Tetrahidropiranos

Current Organic Chemistry, 2007, 11, 925-957 925
The Prins Reaction: Advances and Applications

Isidro M. Pastor and Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain
Abstract: The acid-catalyzed alkene-aldehyde condensation, known as the Prins reaction, is reviewed. Lewis acids, or-
ganic acids and supported catalysts have been reported to assist both the Prins acyclic reaction and the Prins cyclization.
Acetals and oxocarbenium ions (generated from aldehydes and alcohols) have been described as reacting systems in the
Prins reaction. Prins cyclizations have been used to form mainly five- and six-membered rings, albeit formation of seven
to nine rings have been described. The Prins reaction (and cyclization) has been developed as a key strategic element in
the total synthesis of different natural products.
1. INTRODUCTION R2 R2
R4 R4
The Prins reaction is an important carbon-carbon bond R3 R3
R1 or R1
forming reaction consisting in the acid-catalyzed condensa-
tion of aldehydes with alkenes. The outcome of the reaction OH OH
depends on the substrate structure and the reaction condi- 2a 2b
tions, resulting in a variety of products, such as 1,3-diols,
1,3-dioxanes or unsaturated alcohols [1]. The carbenium ion
R2 R2
1, generated by addition of the olefin to the activated car- R1 R2 R4 R4
bonyl compound, can be initially considered as the interme- + R3 Nu R3
R1 R1
diate for this stepwise reaction, which can eliminate a proton H
giving an unsaturated alcohol 2 or can add water producing OH Y OH
O 1
the corresponding diol 3 (Y = OH). Moreover, other nucleo- 3
philic species (such as, acetate or chloride) present in the R3 R4 R3R4CO
reaction medium can react with the cationic intermediate.
Neighboring-group stabilization assistance has been pro- R2
posed in some cases to explain the anti stereoselectivity, but R4
this is not a general behavior and the outcoming stereochem- R3
R1
istry also depends on the reactants and reaction conditions.
O O
Alternatively, the reaction of the intermediate 1 with an ex-
cess of the carbonylic reagent produces the dioxane 4 R4 R3
(Scheme 1). 4
The carbonyl-ene reaction is closely related to the Prins [Nu = H2O, Cl-, AcOH, ...]
reaction, producing an unsaturated alcohol. When the reac- Scheme 1.
tion is performed thermally, a concerted mechanism is in-
volved and the corresponding homoallylic alcohol 2b is R1 R1
formed in a single step (Scheme 2) [2]. However, when us- OH
H
ing a Lewis acid to activate the carbonyl compound, the re- O
action does not proceed through either a concerted mecha- R3
nism (pericyclic reaction) or a simple stepwise mechanism R4 R4
R3 R2
(with a cation intermediate like in a formal Prins reaction), R2
but rather through a more complex stepwise mechanism [3]. 2b
Albeit the use of this carbon-carbon bond forming reac- Scheme 2.
tion in organic synthesis has been restricted in some cases
due to the operating conditions required and the fact that it 2. CLASSICAL PRINS REACTION
often yields a complex mixture of products, it is one of the 2.1. Catalysis by a Lewis or An Organic Acid
most effective reactions for the synthesis of tetrahydropyran
The Prins-type reaction of different aldehydes and termi-
and dioxane moieties. Since the last review on this topic [4]
nal olefins in the presence of alkoxytrimethylsilane and un-
there are important advances and applications in the Prins
der mild conditions, using a catalytic system consisting in a
reaction that are worthy to be taken into account, so we will
mixture of trimethylsilyl chloride, tin(II) chloride and lith-
consider herein the literature from 1977 to 2005. ium perchlorate to give homoallylic alcohol derivatives 5-9
was described (Scheme 3) [5] any other side product not
*Address correspondence to this author at the Departamento de Química being reported using this protocol. The same catalytic system
Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 (SnCl2-TMSCl-LiClO4) allowed the use of the corresponding
Alicante, Spain; Tel: (+34) 965 903548; Fax: (+34) 965903549; E-mail:
yus@ua.es aldehyde dimethylacetals and olefins to obtain the same
1385-2728/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

926 Current Organic Chemistry, 2007, Vol. 11, No. 10 Pastor and Yus
O R3 OR4 R2
SnCl2 TMSCl (10 mol%)
+ R3
R1 H R4OTMS, LiClO4 R1
R2
OR' 5-9
R
5 (71%): R = Ph; R' = Me
6 (58%): R = Ph(CH2)2; R' = Me
OR'
7 (72%): R = Ph; R' = Me

8 (77%): R = Ph; R' = Bn
9 (60%): R = Ph(CH2)2; R' = Bn
Scheme 3.
products, in this case alkoxytrimethylsilane being not neces- one formed (75/25 trans/cis-25 diastereomeric ratio) what
sary for the reaction to proceed. The authors suggested [6] can be explained by the preferred carbenium ion transition
the formation of an intermediate type 10 which then reacts state 26, where the aromatic group adopts a pseudoequatorial
with the alkene. position (Scheme 5).
(CH2O)n, 13 (10 mol%) O O

O O Ar
dioxane, 70-110 °C, 8-24 h Ar
14-24
[SnCl3]- R1 [SnCl3]- R1
O O
O O
10
R
Bach and Löbel tested different boron catalysts (11-13) R

[7] in the Prins reaction of several styrenes with formalde-
hyde to form exclusively the corresponding 1,3-dioxane de- 14 (95%): R = H 20 (55%): R = Cl
rivatives 14-24. While diaryloxyboron fluoride 11 and 15 (97%): R = Me 21 (35%): R = NHAc
dialkoxyboron fluoride 12 turned out to be not sufficiently 16 (88%): R = Cl
active, the aryloxyboron difluoride 13 showed to be effective 17 (65%): R = OMe
Cl O O
as catalyst in the Prins reaction of styrenes. Performing the
18 (99%): R = OAc
reaction with paraformaldehyde in 1,4-dioxane with a 10
19 (56%): R = NHAc
mol% catalyst loading, the products 14-24 were obtained
with moderate to good yields (Scheme 4). In general, sty-
renes with electron-donating substituents showed to be more 22 (81%)
reactive and allowed to carry out the reaction at lower tem- O O O O
peratures than when using styrenes with electron-
withdrawing groups. Since experiments conducted either
with a cis/trans-mixture of 1-phenyl-1-propene or with the S
S
pure trans-isomer identical yields and stereoselectivities
were obtained, the diastereomeric ratio was not dependent on 23 (80%) 24 (67%)
the configuration of the styrene derivative. In both cases the Scheme 4.
corresponding trans-1,3-dioxane (trans-25) was the major
Bismuth(III) triflate was also found to be an efficient
catalyst for the Prins reaction of styrenes to form 1,3-
But dioxanes [8]. Compounds 14-18, 25 and 27 were obtained in
But
good yields by reaction of alkenes with paraformaldehyde
But
But
using 5 mol% of the bismuth salt in refluxing acetonitrile as
O O O
BF the optimum conditions (Scheme 6). Using other solvents
BF BF2
But (such as chloroform or toluene) or a lower catalyst loading
2
But But (ca. 1 mol%) slowed down the reaction and no products were
2
11 12 13 obtained in the absence of catalyst.

The Prins Reaction: Advances and Applications Current Organic Chemistry, 2007, Vol. 11, No. 10 927
O O O O
(CH2O)n, 13 (10 mol%)
Ph Ph + Ph
dioxane
(88%; dr = 75/25) trans-25 cis-25
H
ArOF2B O O
Me
Ph
H
26
Scheme 5. O O
R2
R3 (CH2O)n, Bi(OTf)3 (5 mol%)
R2
acetonitrile, reflux, 4-10 h R3
R 1 R1
14-18, 25, 27
O O O O O O
14 (90%): R = H 25 (85%) 27 (89%)

15 (88%): R = Me
16 (82%): R = Cl
17 (87%): R = OMe
18 (77%): R = OAc
Scheme 6.
A comparative study of the conventional heating and mi- O O

R2
crowave irradiation in the Prins reaction catalyzed by TaCl5– TaCl5 - SiO2 (10 mol%), (CH2O)n
R3 R1
SiO2 was reported by Chandrasekhar [9]. The experiments R1 R2
[dioxane, reflux or μw] R3
showed that the conventional heating (dioxane reflux) re-
14-16, 25, 27-31
quired longer reaction times than microwave irradiation go-
ing from 10-13 hours to 3-5 min and with similar or better O O O O
yields. Different styrenes were condensed with paraformal-
dehyde under these conditions to produce the corresponding
1,3-dioxane derivatives 14-16, 25 and 27-30. Moreover, the
alkylic olefin methyl 10-undecenoate was subjected to this R R
14 [(80%, 12 h, reflux); 25 [(80%, 10 h, reflux);
protocol giving the expected dioxane 31 (Scheme 7).
(90%, 3 min, μw)]: R = H (86%, 3 min, μw)]: R = H
Some alkenes, mainly styrene derivatives, underwent
condensation with paraformaldehyde in the presence of a 15 [(80%, 10 h, reflux); 29 [(80%, 10 h, reflux);
catalytic amount of InBr3 (10 mol%) under mild conditions (88%, 3 min, μw)]: R = Me (90%, 3 min, μw)]: R = Me
in ionic liquids (such as 1-butyl-3-methylimidazolium hexa 16 [(78%, 12 h, reflux); O O
fluorophosphate [bmim]PF6 or tetrafluoroborate [bmim]BF4) (85%, 4 min, μw)]: R = Cl
to afford the corresponding 1,3-dioxanes 14-17, 25, 27, 30, 28 [(70%, 13 h, reflux);
32-36 in moderate to excellent yields (Scheme 8) [10]. The (80%, 5 min, μw)]: R = NO2
efficiency of the reaction was strongly influenced by the
O O
nature of the ionic liquid, so other systems such as tetrabutyl
ammonium chloride or 1-butyl-3-methylimidazolium chlo- 30 [(78%, 13 h, reflux);
ride did not produce any turnover in the reaction. The
(85%, 4 min, μw)]
authors remarked the ease of recovery and reuse of this novel
reaction medium without loss of the catalytic activity. O O
27 [(82%, 10 h, reflux);
Wells-Dawson type heteropolyacids [H6+nP2Mo18-nVnO62 OMe
(88%, 3 min, μw)]
(n = 1,2,4)] were tested as catalysts for the Prins reaction 7
between alkenes and paraformaldehyde [11]. Different reac- O
tion parameters were optimized, the best reaction conditions 31 [(70%, 13 h, reflux);
resulting as follows: 1,2-dichloroethane as solvent, room (78%, 4 min, μw)]
Scheme 7.
O O O SiMe3
R2
InBr3 (10 mol%), (CH2O)n O
R3 R1
R1 [bmim]PF6, 25 °C, 3-10 h R2 SnCl4
R3
14-17, 25, 27, 30, 32-36 O
O O O O O
SiMe3
(R)-37
R2
R2 R1 R3
R' (R)-37, CH2Cl2
R R R1 R3
14 (91%): R = H 25 (89%, 1:9 cis/trans): R = H; R' = Me -97 °C, 5 or 12 h SiMe3
O
15 (91%): R = Me 30 (90%, 1:9 cis/trans): R = H; R' = Ph 38-41
16 (85%): R = Cl 32 (85%, 1:9 cis/trans): R = OMe; R' = Me
17 (85%): R = OMe
O O O O R
O
O SiMe3 SiMe3
O O
38 (74%, 81% ee): R = Me 40 (75%,77% ee)
39 (80%, 84% ee): R = Ph
27 (87%) 33 (88%) 34 (85%)
O O
R
Cl
n SiMe3 SiMe3
O O
35 (49%, 90 ˚C): n = 4
41 (92%, 73% ee) 42 : R = Me
36 (55%; 90 ˚C): n = 6
43 : R = Ph
Scheme 8. Scheme 10.
O O ethers was described by Yamamoto and coworkers [12]. The

