To stay as allene or go further? Synthesis of novel phosphono-heterocycles and polycyclics via propargyl alcohols

Article abstract of DOI:10.1039/c1cc10230c

The reaction of aryl-substituted propargyl alcohols possessing o-nitro and o-alkylidene groups with (RO)₂PCl afford novel phosphono(tetrahydro) dibenzazepines, N-hydroxyindolinones or polycyclics (including one with three fused four-membered ri

Full text of DOI:10.1039/c1cc10230c

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COMMUNICATION
To stay as allene or go further? Synthesis of novel
phosphono-heterocycles and polycyclics via propargyl alcoholsw
Venu Srinivas, K. V. Sajna and K. C. Kumara Swamy*
Received 13th January 2011, Accepted 25th March 2011
DOI: 10.1039/c1cc10230c
The reaction of aryl-substituted propargyl alcohols possessing
o-nitro and o-alkylidene groups with (RO)2PCl afford novel
phosphono(tetrahydro)dibenzazepines, N-hydroxyindolinones or
polycyclics (including one with three fused four-membered rings).
crystallization at 0 1C afforded the rather odd-looking hetero-
cycle 7 (see ESIw for X-ray structure) comprising an N–O–
C(O)–C linkage (Scheme 1b). It is rather unstable in the solution
state, and decomposes to compound 8 (that has a structure
analogous to 6) with concomitant elimination of a CO2 mole-
cule, as demonstrated by thermogravimetric analysis (TGA)
[Fig. 1]. This assertion was also corroborated by the 31P and 1H
NMR spectral data of the final compound obtained after
heating.
Allenes and their subclass allenylphosphonates (phosphoryl-
ated allenes) are versatile precursors for diverse applica-
tions.1,2 While several synthetic routes are available for the
general class of allenes,3 only two major but simple routes exist
for accessing allenylphosphonates/allenylphosphine oxides.
The first involves the treatment of a P(III)–Cl precursor with
propargyl alcohol/base and the second elegant route entails
palladium catalyzed reaction of phosphites with propargyl
alcohols.4,5 In pursuit of our efforts to expand the range and
functionalities of such allenes, we have stumbled upon an
array of unprecedented reactions that has led to tetrahydro-
dibenzazepines, N-hydroxyindolinones or polycyclics (including
one with three fused four-membered rings). Dibenzazepines
are pharmaceutically active6 while some N-hydroxyindoles7
have antimicrobial/fungicidal properties. Herein we disclose
our results on the formation of unusual heterocycles via
allenylphosphonates by using P(III)–Cl precursors 1a–e8 and
the nitro-based propargyl alcohols 2a–c/3a–c (Chart 1).9 Also,
by employing propargyl alcohols 4a–b/5a–d,10 multiply fused
polycyclics via intramolecular cycloaddition11 are formed.
In our preliminary experiment, the 31P NMR spectrum of
the reaction mixture of 1a with alcohol 2a/Et3N exhibited a
single peak at d(P) 11.2 that was not in the expected allene
region [d(P) 6–8]. Subjecting this to column chromatography
resulted in an altogether different product, the tricyclic
aromatic benzazepine 6 [d(P): 16.1; see ESIw for X-ray structure]
that contains one carbon and two oxygen atoms less than
expected (Scheme 1a). Puzzled by this, and to unravel the
nature of the intermediate [with d(P) 11.2], we treated 1a with
the chloro-substituted propargyl alcohol 2b at rt/4 h;
Optimization studies (Table S1, ESIw) showed that compound
7 is formed nearly quantitatively (31P NMR evidence) from 1a
and 2b by using THF/Et3N in the absence of silica. In the
presence of silica at 60 1C, compound 8 is formed almost
exclusively (>90% by 31P NMR). Thus choosing the conditions
THF/Et3N/silica/60 1C, synthesis of compounds 10–14 (Chart 2)
was accomplished. Intermediate 9 (see ESIw for X-ray
structure), obtained by using the P–Cl precursor 1c and
alcohol 2a, is analogous to 7 and is relatively more stable in
solution. Analogous intermediates were present in other cases
also, but could not be isolated. In the reaction of Ph2PCl
(1d) with alcohol 2a, an additional minor product 15
[5% (isolated); see ESIw for X-ray structure], in addition to
14, was also obtained. This H2O addition product of
