Palladium(0)/indium iodide-mediated allylations of electrophiles generated from the hydrolysis of Eschenmoser's salt: one-pot preparation of diverse carbocyclic scaffolds

Article abstract of DOI:10.1016/j.tetlet.2010.04.007

A formyl equivalent was generated in situ from Eschenmoser's salt in aqueous THF and was reacted with an allylindium species. Acylnitroso-derived hetero-Diels-Alder adducts and related allyl acetates were shown to be substrates for Pd(0)/InI-mediated allylations of formaldehyde-related species to provide homoallylic alcohols. Hydroxymethyl groups were installed with regio- and diastereocontrol to provide relevant disubstituted carbocyclic scaffolds. Enantiopure anti-disubstituted cyclopentene products were prepared from a chiral allyl acetate.

Full text of DOI:10.1016/j.tetlet.2010.04.007

Tetrahedron Letters 51 (2010) 3050–3052
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Tetrahedron Letters
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Palladium(0)/indium iodide-mediated allylations of electrophiles generated
from the hydrolysis of Eschenmoser’s salt: one-pot preparation of diverse
carbocyclic scaffolds
*
Cara Cesario, Marvin J. Miller
The University of Notre Dame, Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, Notre Dame, IN 46556, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A formyl equivalent was generated in situ from Eschenmoser’s salt in aqueous THF and was reacted with
an allylindium species. Acylnitroso-derived hetero-Diels–Alder adducts and related allyl acetates were
shown to be substrates for Pd(0)/InI-mediated allylations of formaldehyde-related species to provide
homoallylic alcohols. Hydroxymethyl groups were installed with regio- and diastereocontrol to provide
relevant disubstituted carbocyclic scaffolds. Enantiopure anti-disubstituted cyclopentene products were
prepared from a chiral allyl acetate.
Received 1 February 2010
Revised 30 March 2010
Accepted 1 April 2010
Available online 9 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Formaldehyde is one of the most reactive carbonyl electrophiles
used in organic syntheses. Although gaseous formaldehyde may be
generated from paraformaldehyde, self-polymerization has limited
its general use.1 Additionally, commercially available 37% aqueous
formaldehyde is an inadequate source of monomeric formaldehyde
because formaldehyde hydrate exists in solution.2 In order to
achieve high yielding reactions with formaldehyde, stable formal-
dehyde–organoaluminum complexes have been generated3 and
water-tolerant Lewis acids have promoted direct hydroxymethyla-
tions in aqueous formaldehyde solutions.4 We envisioned an alter-
native method to generate formaldehyde or related species (in situ
hydrolysis of Eschenmoser’s salt) and then using the simple syn-
thon as an allylation acceptor to prepare hydroxymethylated car-
bocyclic platforms ( )-1a, (+)-1b, and (+)-1c (Fig. 1).
Carbocycles ( )-1a, ( )-1b, and ( )-1c are precursors to carbocy-
clic nucleosides5 and related carbasugars.6 To date, direct access to
these diverse substrates from a common precursor has not been
achieved. Compound ( )-1a and related derivatives7 have been
prepared from an initial Diels–Alder reaction between a sulfonyl
isocyanate and cyclopentadiene followed by hydrolysis to afford
2-azabicyclo[2.2.1]hept-5-en-3-one (Vince’s lactam); reductive
opening of the lactam provides substrate ( )-1a.8
been reported, the diastereomers are prepared by two unrelated
synthetic methods. In order to develop a direct hydroxymethyla-
tion reaction and synthesize diverse carbocyclic platforms from a
common substrate, Pd(0)/InI-mediated allylations of formaldehyde
and formyl equivalents with hetero-Diels–Alder cycloadduct ( )-
2b and allyl acetate (ꢀ)-8 were investigated to ultimately prepare
(hydroxymethyl)cyclopentenyl scaffolds ( )-1a, (+)-1b, and (+)-1c
(Fig. 1).