R2
H8P2Mo16V2O62 (1.5 mol%) tin complex (R)-37 was used as an equivalent of formalde-
R3 R1 hyde, producing the Prins reaction at low temperature and
R1 ClCH2CH2Cl, 25 °C, 30 min R2
R3 forming the corresponding products 38-41 with good yields
and enantioselectivities (Scheme 10). Products 38 and 39
14, 15, 27, 34-36
O O
were obtained together with the corresponding 3-chloroalkyl
O O
ether 42 and 43, respectively, resulting from the chlorination
of the carbocationic intermediate.
A peculiar Prins-type reaction was described by Hamana
R and Sugasawa, where BCl3 was a useful Lewis acid for the
14 (99%): R = H 27 (31%) condensation of alkenes with electron-deficient nitriles [13].
15 (97%): R = Me Usually, nitriles react as nucleophiles with alkenes in the
O presence of an acid or mercuric salt to give acid amides in a
O O O process known as the Ritter reaction [14], but in this case the
nitrile acts as the electrophilic reagent. Therefore, monosub-
stituted alkenes were reacted with trichloroacetonitrile in the
n presence of a specific Lewis acid (i.e. BCl3 or BBr3) at low
34 (96%) 35 (45%, 80 ˚C): n = 4 temperatures to give the dichloroazirine derivatives 44-48,
36 (27%; 80 ˚C): n = 6 which isomerized with the Lewis acid, at room temperature,
Scheme 9. to the corresponding ,,-trichloroalkylnitriles 49-53
(Scheme 11). The Prins-type acylation occurred when the
temperature, 30 min reaction time and a 200:3 molar ratio of reaction was carried out with 1,1-disubstituted alkenes, giv-
olefin/H8P2Mo16V2O62. Under these conditions various sty- ing a mixture of the corresponding -chloroketones (54a-
renes and aliphatic linear olefins were converted into the 60a) and ,-unsaturated ketones (54b-60b) (Scheme 12).
corresponding 1,3-dioxane derivatives 14, 15, 27 and 34-36 Other Lewis acid, such as AlCl3, TiCl4 or BF3–OEt2, gave no
(Scheme 9). When paraformaldehyde is used, it has been reaction.
suggested that the role of the Lewis acid catalyst is not only Studying the use of trifluoromethanesulfonic acid as cata-
to catalyze the Prins reaction but also to help in the forma- lyst for the hetero Diels-Alder reaction between aldehydes
tion of monomeric formaldehyde [10,11]. and dienes, Aggarwal and coworkers observed that dienes
An enantioselective version of the Prins reaction using with a substituent in the 1-position gave exclusively the cor-
trisubstituted alkenes to give optically active homoallylic responding 1,3-dioxanes 61-62 (Prins products) in moderate
Cl
Cl Cl Cl Cl Cl
CCl3CN, BCl3 BCl3
R1
CH2Cl2, -78 °C R1 N CH2Cl2, r.t. R1 CN
44-48 49-53
44 (90%), 49 (60%): R1 = (CH2)5CH3
45 (90%), 50 (60%): R1 = (CH2)3CH3
46 (90%), 51 (60%): R1 = CH2CH(CH3)2
47 (92%), 52 (60%): R1 = C(CH3)2CH2CH3
48 (44%), 53 (60%): R1 = Bn
Scheme 11.
R2 Cl O R2 O
CCl3CN, BCl3
+
R1 R1 CCl3 R1 CCl3
CH2Cl2, -78 °C R2
54a-60a 54b-60b
54a:54b (80:20, 92%): R1,R2 = -(CH2)5-

55a:55b (86:14, 91%): R1,R2 = -(CH2)3-
56a:56b (47:53, 80%): R1 = R2 = Et
57a:57b (0:100, 95%): R1 = t-Bu, R2 = Me
58a:58b (12:88, 83%): R1 = i-Pr, R2 = Me
59a:59b (0:100, 89%): Limonene
60a:60b (0:100, 75%): Camphene
Scheme 12.
yield, which can be increased using an excess of the alde- Other transition metals such as ruthenium [16], nickel
hyde (Scheme 13) [15]. In addition, not only the Prins adduct [17], zinc [18], or tungsten [19] were reported as catalysts
was formed through the carbocationic intermediate 63, but for the reaction of dienes and activated alkenes with alde-
also the hetero Diels-Alder (D-A) product (Scheme 14). hydes. Albeit, in some cases, typical Prins reaction products
Consequently, when a non-concerted mechanism is involved, were formed, organometallic reagents are involved in these
the pyran derivatives (64-69) were formed by a triflic acid- processes, acting as nucleophiles toward the carbonyl com-
catalyzed Prins reaction of aldehydes with dienes followed pounds.
by nucleophilic attack of the oxygen to the allylic carboca- As commented before, the variety of possible products in
tion 63 (Scheme 15). the Prins reaction is one of the main drawbacks of this pro-
Ph
R O
HOTf (1 mol%) O O
+
Ph H R
toluene, r.t., 16 h Ph
(3 eq.)
61-62
61 (85%): R = H
62 (60%): R = Me
Scheme 13.
O
+
R H
R O
H H
O O R H OH O O
R R R R
63
Hetero D-A
product
R
O O
R
Prins reaction
product
Scheme 14.
O R2 R3 HOTf (1 mol%) R2
O
+
R1 H toluene, r.t., 16 h
R1 R3
64-69
O O
MeO
R
64 (72%): R = H 68 (45%)
65 (65%): R = Me O
66 (68%): R = Cl
67 (40%): R = NO2
69 (85%)
Scheme 15.
OR2 TMSOTf (1 eq.), CH2Cl2 OR2
PhMe2Si +
R1 OR2 R1
But N But
70 71-78
R' (1.1 eq.)

O
R'
O
R
R
71 (88%): R = H, R' = Me 74 (40%): R = CO2Et, R' = Et
72 (61%): R = NO2, R' = Me 75 (43%): R = C CH, R' = Et
73 (59%): R = CHO, R' = Et 76 (60%): R = CH2OMe, R' = Me
77 (79%): R = CH2Br, R' = Me
78 (68%): R = CH2Cl, R' = Me
Scheme 16.
cedure, but the methodology becomes more interesting if the ylsilane terminated Prins reaction was prepared by Brad-
evolution of the cation intermediate can be controlled, for dock’s group with the aim of improving the atom economy
instance by an adjacent group. In this approach to solve the of the mentioned methodology [23]. Thus, tetrakis[(2-
problem, Braddock presented the use of the silylmethylcy- vinylcyclopropyl)methyl]silane (90), which was synthesized
clopropane functionality to terminate the Prins reaction [20]. as a mixture of all possible diastereoisomers starting from
Thus, the reaction of 1-phenyldimethylsilylmethyl-2-vinyl tetraallylsilane, was tested in the standard procedures previ-
cyclopropane (70) with different acetals under the influence ously commented in Schemes 16 and 18, giving the diene
of TMSOTf proceeded smoothly to provide skipped dienes ether 71 in 65% yield or the alcohol 79 in 22% yield, respec-
71-78 with exclusive E-geometry regardless of the initial tively. This reagent seems to transfer three substituents when
cis/trans configuration of the starting cyclopropane (Scheme using the protocol described in Scheme 16 but only one of
16). The authors suggested a stereoelectronic control due to the vinylcyclopropane groups participates in the reaction
the stabilization of the intermediate Prins cation by the adja- with the aldehyde under the reaction conditions shown in
cent cyclopropyl ring in a conformation where the alkyl Scheme 18. The reaction occurred under the same stereoelec-
chain orientates itself anti to that ring. Then, the silicon moi- tronic control than when using the reagent 70 and products
ety directed the collapse leading to the (E)-alkene, independ- with E-configuration were obtained.
ently of the cyclopropane configuration (Scheme 17) [21].
Afterward, Braddock and coworkers showed that under the
influence of dimethylaluminium chloride, aldehydes (instead R2O
R1 OR2
of acetals) could be used in the cyclopropylmethylsilane H
terminated Prins reaction to generate the corresponding die- H
nes [22]. Thus, unsaturated alcohols 79-89 were isolated R1
H
after reaction of 1-phenyldimethylsilyl-2-vinyl cyclopropane PhMe2Si
H
(70) with 2 equivalents of an aldehyde and Me2AlCl in di-
chloromethane at low temperature (Scheme 18). A novel
tetrafunctionalized silicon reagent for the cyclopropylmeth- Scheme 17.
O OH
Me2AlCl (2 eq.)
PhMe2Si +
R1 H CH2Cl2, -78 °C R1
70 (2 eq.) 79-89
OH OH
Cl
R
79 (88%): R = H 82 (83%)
80 (90%): R = Cl
81 (80%): R = NO2 OH
R OH R
85 (80%): R = (CH2)5CH3
86 (73%): R = (CH2)8CH3
87 (84%): R = Pri
83 (38%): R = Cl 88 (53%): R = But
84 (42%): R = NO2 89 (54%): R = CO2Et
Scheme 18.
terminated Prins reaction, this reaction is also known as the

Sakurai-Hosomi reaction [24].
2.2. Solid Supported Catalysts

Delmas and coworkers showed that cation-exchange res-
Si ins in their acid forms (e.g. Amberlyst 15, C 350, Dowex
MSC 1, and IR 120) catalyzed the condensation of styrene
with formol, giving the corresponding 4-phenyl-1,3-dioxane
(14) up to 92% yield [25]. Using a mixture of benzene/water
it was possible to reduce both the presence of by-products
90
and the degradation of the resins, allowing the reuse of the
catalyst. Delmas and Gaset reported the reaction of styrene
derivatives with paraformaldehyde in dioxane catalyzed by
Although the reaction between allylsilanes and carbonyl the acidic form of the macroporous cation exchange resin
compounds in the presence of a Lewis acid to give the corre- Lewatit SP 120, yielding the corresponding 1,3-dioxanes 14,
sponding homoallylic alcohols can be considered as a silyl- 16, 25, 28, 32, 91-95 without any by-product (Scheme 19)
O O
R2 R3 (CH2O)n, Lewatit SP 120 R2
dioxane, 60 °C, 0.5-5 h R3

R1 R1
14,16,25,28,32,91-95
O O O O
R'
R R
14 (91%): R = H 25 (95%): R = H; R' = Me
16 (83%): R = Cl 32 (97%): R = OMe; R' = Me
28 (15%): R = NO2 93 (98%): R = OMe; R' = Pr
91 (94%): R = F
92 (78%): R = Br O O O O
MeO O
HO O
94 (94%) 95 (97%)
Scheme 19.
R3
R2 O O
R3CHO (2 eq.), Lewatit
R3
R2
toluene, 20-40 °C, 12-192 h
R1 R1
96-107
R R
O O O O
R R
MeO
96 (90%): R = Me 102 (88%): R = Me
97 (76%): R = Et 103 (70%): R = Et
98 (78%): R = (CH2)4CH3 104 (69%): R = (CH2)4CH3
99 (94%): R = Ph 105 (90%): R = Ph
100 (88%): R = 3-ClC6H4 106 (81%): R = 3-ClC6H4
101 (76%): R = 2-FC6H4 107 (78%): R = 2-FC6H4
Scheme 20.
[26]. The catalytic activity of the resin remained unchanged the Ce3+–montmorillonite, which could be recycled at least
after the reaction and could be reused many times without three times without losing its effectiveness. The protocol
regeneration. Generally, the cross linkage of the resins has using the Ce3+–montmorillonite allowed to obtain the di-
no significant influence in the outcome of the reaction, but oxanes 16 (79%), 25 (61%), 27 (40%) and 32 (99%, with
for the Lewatit gel resins yields decrease regularly when the 9:91 cis/trans ratio). Other aldehydes were also used under
proportion of divinylbenzene increases [27]. The same these conditions and using the Fe3+–montmorillonite, giving
methodology was extended to other aldehydes allowing the the corresponding products 108-111 (Scheme 21).
preparation of substituted 1,3-dioxanes 96-107, which are Zeolites were also active as catalysts for the Prins reac-
hardly accessible by using inorganic acids (Scheme 20) [28]. tion, the beta (75) zeolite being the most effective and selec-
R1
O O
R1CHO (2 eq.), Fe3+-mont
R1
toluene, 80 °C, 12 h
108 (87%): R1 = Me 108-111

