Ei-ichi Negishi
I
Syracuse University Syracuse, New York 13210
Organoboranes and Organoborate Anions New classes of electrophiles and nucleophiles in organic synthesis
One of the most troublesome problems chemists face today is that of keeping up with new discoveries and developments. As a means of overcoming such problems, chemists have long found it useful to organize a wide variety of reactions into patterns of mechanistically related transformations. Let us consider the reactions permitting carbon-carbon hond formation. Ionic reactions of carbon nucleophiles with carbon electrophiles play the major role in the carbon-carbon hond formation. Frequently used carbon nucleophiles and electrophiles may conveniently beclassified as shown in the table. By combining these nucleophiles and electrophiles we amve a t 12 categorically different types of reactions (Type 1.1. through Type IV.3.). Such a classification can now he used to facilitate our understanding" and oreanizing of an enormous number of carbon-carbon bondformine reactions that have alreadv been developed or will be developed in the future. Such an approach can even provide us with some creative think in^. For example, we now clearly rec~gnizethat most organ; texthooks~hardlydiscuss the reactions of ylides (Type ID nucleophiles) with the T w e 1and 3 electroohiles. Are these combinations useless? Or, have they simply been overlooked in the past? It is quite conceivable that some of such considerations can lead us to the discovery and development of useful synthetic reactions. The major objective of the present article is to close up some of the key features common to various reactions of organohoranes and interpret these reactions in terms of a few common mechanistic schemes. It is hoped that this review not only helps students and practicing synthetic chemists understand the organohorane reactions, but invites a number of future applications and explorations in this area.
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".
Organoboranes-A
Class of Electrophiles
Recently, organoboranes have emerged as highly versatile intermediates for organic synthesis ( I ) . Their reactions appear highly unique and quite different from those involving conventional organometallics, such as Grignard reagents. What are organoboranes? How are they different from Grignard reagents or organolithiums? Organohoranes normally exist as electron deficient trizonal soecies with the ematv boron o-orbital.1 The carson-boron bonds are highl;c&alent. ~ h u s organoboranes , act as Lewis acids or electroohiles, hut seldom as nucleophiles. This simple consideGation alone helps us understand why oraanohoranes, unlike Grignard reagents, generallv do not undereo ionic reactions with tvoical oreanic elec&ophiles (Type;-3 electrophiles), such"is methi1 iodide, cyclohexanone, and ethylene oxide.2 1 Most
mono- and dialkylborenes exist as bridged dimera. For practical purposes, however, they can be treated as monomeric
Classification of Carbon Nucleophiles and Electrophiles Carbon Nueleophile
Carbon Electrophile
I. Nucleophilic organometallirs
1. Organic halides and related do"uativ.8
R - M ( e r CH,MaBr,n-C,H&i)
H X ~CH.,I.@T~I .
11, Enolate anions and related
2. Carbonyl deriuativcs and rolstod compounds
derivativaa
T ~ i c o oll.~ t
iex.
irr
@.CHFCHCOCH,I
3. Eparides
111. Ylidca
.w
I I -c-;L, -~.-;L.-~-;/ e,r I I ' I -
- +
'
rer CH,P(C,,H,), CHSMcl
rer.
T7 0
.