compound 15 might have formed after water work-up.
School of Chemistry, University of Hyderabad, Hyderabad 500 046,
A. P., India. E-mail: kckssc@uohyd.ernet.in, kckssc@yahoo.com;
Fax: (+91)-40-23012460; Tel: (+91)-40-231348560
w Electronic supplementary information (ESI) available: Experimental
details (optimization Table S1), plausible mechanism, X-ray structures
of the compounds 6, 7, 9, 15, 16, 22, 24 and 30, copies of 1H/13C NMR
spectra, and CIF data. CCDC 804470–804477. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c1cc10230c
Chart 1 Precursors (1–5) used in the present study.
Chem. Commun., 2011, 47, 5629–5631 5629
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Chart 2 Heterocycles (9–15) obtained in the present study. Yields
31P NMR): >90% for 9 (in the absence of silica) and 10–14 (in the
(
presence of silica); ca. 8% for 15. Yields (isolated): 42% for 9, 54–72%
for 10–14, and 5% for 15.
Scheme 1 Formation of phosphono-tetrahydrodibenzazepines.
Fig. 1 TGA for the conversion 7 - 8.
Rather surprisingly, use of aryl-substituted propargyl alcohols
3a–c in place of cyclohexenyl substituted alcohols 2a–c afforded
the novel phosphono-N-hydroxyindolinones 16–21 (Scheme 2;
see ESIw for X-ray structure of 16). It is important to note
that the phenyl (unlike cyclohexenyl) moiety is not involved in
the formation of the seven-membered ring. A possible pathway
for the formation of compounds 6 and 16 is given in ESIw
(Scheme S1). Three possible intermediates are I–III.
Scheme 2 Facile formation of N-hydroxyindolinones 16–21.
Inspired by the above results, we focussed our attention on
the alkylidene group containing propargyl alcohols 4–5. Thus
when 1a was treated with alcohols 4a–b, compounds 22–23,
comprising fused polycyclic frameworks, are generated in a
tandem process (Scheme 3). Compounds 22–23 constitute a
rare brand of three-fused cyclobutane ring systems.12 Precursor
1e, bearing a sterically crowded phosphorus, upon reaction
with 4a–b afforded compounds 24–25 that can be considered
as monomeric forms of 22–23. Thus dimeric compounds 22–23
might have formed by intramolecular [2+2] cycloaddition13 of
Scheme 3 Formation of fused polycyclics 22–25.
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We acknowledge DST and UGC (both in New Delhi)
for funding and equipment. V. S. and K. V. S. thank CSIR
for fellowships. K. C. K. also thanks DST for a J. C. Bose
fellowship.
Scheme 4 Pathway for the generation of the fused polycycle 22.
Notes and references
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Scheme 5 Formation of tetracycles 26–33.
the allene part and alkylidene moiety (cf. structure IV;
Scheme 4), followed by a second [2+2] cycloaddition of the
corresponding monomer V. Structures of compounds 22 and
24 (see ESIw) were confirmed by X-ray crystallography.
The reaction of 1a or 1e with phenyl substituted alcohols
5a–d led to the unexpected phosphono-tetracyclics 26–33
(Scheme 5). The yields of the resulting products are good
to excellent. Intramolecular [4+2] cycloaddition involving the
a-phenyl group in the intermediate allene VI14 leads the
formation of the product 26 via VII after aromatization.
Formation of compounds 27–33 (see ESIw for X-ray structure
of compound 30) also can be explained similarly. Even though
cycloaddition reactions of allenes with other substrates are
well known,11 formation of these novel polycyclics in a tandem
process by using propargyl alcohols are not reported in the
literature.
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In conclusion, a facile and efficient synthesis of novel
phosphono-(tetrahydro)dibenzazepines and N-hydroxyindo-
linones is discovered. New fused polycyclic compounds have
been generated by tandem intramolecular [2+2] and [4+2]
cycloaddition reactions. As a result of the ready availability of
starting materials and the simple operation, these reactions
may have potential utility in synthetic chemistry. Further
investigations on other reaction partners (e.g. arylsulfenyl
chloride) for propargyl alcohols and on the utility of the final
products are underway.
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