Amine-directed hydroboration: Scope and limitations

Article abstract of DOI:10.1021/ja0774663

Iodine activation induces intramolecular hydroboration of homoallylic and bis-homoallylic amine boranes with good to excellent control of regiochemistry compared to control experiments using excess THF?BH₃. Deuterium labeling and other evidence confirm that the iodine-induced hydroboration reaction of homoallylic amine boranes occurs via an intramolecular mechanism equivalent to the classical 4-center process and without competing retro-hydroboration. Longer carbon chain tethers result in lower regioselectivity, whereas the shorter tether in allylic amines results in a switch to dominant intermolecular hydroboration. Regioselectivity in THF?BH₃ control experiments is higher for the allylic amine boranes compared to the iodine activation experiments, whereas the reverse is true for homoallylic amine borane activation.

Full text of DOI:10.1021/ja0774663

Published on Web 06/13/2008
Amine-Directed Hydroboration: Scope and Limitations
Matthew Scheideman, Guoqiang Wang, and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received October 2, 2007; E-mail: edved@umich.edu
Abstract: Iodine activation induces intramolecular hydroboration of homoallylic and bis-homoallylic amine
boranes with good to excellent control of regiochemistry compared to control experiments using excess
THF•BH3. Deuterium labeling and other evidence confirm that the iodine-induced hydroboration reaction
of homoallylic amine boranes occurs via an intramolecular mechanism equivalent to the classical 4-center
process and without competing retro-hydroboration. Longer carbon chain tethers result in lower regiose-
lectivity, whereas the shorter tether in allylic amines results in a switch to dominant intermolecular
hydroboration. Regioselectivity in THF•BH3 control experiments is higher for the allylic amine boranes
compared to the iodine activation experiments, whereas the reverse is true for homoallylic amine borane
activation.
Introduction
Unsaturated amine borane complexes have been known for
many years to be isolable molecules that easily survive exposure
to the air at room temperature.1 This stability can be attributed
to the strength of the bond between nitrogen and boron in the
Lewis acid-Lewis base complex and is consistent with prior
reports that demonstrate conversion of alkenylamine boranes
into isomeric hydroboration products upon heating (eq 1).1b Like
other simple hydroborations,2 this process likely involves
reversible dissociation to borane and the free Lewis base ligand
(i.e., the amine), followed by a conventional intermolecular
hydroboration and subsequent internal N-B bond formation to
afford the cyclic borane complex 1. In related studies, thermally
induced borane transfer has been demonstrated from a saturated
amine borane to an unsaturated amine, as shown in eq 1 using
trimethylamine borane as the source of borane.1c Formation of
2 requires cleavage of the N-B bond at some stage prior to
hydroboration and is most easily understood if this occurs by a
simple dissociative event. Also consistent is the well-known
dissociation of amine boranes at similar temperatures in the
absence of alkenes.3
We could find no cases in the prior literature to suggest that
unsaturated amine boranes are capable of hydroboration by an
intramolecular mechanism that might occur below the temper-
ature for N-B dissociation. Similar conclusions have been
reached for the comparably stable unsaturated phosphines
boranes.4 These issues are relevant to the prospects for hetero-
atom-directed intramolecular hydroboration,5 a problem in
hydroboration chemistry that was recognized long ago.6 Prior
to our work, the only well-defined examples of heteroatom
direction via bonding interactions involving Lewis basic electron
pairs are in the transition metal catalyzed hydroborations.7 These
reactions are believed to take place via an O-M bonding
interaction, and not an O-B interaction.
As part of a program designed to develop new methods for
heteroatom-directed hydroboration, we have initiated a study
of amine borane activation. A preliminary account of this work
has appeared,8 as well as a report describing the analogous
activation of phosphine boranes.9 We now describe the activa-
tion of unsaturated amine boranes in detail.
(1) (a) Dewar, M. J. S.; Gleicher, G. J.; Robinson, B. P. J. Am. Chem.
Soc. 1964, 86, 5698. (b) Dewar, M. J. S.; Rona, P. J. Am. Chem. Soc.
1967, 89, 6294. (c) Pol´ıvka, Z.; Ferles, M. Collect. Czech. Chem.
Commun. 1969, 34, 3009. (d) Pol´ıvka, Z.; Kubelka, V.; Holubova´,
N.; Ferles, M. Collect. Czech. Chem. Commun. 1970, 35, 1131. (e)
Wille, H.; Goubeau, J. Chem. Ber. 1972, 105, 2156. (f) Baboulene,
M.; Torregrosa, J.-L.; Speziale, V.; Lattes, A. Bull. Chim. Soc. Fr.
1980, II-565. (g) Midland, M, M.; Kazubski, A. J. Org. Chem. 1992,
57, 2953.
According to the classical dissociative mechanism, hydrobo-
ration (HB) requires a trivalent borane to access the 4-center
transition state. However, initial formation of an olefin borane
π-complex via SN2-like alkene bonding at the backside of the
(5) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(6) Schulte-Elte, K. H.; Ohloff, G. HelV. Chim. Acta 1967, 50, 153.
(7) (a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1988,
110, 6917. (b) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113,
4042. (c) Evans, D. A.; Muci, A. R.; Stu¨rmer, R. J. Org. Chem. 1993,
58, 5307.
