Construction of tetrahydrofurans by PdII/PdIV- catalyzed aminooxygenation of alkenes

Article abstract of DOI:10.1002/anie.200701454

(Chemical Equation Presented) Resolute in the face of elimination: Substituted 3-aminotetrahydrofurans were prepared in good yield and with modest to high diastereoselectivity by the Pd-catalyzed reaction shown in the scheme (Phth = phthaloyl). Mechanisti

Full text of DOI:10.1002/anie.200701454

Angewandte
Chemie
DOI: 10.1002/anie.200701454
Palladium Catalysis
Construction of Tetrahydrofurans by PdII/PdIV-Catalyzed
Aminooxygenation of Alkenes**
Lopa V. Desai and Melanie S. Sanford*
Catalytic transformations involving PdII s-alkyl or s-aryl
intermediates are widely used in organic synthesis and offer
attractive routes to many valuable products.[1] However,the
vast majority of these reactions proceed by Pd0/PdII mecha-
nisms. As a result,the diversity of structures/bonds that can be
constructed is constrained by the limitations of this redox
cycle. Recent studies have explored the generation of PdII s-
alkyl/aryl species in the presence of strong oxidants (e.g.,
PhI(OAc)2,oxone, N-halosuccinimides,iodine) to access
alternative PdII/PdIV reaction manifolds.[2–4] Importantly,
these oxidative transformations often yield highly comple-
mentary organic products to those formed by traditional Pd0/II
catalysis.[2–4]
oxygenated products,which are valuable building blocks in
organic synthesis.[6] Importantly,while this work was in
progress,several other groups disclosed related transforma-
tions.[3] We report herein the successful application of this
strategy to the stereospecific and diastereoselective conver-
sion of 3-alken-1-ols into 3-aminotetrahydrofurans.[6] Mech-
anistic details are discussed and offer insights into the further
design and development of PdII/PdIV-catalyzed reactions.
Our initial studies focused on generating PdII b-amino-
alkyl species A by the intermolecular aminopalladation of 1-
octene with phthalimide (Scheme 1).[3a] Complex A would
typically undergo b-hydride elimination; however,we antici-
pated that this species could react competitively with PhI-
(OAc)2 to generate a PdIV intermediate. Reductive elimina-
tion from this intermediate should then provide amino-
acetoxylated product 1a. We were pleased to find that
treatment of 1-octene with 5 mol% Pd(OAc)2,one equivalent
phthalimide,and two equivalents PhI(OAc) 2 for 12 h at 608C
afforded 1a in 41% yield. However,consistent with results
recently disclosed by Liu and Stahl,[3a] the b-hydride product
1b was also obtained in 27% yield.[7]
Our group is interested in exploiting PdII/PdIV catalytic
cycles for the development of new organic transforma-
II
tions.[2a–e,4a] As part of these efforts,we reasoned that Pd b-
aminoalkyl species (generated by the aminopalladation of
olefins)[5] might be oxidatively intercepted with PhI(OAc)2
(Scheme 1). If successful,such reactions would provide an
attractive PdII/PdIV-catalyzed route from alkenes to amino-
We hypothesized that competing b-hydride elimination
might be suppressed by tethering a hydroxyl group to the
alkene. In a substrate like 3-buten-1-ol (2),the hydroxyl group
could coordinate to the Pd center during/after aminopallada-
tion to form palladacycle B (Scheme 2),thereby slowing b-
hydride elimination relative to oxidative functionalization.
Gratifyingly,treatment of 2 with 5 mol% Pd(OAc)2,one
equivalent phthalimide,and two equivalents PhI(OAc) did
2
not produce any of the b-hydride elimination product 2d.
However,surprisingly,the intermolecular aminoacetoxylated
species 2c was not observed in this reaction. Instead,
tetrahydrofuran product 2a,resulting from an intramolecular
oxygenation,was formed in a modest 30% yield along with a
second THF compound (2b).[8,9] A screening of reaction
additives revealed that 10 mol% AgBF4 increased the yield of
2a to 37%.[10] Two sequential additions of catalyst,silver salt,
oxidant,and alcohol further improved the yield of 2a to 45%
(based on phthalimide as the limiting reagent). Importantly,
control reactions (in the absence of Pd or oxidant) did not
afford any of the tetrahydrofuran products 2a or 2b.