IV. Masked carbonyl derivative%
On the other hand, organoboranes react readily with a variety of nucleophiles to form the corresponding "ate" complexes (eqn. (1)) X,BR organoborane
+
ex. (n-C,H,XB
-
Ynucleaphile
+
LiC,H,-n
-+
[XaRYIorganoborate anior. LiB(C,H,-n),
Appropriately a-Substituted Organoborate Anion-Key Intermediates in Ionic Organoborane Reactions
The "ate" complexes derived from organohoranes and nucleophiles are in many cases thermally stable and do not undergo further spontaneous reactions. However, when the nucleophiles are appropriately substituted, the following spontaneous 1,2-migration reactions take place (esn. (2))
XzBR
+
-Y-Z
-
r-K-; ; X-B-Y
;.*I
,
&--I-: zI> 'i
--t
X :---A (1)
electron-deficienttrigonal species. ZOr~anoboranesundereo a facile free-radical reaction with a. 0-unsaturated carbonyl derivatives. See, for example, Chap. 19 0fRef. ( l o ) . Volume 52, Number 3. March 1975
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159
where Y - Z = appropriately substituted nucleophile. For example, the alkaline hydrogen peroxide oxidation of organoboranes is believed to involve the following mechanistic scheme (2) (eqn. (3))
way was discussed earlier (eqn. (3)). The alkoxyborane formed uia the "ate" complexation-1,2-migration sequence is readily hydrolyzed, since the reaction is carried out under aqueous conditions. This reaction also proceeds with retention of configuration (5). Elimination p-Hetero derivatives of organoboranes readily undergo either spontaneous or base-promoted elimination to form olefins3 (eqn. ( 6 ) )
X-B-b I
+
OH-
(3)
The spontaneous or thermal reaction usually involves a syn elimination (eqn. ( 7 ) ) , whereas the base-promoted reaction involves an anti elimination (6) (eqn. (8))
As will become clear from the subsequent discussion, the appropriately a-substituted organoborate anion (1) is indeed the key intermediate or transient species in the great majority of the ionic organoborane reactions applicable to organic synthe.& Three General Methods for the Conversion of Borane Derivatives into Organic Compounds
The product of the transformation shown by eqn. (2) is a borane derivative. In order to complete an organic synthesis, therefore, this horane derivative must be converted further into the corresponding organic compound. This is usually accomplished by one of the following three methods: (1) protonolysis, (2) oxidation, or (3) elimination. Protonolysis Although thermodynamically quite stable, the B-N, B-0, and B-S bonds are solvolytically highly labile. Thus, hydrolysis of borane derivatives containing these bonds readily produces the corresponding amines, alcohols, and thioalcohols.
In summary, the 1,2-migration reaction of appropriately a-substituted organoborate anions (I) followed by protonolysis, oxidation, or elimination represents one of the most common mechanistic schemes in organic syntheses involving organoboranes. In the following sections, a number of organoborane reactions are interpreted in terms of the general mechanistic scheme discussed above. Reactions of Organoboranes with Appropriately Substituted Nucleophiles (Type A Reaction)
On the other hand, the B-C bond is generally quite resistant to hydrolysis. However, it can be cleaved in most cases by treating an organohorane with a carboxylic acid, such as acetic acid (3). Other stronger acids, such as hydrochloric acid, are less effective. The unique effectiveness of carboxylic acids has been interpreted in terms of the following cyclic mechanism (eqn. (5))
I t is important to note that the reaction proceeds with retention of configuration of the organic group ( 4 ) . Oxidation Oxidation of organoboranes can be carried out by a number of methods. At present, however, the alkaline hydrogen peroxide oxidation appears to he the most convenient and dependable one. Its probable mechanistic path160 /
Journal of Chemical Education
Reactions with Nucleophilic Organometallics (Type I Carbon Nucleophilesj It has recently been established that the reaction of organohoranes with a-haloalkyllithiums, followed by oxidation, produces a variety of organic products, such as alcohols and ketones (eqns. (9) and (10))
I I I R OCH.,
R-B%-CI
+---
-
NaOH
CH,O
Hp, (9)
3Although much less frequently observed, organoboranes c a w ing hetero ~ubstituentsin more remote positions can undergo similar reactions. See for example, Ref. ( l a ) , p. 336-340.
CH:,
H-~3
KCHB~COOE~
R'OH
Those appropriately substituted organolithiums which have been investigated include LiCHCI, (77, LiCC13, LiCCI2F, LiCCIFz, and LiCClzOCH3. (8). Particularly useful is LiCCIZOCH3 readily obtainable by treating n,adichlorodimethyl ether with lithium triethylcarhoxide. Reacfions with Enolafe Anions (Type I1 Carbon Nucleophiles) The reaction of organohoranes with a-halo enolate anions provides a highly useful method for the a-alkylation of carhonyl derivatives (9). A plausible mechanistic scheme for one such reaction is shown in eqn. (11)
,---I ? ;
I
R-B-CHCOOEt
I
R OH )
prot0no1y.lm
R BOR'
+
