PPh3-mediated intramolecular conjugation of alkyl halides with electron-deficient olefins: Facile synthesis of chromans and relevant analogues

Article abstract of DOI:10.1039/c3cc41435c

With the mediation of phosphine, the direct intramolecular coupling of two electrophiles-alkyl halides with electron-deficient olefins-has been successfully realized in an intramolecular conjugate addition manner. The reaction provides a new approach for

Full text of DOI:10.1039/c3cc41435c

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PPh3-mediated intramolecular conjugation of alkyl
halides with electron-deficient olefins: facile synthesis
of chromans and relevant analogues†
Cite this: Chem. Commun., 2013,
49, 4570
Received 25th February 2013,
Accepted 28th March 2013
Jian-Bo Zhu, Peng Wang, Saihu Liao* and Yong Tang*
DOI: 10.1039/c3cc41435c
www.rsc.org/chemcomm
With the mediation of phosphine, the direct intramolecular coupling
of two electrophiles – alkyl halides with electron-deficient olefins –
has been successfully realized in an intramolecular conjugate addition
manner. The reaction provides a new approach for the synthesis of
chromans and relevant analogues.
A common strategy for conjugating the alkyl group of simple halides
with electron-deficient olefins is by radical cyclization or to convert alkyl
halides into the corresponding organometallic reagents such as the
Grignard reagents, organolithium or zinc compounds etc. and then
run a conjugate addition, normally in the presence of a catalytic
amount of dry cuprous salts.1–5 However, this strategy proved to be
inefficient for the intramolecular reactions of the substrates shown in
Scheme 1a.4,5 Recently, during the course of our investigation of the
ylide-initiated Michael addition cyclization reactions (YIMAC),6 we
discovered a non-metal phosphine-mediated approach to realize this
coupling by integrating a hydrolysis step7 to reduce the betaine
intermediates. In this tandem reaction, phosphine mediates a formal
reactivity umpolung of the alkyl halides, different from typical phos-
phorus ylide reactions like the Wittig reaction and small ring formation
reactions in which the phosphines are more like a ‘‘RHC:’’ carrier
(Scheme 1b).7g This new reaction allows a facile conjugation of two
Scheme 1 Reaction of electron-deficient olefins with alkyl halides.
electrophilic units in the presence of water, and is compatible with product 2a, which indicates an unusual conjugation reaction of two
ester solvents and various functionalities like halide, ketone, ester, electrophilic moieties (the benzyl halide and a,b-unsaturated car-
amide, nitrile, ether etc., in contrast to the harsh reaction conditions boxylic ester) and encouraged us to further explore this reaction in
required when handling organometallic reagents.1–3 Importantly, this detail. Initially, the reactions were performed using a one-pot protocol
reaction also provides a novel and facile approach for the syntheses of at 80 1C using isopropyl acetate as the solvent, and the base effect was
other chroman analogues such as thiochromans, tetrahydroquinolines, first examined. As shown in Table 1, the presence of base proved to be
and tetralines, which are useful synthetic intermediates and also of crucial to this reaction. Potassium tert-butoxide and organic bases like
broad biological and pharmaceutical importance.8 In this communica- DBU and DMAP all gave a messy reaction and no desired product was
tion, we wish to report the preliminary results.
observed (entries 1, 6 and 7). KOH or Na2CO3 gave promising yields,
In our investigation of a PPh3-mediated tandem reaction with but substantial amounts of compound 3a were obtained (entries 2
compound 1a, unexpectedly, we isolated a small amount of cyclization and 3), which probably resulted from the hydrolysis of the corre-
sponding phosphonium ylides of the starting halide. To our delight,
Cs2CO3 gave 2a in a much higher yield, and only a trace amount of 3a
was detected by proton NMR (entry 5). Further evaluation of different
solvents revealed that ethyl acetate is the solvent of choice, giving the
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: shliao@sioc.ac.cn, tangy@sioc.ac.cn; Fax: +86-21-54925078
desired product in 84% yield, and notably the formation of 3a was
completely suppressed (entry 13). Regarding the influence of the
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc41435c
c
4570 Chem. Commun., 2013, 49, 4570--4572
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Table 1 Reaction optimizationa
Table 2 Reaction scopea
Entry
X
R1,R2
EWG
Prod.