Allylindium reagents are mild nucleophilic species that readily
react with aldehydes and ketones to afford homoallylic alcohols.14
Our group has previously developed Pd(0)/InI-mediated allylations
of diverse electrophiles with hetero-Diels–Alder cycloadducts ( )-
2a and ( )-2b.15
In an initial attempt to affect hydroxymethylation, phenylacetyl
cycloadduct ( )-2a was treated with Pd(0) and InI in the presence
of 37% aqueous formaldehyde (1.5 equiv) to afford an equal distri-
bution of syn-1,4, anti-1,4, and anti-1,2 allylation products ( )-3a,
( )-3b, and ( )-3c, respectively, in an overall 30% isolated yield
(Scheme 1).15b
We shifted our focus to formyl equivalents and related electro-
philes as alternative options to install the requisite hydroxymethyl
group by using Pd(0)/InI allylation chemistry. Unfortunately,
several electrophiles (i.e., s-trioxane, trifluoroethyl formate, ben-
zylozymethyl chloride, methyl cyanoformate, CO2, and DMF ace-
tals) were unreactive toward Pd(0)/InI allylation conditions in the
Conversely, a multi-step synthetic sequence may be employed
to prepare carbocyclic scaffolds bearing 40-hydroxymethyl groups.
For example, the C40–C50 bond has been installed by Pd(0)-cata-
lyzed allylic alkylations with nitromethane,9 ethyl nitroacetate,10
and (phenylsulfonyl)-nitromethane.11 In each case, the 40-hydroxy-
methyl group was then ultimately revealed through an oxidation–
reduction sequence. Although scaffolds ( )-1a12 and ( )-1b13 have
H
N
O
H
H
5'
5'
4'
4'
N
N
O
O
HO
HO
O
O
O
1a
1b
1c
HO
* Corresponding author. Tel.: +1 574 631 7571; fax: +1 574 631 6652.
E-mail address: mmiller1@nd.edu (M.J. Miller).
Figure 1. Carbocyclic target molecules.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.007

C. Cesario, M. J. Miller / Tetrahedron Letters 51 (2010) 3050–3052
3051
37% aq.
formaldehyde
(1.5 eq)
H
O
Ln
In
O
H
3a:3b:3c
N
N
Bn
O
5
H
1:1:1
I
(1.2 eq)
Pd(OAc)2 (0.1 eq)
PPh3 (0.5 eq)
InI (1.5 eq)
THF:H2O (10:1)
30%
H
N
R
( )-2a
N
O
R
O
( )-2b
Pd(dba)2 (0.1 eq)
PPh3 (0.3 eq)
InI (1.2 eq)
H
O
H
O
R = OC(CH3)3
6
leads to 7a
THF: H2O (9:1)
OH
OH
OH
N
OH
OH
N
OH
N
N
N
Bn
Bn
Bn
N
R
R
R
HO
HO
HO
R1
O
O
O
O
O
( )-7b
( )-7d
O
( )-3a
( )-3b
( )-3c
( )-7a
( )-7c
R
R
1 = OH
HO
1 = NMe2
HO
Scheme 1. Pd(0)/InI-mediated allylation of aqueous formaldehyde.
product
distribution (%) yield
total
entry
order of reagent addition
presence of cycloadducts ( )-2a and ( )-2b even with increased
temperatures.16 When more reactive electrophiles (i.e., Vilsmeier’s
reagent, Viehe’s salt, and 1,3-benzodithiolylium tetrafluoroborate)
were used for the Pd(0)/InI allylation chemistry, cycloadducts ( )-
2a and ( )-2b were consumed and complex product mixtures were
obtained.
Although we had extensively explored formyl equivalents and
related electrophiles as potential substrates for Pd(0)/InI-medi-
ated allylation chemistry with cycloadducts ( )-2a and ( )-2b, a
related indium-allylation reaction led us to discover an appropri-
ate source of a formyl species. During the course of identifying
iminium species for Pd(0)/InI-mediated allylation chemistry, we
recognized that treatment of Boc cycloadduct ( )-2b with Pd(0)
and InI in the presence of N-benzylidenemethylamine did not
produce the anticipated homoallylic amine ( )-4a (Scheme 2).17
We isolated homoallylic alcohol ( )-4b in 42% yield. These results
are consistent with the in situ hydrolysis of N-benzylidenemeth-
ylamine to provide benzaldehyde and subsequent allylation to af-
ford ( )-4b.