109 (44%): R1 = Et
110 (47%): R1 = Bu
111 (27%): R1 = (CH2)4CH3
Scheme 21.
OH O O
(CH2O)n, catalyst OH
+ +
CHCl3, 60 °C, 2 h OH
112 113 114
Scheme 22.
Uemura and coworkers described the Prins reaction of tive one [30]. Thus, different styrene derivatives, such as
styrenes with paraformaldehyde or 1,3,5-trioxane in toluene styrene, trans--methylstyrene and -methylstyrene, were
at 80 ºC in the presence of cation-exchanged montmorillo- reacted with paraformaldehyde in the presence of the men-
nite [29]. Among the 21 examined Mn+–montmorillonites, tioned zeolite to produce exclusively the corresponding 1,3-
the corresponding Ce3+ and Fe3+ ones revealed to be quite dioxanes 14 (40%), 25 (50%) and 27 (32%), respectively.
effective, giving the dioxane 14 in 90% and 93% yield re- Reusable Lewis acid catalysts were prepared by anchor-
spectively. The regeneration of the catalyst was studied with ing tin chloride on quaternary ammonium chloride function-
alized silica gel and MCM-41 support [31]. Different cata- O

lysts were tested in the Prins condensation of isobutene with O
formaldehyde (Scheme 22). Complexation of the tin chloride X
with quaternary ammonium chloride improved the selectivity
X
towards the formation of 3-methyl-3-butene-1-ol (114) and
the complex immobilized on MCM-41 showed the highest
yield on the unsaturated alcohol 114 (90%). 118 119 (X = H)
The Prins reaction between styrene and trioxane in di- 120 (X = Cl)
oxane at 75 ºC was used by Alexandratos and Miller to study
the microenvironmental effect of polymer-supported sulfonic
acid catalysts, regarding to the influence of the neighboring O
group content on the catalytic efficiency [32]. OH CO2H
NH
2.3. Prins Reaction in Synthesis
In 1976, it was described the preparation of the lactone N O
116, which is an important key intermediate in the Corey’s O
synthesis of natural prostaglandins, starting from compound
115 and formaldehyde under standard Prins reaction condi-
tions (Scheme 23). In the course of the reaction the authors C5H11
HO HO OH
suggested the intermediate 117 to be involved, what made
the reaction to be very specific, noticing no other regio- or 121 122
stereoisomeric product in the reaction mixture [33]. Other
related bicyclic derivatives, such as 118-120, were subjected HO2C HO2C
to the same protocol giving the corresponding diacetates
with less positive results, both in terms of yield and selectiv- O
ity [34]. The functionalized lactone 116, obtained through
this protocol, was employed in a novel synthesis of (±)-
prostaglandin D2 (121) [35], and in the preparation of the
carbocyclic thymidine 122 [36]. A synthetic procedure start- HO HO
ing with a Prins reaction on 7,7-dichlorobicyclo[3.2.0]hept- C5H11 R
2-en-6-one (120) was developed for preparing (±)- HO HO
carbacyclines (compounds related to prostaglandins), such as
123 [37]. Other prostaglandin related compounds with simi- 123 124 [R = C5H11]
lar antiplatelet activity, for instance 5,6,7-trinor-4,8-inter-m- 125 [R = CH(CH3)CH2 C CCH3]
phenylene PGI2 (124) [38] and beraprost (125), were synthe-
sized starting with a Prins reaction: [39] treatment of the
dibromo compound 126 with paraformaldehyde and sulfuric
Br
acid in acetic acid provided a mixture of the diol 127 and its Br
mono- and diacetates, which was successively converted to
O
the pure diol by alkaline hydrolysis (Scheme 24). O 1) (CH2O)n, Br
Br H2SO4 (cat.), AcOH
O
2) NaOH (aq.)
O O
HO OH
O
(CH2O)n, H2SO4 (cat.) 126 127
AcOH, 60-80 °C Scheme 24.

AcO OAc
115 116 (85%)
phene, which was treated under Prins reaction conditions
(paraformaldehyde in acetic acid glacial) producing a mix-
OH ture of products that were converted, by saponification, into
the mixture of alcohols 131 (Scheme 25) [40]. The Prins
H reaction of camphene was also applied to the synthesis of
AcO O isosantalene (130) and related derivatives [41]. During the
study of the stereoselectivity control of electrophilic addi-
O tions to different isopropylidenenorbornene derivatives,
Paquette and Gleiter considered their hydroxymethylation
117 (Prins reaction) [42].
During the study of compounds with related structure to
Scheme 23.
the aryltetralin class of lignans, such as the antitumor agent
The synthesis of dihydro-iso-santalol (128) and tetrahy- podophyllotoxin (132), the reaction of styrene derivatives
dro-iso-santalol (129) were described starting from cam- 133 with paraformaldehyde in the presence of dimethylalu-
(136) was constructed starting from a Prins reaction. Thus

(1S)--pinene was coupled with a substituted benzaldehyde
using dimethylaluminum chloride as catalyst, forming the
corresponding alcohols 137 (Scheme 27) [44]. -Pinene was
also utilized for the synthesis of nopol (138) by a Prins con-
densation with paraformaldehyde using the heterogeneous
OH OH
catalyst MCM-41 (Scheme 28) [45].
128 129 Lewis acid-promoted Prins reactions of steroidal olefins
were performed as valuable method for the preparation of
biologically interesting steroids. Therefore, compounds 139
and 141 underwent dimethylaluminum chloride-mediated
condensation with paraformaldehyde to furnish homoallylic
alcohol derivatives 140 and 142, respectively (Scheme 29)
[46]. The same protocol of the Prins reaction was also used
130 in a key step during the synthesis of chatancin (143). Thus,
the adduct 145 was obtained by reacting compound 144 with
paraformaldehyde in the presence of dimethylaluminum
chloride at low temperature (Scheme 30) [47].
1) (CH2O)n, AcOH The cis-diacetate 146 was readily prepared using a p-
toluenesulfonic acid-catalyzed Prins reaction between cy-
2) NaOH (aq.) clopentadiene and paraformadehyde in acetic acid: the reac-
OH
131 tion was not completely stereo- and regioselective, giving
also the other three isomers [48]. Compound 146 and the
Scheme 25. corresponding deprotected diol are synthetically interesting
minum chloride (as Lewis catalyst) was considered. A cati- because can be transformed into carbocyclic nucleoside de-
onic intermediate (134) is involved, which then cyclizes to rivatives [49]. Moreover, the remaining double bodn in 146
give compounds 135 (Scheme 26) [43]. was dihydroxylated and transformed into pseudo-
ribofuranoses, which can also be used to prepare other nu-
The spiro[3,4-dihydro-2H-1-benzopyran-2,2’-bibyclo[3. cleoside derivatives.
1.1]heptane] framework of natural products robustadials
OH
O
O
O
O
MeO OMe
OMe
132
R1 R1 R1
O[Al] OH
R2 (CH2O)n, Me2AlCl R2 R2
CH2Cl2, 0 °C
R3 R5 R3 R5 R3 R5
R4 R4 R4
133 135
134
135a (95%): R1 = H, R2 = H, R3 = H, R4 = H, R5 = H
135b (88%): R1 = H, R2 = H, R3 = OMe, R4 = OMe, R5 = H
135c (62%): R1 = H, R2 = H, R3 = OMe, R4 = OMe, R5 = OMe
135d (38%): R1 = H, R2 = H, R3-R4 = OCH2O, R5 = H
135e (82%): R1 = OMe, R2 = OMe, R3 = H, R4 = H, R5 = H
135f (25%): R1-R2 = OCH2O, R3 = H, R4 = H, R5 = H
Scheme 26.
O OH
HO O
H O
136a (4β-H)
136b (4α-H)
R1 O OH R1
R2 R2
H Me2AlCl
+
R 1 OMs MsO R1
2 2
R 137 R
137a (93%): R1 2
= H, R = H
137b (60%): R1 = OMe, R2 = Br
Scheme 27.
(CH2O)n, MCM-41 OH
AcO
toluene, 90 °C OAc
138
146
Scheme 28.
The effectiveness of the catalyst (R)-37 was proved in the o-geranylphenol with the catalyst under the conditions de-
enantioselective cyclization of polyprenoids. The reaction of scribed in Scheme 10 gave the trans-fused tricyclic com-
OTBDMS OTBDMS
(CH2O)n, Me2AlCl
ClCH2CH2Cl, -10 °C
OH
MeO MeO
139 140
OTBDMS OTBDMS
(CH2O)n, Me2AlCl
ClCH2CH2Cl, -10 °C
MeO MeO OH
141 142
Scheme 29.
OH CO2Me
143
(CH2O)n, Me2AlCl
CH2Cl2, -80 to 15 °C
OPiv OH OPiv
144 145
Scheme 30.
SiMe3
HO
(R)-37 O
CH2Cl2, -97 °C O
H
147 (27%, 54% ee)
Scheme 31.
pound 147 as the major diastereomer (up to 54% ee) dioxane derivative 153 in 41% yield, as a single diastereo-
(Scheme 31) [12]. mer. However, significant amounts of by-products were
A novel, stereoselective Prins reaction of the chiral alky- formed in the course of the reaction. Changing the solvent to
lidene morpholinone derivative 152, prepared from (1R,2S)- acetic acid was beneficial for the reaction, and so compound
ephedrine and 3-methyl-2-oxobutanoic acid, was employed 152 reacted with paraformaldehyde in the presence of a cata-
in the synthesis of (S)-pantolactone (148). Aqueous formal- lytic amount of sulfuric acid to provide compound 153 in
dehyde reacted with compound 152 in dioxane at 80 ºC, un- 72% yield (Scheme 32) [50]. Other ,-dialkyl -hydroxy -
der sulfuric acid catalysis, giving the corresponding 1,3- butyrolactones (149-151), analogues of pantolactone, were
prepared employing this stereoselective Prins reaction as the
O O key step [51].
The cyclopropylmethylsilane terminated Prins reaction
O O
OH OH using the silicon-centred tetrafunctionalized reagent 90 was
also utilized in the synthesis of Lyngbic acid (154) with a
complete control of the 4E-olefin geometry [23].
148 149
O
O OMe O
O
OH O
OH OH
154
150 151
3. PRINS CYCLIZATIONS
Ph Ph
3.1. Five Membered Rings Formation
N N Some catalysts (i.e. Me2AlCl, Et2AlCl, EtAlCl2, SnCl4,
(CH2O)n
O O TiCl4) were studied in the cyclization of olefinic aldehydes
O O (such as 155) by an internal Prins and/or ene mechanism to
AcOH, 80 °C O
afford five-membered rings giving a mixture of products
O 156-158. Although tin(IV) chloride and dimethylaluminum
152 153 (72%) chloride were considered superior for the cyclization proc-
ess, titanium(IV) chloride gave mainly chlorhydrins (157)
Scheme 32. (Scheme 33) [52].
Cl
catalyst OH
n n n
OH + n OH +
CHO
m
R
m m m
155a: (n = 1, m = 1) 156a 157a 158a

155b: (n = 2, m = 0) 156b 157b 158b
Cl
catalyst n
OH
n n n
CHO + +
OH OH R
m m m m
155c: (n = 0, m = 1) 156c 157c 158c

