Preparation of tethered aldehyde ynoates and ynones by ring fragmentation of cyclic γ-oxy-β-hydroxy-α-diazo carbonyls

Article abstract of DOI:10.1021/jo902405f

(Chemical Equation Presented) Cyclic γ-oxy-β-hydroxy-α- diazo carbonyls undergo Lewis acid induced ring fragmentation to provide either ynoates or ynones tethered to an aldehyde, ketone, or ester. The fragmentation precursors are convenient to prepare by adding lithiated α-diazo carbonyls to α-oxy ketones. The fragmentation appears general and provides a variety of functional group-rich products in good to excellent yield.

Full text of DOI:10.1021/jo902405f

pubs.acs.org/joc
Preparation of Tethered Aldehyde Ynoates and Ynones by Ring
Fragmentation of Cyclic γ-Oxy-β-hydroxy-r-diazo Carbonyls
Ali Bayir, Cristian Draghici, and Matthias Brewer*
Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405
matthias.brewer@uvm.edu
Received November 10, 2009
Cyclic γ-oxy-β-hydroxy-R-diazo carbonyls undergo Lewis acid induced ring fragmentation to
provide either ynoates or ynones tethered to an aldehyde, ketone, or ester. The fragmentation
precursors are convenient to prepare by adding lithiated R-diazo carbonyls to R-oxy ketones. The
fragmentation appears general and provides a variety of functional group-rich products in good to
excellent yield.
Introduction
fragmentations.6-8 These transformations, now termed
Grob fragmentations, occur when an electron-rich atom
and a leaving group are separated by two intervening carbon
atoms. In this process, two bonds are broken, and if one of
the cleaved bonds is contained within a ring, then the ring is
fragmented. For example, Wharton and Hiegel9 reported
that 1,10-decalinediol monotosylate 1 (Scheme 1, eq 2)
smoothly fragments to ketone 2 upon treatment with base.
Few ring fragmentations result in the formation of alky-
nes.2 The most notable example is the Eschenmoser-
Tanabe fragmentation10-13 in which the tosylhydrazone of
an R,β-epoxy ketone fragments to provide an alkyne-teth-
ered ketone or aldehyde. For example, R,β-epoxy cyclohexe-
none 3 (Scheme 1, eq 3) fragmented to tethered alkynyl ketone
4 upon treatment with tosylhydrazine.14 More recently,
Dudley and co-workers15-18 reported an alternative route to
tethered alkynyl ketones based on a nucleophile-induced
Reactions that result in the cleavage of a carbon-carbon
bond hold a special position in organic synthesis because
they can unmask latent functional groups under chemo-
selective reaction conditions and they can provide functiona-
lized synthetic intermediates that are otherwise difficult to
prepare.1-3 From a strategic standpoint, cleaving a ring
system can be particularly useful in synthesis because (1)
the resulting product will contain two newly formed func-
tional groups that can be used in subsequent manipulations,
(2) the new functional groups are tethered at a predefined
distance determined by the ring size, (3) the fragmentation
can provide a big structural change in the molecule that is not
possible to achieve by other means, and (4) cyclic systems
that contain stereocenters can fragment to linear compounds
that contain the stereocenters. Unfortunately, only a limited
number of synthetically useful ring cleaving reactions are
known. For example, the ozonolysis of cyclic olefins and the
oxidative cleavage of cyclic 1,2-diols are methods often used
to prepare tethered dicarbonyl compounds.4,5
(6) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594.
(7) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1.
(8) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535.
(9) Wharton, P. S.; Hiegel, G. A. J. Org. Chem. 1965, 30, 3254.
(10) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50,
708.
Reactions in which a molecule is broken into three
fragments, a nucleofuge, an unsaturated fragment, and
an electrofuge (Scheme 1, eq 1), were defined by Grob as
(11) Felix, D.; Shreiber, J.; Ohloff, G.; Eschenmoser, A. Helv. Chim. Acta
1971, 54, 2896.
(12) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943.
(13) Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G. Tetrahedron Lett.
1967, 3739.
(14) Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900.
