Copper(I)-catalyzed addition of grignard reagents to in situ-derived N -sulfonyl azoalkenes: An umpolung alkylation procedure applicable to the formation of up to three contiguous quaternary centers

Article abstract of DOI:10.1021/ja100932q

The α-alkylation of N-sulfonyl hydrazones via in situ-derived azoalkenes provides an umpolung approach to ketone α-alkylation that has considerable potential with regard to catalysis and the direct incorporation of functionality not amenable to the use of enolate chemistry. Herein, we describe the first Cu(I)-catalyzed addition of Grignard reagents to in situ-derived N-sulfonyl azoalkenes. This method is remarkable in its ability to deliver highly sterically hindered compounds that would be difficult or impossible to synthesize via traditional enolate chemistry, including those having up to three contiguous quaternary centers.

Full text of DOI:10.1021/ja100932q

Published on Web 03/16/2010
Copper(I)-Catalyzed Addition of Grignard Reagents to in Situ-Derived
N-Sulfonyl Azoalkenes: An Umpolung Alkylation Procedure Applicable to the
Formation of Up to Three Contiguous Quaternary Centers
John M. Hatcher and Don M. Coltart*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
Received February 2, 2010; E-mail: don.coltart@duke.edu
Scheme 1. Selected Approaches to R-Alkylation
Ketone R-alkylation is fundamental to organic synthesis. Not-
withstanding the structural limitations of the electrophile, it is most
often achieved by the addition of an alkyl halide to a preformed
enolate/azaenolate (Scheme 1a). Transition metals have been
investigated recently for catalytic ketone R-alkylation using a variety
of enolate species or precursors.1 Despite the impressive advances
resulting from this work, a general catalytic alkylation method
remains elusive. Umpolung alkylation, wherein an organometallic
species adds to an electrophilic R-carbon provides an attractive
alternative to enolate-based methods.2 This strategy is well-suited
to catalysis and also should prove to be general given the wide
range of structures available as organometallic reagents (e.g., 1°,
2°, and 3° alkyl, aryl, vinyl, alkynyl). Herein, we describe the first
Cu(I)-catalyzed addition of Grignard reagents to in situ-derived
N-sulfonyl azoalkenes. This method is remarkable in its ability to
deliver highly sterically hindered compounds that would be difficult
or impossible to synthesize via traditional enolate chemistry,
including those having up to three contiguous quaternary centers.
Scheme 2. Proposed Cu(I)-Catalyzed Grignard Addition to in
Situ-Derived N-Sulfonyl Azoalkenes
Our efforts were inspired by the realization that N-sulfonyl
hydrazones offer a convenient entry point to umpolung alkylation
(Scheme 1b). A two-electron oxidation would lead to an azoalkene
intermediate (4 f 5) that is susceptible to conjugate addition3 (5
f 6) at the original R-carbon. Because of the highly reactive nature
of azoalkenes, a stepwise alkylation procedure requiring their
isolation is impractical. We reasoned, however, that if in situ
azoalkene formation could be rendered compatible with a catalytic
cycle leading to the production of a nucleophile capable of conjugate
addition (cf. 5 f 6), then a general catalytic R-alkylation method
should be attainable. Fuchs has shown that treatment of R-halo-
N-sulfonyl hydrazones with 2.5 to 3 equiv of phenylcuprate leads
to the formation of the corresponding azoalkenes, which undergo
conjugate addition to provide the R-phenylated derivatives.3,4 On
this basis, we anticipated the development of a Cu(I)-catalyzed
addition of Grignard reagents to in situ-derived N-sulfonyl azoalk-
enes, as outlined in Scheme 2. An R-halo-N-sulfonyl hydrazone
(7) would be combined with at least 2 equiv of a Grignard reagent
and a catalytic amount of a Cu(I) salt. The Grignard reagent would
both act as a Brønsted base to generate the azoalkene (7 f 8) and
undergo in situ transmetalation with the Cu(I) catalyst to form a
cuprate (11)5 capable of conjugate addition to 8. Transmetalation
of the product (9) with MgX2 would liberate the catalyst and 10,
the latter providing the R-alkylated product (6) on workup.
Scheme 3. CuCl-Catalyzed Ethylation of 12
With suitable alkylation conditions available, we examined the
scope of the transformation (Table 1). Primary, secondary, and
tertiary Grignard reagents smoothly underwent the desired trans-