155d: (n = 1, m = 0) 156d 157d 158d
[catalyst = Me2AlCl, Et2AlCl, EtAlCl2, SnCl4, TiCl4]
Scheme 33.
A route to substituted tetrahydrofurans was described by If the cationic intermediate structure is suitable, a pinacol
Mikami and coworkers performing a Lewis acid-promoted rearrangement can be the terminating step of a Prins cycliza-
Prins reaction between a bishomoallyl silyl ether (159) and tion. Consequently, the tandem Prins-pinacol reaction was
methyl glyoxylate, the cationic intermediate 160 being developed as a useful family of reactions for forming five-
trapped by internal attack of the silyloxy group, giving the membered rings, as depicted in Scheme 35, a new approach
corresponding products 161-165 (Scheme 34). Among the for the stereocontrolled preparation of substituted tetrahydro-
screened silyl protecting groups, the less bulky but relatively furans being reported. Thus a diastereomeric mixture of
stable dimethyl(isopropyl)silyl was found to be the best of compounds 166 (prepared by acid-catalyzed condensation of
choice. The observed selectivity in the reaction, independ- the corresponding aldehyde and a diol) was treated with tin
ently of the substituent position, could be reasonably ex- tetrachloride at low temperature to give the corresponding 3-
plained by the transition state 160 [53]. A lactonization proc- acyltetrahydrofurans 167 in good yields, bearing substituents
ess was reported to terminate the Prins reaction when a car- R1, R3 and R2CO in cis-position (Scheme 36). The authors
boxyl group was present in the structure [54]. suggested the existence of an equilibrium between the allyl-
[Si] MeO2C OH
R2 R4 R4
O R3
MeO2CCHO, SnCl4 (1 eq.)
R1 O
R1 OSiR3 R1 O R4
CH2Cl2, -78 °C
R3 R2
MeO SnCl4 R2
O R3
159
160 161-165
MeO2C OH
MeO2C MeO2C OH MeO2C
OH OH
O
O O O
Pri
R
161 (48%) 162 (67%) 163 (64%: R = Me) 165 (44%)
(91% stereoselectivity) (75/25 : cis/trans) (80/20 : cis/trans) (77/23 : cis/trans)
164 (56%: R = Pri)
(89/11 : cis/trans)
Scheme 34. Y
XR
Y XR Y XR
Prins pinacol
HO HO
O
Scheme 35.
O
R2 R2
O SnCl4 (2-4 eq.)
R3
O CH2Cl2, -78 to -23 °C R1 R3
R1 166 O
167
167a (77%): R1 = Me, R2 = Me, R3 = Me
167b (76%): R1 = Me, R2 = Me, R3 = Et
167c (81%): R1 = Me, R2 = Me, R3 = Pri
167d (92%): R1 = Me, R2 = Me, R3 = CH2CH2Ph
167e (60%): R1 = Me, R2 = Me, R3 = CH=CH2
167f (66%): R1 = Me, R2 = Me, R3 = Ph
167g (82%): R1 = Me, R2 = Bu, R3 = Me
R2
OSnCl4-
R2 R2
R1 O SnCl4 O SnCl4
R3
-Cl4SnO R3 O R1 O R3
R1
168 166 169
Scheme 36.
O
R2 R2
O SnCl4 (2-4 eq.) n
n R1
CH2Cl2, -78 to -23 °C R1
O O
H
170 171
171a (76%): n = 1, R1 = Pr, R2 = H

171b (74%): n = 1, R1 = Me, R2 = H
171c (63%): n = 1, R1 = Ph, R2 = H
171d (93%): n = 1, R1 = Me, R2 = Ph
171e (80%): n = 0, R1 = Me, R2 = Ph
Scheme 37.
R3Si R1 O O
O R2 R2
R1 R1
SnCl4 (1.1 eq.) RuO4
2 OMe O
R
CH2Cl2, -78 to -23 °C MeCN/H2O
n
n H n H
MeO OMe
173 174
172
174a (69%): n = 1, R3Si = TMS, R1 = Me, R2 = H
174b (62%): n = 1, R3Si = TMS, R1 = Me, R2 = Me
174c (58%): n = 1, R3Si = TBDMS, R1 = H, R2 = H
174d (62%): n = 2, R3Si = TMS, R1 = Me, R2 = H
174e (55%): n = 7, R3Si = TMS, R1 = Me, R2 = H
Scheme 38.
carbenium ion 168 (which would regenerate the starting car- best accomplished under the same conditions (1.1 eq. of
bonyl component and produce an enone product) and the SnCl4 in dichloromethane at -78 ºC), the annulated products
oxocarbenium ion 169 (which would give Prins cyclization), being produced as mixtures of methoxy epimers (173) that
the cyclization rate being high enough to form tetrahydro- were directly oxidized with RuO4 to the diones 174 (Scheme
furan products in good yields (Scheme 36) [55]. Similar de- 38) [59]. The reaction of compounds 172 is believed to occur
rivatives 170, obtained from the corresponding cyclic cis- by a 6-endo Prins cyclization of the oxocarbenium ion inter-
diols, underwent the same transformation to form the subse-
quent bicyclic furanones 171 (Scheme 37) [56]. In contrast, OMe OMe
isomeric cyclic trans-diols reacted directly with the aldehyde OTMS
under acid-catalysis giving the corresponding bicyclic prod- OMe TMSOTf
ucts.
CH2Cl2, 23 °C
The Prins-pinacol synthesis of acyltetrahydrofuran de-
R1 O
rivatives using isomerically pure allylic diols was also inves- R1 175
tigated by Overman’s research group. Thus, in the anti series 176-178
(acetals type 166 were prepared form anti-diols), the stereo- OMe OMe
chemical outcome of the reaction was found to depend dra-
matically on the nucleophilicity of the alkene and the size of
OMe
the allylic substituent (R2 in 166). On the other hand, in the
syn series (acetals prepared from syn-diols) a single stereoi-
somer (having a cis relationship between the acyl group and O But O But O
the C2 and C5 ring substituents) was preferentially formed
176 (82%) 177 (70%) 178 (70%)
for all the investigated substrates [57]. Additionally, 2,2-
disubstituted 1,3-dioxanes (from the condensation of allylic
OMe
diols with unsymmetrical ketones) were also subjected to the
same protocol (SnCl4 in dichloromethane at low tempera- a
b
ture) to obtain the corresponding 2,2-disubstituted 4-acyl- R1
tetrahydrofurans [58]. OTMS
Other olefinic acetal systems were studied in order to ex- 179
pand the scope of the Prins-pinacol synthesis of carbocyclic
ring products. The transformation of compounds 172 was Scheme 39.
presence of an acid catalyst. However, as commented before,

this reaction can be considered as a Sakurai-Hosomi reaction
TiCl4 (1.1 eq.)
X Cl [24].
X
CHO CH2Cl2, -78 °C OH
3.2. Six Membered Rings Formation
180 181 The benzoannelation Prins reaction was reported by an
intramolecular cationic cyclization. Thus, refluxing com-
181a (79%): X = CH2
pounds of type 182 in benzene with a substoichiometric
181b (82%): X = NTs amount of p-toluensulfonic acid gave the corresponding cy-
clization to form the expected aromatic compounds 183-188
(Scheme 42) [65].
X The allylic alcohol 190 was obtained by a Lewis acid-
O Cl promoted Prins reaction of the -unsaturated trifluorometh-
ylketone 189 (Scheme 43). Using diethylaluminum chloride,
182 the reaction was very selective and only the product 190 was
isolated. However, titanium tetrachloride afforded a mixture
Scheme 40. of 190 and 191, and also dienes 192 and 193 with longer
reaction times. Other related systems were tested under these
mediate, followed by pinacolic rearrangement. The analo-
conditions, and the corresponding homoallylic alcohols were
gous diphenylthio acetal derived from compounds 172 were
OH
O R1 OH
SiMe3
R 1 BF3-OEt2 R 1
H CbzN +
NHCbz CH2Cl2, -10 °C NHCbz
SiMe3
O R1
CAN or CTAN O
SnBu3 MeCN/CH2Cl2, 25 °C
R1
SiMe3
O R1
Ph
OH R1COR2, TMSOTf
SiMe3 R2
Ph Et2O, -78 °C
·
Scheme 41.
subjected to the Prins-pinacol reaction in the presence of

dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) R1 R1
to yield the corresponding phenylthio ether derivatives of
173 [60]. TsOH (0.3 eq.)
In addition, the tandem Prinspinacol reaction was re- CHO

benzene, reflux
ported to be useful in spiroannulations. Thus, spiro[4.5]decan-
6-ones 176-178 were prepared from the corresponding meth- R2 R3 R2 R3
ylenecyclohexane silyloxy acetals 175 by a Lewis acid pro- 182 183-188
moted cyclization (Scheme 39). Alike, olefinic diethylthio
acetal derivatives worked also in the cyclization giving the
corresponding 2-ethylthio spiro[4.5]decanone. A complete
regioselectivity of the pinacol rearrangement was detected in But
this process, and only the mentioned products were formed 183 (58%) 184 (77%) 185 (81%)
(exclusive migration of bond a in the intermediate 179) [61].
An intramolecular Prins-type cyclization of unsaturated
cyclopropylic aldehydes 180 promoted by TiCl4 under mild
reaction conditions to form cis-products 181 was accom-
plished in a general and efficient manner (Scheme 40). From
a mechanistic point of view, a chloride opened the cyclopro-
pyl moiety to terminate the cationic intermediate 182 [62]. MeO
As shown in Scheme 41, allylsilyl [63] and propargylsilyl 186 (87%) 187 (72%) 188 (84%)
[64] moieties were described to give five-membered cycliza-
tion when condensing with carbonyl or acetal groups in the Scheme 42.
O HO CF3 Stereoselective Prins cyclizations of ,-unsaturated ke-

