A tandem olefin migration and Prins cyclization using Cu(OTf) 2-bisphosphine complexes: An improved synthesis of functionalized tetrahydropyrans

Article abstract of DOI:10.1016/j.tetlet.2012.04.006

In situ-generated (bis-DPPMB)-Cu(OTf)₂ complex has been examined to catalyze a tandem olefin migration and Prins cyclization of an alkenol with various aldehydes. The reaction proceeded with electron-rich aromatic aldehydes at room temperature

Full text of DOI:10.1016/j.tetlet.2012.04.006

Tetrahedron Letters 53 (2012) 3699–3702
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A tandem olefin migration and Prins cyclization using Cu(OTf)2
–bisphosphine complexes: an improved synthesis of functionalized
tetrahydropyrans
⇑
Arun K. Ghosh , Daniel R. Nicponski, Jorden Kass
Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In situ-generated (bis-DPPMB)–Cu(OTf)2 complex has been examined to catalyze a tandem olefin migra-
tion and Prins cyclization of an alkenol with various aldehydes. The reaction proceeded with electron-rich
aromatic aldehydes at room temperature and provided functionalized tetrahydropyrans in good yields.
An efficient synthesis of the bis-DPPMB ligand has also been described.
Received 6 December 2011
Revised 29 March 2012
Accepted 2 April 2012
Available online 9 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phosphine ligand
Prins cyclization
Phosphine–borane adduct
Tetrahydropyrans
Prins chemistry
Functionalized tetrahydropyran derivatives are of considerable
interest because of their broad application to synthetic and medic-
inal chemistry.1,2 We recently reported that Cu(OTf)2–bisphos-
phine ligand complexes catalyzed a tandem olefin migration and
6-(3,5)-Prins-type cyclization, as shown in Scheme 1.3 This led to
the formation of substituted tetrahydropyrans (THPs) in excellent
diastereoselectivities and isolated yields. The overall process is
attractive, as the chemistry does not involve pericyclic pathways,
proceeding instead through an atypical Prins cyclization, and pre-
cludes an Oxonia-Cope process.4 As shown, we previously utilized
Z-1,2-bis(diphenylphosphino)ethylene (L1) or a 1,2-bis(diphenyl-
phosphino)benzene (L2) ligand in combination with Cu(OTf)2,
and showed that the reaction is suitable for a variety of aldehydes,
such as benzyloxyacetaldehyde 2, and various aliphatic and aro-
matic aldehydes. However, the results obtained with electron-rich
aromatic aldehydes were less satisfactory. This shortcoming has
been reported in related methodologies involving Prins-cycliza-
tions.5 In an attempt to expand the scope of our olefin migration
and Prins cyclization process, we sought to investigate a new
diphosphine ligand (L3) with an inter-phosphorus bridge contain-
made with L1 or L2 ligands. Herein, we report the results of this
investigation. We have developed an efficient synthesis of 1-
(diphenylphosphino)-2-(diphenylphosphinomethyl)benzene (bis-
DPPMB) from readily available 2-bromotoluene. The bis-DPPMB
ligand is easy to handle and can be quickly weighed out without
the use of air-sensitive techniques. The Cu(OTf)2–L3 complexes
provided an improvement of reaction yields with electron-rich aro-
matic aldehydes. Furthermore, the reaction proceeded at room
temperature and the catalytic system worked well with those
aliphatic and aromatic conjugated aldehydes examined.
The synthesis of bisphosphine ligand 6 (L3) is shown in Scheme 2.
