Investigation of a domino heck reaction for the rapid synthesis of bicyclic natural products

Article abstract of DOI:10.1002/chem.201001689

(Figure Presented) Unexpected Heck: During efforts toward the synthesis of FR900482, an unexpected domino Heck product was isolated (see scheme). Although this pathway was ultimately not productive for the aforementioned natural product synthesis, efforts were made to extend the methodology to the synthesis of amurensinine. To our knowledge this domino reaction was the first such tandem Heck-alkylation pathway in the presence of a geometrically favorable β-hydrogen elimination.

Full text of DOI:10.1002/chem.201001689

DOI: 10.1002/chem.201001689
Investigation of a Domino Heck Reaction for the Rapid Synthesis of Bicyclic
Natural Products
Barry M. Trost,*[a] Brendan M. OꢀBoyle,[b] and Daniel Hund[c]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
The Heck reaction has proven to be an exceptionally
useful tool for the construction of carbon–carbon bonds.
The traditional Heck reaction consists of oxidative addition
by palladium(0) to a carbon–halogen bond, followed by mi-
gratory insertion into a carbon–carbon p-system and finally
b-hydrogen elimination. A number of clever domino reac-
tions[1] have been implemented using either sequential Heck
reactions[2] or an initial Heck reaction in tandem with anoth-
er palladium catalyzed process.[3]
During efforts toward the synthesis of FR900482,[4] we in-
tended to utilize an 8-exo-trig Heck reaction to forge the
Scheme 1. Synthetic planning toward (+)-FR900482 utilizing a Heck cou-
pling.
benzazacine core of the molecule (Scheme 1). Instead when
3 was exposed to Heck reaction conditions[5] a remarkable
result was obtained. Rather than the expected exocyclic
olefin 2, bicycle 6 was formed in remarkable yield with no
trace of the expected Heck product [Eq. (1)]. This result
represented an unprecedented domino Heck/alkylation,
even in the presence of geometrically accessible b-hydrogen
atoms. We were intrigued by this demonstration that b-hy-
drogen elimination may not always be kinetically preferred
over alternative terminating steps. This possibility would
open many alternative synthetic disconnections if it could be
employed in a predictable manner.
Several mechanistic scenarios could account for this re-
markable transformation (Scheme 2). We believe the most
likely mechanism for the observed product is oxidative addi-
tion of Pd0 to the carbon–iodine bond of 3 yielding 3a, fol-
lowed by migratory insertion through an 8-exo-trig pathway
to afford intermediate 3d. Rather than the expected b-hy-
drogen elimination, which is not geometrically inaccessible,
a transannular alkylation reaction ensued. This most likely
occurs by nucleophilic displacement of palladium by nitro-
gen, which regenerated the Pd0 catalyst and yielded tetracy-
[a] Prof. B. M. Trost
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (+1)650-725-0002
E-mail: bmtrost@stanford.edu
[b] Dr. B. M. OꢀBoyle
Merck Research Laboratories:
BMB 3-114, 33 Avenue Louis Pasteur
Boston, MA 02115 (USA)
[c] D. Hund
Institute of Inorganic and Analytical Chemistry
University Freiburg, Albertstrasse 21
77871 Freiburg (Germany)
À
cle 6. A reductive elimination pathway to form the C N
À
bond is also conceivable, however, the lack of reported C N
reductive elimination with this catalyst system causes us to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001689.
favor an alkylation pathway. The surprising reluctance of 3d
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COMMUNICATION
Disconnection of the indicated carbon–nitrogen bond of 7
would lead to organopalladium intermediate 8 prior to
transannular alkylation (Scheme 3). Bromide 9 would then
represent the immediate precursor to the natural product,
and could be accessed in a few steps from aromatic frag-
ments, such as 10 and 11. These fragments were easily pre-
pared through a known procedure for 11 and through a Mo-
lander/Suzuki[9] coupling between commercially available
potassium vinyltetrafluoroborate and 5-bromopiperanal (12,
[Eq. (2)]).