(15) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028.
(16) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936.
(17) Kamijo, S.; Dudley, G. B. Tetrahedron Lett. 2006, 47, 5629.
(18) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499.
(1) Hendrickson, J. B. J. Am. Chem. Soc. 1986, 108, 6748.
(2) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1.
(3) Corey, E. J.; Jorgensen, W. L. J. Am. Chem. Soc. 1976, 98, 189.
(4) Shing, T. K. M. In Comprehensive Organic Synthesis Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 703.
(5) Lee, D. G.; Chen, T. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 541.
296 J. Org. Chem. 2010, 75, 296–302
Published on Web 12/18/2009
DOI: 10.1021/jo902405f
r
2009 American Chemical Society

Bayir et al.
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SCHEME 1. Examples of Synthetically Useful Fragmentation
Reactions
SCHEME 2. Initial Observation of Fragmentation
SCHEME 3. Application to the Fragmentation of a Ring
seemed logical to make the γ-oxygen more electron rich,
and to test our hypothesis we prepared R-diazo ester 10
(Scheme 3) as a model system. Although R-diazo ester 10
may at first glance appear fairly complex, it is in fact trivial to
prepare by simply adding LDA to a premixed solution of
R-silyloxy ketone 9 and commercially available ethyl
diazoacetate.23-26
Consistent with our hypothesis, treating diazo 10 with
indium triflate resulted in vigorous gas evolution and pro-
vided tethered aldehyde ynoate 11 in 87% yield. In subse-
quent studies we observed that freshly dried indium triflate
and freshly distilled tin tetrachloride most efficiently pro-
moted the fragmentation; BF3 OEt2, MgBr2 OEt2, scan-
3
3
dium triflate, titanium tetrachloride, and anhydrous HCl
provided more complex product mixtures, and dibutyl tin
dichloride, lithium perchlorate, and titanium isopropoxide
failed to react. Due to the limited solubility of indium triflate
in CH2Cl2, tin tetrachloride was chosen as the Lewis acid of
choice and reproducibly provided the fragmentation product
in 94% yield. Reducing the quantity of tin tetrachloride to
10 mol % promoted the fragmentation reaction, but unfor-
tunately reduced the product yield to 85%. Changing the
solvent from CH2Cl2 to toluene had little effect on the
reaction, whereas DMF inhibited the reaction completely.
It is interesting to note that when the Lewis acid was added to
the diazo compound below -20 °C the solution immediately
lost its characteristic yellow diazo color, but gas did not
evolve until the temperature was increased to -20 °C. Good
results were consistently obtained when the reaction was
maintained at 0 °C.
In considering a possible mechanism for this fragmenta-
tion we noted Wenkert and McPherson’s27 report that β-
hydroxy-R-diazo esters derived from aldehydes (e.g., 12,
Scheme 4, eq 1) reacted with Lewis acids to provide ynoates.
To account for this reactivity they proposed that the Lewis
acid promotes elimination of the β-hydroxy substituent to
provide a vinyl diazonium intermediate (14), which in turn
eliminates molecular nitrogen to provide the ynoate product.
Subsequent studies by Padwa and co-workers have shown
that β-hydroxy-R-diazo esters derived from ketones (e.g., 16,
fragmentation of vinylogous acyl triflates (e.g., Scheme 1,
eq 4).
We recently reported our discovery that cyclic γ-silyloxy-
β-hydroxy-R-diazo ethyl esters fragment when treated with
Lewis acid to provide tethered aldehyde ethyl ynoate pro-
ducts in high yield.19,20 The success of this fragmentation
reaction, the small number of synthetically useful fragmen-
tation reactions available, and our need for convenient
access to tethered carbonyl alkynes for other ongoing studies
in our laboratories21,22 encouraged us to explore this reac-
tivity profile further and we present our results here.
Results and Discussion
The first indication that β-hydroxy-R-diazo carbonyls
with an additional oxygen substituent at the γ-position
might be competent substrates in a fragmentation reaction
occurred while working with R-diazo ester 7 (Scheme 2).
