Remote Nucleophilic Allylation by Allylrhodium Chain Walking

Article abstract of DOI:10.1002/chem.201803574

Metal migration through a carbon chain is a versatile method for achieving remote functionalization. However, almost all known examples involve the overall net migration of alkylmetal species. Here, we report that allylrhodium species obtained from hydrorhodation of 1,3-dienes undergo chain walking toward esters, amides, or (hetero)arenes over distances of up to eight methylene units. The final, more highly conjugated allylrhodium species undergo nucleophilic allylation with aldehydes and with an imine to give Z-homoallylic alcohols and amines, respectively.

Full text of DOI:10.1002/chem.201803574

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Title: Remote Nucleophilic Allylation by Allylrhodium Chain Walking
Authors: Alistair Groves, Jose I Martínez, Joshua J Smith, and Hon
Wai Lam
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Remote Nucleophilic Allylation by Allylrhodium Chain Walking
Alistair Groves, Jose I. Martínez+, Joshua J. Smith+, and Hon Wai Lam*
Abstract: Metal migration through a carbon chain is a versatile
method for achieving remote functionalization. However, almost all
known examples involve the overall net migration of alkylmetal
species. Here, we report that allylrhodium species obtained from
hydrorhodation of 1,3-dienes undergo chain walking toward esters,
amides, or (hetero)arenes over distances of up to eight methylene
units. The final, more highly conjugated allylrhodium species
undergo nucleophilic allylation with aldehydes and an imine to give
Z-homoallylic alcohols and amines, respectively.
Remote functionalization reactions are those in which an initial
interaction of a functional group with a reagent or catalyst leads
to eventual reaction at a distal site.[1] Although achieving high
efficiency and selectivity in such processes is often challenging,
developments in this area can facilitate the activation of
otherwise unreactive C–H and C–C bonds, thus providing
powerful new tools for synthesis. Of the available methods for
remote functionalization, metal migration through a carbon chain,
or “chain walking”, is particularly versatile as it dispenses with
the need for complex directing groups (Scheme 1A).[1g–i, 2 , 3 ]
However, most known metal chain walking reactions effectively
result in the overall net migration of alkylmetal species (Scheme
1A). Chain walking of organometallics beyond simple
alkylmetals, such as allylmetal species (Scheme 1B), could
dramatically expand the scope of remote functionalizations, but
to our knowledge, there are such few examples.[4]
During our studies of enantioselective nucleophilic allylations
of imines,[4b,5] we discovered the first examples of allylrhodium
chain walking (Scheme 1C).[4b] These reactions employ δ-
trifluoroboryl α,β-unsaturated esters as precursors to
allylrhodium species A. Chain walking of A towards the ester is
proposed to occur via a 1,3-diene-ligated rhodium hydride B to
give the more highly conjugated, and presumably
thermodynamically more stable allylrhodium species C, which
Scheme 1. Metal chain walking.
and in principle, any of the intermediate allylrhodium species can
react with the electrophile to give complex mixtures of products.
Herein, we describe remote nucleophilic allylations of aldehydes
and an imine, in which allylrhodium chain walking occurs
through up to eight methylene units (Scheme 1D).
then reacts with the imine in
a highly diastereo- and
enantioselective nucleophilic allylation.[4b]
To increase the synthetic utility of allylrhodium chain walking,
we wondered whether migration could be accomplished through
more than just one methylene carbon. This goal was expected to
be challenging because rhodium must participate in a greater
number of steps before the final allylrhodium species is formed,
For this study, the use of allylrhodium precursors that are
simpler to prepare than allyltrifluoroborates was desirable. We
therefore considered generating allylrhodium species by the
hydrorhodation of 1,3-dienes, as described by Kimura and co-
6
]
workers in related reductive nucleophilic allylations.[
Accordingly, substrate 1a was reacted with benzaldehyde (1.2
equiv) in the presence of [Rh(cod)OH]2 (5 mol%) and Et3B (2.0
equiv) in THF at 50 °C for 16 h.[6] Pleasingly, this reaction gave
[]
A. G. Groves, Dr. J. I. Martinez, Dr. J. J. Smith, Prof. H. W. Lam
The GlaxoSmithKline Carbon Neutral Laboratories for Sustainable
Chemistry, University of Nottingham, Jubilee Campus, Triumph
Road, Nottingham, NG7 2TU (UK)
homoallylic alcohol 2a, which was isolated as
a single
diastereomer in 60% yield [Eq. (1) and Table 1, entry 1].[7] The
use of Et3SiH in place of Et3B gave no reaction.
E-mail: hon.lam@nottingham.ac.uk
Homepage: http://www.nottingham.ac.uk/~pczhl/
Dr. J. I. Martinez, Dr. J. J. Smith, Prof. H. W. Lam
School of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD (UK)
[+] These authors contributed equally.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/
A possible catalytic cycle is shown in Scheme 2. First, the
reaction of [Rh(cod)OH]2 with Et3B generates the ethylrhodium
species 3, which undergoes β-hydride elimination to give
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Table 1. Scope of the 1,3-diene.[a]
entry
diene
method product
yield (%)[b]
walking through one carbon:
1
2
1a
1b
A
A
2a
2b
60
65
walking through two carbons:
Scheme 2. Proposed catalytic cycle.