Yieldb (%)
1
2
3
4
5
6
7
8
4-Cl
H
4-Me
4-OMe
5-OMe
6-F
4-Br
3,4-Benzo
5,6-Benzo
H
H
4-Br
H
H
H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
Me, H
H, Me
H, H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
87
96
93
92
72
92
83
63
97
96c
79e
79
90
83
82
87
77
93
91
86
Entry
Base
Solvent
t/h
Yieldb (%) 2a/3a
c
1
2
3
4
5
6
7
8
t-BuOK
KOH
Na2CO3
K2CO3
Cs2CO3
DBU
DMAP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
DCE
CH3CN
Dioxane
t-BuOH
n-BuOAc
EtOAc
24
18
28
15
28
24
24
21
24
24
21
24
24
24
25
—
50/20
20/20
65/16
75/–
—
9
—
10
11d
12
13
14
15f
16f
17f
18
19g
20
53/13
39/–
46/51
—
71/–
84/–
51/32
87/–
9
CO2Et
10
11
12
13
14d
15e
t
CO2 Bu
CON(Me)OMe
COPh
COPh
CO(2-thienyl)
CN
CN
4-Me
H
H
H
4-Br
EtOAc
EtOAc
a
2r
2s
1a (0.3 mmol), PPh3 (0.36 mmol), base (0.9 mmol), H2O (2.5 equiv.), solvent
(4 mL). b 2a + 3a, ratios were determined by 1H NMR of the crude product.
c Trace was detected by 1H NMR. d With 10 equiv. of water. e Pre-mixing of
1a (0.3 mmol) and PPh3 (0.45 mmol) in EtOAc (4 mL) at 60 1C for 5 h, then
Cs2CO3 (0.9 mmol), water (2.5 equiv.), and EtOAc (2 mL), at 80 1C.
CN
a
Pre-mixing of 1 (0.3 mmol) and PPh3 (0.45 mmol) in EtOAc (4 mL) at
60 1C, then Cs2CO3 (0.9 mmol), H2O (2.5 equiv.), and EtOAc (2 mL), at
80 1C. b Isolated yield. c dr = 1.3/1. d With PMe3. No 2k was produced with
PPh3. e dr = 1.7/1. f 20 equiv. of H2O, 40 1C. g With the Z-isomer of 1r.
amount of water, 2.5 equivalents of water proved to be optimal.9 The
reaction without additional water is slower, while adding excess and mesylate of 1b also reacted well and furnished the desired
amounts of water led to severe hydrolysis of the phosphonium salt chroman product 2b in good yield.9
of 1a forming 3a (32%, entry 14). On the other hand, lowering the
Encouraged by these results, we moved to the extension of this
temperature to 40 1C or 60 1C decreased the yield.9 However, the reaction to the syntheses of other benzocycles like thiochromans,
isolated yield of 2a can be further increased slightly to 87% by pre- tetrahydroquinolines, tetralines, and dihydroindenes, which are
mixing the halide and phosphine for 5 h at 60 1C before the addition useful synthetic intermediates and common structures in many
of base (entry 15). It is worth mentioning that in the current reaction molecules that exhibit various biological activities.5a,8 Gratifyingly,
no Morita–Baylis–Hillman (MBH)-type alkylation product was as exemplified in Scheme 2, the approach works well with all
obtained, though both the phosphine and the a,b-unsaturated ester these substrates, delivering the desired benzocyclic products in
group were present in the reaction.10
good to high yields.9 Notably, the present reaction provides a new
Under the optimized reaction conditions, the reaction scope was C3–C4 disconnection method in the retro-synthetic analysis of
evaluated next. As shown in Table 2, functional groups such as –Cl, these benzoheterocycles.8a,11
–Br, –OMe, –F, ketone, ester, amide, and nitrile are all well tolerated in
The current reaction is potentially useful in organic synthesis. For
this reaction, giving the desired product in good to high yields. example, product 2r is a key intermediate for the synthesis of a series
Electron-donating groups on the benzene ring generally gave better of dyslipidemia-modulating agents. The patent method required
yields (entries 1–4), but the 5-methoxy substituted bromide 1e seven steps to make this compound, starting from salicylaldehyde.12
afforded a little bit of lower yield due to its instability (72%, entry 5).