7a 7b 7c 7d
1
2
3
4
5
6
Stir 2b, Pd(0), InI for 90 min; add 5a 67
Stir 2b, Pd(0), InI for 90 min; add 5b 84 14
Stir 2b, Pd(0), InI for 0 min; add 5b,c 38 22 34
Stir 2b, 5, InI for 0 min; add Pd(0)d
42 18 34
Stir 2b, 5, InI for 0 min;e add Pd(0)d 66 15 11
Stir 2b, 5, InI for 10 min; add Pd(0)d 67 19 14
8
14 11 N/A
f
2
0
5
6
8
0
38%
N/A
57%g
N/A
78%g
Scheme 3. Pd(0)/InI-mediated allylations of formaldehyde (generated in situ from
Eschenmoser’s salt). Reagents and conditions: (a) a THF/H2O solution of Eschenmo-
ser’s salt 5 was prepared and added immediately; (b) a THF/H2O solution of
Eschenmoser’s salt 5 was stirred for 10 min prior to addition; (c) a THF/H2O solution
of Eschenmoser’s salt 5 was added dropwise over 30 min; (d) a THF solution of
Pd(0) was stirred for 10 min prior to addition; (e) the reaction was cooled to 0 °C; (f)
isolated yield for ( )-7a; (g) isolated yields for combined products ( )-7a, ( )-7b,
and ( )-7c.
conditions provided highly enriched amounts of the syn-1,4 prod-
uct ( )-7a.
The hydrolysis conditions were reproduced by treating Boc cyc-
loadduct ( )-2b with Pd(0) and InI in the presence of Eschenmo-
ser’s salt 5 in THF/H2O (Scheme 3). After 90 min at rt, 1H NMR
integration of the crude reaction mixture revealed a mixture of
syn-1,4, anti-1,4, anti-1,2, and anti-1,4 allylation products ( )-7a,
( )-7b, ( )-7c, and ( )-7d, respectively (Scheme 3, entry 1).18 The
preference for syn-1,4 product ( )-7a was rationalized with transi-
tion state 6. If formaldehyde was the reactive species, indium may
coordinate to the N-hydroxy carbamate oxygen and the carbonyl
oxygen of formaldehyde as shown in complex 6. Encouraged by
this result, we investigated conditions to improve the ratio of
syn-1,4 product ( )-7a. Accordingly, production of ( )-7d was sup-
pressed by stirring Eschenmoser’s salt in THF/H2O for 10 min prior
to allylation (entries 2 and 6).19
An increase of syn-1,4 product ( )-7a was observed when cyc-
loadduct ( )-2b was stirred with Pd(0) and InI for 90 min followed
by treatment with a THF/H2O solution of Eschenmoser’s salt
(Scheme 3, entry 2). 1H NMR integrations confirmed syn-1,4 prod-
uct ( )-7a as the major component of the reaction mixture. After
column chromatography, syn-1,4 product ( )-7a was isolated in
38% yield (>97% de). Despite the low isolated yield, these reaction
Alternatively, syn-1,4 product ( )-7a was produced by stirring
cycloadduct ( )-2b with InI and Eschenmoser’s salt in THF/H2O
for 10 min followed by addition of a THF solution of Pd(0) (Scheme
3, entry 6). Although these reaction conditions afforded the highest
isolated yield of all allylation products, syn-1,4 product ( )-7a
could not be exclusively isolated by this method because separa-
tion by column chromatography was complicated by increased
amounts of ( )-7b and ( )-7c. When cycloadduct ( )-2b was stirred
with InI, formaldehyde, and dimethylamine in THF/H2O for 10 min
followed by the addition of a THF solution of Pd(0), starting mate-
rial was consumed and compounds ( )-7a, ( )-7b, ( )-7c, or ( )-7d
were not observed.
N-Hydroxy carbamates ( )-7a and ( )-7c were reduced to
carbamates ( )-1a and ( )-1c, respectively, with Cp2TiCl20
(Scheme 4). Compound ( )-1a represents a key carbocyclic scaffold
for the syntheses of carbocyclic nucleoside target molecules and
related analogs.
A
complementary route was developed to provide anti-
(hydroxymethyl)cyclopentenyl derivatives as the exclusive prod-
ucts. Allyl acetate (ꢀ)-8 was selected as an appropriate substrate
Cp2TiCl2, Zn
OH
N
H
H
−30 °C to −10 °C
THF/MeOH
1 h, 58%
N
O
O
O
N
HO
HO
O
(1.1 eq)
O
O
N
O
OH
N
( )-7a
( )-1a
H
( )-2b Pd(dba)2 (0.1 eq)
O
OH
N
H
O
H
PPh3 (0.3 eq)
InI (1.2 eq)
THF, rt, 1.5 h
42%
Cp2TiCl2, Zn
R
N
O
O
−30 °C to −10 °C
THF/MeOH
1 h, 60%
R = NHMe ( )-4a: not observed
O
( )-7c
O
( )-1c
( )-4b: isolated product
R = OH
HO
HO
Scheme 2. Pd(0)/InI-mediated allylation of benzaldehyde (generated in situ from
N-benzylidenemethylamine).
