A direct synthesis of allenes by a traceless petasis reaction

Article abstract of DOI:10.1021/ja301489n

A one-pot synthesis of allenes by the 2-nitrobenzenesulfonylhydrazide- mediated coupling of hydroxyaldehydes or ketones with alkynyl trifluoroborate salts is reported. This mild process involves in situ formation of a sulfonylhydrazone that reacts with alkynyl trifluoroborates to generate a transient propargylic hydrazide species. Decomposition of this unstable hydrazide via an intermediate monoalkyldiazine produces the allene products through an alkene walk mechanism.

Full text of DOI:10.1021/ja301489n

Communication
pubs.acs.org/JACS
A Direct Synthesis of Allenes by a Traceless Petasis Reaction
Devon A. Mundal, Kelly E. Lutz, and Regan J. Thomson*
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
S
* Supporting Information
product. Related additions of organometal species into
preformed tosylhydrazones have been reported,8,9 while
precedent for the reductive transposition of propargylic diazines
is found within the elegant work by the Myers group, who
reported the synthesis of allenes from propargylic alcohols via
intermediates akin to III.10 In this communication, we report
the successful development of a new one-pot synthesis of
allenes that proceeds through the coupling of a hydroxy
aldehyde or ketone with 2-nitrobenzenesulfonylhydrazine
(NBSH) and an alkynyl trifluoroborate salt. We refer to this
new process as a traceless Petasis reaction.
ABSTRACT: A one-pot synthesis of allenes by the 2-
nitrobenzenesulfonylhydrazide-mediated coupling of hy-
droxyaldehydes or ketones with alkynyl trifluoroborate
salts is reported. This mild process involves in situ
formation of a sulfonylhydrazone that reacts with alkynyl
trifluoroborates to generate a transient propargylic
hydrazide species. Decomposition of this unstable
hydrazide via an intermediate monoalkyldiazine produces
the allene products through an alkene walk mechanism.
We initiated our studies using the phenyl-substituted alkynyl
trifluoroborate salt 1a,11,12 glycoaldehyde dimer (2), and p-
tosylhydrazide (3a). Combining all three reagents in an
equimolar ratio afforded none of the desired product (4a,
Table 1, entry 1).
he one-pot coupling of a boronic acid with an amine and
T
an aldehyde, as first reported by Petasis and co-workers in
1993,1 constitutes one of the most direct and mild methods for
preparing stereogenic carbinamines.2 Not only does this
powerful reaction, now known as the Petasis borono-Mannich
reaction, facilitate the generation of stereogenic carbinamines, it
is also an exceptionally efficient fragment coupling reaction that
can proceed with high levels of both enantioselectivity3 or
diastereoselectivity.4 Our entry point into Petasis-type chem-
istry stemmed from our interest in developing fragment
couplings via hydrazone intermediates.5 We envisioned a
scenario wherein an arenesulfonylhydrazide might participate
in a Petasis-type coupling reaction with an α-hydroxyaldehyde
and an alkynyl boron nucleophile, to generate an allene product
instead of the usual amine adduct (Figure 1). The allene
Lewis acids such as Sc(OTf)3 are known to promote
hydrazone formation,13 and we anticipated that the addition of
such a metal salt to our reaction mixture might facilitate both
hydrazone formation and alkyne addition (i.e., the formation of
I and II in Figure 1). Indeed, the addition of 10 mol %
Sc(OTf)3 led to formation of a new product we identified as
the intermediate propargyl hydrazide (i.e., II), but it was found
that elimination of the sulfinic acid residue was not facile under
the reaction conditions (Table 1, entry 2). During their studies
on the reductive transposition of propargylic alcohols, Myers
and co-workers found that 2-nitrobenzenesulfonylhydrazides
were superior precursors to diazine species, losing 2-nitro-
benzenesulfinic acid much more rapidly than the corresponding
p-tosyl derivatives.10c,14 As we had hoped, using NBSH (3b, Ns
= 2-nitrobenzenesulfonyl) in place of p-tosylhydrazide (3a)
gave rise to the desired allene product (i.e., 4a) in 49% yield in
the absence of any catalyst (Table 1, entry 3). The addition of
10 mol % Sc(OTf)3, however, gave a much cleaner reaction and
allowed the isolation of allene 4 in 66% yield (Table 1, entry 4).
A survey of various Lewis acids revealed that 10 mol %
La(OTf)3 provided allene 4 in the greatest isolated yield (78%,
Table 1, entry 8). During this development stage and in
preliminary investigations into the use of other alkyne salts, we
noted that homogeneous reaction mixtures were never
obtained, and product yields were inconsistent. A solvent
screen revealed that acetonitrile provided superior solubility of
all reagents with the added benefit of an improved isolated yield
of 86% for 4a (Table 1, entry 9).
Figure 1. Traceless Petasis reaction.
substructure is found within numerous biologically active
compounds6 and is a versatile handle for a number of powerful
transformations.7 As such, new methods for the straightforward
and efficient generation of allenes are highly desirable.
Key to the success of this proposed reaction would be the
addition of the alkynyl nucleophile into hydrazone I to generate
propargyl hydrazide II. Loss of sulfinic acid to afford diazine III
and subsequent extrusion of nitrogen through an alkene walk
pathway (retro-ene process) would produce the desired allene
A variety of aryl and alkyl acetylide salts11 participated in the
reaction to afford the corresponding allenes in good to
excellent yield (Table 2). In general, aryl acetylides afforded
Received: February 14, 2012
Published: March 27, 2012
© 2012 American Chemical Society
5782
dx.doi.org/10.1021/ja301489n | J. Am. Chem. Soc. 2012, 134, 5782−5785