(2) Brown, H. C.; Chandrasekharan, J. J. Am. Chem. Soc. 1984, 106, 1863.
(3) (a) Brown, H. C.; Bartholomay, H., Jr; Taylor, M. D. J. Am. Chem.
Soc. 1944, 66, 435. (b) Haaland, A. Angew. Chem, Int. Ed. Engl. 1989,
28, 992. (c) Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz,
M. J. Org. Chem. 2000, 65, 4655.
(4) (a) Schmidbaur, H.; Sigl, M.; Schier, A. J. Organomet. Chem. 1997,
529, 323. (b) Gaumont, A.-C.-C.; Bourumeau, K.; Denis, J.-M.;
Guenot, P J. Organomet. Chem. 1994, 484, 9.
(8) Scheideman, M.; Shapland, P.; Vedejs, E. J. Am. Chem. Soc. 2003,
125, 10502.
(9) Shapland, P.; Vedejs, E. J. Org. Chem. 2004, 69, 4094.
9
10.1021/ja0774663 CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 8669–8676 8669

A R T I C L E S
Scheideman et al.
Scheme 1
Scheme 2
amine borane N-B bond might also be considered, by analogy
to the mechanism suggested for borane etherate hydroborations
based on computational studies.10 If such a pathway were to
operate for unsaturated amine boranes 3, then a slow reaction
would be expected for two reasons. First, the inherent stability
of the N-B bond works against any mechanism that requires
N-B bond cleavage, including an SN2-like pathway. Second,
and more important, the orbital requirements for internal
nucleophilic attack are not satisfied in the case of 3 or related
homoallylic and bis-homoallylic amine boranes because the
potential nitrogen leaving group bond would be endocyclic with
respect to the hypothetical cyclic transition state.11 This means
that there should be no rate advantage for HB via an internal
SN2-like displacement process involving the CdC subunit of
an unsaturated amine borane acting in the role of the nucleophile,
as long as the amine nitrogen acts as the leaving group. The
above analysis implies that 3 would have to react via a
dissociative pathway, presumably via π-complexes such as 4
or 5. These intermediates may well undergo further reaction
with a preference for one of the two regioisomeric 4-center
transition states due to electronic factors associated with the
amine or amine borane subunits, but such effects are poorly
understood and their role is difficult to anticipate. The goal of
the present study was to determine whether a more predictable
version of regiocontrolled hydroboration is feasible via amine
borane intermediates where the N-B bond remains intact.
We began with the premise that an internal hydroboration
may be possible starting from a stable amine borane of general
structure 3 if a good exocyclic leaving group is introduced at
boron, as in the iodoborane complex 6 (Scheme 1). We could
imagine a dissociative SN1-like mechanism via an ion pair 7,
or an SN2-like internal nucleophilic substitution process via the
bonding interactions shown for 8. In either event, the initial
result would be the formation of a tethered olefin π-complex
ion pair 9. Bond reorganization via the fused bicyclic 4-center
transition state 10 with subsequent ion pair recombination would
then afford 11. Competition by a bridged bicyclic transition state
12 to give the regioisomeric product 13 is also conceivable,
but this was expected to be the minor pathway.
Results and Discussion
To test the above premise, a series of homoallylic amines
were prepared, usually from the alcohols 14 by aminolysis of
the tosylates 15 (Scheme 2). Amines 16, 18, and 20 were then
easily converted into the isolable amine boranes 17, 19, and 21
by treatment with THF•BH3. Similar conventional methods were
used to prepare homologous alkenylamine boranes 25, 27, and
31, 33.
After a preliminary survey of common electrophiles, we
quickly settled on iodine as the activating agent. Iodination of
amine boranes is fast, easy to do, and has a long history.12
According to the stoichiometry, molecular iodine is fully utilized
in conversion of 3 to 6. Apparently, the initially formed
byproduct HI reacts with 3 to generate a second equivalent of
the iodoborane complex 6, together with hydrogen gas. When
the iodine activation method was applied to homoallylic amine
(10) (a) Clark, T.; Wilhelm, D.; Schleyer, P. V. R. J. Chem. Soc., Chem.
Commun. 1983, 606. For relevant mechanistic studies, see: (b) Pasto,
D.; Lepeska, B.; Cheng, T.-C. J. Am. Chem. Soc. 1972, 94, 6083. (c)
Pasto, D. J.; Lepeska, B.; Balasubramaniyan, V. J. Am. Chem. Soc.
1972, 94, 6090.
(12) (a) Ryschkewitsch, G. E.; Garrett, J. M. J. Am. Chem. Soc. 1967, 89,
4240. (b) Nainan, K. C.; Ryschkewitsch, G. E. J. Am. Chem. Soc.
1969, 91, 330. For generation of diiodoborane amine complexes and
applications for selective hydroboration, see: (c) Reddy, C. K.;
Periasamy, M. Tetrahedron 1992, 48, 8329.
(11) Beak, P. Acc. Chem. Res. 1992, 25, 215.
