Templated carbene metathesis reactions from the modular assembly of enol-diazo compounds and propargyl acetates

Article abstract of DOI:10.1002/ejoc.201301000

A Lewis acid mediated coupling reaction of enol-diazo nucleophiles and propargyl acetates has provided rapid and diverse access to complex alkynyl-tethered diazocarbonyl compounds. The ability of the coupling reaction to vary critical functionality flanking the diazo group was explored as a way to direct the outcome of a series of metal-catalyzed carbene metathesis cascade reactions. These cascade reactions provided diverse, biologically interesting carbocyclic and heterocyclic compounds in only a few steps from readily available materials. A general coupling strategy for the formation of alkynyl-substituted diazocarbonyl templates for catalytic cascade reactions is described. With the synthetic flexibility imparted to the coupling process and the facile cyclization of the first-formed metal carbene to secondary vinyl carbene templates, selective ylide, C-H insertion, and atom-transfer processes provide directed functionalization in cyclic compounds.

Full text of DOI:10.1002/ejoc.201301000

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301000
Templated Carbene Metathesis Reactions from the Modular Assembly of Enol-
diazo Compounds and Propargyl Acetates
Yu Qian,[a,b] Charles S. Shanahan,[a] and Michael P. Doyle*[a]
Keywords: Domino reactions / Metathesis / Rearrangement / Carbenes / Diazo compounds
A Lewis acid mediated coupling reaction of enol-diazo nu-
cleophiles and propargyl acetates has provided rapid and di-
verse access to complex alkynyl-tethered diazocarbonyl
compounds. The ability of the coupling reaction to vary criti-
cal functionality flanking the diazo group was explored as a
way to direct the outcome of a series of metal-catalyzed carb-
ene metathesis cascade reactions. These cascade reactions
provided diverse, biologically interesting carbocyclic and
heterocyclic compounds in only a few steps from readily
available materials.
tethered diazo compounds 1 that have a diversity of diazo
substituents Z, particularly those bearing an all-carbon
backbone (e.g., 1, X = C). To overcome this limitation, we
have developed a more efficient and general method to pre-
pare 1 with the capability to vary the R1–R3 and Z substitu-
ents easily, and we demonstrate its general applicability in
cascade processes for a broad diversity of templated reac-
tions of secondary vinyl carbene 3 with the Z group
(Scheme 1).
Introduction
The diazocarbonyl functional group is one of the more
versatile structural units in organic synthesis owing to the
highly selective dual reactivity offered by the intermediate
metal carbenes derived from catalytic dinitrogen extrusion
reactions.[1] Furthermore, the ability to tune the reactivity
and stability of the diazocarbonyl unit by placement of
proximal functionality by using a variety of synthetic tech-
niques offers a remarkable number of accessible reactivity
and stability profiles. Some of the most impressive transfor-
mations of complex diazo compounds are the carbene-initi-
ated cascade reactions that have been applied directly to
the highly efficient synthesis of biologically active natural
products.[2]
Early examples of carbene-initiated cascade reactions in
the seminal work of Padwa[3] and Hoye[4] illustrated that
alkynyl-tethered diazocarbonyl compounds such as 1 can
undergo rhodium-catalyzed transformations to provide
complex products in a single operation (Scheme 1). These
reactions proceeded through net carbene metathesis of first-
formed metal carbene 2 to give secondary vinyl carbene 3
that formed highly functionalized cyclopentenone (X =
C),[5] butenolide (X = O), and pyrrolidinone (X = N) ring
systems,[6] but they have been limited to simple diazo
ketones and diazo esters.[3c] Although prior art related to
this intriguing metathesis reaction demonstrated the poten-
tial utility of such cascades, their broad applicability has
been impeded by the limited availability of complex alkynyl-
Scheme 1. Templated metal carbene metathesis cascade reactions.