Journal of the American Chemical Society
Communication
a
Table 1. Development of the Traceless Petasis Coupling
catalyst
(10 mol %)
yield 4a
b
entry
Hydrazide
(%)
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3b
3b
3b
3b
3b
−
0
c
Sc(OTf)3
0 (90%)
−
49
66
0
Sc(OTf)3
Cu(OTf)2
Yb(OTf)3
Hf(OTf)4
La(OTf)3
La(OTf)3
73
62
78
86
d
9
a
b
c
1 (0.75 mmol), 2 (0.25 mmol), 3 (0.5 mmol) in CH2Cl2, rt. Isolated yield after chromatography. Isolated yield of intermediate propargylic
d
hydrazide. Reaction conducted in CH3CN.
a
a
Table 2. Alkynyl Partners in the Traceless Petasis Coupling
Scheme 1. Utility of Allenyl Alcohol Products
a
Conditions: (i) AgNO3 (20 mol %), acetone, reflux; (ii) Br2 or I2;
(iii) Dess−Martin periodinane; (iv) (EtO)2P(O)CH2CO2Me, NaH,
−78 °C.
(i.e., 8).7 Allene 4m could be prepared in 82% yield and
converted to the sensitive triene 9, which is the sex attractant of
the dried bean beetle.15
Examples of the Petasis borono-Mannich reaction typically
require the use of an aldehyde that has an α-hydroxyl group, or
a related group that is capable of directing the addition of the
boron species to the C−N π-bond (i.e., glyoxylic acid and
salicaldehyde).2 The traceless Petasis reaction did not work well
with aldehydes lacking an α-hydroxyl group; benzyloxyacetal-
dehyde gave only a 23% isolated yield of the allene product
(not shown). Thus, in a manner analogous to the proposed
mechanism for the regular Petasis reaction,2 the alkyne is most
likely delivered to the intermediate hydrazone intramolecularly
via an activated borate species. High levels of diastereocontrol
for anti-amino alcohols, consistent with internal delivery, have
been reported for several chiral α-hydroxyl aldehydes
participating in the Petasis borono-Mannich reaction.16 For
the traceless Petasis reaction herein, we found that protected
aldehyde 10 gave rise to allene 12 as a 2:1 mixture of
diastereomers (88% yield, Scheme 2). Enantioenriched 10
could be employed with no loss of optical activity.11 The major
diastereomer was converted to tetrahydrofuran 13 by Au-
catalyzed stereospecific cycloetherification17 followed by an
NBSH-derived diimide reduction (60% over 2 steps). The
presence of strong reciprocal NOE signals between H2 and H5
indicated a 2,5-syn stereochemical arrangement in 13. Thus, we
established that the allene adduct 12 possessed the shown
a
1 (0.75 mmol), 2 (0.25 mmol), 3b (0.5 mmol) in CH3CN, rt. Yields
refer to isolated yields after chromatography.
the cleanest and highest yielding reactions (Table 2, 4a−4g).
These reactions also tended to proceed in the shortest time, an
observation that is consistent with the enhanced migratory
aptitude of the more electron-rich triple bond. A number of
aliphatic alkynes underwent the reaction (Table 2, 4h−4m).
Benzyl ether derivatives behaved well (i.e., 4j and 4k), as did a
TBDPS ether derivative (i.e., 4l). In contrast, an alkynyl
trifluoroborate possessing a TBS protected alcohol proved
unstable and delivered the corresponding allene in low yield.
These allenes are useful precursors to a variety of compounds
(Scheme 1), including dihydrofurans 5−7 and allenic aldehydes
5783
dx.doi.org/10.1021/ja301489n | J. Am. Chem. Soc. 2012, 134, 5782−5785