Scheme 1. Pd-catalyzed aminoacetoxylation of 1-octene.
[*] L. V. Desai, Prof. M. S. Sanford
Department of Chemistry
University of Michigan
930 North University Ave., Ann Arbor, MI 48109-1055 (USA)
Fax: (+1)734-647-4835
E-mail: mssanfor@umich.edu
[**] This research was partially supported by the NIH NIGMS (R01
GM073836) and the Petroleum Research Fund. We also gratefully
acknowledge the Arnold and Mabel Beckman Foundation as well as
Abbott, Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers
Squibb, Eli Lilly, GlaxoSmithKline, and Merck Research Laboratories
for funding. L.V.D. thanks Bristol Myers Squibb for a graduate
fellowship. We are also grateful to Jeff Kampf (X-ray crystallography)
and Dipannita Kalyani and Kami Hull (editorial assistance).
With these results in hand,we next sought to investigate
the mechanism of the Pd-catalyzed formation of 2a. We
initially hypothesized that 2a might be formed in a two-step
sequence. In the first step,Pd-catalyzed reaction between 2
and PhI(OAc)2 would afford either 2b[9,11] or 2c (Scheme 2).
Product 2b could then undergo an intermolecular SN2
reaction with free phthalimide (Scheme 3,route a),or
2c
could undergo intramolecular SN2 ring closure (Scheme 3,
route b) to afford 2a. To test the viability of these pathways,
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 5737 –5740
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5737

Communications
cis or trans aminopalladation. As such,the reaction of
substrate 3 was next carried out using O2 (rather than
PhI(OAc)2) as the terminal oxidant. Under these
conditions,Pd IV intermediates should not be accessible;
therefore,the Pd II b-aminoalkyl complex is expected to
decompose by b-hydride elimination to afford an
olefin,[5] whose geometry should establish the stereo-
chemistry of the aminopalladation.[3a] Subjecting 3 to
5 mol% Pd(OAc)2 and 10 mol% AgBF4 under O2
produced a greater than 10:1 ratio of 3b relative to
3b’,albeit in low (ca. 3%) yield of isolated product
(Scheme 5).[14] This result suggests that 3a is formed predom-
inantly by cis aminopalladation;[3a,15] therefore,we propose
Scheme 2. Pd-catalyzed aminooxygenation of 3-buten-1-ol.
Scheme 3. Possible SN2 mechanisms for aminooxygenation.
authentic samples of 2c and 2b’ (in which O2CMe is
substituted with O2CPh)[9] were subjected to the catalytic
reaction conditions. However,in both cases,product 2a was
not observed by GC or 1H NMR spectroscopy,indicating that
neither mechanism is operational.
Scheme 5. Determination of stereochemistry of aminopalladation.
that mechanism c,involving cis aminopalladation and subse-
Four alternative PdII/PdIV-catalyzed routes to 2a were
next considered.[12] The first two (Scheme 4,routes c and d)
À
quent C O bond-forming reductive elimination with reten-
tion of stereochemistry,[16,17] is likely operating in this system.
These mechanistic experiments suggested that palladacy-
clic intermediates B and C (Schemes 2 and 4) were likely
involved in the formation of tetrahydrofuran 3a. Therefore,
we reasoned that incorporation of substituents along the alkyl
chain of the substrate would promote metallacycle formation
and thereby increase the yields of these reactions. Addition-
ally,since such cyclic intermediates often assume highly
ordered transition states,we anticipated that these trans-
formations might proceed stereoselectively. Consistent with
these hypotheses,2-phenyl-3-buten-1-ol ( 4) underwent Pd-
catalyzed oxidative cyclization to afford 4a in 77% yield;
furthermore,this product was formed with high (10:1)
selectivity for the trans diastereomer (Table 1,entry 1). A
variety of related substrates containing allylic aryl groups also
reacted to form 3,4-trans-disubstituted tetrahydrofurans in
comparable yields and with modest to excellent diastereose-
lectivities (entries 2–9). Interestingly,the stereoselectivity of
these transformations was sensitive to substitution on the
Scheme 4. Possible PdII/PdIV mechanisms for aminooxygenation.
