Acyclic ketene aminal phosphates derived from N,N-diprotected acetamides: stability and cross-couplings

Article abstract of DOI:10.1016/j.tetlet.2009.09.159

The synthesis of a stable ketene aminal phosphate (α-phosphoryloxy enecarbamate) derived from N,N-diprotected acetamide, bearing two different removable protecting groups, is disclosed. This synthetic intermediate underwent successful palladium-catalyzed cross-coupling reactions to afford functionalized enynes and dienes.

Full text of DOI:10.1016/j.tetlet.2009.09.159

Tetrahedron Letters 50 (2009) 6977–6980
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acyclic ketene aminal phosphates derived from N,N-diprotected acetamides:
stability and cross-couplings
*
Alessandro B. C. Simas , Daniel L. de Sales, Karla C. Pais
Núcleo de Pesquisas de Produtos Naturais (NPPN), Universidade Federal do Rio de Janeiro, Laboratório Roderick A. Barnes, Ilha do, Fundão,
Prédio do CCS, bloco H, Av. Carlos Chagas Filho, 373, Rio de Janeiro, RJ 21941-902, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a stable ketene aminal phosphate (a-phosphoryloxy enecarbamate) derived from N,N-
Received 8 September 2009
Revised 23 September 2009
Accepted 25 September 2009
Available online 1 October 2009
diprotected acetamide, bearing two different removable protecting groups, is disclosed. This synthetic
intermediate underwent successful palladium-catalyzed cross-coupling reactions to afford functionalized
enynes and dienes.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Stille reaction
Suzuki reaction
Catalysis
Enyne
Diene
Transition metal-catalyzed cross-coupling reactions of alkenyl
triflates (such as 2a) and phosphates (such as 2b) allow a1 retro-
synthetic (hence, strategic) relationship between a substituted
alkenyl carbon atom (as in 3) and a (enolizable) carbonyl carbon
atom (as in 1). Due to geometric constraints in their structure, such
transformations are generally more useful in the cases of cyclic
carbonyl derivatives (Scheme 1).
This chemistry has been particularly fruitful in the construction
of more functionalized heterocycles from lactones2 and lactams.3
In recent years, there has been a growing interest in the catalyzed
cross-coupling reactions of lactam-derived ketene aminal phos-
removable protecting groups at the nitrogen atom. This may
broaden the scope of the methodology. As the following discussion
will show, a good deal of work had to be done to reconcile a suit-
able substitution pattern and stability.
Our first hypothesis was that phosphate 6a (Scheme 3), bearing
a nitrogen atom protected with Boc, might serve our purpose of
scrutinizing the reactivity of this class of synthetic blocks. Thus,
N-benzyl acetamide 7 (prepared by acetylation of BnNH2) was pro-
tected with a Boc group via the usual procedure to give N,N-dipro-
tected acetamide 7. This substance was subjected to enolization
phates (a-phosphoryloxy enecarbamates) as alternatives to the
OX
O
R
corresponding triflates.4,5 A reason for this is cost as more afford-
able chlorophosphate reagents (typically (PhO)2POCl) are em-
ployed in the synthesis of enol phosphates. Moreover, it has also
been shown that these compounds may be more stable than the
triflate counterparts.5
R´
R´
R-M
R´
via
enolization
catalyst
1
2a: X = CF3SO2
2b: X = PO(OR)2
3
M = activating group(BR 2,SnR3) or H
Our attention was drawn to the study of the synthesis of func-
tionalized N-carbonyl enamines 4 and 5 (Scheme 2), potential pre-
cursors of functionalized carbon frameworks. These compounds
could be prepared via cross-coupling of ketene aminal phosphate
6, which could be derived from N,N-diprotected acetamides. Only
over the past two years, the first studies on synthesis and reactions
of acyclic ketene aminal phosphates, have been disclosed.6,7 We re-
stricted our choice of precursors 6 to compounds bearing two
Scheme 1. Transformation of carbonyl compounds into olefins via alkenyl phos-
phates and triflates.
P'
P'
P'
N
P
N
P
OPO(OPh)2
N
P
R
or
5
6
R
4
* Corresponding author. Tel.: +55 21 2652 6792; fax: +55 21 2562 6512.
E-mail address: abcsimas@nppn.ufrj.br (A.B.C. Simas).