Scheme 2. Mechanism of the unexpected domino-Heck alkylation reac-
tion.
With fragments 10 and 11 in hand, efforts turned toward
completion of the domino-Heck substrate (Scheme 4). Mon-
ometallation of bis-bromide 11 in the presence of magnesi-
um proved more difficult than expected. Barbier conditions
to participate in b-hydrogen elimination is convincing evi-
dence that the relative rate of the elimination is dramatically
less than that of alkylation. The former may be hindered by
the bulky groups flanking palladium in 3d, which inhibit the
requisite syn conformation between palladium and the ben-
zylic hydrogen needed for elimination to occur. Also, the
conformation of 3d may enhance the rate of alkylation.
Within an 8-membered ring transannular events are particu-
larly favorable, which may further bias the reaction toward
bicycle formation.
The above result is reminiscent of the work of Grigg,[6] in
which similar organopalladium intermediates underwent
substitution with nucleophiles, such as acetate and cyanide.
To the best of our knowledge, no previous reactions of this
type have been reported when geometrically accessible b-
hydrogen atoms were present. We were intrigued by the po-
tential synthetic impact of this domino-Heck methodology.
To test whether the reaction could be extended to other sys-
tems, we devised a synthetic approach to amurensinine
(7),[7,8] that relied on this domino-Heck reaction manifold as
a key step (Scheme 3).
Scheme 4. Preparation of the domino-Heck substrate.
(In0, NH4Cl (aq), THF) failed to provide the desired prod-
uct as well, as did Nozaki–Hiyama–Kishi conditions (CrCl2,
NiCl2, DMSO). Particularly in light of the eventual need for
an asymmetric synthesis, an umpolung coupling with an acyl
anion equivalent, followed by reductive amination appeared
to be a promising alternative. Formation of the trimethylsi-
lylcyanohydrin (10, cat. ZnI2, trimethylsilylcyanide
(TMSCN), 1,2-dichloroethane (DCE)) was accomplished in
excellent yield. Metallation, coupling, and base induced
cleavage of the cyanohydrin were accomplished in one pot
yielding benzylic ketone 13.
Installation of the amino group was attempted by reduc-
tion and nucleophilic substitution (1. NaBH4, MeOH;
2. PPh3Br2, PhNH2, THF). Unfortunately, only elimination
resulted in this case or with mesylation and attempted nu-
cleophilic substitution. Low reactivity was observed under
typical reductive amination conditions (NaBH3CN, MeOH,
AcOH, PhNH2). However, forcing conditions (TiCl4,
PhNH2, Et3N, 1,2-dimethoxyethane (DME)) finally rem-
edied the problem and provided either the N-phenyl or
Scheme 3. Proposed domino-Heck reaction.
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B. M. Trost et al.
benzyl substituted secondary amines (14 and 15). It was en-
visioned that the phenyl group could be readily cleaved with
methylation under the conditions reported by MacMillan
and co-workers.[10]
Hartwig coupling should be disfavored due to the ring strain
of 21. Furthermore, one possible explanation for the forma-
tion of the normal Heck product would be if the amino and
organopalladium intermediate were trans to one another
yielding epi-18 after migratory insertion. As the amine in in-
termediate 20 might be more disposed to coordinate to pal-
ladium, it seemed possible that this Heck reaction might
have a better chance for success.
To test this possibility cyanohydrin 22 and benzyl bromide
24 were prepared [Eq. (3) and (4)]. It proved to be benefi-
cial to the yield of the umpolung coupling to purify 22
through filtration through a plug of Fluorosil.
With 14 and 15 in hand, attention turned toward the cru-
cial domino-Heck reaction. Conditions completely analo-
gous to the successful formation of 2 failed entirely due to
complete oxidative decomposition of the starting material in
the presence of silver(I)carbonate. Fortunately, use of the
less oxidizing silver phosphate alleviated this problem and
good conversion and recovery could be obtained. Unfortu-
nately, the best conditions examined gave a mixture of the
normal Heck product and the Buchwald/Hartwig product in
a combined 87% yield (Scheme 5). Moving to more elec-
tron-withdrawing ligands was envisioned to disfavor the
Buchwald/Hartwig coupling and hopefully speed the rate of
transannular nucleophilic alkylation. However, no conver-
sion was witnessed under these reaction conditions.