9
8670 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008

Amine-Directed Hydroboration
A R T I C L E S
Table 1
amine
borane
yield
from amine
entrya
R1, R2
R
n
products
ratiob
yield
1
2
3
4
5
6
7
8
17a
77%
79%
79%
H, H
H
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
34a:35a
34b:35b
34b:35b
36a:37b
36b:37b
36b:37b
36b:37b
36b:37b
36c:37c
36d:37d
36d(D1):37d(D1)
38c:39c
40a:41a
40b:41b
40b:41b
42a:43a
42b:43b
42b:43b
44:45
1:1
43:1
38:1d
1:3
13:1
18:1e
10:1f
>20:1
10:1
2:1
69%c
85%c
83%c
90%
83%
79%
79%
87%
82%
82%
NA
92%
35%
84%
92%
71%
76%
80%
95%
91%
63%
E-17b
E-17bd
19a
H, Me
H, Me
H, Bn
H, Bn
H, Bn
H. Bn
H. Bn
H, Bn
H, Bn
H, Bn
(CH2)4
H,H
H,H
H,H
H,Bn
H,Bn
H,Bn
H,H
Me
Me
H
Me
Me
Me
Me
Et
>90%
>90%
76%
>90%
>90%
>90%
>90%
73%
77%
41%
55%
71%
63%
92%
83%
63%
54%
83%
E-19b
E-19b
E-19b
Z-19b
E-19c
E-19d
E-19d(D3)
Z-21c
9
10
11
12
13
14
15
16
17
18
19
20
21
Ph
Ph
Et
3:1
>30:1
1:1.5
4:1
14:1
1:3
4:1
39:1
2:1
25a
H
E-25b
Z-25b
27a
E-27b
Z-27b
E-31b
Z-31b
Z-33b
Me
Me
H
Me
Me
Me
Me
Me
H,H
H,Bn
44:45
46:47
2:1
1.5:1
a Conditions, 50 mol% I2/DCM, rt; yields refer to aminoalcohols isolated by chromatogaphy as a mixture of regioisomers after workup with NaOOH.
b NMR assay. c Reaction quenched after 30 min. d Catalytic activation with 10 mol% I2. e Recrystallized substrate. f Activation using TfOH.
boranes, HB occurred at room temperature on a time scale of
hours according to product assay after standard oxidative workup
with alkaline hydrogen peroxide. However, initial attempts to
characterize the presumed intermediates 6 or the initial products
11 and 13 using NMR methods were not informative. Numerous
signals were observed in the crude 1H NMR spectrum prior to
oxidative workup, as would be expected from the presence of
diastereomers involving stereogenic boron as well as regioiso-
mers, but the sheer complexity of the spectrum suggested the
presence of additional unknown species. Thus, structures 6, 11,
and 13 were tentatively drawn based on stoichiometry and
product assay after oxidative workup.
As shown in Table 1, activation with 50 mol% I2 in CH2Cl2
converts a broad range of unsaturated amines into amino
alcohols. Good to excellent regiocontrol was observed in the
representative case of E-19b (entry 5; 13:1 36b:37b) as well as
a number of other examples (entries 2, 6, 8, 12, 15, 18), leaving
little doubt that an internally directed HB had been achieved.
Somewhat improved 18:1 selectivity for 36b:37b was obtained
in the iodine experiments when E-19b was recrystallized prior
to activation (entry 6), but the 13:1 ratio using E-19b partially
purified by simple plug filtration over silica gel (entry 5) has
been retained in Table 1 to allow better comparisons with other
entries where the amine borane substrate could not be crystallized.
from ꢀ-methylstyrene were detected (<10%). Thus, the internal
hydroboration was not suppressed by the external alkene.
Activation with triflic acid as the electrophile9 was briefly
compared with the iodine method using E-19b as the substrate
(entry 7). Internal HB occurred on a similar time scale, but
regiocontrol was lower (10:1 36b:37b). In view of the incon-
venience of handling triflic acid compared to iodine, the
procedure was not pursued further.
Higher regioselectivity was observed for the iodine-induced
internal HB of Z-alkenes compared to the E-isomers (compare
entries 8 vs 5, 15 vs 14, or 18 vs 17). Thus, with Z-19b as the
substrate, the standard activation; oxidation procedure gave a
single product 36b by NMR assay (entry 8). To establish
detection limits, authentic1,4-amino alcohol 37b was prepared
independently.13 According to a calibration study, 37b would
have been detected at the 5% level, indicating >20:1 36b:37b
selectivity for the iodine-induced hydroboration of Z-19b. The
role of olefin geometry was more pronounced for the bis-
homoallylic amine boranes, especially for the N-benzyl deriva-
tives (entries 18 vs 17). However, the relatively modest
selectivities for some, but not all of the E-alkenylamine boranes
indicate that the directing effect arises from a combination of
factors. In this light, it was no surprise to find that the directing
effect is not sufficient to overwhelm other factors that contribute
to HB regioselectivity. For example, terminal alkenes reacted
with low selectivity (entries 1, 4, 13, 16), as did a phenyl-
substituted substrate (entry 10). In the latter example, the result
can be understood by comparing the product ratio with that
expected from the standard (intermolecular) HB selectivity for
ꢀ-methyl-styrene, 86:14 in favor of the benzylic alcohol after
oxidative workup.14 For the amine-directed HB reaction (entry
11), the benzylic alcohol is the minor product (1:3 ratio).
