Preparation of allenephosphoramide and its utility in the preparation of 4,9-Dihydro-2 H -benzo[ f ]isoindoles

Article abstract of DOI:10.1021/ol102992n

Allenephosphoramides were prepared from propargyl alcohols and diethyl arylphosphoramides using Yb(OTf)₃ as catalyst. In the presence of iodine, 4,9-dihydro-2H-benzo[f]isoindole derivatives could be efficiently constructed from the same two sta

Full text of DOI:10.1021/ol102992n

ORGANIC
LETTERS
2011
Vol. 13, No. 5
940–943
Preparation of Allenephosphoramide and
Its Utility in the Preparation of 4,9-Dihydro-
2H-benzo[f ]isoindoles
Guangwei Yin,† Yuanxun Zhu,† Li Zhang,† Ping Lu,*,† and Yanguang Wang*,†,‡
†Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. China, and
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China
orgwyg@zju.edu.cn; pinglu@zju.edu.cn
Received December 10, 2010
ABSTRACT
Allenephosphoramides were prepared from propargyl alcohols and diethyl arylphosphoramides using Yb(OTf)3 as catalyst. In the presence of
iodine, 4,9-dihydro-2H-benzo[f]isoindole derivatives could be efficiently constructed from the same two starting materials in a single step.
Allene has been widely investigated because of its high
reactivity in a number of reaction patterns and its applica-
tions as the key building block in constructing various
compounds with multifunctionalities.1 Allenamine,2 in
which a terminal carbon of allene is substituted by a
nitrogen atom, enriches the electron density of the CdC
bond and makes the chemistry of allene more prosperous.
However, for the same reason, allenamine is unstable and
cannot easily be handled and isolated, which has largely
limited its utility in organic synthesis. In order to overcome
this drawback, allenamide as a more stable allenamine
equivalent has been derived and applied in the construc-
tion of complicated molecules. For example, epoxidation
of allenamide led to the formation of nitrogen-stabilized
oxyallyl cation, which could be used as a 1,3-dipolar
substituent in [4 þ 3] cycloaddition.3 It could also function
as dienophile in [4 þ 2] cycloaddition.4 Furthermore, one
of the CdC bonds of allenamide could be nucleophilically
attacked to afford enamide under a gold catalyst.5 Tradi-
tionally, allenamide was prepared by base-catalyzed iso-
merization of propargylic amide,6 Claisen rearrange-
ment,7and aminocyclization.8 It was also reported that
copper-catalyzed coupling of allenyl halide with amide
could afford allenamide.9
(4) (a) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430. (b) Song,
Z.; Hsung, R. P. Org. Lett. 2007, 9, 2199.
(5) (a) Hill, A. W.; Elsegood, M. R. J.; Kimber, M. C. J. Org. Chem.
2010, 75, 5406. (b) Kimber, M. C. Org. Lett. 2010, 12, 1128.
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(b) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron Lett.
1999, 40, 6903. (c) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.;
Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
(1) For a compendium on the chemistry of allenes, see: Krause, N.;
Hashmi, A. S. K. Modern Allene Chemistry; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2004; Vols. 1 and 2.
(7) (a) Balasubramanian, K. K.; Venugopalan, B. Tetrahedron Lett.
1974, 15, 2643. (b) Overman, L. E.; Marlowe, C. K.; Clizbe, L. A.
Tetrahedron Lett. 1979, 20, 599.
(2) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773.
(3) (a) Harmata, M. Adv. Synth. Catal. 2006, 348, 2297. (b) Huang, J.;
Hsung, R. P. J. Am. Soc. Chem. 2005, 127, 50. (c) Antoline, J. E.; Hsung,
R. P.; Huang, J.; Song, Z.; Li, G. Org. Lett. 2007, 9, 1275. (d) MaGee,
D. I.; Godineau, E.; Thornton, P. D.; Walters, M. A.; Sponholtz, D. J.
Eur. J. Org. Chem. 2006, 3667.
(8) (a) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499.
(b) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869.
(9) (a) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117. (b) Shen, L.;
Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7,
3081. (c) Persson, A. K. A.; Johnston, E. V.; Backvall, J. -E. Org. Lett.
2009, 1, 3814.
€
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10.1021/ol102992n
Published on Web 01/24/2011
2011 American Chemical Society