formation with several different primary, secondary, and tertiary
R-chloro-N-sulfonyl hydrazones derived from both ketones and
aldehydes. Of particular note is the transformation in entry 18, in
which compound 35 having two contiguous quaternary carbon
centers was produced in 64% yield.
We next investigated the possibility of conducting one-pot R,R-
bisalkylations beginning from R,R-dichloro-N-sulfonyl hydrazones.
The success of these transformations would require that the
sequential elimination of chloride and addition of the cuprate to
the resulting azoalkene (cf. 7 f 8 f 9, Scheme 2) occur twice in
a cascading fashion. Our results are summarized in Table 2.
Treatment of different R,R-dichloro-N-sulfonyl hydrazones with a
Grignard reagent and CuCl catalyst indeed resulted in the incor-
poration of two identical alkyl groups (entries 1-6) in very good
yield, considering that two alkylations had occurred. An especially
impressive transformation is seen in entry 6, in which a bisalkylated
We began our study by attempting the ethylation of R-chloro-
N-sulfonyl hydrazone 12 with EtMgBr (Scheme 3) and catalytic
amounts of various Cu(I) salts.6 Gratifyingly, the reaction proceeded
very well with a range of Cu(I) salts7 at catalyst loadings as low
as 2 mol %. However, somewhat better results were obtained when
10 mol % CuCl was used, so these conditions were employed for
the remainder of our studies.
9
4546 J. AM. CHEM. SOC. 2010, 132, 4546–4547
10.1021/ja100932q  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope of the Cu(I)-Catalyzed Grignard Addition Reaction
Table 3. Sequential Oxidation/Alkylation of N-Sulfonyl Hydrazones
entry
R1
R2
R3
yield (%)
1
2
3
4
5
6
-CH2CH2CH2CH2-
Et
63
60
52
74
68
58
-CH2CH2CH2CH2-
i-Pr
t-Bu
Et
i-Pr
t-Bu
-CH2CH2CH2CH2-
Ph
Ph
Ph
H
H
H
Scheme 4. Concise Synthesis of the Trichodiene Core
Finally, the synthetic potential of this catalytic alkylation method
was tested by carrying out a concise synthesis of the core framework
of the natural product trichodiene (39, Scheme 4).9 To do so, 18
was treated with 1-methylcyclopentylmagnesium chloride to pro-
duce 40 in 74% yield, enabling the direct linkage of the adjacent
quaternary carbon centers in a single step.
In conclusion, we have developed the first Cu(I)-catalyzed
addition of Grignard reagents to in situ-derived N-sulfonyl azoalk-
enes. This umpolung alkylation reaction enables the synthesis of
extremely hindered compounds that would be inaccessible using
traditional enolate chemistry and also provides a unique approach
to regiocontrolled R,R-bisalkylation. Studies of the development
of an asymmetric version of this transformation are underway.
Table 2. R,R-Bisalkylation of R,R-Dichloro-N-sulfonyl Hydrazones
Acknowledgment. J.M.H. holds a C. R. Hauser Fellowship from
Duke University Department of Chemistry. This work was sup-
ported by Duke University and NCBC (2008-IDG-1010).
entry
R1
R2
R3
R4
X
yield (%)
1a
Me
Me
Me
H
H
H
Me
Me
Me
H
H
H
Me
Me
Me
Et
Et
Et
Me
Me
Me
Et
Et
Et
Et
Et
Br
Br
Cl
Br
Br
Cl
Br
Cl
Br
Br
Cl
Br
68
62
48
64
62
58
58
56
52
58
56
52
2a
i-Pr
t-Bu
Et
i-Pr
t-Bu
Et
Et
Et
Et
Et
i-Pr
t-Bu
Et
i-Pr
t-Bu
i-Pr
t-Bu
CH2t-Bu
i-Pr
t-Bu
CH2t-Bu
3a
4a
Supporting Information Available: Experimental procedures and
analytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
5a
6a
7b
8b
References
9b
10b
11b
12b
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product having three contiguous quaternary centers was produced
in 58% yield. We next attempted the bisalkylation using two
different Grignard reagents (entries 7-12). To do so, the initial
azoalkene was generated using NaH and then treated with the first
Grignard reagent and copper catalyst. After 1.5 h, the second
Grignard reagent was added. In each case, the desired bisalkylated
compound having two different alkyl groups was generated.
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with the catalytic alkylation reaction, N-sulfonyl hydrazones were
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generate the R-bromo-N-sulfonyl hydrazones8 and then exposed
to the catalytic alkylation conditions (Table 3). We were pleased
to find that in every case the desired R-alkylated product was
produced from this sequential transformation.
(6) See the Supporting Information for details.
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