To test for competition by an intermolecular hydroboration
pathway, the iodine activation of crystallized E-19b was
conducted at two different concentrations. However, the ratio
of regioisomeric aminoalcohols obtained with 0.1 or 1.0 M
solutions of the purified substrate was identical (18:1 36b:37b),
suggesting an intramolecular pathway. Additional evidence was
provided by a control experiment where E-19b was treated with
excess borane in THF (2 equiv). This gave a much lower ratio
of 36b:37b (2.4:1) as expected for conventional intermolecular
HB. Finally, E-19b was activated in the usual way, but in the
presence of added ꢀ-methylstyrene (2 equiv) as a potential trap
for dissociated borane species or other species capable of
intermolecular HB. After oxidative workup, this experiment gave
conversion of E-19b to 36b:37b as usual, along with recovered
ꢀ-methylstyrene. Only traces of the alcohol products derived
Attempts to extend the amine-directed hydroboration to
tertiary amine derivatives encountered complications. The
alkenyl pyrrolidine borane Z-21c was relatively well behaved,
(13) Crich, J.; Picione, R. Org. Lett. 2003, 5, 781.
(14) (a) Brown, H. C.; Sharp, R. L. J. Am. Chem. Soc. 1966, 88, 5851. (b)
Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1960, 1960, 4708.
9
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A R T I C L E S
Scheideman et al.
Scheme 3
Scheme 4
therefore repeated without oxidative workup, and formation of
50 was confirmed by isolation after chromatography (41%
yield).
The catalytic iodine procedure was also performed with
E-19b. Initial attempts to oxidize the reaction mixture from
hydroboration led to variable product recovery and a 7:1 ratio
of amino alcohols 36b and 37b. The problem was traced to
lower reactivity in the oxidative cleavage step for the presumed
cyclic amine borane intermediates 53 and 54, structures that
are relatively stable compared to the precursor iodoboranes 51
and 52 that accumulate under conditions of stoichiometric
activation. Improved reactivity in the oxidative cleavage was
achieved by the addition of 40 mol% of iodine to the product
mixture obtained from catalytic hydroboration to force the
conversion of 53 and 54 back to 51 and 52. This gave a 10:1
ratio of amino alcohol products E-36b:E-37b (79% yield). Of
course, reactivation by adding iodine negates any practical
advantage for catalytic activation in the hydroboration step for
this case. No further attempt was made to characterize the
mixture of regioisomers and epimers 53 and 54 or to identify
the factors responsible for the diminished 10:1 regioselectivity
compared to the stoichiometric activation method.
Iodine activation was explored in substrates 55 and 56,
structures where complications due to regioisomer or epimer
formation were not expected (Scheme 4). Stoichiometric activa-
tion of 55 gave no hydroboration products at rt, consistent with
the pattern of slower reactions for the tertiary amine boranes as
noted earlier. However, the analogous primary amine borane
56 behaved normally using either 50 mol% or 10 mol% iodine
at rt. In the stoichiometric reaction, oxidative workup afforded
the amino alcohol 60, but purification was easier after benzoy-
lation to give the bis-benzoyl derivative 61. The latter structure
provided an opportunity to determine whether the stereochem-
istry corresponds to the typical syn delivery of boron and hydride
to the olefin via a 4-center hydroboration pathway. This was
confirmed by the diaxial trans relationship for Ha and Hb in 61,
assigned from the vicinal coupling constant (J ) 9.5 Hz).
The catalytic activation method using 10 mol% iodine at rt
also worked well with 56. Complete consumption of olefin
required less than two hours and cyclic amine borane 59 was
isolated from the mixture in 46% yield after chromatography.
Under these reaction conditions, propagation of the catalytic
cycle likely occurs by reversible transfer of iodine from 58 to
56 to regenerate the activated iodoborane complex 57. The
catalytic hydroboration could also be initiated by the addition
of 10 mol% of Et3N· BH2I to 56, as expected according to the
proposed catalytic cycle via reversible H/I exchange. The cyclic
and conversion of the alkene occurred within 5 h at rt, although
the amino alcohol 38c was not recovered cleanly due to
competing formation of the N-oxide during oxidative workup.
In contrast, the dibenzylated analog of amine borane E-19b (R1,
R2 ) Bn) gave low conversion under the standard conditions,
and unreacted amine was recovered together with the regioi-
someric amino alcohols (1.0:3.5:1.5 ratio).
Deuterium labeling experiments were utilized to probe the
amine-directed hydroborations in greater detail. Labeled
E-19d(D3) was prepared by the addition of the parent amine to
THF•BD3 (generated in situ from NaBD4 + iodine).15 An
equivalent of E-19b was then added to E-19d(D3) and the
mixture was activated with iodine as usual. After oxidative
workup, the resulting amino alcohol products were analyzed
for the presence of deuterium. Within limits of detection by
ESMS(+) and 1H NMR, neither 36b nor 37b contained
deuterium that might be traced to intermolecular crossover or
disproportionation events involving E-19d(D3). Furthermore, 1H
NMR integration revealed the presence of 36d(D1) and 37d(D1),
the expected products of intramolecular deuteroboration. The
control experiment using E-19d(D3) as the only substrate in the
iodine activation gave identical spectral data for the signals
assigned to 36d(D1) and 37d(D1). These results rule out a
significant (>5%) role for retro-hydroboration and deuterobo-
ration pathways that would be expected to produce 36d(D2) and
37d(D2) by H/D scrambling. Therefore, the reaction of
E-19d(D3) with iodine involves a kinetically controlled, in-
tramolecular hydroboration.