Prior investigations have illustrated the high potential of
coupling reactions of enol-diazoacetates 4 to provide com-
plex organodiazo frameworks (Scheme 2) with a variety of
different electrophilic partners in Lewis acid catalyzed ald-
ol,[7a–7c] Michael,[7d–7f] and Mannich[7g] reactions, in which
[a] Department of Chemistry and Biochemistry, University of
Maryland,
College Park, MD 20742, USA
E-mail: mdoyle@umd.edu
Homepage: www2.chem.umd.edu/groups/mdoyle/index.php
[b] Department of Chemistry, East China Normal University,
3663 Zhongshan Bei Road, Shanghai 200062, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301000.
Scheme 2. Enol-diazoacetate/propargyl acetate coupling process.
TBS = tert-butyldimethylsilyl, Tf = trifluoromethylsulfonyl.
6032
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6032–6037

Templated Carbene Metathesis Reactions
the diazo function is maintained. However, these reactions mere minutes, and the formation of elimination product 7
have been limited to the couplings of acetoacetate-derived was less problematic. Other solvents, including PhMe,
enol-diazo compounds 4 (Z = COOR). In an effort to ex- CHCl3, and THF, led to significant increases in reaction
pand the scope of these coupling processes, especially those time and higher amounts of elimination byproduct 7. In
directed towards 1 with variable R1–R3 and Z substituents, MeCN, the reaction temperature could be lowered to 0 °C
we used Lewis acid catalyzed SN1 reactions of enol-diazo without a significant decrease in reaction rate, and the 1a/7
compounds 4 to couple with propargyl acetates 5 via corre- ratio was further increased to 85:15 (Table 1, entry 13). Fi-
sponding propargyl cation 6 (Scheme 2).[8] Given that both nally, by raising the molar equivalents of 4a to 1.5 relative
enol-diazo compounds 4 and propargyl acetates 5 are read- to propargyl acetate 5a, the 1a/7 ratio was improved to
ily available, this approach represents a remarkably efficient Ͼ95:5, thus affording 1a in 90% isolated yield (Table 1, en-
tactic by which to synthesize 1.
try 14). Alternatively, with the use of a stoichiometric
amount of TMSOTf in MeCN at –40 °C (Table 1, entry 15),
1a was formed in 84% yield.
With this optimized reaction protocol, we strategically
modified the substitution of enol-diazo compounds 4 and
propargyl acetates 5 to accomplish our goal (cf. Scheme 1)
to effect discrete changes in the outcome of the impending
carbene metathesis cascade reactions. Thus, we expanded
the scope of the coupling reaction to include a variety of
enol-diazo compounds 4 bearing esters, ketones, and sulf-
ones as Z substituents (Table 2). The synthesis of methyl
diazoacetoacetate 1b was also accomplished in 82% yield.
Diazo ketone 1c, however, was formed in only approxi-
mately 60% yield by using Sc(OTf)3 as the catalyst, but the
use of a stoichiometric amount of TMSOTf as the Lewis
acid promoter gave an improved 82% yield of 1c. The reac-
tion of diethyl-substituted propargyl acetate 5 (R = Et) un-
der stoichiometric TMSOTf conditions produced 1d in a
similar 78% yield. Finally, the synthesis of diazosulfones (Z
= SO2Ar) also occurred in higher yield by using TMSOTf-
mediated conditions. In this way, diazosulfone 1e bearing a
p-tolylsulfonyl group as the Z substituent was produced in
83% yield, whereas the more sterically demanding mes-
Results and Discussion
To optimize the propargyl acetate coupling reaction,
enol-diazoacetate 4a (Z = COOAllyl) and propargyl acetate
5a (R1 = Ph; R2, R3 = Me) were chosen as test substrates,
and the activities of metal-based Lewis acid catalysts, in-
cluding those of scandium, zinc, indium, and tin triflates as
well as AuCl3 and Cu(hfacac)2 (hfacac = hexafluoroacet-
ylacetonate), were assayed in CH2Cl2 at room temperature
(Table 1, entries 1–7). Of these, Sc(OTf)3 (5 mol-%) pro-
vided the highest reactivity in forming a mixture (62:38) of
desired product 1a and elimination byproduct 7. The cou-
pling reactions in MeCN and 1,2-dichloroethane (DCE) at
room temperature, in contrast, exhibited reaction times of
Table 1. Catalyst screening and optimization of the reaction condi-
tions.[a]
Table 2. Substrate scope of the coupling reaction.