Scheme 2. Acetamide-derived ketene aminal phosphates 6 as precursors of enynes
4 and dienes 5.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.159

6978
A. B. C. Simas et al. / Tetrahedron Letters 50 (2009) 6977–6980
NaHMDS or KHMDS. As anticipated, we found that both
b
P'
a
R1
R1
compounds are substantially more stable than 6b. However, 6d
showed a clearly higher stability compared to 6c, which could also
be synthetically useful. The lesser stability of phosphate 6c, bear-
ing the Boc group, is certainly intriguing. Some of the prepared
samples of 6d withstood stocking under cooling for several months
with little noticeable degradation. In order to gain more insight
into the impact of the O-alkyl carbamate function on the stability
of substances 6, we synthesized known phosphate 6e6a (Table 1,
entry 5) (single experiment). Contrary to analogous 6c, this N-
Boc-containing substance showed very good stability. This proves
that it is the combination of both Boc and PMP group which brings
about lesser stability. We tentatively suggest that the electron rich
olefinic moiety weakens the (CH3)3C–O bond (in 6c) more substan-
tially than the Bn–O (in 6d) as a tertiary carbocation may be
formed the C–O bond cleavage in the former case. The stability dif-
ferences among phosphates 6 were consistent and significant.
With robust phosphate 6d in hand, the study on catalyzed
cross-coupling reactions was initiated (Scheme 4, Table 2). As a
comparison to the limited literature data on similar substances,6,7
we have also assayed phosphate 6d in a Suzuki coupling with
PhB(OH)2.9 The successful formation of 2-phenyl enecarbamate
19 (Table 2, entry 1) parallels those previous results and confirms
the usefulness of 6d as well. Sonogashira reaction10 of 6d with phe-
N
P
OPO(OPh)2
N
O
N
H
O
See table1
R2
6a: R1 = Bn; R2 = Boc
6b: R1 = Bn; R2 = Bz
6c: R1 = PMP; R2 =Boc
6d: R1 = PMP; R2 = CBz
6e: R1 = Ph; R2 = Boc
10: R1 = Bn; R2 = Boc (74%)
11: R1 = Bn; R2 = Bz (97%)
12 R1 = PMP; R2 =Boc (94%)
13: R1 = PMP; R2 = CBz (86%)
14: R1 = Ph; R2 = Boc (94%)
7: R1 = Bn
8: R1 = PMP
9: R1 = Ph
Scheme 3. Conversion of N-substituted acetamides into ketene aminal phosphates
6. Reagents and conditions: (a) for 10, 12 and 14: DMAP, TEA, (Boc)2O, CH2Cl2, 0 °C
(30 min), rt (24 h); for 11: DMAP, TEA, BzCl, CH2Cl2, 0 °C (30 min), rt (24 h); for 13:
(i) LDA, À78 °C, THF, 1 h; (ii) CbzCl, À78 °C (30 min), rt (24 h).
Table 1
Synthesis of ketene aminal phosphates 6
Entry
Acetamidea
Productb
Yieldc (%)
Stability
1
2
3
4
5
10
11
12
13
14‘
6a
6b
6c
6d
6e
38
50
70
87
50
Poor
Low
Fair
Good
Good
a
See Scheme 3.
b
Reagents and conditions: for 6a, 6b: (i) NHMDS, THF, À78 °C, 1 h; (ii) ClO-
P(OPh)2, À78 °C (30 min) to 0 °C; for 6c, 6d, 6e: (i) LDA, À78 °C, THF, 1 h; (ii)
ClPO(OPh)2, THF, À78 °C (1 h) to À20 °C.
´
nyl acetylene, 15, in the presence of ZnCl2/Et3N (Negishis ver-
sion),11 led to desired enyne 4a albeit in moderate yield (50%
based upon recovered 6d; note the lower yield in the reaction of
6b) (Table 2, entry 2). The classic condition for the same reaction
(use of CuI) did not afford any detectable amount of product. Sat-
c
Pure compounds.