using Yb(OTf)3 as catalyst and isolated the anticipated
allenephosphoramide in 10% yield. To our delight, when
phosphoramidate 2a was used as substrate instead of diet-
hyl benzylphosphoramidate, we obtained allenephosphor-
amide 3a13 in 62% yield.
Table 1. Optimization of Reaction Conditionsa
Encouraged by this result, we optimized the reaction con-
ditions (Table 1). The yield of 3a was increased when the
reaction temperature was raised to 50 °C (Table 1, entry 2).
However, higher temperature (80 °C) led to a decrease in
yield and the formation of byproduct 4a14 (Table 1, entry 3).
Lowering the temperature would decrease the yield as
well (Table 1, entry 4). AgOTf, Zn(OTf)2, Cu(OTf)2, and
trifluoroborane also catalyzed the reaction, but with rela-
tively lower yields (Table 1, entries 5-8). Neither alumi-
num trichloride nor iron trichloride allowed this reaction
to proceed (Table 1, entries 9 and 10). The desired product
was not detected (n.d.) or only formed in a trace amount if
the solvent was changed to THF, acetonitrile, DMF, or
toluene (Table 1, entries 11-14). A 5 mol % ratio of
catalyst to propargylic alcohol was enough (Table 1,
entries 2 and 15). Without 4 A molecular sieves, the reac-
tion was not effective (Table 1, entries 2, 16, and 17). Short-
ening the reaction time reduced the yield (Table 1, entry 18).
entry
catalyst
solvent
temp (°C)
yieldb (%)
1
2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
AgOTf
DCE
DCE
DCE
DCM
DCE
DCE
DCE
DCE
DCE
DCE
THF
CH3CN
DMF
toluene
DCE
DCE
DCE
DCE
rt
50
80
0
62
75
3
61c
54
4
5
50
50
50
50
50
50
50
50
50
50
50
80
50
50
63
6
Zn(OTf)2
Cu(OTf)2
53
7
56
8
BF3 Et2O
32
3
9
AlCl3
n.d.
trace
trace
n.d.
n.d.
n.d.
75
10
11
12
13
14
15
16
17
18
FeCl3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
d
Yb(OTf)3
e
Yb(OTf)3
trace
13
e
Yb(OTf)3
f
Yb(OTf)3
63
Table 2. Substrate Diversity of the Transformationa
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), Yb(OTf)3
(0.025 mmol), 4 A MS (200 mg), DCE (3 mL), 12 h. b Isolated yields.
c 4a was isolated in 10%. d 10% catalyst. e Without 4 A MS. f 8 h.
entry
1 (R1 / R2/ R3)
1a (H/H/H)
2 (R4)
yieldb (%)
1
2a (CH3)
2b (H)
2c (OCH3)
2d (Br)
2e (Cl)
2a
3a/75
3b/62
3c/82
3d/62
3e/60
3f/62
3g/77
3h/82
3i/81
3j/84
3k/41
3l/69
Although allenamide has attracted considerable atten-
tion in recent years, allenesulfonamide10 and allenephos-
phoramide11 have seldom been reported. Typically, as in
the case of allenephosphoramide and its related chemistry,
it is a comparatively virgin territory relative to the well-
known allenamide. Enlightened by the chemistry of alle-
namide, we report a facile preparation of allenephosphor-
amide and its extension to 4,9-dihydro-2H-benzo[f]isoin-
dole derivatives.
2
1a
3
1a
4
1a
5
1a
6
1b (H/H/F)
1c (H/H/C2H5)
1c
7
2a
8
2c
9c
10c
11
12
1d (CH3O/CH3O/H)
1d
2a
2c
1e (Cl/Cl/H)
1f (Cl/CH3O/H)
2c
As we predicted, propargyl alcohol 1a could be trans-
ferred to propargylic carbocation under acidic conditions,
which would possess a resonance structure of allenic
carbocation.12 Therefore, we first treated 1a with diethyl
benzylphosphoramidate in 1,2-dichloroethane (DCE)
2a
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Yb(OTf)3 (0.025
mmol), 4 A MS (200 mg), DCE (3 mL), 50 °C, 12 h. b Isolated yield.
c Room temperature.
With the optimized reaction conditions in hand, we
subsequently tested the substrate diversity (Table 2). The
substrates bearing an electron-donating group on the para
position of the aryl of 2 gave higher yields than those
(10) (a) Horino, Y.; Kimura, M.; Wakamiya, Y.; Okajima, T.;
Tamaru, Y. Angew. Chem., Int. Ed. Engl. 1999, 38, 121. (b) Kinderman,
S. S.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes,
F. P. T. Org. Lett. 2001, 3, 2045.
(11) (a) Corbel, B.; Paugam, J.-P.; Dreux, M.; Savignac, P. Tetra-
hedron Lett. 1976, 17, 835. (b) Danowitz, A. M.; Taylor, C. E.; Shrikian,
T. M.; Mapp, A. K. Org. Lett. 2010, 12, 2574.
(12) (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71,
429. (b) Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli,
M. D. J. Org. Chem. 1977, 42, 3403.
(13) CCDC 800666 contains the crystallographic data of 3a. It can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(14) CCDC 800667 contains the crystallographic data of 4a.
Org. Lett., Vol. 13, No. 5, 2011
941