There is no satisfactory route to bisphosphine ligand 6 (L3) in the
literature. We therefore devised an efficient route for the synthesis
Cu(OTf)2 (15 %)
L1 or L2 (15 %)
H
O
+
CH2Cl2, 40 °C
40 h
O
OBn
OH
1
2
3
OBn
PPh2
ing four bonds and possessing
r-donor ability through an electron-
neutral triarylphosphine.6 We speculated that such a bisphosphine
ligand–Cu(OTf)2 complex may exhibit more effective catalysis due
to bite angle change of L3 as compared to metal–ligand complexes
σ
-donor
4-bond tether
PPh2
PPh2
PPh2
(inter-phosphorus)
Bisphosphine ligand
PPh2
PPh2
6 (bis-DPPMB, L3)
4 (L1)
5 (L2)
⇑
Corresponding author.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
Scheme 1. Tandem olefin migration and Prins cyclization routes to functionalized
tetrahydropyrans.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.006

3700
A. K. Ghosh et al. / Tetrahedron Letters 53 (2012) 3699–3702
Table 2
Br
O
Me
O
PPh2
Reduction of bisphosphine monoxide 9 to 10
PPh2
NBS, AIBN
PhH, reflux
BH3
Ph2P
BH3
Ph2P
7
O
8a (91%)
Ph2P(BH3)H,
n-BuLi, HMPA
PPh2
PPh2
(91%)
+
Conditions
BH3
Ph2P
Br
Br
O
9
10
O
PPh2
PPh2
Entry
Conditions
Yield (%)
1
2
3
4
5
6
Cl3SiH, Et3N, xylene, heat
PMHS, Et3N, xylene, heat
Mel, LAH, DME, heat
LAH, CeCl3, THF
DlBAL-H, PCy3, CH2Cl2
AlH3ÁTHF, THF
0
0
39
34
38
96
9
8b (9%)
(96%)
AlH3, THF
BH3
Ph2P
10
6 (L3)
PPh2
10
Et2NH
(99 %)
AlH3 reduction15 proved to be the most effective, furnishing the re-
duced product 10 in 96% yield (entry 6). While the reduction of
phosphine oxides with AlH3 has been previously reported by
Wyatt et al.16 the present reduction of a phosphine oxide in the
presence of a phosphine–borane adduct is unprecedented. The
subsequent deprotection of the phosphine–borane adduct was
accomplished by treatment with neat diethylamine,17 providing
bisphosphine ligand 6 in near-quantitative yield. Interestingly, this
ligand was found to degrade at a rather slow pace upon exposure
to atmospheric oxygen (ꢀ70% oxidation after 24 h by 31P NMR
studies). This stability makes it easier to handle and quickly weigh
out without the use of air-sensitive techniques. The bisphosphine
precursor 10 was recrystallized in acetonitrile under inert
atmosphere at 0 °C for 7 days (mp 155–160 °C; decomposition).
An ORTEP diagram of the X-ray crystal structure of 10 is shown
in Figure 1.18,19 The structure clearly shows that the phosphine–
borane adduct remained fully intact on the more electron-rich
alkyldiphenylphosphine.20
We then examined the bis-DPPMB–Cu(OTf)2-catalyzed
(15 mol %) reaction of 5-methylhex-5-en-1-ol (1) with six repre-
sentative aldehydes including three electron-rich aromatic
aldehydes, an electron-poor aldehyde, a conjugated aromatic alde-
hyde, and an aliphatic aldehyde. We have compared these results
with bisphosphine ligands L1 and L2 and results are shown in
Table 3. A number of observations are noteworthy here. First of
all, the tandem olefin migration and Prins cyclization of alkenol 1
Scheme 2. Synthesis of bis-DPPMB (L3) from o-tolyldiphenyl-phosphine oxide 7.
of this bisphosphine ligand whichprovided gram quantities. Tolyldi-
phenylphosphine oxide 7 was readily prepared from commercial 2-
bromotoluene as reported by Zhou et al.7 Bromination of 7 with NBS
in the presence of a catalytic amount of AIBN in benzene at reflux
provided a mixture (10:1) of mono- and di-brominated derivatives
8a and 8b, respectively, in near quantitative yield. These products
were separated by silica gel chromatography. As shown in
Table 1, our direct alkylation8,9 of 8a with diphenylphosphine or
diphenylphosphine oxide in the presence of triethylamine resulted
in no desired product (entries 1 and 2). The corresponding
borophosphanylation with a diphenylphosphine–borane adduct
resulted in a small amount of the desired product (ꢀ5%, entry 3).
Formation of the phosphine-borane anion10 with n-BuLi in THF at
À78 °C afforded bisphosphine product 9 in 38% yield (entry 4).
However, the addition of HMPA (1:1 ratio with THF) after the forma-
tion of the phosphine-borane anion, followed by reaction with bro-
mide 8a provided 9 in 91% yield (entry 5). It is interesting to note that
the presence of HMPA during depronation with n-BuLi resulted in no
alkylation product 9. These results indicated that the addition of
HMPA likely facilitated the reaction by assisting in the breakup of
unreactive oligomers.