Treating diazo 7 with indium(III) triflate provided a complex
mixture of products from which ethyl 3-phenylpropiolate (8)
was isolated in 17% yield. The formation of propiolate 8
appeared to involve loss of the β-silyloxy group, loss of
molecular nitrogen, and fragmentation of the Cβ-Cγ bond.
With the above result in hand, we hypothesized that γ-oxy-
β-hydroxy-R-diazo esters in which the Cβ-Cγ bond was
contained within a ring would undergo efficient Lewis acid
mediated ring fragmentation to provide tethered aldehyde
ynoates. In order to promote the fragmentation step it
€
(23) Schollkopf, U.; Frasnelli, H. Angew. Chem., Int. Ed. Engl. 1970, 9,
(19) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766.
(20) Draghici, C. Discovery of a novel ring fragmentation reaction;
Efficient preparation of tethered aldehyde ynoates and N-containing hetero-
cycles; Radical addition approach to asymmetric amine synthesis. Ph.D.,
University of Vermont, Burlington, VT, February 2009.
301.
(24) Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972, 94, 8084.
(25) Ye, T.; Mckervey, M. A. Chem. Rev. 1994, 94, 1091.
(26) Doyle, M. P.; Mckervey, M. A.; Ye, T. In Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
Wiley: New York, 1998; Chapter 10.
(21) Javed, M. I.; Wyman, J. M.; Brewer, M. Org. Lett. 2009, 11, 2189.
(22) Draghici, C.; Huang, Q.; Brewer, M. J. Org. Chem. 2009, 74, 8410.
(27) Wenkert, E.; McPherson, C. A. Synth. Commun. 1972, 2, 331.
J. Org. Chem. Vol. 75, No. 2, 2010 297

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SCHEME 4. Known Reactivity of β-Hydroxy-R-diazo Compounds
SCHEME 5. Proposed Mechanism
TABLE 1. Fragmentation Applied to Various Ring Systems
Scheme 4, eq 2) also react with Lewis acids to provide vinyl
diazonium intermediates that in turn lose molecular nitrogen
to provide the corresponding vinyl cations (e.g., 18) which
react further.28
With the above data in mind, we propose that the ring
fragmentation we observed occurs as shown in Scheme 5.
Similar to the above cases, Lewis acid induced elimination of
the β-hydroxy group from diazo 10 would provide vinyl
diazonium intermediate 20. However, unlike the previous
examples, intermediate 20 would be able to undergo a Grob-
type fragmentation in which electron donation from the
γ-oxygen and loss of molecular nitrogen would provide the
alkyne product. Subsequent loss of the tert-butyldimethyl-
silyl group would provide tethered aldehyde ynoate 11.
To test the generality of this diazo-based fragmentation
reaction, we prepared a variety of substrates such that the
ring that fragments differs (Table 1). Overall, this transfor-
mation appears to be fairly general, and changing the initial
ring size from 6 to 7 members had no effect on product yield
(94% vs 91%), whereas 5-membered rings fragmented in
slightly lower yield (71% and 76%). Aryl rings and olefins
were well tolerated in this transformation, and when these
groups were adjacent to the β-carbon, conjugated ynoate
products were formed in high yield. As a more structurally
complex example, a steroid derivative productively fragmen-
ted to give ynoate 26 in 76% yield. This latter substrate shows
the stability of both distal olefins and silyl ethers to the
reaction, and highlights the important point that tethered
aldehyde ynoates bearing chiral centers along the tether can
be formed using this methodology.