3
4
1c
1d
A
B
2b
2c
41
51
rhodium hydride 4. Hydrorhodation of 1,3-diene 1a with 4 then
provides allylrhodium species 5A, which undergoes σ-π-σ
isomerization to give 5B.[8] β-Hydride elimination of 5B gives a
rhodium hydride coordinated to benzyl sorbate (as in 6).
Hydrorhodation of the alkene distal to the ester gives
allylrhodium species 7, resulting in an overall 1,4-hydrogen shift
from the carbon adjacent to the carbonyl group, to the
methylene carbon adjacent to the methyl group. Allylrhodium
species 7 then reacts with benzaldehyde in a nucleophilic
allylation through conformation 8, in which the ethyl group
occupies a pseudoaxial position to minimize unfavorable non-
bonding interactions with the cyclooctadiene ligand. Reaction of
the resulting rhodium alkoxide 9 with Et3B or Et2BOH gives 10
(which upon workup gives the product 2a) and regenerates the
ethylrhodium species 3.
Having established proof of principle, the scope with respect
to the diene was investigated (Table 1). One of two sets of
conditions were employed. Method A used 2.0 equivalents of
Et3B in THF at 50 °C, whereas method B used 3.0 equivalents of
Et3B in dioxane at 80 °C. Method B was used for reactions that
did not proceed in high conversion with method A. Pleasingly, a
range of dienes reacted successfully with benzaldehyde to give
products of chain walking–nucleophilic allylation 2 in up to 65%
yield. These reactions also gave complex mixtures of other
products in ca. 20% yield, which were tentatively identified as
nucleophilic allylation products resulting from various
intermediate allylrhodium species.[ 9 ] The complexity of the
reactions prevented determination of the diastereoselectivities
by 1H NMR analysis, but with a few exceptions (entries 7–9), the
products 2 were isolated as single diastereomers. In addition to
chain walking through one carbon (entries 1 and 2), walking
through two carbons (entries 3–8) and three carbons is possible
(entries 10 and 11). As well as terminal dienes (R2 = H, entries 1,
3, and 10), the process is compatible with internal dienes with
various alkyl groups at R2 (entries 2, 4, 6–8, and 11). However,
5
1e
B
2d
<5
6
7
8
1f
B
B
B
2e
2f
35
1g
1h
46 (11:1 d.r.)[c]
43 (9:1 d.r.)[c]
2g
9
1i
B
2h
23 (3:1 d.r.)[d,e]
walking through three carbons:
1j
B
10
2c
2i
53
56
11
1k
B
[a] Reactions were conducted with 0.30 mmol of 1. [b] Yield of isolated product.
Unless stated otherwise, the products were isolated as single diastereomers.
[c] Conducted with 0.24 mmol of 1i. [d] Isolated as a mixture of inseparable
diastereomers in the ratio indicated in parentheses. [e] The reaction time was
40 h.
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diene 1e, which contains a 1-chlorobutyl group, only returned
unchanged starting materials (entry 5).[ 10 ] Methyl and phenyl
esters are also tolerated (entries 7 and 8). An amide also
promotes chain walking, but with lower efficiency (entry 9).
Chain walking over greater distances is possible, as shown
by the reaction of diene 1l, which contains eight methylene units
between the diene and the ester [Eq. (2)].
The discovery that arenes also promote allylrhodium chain
walking significantly increases the possibilities of this chemistry,
and this aspect was explored further in the reaction of dienes
13a–13g with benzaldehyde (Scheme 4). As expected, the
phenyl-terminated diene 13a reacted successfully to give 14a in
50% yield.[7] Other arenes that bring about chain walking include
2-naphthyl (14b), 2-fluorophenyl (14c), and 3-methoxyphenyl
groups (14d). Pleasingly, heteroarenes such as 2-pyridyl (14e),
2-furyl (14f), and 2-thienyl (14g) groups are also effective.
Next, variation of the aldehyde was investigated with diene
1d (Scheme 3). Aromatic aldehydes containing various para-,
meta-, or ortho-substituents are tolerated to give 11a, 11b, 11d,
and 11e in 50‒62% yield. 4-Bromobenzaldehyde returned only
unchanged starting materials,[10] whereas 2-furaldehyde gave
11f in 40% yield. Linear and branched aliphatic aldehydes are
also tolerated (11f–11j). Tetrahydro-2H-pyran-2-ol reacted
successfully to give 11k in 58% yield.
Scheme 4. Scope of the 1,3-dienes with a (hetero)arene terminus. Reactions
were conducted with 0.30 mmol of 13. Unless stated otherwise, yields are of
isolated, single diastereomers. [a] The diastereoselectivity was >19:1 d.r. as
determined by 1H NMR analysis of the crude reaction mixture. [b] Isolated as a
mixture of inseparable diastereomers in the ratio indicated in parentheses.