tones (199) mediated by TiCl4 were reported by Coates, giv-
Et2AlCl (1.1 eq.)
CF3 ing the corresponding chlorohydrins 200 [71]. The results
CH2Cl2, 0 °C, 4 h indicated that the titanium tetrachloride catalyzed cycliza-
Ph Ph tions were selective towards formation of cis-chlorohydrins,
190 (68%) which were obtained in a 7:1 proportion for 200a and 13:1
189
for 200b (Scheme 45). However, the use of HCl to perform
HO CF3 CF3 CF3 this transformation gave almost exclusively the trans-isomer
(ratio cis/trans <1:99) with similar yields. Chlorohydrins
201, 202 were also prepared by this methodology.
Ph Ph Ph
R1 H
191 192 193 H
Scheme 43. TiCl4 (1 eq.)
R1
CH2Cl2, -78 °C
O2CCF3 O OH Cl
H
199 200
1 200a (62%, cis/trans: 7/1): R1 = H
R
200b (55%, cis/trans: 13/1): R1 = Me
H R2 OH
HO CF3 R1 R2
194 195
Scheme 45.
R1 = R2 = H R1 = R2 = H
R1 = CO2Et, R2 = Me R1 = Me, R2 = H Cl
R1 = H, R2 = Me
H
HO Cl HO
produced. The authors pointed out an ene mechanism for
these latter processes [66]. 201 (93%) 202 (63%)
(Trifluoromethyl)decalin derivatives (such as 194) were
prepared from the corresponding (cyclohexenyl)propyl
trifluromethyl ketones by the same methodology [67]. Re- A diastereoselective synthesis of cis and trans 3,4-
garding to other decalin derivatives (compounds of type disubstituted piperidines (204 and 205, respectively) from
195), they were achieved as a single trans fused diastereo- simple acyclic precursors 203 was reported by Snaith and
mer by treating the corresponding 5-cyclodecenone with coworkers. The trans compounds (205) were preferentially
trifluoroacetic acid [68]. Additionally, trifluroacetic acid was formed when the cyclization was catalyzed by methyl alumi-
efficiently used to catalyze a Prins cyclization [69] of enol num dichloride in refluxing chloroform. In contrast, the Prins
ethers 196 to provide a mixture of tetrahydropyrans 197 and cyclization of 203 catalyzed by hydrochloric acid at low
198 after ester ethanolysis under basic conditions (Scheme temperatures afforded selectively the cis-compunds 204
44) [70]. Using Lewis acids such as TiCl4, TiBr4, SnBr4 as (Scheme 46) [72].
catalysts, the corresponding 4-halotetrahydropyrans were Cyclopropylvinylic aldehydes of type 206 suffered the
obtained, but with lower chemical yield (ca. 65%) and selec- same cyclization described above for systems 180, but pro-
tivity. ducing the corresponding 4-chloro-1-butenylcyclohexanol
CO2Et CO2Et
O 1 O R1
R
O R1 1) TFA (10 eq.), CH2Cl2, rt
EtO2C +
2) K2CO3, EtOH
OH OH
196
197 198
197a/198a (85%, 91/9): R1 = (CH2)5CH3
197b/198b (77%, 95/5): R1 = Ph
197c/198c (58%, 50/50): R1 = CH2OBn
197d/198a (66%, 57/43): R1 = CH2OTBDPS
197e/198e (78%, 91/9): R1 = CH2CH2Bn
197f/198f (72%, 91/9): R1 = CH=CH2
197g/198g (42%, 80/20): R1 = C C TMS
Scheme 44.
Ts Ts Ts
N N N
MeAlCl2 (1 eq.), CHCl3, reflux
+
R1 or HCl (3 eq.), CH2Cl2, -78 °C R1 R1
O OH OH
R1 R1 R1
203
204 205
204a/205a (>95%, 8/92, MeAlCl2): R1 = H
(>95%, 95/5, HCl): R1 = H
204b/205b (70%, 22/78, MeAlCl2): R1 = Me
(86%, 98/2, HCl): R1 = Me
204c/205c (75%, 30/70, MeAlCl2): R1-R1 = (CH2)2
(78%, 90/10, HCl): R1-R1 = (CH2)2
204d/205d (78%, 7/93, MeAlCl2): R1-R1 = (CH2)3
(81%, 89/11, HCl): R1-R1 = (CH2)3
204e/205e (81%, 25/75, MeAlCl2): R1-R1 = (CH2)4
(74%, 80/20, HCl): R1-R1 = (CH2)4
Scheme 46.
derivatives 207 in good yields and with cis-selectivity of ,-unsaturated -hydroxy aldehydes 208 with tert-
(Scheme 47) [62]. The use of a mixture of Zn and TMSCl butyldimethylsilyl triflate (TBSOTf) and a hindered base
was reported also to catalyze this type of cyclization [73]. (such as 2,6,di-tert-butyl-4-methylpyridine: DBMP) afforded
products 209 in 84-92% yield via a double cyclization
(Scheme 48) [74]. The reaction presumably goes through the
silylated intermediate 210, which is attacked by the double
TiCl4 (1.1 eq.) X bond to produce the tertiary carbocation 211. This cation is
X CHO Cl then trapped by the alcohol group giving the second cycliza-
CH2Cl2, -78 °C OH tion process (Scheme 48).
206 207 Differently substituted tetrahydropyrans (THPs) can be
prepared in the course of a Prins type cyclization starting
207a (74%): X = CH2
from homoallylic acetals, the generated carbocation at C4
207b (76%): X = NTs being trapped by nucleophilic species. Thus, acetals 212
207c (82%): X = C(CO2Et)2 were treated with titanium tetrachloride to give the corre-
Scheme 47. sponding 4-chloro-2-substituted tetrahydropyrans 213
(Scheme 49) [75]. The reaction seemed to be very selective,
Jung and coworkers reported an intramolecular Prins thus the 2-methoxyethoxymethyl (MEM) ether derived from
double cyclization with high diastereoselectivity. Treatment (E)-3-hexenol (214) cyclized under these conditions to pro-
TBSO H
R3
R1 CHO
TBSOTf (1.5 eq.) O
R2 OH R2
R3 DBMP (2 eq.), CH2Cl2
208 209 R1
TBSO H TBSO H
R3 R3
OH OH
R2 R2
R1 R1
210 211
209a (89%): R1 = R2 = R3 = Me
209b (84%): R1 = R2 = Me, R3 = Et
209c (92%): R1 = H, R2 = Ph, R3 = Me
Scheme 48.
R2 R2 MEM-(Z)-3-hexenol derivative gave the cis isomer (95% cis,

1 92% yield). Alternatively, the 1-ethoxyethyl (EE) ether de-
R TiCl4 (1 eq.)
O O O rived from (E)-2-hexenol (216) produced one of the four
CH2Cl2, 0 °C
diastereomers (96% all-trans product 217, 85% yield) with
Cl almost complete selectivity, and the EE-(Z)-3-hexenol gave
212 213 the corresponding all-cis isomer with the same selectivity
O [76]. The same sort of products (220) were obtained, under
identical reaction conditions, condensing symmetric acetals
218 (derived from formaldehyde, acetaldehyde, acetone,
O O O O O O cyclohexanone and cyclopentenone) with homoallylic alco-
hols 219 (Scheme 50) [77]. In addition, homopropargylic
alcohols suffered cyclization in the presence of titanium tet-
212a 212b 212c rahalide to produce the corresponding 4-halo-dihydropyrans
213a (87%): R2 = H [75,77].
213b (95%): R2 = Me Rychnovsky and coworkers studied the Prins cyclization
213c (92%): R2 = (CH2)3CH2OH of 4-allyl-1,3-dioxanes 221 with TiCl4 as catalyst, which
proceeded as described above giving the corresponding 4-
Scheme 49. chlorotetrahydropyran. However the use of boron trifluoride
in the presence of acetic acid allowed to produce the related
O Et 4-acetoxy derivatives 222 with high cis selectivity between
O O O the acetoxy and R2 substituents (Scheme 51) [78]. This
methodology was used in a desymmetrization of a C2-
Cl symmetric diol (221c) [79]. Other 1,3-dioxanes with a meth-
214 215 ylene substituent 223, in the presence of triisobutylaluminum
Me at -78 ºC generated the oxocarbenium intermediates 224,
which then cyclized to the corresponding THP derivatives
Et
O O O 225 (Scheme 52) [80].
2,4,5-Trisubstituted tetrahydropyrans 227 were prepared
X by cyclization of homoallylic acetals 226 under acidic condi-
216 217 tions. The reaction was very selective giving mainly one
isomer and different nucleophilic substituents were intro-
duced in C4 by varying the reaction conditions (Scheme 53)
duce predominantly the trans isomer (92% trans, 94% yield)
of the corresponding tetrahydropyran 215, whereas the [81].
R2 R3
R2 R3 R4 R5
TiCl4 (2 eq.) O
+ R5
R1O OR1 HO CH2Cl2, 0 or 22 ˚C
Cl R4
218 219
220
220a (97%): R1 = (CH2)2OMe, R2 = R3 = R4 = R5 = H
220b (98%): R1 = (CH2)2OMe, R2 = R3 = R4 = H, R5 = Et
220c (93%): R1 = (CH2)2OMe, R2 = Me, R3 = R4 = R5 = H
220d (99%): R1 = (CH2)2OMe, R2 = Me, R3 = R4 = H, R5 = Et
220e (85%): R1 = OMe, R2 = R3 = R4 = Me, R5 = H
220f (77%): R1-R1 = (CH2)2, R2-R3 = (CH2)5, R4 = R5 = H
220g (99%): R1-R1 = (CH2)2, R2-R3 = (CH2)5, R4 = Me, R5 = H
220h (98%): R1-R1 = (CH2)2, R2-R3 = (CH2)4, R4 = R5 = H
220i (96%): R1-R1 = (CH2)2, R2-R3 = (CH2)4, R4 = Me, R5 = H
Scheme 50.
R2 R2
O O BF3·OEt2 (4 eq.), AcOH (10 eq.) OAc O

cyclohexane, 23 °C
R1 R1 OAc
221 222
222a (84%, 94% cis-R2 and OAc): R1 = Bui, R2 = Pri
222b (95%, 95% cis-R2 and OAc): R1 = (CH2)5CH3, R2 = Pri
222c (51%): R1 = allyl, R2 = (CH2)2OBn
Scheme 51.
OH The intramolecular Prins-type reaction of compounds

R3 R3 having both functionalities, a homolallyl alcohol and an
R2 O Bui3Al (2 eq.) R2 acetal moiety (228), was described using indium trichloride
as catalyst. The authors proposed that the catalyst provokes
R1 O R4 toluene, -78 °C R1 O R4 the transacetalization to form intermediates 229, which give
the oxocarbenium ions 230, the subsequent Prins cyclization
223 225
to intermediates 231 and final reaction with a nucleophile
producing products 232 (Scheme 54) [82].
Other alkenyl acetals, analogous of compound 172 with
R3 one more carbon atom underwent a tandem Prins-pinacol
rearrangement (using the reaction conditions depicted in
R2
1 O R4 Scheme 38) to form the corresponding cis-bicyclo[n+4.4.0]
R
alkanones 233 [83]. Overman’s group also studied the cycli-
O
[Al] zation of compound 234 to produce compound 235 [84].
Another strategy for the synthesis of tetrahydropyrans is
224 the acid-promoted Prins-type reaction involving the cycliza-
225a (91%): R1 = H, R2 = R3 = Me, R4 = Ph tion of an oxocarbenium ion generated in situ by reaction of
225b (81%): R1 = Me, R2 = R3 = H, R4 = But a homoallylic alcohol and an aldehyde. Scandium triflate
225c (96%): R = Me, R2 = R3 = H, R4 = (CH2)2Ph
1 catalyzed the formation of 2-substituted-4-tetrahydro-
225d (93%): R1 = Me, R2 = R3 = H, R4 = (CH2)9CH3 pyranols (236) and related ethers (237) from 3-buten-1-ol
225e (90%): R1 = Me, R2 = R3 = H, R4 = Ph
and different aldehydes, in good overall yields and with cis
diastereoselectivity (Scheme 55) [85]. Although indium tri-
225f (88%): R1 = R3 = H, R2 = Ph, R4 = Pri
flate showed the same catalytic activity for this trans-
225g (90%): R1 = R2 = H, R3 = Ph, R4 = Pri
formation, ytterbium triflate diminished considerably the
225h (92%): R1 = Ph, R2 = Bn, R3 = H, R4 = But
yield [86]. Performing the reaction with a catalytic amount
Scheme 52. of In(OTf)3 in the presence of an excess of anisole, and using
an ionic liquid as solvent, derivatives 238 and 239 were pre-
pared via what the authors called a three-component Prins-
OMEM Friedel-Crafts reaction (Scheme 56) [87]. In combination
conditions O
with trimethylsilyl halides, indium(III) triflate catalyzed the
OR1 OR1
X coupling between 1-phenyl-5-hexen-3-ol and various alde-
226 227
hydes, accomplishing stereoselectively the formation of all-
cis-4-halo-2,6-disubstituted THP derivatives 240, as a result
227a (63%): X = Cl, R1 = H, [conditions: TiCl4, CH2Cl2] of a carbocation-trapping by a halide (Scheme 57) [88,89]. A
227b (74%): X = Cl, R1 = TBDPS, [conditions: TiCl4, CH2Cl2] highly efficient synthesis of 4-iodotetrahydropyran deriva-
227c (85%): X = Br, R1 = TBDPS, [conditions: TiBr4, CH2Cl2] tives was also achieved by reaction of aldehydes with ho-
227d (72%): X = OH, R1 = H, [conditions: (1) anh. TFA, CH2Cl2, (2) K2CO3] moallyl alcohols in the presence of trimethylsilyl iodide
227e (53%): X = OAc, R1 = H, [conditions: BF3·OEt2, AcOH, TMSOAc] (generated in situ from trimethylsilyl chloride and sodium
227f (95%): X = NHAc, R1 = TBDPS, [conditions: CF3SO3H, CH3CN] iodide), although this methodology gave a mixture of di-
astereomers [90].
Scheme 53.
O
OH OMe
InCl3 X
O
OMe R1
R2 CHCl3, 23 °C
1 R2
R O
228 232
Nu O
R1 O OMe R1 O
R2 R2
R1
O R2
O O
229 230 231
232a (55%): X = OMe, R1 = H, R2 = Me
232b (54%): X = OMe, R1 = R2 = H
Scheme 54. 232c (30%): X = OMe, R1 = R2 = Me
O Regarding to other Lewis acid catalysts, niobium(V)