For the reduction of the diphosphine monoxide 9, we have
investigated a variety of conditions. As shown in Table 2, direct
reduction with silanes11,12 did not result in any desired product
(entries 1 and 2). The attempted reductions with various alumi-
num reagents provided mixed results (entries 3–5).13,14 However,
Table 1
Conditions for the borophosphanylation of 8a
Br
X
O
O
PPh2
PPh2
Conditions
9
8a
Entry
Conditions
X
Yield (%)
1
2
3
4
5
Ph2PH, Et3N, CH2Cl2
Ph2P(O)H, Et3N, CH2Cl2
Ph2P(BH3)H, Et3N, CH2Cl2
Ph2P(BH3)H, n-BuLi, THF
Ph2P(BH3)H, n-BuLi, HMPA/THF
PPh2
Ph2P@O
Ph2P–BH3
Ph2P–BH3
Ph2P–BH3
0
0
5
38
91
Figure 1. ORTEP drawing of 10. White = hydrogen, grey = carbon, pink = boron, and
orange = phosphorus. Ellipsoids are shown at the 50% probability level.

A. K. Ghosh et al. / Tetrahedron Letters 53 (2012) 3699–3702
3701
Table 3
Cu(OTf)2–bisphosphine catalyzed reactions with aldehydes
dr b
Entry
Aldehyde
Product
Conditions
Ligand
Yield (%)a
OMe
1
2
3
a
a
b
L1
L2
L3
>20:1
42
20
69
MeO
O
>20:1
>20:1
O
11
12
MeO
O
4
5
6
a
a
b
L1
L2
L3
>20:1
22
27
34
>20:1
>20:1
O
O
MeO 13
14
O
O
O
7
8
9
a
a
b
L1
L2
L3
>20:1
36
29
46
O
O
>20:1
>20:1
15
16
NO2
10
11
12
a
a
b
L1
L2
L3
80
62
63
>20:1
>20:1
11:1
O2N
O
O
17
18
c
c
b
L1
L2
L3
13
14
15
59
53
74
>20:1
>20:1
>20:1
O
O
O
Ph
19
20
16
c
c
b
L1
L2
L3
59
62
70
>20:1
>20:1
16:1
O
17
18
21
22
Reactions were carried out with 5-methylhex-5-en-1-ol (1) (1.25 equiv), aldehyde (1 equiv), Cu(OTf)2 (0.15 equiv), ligand (0.15 equiv), in
0.1 M in CH2Cl2. Conditions: (a) 40 °C, 2 h; (b) 23 °C, 18 h; (c) 40 °C, 40 h.
a
Isolated yield of 2,3-trans-THP.
b
Determined by 1H NMR analysis.
and 4-methoxybenzaldehyde 11 with Cu(OTf)2 (15 mol %) pro-
ceeded sluggishly at 40 °C for 2 h to provide tetrahydropyran 12
in about 20% yield. Secondly, the reaction does not proceed in the
presence of 4 Å MS for 48 h at 40 °C. However, the reaction did pro-
ceed once a catalytic amount of triflic acid was added. Thus, it ap-
9). We have surveyed reactions with electron poor 4-nitrobenzal-
dehyde 17 (entries 10–12). The Cu(OTf)2-L3 catalyzed reaction
showed similar results as ligand L2 however, the reaction yield
was significantly better with ligand L1. The Cu(OTf)2-L3 catalyzed
reaction with cinnamaldehyde proceeded with improved yields
and excellent diastereoselectivitity, providing tetrahydropyran 20
in 74% yield and dr >20:1 (entries 13–15). The reaction with isoval-
eraldehyde also provided improved yields and comparable diaste-
roselectivity (entries 16–18).
In summary, we have investigated the scope of Cu(OTf)2–bis-
phosphine catalyzed tandem olefin migration and Prins cyclization
with a number of aldehydes, particularly with electron-rich aro-
matic aldehydes. In this context, we prepared a stable bisphos-
phine ligand, bis-DPPMB to further improve these tandem
reactions over L1 and L2-ligands. The (bis-DPPMB)–Cu(OTf)2 com-
plex provided some improvement with electron-rich aromatic
aldehydes, conjugated aromatic, and aliphatic aldehydes and the
reactions proceeded at room temperature. This bis-DPPMB ligand
is quite stable and can also be handled without the use of air-sen-
sitive techniques. Further improvement of the catalytic system is
the subject of ongoing studies.
pears that
a protic acid is possibly required for the olefin
rearrangement step. For the Cu(OTf)2–L3 complex catalyzed reac-
tion, we found that the reaction can be carried out at 23 °C.