and treated with (PhO)2POCl to produce the desired phosphate, 6a
(Table 1, entry 1). This substance, however, proved to be too labile
to be synthetically useful.8 The unsatisfactory yield in the prepara-
tion of this substance may possibly result from its low stability. It
is noteworthy that we could still obtain a pure sample of 6a. We
then presumed that a decrease in electron density at the olefinic
portion of substances 6 would make them more stable. Thus, we
elected N-benzoyl derivative 6b (Scheme 3) as the next potential
precursor of substances 4 and 5. N-Benzoylation of acetamide 10
gave imide 11 which was transformed into phosphate 6b as it
had been done with counterpart 6a (Table 1, entry 2). The use of
the stronger electron-withdrawing benzoyl group did make phos-
phate 6b more stable than 6a. The stability of 6b was limited,
tough. Even when stocked under cooling, significant degradation
of this compound was noticed. We nonetheless made the first at-
tempts of cross-coupling reactions of this substance. Sonogashira
isfyingly, we found that the Stille coupling12 involving 1-stannylat-
13
´
ed derivative 16a, under Farinas conditions, led to enyne 4a in
good yield (entry 3) in a fast reaction run under mild condition.
The catalytic system based on arsine ligand is knowingly less reac-
tive in the oxidative addition than transmetalation step of the cat-
alytic cycle. From these facts and the good result in the catalyzed
reaction of 6d with 16a (entry 3), we presume that the low effi-
ciency in the reaction of terminal acetylene 15 (entry 2), wherein
a PPh3-based catalyst is employed, may be originated by a slow
transmetalation, and not due to a problem in oxidative addition.
It appears unlikely that the problem is related to the in situ meta-
lation (with ZnCl2), as Negishi group reported good results of appli-
cation of this protocol in reactions of the same co-substrate (15)
run at room temperature. Indeed, we found that the reaction of
6d with more acidic ethyl propiolate, under the same conditions,
produced the alkynyl-substituted product in lower yield (26%).
The activation via stannylation also allowed the synthesis of
TMS-substituted enyne 4b (Entry 4) in moderate yield. Some yield
loss may have occurred during work-up and purification as we ob-
served that product 4b shows higher lability compared to the other
products presented here.
The Stille reaction of 6d with vinyl stannane 17a also proved
feasible (Entry 5). Diene 5a was obtained in high yield. Conversely,
when the same catalytic protocol was applied to the reaction of 2-
alkyl substituted stannane 17b,14 the expected product 5b was not
formed (Entry 6). In this reaction, both phosphate 6d and vinyl
stannane 17b were consumed, with the latter reactant being con-
sumed at a fast rate. Satisfyingly, this problem was overcome by
employment of the classical Stille protocol in the reaction of the
´
coupling with phenylacetylene, under Negishis modified protocol
(vide infra) could be carried out but in low yield (13%). Although
the immediate use of rather unstable phosphates in crude form
in couplings is possible and could make such intermediates (espe-
cially more robust 6b) useful, this is not desirable. Indeed, it would
make the optimization of coupling reactions, if needed, far more
difficult or even make the use of phosphates unviable in cases
requiring extensive experimentation.
The latter results confirmed the stabilization role of the protect-
ing groups at the nitrogen atom of substances 6. An attempt to
make them even more robust by further tuning the electron den-
sity at enol phosphate C–C double bond was made. Thus, we
planned the use of both p-methoxyphenyl (PMP) and an alcoxycar-
bonyl group for protection of the nitrogen atom of 6. We expected
that the combination of two electron-withdrawing protecting
groups might foster significant stabilization on substances 6. Thus,
N-acetamide derived from p-anisidine, 8 (Scheme 3), was protected
with either a Boc or CBz group, under suitable conditions, giving
derivatives 12 and 13, respectively. Enolization of these com-
pounds, followed by treatment with the chlorophosphate reagent,
led to ketene aminal phosphates 6c and 6d, respectively (Table 1,
entries 3 and 4). LDA as base afforded better results compared to
PMP
PMP
R-M or R-H
cat.
N
OPO(OPh)2
N
R
CBz
CBz
4, 5, 19
6d
Scheme 4. Palladium-catalyzed cross-couplings of compound 6d.