An experiment was carried out with substrate E-17b to learn
whether a catalytic amount of iodine would be sufficient for
conversion of the amine borane (Table 1, entry 3) to hydrobo-
ration products (Scheme 3). Treatment with 10 mol% iodine
resulted in a somewhat slower conversion of the substrate
compared to the experiment using 50 mol% iodine (2 h vs 0.3 h
at rt), but oxidative workup gave the amino alcohol 34b as the
dominant product with nearly the same yield and excellent
selectivity (Table 1, entry 4 vs entry 3). This observation
indicates that the initially formed hydroboration product 49 can
react with the substrate E-17b by reversible hydride-iodide
exchange, a process that would regenerate the activated 48 as
well as the cyclic amine borane 50. The experiment was
(15) Narayanan, C.; Periasamy, M. J. Organomet. Chem. 1987, 323, 145.
9
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Amine-Directed Hydroboration
A R T I C L E S
Scheme 5
Scheme 7
comparison, the allylic amine borane activations required
carefully optimized inert atmosphere conditions to achieve
substantial conversion. Despite these precautions, iodine activa-
tion of crotylamine borane 68a rarely gave better than 50% yield
of amino alcohols 69a and 70a (5-7:1 ratio), and some
experiments gave no amino alcohol products at all. Furthermore,
several tries with the secondary N-benzylcrotylamine borane
68b afforded no hydroboration products upon treatment with
50 mol% of iodine at rt. Heating the reaction mixture at 45 °C
did give partial conversion on a time scale of hours (6:1 ratio
of 69b:70b along with ca. 20% recovered N-benzylcrotylamine),
but iodine activation of the tertiary substrate 68 (R1 ) R2 )
Bn) gave no hydroboration regardless of temperature. Routine
control experiments using excess THF•BH3 also gave unex-
pected results. Thus, treatment of 68a or 68b with excess
THF•BH3 followed by NaOOH gave improved ratios of 69:70
after 2 h at 0 °C (a, 9:1; b, 10-13:1) compared to the iodine
activation experiments.
Scheme 6
amine borane 59 could be oxidized with NaOOH to the amino
alcohol 60 in 87% yield without further activation, provided
that the oxidation was allowed to proceed for >8 h at rt. The
stereochemistry of 60 obtained using the catalytic iodine method
was confirmed by conversion to 61.
Further tests were conducted using the cyclic allylic amine
boranes 71a,b to determine whether the stereochemistry of HB
products would correspond to an internal hydroboration pathway
(Scheme 7). However, 71a gave 1,2-trans amino alcohol 72a
as the major product (g3:1 72:73; iodine activation at rt over
4-5 h, followed by oxidative workup) while 71b gave no amino
alcohols at room temperature. Formation of the trans isomer
72 suggests competition by an intermolecular mechanism, so
the experiment was repeated in the presence of 1 equiv of
ꢀ-methylstyrene in an attempt to shut down intermolecular
pathways. This experiment should favor 73, the presumed
product of the nitrogen-directed intramolecular pathway, but the
major amino alcohol was the same trans-isomer 72 (2:1 72:73)
although the product ratio was lower. Alcohols 74 and 75 were
also obtained from this experiment, providing clear evidence
for competing intermolecular HB. When iodine activation of
71a was performed in the presence of 3 equiv of ꢀ-methylsty-
rene, alcohols 74 and 75 were the exclusive products (6.5:1
ratio). This ratio is similar to the result from reaction of
ꢀ-methylstyrene with THF•BH3 (74:75 ) 5.7:1). The above
experiments show that intermolecular HB pathways are not only
accessible, but potentially dominant in the reaction of 71a under
the conditions of iodine activation, in contrast to the behavior
of homoallylic amine boranes.
As an additional probe of the stereochemical consequences
of internal hydroboration, the bis-homoallylic amine borane 62
(obtained as a mixture of inseparable N-epimers) was subjected
to the iodine activation conditions at rt (Scheme 5). Hydrobo-
ration was sluggish compared to the substrates of Table 1 (24
h for complete alkene consumption), but warming to 45 °C gave
conversion within 4-5 h. Oxidation with NaOOH then afforded
1,3- and 1,4-amino alcohols 63 and 65 as major products in a
10:3 ratio. The syn stereochemistry obtained for each of these
compounds is consistent with an internal mechanism. None of
the 1,3-trans isomer 64 was found and only a small amount of
66 was detected, presumably resulting from some form of
intermolecular hydroboration due to the higher temperature. The
major product 63 was identified by comparison with the mixture
of isomers 63 + 64 obtained by LAH reduction from ketone
67.16 In contrast to the iodine-promoted reaction, intermolecular
hydroboration of 62 using excess THF•BH3 gave a nearly equal
mixture of all four possible isomers 63-66 by NMR assay.