Journal of the American Chemical Society
Communication
for the three contiguous stereogenic elements constructed. The
stereochemistry of the allene 25 was proved by stereospecific
cyclization20 to pyran 26, indicating that the reaction sequence
from 21 likely proceeded via diazine 24, which in turn was
generated by hydroxyl directed addition of the alkyne from an
intermediate such as 23.
Scheme 2. Diastereoselective Allene Synthesis
In summary, we have developed an efficient La(OTf)3-
catalyzed synthesis of allenes by the sulfonylhydrazine-mediated
coupling of hydroxyaldehydes and ketones with alkynyl
trifluoroborates. This new traceless Petasis process offers
́
significant advantages over the related Crabbe synthesis of
allenes,21 in that it proceeds under much milder reaction
conditions and displays a wider substrate scope. The ability of
chiral precursors to impart useful levels of stereoselectivity in
this allene construction will pave the way for application of this
reaction in complex synthetic sequences, especially when
merged with a subsequent stereospecific etherification. Such
applications, as well as the potential for developing catalytic
enantioselective variants of the reaction, offer exciting prospects
for the future.
relative configuration, a result consistent with the stereospecific
extrusion of dinitrogen from the anti-configured diazine 11.
Since we had established that a free hydroxyl group was
necessary for a highly efficient reaction, this stereochemical
outcome can be rationalized by a preference for directed alkyne
addition via A(1,2)-minimized conformer 14 in favor of
conformer 15.
Further studies showed that (D)-(+)-glyceraldehye could be
used as a coupling partner to provide the corresponding allenes
16 and 17 with good efficiency (Figure 2). Moreover, we found
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, stereochemical proofs, and
spectra data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
Figure 2. Additional substrates explored.
r-thomson@northwestern.edu
Notes
that α-hydroxyketones were competent reaction partners. α-
Hydroxyacetone and 1-hydroxyhexan-2-one afforded allenes 18
and 19 in 74% and 66% yield, respectively. 2-Hydroxycyclohex-
anone gave the desired allene product 20 in 62% yield and with
20:1 stereoselectivity, indicating that high levels of stereo-
induction are possible in these cyclic systems.18
We also investigated the possibility that β-hydroxy aldehydes
might participate in this new allene synthesis, and to this end
we report the one-pot enantioselective intramolecular aldol
reaction/traceless Petasis reaction (Scheme 3). Treatment of
dialdehyde 21 with (L)-proline19 provided aldehyde 22 (10:1
dr), to which was added directly alkyne 1a, NBSH (3b), and 10
mol % La(OTf)3. In this manner, allene 25 was isolated in 53%
yield with high levels of both enantio- and diastereoselectivity
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Science
Foundation (CHE0845063), Amgen Inc., Dow Chemical
Company, and Northwestern University. We thank Prof.
Gary Molander (University of Pennsylvania) for a helpful
discussion.
REFERENCES
■
(1) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583−586. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 53, 16463−16470. (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem.
Soc. 1997, 119, 445−446. (d) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1998, 120, 11798−11799.
Scheme 3. One-Pot Aldol/Traceless Petasis Reaction
(2) For a recent review of the Petasis borono-Mannich reaction, see:
Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Chem.
Rev. 2010, 110, 6169−6193.
(3) (a) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc.
2007, 129, 6686−6687. (b) Lou, S.; Schaus, S. E. J. Am. Chem. Soc.
2008, 130, 6922−6923. (c) Bishop, J. A.; Lou, S.; Schaus, S. E. Angew.
Chem., Int. Ed. 2009, 48, 4337−4340.
(4) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2006, 45, 3635−3638. (b) Muncipinto, G.; Moquist, P. N.;
Schreiber, S. L.; Schaus, S. E. Angew. Chem., Int. Ed. 2011, 50, 8172−
8175.
(5) (a) Mundal, D. A.; Lee, J. J.; Thomson, R. J. J. Am. Chem. Soc.
2008, 130, 1148−1149. (b) Mundal, D. A.; Lutz, K. E.; Thomson, R. J.
Org. Lett. 2009, 11, 465−468. (c) Mundal, D A.; Avetta, C. A. Jr.;
Thomson, R. J. Nat. Chem. 2010, 2, 294−297. (d) Lutz, K. E.;
Thomson, R. J. Angew. Chem., Int. Ed. 2011, 50, 4437−4440.
5784
dx.doi.org/10.1021/ja301489n | J. Am. Chem. Soc. 2012, 134, 5782−5785