Scheme 4. Cp2TiCl-mediated N–O bond reductions.

3052
C. Cesario, M. J. Miller / Tetrahedron Letters 51 (2010) 3050–3052
Ln
Supplementary data
Ln
In
N
H
H
Cl
(1.2 eq)
In
H
H
AcO
NHBoc
Ln
Supplementary data (General methods, experimental details
and characterization for compounds ( )-1a, (+)-1b, (+)-1c, ( )-4b
and ( )-7a–c.) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.04.007.
Pd(dba)2 (0.1 eq)
PPh3 (0.3 eq)
InI (1.2 eq)
THF: H2O (9:1)
71%
O
O
O
H
H
N
O
(−)-8
O
HN
H
R
9
10
leads to 1c
leads to 1b
References and notes
H
N
H
O
N
O
1. (a) Okachi, T.; Fujimoto, K.; Onaka, M. Org. Lett. 2002, 4, 1667–1669; (b)
Harayama, H.; Kimura, M.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 1998, 39,
8475–8478.
2. Martin, R. J. L. Aust. J. Chem. 1954, 7, 400–405. and references therein.
3. (a) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am. Chem. Soc. 1982, 104,
555–563; (b) Maruoka, K.; Concepcion, A. B.; Hirayama, N.; Yamamoto, H. J. Am.
Chem. Soc. 1990, 112, 7422–7423.
HO
O
O
(+)-1b
(+)-1c
HO
1b:1c
(2:1)
Scheme 5. Pd(0)/InI-mediated allylations of formaldehyde (generated in situ from
Eschenmoser’s salt).
4. (a) Ogawa, C.; Kobayashi, S. Chem. Lett. 2007, 36, 56–57; (b) Kobayashi, S. Chem.
Lett. 1991, 20, 2187–2190.
5. For a review of synthetic routes to cyclopentyl carbocyclic nucleosides, see:
Crimmins, M. T. Tetrahedron 1998, 54, 9229–9272.
6. For a review of synthetic routes to carbasugars, see: Arjona, O.; Gomez, A. M.;
Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–2036.
7. (a) Jung, M. E.; Hakjune, R. J. Org. Chem. 1994, 59, 4719–4720; (b) Daluge, S.;
Vince, R. J. Org. Chem. 1978, 43, 2311–2320.
8. (a) Griffiths, G. J.; Previdoli, F. E. J. Org. Chem. 1993, 58, 6129–6131; (b) Jagt, J. C.;
Van Leusen, A. M. J. Org. Chem. 1974, 39, 564–566.
9. In the synthesis of BXC-1812, see: Mineno, T.; Miller, M. J. J. Org. Chem. 2003,
68, 6591–6596.
10. In the synthesis of carbovir, see: Peel, M. R.; Sternbach, D. D.; Johnson, M. R. J.
Org. Chem. 1991, 56, 4990–4993.
because it is easily prepared from Boc cycloadduct ( )-2b in three
steps and provides enantioenriched allylation products.21
Additionally, substrate (ꢀ)-8 lacks a coordinating hydroxamate
oxygen and, in this case, allylation was anticipated to proceed anti
to the carbamate substituent. Indeed, Pd(0)/InI-mediated allylation
of (ꢀ)-8 provided anti-1,4 and anti-1,2 scaffolds (+)-1b and (+)-1c,
respectively, in a 2:1 ratio and in overall 71% isolated yield
(Scheme 5). If formaldehyde was the reactive species, the prefer-
ence for anti-1,4 product (+)-1b may be consistent with transition
state 9 in which indium coordinates to the carbamate oxygen and
formaldehyde. In transition state 10, indium may be unable to
coordinate to the carbamate as an unfavorable bridged species
would result. In-mediated allylation provides anti-1,2 carbocycle
(+)-1c as the minor product. This method was a dramatic improve-
ment to previously reported conditions. Pd(0)/InI-mediated allyla-
tion of 37% aqueous formaldehyde with allyl acetate ( )-8 provided
anti-1,4 product ( )-1b in 10% isolated yield.15b
Diverse cyclopentene scaffolds ( )-1a, (+)-1b, and (+)-1c have
been prepared from cycloadduct ( )-2b and/or allyl acetate (ꢀ)-8.