A. B. C. Simas et al. / Tetrahedron Letters 50 (2009) 6977–6980
6979
Table 2
Cross-couplings of phosphate 6da
Entry
R–M/R–H
Conditions
Products
Yield (%)
Ph
19
1
PhB(OH)2
PdCl2(PPh3)2, Na2CO3, EtOH, THF, 80 °C, 20 min
64
39
PMP
PMP
N
N
CB z
Ph
Ph
2
3
4
5
6
7
Pd(OAc)2, PPh3, ZnCl2, THF/TEA (2:1), 24 h
Pd2dba3ÁCHCl3, AsPh3, DIPEA, NMP, 2 h
Pd2dba3ÁCHCl3, AsPh3, DIPEA, NMP, rt, overnight
Pd2dba3ÁCHCl3, AsPh3, DIPEA, NMP, rt, overnight
Pd2dba3ÁCHCl3, AsPh3, DIPEA, NMP, rt, overnight
Pd(PPh3)4, LiCl, THF, 70 °C, 2 h
15
4a
CBz
CBz
CBz
Ph
Bu3Sn
Ph
65
16a
PMP
PMP
N
N
N
N
4a
4b
TMS
TMS
Bu3Sn
Bu3Sn
46–51
16b
83
5a
PMP
PMP
17a
CBz
CBz
CBz
O
O
Bu3Sn
Bu3Sn
—
O
17b
5b
5b
5c
64
O
PMP
PMP
N
N
17b
O
B
(CH2)4
(CH2)4
8
PdCl2(PPh3)2, Na2CO3 aq, THF, 65 °C, 2.5 h
66
O
18
CBz
a
See Scheme 4.
same vinyl stannane 17b (Entry 7). Interestingly, PdCl2(PPh3)2
could not replace Pd(PPh3)4 in this transformation, as no reaction
occurred in the presence of the former catalyst. This failed experi-
ment could be rescued when a mixture Pd2dba3ÁCHCl3 and PPh3 in
THF was added and the resulting mixture was heated. Finally, the
successful reaction of 6d and boronate 1815 shows the Suzuki cou-
plings to be alternative for the synthesis of dienes 5 (Entry 8).16 In
summary, we identified acetamide-derived ketene aminal phos-
phate, 6d, as a quite stable synthetic block.17 The stability of phos-
phates 6 depends heavily on the substitution pattern of the
nitrogen atom. Our study established that these compounds under-
go palladium-catalyzed cross-couplings to produce enynes18a and
dienes.18b,c We have shown that the activation of 1-alkynes via
stannylation expedites the production of the desired enynes. More-
over, an interesting differential behavior of alkyl-substituted-1-
stannyl olefins in Stille couplings of phosphate 6d, under the Farina
protocol, has been uncovered. To the best of our knowledge, flexi-
ble synthetic methodologies for compounds with the same substi-
tution pattern have not been previously reported.19,20 The enynes
and dienes built by the methodology advanced herein are potential
precursors of natural products or other bioactive substances.
Acknowledgment
FAPERJ, CNPq, CAPES for funding and/or fellowships; CNRMN-
IBM/UFRJ and Central Analítica-NPPN for analytical data.
References and notes
1. Palladium in Organic Synthesis; Tsuji, J., Ed.; Springer: Berlin/Heidelberg, 2005.
2. (a) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Gärtner, P.; Yang, Z. J. Am. Chem. Soc.
1997, 119, 5467. and cited refs; (b) Fugami, K.; Oshima, K.; Utimoto, K. Chem.
Lett. 1987, 2203; (c) See Ref. 6d for an updated review.
3. (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001, 66, 2459; (b)
Occhiato, E. G.; Trabocchi, A.; Guarna, A. Org. Lett. 2000, 2, 1241; (c) Luker, T.;
Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1996, 37, 8257; (d) Bernabé, P.;
Rutjes, F. P. J. T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1996, 37,
3561; (e) Okita, T.; Isobe, M. Tetrahedron 1995, 51, 3737; (f) Foti, C. J.; Comins,
D. L. J. Org. Chem. 1995, 60, 2656.
4. (a) Nicolaou, K. C.; Shi, G.; Namoto, K.; Bernal, F. Chem. Commun. 1998, 1757;
(b) Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J. J. Am. Chem.

6980
A. B. C. Simas et al. / Tetrahedron Letters 50 (2009) 6977–6980
0.258 mmol) in deoxygenated NMP (1.5 mL) was added followed by
Soc. 1999, 121, 593; (c) Coudert, G.; Buon, C.; Chacun-Lefevre, L.; Rabot, R.;
a
Bouyssou, P. Tetrahedron 2000, 56, 605.
solution of stannane 16a (0.201 g, 0.515 mmol) in NMP (1.5 mL) and DIPEA
5. Occhiato, E. G. Mini-Rev. Org. Chem. 2004, 1, 149.
(0.067 g, 0.515 mmol). The reaction proceeded overnight under these
6. (a) Cottineau, B.; Gillaizeau, I.; Farard, J.; Auclair, M.; Coudert, G. Synlett 2007, 12,
1925; (b) Fuwa, H.; Sasaki, M. Chem. Commun. 2007, 2876; (c) Fuwa, H.; Sasaki, M.