begin with cis aminopalladation of the olefin,while the latter
two (Scheme 4,routes e and f) involve an initial trans-amino-
palladation step. Oxidation of the resulting PdII intermediate
to PdIV could then form cyclic or acyclic complexes,which
could undergo direct reductive elimination with retention of
the stereochemistry (Scheme 4,routes c and e) or S N2-type
reductive elimination with inversion of the stereochemistry
(Scheme 4,routes d and f). To gain insights into these
mechanistic possibilities, Z olefin 3 was examined as a
substrate. Subjection of 3 to our standard conditions afforded
trans-disubstituted tetrahydrofuran 3a in 60% yield of
isolated product as a single diastereomer.[13] This result rules
out mechanistic possibilities d and e,which should both
selectively provide the cis-disubstituted isomer 3a’.
arene. In particular,substitution at the
ortho position
(entries 4 and 9) resulted in substantially decreased levels of
diastereoselectivity. Furthermore,modest yields and selectiv-
ities were observed with allylic Me,benzyl,or isopropyl
groups (entries 10–12). Both experimental and computational
efforts are currently underway to develop a transition-state
model consistent with all of these observations.
The work described herein reveals several new mecha-
nistic features of PdII/PdIV-catalyzed transformations. First,it
À
establishes that C O bond-forming reductive elimination
from PdIV can proceed with clean retention of configura-
tion.[16,17] This unusual observation is in sharp contrast to
À
To distinguish between mechanisms c and f,we needed to
closely related studies with PhI(OAc)2,in which C OAc
coupling took place with inversion of configuration at the
À
determine whether initial C N bond formation proceeded by
5738
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5737 –5740

Angewandte
Chemie
Table 1: Scope of palladium-catalyzed formation of 3-aminotetrahydrofuran derivatives.[a]
on the benzoate ligand.[18] Notably,
understanding the relative rates of
Entry
Alcohol
Substituents
Major product
Product no.
Yield [%] (d.r.)
IV
À
different C X couplings at Pd
centers will likely be critical for
the design of catalysts and oxidants
for future PdII/PdIV-catalyzed trans-
formations.
1
Ar=Ph (4)
4a
77 (10:1)
2
Ar=p-MeOC6H4 (5)
Ar=m-MeOC6H4 (6)
Ar=o-MeOC6H4 (7)
Ar=p-CF3C6H4 (8)
Ar=m-CF3C6H4 (9)
Ar=p-BrC6H4 (10)
Ar=2-naphthyl (11)
Ar=mesityl (12)
5a
62 (15:1)
55 (5.4:1)
63 (7.8:1)
54 (>20:1)
60 (16:1)
56 (>20:1)
80 (12:1)
72 (1.4:1)
30 (1.4:1)
27 (1.5:1)
<5
In conclusion,we have demon-
strated that Pd-catalyzed alkene
aminopalladation to generate s-
alkyl Pd species can be followed
by intramolecular oxidative func-
tionalization to stereoselectively
afford tetrahydrofuran products.
Mechanistic studies suggest that
these transformations proceed by
cis aminopalladation and subse-
3
6a
4
7a
5
8a
À
quent C O bond-forming reductive
6
9a
elimination with unusual retention
of stereochemistry at the carbon
atom. Future studies will further
probe the mechanism and expand
the scope of this reaction.
7
10a
11a
12a
13a
14a
15a
16a
8
Received: April 4,2007
Published online: June 28,2007
9
Keywords: allylic compounds ·
.
aminopalladation · oxidation ·
palladium · tetrahydrofurans
10
11
12
13
R=benzyl (14)
R=isopropyl (15)
[1] a) N. Miyaura,A. Suzuki, Chem.
Rev. 1995, 95,2457 – 2483; b) S.
Kotha,K. Lahiri,D. Kashinath,
Tetrahedron 2002, 58,9633 – 9695;
c) J. K. Stille, Angew. Chem. 1986,
98,504 – 519; Angew. Chem. Int.