As can be seen, the reaction of 1 with electron rich 4-methoxy-
benzaldehyde 11 in the presence of Cu(OTf)2–L3 complex pro-
ceeded at 23 °C for 18 h to provide 12 in 69% yield with excellent
diastereoselectivity (dr >20:1, entry 3).20 The corresponding reac-
tions with ligands L1 and L2 were less satisfactory (entries 1 and
2) and were very slow at room temperature. These reactions were
carried out at 40 °C for 2 h (conditions b). Reaction of electron-rich
2-anisaldehyde 13 with Cu(OTf)2–L3 complex provided tetrahy-
dropyran 14 in 34% yield at 23 °C for 24 h. The corresponding reac-
tion with L1 and L2 ligands provided lower yields of 14 (entries 4–
6). Reaction of piperonal 15 using Cu(OTf)2–L3 complex provided
tetrahydropyran 16 in 46% yield and the corresponding reaction
using L1 or L2 ligands afforded 16 in lower yields (entries 8 and

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A. K. Ghosh et al. / Tetrahedron Letters 53 (2012) 3699–3702
water and brine, then concentrated, and purified by flash column
Acknowledgments
chromatography to give 8a (6.27 g, 91%). 1H NMR (400 MHz, CDCl3); d 7.70–
7.00 (m, 14H), 5.02 (s, 2H). 13C NMR (100 MHz, CDCl3); d 142.8–127.4 (Ph), 31.0
3
(d, J1P-C = 16.4 Hz). 31P NMR (121 MHz, CDCl3); d 33.0 (s, 1P).
Financial support by the National Institute of Health is grate-
fully acknowledged. We thank Mr. Chad Keys (Purdue University)
for preliminary experimental assistance.
Preparation of (2-diphenylphosphinoyl)phenylmethyl-diphenylphosphine-borane
adduct (9): To a solution of Ph2P(BH3)H (4.06 g, 20.3 mmol) in THF (200 mL)
was added 12.8 mL n-BuLi (1.6 M in hexanes) dropwise over 10 min at À78 °C.
HMPA (200 mL) was added after 10 min and the resulting solution was stirred
for a further 10 min. Phosphine oxide 8a (6.27 g, 16.9 mmol) was added as a
solution in THF (56 mL) via cannula. After stirring for 20 min, the solution was
warmed to 25 °C over 40 min. The reaction was quenched with aqueous
(NH4)2SO4 and the reaction mixture was washed with water and brine.
Removal of the solvent provided a residue which was purified by flash column
chromatography. Recrystallization of the product from warm diethyl ether
furnished 9 (7.53 g, 91%). 1H NMR (400 MHz, CDCl3); d 7.92–6.88 (m, 24H), 4.39
Supplementary data
Supplementary data (1H, 11B, 13C, and 31P NMR spectra for all
new compounds) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.006.
2
(d, J1PH = À12.8 Hz, 2H), 1.60–1.20 [q(br), 3H]. 11B NMR (96 MHz, CDCl3); d
À37.0 [s(br), 1B]. 13C NMR (100 MHz, CDCl3); d 139.0–126.1 (Ph), 30.8, (d,
1J1PC = 56.9 Hz). 31P NMR (121 MHz, CDCl3); d 33.9 (s, 1P), 18.3 [s(br), 1P]. LRMS
(ESI) (MÀH)+ = 489, M+ = 490, (MÀBH3+ONa)+ = 515.
References and notes
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Preparation of (2-diphenylphosphino)phenylmethyldiphenylphosphine-borane
adduct (10): Diphosphine-borane monoxide
9 (600 mg, 1.22 mmol) was
dissolved in THF (25 mL). Alane–THF adduct (ꢀ0.5 M, 1 equiv) was added
dropwise over 10 min at 0 °C. After stirring for 30 min, an additional equivalent
of alane was added, and the solution was warmed to room temperature over
1 h. Methanol was added to quench the excess alane, then the mixture was
passed through celite. The filtrate was concentrated, and the crude product
was purified by flash column chromatography to give pure 10 (560 mg, 96%) as
an amorphous solid. 1H NMR (400 MHz, CDCl3); d 7.72–6.78 (m, 24H), 4.03
4
2
[d(d), J1PH = À2.4 Hz, J2PH = À11.6 Hz, 2H], 1.59–0.95 [d(d{br}), 3H]. 11B NMR
(96 MHz, CDCl3); d À37.3 [s(br), 1B]. 13C NMR (100 MHz, CDCl3); d 137.4–127.4
(Ph), 31.2, [d(d), 3J1PC = 25.2 Hz, 1J2PC = 31.2). 31P NMR (121 MHz, CDCl3); d 19.8
[s(br), 1P], À14.6 (s, 1P). LRMS (ESI) (M+H)+ = 475, (M+Na)+ = 497,
(M+K)+ = 513.