Two key synthetic transformations, Pd(0)/InI allylations of a formyl
species generated in situ from Eschenmoser’s salt and Ti(III)-med-
iated N–O bond reductions, were used to prepare the isomeric
products. Syntheses of targeted carbocyclic nucleosides from sub-
strates ( )-1a and (+)-1b are reported in the subsequent Letter.22
11. In the synthesis of (ꢀ)-carbovir, (ꢀ)-aristeromycin, (ꢀ)-neplanocin
A and
related compounds, see: Trost, B. M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am.
Chem. Soc. 2000, 122, 5947–5956. and references therein.
12. For the synthesis of 1a, see: (a) McGuigan, C.; Hassan-Abdallah, A.; Srinivasan,
S.; Wang, Y.; Siddiqui, A.; Daluge, S. M.; Gudmundsson, K. S.; Zhou, H.; McLean,
E. W.; Peckham, J. P.; Burnette, T. C.; Marr, H.; Hazen, R.; Condreay, L. D.;
Johnson, L.; Balzarini, J. J. Med. Chem. 2006, 49, 7215–7226; (b) Daluge, S. M.;
Martin, M. T.; Sickles, B. R.; Livingston, D. A. Nucleosides Nucleotides Nucleic
Acids 2000, 19, 297–327; (c) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17–21.
13. For the synthesis of 1b, see: Grumann, A.; Marley, H.; Taylor, R. J. K. Tetrahedron
Lett. 1995, 36, 7767–7768.
14. For reviews: (a) Araki, S.; Hirashita, T. In Comprehensive Organometallic
Chemistry III; Crabtree, R. H., Mignos, D. M. P., Eds.; Elsevier: Oxford, 2007;
Vol. 9, Chapter 9.14; (b) Podlech, J.; Maier, T. C. Synthesis 2003, 5, 633–655.
15. (a) Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 1293–1295; (b) Lee, W.; Kim, K.
H.; Surman, M. D.; Miller, M. J. J. Org. Chem. 2003, 68, 139–149.
16. Electrochemical indium-catalyzed allylations of esters have been achieved,
see: (a) Hilt, G.; Smolko, K. I. Angew. Chem., Int. Ed. 2001, 40, 3399–3402;
Allylindium(III) species, prepared from allylhalide and indium metal in DMF, is
unreactive towards esters and cyano groups, see: (b) Araki, S.; Ito, H.; Butsuga,
Y. J. Org. Chem. 1988, 53, 1833–1835.
17. Indium-mediated allylations of aldamines have been achieved, see: Vilaivan,
T.; Winotapan, C.; Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2001, 42, 9073–
9076.
18. In contrast to our observations, zinc-mediated allylations of iminium
electrophiles (generated in situ from formaldehyde and amine in water)
provide homoallylic amine products, see: Estevam, I. H. S.; Bieber, L. W.
Tetrahedron Lett. 2003, 44, 667–670.
19. Compound 7d has been synthesized by using Pd(0)/InI allylation with
cycloadduct 2b in the presence of Eschenmoser’s salt under anhydrous
conditions, see Ref. 15a.
20. Cesario, C.; Tardibono, L. P.; Miller, M. J. J. Org. Chem. 2009, 74, 448–451.
21. Allyl acetate (ꢀ)-8 is available from kinetic enzymatic resolution with Candida
antarctica B lipase. See: Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem.
1998, 63, 3357–3363.
Acknowledgments
We would like to thank Dr. Jed Fisher (University of Notre
Dame) for helpful discussions, Dr. Bill Boggess (University of Notre
Dame) and Nonka Sevova (University of Notre Dame) for mass
spectroscopic analyses, and Dr. Jaroslav Zajicek (University of No-
tre Dame) for NMR assistance. Cara Cesario is grateful for a Wolf
Fellowship. We acknowledge The University of Notre Dame and
NIH (GM068012) for support of this work.
22. Cesario, C.; Tardibono, L. P.; Miller, M. J. Tetrahedron Lett., in press.