R1 chloride catalyzed the same coupling between aldehydes and
3-buten-1-ol, 4-chlorotetrahydropyran derivatives 241 being
n OMe afforded under these conditions (Scheme 58) [91]. The use
of iron(III) chloride as Lewis acid showed that the reaction
H proceeded satisfactorily, giving the corresponding cis-4-
233 chloro-2-substituted tetrahydropyrans 241 in good yields [i.e.
R1 = Me, n = 0, 1, 2 97% for 241a (R1 = Ph), 83% for 241e (R1 = 4-O2NC6H4),
R1 = Ph, n = 0, 1, 2 90% for 241i (R1 = cyclohexyl), 93% for 241j (R1 = Bui)].
TIPSO O Employing iron(III) bromide as catalyst, the corresponding
4-bromo derivatives were isolated with similar yields [92].
Moreover, it was demonstrated that the iron(III)-catalyzed
Prins cyclization worked with 3-hexyn-1-ol producing the
H
MeO corresponding dihydropyrans 242 (Scheme 59) [92,93].
OMe MeO
Homoallylic alcohols 243 were condensed with alde-
234 235 hydes in the presence of bismuth(III) triflate to produce
OH O
OH O
Sc(OTf)3 (5 mol%)
+ +
R1 H CHCl3, reflux
R1 O R1 O
236a/237a (77%, 18/82): R1 = Ph 236 237

1
236b/237b (84%, 15/85): R = 2-ClC6H4
236c/237c (83%, 18/82): R1 = 4-C6H4
236d/237d (76%, 14/86): R1 = 3-ClC6H4
236e/237e (69%, 17/83): R1 = 3-FC6H4
236f/237f (86%, 16/84): R1 = 3-BrC6H4
236g/237g (78%, 26/74): R1 = 2-MeC6H4
236h/237h (75%, 17/83): R1 = 3-MeC6H4
236i/237i (82%, 22/78): R1 = 4-MeC6H4
236j/237j (86%, 15/85): R1 = 4-(O2N)C6H4
236k/237k (79%, 11/89): R1 = 1-naphthyl
236l/237l (71%, 24/76): R1 = But
236m/237m (72%, 17/83): R1 = (CH2)4CH3
Scheme 55.
OMe
MeO
OH O In(OTf)3 (5 mol%), anisole
+ +
R1 H [bmim]PF6, 23 °C
R1 O R1 O
1
238a/239a (79%, 51/49): R = Ph 238 239
238b/239b (71%, 54/46): R1 = 4-FC6H4
238c/239c (70%, 54/46): R1 = 4-ClC6H4
238d/239d (79%, 73/27): R1 = 4-MeOC6H4
238e/239e (46%, 53/47): R1 = 4-MeC6H4
238f/239f (60%, 57/43): R1 = 4-(NC)C6H4
238g/239g (68%, 58/42): R1 = 4-(O2N)C6H4
238h/239h (73%, 67/33): R1 = CHEt2
238i/239i (50%, 49/51): R1 = But
Scheme 56.
OH Ph O In(OTf)3 (20 mol%) Ph

+
R1 H TMSX (1.2 eq.), CH2Cl2, 0 °C R1 O
240
240a (71%): X = Cl, R1 = Et
240b (76%): X = Br, R1 = Et
240c (82%): X = I, R1 = Et
240d (74%): X = Cl, R1 = Ph
240e (82%): X = Br, R1 = Ph
240f (82%): X = I, R1 = Ph
240g (77%): X = Cl, R1 = CH=CHCH2CH3
240h (82%): X = Br, R1 = CH=CHCH2CH3
240i (83%): X = I, R1 = CH=CHCH2CH3
240j (94%): X = Cl, R1 = (CH2)2Ph
240k (83%): X = Br, R1 = (CH2)2Ph
240l (86%): X = I, R1 = (CH2)2Ph
Scheme 57.
Cl cis-diastereoselectivity [97]. Yadav and coworkers also re-

ported the use of chloroaluminate ionic liquids as an alterna-
OH O tive Lewis acid reaction medium to perform this Prins cycli-
NbCl5 (20 mol%)
+ zation [98]. Soluble polymer-anchored homoallyl alcohols
R1 H CH2Cl2, 23 °C R1 O were cyclized with aldehydes in the presence of boron
241 trifluoride in order to prepare mixtures of 4-hydroxy- and 4-
241a (92%): R1 = Ph fluoro-2,6-disubstituted THPs after final cleavage from the
241b (95%): R1 = 2-ClC6H4 support [99].
241c (89%): R1 = 4-FC6H4
241d (93%): R1 = 4-NCC6H4 OH
241e (91%): R1 = 4-O2NC6H4
O OH Bi(OTf)3 (5 mol%)
241f (78%): R1 = Et
+
241g (82%): R1 = (CH2)2Ph R2
R1 H acetonitrile, reflux R1 O R2
241h (80%): R1 = (CH2)4CH3
243 244
Scheme 58. 244a (73%): R1 = cyclohexyl, R2 = Ph
X 244b (65%): R1 = cyclohexyl, R2 = 4-O2NC6H4
244c (78%): R1 = cyclohexyl, R2 = 4-MeOC6H4
OH O
FeX3 (1 eq.) 244d (82%): R1 = Ph, R2 = 4-ClC6H4
+
R1 H CH2Cl2, 23 °C
R1 O Scheme 60.
242a (30%): X = Cl, R1 = Ph 242
242b (75%): X = Cl, R1 = Bn Cloninger and Overman reported a tandem Prins-pinacol
242c (80%): X = Cl, R1 = cyclohexyl reaction of compound 245 to give the 2,4,6-trisubstituted
242d (90%): X = Cl, R1 = Bui THPs 246 (Scheme 61). Good yields and stereoselectivities
242e (92%): X = Br, R1 = Bn (ranging from 6:1 to 18:1, always in favor of the all-cis iso-
242f (93%): X = Br, R1 = cyclohexyl
mer) were obtained with both trifluoromethanesulfonic acid
and tin(IV) chloride as catalysts [100].
242g (98%): X = Br, R1 = Bui
Scheme 59.
An organic acid, such as trifluoroacetic acid, was also de-
scribed in the catalysis of Prins cyclizations to form THP
2,4,6-trisubstituted tetrahydropyrans 244 in good yields derivatives. Therefore, the reaction of homoallylic alcohols
(Scheme 60) [8]. Aluminum trichloride was also effective in with aldehydes under acid catalysis gave, after hydrolysis of
this reaction [94,95]. Besides, the preparation of compounds the ester functionality, 4-hydroxy-2,3,6-trisubstituted tetra-
of type 244 was described using a solid acid catalyst, such as hydropyrans with the creation of three new stereocenters.
montmorillonite KSF, under dichloromethane reflux (e.g. The utility of this approach was extended to the enantioselec-
70% yield for 244a, 86% yield for 244d) [96]. Other tested tive synthesis of THP derivatives (247) with >99% ee
solid acids, such as H-ZSM-5 zeolite and Amberlyst-15 ion- (Scheme 62) [101], and to the preparation of trans-1,3-diol
exchange resin, carried out the reaction in ionic liquids form- frameworks by combining the Prins cyclization with a reduc-
ing the corresponding THPs in high yields (82-92%) with tive ring opening of pyrans [102].
Me OH Me O
O CF3SO3H or SnCl4
Ph + Ph
R1 H MeNO2, -25 °C
OH O R1
245 246
246a (73%,TfOH): R1 = Me
(66%, SnCl4): R1 = Me
246b (61%,TfOH): R1 = Ph
(76%, SnCl4): R1 = Ph
246c (68%,TfOH): R1 = But
(76%, SnCl4): R1 = But
246d (81%,TfOH): R1 = (CH2)2Ph
(65%, SnCl4): R1 = (CH2)2Ph
Scheme 61.
MeO
OH
O 1) TFA, CH2Cl2
OH
+
OMe R1 H 2) K2CO3, MeOH
R1 O
1
247a (66%, >99% ee): R = (CH2)2Ph 247
247b (81%, >99% ee): R1 = 4-MeOC6H4
Scheme 62.
Since oxocarbenium ions are the main intermediates for the C4 position of the tetrahydropyran. The homopropargylic
the Prins cyclizations, -acetoxy ethers are useful substrates -acetoxy ether 251 yielded the corresponding dihydropyran
in order to generate this ionic species, because the acetate under the same reaction conditions but with low selectivity
group is solvolyzed regioselectively upon treatment with a (only 24% of the DHP), the major isomer being a tetrahydro-
Lewis acid, so they can react with unsaturated carbon-carbon furan derivative resulting from a 5-exo-dig cyclization [105].
bonds to produce a Prins cyclization. Rychnovsky showed Acetoxyalkoxyacetic esters (compounds of type 248 with R2
that -acetoxy ethers 248, prepared easily from the related = CO2 Me) were also cyclized under the influence of tin tet-
esters [103], are appropiate starting materials to prepare THP rachloride [106].
units via the Prins route. Treatment of compound 248 with a
Lewis acid [i.e. TiCl4 or trifluoroacetic anhydride (TFAA)]
produced an oxocarbenium ion, which subsequently cyclized R1
to give the all-cis-tetrahydropyrans 249, after trapping the R2 OAc
carbocation intermediate by a nucleophile (Scheme 63)
[104]. In addition, -acetoxy ethers type 250 with an aro- O Ph O
matic ring instead of an olefin behaved similarly and were Cl
transformed into the corresponding isochroman derivatives OAc
with excellent yields. Other catalytic systems were able to 250 251
promote the cyclization process: tin tetrabromide (dichloro-
methane at -78 ºC) or boron trifluoride (acetic acid/hexanes R1 = Me, R2 = H
at 0 ºC), introduced a bromine or a fluorine, respectively, at R1 = H, R2 = (CH2)5CH3
OAc R2 Several studies related to the Prins cyclization mecha-

nism have been reported [107-109]. The mechanism is not
R2 O TiCl4 (2 eq.) O simple and there is evidence for the participation of oxonia-
Cope rearrangements, so when the oxocarbenium ion 252 is
R1 CH2Cl2, -78 °C Cl R1 formed it can undergo either a Prins cyclization followed by
248 249 a nucleophilic capture of the carbocation (forming compound
253) or an oxonia-Cope rearrangement giving a new oxocar-
249a (80%, >99% all-cis): R1 = (CH2)5CH3, R2 = Me benium 254 which then cyclizes to form also compound 253
249b (95%, 88% all-cis): R1 = (CH2)5CH3, R2 = CH2Cl (Scheme 64) [108]. It has been demonstrated that the oxonia-
249c (65%, 40% all-cis): R1 = (CH2)2Ph, R2 = CF3 Cope rearrangement is a rapid process compared to the Prins
cyclization even at low temperatures (-78 ºC). Therefore,
Scheme 63. treatment of an enantiomerically enriched -acetoxy ether
an intimate ion pair of the oxocarbenium ion and bromide

allowing the attack to take place to the pseudoaxial position,
R1 O R2 after the cyclization [111].
252 Nu
Prins oxonia-Cope R1 R1
O a O
X R2 R2 X
b H
H
Prins 259 all-cis-THP
R1 O R2 R1 O R2
Scheme 66.
253 254
The former mechanistic feature of the Prins cyclization
has brought interesting consequences. An oxonia-Cope Prins
Scheme 64.
(OCP) process was described to prepare tetrahydropyrans
(S)-255 with a Lewis acid (i.e. SnBr4) provided a low enan- with quaternary carbon centers, synthetic targets that were
tioenriched product 258, which indicates that the first gener- normally not accessible by Prins cyclization strategies [112].
ated oxocarbenium 256 suffers rapidly an oxonia-Cope rear- As shown in Scheme 67, -acetoxy ethers 260 were treated
rangement producing the achiral intermediate 257, which with TMSOTf to generate the oxocarbenium 261, which
after cyclization gives the final racemic compound 258 should be in rapid equilibrium with the ion 262 via an oxo-
(Scheme 65) [108,109]. nia-Cope process. At that point, the silyl enol ether present in
OAc
L.A. 1) Prins
1 O 1 O R1 O
R R 2) Nu
(S)-255 (S)-256 chiral 258
oxonia-Cope
1) Prins
R1 O 2) Nu R1 O
257 racemic 258
achiral intermediate
Scheme 65.
Another interesting aspect of the Prins cyclization is its the molecule played its role, as the best nucleophile, and
selectivity to yield the corresponding all-cis tetrahydropyran. through the chair-like transition state formed the final prod-
A rationale for this result was set forth by the computational uct 263.
work of Alder and coworkers [110], who suggested that the A very interesting tandem reaction is the Mukaiyama al-
initial Prins cyclization of an oxocarbenium ion through a dol-Prins (MAP) cyclization [113]. Unsaturated enol ethers
chair-like transition state would lead to the tetrahydropyranyl 264 coupled with aldehydes in the presence of titanium bro-
cation 259. This intermediate increased its stability due to mide to yield 4-bromo tetrahydropyran derivatives 265
the delocalizaton (specifically, bonds a and b and the lone (Scheme 68). In all these experiments, compound 265 was
pair on oxygen are in alignment with the empty p orbital, obtained as a ca. 1:1 mixture of diastereomers at the alco-
creating a six-electron system in the equatorial plane of the holic stereogenic center, but the selectivity for the equatorial
ring), which gave an optimal geometry that placed the C4 bromide was >95:5. The MAP cyclization was also de-
hydrogen in a pseudoaxial geometry, thereby favoring the
scribed to be effective with ketones [114].
nucleophilic trapping from an equatorial trajectory (Scheme
66). Rychnovsky developed an axial-selective Prins cycliza- If the alkene moiety bears a silyl substitutent, after occur-
tions, where the nucleophile (bromine) attacks from the other ring the Prins cyclization the reaction can be terminated by
side as shown in Scheme 66. The reaction of a compound of elimination of the silyl group, giving an unsaturation. Ac-
type 255 with TMSBr gave a substitution of the acetate to cording to this protocol, acetal-vinylsilane systems 266 un-
form the corresponding -bromo ether, which then provided derwent Prins cyclization, using TiCl4 or SnCl4 as the Lewis
OAc OTBS OTBS

