Vinyl diazophosphonates as precursors to quaternary substituted indolines and cyclopentenes

Article abstract of DOI:10.1021/ol102931n

Vinyl diazophosphonates can be stereoselectively synthesized and, depending upon their substitution pattern, undergo intramolecular C-H insertion reactions or sulfonium ylide rearrangements when exposed to Rh₂(OAc) ₄.

Full text of DOI:10.1021/ol102931n

ORGANIC
LETTERS
2011
Vol. 13, No. 4
700–702
Vinyl Diazophosphonates as Precursors
to Quaternary Substituted Indolines
and Cyclopentenes
Jin Wang, Vyacheslav Boyarskikh, and Jon D. Rainier*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States
rainier@chem.utah.edu
Received December 3, 2010
ABSTRACT
Vinyl diazophosphonates can be stereoselectively synthesized and, depending upon their substitution pattern, undergo intramolecular C-H
insertion reactions or sulfonium ylide rearrangements when exposed to Rh2(OAc)4.
Despite the important role that phosphonates play in
synthetic and medicinal chemistry,1,2 vinyldiazophospho-
nates have receivedrelatively little attention from the chem-
ical synthesis community.3 We believe that this has been at
least partly due to the inability of simple vinyl and allyl
phosphonates to undergo diazo transfer chemistry (Scheme 1).
From an interest in utilizing vinyldiazophosphonates as
precursors to more elaborate structures, we became fasci-
nated by the possibility that phosphonocrotonates might
enable us to overcome the diazo transfer limitation. Our
initial results in this area are described here.
and base,4 we turned to the corresponding substituted
variants.
Scheme 1. Diazophosphonates from Diazotransfer?
After finding that the parent diethylphosphonocroto-
nate 4 does not undergo selective diazo transfer chemistry
when treated with p-acetamidobenzenesulfonyl azide (ABSA)
The 2002 report by Solberghe and Marko of the stereo-
selective synthesis of a number of monoalkyl substituted
phosphonocrotonates from the anionic alkylation of phos-
phonocrotonate 4 was critical to the success of this work.5
As indicated in Table 1, by subjecting 4 to LiHMDS and
primary alkyl halides and triflates, we were able togenerate
(1) De Clercq, E. Expert Rev. Anti-infec. Ther. 2003, 1, 21–43.
(2) For reviews on the use of phosphonates in synthetic chemistry,
see: (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. (b)
Heron, B. M. Heterocycles 1995, 41, 2357–2381. (b) Nicolaou, K. C.;
€
Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann./Recueil 1997,
1273–1301. (c) Rein, T.; Pedersen, T. M. Synthesis 2002, 579–594.
(3) For previously reported syntheses of vinyl diazophosphonates,
see: (a) Marmor, R. S.; Seyferth, D. J. Org. Chem. 1971, 36, 128–136. (b)
Theis, W.; Regitz, M. Tetrahedron 1985, 41, 2625–2634. (c) Davies,
H. M. L.; Houghland, P. W.; Cantrell, W. R., Jr. Synth. Commun. 1992,
22, 971–978.
(5) Solberghe, G. F.; Marko, I. E. Tetrahedron Lett. 2002, 43, 5061–
(4) We suspect diazirine formation and decomposition.
5065.
r
10.1021/ol102931n
Published on Web 01/14/2011
2011 American Chemical Society