Entry Lewis acid
Solvent
Time
[h]
Conv.
[%]
Ratio
1a/7[b]
1
2
3
4
5
6
7
8
Zn(OTf)2
CuPF6
Cu(hfacac)2 CH2Cl2
CH2Cl2
CH2Cl2
12
12
12
12
12
12
12
1
85
53:47
85:15
–
40:60
62:38
60:40
95:5
71:29
77:23
44:56
60:40
36:64
85:15
66
trace
95
Ͼ95
Ͼ95
30
Ͼ95
Ͼ95
68
Sn(OTf)2
Sc(OTf)3
In(OTf)3
AuCl3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
MeCN
PhMe
CHCl3
THF
MeCN
MeCN
MeCN
9
1
10
11
12
13[c]
12
12
12
1
1
1
63
44
Ͼ95
14[c,d] Sc(OTf)3
Ͼ95 (90)[e] Ͼ95:5
15[f]
TMSOTf
Ͼ95 (84)[e]
90:10
[a] Reaction conditions:
A mixture of enol-diazoacetate 4a
(1.2 equiv.), propargyl acetate 5a (1.0 equiv.), and Sc(OTf)3 (5 mol-
%) in the specified solvent (0.5 m) was stirred at r.t. for the recorded
time. [b] Determined by analysis of the reaction mixture by 1H
NMR spectroscopy. [c] Reaction was performed at 0 °C. [d] 4a
(1.5 equiv.). [e] Yield of the isolated product. [f] TMSOTf (1 equiv.)
at –40 °C.
[a] Conditions A: Enol-diazo 4 (1.5 equiv.), propargyl acetate 5
(1.0 equiv.), and Sc(OTf)3 (5.0 mol-%) in MeCN (0.5 m) at r.t.
[b] Conditions B: Enol-diazo 4 (1.5 equiv.), propargyl acetate 5
(1.0 equiv.), and TMSOTf (1.0 equiv.) in MeCN (0.5 m) at –40 °C.
Eur. J. Org. Chem. 2013, 6032–6037
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6033

Y. Qian, C. S. Shanahan, M. P. Doyle
SHORT COMMUNICATION
itylsulfonyl group as the Z substituent provided 1f in a not terminate at the alkoxyfuran as did the reactions of
slightly diminished 72% yield. methyl ester analogue 1b (cf. Scheme 4). In fact, the reac-
To gain access to functionalized diazo ketones 1 in which tion provided mixtures of products that favored Claisen re-
Z = H (1g–h), benzoyl-substituted coupling products 1c arrangement product 12 (Scheme 5). However, Claisen
(Z = COPh; R1, R2 = Me) and 1d (Z = COPh; R1, R2 = product 12 was also found to undergo further rearrange-
Et) were subjected to mild aluminum oxide diazo ketone ment through a thermally induced Cope-type reaction to
cleavage conditions (Scheme 3).[9] Although the reaction of give butenolide 13, the X-ray structure of which is shown in
neutral alumina in CH2Cl2 with 1c could have cleaved either Figure 1. Upon optimization of this reaction (catalyst and
the aryl or aliphatic ketone, reaction with 1c favored ad- conditions), we found that a catalytic amount of Cu-
dition to the carbonyl group of the aryl ketone with cleav- (hfacac)2 in superheated DCE provided fully rearranged bu-
age of the aryl ketone/diazo carbon bond to provide a mix- tenolide product 13 in 76% yield.[13] As competitive intra-
ture (9:1) of 1g/8, which upon chromatographic purification molecular cyclopropanation to provide 14 was not observed
provided 1g in 81% yield. The same cleavage reaction with in this reaction, carbene/alkyne metathesis occurs at a faster
more sterically biased diazo ketone 1d provided exclusively rate than cyclopropanation of diazoacetoacetate 1a. This is
diazo ketone 1h in 82% yield with no observable formation especially striking considering that the alkyne was neopen-
of 8. More generally, this novel debenzoylation reaction tyl, which makes metathesis more sterically demanding than
could be paired with the myriad reactivity of enol-diazo the cyclopropanation pathway. This cascade process is syn-
nucleophiles 4 and electrophiles[7] to offer a unique and thetically notable in that highly substituted bicyclic butenol-
mild method to synthesize complex mono-diazo ketones ide 13 is formed in one step from readily available alkynyl
that would be considerably more difficult to synthesize by diazoacetate 1a bearing fully substituted centers at the re-
traditional means.[10]
mote C4 and C6 positions.