Benzyl bromide 24 was quite sensitive to decomposition,
but could be isolated without special precaution so long as it
was immediately used in the umpolung coupling
(Scheme 7). The corresponding benzylic ketone 25 was pre-
pared in an analogous manner as before. Reductive amina-
tion gave amine 19 in superior yield to the previous exam-
ple.
Scheme 5. Attempted domino Heck/alkylation reaction.
At this point, an alternative disconnection was investigat-
ed (Scheme 6). Transposition of the vinyl and bromo sub-
stituents on the domino-Heck substrate would produce or-
ganopalladium intermediate 18 directly from bromide 15
after oxidative addition. Through this alteration, Buchwald/
Scheme 7. Preparation of a second domino-Heck substrate.
The domino-Heck reaction was reinvestigated employing
19 as the substrate. Qualitatively, it seemed that this sub-
strate was more sluggish in the Heck reaction. Employing
the optimal conditions from the previous example or
[PdCl2·dppf] (dppf=1,1’-bis(diphenylphosphino)ferrocene)
failed to give appreciable conversion. Palladium bis(triphe-
nylphosphinedichloride) gave only slight conversion to the
same normal Heck product as before. Only palladium(II)a-
cetate with tri(tert-butyl)phosphine tetrafluoroborate adduct
gave a good yield, again for the normal Heck product
(Scheme 8). The Buchwald/Hartwig coupling product that
Scheme 6. Rethinking the domino-Heck reaction.
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Domino-Heck Reaction for the Synthesis of Natural Products
COMMUNICATION
favor the desired product formation, although modification
of the substrate in this manner would not be trivial.
In conclusion, we report the first example of an abnormal
domino-Heck alkylation reaction in which geometrically ac-
cessible b-hydrogen elimination does not occur. This finding
is significant because the underlying assumption that the
Heck reaction must terminate in b-elimination greatly limits
the possible synthetic scope of the process. Although our at-
tempt to employ this reaction in the synthesis of amurensi-
nine (7) has not yet proved fruitful, sufficient understanding
of the Heck reaction would provide access to such polycyclic
structures in a streamlined and atom economical[11] manner.
To successfully implement this reaction manifold, greater
understanding must be obtained concerning the factors that
govern the relative rates of multiple possible terminating el-
ementary steps. For example, is the failure of 19 to partici-
pate in the desired alkylation most strongly influenced by
the conformation of intermediate 18? Perhaps alternate li-
gands or nitrogen protecting groups would positively impact
formation of the desired product rather than the normal
Heck product. Or perhaps only in the presence of suitable
coordinating or flanking groups (compare 18 and 26,
Scheme 9) will the desired reaction prove feasible.
Further investigation is certainly warranted to delineate
these factors. In a similar vein, Fuꢀs[12] extension of the
scope of Suzuki coupling to sp3–sp3 systems has proven pivo-
tal in opening new synthetic disconnections and furthering
understanding of organometallic chemistry required for
carbon–carbon bond construction. This development was ac-
complished by challenging conventional assumptions regard-
ing the Suzuki reaction. A similar approach to the Heck re-
action is likely to provide similar rewards.
Scheme 8. Preparation of a second domino-Heck substrate.
had dominated in the previous substrate was not observed.
The structure of 17 was confirmed through X-ray diffraction
analysis. Although completion of the synthesis through 17
probably could have been accomplished, pursuing this task
failed to address the real purpose of this methodology study.
The source of the difference in product distribution when
3 was employed under Heck conditions versus when 14, 15,
or 19 were employed may be manifold. The simplest explan-
ation is that the requisite cis stereochemistry between palla-
dium and the amine required for alkylation was not formed.