Table 1. Vinyl Diazophosphonate Synthesis
monoalkylated phosphonocrotonates 5-11. Although the
yields for the alkylation reactions generally fell in the low
to moderate range, the relatively facile separation of 5-11
from the major byproduct of the reaction, the correspond-
ing dialkylated phosphonocrotonates, made these trans-
formations synthetically useful. Of additional note is that
phosphonocrotonates 5-11 were isolated exclusively as
the E-enoate isomer having the alkyl substituent R to the
ester. Having ready access to 5-11, we were prepared to
examine their conversion to the corresponding vinyl diazo
substrates. We were delighted to find this conversion to be
uneventful under standard diazo transfer conditions (DBU
and ABSA, Table 1).6
substituted indoline 20 in 87% isolated yield as a single
diastereomer (Scheme 2). As we have described previously
for the diazoester couplings,7 we believe that the reaction to
20 proceeds via sulfonium ylide intermediate 21 and a
subsequent [3,3] sigmatropic rearrangement. We were
impressed that the diazophosphonate coupling of 12 com-
pares favorably with the related diazoester reaction with
respect to yield and selectivity.
Scheme 3. Competitive C-H Insertion of 13
With the requisite diazo substrates in hand, we next ex-
plored their reactivity. From our interest in the synthesis of
quaternary substituted indolines from the coupling of
2-thioindoles with vinyl diazoesters,7 we initially examined
the coupling of thioindole 19 with methyl-substituted phos-
phonate 12. The addition of 12 to a solution of 19 and Rh2-
(OAc)4 at rt resulted in the formation of vicinal quaternary-
Scheme 2. Diazophosphonate-Thioindole Coupling
In contrast to the results with 12, when ethyl-substituted
diazophosphonate 13 was exposed to Rh2(OAc)4 and indole
19 we not only isolated the desired quaternary substituted
indoline 22 but also a significant quantity of cyclopentenyl
phosphonate 23 that presumably resulted from a compe-
titive intramolecular C-H insertion reaction (Scheme 3).
(6) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley & Sons:
New York, 1998; pp 1-60.
(7) (a) Boyarskikh, V.; Nyong, A.; Rainier, J. D. Angew. Chem., Int.
Ed. 2008, 47, 5374. (b) Nyong, A.; Rainier, J. D. J. Org. Chem. 2005, 70,
746. (c) Novikov, A. N.; Kennedy, A. R.; Rainier, J. D. J. Org. Chem.
2003, 68, 993–996. (d) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. Org.
Lett. 2001, 3, 2407.
Org. Lett., Vol. 13, No. 4, 2011
701

general, would represent a powerful entry into structurally
rich cyclopentenyl phosphonates we opted to study its scope.
As illustrated in Table 2, alkyl, benzyl, and even homoallyl
diazophosphonates undergo C-H insertion reactions in high
yields to give the corresponding cyclopentenyl phosphonates
when exposed to catalytic Rh2(OAc)4.
Table 2. C-H Insertion Reactions of Vinyl Diazophosphonates
The mixture of cis- and trans-phosphonates 24, 26, and
27 were equilibrated to the trans diastereomer by simply
subjecting the mixture to DBU for 30 min (Scheme 4).
entry
R
R0
R00
cyclopentene
dr
yield (%)
1
2
3
4
5
CH3
CH3CH2
(CH3)2CH CH3
H
H
23
24
25
26
27
67
89
87
78
82
Me
H
5:1a
CH3
H
Scheme 5. Stereoselective C-H Insertion to 28
Bn
Ph
2:1b
2:1a
allyl
vinyl
H
a Determined by 1H NMR of the crude reaction mixture; b Deter-
mined by HPLC of the crude reaction mixture
The conversion to cyclopentene 23 could be improved
to 67% yield by simply carrying out the reaction in the
absence of thioindole 19 (Table 2, entry 1).
Optically active phosphonocrotonate 18 also underwent
a C-H insertion reaction resulting in the generation of
cyclopentene 28 in 91% yield as a 3:2 mixture of diaste-
reomers (Scheme 5). We were pleased to find that the major
28 diastereomer existed as a single enantiomer. Based on
Taber’s precedent,14 we presume that the C-H insertion
reaction proceeded with retention of absolute configuration.
In summary, we have demonstrated both the synthesis
and the reactivity of vinyl diazophosphonates in C-H inser-
tions and sulfonium ylide transformations. Both reactions
deliver relatively complex substrates from simple starting
material. Our future efforts in this area will be focused
on examining the scope of vinyl diazophosphonate reactivity
and the application of the products from these efforts in the
synthesis of complex substrates including natural products.
Scheme 4. Equilibration to trans-Phosphonates
While intramolecular C-H insertions of Rh carbenes
are well-known,8 to the best of our knowledge very few of
these transformations have utilized vinyl diazo substrates
as precursors.7c,8,9 Additionally, very few C-H insertion
reactions of diazophosphonates have been reported.10 In
contrast, intermolecular C-H insertions of vinyl diazoe-
sters and O-H and N-H insertions of diazophosphonates
have been demonstrated to be powerful synthetic transforma-
tions.11-13 In light of this and because this transformation, if
Acknowledgment. We are grateful to the National Science
Foundation for support of this work (CHE 1012670). We
thank the support staff at the University of Utah and espe-
cially Dr. Peter Flynn (NMR) and Dr. Jim Muller (mass
spectrometry) for help in obtaining data. We also thank
Professor Douglass F. Taber (University of Delaware) for
insightful discussions.
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6450–6453. (b) Taylor, E. C.; Davies, H. M. L. Tetrahedron Lett. 1983,
24, 5453–5456.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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