FIGURE 1. Proposed steric inhibition of fragmentation.
fragment to the more structurally complex steroid derivative
provided isolable quantities of the trans-diol product. We
were interested to observe that subjecting the trans-diol
diastereomer to the fragmentation conditions provided dra-
matically lower yield of the ynoate product than the corres-
ponding cis-diol diastereomer; whereas the cis-diol diastereo-
mer fragmented to give the desired product in 76% yield,
the trans-diol diastereomer (Figure 1) afforded the ynoate in
only 5% yield. We hypothesize that the difference in reactiv-
ity between these diastereomers is the consequence of sub-
optimal stereoelectronics in the trans-diol diastereomer
which inhibit the first step of the fragmentation pathway,
In most of the above examples, addition of the ethyl
lithiodiazoacetate to the ketone occurred preferentially from
the face opposite the R-silyloxy group to give the cis-diol
isomer as the major product. In fact, R-silyloxy cyclohex-
anone reacted to give the cis-diol product almost exclusively
(30:1 cis to trans ratio). However, addition of the diazo
(28) Pellicciari, R.; Natalini, B.; Sadeghpour, B. M.; Marinozzi, M.;
Snyder, J. P.; Williamson, B. L.; Kuethe, J. T.; Padwa, A. J. Am. Chem.
Soc. 1996, 118, 1.
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TABLE 2. Fragmentation of Substrates with Modified γ-Oxy Substi-
tuents
SCHEME 6. Possible Mechanisms for Loss of Benzyl
intermediate 27 (Scheme 6). Loss of the benzyl group could
then occur either by way of hemiacetal 28 (path a), or more
directly by nucleophilic attack at the benzylic carbon
(path b). Enol ether 29, a potential alternative product,
was not observed.
γ-Acetoxy derivative 32 and enol ether 33 were not
competent fragmentation substrates, and upon treatment
with SnCl4, both returned complex product mixtures. These
results are consistent with the mechanism discussed above as
the fragmentation of these substrates would result in high-
energy acyloxycarbenium ion29 or ketenium ion30 intermedi-
ates respectively. Substrate 34 (entry 5), in which the γ-oxy
functionality was derived from a tertiary alcohol, success-
fully fragmented to provide keto ynoate 35, albeit in a more
modest 27% yield. In this case, the low yield may again be
due to steric interactions between the substituents at the
γ-quaternary center and the diazo ester impeding the diazo
ester from adopting the conformation required for elimina-
tion of the β-hydroxyl. Finally, we were pleased to observe
that dimethyl acetal derivative 36 (entry 6) successfully
fragmented to provide tethered diester 37 in 45% yield.
These later two results were obtained using the standard
reaction conditions and it is possible that product yield may
improve with optimized reaction conditions or by using an
alternative Lewis acid.
Having successfully modified both the ring that fragments,
and the γ-oxy group, we sought to further explore the scope
of this fragmentation reaction by varying the diazo portion
of the fragmentation precursor. To this end, we are pleased
to report that γ-silyloxy-β-hydroxy-R-diazoketones (e.g., 38,
Table 3) are also viable fragmentation precursors that pro-
vide tethered aldehyde ynone products (e.g., 39) in good
overall yield. Ynones are versatile synthetic intermediates
that undergo a variety of reactions including 1,4-additions,31
1,2-additions,32 isomerization to dienes,33 [4 þ 2] cycloaddi-
tions,34 and R-additions.32
Each of the γ-silyloxy-β-hydroxy-R-diazoketone fragmen-
tation precursors shown in Tables 3-5 were conveniently
prepared by the aldol-type condensation of the correspond-
ing lithiated diazo ketone with 2-tert-butyldimethylsilyloxy
cyclohexanone (9).24,26 The versatility of this method lies in
the fact that a wide variety of R-diazo ketones can be
conveniently prepared by treating carboxylic acid chlorides
the elimination of the β-hydroxyl. That is, steric interac-
tions between the γ-silyloxy group and the diazo ester in the
trans-diol diastereomer likely prevent the diazo ester from
adopting the conformation required for productive
orbital overlap leading to elimination of the β-hydroxyl
(Figure 1).
To further probe the scope of this fragmentation, and to
explore the ability of this fragmentation reaction to provide
ynoates tethered to functional groups other than aldehydes,
we prepared several fragmentation precursors in which the
γ-oxy group was modified to something other than a tert-
butyldimethylsilyl ether. As shown in Table 2, changing the
γ-oxy substituent to a triethylsilyl ether had no effect on
the fragmentation and the expected aldehyde ynoate 11 was
isolated in 95% yield. Benzyl ether derivative 31 (entry 2) was
also a competent fragmentation substrate and we were
interested to observe that once again aldehyde ynoate 11
was the isolated product (90% yield). In this case, the
fragmentation likely proceeds by a mechanism similar
to that shown in Scheme 5 above to provide oxonium
(29) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.