Having shown that homoallylic and bis-homoallylic amine
boranes undergo intramolecular hydroboration upon treatment
with iodine, we turned to the allylic amine analogues to learn
whether an amine-directed HB pathway would be possible with
the shorter tether (Scheme 6). The expected amino alcohol
products did form in some examples using iodine activation
and oxidative workup, but reproducibility was poor. This was
surprising because the iodine activation of homoallylic amine
boranes had consistently afforded HB products even though
minimal precautions were taken to exclude air or moisture. By
Similar reactivity trends were found in a comparison of amine
boranes 76a and 76b, although conversion to hydroboration
products was slower (Scheme 8). HB did occur if the resulting
mixture was heated at 45-50 °C (2 h), resulting in the amino
alcohol 78a (74%) after oxidative workup along with ca. 10%
of cyclohexenylmethylamine. On the other hand, the corre-
sponding sequence starting with 76b gave at most 10% of 78b,
(16) White, D. A.; Baizer, M. M. J. Chem. Soc., Perkin Trans. 1 1973,
2230.
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A R T I C L E S
Scheideman et al.
Scheme 8
as the N-B bond is cleaved. This would explain why the allylic
amine borane reactions are highly sensitive to experimental
variables, why the products are mostly those expected from an
intermolecular hydroboration, and why some of our experiments
with the allylic amines gave no hydroboration products even
though the reactions were conducted under nitrogen. Dichlo-
romethane is not an ideal solvent for hydroborations because
the borane-solvent complex is labile, at least compared to
THF•BH3, and is easily destroyed by contaminants.
Given the insights obtained from the study of 76a, we
reexamined the reactions of the crotylamine borane 68a.
Immediately upon addition of iodine (ca. 5 mol%) to 68a, a
broad singlet appeared at δ 7.35 ppm that shifted to δ 7.55 ppm
as more iodine (50 mol% total) was added. Over the same time
scale, the broad signal due to the complexed NH2 protons shifted
from ca. δ 3.65 to 4.45 ppm. New olefinic signals also appeared,
and basic oxidative workup returned unreacted crotylamine, as
would be expected assuming that crotylammonium iodide is
formed during activation. If sufficient care was taken to maintain
inert conditions, the amino alcohols 69a and 70a were also
recovered after oxidative workup (69% yield). However, we
could not extract meaningful structural evidence regarding the
hydroboration products prior to oxidative workup from the
and ca. 90% of the material was recovered as the unreacted
N-benzylcyclohexenylmethylamine.
In an attempt to understand the puzzling reactivity and
reproducibility trends, the crude product after iodine activation
1
complex H or 11B NMR spectra.
1
of 76a was examined at rt using H NMR spectroscopy. The
In response to reviewer comments, one more series of NMR
experiments was initiated in an attempt to obtain more evidence
regarding the activated borane intermediates using simple model
amine boranes as well as the well-behaved, primary homoallylic
amine-derived borane E-17b. The latter substrate affords the
best overall combination of regioselectivity (43:1) and product
yield (>80%) in amine-directed HB, and has the simplest
structure. Nevertheless, the 1H NMR spectrum after activation
using 50 mol% iodine (0 °C to rt, 40 min) could not be
interpreted beyond noting a broad signal at δ 7.45 ppm (ca.
0.1-0.15 H) suggesting minor formation of ammonium salts,
as well as six maxima between δ 3.1 to 3.6 ppm with extensive
splitting and overlap in the expected CH2NH region. Minor
broad signals were also present, along with complex, overlap-
ping upfield signals. The 11B NMR spectrum showed several
maxima between δ 6 and δ -25 ppm. In striking contrast, when
the same substrate E-17b was treated with 5 mol% iodine
(catalytic conditions), the 11B NMR spectrum was relatively
clean and consisted of the signals for unreacted E-17b together
with the cyclized product amine borane 50. Evidently, the NMR
complexity using 50 mol% iodine is due at least in part to the
formation of N-B-I species, but control experiments with
simple models (see below) suggest that the presence of N-H
bonds in the substrate E-17b is the main problem. As already
reported in the early literature, amine boranes lacking N-H
bonds react cleanly with iodine. For example, treatment of the
tertiary amine borane Me3NBH3 with iodine affords the io-
doborane complex Me3NBH2I as a single species.18a We also
observe a single well-resolved NMR signal with the expected
triplet coupling (δ 11B ) -9.3 ppm, t, J ) 131 Hz). On the
other hand, reaction of the known primary amine borane
olefinic signal of the starting complex 76a (δ ca. 5.65 ppm)
was replaced by two new signals at δ ca. 5.85 ppm and 6.0
ppm together with several minor maxima. The major signal at
6.0 ppm, along with a broad absorption at δ ca. 7.5-7.8 ppm
and a broad singlet at 3.6 ppm, were identified by comparison
with the corresponding signals of cyclohexenylmethylammo-
nium iodide 79. Evidence regarding the new signal at δ 5.85
ppm is less conclusive, but this absorption was enhanced by
addition of free cyclohexenylmethylamine to freshly activated
76a, presumably containing 77a. This suggests a boronium salt
structure 80 as the species responsible for the δ 5.85 ppm signal,
but 80 could not be isolated to confirm this assignment.
Furthermore, the presence of 77a after iodine addition could
not be established due to the complexity of the 11B NMR
spectrum.
