksana Pavlyuk a, Henrik Teller a,b, Mark C. McMills a,
*
a Department of Chemistry and Biochemistry, 380 Clippinger Laboratories, Ohio University, Athens, OH 45701, USA
b Department of Chemistry and Mineralogy, University of Leipzig, 04103 Leipzig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of five- to eight-membered nitrogen-containing heterocycles were prepared via a general and
efficient one-pot, two-component sequence featuring rhodium-catalyzed insertion of a vinyl-substituted
Received 17 February 2009
Accepted 11 March 2009
Available online 16 March 2009
a
-diazocarbonyls into the N–H bond of a series of tert-butoxycarbonyl-(Boc)-protected amines, followed
by ring-closing metathesis catalyzed by ruthenium benzylidene complexes. This methodology allows
easy and convenient access to highly functionalized azacycloalkenes in moderate yields and excellent
chemoselectivity in a single transformation.
Keywords:
Diazo
N–H Insertion
Azacycle
Ó 2009 Elsevier Ltd. All rights reserved.
Metathesis
Heterocyclic systems of the general type shown in Figure 1 are
common structural motifs present in a variety of alkaloids1 and so
the development of new methods for their synthesis is of consider-
able interest to organic and medicinal chemists. A number of ap-
proaches for the synthesis of N-containing heterocycles have
been developed, most lead to the formation of five- and six-mem-
bered ring systems, while the construction of eight- and nine-
membered heterocycles is still quite limited.2 One reaction class
that has received considerable attention in recent years for the
synthesis of oxygen and nitrogen heterocycles is ring-closing olefin
metathesis (RCM).3 For example, syntheses of medium-sized bicy-
clic lactams and six- to seven-membered oxoazacycloalkenes are
known via this methodology.4 Moreover, exceptional progress
has been observed in the development of new synthetic methodol-
ogies for the construction of heterocyclic systems based on the
chemistry of rhodium(II)-stabilized carbenoid intermediates.5
ety with p-ABSA as a diazo transfer reagent and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) as the base yielding the
corresponding methyl styryldiazoacetate 1.7 This type of electron
acceptor/electron donor substituted diazocarbon is less stable at
room temperature than comparable acceptor/acceptor substrates
and is more reactive in metal-catalyzed decomposition.5d Freshly
prepared styryldiazoacetate 1 (Scheme 1) was immediately used
in the N–H insertion reaction in order to minimize the electrocyc-
lization of the
a-diazocarbonyl and pendent olefin to the corre-
sponding 3H-pyrazole8 and to ensure the effective formation of a
styrylcarbenoid intermediate. In addition, an excess of the carba-
mate trapping agent was used to ensure the effective capture of
the rhodium-stabilized carbenoid intermediate.9 The chemical
yields of the insertion products of styryldiazoacetate 1 into the
N–H bond of a series of carbamates were modest to good (Table
1). Screening of alternative dirhodium catalysts (Rh2(pfb)4,
Rh2(OAc)4) and solvents (hexane, pentane, and benzene) did not
have any significant effect on the reaction outcome. Additionally,
when the Boc-protected alkenyl amines were used as limiting
reagents, complex mixtures of products were obtained. Thus, it
became apparent that the more stable and thus more selective
Thus, by utilizing the ability of an
regioselectively into the N–H bonds of amines, amides, or carba-
mates a variety of -amino ketones, -amino esters and nitro-
gen-containing heterocycles have been prepared.6 In this report,
we have applied an -diazocarbonyl N–H insertion reaction in tan-
a-diazocarbonyl moiety to insert
a
a
a
dem with ring-closing metathesis to develop a general and effi-
cient strategy for the construction of heterocycles containing
various combinations of five- to eight-membered rings.
Synthesis of azacycles via a sequential two-step procedure: The
methyl ester of commercially available trans-styryl acetic acid
was used successfully as a substrate for the transfer of a diazo moi-
CO2R
NH
n
R = alkyl, n = 1-4
* Corresponding author. Tel.: +1 740 593 1750; fax: +1 740 593 0148.
E-mail address: mcmills@ohio.edu (M.C. McMills).
Figure 1. Nitrogen-containing heterocyclic systems.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.085

O. Pavlyuk et al. / Tetrahedron Letters 50 (2009) 2716–2718
2717
Table 2
O
Comparison of the two-step process and the one-pot approach
O
Ph
i)
Substrate
Two-step (yield %)a
One pot (yield %)a
MeO
Boc
Ph
MeO
N
4a
4b
4c
4d
48%
48%
36%
32%
42%
57%
31%
30%
N2
n
3a-d
1
ii)
a
Isolated yield after chromatography.
+
i) then ii)
CO2Me
Boc
NHBoc
lysts for the metathesis of the nitrogen-tethered dienes leading to
the unsaturated monocyclic azacycles (Table 1). Each of the five- to
eight-membered azacycloalkenes was isolated as a mixture of Boc-
rotamers in excellent yields. A small decrease in yield was ob-
served for the ring-closing metathesis of the eight-membered
azacycle.