Journal of the American Chemical Society
Communication
(6) For a review on the synthesis and properties of allenic natural
products, see: Hoffman-Roder, A.; Krause, N. Angew. Chem., Int. Ed.
̈
2004, 43, 1196−1216.
(7) For useful reviews on the synthetic utility of allenes, see: (a) Ma,
S. Chem. Rev. 2005, 105, 2829−2871. (b) Ma, S. Aldrichimica Acta
2005, 40, 91−102. (c) Krause, N.; Winter, C. Chem. Rev. 2011, 111,
1994−2009.
(8) (a) Vedejs, E.; Stolle, W. T. Tetrahedron Lett. 1977, 18, 135−138.
(b) Bertz, S. H. Tetrahedron Lett. 1980, 21, 3151−3154. (c) Myers, A.
G.; Kukkola, P. J. J. Am. Chem. Soc. 1990, 112, 8208−8210. (d) Myers,
A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891−8892.
(e) Smith, A. B.; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 1999,
121, 7423−7424.
(9) Barluenga and coworkers have reported a coupling of
tosylhydrazones with boronic acids that proceeds under basic
conditions via diazo-intermediates rather than monoalkyldiazines;
see: Barluenga, J.; Tomas
Chem. 2009, 1, 494−499.
́ ́
-Gamasa, M.; Aznar, F.; Valdes, C. Nat.
(10) (a) Myers, A. G.; Finney, N. S.; Kuo, E. Y. Tetrahedron Lett.
1989, 40, 5747−5750. (b) Myers, A. G.; Finney, N. S. J. Am. Chem.
Soc. 1990, 112, 9641−9643. (c) Myers, A. G.; Zheng, B. J. Am. Chem.
Soc. 1996, 118, 4492−4493. Also see: (d) Movassaghi, M.; Ahmad, O.
K. J. Org. Chem. 2007, 72, 1838−1841.
(11) See Supporting Information for full experimental details.
(12) For examples of trifluoroborates participating in Petasis borono-
Mannich reactions, see: (a) Stas, S.; Abbaspour Tehrani, K.
Tetrahedron 2007, 63, 8921−8931. (b) Konev, A. S.; Stas, S.;
Novikov, M. S.; Khlebnikov, A. F.; Abbaspour Tehrani, K. Tetrahedron
2008, 64, 117−123. (c) Stas, S.; Abbaspour Tehrani, K.; Laus, G.
Tetrahedron 2008, 64, 3457. (d) Abbaspour Tehrani, K.; Stas, S.;
Lucas, B.; Kimpe, N. D. Tetrahedron 2009, 65, 1957−1966. (e) Petasis,
N. A.; Butkevich, A. N. J. Organomet. Chem. 2009, 694, 1747−1753.
(f) Jury, J. C.; Swamy, N. K.; Yazici, A.; Willis, A. C.; Pyne, S. G. J. Org.
Chem. 2009, 74, 5523−5527.
(13) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436−
5445.
(14) For the preparation of NBSH, see: Myers, A. G.; Zheng, B.;
Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
(15) Horler, D. F. J. Chem. Soc. (C) 1970, 859−862.
(16) For selected examples of diastereoselective Petasis borono-
Mannich reactions of α-hydroxy aldehydes, see refs 1d, 4, 12f, and the
following: (a) Surya Prakask, G. K.; Mandal, M.; Schweizer, S.; Petasis,
N. A.; Olah, G. A. Org. Lett. 2000, 2, 3173−3176. (b) Davis, A. S.;
Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2004, 69,
3139−3143. (c) Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71,
7097−7099. (d) Hong, Z.; Liu, L.; Sugiyama, M.; Fu, Y.; Wong, C.-H.
J. Am. Chem. Soc. 2009, 131, 8352−8353. (e) Au, C. W. G.; Nash, R. J.;
Pyne, S. G. Chem. Commun. 2010, 46, 713−715.
(17) Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537−2538.
̈
(18) Stereoselective approaches to such α-allenols by the nucleophilic
opening of propargyl epoxides have been reported. For examples, see:
(a) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetrahedron
1991, 47, 1677−1696. (b) Miura, T.; Shimada, M.; Ku, S.-Y.; Tamai,
T.; Murakami, M. Angew. Chem., Int. Ed. 2007, 46, 7101−7103.
(c) Miura, M.; Shimada, M.; de Mendoza, P.; Deutsch, C.; Krause, N.;
Murakami, M. J. Org. Chem. 2009, 74, 6050−6054.
(19) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int.
Ed. 2003, 42, 2785−2788. For a related one-pot aldol/Wittig reaction,
see: Hu, D. X.; Clift, M. D.; Lazarski, K. E.; Thomson, R. J. J. Am.
Chem. Soc. 2011, 133, 1799−1804.
(20) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485−4488.
́
(21) The Crabbe allene synthesis involves the high temperature
decomposition of N-alkylpropargylic amines through a retro-ene
fragmentation. Modest yields and a narrow substrate tolerance have
limited the use of this interesting reaction. See: Crabbe,
́
P.; Fillion, H.;
Andre, D.; Luche, J. L. J. Chem. Soc., Chem. Commun. 1979, 859−860.
́
5785
dx.doi.org/10.1021/ja301489n | J. Am. Chem. Soc. 2012, 134, 5782−5785