(30) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204.
(31) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147.
(32) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett. 2006, 8, 5417.
(33) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(34) Wills, M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378.
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TABLE 3. Fragmentations Yielding Tethered Aldehyde Alkyl Ynones
TABLE 4. Fragmentations Yielding Tethered Aldehyde Aryl Ynones
aCombined yield of cis and trans diastereomers. bYield of product
from reaction of major diastereomer. c2 equiv of SnCl4 was used.
aCombined yield of cis and trans diastereomers. bYield of product
from reaction of major diastereomer.
or anhydrides with diazomethane.25,35,36 Interestingly, in
these cases the diastereoselectivity of the aldol-type addition
varied significantly, which may be a reflection of the known
reversibility of the addition process.24
this later transformation, perhaps because the oxygen-rich
side chain can bind 1 equiv of the Lewis acid.
Aryl diazo ketones (Table 4) were also competent frag-
mentation substrates but provided slightly diminished iso-
lated yields relative to the alkyl ketone substrates. The
isolated yield of the product depended on the electronics of
the system and the lower isolated yields may be due to the
reactive nature of the aryl ynone products, which appear to
decompose during purification by column chromatography.
Electron-rich and neutral aryl species provided product in
higher isolated yield (entries 1-3, 60-70%) than an aryl ring
bearing an electron-withdrawing group (entry 4, 41%).
Of final note, several fragmentation precursors in which
the R-diazo ketone was derived from N-Cbz protected
R-amino acids (Table 5) were prepared. These more complex
and heteroatom-rich substrates were formed as a mixture
of two diastereomers, and these diastereomeric mixtures
successfully fragmented to provide tethered R-amino-ynone
aldehyde products in good yield (entries 1-4). R-Amino
ynones have recently been shown to be precursors of
pyrrolin-4-ones.38 Exchanging the CBZ protecting group
for Boc (entry 5) afforded the N-Boc-protected R-amino
ynone 63 in a modest 36% yield. In this case, greater
than normal gas evolution was observed during the
Treating alkyl diazoketones (Table 3) with 1 equiv of
SnCl4 at 0 °C provided the corresponding tethered aldehyde
alkyl ynones in nearly pure form in the crude reaction
mixtures. In contrast to the steroid case discussed above
(Figure 1), here both diastereomers appear to fragment in
comparable yields. This difference in reactivity is likely due
to the increased conformational flexibility of the more
structurally simple cyclohexane based ring systems, which
would alleviate the steric hindrance described in the steroid
case.37 It is interesting to note that the steric bulk of the alkyl
substituent played no role in the reaction outcome; diazo-
ketones bearing n-butyl (38), cyclohexyl (40), and tert-butyl
(42) substituents fragmented to the corresponding ynone
products in 82%, 83% and 80% yield, respectively. Incor-
porating a benzyl ether into the diazo portion of the frag-
mentation precursor (44) provided the more functionalized
ynone derivative 45 albeit in a more modest 50% isolated
yield. A 2 equiv portion of SnCl4 was necessary to facilitate
(35) Ye, T.; McKervey, M. A. Tetrahedron 1992, 48, 8007.
(36) Scott, L. T.; Minton, M. A. J. Org. Chem. 1977, 42, 3757.
(37) The results shown in Tables 3 and 4 are for the fragmentation of the
isolated major diastereomer. In several cases, the minor diastereomer was
also subjected to fragmentation and provided comparable yields of product.
The results shown in Table 5 are for mixtures of diastereomers.
ꢀ
(38) Gouault, N.; Le Roch, M.; Cornee, C.; David, M. l.; Uriac, P. J. Org.
Chem. 2009, 74, 5614.