TMSOTf, 2,6-DTBMP
1
Bn R Bn R1
O CH2Cl2, -78 °C O
R2 261 R2
260
263a (92%): R1 = R2 = Me oxonia-Cope

263b (93%): R1-R2 = (CH2)5
263c (88%): R1 = Ph, R2 = Me
263d (77%): R1 = CH2OTBDPS, R2 = Me
OTBS
Bn R1
O
R2
262
O
Bn R1 R1
OTBS
R2
O Bn
O
R2
263
Scheme 67.
Br
O Ph OH
TiBr4 (2 eq.), 2,6-DTBMP
+
Ph O R1 H CH2Cl2, -78 °C O R1
264
265
265a (53%): R1 = Ph
265b (74%): R1 = But
265c (78%): R1 = Pri
265d (82%): R1 = cyclohexyl
265e (80%): R1 = (CH2)2Ph
265f (70%): R1 = (CH2)2OTBDPS
265g (75%): R1 = (CH2)2OBn
Scheme 68.
acid catalyst, the subsequent silyl elimination producing the dihydrothiapyrans 270 and the tetrahydropyridines 271 were
expected dihydropyran derivatives 267 (Scheme 69) [115]. obtained, in the latest case the selectivity being unexpectedly
trans [117]. Silyl ethers related to alcohols 268 were also
R2 employed in the condensation with aldehydes to provide
R2 OMEM
R1
R1 TiCl4 (3 eq.) or SnCl4 (5 eq.) OH
O InCl3 (1 eq.)
TMS CH2Cl2, -20 °C O R2
266 267 + CH2Cl2, 23 °C
R1 H TMS R2 O R1
267a (78%): R1 = Br, R2 = H
268 269
267b (83%): R1 = (CH2)3Ph, R2 = H
269a (39%): R1 = Ph, R2 = H
267c (71%): R1 = R2 = H
269b (88%): R1 = CH2Ph, R2 = H
267d (65%): R1 = H, R2 = Me
269c (86%): R1 = 4-O2NC6H4, R2 = H
Scheme 69.
269d (54%): R1 = 4-F3CC6H4, R2 = H
The reaction of 4-trimethylsilyl-3-buten-1-ols 268 with 269e (72%): R1 = cyclohexyl, R2 = H
aldehydes under mild Lewis acid conditions gave substituted 269f (50%): R1 = CH2Ph, R2 = Me
dihydropyrans 269 in excellent yields (Scheme 70) [116]. 269g (60%): R1 = 4-O2NC6H4, R2 = Me
Sulfur- and nitrogen-containing analogues of 268 were pre- 269h (69%): R1 = cyclohexyl, R2 = Me
pared and used in the Prins cyclization under the same react-
ing conditions depicted in Scheme 70, so the corresponding Scheme 70.
condense enecarbamate alcohols 272 with aldehydes

(R2CHO) providing the corresponding all-cis-tetrahydro-
pyran-4-ones 273 after cyclization and elimination of N-
R2 N R1
1
BOC-octylamine [119].
R2 S R R3 The 3-trimethylsilylallyltributylstannane 274 was reacted
270 271 with two molecules of aldehyde under indium chloride ca-
R1 = Bn, R2 = H R1 = R3 = Bn, R2 = H talysis giving dihydropyrans 275 (Scheme 71), the reaction
R1 = (CH2)4CH3, R2 = H R1 = (CH2)4CH3, R2 = H, R3 = Ph proceeding via an allylation-Prins cyclization tandem reac-
R1 = (CH2)2Ph, R2 = Me R1 = Bn, R2 = H, R3 = Pr tion [120].
R1 = (CH2)4CH3, R = Me 2 R1 = R3 = Bn, R2 = Me The cyclopropylic compound 276 on treatment with
R = (CH2)4CH3, R2 = Me, R3 = Bn
1 trifluoroacetic acid gave a cyclopropyl carbonyl cation which
R1 = Bn, R2 = Me, R3 = Pr underwent ring opening to give the homoallyl cation 277
R1 = (CH2)4CH3, R2 = Me, R3 = Pr
stabilized by the silyl moiety. An interaction of this cation
Boc (CH2)7CH3 with an aldehyde produced the oxocarbenium intermediate
N O
278, which upon cyclization generated tetrahydropyrans 279
(Scheme 72) [121].
Allylsilyl [122], propargylsilyl [123] and homoallenyl-
R1 OH R2 O R1 silyl [124] moieties were used to give a six-membered cycli-
zation by condensing with aldehydes or acetals in the pres-
273
272 ence of an acid catalyst (Scheme 73). However, as com-
R1 = H, Me, Ph R1 = Me, R2 = (CH2)2Ph mented before, this reaction can be considered as a Sakurai-
R1 = Me, R2 = CH=CHCH3 Hosomi reaction [24].
R1 = Ph, R2 = Et
R1 = Ph, R2 = 4-MeC4H6 3.3. Seven, Eight and Nine Membered Rings Formation
R1 = H, R2 = Ph Aluminum halides were reported to catalyze the Prins re-
action between aldehydes and trans-2-allylcyclohexanols
dihydropyrans via a cyclization-elimination process [118]. forming the corresponding oxepanes 280 (Scheme 74) [95].
This methodology was also used by Cossey and Funk to The synthesis of 2-benzoxepine derivatives via treatment of
O TMS InCl3
2 +
R1 H SnBu3 CH2Cl2, 23 °C R1 O R1
274 275
275a (68%): R1 = CH2Ph

275b (57%): R1 = (CH2)2Ph
275c (69%): R1 = cyclohexyl
275d (51%): R1 = (CH2)9Br
275e (55%): R1 = (CH2)6CH3
Ph OH
Scheme 71.
1) TFA (10 eq.), R1CHO,
HO
TBDPS CH2Cl2, -30 °C
Ph TBDPS
2) NaHCO3 (aq. sol.) R1 O
276 279
TFA
NaHCO3 (aq. sol.)
R1
[Si] O
R1CHO
Ph [Si] Ph
H
277 278
279a (78%): R1 = Ph
279b (72%): R1 = Pr
279c (61%): R1 = 4-MeOC6H4
279d (60%): R1 = 4-O2NC6H4
279e (65%): R1 = CH=CHPh
Scheme 72.
O
Ce(NO3)3·6H2O (10 mol%) OH
O
NaO3SOC12H25, H2O, 23 °C O
TMS
OH TMSOTf ·
TMS
Et2O, -78 °C
O Ph
O OH · TMSOTf
+
R1 H R2 Et2O, -78 °C R1 O R2
Scheme 73.
O
AlX3 (1 eq.)
+
R1 H OH CH2Cl2, 0 °C O
R1
280
280a (78%): X = Cl, R1 = Pr
280b (65%): X = Br, R1 = Pri
Scheme 74.
Baylis-Hillman adducts with formaldehyde in the presence The cyclic acetal 285 gave the bicyclic product 286 in
of sulfuric acid was also reported [125]. good yield through a cyclization process induced by tin tet-
Different acetals were also used as oxocarbenium inter- rachloride (Scheme 77) [129]. As described previously, an-
mediate precursors. Thus, the acetoxyalkoxyacetic ester 281 other reaction catalyzed by tin tetrachloride was the Prins-
cyclized under tin tetrachloride catalysis forming the corre- pinacol procedure, where starting from the compound 287
sponding tetrahydrooxepine 282 in moderate yield (Scheme the formation of the seven membered ring 12-oxatricyclo
75) [106]. Mixed acetals 283 had the same behavior under [6.3.1.02,7]dodecane 288 ocurred (Scheme 77) [130].
Lewis acid catalysis (either SnCl4 or EtAlCl2) and the corre-
sponding seven membered heterocycles 284 were isolated OMe
(Scheme 76) [126]. The same authors reported the cycliza-
SnCl4 (1 eq.)
tion of 5-alkenyl or 6-alkenyl acetals using tin tetrachloride O O Cl
as Lewis acid, forming the eight- [127] or nine-membered CH2Cl2, -78 °C Me
ring ethers, respectively [128]. TMS TMS
285 286 (82%)
Cl OTES CHO
H
MeO O SnCl4 (1 eq.)
O SnCl4 (2 eq.) O
CO2Me CO2Me CH2Cl2, 0 °C
CH2Cl2, -70 °C H
AcO O
287 288 (81%)
281 282 (43%)
Scheme 77.
Scheme 75.
Cl Silylated homoallenyl alcohols were reported to give
seven and eight membered cyclization in the presence of
O
TMSOTf, so a diastereoselective synthesis of oxabicycles
SnCl4 or EtAlCl2 (3 eq.) was carried out (Scheme 78) [131]. Nevertheless, as com-
R2 R1 R2
CH2Cl2, -78 °C
O mented before, this reaction can be considered as a Sakurai-
MeO R1
Hosomi reaction [24].
283 284
284a (66%): R1 = (CH2)2Ph, R2 = H 3.4. Prins Cyclization in Synthesis
284b (75%): R1 = Me, R2 = (CH2)2Ph Yohimbane derivatives (289) were synthesized using a
Prins cyclization reaction (Scheme 79). The reaction was
Scheme 76.
carried out with HCl as catalyst finding that depending on
m m
O
m
TMSOTf
n O n
HO O
Et2O, -78 °C
H
n
· ·
TMS TMS
m = 1-3, n = 1, 2
Scheme 78.
N N
H H X
N HCl N
H H H H
solvent
H H
R1 R1
O OH
X = OH, R1 = H 289
X = Cl, R1 = CO2Me
Scheme 79.
O O
O O
O OH
Me
THF/AcOH/TFA/H2O
Me Me
H H OH
AcO AcO
H H
290
Scheme 80.
the solvent, a hydroxyl group (performing the reaction in acetal derived from 2-hydroxymethyl-3-buten-1-ol in order
water) or chlorine (in acetone) was included in the product as to prepare an intermediate for the synthesis of (±)-talaro-
nucleophile [132]. mycin B [139].
The steroid derivative 290 was obtained as a mixture of An intramolecular oxidative Prins cyclization was per-
isomers by a mild acid catalyzed intramolecular Prins cycli- formed on the alcohol 300 with pyridinium chlorochromate
zation (Scheme 80) [133]. The same cyclization process was in dichloromethane producing the tricyclic ketone 301 in
used in the preparation of steroid intermediates which were 67% yield during the synthesis of (±)-isocycloseychellene
afterwards coupled to give cephalostatin 1 (291) [134]. The (302), which is related to the natural sesquiterpene seychel-
unsaturated aldehyde 292 (or its 13 isomer) underwent a lene (Scheme 82) [140]. In the synthesis of the sesquiterpene
Prins reaction on treatment with a Lewis acid (such as SnCl4 , (±)--isocomene, a Prins cyclization was also the key step,
ZnBr2 or BF3·OEt2) to give the corresponding 16-halo- so the tricyclic intermediate 304 was formed by treating the
genated homoestrone derivatives 293 chemoselectively bicyclic aldehyde 303 with titanium tetrachloride [141]. In
[135]. Bridged steroids with hormonal activity were also the course of the synthesis of a related (–)-anisatin com-
prepared by this methodology, so compound 294 was ob- pound, the tricyclic derivative 306 was prepared from the
tained by treatment of the aldehyde 295 with zinc iodide enol ether 305, which under acidic catalysis gave the corre-
[136], and the steroid 296 was achieved from compound 297 sponding aldehyde and then cyclization [142]. A similar
in the presence of titanium tetrachloride [137]. process was used to cyclize the enol ether 307 during the
Spiroketals are structural elements present in several synthesis of cis--irone (308) [143].
natural compounds and antibiotics. The pheromone compo- Molybdenum and tungsten catalysts were used in the cy-
nent of the female olive fly Dacus oleae 299 was prepared clization of citronellal and other related unsaturated alde-
from the compound 298, which was obtained from the corre- hydes. Depending on the surrounding ligands of the metal
sponding unsaturated acetal by a Prins cyclization (Scheme the cyclization of citronellal (309) gave either a mixture of
81) [138]. The same group applied this methodology to an two diastereomers of isopulegol (310) or a mixture of the
Me OH
Me O
HO
Me
O OH
Me
N
OH
H
N
Me
O
Me O O 291
Me OH OH
Me Me
13 O
H H H H 16
X
H H
MeO MeO
293
292
X = F, Cl, Br or I
HO O
OAc OAc
H H
MeO MeO
294 295
OAc OAc
Me O Me
HO
AcO AcO
Cl
296 297
OH
O
BF3·OEt2 O
O CCl3
OH
CCl3CH2OH
O O O
298 299
Scheme 81.
PCC
CH2Cl2
OH O
300 301 302