Scheme 3. Selective diazo ketone cleavage by debenzoylation.
The diversity of reactions of 1 that can be performed by
using the carbene metathesis cascade is exemplified in five
applications. With 1b (Z = COOMe), reaction with a cata-
lytic amount of Rh2(Oct)4 (1 mol-%, Oct = n-octanoate) in-
itiated a cascade event that terminated in secondary carb- Scheme 5. Carbene metathesis/Claisen/Cope cascade reaction.
ene 9 forming a carbonyl ylide with the adjacent methyl
ester (Scheme 4). This ylide spontaneously eliminated
Rh2(Oct)4 to produce bicyclic furan 10b in 68% yield. Alk-
oxyfurans such as this are known to be unstable; however,
facile hydrolysis of these systems provides biologically im-
portant butenolides.[11] Moreover, 2-alkoxyfurans are reac-
tive dienes in [4+2] cycloaddition reactions.[6a,12] If Z was a
phenyl ketone (1c), the same cascade transformation oc-
curred to provide diarylfuran 10c in 86% yield.
Scheme 4. Carbene metathesis/carbonyl ylide formation reactions.
Figure 1. ORTEP view of 13. Ellipsoids are shown at 30% prob-
ability.
During the course of investigating the initial rhodium-
catalyzed furan synthesis, we found that reactions of allyl
The outcome of the cascade reaction with a sulfonyl Z
ester substituted diazoacetoacetate 1a (Z = COOAllyl) did substituent was remarkably different from that of the carb-
6034
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6032–6037

Templated Carbene Metathesis Reactions
Scheme 6. Effect of aryl sulfone substitution cascade outcome.
onyl series (Scheme 6). With substrate 1e (Z = p-tolylsulf-
onyl), secondary carbene 15 reacted with the sulfone to pro-
vide an intermediate sulfoxonium ylide that underwent O-
atom transfer to deliver racemic sulfoxide 16 in 90% yield.
Surprisingly, if the arylsulfone was changed to mesityl-sub-
stituted system 1f, the O-atom transfer process no longer
occurred; instead, secondary carbene 15 underwent benz-
ylic 1,7-C–H insertion to provide benzothiepine ring system
17 in 80% yield. Benzothiepine compounds have been
shown to demonstrate a range of biologically activity,[14]
and this approach represents a unique and potentially ver-
satile way to access polyfunctionalized benzothiepines. Al-
though ylide formation is believed to be kinetically favored
over other carbene reactions (especially to form five-mem-
bered ylides), the preference for the cascade reaction of 1f
to selectively target the benzylic C–H bond is surprising and
seems to indicate a conformational bias in the transition
state brought about by the sterically encumbered mesityl
group.
Scheme 7. Carbene metathesis/C–H insertion cascade reaction.
In the absence of a reactive functional group at the Z
position, gem-diethyl diazo ketone 1h provided a unique op-
portunity to direct the cascade reaction by terminating the
cascade through intramolecular C–H insertion (Scheme 7).