substrates with an electron-withdrawing group on the para
position of the aryl of 2 (Table 2, entries 1-5). A similar
electronic effect was observed for the aryl of propargyl
alcohols (Table 2, entries 6 and 7). With methoxy groups
on both the phosphoramide and propargyl alcohol sides, the
highest yield was reached (Table 2, entry 10). Compound 1f,
derived from unsymmetrical ketone precusor, afforded 3l
successfully (Table 2, entry 12). However, an acetophenone-
derived propargyl alcohol did not work for this transforma-
tion. It means that two aryl groups connected to the carbon
substituted by a hydroxy group in propargyl alcohols are
necessary to trigger the formation of propargylic carboca-
tion and proceed with the subsequent steps in the reaction.
to trap the allenic carbocation directly. To our surprise,
when 2i was used as the substrate, 4b16 was isolated in 32%
yield. When the molar ratio of 1a to 2i was adjusted to 2:1,
the yield of 4b was increased to 60%. The electron density
of the para position of the aryl group of 2i was enriched by
both nitrogen and oxygen, and thus it trapped allenic
carbocation directly. Compound A was generated in situ,
similar to the formation of 5. In the structure of A, the
electron density of the ortho position of the aryl of phos-
phoramide was doubly enriched. In cooperation with the
nitrogen atom, this carbon trapped one more allenic carbo-
cation. Finally, 4b was constructed. The reaction was a three-
component reaction, and 1a was used as substrate twice.
Scheme 1. Formation of 3m and 3n
Scheme 3. Formation of 6a from 3a and 1a
The chemistry of allenephosphoramide is immature and
has not been widely explored since 1976.12 All synthesized
allenephosphoramides 3a-n are sensitive to moisture and
should be stored in the refrigerator. Hydrolysis of 3a under
acid conditions afforded 1,3,3-triphenylprop-2-en-1-one17
accordingly. Itwasalsofound that3acouldreactwith1ain
the presence of iodine to give 6a18 (Scheme 3). Since 3a was
indeed prepared from 1a and 2a with Yb(OTf)3 as catalyst,
we directly combined 1a and 2a in a 1:0.6 ratio and used
2 molar equiv of iodine against 1a to trigger the reaction. As
When 1g was used as the precursor of allenic carboca-
tion, 3m was formed as the major product, as we expected.
A similar situation was observed for the reaction between
1g and 2c (Scheme 1).
Scheme 2. Formation of 5 and 4b
Table 3. Substrate Diversity of Three-Component Synthesis of 6a
entry
1 (R1)
2 (R2)
yieldb (%)
Interestingly, when the ortho or meta position of the aryl
of phosphoramidate was altered by a methyl group (2f
or 2g), the allenic system could still be approached, but
with four aryls attached (5a and 5b) (Scheme 2). A similar
situation was observed for 2h, which afforded 5c15 in 70%
yield. In these cases, the para position of the aryl of
phosphoramidate (2f, 2g, and 2h) was electron rich enough
1
2
3
4
5
6
7
8
9
1a (H)
1a
2a (CH3)
2b (H)
2c (OCH3)
2d (Br)
2e (Cl)
2a
6a/63
6b/54
6c/68
6d/61
6e/60
6f/67
6g/71
6h/72
6i/84
1a
1a
1a
1h (CH3)
1h
2c
1i (Br)
1i
2a
(15) CCDC 800668 contains the crystallographic data of 5c.
(16) CCDC 800670 contains the crystallographic data of 4b.
(17) Katritzky, A. R.; Denisenko, S. N.; Oniciu, D. C.; Ghiviriga, I.
J. Org. Chem. 1998, 63, 3450.
2c
a Reaction conditions: 1 (1 mmol), 2 (0.6 mmol), iodine (2 mmol), 4 A
MS (400 mg), DCE (3 mL), 80 °C, 8 h. b Isolated yield.
(18) CCDC 800669 contains the crystallographic data of 6a.
942
Org. Lett., Vol. 13, No. 5, 2011