Ed. Engl. 1986, 25,508 – 524; d) E.
Negishi,L. Anastasia, Chem. Rev.
2003, 103,1979 – 2018; e) A. R.
Muci,S. L. Buchwald, Top. Curr.
Chem. 2002, 219,131 – 209; f) N. R.
47
[a] Reagents and conditions: 1 equiv phthalimide, 3 equiv PhI(OAc)2, 3 equiv 3-alken-1-ol, 10 mol%
Pd(OAc)2, 20 mol% AgBF4 in 1.4 mLCH 3CN at 608C.
carbon atom.[3a] The stereochemical outcome of the current
reactions may be due to the more basic nature of the
nucleophile (alkoxide versus acetate) and/or the intramole-
cularity of the reductive elimination event.
This transformation also presents a system in which the
key s-alkyl PdIV intermediate likely contains multiple differ-
ent oxygen-donor ligands,including a tethered alkoxide (OR)
and at least one acetate (OAc) ligand. This study clearly
shows that C OR bond formation is favored with high
selectivity over C OAc coupling. This may result from the
intramolecularity of the ether-forming reductive elimination,
but is more likely due to the higher basicity/nucleophilicity of
the alkoxide relative to the OAc ligand. Consistent with this
Deprez,M. S. Sanford, Inorg. Chem. 2007, 46,1924 – 1935.
[2] For examples,see: a) A. R. Dick,K. L. Hull,M. S. Sanford,
Am. Chem. Soc. 2004, 126,2300 – 2301; b) L. V. Desai,K. L.
J.
Hull,M. S. Sanford, J. Am. Chem. Soc. 2004, 126,9542 – 9543;
c) L. V. Desai,H. A. Malik,M. S. Sanford, Org. Lett. 2006, 8,
1141 – 1144; d) D. Kalyani,A. R. Dick,W. Q. Anani,M. S.
Sanford, Org. Lett. 2006, 8,2523 – 2526; e) K. L. Hull,W. Q.
Anani,M. S. Sanford, J. Am. Chem. Soc. 2006, 128,7134 – 7135;
f) R. Giri,X. Chen,J.-Q. Yu, Angew. Chem. 2005, 117,2150 –
2153; Angew. Chem. Int. Ed. 2005, 44,2112 – 2115; g) R. Giri,X.
Chen,J.-Q. Yu, Org. Biomol. Chem. 2006, 4,4041 – 4047; h) O.
Daugulis,V. G. Zaitsev, Angew. Chem. 2005, 117,4114 – 4116;
Angew. Chem. Int. Ed. 2005, 44,4046 – 4048; i) B. V. S. Reddy,
L. R. Reddy,E. J. Corey, Org. Lett. 2006, 8,3391 – 3394.
À
À
[3] a) G. Liu,S. S. Stahl, J. Am. Chem. Soc. 2006, 128,7179 – 7181;
b) E. J. Alexanian,C. Lee,E. J. Sorensen, J. Am. Chem. Soc.
2005, 127,7690 – 7691; c) J. Streuff,C. H. Hovelmann,M. Nieger,
K. Muniz, J. Am. Chem. Soc. 2005, 127,14586 – 14587.
À
hypothesis,stoichiometric C O bond-forming reductive elim-
ination from PdIV aryl benzoate complexes was shown to
proceed significantly faster with electron-donor substituents
Angew. Chem. Int. Ed. 2007, 46, 5737 –5740
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5739

Communications
[4] a) L. L. Welbes,T. W. Lyons,K. A. Cychosz,M. S. Sanford,
J.
was also considered. However,this mechanism was deemed
unlikely based on prior work (references [3a],[9],[11],[15b]).
Furthermore,if this mechanism were operating,the exclusion of
PhI(OAc)2 would lead to formation of dihydrofuran products by
b-hydride elimination from the s-alkyl Pd product of 5-endo-trig
oxypalladation. Such products were not observed in reactions of
3 under O2.
Am. Chem. Soc. 2007, 129,5836 – 5837; b) X. Tong,M. Beller,
M. K. Tse, J. Am. Chem. Soc. 2007, 129,4906 – 4907.
[5] a) J. L. Brice,J. E. Harang,V. I. Timokhin,N. R. Anastasi,S. S.