Org. Lett. 2007, 9, 3347; (d) Fuwa, H.; Sasaki, M. J. Org. Chem. 2009, 74, 212.
conditions. A 4:6 EtOAc/hexane mixture was added and the resulting
mixture was washed with H2O, dried with Na2SO4, and evaporated under
reduced pressure. The residue was purified by flash chromatography
(neutralized silica gel, 2% TEA) to afford enyne 4a (0.065 g, 65%).1H NMR
(400 MHz, CDCl3) d 7.29–7.24 (m, 5H), 6.88 (s, 2H), 6.86 (s, 2H), 5.54 (s, 1H)
5.50 (s, 1H), 5.21 (s, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3) d 158.5 (C),
154.3 (C), 136.3 (C), 134.1 (C), 131.7 (C), 129.5 (CH), 128.7 (CH), 128.5 (CH),
128.3 (CH), 127.8 (CH), 122.4 (C), 119.9 (CH), 118.7 (CH2), 115.5 (CH), 114.2
(CH), 89.6 (C), 86.4 (C), 67.7 (CH2), 55.5 (CH3). MS (ESI): m/z 384.2 (M+H+),
406.3 ((M+Na+). Calcd (%) for C25H21NO3: C, 78.31; H, 5.52; N, 3.65. Found: C,
77.57; H, 5.84; N, 3.66. IR (film): 2930, 1701, 1246 cmÀ1. (b) Synthesis of diene
5b: A mixture of phosphate 6d (0.116 g, 0.218 mmol), stannane 17b (0.164 g,
0.437 mmol), LiCl (0.028 g, 0.656 mmol) and Pd(PPh3)4 (0.012 g, 0.011 mmol)
in dry THF (5.0 mL) was refluxed under Ar for 2 h. Finally, the reaction mixture
was evaporated under reduced pressure and the residue was purified by flash
chromatography (neutralized silica gel, 2% TEA) to afford diene 5b (0.051 g,
64%). 1H NMR (400 MHz, CDCl3) d 7.38–7.29 (m, 5H), 7.24 (d, J = 8.80, 2H), 6.82
(d, J = 8.90, 2H), 6.13 (s, 1H), 5.79 (m, 1H) 5.22 (s, 1H), 5.18 (s, 2H), 5.06 (s, 1H),
3.77 (s, 3H), 3.39 (t, J = 6.72, 2H), 3.28 (s, 3H), 2.33 (q, J = 6.72, 2H). 13C NMR
(100 MHz, CDCl3) d 156.9 (C), 154.2 (C), 145.7 (C), 136.0 (C), 134.6 (C), 128.9
(CH), 128.5 (CH), 127.9 (CH), 127.44 (CH), 127.37 (CH), 125.9 (CH), 114.6 (CH2),
113.4 (CH), 71.3 (CH2), 66.9 (CH2), 58.1 (CH3), 54.9 (CH3), 32.1 (CH2). MS(ESI):
m/z 368.2 (M+H+), 390.1 (M+Na+). Calcd (%) for C22H25NO4: C, 71.91; H, 6.86; N,
3.81. Found: C, 71.73; H, 6.84; N, 3.86. (c) Synthesis of diene 5c: phosphate 6d
(0.1029 g, 0.194 mmol) in dry THF (2.0 mL) was added to a stirred solution of
PdCl2(PPh3)2 (0.0135 g, 0.019 mmol) in dry THF (0.5 mL). After 15 min, a 0.6 M
solution of boronate 18 (0.77 mL, 0.290 mmol), aq 2 M Na2CO3 (0.29 mL,
0.581 mmol) and three drops of EtOH were added and the resulting mixture
was heated at 65 °C for 2.5 h. After the usual aqueous work-up, the obtained
residue was purified by flash chromatography (neutralized silica gel, 2% TEA)
to afford diene 5c (0.049 g, 66%). 1H NMR (400 MHz, CDCl3) d 7.21–6.71 (m,
9H), 5.71 (m, 1H), 5.28 (s, 1H), 5.26 (s, 1H), 4,94 (s, 1H), 3.69 (s, 3H), 2.09 (t,
J = 2.10, 2H), 1.15 (m, 6H), 0.77 (s, 3H). 13C NMR (100 MHz, CDCl3) d 158.5 (C),
154.3 (C), 136.3 (C), 134.1 (C), 131.7 (C), 129.5 (CH), 128.7 (CH), 128.5 (CH),
128.3 (CH), 127.8 (CH), 122.4 (C), 119.9 (CH), 118.7 (CH2), 115.5 (CH), 114.2
(CH), 89.6 (C), 86.4 (C), 67.7 (CH2), 55.5 (CH3). MS (ESI): m/z 384.2 (M+H+),
´
7. de Sales, D. L. Master Degrees Dissertation; Universidade Federal do Rio de
Janeiro: Brazil, 2006.