The most important observation from the above study is that
formation of the ammonium salt 79 is a major pathway resulting
from iodine activation of 76a. We do not have detailed evidence
regarding how 79 is formed, although the HI generated in the
first stage of iodine activation would have to be the principal
suspect. Direct protonation of the N-B bond via a three-center
two-electron interaction is one possibility, and another is
dissociation of the amine-BH2I complex followed by protonation
at nitrogen. In either case, the results would indicate a weaker
N-B bond for the allylic amine boranes compared to the
homoallylic or bis-homoallylic amine complexes. This is
consistent with the electron-withdrawing inductive effect of the
olefinic sp2 carbon, a factor that is responsible for the lower
pKa (by ca. 1 pKa unit) of ammonium salts derived from allylic
amines compared to their saturated amine analogues.17 The same
inductive effect should lower the stability of allylic amine
boranes, and could be the reason why allylic amine nitrogen
becomes partially protonated during iodine activation. In any
case, N-protonation requires that one or more trivalent boron
species (presumably, BH3 or BH2I) would have to be released
18b
nBuNH2BH3 with 50 mol% iodine in chloroform produces
multiple 11B maxima. Minor signals observed at δ 18.1 ppm
(diborane by chemical shift comparisons)19 and δ -23 ppm
(N-BH2X, br t, JBH ) ca. 135 Hz) were relatively sharp, but
accounted for less than 4% of total signal intensity. Two major
peaks (δ -7 and -17 ppm) were also observed, but these
resonances were broad and featureless, and could not be assigned
with certainty, although the chemical shifts are near the range
(17) Brown, H. C.; McDaniel, D. H.; Hafliger, O. Determination of Organic
Structures by Physical Methods; Academic Press: New York, 1955;
Vol. 1, p 567.
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Amine-Directed Hydroboration
A R T I C L E S
reported for dimeric hydrogen bridged amine boranes (δ 4 to
-11 ppm) that might be formed via elimination of HI from
nBuNH2BH2I, followed by 2 + 2 combination of the transient
monomer [nBuNHBH2].20
the homoallylic and bis-homoallylic amine boranes, but
actually lowers selectivity for the allylic analogues compared
to the excess THF•BH3 control experiments. Several early
reports describing the intermolecular hydroborations of allylic
amine substrates with THF•BH3 have encountered similar
regioselectivity,22,23 but we have found no prior reports of
directed (i.e., intramolecular) hydroborations via intermedi-
ates having an intact N-B bond throughout the sequence.
The possibility that certain amine boranes may be capable
of intermolecular hydroboration with N-B bonding in the
transition state has been raised, based on experiments using
chiral amine boranes.24 Mechanistically, this proposal con-
stitutes a plausible extension of the idea that some hydrobo-
Although definitive structural evidence was not obtained
despite considerable effort, the NMR studies do show that
complexity is inherent in the iodine activation of amine boranes
that contain N-H bonds, such as the primary amine borane
E-17b. Despite this complexity, the amine-directed hydrobo-
rations proceed with good to excellent regioselectivity and
conversion in a number of cases. Because multiple species are
present in solutions containing the iodine-activated intermedi-
ates, the isolation of internal hydroboration products in good
yields supports the notion that the unidentified activated
intermediates are formed reversibly. According to this inter-
pretation, the byproducts of iodine activation undergo intercon-
version with iodoborane complexes such as 6, and internal HB
eventually drives the equilibrium to cyclic amine boranes.
(21) (a) Preferred formation of 2-aminoalcohol derivatives has also been
observed using N-protected allylic amine substrates that contain
electron withdrawing substituents at nitrogen: Fujita, Y.; Irreverre, F.;
Witkop, B. J. Am. Chem. Soc. 1964, 86, 1844. (b) Burgess, K.;
Ohlmeyer, M. J. J. Org. Chem. 1991, 56, 1027. (c) Sibi, M. P.; Li, B.
Tetrahedron Lett. 1992, 33, 4115. (d) Hodgson, D. M.; Thompson,
A. J.; Wadman, S.; Keats, C. J. Tetrahedron 1999, 55, 10815.
(22) (a) Lyle, R. E.; Carle, K. R.; Ellefson, C. R.; Spicer, C. K. J. Org.
Chem. 1970, 35, 802. (b) Caron-Sigaut, C.; Le Men-Olivier, L.; Hugel,
G.; Levy, J.; Le Men, J. Tetrahedron 1979, 35, 957. (c) Mirand, C.;
Massiot, G.; Le Men-Olivier, L.; Levy, J. Tetrahedron Lett. 1982,
23, 1257.
Summary
Homoallylic or bis-homoallylic amine borane activation using
molecular iodine occurs via an intramolecular mechanism to
favor the products expected from a bicyclic hydroboration
transition state. The process satisfies the requirements for a
simple intramolecular mechanism, including tests based on
regiocontrol, stereochemistry, and deuterium labeling. Added
external alkene does not compete effectively for the reactive
hydroborating agent, although there is minor release of active
hydroborating species capable of intermolecular HB in some
cases, as evidenced by the formation of the trans-amino alcohol
66 (ca. 7% relative yield) starting from 62. In general, the amine-
directed reaction is not very sensitive to the presence of traces
of air or moisture, and requires only minimal precautions as
long as there is sufficient reactivity for internal HB at room
temperature. Finally, formation of the expected cyclic amine
borane products has been confirmed by isolation from experi-
ments conducted under mild catalytic conditions using 5 mol%
iodine.