In this case, the reaction of 1h with a catalytic amount of
Rh2(esp)2 (esp = α,α,αЈ,αЈ-tetramethyl-1,3-benzenedipro-
pionate) provided cyclopentenone product 19 in 72% yield
as a single diastereomer. Interestingly, the reaction of the
primary carbene of 1h was selective toward carbene/alkyne
metathesis to form secondary phenylvinyl carbene 18 in
preference to intramolecular C–H insertion that would
form 20, which was not observed. Recently, May reported
Scheme 8. Intramolecular ylide formation/dipolar cycloaddition.
a similar catalyst-induced cascade of propargyl diazoacet- ence of a catalytic amount of Rh2(esp)2 in an attempt to
ates to provide bridged bicyclic butenolide products;[15] generate carbonyl ylide 21 (Scheme 8). Under these condi-
however, that approach does not provide access to the con- tions, the reaction of 1g with PMPCHO afforded dihy-
siderably more challenging all-carbon systems.
drofuran 22 in 81% yield as a single diastereomer, presum-
Having successfully demonstrated that the outcomes of ably through intramolecular 1,3-dipolar cycloaddition of
various carbene/alkyne metathesis reactions can be directly ylide 21. This result demonstrates that intermolecular carb-
engineered by changes in the pivotal Z group and having onyl ylide formation proceeds at a faster rate than carbene/
developed a clearer picture of the rate of carbene/alkyne alkyne metathesis, as competing cycloaddition product 25
metathesis relative to other competitive carbene transfor- was not observed. This result also exemplifies that ylide for-
mations, we queried whether the primary carbene (cf. 3) mation/dipolar cycloaddition can be used as a method to
could be trapped prior to the alkyne metathesis event. For utilize alkynyl-tethered diazo ketones 1 independent of the
this experiment, we treated protio-substituted diazo ketone carbene/alkyne metathesis reaction, thus enhancing the
1g with p-methoxybenzaldehyde (PMPCHO) in the pres- value of the incipient enol-diazo coupling methodology.
Eur. J. Org. Chem. 2013, 6032–6037
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6035

Y. Qian, C. S. Shanahan, M. P. Doyle
SHORT COMMUNICATION
Cyclopropanes to Ylides, Wiley, New York, 1998; for reviews,
see: b) M. P. Doyle, R. Duffy, M. O. Ratnikov, L. Zhou, Chem.
Rev. 2010, 110, 704–724; c) C. A. Merlic, A. L. Zechman, Syn-
thesis 2003, 1137–1156; d) H. M. L. Davies, R. E. J. Beckwith,
Chem. Rev. 2003, 103, 2861–2904; e) H. M. L. Davies, E. G.
Antoulinakis, Org. React. 2001, 57, 1–326; f) D. M. Hodgson,
F. Y. T. M. Pierard, P. A. Stupple, Chem. Soc. Rev. 2001, 30,
50–61.
a) R. Sarpong, J. T. Su, B. M. Stoltz, J. Am. Chem. Soc. 2003,
125, 13624–13625; b) W. G. Dauben, J. Dinges, T. C. Smith, J.
Org. Chem. 1993, 58, 7635–7637; c) A. Padwa, A. T. Price, J.
Org. Chem. 1995, 60, 6258–6259; d) H. M. L. Davies, J. J. Mat-
asi, M. Hodges, N. J. S. Huby, C. Thornley, N. Kong, J. H.
Housler, J. Org. Chem. 1997, 62, 1095–1105; e) C. Fang, C. S.
Shanahan, D. H. Paull, S. F. Martin, Angew. Chem. 2012, 124,
10748–10751; Angew. Chem. Int. Ed. 2012, 51, 10596–10599.
a) A. Padwa, K. E. Krumpe, L. Zhi, Tetrahedron Lett. 1989,
30, 2633–2636; b) A. Padwa, U. Chiacchio, Y. Garreau, J. M.
Kassir, K. E. Krumpe, A. M. Schoffstall, J. Org. Chem. 1990,
55, 414–416; c) A. Padwa, M. D. Weingarten, Chem. Rev. 1996,
96, 223–269.
a) P. F. Korkowski, T. R. Hoye, D. B. Rydberg, J. Am. Chem.