It is also possible that 18 was formed, but that a lower barri-
er for a co-planar conformation was required for the b-hy-
drogen elimination than was the case for 3a due to lessened
steric hindrance limiting the formation of the requisite co-
À
À
planer relationship between the C Pd and C H bonds
(Scheme 9). Analysis of 3a, the organopalladium intermedi-
Experimental Section
Tetracycle 6: A dry flask was charged with 3 (184.7 mg, 0.26 mmoles),
palladium acetate (5.9 mg, 26 mmoles), triphenyphosphine (33.4 mg,
0.104 mmoles) and silver carbonate (144.3 mg, 0.522 mmoles). Freshly
distilled dioxane was injected (7 mL) and the reaction was warmed to
608C in an oil bath. After 3 h the starting material was consumed as de-
termined by TLC analysis (8:1:1 petroleum ether/EtOAc/CH2Cl2) and
the fact that a significant amount of palladium black had precipitated
from the reaction mixture. The reaction was allowed to cool to ambient
temperature and filtered though a plug of Celite. The filter cake was
washed with ethyl acetate and the combined filtrate was concentrated
under reduced pressure. Flash chromatography (85:10:5 hexane/ethyl
acetate/CH2Cl2) gave tetracycle 6 as a clear oil (132.7 mg, 87%). [a]D =
À7.28 (c=0.32, CHCl3); 1H NMR (600 MHz, CDCl3): d=7.42–7.30 (m,
5H), 7.10 (d, 1H, J=1.2 Hz), 6.85 (d, 1H, J=1.2 Hz), 5.14–5.09 (m, 2H),
4.04 (d, 1H, J=8.4 Hz), 4.01 (d, 1H, J=12.6 Hz), 3.87 (s, 3H), 3.27 (dd,
1H, J=8.4, 16.2 Hz), 3.02 (ddd, 1H, J=8.4, 8.4, 10.8 Hz), 2.94 (dd, 1H,
J=2.4, 10.2 Hz), 2.84 (dd, 1H, J=1.8, 6.6 Hz), 2.65 (d, 1H, J=6.0 Hz),
2.51 (dd, 1H, J=11.0, 16.2 Hz), 1.44 (s, 9H), 0.95 (s, 9H), 0.21–0.17 ppm
(d, 6H); 13C NMR (125 MHz, CDCl3): d=167.8, 161.8, 155.2, 153.7,
137.6, 131.5, 129.1, 128.5, 128.0, 122.2, 106.5, 103.3, 82.1, 72.0, 70.8, 68.1,
52.7, 45.4, 43.4, 37.3, 32.2, 28.6, 26.4, 15.5, À3.6, À4.1 ppm; IR (neat): n˜ =
Scheme 9. Comparing successful and unsuccessful domino-Heck sub-
strates.
ate responsible for formation of 2, reveals that there are
likely to be significant non-bonding interactions between
the groups flanking palladium, which may explain the differ-
ence in the competitive rates for b-hydrogen elimination
versus alkylation. Although intermediate 18 was envisioned
to have hindered rotation as well, it is apparent from experi-
mental evidence that this was not the case or alternatively
that the epimeric organopalladium intermediate may be fa-
2954, 2931, 2857, 1722 (sharp) cmÀ1 HRMS (EI+): m/z: calcd for
;
[C32H44N2NaO6Si]+: 580.2969; found: 580.2968.
À
vored, causing the C N bond formation to be geometrically
inaccessible. Incorporating trimethylsilyl groups (26), might
Normal Heck product 17: A flask containing 19 (22.0 mg), silver carbon-
ate (7.0 mg), potassium carbonate (9.4 mg), palladium acetate (0.9 mg)
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B. M. Trost et al.
and tri(tert-butyl)phosphine tetrafluroborate (1.7 mg) was charged with
dry dioxane (1 mL) and stirred at 1008C for 18 h. After cooling to ambi-
ent temperature, the reaction was diluted with EtOAc and water. The or-
ganic phase was washed with water once more, and dried over magnesi-
um sulfate. The crude product was purified by flash chromatography
(3% EtOAc in toluene) to give 17 as a white solid (16.5 mg, 90%).