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TABLE 5. Fragmentations Yielding Tethered R-Amino Ynone Alde-
hydes
Experimental Section
2-(2-(tert-Butyldimethylsilyloxy)-1-hydroxycyclohexyl)-1-
cyclohexyl-2-diazoethanone (40): A solution of lithium diisopro-
pylamide [prepared by the addition of n-butyllithium in hexanes
(2.32 mL, 3.29 mmol) to a solution of diisopropylamine (0.52
mL, 3.73 mmol) in THF (10 mL) at -78 °C] was added via
cannula over a period of 30 min to a stirred -78 °C solution of
2-(tert-butyldimethylsilyloxy)cyclohexanone (9) (0.50 g, 2.19
mmol) and 1-cyclohexyl-2-diazoethanone (0.54 g, 3.5 mmol)
in THF (10 mL). The mixture was maintained at -78 °C until
complete conversion was achieved as monitored by TLC (ca. 1 h).
Saturated aqueous NH4Cl solution (40 mL) was added to the
cold reaction mixture, and upon reaching room temperature the
mixture was diluted further with saturated aqueous NH4Cl. The
aqueous layer was extracted with two 40 mL portions of EtOAc,
and the combined organic layers were washed with brine
(40 mL), dried over anhydrous CaCl2, and concentrated under
reduced pressure to provide the product as a separable mixture
of diastereomers in a 9:1 ratio. The residue was subjected to flash
silica gel chromatography (5:1 hexane/Et2O) to afford the major
diastereomer of γ-silyloxy-β-hydroxy-R-diazoketone 40 (0.65 g,
78% yield): 1H NMR (500 MHz, CDCl3) δ 4.20 (dd, J=10.6, 5.7
Hz, 1H), 3.23 (d, J=2.1 Hz, 1H), 2.47 (tt, J=11.5, 3.3 Hz, 1H),
2.10 (tq, J=13.6, 2.2 Hz, 1H), 1.81 - 1.18 (m, 17H), 0.9 (s, 9H),
0.04 (s, 3H), -0.03 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 197.0, 73.8, 72.1, 71.6, 47.2, 33.5, 31.5, 29.7, 28.4, 26.0,
25.7, 23.7, 21.0, 18.0, -4.0, -4.7; MS (ESI) calcd for [C20H36
N2O3SiNa]þ 403.2393, found 403.2379.
8-Cyclohexyl-8-oxooct-6-ynal (41). SnCl4 (0.52 mmol, 0.52
mL of a 1 M solution in CH2Cl2) was added in a steady stream to
a 0 °C solution of γ-silyloxy-β-hydroxy-R-diazoketone 40 (0.20
g, 0.52 mmol, 1 equiv) in anhydrous CH2Cl2 (8 mL) under a
nitrogen atmosphere. The yellow solution turned colorless, and
gas evolution was observed. After gas evolution ceased com-
pletely (ca. 10 to 30 min), saturated aqueous NaHCO3 (10 mL)
was added, and the mixture was transferred with the aid of
CH2Cl2 (10 mL) into a separatory funnel containing additional
saturated aqueous NaHCO3 (10 mL). The layers were sepa-
rated, and the aqueous layer was extracted three times with
CH2Cl2 (20 mL). The organic layers were combined, washed
with water (80 mL) and brine (80 mL), and dried over anhydrous
CaCl2. The solvents were removed in vacuo, and the residue was
subjected to flash silica gel chromatography (4:1 hexane/ethyl
acetate) to afford 8-cyclohexyl-8-oxooct-6-ynal (41, 0.095 g,
83% yield): 1H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 2.50 (t,
J=7.2, 2H), 2.41 (t, J=7.2, 2H), 2.36 (tt, J=10.6, 3.7 Hz, 1H), 1.96
(d, J=10.4 Hz, 1H), 1.80- 1.74 (m, 3H), 1.65-1.61(m, 4H), 1.40
(qd, J=11.7, 2.6 Hz, 2H), 1.45-1.19 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 201.7, 191.5, 93.6, 80.5, 52.2, 43.2, 28.2, 27.1, 25.8,
aCombined yield of diastereomers. bYield of product from reaction of
diastereomer mixture.