8. The following works dealt with the stability problem in cyclic ketene aminal
phosphates and triflates. Our experience has shown that the acyclic
counterparts may be as labile as the ones derived from five-membered
lactams (Ref. 8a): (a) Lepifre, F.; Clavier, S.; Bouyssou, P.; Coudert, G.
Tetrahedron 2001, 57, 6969; (b) See Ref. 3c
9. (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (b) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457.
10. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
11. Negishi, E.; Anastásia, L. Org. Lett. 2001, 3, 3111.
12. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; Kosugi, M.; Fugami, K. J.
Organomet. Chem. 2002, 653, 50.
13. Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1; Farina, V.;
Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem. 1993, 58, 5434; Farina, V.;
Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585; Simas, A. B. C.; de Sales, D. L.;
Cavalcante, S. F. A.; de Medeiros, C. M.; Moraes, S. H. S.; de Carvalho, E. M. Lett.
Org. Chem. 2008, 5, 587.
14. Stannane 17b was prepared by hydrostannylation of 3-butyn-1-ol under the
conditions advanced by Chong‘s group, followed by O-methylation: Darwish,
A.; Lang, A.; Kim, T.; Chong, J. M. Org. Lett. 2008, 10, 861.
15. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
16. Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985, 107,
972.
17. Synthesis of ketene aminal phosphate 6d: A solution of BuLi 1.3 M in hexanes
(1.54 mL) was added to i-Pr2NH (0.31 mL, 2.24 mmol) in dry THF (1.5 mL)
under Ar at 0 °C. After 20 min, amide 13 (0.384 g, 1.60 mmol) in dry THF
(1.5 mL) was added at À78 °C and the mixture was stirred for 1 h under the
same conditions. Then, a solution of (PhO)2POCl (0.41 mL, 2.00 mmol) in THF
(1.5 mL) was added dropwise and stirring proceeded for 1 h. Then, 5% aq
NH4OH was added and after regular work-up, the obtained residue was
purified by flash chromatography (neutralized silica gel, 2% TEA) to afford
phosphate 6d (0.383 g, 87%).1H NMR (400 MHz, CDCl3) d 7.35–7.06 (m, 9H),
6.80 (d, J = 12.1 Hz, 2H), 5.26 (s, 1H), 5.15 (s, 2H), 4.89 (dd, J = 3.0 Hz, J = 2.0 Hz,
1H), 3.79–3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) d 158.6 (C), 153.9 (C), 150.3
(C), 146.1 (C), 135.8 (C), 132.2 (C), 129.8 (CH), 127.9 (CH), 125.6 (CH), 120.1
(CH), 114.3 (CH), 97.7 (CH2), 68.1 (CH2), 55.4 (CH3). MS (ESI): m/z 532.2
(M+H+), 554.2 ((M+Na+).
406.3 (M+Na+). IR (film): 2930, 1701, 1246 cmÀ1
.
19. Enynes and dienes displaying similar functional features, for the most part,
have been incidentally generated: (a) Meffre, P.; Gauzy, L.; Branquet, E.;
Durand, P.; Le Goffic, F. Tetrahedron 1996, 52, 11215; (b) Reginato, G.; Mordini,
A.; Caracciolo, M. J. Org. Chem. 1997, 62, 6187.
18. (a) Synthesis of enyne 4a (Stille coupling): A mixture of Pd2dba3ÁCHCl3 (0.013 g,
0.013 mmol) and AsPh3 (0.032 g, 0.103 mmol) in deoxygenated NMP (0.5 mL)
was stirred for 10 min under Ar at rt. Then, phosphate 6d (0.137 g,
20. For a designed methodology towards similar enyne via a double elimination:
Saito, S.; Uchiyama, N.; Gevorgyan, V.; Yamamoto, Y. J. Org. Chem. 2001, 65,
4338.