RCH,COOEt (11)
The scope of these reactions has been discussed in detail by Brown (9) andRogif (11). Related to these alkylation reactions are the reactions of organohoranes with a-diazo carbonyl derivatives (12). A recent study in this area has developed the following useful, alternate procedure for alkylation involving the use of monoalkyldichlorohoranes (13) (eqn. (16))
The unusually facile pmtonolysis of the intermediate trialkylborane evidently involves its tautomerization to form the corresponding en01 borinate followed by the cleavage of the B-0 bond (10)(eqn. (12))
1
RIB-CHCOOEt
-
1
K'OH
R2B-4-C=CHR R,BOR' RCH,COOEt
+
R
(la
A wide variety of a-halo enolate anions, such as those derived from the following compounds, undergo this alkylation reaction
I
CLB4HCOOEt
-
OEt
1
C1.R-0-C=CHR
HO
(
H 011
RCH COOEt
(16)
Reactions with Ylides (Type 111 Carbon Nucleophiles) Simple \ l ~ d c cthrmstlvt,- are appropriutely w h ~ l i t ~ t c d nucleophilr;, as illustrored by thr, fnllorring ex;imples I id,. (eqns. (17) and ( 1 8 ) )
This new alkylation reaction permits the following noteworthy transformations: (a) a two-carbon homologation of olefinfi (eqn. (13)), (b) incorporation of a stereochemically defined group in the c-position of carhonyl derivatives (eqn. (14)), and (c) a convenient synthesis of a-halo carbony1 derivatives (eqn. (1511
Volume 52. Number3. March 1975
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161
R-B-CH,
I
I
NaOH
H.O>
2ROH
+
RCHPH
(18)
R Although highly promising, few of these reactions have been developed into synthetically useful reactions. The reactions as they are performed at present utilize only one of the three R groups of the organohorane. These reactions are apparently quite sensitive to the steric requirements of organoboranes thus considerably limiting their scope. This area appears to require and deserve further careful and detailed investigation. It is now clear that organohoranes can react with a variety of carbon nucleophiles to form new carhon-carbon bonds. One thing we should hear in mind is that the reactions discussed so far require appropriately suhstituted carhon nucleophiles. The reaction of masked carhonyl anions (Type IV carbon nucleophiles) has been studied recently. Both cyanide (15) and dithiane anions (16) form relatively stable borate anions which do not undergo further spontaneous reactions. However, as will he discussed later, even in these cases further reactions can he induced so that these borate anions can he utilized in organic synthesis.
Nitrogen Nucieophiles-Amination The ability to participate in the Type A reaction is not restricted to the carhon nucleophiles. Several types of nitrogen nucleophiles have been shown to undergo synthetically useful reactions with organoboranes (17). At present, the best procedure for the conversion of organoboranes into primary amines involves the use of hydroxylamineO-sulfonic acid (18) (eqn. (19))
Oxygen Nucleophiles-Oxidation A plausible mechanistic pathway for the alkaline hydrogen peroxide oxidation was discussed earlier. Although much less convenient, trialkylamine oxides, such as trimethylamine oxide, can oxidize organohoranes in a similar manner (23) (eqn. (23))
Reactions of Appropriately Substituted Boranes with Nucleophiles (Type B Reaction) Inspection of the structure of the key intermediate (I) suggests that, in addition to the reaction of organohoranes (XzBR) with appropriately suhstituted nucleophiles (-Y-Z), the reaction of appropriately suhstituted boranes with nucleophiles should also produce (I) (eqn. (24))
z X-B-Y
Chloramine is less satisfactory but undergoes a similar reaction (19). Secondary and tertiary amines can also he synthesized, as exemplified by the following reactions (20-22) (eqns. (20)-(22))
+
/ R-
x i (I)
At present, there are two general and synthetically useful routes to appropriately suhstituted boranes, uiz. (1) bromination of organoboranes and (2) hydrohoration of haloalkenes and haloalkynes. Via Bromination of Organoboranes Bromination of organohoranes has been extensively reviewed (24). It involves a free-radical chain reaction resulting in the formation of a-hromoorganoboranes. Treatment of these organohoranes with almost any nucleophiles causes migration of one of the alkyl groups which evidently proceeds uia (II) (eqn. (25)). The.product can undergo further similar transformations
The synthetic utility of such a sequence of transforma162
/ Journal 01 Chemical Education
tions is indicated by the following examples (25) (eqns. (26) and (27))
P
t t B
\CH,CH,CH~C~OR
NaOH
w
H,O,
This transformation may be viewed as a boron-participated S N ~ - l i kreaction e in which the built-in nucleophile (R) attacks the carbon atom adjacent to the boron atom fmm the side opposite to the leaving group. The configuration of the migrating group is completely retained (27). The highly regio- and stereo-selective nature of this sequence of reactions makes possible a number of attractive syntheses of olefinic compounds (28-30) (eqns. (31)-(33)).