1H NMR (500 MHz, CDCl3): d=7.20–7.10 (m, 2H), 6.90–6.60 (m, 6H),
6.65 (s, 1H), 5.95 (d, J=10.5 Hz, 2H), 5.42 (d, J=1.2 Hz, 1H), 5.40 (d,
J=1.2 Hz, 1H), 4.95–4.90 (m, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.38–
3.18 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d=150.6, 148.3, 147.3,
146.8, 146.5, 133.9, 132.7, 129.3, 128.9, 128.6, 126.4, 117.6, 116.5, 113.7,
112.9, 111.2, 108.5, 108.2, 101.0, 56.0, 55.9, 53.9, 37.8 ppm; IR (thin film):
n˜ =3392, 2908, 1601, 1505, 1481, 1237 cmÀ1; HRMS (ESI+): m/z: calcd
for C25H24NO4: 402.1627 [M+H]+; found: 402.1620.
[2] The palladium-catalyzed zipper reaction, although not technically a
Heck reaction is an excellent example of multiple bond formation
through sequential carbopalladation: a) B. M. Trost, Y. Shi, J. Am.
Chem. Soc. 1991, 113, 701; b) T. Sugihara, C. Coperet, Z. Owczarc-
zyk, L. S. Harring, E. Negishi, J. Am. Chem. Soc. 1994, 116, 7923.
[3] Selected examples of domino-Heck methodology: a) Y. Zhang, G.
Wu. , G. Agnel, E. Negishi, J. Am. Chem. Soc. 1990, 112, 8590;
b) B. M. Trost, J. Dumas, J. Am. Chem. Soc. 1992, 114, 1924; c) L. F.
Tietze, T. Nçbel, M. Spescha, J. Am. Chem. Soc. 1998, 120, 8971;
d) L. F. Tietze, H. Braun, P. L. Steck, S. A. A. El Bialy, N. Tçlle, A.
Dꢂfert, Tetrahedron 2007, 63, 6437; e) L. E. Overman, Pure Appl.
Chem. 1994, 66, 1423.
[4] B. M. Trost, B. M. OꢀBoyle, Org. Lett. 2008, 10, 1369.
[5] M. M. Abelman, L. E. Overman, V. D. Tran, J. Am. Chem. Soc.
1990, 112, 6959.
[6] R. Grigg, V. Sridharan, J. Organomet. Chem. 1999, 576, 65 and refer-
ences therein.
[7] Application in nervous system disorders: W. E. Childers, Jr., M. A.
Abou-Gharbia, U. S. Patent 4940789, 1990.
Acknowledgements
[8] Synthetic studies: a) U. K. Tambar, D. C. Ebner, B. M. Stoltz, J. Am.
Chem. Soc. 2006, 128, 11752; b) L. Carrillo, D. Badia, E. Domi-
nguez, J. L. Vicario, I. Tellitu, J. Org. Chem. 1997, 62, 6716.
[9] G. A. Molander, M. R. Rivero, Org. Lett. 2002, 4, 107.
[10] N. A. Paras, B. Simmons, D. W. C. MacMillan, Tetrahedron 2009, 65,
3232.
We acknowledge S. Lynch for his invaluable help in the acquisition of
2D NMR spectroscopy data and A. Oliver for the acquisition of X-ray
data. We thank the Stanford Graduate Fellowship Program and NIH
(GM 13598) for their generous financial support of our program and
Johnson Matthey for their supply of precious metal salts.
[11] a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost, Angew.
Chem. 1995, 107, 285.
[12] B. Saito, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 6694 and references
therein.
Keywords: amurensinine
reaction · palladium · synthetic methods
·
domino reactions
·
Heck
[1] a) L. F. Tietze, T. Kinzel, Pure Appl. Chem. 2007, 79, 629; b) K. C.
Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118,
7292; Angew. Chem. Int. Ed. 2006, 45, 7134.
Received: June 14, 2010
Published online: July 28, 2010
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Chem. Eur. J. 2010, 16, 9772 – 9776