expected, 6a was obtained in 63% yield after the mixture
was heated at 80 °C for 8 h. The yield was slightly increased
when the iodine was fed in 2.5 molar equiv to 1a, while it
was decreased when the temperature lowered to 50 °C. The
substitution effect of 1 and 2 was further explored, and the
results are summerized in Table 3. No significant electronic
effect was seen in these cases. The best yield was obtained
when 1i reacted with 2c (Table 3, entry 9). However,
substrates 1d, 1f, and 1g did not allow this three-compo-
nent reaction to proceed, although all of these starting
materials disappeared on the basis of the TLC tracking.
Scheme 5. Equivalent Formation of 6ja and 6jb
Scheme 4. Postulated Mechanism of Formation of 3a and 6a
intramolecularly attacked R,β-unsaturated iminium and
the second cyclization casually happened.20,21 Aromatization
of the resulting F formed G, which was hydrated to
afford 6a.
In order to support the postulated mechanism, we
carried out the reaction of 3c with 1h. As we anticipated,
a mixture of 6ja and 6jb was isolated in a 1:1 ratio
(Scheme 5). This result demonstrated that the process from
D to E (Scheme 4) might have two comparable opportu-
nities when 1h was used as the substrate, and the regio-
selectivity was then lost.
In conclusion, we have demonstrated that allenepho-
sphoramides could be directly synthesized from phosphor-
amides and propargyl alcohols using Yb(OTf)3 as catalyst.
By elaborately adjusting the electron density of the aryl of
phosphoramides via various substituents, 1,2-hydroquino-
lines and tetraaryl allenescould be successfully synthesized.
More significantly, 4,9-dihydro-2H-benzo[f]isoindoles could
be efficiently constructed from propargyl alcohols and
phosphoramides in the presence of iodine in a single step.
Furtherinvestigations onthe chemistry of allenephosphor-
amides are ongoing.
On the basis of these results, we postulated a mechanism
for the formation of 3a and 6a (Scheme 4). In the presence
of iodine, 1a is converted to B, which possesses another
resonance structure C.12 The nitrogen of 2a nucleophili-
cally attacks C,19 followed by deprotonation, to give 3a.
However, 3a is unstable and can be hydrolyzed very easily.
If enough C exists in the solution, C can be trapped by the
hydrolyzed product of 3a. Diallenamine D is thus formed
in situ. Isolation of D was a futile effort because of its
unstability. Compound D immediately underwent the first
cyclization to form E. Subsequently, the phenyl ring of E
Acknowledgment. We thank the National Nature Science
Foundation of China (No. 21032005 and 20972137) and the
Fundamental Research Funds for the Central Universities
(2010QNA3011) for financial support.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
and crystallographic information files (CIF) for com-
pounds 3a, 4a,b, 5c, and 6a. This material is available
free of charge via the Internet at http://pubs.acs.org
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