(z)
Q - C H ~ C H ~ C H ~ O R OH
Via Hydroboration of Haloalkenes and Haloalkynes Due to the electron-withdrawing inductive effect of the halogen atoms, hydroboration of vinyl halides or l-halo-lalkynes has a strong tendency to form a-haloorganoboranes (eqn. (28))
Especially noteworthy is the nearly exclusive formation of l-halo-l-alkenylborane (111) in a regio- and stereo-selective manner (26c) (eqn. (29))
In summary, both Type A and Type B reactions proceed uin the appropriately substituted borate anion (I), although its formation in these two cases involves quite different reaction paths (eqn. (24)). Reactions of Orgamboranes Proceeding via "Inverse" Boron Ylides and Related Species (Type C Reaction)
Even more spectacular is the reaction of (III) with nucleophiles, such as sodium methoxide (eqn. (30))
We have equated the organoborane reactions proceeding uia appropriately a-suhstituted borate anions (I) to an intramolecular SNZ-like reaction involving the Walden inversion. Is it not possible to observe its SN1-like counterpart? If so, such a reaction would proceed through a hypothetical intermediate (IV) which may loosely he termed an "inverse" boron ylide (31) (eqn. (34))
Carbonylation
It involves a complete inversion of the configuration at the migration terminus. Such an inversion at an spz-hybridized carbon center has rarely been observed in the past.
Carbonylation of organoboranes represents one of the most general and versatile reactions which organoboranes undergo. A variety of primary, secondary, and. tertiary alcohols, aldehydes, and ketones have been synthesized by this reaction. Since the reaction has been extensively reviewed (32), our discussion here is minimal. The following examples demonstrate unique synthetic capabilities of the carbonylation reaction (33) (eqns. (35) and (36)) Volume 52, Number 3, March 1975
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163
philes can induce a number of unique transformations. A few synthetically useful examples follow (3435) (eqns. (38) and (39)) R -
I
d=@H R--B-R
YR.,
I
CH,
H l 0 W trans H \
E
.
"@
2 A
I. CO. i C H O H I 2 NaOH.
H,0:
Although no detailed mechanistic study has been made, the following is consistent with the experimental ohsewations and suggests possible intermediacy of "inverse" boron ylides (V) and (VI)
R
R
1 7 R-B--C
R
1
-
R-B4
I
NaOH
ROH
+ O=L. ( 39
I
The non-stereoselective nature of the transformation shown by eqn. (40) strongly suggests that the reaction involves, a t least partially, the intermediacy of the "inverse" ylide (VIII) (36).
R AC==C/~ -B
I
/
\R,!
4
RCH=CR'R" cis and trans
(101
On the other hand, the reaction of (IX) with iodine is stereospecific and, therefore, may or may not involve the intermediacy of a free carhonium ion. The intermediacy of the halonium ion (X) has been suggested (27) (eqn. (41)) R
Reactions of n, P-Unsaturated Borate Anions with Electrophiles Alkenyl-, alkynyl-, aryl- and cyanohorate anions are generally thermally stable and do not undergo further spontaneous reactions. However, treatment of these a, 6unsaturated organoborate anions with appropriate electro164
/ Journal ot Chemical Education
Literature Cited
Regardless of the detail of the mechanistic pathways, these reactions (eqn. (38)-(41)) have added a new dimension to organohoron chemistry and provided a significant new guiding principle. Namely, even when organoborate anions are thermally stable and, hence, do not undergo further spontaneous reactions, treatment of these species with electrophiles caninduce further synthetically useful transformations (eqn. (42)). In other words, the organohorate anions are now acting as a unique class of nucleophiles in these reactions. Borate anion + Electrophile Product (42)
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11) la1 B m m . H. C., "8oraner in Organic Chemistry." Cwaell University Press, Ithsca, Now Yark, 1972; lhl Crag$. G. M. L., "Olganohoranes in Organic Synthesis." Marcel Dekker. New York. 1973. (21 Is1 Kuivila. H. G.. J. Amar Chpm Soc.. 76. 670 119541: 77. 4014 119551; lbl Kuiand Wiles, R. A . J. Amer Chem. Sac, 77. 4830 119551: lcl Kuiviia, vils, H. 0.. H.G., and Amour. A. G.. J. Amer Chem S o c , 79,5659 119571. (31 (a1 Meewein. H., Hinz, G., Majert. H., and Sonke. H.. J. P m k t Chem.. 147. 226 (18361; (bl Goubeau, J.. Epple. R. Ulmschneider, D.. and Lehmann, H.. Angem. Chem.. 67, 110 (1955); 1cl B m w . H. C., end Murray, K., J~A m w Chem Soe.. sf r,ns,,Q