Soc. 1988, 110, 2676; b) T. R. Hoye, C. J. Dinsmore, D. S. John-
son, P. F. Korkowski, J. Org. Chem. 1990, 55, 4518–4520.
a) A. Padwa, M. D. Weingarten, J. Org. Chem. 2000, 65, 3722–
3732; b) A. Padwa, J. M. Kassir, M. A. Semones, M. D. Wein-
garten, J. Org. Chem. 1995, 60, 53–62; c) A. Padwa, D. J. Aus-
tin, Y. Gareau, J. M. Kassir, S. L. Xu, J. Am. Chem. Soc. 1993,
115, 2637–2647.
a) A. Padwa, C. S. Straub, J. Org. Chem. 2003, 68, 227–239; b)
C. S. Straub, A. Padwa, Org. Lett. 2000, 2, 2093–2095; c) A.
Padwa, F. R. Kinder, J. Org. Chem. 1993, 58, 21–28; d) A.
Padwa, D. C. Dean, D. J. FairFax, S. L. Xu, J. Org. Chem.
1993, 58, 4.
Conclusions
In summary, we have developed an efficient protocol for
the coupling of enol-diazo compounds 4 and propargyl
acetates 5 to provide a diverse series of alkynyl-tethered di-
azo ketones 1 that undergo facile cascade transformations,
the outcomes of which are controlled by the substituents of
1. We have shown that the nucleophilic behavior of enol-
diazo compounds 4 is not limited only to systems derived
from acetoacetates (i.e., Z = ester) and that by varying the
αЈ-substitution of these building blocks the outcome of
carbene metathesis cascade reactions can be templated. In
this way, the choice of enol-diazo nucleophile provides the
embedded information required to direct the outcome of
the carbene cascade to a number of diverse and discrete
outcomes (exemplified, but not limited to, those in
Scheme 9). As a result of these studies, the rate of carbene/
alkyne metathesis relative to that of competitive processes
(i.e., cyclopropanation, ylide formation, and C–H insertion)
in complex environments has been clearly elucidated.[16]
Furthermore, a number of novel processes have been made
possible by the enol-diazo coupling that were previously un-
known, namely, the benzylic C–H insertion of o,o-disubsti-
tuted arylsulfonyl systems and the tandem carbene cascade/
Claisen/Cope rearrangements of allyl ester substituted sys-
tems. We are currently investigating additional applications
and asymmetric variations of these cascade processes.
[2]
[3]
[4]
[5]
[6]
[7]
a) M. P. Doyle, K. Kundu, A. E. Russell, Org. Lett. 2005, 7,
5171–5174; b) P. Truong, X. Xu, M. P. Doyle, Tetrahedron Lett.
2011, 52, 2093–2096; c) L. Zhou, M. P. Doyle, Org. Lett. 2010,
12, 796–799; d) Y. Liu, Y. Zhang, N. Jee, M. P. Doyle, Org.
Lett. 2008, 10, 1605–1608; e) X. Xu, W. Hu, M. P. Doyle, An-
gew. Chem. 2011, 123, 6516–6519; Angew. Chem. Int. Ed. 2011,
50, 6392–6395; f) P. Truong, C. S. Shanahan, M. P. Doyle, Org.
Lett. 2012, 14, 3608–3611; g) X. Xu, M. O. Ratnikov, P. Y. Zav-
alij, M. P. Doyle, Org. Lett. 2011, 13, 6122–6125.
[8]
a) P. Rubenbauer, E. Herdtweck, T. Strassner, T. Back, Angew.
Chem. 2008, 120, 10260–10263; Angew. Chem. Int. Ed. 2008,
47, 10106–10109; b) Z. Zhan, S. Wang, X. Cai, H. Liu, J. Yu,
Y. Cui, Adv. Synth. Catal. 2007, 349, 2097–2102; c) Z. Zhan,
X. Cai, S. Wang, J. Yu, H. Liu, Y. Cui, J. Org. Chem. 2007, 72,
9838–9841.