25.3, 21.2, 18.8; IR (film): 2929, 2854, 2209, 1706, 1664, 1449 cm-1
;
fragmentation, and it is likely that the low product yield is
due to the instability of the Boc group under the Lewis-acidic
reaction conditions.
MS (ESI) calcd for [C14H20O2Na]þ 243.1361, found 243.1362.
(S)-Benzyl 3,10-Dioxo-1-phenyldec-4-yn-2-ylcarbamate (59).
SnCl4 (0.31 mmol, 0.31 mL of a 1 M solution in CH2Cl2) was
added in a steady stream to a 0 °C solution of γ-silyloxy-β-
hydroxy-R-diazoketone 58 (0.171 g, 0.31 mmol, 1 equiv) in
anhydrous CH2Cl2 (3 mL) under a nitrogen atmosphere.
The yellow solution turned colorless, and gas evolution was
observed. After gas evolution ceased completely (ca. 10 to
30 min), water (10 mL) was added, and the mixture was
transferred with the aid of CH2Cl2 (10 mL) into a separatory
funnel containing additional water (10 mL). The layers were
separated, and the aqueous layer was extracted three times
with CH2Cl2 (20 mL). The organic layers were combined,
washed with water (80 mL) and brine (80 mL), and dried over
anhydrous CaCl2. The solvents were removed in vacuo, and the
residue was subjected to flash chromatography on Davisil solid
support (4:1 to 3:1 hexane/ethyl acetate) to afford (S)-benzyl
In conclusion, the fragmentation of γ-oxy-β-hydroxy-R-
diazo carbonyls appears to be quite general and provides
either ynoates or ynones tethered to an aldehyde, ketone, or
ester in good to excellent yield. The ring that fragments, the
γ-oxy group, and the diazo portion of the fragmentation
precursor can each be modified, thus providing access to a
wide variety of functional group rich products. The effi-
ciency of the fragmentation is notable; proton NMR of the
crude reaction mixtures are very clean and show few if any
side products.39
(39) In some cases the aldehyde product was susceptible to oxidation and
during purification, or upon standing, would convert to the corresponding
tethered ynone carboxylic acid.
J. Org. Chem. Vol. 75, No. 2, 2010 301

Bayir et al.
JOCFeatured Article
3,10-dioxo-1-phenyldec-4-yn-2-ylcarbamate (59, 0.090 g, 74%
yield): 1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.36-7.21
(m, 8H), 7.13 (d, J=7.5 Hz, 2H), 5.30 (d, J=7.8 Hz, 1H), 5.09
(s, 2H), 4.71 (dd, J=13.5, 6.1 Hz, 1H), 3.25 (dd, J=14.2, 5.7 Hz,
1H), 3.19 (dd, J=14.1, 5.9 Hz, 1H), 2.47 (t, J=7.1 Hz, 2H), 2.40
and Dr. Bruce Deker (University of Vermont) for assistance
with NMR characterization. Acknowledgment is made to
the Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research. This
material is based upon work supported by the National
Science Foundation under CHE-0748058 and instrumenta-
tion grant CHE-0821501.
(t, J=6.9 Hz, 2H), 1.76-1.70 (m, 2H), 1.63-1.57 (m, 2H); 13
C
NMR (125 MHz, CDCl3) δ 201.8, 185.5, 155.7, 136.4, 135.6,
129.6, 128.7, 128.6, 128.3, 128.2, 127.2, 98.1, 79.6, 67.1, 62.4,
43.2, 37.3, 27.1, 21.3, 19.1; IR (film) 3323.1, 2933.5, 2210.7,
1701.6, 1674.3; MS (ESI) calcd for [C24H25O4NNa]þ 414.1681,
found 414.1687; [R]20D þ17.6 (c 1.00, CH2Cl2).
Supporting Information Available: General experimental
methods, detailed experimental procedures, as well as charac-
terization data and NMR spectra for compounds 11, 30, 31, and
36-63. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We thank Dr. John Greaves (Univer-
sity of California, Irvine) for obtaining mass spectral data
302 J. Org. Chem. Vol. 75, No. 2, 2010