Fused tricyclic benzochromans can also be synthesized using the
current reaction (entries 8 and 9). In the case of 1k, the use of PPh3
only gave the hydrolysis product 3k and no desired product 2k was
isolated, which can be attributed to the sensitivity of the PPh3 group
to the steric hindrance on the double bond. Nevertheless, less steric
and more nucleophilic phosphines like PMe3 can substantially
alleviate this steric repulsion and improve the yield (entry 11). To
our delight, apart from the carboxylic ester groups, the reaction also
works well with other electron-withdrawing groups like ketone,
amide, and nitrile (entries 14–20). Importantly, the yield is almost
independent of the configuration of the double bond in the
Scheme 2 Extension to the syntheses of chroman analogues.
substrate (entry 18 vs. 19). In addition, the corresponding chloride
c
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2 For an overview of transmetallation reactions leading to organo-
copper complexes, see: C. J. Rosenker and P. Wipf, in The Chemistry
of Organocopper Compounds, Part 2, ed. Z. Rappoport and I. Marek,
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3 An elegant methodology for the water-sensitive copper-catalyzed
conjugate additions of RM to enones in water has been recently
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N. A. Isley, J. Am. Chem. Soc., 2012, 134, 19985–19988.
4 We performed the reactions of 1b with Mg, Zn and Cu salts under
several typical conditions, but failed to obtain the desired coupling
product 2b.
5 Free radical cyclization (FRC) of 1b was also attempted with
Bu3SnH/AIBN or Et3B, but no cyclization product formed. For FRC
reactions with similar substrates, see: (a) D. Badone, J. Bernassau,
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To further demonstrate the synthetic potential of this reaction, a route
based on product 2l was designed for the synthesis of compound 8
(Scheme 3), the (S)-isomer (MS-180) of which is a potential drug
selected for clinical evaluation for the treatment and prevention of
thrombosis (glycoprotein IIb–IIIa antagonist) in patients.13 Palladium-
catalyzed coupling of 2l with amide 6, followed by treatments in
ethanol in the presence of anhydrous hydrogen chloride and later
with morpholine, gave the benzimidamide intermediate. Subsequent
precipitation in dry HCl–EtOH delivered the target product 8 in 62%
yield over three steps. It is worth mentioning that the overall yield for
8 from 4-bromosalicylaldehyde is 42%, while in comparison, the
overall yield reported in the literature is ca. 17%, starting from much
more expensive 6-nitrochroman-4-one.13
In summary, a phosphine-mediated intramolecular conjugation
of alkyl halides with electron-deficient CQC double bonds has
been successfully developed. The reaction conditions are mild and
no conversion of the alkyl halide to the organometallic reagent is
required. This direct connection of two electrophilic moieties
provides a new and facile synthetic route for the preparation of
chroman derivatives, and can also be extended to the construction
of other relevant analogues such as tetrahydroquinolines, thio-
chromans, and tetralines. Based on this reaction, a short synthetic
route to a potent glycoprotein IIb–IIIa antagonist has also been
developed. Application of the current method in natural product
synthesis and the development of an asymmetric version are
currently ongoing in our laboratory.
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We are grateful for the financial support from the Natural Science
Foundation of China (No. 20932008, 21121062, 21272248), the
9 For more details, please see the ESI†.
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