Stahl, J. Am. Chem. Soc. 2005, 127,2868 – 2869; b) L. S. Hegedus,
Tetrahedron 1984, 40,2415 – 2434.
[6] For a review on the synthetic utility of vicinal amino alcohols,
see: S. C. Bergmeier, Tetrahedron 2000, 56,2561 – 2576; for
examples of the 3-aminotetrahydrofuran motif in synthesis,see:
a) K. Oscarsson,M. Lahmann,J. Lindberg,J. Kangasmetsa,T.
[13] (E)-3 did not form any THF product under these conditions;
therefore,the stereochemical outcome of reactions with ( Z)-3
appears to reflect a stereospecific transformation of the Z isomer
and not isomerization to (E)-3 with subsequent aminocycliza-
tion.
Unge,S. Oscarson,A. Hallberg,B. Samuelsson,
Bioorg. Med.
Chem. 2003, 11,1107 – 1115; b) A. T. Hewson,J. Jeffery,N.
Szczur, Tetrahedron Lett. 1995, 36,7731 – 7734; c) M. E. Bun-
nage,S. G. Davies,P. M. Roberts,A. D. Smith,J. M. Withey, Org.
Biomol. Chem. 2004, 2,2763 – 2776.
[14] The low yield of 3b appears to be due to fast catalyst
decomposition under these conditions. The remainder of the
material is predominantly (ca. 72%)
a mixture of E and
[7] b-Hydride elimination remained competitive under all reaction
conditions examined.
Z isomers of 3. See the Supporting Information for a full
discussion.
[8] The modest yield of 2a was due to competitive formation of 2b
and competitive decomposition of alcohol 2 to an intractable
mixture of oxidation products.
[15] For rare examples of cis aminopalladation,see reference [3a]
and: a) J. E. Ney,J. P. Wolfe, Angew. Chem. 2004, 116,3689 –
3692; Angew. Chem. Int. Ed. 2004, 43,3605 – 3608; b) G. Liu,
S. S. Stahl, J. Am. Chem. Soc. 2007, 129,6328 – 6335.
[16] Retention of configuration has been observed in some Pd-
catalyzed oxidative transformations with CuCl2; for example,
[9] Compound 2b’ was isolated from the Pd-catalyzed reaction of 1
with PhI(O2CPh)2 (see the Supporting Information for details).
Compound 2b’ was formed in similar yield when the Pd(OAc)2
catalyst was substituted with Sc(OTf)3,Cu(OTf) ,BF ·Et2O,or
see: G. Zhu,S. Ma,X. Lu,Q. Huang,
J. Chem. Soc. Chem.
2
3
AuCl3. This result suggests that Pd(OAc)2 is likely to act as a
Lewis acid catalyst for this cyclization rather than to promote a
rare 5-endo-trig oxypalladation/acetoxylation sequence.
[10] The role of AgBF4 remains to be definitively elucidated. We
speculate that it may render the Pd center more electrophilic
and thereby promote coordination of the alcohol.
[11] For a rare example of 5-endo-trig oxypalladation,see: S. Saito,T.
Hara,N. Takahashi,M. Hirai,T. Moriwake, Synlett 1992,237 –
238.
Commun. 1995,271 – 273.
À
[17] For examples of oxidative C O bond formation at Pd that
proceed with inversion,see: a) J. E. Bꢀckvall,E. E. Bjoerkman,
J. Org. Chem. 1980, 45,2893 – 2898; b) P. M. Henry,M. Davies,
G. Ferguson,S. Phillips,R. Restivo,
Commun. 1974,112 – 113; c) P. K. Wong,J. K. Stille, J. Organo-
met. Chem. 1974, 70,121 – 132.
J. Chem. Soc. Chem.
[18] A. R. Dick,J. W. Kampf,M. S. Sanford, J. Am. Chem. Soc. 2005,
127,12790 – 12791.
[12] A mechanism involving i) 5-endo-trig oxypalladation,ii) oxida-
IV
À
tion to Pd ,and iii) C N bond-forming reductive elimination
5740
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5737 –5740