Synthesis of azacycles via a‘one pot’ tandem N–H insertion/RCM se-
quence: Having found reaction conditions for the rhodium-cata-
lyzed N–H insertion and subsequent RCM that provided a good
yield of the azacycle, we turned our attention to developing a pro-
tocol for a one-pot process. Tandem reactions are recognized as
industrially applicable and highly atom economical transforma-
tions10 so the extension of this methodology toward the multistep
one-pot process was particularly appealing. In a recent example,
Davies and co-workers have developed an enyne metathesis/Rh-
catalyzed [4+3]-cycloaddition coupling strategy for the enantiose-
lective synthesis of highly functionalized cycloheptadienes.11 Sim-
or
n
(One Pot)
N
n=1-4
2a-d
n
Scheme 1. General Strategy for the Synthesis of Azacycles. Reagents and condi-
tions: (i) 1 mol% Rh2(S-DOSP)4, DCE, rt, 0.5 h; (ii) 8–10 mol% Grubbs or Hoveyda-
Grubbs 2nd Generation, DCM, reflux, 1.5–3.5 h.
rhodium styrylcarbenoid was not electrophilic enough to insert
efficiently into the N–H bond of an alkenyl carbamate, but did pro-
vide a usable chemical yield of insertion product. Fortunately, no
cyclopropanation of the mono-substituted double bond was ob-
served with carbenoids of this type, and this unique chemoselec-
tivity allowed us to utilize the pendent olefin in the subsequent
metathesis. Grubbs second generation catalyst or Hoveyda-Grubbs
ruthenium benzylidene complexes were found to be suitable cata-
ilarly, Hodgson has shown that
a one-pot cross metathesis
reaction in tandem with carbonyl ylide formation/intramolecular
cycloadditon can be executed with unsaturated 2-diazo-3,6-
diketoesters.12
Table 1
N–H insertion/RCM of styryl diazoacetate 1 with N-Boc amines 2a–d
This study appears to be the first example of combining the N–H
insertion/RCM reactions in a one-pot procedure for the construc-
tion of the nitrogen-containing monocycles. To ensure the success
of the tandem process, several factors needed to be considered. For
example, the initial N–H insertion must be chemoselective at low
catalyst loading, in the presence of minimal quantities of the trap-
ping reagent. In addition, reaction conditions of each step in the se-
quence had to be tuned carefully to minimize any byproduct
formation that could suppress the subsequent metathesis step in
the sequence. For this reason, 1 mol % or less of the rhodium cata-
lyst was used, while the optimum loading of the corresponding t-
boc alkenyl amine was determined to be 1.5 mol equiv based on
methyl styryldiazoacetate 1. The progress of the N–H insertion
reaction was monitored by TLC and following the disappearance
of methyl styryldiazoacetate 1; Grubbs catalyst was added to the
reaction mixture. Unfortunately, under these conditions no
metathesis products were isolated, prompting us to consider an
alternative of adding a solution containing rhodium catalyst and
the N–H insertion products to a solution of the Grubbs catalyst.
Thus, the subsequent carbamate tethered-diene products 3a–d
were added via cannula to a solution of the Grubbs catalyst at re-
flux and the reaction mixture was continued at reflux until the dis-
appearance of the starting material was seen, as monitored by TLC.
Gratifyingly, this tactic was successful, resulting in the formation
of azaheterocycles 4a–d in yields comparable to, or in one case bet-
ter than the sequential process (Table 2). It is noteworthy to men-
tion that the procedure developed by Diver and co-workers.13 for
work-up (CNCH2CO2K, 6 equiv in MeOH) was utilized to quench
the reaction mixture followed by removal of the inactive polar
metathesis catalyst via filtration through a short plug of silica.
In conclusion, a general synthetic strategy has been developed
to construct five- to eight-membered azacycloalkenes. The newly
devised methodology is a one-pot, two-component coupling pro-
cess, consisting of the intermolecular N–H insertion of rho-
Entry
N–H insertion product (yield %)a
RCM product (yield %)a
O
CO2Me
Ph
MeO
Boc
N
1
N
Boc
3a(55%)
4a (88%)
CO2Me
O
Boc
Ph
N
MeO
2
N
Boc
4b(94%)
3b(51%)
O
CO2Me
Boc
Ph
N
MeO
3
4
N
Boc
4c(80%)
3c(45%)
O
CO2Me
Ph
Boc
MeO
N
N
Boc
4d(65%)
3d(50%)
a
Isolated yield after chromatography.

2718
O. Pavlyuk et al. / Tetrahedron Letters 50 (2009) 2716–2718
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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.P. thanks BMIT for financial support
in the form of a Research Fellowship. H.T. thanks the DAAD, the
University of Leipzig and the Office of Research and Sponsored Pro-
grams, Ohio University for financial support.
Supplementary data
Detailed experimental procedures and characterization data for
new compounds are provided. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.085.
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