[9]
[10]
S. Korneev, C. Richter, Synthesis 1995, 10, 1248–1250.
a) T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett. 2007, 9,
3195–3197; b) M. Regitz, G. Maas, Diazo Compounds: Proper-
ties and Synthesis Academic Press, Orlando, 1986.
[11]
a) N. B. Carter, A. E. Nadany, J. B. Sweeney, J. Chem. Soc. Per-
kin Trans. 1 2002, 21, 2324–2342; b) M. V. N. de Souza, Mini-
Rev. Org. Chem. 2005, 2, 139–145; c) S. P. Brown, N. C. Good-
win, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 1192–
1194.
a) Y. W. Goh, B. R. Pool, J. M. White, J. Org. Chem. 2008, 73,
151–156; b) A. E. Goetz, N. K. Garg, Nat. Chem. 2013, 5, 54–
60; c) R. G. F. Giles, A. B. Hughes, M. V. Sargent, J. Chem.
Soc. Perkin Trans. 1 1991, 6, 1581–1587.
CCDC-935742 (for 13) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
a) S. J. Tremont, L. F. Lee, H.-C. Huang, B. T. Keller, S. C.
Banerjee, S. R. Both, A. J. Carpenter, C.-C. Wang, D. J. Gar-
land, W. Huang, C. Jones, K. J. Koeller, S. A. Kolodziej, J. Li,
R. E. Manning, M. W. Mahoney, R. E. Miller, D. A. Mischke,
Scheme 9. Modular assembly of enol-diazo compounds and pro-
pargyl acetates for templated carbene metathesis reactions.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H NMR
and 13C NMR spectra for all new compounds.
[12]
[13]
[14]
Acknowledgments
The authors would like to thank the National Institutes of Health
(NIH) (GM 465030) for support of this research and Peter Zavalij
for X-ray crystallography data and interpretation.
[1] a) M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
6036
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6032–6037

Templated Carbene Metathesis Reactions
N. P. Rath, T. Fletcher, E. J. Reinhard, M. B. Tollefson, W. F.
Vernier, G. M. Wagner, S. R. Rapp, J. Beaudry, K. Glenn, K.
Regina, J. R. Schuh, M. E. Smith, J. S. Trivedi, D. B. Reitz, J.
Med. Chem. 2005, 48, 5837–5852; b) H.-C. Huang, S. J. Tre-
mont, L. F. Lee, B. T. Keller, A. J. Carpenter, C.-C. Wang, S. C.
Banerjee, S. R. Both, T. Fletcher, D. J. Garland, W. Huang, C.
Jones, K. J. Koeller, S. A. Kolodziej, J. Li, R. E. Manning,
M. W. Mahoney, R. E. Miller, D. A. Mischke, N. P. Rath, E. J.
Reinhard, M. B. Tollefson, W. F. Vernier, G. M. Wagner, S. R.
Rapp, J. Beaudry, K. Glenn, K. Regina, J. R. Schuh, M. E.
Smith, J. S. Trivedi, D. B. Reitz, J. Med. Chem. 2005, 48, 5853–
5868.
[15] For a recent example of a C–H insertion terminated carbene
cascade reaction, see: S. Jansone-Popova, J. A. May, J. Am.
Chem. Soc. 2012, 134, 17877–17880.
[16] For comparative studies between competitive metal carbene
transformations, see: a) A. Padwa, D. J. Austin, S. F. Hornbuc-
kle, M. A. Semones, M. P. Doyle, M. N. Protopopova, J. Am.
Chem. Soc. 1992, 114, 1874–1876; b) A. Padwa, D. J. Austin,
A. T. Price, M. A. Semones, M. P. Doyle, M. N. Protopopova,
W. R. Winchester, A. Tran, J. Am. Chem. Soc. 1993, 115, 8669–
8680.
Received: July 4, 2013
Published Online: August 15, 2013
Eur. J. Org. Chem. 2013, 6032–6037
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6037