(23) (a) Nemia, M. M. B.; Lee, J.; Joullie´, M. M. Synth. Commun. 1983,
13, 1117. (b) Torregrosa, J. J.; Baboulene, M.; Speziale, V.; Lattes,
M. Tetrahedron 1983, 39, 3101. (c) Torregrosa, J. L.; Baboulene, M.;
Speziale, V.; Lattes, A. C. R. Acad. Sci. Paris II 1983, 297, 297. (d)
Brown, H. C.; Vara Prasad, J. V. N.; Gupta, A. K. J. Org. Chem.
1986, 51, 4296. (e) Brown, H. C.; Vara Prasad, J. V. N. Heterocycles
1987, 25, 641.
(24) (a) Naryana, C.; Periasamy, M. J. Chem. Soc., Chem. Commun. 1987,
1857. (b) Andres, C.; Delgado, M.; Pedrosa, R. Anal. Quim. 1993,
89, 629.
(25) (a) Reference 24a describes several reactions of alkenes in the presence
of chiral tertiary N-phenylamines. By far the highest enantioselectivities
were reported with 2,3-dihydrofuran (0.7 g scale, benzene solution)
in the presence of a 1:1 ratio of in situ generated amine boranes i
(11.6 ( 2.3% ee for 3-hydroxytetrahydrofuran) or ii (19.2 (2.4% ee
for 3-hydroxytetrahydrofuran) using a workup consisting of standard
base/peroxide oxidative cleavage followed by distillation from the
crude product mixture,
In contrast, the allylic amine borane activation experiments
do not satisfy any of the tests for an intramolecular reaction.
Although we cannot exclude minor competition by an
intramolecular mechanism in some of the allylic substrates,
there is no compelling reason to propose that the relatively
strained internal hydroboration transition states are feasible
in the allylic series. To the contrary, there is evidence
suggesting substantial cleavage of the N-B bond already at
room temperature.
chromatography, redistillation, and ee assay based on optical rotation.
In two attempts to repeat the reaction using i (0.107 and 0.056 g scale),
we opted not to perform the distillations due to the smaller quantities.
The usual uncertainties involving optical rotation were another
consideration. Starting with i (found RD +19.2, c 3.2, CHCl3; reported
RD +17.29, c 3.92, CHCl3), the hydroboration and oxidative cleavage
In another contrast between the homoallylic and allylic
amine boranes, the latter undergo regioselective intermo-
lecular hydroboration using the standard THF•BH3 procedure
to form primarily the 1,2-amino alcohols21 after oxidative
workup, while the homoallylic substrates react nonselectively.
Iodine activation dramatically improves regioselectivity with
were done following ref 24a, but gave a titrated amine borane
concentration of 0.17 M (reported data correspond to 0.25 M amine
borane). The weights and volumes were adjusted for the smaller scale,
but purification of 3-hydroxytetrahydrofuran was performed by flash
chromatography (37% yield). This was followed by conversion to the
Mosher ester to allow NMR assay by 19F NMR spectroscopy (found
dr ) 1.02:1.00). According to this procedure, the alcohol product is
racemic within experimental uncertainty. We briefly considered
repeating the analogous reaction with ii, but were unable to find the
citation describing the method of synthesis. Using an alternative
method, the amine precursor of ii was obtained according to NMR
comparisons. This study was discontinued when the amine did not
match the optical rotation (found RD -8.4, c 5.87, EtOH; reported
RD -22, c 6, EtOH) in ref 24a. (b) In principle, asymmetric induction
could be due to the SN2-like displacement of amine by alkene as
proposed in ref 24, or to non-covalent interactions involving the chiral
amine in the transition state. Except for the experiments using i or ii
with 2,3-dihydrofuran in ref 24a, the other examples described in ref
24a, b report ee values in the range of 1-5% ee based on optical
rotation.
(18) (a) Denniston, M. L.; Chiusano, M.; Brown, J.; Martin, D. R. J. Inorg.
Nucl. Chem. 1976, 38, 379. The reported chemical shift is “27.2 ppm
upfield from trimethyl borate” in benzene; our chemical shift value is
referenced to boron trifluoride etherate in deuterochloroform. (b)
Yamamoto, Y.; Miyamoto, K.; Nakatani, Y.; Yamamoto, T.; Miyaura,
N. J. Organomet. Chem. 2006, 4909.
(19) A value of δ 17.6 ppm is reported for diborane in chloroform by Kanth,
J. V. B.; Brown, H. C. Tetrahedron Lett. 2000, 41, 9361.
(20) (a) Beachley, O. T.; Washburn, B. Inorg. Chem. 1976, 15, 725. (b)
Boddeker, K. W.; Shore, S. G.; Bunting, R. K. J. Am. Chem. Soc.
1966, 88, 4396.
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A R T I C L E S
Scheideman et al.
rations may involve an SN2-like mechanism,10 but other
explanations for low ee merit consideration. Our work has
not addressed intermolecular reactions beyond attempts to
repeat one of the chiral amine examples24a on small scale.25
Our studies as described above establish that activation of
the isolable homoallylic amine borane complexes follows an
intramolecular mechanism, and that related reactions can be
exploited for the regiocontrolled synthesis of 3-aminoalco-
hols.
Acknowledgment. This work was supported by the National
Institutes of Health (GM067146). We dedicate this paper to Prof.
E. J. Corey on the occasion of his 80th birthday.
Supporting Information Available: Experimental procedures
and spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA0774663
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8676 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008