9. Carboni, B.; Monnier, L. Tetrahedron 1999, 55, 1197–1248.
10. Gaumont, A.-C.; Bourumeau, K.; Denis, J.-M. J. Organomet. Chem. 1997, 529,
205–213.
Preparation of 1-(diphenylphosphino)-2-(diphenylphosphinomethyl)benzene (bis-
DPPMB) (L3): Diphosphine–borane adduct 10 (250 mg, 0.527 mmol) was
dissolved in 35 mL diethylamine. After stirring for 12 h, 100 ml H2O was
added, and the product was extracted with EtOAc. After concentrating, the
crude bisphosphine was purified by silica gel plug filtration to give L3 in
quantitative yield. 1H NMR (400 MHz, CDCl3); d 7.94–6.81 (m, 24H), 3.74 (s,
2H). 13C NMR (100 MHz, CDCl3); d 138.4–126.4 (Ph), 34.6. 31P NMR (121 MHz,
11. (a) Hayashi, T.; Uozumi, Y. Pure Appl. Chem. 1992, 64, 1911–1916; (b)
Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 7012–7023.
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18. Single-crystal X-ray analysis was performed in-house. Dr. Phil Fanwick, X-Ray
Crystallography Laboratory, Department of Chemistry, Purdue University,
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19. CCDC 852880 contains the supplementary crystallographic data for compound
10. These data may be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
20. All new compounds gave satisfactory spectroscopic and analytical results.
Preparation of 2-(bromomethyl)phenyl diphenylphosphine oxide (8a): O-
Tolyldiphenylphosphine oxide 7 (6.83 g, 23.4 mmol) was dissolved in 235 mL
benzene. NBS (4.24 g) and AIBN (385 mg) were added, and the solution was
refluxed for 40 h, then cooled to 25 °C. The reaction mixture was washed with
4
4
CDCl3); d À9.1 (d, 1P, J1PP = À24.0 Hz), À15.7 (d, 1P, J1PP = À24.0 Hz). HRMS
(ESI) m/z calcd for C31H26P2 461.1588, found 461.1583.
Synthesis of tetrahydropyran derivative 12: Cu(OTf)2 (43 mg, 0.12 mmol,
0.15 equiv) was added to a solution of bisphosphine L3 (55 mg, 0.12 mmol,
0.15 equiv) in CH2Cl2 (5 mL) under an argon atmosphere. This solution was
stirred for 1 h then 4-methoxybenzaldehyde 11 (136 mg, 1 mmol) and alkenol
1
(143 mg, 1.25 mmol) were added to the solution in CH2Cl2 (5 mL) via
cannula. After stirring for 18 h, the reaction mixture was diluted with CH2Cl2
and washed with aq NaHCO3 (20 mL) and brine (20 mL). The organic layer was
dried with Na2SO4 and concentrated. Crude THP was purified via column
chromatography to provide 12 (160 mg, 69%). 1H NMR (400 MHz, CDCl3); d
7.22 (d, J1 = 5.0 Hz, 2H), 6.82 (d, J1 = 5.0 Hz, 2H), 4.62 & 4.61 (s & s, 1H & 1H),
4.10 (m, 2H), 3.77 (s, 3H), 3.58 [t(d), J1 = 5.0, J2 = 2.3 Hz, 1H], 2.33 [t(d), J1 = 5.0,
J2 = 2.4 Hz, 1H], 1.92–1.71 (m, 4H), 1.43 (s, 3H). 13C NMR (100 MHz, CDCl3); d
159.0, 146.5, 133.5, 128.5, 113.4, 111.9, 84.0, 68.9, 55.2, 50.4, 30.4, 26.4, 21.5.
HRMS (EI/CI) m/z calcd for C15H20O2 232.1463, found 232.1465.