Scheme 82.
cyclic diols 311 [144]. A stereoselective preparation of l- Phorboxazoles A and B are very interesting targets in to-
isopulegol was reported by using zinc halides as catalysts tal synthesis due to their high anticancer activity, tetrahydro-
(70% yield and 94% of the expected isomer) [145]. On the pyran rings being present in their structures, so different
other hand, scandium triflate was also found to be an effi- segments of these compounds were synthesized by a Prins
cient catalyst for the cyclization of citronellal [146]. cyclization. Thus, the C20-C26 segment of phorboxazole A
Cl
OH
O O OH OH
303 304 OH
OH
OMe 309 310 311
protocol using SnBr4 [149] or InBr3 [89] as catalyst, the ra-

H H
cemic synthesis of this antibiotic being also achieved by
condensation of an aldehyde with an allylic alcohol in the
305 306
presence of trimethylsilyl iodide [90]. The enantioselective
CO2Me synthesis of the C18-C25 segment of lasonolide A was re-
ported using compound 316 as precursor of an oxonia-Cope
O
Prins reaction what allowed the introduction of a quaternary
O center in the tetrahydropyran ring [150]. The C16-C23 dihy-
dropyran fragment of spirolides B and D 317 was prepared
by a Prins cyclization of (2S,4Z)-1-(benzyloxy)-5-(trimethyl-
silyl)-4-penten-2-ol and 3-bromopropanal acetal catalyzed by
307 308 indium trichloride [151].
The reaction of the compound 318 with hexanal under
acidic conditions gave the corresponding 2,4,6-trisubstituted
312 was obtained by cyclization of the -acetoxy ether 313
with 10 mol% of boron trifluoride in the presence of acetic tetrahydropyran, which was further transformed into the
acid [147]. The same methodology was employed in the cy- natural product 319 [152]. Clavosolide A, a sponge metabo-
clization of the -acetoxy ether 314 to give a precursor for lite with a tetrahydropyran core, was synthesized from the
(S)-enol ether 320 by a trifluoroacetic acid mediated cycliza-
the synthesis of the C3-C19 segment of phorboxazole B
tion that created three new asymmetric centres in the THP
[148]. The synthesis of the tetrahydropyran ring of (–)-
ring with complete stereocontrol [153]. The racemic [154]
centrolobine (315) was achieved in optically pure form from
the corresponding -acetoxy ether by a Prins cyclization and the enantioselective [155] synthesis of the antinocicep-
OBn OAc
O
26 O OTBDPS
OBn
20
AcO
Me
Me OTBDPS
312 313
OAc OBn
N
Br
19 O O
Cl
O
O
BnO
3
TsO
314 315
O O OAc 18 Br
O 25 OTBDPS 16
OBn
O
23
316 317
HO
AcO
O
HO
OH
AcO
319 OR1
318 1
R = H, Ac
OBn R1 O O
O HO2C O
CO2Me Me
OH
320 321 322
R1 = Me, Pri, CH=CHCH3
tive cis-(6-ethyltetrahydropyran-2-yl)formic acid 321 were

accomplished using a efficient Prins cyclization strategy for Me
the construction of the THP skeleton. The preparation of OH
natural functionalized chiral -lactones 322 [(+)-prelactones]
was described involving a Prins cyclization as the key step O OMe O
[156] and this type of -lactones have been used as interme-
diate in the stereoselective synthesis of (–)-tetrahydro- O
lipstatin [157]. The enecarbamate 323 condensed with cro-
tonaldehyde in the presence of indium trichloride to furnish O
the tetrahydropyranone 324 as a single diastereomer, which
was subsequently used in the synthesis of (+)-ratjadone A
[119]. Functionalized tetrahydropyran 222c, prepared by 325
desymmetrization of compound 221c as described in Scheme
Me
51, was used in the synthesis of the antibiotic 17-deoxy-
roflamycoin [79]. TMS
CHO
O O
Boc (CH2)7CH3
N OBn TIPSO
O
326 327
HO O
OTBS O OMe
OTBS H O
323 324 N H
OMe N
OH
Leucascandrolide A (325) was isolated from the sponge n
Leucascandra cavelolata and shows potent cytotoxicity O n OR1
O
against P388 cancer cells. The aldehyde 326 and the enol
ether 327 were used as building blocks to produce most of 328a n = 0 329a n = 0, R1 = H, Me
the leucascandrolide A skeleton by a Mukaiyama aldol-Prins 328b n = 1 329b n = 1, R1 = H, Me
cyclization [113]. In the total synthesis of (+)-dactylolide a
cyclization to a tetrahydropyran ring from an allyl silane
derivative was used [158].
The norlapachol amino derivative 328a was cyclized un- cyclic and carbocyclic natural products, an interesting ac-
der formic acid catalysis to the corresponding 1-aza-anthra- count on this topic having been recently published [161].
quinones 329a, which exhibit molluscicidal activity [159].
4. CONCLUSIONS
The intramolecular Prins reaction of the corresponding lapa-
chol amino derivative 328b gave the expected azepine de- The Prins reaction is a very interesting route to form car-
rivatives 329b [160]. bon-carbon bonds. New and different acid catalysts (Lewis
acids, organic acids, solid-supported catalysts) have been
Pinacol terminated Prins cyclizations have been em-
studied in order to control the outcome of the reaction. In
ployed as key steps in the stereocontrolled synthesis of oxa-
combination with other reactions (such as pinacol rear-
rangement, Mukaiyama aldol, silyl-terminated reactions) [28] (a) El Gharbi, R.; Delmas, M.; Gaset, A. Synthesis, 1981, 361; (b)
interesting tandem reactions have been developed. The cy- El Gharbi, R.; Delmas, M.; Gaset, A. Chimia, 1981, 35, 478.
[29] Tateiwa, J.-i.; Hashimoto, K.; Yamauchi, T.; Uemura, S. Bull.
clic version of the reaction (Prins cyclization) results an at- Chem. Soc. Jpn., 1996, 69, 2361.
tractive method for the preparation of five and six membered [30] Aramendia, M. A.; Borau, V.; Jimenez, C.; Marinas, J. M.; Rome-
rings, specially furan and pyran derivatives. Finally, the ro, F. J.; Urbano, F. J. Catal. Lett., 2001, 73, 203.
Prins cyclization and the corresponding tandem reaction [31] (a) Jyothi, T. M.; Kaliya, M. L.; Herskowitz, M.; Landau, M. V.
Chem. Commun., 2001, 992; (b) Jyothi, T. M.; Kaliya, M. L.; Lan-
have become a key strategic process in the total synthesis of dau, M. V. Angew. Chem. Int. Ed., 2001, 40, 2881.
heterocyclic and carbocyclic natural products. [32] Alexandratos, S. D.; Miller, D. H. J. Macromolecules, 2000, 33,
2011.
ACKNOWLEDGMENT [33] Tomoskozi, I.; Gruber, L.; Kovacs, G.; Szekely, I.; Simonidesz, V.
Tetrahedron Lett., 1976, 4639.
The Spanish Ministerio de Ciencia y Tecnología [34] Tomoskozi, I.; Gruber, L.; Baltz-Gacs, E. Tetrahedron, 1992, 48,
(MCyT), the Generalitat Valenciana and the Universidad de 10345.
Alicante are gratefully acknowledged for continuous finan- [35] Collington, E. W.; Wallis, C. J.; Waterhouse, I. Tetrahedron Lett.,
cial support. 1983, 24, 3125.
[36] Otvos, L.; Beres, J.; Sagi, G.; Tomoskozi, I.; Gruber, L. Tetrahe-
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Current Organic Chemistry, 2007, 11, 925-957 925

The Prins Reaction: Advances and Applications

1385-2728/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

7 (72%): R = Ph; R' = Me

(CH2O)n, 13 (10 mol%) O O

Bach and Löbel tested different boron catalysts (11-13) R

11 12 13 obtained in the absence of catalyst.

14 (90%): R = H 25 (85%) 27 (89%)

A comparative study of the conventional heating and mi- O O

O O ethers was described by Yamamoto and coworkers [12]. The

54a:54b (80:20, 92%): R1,R2 = -(CH2)5-

R' (1.1 eq.)

terminated Prins reaction, this reaction is also known as the

2.2. Solid Supported Catalysts

R2 R3 (CH2O)n, Lewatit SP 120 R2

dioxane, 60 °C, 0.5-5 h R3

108 (87%): R1 = Me 108-111

alized silica gel and MCM-41 support [31]. Different cata- O

AcOH, 60-80 °C Scheme 24.

(136) was constructed starting from a Prins reaction. Thus

155a: (n = 1, m = 1) 156a 157a 158a

155c: (n = 0, m = 1) 156c 157c 158c

171a (76%): n = 1, R1 = Pr, R2 = H

presence of an acid catalyst. However, as commented before,

subjected to the Prins-pinacol reaction in the presence of

In addition, the tandem Prinspinacol reaction was re- CHO

O HO CF3 Stereoselective Prins cyclizations of ,-unsaturated ke-

R2 R2 MEM-(Z)-3-hexenol derivative gave the cis isomer (95% cis,

O O BF3·OEt2 (4 eq.), AcOH (10 eq.) OAc O

OH The intramolecular Prins-type reaction of compounds

O Regarding to other Lewis acid catalysts, niobium(V)

236a/237a (77%, 18/82): R1 = Ph 236 237

OH Ph O In(OTf)3 (20 mol%) Ph

Cl cis-diastereoselectivity [97]. Yadav and coworkers also re-

OAc R2 Several studies related to the Prins cyclization mecha-

an intimate ion pair of the oxocarbenium ion and bromide

OAc OTBS OTBS

263a (92%): R1 = R2 = Me oxonia-Cope

condense enecarbamate alcohols 272 with aldehydes

275a (68%): R1 = CH2Ph

300 301 302

protocol using SnBr4 [149] or InBr3 [89] as catalyst, the ra-

tive cis-(6-ethyltetrahydropyran-2-yl)formic acid 321 were

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