An advantageous feature of these reactions is that the
stereochemistry of the starting dienes appears inconsequential,
which removes the need to prepare the substrates in high
stereoisomeric purity. For example, the reaction of diene
(3E,5Z)-13a with benzaldehyde gave results that are
comparable with its (E,E)-counterpart [Eq. (4), compare with
Scheme 4]. A mixture of all four possible stereoisomers of 13a
can also be used with similar efficiency [Eq. (5)].
Scheme 3. Scope of the aldehyde. Reactions were conducted with 0.30 mmol
of 1d. Unless stated otherwise, yields are of isolated, single diastereomers. [a]
The diastereoselectivity was >19:1 d.r. as determined by 1H NMR analysis of
the crude reaction. [b] Isolated as a mixture of inseparable diastereomers in
the ratio indicated in parentheses.
Interestingly, diene 1m, which contains an ester and a
phenyl group at the termini, reacted with benzaldehyde to give a
mixture of products differing in the direction of chain walking [Eq.
(3)]. The product of chain walking towards the ester (2k) was
isolated in 15% yield, while product 12, resulting from chain
walking towards the phenyl group, was obtained in 31% yield.
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The reaction of benzaldehyde with the doubly deuterium-
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purity, in which one deuterium atom was transferred to the
homoallylic methylene carbon, with no evidence of deuteration
at other sites [Eq. (6)]. This overall 1,4-deuterium shift is
consistent with the mechanism shown in Scheme 2 (see the
Supporting Information for details).
Finally, this process is not limited to aldehyde electrophiles.
Although cyclic imines (Scheme 1C) and ketones are not
suitable substrates, diene 15 reacted with the formaldimine
derived from cracking of 1,3,5-tris(4-methoxyphenyl)-1,3,5-
triazinane to give homoallylic amine 16 in 52% yield [Eq. (7)].
The inclusion of 3 Å molecular sieves was beneficial in
increasing the yield of this reaction.
[2]
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In conclusion, we have reported the rhodium-catalyzed
reductive nucleophilic allylation of aldehydes or an imine with
1,3-dienes, in which carbon–carbon bond formation occurs at a
site remote from the initiation site by the overall net migration of
allylrhodium species. This study illustrates the potential utility of
allylmetal chain walking in remote C‒H functionalization, which
complements much more well-known alkylmetal chain walking
processes. Compared with our previous work (Scheme 1C),[4b]
we have shown that chain walking can proceed through greater
distances (up to eight methylene units). Furthermore, an
expanded range of functional groups was shown to promote
chain walking, which includes esters, amides, and
(hetero)arenes. Our future work will include the development of
enantioselective variants of this process.[11]
[4]
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Received:
((will
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in
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staff))
[6]
[7]
M. Kimura, D. Nojiri, M. Fukushima, S. Oi, Y. Sonoda, Y. Inoue, Org.
Lett. 2009, 11, 3794-3797.
Published online on ((will be filled in by the editorial staff))
The relative configurations of products 2f and 14a were determined by
converting them into cyclic derivatives, followed by 1H NMR analysis of
vicinal coupling constants. See the Supporting Information for details.
The relative configurations of the remaining products were assigned by
analogy.
Acknowledgements
This work was supported by the Engineering and Physical
Sciences Research Council [grant numbers EP/M50810X/1 and
EP/K504348/1]; the Basque Country government; the
Leverhulme Trust [grant number RPG-2016-341]; and
GlaxoSmithKline.
[8]
[9]
Under different reaction conditions, the reaction of rhodium hydrides
with activated 1,3-dienes has been proposed to occur via 1,4-
hydrorhodation. See: R. Dada, Z. Wei, R. Gui, R. J. Lundgren, Angew.
Chem., Int. Ed. 2018, 57, 3981-3984.
These other products were generally not isolated, except in the case of
the reaction producing 14a (see Scheme 4). See the Supporting
Information for details.
Keywords: allylation • chain walking • homogeneous catalysis •
isomerization • rhodium
[10] The reasons for halogen-containing substrates being ineffective are not
currently known, but one possibility is undesired oxidative addition of
Rh(I) with the carbon–halogen bond. For selected examples of
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Çelenligil-Çetin, C. Guo, B. M. Foxman, O. V. Ozerov, J. Am. Chem.
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[11] Using various chiral diene‒rhodium complexes in these reactions led to
low conversions and enantioselectivities.
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A. Groves, J. I. Martínez, J. J. Smith, H.
W. Lam*
Page No. – Page No.
Remote Nucleophilic Allylation by
Allylrhodium Chain Walking
Allylrhodium species obtained from hydrorhodation of 1,3-dienes undergo chain
walking toward esters, amides, or (hetero)arenes over distances of up to eight
methylene units. The final, more highly conjugated allylrhodium species undergo
nucleophilic allylation with aldehydes and an imine to give Z-homoallylic alcohols
and amines, respectively.
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